Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
2000-01-28
2000-09-26
Reamer, James
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544233, A61K 31435
Patent
active
06124290&
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to new polycyclic phthalazine derivatives, particularly 2-carboxyalkyl- and 2-carboxyaryl-substituted maduraphthalazines (10,12,15,16-tetrahydroxy-8-methoxy-11-methyl-1,9,14-trioxo-1,2,6,7,9,14-h exahydronaphthaceno-[1,2-g]-phthalazines) as well is salts, esters and amides thereof. They constitute substances which exhibit a strong antibacterial effect against Staphylococci, particularly against gram-positive Staphylococci, and especially against multi-resistant Staphylococci (MRSA) and resistant Enterococci, and can be used for combatting infectious diseases in humans and animals. These compounds are suitable for the production of very different pharmaceutical preparations and forms of application.
The compounds are the first representatives of a hitherto unknown ring system, namely of naphthaceno-[1,2-g]-phthalazine. They are derived from madurahydroxylactone or maduranic acid, which can be obtained by a biotechnology route from Actinomadura rubra (W. Fleck, D. G. Strauss, J. Meyer, Z. Allg. Mikrobiol. 18, 368-398 (1978)). The structure of madurahydroxylactone (formula II) has been elucidated by Paulus and co-workers (E. F. Paulus, K. Dornberger, W. Werner, D. Fenske, Acta Cryst. (1994) C50, 2064-2067). Madurahydroxylactone itself only exhibits an unsatisfactory biological efficacy. Madurahydroxylactone forms part of the benzonaphthacenequinone class, from which benanomycins and pradimycins in particular have recently become known as antifungal substances of interest (T. Oki in "Recent Progress in Antifungal Chemotherapy", Eds. H. Yamaguchi, G. S. Kobayachi, H. Takahashi, Marcel Dekker, Inc., New York, Basle, Hong Kong, 1992, page 38).
SUMMARY OF THE INVENTION
The present invention serves to provide 2-substituted, particularly 2-carboxyalkyl- and 2-carboxyaryl-substituted, Maduraphthalazines (10,12,15,16-tetrahydroxy-8-methoxy-11-methyl-1,9,14-trioxo-1,2,6,7,9,14-h exahydro-naphthaceno-[1,2-g]-phthalazines) and the corresponding salts, esters and amides, and also relates to the use thereof. With these compounds, efforts have been made to increase the range of antibacterial preparations, especially preparations which are effective against grain-positive bacteria and which are effective against multi-resistant Staphylococci in particular. These new compounds are advantageous for the achievement of this object because the compounds or anti-infection preparations which were known hitherto possess serious disadvantages, such as insufficient effectiveness against super-resistant bacterial strains for example (W. Witte, C. Braulke, D. Heuck, C. Cuny; "Analysis of nosocomial outbreaks with multiple- and methicillin-resistant Staphylococcus aureus (MRSA) in Germany: implications for hospital hygiene", Infection 22, (1994), Suppl. 2, 128-134; G. M. Eliopulos, "Increasing problems in the therapy of enterococcal infection", Eur. J. Clin. microbiol. Infect. Dis. 12 (1993) 409-412.
This object is achieved according to the invention by the provision of new polycyclic phthalazine derivatives of general formula I ##STR1## wherein R.sup.1 denotes carboxyalkyl or carboxyaryl and R.sup.2 and R.sup.3, independently of each other, represent hydrogen or acyl, as well as salts, esters and amides of compounds of formula I, with the proviso that R.sup.1 is different from a carboxyphenyl group, which is optionally substituted, if R.sup.3 denotes C.sub.1-8 alkanoyl.
Within the scope of the present invention, the term "alkyl" (in compound words also, such as alkoxy or carboxyalkyl) denotes a C.sub.1-10 alkyl which may be a straight-chain or branched-chain alkyl, preferably a C.sub.1-4 alkyl, whilst an aryl radical (including any one of the aryl radicals which are further cited below, or in compound words such as aralkyl) is to be understood to mean a substituted or unsubstituted aryl group, particularly a corresponding phenyl group, the substituents of which can be OH, O-alkyl, O-aryl, a halogen, alkyl or aryl. Within the scope of the present invention, the term "acyl" primarily
REFERENCES:
Fleck et al., "Fermentation, Isolation, and Biological Activity of Maduramycin: A New Antibiotic from Actinomadura rubra", Zeitschrift fur allgemeine Mikrobiologie 18:389-398 (1978).
Paulus et al., "Madurahydroxylactone". Acta Crystallographica Section C C50:2064-67 (1994).
Oki, "A New Family of Antibiotics: Benzo[ .alpha.] Naphthacenequinones". Recent Progress in Antifungal Chemotherapy 381-402 (1990).
Witte et al., "Analysis of Nosocomial Outbreaks with Multiply and Methicillin-Resistant Staphylococcus aureus (MRSA) in Germany: Implications for Hospital Hygiene". Infection 22:128-133 (1994).
Eliopoulos, "Increasing Problems in the Therapy of Enterococcal Infections". Eur. J. Clin. Microbiol. Infect. Dis. 12:409-412 (1993).
Cuny Christiane
Graefe Udo
Heinisch Lothar
Moellmann Ute
Roemer Ernst
Gruenenthal GmbH
Reamer James
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