JPH0769890A - Pharmaceutical composition containing quinoline or quinazoline derivative - Google Patents

Abstract

PURPOSE:To obtain a bone resorption suppressing agent and osteoporosis preventing and treating agent containing a specific compound as an active component and exhibiting excellent bone resorption inhibiting action by directly acting on the bone. CONSTITUTION:This treating agent contains a compound of the formula [Y is N or C-G (G is carboxyl or hydroxymethyl); R is (substituted) hydrocarbon residue or (substituted)heterocyclic group; X is O or S; (n) and (k) are 0 or 1; G and R may be bonded together to form a ring; rings A and B may have each substituent], preferably 4-(3,4-dimethoxyphenyl)-2-ethyl-6,7-dimethoxyquinoline-3-carboxylic acid methyl ester as an active component.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition comprising a quinoline or quinazoline derivative having a bone resorption inhibitory effect and useful as a prophylactic / therapeutic agent for osteoporosis.

[0002]

2. Description of the Related Art Osteoporosis is a pathological condition or disease in which the quantity of bone is reduced to a certain extent or more, which causes some symptoms or danger. Its main symptoms are kyphosis of the spine, lumbar spine and vertebral bodies, femoral neck, lower radius, ribs, upper humerus and other fractures. In bone tissue, bone formation and bone destruction due to bone resorption are constantly repeated in a balanced manner, and osteoblasts play a central role in bone formation and osteoclasts play a central role in bone resorption. When bone resorption occurs more strongly than bone formation due to an imbalance between bone formation and bone destruction due to bone resorption, it is accompanied by a quantitative decrease in bone. Therefore, agents that suppress bone resorption are considered to be useful for the prevention and treatment of osteoporosis, and bone resorption inhibiting substances such as estrogen agents and calcitonin have been administered as therapeutic agents for osteoporosis.

[0003]

However, when these therapeutic agents are administered, there are some cases where the administration subject is limited and the effects are uncertain, and sufficient effects are not obtained. Therefore, development of a new preventive and therapeutic method for bone resorption promotion is desired.

[0004]

[Means for Solving the Problems] The present inventors have conducted earnest research for the purpose of developing a more general drug that directly acts on bone and suppresses bone resorption. As a result, the following general formula
The present invention was completed by finding that the quinoline or quinazoline derivative represented by (I) directly acts on bone and exhibits an excellent bone resorption inhibiting effect. That is, the present invention provides (1)
General formula (I):

[0005]

[Chemical 3]

[Wherein Y represents a nitrogen atom or C-G (G represents a carboxyl group which may be esterified or amidated, or a hydroxymethyl group), and R represents a carbon atom which may be substituted. A hydrogen residue, an optionally substituted heterocyclic group, X is an oxygen atom or an optionally sulfur atom, n is 0 or 1, and k is 0 or 1. G and R may combine with each other to form a ring. Ring A and ring B may each have a substituent. ] The bone resorption inhibitor containing the compound represented by these or its pharmaceutically acceptable salt as an active ingredient, (2) The bone resorption inhibitor of said (1) whose n is 0, (3) n is 0
And an optionally substituted hydrocarbon residue represented by R is —CH ₂ —X ¹ —Z ¹ [wherein, X ¹ is an oxygen atom, an optionally oxidized sulfur atom, or - (CH _{2) m} - a (m is an integer of 0 to 5), Z
¹ represents a hydrocarbon residue which may be substituted, a heterocyclic group which may be substituted or an amino group which may be substituted. ] The bone resorption inhibitor according to (1) above, which is a group represented by the following formula, (4) The bone resorption inhibitor according to (3) above, wherein X ¹ is a thio group, a sulfinyl group or a sulfonyl group,
(5) The bone resorption inhibitor according to the above (4), wherein X ¹ is a thio group, (6) The above (3), wherein X ¹ is-(CH ₂ ) _m- , and m is 1 or 2. Bone resorption inhibitor described in (7) Z
^The optionally substituted heterocyclic group represented by ^1, which is an aromatic 5-membered heterocyclic group containing 2 to 3 heteroatoms (3) or (6), (8)
The above (3), wherein Z ¹ is an optionally substituted amino group
Alternatively, the bone resorption inhibitor according to the above (6), (9) one optionally substituted heterocyclic group represented by R may be substituted with one sulfur atom, nitrogen atom or oxygen atom. 5 to 7 membered heterocyclic group containing 5 to 6 membered heterocyclic group containing 2 to 4 nitrogen atoms, or 5 to 6 membered containing 1 to 2 nitrogen atoms and 1 sulfur atom or oxygen atom The bone resorption inhibitor according to (1) above, which is a heterocyclic group, (10) Y is C
The bone resorption inhibitor according to (1) above, which is -G, (11) G
Is a C _1-6 alkyloxycarbonyl group (1
(0) The bone resorption inhibitor, (12) The bone resorption inhibitor according to (10) above, wherein G is an ethoxycarbonyl group, (1)
3) The bone resorption inhibitor according to the above (1), wherein the A ring is substituted with at least one alkoxy group, (14) The above (1) wherein the A ring is substituted with at least one methoxy group.
Bone resorption inhibitor described in (1) above, wherein (15) ring A is substituted with two alkoxy groups that are the same or different, (16) ring A is substituted with two methoxy groups. The bone resorption inhibitor according to the above (1), (17) A
The bone resorption inhibitor according to the above (1), wherein the ring is substituted with two methoxy groups at the 6- and 7-positions of the quinoline ring or the quinazoline ring, (18) The ring B is substituted with at least one alkoxy group. (1) The bone resorption inhibitor according to (1) above, (19) The bone resorption inhibitor according to (1) above, wherein ring B is substituted with at least one methoxy group.
The bone resorption inhibitor according to (1) above, wherein ring B is substituted with at least one isopropoxy group, (21) above (1), wherein ring B is substituted with two alkoxy groups which are the same or different. A bone resorption inhibitor according to (1) above, wherein (22) B ring is substituted with one methoxy group, (23) B ring through an isopropoxy group at the 3-position, and 4 (1) substituted with a methoxy group at position
The bone resorption inhibitor as described in (1) above, wherein (24) k is 0.
The bone resorption inhibitor described in (25), the compound represented by the general formula (I) is 4- (3,4-dimethoxyphenyl) -2-
Ethyl-6,7-dimethoxyquinoline-3-carboxylic acid methyl ester, 6-chloro-2-methyl-4- (3,
4-dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester, 6,7-dimethoxy-9-phenylfuro
[3,4-b] quinolin-1 (3H) -one, 4- (3,4
-Dimethoxyphenyl) -6,7-dimethoxy-2-
[(1-Methylimidazol-2-yl) thiomethyl] quinoline-3-carboxylic acid ethyl ester, 4- (3,4
-Dimethoxyphenyl) -2- (2-hydroxyethylthiomethyl) -6,7-dimethoxyquinazoline, 4-
(3,4-dimethoxyphenyl) -6,7-dimethoxy-
2-[(4-methyl-1,2,4-triazol-3-yl) thiomethyl] quinazoline, 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-[(1-methylimidazole- 2-yl) ethyl] quinoline-3-carboxylic acid ethyl ester, 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-3-methoxycarbonylquinoline-2-acetic acid methyl ester, 4- (3,4 -Dimethoxyphenyl) -6,7-dimethoxy-2- (1,2,
4-triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester, 4- (3-isopropoxy-
4-methoxyphenyl) -6,7-dimethoxy-2-
(1,2,4-Triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester, 4- (4-hydroxy-3-methoxyphenyl) -6,7-dimethoxy-2
-(1,2,4-Triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester, 7-hydroxy-
6-methoxy-4- (3,4-dimethoxyphenyl)-
2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester, 4- (3,4-
Dimethoxyphenyl) -6,7-dimethoxy-2- (1,
2,4-triazol-1-ylmethyl) quinoline-3
-Carboxylic acid ethyl ester 1-oxide or 2-
(N, N-Diethylaminomethyl) -4- (3,4-dimethoxyphenyl) -6,7-dimethoxyquinoline-3-
The bone resorption inhibitor according to (1) above, which is a carboxylic acid ethyl ester, and (26) the general formula (I):

[0007]

[Chemical 4]

[In the formula, Y is a nitrogen atom or C-G (G is a carboxyl group which may be esterified or amidated, or a hydroxymethyl group), and R is a carbon atom which may be substituted. A hydrogen residue, an optionally substituted heterocyclic group, X is an oxygen atom or an optionally sulfur atom, n is 0 or 1, and k is 0 or 1. G and R may combine with each other to form a ring. Ring A and ring B may each have a substituent. ] It relates to an osteoporosis preventive / therapeutic agent containing the compound represented by the formula or a pharmaceutically acceptable salt thereof as an active ingredient. Some of the compounds included in the compound (I) used in the present invention are novel, and the applicant has already filed a patent application therefor (Japanese Patent Application Nos. 0-012628 and 5-095780). ).

The hydrocarbon residue in the optionally substituted hydrocarbon residue represented by R or Z ¹ in the general formula (I) is an aliphatic hydrocarbon residue or an alicyclic hydrocarbon residue. Group, alicyclic-aliphatic hydrocarbon residue, aromatic carbocyclic-aliphatic hydrocarbon residue, and aromatic hydrocarbon residue.

Examples of such an aliphatic hydrocarbon residue include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl,
1 to 1 carbon atoms such as isopentyl, neopentyl, t-pentyl, hexyl, isohexyl, heptyl and octyl
8 saturated aliphatic hydrocarbon residues, such as ethenyl, 1-
Propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1
-Pentenyl, 2-pentenyl, 3-pentenyl, 4-
Pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,
2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5
-Hexinyl, 1-heptynyl, 1-octynyl, and the like, include unsaturated aliphatic hydrocarbon residues having 2 to 8 carbon atoms.

Examples of such alicyclic hydrocarbon residue include cyclopropyl, cyclobutyl, cyclopentyl,
C3-C7 saturated alicyclic hydrocarbon residues such as cyclohexyl and cycloheptyl, and 1-cyclopentenyl, 2
-Cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2,4-cycloheptadienyl and the like having 5 to 7 carbon atoms Unsaturated alicyclic hydrocarbon residue of.

The alicyclic-aliphatic hydrocarbon residue has 4 to 9 carbon atoms, for example, cyclopropylmethyl, among the alicyclic hydrocarbon residue and the aliphatic hydrocarbon residue bonded to each other. , Cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, cyclo Heptyl ethyl and the like can be mentioned.

Examples of such aromatic carbocyclic-aliphatic hydrocarbon residue include benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-phenylpropyl, and other phenylalkyl having 7 to 9 carbon atoms. , Α-naphthylmethyl, α-naphthylethyl,
β-naphthylmethyl, β-naphthylethyl and other carbon atoms 1
The naphthylalkyl of 1-13 is mentioned. Examples of such aromatic hydrocarbon residues include phenyl and naphthyl.
(α-naphthyl, β-naphthyl) and the like.

The optionally substituted hydrocarbon residue represented by R is preferably --CH ₂ --X ¹ --Z ¹ [wherein, X ¹ is an oxygen atom or an optionally oxidized sulfur atom]. or - (CH _{2) m} - a (m is an integer of 0 to 5), Z
¹ represents a hydrocarbon residue which may be substituted, a heterocyclic group which may be substituted, or an amino group which may be substituted]. Examples of the optionally oxidized sulfur atom represented by X ¹ include a thio group, a sulfinyl group and a sulfonyl group, and among these, a thio group is preferable. X ¹ is preferably, - a (m is 1 or _{2) - (CH 2) m} . Examples of the optionally substituted hydrocarbon residue represented by Z ¹ include the same as the optionally substituted hydrocarbon residue represented by R above. Z ¹
Examples of the optionally substituted heterocyclic group represented by are the same as the optionally substituted heterocyclic group represented by R below. Among these, an aromatic 5-membered heterocyclic group containing 2 to 3 hetero atoms (eg, oxygen atom, nitrogen atom and sulfur atom) is preferable, and 1,2,4-triazol-1-yl is more preferable.

In the above general formula (I), the heterocyclic group represented by R or Z ¹ which may be substituted includes, for example, 5 heterocyclic groups containing one sulfur atom, nitrogen atom or oxygen atom. To a 7-membered heterocyclic group, a 5 to 6-membered heterocyclic group containing 2 to 4 nitrogen atoms, a 5 to 6-membered heterocyclic group containing 1 to 2 nitrogen atoms and one sulfur atom or an oxygen atom, Used, these heterocyclic groups containing not more than 2 nitrogen atoms 6
It may be condensed with a member ring, a benzene ring or a 5-membered ring containing one sulfur atom.

Specific examples of such a heterocyclic group include, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl and 2-pyridyl.
Pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,
6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 2-pyrrolyl, 3-pyrrolyl, 2
-Imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, isothiazolyl, isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2 , 4-triazole-3
-Yl, 1,3,4-triazol-2-yl, 1,2,3
-Triazol-4-yl, tetrazol-5-yl,
Benzimidazol-2-yl, indol-3-yl, benzpyrazol-3-yl, 1H-pyrrolo [2,3
-B] pyrazin-2-yl, 1H-pyrrolo [2,3-b] pyridin-6-yl, 1H-imidazo [4,5-b] pyridine-
2-yl, 1H-imidazo [4,5-c] pyridin-2-yl, 1H-imidazo [4,5-b] pyrazin-2-yl and the like can be mentioned.

In the general formula (I), the hydrocarbon residue and the heterocyclic group represented by R or Z ¹ may have 1 to 3 substituents at arbitrary positions on the ring. .. As such a substituent, an aliphatic chain hydrocarbon group, an alicyclic hydrocarbon group,
Aryl group, aromatic heterocyclic group, non-aromatic heterocyclic group, halogen atom, nitro group, optionally substituted amino group,
Examples thereof include an optionally substituted acyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, and an optionally esterified carboxyl group.

The aliphatic hydrocarbon group represented by R or Z ¹ as the substituent of the hydrocarbon residue and the heterocyclic group is a linear or branched aliphatic hydrocarbon group,
Examples thereof include an alkyl group, preferably an alkyl group having 1 to 10 carbon atoms, an alkenyl group, preferably an alkenyl group having 2 to 10 carbon atoms, an alkynyl group and the like. 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 Examples include 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, hexyl, pentyl, octyl, nonyl and decyl. Preferable 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 can be mentioned. 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.

The alicyclic hydrocarbon group represented as the substituent of the hydrocarbon residue and the heterocyclic group represented by R or Z ¹ is a saturated or unsaturated alicyclic hydrocarbon group such as a cycloalkyl group. , A cycloalkenyl group, a cycloalkadienyl group and the like. Preferable 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, bicyclo
[4.3.1] Decyl and the like can be mentioned. Preferred examples of the cycloalkenyl group include cycloalkenyl groups having 5 to 7 carbon atoms, such as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl and 3-cyclohexene-1. -Ill and the like.
A preferred example of the cycloalkadienyl group has 5 carbon atoms.
To 7 cycloalkadienyl groups, for example, 2,4-cyclopentadiene-1-yl, 2,4-cyclohexadiene-1-yl, 2,5-cyclohexadiene-1-yl and the like.

The aryl group shown as the substituent of the hydrocarbon residue and the heterocyclic group represented by R or Z ¹ means a monocyclic or condensed polycyclic aromatic hydrocarbon group, which is a preferred example. For example, phenyl, naphthyl, anthryl,
Examples thereof include phenanthryl and acenaphthylenyl. Among them, phenyl, 1-naphthyl, 2-naphthyl and the like are preferable.

Preferable examples of the aromatic heterocyclic group shown as the substituent of the hydrocarbon residue and the heterocyclic group represented by R or Z ¹ include, for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, Isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-
Oxadiazolyl, flazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, Aromatic monocyclic heterocyclic groups such as pyrimidinyl, pyrazinyl, triazinyl; for example, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzo Isoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-
Benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxalinyl. , Thianthrenyl, phenatridinyl, phenatorolinyl, 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
Examples include condensed aromatic heterocyclic groups such as -triazolo [4,3-a] pyridyl and 1,2,4-triazolo [4,3-b] pyridazinyl.

Preferable examples of the hydrocarbon residue represented by R or Z ¹ and the non-aromatic heterocyclic group shown as the substituent of the heterocyclic group include, for example, oxiranyl, azetidinyl,
Examples include oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like. Examples of the halogen shown as the substituent of the hydrocarbon residue and the heterocyclic group represented by R or Z include fluorine, chlorine, bromine and iodine, with fluorine and chlorine being particularly preferable.

The optionally substituted amino group shown as the substituent of the hydrocarbon residue and the heterocyclic group represented by R or Z ¹ includes, in addition to the amino group, alkyl having 1 to 10 carbons and carbon. Substituted with 1 or 2 amino groups (-NH ₂ groups) of alkenyl or aromatic groups of the numbers 1-10
(E.g., methylamino, dimethylamino, ethylamino,
Diethylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino, N-methyl-N
-Phenylamino and the like).

The optionally substituted acyl group shown as the substituent of the hydrocarbon residue and the heterocyclic group represented by R or Z ¹ is formyl or alkyl having 1 to 10 carbons, and 1 to 1 carbons. Bonded alkenyl or aromatic group and carbonyl group of 10 (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl) , Crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl, etc.).

As the optionally substituted hydroxyl group shown as the substituent of the hydrocarbon residue and heterocyclic group represented by R or Z ¹ , a hydroxyl group and an appropriate substituent for this hydroxyl group, especially a hydroxyl group-protecting group And aryloxy in addition to those having those used as, for example, alkoxy, alkenyloxy, aralkyloxy, acyloxy and the like. As alkoxy, alkoxy having 1 to 10 carbon atoms (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t
(ert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.) are preferred.
Examples of the alkenyloxy include those having 1 to 10 carbon atoms such as allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy and 2-cyclohexenylmethoxy. Aralkyloxy includes, for example, phenyl-C.
_1-4 alkyloxy (eg, benzyloxy, phenethyloxy, etc.) can be mentioned. As acyloxy, alkanoyloxy having 2 to 4 carbon atoms (eg, acetyloxy,
Propionyloxy, n-butyryloxy, iso-butyryloxy and the like) are preferred. Examples of aryloxy include phenoxy and 4-chlorophenoxy.

The thiol group which may be substituted, which is shown as the substituent of the hydrocarbon residue and the heterocyclic group represented by R or Z ¹ , is a thiol group and an appropriate substituent for the thiol group, particularly thiol group. Examples thereof include those used as a protecting group for groups, such as alkylthio, aralkylthio, and acylthio. As alkylthio, 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 aralkylthio include phenyl-C _1-4 alkylthio (eg, benzylthio, phenethylthio, etc.). As acylthio, alkanoylthio having 2 to 4 carbon atoms (eg, acetylthio, propionylthio, n-butyrylthio, iso-butyrylthio, etc.) is preferable.

As the carboxyl group which may be esterified as the substituent of the hydrocarbon residue and the heterocyclic group represented by R or Z ¹ , in addition to the carboxyl group, the carboxyl group and the carbon number of 1 to 6 are included. Bound to an alkyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, se
c-butoxycarbonyl, tert-butoxycarbonyl,
Pentyloxycarbonyl, hexyloxycarbonyl, etc., in which a carboxyl group and an alkenyl group having 3 to 6 carbon atoms are bonded, allyloxycarbonyl, crotyloxycarbonyl, 2-pentenyloxycarbonyl, 3-hexenyloxycarbonyl, etc., Examples thereof include those in which a carbonyl group and an aralkyl group are bonded, such as benzyloxycarbonyl and phenethyloxycarbonyl.

In the general formula (I), the hydrocarbon residue represented by R or Z ¹ and the substituents on the heterocyclic group each have 1 or more, preferably 1 to 3 appropriate substituents. You may have. Examples of such a 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. Group, N, N-disubstituted amino group, amidino group, acyl group, carbamoyl group, N-monosubstituted carbamoyl group,
N, N-disubstituted carbamoyl group, sulfamoyl group, N
-Mono-substituted sulfamoyl group, N, N-disubstituted sulfamoyl group, carboxyl group, lower alkoxycarbonyl group, hydroxyl group, lower alkoxy group, lower alkenyloxy group, cycloalkyloxy group, lower alkylthio group, aralkylthio group, arylthio group , Sulfo group,
Examples thereof include a cyano group, an azide group, a halogen atom, a nitro group, a nitroso group and the like. Examples of such a substituent include those shown as the substituents on the hydrocarbon residue and heterocyclic group represented by R or Z ¹ .

In the general formula (I), R is —CH ₂ —X ¹ —Z.
^When it is ¹ , the optionally substituted amino group represented by Z ¹ is -N (R ¹ ) (R ² ) (R ¹ and R ² are the same or different and are hydrogen or substituted. Represents a hydrocarbon residue which may be substituted or a heterocyclic group which may be substituted).
Examples of the hydrocarbon residue or the optionally substituted heterocyclic group in the optionally substituted hydrocarbon residue represented by R ¹ and R ² include the same as those exemplified as R. . R ¹ and R ² may combine with each other to form a ring, and examples of such —N (R ¹ ) (R ² ) include 1-pyrrolidinyl, 1-imidazolidinyl, 1-
Pyrazolidinyl, 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, 4-thiomorpholinyl, homopiperazin-1-yl, 1,2,4-triazol-1-yl, 1,3,4-triazol-1-yl, pyrazole −
1-yl, imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, tetrazol-1-yl, benzimidazol-1
-Yl, indol-1-yl, 1H-indazole-
1-yl and the like can be mentioned. The hydrocarbon residue and the heterocyclic group represented by R ¹ and R ² may have 1 to 3 substituents at arbitrary positions on the ring. As such a substituent,
The same as those exemplified as the substituent on the hydrocarbon residue and the heterocyclic group represented by R can be mentioned. These R
^The hydrocarbon residue represented by ¹ and R ² and the substituent on the heterocyclic group each may further have one or more, and preferably 1 to 3, suitable substituents. Is, for example, 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, 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-disubstituted sulfamoyl group, carboxyl group, lower alkoxycarbonyl group, hydroxyl group, lower alkoxy group, lower alkenyloxy group, cycloalkyloxy group, aralkyloxy group, aryloxy group, mercapto group, lower alkylthio group, aralkylthio group Group, arylthio group,
Examples thereof include a sulfo group, a cyano group, an azide group, a nitro group, a nitroso group, and a halogen. Examples of such a substituent include those shown as a substituent on the ring of the hydrocarbon residue and the heterocyclic group represented by R. Examples of the optionally oxidized sulfur atom represented by X include a thio group, a sulfinyl group and a sulfonyl group,
Of these, a thio group is preferable.

In formula (I), ring A and ring B may have a substituent, and examples of such a substituent include a halogen atom, a nitro group, an optionally substituted alkyl group, and a substituted group. Optionally substituted hydroxyl group, optionally substituted thiol group, optionally substituted amino group, optionally substituted acyl group, optionally esterified carboxyl group or optionally substituted An aromatic ring group is used.

Examples of the halogen shown as the substituents on the ring A and the ring B include fluorine, chlorine, bromine and iodine, with fluorine and chlorine being particularly preferable. Ring A
And the optionally substituted alkyl group shown as the substituent of ring B has a linear or branched chain having 1 to 10 carbon atoms,
It may be any cyclic, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl,
Examples thereof include cyclohexyl and cycloheptyl.

As the optionally substituted hydroxyl group shown as the substituents of the ring A and the ring B, for example, an alkoxy group having a hydroxyl group and an appropriate substituent for the hydroxyl group, particularly one used as a protective group for the hydroxyl group, In addition to alkenyloxy, aralkyloxy, acyloxy and the like, aryloxy can be mentioned. As the alkoxy, alkoxy having 1 to 10 carbon atoms (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like) are preferable. The alkenyloxy is allyl
(allyl) oxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, 2-cyclohexenylmethoxy and the like having 1 to 1 carbon atoms
0 can be mentioned. As the aralkyloxy,
For example, phenyl-C _1-4 alkyloxy (eg, benzyloxy, phenethyloxy, etc.) can be mentioned. The acyloxy includes alkanoyloxy having 2 to 4 carbon atoms.
(Eg, acetyloxy, propionyloxy, n-butyryloxy, iso-butyryloxy, etc.) are preferred. Examples of the aryloxy include phenoxy and 4-chlorophenoxy.

As the optionally substituted thiol group shown as the substituents of the ring A and the ring B, there are a thiol group and an appropriate substituent for the thiol group, particularly a group used as a protective group for the thiol group. Examples include alkylthio, aralkylthio, acylthio and the like. The alkylthio is an alkylthio having 1 to 10 carbon atoms.
(For example, 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.). As the acylthio, alkanoylthio having 2 to 4 carbon atoms (eg, acetylthio, propionylthio, n-butyrylthio, iso-butyrylthio, etc.) is preferable.

The optionally substituted amino group shown as the substituent of ring A and ring B is an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 1 to 10 carbon atoms or an amino group having 1 or 2 aromatic groups. Substituted with a group (-NH ₂ group)
(E.g., methylamino, dimethylamino, ethylamino,
Diethylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino, N-methyl-N
-Phenylamino and the like). The optionally substituted acyl group represented as the substituent of ring A and ring B is a formyl group or an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 1 to 10 carbon atoms or an aromatic group and a carbonyl group bonded to each other. (E.g., acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl, etc.) Can be mentioned.

Examples of the optionally esterified carboxyl group shown as the substituents of the ring A and the ring B are those in which, in addition to the carboxyl group, a carboxyl group and an alkyl group having 1 to 6 carbon atoms are bonded, for example, methoxycarbonyl. ,
Ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc., in which a carboxyl group and an alkenyl group having 3 to 6 carbon atoms are bonded. Thing, allyloxycarbonyl, crotyloxycarbonyl, 2-pentenyloxycarbonyl, 3-hexenyloxycarbonyl, etc.
Examples thereof include those in which a carbonyl group and an aralkyloxy group are bonded, such as benzyloxycarbonyl and phenethyloxycarbonyl. Examples of the optionally substituted aromatic ring group shown as the substituents of ring A and ring B include phenyl, naphthyl, anthryl and the like C _6-14 aromatic hydrocarbon residue, as well as pyridyl, furyl, thienyl and imidazolyl. And heteroaromatic residues such as thiazolyl.

The substituents on the ring A and the ring B may be substituted at any position of the respective rings, and may be the same or different and each may be substituted by 1 to 4.
When substituents on ring A or ring B are adjacent to each other, linked substituents adjacent, - (CH _{2) t} - or -
O- (CH _{2) 1} -O- (wherein, t is an integer of 3 to 5, l is an integer of 1 to 3) may form a ring represented by, such rings include a benzene ring 5 to 7 membered ring formed with the carbon atoms of

Preferably ring A is substituted with at least one alkoxy group, more preferably at least one methoxy. More preferably, ring A is substituted with two identical or different alkoxy groups, preferably methoxy. Further, it is particularly preferable that the ring A is substituted with two methoxy groups at the 6-position and the 7-position of the quinoline ring or the quinazoline ring. Preferably, ring B is substituted with at least one alkoxy group, more preferably at least one methoxy or isopropoxy. More preferably, ring B is substituted with two same or different alkoxy groups. Further, it is particularly preferable that the ring B is substituted at the 3-position with an isopropoxy group and at the 4-position with a methoxy group.

In the general formula (I), when Y is a quinoline derivative represented by CG, the optionally esterified carboxyl group represented by G is a carboxyl group,
Examples thereof include an alkyloxycarbonyl group and an aralkyloxycarbonyl group. Examples of the alkyl group in the alkyloxycarbonyl group include alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like. The aralkyl group in the aralkyloxycarbonyl group means an alkyl group having an aryl group as a substituent (arylalkyl group). Examples of the aryl group include phenyl and naphthyl, and these may have the same substituents as the ring A has. The alkyl group has 1 carbon atom
Lower alkyl groups of 6 are preferred. Preferable examples of the aralkyl group include benzyl, phenethyl and 3-
Phenylpropyl, (1-naphthyl) methyl, (2-naphthyl) methyl and the like can be mentioned, and among them, benzyl, phenethyl and the like are preferable. When G is an amidated carboxyl group, such amidated carboxyl group is represented by ^{-CON (R 1) (R 2} ) ( In the formula, R ¹ and R ² are as defined above) . In the general formula (I), when Y is a quinoline derivative represented by CG, R and G may combine with each other to form a 5-membered ring. This structure is
It is represented by (II) and (III).

[0039]

[Chemical 5]

[In the formula, R ³ represents hydrogen, an optionally substituted hydrocarbon residue or an optionally substituted heterocyclic group, and the other symbols have the same meanings as described above. In the formulas (II) and (III), the optionally substituted hydrocarbon residue represented by R ³ and the optionally substituted heterocyclic group are the same as those exemplified above for R and Z ^1. The same thing is mentioned. In the general formula (I), Y is preferably C-G, and among these, those in which G is a C _1-6 alkyloxycarbonyl group are more preferable, and those in which G is an ethoxycarbonyl group are particularly preferable. N in the general formula (I) is preferably 0. K in the general formula (I) is
Preferably 0

Among the compounds represented by the general formula (I), particularly preferable compounds are Y for CG (G is ethoxycarbonyl), R for --CH ₂ --Z ¹ and Z ¹ for 1,2,4. -Triazol-1-yl, a methoxy group whose A ring substituent is located at the 6- and 7-positions of the quinoline ring, a methoxy group whose B ring substituent is located at the 3- and 4-positions of the B ring, n is 0, And k is 0
Is a compound. Preferred specific examples of the compound represented by formula (I) are shown below. 4- (3,4-dimethoxyphenyl) -2-ethyl-6,7-dimethoxyquinoline-3-carboxylic acid methyl ester, 6-chloro-2-
Methyl-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester, 6,7-dimethoxy-9-phenylfuro [3,4-b] quinoline-1 (3H)-
On, 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-[(1-methylimidazol-2-yl) thiomethyl] quinoline-3-carboxylic acid ethyl ester, 4- (3,4- Dimethoxyphenyl) -2- (2
-Hydroxyethylthiomethyl) -6,7-dimethoxyquinazoline, 4- (3,4-dimethoxyphenyl) -6,
7-dimethoxy-2-[(4-methyl-1,2,4-triazol-3-yl) thiomethyl] quinazoline, 4-
(3,4-dimethoxyphenyl) -6,7-dimethoxy-
2-[(1-Methylimidazol-2-yl) ethyl] quinoline-3-carboxylic acid ethyl ester, 4- (3,4
-Dimethoxyphenyl) -6,7-dimethoxy-3-methoxycarbonylquinoline-2-acetic acid methyl ester,
4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl)
Quinoline-3-carboxylic acid ethyl ester, 4- (3-
Isopropoxy-4-methoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester, 4-
(4-Hydroxy-3-methoxyphenyl) -6,7-
Dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester, 7
-Hydroxy-6-methoxy-4- (3,4-dimethoxyphenyl) -2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester,
4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl)
Quinoline-3-carboxylic acid ethyl ester 1-oxide, and 2- (N, N-diethylaminomethyl) -4
-(3,4-Dimethoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylic acid ethyl ester.

The salt of compound (I) used in 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, or an organic acid. Examples thereof include salts and salts with basic or 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 salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, 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, arginine, lysine,
Examples thereof include salts with ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like.

The compound (I) used in the present invention is blended with a pharmaceutically acceptable carrier to give tablets, capsules, granules,
It can be orally or parenterally administered as a solid preparation such as a powder; or a liquid preparation such as a syrup and an injection. As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances conventionally used as formulation materials are used, and excipients in solid formulations, lubricants, binders, disintegrants; solvents in liquid formulations, solubilizing agents. , Suspending agents, isotonic agents,
It is used as a buffer and soothing agent. If necessary, formulation additives such as antiseptics, antioxidants, coloring agents and sweeteners can also be used.

Suitable examples of excipients include lactose,
White sugar, D-mannitol, starch, crystalline cellulose,
Examples include light anhydrous silicic acid. 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, 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. Suitable examples of the suspending agent include stearyl triethanolamine,
Surfactants such as sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride and glycerin monostearate;
For example, polyvinyl alcohol, polyvinylpyrrolidone,
Hydrophilic polymers such as sodium carboxymethyl cellulose, methyl cellulose, 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 compound (I) used in the present invention has low toxicity. For example, the compounds of Examples 142 and 181 are 1000
No cases of death were observed even after oral administration to mice at a rate of mg / kg. Thus, mammals (eg, humans, horses,
It is useful as a bone resorption inhibitor and an osteoporosis preventive / therapeutic agent for cattle, pigs, dogs, cats, etc.).

The dose of the compound (I) used in the present invention can be variously selected depending on the administration route and the symptoms of the patient to be treated, but usually, per adult, in the case of oral administration, it is 10
In the case of parenteral administration, the dose can be selected from the range of 1 mg to 100 mg, and these can be administered in 1 to 3 times daily.

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

[0051]

[Chemical 6]

[In the formula, Q represents an optionally substituted hydrocarbon residue, R ⁴ represents a lower alkyl group, and other symbols have the same meanings as described above. ] In formulas (I-1) and (V-1),
Examples of the optionally substituted hydrocarbon residue represented by Q are the same as those exemplified as R and Z ¹ above. In formulas (I-1) and (V-1), as the lower alkyl group represented by R ⁴ , methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like having 1 to 1 carbon atoms 4 are listed.

In this method, the 2-aminobenzophenone derivative (IV) is reacted with (V-1) in the presence of an acid to produce (I-1). The reaction of (IV) and (V-1) 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, alcohols such as methanol, ethanol and propanol,
N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, acetic acid and the like can be mentioned. The reaction of (IV) and (V-1) is carried out in the presence of a Lewis acid such as aluminum chloride or zinc chloride, or an appropriate acid such as hydrochloric acid, sulfuric acid, trifluoroacetic acid or p-toluenesulfonic acid. The amount used of the compound is 0.4 with respect to the compound (IV).
It is preferably about 05 to 2.0 mol. This reaction is usually at 20 ℃
To 200 ° C, preferably about 30 ° C to 150 ° C. The reaction time is 0.5 to 20 hours, preferably 1 to 10
It's time. The compound (I-1) thus obtained can be separated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction,
It can be isolated and purified by crystallization, recrystallization, phase transfer, chromatography and the like. Method B

[0054]

[Chemical 7]

[In the formula, each symbol has the same meaning as described above. ]
In this method, a 2-aminobenzophenone derivative (IV) is reacted with a nitrile derivative (VI-1) to give a quinazoline derivative.
(I-2) is produced. The reaction of (IV) and (VI-1) is carried out in a suitable solvent. Examples of the solvent include benzene,
Aromatic hydrocarbons such as toluene and xylene, ethers such as dioxane, tetrahydrofuran and dimethoxyethane, N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetra Examples include chloroethane and acetic acid.

The reaction of (IV) with (VI-1) is carried out in the presence of a Lewis acid such as aluminum chloride or zinc chloride, an appropriate acid such as sulfuric acid, trifluoroacetic acid or p-toluenesulfonic acid. The amount of acid used is about 1-5 mol, preferably about 1-2 mol, relative to compound (IV). This reaction is generally carried out at 20 ° C to 200 ° C, preferably about 30 ° C to 150 ° C. The reaction time is 0.5 to 20 hours, preferably 1
~ 10 hours. The reaction can be performed in the same manner by using an excess (VI-1) as a solvent. The quinazoline derivative (I-2) 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. C method

[0057]

[Chemical 8]

[Wherein X ² is an oxygen atom or a sulfur atom,
Z ² represents an optionally substituted hydrocarbon residue or an optionally substituted heterocyclic group bonded to X ² by a ring-constituting carbon atom, and other symbols have the same meanings as described above. ]formula
In (VII) and (I-4), examples of the optionally substituted hydrocarbon residue represented by Z ² include the same as those exemplified as R and Z ¹ above. Further, as the heterocyclic group in the optionally substituted heterocyclic group which is bonded to X ² by a ring-constituting carbon atom, the above-mentioned R and Z can be mentioned.
^{The same as the one} exemplified as ¹ . In this method, (I-3) was produced in the same manner as in method A, and then (V
Reaction with II) produces (I-4). (IV) and (V-
The reaction 2) is carried out in the same manner as in Method A. (I-3) and (VI
The reaction of I) 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, alcohols such as methanol, ethanol and propanol, ethyl acetate, acetonitrile, pyridine and N, N-dimethyl. Formamide, dimethyl sulfoxide, chloroform, dichloromethane,
1,2-dichloroethane, 1,1,2,2-tetrachloroethane, acetone, 2-butanone and a mixed solvent thereof may be used.

The reaction between (I-3) and (VII) is carried out by using an alkali metal salt such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate or sodium hydrogen carbonate, or silver carbonate.
(Ag ₂ CO ₃ ), pyridine, triethylamine, amines such as N, N-dimethylaniline and the like, and sodium hydride, potassium hydride and the like in the presence of an appropriate base. It is preferably about 1 to 5 mol relative to -3). This reaction is generally carried out at -20 ° C to 150 ° C, preferably about -10 ° C to 100 ° C. The quinoline derivatives (I-3) and (I-4) thus obtained can be isolated and purified by known methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization,
It can be isolated and purified by recrystallization, phase transfer, chromatography and the like. Method D

[0060]

[Chemical 9]

[In the formula, each symbol has the same meaning as described above. ]
In this method, (I-5) was produced in the same manner as in Method B, and then
Reaction with (VII) produces (I-6). (I-5)
The reaction of (VII) is carried out in the same manner as the reaction of (I-3) and (VII) in Method C. The quinazoline derivatives (I-5) and (I-6) thus obtained are 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. can do. E method

[0062]

[Chemical 10]

[In the formula, each symbol has the same meaning as described above. ]
In this method, by subjecting compound (I-7) to a reduction reaction,
The alcohol compound (I-8) is produced. 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 carried out by treating compound (I-7) 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 (Triphenyltin, etc.), nickel compounds, metals such as zinc compounds and metal salts, catalytic reducing agents using transition metal catalysts such as palladium, platinum, rhodium and hydrogen, and diborane.

This reaction 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, 1,1,2,2-tetrachloroethane. Ethers such as diethyl ether, tetrahydrofuran, dioxane, methanol, ethanol, propanol, isopropanol, 2
-Alcohols such as methoxyethanol, amides such as N, N-dimethylformamide, and mixed solvents thereof are appropriately selected and used according to the kind of the reducing agent. The reaction temperature is -20 ° C to 150 ° C, especially 0 ° C to 1
00 ° C. is suitable, and the reaction time is about 1 to 24 hours. The quinoline derivative (I-
8) can be isolated and purified by known separation / purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. F method

[0065]

[Chemical 11]

[In the formulas (IX), (I-10) and (I-11), q
Is an integer of 1 to 5 in formulas (I-9), (VIII), (I-
10) and (I-11), Y'is a nitrogen atom or C-COO.
Representing R ⁴ , other symbols have the same meanings as described above. In this method, first, a compound represented by the general formula (VI) is reacted with an amount of triphenylphosphine corresponding to the reaction,
A phosphonium salt derivative represented by II) is produced. This reaction is carried out in a solvent, and examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran, dioxane and dimethoxyethane, acetonitrile and a mixed solvent thereof. This reaction is 10 ° C to 200 ° C, preferably 30 ° C to 1
It is carried out at 50 ° C. for 0.5 to 50 hours.

Then, the phosphonium salt (VIII) and the aldehyde derivative (IX) are subjected to a condensation reaction to produce (I-10). The condensation reaction of (VIII) and (IX) is carried out in a suitable solvent in the presence of a base. As the solvent, alcohols such as methanol, ethanol and propanol,
Ethers such as ethyl ether, dioxane, tetrahydrofuran, dimethoxyethane, aromatic hydrocarbons such as benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, N, N-dimethylformamide, dimethyl sulfoxide and mixed solvents thereof Can be mentioned. Examples of the base include alkali metal hydrides such as sodium hydride and potassium hydride, sodium ethoxide, sodium methoxide, potassium ethoxide, potassium tert. Alkoxides such as butoxide,
Organolithium compounds such as methyllithium, butyllithium and phenyllithium, sodium amide and the like are used. The amount of these bases used is preferably about 1 to 1.5 mol with respect to compound (VIII). This reaction is usually -50 ° C.
-100 degreeC, Preferably it is -20 degreeC-50 degreeC. The reaction time is 0.5 to 20 hours.

(I-10) is obtained as a mixture of isomers of the (E) -form and the (Z) -form with respect to the newly formed double bond, and these (E) -form and (Z) -form are isolated after isolation. Each
Alternatively, the mixture is subjected to a reduction reaction without isolation, and (I
-11) is produced. This reduction reaction is carried out in a solvent according to a conventional method,
It is carried out in a hydrogen atmosphere in the presence of a catalyst such as a palladium catalyst (palladium carbon, palladium black, etc.), a platinum catalyst (platinum dioxide, etc.), Raney nickel, etc. As the solvent, alcohols such as methanol, ethanol and propanol,
Ethers such as ethyl ether, dioxane, tetrahydrofuran, dimethoxyethane, aromatic hydrocarbons such as benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, ethyl acetate, acetonitrile, acetone, 2-butanone, N, N- Examples thereof include dimethylformamide, dimethylsulfoxide and a mixed solvent thereof. The hydrogen atmosphere pressure is 1 to 150 atm, preferably 1 to 20 atm. The quinoline or quinazoline derivative (I-10) thus obtained and
(I-11) can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. G method

[0069]

[Chemical 12]

[In the formula, each symbol has the same meaning as described above. ]
In this method, first, the quinoline ester derivative (I-7) is subjected to a hydrolysis reaction to produce a carboxylic acid derivative (I-12). This hydrolysis reaction is performed in a solvent in the presence of an acid or a base according to a conventional method. As the solvent, for example, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, N, N-dimethylformamide, dimethyl sulfoxide, acetone and the like and a mixed solvent of water can be appropriately used. Examples of the base include potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, potassium tert. Butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide and the like are used. Examples of the acid include hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid and the like. The acid or base is in excess (base: 1.2 to 10 equivalents, relative to compound (I-7),
Acid: 2 to 50 equivalents) are preferably used. This reaction is generally -20 ° C to 150 ° C, preferably about -10 ° C to 100 ° C.
It is performed at ℃.

Then, the compound (I-12) is subjected to an amidation reaction to produce (I-13). This amidation reaction is carried out by reacting compound (I-12) with compound (X).
The condensation reaction of (I-13) and (X) is carried out by a usual peptide synthesis means. The peptide synthesizing means may follow any known method, for example, M. Bodanski (MB
odansky) and M. Ondetti (MA).
Ondetti), Peptide Synt
hesis), Interscience, New York, 1966
Year; FM Finn and K. Hofmann, The Proteins (Th
e Proteins), Volume 2, H. Nenra
th), edited by RL Hill, Academic Press, Inc., New York, 1976;
Nobuo Izumiya et al., "Fundamentals and Experiments of Peptide Synthesis," Maruzen
Ltd., 1985, for example, azide method, chloride method, acid anhydride method, mixed acid anhydride method, DC
C method, active ester method, method using Woodward reagent K, carbonyldiimidazole method, redox method, DCC
In addition to the / HONB method and the like, a method using DEPC (diethyl cyanophosphate) can be mentioned. This condensation reaction can be carried out in a solvent. Examples of the solvent include anhydrous or hydrous dimethylformamide, dimethylsulfoxide,
Pyridine, chloroform, dichloromethane, tetrahydrofuran, acetonitrile or an appropriate mixture thereof may be mentioned. The reaction temperature is usually about -20 ° C to about 5 ° C.
It is 0 ° C, preferably -10 ° C to 30 ° C. The reaction time is 1 to 100 hours, preferably 2 to 40 hours. The quinoline derivative (I-12) thus obtained and
(I-13) 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. H method

[0072]

[Chemical 13]

[Each symbol in the formula has the same meaning as described above. ]
The reaction of compound (IV) with malonic acid ester derivative (XI) is carried out in the presence of a base according to a method known per se. Examples of the base include trialkylamine (eg, trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4- Organic bases such as diazabicyclo [2.2.2] non-5-ene, 1,8-diazabicyclo [5.4.0] -7-undecene are mentioned. The amount of these bases used is 1 with respect to compound (IV).
It is preferably about 5 to 5 mol. This reaction is usually 0 ° C to 200 ° C.
C., preferably about 20 to 150.degree. Then, the compound (XII) is chlorinated to produce (XIII).
This method is performed according to a known method. For example, phosphorus pentachloride,
It is carried out by heating with phosphorus oxychloride, thionyl chloride, or oxalyl chloride in a solvent or without a solvent.

Compound (XIII) can be converted to quinoline derivative (I-14) by reaction with (VII). (XI
The reaction of II) and (VII) is carried out in a suitable solvent. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, dioxane, tetrahydrofuran,
Ethers such as dimethoxyethane, alcohols such as methanol, ethanol and propanol, ethyl acetate, acetonitrile, pyridine, N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2, 2-Tetrachloroethane, acetone, 2-butanone and a mixed solvent thereof may be mentioned. The reaction between (XIII) and (VII) is carried out by alkali metal salts such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogen carbonate, amines such as pyridine, triethylamine and N, N-dimethylaniline, hydrogenation. It is carried out in the presence of an appropriate base such as sodium or potassium hydride, and the amount of these bases to be used is preferably about 1 to 5 mol relative to the compound (XIII). This reaction is generally carried out at -20 ° C to 150 ° C, preferably about -10 ° C to 100 ° C. The quinoline derivative (I-14) 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 I

[0075]

[Chemical 14]

[In the formula (I-16), r represents 1 or 2,
Other symbols have the same meanings as described above. In this method, compound (I-16) obtained by method C or method D is subjected to an oxidation reaction to produce compound (I-16). This oxidation reaction is carried out according to a conventional method using an oxidizing agent such as m-chloroperbenzoic acid, hydrogen peroxide, peresters, sodium metaperiodate and the like. This oxidation is an organic solvent which is inert under the reaction conditions, such as halogenated hydrocarbons.
(Eg, methylene chloride, chloroform, dichloroethane, etc.), or hydrocarbons (eg, benzene, toluene, etc.), alcohols (methanol, ethanol, propanol, etc.)
It is carried out advantageously in. When the oxidizing agent is used in an equimolar amount or in an equimolar amount or less with respect to the compound (I-15), it has the formula:
Among (I-16), the compound in which r is 1 is preferentially produced.
The compound of the formula (I-16) in which r is 2 is formed by further oxidizing the compound of the formula (I-16) in which r is 1 when the oxidizing agent is used in excess of an equimolar amount. This reaction is carried out at room temperature or lower, preferably at a temperature of about −50 ° C. to 20 ° C., usually for 0.5 to 10 hours. The quinoline or quinazoline derivative (I-16) 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. . J method

[0077]

[Chemical 15]

[In the formula, each symbol has the same meaning as described above. ]
In this method, a compound (I-17) in which X ² is a sulfur atom among compounds obtained by Method H is subjected to an oxidation reaction to give a compound
(I-18) is produced. This oxidation reaction is carried out in the same manner as in Method I. The quinoline derivative (I
-18) is a known separation and purification means such as concentration, concentration under reduced pressure,
It can be isolated and purified by solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. K method

[0079]

[Chemical 16]

[In the formulas (I-19) and (I-20), Q'represents a leaving group, and other symbols have the same meanings as described above. The leaving group represented by Q ′ is, for example, a halogen atom, preferably chlorine, bromine or iodine, or a hydroxyl group activated by esterification, 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 this method, the compound (I-19) is first subjected to an oxidation reaction to produce the compound (I-20). This oxidation reaction is carried out in the same manner as in Method I using an oxidizing agent such as m-chloroperbenzoic acid, hydrogen peroxide, peresters, sodium metaperiodate and the like. This oxidation is an organic solvent which is inert under the reaction conditions, for example, a halogenated hydrocarbon (eg, methylene chloride, chloroform, dichloroethane, etc.), or a hydrocarbon (eg, benzene, toluene, etc.), alcohols (methanol, (Ethanol, propanol, etc.)
It is carried out advantageously in. The oxidizing agent is used in the amount of 1-5 mol equivalents, preferably 1-2 mol equivalents, relative to compound (I-19). The present reaction is 0 to 120 ° C, preferably about 10 ° C to
It is usually performed at a temperature of 100 ° C. for 0.5 to 10 hours. Then, the compound (I-20) was converted to the compound (I-5) in Method D.
Compound (I-21) is produced by reacting with Compound (VII) in the same manner as in the reaction of Compound (I-6). The quinoline or quinazoline derivative (I-20) and (I-21) thus obtained can be 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. Among the compounds (I-21) produced by Method K, the compound in which X ² is a sulfur atom can be converted into a sulfinyl body or a sulfonyl body in the same manner as Method I. L method

[0081]

[Chemical 17]

[In the formula, each symbol has the same meaning as described above. ]
In this method, compound (II-1) is produced by reacting compound (IV) with tetronic acid derivative (XIV). This reaction is carried out in the same manner as Method A. The quinoline (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. M method

[0083]

[Chemical 18]

[In the formula, each symbol has the same meaning as described above. ]
In this method, compound (III-1) is produced by reacting compound (I-22) with amine derivative (XV). (I-22)
The reaction between (XV) and (XV) 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, methanol, ethanol, and the like.
Alcohols such as propanol, ethyl acetate, acetonitrile, pyridine, N, N-dimethylformamide,
Examples thereof include dimethyl sulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, acetone, 2-butanone and a mixed solvent thereof. The reaction of (I-22) and (XV) is carried out by using alkali metal salts such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogen carbonate, amines such as pyridine, triethylamine and N, N-dimethylaniline, It is carried out in the presence of an appropriate base such as sodium hydride or potassium hydride, and the amount of these bases to be used is preferably about 1-5 mol relative to compound (I-22). This reaction is generally -20 ° C to 150 ° C, preferably about -10 ° C.
It is carried out at -100 ° C. The quinoline (III-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. N method

[0085]

[Chemical 19]

[In the formula, each symbol has the same meaning as described above. ]
The reaction of (I-23) and (X) is carried out in a suitable solvent. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, dioxane, tetrahydrofuran,
Ethers such as dimethoxyethane, alcohols such as methanol, ethanol and propanol, ethyl acetate, acetonitrile, pyridine, N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2, 2-Tetrachloroethane, acetone, 2-butanone and a mixed solvent thereof may be mentioned. This reaction is sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate,
Alkali metal salts such as sodium hydrogen carbonate, pyridine,
It is carried out in the presence of an amine such as triethylamine and N, N-dimethylaniline, and an appropriate base such as sodium hydride and potassium hydride.
About 1 to 5 mol is preferable with respect to (I-23). This reaction is generally -20 ° C to 150 ° C, preferably about -10 ° C to 10 ° C.
It is carried out at 0 ° C. In this reaction, (X) can be used as a base by using an excess of (X). The quinoline or quinazoline derivative (I-
24) 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 quinoline derivative produced by the L method and the M method is quinoline 1-
It can be an oxide. O method

[0087]

[Chemical 20]

[Each symbol in the formula has the same meaning as described above. ]
In this method, compound (XII) is converted to mercapto derivative (XVI).
And then reacting with compound (XVII) to give compound (I-
25) is manufactured. The reaction from (XII) to (XVI) is
Phosphorus pentasulfide (P ₂ S ₅ ) or Lawesson in solvent
It is performed by using a sulfiding agent such as a reagent. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran and dimethoxyethane, pyridine, chlorobenzene, dichlorobenzene, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2. Examples include 2,2-tetrachloroethane and a mixed solvent thereof. The amount of the sulfiding agent used is preferably about 1 to 5 mol based on the compound (XII). This reaction is generally 0 ° C to 200 ° C, preferably about 10 ° C.
It is carried out at a temperature of 180 ° C to 180 ° C. Compound (XVI) and compound (X
The reaction of VII) is carried out in the same manner as the reaction of the compounds (I-3) and (VII) of Method C. The quinoline derivative (I-25) 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 P 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. , A-ring by converting the isopropoxy group to a hydroxyl group, B
A compound whose ring 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, and -50 ° C to 10 ° C.
0 ° C., preferably -20 ° C. to 80 ° C.

The bone resorption inhibiting action of the pharmaceutical composition of the present invention will be described below with reference to test examples. Test Example 1 [Bone resorption inhibitory action] Bone resorption activity was measured by the method of Royce [Journal of Clinical Investigation]
(J. Clin. Invest.), 44 , 103-116 (196).
5)] That is, Sprague on the 18th day of pregnancy
⁴⁵ Ca per Sprague-Dawley rat
(Calcium isotope, CaCl ₂ solution) was subcutaneously injected at 50 μCi, the abdomen was opened on the next day, and the fetal rat was aseptically removed.
Left and right forearm bones (radius, ulna) of fetal rats under a dissecting microscope
Was separated from the trunk, and the connective tissue and cartilage were removed as much as possible to obtain a bone culture sample. Fitton-Jackson modific
ation) (BGJb Medium; GIBCOLaboratorie
s, USA), bovine serum albumin (final concentration 2 mg / ml) was added to 0.6 ml of medium, and bone was added to each at 24 ° C at 37 ° C.
Incubated for hours. The bone was treated with a compound (final concentration 1 μg / ml,
It was cultured for 2 days in the above medium supplemented with 10 μg / ml or 10 μM). ⁴⁵ Ca released from bone into the medium
The ratio (%) was determined according to the following equation by measuring the radioactivity of ⁴⁵ Ca in medium and the radioactivity of ⁴⁵ Ca in bone.

[0093]

[Equation 1] Bone obtained from a litter of fetuses was similarly cultured for 2 days without adding a compound, which was used as a control group. The average value ± standard deviation of the values obtained from 5 bones in each group was determined, and the ratio (%) of this value to the value of the control group was determined and is shown in Table 1.

[Table 1]

[0094]

EXAMPLES Next, the present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited thereto. Example 1 2-Amino-3 ′, 4′-dimethoxy-4,5-ethylenedioxybenzophenone (6.5 g), ethyl 4-chloroacetoacetate (3.7 g) and acetic acid (60 ml) in 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 and 2N N
It was made alkaline with aOH and extracted with chloroform. The chloroform layer was washed with water, dried and the solvent was distilled off (MgSO ₄₎ After vacuo, and the residue was subjected to silica gel column chromatography. 2-Chloromethyl-4- (3,4-dimethoxyphenyl) -6,7-ethylenedioxyquinoline-3 from the portion eluted with chloroform-ethyl acetate (7: 3, v / v).
-Carboxylic acid ethyl ester (5.5 g, 60%) was obtained.
This was recrystallized from acetone. Colorless prism crystals. Melting point 197-198 [deg.] C. Elemental analysis C ₂₃ H ₂₂ NO ₆ calculated for Cl: C, 62.24; H, 5.
00; N, 3.16. Analytical value: C, 61.95; H, 5.15; N, 3.0
1. Examples 2 to 26 The compounds of Tables 2 to 4 were obtained in the same manner as in Example 1.

[0095]

[Table 2]

Note 1) NMR (δ ppm) in CDCl ₃ : 0.92
(3H, t, J = 7.2Hz), 4.06 (2H, q, J = 7.2H
z), 5.03 (2H, s), 7.33-7.37 (2H, m), 7.5
0-7.55 (3H, m), 7.90-7.98 (2H, m), 8.2
6 (1H, d, J = 9.4Hz).

[0097]

[Table 3] Note 1) 2-chloromethyl-4- (3,4-dimethoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylic acid methyl ester

[0098]

[Table 4]

Example 27 Concentrated sulfuric acid was added to a mixture of 2-amino-4,5,3 ', 4'-tetramethoxybenzophenone, ethyl acetoacetate and acetic acid, and the same treatment as in Example 1 was carried out to give 6,7-. Dimethoxy-4- (3,4-dimethoxyphenyl) -2-methylquinoline-3-carboxylic acid ethyl ester (83%) was obtained.
This was recrystallized from ethanol. Colorless prism crystals. Melting point 147-148 [deg.] C. Examples 28 to 49 In the same manner as in Example 27, the compounds shown in Tables 5 to 9 were obtained.

[0100]

[Table 5]

[0101]

[Table 6]

[0102]

[Table 7]

[0103]

[Table 8]

[Table 9]

Example 50 2-Amino-4,5,3 ', 5'-tetramethoxy-4'-hydroxybenzophenone (0.333 g), tetronic acid (tetrahydrofuran-2,4-dione) (0.11 g) Concentrated sulfuric acid (1 drop) was added to a mixture of acetic acid (10 ml) and the mixture was stirred at 100 ° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure, the residual oil was poured into water, neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The chloroform layer was washed with water and dried was distilled off (MgSO ₄₎ the solvent, 6,7-dimethoxy-9- (4-hydroxy-3,5-dimethoxyphenyl) furo [3,4-b] quinoline -1 ( 3H) -ON (0.34)
9 g, 88%) was obtained. Recrystallized from methanol. Pale yellow needles. Melting point 247-248 [deg.] C. Examples 51 to 55 In the same manner as in Example 50, the compounds in Table 10 were obtained.

[0105]

[Table 10]

Example 56 2-Chloromethyl-6,7-dimethoxy-4- (3,4-
Dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester (3.0 g), metachloroperbenzoic acid (85%, 2.
A mixture of 3 g) and methanol (40 ml) was 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. Wash the chloroform layer with water,
Drying the solvent was distilled off under reduced pressure (MgSO _4), and 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, 65%) was obtained. This was recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 193-194 [deg.] C. Elemental analysis C ₂₃ H ₂₄ NO ₇ Calculated as Cl: C, 59.81; H, 5.
24; N, 3.03. Analytical value: C, 59.69; H, 5.32; N, 3.0
5.

Example 57 Powdered aluminum chloride (6.7g) was added to a mixture of 2-amino-4,5,3 ', 4'-tetramethoxybenzophenone (8.0g) and chloroacetonitrile (25ml) at 100 ° C.
Stirred for 2 hours. The reaction mixture was poured into water and extracted with chloroform. The chloroform layer was washed with water and dried (MgSO
₄ ) After that, the solvent was distilled off, and the residue was subjected to silica gel column chromatography. Chloroform-ethyl acetate (10:
1, v / v), 2-chloromethyl-6,
7-Dimethoxy-4- (3,4-dimethoxyphenyl) quinazoline (4.9 g, 52%) was obtained. Recrystallized from acetone. Colorless prism crystals. Melting point 183-184 [deg.] C.

Example 58 Sodium iodide (1.68 g) and methyl ethyl ketone
After stirring the mixture (15 ml) at 80 ° C. for 1 hour, 2-
Chloromethyl-6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester (2.0 g)
Was added, and the mixture was stirred at the same temperature for 12 hours. The insoluble solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and freed from dried (MgSO ₄₎ and the solvent. The remaining oily substance was subjected to silica gel column chromatography, and eluted with chloroform-ethyl acetate (1: 1, v / v) from the portion 6,7-.
Dimethoxy-4- (3,4-dimethoxyphenyl) -2-
Iodomethylquinoline-3-carboxylic acid ethyl ester
(1.4 g, 58%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 170-171 [deg.] C. Calculated for elemental analysis _{C 23 H 24 NO 6 J:} C51.41; H, 4.5
0; N, 2.61. Analytical value: C, 51.25; H, 4.53; N, 2.5
8.

Example 59 2-Chloromethyl-6,7-dimethoxy-4- (3,4-
Dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester (3.0 g), 1-ethyl-2-mercaptoimidazole (1.0 g), potassium carbonate (1.1 g) and N, N-.
A mixture of dimethylformamide (30 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and freed from dried (MgSO ₄₎ the solvent under reduced pressure. The residue was subjected to silica gel column chromatography, and chloroform-ethyl acetate (3: 2, v /
2-[(1-ethylimidazole-
2-yl) thiomethyl] -6,7-dimethoxy-4- (3,
4-Dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester (2.8 g, 78%) was obtained. This was recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 1
57-158 ° C. Elemental analysis C ₂₈ H ₃₁ N ₃ O ₆ Calculated as S: C, 62.55; H, 5.
81; N, 7.82. Analytical value: C, 62.55; H, 5.84; N, 7.7
9.

Example 60 6,7-Dimethoxy-4- (3,4-dimethoxyphenyl)
-2-[(1-methylimidazol-2-yl) thiomethyl] quinoline-3-carboxylic acid ethyl ester (3.0 g)
To a dichloromethane (75 ml) solution of was added metachloroperbenzoic acid (85%, 830 mg) little by little under ice cooling. The reaction mixture was stirred at room temperature for 2.5 hours and then 5% NaHSO ₃
Aqueous, saturated sodium bicarbonate solution, then with water, dried (MgSO _4). After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography, and was eluted with ethyl acetate-methanol (10: 1, v / v) from 6,7-dimethoxy-4- (3,4-). (Dimethoxyphenyl)
-2-[(1-Methylimidazol-2-yl) sulfinylmethyl] quinoline-3-carboxylic acid ethyl ester
(1.8 g, 58%) was obtained. This was recrystallized from acetone-ethyl ether. Colorless prism crystals. Melting point 193-1
94 ° C. Elemental analysis C ₂₇ H ₂₉ N ₃ O ₇ calculated for S: C, 60.10; H, 5.
42; N, 7.79. Analytical value: C, 59.80; H, 5.
60; N, 7.51.

Example 61 2-[(2-Benzimidazolyl) sulfinylmethyl] -6,7-dimethoxy-4-as in Example 60.
(3,4-dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester was obtained. This was recrystallized from acetone. Colorless prism crystals. Melting point 160-161 [deg.] C. Calculated for elemental analysis _{C 30 H 29 N 3 O 7} S: C, 62.60; H, 5.
08; N, 7.30. Analytical value: C, 62.21; H, 5.10; N, 7.0
9.

Example 62 6,7-Dimethoxy-4- (3,4-dimethoxyphenyl)
-2-[(1-Methylimidazol-2-yl) thiomethyl] quinoline-3-carboxylic acid ethyl ester (2.5 g)
To a dichloromethane (60 ml) solution of was added metachloroperbenzoic acid (85%, 2.5 g) little by little under ice cooling. The reaction mixture was stirred at room temperature for 4 hours, then washed with 5% NaHSO ₃ aqueous solution, saturated sodium hydrogen carbonate aqueous solution, and water in this order,
Dried (MgSO ₄₎ and the. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-methanol (10: 1, v / v) from the portion of 6,7.
-Dimethoxy-4- (3,4-dimethoxyphenyl) -2
-[(1-Methylimidazol-2-yl) sulfonylmethyl] quinoline-3-carboxylic acid ethyl ester (1.5
g, 58%). This was recrystallized from acetone-ethyl ether. Colorless prism crystals. Melting point 183-184
° C. Elemental analysis C ₂₇ H ₂₉ N ₃ O ₈ calculated for S: C, 58.37; H, 5.
26; N, 7.56. Analytical value: C, 58.46; H, 5.24; N, 7.2
0.

Example 63 In the same manner as in Example 62, 2-[(2-benzimidazolyl) sulfonylmethyl] -6,7-dimethoxy-4- (3,
4-Dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester was obtained. This was recrystallized from acetone-isopropyl ether. Colorless prism crystals. Melting point 181-
182 ° C. Calculated for elemental analysis _{C 30 H 29 N 3 O 8} S: C, 60.90; H, 4.
94; N, 7.10. Analytical value: C, 60.76; H, 4.86; N, 7.0
9.

Example 64 6,7-Dimethoxy-4- (3,4-dimethoxyphenyl)
-2-[(1-Methylimidazol-2-yl) thiomethyl] quinoline-3-carboxylic acid ethyl ester (4.9 g)
To an ethanol (100 ml) solution of hydrogen chloride was added dropwise an ethanol solution of hydrogen chloride (27%, 1.3 g) at room temperature. About 2 / under reduced pressure
The solvent of 3 was distilled off, ethyl ether was added to the residue, and the precipitated crystals were collected by filtration. The crystals collected by filtration were recrystallized from isopropanol to give 6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2-[(1-methylimidazole-
2-yl) Thiomethyl] quinoline-3-carboxylic acid ethyl ester hydrochloride monohydrate (3.0 g, 55%) was obtained. Colorless prism crystals. Melting point 133-134 [deg.] C. Elemental analysis _{C 27 H 29 N 3 O 6} S · HCl · H 2 calculated for O: C, 5
6.10; H, 5.58; N, 7.27. Analytical value: C, 55.84; H, 5.72; N, 7.1
6.

Example 65 In the same manner as in Example 59, 6,7-dimethoxy-4- (2
-Methoxyphenyl) -2-[(1-methylimidazol-2-yl) thiomethyl] quinoline-3-carboxylic acid ethyl ester (89%) was obtained as an oil. NMR (δ ppm) in CDCl ₃ : 0.90 (3H, t, J = 7H
z), 3.34 (3H, s), 3.70 (3H, s), 3.74 (3H,
s), 3.98 (2H, q, J = 7Hz), 4.03 (3H, s), 4.6
4 (2H, s), 6.66 (1H, s), 6.86 (1H, s), 7.01
-7.16 (4H, m), 7.34 (1H, s), 7.45 (1H, dou
blet, J = 8 and 2 Hz).

This oil was dissolved in ethanol (15 ml) and hydrogen chloride in ethanol (23%, 1.2 g) was added. The solvent was distilled off under reduced pressure, and 6,7-dimethoxy-4-
(2-Methoxyphenyl) -2-[(1-methylimidazol-2-yl) thiomethyl] quinoline-3-carboxylic acid ethyl ester hydrochloride (2.0 g) was obtained. This was recrystallized from ethanol-ether. Pale yellow prism crystal. Melting point 1
80-181 ° C. Elemental analysis _{C 26 H 27 N 3 O 5} S · HCl · 1 / 2H 2 calculated for O: C, 57.93; H, 5.42; N, 7.80. Analytical value: C, 58.05; H, 5.32; N, 7.7
2.

Example 66 In the same manner as in Example 59, 6,7-dimethyl-4- (3,
4-dimethylphenyl) -2-[(1-methylimidazo
Lu-2-yl) thiomethyl] quinoline-3-carboxylic acid
The chill ester (97%) was obtained as an oil. NMR (δ ppm) CDCl₃Medium: 0.93 (3H, t,J= 7H
z), 2.31 (3H, s), 2.32 (3H, s), 2.35 (3H,
s), 2.44 (3H, s), 3.42 (3H, s), 4.03 (2H, q,
J= 7 Hz), 4.61 (2H, s), 6.88 (1H, d,J= 1H
z), 7.03-7.10 (3H, m), 7.23 (1H, d,J= 8
Hz), 7.35 (1H, s), 7.78 (1H, s).

This oil was dissolved in ethanol (10 ml) and hydrogen chloride in ethanol (23%, 0.584 g) was added. The solvent was distilled off under reduced pressure, and 6,7-dimethyl-4
There was obtained-(3,4-dimethylphenyl) -2-[(1-methylimidazol-2-yl) thiomethyl] quinoline-3-carboxylic acid ethyl ester hydrochloride (1.1 g). Recrystallized from ethanol-ether. Pale yellow prism crystal. Melting point 1
33-134 ° C. Elemental analysis _{C 27 H 29 N 3 O 2} S · HCl · 3 / 2H 2 calculated for O: C, 62.00; H, 6.36; N, 8.03. Analytical value: C, 62.31; H, 6.01; N, 7.9
8.

Example 67 In the same manner as in Example 59, 6,7-dimethoxy-4-
There was obtained (3,4-dimethoxyphenyl) -2-[(1-methylimidazol-2-yl) thiomethyl] quinoline-3-carboxylic acid ethyl ester 1-oxide (69%). This was recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 171-172 [deg.] C. Elemental analysis C ₂₇ H ₂₉ N ₃ O ₇ calculated for S: C60.10; H, 5.
42; N, 7.79. Analytical value: C, 60.29; H, 5.53; N, 7.4
9.

Examples 68 to 130 In the same manner as in Example 59, the compounds shown in Tables 11 to 20 were obtained.

[0121]

[Table 11]

[0122]

[Table 12]

[0123]

[Table 13]

[0124]

[Table 14]

[0125]

[Table 15]

[0126]

[Table 16]

[0127]

[Table 17]

[0128]

[Table 18]

[0129]

[Table 19]

[0130]

[Table 20]

Example 131 2-Chloromethyl-6,7-dimethoxy-4- (3,4-
A mixture of dimethoxyphenyl) quinazoline (4.5 g), 2-mercaptoethanol (1.13 g), potassium carbonate (2.8 g) and N, N-dimethylformamide (50 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄₎
After that, the solvent was distilled off to obtain 6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2- (2-hydroxyethylthiomethyl) quinazoline (4.1 g, 82%). Recrystallized from ethanol. Colorless brism crystal. Melting point 154-155
℃

Examples 132 to 138 The compounds in Table 21 were obtained in the same manner as in Example 131.

[0133]

[Table 21]

Examples 139 to 141 The compounds in Table 22 were obtained in the same manner as in Example 60.

[0135]

[Table 22]

Example 142 [6,7-Dimethoxy-4- (3,4-dimethoxyphenyl)
) -3-Ethoxycarbonylquinolin-2-yl] methyl
Rutriphenylphosphonium chloride (17.4g)
Ethanol solution of lithium ethoxide [Na (0.62g) and ethanol
Prepared from tanol (150 ml)] at room temperature. Incidentally
2-Formyl-1-methylimidazole (3.7 g)
A solution of Nol (20 ml) was added dropwise. Mix for 3 hours at room temperature
After stirring, the mixture was poured into water and extracted with ethyl acetate. Acetic acid
The ethyl layer was washed with water and dried (MgSO_Four) After removing the solvent,
The distillate was subjected to silica gel column chromatography.
Elute with chloroform-methanol (100: 1, v / v)
From (E) -6,7-dimethoxy-4- (3,4-
Dimethoxyphenyl) -2- [2- (1-methylimidazo
2-l) Vinyl] quinoline-3-carboxylic acid ethi
Luster (8.3 g, 67%) was obtained. Re from ethyl acetate
It crystallized. Colorless prism crystals. Melting point 206-208 [deg.] C. One
(Z) -6,7-dimethoxy-4-
(3,4-dimethoxyphenyl) -2- [2- (1-methyl
Imidazol-2-yl) vinyl] quinoline-3-carbo
Obtained acid ethyl ester (2.6 g, 21%) as an oil.
It was NMR (δ ppm) CDCl₃Medium: 0.96 (3H, t,J= 7H
z), 3.35 (3H, s), 3.78 (3H, s), 3.87 (3H,
s), 3.96 (3H, s), 3.97 (3H, s), 3.98 (2H, q,
J= 7Hz), 6.69 (1H, d,J= 12 Hz), 6.8-7.
1 (7H, m), 7.13 (1H, s).

(E)-and (Z) -6,7-dimethoxy-
4- (3,4-dimethoxyphenyl) -2- [2- (1-methylimidazol-2-yl) vinyl] quinoline-3-carboxylic acid ethyl ester was treated with ethanol-tetrahydrofuran (1: 1, v / v), respectively. In the presence of 5% palladium carbon in a hydrogen atmosphere at 1 atm for hydrogenation reaction 6,7-
Dimethoxy-4- (3,4-dimethoxyphenyl) -2-
[2- (1-Methylimidazol-2-yl) ethyl] -quinoline-3-carboxylic acid ethyl ester was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 147-1
48 ° C.

Example 143 [6,7-Dimethoxy-4- (3,4-dimethoxyphenyl) quinazolin-2-yl] methyltriphenylphosphonium chloride (9.1 g) was added to an ethanol solution of sodium ethoxide [Na (0. Prepared from .394 g) and ethanol (100 ml)] at room temperature. Then, a solution of 2-formyl-1-methylimidazole (1.7 g) in ethanol (10 ml) was added dropwise. The mixture was stirred at room temperature for 3 hours, poured into water and extracted with chloroform. Wash the chloroform layer with water,
Drying was distilled off (MgSO ₄₎ the solvent, silica gel and the residue
It was subjected to column chromatography. From the part eluted with chloroform-methanol (20: 1, v / v), (E)-
6,7-dimethoxy-4- (3,4-dimethoxyphenyl)
2- [2- (1-Methylimidazol-2-yl) vinyl] quinazoline (5.1 g, 82%) was obtained. Ethanol-
Recrystallized from chloroform. Colorless prism crystals. Melting point 2
54-255 ° C. Elemental analysis Calculated value for C ₂₄ H ₂₄ N ₄ O ₄ 3 / 2H ₂ O: C, 62.
73; H, 5.92; N, 12.19 Analytical value: C, 62.62; H, 5.85; N, 11.90

Then, from the eluting portion, (Z) -6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2- [2
-(1-Methylimidazol-2-yl) vinyl] quinazoline (0.61 g, 10%) was obtained. Recrystallized from ethanol-chloroform. Colorless plate crystals. Melting point 180-181
° C. Elemental analysis _{C 24 H 24 N 4 O 4} · 1 / 2H 2 calculated for O: C, 65.
29; H, 5.71; N, 12.69 Analytical value: C, 65.28; H, 5.66; N, 12.42 (E)-and (Z) -6,7-dimethoxy-4- (3,4-
Dimethoxyphenyl) -2- [2- (1-methylimidazol-2-yl) vinyl] quinazoline in chloroform-ethyl acetate (1: 1, v / v) in the presence of 5% palladium carbon under hydrogen atmosphere 1 Subject to hydrogenation reaction at atmospheric pressure 6,
7-dimethoxy-4- (3,4-dimethoxyphenyl)-
2- [2- (1-methylimidazol-2-yl) ethyl]
I got quinazoline. Recrystallized from ethyl acetate. Colorless prism crystals. Melting point 170-171 [deg.] C.

Examples 144 to 149 The compounds in Table 23 were obtained in the same manner as in Example 142.

[0141]

[Table 23]

Example 150 6,7-Dimethoxy-4- (3,4-dimethoxyphenyl)
-2- [2- (1-Methylimidazol-2-yl) ethyl] quinoline-3-carboxylic acid ethyl ester (9.0 g)
Suspended in ethanol (40 ml) and ethanolic hydrogen chloride
(22%, 10 g) was added. After stirring the mixture for 5 minutes at room temperature, ether (150 ml) was added and the precipitated crystals were collected by filtration.
Recrystallized from ethanol-ether, 6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2- [2- (1-
Methylimidazol-2-yl) ethyl] quinoline-3-
Carboxylic acid ethyl ester dihydrochloride (9.1 g) was obtained.
Pale yellow prism crystal. Melting point 158-160 [deg.] C. Elemental analysis C ₂₈ H ₃₁ N ₃ O ₆・ 2HCl ・ 1 / 3C ₂ H ₅ OH ・ 1/2
Calculated for H ₂ O: C, 57.11; H, 6.02; N, 6.
97 Analytical value: C, 57.03; H, 6.15; N, 7.0
0

Example 151 [6,7-Dimethoxy-4- (3,4-dimethoxyphenyl) -3-ethoxycarbonylquinolin-2-yl) methyltriphenylphosphonium chloride (3.0 g) was added to sodium ethoxide in ethanol. The solution [prepared from Na (0.13 g) and ethanol (45 ml)] was added at room temperature. Then 3
-(1-Methylimidazol-2-yl) propionaldehyde (0.787 g) was added. The mixture was stirred at room temperature for 3 hours, 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 subjected to silica gel column chromatography. From the portion eluted with ethyl acetate-methanol (30: 1, v / v), (E) -6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2- [2- [2- (1 -Methylimidazol-2-yl) ethyl] vinyl] quinoline-3-carboxylic acid ethyl ester (0.36 g, 15%) was obtained as an oil. NMR (δ ppm) in CDCl ₃ : 1.03 (3H, t, J = 7H
z), 2.7-3.0 (4H, m), 3.60 (3H, s), 3.79 (3
H, s), 3.87 (3H, s), 3.97 (3H, s), 4.05 (3
H, s), 4.09 (2H, q, J = 7Hz), 6.7-7.2 (8H,
m), 7.43 (1 H, s).

Then, from the eluted portion, (Z) -6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2- [2
-[2- (1-Methylimidazol-2-yl) ethyl] vinyl] quinoline-3-carboxylic acid ethyl ester (0.2
g, 8%) as an oil. NMR (δ ppm) in CDCl ₃ : 1.02 (3H, t, J = 7H
z), 2.8-3.2 (4H, m), 3.58 (3H, s), 3.80 (3
H, s), 3.88 (3H, s), 3.96 (3H, s), 4.05 (3
H, s), 4.07 (2H, q, J = 7Hz), 6.08 (1H, dt, J
= 7.4 & 11.4 Hz), 6.6-7.0 (7H, m), 7.42
(1H, s).

(E)-and (Z) -6,7-dimethoxy-
4- (3,4-dimethoxyphenyl) -2- [2- [2- (1
-Methylimidazol-2-yl) ethyl] vinyl] quinoline-3-carboxylic acid ethyl ester mixture in ethanol-tetrahydrofuran (1: 4, v / v) in the presence of 5% palladium carbon under a hydrogen atmosphere at 1 atm. It was subjected to a hydrogenation reaction and treated with ethanolic hydrochloric acid to give 6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2- [4- (1-
Methylimidazol-2-yl) butyl] quinoline-3-
Obtained carboxylic acid ethyl ester. Recrystallized from chloroform-ethyl acetate. Pale yellow crystals. Melting point 180-18
3 ° C. Elemental analysis _{C 30 H 35 N 3 O 6} · 2HCl · H 2 calculated for O: C, 5
7.69; H, 6.29; N, 6.73 Analytical value: C, 57.48; H, 6.09; N, 6.60

Example 152 2-Chloromethyl-6,7-dimethoxy-4- (3,4-
Dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester (1.5 g), 2-hydroxy-6-methylpyridine (0.4 g), potassium carbonate (0.511 g) and N, N-.
Mix a mixture of dimethylformamide (20 ml) at 120 ° C for 2
After stirring for a period of time, the mixture was poured into water and extracted with ethyl acetate.
The ethyl acetate layer was washed with water and freed from dried (MgSO ₄₎ and the solvent. The residual oily substance was subjected to silica gel column chromatography, and was eluted with ethyl acetate to obtain 6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2-.
[(2-Methyl-6-pyridyl) oxymethyl] quinoline-
3-Carboxylic acid ethyl ester (0.79 g, 46%) was obtained. Recrystallized from chloroform-hexane. Yellow prism crystal. Melting point 173-174 [deg.] C. Calculated for elemental analysis _{C 29 H 30 N 2 O 7} : C, 67.17; H, 5.8
3; N, 5.40 analytical value: C, 66.97; H, 6.02; N, 5.16

Example 153 2-iodomethyl-6,7-dimethoxy-4- (3,4-
Dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester (9.0 g), 2-hydroxy-1-methylimidazole (1.8 g), silver (I) carbonate (Ag ₂ CO ₃ ) (5.1 g) and benzene ( After stirring the mixture (100 ml) at 50 ° C. for 18 hours, the insoluble solid was filtered off. The filtrate is washed with water and dried
After (MgSO ₄ ), the solvent was distilled off. The residual oily substance was subjected to silica gel column chromatography, and chloroform-
From the portion eluted with ethyl acetate (5: 1, v / v), 6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2-
[(1-Methyl-2-imidazolyl) oxymethyl] quinoline-3-carboxylic acid ethyl ester (0.8 g, 9%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 151-152 [deg.] C. Calculated for elemental analysis _{C 27 H 29 N 3 O 7} : C, 63.90; H, 5.8
7; N, 8.28 Analytical value: C, 63.74; H, 5.87; N, 7.99

Example 154 6,7-dimethoxy-4- (3,4-dimethoxyphenyl)
-2-[(1-methylimidazol-2-yl) thiomethyl] quinoline-3-carboxylic acid ethyl ester (0.6 g),
A mixture of 2N NaOH (1.7 ml) and ethanol (12 ml) was refluxed for 6 hours. The reaction mixture was concentrated in vacuo. The residue was diluted with water, washed with ethyl acetate, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The extracts washed with water, dried (MgSO _4), to give crystals and concentrated in vacuo. Recrystallization from ethanol-ethyl ether gave 6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2-[(1-methylimidazol-2-yl) thiomethyl] quinoline-3.
-Carboxylic acid (0.3 g, 53%) was obtained as colorless prism crystals. Melting point 213-214 [deg.] C. Elemental analysis Calculated value as C ₂₅ H ₂₅ N ₃ O ₆ S.1 / 2H ₂ O: C, 5
9.51; H, 5.19; N, 8.32 Analytical value: C, 59.38; H, 5.40; N, 7.93

Example 155 6,7-Dimethoxy-4- (3,4-dimethoxyphenyl)
-2 (1H) -quinolone-3-carboxylic acid ethyl ester
To a solution of (0.5 g) N, N-dimethylformamide (20 ml) was added oily sodium hydride (60%, 0.1 g) under ice cooling, and the mixture was stirred at room temperature for 30 minutes, and then 2-bromopropane ( 0.5 ml) was added. The mixture was stirred at 60 ° C. for 5 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, then evaporated dried (MgSO ₄₎ the solvent, 6,
7-dimethoxy-4- (3,4-dimethoxyphenyl)-
2-isopropoxyquinoline-3-carboxylic acid ethyl ester (0.388 g, 70%) was obtained. Recrystallized from ether. Melting point 142-143 [deg.] C.

Example 156 2-Hydroxymethyl-1-methylimidazole (0.0
To a solution of 85 g of N, N-dimethylformamide (7 ml) was added oily sodium hydride (60%, 0.033 g) under ice cooling, and the mixture was stirred at the same temperature for 10 minutes, and then 2-chloro-
6,7-dimethoxy-4- (3,4-dimethoxyphenyl)
Quinoline-3-carboxylic acid ethyl ester (0.3 g) was added. The mixture is kept under ice cooling for 1 hour and at room temperature for 20 hours.
Stir the time. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, was subjected dried (MgSO ₄₎ and the solvent was distilled off and the residual oil is applied to silica gel column chromatography. Ethyl acetate-methanol (30:
1,7 / dimethoxy-4-from the part eluted with (1, v / v)
There was obtained (3,4-dimethoxyphenyl) -2- (1-methylimidazol-2-yl) methoxyquinoline-3-carboxylic acid ethyl ester (0.26 g, 73%). Recrystallized from ethyl acetate-hexane. Melting point 209-210 [deg.] C.

Example 157 6,7-dimethoxy-4- (3,4-dimethoxyphenyl)
2-Mercaptoquinoline-3-carboxylic acid ethyl ester (0.2 g), 2-chloromethyl-1-methylimidazole (0.09 g) and N, N-dimethylformamide (8
oily sodium hydride (60%, 0.05 g) in a mixture of
Was added under ice-cooling, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried (MgSO ₄₎ and the solvent was distilled off and the residual oil was subjected to silica gel column chromatography. Ethyl acetate-methanol (30: 1, v / v)
6,7-dimethoxy-4- (3,4-
Dimethoxyphenyl) -2-[(1-methylimidazol-2-yl) methylthio] quinoline-3-carboxylic acid ethyl ester (0.214 g, 87%) was obtained. Melting point 141
~ 142 ° C.

Example 158 2-chloromethyl-6,7-dimethoxy-4- (3,4-
Dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester (0.58 g), 2-aminomethyl-1-methylimidazole hydrochloride (0.24 g), potassium carbonate (0.63 g)
And a mixture of N, N-dimethylformamide (15 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried
After (MgSO ₄ ) the solvent was evaporated and the residual oil was subjected to silica gel column chromatography. Chloroform-methanol (50: 1, v / v) was used to elute 2,3-dihydro-6,7-dimethoxy-9- (3,4-dimethoxyphenyl) -2- (1-methylimidazole-2- Ilmethyl) -1-oxo-1H-pyrrolo [3,4-b] quinoline (the structural formula below) (0.27 g, 43%) was obtained. Recrystallized from ethyl acetate. Melting point 245-246 [deg.] C.

[0153]

[Chemical 21]

Example 159 A mixture of 2-amino-4,5,3 ', 4'-tetramethoxybenzophenone (1.55 g), acetonedicarboxylic acid dimethyl ester (0.936 g) and acetic acid (30 ml) in concentrated sulfuric acid.
(3 drops) was added and stirred at 100 ° C. for 2.5 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. The chloroform layer was washed with water, dried was distilled off (MgSO ₄₎ the solvent under reduced pressure, the residue was recrystallized from acetone, 6,
7-dimethoxy-4- (3,4-dimethoxyphenyl)-
3-Methoxycarbonylquinoline-2-acetic acid methyl ester (1.41 g, 64%) was obtained. Colorless prism crystals. Melting point 170-171 [deg.] C.

Example 160 In the same manner as in Example 159, 6,7-dimethoxy-4-
(3,4-Dimethoxyphenyl) -3-ethoxycarbonylquinoline-2-acetic acid ethyl ester was obtained. Recrystallized from ethyl acetate-isopropyl ether. Colorless prism crystals. Melting point 146-147 [deg.] C.

Example 161 2-Amino-5-chloro-3 ′, 4′-dimethoxybenzophenone (0.23 g) and cyanoacetic acid methyl ester
Powdered aluminum chloride (0.21 g) was added to the mixture (5 ml), 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 subjected to silica gel column chromatography. Hexane-ethyl acetate
From the portion eluted at (4: 1, v / v), 6-chloro-4-
(3,4-dimethoxyphenyl) quinazoline-2-acetic acid
Methyl ester (0.161 g, 55%) was obtained. Recrystallized from isopropyl ether. Colorless needles. Melting point 144
~ 145 ° C.

Example 162 6-Chloro-4-phenylquinazoline-2-acetic acid methyl ester was obtained in the same manner as in Example 161. Recrystallized from isopropyl ether. Colorless needles. Melting point 122
~ 123 ° C.

Example 163 In the same manner as in Example 161, 6,7-dimethoxy-4-
(3,4-dimethoxyphenyl) quinazoline-2-acetic acid
The methyl ester was obtained. Recrystallized from isopropyl ether. Colorless needles. Melting point 152-153 [deg.] C.

Example 164 6,7-dimethoxy-4- (3,4-dimethoxyphenyl)
A solution of -3-ethoxycarbonylquinoline-2-acetic acid ethyl ester (5.8g) in tetrahydrofuran (100ml) was added dropwise to a suspension of lithium aluminum hydride (0.455g) in tetrahydrofuran (50ml) at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 hr, water (2.5 ml) was added dropwise, and the mixture was further stirred for 30 min. The insoluble solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and chloroform-ethyl acetate (1:
1, (v / v) to elute 2- (2-hydroxyethyl) -6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester (1.7
5 g, 33%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 150-151 [deg.] C.

Example 165 Phosphorus tribromide (PBr ₃ ) (1.0 g) was added to 2- (2-hydroxyethyl) -6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3- Carboxylic acid ethyl ester
A solution of (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 was washed with water, then evaporated dried (MgSO ₄₎ the solvent, the residue was subjected to silica gel column chromatography using chloroform - ethyl acetate (1: 1, v / v ) from the fraction eluted with 2- (2 -Bromoethyl) -6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3-
Obtained carboxylic acid ethyl ester (0.49 g, 26%).
Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 132-133 [deg.] C.

Example 166 Oily sodium hydride (60%, 0.323 g) was added to a solution of 2-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 at 80 ° C
After stirring for 1 hour, the mixture was poured into water and the precipitated crystals were collected by filtration. Recrystallized from ethanol, 2- (2-ethylimidazol-1-ylmethyl) -6,7-dimethoxy-4- (3,4-
Dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester (2.5 g, 74%) was obtained. Colorless prism crystals.
Melting point 163-164 [deg.] C. Examples 167 to 176 In the same manner as in Example 166, the compounds shown in Table 24 and Table 25 were obtained.

[0162]

[Table 24]

[0163]

[Table 25]

Example 177 Oily sodium hydride (60%, 0.044 g) was added to imidazole (0.075 g) N, N-dimethylformamide (5 m).
l) Add to the solution and stir for 15 minutes at room temperature. Then, 2-
(2-Bromoethyl) -6,7-dimethoxy-4- (3,4
-Dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester (0.46g) was added. Mix at 80 ° C for 1
The mixture was stirred for time, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and freed from dried (MgSO ₄₎ the solvent under reduced pressure. The residue was subjected to silica gel column chromatography, and 2- [2- (1-imidazolyl) ethyl] -6, from the portion eluted with ethyl acetate-methanol (10: 1, v / v).
7-Dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester (0.295 g,
66%). Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 173-174 [deg.] C.

Examples 178 to 180 In the same manner as in Example 177, the compounds shown in Table 26 were obtained.

[0166]

[Table 26]

Example 181 Oily sodium hydride (60%, 0.323 g) was added to 1H-1,
2,4-Triazole (0.558 g) was added to a solution of 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. Mix 8
The mixture was stirred at 0 ° C for 1 hr, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and freed from dried (MgSO ₄₎ the solvent under reduced pressure. The residue was subjected to silica gel column chromatography, and chloroform-methanol (40: 1, v /
From the first eluting part in v), 6,7-dimethoxy-4-
(3,4-dimethoxyphenyl) -2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylic acid
Ethyl ester (1.7 g, 53%) was obtained. Ethyl acetate-
Recrystallized from hexane. Colorless prism crystals. Melting point 176
~ 177 ° C.

Example 182 In the column chromatography of Example 181, 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. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 226-22
7 ° C.

Example 183 In the same manner as in Example 181, 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 184 In the column chromatography of Example 183, 6,7-dimethoxy-4- (4-methoxyphenyl) -2- (1,2,4-triazole-4-) was then extracted from the eluted portion.
Ilmethyl) quinoline-3-carboxylic acid ethyl ester was obtained. Recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 218-219 [deg.] C.

Example 185 In the same manner as in Example 181, 6,7-dimethoxy-4-
(4-Methoxyphenyl) -2- (1,2,4-triazol-1-ylmethyl) quinazoline was obtained. Recrystallized from dichloromethane-ethyl ether. Colorless prism crystals.
Melting point 206-207 ° C.

Example 186 In the column chromatography of Example 185, 6,7-dimethoxy-4- (4-methoxyphenyl) -2- (1,2,4-triazole-4-) was extracted from the eluted portion.
Ilumethyl) quinazoline was obtained. Recrystallized from dichloromethane-ethyl ether. Colorless needles. Melting point 212-
213 ° C.

Example 187 Methyl 2-ethyl-6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylate (0.5
g) A mixture of 4N NaOH (20 ml) and methanol was stirred under reflux for 14 hours, poured into water to acidify and extracted with chloroform. Chloroform layer is washed with water and dried
After (MgSO ₄ ), the solvent was distilled off and 6,7-dimethoxy-4-
(3,4-dimethoxyphenyl) -2-ethylquinoline-
3-Carboxylic acid (0.343 g, 71%) was obtained. Recrystallized from acetone-methanol. Melting point 264-267 [deg.] C.

Example 188 2-Ethyl-6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylic acid (0.2 g), oxalyl chloride (0.05 ml) and tetrahydrofuran (1
N, N-dimethylformamide (1 drop) was added to the mixture (0 ml) and the mixture was stirred at room temperature for 1 hr and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 ml) and this solution was added to 2-aminoethylphosphonic acid diethyl ester (0.19).
5 g), triethylamine (0.1 ml) and tetrahydrofuran (10 ml) were added dropwise. The reaction mixture was stirred at room temperature for 1 hour and further refluxed for 3 hours, poured into water and extracted with chloroform. The chloroform layer was washed with 2N hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and water in this order,
Drying was distilled off (MgSO ₄₎ and the solvent N-(2-diethoxyphosphoryl ethyl) -6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2-ethyl-quinoline-3-carboxamide (0. 21 g, 75%) was obtained. Recrystallized from ether. Melting point 157-158 [deg.] C.

Example 189 6,7-Dimethoxy-4- (3,4-dimethoxyphenyl)
Methyl 2-methylquinoline-3-carboxylate (0.4 g)
Was added dropwise to a suspension of lithium aluminum hydride (LiAlH ₄ ) (0.114 g) in tetrahydrofuran (10 ml) at room temperature. 1.At room temperature
After stirring for 5 hours, water was added and the mixture was extracted with ethyl acetate.
The ethyl acetate layer was washed with water, dried (MgSO ₄₎ and the solvent collected by filtration distilled off crystals, recrystallized 3-hydroxymethyl-6,7-dimethoxy-4- (3,4-dimethoxyphenyl) methanol - 2-Methylquinoline (0.326 g, 88%) was obtained. Melting point 200-201 ° C.

Example 190 2-Ethyl-3-hydroxymethyl-6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinoline was obtained in the same manner as in Example 189. Recrystallized from acetone-isopropyl ether. Melting point 192-193 [deg.] C.

Example 191 6,7-Dimethoxy-4- (3,4-dimethoxyphenyl)
2- (1-Methylimidazol-2-yl) methylthioquinoline-3-carboxylic acid ethyl ester (3.0 g) in dichloromethane (90 ml) was added to ice-cooled metachloroperbenzoic acid (80%, 1.4 g). Was added and the mixture was stirred at the same temperature for 3 hours. The reaction solution, a saturated aqueous NaHSO _3, saturated NaHCO ₃
Aqueous solution, washed successively with water, distilling off the dried (MgSO ₄₎ the solvent was subjected and the residual oil was applied to a silica gel column chromatography. From the portion eluted with ethyl acetate-dichloromethane (4: 1, v / v), 6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2- (1-methylimidazole-2)
Ethyl -ylmethylsulfinyl) quinoline-3-carboxylate (2.17 g, 70%) was obtained. Melting point 151-15
2 ° C.

Example 192 In the column chromatography of Example 191, 6,7-dimethoxy-4- (3,4
Obtained ethyl-dimethoxyphenyl) -2- (1-methylimidazol-2-ylmethylsulfonyl) quinoline-3-carboxylate (0.47 g, 14%). Melting point 132-1
33 ° C.

Example 193 6,7-dimethoxy-4- (3,4-dimethoxyphenyl)
-2-Methylquinoline-3-carboxylic acid ethyl ester
(411 mg), N-bromosuccinimide (214 mg), 2,
A mixture of 2'-azobis (isobutyronitrile) (10 mg) and carbon tetrachloride (10 ml) was stirred under reflux for 5 hours. The reaction mixture is washed with water, dried and the solvent was distilled off under reduced pressure (MgSO _4), and the residue was subjected to silica gel column chromatography. 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%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 135-136 [deg.] 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

Example 194 2-Bromomethyl-6,7-in the same manner as in Example 193.
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. Calculated elemental analysis _{C 24 H 26 NO 6 Br:} C, 57.15; H, 5.20; N, 2.78 Analytical values: C, 56.75; H, 5.30 ; N, 2.68 Example 195 In the same manner as in Example 193, 2-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

Example 196 In the same manner as in 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 to 128 ° C. Example 197 6,7-dimethoxy-4- (3,4-dimethoxyphenyl)
Quinazoline-2-acetic acid methyl ester (4.0 g), sodium borohydride (1.9 g) and tetrahydrofuran
Methanol (15 ml) was added dropwise to a mixture of (80 ml) under reflux. The mixture was stirred under reflux for 2 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried
(MgSO ₄ ) and then the solvent was distilled off under reduced pressure to obtain 6,7-dimetho-4- (3,4-dimethoxyphenyl) -2- (2-hydroxyethyl) quinazoline (3.0 g, 81%). It was Recrystallized from ethyl acetate. Colorless needles. Melting point 165-166
° C. Example 198 In analogy to Example 165, 2- (2-bromoethyl)-
6,7-dimethoxy-4- (3,4-dimethoxyphenyl)
I got quinazoline. Recrystallized from ethyl acetate. Colorless needles. Melting point 166-167 [deg.] C. Examples 199 to 205 In the same manner as in Example 1, the compounds in Table 27 were obtained.

[0182]

[Table 27]

Examples 206 to 214 The compounds in Table 28 were obtained in the same manner as in Example 181.

[0184]

[Table 28]

1) Indeterminate solid body. NMR (δppm) CDCl ₃
Medium: 0.87 (3H, t, J = 7.2Hz), 1.33 (6H, d, J
= 6.0 Hz), 3.85 (3H, s), 3.93 (2H, q, J = 7.
2Hz), 3.96 (3H, s), 4.02 (3H, s), 4.43 (1
H, m), 5.68 (1H, d, J = 14.8Hz), 5.77 (1H,
d, J = 14.8 Hz), 6.82-7.01 (4 Hz, m), 7.41
(1H, s), 7.93 (1H, s), 8.27 (1H, s). 2) NMR (δppm) in CDCl ₃ : 0.84 (3H, t, J = 7.
2Hz), 1.26-1.45 (18H, m), 3.93 (2H, q,
J = 7.0 Hz), 4.02 (3 H, s), 4.21 (1 H, m), 4.
51 (1H, m), 4.56 (1H, m), 5.73 (2H, s), 6.8
0-6.92 (3H, m), 7.01 (1H, d, J = 8.2Hz),
7.41 (1H, s), 7.93 (1H, s), 8.27 (1H, s).

Example 215 6,7-Dimethoxy-4- (4-isopropoxy-3-methoxyphenyl) -2- (1,2,4-triazole-1-
Ilmethyl) quinoline-3-carboxylic acid ethyl ester
Titanium tetrachloride (TiCl ₄ ) (125 mg) was added to a solution of (55.6 mg) in dichloromethane (2 ml) 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 and water, dried (MgSO _4), and evaporated. 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 ppm) 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 (1H, s), 7.94 (1H, s), 8.27 (1H, s). Examples 216 to 218 The compounds of Table 29 were obtained in the same manner as in Example 215.

[0187]

[Table 29]

1) NMR (δ ppm) in CDCl ₃ : 0.88 (3
H, t, J = 7.2Hz), 3.84 (3H, s), 3.86 (3H,
s), 3.95 (2H, q, J = 7.2Hz), 3.97 (3H, s),
5.73 (2H, s), 6.88-7.01 (5H, m), 7.52
(1H, s), 7.94 (1H, s), 8.37 (1H, s). 2) NMR (δppm) in CDCl ₃ : 0.86 (3H, t, J = 7.
0Hz), 3.85 (3H, s), 3.94 (2H, q, J = 7.0H
z), 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).

Example 219 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), 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, dried (MgSO _4), and evaporated. The residual oily substance was subjected to silica gel column chromatography, and 4- (3,4-dihydroxyphenyl)-was extracted from the portion eluted with ethyl acetate-chloroform (7: 3, v / v).
6,7-dimethoxy-2- (1,2,4-triazole-1
Obtained ethyl-ylmethyl) quinoline-3-carboxylic acid ester (20.0 mg, 21%). Melting point 122-124 [deg.] C. NMR (δ ppm) in CDCl ₃ : 0.78 (3H, t, J = 7.0H
z), 3.78 (3H, s), 3.86 (2H, q, J = 7.0Hz),
4.00 (3H, s), 5.71 (2H, s), 6.60 (1H, broad)
s), 6.68-6.79 (2H, m), 6.92 (1H, s), 6.
97 (1H, d, J = 8.0Hz), 7.37 (1H, s), 7.95
(1H, s), 8.35 (1H, s), 8.70 (1H, broad s).

Example 220 Ethyl 4- (3,4-diisopropoxyphenyl) -6-isopropoxy-7-methoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate Titanium tetrachloride (TiCl ₄ ) (316 mg) was added to a solution of the ester (96.0 mg) in dichloromethane (1.0 ml) at 0 ° C.,
Stir 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 bicarbonate solution and water, dried (MgSO _4),
The solvent was distilled off. The residual oil was subjected to silica gel column chromatography, and ethyl acetate-methanol (10:
1, (v / v), the part eluted with 4- (3,4-dihydroxyphenyl) -6-hydroxy-7-methoxy-2-
(1,2,4-triazol-1-ylmethyl) quinoline-
3-Carboxylic acid ethyl ester (19.0 mg, 26%) was obtained. Melting point 264-266 [deg.] C. NMR (δppm) in CDCl ₃ : 0.88 (3H, t, J = 7.0)
Hz), 3.93 (2H, q, J = 7.0Hz), 3.94 (3H, s),
5.63 (2H, s), 6.52 (1H, dd, J = 8.2 & 2.2H
z), 6.67 (1H, d, J = 2.2Hz), 6.85 (1H, d, J
= 8.2Hz), 6.98 (1H, s), 7.29 (1H, s), 7.9
4 (1H, s), 8.57 (1H, s), 9.17 (1H, s), 9.21
(1H, s), 10.0 (1H, s).

Example 221 2-Amino-4,5,3 ', 4'-tetramethoxybenzophenone (453 mg), 6- (1-imidazolyl) -3-oxohexanoic acid ethyl ester (320 mg) and acetic acid (5 m
Concentrated sulfuric acid (0.03 ml) was added to the mixture of l) and the mixture was added at 100 ° C for 2 hours.
Stir the time. The reaction mixture was concentrated under reduced pressure, the residue was poured into water and made alkaline with 2N sodium hydroxide,
It was extracted with chloroform. The chloroform layer was washed with water and dried (MgSO _4), and evaporated. The residual oil was subjected to silica gel column chromatography, and chloroform-
From the part eluted with methanol (50: 1, v / v)
-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 222 6,7-Dimethoxy-4-as in Example 221
(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 [deg.] C. Example 223 In the same manner as in Example 221, 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 224 6,7-dimethoxy-4- (3,4-dimethoxyphenyl)
2- (1,2,4-Triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester (3.0 g), 2N sodium hydroxide (15.6 ml) and ethanol (50 ml)
The mixture was stirred at 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 oily substance was subjected to silica gel column chromatography, and from the portion eluted with chloroform-methanol (4: 1, v / v), 6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2- (was obtained. 1,2,4-triazole-1-
Ilmethyl) quinoline-3-carboxylic acid (1.3 g, 46%)
Got Recrystallized from dichloromethane-ethanol.
Colorless prism crystals. Melting point 270-271 [deg.] C (decomposition).

Example 225 Oily sodium hydride (60%, 0.156 g) was added to 1H-
Add 1,2,4-triazole (0.27g) to a solution of N, N-dimethylformamide (DMF) (20ml) at room temperature for 15
Stir for a minute. 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. Dichloromethane layer was washed with water, dried (MgSO _4), and evaporated. The residual oily substance was subjected to silica gel column chromatography, and 6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2- [from the portion eluted with chloroform-methanol (30: 1, v / v). (1,2,4-triazole-1-
Ilyl) methyl] quinoline-3-carboxylic acid ethyl ester 1-oxide (0.8 g, 50%) was obtained. Recrystallized from dichloromethane-hexane. Colorless prism crystals. Melting point 2
21-222 ° C.

Example 226 In the same manner as in Example 181, 6,7-dimethoxy-4-
(3-propoxy-4-methoxyphenyl) -2- (1,
2,4-triazol-1-ylmethyl) quinoline-3-
Obtained carboxylic acid ethyl ester. Recrystallized from ethanol. Colorless prism crystals. Melting point 127-128 [deg.] C. Example 227 In the column chromatography of Example 226, 6,7-dimethoxy-4- (3-propoxy-4-methoxyphenyl) -2- (1,2,4-triazol-4-ylmethyl) was then extracted from the eluted portion. ) Quinoline-3-carboxylic acid ethyl ester was obtained. Recrystallized from ethanol.
Colorless needles. Melting point 154-155 [deg.] C. Example 228 In the same manner as in Example 181, 4- (3,4-dimethoxyphenyl) -6,7-ethylenedioxy-2- (1,2,4-
Obtained triazol-1-ylmethyl) quinoline-3-carboxylic acid ethyl ester. Recrystallized from ethanol. Colorless needles. Melting point 138-140 [deg.] C. Example 229 In the column chromatography of Example 228, 4- (3,4-dimethoxyphenyl) -6,7-ethylenedioxy-2- (1,2,4-triazol-4-ylmethyl) was then extracted from the eluted portion. ) Quinoline-3-carboxylic acid ethyl ester was obtained. Recrystallized from ethanol. Colorless needles. Melting point 237-239 [deg.] C.

Example 230 In the same manner as in Example 181, 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 195-196 [deg.] C. Elemental analysis value Calculated as C ₂₅ H ₂₆ N ₄ O ₆ .1 / 4C ₂ H ₅ OH: C, 62.50; H, 5.66; N, 11.43 Analytical value: C, 62.29; H , 5.53; N, 11.30 Example 231 In the column chromatography of Example 230, 6,7-dimethoxy-4- (3,4) was then extracted from the eluted portion.
-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, 11.17 Analytical value: C, 61.98; H , 5.69; N, 11.10 Example 232 In the column chromatography of Example 211, 6,7-dimethoxy-4- (3-isopropoxy-4-methoxyphenyl) -2- (from the eluting portion was then extracted. 1, 2, 4
-Triazol-4-ylmethyl) quinoline-3-carboxylic acid ethyl ester was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 170-171
° C.

Example 233 In the column chromatography of Example 212, 6,7-dimethoxy-4- (4-isopropoxy-3-methoxyphenyl) -2- (1,2,4) was extracted from the eluted portion.
-Triazol-4-ylmethyl) quinoline-3-carboxylic acid ethyl ester was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 178-179
° C. Example 234 Oily sodium hydride (60%, 0.117 g) was added to a solution of 2-hydroxypyridine (0.277 g) in N, N-dimethylformamide (DMF) (10 ml), 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 (1.2 g) was added. The mixture was stirred at room temperature for 8 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried was distilled off (MgSO ₄₎ the solvent was subjected and the residual oil was applied to a silica gel column chromatography. Chloroform-ethyl acetate (10:
1, (v / v), the 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 [deg.] C. Example 235 It carried out similarly to Example 177, and obtained 2- [2- (1-imidazolyl) ethyl] -6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinazoline. Recrystallized from ethyl acetate. Colorless prism crystals. Melting point 147-148 [deg.] C. Example 236 In the same manner as in Example 166, 2-bromomethyl-6,7
2- (benzimidazole-1-) was obtained by reacting -dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester with benzimidazole.
Ilmethyl) -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 237 In the same manner as in Example 181, 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 [deg.] C. Example 238 In the same manner as in Example 166, 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- (imidazole- 1-ylmethyl) quinoline-3-carboxylic acid propyl ester was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 166-168 [deg.] C. Example 239 In the same manner as in Example 166, 2-bromomethyl-6,7
-Dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylic acid butyl ester was reacted with imidazole to give 6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2- (imidazole- 1-ylmethyl) quinoline-3-carboxylic acid butyl ester was obtained.
Recrystallized from ethanol. Colorless prism crystals. Melting point 14
0-141 ° C. Example 240 6-Chloro- was prepared by reacting 6-chloro-2-chloromethyl-4-phenylquinoline-3-carboxylic acid ethyl ester with 1H-1,2,4-triazole in the same manner as in Example 181. 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 241 to 248 The compounds in Table 30 were obtained in the same manner as in Example 166.

[0198]

[Table 30]

Example 249 6,7-Dimethoxy-4- (3-isopropoxy-4-methoxyphenyl) -2- (1,2,4-triazole-1-
Ilmethyl) quinoline-3-carboxylic acid ethyl ester
(0.5 g) ethanol (10 ml) -dichloromethane (2 ml)
A suspension of hydrogen chloride in ethanol (23%, 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. Recrystallize from ethanol,
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 ° C.

Example 250 Oily sodium hydride (60%, 0.27 g) was added to morpholine.
(0.537 g) N, N-dimethylformamide (20 ml)
The mixture was added to the solution and stirred at room temperature for 15 minutes. Then, 2-chloromethyl-4- (3,4-dimethoxyphenyl) -6,7
Ethyl dimethoxyquinoline-3-carboxylate (2.5 g)
Was added. The mixture was stirred at 100 ° C. for 2 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and freed from dried (MgSO ₄₎ and the solvent. The residual crystals were collected by filtration and recrystallized from ethanol to give ethyl 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-morpholinomethylquinoline-3-carboxylate (1.9 g, 68%). Obtained. Colorless prism crystals. Melting point 146-147 [deg.] C.

Example 251 2-chloromethyl-4- (3,4-dimethoxyphenyl)
Ethyl-6,7-dimethoxyquinoline-3-carboxylate
(1.0 g), piperazine (1.15 g) and methanol (1
5 ml) was stirred at room temperature for 36 hours. The reaction mixture was concentrated under reduced pressure and 6N HCl (30 ml) was added to the residue.
Was added and washed with dichloromethane. Aqueous layer is 2N Na
It was neutralized with OH and extracted with dichloromethane. Dichloromethane layer was washed with water and freed from the solvent dried (MgSO _4). The residual crystals were collected by filtration and recrystallized from dichloromethane-hexane to give ethyl 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-piperazinomethylquinoline-3-carboxylate (0.43 g, 39%). Colorless prism crystals. Melting point 192-193 [deg.] C.

Example 252 Oily sodium hydride (60%, 0.753 g) was added to thiomorpholine (1.8 g) in N, N-dimethylformamide (50 m).
l) Add to the solution and stir for 15 minutes at room temperature. Then, 2-
Chloromethyl-4- (3,4-dimethoxyphenyl) -6,
Ethyl 7-dimethoxyquinoline-3-carboxylate (6.0
g) was added. The mixture was stirred at room temperature overnight, poured into water and extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried
After (MgSO ₄ ), the solvent was distilled off. The residue was subjected to silica gel column chromatography, and 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-thio was extracted from the portion eluted with chloroform-ethyl acetate (7: 3, v / v). Ethyl morpholinomethylquinoline-3-carboxylate (1.4 g, 4
2%). Recrystallized from ethanol. Colorless prism crystals. Melting point 148-149 [deg.] C.

Example 253 Oily sodium hydride (60%, 0.466 g) was added to a solution of N-methylhomopiperazine (1.23 g) in N, N-dimethylformamide (40 ml), and the mixture was stirred at room temperature for 15 min.
Then ethyl 2-chloromethyl-4- (3,4-dimethoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylate (4.0 g) was added. The mixture was stirred at 100 ° C. for 3.5 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and freed from dried (MgSO ₄₎ and the solvent. The residue was subjected to silica gel column chromatography, and 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-[(from the portion eluted with chloroform-methanol (5: 1, v / v). Ethyl 4-methylhomopiperazino) methyl] quinoline-3-carboxylate (1.0 g, 22%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals.
Melting point 157-159 [deg.] C.

Example 254 2-chloromethyl-4- (3,4-dimethoxyphenyl)
Ethyl-6,7-dimethoxyquinoline-3-carboxylate
(4.0 g), diethylamine (1.28 g) and methanol
The mixture (45 ml) was stirred at room temperature for 4 days. The reaction mixture was poured into water and extracted with dichloromethane. Dichloromethane layer was washed with water and freed from the solvent dried (MgSO _4).
The residue was subjected to silica gel column chromatography,
From the portion eluted with ethyl acetate, 2- (N, N-diethylaminomethyl) -4- (3,4-dimethoxyphenyl)-
Ethyl 6,7-dimethoxyquinoline-3-carboxylate
(0.51 g, 18%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 130-131 [deg.] C.

Example 255 Ethyl 2-chloromethyl-6,7-dimethoxy-4- (4-methoxyphenyl) quinoline-3-carboxylate (2.0
A mixture of g), morpholine (2.5 g) and methanol (30 ml) was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, washed with water was added dichloromethane to the residue, and the mixture was dried (MgSO _4). The crystals obtained by distilling off the solvent were collected by filtration and recrystallized from ethanol to give 6,7-dimethoxy-4.
Obtained ethyl-(4-methoxyphenyl) -2-morpholinomethylquinoline-3-carboxylate (1.65 g, 74%). Colorless prism crystals. Melting point 165-166 [deg.] C.

Example 256 In the same manner as in Example 255, 6,7-dimethoxy-4-
Ethyl (4-methoxyphenyl) -2-piperidinomethylquinoline-3-carboxylate was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 129-130 [deg.] C.

Example 257 Ethyl 2-chloromethyl-6,7-dimethoxy-4- (2-methoxyphenyl) quinoline-3-carboxylate (1.0
g), morpholine (1.25 g) and ethanol (13 ml) were stirred at room temperature for 3 days, and the precipitated crystals were collected by filtration and recrystallized from ethyl acetate-hexane to give 6,7-dimethoxy-4- ( Ethyl 2-methoxyphenyl) -2-morpholinomethylquinoline-3-carboxylate (0.76 g, 68
%). Colorless prism crystals. Melting point 153-154 [deg.] C.

Example 258 In the same manner as in Example 255, ethyl 4- (3,4-dimethoxyphenyl) -6,7-ethylenedioxy-2-morpholinomethylquinoline-3-carboxylate was obtained. Recrystallized from ethanol. Colorless needles. Melting point 174-175
° C.

Example 259 In the same manner as in Example 255, ethyl 4- (3,4-dimethoxyphenyl) -6,7-ethylenedioxy-2-piperidinomethylquinoline-3-carboxylate was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 158-16
0 ° C.

Example 260 In the same manner as in Example 255, ethyl 4- (3,4-dimethoxyphenyl) -6,7-diethoxy-2-morpholinomethylquinoline-3-carboxylate was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 147-148 [deg.] C.

Example 261 In the same manner as in Example 255, ethyl 4- (3,4-dimethoxyphenyl) -6,7-diethoxy-2-piperidinomethylquinoline-3-carboxylate was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 154-155 [deg.] C.

Example 262 In the same manner as in Example 255, ethyl 6-chloro-2-morpholinomethyl-4-phenylquinoline-3-carboxylate was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 161-163 [deg.] C.

Example 263 Ethyl 2-chloromethyl-4- (3-isopropoxy-4-methoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylate (3.0 g), morpholine (2.76 g) and A mixture of ethanol (50 ml) -dichloromethane (5 ml) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure,
Dichloromethane (50 ml) was added to the residue. Dichloromethane layer was washed with water and freed from the solvent dried (MgSO _4). The residue was subjected to silica gel column chromatography, and eluted with chloroform-ethyl acetate (1: 1, v / v) to give 4- (3-isopropoxy-4-methoxyphenyl).
An oily product of ethyl-6,7-dimethoxy-2-morpholinomethylquinoline-3-carboxylate was obtained. This oily substance was dissolved in ethanol (20 ml), an ethanol solution of hydrogen chloride (23%, 1.05 g) was added, and the mixture was stirred at room temperature for 10 min. The solvent was distilled off under reduced pressure, and the crystals were collected by filtration. Recrystallized from ethanol-ether to give 4- (3-isopropoxy-4-methoxyphenyl) -6,7-dimethoxy-2-morpholinomethylquinoline-3-carboxylic acid ethyl hydrochloride.
(1.62 g, 45%) was obtained. Colorless crystals. Melting point 185-1
88 ° C. Elemental analysis Calculated as C ₂₉ H ₃₇ N ₂ O ₇ Cl · H ₂ O: C, 60.15; H, 6.79; N, 4.84 Analytical value: C, 60.51; H, 6.58 N, 4.73

Example 264 In the same manner as in Example 263, ethyl 4- (3-isopropoxy-4-methoxyphenyl) -6,7-dimethoxy-2-piperidinomethylquinoline-3-carboxylic acid hydrochloride was prepared. Obtained. Recrystallized from ethanol-ether. Colorless crystals. Melting point 207-210 [deg.] C. Elemental analysis Calculated as C ₃₀ H ₃₉ N ₂ O ₆ Cl · 1 / 2H ₂ O: C, 63.43; H, 7.10; N, 4.93 Analytical value: C, 63.15; H, 7 .02; N, 4.80

Example 265 In the same manner as in Example 263, 2- (N, N-dipentylaminomethyl) -4- (3,4-dimethoxyphenyl) -6,
Ethyl 7-dimethoxyquinoline-3-carboxylate dihydrochloride was obtained. Recrystallized from dichloromethane-ethyl acetate. Yellow powder. Melting point 93-95 [deg.] C. Elemental analysis Calculated as C ₃₃ H ₄₈ N ₂ O ₆ Cl ₂ · 3 / 2H ₂ O: C, 59.45; H, 7.71; N, 4.20 Analytical value: C, 59.58; H, 7.88; N, 4.14

Example 266 In the same manner as in Example 250, ethyl 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-piperidinomethylquinoline-3-carboxylate was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 148-149 [deg.] C.

Example 267 In the same manner as in Example 250, ethyl 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-pyrrolidinomethylquinoline-3-carboxylate was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 139-
140 ° C.

Example 268 2-Bromomethyl-4- (3,4-dimethoxyphenyl)
A mixture of -6,7-dimethoxyquinoline-3-carboxylic acid propyl ester (1.5 g), piperidine (1.27 g) and dichloromethane (30 ml) was stirred at room temperature for 2 days. The reaction mixture was washed with water and freed from dried (MgSO ₄₎ and the solvent. The residue was subjected to silica gel column chromatography and eluted with chloroform-ethyl acetate (10: 1, v / v) to give 4- (3,4-dimethoxyphenyl) -6,7.
-Dimethoxy-2-piperidinomethylquinoline-3-carboxylic acid propyl ester (0.8 g, 53%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals.
Melting point 129-131 [deg.] C.

Example 269 In the same manner as in Example 268, 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-piperidinomethylquinoline-3-carboxylic acid butyl ester was obtained. Recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 15
4-155 ° C.

Examples 270 to 277 The compounds of Table 31 were obtained in the same manner as in Example 254.

[0221]

[Table 31]

1) Hemihydrate. 2) 1/4 hydrate. 3) Amorphous solid. NMR (δ ppm in CDCl ₃ ): 0.9
7 (3H, t, J = 7Hz), 3.59 (4H, s), 3.78 (3H,
s), 3.88 (3H, s), 3.97 (3H, s), 3.99 (2H, q,
J = 7Hz), 4.04 (3H, s), 4.13 (2H, s), 6.84
-7.02 (4H, m), 7.10-7.40 (10H, m), 7.4
2 (1H, s).

Example 278 2-chloromethyl-4- (3,4-dimethoxyphenyl)
-6,7-Dimethoxyquinazoline (2.0 g), piperidine
(2.27 g) and ethanol (40 ml) -dichloromethane
The mixture (10 ml) was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure and the residue was diluted with dichloromethane (50 ml).
Was added. Dichloromethane layer was washed with water, dried (MgSO ₄₎
After that, the solvent was distilled off. The residue was subjected to silica gel column chromatography, and chloroform-ethyl acetate (1: 1, v
/ (V) eluate to give 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-piperidinomethylquinazoline (1.46 g, 65%). Recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 130-132
° C.

Example 279 In the same manner as in Example 278, 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-morpholinomethylquinazoline was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 148-150 [deg.] C.

Example 280 In the same manner as in Example 278, 2- (N, N-diethylaminomethyl) -4- (3,4-dimethoxyphenyl) -6,7 was prepared.
-Dimethoxyquinazoline was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 111-113
° C.

Example 281 In the same manner as in Example 278, 2-bromomethyl-4-
2- (N-Ethyl-N-propylaminomethyl) -4 was obtained by the reaction of ethyl (3,4-dimethoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylate with N-ethyl-n-propylamine. Obtained ethyl-(3,4-dimethoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylate. Recrystallized from ethyl acetate-hexane.
Colorless prism crystals. Melting point 105-106 [deg.] C.

Example 282 2- (2-Bromoethyl) -4- (3,4-dimethoxyphenyl) -6,7-dimethoxyquinazoline (0.486)
A mixture of g), diethylamine (0.41 g) and dichloromethane (10 ml) was stirred under reflux for 6 hours. The reaction mixture was poured into water and extracted with dichloromethane. Dichloromethane layer was washed with water and freed from the solvent dried (MgSO _4). The residue was subjected to silica gel column chromatography, and eluted with chloroform-ethyl acetate (1: 1, v / v) to give 2- [2- (N, N-diethylamino).
Ethyl] -4- (3,4-dimethoxyphenyl) -6,7-
Dimethoxyquinazoline (0.040 g, 8%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals.
Melting point 164-166 [deg.] C.

Example 283 Ethyl 2-chloromethyl-4- (3,4-dimethoxyphenyl) -6,7-dimethoxyquinoline-3-carboxylate (3.0 g), N-methyl-N-cyclohexylamine (2 A mixture of 0.28 g) and ethanol (45 ml) was stirred under reflux for 6 hours. The reaction mixture was poured into water and extracted with dichloromethane. The dichloromethane layer is washed with water,
Drying was distilled off (MgSO ₄₎ and the solvent. The residue was subjected to silica gel column chromatography, and 2- (N-cyclohexyl-N-methylaminomethyl) -4- (3,4-dimethoxyphenyl)-was extracted from the portion eluted with chloroform.
Ethyl 6,7-dimethoxyquinoline-3-carboxylate (2.80 g, 80%) was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 172-174 [deg.] C.

Examples 284 to 290 The compounds in Table 32 were obtained in the same manner as in Example 283.

[0230]

[Table 32]

Example 291 In the same manner as in Example 263, 2-chloromethyl-4-
(3-isopropoxy-4-methoxyphenyl) -6,
2- (N, N-diethylaminomethyl) -4- (3-isopropoxy-4-methoxyphenyl) -6,7-dimethoxyquinoline-3 was obtained by the reaction of ethyl 7-dimethoxyquinoline-3-carboxylate with diethylamine. -Ethyl carboxylate dihydrochloride was obtained. Recrystallized from ethyl acetate-ether. Yellow powder. Melting point 122-124 [deg.] C. Elemental analysis Calculated as C ₂₉ H ₄₀ N ₂ O ₆ Cl ₂ .1 / 2H ₂ O: C, 58.78; H, 6.97; N, 4.73 Analytical value: C, 58.84; H, 7.00; N, 4.69

Example 292 In a manner analogous to Example 282, 6-chloro-4- was prepared by reacting ethyl 6-chloro-2-chloromethyl-4- (4-chlorophenyl) quinoline-3-carboxylate with diethylamine. Ethyl (4-chlorophenyl) -2- (N, N-diethylaminomethyl) quinoline-3-carboxylate was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 132-133 [deg.] C.

Example 293 In a manner analogous to Example 282, the reaction of ethyl 6-chloro-2-chloromethyl-4-phenylquinoline-3-carboxylate with diethylamine gave 6-chloro-2- (N,
N-diethylaminomethyl) -4-phenylquinoline-
Obtained ethyl 3-carboxylate. Recrystallized from ethanol. Colorless prism crystals. Melting point 107-108 [deg.] C.

Reference Example 1 2-Amino-4,5,3 ', 4'-tetramethoxybenzophenone (10.0 g), diethyl malonate (6.0 g) and 1,8-diazabicyclo [5,4,0]. -7-Undecene (D
BU) (0.396 g) was stirred at 180 ° C for 10 minutes. After cooling the reaction mixture, ethanol was added, and the precipitated crystals were collected by filtration, and 6,7-dimethoxy-4- (3,4-dimethoxyphenyl) -2 (1H) -quinolone-3-carboxylic acid ethyl ester (12.0 g, 91%). Recrystallized from chloroform-acetone. Melting point 273-276 [deg.] C.

Reference Example 2 6,7-Dimethoxy-4- (3,4-dimethoxyphenyl)
-2 (1H) -quinolone-3-carboxylic acid ethyl ester
(6.8 g), Lawesson's reagent (8.0
A mixture of g) and toluene (250 ml) was stirred under reflux for 18 hours. After cooling the reaction mixture, the precipitated crystals were collected by filtration,
6,7-dimethoxy-4- (3,4-dimethoxyphenyl)
2-Mercaptoquinoline-3-carboxylic acid ethyl ester (5.0 g, 70%) was obtained. Recrystallized from acetone. Melting point 265-266 [deg.] C.

Reference Example 3 6,7-dimethoxy-4- (3,4-dimethoxyphenyl)
-2 (1H) -quinolone-3-carboxylic acid ethyl ester
A mixture of (5.0 g) and phosphorus oxychloride (POCl ₃ ) (6.0 ml) was stirred at 100-110 ° C for 80 minutes. The reaction mixture was concentrated under reduced pressure, the residual oil was poured into water, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The chloroform layer was washed with water and dried was distilled off (MgSO ₄₎ the solvent was subjected and the residual oil was applied to a silica gel column chromatography. From the portion eluted with chloroform, 2-chloro-6,7-dimethoxy-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester (3.
8 g, 73%). Recrystallized from ethyl acetate-hexane. Melting point 168-169 [deg.] C.

Reference Example 4 2-Chloromethyl-6,7-diethoxy-4- (3,4-
A mixture of dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester (7.1 g), triphenylphosphine (3.9 g) and toluene (70 ml) was stirred under reflux for 2 hours. After cooling, the precipitated solid was collected by filtration [6,7-diethoxy-
4- (3,4-Dimethoxyphenyl) -3-ethoxycarbonylquinolin-2-yl] methyltriphenylphosphonium chloride (9.6 g, 87%) was obtained. Melting point 172
~ 174 ° C (decomposition).

Reference Example 5 In the same manner as in Reference Example 4, [6,7-dimethoxy-4- (3,4
-Dimethoxyphenyl) -3-ethoxycarbonylquinolin-2-yl] methyltriphenylphosphonium chloride was obtained. Melting point 200-202 ° C (decomposition).

Reference Example 6 In the same manner as in Reference Example 4, [6,7-dimethoxy-4- (4-
Methoxyphenyl) -3-ethoxycarbonylquinolin-2-yl] methyltriphenylphosphonium chloride was obtained. Melting point 178-180 ° C (decomposition).

Reference Example 7 In the same manner as in Reference Example 4, [6,7-dimethoxy-4- (3,4
-Dimethoxyphenyl) quinazolin-2-yl] methyltriphenylphosphonium chloride was obtained. Melting point 208
~ 210 ° C (decomposition). Reference Example 8 4-Bromobutyric acid benzyl ester (23.7 g), imidazole (8.1 g), potassium carbonate (14.0 g) and acetone
The mixture (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,
From the portion eluted with ethyl acetate-methanol (20: 1, v / v), 4- (1-imidazolyl) butyric acid benzyl ester was obtained.
(7.3 g, 33%) was obtained as an oil. NMR (δ ppm) in CDCl ₃ : 2.11 (2H, m), 2.34
(2H, t, J = 6.8Hz), 3.99 (2H, t, J = 6.8H
z), 5.12 (2H, s), 6.87 (1H, s), 7.05 (1H,
s), 7.30-7.40 (5H, m).

Reference Example 9 In the same manner as in Reference Example 8, 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), 7.3
0-7.43 (5H, m), 7.94 (1H, s), 7.99 (1H,
s). Reference Example 10 In the same manner as in Reference Example 8, 5- (1-imidazolyl) was obtained by reacting 5-bromovaleric acid benzyl ester with imidazole.
Valeric acid benzyl ester was obtained as an oil. 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 (1H, s).

Reference Example 11 4- (1-imidazolyl) butyric acid benzyl ester (7.4
g), 5% palladium-carbon (1.0 g) and ethanol
The mixture (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, and the residual crystals were recrystallized from ethanol to give 4- (1-imidazolyl) butyric acid.
(3.4 g, 75%) was obtained. Colorless prism crystals. Melting point 125
~ 126 ° C. Reference Example 12 In the same manner as in Reference Example 11, 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- I've got butyric acid. Recrystallized from ethanol. Colorless prism crystals. Melting point 137-138 [deg.] C. Reference Example 13 In the same manner as in Reference Example 11, 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 14 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 (O
COCH 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. Dichloromethane layer was washed with water, dried was distilled off (MgSO ₄₎ the solvent was subjected and the residual oil was applied to a silica gel column chromatography.
From the fraction eluted with chloroform-methanol (30: 1, v / v), 6- (1-imidazolyl) -3-oxohexanoic acid ethyl ester (0.32 g, 44%) was obtained as an oil. NMR (δ ppm) in CDCl ₃ : 1.28 (3H, t, J = 7.4)
Hz), 2.08 (2H, m), 2.53 (2H, t, J = 6.6Hz),
3.41 (2H, s), 4.00 (2H, t, J = 6.6Hz), 4.1
9 (2H, q, J = 7.4Hz), 6.91 (1H, s), 7.07 (1
H, s), 7.46 (1H, s).

Reference Example 15 In the same manner as in Reference Example 14, 4- (1,2,4-triazol-1-yl) butyric acid was used to prepare 6- (1,2,4-triazole-
1-yl) -3-oxohexanoic acid ethyl ester was obtained as an oil. NMR (δ ppm) in CDCl ₃ : 1.28 (3H, t, J = 7.2
Hz), 2.19 (2H, m), 2.59 (2H, t, J = 6.6Hz),
3.43 (2H, s), 4.19 (2H, q, J = 7.2Hz), 4.2
3 (2H, t, J = 6.6Hz), 7.94 (1H, s), 8.07 (1
H, s). Reference Example 16 In the same manner as in Reference Example 14, 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 = 7.4
Hz), 1.50-1.90 (4H, m), 2.58 (2H, t, J =
6.6 Hz), 3.41 (2H, s), 3.95 (2H, t, J = 7.0)
Hz), 4.19 (2H, q, J = 7.4Hz), 6.90 (1H, s),
7.06 (1H, s), 7.47 (1H, s).

[0244]

INDUSTRIAL APPLICABILITY According to the present invention, there is provided a pharmaceutical composition containing quinoline or a quinazoline derivative which directly acts on bone and exhibits an excellent inhibitory effect on bone resorption and which is useful as a prophylactic / therapeutic agent for osteoporosis.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 239/76 513/04 351 C07F 9/60 9155-4H // C07D 215/54 215/60 401 / 06 209 213 231 233 243 243 249 401/12 213 233 235 239 249 403 403/06 233 239 403/12 239 405/04 215 405/14 215 413/12 215 417/12 215 471/04 101 107 107 487/04 144 7019-4C 491/048 7019-4C 491/056 7019-4C

Claims (26)

[Claims] 1. A compound represented by the general formula (I): [In the formula, Y represents a nitrogen atom or C-G (G represents a carboxyl group which may be esterified or amidated, or a hydroxymethyl group), and R represents a hydrocarbon residue which may be substituted. , A heterocyclic group which may be substituted,
X is an oxygen atom or an optionally oxidized sulfur atom,
n represents 0 or 1, and k represents 0 or 1. G and R are
They may be bonded to each other to form a ring. Ring A and ring B may each have a substituent. ] A bone resorption inhibitor containing a compound represented by the formula or a pharmaceutically acceptable salt thereof as an active ingredient. 2. The bone resorption inhibitor according to claim 1, wherein n is 0. 3. An optionally substituted hydrocarbon residue represented by R, wherein n is 0, is —CH ₂ —X ¹ —Z ¹ [wherein, X ¹ is an oxygen atom or an oxidation group]. Optionally a sulfur atom or — (CH ₂ ) _m — (m represents an integer of 0 to 5)
¹ represents a hydrocarbon residue which may be substituted, a heterocyclic group which may be substituted or an amino group which may be substituted. ] The bone resorption inhibitor according to claim 1, which is a group represented by: 4. The bone resorption inhibitor according to claim 3, wherein X ¹ is a thio group, a sulfinyl group or a sulfonyl group. 5. The bone resorption inhibitor according to claim 4, wherein X ¹ is a thio group. 6. The bone resorption inhibitor according to claim 3, wherein X ¹ is — (CH ₂ ) _m — and m is 1 or 2. 7. The bone according to claim 3 or 6, wherein the optionally substituted heterocyclic group represented by Z ¹ is an aromatic 5-membered heterocyclic group containing 2 to 3 heteroatoms. Absorption inhibitor. 8. The bone resorption inhibitor according to claim 3 or 6, wherein Z ¹ is an optionally substituted amino group. 9. An optionally substituted heterocyclic group represented by R, each of which may be substituted, is a 5- to 7-membered heterocyclic group containing one sulfur atom, nitrogen atom or oxygen atom,
5- or 6-membered heterocyclic group containing 2 to 4 nitrogen atoms, or 1
The bone resorption inhibitor according to claim 1, which is a 5- to 6-membered heterocyclic group containing 2 to 2 nitrogen atoms and 1 sulfur atom or oxygen atom. 10. The bone resorption inhibitor according to claim 1, wherein Y is CG. 11. The bone resorption inhibitor according to claim 10, wherein G is a C _1-6 alkyloxycarbonyl group. 12. The bone resorption inhibitor according to claim 10, wherein G is an ethoxycarbonyl group. 13. The bone resorption inhibitor according to claim 1, wherein ring A is substituted with at least one alkoxy group. 14. The bone resorption inhibitor according to claim 1, wherein ring A is substituted with at least one methoxy group. 15. The bone resorption inhibitor according to claim 1, wherein ring A is substituted with two alkoxy groups which are the same or different. 16. The bone resorption inhibitor according to claim 1, wherein ring A is substituted with two methoxy groups. 17. The bone resorption inhibitor according to claim 1, wherein ring A is substituted with two methoxy groups at the 6-position and 7-position of the quinoline ring or quinazoline ring. 18. The bone resorption inhibitor according to claim 1, wherein ring B is substituted with at least one alkoxy group. 19. The bone resorption inhibitor according to claim 1, wherein ring B is substituted with at least one methoxy group. 20. The bone resorption inhibitor according to claim 1, wherein ring B is substituted with at least one isopropoxy group. 21. The bone resorption inhibitor according to claim 1, wherein ring B is substituted with two same or different alkoxy groups. 22. The bone resorption inhibitor according to claim 1, wherein ring B is substituted with one methoxy group. 23. The bone resorption inhibitor according to claim 1, wherein ring B is substituted with an isopropoxy group at the 3-position and a methoxy group at the 4-position. 24. The bone resorption inhibitor according to claim 1, wherein k is 0. 25. The compound represented by the general formula (I) is 4- (3,4-dimethoxyphenyl) -2-ethyl-6,
7-dimethoxyquinoline-3-carboxylic acid methyl ester, 6-chloro-2-methyl-4- (3,4-dimethoxyphenyl) quinoline-3-carboxylic acid ethyl ester, 6,7-dimethoxy-9-phenylfuro [3 , 4-b] Quinolin-1 (3H) -one, 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-[(1-methylimidazol-2-yl) thiomethyl] quinolin-3- Carboxylic acid ethyl ester, 4- (3,4-dimethoxyphenyl) -2- (2-hydroxyethylthiomethyl) -6,7-dimethoxyquinazoline, 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy -2-[(4-methyl-1,2,4-triazole-3
-Yl) thiomethyl] quinazoline, 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2-[(1-methylimidazol-2-yl) ethyl] quinoline-3-carboxylic acid ethyl ester, 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-3-methoxycarbonylquinoline-2-acetic acid methyl ester, 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2- (1,2) , 4-triazol-1-ylmethyl)
Quinoline-3-carboxylic acid ethyl ester, 4- (3-isopropoxy-4-methoxyphenyl)-
6,7-dimethoxy-2- (1,2,4-triazole-
1-ylmethyl) quinoline-3-carboxylic acid ethyl ester, 4- (4-hydroxy-3-methoxyphenyl) -6,
7-dimethoxy-2- (1,2,4-triazole-1-
Ilmethyl) quinoline-3-carboxylic acid ethyl ester, 7-hydroxy-6-methoxy-4- (3,4-dimethoxyphenyl) -2- (1,2,4-triazole-1-
Ilmethyl) quinoline-3-carboxylic acid ethyl ester, 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl)
Quinoline-3-carboxylic acid ethyl ester 1-oxide, or 2- (N, N-diethylaminomethyl) -4- (3,4-
Dimethoxyphenyl) -6,7-dimethoxyquinoline-
The bone resorption inhibitor according to claim 1, which is 3-carboxylic acid ethyl ester. 26. General formula (I): [In the formula, Y represents a nitrogen atom or C-G (G represents a carboxyl group which may be esterified or amidated, or a hydroxymethyl group), and R represents a hydrocarbon residue which may be substituted. , A heterocyclic group which may be substituted,
X is an oxygen atom or an optionally oxidized sulfur atom,
n represents 0 or 1, and k represents 0 or 1. G and R are
They may be bonded to each other to form a ring. Ring A and ring B may each have a substituent. ] An osteoporosis preventive / therapeutic agent containing the compound represented by the formula or a pharmaceutically acceptable salt thereof as an active ingredient.