Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-29
2003-07-15
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S165000, C514S166000, C514S925000, C514S926000, C514S927000
Reexamination Certificate
active
06593339
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to a new use of nitric oxide-releasing Non Steriodal Antiinflammatory Drugs (NO-releasing NSAIDs). More particularly the invention is directed to the use of NO-releasing NSAIDs for the manufacture of a medicament for the treatment of bacterial infections, paticularly caused or mediated by
Helicobacter pylori
as well as a combination with acid susceptible proton pump inhibitors for the treatment of bacterial infections.
BACKGROUND OF THE INVENTION AND PRIOR ART
NSAIDs, are among the most commonly prescribed and used drugs worldwide. Despite the therapeutic benefits of NSAIDs, their use is limited. The use of NSAIDs may lead to gastric mucosal damage due to inhibited production of prostaglandins which increases the risk of gastrointestinal side-effects.
A recent proposal for reducing the side-effects associated with NSAIDs treatment is to use nitric oxide-releasing NSAID derivatives (NO-releasing NSAIDs) (del Soldato P et al.,
NO-releasing NSAID:s, A novel class of safer and effective antiinflammatory agents; Inflammopharmacology
, 1996; 4; 181-188). NO-releasing NSAIDs reduce the gastrointestinal side-effects but still have the pharmacological activity characteristic of the frequently used NSAIDs.
NO-releasing NSAIDs and pharmaceutically acceptable salts thereof are for instance described in WO 94/04484, WO 94/12463, WO 95/09831 and WO 95/30641.
Helicobacter pylori
is a gram-negative spirilliform bacteria which colonises in the gastric mucosa. The relationship between gastrointestinal disorders and infections with
Helicobacter pylori
proposed in 1983 by Warren (Warren J R Lancet 1983; 1.1273) is well established today.
A number of different therapies have been proposed for the treatment of
Helicobacter pylori
infections. Combination therapies are commonly used. The most commonly used comprise a proton pump inhibitor in combination with one or more antibacterial compounds such as claritromycin and amoxicillin. For instance WO 93/00327 discloses the combination of a substance with inhibiting effect on the gastric acid secretion which increases the intragastric pH, and an acid degradable antibacterial compound. Some of these therapies also comprise a bismuth compound, se for instance WO 98/03219 and WO 98/22117, which latter application discloses a composition containing bismuth, an antimicrobial agent and a non-steriodal antiinflammatory agent for the treatment of gastrointestinal disorders caused or mediated by
Helicobacter pylori.
In view of the vast number of the population suffering from gastrointestinal disorders caused or mediated by bacterial infections, such as
Helicobacter pylori
infections, and also in view of the fact that many bacterial strains develop a resistance to commonly used antibiotics, a continuing need exists for a safe and effective medicament having an antibacterial effect, especially for the treatment of
Helicobacter pylori
infections.
OUTLINE OF THE INVENTION
It has now surprisingly been found that NO-releasing NSAIDs have an antibacterial effect, which makes them useful for the treatment of bacterial infections.
The present invention is related to the use of a NO-releasing NSAID as well as pharmaceutically acceptable salts or enantiomers thereof, for the manufacture of a medicament for the treatment of bacterial infections.
Preferably the NO-releasing NSAID is defined by the formula I
wherein M is selected from anyone of
and X is a spacer, i.e. a compound forming a bridge between the nitrogen oxide donating group and the NSAID moiety, or a pharmaceutically acceptable salt or enantiomer thereof;
X is preferably selected from linear, branched or cyclic —(CH
2
)—
n
wherein n is an integer of from 2 to 10; —(CH
2
)
m
—O—(CH
2
)
p
— wherein m and p are integers of from 2 to 10; and —CH
2
—pC
6
H
4
—CH
2
—.
M is not limited by the above definition but may be any other compound giving the corresponding NSAID by hydrolysis of the compound according to formula I.
In a preferred embodiment of the invention M is selected from
and X is selected from
linear —(CH
2
)
n
— wherein n is an integer of from 2 to 6; —(CH
2
)
2
—O—(CH
2
)
2
— and —CH
2
—pC
6
H
4
—CH
2
—.
In an even more preferred embodiment of the invention the NO-releasing NSAID is a compound according to any one of the formulas
In a particularly preferred embodiment of the invention the NO-releasing NSAID is a compound according to formula Ia.
A further aspect of the invention is the use of a NO-releasing NSAID, preferably a compound of the formula I above, in the manufacture of a medicament for use in the treatment of
Helicobacter pylori
infections, especially in the treatment of gastrointestinal disorders caused or mediated by
Helicobacter pylori.
Still a further aspect of the invention is a method for the treatment of bacterial infections, in particular
Helicobacter pylori
infections, whereby an effective amount of a medicament comprising a NO-releasing NSAID, preferably a compound of the formula I, as active agent is administered to a subject suffering from said bacterial infection.
Also a pharmaceutical formulation suitable for use in the treatment of bacterial infections, which formulation comprising a NO-releasing NSAID, preferably a compound of the formula I, is within the scope of the invention.
Furthermore, the invention is related to the use of a NO-releasing NSAID, preferably a compound of the formula I, in combination with an acid susceptible proton pump inhibitor or a salt thereof or an enantiomer or a salt of the enantiomer in the manufacture of pharmaceutical formulations intended for simultanous, separate or sequential administration in the treatment of bacterial infections, especially
Helicobacter pylori
infections.
The invention may be applied in combination with other agents generally associated with treatment of bacterial infections, such as for instance antibacterial agents.
An acid susceptible proton pump inhibitor is, for instance, a compound of the general formula II
wherein
wherein
N in the benzimidazole moiety means that one of the carbon atoms substituted by R
6
-R
9
optionally may be exchanged for a nitrogen atom without any substituents;
R
1
, R
2
and R
3
are the same or different and selected from hydrogen, alkyl, alkoxy optionally substituted by fluorine, alkylthio, alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenyl and phenylalkoxy;
R
4
and R
5
are the same or different and selected from hydrogen, alkyl and aralkyl;
R
6
′ is hydrogen, halogen, trifluoromethyl, alkyl and alkoxy;
R
6
-R
9
are the same or different and selected from hydrogen, alkyl, alkoxy, halogen, halo-alkoxy, alkylcarbonyl, alkoxycarbonyl, oxazolyl, trifluoroalkyl, or adjacent groups R
6
-R
9
form ring structures which may be further substituted;
R
10
is hydrogen or forms an alkylene chain together with R
3
and
R
11
and R
12
are the same or different and selected from hydrogen, halogen or alkyl, alkyl groups, alkoxy groups and moities thereof. The substituents may be branched or straight C
1
-C
9
—chains or comprise cyclic alkyl groups, such as cycloalkyl-alkyl.
Examples of proton pump inhibitors according to formula II are
The proton pump inhibitor may also be used in the form of a pharmaceutical acceptable salt or a single enantiomer in the claimed combination.
Preferably the proton pump inhibitor omeprazole, or an alkaline salt of omeprazole, such as the magnesium salt, or (S)-omeprazole or an alkaline salt of (S)-omeprazole, such as the magnesium salt is used in the claimed combination.
Suitable proton pump inhibitors are for example disclosed in EP-A1-0005129, EP-A1-174 726, EP-A1-166 287, GB 2 163 747 and WO90/06925, and further the especially suitable compounds are described in WO95/01977 and WO94/27988.
According to the invention there is further provided a method for treating bacterial infections, particularly
Helicobacter Pylori
infections, which method comprises simultaneous, separate or sequential administration to a subject suffering from a bacterial infection one or mor
Eek Arne
Raud Johan
AstraZeneca AB
Fitch Even Tabin & Flannery
Krass Frederick
Ostrup Clinton
Sanzo Michael A.
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