Moenomycin and its derivatives for the production of pharmaceuticals, and pharmaceuticals containing moenomycin or its derivatives

Moenomycin and its derivatives are suitable for the production of pharmaceuticals for the treatment of gastric ulcers and for the control of Helicobacter pylori.

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.sub.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:
 ##STR1##
 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
 ##STR2##
 in which the individual substituents have the following meanings,

X Y R.sup.1 R.sup.2
 1 CH.sub.3 OH ##STR3## H
 3 CH.sub.3 OH H H
 4 CH.sub.3 OH OH H
 5 CH.sub.3 OH OH OH
 6 OH H H H
 ##STR4##
 in which R.sub.1 and R.sub.2 have the following meanings,

R.sup.1 R.sup.2
 7 ##STR5## H
 8 NH.sub.2 H
 9 NH.sub.2 CH.sub.3
 ##STR6##
 in which R is hydrogen or
 ##STR7##
 ##STR8##
 The compounds 11-15 represent the degradation products of moenomycin
 C.sub.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
 ##STR9##
 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.sub.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,
 Wurtt., Merck Index, 11.sup.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 granules, emulsions, hard or soft capsules, syrup
 or elixir. Compositions intended for oral administration can be prepared
 according to any appropriate method according to the prior art for the
 production of pharmaceutical compositions, and these compositions can
 contain one or more substances from the sweeteners, flavorings, colorants
 and preservatives group in order to obtain a pharmaceutically elegant and
 readily administrable preparation.
 Formulations for oral administration comprise tablets which contain the
 active compound in a mixture with non-toxic, pharmaceutically acceptable
 excipients. These excipients can be, for example, inert extenders (such
 as, for example, sodium chloride, lactose, calcium phosphate or sodium
 phosphate), granulating or disintegrants (for example potato starch,
 alginic acid), binders (such as, for example, starch, gelatin or gum
 arabic) and lubricants (such as, for example, magnesium stearate, stearic
 acid or talc). The tablets can be uncoated or they can be coated by means
 of the known techniques in order to delay dissolution and absorption in
 the stomach and thus to give a lasting action over a relatively long
 period of time. A time-delaying substance, for example, such as glyceryl
 monostearate or glyceryl distearate can thus be employed.
 Formulations for oral administration can also be made available in the form
 of hard gelatin capsules in which the active compound is mixed with an
 inert, solid extender, for example calcium phosphate or kaolin, or in the
 form of soft gelatin capsules in which the active compound is mixed with
 water or an oily medium, for example groundnut oil, liquid paraffin or
 olive oil.
 Of course, the therapeutic dose spectrum of the compounds according to the
 invention varies depending on the size and needs of the patients and the
 pains or disease symptoms to be treated in each case. The amount of active
 compound which can be combined with the excipient substances in order to
 form a single administration form varies depending on the host to be
 treated and the particular type of administration. Thus, for example, for
 a formulation for oral administration intended for humans, the amount is
 preferably between 5 mg and 5 g of the respective active compound(s), it
 being intended for the pharmaceutical to contain an appropriate and useful
 amount of excipients, which can make up between 5 and 95 % of the total
 composition.
 It is understood that the specific dose for each individual patient is
 dependent on a plurality of factors, including efficacy of the specific
 compound which is employed, age, body weight, general state of health,
 sex, nutrition, administration time, administration route, excretion rate,
 interactions with other pharmaceuticals and severity of the disorder
 treated in each case.
 The present invention is intended to be illustrated in greater detail by
 the following exemplary embodiments:

EXAMPLE 1
 For the rapid determination of the activity of moenomycin, defined amounts
 of moenomycin in aqueous solution are added dropwise to small filter
 plates. After drying, the small plates are placed on nutrient agar plates
 which have been inoculated with Helicobacter pylori.
 Various clinical isolates of Helicobacter pylori are cultured in liquid
 nutrient medium. The nutrient medium consists of Muller-Hinton broth, to
 which are added 4% fetal calf serum, 10 mg/l of vancomycin and 500 mg/l of
 Actidione (the last two to avoid contamination). The inoculated nutrient
 medium is stirred at 37.degree. C. under specific gas conditions
 (Anaerocult.RTM. C) for two days. 100 .mu.l of the bacterial suspension
 are spread out on the surface of the nutrient agar plate with a spatula.
 The nutrient agar consists of Columbia agar containing 5% wether's blood,
 to which 10 mg/l of vancomycin and 500 mg/l of Actidione.RTM. are in turn
 added. After laying on the moenomycin-containing small filter plates, the
 plates are incubated first for 1 h at 4.degree. C. and then for 4 days at
 37.degree. C. under the same gas conditions as the liquid cultures.
 The small plates typically contain 25, 12.5, 6.25, 3.12 etc. .mu.g of
 moenomycin.
 For assessment, the bacteria-free inhibition halo which surrounds a small
 plate after incubation is measured. The diameter of the small filter
 plates on their own is 6 mm.
 If moenomycin A and the bacterial strain Helicobacter pylori P22 is used,
 the following result is obtained:

[Moenomycin A] 25 12.5 6.25 3.12 1.56 0.78 0.39 0.19
 Inhibition halo 34 32 30 28 23 20 16 11
 (mm)
 EXAMPLE 2
 If the procedure is as described in Example 1, but a commercially available
 antacid (e.g. Maalox.RTM. 70 in the recommended dose) is added to the
 moenomycin solution before adding it dropwise to the small filter plates,
 the following result is obtained when using moenomycin A and the
 Helicobacter pylori strain P22: