Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1993-05-20
1995-04-04
Rollins, John W.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 72, C07H 1708
Patent
active
054039231
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to antibiotics for use in chemotherapy of infectious diseases by bacteria, and more detailedly to erythromycin A derivatives exhibiting a high antimicrobial activity also against Gram-negative bacteria, their pharmaceutically acceptable salts and intermediates for preparation thereof.
1. Background Art
A macrolide antibiotic erythromycin A exhibits a desirable antimicrobial activity against many Gram-positive bacteria, mycoplasmas, etc., and is clinically and widely used. However, erythromycin A has only a weak antimicrobial activity against Gram-negative bacteria, and it was impossible to expect a sufficient therapeutic effect.
The object of this invention lies in providing novel erythromycin A derivatives having a strong antimicrobial activity against Gram-negative bacteria, and having against Gram-positive bacteria also a much stronger effect than compounds so far known.
2. Disclosure of Invention
The present inventors found that novel compounds having a tricyclic basic nuclear structure obtained by combining the 11- and 12-positions of 6-O-methylerythromycin A to give a cyclic carbamate compound, and further by combining the nitrogen atom of the carbamate with the 9-position through an ethylene chain or a substituted ethylene chain to give a cyclic imine compound or a nitron compound, not only exhibit a strong antimicrobial activity against Gram-positive bacteria, but also exhibit a strong antimicrobial activity against Gram-negative bacteria, and completed this invention.
Thus, this invention relates to 6-O-methyl-erythromycin A derivatives represented by the following formula (I) ##STR2## (wherein R.sup.1 and R.sup.2 each represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and A represents a nitrogen atom or a N.fwdarw.O group) the following formula (II), which are intermediates for preparation of the compounds of the formula (I) ##STR3## (wherein R represents an acetyl group or a trimethylsilyl group).
As pharmaceutically acceptable salts in this invention, there can, for example, be mentioned acetates, propionates, butyrates, formates, trifluoroacetates, maleates, tartrates, citrates, stearates, succinates, ethylsuccinates, lactobionates, gluconates, glucoheptonates, benzoates, methanesulfonates, ethanesulfonates, 2-hydroxyethanesulfonates, benzenesulfonates, p-toluenesulfonates, lauryl sulfates, malates, aspartates, glutamates, adipates, cysteine salts, hydrochlorides, hydrobromides, phosphates, sulfates, hydroiodides, nicotinates, oxalates, picrates, thiocyanates, undecanoates, acrylic acid polymer salts, carboxyvinyl polymer salts, etc.
The compounds of the formula (I) of this invention can, for example, be prepared as follows from the compounds of the formula (II).
That is, represented by the following formula (III) ##STR4## (wherein R.sup.1 and R.sup.2 are as defined above) in a suitable solvent (for example, acetonitrile, tetrahydrofuran or a mixture thereof, or the like) to give a compound represented by the following formula (IV) ##STR5## (wherein R.sup.1 and R.sup.2 are as defined above, and R is a trimethylsilyl group or an acetyl group). tetranormalbutylammonium fluoride or a suitable acid (for example, formic acid, acetic acid or the like) to remove the trimethylsilyl group, or in case of a compound of the formula (IV) wherein R is an acetyl group, the compound can be heat treated in methanol to remove the acetyl group, and then the resultant compound can be boiled with a small excessive amount of acetic acid in ethanol to give a compound of this invention of the formula (I) wherein A is a nitrogen atom.
When an acid is used for the detrimethylsilylation, there is a case where cyclization reaction to the 9-position takes place at the same time with the detrimethylsilylation to give a compound of this invention of the formula (I) wherein A is a nitrogen atom. obtained by oxidizing a compound of the formula (I) wherein A is a nitrogen atom with m-chloroperbenzoic acid, and regenerating the dimethylamino group which was oxidized a
REFERENCES:
patent: 4640910 (1987-02-01), Faubl et al.
patent: 4742049 (1988-05-01), Baker et al.
Journal of Organic Chemistry, vol. 53, No. 10 pp. 2340 to 2345, Baker et al.
Asaka Toshifumi
Hatayama Katsuo
Kashimura Masato
Morimoto Shigeo
Peselel Elli
Rollins John W.
Taisho Pharmaceutical Co. Ltd.
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