Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1999-09-21
2000-10-31
Minnifield, Nita
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 74, 514 29, 574 29, C07H 1708, A61K 3170
Patent
active
061404799
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to antibiotic erythromycin A derivatives.
BACKGROUND ART
Erythromycin A is an antibiotic widely used as an agent for treating infectious diseases caused by Gram-positive bacteria, mycoplasmas, etc. However, erythromycin is decomposed by gastric acid due to its instability to acids, and thus has a drawback of no constancy of movement in the body. Hitherto many erythromycin derivatives have been prepared for the purpose of the improvement of such biological or pharmacological properties. For example, it is reported that 6-O-methylerythromycin A derivatives have an improved stability to acids and have a superior in vivo antibacterial activity in comparison with erythromycin A when administered orally (U.S. Pat. No. 433,803). There are also recent reports relating to 11,12-cyclic carbamate derivatives of erythromycin with the aim of expansion of antibacterial spectrum as well as a stability to acids (EP. patent No. 487411, U.S. Pat. No. 4742049, EP. patent No. 676409 and EP. patent No. 638584), and further reports relating to erythromycin derivatives wherein an acyl group has been introduced at the 3-position (EP. Patent No. 619320).
An object of the present invention is to provide novel antibiotics having a strong antibacterial activity not only against previous erythromycin-sensitive bacteria but also against Haemophilus influenzae and erythromycin-resistant bacteria which recently show a tendency to increase.
DISCLOSURE OF THE INVENTION
As a result of various researches on the antibacterial activity of erythromycin derivatives, the present inventors have found that, among the 11,12-cyclic carbamate derivatives of 6-O-methylerythromycin A, the compounds containing a certain type of acyl group introduced at the 3-position have a strong antibacterial activity not only against previous erythromycin-sensitive bacteria but also against Haemophilus influenzae and certain erythromycin-resistant bacteria, thereby the present invention has been accomplished.
The present invention relates to an erythromycin derivative represented by Formula (I): ##STR2## wherein R is a pyridyl group, a quinolyl group, a nitrophenyl group or a methoxyphenyl group; or a pharmaceutically acceptable salt thereof.
In the present invention, the pharmaceutically acceptable salt refers to a salt used in chemotherapy or prophylaxis of bacterially infectious diseases. It includes, for example, a salt with an acid such as acetic acid, propionic acid, butyric acid, formic acid, trifluoroacetic acid, maleic acid, tartaric acid, citric acid, stearic acid, succinic acid, ethylsuccinic acid, lactobionic acid, gluconic acid, glucoheptonic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, laurylsulfuric acid, malic acid, aspartic acid, glutaminic acid, adipic acid, cysteine, N-acetylcysteine, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, hydroiodic acid, nicotinic acid, oxalic acid, picric acid, thiocyanic acid, undecanic acid, polyacrylate and carboxyvinyl polymer.
The compounds of the present invention can be prepared, for example, as follows. ##STR3##
Step (1); 10,11-Anhydro-2',4"-di-O-acetyl-12--imidazolylcarbonyl-6-O-methylerythromy cin A described in EP patent No. 638584 is reacted with hydrazine or ydrazine monohydrate in an inert solvent at a temperature of from -30 to 100.degree. C., preferably from 0.degree. C. to room temperature, to give an 11,12-cyclic carbamate compound, which is then reacted in a lower alcohol or an aqueous lower alcohol (if desired, a base such as sodium bicarbonate may be added herein) at a temperature of from 0 to 100.degree. C for removal of the protective group at the 2'-position, thereby there is obtained a compound represented by Formula (a). Examples of the inert solvent to be used herein are acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane, ethyl acetate, N-methylpyrrolidone, an aqueous solvent thereof and a mixture thereof. Examples of
REFERENCES:
patent: 3923784 (1975-12-01), Kierstead et al.
patent: 4331803 (1982-05-01), Watanabe et al.
patent: 4742049 (1988-05-01), Baker et al.
patent: 5631354 (1997-05-01), Asaka et al.
patent: 5656607 (1997-08-01), Agouridas et al.
patent: 5770579 (1998-06-01), Agouridas et al.
Asaka Toshifumi
Ishii Takaaki
Kashimura Masato
Tanikawa Tetsuya
Baskar Padma
Minnifield Nita
Taisho Pharmaceuticals Co., Ltd.
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