Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-07-29
2003-11-25
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S308000
Reexamination Certificate
active
06653333
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a therapeutic or preventive agent containing as an active ingredient a diaminotrifluoromethylpyridine derivative or its salt, useful for digestive system diseases such as inflammatory bowel diseases, gastritis and peptic ulcer.
BACKGROUND ART
Japanese Patent No. 2762323 and U.S. Pat. No. 5,229,403 disclose that a diaminotrifluoromethylpyridine derivative or its salt has a phospholipase A
2
inhibitory action and is useful as an active ingredient of an anti-inflammatory agent or an anti-pancreatitis agent. They also disclose that (1) phospholipase A
2
is secreted or activated in platlets or inflammatory cells by stimulations and contributes to the production of a platlet activating factor (PAF) and arachidonic acid metabolites, (2) the arachidonic acid metabolites are closely related to various diseases, for example, inflammatory symptoms such as rheumatic arthritis, arthritis deformans, tendinitis, bursitis, psoriasis and related dermatitis; nasal and bronchial airway troubles such as allergic rhinitis and allergic bronchial asthma; and immediate hypersensitive reactions such as allergic conjunctivitis, (3) on the other hand, phospholipase A
2
secreted from pancreas is activated in the intestine and exhibits a digestive action, but once activated in the pancreas, it is believed to be one of the factors causing pancreatitis, and (4) the above diaminotrifluoromethylpyridine derivative inhibits phospholipase A
2
and thus is effective for treatment of diseases related to phospholipase A
2
such as inflammatory symptoms, nasal and bronchial airway troubles, immediate hypersensitive reactions or pancreatitis, and can be used as an anti-inflammatory agent, an agent for treating bronchial asthma, an anti-allergy agent, an anti-pancreatitis agent, an anti-nephritis agent or an anti-multiple organ failure agent.
Further, U.S. Pat. No. 5,492,908 discloses that such compounds can be used as a therapeutic agent for rheumatoid arthritis, and JP-A-10-298076 discloses that some of these compounds are effective as an anticancer agent having a carcinogenesis inhibitory effect.
Among digestive system diseases, diseases for which new therapeutic agents are particularly required, may, for example, be inflammatory bowel diseases, gastritis and peptic ulcer. The inflammatory bowel diseases are meant for enteritis developed at small intestine (including duodenum, jejunum and ileum) or large intestine (including cecum, colon and rectum), and they include enteritis, the causes of which are clear, such as infectious enteritis, ischemic enteritis, radioenteritis, drug enteritis and irritable bowel syndrome, intractable inflammatory bowel diseases, the causes of crises of which have not been clear yet, such as ulcerative colitis (nonspecific idiopathic colitis), Crohn's disease (regional enteritis), Crohn's disease of large bowel (granulomatous colitis or regional colitis) and entero-Behcet's disease, and further include enteritis, not only the causes of which have not been understood yet but also which themselves have not been specified.
Human ulcerative colitis is nonspecific idiopathic inflammatory bowel disease which forms erosion or ulcer on lamina propria mucosa or submucosa of large intestine mucosa from rectum to cecum, and it has conventionally been a relatively rare disease, however, the number of patients are rapidly increasing in recent years. As its clinical symptoms, characteristic pathognomonic findings such as diarrhea, bloody stool, abdominal pain and weight reduction may be mentioned, and it is an intractable disease with repetition of recurrence and remission. Its detailed cause and morbidity have not been clearly understood yet, but immunopathological mechanism and psychological factor are considered to be related. On the other hand, Crohn's disease is a disease wherein inflammation is formed not only on the mucosa but on entire bowel wall and non-diffusive and discontinuous lesion is formed on the entire digestive canal from the mouth cavity to the anus, and its detailed cause of disease has not been understood yet. During progress of the disease, in addition to denutrition, various serious digestive organ and parenteral symptoms such as intestinal stenosis, intestinal perforation, abdominal abscess and massive bleeding are likely to coincide, and the recurrence rate after operations is high with this disease.
As medical treatment for the ulcerative colitis, steroid hormone, Salazosulfapyridine (SASP) [Salazopyrin®, registered trademark] and metronidazole [Flagyl®, registered trademark] are mainly used [New England Journal of Medicine, vol. 25, p.1499 (1980), The Merck Manual, Seventeenth Edition, p.309, (1999)]. SASP used as the first choice drug particularly for active ulcerative colitis at a minor to moderate stage, which is an azo compound of 5-aminosalicylic acid (5-ASA) and sulfapyridine, is effective only when lesion is present in the large intestine, its effect is relatively weak at a severe stage, and it is in many cases used together with another agent such as a steroid drug even at a minor stage. Further, it is also pointed out that the effect is insufficient at an acute stage of inflammation. Its detailed mechanism of action is still unclear in many points even though its various actions have been reported such as prostaglandin synthesis inhibitory action, leukotriene synthesis inhibitory action, leukocyte chemotaxis inhibitory action, oxygen radical production inhibitory and erasing action, immunosuppressive action and anti-inflammatory action. Further, by taking the drug, adverse reactions such as liver function failure, nausea and vomiting, headache, pyrexia, hemolytic anemia, male sterility, abdominal dysphoria, rash, lymph node swelling, granulocytopenia and folic acid deficiency appear, and the frequency reaches 10 to 20% [Gastrointestinal Pharmacology, vol.21, p.643-658 (1992)]. With a purpose of decreasing such adverse reactions, mesalazine which is a sustained release preparation coated so that 5-ASA is formed by the pH in the intestine has been developed and used clinically, but the same problems as in the case of the above-described SASP have been reported, and its effect does not exceed SASP [Japanese Pharmacology & Therapeutics, vol.22, p.93-121 (1994)]. On the other hand, adrenocorticosteroids such as Predonine or Rinderon have commonly been used, however, on the other side of the therapeutic effect, other adverse reactions due to virus and bacterial infection or suppression of pituitary gland and adrenal cortex function have been pointed out as problems [Sogo Rinsho (Comprehensive Clinic), vol.43, p.1725-1729 (1994)], and because the prescription is very difficult, careful administration under hospitalization control is basically required. As therapeutic agents effective for Crohn's disease, SASP, 5-ASA, mercaptopurine, adrenocorticosteroid and metronidazole may, for example, be mentioned, but none of them is considered to have a sufficient clinical effect.
In recent years, for such inflammatory bowel diseases, new therapeutic agents such as a lipoxygenase inhibitor, a thromboxane A
2
receptor antagonist, a thromboxane A
2
synthetase inhibitor, an oxygen radical removing agent, an interleukin 1 (IL-1) antagonist (JP-A-9-157182) and a neutralizing antibody against tumor necrosis factor (TNF-&agr;), and leukocytapheresis have been developed, however, development of more effective and safer therapeutic agents has been desired.
On the other hand, digestive ulcer such as gastric ulcer or duodenal ulcer exhibits various symptoms depending upon the location of the ulcer and the age of the patient, and the main cause has classically been considered as hypersecretion of gastric acid. As gastric acid hypersecretion inhibitors, H
2
blockers having a H
2
receptor antagonistic action (such as cimetidine, ranitidine, famotidine, roxatidine acetate and nizatidine) and proton pump inhibitors (PPI: such as omeprazole and lansoprazole)
Bamba Tadao
Kimura Hirohiko
Yotsuya Shuichi
Davis Zinna Northington
Ishihara Sangyo Kaisha Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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