2'-position modified compound of erythromycin or its derivative

Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives

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536 72, C07H 1708

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active

053508394

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BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to a 2'-position modified compound of erythromycins. More particularly, it relates to a 2'-position modified compound of erythromycins which shows an extremely relieved bitterness at administration and an improved absorbability in vivo when formulated into a drug.


BACKGROUND ART

In most cases, erythromycins, which are used in chemotherapy for various bacterial infections, are orally administered. When these compounds are to be administered via internal use, the characteristic bitterness thereof makes it necessary to formulate them into capsules or coated tablets. For-those who cannot smoothly swallow down these drugs such as children and aged persons, however, it is desirable to formulate these compounds into solutions or granules. In these cases, the bitterness cannot be fully relieved by simply masking them. In order to solve these problems, attempts have been made to develop various esters which show no bitterness at the administration but return into the original active compounds at or after the absorption in vivo.
Examples of these esters include erythromycin ethylsuccinate [Antibiotics and Chemotherapy, 7 (9), 487 (1957).sub.], erythromycin propionate lauryl sulfate [Journal of the American Pharmaceutical Association, .48 (11), 620 (1959)], allyl, ethyl and benzyl carbonates of erythromycin [Antibiotics Annual, 1953-1954, 500 (1954)]and 2'-ester of O-methylerythromycin derivative (JP-A-61-200998).
However these known compounds are generally insufficient in absorbability in vivo. Further, these compounds per se generally have a weak antibacterial activity. Therefore, they should be rapidly converted into the original active compounds in vivo. However, these compounds are hardly converted into the original active compounds in vivo in practice, which makes it impossible to achieve satisfactory therapeutic effects.


DISCLOSURE OF THE INVENTION

Therefore, the present inventors have conducted extensive studies on 2'-modifying groups of various erythromycins and, consequently, found out that a 2'-position modified compound of erythromycins, which shows an extremely relieved bitterness at administration and an improved absorbability in vivo and can rapidly return into the original active compound in vivo, can be obtained by introducing a group represented by the following formula:
The present invention relates to a compound having a group represented by the following formula (I): represents an integer of from 2 to 4, and n represents an integer of from 1 to 7) at the 2'-position of erythromycins or a salt thereof.
The term "erythromycins" as used herein means compounds having an erythromycin skeleton and those derived from erythromycin. Examples thereof include erythromycin (for example, erythromycin A, erythromycin B), 6-0-methyl-erythromycin A (clarithromycin), erythromycin A 9-{0-[(2-methoxyethoxy)methyl]oxime}(roxithromycin), 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A (azithromycin), erythromycin 11, 12-carbonate (davercin), 8-fluoroerythromycin A (flurithromycin), halogen-substituted benzyloxime derivatives of 6-0-methylerythromycin A {for example, 6-0-methylerythromycin A 9-[0-(2,6-difluorobenzyl)oxime], 6-0-methylerythromycin A 9-[0-(4-bromobenzyl)oxime]}, 9-deoxo-11,12-dideoxy-9,12-epoxy-ll-oxo-9,10-didehydro-erythromycin A, 11-amino-9-deoxo-11,12-dideoxy A, 9-deoxo-9-(4,4-dimethyl)piperidino-erythromycin A, 11-deoxy-11-[carboxy-(N-methyl, N-benzyl-aminoethy1)amino]-6-0-methylerythromycin A 11,12-cyclic ester, 4"-deoxyerythromycin A and 4"-deoxyerythromycin A 11,12-cyclic carbonate.
The alkyl group having from 1 to 12 carbon atoms involves straight- or branched-chain groups.
Examples of the salt include those formed with acids such as acetic acid, propionic acid, butyric acid, formic acid, trifluoroacetic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, stearic acid, succinic acid, ethylsuccinic acid, lactobionic acid, glycolic acid, glucoheptonic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesul

REFERENCES:
patent: 4382086 (1983-05-01), Sciavolino et al.
patent: 4668664 (1987-05-01), Rougier et al.
patent: 4677097 (1987-06-01), Omura et al.
patent: 4948782 (1990-08-01), Omura et al.

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