Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1997-05-16
1998-12-08
Kunz, Gary L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
514 29, C12P 1962, A01K 3170
Patent
active
058470921
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to Erythromycin A derivatives endowed with antibiotic activity, useful in the treatment of infectious diseases and, derivatives endowed with antibiotic activity against Gram-positive and 3626! is a well-known naturally occurring macrolide endowed with antibiotic activity, having the following structure ##STR1## Besides being active against some non-bacterial microorganisms such as rickettsiae and mycoplasmas, Erythromycin A is endowed with antibacterial activity mainly against Gram-positive microorganisms such as streptococci, staphylococci and pneumococci, but it results effective as well against some Gram-negative microorganisms such as, for instance, Haemophilus influenzae, Neisseria gonorrhoeae and Bordetella pertussis.
In addition to the well-known activity against the aforementioned prokaryotes, it has been recently described in the literature that Erythromycin A and other macrolide antibiotics are active against 307-343 (1994)!.
Also in the case of Erythromycin A, likewise other antibacterial drugs, phenomena of resistance were observed with some bacterial strains.
In particular, the phenomenon was observed in the treatment of infections caused by staphylococci following to prolonged administration of Comprehensive Review with Clinical Emphasis, William Heinemann Medical, IV Ed., (1987) 851-882!.
The interest towards macrolide antibiotics derives from their use in clinical and veterinary therapy in the treatment of several infectious diseases such as, for instance, the infections of the respiratory tract, of the gastrointestinal tract, of the urogenital tract and of the external organs like skin, eye and ear.
Because of its high instability in acidic environment Erythromycin A is irreversibly converted, for instance in the gastrointestinal tract following to oral administration, into derivatives devoid of antibiotic A. Kirst, Annual Reports in Medicinal Chemistry, 25, 119-128 (1989)!.
In order to overcome the above drawbacks, the research was addressed to compounds which, while maintaining the good antibiotic properties of Erythromycin A, resulted to be characterized by a superior stability to the acids and better pharmacokinetic properties such as, for instance, superior oral bioavailability, haematic concentration, tissue penetration and half-life.
Within this field, we can cite as an example the carbamates and carbonates of Erythromycin A or Erythromycin A 9-0-oxime described in the European patent applications No. 0216169 and No. 0284203 (both in the name of Beecham Group PLC) and the compounds described in the European patent application No. 0033255 (Roussel-Uclaf). The European patent application No. 0033255, in particular, describes derivatives of Erythromycin A 9-0-oxime of formula is in place of the carbonyl group in position 9 (0=Ery); A represents a straight or branched alkyl group with from 1 to 6 carbon atoms; R represents, inter alia, an optionally substituted alkoxy group with from 1 R.sub.2, the same or different, represent a hydrogen atom or an optionally substituted alkyl group with from 1 to 6 carbon atoms.
The compounds described in the European patent application No. 0033255 such Index, XI Ed., No. 8253!, Erythromycin A comparable to that of Erythromycin A but are endowed with a superior stability to the acids and better pharmacokinetic properties.
Said compounds, therefore, present an antibiotic activity against Gram-positive bacteria such as staphylococci, streptococci and pneumococci and against some Gram-negative bacteria such as, for instance, Haemophilus influenzae and Haemophilus pertussis.
Now we have found compounds derivative of Erythromycin A 9-0-oxime and, more particularly, compounds derivative of Erythromycin A European patent application No. 0033255, which have a wider spectrum of antibacterial activity against Gram-positive microorganisms and, particularly, against Gram-negative microorganisms, and improved pharmacokinetic properties such as, for instance, a superior duration of action and a superior half-life of tissue elimination,
REFERENCES:
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patent: 5302705 (1994-04-01), Misawa et al.
patent: 5444051 (1995-08-01), Agouridas et al.
Journal of Antibiotics, vol. 44, No. 3, Mar. 1991, Tokyo, JP, pp. 313-330, XP000567789, J. Gasc et al: "New ether oxime derivatives of erythromycin A. A structure-activity relationship study".
Albini Enrico
Botta Daniela
Pellacini Franco
Romagnano Stefano
Santangelo Francesco
Kunz Gary L.
Zambon Group S.p.A.
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