PDEs are enzymes which hydrolyze intracellular cyclic AMP (cAMP) and intracellular cyclic GMP (cGMP) and widely distributed in vivo in various tissues and organs. Up to now, it has been known that PDEs are classified into 7 isoenzyme families, i.e., type I to VII PDEs (PDE I to VII), according to their properties. Among them, PDE IV is known to be an enzyme which is predominantly present in airway smooth muscle cells and a wide variety of inflammatory cells, i.e., neutrophils, eosinophils, lymphocytes, etc. and selectively breaks down cAMP.
In addition, it has been known that an elevation of cAMP levels in airway smooth muscle cells leads to relaxation of the airway smooth muscles. An increase of cAMP levels in inflammatory cells has also been known to suppress an activation of inflammatory cells, including, for example, a release of cytotoxic proteins from eosinophils, etc.
Therefore, if PDE IV predominantly located in airway smooth muscle cells and inflammatory cells is inhibited by inhibitors selective for said isozyme form, an elevation of cAMP levels would be induced in such cells. As a result, it would be expected to elicit bronchodilator actions via relaxing airway smooth muscles and anti-inflammatory actions through suppressing inflammatory cell activation. As seen, for example, in Barnette, PROGRESS IN DRUG RESEARCH, USA, Vol. 53, pp. 193-229 (1999) (non-patent document No. 1), such selective inhibitors of PDE IV would be expected to become excellent anti-asthmatic agents and therapeutic agents for chronic obstructive pulmonary disease (COPD).
Up to now, it has been known that theophylline which is a xanthine derivative, rolipram, which is a catechol derivative, etc., are inhibitors of PDE IV. Theophylline inhibits PDE in various tissues due to its non-selectivity for individual isozymes, thereby exerting not only a bronchodilator activity to be targeted but also extra actions on heart, CNS, etc. Although rolipram is observed to be selective for PDE IV, it is easily transferred into the CNS due to its property of being absorbed. Therefore, rolipram has a drawback that it induces adverse central side-effects such as an emetic action.
Over the past decade, many pharmaceutical companies have focused on the inhibition of PDE IV for the treatment of asthma. The biological studies on the PDE IV isozyme and the structure-activity relationship of said inhibitors have recently been reviewed in the literature. In such processes, it has been pointed out that in general the therapeutic utility of selective PDE IV inhibitors, such as the prototypical agent rolipram, have been hampered by nausea and emesis limiting their therapeutic potential (J. Med. Chem., 41: 2268 to 2277 (1998): non-patent document No. 2).
It recently becomes known that PDE IV inhibitors produce inhibition of drug-metabolizing enzymes such as CYP2D6 and CYP3A4, thereby raising a variety of adverse side-actions. Therefore, there is still a desire to develop a PDE IV inhibitor free of affecting the drug-metabolizing enzymes.
Under these circumstances, in order to find out pharmaceutical drugs having an excellent anti-asthmatic efficacy and/or a prophylactic or therapeutic efficacy on COPD via minimizing undesirable side-effects in tissues and organs other than bronchial smooth muscles and inflammatory cells, various PDE IV inhibitors have been screened and examined.
For instance, with an aim at such inhibitors with improved selectivity for PDE IV, various compounds have been proposed including naphthalene derivatives (e.g., Patent document No. 1: JP, A, 10-226647 (1998)), catechol diethers derivatives (e.g., Patent document No. 2: JP, A, 2001-527508), 2,3-di-substituted pyridine derivatives (e.g., Patent document No. 3: JP, A, 2001-354655), etc. Further, for the purpose of developing not only anti-asthmatic agents but also pharmaceutical agents for preventing and treating a wide range for diseases, PDE IV-inhibitory compounds having a naphthyridine ring have been proposed (for example, Patent document No. 4: JP, A, 7-10875 (1995); Patent document No. 5: WO, A, 96/06843; Patent document No. 6: JP, A, 11-106385 (1999); Patent document No. 7: JP, A, 2002-138089; Patent document No. 8: WO, A, 99/02527; Patent document No. 9; WO, A, 99/38867; Patent document No. 10; WO, A, 01/42244; etc.).
Whereas, in connection with compounds where a heterocyclic ring is condensed to a naphthyridine ring are disclosed compounds having anti-inflammatory, immunoregulatory, analgesic, and antipyretic actions (for example, Patent document No. 11: JP, A, 5-132484 (1993), Patent document No. 12: JP, A, 6-100561 (1994)) and compounds having anti-inflammatory, immunoregulatory, bronchodilator, and hair-growing actions (for example, Patent document No. 13: JP, A, 5-194515 (1993), Patent document No. 14: JP, B2, 3016905); however, no inhibitory action on PDE IV is indicated in these prior art compounds.    [Patent document No. 1] JP, A, 10-226647 (1998)    [Patent document No. 2] JP, A, 2001-527508    [Patent document No. 3] JP, A, 2001-354655    [Patent document No. 4] JP, A, 7-10875 (1995)    [Patent document No. 5] WO, A, 96/06843    [Patent document No. 6] JP, A, 11-106385 (1999)    [Patent document No. 7] JP, A, 2002-138089    [Patent document No. 8] WO, A, 99/02527    [Patent document No. 9] WO, A, 99/38867    [Patent document No. 10] WO, A, 01/42244    [Patent document No. 11] JP, A, 5-132484 (1993)    [Patent document No. 12] JP, A, 6-100561 (1994)    [Patent document No. 13] JP, A, 5-194515 (1993)    [Patent document No. 14] JP, B2, 3016905    [Non-patent document No. 1] PROGRESS IN DRUG RESEARCH, (USA), 53, pp. 193-229 (1999)    [Non-patent document No. 2] JOURNAL OF MEDICINAL CHEMISTRY, (USA), 41, pp. 2268-2277 (1999)
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