Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1994-11-28
2001-06-05
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S053000, C536S016800, C536S017200
Reexamination Certificate
active
06242424
ABSTRACT:
The present invention relates to moenomycin and its derivatives for the production of pharmaceuticals, and pharmaceuticals containing moenomycin or its derivatives.
The present invention is based on the object of finding an effective medicament for the control of gastric ulcers and for the prophylaxis of cancer of the stomach. Hitherto, e.g. so-called antacids and, with particular success, H
2
-receptor blockers were used in the indication area mentioned.
Furthermore, it was already known that Helicobacter pylori infections are frequently responsible for stomach disorders. Infection of the human stomach with the pathogenic gram-negative bacterium
Helicobacter pylori
causes temporary dyspeptic symptoms.
H. pylori
is additionally the underlying pathogen in the chronically active type b gastritis and a significant risk factor for the occurrence of cancer of the stomach. The pathophysiological mechanisms by which
H. pylori
causes diseases of the stomach are still relatively unclear. It is known that the microorganism produces a number of potentially toxic enzymes and chemicals (urease, ammonia, vacuolizing cytotoxin). The persistence of the bacterium and the lasting antigenic stimulus are probably the cause of the long-term destruction of the gastric mucous membrane.
The therapeutic aim is the complete eradication of
H. pylori
. The therapy of choice at the moment is a triple combination which consists of a bismuth salt, metronidazole and amoxicillin or tetracycline. However, it has some serious side effects. These include exhaustion, dryness of the mouth, diarrhea and nausea. The patient must additionally give up alcohol during therapy. Even with good compliance, eradication rates of only about 90% are achieved (A.T.R. Axon, 1993, J. Antimicrob. Chemother. 32, Suppl. A, 61 to 68).
Surprisingly, it has now been found that moenomycin is outstandingly effective against all previously investigated
Helicobacter pylori
strains. This is particularly surprising, because until now moenomycin was known to be almost exclusively effective against gram-positive microorganisms (Welzel et al., 1983, Tetrahedron Vol. 39, No. 9, 1583 to 1591).
The invention accordingly relates to the use of moenomycin and/or one or more of its derivatives for the production of a pharmaceutical for the control of gastric ulcers and for the prophylaxis of cancer of the stomach, and generally the use of moenomycin and/or one or more of its derivatives for the production of a pharmaceutical for the control of
Helicobacter pylori
infections.
Moenomycin and many of its derivatives have already been known for a long time (cf. German Offenlegungsschrift 3,704,659, EP 0,355,679, G. Huber in “Antibiotics”, ed. F. Hahn, Springer Verlag, Berlin 1979, Vol. IV, page 135 ff., Welzel et al. in Tetrahedron loc. cit.). Moenomycins, e.g. moenomycin A, are preferably obtained by fermentation of microorganisms and subsequent purification.
The term moenomycin in the sense of the present patent application is to be understood as meaning a complex of moenomycin components (e.g. as is formed by microorganisms) and also the individual components. This means that the moenomycin can be administered in the form of one or more components in a variable composition. The administration of the largely pure particularly effective individual components, in particular of moenomycin A, is preferred. Said moenomycin A has the following structural formula:
Microorganisms which produce moenomycin complexes are e.g.
Streptomyces bambergiensis, ghanaensis, ederensis
and
geysirensis. Streptomyces bambergiensis
is particularly preferred (cf. in this connection Huber loc. cit.). The term “derivatives of moenomycin” should generally be taken hitherto and in future to mean synthesized moenomycin derivatives. Particularly suitable moenomycin components or derivatives of moenomycin are the compounds of the following formulae
in which the individual substituents have the following meanings,
X
Y
R
1
R
2
1
CH
3
OH
H
3
CH
3
OH
H
H
4
CH
3
OH
OH
H
5
CH
3
OH
OH
OH
6
OH
H
H
H
in which R
1
and R
2
have the following meanings,
R
1
R
2
7
H
8
NH
2
H
9
NH
2
CH
3
in which R is hydrogen or
The compounds 11-15 represent the degradation products of moenomycin C
3
. Analogous degradation products of the compounds 2, 4, 5 and 6 can be employed according to the invention in a similar manner.
Mixtures of said compounds are additionally particularly suitable according to the invention.
Said compounds can be prepared as described e.g. in G. Huber, loc. cit., German Offenlegungsschrift 37 04 659, Tetrahedron, Vol. 49, No. 35, pp. 7667-7678, 1993 and P. Welzel in “Antibiotics and Antiviral Compounds”, VCH Weinheim, 1993.
Moreover suitable for the use according to the invention are further degradation products of moenomycin, such as the degradation products which are described in the above references, or the degradation product of the following formula
whose preparation is described in EP 0,355,679.
The use of moenomycin in the therapy of
H. pylori
infections has a number of advantages compared with conventional therapy:
The antibiotic is not absorbed and is excreted again almost unchanged.
Moenomycin has not been used until now in human medicine. The problem of cross-resistance with other bacterial species does not arise.
Moenomycin is extremely well tolerated. High doses can therefore be used.
Moenomycin is able to penetrate the mucus layer of the gastric mucous membrane and to reach the actual site of residence of the infecting microorganism.
Moenomycin has no antigen or hapten properties which could lead to allergies.
Further advantages in therapy with moenomycin can be achieved if the moenomycin or its derivatives are administered together with other active compounds, auxiliaries and/or excipients.
Suitable additional active compounds for said therapy are derived e.g. from the antacids group, such as e.g. sodium hydrogen carbonate, aluminum hydroxide, magnesium hydroxide, magnesium trisilicate, aluminum magnesium silicate hydrate, aluminum sodium carbonate dihydroxide, magnesium carbonate, calcium carbonate or hydrotalcite. Other suitable additional active compounds are derived from the H
2
-receptor blocker group such as e.g. famotidine, nizatidine, roxatidine acetate, ranitidine or cimetidine. Other suitable additional active compounds are muscarin receptor blockers such as propantheline bromide, pirenzipine or other antiulcer agents such as omeprazole, lansoprazole, misoprostol or bismuth salts such as bismuth nitrate, bismuth carbonate, bismuth salicylate or bismuth citrate. Additional active compounds which are further suitable for the therapy according to the invention belong to the antibiotics group such as e.g. tetracycline, metronidazole, amoxycillin, nisin, clarithromycin, imipenem, or amikacin. The above-mentioned additional active compounds are mainly commercial products and obtainable by generally known methods (cf. Rote Liste 1993, Editio Cantor, Aulendorf, Württ., Merck Index, 11
th
Ed., Merck & Co., Rahway, N.J., 1989).
It can also be useful to carry out the moenomycin therapy using a mixture of the abovementioned additional active compounds.
The administration of moenomycin together with amoxycillin and/or metronidazole, tetracycline, omeprazole, ranitidine and/or a bismuth salt is particularly preferred.
The administration of the components of said combination preparations can take place in the form of a single administration or alternatively be performed in chronological order.
The pharmaceutical preparation of the pharmaceuticals according to the invention is carried out according to prior art methods, e.g. in the form of solutions, suspensions, capsules, tablets, treatments where the patient takes medicine, lies for five minutes on his back, five minutes on his side, then on his front etc., or the like.
The pharmaceutical compositions which contain the active compound or compounds can be in a suitable form for oral administration, for example as tablets, pastilles, lozenges, aqueous suspensions or solutions, dispersible powders or gr
Hedtmann Udo
Riess Gunther
Seibert Gerhard
Aventis Pharma Deutschland GmbH
Finnegan, Henderson Farabow, Garrett and Dunner L.L.P.
Peselev Elli
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