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
2003-12-16
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
06664279
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a therapeutic or preventive agent for liver diseases, containing as an active ingredient a diaminotrifluoromethylpyridine derivative or its salt.
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.
As liver diseases, many diseases have been known such as acute hepatitis, fulminant hepatitis, chronic hepatitis, hepatic cirrhosis, fatty liver, alcoholic hepatopathy, drug induced hepatopathy (drug addiction hepatitis), congestive hepatitis, autoimmune hepatitis, primary biliary cirrhosis and hepatic porphyria, and pericholangitis, sclerosing cholangitis, hepatic fibrosis and chronic active hepatitis, which have been reported to occur with a high frequency as complications of inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. Their causes are also various, and acute or chronic hepatopathy based on various causes such as hepatitis virus, drug, alcohol, poisonous substance, autoimmune dysfunction, dysbolism, abnormality of hepatic circulatory system and biliary obstruction, is related by itself or compositely. The treatment of the liver diseases is in principle prevention of progress of hepatic necrocytosis, acceleration of hepatic regeneration, curing of dysbolism, countermeasure of complications and removal of the cause such as virus. Further, it has been clarified that most of liver cancer occurs based on hepatic cirrhosis, and accordingly early treatment with a purpose of preventing the symptoms from being fulminant and progressing to hepatic cirrhosis is considered to be clinically important in treatment of acute hepatitis and chronic hepatitis.
As therapeutic agents of the liver diseases based on this principle, two types of drugs i.e. drugs oriented towards palliative treatment represented by a liver function improving agent (liver protecting agent) and drugs oriented towards liver function improvement and causal treatment, have been used. As examples of the former, nutritional supplementary agents such as a special composition amino acid transfusion and a glucose liquid, glycyrrhizin preparations, germanium preparations (such as propagermanium), Chinese herbal remedy Sho saiko-to, glutathione, cysteine, liver extract agents, polyenephosphatidylcholine, diisopropylamine-dichloroacetate, tiopronin, protoporphyrin, methyl-methionine-sulfonium-chloride, adenosine triphosphate and ursodeoxycholic acid are known. On the other hand, as examples of the latter, adrenocortical hormones such as predonisolone, anti-inflammatory and immunosuppressant agents such as 6-mercaptopurine and D-penicillamine, antiviral agents such as vidarabine (Ara-A) and interferon agents are known. Further, together with the treatment with such drugs, treatment by means of an artificial liver assisting apparatus such as plasma exchange, active carbon hemoperfusion or high permeability hemodialysis, with a purpose of curing dysbolism, may be carried out in some cases. Further, in recent years, new therapeutic agents against the liver diseases have been developed. For example, recombinant human hepatocyte growth factor (JP-A-5-111383), a 1,3-benzoxathiol-2-thione derivative (JP-A-6-239856), a cholestanone derivative (JP-A-7-69898) and a 3-hydroxy-2,3-dihydrobenzofuran derivative (JP-A-11-228563) have been known to be useful as an active ingredient for treatment of the liver diseases. However, although treatment with an existing commercially available drug achieves a certain result on each indication, since causes of the disease, underlying diseases and complications of the liver diseases are various, effectiveness by single administration is limited. Further, there is a fear of adverse reactions and harmful phenomena by drug treatment. For example, with respect to the glycyrrhizin preparation, a case has been reported where adverse reactions along with appearance of pseudo-aldosterone action become problematic. With respect to treatment with a drug having SH groups such as glutathione or cysteine, although detoxication due to the active SH groups is obtained, such a drug may decrease the efficacy of other drug to be used together in some cases. Further, treatment with an adrenocortical hormone may cause infectious diseases or adverse reactions such as thymus or adrenal gland atrophy, and careful administration under hospitalization control is basically required. Further, with respect to the interferon preparation, adverse reactions such as pyrexia and hypoleukocytemia occur with a high frequency, and severe adverse reactions such as pneumonitis (pulmonary fibrosis), autoimmune disease (thyroiditis), neuropsychological dysfunction and cardiomyopathy may occur by its long-term administration. Under these circumstances, development of more effective and safer therapeutic agents for liver diseases has been desired in the clinical field.
DISCLOSURE OF THE INVENTION
The present inventors have conducted extensive studies on pharmacological effects of diaminotrifluoromethylpyridine derivatives or their salts and as a result, found that these compounds are extremely effective as a therapeutic or preventive agent for liver diseases, and the present invention has been accomplished on the basis of this discovery.
The present invention provides a therapeutic agent for liver diseases, containing as an active ingredient a diaminotrifluoromethylpyridine derivative represented by the formula (I) or its salt:
wherein X is a —CW
1
R
1
group, a —COCOR
2
group, a —CW
1
NHCOR
2
group, a —C(═W
1
)W
2
R
3
group or a —CW
1
N(R
4
)R
5
group; Y is an alkyl group, a —CW
3
R
6
group, a —COCOR
7
group, a —NHCOR
7
group, a —C(═W
3
)W
4
R
8
group, a —(NH)
m
SO
2
R
9
group, a —(NH)
m
SO
2
OR
10
group or a —(NH)
m
SO
2
N(R
11
)R
12
group; each of R
1
, R
6
and R
9
which are independent of one another, is a chain hydrocarbon group which may be substituted, a monocyclic hydrocarbon group which may be substituted, a polycyclic hydrocarbon group which may be substituted, a monocyclic heterocycle group which may be substituted or a polycyclic heterocycle group which may be substituted; each of R
2
and R
7
which are independent of each other, is an alkyl group which may be substituted, an alkoxy group which may be substituted, a phenyl group which may be substi
Sakai Kimie
Yotsuya Shuichi
Davis Zinna Northington
Ishihara Sangyo Kaisha Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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