Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-06-01
1997-08-19
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514254, 514255, 514256, 544333, 544336, 544362, 544405, 546122, A61K 3144, A61K 3156, A61K 31505, C07D47004
Patent
active
056589247
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This application is the national phase of ACT/JP92/01575 filed Dec. 1, 1992.
The present invention relates to 1,8-naphthyridin-2-one derivatives, pharmaceutically acceptable acid addition salts and therapeutic agents for the diseases such as peripheral diseases (e.g. hypertension, renal failure, heart failure, angina pectoris, myocardial infarction and peripheral circulatory disorders), circulatory diseases and respiratory diseases (e.g. arteriosclerosis, romsoongiitis obliterans, aortitis syndrome and bronchial asthma), central nervous system diseases (e.g. depression, degradation of central nervous function after cerebrovascular obliteration, cerebrovascular dementia, senile dementia, Alzheimer dementia and memory learning function disorders), various inflammations, and obesity, which comprise said compound as an active ingredient.
BACKGROUND ART
(1) An endothelin is a strong vasoconstrictive peptide derived from endotheliocytes, which consists of 21 amino acids, and was isolated and identified by Yanagisawa et al in 1988 [M. Yanagisawa et al., Nature 332, 411 (1988)]. The vasoconstriction by endothelin is stronger than that by known vasoconstrictive substances such as angiotensin II, vasopressin and neuropeptide Y. Although the constriction is moderate, it lasts for a long time. Endothelin also shows contractive action on various blood vessels inclusive of microvessels of various animals.
The contraction by endothelin is not affected by receptor antagonists and synthesis inhibitors of known blood vessel agonists, such as norepinephrine, histamine, acetylcholine, serotonin, leukotriene and thromboxane A.sub.2, and is known to be only suppressed by potential-dependent calcium channel antagonists and endotheline receptor antagonistic substances.
It is also known that endothelin induces not only vasoconstriction, but also strong airway stenosis [Y. Uchida et al., Eur. J. Pharmacol. 154, 227 (1988)]. It has been gradually clarified that endothelin has various physiological actions such as promotion of release of atrial sodium diuretic hormone in cultured atrial muscle of rats and suppression of renin secretion in pararenal glomerular cells.
Although its action in the living body and pathological involvement have not been entirely elucidated, endothelin is considered to be involved in various diseases, in view f the wide distribution of endothelin receptors and a variety of actions it shows. In fact, the involvement of endothelin has been pointed out in various diseases and experimental animal models. To be specific, patients and pathological animal models with pulmonary hypertension [D. J. Stewart et. al., Am. Col. Physic. 114, 464 (1991)], renal failure [M. Shichiri et al., Hypertension 15, 493 (1990)], heart failure [K. B. Margulies, Circulation 82, 2226 (1990)], angina pectoris [T. Toyo-oka et al., Circulation 83, 476 (1991)], myocardial infarction [Lancet Jul. 1, 53 (1989)], ischemic brain, peripheral diseases, arteriosclerosis, romsoongitis obliterans (Bueger's disease), aortitis syndrome (Takayasu's disease) [JAMA, 264, 2868 (1990)] or bronchial asthma show increased endothelin level in plasma, thus suggesting the possibility of endothelin being deeply involved in the onset and cause, retention and progress of the diseases.
(2) A cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which are tntracellular second messengers, are decomposed and inactivated by phosphodiesterase (PDE). It has been known that PDE is widely distributed in the tissues in the body, and that PDE inhibitors provide various pharmacological actions by increasing cAMP and cGMP levels in the cells by inhibiting PDE. For example, they provide relaxing action in vascular smooth muscles and tracheal smooth muscles, as well as positive inotropic action and chronotropic action in the heart. They also control the central nervous function caused by increased cAMP in the central nervous system; namely, they show antidepression and memory learning function-improving action. Besides these, they
REFERENCES:
patent: 3993656 (1976-11-01), Rooney
patent: 4735948 (1988-04-01), Wright
Rubanyi GM; Botelho LH (1991) FASEB J, 5 (12) 2713-20. Sep. 1991.
Ashizawa Naoki
Hase Takema
Matsuura Akihiro
Huang Evelyn
Ivy C. Warren
The Green Cross Corporation
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