Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-12-06
1998-11-24
Lambkin, Deborah C.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
549218, 549220, 558185, 558199, 558200, 5483094, 548180, 548217, 514448, 514468, 514471, 514120, 514137, 514394, 514367, 514375, C07D33300, C07F 906, A61K 3138, A61K 3134
Patent
active
058409173
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP96/02769 filed Sep. 25, 1996, published as WO97/11705 Apr. 3, 1997.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to phosphorylamides, their preparation and use. More specifically this invention relates to a phosphorylamide derivative possessing excellent antibacterial activity based on excellent anti-urease activity, especially potent antibacterial activity against Helicobacter bacteria such as Helicobacter pylori, a method for producing the phosphorylamide derivative, and an anti-Helicobacter pylori agent which comprises the phosphorylamide derivative and antacid or an acid secretion inhibitor.
2. Background Art
Among the bacteria showing toxic action, Helicobacter pylori which is a gram-negative, slightly aerobic bacterium belonging to the genus Helicobacter is considered to be a major cause of recurrent gastritis, duodenal ulcer, gastric ulcer etc.
Helicobacter bacteria, especially Helicobacter pylori, possessing potent urease activity, reportedly survive in the stomach, in which they neutralize strong acidity around them by producing ammonia from urea.
Various diseases caused by Helicobacter pylori are now treated by double chemotherapy with a bismuth preparation and an antibiotic, or by 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 an antibiotic. These bismuth preparations, antibiotics, metronidazole etc. are administered orally.
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, and this produces in many problems, including adverse effects such as vomiting and diarrhea.
On the other hand, some phosphorylamide derivatives are known to possess anti-urease activity (e.g., U.S. Pat. No. 3,317,637, U.S. Pat. No. 4,517,003, U.S. Pat. No. 4,528,020, EP 210703, U.S. Pat. No. 4,182,881, U.S. Pat. No. 4,221,730 Japanese Patent Unexamined Publication No. 99490/1983, Japanese Patent Examined Publication No. 7379/1967, U.S. Pat. No. 4,629,491 and J. Pharm. Sci., 189, 57 (1968)), but there is no disclosure that these phoaphorylamide derivatives exhibit antibacterial action, especially anti-Helicobacter pylori action, in vivo.
SUMMARY OF THE INVENTION
The present invention provides a phosphorylamide derivative or a salt thereof possessing excellent antibacterial activity, especially potent antibacterial activity against Helicobacter bacteria such as Helicobacter pylori, and an anti-Helicobacter pylori agent comprising the phosphorylamide derivative and antacid or an acid secretion inhibitor.
After extensive investigation in view of the above problem, the present inventors found that a phosphorylamide derivative possessing excellent anti-urease activity exhibits potent antibacterial action in vivo against bacteria (e.g., Helicobacter bacteria such as Helicobacter pylori) showing toxic action in the digestive tract. The inventors conducted further research based on this finding, and completed the present invention.
Accordingly, the present invention relates to: ##STR2## wherein R represents an amino group which may be substituted, or a pharmaceutically acceptable salt thereof, for the preparation of an anti-Helicobacter pylori agent which is used in combination with an antacid or an acid secretion inhibitor; pharmaceutically acceptable salt thereof, for the preparation of an anti-Helicobacter pylori agent for prophylaxis of recurrence of ulcer in combination with an antacid or an acid secretion inhibitor; the general formula (I) or a pharmaceutically acceptable salt thereof, and an antacid or an acid secretion inhibitor; ##STR3## wherein R' represents (a) a heterocyclic group which may be substituted (except a fury
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Inatomi Nobuhiro
Nagaya Hideaki
Nakao Masafumi
Oi Satoru
Yukimasa Hidefumi
Lambkin Deborah C.
Takeda Chemical Industries Ltd.
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