JPH08208645A - Quinoline derivative - Google Patents

Abstract

PURPOSE: To obtain a new compound, having inhibiting actions on synthases for TXA2 which is a thromboxane analog and antagonistic actions on LTD4 that is a leukotriene analog and useful as a therapeutic agent for cerebral infarction, bronchial asthma, etc. CONSTITUTION: This compound of formula I (A<1> is CN, tetrazolyl, etc.; L<11> to L<14> are each a single bond or a 1-6C alkylene; X<1> is a heterocyclic ring containing nitrogen; Y<1> is O or S; the double line of the broken line and the solid line is a single bond or a double bond) and its salt, e.g. 5-(imidazol-1- ylmethyl)-7-[4-(quinolin-2ylmethyloxy)phenylmethyloxy]benzo[b]furan-2- carboxylic acid. The compound is obtained by reacting, e.g. a compound of formula II with a compound of formula III, then reacting the resultant ractional product with thionyl chloride of the formula SOCl2 in dry chloroform and further reacting the prepared product with a compound of formula IV.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel quinoline derivative. The present invention particularly relates to a quinoline derivative effective as a novel antiallergic agent having TXA ₂ synthase inhibitory activity and LTD ₄ antagonistic activity.

[0002]

2. Description of the Related Art Prostaglandins (PG), thromboxane (TX) or leukotrienes (LT), which are arachidonic acid metabolites, have various physiological, pathological and pharmacological actions and are involved in various diseases. It has been known.

Of these, TXA ₂ which is an analogue of thromboxane is known to be a strong platelet aggregating substance and a strong smooth muscle contracting substance at the same time. Therefore,
(E) -3- [p which is a known TXA ₂ synthase inhibitor
-(1H-imidazol-1-ylmethyl) phenyl]
Propenoic acid (generic name: ozagrel) and its sodium salt are known to be useful as a therapeutic agent for bronchial asthma or a therapeutic agent for cerebral thrombosis (JP-A-55-313). Ozagrel has the following chemical structure, and its structural feature is that it has an imidazole structure and an acidic group (carboxyl). As a substance having a TXA ₂ synthase inhibitory action having the same characteristics, other than ozagrel, 1- [3- (4-benzhydryl-1
-Piperazinyl) propyl] -3- (1H-imidazol-1-ylmethyl) -1H-indole-6-carboxylic acid (described in WO 93/20065), and (E) -3- [3- (1H-imidazol-1-ylmethyl) -2-methyl-1H-indole-
1-yl] propanoic acid (J. Med. Chem. 1986, 29, p342
(Described in) is known.

[0004]

[Chemical 9]

Leukotrienes also have various analogs.
Of the analogs, LTD ₄ is known to have the actions of causing bronchoconstriction, enhancing mucus secretion, and enhancing vascular permeability. Therefore, 8- [p- (4-phenylbutoxy) benzoyl] amino-2- (tetrazol-5-yl) -4-oxo-4H-1-benzopyran (generic name: pranlukast) having LTD ₄ antagonism ) Is reported to be useful as an antiallergic agent (JP-A-61-50977). This pranlukast has the following chemical structure, and its structural feature is that it has an arylalkyloxyphenyl structure and an acidic group (tetrazole). Compounds having similar characteristics include 5- [2- [4- (quinoline-2
-Ylmethyloxy) phenyloxymethyl] phenylmethyl] tetrazole (described in US Pat. No. 4,920,131), quinolin-2-ylmethoxyphenylalkanoic acid derivative (European Patent Publication No. 349062, 339).
Nos. 416 and 344519), and 1- (quinolin-2-ylmethoxyphenylmethyl) indole having an acidic group as a substituent (JP-A-5-3
(Described in Japanese Patent No. 45778). However, the pharmacological actions of both ozagrel and pranlukast (TXA ₂ synthase inhibitory action and LTD ₄ antagonistic action)
A compound having both is not known.

[0006]

[Chemical 10]

[0007]

The object of the present invention is to provide a TX
It is intended to provide a novel compound having an A ₂ synthase inhibitory action and an LTD ₄ antagonistic action.

[0008]

Means for Solving the Problems The present inventor was conducting research on antiallergic agents and found that the following formula (I)
All the quinoline derivatives represented by (IV) are TXA
_The present invention has been completed based on the finding that it has both a ₂ synthase inhibitory action and an LTD ₄ antagonistic action.

[0009]

[Chemical 11]

(A ¹ is --CO ₂ R ¹¹ , --CN, --CO
_{^{NHSO 2 R 12, -CONR 13 R}} 14, -OR 15, a tetrazolyl or substituted tetrazolyl, R ^11, R ^13,
R ¹⁴ and R ¹⁵ are each a hydrogen atom, alkyl or alkali metal, R ¹² is a hydrogen atom, alkyl, haloalkyl, aryl or aralkyl, and the substituent of the substituted tetrazolyl is alkyl, carboxyalkyl or alkoxycarbonyl. Is alkyl; L
¹¹ is a single bond or alkylene having 1 to 6 carbon atoms; X ¹ is a nitrogen-containing heterocyclic group; L ¹² is a single bond or alkylene having 1 to 6 carbon atoms; L
¹³ is a single bond or alkylene having 1 to 6 carbon atoms; Y ¹ is an oxygen atom or a sulfur atom; L ¹⁴
Is a single bond or alkylene having 1 to 6 carbon atoms; and a double line consisting of a broken line and a solid line means a single bond or a double bond)

[0011]

[Chemical 12]

(A ² is --CO ₂ R ²¹ , --CN, --CO
_{^{NHSO 2 R 22, -CONR 23 R}} 24, -OR 25, a tetrazolyl or substituted tetrazolyl, R ^21, R ^23,
R ²⁴ and R ²⁵ are each a hydrogen atom, alkyl or an alkali metal, R ²² is a hydrogen atom, alkyl, haloalkyl, aryl or aralkyl, and the substituent of the substituted tetrazolyl is alkyl, carboxyalkyl or alkoxycarbonyl. Is alkyl; L
²¹ is a single bond or alkylene having 1 to 6 carbon atoms; X ² is a nitrogen-containing heterocyclic group; L ²² is a single bond or alkylene having 1 to 6 carbon atoms; L ^22
23 is a single bond or alkylene having 1 to 6 carbon atoms; Y ² is an oxygen atom or a sulfur atom; and L ²⁴ is a single bond or alkylene having 1 to 6 carbon atoms)

[0013]

[Chemical 13]

(A ³ is --CO ₂ R ³¹ , --CN, --CO
_{^{NHSO 2 R 32, -CONR 33 R}} 34, -OR 35, a tetrazolyl or substituted tetrazolyl, R ^31, R ^33,
R ³⁴ and R ³⁵ are each a hydrogen atom, alkyl, carboxyalkyl or an alkali metal, R ³² is a hydrogen atom, alkyl, haloalkyl, aryl or aralkyl, and the substituent of the substituted tetrazolyl is alkyl, carboxyalkyl. Or alkoxycarbonylalkyl; L ³¹ is a single bond or alkylene having 1 to 6 carbon atoms; X ³ is a nitrogen-containing heterocyclic group; L ³² is a single bond or 1 carbon atom. L ³³ is a single bond or an alkylene having 1 to 6 carbon atoms; Y ³ is an oxygen atom or a sulfur atom; and L ³⁴ is a single bond or 1 carbon atom. To 6 alkylenes)

[0015]

Embedded image

(A ⁴ is -CO ₂ R ⁴¹ , -CN, -CO
_{^{NHSO 2 R 42, -CONR 43 R}} 44, -OR 45, a tetrazolyl or substituted tetrazolyl, R ^41, R ^43,
R ⁴⁴ and R ⁴⁵ are each a hydrogen atom, alkyl, carboxyalkyl or an alkali metal, R ⁴² is a hydrogen atom, alkyl, haloalkyl, aryl or aralkyl, and the substituent of the substituted tetrazolyl is alkyl, carboxyalkyl. Or alkoxycarbonylalkyl; L ⁴¹ is a single bond or alkylene having 1 to 6 carbon atoms; X ⁴ is a nitrogen-containing heterocyclic group; L ⁴² is —CONH— or —NHCO— L ⁴³ is a single bond or alkylene having 1 to 6 carbon atoms; Y ⁴ is an oxygen atom or a sulfur atom; and L ⁴⁴ is a single bond or alkylene having 1 to 6 carbon atoms. is there)

The formulas (I) to (IV) will be described in detail below. In formula (I), A ¹ is an acidic group or a derivative of an acidic group, and specifically, —CO ₂ R ¹¹ , —CN,
_{^{-CONHSO 2 R 12, -CONR 13 R}} 14, -OR 15,
It is tetrazolyl or substituted tetrazolyl. -CO ₂
R ¹¹ and tetrazolyl are preferred, and —CO ₂ R ¹¹ is particularly preferred. The above R ¹¹ , R ¹³ , R ¹⁴ and R ¹⁵ are each a hydrogen atom, an alkyl or an alkali metal. The above R ¹² is a hydrogen atom, alkyl, haloalkyl, aryl or aralkyl. The substituent of the substituted tetrazolyl is alkyl, carboxyalkyl or alkoxycarbonylalkyl. The number of carbon atoms in the above alkyl and alkoxy is preferably 1 to 6. Examples of alkyl include methyl, ethyl and propyl. Examples of alkali metals include sodium and potassium. The haloalkyl preferably has 1 to 6 carbon atoms. Examples of haloalkyl include chloromethyl, chloroethyl and fluoroethyl. Examples of the above aryl include phenyl and naphthyl. Examples of the above aralkyl include benzyl, phenethyl and benzhydryl. The carboxyalkyl preferably has 2 to 7 carbon atoms.
Examples of carboxyalkyl include carboxyethyl. The number of carbon atoms in the alkoxy portion and the alkyl portion of the above alkoxycarbonylalkyl is preferably 1 to 6, respectively. Examples of alkoxycarbonylalkyl include ethoxycarbonylethyl.

In the formula (I), L ¹¹ is a single bond or alkylene having 1 to 6 carbon atoms. A single bond or alkylene having 1 to 3 carbon atoms is preferable, and methylene and ethylene are particularly preferable. L ¹¹ is benzo [b]
3rd, 4th, 5th or 6th, or 2, of the furan ring
2-position, 3-position, 4 of 3-dihydrobenzo [b] furan ring
It can be attached at position 5, 5 or 6. L ¹¹ is
It is particularly preferable to bond to the 5-position of the above ring. X ¹
Is a nitrogen-containing heterocyclic group. The nitrogen-containing heterocycle is preferably a 3-membered to 7-membered ring, more preferably a 5-membered or 6-membered ring. The number of nitrogen atoms contained in the heterocycle is preferably 1 to 3. Further, the atoms constituting the heterocycle are preferably composed only of nitrogen atoms and carbon atoms. Further, the heterocycle is preferably unsaturated and has aromaticity. The heterocycle may have a substituent.
Examples of the substituents include alkyl. The alkyl preferably has 1 to 6 carbon atoms. Examples of alkyl include methyl and ethyl. Examples of the nitrogen-containing heterocyclic group include imidazolyl and pyridyl. Imidazolyl, especially imidazol-1-yl, is preferred. In formula (I), L ¹² is a single bond or alkylene having 1 to 6 carbon atoms. A single bond or an alkylene having 1 to 4 carbon atoms is preferable, and an alkylene having 1 to 3 carbon atoms is particularly preferable. L ¹³ is
A single bond or alkylene having 1 to 6 carbon atoms. A single bond or methylene is preferred, and a single bond is particularly preferred. L ¹² and L ¹³ may be bonded to the intervening benzene ring at any position of ortho, meta and para. Y ¹ is an oxygen atom or a sulfur atom. An oxygen atom is preferred. L ¹⁴ is a single bond or has 1 carbon atom.
To alkylene. Alkylene having 1 to 3 carbon atoms is preferable, and methylene or ethylene is particularly preferable. L ¹⁴ is preferably bonded to the 2-position of the quinoline ring. In the formula (I), a double line consisting of a broken line and a solid line means a single bond or a double bond. It is preferably a double bond, that is, the condensed ring containing an oxygen atom represented by formula (I) is a benzo [b] furan ring. Particularly preferred quinoline derivatives are represented by the following formula (I-
Shown in a).

[0019]

[Chemical 15]

In the formula, A ¹ and X ¹ have the same meaning as in formula (I). “I” is 1 or 2. m is 1, 2 or 3. n is 1 or 2.

In the formula (II), A ² is an acidic group or a derivative of an acidic group, and specifically, --CO ₂ R ²¹ , --C.
^{_{N, -CONHSO 2 R 22, -CONR}} 23 R 24, -OR
²⁵ , tetrazolyl or substituted tetrazolyl. -C
O ₂ R ²¹ and tetrazolyl are preferred, and -CO ₂ R ²¹
Is particularly preferable. The above R ²¹ , R ²³ , R ²⁴ and R ²⁵ are
Each is a hydrogen atom, an alkyl or an alkali metal. R ²² is a hydrogen atom, alkyl, haloalkyl,
Aryl or aralkyl. The substituent of the substituted tetrazolyl is alkyl, carboxyalkyl or alkoxycarbonylalkyl. The alkyl preferably has 1 to 6 carbon atoms. Examples of alkyl include methyl, ethyl and propyl. Examples of alkali metals include sodium and potassium. The haloalkyl preferably has 1 to 6 carbon atoms. Examples of haloalkyl include chloromethyl, chloroethyl and fluoroethyl. Examples of the above aryl include phenyl and naphthyl. Examples of the above aralkyl include benzyl, phenethyl and benzhydryl. The carboxyalkyl preferably has 2 to 7 carbon atoms. Examples of carboxyalkyl include carboxyethyl. The number of carbon atoms in the alkoxy portion and the alkyl portion of the above alkoxycarbonylalkyl is preferably 1 to 6, respectively. Examples of alkoxycarbonylalkyl include ethoxycarbonylethyl.

In the formula (II), L ²¹ is a single bond or alkylene having 1 to 3 carbon atoms. Particularly preferred is alkylene having 1 to 2 carbon atoms. L ²¹ can be attached to the 3-position, 4-position, 5-position or 6-position of the benzene ring. It is particularly preferable that L ²¹ is bonded to the 4-position.
X ² is a nitrogen-containing heterocyclic group. The nitrogen-containing heterocycle is preferably a 3-membered to 7-membered ring, more preferably a 5-membered or 6-membered ring. The number of nitrogen atoms contained in the heterocycle is 1 to 3
It is preferred that Further, the atoms constituting the heterocycle are preferably composed only of nitrogen atoms and carbon atoms.
Further, the heterocycle is preferably unsaturated and has aromaticity. The heterocycle may have a substituent. Examples of the substituents include alkyl. The alkyl preferably has 1 to 6 carbon atoms. Examples of alkyl include methyl and ethyl. Examples of the nitrogen-containing heterocyclic group include imidazolyl and pyridyl. Imidazolyl, especially imidazol-1-yl, is preferred. In the formula (II), L ²² is a single bond or alkylene having 1 to 4 carbon atoms. Particularly preferred is alkylene having 1 to 3 carbon atoms. L ²³ is a single bond or methylene. A single bond is preferred. L ²² and L ²³ may be bonded to the intervening benzene ring at any position of ortho, meta and para. Y ² is
It is an oxygen atom or a sulfur atom. An oxygen atom is preferred.
L ²⁴ is a single bond or alkylene having 1 to 3 carbon atoms. Particularly preferred is methylene or ethylene. L ²⁴ is preferably bonded to the 2-position of the quinoline ring. In the formula (II), the partial structure represented by —CH═CHA ² may be trans type or cis type. A particularly preferred quinoline derivative is represented by the following formula (II
-A).

[0023]

Embedded image

In the formula, A ² and X ² have the same meaning as in formula (II). “I” is 1 or 2. m is 1, 2 or 3. n is 1 or 2.

In the formula (III), A ³ is an acidic group or a derivative of an acidic group, and specifically, --CO ₂ R ³¹ , --C.
^{_{N, -CONHSO 2 R 32, -CONR}} 33 R 34, -OR
³⁵ , tetrazolyl or substituted tetrazolyl. -O
R ³⁵ , —CO ₂ R ³¹ and tetrazolyl are preferred,
CO ₂ R ³¹ is particularly preferred. A ³ can be bonded to any position of the benzene ring. It is particularly preferable that A ³ is bonded to the position adjacent to L ³² below. R ³¹ above,
R ³³ , R ³⁴ and R ³⁵ are each a hydrogen atom, alkyl, carboxyalkyl or alkali metal. The above R ³² is a hydrogen atom, alkyl, haloalkyl, aryl or aralkyl. The substituents on the substituted tetrazolyl are alkyl, carboxyalkyl or alkoxycarbonylalkyl. The alkyl preferably has 1 to 6 carbon atoms. Examples of alkyl include methyl, ethyl and propyl. Examples of alkali metals include sodium and potassium. The haloalkyl preferably has 1 to 6 carbon atoms. Examples of haloalkyl include chloromethyl, chloroethyl and fluoroethyl. Examples of the above aryl include phenyl and naphthyl. Examples of the above aralkyl include benzyl, phenethyl and benzhydryl. The carboxyalkyl preferably has 2 to 7 carbon atoms. Examples of carboxyalkyl include carboxymethyl and carboxyethyl. The number of carbon atoms in the alkoxy portion and the alkyl portion of the above alkoxycarbonylalkyl is preferably 1 to 6, respectively. Examples of alkoxycarbonylalkyl include ethoxycarbonylethyl.

In the formula (III), L ³¹ is a single bond or alkylene having 1 to 3 carbon atoms. Particularly preferred is alkylene having 1 to 2 carbon atoms. L ³¹ can be bonded to any position of the benzene ring. L ³¹ is
It is particularly preferable to bond to the 4-position (the bonding position of A ³ is the 1-position). X ³ is a nitrogen-containing heterocyclic group. The nitrogen-containing heterocycle is preferably a 3-membered to 7-membered ring, more preferably a 5-membered or 6-membered ring. The number of nitrogen atoms contained in the heterocycle is preferably 1 to 3. Further, the atoms constituting the heterocycle are preferably composed only of nitrogen atoms and carbon atoms. Further, the heterocycle is preferably unsaturated and has aromaticity. The heterocycle may have a substituent. Examples of the substituents include alkyl. The alkyl preferably has 1 to 6 carbon atoms. Examples of alkyl include methyl and ethyl. Examples of the nitrogen-containing heterocyclic group include imidazolyl and pyridyl. Imidazolyl, especially imidazol-1-yl, is preferred. In formula (III), L
³² is a single bond or alkylene having 1 to 4 carbon atoms. Particularly preferred is alkylene having 1 to 3 carbon atoms. L ³³ is a single bond or methylene. A single bond is preferred. L ³² and L ³³ may be bonded to the intervening benzene ring at any position of ortho, meta and para. Y ³ is an oxygen atom or a sulfur atom. An oxygen atom is preferred. L ³⁴ is a single bond or has 1 carbon atom.
To 3 alkylene. Particularly preferred is methylene or ethylene. L ³⁴ is preferably bonded to the 2-position of the quinoline ring. A particularly preferred quinoline derivative is represented by the following formula (III-a).

[0027]

[Chemical 17]

In the formula, A ³ and X ³ have the same meaning as in formula (III). “I” is 1 or 2. m is 1, 2 or 3. n is 1 or 2. Also, attached to the benzene ring - (CH _{2) n} O- and - the positional relationship (CH ₂₎ m-A, it is preferable that the positional relation of the meta (m) or para (p).

In the formula (IV), A ⁴ is an acidic group or a derivative of an acidic group, specifically, --CO ₂ R ⁴¹ , --C.
^{_{N, -CONHSO 2 R 42, -CONR}} 43 R 44, -OR
⁴⁵ , tetrazolyl or substituted tetrazolyl. -C
O ₂ R ⁴¹ , —OR ⁴⁵ and tetrazolyl are preferable,
OR ⁴⁵ is particularly preferred. A ⁴ can be bonded to any position on the benzene ring, but it is particularly preferable to bond to A ⁴ adjacent to the following L ⁴² or the position next thereto. The above R ⁴¹ , R ⁴³ , R ⁴⁴ and R ⁴⁵ are each independently a hydrogen atom, alkyl, carboxyalkyl or alkali metal. R ⁴² is a hydrogen atom, alkyl, haloalkyl, aryl or aralkyl. The substituents on the substituted tetrazolyl are alkyl, carboxyalkyl or alkoxycarbonylalkyl. The alkyl preferably has 1 to 6 carbon atoms. Examples of alkyl include methyl, ethyl and propyl. Examples of alkali metals include sodium and potassium. The haloalkyl preferably has 1 to 6 carbon atoms. Examples of haloalkyl include chloromethyl, chloroethyl and fluoroethyl.
Examples of the above aryl include phenyl and naphthyl. Examples of the above aralkyl include benzyl, phenethyl and benzhydryl. The carboxyalkyl preferably has 2 to 7 carbon atoms. Examples of carboxyalkyl include carboxymethyl and carboxyethyl. The number of carbon atoms in the alkoxy part and the alkyl part of the above alkoxycarbonylalkyl is
It is preferably 1 to 6, respectively. Examples of alkoxycarbonylalkyl include ethoxycarbonylethyl.

In the formula (IV), L ⁴¹ is a single bond or alkylene having 1 to 3 carbon atoms. Particularly preferred is alkylene having 1 to 2 carbon atoms. L ⁴¹ can be bonded to any position of the benzene ring. L ⁴¹ is
It is particularly preferable to bond at the 4-position or the 5-position (the bonding position of A ⁴ is the 1-position). X ⁴ is a nitrogen-containing heterocyclic group. The nitrogen-containing heterocycle is preferably a 3- to 7-membered ring,
More preferably, it is a 5- or 6-membered ring. The number of nitrogen atoms contained in the heterocycle is preferably 1 to 3. Further, the atoms constituting the heterocycle are preferably composed only of nitrogen atoms and carbon atoms. Further, the heterocycle is preferably unsaturated and has aromaticity. The heterocycle may have a substituent. Examples of the substituents include alkyl. The alkyl preferably has 1 to 6 carbon atoms. Examples of alkyl include methyl and ethyl. Examples of the nitrogen-containing heterocyclic group include imidazolyl and pyridyl. Imidazolyl, especially imidazol-1-yl, is preferred. Formula (IV)
In, L ⁴² is -CONH- or -NHCO-
It is. L ⁴³ is a single bond or methylene. A single bond is preferred. L ⁴² and L ⁴³ may be bonded to the intervening benzene ring at any position of ortho, meta and para. Y ⁴ is an oxygen atom or a sulfur atom.
An oxygen atom is preferred. L ⁴⁴ is a single bond or alkylene having 1 to 3 carbon atoms. Particularly preferred is methylene or ethylene. L ⁴⁴ is preferably bonded to the 2-position of the quinoline ring. A particularly preferred quinoline derivative is represented by the following formula (IV-a).

[0031]

Embedded image

Where A ⁴ , X ⁴ , and L ⁴² are defined by the formula (I
V) has the same meaning. “I” is 1 or 2. n
Is 1 or 2. -(CH ₂ ) on the benzene ring
The positional relationship between _n − and −L ⁴² − is preferably the positional relationship of meta (m).

In the above equations, L ¹⁴ , L ²⁴ ,
The quinoline ring to which L ³⁴ or L ⁴⁴ is bonded may have a substituent. Substituents include halogen, alkyl and alkoxy. Examples of halogen include chlorine, bromine and fluorine. The alkyl preferably has 1 to 6 carbon atoms. Examples of alkyl include methyl and ethyl. The alkoxy preferably has 1 to 6 carbon atoms. Examples of alkoxy include methoxy and ethoxy.

Examples of the pharmacologically acceptable salt of the compound of the present invention include acidic salts such as hydrochloric acid and acetic acid and basic salts such as alkali metals (eg sodium, potassium). Specific examples of the quinoline derivatives represented by formulas (I) to (IV) are shown below.

(I-1) 5- (imidazol-1-ylmethyl) -7- [4- (quinolin-2-ylmethyloxy) phenylmethyloxy] benzo [b] furan-2-
carboxylic acid

[0036]

[Chemical 19]

(I-2) 5- (imidazol-1-ylmethyl) -7- [3- (quinolin-2-ylmethyloxy) phenylmethyloxy] benzo [b] furan-2-
carboxylic acid

[0038]

Embedded image

(I-3) 5- (imidazol-1-ylmethyl) -7- [2- (quinolin-2-ylmethyloxy) phenylmethyloxy] benzo [b] furan-2-
carboxylic acid

[0040]

[Chemical 21]

(I-4) 5- [5- (imidazole-1
-Ylmethyl) -7- [4- (quinolin-2-ylmethyloxy) phenylmethyloxy] benzo [b] furan-2-yl] tetrazole

[0042]

[Chemical formula 22]

(I-5) 5- (imidazol-1-ylmethyl) -7- [4- (quinolin-2-ylmethyloxy) phenylmethyloxy] benzo [b] furan-2-
Carboxylic acid ethyl ester

[0044]

[Chemical formula 23]

(I-6) 5- (imidazol-1-ylmethyl) -7- [4- (quinolin-2-ylmethyloxy) phenylmethyloxy] benzo [b] furan-2-
carboxylic acid

[0046]

[Chemical formula 24]

(I-7) 5- [5- (imidazole-1
-Ylmethyl) -7- [4- (quinolin-2-ylmethyloxy) phenylmethyloxy] benzo [b] furan-2-yl] -1-methyltetrazole dihydrochloride

[0048]

[Chemical 25]

(I-8) 5- [5- (imidazole-1
-Ylmethyl) -7- [4- (quinolin-2-ylmethyloxy) phenylmethyloxy] benzo [b] furan-2-yl] -2-methyltetrazole dihydrochloride

[0050]

[Chemical formula 26]

(I-9) 5- (imidazol-1-ylmethyl) -7- [4- (quinolin-2-ylmethyloxy) phenylmethyloxy] benzo [b] furan-2-
Carboxamide

[0052]

[Chemical 27]

(I-10) N- [5- (imidazole-
1-ylmethyl) -7- [4- (quinolin-2-ylmethyloxy) phenylmethyloxy] benzo [b] furan-2-carbonyl] -2-methylbenzenesulfonamide

[0054]

[Chemical 28]

(II-1) trans-3- [4- (imidazol-1-ylmethyl) -2- [3- (quinoline-2)
-Ylmethyloxy) phenylmethyloxy] phenyl] propenoic acid

[0056]

[Chemical 29]

(II-2) cis-3- [4- (imidazol-1-ylmethyl) -2- [3- (quinolin-2-ylmethyloxy) phenylmethyloxy] phenyl] propenoic acid

[0058]

Embedded image

(II-3) trans-3- [4- (imidazol-1-ylmethyl) -2- [4- (quinoline-2)
-Ylmethyloxy) phenylmethyloxy] phenyl] propenoic acid

[0060]

[Chemical 31]

(II-4) cis-3- [4- (imidazol-1-ylmethyl) -2- [4- (quinolin-2-ylmethyloxy) phenylmethyloxy] phenyl] propenoic acid

[0062]

Embedded image

(II-5) Trans-N- [3- [4-
(Imidazol-1-ylmethyl) -2- [4- (quinolin-2-ylmethyloxy) phenylmethyloxy]
Phenyl]-(E) -propenoyl] -2-methylbenzenesulfonamide

[0064]

[Chemical 33]

(II-6) trans-5- [2- [4-
(Imidazol-1-ylmethyl) -2- [4- (quinolin-2-ylmethyloxy) phenylmethyloxy]
Phenyl] ethenyl] tetrazole

[0066]

Embedded image

(III-1) 4- (imidazol-1-ylmethyl) -2- [3- (quinolin-2-ylmethyloxy) benzyloxy] benzoic acid

[0068]

Embedded image

(III-2) 4- (imidazol-1-ylmethyl) -3- [3- (quinolin-2-ylmethyloxy) benzyloxy] phenoxyacetic acid

[0070]

Embedded image

(III-3) 4- (imidazol-1-ylmethyl) -3- [4- (quinolin-2-ylmethyloxy) benzyloxy] phenoxyacetic acid

[0072]

Embedded image

(IV-1) 4- (imidazol-1-ylmethyl) -3- [3- (quinolin-2-ylmethyloxy) benzoylamino] phenoxyacetic acid

[0074]

[Chemical 38]

(IV-2) 4- [3- (imidazole-1)
-Yl) propyl] -2- [2-oxo-2- [3-
(Quinolin-2-ylmethyloxy) phenylamino]
Ethyl] benzoic acid

[0076]

[Chemical Formula 39]

(IV-3) 4- [3- (imidazole-1)
-Yl) propyl] -2- [2-oxo-2- [3-
(Quinolin-2-ylmethyloxy) phenylamino]
Ethyl] methyl benzoate dihydrochloride

[0078]

[Chemical 40]

(IV-4) 4- (imidazol-1-ylmethyl) -2- [3- (quinolin-2-ylmethyloxy) benzoylamino] phenoxyacetic acid

[0080]

Embedded image

(IV-5) 4- (imidazol-1-ylmethyl) -2- [4- (quinolin-2-ylmethyloxy) benzoylamino] phenoxyacetic acid

[0082]

Embedded image

(IV-6) 4- (imidazol-1-ylmethyl) -3- [4- (quinolin-2-ylmethyloxy) benzoylamino] phenoxyacetic acid

[0084]

[Chemical 43]

The quinoline derivative represented by the formula (I) can be synthesized, for example, by the following synthetic route. The compounds represented by the formulas (II), (III) and (IV) can also be synthesized by the same synthetic route.

[0086]

[Chemical 44]

The quinoline derivatives and salts thereof of the present invention are
It has both thromboxane A ₂ synthase inhibitory action and leukotriene D ₄ antagonistic action. Therefore, the compound of the present invention can be used as a therapeutic or prophylactic agent for diseases involving TXA ₂ or LTD ₄ . The compound of the present invention is useful, for example, as a therapeutic or prophylactic agent for bronchial asthma, allergic disease, nephritis, thrombosis, stroke, myocardial infarction, angina, and ischemic cerebral circulation disorder.

The compound of the present invention may be administered orally or parenterally. Examples of the dosage form of the orally-administered agent include tablets, capsules, powders, granules and syrups. Parenteral administration methods include mucosal administration, body surface administration, vascular administration, and intratissue administration. For mucosal administration, it is used as an eye drop, an inhalant, a spray or a suppository. For body surface administration, use as an ointment. In the case of vascular administration and tissue administration, it is used as an injection.

The above-mentioned oral administration preparation is manufactured by using a conventional excipient,
It can be carried out using a disintegrant, a binder, a lubricant, a dye or a diluent. Glucose and lactose are generally used as excipients. Examples of disintegrants include starch and carboxymethyl cellulose calcium. Lubricants include magnesium stearate and talc. As the binder, hydroxypropyl cellulose,
Gelatin and polyvinylpyrrolidone are used. The parenteral preparation can also be produced by a usual method. For example, in the case of an injection, ordinary distilled water for injection, physiological saline or Ringer's solution may be used. The dose of the compound of the present invention is
Ordinary adults, 0.1 to 200 mg daily by injection,
Oral administration is 1 to 500 mg daily. Of course, the dose may be increased or decreased according to age, race, symptoms, etc.

[0090]

【Example】

[Synthesis Example 1] 5- (imidazol-1-ylmethyl)-
7- [4- (quinolin-2-ylmethyloxy) phenylmethyloxy] -benzo [b] furan-2-carboxylic acid ethyl ester (I-5), and 5- (imidazol-1-ylmethyl) -7- [4- (quinolin-2-ylmethyloxy) phenylmethyloxy] benzo [b]
Synthesis of furan-2-carboxylic acid (I-1) (1) 5-dimethylaminomethyl-2-hydroxy-3
-Synthesis of methoxybenzaldehyde (reaction formula below) 35% formalin aqueous solution (21.1 g, 246 mmol) and 40% dimethylamine aqueous solution (29.5 g,
262 mmol) was dissolved in ethanol (150 mL), O-vanillin (25.0 g, 164 mmol) was added, and the mixture was heated under reflux for 5 hours. After allowing to cool, the solvent was distilled off under reduced pressure,
Ether was added to the residue to pulverize the solid, and the pulverized product was collected by filtration and washed with ether. This was dried under reduced pressure to obtain 31.2 g (yield 90.9%) of the title compound (1) as a yellow crystalline powder. Melting point: 110.0 to 111.5 ° C. ¹ H-NMR (CDCl ₃ ): δ = 2.25 (6H, s) 3.39 (2H, s) 3.93 (3H, s) 7.09 (1H , D, J = 2 Hz) 7.13 (1H, d, J = 2 Hz) 9.90 (1H, s)

[0091]

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(2) 2-hydroxy-3-methoxy-5
-Synthesis of methylbenzaldehyde (reaction formula is shown below) In a nitrogen atmosphere, the above compound (1) (30.9 g, 148)
24 mmol) in acetic anhydride (150 mL),
Heated to reflux for hours. After cooling, the reaction solvent was evaporated under reduced pressure, concentrated hydrochloric acid (150 mL) was added to the residue, and the mixture was stirred at room temperature for 1 hour and 30 minutes, whereupon crystals of a chloromethyl derivative were precipitated in the reaction mixture. P-dioxane (120 ml) was added to the reaction mixture.
Was added and dissolved by heating at 60 to 70 ° C. To this was added tin chloride dihydrate (50.1 g, 222 mmol), 30
Heated to reflux for minutes. After allowing to cool to room temperature, concentrated hydrochloric acid (60 m
L) was added and diluted, followed by extraction with chloroform (200 mL) three times. The obtained organic layer was washed successively with 6N hydrochloric acid, water and saturated saline, and dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 /
By purifying according to 1), the title compound (2) 1
0.2 g (yield 41.6%) was obtained as yellow crystals. ¹ H-NMR (CDCl ₃ ): δ = 2.34 (3H, s) 3.90 (3H, s) 6.94 (1H, d, J = 1 Hz) 6.95, (1H, d, J = 1Hz) 9.85 (1H, s) 10.9 (1H, s)

[0093]

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(3) Synthesis of 7-methoxy-5-methyl-2-benzofurancarboxylic acid ethyl ester (reaction formula is given below) The above compound (2) (9.18 g, 55.2 mmol),
Ethyl bromoacetate (18.4 mL, 166 mmol) and potassium carbonate (30.5 g, 221 mmol) were mixed and stirred at 140 ° C. for 17 hours. After cooling to room temperature, water (200 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-xane / ethyl acetate = 4/1) to give the title compound (3). 2.63 g (yield 20.3%) was obtained as white crystals. ¹ H-NMR (CDCl ₃ ): δ = 1.41 (3H, t, J = 7Hz) 2.43 (3H, s) 3.99 (3H, s) 4.42 (2H, q, J = 7Hz) ) 6.72 (1H, s) 7.02 (1H, s) 7.43 (1H, s)

[0095]

[Chemical 47]

(4) 5-Bromomethyl-7-methoxy-
Synthesis of 2-benzo [b] furancarboxylic acid ethyl ester (reaction formula is below) Compound (3) (2.60 g, 11.1 mmol),
NBS (= N-bromosuccinimide, 1.98 g, 1
1.1 mmol) and AIBN (= azobisisobutyronitrile, 0.148 g, 0.902 mmol) were suspended in carbon tetrachloride (100 mL), and the mixture was heated under reflux for 6 hours. After cooling to room temperature, the insoluble matter in the reaction mixture was removed by cotton plug filtration, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5/1) to give 2.40 g (yield 69.0%) of the title compound (4) as a pale yellow crystalline powder. Obtained. ¹ H-NMR (CDCl ₃ ): δ = 1.42 (3H, t, J = 7Hz) 4.04 (3H, s) 4.44 (2H, q, J = 7Hz) 4.59 (2H, s) ) 6.95 (1H, d, J = 1 Hz) 7.27 (1H, d, J = 1 Hz) 7.47 (1H, s)

[0097]

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(5) Synthesis of 5- (imidazol-1-ylmethyl) -7-methoxy-2-benzo [b] furancarboxylic acid ethyl ester (reaction formula is given below) Imidazole (0.519 g, 7.63 mmol) Was dissolved in dry DMF (= dimethylformamide, 20 mL) and 60% sodium hydride (0.305 g, 7.63) was added.
(Mmol) and added, and stirred at room temperature for 1 hour and 30 minutes. A solution of the compound (4) (2.39 g, 7.63 mmol) in dry DMF (60 mL) was added dropwise thereto over 10 minutes. After stirring at room temperature for 24 hours, the reaction mixture was poured into ice water (300 mL) and ethyl acetate (100 mL) was added for 3 hours.
Extracted times. The extracted organic layer was washed with water (100 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized in a freezer, n-hexane was added, and the crystals were collected by filtration to give the title compound (5) (1.76 g, yield 76.8%) as white crystals. ¹ H-NMR (CDCl ₃ ): δ = 1.41 (3H, t, J = 7Hz) 3.97 (3H, s) 4.44 (2H, q, J = 7Hz) 5.19 (2H, s) ) 6.67 (1H, d, J = 2Hz) 6.92 (1H, s) 7.04 (1H, d, J = 2Hz) 7.11 (1H, s) 7.45 (1H, s) 7 .58 (1H, s)

[0099]

[Chemical 49]

(6) Synthesis of 7-hydroxy-5- (imidazol-1-ylmethyl) -2-benzo [b] furancarboxylic acid (reaction formula is shown below) Compound (5) (0.073 g, purity: 96) 0.0%,
0.233 mmol) to chlorobenzene (1.5 mL)
It is dissolved in water by heating, and aluminum chloride (0.190 g, 1.
40 mmol) was added and the mixture was heated under reflux for 30 minutes. After the solvent was distilled off under reduced pressure, water was added to the residue to dissolve it, and the residue was washed with ethyl acetate. The aqueous layer is allowed to stand, and the precipitated crystals are collected by filtration, washed with water and air-dried to give the title compound (6)
0.050 g (yield 83.1%) was obtained as a white crystalline powder. ¹ H-NMR (DMSO-d ₆ ): δ = 5.21 (2H, s) 6.75 (1H, s) 6.93 (1H, s) 7.05 (1H, s) 7.18 (1H , S) 7.56 (1H, s) 7.80 (1H, s) 10.4 (1H, brs)

[0101]

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(7) Synthesis of 7-hydroxy-5- (imidazol-1-ylmethyl) -2-benzo [b] furancarboxylic acid ethyl ester (reaction formula is shown below) The above compound (6) (0.047 g, 0 (180 mL) was dissolved in ethanol (1 mL), one drop of concentrated sulfuric acid was added, and the mixture was heated under reflux for 4 hours. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution and dichloromethane were added to the residue, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (7) 0.01
1 g (yield 21.3%) was obtained as a white crystalline powder. ¹ H-NMR (CDCl ₃ / CD ₃₀ D = 10/1):
δ = 1.42 (3H, t, J = 7Hz) 4.43 (2H, q, J = 7Hz) 5.15 (2H, s) 6.74 (1H, d, J = 1Hz) 6.94 ( 1H, s) 6.97 (1H, d, J = 1 Hz) 7.04 (1H, s) 7.47 (1H, s) 7.60 (1H, s)

[0103]

[Chemical 51]

(8) Synthesis of 4- (2-quinolinylmethyloxy) benzyl alcohol (reaction formula is shown below) 60% sodium hydride (11.2 g, 280 mmol) was added to dry DMF (80 mL) under a nitrogen atmosphere. Suspended in water, and dried under ice-cooling 4-hydroxybenzyl alcohol (29.0 g, 234 mmol) in dry DMF (80 m).
L) solution was added dropwise and stirred for 40 minutes. Separately, 2- (chloromethyl) quinoline hydrochloride (50.0 g, 234 mmol) was added to water (400 mL) and dichloromethane (10
(0 mL) and mixed with sodium hydrogen carbonate (23.8 g, 283 mmol) little by little under ice cooling, and the organic layer was separated. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 2- (chloromethyl) quinoline. This was dissolved in dry DMF (65 mL), added dropwise to the above reaction solution under ice cooling, and stirred overnight at room temperature. The reaction solution was poured into water (500 mL), and the precipitated crystals were collected by filtration and washed with water (4
It was washed with 00 mL × 3). The obtained crystals were vacuum dried, dissolved in chloroform (200 mL) by heating, hexane (250 mL) was added while the solution was hot, and the mixture was cooled to room temperature with stirring. The precipitated crystals were collected by filtration, washed with a mixed solvent of chloroform / hexane = 1/1 (100 mL × 3), and dried under vacuum to give 34.8 g (yield 56.0%) of the title compound (8) as a pale solvent. Obtained as yellow crystals. Melting point: 136.4 ° C ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 1.65 (1H, brs) 4.61 (2H, d, J = 5Hz) 5.37 (2H, s) 6.98 -7.03 (2H, m) 7.26-7.31 (2H, m) 7.51-7.57 (1H, m) 7.66 (1H, d, J = 8Hz) 7.74 (1H , Ddd, J = 1Hz, 8Hz, 7H
z) 7.82 (1H, d, J = 8Hz) 8.08 (1H, d, J = 8Hz) 8.18 (1H, d, J = 8Hz)

[0105]

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(9) Synthesis of 4- (2-quinolinylmethyloxy) benzyl chloride (reaction formula is shown below) The above compound (8) (34.8 g, 131 mmol) was suspended in dry chloroform (340 mL). Thionyl chloride (17.2 mL, 237 mmol) was slowly added dropwise under ice cooling. The crystals dissolved upon addition of thionyl chloride. The reaction solution was stirred at room temperature for 30 minutes, and saturated aqueous sodium hydrogen carbonate solution was added under ice cooling until the pH reached 7 to 8, and the organic layer was separated. After drying over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure to obtain 36.9 g (yield 99.2%) of the title compound (9) as pale yellow crystals. Melting point: 103.8 ° C. ¹ H-NMR (CDCl ₃ , 400 MHZ): δ = 4.55 (2H, s) 5.39 (2H, s) 6.96 to 7.03 (2H, m) 7.26 ~ 7.33 (2H, m) 7.51 ~ 7.58 (1H, m) 7.65 (1H, d, J = 8Hz) 7.74 (1H, ddd, J = 2Hz, 8Hz, 7H
z) 7.83 (1H, d, J = 8Hz) 8.08 (1H, d, J = 8Hz) 8.19 (1H, d, J = 8Hz)

[0107]

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(10) 5- (imidazol-1-ylmethyl) -7- [4- (quinolin-2-ylmethyloxy) phenylmethyloxy] -benzo [b] furan-2
-Synthesis of carboxylic acid ethyl ester (I-5) (reaction formula is shown below) To a solution of the compound (7) (0.010 g, 0.035 mmol) in dry DMF (2 mL), 60% hydrogenation under ice cooling. Sodium (0.0014 g, 0.035 mmol) was added and stirred at room temperature for 30 minutes. A dry DMF (2 mL) solution of the compound (9) was added dropwise thereto, and the mixture was stirred at room temperature for 3 hours. After heating and refluxing for another 2 hours, allow to cool,
The reaction mixture was poured into ice water (10 mL). The precipitated crystals were collected by filtration, dried under reduced pressure, and purified by preparative thin layer chromatography (eluent: chloroform / methanol = 10/1) to give the title compound (10) 0.0
14 g (purity 98.3%, yield 73.7%) was obtained as a white crystalline powder. ¹ H-NMR (CDCl ₃ ): δ = 1.41 (3H, t, J = 7Hz) 4.42 (2H, q, J = 7Hz) 5.13 (2H, s) 5.19 (2H, s) ) 5.39 (2H, s) 6.70 (1H, s) 6.86 (1H, s) 7.03 (1H, s) 7.09 (1H, s) 7.36 (1H, d, J) = 8 Hz) 7.44 (1 H, s) 7.52 to 7.57 (1 H, m) 7.58 (1 H, s) 7.67 (1 H, d, J = 8 Hz) 7.71 to 7.76 (1H, m) 7.82 (1H, d, J = 8Hz) 8.08 (1H, d, J = 8Hz) 8.19 (1H, d, J = 8Hz)

[0109]

[Chemical 54]

(11) 5- (imidazol-1-ylmethyl) -7- [4- (quinolin-2-ylmethyloxy) phenylmethyloxy] benzo [b] furan-2-
Synthesis of Carboxylic Acid (I-1) (Reaction Formula is Below) Compound (10) (0.014 g, Purity: 98.3)
%, 0.026 mmol) with ethanol (2 mL) and p
-Dissolved in a mixed solvent of dioxane (1 mL), 0.1N aqueous sodium hydroxide solution (0.78 mL) was added, and the mixture was stirred at room temperature for 22 hours. After confirming the completion of the reaction, the pH was adjusted to 6 by adding 0.1N hydrochloric acid, the solvent was distilled off under reduced pressure at 40 ° C or lower, a small amount of water was added to the dried residue, and the solid was collected by filtration and dried under reduced pressure. , The title compound (11) 0.009 g
(Yield 70.8%) was obtained as a white crystalline powder. ¹ H-NMR (CDCl ₃ / CD ₃₀ D = 10/1):
δ = 5.16 (2H, s) 5.18 (2H, s) 5.38 (2H, s) 6.74 (1H, s) 6.91 (1H, s) 7.02 to 7.07 ( 4H, m) 7.36 to 7.41 (3H, m) 7.58 (1H, t, J = 8Hz) 7.63 (1H, s) 7.70 (1H, d, J = 8Hz) 7. 74 to 7.79 (1H, m) 7.86 (1H, d, J = 8Hz) 8.08 (1H, d, J = 8Hz) 8.26 (1H, d, J = 8Hz) IR (KBr) cm ⁻¹ : 3423, 1608, 159
9, 1514, 1356, 1304, 1248, 120
9, 1138, 1113, 1092, 980, 943,
837, 787, 752

[0111]

[Chemical 55]

[Synthesis Example 2] 5- (imidazol-1-ylmethyl) -7- [3- (quinolin-2-ylmethyloxy) phenylmethyloxy] benzo [b] furan-2
-Synthesis of carboxylic acid (I-2) (1) Synthesis of 3- (2-quinolinylmethyloxy) benzyl alcohol 60% sodium hydride (1.12 g, 28) in dry DMF (8 mL) under a nitrogen atmosphere. 0.0 mmol) was suspended therein, and dried DMF (8 m of 3-hydroxybenzyl alcohol (2.90 g, 23.4 mmol) under ice cooling was added thereto.
L) solution was added dropwise and stirred for 30 minutes. Separately 2-
(Chloromethyl) quinoline hydrochloride (5.0 g, 23.4
Mmol) water (40 mL) and dichloromethane (1
(0 mL) and mixed with sodium hydrogen carbonate (2.38 g, 28.3 mmol) little by little under ice cooling, and the organic layer was separated. After drying over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure to obtain 2- (chloromethyl) quinoline. This was dissolved in dry DMF (6.5 mL), added dropwise to the above reaction solution under ice cooling, stirred overnight at room temperature, poured into ice water (50 mL), extracted with chloroform (30 mL), and water ( After washing with 40 mL × 2), it was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate / hexane = 1 /
Purification by 1) yielded 3.71 g (yield 59.8%) of the title compound (1) as pale yellow crystals. Melting point: 91.4-92.4 ° C ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 1.83 (1 H, t, J = 6 Hz) 4.67 (2 H, d, J = 6 Hz) 5.38 (2H, s) 6.90 to 7.00 (2H, m) 7.04 to 7.10 (1H, m) 7.27 (1H, t, J = 8Hz) 7.50 to 7.58 (1H) , M) 7.67 (1H, d, J = 8Hz) 7.73 (1H, ddd, J = 2Hz, 8Hz, 7H
z) 7.82 (1H, d, J = 8Hz) 8.08 (1H, d, J = 8Hz) 8.18 (1H, d, J = 8Hz)

(2) Synthesis of 3- (2-quinolinylmethyloxy) benzyl chloride The above compound (1) (1.90 g, 7.16 mmol) was dissolved in dichloromethane (14 mL) and chlorinated under ice cooling. Thionyl (0.9 mL, 12.4 mmol) was slowly added dropwise. Crystals precipitated when thionyl chloride was added,
It dissolved after a while. The reaction solution was stirred at room temperature for 30 minutes, and saturated aqueous sodium hydrogen carbonate solution was added to pH 7 under ice cooling.
It was added until ~ 8 and the organic layer was separated. After drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 2.04 g (purity 99.5%, yield 99.9%) of the title compound (2) as pale yellow crystals. Melting point: 54.2-55.8 ° C. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 4.54 (2H, s) 5.39 (2H, s) 6.95-7.01 (2H, m) ) 7.07 to 7.10 (1H, m) 7.26 (1H, t, J = 8Hz) 7.55 (1H, ddd, J = 1Hz, 8Hz, 7H)
z) 7.67 (1H, d, J = 8Hz) 7.74 (1H, ddd, J = 2Hz, 8Hz, 7H
z) 7.83 (1H, d, J = 8Hz) 8.09 (1H, d, J = 8Hz) 8.19 (1H, d, J = 8Hz)

(3) 5- (imidazol-1-ylmethyl) -7- [3- (quinolin-2-ylmethyloxy)
Synthesis of phenylmethyloxy] benzo [b] furan-2-carboxylic acid ethyl ester A solution of the compound (7) obtained in Synthesis Example 1 (146 mg, 0.51 mmol) in dry DMF (4 mL) was added with 60% sodium hydride. (21 mg, 0.53 mmol) was added, and the mixture was stirred at room temperature for 1 hr. In addition, the compound (2) (17)
6 mg, 0.62 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into ice water (20 mL) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then with saturated saline, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give a dark brown oil (420 mg), which was purified by medium pressure silica gel column chromatography (chloroform / methanol = 40/1) to give the title compound (3).
108 mg was obtained as a white crystalline powder. (Yield: 3
9.6%) ¹ H-NMR (CDCl ₃ ): δ = 1.41 (3H, t, J = 7Hz) 4.43 (2H, q, J = 7Hz) 5.08 (2H, s) 5. 25 (2H, s) 5.38 (2H, s) 6.66 (1H, d, J = 1Hz) 6.83 (1H, s), 6.9-7.0 (2H, m) 7.04 (1H, d, J = 8Hz) 7.08 (1H, s) 7.14 (1H, s) 7.29 (1H, dd, J = 8Hz, 8Hz) 7.43 (1H, s) 7.5 ~ 7.6 (2H, m) 7.65 (1H, d, J = 8Hz) 7.72 (1H, ddd, J = 1Hz, 8Hz, 8H
z) 7.81 (1H, d, J = 8Hz) 8.06 (1H, d, J = 8Hz) 8.16 (1H, d, J = 8Hz) IR (KBr) cm ^-1 : 1700, 1595, 158
0, 1300, 1200

(4) 5- (imidazol-1-ylmethyl) -7- [3- (quinolin-2-ylmethyloxy)
Synthesis of Phenylmethyloxy] benzo [b] furan-2-carboxylic acid (I-2) The above compound 14 (107 mg, 0.20 mmol) was dissolved in a mixed solvent of ethanol (4 mL) and p-dioxane (2 mL). , 0.1N sodium hydroxide aqueous solution (4m
L) was added, and the mixture was stirred at room temperature for 3 hours. It was diluted with water (10 mL) and citric acid was added to adjust pH to 5. The precipitated crystals were collected by filtration, washed with water (2 mL) five times, and dried under reduced pressure to give the title compound (4) 88 mg as a white crystalline powder. (Yield: 85%) Melting point: 130 to 134 ° C. ¹ H-NMR (DMSOd ₆ ): δ = 5.23 (2H, s) 5.26 (2H, s) 5.38 (2H, s) 6.91 (1H, s) 7.0-7.3 (6H, m) 7.34 (1H, dd, J = 8Hz, 8Hz) 7.6-7.7 (3H, m) 7.7-7.8 (2H, m) 7.9 to 8.0 (2H, m) 8.39 (1H, d, J = 9Hz) IR (KBr) cm ^-1 : 3400, 1600, 138
0, 1320, 1265, 1210, 1145, 780

[Synthesis Example 3] 5- (imidazol-1-ylmethyl) -7- [2- (quinolin-2-ylmethyloxy) phenylmethyloxy] benzo [b] furan-2
-Synthesis of carboxylic acid (I-3) (1) Synthesis of 2- (2-quinolinylmethyloxy) benzyl alcohol 60% sodium hydride (1.00 g, 25) in dry DMF (8 mL) under a nitrogen atmosphere. 0.0 mmol) was suspended therein, and dried under ice-cooling of 2-hydroxybenzyl alcohol (2.80 g, 22.6 mmol) in dry DMF (8 m).
L) solution was added dropwise and stirred for 30 minutes. Separately, 2- (chloromethyl) quinoline hydrochloride (5.0 g, 23.4 mmol) was added to water (40 mL) and dichloromethane (10 m).
L) was added to the mixed solvent, and sodium hydrogencarbonate (2.38 g, 28.3 mmol) was added little by little under ice cooling, and the organic layer was separated. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 2- (chloromethyl) quinoline. This was dissolved in dry DMF (8 mL), added dropwise to the above reaction solution under ice cooling, and stirred overnight at room temperature, and then ice water (100
(mL), extracted with chloroform (80 mL), washed with water (40 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1), and then dissolved in chloroform (5 mL). Hexane (13 mL) was added to this solution, and the precipitated crystals were collected by filtration and vacuum dried to obtain 4.15 g (yield: 69.0%) of the title compound (1) as white crystals. Melting point: 101.4 to 102.8 ° C ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 4.06 (1H, brs) 4.83 (2H, s) 5.47 (2H, s) 6.94. -7.01 (2H, m) 7.21-7.27 (1H, m) 7.33 (1H, dd, J = 1Hz, 7Hz) 7.53 (1H, d, J = 7Hz) 7.55 (1H, ddd, J = 1Hz, 8Hz, 7H
z) 7.73 (1H, ddd, J = 1 Hz, 8 Hz, 7H
z) 7.82 (1H, dd, J = 1 Hz, 8 Hz) 8.08 (1H, d, J = 8 Hz) 8.18 (1H, d, J = 8 Hz)

(2) Synthesis of 2- (2-quinolinylmethyloxy) benzyl chloride The above compound (1) (1.00 g, 3.77 mmol) was dissolved in dichloromethane (7 mL) and chlorinated under ice cooling. Thionyl (0.47 mL, 6.47 mmol) was added slowly dropwise. Crystals were precipitated when thionyl chloride was added. The reaction solution was stirred at room temperature for 1 hour, saturated aqueous sodium hydrogen carbonate solution was added under ice cooling until the pH reached 7 to 8, and the organic layer was separated. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was suspended in hexane (10 mL). The crystals were collected by filtration and dried under vacuum to give 0.98 g (yield: 91.5
%) Of the title compound (2) as white crystals. Melting point: 108.2 to 109.2 ° C ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 4.79 (2H, s) 5.46 (2H, s) 6.94 to 7.00 (2H, m) ) 7.27 (1H, J = 1Hz, 8Hz) 7.40 (1H, dd, J = 1Hz, 8Hz) 7.56 (1H, t, J = 8Hz) 7.74 (1H, ddd, J = 1Hz) , 8Hz, 7H
z) 7.77 (1H, t, J = 8Hz) 7.84 (1H, d, J = 8Hz) 8.08 (1H, d, J = 8Hz) 8.21 (1H, d, J = 8Hz)

(3) 5- (imidazol-1-ylmethyl) -7- [2- (quinolin-2-ylmethyloxy)
Synthesis of Phenylmethyloxy] benzo [b] furan-2-carboxylic acid ethyl ester Compound (7) obtained in Synthesis Example 1 (286 mg, 1.0
To a solution of 0 mmol) in dry DMF (4 mL) was added 60% sodium hydride (40 mg, 1.0 mmol),
Stir for 30 minutes at room temperature. In addition to this, the compound 17 (3
41 mg, 1.20 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water (20 mL) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 886 mg of white crystals, which was washed with acetone and then with hexane to give 290 mg of the title compound (3).
Was obtained as a white crystalline powder. (Secondary crystal: 75 mg, Yield: 68.4%) Melting point: 145-146 ° C. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 1.40 (3H, t, J = 7 Hz) 4.42 (2H , Q, J = 7 Hz) 5.10 (2H, s) 5.44 (4H, s) 6.82 (1H, d, J = 1 Hz) 6.84 (1H, s) 6.9 to 7.0. (3H, m) 7.06 (1H, s) 7.27 (1H, m) 7.44 (1H, s) 7.5-7.6 (3H, m) 7.66 (1H, d, J = 8Hz) 7.73 (1H, ddd, J = 2Hz, 8Hz, 8H
z) 7.82 (1H, d, J = 8 Hz) 8.06 (1H, d, J = 8 Hz) 8.15 (1H, d, J = 8 Hz) IR (KBr) cm ⁻¹ : 1710, 1600, 158
0, 1490, 1350, 1310, 1255, 120
0,755

(4) 5- (imidazol-1-ylmethyl) -7- [2- (quinolin-2-ylmethyloxy)
Synthesis of Phenylmethyloxy] benzo [b] furan-2-carboxylic acid (I-3) The above compound (3) (267 mg, 0.50 mmol) was added to a mixed solvent of ethanol (10 mL) and p-dioxane (5 mL). It melt | dissolved, 0.1 N sodium hydroxide aqueous solution (10 mL) was added, and it stirred at room temperature for 4 hours. Water (25
(mL) and the pH was adjusted to 5 by adding citric acid. The precipitated crystals were collected by filtration, washed with water (5 mL) four times, and dried under reduced pressure to give the title compound (4) 232 mg as a white crystalline powder. (Yield: 91.8%) Melting point: 215 to 217 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ , 400 MHz): δ = 5.25 (2H, s) 5.39 (2H, s) 5. 46 (2H, s) 6.91 (1H, s) 7.00 (1H, dd, J = 7Hz, 7Hz) 7.14 (1H, d, J = 8Hz) 7.2-7.4 (4H, m) 7.5-7.6 (3H, m) 7.66 (1H, d, J = 9Hz) 7.76 (1H, m) 7.82 (1H, s) 7.92 (1H, d, J = 8 Hz) 7.99 (1H, d, J = 8 Hz) 8.29 (1H, d, J = 9 Hz) IR (KBr) cm ⁻¹ : 3400, 1600, 149
0, 1370, 1350, 1320, 1250, 120
0, 1140, 745

[Synthesis Example 4] trans-3- [4- (imidazol-1-ylmethyl) -2- [3- (quinoline-
Synthesis of 2-ylmethyloxy) phenylmethyloxy] phenyl] propenoic acid (II-1) (1) Synthesis of 7-bromomethylcoumarin 7-Methylcoumarin (5.00 g, 31.2 mmol)
And N-bromosuccinimide (5.56 g, 31.2 mmol) were suspended in carbon tetrachloride (100 mL), 50
The mixture was stirred for 2 hours and 30 minutes under irradiation with a 0 W tungsten lamp. After cooling to room temperature, the crystals were collected by filtration, and carbon tetrachloride (20
(mL). Chloroform (250m)
It was suspended in a mixed solvent of L) and water (150 mL), the insoluble matter was removed by filtration, and the organic layer was separated. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to obtain 6.05 g (yield: 81.1%) of the title compound (1) as pale yellow crystals. Melting point: 176.0 to 178.8 ° C ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 4.52 (2H, s) 6.43 (1H, d, J = 10 Hz) 7.31 (1H, dd) , J = 2Hz, 8Hz) 7.35 (1H, s) 7.46 (1H, d, J = 8Hz) 7.69 (1H, d, J = 10Hz)

(2) Synthesis of 7- (imidazol-1-ylmethyl) coumarin Imidazole (1.71 g, 25.1 mmol) was dissolved in dry DMF (8.5 mL), and hydrogenated at 60% under ice cooling. Sodium (1.01 g, 25.3 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was ice-cooled and the above compound (1) (6.00 g, 25.1 mmol) in dry DM.
After the F (100 mL) solution was added dropwise, the mixture was stirred at room temperature for 19 hours. The reaction solution was poured into ice water (300 mL), 1N aqueous hydrochloric acid solution was added until pH 8 and the precipitated crystals were collected by filtration. After washing with water (100 mL), it was vacuum dried to 4.38.
g (purity: 92.8%, yield: 71.7%) of the title compound (2) was obtained as white brown crystals. Melting point: 133 ° C ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 5.21 (2H, s) 6.44 (1H, d, J = 9 Hz) 6.92 (1H, d, J = 1 Hz) 7 0.01 (1H, dd, J = 1Hz, 8Hz) 7.10 to 7.16 (2H, m) 7.47 (1H, d, J = 8Hz) 7.58 (1H, s) 7.68 (1H) , D, J = 9 Hz)

(3) Synthesis of trans-3- [4- (imidazol-1-ylmethyl) -2-hydroxyphenyl] propenoic acid ethyl ester Sodium metal (0.19 g, 8.26 mmol) was dried with ethanol (4 mL). Dissolved in the above compound (2)
(1.00 g, purity: 92.8%, 4.10 mmol)
Was added and the mixture was heated under reflux for 2 hours. The reaction solution was ice-cooled, poured into a cooled 2N-hydrochloric acid aqueous solution (6 mL), and a 1N sodium hydroxide aqueous solution was added until the pH reached 7. It was extracted with ethyl acetate (30 mL × 3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol / chloroform = 1/20) to give 0.60 g (yield 5
(3.7%) of the title compound (3) was obtained as pale yellow crystals. Melting point: 162.0-163.0 ° C. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 1.34 (3H, t, J = 7 Hz) 4.25 (2H, q, J = 7 Hz) 5.11 (2H, s) 6.33 (1H, d, J = 9Hz) 6.68 (1H, d, J = 16Hz) 6.75 (1H, dd, J = 1Hz, 8Hz) 6.91 (1H, t) , J = 1 Hz) 7.01 (1H, t, J = 1 Hz) 7.45 (1H, d, J = 8 Hz) 7.51 (1H, s) 7.98 (1H, d, J = 16 Hz)

(4) Synthesis of trans-3- [4- (imidazol-1-ylmethyl) -2- [3- (quinolin-2-ylmethyloxy) phenylmethyloxy] phenyl] propenoic acid ethyl ester The above compound ( 3) (0.50 g, 1.84 mmol) was dissolved in dry DMF (3 mL), 60% sodium hydride (74 mg, 1.85 mmol) was added under ice cooling, and 3
After stirring for 0 minutes, the compound (2) (0.5) synthesized in Synthesis Example 2 was used.
2 g, 1.83 mmol) of dry DMF (4 mL) was added dropwise. After stirring at room temperature for 13 hours, the reaction solution was cooled with ice water (70
(mL), extracted with chloroform (30 mL × 3) while appropriately filtering with Celite, and washed with water (70 mL). The extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform to methanol / chloroform = 3/2).
00) to give 0.87 g (purity: 97.9).
%, Yield: 89.6%) of the title compound (4) was obtained as pale yellow crystals. Melting point: 104.4 to 106.4 ° C. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 1.30 (3H, t, J = 7 Hz) 4.24 (2H, q, J = 7 Hz) 5.02 (2H, s) 5.06 (2H, s) 5.38 (2H, s) 6.51 (1H, d, J = 16Hz) 6.59 (1H, d, J = 9Hz) 6.71 (1H , Dd, J = 1 Hz, 8 Hz) 6.81 (1H, t, J = 1 Hz) 6.92 to 7.01 (2H, m) 7.02 to 7.07 (1H, m) 7.09 (1H , S) 7.29 (1H, t, J = 8Hz) 7.45 (1H, d, J = 8Hz) 7.49 (1H, s) 7.50 to 7.57 (1H, m) 7.66 (1H, d, J = 8Hz) 7.68 to 7.76 (1H, m) 7.81 (1H, d, J = 8Hz) 7.99 (1H, d, J = 1) 6Hz) 8.07 (1H, d, J = 8Hz) 8.16 (1H, d, J = 8Hz)

(5) Synthesis of trans-3- [4- (imidazol-1-ylmethyl) -2- [3- (quinolin-2-ylmethyloxy) phenylmethyloxy] phenyl] propenoic acid (II-1) The above compound (4) (0.30 g, purity: 97.9%,
0.57 mmol) was dissolved in ethanol, 1N sodium hydroxide aqueous solution (1.0 mL) was added at room temperature, and the mixture was stirred for 1 hour and 30 minutes, and then 1N sodium hydroxide aqueous solution (0.43 mL) was added. The mixture was stirred for 30 minutes. Three
Ethanol was distilled off under reduced pressure at 0 ° C., water (4 mL) was added to the residue, and 1N aqueous hydrochloric acid solution was added under ice cooling until the pH reached 7. After water was distilled off under reduced pressure, the residue was washed with chloroform (3
(0 mL) and the insoluble material was removed by filtration. The insoluble matter was washed with chloroform, the washing liquid and the filtrate were combined, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, ethanol (5 mL) was added to the residue, and ethanol was distilled off under reduced pressure to give 0.29 g. (Purity: 95.2%, Yield: 9
(8.5%) of the title compound (5) was obtained as a pale yellow amorphous substance. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 4.93 (2H, s) 4.96 (2H, s) 5.36 (2H, s) 6.48 (1H, d, J = 16 Hz) 6 .52 (1H, d) 6.60 (1H, d, J = 7Hz) 6.79 (1H, s) 6.84 (1H, d, J = 7Hz) 6.92 (1H, d, J = 7Hz) ) 7.08 (1H, s) 7.15 to 7.24 (2H, m) 7.37 (1H, d, J = 8Hz) 7.43 to 7.50 (1H, m) 7.51 (1H) , S) 7.60 to 7.70 (2H, m) 7.73 (1H, d, J = 8Hz) 7.96 to 8.19 (3H, m) IR (KBr) cm ⁻¹ : 3398, 3059. , 163
0, 1608, 1601, 1506, 1429, 138
1, 1265, 1157, 1032, 827, 744

[Synthesis Example 5] cis-3- [4- (imidazol-1-ylmethyl) -2- [3- (quinoline-2-)
Ilmethyloxy) phenylmethyloxy] phenyl]
Synthesis of propenoic acid (II-2) Compound (2) synthesized in Synthesis Example 4 (0.25 g, purity:
92.8%, 1.03 mmol) in ethanol (5 m
L) and suspended in sodium hydroxide (0.20 g, 5.0
A solution of 0 mmol) in water (0.3 mL) was added, and the mixture was heated under reflux for 8 hours. After cooling to room temperature, the compound (2) synthesized in Synthesis Example 2 (0.88 g, 3.10 mmol) was added,
After stirring at room temperature for 13 hours, ethanol was distilled off under reduced pressure. Water (10 mL) was added to the residue, and ethyl acetate (5 m
After washing with L), a 1N aqueous hydrochloric acid solution was added until the pH reached 7. The mixture was extracted with chloroform (10 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol / chloroform = 1/10), suspended in chloroform (0.2 mL), added with ethanol / hexane = 1/2 mixed solvent (0.6 mL), and crystallized. Was collected by filtration. The obtained crystals were washed with a mixed solvent of ether / hexane = 1/1 (0.8 mL / 1.2 mL) and dried in vacuum to obtain 94 mg (yield: 18.6%) of the title compound as white crystals. . ^{Mp: 173.0~174.4 ℃ 1 H-NMR (} CD 3 0D / CDCl 3 = 1 / 10,4
00 MHz): δ = 5.01 (2H, s) 5.05 (2H, s) 5.38 (2H, s) 5.99 (1H, d, J = 12Hz) 6.24 (1H, d) 6 .70 (1H, d, J = 8Hz) 6.86 to 6.87 (1H, s) 6.96 (1H, d, J = 8Hz) 7.00 (1H, dd, J = 2Hz, 8Hz) 7 0.02 (1H, s) 7.07 to 7.14 (2H, m) 7.10 (1H, d, J = 12Hz) 7.30 (1H, t, J = 8Hz) 7.51 (1H, d) , J = 8Hz) 7.52 (1H, s) 7.55 to 7.60 (1H, m) 7.70 (1H, d, J = 9Hz) 7.76 (1H, ddd, J = 1Hz, 8Hz , 7H
z) 7.85 (1 H, d, J = 8 Hz) 8.08 (1 H, d, J = 9 Hz) 8.24 (1 H, d, J = 9 Hz) IR (KBr) cm ⁻¹ : 3433, 3116, 163
3, 1595, 1506, 1504, 1429, 142
3, 1275, 1219, 1211, 1161, 111
1, 1093, 1063, 837, 822, 783

[Synthesis Example 6] trans-3- [4- (imidazol-1-ylmethyl) -2- [4- (quinoline-
Synthesis of 2-ylmethyloxy) phenylmethyloxy] phenyl] propenoic acid (II-3) (1) trans-3- [4- (imidazol-1-ylmethyl) -2- [4- (quinolin-2-yl) Synthesis of methyloxy) phenylmethyloxy] phenyl] propenoic acid ethyl ester Compound (3) synthesized in Synthesis Example 4 (100 mg, 0.3
7 mmol) was dissolved in dry DMF (1 mL), 60% sodium hydride (15 mg, 0.38 mmol) was added under ice cooling, and the mixture was stirred for 30 minutes, and then the compound (9) synthesized in Synthesis Example 1 (105 mg). 1.83 mmol) dry DM
F (4 mL) was added dropwise. After stirring at room temperature for 21 hours and 20 minutes, the reaction solution was poured into ice water (14 mL), extracted with chloroform (8 mL × 3) while appropriately filtering with Celite, and washed with water (10 mL × 2). After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol / chloroform = 1/100) to give 180 mg (yield: 94.6%) of the title compound ( 1) was obtained as pale yellow crystals. Melting point: 107.0 to 108.2 ° C ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 1.30 (3H, t, J = 7Hz) 4.23 (2H, q, J = 7Hz) 5.00 (2H, s) 5.07 (2H, s) 5.40 (2H, s) 6.49 (1H, d, J = 16Hz) 6.62 (1H, s) 6.74 (1H, d, J) = 8 Hz) 6.81 to 6.85 (1H, m) 7.01 to 7.06 (2H, m) 7.09 to 7.12 (1H, m) 7.26 to 7.31 (2H, m) ) 7.49 (1H, d, J = 8Hz) 7.52 (1H, s) 7.55 (1H, ddd, J = 1Hz, 8Hz, 7H)
z) 7.68 (1H, d, J = 8Hz) 7.74 (1H, ddd, J = 1Hz, 8Hz, 7H
z) 7.83 (1H, d, J = 8Hz) 7.97 (1H, d, J = 16Hz) 8.07 (1H, d, J = 8Hz) 8.20 (1H, d, J = 8Hz)

(2) Synthesis of trans-3- [4- (imidazol-1-ylmethyl) -2- [4- (quinolin-2-ylmethyloxy) phenylmethyloxy] phenyl] propenoic acid (II-3) The above compound (1) (100 mg, 0.19 mmol) was dissolved in ethanol (1 mL), 1N aqueous sodium hydroxide solution (0.48 mL) was added at room temperature, and the mixture was stirred for 15 hr. Ethanol was distilled off under reduced pressure at 30 ° C, and the residue was washed with water (2
mL) was added, and 1N aqueous hydrochloric acid solution was added under ice cooling until the pH reached 7. The precipitated crystals were collected by filtration and water (10 mL)
After washing with and dried in vacuum, 74 mg (yield: 78.9%)
To give the title compound (2) of as white crystals. Melting point: 78.4 ° C. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 5.01 (2H, s) 5.09 (2H, s) 5.38 (2H, s) 6.50 (1H, d) , J = 16 Hz) 6.67 (1H, s) 6.75 (1H, d, J = 7Hz) 6.87 (1H, s) 7.01 to 7.06 (3H, m) 7.31 (2H) , D, J = 8 Hz) 7.52 (1H, d, J = 8 Hz) 7.55 (1H, s) 7.55 to 7.60 (1H, m) 7.70 (1H, d, J = 8 Hz) ) 7.76 (1H, ddd, J = 1Hz, 8Hz, 7H
z) 7.86 (1H, dd, J = 1 Hz, 8 Hz) 7.89 (1H, d, J = 16 Hz) 8.08 (1H, d, J = 8 Hz) 8.25 (1H, d, J = 8 Hz, m) IR (KBr) cm ⁻¹ : 3398, 3064, 292
4, 1697, 1610, 1512, 1429, 138
3, 1315, 1292, 1246, 1244, 117
4, 1111, 1011, 823

[Synthesis Example 7] cis-3- [4- (imidazol-1-ylmethyl) -2- [4- (quinoline-2-)
Ilmethyloxy) phenylmethyloxy] phenyl]
Synthesis of propenoic acid (II-4) Compound (2) synthesized in Synthesis Example 4 (250 mg, purity:
92.8%, 1.03 mmol) in ethanol (5 m
L) and suspended in sodium hydroxide (100 mg, 5.0
A solution of 0 mmol) in water (0.3 mL) was added, and the mixture was heated under reflux for 8 hours. The mixture was cooled to room temperature, compound (9) (880 mg, 3.10 mmol) synthesized in Synthesis Example 1 was added thereto, and the mixture was stirred at room temperature for 13 hours, and then ethanol was distilled off under reduced pressure. Water (10 mL) was added to the residue, and ethyl acetate (5 mL
After washing with × 2), a 1N aqueous hydrochloric acid solution was added until the pH reached 7. The mixture was extracted with chloroform (10 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. After the residue was purified by silica gel column chromatography (chloroform-methanol / chloroform = 1/10),
It was suspended in chloroform / ethanol = 1/4 (0.5 mL), hexane (0.2 mL) was added, and the crystals were collected by filtration. The obtained crystals were washed with ethanol (1 mL) and dried under vacuum to give 94 mg (purity 99.1%, yield: 18.4).
%) Of the title compound as pale yellow crystals. Melting point: 188.0 to 191.0 ° C ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 4.95 (2H, s) 5.09 (2H, s) 5.38 (2H, s) 5.97. (1H, d, J = 12Hz) 6.67 (1H, s) 6.72 (1H, d, J = 8Hz) 6.90 (1H, s) 7.01 to 7.06 (3H, m) 7 .14 (1H, d, J = 12Hz) 7.27 to 7.32 (2H, m) 7.54 to 7.61 (3H, m) 7.70 (1H, d, J = 8Hz) 7.76 (1H, ddd, J = 1Hz, 8Hz, 7H
z) 7.86 (1H, d, J = 8 Hz) 8.09 (1H, d, J = 9 Hz) 8.24 (1H, d, J = 9 Hz) IR (KBr) cm ⁻¹ : 3433, 1691, 161
0, 1514, 1454, 1429, 1377, 127
5, 1244, 1227, 1201, 1174, 115
3, 1107, 1065, 1024, 823, 820,
748

[Synthesis Example 8] Synthesis of 4- (imidazol-1-ylmethyl) -2- [3- (quinolin-2-ylmethyloxy) benzyloxy] benzoic acid (III-1) (1) 2-hydroxy Synthesis of 4-Methylbenzoic Acid Methyl Ester 2-Hydroxy-4-methylbenzoic acid (20.0 g, 1
31 mmol) in methanol (130 mL),
Under ice-cooling, hydrochloric acid gas was blown in for 30 minutes. The reaction solution was heated under reflux for 16 hours, cooled to room temperature, and then the solvent was distilled off under reduced pressure at 40 ° C or lower. The residue is chloroform (50m
It was dissolved in L) and saturated aqueous sodium hydrogen carbonate solution was added under ice cooling until the pH of the aqueous layer reached 8, and the organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain 20.6 g (yield: 94.7%) of the title compound (1) as a pale brown oily substance. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 2.34 (3H, s) 3.93 (3H, s) 6.69 (1H, dd, J = 1Hz, 8Hz) 6.79 (1H, s) ) 7.11 (1H, d, J = 8Hz) 10.7 (1H, s)

(2) Synthesis of 2-acetyloxy-4-methylbenzoic acid methyl ester The above compound (1) (10.0 g, 60.2 mmol) was dissolved in dry DMF (50 mL), and the mixture was cooled under ice-cooling to 60 % Sodium hydride (2.41 g, 60.3 mL) was added portionwise and stirred for 30 minutes. In addition, acetyl chloride (4.3
mL, 60.5 mmol) in dry DMF (10 mL) was added dropwise and stirred at room temperature for 2 hours. The reaction solution was poured into ice water, extracted with chloroform (50 mL × 2), and water (1
After washing with 00 mL × 2), it was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 13.2 g (purity: 91.9).
%, Yield: 96.8%) of the title compound (2) was obtained as a light brown oil. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 2.34 (3H, s) 2.39 (3H, s) 3.85 (3H, s) 6.91 (1H, d, J = 1Hz) 7 .11 (1H, dd, J = 1Hz, 8Hz) 7.91 (1H, d, J = 8Hz)

(3) Synthesis of 2-hydroxy-4- (imidazol-1-ylmethyl) benzoic acid methyl ester Compound (2) (13.2 g, purity: 91.9%, 5)
8.3 mmol), N-bromosuccinimide (NB
S) (10.4 g, 58.4 mmol), and α,
α'-azobisisobutyronitrile (AIBN) (0.
78 g, 4.75 mmol) with carbon tetrachloride (60 mL)
And was heated and dried under reduced pressure for 7 hours. After cooling to room temperature, the insoluble matter was removed by filtration, and the insoluble matter was washed with a small amount of carbon tetrachloride. The filtrate and the washing solution were combined, the solvent was distilled off under reduced pressure, and NBS (7.80 g, 43.8 mmol) and AIB were added to the residue.
N (0.17 g, 1.04 mmol) and dry benzene (50 mL) were added, and the mixture was heated under reflux for 3 hours and 50 minutes under irradiation with a 500 W tungsten lamp. After cooling the reaction solution with ice,
The insoluble material was removed by filtration, and the insoluble material was washed off with carbon tetrachloride (50 mL). The filtrate and the washing solution were combined, the solvent was evaporated under reduced pressure, carbon tetrachloride (50 mL) was added to the residue, and the insoluble material was removed by filtration. The insoluble matter was washed with carbon tetrachloride (50 mL), the filtrate and the washing solution were combined, and the solvent was evaporated under reduced pressure to obtain 23.3 g of 4-bromomethyl-2-hydroxybenzoic acid methyl ester as a brown oil. This was used in the next reaction without purification. Then imidazole (3.97 g, 58.3 mmol) was added to dry DMF.
Dissolve in (100 mL), add 60% sodium hydride (2.33 g, 58.3 mL) little by little, and add 90 ° C.
It was stirred for 1 hour. After cooling the reaction solution with ice, the above-mentioned 4-bromomethyl-2-hydroxybenzoic acid methyl ester (2
A solution of 3.3 g of dry DMF (50 mL) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction solution is ice water (300 mL)
The mixture was poured into a flask, extracted with chloroform (80 mL × 3), washed successively with water (100 mL × 2) and saturated saline (100 mL), and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform to methanol / chloroform = 1 /
Purification by 100 to 1/50) to give 1.78 g (purity: 83.9%, yield: 11.0%) of the title compound (3) as a brown oil. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 3.95 (3H, s) 5.10 (2H, s) 6.62 (1H, dd, J = 2Hz, 8Hz) 6.76 (1H, d) , J = 2 Hz) 6.90 (1H, s) 7.11 (1H, s) 7.55 (1H, s) 7.81 (1H, d, J = 8 Hz) MS (FAB) m / z * 233 (MH ⁺ )

(4) 4- (imidazol-1-ylmethyl) -2- [3- (quinolin-2-ylmethyloxy)
Synthesis of benzyloxy] benzoic acid methyl ester The above compound (3) (1.78 g, purity: 83.9%,
6.43 mmol) in dry DMF (7 mL),
Ice-cooled, 60% sodium hydride (0.26 g, 6.5
(0 mmol) was added little by little and stirred for 30 minutes. Further, the compound (2) (1.84 g, purity: 99.5%, 6.45 mmol) synthesized in Synthesis Example 2 was dried with DMF (7).
(mL) solution was added dropwise, and the mixture was stirred at room temperature for 6 hours and then at 60 ° C. for 1 hour.
Stir for 7 hours. Pour the reaction solution into ice water (50 mL),
It was extracted with chloroform (50 mL), washed with water (50 mL), and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform-methanol / chloroform = 1 / 100-
2.25 g (Purity: 96.2)
%, And the yield was 68.9% to obtain the title compound (4) as a pale brown oily matter. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 3.89 (3H, s) 5.06,5.07 (4H, each s) 5.39 (2H, s) 6.64 (1H, s) 6.73 (1H, d, J = 8Hz) 6.78 to 6.84 (1H, m) 6.97 (1H, dd, J = 2Hz, 8Hz) 7.03 (1H, d, J = 8Hz) 7.10 (1H, brs) 7.15 (1H, brs) 7.29 (1H, t, J = 8Hz) 7.51 (1H, brs) 7.54 (1H, ddd, J = 1Hz, 8Hz, 7H
z) 7.65 (1H, ddd, J = 8Hz) 7.73 (1H, ddd, J = 2Hz, 8Hz, 7H
z) 7.77 (1H, d, J = 8Hz) 7.80 to 7.83 (1H, m) 8.07 (1H, d, J = 8Hz) 8.16 (1H, d, J = 8Hz)

(5) 4- (imidazol-1-ylmethyl) -2- [3- (quinolin-2-ylmethyloxy)
Synthesis of benzyloxy] benzoic acid (III-1) Compound (4) obtained by the above method (0.25 g,
Purity: 92.2%, 0.48 mmol) was dissolved in methanol (3 mL), 1N aqueous sodium hydroxide solution (1 mL) was added at room temperature, and after stirring for 15 hours and 20 minutes, 1N sodium hydroxide was further added. An aqueous solution (0.50 mL) was added, and the mixture was stirred for 6 hours. After distilling off under reduced pressure at 30 ° C., water (2 mL) was added to the residue, and 1N hydrochloric acid aqueous solution was added to pH under ice cooling.
Add until 7. After water was distilled off under vacuum, the residue was suspended in a mixed solvent of methanol / chloroform = 1/1 (2 mL), insoluble materials were removed by filtration, and the solvent was distilled off under reduced pressure to obtain 0.22 g (purity: 93.8). %, Yield: 91.7%) of the title compound (5) was obtained as a light brown amorphous substance. _{^{1 H-NMR (CD 3 0D}} / CDCl 3 = 1 / 10,4
00 MHz): δ = 5.14 (2H, s) 5.15 (2H, s) 5.39 (2H, s) 6.74 (1H, s) 6.84 (1H, d) 6.87 to 6 .91 (1H, m) 6.95 (1H, d, J = 8Hz) 7.04 (1H, dd, J = 2Hz, 8Hz) 7.09 (1H, s) 7.31 (1H, t, J = 8 Hz) 7.44 (1H, s) 7.55 to 7.62 (2H, m) 7.73 to 7.80 (2H, m) 7.87 (1H, d, J = 7Hz) 7.99 (1H, m) 8.07 (1H, m) 8.26 (1H, d, J = 8Hz) IR (KBr) cm ⁻¹ : 3398,3390,169
1, 1612, 1610, 1506, 1427, 129
2, 1255, 1157, 1082, 1032, 78
1,746

[Synthesis Example 9] 4- (imidazol-1-ylmethyl) -3- [3- (quinolin-2-ylmethyloxy) benzoyloxy] phenoxyacetic acid (III-2)
Synthesis of (1) Synthesis of methyl 2-hydroxy-4-methoxymethoxybenzoate Under a nitrogen atmosphere, 97% methyl 2,4-dihydroxybenzoate (19.0 g, 110 mmol) was added to dry THF.
After dissolving in (100 mL), chloromethyl methyl ether (8.40 mL, 110 mmol) was added dropwise thereto over 3 minutes while cooling with salt ice, and the mixture was stirred for 20 minutes. Then, under ice cooling, dried triethylamine (15.4 mL, 110
(Mmol) was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 15 hours. The solvent was evaporated under reduced pressure, ethyl acetate (200 mL) was added, the insoluble material was filtered off, and the ethyl acetate layer was saturated with brine (2
(00 mL) and dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure, and the obtained crude product was purified by medium-pressure liquid chromatography (chloroform) to obtain 14.7 g (yield 63.1%) of the title compound (1) as a pale yellow oily substance. It was ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 3.47 (3H, s) 3.91 (3H, s) 5.19 (2H, s) 6.53 (1H, dd, J = 2 Hz, 8 Hz) ) 6.61 (1H, d, J = 2Hz) 7.74 (1H, d, J = 8Hz) 10.88 (1H, s)

(2) Synthesis of 2-hydroxy-4-methoxymethoxybenzyl alcohol Under a nitrogen atmosphere, lithium aluminum hydride (729 m
g, 19.2 mmol) was suspended in dry ether (50 mL), and under ice-cooling, the above (1) (3.40 g, 16.0) was suspended.
A solution of (mmol) in dry ether (30 mL) was added dropwise over 10 minutes, the mixture was stirred at room temperature for 3 hours, and then heated under reflux for 4 hours. Ether (50 mL) was added to the reaction solution under ice cooling.
Was added, and then saturated aqueous sodium sulfate solution was added. Then, THF (150 mL) was added and decanted. THF (150 mL) was added again to the residue, the mixture was decanted, combined with the THF layer described above, and evaporated under reduced pressure. Water (100 mL) was added to the residue, and ethyl acetate (100 mL) was added.
It was extracted with. After adding 0.5 N hydrochloric acid to the aqueous layer to adjust the pH to 7, the mixture was extracted with ethyl acetate (100 mL × 2), combined with the ethyl acetate layer described above, and dried over anhydrous sodium sulfate. The title compound (2) obtained by distilling off the solvent under reduced pressure was used in the next reaction as a crude product.

(3) 4-methoxymethoxy-2- [3-
(Quinolin-2-ylmethyloxy) benzyloxy]
Synthesis of benzyl alcohol In a nitrogen atmosphere, the compound (2) (600 mg) was dissolved in dry DMF (5 mL), 60% sodium hydride (157 mg, 3.93 mmol) was added under ice cooling, and the mixture was stirred for 1 hour. . Then, under ice cooling, dry DM of 3- (2-quinolinylmethyloxy) benzyl chloride (Compound (2) of Synthesis Example 2) (926 mg, 3.26 mmol).
The F (5 mL) solution was added, and the mixture was stirred at room temperature overnight. The reaction solution was poured into ice water (200 mL), and ethyl acetate (100 mL) was added.
After extraction with mL × 2), the extract was washed with water (100 mL × 2) and saturated saline (100 mL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by medium pressure liquid chromatography (chloroform-methanol / chloroform = 1/200) to give 820 mg of the title compound (3) (yield from (1): 52.6
%) As a yellow oil. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 2.40 (1 H, t, J = 6 Hz) 3.45 (3 H, s) 4.59 (2 H, d, J = 6 Hz) 5.04 (2 H , S) 5.12 (2H, s) 5.40 (2H, s) 6.58 to 6 ・ 62 (2H, m) 6.97 to 7.16 (4H, m) 7.29 (1H, t) , J = 8 Hz) 7.55 (1H, t, J = 8 Hz) 7.65 (1H, d, J = 8 Hz) 7.73 (1H, ddd, J = 1 Hz, 8 Hz, 7H
z) 7.82 (1H, d, J = 8Hz) 8.09 (1H, d, J = 8Hz) 8.17 (1H, d, J = 8Hz)

(4) 4- (imidazol-1-ylmethyl) -3- [3- (quinolin-2-ylmethyloxy)
Synthesis of benzyloxy] phenol Under a nitrogen atmosphere, imidazole (190 mg, 2.79 mmol) was dissolved in dry DMF (5 mL), and then 60% sodium hydride (223 mg, 5.58 mmol) was added under ice cooling. Addition and stirring for 20 minutes. Separately, under nitrogen atmosphere, the above compound (3) (600 mg, 1.39 mmol) was dissolved in dry methylene chloride (10 mL), and thionyl chloride (0.11 mL, 1.51 mmol) was added under salt ice cooling. After stirring for 30 minutes, the solvent was distilled off under reduced pressure. A solution of this residue in dry DMF (5 mL) was added to the above reaction solution, and the mixture was stirred at room temperature for 5 hours. The reaction solution was added to ice water (150
mL), extracted with ethyl acetate (100 mL × 2), water (100 mL × 2) and saturated saline (100 m)
It was washed with L) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to medium pressure liquid chromatography (chloroform-methanol / chloroform = 1/5
It was roughly purified in 0). This crude product (400 mg) was dissolved in a mixed solvent (THF (10 mL) -methanol (1 mL), 1N hydrochloric acid (3.2 mL) was added under ice cooling, and the mixture was stirred at room temperature overnight. Hydrochloric acid (2.4 mL) was added, and the mixture was heated with stirring for 4 hours at 50 ° C. The solvent was evaporated under reduced pressure, water (20 mL) and 1N hydrochloric acid were added under ice cooling, and p
H7. After filtering the precipitated crystals, water (10 m
After washing with L) and drying under reduced pressure, 152 mg (yield 41.9%) of the title compound (4) was obtained as a white amorphous substance. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 4.79 (2H, s) 4.87 (2H, s) 5.30 (2H, s) 6.40 (1H, dd, J = 2Hz, 8Hz) ) 6.45 (1H, d, J = 2Hz) 6.77 to 6.96 (6H, m) 7.16 (1H, t, J = 8Hz) 7.43 (1H, s) 7.50 (1H) , T, J = 8 Hz) 7.61 (1H, d, J = 8 Hz) 7.68 (1H, ddd, J = 1 Hz, 8 Hz, 7H
z) 7.76 (1H, d, J = 8Hz) 8.05 (1H, d, J = 8Hz) 8.12 (1H, d, J = 8Hz)

(5) Ethyl 4- (imidazole-1-
Synthesis of ylmethyl) -3- [3- (quinolin-2-ylmethyloxy) benzyloxy] phenoxyacetate Under a nitrogen atmosphere, the above compound (4) (150 mg, 0.3
(43 mmol) was dissolved in dry DMF (4 mL),
Under ice cooling, 60% sodium hydride (15 mg, 0.37
(5 mmol) was added and stirred for 20 minutes. Then, under cooling with ice, ethyl bromide acetate (0.04 mL, 0.361 mmol) was added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was poured into ice water (150 mL), and ethyl acetate (100 mL x
After extraction with 2), the extract was washed with water (100 mL x 2) and saturated saline (100 mL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by thin layer chromatography (methanol / chloroform = 1/100) to give 60 mg (yield 33.3%) of the title compound (5) as a pale yellow oil. I got it as a thing. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 1.28 (3H, t, J = 7 Hz) 4.25 (2H, t, J = 7 Hz) 4.56 (2H, s) 4.95 (2H) , S) 4.99 (2H, s) 5.39 (2H, s) 6.36 (1H, dd, J = 2Hz, 8Hz) 6.57 (1H, d, J = 2Hz) 6.84 (1H , S) 6.91 to 7.02 (5H, m) 7.30 (1H, t, J = 8Hz) 7.45 (1H, s) 7.53 (1H, t, J = 8Hz) 7.65 (1H, d, J = 8Hz) 7.72 (1H, ddd, J = 1Hz, 8Hz, 7H
z) 7.80 (1H, d, J = 8Hz) 8.07 (1H, d, J = 8Hz) 8.16 (1H, d, J = 8Hz)

(6) 4- (imidazol-1-ylmethyl) -3- [3- (quinolin-2-ylmethyloxy)
Synthesis of benzyloxy] phenoxyacetic acid (III-2) The above compound (5) (57 mg, 0.11 mmol) was dissolved in ethanol (5 mL), and the mixture was cooled with ice under 1N sodium hydroxide aqueous solution (0.2 mL). Was added and stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and under ice cooling, water (10 mL)
And 1N hydrochloric acid were added to adjust the pH to 7. The precipitated crystals were collected by filtration, washed with water (5 mL), and dried under reduced pressure to give the title compound (6) 41 mg (yield 75.9%).
Was obtained as white crystals. mp: 137-139 ° C. ¹ H-NMR (CD ₃ OD, 400 MHz): δ = 4.46 (2H, s) 5.07 (2H, s) 5.14 (2H, s) 5.37 (2H, s) 6.51 (1H, dd, J = 2, 8Hz) 6.66 (1H, d, J = 2Hz) 6.95 (1H, d, J = 8Hz) 7.02 to 7.25 (5H, m) 7.31 (1H, t, J = 8Hz) 7.61 (1H, t, J = 8Hz) 7.69 (1H, d, J = 8Hz) 7.78 (1H, t, J = 8Hz) 7.93 (1H, d, J = 8Hz) 8.03 (1H, d, J = 8Hz) 8.25 (1H, s) 8.34 (1H, d, J = 8Hz) IR (KBr) cm - ¹ : 3427, 3137, 161
6,1587,1454,1383,1286,117
1,1126,1053,825,762

[Synthesis Example 10] 4- (imidazole-1-)
Ilmethyl) -3- [3- (quinolin-2-ylmethyloxy) benzoylamino] phenoxyacetic acid (IV-1)
Synthesis of (1) Synthesis of 3-nitro-4-methylphenol Water (500 mL) was cooled in an ice bath and concentrated sulfuric acid (183 m
L) was slowly added, 4-amino-2-nitrotoluene (25.0 g, 164 mmol) was added, and then 95 ° C.
The mixture was heated to dissolve the solid. After cooling to 15 ° C, a solution of sodium nitrite (13.4 g, 194 mmol) in water (83 mL) was added dropwise while adding ice so as not to exceed 5 ° C. Further, urea (1025 g, 20.8 mmol) and ice (8 g) were added, and the mixture was left at 0 ° C. (solution A). Separately, in a flask equipped with a cooling device for distillation,
Concentrated sulfuric acid (167 mL), water (167 mL), and sodium sulfate (250 g) were mixed and heated under reflux. The solution A was added dropwise thereto, and the yellow effluent was collected (the dropping speed of the solution A and the outflow speed of the yellow distillate were matched). After the addition was completed, water (300 mL) was added dropwise to the residue and distillation was continued. The effluents were combined, extracted with ether (250 mL, 200 mL), and then 10% aqueous sodium hydroxide solution (400 mL)
And water (100 mL). Concentrated hydrochloric acid was added to the extract to acidify it, and ether (200 mL, 150 m) was added again.
L). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 9.40 g (yield 37.4%) of the title compound (1) as light brown crystals. Water (500 mL) was added to the distillation residue, the mixture was extracted with ether (500 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 6.40 g of the crude title compound (1) as brown crystals. Obtained. mp: 76.6-77.4 ° C. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 2.52 (3H, s) 5.09 (1H, s) 7.00 (1H, dd, J = 2 Hz) , 8Hz) 7.20 (1H, d, J = 8Hz) 7.47 (1H, d, J = 2Hz)

(2) Synthesis of 4-methoxy-2-nitrotoluene The above compound (1) (9.30 g, 60.7 mmol) and anhydrous potassium carbonate (12.6 g, 91.2 mmol) were added with acetonitrile (124 mL). In addition, dimethyl sulfide (7.2 mL, 75.9 mol mol) was added, and the mixture was stirred at room temperature for 5 hours. The solvent was evaporated under reduced pressure, a saturated aqueous solution of glycine (31 mL) was added to the residue, and the mixture was stirred at 50 ° C for 1 hr. After cooling to room temperature, the mixture was extracted with ether (31 mL × 2) and washed with 1N sodium hydroxide aqueous solution (15 mL). The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain 10.0 g (purity 98.3%, yield 96.9%) of the title compound (2) as a yellow oily substance. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 2.53 (3H, s) 3.85 (3H, s) 7.06 (1H, dd, J = 2 Hz, 8 Hz) 7.23 (1H, d) , J = 8 Hz) 7.50 (1H, d, J = 2 Hz)

(3) α- (imidazol-1-yl)-
Synthesis of 4-methoxy-2-nitrotoluene The above compound (2) (8.53 g, purity 98.3%, 5
0.2 mmol) and N-bromosuccinimide (NB
S, 8.93 g, 50.2 mmol) and carbon tetrachloride (60 mL) were suspended in the tungsten lamp (500
W) Stirred for 50 minutes under irradiation. The reaction solution was ice-cooled, insoluble materials were removed by filtration, and carbon tetrachloride (15 m
It was washed with L). After the filtrate and the washing solution were combined, the solvent was distilled off under reduced pressure to obtain residue A. Separately, imidazole (3.42 g, 50.2 mmol) was dissolved in dry dimethylformamide (17 mL), and 60% sodium hydride (2.01,50.3 mmol) was added little by little under ice cooling, and at room temperature. Stir for 30 minutes. The reaction solution was ice-cooled again, a dry DMF (20 mL) solution of the residue A was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction solution is ice water (100 m
L), extracted with chloroform (50 mL × 2),
After washing with water (100 mL × 2), it was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform to methanol / chloroform = 1/50) to obtain 6.38 g (purity: 9
The title compound (3) (7.2%, yield 53.0%) was obtained as a pale yellow oil. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 3.88 (3H, s) 5.48 (2H, s) 6.80 (1H, d, J = 8 Hz) 6.93 (1H, t, J) = 1 Hz) 7.11 (1H, dd, J = 2Hz, 8Hz) 7.13 (1H, brs) 7.57 (1H, s) 7.65 (1H, d, J = 2Hz)

(4) Synthesis of 4- (imidazol-1-ylmethyl) -3-nitrophenol The above compound (3) (6.38 g, purity 7.2%, 26.6).
Mmol) in chlorobenzene (630 mL),
Under ice cooling, anhydrous aluminum trichloride (12.1 g, 9
0.7 mmol) and added at 60 ° C. for 1 hour and 90 ° C. for 2 hours.
Stirred for hours. After ice-cooling the reaction solution, ice water (60 ml)
And concentrated hydrochloric acid (15 mL) were added, and the aqueous layer was separated. Add solid sodium hydroxide to pH 7 under ice cooling,
After removing the precipitated gel-like substance by filtration, the gel-like substance was dried by washing with a mixed solvent of chloroform / methanol = 1/10. The filtrate and the washing solution are combined, the solvent is distilled off under reduced pressure, the residue and the dried gel-like substance are combined, and purified by silica gel column chromatography (chloroform to methanol / chloroform = 2/25) to obtain 3.10 g.
(53.2%) of the title compound (4) was obtained as pale yellow crystals. mp: 213-214 ° C. ¹ H-NMR (CD ₃ OD, 400 MHz): δ = 5.47 (2H, s) 6.98-7.01 (1H, m) 7.01 (1H, d, J = 8Hz) 7.07 to 7.10 (1H, m) 7.08 (1H, dd, J = 2Hz, 8Hz) 7.48 (1H, d, J = 2Hz) 7.71 (1H, s) MS ( FAB): m / z 220 (MH ⁺ )

(5) Ethyl 4- (imidazole-1-)
Synthesis of Ilmethyl) -3-nitrophenoxyacetate Under a nitrogen atmosphere, 1.00 g (4.56) of the above compound (4)
(MMole) dissolved in dry dimethylformamide (30 mL), and under ice cooling, 60 m of 60% sodium hydride
g (5.03 mmol) was added, and the mixture was stirred for 30 minutes. Then, under ice cooling, ethyl bromoacetate (0.51 mL, 4.6
(0 mmol) was added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was poured into ice water (200 mL), and ethyl acetate (100 m
After extraction with L × 2), the extract was washed with water (100 mL × 2) and saturated saline (100 mL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by medium pressure liquid chromatography (loroform-methanol / chloroform = 1/50) to give 916 mg of the title compound (5) (yield: 65.9%). ) Was obtained as light brown crystals. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 1.31 (3H, t, J = 7Hz) 4.28 (2H, q, J = 7Hz) 4.69 (2H, s) 5.49 (2H , S) 6.78 (1H, d, J = 8 Hz) 6.93 (1H, s) 7.11 to 7.14 (2H, m) 7.57 (1H, s) 7.66 (1H, d) , J = 2Hz)

(6) Synthesis of ethyl 3-amino-4- (imidazol-1-ylmethyl) phenoxyacetate After dissolving the above compound (5) (802 mg, 2.63 mmol) in ethanol (40 mL), 10% palladium /
Carbon (240 mg) was added, the atmosphere was replaced with hydrogen, and the mixture was stirred at room temperature for 2 hours. The catalyst was filtered and the mother liquor was distilled off under reduced pressure to obtain 682 mg (yield 94.3%) of the title compound (6) as light brown crystals. mp: 99-101 ° C. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 1.29 (3H, t, J = 7 Hz) 3.81 (2H, brs) 4.25 (2H, q, J = 7 Hz) ) 4.56 (2H, s) 4.99 (2H, s) 6.28 to 6.31 (2H, m) 6.89 (1H, s) 6.94 (1H, d, J = 8Hz) 7 .05 (1H, s) 7.60 (1H, s)

(7) Synthesis of methyl 3- (quinolin-2-ylmethyloxy) benzoate Methyl 3-hydroxybenzoate (5.00 g, 32.9 mmol) was dissolved in dry dimethylformamide (100 mL) under a nitrogen atmosphere. After that, under ice cooling, 60%
1.45 g (36.3 mmol) of sodium hydride was added and stirred for 30 minutes. Then, under ice cooling, chloromethylquinoline (5.84 g, 32.9 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was poured into ice water (300 mL), extracted with ethyl acetate (150 mL × 2), washed with water (100 mL × 2) and saturated saline (100 mL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by medium-pressure liquid chromatography (ethyl acetate / hexane = 1/30 to 1/5) to give 5.40 g of the title compound (7) (yield 56 .0
%) As pale yellow crystals. mp: 54 to 56 ° C. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 3.90 (3H, s) 5.42 (2H, s) 7.22 (1H, m) 7.35 (1H, t , J = 8 Hz) 7.55 (1H, m) 7.65 to 7.68 (2H, m) 7.72 to 7.76 (2H, m) 7.83 (1H, d, J = 8Hz) 8 0.09 (1H, d, J = 8Hz) 8.19 (1H, d, J = 8Hz)

(8) Synthesis of 3- (quinolin-2-ylmethyloxy) benzoic acid The above compound (7) (5.30 g, 18.1 mmol) was dissolved in methanol (50 mL), and the mixture was cooled with ice. 1N aqueous sodium hydroxide solution (54.3 mL) and methanol (100 mL) were added, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and water (100 mL) and 1N hydrochloric acid were added to the residue to adjust the pH to 7. After filtering the precipitated crystals, water (50
After washing with mL × 2) and drying under reduced pressure, 4.74 g (yield 93%) of the title compound (8) was obtained as pale yellow crystals. mp: 182-184 ° C. ¹ H-NMR (CD ₃ OD, 400 MHz): δ = 5.44 (2H, s) 7.31 (1H, dd, J = 2,8 Hz) 7.41 (1H, t, J = 8Hz) 7.63-7.71 (3H, m) 7.76-7.84 (2H, m) 7.98 (1H, d, J = 8Hz) 8.08 (1H, d, J = 8Hz) 8.45 (1H, d, J = 8Hz)

(9) Synthesis of ethyl 4-3- [3- (quinolin-2-ylmethyloxy) benzoylamino] phenoxyacetate In a nitrogen atmosphere, the compound (8) (500 mg, 1.7) was prepared.
9 mmol) under ice cooling, thionyl chloride (1.2 mL)
Was added and stirred for 2 hours. The solvent was evaporated under reduced pressure, the residue was suspended in dry chloroform (5 mL), 1.3 mL (9.33 mmol) of dry triethylamine was added under ice cooling, and the mixture was stirred for 10 minutes. Then, a solution of the compound (6) (492 mg, 1.79 mmol) in dry chloroform (5 mL) was added under ice cooling, and the mixture was stirred at room temperature for 15 hours. Methylene chloride (20 mL) was added to the reaction solution, and the mixture was poured into ice water (50 mL). After extraction with methylene chloride (50 mL), the extract was washed with water (50 mL) and saturated saline (50 mL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by medium pressure liquid chromatography (methanol / chloroform = 1/100 to 1/50) to give 398 mg of the title compound (9) (yield 41 0.5%) was obtained as a pale yellow amorphous substance. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 1.29 (3H, t, J = 7 Hz) 4.26 (2H, q, J = 7 Hz) 4.62 (2H, s) 5.08 (2H , S) 5.42 (2H, s) 6.80 (1H, dd, J = 2, 8Hz) 6.85 (1H, s) 7.06 to 7.09 (2H, m) 7.19 to 7 .23 (2H, m) 7.35 (1H, t, J = 8Hz) 7.43 to 7.49 (2H, m) 7.55 (1H, m) 7.66 (1H, d, J = 8Hz) ) 7.73 (1H, m) 7.83 (1H, d, J = 8Hz) 7.91 (1H, s) 8.07 (1H, d, J = 8Hz) 8.20 (1H, d, J) = 8Hz)

(10) Synthesis of 4- (imidazol-1-ylmethyl) -3- [3- (quinolin-2-ylmethyloxy) benzoylamino] phenoxyacetic acid (IV-1) The above compound (9) (74 mg, 0.697 mmol) was dissolved in ethanol (5 mL), 1N aqueous sodium hydroxide solution (0.9 mL) was added under ice cooling, and the mixture was stirred at room temperature for 14 hr. After distilling off the solvent under reduced pressure, under ice cooling, water (5 mL)
And 1N hydrochloric acid were added to adjust the pH to 7. The precipitated crystals were filtered, washed with water (10 mL), and dried under reduced pressure to give 294 mg of the title compound (10) (yield 83.1).
%) As white crystals. mp: 190-192 ° C. ¹ H-NMR (CD ₃ OD, 400 MHz): δ = 4.57 (2H, s) 5.29 (2H, s) 5.43 (2H, s) 6.93-6. 96 (2H, m) 7.23 to 7.31 (4H, m) 7.44 (1H, t, J = 8Hz) 7.51 to 7.63 (3H, m) 7.74 (1H, d, J = 8Hz) 7.79 (1H, m) 7.95 (1H, d, J = 8Hz) 8.05 (1H, d, J = 8Hz) 8.31 (1H, s) 8.39 (1H, d, J = 8 Hz) IR (KBr) cm ⁻¹ : 3423, 3135, 237
5,1637,1587,1523,1506,142
7,1292,1178,1060,750

[Synthesis Example 11] 4- [3- (imidazol-1-yl) propyl] -2- [2-oxo-2- [3]
-Quinolin-2-ylmethyloxy) phenylamino]
Synthesis of ethyl] benzoic acid (IV-2) (1) Synthesis of 5-aminophthalide Zinc dust (50.0 g, 1.67 mol), copper sulfate (70 m
g, 0.44 mmol), and sodium hydroxide (1
6.0 g, 0.67 mol) was suspended in water (60 mL). 4-aminophthalimide (25.0
g, 0.15 mol) was gradually added, and further water (70 mL) was added.
Was added, and then heated at 70 to 80 ° C. for 10 hours. Insoluble matter was removed by filtration through Celite. Concentrated hydrochloric acid was added to the obtained aqueous solution under ice cooling to adjust the pH to 2, and the mixture was heated under reflux for 2 hours. After cooling this, sodium carbonate was added to adjust the pH to 8 and the precipitated crystals were collected by filtration to quantitatively obtain 22.9 g of the title compound (1) as light brown crystals. ¹ H-NMR (CD ₃ OD, 400 MHz): δ = 5.17 (2H, s) (1H, s) 6.65 (1H, s) 6.73 (1H, dd, J = 8 Hz, 2 Hz) 7 .51 (1H, d, J = 8Hz)

(2) Synthesis of methyl 5-amino-2-methoxycarbonylphenylacetate The above compound (1) (22.9 g, 0.15 mol) and potassium cyanide (11.5 g, 0.18 mol) were combined with dimethyl sulfoxide ( 215 mL), 170-175
Heated at ° C for 11 hours. The solvent was evaporated under reduced pressure, and a 4N aqueous sodium hydroxide solution (120 mL) was added to the obtained residue, which was heated under reflux for 5 hours. Further, the solvent of this reaction solution was distilled off under reduced pressure to obtain a residue, and methanol (250 m
L) and concentrated sulfuric acid (25 mL) were added, and the mixture was heated under reflux for 5 hours. Water was added to the residue obtained by distilling off the solvent, and the mixture was neutralized with a 1N aqueous sodium hydroxide solution. Here, insoluble matter was filtered off and extracted with chloroform. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product thus obtained was recrystallized (chloroform, methanol / ether, hexane) to obtain 5.79 g (yield 16.8%) of the title compound (2) as light brown crystals. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 3.70, 3.80 (6H, each s) 3.87 (2H, s) 3.93 (2H, s) 6.48 (1H, d, J = 2Hz) 6.57 (1H, dd, J = 8Hz, 2Hz) 7.88 (1H, d, J = 8Hz)

(3) Synthesis of methyl 5-iodo-2-methoxycarbonylphenylacetate The above compound (2) (1.56 g, 7.0 mmol) was added to
It was dissolved in a mixed solution of concentrated hydrochloric acid (3.3 mL) and water (4.4 mL), and sodium nitrite (0.53 g, 7.7 mmol) was added under ice-cooling stirring at 5 ° C or below for 10 minutes. 5 ° C
Stirred below for 30 minutes. Potassium iodide (3.92 g, 23.6 mmol) was added to the obtained red suspension,
After stirring at room temperature for 1 hour, the mixture was left standing overnight. The reaction mixture was extracted with ether, washed successively with water, saturated aqueous sodium hydrogen carbonate solution, 5% aqueous sodium bisulfite solution and saturated brine, and dried over sodium sulfate. The solvent was evaporated to give a red oil 1.4
1 g of the product was subjected to medium pressure silica gel column chromatography and eluted with chloroform to obtain 1.04 g (yield 34.2%) of the title compound (3) as a yellow oil. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 3.70 (3H, s) 3.86 (3H, s) 3.95 (2H, s) 7.64 (1H, m) 7.7 to 7 .8 (2H, m) MS (EI): m / z 334 (MH ⁺ ).

(4) Methyl 5- (3-hydroxy-1)
Synthesis of -propynyl) -2-methoxycarbonylphenylacetate The above compound (3) (668 mg, 2 mmol), propargyl alcohol (224 mg, 4 mmol), palladium chloride (7 mg, 0.04 mmol), copper iodide (1
3 mg, 0.068 mmol), triphenylphosphine (19 mg, 0.037 mmol), and diethylamine (8 mL) were mixed, and the mixture was stirred under a nitrogen atmosphere at room temperature for 21 hours. Diethylamine was distilled off under reduced pressure, extracted with ethyl acetate, washed successively with 2N hydrochloric acid, water and then saturated brine, and dried over sodium sulfate. The solvent was distilled off to obtain 678 mg of a dark brown oily substance, which was subjected to medium pressure silica gel column chromatography and eluted with a mixed solvent of methanol / chloroform = 1/100 to give the title compound (4) as pale yellow crystals. 467 mg (yield 89.0%) was obtained. mp: 88-91 ° C ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 1.67 (1H, t, J = 6 Hz) 3.70 (3H, s) 3.87 (3H, s) 3.98 (2H, s) 4.50 (2H, d, J = 6Hz) 7.33 (1H, s) 7.41 (1H, d, J = 8Hz) 7.96 (1H, d, J = 8Hz) IR (KBr) cm ⁻¹ : 3350, 2950, 235
0,2330,1730,1710,1600,143
0, 1420, 1345, 1300, 1275, 126
0, 1200, 1170, 1085, 1010, 740

(5) Synthesis of methyl 5- (3-hydroxypropyl) -2-methoxycarbonylphenylacetate The above compound (4) (127 mg, 0.48 mmol) was dissolved in methanol (2.5 mL) and 10% was added. Palladium on carbon (13 mg) was added, and under hydrogen atmosphere, at room temperature, 18
Stirred for hours. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to obtain 124 mg of a colorless oily substance, which was subjected to medium pressure silica gel column chromatography and eluted with a mixed solvent of methanol / chloroform = 1/100 to give the title compound ( 5 mg was obtained as a colorless oily substance (105 mg, yield 81%). ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 1.27 (1 H, t, J = 5 Hz) 1.90 (2 H, m) 2.75 (2 H, t, J = 8 Hz) 3.68 (2 H , M) 3.70 (3H, s) 3.85 (3H, s) 3.99 (2H, s) 7.09 (1H, d, J = 1Hz) 7.20 (1H, dd, J = 1Hz) , 8Hz) 7.95 (1H, d, J = 8Hz)

(6) Synthesis of methyl 5- (3-bromopropyl) -2-methoxycarbonylphenylacetate The above compound (5) (105 mg, 0.39 mmol),
And carbon tetrabromide (169 mg, 0.51 mmol) were dissolved in dichloromethane (1 mL), and triphenylphosphine (134 mg, 0.51 mmol) was added at room temperature under stirring for 15 minutes. The mixture was stirred at room temperature for 21 hours, concentrated under reduced pressure, and subjected to medium pressure silica gel column chromatography. Elution with chloroform gave the title compound (6) as a colorless oil (119 mg, yield 92%). ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 2.18 (2H, tt, J = 7Hz, 7Hz) 2.82 (2H, t, J = 7Hz) 3.39 (2H, t, J = 7Hz) ) 3.70 (3H, s) 3.86 (3H, s) 3.99 (2H, s) 7.09 (1H, d, J = 1Hz) 7.20 (1H, dd, J = 1Hz, 8Hz) ) 7.96 (1H, d, J = 8Hz)

(7) Synthesis of methyl 5- [3- (imidazol-1-yl) propyl] -2-methoxycarbonylphenylacetate Sodium hydride (18 mg, 0.44 mmol) was added to anhydrous dimethylformamide (0.4 mL). , Imidazole (30 mg, 0.44 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The above compound (6) was added to the obtained solution.
(132 mg, 0.4 mmol) was dissolved in anhydrous dimethylformamide (0.4 mL) and added, and the mixture was stirred at room temperature for 18 hr. Ethyl acetate and water were added to this reaction mixture, and the ethyl acetate layer was extracted with 1N hydrochloric acid. The aqueous layer was made basic with potassium carbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then with saturated saline, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (7) as a colorless oil (80 mg, yield 63%). ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 2.14 (2H, tt, J = 7Hz, 7Hz) 2.64 (2H, t, J = 7Hz) 3.71 (3H, s) 3.86 (3H, s) 3.94 (2H, t, J = 7Hz) 3.99 (2H, s) 6.91 (1H, s) 7.03 (1H, d, J = 2Hz) 7.08 (1H , S) 7.15 (1H, dd, J = 2Hz, 8Hz) 7.46 (1H, s) 7.96 (1H, d, J = 8Hz)

(8) Synthesis of 2- (3-nitrophenoxymethyl) quinoline m-Nitrophenol (1.67 g, 12 mmol) was dissolved in ethanol and powdered sodium hydroxide (0.
96 g, 24 mmol) and 2-chloromethylquinoline.
Hydrochloride (2.14 g, 10 mmol) was added, and the mixture was stirred at room temperature overnight and then heated under reflux for 4 hours. Chloroform was added to the reaction mixture, washed with water, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethanol-hexane to give the title compound (8) (1.88 g, yield 67%) as a white crystalline powder. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 5.45 (2H, s) 7.3 to 8.5 (10H, m)

(9) 3- (2-quinolylmethyloxy)
Synthesis of aniline The compound (8) (1.49 g, 5.3 mmol) was dissolved in a mixture of methanol (12 mL) and acetic acid (12 mL), and tin (II) chloride dihydrate was added at an external temperature of 45 ° C. (9.
5 g) of concentrated hydrochloric acid solution (9.5 mL) was added over 10 minutes, and the mixture was stirred as it was for 8 hours and further stirred at room temperature overnight. The reaction mixtures obtained by carrying out the same reaction from the above compound (8) (0.28 g, 0.1 mmol) were combined, dichloromethane and 1N aqueous sodium hydroxide solution were added, and the insoluble matter was filtered through Celite to obtain an organic layer. Was collected and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate = 3/1). This was crystallized from ether-hexane to give the title compound (9) (1.03 g, yield 65%) as a pale yellow crystalline powder. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 3.65 (2H, s) 5.35 (2H, s) 6.30 (1H, dd, J = 2 Hz, 8 Hz) 6.36 (1H, t) , J = 2 Hz) 6.43 (1 H, dd, J = 2 Hz, 8 Hz) 7.04 (1 H, t, J = 2 Hz) 7.5-7.9 (4 H, m) 8.07 (1 H, d , J = 8 Hz) 8.17 (1H, d, J = 8 Hz)

(10) 4- [3- (imidazol-1-
Synthesis of (yl) propyl] -2- [2-oxo-2- [3- (quinolin-2-ylmethyloxy) phenylamino] ethyl] -benzoic acid (IV-2) Compound (7) (1.17 g) , 3.70 mmol) was dissolved in methanol (30 mL), 1N aqueous sodium hydroxide solution (15 mL) was added, and the mixture was heated under reflux for 5 hr.
The solvent was distilled off under reduced pressure to obtain a disodium salt (A).
This was dissolved in water, acidified with 2N hydrochloric acid, and concentrated under reduced pressure. The residue was dissolved in toluene and concentrated under reduced pressure. The concentration operation was repeated, and the residue was vacuum dried to obtain dicarboxylic acid (B). Then, acetyl chloride (16 mL) was added to the dicarboxylic acid (B), and the mixture was heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was concentrated twice under reduced pressure from toluene by the above method to obtain an acid anhydride (C). The above compound (9) (2.75 g, 11 mmol) was added thereto, and the mixture was stirred at 120 ° C. for 2 hours. The reaction mixture was suspended in methanol and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give 4.5 g of dark red solid, Cosm
It was subjected to medium pressure column chromatography using osil 75C18-OPN (Nacalai Tesque) and eluted with a mixed solvent of water / methanol = 1/2 to obtain 2.1 g of a red oily substance. This was subjected to medium pressure silica gel column chromatography and eluted with a mixed solvent of methanol / chloroform = 1/4 to obtain 0.28 g (yield 15%) of the title compound (10) as a light brown powder. (A) ¹ H-NMR (D ₂ O, 400 MHz): δ = 2.14 (2H, m) 2.60 (2H, t, J = 8 Hz) 3.72 (2H, s) 4.04 (2H , T, J = 7 Hz) 7.0 to 7.2 (4 H, m) 7.39 (1 H, d, J = 8 Hz) 7.67 (1 H, s)

(B) ¹ H-NMR (D ₂ O, 400 MHz): δ = 2.30 (2H, tt, J = 7Hz, 7Hz) 2.78 (2H, t, J = 7Hz) 3.94 ( 2H, s) 4.26 (2H, t, J = 7Hz) 7.1-7.4 (4H, m) 7.86 (1H, d, J = 8Hz) 8.57 (1H, s) (C ) ¹ H-NMR (D ₂ O, 400 MHz): δ = 2.33 (2H, tt, J = 7 Hz, 7 Hz) 2.80 (2H, t, J = 7 Hz) 4.29 (2H, t, J) = 7 Hz) 7.2-7.5 (4 H, m) 7.89 (1 H, d, J = 8 Hz) 8.59 (1 H, s) Compound (10) mp: 250-260 ° C. (decomposition) ¹ H _{-NMR (CD 3 OD, 400MHz)} : δ = 2.12 (2H, m) 2.59 (2H, t, J = 8Hz) 3.96 (2H, s) 4 03 (2H, t, J = 7Hz) 5.29 (2H, s) 6.72 (1H, d, J = 8Hz) 7.0-7.2 (6H, m) 7.39 (1H, s) 7.58 (1H, dd, J = 7Hz, 8Hz) 7.65 (1H, d, J = 9Hz) 7.76 (1H, dd, J = 7Hz, 8Hz) 7.79 (1H, d, J = 8Hz) 7.84 (1H, s) 7.90 (1H, d, J = 8Hz) 8.01 (1H, d, J = 8Hz) 8.31 (1H, d, J = 9Hz)

[Synthesis Example 12] Methyl 4- [3- (imidazol-1-yl) propyl] -2- [2-oxo-]
2- [3- (quinolin-2-ylmethyloxy) phenylamino] ethyl] benzoate dihydrochloride (IV-3)
Synthesis of (1) Methyl 4- [3- (imidazol-1-yl)
Synthesis of propyl] -2- [2-oxo-2- [3- (quinolin-2-ylmethyloxy) phenylamino] ethyl] benzoate Methyl 5- [3- (imidazol-1-yl) propyl] -2- Methoxycarbonylphenylacetate (Compound (7) obtained in Synthesis Example 11) (1.11 g, 3.
51 mmol) was dissolved in methanol (80 mL) and water (18 mL) was added. To this, 1N aqueous sodium hydroxide solution (3.5 mL, 3.5 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 16 hours. Methanol was distilled off under reduced pressure at 40 ° C or lower and washed with dichloromethane. 2 water layers
The mixture was neutralized with normal hydrochloric acid and concentrated under reduced pressure at 50 ° C. 2 in the residue
Normal hydrochloric acid (2 mL) was added, and the mixture was concentrated under reduced pressure. The residue was concentrated twice from toluene under reduced pressure and then dried under vacuum to obtain a mixture (A) of monocarboxylic acid / hydrochloride (white oily substance) and white crystals (sodium salt). Add this to anhydrous dichloromethane (70
mL) and thionyl chloride (0.77 mL, 10.
(5 mmol) was added over 1 minute, the mixture was stirred at room temperature for 17 hours, and heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, anhydrous dichloromethane was further added to the residue, and the concentration was repeated under reduced pressure. This residue was washed with anhydrous dichloromethane (35
mL), and 3- (quinolin-2-ylmethyloxy) aniline (1.75 g, 7 mmol) dissolved in anhydrous dichloromethane (18 mL) was added dropwise to the solution in 10 minutes under ice cooling. The mixture was stirred under ice-cooling for 30 minutes and then at room temperature for 6 hours, saturated aqueous sodium hydrogen carbonate (50 mL) was added,
The dichloromethane layer was washed with saturated saline and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give a red oily substance 3.03
g, and subjected to medium pressure silica gel column chromatography, and eluted with a mixed solvent of methanol / chloroform = 1/20 to obtain 0.39 g (yield 21%) of the title compound (1) as a yellow amorphous substance. Mixture (A) ¹ H-NMR (D ₂ O, 400 MHz): δ = 2.30 (2H, tt, J = 7Hz, 7Hz) 2.77 (2H, t, J = 7Hz) 3.87 (3H, s) 3.98 (2H, s) 4.26 (2H, t, J = 7Hz) 7.18 (1H, s) 7.28 (1H, d, J = 8Hz) 7.36 (1H, s) 7.43 (1H, s) 7.92 (1H, d, J = 8Hz) 8.59 (1H, s)

Compound (1) ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 2.14 (2H, tt, J = 7Hz, 7Hz) 2.64 (2H, t, J = 7Hz) 3.93 ( 2H, s) 3.94 (2H, t, J = 7Hz) 3.95 (3H, s) 5.35 (2H, s) 6.71 (1H, dd, J = 2Hz, 8Hz) 6.92 ( 1H, s) 7.0-7.4 (6H, m) 7.48 (1H, s) 7.54 (1H, dd, J = 7Hz, 8Hz) 7.66 (1H, d, J = 9Hz) 7.72 (1H, ddd, J = 1Hz, 7Hz, 8H
z) 7.81 (1H, dd, J = 1 Hz, 8 Hz) 7.88 (1H, d, J = 8 Hz) 8.07 (1H, d, J = 8 Hz) 8.17 (1H, d, J = 9Hz) 9.20 (1H, s)

(2) Methyl 4- [3- (imidazol-1-yl) propyl] -2- [2-oxo-2- [3
Synthesis of-(quinolin-2-ylmethyloxy) phenylamino] ethyl] benzoate dihydrochloride (IV-3) The above compound (1) (0.17 g, 0.32 mmol) was dissolved in methanol (2 mL). , Concentrated hydrochloric acid (0.055m
L, 0.66 mmol) was added. The operation of concentrating this solution under reduced pressure, adding water to the residue, and concentrating under reduced pressure was repeated 3 times. The residue was dried under vacuum and then pulverized to give the title compound (2) as a yellow amorphous substance in an amount of 0.20 g (yield:
100%) was obtained. ¹ H-NMR (D ₂ O, 400 MHz): δ = 2.27 (2H, tt, J = 7Hz, 7Hz) 2.73 (2H, t, J = 7Hz) 3.76 (3H, s) 4. 03 (2H, s) 4.25 (2H, t, J = 7Hz) 5.67 (2H, s) 6.9 to 7.1 (2H, m) 7.2 to 7.5 (6H, m) 7.88 (1H, d, J = 8Hz) 7.90 (1H, dd, J = 7Hz, 8Hz) 8.02 (1H, d, J = 9Hz) 8.09 (1H, dd, J = 7Hz, 8 Hz) 8.18 (1H, d, J = 8 Hz) 8.21 (1H, d, J = 8 Hz) 8.62 (1H, s) 8.99 (1H, d, J = 9 Hz) IR (KBr) cm ⁻¹ : 1710, 1670, 160
0,1540,1490,1430,1290,127
0,1190,1150,1080

[Synthesis Example 13] 4- (imidazole-1-)
Ilmethyl) -2- [3- (quinolin-2-ylmethyloxy) benzoylamino] phenoxyacetic acid (IV-4)
Synthesis of 4-hydroxy-3-nitrobenzaldehyde 4-hydroxybenzaldehyde (20.0 g, 164
(Mmol) was suspended in acetic acid (80 mL), nitric acid (12.7 mL, specific gravity 1.38, 278 mmol) was added under water cooling, and the temperature was gradually raised. Since an exothermic reaction started at around 27 ° C, the mixture was cooled with ice (internal temperature was raised up to 55 ° C).
After cooling to room temperature, the mixture was stirred at 35 ° C for 5 minutes and ice-cooled again. The precipitated crystals were collected by filtration, washed with water (70 mL × 3), and dried under reduced pressure to give 13.2 g (yield 48.2%) of the title compound (1) as yellow crystals. mp: 141.8 to 143.2 ° C. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 7.32 (1H, d, J = 8 Hz) 8.14 (1H, dd, J = 2 Hz, 8 Hz) 8 .64 (1H, d, J = 2Hz) 9.95 (1H, s) 11.02 (1H, s)

(2) 4-methyloxymethyloxy-3
-Synthesis of nitrobenzaldehyde The above compound (1) (10.0 g, 59.8 mmol) was suspended in acetone (80 mL), and potassium carbonate (8.82 g, 63.8 mmol) and chloromethyl methyl ether (4) were suspended at room temperature. (0.8 mL, 63.8 mmol) was added, and the mixture was stirred overnight. The insoluble material was removed by filtration, and then the solvent was evaporated under reduced pressure. Water (200 mL) was added to the insoluble matter, and the residue was combined with ethyl acetate (200 mL, 100 m).
It was extracted with L) and washed with saturated saline (100 mL).
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
1.0 g (yield (87.1%) of the title compound (2) was obtained as yellow crystals. Mp: 98.4-99.6 ° C. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 3. 55 (3H, s) 5.40 (3H, s) 7.48 (1H, d, J = 8Hz) 8.05 (1H, dd, J = 2Hz, 8Hz) 8.32 (1H, d, J = 2Hz) 9.95 (1H, s)

(3) 4-methyloxymethyloxy-3
-Synthesis of nitrobenzyl alcohol The above compound 2 (5.00 g, 23.7 mmol) was suspended in dry THF (= tetrahydrofuran, 30 mL),
Sodium borohydride (0.50 g, 1
(3.2 mmol) was added little by little, and the mixture was stirred for 1 hour and 30 minutes while cooling with a water bath. The mixture was ice-cooled again, a saturated aqueous solution of sodium sulfate (20 mL) was added little by little, the precipitated crystals were removed by filtration, and THF was distilled off under reduced pressure. The residue was extracted with ethyl acetate (15 mL x 2) and saturated brine (2
After washing with 0 mL × 2), it was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1) to obtain 4.75 g (purity 97.6%, yield 91.7%).
To give the title compound (3) as a yellow oil. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 1.78 (1 H, t, J = 6 Hz) 3.53 (3 H, s) 4.70 (2 H, d, J = 6 Hz) 5.29 (3 H , S) 7.31 (1H, d, J = 8Hz) 7.51 (1H, dd, J = 2Hz, 8Hz) 7.83 (1H, d, J = 2Hz)

(4) 4-methyloxymethyloxy-3
-Synthesis of nitrobenzyl bromide The above compound (3) (1.66 g, purity 97.6%, 7.
60 mmol) and carbon tetrabromide (3.27 g, 9.86 mmol) were dissolved in dichloromethane (11 mL), and triphenylphosphine (2.59 g, 9.87 mmol) was added at room temperature so that the temperature did not rise. Was added little by little to and stirred for 1 hour. The solvent was distilled off under reduced pressure, and the residue was converted to ether (20
(mL) and ice water (10 mL) were added, and the precipitated crystals were removed by filtration. Wash the crystals with a little ether,
The washing solution and the filtrate were combined and separated, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform) to obtain 1.80 g (yield 85.8%) of the title compound (4) as yellow crystals. mp: 87.5 to 89.3 ° C ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 3.53 (3H, s) 4.46 (2H, d, J = 6Hz) 5.30 (3H, s) ) 7.30 (1H, d, J = 8Hz) 7.54 (1H, dd, J = 2Hz, 8Hz) 7.85 (1H, d, J = 2Hz)

(5) α- (imidazol-1-yl)-
Synthesis of 4-Methyloxymethyloxy-3-nitrotoluene Imidazole (0.46 g, 6.76 mmol) was dissolved in dry DMF (2 mL) and 60% sodium hydride (0.27 g, 6. (75 mmol) was added little by little, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was ice-cooled again, a dry DMF (7 mL) solution of the compound (4) (1.70 g, 6.15 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. The reaction solution was poured into ice water (50 mL), extracted with chloroform (15 mL x 3), and water (50 mL x
After washing in 2), it was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform-methanol / chloroform = 1/5).
0) to give 1.47 g (yield 90.7%) of the title compound (5) as a yellow oil. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 3.52 (3H, s) 5.12 (2H, s) 5.29 (2H, s) 6.90 (1H, t, J = 1 Hz) 7 .12 (1H, brs) 7.26 (1H, dd, J = 2Hz, 8Hz) 7.32 (1H, d, J = 8Hz) 7.56 (1H, s) 7.65 (1H, d, J) = 2Hz)

(6) Synthesis of 6- (imidazol-1-ylmethyl) -2-methyloxymethyloxyaniline The compound (5) (1.47 g, 5.5) under a nitrogen atmosphere.
8 mmol) was dissolved in ethanol (10 mL) and 10
% -Palladium on carbon (0.59 g, 0.55 mmol) was added. The inside of the reaction system was replaced with hydrogen gas, and the mixture was stirred for 2 hours. Hydrogen gas was purged from the reaction system, insoluble matters were removed by filtration, and then washed with ethanol (10 mL). When the filtrate and the washing solution were combined and the solvent was distilled off under reduced pressure, the intermediate hydroxylamine compound remained, so the residue was dissolved in ethanol (10 mL), and 10% was added.
-Palladium / carbon (0.59 g, 0.55 mmol)
Was added, the inside of the reaction system was replaced with hydrogen gas, and the mixture was stirred for 1 hour and 30 minutes. Hydrogen gas was expelled from the reaction system, the insoluble matter was removed by filtration, and then washed with ethanol (10 mL).
The filtrate and the washing solution were combined, the solvent was distilled off under reduced pressure, toluene (3 mL) was added to the residue, and the solvent was distilled off under reduced pressure under vacuum to obtain 1.22 g (purity 87.1%, yield 81.7%). The title compound (6) was obtained as yellow crystals. mp: 65.6-68.0 ° C ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 3.49 (3H, s) 4.98 (2H, s) 5.19 (2H, s) 6.49. (1H, d, J = 2Hz) 6.52 (1H, dd, J = 2Hz, 8Hz) 6.89-6.91 (1H, m) 6.98 (1H, d, J = 8Hz) 7.09 (1H, brs) 7.60 (1H, s)

(7) N- [5- (imidazol-1-ylmethyl) -2-methyloxymethyloxyphenyl]
Synthesis of 3- (quinolin-2-ylmethyloxy) benzamide 3- (quinolin-2-ylmethyloxy) benzoic acid (Compound (8) synthesized in Synthesis Example 10 (0.42 g, 1.5
Thionyl chloride (0.96 mL,
(13.2 mmol) was added, and after stirring for 3 hours, excess thionyl chloride was distilled off under reduced pressure. The residue was added to chloroform (2.4
mL), and triethylamine (1.06
(mL, 7.60 mmol) was added and stirred for 10 minutes.
Furthermore, the compound (6) (0.40 g, purity 87.1).
%, 1.49 mmol) of chloroform (1.4 mL)
The solution was added and stirred at room temperature overnight. Add ice water (1
(0 mL) was added and after stirring, the organic layer was separated and washed with a saturated aqueous sodium hydrogen carbonate solution (5 mL). After drying over anhydrous sodium sulfate and evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform-methanol / chloroform = 1/50) to give 0.30 g.
The title compound (7) (yield 40.9%) was obtained as pale yellow crystals. mp: 141.0 to 143.4 ° C ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 3.48 (3H, s) 5.08 (2H, s) 5.23 (2H, s) 5.46. (2H, s) 6.80 (1H, dd, J = 2Hz, 8Hz) 6.94 (1H, t, J = 1Hz) 7.07 (1H, brs) 7.13 (1H, d, J = 8Hz) ) 7.20 to 7.25 (1H, m) 7.40 to 7.47 (2H, m) 7.53 to 7.59 (1H, m) 7.59 to 7.62 (1H, m) 7 0.55 (1H, s) 7.67 (1H, d, J = 8Hz) 7.75 (1H, ddd, J = 1Hz, 8Hz, 7H
z) 7.84 (1H, d, J = 8Hz) 8.10 (1H, d, J = 8Hz) 8.22 (1H, d, J = 8Hz) 8.53 (1H, d, J = 2Hz) 8.53 (1H, s)

(8) Synthesis of N- [2-hydroxy-5- (imidazol-1-ylmethyl) phenyl] -3- (quinolin-2-ylmethyloxy) benzamide The above compound (7) (0.25 g, 0 0.51 mmol) was dissolved in a mixed solvent of THF (2 mL) and methanol (0.6 mL), and 1N hydrochloric acid aqueous solution (1.6
mL) was added and the mixture was stirred at room temperature overnight. To the reaction solution, 1N aqueous hydrochloric acid solution (1.4 mL) was added, and the mixture was stirred at 50 ° C.,
After 4 hours and 5 hours, 1N aqueous hydrochloric acid solution (0.7 mL, 0.7 mL) was added, and the mixture was further stirred at the same temperature for 1 hour.
Stir for 30 minutes. The reaction solution was ice-cooled, saturated aqueous sodium hydrogencarbonate solution was added until pH 7 and water (1
0 mL) was added. The precipitated crystals were collected by filtration, and water (10 m
After washing with L × 2), 0.22 g (yield 9
(6.1%) of the title compound (8) was obtained as pale yellow crystals. mp: 105.6 ° C. ¹ H-NMR (CD ₃ OD / CDCl ₃ = 1/20, 4
00 MHz): δ = 5.06 (2H, s) 5.44 (2H, s) 6.85 (1H, dd, J = 2Hz, 8Hz) 6.92 (1H, d, J = 8Hz) 6.95 (1H, t, J = 1Hz) 7.03 (1H, brs) 7.23 (1H, dd, J = 2Hz, 8Hz) 7.41 (1H, t, J = 8Hz) 7.53 to 7.55 (1H, m) 7.55 (1H, s) 7.56 to 7.61 (1H, m) 7.63 (1H, t, J = 2Hz) 7.71 (1H, d, J = 8Hz) 7 .77 (1H, ddd, J = 1Hz, 7Hz, 8H
z) 7.85 (1H, d, J = 2Hz) 7.86 (1H, d, J = 8Hz) 8.09 (1H, d, J = 8Hz) 8.26 (1H, d, J = 8Hz)

(9) tert-Butyl 4- (imidazol-1-ylmethyl) -2- [3- (quinoline-2-)
Synthesis of (ylmethyloxy) benzoylamino] phenoxyacetate The above compound (8) (0.20 g, 0.44 mmol)
With dry acetone (4 mL) and dry DMF (1 m
L) suspended in a mixed solvent of anhydrous potassium carbonate (64 m
g, 0.46 mmol) and tert-butyl bromoacetate (0.068 mL, 0.46 mmol) were added, and the mixture was stirred at room temperature for 3 hours and then at 60 ° C. for 2 hours 30 minutes. Furthermore, anhydrous potassium carbonate (9 mg,
0.065 mmol) and tert-butyl bromoacetate (0.013 mL, 0.089 mmol) were added, and the mixture was stirred at 60 ° C. for 2 hr, and the solvent was evaporated under reduced pressure. Ice water (5 mL) was added to the residue, and chloroform (10 mL) was added.
(mL), extracted with water (10 mL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform to methanol / chloroform = 3/200) to give 0.20.
The title compound (9) (g, yield 79.5%) was obtained as yellow crystals. mp: 137.6-139.4 ° C. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 1.46 (9H, s) 4.58 (2H, s) 5.09 (2H, s) 5.47 (2H, s) 6.77 (1H, dd, J = 2Hz, 8Hz) 6.83 (1H, d, J = 8Hz) 6.94 (1H, t, J = 1Hz) 7.08 (1H, brs ) 7.22 (1H, dd, J = 2Hz, 8Hz) 7.42 (1H, t, J = 8Hz) 7.54 to 7.58 (1H, m) 7.55 (1H, s) 7.62 (1H, d, J = 8Hz) 7.69 (1H, d, J = 8Hz) 7.71-7.77 (2H, m) 7.84 (1H, d, J = 8Hz) 8.09 (1H , D, J = 8 Hz) 8.20 (1H, d, J = 8 Hz) 8.55 (1H, d, J = 2 Hz) 9.23 (1H, s)

(10) Synthesis of 4- (imidazol-1-ylmethyl) -2- [3- (quinolin-2-ylmethyloxy) benzoylamino] phenoxyacetic acid (IV-4) The above compound (9) (0. 19 g, 0.34 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (0.66 mL, 8.68 mmol) was added under ice cooling,
Stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure, and T was added to the residue.
HF / hexane = 1/3 mixed solvent (8 mL) was added, and the precipitated crystals were collected by filtration and dried under reduced pressure. The obtained crystals were suspended in water (10 mL), and 0.28% ammonia water was added to the suspension.
H7 was added until ethanol (5 mL) was further added, followed by stirring at 40 ° C. for 20 minutes. The crystals were collected by filtration, washed successively with ethanol / water = 1/2 mixed solvent (5 mL), ethanol (0.5 mL), ethanol / hexane = 1/2 mixed solvent (3 mL), and hexane (2 mL), and then depressurized. The crystals were dried below to give 0.10 g (yield 58.8%) of the title compound (10) as white crystals. mp: 97.0 ° C. ¹ H-NMR (CD ₃ OD / CDCl ₃ = 1/20, 4
00 MHz): δ = 4.73 (2H, s) 5.10 (2H, s) 5.54 (2H, s) 6.84 (1H, dd, J = 2Hz, 8Hz) 6.97 (1H, t) , J = 1 Hz) 6.98 (1H, d, J = 8 Hz) 7.05 (1H, brs) 7.26 to 7.36 (1H, m) 7.46 (1H, t, J = 8 Hz) 7 .57 to 7.65 (1H, m) 7.62 (1H, s) 7.73 (1H, d, J = 8Hz) 7.78 (1H, t, J = 8Hz) 7.84 (1H, d) , J = 8 Hz) 7.88 (1H, s) 7.89 (1H, d, J = 8Hz) 8.10 (1H, d, J = 8Hz) 8.32 (1H, d, J = 8Hz) 8 .43 (1H, d, J = 2 Hz) IR (KBr) cm ⁻¹ : 3410, 3064, 166
4,1599,1541,1506,1479,143
9,1404,1325,1271, 1225,746

[Synthesis Example 14] 4- (imidazole-1-)
Ilmethyl) -2- [4- (quinolin-2-ylmethyloxy) benzoylamino] phenoxyacetic acid (IV-5)
Synthesis of (1) Synthesis of methyl 4-[(quinolin-1-ylmethyl) oxy] benzoate Methyl 4-hydroxybenzoate (0.71 g, 4.67)
Mmol) was dissolved in dry DMF (2 mL), and the mixture was cooled with ice.
60% Sodium hydride (0.22 g, 5.50 mmol) was added portionwise and stirred for 30 minutes. A solution of 2-chloromethylquinoline (0.83 g, 4.67 mmol) in dry DMF (3 mL) was added dropwise, and the mixture was stirred at room temperature for 16 hours and then dissolved in dichloromethane (15 mL). This solution was poured into ice water (20 mL) and diluted with dichloromethane (20 m
L), extracted with water (30 mL) and saturated saline (20 mL).
(mL) and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform to methanol / chloroform = 1 /
After crude purification by 100), the obtained crystals were dissolved by heating in ethyl acetate (1 mL), and while hot, hexane (5 m
L) was added. Leave at room temperature, collect the precipitated crystals by filtration,
Ethyl acetate / hexane = 1/5 mixed solvent (3 mL), ethyl acetate / hexane = 1/10 mixed solvent (3 mL) and hexane (3 mL) were sequentially washed, and vacuum dried to obtain 0.94 g (yield 68. 5%) of the title compound (1) was obtained as pale yellow crystals. mp: 114.0 to 115.0 ° C ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 3.88 (3H, s) 5.44 (2H, s) 7.03 to 7.08 (2H, m) ) 7.56 (1H, ddd, J = 1Hz, 7Hz, 8H
z) 7.64 (1H, d, J = 8Hz) 7.75 (1H, ddd, J = 1Hz, 7Hz, 8H
z) 7.83 (1H, d, J = 8Hz) 7.96 to 8.02 (2H, m) 8.09 (1H, d, J = 9Hz) 8.20 (1H, d, J = 9Hz)

(2) Synthesis of 4-[(quinolin-1-ylmethyl) oxy] benzoic acid The above (1) (0.50 g, 1.70 mmol) was added to a mixed solvent of methanol (2 mL) and THF (2 mL). Dissolve and, under ice cooling, 1N aqueous sodium hydroxide solution (3.
4 mL), methanol (3 mL) and THF (5 mL) were added, and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure at 30 ° C. or lower, the residue was suspended in water (2 mL), and 1N aqueous hydrochloric acid solution was added under ice cooling until the pH reached 7. The crystals were collected by filtration, washed with water, and vacuum dried to give 0.30 mg (yield 7.
18%) of the title compound (2) was obtained as pale yellow crystals. mp: 209.0 to 211.4 ° C. (decomposition) ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 5.43 (2H, s) 7.04 to 7.09 (2H, m) 7.59 ( 1H, ddd, J = 1Hz, 7Hz, 8H
z) 7.68 (1H, d, J = 8Hz) 7.77 (1H, ddd, J = 1Hz, 7Hz, 8H
z) 7.86 (1H, d, J = 8Hz) 7.99 to 8.04 (2H, m) 8.09 (1H, d, J = 8Hz) 8.25 (1H, d, J = 8Hz)

(3) N- [5- (imidazol-1-ylmethyl) -2-methyloxymethyloxyphenyl]
Synthesis of 4- (quinolin-2-ylmethyloxy) benzamide To the above compound (2) (0.42 g, 1.50 mmol) under ice cooling, thionyl chloride (0.96 mL, 13.2 mmol) and dichloromethane ( (2 mL) was added and the mixture was stirred at room temperature for 3 hours, and then excess thionyl chloride was distilled off under reduced pressure. The residue was suspended in chloroform (2.4 mL), triethylamine (1.06 mL, 7.60 mmol) was added under ice cooling, and the mixture was stirred for 10 minutes. Furthermore, 6- (imidazole-
1-ylmethyl) -2-methyloxymethyloxyaniline (compound (6) synthesized in Synthesis Example 13) (0.40
g, purity 87.1%, 1.49 mmol) in chloroform (1.4 mL) was added, and the mixture was stirred at room temperature overnight. Ice water (10 mL) was added to the reaction solution, and after stirring, the organic layer was separated and washed with a saturated aqueous sodium hydrogen carbonate solution (5 mL). After drying over anhydrous sodium sulfate and evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform-methanol / chloroform = 1/50) to give 0.24 g (yield 32.9%) of the title compound ( 3) was obtained as yellow crystals. mp: 158.4 to 161.8 ° C ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 3.49 (3H, s) 5.07 (2H, s) 5.25 (2H, s) 5.46. (2H, s) 6.78 (1H, dd, J = 2Hz, 8Hz) 6.93 (1H, t, J = 1Hz) 7.06 (1H, brs) 7.10 to 7.15 (2H, m) ) 7.12 (1H, d, J = 8Hz) 7.54 (1H, s) 7.54 to 7.60 (1H, m) 7.65 (1H, d, J = 8Hz) 7.76 (1H) , Ddd, J = 1Hz, 7Hz, 8H
z) 7.82 to 7.88 (3H, m) 8.10 (1H, d, J = 8Hz) 8.21 (1H, d, J = 8Hz) 8.49 (1H, s) 8.53 ( 1H, d, J = 2Hz)

(4) Synthesis of N- [2-hydroxy-5- (imidazol-1-ylmethyl) phenyl] -4- (quinolin-2-ylmethyloxy) benzamide The above compound (3) (0.20 g, 0 (40 mL) was dissolved in a mixed solvent of THF (1.5 mL) and methanol (0.8 mL), and 1N aqueous hydrochloric acid solution (1.3
mL) was added and the mixture was stirred at room temperature overnight. 1N Hydrochloric acid aqueous solution (1.0 mL) was added to the reaction solution, and the mixture was stirred at 50 ° C., 4
After 1 hour and 5 hours, 1N aqueous hydrochloric acid solution (0.5 mL, 0.5 mL) was added, and the mixture was further stirred at the same temperature for 1 hour.
Stir for 30 minutes. The reaction solution was ice-cooled, saturated aqueous sodium hydrogen carbonate solution was added until the pH reached 7, and then water (10 mL) was added. The precipitated crystals were collected by filtration and washed with water (1
The extract was washed with 0 mL × 2) and dried under reduced pressure to obtain 0.17 g (yield 95.0%) of the title compound (4) as pale yellow crystals. mp: 218.8-222.0 ° C. ¹ H-NMR (CD ₃ OD / CDCl ₃ = 1 / 10,4
00 MHz): δ = 5.05 (2H, s) 5.45 (2H, s) 6.82 (1H, dd, J = 2Hz, 8Hz) 6.90 (1H, d, J = 8Hz) 6.95 (1H, brs) 7.01 (1H, brs) 7.10 to 7.15 (2H, m) 7.54 (1H, s) 7.57 to 7.61 (1H, m) 7.68 (1H) , D, J = 8 Hz) 7.78 (1H, ddd, J = 1 Hz, 7 Hz, 8H
z) 7.87 (1H, d, J = 8Hz) 7.88 to 7.91 (2H, m) 7.92 (1H, d, J = 2Hz) 8.10 (1H, d, J = 8Hz) 8.26 (1H, d, J = 8Hz)

(5) tert-Butyl 4- (imidazol-1-ylmethyl) -2- [4- (quinoline-2-)
Synthesis of Ilmethyloxy) benzoylamino] phenoxyacetate The above compound (4) (0.15 g, 0.33 mmol) was dried with acetone (3 mL) and dried DMF (0.75 mL).
Suspended in a mixed solvent with, and anhydrous potassium carbonate (48 mg,
0.35 mmol) and tert-butyl bromoacetate (0.051 mL, 0.35 mmol) were added, and the mixture was stirred at room temperature for 3 hours and then at 60 ° C. for 2 hours 30 minutes. Furthermore, anhydrous potassium carbonate (14 mg,
0.10 mmol) and tert-butyl bromoacetate (0.019 mL, 0.13 mmol) were added, and the mixture was stirred at 60 ° C. for 2 hr, and the solvent was evaporated under reduced pressure.
Ice water (5 mL) was added to the residue, and chloroform (10 m
L), extracted with water (10 mL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform to methanol / chloroform = 3/100) to give 0.12 g.
The title compound (5) (yield 63.6%) was obtained as pale yellow crystals. mp: 127.4-130.0 ° C ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 1.47 (9H, s) 4.58 (2H, s) 5.08 (2H, s) 5.46 (2H, s) 6.75 (1H, dd, J = 2Hz, 8Hz) 6.82 (1H, d, J = 8Hz) 6.93 (1H, brs) 7.07 (1H, brs) 7.10 ~ 7.15 (2H, m) 7.54 (1H, s) 7.54 to 7.56 (1H, m) 7.67 (1H, d, J = 8Hz) 7.75 (1H, ddd, J = 1Hz, 7Hz, 8H
z) 7.84 (1H, d, J = 8Hz) 7.96 to 8.01 (2H, m) 8.10 (1H, d, J = 8Hz) 8.21 (1H, d, J = 8Hz) 8.54 (1H, d, J = 2Hz) 9.14 (1H, s)

(6) 4- (imidazol-1-ylmethyl) -2- [4- (quinolin-2-ylmethyloxy)
Synthesis of benzoylamino] phenoxyacetic acid (IV-5) The above compound (5) (0.11 g, 0.19 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.37 mL, 4. 87 mmol),
Stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure, and T was added to the residue.
HF / hexane = 1/2 mixed solvent (6 mL) was added, and the precipitated crystals were collected by filtration and dried under reduced pressure. The obtained crystals are suspended in water (6 mL), and 0.28% aqueous ammonia is added to pH.
7 and then ethanol (3 mL) was added, followed by stirring at 40 ° C. for 20 minutes. The crystals were collected by filtration, and sequentially mixed with ethanol / water = 1/2 mixed solvent (3 mL), ethanol (0.3 mL), hexane / ethanol = 1/2 mixed solvent (1.8 mL), and hexane (1.2 mL). After washing, it was dried under reduced pressure to give 0.06 g (yield 63.2).
%) Of the title compound as light brown crystals. mp: 213.8-215.6 ° C. ¹ H-NMR (CD ₃ OD / CDCl ₃ = 1/20, 4
00 MHz): δ = 4.68 (2H, s) 5.10 (2H, s) 5.44 (2H, s) 6.84 (1H, d, J = 8Hz) 6.90 (1H, d, J) = 8 Hz) 6.96 to 7.15 (2H, brs) 7.12 (2H, d, J = 9Hz) 7.55 to 7.62 (1H, m) 7.65 to 7.80 (1H, brs) ) 7.68 (1H, d, J = 8Hz) 7.72 to 7.80 (1H, m) 7.86 (1H, d, J = 8Hz) 7.98 (2H, d, J = 9Hz) 8 0.09 (1H, d, J = 8 Hz) 8.25 (1H, d, J = 8 Hz) 8.41 (1H, d, J = 2 Hz) IR (KBr) cm ⁻¹ : 3398, 3136, 292
6,1664,1601,1545,1510,148
3,1439,1431,1250,1180,105
7,760,758

[Synthesis Example 15] 4- (imidazole-1-)
Ilmethyl) -3- [4- (quinolin-2-ylmethyloxy) benzoylamino] phenoxyacetic acid (VI-6)
Synthesis of (1) Ethyl 4- (imidazol-1-ylmethyl) -3-nitrophenyloxyacetate 4- (imidazol-1-ylmethyl) -3-nitrophenol (Compound (4) synthesized in Synthesis Example 10) (0.
80 g, 3.65 mmol, was added to dry acetone (10 m
L) and dry DMF (1 mL) were suspended in a mixed solvent, anhydrous potassium carbonate (0.56 g, 4.05 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. Then, under ice cooling, ethyl bromoacetate (0.45 mL, 4.04 mmol) was added, and the mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. Ice water (20 mL) was added to the residue, extracted with chloroform (15 mL × 2), washed with water (20 mL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol / chloroform = 1/50) to give 0.49 g (purity 9
The title compound (1) with a yield of 7.6% and a yield of 42.8% was obtained as pale yellow crystals. ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 1.30 (3H, t, J = 7 Hz) 3.57 (2H, brs) 4.27 (2H, q, J = 7 Hz) 4.58 (2H , S) 4.99 (2H, s) 6.30 (1H, d, J = 2Hz) 6.33 (1H, dd, J = 2Hz, 8Hz) 6.90 (1H, t, J = 1Hz) 6 .98 (1H, d, J = 8Hz) 7.09 (1H, brs) 7.57 (1H, s)

(2) Ethyl 4- (imidazole-1-
Synthesis of Ilmethyl) -3- [4- (quinolin-2-ylmethyloxy) benzoylamino] phenoxyacetate 4- (quinolin-1-ylmethyl) oxy] benzoic acid (Compound (2) synthesized in Synthesis Example 14) ( 0.16g,
0.57 mmol) was suspended in dry toluene (1 mL), thionyl chloride (1.37 mL, 18.9 mmol) was added under ice cooling, the mixture was stirred at room temperature for 3 hours and 30 minutes, and thionyl chloride and toluene were distilled off under reduced pressure. I left. The residue was suspended in dry dichloromethane (3 mL), triethylamine (0.41 mL, 2.94 mmol) was added under ice cooling, and the mixture was stirred for 10 minutes. Furthermore, ethyl 3-amino-4- (imidazol-1-ylmethyl) phenoxyacetate (compound (6) synthesized in Synthesis Example 10, 0.15 g, 0.5
A solution of 4 mmol of dry dichloromethane (3 mL) was added, and the mixture was stirred at room temperature overnight and then at 60 ° C. for 1 hour. Ice water (5 mL) was added to the reaction solution, and after stirring, the organic layer was separated and washed with a saturated aqueous sodium hydrogen carbonate solution (4 mL). After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure,
The residue was purified by silica gel column chromatography (chloroform-methanol / chloroform = 1/50) to obtain 57 mg (yield 19.3%) of the title compound (2) as pale yellow crystals. mp: 173.6-175.4 ° C ¹ H-NMR (CDCl ₃ , 400 MHz): δ = 1.28 (3H, s) 4.25 (2H, s) 4.61 (2H, s) 5.08 (2H, s) 5.43 (2H, s) 6.79 (1H, dd, J = 2Hz, 8Hz) 6.84 (1H, brs) 7.03 to 7.11 (3H, m) 7.08 (1H, d, J = 8Hz) 7.21 (1H, d, J = 2Hz) 7.42 (1H, brs) 7.53 to 7.60 (1H, m) 7.64 (1H, d, J) = 8Hz) 7.75 (1H, ddd, J = 1Hz, 7Hz, 8H
z) 7.82 (1H, s) 7.83 (1H, d, J = 8Hz) 7.66 to 7.70 (2H, m) 8.09 (1H, d, J = 8Hz) 8.20 ( 1H, d, J = 8Hz)

(3) 4- (imidazol-1-ylmethyl) -3- [4- (quinolin-2-ylmethyloxy)
Benzoylamino] phenoxyacetic acid The above compound (2) (50 mg, 0.093 mmol) was dissolved in a mixed solvent of ethanol (1.2 mL) and THF (2.4 mL), and 1N aqueous sodium hydroxide solution (0 .2 mL) was added and stirred overnight. Water (4 mL) was added to the reaction solution, and the pH of the 1N aqueous hydrochloric acid solution was adjusted to 7 with ice cooling.
The crystals were collected by filtration. The obtained crystals were washed with water (2 mL) and dried under reduced pressure to give 40 mg (yield 84.9%) of the title compound (3) as pale yellow crystals. mp: 228.4 ° C. ¹ H-NMR (CD ₃ OD / CDCl ₃ = 1/40, 4
00 MHz): δ = 4.59 (2H, s) 5.13 (2H, s) 5.44 (2H, s) 6.84 (1H, dd, J = 2Hz, 8Hz) 6.91 (1H, d) , J = 2 Hz) 6.94 (1H, brs) 7.03 (1H, s) 7.04 (1H, d, J = 8Hz) 7.11 (2H, d, J = 9Hz) 7.59 (1H , T, J = 7 Hz) 7.63 (1H, brs) 7.69 (1H, d, J = 8 Hz) 7.74 to 7.82 (1H, m) 7.82 (2H, d, J = 9 Hz) ) 7.87 (1H, d, J = 8 Hz) 8.09 (1H, d, J = 8 Hz) 8.26 (1H, d, J = 8 Hz) IR (KBr) cm ⁻¹ : 3415, 3267, 313
6,1632, 1610, 1510, 1508, 148
5,1400,1398,1311,1255,118
0,839

[Pharmacological Experiment 1] Thromboxane A ₂ synthase inhibitory action Rabbit platelet homogenate 20 μL (5 μg protein), 1
50 μL of 00 mM Tris-hydrochloric acid buffer (pH 7.4) and 10 μL of the test compound solution (the above Tris-hydrochloric acid buffer containing 1% dimethylsulfoxide) were mixed and mixed.
After pre-incubating at 5 ° C. for 5 minutes, 20 μmL of prostaglandin H ₂ solution (5 μM, the above Tris-HCl buffer containing 1.8% acetone) as a substrate was added, and 4
The reaction was carried out by incubating at 5 ° C for 5 minutes. And stop solution [0.9% NaCl, 0.1% bovine serum albumin and 1 μM OKY-046 (Eur. J. Pharmacol. 9
1, 41 (1983)) hydrochloric acid-containing 100 mM phosphate buffer] was added to stop the reaction. Using 50 μL of the above reaction solution, the amount of thromboxane B ₂ (TXB ₂ ) produced (TXA ₂ is unstable in the buffer solution and is converted into TXB ₂ ) is measured by an enzyme immunoassay method (Amersham Thromboxane EIA system). The method used). The inhibition rate of the test compound was calculated by the following formula, and TXB ₂
The concentration at which production was inhibited by 50% (IC ₅₀ ) was determined.

[0184]

[Equation 1]

(Note) Control: value when test compound is not added Blank: value when stop solution is added before substrate

[Pharmacological Experiment 2] Leukotriene D ₄ Antagonistic Action A membrane fraction was prepared from the lungs of male guinea pigs (Hartley system) by the method described below. Tissue was buffered [50 mM Tris-HCl, pH 7.4, soybean trypsin inhibitor (15 μg / mL), bacitracin (10).
0 μg / mL), benzamidine (10 μg / mL),
PMSF (10 μM)] in a homogenizer (YAM
ATO Ultra-Disperser) was used for homogenization. The homogenate was 10 at 1000 xg and 50000 xg each.
Centrifuge for minutes. The precipitate was resuspended in a buffer solution (50 mM Tris-hydrochloric acid, pH 7.4) and homogenized with a homogenizer. The homogenate was centrifuged at 50,000 xg for 10 minutes and the precipitation was repeated. The final pellet was resuspended in buffer and stored at -80 ° C. Membrane preparation (25
0 μg protein / mL) is [3H] leukotriene D4
(0.5 nM) (NEN, specific activity: 4699 GBq / mmol) and final dose of 250 μL with test compound
Buffer solution (50 mM Tris-HCl, pH 7.4, 10 m
_{M-CaCl 2, 10mM-MgCl} 2, at 25 ° C. in 10mM- cysteine) in and incubated for 30 min. After the reaction, suction filtration was performed with a filter (Whatmann GF / C) using a cell harvester (Brandel M-48R). The filter was washed 3 times with 3 mL of a washing buffer (50 mM Tris-HCl, pH 7.4), and the radioactivity captured on the filter was measured by a liquid scintillation counter (Aloka LSC-3600). The inhibition rate of the test compound was calculated by the following formula.

[0187]

[Equation 2]

The test results of Pharmacological Experiments 1 and 2 for each compound of the present invention synthesized in each Synthesis Example are shown in Table 1 below.

[0189]

[Table 1] Table 1 ──────────────────────────────────── Compound TXA ₂ IC ₅₀ (M ) LTD ₄ (10 ^-5 M%) ──────────────────────────────────── Ozagrel 2.0 × 10 ^-9 −−− Pranlukast −−− 100 ───────────────────────────────────── I-1 3.6 × 10 ^-9 100 I-2 1.4 × 10 ^-9 90 II-1 2.0 × 10 ^-9 60 II-2 3.2 × 10 ^-9 87 II-3 4.4 × 10 ^-9 99 II-4 1.0 × 10 ^-9 95 III-1 8.9 × 10 ^-7 98 III-2 7.2 × 10 ^-11 97 IV-1 <1.0 × 10 ^-8 67 IV-2 9.4 × 10 ^-8 99 IV-4 3.2 × 10 ^-8 92 IV-5 1.0 × 10 ^-7 72 IV-6 1.0 × 10 ^-7 57 ────────────────────────────────────

The above test compounds I-1, I-2, II-1,
II-2, II-3, II-4, III-1, III-1, IV-1, IV
-2, IV-4, IV-5, and IV-6 are referred to herein as
These are the compounds described as specific examples and synthetic examples. First
As is clear from the results shown in the table, the compound of the present invention has a thromboxane A ₂ synthase inhibitory action and, at the same time, an excellent leukotriene D ₄ antagonistic action.

[Pharmacological Experiment 3] Thromboxane A ₂ Synthase Inhibitory Action (Animal Experiment) A test compound was orally administered to male Wistar rats,
One hour later, the abdomen was opened under ether anesthesia, and blood was collected from the abdominal aorta (2 mL). Collected blood at 37 ° C for 2 hours,
After incubation, 10 minutes, 1600 × g
Serum was obtained by subjecting to serum. The amount of thromboxane B ₂ (TXB ₂ ) produced in this serum (TXA ₂ is unstable in the buffer and is converted into TXB ₂ ) was measured by the enzyme immunoassay method (Amersham thromboxane EIA).
The method using the system). The inhibition rate of the test compound was calculated by the method described in Pharmacological Experiment 1 above.

[Pharmacological Experiment 4] Leukotriene D ₄ Induced Action of Vascular Permeability Enhancement The back of a guinea pig was shaved with an electric clipper, and after 3 hours or more, it was used for the experiment. The test compound was orally administered to guinea pigs, and 1 hour after that, Evans blue (0.5 mL) was administered from the hindlimb vein of the guinea pigs.
Was administered orally and immediately after that, leukotriene D ₄ (LTD
₄ ) and physiological saline were orally administered into the dorsal skin at 50 μL / site. Thirty minutes later, exsanguination was performed, and the blue spots caused by LTD ₄ stimulation were collected from the skin. Dip the collected skin in an aqueous potassium hydroxide solution (1 mL) and
The hydrolysis was carried out at 7 ° C. for 18 hours. Phosphoric acid (2.5 mL) and acetone (6.5 mL) were added to this solution, mixed, and then centrifuged at 1600 xg for 15 minutes to measure the amount of Evans blue in the supernatant using a spectrophotometer, The absorption value at 620 nm was measured to determine the inhibition rate with respect to the control.

Table 2 below shows the test results of Pharmacological Experiments 3 and 4 for each compound of the present invention synthesized in each Synthesis Example.

[0194]

[Table 2] Table 2 ──────────────────────────────────── Compound TXA ₂ LTD ₄ ── ────────────────────────────────── IV-2 11.7% (10 mg / kg) 35.0% (10 mg / kg) IV-3 33.7% (10 mg / kg) 50.0% (10 mg / kg) 64.5% (50 mg / kg) 74.5% (50 mg / kg) ────── ──────────────────────────────

The above compounds IV-2 and IV-3 are the compounds described in each specific example and synthetic example. As is clear from the results shown in Table 2, the compound of the present invention has a thromboxane A ₂ synthase inhibitory action and, at the same time, an excellent leukotriene D ₄ antagonistic action.

[0196]

INDUSTRIAL APPLICABILITY The quinoline derivative of the present invention represented by each of the above general formulas is useful for diseases in which TXA ₂ or LTD ₄ is involved. Therefore, for example, the quinoline derivative of the present invention can be used as a therapeutic agent for cerebral infarction, a therapeutic agent for bronchial asthma or a therapeutic agent for allergic diseases.

Continuation of front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display area C07D 233: 56 307: 78)

Claims (8)

[Claims] 1. A quinoline derivative represented by the following formula (I) and a pharmacologically acceptable salt thereof. Embedded image (A ¹ is -CO ₂ R ¹¹ , -CN, -CONHSO ₂ R
¹² , -CONR ¹³ R ¹⁴ , -OR ¹⁵ , tetrazolyl or substituted tetrazolyl, wherein R ¹¹ , R ¹³ , R ¹⁴ and R
¹⁵ is a hydrogen atom, an alkyl or an alkali metal, and R ¹² is a hydrogen atom, an alkyl, a haloalkyl,
Aryl or aralkyl, and the substituent of the substituted tetrazolyl is alkyl, carboxyalkyl or alkoxycarbonylalkyl; L ¹¹ is a single bond or alkylene having 1 to 6 carbon atoms; X ¹
Is a nitrogen-containing heterocyclic group; L ¹² is a single bond or alkylene having 1 to 6 carbon atoms; L ¹³ is a single bond or alkylene having 1 to 6 carbon atoms; Y ¹
Is an oxygen atom or a sulfur atom; L ¹⁴ is a single bond or alkylene having 1 to 6 carbon atoms; and a double line consisting of a broken line and a solid line means a single bond or a double bond. ) 2. A quinoline derivative represented by the following formula (Ia) and a pharmacologically acceptable salt thereof. Embedded image (A ¹ and X ¹ have the meanings of claim 1,
"L" is 1 or 2, m is 1, 2 or 3, and n is 1 or 2.) 3. A quinoline derivative represented by the following formula (II) and a pharmacologically acceptable salt thereof. Embedded image (A ² is -CO ₂ R ²¹ , -CN, -CONHSO ₂ R
²² , -CONR ²³ R ²⁴ , -OR ²⁵ , tetrazolyl or substituted tetrazolyl, wherein R ²¹ , R ²³ , R ²⁴ and R
²⁵ is a hydrogen atom, an alkyl or an alkali metal respectively, and R ²² is a hydrogen atom, an alkyl, a haloalkyl,
Aryl or aralkyl, and the substituent of the substituted tetrazolyl is alkyl, carboxyalkyl or alkoxycarbonylalkyl; L ²¹ is a single bond or alkylene having 1 to 6 carbon atoms; X ²
Is a nitrogen-containing heterocyclic group; L ²² is a single bond or alkylene having 1 to 6 carbon atoms; L ²³ is a single bond or alkylene having 1 to 6 carbon atoms; Y ²
Is an oxygen atom or a sulfur atom; and L ²⁴ is a single bond or alkylene having 1 to 6 carbon atoms) 4. A quinoline derivative represented by the following formula (II-a) and a pharmacologically acceptable salt thereof. [Chemical 4] (A ² and X ² have the same meaning as in formula (II) of claim 3, "l" is 1 or 2, m is 1, 2 or 3, and n is 1 or 2) 5. A quinoline derivative represented by the following formula (III) and a pharmaceutically acceptable salt thereof. Embedded image (A ³ is -CO ₂ R ³¹ , -CN, -CONHSO ₂ R
³² , -CONR ³³ R ³⁴ , -OR ³⁵ , tetrazolyl or substituted tetrazolyl, wherein R ³¹ , R ³³ , R ³⁴ and R
³⁵ is a hydrogen atom, alkyl, carboxyalkyl or alkali metal, respectively, R ³² is a hydrogen atom, alkyl, haloalkyl, aryl or aralkyl, and the substituent of the substituted tetrazolyl is alkyl, carboxyalkyl or alkoxycarbonylalkyl. L ³¹ is a single bond or alkylene having 1 to 6 carbon atoms; X ³ is a nitrogen-containing heterocyclic group; L
³² is a single bond or alkylene having 1 to 6 carbon atoms; L ³³ is a single bond or alkylene having 1 to 6 carbon atoms; Y ³ is an oxygen atom or a sulfur atom; L ³⁴ is a single bond or has 1 to 6 carbon atoms.
Is an alkylene) 6. A quinoline derivative represented by the following formula (III-a) and a pharmacologically acceptable salt thereof. [Chemical 6] (A ³ and X ³ have the same meanings as in formula (III) of claim 5, "l" is 1 or 2, m is 1, 2 or 3, and n is 1 or 2) 7. A quinoline derivative represented by the following formula (IV) and a pharmacologically acceptable salt thereof. [Chemical 7] (A ⁴ is -CO ₂ R ⁴¹ , -CN, -CONHSO ₂ R
⁴² , -CONR ⁴³ R ⁴⁴ , -OR ⁴⁵ , tetrazolyl or substituted tetrazolyl, wherein R ⁴¹ , R ⁴³ , R ⁴⁴ and R
⁴⁵ is a hydrogen atom, alkyl, carboxyalkyl or alkali metal, respectively, R ⁴² is a hydrogen atom, alkyl, haloalkyl, aryl or aralkyl, and the substituent of the substituted tetrazolyl is alkyl, carboxyalkyl or alkoxycarbonylalkyl. L ⁴¹ is a single bond or alkylene having 1 to 6 carbon atoms; X ⁴ is a nitrogen-containing heterocyclic group;
⁴² is -CONH- or -NHCO-; L ⁴³
Is a single bond or alkylene having 1 to 6 carbon atoms; Y ⁴ is an oxygen atom or a sulfur atom; and L ⁴⁴ is a single bond or alkylene having 1 to 6 carbon atoms) 8. A quinoline derivative represented by the following formula (IV-a) and a pharmacologically acceptable salt thereof. Embedded image (A ⁴ , X ⁴ and L ⁴² are respectively represented by the formula (I
V) has the same meaning as "l" is 1 or 2 and n is 1 or 2.)