Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Utility Patent
1999-10-28
2001-01-02
Peselev, Elli (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S007200
Utility Patent
active
06169168
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel derivatives of antibiotic erythromycin A.
BACKGROUND ART
Erythromycin A is an antibiotic widely used as an agent for the treatment of infectious diseases caused by Gram-positive bacteria, mycoplasmas, etc. However, erythromycin A 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 pharmaceutically effective 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. 4,331,803). There are also recent reports relating to 11,12-cyclic carbamate derivatives obtained from 6-O-methylerythromycin A as a starting material with the aim of expansion of antibacterial spectrum as well as a stability to acids (EP. Patent No. 487411, U.S. Pat. No. 4,742,049). In addition, the present inventors have reported the antibacterial activity of the ester derivatives esterified at the 3-position (EP. Patent No. 619320).
An object of the present invention is to provide post-generational macrolide antibiotics having a strong antibacterial activity not only against previous erythromycin-sensitive bacteria but also against erythromycin-resistant bacteria which recently show a tendency to increase.
DISCLOSURE OF THE INVENTION
The present inventors have found that the compounds wherein a certain substituted aminoalkyl group or a certain alkyl group having an arylsulfonamide group has been introduced into the hydroxyl group formed by the reduction of the carbonyl group at the 9-position of erythromycin A have a strong antibacterial activity not only against sensitive bacteria but also resistant bacteria, thereby the present invention has been accomplished.
The present invention relates to an erythromycin A derivative represented by the formula:
wherein n is an integer of from 1 to 8, R
1
is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R
2
is a pyridylmethyl group, a quinolylmethyl group, a pyridylsulfonyl group or a quinolylsulfonyl group, R
3
is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a cinnamyl group, R
4
is a cladinosyloxy group or a group represented by the formula:
wherein m is 0 or 1, R
5
is a pyridyl group, a quinolyl group, a phenyl group, a phenyl group substituted with one, two or three members selected from alkyl groups having 1 to 6 carbon atoms, a nitro group, alkoxy groups having 1 to 3 carbon atoms and halogen atoms, or a pyridyl or quinolyl group substituted with one or two members selected from alkyl groups having 1 to 6 carbon atoms, a nitro group, alkoxy groups having 1 to 3 carbon atoms and halogen atoms; or a pharmaceutically acceptable salt thereof.
In the present invention, examples of the alkyl group having 1 to 6 carbon atoms are a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, an isopropyl group, an isobutyl group, a t-butyl group, an isopentyl group and a cyclohexyl group; examples of the alkoxy group having 1 to 3 carbon atoms are a methoxy group, an ethoxy group, a propoxy group and an isopropoxy group; and the halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
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, undecanoic acid, polyacrylate or carboxyvinyl polymer.
The compounds of the present invention can be prepared according to the bellow-mentioned examples.
The erythromycin A derivatives of the present invention can be administered orally or parenterally. They can be administered in a dosage form such as tablets, capsules, powders, troches, ointments, suspensions, suppositories or injectional preparations, all of which can be prepared by ordinary preparation techniques. The dose is from 100 to 1,000 mg per day for the treatment of adults, and it can be administered once or in several divided portions. This dose can be properly increased or decreased depending on the age, body weight and conditions of the patient.
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention is illustrated in more detail by the following examples and experiment.
REFERENCES:
patent: 4331803 (1982-05-01), Watanabe et al.
patent: 4742049 (1988-05-01), Baker et al.
patent: 5770579 (1998-06-01), Agouridas et al.
patent: 0 487 411 A1 (1992-05-01), None
patent: 0 619 320 A1 (1994-10-01), None
Hunt et al. The Journal of Antibiotics, vol. 42, No. 2, pp. 293-298, Feb. 1989. See PCT search report.
Asaka Toshifumi
Ishii Takaaki
Kashimura Masato
Matsuura Akiko
Sugimoto Tomohiro
Armstrong, Westerman, Hattori, McLelland & Naughton
Peselev Elli
Taisho Pharmaceuticals Co., Ltd.
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