Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-01-30
1998-10-06
Dentz, Bernard
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546122, 546123, A61K 31435, C07D47104
Patent
active
058176705
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP95/01700 filed Aug. 28, 1998 published as WO96/06843 Mar. 7, 1996.
TECHNICAL FIELD
The present invention relates to 1,8-naphthyridine derivatives and salts thereof. These substances are useful in prevention or treatment of diseases in which type IV phosphodiesterase is concerned, particularly bronchial asthma and the like.
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 suppression or prevention of the activation of infiltrative cells are effective means for the treatment of symptoms of asthma.
For the treatment of asthma, compounds having a xanthine nucleus such as aminophylline and theophylline are used. These compounds are used as bronchial dilating agents since they suppress 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 inhibition of phosphodiesterase (PDE) as a
However, compounds having a xanthine nucleus generate systemic side effects 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, resulting in the complicated use. In addition, xanthine derivatives do not exert clear effect against asthma when it involves infiltration of inflammatory cells. From these reasons, these compound are not satisfactory as a therapeutic agent.
In addition, .beta.-stimulators such as procaterol and formoterol have been used as a bronchial dilating agent (Eur. Respir. J., 5, 1126-1136 (1992)), but they are known to 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 PDE, an enzyme which hydrolyses cAMP, is divided into at least four different types of I to IV 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.
Concentration of cAMP in cells is set by the balance of the cAMP production rate by adenylate cyclase and the cAMP degradation 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 suppression of contraction of the airway smooth muscle and suppression of the activation of inflammatory 799-807 (1992)!.
On the other hand, naphthyridine derivatives are disclosed, for example, in an unexamined published Japanese patent application (Kokai) No. 55-164682 and International Patent Publication 94/12499 (1994).
Of these references, an unexamined published Japanese patent application (Kokai) No. 55-164682 discloses 2-oxo-4-phenyl-1,5,7-trimethyl-2H-1,8-naphthyridine which shows diuretic action, but does not disclose the antiasthmatic action by the selective suppression of type IV phosphodiesterase.
Also, International Patent Publication 94/12499 (1994) discloses a compound having the following general formula which has an activity to inhibit phosphodiesterase. ##STR2## (See the aforementioned reference for R.sup.1 and R.sup.2 in the above formula).
However, in comparison with these compounds, the compound of the present invention represented by the general formula which will be described later has a structural difference in which it has a substituent having a ri
REFERENCES:
patent: 4775686 (1988-10-01), Blythin et al.
El-Taweel, J. Prakt. Chem. 332(5), pp. 762-766; Chemical Abstracts vol. 114, 185431 (1991).
Aoki Motonori
Isomura Yasuo
Iwata Masahiro
Niwa Akira
Okamoto Yoshinori
Dentz Bernard
Yamanouchi Pharmaceutical Co. Ltd.
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