JP2001031679A - Naphthyridine derivative and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new naphthyridine derivative having cGMP-specific phosphodiesterase inhibitory activity and useful in the therapies of e.g. bronchial asthma, thrombosis, depression, central nerve hypoparathyroidism after cerebrovascular occlusion. SOLUTION: This new compound is a compound of formula I [ring A is a (substituted) pyridine ring or (substituted) dihydropyridine ring; ring B is a (protective) hydroxy, (substituted) lower alkyl, (substituted) alkoxy or the like; R1 is H, a (substituted) aryl, (substituted) lower alkyl, (substituted) heterocyclic group or the like; R2 is H or an ester residue], e.g. 7,8-dihydro-8-oxo-7- phenyl-5-(3,4,5-trimethoxyphenyl)-1,7-naphthyridine-6-carboxylic acid methyl ester. The compound of formula I is obtained by reaction between a compound of formula II and an amine compound of the formula R1-NH2.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a compound c which is useful as a medicament.
The present invention relates to a novel naphthyridine derivative having a GMP-specific phosphodiesterase (PDE) inhibitory action [PDE V inhibitory action].

[0002]

2. Description of the Related Art In general, cGMP which is an intracellular second messenger is decomposed and inactivated by phosphodiesterase (PDE) which is widely distributed in tissues of a living body. When the PDE activity is inhibited, cGMP of intracellular cGMP is reduced. It is known that the concentration increases, and as a result, various pharmacological actions such as a vascular smooth muscle relaxing action and a bronchial smooth muscle relaxing action are exhibited.

[0003] Further, such cGMP-specific PDE inhibitors (ie, PDEV inhibitors) exhibit platelet aggregation inhibitory action, vasodilatory action, etc. [C. D. Nicholso
n et al., Trends in Pharmacological Sciences, Vol. 12, p. 19 (1991) (Trend
s in Pharmacological Scie
nces)].

[0004] Therefore, PDEV inhibitors are considered to be useful as therapeutic agents for bronchial asthma, thrombosis, depression, central dysfunction after cerebral vascular occlusion, cerebral vascular dementia and heart failure.

In recent years, condensed pyridazine compounds having the above-mentioned PDEV inhibitory activity are useful for the prevention and treatment of hypertension, angina, myocardial infarction, chronic and acute heart failure, pulmonary hypertension, etc. (Japanese Patent Laid-Open No.
225541).

[0006] Further, 1- has a PDEV inhibitory action.
[4-ethoxy-3- (6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3
-D] pyrimidin-5-yl) phenylsulfonyl]-
4-methylpiperazine [generic name: sildenafil (SI
LDENAFIL)] has also been reported to be useful in the treatment of diseases such as penile erectile dysfunction [Boolell M].
Et al., The Journal of Urology Supplements, Vol. 155, No. 5, 495A, pp. 739 (199)
6 years) (The Journal of Ulog)
y, Suppliment), Terrett NK
Et al., Bioorganic and Medicinal Chemistry Letters, Vol. 6, No. 15, p. 1819 (1996) (Bioorganic & Medi)
sinal Chemistry Letters) and Ballard SA, et al., British Journal of Pharmacology Proceeding Supplement, Vol. 118, 153P (1996) (Br).
issue Journal of Pharmaco
logic, Proceeding Supplymen
t)]. However, sildenafil includes headache, flushing of the face, gastrointestinal disorders, rhinitis, abnormal color vision [Irwin G
Et al., The New Ingrad Journal of Medicine, Vol. 338, No. 20, No. 1397-1404
P. (1998) (The New England)
Journal of Medicine), A Mo
rales et al., International Journal of Impotence Research, Vol. 10, No. 2, 69
-73 (1998) (International
Journal of Impotence Res
earch) and Goldenberg MM, Clinical Therapeutics, Vol. 20, No. 6, No. 1.
033-1048 (1998) (Clinical)
Therapeutics)] and persistent erection [ht
tp: // www. fda. gov / bbs / topi
cs / ANSWERS / ANS00926. html]
It has also been reported that there are side effects such as Also, in dog experiments, sildenafil was reported to correlate with PDE VI inhibitory effects on the effects of retinal tissue light response [AMorales et al., International Journal of Impotence Research, Vol. 10, No. 2]. , Pp. 69-73 (1998) (Interna
Tional Journal of Impoten
ce Research), while also reporting that retinal PDE VI plays an important role in visual function [A Morales et al., International Journal of Impotence Research, Vol. 10, No. 2]. , Pp. 69-73 (1998) (In
national Journal of Im
potential Research) and M Estr
ade et al., European Journal of Pharmacology, 352, 157-163 (1998)
Year) (European Journal of Ph)
armacology)].

[0007]

DISCLOSURE OF THE INVENTION The present invention provides a novel naphthyridine derivative having an excellent phosphodiesterase V (PDE V) inhibitory activity and a method for producing the same.

[0008]

According to the present invention, there is provided a compound represented by the general formula [I]:

[0009]

Embedded image

(Wherein ring A is a substituted or unsubstituted pyridine ring or substituted or unsubstituted dihydropyridine ring, ring B is an optionally protected hydroxyl group, substituted or unsubstituted lower alkyl group, substituted or unsubstituted lower alkoxy group The same or different from 2 to 4 selected from
A benzene ring having one or two substituents or a benzene ring having one or two lower alkylenedioxy groups, R ¹ is a hydrogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted lower alkyl group, A cyclic group or a substituted or unsubstituted amino group, R ² represents a hydrogen atom or an ester residue; ) Or a pharmacologically acceptable salt thereof.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The substituent on ring A in the target compound [I] of the present invention includes, for example, a substituted or unsubstituted lower alkoxy group, a halogen atom, a protected hydroxyl group, a substituted or unsubstituted nitrogen-containing heterocyclic group. Cyclic group, substituted or unsubstituted lower alkylthio group, substituted or unsubstituted amino group, substituted or unsubstituted lower alkyl group, substituted or unsubstituted aryl group, heterocyclic group-substituted oxy group, oxide group or oxo group, etc. Can be

Specific examples of the substituted or unsubstituted lower alkoxy group as a substituent on ring A include lower alkylenedioxyphenyl group; benzimidazolyl group; lower alkyl group-substituted imidazolyl group; imidazolyl group; cyano group;
Carboxyl group; pyridyl group; N-oxide pyridyl group; pyridyl group substituted by hydroxyl-substituted lower alkyl group; pyrrolidinyl group; lower alkyl-substituted pyrrolidinyl group; oxo-substituted pyrrolidinyl group; isoquinolyl group; A pyrimidinyl group;
N-oxide pyrimidinyl group; pyrazinyl group; quinazolinyl group; phthalazinyl group; lower alkoxycarbonyl group-substituted piperidyl group; tert-butoxycarbonyl group-substituted pyridyl group; lower alkyl group-substituted piperidyl group; piperidyl group; tert-butoxycarbonyl group-substituted piperazinyl group A lower alkyl group-substituted piperazinyl group; a piperazinyl group; a quinolyl group; a tetrazolyl group; a thiazolyl group; a thienyl group; a furyl group; a pyrrolyl group substituted with a lower alkyl group and a lower alkoxycarbonyl group; a mono- or di-lower alkylamino group; Lower alkoxy group; lower alkoxy group; hydroxyl group; carbamoyl group; lower alkoxycarbonyl group; cyclo lower alkyl group; phenyl group; phenyl group substituted by hydroxyl-substituted lower alkyl group Carboxyl group-substituted phenyl group;
Lower alkoxycarbonyl group substituted phenyl group; benzoyl group; mono or di lower alkoxy group substituted phenyl group; nitro group substituted phenyl group; naphthyl group; mono or dihalogenophenyl group; carbamoyl group substituted phenyl group; sulfamoyl group substituted phenyl group; A phenyl group mono- or di-substituted by an amino group which may be substituted; a biphenylyl group; a phenyl group di-substituted by a halogen atom and a nitro group; a di-lower alkylamino-substituted phenyl group; and a lower alkyl-substituted phenyl group. A lower alkoxy group which may be substituted with a selected group is exemplified.

Specific examples of the protected hydroxyl group as a substituent on ring A include trifluoromethanesulfonyloxy group, lower alkanoyloxy group, tri-lower alkylsilyloxy group, carbamoyloxy group, benzyloxy group and lower alkoxy group. And a substituted benzyloxy group.

Specific examples of the substituted or unsubstituted nitrogen-containing heterocyclic group as a substituent on ring A include a tetrazolyl group,
Substituted with triazolyl group, pyrrolidinyl group, pyrrolidinyl group substituted with hydroxyl-substituted lower alkyl group, hydroxyl-substituted pyrrolidinyl group, piperidyl group, hydroxyl-substituted piperidyl group, morpholinyl group, piperazinyl group, pyrimidinyl group-substituted piperazinyl group, hydroxyl-substituted lower alkyl group A piperazinyl group, a pyridyl group and an imidazolyl group.

Specific examples of the substituted or unsubstituted lower alkylthio group as a substituent on ring A include lower alkylenedioxyphenyl group; benzimidazolyl group; lower alkyl group-substituted imidazolyl group; cyano group; carboxyl group; A pyridyl group substituted with a hydroxyl-substituted lower alkyl group; a pyrrolidinyl group; an isoquinolyl group; a pyrimidinyl group optionally substituted with a lower alkyl group; a pyrazinyl group; a quinazolinyl group; a phthalazinyl group; Group substituted piperidyl group; piperidyl group; quinolyl group; tetrazolyl group; thienyl group; furyl group; pyrrolyl group substituted by lower alkyl group and lower alkoxycarbonyl group; mono- or di-lower alkylamino group; lower alkoxy-substituted lower alkoxy group ; Lower alkoxycarbonyl group; cyclo-lower alkyl group; phenyl group; phenyl group substituted with a hydroxyl-substituted lower alkyl group; carboxy group-substituted phenyl group; lower alkoxycarbonyl group-substituted phenyl group; benzoyl group Mono- or di-lower alkoxy-substituted phenyl; nitro-substituted phenyl; naphthyl; mono- or dihalogenophenyl; carbamoyl-substituted phenyl; sulfamoyl-substituted phenyl; A diphenyl-substituted phenyl group; a biphenylyl group; a phenyl group di-substituted with a halogen atom and a nitro group; a di-lower alkylamino group-substituted phenyl group; and a lower alkyl group-substituted phenyl group. Lower alkyl Oh group.

Specific examples of the substituted or unsubstituted amino group which is a substituent on ring A include an amino group which may be protected; a phenyl group-substituted lower alkyl group, a pyridyl group-substituted lower alkyl group, a lower alkyl group, Lower alkoxy group-substituted lower alkyl group, hydroxyl-substituted lower alkyl group, pyrimidinyl group-substituted lower alkyl group, lower alkyl group substituted with lower alkylamino group, pyridyl group-substituted amino group,
Amino groups having the same or different one or two substituents selected from an amino group substituted with a halogeno lower alkyl group-substituted pyrimidinyl group, a pyridylcarbonyl group-substituted amino group, and an amino group which may be protected.

Specific examples of the substituted or unsubstituted lower alkyl group as a substituent on ring A include lower alkylenedioxyphenyl group; benzimidazolyl group; lower alkyl group-substituted imidazolyl group; cyano group; carboxyl group; A pyridyl group substituted with a hydroxyl-substituted lower alkyl group; a pyrrolidinyl group; an isoquinolyl group; a pyrimidinyl group optionally substituted with a lower alkyl group; a pyrazinyl group; a quinazolinyl group; a phthalazinyl group; Group substituted piperidyl group; piperidyl group; quinolyl group; tetrazolyl group; thienyl group; furyl group; pyrrolyl group substituted by lower alkyl group and lower alkoxycarbonyl group; mono- or di-lower alkylamino group; lower alkoxy-substituted lower alkoxy group ; Low grade Alkoxy group, a hydroxyl group, a carbamoyl group, a lower alkoxycarbonyl group; a lower cycloalkyl group; a phenyl group; hydroxyphenyl group substituted with a lower alkyl group; a carboxyl group-substituted phenyl group; a lower alkoxycarbonyl group-substituted phenyl group; a benzoyl group;
Mono- or di-lower alkoxy-substituted phenyl group; nitro-substituted phenyl group; naphthyl group; mono- or dihalogenophenyl group; carbamoyl-substituted phenyl group; sulfamoyl-substituted phenyl group; Disubstituted phenyl group; biphenylyl group; phenyl group disubstituted with halogen atom and nitro group; di-lower alkylamino group-substituted phenyl group;
And a lower alkyl group which may be substituted with a group selected from a lower alkyl group-substituted phenyl group.

Specific examples of the substituted or unsubstituted aryl group as a substituent on ring A include a phenyl group, a naphthyl group, an indanyl group, a fluorenyl group, an anthracenyl group, a phenanthrenyl group and an indenyl group.

Specific examples of the heterocyclic group-substituted oxy group which is a substituent on the ring A include a tetrahydrofuranyl group-substituted oxy group, an oxo group-substituted tetrahydrofuranyl group-substituted oxy group, and an optionally protected piperidinyl group-substituted group. Examples thereof include an oxy group, an oxo group-substituted piperidinyl group-substituted oxy group, an optionally protected pyrrolidinyl group-substituted oxy group, and an oxo group-substituted pyrrolidinyl group-substituted oxy group.

Of the ring A, preferably, for example, the ring A has the formula:

[0021]

Embedded image

Wherein A ¹ is (1) a hydrogen atom, (2) a substituted or unsubstituted lower alkoxy group,
(3) halogen atom, (4) protected hydroxyl group, (5)
A substituted or unsubstituted nitrogen-containing heterocyclic group, (6) a substituted or unsubstituted lower alkylthio group, (7) a substituted or unsubstituted amino group, (8) a substituted or unsubstituted alkyl group,
(9) a substituted or unsubstituted aryl group, or (10)
Heterocyclic group-substituted oxy groups, include those wherein A ² is (1) a hydrogen atom or (2) a substituted or unsubstituted lower alkyl group, and more preferably, ring A has the formula:

[0023]

Embedded image

Wherein A ¹ is (1) a hydrogen atom, (2) a substituted or unsubstituted lower alkoxy group,
(3) halogen atom, (4) protected hydroxyl group, (5)
A substituted or unsubstituted nitrogen-containing heterocyclic group, (6) a substituted or unsubstituted lower alkylthio group, (7) a substituted or unsubstituted amino group, (8) a substituted or unsubstituted alkyl group,
(9) a substituted or unsubstituted aryl group, or (10)
Heterocyclic group-substituted oxy groups, wherein A ² is (1) a hydrogen atom or (2) a substituted or unsubstituted lower alkyl group.

Specific examples of the substituent A ¹ on the ring A include:
(I) lower alkylenedioxyphenyl group; benzimidazolyl group; lower alkyl-substituted imidazolyl group; imidazolyl group; cyano group; carboxyl group; pyridyl group;
N-oxide pyridyl group; pyridyl group substituted with hydroxyl-substituted lower alkyl group; pyrrolidinyl group; lower alkyl-substituted pyrrolidinyl group; oxo-substituted pyrrolidinyl group;
Isoquinolyl group; lower alkyl-substituted pyrimidinyl group;
Pyrimidinyl group; N-oxide pyrimidinyl group; pyrazinyl group; quinazolinyl group; phthalazinyl group; lower alkoxycarbonyl group-substituted piperidyl group; tert-butoxycarbonyl group-substituted pyridyl group; lower alkyl group-substituted piperidyl group; piperidyl group; tert-butoxycarbonyl group Substituted piperazinyl group; lower alkyl group substituted piperazinyl group; piperazinyl group; quinolyl group; tetrazolyl group; thiazolyl group; thienyl group; furyl group; pyrrolyl group substituted by lower alkyl group and lower alkoxycarbonyl group; A lower alkoxy group; a lower alkoxy group; a lower alkoxy group;
Hydroxyl group; carbamoyl group; lower alkoxycarbonyl group; cyclo-lower alkyl group; phenyl group; phenyl group substituted by hydroxyl-substituted lower alkyl group; carboxy-substituted phenyl group; lower-alkoxycarbonyl-substituted phenyl group; benzoyl group; Lower alkoxy-substituted phenyl; nitro-substituted phenyl; naphthyl; mono- or dihalogenophenyl; carbamoyl-substituted phenyl; sulfamoyl-substituted phenyl;
Benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, tert-butoxycarbonyl group, 2,2,2-
A phenyl group mono- or di-substituted with an amino group optionally protected by a trichloroethyloxycarbonyl group or a lower alkanoyl group; a biphenylyl group;
A phenyl group disubstituted with a halogen atom and a nitro group;
Di-lower alkylamino-substituted phenyl group; and lower alkoxy group which may be substituted with a group selected from lower alkyl-substituted phenyl group, (ii) halogen atom, (i
ii) trifluoromethanesulfonyloxy group, (i
v) tetrazolyl group, (v) triazolyl group, (vi)
A pyrrolidinyl group optionally substituted with a hydroxyl-substituted lower alkyl group or a hydroxyl group, (vii) a piperidyl group optionally substituted with a hydroxyl group, (viii) a morpholinyl group, (ix) a hydroxyl-substituted lower alkyl group or a pyrimidinyl group A piperazinyl group which may be substituted, (x)
Pyridyl group, (xi) imidazolyl group, (xii) lower alkylenedioxyphenyl group; benzimidazolyl group; lower alkyl group-substituted imidazolyl group; cyano group; carboxyl group; pyridyl group;
Pyridyl group substituted with a hydroxyl-substituted lower alkyl group; pyrrolidinyl group; isoquinolyl group; lower alkyl group-substituted pyrimidinyl group; pyrimidinyl group; pyrazinyl group; quinazolinyl group; phthalazinyl group; lower alkoxycarbonyl group-substituted piperidyl group; piperidyl group; quinolyl group A tetrazolyl group; a thienyl group; a furyl group; a pyrrolyl group substituted with a lower alkyl group and a lower alkoxycarbonyl group; a mono- or di-lower alkylamino group; a lower alkoxy-substituted lower alkoxy group; a lower alkoxy group; a hydroxyl group; A lower alkoxycarbonyl group; a cyclo-lower alkyl group; a phenyl group; a phenyl group substituted with a hydroxyl-substituted lower alkyl group; a carboxy group-substituted phenyl group; a lower alkoxycarbonyl group-substituted phenyl group; Or di-lower alkoxy-substituted phenyl group; a nitro group-substituted phenyl group; a naphthyl group;
Mono- or dihalogenophenyl group; carbamoyl-substituted phenyl group; sulfamoyl-substituted phenyl group; benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, tert-butoxycarbonyl group, 2,2 A phenyl group mono- or di-substituted by an amino group which may be protected by a 1,2-trichloroethyloxycarbonyl group or a lower alkanoyl group; a biphenylyl group; a phenyl group di-substituted by a halogen atom and a nitro group; An alkylamino group-substituted phenyl group; and a lower alkylthio group optionally substituted with a group selected from lower alkyl group-substituted phenyl groups, (xiii) benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, 9-fluorenyl Methoxycarbonyl group, tert
-Butoxycarbonyl group, amino group optionally protected by 2,2,2-trichloroethyloxycarbonyl group or lower alkanoyl group, (xiv) phenyl-substituted lower alkyl group; pyridyl group-substituted lower alkyl group; lower alkyl group A lower alkyl group substituted with a lower alkoxy group, a lower alkyl group substituted with a hydroxyl group, a lower alkyl group substituted with a pyrimidinyl group, a lower alkyl group substituted with a lower alkylamino group, a pyridyl group-substituted amino group, and a halogenated lower alkyl group-substituted pyrimidinyl group. Amino group;
Pyridylcarbonyl group-substituted amino group; the same or different one or two substitutions selected from benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, tert-butoxycarbonyl group or amino group optionally substituted by lower alkanoyl group And an amino group having a group, (xv) a lower alkyl group, or (xvi) a tetrahydrofuranyl group-substituted oxy group.

Specific examples of substituent A ² on ring A include lower alkylenedioxyphenyl group; benzimidazolyl group; lower alkyl group-substituted imidazolyl group; imidazolyl group; cyano group; carboxyl group; pyridyl group; Pyridyl group; pyridyl group substituted with hydroxyl-substituted lower alkyl group; pyrrolidinyl group; lower alkyl-substituted pyrrolidinyl group; oxo-substituted pyrrolidinyl group; isoquinolyl group; lower-alkyl-substituted pyrimidinyl group; pyrimidinyl group; N-oxidepyrimidinyl group; Pyrazinyl group;
Quinazolinyl group; phthalazinyl group; lower alkoxycarbonyl group-substituted piperidyl group; tert-butoxycarbonyl group-substituted pyridyl group; lower alkyl group-substituted piperidyl group; piperidyl group; tert-butoxycarbonyl group-substituted piperazinyl group; lower alkyl group-substituted piperazinyl group; piperazinyl A quinolyl group; a tetrazolyl group; a thiazolyl group; a thienyl group; a furyl group; a pyrrolyl group substituted by a lower alkyl group and a lower alkoxycarbonyl group; a mono- or di-lower alkylamino group; a lower alkoxy-substituted lower alkoxy group; A carbamoyl group; a lower alkoxycarbonyl group; a cyclo-lower alkyl group; a phenyl group; a phenyl group substituted with a hydroxy-lower alkyl group; a carboxyl group-substituted phenyl group; Aryloxycarbonyl group-substituted phenyl group; a benzoyl group; a mono- or di-lower alkoxy-substituted phenyl group; a nitro group-substituted phenyl group; a naphthyl group;
Mono- or dihalogenophenyl group; carbamoyl-substituted phenyl group; sulfamoyl-substituted phenyl group; benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, tert-butoxycarbonyl group, 2,2 A phenyl group mono- or di-substituted by an amino group which may be protected by a 1,2-trichloroethyloxycarbonyl group or a lower alkanoyl group; a biphenylyl group; a phenyl group di-substituted by a halogen atom and a nitro group; And a lower alkyl group which may be substituted with a group selected from an alkylamino group-substituted phenyl group; and a lower alkyl group-substituted phenyl group.

The ring B of the objective compound [I] of the present invention may be the same or different 2 selected from an optionally protected hydroxyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkoxy group and a halogen atom. ~ 4
And a benzene ring having 1 to 2 lower alkylenedioxy groups.

Specific examples of the ring B include (1) a hydroxyl group which may be protected by a benzyl group, a phenethyl group, a formyl group, an acetyl group, a propionyl group, a malonyl group, an acryloyl group or a benzoyl group; a lower alkyl group A lower alkoxy group; and a benzene ring having the same or different 2 to 4 substituents selected from halogen atoms or (2) a benzene ring having 1 to 2 lower alkylenedioxy groups.

Of the ring B, preferably, for example, the ring B has the formula:

[0030]

Embedded image

Wherein B ¹ , B ² and B ³ are the same or different and each may be a hydroxyl group, a lower alkyl group, a lower alkoxy group or a halogen atom which may be protected, More preferably, for example, when ring B has the formula:

[0032]

Embedded image

Wherein B ¹ , B ² and B ³ are the same or different and each may be a hydroxyl group, a lower alkyl group, a lower alkoxy group or a halogen atom which may be protected.

When R ¹ of the target compound [I] of the present invention is a substituted or unsubstituted aryl group, the aryl group may be a monocyclic, bicyclic or tricyclic group which may be partially saturated. A 6-14 membered aryl group is mentioned. Examples of the monocyclic aryl group include a phenyl group, a cyclohexadienyl group, a cyclohexenyl group and the like. Examples of the bicyclic aryl group include a naphthyl group, an indenyl group, an indanyl group, and an azulenyl group. Examples of the tricyclic aryl group include a fluorenyl group, a phenanthrenyl group, and an anthracenyl group.

When R ¹ of the object compound [I] of the present invention is a substituted or unsubstituted heterocyclic group, the heterocyclic group may be a monocyclic or bicyclic group which may be partially saturated. Examples thereof include a 5- to 12-membered heterocyclic group of the formula, and specifically, a monocyclic or bicyclic 5 to 12-membered group which may be partially saturated.
Aromatic heterocyclic group or monocyclic or bicyclic 5-
A 12-membered aliphatic heterocyclic group is exemplified.

The monocyclic or bicyclic 5- to 12-membered aromatic heterocyclic group includes a monocyclic or bicyclic monocyclic or bicyclic heterocyclic group containing 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur. Preferred is a 5- to 10-membered aromatic heterocyclic group of the formula, for example, a pyranyl group, an indazolyl group, a benzotriazolyl group, a pyrrolyl group, an imidazolyl group, a furyl group,
Thienyl group, thiazolyl group, isoxazolyl group, oxazolyl group, oxazolinyl group, pyrazolyl group, phthalazinyl group, quinazolinyl group, thienopyrimidinyl group, pyridyl group, pyrimidinyl group, pyridazinyl group, pyrazinyl group, triazinyl group, tetrazolyl group, quinolyl group,
Examples thereof include an isoquinolyl group, a quinoxalinyl group, an indolyl group, a benzothienyl group, a benzothiazolyl group, a benzooxazolyl group, and a benzimidazolyl group.

The monocyclic or bicyclic 5- to 12-membered aliphatic heterocyclic group includes monocyclic 5- to 5-membered aliphatic heterocyclic groups containing 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur. 10
Preferred are membered aliphatic heterocyclic groups, such as piperazinyl, pyrrolidinyl, piperidyl, pyrazolidinyl, quinuclidinyl, thiomorpholino, morpholino, hexahydropyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl or And a dioxanyl group.

When R ¹ of the target compound [I] of the present invention is a substituted lower alkyl group, examples of the substituent on the lower alkyl group include piperidyl group, pyridyl group, lower alkyl group-substituted pyridyl group and lower alkoxy group. Group-substituted pyridyl group, lower alkyl group-substituted N-oxide pyridyl group, imidazolyl group, lower alkyl group-substituted piperidyl group, furyl group, morpholino group, tetrahydrofuryl group, dihydropyridyl group substituted by lower alkyl group and oxo group, piperazinyl Group, lower alkoxycarbonyl group-substituted piperazinyl group, cyclo-lower alkyl group, phenyl group, lower alkylenedioxyphenyl group, lower alkoxycarbonyl group, hydroxyl group, hydroxyl-substituted lower alkoxy group, optionally protected carboxyl group, lower alkoxy group , May be protected Amino group, a carbamoyl group, a di-lower alkylamino group, pyridylcarbonyl group, and the like.

The lower alkyl group for R ¹ may have 1 to 3 same or different substituents.

When R ¹ of the target compound [I] of the present invention is a substituted aryl group, the substituent on the aryl group is
For example, halogen atom, mono- or di-lower alkylamino group, morpholino group, lower alkyl group-substituted pyrimidinyl group, lower alkyl group-substituted pyrazolyl group, hydroxyl-substituted lower alkyl group, optionally protected amino group, lower alkanoyl group-substituted amino Group, lower alkoxy group, lower alkyl group, optionally protected hydroxyl group, carboxyl group-substituted lower alkyl group, lower alkoxycarbonyl group-substituted lower alkyl group, lower alkoxycarbonyl group-substituted lower alkoxy group, carbamoyl group, protected Carboxyl group, lower alkylthio group, lower alkoxycarbonyl group, nitro group, trihalogeno lower alkyl group, morpholinocarbonyl group, carboxyl group-substituted lower alkoxy group, di (lower alkylsulfonyl) amino group, morpholino lower Alkylcarbamoyl group-substituted lower alkoxy group, sulfamoyl group, lower alkyl group optionally substituted with amino group, amino group substituted with lower alkyl group and amino-protecting group, lower alkylenedioxy group, protection A carbamoyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, and the like, which may be substituted with an optionally substituted amino group.

The aryl group for R ¹ may have 1 to 4 identical or different substituents.

When R ¹ of the target compound [I] of the present invention is a substituted heterocyclic group, the substituent on the heterocyclic group is
Hydroxyl group, halogen atom, lower alkyl group, phenyl group-substituted lower alkyl group, hydroxyl group-substituted lower alkyl group, oxo group, lower alkoxy group, optionally protected amino group, mono- or di-lower alkylamino group, phenyl lower alkoxycarbonyl Group, lower alkoxycarbonyl group, carboxyl group, carbamoyl group and the like.

The heterocyclic group for R ¹ may have 1 to 4 of the same or different substituents.

When R ¹ of the target compound [I] of the present invention is a substituted amino group, the substituent on the amino group may be an amino-protecting group, a pyridyl group, a lower alkanoyl group, a lower alkyl group, a hydroxyl-substituted group. Lower alkyl group, phenyl group,
Lower alkanoyloxy group-substituted lower alkyl groups, trihalogeno lower alkanoyl groups and the like can be mentioned.

The amino group for R ¹ may have one or two of the above-mentioned substituents, which may be the same or different.

Specific examples of R ¹ include (i) a hydrogen atom,
(Ii) piperidyl group; pyridyl group; lower alkyl group-substituted pyridyl group; lower alkoxy group-substituted pyridyl group; lower alkyl group-substituted N-oxidepyridyl group; imidazolyl group; lower alkyl group-substituted piperidyl group; furyl group; morpholino group; A dihydropyridyl group substituted with a lower alkyl group and an oxo group; a piperazinyl group; a lower alkoxycarbonyl group-substituted piperazinyl group; a cyclo lower alkyl group; a phenyl group; a lower alkylenedioxyphenyl group; a lower alkoxycarbonyl group;
Hydroxyl group; hydroxyl-substituted lower alkoxy group; carboxyl group; lower alkoxy group; benzyloxycarbonyl group;
Amino group optionally protected by 4-methoxybenzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, tert-butoxycarbonyl group, 2,2,2-trichloroethyloxycarbonyl group or lower alkanoyl group; carbamoyl A lower alkyl group which may be substituted with the same or different 1 to 3 groups selected from the group consisting of a di-lower alkylamino group, and a pyridylcarbonyloxy group; (iii) a halogen atom; a mono- or di-lower alkylamino group; Morpholino group; lower alkyl-substituted pyrimidinyl group; lower alkyl-substituted pyrazolyl group; hydroxyl-substituted lower alkyl group; benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, te
an amino group which may be protected with an rt-butoxycarbonyl group, a 2,2,2-trichloroethyloxycarbonyl group or a lower alkanoyl group; a lower alkanoyl group-substituted amino group; a lower alkoxy group; a lower alkyl group; a benzyl group, phenethyl A hydroxyl group optionally protected with a group, formyl group, acetyl group, propionyl group, malonyl group, acryloyl group or benzoyl group; carboxyl group-substituted lower alkyl group; lower alkoxycarbonyl group-substituted lower alkyl group; lower alkoxycarbonyl group-substituted lower Alkoxy group; carbamoyl group; carboxyl group; lower alkylthio group; lower alkoxycarbonyl group; nitro group; trihalogeno lower alkyl group; morpholinocarbonyl group; carboxyl group-substituted lower alkoxy group; ) Amino group; a morpholino-lower alkylcarbamoyl-substituted lower alkoxy group; a sulfamoyl group; a benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, tert- butoxycarbonyl group,
A lower alkyl group substituted by an amino group which may be protected by a 2,2,2-trichloroethyloxycarbonyl group or a lower alkanoyl group; a benzyloxycarbonyl group, a 4-methoxybenzyloxycarbonyl group,
A protecting group selected from a fluorenylmethyloxycarbonyl group, a tert-butoxycarbonyl group, a 2,2,2-trichloroethyloxycarbonyl group and a lower alkanoyl group, and an amino group substituted with a lower alkyl group; Lower alkylenedioxy group; benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, t
a carbamoyl group substituted with an tert-butoxycarbonyl group, a 2,2,2-trichloroethyloxycarbonyl group or an amino group which may be protected with a lower alkanoyl group; a lower alkylsulfinyl group; and a lower alkylsulfonyl group. A phenyl group or a naphthyl group which may be substituted with the same or different 1 to 4 groups, (iv) a hydroxyl group, a halogen atom, a lower alkyl group;
Phenyl group-substituted lower alkyl group; hydroxyl-substituted lower alkyl group; oxo group; lower alkoxy group; benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, te
an amino group which may be protected with an rt-butoxycarbonyl group, a 2,2,2-trichloroethyloxycarbonyl group or a lower alkanoyl group; a mono or di lower alkylamino group; a phenyl lower alkoxycarbonyl group; a lower alkoxycarbonyl group; The same or different 1-4 selected from a carboxyl group; and a carbamoyl group
Or a 5- to 12-membered heteromonocyclic group or bicyclic group which may be substituted with 5 groups, or (v) a benzyloxycarbonyl group, a 4-methoxybenzyloxycarbonyl group, 9
-Fluorenylmethyloxycarbonyl group, tert-
Butoxycarbonyl group, 2,2,2-trichloroethyloxycarbonyl group, pyridyl group, lower alkanoyl group, lower alkyl group, hydroxyl-substituted lower alkyl group, phenyl group, lower alkanoyloxy group-substituted lower alkyl group or trihalogeno lower alkanoyl group An amino group which may be mono- or di-substituted by the same or different groups selected is exemplified.

R ² of the target compound [I] of the present invention is a hydrogen atom or a substituted or unsubstituted aryl lower alkyl such as a benzyl group, a nitrobenzyl group, an aminobenzyl group which may be protected or a lower alkoxybenzyl group. Group, methyl group, ethyl group, propyl group, lower alkyl group such as butyl group, cyclo lower alkyl group such as cyclopentyl group, cyclo lower alkyl group substitution such as cyclopentylmethyl group, cyclohexylmethyl group Lower alkyl group, lower alkoxy group substitution Lower alkyl group, hydroxyl-substituted lower alkyl group, or trimethylsilylmethyl group, ter
Those which are ester residues such as tri-lower alkylsilyl lower alkyl groups such as t-butyldimethylsilylmethyl group are exemplified.

When the target compound [I] of the present invention has a protected amino group, examples of the protecting group for the amino group include a substituted or unsubstituted lower alkoxycarbonyl group and a lower alkanoyl group. Specifically, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, tert-butoxycarbonyl, 2,2,2
Examples thereof include a 2-trichloroethyloxycarbonyl group, a formyl group, an acetyl group, a propionyl group, and a butyryl group. Of these, a substituted or unsubstituted lower alkoxycarbonyl group is preferred, and specific examples thereof include a benzyloxycarbonyl group and a tert-butoxycarbonyl group.

When the target compound [I] of the present invention has a protected hydroxyl group, examples of the protecting group for the hydroxyl group include a commonly used protecting group such as a substituted or unsubstituted aryl lower alkyl group and an acyl group. be able to. Of these, preferred are, for example, unsubstituted aryl lower alkyl groups such as benzyl group and phenethyl group, and acyl groups such as formyl group, acetyl group, propionyl group, malonyl group, acryloyl group and benzoyl group.

Further, when the target compound [I] of the present invention has a protected carboxyl group, the protecting group for the carboxyl group is a protecting group which can be eliminated by hydrolysis or hydrogenolysis. A lower alkyl group or a halogen atom, a benzyl group which may be substituted with one or two groups selected from a lower alkyl group and a lower alkoxy group, specifically, a methyl group, an ethyl group,
Examples include a propyl group, a tert-butyl group, a benzyl group, a 4-chlorobenzyl group, a 4-fluorobenzyl group, a 4-methylbenzyl group, and a 4-methoxybenzyl group. Of these, preferred are a methyl group, an ethyl group, and a benzyl group.

Among the desired compounds [I] of the present invention, preferred compounds are those wherein R ¹ is a substituted or unsubstituted aryl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted heterocyclic group. Examples of the compound include an amino group.

Among the desired compounds [I] of the present invention, more preferred compounds are those wherein ring A has the formula:

[0053]

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Wherein A ¹ represents one or two identical or different substituents selected from (1) a hydrogen atom, (2) a lower alkoxy group, a hydroxyl-substituted lower alkyl group and a lower alkylamino group. A phenyl group which may be present;
A pyridyl group optionally substituted with a hydroxyl-substituted lower alkyl group; a pyrimidinyl group optionally substituted with a lower alkyl group; an imidazolyl group optionally substituted with a lower alkyl group; a pyrazinyl group;
N-oxide pyrimidinyl group; tetrazolyl group; thiazolyl group; pyrrolidinyl group; lower alkyl group-substituted pyrrolidinyl group; oxo group-substituted pyrrolidinyl group; morpholinyl group; optionally protected piperazinyl group; lower alkyl group-substituted piperazinyl group; A lower alkyl group optionally substituted with a group selected from a piperidyl group; a lower alkyl group-substituted piperidyl group; a lower alkylamino group; a cyano group; a cyclo-lower alkyl group; a lower alkoxy group; and a hydroxyl group; Halogen atom,
(4) trifluoromethanesulfonyloxy group, (5)
A tetrazolyl group, (6) a triazolyl group, (7) a pyrrolidinyl group optionally substituted with a hydroxyl-substituted lower alkyl group or a hydroxyl group, (8) a piperidyl group optionally substituted with a hydroxyl group, (9) a morpholinyl group, 10) a piperazinyl group optionally substituted with a hydroxyl-substituted lower alkyl group or a pyrimidinyl group, (11) a pyridyl group,
(12) imidazolyl group, (13) lower alkylthio group optionally substituted with phenyl group, (14) phenyl group-substituted lower alkyl group, pyridyl group-substituted lower alkyl group, lower alkyl group, lower alkoxy-substituted lower alkyl group A hydroxyl-substituted lower alkyl group, a pyrimidinyl-substituted lower alkyl group, a lower alkyl group substituted with a lower alkylamino group, a pyridyl group-substituted amino group, an amino group substituted with a halogeno lower alkyl-substituted pyrimidinyl group,
The same or different 1 or 2 selected from a pyridylcarbonyl group-substituted amino group and an amino group which may be protected
An amino group having three substituents, (15) a lower alkyl group, or (16) a tetrahydrofuranyl group-substituted oxy group, wherein A ² is selected from (1) a hydrogen atom or (2) a lower alkoxy group and a di-lower alkylamino group A phenyl group optionally having one or two substituents; a pyridyl group; a lower alkoxy group; a hydroxyl group; and a lower alkyl group optionally substituted with a group selected from pyrimidinyl groups, ring B Is the formula:

[0055]

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Wherein B ¹ , B ² and B ³ are the same or different and each may have a protected hydroxyl group, lower alkyl group, lower alkoxy group or halogen atom, and R ¹ is protected. An amino group, an amino group-substituted lower alkyl group optionally protected, a carbamoyl group, an optionally protected carboxyl group, a hydroxyl group-substituted lower alkyl group optionally protected, and A phenyl group which may be substituted with a group selected from a lower alkoxy group; a lower alkyl group-substituted pyridyl group, a lower alkoxy group-substituted pyridyl group, a pyridyl group, a lower alkyl group-substituted N-oxidepyridyl group, a carbamoyl group, a protected group Or a group selected from a carboxyl group which may be optionally protected and a hydroxyl group which may be protected. Alkyl groups; optionally protected amino group optionally; or an amino group moiety protected or unprotected lower alkylamino group, R ² is a hydrogen atom, a lower alkyl group, a cycloalkyl-lower alkyl substituted lower alkyl group or a hydroxy-substituted lower Compounds that are alkyl groups are mentioned.

Among the desired compounds [I] of the present invention, more preferred compounds are those wherein ring A has the formula:

[0058]

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Wherein A ¹ represents one or two same or different substituents selected from (1) a hydrogen atom, (2) a lower alkoxy group, a hydroxyl-substituted lower alkyl group and a lower alkylamino group. A phenyl group which may be present;
A pyridyl group optionally substituted with a hydroxyl-substituted lower alkyl group; a pyrimidinyl group optionally substituted with a lower alkyl group; an imidazolyl group optionally substituted with a lower alkyl group; a pyrazinyl group;
N-oxide pyrimidinyl group; tetrazolyl group; thiazolyl group; pyrrolidinyl group; lower alkyl group-substituted pyrrolidinyl group; oxo group-substituted pyrrolidinyl group; morpholinyl group; optionally protected piperazinyl group; lower alkyl group-substituted piperazinyl group; A lower alkyl group optionally substituted with a group selected from a piperidyl group; a lower alkyl group-substituted piperidyl group; a lower alkylamino group, a cyano group, a cyclo-lower alkyl group, a lower alkoxy group; and a hydroxyl group; Halogen atom,
(4) tetrazolyl group, (5) triazolyl group, (6)
A pyrrolidinyl group optionally substituted with a hydroxyl-substituted lower alkyl group or a hydroxyl group, (7) a piperidyl group optionally substituted with a hydroxyl group, (8) a morpholinyl group, (9)
A piperazinyl group optionally substituted with a hydroxyl-substituted lower alkyl group or a pyrimidinyl group, (10) a pyridyl group, (11) an imidazolyl group, (12) a lower alkylthio group optionally substituted with a phenyl group, (13) phenyl Group-substituted lower alkyl group, pyridyl group-substituted lower alkyl group, lower alkyl group, lower alkoxy group-substituted lower alkyl group, hydroxyl-substituted lower alkyl group, pyrimidinyl group-substituted lower alkyl group, lower alkyl group substituted with lower alkylamino group, The same or different ones selected from a pyridyl group-substituted amino group, an amino group substituted with a halogeno lower alkyl group-substituted pyrimidinyl group, a pyridylcarbonyl group-substituted amino group and an amino group which may be protected;
An amino group optionally having up to 2 substituents, (14)
A lower alkyl group, or (15) a tetrahydrofuranyl group-substituted oxy group, wherein A ² is the same or different one or two substituents selected from (1) a hydrogen atom or (2) a lower alkoxy group and a di-lower alkylamino group A lower alkyl group optionally substituted by a group selected from a phenyl group, a pyridyl group, a lower alkoxy group, a hydroxyl group, and a pyrimidinyl group;

[0060]

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Wherein B ¹ , B ² and B ³ are the same or different and each may have a protected hydroxyl group, lower alkyl group, lower alkoxy group or halogen atom, and R ¹ is protected. An optionally substituted amino group, an amino group-substituted lower alkyl group which may be protected, a phenyl group optionally substituted with a group selected from a carbamoyl group and a lower alkoxy group; a lower alkyl group-substituted pyridyl group, A lower alkoxy-substituted pyridyl group,
A lower alkyl group which may be substituted with a group selected from a pyridyl group, a lower alkyl group-substituted N-oxide pyridyl group, a carbamoyl group and an optionally protected hydroxyl group;
An amino group which may be protected; or a lower alkylamino group whose amino group moiety may be protected, and a compound wherein R ² is a lower alkyl group.

Among the target compounds [I] of the present invention, a compound having a preferred pharmaceutically effect is represented by the following formula:

[0063]

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Wherein A ¹ may have one or two identical or different substituents selected from (1) a lower alkoxy group, a hydroxyl-substituted lower alkyl group and a lower alkylamino group. A phenyl group; a pyridyl group optionally substituted with a hydroxyl-substituted lower alkyl group; a pyrimidinyl group; an imidazolyl group optionally substituted with a lower alkyl group; a pyrazinyl group, an N-oxidepyridyl group;
-Oxide pyrimidinyl group; tetrazolyl group; thiazolyl group; pyrrolidinyl group; lower alkyl-substituted pyrrolidinyl group; oxo-substituted pyrrolidinyl group; morpholinyl group;
A piperazinyl group which may be protected; a lower alkyl-substituted piperazinyl group; a piperidyl group which may be protected; a lower alkyl group-substituted piperidyl group; a lower alkoxy group; and a lower group which may be substituted with a group selected from a hydroxyl group. An alkoxy group, (2) a lower alkylthio group substituted with a phenyl group, (3) an amino group which may be protected, (4) a lower alkylamino group whose amino group moiety may be protected, and (5) a lower alkylamino group. A lower alkylamino group in which the alkyl group part is substituted with a pyridyl group, (6) a di-lower alkylamino group in which the lower alkyl group part may be substituted with a pyridyl group, and (7) a lower alkylamino group substituted with a lower alkylamino group. A substituted amino group, (8) an optionally protected hydrazino group, (9) a pyridyl group-substituted hydrazino group, (10) Lysyl group substituted hydrazino group or (11) tetrahydrofuranyl group substituted oxy group, A ² is di-lower alkoxy group substituted with a substituted phenyl group lower alkyl group, and Ring B wherein:

[0065]

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A benzene ring represented by B ¹ and B ³
Are the same or different and a lower alkoxy group, B ² is a lower alkyl group, a lower alkoxy group or a halogen atom,
¹ is (1) a phenyl group which may be substituted with a group selected from an amino group, an amino group-substituted lower alkyl group, a carbamoyl group and a lower alkoxy group; (2) a lower alkyl group-substituted pyridyl group and a lower alkoxy group-substituted pyridyl Group, pyridyl group, lower alkyl group-substituted N-oxide pyridyl group, lower alkyl group optionally substituted with a group selected from carbamoyl group and hydroxyl group, (3) amino group or (4) lower alkylamino group, R ² Is a lower alkyl group.

Among the target compounds [I] of the present invention, a more preferable compound in terms of pharmacological effect is that ring A has the formula:

[0068]

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Wherein A ¹ is (1) a phenyl group substituted with a lower alkoxy group or a hydroxyl-substituted lower alkyl group; a pyridyl group optionally substituted with a hydroxyl-substituted lower alkyl group; a pyrimidinyl group; An imidazolyl group optionally substituted with a lower alkyl group; a pyrazinyl group; an N-oxidepyridyl group; an N-oxidepyrimidinyl group; a tetrazolyl group; a thiazolyl group; a pyrrolidinyl group; a lower alkyl-substituted pyrrolidinyl group; an oxo-substituted pyrrolidinyl group; A morpholinyl group; an optionally protected piperazinyl group; a lower alkyl group-substituted piperazinyl group; an optionally protected piperidyl group; a lower alkyl group-substituted piperidyl group; a lower alkoxy group; Lower alkoxy group, (2) phenyl group A substituted lower alkylthio group, (3) a lower alkylamino group in which the lower alkyl group part is substituted with a pyridyl group, or (4) a di-lower alkylamino group or a ring in which the lower alkyl group part may be substituted with a pyridyl group B is the formula:

[0070]

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A benzene ring represented by B ¹ and B ³
Are the same or different and a lower alkoxy group, B ² is a lower alkyl group, a lower alkoxy group or a halogen atom,
¹ is a phenyl group which may be substituted with a group selected from (1) an amino group and a lower alkoxy group, or (2) a lower alkyl group-substituted pyridyl group, a lower alkoxy group-substituted pyridyl group, a pyridyl group, a lower alkyl group-substituted N A lower alkyl group which may be substituted with a group selected from an -oxidopyridyl group and a hydroxyl group, and a compound wherein R ² is a lower alkyl group.

Among the desired compounds [I] of the present invention, further preferred compounds having a medicinal effect are those wherein ring A has the formula:

[0073]

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Wherein A ¹ is (1) a lower alkoxy group which may be substituted with a group selected from the group consisting of pyridyl group, pyrazinyl group, pyrimidinyl group, lower alkyl group-substituted imidazolyl group, lower alkoxy group and hydroxyl group. Group, amino group substituted with pyridyl-substituted lower alkyl group, ring B substituted with tri-lower alkoxy-substituted phenyl group, R ¹ substituted with lower alkyl-substituted pyridyl group or lower alkyl-substituted N-oxidepyridyl group And a compound wherein R ² is a lower alkyl group.

Of the above compounds, specifically, A ¹ is 2
-Pyridylmethoxy group, 2-pyrazinylmethoxy group, 2
-Pyrimidinylmethoxy group, 2- (2-pyridyl) ethoxy group, (1-methylimidazol-2-yl) methoxy group, methoxy group, 2-methoxyethoxy group, 2-hydroxyethoxy group, 3-hydroxypropoxy group or 2 -Pyridylmethylamino group, ring B is 3,4,5-trimethoxyphenyl group, R1 is (2-methylpyridine-4)
-Yl) methyl group or (2-methyl-N-oxidepyridin-4-yl) methyl group.

Among the target compounds [I] of the present invention, particularly preferred compounds having a medicinal effect are those wherein ring A has the formula:

[0077]

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Wherein A ¹ is a pyridyl group-substituted lower alkoxy group, a pyrimidinyl group-substituted lower alkoxy group, a (1-methylimidazol-2-yl) lower alkoxy group, a lower alkoxy group-substituted lower alkoxy group, a hydroxyl group A substituted lower alkoxy group, an amino group substituted by a pyridyl group-substituted lower alkyl group, a ring B substituted by a tri-lower alkoxy group-substituted phenyl group, a lower alkyl group substituted by R ¹ with a lower alkyl-substituted pyridyl group, and a lower alkyl group substituted by R ² Compounds that are alkyl groups are mentioned.

Among the above compounds, compounds wherein A ¹ is a lower alkoxy group substituted with a pyrimidinyl group, ring B is a phenyl group substituted with a tri-lower alkoxy group, and R ¹ is a lower alkyl group substituted with a lower alkyl group-substituted pyridyl group Is preferred.

When the substituent on ring A and ring B and / or R ¹ has an asymmetric atom, the target compound [I] of the present invention can exist as an optical isomer based on the asymmetric atom. The present invention includes both of these optical isomers and mixtures thereof.

The target compound [I] of the present invention or a pharmaceutically acceptable salt thereof has cGMP-specific PDE inhibitory activity,
Particularly excellent selective phosphodiesterase V (PDE
V) It has an inhibitory action, and based on PDE V inhibitory action, excellent vasodilatory action, pulmonary artery pressure lowering action, penile pressure increasing action, isolated vasorelaxant action, relaxing corpus cavernosum, vascular smooth muscle growth inhibitory action, cardiac hypertrophy It exhibits an inhibitory action, a platelet aggregation inhibitory action, and the like.

Accordingly, the desired compound [I] of the present invention or a pharmaceutically acceptable salt thereof is useful for chronic heart failure, angina pectoris, penile erectile dysfunction, hypertension, pulmonary hypertension, arteriosclerosis, PTC
It is a pharmaceutical compound useful as a prophylactic / therapeutic agent for post-A restenosis and the like, has little side effects and low toxicity, and thus has high safety as a pharmaceutical.

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. Pharmaceutically acceptable salts of compound [I] include, for example, inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate or hydrobromide, acetate, fumarate, oxalate, and the like. Organic acid salts such as tartrate, citrate, methanesulfonate, benzenesulfonate, tosylate or maleate are exemplified. When the compound has a substituent such as a carboxyl group, a salt with a base (for example, an alkali metal salt such as a sodium salt or a potassium salt or an alkaline earth metal salt such as a calcium salt) is exemplified.

The target compound [I] of the present invention or a salt thereof includes any of its inner salts and adducts, solvates and hydrates thereof.

The object compound [I] of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally, and may be administered as tablets, granules, capsules, powders, and injections. , Can be used as conventional pharmaceutical preparations such as inhalants.

The dose of the target compound [I] of the present invention or a pharmaceutically acceptable salt thereof is determined by the method of administration, age of the patient,
Although it depends on the body weight and condition, it is usually about 0.0001 to 0.5 mg / kg per day for injections, especially about 0.0005 to 0.1 mg / kg per day, About 0.001 to 30 mg / k per day
g, especially about 0.05 to 10 mg / kg.

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

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

[0089]

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(Wherein the symbols have the same meanings as described above) or a salt thereof, and a compound represented by the general formula [II
I]

[0091]

Embedded image

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

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

[0094]

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(Where the symbols have the same meanings as described above) or a salt thereof is subjected to a hydrolysis reaction to give a compound of the general formula [IV]

[0096]

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Wherein the symbols have the same meanings as described above, and then the product [I
V] and the general formula [III]

[0098]

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(Wherein the symbols have the same meanings as described above), and can be produced by reacting with an amine compound or a salt thereof. The compound represented by the general formula [IV] is a tautomer having the following structure in a solution.

[0100]

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Exists as

The compound [I] obtained by these [Method A] and [Method B] can be converted into a pharmaceutically acceptable salt thereof, if desired.

The above [Method A] and [Method B] can be carried out as follows.

[Method A] The reaction of compound [II] or a salt thereof with amine compound [III] or a salt thereof can be carried out in a solvent or without a solvent. As the solvent,
Any solvent that does not inhibit the reaction can be used,
For example, 1,3-dimethyl-2-imidazolidinone,
N, N-dimethylformamide, dimethylsulfoxide, ethylene glycol, N-methylpyrrolidone, xylene, dichloroethane and the like can be suitably used.
This reaction is carried out at 20 to 150 ° C, especially 40 to 130 ° C.
The process proceeds favorably.

[Method B] The hydrolysis reaction of compound [II] or a salt thereof can be carried out in a solvent in the presence of a base. As the base, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, and alkali metal carbonates such as sodium carbonate and potassium carbonate can be suitably used. As the solvent, water or a mixed solvent of methanol, ethanol, tetrahydrofuran, dioxane, N, N-dimethylformamide, and the like and water can be used as appropriate. This reaction suitably proceeds at 0 to 80 ° C, particularly 5 to 60 ° C.

Compound [IV] and amine compound [III]
Alternatively, the reaction with a salt thereof can be carried out in the presence or absence of a deoxidizing agent, in a suitable solvent or without a solvent. As a deoxidizing agent, diisopropylethylamine, N
-Methylmorpholine, triethylamine, pyridine, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and the like can be suitably used. As the solvent, the above [A
Any of the solvents described in [Method] can be suitably used. The reaction is carried out at a temperature of 20 to 140 ° C, especially 30 to 100
Proceeds favorably at ° C.

When R ^{1 of the} amine compound [III] used in the above [Method A] and [Method B] is an amino group or a substituent containing an amino group, the amino group may be protected by a protecting group (for example, tert. It is desirable to carry out this reaction after introducing a substituted or unsubstituted lower alkoxycarbonyl group such as butoxycarbonyl group and benzyloxycarbonyl group, and a lower alkanoyl group such as formyl, acetyl group and propionyl group.

A compound in which R ² of the compound [I] obtained by the above [Method A] and [Method B] is a hydrogen atom, that is, a compound of the general formula [Ia]

[0109]

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(Wherein the symbols have the same meanings as described above). The compound represented by the general formula [Ib] can be obtained by esterification by a conventional method.

[0111]

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(Wherein, R ²¹ represents an ester residue, and other symbols have the same meanings as described above). For example, compound [Ib]
It can be produced by reacting compound [Ia] with an alkylating agent in a solvent in the presence or absence of a deoxidizing agent. As the deoxidizing agent, alkali metal hydroxide,
Inorganic bases such as alkali metal carbonate, N-methylmorpholine, triethylamine, pyridine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8-diazabicyclo [5.4.0] undec-7 -An organic base such as ene can be suitably used. As the alkylating agent,
Diazomethanes such as diazomethane and diazoethane, dimethyl sulfate, dialkyl sulfates such as diethyl sulfate, methyl iodide, methyl bromide, and alkyl halides such as ethyl bromide;
Examples include tri-lower alkylsilyldiazoalkanes such as trimethylsilyldiazomethane, and aryl-lower alkyl halides such as benzyl chloride and benzyl bromide. When a dialkyl sulfate, an alkyl halide or an aryl lower alkyl halide is used as the alkylating agent, the deoxidizing agent is generally used in an amount of 1 to 5 with respect to the compound [Ia].
Equivalent, preferably 1-2 equivalents can be used. This reaction suitably proceeds at 0 to 60 ° C, particularly 5 to 40 ° C. When a diazoalkane is used as the alkylating agent, it is usually 1 to 5 equivalents based on the compound [Ia],
Preferably, 1 to 2 equivalents can be used. This reaction suitably proceeds at 0 to 50 ° C, particularly 5 to 30 ° C. In addition, the compound [Ib] in which R ² is a methyl group,
In the above method, if trimethylsilyldiazomethane is used as the alkylating agent, it can be produced under mild conditions. Examples of the solvent include water, alcohols such as methanol, ethanol, and isopropyl alcohol,
Ethers such as diethyl ether, tetrahydrofuran and dioxane; ketones such as acetone and methyl ethyl ketone; esters such as methyl acetate and ethyl acetate; aromatic hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as methylene chloride and chloroform. Amides such as N, N-dimethylformamide, dimethylacetamide,
Sulfoxide such as dimethylsulfoxide, or a mixed solvent thereof can be used.

In addition, compound [Ib] is compound [I-
a) and a lower alcohol such as methanol, ethanol, propanol, butanol, etc., by a method such as Mitsunobu (Synthesis, pp. 1-28, 1981).
It can also be manufactured according to. Specifically, in the presence of diethyl azodicarboxylate and triphenylphosphine, compound [Ia] and a lower alcohol are converted into tetrahydrofuran, dioxane, ethyl acetate, N, N-dimethylformamide, chloroform, methylene chloride, benzene, toluene And a reaction in a solvent such as dimethoxyethane. This reaction is, for example,-
It proceeds suitably at 10 to 60 ° C, especially at 5 to 40 ° C.

In addition, compound [Ib] is compound [I-
a) under acidic conditions with a lower alcohol such as methanol, ethanol, propanol or butanol, or an aryl lower alcohol such as benzyl alcohol or phenethyl alcohol. As the acid for setting the acidic condition, for example, sulfuric acid, hydrogen chloride, p-toluenesulfonic acid and the like can be used.
The acid is usually used in an amount of 0.01 to
20 equivalents, preferably 0.1 to 10 equivalents can be used. This reaction suitably proceeds in the alcohol under heating to reflux.

Here, when the above compound [Ia] is a ring A,
When a compound having one or more carboxyl groups or mono- or unsubstituted amino groups in ring B and / or R ¹ is reacted with the above-mentioned alkylating agent, the carboxyl group is alkylated. Or a compound wherein the amino group has been converted to a mono- or di-lower alkylamino group.

In preparing the compound [I] according to the present invention, the compounds [Ia], [II], [III] and [IV] can be used in the form of a salt. As, for example, sodium, potassium, alkali metal salts such as lithium, pyridine, triethylamine,
Salts with an organic base such as N-methylmorpholine, hydrogen chloride,
Salts with inorganic acids such as hydrogen bromide, nitric acid, sulfuric acid, acetic acid, formic acid,
Salts with organic acids such as oxalic acid, citric acid, malonic acid and the like can be mentioned.

The target compound [I] of the present invention can be obtained by substituting the substituent and / or the group R on the ring A of the compound obtained as described above.
It can also be produced by converting ¹ into another substituent of interest. The method for converting such a substituent is as follows.
What is necessary is just to select suitably according to the kind of objective substituent, For example, it can implement as following (method a)-(m method).

(Method a): The target compound [I] in which the ring A in the general formula [I], the substituent on the ring A and / or the substituent on R ¹ is a substituted or unsubstituted N-oxidepyridine ring.
Is a compound wherein ring A, a substituent on ring A and / or a substituent on R ¹ is a corresponding substituted or unsubstituted pyridine ring,
It can be produced by oxidizing with an oxidizing agent in the presence of a solvent. As the solvent, for example, methylene chloride,
Chloroform, methanol, water, acetic acid and the like can be mentioned.
Examples of the oxidizing agent include peroxides such as m-chloroperbenzoic acid, peracetic acid, hydrogen peroxide, and pertrifluoroacetic acid, sodium periodate, osmium tetroxide, and sodium bromate. Further, the oxidizing agent is used in an amount of 1 to 1 based on the starting material.
Use 0 equivalents. This reaction is carried out, for example, in the range of 0 to 100.
C., especially at room temperature to 50 C.

(Method b): Ring A in the general formula [I] is
The target compound [I], which is a substituted or unsubstituted oxo group-substituted dihydropyridine ring, is a compound in which ring A is a corresponding substituted or unsubstituted N-oxidepyridine ring, for example,
It can be produced by reacting with an acid anhydride in the presence or absence of a solvent to obtain a rearranged product, followed by base treatment. Examples of the solvent include N, N-dimethylformamide, tetrahydrofuran, toluene, 1,2-dichloroethane, acetic acid and the like. Examples of the acid anhydride include acetic anhydride, trifluoroacetic anhydride and the like. Examples of the base include sodium hydrogen carbonate, potassium carbonate, sodium hydroxide and the like. The reaction with the acid anhydride can be carried out, for example, at 50 to 150 ° C. The base treatment can be performed, for example, at 0 to 60 ° C.

(Method c): The ring A in the general formula [I] is
The target compound [I], which is a pyridine ring substituted with a tetrazolyl group, is obtained by cyanating a compound in which Ring A is a corresponding N-oxidepyridine ring using a cyanating agent and a base in a solvent, for example. Thereafter, the compound can be produced by tetrazolylation using a metal azide in a solvent.
As the solvent for the cyanation reaction, for example, tetrahydrofuran, methylene chloride, chloroform, etc., as the cyanating agent, trimethylsilyl cyanide, tert-butyldimethylsilyl cyanide, etc., as the base, for example,
1,8-diazabicyclo [5.4.0] undec-7-
Ene, triethylamine and the like. This reaction can be carried out, for example, at 20 to 130 ° C. As the solvent for the tetrazolylation reaction, for example, N, N-dimethylformamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, etc., and as the metal azide, for example, sodium azide, azide Tributyltin and the like. This reaction can be carried out, for example, at 40 to 100 ° C.

(Method d): The target compound [I] in which the substituent on the ring A in the general formula [I] has a tetrazolyl group is
A compound in which the substituent on ring A has a corresponding cyano group,
It can be produced by tetrazolylation using a metal azide in a solvent. As the solvent, for example,
N, N-dimethylformamide, N-methylpyrrolidone and the like, and examples of the metal azide include sodium azide and tributyltin azide. The reaction is
For example, it can be carried out at 40 to 100 ° C.

(Method e): General formula [Ic]

[0123]

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(Wherein ring A ₁ is a group represented by the formula:

[0125]

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Wherein A ²¹ represents a substituted or unsubstituted lower alkyl group, and the other symbols have the same meanings as described above. )and/
Or the general formula [Id]

[0127]

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(Wherein ring A ₂ has the formula:

[0129]

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And the other symbols have the same meanings as described above. The compound represented by the general formula [Ie]

[0131]

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(Wherein ring A ₃ is a group represented by the formula:

[0133]

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And the other symbols have the same meanings as described above. Or a salt thereof, and a compound represented by the general formula [V]:

[0135]

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(Wherein, X represents a leaving group, and other symbols have the same meanings as described above).

Examples of the leaving group in the compound [V] include a hydroxyl group, a trifluoromethanesulfonyloxy group, a p-tosyloxy group, a methanesulfonyloxy group and a halogen atom such as a chlorine atom, a bromine atom and an iodine atom.

That is, when the leaving group X is a hydroxyl group, the reaction between the compound [Ie] and the compound [V] can be performed, for example, by a method such as Mitsunobu (Synthesis, 1st to 1st).
28, 1981). Specifically, compound [Ie] and compound [V] are converted into tetrahydrofuran, dioxane, ethyl acetate, N, N-dimethylformamide, chloroform, methylene chloride, benzene in the presence of diethyl azodicarboxylate and triphenylphosphine. , Toluene, dimethoxyethane and the like. This reaction suitably proceeds, for example, at 0 to 60 ° C, particularly preferably at 5 to 40 ° C.

The reaction between compound [Ie] and compound [V] is such that the leaving group X of compound [V] is trifluoromethanesulfonyloxy, p-tosyloxy, methanesulfonyloxy, or chlorine. When it is a halogen atom such as an atom, a bromine atom and an iodine atom, the reaction can be carried out in a solvent in the presence of a base. This reaction can be carried out in the presence or absence of the above base and copper catalyst. As the solvent, for example, tetrahydrofuran,
Dioxane, N, N-dimethylformamide, dimethylsulfoxide and the like. As the base, for example,
Alkali metal hydrides such as sodium hydride; alkali metal alkoxides such as sodium methoxide and potassium tert-butoxide; alkali metal hydroxides such as sodium hydroxide; metal carbonates such as sodium carbonate, potassium carbonate and silver carbonate. And inorganic bases such as 1,8-
Diazabicyclo [5.4.0] undec-7-ene, N
Organic bases such as -methylmorpholine and triethylamine. The amount of the base to be used is generally 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to compound [Ie], but amino group in which group R1 may be monosubstituted may be used. Alternatively, when the amino group is a substituent containing an amino group which may be mono-substituted, the amino group may be a protective group (for example, a lower alkoxycarbonyl group such as tert-butoxycarbonyl group, or an aryl lower alkoxy group such as benzyloxycarbonyl group). It is desirable to carry out this reaction after introducing a carbonyl group, formyl group, acetyl group, lower alkanoyl group such as propionyl group, etc.).

Examples of the copper catalyst include copper (I) iodide, copper (I) bromide, copper powder (0), copper oxide (I), and copper (II) bromide. This reaction suitably proceeds, for example, at 10 to 160 ° C, particularly preferably at 20 to 120 ° C.

(Method f): General Formula [If]

[0142]

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(Wherein ring A ₄ is a group represented by the formula:

[0144]

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Wherein A ¹¹ represents a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted lower alkylthio group or a substituted or unsubstituted amino group, and other symbols have the same meanings as described above. The compound represented by the general formula [Ig]

[0146]

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(Wherein ring A ₅ is a group represented by the formula:

[0148]

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Wherein A ¹² represents a halogen atom, and other symbols have the same meanings as described above. ) Or a salt thereof, and a compound represented by the general formula [V
I]

[0150]

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(Wherein the symbols have the same meanings as described above) can be produced by reacting in a solvent in the presence or absence of a base in a solvent.

Examples of the solvent include N, N-dimethylformamide, N, N-dimethylacetamide, 1,3
-Dimethyl-2-imidazolidinone, tetrahydrofuran, dioxane, dimethylsulfoxide and the like. Examples of the base include an alkali metal hydride such as sodium hydride, an alkali metal amide such as sodium amide, an alkali metal alkoxide such as sodium methoxide and potassium tert-butoxide, and an alkali hydroxide such as sodium hydroxide. Examples thereof include inorganic bases such as metals, metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, and silver carbonate, and organic bases such as N-methylmorpholine, triethylamine, and pyridine. The amount of the base to be used is generally 1-5 equivalents, preferably 1 equivalent, relative to compound [Ig].
Up to 3 equivalents can be used. This reaction is carried out in the presence of a metal catalyst such as palladium acetate and tetrakistriphenylphosphine palladium and an additive such as triphenylphosphine and 1,1′-bis (diphenylphosphino) ferrocene in addition to the above base. Can also. With respect to the use amount of the metal catalyst, for example, 0.02 to 0.5 equivalent can be used based on compound [Ig]. When the group R ¹ is an amino group which may be mono-substituted or a substituent containing an amino group which may be mono-substituted, a protecting group (for example, tert-butoxycarbonyl group) may be added to the amino group. It is desirable to carry out this reaction after introducing an aryl lower alkoxycarbonyl group such as a lower alkoxycarbonyl group or a benzyloxycarbonyl group, or a lower alkanoyl group such as a formyl group, an acetyl group or a propionyl group.

(Method g): Compound [Ig] can be produced by halogenating compound [Id] or a salt thereof in the presence or absence of a solvent.

Examples of the solvent include N, N-dimethylformamide. Examples of the halogenating agent include phosphorus oxychloride.
Further, the amount of the halogenating agent used may be the compound [I-
d), usually 2 to 50 equivalents, preferably 5 to 3 equivalents.
0 equivalents can be used. This reaction is carried out, for example, at 50 to 1
It can be performed at 20 ° C.

(Method h): The substituent on the ring A represented by the general formula [I] and / or the group R ¹ is a substituent containing an amino group (for example, an amino-lower alkyl-substituted aryl group, an amino-substituted group) The target compound [I], which is a lower alkyl group substituted with an aryl group or a lower alkylamino group,
Removing the protecting group for the lower alkanoyl group or the amino group from the corresponding compound [I] wherein the above substituent and / or group R ¹ is a mono- or di-lower alkanoylamino group or a substituent containing a protected amino group; It can be manufactured by the following. The removal of the protecting group or lower alkanoyl group can be carried out by a conventional method (for example, acid treatment, base treatment, catalytic reduction and the like). Of this reaction, the reaction by acid treatment is, for example, 5 to 120 ° C, the reaction by base treatment is 5 to 40 ° C, and the reaction by catalytic reduction is 10 to 120 ° C.
Can be carried out at ４０40 ° C.

(Method i): Compound [Ie] can be produced by hydrolyzing compound [Id] or a salt thereof with an acid in the presence of a solvent.

Examples of the solvent include methylene chloride, chloroform, dioxane, methanol, ethanol, acetic acid, water and the like. Examples of the acid include mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, and Lewis acids such as trichloroborane, titanium tetrachloride and boron trifluoride diethyl ether complex. This reaction can be carried out, for example, at 0 to 100 ° C.

(Method j): General formula [Ih]

[0159]

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(Wherein ring A ₆ is a group represented by the formula:

[0161]

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And the other symbols have the same meanings as described above. Can be produced by reducing compound [Ig] or a salt thereof in the presence of a solvent.

Examples of the solvent include methanol, ethanol, tetrahydrofuran, dioxane, ethyl acetate, acetic acid and the like or a mixed solvent thereof, and examples of the reducing agent include hydrogen-palladium carbon and hydrogen-palladium black. This reaction can be carried out, for example, at 0 to 50 ° C.

(Method k): General formula [Ii]

[0165]

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(Wherein ring A ₇ is a group represented by the formula:

[0167]

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Wherein Tf represents a trifluoromethanesulfonyl group, and other symbols have the same meanings as described above. ) Is a compound [I
-E] or a salt thereof can be produced by trifluoromethanesulfonylation in the presence of a solvent and in the presence of a deoxidizing agent.

Examples of the solvent include methylene chloride, chloroform, N, N-dimethylformamide and the like, and examples of the deacidifier include triethylamine, pyridine, diisopropylethylamine and N-methylmorpholine. Examples of the trifluoromethanesulfonylating agent include trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chloride and the like. The amount of the trifluoromethanesulfonylating agent to be used is generally 1 to 5 equivalents, preferably 1 to 5 equivalents to compound [Ie].
~ 2 equivalents can be used. This reaction is, for example, -2
The reaction can be carried out at 0 to 70 ° C, preferably 0 to 40 ° C. When the group R ¹ is a substituent containing an amino group which may be mono- or di-substituted or a substituent containing a hydroxyl group, It is preferable to carry out this reaction after introducing a protecting group into an amino group and a hydroxyl group.

(Method l): General formula [Ij]

[0171]

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(Wherein ring A ₈ is a group represented by the formula:

[0173]

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Wherein A ¹³ represents a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aromatic heterocyclic group, or a cyano group; Has the same meaning as )
Is a compound [Ig] or a compound [Ii], and a compound represented by the general formula [VII]:

[0175]

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(Where Mtl is a hydroxyl group, a halogen atom,
Represents a metal which may be coordinated by a group selected from a cyano group, a lower alkyl group, an aryl group, a lower alkoxy group, an aryloxy group, and an arylthio group, and other symbols have the same meanings as described above. ) Can be produced by reacting in the presence of a solvent, in the presence of a catalyst, in the presence or absence of an additive.

Examples of the metal include metals such as boron, tin, zinc, magnesium, aluminum, and lithium. As the solvent, N, N-dimethylformamide,
N, N-dimethylacetamide, tetrahydrofuran,
Dioxane, dimethyl sulfoxide and the like. Examples of the catalyst include palladium acetate, tetrakistriphenylphosphinepalladium, bistriphenylphosphinepalladium dichloride and the like. As additives,
Triphenylphosphine, tri-o-toluylphosphine, tri-n-butylphosphine and the like can be mentioned. The amount of compound [VII] to be used is 1 to 3 equivalents, preferably 1 to 1 equivalent, relative to compound [Ig] or compound [Ii].
5 equivalents can be used. The amount of the catalyst to be used is 0.01 to compound (Ig) or compound (Ii).
0.2 equivalent, preferably 0.05 to 0.1 equivalent can be used. This reaction can be carried out, for example, at 0 to 120 ° C, preferably at 10 to 100 ° C.

(Method m): a substituent on ring A represented by the general formula [I] and / or a substituent containing an amino group or a hydrazino group in which group R ¹ is acylated (for example, a lower alkanoylamino group A substituted or unsubstituted arylcarbonylamino group, an amino group substituted with a heterocyclic group-substituted carbonyl group, etc.), the substituent on ring A and / or group R ¹ is an amino group or It can be produced by reacting the corresponding compound [I], which is a substituent containing a hydrazino group, with the corresponding carboxylic acid or a reactive derivative thereof. The acylation reaction is carried out in a conventional manner (for example, a method of converting the corresponding carboxylic acid into an acid halide, a mixed acid anhydride, or the like, and a reaction using a condensing agent).
Can be implemented. This reaction is, for example,-
It can be carried out at 30-60 ° C.

The starting compound [II] is, for example, a compound represented by the general formula [i]:

[0180]

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

[0182]

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(Wherein X ¹ represents a halogen atom and Z ¹ represents a carboxyl-protecting group), and reacted with a malonic acid compound represented by the following general formula: [Iii]

[0184]

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(Wherein the symbols have the same meanings as described above), and then the compound [ii
removing the protecting group from i) (eg, acid treatment, catalytic reduction, etc.)
By doing, the general formula [iv]

[0186]

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(Wherein the symbols have the same meanings as described above), and the product is subjected to decarboxylation and dehydration in the presence or absence of an acid (eg, hydrogen chloride, acetic acid, etc.). The product can be produced by reacting (for example, heat treatment) and, if necessary, esterifying the carboxyl group of the product by a conventional method.

As the protecting group for the carboxyl group of Z ¹ ,
For example, a lower alkyl group, a benzyl group, an allyl group and the like can be mentioned.

The above compound [i] and compound [ii]
By using a weak base (for example, sodium bicarbonate, potassium bicarbonate, etc.) as the base in the reaction with the general formula [vi]

[0190]

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(Wherein the symbols have the same meanings as described above), and then a base (for example,
Potassium carbonate, 1,8-diazabicyclo [5.4.0]
Undec-7-ene, 1,5-diazabicyclo [4.
3.0] None-5-ene or the like) to give compound [iii].

The starting compound [II] has the general formula [II-a]:

[0193]

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(Wherein the symbols have the same meanings as described above), for example, a compound represented by the general formula [ia]

[0195]

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

[0197]

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(Wherein, the symbols have the same meanings as described above) and a reaction with a diazomalonic acid compound represented by the following formula in the presence of a metal catalyst (for example, a rhodium catalyst such as rhodium acetate and rhodium trifluoroacetate). (For example, potassium carbonate, 1,8-diazabicyclo [5.4.
0] undec-7-ene, 1,5-diazabicyclo [4.3.0] none-5-ene, etc.) to give a compound of the general formula [iii-a]

[0199]

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(Wherein the symbols have the same meanings as described above), the protecting group is removed (eg, acid treatment, catalytic reduction, etc.), and the compound is acidified (eg, hydrogen chloride). , Acetic acid or the like) in the presence or absence of a compound, by a decarboxylation reaction and a dehydration reaction (for example, heat treatment) and, if necessary, esterification of the carboxyl group of the product by a conventional method. .

The compound [i] can be produced according to a conventional method. For example, the compound represented by the general formula [vii]

[0202]

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(Wherein Y represents a mono- or di-lower alkylamino group, and other symbols have the same meanings as described above) in a solvent (eg, tetrahydrofuran, diethyl ether, etc.) Formula [viii] in the presence of a base (n-butyllithium, sec-butyllithium, etc.)

[0204]

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(Wherein the symbols have the same meanings as described above), and reacted with a compound of the general formula [ix]

[0206]

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(Wherein the symbols have the same meanings as described above), and the compound is treated with an acid (eg, hydrochloric acid, sulfuric acid, etc.) to give a compound of the general formula [x]

[0208]

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(Wherein the symbols have the same meanings as described above), and in a solvent (for example, water, a mixed solvent of pyridine and water, etc.), the compound is converted to a base (for example, sodium hydroxide or the like). In the presence of an inorganic base) in the presence of an oxidizing agent (potassium permanganate, sodium chlorite, etc.).

The compound [ia] has the general formula [i-
b)

[0211]

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(Where the symbols have the same meanings as described above). After protecting the carboxyl group of the compound represented by the above formula with a protecting group by a conventional method, N-oxidation is carried out in the same manner as in the above (method a). Then, it can be produced by halogenating with a phosphorus oxyhalide or the like, and deprotecting the protecting group at the carboxyl group again.

The compound [ii] has the general formula [xi]

[0214]

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(Wherein the symbols have the same meanings as described above). The compound can be produced by reacting a malonic acid diester represented by the following formula with a halogenating agent. This reaction is desirably performed in the presence of a base. Although it can be carried out in the absence of a solvent, it is preferable to carry out in the presence of a solvent. As the halogenating agent, for example,
N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, bromine, iodine, copper bromide, copper chloride, and the like, among which N-bromosuccinimide and N-chlorosuccinimide Acid imides and the like are preferable, and usually 1.0 to 1.05 equivalents can be used with respect to compound [xi]. Examples of the base include organic bases such as 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] none-5-ene, triethylamine and diisopropylethylamine. Among them, 1,8-diazabicyclo [5.4.
0] undec-7-ene, triethylamine and the like are preferable, and usually 0.001 to 0.1 based on the compound [xi].
Equivalent, preferably 0.005 to 0.05 equivalent can be used. Examples of the solvent include N, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran,
3-dimethyl-2-imidazolidinone, toluene, methylene chloride, chloroform and the like. The reaction is
For example, -30 to 40 ° C, preferably -15 to 25 ° C
C. can be performed.

This reaction was carried out using N-
It proceeds favorably by using bromosuccinimide or the like, 1,8-diazabicyclo [5.4.0] undec-7-ene, triethylamine or the like as a base and N, N-dimethylformamide or the like as a solvent.

Particularly, when Z ¹ is a tert-butyl group, N-bromosuccinimide is used as a halogenating agent;
It proceeds favorably by using 1,8-diazabicyclo [5.4.0] undec-7-ene as a base and N, N-dimethylformamide as a solvent.

In particular, when Z ¹ is a benzyl group,
It proceeds favorably by using N-bromosuccinimide as a halogenating agent, triethylamine as a base and N, N-dimethylformamide as a solvent.

In the present invention, an alkyl group is
Represents an alkyl group having 1 to 16 carbon atoms, and among them, a linear or branched one having 1 to 8 carbon atoms is particularly preferable. The lower alkyl group, lower alkoxy group and lower alkylene group represent an alkyl group having 1 to 6 carbon atoms, an alkoxy group and an alkylene group, among which those having 1 to 4 carbon atoms are particularly preferable. The halogen atom represents fluorine, chlorine, bromine, iodine and the like. The lower alkenyl group and the lower alkynyl group represent an alkenyl group and an alkynyl group having 2 to 7 carbon atoms, and among them, a linear or branched one having 2 to 5 carbon atoms is particularly preferable.
A lower alkylenedioxy group and a lower alkanoyl group are
Represents an alkylenedioxy group and an alkanoyl group having 1 to 7 carbon atoms, and among them, a linear or branched one having 1 to 5 carbon atoms is particularly preferable. Further, the cyclo lower alkyl group refers to a cycloalkyl group having 3 to 8 carbon atoms, and among them, those having 3 to 6 carbon atoms are particularly preferable.

[0220]

EXAMPLES Specific examples (Examples) of the target compound [I] of the present invention synthesized by the above exemplified methods are shown below, but the present invention is not limited thereto.

Example 1 (1) 8-oxo-5- (3,4,5-trimethoxyphenyl) -8H-pyrano [3,4-b] pyridine-6
400 mg of carboxylic acid (compound obtained in Reference Example 34)
A solution of aniline and 306 μl of 1,3-dimethyl-2-imidazolidinone in 3 ml is stirred at 100 ° C. overnight. The reaction mixture was extracted by adding water and ethyl acetate, and the extract was washed, dried, and evaporated to remove the solvent to give 7,8-dihydro-.
This gives 8-oxo-7-phenyl-5- (3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid.

(2) The compound obtained in the above (1) was dissolved in a mixture of 5 ml of ethyl acetate and 1 ml of methanol, and a hexane solution (2M) of trimethylsilyldiazomethane (2M) was added.
Add 60 μl and react for 1 hour at room temperature. The reaction solution is extracted by adding water and ethyl acetate. The extract is separated, washed and dried, the solvent is distilled off, and the residue is subjected to silica gel column chromatography (solvent: chloroform: acetone = 1).
0: 1) to give 7,8-dihydro-8.
92 mg of -oxo-7-phenyl-5- (3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester are obtained.

M. p. > 250 ° C Example 2 (1) The compound obtained in Reference Example 34 and 4-tert-butoxycarbonylaminoaniline were treated in the same manner as in Examples 1 (1) and (2) to give 7- (4 −te
rt-butoxycarbonylaminophenyl) -7,8-
This gives dihydro-8-oxo-5- (3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester.

M. p. 183 ° -185 ° C. (decomposition) (2) 630 mg of the compound obtained in the above (1) is dissolved in a mixed solution of 3 ml of chloroform and 3 ml of methanol, 5 ml of a 4M hydrogen chloride-ethyl acetate solution is added at room temperature, and the mixture is stirred overnight. The precipitated crystals are collected by filtration and washed with diethyl ether to give 7- (4-aminophenyl)-
510 mg of methyl 7,8-dihydro-8-oxo-5- (3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylate hydrochloride is obtained.

M. p. 211-214 ° C (decomposition) Examples 3-4 The corresponding starting compounds are treated in the same manner as in Examples 1 (1) and (2) to give the compounds described in Table 1.

[0226]

[Table 1]

Examples 5 to 7 The corresponding starting compounds were prepared in Examples 1 (1), (2) and 2
By treating in the same manner as in (2), the compounds shown in Table 2 are obtained.

[0228]

[Table 2]

Example 8 The compound obtained in Example 4 was treated in the same manner as in Example 2 (2) to give 2- (2-methylpyridine-4-
Yl) methyl-1,2-dihydro-1-oxo-4-
(3,4,5-trimethoxyphenyl) -2,6-naphthyridine-3-carboxylic acid methyl ester dihydrochloride is obtained.

M. p. 175-178 ° C (decomposition) Example 9 (1) A solution of 28.7 g of the compound obtained in Example 2 (1) in 600 ml of chloroform under ice-cooling was mixed with a solution of 55.1 g of 3-chloroperbenzoic acid in 1200 ml of chloroform. And the mixture is stirred at room temperature overnight. The reaction mixture was washed with an aqueous sodium thiosulfate solution, the extract was washed and dried, the solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent; chloroform: methanol = 20: 1) to give 7-. (4-tert-butoxycarbonylaminophenyl) -7,8-dihydro-8-oxo-5
14.0 g of-(3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester-N-oxide are obtained.

M. p. 246-248 ° C (decomposition) (2) The compound obtained in the above (1) is treated in the same manner as in Example 2 (2) to give 7- (4-aminophenyl) -7,8-dihydro-8. -Oxo-5- (3,4,
5-trimethoxyphenyl) -1,7-naphthyridine-
6-Carboxylic acid methyl ester-N-oxide hydrochloride is obtained.

M. p. 217-220 ° C (decomposition) Example 10 Trimethylsilyl cyanide 27 was added to a solution of 1.0 g of the compound obtained in Example 9 (1) in 20 ml of tetrahydrofuran.
Add 7 μl, then add 1,8-diazabicyclo [5.
[4.0] Undec-7-ene (600 μl) and stir at room temperature overnight. The reaction mixture is extracted by adding water and ethyl acetate, and the extract is washed, dried, and then the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent; n-hexane: ethyl acetate = 2: 1) to give 7-
(4-tert-butoxycarbonylaminophenyl)
-2-cyano-7,8-dihydro-8-oxo-5-
157 mg of (3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester are obtained.

M. p. 190-194 ° C. Example 11 (1) 100 mg of N, N of the compound obtained in Example 10
-28 mg of sodium azide and 23 mg of ammonium chloride were added to 3 ml of dimethylformamide solution,
Stir at 9 ° C. for 9 hours. After the reaction solution was returned to room temperature, water and chloroform were added thereto for extraction, the extract was washed, dried, and then the solvent was distilled off to obtain 7- (4-tert-
(Butoxycarbonylaminophenyl) -7,8-dihydro-8-oxo-2- (tetrazol-5-yl) -5
-(3,4,5-Trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester is obtained.

(2) The compound obtained in the above (1) was treated in the same manner as in Example 2 (2) to give 7- (4-aminophenyl) -7,8-dihydro-8-oxo-2. −
There are obtained 40 mg of tetrazolyl-5- (3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester hydrochloride.

M. p. > 250 ° C Example 12 (1) To a solution of 12.0 g of the compound obtained in Example 9 (1) in 120 ml of N, N-dimethylformamide was added 44.0 g of trifluoroacetic anhydride, and the mixture was stirred at room temperature overnight. The reaction solution is poured into a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. After the extract is washed and dried, the solvent is distilled off to give 7- (4-tert-butoxycarbonylaminophenyl) -2,8-dioxo-.
8.2 g of 1,2,7,8-tetrahydro-5- (3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester are obtained.

(2) Compound 6.5 obtained in (1) above
To a solution of g in 30 ml of chloroform, 30 ml of a 4M hydrogen chloride-dioxane solution is added, and the mixture is stirred at room temperature overnight. The reaction solution is concentrated, and chloroform and saturated aqueous sodium hydrogen carbonate solution are added to the residue for extraction. After the extract was washed and dried, the solvent was distilled off, ethyl acetate was added to the residue, and the crystals were collected by filtration to give 7- (4-aminophenyl) -2,8-dioxo-1,2,7,7. 8-tetrahydro-5- (3,
5.3 g of (4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester are obtained.

M. p. > 250 ° C Example 13 To a solution of 250 mg of the compound obtained in Example 12 (2) in 10 ml of tetrahydrofuran is added 132 mg of 3,5-dimethoxybenzyl alcohol and 206 mg of triphenylphosphine, and the mixture is stirred at room temperature. Next, 124 μl of diethyl azodicarboxylate is added, and the mixture is stirred at room temperature for 30 minutes. The reaction solution is concentrated, and the residue is subjected to silica gel column chromatography (solvent: chloroform: acetone = 1).
0: 1), the previously eluted fraction (a) 7
-(4-Aminophenyl) -1- (3,5-dimethoxybenzyl) -2,8-dioxo-1,2,7,8-tetrahydro-5- (3,4,5-trimethoxyphenyl)
170 mg of 1,7-naphthyridine-6-carboxylic acid methyl ester and the subsequent elution fraction (b) 7- (4-aminophenyl) -7,8-dihydro-2- (3,5-dimethoxybenzyloxy)- 8-oxo-5- (3,4,5
-Trimethoxyphenyl) -1,7-naphthyridine-6
-18 mg of carboxylic acid methyl ester are obtained.

(Example 13 (a)): m.p. p. 207-
209 ° C (decomposition) (Example 13 (b)): m.p. p. 187-188 ° C (decomposition) Examples 14 to 16 The compound obtained in Example 12 (2) and the corresponding starting compound were treated in the same manner as in Example 13 to obtain the third and fourth compounds.
The compounds shown in the table are obtained.

[0239]

[Table 3]

[0240]

[Table 4]

Example 17 (1) To a solution of 300 mg of the compound obtained in Example 12 (2) in 5 ml of N, N-dimethylformamide was added 108 mg of 3-picolyl chloride hydrochloride and potassium carbonate 1
Add 82 mg and stir at 80 ° C. overnight. Ethyl acetate and water were added to the reaction mixture for extraction, and the extract was washed and dried. The solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent; chloroform: methanol = 20: 1). Eluted fraction (a) of 7- (4-aminophenyl) -2,8-dioxo-1- (3-pyridylmethyl) -1,2,7,8-tetrahydro-5- (3,
185 mg of 4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester and the subsequent eluted fraction (b) 7- (4-aminophenyl) -7,8-
Dihydro-8-oxo-2- (3-pyridylmethoxy)
-5- (3,4,5-trimethoxyphenyl) -1,7
-Naphthyridine-6-carboxylic acid methyl ester 25m
g.

(2) Compound (a) obtained in the above (1)
To a solution of 200 mg of chloroform in 3 ml is added 250 μl of a 4 M hydrogen chloride-ethyl acetate solution, and the mixture is stirred for 30 minutes. The reaction mixture was concentrated, ethyl acetate was added to the residue, and the mixture was collected by filtration to give 7- (4-aminophenyl) -2,8-.
Dioxo-1- (3-pyridylmethyl) -1,2,7,
185 mg of 8-tetrahydro-5- (3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester dihydrochloride are obtained.

M. p. 109-111 ° C (decomposition) (3) The compound (b) obtained in the above (1) is converted into the compound (b) in the above (2)
To give 7- (4-aminophenyl) -7,8-dihydro-8-oxo-2- (3-pyridylmethoxy) -5- (3,4,5-trimethoxyphenyl)- 1,7-Naphthyridine-6-carboxylic acid methyl ester dihydrochloride is obtained.

M. p. 163 to 168 ° C (decomposition) Examples 18 to 19 By treating the compound obtained in Example 12 (2) and the corresponding starting compound in the same manner as in Examples 17 (1) and (2), The compounds shown in Table 6 are obtained.

[0245]

[Table 5]

[0246]

[Table 6]

Example 20 (1) To a solution of 1.0 g of the compound obtained in Example 12 (2) in 12 ml of chloroform was added 542 mg of 9-fluorenylmethyloxycarbonyl chloride.
Stir for hours. The reaction solution was extracted by adding a saturated aqueous solution of sodium hydrogen carbonate, and the extract was washed and dried.
The residue was purified by silica gel column chromatography (solvent; chloroform: acetone = 3: 1) to give 7- [4- (9-fluorenylmethyloxycarbonylamino) phenyl] -2,8-dioxo-1, 2,
980 mg of 7,8-tetrahydro-5- (3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester are obtained.

M. p. > 250 ° C. (2) To a solution of 300 mg of the compound obtained in (1) above in 5 ml of toluene, 56 μl of benzyl bromide and 237 mg of silver carbonate are added, and the mixture is stirred at 100 ° C. for 2 hours. After filtering the insolubles in the reaction solution, the filtrate is concentrated, and the residue is dissolved in tetrahydrofuran. Add 42 μl of piperidine to the solution and stir at room temperature overnight. Chloroform and water were added to the reaction mixture, and the mixture was extracted. The extract was washed and dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography (solvent; chloroform: acetone = 10: 1). 7- (4-aminophenyl) -2-benzyloxy-7,8-dihydro-8-oxo-5- (3
200 mg of (4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester are obtained.

M. p. 212-214 ° C Example 21 (1) 2-Chloro-5,8-dihydro-6-hydroxy-8-oxo-5- (3,4,5-trimethoxyphenyl) -6H-pyrano [3,4- b] 1.0 g of pyridine-6-carboxylic acid (compound obtained in Reference Example 42), 4-g
tert-butoxycarbonylaminoaniline 1.0 g
Of 1,3-dimethyl-2-imidazolidinone is stirred at 80 ° C. for 15 minutes. An aqueous saturated sodium hydrogen carbonate solution and ethyl acetate are added to the reaction solution, and the aqueous layer is separated. The aqueous layer was acidified by adding citric acid, extracted with chloroform, and the extract was washed, dried, and evaporated to remove 2-chloro-7,8-dihydro-8-oxo-7-.
(4-tert-butoxycarbonylaminophenyl)
-5- (3,4,5-trimethoxyphenyl) -1,7
-Naphthyridine-6-carboxylic acid is obtained.

(2) N, of the compound obtained in the above (1)
Methyl iodide 1 in 5 ml of N-dimethylformamide solution
82 μl and 337 mg of potassium carbonate are added and reacted at room temperature for 2 hours. Ethyl acetate was added to the reaction solution, the organic layer was separated, washed, dried, and then the solvent was distilled off.
2-chloro-7,8-dihydro-8-oxo-7- (4
-Tert-butoxycarbonylaminophenyl) -5
-(3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester 1.11 g
Get.

M. p. 232-234 ° C (decomposition) (3) To 300 mg of the compound obtained in the above (2) was added 5 ml of a 4M hydrogen chloride-dioxane solution, and the mixture was stirred at room temperature for 3 hours. The reaction solution is concentrated, and ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate are added to the residue for extraction. After washing and drying the organic layer, the solvent is distilled off, diethyl ether is added to the residue, and the residue is collected by filtration to give 7- (4-aminophenyl) -2-chloro-7,8-dihydro-8-oxo-. 5
-(3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester 230 mg
Get.

M. p. 246-253C (decomposition) Example 22 2-Chloro-5,8-dihydro-5- (3,5-dimethoxy-4-methylphenyl) -6-hydroxy-8-oxo-6H-pyrano [3,4 -B] pyridine-6-carboxylic acid (compound obtained in Reference Example 43) and 4-tert
Example 21 with butoxycarbonylaminoaniline
By treating in the same manner as in (1), (2) and (3), 7- (4-aminophenyl) -2-chloro-7,8
-Dihydro-5- (3,5-dimethoxy-4-methylphenyl) -8-oxo-1,7-naphthyridine-6-carboxylic acid methyl ester is obtained.

M. p. 240-250 ° C (decomposition) Example 23 2-Chloro-5,8-dihydro-5- (3,4,5-trimethoxyphenyl) -6-hydroxy-8-oxo-
6H-Pyrano [3,4-b] pyridine-6-carboxylic acid (compound obtained in Reference Example 42) and 4-picolylamine were treated in the same manner as in Example 21 (1) and Example 1 (2). By doing so, 2-chloro-7,8-dihydro-8-
Oxo-7- (4-pyridylmethyl) -5- (3,4,
5-trimethoxyphenyl) -1,7-naphthyridine-
6-Carboxylic acid methyl ester is obtained.

M. p. 173-175 ° C Example 24 (1) (pyrazin-2-yl) methyl alcohol 53m
g in a solution of N, N-dimethylformamide in 1 ml
Add 19 mg of sodium hydride and stir at room temperature for 10 minutes. Compound 20 obtained in Example 21 (3) was added to the reaction solution.
Add 0 mg and stir at room temperature for 3 hours. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted. The extract was washed, dried, evaporated, and the residue was purified by silica gel column chromatography (solvent; chloroform: acetone = 3: 1) to give a residue. 7- (4-aminophenyl) -7,8-
Dihydro-8-oxo-2-[(pyrazin-2-yl)
[Methoxy] -5- (3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester.

(2) The compound obtained in the above (1) was treated in the same manner as in Example 17 (2) to give 7- (4-
Aminophenyl) -7,8-dihydro-8-oxo-2
-[(Pyrazin-2-yl) methoxy] -5- (3,
(4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester hydrochloride 187 mg
Get.

M. p. 140-145 ° C (decomposition) Examples 25-33 The corresponding starting compounds are treated in the same manner as in Examples 24 (1) and (2) or Example 24 (1) to give the compounds described in Table 7.

[0257]

[Table 7]

Example 34 (1) To a solution of 250 mg of the compound obtained in Example 21 (3) in 3 ml of 1,3-dimethyl-2-imidazolidinone was added 651 μl of N-methylbenzylamine, and 12
Stir at 0 ° C. for 3 hours. After the reaction solution was returned to room temperature, ethyl acetate and water were added thereto for extraction, the extract was washed, dried, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (solvent; chloroform: acetone = 10: 1).
By purifying with, 7- (4-aminophenyl)-
2- (N-methylbenzylamino) -7,8-dihydro-8-oxo-5- (3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester is obtained.

(2) The compound obtained in the above (1) was treated in the same manner as in Example 17 (2) to give 7- (4-
Aminophenyl) -2- (N-methylbenzylamino)
-7,8-Dihydro-8-oxo-5- (3,4,5-
Trimethoxyphenyl) -1,7-naphthyridine-6
55 mg of carboxylic acid methyl ester dihydrochloride are obtained.

M. p. 132-136 ° C (decomposition) Examples 35-37 The corresponding starting compounds were treated in the same manner as in Examples 34 (1) and (2) to give the compounds described in Table 8.

[0261]

[Table 8]

Examples 38 to 45 The corresponding starting compounds were treated in the same manner as in Examples 21 (1) and (2) or 21 (1), (2) and (3) to give the compounds described in Table 9. Obtain the compound.

[0263]

[Table 9]

Examples 46 to 54 The corresponding starting compounds were treated in the same manner as in Example 21 (1) and (2) or Example 21 (1) and Example 1 (2) to give the compounds described in Table 10. Get.

[0265]

[Table 10]

Example 55 A solution of 1 g of the compound obtained in Reference Example 42 and 338 mg of 4-aminomethyl-2,6-dimethylpyridine in 15 ml of tetrahydrofuran is stirred at room temperature for 1 hour and at 50 ° C. for 30 minutes. The solvent was distilled off from the reaction solution, 30 ml of methylene chloride was added to the residue for dissolution, 662 mg of methanol and 1.63 g of triphenylphosphine were added, and 1.3 ml of diethylazodicarboxylate was added.
Stir for 0 minutes. Ethyl acetate and aqueous citric acid solution were added to the reaction solution, and the aqueous layer was separated.The aqueous layer was made basic by adding aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, washed, dried, and the solvent was distilled off. I do. By crystallizing the residue by adding diethyl ether, 2-chloro-7,8-
863 mg of methyl dihydro-7- (2,6-dimethylpyridin-4-yl) methyl-8-oxo-5- (3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylate obtain.

M. p. 212-214 ° C Examples 56-58 The corresponding starting compounds are treated in the same manner as in Example 55, to give the compounds listed in Table 11.

[0268]

[Table 11]

Examples 59 to 130 The corresponding starting compounds were treated in the same manner as in Example 24 (1) and (2) or Example 24 (1) to give
The compounds shown in Table 20 are obtained. However, Examples 81 to 84
Uses the acids listed in Table 14 in place of the hydrochloride.

[0270]

[Table 12]

[0271]

[Table 13]

[0272]

[Table 14]

[0273]

[Table 15]

[0274]

[Table 16]

[0275]

[Table 17]

[0276]

[Table 18]

[0277]

[Table 19]

[0278]

[Table 20]

Example 131 90 mg of the compound obtained in Example 118, 55 mg of sodium azide and 46 mg of ammonium chloride were N, N-
The 2 ml suspension of dimethylformamide is stirred at 70 ° C. for 4 hours. Water and ethyl acetate are added to the reaction solution, extracted with ethyl acetate, washed, dried, and the solvent is distilled off. The residue was subjected to silica gel column chromatography (solvent; chloroform:
By purifying with methanol = 10: 1),
7,8-dihydro-7-[(2-methylpyridine-4-
Yl) methyl] -8-oxo-2- (tetrazole-5
9 mg of -yl) methoxy-5- (3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester are obtained as a colorless powder.

Example 132 To a solution of the compound obtained in Example 80 (500 mg) in chloroform (15 ml) was added m-chloroperbenzoic acid (240 mg), and the mixture was stirred at room temperature overnight. Chloroform and an aqueous sodium hydrogen carbonate solution are added to the reaction solution, extracted with chloroform, washed, dried, and the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent; chloroform: acetone = 1: 1) to give 7,8-dihydro-7-[(2-methyl-N-oxidepyridin-4-yl) methyl] -8. -Oxo-2- (2-pyrimidinylmethoxy) -5- (3,4,5-trimethoxyphenyl)
-1,7-naphthyridine-6-carboxylic acid methyl ester (Example 132 (a)) and 7,8-dihydro-7-
[(2-methyl-N-oxidepyridin-4-yl) methyl] -8-oxo-2-[(N-oxidepyrimidin-2-yl) methoxy] -5- (3,4,5-trimethoxyphenyl ) Methyl -1,7-naphthyridine-6-carboxylate (Example 132 (b)).

Example 132 (a): Powder (Example 132 (b)): m.p. p. 147-153 ° C
(Decomposition) Example 133 The compound obtained in Example 119 was treated in the same manner as in Example 132 to give 7,8-dihydro-7-[(2
-Methyl-N-oxidepyridin-4-yl) methyl]
-8-oxo-2-methoxy-5- (3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester is obtained.

M. p. 190-198 ° C (decomposition) Example 134 3 g of the compound obtained in Example 80, 15 ml of concentrated hydrochloric acid and 60 ml of dioxane are stirred at 100 to 110 ° C for 5 days. The reaction solution is allowed to cool, an aqueous solution of sodium hydrogen carbonate and chloroform are added, and the mixture is extracted with chloroform, washed, dried, and the solvent is distilled off. The residue was subjected to silica gel column chromatography (solvent; chloroform: methanol = 20:
Purification in 1) gives 7-[(2-methylpyridin-4-yl) methyl] -2,8-dioxo-1,2,2.
7,8-tetrahydro-5- (3,5-dimethoxy-4
-Hydroxyphenyl) -1,7-naphthyridine-6
Carboxylic acid methyl ester (Example 134 (a)) 28
0 mg and 7-[(2-methylpyridin-4-yl) methyl] -2,8-dioxo-1,2,7,8-tetrahydro-5- (3,4,5-trimethoxyphenyl)-
1,7-Naphthyridine-6-carboxylic acid methyl ester (Example 134 (b)) is obtained.

Example 134 (a): m.p. p. 246
-247 ° C (decomposition) (Example 134 (b)): m.p. p. 177-178 ° C. Example 135 1 g of the compound obtained in Example 80, 5 ml of concentrated hydrochloric acid and 4
M hydrogen chloride-dioxane solution 10 ml at 100 ° C.
Stir for minutes. The reaction solution is allowed to cool, an aqueous solution of sodium hydrogen carbonate and chloroform are added, and the mixture is extracted with chloroform, washed, dried, and the solvent is distilled off. The residue is collected by filtration with ethyl acetate to obtain 832 mg of the compound obtained in Example 134 (b).

Example 136 200 mg of the compound obtained in Example 54 and 440 μl of cyclohexylmethanol in 3 ml of tetrahydrofuran
112 mg of 62% sodium hydride is added to the solution at room temperature, and the mixture is stirred at room temperature for 5 hours. Acetic acid is added to the reaction solution to terminate the reaction. The reaction solution is made alkaline by adding an aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, washed, dried, and the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent; ethyl acetate) to give 7,8.
-Dihydro-7-[(2-methylpyridin-4-yl)
Methyl] -8-oxo-2-cyclohexylmethoxy-
5- (3,4,5-trimethoxyphenyl) -1,7-
Naphthyridine-6-carboxylic acid cyclohexylmethyl ester and 7,8-dihydro-7-[(2-methylpyridin-4-yl) methyl] -8-oxo-2-methoxy-5- (3,4,5-tri Methoxyphenyl) -1,7
-Naphthyridine-6-carboxylic acid cyclohexylmethyl ester is obtained. Each of these compounds was prepared in Example 17
By treating in the same manner as in (2), 7,8-dihydro-7-[(2-methylpyridin-4-yl) methyl]-
8-oxo-2-cyclohexylmethoxy-5- (3,
4,5-Trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid cyclohexylmethyl ester hydrochloride (Example 136 (a)) 55 mg and 7,8-dihydro-7-[(2-methylpyridine- 4-yl) methyl] -8-oxo-2-methoxy-5- (3,4,5-
Trimethoxyphenyl) -1,7-naphthyridine-6
35 mg of carboxylic acid cyclohexylmethyl ester hydrochloride (Example 136 (b)) are obtained.

Example 136 (a): m.p. p. 164
-166 ° C (decomposition) (Example 136 (b)): m.p. p. 203-206 ° C
(Decomposition) Example 137 To a mixed solution of 1 g of the compound obtained in Example 80 in 5 ml of tetrahydrofuran and 5 ml of methanol is added 5 ml of a 2M aqueous sodium hydroxide solution, and the mixture is stirred at room temperature overnight.
The reaction solution is adjusted to pH 4 with an aqueous citric acid solution, extracted with chloroform, washed and dried, and the solvent is distilled off. The residue is crystallized from diethyl ether to give 7,8-dihydro-7-[(2-methylpyridin-4-yl) methyl].
-8-oxo-2-[(pyrimidin-2-yl) methoxy] -5- (3,4,5-trimethoxyphenyl)-
352 mg of 1,7-naphthyridine-6-carboxylic acid are obtained.

M. p. > 250 ° C Examples 138 to 155 By treating the corresponding starting compounds in the same manner as in Examples 34 (1) and (2) or Example 34 (1),
The compounds listed in Table 23 are obtained. However, in Example 140, methanesulfonic acid was used instead of hydrochloric acid.

[0287]

[Table 21]

[0288]

[Table 22]

[0289]

[Table 23]

Example 156 1 g of the compound obtained in Reference Example 46 and 4-aminomethyl-
362 mg of 2-methylpyridine in tetrahydrofuran 1
After stirring the 00 ml suspension at room temperature for 15 minutes and at 50 ° C. for 4 hours, the solvent is distilled off from the reaction solution. The residue was dissolved in 200 ml of methylene chloride and triphenylphosphine 1.94 was obtained.
g, 395 mg of methanol and 859 mg of diethyl azodicarboxylate are added, and the mixture is stirred at room temperature for 2 hours.
The solvent is distilled off from the reaction solution, ethyl acetate and citric acid aqueous solution are added, and the mixture is extracted with citric acid aqueous solution. The aqueous layer is made alkaline with an aqueous potassium carbonate solution and an aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water, dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography (solvent; n-hexane: acetone = 1: 1) and crystallized from diethyl ether to give 2-
(2-Methylpyridin-4-yl) methyl-1,2-dihydro-1-oxo-4- (3,4,5-trimethoxyphenyl) -2,7-naphthyridin-8-methoxy-3
-747 mg of carboxylic acid methyl ester are obtained.

M. p. 167-171 ° C (decomposition) Examples 157 to 158 The corresponding starting compounds are treated in the same manner as in Example 156, to give the compounds described in Table 24.

[0292]

[Table 24]

Example 159 Phosphorus oxychloride was added to a solution of 1.9 g of the compound obtained in Example 156 in 19 ml of N, N-dimethylformamide.
5 ml is added and the mixture is stirred at 80 ° C. for 20 minutes, and further 1.4 ml of phosphorus oxychloride is added and stirred at the same temperature for 20 minutes. After allowing the reaction solution to cool, an aqueous potassium carbonate solution (18 g / 100 ml)
Water) and the crystals are collected by filtration. Crystals are chloroform 15
Dissolve in 0 ml, wash with aqueous sodium bicarbonate, dry and evaporate the solvent. The residue is subjected to silica gel column chromatography (solvent; chloroform: acetone = 10: 1).
To 5: 1) to give 2- (2-methylpyridin-4-yl) methyl-1,2-dihydro-1-oxo-4- (3,4,5-trimethoxyphenyl)-
543 mg of 2,7-naphthyridine-8-chloro-3-carboxylic acid methyl ester are obtained.

M. p. 210-215 ° C Examples 160-161 By treating the corresponding starting compounds in the same manner as in Example 159, the compounds described in Table 25 are obtained.

[0295]

[Table 25]

Example 162 To a mixed solution of 2.27 g of the compound obtained in Example 156 in 30 ml of methanol and 30 ml of dioxane was added 5 ml of concentrated hydrochloric acid, and the mixture was stirred while heating at 60 ° C. for 5 hours. The solvent is distilled off from the reaction solution, chloroform and a saturated aqueous solution of sodium hydrogen carbonate are added, the mixture is extracted with chloroform, washed, dried and the solvent is distilled off. The residue was crystallized from diethyl ether to give 2-[(2-methylpyridin-4-yl) methyl] -1,8-dioxo-1,2,7,8-tetrahydro-4- (3,4,4. 2.38 g of 5-trimethoxyphenyl) -2,7-naphthyridine-3-carboxylic acid methyl ester are obtained.

M. p. 194-197 ° C. Examples 163 to 164 The compounds obtained in Example 162 and the corresponding starting compounds are treated in the same manner as in Example 17, to give the compounds described in Table 26.

[0298]

[Table 26]

Example 165 (1) 200 mg of the compound obtained in Example 162
By treating 312 mg of (tert-butyldimethylsilyloxy) ethyl bromide in the same manner as in Example 17 (1), oily 2-[(2-methylpyridine-4) was obtained.
-Yl) methyl] -7- [2- (tert-butyldimethylsilyloxy) ethyl] -1,8-dioxo-1,
299 mg of 2,7,8-tetrahydro-4- (3,4,5-trimethoxyphenyl) -2,7-naphthyridine-3-carboxylic acid methyl ester are obtained.

(2) Compound 299 obtained in the above (1)
acetic acid 93 μl in 3 ml of tetrahydrofuran solution
And 1.2 ml of tetrabutylammonium fluoride tetrahydrofuran solution (1M), and the mixture is stirred at room temperature overnight. Ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate are added to the reaction mixture, and the mixture is extracted with ethyl acetate. The extract is washed, dried, and evaporated. The residue was subjected to silica gel column chromatography (solvent; chloroform: methanol = 20: 1 to 1).
10: 1) to give 2-[(2-methylpyridin-4-yl) methyl] -7- (2-hydroxyethyl) -1,8-dioxo-1,2,7,8-tetrahydro. -4- (3,4,5-trimethoxyphenyl)-
2,7-Naphthyridine-3-carboxylic acid methyl ester was obtained and further treated in the same manner as in Example 17 (2) to give 2-[(2-methylpyridin-4-yl) methyl] -7- (2 -Hydroxyethyl) -1,8-dioxo-1,2,7,8-tetrahydro-4- (3,4,5
-Trimethoxyphenyl) -2,7-naphthyridine-3
-44 mg of carboxylic acid methyl ester hydrochloride are obtained.

M. p. 186-188 ° C Example 166 By treating the corresponding starting compound in the same manner as in Example 165, the compounds described in Table 27 are obtained.

[0302]

[Table 27]

Example 167 (1) 200 mg of the compound obtained in Example 162, 2-
402 mg of hydroxymethylpyrimidine and 960 mg of triphenylphosphine in 10 m of tetrahydrofuran
Under a nitrogen atmosphere, 1.659 ml of diethyl azodicarboxylate was added to the 1 solution, and the mixture was stirred at room temperature for 1.5 hours.
Ethyl acetate and an aqueous solution of sodium hydrogen carbonate are added to the reaction solution, extracted with ethyl acetate, washed, dried, and the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent; chloroform: acetone = 30: 1) to give 2-[(2-methylpyridin-4-yl) methyl] -7-[(pyrimidin-2-yl) methyl ]-
1,8-dioxo-1,2,7,8-tetrahydro-4
-(3,4,5-trimethoxyphenyl) -2,7-naphthyridine-3-carboxylic acid methyl ester 171 mg
Get.

(2) Compound 171 obtained in the above (1)
mg in the same manner as in Example 17 (2),
2-[(2-methylpyridin-4-yl) methyl] -7
-[(Pyrimidin-2-yl) methyl] -1,8-dioxo-1,2,7,8-tetrahydro-4- (3,4,
5-trimethoxyphenyl) -2,7-naphthyridine-
146 mg of 3-carboxylic acid methyl ester hydrochloride are obtained.

M. p. 190-194 ° C Example 168 The corresponding starting compound is treated in the same manner as in Example 167, to give the compound described in Table 28.

[0306]

[Table 28]

Example 169 (1) To a solution of 300 mg of the compound obtained in Example 159 and 71 mg of 2-hydroxymethylpyrimidine in 80 ml of tetrahydrofuran was added 25 mg of 62.5% sodium hydride, and the mixture was stirred at room temperature for 4.5 hours. . Water and ethyl acetate are added to the reaction solution, the mixture is extracted with ethyl acetate, washed, dried, and the solvent is distilled off. The residue was subjected to silica gel column chromatography (solvent; chloroform: acetone =
1: 1) to give 2- (2-methylpyridin-4-yl) methyl-1,2-dihydro-1-oxo-4- (3,4,5-trimethoxyphenyl) -2,
241 mg of 7-naphthyridin-8- (pyrimidin-2-yl) methoxy-3-carboxylic acid methyl ester are obtained.

M. p. 121-124 ° C (2) Using the compound obtained in the above (1) in Example 17 (2)
To give 2- (2-methylpyridin-4-yl) methyl-1,2-dihydro-1-oxo-4- (3,4,5-trimethoxyphenyl) -2,7
-Naphthyridin-8- (pyrimidin-2-yl) methoxy-3-carboxylic acid methyl ester hydrochloride is obtained.

M. p. 160-163 ° C (decomposition) Examples 170 to 188 The corresponding starting compounds were prepared in Example 169 (1) or Example 1.
Compounds shown in Tables 29 to 33 are obtained by treating in the same manner as in 69 (1) and Example 17 (2).

[0310]

[Table 29]

[0311]

[Table 30]

[0312]

[Table 31]

[0313]

[Table 32]

[0314]

[Table 33]

Example 189 1.7 g of the compound obtained in Example 183 was added to methanol 2
0 ml, 5 ml of acetic acid and 5 ml of water.
Stir at 4 ° C. for 4 hours. Methanol is distilled off from the reaction solution,
To the residue is added a saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated aqueous solution of sodium hydrogen carbonate, water and brine, dried, and the solvent is distilled off. The residue was subjected to silica gel column chromatography (solvent; chloroform to chloroform: acetone = 1: 1).
By purifying in 2) and treating with diisopropyl ether, 2- (2-methylpyridin-4-yl) methyl-1,2-dihydro-1-oxo-4- (3,4,5-
(Trimethoxyphenyl) -2,7-naphthyridine-8-
50 mg of (imidazol-2-yl) methoxy-3-carboxylic acid methyl ester are obtained as a powder.

Example 190 (1) 80 mg of the compound obtained in Example 159 and 2
A solution of 58 mg of-(2-aminoethyl) pyridine in 4 ml of dioxane is stirred at 80 ° C for 5 hours. An aqueous solution of sodium hydrogen carbonate and ethyl acetate are added to the reaction solution, and the mixture is extracted with ethyl acetate, washed, dried, and the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent; chloroform: acetone = 5: 1 to 2: 1) to give 2- (2-methylpyridin-4-yl) methyl-.
1,2-dihydro-1-oxo-4- (3,4,5-trimethoxyphenyl) -2,7-naphthyridine-8-
[2- (Pyridin-2-yl) ethylamino] -3-carboxylic acid methyl ester is obtained.

(2) The compound obtained in the above (1) was treated in the same manner as in Example 17 (2) to give 2- (2-
Methylpyridin-4-yl) methyl-1,2-dihydro-1-oxo-4- (3,4,5-trimethoxyphenyl) -2,7-naphthyridin-8- [2- (pyridine-
44 mg of 2-yl) ethylamino] -3-carboxylic acid methyl ester dihydrochloride are obtained as a powder.

Examples 191 to 222 The corresponding starting compounds were treated in the same manner as in Example 190 to obtain the compounds shown in Tables 34 to 38.

[0319]

[Table 34]

[0320]

[Table 35]

[0321]

[Table 36]

[0322]

[Table 37]

[0323]

[Table 38]

Example 223 (1) 3.0 g of the compound obtained in Example 159, 6.2 g of β-alanine benzyl ester tosylate and 4.2 g of triethylamine, 1,3-dimethyl-2-imidazolidinone The 30 ml mixture is stirred at 80 ° C. for 12 hours. Ethyl acetate and an aqueous solution of sodium hydrogen carbonate are added to the reaction solution, extracted with ethyl acetate, washed with water, dried, and the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent; ethyl acetate) to give 2- (2
-Methylpyridin-4-yl) methyl-1,2-dihydro-1-oxo-4- (3,4,5-trimethoxyphenyl) -2,7-naphthyridin-8- [2- (benzyloxycarbonyl) Ethylamino] -3-carboxylic acid methyl ester is obtained. The compound is treated with tetrahydrofuran 2
It is dissolved in a mixture of 0 ml and methanol 20 ml, 500 mg of palladium carbon (wet) is added, and the mixture is stirred under a hydrogen atmosphere (1 atm) for 2 hours. The palladium carbon was removed from the reaction solution by filtration and the mother liquor was concentrated to give 2- (2-methylpyridin-4-yl) methyl-1,2-dihydro-1-.
Oxo-4- (3,4,5-trimethoxyphenyl)-
2,7-Naphthyridine-8- (2-carboxyethylamino) -3-carboxylic acid methyl ester (Compound A)
1.25 g are obtained as a powder.

Example 224 In a solution of 100 mg of the compound A obtained in Example 223 and 31 mg of morpholine in 1 ml of N, N-dimethylformamide, 33 mg of 1-hydroxybenzotriazole and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide were added. Add 41 mg of hydrochloride and stir at room temperature for 2 hours. Ethyl acetate and water were added to the reaction solution, extracted with ethyl acetate, washed with an aqueous solution of sodium hydrogen carbonate and water, dried, and evaporated to remove 2- (2-methylpyridin-4-yl) methyl-. 1,2-dihydro-1-oxo-4- (3,4,5-trimethoxyphenyl) -2,
7-Naphthyridine-8- [2- (morpholinocarbonyl) ethylamino] -3-carboxylic acid methyl ester is obtained. The compound was treated in the same manner as in Example 17 (2) to give 2- (2-methylpyridin-4-yl) methyl-1,2-dihydro-1-oxo-4- (3,4,5
-Trimethoxyphenyl) -2,7-naphthyridine-8
-[2- (morpholinocarbonyl) ethylamino] -3
-Obtain 76 mg of carboxylic acid methyl ester dihydrochloride as a powder.

Example 225 The corresponding starting compound was treated in the same manner as in Example 224 to obtain the compounds shown in Table 39.

[0327]

[Table 39]

Example 226 Toluene 1 was added to 200 mg of the compound obtained in Example 159.
5 ml, 2-aminopyridine 48 mg, 1,1′-bis (diphenylphosphino) ferrocene 66 mg, palladium acetate 18 mg, and cesium carbonate 524 mg are added in this order, and the mixture is stirred under a nitrogen atmosphere at 100 ° C. for 1.5 hours. Ethyl acetate was added to the reaction solution, and insoluble materials were removed by filtration, followed by washing with water,
After drying, the solvent is distilled off. The residue was subjected to silica gel column chromatography (solvent; chloroform: n-hexane =
5: 1) to give 2- (2-methylpyridin-4-yl) methyl-1,2-dihydro-1-oxo-4- (3,4,5-trimethoxyphenyl) -2,2.
7-naphthyridine-8- (2-pyridylamino) -3-
A carboxylic acid methyl ester is obtained. The compound was prepared in Example 1
7 (2) to give 2- (2-methylpyridin-4-yl) methyl-1,2-dihydro-1
-Oxo-4- (3,4,5-trimethoxyphenyl)
-2,7-Naphthyridine-8- (2-pyridylamino)
-3-Carboxylic acid methyl ester dihydrochloride 243mg
Get.

M. p. 184-193 ° C (decomposition) Example 227 The corresponding starting compound is treated in the same manner as in Example 226, to give the compound described in Table 40.

[0330]

[Table 40]

Example 228 Formic acid (6 ml) was added to the compound (400 mg) obtained in Example 219.
And heat to reflux overnight. Ethyl acetate and aqueous sodium hydrogen carbonate solution were added to the reaction solution, and extracted with ethyl acetate.
After drying, the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent; ethyl acetate-chloroform: methanol = 20: 1) and crystallized from diethyl ether to give 2- (2-methylpyridine-4-
Yl) methyl-1,2-dihydro-1-oxo-4-
195 mg of (3,4,5-trimethoxyphenyl) -2,7-naphthyridine-8-amino-3-carboxylic acid methyl ester are obtained.

M. p. 189-191 ° C (decomposition) Example 229 The compound obtained in Example 204 (332 mg) was treated in Example 2
By treating in the same manner as in (2), 2- (2-methylpyridin-4-yl) methyl-8-hydrazino-1,2
-254 mg of -dihydro-1-oxo-4- (3,4,5-trimethoxyphenyl) -2,7-naphthyridine-3-carboxylic acid methyl ester trihydrochloride are obtained.

M. p. 193-195 ° C (decomposition) Example 230 23 mg of picolinic acid and 54 mg of 1-hydroxybenzotriazole in 1 ml of N, N-dimethylformamide
To the solution, 273 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was added at room temperature for 1 hour.
Stir for 0 minutes. 80 mg of the compound obtained in Example 229 is added to the reaction solution, and the mixture is stirred at room temperature for 3 hours. To the reaction solution is added a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, washed, dried and the solvent is distilled off. The residue was purified by thin-layer silica gel column chromatography (solvent; chloroform: methanol = 9: 1 (developed twice)),
By crystallization with diethyl ether, 2- (2-
Methylpyridin-4-yl) methyl-8- [N '-(pyridin-2-ylcarbonyl) hydrazino] -1,2-
76 mg of dihydro-1-oxo-4- (3,4,5-trimethoxyphenyl) -2,7-naphthyridine-3-carboxylic acid methyl ester are obtained as a powder.

M. p. > 250 ° C. Example 231-232 The corresponding starting compound is treated in the same manner as in Example 230, to give the compound described in Table 41.

[0335]

[Table 41]

Example 233 (1) 1.5 g of the compound obtained in Example 54 was used in Example 2.
By treating in the same manner as in 4 (1), 7,8-dihydro-7-[(2-methylpyridin-4-yl) methyl]-
8-oxo-2- (4-methoxybenzyloxy) -5
-(3,4,5-Trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester is obtained.

(2) The compound obtained in the above (1) is dissolved in chloroform, 4M hydrochloric acid is added, and the mixture is stirred at room temperature for 3 hours. The reaction solution is made alkaline by adding an aqueous solution of sodium hydrogen carbonate, extracted with chloroform, washed and dried, and the solvent is distilled off. The residue was crystallized from an acetone-diethyl ether mixed solution to give 7-[(2-methylpyridin-4-yl) methyl] -2,8-dioxo-.
1,2,7,8-Tetrahydro-5- (3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester (compound obtained in Example 134 (b)) .15 g are obtained.

M. p. 177-178 ° C (3) 100-mg of the compound obtained in the above (2) was treated in the same manner as in Example 17 (2) to give 7-[(2
-Methylpyridin-4-yl) methyl] -2,8-dioxo-1,2,7,8-tetrahydro-5- (3,4,
5-trimethoxyphenyl) -1,7-naphthyridine-
111 mg of 6-carboxylic acid methyl ester hydrochloride are obtained as pale yellow crystals.

M. p. 195-200 ° C (decomposition) Example 234 The compound obtained in Example 159 was treated in the same manner as in Example 233 to give 2-[(2-methylpyridine-4).
-Yl) methyl] -1,8-dioxo-1,2,7,8
-Tetrahydro-4- (3,4,5-trimethoxyphenyl) -2,7-naphthyridine-3-carboxylic acid methyl ester hydrochloride (hydrochloride of the compound obtained in Example 162) is obtained.

M. p. 207-210 ° C. (decomposition) Example 235 To a suspension of 508 mg of the compound obtained in Example 233 and 250 μl of pyridine in 10 ml of methylene chloride at 0 ° C.
208 μl of trifluoromethanesulfonic anhydride was added,
After heating to 10 ° C. to dissolve the crystals, the mixture is stirred at 5 ° C. for 15 minutes. An aqueous solution of sodium hydrogen carbonate and ethyl acetate are added to the reaction solution, and the mixture is extracted with ethyl acetate, washed, dried, and the solvent is distilled off. Diisopropyl ether was added to the residue,
By stirring and crystallizing, 7,8-dihydro-8-oxo-7-[(2-methylpyridin-4-yl) methyl] is obtained.
-2-trifluoromethanesulfonyloxy-5-
552 mg of (3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester are obtained.

M. p. 138-140 ° C Example 236 To a mixed solution of 300 mg of the compound obtained in Example 54 and 84 µl of triethylamine in 5 ml of tetrahydrofuran and 3 ml of methanol, palladium carbon (50% we
t) Add 150 mg and stir overnight at room temperature under a hydrogen atmosphere (1 atm). Filter off the palladium carbon from the reaction solution,
After concentration of the filtrate, the residue was subjected to silica gel column chromatography (solvent; ethyl acetate to chloroform: acetone =
1: 2) to give 7,8-dihydro-8-oxo-7-[(2-methylpyridin-4-yl) methyl] -5- (3,4,5-trimethoxyphenyl)- 1,7-Naphthyridine-6-carboxylic acid methyl ester is obtained. This product is dissolved in methylene chloride, concentrated by adding a 4 M hydrogen chloride-dioxane solution, and crystallized from ethyl acetate to give 7,8-dihydro-8-oxo-
7-[(2-methylpyridin-4-yl) methyl] -5
-(3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester hydrochloride 2
Obtain 00 mg.

M. p. 195-201 ° C (decomposition) Examples 237-240 The corresponding starting compounds are treated in the same manner as in Example 236, to give the compounds listed in Table 42.

[0343]

[Table 42]

Example 241 200 mg of the compound obtained in Example 54, diethyl (3
-Pyridyl) borane 69 mg, palladium acetate 9 mg,
A solution of 24 mg of tri-o-toluylphosphine, 63 mg of sodium carbonate and 1 ml of water in 5 ml of N, N-dimethylformamide is stirred at 90 ° C. for 1 hour under an argon atmosphere. Ethyl acetate and water are added to the reaction solution, extracted with ethyl acetate, washed, dried, and the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent; chloroform: ethyl acetate = 10: 1) to give 7,8-dihydro-8-oxo-7-[(2-methylpyridin-4-yl) methyl]-. 2- (pyridine-3
-Yl) -5- (3,4,5-trimethoxyphenyl)
106 mg of -1,7-naphthyridine-6-carboxylic acid methyl ester are obtained. Dissolve the product in chloroform and add 4
M hydrogen chloride-dioxane solution 43 μl was added and concentrated,
Crystallize with diethyl ether. The obtained crystals are dissolved in methanol, and acetone and diethyl ether are added for crystallization to give 7,8-dihydro-8-oxo-7-[(2-methylpyridin-4-yl) methyl].
65 mg of 2- (pyridin-3-yl) -5- (3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester dihydrochloride is obtained.

M. p. 196-204 ° C (decomposition) Example 242 The compound obtained in Example 159 is treated in the same manner as in Example 241 to give the compounds described in Table 43.

[0346]

[Table 43]

Example 243 200 mg of the compound obtained in Example 54 and (pyridine-
By treating 69.2 mg of 4-yl) boronic acid in the same manner as in Example 241, 7,8-dihydro-8-oxo-7-[(2-methylpyridin-4-yl) methyl]-
136 mg of 2- (pyridin-4-yl) -5- (3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester dihydrochloride are obtained.

M. p. 202-205 ° C (decomposition) Example 244 By treating 200 mg of the compound obtained in Example 54 and 588 μl of triethylborane in the same manner as in Example 241, 7,8-dihydro-8-oxo-7-[(2 -Methylpyridin-4-yl) methyl] -2-ethyl-5-
(3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester hydrochloride 85
mg are obtained as a powder.

Example 245 To a solution of 300 mg of the compound obtained in Example 54 and 35 mg of tetrakistriphenylphosphine palladium in 5 ml of dioxane were slowly added dropwise 882 μl of a 1M n-hexane solution of trimethylaluminum (1M) under a nitrogen atmosphere, and then at room temperature. Stir for 30 minutes and further at 70 ° C. for 1 hour. The reaction solution is cooled on ice, and 2% aqueous potassium carbonate solution is added
After adding ethyl acetate, ethyl acetate was added and the mixture was filtered through celite. The filtrate was extracted with ethyl acetate, washed, dried, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (solvent; ethyl acetate) and crystallized from diethyl ether to give 7,8-dihydro-8-oxo-7-.
[(2-Methylpyridin-4-yl) methyl] -2-methyl-5- (3,4,5-trimethoxyphenyl)-
1,7-Naphthyridine-6-carboxylic acid methyl ester is obtained. Dissolve the product in chloroform and add 4M hydrogen chloride
A dioxane solution was added, the mixture was concentrated, and crystallized from a mixed solution of chloroform and acetone to give 7,8-dihydro-8-oxo-7-[(2-methylpyridin-4-yl) methyl] -2-methyl-. There are obtained 215 mg of 5- (3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester hydrochloride.

M. p. 190-197 ° C (decomposition) Example 246 N, N- of 200 mg of the compound obtained in Example 54, 188 mg of (2-pyridyl) tri-n-butyltin and 28 mg of bistriphenylphosphinepalladium dichloride
A 4 ml solution of dimethylformamide is stirred at 90 ° C. for 1 hour under an argon atmosphere. After cooling the reaction solution to room temperature, an aqueous potassium fluoride solution is added and the mixture is stirred for 30 minutes. The insolubles were filtered through celite, and ethyl acetate and water were added to the filtrate.
After extraction with ethyl acetate, washing and drying, the solvent is distilled off.
The residue was purified by silica gel column chromatography (solvent; ethyl acetate) to give 7,8-dihydro-8-oxo-7-[(2-methylpyridin-4-yl) methyl] -2- (pyridine-2). -Yl) -5-
(3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester is obtained. This product was dissolved in chloroform, 4M hydrogen chloride-dioxane solution was added, concentrated, and crystallized from a mixed solution of chloroform-ethyl acetate to give 7,8-dihydro-8-oxo-7-[(2-methyl Pyridin-4-yl) methyl]
260 mg of 2- (pyridin-2-yl) -5- (3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester dihydrochloride are obtained.

M. p. 185-193 ° C (decomposition) Example 247 To a mixed solution of 888 mg of the compound obtained in Example 54 and 409 mg of zinc cyanide in 9 ml of N, N-dimethylformamide, 80 mg of tetrakistriphenylphosphine palladium is added, and the mixture is treated under a nitrogen atmosphere. Stir at 1.5 ° C. for 1.5 hours. Ethyl acetate is added to the reaction solution, and the insoluble matter is removed by filtration. The filtrate is washed with an aqueous solution of sodium hydrogen carbonate and water, dried, and the solvent is distilled off. The residue was subjected to silica gel column chromatography (solvent; chloroform: acetone = 5:
Purification in 1) and crystallization with a mixed solution of ethyl acetate-diethyl ether gave 2-cyano-7,8-dihydro-7- (2-methylpyridin-4-yl) methyl-.
571 mg of 8-oxo-5- (3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester are obtained.

M. p. 115-118 ° C Example 248 100 mg of the compound obtained in Example 247 was obtained in Example 13
By treating in the same manner as in 1, 2- (tetrazole-
5-yl) -7,8-dihydro-7- (2-methylpyridin-4-yl) methyl-8-oxo-5- (3,4
5-trimethoxyphenyl) -1,7-naphthyridine-
6-Carboxylic acid methyl ester is obtained. The compound was treated in the same manner as in Example 17 (2) to give 2- (tetrazol-5-yl) -7,8-dihydro-7- (2-
Methylpyridin-4-yl) methyl-8-oxo-5-
(3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester hydrochloride 25
mg are obtained as a colorless powder.

Example 249 Example 247 was obtained by using 4.0 g of the compound obtained in Example 159.
To give 2- (2-methylpyridin-4-yl) methyl-1,2-dihydro-1-oxo-4- (3,4,5-trimethoxyphenyl) -2,7
3.15 g of -naphthyridine-8-cyano-3-carboxylic acid methyl ester are obtained.

M. p. 196-197 ° C. (decomposition) Example 250 1.5 mg of the compound obtained in Example 249 and 1.0 g of 10% palladium on carbon (wet) in 30 ml of methanol
Then, 3 ml of a 4M hydrogen chloride-dioxane solution is added to the suspension of 30 ml of tetrahydrofuran and the mixture is stirred under a hydrogen atmosphere (1 atm) at room temperature for 2 days. The catalyst was removed by filtration from the reaction solution, and the mother liquor was concentrated, followed by treatment with ethyl acetate.
2- (2-methylpyridin-4-yl) methyl-1,2
-Dihydro-1-oxo-4- (3,4,5-trimethoxyphenyl) -2,7-naphthyridine-8-aminomethyl-3-carboxylic acid methyl ester trihydrochloride 1.9
3 g are obtained as a powder.

Example 251 By treating 150 mg of the compound obtained in Example 250 and 45 mg of nicotinic acid in the same manner as in Example 230, 2- (2-methylpyridin-4-yl) methyl-
1,2-dihydro-1-oxo-4- (3,4,5-trimethoxyphenyl) -2,7-naphthyridine-8-
51 mg of (nicotinoylaminomethyl) -3-carboxylic acid methyl ester are obtained.

M. p. 164-166 ° C. Reference Example 1 To a solution of 10 g of N-methyl-picolinamide in 150 ml of tetrahydrofuran, 185 ml of a hexane solution of n-butyllithium (1.6 M) was added dropwise at −78 ° C.
Stir for minutes. Then, 50 ml of a tetrahydrofuran solution of 14.4 g of 3,4,5-trimethoxybenzaldehyde
After the dropwise addition of l, the temperature was raised to 0 ° C, and a saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution for extraction. After washing and drying the extract, the solvent is distilled off, the residue is dissolved in dioxane, 10 ml of concentrated hydrochloric acid is added and the mixture is heated under reflux for 1 hour.
The solvent is distilled off from the reaction solution, and chloroform and a saturated aqueous solution of sodium hydrogen carbonate are added to the residue for extraction. After the extract was washed and dried, the solvent was distilled off to obtain 5- (3,3).
9.2 g of 4,5-trimethoxyphenyl) furo [3,4-b] pyridin-7 (5H) -one are obtained.

M. p. 159-160 ° C Reference Example 2 -78 ° C in a solution of 50 ml of 2,2,6,6-tetramethylpiperidine in 800 ml of 1,2-dimethoxyethane
Hexane solution of n-butyl lithium (1.6 M) 18
5 ml is added dropwise and stirred for 1 hour. N, N-
A solution of 40.8 g of diisopropylnicotinamide in 200 ml of 1,2-dimethoxyethane was added and stirred for 15 minutes. Then, a solution of 38.8 g of 3,4,5-trimethoxybenzaldehyde in 200 ml of 1,2-dimethoxyethane was added.
Add. The temperature was raised to 0 ° C., and water and ethyl acetate were added to the reaction solution for extraction. After washing and drying the extract, the solvent was distilled off, and the residue was dissolved in 200 ml of dioxane.
Then, the mixture is refluxed for 3 hours. The solvent is distilled off from the reaction solution, and chloroform and a saturated aqueous solution of sodium hydrogen carbonate are added to the residue, followed by extraction. After the extract was washed and dried, the solvent was distilled off to give 1- (3,4,5-trimethoxyphenyl) furo [3,4-c] pyridine-3 (1H)-.
32.5 g of on are obtained.

M. p. 147-149 ° C. Reference Example 3 To a solution of 20.4 ml of N, N-diisopropylamine in 100 ml of diethyl ether was added dropwise 91 ml of a hexane solution of n-butyllithium (1.6 M) at −20 ° C., and the reaction solution was added at −78. Cool to ° C. Next, 150 ml of a diethyl ether solution of 20 g of N, N-diisopropylisonicotinamide is added to the reaction solution, and the mixture is stirred for 2 hours. A solution of 19 g of 3,4,5-trimethoxybenzaldehyde in 150 ml of tetrahydrofuran was added to the reaction solution,
After the temperature was raised to 0 ° C., water and ethyl acetate were added to the reaction solution for extraction. After washing and drying the extract, the solvent is distilled off.
The residue was dissolved in 200 ml of dioxane and 20 ml of concentrated hydrochloric acid.
And heat to reflux for 1 hour. The solvent is distilled off from the reaction solution,
Chloroform and a saturated aqueous solution of sodium hydrogen carbonate are added to the residue and extracted. After washing and drying the extract, the solvent is distilled off to obtain 7.93 g of 3- (3,4,5-trimethoxyphenyl) furo [3,4-c] pyridin-1 (3H) -one. .

M. p. 144-145 ° C Reference Examples 4 to 8 The corresponding starting compounds are treated in the same manner as in Reference Example 1 to give compounds as shown in Table 44.

[0360]

[Table 44]

Reference Example 9 To a solution of 216 g of N, N-diisopropyl-2-methoxynicotinamide in 2 liters of tetrahydrofuran was added:
77.1 ml of 2,2,6,6-tetramethylpiperidine
And 193 ml of tetramethylethylenediamine, and the mixture is cooled to -70 ° C, and an n-butyllithium hexane solution (1.6 M) is added dropwise over 40 minutes. The reaction solution was -6
After stirring at 5-70 ° C for 20 minutes, 3,4,5-
A solution of 179 g of trimethoxybenzaldehyde in 600 ml of tetrahydrofuran is added dropwise. After stirring at -70 ° C for 30 minutes, 55 g of acetic acid and then 200 ml of water are added dropwise to the reaction solution. About 2 liters of tetrahydrofuran is distilled off from the reaction solution, water and ethyl acetate are added thereto, and the mixture is extracted with ethyl acetate. After washing and drying, the solvent is distilled off. The residue is filtered with a mixed solution of diethyl ether and diisopropyl ether to give N, N-diisopropyl-2-.
Methoxy-4- [hydroxy- (3,4,5-trimethoxyphenyl) methyl] -nicotinamide is obtained. This compound is dissolved in a mixed solution of 400 ml of acetic acid and 500 ml of dioxane and stirred at 80 to 90 ° C. for 4 hours. The solvent is distilled off from the reaction solution, 300 ml of ethyl acetate and 1 liter of water are added, and the mixture is stirred for crystallization. After filtering the crystals, the crystals are washed with water and diethyl ether to give 1- (3,3).
184 g of 4,5-trimethoxyphenyl) -4-methoxy-furo [3,4-c] pyridin-3 (1H) -one are obtained. Ethyl acetate was added to the filtrate for extraction, followed by extraction, washing and drying. The solvent was distilled off, and the residue was washed with diethyl ether to obtain a further 17 g.

M. p. 164-166 ° C. Reference Example 10 To 50 ml of a 20% aqueous potassium hydroxide solution of 108 g of the compound obtained in Reference Example 1, 85 g of potassium permanganate is added at 50 ° C., followed by stirring for 2 hours. The reaction solution is ice-cooled, ethanol is added, and excess potassium permanganate is crushed, and then insolubles are filtered. Concentrated hydrochloric acid is added to the filtrate under ice cooling until the pH becomes 2, and the precipitated crystals are collected by filtration to obtain 110 g of 3- (3,4,5-trimethoxybenzoyl) picolinic acid.

M. p. 157-158 ° C Reference Examples 11 to 16 By treating the corresponding starting compounds in the same manner as in Reference Example 10, the compounds shown in Table 45 are obtained.

[0364]

[Table 45]

REFERENCE EXAMPLE 17 Potassium carbonate was added to a solution of 110 g of the compound obtained in Reference Example 10 in 700 ml of N, N-dimethylformamide.
Add 9 g and 32 ml of methyl iodide and stir at room temperature overnight. The solvent is distilled off from the reaction solution, chloroform and water are added, and the mixture is extracted. After the extract is washed and dried, the solvent is distilled off to obtain 102 g of methyl 3- (3,4,5-trimethoxybenzoyl) picolinic acid.

M. p. 154-157 ° C. Reference Example 18 The compound obtained in Reference Example 13 is treated in the same manner as Reference Example 17 to obtain methyl 3- (3,5-dimethoxy-4-methylbenzoyl) picolinate.

M. p. 166-168 ° C. Reference Example 19 Chloroform 1 of 102 g of the compound obtained in Reference Example 17
To a 000 ml solution, 1500 ml of a chloroform solution of 213 g of 3-chloroperbenzoic acid is added dropwise, and the mixture is stirred at room temperature overnight. The insoluble material is filtered off, and the filtrate is washed with an aqueous solution of sodium thiosulfate. After washing and drying the chloroform layer, the solvent is distilled off to give 3- (3,4,5-trimethoxybenzoyl) picolinic acid methyl ester-N
-42 g of oxide are obtained.

M. p. 166-168 ° C. Reference Example 20 By treating the compound obtained in Reference Example 18 in the same manner as in Reference Example 19, 3- (3,5-dimethoxy-4-methylbenzoyl) picolinic acid methyl ester-N-oxide is obtained. obtain.

M. p. 139-141 ° C. Reference Example 21 A solution of 24.9 g of the compound obtained in Reference Example 19 in 75 ml of phosphorus oxychloride is heated under reflux for 30 minutes. The reaction solution is concentrated, and the residue is poured into a saturated aqueous solution of sodium hydrogen carbonate, and then extracted by adding ethyl acetate. After washing and drying the extract, the solvent is distilled off. The residue was crystallized by adding ethyl acetate to give 6-chloro-3- (3,4,5-trimethoxybenzoyl) picolinic acid methyl ester.
4 g are obtained.

M. p. 127-129 ° C Reference Example 22 By treating the compound obtained in Reference Example 20 in the same manner as in Reference Example 21, 6-chloro-3- (3,5-dimethoxy-4-methylbenzoyl) picolinic acid methyl ester was obtained. obtain.

M. p. 134-136 ° C Reference Example 23 Methanol solution 1 of compound 22g obtained in Reference Example 21
60 ml of a 2 M aqueous sodium hydroxide solution is added to 50 ml, and the mixture is stirred at room temperature for 30 minutes. 2M hydrochloric acid 60m
Add l and chloroform and extract. After the extract is washed and dried, the solvent is distilled off to obtain 19.5 g of the same compound as the compound obtained in Reference Example 14.

Reference Example 24 The compound obtained in Reference Example 22 was treated in the same manner as in Reference Example 23 to give 6-chloro-3- as shown in Table 34.
(3,5-Dimethoxy-4-methylbenzoyl) picolinic acid is obtained.

M. p. 199-201 ° C. Reference Example 25 The compound obtained in Reference Example 7 was treated in the same manner as in Reference Example 10 to give 6-chloro-3- (4-chloro-3,5.
-Dimethoxybenzoyl) picolinic acid is obtained.

M. p. 215-216 ° C Reference Example 26 Potassium carbonate (56.5) was added to a solution of 59 g of the compound obtained in Reference Example 10 in 500 ml of N, N-dimethylformamide.
g, and the mixture is stirred at room temperature for 15 minutes. Then, 81 g of dibenzyl bromomalonate is added, and the mixture is stirred at room temperature for 15 minutes. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted. The extract was washed, dried, and evaporated to remove 5-hydroxy-8-oxo-5- (3,4,5-trimethoxyphenyl). ) -5,8-Dihydro-6H-pyrano [3,4-
b] 72.2 g of pyridine-6,6-dicarboxylic acid dibenzyl ester are obtained.

M. p. 173-175 ° C Reference Examples 27-28 The corresponding starting compounds are treated in the same manner as in Reference Example 26 to give compounds as listed in Table 46.

[0376]

[Table 46]

Reference Example 29 Toluene 50 (2.65 g) of the compound obtained in Reference Example 14
33 mg of rhodium acetate is added to the ml solution, 1.83 g of diazomalonic acid di-tert-butyl ester is added dropwise at 80 ° C., and the mixture is stirred for 2 hours. The reaction solution was cooled to 1,8-
Diazabicyclo [5.4.0] undec-7-ene
Add 13 ml and stir for 15 minutes. Water was added to the reaction solution, the organic layer was separated, washed and dried, the solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent; chloroform: acetone = 30: 1) to give 2 -Chloro-5-hydroxy-8-oxo-5-
(3,4,5-trimethoxyphenyl) -5,8-dihydro-6H-pyrano [3,4-b] pyridine-6,6-
3.1 g of di-tert-butyl dicarboxylic acid are obtained.

M. p. 118-122 ° C Reference Examples 30-33 The corresponding starting compounds are treated in the same manner as in Reference Example 29 to give compounds as listed in Table 47.

[0379]

[Table 47]

Reference Example 34 3.77 g of dioxane 4 of the compound obtained in Reference Example 26
To the 0 ml solution, 200 mg of 10% palladium-carbon and 3 drops of acetic acid were added, and the mixture was added under hydrogen pressure (35 psi) at room temperature.
Shake time. The palladium-carbon is filtered off from the reaction solution, and the filtrate is concentrated. The residue was dissolved in 50 ml of dioxane and heated under reflux for 6 hours, and after the reaction solution was returned to room temperature,
Diethyl ether was added, and the precipitated crystals were collected by filtration to give 8-oxo-5- (3,4,5-trimethoxyphenyl) -8H-pyrano [3,4-b] pyridine-6.
1.8 g of carboxylic acid are obtained.

M. p. 223-224 ° C. Reference Examples 35-36 The corresponding starting compounds are treated in the same manner as in Reference Example 34 to give compounds as listed in Table 48.

[0382]

[Table 48]

Reference Example 37 The compound (3.0 g) obtained in Reference Example 29 was dissolved in 4M hydrogen chloride-
Dissolve in 20 ml of dioxane solution and stir at room temperature overnight. The reaction mixture is concentrated, the residue is dissolved in dioxane (20 ml), and the mixture is heated under reflux for 8 hours. After returning the reaction solution to room temperature, the precipitated crystals were collected by filtration to give 2-chloro-
1.6 g of 8-oxo-5- (3,4,5-trimethoxyphenyl) -8H-pyrano [3,4-b] pyridine-6-carboxylic acid are obtained.

M. p. > 250 ° C. Reference Examples 38 to 40 By treating the corresponding starting compounds in the same manner as in Reference Example 37, compounds shown in Table 49 are obtained.

[0385]

[Table 49]

Reference Example 41 A solution of 1.0 g of the compound obtained in Reference Example 33 in 5 ml of acetic acid was heated and stirred at 120-125 ° C. for 4 hours. The reaction solution was allowed to cool, 5 ml of diethyl ether was added, and the mixture was stirred for 10 minutes. Then, the crystals were collected by filtration to give 8-methoxy-1-oxo-4- (3,4,5-trimethoxyphenyl) -1H.
-Pyrano [3,4-c] pyridine-3-carboxylic acid 45
Obtain 2 mg m. p. 280-282 ° C. (decomposition) Reference Example 42 To a suspension of 5.0 g of the compound obtained in Reference Example 37 in 50 ml of N, N-dimethylformamide was added 14 ml of a 2M aqueous sodium hydroxide solution under ice-cooling, and the mixture was cooled at room temperature to 10 Stir for minutes. Ethyl acetate and aqueous citric acid solution are added to the reaction solution, and the mixture is extracted. After the extract was washed and dried, the solvent was distilled off to give 2-chloro-5,8-dihydro-6-hydroxy-8-oxo-5- (3,4,5-trimethoxyphenyl) -6H-. Pyrano [3,4-b] pyridine-6
4.64 g of carboxylic acid are obtained.

M. p. 122-124 ° C (decomposition) Reference Examples 43 to 46 The corresponding starting compounds are treated in the same manner as in Reference Example 42 to give compounds as shown in Table 50.

[0388]

[Table 50]

Reference Example 47 (1) N, N-dimethylformamide 200 obtained by mixing 20 g of the compound obtained in Reference Example 14 and 5.7 g of potassium hydrogencarbonate.
The suspension was stirred at 50 ° C. for 2 hours, and then a solution of 25.2 g of di-tert-butyl bromomalonate in 40 ml of N, N-dimethylformamide was added dropwise, followed by reaction at the same temperature for 3 hours. The reaction solution was extracted by adding ethyl acetate and water,
The extract is washed with water. After drying, the solvent was distilled off, and the obtained residue was crystallized from a mixed solution of hexane-diethyl ether and collected by filtration to give 2- [6-chloro-3- (3,4,4).
5-trimethoxybenzoyl) pyridine-2-carbonyloxy] malonic acid di-tert-butyl ester 2
3.7 g are obtained.

M. p. 113-115 ° C (2) To a solution of 23.6 g of the compound obtained in the above (1) in 200 ml of toluene was added 6.2 ml of 1,8-diazabicyclo [5.4.0] undec-7-ene under ice-cooling. Add. After reacting at room temperature for 30 minutes, a saturated aqueous ammonium chloride solution is added to the reaction solution. After the organic layer was washed with water and dried, the solvent was distilled off and 2-chloro-5-hydroxy-8-oxo-
5- (3,4,5-trimethoxyphenyl) -5,8-
Dihydro-6H-pyrano [3,4-b] pyridine-6,
6-Dicarboxylic acid di-tert-butyl ester (the compound obtained in Reference Example 29) is obtained.

(3) The compound obtained in the above (2) was
Dissolve in 500 ml of M hydrogen chloride-ethyl acetate solution and react at room temperature overnight. The reaction solution was concentrated to give 2-chloro-5-
Hydroxy-8-oxo-5- (3,4,5-trimethoxyphenyl) -5,8-dihydro-6H-pyrano [3,4-b] pyridine-6,6-dicarboxylic acid is obtained.

(4) The compound obtained in the above (3) was dissolved in 200 ml of dioxane, heated under reflux for 3 hours, and then dioxane was distilled off. Ethyl acetate was added to the residue, and the crystals were collected by filtration to give 2-chloro-8-oxo-.
12.2 g of 5- (3,4,5-trimethoxyphenyl) -8H-pyrano [3,4-b] pyridine-6-carboxylic acid (the compound obtained in Reference Example 37) is obtained.

M. p. :> 250 ° C Reference Example 48 The following compound is obtained by treating the compound obtained in Reference Example 16 in the same manner as in Reference Example 47.

Ditert-butyl 2- [4- (3,4,5-trimethoxybenzoyl) -2-methoxypyridine-3-carbonyloxy] malonate (Reference Example 4)
8 (1)) 4-Hydroxy-8-methoxy-1-oxo-4-
(3,4,5-trimethoxyphenyl) -1,4-dihydro-pyrano [3,4-c] pyridine-3,3-dicarboxylic acid ditert-butyl ester (Reference Example 48)
(2)) 4-hydroxy-8-methoxy-1-oxo-4-
(3,4,5-trimethoxyphenyl) -1,4-dihydro-pyrano [3,4-c] pyridine-3,3-dicarboxylic acid (Reference Example 48 (3)) m. p. 264-267 ° C (decomposition) 1-oxo-4- (3,4,5-trimethoxyphenyl) -8-methoxy-1H-pyrano [3,4-c] pyridine-3-carboxylic acid (Reference Example 48 ( 4)) (Reference Example 3)
Compound obtained in 7) Reference Example 49 2.0 g of the compound obtained in Reference Example 14 and 570 mg of potassium hydrogen carbonate in 20 ml of N, N-dimethylformamide
The suspension is stirred at 50 ° C. for 2 hours. Next, a solution of 2.5 g of di-tert-butyl bromomalonate in 5 ml of N, N-dimethylformamide is added, and the mixture is reacted at the same temperature for 2 hours. Ethyl acetate and water are added to the reaction solution for extraction.
After the extract is washed with water and dried, the solvent is distilled off. The residue was dissolved in 50 ml of toluene, and 8.7 g of 1,8-diazabicyclo [5.4.0] undec-7-ene was added dropwise under ice cooling.
Stir for 30 minutes at the same temperature. Water is added to the reaction solution for washing, the organic layer is washed again with water, dried, and then the solvent is distilled off. Residue is 4M
Dissolve in 300 ml of a hydrogen chloride-ethyl acetate solution and react at room temperature overnight. The reaction solution was concentrated, and the residue was diluted with dioxane 1
Dissolve in 00 ml and heat to reflux for 3 hours. The reaction solution was concentrated, ethyl acetate was added, and the crystals were collected by filtration.
-Chloro-8-oxo-5- (3,4,5-trimethoxyphenyl) -8H-pyrano [3,4-b] pyridine-
6. 6-carboxylic acid (compound obtained in Reference Example 37)
2 g are obtained.

Reference Example 50 N-bromosuccinimide 6 was added to a solution of 100 g of dibenzyl malonate in 300 ml of N, N-dimethylformamide.
After adding 2.6 g and dissolving, 0.489 ml of triethylamine is slowly added dropwise under ice-cooling, followed by stirring for 1 hour. Water and ethyl acetate are added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with water and dried, and the solvent is distilled off to obtain 127 g of oily dibenzyl bromomalonate.

Reference Example 51 N-bromosuccinimide (82.3 g) was added to a solution of 100 g of di-tert-butyl malonate in 300 ml of N, N-dimethylformamide, and the mixture was dissolved. 8-diazabicyclo [5.4.0] undece-
0.69 ml of 7-ene is slowly added dropwise and stirred for 1 hour. Water and ethyl acetate are added to the reaction solution, and the mixture is extracted with ethyl acetate. After the organic layer was washed with water and dried, the solvent was distilled off to obtain oily di-tert-butyl bromomalonate 136.
get g

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 7/02 A61P 7/02 9/00 9/00 9/10 101 9/10 101 9/12 9 / 12 11/00 11/00 11/06 11/06 43/00 111 43/00 111 F-term (Reference) 4C065 AA05 BB09 CC01 DD02 HH03 HH04 HH08 HH09 JJ04 KK02 KK03 KK04 LL03 LL04 LL07 LL09 PP03 PP07 PP09 PP10 PP12 PP13 PP14 PP15 PP16 PP17 QQ01 QQ04 4C086 AA03 AA04 CB09 GA02 GA07 GA08 GA09 GA10 GA12 MA01 NA14 ZA12 ZA15 ZA36 ZA39 ZA40 ZA42 ZA59 ZC20

Claims (23)

[Claims] 1. A compound of the general formula [I] (Wherein ring A is a substituted or unsubstituted pyridine ring or substituted or unsubstituted dihydropyridine ring, ring B is an optionally protected hydroxyl group, substituted or unsubstituted lower alkyl group, substituted or unsubstituted lower alkoxy group, and halogen atom A benzene ring having the same or different 2 to 4 substituents or a benzene ring having 1 to 2 lower alkylenedioxy groups, R ¹ is a hydrogen atom, a substituted or unsubstituted aryl group, substituted or unsubstituted A lower alkyl group, a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted amino group, R ² represents a hydrogen atom or an ester residue) or a pharmaceutically acceptable salt thereof. 2. R ¹ is a substituted or unsubstituted aryl group,
The compound according to claim 1, which is a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted amino group. 3. Ring A is of the formula: Wherein A ¹ is (1) hydrogen atom, (2) substituted or unsubstituted lower alkoxy group, (3) halogen atom, (4) protected hydroxyl group, (5) substituted or unsubstituted nitrogen-containing A heterocyclic group, (6) a substituted or unsubstituted lower alkylthio group, (7) a substituted or unsubstituted amino group,
(8) a substituted or unsubstituted alkyl group, (9) a substituted or unsubstituted aryl group, or (10) a heterocyclic group-substituted oxy group, wherein A ² is (1) a hydrogen atom or (2) a substituted or unsubstituted lower alkyl 3. The compound according to claim 1, which is a group. 4. Ring B is of the formula: 4. The compound according to claim 3, wherein B ¹ , B ² and B ³ are the same or different and each is an optionally protected hydroxyl group, lower alkyl group, lower alkoxy group or halogen atom. 5. Ring A is of the formula: Wherein A ¹ is (1) hydrogen atom, (2) substituted or unsubstituted lower alkoxy group, (3) halogen atom, (4) protected hydroxyl group, (5) substituted or unsubstituted nitrogen-containing A heterocyclic group, (6) a substituted or unsubstituted lower alkylthio group, (7) a substituted or unsubstituted amino group,
(8) a substituted or unsubstituted alkyl group, (9) a substituted or unsubstituted aryl group, or (10) a heterocyclic group-substituted oxy group, wherein A ² is (1) a hydrogen atom or (2) a substituted or unsubstituted lower alkyl 5. The compound according to claim 4, which is a group. 6. Ring A is of the formula: Wherein A ¹ has one or two same or different substituents selected from (1) a hydrogen atom, (2) a lower alkoxy group, a hydroxyl-substituted lower alkyl group and a lower alkylamino group. A pyridyl group optionally substituted with a hydroxyl-substituted lower alkyl group; a pyrimidinyl group optionally substituted with a lower alkyl group; an imidazolyl group optionally substituted with a lower alkyl group;
Pyrazinyl group; N-oxidepyridyl group; N-oxidepyrimidinyl group; tetrazolyl group; thiazolyl group; pyrrolidinyl group; lower alkyl group-substituted pyrrolidinyl group; oxo group-substituted pyrrolidinyl group; morpholinyl group; An alkyl-substituted piperazinyl group; an optionally protected piperidyl group; a lower alkyl-substituted piperidyl group; a lower alkylamino group; a cyano group; a cyclo-lower alkyl group; a lower alkoxy group; Lower alkoxy group, (3) halogen atom, (4) trifluoromethanesulfonyloxy group, (5) tetrazolyl group,
(6) triazolyl group, (7) pyrrolidinyl group optionally substituted with a hydroxyl-substituted lower alkyl group or hydroxyl group, (8) piperidyl group optionally substituted with a hydroxyl group, (9) morpholinyl group, (10) hydroxyl group A piperazinyl group optionally substituted with a substituted lower alkyl group or a pyrimidinyl group, (11) a pyridyl group, (12) an imidazolyl group, (13) a lower alkylthio group optionally substituted with a phenyl group, (14) a phenyl group Substituted lower alkyl group, pyridyl group-substituted lower alkyl group, lower alkyl group, lower alkoxy group-substituted lower alkyl group, hydroxyl-substituted lower alkyl group, pyrimidinyl group-substituted lower alkyl group,
Selected from a lower alkyl group substituted with a lower alkylamino group, a pyridyl group-substituted amino group, an amino group substituted with a halogeno lower alkyl group-substituted pyrimidinyl group, a pyridylcarbonyl group-substituted amino group and an optionally protected amino group An amino group which may have one or two same or different substituents, (15) a lower alkyl group, or (16) a tetrahydrofuranyl group-substituted oxy group, A ²
Is the same or different 1 selected from (1) hydrogen atom or (2) lower alkoxy group and di-lower alkylamino group
A phenyl group optionally having 2 to 2 substituents; a pyridyl group; a lower alkoxy group; a hydroxyl group; and a lower alkyl group optionally substituted with a group selected from pyrimidinyl groups, and ring B has the formula: 6] Wherein B ¹ , B ² and B ³ are the same or different and each may be a protected hydroxyl group, lower alkyl group, lower alkoxy group or halogen atom, R ¹
May be protected amino group, amino group part may be protected amino group-substituted lower alkyl group, carbamoyl group, protected carboxyl group, and hydroxyl group part may be protected hydroxyl group A phenyl group which may be substituted with a group selected from a lower alkyl group and a lower alkoxy group; a lower alkyl group-substituted pyridyl group,
It may be substituted with a group selected from a lower alkoxy group-substituted pyridyl group, a pyridyl group, a lower alkyl group-substituted N-oxide pyridyl group, a carbamoyl group, an optionally protected carboxyl group and an optionally protected hydroxyl group. A lower alkyl group; an amino group which may be protected;
Or the lower alkylamino group in which the amino group part may be protected, and R ² is a hydrogen atom, a lower alkyl group, a cyclo-lower alkyl-substituted lower alkyl group or a hydroxyl-substituted lower alkyl group. . 7. Ring A is of the formula: Wherein A ¹ has one or two same or different substituents selected from (1) a hydrogen atom, (2) a lower alkoxy group, a hydroxyl-substituted lower alkyl group and a lower alkylamino group. A pyridyl group optionally substituted with a hydroxyl-substituted lower alkyl group; a pyrimidinyl group optionally substituted with a lower alkyl group; an imidazolyl group optionally substituted with a lower alkyl group;
Pyrazinyl group; N-oxidepyridyl group; N-oxidepyrimidinyl group; tetrazolyl group; thiazolyl group; pyrrolidinyl group; lower alkyl group-substituted pyrrolidinyl group; oxo group-substituted pyrrolidinyl group; morpholinyl group; An alkyl-substituted piperazinyl group; an optionally protected piperidyl group; a lower alkyl-substituted piperidyl group; a lower alkylamino group; a cyano group; a cyclo-lower alkyl group; a lower alkoxy group; Lower alkoxy group, (3) halogen atom, (4) trifluoromethanesulfonyloxy group, (5) tetrazolyl group,
(6) triazolyl group, (7) pyrrolidinyl group optionally substituted with a hydroxyl-substituted lower alkyl group or hydroxyl group, (8) piperidyl group optionally substituted with a hydroxyl group, (9) morpholinyl group, (10) hydroxyl group A piperazinyl group optionally substituted with a substituted lower alkyl group or a pyrimidinyl group, (11) a pyridyl group, (12) an imidazolyl group, (13) a lower alkylthio group optionally substituted with a phenyl group, (14) a phenyl group Substituted lower alkyl group, pyridyl group-substituted lower alkyl group, lower alkyl group, lower alkoxy group-substituted lower alkyl group, hydroxyl-substituted lower alkyl group, pyrimidinyl group-substituted lower alkyl group,
Selected from a lower alkyl group substituted with a lower alkylamino group, a pyridyl group-substituted amino group, an amino group substituted with a halogeno lower alkyl group-substituted pyrimidinyl group, a pyridylcarbonyl group-substituted amino group and an optionally protected amino group An amino group which may have one or two same or different substituents, (15) a lower alkyl group, or (16) a tetrahydrofuranyl group-substituted oxy group, A ²
Is the same or different 1 selected from (1) hydrogen atom or (2) lower alkoxy group and di-lower alkylamino group
A phenyl group optionally having 2 to 2 substituents; a pyridyl group; a lower alkoxy group; a hydroxyl group; and a lower alkyl group which may be substituted with a group selected from pyrimidinyl groups, wherein R ¹ is protected. A phenyl group optionally substituted with a group selected from an amino group, an amino group-substituted lower alkyl group optionally protected, an carbamoyl group and a lower alkoxy group; a lower alkyl group-substituted pyridyl group, a lower amino group An alkoxy-substituted pyridyl group, a pyridyl group, a lower alkyl group-substituted N-oxidepyridyl group, a carbamoyl group and a lower alkyl group which may be substituted with a group selected from an optionally protected hydroxyl group;
The compound according to claim 6, wherein the compound is an amino group which may be protected; or a lower alkylamino group in which the amino group moiety may be protected. 8. A hydroxyl group in which ring B may be protected by (1) a benzyl group, a phenethyl group, a formyl group, an acetyl group, a propionyl group, a malonyl group, an acryloyl group or a benzoyl group; a lower alkyl group; a lower alkoxy group And a benzene ring having 2 to 4 same or different substituents selected from halogen atoms or (2) 1
3. The compound according to claim 1, which is a benzene ring having from 2 to 2 lower alkylenedioxy groups. 9. Ring A is (1) (i) a lower alkylenedioxyphenyl group; a benzimidazolyl group; a lower alkyl group-substituted imidazolyl group; an imidazolyl group; a cyano group; a carboxyl group; a pyridyl group;
Pyridyl group substituted with a hydroxyl-substituted lower alkyl group; pyrrolidinyl group; lower alkyl group-substituted pyrrolidinyl group; oxo group-substituted pyrrolidinyl group; isoquinolyl group; lower alkyl group-substituted pyrimidinyl group; pyrimidinyl group; N-oxide pyrimidinyl group; A quinazolinyl group;
Phthalazinyl group; lower alkoxycarbonyl group-substituted piperidyl group; tert-butoxycarbonyl group-substituted piperidyl group; lower alkyl group-substituted piperidyl group; piperidyl group; tert-butoxycarbonyl group-substituted piperazinyl group; lower alkyl group-substituted piperazinyl group; Group: tetrazolyl group; thiazolyl group; thienyl group; furyl group; pyrrolyl group substituted by lower alkyl group and lower alkoxycarbonyl group; mono- or di-lower alkylamino group; lower alkoxy group-substituted lower alkoxy group; lower alkoxy group; A carbamoyl group; a lower alkoxycarbonyl group; a cyclo-lower alkyl group; a phenyl group; a phenyl group substituted with a hydroxyl-substituted lower alkyl group; a carboxy-substituted phenyl group; Substituted phenyl group; a benzoyl group;
Mono- or di-lower alkoxy-substituted phenyl; nitro-substituted phenyl; naphthyl; mono- or dihalogenophenyl; carbamoyl-substituted phenyl; sulfamoyl-substituted phenyl; benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl , 9-
A phenyl group mono- or di-substituted with an amino group optionally protected by a fluorenylmethoxycarbonyl group, a tert-butoxycarbonyl group, a 2,2,2-trichloroethyloxycarbonyl group or a lower alkanoyl group; a biphenylyl group A phenyl group di-substituted with a halogen atom and a nitro group; a di-lower alkylamino-substituted phenyl group; and a lower alkoxy group optionally substituted with a group selected from a lower alkyl-substituted phenyl group, (ii) a halogen atom (Iii) a trifluoromethanesulfonyloxy group, (iv) a tetrazolyl group,
(V) a triazolyl group, (vi) a pyrrolidinyl group optionally substituted with a hydroxyl-substituted lower alkyl group or a hydroxyl group, (vii) a piperidyl group optionally substituted with a hydroxyl group, (viii) a morpholinyl group, (ix) a hydroxyl group A piperazinyl group optionally substituted with a substituted lower alkyl group or a pyrimidinyl group, (x) a pyridyl group, (xi)
Imidazolyl group, (xii) lower alkylenedioxyphenyl group; benzimidazolyl group; lower alkyl group-substituted imidazolyl group; cyano group; carboxyl group; pyridyl group; N-oxidepyridyl group; pyridyl group substituted by hydroxyl-substituted lower alkyl group Pyrrolidinyl; isoquinolyl; lower alkyl-substituted pyrimidinyl; pyrimidinyl; pyrazinyl; quinazolinyl; phthalazinyl; lower alkoxycarbonyl-substituted piperidyl; piperidyl; quinolyl; tetrazolyl; thienyl; furyl; lower A pyrrolyl group substituted with an alkyl group and a lower alkoxycarbonyl group; a mono- or di-lower alkylamino group; a lower alkoxy-substituted lower alkoxy group; a lower alkoxy group; a hydroxyl group; a carbamoyl group; A phenyl group substituted with a hydroxyl-substituted lower alkyl group; a carboxy group-substituted phenyl group; a lower alkoxycarbonyl group-substituted phenyl group; a benzoyl group; a mono- or di-lower alkoxy-substituted phenyl group; A nitro group-substituted phenyl group; a naphthyl group; a mono- or dihalogenophenyl group; a carbamoyl-substituted phenyl group; a sulfamoyl-substituted phenyl group; a benzyloxycarbonyl group;
An amino group which may be protected by a 4-methoxybenzyloxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, a tert-butoxycarbonyl group, a 2,2,2-trichloroethyloxycarbonyl group or a lower alkanoyl group; Or a diphenyl-substituted phenyl group; a biphenylyl group; a phenyl group di-substituted with a halogen atom and a nitro group; a di-lower alkylamino group-substituted phenyl group; and a lower alkyl group-substituted phenyl group. A good lower alkylthio group,
(Xiii) a benzyloxycarbonyl group, a 4-methoxybenzyloxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, a tert-butoxycarbonyl group,
An amino group which may be protected by a 2,2,2-trichloroethyloxycarbonyl group or a lower alkanoyl group, (xiv) a phenyl group-substituted lower alkyl group; a pyridyl group-substituted lower alkyl group; a lower alkyl group; A lower alkyl group; a hydroxyl-substituted lower alkyl group; a pyrimidinyl group-substituted lower alkyl group; a lower alkyl group substituted with a lower alkylamino group; a pyridyl group-substituted amino group; a halogeno lower alkyl group-substituted pyrimidinyl-substituted amino group; A carbonyl-substituted amino group; the same or different 1-2 groups selected from a benzyloxycarbonyl group, a 4-methoxybenzyloxycarbonyl group, a tert-butoxycarbonyl group or an amino group which may be substituted with a lower alkanoyl group;
(Xv) a lower alkyl group, or (xvi) a pyridine ring optionally substituted with a group selected from a tetrahydrofuranyl group-substituted oxy group, (2) an N-oxidepyridine ring, or (3) the pyridine ring moiety is substituted with a lower alkylenedioxyphenyl group; a benzimidazolyl group; a lower alkyl group-substituted imidazolyl group; a cyano group; a carboxyl group; a pyridyl group; an N-oxidepyridyl group; Pyridyl group; pyrrolidinyl group; isoquinolyl group; lower alkyl group-substituted pyrimidinyl group; pyrimidinyl group; pyrazinyl group; quinazolinyl group; phthalazinyl group; lower alkoxycarbonyl group-substituted piperidyl group; piperidyl group;
Quinolyl group; tetrazolyl group; thienyl group; furyl group;
A pyrrolyl group substituted by a lower alkyl group and a lower alkoxycarbonyl group; a mono- or di-lower alkylamino group; a lower alkoxy group-substituted lower alkoxy group; a lower alkoxy group; a hydroxyl group; a carbamoyl group; a lower alkoxycarbonyl group; A phenyl group substituted with a hydroxy lower alkyl group; a carboxy group-substituted phenyl group; a lower alkoxycarbonyl group-substituted phenyl group; a benzoyl group; a mono- or di-lower alkoxy-substituted phenyl group;
Naphthyl group; mono or dihalogenophenyl group; carbamoyl group-substituted phenyl group; sulfamoyl group-substituted phenyl group; benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, tert-butoxycarbonyl group, 2,
A phenyl group mono- or di-substituted by an amino group optionally protected by a 2,2-trichloroethyloxycarbonyl group or a lower alkanoyl group; a biphenylyl group; a phenyl group di-substituted by a halogen atom and a nitro group; 9. The compound according to claim 8, which is an oxo-substituted dihydropyridine ring which may be substituted with a lower alkyl group which may be substituted with a group selected from a lower alkylamino group-substituted phenyl group; and a lower alkyl group-substituted phenyl group. . 10. R ¹ is (i) a hydrogen atom, (ii) a piperidyl group; a pyridyl group; a lower alkyl-substituted pyridyl group; a lower alkoxy-substituted pyridyl group; a lower alkyl-substituted N-oxidepyridyl group; an imidazolyl group; Lower alkyl group-substituted piperidyl group; furyl group; morpholino group;
Tetrahydrofuryl group; dihydropyridyl group substituted by lower alkyl group and oxo group; piperazinyl group; lower alkoxycarbonyl group-substituted piperazinyl group; cyclo lower alkyl group; phenyl group; lower alkylenedioxyphenyl group; lower alkoxycarbonyl group; A hydroxyl-substituted lower alkoxy group, a carboxyl group, a lower alkoxy group, a benzyloxycarbonyl group, a 4-methoxybenzyloxycarbonyl group, a 9-fluorenylmethyloxycarbonyl group, a tert-butoxycarbonyl group,
An amino group optionally protected by a 2,2,2-trichloroethyloxycarbonyl group or a lower alkanoyl group; a carbamoyl group; a di-lower alkylamino group; A lower alkyl group which may be substituted with a group, (iii) a halogen atom, a mono- or di-lower alkylamino group, a morpholino group, a lower alkyl-substituted pyrimidinyl group, a lower alkyl-substituted pyrazolyl group, a hydroxyl-substituted lower alkyl group, and benzyloxy. Carbonyl group, 4
-Methoxybenzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, tert-butoxycarbonyl group, 2,2,2-trichloroethyloxycarbonyl group or an amino group which may be protected with a lower alkanoyl group; lower alkanoyl Group substituted amino group; lower alkoxy group; lower alkyl group; benzyl group, phenethyl group, formyl group, acetyl group, propionyl group, malonyl group, acryloyl group or hydroxyl group optionally protected by benzoyl group; carboxyl group-substituted lower alkyl A lower alkoxycarbonyl group-substituted lower alkyl group;
Lower alkoxycarbonyl group-substituted lower alkoxy group; carbamoyl group; carboxyl group; lower alkylthio group;
Lower alkoxycarbonyl group; nitro group; trihalogeno lower alkyl group; morpholinocarbonyl group; carboxyl group-substituted lower alkoxy group; di (lower alkylsulfonyl) amino group; morpholino lower alkylcarbamoyl group-substituted lower alkoxy group; sulfamoyl group; benzyloxycarbonyl group A 4-methoxybenzyloxycarbonyl group, a 9-fluorenylmethyloxycarbonyl group,
a lower alkyl group substituted with an amino group which may be protected with a tert-butoxycarbonyl group, a 2,2,2-trichloroethyloxycarbonyl group or a lower alkanoyl group; a benzyloxycarbonyl group, a 4-methoxybenzyloxycarbonyl group , 9-fluorenylmethyloxycarbonyl group, tert-butoxycarbonyl group, 2,2,2-trichloroethyloxycarbonyl group and a lower alkanoyl group, and a lower alkyl group. Amino group; lower alkylenedioxy group; benzyloxycarbonyl group;
Substitution with an amino group which may be protected with a 4-methoxybenzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, tert-butoxycarbonyl group, 2,2,2-trichloroethyloxycarbonyl group or lower alkanoyl group A carbamoyl group; a lower alkylsulfinyl group; and a phenyl group or a naphthyl group which may be substituted with the same or different 1 to 4 groups selected from lower alkylsulfonyl groups, (iv) a hydroxyl group, a halogen atom, and a lower alkyl. A phenyl group-substituted lower alkyl group; a hydroxyl-substituted lower alkyl group; an oxo group;
Lower alkoxy group; benzyloxycarbonyl group, 4-
An amino group which may be protected with a methoxybenzyloxycarbonyl group, a 9-fluorenylmethyloxycarbonyl group, a tert-butoxycarbonyl group, a 2,2,2-trichloroethyloxycarbonyl group or a lower alkanoyl group; A lower alkylamino group; a phenyl lower alkoxycarbonyl group; a lower alkoxycarbonyl group; a carboxyl group; and a 5- to 12-membered heteromonocyclic group which may be substituted with the same or different 1 to 4 groups selected from carbamoyl groups. Or a bicyclic group, or (v) a benzyloxycarbonyl group, a 4-methoxybenzyloxycarbonyl group, a 9-fluorenylmethyloxycarbonyl group, a tert-butoxycarbonyl group, a 2,2,2-trichloroethyloxycarbonyl group , Pyridyl group, lower An amino group which may be mono- or di-substituted by the same or different groups selected from a lucanoyl group, a lower alkyl group, a hydroxyl-substituted lower alkyl group, a phenyl group, a lower alkanoyloxy group-substituted lower alkyl group and a trihalogeno lower alkanoyl group. A compound according to claim 9. 11. The 5- to 12-membered heteromonocyclic or bicyclic group is a pyranyl group, an indazolyl group, a benzotriazolyl group, a pyrrolyl group, an imidazolyl group, a furyl group, a thienyl group, a thiazolyl group, an isoxazolyl group, Oxazolyl group, oxazolinyl group, pyrazolyl group, phthalazinyl group, quinazolinyl group, thienopyrimidinyl group, pyridyl group, pyrimidinyl group, pyridazinyl group, pyrazinyl group,
The compound according to claim 10, which is a triazinyl group, a tetrazolyl group, a quinolyl group, an isoquinolyl group, a quinoxalinyl group, an indolyl group, a benzothienyl group, a benzothiazolyl group, a benzoxazolyl group or a benzimidazolyl group. 12. R ² is a hydrogen atom; a benzyl group; nitrobenzyl group; an amino group moiety, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl group, a 9
An aminobenzyl group which may be protected by a fluorenylmethoxycarbonyl group, a tert-butoxycarbonyl group, a 2,2,2-trichloroethyloxycarbonyl group or a lower alkanoyl group; a lower alkoxybenzyl group; a lower alkyl group; Alkyl group; tri-lower alkylsilyl lower alkyl group; cyclo-lower alkyl group-substituted lower alkyl group; hydroxyl-substituted lower alkyl group;
12. The compound according to claim 11, which is a lower alkyl group substituted with a lower alkoxy group. 13. Ring A is of the formula: Wherein A ¹ is (1) a lower alkoxy group which may be substituted with a group selected from a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a lower alkyl group-substituted imidazolyl group, a lower alkoxy group and a hydroxyl group; 2) an amino group substituted with a pyridyl group-substituted lower alkyl group, ring B
Is a tri-lower alkoxy-substituted phenyl group, R ¹ is a lower alkyl-substituted pyridyl group or a lower alkyl-substituted N-
A lower alkyl group substituted with an oxidopyridyl group, R ²
3. The compound according to claim 1, wherein is a lower alkyl group. 14. A ¹ is a 2-pyridylmethoxy group, 2-
Pyrazinylmethoxy group, 2-pyrimidinylmethoxy group,
2- (2-pyridyl) ethoxy group, (1-methylimidazol-2-yl) methoxy group, methoxy group, 2-methoxyethoxy group, 2-hydroxyethoxy group, 3-hydroxypropoxy group or 2-pyridylmethylamino group , Ring B is a trimethoxyphenyl group, R ¹ is a (2-methylpyridin-4-yl) methyl group or (2-methyl-
The compound according to claim 13, which is an (N-oxidepyridin-4-yl) methyl group. 15. Ring A is of the formula: Wherein A ¹ is a pyridyl-substituted lower alkoxy group, a pyrimidinyl-substituted lower alkoxy group, (1-
Methylimidazol-2-yl) lower alkoxy group, lower alkoxy group-substituted lower alkoxy group, hydroxyl group-substituted lower alkoxy group, pyridyl group-substituted lower alkyl group-substituted amino group, ring B is a tri-lower alkoxy group-substituted phenyl group, R ¹ is a lower alkyl group substituted with a lower alkyl group substituted pyridyl compound of claim 13 wherein R ² is a lower alkyl group. 16. A ¹ is a pyrimidinyl-substituted lower alkoxy group, Ring B is a tri-lower alkoxy-substituted phenyl group,
The compound according to claim 15, wherein R ¹ is a lower alkyl group substituted with a lower alkyl group-substituted pyridyl group. 17. A mixture of 7,8-dihydro-7-[(2-methylpyridin-4-yl) methyl] -8-oxo-2-
(2-pyridylmethoxy) -5- (3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester 7,8-dihydro-7-[(2-methylpyridine-4-
Yl) methyl] -8-oxo-2- (2-pyrazinylmethoxy) -5- (3,4,5-trimethoxyphenyl)
-1,7-naphthyridine-6-carboxylic acid methyl ester 7,8-dihydro-7-[(2-methylpyridine-4-
Yl) methyl] -8-oxo-2- (2-pyrimidinylmethoxy) -5- (3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester 2-[(2- Methylpyridin-4-yl) methyl]-
1,2-dihydro-1-oxo-4- (3,4,5-trimethoxyphenyl) -2,7-naphthyridine-8-
[(Pyrimidin-2-yl) methoxy] -3-carboxylic acid methyl ester 2-[(2-methylpyridin-4-yl) methyl]-
1,2-dihydro-1-oxo-4- (3,4,5-trimethoxyphenyl) -2,7-naphthyridine-8-
[2- (pyridin-2-yl) ethoxy] -3-carboxylic acid methyl ester 2-[(2-methylpyridin-4-yl) methyl]-
1,2-dihydro-1-oxo-4- (3,4,5-trimethoxyphenyl) -2,7-naphthyridine-8-
[(Pyridin-2-yl) methoxy] -3-carboxylic acid methyl ester 2-[(2-methylpyridin-4-yl) methyl]-
1,2-dihydro-1-oxo-4- (3,4,5-trimethoxyphenyl) -2,7-naphthyridine-8-
[(Pyridin-2-yl) methylamino] -3-carboxylic acid methyl ester 7,8-dihydro-7-[(2-methyl-N-oxidepyridin-4-yl) methyl] -8-oxo-2- Methoxy-5- (3,4,5-trimethoxyphenyl)-
1,7-naphthyridine-6-carboxylic acid methyl ester 7,8-dihydro-7-[(2-methylpyridine-4-
Yl) methyl] -8-oxo-2- (3-hydroxypropyloxy) -5- (3,4,5-trimethoxyphenyl) -1,7-naphthyridine-6-carboxylic acid methyl ester 2-[(2 -Methylpyridin-4-yl) methyl]-
1,2-dihydro-1-oxo-4- (3,4,5-trimethoxyphenyl) -2,7-naphthyridine-8-
[(1-methylimidazol-2-yl) methoxy]-
3-carboxylic acid methyl ester 2-[(2-methylpyridin-4-yl) methyl]-
1,2-dihydro-1-oxo-4- (3,4,5-trimethoxyphenyl) -2,7-naphthyridine-8-
(2-Hydroxyethyloxy) -3-carboxylic acid methyl ester 2-[(2-methylpyridin-4-yl) methyl]-
1,2-dihydro-1-oxo-4- (3,4,5-trimethoxyphenyl) -2,7-naphthyridine-8-
(2-methoxyethyloxy) -3-carboxylic acid methyl ester 2-[(2-methylpyridin-4-yl) methyl]-
1,2-dihydro-1-oxo-4- (3,4,5-trimethoxyphenyl) -2,7-naphthyridine-8-
(3-hydroxypropyloxy) -3-carboxylic acid methyl ester 2-[(2-methylpyridin-4-yl) methyl]-
1,2-dihydro-1-oxo-4- (3,4,5-trimethoxyphenyl) -2,7-naphthyridine-8-
[(2-oxopyrrolidin-5-yl) methoxy] -3
-Carboxylic acid methyl ester 2-[(2-methylpyridin-4-yl) methyl]-
1,2-dihydro-1-oxo-4- (3,4,5-trimethoxyphenyl) -2,7-naphthyridine-8-
(2-morpholinoethyloxy) -3-carboxylic acid methyl ester (S) -2-[(2-methylpyridin-4-yl) methyl] -1,2-dihydro-1-oxo-4- (3,4 ,
5-trimethoxyphenyl) -2,7-naphthyridine-
8-[(pyrrolidin-2-yl) methoxy] -3-carboxylic acid methyl ester or a pharmaceutically acceptable salt thereof. 18. A compound of the general formula [II] (Wherein ring A is a substituted or unsubstituted pyridine ring or substituted or unsubstituted dihydropyridine ring, ring B is an optionally protected hydroxyl group, substituted or unsubstituted lower alkyl group, substituted or unsubstituted lower alkoxy group, and halogen atom A benzene ring having the same or different 2 to 4 substituents or a benzene ring having 1 to 2 lower alkylenedioxy groups, and R ² represents a hydrogen atom or an ester residue. Or a salt thereof, and a compound represented by the general formula [III]: (Wherein, R ¹ represents a hydrogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted amino group) or Reacting the salt with a salt thereof to convert the product into a pharmaceutically acceptable salt, if desired. Wherein the symbols have the same meanings as described above, or a method for producing a naphthyridine derivative or a pharmaceutically acceptable salt thereof. 19. A compound of the general formula [II] (Wherein ring A is a substituted or unsubstituted pyridine ring or substituted or unsubstituted dihydropyridine ring, ring B is an optionally protected hydroxyl group, substituted or unsubstituted lower alkyl group, substituted or unsubstituted lower alkoxy group, and halogen atom A benzene ring having the same or different 2 to 4 substituents or a benzene ring having 1 to 2 lower alkylenedioxy groups, and R ² represents a hydrogen atom or an ester residue. Alternatively, the salt thereof is subjected to hydrolysis to give a compound of the general formula [IV]: (Wherein the symbols have the same meanings as described above), and then the product [IV] and the general formula [I
II] (Wherein, R ¹ represents a hydrogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted amino group) or Reacting with a salt thereof to convert the product into a pharmaceutically acceptable salt, if desired. Wherein the symbols have the same meanings as described above, or a method for producing a naphthyridine derivative or a pharmaceutically acceptable salt thereof. 20. A compound of the formula [Ie] (Wherein ring A ₃ has the formula: An oxo group-substituted dihydropyridine ring represented by the formula: wherein ring B is the same or different 2-4 selected from an optionally protected hydroxyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkoxy group and a halogen atom
A benzene ring having one or two substituents or a benzene ring having one or two lower alkylenedioxy groups, R ¹ is a hydrogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted lower alkyl group, A cyclic group or a substituted or unsubstituted amino group, R ² represents a hydrogen atom or an ester residue; ) Or a salt thereof, and a compound represented by the general formula [V]: (Wherein, A ²¹ represents a substituted or unsubstituted lower alkyl group, and X represents a leaving group), and if desired, the product is converted into a pharmaceutically acceptable salt. The general formula [Ic] (Wherein ring A ₁ has the formula: And the other symbols have the same meanings as described above. )) Or a pharmacologically acceptable salt thereof. 21. A compound of the formula [Ie] (Wherein ring A ₃ has the formula: An oxo group-substituted dihydropyridine ring represented by the formula: wherein ring B is the same or different 2-4 selected from an optionally protected hydroxyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkoxy group and a halogen atom
A benzene ring having one or two substituents or a benzene ring having one or two lower alkylenedioxy groups, R ¹ is a hydrogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted lower alkyl group, A cyclic group or a substituted or unsubstituted amino group, R ² represents a hydrogen atom or an ester residue; ) Or a salt thereof, and a compound represented by the general formula [V]: (Wherein, A ²¹ represents a substituted or unsubstituted lower alkyl group, and X represents a leaving group), and if desired, the product is converted into a pharmaceutically acceptable salt. The general formula [Id] (Wherein ring A ₂ has the formula: And the other symbols have the same meanings as described above. )) Or a pharmacologically acceptable salt thereof. 22. A compound of the general formula [Ig] (Wherein ring A ₅ has the formula: Wherein A ¹² is a halogen atom, ring B is the same or different 2 selected from an optionally protected hydroxyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkoxy group and a halogen atom. ~ 4
A benzene ring having one or two substituents or a benzene ring having one or two lower alkylenedioxy groups, R ¹ is a hydrogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted lower alkyl group, A cyclic group or a substituted or unsubstituted amino group, R ² represents a hydrogen atom or an ester residue; ) Or a salt thereof, and a compound represented by the general formula [VI]: (Wherein A ¹¹ is a substituted or unsubstituted lower alkoxy group,
Represents a substituted or unsubstituted lower alkylthio group or a substituted or unsubstituted amino group. Wherein the product is converted into a pharmaceutically acceptable salt, if desired, by reacting the compound represented by the general formula [If]. (Wherein ring A ₄ has the formula: And the other symbols have the same meanings as described above. )) Or a pharmacologically acceptable salt thereof. 23. The general formula [vi] (Wherein ring A is a substituted or unsubstituted pyridine ring or substituted or unsubstituted dihydropyridine ring, ring B is an optionally protected hydroxyl group, substituted or unsubstituted lower alkyl group, substituted or unsubstituted lower alkoxy group, and halogen atom Or a benzene ring having from 2 to 4 identical or different substituents or a benzene ring having from 1 to 2 lower alkylenedioxy groups, and Z ¹ represents a carboxyl-protecting group. Its salt.