Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-07-25
2003-10-21
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
06635665
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a therapeutic or preventive agent for pulmonary insufficiency 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.
Among pulmonary insufficiencies, as intractable and particularly problematic diseases, acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD) may be mentioned.
ARDS occurs when excessive invasion due to various underlying diseases is applied to the body. The underlying diseases may, for example, be viral pneumonia, bacterial pneumonia, infection, bacteraemia, systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, haemorrhagic shock, cardiogenic shock, anaphylaxis, hypotension, multiple organ failure (MOF), multiple organ dysfunction syndrome (MODS), acute pancreatitis, disseminated intravascular coagulopathy (DIC), direct pulmonary contusion, head injury, multiple severe injury, fat embolism, amniotic embolism, fetal death, oxygen intoxication, drug intoxication, massive deglutition in stomach, drowning and high altitude pulmonary edema. On ARDS patients, usually an acute respiratory failure symptom such as non-cardiogenic pulmonary edema, severe hypoxemia, decrease in pulmonary compliance, severely impaired gas exchange or dyspnea is observed. However, it tends to be difficult to treat ARDS with general oxygen therapy, and treatment by an artificial ventilation method employing positive end-expiratory pressure (PEEP) or pressure cycled artificial ventilation is carried out in many cases. Further, it is attempted to carry out extracorporeal pulmonary assist or nitrogen monooxide inhalation therapy in some cases.
As a drug treatment for ARDS, drugs such as various steroids such as prednisolone, proteinase inhibitors such as ulinastatin, prostaglandin E1, pulmonary surfactant, pentoxifylline and granulocyte colony stimulating factor have clinically been applied, but, because, the underlying diseases for ARDS are various as described above, their effectiveness has not clearly been understood. Further, the mortality rate by ARDS is so high as about 50%. It has been known that human derived anti-thrombin III is useful as a therapeutic agent for ARDS and that a medical composition for bronchoalveolar lavage comprising a surfactant containing polypeptides is effective for treatment of ARDS, however, development of safer and more effective therapeutic or preventive agents containing a low molecular weight compound as an active ingredient has been desired.
On the other hand, COPD is a general term for pulmonary diseases which cause delayed forced expiratory flow, including chronic bronchitis, emphysema, diffuse panbronchiolitis and airway obstruction symptom. Smoking and aging are main causes of crises, and the incidence rate of moist cough and other respiratory symptoms is high particularly among long-term heavy smokers, and their mortality rate also tends to be high. Further, along with progress of environmental pollution in recent years, exposure to powder dust and chemical fume in the air tends to increase, whereby the incidence rate of COPD tends to increase, and the number of patients is rapidly increasing year by year. At the initial stage of COPD, acute pathologic symptoms in the chest characterized by increase of cough, pyogenic expectoration, wheezing and dyspnea, and pyrexia on occasion, are confirmed. Many of them are progressive, tend to worsen successively with repetition of acute exacerbation, and may cause severe hypoxemia accompanied by cyanosis or may cause disease complication such as acute respiratory failure, severe pneumonia, pneumothorax or pulmonary embolism, thus causing the patient to die in some cases.
The accurate cause of crisis of COPD has not been understood, and thus no radical treatment has been developed yet. For its treatment, long term oxygen therapy may be carried out in some cases. Further, as symptomatic drug treatment, a &bgr;
2
agonist such as metaproterenol which accelerates bronchodilation or theophylline which decreases convulsion of the smooth muscle may, for example, be used with a purpose of reducing airway obstruction. Further, anticholinergic agonists, steroid drugs and antibacterial agents may also be used alone or as multiple drug combination, however, if systemic application of a steroid drug is required, its adverse reactions are problematic, and accordingly development of safe and more effective therapeutic agents has been desired.
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 pulmonary insufficiency represented by ARDS or COPD, and the present invention has been accomplished on the basis of this discovery.
The present invention provides a therapeutic or preventive agent for pulmonary insufficiency, 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 substituted or a phenoxy group which may be substituted; each of R
3
, R
8
and R
10
which are independent of one another, is an alkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which ma
Imamura Masashi
Morino Kyuya
Yotsuya Shuichi
Davis Zinna Northington
Ishihara Sangyo Kaisha Ltd.
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