JP3237109B2 - Pharmaceutical composition - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a pharmaceutical composition useful as a phosphodiesterase IV inhibitor and / or a prophylactic / therapeutic agent for asthma.

[0002]

2. Description of the Related Art Naphthalene derivatives having a nitrogen-containing 6-membered heterocyclic group at the 1-position include 1- (5-methyl-2 (1
H) -Pyridone-3-yl) naphthalenes are known, but are known from the Bulletin of the Chemical Society of Japan (BULLETINOF THE CHEM).
ICAL SOCIETY OF JAPAN), Vo
l. 41, 165-167 (1968)], and this compound has no known uses including pharmacological activity. Also, Japanese Patent Application Laid-Open No. H5-222987 discloses 1- [N-
(2-methoxyethyl) -2 (1H) -pyridone-4-
Yl] -2,3-bis (hydroxymethyl) -6,7-
It is described that compounds such as diethoxynaphthalene have an anti-asthmatic effect.However, compounds in which the pyridine ring on the 1-position substituent of the naphthalene skeleton, such as the target compound of the present application, is unsubstituted or substituted with a substituted amino group are described. Not listed.

On the other hand, intracellular second messengers cAMP and cGMP are phosphodiesterase (PD).
Decomposed and inactivated by E). It is known that PDE is widely distributed in tissues in a living body, and PDE inhibitors increase the concentration of cAMP and cGMP in cells by inhibiting the PDE, and have various pharmacological actions.

[0004] For example, it causes a relaxing action in vascular smooth muscle and bronchial smooth muscle, and a positive inotropic and chronotropic action in the heart. In the central region, it also regulates central functions associated with an increase in cAMP, that is, improves antidepressant effects, memory and learning functions. In addition, platelets have an inhibitory effect on aggregation, inflammatory cells have an inhibitory effect on activation, and adipocytes have a lipolytic effect [Trends in Pharmacology Sciences [Trends in Pharmaceuticals].
theoretical Sciences], Volume 12, 1
9-27, 1991].

[0005] Therefore, PDE-inhibiting agents are useful for various diseases such as bronchial asthma, thrombosis, depression, central dysfunction after cerebral vascular obstruction, cerebrovascular dementia, Alzheimer's dementia, various inflammations and obesity. And is considered to be effective as a therapeutic agent for heart failure and the like.

On the other hand, a large number of anti-asthmatic drugs have been known, but existing drugs do not have a sufficient effect of suppressing bronchoconstriction, have insufficient separation from side effects on the heart or the like, or have a sufficient effect of suppressing bronchoconstriction. Even so, there is a problem that the anti-airway inflammatory action is weak, and further development of a new drug is required.

[0007] Theophylline has been conventionally used as a representative PDE inhibitor for the treatment of asthma. However, since the PDE inhibitory action of this drug is non-specific, it has a cardiotonic action and a central action in addition to a bronchial smooth muscle relaxing action, and thus side effects are always a problem. Therefore, among the PDE isozymes, there is a demand for the development of a drug which specifically has an inhibitory action on type IV which is particularly present in bronchial smooth muscle and inflammatory cells.

[0008]

DISCLOSURE OF THE INVENTION The present invention relates to a novel naphthalene derivative which has a selective phosphodiesterase IV (PDE IV) inhibitory action, an excellent bronchoconstriction inhibitory action and / or an anti-airway inflammatory action, and is useful as an anti-asthmatic drug Is provided as a pharmaceutical composition.

[0009]

The present invention provides a compound of the general formula [I]

[0010]

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[0011] (wherein, R ¹ and R ² represents a hydroxyl group which may be hydrogen atom or a protective same or different, R ³
And R ⁴ represents that one of them is a hydroxyl-substituted methyl group which may be protected, and the other is a hydrogen atom, a lower alkyl group or a hydroxyl-substituted methyl group which may be protected, and R ⁵ and R 4 ⁶ is the same or different and represents a hydrogen atom, a lower alkyl group which may be substituted, a phenyl group which may be substituted, or an amino group which may be protected, or may be adjacent to each other by bonding at the terminals It represents that a heterocyclic group which may be substituted together with a nitrogen atom is formed. )) And a pharmacologically acceptable salt thereof as an active ingredient.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION In the naphthalene derivative [I], which is an active ingredient of the present invention, the heterocyclic group formed by bonding R ⁵ and R ^{6 at the} terminal to an adjacent nitrogen atom includes the nitrogen atom In addition, a monocyclic, bicyclic or tricyclic heterocyclic group which may further contain a hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom is exemplified.

Examples of such heterocyclic groups include pyridyl, quinolyl, isoquinolyl, cyclopenta [b]
Pyridyl group, pyro [2,3-b] pyridyl group, imidazo [4,5-b] pyridyl group, pyrido [2,3-d] thiazolyl group, pyrido [2,3-d] oxazolyl group, naphthyridinyl group, Quinoxalinyl group, phthalazinyl group, quinazolinyl group, indolyl group, pyridazinyl group, azepinyl group, azetidyl group, isoindolyl group, pyrrolyl group, benzazepinyl group, phenanthridinyl group, benzothiazinyl group, benzimidazolinyl group, pyrazinyl group, morpholino And the heterocyclic groups may be partially or fully hydrogenated.

The lower alkyl group of R ⁵ and / or R ⁶ in the naphthalene derivative [I] which is the active ingredient of the present invention and the substitutable group on the phenyl group include a hydroxyl group and a mono- or dihydroxy lower alkyl group. Can be

The protecting group for the amino group may be any one which can be a protecting group for the amino group, and examples thereof include a lower alkanoylamino group and a phenyl-lower alkoxycarbonyl group.

In the naphthalene derivative [I], which is an active ingredient of the present invention, when R ¹ and / or R ² is a protected hydroxyl group, the protecting group for the hydroxyl group may be a pharmacologically acceptable protecting group for the hydroxyl group. Any group can be used as long as it is a group. Examples thereof include a lower alkanoyl group which may have a substituent, an alkyl group which may have a substituent, and a cycloalkyl group which may have a substituent. Preferably, an alkyl group, especially a lower alkyl group is used.

In the naphthalene derivative [I] which is an active ingredient of the present invention, when R ³ and / or R ⁴ is a protected hydroxyl-substituted methyl group, a pharmacologically acceptable protecting group for the hydroxyl group may be used. Any protecting group for the hydroxyl group may be used. Specific examples of such a protecting group include those which are decomposed by hydrolysis in a living body and do not produce harmful by-products, such as a lower alkanoyl group which may have a substituent and a substituent. And an optionally substituted alkyl group, a lower alkoxycarbonyl group optionally having a substituent, a cycloalkyl group optionally having a substituent, and the like.

Here, the lower alkanoyl group which may have a substituent may be, for example, one or two lower alkanoyl groups selected from an amino group, a carboxyl group, a lower alkoxycarbonyl group, a hydroxyl group and a lower alkoxy group which may be protected. Lower alkanoyl group which may be substituted with a group of
Examples of the alkyl group which may have a substituent include an alkyl group which may be substituted with a group selected from a lower alkoxycarbonyl group, a lower alkoxy group, an aryl group and a lower alkyl group-substituted piperazinylcarbonyl group. Can be Here, examples of the aryl group include a phenyl group, a lower alkoxyphenyl group, and a naphthyl group.

Further, the protecting group in the protected amino group which can be substituted for the lower alkanoyl group may be any protecting group for the amino group, for example, a lower alkanoyl group such as an acetyl group or a propionyl group, or a lower alkanoyl group. An acyl group such as an alkoxycarbonyl group or a phenyl lower alkoxycarbonyl group such as benzyloxycarbonyl is exemplified.

On the other hand, the heterocyclic group may have a substituent. Examples of the substituent include (1) a lower alkenyl group; (2) a lower alkynyl group; and (3) a lower alkylthio group. (4) cycloalkyl group; (5) trifluoromethyl group; (6) cyano group; (7) tetrazolyl group; (8) formyl group; (9) amino group; (10) morpholino group and monocycloalkyl group. (11) a pyridyl group; (12) a morpholino group, a mono- or di-lower alkylamino group in which the lower alkyl group may be substituted by a substituted amino group, a pyridyl group, an imidazolyl group, a piperidyl group or a pyrrolidinyl group. 13) lower alkyl group-substituted triazolyl group; (14) bis (hydroxy lower alkyl) aminocarbonyl group; (15) bis (tri lower alkyl silyl group) Oxy-lower alkyl) aminocarbonyl group; (16) a morpholinocarbonyl group; (17) a lower alkyl group substituted piperazinylcarbonyl group; (18)
(19) tri-lower alkylsilyloxy lower alkyl-substituted piperazinylcarbonyl group; (20) lower alkoxycarbonyl group; (21) carboxyl group; (2
(2) a lower alkyl group optionally substituted with a morpholino group or a pyridyl group; (23) a lower alkoxy group optionally substituted with a piperidyl group, a pyridyl group, a hydroxyl group or a lower alkoxy group; (24) an oxo group; (26) a pyrimidinyl group; (27) a phenyl group optionally substituted with a di-lower alkylamino group or a halogen atom; (28) a halogen atom; (29) a nitro group; (30) an imidazolyl group; (31) A lower alkylenedioxy group is exemplified. These substituents may be the same or different and may be substituted on two or more heterocyclic groups.

Among the substituted heterocyclic groups, a heterocyclic group substituted with at least an oxo group, a hydroxyl group or an amino group, particularly a heterocyclic group substituted with at least an oxo group, is preferable from the viewpoint of efficacy. The heterocyclic group substituted by at least an oxo group has a partial structural formula

[0022]

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A heterocyclic group having the following formula is preferred. Examples of such a heterocyclic group include:

[0024]

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And the like.

As a specific example of the naphthalene derivative [I] which is an active ingredient of the present invention, R ⁵ and R ⁶ are bonded to each other at the terminal to form a heterocyclic group together with an adjacent nitrogen atom, and When the cyclic group is (1) a morpholino group, a monocycloalkyl group-substituted amino group, a pyridyl group, an imidazolyl group, a piperidino group or a pyrrolidinyl group, a mono- or di- group in which a lower alkyl group part may be substituted.
A lower alkylamino group; a pyridyl group; a morpholino group; a lower alkyl group-substituted triazolyl group; a bis (hydroxy lower alkyl) aminocarbonyl group; a bis (tri lower alkylsilyloxy lower alkyl) aminocarbonyl group;
Morpholinocarbonyl group; lower alkyl group-substituted piperazinylcarbonyl group; hydroxy lower alkyl group-substituted piperazinylcarbonyl group; tri-lower alkylsilyloxy lower alkyl group-substituted piperazinylcarbonyl group; lower alkoxycarbonyl group; carboxyl group; lower alkyl A lower alkoxy group optionally substituted with a hydroxyl group or a lower alkoxy group; and an oxo group (or hydroxy group) -substituted dihydro (or tetrahydro) quinolyl group optionally substituted with a group selected from a hydroxyl group; (2) An oxo group (or hydroxy group) -substituted dihydro (or tetrahydro) quinoxalinyl group, (3) a morpholino group-substituted lower alkyl group; a lower alkoxy group which may be substituted with a piperidyl group, a pyridyl group or a lower alkoxy group; An oxo group (or a hydroxy group) which may be substituted with a substituted group; a dihydro (or tetrahydro) isoquinolyl group; (4) a lower alkyl group which may be substituted with a pyridyl group; a pyrimidinyl group; a lower alkoxy group; An imidazolyl group; a phenyl group optionally substituted with a di-lower alkylamino group or a halogen atom; and an oxo group (or hydroxy group) -substituted dihydro (or tetrahydro) phthalazinyl group optionally substituted with a group selected from hydroxyl groups. , (5) an oxo (or hydroxy) substituted dihydro (or hexahydro) pyridyl group optionally substituted with a group selected from a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, a pyridyl group and an imidazolyl group; (6) oxo group (or hydroxy group) substituted dihydride (Or tetrahydro-) naphthyridinyl group, (7) an oxo group (or hydroxy group) substituted hexa-tetrahydroquinolyl group, (8) an oxo group (or hydroxy group) substituted dihydroindolyl group,
(9) oxo group (or hydroxy group) substituted dihydro (or tetrahydro) benzazepinyl group, (10) dihydro (or tetrahydro) isoquinolyl group, (11) oxo group (or hydroxy group) substituted dihydro (or tetrahydro) benzothiazinyl group, (12) oxo group (or hydroxy group) -substituted dihydro (or tetrahydro) quinazolinyl group which may be substituted with lower alkyl group and / or oxo group, (13) oxo group (or hydroxy group)
Substituted dihydrobenzimidazolinyl group, (14) oxo group (or hydroxy group) substituted dihydrophenanthridinyl group, (15) oxo group (or hydroxy group) substituted dihydro (or Examples of the compound include a tetrahydro) pyrrolyl group, (16) a hexahydroxypyrazinyl group, (17) a lower alkylenedioxy group-substituted hexahydropyridyl group, and (18) a morpholino group.

The oxo (or hydroxy) -substituted dihydro (or tetrahydro) quinolyl group is specifically an oxo-substituted dihydro (or tetrahydro) quinolyl group or a hydroxy-substituted dihydro (or tetrahydro) quinolyl group. Specifically, an oxo group-substituted dihydroquinolyl group, an oxo group-substituted tetrahydroquinolyl group, a hydroxy group-substituted dihydroquinolyl group or a hydroxy group-substituted tetrahydroquinolyl group; an oxo group (or hydroxy group) -substituted dihydro (or tetrahydro) quinoxalinyl group Is specifically an oxo group-substituted dihydro (or tetrahydro) quinoxalinyl group or a hydroxy group-substituted dihydro (or tetrahydro) quinoxalinyl group, more specifically, an oxo group-substituted dihydroquinoxalinyl group or an oxo group-substituted group. Trahydroquinoxalinyl group, hydroxy-substituted dihydroquinoxalinyl group or hydroxy-substituted tetrahydroquinoxalinyl group; oxo group (or hydroxy group) -substituted dihydro (or tetrahydro) isoquinolyl group is oxo-substituted dihydro (or A tetrahydro) isoquinolyl group or a hydroxy-substituted dihydro (or tetrahydro) isoquinolyl group;
More specifically, an oxo group-substituted dihydroisoquinolyl group,
An oxo group-substituted tetrahydroisoquinolyl group, a hydroxy group-substituted dihydroisoquinolyl group or a hydroxy-substituted tetrahydroisoquinolyl group; an oxo group (or hydroxy group) -substituted dihydro (or tetrahydro) phthalazinyl group is an oxo group-substituted dihydro (or A tetrahydro) phthalazinyl group or a hydroxy-substituted dihydro (or tetrahydro) phthalazinyl group, more specifically, an oxo-substituted dihydrophthalazinyl group, an oxo-substituted tetrahydrophthalazinyl group, a hydroxy-substituted dihydrophthalazinyl group or A hydroxy-substituted tetrahydrophthalazinyl group; an oxo (or hydroxy) -substituted dihydro (or hexahydro) pyridyl group is an oxo-substituted dihydro (or hexahydro) pyridyl group or a hydroxy-substituted dihydro group. A oxo (or hexahydro) pyridyl group, more specifically an oxo group-substituted dihydropyridyl group, an oxo group-substituted hexahydropyridyl group, a hydroxy group-substituted dihydropyridyl group or a hydroxy group-substituted hexahydropyridyl group; Group) a substituted dihydro (or tetrahydro) naphthyridinyl group is an oxo-substituted dihydro (or tetrahydro) naphthyridinyl group or a hydroxy-substituted dihydro (or tetrahydro) naphthyridinyl group, more specifically an oxo-substituted dihydronaphthyridinyl group, An oxo group-substituted tetrahydronaphthyridinyl group, a hydroxy-substituted dihydronaphthyridinyl group or a hydroxy-substituted tetrahydronaphthyridinyl group; an oxo group (or hydroxy group) -substituted hexahydroquinolyl group is Kiso-substituted hexamethylene tetrahydroquinolyl group or a hydroxy group-substituted hexamethylene tetrahydroquinolyl group; oxo group (or hydroxy group) substituted dihydroindolyl group, oxo group substituted dihydroindolyl group or hydroxy group-substituted dihydroindolyl group;
The oxo group (or hydroxy group) -substituted dihydro (or tetrahydro) benzoazepinyl group is an oxo group-substituted dihydro (or tetrahydro) benzoazepinyl group or a hydroxy group-substituted dihydro (or tetrahydro) benzoazepinyl group, more specifically, an oxo group-substituted dihydro group. A benzoazepinyl group, an oxo-substituted tetrahydrobenzoazepinyl group, a hydroxy-substituted dihydrobenzoazepinyl group or a hydroxy-substituted tetrahydrobenzoazepinyl group; a dihydro (or tetrahydro) isoquinolyl group is a dihydroisoquinolyl group Or an oxo group (or hydroxy group) -substituted dihydro (or tetrahydro) benzothiazinyl group;
An oxo-substituted dihydro (or tetrahydro) benzothiazinyl group or a hydroxy-substituted dihydro (or tetrahydro) benzothiazinyl group, more specifically an oxo-substituted dihydrobenzothiazinyl group, an oxo-substituted tetrahydrobenzothiazinyl group, or a hydroxy-substituted group Dihydrobenzothiazinyl group or hydroxy-substituted tetrahydrobenzothiazinyl group; oxo group (or hydroxy group) -substituted dihydro (or tetrahydro) quinazolinyl group is oxo-substituted dihydro (or tetrahydro)
A quinazolinyl group or a hydroxy-substituted dihydro (or tetrahydro) quinazolinyl group, more specifically, an oxo-substituted dihydroquinazolinyl group, an oxo-substituted tetrahydroquinazolinyl group, a hydroxy-substituted dihydroquinazolinyl group or a hydroxy group Substituted tetrahydroquinazolinyl group; oxo group (or hydroxy group) substituted dihydrobenzimidazolinyl group is oxo group-substituted dihydrobenzimidazolinyl group or hydroxy group-substituted dihydrobenzimidazolinyl group; oxo group (or hydroxy group) A substituted dihydrophenanthridinyl group is an oxo-substituted dihydrophenanthridinyl group or a hydroxy-substituted dihydrophenanthridinyl group; an oxo group (or hydroxy group) -substituted dihydro (or tetrahydro) pyrrolyl group is A dihydro (or tetrahydro) pyrrolyl group or a hydroxy-substituted dihydro (or tetrahydro) pyrrolyl group, more specifically, an oxo-substituted dihydropyrrolyl group, an oxo-substituted tetrahydropyrrolyl group, or a hydroxy-substituted dihydropyrrolyl group. And a tetrahydropyrrolyl group substituted with a hydroxy group or a hydroxy group, respectively.

Among the specific examples of the naphthalene derivative [I], which is an active ingredient of the present invention, a compound that is preferable in terms of pharmacological effect is a heterocyclic ring in which R ⁵ and R ⁶ are bonded together at the terminal to form an adjacent nitrogen atom. Wherein the formula group is (1) an oxo-substituted dihydro (or tetrahydro) quinolyl group or a hydroxy-substituted dihydro (or tetrahydro) quinolyl group, (2) an oxo-substituted dihydro (or tetrahydro) quinoxalinyl group, (3) an oxo-substituted dihydro (Or tetrahydro) isoquinolyl group, (4) oxo-substituted dihydro (or tetrahydro) phthalazinyl group,
(5) an oxo-substituted dihydro (or hexahydro) pyridyl group, (6) an oxo-substituted dihydro (or tetrahydro) naphthyridinyl group, (7) an oxo-substituted hexahydroquinolyl group, (8) an oxo-substituted dihydroindolyl group, (9) oxo-substituted dihydro (or tetrahydro)
Benzoazepinyl group, (10) dihydro (or tetrahydro) isoquinolyl group, (11) oxo-substituted dihydro (or tetrahydro) benzothiazinyl group, (12) oxo-substituted dihydro (or tetrahydro) quinazolinyl group, (13) oxo-substituted dihydro Benzoimidazolinyl group, (14) oxo-substituted dihydrophenanthridinyl group, (15) oxo-substituted dihydro (or tetrahydro) pyrrolyl group, (16) hexahydroxypyrazinyl group, (17) lower alkylenedioxy Compounds that are a group-substituted hexahydropyridyl group or (18) morpholino group are mentioned.

Particularly preferred examples of the medicinal properties include R ⁵ and R
⁶ is bonded to the terminal at the terminal with each other to form a heterocyclic group together with an adjacent nitrogen atom, wherein (1) an oxo group-substituted dihydro (or tetrahydro) quinolyl group or a hydroxy group-substituted tetrahydroquinolyl group, and (2) an oxo group-substituted group. Dihydroquinoxalinyl group, (3) oxo group-substituted dihydroisoquinolyl group, (4) oxo group-substituted dihydrophthalazinyl group, (5) oxo group-substituted dihydro (or hexahydro) pyridyl group, (6) oxo group Substituted dihydronaphthyridinyl group, (7) oxo-substituted hexahydroquinolyl group, (8) oxo-substituted dihydroindolyl group, (9)
Oxo-substituted dihydrobenzoazepinyl group, (10) tetrahydroisoquinolyl group, (11) oxo-substituted tetrahydrobenzothiazinyl group, (12) oxo-substituted dihydro (or tetrahydro) quinazolinyl group, (13)
An oxo group-substituted dihydrobenzimidazolinyl group, (1
4) an oxo group-substituted dihydrophenanthridinyl group, (1
5) An oxo group-substituted tetrahydropyrrolyl group, (16) a hexahydroxypyrazinyl group, (17) a lower alkylenedioxy group-substituted hexahydropyridyl group or (18) a morpholino group.

Among the naphthalene derivatives [I], which are the active ingredients of the present invention, compounds that are preferable in terms of pharmacological effect include those substituted with R ⁵ and R ⁶ bonded together at the terminal at the terminal and adjacent nitrogen atoms. A good heterocyclic group is
(1) a morpholino group, a monocycloalkyl group-substituted amino group, a pyridyl group, an imidazolyl group, a piperidino group or a pyrrolidinyl group, in which the lower alkyl group is substituted with a mono- or di-lower alkylamino group; a pyridyl group; a morpholino group A lower alkyl group-substituted triazolyl group; a lower alkyl group-substituted piperazinylcarbonyl group; a lower alkoxycarbonyl group; a lower alkyl group;
And an oxo-substituted dihydro (or tetrahydro) quinolyl group or a hydroxy-substituted tetrahydroquinolyl group which may be substituted with a group selected from a hydroxyl group or a lower alkoxy group which may be substituted with a lower alkoxy group; (2) oxo Group-substituted dihydroquinoxalinyl group,
(3) a morpholino group-substituted lower alkyl group; a lower alkoxy group optionally substituted with a piperidyl group, a pyridyl group or a lower alkoxy group; and an oxo group-substituted dihydroisoquinolyl optionally substituted with a group selected from a hydroxyl group. Oxo-substituted dihydrophthal which may be substituted with a group selected from a group selected from the group consisting of: a lower alkyl group substituted with a pyridyl group; a pyrimidinyl group; a lower alkoxy group; a pyridyl group; an imidazolyl group; An oxo-substituted dihydropyridyl group substituted with a group selected from a radinyl group, (5) a lower alkyl group, a lower alkoxy group, a pyridyl group, and an imidazolyl group; (6) an oxo group-substituted dihydronaphthyridinyl group;
(7) oxo group-substituted hexahydroquinolyl group, (8) oxo group-substituted dihydroindolyl group, (9) oxo group-substituted tetrahydrobenzothiazinyl group, (10) oxo optionally substituted with lower alkyl group and oxo group A group-substituted dihydro (or tetrahydro) quinazolinyl group, (1
Examples of the compound include 1) an oxo-substituted dihydrobenzimidazolinyl group and (12) an oxo-substituted dihydrophenanthridinyl group.

Among the naphthalene derivatives [I], which are the active ingredients of the present invention, compounds that are more preferable in terms of efficacy are R
A heterocyclic group formed by bonding ⁵ and R ⁶ together at the terminal with an adjacent nitrogen atom is (1) a morpholino group,
A mono- or di-lower alkylamino group in which the lower alkyl group is substituted by a pyridyl group, an imidazolyl group, a piperidino group or a pyrrolidinyl group; a pyridyl group;
A morpholino group; a lower alkyl group-substituted triazolyl group; a lower alkyl group; and an oxo-substituted dihydro (or tetrahydro) quinolyl which may be substituted with a group selected from a lower alkoxy group which may be substituted with a hydroxyl group or a lower alkoxy group. Or a hydroxy group-substituted tetrahydroquinolyl group, (2) an oxo group-substituted dihydroquinoxalinyl group, (3) a morpholino group-substituted lower alkyl group; a lower alkoxy group substituted by a piperidyl group or a lower alkoxy group; and a hydroxyl group Oxo group-substituted dihydroisoquinolyl group which may be substituted with a group selected from: (4) pyridyl group-substituted lower alkyl group, pyrimidinyl group, pyridyl group, imidazolyl group and lower alkoxy group. Oxo-substituted dihydrophthalazine An oxo-substituted dihydropyridyl group substituted with a group selected from a lower alkyl group, a lower alkoxy group, a pyridyl group and an imidazolyl group, (6) an oxo group-substituted tetrahydrobenzothiazinyl group, or (7) a lower group. Examples of the compound include an oxo group-substituted dihydro (or tetrahydro) quinazolinyl group which may be substituted with an alkyl group and an oxo group.

Among them, more preferred compounds from the pharmacological effect include a heterocyclic group in which R ⁵ and R ⁶ are bonded to each other at the terminal and formed with an adjacent nitrogen atom, and (1) a morpholino group, a pyridyl group, an imidazolyl group. A mono- or di-lower alkylamino group in which a lower alkyl group moiety is substituted with a group or a piperidino group; a pyridyl group; a morpholino group; a lower alkyl group-substituted triazolyl group; and a lower alkoxy group substituted with a lower alkoxy group or a hydroxyl group Oxo group-substituted dihydroquinolyl group or hydroxy group-substituted tetrahydroquinolyl group which may be substituted with a group selected from the group consisting of: (2) a morpholino group-substituted lower alkyl group; a lower group substituted by a piperidino group or a lower alkoxy group Substituted with a group selected from an alkoxy group; and a hydroxyl group An oxo-substituted dihydroisoquinolyl group, (3) a pyridyl-substituted lower alkyl group, a pyrimidinyl group, a pyridyl group, an imidazolyl group and an oxo-substituted dihydrophthal which may be substituted with a group selected from a lower alkoxy group. An oxo group substituted with a group selected from a radinyl group, (4) a lower alkyl group, a lower alkoxy group, a pyridyl group and an imidazolyl group; and (5) a substituted with a lower alkyl group and an oxo group. And a oxo group-substituted dihydro (or tetrahydro) quinazolinyl group.

Among these compounds, particularly preferred compounds from the viewpoint of medicinal properties are those wherein a heterocyclic group in which R ⁵ and R ⁶ are bonded to each other at the terminal with an adjacent nitrogen atom is (1) a morpholino group, a pyridyl group, an imidazolyl group. In which the lower alkyl group is substituted with a group or a piperidino group
Or a di-lower alkylamino group; a pyridyl group; a morpholino group; a lower alkyl group-substituted triazolyl group; and an oxo group-substituted dihydro which may be substituted with a group selected from a lower alkoxy group or a lower alkoxy group substituted with a hydroxyl group. A quinolyl group, (2) an oxo group-substituted dihydroisoquinolyl group which may be substituted with a group selected from a morpholino group-substituted lower alkyl group and a piperidyl group-substituted lower alkoxy group, (3) a pyridyl group-substituted lower alkyl group, An oxo-substituted dihydrophthalazinyl group which may be substituted with a group selected from a pyrimidinyl group, a pyridyl group, an imidazolyl group and a lower alkoxy group, or (4)
Examples of the compound include an oxo-substituted dihydropyridyl group substituted with a group selected from a lower alkyl group, a lower alkoxy group, and an imidazolyl group.

Among the naphthalene derivatives [I], which are the active ingredients of the present invention, other compounds that are preferable from the viewpoint of pharmacological activity include R
A heterocyclic group formed by bonding ⁵ and R ⁶ together at the terminal with an adjacent nitrogen atom is (1) a morpholino group,
A mono- or di-lower alkylamino group in which a lower alkyl group is substituted by a monocycloalkyl group-substituted amino group, pyridyl group, imidazolyl group or piperidino group; pyridyl group; morpholino group; lower alkyl group-substituted piperazinylcarbonyl A lower alkoxycarbonyl group; a lower alkyl group; a hydroxyl group; and an oxo-substituted dihydro (or tetrahydro) quinolyl group which may be substituted with a group selected from a lower alkoxy group which may be substituted with a hydroxyl group or a lower alkoxy group. Or a hydroxy group-substituted tetrahydroquinolyl group, (2) a morpholino group-substituted lower alkyl group; an oxo group that may be substituted with a group selected from a piperidino group, a pyridyl group or a lower alkoxy group substituted with a lower alkoxy group. Dihydroisoquino Oxo group-substituted dihydro which may be substituted with a group selected from a group selected from the group consisting of a lower alkyl group substituted with a pyridyl group, a pyrimidinyl group, a lower alkoxy group, a pyridyl group, an imidazolyl group, and a di-lower alkylamino group substituted phenyl group. A phthalazinyl group, (4) an oxo-substituted dihydropyridyl group substituted with a pyridyl group,
(5) an oxo-substituted dihydronaphthyridinyl group, (6)
Oxo group-substituted hexahydroquinolyl group, (7) oxo group-substituted dihydroindolyl group, (8) oxo group-substituted tetrahydrobenzothiazinyl group, (9) oxo group-substituted dihydro optionally substituted with lower alkyl group and oxo group Examples of the compound include a (or tetrahydro) quinazolinyl group, (10) an oxo group-substituted dihydrobenzimidazolinyl group, and (11) an oxo group-substituted dihydrophenanthridinyl group.

Among the above compounds, as a compound more preferable in terms of efficacy, a heterocyclic group in which R ⁵ and R ⁶ are bonded to each other at the terminal and formed together with an adjacent nitrogen atom is (1) a morpholino group, an imidazolyl group or a pyridyl group. A mono- or di-lower alkylamino group having a lower alkyl group moiety substituted with a group; a morpholino group; and an oxo group-substituted dihydro (or tetrahydro) quinolyl group optionally substituted with a group selected from a lower alkyl group; (2) a morpholino group-substituted lower alkyl group; an oxo group-substituted dihydroisoquinolyl group which may be substituted with a group selected from a pyridyl group or a lower alkoxy group substituted with a lower alkoxy group, and (3) a pyridyl group-substituted group Lower alkyl group; lower alkoxy group; pyridyl group; and di-lower alkylamino group-substituted phenyl group And (4) an oxo-substituted dihydrophenanthridinyl group substituted with an oxo group-substituted dihydrophthalazinyl group.

Among the above compounds, a particularly preferable compound in terms of pharmacological effect is that a heterocyclic group in which R ⁵ and R ⁶ are bonded to each other at the terminal with an adjacent nitrogen atom is (1) a pyridyl group and a lower alkyl group moiety. Is a mono-substituted
Or a di-lower alkylamino group; a morpholino group; and an oxo group-substituted dihydro (or tetrahydro) quinolyl group which may be substituted with a group selected from lower alkyl groups; (2) a morpholino-substituted lower alkyl group; a pyridyl group or An oxo group-substituted dihydroisoquinolyl group which may be substituted with a group selected from a lower alkoxy group substituted with a lower alkoxy group, (3) a pyridyl group-substituted lower alkyl group; a lower alkoxy group; a pyridyl group; Examples of the compound include an oxo group-substituted dihydrophthalazinyl group and (4) an oxo group-substituted dihydrophenanthridinyl group substituted with a group selected from a lower alkylamino group-substituted phenyl group.

Further, as another compound having a preferable medicinal effect, an optionally substituted heterocyclic group formed by bonding R ⁵ and R ^{6 at the} terminal to each other and adjoining a nitrogen atom is represented by (1) morpholino Group in which the lower alkyl group is substituted with a group, imidazolyl group or pyridyl group
Or a di-lower alkylamino group; a morpholino group; and an oxo group-substituted dihydro (or tetrahydro) quinolyl group which may be substituted with a group selected from lower alkyl groups; (2) a morpholino group-substituted lower alkyl group; An oxo-substituted dihydroisoquinolyl group substituted with a group selected from a group-substituted lower alkoxy group,
(3) Compounds which are an oxo-substituted dihydrophthalazinyl group substituted with a group selected from a pyridyl group-substituted lower alkyl group; a lower alkoxy group; and a pyridyl group.

Further, as another compound having a preferable medicinal effect, a heterocyclic group in which R ⁵ and R ⁶ are bonded at the terminal to each other to form an adjacent nitrogen atom is represented by the following formula:

[0039]

Embedded image

(Provided that R ⁹¹ , R ⁹² and R ⁹³ are the same or different and are a hydrogen atom, a hydroxyl group, a lower alkoxy group, a lower alkyl group optionally substituted by a pyridyl group, a di-lower alkylamino group or a halogen atom) A compound represented by an optionally substituted phenyl group, a pyridyl group, a pyrimidinyl group or an imidazolyl group (hereinafter, referred to as a compound [I-a]).

Among these compounds, R ⁹¹ , R ⁹² and R ⁹³ are the same or different and are preferably a hydrogen atom,
Compounds which are a lower alkoxy group, a lower alkyl group substituted with a pyridyl group, a phenyl group substituted with a di-lower alkylamino group or a pyridyl group are exemplified.

Among the preferred examples of the naphthalene derivative [I] which is the active ingredient of the present invention, R ¹ and R ²
Are the same or different and a lower alkoxy group, and a compound in which R ³ and R ⁴ are a hydroxyl-substituted methyl group are preferred.

The naphthalene derivative [I], which is the active ingredient of the present invention, may have optically active isomers based on asymmetric carbon. The naphthalene derivative, which is the active ingredient of the present invention, includes these optical isomers and mixtures thereof. Both of these are included.

The naphthalene derivative [I], which is the active ingredient of the present invention, can be used in a free form or in the form of a pharmaceutically acceptable salt for pharmaceutical use. Such pharmaceutically acceptable salts include, for example, inorganic acid salts such as hydrochloride, sulfate or hydrobromide, acetate, fumarate, oxalate, methanesulfonate or maleate. Organic acid salts and the like. When the compound has a substituent such as a carboxyl group, it can be used as a basic salt (eg, an alkali metal salt such as a sodium salt or a potassium salt or an alkaline earth metal salt such as a calcium salt).

The naphthalene derivative [I] and salts thereof should be construed as including any of inner salts, adducts, solvates and hydrates thereof.

The naphthalene derivative [I] or a salt thereof, which is an active ingredient of the present invention, is administered orally or parenterally (for example,
Intravenous, intramuscular, subcutaneous, etc.)
Also, for example, tablets, granules, capsules,
It can be used as an appropriate pharmaceutical preparation such as a powder, an injection and an inhalant.

The dose of the desired compound [I] of the present invention or a pharmaceutically acceptable salt thereof varies depending on the administration method, age, weight and condition of the patient.
01-10 mg / kg, especially about 0.003-3 mg
/ Kg or so.

The naphthalene derivative [I], which is an active ingredient of the present invention, and its pharmacologically acceptable salt have high selectivity for PDE IV, which is particularly present in bronchial smooth muscle and inflammatory cells, among PDE isozymes. Shows strong inhibitory activity.

Therefore, the naphthalene derivative [I], which is an active ingredient of the present invention, and a pharmaceutically acceptable salt thereof can be used in inflammatory cells (monocytes, neutrophils, eosinophils, etc.) involved in airway inflammation. Suppress activation. For example, it effectively suppresses infiltration of inflammatory cells in airway inflammation induced by antigen. Furthermore, the naphthalene derivative [I] and the pharmaceutically acceptable salt thereof, which are the active ingredients of the present invention, have a stronger bronchoconstriction inhibitory action than theophylline. For example, it effectively suppresses bronchoconstriction induced by histamine or antigen.

As described above, the naphthalene derivative [I], which is the active ingredient of the present invention, and its pharmaceutically acceptable salt are:
It has excellent anti-airway inflammatory action and bronchoconstriction inhibitory action and is extremely useful as an anti-asthmatic drug.

In the case of theophylline, side effects on the heart such as a decrease in blood pressure and an increase in palpitations are known. The naphthalene derivative [I], which is an active ingredient of the present invention, and a pharmaceutically acceptable salt thereof are as follows: It is characterized by showing a bronchoconstriction inhibitory action and an anti-airway inflammatory action with almost no such side effects.

Furthermore, the naphthalene derivative [I], which is an active ingredient of the present invention, and a pharmaceutically acceptable salt thereof are as follows:
Low toxicity and high safety as a medicine. For example,
1- {2- [4- (3-pyridyl) -1 (2H) -phthalazinone-2-yl] -4-pyridyl} -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene hydrochloride , 1- {2- [4- (3-pyridyl) -1 (2
H) -phthalazinone-2-yl] -4-pyridyl}-
2,3-Bis (hydroxymethyl) -6,7-diethoxynaphthalene and its hydrochloride were each administered to mice in an amount of 10%.
No mortality was observed even after subcutaneous administration of 00 mg / kg for 1 day.

The naphthalene derivative [I] as an active ingredient of the present invention can be produced by the following [Method A] to [Method C].

[Method A] The naphthalene derivative which is the active ingredient of the present invention has the general formula [II]

[0055]

Embedded image

(Provided that R ¹¹ and R ²¹ are the same or different and are each a hydrogen atom or an optionally protected hydroxyl group, R ³¹ and R ^21
41 is one of which may be a protected hydroxyl group-substituted methyl group, the other is a hydrogen atom, a lower alkyl group or an optionally protected hydroxyl-substituted methyl group,
X represents a halogen atom. ) And a compound of the general formula [III]

[0057]

Embedded image

(Wherein the symbols have the same meaning as described above) and a base (eg, an alkali metal hydroxide or an alkali metal carbonate) and a copper catalyst (eg, copper (I) iodide) , Copper (I) bromide, copper powder (0), copper oxide (I), copper (II) bromide, etc.) in the presence of a suitable solvent (dimethylformamide, dimethylsulfoxide, dimethylacetamide, toluene, xylene, etc.) Medium, 80 ° C
To 160 ° C. (particularly 120 ° C. to 150 ° C.), wherein R ¹¹ and / or R ²¹ are protected hydroxyl groups,
^{When 31} and / or R ⁴¹ is a protected hydroxyl-substituted methyl group, if desired, all or selected by a method such as hydrolysis, acid treatment, or reduction, according to the type of the hydroxyl-protected group, according to a conventional method. The protecting group is removed, and if necessary, the hydroxyl moiety at the 6-position and / or 7-position or the hydroxymethyl moiety at the 2-position and / or 3-position can be added to each product and groups R ¹ and R ² , Lower alkanoic acid or cycloalkanoic acid corresponding to the protecting group of groups R ³ and R ⁴ , an acid anhydride, an acid halide or a lower alkyl halide which may be substituted with a lower alkoxycarbonyl group or a carboxyl group which may be protected Substituted lower alkylsulfonates and the like are combined with bases (triethylamine, pyridine, dimethylaminopyridine, sodium hydride, hexamethylphosphoric triamide ) In the presence of a condensing agent (dicyclohexylcarbodiimide, water-soluble carbodiimide) in a suitable solvent (methylene chloride, tetrahydrofuran, etc.) or in the absence of a solvent, or with an amino group-substituted lower alkyl carboxylic acid which may be protected. (Derivatives, etc.) in an appropriate solvent (dimethylformamide, methylene chloride, chloroform, etc.) to reactivate and, if necessary, further protect all hydroxy or hydroxymethyl moieties for production. .

[Method B] Of the naphthalene derivatives which are the active ingredients of the present invention,

[0060]

Embedded image

(Provided that R ⁵¹ and R ⁶¹ are bonded to each other at the terminal to form a heterocyclic group substituted with at least an oxo group together with an adjacent nitrogen atom, and other symbols are the same as those described above.) Has the meaning).
General formula [IV]

[0062]

Embedded image

(Wherein the symbols have the same meanings as described above) and a compound of the general formula [V]

[0064]

Embedded image

(Provided that R ⁵² and R ⁶² are bonded to each other at the terminal to form a heterocyclic group substituted with at least a halogen atom together with an adjacent nitrogen atom.)
With a halogeno nitrogen-containing compound represented by the acid catalyst (for example,
In the presence or absence of hydrogen bromide, acetic acid, etc., a suitable solvent (dimethylformamide, dimethylsulfoxide,
80 ° C to 160 ° C (especially 110 ° C)
-150 ° C.), and when R ¹¹ and / or R ²¹ is a protected hydroxyl group and R ³¹ and / or R ⁴¹ is a protected hydroxyl-substituted methyl group, if desired, a protecting group for the hydroxyl group Depending on the type, the protecting group is entirely or selectively removed by a method such as hydrolysis, acid treatment, or reduction according to a conventional method, and if necessary, a hydroxy moiety at the 6-position and / or 7-position or a 2-position and And / or the hydroxymethyl moiety at the 3-position is converted to each of the products R ¹ and R ² ,
Lower alkanoic acid or cycloalkanoic acid corresponding to the protecting group of ³ and R ^4, an anhydride, an acid halide or a lower alkyl halide which may be substituted with a lower alkoxycarbonyl group or a carboxyl group-substituted lower which may be protected. Alkyl sulfonate and the like, in the presence of a base (triethylamine, pyridine, dimethylaminopyridine, sodium hydride, hexamethylphosphoric triamide, etc.) in a suitable solvent (methylene chloride, tetrahydrofuran, etc.) or without solvent, or An optionally protected amino group-substituted lower alkylcarboxylic acid or the like is reacted in a suitable solvent (dimethylformamide, methylene chloride, chloroform, etc.) in the presence of a condensing agent (dicyclohexylcarbodiimide, water-soluble carbodiimide derivative, etc.). To protect again and need more If it can be prepared by protecting all of the hydroxy sites or hydroxymethyl site.

[Method C] Of the naphthalene derivatives which are the active ingredients of the present invention,

[0067]

Embedded image

(Provided that R ⁵³ and R ⁶³ are the same or different and each represent a hydrogen atom, an optionally substituted alkyl group, an optionally substituted phenyl group or an optionally protected amino group, Alternatively, it represents that they are bonded to each other at their terminals and form an optionally substituted heterocyclic group which is stable to a reduction reaction together with an adjacent nitrogen atom, and other symbols have the same meanings as described above.) The compound represented by the general formula [VI]

[0069]

Embedded image

(However, one of R ⁷ and R ^{8 represents} a free or esterified carboxyl group, the other represents a hydrogen atom, a lower alkyl group, or a free or esterified carboxyl group; The symbols have the same meanings as described above, or an intramolecular acid anhydride thereof can be hydrogenated by a suitable reducing agent (for example, when R ⁷ and R ⁸ are esterified carboxyl groups, Sodium boron boron, and when R ⁷ and / or R ⁸ are free carboxyl groups, lithium aluminum hydride etc.)
In the presence of a suitable solvent (eg, tetrahydrofuran,
Ether), under a cooling to heating condition,
^{When 11} and / or R ²¹ is a protected hydroxyl group, the protecting group may be removed as required, and if necessary, a hydroxy moiety at the 6- and / or 7-position or a hydroxymethyl moiety at the 2- and / or 3-position may be used. According to a conventional method, each product and a group R ¹
And R ² , a lower alkanoic acid or a cycloalkanoic acid corresponding to the protecting group of the groups R ³ and R ^4, an anhydride, an acid halide or a lower alkyl halide which may be substituted with a lower alkoxycarbonyl group, or Or a carboxyl-substituted lower alkylsulfonate in a suitable solvent (methylene chloride, tetrahydrofuran, etc.) in the presence of a base (triethylamine, pyridine, dimethylaminopyridine, sodium hydride, hexamethylphosphoric triamide, etc.) or A suitable solvent (dimethylformamide, methylene chloride, chloroform) in a solvent-free state or in the presence of a condensing agent (dicyclohexylcarbodiimide, water-soluble carbodiimide derivative, etc.) etc)
The reaction can be carried out again to protect the product, and if necessary, all hydroxy sites or hydroxymethyl sites can be protected.

The naphthalene derivative [I], which is the active ingredient of the present invention, can also be produced by interconverting the naphthalene derivative obtained as described above into another naphthalene derivative. Such an interconversion reaction between naphthalene derivatives may be appropriately selected according to the type of the substituent of the compound, and can be carried out, for example, as follows.

The compound [Ia] is a compound of the formula [I] wherein R ⁵ is a hydrogen atom and R ⁶ is an amino group (hereinafter referred to as compound [Ib]) or a compound thereof. Salt and general formula [VII]

[0073]

Embedded image

(Wherein the symbols have the same meanings as described above), and can be produced by reacting with a carboxylic acid derivative or a salt thereof.

Further, in the general formula [Ia], the compound [Ia '] in which R ⁹¹ is a hydroxyl group is a compound [Ib] or a salt thereof and a compound of the general formula [VIII]

[0076]

Embedded image

(Wherein, the symbols have the same meanings as described above).

These reactions can be carried out in a suitable solvent (for example, lower alkanol, ethylene glycol, dioxane, toluene, etc.), and preferably proceed at 100 to 140 ° C.

The starting compound [II] of the naphthalene derivative, which is an active ingredient of the present invention, is, for example, a compound represented by the general formula [I
X]

[0080]

Embedded image

(Wherein the symbols have the same meanings as described above), and the resulting 6-halogenobenzaldehyde compound is treated with a halogen (eg, bromine) to obtain an acid catalyst (for example, a strongly acidic resin or the like). ) In the presence of methyl orthoformate and then in the presence of a base (such as n-butyllithium) of the general formula [X]

[0082]

Embedded image

(Wherein the symbols have the same meanings as described above), and the product is further reacted with the general formula [XI]

[0084]

Embedded image

(Wherein, R ⁷¹ and R ⁸¹ represent one of which is an esterified carboxyl group and the other is a hydrogen atom, a lower alkyl group or an esterified carboxyl group). With the general formula [XII]

[0086]

Embedded image

(Wherein the symbols have the same meanings as described above), which is produced by reducing the compound with a reducing agent (eg, alkali metal borohydride, sodium bis (methoxyethoxy) aluminum hydride). be able to.

The starting compound [II] is a compound of the general formula [XIII] in place of the compound [X].

[0089]

Embedded image

In the same manner as described above, using the compound represented by the general formula [XIV] corresponding to the compound [XII]

[0091]

Embedded image

(Wherein the symbols have the same meanings as described above), which is used as an oxidizing agent (metachloroperbenzoic acid, potassium peroxysulfate (2K
HSO ₅ .KHSO ₄ .K ₂ SO ₄ ), hydrogen peroxide, etc.) and oxidized with general formula [XV]

[0093]

Embedded image

(Wherein the symbols have the same meanings as described above), which is treated with a halogenating agent (phosphorus oxychloride, phosphorous oxybromide, etc.) to give compound [XII], which is further reduced. It can also be produced by reduction with an agent (alkali metal borohydride, sodium bis (methoxyethoxy) aluminum hydride, etc.).

In the general formula [XIV], the compound in which R ⁷¹ is an esterified carboxyl group and R ⁸¹ is a hydrogen atom is the same as the compound represented by the general formula [XIII] and the compound in which the carboxyl group has a usual protecting group. Groups (eg, te
tert-butyl group, benzyl group, etc.), and reacting with acrylic acid protected by a conventional method.

[0096]

Embedded image

The compound represented by the general formula [IX]
Is reacted with acetic anhydride and sodium acetate, or sulfur trioxide and N, N-dimethylformamide to obtain a compound of the general formula [XVI]

[0098]

Embedded image

(Wherein the symbols have the same meanings as described above), and this is acid-catalyzed (for example,
Acetic acid-hydrochloric acid mixed solution, aluminum chloride, etc.) to convert into a naphthalene compound, and then esterify the carboxyl group at the 3-position of the naphthalene ring by a conventional method.

The starting compound [IV] of the present invention is, for example,
The compound [XIV] is reduced with a reducing agent (for example, sodium bis (methoxyethoxy) aluminum hydride), and after protecting the hydroxyl group of the obtained 2,3-bis (hydroxymethyl) compound, an oxidizing agent (for example, metachloroperbenzoic acid) Acid) and, if desired, removing the hydroxyl-protecting group from the product to produce the compound.

Further, compound [VI] can be obtained, for example, by compounding compound [XII] and nitrogen-containing compound [III] with compound [I
[I] and the nitrogen-containing compound [III]. Also,
Compound [VI] can also be produced by reacting compound [XV] with a halogeno nitrogen-containing compound [V] under the same conditions as in the reaction of compound [IV] with a halogeno nitrogen-containing compound [V]. it can.

In the present specification, examples of the alkyl group include linear or branched ones having 1 to 16 carbon atoms, especially 1 to 8 carbon atoms. Examples of the lower alkyl group and the lower alkoxy group include lower alkyl groups and lower alkoxy groups. Carbon number 1-6, especially 1-4
One. Examples of the lower alkenyl group, lower alkynyl group, lower alkylenedioxy group and lower alkanoyl group include linear or branched ones having 2 to 7 carbon atoms, especially 2 to 5 carbon atoms. Further, examples of the cycloalkyl group include those having 3 to 8 carbon atoms, particularly those having 3 to 6 carbon atoms. Halogen atoms include chlorine, bromine, fluorine or iodine.

[0103]

[Experimental example]

Experimental Example 1 (antigen-induced bronchoconstriction inhibitory action) Male Hartley guinea pigs were passively sensitized by intravenously administering rabbit anti-ovalbumin antiserum. The next day, α-chloralose (120 mg /
kg, i. v. ), Anesthesia with tracheal cannula, and artificial respiration with gallamine triethiodide (5 mg / k).
g, i. v. ). The effect on the trachea is determined by the Konzet-Roessler method [Naunin-
Schmiedebergs Archeiff Huer Experimental Telepathology und Pharmacology (Naunyn-Schmeideberg's Ar
chiv fur Experimententelle P
athology and Pharmakologi
e) 195, 71, 1940]. Sample compound (compound obtained in Production Example described later) (1 mg /
kg) is the antigen (ovalbumin; 30 μg / kg,
i. v. ) Intravenous administration 2 minutes before administration.

The results are shown in Table 1 below.

[0105]

[Table 1]

Experimental Example 2 (Inhibition of histamine-induced bronchoconstriction) Male Hartley guinea pigs were treated with α-
Anesthetize with chloralose (120 mg / kg, iv), insert tracheal cannula, and apply galamine under artificial respiration.
Immobilized with triethiodide (5 mg / kg, iv). The volume of the artificial respiration was adjusted so that the tracheal pressure was about 10 cmH ₂ O at the peak. The endotracheal pressure is measured by a pressure transducer (trade name:
It was measured by a pressure strain meter (trade name: AP-621G, manufactured by Nihon Kohden) via TP-200T (manufactured by Nihon Kohden) and recorded on a linear coder (WR 3701, manufactured by Graphtec). The bronchodilator effect of the test compound (the compound obtained in the production example described later) was determined by histamine dihydrochloride (His
After the increase in the tracheal pressure (bronchoconstriction) due to t) became constant, the test compound was administered, and it was determined from the inhibition rate against the reaction before the test compound administration. Hist is administered at 10 minute intervals, and the test compound is 1 mg / kg 5 minutes before Hist administration.
Was administered into the duodenum such that

The results are as shown in Table 2 below.

[0108]

[Table 2]

Experimental Example 3 [Anti-airway Inflammatory Action] Hartley (Hartle) sensitized by inhaling a 1% ovalbumin (OA) solution (20 ml) with an ultrasonic nebulizer for 10 minutes twice a week.
y) Male guinea pigs were used in the experiments one week after the last sensitization. The experiment was performed 30 minutes before pyrilamine (10 mg / k
g) was intraperitoneally administered and further dissolved in a physiological saline solution containing 10% dimethyl sulfoxide and 40% ethanol.
-{2- [4- (3-pyridyl) -1 (2H) -phthalazinone-2-yl] -4-pyridyl} -2,3-bis (hydroxymethyl) -6,7-diethoxynaphthalene hydrochloride Was inhaled with an ultrasonic nebulizer for 10 minutes, then antigen (1% OA) was inhaled for 5 minutes, and bronchoalveolar lavage was performed 24 hours later, and the total number of leukocytes and the percentage of eosinophils in the lavage fluid were determined. The test compound showed an inhibitory action on inflammatory cell infiltration, and EC30 was 1.3 mg / ml.

Experimental Example 4 [Inhibition of phosphodiesterase IV] (Preparation of a partially purified preparation of phosphodiesterase IV) A supernatant obtained by centrifuging a lung homogenate extracted from a male Hartley guinea pig was subjected to an anion exchange column. Fractionated by chromatography, the following 1. ~ 4. The fractions satisfying the above conditions were mixed to obtain a partially purified sample of phosphodiesterase IV.

[0111] 1. 1. Selectively hydrolyzing cAMP. 2. Its cAMP hydrolytic activity is not affected by cGMP. C, a selective phosphodiesterase III inhibitor
3. Not inhibited by I-930 Strong inhibition by Rolipram, a phosphodiesterase IV selective inhibitor.

(Measurement of phosphodiesterase IV activity)
Thompson et al. (Advanced in Cyclic Nucleotide Research [Advances in
Cyclic Nucleotide Research
h], Volume 10, Raven Press, New York, 69-
92, 1979). That is, 100 µl of a phosphodiesterase IV partially purified preparation diluted with 50 mM Tris-HCl, pH 8.0 to hydrolyze about 10% of the whole substrate was added to a glass test tube. Reaction buffer solution (50 mM Tris-HCl, p
H 8.0, 12.5 mM MgCl ₂ , 10 mM 2
After adding 200 μl of -mercaptoethanol), 5 μl of a test compound (compound obtained in the following Production Example) (100-fold concentration) dissolved in dimethyl sulfoxide was added. 3
After preincubation for 5 minutes at 0 ° C., 2.5 μM
[ ³ H] cAMP (3.7 kBq / 200 μl) was added to 20
0 μl was added to start the reaction (final concentration 50 mM Tri).
s-HCl, pH 8.0, 5 mM MgCl ₂ , 4 m
M 2-mercaptoethanol). After reaction at 30 ° C. for 30 minutes, the test tube was transferred into a boiling water bath to stop the reaction.
After 90 seconds, the test tube was transferred into an ice water bath, and the temperature of the reaction solution was lowered. After preincubation at 30 ° C for 5 minutes, 1m
g / ml snake venom aqueous solution (100 μl),
The reaction was performed for 0 minutes. After the reaction was stopped by adding 500 μl of methanol, 1 ml of the reaction solution was supplied to a column to which 200 μl of Dowex resin (trade name: Dowex 1 × 8, manufactured by Sigma) had been added in advance. Subsequently, the Dowex resin was washed by adding 1 ml of methanol. The reaction solution passed through the column and the washing solution were combined, and the radioactivity was measured.

A sample in which only the buffer solution was added without adding the enzyme standard was used as a blank, and a sample in which the enzyme standard was added but only dimethyl sulfoxide was added instead of the sample solution was used as a control. The rate was calculated. The IC50 value of each sample was calculated by calculating the inhibition rate at three or more concentrations, and calculating the 4-parameter logistics (4-parameter logist).
eq.).

The results are shown in Table 3 below.

[0115]

[Table 3]

[0116]

PREPARATION EXAMPLES The naphthalene derivatives synthesized by the above-mentioned methods and the naphthalene derivatives of the general formula [I], which are the active ingredients of the present invention, produced by the same production method are summarized below in Nos. 4-1 to 4-1.
The details are shown in Table 7.

[0117]

[Table 4]

[0118]

[Table 5]

[0119]

[Table 6]

[0120]

[Table 7]

[0121]

[Table 8]

[0122]

[Table 9]

[0123]

[Table 10]

[0124]

[Table 11]

[0125]

[Table 12]

[0126]

[Table 13]

[0127]

[Table 14]

[0128]

[Table 15]

[0129]

[Table 16]

[0130]

[Table 17]

[0131]

[Table 18]

[0132]

[Table 19]

[0133]

[Table 20]

[0134]

[Table 21]

[0135]

[Table 22]

[0136]

[Table 23]

[0137]

[Table 24]

[0138]

[Table 25]

[0139]

[Table 26]

[0140]

[Table 27]

[0141]

[Table 28]

Production Example 1 3.5 g of N-oxide of 1- (4-pyridyl) -2,3-bis (acetoxymethyl) -6,7-diethoxynaphthalene and 1.26 g of 1-chloroisoquinoline in 30 ml of mesitylene The suspension is heated and stirred at 150 to 160 ° C. After the reaction, the solvent is distilled off, and methylene chloride and an aqueous solution of sodium hydrogen carbonate are added to the residue, and the methylene chloride layer is separated. The methylene chloride layer was washed and dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography (solvent; chloroform: acetone = 30: 1) to give 1- [2- (1-oxo-) described in Table 4. 1,2-dihydroisoquinolin-2-yl) -4-pyridyl] -2,3-bis (acetoxymethyl) -6,7-diethoxynaphthalene 1.8
5 g are obtained.

M. p. 90-93 ° C Production Example 2 1- (4-pyridyl) -2,3-bis (acetoxymethyl) -6,7-dimethoxynaphthalene N-oxide 2.13 g and 2-chloroquinoline 1.64 g in 5 ml of dimethylformamide Several drops of a hydrogen chloride-dioxane solution are poured into the suspension, and the mixture is heated and stirred at 120 to 130 ° C. After the reaction, the solvent is distilled off, and methylene chloride and an aqueous solution of sodium hydrogen carbonate are added to the residue, and the methylene chloride layer is separated. After the obtained methylene chloride layer was washed and dried, the solvent was distilled off to obtain a residue. 5 ml of pyridine and 1.0 ml of acetic anhydride are added to the obtained residue under ice cooling, and the mixture is stirred at room temperature for 2 hours.
After the reaction, the solvent was distilled off, and ethyl acetate and water were added to the residue.
The ethyl acetate layer is separated. The ethyl acetate layer was washed and dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography (solvent; chloroform: acetone = 5: 1) to give 1- [2- (2-oxo-) described in Table 4. 1,2-dihydroquinolin-1-yl) -4-pyridyl] -2,3
1.20 g of bis (acetoxymethyl) -6,7-dimethoxynaphthalene are obtained.

M. p. 181-184 ° C Production Example 3 3.5 g of N-oxide of 1- (4-pyridyl) -2,3-bis (acetoxymethyl) -6,7-dimethoxynaphthalene and 13.0 of 2-chloro-5-nitropyridine
A few drops of a hydrogen bromide-acetic acid solution are poured into a 30 ml suspension of xylene, and the mixture is heated and stirred at 140 to 150 ° C. After the reaction, the solvent is distilled off, and chloroform and an aqueous solution of sodium hydrogen carbonate are added to the residue, and the chloroform layer is separated. After washing and drying the chloroform layer, the solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent; chloroform: acetone = 50: 1) to obtain 1- [2-
(2-oxo-1,2-dihydro-5-nitropyridin-1-yl) -4-pyridyl] -2,3-bis (acetoxymethyl) -6,7-dimethoxynaphthalene 1.83
g.

M. p. 81-84 ° C Production Example 4 1- [2- (1-Oxo-1,2-dihydroisoquinolin-2-yl) -4-pyridyl] -2,3-bis (acetoxymethyl) -6,7-diethoxy Naphthalene 1.8
To a solution of 4 g of methanol in 50 ml, 0.52 g of sodium methoxide is added under ice cooling. The mixture is stirred at room temperature for 2.5 hours, further added with sodium methoxide (0.17 g) under ice cooling, and stirred at room temperature for 1 hour. 0.74 ml of acetic acid is added to the reaction mixture under ice cooling, and the solvent is distilled off. Methylene chloride and aqueous sodium hydrogen carbonate solution are added to the residue, and the methylene chloride layer is separated. The methylene chloride layer was washed and dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography (solvent; chloroform: ethanol = 25: 1) to give 1- [2- (1-oxo- 1,2-dihydroisoquinolin-2-yl) -4-pyridyl]-
0.95 g of 2,3-bis (hydroxymethyl) -6,7-diethoxynaphthalene is obtained.

M. p. 131-134 ° C Production Example 5 1- [2- (2-oxo-1,2-dihydro-5-nitropyridin-1-yl) -4-pyridyl] -2,3-bis (acetoxymethyl) -6 0.72 g of sodium methoxide is added to a solution of 1.83 g of 7-dimethoxynaphthalene in 50 ml of methanol under ice-cooling. Stir at room temperature for 1 hour. 0.8 ml of acetic acid is added to the reaction mixture under ice cooling, and the solvent is distilled off. Chloroform and aqueous sodium hydrogen carbonate solution are added to the residue, and the chloroform layer is separated.
The chloroform layer was washed and dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography (solvent; chloroform: acetone = 3: 1), crystallized with ethyl acetate, and 1- [2- 0.81 g of (2-oxo-1,2-dihydro-5-nitropyridin-1-yl) -4-pyridyl] -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene is obtained.

M. p. 248-251 ° C (decomposition) Production Example 6 (1) A suspension of 15.0 g of 1- (2-bromo-4-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene in 150 ml of tetrahydrofuran 6.16 g of sodium borohydride is added to the mixture, and the mixture is heated under reflux. A mixture of 60 ml of methanol and 60 ml of tetrahydrofuran is added dropwise to the mixture under reflux over 5 hours. After completion of the reaction, the solvent is distilled off, methylene chloride and an aqueous solution of sodium hydrogen carbonate are added to the residue, and the methylene chloride layer is separated. After washing and drying the methylene chloride layer, the solvent is distilled off, and the residue is crystallized from isopropyl ether to give 1- (2
-Bromo-4-pyridyl) -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene 11.86 g
Get.

M. p. 177-179 ° C (2) A solution of 2.92 g of 2-hydroxyquinoxaline in 20 ml of dimethylformamide was cooled with ice under a nitrogen atmosphere.
Add 0.78 g of 0% sodium hydride and stir at room temperature for 15 minutes. The mixture was then added to copper (I) iodide 4.19.
g and stirred at 120 ° C. for 15 minutes. The mixture is returned to room temperature and 1- (2-bromo-4-pyridyl) -2,3
2.02 g of -bis (hydroxymethyl) -6,7-dimethoxynaphthalene is added, and the mixture is stirred at 120 ° C for 5 hours.
After completion of the reaction, ethyl acetate and aqueous ammonia are added, and the ethyl acetate layer is separated. After filtering the ethyl acetate layer, it is washed and dried, and the solvent is distilled off. The residue was subjected to silica gel column chromatography (solvent; chloroform: methanol = 20:
Purified in 1), and the 1- [2- (2-oxo-
1,2-dihydroquinoxalin-1-yl) -4-pyridyl] -2,3-bis (hydroxymethyl) -6,7-
450 mg of dimethoxynaphthalene are obtained.

M. p. 158-165 ° C. (decomposition) Production Example 7 A solution of 3.26 g of 2-hydroxy-4- [2- (1-piperidino) ethyl] aminoquinoline in 10 ml of dimethylformamide was ice-cooled under a nitrogen atmosphere, and 60% sodium hydride 0 Add .48 g and stir at room temperature for 15 minutes. Then, 2.29 g of copper (I) iodide was added to the mixture, and 12
Stir at 0 ° C. for 30 minutes. The mixture is returned to room temperature and 1-
(2-bromo-4-pyridyl) -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene 2.43
g and stirred at 120 ° C. for 5 hours. After completion of the reaction, ethyl acetate and aqueous ammonia are added, and the ethyl acetate layer is separated. After filtering the ethyl acetate layer, it is washed and dried, and the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent; chloroform: methanol = 6: 1), then several drops of a hydrogen chloride-dioxane solution were poured, crystallized, washed, and dried. -[2-oxo-4- [2- (1-piperidino) ethyl] amino-
1,2-Dihydroquinolin-1-yl] -4-pyridyl {-2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene hydrochloride (210 mg) is obtained.

M. p. > 220 ° C Production Example 8-57 Production Example 1 of 1- (2-bromo-4-pyridyl) -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene and the corresponding nitrogen-containing compound [III] (2) Alternatively, the compound was treated in the same manner as in Production Example 7 to obtain the compounds shown in Table 5.

Production Example 58 (1) 1- (2-Bromo-4-pyridyl) -2,3-bis (methoxycarbonyl) -6-ethoxy-7-methoxynaphthalene was prepared in the same manner as in Production Example 6- (1). Processing 1-
(2-Bromo-4-pyridyl) -2,3-bis (hydroxymethyl) -6-ethoxy-7-methoxynaphthalene is obtained.

M. p. 156-157 ° C (2) Production Example 7 of this product and the corresponding nitrogen-containing compound [III]
1- {2-} 4- (3- (3-
Pyridyl) -1 (2H) -phthalazinone-2-yl] pyridin-4-yl {-2,3-bis (hydroxymethyl) -6-ethoxy-7-methoxynaphthalene hydrochloride is obtained.

M. p. 215-218 ° C (decomposition) (3) 1- {2- [4- (3-pyridyl) -1 (2H)
-Phthalazinone-2-yl] pyridin-4-yl}-
2,3-bis (hydroxymethyl) -6-ethoxy-7
-Methoxynaphthalene sulfate sulfate m. p. > 250 ° C (4) 1- {2- [4- (3-pyridyl) -1 (2H)
-Phthalazinone-2-yl] pyridin-4-yl}-
2,3-bis (hydroxymethyl) -6-ethoxy-7
-Methoxynaphthalene methanesulfonate m. p. 205-215 ° C (decomposition) Production example 59-60 (1) Production example 6 of 1- (2-bromo-4-pyridyl) -2,3-bis (methoxycarbonyl) naphthalene
Treatment in the same manner as in (1) gives 1- (2-bromo-4-pyridyl) -2,3-bis (hydroxymethyl) naphthalene.

M. p. 108-109 ° C (2) Production example 6 of this product and the corresponding nitrogen-containing compound [III]
-(2) or by treating in the same manner as in Production Example 7 to obtain the compounds shown in Table 6.

Production Examples 61 to 62 (1) 1- (2-Bromo-5-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene was prepared in the same manner as in Production Example 6- (1). Treatment gives 1- (2-bromo-5-pyridyl) -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene.

M. p. 185-186 ° C (decomposition) (2) Production Example 6 of this product and the corresponding nitrogen-containing compound [III]
-(2) or by treating in the same manner as in Production Example 7, to obtain the compounds shown in Table 7.

Production Example 63 (1) Lithium borohydride (174 mg) was added to a suspension of 715 mg of 1- (2-bromo-6-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene in 20 ml of tetrahydrofuran. And heat to reflux.
A mixture of 2.2 ml of methanol and 10 ml of tetrahydrofuran is added dropwise to the mixture under reflux over 2 hours. After completion of the reaction, the solvent is distilled off, and ethyl acetate and water are added to the residue, and the ethyl acetate layer is separated. The ethyl acetate layer was washed and dried, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (solvent; chloroform: methanol = 1).
5: 1) to give 1- (2-bromo-6-pyridyl)
505 mg of -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene are obtained.

M. p. 107-108 ° C (2) Production Example 6- (1- (2-bromo-6-pyridyl) -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene and the corresponding nitrogen-containing compound [III] 2)
1- [2- (2-oxo-1,2-dihydroquinolin-1-yl) pyridine-6 shown in Table 8
-Yl] -2,3-bis (hydroxymethyl) -6,7
To obtain dimethoxynaphthalene.

M. p. 142-143 ° C Production Example 64 1- (2-Bromo-4-pyridyl) -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene and a potassium salt of phthalimide were produced according to Production Example 6- (2). In the same manner, 1- (2-phthalimido-4-pyridyl)-
1- (2) described in Table 9 which is a hydrolyzate of 2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene
-Amino-4-pyridyl) -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene is obtained.

M. p. 99-103 ° C Production Example 65 1- (2-bromo-4-pyridyl) -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene and 2
-Oxobenzoxazolidine was treated in the same manner as in Production Example 6- (2) to give 1- [2- (2-oxobenzoxazolidin-3-yl) -4-pyridyl] -2,3-bis (hydroxymethyl). 1- [2- (2-Hydroxyphenyl) amino-4-pyridyl] -2,3-bis (hydroxymethyl) -6,7- described in Table 9 which is a hydrolyzate of -6,7-dimethoxynaphthalene Obtain dimethoxynaphthalene.

M. p. 90-93 ° C Production Example 66 (1) 1- (4-Pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene N-oxide 1.99 g in a 10 ml toluene suspension was dissolved in 2-ml. 3.27 g of chloroquinoline are added. Then, 5 drops of a 30% hydrogen bromide-acetic acid solution are added, and the mixture is heated under reflux for 15 hours. After evaporating the solvent, water and methylene chloride are added to the residue, and then the mixture is adjusted to pH 8 with an aqueous sodium hydrogen carbonate solution. After extraction with methylene chloride, the extract is washed, dried, and the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent; chloroform: acetone = 4: 1) to give 1- [2- (2-
Oxo-1,2-dihydroquinolin-1-yl) -4-
Pyridyl] -2,3-bis (methoxycarbonyl)-
2.60 g of 6,7-dimethoxynaphthalene are obtained.

M. p. > 230 ° C (2) 1- [2- (2-oxo-1,2-dihydroquinolin-1-yl) -4-pyridyl] -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene 2
To a suspension of 00 mg of tetrahydrofuran is added 36 mg of sodium borohydride, and the mixture is heated to reflux. 0.3 ml of methanol is added dropwise to the mixture under reflux over 1 hour. The mixture is allowed to return to room temperature, and sodium borohydride 3
6 mg was added, and 0.3 ml of methanol was added under reflux with heating.
Drip over time. After completion of the reaction, methylene chloride and dilute hydrochloric acid are added to the reaction mixture, and the methylene chloride layer is separated.
The methylene chloride layer was washed and dried, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (solvent; chloroform: methanol = 20: 1) to obtain a compound shown in Table 9
-[2- (2-oxo-1,2-dihydroquinoline-1
-Yl) -4-pyridyl] -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene (90 mg) is obtained.

M. p. > 230 ° C (recrystallized from ethyl acetate) Production Example 67 (1) N-oxide of 1- (4-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene and 4- [3- (1-Imidazolyl) propyl] amino-2-chloroquinoline was treated in the same manner as in Production Example 66- (1) to give 1- {2- [2-oxo-4- [3- ( 1-imidazolyl) propyl] amino-1,2-dihydroquinolin-1-yl] -4-pyridyl {-2,3-bis (methoxycarbonyl) -6,7-
Obtain dimethoxynaphthalene.

M. p. 142-148 ° C (2) To a suspension of 2.2 g of this product in tetrahydrofuran is added 640 mg of sodium borohydride, and the mixture is heated to reflux.
A mixture of 5.4 ml of methanol and 6 ml of tetrahydrofuran is added dropwise to the mixture under reflux over 2 hours.
The mixture is returned to room temperature and the sodium borohydride 400
of methanol, and 3.4 ml of methanol was added under reflux with heating.
Add dropwise over 5 hours. After completion of the reaction, an aqueous solution of sodium hydroxide and methylene chloride were added to the reaction mixture under ice cooling,
The methylene chloride layer is separated. After washing and drying the methylene chloride layer, the solvent is distilled off, and the residue is subjected to silica gel column chromatography (solvent; chloroform: methanol = 2: 1).
After purification, the resultant was dissolved in a dioxane / methanol solution, crystallized by adding 0.29 ml of a hydrogen chloride-dioxane solution, and further washed and dried.
[2-oxo-4- [3- (1-imidazolyl) propyl] amino-1,2-dihydroquinolin-1-yl]-
4-pyridyl} -2,3-bis (hydroxymethyl)-
90 mg of 6,7-dimethoxynaphthalene hydrochloride are obtained.

M. p. > 220 ° C Production Example 68-72 (1) 1- (4-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxy (or diethoxy)
The N-oxide of naphthalene and the corresponding halogeno nitrogen-containing compound [V] are treated in the same manner as in Production Example 66- (1) to obtain compounds shown in Table 18 below.

[0166]

[Table 29]

(2) The product obtained in the above (1) was treated in the same manner as in Preparation Example 66- (2) to obtain the compounds shown in Table 9.

Production Example 73 (1) N-oxide of 1- (4-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene and 2-chloro-4-benzyloxycarbonylmethoxyquinoline Was treated in the same manner as in Production Example 66- (1) to give 1- [2- (2-oxo-4-benzyloxycarbonylmethoxy-1,2-dihydroquinolin-1-yl).
-4-pyridyl] -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene.

M. p. 186-189 ° C (2) The product obtained in the above (1) was prepared in Production Example 66-
The same treatment as in (2) was performed and 1- {2- [2-
Oxo-4- (2-hydroxyethoxy) -1,2-dihydroquinolin-1-yl] -4-pyridyl} -2,3
-Bis (hydroxymethyl) -6,7-dimethoxynaphthalene is obtained.

M. p. 100-110 ° C (decomposition) Production Example 74 (1) N-oxide of 1- (4-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene and 2-chloro-4-morpholinocarbonyl Quinoline was treated in the same manner as in Production Example 66- (1) to give 1- [2-
(2-oxo-4-morpholinocarbonyl-1,2-dihydroquinolin-1-yl) -4-pyridyl] -2,3
-Bis (methoxycarbonyl) -6,7-dimethoxynaphthalene is obtained.

M. p. 247-249 ° C (2) The product obtained in the above (1) was prepared in Production Example 66-
The same treatment as in (2) was performed and 1- {2- [2-
(1-Hydroxymethyl-3-hydroxypropyl) phenylamino] -4-pyridyl {-2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene is obtained.

M. p. 204-207 ° C Production Example 75-81 (1) 1- (2-bromo-4-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene and the corresponding nitrogen-containing compound [III] Production Example 6
Treatment in the same manner as in (2) gives the compounds shown in Table 19 below.

[0173]

[Table 30]

(2) The product obtained in the above (1) was treated in the same manner as in Production Example 66- (2) to obtain the compounds shown in Tables 9 to 10.

Preparation Example 82 (1) Preparation of 1- (2-bromo-4-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene and 4-hydroxyquinoline Preparation Example 6- (2 )) To give 1- [2- (4-oxo-1,4-dihydroquinolin-1-yl) -4-pyridyl] -2,3-
Bis (methoxycarbonyl) -6,7-dimethoxynaphthalene is obtained.

M. p. 264-266 ° C (decomposition) (2) The product obtained in the above (1) was prepared in Production Example 66-
The same treatment as in (2) was performed and 1- [2- (4
-Hydroxy-1,2,3,4-tetrahydroquinolin-1-yl) -4-pyridyl] -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene.

M. p. 90-94 ° C Production Example 83 (1) Production of 1- (2-bromo-4-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene and 5-methyl-2-oxopyrrolidine Example 6
1- [2- (5-Methyl-2)
-Oxopyrrolidin-1-yl) -4-pyridyl]-
2,3-Bis (methoxycarbonyl) -6,7-dimethoxynaphthalene is obtained.

M. p. 184-186 ° C (2) The product obtained in the above (1) was prepared in Production Example 66-
The same treatment as in (2) was performed and 1- [2- (1
-Methyl-4-hydroxybutyl) amino-4-pyridyl] -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene.

M. p. 57-61 ° C. Production Example 84 (1) 1- (2-bromo-4-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene and 2-oxo-1,2,3,4 -Tetrahydroquinoline was treated in the same manner as in Production Example 6- (2) to give 1- [2-
(2-oxo-1,2,3,4-tetrahydroquinolin-1-yl) -4-pyridyl] -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene is obtained.

M. p. 229-233 ° C (2) The product obtained in the above (1) was prepared in Production Example 66-
The same treatment as in (2) was performed and 1- {2- [2
-(3-hydroxypropyl) phenyl] amino-4-
Pyridyl] -2,3-bis (hydroxymethyl) -6
7-Dimethoxynaphthalene is obtained.

M. p. 156-158 ° C Production Example 85 1- [2- (2-oxo-4-methoxymethoxy-1,
2-dihydroquinolin-1-yl) -4-pyridyl]-
1.39 g of 2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene was dissolved in a mixture of 10 ml of dioxane and 5 ml of methanol, and 2 ml of 2N hydrochloric acid was added to the solution.
Add. This solution was heated to 50 ° C., and stirred for 7 hours.
The solvent is distilled off. Chloroform and water are added to the residue, the chloroform layer is separated, washed, dried and the solvent is distilled off.
The residue was purified by silica gel column chromatography (solvent; chloroform: methanol = 10: 1) to give a 10th residue.
1- [2- (2-oxo-4-hydroxy-) described in the table
0.79 g of 1,2-dihydroquinolin-1-yl) -4-pyridyl] -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene is obtained.

M. p. 160-170 ° C Production Example 86 1- [2- (1-oxo-5-methoxymethoxy-1,
2-Dihydroisoquinolin-2-yl) -4-pyridyl] -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene was treated in the same manner as in Production Example 85 to give the first
1- [2- (1-oxo-5-hydroxy-) described in Table 0
1,2-Dihydroquinolin-2-yl) -4-pyridyl] -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene is obtained.

M. p. 138-140 ° C Production Example 87 1- [2- (2-oxo-4-tert-butoxycarbonyl-1,2-dihydroquinolin-1-yl) -4-
Pyridyl] -2,3-bis (hydroxymethyl) -6
0.96 g of 7-dimethoxynaphthalene is added to 25 ml of a 4N hydrogen chloride-dioxane solution under ice-cooling, and the mixture is stirred at room temperature overnight. After distilling off the solvent, the residue was purified by silica gel column chromatography (solvent; chloroform: methanol: acetic acid = 90: 10: 3), crystallized with ethyl acetate, and 1- [2- (2-oxo) described in Table 10. -4-carboxy-1,2-dihydroquinolin-1-yl) -4-pyridyl] -2,3-bis (hydroxymethyl) -6,7-
0.41 g of dimethoxynaphthalene is obtained.

M. p. > 250 ° C Production Example 88 1- {2- [2-oxo-4-bis (2-tert-butyldimethylsilyloxyethyl) aminocarbonyl-
1,2-dihydroquinolin-1-yl] -4-pyridyl {-2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene 1.9 g of tetrahydrofuran 20
2.8 ml of a tetrahydrofuran solution of tetrabutylammonium fluoride (1.0 M) is added to the ml solution under ice-cooling, and the mixture is stirred at room temperature for 1 hour. After completion of the reaction, the solvent is distilled off, methylene chloride and an aqueous solution of sodium hydrogen carbonate are added, and the methylene chloride layer is separated. After washing and drying the methylene chloride layer, the solvent is distilled off, and the residue is subjected to silica gel column chromatography (solvent; chloroform: methanol = 1).
0: 1 to 5: 1), and triturated with ether to give the first
1- {2- [2-oxo-4-bis (2-hydroxyethyl) aminocarbonyl-1,2-dihydroquinolin-1-yl] -4-pyridyl} -2,3-bis (hydroxy 0.68 g of (methyl) -6,7-dimethoxynaphthalene are obtained.

M. p. 65-68 ° C Production Example 89 1- {2- [2-oxo-4- [4- (2-tert-
Butyldimethylsilyloxyethyl) piperazine-1-
Yl] carbonyl-1,2-dihydroquinolin-1-yl] -4-pyridyl} -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene was treated in the same manner as in Production Example 88 and treated in Table 10. 1- {2- [2-oxo-
4- [4- (2-hydroxyethyl) piperazine-1-
Yl] carbonyl-1,2-dihydroquinolin-1-yl] -4-pyridyl {-2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene.

M. p. 150-153 ° C Production Example 90-92 1- [2- (2-oxo-1,2-dihydroquinoline-
A solution of 3.1 g of 1-yl) -4-pyridyl] -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene in 10 ml of dimethylformamide was prepared by adding 2.1 g of tert-butoxycarbonylglycine and 2.1 g of carbonyldiimidazole. 14 g of a 5 ml solution of dimethylformamide is added to the stirred solution for 30 minutes, and the mixture is stirred at room temperature overnight.
Ethyl acetate and water are added to the residue, and the ethyl acetate layer is separated. The ethyl acetate layer was washed and dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography (solvent; chloroform: methanol = 20: 1) to give 1- [2- (2-oxo-) described in Table 11. 1,2-dihydroquinolin-1-yl) -4-pyridyl] -2- (tert-butoxycarbonylaminomethylcarbonyloxymethyl)
0.8 g of -3-hydroxymethyl-6,7-dimethoxynaphthalene (Production Example 90), 1- [2- (2-oxo-
1,2-dihydroquinolin-1-yl) -4-pyridyl] -2-hydroxymethyl-3- (tert-butoxycarbonylaminomethylcarbonyloxymethyl)-
1.2 g of 6,7-dimethoxynaphthalene (Production Example 91)
And 1- [2- (2-oxo-1,2-dihydroquinolin-1-yl) -4-pyridyl] -2,3-bis (te
rt-butoxycarbonylaminomethylcarbonyloxymethyl) -6,7-dimethoxynaphthalene 0.47 g
(Production Example 92) is obtained.

(Production Example 90) m.p. p. 120-122 ° C (Production Example 91) m. p. 136-138 ° C (Production Example 92) Oily Product Production Example 93 1- [2- (2-oxo-1,2-dihydroquinoline-
1-yl) -4-pyridyl] -2-hydroxymethyl-
To 700 mg of 3- (tert-butoxycarbonylaminomethylcarbonyloxymethyl) -6,7-dimethoxynaphthalene, 5 ml of trifluoroacetic acid was added and dissolved, followed by stirring at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off, and methanol and 20 ml of a 15% hydrogen chloride-methanol solution were removed.
Was added. The solvent was distilled off, and the residue was triturated with ether to give 1- [2- (2-oxo-1,2-dihydroquinolin-1-yl) -4-pyridyl] -2-hydroxymethyl- described in Table 11. 510 mg of 3-aminomethylcarbonyloxymethyl-6,7-dimethoxynaphthalene hydrochloride
Get.

M. p. 126-128 ° C (decomposition) Production Example 94 1- [2- (2-oxo-1,2-dihydroquinoline-
1-yl) -4-pyridyl] -2- (tert-butoxycarbonylaminomethylcarbonyloxymethyl)-
3-Hydroxymethyl-6,7-dimethoxynaphthalene was treated in the same manner as in Production Example 93 to give 1- [2
-(2-oxo-1,2-dihydroquinolin-1-yl) -4-pyridyl] -2-aminomethylcarbonyloxymethyl-3-hydroxymethyl-6,7-dimethoxynaphthalene hydrochloride is obtained.

M. p. 146-149 ° C (decomposition) Production Example 95 1- [2- (2-oxo-1,2-dihydroquinoline-
1-yl) -4-pyridyl] -2,3-bis (tert
-Butoxycarbonylaminomethylcarbonyloxymethyl) -6,7-dimethoxynaphthalene was treated in the same manner as in Production Example 93 to give 1- [2- (2-oxo-1,2-dihydroquinoline-1-) shown in Table 11. Yl) -4-pyridyl] -2,3-bis (aminomethylcarbonyloxymethyl) -6,7-dimethoxynaphthalene dihydrochloride.

M. p. 165-168 ° C (decomposition) Production Example 96-97 1- [2- (2-oxo-1,2-dihydroquinoline-
1-yl) -4-pyridyl] -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene 468 mg
Is added to a solution of 5 ml of dimethylformamide, and the mixture is stirred for 30 minutes. The solution is cooled under ice, 0.17 ml of ethyl bromoacetate is added dropwise, and the mixture is stirred overnight. Ethyl acetate and water are added to the residue, and the ethyl acetate layer is separated. The ethyl acetate layer was washed and dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography (solvent; chloroform: acetone = 5: 1) to give a first residue.
1- [2- (2-oxo-1,2-dihydroquinolin-1-yl) -4-pyridyl] -2-ethoxycarbonylmethoxymethyl-3-hydroxymethyl- described in Table 1
6,7-dimethoxynaphthalene 70 mg (Production Example 9
6), 1- [2- (2-oxo-1,2-dihydroquinolin-1-yl) -4-pyridyl] -2-hydroxymethyl-3-ethoxycarbonylmethoxymethyl-6,7
-120 mg of dimethoxynaphthalene (Preparation Example 97) are obtained.

(Production Example 96) m.p. p. 190-192 ° C (Production Example 97) m.p. p. 124-126 ° C Production Example 98 1- [2- (2-oxo-1,2-dihydroquinoline-
1-yl) -4-pyridyl] -2-hydroxymethyl-
200 mg of 3-ethoxycarbonylmethoxymethyl-6,7-dimethoxynaphthalene in 5 m of tetrahydrofuran
0.36 ml of 1N sodium hydroxide solution is added to the 1 solution and stirred. 5 ml of methanol was further added to the solution, and
Heat to reflux for minutes. The reaction solution is cooled to room temperature, and 0.36 ml of 1N hydrochloric acid is added to adjust the pH to about 4. Chloroform is added to the reaction solution, and the chloroform layer is separated. After washing and drying the chloroform layer, the solvent is distilled off. To the residue without purification is added 5 ml of methylene chloride, 83 mg of dicyclohexylcarbodiimide and 61 mg of 1-hydroxybenzotriazole are added, and the mixture is stirred at room temperature for 30 minutes. 50 mg of 1-methylpiperazine is added to the solution and stirred overnight. After washing the reaction solution with water, the solvent is distilled off and silica gel column chromatography (solvent; chloroform: methanol = 10: 10).
Purified in 1), and purified from 1- [2- (2-oxo-1,2-dihydroquinolin-1-yl) -4-pyridyl] -2-hydroxymethyl-3- (4-methylpiperazine described in Table 11 -1-yl) carbonylmethoxymethyl-6,7-
150 mg of dimethoxynaphthalene are obtained.

M. p. 100-102 ° C Production Example 99 (1) 1- (2-chloro-4-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene was treated in the same manner as in Production Example 6- (1). To give 1- (2-chloro-4-pyridyl) -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene.

(2) 1- (2-chloro-4-pyridyl)
A mixture of 2.0 g of 2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene and piperazine was added to 13
Stir at 0 ° C. for 90 minutes. The mixture is returned to room temperature, and after completion of the reaction, methylene chloride and water are added, and the methylene chloride layer is separated. The solvent is distilled off, and the residue is dissolved in ethanol.
2.8 ml of a normal hydrogen chloride-dioxane solution was added to form a hydrochloride, and after distilling off the solvent, crystallization was performed with ethanol.
1.57 g of -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene dihydrochloride is obtained.

M. p. > 250 ° C. Production Examples 100 to 101 1- (2-chloro-4-pyridyl) -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene and the corresponding nitrogen-containing compound [III] are produced in Production Example 99 ( The compound described in Table 12 is obtained by treating in the same manner as in 2).

Production Example 102 1- (2-Chloro-4-pyridyl) -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene
8 g and 1,4-dioxa-8-azaspiro [4,5]
The mixture of decane is stirred at 140 ° C. for 18 hours. The mixture is returned to room temperature, and after completion of the reaction, chloroform and water are added, and the chloroform layer is separated. The solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent; chloroform: acetone = 5: 1).
-[2- (1,4-dioxa-8-azaspiro [4,
5] dec-8-yl) pyridin-4-yl] -2,3-
1.54 g (yield; 62%) of bis (hydroxymethyl) -6,7-dimethoxynaphthalene are obtained.

M. p. 100-103 ° C Production Example 103 1- [2- (1,4-dioxa-8-azaspiro [4,
5] dec-8-yl) pyridin-4-yl] -2,3-
A mixture of 1.40 g of bis (hydroxymethyl) -6,7-dimethoxynaphthalene, 3.62 ml of 70% perchloric acid, 15 ml of tetrahydrofuran and 10 ml of water is stirred at room temperature for 3 days. After completion of the reaction, chloroform and water are added, and the chloroform layer is separated. The solvent was distilled off, the residue was purified by silica gel column chromatography (solvent; chloroform: acetone = 2: 1), dissolved in chloroform, and added with a 4N hydrogen chloride-dioxane solution, and the solvent was distilled off, as shown in Table 12. 828 mg of 1- [2- (4-oxo-1-piperidinyl) -4-pyridyl] -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene hydrochloride is obtained.

M. p. > 250 ° C Production Example 104 (1) 1- (2-Chloro-4-pyridyl) -2,3-bis (methoxycarbonyl) -6-methoxy-7-ethoxynaphthalene was prepared in the same manner as in Production Example 6- (1). Processing 1-
(2-Chloro-4-pyridyl) -2,3-bis (hydroxymethyl) -6-methoxy-7-ethoxynaphthalene is obtained.

M. p. 123-126 ° C (2) A suspension of 16.0 g of 1- (2-chloro-4-pyridyl) -2,3-bis (hydroxymethyl) -6-methoxy-7-ethoxynaphthalene in 50 ml of hydrazine hydrate was prepared. Heat to reflux for 4 hours. The mixture under reflux with heating is returned to room temperature, water is added and the crystals are filtered. The crystals are washed with water and dried to give 1- (2-hydrazino-4-pyridyl)-
2,3-bis (hydroxymethyl) -6-methoxy-7
14.5 g of ethoxynaphthalene are obtained.

M. p. 197-200 ° C (3) 1- (2-hydrazino-4-pyridyl) -2,3
-Bis (hydroxymethyl) -6-methoxy-7-ethoxynaphthalene 2.0 g, (2-carboxyphenyl)
A mixture of 1.35 g of-(3-pyridyl) ketone and 5 ml of ethylene glycol is heated under reflux for 2 hours. The mixture under reflux with heating is returned to room temperature, methylene chloride and water are added, and the methylene chloride layer is separated. After washing and drying the methylene chloride layer, the solvent is distilled off and crystallized from chloroform. The precipitate was dissolved in a chloroform-methanol mixed solution, and then a 4N hydrogen chloride-dioxane solution 0.67
1- {2- [4- (3-pyridyl) -1 (2H) -phthalazinone-2-yl] -4- described in Table 13
Pyridyl {-2,3-bis (hydroxymethyl) -6
Methoxy-7-ethoxynaphthalene hydrochloride 1.43 g
Get.

M. p. 211-215 ° C (decomposition) Production example 105 (1) Production example of 1- (2-chloro-4-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-diethoxynaphthalene 6- (1) To give 1- (2-chloro-4-pyridyl) -2,3-bis (hydroxymethyl) -6,7-diethoxynaphthalene.

M. p. 148-150 ° C (2) 1- (2-chloro-4-pyridyl) -2,3-bis (hydroxymethyl) -6,7-diethoxynaphthalene is treated in the same manner as in Production Example 104- (2). 1- (2-
(Hydrazino-4-pyridyl) -2,3-bis (hydroxymethyl) -6,7-diethoxynaphthalene is obtained.

M. p. 225-230 ° C (decomposition) (3) 1- (2-hydrazino-4-pyridyl) -2,3
-Bis (hydroxymethyl) -6,7-diethoxynaphthalene was treated in the same manner as in Production Example 104- (3) to give
1- {2- [4- (3-pyridyl) -1 (2
H) -phthalazinone-2-yl] -4-pyridyl}-
2,3-bis (hydroxymethyl) -6,7-diethoxynaphthalene hydrochloride is obtained.

M. p. 207-211 ° C. (decomposition) Production Examples 106-107 (1) 1- (2-Bromo-4-pyridyl) -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene Production Example 104- (2) ), And then processing as 1- (2-
(Hydrazino-4-pyridyl) -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene is obtained.

M. p. 214-220 ° C (2) 1- (2-hydrazino-4-pyridyl) -2,3
Production Example 10 of -bis (hydroxymethyl) -6,7-dimethoxynaphthalene and the corresponding carboxylic acid derivative [VII]
Treatment in the same manner as in 4- (3) gives the compounds listed in Table 13.

Production Example 108 A mixture of 2.0 g of 1- (2-hydrazino-4-pyridyl) -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene, 0.92 g of phthalic anhydride and 10 ml of ethylene glycol Is heated and stirred at 130 ° C. for 2 hours. The heated mixture is returned to room temperature, methylene chloride and water are added, and the methylene chloride layer is separated. After washing and drying the methylene chloride layer, the solvent is distilled off and crystallized with ethanol. As a result, 1- [2- (4
-Hydroxy-1 (2H) -phthalazinone-2-yl)
-4-pyridyl] -2,3-bis (hydroxymethyl)
1.68 g of -6,7-dimethoxynaphthalene (yield; 6
1%).

M. p. > 250 ° C Production Example 109 A mixture of 2.0 g of 1- (2-hydrazino-4-pyridyl) -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene and 20 ml of acetic acid is stirred at room temperature for 96 hours. After completion of the reaction, methylene chloride and an aqueous solution of potassium carbonate are added, and the methylene chloride layer is separated. The solvent was distilled off from the methylene chloride layer and crystallized from chloroform, and 1- [2- (2-acetylhydrazino) pyridin-4-yl] -2,3-bis (hydroxymethyl)-described in Table 13 was used.
0.84 g of 6,7-dimethoxynaphthalene is obtained.

M. p. 154-156 ° C Production Example 110-111 (1) 1- (2-bromo-4-pyridyl) -2-methoxycarbonyl-3-methyl-6,7-dimethoxynaphthalene was prepared in the same manner as in Production Example 6- (1). Treatment gives 1- (2-bromo-4-pyridyl) -2-hydroxymethyl-3-methyl-6,7-dimethoxynaphthalene.

M. p. 106-108 ° C (2) Production example 6 of this product and the corresponding nitrogen-containing compound [III]
-Treat in the same manner as in (2) to obtain the compounds shown in Table 14.

Production Examples 112 to 114 (1) 1- (2-Bromo-4-pyridyl) -2-methoxycarbonyl-6,7-dimethoxynaphthalene was treated in the same manner as in Production Example 6- (1) to give 1- (2-Bromo-4-pyridyl) -2-hydroxymethyl-6,7-dimethoxynaphthalene is obtained.

M. p. 150-153 ° C (2) Production Example 6 of this product and the corresponding nitrogen-containing compound [III]
-(2) or by treating in the same manner as in Production Example 7 to obtain the compounds shown in Table 14.

Production Example 115 (1) 1- (2-Chloro-4-pyridyl) -2,3-bis (methoxycarbonyl) -6-benzyloxy-7-
Methoxynaphthalene is treated in the same manner as in Production Example 6- (1) to give 1- (2-chloro-4-pyridyl) -2,3-bis (hydroxymethyl) -6-benzyloxy-7-methoxynaphthalene.

M. p. 215-217 ° C (decomposition) (2) 1- (2-chloro-4-pyridyl) -2,3-bis (hydroxymethyl) -6-benzyloxy-7-methoxynaphthalene was prepared according to Production Example 104- (2). In the same manner, 1- (2-hydrazino-4-pyridyl) -2,3-
Bis (hydroxymethyl) -6-benzyloxy-7-
Obtain methoxynaphthalene.

M. p. 155-157 ° C (3) 1- (2-hydrazino-4-pyridyl) -2,3
-Bis (hydroxymethyl) -6-benzyloxy-7
-Methoxynaphthalene was treated in the same manner as in Production Example 104- (3) to give 1- {2- [4- (3-pyridyl) -1 (2H) -phthalazinone-2-yl] -4- as shown in Table 15. Pyridyl {-2,3-bis (hydroxymethyl) -6-benzyloxy-7-methoxynaphthalene hydrochloride is obtained.

M. p. 219-221 ° C (decomposition) Production Example 116 1- {2- [4- (3-pyridyl) -1 (2H) -phthalazinone-2-yl] -4-pyridyl} -2,3-bis (hydroxymethyl) 0.73 g of -6-benzyloxy-7-methoxynaphthalene in dichloromethane (10 m
1) 0.7 ml of acetic anhydride and 1.3 ml of triethylamine are added dropwise to the solution under ice cooling, and the mixture is stirred at room temperature overnight.
After diluting with dichloromethane, washing with water and drying, the solvent is distilled off. 10% palladium in a solution of the residue in acetic acid (50 ml)
0.1 g of carbon (Pd-C) is added, and the mixture is subjected to medium pressure catalytic reduction at room temperature overnight using a Parr reduction apparatus. After the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure.
0 ml). 0.2 g of sodium methoxide is added to the obtained methanol solution under ice-cooling. 3 at room temperature
After stirring for an hour, dilute hydrochloric acid is added to the reaction mixture under ice cooling, and the solvent is distilled off under reduced pressure. Water is added to the residue and extracted with dichloromethane. After the extract was washed and dried, the solvent was distilled off, the residue was crystallized from ethyl acetate, and then a 4N hydrogen chloride-ethyl acetate solution was added to obtain 1- {2- [4- ( 3-pyridyl) -1 (2H) -phthalazinone-2-yl] -4
-Pyridyl} -2,3-bis (hydroxymethyl) -6
-Hydroxy-7-methoxynaphthalene hydrochloride 0.1
5 g (25% yield) are obtained.

M. p. > 270 ° C Production Example 117 (1) 1- (2-Chloro-4-pyridyl) -2,3-bis (methoxycarbonyl) -6-benzyloxy-7-
Methoxynaphthalene 6.6 g of acetic acid-dioxane (1:
1) 2 g of 10% palladium-carbon (Pd-C) is added to 1000 ml of the mixed suspension, and the mixture is subjected to medium pressure catalytic reduction at room temperature overnight using a Parr reduction apparatus. Further, an acetic acid-dioxane mixed solution (1000 ml) is added, and 2 g of 10% palladium-carbon (Pd-C) is added. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was crystallized from ethanol to give 1- (2-chloro-4-pyridyl) -2,3-bis (methoxycarbonyl) -6-hydroxy. 3.35 g of -7-methoxynaphthalene (yield 62
%).

M. p. 231-233 ° C. (decomposition) (2) 3.34 g of 1- (2-chloro-4-pyridyl) -2,3-bis (methoxycarbonyl) -6-hydroxy-7-methoxynaphthalene in dimethylformamide 15
0.4 g of sodium hydride is added to the 0 ml solution under ice cooling, and the mixture is stirred at room temperature for 30 minutes. 1.8 ml of cyclopentane bromide is added dropwise to the solution and stirred at 80 ° C. overnight. One more
After heating to 30 ° C. and stirring for 2 hours, chloroform and water are added to the residue, and the chloroform layer is separated. After washing and drying the chloroform layer, the solvent is distilled off, and the residue is crystallized with ethanol to give 1- (2-chloro-4-pyridyl) -2,3-bis (methoxycarbonyl) -6-cyclopentyloxy. 1.24 g of -7-methoxynaphthalene
(Yield 32%).

M. p. 179-181 ° C (3) 1- (2-chloro-4-pyridyl) -2,3-bis (methoxycarbonyl) -6-cyclopentyloxy-7-methoxynaphthalene was treated in the same manner as in Production Example 6- (1). To give 1- (2-chloro-4-pyridyl) -2,3-
Bis (hydroxymethyl) -6-cyclopentyloxy-7-methoxynaphthalene is obtained.

M. p. 200-201 ° C (4) 1- (2-Chloro-4-pyridyl) -2,3-bis (hydroxymethyl) -6-cyclopentyloxy-
7-Methoxynaphthalene was treated in the same manner as in Production Example 104- (2) to give 1- (2-hydrazino-4-pyridyl)-
2,3-Bis (hydroxymethyl) -6-cyclopentyloxy-7-methoxynaphthalene is obtained.

M. p. 127-130 ° C (5) 1- (2-hydrazino-4-pyridyl) -2,3
-Bis (hydroxymethyl) -6-cyclopentyloxy-7-methoxynaphthalene was treated in the same manner as in Production Example 104- (3) to give 1- {2- [4- (3-
Pyridyl) -1 (2H) -phthalazinone-2-yl]-
4-pyridyl} -2,3-bis (hydroxymethyl)-
6-cyclopentyloxy-7-methoxynaphthalene.
Obtain the hydrochloride.

M. p. 215-217 ° C (decomposition) Production Example 118 (1) 1- (2-chloro-4-pyridyl) -2,3-bis (methoxycarbonyl) -6-isopropyloxy-
7-methoxynaphthalene was treated in the same manner as in Production Example 6- (1) to give 1- (2-chloro-4-pyridyl) -2,3-bis (hydroxymethyl) -6-isopropyloxy-7.
Obtaining methoxynaphthalene.

M. p. 129-131 ° C (2) 1- (2-chloro-4-pyridyl) -2,3-bis (hydroxymethyl) -6-isopropyloxy-7
-Methoxynaphthalene was treated in the same manner as in Production Example 104- (2) to give 1- (2-hydrazino-4-pyridyl) -2,
3-bis (hydroxymethyl) -6-isopropyloxy-7-methoxynaphthalene is obtained.

M. p. 128-131 ° C (3) 1- (2-hydrazino-4-pyridyl) -2,3
-Bis (hydroxymethyl) -6-isopropyloxy-7-methoxynaphthalene was treated in the same manner as in Production Example 104- (3) to give 1- {2- [4- (3-pyridyl) -1 shown in Table 15. (2H) -phthalazinone-2-yl] -4
-Pyridyl} -2,3-bis (hydroxymethyl) -6
-Isopropyloxy-7-methoxynaphthalene hydrochloride is obtained.

M. p. 203-206 ° C (decomposition) Production Example 119 (1) 1- (2-chloro-4-pyridyl) -2,3-bis (methoxycarbonyl) -6-butoxy-7-methoxynaphthalene Production Example 6- (1) 1)
(2-Chloro-4-pyridyl) -2,3-bis (hydroxymethyl) -6-butoxy-7-methoxynaphthalene is obtained.

M. p. 93-97 ° C (2) 1- (2-chloro-4-pyridyl) -2,3-bis (hydroxymethyl) -6-butoxy-7-methoxynaphthalene was treated in the same manner as in Production Example 104- (2). 1
-(2-Hydrazino-4-pyridyl) -2,3-bis (hydroxymethyl) -6-butoxy-7-methoxynaphthalene is obtained.

M. p. 93-97 ° C (3) 1- (2-hydrazino-4-pyridyl) -2,3
-Bis (hydroxymethyl) -6-butoxy-7-methoxynaphthalene was treated in the same manner as in Production Example 104- (3) to give 1- {2- [4- (3-pyridyl)-
1 (2H) -phthalazinone-2-yl] -4-pyridyl {-2,3-bis (hydroxymethyl) -6-butoxy-7-methoxynaphthalene hydrochloride is obtained.

M. p. 198-201 ° C (decomposition) Production Example 120 (1) 1- (2-Chloro-4-pyridyl) -2,3-bis (methoxycarbonyl) -6-octyloxy-7-
The methoxynaphthalene is treated in the same manner as in Production Example 6- (1) to obtain 1- (2-chloro-4-pyridyl) -2,3-bis (hydroxymethyl) -6-octyloxy-7-methoxynaphthalene.

M. p. 98-102 ° C (2) 1- (2-chloro-4-pyridyl) -2,3-bis (hydroxymethyl) -6-octyloxy-7-methoxynaphthalene was treated in the same manner as in Production Example 104- (2). To give 1- (2-hydrazino-4-pyridyl) -2,3-
Bis (hydroxymethyl) -6-octyloxy-7-
Obtain methoxynaphthalene.

M. p. 98-102 ° C (3) 1- (2-hydrazino-4-pyridyl) -2,3
-Bis (hydroxymethyl) -6-octyloxy-7
-Methoxynaphthalene was treated in the same manner as in Production Example 104- (3) to give 1- {2- [4- (3-pyridyl) -1 (2H) -phthalazinone-2-yl] -4- as shown in Table 15. Pyridyl {-2,3-bis (hydroxymethyl) -6-octyloxy-7-methoxynaphthalene hydrochloride is obtained.

M. p. 190-193 ° C (decomposition) Production Example 121 (1) 1- (2-chloro-4-pyridyl) -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene was produced according to Production Example 104- (2). By performing the same processing, 1- (2
-Hydrazino-4-pyridyl) -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene was obtained, and then this product and the corresponding starting compound [VII] were prepared in Production Example 104.
1- {2- [4- (3-pyridyl) -1 (2H) -phthalazinone-2-yl] -4 by treating in the same manner as in (3).
-Pyridyl} -2,3-bis (hydroxymethyl)-
Crude purified product of 6,7-dimethoxynaphthalene (75.5
g). A solution of the crude product in chloroform-methanol (3: 1) (700 ml) was treated with activated carbon (3.7 g), followed by chloroform-methanol (3: 1) (3: 1).
00 ml). 69 ml of 2N hydrochloric acid is added to the solution.
Is added, and the solvent is distilled off, azeotroped twice with ethanol (150 ml), and the solvent is distilled off. The precipitate was collected by filtration, washed with ethanol (200 ml), and dried by blowing air at 50 ° C. overnight to give 1- {2- [4- (3-pyridyl) -1 (2H).
-Phthalazinone-2-yl] -4-pyridyl} -2,3
84 g of bis (hydroxymethyl) -6,7-dimethoxynaphthalene hydrochloride are obtained. An aqueous solution of potassium carbonate (23 g of potassium carbonate in 300 ml of water) is added to a chloroform-methanol (3: 1) (1000 ml) solution of the product for washing, and the organic layer is dried. . 300 ml of ethanol is added, and chloroform and methanol are further distilled off. Again, ethanol (300 ml) is added, and a part of the solvent is distilled off. The precipitate was collected by filtration, washed with ethanol (300 ml), air-dried at 50 ° C. overnight, and dried at 1- {2- [4- (3-pyridyl) -1 (2H) -phthalazinone-2-yl shown in Table 15. ] -4
-Pyridyl} -2,3-bis (hydroxymethyl)-
66.6 g of 6,7-dimethoxynaphthalene (yield 85
%).

M. p. 269-270 ° C (2) 1- {2- [4- (3-pyridyl) -1 (2H)
-Phthalazinone-2-yl] -4-pyridyl} -2,3
-Bis (hydroxymethyl) -6,7-dimethoxynaphthalene sulfate m. p. > 260 ° C Production Example 122 (1) 1- (2-hydrazino-4-pyridyl) -2,3
-Bis (hydroxymethyl) -6,7-diethoxynaphthalene and the corresponding starting compound [VII] were prepared in Production Example 104-.
The same treatment as in (3) was carried out to give 1- {2- [4- (3-pyridyl) -1 (2H) -phthalazinone-2-yl] -4-.
Pyridyl} -2,3-bis (hydroxymethyl) -6
A crude product of 7-diethoxynaphthalene (6.5 g) is obtained. Ethanol-water (33ml-13m) at room temperature
l) Add the mixture and suspend. 35% hydrochloric acid (2.2 ml) was added dropwise to the suspension to dissolve it, and the temperature was raised to 50 to 55 ° C. After treatment with activated carbon (1.3 g), the activated carbon was filtered off.
Wash with ethanol-water (13 ml-7 ml). The solution was heated to 45 to 50 ° C., and an aqueous sodium hydroxide solution (1 g of sodium hydroxide in 13 ml of water) was added dropwise.
After stirring at ６０60 ° C. for 3 hours, stirring at room temperature overnight and cooling with ice, collecting the precipitate by filtration, washing with 50% ethanol (13 ml), and drying by blowing air at 50 ° C. overnight, described in Table 15. 1- {2- [4- (3-pyridyl) -1 (2H)
-Phthalazinone-2-yl] -4-pyridyl} -2,3
5.6 g (86% yield) of -bis (hydroxymethyl) -6,7-diethoxynaphthalene was obtained.

M. p. 222 ° C. (2) The product obtained in Production Example 122- (1) was treated with sulfuric acid instead of hydrogen chloride in the same manner as in Production Example 104- (3) to give 1- {2- [4- ( 3-pyridyl) -1 (2
H) -phthalazinone-2-yl] -4-pyridyl}-
2,3-Bis (hydroxymethyl) -6,7-diethoxynaphthalene sulfate was obtained.

M. p. > 220 ° C (3) The product obtained in Production Example 122- (1) was treated with methanesulfonic acid instead of hydrogen chloride in the same manner as in Production Example 104- (3) to give 1- {2- [ 4- (3-pyridyl) -1 (2H) -phthalazinone-2-yl] -4-pyridyl {-2,3-bis (hydroxymethyl) -6,7
-Diethoxynaphthalene methanesulfonate was obtained.

M. p. 160-163 ° C (decomposition) Production Example 123 1- (2-Hydrazino-4-pyridyl) -2,3-bis (hydroxymethyl) -6,7-diethoxynaphthalene was prepared in the same manner as in Production Example 104- (3). Processing, 1- ｛2-
[4- (3-pyridyl) -1 (2H) -phthalazinone-
After obtaining a crude product (7.0 g) of 2-yl] -4-pyridyl} -2,3-bis (hydroxymethyl) -6,7-diethoxynaphthalene, ethanol-water (35 ml-1) was obtained.
4 ml), add the mixture, and suspend at room temperature. 35% hydrochloric acid (2.3 ml) was added dropwise to the suspension and dissolved.
The temperature was raised to ° C., activated carbon treatment (1.4 g) was performed, followed by washing with ethanol-water (14 ml-7 ml). The solution was heated to 35 ° C., and an aqueous sodium hydroxide solution (water 1
1.1 g of sodium hydroxide in 4 ml) are added dropwise and the dihydrate is inoculated. After stirring for 1 hour under ice-cooling, the precipitate was collected by filtration, washed with 50% ethanol (14 ml), and air-dried at 50 ° C. overnight to give 1- ｛2 described in Table 15.
-[4- (3-pyridyl) -1 (2H) -phthalazinone-2-yl] -4-pyridyl {-2,3-bis (hydroxymethyl) -6,7-diethoxynaphthalene dihydrate 6 0.4 g (86% yield) are obtained.

M. p. 141 ° C (melting at 141 ° C,
It is made anhydrous by heating and crystals are precipitated. 222-22
(Melting again at 3 ° C.) Production Example 124 (1) 1- (2-chloro-4-pyridyl) -3-methoxycarbonyl-6,7-dimethoxynaphthalene was treated in the same manner as in Production Example 6- (1) to give 1 -(2-Chloro-4-pyridyl) -3-hydroxymethyl-6,7-dimethoxynaphthalene is obtained.

M. p. 115-118 ° C (2) Production Example 1 of 1- (2-chloro-4-pyridyl) -3-hydroxymethyl-6,7-dimethoxynaphthalene
The same treatment as in 04- (2) was carried out to give 1- (2-hydrazino-
4-Pyridyl) -3-hydroxymethyl-6,7-dimethoxynaphthalene is obtained.

M. p. 139-144 ° C (3) 1- (2-hydrazino-4-pyridyl) -3-hydroxymethyl-6,7-dimethoxynaphthalene was treated in the same manner as in Production Example 104- (3), and −
{2- [4- (3-Pyridyl) -1 (2H) -phthalazinone-2-yl] -4-pyridyl} -3-hydroxymethyl-6,7-dimethoxynaphthalene hydrochloride is obtained.

M. p. > 250 ° C Production Example 125 (1) Bishydride hydride at 5 ° C or lower under a nitrogen atmosphere in a suspension of 1- (2-chloro-4-pyridyl) -3-carboxy-6,7-diethoxynaphthalene in 50 ml of tetrahydrofuran. (Methoxyethoxy) aluminum sodium 2
A mixed solution of 9.4 ml (70% toluene solution) and 20 ml of tetrahydrofuran is added dropwise and reacted at the same temperature for 1 hour.
After completion of the reaction, 12 ml of methanol was added, and then 6.2
Add 48 ml of 5N aqueous sodium hydroxide solution, and add
For 1 hour. After separating the tetrahydrofuran layer, methylene chloride is added to the aqueous layer, and after extraction, the methylene chloride layer is separated. After the organic layers were combined, the solvent was distilled off, extracted again with methylene chloride, washed and dried, and the solvent was distilled off. The residue was purified by silica gel chromatography (solvent; chloroform: ethyl acetate = 4: 1). Then, it is crystallized from diethyl ether to obtain 3.94 g of 1- (2-chloro-4-pyridyl) -3-hydroxymethyl-6,7-diethoxynaphthalene.

M. p. 135-137 ° C (2) 3.90 g of 1- (2-chloro-4-pyridyl) -3-hydroxymethyl-6,7-diethoxynaphthalene
Is heated and refluxed for 9 hours. The mixture under heating and refluxing is stirred at room temperature for 10 minutes, then under ice cooling for 10 minutes, methylene chloride and water are added, and the methylene chloride layer is separated. The methylene chloride layer was washed and dried, and the solvent was distilled off. The residue was dissolved in 20 ml of ethanol while heating, and the mixture was allowed to cool and stir overnight to give 1- (2-hydrazino-
3.19 g of 4-pyridyl) -3-hydroxymethyl-6,7-diethoxynaphthalene are obtained.

M. p. 147-149 ° C (3) 1- (2-hydrazino-4-pyridyl) -3-hydroxymethyl-6,7-diethoxynaphthalene 1.0
6g was treated in the same manner as in Production Example 104- (3),
1- {2- [4- (3-pyridyl) -1 (2
H) -Phthalazinone-2-yl] -4-pyridyl} -3
-Hydroxymethyl-6,7-diethoxynaphthalene
1.45 g of the hydrochloride are obtained.

M. p. 197-201 ° C (decomposition) Production Example 126 177 mg of 1- (2-hydrazino-4-pyridyl) -3-hydroxymethyl-6,7-diethoxynaphthalene,
1-carboxy-2-phenylcarbonylbenzene 19
Using 1 mg and 1 ml of ethylene glycol, 1 of Table 17 was obtained in the same manner as in Production Example 104- (3).
-[2- (4-phenyl-1 (2H) -phthalazinone-
2-yl) -4-pyridyl] -3-hydroxymethyl-
206 mg of 6,7-diethoxynaphthalene are obtained.

M. p. 203-204 ° C Production Example 127 1- (2-hydrazino-4-pyridyl) -3-hydroxymethyl-6,7-diethoxynaphthalene 177 mg,
137 mg of 1-carboxy-2- (4-chlorophenylcarbonyl) benzene and 1 ml of ethylene glycol
Using the same operation as in Production Example 104- (3),
247 mg of 1- {2- [4- (4-chlorophenyl) -1 (2H) -phthalazinone-2-yl] -4-pyridyl} -3-hydroxymethyl-6,7-diethoxynaphthalene shown in Table 17 was obtained. obtain.

M. p. 223-225 ° C Production Example 128 1- (2-hydrazino-4-pyridyl) -3-hydroxymethyl-6,7-diethoxynaphthalene 177 mg,
1-carboxy-2-methylcarbonylbenzene 86m
Production Example 10 using g and 1 ml of ethylene glycol.
By the same operation as 4- (3), 1- of Table 17
[2- (4-methyl-1 (2H) -phthalazinone-2-
Yl) -4-pyridyl] -3-hydroxymethyl-6,
This gives 211 mg of 7-diethoxynaphthalene.

M. p. 220-221 ° C. Reference Example 1 (1) 3,4-dimethoxybenzaldehyde 398.8
g in 1.8 liters of acetic acid and 136 ml of bromine at room temperature.
Is added dropwise over 4 hours. After stirring overnight, bromine 60
ml is slowly added dropwise and stirred overnight. The reaction solution is added to 7 liters of water, the precipitated crystals are collected by filtration, and the crystals obtained by washing with water are dissolved in 2 liters of chloroform. The chloroform solution is washed, dried and concentrated, and crystallized from diisopropyl ether to obtain 470 g of 6-bromo-3,4-dimethoxybenzaldehyde as colorless crystals.

M. p. 144-146 ° C (2) 470 g of 6-bromo-3,4-dimethoxybenzaldehyde is suspended in 600 ml of methanol, 1025 ml of methyl orthoformate and IRA-120 (H + type) 1
Add 0 g and heat to reflux for 1 hour. After returning to room temperature, insolubles are filtered off, the filtrate is concentrated under reduced pressure, and the obtained residue is dissolved in ether. After washing and drying, the ether is distilled off and the residue is distilled under reduced pressure to obtain 522 g of 6-bromo-3,4-dimethoxybenzaldehyde dimethyl acetal as a main fraction (133-138 ° C./1 Torr).

Reference Example 2 3,4-Diethoxybenzaldehyde was treated in the same manner as in Reference Example 1 to obtain 6-bromo-3,4-diethoxybenzaldehyde dimethyl acetal.

B. p. 145-150 ° C / 1 Torr Reference Example 3 3-Methoxy-4-ethoxybenzaldehyde is treated in the same manner as in Reference Example 1 to obtain 6-bromo-3-methoxy-4-ethoxybenzaldehyde dimethyl acetal.

B. p. 160-162 ° C./2 Torr Reference Example 4 Benzaldehyde is treated in the same manner as in Reference Example 1 to obtain 2-bromobenzaldehyde dimethyl acetal.

B. p. 90-100 ° C / 1 Torr Reference Example 5 3-Ethoxy-4-methoxybenzaldehyde is treated in the same manner as in Reference Example 1 to obtain 6-bromo-3-ethoxy-4-methoxybenzaldehyde dimethyl acetal.

B. p. 170-175 ° C / 3 Torr Reference Example 6 6-bromo-3,4-dimethoxybenzaldehyde dimethyl acetal 20 g of tetrahydrofuran 100 ml
The solution is cooled to −60 ° C., and under a nitrogen atmosphere, 45.1 ml of a hexane solution of n-butyllithium (1.6 M) is added dropwise over 20 minutes. After reacting at the same temperature for 30 minutes, a solution of 7.36 g of 4-formylpyridine in 50 ml of tetrahydrofuran is added dropwise over 20 minutes. After reacting for 1 hour, water and 200 ml of ethyl acetate were added to the reaction solution, the ethyl acetate layer was separated, washed and dried, and ethyl acetate was distilled off to remove 3,4-dimethoxy-6- (4-pyridyl). 15.4 g of hydroxymethylbenzaldehyde dimethyl acetal are obtained.

M. p. 130-133 ° C. Reference Example 7 6-Bromo-3,4-diethoxybenzaldehyde dimethyl acetal is treated in the same manner as in Reference Example 6 to obtain 3,4-diethoxy-6- (4-pyridyl) hydroxymethylbenzaldehyde dimethyl acetal. .

M. p. 108-109 ° C. Reference Example 8 6-bromo-3-methoxy-4-ethoxybenzaldehyde dimethyl acetal was treated in the same manner as in Reference Example 6 to give 3
-Methoxy-4-ethoxy-6- (4-pyridyl) hydroxymethylbenzaldehyde dimethyl acetal is obtained.

M. p. 125-127 ° C Reference Example 9 2-Bromobenzaldehyde dimethyl acetal is treated in the same manner as in Reference Example 6 to obtain 6- (4-pyridyl) hydroxymethylbenzaldehyde dimethyl acetal.

M. p. 115-116 ° C Reference Example 10 6-Bromo-3-ethoxy-4-methoxybenzaldehyde dimethyl acetal was treated in the same manner as in Reference Example 6 to give 3
-Ethoxy-4-methoxy-6- (4-pyridyl) hydroxymethylbenzaldehyde dimethyl acetal is obtained.

M. p. 114-115 ° C Reference Example 11 6-Bromo-3,4-dimethoxybenzaldehyde dimethyl acetal and 2-bromo-4-formylpyridine were treated in the same manner as in Reference Example 6, and 3,4-dimethoxy-6
(2-Bromo-4-pyridyl) hydroxymethylbenzaldehyde dimethyl acetal is obtained as an oil.

Reference Example 12 6-Bromo-3,4-dimethoxybenzaldehyde dimethyl acetal and 2-formylpyridine were treated in the same manner as in Reference Example 6 to give 3,4-dimethoxy-6- (2-pyridyl) hydroxymethylbenzaldehyde dimethyl. The acetal is obtained as an oil.

Reference Example 13 6-Bromo-3,4-dimethoxybenzaldehyde dimethyl acetal and 3-formylpyridine were treated in the same manner as in Reference Example 6 to give 3,4-dimethoxy-6- (3-pyridyl) hydroxymethylbenzaldehyde dimethyl. The acetal is obtained as an oil.

Reference Example 14 3,4-Dimethoxy-6- (4-pyridyl) hydroxymethylbenzaldehyde dimethyl acetal 18.4 g
8.64 ml of dimethyl maleate is added to a solution of 50 ml of acetic acid in 50 ml of toluene, and the mixture is refluxed for 1 hour. 9.33 ml of methanesulfonic acid was added, and the mixture was refluxed for 8 hours while removing generated water using a Dean-Stark apparatus. After returning to room temperature, the reaction solution was concentrated, and the obtained residue was dissolved in chloroform.
Adjust to The solution was extracted with chloroform, washed, dried and concentrated, and the residue obtained was crystallized from ether to give 1-
13.5 g of (4-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene are obtained.

M. p. 204-206 ° C. Reference Example 15 3,4-diethoxy-6- (4-pyridyl) hydroxymethylbenzaldehyde dimethyl acetal Reference Example 1
Treatment in the same manner as in 4 gives 1- (4-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-diethoxynaphthalene.

M. p. 149-150 ° C Reference Example 16 3-methoxy-4-ethoxy-6- (4-pyridyl) hydroxymethylbenzaldehyde dimethyl acetal was treated in the same manner as in Reference Example 14 to give 1- (4-pyridyl)-
2,3-bis (methoxycarbonyl) -6-methoxy-
7-ethoxynaphthalene is obtained.

M. p. 195-197 ° C Reference Example 17 6- (4-pyridyl) hydroxymethylbenzaldehyde dimethyl acetal was treated in the same manner as in Reference Example 14 to give 1
-(4-Pyridyl) -2,3-bis (methoxycarbonyl) naphthalene is obtained.

M. p. 197-198 ° C Reference Example 18 3-ethoxy-4-methoxy-6- (4-pyridyl) hydroxymethylbenzaldehyde dimethyl acetal was treated in the same manner as in Reference Example 14 to give 1- (4-pyridyl)-
2,3-bis (methoxycarbonyl) -6-ethoxy-
7-methoxynaphthalene is obtained.

M. p. 188-189 ° C Reference Example 19 3,4-Dimethoxy-6- (2-pyridyl) hydroxymethylbenzaldehyde dimethyl acetal was used as Reference Example 1.
Treatment in the same manner as in 4 gives 1- (2-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene.

M. p. 163-165 ° C. Reference Example 20 3,4-Dimethoxy-6- (3-pyridyl) hydroxymethylbenzaldehyde dimethyl acetal Reference Example 1
Treatment in the same manner as in 4 gives 1- (3-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene.

M. p. 95-96 ° C Reference Example 21 Metachloroperbenzoic acid in 300 ml of a methylene chloride solution of 5 g of 1- (4-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene under ice cooling.
Add 1 g, bring to room temperature and stir overnight. Wash the reaction solution,
After drying and concentration, 15.0 g of N-oxide of 1- (4-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene is obtained as crystals.

M. p. 237-239 ° C Reference Example 22 1- (4-Pyridyl) -2,3-bis (methoxycarbonyl) -6,7-diethoxynaphthalene was treated in the same manner as in Reference Example 21 to give 1- (4-pyridyl)- This gives the N-oxide of 2,3-bis (methoxycarbonyl) -6,7-diethoxynaphthalene.

M. p. 177-178 ° C Reference Example 23 1- (4-Pyridyl) -2,3-bis (methoxycarbonyl) -6-methoxy-7-ethoxynaphthalene was treated in the same manner as in Reference Example 21 to give 1- (4-pyridyl). −2,3
N-oxide of -bis (methoxycarbonyl) -6-methoxy-7-ethoxynaphthalene is obtained.

M. p. > 220 ° C Reference Example 24 1- (4-Pyridyl) -2,3-bis (methoxycarbonyl) naphthalene was treated in the same manner as in Reference Example 21 to give 1-
The N-oxide of (4-pyridyl) -2,3-bis (methoxycarbonyl) naphthalene is obtained.

M. p. 215-218 ° C Reference Example 25 1- (4-Pyridyl) -2,3-bis (methoxycarbonyl) -6-ethoxy-7-methoxynaphthalene was treated in the same manner as in Reference Example 21 to give 1- (4-pyridyl). −2,3
N-oxide of -bis (methoxycarbonyl) -6-ethoxy-7-methoxynaphthalene is obtained.

M. p. 230-231 ° C Reference Example 26 1- (2-Pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene was treated in the same manner as in Reference Example 21 to give 1- (2-pyridyl) -2. To give the N-oxide of 2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene.

M. p. 173-175 ° C. Reference Example 27 1- (3-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene was treated in the same manner as in Reference Example 21 to give 1- (3-pyridyl) -2. To give the N-oxide of 2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene.

M. p. 185-186 ° C (decomposition) Reference Example 28 Toluene solution of sodium bis (methoxyethoxy) aluminum hydride in 25 ml of tetrahydrofuran (3.
4M) and cool to -10 ° C. 25 ml of a suspension of 10.0 g of 1- (4-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-diethoxynaphthalene in tetrahydrofuran is added dropwise thereto over 15 minutes. The temperature of the reaction solution was increased, and the mixture was stirred under ice cooling for 1.5 hours.
3.7 ml of 15% aqueous sodium hydroxide solution are added. Water and methylene chloride are added to the reaction mixture, and insolubles are removed by filtration. The filtrate was extracted with methylene chloride, and the extract was washed, dried and concentrated to give 1- (4-pyridyl) -2,3-bis (hydroxymethyl) -6,7-diethoxynaphthalene7.
89 g are obtained.

M. p. 159-161 ° C. Reference Example 29 1- (4-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene was treated in the same manner as in Reference Example 28 to give 1- (4-pyridyl) -2. , 3-Bis (hydroxymethyl) -6,7-dimethoxynaphthalene is obtained.

M. p. 135-138 ° C. Reference Example 30 1- (4-pyridyl) -2,3-bis (hydroxymethyl) -6,7-diethoxynaphthalene (20.0 g) was dissolved in methylene chloride (200 ml), and acetic anhydride was added under ice-cooling. .
6 g and 57.4 g of triethylamine are added dropwise and stirred at room temperature overnight. The residue was diluted with methylene chloride, washed with water, dried and concentrated. The residue was recrystallized from a mixed solution of ethyl acetate and hexane to give 1- (4-pyridyl) -2,3-bis (acetoxymethyl) -6,7-diethoxynaphthalene. 22.4 g are obtained.

M. p. 115-116 ° C Reference Example 31 1- (4-Pyridyl) -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene was treated in the same manner as in Reference Example 30 to give 1- (4-pyridyl) -2. , 3-Bis (acetoxymethyl) -6,7-dimethoxynaphthalene is obtained.

M. p. 165-167 ° C Reference Example 32 19.0 g of metachloroperbenzoic acid at room temperature in a solution of 22.4 g of 1- (4-pyridyl) -2,3-bis (acetoxymethyl) -6,7-diethoxynaphthalene in 100 ml of methylene chloride. And stirred overnight. The reaction solution is washed, dried and concentrated, and the residue is crystallized from ether to give 1- (4-pyridyl) -2,3-bis (acetoxymethyl) -6,7-.
20.8 g of N-oxide of diethoxynaphthalene are obtained.

M. p. 158-159 ° C Reference Example 33 1- (4-Pyridyl) -2 treated with 1- (4-pyridyl) -2,3-bis (acetoxymethyl) -6,7-dimethoxynaphthalene in the same manner as in Reference Example 32. N of 3,3-bis (acetoxymethyl) -6,7-dimethoxynaphthalene
-Obtain the oxide.

M. p. 182-185 ° C. Reference Example 34 A mixture of 30 g of N-oxide of 1- (4-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene and 150 ml of phosphorus oxychloride is heated under reflux for 2 hours. The phosphorus oxychloride is distilled off, methylene chloride and an aqueous solution of potassium carbonate are added, and the methylene chloride layer is separated. After distilling off the solvent, the residue is crystallized from methanol to obtain 26 g of 1- (2-chloro-4-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene.

M. p. 201-203 ° C Reference Example 35 N- of 1- (4-pyridyl) -2,3-bis (methoxycarbonyl) -6-methoxy-7-ethoxynaphthalene
The oxide is treated in the same manner as in Reference Example 34 to obtain 1- (2-chloro-4-pyridyl) -2,3-bis (methoxycarbonyl) -6-methoxy-7-ethoxynaphthalene.

M. p. 196-198 ° C Reference Example 36 1- (4-Pyridyl) -2,3-bis (methoxycarbonyl) naphthalene N-oxide was treated in the same manner as in Reference Example 34 to give 1- (2-chloro-4-pyridyl)- 2,3-bis (methoxycarbonyl) naphthalene is obtained.

M. p. 174-178 ° C Reference Example 37 N- of 1- (4-pyridyl) -2,3-bis (methoxycarbonyl) -6-ethoxy-7-methoxynaphthalene
The oxide is treated in the same manner as in Reference Example 34 to obtain 1- (2-chloro-4-pyridyl) -2,3-bis (methoxycarbonyl) -6-ethoxy-7-methoxynaphthalene.

M. p. 205-208 ° C Reference Example 38 1- (4-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-diethoxynaphthalene N-oxide was treated in the same manner as in Reference Example 34 to give 1- (2- Chloro-4-pyridyl) -2,3-bis (methoxycarbonyl) -6
7-Diethoxynaphthalene is obtained.

M. p. 154-156 ° C. Reference Example 39 1- (2-Pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene N-oxide was treated in the same manner as in Reference Example 34 to give 1- (2-chloro). -6-pyridyl) -2,3-bis (methoxycarbonyl) -6.
7-dimethoxynaphthalene and 1- (4-chloro-2-
Pyridyl) -2,3-bis (methoxycarbonyl)-
A mixture of 6,7-dimethoxynaphthalene is obtained.

MS; 415 (M ⁺ ) Reference Example 40 1- (3-Pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene N-oxide was treated in the same manner as in Reference Example 34. 1- (2-chloro-5-pyridyl) -2,3-bis (methoxycarbonyl) -6
7-dimethoxynaphthalene and 1- (2-chloro-3-
Pyridyl) -2,3-bis (methoxycarbonyl)-
A mixture of 6,7-dimethoxynaphthalene is obtained.

MS; 415 (M ⁺ ) Reference Example 41 1- (2-Chloro-4-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene 2
2.7 g, a mixture of 52 ml of phosphorus tribromide and 100 ml of 1,1,2,2-tetrachloroethane at 100 ° C. for 10 minutes.
Stir for hours. After the reaction, the solvent is distilled off, methylene chloride and an aqueous solution of potassium carbonate are added, and the methylene chloride layer is separated. After distilling off the solvent, the residue is crystallized from methanol to obtain 17.1 g of 1- (2-bromo-4-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene.

M. p. 192-194 ° C. Reference Example 42 1- (2-Chloro-4-pyridyl) -2,3-bis (methoxycarbonyl) naphthalene is treated in the same manner as in Reference Example 41 to give 1- (2-bromo-4-pyridyl). This gives -2,3-bis (methoxycarbonyl) naphthalene.

M. p. 162-163 ° C Reference Example 43 1- (2-Chloro-4-pyridyl) -2,3-bis (methoxycarbonyl) -6-ethoxy-7-methoxynaphthalene was treated in the same manner as in Reference Example 41 to obtain 1- ( This gives 2-bromo-4-pyridyl) -2,3-bis (methoxycarbonyl) -6-ethoxy-7-methoxynaphthalene.

M. p. 203-204 ° C. Reference Example 44 The mixture obtained in Reference Example 39 was treated in the same manner as in Reference Example 41,
Further, silica gel purification was performed to obtain 1- (2-bromo-6-pyridyl) -2,3-bis (methoxycarbonyl) -6.
7-Dimethoxynaphthalene is obtained.

M. p. 199-200 ° C. Reference Example 45 The mixture obtained in Reference Example 40 was treated in the same manner as Reference Example 41,
Further purification by silica gel gave 1- (2-bromo-5-pyridyl) -2,3-bis (methoxycarbonyl) -6,
7-Dimethoxynaphthalene is obtained.

M. p. 182-184 ° C. Reference Example 46 1- (4-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene N-oxide of 106.4 g of a 1,2-dichloroethane suspension in 500 ml of 1,2-dichloroethane was added. 100 g of phosphorus bromide is added and the mixture is refluxed for 5 hours. After completion of the reaction, the solvent and the like are distilled off, and ethyl acetate is added.
The ethyl acetate solution was added to ice water, and the precipitated crystals were collected by filtration.
(2-bromo-4-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene 38.
9 g are obtained.

M. p. 192-194 ° C. Reference Example 47 3,4-Dimethoxy-6- (4-pyridyl) hydroxymethylbenzaldehyde dimethyl acetal and methyl crotonate were treated in the same manner as in Reference Example 14 to give 1- (4-pyridyl) -2-methoxy. Carbonyl-3-methyl-6,7
To obtain dimethoxynaphthalene.

M. p. 152-154 ° C Reference Example 48 3,4-Dimethoxy-6- (4-pyridyl) hydroxymethylbenzaldehyde dimethyl acetal and methyl acrylate were treated in the same manner as in Reference Example 14 to give 1- (4-pyridyl) -2-methoxy. This gives carbonyl-6,7-dimethoxynaphthalene.

M. p. 152-154 ° C Reference Example 49 1- (4-pyridyl) -2-methoxycarbonyl-3-
Methyl-6,7-dimethoxynaphthalene is treated in the same manner as in Reference Example 21 to obtain 1- (4-pyridyl) -2-methoxycarbonyl-3-methyl-6,7-dimethoxynaphthalene N-oxide.

M. p. 230-232 ° C Reference Example 50 1- (4-pyridyl) -2-methoxycarbonyl-6,
7-Dimethoxynaphthalene was treated in the same manner as in Reference Example 21 to give 1- (4-pyridyl) -2-methoxycarbonyl-
The N-oxide of 6,7-dimethoxynaphthalene is obtained.

M. p. 222-224 ° C. Reference Example 51 1- (4-pyridyl) -2-methoxycarbonyl-3-
The N-oxide of methyl-6,7-dimethoxynaphthalene was treated in the same manner as in Reference Example 34 to give 1- (2-chloro-4-
Pyridyl) -2-methoxycarbonyl-3-methyl-
6,7-Dimethoxynaphthalene is obtained.

M. p. 133-136 ° C Reference Example 52 1- (4-pyridyl) -2-methoxycarbonyl-6,
Reference Example 34 N-oxide of 7-dimethoxynaphthalene
1- (2-chloro-4-pyridyl) -2
-Methoxycarbonyl-6,7-dimethoxynaphthalene is obtained.

M. p. 142-145 ° C Reference Example 53 1- (2-Chloro-4-pyridyl) -2-methoxycarbonyl-3-methyl-6,7-dimethoxynaphthalene was treated in the same manner as in Reference Example 41 to give 1- (2-bromo -4-pyridyl) -2-methoxycarbonyl-3-methyl-6,
7-Dimethoxynaphthalene is obtained.

M. p. 148-150 ° C Reference Example 54 1- (2-Chloro-4-pyridyl) -2-methoxycarbonyl-6,7-dimethoxynaphthalene was treated in the same manner as in Reference Example 41 to give 1- (2-bromo-4-pyridyl). ) -2
-Methoxycarbonyl-6,7-dimethoxynaphthalene is obtained.

M. p. 146-148 ° C Reference Example 55 Isovanillin 200g dimethylformamide 500m
After adding 236 g of potassium carbonate to the solution under ice-cooling,
203 ml of benzyl bromide are added dropwise and stirred overnight. The insolubles of the reaction residue were filtered, washed with acetone, the solvent was distilled off, ether and water were added to the residue, washed again, and the solvent was distilled off to give 3-benzyloxy-4-methoxybenzaldehyde ( Oily substance).

Reference Example 56 (1) Reference Example 1- (1) was added to 3-benzyloxy-4-methoxybenzaldehyde in the presence of acetic acid-sodium acetate.
6-bromo-3-benzyloxy-
4-methoxybenzaldehyde is obtained.

M. p. 140-141 ° C (2) 6-bromo-3-benzyloxy-4-methoxybenzaldehyde was treated in the same manner as in Reference Example 1- (2) to give 6-bromo-3-benzyloxy-4-methoxybenzaldehyde dimethyl acetal (Oil).

Reference Example 57 6-Bromo-3-benzyloxy-4-methoxybenzaldehyde dimethyl acetal was treated in the same manner as in Reference Example 6 to give 3-benzyloxy-4-methoxy-6- (4-
Obtain pyridyl) hydroxymethylbenzaldehyde dimethyl acetal (oil).

Reference Example 58 3-benzyloxy-4-methoxy-6- (4-pyridyl) hydroxymethylbenzaldehyde dimethyl acetal was treated at room temperature for 3 days in the same manner as in Reference Example 14 to give 1
-(4-Pyridyl) -2,3-bis (methoxycarbonyl) -6-benzyloxy-7-methoxynaphthalene is obtained.

M. p. 240-242 ° C (decomposition) Reference Example 59 1- (4-Pyridyl) -2,3-bis (methoxycarbonyl) -6-benzyloxy-7-methoxynaphthalene was treated in the same manner as in Reference Example 21 to give 1- (4-pyridyl)
N-oxide of -2,3-bis (methoxycarbonyl) -6-benzyloxy-7-methoxynaphthalene is obtained.

M. p. 254-257 ° C (decomposition) Reference Example 60 1- (4-pyridyl) -2,3-bis (methoxycarbonyl) -6-benzyloxy-7-methoxynaphthalene N-oxide was treated in the same manner as in Reference Example 34. And 1-
(2-Chloro-4-pyridyl) -2,3-bis (methoxycarbonyl) -6-benzyloxy-7-methoxynaphthalene is obtained.

M. p. 260-261 ° C (decomposition) Reference Example 61 1- (4-Pyridyl) -2,3-bis (methoxycarbonyl) -6-benzyloxy-7-methoxynaphthalene was treated in the same manner as in Production Example 117- (1). And 1- (4-
Pyridyl) -2,3-bis (methoxycarbonyl) -6
-Hydroxy-7-methoxynaphthalene is obtained.

M. p. 225-230 ° C (decomposition) Reference Example 62 1- (4-pyridyl) -2,3-bis (methoxycarbonyl) -6-hydroxy-7-methoxynaphthalene and isopropyl iodide are the same as in Production Example 117- (2). To give 1- (4-pyridyl) -2,3-bis (methoxycarbonyl) -6-isopropyloxy-7-methoxynaphthalene.

M. p. 210-212 ° C Reference Example 63 1- (4-Pyridyl) -2,3-bis (methoxycarbonyl) -6-hydroxy-7-methoxynaphthalene and butyl iodide were treated in the same manner as in Production Example 117- (2). hand,
1- (4-pyridyl) -2,3-bis (methoxycarbonyl) -6-butoxy-7-methoxynaphthalene is obtained.

M. p. 149-151 ° C. Reference Example 64 1- (4-Pyridyl) -2,3-bis (methoxycarbonyl) -6-hydroxy-7-methoxynaphthalene and octyl bromide were treated in the same manner as in Production Example 117- (2). hand,
1- (4-pyridyl) -2,3-bis (methoxycarbonyl) -6-octyloxy-7-methoxynaphthalene is obtained.

M. p. 124-126 ° C Reference Example 65 1- (4-Pyridyl) -2,3-bis (methoxycarbonyl) -6-isopropyloxy-7-methoxynaphthalene was treated in the same manner as in Reference Example 21 to give 1- (4- N-oxide of pyridyl) -2,3-bis (methoxycarbonyl) -6-isopropyloxy-7-methoxynaphthalene is obtained.

M. p. 195-200 ° C (decomposition) Reference Example 66 1- (4-Pyridyl) -2,3-bis (methoxycarbonyl) -6-butoxy-7-methoxynaphthalene was treated in the same manner as in Reference Example 21 to give 1- ( 4-pyridyl) -2,
3-bis (methoxycarbonyl) -6-butoxy-7-
This gives the N-oxide of methoxynaphthalene.

M. p. 170-173 ° C Reference Example 67 1- (4-Pyridyl) -2,3-bis (methoxycarbonyl) -6-octyloxy-7-methoxynaphthalene was treated in the same manner as in Reference Example 21 to give 1- (4-pyridyl) -6-octyloxy-7-methoxynaphthalene. Pyridyl)
N-oxide of 2,3-bis (methoxycarbonyl) -6-octyloxy-7-methoxynaphthalene is obtained.

M. p. 143-146 ° C Reference Example 68 1- (4-Pyridyl) -2,3-bis (methoxycarbonyl) -6-isopropyloxy-7-methoxynaphthalene N-oxide was treated in the same manner as in Reference Example 34 to give 1
-(2-Chloro-4-pyridyl) -2,3-bis (methoxycarbonyl) -6-isopropyloxy-7-methoxynaphthalene is obtained.

M. p. 195-200 ° C (decomposition) Reference Example 69 N- of 1- (4-pyridyl) -2,3-bis (methoxycarbonyl) -6-butoxy-7-methoxynaphthalene
The oxide is treated in the same manner as in Reference Example 34 to obtain 1- (2-chloro-4-pyridyl) -2,3-bis (methoxycarbonyl) -6-butoxy-7-methoxynaphthalene.

M. p. 143-147 ° C. Reference Example 70 1- (4-pyridyl) -2,3-bis (methoxycarbonyl) -6-octyloxy-7-methoxynaphthalene N-oxide was treated in the same manner as in Reference Example 34 to give 1 −
(2-Chloro-4-pyridyl) -2,3-bis (methoxycarbonyl) -6-octyloxy-7-methoxynaphthalene is obtained.

M. p. 93-97 ° C. Reference Example 71 Under a nitrogen atmosphere, 78.7 g of 4-carboxy-2-chloropyridine is gradually added to a suspension of 28.4 g of sodium borohydride in 750 ml of tetrahydrofuran, and then boron trifluoride / diethyl ether After dropping 123 ml of the complex salt, the mixture is reacted at room temperature for 6 hours. 960 ml of 6N hydrochloric acid was added dropwise to the reaction-terminated liquid, the organic solvent was distilled off, the mixture was made alkaline with sodium hydroxide, and extracted with chloroform. The chloroform layer is washed with a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent is distilled off, to obtain 62.2 g of 2-chloro-4-hydroxymethylpyridine.

M. p. 63-65 ° C. Reference Example 72 (1) A solution of oxalyl chloride (42.2 ml) in methylene chloride (1100 ml) was added dropwise at −60 ° C. to −50 ° C. with 68.7 ml of dimethyl sulfoxide in methylene chloride (220 ml). At the same temperature, a solution of 63.2 g of 2-chloro-4-hydroxymethylpyridine in methylene chloride 4
After dropping 40 ml, the mixture is stirred for 15 minutes. Next, 306.6 ml of triethylamine is added dropwise at the same temperature, and the mixture is stirred for 5 minutes and then brought to room temperature. 2.2 l of water is added to the reaction-terminated liquid, the methylene chloride layer is separated, and the aqueous layer is extracted again with 2.2 l of methylene chloride and combined with the previous methylene chloride layer. The combined methylene chloride layer was washed with a saturated aqueous solution of sodium bicarbonate, dried, and the solvent was distilled off.
Obtain carbaldehyde.

(2) A solution of 2-chloropyridine-4-carbaldehyde in dimethylformamide (150 ml) was added dropwise to a suspension of 5.2 g of sodium cyanide in 200 ml of dimethylformamide over a period of 5 minutes. A solution of 61.4 ml of tert-butyl ester in dimethylformamide (350 ml) was added dropwise over 10 minutes,
Stir overnight. Ethyl acetate and water were added to the reaction solution,
The ethyl acetate layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, dried, and the solvent was distilled off. The residue was purified by silica gel chromatography (solvent; hexane: ethyl acetate = 4: 1), and then 4- (2-chloropyridine- 4-yl) -4-oxo-butyric acid tert-butyl ester (oil)
82.8 g are obtained.

Reference Example 73 4- (2-chloropyridin-4-yl) -4-oxo-
118 ml of trifluoroacetic acid was added to 82.8 g of tert-butyl butyrate under ice-cooling, and the mixture was stirred for 15 minutes and reacted at room temperature for 1 hour. Further, 24 ml of trifluoroacetic acid is added and reacted at room temperature for 2 hours. The trifluoroacetic acid was distilled off, trifluoroacetic acid was azeotropically distilled with toluene, and then crystallized with diethyl ether to give 4- (2-chloropyridin-4-yl) -4-oxo-butyric acid 53.8.
g.

M. p. 118-120 ° C Reference Example 74 4- (2-chloropyridin-4-yl) -4-oxo-
A mixture of 2.14 g of butyric acid, 1.66 g of 3,4-dimethoxybenzaldehyde, 0.82 g of sodium acetate and 5.66 ml of acetic anhydride is stirred at 80 ° C. for 2 hours. Acetic acid and 50 ml of concentrated hydrochloric acid are added dropwise, and the mixture is heated under reflux for 2 hours.
The reaction solution was washed with ether, and pH = 4 with sodium hydroxide.
After drying, the solvent was distilled off, and the residue was extracted with an organic solvent (chloroform: methanol = 9: 1).
-Chloro-4-pyridyl) -3-carboxy-6,7-
Dimethoxynaphthalene (yield; 67%) is obtained.

M. p. > 250 ° C Reference Example 75 1- (2-chloro-4-pyridyl) -3-carboxy-
To a solution of 2.3 g of 6,7-dimethoxynaphthalene in 60 ml of tetrahydrofuran (THF) was added dropwise a solution of 2.36 ml of sodium bis (methoxyethoxy) aluminum hydride (70% toluene solution) at −10 ° C. Stir for 1 hour at room temperature. 1.57 ml of sodium bis (methoxyethoxy) aluminum hydride
A THF solution (5 ml) of (70% toluene solution) was added dropwise, and the mixture was further heated and stirred at 40 ° C. for 1 hour. After adding methanol to the reaction solution, aqueous sodium hydroxide solution (20 ml of water)
1.6 g of sodium hydroxide in water) and added at 50.degree.
Stir for minutes.

The reaction residue is extracted with ethyl acetate and further extracted with dichloromethane. The organic layer was washed with water, dried, and the solvent was distilled off. The residue was treated with silica gel column chromatography (solvent; chloroform: acetone = 19: 1) and crystallized with ether to give 1- (2-chloro-
There are obtained 531 mg (yield 24%) of 4-pyridyl) -3-hydroxymethyl-6,7-dimethoxynaphthalene.

M. p. 115-118 ° C Reference Example 76 3,4-diethoxybenzaldehyde 54.2 g, 4-
A mixture of 59.6 g of (2-chloropyridin-4-yl) -4-oxo-butyric acid, 22.9 g of sodium acetate and 158 ml of acetic anhydride is stirred under a nitrogen atmosphere at 80 ° C. for 2 hours. After allowing to cool for 30 minutes, 1.4 l of acetic acid and 1.4 l of concentrated hydrochloric acid are added, and the mixture is refluxed for 2 hours. The mixture under reflux with heating is ice-cooled, 672 g of sodium hydroxide is added, and then 1.4 l of water, 2.5 l of chloroform and 0.3 l of methanol are added. After drying the chloroform layer, the solvent is distilled off and the residue is crystallized from diethyl ether to obtain 70.4 g of 1- (2-chloro-4-pyridyl) -3-carboxy-6,7-diethoxynaphthalene.

M. p. > 250 ° C

──────────────────────────────────────────────────続 き Continued on front page (51) Int.Cl. ⁷ Identification code FI A61K 31/517 A61K 31/517 31/5377 31/5377 31/54 31/54 A61P 11/06 A61P 11/06 11/08 11 / 08 43/00 111 43/00 111 // C07D 213/74 C07D 213/74 237/30 237/30 239/72 239/72 239/96 239/96 279/16 279/16 401/04 401/04 417/04 417/04 471/04 113 471/04 113 114 114 (56) References JP-A-7-101861 (JP, A) Patent 3033090 (JP, B2) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 31/00-31/54 A61P 11/08 A61P 43/00 111 CA (STN) REGISTRY (STN)

Claims (29)

(57) [Claims] 1. A compound of the general formula [I] (However, R ¹ and R ² may be the same or different and are (1) a hydrogen atom or (2) (i) a lower alkanoyl group,
Protected by a bonyl group or a phenyl lower alkoxycarbonyl group.
Protected amino group; carboxyl group;
Alkoxycarbonyl group; hydroxyl group; and lower alkoxy group
Lower optionally substituted with one or two groups selected from
Alkanoyl group, (ii) lower alkoxycarbonyl
Group, lower alkoxy group, aryl group and lower alkyl group
Substituted with a group selected from substituted piperazinylcarbonyl groups
An optionally substituted alkyl group, and (iii) cycloal
A hydroxyl group which may be protected by a group selected from a kill group , and one of R ³ and R ⁴ is (1) a lower alkanoyl group or a lower alkoxycarbonyl
Or a phenyl lower alkoxycarbonyl group
Optionally substituted amino group; carboxyl group; lower alkoxy
Selected from cicarbonyl groups; hydroxyl groups; and lower alkoxy groups.
Lower alka which may be substituted with 1 to 2 groups
Noyl group, (2) lower alkoxycarbonyl group, lower alkoxy
Group, aryl group and lower alkyl group-substituted piperazinylka
Alun optionally substituted with a group selected from a rubonyl group
Kill group, (3) a lower alkoxycarbonyl group, and (4) an optionally protected hydroxy-substituted methyl group with a group selected from cycloalkyl group and the other (1) hydrogen atom, (2) a lower alkyl group Or (3) (i) a lower alkanoyl group, a lower alkoxycar
Protected by a bonyl group or a phenyl lower alkoxycarbonyl group.
Protected amino group; carboxyl group;
Alkoxycarbonyl group; hydroxyl group; and lower alkoxy group
Lower optionally substituted with one or two groups selected from
Alkanoyl group, (ii) lower alkoxycarbonyl
Group, lower alkoxy group, aryl group and lower alkyl group
Substituted with a group selected from substituted piperazinylcarbonyl groups
An optionally substituted alkyl group, (iii) lower alkoxy
Selected from a carbonyl group and (iv) a cycloalkyl group
It indicates that the is a protected unprotected hydroxy-substituted methyl group in group, R ⁵ and R ⁶ are the same or different, a hydrogen atom, an optionally substituted lower alkyl group, optionally substituted phenyl Represents a group or an amino group which may be protected, or represents that a heterocyclic group which may be substituted together with an adjacent nitrogen atom at the terminal of each other may be substituted. A pharmaceutical composition comprising, as an active ingredient, a naphthalene derivative represented by the following formula or a pharmaceutically acceptable salt thereof. 2. The pharmaceutical composition according to claim 1, wherein R ¹ and R ² are the same or different and each is a hydrogen atom or a lower alkoxy group. 3. A heterocyclic group in which R ⁵ and R ⁶ are bonded to each other at the terminal and formed together with an adjacent nitrogen atom is a heteroatom further selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to the nitrogen atom. Monocyclic, which may contain
3. The pharmaceutical composition according to claim 1, which is a bicyclic or tricyclic heterocyclic group. 4. A heterocyclic group formed by R ⁵ and R ⁶ bonded to each other at the terminal with an adjacent nitrogen atom is a pyridyl group, a quinolyl group, an isoquinolyl group, a cyclopenta [b] pyridyl group, a pyro [2 , 3-b] pyridyl group, imidazo [4,5-b] pyridyl group, pyrido [2,3-
d) thiazolyl group, pyrido [2,3-d] oxazolyl group, naphthyridinyl group, quinoxalinyl group, phthalazinyl group, quinazolinyl group, indolyl group, pyridazinyl group, azepinyl group, azetidyl group, isoindolyl group,
A pyrrolyl group, a benzazepinyl group, a phenanthridinyl group, a benzothiazinyl group, a benzimidazolinyl group, a pyrazinyl group or a morpholino group (these heterocyclic groups may be partially or completely hydrogenated). Item 4. The pharmaceutical composition according to Item 3, 5. A group in which R ⁵ and R ⁶ are terminally bonded to each other and can be substituted with a heterocyclic group formed together with an adjacent nitrogen atom, are (1) a lower alkenyl group; (2) a lower alkynyl group; (3) lower alkylthio group; (4) cycloalkyl group; (5) trifluoromethyl group; (6) cyano group; (7) tetrazolyl group; (8) formyl group;
An amino group; (10) a morpholino group, a monocycloalkyl group-substituted amino group, a pyridyl group, an imidazolyl group, a piperidyl group, or a mono- or di-lower alkylamino group in which a lower alkyl group part may be substituted with a pyrrolidinyl group; (11) pyridyl group; (12) morpholino group; (13) lower alkyl-substituted triazolyl group;
4) bis (hydroxy lower alkyl) aminocarbonyl group; (15) bis (tri-lower alkylsilyloxy lower alkyl) aminocarbonyl group; (16) morpholinocarbonyl group; (17) lower alkyl-substituted piperazinylcarbonyl group; 18) a hydroxy lower alkyl group-substituted piperazinylcarbonyl group; (19) a tri-lower alkylsilyloxy lower alkyl group-substituted piperazinylcarbonyl group; (20) a lower alkoxycarbonyl group;
A carboxyl group; (22) a lower alkyl group optionally substituted with a morpholino group or a pyridyl group; (23)
A lower alkoxy group optionally substituted with a piperidyl group, a pyridyl group, a hydroxyl group or a lower alkoxy group; (2
(25) hydroxyl group; (26) pyrimidinyl group; (27) phenyl group optionally substituted with di-lower alkylamino group or halogen atom; (28) halogen atom; (29) nitro group; 30. The pharmaceutical composition according to any one of claims 1 to 4, which is one or more same or different groups selected from imidazolyl group; and (31) lower alkylenedioxy group. 6. The heterocyclic group in which R ⁵ and R ⁶ are bonded to each other at the terminal and formed together with an adjacent nitrogen atom is a heterocyclic group substituted with at least an oxo group.
A pharmaceutical composition according to claim 1. 7. A heterocyclic group substituted by at least an oxo group has a partial structural formula: The pharmaceutical composition according to claim 6, which is a heterocyclic group having the formula: 8. The heterocyclic group which may be substituted and which is formed together with an adjacent nitrogen atom by bonding R ⁵ and R ^{6 at the} terminal to each other is (1) a morpholino group or a monocycloalkyl group-substituted amino group. A mono- or di-lower alkylamino group in which a lower alkyl group may be substituted with a pyridyl group, an imidazolyl group, a piperidino group or a pyrrolidinyl group; a pyridyl group; a morpholino group; a lower alkyl-substituted triazolyl group; Lower alkyl)
Aminocarbonyl group; bis (tri-lower alkylsilyloxy lower alkyl) aminocarbonyl group; morpholinocarbonyl group; lower alkyl group-substituted piperazinylcarbonyl group; hydroxy lower alkyl group-substituted piperazinylcarbonyl group; tri-lower alkylsilyloxy lower alkyl Group substituted piperazinylcarbonyl group; lower alkoxycarbonyl group; carboxyl group; lower alkyl group; lower alkoxy group optionally substituted by hydroxyl group or lower alkoxy group; and oxo optionally substituted by group selected from hydroxyl group. Group (or hydroxy group) substituted dihydro (or tetrahydro) quinolyl group, (2) oxo group (or hydroxy group) substituted dihydro (or tetrahydro) quinoxalinyl group, (3) morpholino group substituted lower alkyl group; piperidyl group, A lower alkoxy group which may be substituted with a lysyl group or a lower alkoxy group; and an oxo group (or hydroxy group) substituted dihydro (or tetrahydro) isoquinolyl group which may be substituted with a group selected from a hydroxyl group, and (4) pyridyl A lower alkyl group which may be substituted with a group; a pyrimidinyl group; a lower alkoxy group; a pyridyl group; an imidazolyl group; a phenyl group which may be substituted with a di-lower alkylamino group or a halogen atom; Optionally substituted oxo group (or hydroxy group) substituted dihydro (or tetrahydro) phthalazinyl group, (5) substituted with a group selected from halogen atom, lower alkyl group, lower alkoxy group, nitro group, pyridyl group and imidazolyl group Optionally substituted oxo (or hydroxy) substituted diphenyl B (or hexahydro) pyridyl group, (6) oxo group (or hydroxy group) substituted dihydro (or tetrahydro) naphthyridinyl group, (7) oxo group (or hydroxy group) substituted hexahydroquinolyl group, (8) oxo group (or Hydroxy group)
Substituted dihydroindolyl group, (9) oxo group (or hydroxy group) substituted dihydro (or tetrahydro) benzazepinyl group, (10) dihydro (or tetrahydro) isoquinolyl group, (11) oxo group (or hydroxy group)
A substituted dihydro (or tetrahydro) benzothiazinyl group, (12) an oxo (or hydroxy) -substituted dihydro (or tetrahydro) quinazolinyl group which may be substituted with a lower alkyl group and / or an oxo group, (13)
Oxo group (or hydroxy group) substituted dihydrobenzimidazolinyl group, (14) oxo group (or hydroxy group)
A substituted dihydrophenanthridinyl group, (15) an oxo group (or hydroxy group) -substituted dihydro (or tetrahydro) pyrrolyl group which may be substituted with a lower alkyl group,
The pharmaceutical composition according to claim 5, which is (16) a hexahydroxypyrazinyl group, (17) a lower alkylenedioxy group-substituted hexahydropyridyl group or (18) a morpholino group. 9. An optionally substituted heterocyclic group formed by bonding R ⁵ and R ^{6 at the} terminal to each other with an adjacent nitrogen atom is (1) an oxo group-substituted dihydro (or tetrahydro) quinolyl group. Or a hydroxy-substituted dihydro (or tetrahydro) quinolyl group, (2) an oxo-substituted dihydro (or tetrahydro) quinoxalinyl group,
(3) an oxo group-substituted dihydro (or tetrahydro) isoquinolyl group, (4) an oxo group-substituted dihydro (or tetrahydro) phthalazinyl group, (5) an oxo group-substituted dihydro (or hexahydro) pyridyl group, (6) an oxo group-substituted dihydro ( Or tetrahydro) naphthyridinyl group,
(7) an oxo-substituted hexahydroquinolyl group, (8) an oxo-substituted dihydroindolyl group, (9) an oxo-substituted dihydro (or tetrahydro) benzoazepinyl group,
(10) dihydro (or tetrahydro) isoquinolyl group, (11) oxo-substituted dihydro (or tetrahydro) benzothiazinyl group, (12) oxo-substituted dihydro (or tetrahydro) quinazolinyl group, (13) oxo-substituted dihydrobenzoimidazoly An oxo group-substituted dihydrophenanthridinyl group, (15) an oxo group-substituted dihydro (or tetrahydro) pyrrolyl group,
The pharmaceutical composition according to claim 8, which is (16) a hexahydroxypyrazinyl group, (17) a lower alkylenedioxy group-substituted hexahydropyridyl group or (18) a morpholino group. 10. An optionally substituted heterocyclic group formed by bonding R ⁵ and R ^{6 at the} terminal to each other and forming an adjacent nitrogen atom is (1) an oxo group-substituted dihydro (or tetrahydro) quinolyl group. Or a hydroxy-substituted tetrahydroquinolyl group, (2) an oxo-substituted dihydroquinoxalinyl group, (3) an oxo-substituted dihydroisoquinolyl group, (4) an oxo-substituted dihydrophthalazinyl group,
(5) an oxo-substituted dihydro (or hexahydro) pyridyl group, (6) an oxo-substituted dihydronaphthyridinyl group, (7) an oxo-substituted hexahydroquinolyl group,
(8) oxo group-substituted dihydroindolyl group, (9) oxo group-substituted dihydrobenzoazepinyl group, (10) tetrahydroisoquinolyl group, (11) oxo group-substituted tetrahydrobenzothiazinyl group, (12) oxo group substitution Dihydro (or tetrahydro) quinazolinyl group, (13) oxo-substituted dihydrobenzimidazolinyl group, (14) oxo-substituted dihydrophenanthridinyl group, (15) oxo-substituted tetrahydropyrrolyl group, (16) hexahydroxy The pharmaceutical composition according to claim 9, which is a piperazinyl group, (17) a lower alkylenedioxy group-substituted hexahydropyridyl group or (18) a morpholino group. 11. An optionally substituted heterocyclic group which is formed together with an adjacent nitrogen atom by bonding R ⁵ and R ^{6 at the} terminal to each other is (1) a morpholino group or a monocycloalkyl group-substituted amino group. , Pyridyl group, imidazolyl group,
A mono- or di-lower alkylamino group in which the lower alkyl group is substituted by a piperidino group or a pyrrolidinyl group; a pyridyl group; a morpholino group; a lower alkyl-substituted triazolyl group; a lower alkyl-substituted piperazinylcarbonyl group; A carbonyl group; a lower alkyl group; a hydroxyl group; and an oxo group-substituted dihydro (or tetrahydro) quinolyl group or a hydroxy group, which may be substituted with a group selected from a hydroxyl group and a lower alkoxy group which may be substituted with a lower alkoxy group. A tetrahydroquinolyl group, (2) an oxo group-substituted dihydroquinoxalinyl group, (3) a morpholino group-substituted lower alkyl group; a lower alkoxy group optionally substituted with a piperidyl group, a pyridyl group or a lower alkoxy group; and a hydroxyl group Substituted with a group selected from Oxo group-substituted dihydroisoquinolyl group, (4) pyridyl group-substituted lower alkyl group; pyrimidinyl group; lower alkoxy group; pyridyl group; imidazolyl group; and di-lower alkylamino group-substituted phenyl group. An oxo group-substituted dihydrophthalazinyl group which may be substituted, (5) a lower alkyl group; a lower alkoxy group; a pyridyl group; and an oxo group-substituted dihydropyridyl group substituted with a group selected from imidazolyl groups; Oxo group-substituted dihydronaphthyridinyl group,
(7) oxo group-substituted hexahydroquinolyl group, (8) oxo group-substituted dihydroindolyl group, (9) oxo group-substituted tetrahydrobenzothiazinyl group, (10) oxo optionally substituted with lower alkyl group and oxo group A group-substituted dihydro (or tetrahydro) quinazolinyl group, (1
The pharmaceutical composition according to claim 10, which is 1) an oxo-substituted dihydrobenzimidazolinyl group or (12) an oxo-substituted dihydrophenanthridinyl group. 12. An optionally substituted heterocyclic group wherein R ⁵ and R ⁶ are bonded to each other at the terminal and formed together with an adjacent nitrogen atom is (1) a morpholino group, a pyridyl group,
Mono- or di- in which the lower alkyl group is substituted with an imidazolyl group, a piperidino group or a pyrrolidinyl group
Oxo optionally substituted with a lower alkylamino group; a pyridyl group; a morpholino group; a lower alkyl group-substituted triazolyl group; a lower alkyl group; and a lower alkoxy group optionally substituted with a hydroxyl group or a lower alkoxy group. A group-substituted dihydro (or tetrahydro) quinolyl group or a hydroxy-substituted tetrahydroquinolyl group,
(2) an oxo-substituted dihydroquinoxalinyl group, (3)
A morpholino-substituted lower alkyl group; a lower alkoxy group substituted with a piperidyl group or a lower alkoxy group; and an oxo-substituted dihydroisoquinolyl group which may be substituted with a group selected from a hydroxyl group, and (4) pyridyl group substitution Lower alkyl group, pyrimidinyl group, pyridyl group,
An oxo group-substituted dihydrophthalazinyl group which may be substituted with a group selected from an imidazolyl group and a lower alkoxy group, and (5) a group selected from a lower alkyl group, a lower alkoxy group, a pyridyl group and an imidazolyl group 11. An oxo-substituted dihydropyridyl group, (6) an oxo-substituted tetrahydrobenzothiazinyl group, or (7) an oxo-substituted dihydro (or tetrahydro) quinazolinyl group optionally substituted with a lower alkyl group and an oxo group. A pharmaceutical composition according to claim 1. 13. An optionally substituted heterocyclic group in which R ⁵ and R ⁶ are bonded to each other at the terminal at the terminal, and may be formed together with an adjacent nitrogen atom, is (1) a morpholino group, a pyridyl group,
A mono- or di-lower alkylamino group in which a lower alkyl group is substituted with an imidazolyl group or a piperidino group; a pyridyl group; a morpholino group; a lower alkyl group-substituted triazolyl group; and a lower group substituted with a lower alkoxy group or a hydroxyl group An oxo group-substituted dihydroquinolyl group or a hydroxy group-substituted tetrahydroquinolyl group which may be substituted with a group selected from an alkoxy group, (2) a morpholino group-substituted lower alkyl group; substituted with a piperidino group or a lower alkoxy group A lower alkoxy group; and an oxo group-substituted dihydroisoquinolyl group which may be substituted with a group selected from a hydroxyl group, (3) a pyridyl group-substituted lower alkyl group, a pyrimidinyl group, a pyridyl group, an imidazolyl group and a lower alkoxy group. Which may be substituted with a group Substituted dihydrophthalazinyl group,
(4) an oxo-substituted dihydropyridyl group substituted by a group selected from a lower alkyl group, a lower alkoxy group, a pyridyl group and an imidazolyl group, or (5) an oxo group optionally substituted by a lower alkyl group and an oxo group The pharmaceutical composition according to claim 12, which is a substituted dihydro (or tetrahydro) quinazolinyl group. 14. An optionally substituted heterocyclic group wherein R ⁵ and R ⁶ are bonded to each other at the terminal and formed together with an adjacent nitrogen atom is (1) a morpholino group, a pyridyl group,
A mono- or di-lower alkylamino group in which a lower alkyl group is substituted with an imidazolyl group or a piperidino group; a pyridyl group; a morpholino group; a lower alkyl group-substituted triazolyl group; and a lower group substituted with a lower alkoxy group or a hydroxyl group An oxo group-substituted dihydroquinolyl group which may be substituted with a group selected from an alkoxy group,
(2) an oxo-substituted dihydroisoquinolyl group which may be substituted with a group selected from a morpholino group-substituted lower alkyl group and a piperidyl group-substituted lower alkoxy group;
An oxo group-substituted dihydrophthalazinyl group which may be substituted with a group selected from a pyridyl group-substituted lower alkyl group, a pyrimidinyl group, a pyridyl group, an imidazolyl group and a lower alkoxy group; or (4) a lower alkyl group, a lower alkoxy group; 14. The pharmaceutical composition according to claim 13, which is an oxo-substituted dihydropyridyl group substituted with a group selected from an imidazolyl group. 15. An optionally substituted heterocyclic group formed by bonding R ⁵ and R ^{6 at the} terminal to each other and forming an adjacent nitrogen atom is (1) a morpholino group or a monocycloalkyl-substituted amino group. A mono- or di-lower alkylamino group in which the lower alkyl group is substituted with a pyridyl group, an imidazolyl group or a piperidino group; a pyridyl group; a morpholino group; a lower alkyl group-substituted piperazinylcarbonyl group; a lower alkoxycarbonyl group; A lower alkyl group; a hydroxyl group; and an oxo-substituted dihydro (or tetrahydro) quinolyl group or a hydroxy-substituted tetrahydroquinolyl group optionally substituted with a group selected from a hydroxyl group and a lower alkoxy group optionally substituted with a lower alkoxy group. A (2) morpholino group-substituted lower alkyl group; a piperidino group, An oxo group-substituted dihydroisoquinolyl group which may be substituted with a group selected from a lysyl group or a lower alkoxy group substituted with a lower alkoxy group, (3) a pyridyl group-substituted lower alkyl group; a pyrimidinyl group; a lower alkoxy group Pyridyl group; imidazolyl group; and oxo group-substituted dihydrophthalazinyl group which may be substituted with a group selected from di-lower alkylamino group-substituted phenyl group, and (4) oxo group-substituted dihydro substituted with pyridyl group. Pyridyl group, (5) oxo-substituted dihydronaphthyridinyl group, (6) oxo-substituted hexahydroquinolyl group, (7) oxo-substituted dihydroindolyl group, (8) oxo-substituted tetrahydrobenzothiazinyl group, (9) ) An oxo-substituted dihydro (or tertiary alkyl) group which may be substituted with a lower alkyl group and an oxo group; Rahidoro)
The pharmaceutical composition according to claim 11, which is a quinazolinyl group, (10) an oxo-substituted dihydrobenzimidazolinyl group, or (11) an oxo-substituted dihydrophenanthridinyl group. 16. An optionally substituted heterocyclic group formed by bonding R ⁵ and R ^{6 at the} terminal to each other and forming an adjacent nitrogen atom is (1) a morpholino group, an imidazolyl group or a pyridyl group. An alkyl-substituted mono- or di-lower alkylamino group; a morpholino group; and an oxo group-substituted dihydro (or tetrahydro) which may be substituted with a group selected from lower alkyl groups.
Quinolyl group, (2) morpholino group-substituted lower alkyl group;
An oxo group-substituted dihydroisoquinolyl group which may be substituted with a group selected from a pyridyl group or a lower alkoxy group substituted with a lower alkoxy group, (3) a pyridyl group-substituted lower alkyl group; a lower alkoxy group; a pyridyl group ;
16. The pharmaceutical composition according to claim 15, which is an oxo-substituted dihydrophthalazinyl group or (4) an oxo-substituted dihydrophenanthridinyl group substituted with a group selected from a phenyl group and a di-lower alkylamino group. 17. An optionally substituted heterocyclic group wherein R ⁵ and R ⁶ are bonded to each other at the terminal at the terminal thereof and which is formed together with an adjacent nitrogen atom, is (1) a lower alkyl group moiety substituted with a pyridyl group. A mono- or di-lower alkylamino group; a morpholino group; and an oxo group-substituted dihydro (or tetrahydro) quinolyl group which may be substituted with a group selected from lower alkyl groups, and (2) a morpholino group-substituted lower alkyl group An oxo-substituted dihydroisoquinolyl group which may be substituted with a group selected from a pyridyl group or a lower alkoxy group substituted with a lower alkoxy group, (3) a pyridyl group-substituted lower alkyl group; a lower alkoxy group; And an oxo-substituted dihydrophthalazine substituted with a group selected from a di-lower alkylamino-substituted phenyl group Group or (4) a pharmaceutical composition according to claim 16, wherein an oxo group substituted dihydro phenanthridinyl group. 18. The heterocyclic group which may be substituted, wherein R ⁵ and R ⁶ are bonded to each other at the terminal at the terminal and which are formed together with an adjacent nitrogen atom, is (1) a morpholino group, an imidazolyl group or a pyridyl group. An alkyl-substituted mono- or di-lower alkylamino group; a morpholino group; and an oxo group-substituted dihydro (or tetrahydro) which may be substituted with a group selected from lower alkyl groups.
Quinolyl group, (2) morpholino group-substituted lower alkyl group;
And an oxo-substituted dihydroisoquinolyl group substituted with a group selected from a lower alkoxy group and a lower alkoxy group; (3) a lower alkyl group substituted with a pyridyl group; a lower alkoxy group; and a group selected from a pyridyl group. The pharmaceutical composition according to claim 10, which is an oxo-substituted dihydrophthalazinyl group. 19. R ¹ and R ² are the same or different, and (1) a lower alkanoyl group or a lower alkoxycarbonyl
Or a phenyl lower alkoxycarbonyl group
Optionally substituted amino group; carboxyl group; lower alkoxy
Selected from cicarbonyl groups; hydroxyl groups; and lower alkoxy groups.
Lower alka which may be substituted with 1 to 2 groups
Noyl group, (2) lower alkoxycarbonyl group, lower alkoxy
Group, aryl group and lower alkyl group-substituted piperazinylka
Alun optionally substituted with a group selected from a rubonyl group
A hydroxyl group protected with a group selected from a kill group and (3) a cycloalkyl group, and R ³ and R ⁴ are hydroxyl-substituted methyl groups.
The pharmaceutical composition according to 7, 11, 15, 16, 17 or 18. 20. The pharmaceutical composition according to claim 19, wherein the protected hydroxyl group is a hydroxyl group protected by a lower alkyl group. 21. 1- [2- (2-oxo-1,2-dihydroquinolin-1-yl) -4-pyridyl] -2,3
-Bis (hydroxymethyl) -6,7-dimethoxynaphthalene, 1- {2- [2-oxo-4- (2-piperidinoethyl) amino-1,2-dihydroquinolin-1-yl] -4-pyridyl}- 2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene, 1- {2- [2
-Oxo-4- (4-pyridyl) -1,2-dihydroquinolin-1-yl] -4-pyridyl} -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene, 1- [2- (2-oxo-3-morpholino-1,2
-Dihydroquinolin-1-yl) -4-pyridyl]-
2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene, 1- {2- [4- (3-pyridyl) -1
(2H) -phthalazinone-2-yl] -4-pyridyl}
-2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene, 1- {2- [4- (3-pyridylmethyl) -1 (2H) -phthalazinone-2-yl] -4-pyridyl}- 2,3-bis (hydroxymethyl) -6,7
-Dimethoxynaphthalene, 1- {2- [6,7-dimethoxy-4- (3-pyridyl) -1 (2H) -phthalazinone-2-yl] -4-pyridyl} -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene, 1-
{2- [4- (3-pyridyl) -1 (2H) -phthalazinone-2-yl] -4-pyridyl} -2,3-bis (hydroxymethyl) -6,7-diethoxynaphthalene, 1
-{2- [4- (3-pyridyl) -1 (2H) -phthalazinone-2-yl] -4-pyridyl} -2,3-bis (hydroxymethyl) -6-methoxy-7-ethoxynaphthalene or the like A pharmaceutical composition comprising, as an active ingredient, a pharmacologically acceptable salt of 22. 1- [2- (2-Oxo-3-morpholino-1,2-dihydroquinolin-1-yl) -4-pyridyl] -2,3-bis (hydroxymethyl) -6,7
-A pharmaceutical composition comprising dimethoxynaphthalene or a pharmaceutically acceptable salt thereof as an active ingredient. 23. 1- {2- [4- (3-pyridyl)-
Pharmaceutical composition comprising 1 (2H) -phthalazinone-2-yl] -4-pyridyl} -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene or a pharmaceutically acceptable salt thereof as an active ingredient . 24. 1- {2- [4- (3-Pyridylmethyl) -1 (2H) -phthalazinon-2-yl] -4-pyridyl} -2,3-bis (hydroxymethyl) -6,7
-A pharmaceutical composition comprising dimethoxynaphthalene or a pharmaceutically acceptable salt thereof as an active ingredient. 25. 1- {2- [4- (3-pyridyl)-
Pharmaceutical composition comprising 1 (2H) -phthalazinone-2-yl] -4-pyridyl} -2,3-bis (hydroxymethyl) -6,7-diethoxynaphthalene or a pharmaceutically acceptable salt thereof as an active ingredient object. 26. The pharmaceutical composition according to any one of claims 1 to 25, which is a phosphodiesterase IV inhibitor. 27. The pharmaceutical composition according to any one of claims 1 to 25, which is an anti-asthmatic drug. 28. A bronchoconstriction inhibitor according to claims 1-2.
6. The pharmaceutical composition according to any one of 5 above. 29. The pharmaceutical composition according to any one of claims 1 to 25, which is an anti-airway inflammatory agent.