Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-12-23
2001-04-24
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S128000
Reexamination Certificate
active
06221864
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a pharmaceutical agent containing (S)-1-cyclopropyl-1,4-dihydro-7-[2-(N,N-dimethylaminomethyl)morpholino]-6-fluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof, which agent is useful for the prophylaxis and treatment of diseases caused by Helicobacter infections, particularly gastritis, gastric ulcer, duodenal ulcer, gastric malignant lymphoma and gastric cancer.
BACKGROUND ART
By the development of antisecretory drugs, such as histamine H
2
antagonist and proton pump inhibitor, peptic ulcers, inclusive of a number of ulcers that heretofore required an operation, can now be cured by drug therapy. In view of the fact that most of the ulcers once cured are subject to recurrence and relapse, however, a maintenance therapy over a long period of time is considered to be necessary even after a complete cure, and even during the maintenance therapy, recurrence and relapse are highly frequently observed.
In 1988, Marrshall B. J. et. al. (Lancet ii: 1437-42, 1988) applied eradication of
Helicobacter pylori
(
H. pylori
) to
H. pylori
positive gastric/duodenal ulcer cases, and reported a noticeable decrease in the relapse of duodenal ulcer. Thereafter in 1992, Graham D. Y. et. al. (Ann. Intern. Med. 116:705-708, 1992.) and in 1993, Hentschel E. et. al. (N. Engl. J. Med. 328:308-312, 1993) successively reported that relapse of peptic ulcer decreased significantly in the group subjected to eradication of
H. pylori
. Given the strong suggestion of the relationship between
H. pylori
infection, and gastritis and gastric/duodenal ulcer, a bacterial eradication therapy has been tentatively applied to patients with gastric/duodenal ulcer.
In February 1994, the United States National Institutes of Health (NIH) recommended that bacterial eradication therapy should be applied to duodenal ulcer and gastric ulcer, whether on first presentation with illness or recurrence (NIH Consensus Conference:
Helicobacter pylori
in peptic ulcer disease. JAMA 272:65-69, 1994), and in this year, WHO/IARC reported that
H. pylori
belonged to group 1 (definite carcinogenic substance) of gastric cancer (WHO International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risks to humans. Schistomsomes, Liver flukes and
Helicobacter pylori
. Lyon. 61, 177-241, 1994). This report suggests that the target of bacterial eradication therapy for
H. pylori
is spreading to the treatment and prophylaxis of gastric cancer and gastric malignant lymphoma (Personnet J. et. al., N. Engl. J. Med. 325:1127-1131, 1991, Uemura N. et. al., Gastroenterology 110:A525, 1996).
Considering from these standpoints, bacterial eradication therapy for
H. pylori
has been actively studied at present. The bacterial eradication therapy for
H. pylori
include (1) monotherapy represented by amoxicillin, (2) classic triple therapy typically using the combination of a bismuth preparation, metronidazole and tetracycline, (3) dual therapy using a proton pump inhibitor and an antibiotic in combination, and (4) new triple therapy consisting of dual therapy plus an antibiotic, by using proton pump inhibitor and two kinds of antibiotics. However, these therapies are associated with many problems in terms of utility, side effects, emergence of resistant strains and compliance, and there has not been established a safe and reliable bacterial eradication therapy. In addition, since many are combined therapies, the dose and administration period of the drugs have not been necessarily consistent. This explains difference in bacterial eradication rates that varied depending on the organizations that enforced the investigation.
Taking note of the superior antibacterial property of new quinolone compounds, there have been recently reported extended application as an anti-
H. pylori
drug of available levofloxacin, and antibacterial activity of trovafloxacin (34th ICAAC (Orlando, USA): F-24, 1994) and DU-6859a (33rd ICAAC (New Orleans, USA): Abstr. 1188, 1993) against
H. pylori.
In these studies in vitro antibacterial activity against
H. pylori
and in vivo bacterial eradication effect do not always correlate, and they have not amounted to the establishment of a safe and reliable bacterial eradication treatment.
In view of the above, there is a demand for a pharmaceutical agent having superior anti-
H. pylori
activity in vitro and superior bacterial eradication of
H. pylori
in vivo, which is useful for the eradication of
H. pylori
from the patients with gastritis/peptic ulcer, for the treatment of gastritis/peptic ulcer or for the prevention of recurrence/relapse thereof.
DISCLOSURE OF THE INVENTION
The present inventors have conducted intensive studies in an attempt to achieve the above-mentioned objects and found that the compound of the present invention has superior in vitro antibacterial activity against the genus Helicobacter and shows superior in vivo bacterial eradication effect in animal models, such that the compound is useful for the prophylaxis and treatment of the diseases caused by Helicobacter infections, namely, gastritis, gastric ulcer, duodenal ulcer, gastric malignant lymphoma and gastric cancer, which resulted in the completion of the present invention.
The compound of the present invention is effective even when used alone in a small dose for a short time, shows effect against the resistant strains to other antibiotics such as amoxicillin and clarithromycin, is almost free of problematic side effects such as tolerance to the compound of the present invention itself and diarrhea, and is low toxic and capable of safe and reliable bacterial eradication.
In addition, the compound of the present invention shows superior physicochemical properties with excellent stability (e.g, photosensitive stability).
Moreover, the compound of the present invention shows more superior bacterial eradication effect by co-treatment with the antisecretory drugs, and an antibiotic or antiprotozoal drug, as seen in a two-agent or three-agent combined therapy, and is useful for the prophylaxis and treatment of diseases caused by Helicobacter infections, particularly, gastritis, gastric ulcer, duodenal ulcer, gastric malignant lymphoma and gastric cancer, or for the prevention of recurrence or relapse thereof.
Accordingly, the present invention provides the following.
(1) An agent for the prophylaxis or treatment of a disease caused by Helicobacter infections, which comprises (S)-1-cyclopropyl-1,4-dihydro-7-[2-(N,N-dimethylaminomethyl)morpholino]-6-fluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof.
(2) The agent of (1) above, wherein the disease caused by the Helicobacter infections is gastritis, gastric ulcer or duodenal ulcer.
(3) The agent of (1) above, wherein the disease caused by the Helicobacter infections is gastric malignant lymphoma or gastric cancer.
(4) The agent of any of (1) to (3) above, wherein the agent is used in combination with an antisecretory drug.
(5) The agent of (4) above, wherein the agent is used in combination with an antibiotic or antiprotozoal drug.
(6) Use of (S)-1-cyclopropyl-1,4-dihydro-7-[2-(N,N-dimethylaminomethyl)morpholino]-6-fluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof for the production of an agent for the prophylaxis or treatment of a disease caused by Helicobacter infections.
(7) The use of (6) above, wherein the disease caused by the Helicobacter infections is gastritis, gastric ulcer or duodenal ulcer.
(8) The use of (6) above, wherein the disease caused by the Helicobacter infections is gastric malignant lymphoma or gastric cancer.
(9) A method for the prophylaxis or treatment of a disease caused by Helicobacter infections, which comprises administering an effective amount of (S)-1-cyclopropyl-1,4-dihydro-7-[2-(N,N-dimethylaminomethyl)morpholino]-6-fluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof to a patie
Hirayama Fumihiro
Sakurai Nobuhiro
Sano Mitsuharu
Yokoyama Yoshito
Ramsuer Robert W.
Welfide Corporation
Wenderoth , Lind & Ponack, L.L.P.
LandOfFree
Prophylactic or therapeutic agent for diseases attributable... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Prophylactic or therapeutic agent for diseases attributable..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Prophylactic or therapeutic agent for diseases attributable... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2476492