Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-11
2003-11-04
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S113000
Reexamination Certificate
active
06642250
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel 1,8-naphthyridin-2(1H)-one derivatives that selectively inhibit phosphodiesterase (hereinafter, referred to as “PDE”) IV, or pharmaceutically acceptable salts thereof, and to pharmaceutical compositions comprising the same. The present invention also relates to prophylactic and/or therapeutic drugs (including antiasthmatics) for diseases associated with PDE IV actions, which comprise each an effective amount of at least one member selected from the 1,8-naphthyridin-2(1H)-one derivatives and salts thereof.
BACKGROUND OF THE INVENTION
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. Such selective inhibitors of PDE IV would be expected to become excellent anti-asthmatic agents.
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 TV. 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-actions such as an emetic action.
Under these circumstances, in order to find out pharmaceutical drugs having an excellent anti-asthmatic efficacy via minimizing undesirable side-actions in tissues and organs other than bronchial smooth muscles and inflammatory cells, inhibitors with improved selectivity for PDE IV have been screened and examined.
For instance, with an aim at such inhibitors, various compounds including diazepinoindoles (JP, A, 10-507447 (1998)), tri-substituted phenyl derivatives (JP, A, 10-504530 (1998), JP, A, 10-503174 (1998), JP, A, 10-503173 (1998), etc.), naphthalene derivatives (JP, A, 10-226647 (1998)), etc., have been proposed.
Besides these, for the purpose of developing not only anti-asthmatics but also pharmaceutical drugs for preventing and treating a wide range for diseases, PDE IV-inhibitory compounds having a naphthyridine ring have been proposed in WO 94/12499, A1; JP, A, 7-10875 (1995); WO 96/6843, A1; JP, A, 11-106385 (1999); etc.
Further, JP, A, 63-159382 (1988) discloses 1-substituted naphthyridine derivatives having, on the position 3, a substituent selected from alkyl, cycloalkyl, phenyl, phenylalkyl, etc., which are deemed useful in the treatment of allergy, inflammation, and the like, though no mention is made of PDE IV-inhibiting actions.
Such compound groups are, however, unsatisfactory in view of solving the aforementioned problems. There is still a demand for anti-asthmatics which exert more selective PDE IV-inhibiting actions and have advantageous properties from aspects regarding efficacy and safety.
For instance, over the past decade, many pharmaceutical companies have focused on the inhibition of PDE IV for the treatment of asthma. The biology of the PDE IV isozyme and the structure-activity relationship of already-reported 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)).
SUMMARY OF THE INVENTION
The present inventors have conducted an extensive research on various compounds in order to solve the above problems. As a result, the present inventors have succeeded in producing novel 1,8-naphthyridin-2(1H)-one derivatives which exert selective inhibition against PDE IV. Further, the present inventors have found that the compounds of the present invention are not only unexpectedly advantageous over the conventional PDE IV inhibitors but also qualified as potent inhibitors of PDE IV from aspects of pharmacological action and safety, and succeeded in accomplishing this invention.
The present invention, as described hereinbelow, encompasses 1,8-naphthyridin-2(1H)-one derivative compounds having a heteroaryl group, or a fused benzene ring in which any of the heteroaryl groups is fused to a benzene ring, via 1 to 8 methylene chains on the 3 position of the 1,8-naphthyridin-2(1H)-one nucleus and pharmaceutical compositions comprising an effective amount of the said compound. Since the compounds of the invention are naphthyridine derivatives having a heteroaryl group, or a fused benzene ring in which any of the heteroaryl groups is fused to a benzene ring, via 1 to 8 methylene chains on the 3 position of the 1,8-naphthyridine nucleus, it is apparent that the inventive compounds are structurally different from 1-substituted naphthyridine derivatives disclosed in JP, A, 63-159382 (1988). As described hereinbelow, the compounds of the invention are also distinct from the compounds disclosed in JP, A, 63-159382 (1988) because their PDE IV-inhibiting activity is significantly superior to that of the prior art compounds.
The present invention provides the following:
1) A compound of the formula (1):
wherein:
A is an unsubstituted or optionally substituted 5 or 6 membered heteroaryl group or a fused benzene ring in which any of the above-defined heteroaryl groups is fused to a benzene ring,
B is carbon or nitrogen,
R
1
is hydrogen, lower alkyl, trifluoromethyl, hydroxyl, lower alkoxy, a residue derived from a carboxylic acid or a derivative thereof, amino, or an amino nitrogen-containing group,
R
2
is hydrogen, halogen, cyano, nitro, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, trifluoromethyl, hydroxyl, lower alkoxy, a residue derived from a carboxylic acid or a derivative thereof, amino, or an amino nitrogen-containing group, and
m is an integer of from 1 to 8, both inclusive; or a pharmaceutically acceptable salt thereof.
2) The compound according to the above 1), wherein A is a 5 or 6 membered heteroaryl group and B is carbon; or a pharmaceutically acceptable salt thereof.
3) The compound according to the above 2), wherein A is pyridyl, 1-oxypyridyl, thienyl, furyl, or thiazolyl; or a pharmaceutically acceptable salt thereof.
4) The compound according to the above 2), wherein A is pyridyl or 1-oxypyridyl, and m is from 1 to 5, both inclusive; or a pharmaceutically acceptable salt thereof.
5) The compound according to the above 1), wherein A is a 5 or 6 membered heteroaryl group, and B is nitrogen; or a pharmaceutically acceptable salt thereof.
6) The compound according to the above 5), wherein A is pyridyl, 1-oxypyridyl, thienyl, furyl, or thiazolyl; or a pharmaceutically acceptable salt thereof.
7) The compound according to the above 1), wherein A is a fused benzene ring in which any of the above-defined 5 or 6 membered heteroaryl groups is fus
Aotsuka Tomoji
Ishitani Kouki
Kumazawa Kentarou
Wagatsuma Nagatoshi
Grelan Pharmaceutical Co. Ltd.
Robinson Binta
Wenderoth , Lind & Ponack, L.L.P.
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