WO1996010569A1 - Quinoline derivative - Google Patents

Abstract

A novel quinoline derivative useful in treating diseases relative to TXA2 or LTD4 and usable as a remedy for cerebral infarction, bronchial asthma or allergic diseases. This novel quinoline derivative has a characteristic chemical structure wherein an acidic group or derivative thereof is bonded to a benzofuran (or phenyl) group having a heterocyclic group via linkage groups composed of alkylene (or -NHCO- or -CONH-), phenylene and alkylene.

Description

 Specification

 Quinoline derivatives

 [Technical field]

The present invention relates to novel quinoline derivatives. The present invention particularly relates to a quinoline derivative which is effective as a novel anti-allergic agent having TXA ₂ synthase P harmful activity and LTD ₄ antagonistic activity.

[Background technology]

 The arachidonic acid metabolites brostaglandin (PG.), Thromboxane (TX) or leukotriene (LT) have a wide variety of physiological, pathological and pharmacological actions and are involved in various diseases. *Are known.

Among, TXA ₂ is a analogue of Bok Ronbokisan is known to be a potent blood / H¾ simultaneously potent smooth muscle contractile agents If it is aggregated material. Therefore, the known TXA ₂ synthase inhibitor (E) —3- [p— (1H-imidazole-11-ylmethyl) phenyl] propenoic acid (generic name: ozagrel) and its sodium salt are It is known that it is useful as a therapeutic agent for asthma or cerebral thrombosis (Japanese Patent Application Laid-Open No. 55-313). Ozagrel has the following chemical structure, and its structural features include an imidazole structure and an acidic group (carboxyl). Substances having TXA ₂ synthase inhibitory activity having similar characteristics include, in addition to ozagrel, 1- [3- (4-benzhydryl-1-1-biperazinyl) propyl] 13- (1H-imidazole-1-ylmethyl 1) H-indole-1-carboxylic acid (as described in WO 93/20065) and (E) -3- [3- (1H-imidazole-1-ylmethyl) 1-2-methyl-1 H—Indone-l-yl] propanoic acid (described in 丄 Med. Chem. 1986, 29, p342) is known.

(Ozagrel)

Leukotriene also has various analogs. Among the analogs, LTD ₄ is known to have an effect of causing bronchoconstriction, enhancing mucus secretion, and enhancing vascular permeability. For this reason, 8- [P- (4-phenylbutoxy) benzoyl] amino-2- (tetrazol-5-yl) 1-4 H-oxo-4 H-1 Benzovirane (Generic name: pranluca), which has LTD * antagonistic activity Has been reported to be useful as an antiallergic agent (JP-A-61-50977). This branlukast has the following chemical structure, and its structural features are that it has an arylalkyloxyphenyl structure and an acidic group (tetrazole). Compounds having similar characteristics include 5- [2- [4-1- (quinolin-12-ylmethyloxy) phenyloxymethyl] phenylmethyl] tetrazole (described in U.S. Pat. No. 4,939,011), quinoline 12-ylmethyoxyphenylalkanoic acid derivatives (described in European Patent Publication Nos. 349062, 339416 and 344519), and 11- (quinoline-2-ylmethoxyphenyl) having an acidic group as a substituent methyl) indole (mounting serial in JP-a-5 345 778) are known power ^s. However, for Ozagureru and both pharmacological action of Buranru Kast (TXA ₂ synthase inhibitory activity and LTD antagonism) together with reduction compound, not known.

(Pranle Cast)

An object of the present invention is to provide a novel compound having TXA ₂ synthase inhibitory activity and LTD antagonistic activity.

[Disclosure of the Invention]

The present inventor has been conducting research on antiallergic agents. The inventors have found that all of the quinoline derivatives represented by (IV) to (IV) have both TXA ₂ synthase inhibitory activity and LTD antagonism, and completed the present invention.

(I)

(A ¹ is one C0 ₂ R '', one CN, -CONHSOz R ^12, one ^{C0NR 13 R '4, -OR'} 6, a tetrazolyl or substituted ^{tetrazolyl, R 'l, R 13,} R " Contact And R ¹⁶ are each a hydrogen atom, an alkyl or an alkali metal, R ′ ² is a hydrogen atom, an alkyl, a haloalkyl, an aryl or an aralkyl, and the S substituent of the substituted tetrazolyl is an alkyl, carboxyalkyl or alkoxycarbonyl L is a single bond or an alkylene having 1 to 6 carbon atoms; X 'is a nitrogen-containing heterocyclic group; L' ² is a single bond or an alkylene having 1 to 6 carbon atoms. L ¹³ is a single bond or an alkylene having 1 to 6 carbon atoms; Y ′ is an oxygen atom or a sulfur atom; L ″ is a single bond or 1 to 6 carbon atoms Is an alkylene of 6 Then, the two main ing from the broken line and the solid line means a single bond or a double bond)

(Π)

(A ^a is -C0 ₂ R ^a \ -CN, -CONHSO ^ R ²² , one C0NR ²³ R ^a4 , -OR ", a tetrazolyl or substituted Te Bok Razoriru, R ^2l, R ^23, Contact and R ^2S are each a hydrogen atom, an alkyl or an alkali metal, R ²² is a hydrogen atom, alkyl, haloalkyl, Ariru or Aralkyl, and the substituent of the substituted tetrazolyl is alkyl, carboxyalkyl or alkoxycarbonylalkyl; L ²¹ is a single bond or an alkylene having 1 to 6 carbon atoms; X ² is is nitrogen heterocycles璟基; L ²² represents a single bond or a carbon atoms is alkylene of 1 to 6; L ²³ represents a single bond or a carbon atoms is alkylene of 1 to 6; Y ² represents an oxygen Is an atom or a sulfur atom; and L "is a single bond or an alkylene having 1 to 6 carbon atoms.

(ΠΙ)

(A ³ are, -C0 ₂ R ^31, one CN, -C0NHS0 ₂ R ^32, one C0NR ³³ R ", a -OR ^86, tetrazolyl or conversion ^{tetrazolyl, R 3 ', R 33,} R" Contact and R "Is a hydrogen atom, alkyl, carboxyalkyl or alkali metal, respectively, R" is a hydrogen atom, alkyl, haloalkyl, aryl or aralkyl, and the substituent of the substituted tetrazolyl is alkyl, carboxyalkyl or L ³¹ is a single bond or an alkylene having 1 to 6 carbon atoms; X ^s is a nitrogen-containing heterocyclic group; L ^3Z is a single bond or 1 carbon atom. or is a 6 alkylene; L ³³ represents a single bond or a carbon atoms is alkylene of 1 to 6; Y ³ is an oxygen atom or a sulfur atom; and is a single bond or a carbon atoms 1 to 6 Is an alkylene) (IV)

(A ⁴ shows an C0 ₂ R a ', one CN, -CONHSO2 R ^42, one C0NR ⁴³ R ", -OR ^45, tetrazolyl or g conversion tetrazolyl, R, R', R" Contact and are each Is a hydrogen atom, alkyl, carboxyalkyl or alkali metal, is a hydrogen atom, alkyl, haloalkyl, aryl or aralkyl, and the S substituent of substituted tetrazolyl is alkyl, carboxyalkyl or alkoxycarbonylalkyl L ⁴¹ is a single bond or an alkylene having 1 to 6 carbon atoms; X ⁴ is a nitrogen-containing heterocyclic group; is one CONH— or one NHCO—; L ⁴³ is Is a single bond or an alkylene having 1 to 6 carbon atoms; is an oxygen atom or a sulfur atom; and is a single bond or an alkylene having 1 to 6 carbon atoms)

[Best Mode for Carrying Out the Invention]

 Hereinafter, the formulas (I) to (IV) will be described in detail.

In formula (I), A ¹ is a derivative of an acidic group or an acidic group, specifically -C0 ₂ R ^ll, one ^{CN, -CONHSO2 R l2, -CONR,} s R '\ -OR 15, tetrazolyl Or a substituted tetrazolyl. One C0 ₂ and tetrazolyl preferably, a C0 ₂ R ¹¹ forces particularly preferred.

R ″, R ¹³ , R ¹⁴ and R ¹⁶ are each a hydrogen atom, alkyl or alkali metal. The R ^ia represents a hydrogen atom, alkyl, haloalkyl, was Ariru or a Ararukiru. The substituent of the substituted tetrazolyl is alkyl, carboxyalkyl or alkoxycarbonylalkyl. The alkyl and alkoxy preferably have 1 to 6 carbon atoms. Examples of alkyl include methyl Le, ethyl and provir. 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 aryls include phenyl and naphthyl. Examples of the above aralkyls include benzyl, phenethyl and benzhydryl. The carboxyalkyl preferably has 2 to 7 carbon atoms. Examples of carboxyalkyl include carboxyethyl. The alkoxy portion and the alkyl portion of the alkoxycarbonylalkyl preferably have 1 to 6 carbon atoms, respectively. Examples of the alkoxycarbonylalkyl include ethoxycarbonylethyl.

In the formula (I), L ¹ ′ is a single bond or an alkylene having 1 to 6 carbon atoms. A single bond or an alkylene having 1 to 3 carbon atoms is preferred, and methylene and ethylene are preferred. L ¹¹ is the 3-, 4-, 5- or 6-position of a benzo [b] furan ring, or the 2-, 3-, 4-, or 5-position of a 2,3-dihydrobenzo [b] furan ring Or it can be linked to position 6. L ^'1 is Rukoto force to bind to the 5-position of the ring ⁵ particularly preferred.

 X ′ is a nitrogen-containing heterocyclic group. The nitrogen-containing heterocyclic ring preferably has 3 to 7 members, more preferably 5 or 6 members. The number of nitrogen atoms contained in the heterocyclic ring is preferably 1 to 3. The atoms constituting the heterocyclic ring are preferably composed of only a nitrogen atom and a carbon atom. Further, it is preferable that the heterocyclic ring is unsaturated and has aromaticity. The complex may have a substituent. Examples of the substituent include alkyl. The alkyl has preferably 1 to 6 carbon atoms. Examples of alkyl include methyl and ethyl. Examples of the nitrogen-containing hetero II group include imidazolyl and pyridyl. Imidazolyl, particularly imidazolyl, is preferred.

In the formula (I), L ¹² is a single bond or alkylene having 1 to 6 carbon atoms. A single bond or an alkylene force having 1 to 4 carbon atoms is preferable, and an alkylene force having 1 to 3 carbon atoms i is particularly preferable.

^Lia is a single bond or alkylene having 1 to 6 carbon atoms. Single bond or Is preferably a methylene atom, and a single bond is particularly preferred.

L ¹² and L ^'3, to the benzene ring interposed, ortho, may be attached at any position of the meta and para.

V ¹ is an oxygen atom or a sulfur atom. An oxygen atom is preferred.

 L "is a single bond or an alkylene having 1 to 6 carbon atoms. Alkylene having 1 to 3 carbon atoms is preferable, and methylene or ethylene is particularly preferable. L" is 2-position of the quinoline ring. It is preferable to bind to

 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 preferred that the condensed ring containing an oxygen atom represented by the formula (I) be a benzo [b〗 furan ring].

 Particularly preferred quinoline derivatives are represented by the following formula (I-a).

(I-a)

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

In formula (II), A ² is a derivative of an acidic group or an acidic group, in particular one C0 ₂ R ", one CN, -CONHSO2 R ^22, one C0NR ²³ R ^24, -OR ^25, tetrazolyl or substituted tetrazolyl. one C0 ₂ R ² 'and tetrazolyl, and particularly preferably one C0 ₂ R ^21.

R ²¹ , R ^2a and R ″ are each a hydrogen atom, an alkyl or an alkali metal. R ^aa is a hydrogen atom, an alkyl, a haloalkyl, an aryl or an aralkyl. The substituent of the substituted tetrazolyl Is an alkyl, carboxyalkyl or alkoxyl alkenylalkyl. The alkyl preferably has 1 to 6 carbon atoms.Examples of alkyl include methyl, ethyl and Propyl. Examples of the alkali metal include sodium and potassium. The haloalkyl preferably has 1 to 6 carbon atoms. Examples of haloalkyl include chloromethyl, cloethyl, and fluoroethyl. Examples of the above aryls include phenyl and naphthyl. Examples of the above aralkyls include benzyl, phenethyl and Benzhydryl forces. The carboxylalkyl preferably has 2 to 7 carbon atoms. Examples of carboxyalkyl include carboxyethyl carb. The alkoxycarbonyl and alkyl portions of the alkoxycarbonylalkyl preferably have 1 to 6 carbon atoms, respectively. Examples of the alkoxycarbonylalkyl include ethoxycarbonylethyl.

In formula (II), L ^{2 1} is a single bond or a carbon atoms is an alkylene of 1 to 3. Alkylene forces having 1 or 2 carbon atoms are particularly preferred. L ^{2 1} is 3-position of the benzene ring, 4-position, can be attached to the 5-position or 6-position. L ^{2 1} is particularly preferably bound to the 4-position.

X ² is a nitrogen-containing heterocyclic group. The nitrogen-containing heterocycle is preferably a 3- to 7-membered ring, more preferably a 5- or 6-membered ring. The number of nitrogen atoms contained in the heterocycle is preferably 1 to 3. The atoms constituting the heterocyclic ring are preferably composed of only a nitrogen atom and a carbon atom. Further, the complex is preferably unsaturated and has aromaticity. The heterocyclic ring may have a substituent. Examples of the substituent include alkyl. The alkyl has preferably 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 imidazole-1-ylka, is preferred.

In the formula (II), L ²² is a single bond or an alkylene having 1 to 4 carbon atoms. Alkylene having 1 to 3 carbon atoms is particularly preferred.

L ²³ is a single bond or methylene. Single bonds are preferred. L ²² and L ^23, to the benzene ring interposed, Ol Bok, may be attached at any position of the meta and para.

Y ^a is oxygen atom or sulfur atom. An oxygen atom is preferred. L "is a single bond or alkylene having 1 to 3 carbon atoms. Methylene or ethylene is particularly preferable. L" is a bond capable of bonding to the 2-position of quinoline i is preferable. .

In the formula (Π), the partial structure represented by one CH = CHA ² may be a trans type or a cis type.

 Particularly preferred quinoline derivatives are represented by the following formula (II-a).

(Π-a)

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

In formula (ΠΙ), A ³ is a derivative of an acidic group or an acidic group, in particular one C0 ₂ R ", one ^{CN, -CONHSO2 R '2, -C0NR} a3 R 3 \ -OR 36. Tetrazolyl or B conversion tetrazolyl. one 0R ^{the as,} one C0 ₂ R ³¹ and Te Torazoriruka preferably, particularly preferred C0 ₂ R ^ai is. a ³ may be coupled to the position of the arbitrary benzene ring. a ³ is this a force i particularly preferably bonded to a position adjacent to the following L ^32.

R ³ ′, R ″ and R ^as are each a hydrogen atom, alkyl, carboxyalkyl or alkali metal. R ³² is a hydrogen atom, alkyl, haloalkyl, aryl or aralkyl. The substituent is alkyl, carboxyalkyl or alkoxycarbonylalkyl, wherein the alkyl has preferably 1 to 6. Examples of alkyl include methyl, ethyl and propyl. Examples include sodium and potassium forces. The haloalkyl preferably has 1 to 6 carbon atoms. Examples of haloalkyl include chloromethyl, chloroethyl and fluoro. Includes ethyl. Examples of the above aryl include phenyl and naphthyl. Examples of the above aralkyls include benzyl, phenethyl and benzhydryl. The carboxyalkyl preferably has 2 to 7 carbon atoms. Examples of carboxyalkyl include carboxymethyl and carboxyethyl. The alkoxy and alkyl portions of the alkoxycarbonylalkyl preferably have 1 to 6 carbon atoms. Examples of the alkoxycarbonylalkyl include ethoxycarbonylethyl.

In the formula (III), L ³ ′ is a single bond or alkylene having 1 to 3 carbon atoms. Alkylene having 1 or 2 carbon atoms is particularly preferred. L ³ 'can be bonded to any position on the benzene ring. L ³ ′ is particularly preferably a compound that binds to position 4 (the binding position of A ³ is position 1).

X ³ is a nitrogen-containing heterocyclic group. The nitrogen-containing heterocycle is preferably a 3- to 7-membered ring, more preferably a 5- or 6-membered ring. The number of nitrogen atoms contained in the heterocycle is preferably 1 to 3. The atoms constituting the complex are preferably composed of only a nitrogen atom and a carbon atom. Further, it is preferable that the heterocyclic ring is unsaturated and has aromaticity. The heterocyclic ring may have a substituent. Examples of the substituent include alkyl. The alkyl has preferably 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 imidazole-11-yl, is preferred.

In the formula (III), L ³² is a single bond or alkylene having 1 to 4 carbon atoms. Alkylenes having 1 to 3 carbon atoms are particularly preferred.

Is a single bond or methylene. Single bonds are preferred. L ³² and L ", to the benzene ring interposed, ortho, it may be attached at any position of the meta and para.

Y ³ is an oxygen atom or a sulfur atom. An oxygen atom is preferred.

Is a single bond or an alkylene having 1 to 3 carbon atoms. The ability to be methylene or ethylene is particularly preferred. L "is preferably a force capable of bonding to the 2-position of the quinoline ring. Particularly preferred quinoline derivatives are represented by the following formula (III-a):

(ΠΙ-a)

In the formula, A ³ and X ³ have the same meaning as in formula (III). “Γ1” is 1 or 2. m is 1, 2 or 3. n is 1 or 2. Further, the positional relationship between 1- (CH ₂ ) „0- and-(CH ₂ ) m- attached to the benzene ring is preferably a meta- (m) or para- (p) positional relationship.

In formula (IV), A ⁴ is a derivative of an acidic group or an acidic group, one particular C0 ₂ R ⁴ is the 'one CN, -CONHSOa R ^42, one CONR "R", -OR ^46, tetrazolyl Or a substituted tetrazolyl. One C0 ₂ R ⁴ one OR "and Te Torazoriru preferably one OR" force i particularly preferred. Can be bonded to any position of the benzene, but it is particularly preferable to bond to the position adjacent to the following or the position next to the position below.

The above R ", R", R "and R" are each a hydrogen atom, an alkyl, a carbonyloxyalkyl or an alkali metal. Is a hydrogen atom, alkyl, amino, alkyl, aryl or aralkyl. The substituent of the above substituted tetrazolyl is alkyl, carboxyalkyl or alkoxycarbonylalkyl. The alkyl has preferably 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, chloromethyl and fluormethyl. Examples of the above aryl include phenyl and naphthyl. Examples of the above aralkyls include benzyl, phenethyl and benzhydryl. The carboxyalkyl preferably has 2 to 7 carbon atoms. Examples of carboxyalkyl include carboxymethyl and carboxyethyl. The alkoxy and alkyl portions of the alkoxycarbonylalkyl preferably have 1 to 6 carbon atoms. Examples of the alkoxycarbonylalkyl include ethoxycarbonylethyl.

In formula (IV), L "represents a single bond or the number of carbon purple atom is alkylene of 1 to 3. Alkylene force of carbon atoms 1 to 2 i particularly preferred. L ^{4 1} may be any of a benzene ring It is particularly preferred that the bond to position ⁴ or 5 (the position of A4 binding is position 1).

X ⁴ is a nitrogen-containing heterocyclic group. The nitrogen-containing heterocycle is preferably a 3- to 7-membered, more preferably a 5- or 6-page ring. The number of nitrogen atoms contained in the heterocycle is preferably 1 to 3. The atoms constituting the heterocyclic ring are preferably composed of only a nitrogen atom and a carbon atom. Further, the complex is preferably unsaturated and has aromaticity. The heterocyclic ring may have a substituent. Examples of the substituent include alkyl. The alkyl has preferably 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 imidazole-1-ylka, is preferred.

 In the formula (IV), L "is one C ONH— or one NHCO—.

L ^4a is a single bond or methylene. Single bonds are preferred. And may be bonded to the intervening benzene ring at any of ortho, meta and para positions.

 Is an oxygen atom or a sulfur atom. An oxygen atom is preferred.

 L "is a single bond or an alkylene having 1 to 3 carbon atoms. Methylene or ethylene is particularly preferable. It is preferably bonded to the 2-position of the quinoline ring.

 Particularly preferred quinoline derivatives are represented by the following formula (IV-a).

Two (IV-a)

Wherein A ⁴ , X ⁴ and L ⁴² have the same meaning as in formula (IV). "1 J is 1 or 2. n is 1 or 2. One (CH _a )„ one and one L attached to the benzene ring is the same as the meta ( _m ). Power ^{5 is} preferred.

In the above formulas, the quinoline ring to which L ", L", L "or is bonded may have a substituent. Examples of the substituent 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. Has preferably 1 to 6. Examples of alkoxy include methoxy and ethoxy.

Examples of the pharmacologically acceptable salts of the compounds of the present invention include acidic salts such as hydrochloric acid and acetic acid and basic salts such as alkali metals (eg, sodium and potassium).

 Hereinafter, specific examples of the quinoline derivatives represented by the formulas (I) to (IV) are shown.

 (I-1) 5- (imidazole- 1 -ylmethyl) 1 7-[4-1 (quinoline-1-2-methyloxy) phenylmethyloxy] benzo [b] Furan-1-carboxylic acid

(1-1)

(1 -2) 5- (imidazoyl-1-ylmethyl) —7— [3- (quinoline-1-ylmethyloxy) phenylmethyloxy] benzo [b〗 furan-1-carbonic acid

 (1-2)

(1-3) 5- (imidazole-1-ylmethyl) 1 7— [2— (quinoline 1 2- (methylmethyloxy) phenylmethyloxy] benzo [b] furan-1-carbonic acid

 (1-3)

(1 -4) 5- [5- (imidazole-l-^-methyl) -1- 7- [4- (quinoline-l-ylmethyloxy) phenylmethyloxy] benzo [b] furan-l-yl] tetrazole

 (1-4)

 (1 -5) 5- (imidazole-1-ylmethyl) 1 7— [4-1 (quinoline-1-ylmethyloxy) phenylmethyloxy] benzo [b] furan-1-ethyl carboxylate

(1-5)

(1 -6) 5— (imidazole-1-ylmethyl) 1 7— [4- (quinoline-1-ylmethyloxy) phenylmethyloxy] benzo [b] furan-1-carbonic acid

 (1-6)

(1 -7) 5- [5- (imidazole-1-ylmethyl) 1 7— [4-1 (quinoline-1-ylmethyloxy) phenylmethyloxy] benzo [b] furan-1-yl] 1-1-1 Methyltetrazole dihydrochloride

 (1-7)

(1 -8) 5- [5- (imidazole-1-ylmethyl) 1 7— [4-1 (quinoline-1-ylmethyloxy) phenylmethyloxy] benzo [b] furan-1-yl] 1 2— Methyl tetrazole dihydrochloride

(1-8)

(1 -9) 5— (imidazole-1-ylmethyl) 1 7— [4- (quinoline-1-ylmethyloxy) phenylmethyloxy] benzo [b] furan-1-carboxamide

 (1-9)

(1-10) N— [5- (imidazole-1-ylmethyl) 1 7— [4-1 (quinoline-2-ylmethyloxy) phenylmethyloxy] benzo [b] furan-1-2-carbonyl〗 1-2-methylbenzene Sulfonamide

 (M0)

(II-1) trans-3- (4- (imidazole-11-ylmethyl) -12- [3- (quinoline-12-ylmethyloxy) phenylmethyloxy] phenyl] butanoic acid

(IM)

(Π-2) cis-1- [4-1- (imidazole-1-ylmethyl) 1-2- [3- (quinoline-1-ylmethyloxy) phenylmethyloxy] phenyl] bronamic acid

(II-1 3) trans 1-3- [4- (imidazole-11-ylmethyl) 1-2- [4- (quinoline-1-ylmethyloxy) phenylmethyloxy] phenyl] butanoic acid

(II-4) cis-3- (4-1 (imidazole-11-ylmethyl) -12- [4- (quinoline-12-ylmethyloxy) phenylmethyloxy] phenyl] butanoic acid (Π-4)

(II-5) Trans-N- [3-[4- (Imidazole-1-ylmethyl)]-[4- (quinoline-1-ylmethyloxy) phenylmethyloxy] ----] (E) -Bro Noyl] 1-methylbenzenesulfonamide

(Π-5)

(Π-6) trans-5- [2-[4- (imidazole-1-ylmethyl)]-[4- (quinoline-1-ylmethyloxy) phenylmethyloxy] phen.] Ether] tetrazole

₍ Chem. 34) ₍₍ . ₆₎

(III-1-1) 41- (imidazole-11-ylmethyl) -1-2- [3- (quinoline-ylmethyloxy) benzyloxy] benzoic acid (ΙΠ-1)

(III-2) 41- (imidazole-l-ylmethyl) -l 3- [3- (quinoline-ylmethyloxy) benzyloxy] phenoxysuccinic acid

 (ΠΙ-2)

(III-1 3) 4- (imidazo-1-ylmethyl) 1-3- [4- (quinoline-1-ylmethyloxy) benzyloxy] phenoxyacetic acid

 (ΙΠ-3)

(IV-1) 41- (imidazole-11-ylmethyl) 1-3- [3- (quinoline-ylmethyloxy) benzoylamino] phenoxyacetic acid (IV-1)

(IV—2) 4— [3— (imidazole-1-yl) provir] 1—2— [2-year-old Kiso 2-—3- (3- (quinoline-1-2-methylmethyloxy) phenylamino) ethyl〗 benzoic acid

 (IV-2)

(IV-3) 4- [3- (imidazole-11-yl) provir] 1-2- [2-year-old xo 2- [3- (quinoline-1-ylmethyloxy) phenylamino] ethyl] Methyl benzoate dihydrochloride

(IV-3)

(IV-4) 41- (imidazole-11-ylmethyl) -1-2- [3- (quinoline-ylmethyloxy) benzoylamino] phenoxyacetic acid

(IV-4)

(IV-5) 4- (imidazole-1-1-ylmethyl) -1-2- [4-1- (quinolin-1-ylmethyloxy) benzoylamino] phenoxysulfuric acid

 (IV-5)

 (IV-6) 4— (imidazo-1-ylmethyl) 13- [4-1 (quinolin-1-ylmethyloxy) benzoylamino] phenoxyacetic acid

(IV-6)

0 8 C0 ₂ H The quinoline derivative represented by the formula (I) can be synthesized, for example, by the following synthetic route. The compounds represented by formulas (II), (III) and (IV) can be synthesized by the same synthetic route.

soa ₂ / CHa ₃

Formula ω The quinoline derivative of the present invention and a salt thereof both have an inhibitory action on tocopomboxane A ₂ synthase and an antagonistic action on leukotriene D <. Therefore, it is possible to use the compounds of the present invention as a therapeutic agent or prophylactic agent for a disease TXA ₂ or LTD ₄ are involved. The compound of the present invention is useful, for example, as a therapeutic or preventive agent for bronchial asthma, allergic disease, Sf inflammation, thrombosis, stroke, myocardial infarction, angina pectoris, ischemic cerebral circulation disorder.

The method of administering the compound of the present invention may be oral or parenteral. Oral dosage forms include tablets, capsules, powders, granules and syrups. You. Methods of parenteral administration include mucosal administration, body surface administration, vascular administration, and tissue administration. For mucosal administration, use as eye drops, inhalant, spray or suppository. In the case of administration to the body surface, it is used as a soft sox In the case of intravascular or intravascular administration, use as an injection.

 The above-mentioned oral administration preparation can be produced using ordinary excipients, disintegrants, binders, lubricants, pigments and diluents. As an excipient, glucose and lactose are generally used. Examples of disintegrants include starch and calcium carboxymethylcellulose. Lubricants include magnesium stearate and talc. As binders, hydroxybutyl cellulose, gelatin and polyvinylidone are used.

 Preparations for parenteral administration can also be produced in a usual manner. 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 0.1 to 200 mg / day for injection and 1 to 500 mg / day for oral administration for normal adults. Of course, the dosage will vary according to age, race, symptoms, etc.

 【Example】

 [Synthesis Example 1] 5- (imidazole-1-ylmethyl) 1 7- [4-1 (quinoline-1-ylmethyloxy) phenylmethyloxy] 1-benzo [b] furan-1 2-force 5), and 5— (imidazoyl-1-ylmethyl) 1-7— [4- (quinoline-1-ylmethyloxy) phenylmethyloxy] benzo [b] furan-2-fluorocarboxylic acid (I-1) Synthesis

 (1) Synthesis of 5-dimethylaminomethyl-2-hydroxy-3-methoxybenzaldehyde (The reaction formula is shown below)

A 35% aqueous solution of formalin (21.1 g, 246 mmol) and a 40% aqueous solution of dimethylamine (29.5 g, 262 mmol) were dissolved in ethanol (150 mL), and 0-vanillin (25.0 g, 164 mmol) was dissolved in ethanol. The mixture was heated under reflux for 5 hours. After cooling, the solvent was distilled off under reduced pressure, ether was added to the remaining port, and the solid was pulverized. The powder was collected and washed with ether. This was dried under reduced pressure to give 31.2 g (yield 90.9%) of the title compound (1) as a yellow crystalline powder. Melting point: 110.0-111.5

 Ή-NMR (CDC 1 a): 6 =

 2.25 (6H, s)

 3.39 (2H, s)

 3.93 (3H, s)

 7.09 (1 H, d, J = 2Hz)

 7.13 (1 H, d. J = 2 Hz)

 9.90 (1 H, s)

(2) Synthesis of 2-hydroxy-3-methoxy-5-methylbenzaldehyde (The reaction formula is as follows)

Under a nitrogen atmosphere, the above compound (1) (30.9 g, 148 mmol) was dissolved in acetic anhydride (150 mL), and the mixture was heated under reflux for 24 hours. After cooling, the reaction solvent was distilled off 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. As a result, chloromethyl crystals were precipitated in the reaction mixture. To this reaction mixture was added p-dioxane (120 ml) and dissolved by heating at 60-70. To this was added stannic chloride hydrate (50.1 _g , 222 mmol), and the mixture was heated under reflux for 30 minutes. After allowing to cool to room temperature, hydrochloric acid (60 mL) was added for dilution, and the mixture was extracted three times with black-mouthed form (200 mL). The obtained organic calendar was washed sequentially with 6N hydrochloric acid, water, and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: n-hexane Z ethyl acetate == 3Z1) to give 10.2 g of the title compound (2) (yield 41.6). %) As yellow crystals. H-NMR (CDC 1 a): 6 =

 2.34 (3H, s)

 3.90 (3H, s)

 6.94 (1 H, d, J = 1 Hz)

 6.95, (1 H, d, J = 1 Hz)

 9.85 (1 H, s)

 10.9 (1 H, s)

(3) Synthesis of ethyl 7-methoxy-5-methyl-2-benzofurancarboxylate (reaction formula is shown 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. Stirred for hours. After cooling to room temperature, water (200 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (50 mL). After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: n-ethyl ester = 4Z1) to give the title compound (3) 2. 63 g (yield 20.3%) were obtained as white crystals.

 Ή-NMR (CDC 1 a): δ =

 1.41 (3 Η, t. J = 7Hz)

 2.43 (3H.s)

3.99 (3H, s) 4.42 (2H, q, J = 7Hz)

 6.72 (1 H, s)

 7.02 (1 H, s)

 7.43 (1 H, s)

(4) Synthesis of 5-bromomethyl-17-methoxy-1-benzo [b] furancarboxylic acid ethyl ester (The reaction formula is shown below)

 Compound (3) (2.60 g, 11.1 mmol), NBS (= N-bromosuccinimide, 1.98 g, 11.1 mmol), AIBN (= azobisisobutyronitrile, 0.148 g, 0.902 mmol) ) Was suspended in carbon tetrachloride (100 mL) and heated to reflux for 6 hours. After cooling to room temperature, insolubles in the reaction mixture were removed with a cotton plug and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: n-hexane Z-ethyl acetate-5Z1) to give 2.40 g (yield 69.0%) of the title compound (4) as a pale yellow crystalline powder. Was.

 Ή-NMR (CDC 13): δ =

 1.42 (3Η, t, J = 7Hz)

 4.04 (3H, s)

 4.44 (2H, q. J = 7Hz)

 4.59 (2H, s)

 6.95 (1 H, d, J = 1 Hz)

 7.27 (1 H, d, J = 1 Hz)

7.47 (1 H, s) O ヽ C0 ₂ C ₂ H ₅

 OCH

 (Four)

 (3)

(5) Synthesis of 5- (imidazole-1-ylmethyl) -17-methoxy-2-benzo [b] furancarboxylic acid ethyl ester (The reaction formula is shown below)

 Imidazole (0.519 g, 7.63 mmol) was dissolved in dry DMF (= dimethylformamide, 20 mL), 60% sodium hydride (0.305 g, 7.63 mmol) was added, and the mixture was stirred at room temperature for 1 hour 30 minutes. Stirred. In addition, the above compound

 (4) A solution of (2.39 g, 7.63 mmol) in ^ DMF (60 mL) was added dropwise over 10 minutes. After stirring at room temperature for 24 hours, the reaction mixture was poured into ice water (300 mL) and extracted three times with ethyl acetate (100 mL). Extract the extracted organic layer with water

 (100 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized in a freezer, n-hexane was added, and the crystals were collected to give 1.76 g (yield: 76.8%) of the title compound (5) as white crystals.

Ή-NMR (CDC 1 _s ): δ-

1-41 (3Η.t, J = 7Hz)

 3.97 (3Η, s)

 4.44 (2 Η, q, J = 7Hz)

 5.19 (2 Η, s)

 6.67 (1 H, d, J = 2 H z)

 6.92 (1 Η, s)

 7. 04 (1 Η, d, J = 2 Hz)

 7.1 1 (1 Η, s)

 7.45 (1 Η, s)

7.58 (1 Η, s)

 (Five)

 (Four)

(6) Synthesis of 7-hydroxy-5- (imidazole-1-ylmethyl) -12-benzo [b] furancarboxylic acid (reaction formula is as follows)

 The above compound (5) (0.073 g, purity: 96.0%, 0.233 mmol) was dissolved in warm benzene (1.5 mL) by heating, and aluminum chloride (0.190 g, 1.40 mmol) was dissolved. ) 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 the residue, and the residue was washed with ethyl acetate. The aqueous layer was allowed to stand, and the precipitated crystals were collected, washed with water and air-dried to give the title compound (6) 0.050 g

(83.1% yield) was obtained as a white crystalline powder.

lH-NMR (DMS0-d ₆ ): ό =

 5.21 (2Η, s)

 6.75 (1 H, s)

 6.93 (1 H, s)

 7.05 (1 H, s)

 7.18 (1 H, s)

 7.56 (1 H, s)

 7.80 (1 H, s)

 10.4 (1 H, br s)

(5) (6) (7) Synthesis of 7-hydroxy-5- (imidazole-11-ylmethyl) -12-benzo [b] furancarboxylic acid ethyl ester (The reaction formula is shown below.)

 The above compound (6) (0.047 g, 0.180 mmol) was dissolved in ethanol (1 m2), 1 drop of concentrated sulfuric acid was added, and the mixture was heated under reflux for 4 hours. After evaporating the solvent under reduced pressure, a saturated aqueous solution of sodium hydrogen carbonate and dichloromethane were added to the residue, and the mixture was extracted with dichloromethane. The organic residue is washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent is distilled off to give 0.011 g (yield 21.3%) of the title compound (7) as a white crystalline powder. As obtained.

lH-NMR (CDC 13 / CD ₃ 0D = 10/1): δ =

 1.42 (3Η, t, J = 7Hz)

 4.43 (2 Η, q. J = 7Hz)

 5.15 (2 Η, s)

 6.74 (1Η, d, J = 1 Hz)

 6.94 (1 Η, s)

 6.97 (1 Η, d, J = 1 Hz)

 7. 04 (1 Η, s)

 7.47 (1 Η, s)

 7.60 (1 H, s)

(6) (7) (8) Synthesis of 4- (2-quinolinylmethyloxy) pendyl alcohol (reaction formula below)

 Under a nitrogen atmosphere, 60% sodium hydride (11.2 &, 280 mmol) is suspended in dry DMF (80 mL), and 4-hydroxybenzyl alcohol (29.0 g, 234 mmol) is added thereto under ice cooling. A solution of dried DMF (80 mL) was added dropwise, and the mixture was stirred for 40 minutes.

Separately, add 2- (chloromethyl) quinoline hydrochloride (50. Og, 234 mmol) to a mixed solvent of water (400 mL) and dichloromethane (100 mL), and add sodium hydrogen carbonate (23.8 g, 283 mmol) under ice-cooling. ) Was added little by little, 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 ^ DMF (65 mL), added dropwise to the previous reaction solution under ice cooling, and stirred at room temperature overnight. The reaction solution was poured into water (500 mL), and the precipitated crystals were collected and washed with water (400 mL × 3). The obtained crystals were dried under vacuum, dissolved in chloroform (200 mL) by heating, hexane (250 mL) was added while the solution was hot, and the solution was cooled to room temperature with stirring. The precipitated crystals are collected and washed with a mixed solvent of chloroform-hexane = 1: 1 (100 mL × 3), dried in vacuo, and 34.8 _g (yield 56.0%) of the title compound (8 ) Was obtained as pale yellow crystals.

 Melting point: 136.4

 Ή-NMR (CDC 1 a, 400MHz): δ =

 1 · 65 (1 Η, b r s)

 4.61 (2H, d, J = 5Hz)

 5.37 (2 H, s)

 6. 98-7. 03 (2H, m)

 7.26〜7.31 (2H, m)

 7.51-7.57 (1 H, m)

 7.66 (1 H, d, J = 8Hz)

 7.74 (1 H, ddd, J = 1 Hz. 8 Hz, 7 Hz)

7.82 (1 H, d, J = 8 Hz) 8.08 (1 H, d, J = 8 Hz)

 8.18 (1 H, d, J = 8 Hz)

(9) Synthesis of 4- (2-quinolinylmethyloxy) benzyl chloride (The reaction formula is as follows)

 The above compound (8) (34.8 g, 131 mmol) was turbidized in dry chloroform (34 OmL), and thionyl chloride (17.2 mL, 237 mmol) was slowly added dropwise under ice-cooling. The crystals dissolved when thionyl chloride was added. The reaction solution was stirred at room temperature for 30 minutes, and a saturated aqueous solution of sodium hydrogen carbonate was added under ice cooling until the pH became 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

 Ή-NMR (CDC 1, 400ΜΗΖ): δ =

 4.55 (2 H, s)

 5.39 (2 Η, s)

 6.96-7.03 (2Η, m)

 7.26〜7.33 (2Η, m)

 7.51-7.58 (1 1, m)

 7.65 (1 Η, d, J = 8H ζ)

7.74 (1 Η, ddd, J = 2 Hz, 8 Η ζ, 7 Hz) 7.83 (1H, d, J = 8Hz)

 8.08 (1 H, d, J = 8 H z)

 8.1 9 (1 H, d, J = 8Hz)

(10) 5- (imidazo-1-ylmethyl) 1 7— [4-1 (quinoline-1-ylmethyloxy) phenylmethyloxy] 1-benzo [b] furan-2-ethyl carboxylate (I-I Synthesis of 5) (reaction formula below)

 To a dry DMF (2 mL) solution of the compound (7) (0.010 g, 0.035 mmol) was added 60% sodium hydride (0.0014 g, 0.035 mmol) under ice-cooling, and the mixture was cooled to room temperature. For 30 minutes. A solution of the above compound (9) in dry DMF (2 mL) was added dropwise thereto, and the mixture was stirred at room temperature for 3 hours. After heating under reflux for another 2 hours, the mixture was allowed to cool, and the reaction mixture was poured into ice water (10 mL). The precipitated crystals were collected, dried under reduced pressure, and purified by preparative thin-layer JS chromatography (eluent: chloroform / methanol = 10/1) to give 0.014 g of the title compound (10). (Purity 98.3%; yield 73.7%) as a white crystalline powder.

 'H-NMR (CDC 1 a): 6 =

 1.4 1 (3H, t, J = 7Hz)

 4.42 (2 H, q, J = 7 Hz)

 5.1 3 (2H, s)

 5.19 (2H, s)

 5.39 (2H, s)

 6.70 (1 H, s)

 6.86 (1 H, s)

7.03 (1 H, s) 7.09 (1 H, s)

 7.36 (1 H, d, J = 8 Hz)

 7.44 (1 H, s)

 7.52-7.57 (1 H, m)

 7.58 (1 H, s)

 7.67 (1 H, d, J = 8Hz)

 7.71-7.76 (1H, m)

 7.82 (1 H, d, J = 8 Hz)

 8.08 (1 H, d, J = 8Hz)

 8.19 (1 H, d, J = 8 Hz)

(1 1) 5- (imidazole-1-ylmethyl) 17- [4-1 (quinoline- 2-methylmethyl) phenylmethyloxy] benzo [b] furan-2-carboxylic acid (I-1) Synthesis (reaction formula is below)

The above compound (10) (0.014 g, purity: 98.3%, 0.026 mmol) was dissolved in a mixed solvent of ethanol (2 mL) and p-dioxane (1 mL), and a 0.1 N aqueous sodium hydroxide solution ( (0.78 niL) was added and the mixture was stirred at room temperature for 22 hours. After confirming the completion of the reaction, adjust to pH 6 by adding 0.1 N hydrochloric acid, distill off the solvent under reduced pressure at 40 or less, add a small amount of water to the dried residue, collect the solid, and dry under reduced pressure. Thus, 0.009 g (yield: 70.8%) of the title compound (11) was obtained as a white crystalline powder. _{Ή-NMR (CDC 1 3 /} CD 3 0D = 10/1): δ =

 5.16 (2 H, s)

 5.18 (2 H, s)

 5.38 (2H, s)

 6.74 (1 H, s)

 6.91 (1 H, s)

 7. 02-7. 07 (4H, m)

 7.36-7.41 (3H, m)

 7.58 (1 H, t, J = 8 Hz)

 7.63 (1 H, s)

 7.70 (1 H, d, J = 8Hz)

 7.74-7.79 (1H, m)

 7.86 (1 H, d, J = 8Hz)

 8.08 (1 H, d, J = 8 Hz)

 8.26 (1 H, d. J = 8Hz)

 I R (KB r) cm- ':

3423, 1608, 1599, 1514, 1356, 1304, 124, 1209, 1138, 1 113, 1092, 980, 943, 837, 78, 752

[Synthesis Example 2] 5- (Imidazoyl-1-ylmethyl) -1-7- [3- (quinoline-1-ylmethyloxy) phenylmethyloxy] benzo [b] furan-1-carbonic acid (1-2) Synthesis of

 (1) Synthesis of 3- (2-quinolinylmethyloxy) benzyl alcohol Suspension of 60% sodium hydride (1.12 g, 28.0 mmol) in dry DMF (8 mL) under a nitrogen atmosphere A solution of 3-hydroxybenzyl alcohol (2.90 g, 23.4 mmol) in dry DMF (8 mL) was added dropwise thereto under ice cooling, and the mixture was stirred for 30 minutes.

Separately, 2- (chloromethyl) quinoline hydrochloride (5.0 g, 23.4 mmol) was added to a mixed solvent of water (40 mL) and dichloromethane (10 mL), and sodium bicarbonate (2.38 g, 28.3 mmol) was added little by little, 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. Dissolve this in dry DMF (6.5 mL) and cool on ice The solution was added dropwise to the above reaction solution, stirred at room temperature overnight, poured into ice water (50 mL), extracted with chloroform (30 mL), washed with water (40 mL x 2), and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate Z hexane = 1Z1) to give 3.71 g (yield 59.8%) of the title compound (1 ) Was obtained as pale yellow crystals.

 Melting point: 91. 4-92. 4

_{Ή-NMR (CDC 1 3,} 400ΜΗζ): δ =

 1.83 (1 H, t, J = 6 Hz)

 4.67 (2 H, d, J = 6Hz)

 5.38 (2H, s)

 6.90-7.00 (2H, m)

 7. 04-7. 10 (1 H, m)

 7.27 (1 H, t. J = 8 Hz)

 7.50-7.58 (1 H, m)

 7.67 (1 H, d, J = 8Hz)

 7.73 (1 H, ddd, J = 2 Hz, 8 Hz, 7 Hz)

 7.82 (1 H, d, J = 8 Hz)

 8.08 (1 H, d, J = 8 Hz)

 8.18 (1 H, d, J = 8 Hz)

 (2) Synthesis of 3- (2-quinolinylmethyloxy) pendyl chloride The above compound (1) (1.90 g, 7.16 mmol) was dissolved in dichloromethane (14 mL) and thionyl chloride was added under ice cooling. (0.9 mL, 12.4 mmol) was slowly added dropwise. When thionyl chloride was added, crystallinity was precipitated, but it dissolved after a while. The reaction solution was stirred at room temperature for 30 minutes, and an aqueous saturated sodium hydrogen carbonate solution was added under ice cooling until ρΗ7Η8, and the organic layer was separated. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 2.04 g (purity: 99.5¾, yield: 99.9%) of the title compound (2) as pale yellow crystals.

 Melting point: 54. 2-55. 8

Ή-NMR (CDC 1 a, 400MHz): 6 = 4.54 (2H, s)

 5.39 (2H, s)

 6.95-7.01 (2H, m)

 7.07-7.10 (1H, m)

 7.26 (1 H, t, J = 8 Hz)

 7.55 (1 H, ddd, J = 1 Hz, 8 Hz, 7 Hz)

 7.67 (1 H, d, J = 8 Hz)

 7.74 (1 H, ddd, J = 2 Hz, 8 Hz, 7 Hz)

 7.83 (1 H, d, J = 8Hz)

 8.09 (1 H, d, J = 8 Hz)

 8.19 (1 H, d, J = 8 Hz)

 (3) Synthesis of 5- (imidazole-1-ylmethyl) -17- [3- (quinoline-12-ylmethyloxy) phenylmethyloxy] benzo [b] furan-12-potassium ester

 To a solution of the compound (7) (146 mg, 0.51 mmol) obtained in Synthesis Example 1 in dry DMF (4 mL) was added 60% sodium hydride (21 mg, 0.53 mmol), and the mixture was stirred at room temperature for 1 hour. did. The above compound (2) (176 mg, 0.62 mmol) was added thereto, 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 a saturated saline solution, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 420 mg of a dark brown oily substance, which was purified by medium pressure silica gel column chromatography (cloform form Z methanol = 40/1) to give 108 mg of the title compound (3) as white Obtained as crystalline powder. (Yield: 39.6%)

 Ή-NMR (CDC 1 a): 6 =

 1.41 (3 H, t, J = 7Hz)

 4.43 (2 H, q, J = 7 Hz)

 5.08 (2 H, s)

 5.25 (2H, s)

5.38 (2H, s) 6.66 (1 H, d, J = 1 Hz)

 6.83 (1 H.s), 6.9 to 7.0 (2H, m)

 7.04 (1 H, d, J = 8Hz)

 7.08 (1 H, s)

 7.14 (1H, s)

 7.29 (1 H, dd, J = 8 Hz, 8 Hz)

 7.43 (1 H.s)

 7.5 to 7.6 (2H, m)

 7.65 (1 H, d, J = 8 Hz)

 7.72 (1 H, ddd, J = 1 Hz, 8 Hz, 8 Hz)

 7.81 (1 H, d, J = 8Hz)

 8.06 (1 H, d, J = 8 Hz)

 8.16 (1 H, d, J = 8Hz)

 I R (KBr) cm_ ':

 1700, 1595, 1580, 1300, 1200

 (4) Synthesis of 5- (imidazole-l-ylmethyl) -17- [3- (quinoline-l- 2-methylmethyloxy) phenylmethyloxy] benzo [b] furan-l-2-carboxylic acid (I-12)

 Compound 14 (107 mg, 0.20 mmol) was dissolved in a mixed solvent of ethanol (4 mL) and P-dioxane (2 mL), 0.1 N aqueous sodium hydroxide solution (4 mL) was added, and the mixture was stirred at room temperature for 3 hours. did. It was diluted with water (1 OmL) and adjusted to PH5 by adding citric acid. The precipitated crystals were collected, washed five times with water (2 mL), and dried under reduced pressure to obtain 88 mg of the title compound (4) as white crystalline powder. (Yield: 85%)

 Melting point: 130-134

Ή-NMR (DMSOd _e ) δ =

 5.23 (2H, s)

 5.26 (2 H, s)

5.38 (2H, s) 6.91 (1 H, s)

 7.0 to 7.3 (6 H, m)

 7.34 (1 H, dd, J = 8 Hz, 8 Hz)

 7.6 to 7.7 (3H, m)

 7.7 to 7.8 (2H, m)

 7. 9 to 8.0 (2 H, m)

 8.39 (1 H, d, J = 9 Hz)

IR (KB r) cm- ¹ :

 3400, 1600, 1380, 1320, 1265, 1210, 1145, 780

 [Synthesis Example 3] Synthesis of 5- (imidazole-11-ylmethyl) —7— [2- (quinolin-1-ylmethyloxy) phenylmethyloxy] benzo [b] furan-12-carboxylic acid (I-13)

 (1) Synthesis of 2- (2-quinolinylmethyloxy) benzyl alcohol Under nitrogen atmosphere, dry DMF (8 mL) was turbidized with 60% sodium hydride (1.00 g, 25.0 mmol). Under ice-cooling, a solution of 2-hydroxybenzyl alcohol (2.80 g, 22.6 mmol) in dry DMF (8 mL) was added dropwise, and the mixture was stirred for 30 minutes.

 Separately, 2- (chloromethyl) quinoline hydrochloride (5. Og, 23.4 mmol) was added to a mixed solvent of water (40 mL) and dichloromethane (10 mL), and sodium bicarbonate (2.38 g, 28 (3 mmol) was added little by little, 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, stirred at room temperature for one hour, poured into ice water (100 mL), extracted with black hole form (80 mL), and extracted with water. (40mLx2), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography.

After purification with (ethyl ethyl hexane-1Z1), the residue was dissolved in chloroform (5 mL). Hexane (13 mL) was added to this solution, and the precipitated crystals were collected and dried in vacuo to give 4.15 (yield: 69.0%) of the title compound (1) as white crystals. Obtained.

 Melting point: 101.4-102.8 * 0

 • H-NR (CDC 1 a, 400MHz): δ =

 4. 06 (1 Η, br s)

 4.83 (2H, s)

 5.47 (2 H, s)

 6.94-7. 0 1 (2 H, m)

 7.2 1 to 7.27 (1H, m)

 7.33 (1 H, dd. J = 1 Hz, 7 Hz)

 7.53 (1 H, d, J = 7 Hz)

 7.55 (1 H, ddd, J = 1 Hz, 8 Hz, 7 Hz)

 7. 73 (1 H, ddd, J = l Hz, 8 Hz, 7 Hz)

 7.82 (1 H, dd, J = 1 H z, 8Hz)

 8.08 (1 H, d, J = 8Hz)

 8.18 (1 H, 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 cooled under ice-cooling. Thionyl chloride (0.47 mL, 6.47 mmol) was slowly added dropwise. When thionyl chloride was added, crystals precipitated. The reaction solution was stirred at room temperature for 1 hour, and a saturated aqueous solution of sodium hydrogen carbonate was added under ice cooling until the pH became 7 to 8, and the organic layer was separated. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was suspended in hexane (10 mL). The crystals were collected and dried in vacuo to give 0.98 g (yield: 91.5%) of the title compound (2) as white crystals.

 Melting point: 108.2-10.9.2Ό

 Ή-N R (CDC 1 a, 400MHz): δ =

 4.79 (2 Η, s)

 5.46 (2H, s)

 6.94-7.00 (2 H, m)

7.27 (1 H, J = 1 Hz, 8 Hz) 7.40 (1 H, dd, J = 1 Hz, 8 Hz)

 7.56 (1 H, t, J = 8 Hz)

 7.74 (1 H, ddd, J = 1 Hz, 8 Hz, 7 Hz)

 7.77 (1 H, t, J = 8 Hz)

 7.84 (1 H, d, J = 8 Hz)

 8.08 (1 H, d, J = 8 Hz)

 8.21 (1 H, d, J = 8 Hz)

 (3) Synthesis of 5- (imidazole-11-ylmethyl) -17- [2- (quinoline-2-ylmethyloxy) phenylmethyloxy] benzo [b] furan-12-potassium ethyl ester

To a solution of compound (7) (286 mg, 1.00 mmol) obtained in Synthesis Example 1 in dry DMF (4 mL) was added 60% sodium hydride (40 mg, 1.0 mmol), and the mixture was stirred at room temperature for 30 minutes. did. To this was added the above compound 17 (341 mg, 1.20 mmol), 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 with a saturated saline solution, and dried over sodium sulfate. The solvent was distilled off under EE to obtain 886 _mg of a white crystal, which was washed with acetone and then with hexane to obtain 290 mg of the title compound (3) as a white crystalline powder. (Secondary crystal: 75mg, Yield: 68.4%)

 Melting point: 145 ~ 146 ° C

 Ή-NMR (CDC 1 a, 400MHz): δ =

 1.40 (3 Η, t, J = 7Hz)

 4.42 (2 Η, q, J = 7Hz)

 5.10 (2H, s)

 5.44 (4H, s)

 6.82 (1 H, d, J = 1 Hz)

 6.84 (1 H, s)

 6. 9 to 7.0 (3 H, m)

 7.06 (1 H, s)

7.27 (1 H, m) 7.44 (1 H, s)

 7.5 to 7.6 (3 H, m)

 7.66 (1 H, d, J = 8 Hz)

 7.73 (1 H, ddd, J = 2 Hz, 8 Hz, 8 Hz)

 7.82 (1 H, d, J = 8Hz)

 8.06 (1 H, d, J = 8 Hz)

 8.15 (1 H, d, J = 8Hz)

 I R (KBr) cm- ':

 1710, 1600, 1580, 1490, 1350, 1310, 125 5, 1200, 755

 (4) Synthesis of 5- (imidazoyl-1-ylmethyl) -17- [2- (quinoline-1-ylmethyloxy) phenylmethyloxy] benzo [b] furan-12-dicarboxylic acid (I-13)

Dissolving the compound (3) (267mg _¾ 0. 50 mmol) in a mixed solvent of ethanol (10 m L) and P- Jiokisan (5 mL), a 0. 1 N aqueous sodium hydroxide solution (1 OML) was added, at room temperature For 4 hours. The mixture was diluted with water (25 mL), and quenic acid was added to adjust to PH5. The precipitated crystals were collected, washed with water (5 mL) four times, and dried under reduced pressure to obtain 232 mg of the title compound (4) as white crystalline powder. (Yield: 91.8%)

 Melting point: 215-217 (decomposed)

 Ή-NMR (DMSO-de, 400MHz): δ =

 5.25 (2 H, s)

 5.39 (2 H, s)

 5.46 (2 H, s)

 6.91 (1 H, s)

 7.00 (1 H, dd, J = 7 Hz, 7 Hz)

 7.14 (1 H, d, J = 8Hz)

 7.2 to 7.4 (4H, m)

7.5 to 7.6 (3H, m) 7.66 (1 H, d, J = 9 Hz)

 7.76 (1 H, m)

 7.82 (1 H, s)

 7.92 (1 H, d, J = 8Hz)

 7.99 (1 H, d, J = 8Hz)

 8.29 (1 H, d, J = 9 Hz)

IR (KBr) cnT ¹ :

 3400, 1600, 1490, 1370, 1350, 1320, 125 0, 1200, 1140, 745

 [Synthesis Example 4] trans- 1- [4- (imidazole-1-ylmethyl) 1-2- [3- (quinoline-1-ylmethyloxy) phenylmethyloxy] phenyl] pentopenic acid (Π-1) Synthesis of

 (1) Synthesis of 7-bromomethylcoumarin

 7-Methylcoumarin (5.00 g, 31.2 mmol) and N-bromosuccinimide (5.56, 31.2 mmol) were suspended in carbon tetrachloride (1 OOmL) and irradiated under a 500 W tungsten lamp. The mixture was stirred for 30 minutes. After cooling to room temperature, the crystals were oiled and washed with carbon tetrachloride (20 mL). The crystals were suspended in a mixed solvent of pore-form (250 mL) and water (150 mL), and insolubles were removed by filtration. Then, the organic layer was separated. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give 6.05 g (yield: 81.1%) of the title compound (1) as pale yellow crystals.

 Melting point: 176. 0-178. 8

 Ή-N R (CDC 13, 400MHz): δ =

 4.52 (2 H, s)

 6.43 (1 H, d, J = 1 OHz)

 7.31 (1 H, dd, J = 2 Hz, 8Hz)

 7.35 (1 H, s)

 7.46 (1 H, d, J = 8Hz)

7.69 (1 H, d, J = 1 OHz) (2) Synthesis of 7— (imidazole-1-ylmethyl) coumarin

 Imidazole (1.71 g, 25.1 mmol) was dissolved in dry DMF (8.5 mL), and 60% sodium hydride (01 g, 25.3 mmol) was added under ice-cooling. For a minute. The reaction solution was cooled with ice, a solution of the above compound (1) (6.00 g, 25.1 mmol) in dry DMF (1 OOmL) was added dropwise, and the mixture was stirred at room temperature for 19 hours. The reaction solution was poured into ice water (300 mL), and a 1 N aqueous hydrochloric acid solution was added until the pH became 8, and the precipitated crystals were collected. After washing with water (100 mL), the residue was dried in vacuo to give the title compound (2) (4.38 g .: 92.8%, yield: 71.7%) as white-brown crystals.

 Melting point: 133

 Ή-NMR (CDC 1 a, 400MHz): δ =

 5.21 (2Η, s)

 6.44 (1 Η, d, J = 9Hz)

 6.92 (1 H, d, J = 1 Hz)

 7.01 (1 H, dd, J = 1 Hz. 8 Hz)

 7.10 to 7.16 (2H, m)

 7.47 (1 H, d. J = 8Hz)

 7.58 (1 H. s)

 7.68 (1 H, d, J = 9 Hz)

 (3) Synthesis of trans-1- [4- (imidazole-1-ylmethyl) -12-hydroxyphenyl] ethyl propenoate

Gold sodium sodium (0.19 g, 8.26 mmol) was dissolved in dry ethanol (4 mL), and the above compound (2) (1.00 g, purity: 92.8%, 4.10 mmol) was added. The mixture was heated under reflux for 2 hours. The reaction solution was ice-cooled, poured into a cooled 2N aqueous hydrochloric acid solution (6 mL), and a 1N aqueous sodium hydroxide solution was added until pH7. After extraction with ethyl acetate (30 mL × 3) and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (form of chloroform to form of methanol to form of methanol = 120) to give 0.60 g (yield 53.7%) of the title compound (3) as pale yellow crystals. Melting point: 162.0-163.0

 Ή-NMR (CDC 13, 400MHz): δ =

 1.34 (3 H, t, J = 7Hz)

 4.25 (2 H, q, J = 7 Hz)

 5.1 1 (2H, s)

 6.33 (1 H, d, J = 9 Hz)

 6.68 (1 H, d, J = 16Hz)

 6.75 (1 H, dd, J = 1 Hz, 8 Hz)

 6.91 (1 H, t, J = 1 Hz)

 7.01 (1 H, t, J = 1 H z)

 7.45 (1 H, d, J = 8 Hz)

 7.51 (1 H, s)

 7.98 (1 H, d, J = 16 Hz)

 (4) Synthesis of trans-3-1- [4-1- (imidazo-1-ylmethyl) -1-2- [3- (quinoline-1-ylmethyloxy) phenylmethyloxy] phenyl] ethyl ethyl bromate

 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 the mixture was stirred for 30 minutes. Dry DMF (4 mL) of the compound (2) (0.52 g, 1.83 mmol) synthesized in Synthesis Example 2 was added dropwise. After stirring at room temperature for 13 hours, the reaction solution was poured into ice water (70 mL), extracted with chloroform (30 mL × 3) while passing through celite, and washed with water (70 mL). After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (form: chromatoform-methanol Zform: 3Z200) to obtain 0.87 g (purity: 97. 9%, yield: 89.6%) to give the title compound (4) as pale yellow crystals.

 Melting point: 104. 4-106. 4 ° C

 Ή-NMR (CDC 13, 400MHz): 5 =

1.30 (3H, t, J = 7Hz) 4.24 (2H, q, J = 7Hz)

 5.02 (2H, s)

 5.06 (2H, s)

 5.38 (2H, s)

 6.51 (1 H, d, J = 16 Hz)

 6.59 (1 H, d, J = 9 Hz)

 6.71 (1 H, dd, J- 1 Hz, 8Hz)

 6.81 (1 H, t, J = 1 Hz)

 6.92〜7.01 (2H, m)

 7. 02-7. 07 (1 H, m)

 7.09 (1 H, s)

 7.29 (1 H, t, J = 8H z)

 7.45 (1 H, d, J = 8 Hz)

 7.49 (1 H, s)

 7.50 ~ 7.57 (1H, m)

 7.66 (1 H, d, J = 8Hz)

 7.68-7.76 (1H, m)

 7.81 (1 H, d, J = 8Hz)

 7.99 (1 H, d, J = 16Hz)

 8.07 (1 H, d, J = 8 Hz)

 8.16 (1 H, d, J = 8 Hz)

 (5) Trans 1-3- [4-1 (Imidazo-1-ylmethyl) 1-2- [3- (Quinolin-1-ylmethyloxy) phenylmethyloxy] phenyl] Butanoic acid (II-1) Synthesis of

The above compound (4) (0.30 g, purity: 97.9%, 0.57 mmol) is dissolved in ethanol, and a 1N aqueous sodium hydroxide solution (1. OmL) is added at room temperature, followed by stirring for 1 hour and 30 minutes. Thereafter, a 1N aqueous sodium hydroxide solution (0.43 mL) was further added, and the mixture was stirred for 13 hours and 30 minutes. Ethanol was distilled off under reduced pressure at 30. Water (4 mL) was added to the residue, and a 1N aqueous hydrochloric acid solution was added under ice-cooling until the pH reached 7. The water After evaporating under reduced pressure in vacuo, the residue was suspended in chloroform (30 mL), and insolubles were removed by filtration. The insoluble material is washed with a mouthpiece form, the washing solution and the base solution are combined, dried over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure, ethanol (5 mL) is added to the residue, and the ethanol is distilled off under reduced pressure in vacuo. 0.29 g (purity: 95.2%, yield: 98.5%) of the title compound (5) was obtained as a pale yellow amorphous.

 Ή-NMR (CDC 1 a, 400MHz): δ- 4.93 (2Η, s)

 4.96 (2 Η, s)

 5.36 (2H, s)

 6.48 (1 H, d, J = 16 Hz)

 6.52 (1 H, d)

 6.60 (1 H, d, J = 7 Hz)

 6.79 (1 H, s)

 6.84 (1 H, d, J = 7 Hz)

 6.92 (1 H, d, J = 7 Hz)

 7.08 (1 H, s)

 7.15-5.24 (2H, m)

 7.37 (1 H, d, J = 8 Hz)

 7.43-7.50 (1H, m)

 7.51 (1 H, s)

 7.60-7.70 (2 H, m)

 7.73 (1 H, d, J = 8 Hz)

 7.96 to 8.19 (3H, m)

 I R (KB r) cm:

 3398, 3059, 1630, 1608, 1601, 1506, 12.9, 1381, 1265, 1157, 1032, 827, 744

[Synthesis Example 5] Synthesis of cis-3- [4- (imidazole-11-ylmethyl) -12- [3- (quinoline-12-ylmethyloxy) phenylmethyloxy] phenyl] bronic acid (II-12) Compound (2) (0.25 g, purity: 92.8%, 1.03 mmol) synthesized in Synthesis Example 4 was suspended in ethanol (5 mL), and sodium hydroxide (0.20 g, 500 mmol) was added. ) In water (0.3 mL), and the mixture was heated under reflux for 8 hours. After cooling to room temperature, the compound (2) (0.88 g, 3.10 mmol) synthesized in Synthesis Example 2 was added, and the mixture was stirred at room temperature for 13 hours. Water (1 OmL) was added to the remaining port, washed with ethyl acetate (5 mL), and a 1N aqueous hydrochloric acid solution was added until the pH reached 7. After extraction with chloroform (10 mL) and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform form-methanol / chloroform form = 1-10), then messed up with chloroform form (0.2 mL), and ethanol Z hexane = 1/2 mixed solvent (0%). 6 mL) was added to remove crystals. The obtained crystals were washed with a mixed solvent of ether Z hexane = 1Z1 (0.8 mL Zl. 2 mL), and dried under vacuum to give 94 mg (yield: 18.6%) of the title compound as white crystals.

 Melting point: 173.0 ~ 174.4

_{Ή-NMR (CD 3 0 D} / CDC 1 3 = 1/10, 400MHz): δ =

 5.01 (2 Η, s)

 5.05 (2 Η, s)

 5.38 (2H, s)

 5.99 (1 H, d, J = 12Hz)

 6.24 (1 H, d)

 6.70 (1 H, d, J = 8 Hz)

 6.86 to 6.87 (1 H, s)

 6.96 (1 H, d, J = 8 Hz)

 7.00 (1 H, dd, J = 2 Hz, 8 Hz)

 7.02 (1 H, s)

 7. 07 to 7.14 (2H, m)

 7.10 (1 H, d, J = 12 Hz)

 7.30 (1 H, t, J = 8 Hz)

7.51 (1 H, d, J = 8 Hz) 7.52 (1 H, s)

 7.55-7.60 (1H, m)

 7.70 (1 H, d, J = 9Hz)

 7.76 (1 H, ddd, J = 1 Hz, 8 Hz, 7 Hz)

 7.85 (1 H, d, J = 8 Hz)

 8.08 (1 H, d, J = 9 Hz)

 8.24 (1 H, d, J = 9Hz)

IR (Br) cm- ¹ :

 3433, 31 16, 1633, 1595, 1506, 1504, 142 9, 1423, 1275, 1219, 121 1, 1 161, 1 1 1 1, 1093, 1063, 837, 822, 783

 [Synthesis Example 6] Synthesis of trans-3- (4-1 (imidazole-11-ylmethyl) -12- [4-1 (quinoline-12-ylmethyloxy) phenylmethyloxy] phenyl] butanoic acid (II-13)

 (1) Trans-3- (4- (imidazo-1-ylmethyl) -2— [4-

Synthesis of (quinoline-1-ylmethyloxy) phenylmethyloxy] phenyl] proethylate

 The compound (3) (100 mg, 0.37 mmol) synthesized in Synthesis Example 4 was dissolved in dry DMF (1 mL), and the mixture was cooled on ice with 60% sodium hydride (15 mg, 0.38 mmol). ) Was added, and the mixture was stirred for 30 minutes, and then dried DMF (4 mL) of the compound (9) (105 mg, 1.83 mmol) synthesized in Synthesis Example 1 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 passing through a suitable filter, and washed with water (10 mL × 2). After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (form: chromate form to methanol Z form: 1Z100) to give 180 mg (yield: 94.6%). The title compound (1) was obtained as pale yellow crystals.

 Melting point: 107.0 ~ 108.2

_{Ή-NMR (CDC 1 3,} 400MHz): δ = 1.30 (3H,, J = 7Hz)

 4.23 (2 H, q, J = 7 Hz)

 5.00 (2H, s)

 5.07 (2H, s)

 5.40 (2 H, s)

 6.49 (1 H, d, J = 16 Hz)

 6.62 (1 H, s)

 6.74 (1 H, d, J = 8 Hz)

 6.81 to 6.85 (1H, m)

 7.00 7.06 (2H, m)

 7.09-7.12 (1 H, m)

 7.26〜7.31 (2H, m)

 7.49 (1 H, d, J = 8 Hz)

 7.52 (1 H, s)

 7.55 (1 H, ddd, J = 1 Hz, 8Hz, 7Hz)

 7.68 (1 H, d, J = 8Hz)

 7.74 (1 H, ddd, J = 1 Hz, 8 Hz, 7 Hz)

 7.83 (1 H, d, J = 8 Hz)

 7.97 (1 H, d, J = 16Hz)

 8.07 (1 H, d, J = 8 Hz)

 8.20 (1 H, d, J = 8 Hz)

 (2) Synthesis of trans-3- [4-1- (imidazole-l-ylmethyl) 1-2- [4-1- (quinoline-l-ylmethyloxy) phenylmethyloxy] phenyl] bronic acid (Π-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 hours. Ethanol was distilled off at 2 for 30 minutes, water (2 mL) was added to the residue, and a 1N aqueous hydrochloric acid solution was added under ice-cooling until the pH became 7. The precipitated crystals were collected, washed with water (10 mL), and dried under vacuum to give 74 mg (yield: 78.9%) of the title. Compound (2) was obtained as white crystals.

 Melting point: 78.4

 Ή-NMR (CDC 1 a, 400 MHz) 6 =

 5.01 (2 Η, s)

 5.09 (2Η, s)

 5.38 (2 Η, s)

 6.50 (1 Η, d, J = 16Hz)

 6. 67 (1 Η, s)

 6.75 (1 Η, d, J = 7 Hz)

 6.87 (1 Η, s)

 7.01 to 7.06 (3 Η, m)

 7.31 (2 H. d.J = 8 Hz)

 7.52 (1 H, d, J = 8Hz)

 7.55 (1 H, s)

 7.55 to 7.60 (1H, m)

 7.70 (1 H, d, J = 8 Hz)

 7.76 (1 H. d d d, J = 1 Hz, 8 Hz, 7 Hz)

 7.86 (1 H, d d, J = 1 Hz, 8 Hz)

 7.89 (1 H, d, J = 16 Hz)

 8.08 (1 H, d, J = 8Hz)

 8.25 (1 H, d, J = 8Hz, m)

 I R (KB r) cm '':

 3398, 3064, 2924, 1697, 1610, 1512, 142 9, 1383, 1315, 1292, 1246, 1244, 1 174, 1 1 1 1, 101 1, 823

 [Synthesis Example 7] Synthesis of cis-3- [4-1 (imidazole-1-ylmethyl) 1-2- [4-1 (quinolin-12-ylmethyloxy) phenylmethyloxy] phenyl] bronic acid (Π-4)

Compound (2) synthesized in Synthesis Example 4 (250 mg, purity: 92.896, 1.03 ) Was added to ethanol (5 mL), a solution of sodium hydroxide (10 Omg, 5.00 mmol) in water (0.3 mL) was added, and the mixture was refluxed for 8 hours. After cooling to room temperature, the compound (9) (880 mg, 3.10 mmol) synthesized in Synthesis Example 1 was added thereto, and after stirring at room temperature for 13 hours, ethanol was distilled off from the ME. Water in the afterglow

(1 OmL), and the mixture was washed with ethyl acetate (5 mL × 2). The mixture was extracted with chloroform (10 mL), dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (black mouth form-methanol Z black mouth form = 1-10), suspended in black mouth form Z ethanol = 14 (0.5 mL), and hexane ( (0.2 mL), and the crystals were oiled. The obtained crystals were washed with ethanol (1 mL) and dried in vacuo to give 94 mg (purity: 99.1%, yield: 18.4%) of the title compound as pale yellow crystals.

 Melting point: 188. 0-19 1.0

 lH-NMR (CDC 1 a, 400MHz): δ =

 4.95 (2 Η, s)

 5.09 (2 Η, s)

 5.38 (2Η, s)

 5.97 (1 H, d, J = 1 2 H z)

 6.67 (1 H, s)

 6.72 (1 H, d, J = 8 Hz)

 6.90 (1 H, s)

 7.01 to 7.06 (3H, m)

 7.14 (1 H, d, J = 12 Hz)

 7.27〜7.32 (2H, m)

 7.54—7.61 (3H, m)

 7.70 (1 H, d, J = 8Hz)

 7.76 (1 H, ddd, J = 1 Hz, 8 Hz, 7 Hz)

 7.86 (1 H, d, J = 8 Hz)

8.09 (1 H, d, J = 9 Hz) 8.24 (1 H, d, J = 9 Hz)

 I R (KB r) cm ":

 3433, 1691, 1610, 1514, 1454, 1429, 137 7, 1275, 1244, 1227, 1201, 1 174, 1 153, 1 107, 1065, 1024, 823, 820, 748

 [Synthesis Example 8] Synthesis of 4- (imidazole-11-ylmethyl) 1-2- [3- (quinolin-2-ylmethyloxy) benzyloxy] benzoic acid (III-11)

 (1) Synthesis of methyl 2-hydroxy-4-methylbenzoate

 2-Hydroxy-4-methylbenzoic acid (20.Og, 131 mmol) was dissolved in methanol (130 mL), and hydrochloric acid gas was blown in under ice-cooling 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 or less. The residue was dissolved in chloroform (50 mL), and a saturated aqueous sodium hydrogen carbonate solution was added under ice-cooling until the aqueous layer became PH8. The organic layer was separated, and washed with saturated saline. Solvent was removed with anhydrous sodium sulfate, and the solvent was distilled off.

: 94.7%) of the title compound (1) as a pale brown oil.

_{Ή-NMR (CDC 1 3,} 400MHz): δ =

 2.34 (3Η, s)

 3.93 (3H, s)

 6.69 (1 H, dd, J = 1 Hz, 8 Hz)

 6.79 (1 H, s)

 7.1 1 1 (1 H, d, J = 8 Hz)

 10.7 (1 H, s)

 (2) Synthesis of 2-acetyloxy 4-monomethylbenzoic acid methyl ester Dry the above compound (1) (10. Og, 60.2 mmol) in dry DMF (5 OmL)

), 60% sodium hydrogen hydride (2.41 g, 60.3 mL) was added little by little under ice-cooling, and the mixture was stirred for 30 minutes. Further, a solution of acetyl chloride (4.3 mL, 60.5 mmol) in dry DMF (1 OmL) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into iced water, extracted with black-mouthed form (50 mL × 2), washed with water (100 mL × 2), and dried over anhydrous sodium sulfate. Evaporate the solvent under reduced pressure. g (purity: 91.9%, yield: 96.8%) of the title compound (2) was obtained as a pale brown oil.

_{Ή-NMR (CDC 1 3,} 400MHz): 5 =

 2.34 (3H, s)

 2.39 (3H, s)

 3.85 (3H, s)

 6.91 (1 H, d, J = 1 Hz)

 7.1 1 (1 H, dd, J = 1 Hz, 8 Hz)

 7.91 (1 H, d, J = 8 Hz)

 (3) Synthesis of 2-hydroxy-41- (imidazo-1-ylmethyl) benzoate methyl ester

 Compound (2) (13.2 g, purity: 91.9%, 58.3 mmol), N-promosuccinimide (NBS) (10.4 g, 58.4 mmol), and α, α′-α Zobisisobutyronitrile (AI II) (0.78 g, 4.75 mmol) was suspended in carbon tetrachloride (60 mL) and heated to dryness for 7 hours. After cooling to room temperature, insolubles were removed by filtration, and the insolubles were washed with a small amount of carbon tetrachloride. The solvent and washing solution were combined, the solvent was distilled off under reduced pressure, and NBS (7.80 g, 43.8 mmol), AIBN (0.17 g, 1.04 mmol) and dry benzene (5 OmL) were added to the residue. ) And heated to reflux for 3 hours and 50 minutes under irradiation with a 500 W tungsten lamp. After the reaction solution was cooled on ice, insolubles were removed by filtration, and the insolubles were washed away with carbon tetrachloride (5 OmL). The rutile solution and the washing solution were combined, the solvent was distilled off under reduced pressure, carbon tetrachloride (50 mL) was added to the residue, and insolubles were removed by filtration. The insolubles were washed with carbon tetrachloride (50 mL), and the solvent and the washing solution were combined. Obtained. This was used for the next reaction without purification.

Next, imidazole (3.97 g, 58.3 mmol) was dissolved in dry DMF (100 mL), and 60% sodium hydride (2.33 g, 58.3 mL) was added little by little. Stirred. After cooling the reaction solution on ice, the above 4-bromomethyl-12-hydroxybenzoic acid methyl ester (23.3 g) in dry DMF (50 The solution was added dropwise and stirred at room temperature for 30 minutes. The reaction solution was poured into ice-water (300 mL), extracted with black hole form (80 mL × 3), washed sequentially with water (100 mL × 2) and saturated saline (100 mL), and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (form: toguchi / methanol / form: 1Z100 to: IZ50) to obtain 1.78 g (purity: 83.9%, yield: 11) (0%) to give the title compound (3) as a brown oil.

 • H-NMR (CDC 13, 400MHz): δ =

 3.95 (3 H. s)

 5.10 (2 H, s)

 6.62 (1 H, dd, J = 2 Hz, 8 Hz)

 6.76 (1 H, d, J = 2 Hz)

 6.90 (1 H, s)

 7.1 1 1 (1 H, s)

 7.55 (1 H, s)

 7.81 (1 H, d, J = 8Hz)

 MS (FAB) m / z * 233 (MH *)

 (4) Synthesis of methyl 4- (imidazole-1-ylmethyl) 1-2- [3- (quinoline-2-ylmethyloxy) benzyloxy] benzoate

The above compound (3) (1.78 g, purity: 83.9%, 6.43 mmol) was dissolved in dry DMF (7 mL), cooled on ice, and 60% sodium hydride (0.26 g, 6.50 mmol). (Mmol) was added little by little and stirred for 30 minutes. Further, a solution of the compound (2) (1.84 g, purity: 99.5%, 6.45 mmol) synthesized in Synthesis Example 2 in dry DMF (7 mL) was added dropwise, and the mixture was stirred at room temperature for 6 hours and then stirred at 60. The mixture was stirred for 17 hours. The reaction solution was poured into ice-water (50 mL), extracted with black hole form (50 mL), washed with water (50 mL), and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (form: black form-methanol Z form: 1100-1Z25) to obtain 2.21 g (purity: 96.2%. Yield 68. 9%) of the title compound (4) was obtained as a pale brown oil. Ή-NMR (CDC ", 400MHz) 6 =

 3.89 (3H, s)

 5.06, 5.07 (4H, each s)

 5.39 2H, s)

 6.64 1 H, s)

 6.73 1 H, d, J = 8 Hz)

 6.78 to 6.84 (1 H, m)

 6.97 (1 H, dd, J = 2 Hz, 8 Hz)

 7.03 (1 H, d, J = 8Hz)

 7.10 (1 H, br s)

 7.15 (1 H, b r s)

 7.29 (1 H, t, J = 8 Hz)

 7.51 (1 H, br s)

 7.54 (1 H, ddd, J = 1 Hz, 8 Hz, 7 Hz)

 7.65 (1 H, ddd, J = 8 Hz)

 7.73 (1 H, ddd, J = 2 Hz, 8 Hz, 7 Hz)

 7.77 (1 H, d, J = 8Hz)

 7.80-783 (1H, m)

 8.07 (1 H, d. J = 8 Hz)

 8.16 (1 H, d, J = 8Hz)

 (5) Synthesis of 4- (imidazole-11-ylmethyl) 1-2- [3- (quinoline-12-ylmethyloxy) benzyloxy] benzoic acid (III-11)

Compound (4) (0.25 g, purity: 92.2%, 0.48 mmol) obtained by the above method was dissolved in methanol (3 mL), and 1N aqueous sodium hydroxide solution (1. mL), and the mixture was stirred for 15 hours and 20 minutes. Then, 1N aqueous sodium hydroxide solution (0.50 mL) was added, and the mixture was stirred for 6 hours. After evaporating under reduced pressure at 30, water (2 mL) was added to the remaining port, and a 1N aqueous hydrochloric acid solution was added under ice cooling until pH 7 was reached. After water was distilled off in vacuo, the residue was mixed with methanol / chloroform = 1Z1 mixed solvent (2 mL), insolubles were removed by filtration, and the solvent was distilled off under reduced pressure. 2 g (purity: 93.8%, yield: 91.7%) of the title compound (5) was obtained as a pale brown amalfas compound.

_{Ή-NMR (CD 3 OD /} CDC 1 3 = 1/10, 40 OMH z): δ =

5.14 (2Η, s)

 5.15 (2 H, s)

 5.39 (2 H, s)

 6.74 (1 H, s)

 6.84 (1 H, d)

 6.87—6.91 (1 H, m)

 6.95 (1 H, d, J = 8 Hz)

 7. 04 (1 H, dd, J = 2Hz, 8Hz)

 7.09 (1 H, s)

 7.31 (1 H, t, J = 8Hz)

 7.44 (1 H, s)

 7.55 to 7.62 (2 H, m)

 7.73 to 7.80 (2H, m)

 7.87 (1 H, d, J = 7Hz)

 7.99 (1H, m)

 8.07 (1 H, m)

 8.26 (1 H, d, J = 8 Hz)

IR (KB r) cm " ¹ :

3398, 3390, 1691, 1612, 1610, 1506, 142 7, 1292, 1255, 1 157, 1082, 1032, 781, 746 [Synthesis Example 9] Synthesis of 4-((imidazole-11-ylmethyl) -13- [3- (quinolin-12-ylmethyloxy) benzoyloxy] phenoxyacetic acid (III-12)

(1) Synthesis of methyl 2-hydroxy-4-methoxymethoxybenzene 97% of methyl 2,4-dihydroxybenzoate (19.0 g,

After dissolving 110 millimoles) in dry THF (10 OmL), chloromethyl methyl ether (8.4 OmL, 110 mmol) was added dropwise over 3 minutes under salt ice cooling. Stirred for 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 distilled off under reduced pressure, ethyl acetate (20 OmL) was added, and the insolubles were filtered. The ethyl acetate layer was washed with saturated saline (20 OmL) 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 (black-mouthed form) to give 14.7 g (yield 63.1%) of the title compound (1) as a pale yellow color Obtained as an oil.

 Ή-NM R (C D C 13, 400 MHz): 5 =

 3.47 (3 H, s)

 3.91 (3 H, s)

 5. 1 9 (2 H, s)

 6.53 (1 H, d d, J = 2 H z, 8 H z)

 6.6 1 (1 H, d, J = 2 H z)

 7.74 (1 H, d, J = 8 H z)

 1 0.88 (1 H, s)

 (2) Synthesis of 2-hydroxy-4-methoxyethoxybenzyl alcohol Lithium aluminum hydride (729 mg, 19.2 mmol

) Was suspended in dry ether (5 OmL), and a solution of (1) (3.40 g. 16.0 mmol) in dry ether (30 mL) was added dropwise over 10 minutes under ice-cooling. After stirring at room temperature for 3 hours, the mixture was heated and refluxed for another 4 hours. Under ice-cooling, ether (5 OmL) was added to the reaction solution, and then a saturated aqueous solution of sodium sulfate was added. Then, THF (150 mL) was added and decantation was performed. THF (150 mL) was added to the residue again, decanted, and distilled off under reduced pressure together with the THF layer described above. Zanhama To the mixture was added water (10 OmL), and extracted with ethyl acetate (10 OmL). 0.5N hydrochloric acid was added to the aqueous layer to adjust the pH to 7, and then extracted with ethyl acetate (100 mL × 2). The extract was combined with the above ethyl acetate layer and dried over anhydrous sodium sulfate. The title compound (2) obtained by evaporating the solvent under reduced pressure was used for the next reaction as a crude product.

 (3) Synthesis of 4-methoxyethoxy-2- [3- (quinolin-1-ylmethyloxy) benzyloxy] benzyl alcohol

 The above compound (2) (60 Omg) was dissolved in dry DMF (5 mL) under nitrogen atmosphere, and 60% sodium hydride (157 mg, 3.93 mmol) was added under ice-cooling. And stirred for 1 hour. Then, a solution of 3- (2-quinolinylmethyloxy) benzyl chloride (compound (2) of Synthesis Example 2) (926 mg, 3.26 mmol) in dry DMF (5 mL) was added under ice-cooling. The mixture was stirred at room temperature for 10 minutes. The reaction solution was poured into ice water (20 OmL), extracted with ethyl acetate (10 OmL X 2), washed with water (100 mL X 2) and saturated saline (100 mL), and dried over anhydrous sodium sulfate. It was dried in a realm. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by medium pressure liquid chromatography (chloroform-methanol / chloroform = 1200) to give the title compound (3) 82 Omg ((1) From 52.6%) as a yellow oil.

H-NMR (CDC13, 400MHz): δ =

 2.40 (1 H, t, J = 6 H z)

 3.45 (3 H, s)

 4.59 (2 H, d, J = 6 H z)

 5.04 (2H, s)

 5. 1 2 (2 H, s)

 5.40 (2H, s)

 6.58-662 (2H, m)

 6.97-.16 (4H, m)

 7.29 (1 H, t, J = 8 H z)

 7.55 (1 H, t, J = 8 H z)

7.65 (1 H, d, J = 8 H z) 7.73 (1H, ddd, J = 1Hz, 8Hz, 7Hz)

 7.82 (1 H, d, J = 8 H z)

 8.09 (1 H, d, J = 8 H z)

 8.1 7 (1 H, d, J = 8 H z)

 (4) Synthesis of 4- (imidazo-1-ylmethyl) -1-3- [3- (quinoline-1-ylmethyloxy) benzyloxy] phenol

 Dry imidazole (190 mg, 2.79 mmol) in a nitrogen atmosphere

(5 mL), and then add 60% sodium hydride (223 mg, 5.

(58 mmol) and stirred for 20 minutes.

 Separately, the above compound (3) (60 O mg, 1.39 mmol) was dissolved in dry methylene chloride (10 mL) under nitrogen atmosphere, and then thionyl chloride (0. 1

(1 mL, 1.51 mmol), and the mixture was stirred for 30 minutes, and the solvent was distilled off under reduced pressure. A dry DMF (5 mL) solution of the residue was added to the above reaction solution, and the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into ice water (150 mL), extracted with ethyl acetate (100 mL x 2), and then extracted with water (100 mL x 2) and saturated saline (100 mL). It was washed and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was roughly purified by medium-pressure liquid chromatography (form of chromatoform / methanol / form of chloroform = 1Z50). This crude product (40 O mg) was mixed with 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. Further, 1N hydrochloric acid (2.4 mL) was added, and the mixture was heated with stirring at 50 for 4 hours. The solvent was distilled off under reduced pressure, and water (2 O mL) and 1 N hydrochloric acid were added under ice cooling to adjust the pH to 7. The precipitated crystals were filtered off, washed with water (1 O mL), and dried under reduced pressure to give 152 mg (yield 41.9%) of the title compound (4) as a white amorphous substance. Obtained.

 'H-NMR (CDC13, 400 MHz): 5 =

 4. 7 9 (2 H, s)

 4.87 (2 H, s)

 5.30 (2 H, s)

6.40 (1 H, dd, J = 2 H z, 8 H z) 6 4 5 (1 H, d, J = 2 H z)

 6 7 7 to 6.96 (6H, m)

 7 1 6 1 H, t, J = 8 H z)

 7 4 3 1 H, s)

 7 50 1 H, t, J = 8 H z)

 7 6 11 H, d, J = 8 Hz)

 7 68 1 H, d d d, J = 1 Hz 8 Hz, 7 Hz)

 7 7 6 1 H, d, J = 8 H z)

 8 0 5 1 H, d, J = 8 H z)

 8 1 2 1 H, d, J = 8 H z)

 (5) Synthesis of ethyl 4- (imidazole-11-ylmethyl) -13- [3- (quinolin-2-ylmethyloxy) benzyloxy] phenoxyacetate The above compound (4) (150 mg, 0.1 mg 343 mmol) was dissolved in dry DMF (4 mL), and then 60% sodium hydride (15 mg, 0.375 mmol) was added under ice cooling, followed by stirring for 20 minutes. Then, under ice-cooling, 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), extracted with ethyl acetate (100 mL X 2), and 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 = 1Z100) to give 60 mg (yield 33.3%) of the title compound (5). Obtained as a pale yellow oil.

 lH-N M R (CDC l a, 400 M H z): δ =

 1.2 8 (3 H, t, J = 7 H z)

 4.25 (2 H, t, J = 7 H z)

 4.5 6 (2 H, s)

 4.95 (2H, s)

 4.99 (2 H, s)

 5.39 (2H, s)

6.36 (1 H, dd, J = 2 H z, 8 H z) 6 57 1 H. D, J = 2 H z)

 6 84 1 H, s)

 6 9 1 7.02 (5 H, m)

 7 30 1 H, t, J = 8 H z)

 7 45 1 H, s)

 7 53 1 H, t, J = 8 H z)

 7 65 1 H, d, J = 8 H z)

 7 72 1 H, d d d, J = 1 Hz 8 Hz, 7 Hz)

 7 80 1 H, d, J = 8 H z)

 8 07 1 H, d, J = 8 H z)

 8 1 6 1 H, d, J = 8 H z)

 (6) Synthesis of 4- (imidazole-1-ylmethyl) -3- [3- (quinoline-1-ylmethyloxy) benzyloxy] fuunoxyacetic acid (III-12) Compound (5) (57 mg, 0.11 mi) Was dissolved in ethanol (5 mL), 1N aqueous sodium hydroxide solution (0.2 mL) was added under ice-cooling, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and water (10 mL) and 1 N hydrochloric acid were added under ice-cooling to obtain pH 7. After filtering the precipitated crystals, the crystals were washed with water (5 mL) and dried under reduced pressure to obtain 41 mg (yield: 75.9%) of the title compound (6) as white crystals.

 m p: 1 37 to 1 39

 Ή-NM R (CD, 0 D, 400 MHz): 6 =

 4.46 (2 H. s)

 5 07 (2 H s)

 5 14 (2 H s)

 5 37 (2 H s)

 6 5 1 (1 H d d J = 2, 8 H z

 6 66 (1 H, d, J = 2 H z)

 6 95 (1 H, d, J = 8 H z)

7 02〜7.25 (5H, m) 7 3 1 (1 H, t, J 8 H z)

 7 6 1 (1 H. T, J 8 H z)

 7 69 (1 H, d, J 8 H z)

 7 78 (1 H, t, J 8 H z)

 7 93 (1 H, d, J 8 H z)

 8 03 (1 H, d, J 8 H z)

 8 25 (1 H, s)

 8 34 (1 H, d, J = 8 H z)

IR (KBr) cm " ¹ :

 3427, 3 1 37, 1 6 1 6, 1 587, 1454, 1 383, 1 286, 1 1 7 1, 1 1 26, 1 053, 825.762

 [Synthesis Example 10] Synthesis of 4-((imidazole-11-ylmethyl) -13- [3- (quinoline-12-ylmethyloxy) benzoylamino] phenoxyacetic acid (IV-1) (1) 3-nitro-14-methylphenol Synthesis of

 Water (50 OmL) was cooled in an ice bath, concentrated sulfuric acid (183 mL) was slowly added, and 4-amino-2-nitrotoluene (25.0 g, 164 mmol) was added. Warm up to dissolve solids. After cooling to 15X, 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. Further, urea (1025 g, 20, 8 mmol) and ice (8 g) were added, and the mixture was released at 0 (solution A).

Separately, concentrated sulfuric acid (167 mL), water (167 mL), and sodium sulfate (250 g) were mixed in a flask equipped with a cooling device for distillation, and heated to reflux. The solution A was dropped therein, and a yellow effluent was collected (the dropping speed of the solution A and the flowing speed of the yellow distillate were combined). After the addition was completed, water (30 OmL) was added dropwise to the residue, and the distillation was continued. The effluents were combined, extracted with ether (250 mL, 200 mL), and then extracted with a 10% aqueous sodium hydroxide solution (40 OmL) and water (10 OmL). The extract was acidified by adding concentrated hydrochloric acid, and extracted again with ether (200 mL, 15 OmL). After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 9.40 g (yield: 37.4%) of the title compound (1) as pale brown crystals. In addition, water (50 O mL), extracted with ether (500 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove 6.4 O g of the crude product of the title compound (1) in brown. Obtained as crystals.

 mρ: 76.6 to 77.4 4

 1 H-N M R (CDC 13, 400 MHz): δ =

 2.52 (3 Η, s)

 5.09 (1 Η, s)

 7.00 (1 Η, d d, J = 2 Η ζ, 8 Η ζ)

 7.20 (1 Η, d, J = 8 Η ζ)

 7. 4 7 (1 Η, d, J = 2 Η ζ)

 (2) Synthesis of 4-methoxy-2-nitrotoluene

 Acetonitrile (124 mL) was added to the above compound (1) (9.30 g, 60.7 mimol) and anhydrous potassium carbonate (12.6 g, 91.2 mimol), and dimethyl sulfide was added. (7.2 mL, 75.9 mol) was added, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, a saturated aqueous solution of glycine (31 mL) was added to the residue, and the mixture was stirred at 50 for 1 hour. After cooling to room temperature, the mixture was extracted with ether (31 mL × 2), and washed with iN aqueous sodium hydroxide solution (15 mL). After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and 10.0 g (purity: 98.3%, yield: 96.9%) of the title compound (2) was obtained as a yellow oil. Obtained.

 Ή-NMR (CDC 1 s. 400 MHz): δ =

 2.53 (3 Η, s)

 3.85 (3 Η, s)

 7.06 (1 Η, d d, J = 2 Η ζ, 8 Η ζ)

 7.2 3 (1 Η, d, J = 8 Η ζ)

 7.50 (1 Η, d, J = 2 Η ζ)

 (3) Synthesis of α- (imidazole-1-yl) 1-4-methoxy-2-nitrotoluene

Compound (2) (8.53 g, purity 98.3%, 50.2 mmol) and N-promosquenimide (NBS, 8.93 g, 50.2 mmol) were treated with carbon tetrachloride. Suspended in nitrogen (60 mL) and stirred for 50 minutes under irradiation with a tungsten lamp (500 W). After cooling the reaction solution on ice, insolubles were removed by filtration and washed with carbon tetrachloride (15 mL). After combining the base solution and the washing solution, the solvent was distilled off under reduced pressure to obtain residue A.

 Separately, imidazole (3.42 g. 50.2 mmol) is dissolved in dry dimethylformamide (17 mL), and the mixture is cooled with ice and cooled to 60% sodium hydride (2.0, 50.3 mmol). Was added little by little, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was again ice-cooled, and a solution of the above-mentioned residue A in dry DMF (2 OmL) was added dropwise, followed by stirring at room temperature for 2 hours. The reaction solution was poured into ice water (10 OmL), extracted with a black hole form (5 OmL x 2), washed with water (100 mL x 2), 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 form to methanol / chloroform form = 1 to 50) to give 6.38 g (purity: 97.2%, yield: 53.0%) )) Was obtained as a pale yellow oil.

 Ή-NM R (CDC1a, 400MHz): 6 =

 3.88 (3H, s)

 5.48 (2 H, s)

 6.80 (1 H, d, J = 8 H z)

 6. 93 (1 H, t, J = 1 Η ζ)

 7.1 1 (1 Η, d d, J = 2 Η ζ, 8 Η ζ)

 7.13 (1 1, b rs)

 7.57 (1 Η, s)

 7.65 (1 Η, d, J = 2 Η ζ)

(4) Synthesis of 4-((imidazole-11-ylmethyl) -13-nitrophenol) The above compound (3) (6.38 g, purity 7.2%, 26.6 mmol) was dissolved in benzene (63 OmL). Under ice-cooling, anhydrous aluminum trichloride (12.1 g. 90.7 mmol) was added, and the mixture was stirred at 60 for 1 hour and at 90 for 2 hours. After cooling the reaction solution with ice, ice water (6 Oml) and concentrated hydrochloric acid (15 mL) were added, and the aqueous layer was separated. Under ice-cooling, add solid sodium hydroxide until the pH becomes 7, remove the precipitated gel-like substance by filtration, and then form / methanol = 1/10 mixed solvent And the gel was dried. The solution a and the washing solution are combined, the solvent is distilled off under reduced pressure, the residue is combined with the dried gel substance, and silica gel column chromatography is performed.

Purification was carried out using (form: methanol to methanol Z form: 2Z25) to give 3.10 S (53.2%) of the title compound (4) as pale yellow crystals.

 m p: 2 13 to 2 14

_{Ή - NM R (CD 3 0} D, 4 00 MH z): δ =

 5.47 (2 H, s)

 6.98 to 7.01 (1H, m)

 7.01 (1H, d, J = 8Hz)

 7.07 to 7.10 (1H, m)

 7.08 (1 H, d d, J = 2 H z, 8 H z)

 7. 4 8 (1 H, d, J = 2 H z)

 7.7 1 (1 H, s)

 M S (FAB): m / z 220 (MH

 (5) Synthesis of ethyl 4- (imidazole-11-ylmethyl) 1-3-2 trophenoxyacetate

 In a nitrogen atmosphere, the above compound (4) was dissolved in 1.00 g (4.56 mmol) of dry dimethylformamide (3 O mL), and then cooled to 60% sodium hydrogen hydride under ice-cooling. mg (5.03 mmol) was added and stirred for 30 minutes. Then, ethyl ethyl bromoacetate (0.51 mL, 4.60 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 6 hours. The reaction solution was poured into ice water (200 mL), extracted with ethyl acetate (100 mL X 2), and 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 resulting crude product was purified by medium-pressure liquid chromatography (chloroform-methanol-chloroform = 1/50) to give 916 mg of the title compound (5) (yield 6%). 5.9%) as pale brown crystals.

 'Η-NMR (CDC1a, 400 MHz): δ =

 1.3 1 (3 Η, t, J = 7 Hz)

4.28 (2 H, q, J = 7 H z) 4.69 (2H, s)

 5.49 (2 H, s)

 6.78 (1 H, d, J = 8 H z)

 6.93 (1 H, s)

 7.1 1 to 7.1 4 (2H, m)

 7.57 (1 H, s)

 7.66 (1 H, d, J = 2 H z)

 (6) Synthesis of ethyl 3-amino-4-1 (imidazole-11-ylmethyl) phenoxy acetate

 After dissolving the above compound (5) (802 mg, 2.63 mmol) in ethanol (40 mL), 10% palladium Z-carbon (24 Omg) was added, the atmosphere was replaced with hydrogen, and the mixture was stirred at room temperature for 2 hours. The catalyst was removed, and the mother liquor was distilled off under reduced pressure to obtain 682 mg (yield: 94.3%) of the title compound (6) as pale brown crystals.

 m p: 99 one 1 0 1

 lH-NMR (CDC1a, 400MHz): δ =

 1.29 (3 Η, t, J = 7 Η ζ)

 3 8 1 (2 Η, b r s)

 4 25 (2 Η, q, J = 7 Η ζ)

 4 56 (2Η, s)

 4 99 (2 Η, s)

 6 28〜6.3 1 (2 Η, m)

 6 89 (1Η, s)

 6 94 (1 Η, d, J = 8 Η ζ

 7 05 (1 Η, s)

 7 60 (1 Η, s)

(7) Synthesis of methyl 3- (quinoline-2-ylmethyloxy) benzoate Under a nitrogen atmosphere, methyl 3-hydroxybenzoate (5.00 g, 32.9 mmol) was dried in dimethylformamide (10 OmL). ), Add 1.45 g (36.3 mimol) of 60% sodium hydride under ice-cooling, and stir for 30 minutes. did. 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 X 2), and 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 resulting crude product was purified by medium pressure liquid chromatography (ethyl acetate hexane = 1/30-IZ5) to give 5.40 g of the title compound (7). (Yield 56.0%) as pale yellow crystals.

 m p: 54 ~ 5 6

 'Η-NMR (CDC 13, 400 MHz): δ =

 3.90 (3 Η, s)

 5. 4 2 (2 Η, s)

 7.2 2 (1,, m)

 7.35 (1 H, t, J = 8 Hz)

 7.5 5 (1 H, m)

 7.65 to 7.6.8 (2H, m)

 7.72 to 77.6 (2H, m)

 7.83 (1 H, d, J = 8 H z)

 8.09 (1 H, d, J = 8 H z)

 8.1 9 (1 H, d, J = 8 H z)

 (8) Synthesis of 3- (quinoline-1- 2-methylmethyloxy) benzoic acid

 The above compound (7) (5.30 g, 18.1 millimol) was dissolved in methanol (50 mL), and the mixture was dissolved in ice-cooled 1N aqueous sodium hydroxide solution (54.3 mL) and Methanol (10 O mL) was added, and the mixture was stirred at room temperature for one hour. The solvent was distilled off under reduced pressure, and water (100 mL) and 1 N hydrochloric acid were added to the residue to adjust the pH to 7. The precipitated crystals were filtered, washed with water (50 mL × 2), and dried under reduced pressure to obtain 74 g (yield: 93%) of the title compound (8) as pale yellow crystals.

 m p: 1 82 to 1 84

_{Ή - NM R (CD 3 0} D, 4 00 ΜΗ ζ): δ =

5.44 (2 Η, s) 7.3 1 (1 H, dd, J = 2, 8 H z)

 7.4 1 (1 H, t, J = 8 Hz)

 7.6 3 to 7.7 1 (3H, m)

 7.76 to 7.84 (2H, m)

 7.98 (1 H, d, J = 8 H z)

 8.08 (1 H, d, J = 8 H z)

 8.45 (1 H, d, J = 8 H z)

 (9) Synthesis of ethyl 4- 3 — [3- (quinoline-2-ylmethyloxy) benzoylamino] phenoxyacetate

 Under a nitrogen atmosphere, thionyl chloride (1.2 mL) was added to the above compound (8) (500 mg, 1.79 mmol) under ice-cooling, followed by stirring for 2 hours. The solvent was distilled off under reduced pressure, and the residue was suspended in dry form (5 mL). Under ice cooling, 1.3 mL (9.33 mmol) of dry triethylamine was added, and the mixture was stirred for 10 minutes. did. Then, a solution of the above 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 (2 O mL) was added to the reaction solution, and the mixture was poured into ice water (5 O mL). After extraction with methylene chloride (5 O mL), the extract was washed with water (5 O mL) and saturated saline (5 O mL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by medium-pressure liquid chromatography (methanol-nocrophore form = 110 to 1 Z50) to give the title compound (9) 398 mg (Yield 41.5%) was obtained as a pale yellow amorphous compound.

 Ή-NM R (C DC 1 a, 400 MHz): δ =

 1.2 9 (3 Η, t, J = 1 Hz)

 4 2 6 (2 H, q, J = 7 H z)

 4 6 2 (2 H, s)

 5 0 8 (2 H, s)

 5 4 2 (2 H, s)

 6 8 0 (1 H, d d, J = 2, 8 H z

 6 8 5 (1 H, s)

7 0 6 to 7.09 (2H, m) 7 1 9 ~ 7.23 (2H, m)

 7 35 (1 H, t, J = 8 H z)

 7 43-7.49 (2H, m)

 7 55 (1 H m)

 7 66 (1 H d, J = 8 H z)

 7 73 (1 H m)

 7 83 (1 H d, J = 8 H z)

 7 9 1 (1 H s)

 8 07 (1 H d, J = 8 H z)

 8 20 (1 H, d, J = 8 H z)

 Synthesis of (10) 4-Imidazole-1-ylmethyl) 13- [3- (quinolin-1-ylmethyloxy) benzoylamino] phenoxyacetic acid (IV-1) 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 hours. After evaporating the solvent under reduced pressure, water (5 mL) and 1 N hydrochloric acid were added under ice-cooling to give pH 7. The precipitated crystals were filtered, washed with water (1 OmL), and dried under reduced pressure to obtain 294 mg (yield: 83.1%) of the title compound (10) as white.

 m: 1 90 ~ 1 92

¹ H-NMR (CD ₃₀ D, 400 MHz): δ =

 4.57 (2 H, s)

 5.29 (2 H, s)

 5.43 (2 H, s)

 6.93 to 6.96 (2H, m)

 7.23〜7.3 1 (4 H, m)

 7.44 (1 H. t, J = 8 H z)

 7.5 1 to 7.63 (3H, m)

 7.74 (1 H, d, J = 8 H z)

7.79 (1 H, m) o

CO

89 ^ ΐ ΐ

 0 o ω ^ 0 Λ-

N N N

X X X in

 00 O 00 t 00

II II II CO

 -3 -3 <n T) M -a ΙΛ

 CO CM

 ε t CD o n CM

ΙΩ in Oi O

[Synthesis example 1 1] 4- [3- (Imidazo-l-l-yl) provir] 1-2- [2-oxo-l 2- [3-quinolin-l-yl-methyloxy) phenylaminodiethyl] benzoic acid ( IV-2)

 (1) Synthesis of 5-aminophthalide

Zinc dust (50.0 g, 1.67 mol), copper sulfate (70 mg, 0.44 mmol), and sodium hydroxide (16.0 g, 0.67 mol) were added to water (6 OmL). Suspended. Under ice-cooling, gradually add 4-aminophthalimide (25.0 g, 0.15 mol), add water (7 OmL), and add 10 to 70-80 * C. Time Heated. Insolubles were removed by filtration through celite. Concentrated hydrochloric acid was added to the resulting aqueous solution under ice-cooling to adjust the pH to 2, and the mixture was heated under reflux for 2 hours. After cooling, sodium carbonate was added to adjust the pH to 8, and the precipitated crystals were collected to quantitatively obtain 22.9 _g of the title compound (1) as light brown crystals.

Ή-NMR (CD ₃₀ D, 40 OMH z): δ =

 5.1 7 (2 H, s) (1 H, s)

 6.65 (1 H, s)

 6.73 (1 H, d d, J = 8 H z, 2 H z)

 7.51 (1 H, d, J = 8 H z)

 (2) Synthesis of methyl 5-amino-2-methoxycarbonylphenyl acetate

The above compound (1) (22.9 g, 0.15 mol) and potassium cyanide (11.5 g, 0.18 mol) were suspended in dimethyl sulfoxide (2 15 mL), and the suspension was 170 to 175 For 1 hour. To the residue obtained by evaporating the solvent under reduced pressure was added a 4N aqueous solution of sodium hydroxide (12 OmL), and the mixture was heated under reflux for 5 hours. Further, methanol (250 mL) and concentrated sulfuric acid (25 mL) were added to the residue obtained by evaporating the solvent of the reaction solution under reduced pressure, and the mixture was refluxed for 5 hours. Water was added to the residue obtained by distilling off the solvent, and the residue was neutralized with a 1N aqueous sodium hydroxide solution. Here, insolubles were separated and extracted with black-mouth form. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The crude product thus obtained was recrystallized (chloroform, methanol ether, hexane) to give the title compound (2) 5. 79 g (yield 16.8%) were obtained as pale brown crystals.

 Ή-NMR (CDC1a, 400 MHz): δ =

 3.70, 3.80 (6Η, each s)

 3.87 (2 H, s)

 3.93 (2 H, s)

 6.48 (1 H. D, J = 2 H z)

 6.5 7 (1 H, d d, J = 8 H z, 2 H z)

 7.88 (1 H, d, J = 8 H z)

 (3) Synthesis of methyl 5-iodo-2-methoxycarbonylphenylacetate

The above compound (2) (1.56 g, 7.0 mmol) was dissolved in a mixture of concentrated hydrochloric acid (3.3 mL) and water (4.4 mL), and sodium nitrite (0. 53 g, 7. 7 mmol) cooled under stirring, addition takes 1 0 minutes 5 below were攢拌3 0 minutes at below 5 ^e C. Potassium iodide (3.92 g, 23.6 mmol) was added to the obtained red suspension, and the mixture was stirred at room temperature for 1 hour and left to stand still. The reaction mixture was extracted with ether, washed sequentially with water, saturated aqueous sodium bicarbonate, 5% aqueous sodium bisulfite, and then with saturated saline, and dried over sodium sulfate. The solvent was evaporated to give a red oil (1.41 g), which was subjected to medium pressure silica gel column chromatography, and eluted with chloroform to give 1.04 g (yield) of the title compound (3) as a yellow oil. Rate 34.2%).

 Ή-M R (C D C 1 a, 400 MHz): δ =

 3.70 (3 Η, s)

 3.86 (3 Η, s)

 3.95 (2 Η, s)

 7.64 (1 Η, m)

 7.7 to 7.8 (2H, m)

MS (EI): m / z 334 (MH ⁺ )

 (4) Synthesis of methyl 5- (3-hydroxy-1-bromovinyl) -12-methoxycarbonyl phenylacetate

The above compound (3) (666 mg, 2 mmol), propargyl alcohol (2 24 mg, 4 Mi Rimoru), palladium chloride (7m g, 0. 04 Mi Rimoru), copper iodide (1 3m _g, 0. 068 mmol), Bok riff enyl phosphine Lee emissions (1 9 mg, 0. 037 Mi ) And getylamine (8 mL) were mixed and stirred at room temperature under a nitrogen atmosphere for 21 hours. Diethylamine was distilled off under reduced pressure, extracted with ethyl acetate, washed successively with 2N hydrochloric acid, water, and then with saturated saline, 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). 467 mg (yield: 89.0%) were obtained as slightly yellow crystals.

 mp: 88 to 91 X:

 H-NMR (C D C 13, 400 MHz) δ =

 1.67 (1 H, t, J = 6 Η ζ)

 3.70 (3 H, s)

 387 (3 H, s)

 3.98 (2 H, s)

 4.50 (2 H, d, J = 6 Η ζ)

 7.33 (1 H, s)

 7.41 (1 Η, d, J = 8 Η ζ)

 796 (1 Η, d, J = 8 Η ζ)

 I R (Κ Β r) cm- ':

 3350, 2950, 2350, 2330, 1 730, 1 7 1 0, 1 60 0, 1430, 1 420, 1 345, 1 300, 1 275, 1 260, 1 200, 1 1 70, 1 085.1 0 1 0, 740

 (5) Synthesis of methyl 5- (3-hydroxypropyl) 1-2-methoxycarbonylphenylacetate

The above compound (4) (127 mg, 0.48 mmol) was dissolved in methanol (2.5 mL), 10% palladium / carbon (13 mg) was added, and the mixture was heated to room temperature under a hydrogen atmosphere at room temperature. Stirred for hours. The insolubles were separated, and the resulting solution was concentrated under reduced pressure to obtain 124 mg of a colorless oily substance. The compound (5) was eluted with a mixed solvent of the following solvent: 11.5 mg (yield 81%) as a colorless oil.

 Ή-NM R (C D C 13, 400 MHz): δ =

 1. 2 7 (1 Η, t, J = 5 Η ζ)

 1.90 (2 Η, m)

 2.75 (2 Η, t, J = 8 Η ζ)

 3.68 (2 Η, m)

 3.70 (3 Η, s)

 3.85 (3 Η, s)

 3. 9 9 (2 Η, s)

 7.09 (1 Η, d, J = 1 Η ζ)

 7.20 (1 Η, d d, J = 1 Η ζ, 8 8 ζ)

 7.95 (1 Η, d, J = 8 Η ζ)

 (6) Synthesis of methyl 5- (3-bromobromo) 1-2-methoxycarbonylphenylacetate

 The above compound (5) (105 mg, 0.39 mmol) and carbon tetrabromide (169 mg, 0.51 mmol) were dissolved in dichloromethane (lmL), and triphenylphosphine (1 34 mg, 0.51 mmol) was added over 15 minutes at room temperature with stirring. The mixture was stirred at room temperature for 21 hours, concentrated under reduced pressure, and subjected to medium pressure silica gel column chromatography. The residue was eluted with chloroform to give the title compound (6) as a colorless oil (119 mg, yield 92%).

 'H-NMR (CDC13, 400 MHz): δ =

 2.18 (2 Η, t t, J = 7 Η ζ, 7 Η ζ)

 2.82 (2 Η, t, J = 7 Η ζ)

 3.3 9 (2 Η, t, J = 7 Η ζ)

 3.70 (3 Η, s)

 3. 8 6 (3 Η, s)

 3. 9 9 (2 Η, s)

7.09 (1 Η, d, J = 1 Η ζ) 720 (1 H, dd, J = 1 H z, 8 H z)

 7.96 (1 H, d, J = 8 H z)

 (7) Methyl 5- [3- (imidazoyl 11-yl) Provir II-1-Methyl Synthesis of xycarbonylphenylacetate

 It was dissolved in sodium hydride (18 mg. 0.44 mmol)% anhydrous dimethylformamide (0.4 mL), imidazole (30 mg, 0.44 mmol) was added, and the mixture was stirred at room temperature for 1 hour. To the resulting solution, the above compound (6) (132 mg, 0.4 mmol) dissolved in anhydrous dimethylformamide (0.4 mL) was added, and the mixture was stirred at room temperature for 18 hours. To this reaction mixture, ethyl acetate and water were added, and the ethyl acetate layer was extracted with 1 N hydrochloric acid. The aqueous layer was made basic with potassium carbonate and extracted with ethyl acetate. This ethyl acetate layer was washed with water and then with a saturated saline solution, 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%).

 'Η— NMR (CDC1a, 400MHz): δ =

 2 1 4 (2 Η t t, J = 7 Η ζ 7 Η ζ)

 2 64 (2 Η, J = 7 Η ζ)

 3 7 1 (3 Η s)

 3 86 (3 Η s)

 3 94 (2 Η t, J = 7 Η ζ)

 3 99 (2 Η s)

 6 9 1 (1 Η s)

 7 03 (1 Η, d, J = 2 Η ζ)

 7 08 (1 Η, s)

 7 1 5 (1 Η, d d, J = 2 Η ζ, 8 Hz)

 7 46 (1 Η, s)

 7 96 (1 Η, d, J = 8 Η ζ)

 (8) Synthesis of 2- (3-nitrophenol) quinoline

m-Ditrophenol (1.67 g, 12 mmol) was dissolved in ethanol, and powdered sodium hydroxide (0.96 g, 24 mmol) and 2-chloromethylkis Phosphorus hydrochloride (2.14 g, 10 mmol) was added, and the mixture was stirred at room temperature overnight and heated under reflux for 4 hours. To the reaction mixture was added chloroform, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was crystallized from ethanol-hexane to obtain the title compound (8) (1.88 g, yield 67%) as a white crystalline powder.

 Ή-NM R (CDC 1a, 400MHz): δ =

 5.45 (2 Η, s)

 7.3 to 8.5 (10 Η, m)

 (9) Synthesis of 3- (2-quinolylmethyloxy) aniline

 The above 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 at an external temperature of 45. A solution of the product (9.5 g) in concentrated hydrochloric acid (9.5 mL) was added over 10 minutes, and the mixture was stirred for 8 hours and further stirred at room temperature overnight. The reaction mixture obtained by performing the same reaction from the above compound (8) (0.28 g, 0.1 mmol) was combined, and dichloromethane and 1N aqueous sodium hydroxide solution were added thereto to remove insolubles. After passing through celite, the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (form-form Z-ethyl acetate = 3Z 1). This was crystallized from ether-hexane to give the title compound (9) (1.03 g, yield 65%) as a pale yellow crystalline powder.

 1H-NMR (CDC1a, 400MHz): b:

 3.65 (2 H, s)

 5.35 (2 H, s)

 6-30 (1 H, d d, J = 2 Η ζ, 8 Η ζ)

 6.36 (1 Η, t, J = 2 Η ζ)

 6.43 (1 Η, d d, J = 2 Η ζ, 8 Η ζ)

 7. 04 (1 Η,, J = 2 Η ζ)

 7-5 ~ 7.9 (4 Η, m)

 8.07 (1 Η, d, J = 8 Η ζ)

8-1 7 (1 Η, d, J = 8 Η ζ) (1 0) 4— [3— (imidazole-11-yl) provir] 1-2— [2-oxo-2 -— [3- (quinolin-1-ylmethyloxy) phenylamino] ethyl] monobenzoic acid (IV -2)

 The compound (7) (1.17 g, 3.70 mmol) was dissolved in methanol (30 mL), a 1N aqueous sodium hydroxide solution (15 mL) was added, and the mixture was heated under reflux for 5 hours. The solvent was distilled off under reduced pressure to obtain a dinatrium salt (A). This was dissolved in water, acidified with 2N hydrochloric acid, and concentrated under reduced pressure. The residue was dissolved in toluene, which was concentrated under reduced pressure. This concentration operation was performed again, and then dried under vacuum 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 under reduced pressure twice from toluene to obtain an acid anhydride (C). The above compound

(9) (2.75 g, 11 mmol) was added, and the mixture was stirred at 120 for 2 hours. This reaction mixture was suspended in methanol, and insolubles were separated. This solution was concentrated under reduced pressure to obtain 4.5 g of a dark red solid, which was subjected to medium-pressure ram chromatography using Cosmosil 75C18-0PN (Nacalai Tesque), and mixed with a mixed solvent of water and methanol in 1 Z2. Removal of m gave 2.1 g of a red oil. This was subjected to medium pressure silica gel column chromatography, and eluted with a mixed solvent of methanol and Z-form (1 Z4) to give 0.28 g of the title compound (10) as a pale brown powder (yield: 15 %) Obtained.

 (A)

Η-ΝΜ R (D _a 0 400MHz): δ =

 2.14 (2 Η m)

 2.60 (2 Η t, J = 8 Η ζ)

 3.72 (2 Η s)

 4. 0044 ((22 ΗΗ, t, J = 7 Η ζ))

 7.0 to 7.2 (4 Η.m)

 7.39 (1 Η, d, J = 8 Η ζ)

 7.67 (1 Η, s)

 (Β)

Ή-Ν Μ R (D20, 400MHz): δ = 2.30 (2 H, tt, J = 7 Hz, 7 Hz)

2.78 (2 H, t, J = 7 H z)

 3.94 (2 H, s)

 4.26 (2 H, t, J = 7 H z)

 7.1 to 7.4 (4H, m)

 7.86 (1 H, d, J = 8 H z)

 8.57 (1 H, s)

 (O

 'H-NMR (D20, 400MHz): δ =

 2.33 (2 H. T t, J = 7 H z, 7 H z) 2.80 (2 H, t, J = 7 H z)

 4.29 (2 H, t, J = 7 H z)

 7.2 to 7.5 (4 H.m)

 7.89 (1 H, d, J = 8 H z)

 8.59 (1 H, s)

Compound (10)

 mp: 250 to 260 ° C (decomposition)

H-NMR (CD ₃₀ D, 400 MHz) b

2 1 2 (2 H m)

 2 59 (2 H t, J = 8 H z)

 3 96 (2 H s)

 4 03 (2 H t, J = 7 H z)

 5 29 (2 H s)

 6 72 (1 H d, J = 8 H z)

 7 0-7.2 (6 H, m)

 7 39 (1 H, s)

 7 58 (1 H, d d, J = 7 H z 8 H z) 7 65 (1 H, d, J = 9 H z)

7 76 (1 H, dd, J = 7 Hz 8 Hz) 7.79 (1 H, d, J = 8 Hz)

 7.84 (1 H, s)

 7.90 (1 H, d, J = 8H z)

 8.01 (1 H, d, J = 8 H z)

 8.3 1 (1 H, d, J = 9 H z)

 [Synthesis Example 1 2] Methyl 4- [3- (imidazole-1-yl) propyl] 1-21- [2-oxo-1-2- [3- (quinoline-1-ylmethyloxy) phenylamino] ethyl] benzoate ' Synthesis of dihydrochloride (IV-3)

 (1) Synthesis of methyl 4- [3- (imidazole-l-yl) propyl] -l- [2-oxo-l- 2- [3- (quinoline-l-yl-methyloxy) phenylamino] ethyl] benzoate

Methyl 5- [3- (imidazo-l-l-yl) provir] -l-2-methoxy-alponylphenyl acetate (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 was added a 1N aqueous sodium hydroxide solution (3.5 mL, 3.5 mmol) under ice cooling, and the mixture was stirred at room temperature for 16 hours. The methanol was distilled off under reduced pressure at 40 or less and washed with dichloromethane. The aqueous layer was neutralized with 2N hydrochloric acid, and cultivated at 50 under reduced pressure. 2N hydrochloric acid (2 mL) was added to the residue, and the mixture was concentrated under reduced pressure. The residue was concentrated twice under reduced pressure from toluene, and dried under vacuum to obtain a mixture (A) of monocarboxylic acid hydrochloride (white oil) and white crystals (salt). This was suspended in anhydrous dichloromethane (70 mL), and thionyl chloride (0.77 mL, 10.5 mmol) was added in 1 minute. After stirring at room temperature for 17 hours, the mixture was heated and refluxed for 2 hours. did. The reaction mixture was concentrated under reduced pressure, and anhydrous dichloromethane was added to the residue. The residue was suspended in anhydrous dichloromethane (35 mL), and a solution of 3- (quinoline-1-ylmethyloxy) aniline (1.75 g, 7 mmol) in anhydrous dichloromethane (18 mL) was added under ice-cooling. It was added dropwise over 10 minutes. After 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, and the dichloromethane layer was washed with saturated saline and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 3.03 g of a red oil, which was subjected to medium pressure silica gel column chromatography. The mixture was treated with O and eluted with a mixed solvent of methanol and Z-form form-1Z20 to give 0.39 g (yield 21%) of the title compound (1) as a yellow amorphous.

Mixture (A)

 Ή-ΝΜ R (D a 0 400 MHz): δ =

 2 30 2 Η t t, J = 7 Η ζ, 7 Η ζ)

 2 77 2 Η t, J = 7 Η ζ)

 3 87 3 Η s)

 3 98 2 Η s)

 4 26 2 Η t, J = 7 H z)

 7 1 8 1 Η s)

 7 28 1 Η d, J = 8 Hz)

 7 36 1 Η s)

 7 43 1 Η s)

 7 92 1 Η d, J = 8 H z)

 8 59 1 Η s)

Compound (1)

 Ή-ΝΜ R (C D C ", 400 MHz) δ =

 2.14 H, t t, J = 7 H z, H z)

 2 64 2 H, t, J = 7 H z)

 3 93 2 H, s)

 3 94 2 H, t, J = 7 H z)

 3 95 3 H, s)

 5 35 2 H, s)

 6 7 1 1 H, d d, J = 2 H z, 8 H z)

 6.92 1 H, s)

 7.0-7.4 (6 H, m)

 7.48 1 H, s)

 7.54 1 H, d d, J = 7 H z, 8 H z)

7.66 1 H, d, J = 9 H z) 7.72 (1 H, ddd, J = 1 Hz, 7 Hz, 8 Hz)

 7.81 (1 H, d d, J = 1 H z, 8 H z)

 7.88 (1 H, d, J = 8 H z)

 8.07 (1 H, d, J = 8 H z)

 8.1 7 (1 H, d, J = 9 H z)

 9.20 (1 H, s)

 (2) Methyl 4- [3- (imidazole-11-yl) propyl] 1-2- [2 1-year-old xo 2- [3- (quinolin-12-ylmethyloxy) phenylamino] ethyl] benzoate dihydrochloride Synthesis of salt (IV-3)

 The above compound (1) (0.17 g, 0.32 mmol) was dissolved in methanol (2 mL), and concentrated hydrochloric acid (0.055 mL, 0.66 mmol) was added. . This solution was concentrated under reduced pressure, water was added to the residue, and the operation of concentration under reduced pressure was repeated three times. The residue was dried under vacuum and pulverized to obtain 0.20 g (yield: 100%) of the title compound (2) as a yellow amorphous.

 Ή-NM R (D 20, 400 MHz): δ =

 2 2 7 (2 H. t t, J = 7 Η ,, 7 Η ζ)

 2 7 3 (2 Η, t, J = 7 Η ζ)

 3 7 6 (3 Η, s)

 4 0 3 (2 Η, s)

 4 2 5 (2 Η, t, J = 7 Η ζ)

 5 6 7 (2 Η.s)

 6 9 to 7.1 (2Η, m)

 7 2 to 75 C 6 Η, m)

 7.88 (1 Η, d, J = 8 Η ζ)

 7.90 (1 Η, d d, J = 7 Η ζ 8 Η ζ)

 8.02 (1 Η, d, J = 9 Η ζ)

 8.09 (1 Η, d d, J = 7 Η ζ 8 Η ζ)

 8. 1 8 (1 Η, d, J = 8 Η ζ)

8.2 1 (1 Η, d, J = 8 Η ζ)

080 1 '0 S T T '06 ΐ ΐ Ό L Z' 0 Z I 'οε¾ '06 I' 0 2 '009 I Ό L 9 T' O I L!

_: I _ UI O (J g) HI (2 H 6 = Γ 'P' HI) 66-8

 (s' H I) Z 9

₈ 6610 / _S 6df / X3d image 9 [Synthesis Example 13] Synthesis of 4-((imidazole-11-ylmethyl) 1-2- [3- (quinolin-2-ylmethyloxy) benzoylamino] phenoxyacetic acid (IV-4)

(1) Synthesis of 4-hydroxy-1--3-nitrobenzaldehyde

4-Hydroxybenzaldehyde (20.0 g, 164 mmol) is suspended in sulfuric acid (8 OmL), and nitric acid (12.7 mL, specific gravity 1.38, 278 mmol) is cooled with water. Was added, and the temperature was gradually increased. Since an exothermic reaction started around 27, it was cooled on ice (the internal temperature rose to 55 * 0). After cooling to room temperature, the mixture was stirred at 35 * 0 for 5 minutes and cooled again with ice. The precipitated crystals were collected, washed with water (70 mL x 3), and dried under reduced pressure to obtain 13.2 _g (yield: 48.2%) of the title compound (1) as yellow crystals. .

 m p: 141.8 to 143.2

 lH-NMR (CDC1a, 400MHz): δ =

 7.32 (1 H, d, J = 8 H 2)

 8.14 (1 H, d d, J = 2 Hz, 8 Hz)

 8.64 (1 H, d, J = 2 H z)

 9.95 (1 H, s)

 1 1.02 (1H, s)

 (2) Synthesis of 4-methyloxymethyloxy 1-3-benzaldehyde The above compound (1) (10. Og, 59.8 mmol) was suspended in acetone (80 mL). At room temperature, potassium carbonate (8.82 g, 63.8 mmol) and chloromethyl methyl ether (4.8 mL, 63.8 mmol) were added, and the mixture was stirred for a while. Insolubles were removed by ill filtration, and the solvent was distilled off under reduced pressure. Water (200 mL) was added to the insoluble matter, and the residue was combined with the remaining S, extracted with ethyl acetate (200 mL, 100 mL), and washed with saturated saline (10 OmL). After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 11.0 g (yield (87.1%)) of the title compound (2) as yellow crystals.

 m p: 98.4 to 99.6 * C

 Ή-NMR (CDC1a, 400MHz): 5 =

3.55 (3 H, s) 5.40 (3 H, s)

 7.48 (1 H, d. J = 8 H z)

 8.05 (1 H, d d, J = 2 H z, 8 H z)

 8.32 (1 H, d, J = 2 H z)

 9.95 (1 H, s)

 (3) Synthesis of 4-methyloxymethyloxy 1-3-nitrobenzyl alcohol The above compound 2 (5.00 g, 23.7 mmol) was dried in THF (= tetrahydrofuran, 30 mL). ), Sodium borohydride (0.50 g, 13.2 mmol) was added little by little under ice cooling, and the mixture was stirred for 1 hour and 30 minutes while cooling in a water bath. The mixture was cooled on ice again, a saturated aqueous sodium sulfate solution (20 mL) was added little by little, and the precipitated crystals were removed by filtration, and THF was distilled off under reduced pressure. The residue was extracted with ethyl acetate (15 mL × 2), washed with saturated saline (20 mL × 2), and 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-11) to give 4.75 g (purity 97.6 96, yield 91.7%). Compound (3) was obtained as a yellow oil.

_{Ή - MR (CDC 1 a,} 400MH z): δ =

 1.78 (1 layer, J = 6 Hz)

 3.53 (3 H, s)

 4.70 (2 H, d, J = 6 H z)

 5.29 (3 H, s)

 7.3 1 (1 H, d, J = 8 H z)

 7.5 1 (1 H, d d. J = 2 H z, 8 H z)

 7.83 (1 H, d, J = 2 H z)

(4) Synthesis of 4-methyloxymethyloxy-3-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 (1 mL), and triphenylphosphine (2.59 g, 9.87 mmol) was added at room temperature to prevent the temperature from rising. , And stirred for 1 hour. The solvent was distilled off under reduced pressure, and ether (2 O mL) and ice water (1 OmL) were added to the residue. Removed. The crystals were washed with a small amount of ether, and the washing solution and the aqueous solution were combined and separated, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (Rica gel force chromatography) to obtain 1.80 g (yield: 85.8%) of the title compound (4) as yellow crystals.

 m p: 87.5 to 89.3

 Ή-NM R (C DC 1 a, 400 MHz): δ =

 3.53 (3H, s)

 4.46 (2 H, d, J = 6 H z)

 5.30 (3 H, s)

 7.30 (1 H, d, J = 8 H z)

 7.54 (1 H, d d, J = 2 H z, 8 H z)

 7.85 (1 H, d, J = 2 H z)

 (5) Synthesis of a- (imidazole-11-yl) -14-methyloxymethyloxy-13-toluene

 Imidazole (0.46 g, 6.76 mmol) was dissolved in dry DMF (2 mL), and a small amount of 60% sodium hydride (0.27 g, 6.75 mmol) was added under ice-cooling. The mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled again with ice, and the above compound

(4) A solution of (1.70 g, 6.15 mmol) in dry DMF (7 mL) was added dropwise, followed by stirring at room temperature for one minute. Pour the reaction solution into ice water (50 mL),

(15 mL × 3), extracted with water (50 mL × 2), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue S was purified by silica gel column chromatography (form: black form to methanol Z: form 50 = 50) to obtain 1.47 g.

(Yield 90.7%) of the title compound (5) was obtained as a yellow oil.

 Ή-NMR (C D C 1a, 400 Hz): δ =

 3.52 (3 Η s)

 5. 1 2 (2 Η s)

 5.29 (2 Η s)

 6.90 (1 Η t, J = 1 Hz)

7. 1 2 (1 Η brs) 7.26 (1H, dd, J = 2Hz, 8Hz)

 7.32 (1 H, d, J = 8 H z)

 7.5 6 (1 H, s)

 7.65 (1 H, d, J-2 H z)

 (6) Synthesis of 6- (imidazole-11-ylmethyl) -12-methyloxymethyloxyaniline

Under a nitrogen atmosphere, the above compound (5) (1.47 g, .5.5.58 mimol) was dissolved in ethanol (1 O mL), and 10% —palladium Z carbon (0.59 g, 0.55 mmol). The inside of the reaction system was replaced with hydrogen gas and stirred for 2 hours. Water purple gas was expelled from the reaction system, and the insolubles were removed by filtration, followed by washing with ethanol (10 mL). The solution and the washing solution were combined, and the solvent was distilled off under reduced pressure. Since the hydroxylamine compound as an intermediate remained, the residue was dissolved in ethanol (1 O mL) and 10% —palladium carbon (0.59 g, 0.555 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. After purging hydrogen gas from the reaction system and removing insolubles by filtration, the _β- based solution washed with ethanol (1 O mL) and the washing solution were combined, the solvent was distilled off under reduced pressure, and toluene (3 mL) was added to the residue. ) Was added and the solvent was distilled off under reduced pressure under vacuum to obtain 1.22 g (purity: 87.1%, yield: 81.7%) of the title compound (6) as yellow crystals.

 m p: 65.6 to 68.0

 Ή-NM R (C DC 1 a, 400 MHz): 6 =

 3.49 (3 H, s)

 4.98 (2 H, s)

 5. 1 9 (2 H, s)

 6.49 (1 H, d, J = 2 H z)

 6.5 2 (1 H, d d, J = 2 Η,, 8 Η ζ)

 6.89 to 6.91 (1 Η.m)

 6. 9 8 (1 Η, d. J = 8 Η ζ)

 7.09 (1 Η, b r s)

7.60 (1 Η, s) (7) Synthesis of N— [5— (imidazole-1-ylmethyl) -12-methyloxymethyloxyphenyl) 13— (quinolin-12-ylmethyloxy) penzamide

 3- (Quinolin-2-ylmethyloxy) benzoic acid (0.42 g, 50 mmol) synthesized in Synthesis Example 10 was added to thionyl chloride (0.96 mL, 13.2) under ice-cooling. After stirring for 3 hours, excess thionyl chloride was distilled off under reduced pressure, and the residue was dissolved in chloroform (2.4 mL), and triethylamine (1,06 mL, The mixture was stirred for 10 minutes, and a solution of the above compound (6) (0.40 g, purity 87.1%, 1.49 mmol) in chloroform (1.4 mL) was added. 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 and distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (cloth form to methanol Z form: 1/50). Title compound manufactured to 0. 30 g (yield: 40.9%) of (7) was obtained as a pale white crystals.

 m p: 141.0-; 143.4

lH-NM R (CDC l _a , 400MHz): δ =

 3.48 (3 H, s)

 5.08 (2 H, s)

 5.23 (2 H, s)

 5.46 (2 H, s)

 6.80 (1 H. d d, J = 2 H z, 8 H z)

 6.94 (1 H, t, J = 1 Hz)

 7.07 (1 H, b r s)

 7.13 (1 H, d. J = 8 Hz)

 7.20-7.25 (1H, m)

 7.40-7.47 (2H, m)

 7.53 to 7.59 (1 H.m)

7.59 to 7.62 (1 H.m) 7.5 5 (1 H, s)

 7.67 (1 H, d, J = 8 H z)

 7.75 (1 H, d d d, J = 1 Hz 8 Hz, 7 Hz)

 7.84 (1 H, d, J = 8 H z)

 8.10 (1 H, d, J = 8 H z)

 8.2 2 (1 H, d, J = 8 H z)

 8.5 3 (1 H, d, J = 2 H z)

 8.5 3 (1 H, s)

 (8) Synthesis of N- [2-hydroxy-5- (imidazole-11-methyl) phenyl] -13- (quinolin-12-ylmethyloxy) penzamide

 The above compound (7) (0.25 g, 0.51 mmol) was dissolved in a mixed solvent of HF (2 mL) and methanol (0.6 mL), and the mixture was cooled under ice-cooling. A 1N aqueous hydrochloric acid solution (1.6 mL) was added, and the mixture was stirred at room temperature for one minute. To the reaction solution was added a 1N aqueous hydrochloric acid solution (1.4 mL), and the mixture was stirred at 50 * Ό. After 4 hours and 5 hours, 1N aqueous hydrochloric acid solution (0.7 mL, 0.7 mL) was added. L) was added, and the mixture was stirred at the same temperature for 1 hour and 30 minutes. The reaction solution was cooled on ice, a saturated aqueous solution of sodium hydrogen carbonate was added until the pH became 7, and then water (1 O mL) was added. The precipitated crystals were collected, washed with water (1 Om LX 2), and dried under reduced pressure to obtain 0.22 g (yield 96.1) of the title compound (8) as pale yellow crystals. Was.

 m p: 1 0 5.6 6

^{1 H - NMR (CD, O} DZC DC la = 1/2 0. 400 MH z): δ:

 5.06 (2 Η, s)

 5.44 (2 Η, s)

 6.85 (1 Η, d d, J = 2 Η ζ, 8 Η Η)

 6.92 (1 Η, d, J = 8 Η ζ)

 6.95 (1 Η, t, J = I Η ζ)

 7.03 (1 Η, b r s)

 7.2 3 (1 Η, d d, J = 2 Η ζ, 8 Η ζ)

7.4 1 (1 Η, t, J = 8 Η ζ) 7.53-7.55 (1H, m)

 7.55 (1 H, s)

 7.56 ~ 7.61 (1H, m)

 7.63 (1 H, t, J = 2 H z)

 7.71 (1 H, d, J = 8 Hz)

 7.77 (1 H, d d d, J = 1 Hz 7 Hz, 8 Hz)

 7.85 (1 H, d, J = 2 H z)

 7.86 (1 H, d, J = 8 Hz)

 8.09 (1 H, d, J = 8 H z)

 8.26 (1 H. d, J = 8 H z)

 (9) Synthesis of tert-butyl 4- (imidazole-11-ylmethyl) 1-2- [31- (quinolin-12-ylmethyloxy) benzoylamino] phenoxyacetate

 The above compound (8) (0.20 g, 0.44 mimol) was suspended in a mixed solvent of dry acetone (4 mL) and dry DMF (1 mL), and anhydrous potassium carbonate (64 mg, 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. Further, anhydrous potassium carbonate (9 mg, 0.065 mmol) and tert-butyl bromoacetate (0.013 mL, 0.089 mmol) were added to the reaction solution, and the mixture was stirred at 60 ° C for 2 hours. Was distilled off under reduced pressure. Ice water (5 mL) was added to the remaining S, extracted with chloroform (1 OmL), washed with water (1 OmL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the remaining S was purified by silica gel column chromatography (form: black form to methanol Z: form 200) to give 0.20 g (yield 79.5%) of the title compound ( 9) was obtained as yellow crystals.

 m p: 137.6-139.4 Ό

 Ή-NMR (CDC1a. 400MHz): 6 =

 1.46 (9 H, s)

4.58 (2 H. s) 5 09 2 H, s)

 5 47 2 H, s)

 6 77 1 H, d d, J = 2 Hz 8 Hz)

 6 83 1 H, d, J = 8 H z)

 6 94 1 H, t, J = 1 H z)

 7 08 1 H, b r s)

 7 22 1 H, dd, J = 2 Hz 8 Hz)

 7 42 1 H, t, J = 8 H z)

 7 54 7.58 (1 H, m)

 7 55 1 H, s)

 7 62 1 H, d, J = 8 H z)

 7 69 1 H, d, J = 8 H z)

 7 1 to 7.77 (2H, m)

 7 84 (1 H, d, J = 8 H z)

 8 09 (1 H, d. J = 8 H z)

 8 20 (1 H, d. J = 8 H z)

 8 55 (1 H, d, J = 2 H z)

 9 23 (1 H, s)

(10) Synthesis of 41-imidazole-1-ylmethyl) 1-2- [3- (quinolinyl-ylmethyloxy) benzoylamino] phenoxyacetic acid (IV-4) Compound (9) (0.19 g, 0.19 g 34 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.66 mL, 8.68 mmol) was added under ice-cooling, followed by stirring at room temperature for 16 hours. The solvent was distilled off under reduced pressure, a mixed solvent of THFZ hexane = 1-3 (8 rnL) was added to the residue, and the precipitated crystals were collected and dried under reduced pressure. The obtained crystals were suspended in water (1 OmL), 0.28% aqueous ammonia was added until the pH reached 7, ethanol (5 mL) was further added, and the mixture was stirred at 40 for 20 minutes. The crystals were collected and washed with ethanol Z water-1Z2 mixed solvent (5 mL), ethanol (0.5 mL), ethanol hexane-1Z2 mixed solvent (3 mL), and hexane (2 mL), followed by drying under reduced pressure. 0.10 g (58.8% yield) Compound (10) was obtained as white crystals.

 m p: 97.0

 Ή-NM R (C Ds O D / C DC 1, = 1/20, 400 MHz) δ =

4 73 2 Η, s)

 5 1 0 2 Η, s)

 5 54 2 Η, s)

 6 84 1 Η, d d, J = 2 Η ζ 8 Η ζ)

 6 97 1 Η, t, J = 1 Η ζ)

 6 98 1 Η, d, J = 8 Η ζ)

 7 05 1 Η, b r s)

 7 26〜7.36 (1 Η, m)

 7 46 1 Η, t, J = 8 Η ζ)

 7 57 7.65 (1 Η, m)

 7 62 1 Η, s)

 7 73 1 Η d. J = 8 Η ζ)

 7 78 1 Η t, J = 8 Η ζ)

 7 84 1 Η d, J = 8 Η ζ)

 7 88 1 s s)

 7 89 1 Η d, J = 8 Η ζ)

 8, 1 0 1 Η d J = 8 Η ζ)

 8.32 1 Η d J = 8 Η ζ)

 δ. 43 1 Η d J = 2 Η ζ)

 I R (Β r) cm- ':

 34 1 0, 3064 1 664, 1 599, 1 541, 1 506, 147 9, 1 439, 1 404, 1 325, 1 271, 1 225.746

[Synthesis Example 14] Synthesis of 4- (imidazole-11-ylmethyl) 1-2- [4- (quinoline-12-ylmethyloxy) benzoylamino] phenoxyacetic acid (IV-5) (1) Methyl 4-[(quinoline-11) Synthesis of benzoyl) benzoate Methyl 4-hydroxybenzoate (0.71 g, 4.67 mmol) was dissolved in dry DMF (2 mL), and cooled to 60% sodium hydride (0.22 g, 5 mL) under ice-cooling. (50 mmol) was added in small portions 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 dichloromethane (15 mL) was added. ). The solution was poured into ice water (2 O mL), extracted with dichloromethane (20 mL), washed with water (30 mL) and saturated saline (2 O mL), and then dried over anhydrous sodium sulfate. Dried. The solvent was distilled off under reduced pressure, and the remaining S was roughly purified by silica gel column chromatography (form from chloroform to methanol / chloroform-1 / 100), and the obtained crystals were dissolved in ethyl acetate (lmL) by heating. Hexane (5 mL) was added while hot. Released at room temperature, and the precipitated crystals were collected. Ethyl acetate Z hexane = 15 mixed solvent (3 mL), ethyl acetate Z hexane = 1/10 mixed solvent (3 mL), and H The residue was washed with xanthine (3 mL), and dried in vacuo to give 0.94 g (yield 68.5%) of the title compound (1) as pale yellow crystals.

 m p: 1 14.0 to 1 15.0 * C

 Ή-NMR (CDC1a, 400 MHz): 5-3.88 (3H, s)

 5.44 (2 H, s)

 7.0 0 to 7.08 (2H, m)

 7.5 6 (1 H, d d d, J = 1 Hz 7 Hz, 8 Hz)

 7.64 (1 H, d, J = 8 H z)

 7.75 (1 H, d d d, J = 1 H z 7 H z, 8 H z

 7.83 (1 H, d. J = 8 H z)

 7.96 to 8.02 (2H, m)

 8.09 (1 H, d, J = 9 H z)

 8.2 0 (1 H, d, J = 9 H z)

 (2) Synthesis of 4-[(quinoline-1-ylmethyl) oxy] benzoic acid

The above (1) (0.50 g, 1.70 mmol) was dissolved in a mixed solvent of methanol (2 mL) and THF (2 mL), and the solution was cooled with ice to give a 1N aqueous solution of sodium hydroxide. (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 or less, the residue was suspended in water (2 mL), and a 1N aqueous hydrochloric acid solution was added under ice-cooling until pH 7 was reached. The crystals are collected, washed with water, and dried under vacuum to obtain 0.3 Omg (yield 7.18%) of the title compound (2) as pale yellow fe.

 m ρ: 209.0-2 11.4 (decomposition)

 lH-NMR (C DC ", 400 MHz): δ =

 5.43 (2 H, s)

 7.04 to 7.09 (2 Η, m)

 7.59 (1 Η, d d d, J = 1 Η ζ 7 Hz, 8 Hz)

 7.68 (1 Η, d, J = 8 Η ζ)

 7.77 (1 Η, d d d, J = 1 Η ζ 7 Hz, 8 Hz)

 7.86 (1 Η, d, J = 8 Η ζ)

 7. 99-8. 04 (2 Η, m)

 8.09 (1 Η, d, J = 8 Η ζ)

 8.25 (1 Η, d, J = 8 Η ζ)

 (3) Synthesis of Ν- [5- (imidazole-11-methyl) 1-2-methyloxymethyloxyphenyl] 141- (quinoline-12-ylmethyloxy) benzamide

To the above compound (2) (0.42 g, 1.50 mmol) was added thionyl chloride (0.96 mL, 13.2 mmol) and dichloromethane (2 mL) under ice cooling, and the mixture was stirred at room temperature for 3 hours. After that, excess thionyl chloride was distilled off under reduced pressure. The residue was suspended in black-mouthed form (2.4 mL), and triethylamine (06 mL, 7.60 mimol) was added under ice-cooling, and the mixture was searched for 10 minutes. Furthermore, 6- (imidazoyl-1-ylmethyl) -12-methyloxymethyloxyaniline (Compound (6) synthesized in Synthesis Example 13) (0.40 g, purity 87.1%, 1 (49 mmol) in chloroform (1.4 mL) and stirred overnight at room temperature. Ice water (1 OmL) was added to the reaction solution, and after stirring, the organic eyebrow was separated and washed with saturated aqueous sodium hydrogen carbonate solution (5 mL) .Dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Silica gel port Purification by column chromatography (chloroform-methanol Z methanolic form = 1Z50) afforded 0.24 g (yield 32.9¾) of the title compound (3) as yellow crystals.

 m: 158.4 to 161.8 * C

_{• H - NMR (CDC 1 3} , 400MHz) δ =

 3 49 3 Η, s)

 5 07 2 Η, s)

 5 25 2 Η, s)

 5 46 2 Η.s)

 6 78 1 Η, d d, J = 2 Η ζ, 8 Η Η)

 6 93 1 Η, t, J = 1 Η ζ)

 7 06 1 Η, b r s)

 7 10 7.15 (2 Η, m)

 7 12 1 Η, d, J = 8 Η ζ)

 7 54 1 Η, s)

 7 54 7.60 (1 Η, m)

 7 65 1 Η, d, J = 8 Η ζ)

 7 76 1 Η, d d d, J = 1 Η ζ 7 Η ζ, 8 Η ζ)

 7 82-7.88 (3 Η, m)

 8 10 (1 Η, d, J = 8 Η ζ)

 8 21 (1,, d. J = 8 Η)

 8 49 (1 Η, s)

 8 53 (1 Η, d, J = 2 Η ζ)

 (4) Synthesis of Ν- [2-hydroxy-5- (imidazole-11-ylmethyl) phenyl] -4-1 (quinolin-12-ylmethyloxy) benzamide

The above compound (3) (0.20 g, 0.40 mmol) was dissolved in a mixed solvent of THF (1.5 mL) and methanol (0.8 mL), and 1N hydrochloric acid aqueous solution (1.3 mL) was added under ice-cooling. ) And stirred overnight at room temperature. A 1N aqueous hydrochloric acid solution (1.0 mL) was added to the reaction solution, and the mixture was stirred at 50.After 4 hours and 5 hours, 1N each was added. An 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 and 30 minutes. The reaction solution was ice-cooled, a saturated aqueous solution of sodium carbonate in purple sodium hydroxide was added until the pH became 7, and then water (IOmL) was added. The precipitated crystals were collected, washed with water (1 OmL x 2), and dried under reduced pressure to obtain 0.17 g (yield 95.0%) of the title compound (4) as pale yellow crystals. ,

 rap: 2 18.8-222.0 l

 Ή-NM R (CD, 0 D / C D C 1, = 1/1/10, 400 MHz): 5 =

 5.05 (2 H, s)

 5 45 (2 H, s)

 6 82 (1 H, d d, J = 2 Hz 8 Hz)

 6 90 (1 H, d, J = 8 H z)

 6 95 (1 H, b r s)

 7 0 1 (1 H, b r s)

 1 0〜7.15 (2 H, m)

 7 54 (1 H, s)

 7 57 to 7.6 1 (1 H, m)

 7 68 (1 H, d, J = 8 H z)

 7 78 (1 H, d d d, J = 1 Hz 7 Hz, 8 Hz)

 7 87 (1 H, d, J = 8 H z)

 7 88 ~ 7.9 1 (2 H, m)

 7 92 (1 H, d, J = 2 H z)

 8 1 0 (1 H, d, J = 8 H z)

 8 26 (1 H, d, J = 8 H z)

 (5) Synthesis of tert-butyl 4- (imidazole-11-ylmethyl) -12- [4- (quinoline-1-ylmethyloxy) benzoylamino] phenoxyacetate

Compound (4) (0.15 g, 0.33 mmol) was used as a mixed solvent of dry acetone (3 mL) and dry DMF (0.75 mL), and anhydrous potassium carbonate (48 mg, 0.35 mmol) was added. ) And tert-butyl bromoacetate (0. The mixture was stirred at room temperature for 3 hours, and then stirred at 60 ° C for 2 hours and 30 minutes. Further, anhydrous potassium carbonate (14 mg, 0.10 mmol) and tert-butyl bromoacetate (0.019 mL, 0.13 mmol) were added to the reaction solution, and the mixture was stirred at 60 for 2 hours. The solvent was distilled off under reduced pressure. Ice water (5 mL) was added to the remaining beach, extracted with black-mouthed form (1 OmL), washed with water (1 OmL), 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 Z-chloroform = 3/100) to obtain 0.12 g (yield 63.6%) of the title compound. (5) was obtained as pale yellow crystals.

 m p: 1 27.4 to 1 30.0

 Ή-NM R (C DC 13, 400 Hz): δ

 1 479 H, s)

 4 58 2 H, s)

 5 08 2 H, S)

 5 46 2 H, S)

 6 75 1 H, d d, J = 2 H z. 8 H z)

 6 82 1 H, d, J = 8 H z)

 6 93 1 H, b r s)

 7 07 1 H, b r s)

 1 0〜7.15 (2 H, m)

 7 54 1 H, s)

 7 54-7.5.6 (1 H, m)

 7 67 1 H. D, J = 8 H z)

 7 75 1 H, d d d. J = 1 Hz 7 Hz, 8 Hz)

 7 84 1 H, d, J = 8 H z)

 7 96 8.01 (2 H, m)

 8 10 1 H, d, J = 8 H z)

 8 2 1 1 H, d .J = 8 H z)

8 54 1 H, d, J 2 Hz) 9.14 (1 H, s)

 (6) Synthesis of 4- (imidazole-11-ylmethyl) 1-2- [4-1- (quinolin-12-ylmethyloxy) benzoylamino] phenoxyacetic acid (IV-5) Compound (5) above (0.1-1 g, 0 19 mmol) was dissolved in dichloromethane (2 mL), trifluorosulfonic acid (0.37 mL, 4.87 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure. A mixed solvent of THF / hexane = 1Z2 (6 mL) was added to the remaining S, and the precipitated crystals were collected and dried under reduced pressure. The obtained crystals were attracted to water (6 mL), and 0.28% aqueous ammonia was added. Was added to ρH7, and ethanol (3 mL) was further added, followed by stirring at 40 * 0 for 20 minutes. The crystals are taken out of the furnace and mixed with ethanol / water = 12 mixed solvent (3 mL), ethanol (0.3 mL), hexane ethanol-12 mixed solvent (1.8 mL), and hexane (1.2 mL). After washing sequentially, drying under reduced pressure gave 0.06 g (yield 63.2%) of the title compound as pale brown crystals.

 m p: 213.8 to 215.6 * C

Ή-NM R (CD ₃₀ D / CDC 1 _s = 1/20, 400 MHz): δ =

 4.68 (2 H, s)

 5.10 (2 H, s)

 5.44 (2 H, s)

 6.84 (1 H, d, J = 8 H z)

 6.90 (1 H, d, J = 8 H z)

 6.96-7.15 (2H, brs)

 7.12 (2H, d, J = 9 Hz)

 7.55 to 7.62 (1H, m)

 7.65-7.80 (1H.brs)

 7.68 (1 H, d, J = 8 H z)

 7.72 to 7.80 (1H, m)

 7.86 (1 H, d, J = 8 H z)

 7.98 (2 H, d. J = 9 H z)

8.09 (1 H, d, J = 8 H z)

8 S

'09 M 'L 90 I '08 I Τ Ό 92 I' ΐ 8 t7 T '68 ^ 1 'ε 8 ΐ' 0 I 9 I '9 ^ 9 1 * I 09 ΐ '99 1' 9262 ⁴ 9 ε I ε '86 S 8

: ぃ UJ O (ae ¾) Η I (ζ Η 2 = Γ ¹ Ρ Ή Τ) ΐ ^-8 (ζ Η 8 = Γ 'Ρ' Η I) 9 Ζ '8

69501/96 Ο / Α

866I0S6df / XD <I [Synthesis Example 15] Synthesis of 4- (imidazole-11-ylmethyl) 13- [4-1 (quinoline-12-ylmethyloxy) benzoylamino] phenoxyacetic acid (VI-6)

(1) Synthesis of ethyl 4- (imidazole-11-ylmethyl) 1-3-2-trophenyloxyacetate

 4-Imidazole-1-ylmethyl-1-3-nitrophenol (the compound synthesized in Synthesis Example 10 ^ (4)) (0.80 g, 3.65 mmol) was converted to I ^ acetone

(10mL) and! ^ IDMF (ImL) in a mixed solvent of anhydrous potassium carbonate

CO. 56 g, 4.05 mmol) and stirred at room temperature for 10 minutes. Then, under cooling with ice, ethyl bromoproate (0.45 mL, 4.04 mmol) was added, and the mixture was stirred at room temperature for one minute, and the solvent was distilled off. Add ice water (2 OmL) to S;

(15 mL × 2), washed with water (20 mL), and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (form: black form to methanol / form: 1/50). 0.49 g (purity 97.6%, yield 42.8%) (1) was obtained as pale yellow crystals. lH-NMR (CDC 1 a, 400MHz): δ =

 1.30 (3Η, t, J = 7Hz)

 3.57 (2H, brs)

 4.27 (2H, q, J = 7Hz)

 4.58 (2H, s)

 4.99 (2H, s)

 6.30 (1 H, d, J = 2Hz)

 6.33 (1H, dd, J = 2Hz, 8Hz)

 6.90 (1 H, t, J- 1 Hz)

 6.98 (1 H, d, J = 8 Hz)

 7.09 (1H, brs)

 7.57 (1 H, s)

 (2) Synthesis of ethyl 4- (imidazole-11-ylmethyl) 1-3- [4-1 (quinolin-2-ylmethyloxy) benzoylamino diphenoxy acetate

41- (quinoline-1-ylmethyl) benzoic acid (synthesized in Synthesis Example 14) Compound (2)) (0.16 g, 0.57 mmol) was suspended in dry toluene (1 mL), and thionyl chloride (1.37 mL, 18.9 mmol) was added under ice-cooling. After stirring for 30 minutes, thionyl chloride and toluene were distilled off under reduced pressure. The residue was suspended in dry dichloromethane (3 mL), and triethylamine (0.41 mL, 2.94 mmol) was added under ice cooling, and the mixture was stirred for 10 minutes. Furthermore, dry dichloromethane (3 mL) of ethyl 3-amino 41- (imidazo-1-ylmethyl) phenoxyacetate (0.15 g, 0.54 mmol, compound (6) synthesized in Synthesis Example 10) was added. ) The solution was added, and the mixture was stirred at room temperature overnight and then stirred at 60 ° C for 1 hour. Ice water (5 mL) was added to the reaction solution, and then the organic layer was separated and washed with saturated aqueous sodium hydrogen carbonate (4 mL). After drying over anhydrous sodium sulfate and evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform to methanol-chloroform = 150) to give 57 mg (yield 19.3%) of the title. Compound

(2) was obtained as pale yellow crystals.

 mp: 173.6 ~: I 75.4 ° C

^J H-NMR (CDC 1a, 400MHz) δ =

 1.28 3Η, s)

 4.25 2 Η, s)

 4.61 2Η, s)

 5.08 2 Η, s)

 5.43 2Η, s)

 6.79 1 H, dd, J = 2 Hz, 8 Hz)

 6.84 1 H, br s)

 7. 03 '7.1 1 1 (3H, m)

 7.08 1 H, d, J = 8Hz)

 (7.21 1 H, d, J = 2 Hz)

 7.42 1 H, b r s)

 7.53 '7.60 (1 H, m)

 7.64 1 H, d, J = 8Hz)

(7.75 1 H, ddd, J = 1 Hz, 7 Hz, 8 Hz) 7.82 (1 H, s)

 7.83 (1 H, d, J = 8Hz)

 7. 66-7. 70 (2H, m)

 8.09 (1 H, d, J = 8 Hz)

 8.20 (1 H, d, J = 8 Hz)

 (3) 4- (imidazole-l-ylmethyl) -l- [4- (quinoline-l-yl-methyloxy) benzoylamino] phenoxyacetic acid

 The above compound (2) (5 Omg, 0.093 mmol) was dissolved in a mixed solvent of ethanol (1.2 mL) and THF (2.4 mL), and a 1N aqueous solution of sodium hydroxide (0. 2 mL), and the mixture was stirred overnight. Water (4 mL) was added to the reaction solution, and a 1 N hydrochloric acid aqueous solution was added under ice-cooling until the pH reached 7, and then crystals were collected. The obtained crystals were washed with water (2 mL) and dried under reduced pressure to give 4 Omg (yield 84.9%) of the title compound (3) as pale yellow crystals.

 mp: 228. 4X,

_{Ή-NMR (CD 3 OD /} CDC 1 3 = 1/40, 400MHz): δ =

4.59 2Η, s)

 5.13 2H, s)

 5.44 2H, s)

 6.84 1 H, dd, J = 2 Hz, 8 Hz

 6.91 1 H, d, J = 2 Hz)

 6.94 1 H, br s)

 7. 03 1 H, s)

 7.04 1 H, d, J = 8 Hz)

 (7.12H, d, J = 9Hz)

 7.59 1 H, t, J = 7Hz)

 7.63 1 H, b r s)

 7.69 1 H, d, J = 8 Hz)

 7.74 '7.82 (1 H, m)

 7.82 (2H, d, J = 9Hz

0 3 7.87 (1 H, d, J = 8Hz)

 8.09 (1 H, d, J = 8Hz)

 8.26 (1 H, d, J = 8 Hz)

IR (KBr) cm- ¹ :

3415, 3267, 3136, 1632, 1610, 1510, 150 8, 1485, 1400, 1398, 1311, 1255, 1180, 839 [Pharmacological experiment 1] Thromboxane A ₂ synthesis inhibitory action

ゥ Eg heron blood / fi homogenate 20 uL (5 ug protein), lOOmM Tris-HCl buffer (PH7.4) 5 OuL and test compound solution (tris-HCl buffer containing 1% dimethylsulfoxide) l OwL and, after 5 min shaking and incubated at 4 ° C, the broth tag orchid Jin H ₂ solution is a substrate (5txM, 1. the Bok squirrel-HCl buffer containing 8% acetone) to 20nmL added, 5 minutes at 4 The reaction was carried out by incubating for a while. The stop solution [0. 9% NaCl, 0. 1 % © shea serum albumin and _{1 U M 0KY-046 (Eur} . J. Pharmacol. 91, 41 (1983)) containing hydrochloric acid 1 OOmM phosphate buffer] was added The reaction was stopped.

Using 50 xL of the above reaction mixture, the amount of thromboxane B ₂ (TXB ₂ ) (T XA ₂ is unstable in a buffer solution and converted to TXB ₂ ) was determined using the enzymimnoatsy method (Amersham). (Method using a thromboxane EIA system manufactured by KK).

The inhibition rate of the test compound was calculated by the following formula, and the concentration (IC ₅ ) at which TXB ₂ production was inhibited by 50% was determined.

TXB2 generation amount when adding test compound-TXB2 generation amount of blank Inhibition rate (%) 1--■ X 100

 Control console TXB2 generation—Blank TXB2 generation

(Note) Control: Value when no fiber compound is added

Blank: value when the stop solution is added before the base [Pharmacological experiment 2〗 Leukotrien D antagonism

 The membrane fraction was prepared from the lungs of male guinea pigs (Hartley) by the method described below.

Tissues were buffered [5 OmM Tris-HCl, pH 7.4, ^ Tribcine inhibitor (15 wg / mL), bacitracin (bacitracin, 100 jug / mL), benzamidine (10 wg / m), PMSF (1 OuM)〗 was homogenized using a homogenizer (YA ATO Ultra-Disperser). The homogenate was centrifuged at 1000 × _g and 50,000 × g for 10 minutes each.

 The sediment was resuspended in buffer (5 OmM Tris-HCl, pH 7.4) and homogenized with a homogenizer. The homogenate was separated at 500 OOxg for 10 minutes and the same procedure was repeated on the precipitate. The final precipitate was ¾g in buffer -80. Saved in C.

Membrane preparation (250 ug protein ZmL) was prepared using [3 H〗 leukotriene D 4 (0.5 nM) (NEN, specific activity: 4699 GBqZ mmol) and test solution ^ I in a final volume of 250 "L buffer. (5 Omm Bok squirrel _{monohydrochloride, P H7. 4, 1 OmM-} CaCl 2, 1 OmM-MgC 1 2. 1 OmM- cysteine) at in at 25 "C, and Inkyupeto 30 minutes. After the reaction, the cells were aspirated with a filter (Whatmann GF / C) using a cell harvester (Brandei M-48R).

 The filter was washed three times with 3 mL of a washing buffer (50 mM Tris-HCl, pH 7.4), and the activity captured on the filter was measured with a liquid scintillation counter (AROKA LSC-3600).

 The inhibition rate of the test compound was calculated by the following equation. Radioactivity in the presence of analyte K-unspecific radioactivity

 Inhibition rate (¾) 1― ■ X 1 00 Injection activity in the absence of test substance R-non-specific SIS combined radioactivity

Table 1 shows the test results of pharmacological experiments 1 and 2 for each compound of the present invention synthesized in each synthesis example. Table 1 Compound TXAa I Cso () LTD4 (10 " ⁵ M¾) Zagrel 2.0 X10 ' ⁹

Blanrukast 00

τ 2 1

 II- 23.2 x10 87

II 41.0 X 10 " ⁹ 95

III- 1 8. 9 10 " ⁷ 98

 III- 27.2 X 10- "97

IV-1 <1.0 X 10 " ⁸ 67

IV- 2 9.4 X 10 ^-8 99

IV- 4 3.2 X 10 ^-8 92

Ox io- ⁷ 57 Test compound I 1 1-2 II-1, II 2 11-3 II 4 111-1 111-1 IV-1, IV-2, IV-4 IV-5 And IV-6 is a compound described as a specific example and a synthesis example in this specification.

As is clear from the results shown in Table 1, the compounds of the present invention have a thromboxane- ₂ synthase inhibitory activity and an excellent leukotriene antagonistic activity at the same time.

[Pharmacological experiment 3] Thromboxane A _a synthesis S ^ inhibitory effect (animal experiment)

Oral administration of Ιί ^ compound to male Wistar rats and 1 hour later The abdomen was opened under intoxication, and blood was collected from the abdominal aorta (2 mL). The collected blood was incubated at 37 ° C. for 2 hours, and then centrifuged at 1,600 × g for 10 minutes to obtain serum. Thromboxane B ₂ produced in this serum (TXB _2.) Amount (T XA ₂ is unstable in buffer, is converted into TXB ₂₎ E a stanza I Mui Takeno mediation Si method (Amersham thrombospondin Xan EIA system).

 The inhibition rate of the test compound was calculated by the method described in the above-mentioned pharmacological experiment 1.

 [Pharmacological experiment 4] Leukotriene-induced vascular permeability enhancement

 The back of the guinea pig was shaved with an electric clipper and used after 3 hours or more for the experiment.

A test compound was orally administered to a guinea pig, and one hour later, Evans blue (0.5 mL) was orally administered from the hind limb of the guinea pig, and immediately thereafter, leukotriene D ₄ (LTD,) and physiological Saline was orally administered intradermally at the back at 50 tiL / site. Thirty minutes later, the animals were sacrificed by exsanguination, and the blue spots that appeared after stimulation with LTD ₄ were collected from the skin. The collected skins were immersed in an aqueous solution of potassium hydroxide (1 mL) and hydrolyzed at 37 for 18 hours. Phosphoric acid in this solution

(2.5 mL) and acetone (6.5 mL) were added, mixed, centrifuged at 1600 X g for 15 minutes, and the amount of Evans Blue in the supernatant was measured at 620 nm using a spectrophotometer. The values were measured to determine the percentage inhibition relative 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.

 Table 2 Compounds TXA: LTDH

IV- 2 1 1.7% (1 Omg / kg) 35.0% (1 Omg / kg) IV-3 33.7% (1 Omg / kg) 50.0% (1 Omg / kg)

64.5% (5 Omg / kg) 74.5% (5 Omg / kg) The compounds IV-2 and IV-3 are the compounds described in the specific examples and the synthesis examples.

As it is apparent from the results shown in Table 2, the compounds of the present invention, at the same time has a Toronboki San A ₂ synthase inhibitory activity, having a good Roikotoryen D ₄ antagonistic operation.

 [Industrial applicability]

Quinoline derivatives of the present invention represented by the general formula above, is useful in diseases involving TXA ₂ or LTD.. Accordingly, 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.

Claims

The scope of the claims

 1- A quinoline derivative represented by the following formula (I) and its pharmacologically acceptable.

 (D

(A ^l is one C0 ₂ R ^l \ one CN, -CONHSO2 R ' ² , -C0NR' ³ R ", -OR ¹⁵ , tetrazolyl or substituted tetrazolyl, and R ^ll , R ^l R" and Is hydrogen, alkyl or alkali metal, respectively; R ¹² is hydrogen, alkyl, haloalkyl, aryl or aralkyl, and the substituent of g-substituted tetrazolyl is alkyl, carboxyalkyl or alkoxycarbonylalkyl; L ¹¹ is a single bond or an alkylene having 1 to 6 carbon atoms; X ¹ is a nitrogen-containing heterocyclic group; L ¹² is a single bond or an alkylene having 1 to 6 carbon atoms L ¹³ is a single bond or an alkylene having 1 to 6 carbon atoms; Y ¹ is an acid purple atom or a sulfur atom; L "is a single bond or an alkylene having 1 to 6 carbon atoms. There; and TO Two main line ing from a solid line means a single bond or a double bond)

 2. The quinoline derivative according to claim 1 represented by the following formula (I-a) and a pharmacologically acceptable salt thereof.

(Ia)

(A ¹ and X ¹ have the meanings described in claim 1, "1" 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 (Π) and its pharmacologically acceptable

(Π)

(A ² is one C0 ₂ R ^21, One CN, -CONHSOz R ^22, one C0NR ²³ R ^24, a -OR ^23. Tetrazolyl or substituted tetrazolyl, R ² ', R ^23, Contact and R ^2S is R ²² is a hydrogen atom, an alkyl, an octaalkyl, an aryl or an aralkyl, respectively, and a substituent of the substituted tetrazolyl is an 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 "represents a single bond or a carbon atoms is alkylene of 1 to 6; Y ² is an oxygen atom or a sulfur atom; and, L" is a single bond or a number of carbon atoms is 1 to 6 alkylene is there)

 4. The quinoline derivative according to claim 3 represented by the following formula (式 -a) and a pharmacologically acceptable salt thereof.

(Π-a)

96/10569

(A ^a and X ^a have the same meaning as the formula (Π) in Claim 3, where “1” 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 pharmacologically acceptable salt thereof.

 (ΠΙ)

(A ³ is -C0 ₂ R ³ -CN, -CONHSO2 R ³² , -C0NR ³³ R ³ \ -OR ³⁵ , tetrazolyl or S-substituted tetrazolyl, and R ³¹ , R ³³ , R "and R ^3S are each a hydrogen atom, alkyl, carboxyalkyl, or an alkali metal, R ³² is a hydrogen atom, an alkyl, haloalkyl, Ariru or § La alkyl, and the substituent of the substituted Te Bok Razoriru is alkyl, Karubokishiaru L ^ai is a single bond or an alkylene having 1 to 6 carbon atoms; X ′ is a nitrogen-containing heterocyclic group; L ″ is a single bond or carbon atoms L ³³ represents a single bond or a carbon atoms is alkylene of 1 to 6; which in some but alkylene of 1 to 6 Y ^a is oxygen atom or sulfur atom; and L "is a single bond or a number of carbon atoms Are 1 to 6 Is Lukylen)

6. The quinoline derivative according to claim 5, represented by the following formula (式 -a), and a pharmacologically acceptable salt thereof.

(m-a)

(A ³ and X ³ have the same meaning as in Formula (III) in Claim 5, Γ 1 J 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 its pharmacologically acceptable ίηο

 (IV)

(Alpha ⁴ _{is, -C0 2 R ", -CN,} -C0NHS0 2 R 42, -C0NR 43 R", -OR 45, a Te Bok Razoriru or substituted Te Bok Razoriru, R ", R", Contact and Is a hydrogen atom, alkyl, carboxyalkyl or alkali metal, respectively, is a hydrogen atom, alkyl, haloalkyl, aryl or aralkyl, and the substituent of β-substituted tetrazolyl is alkyl, carboxyalkyl or L ⁴¹ is a single bond or an alkylene having 1 to 6 carbon atoms; X ⁴ is a nitrogen-containing heterocyclic group; L ″ is —CONH— or 1 NHC 0 —. L has a single bond or a number of carbon atoms

Is an oxygen atom or a sulfur atom; and L "is a single bond or an alkylene having 1 to 6 carbon atoms.

 8. The quinoline derivative according to claim 7 represented by the following formula (IV-a) and a pharmacologically acceptable salt thereof.

(rv-a)

χ4 "(α¾) (A ⁴ , X ⁴ and each have the same meaning as in Formula (IV) in Claim 7; “1 J is 1 or 2 and n is 1 or 2)