Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-04-30
2000-10-24
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546279, A61K 31505, C07D47104
Patent
active
061368105
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to novel pyrido[2,3-d]pyrimidine derivatives useful as medicines, particularly as type IV phosphodiesterase inhibitors, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, use thereof for the production of medicaments and a preventing or treating method in which an effective amount thereof is administered.
BACKGROUND ART
Asthma is a respiratory disease which repeats stridor and attack due to airway contraction. The number of the asthma patients has been increasing constantly and is considered to further increase in the future.
Main morbid states of asthma are a) sudden contraction of smooth muscle which surrounds the airway and b) inflammatory reaction caused by the activation of infiltrative cells in respiratory organs including the lungs. Therefore, it is considered that inhibition of the airway smooth muscle contraction and inhibition or prevention of the activation of infiltrative celis are considered to be effective means for the treatment of symptoms of asthma.
For the treatment of asthma, xanthine derivatives such as aminophylline, theophylline and .beta.-stimulators such as procaterol are now mainly used as drugs which remit symptoms of asthma by dilating the bronchus. The action mechanism of these compounds is that they inhibit contraction of airway smooth muscle. through the increment of the concentration of cyclic adenosine 3',5'-monophosphate (cAMP) in the cells of the airway smooth muscle, which is effected by the activation of adenylate cyclase as a cAMP producing enzyme or by the inhibition of phosphodiesterase (PDE) as a cAMP hydrolyzing enzyme [Thorax, 46, 512-523 (991)].
However, xanthine derivatives generate systemic side effects such as decrease in blood pressure, cardiotonic action and the like [J. Cyclic Nucleotide and Protein Phosphorylation Res., 10, 551-564 (1985)] and, therefore, it is necessary to monitor its concentration in blood in order to prevent these systemic side effects. In addition, xanthine derivatives do not exert clear effect against asthma when it involves infiltration of inflammatory cells.
On the other hand, it is known that .beta.-stimulators generate side effects such as finger tremor, palpitation and the like, when the dose is increased because of their aptness to generate desensitization.
Studies conducted thereafter have revealed that the DPE, an enzyme which hydrolyses cAMP, is divided into at least four different types of I to IV having different distributions and functions [Pharmacological Therapy, 51, 13-33 (1991)]. Particularly, the type IV PDE hydrolyses cAMP in a specific fashion without acting upon cyclic guanosine 3',5'-monophosphate (cGMP) among nucleotides, and its presence is found in both airway smooth muscle and infiltrative cells.
Incidentally, PDE V is known as an enzyme which degrades cGMP.
Concentration of cAMP in cells is set by the balance of the cAMP production rate by adenylate cyclase and the cAMP hydrolyzation rate by PDE. In consequence, intracellular cAMP concentration can be increased by stimulating adenylate cyclase or inhibiting PDE. Increase in the intracellular cAMP concentration induces inhibition of contraction of the airway smooth muscle and inhibition of the activation of inflammatory cells [Clin. Exp. Allergy, 22, 337-344 (1992), Drugs of the Future, 17, 799-807 (1992)].
Also, it has been reported that a type IV PDE inhibitor shows an action to inhibit eosinophiles infiltration by antigen and platelet activating factor in guinea pigs [Eur. J. Pharmacol., 255, 253-256 (1994)] and inhibits release of cytotoxic proteins (MBP, ECP) from eosinophiles [Br. J. Pharmacol., 115, 39-47 (1995)]. It has been reported also that it shows an action to inhibit contraction of the airway smooth muscle caused by contractile substances (histamine, LTD.sub.4, methacholine) [Br. T. Pharmacol., 113, 1423-1431 (1994)], inhibits production of IL-4 which is a member of cytokine which is considered to be concerned deeply in asthma [J. Invest. Dermatol., 100, 681-684 (1993)], expre
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The effect of a novel orally active selective PDE4 isoenzyme inhibitor (CDP840) on alergen-induced responses in asthmatic subjects, P.L. Harbinson, et al., European Respiratory Journal, ISSN 0903--1936; p. 10: 1008-1014 (1997).
Acute versus chronic administration of posphodiesterase inhibitors on allergen-induced pulmonary cell influx in sensitized guinea-pigs, Katharine H. Banner & Clive P. Page, British Journal of Pharmacology, 114; p. 93-98 (1995).
Aoki Motonori
Hisamichi Hiroyuki
Iwata Masahiro
Kubota Hideki
Takayama Kazuhisa
Raymond Richard L.
Yamanouchi Pharmaceutical Co. Ltd.
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