Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1994-10-17
1997-05-20
Peselev, Elli
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 72, C07H 1708
Patent
active
056313551
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to novel derivatives of an antibiotic erythromycin, and more particularly relates to novel 5-O-desosaminyl-erythronolide A derivatives, pharmaceutically acceptable acid addition salts thereof and intermediates for the preparation thereof.
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/or 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 novel antibiotics having a strong antibacterial activity.
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 tricyclic carbamates substituted by a methoxy group at the 6-position have a strong antibacterial activity, and the present invention has been accomplished.
The present invention relates to 5-O desosaminylerythronolide A derivatives represented by the formula: ##STR3## [wherein -A- - is a group of --N(R.sup.3)-- (wherein R.sup.3 is a hydrogen atom or an alkyl group having 1-3 carbon atoms) or a group represented by --N.dbd., and R.sup.1 and R.sup.2 are each a hydrogen atom or an alkyl group having 1-3 carbon atoms], and a pharmaceutically acceptable acid addition salt thereof, and a 10,11-anhydro-12-O-imidazolylcarbonyl-6-O-methylerythromycin A protected by the same acyl groups at the 2'- and 4"-positions represented by the formula: ##STR4## (wherein R.sup.4 is an acetyl group or a propionyl group) which is a useful intermediate for the preparation of the 3-ketone form of 5-O-desosaminylerythronolide A derivatives.
In the present invention, the alkyl group having 1-3 carbon atoms is one which is a straight or branched chain. 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-hydroxyethane-sulfonate, 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. Material
Step (1); 6-O-Methylerythromycin A is first reacted with an acid anhydride represented by the formula R.sup.4.sub.2 O (wherein R.sup.4 is as defined above) or an acid halide represented by the formula R.sup.4 X (wherein R.sup.4 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 hydroxyl groups at the 2'- and 4"-positions at the same time to give a compound represented by the formula (a): ##STR5## (wherein R.sup.4 is as defined above). Preferable examples of the inert solvent to be used herein are dichloromethane, dichloroethane, acetone and tetrahydrofuran. 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 of the present invention represented by the formula (b): ##STR6## (wherein R.sup.4 is as defined above). Examples of the suitable solvent to be used herein are N,N-dimethyl-formamide, N-methylpyrrolido
REFERENCES:
patent: 4742049 (1988-05-01), Baker et al.
patent: 5175150 (1992-12-01), Omura et al.
patent: 5403923 (1995-04-01), Kashimura et al.
patent: 5444051 (1995-08-01), Agouridas et al.
Antimicrobial Agents & Chemotherapy, vol. 6, No. 4 pp. 479-488 (1974).
Journal of Medicinal Chemistry, vol. 17, No. 9 pp. 953-956 (1974).
Asaka Toshifumi
Hatayama Katsuo
Kashimura Masato
Misawa Yoko
Morimoto Shigeo
Peselev Elli
Taisho Pharmaceutical Co. Ltd.
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