Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-11-09
2002-07-02
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S340000
Reexamination Certificate
active
06414003
ABSTRACT:
TECHNICAL FIELD
The present invention relates to an anti-
Helicobacter pylori
agent comprising an oxazolin-4-one derivative useful as a therapeutic agent for gastric and duodenal ulcer etc.
BACKGROUND ART
As therapeutic agents for ulcer, there have been developed antacids, anticholinergic agents, antigastrin agents, gastrointestinal hormones, antipepsine agents, histamine H
2
receptor antagonists, tissue repairing agents, mucosa-protecting agents, microcirculation-improving agents, proton pump inhibitors etc. The development of histamine H
2
receptor antagonists and proton pump inhibitors, both possessing potent acid secretion-suppressing activity, in particular, has facilitated ulcer treatment.
However, these therapeutic agents for ulcer are unsatisfactory in terms of suppressing effect on recurrent ulcer. On the other hand,
Helicobacter pylori
, a gram-negative microaerophilic bacterium belonging to the genus Helicobacter, has been suggested as a potential major cause of recurrence of gastritis, duodenal ulcer, gastric ulcer etc. Although many antibacterial agents readily inhibit the proliferation of the-respective microorganisms belonging to the genus Helicobacter in vitro, their efficacy in humans and animal experiments is very low when administered singly in vivo.
Various diseases caused by
Helicobacter pylori
as such are treated by chemotherapies such as double chemotherapy with a bismuth preparation and an antibiotic, and triple chemotherapy with a bismuth preparation, metronidazole (U.S. Pat. No. 2,944,061) and either tetracycline (e.g., U.S. Pat. No. 2,712,517) or amoxicillin (U.S. Pat. No. 3,192,198). Metronidazole, an imidazole derivative possessing anti-
Helicobacter pylori
activity is used in combination with antibiotics. These bismuth preparations, antibiotics, metronidazole etc. are administered orally. Also, clinical studies have shown that eradication of this microorganism results in healing and decreased recurrence rates in ulcer.
However, these bismuth preparations, antibiotics, metronidazole etc. must be administered at high daily doses to maintain sufficient concentrations to inhibit
Helicobacter pylori
proliferation at the sites of their proliferation, resulting in many problems, including adverse effects such as vomiting and diarrhea.
There have been developed various compounds possessing anti-
Helicobacter pylori
activity. For example, Japanese Patent Unexamined Publication No. 117268/1993 discloses a pyridine derivative possessing anti-
Helicobacter pylori
activity, and European Patent EPO 535528A1 discloses an imidazole derivative possessing anti-
Helicobacter pylori
activity.
DISCLOSURE OF INFORMATION
After extensive investigation in view of the above problems, the present inventors found that a particular oxazolin-4-one derivative exhibits very specific and excellent antibacterial activity against the bacteria of the genus Helicobacter, represented by
Helicobacter pylori
. The inventors conducted further investigation based on this finding, and developed the present invention.
Accordingly, the present invention relates to
(1) an anti-
Helicobacter pylori
composition comprising a compound of the formula:
wherein A represents an aromatic group which may be substituted, R
1
and R
2
independently represent a hydrogen atom or a hydrocarbon group which may be substituted, R
3
and R
4
independently represent a hydrogen atom, a hydrocarbon group which may be substituted, an acyl group, a carbamoyl group which may be substituted, or a carboxyl group which may be esterified, or a salt thereof, and a pharmacologically acceptable diluent, excipient or carrier,
(2) the anti-
Helicobacter pylori
composition according to the description in (1) above, wherein A is an aromatic heterocyclic group which may be substituted,
(3) the anti-
Helicobacter pylori
composition according to the description in (1) above, wherein A is a group represented by the formula:
wherein ring B is a 6-membered aromatic ring which may be substituted, x represents CH or N, Y represents O, S or —N—R
5
(R
5
represents a hydrogen atom or a hydrocarbon group which may be substituted),
(4) the anti-
Helicobacter pylori
composition according to the description in (1) above, wherein A is a group represented by the formula:
wherein ring B is a 6-membered aromatic ring which may be substituted, R
5
represents a hydrogen atom or a hydrocarbon group which may be substituted,
(5) the anti-
Helicobacter pylori
composition according to the description in (1) above, wherein A represented indolyl which may be substituted by 1 to 3 substituents selected from the group consisting of hydroxyl, halogen, nitro, cyano, lower alkyl which may be substituted by 1 to 5 halogens and lower alkoxy which may be substituted by 1 to 5 halogens, R
1
and R
2
independently represent hydrogen or lower alkyl which may be substituted by 1 to 5 halogens, R
3
and R
4
independently represent hydrogen or lower alkyl,
(6) the anti-
Helicobacter pylori
composition according to the description in (5) above, wherein A is indolyl, R
1
and R
3
are hydrogen, and R
2
and R
4
are C
1-7
alkyl,
(7) the anti-
Helicobacter pylori
composition according to the description in (6) above, wherein A is 3-indolyl, R
2
and R
4
are methyl,
(8) the anti-
Helicobacter pylori
composition according to the description in (1) above, wherein the compound is indolmycin,
(9) the anti-
Helicobacter pylori
composition according to the description in (1) above, as an agent for prevention or treatment of a disease associated with
Helicobacter pylori
infection,
(10) the anti-
Helicobacter pylori
composition according to the description in (9) above, wherein the disease associated with
Helicobacter pylori
infection is gastric or duodenal ulcer, gastritis or gastric cancer,
(11) the anti-
Helicobacter pylori
composition according to the description in (1) above, which is used in combination with an antibacterial agent,
(12) the anti-
Helicobacter pylori
composition according to the description in (1) above, which is used in combination with antiulcer agent,
(13) the anti-
Helicobacter pylori
composition according to the description in (1) above, which is used in combination with antibacterial agent and antiulcer agent,
(14) use of compound of the formula:
wherein A represents an aromatic group which may be substituted, R
1
and R
2
independently represent a hydrogen atom or a hydrocarbon group which may be substituted, R
3
and R
4
independently represent a hydrogen atom, a hydrocarbon group which may be substituted, an acyl group a carbamoyl group which may be substituted, or a carboxyl group which may be esterified, or a salt thereof for the preparation of an anti-
Helicobacter pylori
agent,
(15) a method for prevention or treatment of a disease associated with
Helicobacter pylori
infection in a mammal which comprises administering to a subject in need an effective amount of a compound of the formula (I):
wherein A represents an aromatic group which may be substituted, R
1
and R
2
independently represent a hydrogen atom or a hydrocarbon group which may be substituted, R
3
and R
4
independently represent a hydrogen atom, a hydrocarbon group which may be substituted, an acyl group, a carbamoyl group which may be substituted, or a carboxyl group which may be esterified, or a salt thereof,
(16) a method for producing an anti-
Helicobacter pylori
composition comprising mixing a compound of the formula (I):
wherein A represents an aromatic group which may be substituted, R
1
and R
2
independently represent a hydrogen atom or a hydrocarbon group which may be substituted, R
3
and R
4
independently represent a hydrogen atom, a hydrocarbon group which may be substituted, an acyl group, a carbamoyl group which may be substituted, or a carboxyl group which may be esterified, or a salt thereof with a pharmacologically acceptable diluent, excipient or/and carrier,
(17) a compound of the formula:
wherein A represents an aromatic group which may be substituted, R
1
a
Kamiyama Keiji
Kanamaru Tsuneo
Nakao Masafumi
Tawada Hiroyuki
Fitzpatrick ,Cella, Harper & Scinto
Stockton Laura L.
Takeda Chemical Industries Ltd.
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