JPS6330920B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel macrolide antibiotic. Various 16-membered ring macrolide antibiotics such as the leucomycin group, tylosin, and coelamycin are known. These exhibit particularly strong antibacterial activity against Gram-positive bacteria, but they have a common drawback in that their antibacterial activity against certain Gram-negative bacteria is relatively weak. Therefore, it has been desired to provide a 16-membered ring macrolide antibiotic that exhibits strong antibacterial activity against both Gram-negative and Gram-positive bacteria. The present invention is based on the finding that novel compounds derived from certain known 16-membered ring macrolide antibiotics have strong antibacterial activity against both Gram-positive and Gram-negative bacteria. Furthermore, the novel derivatives according to the present invention are easy to produce. Accordingly, an object of the present invention is to provide a 16-membered ring macrolide antibiotic that has improved antibacterial activity and can be easily produced. The present invention provides a compound represented by the following general formula () and a pharmacologically acceptable salt thereof. (In the formula, R ₁ represents a hydrogen atom, a methyl group, a -CHO group, or a -CH ₂ OH group, R ₂ represents a hydrogen atom, a methyl group, or an ethyl group, and R ₃ represents a hydrogen atom or an OH group. A is

[Formula] or C=O, and B represents a single bond or an oxygen atom. X represents iodine. ) The object compound of the present invention () shows significant improvement in antibacterial activity against Gram-positive and Gram-negative bacteria compared to other 16-membered ring macrolide antibiotics, the leucomycin group, tylosin, and coelamycin. . In particular, known macrolide antibiotics show weak antibacterial activity against Gram-negative bacteria, but () have strong antibacterial activity against all Gram-negative bacteria except Pseudomonas aeruginosa P-3. It is also superior to the raw materials tylosin and mycaminosyl tylonolide. A compound represented by formula () can be derived from the compound () according to the present invention. (In the formula, R ₁ , R ₂ , A, and B have the same meanings as above, and R ₃ , R ₄ , and R ₅ are acetyl, propionyl,
selected from butyryl, isobutyryl, or isovaleryl groups. R ₃ .R ₄ and R ₅ may be the same or different. ) Compound () has antibacterial activity against Gram-positive and Gram-negative bacteria, and has antibacterial properties comparable to tylosin and mycaminosyltylonolide, but a particularly sustained increase in blood concentration was observed. . Pharmaceutically acceptable salts of the compounds of formulas () and () include, for example, salts with inorganic acids such as hydrochloric acid and phosphoric acid, and salts with organic acids such as acetic acid, propionic acid, citric acid, tartaric acid, and sulfonic acid. Salt is an example. Examples of the physicochemical properties of the compound according to the present invention are as follows. (a) In the formula [], R ₁ is a CHO group, R ₂ is an ethyl group, R ₃ is an OH group, A is a carbonyl group, B is a single bond, and X is an iodine (see Example 1) Elemental analysis value, Molecular formula and molecular weight Actual value C; 52.56 H; 7.15 N; 1.97 I; 17.92 Calculated value C; 52.61 H; 7.12 N; 1.98 I; 17.93 C ₃₁ H ₄₉ NO ₉ I (molecular weight 707) Melting point: 116.3-117.0°C Specific rotation degree [α] ²⁸ _D = -40.5° (c = 1, methanol) Ultraviolet absorption spectrum λ ^CH3OH _nax 282nm (ε18950) Infrared absorption spectrum As shown in Figure 1 (KBr method) Mass spectrum M ⁺ m/z; 707 592, 560, 517, 190, 145, 131, 115 Thin layer chromatography E-Merck TLC plate, Kieselgel
GF254 Developing solvent: Chloroform/methanol/concentrated aqueous ammonia (100:15:0.3) Rf=0.74 Hydrogen nuclear magnetic resonance spectrum The 100MHz nuclear magnetic resonance spectrum in deuterated chloroform is shown in Figure 2. Note that tetramethylsilane was used as an internal standard. (b) In formula [], R ₁ is a CHO group, R ₂ is an ethyl group, R ₃ is an acetoxyl group, A is a carbonyl group,
When B is a single bond and R ₄ and R ₅ are acetyl groups (see Reference Example 1) Elemental analysis, molecular formula and molecular weight Actual value C; 53.40 H; 6.63 N; 1.67 I; 15.26 Calculated value C; 53.36 H; 6.65 N; 1.68 I; 15.24 C ₃₇ H ₅₆ NO ₁₂ I (molecular weight 833) Melting point: 110-113℃ Specific rotation [α] ²⁸ _D = -35.6° (c = 1, methanol) Ultraviolet absorption spectrum λ ^CH3OH _nax = 282 nm (ε17700) Infrared absorption spectrum As shown in Figure 3 (KBr method) Mass spectrum M ⁺ m/z; 838 706, 676, 559, 258, 216 Thin layer chromatography E-Merck TLC plate, Kieselgel
GF254 Developing solvent: Chloroform/methanol/concentrated ammonia water (100:10:0.3) Rf=0.77 The acute toxicity of the compound according to the present invention (oral and intracavitary administration in mice) is similar to that of other 16-membered ring macrolide antibiotics. It is approximately the same level. The antibacterial spectrum of the compounds according to the invention is significantly expanded and improved compared to known 16-membered ring macrolide antibiotics and other antibiotics. The compounds according to the invention are therefore novel antibiotics;
It is expected to have uses as a human and veterinary drug. Table 1 shows examples of the antibacterial spectra of the compounds according to the present invention and comparisons with known antibiotics.

[Table] As is clear from Table 1, compared to the known antibiotics tylosin and leucomycin A ₃ , compound A (23-iodo-23-deoxymycaminosyltylonolide) is more effective against Gram-positive bacteria, especially Bacillus.・Subtilis PCI219 and Sarcina lutea
It showed strong activity against PCI1001. It also showed strong antibacterial activity against various Gram-negative bacteria. Examples of methods for producing compounds according to the present invention are as follows. General formula with tylosin as the representative compound [] (In the formula, R ₁ , R ₂ , R ₃ , A, B have the same meanings as above) is used as a starting material, and an inorganic acid such as hydrochloric acid or sulfuric acid is used to adjust the concentration of the acid. By increasing the heating temperature or increasing the heating time, the mycarose and mycinose moieties are sequentially eliminated, and the general formula [] (wherein R ₁ , R ₂ , R ₃ , A, and B have the same meanings as above) (US Patent 3433711, Tetrahedron Lett. No. 34, 2339)
(1964), ditto No. 40, 4737 (1970). Next, the 16-membered ring lactone compound represented by the general formula [] is dissolved in an organic solvent. The organic solvent used for this is dimethylformamide,
Sulfolane, hexadimethylphosphoamide, benzene, toluene, xylene, acetonitrile, etc. are used. Then, triphenylphosphine and iodine, bromine, chlorine gas or fluorine gas, triphenoxyphosphine and iodine, bromine, chlorine gas or fluorine gas, potassium iodide, potassium bromide, potassium chloride or fluorine gas are used as halogenating reagents. Potassium chloride and polyphosphoric acid are used. This halogenation reaction usually proceeds at room temperature, but depending on the case, the reaction may be controlled by heating or cooling and may be carried out in an inert gas such as nitrogen gas or argon gas. The reaction solution obtained as described above is poured into water, made slightly alkaline, and then extracted with an organic solvent such as benzene, ethyl acetate, chloroform, etc. The organic solvent layer is collected and concentrated, and the general formula A coarse powder of the compound represented by [ ] is obtained. This crude powder can be purified using known methods for separating and purifying macrolide antibiotics, such as extraction, dissolution,
This is carried out by means of column chromatography using an adsorbent such as silica gel or alumina. By acylating the halogenated macrolide compound thus purified by a conventional method, a compound represented by the formula [] can be obtained. That is, in the presence of an acylation reaction solvent for a halogenated macrolide compound, such as pyridine, triethylamine, p-toluenesulfonic acid, etc., a carboxylic acid anhydride or acid halide having 2 to 4 carbon atoms is used as the acylating agent. This is generally carried out at room temperature, but if necessary, measures such as cooling with ice or heating may be taken. The quantitative ratio of the acylating agent used in the acylation reaction may be appropriately selected within the range of 1 to 10 times the mole. Acylated reaction product obtained in this way []
recrystallize using a recrystallization solvent, or perform column chromatography using alumina, silica gel, etc., separate only the target substance fraction, and precipitate crystals by operations such as concentration. Purify and separate. If desired, a pharmacologically acceptable salt can be obtained from the compound of formula [] or [] by a conventional method. Example 1 23-iodo-23-deoxymycaminosyltylonolide Using 500mg of mycaminosyltylonolide obtained by hydrolyzing tylosin with 0.1N hydrochloric acid as a starting material, 440mg of triphenylphosphine was dissolved in 1ml of dimethylformamide. Dissolve and replace the air in the reaction vessel with argon gas. Then, while stirring at room temperature, a solution of 220 mg of iodine dissolved in 1 ml of dimethylformamide was gradually added dropwise over 10 minutes. After the dropwise addition, stirring was continued for 1 hour, and then the reaction solution was poured into water, adjusted to be slightly alkaline with sodium bicarbonate, and extracted with chloroform. The chloroform layer was washed with saturated saline, dried over anhydrous sodium sulfate, and further concentrated to dryness under reduced pressure to give a white powder.
Obtained 450 mg. This powder was dissolved in a small amount of chloroform, passed through a column packed with 15 g of silica gel (Kieselgel G. Merck & Co.), eluted with chloroform-methanol (20:3) as a developing solvent, and 23-iodo- 122 mg of 23-deoxymycaminosyltylonolide was obtained as a white powder. The physicochemical properties of this substance are as described above. Reference example 1 3,2',4'-triacetyl-23-iodo-23-
Deoxymycaminosyltylonolide 100mg of 23-iodo-23-deoxymycaminosyltylonolide was dissolved in 1ml of anhydrous pyridine.
Add 0.7 ml of acetic anhydride to this solution and leave it at room temperature for 24 hours. The reaction solution was poured into ice water, then the excess acid was neutralized with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous sodium sulfate, and further concentrated to dryness under reduced pressure to obtain 110 mg of white powder. This powder was dissolved in a small amount of benzene, passed through a column packed with 3 g of silica gel (Kieselgel G. Merck & Co.), and 3,2',4' -Triacetyl-
85 mg of 23-iodo-23-deoxymycaminosyltylonolide was obtained as a white powder. The physicochemical properties of this substance are as described above.

[Brief explanation of the drawing]

FIG. 1 shows the infrared absorption spectrum of the material according to Example 1, FIG. 2 shows its nuclear magnetic resonance spectrum, and FIG. 3 shows the infrared absorption spectrum of the material according to Reference Example 1.

Claims (1)

[Claims] 1. The following general formula [] (In the formula, R ₁ represents a hydrogen atom, a methyl group, a -CHO group, or a -CH ₂ OH group, R ₂ represents a hydrogen atom, a methyl group, or an ethyl group, and R ₃ represents a hydrogen atom or an OH group. A is represented by the following formula or C=0, B is a single bond or an oxygen atom, and X is iodine) and pharmacologically acceptable salts thereof.