JP2646995B2 - Quinoline or quinazoline derivatives and medicaments containing them - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention 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 a therapeutic agent for arthritis.

[0002]

2. Description of the Related Art Arthritis is an inflammatory disease of the joint, and the main diseases include rheumatoid arthritis and related diseases in which inflammation is recognized in the joint. In particular, rheumatoid arthritis is also referred to as rheumatoid arthritis, and is a chronic polyarthritis whose main lesion is inflammatory changes in the synovium of the lining of the joint capsule. Arthritis, such as rheumatoid arthritis, is progressive and causes joint disorders such as joint deformation and tonicity,
If they get worse without effective treatment, they often lead to severe physical disability. Conventionally, in the treatment of these arthritis, steroids such as cortisone and other corticosteroids; non-steroidal anti-inflammatory drugs such as aspirin, piroxicam and indomethacin; gold thiomalate and other gold drugs; 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 have side effects that make serious or long-term use difficult, are ineffective, or have been used for arthritis that has already developed. There were problems such as not being effective. Therefore, in the clinical practice of arthritis, a drug with low toxicity and excellent in prevention and treatment of arthritis is still desired.

[0004]

Various compounds have been conventionally synthesized as quinoline or quinazoline derivatives. 4
Examples of compounds having an aminomethyl group at the 2-position of -phenylquinoline or 4-phenylquinazoline skeleton include 2-dimethylaminomethyl and 2-morpholinomethyl described in Synthesis, vol. 9, p. 718 (1979). And the like, and Chemical Abstract (Chemical Ab
stracts), 112 volumes, 171720v (1990)
[Pharmaco, 44, 555 (198
9))] are known. However, there is no disclosure of a compound in which the 2-position of 4-phenylquinoline or 4-phenylquinazoline skeleton is bonded to a nitrogen atom of a nitrogen-containing unsaturated heterocycle via an alkylene group as in the present invention. The present inventors have found that a compound in which the 2-position of 4-phenylquinoline or 4-phenylquinazoline skeleton is bonded to a nitrogen atom of a nitrogen-containing unsaturated heterocycle via an alkylene group has an anti-arthritic effect and has an arthritis inhibitor. As a result, the present invention has been completed.

That is, the present invention relates to (1) a compound represented by the general formula (I)

Embedded image [Wherein, Y represents a nitrogen atom or CG (G represents a carboxyl group which may be esterified), ring R represents a nitrogen-containing unsaturated heterocyclic group which may be substituted, 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. Or a salt thereof.

(2) General formula (II)

Embedded image [Wherein, Y represents a nitrogen atom or CG (G represents a carboxyl group which may be esterified), Q represents a leaving group, and ring A and ring B each have a substituent. May be. n represents an integer of 1 to 4, and k represents 0 or 1. And a salt thereof and a compound represented by the general formula (II)
I)

Embedded image [In the formula, ring R represents a nitrogen-containing unsaturated heterocyclic group which may be substituted. Characterized by reacting with a compound represented by the formula or a salt thereof,

Embedded image Wherein Y, ring R, ring A, ring B and n and k are as defined above, or a salt thereof.

(3) General formula

Embedded image [Wherein, Y represents a nitrogen atom or CG (G represents a carboxyl group which may be esterified), ring R represents a nitrogen-containing unsaturated heterocyclic group which may be substituted, 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. And a salt thereof. Descriptions of the above general formulas and definitions included within the scope of the present invention and preferred examples thereof are set forth below.

In the general formulas (I) and (III), the optionally substituted nitrogen-containing unsaturated heterocyclic group represented by ring R is an unsaturated heterocyclic group containing at least one nitrogen atom as a ring-constituting atom. Rings. Such unsaturated heterocyclic groups include, for example, imidazole-1-yl, pyrazol-yl
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, tetrazol- 1-yl, 2
-Pyrolin-1-yl, 3-pyrolin-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, benzotriazol-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,
3-d] oxazol-1-yl, 4H-imidazo [4,5-d] thiazol-4-yl and the like. Further, 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. Are also mentioned. Further, these unsaturated heterocyclic groups may have 1 to 3 substituents at any position on the ring. Examples of such a 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 an optionally substituted amino. Group, an optionally substituted acyl group, an optionally substituted hydroxyl group, an optionally substituted thio-
And a carboxyl group which may be esterified.

As the aliphatic chain hydrocarbon group, 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 Examples thereof include alkenyl groups and alkynyl groups having the number of 2 to 10. Preferred 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 include dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, hexyl, pentyl, octyl, nonyl, decyl and the like. Preferred examples of the alkenyl group include, for example, 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-
Hexenyl, 5-hexenyl and the like. 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-pentynyl Hexinyl, 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, for example, a cycloalkyl group, a cycloalkenyl group, and a cycloalkadienyl group.

Preferred examples of the cycloalkyl group include, for example, 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 and bicyclo [4.3.1] decyl. Preferable examples of the cycloalkenyl group include, for example, 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-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl and the like can be mentioned. The aryl group means a monocyclic or condensed polycyclic aromatic hydrocarbon group, and as a preferable example,
For example, phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like can be mentioned, among which phenyl, 1-naphthyl, 2-naphthyl and the like are preferable.

Preferable examples of the aromatic heterocyclic group include, for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl , 1,3,4-oxadiazolyl, furazanil, 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 and triazinyl; for example, benzofuranyl, isobenzofura Nil, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl , Quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-
Carbolinyl, 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] an aromatic fused heterocyclic group such as pyridazinyl;

Preferred examples of the non-aromatic heterocyclic group include:
Examples include oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, 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 preferred. As the amino group, one or two amino groups (-NH
Those substituted with ₂ groups) (e.g., methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino, N- methyl -N- phenylamino, acetylamino, propionylamino, benzoylamino Etc.). As the acyl, formyl or carbon number 1
10 to 10 alkyl, 1 to 10 carbon alkenyl or an aromatic group bonded to a carbonyl group (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanoyl, Cyclopentanoyl, cyclohexanoyl, cycloheptanoyl,
Crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl, etc.).

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

The 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, te
rt-butylthio, pentylthio, isopentylthio,
Neopentylthio, hexylthio, heptylthio, nonylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, etc.) are preferred. The aralkylthio, for example, phenyl -C _1-4 alkylthio (e.g., benzylthio, etc. phenethylthio) and the like. As acylthio, 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. As the alkyl group in the alkyloxycarbonyl group, an alkyl group having 1 to 6 carbon atoms, for example, methyl,
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, and these may have the same substituent as the aryl group in the ring R has. As the alkyl group, a lower alkyl group having 1 to 6 carbon atoms is preferable. Preferable examples of the aralkyl group include, for example, benzyl, phenethyl, 3-phenylpropyl, (1-naphthyl) methyl, (2-naphthyl) methyl and the like, among which benzyl, phenethyl and the like are preferable. The above-mentioned aliphatic chain hydrocarbon group, alicyclic hydrocarbon group, aryl group, heterocyclic group and the like may each have one or more, preferably 1 to 3 suitable 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, ant 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 carboxyl group which may be esterified represented by G includes:
Examples thereof include a carboxyl group, an alkyloxycarbonyl group, and an aralkyloxycarbonyl group. The alkyl group in the alkyloxycarbonyl group has 1 carbon atom.
And 6 alkyl groups such as methyl, 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 and the like, which may have the same substituent as the aryl group in the ring R has. As the alkyl group, a lower alkyl group having 1 to 6 carbon atoms is preferable. Preferred examples of the aralkyl group include:
For example, benzyl, phenethyl, 3-phenylpropyl, (1-naphthyl) methyl, (2-naphthyl) methyl and the like can be mentioned, among which benzyl, phenethyl and the like are preferable. 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) Sulfonyloxy group, methanesulfonyloxy group, etc.) and diphenylphosphoryloxy group, dibenzylphosphoryloxy group, dimethylphosphoryloxy group, etc., which are residues of organic phosphoric acid.

In the general formulas (I) and (II), ring A and ring B may have a substituent. Examples of such a substituent include a halogen atom, a nitro group and a substituent. Alkyl group, hydroxyl group which may be substituted, thiol group which may be substituted, amino group which may be substituted, acyl group which may be substituted, carboxyl group which may be esterified Alternatively, an aromatic ring group which may be substituted is used. Examples of such a halogen atom as a substituent include fluorine, chlorine, bromine and iodine, and fluorine and chlorine are particularly preferred. 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. Optionally substituted hydroxyl groups include hydroxyl groups and protected hydroxyl groups such as alkoxy, alkenyloxy, aralkyloxy, acyloxy and the like, as well as aryloxy. Examples of the alkoxy include 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, etc.) are preferred. As the alkenyloxy, allyl (ally
l) oxy, crotyloxy, 2-pentenyloxy, 3
-Hexenyloxy, 2-cyclopentenylmethoxy,
Those having 1 to 10 carbon atoms such as 2-cyclohexenylmethoxy include, for example, phenyl-
C _1-4 alkyloxy (eg, benzyloxy, phenethyloxy, etc.). The acyloxy includes alkanoyloxy having 2 to 4 carbon atoms (eg, acetyloxy, propionyloxy, n-butyryloxy, i
and so-butyryloxy are preferred. Examples of the aryloxy include phenoxy, 4-chlorophenoxy and the like. Examples of the thiol group which may be substituted include 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. As the aralkylthio, for example, phenyl-C
_1-4 alkylthio (eg, benzylthio, phenethylthio, etc.) can be mentioned. The acylthio may have 2 carbon atoms.
Preferred are alkanoylthio (e.g., acetylthio, propionylthio, n-butyrylthio, iso-butyrylthio, etc.). Examples of the amino group which may be substituted include an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 1 to 10 carbon atoms, or an aromatic group having 1 or 2 amino groups (-NH
Those substituted with ₂ groups) (e.g., methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino, N- methyl -N- phenylamino etc.).

Examples of the optionally substituted acyl include formyl and alkyl having 1 to 10 carbons and 1 to 1 carbons.
0 wherein an alkenyl or aromatic group is bonded to a carbonyl group (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanoyl, cyclopentanoyl, cyclohexanoyl, cyclohexanoyl) Heptanoyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl, etc.).
As the carboxyl group which may be esterified,
Examples thereof include a carboxyl group, an alkyloxycarbonyl group, and an aralkyloxycarbonyl group. As the alkyl group in the alkyloxycarbonyl group, an alkyl group having 1 to 6 carbon atoms, for example, methyl, 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, and these may have the same substituent as the aryl group in the ring R has. As the alkyl group, a lower alkyl group having 1 to 6 carbon atoms is preferable. Preferable examples of the aralkyl group include, for example, benzyl, phenethyl, 3-phenylpropyl, (1-naphthyl) methyl, (2-naphthyl) methyl and the like, among which 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 include heteroaromatic residues such as imidazolyl and thiazolyl.

The substituents on ring A and ring B may be substituted at any position of each ring, and may be substituted with 1 to 4 identical or different rings.
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
-(L represents an integer of 1 to 3), and the ring may include a 5- to 7-membered ring formed together with a carbon atom of a benzene ring. The salt of the target 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, basic or And salts with acidic amino acids. Preferred examples of the salt with an inorganic base include, for example, 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. Preferred examples of the salt with an organic base include:
For example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine,
Salts with N, N'-dibenzylethylenediamine and the like can be mentioned. Preferred examples of the salt with an inorganic acid include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Preferred 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,
Salts with methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like can be mentioned. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, and preferred examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Can be Object compound (I) of the present invention
Is a solid formulation such as tablets, capsules, granules, powders, etc .;
It can be orally or parenterally administered to mammals including humans as a liquid preparation such as an injection.

As the pharmaceutically acceptable carrier, various organic or inorganic carrier materials commonly used as a preparation material are used, and excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations, It is formulated as a solubilizer, suspending agent, tonicity agent, buffer, soothing agent and the like. If necessary, formulation additives such as preservatives, antioxidants, coloring agents and sweeteners can also be used. Preferred examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid, and the like. Preferred examples of the lubricant include, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferred examples of the binder include, for example, crystalline cellulose, sucrose, D-mannitol,
Dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like can be mentioned. Preferable examples of the disintegrant include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium carboxymethyl starch 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 solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Preferred examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol , Polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose,
Examples include hydrophilic polymers such as hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Suitable examples of the tonicity agent include, for example, sodium chloride, glycerin, D-mannitol and the like. Preferred examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Preferred examples of the soothing agent include benzyl alcohol and the like. Preferable examples of the preservative include, for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the antioxidant include, for example, sulfite, ascorbic acid and the like.

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

Embedded image Wherein 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 between (II) and (III) is performed in an appropriate 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. (II)
The reaction of (III) with alkali metal salts such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, amines such as pyridine, triethylamine, N, N-dimethylaniline, sodium hydride, hydrogen The reaction is carried out in the presence of an appropriate base such as potassium iodide, and the amount of the base used is 1 to 1 relative to the compound (II).
About 5 mol is preferable. This reaction is usually carried out at -20 ° C to 1
It is carried out at 50 ° C, preferably at 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

Embedded image [In the formula, G ′ represents an esterified carboxyl group, and other symbols have the same meanings as described above. As the esterified carboxyl group represented by G ′, those similar to the esterified carboxyl group represented by G can be mentioned. In this method, the 2-aminobenzophenone derivative (IV) is reacted with (V) in the presence of an acid (II
-1) is manufactured. The reaction between (IV) and (V) is performed in an appropriate 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, 1,1,2,2-tetrachloroethane, acetic acid and the like. The reaction between (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. About 0.01 to 2.0 molar equivalents, preferably about 0.05 to 0.5 molar equivalents are preferred. This reaction is carried out usually at 20 ° C to 200 ° C, preferably at about 30 ° C to 150 ° C. Reaction time is 0.5 ~
It is 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

Embedded image Wherein each symbol has the same meaning as described above. In this method, 2
-Aminobenzophenone derivative (IV) is reacted with an acetoacetic ester derivative (VI) in the presence of an acid to produce (VII), followed by bromination to produce a 2-bromomethylquinoline derivative (II-2). The reaction between (IV) and (VI) is carried out in the same manner as in Method B. Bromination of (VII) is performed in an appropriate solvent according to a conventional method. Examples of the solvent include carbon tetrachloride, chloroform, dichloromethane,
Halogenated hydrocarbons such as 1,2-dichloroethane and 1,1,2,2-tetrachloroethane are exemplified. (VI
In the bromination reaction of I), benzoyl peroxide, 2,2′-
The reaction is performed in the presence of a radical reaction initiator such as azobis (isobutyronitrile), and the amount of the radical reaction initiator to be used is preferably about 0.001 to 0.01 molar equivalents relative to compound (VII). This reaction is carried out usually at 20 ° C to 150 ° C, preferably at 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 a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

Method D

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

Embedded image Wherein each symbol has the same meaning as described above. In this law,
Reaction of 2-aminobenzophenone derivative (IV) with acetonitrile to give 2-methylquinazoline derivative (IX)
And then subjecting (IX) to a bromination reaction to produce the 2-bromomethylquinazoline derivative (II-4).
The reaction between (IV) and acetonitrile is performed in the same manner as in Method D. The bromination of (IX) is performed 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.

F method

Embedded image Wherein each symbol has the same meaning as described above. In this law,
The quinazoline derivative (XI) is produced by reacting the 2-aminobenzophenone derivative (IV) with the cyanoacetate derivative (X). The reaction between (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.

G method

Embedded image Wherein each symbol has the same meaning as described above. In this law,
The 2-aminobenzophenone derivative (IV) is reacted with the acetone dicarboxylic acid ester derivative (XII) to produce a quinoline derivative (XIII). (IV) and (XI)
The reaction of I) is carried out in the same manner as in Method B. The quinoline derivative (XIII) thus obtained can be obtained by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization,
It can be isolated and purified by phase transfer, chromatography and the like.

H method

Embedded image Wherein Y ′ is a nitrogen atom or CG ′, and other symbols are as defined above. In this method, an alcohol (XIV) is produced by subjecting the compounds (XI) and (XIII) obtained by the methods F and G to a reduction reaction. This reduction reaction can be performed by a method known per se. For example, reduction with a metal hydride, reduction with a metal hydride complex compound, reduction with diborane and substituted borane, catalytic hydrogenation, and the like are used. That is, this reaction is carried out with the compound (X
It is carried out by treating I) and (XIII) with a reducing agent. Examples of the reducing agent include alkali metal borohydride (eg, sodium borohydride, lithium borohydride, etc.), metal hydride complex compounds such as lithium aluminum hydride, metal hydrides such as sodium hydride, and organotin compounds (hydrogen Triphenyltin, etc.), nickel compounds,
Examples include a metal and metal salt such as a zinc compound, a catalytic reducing agent using a transition metal catalyst such as palladium, platinum and rhodium and hydrogen and diborane. This reaction is
The reaction is performed in an organic solvent that does not affect the reaction. Examples of the solvent include, for example, aromatic hydrocarbons such as benzene, toluene, and xylene; and halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, and 1,1,2,2-tetrachloroethane. Ethers such as diethyl ether, tetrahydrofuran and dioxane; alcohols such as methanol, ethanol, propanol, isopropanol and 2-methoxyethanol;
An amide such as N, N-dimethylformamide, or a mixed solvent thereof is appropriately selected and used depending on 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

Embedded image Wherein 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 this case, Q is represented by chlorine or bromine (II
-5) is generated. This reaction is carried out in a suitable inert solvent (eg, benzene, toluene, xylene, chloroform, dichloromethane, or the like) or at −10 to 80 ° C. using an excess of a halogenating agent as a solvent. The amount of the halogenating agent to be 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 each represented by 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.) in a base (eg, triethylamine, N-methylmorpholine, sodium hydrogen carbonate, hydrogen bicarbonate). (Potassium, sodium carbonate, potassium carbonate, etc.) at -10 to 30 ° C. The amounts of the sulfonylating agent and the base to be used are respectively 1 to 1.2 mol per 1 mol of (XIV). Q is iodine when 1 mol of the compound (II-5) in which Q formed as described above is chlorine, bromine or sulfonyloxy is reacted with 1 to 1.5 mol of sodium iodide or potassium iodide ( II-5) can also be produced. In this case, the reaction can be carried out in a solvent such as acetone, methyl ethyl ketone, methanol and ethanol at 20 to 80 ° C.

J method

Embedded image Wherein each symbol has the same meaning as described above. In this law,
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, using an oxidizing agent such as m-chloroperbenzoic acid, hydrogen peroxide, or a perester (peres).
ters) and sodium metaperiodate. This oxidation is an organic solvent that is inert under the reaction conditions,
For example, halogenated hydrocarbons (eg, methylene chloride,
It is advantageously performed with chloroform, dichloroethane, etc.), hydrocarbons (eg, benzene, toluene, etc.), and alcohols (methanol, ethanol, propanol, etc.). The oxidizing agent is a compound (II-1), (II-2), (I
1 for (I-3), (II-4) or (II-5)
The reaction is carried out using up to 5 molar equivalents, preferably 1 to 3 molar equivalents. The reaction temperature is from -10C to 150C, preferably about 0C
The reaction is usually performed at a temperature of １００100 ° C. for 0.5 to 10 hours. The quinoline 1-oxide or quinazoline 1-oxide derivative (II-6) thus obtained can be isolated by 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.

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

Embedded image Wherein each symbol has the same meaning as described above. In this law,
First, compound (I-1) is produced by reacting compound (IV) with compound (XV). Compound (IV) and compound (X
The reaction of V) is carried out in the same manner as in Method B. Next, compound (I-2) is subjected to an oxidation reaction to produce compound (I-2). This oxidation reaction is performed in the same manner as in the J method. L method

Embedded image Wherein each symbol has the same meaning as described above. In this law,
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 aqueous solvent, a mixture of water and an alcohol (eg, methanol, ethanol), an ether (eg, tetrahydrofuran, dioxane), N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, or acetone can be used. The reaction is carried out with a base such as, for example, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, or lithium, or, for example, hydrochloric acid,
It is carried out in the presence of an acid such as sulfuric acid, acetic acid or hydrobromic acid. Preferably, the acid or the base is a compound (I-1)
Alternatively, an excess amount (base: 1.2 to 6 equivalents) and an acid (2 to 50 equivalents) are used relative to (1-2). This reaction is usually carried out
The reaction is carried out at 20 ° C to 150 ° C, preferably at -10 ° C to 100 ° C.

Method M In this method, when ring A and ring B of compound (I) contain an isopropoxy group as a substituent, this is treated with titanium tetrachloride, titanium trichloride, boron trichloride, silicon tetrachloride or the like. By converting the isopropoxy group to a hydroxyl group, ring 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, such as carbon tetrachloride, dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-
Examples thereof include tetrachloroethane, acetonitrile, and a mixed solvent thereof. The amount of titanium tetrachloride, boron trichloride, silicon tetrachloride, etc. used is 1 to 10 molar equivalents per isopropoxy group, preferably 1 to 6 molar equivalents,
It is carried out at -50 ° C to 100 ° C, preferably at -20 ° C to 80 ° C.

[0032]

The compound (I) provided by the present invention
Alternatively, their salts have an anti-inflammatory effect and an antipyretic analgesic effect, and an excellent anti-arthritis effect was confirmed in an experimental model of adjuvant arthritis that develops arthritis similar to human rheumatoid arthritis. Further, the toxicity of the compound of the present invention is low. For example, the compound synthesized in Examples 2 and 16
00 mg / kg, orally administered to mice.
No mortality was observed even when the compound synthesized in the above was orally administered to rats at 2000 mg / kg. Therefore, the target compound of the present invention can be applied to all arthritis exhibiting inflammatory symptoms in joints. The dose of the compound (I) used in the present invention can be variously selected depending on the administration route and the condition of the patient to be treated.
g-1000 mg, 1 mg-100 for parenteral administration
The dose can be selected from the range of mg and these can be divided and administered once to three times a day. Next, test methods for confirming the pharmacological action of the compound (I) of the present invention or a salt thereof and the results thereof will be described.

Test Example 1: Effect on rat adjuvant arthritis Freund's complete adjuvant (0.5% liquid tuberculosis suspension of Mycobacterium tuberculosis) in the skin of the right hind footpad of male Lewis rats (Clea Japan, 7 weeks) 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 the sensitization (Day 0) and on the 14th day (Day 14), the volume and weight of the left hind limb were measured, and the rate of inhibition of footpad swelling (%) and the rate of weight gain (%) relative to non-sensitized rats were determined. The results are expressed as the mean ± SE of each group (N = 6).
s test was used to compare and test. A significance level of less than 5% was considered significant. As shown in Table 1, the compound of the present invention was effective in suppressing foot pad edema and improving systemic symptoms seen in weight gain.

[Table 1]

Reference Example 1 In 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). Concentrated sulfuric acid (0.3 ml) was added, and the mixture was stirred at 100 ° C for 3 hours. 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 is washed with water and dried (MgSO ₄ )
Thereafter, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. From the portion 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%). Recrystallized from acetone. Colorless prism crystals. 197-198 ° C. Elemental analysis As C ₂₃ H ₂₂ NO ₆ Cl Calculated value: C, 62.24; H, 5.00; N, 3.16 Analytical value: C, 61.95; H, 5.15; N, 3.01 Reference Examples 2 to 12 Same as Reference Example 1 To obtain the compounds shown in Tables 2 and 3. 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 the mixture was 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%)
I got Recrystallized from ethanol. Colorless prism crystals.
147-148 ° 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. Dimethoxy-4- (3,4-dimethoxyphenyl) -2-methylquinoline-3-carboxylic acid propyl ester (79
%). Recrystallized from ethyl acetate-isopropyl ether. Colorless prism crystals. 153-155 ° 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. -(3,4-dimethoxyphenyl) -2-methylquinoline-3-carboxylic acid butyl ester (53%)
I got Recrystallized from ethyl acetate-hexane. Colorless prism crystals. 119-120 ° 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)
(10 mg) and carbon tetrachloride (10 ml) were 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. From a portion eluted with chloroform-ethyl acetate (10: 1, v / v), 2-bromomethyl-6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester (285 mg, 58 %). Recrystallized from ethyl acetate-hexane. Colorless prism crystals. 135-1
36 ° C. Elemental analysis: As C ₂₃ H ₂₄ NO ₆ Br Calculated: C, 56.34; H, 4.93; N, 2.86 Analytical: 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. 144-145 ° C. Elemental analysis: As C ₂₄ H ₂₆ NO ₆ Br Calculated: C, 57.15; H, 5.20; N, 2.78 Analytical value: C, 56.75; H, 5.30; N, 2.68 Reference Example 18 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. 160-161 ° C. Calculated elemental analysis _{C 25 H 28 NO 6 Br:} C, 57.92; H, 5.44; N, 2.70 Analytical values: C, 57.96; H, 5.53 ; N, 2.50 Reference Example 19 2-Chloro-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, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure.
The residue was subjected to silica gel column chromatography. From the part 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%). Recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 193-194 [deg.] C. Elemental analysis As C ₂₃ H ₂₄ NO ₇ Cl Calculated: C, 59.81; H, 5.24; N, 3.03 Analytical value: C, 59.69; H, 5.32; N, 3.05

Reference Example 20 Powdered aluminum chloride (6.7 g) was added to a mixture of 2-amino-4,5,3 ', 4'-tetramethoxybenzophenone (8.0 g) and chloroacetonitrile (25 ml).
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 (MgSO ₄ ), and the solvent was distilled off. The residue was subjected to silica gel column chromatography. 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. 183-184 ° 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 at 100 ° C.
Stir for 5 hours. The reaction mixture was concentrated under reduced pressure, the residue was poured into water, neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with chloroform. The chloroform layer is washed with water,
After drying (MgSO ₄ ), the solvent was distilled off under reduced pressure, and the remaining crystals were recrystallized from acetone to give 6,7-dimethoxy-4- (3,4
-Dimethoxyphenyl) -3-ethoxycarbonylquinoline-2-acetic acid ethyl ester (1.41 g, 64%)
I got Colorless prism crystals. 146-147 ° C.

REFERENCE EXAMPLE 22 Powdered aluminum chloride (5.3 g) was added to a mixture of 2-amino-4,5,3'4'-tetramethoxybenzophenone (6.3 g) and cyanoacetate methyl ester (23 ml).
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 (MgSO ₄ ), and the solvent was distilled off. The residue was subjected to silica gel column chromatography. 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. 152-153 ° C.

REFERENCE EXAMPLE 23 A mixture of sodium iodide (1.68 g) and 2-butanone (15 ml) was stirred 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 hours. The reaction mixture was concentrated under reduced pressure, and the residue was poured into water and extracted with ethyl acetate. The ethyl acetate layer is washed 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 portion eluted with chloroform-ethyl acetate (1: 1, v / v), ethyl 6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2-iodomethylquinoline-3-carboxylate (1. 4 g, 58%). Ethyl acetate
Recrystallized from hexane. Colorless prism crystals. Melting point 170
~ 171 ° C. Reference Example 24 Tetrahydrofuran (100 g) of 6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -3-ethoxycarbonylquinoline-2-acetic acid ethyl ester (5.8 g)
ml) solution with lithium aluminum hydride (0.45
5 g) in tetrahydrofuran (50 ml) suspension at 0 ° C.
Was dropped. 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 from a portion eluted with chloroform-ethyl acetate (1: 1, v / v), 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. 150-151 ° 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- The solution was added dropwise to a solution of ethyl carboxylate (1.7 g) in benzene (50 ml) at room temperature. The mixture was stirred at 80 ° C. for 1 hour, poured into ice water, neutralized with a saturated aqueous solution of sodium hydrogen carbonate 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. From the part eluted with chloroform-ethyl acetate (1: 1, v / v), 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. 132-1
33 ° C. Reference Examples 26 to 32 The compounds of [Table 4] were obtained in the same manner as in Reference Example 1.

Reference Example 33 A mixture of 4-bromobutyric acid benzyl ester (23.7 g), imidazole (8.1 g), potassium carbonate (14.0 g) and acetone (400 ml) was stirred under reflux for 6 hours. After cooling to room temperature, the insoluble solid was filtered off and the filtrate was concentrated. The residual oil was subjected to silica gel column chromatography, and ethyl acetate-methanol (20: 1, 20: 1).
From the portion eluted with (v / v), benzyl 4- (1-imidazolyl) butyrate (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, benzyl 4- (1,2,4-triazol-1-yl) butyrate (88% yield) )
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 oil by reacting 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 Benzyl 4- (1-imidazolyl) butyrate (7.
4 g), a mixture of 5% palladium-carbon (1.0 g) and ethanol (400 ml) was subjected to a catalytic reduction reaction at room temperature and 1 atm. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure.
The remaining crystals were recrystallized from ethanol to give 4- (1-imidazolyl) butyric acid (3.4 g, 75%). Colorless prism crystals. 125-126 ° 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 a catalytic reduction reaction to give 4- (1,2,4-triazol-1-yl). Ill)
Butyric acid was obtained. Recrystallized from ethanol. Colorless prism crystals. 137-138 ° 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. 157-158 ° C. Reference Example 39 To a suspension of 4- (1-imidazolyl) butyric acid (0.5 g) in tetrahydrofuran (35 ml) was added 1,1'-carbonyldiimidazole (0.578 g), 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, dried (MgSO ₄ ), and the solvent was distilled off. The residual oil 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 = 7.4 Hz), 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 converted to 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 = 7.2 Hz), 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, ethyl 7- (1-imidazolyl) -3-oxoheptanoate was obtained as an oil 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 (2H, s)
(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 g).
5 ml) were 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 then the solvent was distilled off under reduced pressure to give 6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2- (2-hydroxyethyl) quinazoline (3. 0 g, 81%). Recrystallized from ethyl acetate. Colorless needles. 165-166 ° 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. 166-167 ° C.

Example 1 Oily sodium hydride (60%, 0.323 g) was added to 2-
The mixture was added to a solution of ethyl imidazole (0.776 g) in N, N-dimethylformamide (30 ml) and stirred at room temperature for 15 minutes. Then, ethyl 2-chloromethyl-6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylate (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%)
I got Colorless prism crystals. 163-164 ° C. Examples 2 to 11 The compounds of [Table 5] were obtained in the same manner as in Example 1.

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 hour, 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. The residue was subjected to silica gel column chromatography, and ethyl acetate-methanol (1
0: 1, v / v) to the 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. 173-174 ° C.

Examples 13 to 15 In the same manner as in Example 12, the compounds shown in Table 6 were obtained. Example 16 Oily sodium hydride (60%, 0.323 g) was added to 1H
N, N of -1,2,4-triazole (0.558 g)
-Dimethylformamide (30 ml) solution and 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 extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and chloroform-
6,7-Dimethoxy-4- (3,4-dimethoxyphenyl) -2- (1,2,4-triazole-1) (-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, 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 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. 150-151 ° C.

Example 19 In the column chromatography of Example 18, the portion eluted from the eluted portion was converted to 6,7-dimethoxy-4- (4-methoxyphenyl) -2- (1,2,4-triazole-
4-ylmethyl) quinoline-3-carboxylic acid ethyl ester was obtained. Recrystallized from ethyl acetate-hexane. Colorless needles. 218-219 ° C. Examples 20 to 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-
To a solution of methoxyphenyl) -2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester (55.6 mg) in dichloromethane (2 ml), titanium tetrachloride (TiCl ₄ ) (125 mg) was added. 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 is washed with a saturated aqueous solution of sodium carbonate and water, and dried (MgSO ₄ ).
Thereafter, the solvent was distilled off. The residual oil was subjected to silica gel column chromatography, and from the portion eluted with ethyl acetate-chloroform (3: 2, v / v), 6,7-dimethoxy-4- (4-hydroxy-3-methoxyphenyl)- 2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester (24.
(5 mg, 48%). Recrystallized from ethyl acetate-hexane. Melting point 176-178 [deg.] C. NMR (δ in CDCl ₃ ): 0.88 (3H, t, J = 7.2 Hz), 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). Examples 30 to 32 The compounds of [Table 8] were obtained in the same manner as in Example 29.

Example 33 4- (3,4-diisopropoxyphenyl) -6,7-
In a dichloromethane (2.5 ml) solution of dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester (116.0 mg), titanium tetrachloride (TiCl ₄ ) (288 mg) was added. 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 is washed with a saturated aqueous solution of sodium hydrogen carbonate and water, and dried (MgS
After O ₄ ), the solvent was distilled off. The residual oil 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%). 122-124 ° C. NMR (δ in CDCl ₃ ): 0.78 (3H, t, J = 7.0 Hz), 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 a saturated aqueous solution of sodium hydrogen carbonate and water, dried (MgSO ₄ ), and the solvent was distilled off. The residual oil 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. 264-2 melting point
66 ° C. NMR (δ ppm in CDCl ₃ ): 0.88 (3H, t, J = 7.0 Hz), 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,
Example 35 2-amino-4,5,3 ', 4'-tetramethoxybenzophenone (453 mg), 6-s), 9.17 (1H, s), 9.21 (1H, s), 10.00 (1H, s). (1-imidazolyl)-
Concentrated sulfuric acid (0.03 ml) was added to a mixture of ethyl 3-oxohexanoate (320 mg) and acetic acid (5 ml).
And 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 extracted with chloroform. After the chloroform layer was washed with water and dried (MgSO ₄ ), the solvent was distilled off. The residual oil was subjected to silica gel column chromatography, and chloroform-methanol (50: 1, v / v
From the part eluted in v), 6,7-dimethoxy-4-
(3,4-Dimethoxyphenyl) -2- [3- (1-imidazolyl) propyl] quinoline-3-carboxylic acid ethyl ester (310.0 mg, 43%) was obtained. 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 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. 119-120 ° 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)
And a mixture of 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 insolubles were 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),
6,7-Dimethoxy-4- (3,4-dimethoxyphenyl) -2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid (1.3 g, 46%) was obtained. Recrystallized from dichloromethane-ethanol. Colorless prism crystals. 270-271 ° C (decomposition).

Example 39 Oily sodium hydride (60%, 0.156 g) was added to 1
N, N of H-1,2,4-triazole (0.27 g)
-Dimethylformamide (DMF) (20 ml) solution and stirred at room temperature for 15 minutes. 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 minutes. The reaction mixture was poured into water and extracted with dichloromethane. The dichloromethane layer is washed with water and dried (MgSO ₄ )
Thereafter, the solvent was distilled off. The residual oil was subjected to silica gel column chromatography, and from a portion eluted with chloroform-methanol (30: 1, v / v), 6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2-
[(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
-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 the same manner as in 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. 138-140 ° C. Example 43 In the column chromatography of Example 42, 4- (3,4-dimethoxyphenyl) -6,7-ethylenedioxy-2- (1,2,4-
Triazole-4-ylmethyl) quinoline-3-carboxylic acid ethyl ester was obtained. Recrystallized from ethanol. Colorless needles. 237-239 ° C.

Example 44 As in Example 16, 6,7-dimethoxy-4-
(3,4-dimethoxyphenyl) -2- (1,2,3-
Triazole-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: C ₂₅ H ₂₆ N ₄ O ₆ .1 / 4 C ₂ H ₅ OH Calculated: 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. 163-164 ° C. Elemental analysis: C ₂₅ H ₂₆ N ₄ O ₆ .1 / 2C ₂ H ₅ OH Calculated: 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, the portion eluted from the column eluted with 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, the portion eluted from the eluted portion was 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%, 0.117 g) was added to 2-
Hydroxypyridine (0.277 g) was added to a solution of N, N-dimethylformamide (DMF) (10 ml), and the mixture was stirred at room temperature for 15 minutes. To this solution, 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,
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. The residual oil 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 In the same manner as in Example 12, 2- [2- (1-imidazolyl) ethyl] -6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinazoline was obtained. Recrystallized from ethyl acetate. Colorless prism crystals. 147-148 ° C. Example 50 In the same manner as in 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- ( There was obtained ethyl benzimidazol-1-ylmethyl) -6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylate. 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 As in Example 1, 2-bromomethyl-6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylic acid propyl ester was reacted with imidazole to give 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 By the reaction of 2-bromomethyl-6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylic acid butyl ester and imidazole in the same manner as in Example 1, 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 Analogously to Example 16, 6-chloro-2-chloromethyl-4-phenylquinoline-3-carboxylic acid ethyl ester was reacted with 1H-1,2,4-triazole to give 6-chloro- There was obtained ethyl 4-phenyl-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate. Recrystallized from ethanol.
Colorless prism crystals. 114-116 ° C.

Examples 55 to 62 In the same manner as in Example 1, the compounds shown in Table 9 were obtained. Example 63 6,7-Dimethoxy-4- (3-isopropoxy-4-
Methoxyphenyl) -2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester (0.5 g) in ethanol (10 ml) -dichloromethane (2 ml) suspension in ethanol of hydrogen chloride Solution (2
(3%, 0.172 g) was added dropwise at room temperature. The mixture was stirred at room temperature for 15 minutes, then 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%)
I got Yellow crystals. 93-95 ° C.

[0057]

[Table 2] Note 1) NMR (δ ppm) 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) Indefinite solid. 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 (18H, m),
3.93 (2H, q, J = 7.0 Hz), 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 = 8.2 Hz), 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 (3H
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 = 7.0 Hz), 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]

──────────────────────────────────────────────────の Continuation of the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical display location A61K 31/505 ABG A61K 31/505 ABG C07D 403/06 231 C07D 403/06 231 233 233 239 239

Claims (21)

(57) [Claims] 1. A compound of the general formula [Wherein, Y represents a nitrogen atom or CG (G represents a carboxyl group which may be esterified), ring R represents a nitrogen-containing unsaturated heterocyclic group which may be substituted, 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. Or a salt thereof. 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 a nitrogen-containing unsaturated heterocyclic group is imidazol-1-yl, pyrazol-1-yl, 1,2,4,
The compound according to claim 2, which is -triazol-1-yl, 1,2,4-triazol-4-yl, 1,2,3-triazol-1-yl, pyrrol-1-yl or 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 CG, 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 and a B ring each independently represent a halogen atom, a nitro group, an optionally substituted alkyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, The same or different ones 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-
The compound according to claim 1, which may form a ring represented by (CH ₂ ) ₁ -O- (where m represents an integer of 3 to 5, and 1 represents an integer of 1 to 3) or a salt thereof. . 9. The compound according to claim 8, wherein the optionally substituted hydroxyl group is a methoxy group, or a salt thereof. 10. The compound according to claim 8, wherein the optionally substituted hydroxyl group is a hydroxyl group, or a salt thereof. 11. The compound according to claim 1, wherein the substituent on the ring A is methoxy located at the 6-position and the 7-position of the quinoline ring. 12. The compound or a salt thereof according to claim 1, wherein the substituent on the ring B is methoxy located at the 3- and 4-positions of the benzene 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-hydroxy-4-methoxyphenyl) -2- (1,2,4-triazole-1
-Ylmethyl) quinoline-3-carboxylic acid ethyl ester, 4- (3,4-dimethoxyphenyl) -7-hydroxy-6-methoxy-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 or 6,7-dimethoxy-4- (4-isopropoxy-3-methoxyphenyl) -2- (1 The compound according to claim 1, which is 2,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester, or a salt thereof. 14. An ethyl ester of 6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid. Or a salt thereof. 15. A compound of the general formula [Wherein, Y represents a nitrogen atom or CG (G represents a carboxyl group which may be esterified), Q represents a leaving group, and ring A and ring B each have a substituent. May be. n represents an integer of 1 to 4, and k represents 0 or 1. Or a salt thereof, and a compound represented by the general formula: [In the formula, ring R represents a nitrogen-containing unsaturated heterocyclic group which may be substituted. A compound represented by the following general formula: or a salt thereof. Wherein Y, ring R, ring A, ring B, n and k are as defined above, or a salt thereof. 16. The process according to claim 15 , wherein Q is a halogen or a hydroxyl group esterified with an organic sulfonic acid or an organic phosphoric acid. 17. The method according to claim 17, wherein the halogen is chlorine, bromine or iodine, the organic sulfonic acid is p-toluenesulfonyloxy or methanesulfonyloxy, and the organic phosphoric acid is diphenylphosphoryloxy, dibenzylphosphoryloxy or dimethylphosphoryloxy. Item 18. The production method according to Item 16 . 18. The method according to claim 15 , wherein Q is chlorine or bromine. 19. A compound of the general formula [Wherein, Y represents a nitrogen atom or CG (G represents a carboxyl group which may be esterified), ring R represents a nitrogen-containing unsaturated heterocyclic group which may be substituted, 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. ] Or a salt thereof. 20. A compound of the general formula [Wherein, Y represents a nitrogen atom or CG (G represents a carboxyl group which may be esterified), ring R represents a nitrogen-containing unsaturated heterocyclic group which may be substituted, 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. ] Or a salt thereof. 21. A compound of the general formula [Wherein, Y represents a nitrogen atom or CG (G represents a carboxyl group which may be esterified), ring R represents a nitrogen-containing unsaturated heterocyclic group which may be substituted, 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. An anti- rheumatic rheumatoid arthritis agent comprising the compound represented by the formula (I) or a salt thereof.