JP3033090B2 - Naphthalene derivative, its production method and its synthetic intermediate - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel naphthalene derivative having an anti-asthmatic effect and a synthetic intermediate thereof.

[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) naphthalene is known, but is known from [Bulletin of the Chemical Society of Japan (BULLETINOF THE CHE).
MICAL SOCIETY OF JAPAN), V
ol. 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 aggregation inhibiting effect, inflammatory cells have an activation inhibiting effect, and adipocytes have a lipolytic effect [C. D. Nicholson et
al. , Trendsin Pharmacol. , 1
2, 19 (1991)].

[0005] Therefore, drugs that inhibit PDE are used for various diseases such as bronchial asthma, thrombosis, depression, central dysfunction after cerebral vascular obstruction, cerebrovascular dementia, Alzheimer's dementia, various inflammations, obesity. It is considered to be effective as a therapeutic agent for diseases and heart failure.

On the other hand, a number of anti-asthmatic drugs have been known, but existing drugs have drawbacks such as an insufficient effect of suppressing bronchoconstriction or insufficient separation from side effects on the heart and the like. Further development of new drugs 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]

SUMMARY OF THE INVENTION The present invention provides a novel naphthalene derivative which has an excellent bronchoconstriction inhibitory action and / or a selective phosphodiesterase IV (PDE IV) inhibitory action and is useful as an anti-asthmatic drug. is there. The present invention also provides a method for producing such a novel naphthalene derivative and a synthetic intermediate thereof.

[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.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The object compound [I] of the present invention or a salt thereof is a pharmaceutical compound having a strong bronchoconstriction inhibitory activity and useful as an agent for preventing or treating asthma. For example, the target compound [I] has a strong effect of suppressing bronchoconstriction, such as a stronger effect of suppressing antigen-induced bronchoconstriction than theophylline, and has the characteristics of not exhibiting side effects on the heart and the like.

The heterocyclic group in which R ⁵ and R ⁶ in the target compound [I] of the present invention are bonded together at the terminal at the terminal and formed with an adjacent nitrogen atom includes, in addition to the nitrogen atom, a nitrogen atom and an oxygen atom And a monocyclic, bicyclic or tricyclic heterocyclic group which may contain a hetero atom selected from sulfur atoms and sulfur atoms.

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.

Examples of the substitutable group on the lower alkyl group and the phenyl group of R ⁵ and / or R ⁶ in the target compound [I] of the present invention include a hydroxyl group and a mono- or dihydroxy lower alkyl group.

The amino-protecting group is not particularly limited as long as it can serve as an amino-protecting group, and examples thereof include a lower alkanoylamino group and a phenyl-lower alkoxycarbonyl group.

In the target compound [I] of the present invention, R ¹
And / or when R ² is a protected hydroxyl group, the hydroxyl-protecting group may be any pharmacologically acceptable hydroxyl-protecting 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 object compound [I] of the present invention, when R ³ and / or R ⁴ is a protected hydroxyl-substituted methyl group, the protecting group for the hydroxyl group may be a pharmacologically acceptable hydroxyl group. Any protective 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 includes one or two 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 above 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 a lower alkyl group part 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 alkylsilyl group) Shi-lower alkyl) aminocarbonyl group; (16) a morpholinocarbonyl group; (17) a lower alkyl group substituted piperazinylcarbonyl group; (18) a hydroxy-lower alkyl group substituted piperazinylcarbonyl group;
(19) tri-lower alkylsilyloxy lower alkyl-substituted piperazinylcarbonyl group; (20) lower alkoxycarbonyl group; (21) carboxyl group; (22) lower alkyl group optionally substituted with morpholino group or pyridyl group (23) a piperidyl group, a pyridyl group,
A lower alkoxy group which may be substituted with a hydroxyl group or a lower alkoxy group; (24) an oxo group; (25) a hydroxyl group;
(26) a pyrimidinyl group; (27) a di-lower alkylamino group or a phenyl group optionally substituted with a halogen atom; (28) a halogen atom; (29) a nitro group;
0) an imidazolyl group; and (31) a lower alkylenedioxy group. 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

[0023]

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And the like.

Specific examples of the object [I] of the present invention include:
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 the heterocyclic group is (1) a morpholino group, a monocycloalkyl-substituted amino group, a pyridyl group, A mono- or di-lower alkylamino group in which a lower alkyl group part may be substituted by an imidazolyl group, a piperidino group or a pyrrolidinyl group; a pyridyl group; a morpholino group; a lower alkyl group-substituted triazolyl group; bis (hydroxy lower alkyl) amino Carbonyl 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; low A lower alkoxy group which may be substituted with a hydroxyl group or a lower alkoxy group; and an oxo group (or hydroxy group) substituted dihydro group which may be substituted with a group selected from a hydroxyl group. (Or tetrahydro) quinolyl group, (2) oxo group (or hydroxy group)
Substituted dihydro (or tetrahydro) quinoxalinyl 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 (or a hydroxy group) optionally substituted with a group selected from a hydroxyl group. Substituted dihydro (or tetrahydro) isoquinolyl group,
(4) a lower alkyl group optionally substituted with a pyridyl group; a pyrimidinyl group; a lower alkoxy group; a pyridyl 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 a hydroxyl group. (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) an 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) benzoazepinyl group, (10) dihydro (or tetrahydro) isoquinolyl group, (11) oxo group (or hydroxy group) substituted dihydro (or tetrahydro) benzothiazinyl group, (1
2) an oxo group (or hydroxy group) -substituted dihydro (or tetrahydro) quinazolinyl group which may be substituted with a lower alkyl group and / or an oxo group, or (13) an oxo group (or hydroxy group) -substituted dihydrobenzimidazolinyl group , (14) an oxo group (or hydroxy group) -substituted dihydrophenanthridinyl group, (15) an oxo group (or hydroxy group) which may be substituted with a lower alkyl group
A substituted dihydro (or tetrahydro) pyrrolyl group, (1
6) hexahydroxypyrazinyl group, (17) lower alkylenedioxy group-substituted hexahydropyridyl group or (1)
8) Compounds that are morpholino groups.

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. Oxo-substituted dihydroquinolyl, oxo-substituted tetrahydroquinolyl, hydroxy-substituted dihydroquinolyl or hydroxy-substituted tetrahydroquinolyl; oxo (or hydroxy)
The substituted dihydro (or tetrahydro) quinoxalinyl group is specifically an oxo-substituted dihydro (or tetrahydro) quinoxalinyl group or a hydroxy-substituted dihydro (or tetrahydro) quinoxalinyl group, and more specifically, an oxo-substituted dihydroquinoxalinyl group. An oxo group (or a hydroxy group) substituted dihydro (or tetrahydro) isoquinolyl group; an oxo group (or a hydroxy group) substituted dihydro (or tetrahydro) isoquinolyl group; an oxo group-substituted tetrahydroquinoxalinyl group, a hydroxy group-substituted dihydroquinoxalinyl group or a hydroxy group-substituted tetrahydroquinoxalinyl group; An oxo-substituted dihydro (or tetrahydro) isoquinolyl group or a hydroxy-substituted dihydro (or tetrahydro) isoquinolyl group, more specifically an oxo-substituted dihydroisoquinolyl group, an oxo-substituted tetrahydroisoquinolyl group, A droxy 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-substituted dihydro (or tetrahydro) phthalazinyl group or a hydroxy-substituted dihydro group; (Or tetrahydro) phthalazinyl group, more specifically, oxo-substituted dihydrophthalazinyl group, oxo-substituted tetrahydrophthalazinyl group, hydroxy-substituted dihydrophthalazinyl group or hydroxy-substituted tetrahydrophthalazinyl group; The oxo group (or hydroxy group) substituted dihydro (or hexahydro) pyridyl group is an oxo group substituted dihydro (or hexahydro) pyridyl group or a hydroxy group substituted dihydro (or hexahydro) pyridyl group, and more specifically. Oxo-substituted dihydropyridyl, oxo-substituted hexahydropyridyl, hydroxy-substituted dihydropyridyl or hydroxy-substituted hexahydropyridyl; oxo (or hydroxy) -substituted dihydro (or tetrahydro) naphthyridinyl is substituted with oxo A dihydro (or tetrahydro) naphthyridinyl group or a hydroxy-substituted dihydro (or tetrahydro) naphthyridinyl group, more specifically an oxo-substituted dihydronaphthyridinyl group, an oxo-substituted tetrahydronaphthyridinyl group, a hydroxy-substituted dihydronaphthyridinyl group Oxo group (or hydroxy group) -substituted hexahydroquinolyl group is an oxo group-substituted hexahydroquinolyl group or a hydroxy group-substituted hexahydroquino group. An oxo group (or hydroxy group) -substituted dihydroindolyl group is an oxo group-substituted dihydroindolyl group or a hydroxy group-substituted dihydroindolyl group; an oxo group (or hydroxy group) -substituted dihydro (or tetrahydro) benzoazepinyl group is An oxo-substituted dihydro (or tetrahydro) benzoazepinyl group or a hydroxy-substituted dihydro (or tetrahydro) benzoazepinyl group, more specifically, an oxo-substituted dihydrobenzoazepinyl group, an oxo-substituted tetrahydrobenzoazepinyl group, A group-substituted dihydrobenzoazepinyl group or a hydroxy-substituted tetrahydrobenzoazepinyl group;
A dihydro (or tetrahydro) isoquinolyl group is a dihydroisoquinolyl group or a tetrahydroisoquinolyl group;
The oxo group (or hydroxy group) -substituted dihydro (or tetrahydro) benzothiazinyl group is an oxo group-substituted dihydro (or tetrahydro) benzothiazinyl group or a hydroxy-substituted dihydro (or tetrahydro) benzothiazinyl group, and more specifically, oxo group. Group-substituted dihydrobenzothiazinyl group, oxo-substituted tetrahydrobenzothiazinyl group, hydroxy-substituted dihydrobenzothiazinyl group or hydroxy-substituted tetrahydrobenzothiazinyl group; oxo group (or hydroxy group) -substituted dihydro (or tetrahydro) quinazolinyl group is oxo group A substituted dihydro (or tetrahydro) quinazolinyl group or a hydroxy-substituted dihydro (or tetrahydro) quinazolinyl group, more specifically, an oxo group-substituted dihydroquinazolinyl group or an oxo group Conversion tetrahydroquinolinyl tracing group, hydroxy group-substituted dihydroquinazolinyl group or a hydroxy group-substituted tetrahydroquinolinyl tracing sulfonyl group; oxo group (or hydroxy group) substituted dihydro benzimidazolinyl group,
An oxo-substituted dihydrobenzimidazolinyl group or a hydroxy-substituted dihydrobenzimidazolinyl group; an oxo group (or hydroxy group) -substituted dihydrophenanthridinyl group is an oxo-substituted dihydrophenanthridinyl group or a hydroxy-substituted dihydro group; A phenanthridinyl group; an oxo group (or hydroxy group) -substituted dihydro (or tetrahydro) pyrrolyl group is an oxo group-substituted dihydro (or tetrahydro) pyrrolyl group or a hydroxy group-substituted dihydro (or tetrahydro) pyrrolyl group; Represents an oxo-substituted dihydropyrrolyl group, an oxo-substituted tetrahydropyrrolyl group, a hydroxy-substituted dihydropyrrolyl group or a hydroxy-substituted tetrahydropyrrolyl group.

Among the specific examples of the target compound [I] of the present invention, a preferable compound is 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, represented by (1) Oxo-substituted dihydro (or tetrahydro) quinolyl group or hydroxy-substituted dihydro (or tetrahydro) quinolyl group, (2) oxo-substituted dihydro (or tetrahydro) quinoxalinyl group, (3) oxo-substituted dihydro (or tetrahydro) isoquinolyl group , (4) oxo-substituted dihydro (or tetrahydro)
Phthalazinyl group, (5) oxo-substituted dihydro (or hexahydro) pyridyl group, (6) oxo-substituted dihydro (or tetrahydro) naphthyridinyl group, (7) oxo-substituted hexahydroquinolyl group, (8) oxo-substituted dihydroin Drill 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 dihydrobenzimidazolinyl group, (14) oxo-substituted dihydrophenanthridinyl group, (15) oxo-substituted dihydro (or tetrahydro) pyrrolyl group, (16) Hexahydroxypyrazinyl , Compounds (17) a lower alkylenedioxy-substituted hexamethylene tetrahydropyridyl group or (18) a morpholino group.

As a particularly preferred example, 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) an oxo-substituted dihydro (or tetrahydro) quinolyl group or a hydroxy group. A substituted tetrahydroquinolyl group, (2) an oxo group-substituted dihydroquinoxalinyl group, (3) an oxo group-substituted dihydroisoquinolyl group, (4) an oxo group-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 Examples of the compound include a pyrazinyl group, (17) a lower alkylenedioxy group-substituted hexahydropyridyl group, and (18) a morpholino group.

Among the compounds of interest [I] of the present invention, compounds that are preferable in terms of pharmacological effect include an optionally substituted heterocyclic group formed by bonding R ⁵ and R ^{6 at the} terminals to an adjacent nitrogen atom. The 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-substituted triazolyl group; a lower alkyl-substituted piperazinylcarbonyl group; a lower alkoxycarbonyl group; a lower alkyl group; a hydroxyl group; and a lower alkoxy group which may be substituted with a hydroxyl group or a lower alkoxy group. Oxo group-substituted dihydro (or tetrahydro) which may be substituted with A quinolyl group or a hydroxy group-substituted tetrahydroquinolyl group, (2) an oxo group-substituted dihydroquinoxalinyl group, (3) a morpholino group-substituted lower alkyl group, which may be substituted with a piperidyl group, a pyridyl group or a lower alkoxy group An oxo group-substituted dihydroisoquinolyl group which may be substituted with a group selected from a lower alkoxy group; and a hydroxyl group; (4) a pyridyl group-substituted lower alkyl group; a pyrimidinyl group; a lower alkoxy group; a pyridyl group; an imidazolyl group; An oxo group-substituted dihydrophthalazinyl group which may be substituted with a group selected from a di-lower alkylamino-substituted phenyl group, (5) a lower alkyl group; a lower alkoxy group; a pyridyl group; and a group selected from an imidazolyl group. Substituted oxo-substituted dihydropyridyl group, (6) oxo-substituted dihydropyridyl group Ronafuchirijiniru group, (7) an oxo-substituted hexamethylene tetrahydroquinolyl group,
(8) an oxo group-substituted dihydroindolyl group, (9) an oxo group-substituted tetrahydrobenzothiazinyl group, (10) an oxo group-substituted dihydro (or tetrahydro) quinazolinyl group which may be substituted with a lower alkyl group and an oxo group, Examples of the compound include 11) an oxo-substituted dihydrobenzimidazolinyl group and (12) an oxo-substituted dihydrophenanthridinyl group.

Among the desired compounds [I] of the present invention, a more preferable compound from the viewpoint of efficacy is 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. ) A mono- or di-lower alkylamino group in which the lower alkyl group is substituted by a morpholino group, 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; An oxo group-substituted dihydro (or tetrahydro) quinolyl group or a hydroxy-substituted tetrahydroquinolyl group which may be substituted with a group selected from a hydroxyl group and a lower alkoxy group which may be substituted with a hydroxyl group or a lower alkoxy group; ) Oxo-substituted dihydroquinoxalinyl group, (3) morpholino-substituted lower alkyl A lower alkoxy group substituted with a piperidyl group or a lower alkoxy group; and an oxo group-substituted dihydroisoquinolyl group optionally substituted with a group selected from a hydroxyl group; (4) a pyridyl group-substituted lower alkyl group; A pyrimidinyl group, a 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,
(5) 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 alkyl group; Examples of the compound include an oxo group-substituted dihydro (or tetrahydro) quinazolinyl group which may be substituted with an oxo group.

Among them, more preferable compounds from the viewpoint of medicinal properties are those in which 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. A mono- or di-lower alkylamino group in which a lower alkyl group moiety is substituted with a group or 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 An oxy group which may be substituted with a group selected from an alkoxy group; and a hydroxyl group So-substituted dihydroisoquinolyl group,
(3) an oxo-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; (4) a lower alkyl group, a lower alkyl group An oxo-substituted dihydropyridyl group substituted by a group selected from an alkoxy group, a pyridyl group and an imidazolyl group or (5) an oxo-substituted dihydro (or tetrahydro) quinazolinyl group optionally substituted by a lower alkyl group and an oxo group The compound which is is mentioned.

Among these compounds, particularly preferred compounds from the viewpoint of pharmacological effect include a heterocyclic group in which R ⁵ and R ⁶ are bonded to each other at the terminal 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 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 An oxo group-substituted dihydroquinolyl group which may be substituted with a group selected from groups, (2) an oxo group-substituted 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. Dihydroisoquinolyl group, (3) pyridyl group-substituted lower alkyl group,
An oxo group-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) a group selected from a lower alkyl group, a lower alkoxy group and an imidazolyl group. Compounds that are substituted oxo-substituted dihydropyridyl groups are mentioned.

Among the target compounds [I] of the present invention, other compounds that are preferable from the viewpoint of pharmacological effect include 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. 1) a morpholino group, a monocycloalkyl group-substituted amino group, a pyridyl group, an imidazolyl group or a piperidino 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 A substituted piperazinylcarbonyl group; a lower alkoxycarbonyl group; a lower alkyl group; a hydroxyl group; and an oxo group-substituted dihydro which may be substituted with a group selected from a hydroxyl group and a lower alkoxy group which may be substituted with a hydroxyl group or a lower alkoxy group. Or tetrahydro) quinolyl group or hydroxy-substituted tetrahydroquinolyl group, (2) morpho A linyl group-substituted lower alkyl group; an oxo group-substituted dihydroisoquinolyl group which 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, (3)
An oxo-substituted dihydrophthalazinyl group which may be substituted with a group selected from a pyridyl group-substituted lower alkyl group; a pyrimidinyl group; a lower alkoxy group; a pyridyl group; an imidazolyl group; and a di-lower alkylamino group-substituted phenyl group; 4) an oxo-substituted dihydropyridyl group substituted with a pyridyl group, (5) an oxo-substituted dihydronaphthyridinyl group, (6) an oxo-substituted hexahydroquinolyl group, (7) an oxo-substituted dihydroindolyl group, (8)
Oxo-substituted tetrahydrobenzothiazinyl group, (9)
An oxo group-substituted dihydro (or tetrahydro) quinazolinyl group which may be substituted with a lower alkyl group and an oxo group, (10) an oxo group-substituted dihydrobenzimidazolinyl group or (11) an oxo group-substituted dihydrophenanthridinyl group Certain compounds are mentioned.

Among these compounds, a compound more preferable in terms of efficacy is a heterocyclic group in which R ⁵ and R ⁶ are bonded together at the terminal to form an adjacent nitrogen atom, and (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 Selected from lower alkyl groups; lower alkoxy groups; pyridyl groups; and di-lower alkylamino group-substituted phenyl groups. And (4) an oxo-substituted dihydrophenanthridinyl group substituted with an oxo group-substituted dihydrophthalazinyl group.

Among the above compounds, a particularly preferable compound from the viewpoint 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 or 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 group-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.

[0036] Further, as another compound which is preferable from the viewpoint of pharmacological effect, an optionally substituted heterocyclic group formed by bonding R ⁵ and R ^{6 at the} terminal to an adjacent nitrogen atom is represented by (1) morpholino A mono- or di-lower alkylamino group in which a lower alkyl group moiety is substituted with a group, an imidazolyl group or a pyridyl group; a morpholino group; and an oxo group-substituted dihydro which may be substituted with a group selected from a lower alkyl group. Or tetrahydro) quinolyl group,
(2) an oxo-substituted dihydroisoquinolyl group substituted with a group selected from a morpholino-substituted lower alkyl group; and a lower alkoxy group-substituted lower alkoxy group;
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, other compounds that are preferable from the viewpoint of pharmacological activity include 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.

[0038]

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(Provided that R ⁹¹ , R ⁹² and R ⁹³ are the same or different and are each 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.

Of these preferred compounds of the object compound [I] of the present invention, those compounds in which R ¹ and R ² are the same or different and are a lower alkoxy group and R ³ and R ⁴ are hydroxyl-substituted methyl groups are preferred.

The target compound [I] of the present invention may exist in an optically active form based on an asymmetric carbon, and the present invention includes all of these optical isomers and a mixture thereof.

The target compound [I] 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).

Accordingly, the target compound [I] and a salt thereof are
It should be construed to include any of its inner salts, adducts, solvates or hydrates.

The target compound [I] of the present invention or a salt thereof can be administered orally or parenterally.
For example, tablets, granules, capsules, powders,
It can be used as an appropriate pharmaceutical preparation such as an injection or an inhalant.

The dosage 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.

According to the present invention, the target compound [I] can be produced by the following [Method A] to [Method C].

[Method A] The target compound [I] of the present invention has the general formula [II]

[0049]

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(Provided that R ¹¹ and R ²¹ are the same or different and are 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]

[0051]

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(Wherein the symbols have the same meanings as described above), and R ¹¹ and / or R ²¹ is a protected hydroxyl group, and R ³¹ and / or R ⁴¹ are In the case of a protected hydroxyl group-substituted methyl group, if necessary, the protective group is completely or selectively removed depending on the type of the protective group of the hydroxyl group, and if necessary, the 6-position and / or 7-position hydroxy site or It can be produced by protecting the hydroxymethyl moiety at the 2-position and / or 3-position again, and further protecting all the hydroxy moiety or hydroxymethyl moiety if necessary.

[Method B] Of the target compounds of the present invention,

[0054]

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(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]

[0056]

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

[0058]

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(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.)
Wherein 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 necessary, depending on the type of the protecting group of the hydroxyl group, the protecting group is completely or selectively removed, and if necessary, the 6-position and / or
Alternatively, it can be produced by protecting the hydroxy site at the 7-position or the hydroxymethyl site at the 2- and / or 3-position again and, if necessary, protecting all the hydroxy sites or the hydroxymethyl sites.

[Method C] Of the target compounds of the present invention,

[0061]

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(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]

[0063]

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(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, and Wherein the symbols have the same meanings as described above) or an intramolecular acid anhydride thereof is subjected to a reduction reaction, and when R ¹¹ and / or R ²¹ is a protected hydroxyl group, if desired, the protecting group To remove
If necessary, the hydroxy site at position 6 and / or 7 or the hydroxymethyl site at position 2 and / or 3 can be protected again, and if necessary, all hydroxy sites or hydroxymethyl sites can be protected. it can.

These [Method A] to [Method C] can be carried out as follows.

[Method A] The reaction between the compound [II] and the nitrogen-containing compound [III] can be carried out in a suitable solvent in the presence of a base and a copper catalyst. As the base, an alkali metal hydride, an alkali metal carbonate or the like is used. As the copper catalyst, copper (I) iodide, copper (I) bromide, copper powder (0), copper oxide (I), copper bromide ( II) and the like can be suitably used. Further, as the solvent, dimethylformamide, dimethylsulfoxide, dimethylacetamide, toluene,
Xylene or the like can be used as appropriate. This reaction is 80
C. to 160.degree. C., especially 120.degree.

[Method B] The reaction of the compound [IV] with the halogeno nitrogen-containing compound [V] is carried out in the presence or absence of an acid catalyst.
It can be carried out in a suitable solvent. Hydrogen bromide, hydrogen chloride, acetic acid and the like can be used as an acid catalyst, and dimethylformamide, dimethylsulfoxide, toluene, xylene, mesitylene, di, tri or tetrachloroethane and the like can be used as solvents. This reaction is 8
It proceeds suitably at 0 ° C to 160 ° C, especially at 110 ° C to 150 ° C.

[Method C] The reduction reaction of compound [VI] or an intramolecular acid anhydride thereof can be carried out in a solvent using a suitable reducing agent. In the compound [VI], the esterified carboxyl group may be any one which can be converted into a hydroxymethyl group by a reduction reaction, and examples thereof include a lower alkoxycarbonyl group. The reducing agent may be appropriately selected depending on the kind of R ⁷ and R ^8.
For example, when R ⁷ and R ⁸ are esterified carboxyl groups, metal hydrides such as lithium aluminum hydride, sodium bis (methoxyethoxy) aluminum hydride, sodium borohydride, especially hydrogen hydride Sodium boron can be suitably used. This reaction can be suitably carried out in a suitable solvent, for example, a mixed solvent of an ether solvent such as tetrahydrofuran or ether and a lower alkanol under heating. On the other hand, when R ⁷ and / or R ⁸ is a free carboxyl group, for example, lithium aluminum hydride or the like can be suitably used. Further, the compound [VI]
Can be prepared by subjecting a compound [VI] wherein R ⁷ and R ⁸ are free carboxyl groups to an intramolecular dehydration reaction, and the reduction reaction is carried out by R ⁷ and / or R ⁸
Is a free carboxyl group. These reactions can be suitably carried out in a suitable solvent, for example, an ether solvent such as tetrahydrofuran, ether or dioxane under cooling.

In the above [Method A] and [Method B], R ¹¹ and / or R ²¹ are protected hydroxyl groups, R ³¹ and / or R ⁴¹
When is a protected hydroxyl-substituted methyl group, the removal of the protecting group from the product should be carried out by a usual method such as hydrolysis, acid treatment, or reduction according to a conventional method, depending on the type of the protecting group. Can be. Furthermore, in the above [Method A] to [Method C], protection of the 6-position and / or 7-position hydroxy moiety, the 2-position and / or 3-position hydroxymethyl moiety may be carried out according to a conventional method with each product and groups R ¹ and R ^2. , An acid anhydride of a lower alkanoic acid or a cycloalkanoic acid corresponding to the protecting group of the groups R ³ and R ⁴ , an acid halide or a lower alkyl halide which may be substituted with a lower alkoxycarbonyl group, or a carboxyl which may be protected. It can be carried out by a condensation reaction with a group-substituted lower alkylsulfonate or the like. The reaction can be suitably carried out in the presence of a base (triethylamine, pyridine, dimethylaminopyridine, sodium hydride, hexamethylphosphoric triamide, etc.) in a suitable solvent (methylene chloride, tetrahydrofuran, etc.) or without a solvent.
Further, the reaction can be carried out by reacting each product with an optionally protected amino-substituted lower alkylcarboxylic acid corresponding to the protecting groups of the groups R ¹ and R ² and the groups R ³ and R ⁴ . The reaction can be suitably carried out in a suitable solvent (dimethylformamide, methylene chloride, chloroform) in the presence of a condensing agent (dicyclohexylcarbodiimide, a water-soluble carbodiimide derivative). In this case, since the hydroxymethyl moiety at the 3-position is more reactive than the hydroxymethyl moiety at the 2-position, an equimolar amount of an acid anhydride of a lower alkanoic acid, an acid halide or a lower alkyl halide is used per mole of the product. Then, the target product in which only the 3-position hydroxymethyl moiety is protected is mainly produced, and when 2 mol or more is used, the target product in which both the 2-position and the 3-position are protected can be obtained. As the carboxyl group and / or amino group protecting group, a conventional carboxyl group and / or amino group protecting group can be used and can be removed by a conventional method.

The target substance [I] of the present invention can also be produced by interconverting the target substance obtained as described above into another target substance. Such an interconversion reaction between the objective substances 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]

[0072]

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(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]

[0075]

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

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

The starting compound [II] of the present invention can be prepared , for example, by reacting a compound of the general formula [IX]

[0079]

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(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]

[0081]

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

[0083]

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(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]

[0085]

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

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

[0088]

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

[0090]

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(Wherein the symbols have the same meaning as described above), and this compound 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]

[0092]

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(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.

[0095]

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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]

[0097]

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(Wherein the symbols have the same meanings as described above), and this is an acid catalyst (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] is also a novel compound, for example, compound [XII] and nitrogen-containing compound [III]
Can be produced under the same conditions as in the reaction of the compound [II] with the nitrogen-containing compound [III]. Compound [VI] is produced by reacting compound [XV] with halogeno nitrogen-containing compound [V] under the same conditions as the reaction of compound [IV] with halogeno nitrogen-containing compound [V]. You can also.

In the present invention, 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 carbon atoms. Numerical formulas 1 to 6, especially 1 to 4, are mentioned. 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.

[0102]

The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the invention. Further, the compounds synthesized by the above exemplified methods and the compounds of the general formula [I] of the present invention by the same production method are collectively shown in Tables 1 to 14 below.

[0103]

[Table 1]

[0104]

[Table 2]

[0105]

[Table 3]

[0106]

[Table 4]

[0107]

[Table 5]

[0108]

[Table 6]

[0109]

[Table 7]

[0110]

[Table 8]

[0111]

[Table 9]

[0112]

[Table 10]

[0113]

[Table 11]

[0114]

[Table 12]

[0115]

[Table 13]

[0116]

[Table 14]

[0117]

[Table 15]

[0118]

[Table 16]

[0119]

[Table 17]

[0120]

[Table 18]

[0121]

[Table 19]

[0122]

[Table 20]

[0123]

[Table 21]

[0124]

[Table 22]

[0125]

[Table 23]

[0126]

[Table 24]

[0127]

[Table 25]

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 1. 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. Example 2 5 ml of dimethylformamide of 2.13 g of N-oxide of 1- (4-pyridyl) -2,3-bis (acetoxymethyl) -6,7-dimethoxynaphthalene and 1.64 g of 2-chloroquinoline 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 1. 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. Example 31 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 suspension of 30 g of xylene in 30 ml, 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 give 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 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-) described in Table 1. 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 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 then 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) 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:
After purification in 1), 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) 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, further washed and dried, and 1- {2} described in Table 2. -[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 Example 8 to 57 Example 1 was performed using 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 Example 7 to obtain the compounds described in Tables 1 and 2.

Example 58 (1) 1- (2-Bromo-4-pyridyl) -2,3-bis (methoxycarbonyl) -6-ethoxy-7-methoxynaphthalene was prepared in the same manner as in 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) This product and the corresponding nitrogen-containing compound [III] were used in Example 7.
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) Examples 59-60 (1) 1- (2-bromo-4-pyridyl) -2,3-bis (methoxycarbonyl) naphthalene was prepared in Example 6
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) Example 6 using this product and the corresponding nitrogen-containing compound [III]
-(2) or by treating in the same manner as in Example 7 to obtain the compounds shown in Table 3.

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 Example 6- (1). Treatment gives 1- (2-bromo-5-pyridyl) -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene.

M. p. 185-186 ° C (decomposition) (2) This product and the corresponding nitrogen-containing compound [III] were used in Example 6.
-(2) or by treating in the same manner as in Example 7, to obtain the compounds shown in Table 4.

Example 63 (1) 174 mg of lithium borohydride 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) 1- (2-Bromo-6-pyridyl) -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene and the corresponding nitrogen-containing compound [III] were prepared in Example 6- ( 2)
1- [2- (2-oxo-1,2-dihydroquinolin-1-yl) pyridine-6 shown in Table 5
-Yl] -2,3-bis (hydroxymethyl) -6,7
To obtain dimethoxynaphthalene.

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

M. p. 90-93 ° C. Example 66 (1) 1- (4-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene N-oxide 1.99 g in a toluene 10 ml suspension 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.
After washing and drying the methylene chloride layer, the solvent is distilled off, and the residue is purified by silica gel column chromatography (solvent; chloroform: methanol = 20: 1) to obtain a residue described in Table 6.
-[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) 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 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 dissolving in dioxane / methanol solution, 0.29 ml of hydrogen chloride-dioxane solution was added to crystallize, further washed and dried, and 1- {2-
[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 Examples 68 to 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 Example 66- (1) to give the compounds shown in Table 15 below.

[0152]

[Table 26]

(2) The product obtained in the above (1) was treated in the same manner as in Example 66- (2) to obtain the compounds shown in Table 6.

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 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 treated in Example 66-
The same treatment as in (2) was carried out, 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) 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 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 treated in Example 66-
The same treatment as in (2) was carried out, 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 Examples 75-81 (1) 1- (2-bromo-4-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene and the corresponding nitrogen-containing compound [III] Example 6
Treatment in the same manner as in (2) gives the compounds shown in Table 16 below.

[0159]

[Table 27]

(2) The product obtained in the above (1) was treated in the same manner as in Example 66- (2) to obtain the compounds shown in Tables 6 and 7.

Example 82 (1) 1- (2-Bromo-4-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene and 4-hydroxyquinoline were prepared in 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 Example 66-
The same treatment as in (2) was performed and 1- [2- (4-
Hydroxy-1,2,3,4-tetrahydroquinoline-
1-yl) -4-pyridyl] -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene is obtained.

M. p. 90-94 ° C Example 83 (1) 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 treated in 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 is obtained.

M. p. 57-61 ° C 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 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 treated in 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
To obtain dimethoxynaphthalene.

M. p. 156-158 ° C 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 after stirring 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 1- [2- (2-oxo-4-hydroxy-1,
2-dihydroquinolin-1-yl) -4-pyridyl]-
0.79 g of 2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene is obtained.

M. p. 160-170 ° C 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 Example 85 to give a seventh compound.
In the table, 1- [2- (1-oxo-5-hydroxy-
1,2-Dihydroquinolin-2-yl) -4-pyridyl] -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene is obtained.

M. p. 138-140 ° C 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 7 0.41 g of -4-carboxy-1,2-dihydroquinolin-1-yl) -4-pyridyl] -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene is obtained.

M. p. > 250 ° C 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
1- {2- [2-oxo-4-bis (2-hydroxyethyl) aminocarbonyl-1,2-dihydroquinolin-1-yl] -4-pyridyl} -2,3-bis (hydroxymethyl ) 0.68 g of -6,7-dimethoxynaphthalene is obtained.

M. p. 65-68 ° C Example 89 1- {2- [2-oxo-4- [4- (2-t-butyldimethylsilyloxyethyl) piperazin-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 Example 88 to give 1- {2- [2-oxo-4- [4
-(2-hydroxyethyl) piperazin-1-yl] carbonyl-1,2-dihydroquinolin-1-yl] -4
-Pyridyl} -2,3-bis (hydroxymethyl)-
6,7-Dimethoxynaphthalene is obtained.

M. p. 150-153 ° C Examples 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 8. 1,2-dihydroquinoline-
1-yl) -4-pyridyl] -2- (tert-butoxycarbonylaminomethylcarbonyloxymethyl)-
0.8 g of 3-hydroxymethyl-6,7-dimethoxynaphthalene (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 (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
(Example 92) is obtained.

Example 90 m.p. p. 120-122 ° C (Example 91) m. p. 136-138 ° C (Example 92) Oily substance 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 8. 510 mg of 3-aminomethylcarbonyloxymethyl-6,7-dimethoxynaphthalene hydrochloride are obtained.

M. p. 126-128 ° C (decomposition) 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 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) 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 Example 93 to give 1- [2- (2-oxo-
1,2-Dihydroquinolin-1-yl) -4-pyridyl] -2,3-bis (aminomethylcarbonyloxymethyl) -6,7-dimethoxynaphthalene dihydrochloride is obtained.

M. p. 165-168 ° C (decomposition) Examples 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 then the solvent was distilled off. The residue was purified by silica gel column chromatography (solvent; chloroform: acetone = 5: 1) to obtain an octaethyl acetate.
1- [2- (2-oxo-1,2-dihydroquinolin-1-yl) -4-pyridyl] -2-ethoxycarbonylmethoxymethyl-3-hydroxymethyl-6 in the table.
7-dimethoxynaphthalene 70 mg (Example 96), 1
-[2- (2-oxo-1,2-dihydroquinoline-1
-Yl) -4-pyridyl] -2-hydroxymethyl-3
120 mg of ethoxycarbonylmethoxymethyl-6,7-dimethoxynaphthalene (Example 97) are obtained.

Example 96 m.p. p. 190-192 ° C (Example 97) m.p. p. 124-126 ° C 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).
After purification in 1), 1- [2- (2-oxo-
1,2-dihydroquinolin-1-yl) -4-pyridyl] -2-hydroxymethyl-3- (4-methylpiperazin-1-yl) carbonylmethoxymethyl-6,7-
150 mg of dimethoxynaphthalene are obtained.

M. p. 100-102 ° C Example 99 (1) 1- (2-chloro-4-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-dimethoxynaphthalene was treated in the same manner as in 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 Examples 100 to 101 1- (2-Chloro-4-pyridyl) -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene and the corresponding nitrogen-containing compound [III] in Example 99 ( The compound shown in Table 9 is obtained by treating in the same manner as in 2).

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-bis (hydroxymethyl) -6,7-dimethoxynaphthalene (1.54 g, yield: 62%) is obtained.

M. p. 100-103 ° C 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, and the residue was purified by silica gel column chromatography (solvent; chloroform: acetone = 2: 1), dissolved in chloroform, 4N hydrogen chloride-dioxane solution was added, and the solvent was distilled off, as shown in Table 9. 1- [2- (4-oxo-1-piperidinyl) -4-pyridyl] -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene hydrochloride 8
28 mg are obtained.

M. p. > 250 ° C Example 104 (1) 1- (2-chloro-4-pyridyl) -2,3-bis (methoxycarbonyl) -6-methoxy-7-ethoxynaphthalene was prepared in the same manner as in 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 10
Pyridyl {-2,3-bis (hydroxymethyl) -6
Methoxy-7-ethoxynaphthalene hydrochloride 1.43 g
Get.

M. p. 211-215 ° C (decomposition) Example 105 (1) 1- (2-chloro-4-pyridyl) -2,3-bis (methoxycarbonyl) -6,7-diethoxynaphthalene was prepared in Example 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 was treated in the same manner as in 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 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) Examples 106-107 (1) 1- (2-Bromo-4-pyridyl) -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene was prepared in 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
-Bis (hydroxymethyl) -6,7-dimethoxynaphthalene and the corresponding carboxylic acid derivative [VII] were prepared in Example 10
Treatment in the same manner as in 4- (3) gives the compounds shown in Table 10.

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 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, crystallized with chloroform, and 1- [2- (2-acetylhydrazino) pyridin-4-yl] -2,3-bis (hydroxymethyl)-described in Table 10.
0.84 g of 6,7-dimethoxynaphthalene is obtained.

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

M. p. 106-108 ° C (2) This product and the corresponding nitrogen-containing compound [III] were used in Example 6.
-Treat in the same manner as in (2) to obtain the compounds described in Table 11.

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

M. p. 150-153 ° C (2) Example 6 using this product and the corresponding nitrogen-containing compound [III]
-(2) or by treating in the same manner as in Example 7, to obtain the compounds shown in Table 11.

Example 115 (1) 1- (2-Chloro-4-pyridyl) -2,3-bis (methoxycarbonyl) -6-benzyloxy-7-
The methoxynaphthalene is treated in the same manner as in Example 6- (1) to obtain 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 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 Example 104- (3) to give 1- {2- [4- (3-pyridyl) -1 (2H) -phthalazinone-2-yl] -4- as shown in Table 12. Pyridyl {-2,3-bis (hydroxymethyl) -6-benzyloxy-7-methoxynaphthalene hydrochloride is obtained.

M. p. 219-221 ° C (decomposition) 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 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 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 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 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 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) Example 118 (1) 1- (2-Chloro-4-pyridyl) -2,3-bis (methoxycarbonyl) -6-isopropyloxy-
7-Methoxynaphthalene was treated in the same manner as in 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 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 Example 104- (3) to give 1- {2- [4- (3-pyridyl) -1 shown in Table 12. (2H) -phthalazinone-2-yl] -4
-Pyridyl} -2,3-bis (hydroxymethyl) -6
-Isopropyloxy-7-methoxynaphthalene hydrochloride is obtained.

M. p. 203-206 ° C (decomposition) Example 119 (1) 1- (2-Chloro-4-pyridyl) -2,3-bis (methoxycarbonyl) -6-butoxy-7-methoxynaphthalene was prepared in 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 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 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) 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 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 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 Example 104- (3) to give 1- {2- [4- (3-pyridyl) -1 (2H) -phthalazinone-2-yl] -4- as shown in Table 12. Pyridyl {-2,3-bis (hydroxymethyl) -6-octyloxy-7-methoxynaphthalene hydrochloride is obtained.

M. p. 190-193 ° C (decomposition) Example 121 (1) 1- (2-chloro-4-pyridyl) -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene was prepared in the same manner as in 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 used in 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 described in Table 12. ] -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 Example 122 (1) 1- (2-hydrazino-4-pyridyl) -2,3
Example 104- using bis (hydroxymethyl) -6,7-diethoxynaphthalene and the corresponding starting compound [VII]
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, the anhydride is inoculated. After stirring at room temperature overnight, the mixture was ice-cooled, and the precipitate was collected by filtration, washed with 50% ethanol (13 ml), and dried at 50 ° C. overnight by blowing air to obtain 1- {2- [4- (3-pyridyl) -1 (2H) -phthalazinone-2-yl] -4-
Pyridyl} -2,3-bis (hydroxymethyl) -6
5.6 g (86% yield) of 7-diethoxynaphthalene are obtained.

M. p. 222 ° C. (2) 1- {2- [4- (3-pyridyl) -1 (2H)
-Phthalazinone-2-yl] -4-pyridyl} -2,3
-Bis (hydroxymethyl) -6,7-diethoxynaphthalene / sulfate m. p. > 220 ° C (3) 1- {2- [4- (3-pyridyl) -1 (2H)
-Phthalazinone-2-yl] -4-pyridyl} -2,3
-Bis (hydroxymethyl) -6,7-diethoxynaphthalene methanesulfonate m. p. 160-163 ° C (decomposition) Example 123 1- (2-Hydrazino-4-pyridyl) -2,3-bis (hydroxymethyl) -6,7-diethoxynaphthalene was prepared in the same manner as in 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) was added.
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 shown in Table 12.
-[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.) Example 124 (1) 1- (2-chloro-4-pyridyl) -3-methoxycarbonyl-6,7-dimethoxynaphthalene was treated in the same manner as in Example 6- (1) to give 1 -(2-Chloro-4-pyridyl) -3-hydroxymethyl-6,7-dimethoxynaphthalene is obtained.

M. p. 115-118 ° C (2) 1- (2-chloro-4-pyridyl) -3-hydroxymethyl-6,7-dimethoxynaphthalene was prepared in Example 1.
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 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 Example 125 (1) A suspension of 1- (2-chloro-4-pyridyl) -3-carboxy-6,7-diethoxynaphthalene in 50 ml of tetrahydrofuran under a nitrogen atmosphere at 5 ° C or less under a nitrogen atmosphere. (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 in the same manner as in 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) Example 126 1- (2-Hydrazino-4-pyridyl) -3-hydroxymethyl-6,7-diethoxynaphthalene 177 mg,
1-carboxy-2-phenylcarbonylbenzene 19
Using 1 mg and 1 ml of ethylene glycol, 1 of Table 14 was obtained by the same operation as in 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 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 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 14 was added. obtain.

M. p. 223-225 ° C Example 128 1- (2-Hydrazino-4-pyridyl) -3-hydroxymethyl-6,7-diethoxynaphthalene 177 mg,
1-carboxy-2-methylcarbonylbenzene 86m
g and 1 ml of ethylene glycol,
By the same operation as 4- (3), 1- of Table 14
[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 was added to a 50 ml solution of acetic acid in 50 ml of toluene, and the mixture was 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 46 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) in the presence of 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 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 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 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 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 200 ml of a suspension of 5.2 g of sodium cyanide in 200 ml of dimethylformamide, and the mixture was stirred for 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

[0308]

The object compound [I] of the present invention or a pharmaceutically acceptable salt thereof has an excellent bronchoconstriction inhibitory effect and is useful as an agent for preventing or treating asthma. That is, the target compound [I] of the present invention is histamine, U-4661
9, the bronchoconstriction induced by various spasmogens and antigens such as leukotriene D _4, effectively suppressing. For example, the target compound of the present invention, 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- (1-oxo-5-methoxymethoxy-1,2-dihydroisoquinolin-2-yl) -4-pyridyl] -2,3-bis (hydroxymethyl) -6 , 7-dimethoxynaphthalene, 1
-{2- [1-oxo-5- (2-piperidinoethyloxy) -1,2-dihydroisoquinolin-2-yl]-
4-pyridyl} -2,3-bis (hydroxymethyl)-
6,7-dimethoxynaphthalene, 1- [2- (3-oxo-2,3-dihydroisoquinolin-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-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 (2
H) -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 a pharmaceutically acceptable salt thereof is 30 times more than theophylline. It shows an antigen-induced bronchoconstriction inhibitory action more than twice as strong.

Further, the target compound [I] of the present invention or a pharmacologically acceptable salt thereof has almost no side effects on the heart and the like, selectively exhibits a bronchoconstriction inhibitory action, has low toxicity, and has a low toxicity. It has excellent characteristics of showing high safety. In the case of theophylline, lowering blood pressure,
Although side effects on the heart such as palpitations are known, the target compound [I] of the present invention or a pharmaceutically acceptable salt thereof has substantially no such side effects and has an excellent anti-asthmatic effect.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI C07D 491/113 C07D 491/113 // A61K 31/435 A61K 31/435 31/4353 31/4353 31/44 31/44 31 / 4709 31/4709 31/4725 31/4725 31/498 31/498 31/502 31/502 31/505 31/505 31/517 31/517 31/5377 31/5377 31/5415 31/5415 31/55 31 / 55 A61P 11/08 A61P 11/08 43/00 43/00 (56) References JP-A-7-101861 (JP, A) JP-A-5-229987 (JP, A) (58) Fields investigated ( Int.Cl. ⁷ , DB name) C07D 213/00-213/64 C07D 417/00-417/04 C07D 471/00-471/04 C07D 491/00-491/113 CA (STN) REGISTRY (STN)

Claims (31)

(57) [Claims] 1. A compound of the general formula [I] (Provided that R ¹ and R ² are 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, (iii) cycloalkyl
A hydroxyl group which may be protected by a group selected from the group consisting of: R ³ and R ⁴ each being either (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) lower alkoxycarbonyl group, (4) be protected with a group selected from cycloalkyl groups are also good hydroxyl-substituted methyl group, the other is (1) hydrogen atom, (2) a lower alkyl group or (3) (i) lower alkanoyl group, lower alkoxy carb
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) cycloalkyl
Represents a hydroxyl-substituted methyl group which may be protected by a group selected from the group consisting of R ⁵ and R ^{6, which} are the same or different, and are (1) a hydrogen atom, (2) a lower alkyl group, (3) phenyl Group or (4) lower alkanoyl group, lower alkoxycarbonyl
Or group or a phenyl-lower alkoxycarbonyl which may be protected by an amino group by group, or (5) the adjacent nitrogen atom bonded terminally with each other
(I) a lower alkenyl group; (ii) a lower alkynyl group;
(Iii) a lower alkylthio group; (iv) cycloalkyl
(Vi) trifluoromethyl group; (vi) cyano
(Vii) tetrazolyl group; (viii) formyl
Group; (ix) amino group; (x) morpholino group, monocycl
Amino group, pyridyl group, imidazolyl
Group, piperidyl group or pyrrolidinyl group and lower alkyl group
A mono- or di-lower alkyl group in which
Alkylamino group; (xi) pyridyl group; (xii ) mole
Holino group; (xiii) lower alkyl group-substituted triazolyl
(Xiv) bis (hydroxy lower alkyl) amido
Nocarbonyl group; (xv) bis (tri-lower alkylsilyl)
(Xoxy lower alkyl) aminocarbonyl group; (xv
i) morpholinocarbonyl group; (xvii) lower alkyl
Group-substituted piperazinylcarbonyl group; (xviii)
Droxy-lower alkyl-substituted piperazinylcarbonyl
Group; (xix) tri lower alkyl silyl-lower al
A killed group-substituted piperazinylcarbonyl group; (xx) a lower radical
(Oxy) carbonyl group; (xxi) carboxyl group;
(Xxii) substituted with a morpholino group or a pyridyl group
An optionally substituted lower alkyl group; (xxiii) piperi
Substituted with a jyl group, pyridyl group, hydroxyl group or lower alkoxy group
A lower alkoxy group which may be substituted; (xxiv)
Oxo group; (xxv) hydroxyl group; (xxvi) pyrimidinyl
(Xxvii) a di-lower alkylamino group or a halogeno group
A phenyl group optionally substituted with a phenyl atom; (xxvi
(ii) a halogen atom; (xxix) a nitro group; (xx
x) imidazolyl group; and (xxxi) lower alkylene
One or more identical or selected from dioxy groups
Represents that a heterocyclic group which may be substituted with a different group is formed. Or a pharmacologically acceptable salt thereof. 2. The compound 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 at the terminal and are formed together with an adjacent nitrogen atom, is a heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to the nitrogen atom. The compound according to claim 1 or 2, which is a monocyclic, bicyclic or tricyclic heterocyclic group which may contain 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 7. The compound according to Item 3. 5. 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 .
The compound according to 2, 3, or 4 . 6. A heterocyclic group substituted by at least an oxo group has a partial structural formula: The compound according to claim 5, which is a heterocyclic group having the formula: 7. 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-substituted piperazinylcarbonyl group; hydroxy-lower alkyl group-substituted piperazinylcarbonyl group; tri-lower alkylsilyl Oxy-lower alkyl-substituted piperazinyl A lower alkoxycarbonyl group; a carboxyl group; a lower alkyl group; a lower alkoxy group which may be substituted with a hydroxyl group or a lower alkoxy group; and an oxo group (or hydroxy group which may be substituted with a group selected from a hydroxyl 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;
A lower alkoxy group which may be substituted with a piperidyl group, a pyridyl group or a lower alkoxy group; and an oxo group (or a hydroxy group) substituted dihydro (or tetrahydro) isoquinolyl group which may be substituted with a group selected from a hydroxyl group; 4) a lower alkyl group optionally substituted with a pyridyl group; a pyrimidinyl group; a lower alkoxy group; a pyridyl group; an imidazolyl group; a phenyl group optionally substituted with a di-lower alkylamino group or a halogen atom; Selected from an oxo group (or hydroxy group) -substituted dihydro (or tetrahydro) phthalazinyl group, (5) a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, a pyridyl group and an imidazolyl group which may be substituted with An oxo group (or a hydroxy group) Group) substituted dihydro (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,
(16) hexahydroxy pyrazinyl group, (17) a lower alkylenedioxy-substituted hexamethylene tetrahydropyridyl group or (18) a morpholino group claim 1, 2, 3, or 4
A compound as described. 8. The heterocyclic group which may be substituted, wherein R ⁵ and R ⁶ are bonded at the terminal to each other at the terminal and which are formed together 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 compound according to claim 7, which is (16) a hexahydroxypyrazinyl group, (17) a lower alkylenedioxy group-substituted hexahydropyridyl group or (18) a morpholino group. 9. 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 may be formed together with an adjacent nitrogen atom, is (1) an oxo-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)
Oxo group-substituted hexahydroquinolyl group, (8) oxo group-substituted dihydroindolyl group, (9) oxo group-substituted dihydrobenzoazepinyl group, (10) tetrahydroisoquinolyl group, (11) oxo group-substituted tetrahydrobenzothiazinyl (12) oxo-substituted dihydro (or tetrahydro) quinazolinyl group, (13) oxo-substituted dihydrobenzimidazolinyl group, (14) oxo-substituted dihydrophenanthridinyl group, (15) oxo-substituted tetrahydropyrroli 9. The compound according to claim 8, which is (16) a hexahydroxypiperazinyl group, (17) a lower alkylenedioxy group-substituted hexahydropyridyl group or (18) a morpholino group. 10. A heterocyclic group which may be substituted with R ⁵ and R ^{6 at the} terminal thereof and which is formed together with an adjacent nitrogen atom is (1) a morpholino group or a monocycloalkyl group-substituted amino 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-substituted triazolyl group; A lower alkoxycarbonyl group; a lower alkyl group; a hydroxyl group; and an oxo-substituted dihydro (or tetrahydro 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. ) A quinolyl group or a hydroxy-substituted tetrahydroquinolyl group, (2) Oxo group-substituted dihydroquinoxalinyl group, (3) morpholino group-substituted lower alkyl group; lower alkoxy group optionally substituted with piperidyl group, pyridyl group or lower alkoxy group; and hydroxyl group. 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 compound according to claim 7, which is 1) an oxo-substituted dihydrobenzimidazolinyl group or (12) an oxo-substituted dihydrophenanthridinyl group. 11. The heterocyclic group which may be substituted, wherein R ⁵ and R ⁶ are bonded together at the terminal at the terminal and which are formed together with an adjacent nitrogen atom, is (1) a morpholino group, a pyridyl group, an imidazolyl group, a piperidino group. A mono- or di-lower alkylamino group in which a lower alkyl group is substituted with a group or a pyrrolidinyl group; a pyridyl group; a morpholino group; a lower alkyl group-substituted triazolyl group; a lower alkyl group; and a hydroxyl group or a lower alkoxy group. An oxo-substituted dihydro (or tetrahydro) quinolyl group or a hydroxy-substituted tetrahydroquinolyl group which may be substituted with a group selected from a lower alkoxy group which may be substituted;
(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 oxo-substituted dihydropyridyl group which are, according to claim 7 which is (6) an oxo group substituted tetrahydro benzothiazinyl group or (7) a lower alkyl group and which may be oxo-substituted dihydro (or tetrahydro-) substituted with an oxo group quinazolinyl A compound as described. 12. The heterocyclic group which may be substituted, wherein R ⁵ and R ⁶ are terminally bonded to each other to form an adjacent nitrogen atom, is (1) a morpholino group, a pyridyl group, an imidazolyl group or a piperidino group. A mono- or di-lower alkylamino group in which a lower alkyl group moiety is substituted with a group; a pyridyl group; a morpholino group; a lower alkyl group-substituted triazolyl group; and a lower alkoxy group or a lower alkoxy group substituted with a hydroxyl group. An oxo group-substituted dihydroquinolyl group or a hydroxy group-substituted tetrahydroquinolyl group which may be substituted with a group to be substituted; (2) a morpholino group-substituted lower alkyl group; a lower alkoxy group substituted with a piperidino group or a lower alkoxy group; And an oxo-substituted dihydroisoxyl which may be substituted with a group selected from a hydroxyl group Lil group, (3) pyridyl-substituted lower alkyl group, a pyrimidinyl group, a pyridyl group, an oxo group may be substituted with a group selected from the imidazolyl group and a lower alkoxy-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 compound according to claim 11, which is a substituted dihydro (or tetrahydro) quinazolinyl group. 13. 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, a pyridyl group, an imidazolyl group or a piperidino group. A mono- or di-lower alkylamino group in which a lower alkyl group moiety is substituted with a group; a pyridyl group; a morpholino group; a lower alkyl group-substituted triazolyl group; and a lower alkoxy group or a lower alkoxy group substituted with a hydroxyl group. An oxo-substituted dihydroquinolyl group which may be substituted with a group
An oxo-substituted dihydroisoquinolyl group which may be substituted with a group selected from a morpholino-substituted lower alkyl group and a piperidyl-substituted lower alkoxy group, (3) a pyridyl-substituted lower alkyl group, a pyrimidinyl group, a pyridyl group, and an imidazolyl group Group substituted with an oxo group which may be substituted with a group selected from a group selected from a group selected from a lower alkoxy group and an oxo group substituted with a group selected from (4) a lower alkyl group, a lower alkoxy group and an imidazolyl group. 13. The compound according to claim 12, which is a dihydropyridyl group. 14. 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. A mono- or di-lower alkylamino group in which a lower alkyl group part is substituted by 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 a group selected from a lower alkoxy group which may be substituted with a hydroxyl group or a lower alkoxy group. Good oxo group-substituted dihydro (or tetrahydro) quinolyl group or hydroxy group-substituted tetrahydroquinolyl group, (2) morpholino group-substituted lower alkyl group; selected from piperidino group, pyridyl group and lower alkoxy group substituted with lower alkoxy group Oxo group-substituted dihydroisoquinolyl group which may be substituted with a group, (3) pyridyl group-substituted lower alkyl group; pyrimidinyl group; lower alkoxy group; pyridyl group; imidazolyl group; and di-lower alkylamino group-substituted phenyl group Substituted with the selected group A good oxo-substituted dihydrophthalazinyl group, (4) an oxo-substituted dihydropyridyl group substituted with a pyridyl group, (5) an oxo-substituted dihydronaphthyridinyl group, (6) an oxo-substituted hexahydroquinolyl group, (7) an oxo-substituted dihydroindolyl group, (8) an oxo-substituted tetrahydrobenzothiazinyl group, (9) an oxo-substituted dihydro (or tetrahydro) which may be substituted with a lower alkyl group and an oxo group.
The compound according to claim 10, which is a quinazolinyl group, (10) an oxo-substituted dihydrobenzimidazolinyl group, or (11) an oxo-substituted dihydrophenanthridinyl group. 15. An optionally substituted heterocyclic group formed by R ⁵ and R ⁶ bonded to each other at the terminal 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-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; an oxo-substituted dihydroisoquinolyl group which may be substituted with a group selected from a lower alkoxy group substituted with a pyridyl group or a lower alkoxy group, and (3) a pyridyl group-substituted lower alkyl group A lower alkoxy group; a pyridyl group; and a di-lower alkylamino group-substituted phenyl group. Oxo-substituted dihydrophthalazinyl group, or (4) a compound according to claim 14, wherein an oxo group substituted dihydro phenanthridinyl group. 16. 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 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 optionally substituted with a group selected from a lower alkoxy group substituted with a pyridyl group or a lower alkoxy group,
(3) an oxo-substituted dihydrophthalazinyl group substituted with a group selected from a pyridyl group-substituted lower alkyl group; a lower alkoxy group; a pyridyl group; and a di-lower alkylamino group-substituted phenyl group; or (4) an oxo group substitution. The compound according to claim 15, which is a dihydrophenanthridinyl group. 17. An optionally substituted heterocyclic group formed by R ⁵ and R ⁶ bonded to each other at the terminal 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-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; and an oxo-substituted dihydroisoquinolyl group substituted with a group selected from a lower alkoxy group-substituted lower alkoxy group; (3) a pyridyl-substituted lower alkyl group; a lower alkoxy group; and a pyridyl group from an oxo group substituted dihydrophthalazinyl group which is substituted by a group selected claim 7
A compound as described. 18. R ¹ and R ² may be 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 kill group, (3) a hydroxyl group protected with a group selected from cycloalkyl groups, and R ³ and R ⁴ are hydroxyl-substituted methyl groups.
The compound according to 4, 5, 6 , 10 , 14, 15, 16 , or 17 . 19. The compound according to claim 18 , wherein the protected hydroxyl group is a hydroxyl group protected by a lower alkyl group. 20. 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 Pharmacologically acceptable salts. 21. 1- [2- (2-oxo-3-morpholino-1,2-dihydroquinolin-1-yl) -4-pyridyl] -2,3-bis (hydroxymethyl) -6,7
-Dimethoxynaphthalene or a pharmaceutically acceptable salt thereof. 22. 1- {2- [4- (3-pyridyl)-
1 (2H) -phthalazinone-2-yl] -4-pyridyl} -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene or a pharmaceutically acceptable salt thereof. 23. 1- {2- [4- (3-Pyridylmethyl) -1 (2H) -phthalazinone-2-yl] -4-pyridyl} -2,3-bis (hydroxymethyl) -6,7
-Dimethoxynaphthalene or a pharmaceutically acceptable salt thereof. 24. 1- {2- [4- (3-pyridyl)-
1 (2H) -phthalazinone-2-yl] -4-pyridyl} -2,3-bis (hydroxymethyl) -6,7-diethoxynaphthalene or a pharmaceutically acceptable salt thereof. 25. A compound of the general formula [II] (Provided that R ¹¹ and R ²¹ are the same or different and represent a hydrogen atom or a hydroxyl group which may be protected, and R ³¹ and R ⁴¹ each represent a hydroxyl-substituted methyl group which may be protected, and Atom, lower alkyl group or optionally substituted hydroxyl-substituted methyl group, and X represents a halogen atom) and a compound represented by the general formula [II
I] (Provided that R ⁵ and R ⁶ are the same or different and each represent a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted phenyl group or an optionally protected amino group, or At the terminal to form a heterocyclic group which may be substituted together with an adjacent nitrogen atom.), And R ¹¹ and / or R ²¹ are protected. A hydroxyl group,
^{When 31} and / or R ⁴¹ is a protected hydroxyl-substituted methyl group, if necessary, the protective group is completely or selectively removed depending on the type of the protective group, and if necessary, the 6-position and / or Or the hydroxy position at position 7 or the hydroxymethyl position at positions 2 and / or 3 are protected again, if necessary all the hydroxy positions or hydroxymethyl positions are protected, and if necessary the product is pharmacologically treated. General formula [I], which is an acceptable salt. (Provided that R ¹ and R ² are the same or different and are a hydrogen atom or a hydroxyl group which may be protected, R ³ and R ⁴ are a hydroxyl-substituted methyl group which one of them may be protected, the other is a hydrogen atom, A lower alkyl group or a hydroxy-substituted methyl group which may be protected, and other symbols have the same meanings as described above.) Or a pharmacologically acceptable salt thereof. 26. The general formula [IV] (Provided that R ¹¹ and R ²¹ are the same or different and are a hydrogen atom or a hydroxyl group which may be protected, R ³¹ and R ⁴¹ are a hydroxyl-substituted methyl group which one of them may be protected, the other is a hydrogen atom, A lower alkyl group or an optionally protected hydroxyl-substituted methyl group) and a compound represented by the general formula [V]: (However, 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). React and react R ¹¹ and / or R ²¹
Is a protected hydroxyl group, and when R ³¹ and / or R ⁴¹ is a protected hydroxyl-substituted methyl group, the protecting group can be removed altogether or selectively according to the type of the protecting group of the hydroxyl group, if desired. And, if necessary, reprotecting the 6- and / or 7-position hydroxy moiety or the 2- and / or 3-position hydroxymethyl moiety, and, if necessary, converting the product into a pharmaceutically acceptable salt thereof. A general formula characterized by (Provided that R ¹ and R ² are the same or different and are a hydrogen atom or a hydroxyl group which may be protected, R ³ and R ⁴ are a hydroxyl-substituted methyl group which one of them may be protected, the other is a hydrogen atom, Represents a lower alkyl group or an optionally protected hydroxyl-substituted methyl group, and 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 the other symbols have the same meanings as described above.) Or a pharmacologically acceptable salt thereof. 27. The general formula [VI] (Provided that R ¹¹ and R ²¹ are the same or different and are a hydrogen atom or a hydroxyl group which may be protected, R ⁵³ and R ⁶³ are the same or different and are a hydrogen atom, a lower alkyl group which may be substituted, Represents a phenyl group or an amino group which may be protected, or forms an optionally substituted heterocyclic group which is stable to a reduction reaction together with an adjacent nitrogen atom by bonding at the terminals. R ⁷ and R ⁸ represent that one of them is a free or esterified carboxyl group and the other is a hydrogen atom, a lower alkyl group, or a free or esterified carboxyl group ) Or its intramolecular acid anhydride is subjected to a reduction reaction, and when R ¹¹ and / or R ²¹ is a protected hydroxyl group, the protecting group is removed if necessary, and if necessary. The hydroxy site at position 6 and / or 7 or the hydroxymethyl site at position 2 and / or 3 are protected again, if necessary all hydroxy or hydroxymethyl sites are protected, and if necessary the product is protected. A general formula characterized by being a pharmacologically acceptable salt thereof. (Provided that R ¹ and R ² are the same or different and are a hydrogen atom or a hydroxyl group which may be protected, R ³ and R ⁴ are a hydroxyl-substituted methyl group which one of them may be protected, the other is a hydrogen atom, A lower alkyl group or a hydroxy-substituted methyl group which may be protected, and other symbols have the same meanings as described above.) Or a pharmacologically acceptable salt thereof. 28. A compound of the general formula [Ib] (Provided that R ¹¹ and R ²¹ are the same or different and represent a hydrogen atom or a hydroxyl group which may be protected, and R ³¹ and R ⁴¹ each represent a hydroxyl-substituted methyl group which may be protected, and Or a lower alkyl group or a hydroxyl-substituted methyl group which may be protected.) Or a salt thereof, and a compound represented by the general formula [VII]: (However, R ⁹¹ , R ⁹² and R ⁹³ are the same or different and are each substituted by 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. It is a phenyl group, a pyridyl group, by reacting a carboxylic acid derivative or a salt thereof represented by the representative.) pyrimidinyl group or an imidazolyl group, a hydroxyl group R ¹¹ and / or R ²¹ is protected, R ³¹ and And / or when R ⁴¹ is a protected hydroxyl-substituted methyl group, if necessary, the protective group is completely or selectively removed depending on the type of the protective group of the hydroxyl group, and if necessary, the 6-position and / or 7-position Hydroxy site at position 2 or
To protect the hydroxymethyl moiety at the 3rd and / or 3rd position again, and if necessary, to protect all hydroxy or hydroxymethyl moieties, and, if necessary, to make the product a pharmaceutically acceptable salt thereof. Characteristic general formula [Ia] (However, R ¹ and R ² are the same or different and each represents a hydrogen atom or a hydroxyl group which may be protected, and R ³ and R ⁴ each represent a hydroxyl-substituted methyl group which may be protected. A naphthalene derivative represented by an atom, a lower alkyl group or an optionally protected hydroxyl-substituted methyl group, and the other symbols having the same meanings as described above) or a pharmaceutically acceptable salt thereof. . 29. A compound of the formula [Ib] (Provided that R ¹¹ and R ²¹ are the same or different and represent a hydrogen atom or a hydroxyl group which may be protected, and R ³¹ and R ⁴¹ each represent a hydroxyl-substituted methyl group which may be protected, and And a salt thereof, which is an atom, a lower alkyl group or an optionally protected hydroxyl-substituted methyl group) or a salt thereof and a compound of the general formula [VIII] (However, R ⁹² and R ⁹³ may be the same or different and may be substituted with a hydrogen atom, a hydroxyl group, a lower alkoxy group, a lower alkyl group optionally substituted with a pyridyl group, a di-lower alkylamino group or a halogen atom. Represents a phenyl group, a pyridyl group, a pyrimidinyl group or an imidazolyl group)
Wherein 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, Depending on the type of the protecting group, the protecting group is completely or selectively removed, and if necessary, the hydroxy moiety at the 6- and / or 7-position or the hydroxymethyl moiety at the 2- and / or 3-position is protected again. General formula [Ia '] wherein all hydroxy or hydroxymethyl moieties are protected if necessary, and if necessary, the product is converted into a pharmaceutically acceptable salt thereof. (However, R ¹ and R ² are the same or different and each represents a hydrogen atom or a hydroxyl group which may be protected, and R ³ and R ⁴ each represent a hydroxyl-substituted methyl group which may be protected. A naphthalene derivative represented by an atom, a lower alkyl group or an optionally protected hydroxyl-substituted methyl group, and the other symbols having the same meanings as described above) or a pharmaceutically acceptable salt thereof. . 30. A compound of the formula [II-a] (Provided that R ¹¹ and R ²¹ are the same or different and are (1) a hydrogen atom or (2) (i) a lower alkanoyl group,
Boniru group or coercive phenyl low grade 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) cycloalkyl
One of R ³¹ and R ⁴¹ which may be protected by a group selected from the group consisting of (1) a lower alkanoyl group and 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) lower alkoxycarbonyl group, (4) a cycloalkyl group which may be protected hydroxy-substituted methyl group selected from the group, the other is (1) hydrogen atom, (2) a lower alkyl group or (3 ) (I) lower alkanoyl group, 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) cycloalkyl
X represents a hydroxyl-substituted methyl group which may be protected by a group selected from groups, and X ¹ represents chlorine or bromine. ). 31. A compound of the general formula [VI] (Provided that R ¹¹ and R ²¹ are 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, (iii) cycloalkyl
A hydroxyl group which may be protected by a group selected from the groups, R ⁵³ and R ⁶³ are the same or different, and are (1) a hydrogen atom, (2) a lower alkyl group, (3) a phenyl group, or (4) a lower alkanoyl group. , Lower alkoxycarbonyl
Represents an amino group which may be protected by a phenyl group or a phenyl lower alkoxycarbonyl group , or (5 ) a lower alkenyl group which is bonded to the terminal at each other and is stable to a reduction reaction together with an adjacent nitrogen atom ; (ii) Low
A lower alkynyl group; (iii) a lower alkylthio group;
v) cycloalkyl group; (v) trifluoromethyl group;
(Vi) cyano group ; (vii) tetrazolyl group; (vi
ii) formyl group; (ix) amino group; (x) morpholine
Amino group, monocycloalkyl group-substituted amino group, pyridyl
Group, imidazolyl group, piperidyl group or pyrrolidinyl group
And the lower alkyl group may be substituted with mono-
Or a di-lower alkylamino group; (xi) pyridyl
(Xiii) a morpholino group; (xiii) a lower alkyl
Group-substituted triazolyl group; (xiv) bis (hydroxy
A lower alkyl) aminocarbonyl group; (xv) bis (g
Lower alkylsilyloxy lower alkyl) aminocar
(Xvi) a morpholinocarbonyl group; (xv
ii) a lower alkyl-substituted piperazinylcarbonyl group;
(Xviii) piperazine substituted with hydroxy lower alkyl group
Nylcarbonyl group; (xix) tri-lower alkylsilyl
An oxy lower alkyl group-substituted piperazinylcarbonyl group;
(Xx) a lower alkoxycarbonyl group; (xxi)
Boxyl group; (xxii) morpholino group or pyridi
(Xxi) a lower alkyl group which may be substituted with
ii) piperidyl group, pyridyl group, hydroxyl group or lower alkyl
A lower alkoxy group optionally substituted with a oxy group;
(Xxiv) an oxo group; (xxv) a hydroxyl group; (xxv)
(xxvi) a di-lower alkyl group
Phenyl which may be substituted with a amino group or a halogen atom
(Xxviii) a halogen atom; (xxix) d
Toro group; (xxx) imidazolyl group; and (xxxi)
One or two selected from lower alkylenedioxy groups
Represents a heterocyclic group which may be substituted with two or more same or different groups , wherein R ⁷ and R ⁸ are either free or esterified carboxyl groups, and the other is It represents a hydrogen atom, a lower alkyl group, or a free or esterified carboxyl group. ) Or an intramolecular acid anhydride thereof.