Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-20
2004-01-06
Fan, Jane (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S273700
Reexamination Certificate
active
06673819
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel compounds, and pharmaceutically acceptable salts thereof, useful as antibacterial agents. The compounds of the present invention are nitric oxide releasing derivatives of proton pump inhibitors (NO-releasing PPIs). In further aspects, the invention relates to compounds of the invention for use in therapy; to processes for preparation of such new compounds; to pharmaceutical compositions containing at least one compound of the invention, as active ingredient; and to the use of the active compounds in the manufacture of medicaments for the medical use as an antibacterial agent. The invention also relates to new intermediates for the preparation of the novel compounds. Additionally, the present invention relates to co-administration of NO-releasing PPIs with other known medicaments.
BACKGROUND ART
The compound 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, having the generic name omeprazole, as well as pharmaceutically acceptable salts thereof, are described in EP 5129. Omeprazole is the first member in a family called proton pump inhibitors. Proton pump inhibitors are effective in inhibiting gastric acid secretion, and are consequently useful as antiulcer agents and have revolutionized the treatment of gastrointestinal disorders. Omeprazole is also known from EP 414 847 to have an antibacterial effect.
Other proton pump inhibitors, such as pantoprazole, lanzoprazole, rabeprazole and leminoprazole, are all substituted benzimidazoles and therefore structurally closely related to omeprazole. Unfortunately, omeprazole and other structurally related benzimidazoles suffer from chemical instability, especially in acidic and neutral media. This makes omeprazole and other structurally related benzimidazoles difficult to handle, store and formulate.
Nitric oxide (NO) is a molecule of versatility and importance in many guises. In the atmosphere it is a noxious chemical, but in the body in small and controlled doses it is extraordinary beneficial. It helps maintain blood pressure by dilating blood vessels, helps kill foreign invaders in the immune response, is a major biochemical mediator of penile erections, and is proposed to be a major biochemical component of long-term memory.
Helicobacter pylori
is a gram-negative bacterium which colonises in the gastric mucosa in mammalian animals, including human beings. A number of different therapies have been proposed for the treatment of
Helicobacter pylori
infections, including combination therapies. The most commonly used combination therapy comprises a proton pump inhibitor in combination with one or more antibacterial compounds, such as claritromycin and/or amoxicillin, see WO93/21920.
In view of the vast number of human beings suffering from gastrointestinal disorders caused or mediated by bacterial 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.
SUMMARY OF THE INVENTION
It has surprisingly been found that compounds of the Formula I below, are particularly effective as antibacterial agents. The compounds of the invention are especially suitable for treatment of infections caused by
Helicobacter pylori.
The compounds of the present invention are characterized as being NO-releasing proton pump inhibitor derivatives (NO-releasing PPI or NO-PPI). A NO-releasing proton pump inhibitor is a compound which upon administration to a mammal, e.g. a human being, generates nitric oxide and a proton pump inhibitor.
One object of the present invention is to provide novel compounds that are effective as antibacterial agents.
In one aspect, the present invention thus relates to compounds of the Formula I:
wherein,
R
1
is hydrogen or C
1
-C
6
alkyl,
R
2
is hydrogen or C
1
-C
6
alkyl,
R
3
is methoxy linked to the carbon atom in position 5 or linked to the carbon atom in position 6 of the benzimidazole moiety,
or a single bond,
Y is —(CH
2
)
n
—, —(CH
2
)
m
—O—(CH
2
)
p
—, or a single bond, and
m, n, and p are integers and independently selected from 1 to 10,
or a pharmaceutically acceptable salt or enantiomer thereof.
In accordance with one embodiment of the invention, compounds of the present invention include those compounds of formula I wherein
R
1
and R
2
are hydrogen,
R
3
is methoxy linked to the carbon atom in position 5 or linked to the carbon atom in position 6 of the benzimidazole moiety,
or a single bond,
Y is —(CH
2
)
n
—, or a single bond, and
n is an integer from 1 to 10.
In accordance with another embodiment of the invention, compounds of the present invention include 1-nitrooxymethyl-(5-methoxy) 2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole and 1-nitrooxymethyl-(6-methoxy)-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole.
Furthermore any pure enantiomer, mixture of enantiomers, and pharmaceutically acceptable salt of the compounds of the invention are within the scope of the present invention.
As used herein, the term “C
1
-C
6
alkyl” denotes a straight or branched alkyl group having from 1 to 6 carbon atoms. Examples of said C
1
-C
6
alkyl includes, but is not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl.
It should be clear for a person skilled in the art, that compounds of formula I is wherein X and Y may each and independently be “a single bond” means that X and Y may each and independently be directly linked to oxygen in ONO
2
.
Preparation
The present invention also provides the following processes A and B for the manufacture of compounds of the Formula I.
Process A
a) Compounds of Formula II
wherein R
1
is hydrogen or C
1
-C
6
alkyl,
R
2
is hydrogen or C
1
-C
6
alkyl, and
R
3
is methoxy linked to the carbon atom in position 5 or linked to the carbon atom in position 6 of the benzimidazole moiety, is reacted with thionyl chloride, or any other similar reagent, in dichloromethane, or any other similar solvent, under standard conditions to give a compound of formula III
wherein R
1
is hydrogen or C
1
-C
6
alkyl,
R
2
is hydrogen or C
1
-C
6
alkyl,
R
3
is methoxy linked to the carbon atom in position 5 or linked to the carbon atom in position 6 of the benzimidazole moiety, and
X
1
is halogen, such as chloride.
b) Compounds of Formula III is thereafter reacted with silver nitrate in a suitable solvent, such as acetonitrile under standard conditions to give compounds of Formula I wherein
R
1
is hydrogen or C
1
-C
6
alkyl,
R
2
is hydrogen or C
1
-C
6
alkyl,
R
3
is methoxy linked to the carbon atom in position 5 or linked to the carbon atom in position 6 of the benzimidazole moiety, and
X and Y are a single bonds
Process B
a) Compounds of Formula II
wherein R
1
is hydrogen or C
1
-C
6
alkyl,
R
2
is hydrogen or C
1
-C
6
alkyl,
R
3
is methoxy linked to the carbon atom in position 5 or linked to the carbon atom in position 6 of the benzimidazole moiety, and is reacted with a compound of the formula IV
wherein L is —Br or —Cl,
A is —N—, —O—, or —CH
2
—,
B is —Br or —Cl,
Y is —(CH
2
)
n
—, or —(CH
2
)
m
—O—(CH
2
)
p
—, or a single bond;
m, n, and p are integers and independently selected from 1 to 10, under standard conditions to give a compound of Formula V
wherein
R
1
is hydrogen or C
1
-C
6
alkyl,
R
2
is hydrogen or C
1
-C
6
alkyl,
R
3
is methoxy linked to the carbon atom in position 5 or linked to the carbon atom in position 6 of the benzimidazole moiety,
B is —Br or —Cl,
Y is —(CH
2
)
n
—, —(CH
2
)
m
—O—(CH
2
)
p
—, or a single bond, and
m, n, and p are integers and independently selected from 1 to 10.
b) Compounds of Formula V is thereafter reacted with silver nitrate in a suitable solvent, such as acetonitrile under standard conditions to give compounds of Formula I wherein
R
1
is
Bergman Rolf
Eek Arne
Lindberg Per
Olsson Lars-Inge
AstraZeneca AB
Fan Jane
White & Case LLP
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