Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-09-29
2001-12-18
Dentz, Bernard (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S123000
Reexamination Certificate
active
06331548
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a 1-cycloalkyl-1,8-naphthyridin-4-one derivative having a selective type IV phosphodiesterase inhibiting action and a salt, and solvate thereof as well as a type IV phosphodiesterase inhibitor and a pharmaceutical composition for preventing or treating of cytokine related diseases containing the same as an effective component.
BACKGROUND ART
The intracellular second messenger cAMP or cGMP is broken down and deactivated by phosphodiesterase (PDE), which is classified into at least types I to VII. PDE is widely distributed in the tissue and organs of the body. Among these, type IV phosphodiesterase selectively breaks down cAMP and is found in the central tissue and in the heart, lungs, kidneys, and other organs and in the various hemocyte components etc. Further, it is known to be involved in the derivation of IL-1 and IL-6, TNF-&agr;, and other various cytokines.
Catechol type derivatives such as rolipram, known to be a selective inhibitor of type IV phosphodiesterase, quinazoline type derivatives such as nitraquazone, xanthine type derivatives such as theophylline and denbufylline, etc. are being used or developed as antidepressants, antiasthmatics, antiinflamatorics, etc. No drug has however yet been developed which solves the problems such as the selectivity with other isoenzymes and various side effects. There is no satisfactory medicine which has this enzyme inhibiting action as the main mechanism for achieving the medicinal effect.
On the other hand, as a compound having a naphthyridinone skeleton, for example, as a compound having a carbonyl group at the 2-position in the 1,8-naphthylidine skeleton, there are known those described in JP-A-55-164682, and as a compound having a carbonyl group at the 2-position and a PDE IV inhibiting action, there are known those described in WO-A-94-12499, WO-A-96-06843, etc.
Further, as a compound having a PDE IV inhibiting action and a carbonyl group at the 4-position in a 1,8-naphthyridine skeleton, WO-A-97-04775 describes one where the 1-position substituent group is an ethyl group. Further, as the method of synthesis described in this publication, the method shown in the following formula was used, based on the method of Kaminsky et al. (J. Med. Chem. 1968, 11, 160). However, the 1-position substituent group disclosed in this method is only an alkyl group.
In the above reaction process, it is only possible to use a substitution reaction using a highly reactive alkyl halide (A—CH
2
—Y), and therefore, the substituent groups which can be introduced to the 1-position are limited.
DISCLOSURE OF INVENTION
The inventors engaged in intensive research to develop a compound having a superior type IV phosphodiesterase inhibiting action and a process for producing the same and, as a result, found that a compound having the formula (I) or (I′) with a carbonyl group at the 4-position in the 1,8-naphthyridine skeleton and a cycloalkyl group or a heterocycloalkyl group as the 1-position substituent group has a superior type IV phosphodiesterase inhibiting action, whereby the present invention was completed.
The objects of the present invention are to provide a compound or a salt or solvate thereof, useful as a medicine for the prevention or treatment of bronchial asthma, chronic bronchitis, and other respiratory diseases, diseases relating to abnormality of nervous system such as impaired learning, memory, and recognition relating to Alzheimer's disease, Parkinson's disease, and the like, diseases relating to mental abnormality such as maniac depression and schizophrenia, atopic dermitis, conjunctivitis, acquired immunity disorder syndrome and other inflammatory diseases, osteoarthritis, rheumatoid arthritis, and other general or local joint diseases, rheumatoid arthritis, sepsis, Crohn disease and other diseases which are related to various cytokines such as tumor necrosis factor (TNF-&agr;), and the like by selectively inhibiting the type IV phosphodiesterase and further inhibiting the production of TNF-&agr;.
In accordance with the present invention, there are provided a pharmaceutical composition as well as a type IV phosphodiesterase inhibitor and an agent for prevention or treatment of cytokine related diseases comprising, as an effective component, a 1-cycloalkyl-1,8-naphthylidin-4-one derivative having the formula (I):
wherein R
1
indicates a substituted or unsubstituted cycloalkyl group or a substituted or unsubstituted heterocycloalkyl group,
R
2
, R
3
, and R
4
independently indicate a hydrogen atom, a substituted or unsubstituted lower alkyl group, or a halogen atom,
X indicates a group NR
5
R
6
or a group OR
7
, wherein R
5
and R
6
independently indicate a hydrogen atom, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, and R
7
indicates a hydrogen atom, a substituted or unsubstituted lower alkyl group, or a substituted or unsubstituted cycloalkyl group or a pharmaceutically acceptable salt or solvate thereof.
In accordance with the present invention, there is also provided a 1-cycloalkyl-1,8-naphthyridin-4-one derivative having the formula (I′):
wherein R
1
indicates a substituted or unsubstituted cycloalkyl group or a substituted or unsubstituted heterocycloalkyl group,
R
2′
, R
3′
, and R
4′
independently indicate a hydrogen atom, or a substituted or unsubstituted lower alkyl group,
X′ indicates a group NR
5
R
6
, wherein R
5
and R
6
independently indicate a hydrogen atom, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group or a salt or solvate thereof, which is useful as a type IV phosphodiesterase inhibitor.
BEST MODE FOR CARRYING OUT THE INVENTION
The preferable examples of the cycloalkyl group of the substituted or unsubstituted cycloalkyl group indicated by R
1
in the formulae (I) and (I′) according to the present invention are a cycloalkyl group having 3 to 8 carbon atoms such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, etc. More preferable examples are a cyclopropyl group, a cyclopentyl group, a cyclohexyl group. The cycloalkyl group may be substituted with one or more substituents. The Examples of such substituents are a C
1
-C
6
linear, branched or cyclic lower alkyl group such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an isobutyl group, a t-butyl group, a cyclohexyl group, etc.; an aralkyl group such as a benzyl group, a phenethyl group, etc.; an aryl group such as a phenyl group, a methoxyphenyl group, a pyridyl group, etc.; a heterocyclic group such as a morpholinyl group, a piperazinyl group, etc.; a halogen atom such as fluorine, chlorine, bromine, iodine, etc.; an oxygen atom; a sulfur atom; a hydroxyl group; a C
1
-C
6
linear or branched lower alkoxy group such as a methoxy group, an ethoxy group, an n-propoxy group, an isobutyloxy group, a t-butyloxy group, etc.; a cyano group; a nitro group; an amino group; a C
1
-C
6
linear or branched lower alkylamino group such as a methylamino group, an ethylamino group, an n-propylamino group, an isopropylamino group, an isobutylamino group, a t-butylamino group; an acylamide group such as a formamide group, an acetamide group, a benzamide group, etc.; an acylthioamide group such as a formthioamide group, an acetothioamide group, a benzthioamide group, etc.; a lower alkoxycarbonyl amino group such as a methoxycarbonyl amino group, a t-butoxycarbonyl amino group, etc.; an aralkyloxycarbonyl amino group such as benzyloxycarbonyl amino group, a phenetyloxycarbonyl amino group, etc.; a lower alkylaminocarbonyl amino group such as a methylaminocarbonyl amino group, a dimethylaminocarbonyl amino group, etc.; a lower alkylaminothiocarbonyl amino group such as a thiocarbamoyl amino group, a methy
Hayashi Yasuhiro
Inoue Hidekazu
Shimamoto Tetsuo
Burns Doane Swecker & Mathis L.L.P.
Dentz Bernard
Suntory Limited
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