JPH07118266A - Quinoline or quinazolien derivative and medicine containing the same - Google Patents

Abstract

PURPOSE:To provide a new compound having an anti-inflammatory effect, an antipyretic and analgesic effect and an antiarthritic effect, reduced in toxicity and useful as an anti-inflammatory drug, especially a therapeutic agent for arthritis. CONSTITUTION:A compound is represented by formula I [Y is N or CG (G is carboxyl); Ring R is a nitrogen-containing unsaturated heterocycle; (n) is 1 to 4; (k) is 0 to 1] or its salt, e.g. 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(2- ethylimidazol-1-ylmethyl)quinoline-3-carboxylic acid ethyl ester. This compound is synthesized by reacting a compound of formula II (Q is an eliminable group) or its salt with a compound of formula III or its salt in the presence of a base such as sodium hydride in a solvent such as DMF preferably at -10 to 100 deg.C. In addition, the raw material compound of formula II is obtained, e.g. by reacting a 2-aminobenzophenone derivative of formula IV with a compound of the formula QCH2COCH2G' (G' is an esterified carboxyl) in the presence of an acid such as sulfuric acid.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel quinoline or quinazoline derivative or a salt thereof which is useful as an anti-inflammatory agent, particularly as an agent for treating arthritis.

[0002]

2. Description of the Related Art Arthritis is an inflammatory disease of the joint, and its main diseases include rheumatoid arthritis and related diseases in which inflammation is observed in the joint. In particular, rheumatoid arthritis, which is also called rheumatoid arthritis, is a chronic polyarthritis having inflammatory changes in the synovium of the joint capsule inner layer as a major lesion. Arthritis such as rheumatoid arthritis is progressive and causes joint disorders such as joint deformation and ankylosis.
If they get worse without effective treatment, they often lead to severe disability. Conventionally, in the treatment of these arthritis, steroids such as cortisone and other adrenocortical hormones as drug therapy; nonsteroidal anti-inflammatory agents such as aspirin, piroxicam and indomethacin; gold thiomalate and other gold agents, chloroquine preparations and Anti-rheumatic agents such as D-penicillamine; anti-gout agents such as colchicine;
Immunosuppressants such as cyclophosphamide, azathioprine, methotrexate and levamisole have been used.

[0003]

However, these drugs are not effective against severe or long-term side effects that make them difficult to use, their effects are insufficient, or arthritis that has already developed. There was a problem that it was not effective. Therefore, in the clinical field of arthritis, there is still a demand for a drug having low toxicity and excellent in prevention and treatment of arthritis.

[0004]

Various compounds have hitherto been synthesized as quinoline or quinazoline derivatives. Four
Examples of the compound having an aminomethyl group at the 2-position of -phenylquinoline or 4-phenylquinazoline skeleton include 2-dimethylaminomethyl compound and 2-morpholinomethyl compound described in Synthesis, Volume 9, page 718 (1979). , But also Chemical Abstract (Chemical Ab
stracts), Volume 112, 171720v (1990)
[Farmaco, Vol. 44, page 555 (198
9)]] and the like, 2-alkylaminomethylquinoline derivatives and the like are known. However, a compound in which 4-phenylquinoline or 4-phenylquinazoline skeleton 2-position is bonded to a nitrogen atom of a nitrogen-containing unsaturated heterocycle via an alkylene group is not disclosed. The present inventors have found that a compound in which the 2-position of 4-phenylquinoline or 4-phenylquinazoline skeleton is bonded to the nitrogen atom of a nitrogen-containing unsaturated heterocycle through an alkylene group has an anti-arthritic effect and a joint destruction inhibitor. The present invention was completed by finding out that it is useful as.

That is, the present invention provides (1) general formula (I)

[Chemical 6] [In the formula, Y represents a nitrogen atom or CG (G represents an optionally esterified carboxyl group), and ring R represents an optionally substituted nitrogen-containing unsaturated heterocyclic group, and A The ring and the B ring may each have a substituent. n represents an integer of 1 to 4, and k represents 0 or 1. ] The compound or its salt represented by these.

(2) General formula (II)

[Chemical 7] [In the formula, Y represents a nitrogen atom or C-G (G represents an optionally esterified carboxyl group), Q represents a leaving group, and A ring and B ring each have a substituent. May be. n represents an integer of 1 to 4, and k represents 0 or 1. ] The compound or its salt represented by these, and general formula (II
I)

[Chemical 8] [In the formula, ring R represents an optionally substituted nitrogen-containing unsaturated heterocyclic group. ] The compound represented by the following or its salt is made to react, General formula

[Chemical 9] [Wherein Y, ring R, A ring, B ring, and n and k have the same meanings as defined above], or a method for producing a salt thereof.

(3) General formula

[Chemical 10] [In the formula, Y represents a nitrogen atom or CG (G represents an optionally esterified carboxyl group), and ring R represents an optionally substituted nitrogen-containing unsaturated heterocyclic group, and A The ring and the B ring may each have a substituent. n represents an integer of 1 to 4, and k represents 0 or 1. ] It relates to an anti-inflammatory agent comprising a compound represented by the following or a salt thereof. A description of the above general formulas and definitions included in the scope of the present invention, and preferable examples thereof are described below.

In formulas (I) and (III), the optionally substituted nitrogen-containing unsaturated heterocyclic group represented by ring R is an unsaturated heterocyclic group containing one or more nitrogen atoms as ring-constituting atoms. A ring is included. Examples of such unsaturated heterocyclic groups include imidazol-1-yl and pyrazol-
1-yl, 1,2,4-triazol-1-yl, 1,
2,4-triazol-4-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, pyrrol-1-yl, tetrazole- 1-yl, 2
-Pyrrolin-1-yl, 3-pyrrolin-1-yl, 2-
Imidazolin-1-yl, 2-pyrazolin-1-yl,
A 5-membered nitrogen-containing unsaturated heterocyclic group such as 3-pyrazolin-1-yl is preferable, and these may form a condensed ring (eg, benzimidazol-1-yl, indole-1).
-Yl, 1H-indazol-1-yl, benztriazol-1-yl, benzotriazol-2-yl, isoindol-2-yl, 7-purinyl, 1H-pyrrolo [1,2-a] imidazole-1 -Yl, 1H-pyrrolo [1,2-b] [1,2,4] triazol-1-yl, 1,8a-dihydroimidazo [1,2-a] pyridin-1-yl, 1,8a-dihydro [1,2,4] triazolo [1,5-a] pyridin-1-yl, 3,3a-
Dihydro [1,2,4] triazolo [1,5-a] pyrimidin-3-yl, 1,8a-dihydroimidazo [1,
2-a] pyrimidin-1-yl, 1H-pyrazolo [4,4
3-d] oxazol-1-yl, 4H-imidazo [4,5-d] thiazol-4-yl etc.). In addition to these 5-membered nitrogen-containing unsaturated heterocyclic groups, 6-membered nitrogen-containing unsaturated heterocyclic groups such as 1,4-dihydropyridin-1-yl and 1,2-dihydropyridin-1-yl. Can also be mentioned. Furthermore, these unsaturated heterocyclic groups may have 1 to 3 substituents at any position on the ring. Examples of the substituent include an aliphatic chain hydrocarbon group, an alicyclic hydrocarbon group, an aryl group, an aromatic heterocyclic group, a non-aromatic heterocyclic group, a halogen atom, a nitro group, and optionally substituted amino. Group, optionally substituted acyl group, optionally substituted hydroxyl group, optionally substituted thio-
And a carboxyl group which may be esterified.

The aliphatic chain hydrocarbon group is a linear or branched aliphatic hydrocarbon group, for example, an alkyl group, preferably an alkyl group having 1 to 10 carbon atoms, an alkenyl group, preferably carbon. Examples include alkenyl groups and alkynyl groups having a number of 2 to 10. Preferable examples of the alkyl group include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
Pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-
Examples thereof include dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, hexyl, pentyl, octyl, nonyl and decyl. Suitable examples of the alkenyl group include vinyl, allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 3 -Methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-
Examples include hexenyl and 5-hexenyl. Suitable examples of the alkynyl group include, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-. Hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like can be mentioned. Examples of the alicyclic hydrocarbon group include a saturated or unsaturated alicyclic hydrocarbon group such as a cycloalkyl group, a cycloalkenyl group and a cycloalkadienyl group.

Preferable examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl,
Cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [ 4.2.1] nonyl, bicyclo [4.3.1] decyl and the like. Preferable examples of the cycloalkenyl group include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like. Preferred examples of the cycloalkadienyl group include:
For example, 2,4-cyclopentadiene-1-yl, 2,4-cyclohexadiene-1-yl, 2,5-cyclohexadiene-1-yl and the like can be mentioned. The aryl group means a monocyclic or condensed polycyclic aromatic hydrocarbon group, and suitable examples include:
Examples thereof include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like, among which phenyl, 1-naphthyl, 2-naphthyl and the like are preferable.

Preferred examples of the aromatic heterocyclic group include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl. , 1,3,4-oxadiazolyl, flazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,
Aromatic monocyclic heterocyclic groups such as 3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl; for example, benzofuranyl, isobenzofuran Nyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl , Quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-
Carbinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenatridinyl, phenatrolinyl, indolizinyl,
Pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a]
Pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4,3- b] Aromatic condensed heterocyclic groups such as pyridazinyl.

Preferable examples of the non-aromatic heterocyclic group include:
Examples thereof include oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like. Examples of the halogen atom include fluorine, chlorine, bromine and iodine, and fluorine and chlorine are particularly preferable. As the amino group, 1 or 2 alkyl groups having 1 to 10 carbon atoms, alkenyl having 1 to 10 carbon atoms, an aromatic group or an acyl group having 1 to 10 carbon atoms (-NH
₂ groups) (eg, methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino, N-methyl-N-phenylamino, acetylamino, propionylamino, benzoylamino) Etc.). The acyl is formyl or has 1 carbon atom.
-10 alkyl, alkenyl having 1 to 10 carbon atoms or a bond of an aromatic group and a carbonyl group (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanoyl, Cyclopentanoyl, cyclohexanoyl, cycloheptanoyl,
Crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl and the like).

Examples of the hydroxyl group include a hydroxyl group and a protected hydroxyl group such as alkoxy, alkenyloxy, aralkyloxy, acyloxy and the like, as well as aryloxy. As the alkoxy, an alkoxy having 1 to 10 carbon atoms (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy,
Hexyloxy, heptyloxy, nonyloxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy and the like) are preferred. As alkenyloxy, allyl
(allyl) oxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, 2-cyclohexenylmethoxy and the like having 1 to 1 carbon atoms
Examples of aralkyloxy having 0 are phenyl-C _1-4 alkyloxy (eg, benzyloxy, phenethyloxy, etc.). Examples of acyloxy include alkanoyloxy having 2 to 4 carbon atoms (eg, acetyloxy, propionyloxy, n-butyryloxy, i
So-butyryloxy and the like) are preferred. Examples of aryloxy include phenoxy and 4-chlorophenoxy.

The thiol group includes a thiol group and a protected thiol group such as alkylthio, aralkylthio, acylthio and the like. Examples of alkylthio include alkylthio having 1 to 10 carbon atoms (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, te.
rt-butylthio, pentylthio, isopentylthio,
Neopentylthio, hexylthio, heptylthio, nonylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, etc.) are preferred. Examples of aralkylthio include phenyl-C _1-4 alkylthio (eg, benzylthio, phenethylthio, etc.). Examples of acylthio include alkanoylthio having 2 to 4 carbon atoms (eg,
Acetylthio, propionylthio, n-butyrylthio,
iso-butyrylthio) is preferred. Examples of the carboxyl group include a carboxyl group, an alkyloxycarbonyl group, and an aralkyloxycarbonyl group. The alkyl group in the alkyloxycarbonyl group is an alkyl group having 1 to 6 carbon atoms, for example, methyl,
Examples thereof include ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like.

The aralkyl group in the aralkyloxycarbonyl group means an arylalkyl group. Examples of the aryl group include phenyl and naphthyl, which may have the same substituents as the aryl group in the ring R has. The alkyl group is preferably a lower alkyl group having 1 to 6 carbon atoms. Preferable examples of the aralkyl group include benzyl, phenethyl, 3-phenylpropyl, (1-naphthyl) methyl, (2-naphthyl) methyl and the like. Of these, benzyl, phenethyl and the like are preferable. The aliphatic chain hydrocarbon group, alicyclic hydrocarbon group, aryl group, heterocyclic group and the like each may have one or more, and preferably 1 to 3 appropriate substituents. Examples of the substituent include a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, an aryl group, an aromatic heterocyclic group, a non-aromatic heterocyclic group, an aralkyl group, an amino group and an N-monosubstituted amino group. , N, N-disubstituted amino group, amidino group, acyl group, carbamoyl group, N-monosubstituted carbamoyl group, N, N-disubstituted carbamoyl group, sulfamoyl group, N-monosubstituted sulfamoyl group, N, N-di Substituted sulfamoyl group, carboxyl group, lower alkoxycarbonyl group, hydroxyl group, lower alkoxy group, lower alkenyloxy group, cycloalkyloxy group, aralkyloxy group, ari Aryloxy group, a mercapto group, a lower alkylthio group, aralkylthio group, an arylthio group, a sulfo group, a cyano group, azido group, nitro group, nitroso group and halogen.

In the general formulas (I) and (II), Y is C-
When the quinoline derivative represented by G, the optionally esterified carboxyl group represented by G is:
Examples thereof include a carboxyl group, an alkyloxycarbonyl group and an aralkyloxycarbonyl group. The alkyl group in the alkyloxycarbonyl group has 1 carbon atom.
~ 6 alkyl groups, such as methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl, tert
-Butyl and the like can be mentioned. The aralkyl group in the aralkyloxycarbonyl group means an arylalkyl group. Examples of the aryl group include phenyl,
Examples thereof include naphthyl, which may have the same substituents as the aryl group in the ring R has. The alkyl group is preferably a lower alkyl group having 1 to 6 carbon atoms. Preferable examples of the aralkyl group include:
For example, benzyl, phenethyl, 3-phenylpropyl, (1-naphthyl) methyl, (2-naphthyl) methyl and the like can be mentioned, with preference given to benzyl and phenethyl. In the general formula (II), the leaving group represented by Q is, for example, a halogen atom, preferably chlorine, bromine or iodine, or an esterified hydroxyl group, for example, a residue of an organic sulfonic acid (eg, p-toluene). (A sulfonyloxy group, a methanesulfonyloxy group, etc.) and a residue of an organic phosphoric acid such as a diphenylphosphoryloxy group, a dibenzylphosphoryloxy group, and a dimethylphosphoryloxy group.

In formulas (I) and (II), ring A and ring B may have a substituent, and such a substituent may be, for example, a halogen atom, a nitro group, or a substituent. Alkyl group, optionally substituted hydroxyl group, optionally substituted thiol group, optionally substituted amino group, optionally substituted acyl group, optionally esterified carboxyl group Alternatively, an optionally substituted aromatic ring group is used. Examples of the halogen atom as such a substituent include fluorine, chlorine, bromine and iodine, with fluorine and chlorine being particularly preferable. The alkyl group which may be substituted may be linear, branched or cyclic having 1 to 10 carbon atoms, for example, methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Examples of the optionally substituted hydroxyl group include a hydroxyl group and a protected hydroxyl group such as alkoxy, alkenyloxy, aralkyloxy, acyloxy and the like, and aryloxy as well. The alkoxy has 1 to 10 carbon atoms (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy, nonyloxy, Cyclobutoxy, cyclopentoxy, cyclohexyloxy, etc.) are preferred. The alkenyloxy includes allyl
l) oxy, crotyloxy, 2-pentenyloxy, 3
-Hexenyloxy, 2-cyclopentenylmethoxy,
The aralkyloxy having 1 to 10 carbon atoms such as 2-cyclohexenylmethoxy is, for example, phenyl-
Examples thereof include C _1-4 alkyloxy (eg, benzyloxy, phenethyloxy, etc.). Examples of the acyloxy include alkanoyloxy having 2 to 4 carbon atoms (eg, acetyloxy, propionyloxy, n-butyryloxy, i
So-butyryloxy and the like) are preferred. Examples of the aryloxy include phenoxy and 4-chlorophenoxy. The optionally substituted thiol group includes a thiol group and a protected thiol group, for example, alkylthio, aralkylthio, acylthio and the like. Examples of the alkylthio include alkylthio having 1 to 10 carbon atoms (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio,
sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, nonylthio, cyclobutylthio,
Cyclopentylthio, cyclohexylthio, etc.) are preferred. Examples of the aralkylthio include phenyl-C
_1-4 alkylthio (eg, benzylthio, phenethylthio, etc.) can be mentioned. The acylthio has 2 carbon atoms.
Alkanoylthio of 4 to 4 (eg, acetylthio, propionylthio, n-butyrylthio, iso-butyrylthio, etc.) are preferable. The optionally substituted amino group is an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 1 to 10 carbon atoms or an aromatic group or 2 amino groups (-NH
₂ groups) (eg, methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino, N-methyl-N-phenylamino, etc.).

As the acyl which may be substituted, formyl or alkyl having 1 to 10 carbons, 1 to 1 carbons
A bond of an alkenyl or aromatic group of 0 and a carbonyl group (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanoyl, cyclopentanoyl, cyclohexanoyl, cyclo Heptanoyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl and the like).
As the carboxyl group which may be esterified,
Examples thereof include a carboxyl group, an alkyloxycarbonyl group, and an aralkyloxycarbonyl group. The alkyl group in the alkyloxycarbonyl group is an alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl and the like can be mentioned. The aralkyl group in the aralkyloxycarbonyl group means an arylalkyl group. Examples of the aryl group include phenyl and naphthyl, which may have the same substituents as the aryl group in the ring R has. The alkyl group is preferably a lower alkyl group having 1 to 6 carbon atoms. Preferable examples of the aralkyl group include benzyl, phenethyl, 3-phenylpropyl, (1-naphthyl) methyl, (2-naphthyl) methyl and the like. Of these, benzyl, phenethyl and the like are preferable. The aromatic ring group which may be substituted, phenyl, naphthyl, in addition to anthryl _{C. 6 to 14} aromatic hydrocarbon residues pyridyl, furyl, thienyl,
Examples thereof include heteroaromatic residues such as imidazolyl and thiazolyl.

The substituents on the A ring and the B ring may be substituted at any position of the respective rings, and may be the same or different and 1 to 4 substituents.
When substituents on ring A or ring B are adjacent to each other, linked substituents _{adjacent, - (CH 2) m -} (. M represents an integer from 3 5) or -O- (CH _{2) l} -O
A ring represented by-(l represents an integer of 1 to 3) may be formed, and the ring includes a 5- to 7-membered ring formed together with the carbon atom of the benzene ring. The salt of the object compound (I) of the present invention is preferably a pharmaceutically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a basic or Examples thereof include salts with acidic amino acids. Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt and ammonium salt. Preferable examples of the salt with an organic base include:
For example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine,
Examples thereof include salts with N, N′-dibenzylethylenediamine and the like. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid,
Tartaric acid, maleic acid, citric acid, succinic acid, malic acid,
Examples thereof include salts with methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. Suitable examples of salts with basic amino acids include, for example, salts with arginine, lysine, ornithine, and suitable examples of salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid, etc. To be Object compound (I) of the present invention
Is a solid formulation such as a tablet, capsule, granule, powder, or the like, which is blended with a pharmaceutically acceptable carrier; or a syrup,
It can be orally or parenterally administered to mammals including human as a liquid preparation such as an injection.

As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances conventionally used as formulation materials are used. Excipients, lubricants, binders, disintegrants in solid formulations; solvents in liquid formulations, It is added as a solubilizing agent, suspending agent, isotonicity agent, buffer, soothing agent and the like. If necessary, formulation additives such as antiseptics, antioxidants, coloring agents and sweeteners can also be used. Preferable examples of excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like. Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include crystalline cellulose, sucrose, D-mannitol,
Examples thereof include dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and the like. Preferable examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium and the like. Preferable examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Preferable examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Preferable examples of the suspending agent include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; and polyvinyl alcohol. , Polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose,
Hydrophilic polymers such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like can be mentioned. Preferable examples of the isotonicity agent include sodium chloride, glycerin, D-mannitol and the like. Preferable examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like. Preferable examples of soothing agents include benzyl alcohol and the like. Preferable examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the antioxidant include sulfite, ascorbic acid and the like.

The above compound (I) can be produced, for example, as follows. That is, method A

[Chemical 11] [In the formula, each symbol has the same meaning as described above. In this method, (II) is reacted with (III) in the presence of a base to give (I)
To manufacture. The reaction of (II) and (III) is performed in a suitable solvent. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran and dimethoxyethane,
Alcohols such as methanol, ethanol and propanol
, Ethyl acetate, acetonitrile, pyridine, N, N
-Dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, 1,2-dichloroethane,
1,1,2,2-tetrachloroethane, acetone, 2-
Butanone and a mixed solvent thereof may be mentioned. (II)
The reaction of (III) with (III) is an alkali metal salt such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, amines such as pyridine, triethylamine, N, N-dimethylaniline, sodium hydride, hydrogen. It is carried out in the presence of an appropriate base such as potassium iodide, and the amount of these bases used is 1 with respect to compound (II).
It is preferably about 5 to 5 mol. This reaction is usually at -20 ° C to 1
It is carried out at 50 ° C, preferably about -10 ° C to 100 ° C. The quinoline or quinazoline derivative (I) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

The starting compound (II) of the present invention can be produced, for example, by the following method. Method B

[Chemical 12] [In the formula, G ′ represents an esterified carboxyl group, and other symbols have the same meanings as described above. Examples of the esterified carboxyl group represented by G ′ include the same as those listed as the esterified carboxyl group represented by G. In this method, the 2-aminobenzophenone derivative (IV) is reacted with (V) in the presence of an acid (II
-1) is manufactured. The reaction of (IV) and (V) is carried out in a suitable solvent. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran and dimethoxyethane, N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, Examples include 1,1,2,2-tetrachloroethane and acetic acid. The reaction of (IV) and (V) is carried out in the presence of a Lewis acid such as aluminum chloride and zinc chloride, and an appropriate acid such as sulfuric acid and trifluoroacetic acid. The amount is preferably about 0.01 to 2.0 molar equivalents, more preferably about 0.05 to 0.5 molar equivalents. This reaction is generally carried out at 20 ° C to 200 ° C, preferably about 30 ° C to 150 ° C. Reaction time is 0.5 ~
20 hours, preferably 1 to 10 hours. The compound (II-1) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

Method C

[Chemical 13] [In the formula, each symbol has the same meaning as described above. ] In this method, 2
-Aminobenzophenone derivative (IV) is reacted with acetoacetic acid ester derivative (VI) in the presence of an acid to produce (VII), which is brominated to produce 2-bromomethylquinoline derivative (II-2). The reaction of (IV) and (VI) is carried out in the same manner as in Method B. Bromination of (VII) is carried out in an appropriate solvent according to a conventional method. Examples of the solvent include carbon tetrachloride, chloroform, dichloromethane,
Examples include halogenated hydrocarbons such as 1,2-dichloroethane and 1,1,2,2-tetrachloroethane. (VI
The bromination reaction of I) is performed by benzoyl peroxide, 2,2′-
It is carried out in the presence of a radical reaction initiator such as azobis (isobutyronitrile), and the amount of these radical reaction initiators used is preferably about 0.001 to 0.01 molar equivalents relative to compound (VII). This reaction is generally carried out at 20 ° C to 150 ° C, preferably about 30 ° C to 100 ° C. The reaction time is 0.5 to 20 hours, preferably 1 to 10 hours. The compound (II-2) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

Method D

[Chemical 14] [In the formula, Q ′ represents a halogen atom, and other symbols have the same meanings as described above. ] Formula (VIII) and (II-3)
Examples of the halogen atom represented by Q ′ include chlorine, bromine and iodine. In this method, a 2-aminobenzophenone derivative (IV) is reacted with a halogenoacetonitrile derivative (VIII) to produce a 2-halogenomethylquinazoline derivative (II-3). (IV) and (VI
The reaction of II) uses an excess of (VIII) as a solvent,
It is carried out in the presence of acid. As the acid, those mentioned in Method B are used. The amount of these acids used is about 1 to 5 molar equivalents, preferably 1 to 2 molar equivalents, relative to compound (IV). This reaction is generally 0.5 to 30 hours, preferably 1 to 1
It's 0 hours. The reaction temperature is generally 20 ° C to 200 ° C, preferably 30 ° C to 150 ° C. The quinazoline derivative (II-3) thus obtained can be isolated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization,
It can be isolated and purified by phase transfer, chromatography and the like. E method

[Chemical 15] [In the formula, each symbol has the same meaning as described above. ] In this method,
2-Aminobenzophenone derivative (IV) is reacted with acetonitrile to give 2-methylquinazoline derivative (IX)
And then (IX) is subjected to a bromination reaction to produce a 2-bromomethylquinazoline derivative (II-4).
The reaction of (IV) with acetonitrile is performed in the same manner as in the method D. The bromination of (IX) is carried out in the same manner as the bromination of (VII) in Method C. The quinazoline derivative (II-4) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

Method F

[Chemical 16] [In the formula, each symbol has the same meaning as described above. ] In this method,
The 2-aminobenzophenone derivative (IV) is reacted with the cyanoacetic acid ester derivative (X) to produce a quinazoline derivative (XI). The reaction of (IV) and (X) is carried out in the same manner as in Method D. The quinazoline derivative (XI) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

Method G

[Chemical 17] [In the formula, each symbol has the same meaning as described above. ] In this method,
The quinoline derivative (XIII) is produced by reacting the 2-aminobenzophenone derivative (IV) with the acetone dicarboxylic acid ester derivative (XII). (IV) and (XI
The reaction I) is carried out in the same manner as in the method B. The quinoline derivative (XIII) thus obtained is separated by known means of separation and purification, such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization,
It can be isolated and purified by phase transfer, chromatography and the like.

Method H

[Chemical 18] [In the formula, Y'is a nitrogen atom or CG ', and other symbols have the same meanings as described above. In this method, the alcohol compound (XIV) is produced by subjecting the compounds (XI) and (XIII) obtained by Method F and Method G to a reduction reaction. This reduction reaction can be carried out by a method known per se. For example, reduction with a metal hydride, reduction with a metal-hydrogen complex compound, reduction with diborane and substituted borane, catalytic hydrogenation and the like are used. That is, this reaction is
It is carried out by treating I) and (XIII) with a reducing agent. As the reducing agent, an alkali metal borohydride (eg, sodium borohydride, lithium borohydride, etc.), a metal hydride complex compound such as lithium aluminum hydride, a metal hydride such as sodium hydride, an organic tin compound (hydrogen Triphenyl tin, etc.), nickel compounds,
Examples thereof include metals and metal salts such as zinc compounds, catalytic reducing agents using transition metal catalysts such as palladium, platinum and rhodium and hydrogen, and diborane. This reaction is
It is carried out in an organic solvent that does not affect the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane. , Ethers such as diethyl ether, tetrahydrofuran, dioxane, etc., alcohols such as methanol, ethanol, propanol, isopropanol, 2-methoxyethanol, etc.,
Amides such as N, N-dimethylformamide or a mixed solvent thereof are appropriately selected and used according to the type of the reducing agent. The reaction temperature is -20 ° C to 150 ° C, especially 0
C. to 100.degree. C. is suitable, and the reaction time is about 1 to 24 hours.

Method I

[Chemical 19] [In the formula, each symbol has the same meaning as described above. In this method, compound (XIV) is reacted with a halogenating agent or a sulfonylating agent to produce (II-5). As such a halogenating agent, thionyl chloride, phosphorus tribromide and the like are preferably used, in which case Q is represented by chlorine or bromine (II
-5) is generated. This reaction is carried out at -10 to 80 ° C in a suitable inert solvent (eg, benzene, toluene, xylene, chloroform, dichloromethane, etc.) or using an excess halogenating agent as a solvent. The amount of the halogenating agent used is 1 to 20 mol based on (XIV). As the sulfonylating agent, mesyl chloride, tosyl chloride, benzenesulfonyl chloride and the like are preferably used, and (II-5) in which Q is respectively mesyloxy, tosyloxy and benzenesulfonyloxy is produced. This reaction is carried out in a suitable inert solvent (eg, benzene, toluene, xylene, ethyl ether, ethyl acetate, tetrahydrofuran, chloroform, dichloromethane, etc.) with a base (eg, triethylamine, N-methylmorpholine, sodium hydrogen carbonate, hydrogen carbonate). Potassium, sodium carbonate, potassium carbonate, etc.) at -10 to 30 ° C. The amount of the sulfonylating agent and the amount of the base used are each 1 to 1.2 mol with respect to 1 mol of (XIV). When 1 mol of the compound (II-5) in which Q generated as described above is chlorine, bromine or sulfonyloxy is reacted with 1 to 1.5 mol of sodium iodide or potassium iodide, Q is iodine ( II-5) can also be produced. In this case, the reaction can be carried out at a temperature of 20 to 80 ° C. in a solvent such as acetone, methyl ethyl ketone, methanol or ethanol.

Method J

[Chemical 20] [In the formula, each symbol has the same meaning as described above. ] In this method,
Compounds prepared by Method B, Method C, Method D, Method E, Method I (II
-1), (II-2), (II-3), (II-4) and (II-5) are oxidized to produce compound (II-6). This oxidation reaction is carried out according to a conventional method by using an oxidizing agent such as m-chloroperbenzoic acid, hydrogen peroxide, and peresters.
ters), sodium metaperiodate and the like. This oxidation is an organic solvent which is inert under the reaction conditions,
For example, halogenated hydrocarbons (eg methylene chloride,
Chloroform, dichloroethane, etc.) or hydrocarbons (eg, benzene, toluene etc.) and alcohols (methanol, ethanol, propanol etc.) are advantageously used. The oxidants are compounds (II-1), (II-2), (I
1 for I-3), (II-4) or (II-5)
~ 5 molar equivalents, preferably 1 to 3 molar equivalents. The reaction temperature is -10 ° C to 150 ° C, preferably about 0 ° C.
It is usually performed at a temperature of -100 ° C for 0.5-10 hours. The quinoline 1-oxide or quinazoline 1-oxide derivative (II-6) thus obtained is isolated by a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. It can be purified separately.

Compound (I) can be prepared by the following K method, L method and M method.
It can also be manufactured by the method. K method

[Chemical 21] [In the formula, each symbol has the same meaning as described above. ] In this method,
First, compound (I-1) is produced by reacting compound (IV) with compound (XV). Compound (IV) and compound (X
The reaction V) is carried out in the same manner as in the method B. Then, the compound (I-2) is subjected to an oxidation reaction to produce the compound (I-2). This oxidation reaction is performed in the same manner as the J method. L method

[Chemical formula 22] [In the formula, each symbol has the same meaning as described above. ] In this method,
Compounds (I-1) and (I-2) are subjected to a hydrolysis reaction to produce a carboxylic acid derivative (I-3). This hydrolysis reaction is carried out in water or a water-containing solvent according to a conventional method.
As the water-containing solvent, a mixture of water and alcohol (eg, methanol, ethanol), ether (eg, tetrahydrofuran, dioxane), N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, or acetone can be used. The reaction may be a base such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, or lithium, or hydrochloric acid, for example.
Performed in the presence of an acid such as sulfuric acid, acetic acid or hydrobromic acid. Preferably, the acid or the base is converted to the compound (I-1).
Alternatively, an excess amount (base: 1.2 to 6 equivalents) and an acid (2 to 50 equivalents) are used with respect to (1-2). This reaction is usually
It is carried out at 20 ° C to 150 ° C, preferably -10 ° C to 100 ° C.

Method M In this method, when ring A or ring B of compound (I) contains an isopropoxy group as a substituent, it is treated with titanium tetrachloride, titanium trichloride, boron trichloride, silicon tetrachloride or the like. To convert the isopropoxy group to a hydroxyl group,
A compound (I-4) in which ring B has a phenolic hydroxyl group as a substituent is produced. This reaction is carried out in an appropriate solvent, and as the solvent, carbon tetrachloride, dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-
Tetrachloroethane, acetonitrile, or a mixed solvent thereof may be used. The amount of titanium tetrachloride, boron trichloride, silicon tetrachloride or the like used is 1 to 10 molar equivalents, preferably 1 to 6 molar equivalents per one isopropoxy group,
-50 ° C to 100 ° C, preferably -20 ° C to 80 ° C.

[0032]

EFFECT OF THE INVENTION Compound (I) provided by the present invention
Alternatively, the salts thereof have anti-inflammatory and antipyretic analgesic effects, and further, an excellent anti-arthritic effect was confirmed in an experimental model of adjuvant arthritis that develops arthritis similar to human rheumatoid arthritis. In addition, the toxicity of the compound of the present invention is low, and for example, the compounds synthesized in Examples 2 and 16 are 10
Oral administration to mice at 00 mg / kg, Example 16
No compound died even when the compound synthesized in 1. was orally administered to rats at 2000 mg / kg. Therefore, the compound of interest of the present invention can be applied to all arthritis in which joints exhibit inflammatory symptoms. The dose of the compound (I) used in the present invention can be variously selected depending on the administration route and the symptom of the patient to be treated.
g-1000 mg, 1 mg-100 for parenteral administration
It can be selected from the range of mg, and these can be administered in 1 to 3 times per day. Next, a test method for supporting the pharmacological action of the compound (I) of the present invention or a salt thereof and the result thereof will be shown.

Test Example 1 Action on Rat Adjuvant Arthritis Freund's complete adjuvant (0.5% liquid paraffin suspension of killed Mycobacterium tuberculosis) 0.05 It was sensitized by injecting ml. The test drug (12.5 mg / kg) was suspended in 5% gum arabic and orally administered once a day for 14 days immediately before sensitization (day 0). Immediately before sensitization (Day 0) and on Day 14 (Day 14), the volume and weight of the left hind limb were measured to determine the rate of footpad swelling inhibition (%) and the rate of body weight increase (%) in non-sensitized rats. Results are expressed as the mean ± SE of each group (N = 6) Dunnett '
It was compared and tested with s test. A risk rate of less than 5% was considered significant. As shown in [Table 1], the compound of the present invention was effective in suppressing the edema of the foot pads and improving the general symptoms observed in weight gain.

[Table 1]

Reference Example 1 A mixture of 2-amino-3 ', 4'-dimethoxy-4,5-ethylenedioxybenzophenone (6.5 g), ethyl 4-chloroacetoacetate (3.7 g) and acetic acid (60 ml) was added. Concentrated sulfuric acid (0.3 ml) was added, and the mixture was stirred at 100 ° C for 3 hr. The reaction mixture was concentrated under reduced pressure, the residue was poured into water, made alkaline with 2N NaOH, and extracted with chloroform. The chloroform layer was washed with water, dried (MgSO ₄₎
After that, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. From the part eluted with chloroform-ethyl acetate (7: 3, v / v), 2-chloromethyl-4- (3,4-dimethoxyphenyl) -6,7-ethylenedioxyquinoline-3-carboxylic acid ethyl ester ( 5.5 g, 60%) was obtained. Recrystallized from acetone. Colorless prism crystals. Melting point 197-198 [deg.] C. Elemental analysis Calculated as C ₂₃ H ₂₂ NO ₆ Cl: C, 62.24; H, 5.00; N, 3.16 Analytical value: C, 61.95; H, 5.15; N, 3.01 Reference Example 2 to Reference Example 12 Same as Reference Example 1 Then, the compounds shown in Tables 2 to 3 were obtained. Reference Example 13 Concentrated sulfuric acid was added to a mixture of 2-amino-4,5,3 ', 4'-tetramethoxybenzophenone, ethyl acetoacetate and acetic acid, and treated in the same manner as in Reference Example 1 to give 6,7-dimethoxy-4. -(3,4-Dimethoxyphenyl) -2-methylquinoline-3-carboxylic acid ethyl ester (83%)
Got Recrystallized from ethanol. Colorless prism crystals.
Melting point 147-148 [deg.] C.

Reference Example 14 Concentrated sulfuric acid was added to a mixture of 2-amino-4,5,3 ', 4'-tetramethoxybenzophenone, propyl acetoacetate and acetic acid, and the same treatment as in Reference Example 1 was carried out to give 6,7-. Dimethoxy-4- (3,4-dimethoxyphenyl) -2-methylquinoline-3-carboxylic acid propyl ester (79
%) Was obtained. Recrystallized from ethyl acetate-isopropyl ether. Colorless prism crystals. Melting point 153-155 [deg.] C. Reference Example 15 Concentrated sulfuric acid was added to a mixture of 2-amino-4,5,3 ', 4'-tetramethoxybenzophenone, butyl acetoacetate and acetic acid, and treated in the same manner as in Reference Example 1 to give 6,7-dimethoxy-4. -(3,4-Dimethoxyphenyl) -2-methylquinoline-3-carboxylic acid butyl ester (53%)
Got Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 119-120 [deg.] C. Reference Example 16 6,7-Dimethoxy-4- (3,4-dimethoxyphenyl) -2-methylquinoline-3-carboxylic acid ethyl ester (411 mg), N-bromosuccinimide (214
mg), 2,2'-azobis (isobutyronitrile)
A mixture of (10 mg) and carbon tetrachloride (10 ml) was stirred under reflux for 5 hours. The reaction mixture was washed with water and dried (M
After gSO ₄ ) the solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography. 2-Bromomethyl-6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester (285 mg, 58) from the portion eluted with chloroform-ethyl acetate (10: 1, v / v). %) Was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 135-1
36 ° C. Elemental analysis Calculated as C ₂₃ H ₂₄ NO ₆ Br: C, 56.34; H, 4.93; N, 2.86 Analytical value: C, 55.98; H, 5.23; N, 2.62

Reference Example 17 In the same manner as in Reference Example 16, 2-bromomethyl-6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylic acid propyl ester (48%) was obtained. Recrystallized from ethyl acetate-isopropyl ether. Colorless prism crystals. Melting point 144-145 [deg.] C. Elemental analysis Calculated as C ₂₄ H ₂₆ NO ₆ Br: C, 57.15; H, 5.20; N, 2.78 Analytical value: C, 56.75; H, 5.30; N, 2.68 Reference Example 18 Same as Reference Example 16 Bromomethyl-6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylic acid butyl ester (56%) was obtained.
Recrystallized from ethyl acetate-ether. Colorless prism crystals. Melting point 160-161 [deg.] C. Elemental analysis Calculated as C ₂₅ H ₂₈ NO ₆ Br: C, 57.92; H, 5.44; N, 2.70 Analytical value: C, 57.96; H, 5.53; N, 2.50 Reference Example 19 2-Chloromethyl-6,7- Dimethoxy-4- (3,4
-Dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester (3.0 g), metachloroperbenzoic acid (85
%, 2.3 g) and methanol (40 ml) were stirred under reflux for 2 hours. The solvent was distilled off from the reaction mixture under reduced pressure, and the residue was poured into chloroform. The chloroform layer was washed with water and dried (MgSO ₄ ) and then the solvent was distilled off under reduced pressure.
The residue was subjected to silica gel column chromatography. From the portion eluted with chloroform-ethyl acetate (6: 4, v / v), 2-chloromethyl-6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3-
Carboxylic acid ethyl ester 1-oxide (2.0 g, 6
5%) was obtained. Recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 193-194 [deg.] C. Elemental analysis C ₂₃ H ₂₄ NO ₇ Calculated Cl: C, 59.81; H, 5.24; N, 3.03 Analytical values: C, 59.69; H, 5.32 ; N, 3.05

Reference Example 20 A mixture of 2-amino-4,5,3 ', 4'-tetramethoxybenzophenone (8.0 g) and chloroacetonitrile (25 ml) was added to powdered aluminum chloride (6.7 g).
g) was added and the mixture was stirred at 100 ° C. for 2 hours. The reaction mixture was poured into water and extracted with chloroform. The chloroform layer was washed with water, dried was distilled off (MgSO ₄₎ the solvent, the residue was silica gel column chromatography - was subjected to. From the portion eluted with chloroform-ethyl acetate (10: 1, v / v), 2-chloromethyl-6,7-dimethoxy-4-
(3,4-dimethoxyphenyl) quinazoline (4.9
g, 52%). Recrystallized from acetone. Colorless prism crystals. Melting point 183-184 [deg.] C. Reference Example 21 2-amino-4,5,3 ′, 4′-tetramethoxybenzophenone (50.0 g), acetonedicarboxylic acid diethyl ester (35.0 g) and acetic acid (400 ml)
Concentrated sulfuric acid (1.5 ml) was added to the mixture of 1., and the mixture was added at 100 ° C. for 2.
Stir for 5 hours. The reaction mixture was concentrated under reduced pressure, the residue was poured into water, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. Wash the chloroform layer with water,
After drying (MgSO ₄ ), the solvent was distilled off under reduced pressure, the residual crystals were recrystallized from acetone, and 6,7-dimethoxy-4- (3,4
-Dimethoxyphenyl) -3-ethoxycarbonylquinoline-2-acetic acid ethyl ester (1.41 g, 64%)
Got Colorless prism crystals. Melting point 146-147 [deg.] C.

Reference Example 22 A mixture of 2-amino-4,5,3'4'-tetramethoxybenzophenone (6.3 g) and methyl cyanoacetic acid (23 ml) was mixed with powdered aluminum chloride (5.3 g).
g) was added and the mixture was stirred at 100 ° C. for 2.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried was distilled off (MgSO ₄₎ the solvent, the residue was silica gel column chromatography - was subjected to. From the portion eluted with hexane-ethyl acetate (4: 1, v / v), 6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinazoline-2-acetic acid methyl ester (4.4
g, 55%). Recrystallized from isopropyl ether. Colorless needles. Melting point 152-153 [deg.] C.

Reference Example 23 After stirring a mixture of sodium iodide (1.68 g) and 2-butanone (15 ml) at 80 ° C. for 1 hour,
2-chloromethyl-6,7-dimethoxy-4- (3,4
-Dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester (2.68 g) was added, and the mixture was stirred at 80 ° C for 12 hr. The reaction mixture was concentrated under reduced pressure, the residue was poured into water and extracted with ethyl acetate. Wash the ethyl acetate layer with water,
After drying (MgSO ₄ ), the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. From the part eluted with chloroform-ethyl acetate (1: 1, v / v), 6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2-iodomethylquinoline-3-carboxylic acid ethyl ester (1. 4 g, 58%) was obtained. Ethyl acetate-
Recrystallized from hexane. Colorless prism crystals. Melting point 170
~ 171 ° C. Reference Example 24 6,7-Dimethoxy-4- (3,4-dimethoxyphenyl) -3-ethoxycarbonylquinoline-2-acetic acid ethyl ester (5.8 g) in tetrahydrofuran (100
ml) solution to lithium aluminum hydride (0.45
5g) in a tetrahydrofuran (50ml) suspension at 0 ° C
It was dripped at. After stirring the reaction mixture at 0 ° C. for 1 hour,
Water (2.5 ml) was added dropwise, and the mixture was further stirred for 30 minutes.
The insoluble solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with chloroform-ethyl acetate (1: 1, v / v) to obtain 6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2- (2). -Hydroxyethyl) quinoline-3
-Carboxylic acid ethyl ester (1.75 g, 33%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 150-151 [deg.] C.

Reference Example 25 Phosphorus tribromide (PBr ₃ ) (1.0 g) was added to 2- (2-hydroxyethyl) -6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3- A solution of carboxylic acid ethyl ester (1.7 g) in benzene (50 ml) was added dropwise at room temperature. The mixture was stirred at 80 ° C for 1 hr, poured into ice water, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The chloroform layer is washed with water and dried (MgS
After O ₄ ), the solvent was distilled off, and the residue was subjected to silica gel column chromatography and eluted with chloroform-ethyl acetate (1: 1, v / v) from 2- (2-bromoethyl) -6,7. -Dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester (0.49 g, 26%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 132-1
33 ° C. Reference Examples 26 to 32 In the same manner as in Reference Example 1, the compounds in [Table 4] were obtained.

Reference Example 33 4-Bromobutyric acid benzyl ester (23.7 g), imidazole (8.1 g), potassium carbonate (14.0 g) and acetone (400 ml) were stirred under reflux for 6 hours. After cooling to room temperature, the insoluble solid was filtered off and the filtrate was concentrated. The residual oily substance was subjected to silica gel column chromatography, and ethyl acetate-methanol (20: 1,
From the fraction eluted with v / v), 4- (1-imidazolyl) butyric acid benzyl ester (7.3 g, 33%) was obtained as an oil. NMR (δ ppm in CDCl ₃ ): 2.11 (2H, m), 2.34 (2H, t, J = 6.8H
z), 3.99 (2H, t, J = 6.8Hz), 5.12 (2H, s), 6.87 (1H, s), 7.
05 (1H, s), 7.30-7.40 (5H, m). Reference Example 34 In the same manner as in Reference Example 33, 4- (1,2,4-triazol-1-yl) butyric acid benzyl ester (yield 88% )
Was obtained as an oil. NMR (δ ppm in CDCl ₃ ): 2.14-2.42 (4H, m), 4.24 (2H, t, J
= 6.4Hz), 5.13 (2H, s), 7.30-7.43 (5H, m), 7.94 (1H, s),
7.99 (1H, s). Reference Example 35 In the same manner as in Reference Example 33, 5- (1-imidazolyl) valeric acid benzyl ester was obtained as an oily substance by the reaction of 5-bromovaleric acid benzyl ester with imidazole. NMR (δ ppm in CDCl ₃ ): 1.55-1.90 (4H, m), 2.38 (2H, t, J
= 6.8Hz), 3.93 (2H, t, J = 7.0Hz), 5.11 (2H, s), 6.87 (1H,
s), 7.05 (1H, s), 7.25-7.50 (5H, m), 7.94 (1H, s), 7.99 (1
H, s).

Reference Example 36 4- (1-Imidazolyl) butyric acid benzyl ester (7.
4 g), a mixture of 5% palladium-carbon (1.0 g) and ethanol (400 ml) was subjected to catalytic reduction reaction at room temperature and 1 atm. The catalyst was filtered off, the filtrate was concentrated under reduced pressure,
The residual crystals were recrystallized from ethanol to give 4- (1-imidazolyl) butyric acid (3.4 g, 75%). Colorless prism crystals. Melting point 125-126 [deg.] C. Reference Example 37 In the same manner as in Reference Example 36, 4- (1,2,4-triazol-1-yl) butyric acid benzyl ester was subjected to catalytic reduction reaction to give 4- (1,2,4-triazole-1- Ill)
Butyric acid was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 137-138 [deg.] C. Reference Example 38 In the same manner as in Reference Example 36, 5- (1-imidazolyl) valeric acid benzyl ester was subjected to a catalytic reduction reaction to give 5- (1
-Imidazolyl) valeric acid was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 157-158 [deg.] C. Reference Example 39 1,1′-Carbonyldiimidazole (0.578 g) was added to a suspension of 4- (1-imidazolyl) butyric acid (0.5 g) in tetrahydrofuran (35 ml), and the mixture was stirred at room temperature for 6 hours. Then, malonic acid monoethyl ester magnesium salt [Mg (OCOCH ₂ COOC ₂ H ₅ ) ₂ ] (1.02 g) was added, and the mixture was further stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane. The dichloromethane layer was washed with water and dried (MgSO ₄ ), the solvent was distilled off, and the residual oily substance was subjected to silica gel column chromatography. Chloroform-methanol (30: 1, v / v)
6- (1-imidazolyl) -3-
Oxohexanoic acid ethyl ester (0.32 g, 44
%) As an oil. NMR (δ ppm in CDCl ₃ ): 1.28 (3H, t, J = 7.4Hz), 2.08 (2
H, m), 2.53 (2H, t, J = 6.6Hz), 3.41 (2H, s), 4.00 (2H, t, J =
6.6Hz), 4.19 (2H, q, J = 7.4Hz), 6.91 (1H, s), 7.07 (1H,
s), 7.46 (1H, s).

Reference Example 40 In the same manner as in Reference Example 39, 4- (1,2,4-triazol-1-yl) butyric acid was used to prepare 6- (1,2,4-triazol-1-yl) -3-oxo. Hexanoic acid ethyl ester was obtained as an oil. NMR (δ ppm in CDCl ₃ ): 1.28 (3H, t, J = 7.2Hz), 2.19 (2
H, m), 2.59 (2H, t, J = 6.6Hz), 3.43 (2H, s), 4.19 (2H, q, J =
7.2Hz), 4.23 (2H, t, J = 6.6Hz), 7.94 (1H, s), 8.07 (1H,
s). Reference Example 41 In the same manner as in Reference Example 39, 7- (1-imidazolyl) -3-oxoheptanoic acid ethyl ester was obtained as an oily substance from 5- (1-imidazolyl) valeric acid. NMR (δ ppm in CDCl ₃ ): 1.27 (3H, t, J = 7.4Hz), 1.50-
1.90 (4H, m), 2.58 (2H, t, J = 6.6Hz), 3.41 (2H, s), 3.95 (2
H, t, J = 7.0Hz), 4.19 (2H, q, J = 7.4Hz), 6.90 (1H, s), 7.06
(1H, s), 7.47 (1H, s). Reference Example 42 In the same manner as in Reference Example 1, 2-chloromethyl-6,7-dimethoxy-4- (4-methoxy-3-propoxyphenyl) quinoline-3. -Carboxylic acid ethyl ester was obtained.
Recrystallized from ethanol. Colorless prism crystals. Melting point 12
6-128 ° C. Reference Example 43 6,7-Dimethoxy-4- (3,4-dimethoxyphenyl) quinazoline-2-acetic acid methyl ester (4.0
g), sodium borohydride (1.9 g) and tetrahydrofuran (80 ml) in a mixture of methanol (1
5 ml) was added dropwise under reflux. The mixture was stirred under reflux for 2 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄ ) and the solvent was distilled off under reduced pressure to obtain 6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2- (2-hydroxyethyl) quinazoline (3. 0 g, 81%). Recrystallized from ethyl acetate. Colorless needles. Melting point 165-166 [deg.] C. Reference Example 44 In the same manner as in Reference Example 25, 2- (2-bromoethyl)-
6,7-Dimethoxy-4- (3,4-dimethoxyphenyl) quinazoline was obtained. Recrystallized from ethyl acetate. Colorless needles. Melting point 166-167 [deg.] C.

Example 1 Oily sodium hydride (60%, 0.323 g) was added to 2-
It was added to a solution of ethylimidazole (0.776 g) in N, N-dimethylformamide (30 ml), and the mixture was stirred at room temperature for 15 minutes. Then 2-chloromethyl-6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester (3.0 g) was added. The mixture was stirred at 80 ° C. for 1 hour, poured into water and the precipitated crystals were collected by filtration. Recrystallized from ethanol, 6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2-
(2-Ethylimidazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester (2.5 g, 74%)
Got Colorless prism crystals. Melting point 163-164 [deg.] C. Examples 2 to 11 In the same manner as in Example 1, compounds shown in [Table 5] were obtained.

Example 12 Oily sodium hydride (60%, 0.044 g) was added to a solution of imidazole (0.075 g) in N, N-dimethylformamide (5 ml), and the mixture was stirred at room temperature for 15 minutes.
Then, 2- (2-bromoethyl) -6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3.
-Carboxylic acid ethyl ester (0.46 g) was added.
The mixture was stirred at 80 ° C. for 1 hr, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and ethyl acetate-methanol (1
2- [2- (1-
Imidazolyl) ethyl] -6,7-dimethoxy-4-
(3,4-Dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester (0.295 g, 66%) was obtained.
Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 173-174 [deg.] C.

Examples 13 to 15 In the same manner as in Example 12, compounds shown in Table 6 were obtained. Example 16 Oily sodium hydride (60%, 0.323g) was added to 1H.
-1,2,4-triazole (0.558 g) N, N
-Add to the dimethylformamide (30 ml) solution and stir for 15 minutes at room temperature. Then, 2-chloromethyl-6,
7-dimethoxy-4- (3,4-dimethoxyphenyl)
Quinoline-3-carboxylic acid ethyl ester (3.0
g) was added. The mixture was stirred at 80 ° C. for 1 hr, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, chloroform-
6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2- (1,2,4-triazol-1) starting from the first elution with methanol (40: 1, v / v) -Ylmethyl) quinoline-3-carboxylic acid ethyl ester (1.7 g, 53%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 176-177 [deg.] C. Example 17 In the column chromatography of Example 16, the 6,7-dimethoxy-4- (3,4
-Dimethoxyphenyl) -2- (1,2,4-triazol-4-ylmethyl) quinoline-3-carboxylic acid ethyl ester (0.07 g, 2%) was obtained. Ethyl acetate-
Recrystallized from hexane. Colorless prism crystals. Melting point 226
~ 227 ° C. Example 18 In the same manner as in Example 16, 6,7-dimethoxy-4-
(4-Methoxyphenyl) -2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 150-151 [deg.] C.

Example 19 In the column chromatography of Example 18, the 6,7-dimethoxy-4- (4-methoxyphenyl) -2- (1,2,4-triazol-
4-ylmethyl) quinoline-3-carboxylic acid ethyl ester was obtained. Recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 218-219 [deg.] C. Example 20 to Example 28 The compounds of [Table 7] were obtained in the same manner as in Example 12. Example 29 6,7-Dimethoxy-4- (4-isopropoxy-3-
A solution of methoxyphenyl) -2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester (55.6 mg) in dichloromethane (2 ml) was added with titanium tetrachloride (TiCl ₄ ) (125 mg). Was added at 0 ° C., and the mixture was stirred at the same temperature for 6 hours. The reaction mixture was poured into water and extracted with chloroform. The chloroform layer was washed with saturated aqueous sodium carbonate solution and water and dried (MgSO ₄ ).
After that, the solvent was distilled off. The residual oily substance was subjected to silica gel column chromatography, and 6,7-dimethoxy-4- (4-hydroxy-3-methoxyphenyl)-was obtained from the portion eluted with ethyl acetate-chloroform (3: 2, v / v). 2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester (24.
5 mg, 48%) was obtained. Recrystallized from ethyl acetate-hexane. Melting point 176-178 [deg.] C. NMR (δ in CDCl ₃ ): 0.88 (3H, t, J = 7.2Hz), 3.80 (3H,
s), 3.88 (3H, s), 3.96 (2H, q, J = 7.2Hz), 4.05 (3H, s), 5.
73 (2H, s), 5.80 (1H, broad s), 6.80-7.06 (4H, m), 7.42 (1
H, s), 7.94 (1H, s), 8.27 (1H, s). Example 30 to Example 32 The compounds of [Table 8] were obtained in the same manner as in Example 29.

Example 33 4- (3,4-diisopropoxyphenyl) -6,7-
Dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester (116.0 mg) in dichloromethane (2.5 ml) was added to titanium tetrachloride (TiCl ₄ ) (288 mg). Was added at 0 ° C., and the mixture was stirred at the same temperature for 6 hours. The reaction mixture was poured into water and extracted with chloroform. The chloroform layer was washed with saturated aqueous sodium hydrogen carbonate solution and water and dried (MgS
After O ₄ ) the solvent was distilled off. The residual oily substance was subjected to silica gel column chromatography, and from the portion eluted with ethyl acetate-chloroform (7: 3, v / v), 4-
(3,4-Dihydroxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester (20.
0 mg, 21%) was obtained. Melting point 122-124 [deg.] C. NMR (δ in CDCl ₃ ): 0.78 (3H, t, J = 7.0Hz), 3.78 (3H,
s), 3.86 (2H, q, J = 7.0Hz), 4.00 (3H, s), 5.71 (2H, s), 6.6
0 (1H, broad s), 6.68-6.79 (2H, m), 6.92 (1H, s), 6.97 (1
H, d, J = 8.0Hz), 7.37 (1H, s), 7.95 (1H, s), 8.35 (1H, s),
8.70 (1H, broad s).

Example 34 Ethyl 4- (3,4-diisopropoxyphenyl) -6-isopropoxy-7-methoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate Ester (96.0 mg) in dichloromethane (1.0
ml) solution, titanium tetrachloride (TiCl ₄ ) (316 mg)
Was added at 0 ° C., and the mixture was stirred at the same temperature for 10 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate solution and water, dried (MgSO ₄ ) and the solvent was evaporated. The residual oily substance was subjected to silica gel column chromatography, and ethyl acetate-
From the part eluted with methanol (10: 1, v / v),
4- (3,4-dihydroxyphenyl) -6-hydroxy-7-methoxy-2- (1,2,4-triazole-
1-ylmethyl) quinoline-3-carboxylic acid ethyl ester (19.0 mg, 26%) was obtained. Melting point 264-2
66 ° C. NMR (δ ppm in CDCl ₃ ): 0.88 (3H, t, J = 7.0Hz), 3.93 (2
H, q, J = 7.0Hz), 3.94 (3H, s), 5.63 (2H, s), 6.52 (1H, dd, J
= 8.2 & 2.2Hz), 6.67 (1H, d, J = 2.2Hz), 6.85 (1H, d, J = 8.2H
z), 6.98 (1H, s), 7.29 (1H, s), 7.94 (1H, s), 8.57 (1H,
s), 9.17 (1H, s), 9.21 (1H, s), 10.00 (1H, s). Example 35 2-amino-4,5,3 ', 4'-tetramethoxybenzophenone (453 mg), 6- (1-Imidazolyl)-
Concentrated sulfuric acid (0.03 ml) in a mixture of 3-oxohexanoic acid ethyl ester (320 mg) and acetic acid (5 ml).
Was added and the mixture was stirred at 100 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was poured into water, made alkaline with 2N sodium hydroxide, and then extracted with chloroform. The chloroform layer was washed with water and dried (MgSO ₄ ), and then the solvent was distilled off. The residual oil was subjected to silica gel column chromatography, and chloroform-methanol (50: 1, v /
From the part eluted in v), 6,7-dimethoxy-4-
There was obtained (3,4-dimethoxyphenyl) -2- [3- (1-imidazolyl) propyl] quinoline-3-carboxylic acid ethyl ester (310.0 mg, 43%). Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 164-165 [deg.] C.

Example 36 In the same manner as in Example 35, 6,7-dimethoxy-4-
(3,4-dimethoxyphenyl) -2- [3- (1,
2,4-triazol-1-yl) propyl] quinoline-3-carboxylic acid ethyl ester was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 141-142
° C. Example 37 In the same manner as in Example 35, 6,7-dimethoxy-4-
(3,4-Dimethoxyphenyl) -2- [4- (1-imidazolyl) butyl] quinoline-3-carboxylic acid ethyl ester was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 119-120 [deg.] C. Example 38 6,7-Dimethoxy-4- (3,4-dimethoxyphenyl) -2-[(1,2,4-triazol-1-yl)
Methyl] quinoline-3-carboxylic acid ethyl ester (3.0 g), 2N sodium hydroxide (15.6 ml)
A mixture of and ethanol (50 ml) was stirred under reflux for 8 hours. The reaction mixture was ice-cooled, adjusted to pH 5 with 2N hydrochloric acid, and concentrated under reduced pressure. The residue was dissolved in ethanol, the insoluble material was filtered off, and the filtrate was concentrated. The residual oil was subjected to silica gel column chromatography, and chloroform-
From the part eluted with methanol (4: 1, v / v),
Obtained 6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid (1.3 g, 46%). Recrystallized from dichloromethane-ethanol. Colorless prism crystals. Melting point 270-271 [deg.] C (decomposition).

Example 39 Oily sodium hydride (60%, 0.156 g) was added to 1 part.
H-1,2,4-triazole (0.27 g) N, N
-Add dimethylformamide (DMF) (20 ml) solution and stir for 15 minutes at room temperature. Then, 2-chloromethyl-6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester 1-oxide (1.5 g) was added, and the mixture was stirred at 80 ° C for 45 min. The reaction mixture was poured into water and extracted with dichloromethane. Dichloromethane layer was washed with water, dried (MgSO ₄₎
After that, the solvent was distilled off. The residual oily substance was subjected to silica gel column chromatography, and 6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2- was obtained from the portion eluted with chloroform-methanol (30: 1, v / v).
[(1,2,4-Triazol-1-yl) methyl] quinoline-3-carboxylic acid ethyl ester 1-oxide (0.8 g, 50%) was obtained. Recrystallized from dichloromethane-hexane. Colorless prism crystals. Melting point 221-22
2 ° C.

Example 40 In the same manner as in Example 16, 6,7-dimethoxy-4-
(3-propoxy-4-methoxyphenyl) -2-
(1,2,4-Triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 127-128
° C. Example 41 In the column chromatography of Example 40, 6,7-dimethoxy-4- (3-propoxy-4-methoxyphenyl) -2- (1,2,4) was then extracted from the eluted portion.
-Triazol-4-ylmethyl) quinoline-3-carboxylic acid ethyl ester was obtained. Recrystallized from ethanol. Colorless needles. Melting point 154-155 [deg.] C. Example 42 In a manner similar to Example 16, 4- (3,4-dimethoxyphenyl) -6,7-ethylenedioxy-2- (1,2,2
4-Triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester was obtained. Recrystallized from ethanol. Colorless needles. Melting point 138-140 [deg.] C. Example 43 In the column chromatography of Example 42, 4- (3,4-dimethoxyphenyl) -6,7-ethylenedioxy-2- (1,2,4-) was then extracted from the eluted portion.
Triazol-4-ylmethyl) quinoline-3-carboxylic acid ethyl ester was obtained. Recrystallized from ethanol. Colorless needles. Melting point 237-239 [deg.] C.

Example 44 In the same manner as in Example 16, 6,7-dimethoxy-4-
(3,4-dimethoxyphenyl) -2- (1,2,3-
Triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester was obtained. Recrystallized from ethanol-dichloromethane. Colorless prism crystals. Melting point 195-19
6 ° C. Elemental analysis value C ₂₅ H ₂₆ N ₄ O ₆ .1 / 4C ₂ H ₅ OH Calculated value: C, 62.50; H, 5.66; N, 11.4
3 Analytical values: C, 62.29; H, 5.53; N, 11.3
0 Example 45 In the column chromatography of Example 44, 6,7-dimethoxy-4- (3,4
-Dimethoxyphenyl) -2- (1,2,3-triazol-2-ylmethyl) quinoline-3-carboxylic acid ethyl ester was obtained. Recrystallized from ethanol-dichloromethane. Colorless needles. Melting point 163-164 [deg.] C. Elemental analysis value, calculated as C ₂₅ H ₂₆ N ₄ O ₆ .1 / 2C ₂ H ₅ OH: C, 62.27; H, 5.83; N, 11.1
7 Analytical values: C, 61.98; H, 5.69; N, 11.1
0 Example 46 In the column chromatography of Example 25, 6,7-dimethoxy-4- (3-isopropoxy-4-methoxyphenyl) -2- (1,
2,4-triazol-4-ylmethyl) quinoline-3
-Carboxylic acid ethyl ester was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 170-1
71 ° C.

Example 47 In the column chromatography of Example 26, 6,7-dimethoxy-4- (4-isopropoxy-3-methoxyphenyl) -2- (1,
2,4-triazol-4-ylmethyl) quinoline-3
-Carboxylic acid ethyl ester was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 178-1
79 ° C. Example 48 Oily sodium hydride (60%, 0.117g) in 2-
A solution of hydroxypyridine (0.277 g) in N, N-dimethylformamide (DMF) (10 ml) was added, and the mixture was stirred at room temperature for 15 minutes. To this solution was added 6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2-iodomethylquinoline-3-carboxylic acid ethyl ester (1.
2g) was added. After stirring the mixture at room temperature for 8 hours,
It was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), the solvent was distilled off, and the residual oily substance was subjected to silica gel column chromatography. From the portion eluted with chloroform-ethyl acetate (10: 1, v / v), 2- (1,2-dihydro-2-oxopyridin-1-ylmethyl) -6,7-dimethoxy-4-
(3,4-Dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester (0.64 g, 57%) was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 154
-156 ° C. Example 49 2- [2- (1-Imidazolyl) ethyl] -6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinazoline was obtained in the same manner as in Example 12. Recrystallized from ethyl acetate. Colorless prism crystals. Melting point 147-148 [deg.] C. Example 50 In a manner similar to Example 1, 2- (2-bromomethyl-6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester was reacted with benzimidazole to give 2- ( Benzimidazol-1-ylmethyl) -6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 99-100 [deg.] C.

Example 51 In the same manner as in Example 16, 2-chloromethyl-6,7-
Dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3,4-carboxylic acid methyl ester and 1H-1,
By reaction with 2,4-triazole, 6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2-
(1,2,4-Triazol-1-ylmethyl) quinoline-3-carboxylic acid methyl ester was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 218-220
° C. Example 52 In the same manner as in Example 1, the reaction of 2-bromomethyl-6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylic acid propyl ester with imidazole gave 6,7- Dimethoxy-4- (3,4-dimethoxyphenyl) -2- (imidazol-1-ylmethyl) quinoline-3-carboxylic acid propyl ester was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 166-168 [deg.] C. Example 53 In the same manner as in Example 1, by reacting 2-bromomethyl-6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylic acid butyl ester with imidazole, 6,7- Dimethoxy-4- (3,4-dimethoxyphenyl) -2- (imidazol-1-ylmethyl) quinoline-3-carboxylic acid butyl ester was obtained.
Recrystallized from ethanol. Colorless prism crystals. Melting point 14
0-141 ° C. Example 54 In a manner analogous to Example 16 by reacting 6-chloro-2-chloromethyl-4-phenylquinoline-3-carboxylic acid ethyl ester with 1H-1,2,4-triazole, 6-chloro- 4-Phenyl-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester was obtained. Recrystallized from ethanol.
Colorless prism crystals. Melting point 114-116 [deg.] C.

Examples 55 to 62 In the same manner as in Example 1, compounds shown in Table 9 were obtained. Example 63 6,7-Dimethoxy-4- (3-isopropoxy-4-
Ethanol (10 ml) -dichloromethane (2 ml) suspension of methoxyphenyl) -2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester (0.5 g) in ethanol with hydrogen chloride. Solution (2
3%, 0.172 g) was added dropwise at room temperature. The mixture was stirred at room temperature for 15 minutes, concentrated under reduced pressure, the residue was treated with isopropyl ether, and the solid was collected by filtration. Recrystallized from ethanol to give 6,7-dimethoxy-4- (3-isopropoxy-4-methoxyphenyl) -2- (1,2,4
-Triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester hydrochloride (0.211 g, 39%)
Got Yellow crystals. Melting point 93-95 [deg.] C.

[0057]

[Table 2] Note 1) NMR (δppm) in CDCl ₃ : 0.92 (3H, t, J = 7.2H
z), 4.06 (2H, q, J = 7.2Hz), 5.03 (2H, s), 7.33-7.37 (2H,
m), 7.50-7.55 (3H, m), 7.90-7.98 (2H, m), 8.26 (1H, d, J =
9.4Hz) ...

[0058]

[Table 3]

[0059]

[Table 4]

[0060]

[Table 5]

[0061]

[Table 6]

[0062]

[Table 7] 1) Indeterminate solid body. NMR (δ ppm in CDCl ₃ ): 0.87 (3H, t, J = 7.
2Hz), 1.33 (6H, d, J = 6.0Hz), 3.85 (3H, s), 3.93 (2H, q, J =
7.2Hz), 3.96 (3H, s), 4.02 (3H, s), 4.43 (1H, m), 5.68 (1
H, d, J = 14.8Hz), 5.77 (1H, d, J = 14.8Hz), 6.82-7.01 (4H,
m), 7.41 (1H, s), 7.93 (1H, s), 8.27 (1H, s). 2) NMR (δ ppm in CDCl ₃ ): 0.84 (3H, t, J =
7.2 Hz), 1.26-1.45 (18 H, m),
3.93 (2H, q, J = 7.0Hz), 4.02
(3H, s), 4.21 (1H, m), 4.51
(1H, m), 4.56 (1H, m), 5.73
(2H, s), 6.80-6.92 (3H, m),
7.01 (1H, d, J = 8.2Hz), 7.41 (1
H, s), 7.93 (1H, s), 8.27 (1
H, s).

[0063]

[Table 8] 1) NMR (δ ppm in CDCl ₃ ): 0.88 (3H, t, J = 7.2Hz),
3.84 (3H, s), 3.86 (3H, s), 3.95 (2H, q, J = 7.2Hz), 3.97 (3
H, s), 5.73 (2H, s), 6.88-7.01 (5H, m), 7.52 (1H, s), 7.9
4 (1H, s), 8.37 (1H, s). 2) NMR (δ ppm in CDCl ₃ ): 0.86 (3H, t, J =
7.0 Hz), 3.85 (3H, s), 3.94
(2H, q, J = 7.0Hz), 3.98 (3H,
s), 4.07 (3H, s), 5.73 (2H,
s), 6.20 (1H, broad), 6.82-
6.98 (3H, m), 7.08 (1H, s), 7.
42 (1H, s), 7.93 (1H, s), 8.27
(1H, s).

[0064]

[Table 9]

Claims (18)

[Claims] 1. A general formula: [In the formula, Y represents a nitrogen atom or CG (G represents an optionally esterified carboxyl group), and ring R represents an optionally substituted nitrogen-containing unsaturated heterocyclic group, and A The ring and the B ring may each have a substituent. n represents an integer of 1 to 4, and k represents 0 or 1. ] The compound or its salt represented by these. 2. The compound according to claim 1, wherein the nitrogen-containing unsaturated heterocyclic group is a 5-membered ring, or a salt thereof. 3. The compound according to claim 1, wherein the nitrogen-containing unsaturated heterocyclic group contains 1 to 4 nitrogen atoms, or a salt thereof. 4. The 5-membered ring of the nitrogen-containing unsaturated heterocyclic group is imidazol-1-yl, pyrazol-1-yl, 1,2,4.
-Triazol-1-yl, 1,2,4-triazol-4-yl, 1,2,3-triazol-1-yl, pyrrol-1-yl, tetrazol-1-yl. Or its salt. 5. The compound according to claim 1, wherein n is 1, or a salt thereof. 6. The compound according to claim 1, wherein Y is C-G, and G is a C _1-6 alkyloxycarbonyl group, or a salt thereof. 7. The compound according to claim 6, wherein G is ethoxycarbonyl, or a salt thereof. 8. A ring A and a ring B are each independently a halogen atom, a nitro group, an optionally substituted alkyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, and a substituted group. The same or different 1 selected from the group consisting of an optionally substituted amino group, an optionally substituted acyl group, an optionally esterified carboxyl group and an optionally substituted aromatic ring group.
May be substituted by to 4 substituents, further, linked substituents adjacent, - (CH ₂₎ m- or -O-
(CH ₂ ) _l —O— (where m is an integer of 3 to 5 and l is 1
The compound of claim 1 or a salt thereof, which may form a ring represented by the formula: 9. The compound or salt thereof according to claim 8, wherein the optionally substituted hydroxyl group is a methoxy group. 10. The compound or its salt according to claim 8, wherein the optionally substituted hydroxyl group is a hydroxyl group. 11. The compound or a salt thereof according to claim 1, wherein the substituent on the A ring is methoxy located at the 6-position and 7-position of the quinoline ring. 12. The compound or a salt thereof according to claim 1, wherein the substituent on the B ring is methoxy at the 3- and 4-positions of the quinoline ring. 13. The compound is 6,7-dimethoxy-4-.
(3,4-dimethoxyphenyl) -2- (1,2,4-
Triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester, 6,7-dimethoxy-4- (3-isopropoxy-4-
Methoxyphenyl) -2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester, 6,7-dimethoxy-4- (4-hydroxy-3-methoxyphenyl) -2- ( 1,2,4-triazole-1
-Ylmethyl) quinoline-3-carboxylic acid ethyl ester, 6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2- (2-ethylimidazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester, 6,7-Dimethoxy-4- (3,4-dimethoxyphenyl) -2- (pyrazol-1-ylmethyl) quinazoline, 6,7-dimethoxy-4- (4-methoxyphenyl)-
2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester, 6,7-dimethoxy-4- (4-isopropoxy-3-
The compound according to claim 1, which is methoxyphenyl) -2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester, or a salt thereof. 14. A general formula: [In the formula, Y represents a nitrogen atom or C-G (G represents an optionally esterified carboxyl group), Q represents a leaving group, and A ring and B ring each have a substituent. May be. n represents an integer of 1 to 4 and k represents 0 or 1. ] The compound or its salt represented by the following general formula: [In the formula, ring R represents an optionally substituted nitrogen-containing unsaturated heterocyclic group. ] A compound represented by the general formula: [Wherein Y, ring R, A ring, B ring, n and k have the same meanings as defined above], or a method for producing a salt thereof. 15. The method according to claim 14, wherein Q is a halogen, or a hydroxyl group esterified with an organic sulfonic acid or an organic phosphoric acid. 16. The halogen is chlorine, bromine, iodine, the organic sulfonic acid is p-toluenesulfonyloxy, methanesulfonyloxy, and the organic phosphoric acid is diphenylphosphoryloxy, dibenzylphosphoryloxy or dimethylphosphoryloxy. The manufacturing method described. 17. The method according to claim 15, wherein the halogen is chlorine or bromine. 18. A general formula: [In the formula, Y represents a nitrogen atom or CG (G represents an optionally esterified carboxyl group), and ring R represents an optionally substituted nitrogen-containing unsaturated heterocyclic group, and A The ring and the B ring may each have a substituent. n represents an integer of 1 to 4 and k represents 0 or 1. ] The anti-inflammatory agent containing the compound or its salt represented by these.