Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-12-01
2001-04-10
Qazi, Sabiha N. (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S144000, C546S014000, C546S152000, C546S156000, C546S304000, C546S141000, C546S139000, C544S106000, C544S111000, C544S358000, C544S194000, C544S359000, C544S360000, C544S361000, C544S363000, C544S180000, C544S001000, C514S352000, C514S231500, C514S311000, C514S333000, C514S334000
Reexamination Certificate
active
06214996
ABSTRACT:
TECHNICAL FIELD
This invention relates to novel naphthalene derivatives having antiasthmatic activity and intermediates for the preparation of said compounds.
PRIOR ART
There is known 1-(5-methyl-2(1H)-pyridon-3-yl)naphthalene [cf. Bulletin of The Chemical Society of Japan, Vol. 41, pp. 165-167 (1968)], but any pharmacological activity or any utility of this compound has never been known. There are also known certain naphthalene derivatives such as 1-[N-(2-methoxyethyl)-2(1H)-pyridon-4-yl]-2,3-bis(hydroxymethyl)-6,7-diethoxynaphthalene having antiasthmatic activity [cf. European Patent Publication EP-557016-A1 (=U.S. Pat. No. 5,342,941)]. However, EP-557016-A1 does not disclose 1-pyridylnaphthalene derivatives in which the pyridyl group on 1-position of the naphthalene ring is substituted by a substituted or unsubstituted amino group.
It is known that intracellular second messengers such as cAMP and cGMP are decomposed and inactivated by phosphodiesterase (abbreviated as “PDE”). Currently, at least 7 different PDE isozyme gene families are recognized and these PDEs are widely distributed in many cell types and tissues. A PDE inhibitor increases the concentration of cAMP and cGMP in tissue cells and exhibits various pharmacological activities, for example, relaxation of vascular smooth muscle and airway smooth muscle, and induction of positive inotropic action and chronotropic action in the heart. Moreover, the PDE inhibitor can control the central function owing to increase of cAMP in the central system, that is, it can exhibit an antidepressant activity and improves memory and learning functions. In addition, it shows inhibition of platelet aggregation and inhibition of activation of inflammatory cells, and further shows lipocatabolic action in fatty cells [cf. C. D. Nicholson et al., Trends in Pharmacol., Vol. 12, p. 19 (1991)].
Accordingly, the PDE inhibitory agent is useful for the treatment of various diseases, such as bronchial asthma, thrombosis, depression, central hypofunction after cerebrovascular obstruction, cerebrovascular dementia, Alzheimer's type dementia, various inflammations, obesity, heart failure, and the like.
On the other hand, various antiasthmatic agents have been known, but those known agents have some defects such as insufficiency in effects for inhibiting bronchoconstriction and further insufficient removal of side effects on the heart, and hence, it has been demanded to develop a new type of antiasthmatic agent.
Theophylline is known as one of the representative PDE inhibitory agents and has hitherto been used for the treatment of asthma. However, since the PDE inhibitory activity of this agent is non-specific, it shows cardiotonic and central activities in addition to the bronchial smooth muscle relaxation. Thus, careful attention has to be paid to this agent in view of such side effects. Accordingly, it has been desired to develop a new medicament which can selectively inhibit phosphodiesterase IV (PDE IV) which largely exists much more in bronchial smooth muscle and inflammatory cells.
BRIEF DESCRIPTION OF THE INVENTION
An object of the invention is to provide novel naphthalene derivatives which have excellent bronchoconstriction inhibitory activity and/or selective PDE IV inhibitory activity and hence are useful as an antiasthmatic agent. Another object of the invention is to provide a process for the preparation of the novel naphthalene derivatives. A further object of the invention is to provide intermediates for the preparation of the above naphthalene derivatives.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel naphthalene derivatives of the formula [I]:
wherein R
1
and R
2
are the same or different and are each a hydrogen atom or a protected or unprotected hydroxy group; either one of R
3
and R
4
is a protected or unprotected hydroxy-substituted methyl group, and another is a hydrogen atom, a lower alkyl group, or a protected or unprotected hydroxy-substituted methyl group; R
5
and R
6
are the same or different and are each a hydrogen atom, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted phenyl group, or a protected or unprotected amino group, or both bond at their termini and combine with the adjacent nitrogen atom to form a substituted or unsubstituted heterocyclic group, and a pharmaceutically acceptable salt thereof.
The compounds [I] of this invention and salts thereof have potent bronchoconstriction inhibitory activity and are useful for the prophylaxis and treatment of asthma. The desired compounds [I] of this invention are characteristic in the excellent bronchoconstriction inhibitory activity with less side effects on the heart, for example, the compounds show more potent inhibitory activity to the bronchoconstriction induced by an antigen in comparison with theophylline.
The heterocyclic group formed by combining R
5
and R
6
together with the adjacent nitrogen atom includes monocyclic, bicyclic and tricyclic heterocyclic groups which may contain one or more additional heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to said adjacent nitrogen atom.
Suitable examples of the heterocyclic groups are pyridyl, quinolyl, isoquinolyl, cyclopenta[b]pyridyl, pyrro[2,3-b]pyridyl, imidazo[4,5-b]pyridyl, pyrido[2,3-d]thiazolyl, pyrido[2,3-d]oxazolyl, naphthyridinyl, quinoxalinyl, phtharazinyl, quinazolinyl, indolyl, pyridazinyl, azepinyl, azetidyl, isoindolyl, pyrrolyl, benzazepinyl, phenanthridinyl, benzothiadinyl, benzimidazolinyl, pyradinyl, morpholino, and the like. These heterocyclic groups may be partially or wholly hydrogenated.
The substituents for the lower alkyl group and phenyl group for R
5
and/or R
6
in the desired compounds [I] include a hydroxy group, mono- or di-hydroxy-lower alkyl group, and the like.
The protecting group of an amino group includes any conventional protecting groups for an amino group, for example, a lower alkanoyl group, and a phenyl-lower alkoxycarbonyl group.
In the desired compound [I] of this invention, wherein R
1
and/or R
2
is a protected hydroxy group, the protecting group for the hydroxy group may be any conventional pharmaceutically acceptable protecting group. For example, the protecting group in R
1
and/or R
2
is a substituted or unsubstituted lower alkanoyl group, a substituted or unsubstituted lower alkyl group and a substituted or unsubstituted cycloalkyl group. Preferred protecting group in R
1
and/or R
2
is an alkyl group, particularly a lower alkyl group.
In the desired compounds [I] of this invention, where R
3
and/or R
4
is a protected hydroxy group, the protecting group for the hydroxy group may be any conventional pharmaceutically acceptable protecting group. The protecting group are the groups which are hydrolyzed within the biobody and do not give any harmful by-product, for example, a substituted or unsubstituted lower alkanoyl group, a substituted or unsubstituted lower alkyl, lower alkoxycarbonyl or cycloalkyl group.
The substituted or unsubstituted lower alkanoyl group denotes lower alkanoyl groups which may optionally be substituted by 1 to 2 substituents selected from a protected or unprotected amino group, a carboxyl group, a lower alkoxycarbonyl group, a hydroxy group and a lower alkoxy group, and the substituted or unsubstituted alkyl group denotes alkyl groups which may optionally be substituted by a member selected from a lower alkoxycarbonyl group, a lower alkoxy group, an aryl group, and a lower alkyl-substituted piperazinylcarbonyl croup. The aryl group includes a phenyl croup, a lower alkoxy-substituted phenyl group, a naphthyl group.
The protecting group for the above protected amino group to be substituted onto the lower alkanoyl group may be any conventional protecting group for an amino group, for example, acyl groups such as a lower alkanoyl group (e.g. acetyl, propionyl), a lower alkoxycar
Ikezawa Katsuo
Ukita Tatsuzo
Yamagata Shinsuke
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Qazi Sabiha N.
Tanabe Seiyaku Co. Ltd.
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