JPS6159637B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to new derivatives of the antibiotic tylosin. More specifically, the present invention is 20-deoxodesmycosine (20-deoxo-4'-demycarosyltylosin) or a salt thereof. The compound of the present invention is a novel compound and has the formula It is expressed as The above salts are pharmaceutically acceptable salts. Such suitable salts include hydrochloric acid, sulfuric acid,
Included are salts with inorganic acids such as phosphoric acid, and salts with organic acids such as acetic acid, propionic acid, tartaric acid, citric acid, succinic acid, malic acid, aspartic acid, and glutamic acid. Other non-toxic salts are also included. It is clear from Table 1 that the above new compound [] has extremely stronger antibacterial activity against Gram-positive bacteria than the raw material tylosin, and is a substance that is expected to have clinically excellent infection treatment effects. . It is also useful as a therapeutic drug for animals and a feed additive.

[Table] The above target compound [] is at position 19 of tylosin.
CHO group is reduced to CH ₂ OH group, and this CH ₂ OH group is
It can be obtained by converting it into a CH ₃ group and de-4'-mycarosylating the obtained 20-deoxotylosine with a dilute acid. The reduction of the 19-position CHO group to the CH ₂ OH group is performed by reducing the 9-position CHO group to the
The reduction is carried out using a known reduction method that performs reduction under mild conditions that do not reduce the CO group. Suitable methods include methods using _NaBH4 , preferably Antimicrobial Agents and
Chemotherapy 1963, 45 (1964). For example, NaBH ₄ may be reacted at room temperature in aqueous methanol having a pH of around 7.5. Since the reaction time can be monitored by thin layer chromatography using silica gel or the like, the reaction can be appropriately terminated after waiting for the disappearance of tylosin.
The obtained product is collected by extracting the reaction solution with a non-hydrophilic organic solvent, such as chloroform, and can be used in the next reaction without particular purification. The CH ₂ OH group at position 19 can be converted to a CH ₃ group by various known methods. For example, the OH group of CH ₂ OH group is tosylated and then NaI+
This can be carried out by a method in which p-toluenesulfonic acid ester is reductively eliminated using Zn. The above tosylation is carried out in the presence of a tertiary organic amine, e.g. pyridine, as a deoxidizing agent and as a solvent.
- by reacting toluenesulfonyl halide. Since the progress of the reaction can be monitored by thin layer chromatography using silica gel or the like, the reaction can be appropriately terminated after waiting for the disappearance of the product, ie, the 20-dihydro compound. After the reaction, the mixture is poured into water, the pH is adjusted to 8 to 10, and the mixture is extracted with a suitable non-hydrophilic organic solvent such as chloroform.
A product in which the OH group is tosylated can be collected. This product can be used in the next reaction without particular purification. Next, this p-toluenesulfonic acid ester is removed reductively, and this reaction is carried out in a suitable organic solvent, such as ethylene glycol dimethyl ether.
This is done by heating in the presence of NaI and Zn. In the above reaction, the CH ₂ O-tosyl group is first converted into CH ₂ I
This is reduced by Zn and converted to CH ₃ . Since the progress of the reaction can be monitored by thin layer chromatography using silica gel or the like, the reaction can be appropriately terminated after waiting for the disappearance of the product in which the OH group at the 20-position is tosylated. In order to collect the 20-deoxotylosine thus obtained from the reaction solution, the reaction solution from which Zn has been removed is poured into water and extracted with a non-hydrophilic organic solution, such as chloroform. Next, this 20-deoxotylosine is de-4'-mycarosylated, and this reaction is carried out using a dilute acid,
For example, it may be hydrolyzed with about 0.5N hydrochloric acid.
Since the hydrolysis time can be tracked by thin layer chromatography using silica gel or the like, the reaction can be appropriately terminated after waiting for the disappearance of 20-deoxotylosine. Moreover, the above-mentioned target compound [] can also be produced by the following alternative method. That is, in the above production process, the 19-position CHO group is de-4'-mycarosylated before being reduced to a CH ₂ OH group.
The reaction in each step in this case may be carried out under the same conditions as in the reaction step. In order to collect the 20-deoxodesmycosine thus obtained from the reaction solution, the reaction solution is neutralized with an alkali such as aqueous ammonia and extracted with an appropriate non-hydrophilic organic solvent such as chloroform. This is done by If further purification is required, it can be purified by column chromatography using an adsorbent such as silica gel, activated alumina, or adsorption resin. Next, production examples of the present invention will be specifically explained with reference to Examples. The Rf values in the examples were measured by thin layer chromatography (TLC) using the following carrier and developing solvent, unless otherwise specified. Carrier: Merck silica gel 60 plate
Art5721 Developing solvent: Chloroform-methanol-acetic acid water (80:7:7:1) Example 1 20-deoxodesmycocin 5 g of tylosin in 0.2M phosphate buffer (PH7.5)
-Dissolved in 150 ml of methanol (1:1) mixture,
A solution of 150 mg of NaBH ₄ dissolved in 10 ml of the above mixture was added to this, and after stirring at room temperature for 1.5 hours, the pH was adjusted to 9.5 with dilute ammonia water, and the reaction solution was extracted with 100 ml of chloroform. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate, and dried under reduced pressure to obtain crude 20-dihydrotylosin (UVλ ^EtoH _nax 283 nm, Rf=0.1
Five)
get. The above product was dissolved in 20 ml of pyridine, 1.25 g of tosyl chloride was added thereto, and the mixture was stirred at room temperature for 16 hours.
Add 5 ml of concentrated ammonia water to the reaction solution, stir for 15 minutes, pour into 500 ml of water, and extract with 100 ml of chloroform. The chloroform layer is washed successively with water, dilute hydrochloric acid, water, and dilute ammonia water, dried over anhydrous magnesium sulfate, and then dried under reduced pressure. 3.3g of powder obtained
was dissolved in 30 ml of ethylene glycol dimethyl ether, 2.3 g of sodium iodide and 2 g of zinc powder were added thereto, and the mixture was heated under reflux for 3 hours. The reaction mixture was filtered to remove zinc powder, 100 ml of water was added to the solution, the pH was adjusted to 9.5 with dilute ammonia water, and 100 ml of chloroform was added.
Extract in ml. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate, and dried under reduced pressure to obtain crude 20
-Deoxotylosin (Rf=0.24) is obtained. Dissolve the above product in 50ml of 0.5N hydrochloric acid and let it stand at room temperature.
Stir for 18 hours. The reaction solution was adjusted to PH9.5 with aqueous ammonia.
and extract with 100 ml of chloroform. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate, and dried under reduced pressure to obtain 2.2 g of crude powder of 20-deoxodesmycocin. This powder was mixed with chloroform.
Purified by silica gel column chromatography using methanol (15:1) to obtain 780 mg of purified product.
get. TLC; Rf=0.32 UVλ ^EtoH _nax 283nm (ε=19700) Mass (m/
e); 757 (M ⁺ ), 739, 612, 567, 394, 393,
377, 359, 358, 190, 174, 173 NMR (100MHz, _CDCl3 ); 1.79 (12- _CH3 ),
2.51 (3'-N( _CH3 ) ₂ ), 3.42 and 3.49
(OCH ₃ )ppm, aldehyde disappearance

Claims (1)

[Claims] 1 20-deoxodesmycosin or its salt.