5-O-desosaminylerythronolide a derivative

Details 5-O-desosaminylerythronolide a derivative 5-O-desosaminylerythronolide a derivative

1994-10-14

1997-01-07

Peselev, Elli

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

536 72, C07H 1708

Patent

active

055918379

DESCRIPTION:

BRIEF SUMMARY
DESCRIPTION

1. Technical Field
The present invention relates to a novel derivative of an antibiotic erythromycin, and more particularly relates to a novel 5-O-desosaminylerythronolide A derivative and pharmaceutically acceptable acid addition salts thereof.
2. Background of Art
Erythromycins are antibiotics clinically widely used as agents for treating infectious diseases caused by Gram-positive bacteria, some Gram-negative bacteria, mycoplasmas, etc. Many erythromycin derivatives have been prepared for the improvement of biological and pharmaceutical properties of erythromycins. Certain ketone forms at the 3-position of 5-O-desosaminylerythronolide A have been described in Antimicrobial Agents and Chemotherapy, vol. 6, No. 4, page 479 (1974) and Journal of Medicinal Chemistry, vol. 17, No. 9, page 953 (1974), but generally they have extremely weak antibacterial activity. An object of the present invention is to provide a novel antibiotic having a strong antibacterial activity.
3. Disclosure of the Invention
As a result of various researches on the antibacterial activity of 3-ketone forms of 5-O-desosaminylerythronolide A derivatives, the present inventors have found that a 5-O-desosaminylerythronolide A derivative, which falls within the formula of the specification of EP patent No. 0487411 but is not specifically described therein, has a extremely strong antibacterial activity, and the present invention has been accomplished.
The present invention relates to 11-amino-3,11-dideoxy-3-oxo-5-O-desosaminyl-6-O-methyl-erythronolide A 11-N,12-O-cyclic carbamate and a pharmaceutically acceptable acid addition salt thereof.
In the present invention, the pharmaceutically acceptable acid addition salt means, for example, acetate, propionate, butyrate, formate, trifluoroacetate, maleate, tartrate, citrate, stearate, succinate, ethylsuccinate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, p-toluenesulfonate, laurylsulfate, malate, aspartate, glutaminate, adipate, cysteine salt, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinate, oxalate, picrate, thiocyanate, undecanoate, polyacrylate or carboxyvinyl polymer salt.
The compounds of the present invention can be prepared, for example, as follows.


Preparation Method 1



Method using 6-O-methyl-erythromycin A as a starting material

Step (1); 6-O-Methylerythromycin A is first reacted with an acid anhydride represented by the formula R.sub.2 O (wherein R is an acetyl group or a propionyl group) or an acid halide represented by the formula RX (wherein R is as defined above, and X is a halogen atom) and a base in an inert solvent at from 0.degree. C. to 30.degree. C. for protection of the hydroxyl groups at the 2'- and 4"-positions at the same time to give a compound represented by the formula (a): ##STR1## (wherein R is as defined above). Preferable examples of the inert solvent to be used herein are dichloromethane, dichloroethane, acetone and pyridine. The acid anhydride and acid halide to be used are those of acetic acid and propionic acid. Examples of the base to be used are pyridine and 4-dimethylaminopyridine.
Step (2); The compound (a) is reacted with 1,1'-carbonyldiimidazole and a base in a suitable solvent at room temperature to give a compound represented by the formula (b): ##STR2## (wherein R is as defined above). Examples of the suitable solvent to be used herein are N,N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile and a mixture thereof. Examples of the base to be used are sodium hydride, potassium hydroxide and sodium bis-trimethylsilylamide.
Step (3); The compound (b) is reacted by adding ammonia and sodium hydride in a suitable solvent to give an 11,12-cyclic carbamate represented by the formula (c): ##STR3## (wherein R is as defined above). The inert solvent to be used herein is the same as used in Step (2).
Step (4); The compound (c) is reacted with an acid to give a compound of the formula (d): ##STR4## (wherein R is as de

REFERENCES:
patent: 5444051 (1995-08-01), Agouridas et al.
Antimicrobial Agents & Chemotherapy vol. 5, #4, pp. 479-488.
Journal of Medicinal Chemistry vol. 17, #9, pp. 953-956 (1974).
Journal of Organic Chemistry, vol. 53 No. 10, pp. 2340-2345 (1988).

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