Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-05-26
1999-08-10
Davis, Zinna Northington
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546296, C07D21369, A61K 3144
Patent
active
059359773
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a novel substituted vinylpyridine derivative and salts thereof, which are endowed with strong and selective phosphodiesterase (PDE) IV inhibitory action and strong inhibitory action against production of the tumor necrotizing factor (TNF-.alpha.), as well as with high safety. The invention also relates to drugs containing the derivative or salts and useful for the prevention and treatment of a broad range of inflammatory diseases and autoimmune diseases.
BACKGROUND ART
PDE is an enzyme which acts as a catalyst in hydrolysis of cyclic adenosine 3',5'-phosphate (cAMP) or cyclic guanosine 3',5'-phosphate (cGMP) into 5'-monophosphate. cAMP and cGMP are produced from ATP and GTP, respectively, following activation of adenylate cyclase or guanylate cyclase in response to a hormone or chemical transmission substance, and work as intracellular second messengers. PDE inhibitory agents block the activity of PDE to increase the amounts of intracellular cAMP and cGMP, to thereby suppress cellular response. At present, PDE is known to have type I to type VIII isozymes. These are found in the central nervous system, circulatory system, respiratory system, digestive system, reproductive system, and blood cell system. The distribution of these isozymes differs according to the tissue. This suggests that a PDE-isozyme-specific inhibitor may increase the amount of cAMP in certain specific tissue.
In recent years, considerable efforts have been devoted to research and development of highly specific PDE isozyme inhibitors. For example, attempts have been made to develop drugs that exhibit organ specificity attributable to localization of respective isozymes. As a result of such attempts, PDE IV is considered to be a potential agent effective for both asthmatic attack and chronic respiratory tract inflammation, due to the facts that PDE IV is present predominantly in the airway tissue or inflammatory cells, such as eosinocytes and neutrophilic leukocytes, which are intimately related to asthmatic symptoms and that drugs that inhibit the action of PDE IV exhibit bronchodilatation action as well as inhibitory action against activation of inflammatory leukocytes. Thus, active studies have been performed worldwide focusing on development of a selective inhibitor against PDE IV as a new remedy for bronchial asthma.
PDE IV, which also exists in the central nervous system, is expected to improve memory and mitigate anxiety, based on the consideration that a rolipram, a selective PDE IV inhibitor, specifically localizes in the brain tissue to increase noradrenergic nervous transmission on a synapse or post-synapse level in response to an increased amount of cAMP, which is a second messenger of noradrenalin.
TNF-.alpha. is a cytokine produced by an activated macrophage. Although TNF-.alpha. was first discovered to be a factor which induces hemorrhagic necrosis in a tumor site, it is now recognized as a mediator which widely participates in inflammatory reactions and the immune mechanism. Excessive production of TNF-.alpha., however, induces disorders in tissue to cause a variety of pathological conditions. Rapid release of TNF-.alpha. induced by intracellular toxins is responsible for the lethality.
TNF-.alpha. promotes production of platelet-activating factor (PAF), a variety of inflammatory arachidonic metabolites, and activated oxygen. Moreover, it induces production of interleukin (IL)-1, IL-6, and IL-8. As is understood from this, excessive production of TNF-.alpha. aggravates inflammatory reactions and, in the case of chronic inflammatory diseases such as rheumatism, osteoporosis, and terminal cancers, results in a persistence of complication of diseases, in which the concentrations of these cytokines are maintained consistently so as exacerbate the symptoms. Accordingly, in pathological conditions in which TNF-.alpha. is produced excessively, control of its release is strongly sought by clinicians.
So far, molecular design of a selective PDE IV inhibitor has not yielded satisf
REFERENCES:
Lee et al, Circ. Shock, vol. 44(3) pp. 97-103, 1995.
Hasegawa Hiroshi
Kawamoto Noriyuki
Kohya Hidehiko
Mikami Tadashi
Ogawa Yoichiro
Davis Zinna Northington
SS Pharmaceutical Co., Ltd.
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