Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-19
2003-04-01
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S256000, C514S275000, C514S300000, C544S331000, C544S405000, C546S300000
Reexamination Certificate
active
06541480
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a 1-aryl-1,8-naphthylidin-4-one derivative as a selective type IV phosphodiesterase (i.e., “PDE”) inhibitor and a salt, and solvate thereof and a pharmaceutical composition and a type IV phosphodiesterase inhibitor containing the same as an effective component as well as an agent of preventing or treating for cytokine related diseases.
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 this enzyme, 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 PDE IV inhibiting action and a naphthylidinone 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, WO-A-94-12499, WO-A-96-06843, etc.
Further, as a compound having a PDE IV inhibiting action and carbonyl group at the 4-position in a 1,8-naphthylidine 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 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, atbpic 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 is provided a 1-aryl-1,8-naphthylidin-4-one derivative having the formula (I):
wherein R
1
indicates a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl 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 the group NR
5
R
6
or 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 salt or solvate thereof.
In accordance with the present invention, there is also provided a 1-aryl-1,8-naphthylidin-4-one derivative having the formula (I′):
wherein R
1
indicates a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group,
R
2′
, R
3′
, and R
4′
independently indicate a hydrogen atom, or a substituted or unsubstituted lower alkyl group,
X′ indicates the group NR
5
R
6
,
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.
In accordance with the present invention, there is also provided a pharmaceutical composition and a type IV phosphodiesterase inhibitor as well as an agent of preventing or treating for cytokine related diseases, containing a 1-aryl-1,8-naphthylidin-4-one derivative as set forth in the above formula (I) or (I′) or its pharmaceutically acceptable salt or solvate as the effective ingredient.
Further, according to the present invention, it is possible to provide a synthesis intermediate useful for the production of a 1-aryl-1,8-naphthylidin-4-one derivative as set forth in the above general formula (I) or (I′).
BEST MODE FOR CARRYING OUT THE 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-naphthylidine skeleton and an aryl group or heteroaryl group as the 1-position substituent group has a superior type IV phosphodiesterase inhibiting action, whereby the present invention was completed.
The preferable examples of the aryl group of the substituted or unsubstituted aryl group indicated by R in the formula (I) and (I′) according to the present invention are C
6
to C
14
aryl group, for example, a phenyl group, naphthyl group, indenyl group, anthryl group, etc. More preferable example is a phenyl group. Preferable examples of the substituents for the aryl group are a hydroxyl group, a lower alkyl group, a halogen atom such as a fluorine, chlorine, bromine or iodine atom, an oxygen atom, a sulfur atom, an alkoxy group, a cyano group, a nitro group, an amino group, an alkylamino group, an amide group, an acyl group, an acyloxy group, a carboxyl group, a lower alkoxycarbonyl group, an aralkyloxycarbonyl group, a carbamoyl group, a thiol group, an alkylthio group, a sulfonyl group, etc.
In the specification, “lower”, unless otherwise alluded to, means 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms.
Preferable examples of the heteroaryl group of the substituted or unsubstituted heteroaryl group indicated by R
1
in the formula (I) or (I′) of the present invention are a monocyclic or polycyclic heteroaryl group having a 5- to 7-member ring including 2 to 8 carbon atoms and 1 to 4 hetero atoms of an oxygen atom, a nitrogen atom, or a sulfur atom, for example, a pyrrole group, a furyl group a thienyl group, an imidazolyl group, a thiazolyl group, a pyridyl group, a pyrazinyl group, an indolyl group, a quinolyl group, an isoquinolyl group, etc. may be mentioned. The more preferable example is a pyridyl group. Examples of the preferable substituent groups of the heteroaryl group are ahydroxyl group, a lower alkyl group, a halogen atom such as a fluorine, chlorine, bromine or iodine atom, an oxygen atom, a sulfur atom, an alkoxy group, a cyano group, a nitro group, an amino group, are alkylamino group, an amide group, an acyl group, an acyloxy group, a carboxyl group, a lower alkoxycarbo
Hayashi Yasuhiro
Inoue Hidekazu
Shimamoto Tetsuo
Burns Doane , Swecker, Mathis LLP
Huang Evelyn Mei
Suntory Limited
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