Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-11-08
2002-08-13
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S230200, C514S230500, C544S066000, C544S073000, C544S105000
Reexamination Certificate
active
06432948
ABSTRACT:
The invention relates to the use of quinolone- and naphthyridonecarboxylic acid derivatives which are substituted in the 7-position by a 2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl radical, and their salts for the therapy of
Helicobacter pylori
infections and the gastroduodenal disorders associated therewith.
With the rediscovery of
Helicobacter pylori
(
H. pylori;
formally
Campylobacter pylori
) by Warren and Marshall in 1983, in the following years it was possible to fundamentally further develop the pathophysiological ideas about the origin of gastroduodenal disorders of man.
H. pylori
is regarded as a cause of type B gastritis and appears to play a causal role in the perpetuation of peptic ulcer. Epidemiological and pathological investigations likewise point to a relationship between long-term colonization of the gastric mucosa with the bacterium and the origin of certain forms of carcinoma of the stomach.
H. pylori
was therefore classified in 1994 as a carcinogen of the first class (most dangerous carcinogenic category). A rare stomach cancer, MALT lymphoma (mucosa-associated lymphoid tissue), likewise often appears to be caused by the bacterium. In initial case reports, after
H. pylori
eradication not only the reactive infiltrates actually disappeared, but also a part of the poorly malignant MALT lymphoma. Relationships with hypertrophic gastritis are also discussed. The role of
H. pylori
in functional gastropathy (nonulcerative dyspepsia) is still unclear.
Various epidemiological studies come to the conclusion that about half the world population is infected with the bacterium. The probability of the colonization of the stomach with Helicobacter increases with age. The optimum adaptation of Helicobacter to the living conditions in the unusual, low-competition habitat [lacuna] stomach appears to be the prerequisite for the successful establishment of the chronic infection and for the wide distribution of this pathogenic species.
The pathogenic organisms with their flagella are very mobile not only in the liquid medium, but also in the viscous mucus of the gastric mucous membrane, adhere to the gastric epithelial cells and proliferate best at an oxygen content of 5%, as prevails in the mucus of the gastric wall. Moreover, the bacteria form large amounts of the enzyme urease, which splits urea into ammonia and carbon dioxide. Possibly, the resulting ‘ammonia cloud’ helps to neutralize the acidic medium in the microenvironment and thus to protect from the aggressive gastric acid.
Peptic Ulcer
The introduction of the histamine H
2
receptor antagonists in the 70s was a milestone in the therapy of peptic ulcer. The frequency of surgical interventions for treatment of the ulcer sufferer thus decreased dramatically worldwide. This principle of acid blockage was improved still further by the development of the even more strongly active proton pump inhibitors.
As a result of the antacid therapy, however, only the symptoms of the ulcer, not the natural course of the disorder, which is characterized by the occurrence of relapses, can be influenced causally—say due to bactericidal treatment. Since virtually all duodenal ulcer patients and the predominant majority of patients with stomach ulcer have an
H. pylori
infection of the stomach and thus suffer from infectious diseases. Only ulcerations which are caused by non-steroidal anti-inflammatories are not associated with an
H. pylori
infection.
Therefore, according to the recommendations of a consensus conference, which was organized in 1994 by the American Public Health Authority (NIH), in the case of positive detection of bacteria all patients with peptic ulcers should be subjected to eradication therapy directed against
H. pylori
(NIH Consensus Statement 1: 1-23; 1994). The arguments were supplied by controlled therapy studies, in which it was possible to show that after successful eradication of bacteria the ulcer recurrence rates fall drastically(0%-29% versus 61%-95%).
H. pylori
Therapy
The present eradication of
H. pylori
turns out to be problematic in practice. A simple and yet reliably effective therapy is not available. The bacterium turns out to be well protected and difficult to attack under the mucous layer.
H. pylori
is sensitive in vitro to numerous antibiotics. These are, however, not effective in vivo as a monotherapy. These include, inter alia, penicillin, amoxicillin, tetracyclin, erythromycin, ciprofloxacin, metronidazole and clarithromycin. Bismuth salts and, to a small extent, even proton pump inhibitors (omeprazole, lansoprazole) are antibacterially active in vitro, but not in vivo.
Among all therapy modalities hitherto used for the eradication of
H. pylori,
at present only the following triple therapies are sufficiently active:
1. classical bismuth triple therapy (bismuth salt plus two antibiotics) and the
2. modified triple therapy (acid inhibitor plus two antibiotics).
However, these regimes are involved eradication procedures with poor compliance, which can be affected up to 35% by side effects (abdominal pain, nausea, diarrhoea, dryness of the mouth, taste disorders and allergic skin reactions, etc.). Wide use is therefore made difficult. A further great disadvantage is the high number of medicaments to be taken daily (12-16 tablets/day). This is particularly marked in the quadruple therapy, in which an acid secretion inhibitor is administered simultaneously to the classical triple therapy.
The better tolerated dual therapy propagated in Germany (combination of amoxicillin with omeprazole) is, however, only poorly effective and appears to fail even largely in patients pretreated with omeprazole and in smokers.
In the triple therapies, the antibiotic components as a rule administered are amoxicillin, nitroimidazole compounds (metronidazole, tinidazole), tetracyclin and recently macrolides (clarithromycin) [in 3-4 sub-doses].
Worldwide, eradication rates of 70-90% are achieved. Various factors can, however, influence this eradication result:
1. In the first place, the resistance of the bacterium (developing countries: up to 60%, Germany: up to 10%) against metronidazole, the most frequently employed antibiotic in triple therapy, can be mentioned. Even in the case of treatment with clarithromycin, the disadvantage of a development of resistance of up to 10% is to be pointed out.
2. As a further factor, the abovementioned compliance of the patients can be mentioned.
Animal Model
An
H. felis
mouse model has been described as a suitable animal model [A. Lee et al., Gastroentrology 99: 1315-1323 (1990)] and has been modified by us so that it is very highly suitable for the screening and the comparative assessment of abovementioned compounds.
In spite of large morphological differences, the corkscrew-like, urease-forming bacterium
H. felis
is very closely related to
H. pylori. H. felis
is a natural inhabitant of the gastric mucosa of dogs and cats. After oral inoculation, the pathogenic bacteria also colonize the mouse stomach in a similar manner to that in which
H. pylori
colonizes the stomach of man. The established chronic long-term infection leads in mice to active gastritis and induces a corresponding immune response.
The therapeutic effectiveness of test preparations determined in the
H. felis
mouse model is regarded in the literature as predictive of the corresponding clinical efficacy.
In spite of very good in-vitro activity of antibiotics (e.g. amoxicillin or erythromycin) against
H. pylori,
after monotherapeutic use clinically these show no significant therapeutic action. This fact is also repeated by the
H. felis
mouse model. Correspondingly, it was also possible to confirm the clinically recognized eradicative action of the classical triple therapy in the
H. felis
mouse model.
Antibacterially active 7-(2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-quinolone- and naphthyridonecarboxylic acid derivatives have already been disclosed in EP-A-350733 and EP-A-550 903 (Bayer). In JP 8048629 (Dainippon), it was described that compou
Baasner Bernd
Bartel Stephan
Himmler Thomas
Jaetsch Thomas
Labischinski Harald
Norris & McLaughlin & Marcus
Raymond Richard L.
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