WO1998008820A1 - Benzenesulfone compounds and salts thereof - Google Patents

Abstract

Benzenesulfone compounds represented by general formula (I) or pharmaceutically acceptable salts thereof, useful as pharmaceuticals having a combination of leucotriene antagonism with thromboxane A2 antagonism and good oral absorbability, especially as agents for preventing and treating diseases and which leucotriene and thromboxane A2 participate, such as bronchial asthma, wherein B represents an optionally substituted quinolyl group; D represents an optionally substituted phenyl group; E represents a group represented by formulas (a), (b), or (c); one of A?1 and A2¿ represents an optionally substituted methylene group or an optionally substituted ethylene group with the other representing a single bond, an optionally substituted methylene group, or an optionally substituted ethylene group, provided that when 1 is 1 and Y represents an optionally substituted phenylene group, each of A?1 and A2¿ may represent a single bond; X represents an oxygen atom or a sulfur atom; Y represents an optionally substituted phenylene group, an optionally substituted phenyleneoxy group, or an optionally substituted spirocyclopropinyl group; Z represents a group represented by the formula: -CH=CH-, -CH¿2?-CH2-, -CH2O-, or -O-CH2-; R represents a carboxyl group or tetrazolyl group which may be optionally substituted with an ester residue; 1, n, p, and q, which may be the same or different, are each 0 or 1; and m represents 1, 2, or 3.

Description

 Description Benzene sulfone compound or salt thereof

INDUSTRIAL APPLICABILITY The present invention is useful as a medicament, in particular, a prophylactic or therapeutic agent for a disease associated with leukotriene (L Ts) antagonism and toxin oxoxane (TX) A ₂ antagonism, in which these mediators are involved. A novel benzenesulfone compound or a salt thereof, and a pharmaceutical composition containing the compound as an active ingredient. Background art

There have been various cases of asthma in the past, including dyspepsia, allergic asthma, atopic asthma, bronchial asthma, bacterial asthma, and cardiac asthma. In particular, there are many patients with bronchial asthma among the above cases, and research on preventive / therapeutic drugs or methods is ongoing. As a drug against bronchial asthma, it has been studied from the two aspects of bronchodilator action or anti-inflammatory action, and many therapeutic and prophylactic agents have been developed to date. 3 ₂ stimulants as the bronchodilators, methylxanthines, anti-choline agents are exemplified, also steroids include mediator inhibitors as anti-inflammatory agents. However, the current drawbacks of asthma drugs are that bronchodilators have strong side effects, and anti-inflammatory drugs have less effective therapeutic and prophylactic effects than other drugs. There is a demand for a new asthma prevention and treatment drug.

In recent years, mediator inhibitors among anti-inflammatory drugs. For example, PAF antagonists, thromboxane A ₉ (TXA ₂ ) antagonists, and leukotriene (LT s) antagonists have been applied to asthma and their efficacy Is being recognized. However, it has been reported that each of these drugs alone has a therapeutic effect on asthma (effective rate of drug improvement of moderate or higher) of about 50%. (Ayumi of medicine, 168 (4), 295 (1994) and Ayumi of medicine, 164 (4), 225 (1993)), the mediators that are the main causes differ among asthma patients Therefore, it has been pointed out that it is difficult to obtain a high effective rate with conventional single mediator inhibitors.

Particularly in the development of asthma pathology, both mediators LTs and TXAQ is strongly induced airway resistance increase due to exacerbated and bronchoconstriction effects of the inflammatory response, further TXA ₂ is known to be involved into the airway hyperresponsiveness By suppressing these two mediators together, it is expected that not only the efficacy rate will be improved, but also the synergistic effect of both mediator suppression effects will provide an excellent asthma pathological improvement effect. I have. In fact, alone higher effect administration has confirmed that the obtained these two agents in combination LTs drugs and TXA ₂ inhibitors also in clinical by combination with LTs inhibitor and TXA ₂ inhibitors in animal models Have been tried. However, there are concerns about unexpected side effects of the combined use of the two drugs, and improvements are desired in terms of economics, convenience, and the like.

From this point of view, recently it has been carried out both mediators one inhibitor studies the LTs and TXA _2, have already been reported several compounds. For example, Japanese Patent Application Laid-Open No. 4-154766 discloses a funoxyacetic acid derivative represented by the following formula having both TXA ₂ antagonistic activity and LTs antagonistic activity. Further, JP-5 - 279336 and JP-off phenoxy acetic acid derivatives which antagonize TXA ₂ and LTs in Gazette and JP-A-5 262 736 JP-A-3 258 759 is disclosed. However, clinically both mediation evening one inhibitor usefulness was confirmed LTs and TXA ₂ has not yet been reported, the creation of the two mediators inhibitors having high inhibitory effect and good oral absorbability crave Have been.

一方， 特開平 5— 105664号公報， 特開平 5 - 105665号公報， 特 開平 5— 25135号並びに EP 233763号公報には， ロイコ ト リェン 拮抗作用を有するキノ リ ン誘導体が開示されている。 中でも特開平 5― 105665号公報には下式で示される口ィコ ト リエン拮抗薬として 開発中の MK - 476の治験番号を有する化合物 （実施例 161 ) が開 示されている。

On the other hand, JP-A-5-105664, JP-A-5-105665, JP-A-5-25135 and EP 233763 disclose quinoline derivatives having leukotriene antagonistic activity. Above all, Japanese Patent Application Laid-Open No. 5-105665 discloses a compound having a clinical trial number of MK-476 (Example 161) which is being developed as an oral cotriene antagonist represented by the following formula.

しかしながら， これらのキノ リ ン誘導体は， L T s拮抗作用を有す るものの， T XA ₂拮抗作用を有しておらず， 多重メデイエ一ター抑 制薬では無い点において， 本願発明化合物とは有用性を全く異にす る。 また， 本願発明化合物はベンゼンスルホン若しく はベンゼンス ルホンァミ ド構造を有する点でこれらの化合物とは構造を異にする。 発明の開示

However, these quinoline derivatives have LTs antagonism but do not have T XA ₂ antagonism and are not multiple mediator inhibitors, and are therefore useful with the compounds of the present invention. Sex is completely different. Further, the compounds of the present invention differ from these compounds in that they have a benzene sulfone or benzene sulfonamide structure. Disclosure of the invention

An object of the present invention is to provide a compound useful as a multiple mediator inhibitor having both TXA ₂ antagonism and LTs antagonism, and a medicament containing the compound as an active ingredient.

The present inventors have found that by creating drugs that inhibit two or more mediators (multiple mediator inhibitors), multiple mediator inhibitors can be effective drugs for allergic diseases such as asthma with a high effective rate. think, predicted to be particularly TXA ₀ antagonism and L in case of having both the both effects of Ts antagonism as an antiasthmatic synergistic therapeutic effect can be expected, it has extensive research. As a result, they have found that the novel benzenesulfone compound represented by the following general formula (I) or a salt thereof has both of the above two effects and has good oral absorption, and LTs and TXA. Both The present inventors have found that they can be effective and powerful anti-asthmatics in a wide range as a data inhibitor, and have completed the present invention.

That is, the present invention relates to a benzenesulfone compound represented by the following general formula (I) or a salt thereof, a pharmaceutical composition containing the compound as an active ingredient, preferably leukotriene and thromboxane A: _{2 For} both antagonists.

(The symbols in the formula have the following meanings.

 B: quinolyl group which may be substituted,

基 D: phenyl group which may be substituted, E: represented by the formula

Base

A ¹ , A ² : One of them is a methylene group which may be substituted or an ethylene group which may be substituted, and the other is a single bond, a methylene group which may be substituted or a substituted group. When 1 is 1 and Y is a phenylene group which may be substituted, A ¹ and Α may both be a single bond;

 X: oxygen or sulfur atom,

 Υ: a phenylene group which may be substituted, a phenylene group which may be substituted or a spirocyclopropynyl group which may be substituted;

Zeta: wherein one CH = CH-, wherein one CH ₂ - CH ₂ -, the formula - CH ₂ 0 - or the formula - 0 one CH _n -, a group represented by

R: carboxyl group or tet which may be substituted by ester residue Lazolyl group,

 1, n, p, q: same or different 0 or 1,

 m: 1, 2, or 3)

 Among the compounds represented by the above general formula (I), preferred compounds are

(1) B force halogen atom, hydroxyl group, lower alkoxy group, cyano group, amino group, mono- or di-lower alkylamino group, nitro group and lower alkyl group (the lower alkyl group is , A halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group, a mono or di-lower alkylamino group, a nitro group, an aryloxy group and an aralkyloxy group. A quinolyl group which may be substituted with a group selected from the group consisting of: a D atom, a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group, a mono or Di-lower alkylamino group, nitro group and lower alkyl group (the lower alkyl group is a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group, a mono- or di-alkyl group). A phenyl group which may be substituted with a group selected from the group consisting of a quaternary alkylamino group, a nitro group, an aryloxy group and an aralkyloxy group. The optionally substituted phenylene group, the optionally substituted phenyleneoxy group or the optionally substituted spirocyclopropyl group may be a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group, respectively. Group, mono or di-lower alkylamino group, nitro group and lower alkyl group (the lower alkyl group is a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group, a monoalkyl group). Or a group selected from the group consisting of di-lower alkylamino, nitro, aryloxy and aralkyloxy. Good Fuweniren group optionally substituted with a group selected from a) a Fuenirenokishi group or scan Pironku Ropuropiru group, and, A ^1, definitive this, substituted An optionally substituted methylene group or an optionally substituted ethylene group is a halogen atom, a hydroxyl group, a lower alkoxy group, an aryl group or a lower alkyl group (the lower alkyl group is a halogen atom, a hydroxyl group, One or more groups selected from a lower alkoxy group, an amino group, a mono or di-lower alkylamino group, an aryloxy group and an aryl group. A benzenesulfone compound or a pharmaceutically acceptable salt thereof, which is a methylene group or an ethylene group which may be substituted with

(2) B-force is a 2-quinolyl group which may be substituted with a halogen atom, and which may be substituted with a D-force, ', a halogen atom, a lower alkoxy group, a nitro group and a halogen atom. A phenyl group which may be substituted with a group selected from good lower alkyl groups, and a phenylene group which may be substituted with a group selected from halogen atoms and lower alkoxy groups; A phenyleneoxy group or a spironcropropyl group, wherein A ¹ or A may be substituted with a group selected from a lower alkyl group, an aryl group and an aralkyl group; An ethylene group which may be substituted with a group selected from an alkyl group, an aryl group and an aralkyl group, and the other is a single bond, a methylene group or an ethylene group, provided that 1 is 1 and Y is When a phenylene group may be filed by A ¹ and A ² are both single bonds, Z force, the formula - CH = CH-, wherein _ CH ₂ - CH. A group represented by one or Formula one CH ₂ 0 one, p is 0, q is 1, and, but is allowed a carboxyl group or a sulfonic compound is Te Torazoriru group or a pharmaceutically Salt,

 X—

 (3) a benzenesulfone compound or a pharmaceutically acceptable salt thereof, wherein E is a group represented by the formula

(4) Z-force, benzenesulfonation, a group represented by the formula Compound or a pharmaceutically acceptable salt thereof,

 (5) X is a sulfur atom, a benzenesulfone compound or a pharmaceutically acceptable salt thereof,

 (6) a benzenesulfone compound wherein R is a carboxyl group or a pharmaceutically acceptable salt thereof,

 (7) a benzenesulfone compound or a pharmaceutically acceptable salt thereof, wherein n is 1,

(8) Benzene sulfone in which 1 is 1, Y is a phenylene group which may be substituted with a group selected from a halogen atom and a lower alkoxy group, and A ¹ is a methylene group and is a single bond. The compound or a pharmaceutically acceptable salt thereof.

 Particularly preferred compounds include

 3-[[3- (4-Cro- mouth phenylsulfonylamino) -1-] [3- (2-quinolinylmethoxy) phenyl] propyl] thio] propionic acid,

4-[[[[2- (4-Cross-phenylphenylsulfonylamino)] 1-1- [3-[2- (7-chloro-2-quinolyl) vinyl] phenyl] ethyl] thio] Chill] benzoic acid,

 4-[[[1-[3--2- (7-Chloro-2-quinolyl) vinyl] phenyl] -1-2- (4-methoxyphenylsulfonylamino) ethyl] thio] methyl] Benzoic acid, and

 4-[[[1- [3- [2- (7-Chloro-2-quinolyl) vinyl] phenyl] -1-2- (4-methylphenylsulfonylamino) ethyl] thio] methyl] benzoic acid,

Or pharmaceutically acceptable salts thereof. The compound of the present invention is described in more detail as follows.

 In the definition of the general formula of the present invention, unless otherwise specified, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms.

The “optionally substituted quinolyl group” in B is quinolyl. Any carbon atom on the ring of the phenyl group is substituted with 1 to 6 substituents or an unsubstituted quinolyl group. The substituent is a general substituent that can be substituted on a quinolyl group, and specifically, for example, a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group, a mono- or mono- or G-lower alkylamino group, nitro group, lower alkyl group (the lower alkyl group is a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group, a mono- or lower G-alkylamino group, May be substituted with a group selected from a toro group, an aryloxy group and an aralkyloxy group). Preferably, it is a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, a nitro group, or a lower alkyl group substituted with a halogen atom, more preferably a halogen atom.

 The bond of the quinolyl group to Z may come from any carbon atom on the quinoline ring, but is preferably a 2-quinolyl group or a 3-quinolyl group, more preferably a 2-quinolyl group. It is a ril group.

The “optionally substituted phenyl group” in D is an unsubstituted phenyl group in which any carbon atom on the ring of the phenyl group is substituted with 1 to 6 substituents. . The substituent is a general substituent that can be substituted on a phenyl group, and specifically includes, for example, a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group, a mono- or di-lower alkylamino group. A lower alkyl group such as a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group, a mono or di-lower alkylamino group, a nitro group; , An aryloxy group and an aralkyloxy group which may be substituted). Preferably, a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, a nitro group, a lower alkyl group (the lower alkyl group may be substituted with a group selected from a halogen atom and a lower alkoxy group) And more preferably a halogen atom, a lower alkoxy group, a nitrogen atom, or a halogen atom. A lower alkyl group which may be substituted with a substituent.

In A ¹ and A ² , the “optionally substituted methylene group or the optionally substituted ethylene group” refers to any one or more hydrogen atoms of a methylene group or an ethylene group; Preferably, one or two are a methylene group or an ethylene group substituted with an arbitrary substituent, and an unsubstituted methylene group or an ethylene group. The substituent is a general substituent capable of substituting for a methylene group or an ethylene group, and specifically, for example, a halogen atom, a hydroxyl group, a lower alkoxy group, an aryl group, a lower alkyl group (for example, The lower alkyl group is substituted with a group selected from a halogen atom, a hydroxyl group, a lower alkoxy group, an amino group, a mono- or di-lower alkylamino group, an aryloxy group and an aryl group. And the like). Preferably, it is a halogen atom, a lower alkoxy group, an aryl group or a lower alkyl group (the lower alkyl group may be substituted with a group selected from a halogen atom, a lower alkoxy group and an aryl group). And more preferably a lower alkyl group, an aryl group or an aralkyl group.

 The “carboxyl group optionally substituted by an ester residue” in R is an unsubstituted carboxyl group or a carboxyl group substituted by an ester residue.

Here, the “ester residue” includes a lower alkyl group, a lower alkenyl group, a halogeno lower alkyl group (such as a chloromethyl group and a trifluoromethyl group), and an aralkyl group (such as a benzyl group and a lower alkoxybenzyl group). Ester residues such as benzyl group, nitrobenzyl group, benzhydrinole group, lower alkoxybenzylhydryl group, phenethyl group, and 1-naphthylmethyl group), or are hydrolyzed by metabolism in vivo. Ester residues such as lower alkanoyloxy lower alkyl groups (such as acetyloxymethyl group, acetyloxyxethyl group, tert-butanoloxymethyl group), lower alkenyl lower alkyl groups (vinyl carboxymethyl group, vinyl group) Carbonylethyl group, etc.), cycloalkylcar Bonyloxy lower alkyl groups (cyclopropylcarbonyloxymethyl group, cyclobutylcarbonyloxy group, cyclopentylcarbonyloxymethyl group, etc.), lower alkenyloxy lower alkyl groups (vinylcarbonyloxymethyl group, vinylcarbonyloxy group) A lower alkoxy lower alkyl group (a methoxymethyl group, a methoxyxyl group, an ethoxymethyl group, etc.), a lower alkoxy lower alkoxy lower alkyl group (a methoxymethoxy methyl group, etc.), a lower alkoxycarbonyl group, etc. Oxy-lower alkyl groups (methoxycarbonyloxymethyl group, ethoxycarbonylmethyl group, tert-butoxycarboxyloxymethyl group, etc.), benzoyloxy lower alkyl groups (benzoyloxymethyl group, benzoylo group Ixetyl group, etc.), 2—year-old oxotetrahydrofuran-1-5-yl group, 2-oxo-1-5-lower alkyl-1,1-alkyl

3-dioxolen-1-ylmethyl group

Examples include lahydrofuranylcarbonyloxymethyl group and phthalidyl group.

 Preferably, lower alkyl group, aralkyl group, lower alkanoyloxy lower alkyl group, phthalidyl group, 2-oxo-15-lower alkyl—1,3, -dioxolen-14-ylmethyl group, lower alkoxycarbonyloxy lower alkyl group Group. Among them, lower alkyl groups such as methyl group, ethyl group, propyl group, isopropyl group and butyl group are preferred.

The “optionally substituted phenylene group” in Y means that any carbon atom on the ring of the phenylene group is substituted with 1 to 4 substituents or unsubstituted phenylene group. is there. The substituent is a general substituent that can be substituted on a phenylene group, and specifically includes, for example, a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group, and a monohydroxy group. Di-lower alkylamino group, nitro group, lower alkyl Group (the lower alkyl group is a group selected from a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group, a mono- or di-lower alkylamino group, a dinitro group, an aryloxy group and an aralkyloxy group. May be substituted). Preferably, a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, a nitro group or a lower alkyl group (the lower alkyl group may be substituted by a group selected from a halogen atom and a lower alkoxy group). And more preferably a halogen atom or a lower alkoxy group.

 The “phenylene group” includes 1,2-phenylene group, 1,3-phenylene group and 1,4-phenylene group. It is preferably a 1,3-phenylene group or a 1,4-phenylene group, and more preferably a 1,4-phenylene group.

で示される基が好ま しい。 The “optionally substituted phenylene group” is a group in which an optionally substituted phenylene group is further bonded to a phenyl group.

The group represented by is preferred.

 The “optionally substituted spirocyclopropyl group” for Y includes a spirocyclopropyl group in which any carbon atom on the ring of the spirocyclopropyl group is substituted with 1 to 4 substituents or unsubstituted. It is.

The substituent is a general substituent that can be substituted on a spirocyclopropyl group, and specifically, for example, a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group, a mono- or mono- or G lower alkylamino group, nitro group, lower alkyl group (the lower alkyl group is a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group, a mono- or di-lower alkylamino group) Group, Nitro group, aryloxy May be substituted with a group selected from a group and an aralkyloxy group). Preferably, a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, a nitro group or a lower alkyl group (the lower alkyl group may be substituted with a group selected from a halogen atom and a lower alkoxy group) And more preferably a halogen atom or a lower alkoxy group.

 In the present specification, the “lower alkyl group” includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, Pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl Group, 2-methylpentyl group, 3-methylpentyl group, 1,1 dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethyl group T-butyl group, 3,3—dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2—trimethylpropyl group, 1,2,2—trimethylpropyl group, 1-ethyl- Examples include 1-methylpropyl group and 1-ethyl-2-methylpropyl group. Among them, those having 1 to 4 carbon atoms are preferable, and a methyl group, an ethyl group, a propyl group and an isopropyl group are particularly preferable.

 Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Preferably, they are a fluorine atom and a chlorine atom.

 The “lower alkyl group substituted by a halogen atom” includes chloromethyl group, bromomethyl group, fluoromethyl group, trifluoromethyl group, 1-chloroethyl group, 2,2-dichloroethyl group, and 3-octyl group. Examples thereof include a ropyl pill group, and a trifluoromethyl group is preferable.

Examples of the “lower alkoxy group” include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, sec —butoxy group, tert —butoxy group, pentyloxy (amiroxy) group, isopentyloxy group, tert —pentyloxy group, neopentyloquine group, 2-methylbutoxy group, 1,2-dimethylpropo Examples thereof include a xy group, a 1-ethylpropoxy group, and a hexyloxy group. Among them, those having 1 to 4 carbon atoms are preferable, and a methoxy group and an ethoxy group are particularly preferable.

 The “mono or di-lower alkylamino group” is an amino group in which one or two hydrogen atoms have been substituted with the above-mentioned alkyl group. In the case of a di-lower alkylamino group, the two alkyl groups may be the same or different. Examples of the mono-lower alkylamino group include a methylamino group, an ethylamino group, a propylamino group, a poramino group, a butylamino group, an isobutylamino group, and a poramino group. sec-butylamino group, tert-butylamino group, pentylamino group and the like. Examples of the di-lower alkylamino group include dimethylamino group, getylamino group, dipropylamino group, methylethylamino group, methylpropylamino group, methylisopropylamino group, and methylisopropylamino group. Groups, a methylbutylamino group, a methylisopropylamino group, an ethylpropylamino group, an ethylisopropylamino group, and the like.

The “lower alkenyl group” is a straight-chain or branched alkenyl group having 2 to 6 carbon atoms, specifically, a vinyl group, an aryl group, a 1-propenyl group, a 1-methylvinyl group, Butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methylaryl, 1-methyl-1-propenyl, 1-methylaryl, 1-pentenyl, 2- Pentenyl group, 3-pentenyl group, 4-pentenyl group, 3-methyl-1-butenyl group, 3-methyl-2-butenyl group, 3-methyl-13-butenyl group, 2-methyl-1-butenyl group, 1,, 1-dimethylaryl group, 1,2-dimethyl-1-propenyl group, 1-ethyl-2-propenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 1,1-Dimethyl-3-butenyl group, 3,3-Dimethyl Ruichi 1— Examples thereof include a butenyl group, 1-methyl-4-pentenyl group, 4-methyl-1-pentenyl group, and 4-methyl-3-pentenyl group. Among them, an alkenyl group having 3 to 4 carbon atoms is preferable.

 The term "aryl group" means an aromatic hydrocarbon ring group, preferably an aryl group having 6 to 14 carbon atoms, specifically, a phenyl group or a naphthyl group. , An indenyl group, an anthryl group, a phenyl group and the like. Preferable is a phenyl group and a naphthyl group, and more preferable is a fuunyl group.

 The “aralkyl group” is a group in which an arbitrary hydrogen atom of the above “lower alkyl group” is substituted with the above “aryl group”. Specifically, a benzyl group, a phenethyl group, —Phenylenyl, 3-phenylpropyl, 2-phenylpropyl, 1-phenylbutyl, 5-phenylpentyl, 1-naphthylmethyl, 2-naphthylmethyl and the like. It is preferably a benzyl group.

 The "aralkyloxy group" is a group in which a hydrogen atom of a hydroxyl group is substituted with the above-mentioned aralkyl group, and examples thereof include a benzyloxy group, a phenethyloxy group, and a naphthylmethyloxy group. Preferable is a benzyloxy group.

 The “aryloxy group” is a group in which a hydrogen atom of a hydroxyl group is substituted with the above-mentioned aryl group, and examples thereof include a phenoxy group and a naphthyloxy group. Preferably it is a phenyl group.

The compound of the general formula (I) of the present invention may form a salt. The present invention includes these pharmaceutically acceptable salts. Examples of such salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, formic acid, acetic acid. Propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid. , Pivalic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, citric acid, malic acid, tartaric acid, carbonic acid, methansulphonic acid, ethanesulfonic acid, glutamic acid, asparagine And acid addition salts with organic acids such as acids. Examples of the salt with a base include inorganic bases such as sodium, potassium, magnesium, potassium, and aluminum; organic bases such as methylamine, ethylamine, and ethanolamine; Examples include salts with basic amino acids such as gin, arginine, and ornithine, and ammonium salts. Further, the compound of the general formula (I) may have an asymmetric carbon atom or a double bond depending on the type of the substituent, and the present invention provides an optical isomer, a geometric isomer and a tautomer based on these. It includes isolated isomers of various isomers such as sex forms and mixtures thereof.

 Further, depending on the production conditions, the compound of the general formula (I) of the present invention may be used as a hydrate thereof or as various solvates such as an ethanol solvate. Since the compound of the general formula (I) of the present invention may be isolated as a substance having a form, the compound of the general formula (I) of the present invention may have any of these hydrates. Contains substances.

 The compound of the present invention and a pharmaceutically acceptable salt thereof can be produced by applying various known synthetic methods, utilizing characteristics based on the basic skeleton or the types of substituents. At that time, depending on the type of the functional group, it is effective in manufacturing technology to replace the functional group with an appropriate protecting group, that is, a group that can be easily converted to the functional group at the stage of the raw material or intermediate. May be important. Thereafter, the desired compound can be obtained by removing the protecting group as necessary. Examples of such a functional group include a hydroxyl group and a carboxyl group, and examples of such a protective group include Green and Wuts. Protective Groups in Organic Synthetic. s ", and the protecting groups described in the second edition can be used, and these may be appropriately used according to the reaction conditions.

Hereinafter, a typical production method of the compound of the present invention will be described. First manufacturing method

Removal)

(In the formula, A ¹ , A ² , B, D, R, E, Y, Z, 1 and m are as described above.)

 In this production method, the compound of the present invention (la) is obtained by deprotecting the phthalimide derivative represented by the general formula (Π) and then subjecting it to a sulfonamidation reaction to remove the protecting group if desired. Is the way.

 Solvents used for the deprotection of 1) include protonic solvents such as methanol, ethanol, propanol, and water; diisopropyl ether; tetrahydrofuran; 4 Non-dioxane, benzene, toluene, xylene, pyridine, dichloromethane, cycloform, 1,2-dichloroethane, acetonitrile, dimethylformamide, dimethylsulfoxide Protonic solvents and their mixtures are used. As the reaction reagent, ammonia, hydrazine, methylhydrazine, methylamine, ethylamine, etc. are used in an amount of 1 equivalent to an excess amount at room temperature or under heating conditions. Alternatively, it is deprotected by using the conditions of hydrolysis. Deprotection can also be achieved by reductive treatment using sodium borohydride or the like, followed by acidic conditions such as acetic acid.

2) The sulfonyl chloride is a reactive derivative of sulfonamide Id ゃ sulfonic anhydride derivatives and the like can be used, and 1 equivalent to an excess amount thereof can be used under ice cooling to room temperature or room temperature to heating conditions. Solvents used are diisopropyl ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene, xylene, pyridine, dichloromethane, chloroform, 1,2-dichloroethane, and acetone. Reactive solvents such as tonitrile, dimethylformamide, dimethylsulfoxide, and water are used. During the reaction, organic bases such as triethylamine, pyridine, picolin, norethidine, N, N-dimethylaniline, N-methylmorpholine, cesium carbonate, lithium carbonate, sodium hydrogencarbonate Addition of an inorganic base such as sodium hydroxide or sodium hydroxide in an amount of 1 equivalent to an excessive amount may be advantageous for smoothly proceeding the reaction.

If desired, deprotection of the carboxylic acid ester is performed by a conventional method in organic chemistry. For example, in a solvent inert to the reaction, in the presence of a base such as sodium carbonate or sodium hydroxide, by hydrolysis with alkali, or in the presence of an acid such as trifluoroacetic acid or hydrochloric acid, A conventional method of acid hydrolysis can be applied, and the reaction is preferably carried out at room temperature to 100 ° C. Depending on the type of the ester, a hydrogenation reaction or a method using a strong acid such as trifluoroacetic acid can be used. Second manufacturing method

HX—A ^1- (Y) “A2- _{R (IV} )

 (Removal of protecting group if desired)

, X—A ^1- (Y) “A2 ~ R

(lb) (Where A ¹ , A ² , B, D, R, X, Y, Z, 1, m, and n are as described above.)

 In this production method, the benzenesulfone compound represented by the general formula (m) is reacted with the alcohol or thiol derivative represented by the general formula (IV), and the protecting group is removed as required. It is a method to obtain I b).

 If desired, the hydroxyl group of compound (III) or the hydroxyl group or mercapto group of compound (IV) may be converted to an active group and used. The conversion is the same as in 2) of the first production method, in the solvent, temperature, and catalyst. It can be performed under the following conditions. Activating reagents include thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, oxalyl chloride, carbon tetrachloride and triphenylphosphine, carbon tetrabromide and trichloride. Examples include halogenating reagents such as phenylphosphine, sulfonylating reagents using alkyl or arylsulfonyl chloride, and dialkylazodicarboxylic acids and triphenylphosphine.

The reaction with the compound represented by the general formula (IV) can be carried out under the same conditions as in 2) of the first production method, in a solvent and at the same temperature. In the reaction, the organic base or inorganic compound mentioned in 2) of the first production method is used. Not only bases, but also organometallic reagents such as sodium hydrogen butyl lithium, inorganic salts such as sodium iodide, lithium iodide, and potassium bromide, tetrabutyl bromide Layer transfer catalysts such as ammonium and tetrabutylammonium iodide; mineral acids such as sulfuric acid and phosphoric acid; organic acids such as trifluoracetic acid and trifluoromethansulfonic acid; boron trifluoride; It may be advantageous to add a Lewis acid such as titanium chloride, alone or simultaneously, in a catalytic amount to 1 equivalent or 1 equivalent to excess in order to make the reaction proceed smoothly. Further, when X is an oxygen atom, examples of the reaction solvent include ethers such as ethyl ether and tetrahydrofuran, toluene, hexane, N-methylbiperidone, dimethylformamide, and dimethylsulfoxy. Inactive in reactions of N, N, N'-dimethylimigzolinone It is preferable to use a neutral solvent alone or as a mixture. The reaction temperature varies depending on the reaction, and the reaction is suitably carried out at a temperature of from 178 to ice cooling, from ice cooling to room temperature, or from room temperature to heating.

Third manufacturing method

i) HX-A ^1- (Y)!-A ² -CN (X)

ii) R'3 SnN ₃ or NaNs (XI)

 (I c)

(In the formula, A ¹ , A ² , B, D, X, Y, Z, 1, m and n are as described above, and R ′ represents a lower alkyl group or an aryl group.)

 The third production method comprises the steps of: i) reacting a compound represented by the general formula (m) with a cyano compound represented by the formula (X); ii) further reacting a trialkyltin azide represented by the general formula (XI); This is a process for obtaining the compound (Ic) of the present invention by reacting a free tin azide or a sodium azide.

The reaction of i) with the cyano compound can be carried out in the same manner as in the second production method. The reaction (ii) is carried out in the presence of trialkyltin azide or triaryltin azide in an inert solvent such as benzene or toluene at room temperature or under reflux conditions for several days to several hours. be able to. It can also be synthesized by stirring in dimethylformamide in the presence of sodium azide and ammonium chloride at room temperature or under reflux for several hours to several days. 4th manufacturing method

(Where A ¹ , A ² , B, D, R, X, Y, Z, 1, m, and n are, as described above, G and: ， are both reacted to form the formula — CH = CH— , Formula 1 CH ₂ —CH ₂ 1, Formula 1 CH „0— or Formula 1 0-CH _n —, forming a group represented by a halogen atom, a methyl group, a monohalogenomethyl group, a dihalogeno group Methyl group, vinyl group, carboxyl group, formyl group, hydroxyl group, lower alkoxyl group, cyano group, formula HOCH ₂ —, formula R ''-OOC-, formula R, ' ₃ P—CH ₂ —, formula (R '' 0) P (= 0) — CH _2- , and the formula (R '"0) ₂ CH-where R'',R,' is a lower alkyl group or an aryl group; However, a ring structure may be formed by bonding of R '''to each other.) A group selected from the group shown in the above) is selected as appropriate.) The reaction is performed in the same manner as 1) or 2) in the first production method. Using a similar solvent, at -78 ° C to reflux temperature Cormorants can and child. During the reaction, organic acids such as acetic acid, propionic acid, trifluoroacetic acid, 4-toluenesulfonic acid and methansulfonic acid, boron trifluoride getyl ether complex, Louis iodide and zinc chloride, etc. Acid, triethylamine, diisopropylamine, N-methylmorpholine, piperidine, pyrrolidine, morpholine, butylamine, isoptilamine, isopropylamine, Organic bases such as propylamine, sodium acetate, acetic acid Organic acid salts such as sodium, alkali metal reagents such as sodium hydride and butyllithium, inorganic bases such as potassium carbonate, sodium carbonate and sodium hydroxide, tetrakis (Triphenylphosphine) Addition of a transition metal reagent such as palladium or palladium chloride (II) in a catalytic amount or 1 equivalent to an excess amount may be advantageous for smooth progress of the reaction. .

i) U— A¹- (Υ)_ΓΑ2- R (XVI) Fifth manufacturing method

^{i) U- A 1 - (Υ} ) Γ Α2- R (XVI)

») HOOC— (CH ₂ ) sr (H) _n- (X)

(Where A ¹ , A ² , B, D, R, Y, Z, 1, m, p and n are as described above, and U is a halogen atom, a lower alkylsulfonyloxy group, an arylsulfonyl A leaving group such as an oxy group, a formyl group, a carboxyl group or a lower alkyloxy group.)

 This production method comprises the steps of: i) alkylating an amino group of an amino derivative represented by the general formula (XV) with a compound represented by the general formula (XVI); and ii) carboxylic acid represented by the general formula (XVII). This is a process for obtaining the compound (Id) of the present invention by performing acylation with a derivative and removing a protecting group as required.

The reaction of i) can be carried out in a solvent inert to the same reaction as the solvent exemplified in 1) of the first production method, under the conditions of from 178 to ice cooling to room temperature to reflux temperature. When U is a formyl group, the reaction is carried out by catalytic hydrogenation using a metal such as platinum, palladium, rhodium or Raney nickel, sodium borohydride, lithium borohydride, This can be performed by a hydride reduction reaction using lithium aluminum hydride, sodium triacetoxyborohydride, or the like. During the reaction, organic acids such as formic acid, acetic acid, and propionic acid; ammonium salts such as ammonium chloride and ammonium formate; mineral acids such as hydrochloric acid and sulfuric acid; and Louis acids such as iron chloride (ΙΠ) and cerium chloride (ΙΠ). An organic base such as an acid, triethylamine, piberidine, pyrrolidine, morpholine, butylamine, isopropylamine, or propylamine may be added in a catalytic amount or 1 equivalent to an excess amount. In some cases, it is advantageous for the reaction to proceed smoothly.

 When U is a carboxyl group or a lower alkyloxycarbonyl group, it can be produced by a reduction reaction after passing through an amide derivative by an amidation reaction. The amidation reaction can be carried out by a conventional method such as a thermal method, various active esterification methods, an acid chloride method, and an azidation method. The reduction reaction is performed by a hydride reduction method using lithium aluminum hydride, sodium borohydride, a borane complex, or the like, or by reaction with thionyl chloride, phosphorus pentachloride, or the like. After that, a method easily understood by those skilled in the art, such as a method using a hydride reduction method, is applied.

 When U is a leaving group, an organic base such as triethylamine, diisopropylethylamine, or an inorganic base such as potassium carbonate, sodium hydroxide, or potassium hydroxide; The reaction can be carried out by using an alkali metal reagent such as lithium or butyllithium, and optionally adding sodium iodide, potassium iodide, and various interlayer transfer catalysts.

The amidation reaction of ii) can be carried out in the same manner as the amidation reaction described in i) above. 6th manufacturing method

(Where A ¹ , A ² , B, D, R, Y, Z, 1, m, Q, and n are as described above.)

 In this production method, amidation is carried out using a carboxylic acid derivative represented by the general formula (XVI) and an amine derivative represented by the general formula (XIX), and a protective group is removed as required. This is a process for obtaining the compound (Ie) of the present invention. The amidation reaction can be carried out in the same manner as the amidation reaction described in the fifth production method i).

 Among the compounds of the present invention, a compound in which R is a carboxyl group can be converted to a compound of the present invention in which R is a carboxyl group substituted with an ester residue by esterification. Esterification can be easily carried out by a conventional esterification reaction using an esterifying agent such as an alcohol or a halide thereof, a sulfate, or a diazo compound. Other esters can be introduced using a conventional transesterification reaction.

The raw material for producing the compound of the present invention can be easily produced by a conventional method known to those skilled in the art. A typical manufacturing method is described below. (Production method A of raw material compounds)

HX—A ^1- (Y) “ALR (IV)

(Where A ¹ , A ² , BD, R, X, Y, Z, 1, m and n are as described above.)

 In this production method, the compound (νπ) is converted from the amide compound represented by the general formula (VI) to an alcohol or thiol derivative represented by the general formula (IV), and then the raw material intermediate ( This is a method for obtaining the phthalimide derivative of the above (ii).

In the reaction of the general formula (VO to compound (W), a reagent of an orthophthalic acid derivative such as phthalic anhydride or Ν-carboethoxyphthalimide is used. The reaction conditions are 2) of the first production method, a solvent, The reaction may be carried out under similar conditions at temperature and catalyst, or only the reagent may be reacted without adding solvent. In addition, if the reaction is carried out under azeotropic dehydration or reduced pressure conditions in the presence of a dehydrating agent such as diphosphorus pentoxide in addition to the catalyst of 2) in the first production method, the reaction may proceed smoothly. The reaction from compound (W) to compound (II) is performed in the same manner as in the second production method. (Production method B of raw material compounds)

 Sulfonamide or sulfonation

(K)

(ΠΙ)

 (In the formula, B, D, R, X, Y, Z, m, and n are as described above.) In this production method, the carbonylethene derivative represented by the general formula () is sulfonated or sulfonamided. In this method, a benzenesulfone or benzenesulfonamide derivative of the general formula (K) is obtained and further reduced to obtain a benzenesulfone compound as a raw material intermediate (II).

 In the reaction from compound () to compound (K), the solvent and temperature are the same as in the first production method 2). As the reaction reagent, sulfonamide derivatives and alkali metal salts of sulfinic acid or sulfinic acid are used, and organic bases such as triethylamine, N, N-dimethylaniline, N-methylmorpholine, and carbonic acid are used. Inorganic bases such as cesium, potassium carbonate and sodium hydroxide, alkali metal reagents such as sodium hydride and potassium tert-butoxide, or organic acids such as acetic acid and propionic acid are used. It may be advantageous to add an equivalent amount or an excess amount to make the reaction proceed smoothly.

In the reaction of the compound (DO to compound (II)), the solvent and temperature are the same as in the first production method 1). As the reaction reagent, those used in general reduction reactions are used. For example, sodium borohydride Aluminum, sodium cyanoborohydride, sodium hydrogentriacetoxyborohydride, aluminum aluminum hydride, lithium aluminum borohydride, lithium aluminum borohydride, etc. Hydrogenation reaction under normal pressure or pressure using a metal hydride reagent, palladium, platinum or rhodium catalyst.

 In these reactions, an optically active ligand is added at the same time, or an optically active compound is prepared by using an optically active reducing reagent.

(m). In the reaction, a mineral acid such as hydrochloric acid, sulfuric acid and phosphoric acid, an organic acid such as trifluoroacetic acid and acetic acid, and a Lewis acid such as boron trifluoride and cerium trichloride are used alone or simultaneously in a catalytic amount of 1 to 1 equivalent. Alternatively, addition of 1 equivalent to an excess amount may be advantageous for smooth progress of the reaction.

(Production method C of raw material compounds)

 (IV)

iu

 iii) Sulfonamide

(In the formula, A ¹ , A, D, R, X, Y, 1, m, and J are as described above.)

The compound represented by the general formula (Xla) is obtained by i) simultaneous addition or stepwise addition of nitromethane and an alcohol or thiol derivative represented by the general formula (IV) to a benzaldehyde derivative represented by the general formula (XX). The compound (XIV) is obtained by the reaction, followed by ii) reduction of the nitro group, and further iii) sulfonation of the amino group and, if desired, removal of the protecting group. Can be obtained by

 The reaction i) can be carried out in a solvent inert to the same reaction as the solvent exemplified in 1) of the first production method, at room temperature to reflux temperature. During the reaction, organic acids such as acetic acid, propionic acid, trifluoroacetic acid, 4-toluenesulfonic acid and methanesulfonic acid, boron trifluoride-diethyl ether complex, ruisic acid such as zinc iodide and zinc chloride, Triethylamine, diisopropylethylamine, N-methylmorpholine, piperidine, pyrrolidine, morpholine, butylamine, isobutylamine, isopropylamine, propylamine Addition of a catalytic amount or 1 equivalent to an excessive amount of an organic base such as min, an organic acid salt such as sodium acetate or potassium acetate, or an ammonium salt such as ammonium acetate or ammonium chloride is performed. There are cases where it is advantageous to make the progress smoothly.

 The reduction reaction of the nitro group of ii) can be carried out at room temperature to reflux temperature using a solvent which is inert to the same reaction as the solvent exemplified in 1) of the first production method. The reaction is carried out by catalytic hydrogenation using metals such as platinum, palladium, rhodium and Raney nickel, gold reduction using zinc, tin, iron, tin chloride (Π), etc., sodium sulfide, and hydrosulfur. Conventional methods such as a reduction method using a sulfur compound using sodium or the like and a hydride reduction method using lithium aluminum hydride or sodium borohydride can be applied. In the reaction, addition of a catalytic amount, 1 equivalent or an excess amount of an organic acid such as acetic acid or formic acid, a mineral acid such as hydrochloric acid or sulfuric acid, or a Lewis acid such as nickel chloride (Π) or titanium tetrachloride is performed. It may be advantageous for smooth progress.

 The reaction of i i i) can be carried out in the same manner as in 2) of the first production method.

Substituent of compound (XX):! If is a group that participates in the above reaction, it can be converted to the desired substituent J by protecting the above with an appropriate protecting group and then performing the above reaction and finally removing the protecting group. Alternatively, a compound (XX) having a group inert to the reaction in place of the substituent J is reacted. Finally, a substituent may be introduced at the end. In this case, the introduction and deprotection of the protecting group and the introduction of the substituent J can be carried out by a conventional method known to those skilled in the art.

 If desired, optical resolution using an organic acid may be performed on an appropriate intermediate compound.

(Production method D of raw material compounds)

 The compound represented by the general formula (Cor) has the following formulas in the first, second, third and fifth production methods, where 中 and Ζ are as described above.

Can be produced by reacting a compound having a group represented by the formula (wherein J is as defined above) as a starting compound in the same manner. At this time, protection and deprotection of functional groups, introduction of substituents, optical division, etc. may be performed as necessary.

 The reaction products obtained by each of the above methods are isolated and purified as various solvates such as free compounds, their salts or hydrates. The salt can be produced by subjecting it to a usual salt formation reaction.

 Isolation and purification are carried out by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography.

Various isomers can be isolated by a conventional method using the physicochemical difference between the isomers. For example, the optical isomers can be separated by a common method of resolving in a semi-semiconductor such as fractional crystallization or chromatography. Optical isomers can also be synthesized from appropriate optically active starting compounds. As the fractional crystallization, fractional crystallization using an optically active organic acid such as a tartaric acid derivative, a mandelic acid derivative, or a camphorsulfonic acid derivative is suitably performed. As the solvent, a solvent that can efficiently perform optical resolution is appropriately selected. Industrial applicability

The compound of the present invention is a drug that has both TXA ₂ antagonistic action and LTs antagonistic action and has good oral absorbability. Accordingly the present invention compounds prevention of diseases involving disorders and LTs which TXA ₂ is involved. As a therapeutic agent useful, for example, allergic diseases (e.g. bronchial asthma, allergic rhinitis, urticaria, etc.), ischemic It is useful as a preventive and therapeutic agent for heart disease, brain disease, thrombosis, angina pectoris, inflammatory peptic ulcer, and liver disease. It is particularly useful for the prevention or treatment of allergic diseases involving both mediators (eg, bronchial asthma, allergic rhinitis, urticaria, etc.), ischemic heart / brain disease, and thrombosis.

The TXA ₂ antagonism and LTs antagonism of the compound of the present invention, and the effect of oral administration, were confirmed by the following experimental examples. Experimental example

 (1) Inhibition test for platelet aggregation caused by U-46619 Method:

From the abdominal vena cava of a male Hartley guinea pig weighing about 800 g, 9 volumes of blood were collected in a plastic syringe containing 1 volume of a 3.8% aqueous solution of sodium citrate. Platelet rich plasma (PRP) was obtained by centrifuging blood at 270 X g for 10 minutes, and the remaining blood was further centrifuged at 1100 X g for 10 minutes to obtain platelet poor plasma (PPP). . After diluting PRP with PPP to adjust the platelet count to 500,000, the stable analog of TXA ₂ , U-46619 (Chemical name: 9,11-dideoxy 9 or 11) Grandin F ₂ a) bone platelet aggregation by a cross was measured by the method of "journal O blanking Fi Geology, the first Vol. 168, pp. 178-195 (1963)".

In other words, using the Ma tracer to the NBS, U- to 46619 (10- ⁶ M) The change in light transmittance of the PRP was measured. The compound is U- 46619 was added to 2 minutes before the addition were determined IC _5Q values (50% inhibitory concentration) from inhibition rate relative to the maximum light transmittance by U- 46619 in the control. Table 1 shows the results.

(2) Inhibition test of guinea pig ileum contraction by LTD ₄

Method :

Male Hartley guinea pigs weighing 500-700 were killed by head bruising. The ileum was suspended at 37 ° C under a tension of l.Og in a Magnus bath containing 10 ml of Ty rode solution aerated with 95% O ₂ + 5% CO ₂ gas mixture. The tension generated by the tissue was measured isometrically with a strain gauge transuser. The ileal contractile response to LTD ₄ (10 to ⁹ M) was measured in the absence of drug and subsequently in the presence of various concentrations of test compound. The drug incubation time was 20 minutes. Table 1 shows the results.

 (3) Oral administration of U-46619-induced increase in guinea pig airway resistance

Method :

 Hartley male guinea pigs (500 to 800 g) were anesthetized with urethane (1.2 gZ kg, i.p.), fixed in a dorsal position, and tracheal force neurons were introduced. Spontaneous respiration was stopped with gallamine (lmg / kg, i.v.), and artificial respiration was performed at a rate of 60 strokes / min, volume 1 ml / 100 g body weight / cycle. U-46619 (3 g / kg) was administered intravenously in the common jugular vein, and the increasing airway resistance was measured with a respiratory function measurement device (Model 6, Buxco Electronics Inc.). The drug was orally administered 1 hour before administration of U-46619 as a dimethyl sulfoxide solution or as a methylcellulose suspension.

 The results were obtained as the rate of inhibition of airway resistance upon administration of the drug lOmgZkg. Table 2 shows the results of representative compounds. The airway resistance inhibitory effect upon administration of the compound of the present invention, lOmgZkg, significantly persisted until 8 hours after administration.

(4) Oral administration of LTD ₄ suppresses vascular hyperpermeability On the day before the experiment, a 1% aqueous solution of Evans blue (lmlZanimal) was intravenously administered to male Hartley guinea pigs whose backs were shaved. Two minutes later, LTD ₄ (5 ng / site) was administered intradermally to the back of the guinea pig, and 30 minutes later, the animals were killed by decapitation. Skin LTD ₄ intradermal sites were collected and extracted leaked dye intradermally. The amount of the leaked dye was calculated by measuring the absorbance at 620 nm and used as an index of vascular permeability. The test drug was orally administered as a dimethyl sulfoxide solution one hour before intradermal administration of LTD ₄ . The results were calculated as the inhibition rate after lmgZkg of the drug. Table 2 shows the results of representative compounds. The inhibitory action on vascular hyperpermeability upon administration of the compound of the present invention, lOmgZkg, significantly persisted until 8 hours after administration.

 (5) Suppression test for active sensitized guinea pig antigen-induced increase in airway resistance

Hartley male guinea pigs were sensitized by intraperitoneal administration of ovalbumin (OA) and Al (OH) ₃ as antigens three times at 2-week intervals. One to two weeks after the last sensitization, the sensitized guinea pigs were intravenously administered with antigen (OA) under anesthesia and artificial respiration, and the airway resistance was measured over time. Galamine (lmgZkg) 10 minutes before antigen administration, indomethacin (2 mgZkg) 3 minutes before antigen administration, mepyramin (2 mgZkg) 2 minutes before administration, and oral branolol (O. SmgZkg) was administered intravenously. The test drug was orally administered 1 hour before the antigen administration. The rate of change in airway resistance after antigen administration was calculated, and the effect of the test drug was examined using the inhibitory effect on airway resistance increase as an index. In this test, the compound of the present invention had a good inhibitory effect on the increase in airway resistance.

table 1

比較化合物 Α ： 特開平 5 - 105665号公報 実施例 1 61の化合物

Comparative compound Α: Japanese Patent Application Laid-Open No. 5-105665 Compound of Example 161

表 2 被験化合物 試験 (3) , 抑制率 （％) 試験 (4) , 抑制率 （％) 実施例 15 68 (DMSO) 82 (DMSO) 実施例 16 81 (DMSO) 73 (DMSO) 比較化合物 B 27 (DMSO) 35 (DMSO) * 比較化合物 B ： 特開平 4 - 1 54766号公報 実施例 2の化合物

Table 2 Test compounds Test (3), inhibition rate (%) Test (4), inhibition rate (%) Example 15 68 (DMSO) 82 (DMSO) Example 16 81 (DMSO) 73 (DMSO) Comparative compound B 27 (DMSO) 35 (DMSO) * Comparative compound B: JP-A-4-154766 Compound of Example 2

D MSO: Administered as dimethyl sulfoxide solution

* l O m g Zk g

 Pharmaceutical compositions containing one or more of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient can be prepared by using a commonly used carrier or excipient for a pharmaceutical preparation. Tablets, powders, fine granules, granules, capsules, pills, liquids, injections, suppositories, ointments, patches, etc., using other additives, orally or parenterally. Is administered. The clinical dose of the compound of the present invention to humans is appropriately determined in consideration of the symptoms, weight, age, sex, etc. of the patient to which the compound is applied. ~ 500mg, parenteral 0.01 ~:! OOmg, given once or divided into several doses. Since the dose varies under various conditions, a dose smaller than the above range may be sufficient.

Tablets, powders, granules and the like are used as the solid composition for oral administration according to the present invention. In such a solid composition, the one or more active substances may include at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch. , Polyvinylpyrrolidone, metasilicate, and magnesium aluminate. In a conventional manner, the composition may contain additives other than inert diluents, for example, lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, and stabilizers such as lactose. And solubilizing or solubilizing agents such as glutamate or aspartic acid. The pills and pills are gastric-soluble, such as sucrose, gelatin, hydroxypropylcellulose, and hydroxypropylmethylcellulose phthalate, as necessary. Alternatively, it may be coated with a film of an enteric substance.

 Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, and commonly used inert diluents. Contains, for example, purified water and ethyl alcohol. The composition may contain, in addition to the inert diluent, solubilizing or solubilizing agents, wetting agents, auxiliary agents such as suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.

 Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Diluents for aqueous solutions and suspensions include, for example, distilled water for injections and physiological saline. Non-water-soluble solutions. Examples of diluents for suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethyl alcohol, and polysol. There are 80 (brand name) etc. Such compositions may also contain additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing aids. Good. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. They can also be used in the manufacture of sterile solid compositions which are dissolved in sterile water or sterile injectable solvents before use.

When the solubility of the compound of the present invention is low, a solubilization treatment may be performed. For the solubilization treatment, known methods applicable to pharmaceutical preparations, for example, surfactants (polyoxyethylene hydrogenated castor oils, polyoxyethylene sorbitan higher fatty acid esters, polyoxyethylene polyoxypropylene glycols, sucrose) Fatty acid esters, etc.), drugs and solubilizers such as polymers (hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), etc. Water-soluble polymer, hydroxypropylmethyl cellulose (CMEC), hydroxypropyl methylcellulose cellulose phthalate (HPMCP), methyl methacrylate A method of forming a solid dispersion with a phosphoric acid copolymer (an enteric polymer such as Eudragit L, S, trade name; manufactured by Rohm and Haas Co.). If necessary, a method of forming a soluble salt, a method of forming an inclusion compound using cyclodextrin, or the like can also be employed. The method of solubilization can be changed as appropriate depending on the target drug ["Recent drug technology and its application I", Isamu Utsumi, Pharmaceutical Journal 157-159 (1983) and "Pharmaceutical Monograph No. 1, Bioavailability ”, Tsuneji Nagai et al., Soft Science, 78-82 (1988)].

 Of these, a method of improving the solubility by forming a solid dispersion of the drug and the solubilizing agent is preferably employed (JP-A-56-49314, FR2460667). BEST MODE FOR CARRYING OUT THE INVENTION

 Next, the target compound and the production method of the present invention will be further described with reference to examples, but the present invention should not be limited by these examples. Reference example 1

(Sat) 1- [3- (2-Quinolylmethoxy) phenyl] -2-propene-1-ol 7.85 g (26.9 mmol), 200 g of manganese dioxide and 200 ml of dichloromethane added at room temperature Stir for 12 hours. Further, 50 g of manganese dioxide and 50 ml of dichloromethane were added to the reaction solution, and the mixture was stirred at room temperature for 12 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate Z hexane = 1 Z4), and the obtained residue was dried in vacuo to give 1- [3-1-1 [(E) 1-2- (7- 5.36 g of Rollo 2-quinolyl) vinyl] phenyl] proponone were obtained. Reference example 2

 A solution of 2.27 g (18.5 mmol) of phthalimide and 0.05 g of sodium methoxide (catalytic amount) in 10 ml of dimethylformamide was stirred at room temperature while stirring 1- [3- (2-quinolylmetholide). A solution prepared by dissolving 2.72 g (18.5 mmol) of toxic / phenyl] propionone in 20 ml of dimethylformamide was added dropwise. After stirring the reaction solution for 1 hour, water was added to the reaction solution to remove insolubles. The obtained solid is washed successively with water and getyl ether, dried in vacuo, and N- [3-oxo-1-3- [3- (2-quinolylmethoxy) phenyl] propyl] phthalimide 8.10 g I got Reference example 3

[3-oxo-1-3- [3- (2-quinolylmethoxy) phenyl] propyl] phthalimide 5.17 g (11.8 mmol), 200 ml of tetrahydrofuran and 100 ml of methanol were added to the solution. 3.50 g of sodium borohydride was added, and the mixture was stirred at room temperature for 3 hours. Further, 3.00 g of sodium borohydride was added to the reaction solution, and the mixture was stirred for 50 hours. Next, 50 ml of tetrahydrofuran and 2.50 g of sodium borohydride were added to the reaction solution, and the mixture was stirred for 3 hours. Acetone was added to the reaction solution, and the mixture was stirred for about 15 minutes. Water was added to the solution, and the product was extracted with chloroform. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform = 1/20), and 4.09 g of the obtained residue was dissolved in 50 ml of tetrahydrofuran and 30 ml of acetic acid. The reaction was performed at C for 12 hours. The reaction solution was concentrated under reduced pressure, 1N sodium hydroxide was added to the obtained residue, and the product was extracted with methanol-chloroform (110). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform: 1/10), and (Sat) 13-amino-11- [3- (2-quinolinol) There was obtained 1.77 g of phenol / propanol. Reference example 4

 (Sat) 13-Amino 11- [3- (2-quinolylmethoxy) phenyl] propanol 1.71 g (5.5 mmol) in 30 ml of clog form, 30 ml of water, and 0.56 g of sodium hydrogen carbonate In addition, a solution of 1.17 g of 41-hole benzenesulfonyl chloride dissolved in 5 ml of chloroform was added at room temperature while stirring the two layers of the solution. The reaction solution was stirred for 2 hours, and the precipitated solid was collected by filtration. The resulting solid was digested in a black form, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from chloroform-formyl-ethyl ether to give (Sat.) 141-chloro-N- [3-hydroxy-3- [3- (2-quinolylmethoxy) phenyl]. [Propyl] 1.76 g of benzenesulfonamide was obtained. Reference example 5

 1.41-chloro-N- [3-hydroxy-3-[3- (2-quinolylmethoxy) phenyl] propyl] 1.76 g (3.6 mmol) of benzenesulfonamide dissolved in 50 ml of pyridine Then, 0.57 ml of methanesulfonyl chloride was added and reacted at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the product was extracted with a stoichiometric form. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate hexane = 1 to 3), and (Sat.) 14-close-mouth—N— [3-chloro-3— [3 -— (2-— Quinolinolemethoxy) phenyl] propyl] benzenesulfonamide 0.53 g was obtained. Reference example 6

(Earth) 1 4 1 N- [3-N-3- [3- (2-quinolylmethoxy) phenyl] propyl] benzenesulfonamide 0.23 g (0.45 mmol), cesium carbonate 0.44 g ( 14 mmol), methyl 2-mercaptopropionate O.llg (0.92 mmol) in 5 ml of dimethyl sulfoxide Then, the mixture was stirred at 50 ° C for 1 hour. After cooling the reaction solution, water was added to the reaction solution, and the product was extracted with toluene monoethyl acetate (1-5). The organic layer was washed sequentially with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 13 → ethyl acetate / hexane = 1 2), and (Sat) 1 3 — [[3— (4 [Phenylsulfonylamino] -111 [3- (2-quinolylmethoxy) phenyl] propyl] thio] methyl propionate 0.17 g was obtained. Reference Example 7

 8.61 ml (91.2 mmol) of acetic anhydride was added to a solution of 5.40 g (30.4 mmol) of 7-clonal quinaldine and 5.99 g (36.5 mmol) of methyl isophthalaldehyde in 54 ml of xylene, and the mixture was heated under reflux for 8 hours. After cooling the reaction solution, the solvent was distilled off under reduced pressure. After adding getyl ether to the residue, the solid was collected by filtration from the suspension to obtain 4.65 g of methyl 3-[(E)-2- (7-chloro-2-quinolyl) vinyl] benzoate. Was. Reference Example 8

 4.60 g (14.21 mmol) of [(E)-(2- (7-cyclo-2--2-quinolyl) vinyl) methyl benzoate] was dissolved in a mixed solvent of 46 ml of tetrahydrofuran and 23 ml of methanol. To the solution, 21.31 ml of 1N aqueous sodium hydroxide solution was added and reacted at 40 for 3 hours. Ice and a 10% aqueous solution of citric acid were added to the reaction solution, and the precipitated solid was collected by filtration. The obtained solid was washed successively with water and a small amount of methanol to obtain 4.40 g of 3-[(E) -2- (7-chloro-2-quinolyl) vinyl] benzoic acid. Reference Example 9

[(E) 12- (7-Chloro-2-quinolyl) vinyl] 4.70 g (15.2 mmol) of benzoic acid was dissolved in 70 ml of dimethylformamide, and then dissolved. To the solution were added 5. Olg (30.3 mmol) of potassium carbonate hemihydrate and 2.23 g (19.7 mmol) of ethyl isocyanoacetate, and the mixture was stirred at room temperature for 5 minutes. Then, the reaction solution was cooled to 5 ° C, 5. Olg (18.2 mmol) of diphenylphosphoryl azide was added, and the mixture was stirred at room temperature for 20 hours. The reaction solution was poured into ice water, and the product was extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / chloroform = 1119), and the obtained residue was crystallized by chromatographic form-ethyl acetate. [(E) —2- (7-Chloro-2-quinolyl) vinyl] phenyl] oxazolyl-4-ethyl ethyl carbonate 5. Olg was obtained. Reference Example 10

 [3-[(E) -12- (7-chloro-1-2-quinolyl) vinyl] vinyl] oxazol-4 4 ethyl rubonate 5. Ethanol to OOg (12.4mmol) 25 ml and 25 ml of concentrated hydrochloric acid were added, and the mixture was heated under reflux for 6 hours. The reaction solution was cooled, and the precipitated crystals were collected by filtration. The obtained crystals are washed with methanol, and 2-amino 1-[3- [(E)-2-(7-1-quinolinyl) vinyl] phenyl] 4.80 g of ethanonone dihydrochloride was obtained. Reference Example 11

580 ml of ethanol was added to 25.30 g (198.2 mmol) of sodium carbonate and 5.54 g (146.6 mmol) of sodium borohydride, and the mixture was stirred under ice cooling. Then, at 15 and below, 2-amino-1— [3 -— ((E) -2- (7-chloro-2-quinolinyl) vinyl] phenyl] ethanone'dihydrochloride The mixture was added to the suspension and stirred at room temperature for 1 hour. The reaction solution was poured into ice water, and the precipitated crystals were collected by filtration. The obtained crystals are washed successively with water and acetonitrile, and (Sat) —2-amino-11- [3-[(E) -12- (7-cyclo1-2-2-quinolyl) vinyl] phenyl] Ethanol 21.20 g were obtained. Reference Example 12

 2-amino-1- (3-[(E) -12- (7-chloro-2-quinolyl) vinyl] phenyl] ethanol 16.10 g (49.6 mmol), 7.34 g of phthalic anhydride (49.6 mmol) was added to 20 ml of toluene, and the temperature of the suspension was gradually raised while stirring the mixture. After the temperature of the reaction solution reached 160 ° C, the reaction was kept under reduced pressure (3 mmHg) and allowed to react for 3 hours. Subsequently, the reaction residue was cooled and dissolved in a black hole form. The solvent was distilled off under reduced pressure, acetonitrile was added to the obtained residue, and the precipitated solid was collected by filtration. (Sat) 1 N— [2— [3 — [(E) —2— ( 7.82 g of 7-chloro-2-quinolyl) vinyl] phenyl] —2-hydroxyoxethyl] phthalimid were obtained. Reference Example 13

(Earth) 1 N— [2— [3 — [(E) 1—2— (7—Cross—1—Quinolyl) vinyl] phenyl] —2—Hydroxitytyl] phthalimid 17.80 g (39.1 mmol) was dissolved in 53 ml of pyridine and 89 ml of 1,2-dichloroethane. To the solution was added methanesulfonyl chloride 3.36m] (47.0mmol) with stirring under ice-cooling, and the mixture was stirred at room temperature for 12 hours. Ice and a 10% aqueous solution of citric acid were added to the reaction solution, and the product was extracted with a black hole form. The organic layer was washed successively with a 10% aqueous solution of citric acid, a 5% aqueous solution of potassium carbonate, and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from chloroform-acetonitrile to give (Sat.) 1- [3-[(E) -2- (7-chloro-2--2-quinolyl) vinyl] phenyl] 18.2-g of 2- (phthalimidethyl) methanthone was obtained. Reference Example 14

 (Sat) 11-1 [3 — [(E) 12— (7—Cro 1-2—Quinolyl) vinyl] phenyl] -12-phthalimidethyl = medium sulfonet 3.00g (5.6 1.54 g (8.4 mmol) of methyl 4-mercaptomethylbenzoate was dissolved in 90 ml of dimethyl sulfoxide, and then 3.96 g (11.3 mmol) of cesium carbonate was added to the solution at 20 ° C. After the reaction solution was stirred at room temperature for 1 hour, benzene, ice and water were added to the reaction solution and stirred well. The precipitated unnecessary substances were filtered off, the organic layer was collected, and the organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (benzene-ethyl acetate / benzene = 119), and the obtained residue was crystallized from ethyl acetate-ethanol to give (Sat.) [[1- [3-[(E) -2- (7-chloro-1-2-quinolyl) vinyl] phenyl] -12-phthalimidoethyl] thio] methyl] methyl benzoate 1.54 g Was. Reference Example 15

(S) 1 4 1 [[[1-[3-[(E) — 2— (7-Chlorol 2-quinolyl) vinyl] phenyl] 12-phthalimidoethyl] thio] methyl] methyl benzoate To 1.50 g (2.4 mmol), 1,4-dioxane (10 ml) and ethanol (20 ml) were added and dissolved by heating. Then, methylhydrazine (1.55 ml, 29.0 mmol) was added. Then, the reaction solution was heated to reflux for 7 hours. After cooling the reaction solution, ice and a 5% aqueous solution of potassium carbonate were added to the reaction solution, and the product was extracted with 1,2-dichloroethane. The organic layer was washed successively with a 5% aqueous solution of potassium carbonate and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 30 ml of 1,2-dichloroethane, and cooled to 5 ° C, and 0.51 ml (3.6 mmol) of triethylamine, 0.61 g (2.9 mmol) of 4-benzene-sulfonyl chloride was obtained. ) Was added to the solution and reacted for 12 hours. Ice, 10% quen After adding an aqueous acid solution, the organic layer was separated, and the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel gel chromatography (ethyl acetate benzene = 3Z97-ethyl acetate Z benzene = 1/19), and the resulting residue was crystallized from acetonitril. , (Sat) 1 4-[[[[2- (4-Chlorophenylsulfonylamino)] 1-11- [3 — [(E) —2— (7-Chloro-2-quinolyl) vinyl] [Phenyl] ethyl] thio] methyl] methyl benzoate (1.03 g) was obtained. Reference Example 16

 (Sat) 1-11 [3 — [(E) —2— (7-Cro-2-1-quinolyl) vinyl] phenyl] —2-propene-1-ol 26,20 g (81.4 mmol), To 131 g of manganese dioxide was added 500 ml of toluene, and the mixture was refluxed for 3 hours. After cooling the reaction solution, the reaction solution was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / chloroform / hexane = 3/30/70). Crystallization with xan gave 10.59 g of [3-[(E) -2- (7-chloro-2-quinolyl) vinyl] phenyl] probenone. Reference Example 17

[3-1 [(E) -12- (7-chloro-2-oxolyl) vinyl] phenyl] propionone 8.70 g (27.2 mmol), 4-cyclobenzene benzenesulfonamide 5.73 g (29.9 mmol) and 0.10 g (catalyst amount) of tert-butoxylium were added with 80 ml of 1,4-dioxane and 80 ml of benzene, and reacted at 80 ° C for 10 hours. After cooling the reaction solution, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform-2Z1000), and the obtained residue was crystallized from methanol to obtain 41-chloro-N- [3 — [3— [(E) — 2— (7—Kurorow 2 —Quinolyl) vinyl] phenyl! -13-oxopropyl] benzenesulfonamide 8.10 g was obtained. Reference Example 18

 4-—Chlorone N— [3-—3 -— ((E) —2 -— (7-Chlorol-2-quinolyl) vinyl] phenyl] -13-oxopropyl] benzenesulfonamide 8.40 g (17.7 mmol ) Was dissolved in 4 ml of tetrahydrofuran and 40 ml of ethanol, and 0.33 g (8.8 mmol) of sodium borohydride was added to the solution while stirring at 5 ° C. After allowing the reaction to proceed at room temperature for 1 hour, ice and a 10% aqueous solution of citric acid were added to the reaction solution, and the product was extracted with a port form. The organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue is dried in a vacuum, and is dried in a vacuum. 1.3-Hydroxypropyl] benzenesulfonamide (8.50 g) was obtained as a yellow foam. Reference Example 19

(Sat) 1-4-Chlorone N— [3- [3 — [(E) —2 -— (7-Chloro 1-2-quinolyl) vinyl] phenyl] 1-3-Hydroxypropyl] benzene 8.40 g (16.4 mmol) of sulfonamide was dissolved in 160 ml of 1,2-dichloromethane and 1.43 ml (19.6 mmol) of thionyl chloride was added to the solution while stirring at 5. After allowing the reaction to proceed at room temperature for 5 hours, ice and a saturated aqueous solution of sodium hydrogencarbonate were added to the reaction solution, and the product was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by a silica force gel strength La Mukuroma preparative chromatography (hexane = ₃ 7 to acetic Echiru Z hexane = 1 Bruno 4 → acetate Echiru), and vacuum dried resulting residue, (Sat) - 4 Ichiku Rollo N— [3-Chloro-1-3- (3-[(E) -2- (7-Chloro-2-quinolyl) vinyl] phenyl] propyl] benzenesulfo 8.52 g of amide was obtained as a yellow foam. Reference Example 20

 (Sat) 1-41-Chlor N— [3-Chlor 3-—3-((E) 1-2— (7—Chlor 2-quinolyl) vinyl] phenyl] propyl] benzensulfonami 0.50 g (0.9 mmol) is dissolved in 10 ml of N, N'-dimethylimidazolinone, and at 10 cesium carbonate 1.61 g (1.9 mmol) and methyl 3-mercaptopropionate 0.17 g (1.4 mmol) Was added. After reacting at 40 ° C for 12 hours, ice and water were added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate Z hexane = 1/3), and the obtained residue was dried in vacuo to give (Sat) — 4 — [[3 -— (4-1 0.31 g of methyl phenylsulfonylamino) 1-11 [3 — [(E) —2— (7-chloro-2-quinolyl) vinyl] phenyl] propyl] thio] methyl propionate Obtained as a foam. Reference Example 21

To 87.6 g (0.41 mol) of 2-chloromethylquinoline hydrochloride was added 500 ml of dimethylformamide, and the mixture was stirred under ice-cooling. Next, 124 g (0.90 mol) of lithium carbonate and 50.0 g (0.41 mol) of 3-hydroxybenzaldehyde were added to the solution and reacted at 70 ° C for 3 hours. After cooling the reaction solution, the insolubles were filtered, water was added to the filtrate, and the product was extracted with ethyl acetate toluene (1-1). The organic layer was washed with 1N sodium hydroxide, water, and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from acetonitrile to obtain 67.2 g of 3- (2-quinolylmethoxy) benzaldehyde. Reference Example 22

 (2-Quinolylmethoxy) To 30.0 g (114 mmol) of benzaldehyde, 30 ml of water and 5.58 g (114 mmol) of sodium cyanide were added. An aqueous solution in which 16 g of sodium hydrogen sulfate was dissolved in 40 ml of water was added to the suspension while stirring at 20 ° C or lower. The reaction solution was stirred for 12 hours, and the insoluble material was collected by filtration. The obtained solid was washed with water and dried under vacuum to obtain 27.0 g of (Sat) 11-hydroxy-11- [3- (2-quinolylmethoxy) phenyl] acetonitrinole. Reference Example 23

 (1) 1-Hydroxy 1- [3- (2- (2-quinolylmethoxy) phenyl] acetonitrinolane 26.9 g (92.7 mmol) in 140 ml of 1N borane-tetrahydrofuran complex A solution dissolved in 300 ml of trahydrofuran was slowly added. The reaction solution was refluxed for 4 hours, cooled on ice, and 180 ml of ethanol was added dropwise. Next, 100 ml of 1 N hydrochloric acid was added to the reaction solution, and the mixture was heated under reflux for 30 minutes. The reaction solution was cooled, and the solvent was distilled off under reduced pressure. 1N Hydrochloric acid was added to the residue, and the mixture was washed with chloroform. 1N sodium hydroxide was added to the aqueous layer. The precipitated solid was collected by filtration, and the obtained solid was washed successively with water and getyl ether, dried under vacuum, and washed with (sat) 12-amino-11- [3- (2-quinolylmethoxy). 2) g of ethanol] was obtained. Reference Example 24

(Sat) 1-2-Amino 1- [3- (2-quinolylmethoxy) phenyl] Ethanol (19.3 g) and phthalic anhydride (9.7 g) were heated at 160 under reduced pressure (lmmHg or less) at 160 for 2 hours. After the reaction was cooled, it was dissolved in chloroform. The solvent was distilled off under reduced pressure until a solid was deposited. Acetonitrile was added to the suspension, and the mixture was stirred for 1 hour. The insoluble material was collected by filtration, and (Sat) —N— [2-hydroxy-2- — (2-quinolylmethoxy) phenyl] ethyl] 27.4 g of phthalimid was obtained. Reference Example 25

 (Sat) 1 N— [2-hydroxy-2- (3- (2-quinolylmethoxy) phenyl] ethyl] phthalimide 26.3 g (62.0 mmol), 350 ml of dichloromethane, and ice-cooling Stirred. Next, 12.9 ml (93.0 mmol) of triethylamine was added to the reaction solution, and 11.7 ml (74.4 mmol) of methanesulfonyl chloride was further added dropwise. After stirring the reaction solution for 1 hour at room temperature, ice and water were added to the reaction solution. The product was extracted with dichloroethane, and the organic layer was washed successively with a 10% aqueous solution of citric acid, water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was pulverized with getyl ether, and the insolubles were collected by filtration. (Sat) 1-2-phthalimid-1-1 [3- (2-quinolylmethoxy) phenyl] ethyl = methyl sulfone 28.4 g was obtained. Reference Example 26

(Sat) 1-2-phthalimidamide 11- [3- (2-quinolylmethoxy) phenyl] ethyl = methansulfonate 0.42 g (0.84 mmol), 0.18 g of lithium carbonate and 20 ml of dimethylformamide After adding 0.11 ml of methyl 3-mercaptopropionate, the mixture was stirred at 100 ° C for 5 hours. Water was added to the reaction solution, and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate Z hexane = 1Z3 → ethyl acetate Z hexane-1/2), and the obtained residue was dried in vacuo to give (Sat) 1-3 — [[2 —Phthalimid-111 [3- (2-Quinolylmethoxy) phenyl] ethyl] thio] methyl methyl pionate 0.22 g was obtained. Reference Example 27

 (Sat) 1-[[2-phthalimidido 11- [3- (2-quinolylmethoxy) phenyl] thiol] thio] Methyl propionate 0.22 g (0.42 mmol) in 2 ml methanol 0.06 ml of drazine monohydrate was added. The mixture was heated to reflux for 6 hours. After cooling the reaction mixture, ice and a 5% aqueous solution of potassium carbonate were added to the reaction mixture, and the product was extracted with dichloromethane. The organic layer was washed successively with a 5% aqueous solution of potassium carbonate and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 10 ml of dichloromethane, and 0.12 ml (0.86 mmol) of triethylamine and 0.09 g (0.42 mmol) of benzenesulfonyl chloride were added to the solution under cooling at 5 ° C. In addition, the reaction was carried out for 12 hours. After adding ice and a 10% aqueous solution of citric acid to the reaction solution, the organic layer was separated, and the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1 to 2), and the obtained residue was dried in vacuo to give (Sat) — 3 — [[2- (4-chlorophenylsulfonylamino). G) 0.11 g of [3- (2-quinolylmethoxy) phenyl] ethyl] thio] methyl propionate was obtained. Reference Example 28

(Sat) 1-41-chloro N- [3-[3-((E) -2- (7-chloro-l2-quinolyl) vinyl] phenyl] 3-hydroxypropyl] Benzens-Hongami To a solution of 5.00 g of dichloroethane in 200 ml of dichloroethane, 2.92 g of (R)-(-)-namethoxyphenylacetic acid, 3.90 g of dicyclohexylcarbodiimide, and 243 mg of 4-dimethylaminopyridine were added and stirred at room temperature for 1 hour. did. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (clo-form form). The Rf value (clo-form form Z ethyl acetate = 10-1) was 0.61 (reference). (1R or 1S) of Example 28—a) and 0.46 (Reference Example 28—b) — 3— (4-chlorophenylsulfonylamino) 1 1 1 [3 — [(E) —2— (arc Loro-2-quinolyl) vinyl] phenyl] propyl (2R) — 2-methoxyethoxy acetate 0.75 g and 0.29 g, respectively, were obtained as yellow oils. Reference Example 29

 (1R or 1S) -3- (4-chlorophenylsulfonylamino) 1-1- [3-[(E) -12- (7-chloro-2-quinolyl) vinyl] phenyl] propyl (2R) — 2-Methoxyphenylacetate (Reference Example 28-a (fraction of chloroformformoacetate = 10/1)) 0.75 g of 1N hydroxylic acid aqueous solution in 10 ml of ethanol 1.7 ml was added, and the mixture was stirred at room temperature for 30 minutes. 10 ml of water and 10 ml of ethyl acetate were added to the reaction mixture, and the obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane ethyl acetate = 52) to give (R or S) —4-chloro-N— [3 -— [3 -— ((E) -442 mg of 2- (7-chloro-2-quinolyl) vinyl] phenyl] -3-hydroxypropyl] -benzenesulfonamide was obtained as a colorless oil. Reference Example 30

(R or S) — 4-—N- [3-—3 -— ((E) — 2 -— (7-Chloro-2-quinolyl) vinyl] phenyl] -1-3-hydroxypropyl] — A solution of 440 mg of benzenesulfonamide in 20 ml of dichloroethane was cooled to 120, and triethylamine 4311 and methansulfonyl chloride 186β1 were added, followed by stirring at −10 or less for 1.5 hours. After adding saturated aqueous sodium hydrogen carbonate to the reaction mixture, the obtained organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was dissolved in 10 ml of dimethyl sulfoxide. 279 mg of 3,3-dimethyl-41-mercaptobutyric acid methyl ester and 841 mg of cesium carbonate were added. For 1 hour. The reaction mixture was ice-cooled, and saturated saline and ethyl acetate were added. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane Z ethyl acetate = 52) to give 4-[[((1R or 1S))-3- (4-cyclophenylphenylsulfur). Honylamino) 1 1 1 [3 — [(E) —2— (7-chloro-2-quinolyl) -vinyl] phenyl] propyl] thio] 13,3-dimethylbutyric acid methyl ester 343 mg Obtained as a pale yellow oil. Reference Example 31

 (Sat) 1-41 [[[1-1-1 [3-[(E) -12- (7-chloro-1-2-quinolyl) vinyl] phenyl] -12-phthalimidethyl] thio] methyl] methyl benzoate To a solution of 600 mg of the chill ester in 10 ml of ethanol and 10 ml of 1,4-dioxane was added 0.62 ml of methylhydrazine, and the mixture was refluxed for 9 hours. The reaction mixture was distilled off, a 10% aqueous solution of potassium carbonate and ethyl acetate were added, and the obtained organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then the solvent was distilled off. did. The obtained residue was dissolved in 10 ml of toluene. 223 mg of 4-chlorophenyl isocyanate was added, and the mixture was stirred at room temperature for 3 days. Water and ethyl acetate were added to the reaction mixture, and the obtained organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel gel chromatography (hexane Z ethyl acetate = 4-1 → chloroform-form) to obtain the residue. 3- (4-Chlorophenyl) ureido] 1-111 [3-[(E) 1-2- (7-Chlorolo-2-quinolyl) vinyl] phenyl] ethyl] thio] methyl] methyl benzoate 618 mg of the ester were obtained as a yellow amorphous. Reference Example 32

1-[3-[(E) — 2— (7-chloro-2-quinolyl) vinyl] 8.35 g (26.1 mmol) of [nyl] propionone were dissolved in 160 ml of toluene and 40 ml of acetic acid, and 5.70 g (28.7 mmol) of sodium 4-benzene benzenesulfonate was added, followed by stirring at room temperature for 1 hour. Further, 1.50 g (7.6 mmol) of sodium 4-benzene benzenesulfinate was added, and the mixture was stirred at room temperature for 30 minutes. The solid precipitated from the reaction solution is filtered and 3- (4-chlorophenylylsulfonyl) -13 '-[(E) -2- (7-chloro-2-quinolyl) vinyl] propionone 11.4 g (23.0 mmol) was obtained as a white solid. Reference Example 33

 3- (4-chlorophenylsulfonyl) -1 3 '-[(E) -2- (7-chloro-2-quinolyl) vinyl] propiophenone 11.4 g (23.0 mmol) in 55 ml of tetrahydrofuran and The residue was dissolved in 55 ml of Tanomono, and 1.04 g (27.5 mmol) of sodium borohydride was added under ice-cooling, followed by stirring at room temperature for 1 hour. Distilled water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residual white solid was washed with hexane / ether. (Sat) -a- [2- (4-Chlorophenylsulfonyl) ethyl] —3 -— [(E) -1-2— (7-Chloro-2-quinolyl) 8.43 g (16.9 mmol) of vinyl] benzyl alcohol were obtained. Reference example 34

(Earth) 1 α- [2-((4-chlorophenylsulfonyl) ethyl) 13-[(E) 12- (7-chloro-2-quinolyl) vinyl] benzyl alcohol 500 mg (lOOOOmmol) ) Was dissolved in 10 ml of 1,2-dichloroethane, triethylamine 1681 and methansulfonyl chloride 931 were added, and the mixture was stirred at room temperature for 30 minutes. 20 ml of distilled water was added to the reaction solution, and the mixture was extracted with a black form. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. 642 mg of the obtained residue Was dissolved in 6 ml of dimethyl sulfoxide, 366 mg (2.01 mmol) of 4-methoxycarbonylbenzylthiol and 980 mg (3.01 mmol) of cesium carbonate were added, and the mixture was stirred at room temperature for 1 hour. 30 ml of distilled water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl hexanoacetate-2/1). (Sat) 1-4 [[[[3- (4-cyclophenylphenylsulfonyl)]-11 [3— [ (E) 501 mg (0.756 mmol) of 12- (7-chloro-2-quinolyl) vinyl] phenyl] propyl] thio] methyl benzoate was obtained as a pale yellow oil. Reference Example 35

(Sat) One α- [2-((4-chlorophenylsulfonyl) ethyl) -13-[(E) -12- (7-chloro-2-quinolyl) vinyl] benzyl alcohol (300 mg, 0.602 mmol) Dissolve in 15.0 ml of dimethylformamide, add 30 mg of sodium hydride (60%), a catalytic amount of tetrasulfurmonium hydrogensulfate and 126 mg of ethyl 5-bromo valerate in an ice bath, and add at room temperature. Stir for 14 hours. (Earth) 1 α- [2- (4-chlorophenylsulfonyl) ethyl] — 3 — [(E) 12- (7-chloro-2-quinolyl) vinyl] Using 200 mg (0.401 mmol) of benzyl alcohol 50 ml of distilled water was added to a mixture of the same reaction solution and the above-mentioned reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane ethyl acetate = 2 Z 1). (Sat) 1-4-[3-(4-chlorophenylsulfonyl) 1-1 [3-[(E) -359 mg (0.573 mmol) of 2- (7-chloro-2-quinolyl) vinyl] phenyl] propoxy] pentanoate was obtained as a colorless oil. Reference Example 36

 Dissolve 4.56 g (15.9 mmol) of 3-bromophenoxy-1- (1,1-dimethylethyl) dimethylsilane in 23 ml of tetrahydrofuran and add 10.2 ml of 1.64 M n-butyllithium lithium hexane solution at 178 ° C. The reaction solution stirred for 30 minutes was added dropwise to a solution of 3.52 g (15.1 mmol) of 3- (4-chlorophenylsulfonyl) propanal in 35 ml of tetrahydrofuran at -78 ° C and stirred for 30 minutes. . 100 ml of a saturated aqueous solution of ammonium chloride and 30 ml of distilled water were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. 4.53 g of the obtained residue was dissolved in 90 ml of tetrahydrofuran, and 11.3 ml of a 1.0 M tetrabutylammonium fluoride tetrahydrofuran solution was added, followed by stirring at room temperature for 5 hours. 200 ml of distilled water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with saturated saline and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexyl acetate = 21 → 1: 1) (Sat.) — 3— [3- (4-chlorophenylphenylsulfonyl) -11-hydrogen Roxypropyl] phenol 1.17 g (3.58 mmol) was obtained as a white solid. Reference Example 37

(Sat) 1-3- [3- (4-Chlorophenylsulfonyl) 1-1-hydroxypropyl] fuyunol 1.17 g (3.58 mmol) was dissolved in 36 ml of dimethylformamide and potassium carbonate 1.29 g (93.3 mmol) and 2- (chloromethyl) quinoline hydrochloride l.OOg (46.7 mmol) were added, and the mixture was stirred at 6 CTC for 17 hours. After confirming the completion of the reaction, 200 ml of distilled water was added to the reaction solution, and the mixture was extracted with a mixed solvent (ethyl acetate / n-hexane = 2/1). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4 → 3 → 11) to give the compound (Earth) —naichi [2-- Phenyl (sulfonyl) ethyl] -3- (2-quinolinylmethoxy) benzyl alcohol 760 mg (1.62 mmol) Obtained as a white solid. Reference example 38

 (Sat) — a — [2- (4-Cross-phenylphenylsulfonyl) ethyl] — 3- (2-quinolylmethoxy) benzyl alcohol 170 mg (0.363 mmol) is dissolved in 1,2-dichloroethane 20 ml. , Triethylamine 300-1 and methanesulfonyl chloride mouth 1501 were added and stirred at room temperature for 30 minutes. After confirming the completion of the reaction, 30 ml of distilled water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. 252 mg of the obtained residue was dissolved in 10 ml of dimethyl sulfoxide, 131 mg (1.09 mmol) of methyl 3-mercaptopropionate and 354 mg (1.09 mmol) of cesium carbonate were added, and the mixture was stirred at 40 ° C for 1 hour. 50 ml of distilled water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1). (Sat) — 4 1 —190 mg (0.333 mmol) of methyl quinolylmethoxy) phenyl] propyl] thio] propionate was obtained as a pale yellow oil. Reference example 39

3-Hydroxymethylbenzaldehyde (1.92 g, H.lmmol) was dissolved in 40 ml of ethanol, and 476 mg (7.05 mmol) of methylamine hydrochloride, 487 mg (3.52 mmol) of carbonated carbonate, and nitromethane 764 1 ( H.lmmol) and 2.77 g (14.1 mmol) of methyl 4-mercaptomethylbenzoate, and the mixture was stirred at 50 晚 for 1 晚. After completion of the reaction, the reaction solution was concentrated under reduced pressure, distilled water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = Purify in 3: 2) and give 2.93 g (8.11 mmol) of 14-[[[11- (3-hydroxymethylphenyl) -1-2-troethyl] thio] methyl] methylbenzoate Obtained as a pale yellow oil. Reference example 40

 (Sat) 14-[[[1- (3-hydroxymethyiphenyl) 1-2-2 troethyl] thio] methyl] Methyl benzoate 2.42 g (6.70 mmol) in 24 ml of methanol and acetic acid 5.0 Then, 4.78 g (73.1 mmol) of zinc powder was added, and the mixture was stirred at 50 ° C for 4 hours. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate and a 1N aqueous solution of sodium hydroxide were added to the residue, and the mixture was stirred. The resulting solid was removed by filtration. The filtrate was separated and extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. (Sat) 1-4 [[[2-amino-1- (3-hydroxymethylphenyl) ethyl] thio] [Methyl] 2.16 g (6.52 mmol) of methyl benzoate was obtained as a pale yellow oil. Reference Example 41

(Sat) 1-41 [[[2-amino-11- (3-hydroxymethylphenyl) ethyl] thio] methyl] methyl benzoate 2.02 g (6.09 mmol) in 1,2-dichloroethane 40 ml The mixture was dissolved, 1.29 g (6.11 mmol) of benzenesulfonyl chloride and triethylamine 934/1 (6.70 mmol) were added in an ice bath, and the mixture was stirred at room temperature for 4 hours. After the completion of the reaction, distilled water was added to the reaction solution, and the mixture was separated. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. 2-Propanol and n-hexane are added to the residue, and the mixture is stirred. The sediment is removed from the furnace, and the resulting precipitate is removed from the furnace. (Sat) — 4-1 [[[2- 3-Hydroxymethylphenyl) ethyl] thio] methyl] methyl benzoate (2.90 g, 5.73 mmol) as a colorless solid I got it. Reference Example 42

 (Sat) 1-41 [[[2- (4-chlorophenylsulfonylamino) 1-1- (3-hydroxymethylphenyl) ethyl] thio] methyl] methyl benzoate 2.82 g ( 5.57 mmol) was dissolved in 56 ml of 1,2-dichloroethane, 28.2 g of manganese dioxide was added, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 2). (Sat) 14-[[[2- (4-Chlorophenylsulfonylamino) 1-1 1 (3 —1.42 g (2.82 mmol) of methyl benzoate was obtained as a colorless oil. Reference Example 43

(S) 1-[[[[2- (4-Cross-phenylphenylsulfonylamino) 1-1- (3-formylphenyl) ethyl] thio] methyl] methyl benzoate 963 mg (1.91 mmol) in benzene The residue was dissolved in 50 ml, 201 mg (2.75 mmol) of n-butylamine was added, and the mixture was heated under reflux for 1 hour under azeotropic dehydration. The reaction solution was concentrated under reduced pressure, and 1.45 g of the residue obtained was dissolved in 30 ml of acetic acid. To the solution was added 356 mg (2.00 mmol) of 7-methyl-1-methylquinoline, and the mixture was refluxed for 7 hours. The reaction solution was concentrated under reduced pressure, distilled water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. Acetonitrile was added to the residue and the mixture was stirred, and the precipitated solid was collected by filtration. (Sat) 14-[[[[2- (4-Cross-phenylphenylsulfonylamino) 1-1- [3 — [(E) —2- (7-chloro-2-quinolyl) vinyl] phenyl] ethyl] thio] methyl] methyl benzoate (904 mg, 1.36 mmol) was obtained as a pale yellow solid. Reference example 44

 To a solution of 500 mg of 3- (1,3-dioxolan-1-yl) benzaldehyde in 10 ml of ethanol was added nitromethane 1521, methylamine hydrochloride 19 mg and potassium carbonate 8 mg, and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added a solution of 512 mg of methyl 4-mercaptomethylbenzoate in 10 ml of ethanol, and the mixture was added at room temperature for 1 day and further 60. The mixture was stirred at C for 5 hours. The reaction mixture was concentrated under reduced pressure, water and ethyl acetate were added to the residue, and the obtained organic layer was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue obtained was purified by silica gel column chromatography (hexane Z-ethyl acetate = 4Z1), and (Sat) 14-[[[1- [3- (1,3-dioxolan-1-2-) Yl) phenyl] 1-2-2-troethyl] thio] methyl] methyl benzoate (638 mg) was obtained as a colorless oil. Reference example 45

 (Sat) 14-[[[[1- [3- (1,3-dioxolan-2-yl) phenyl]] 1-2-2 Troethyl] thio] methyl] methyl benzoate lOOmg in methanol 5ml, After adding 1 ml of acetic acid and 162 mg of zinc, the mixture was stirred at 50 ° C for 1 hour. The insoluble matter of the reaction mixture was separated by filtration through celite, washed with methanol, and the obtained filtrate was concentrated under reduced pressure, benzene was added twice to the residue, and the mixture was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate and ethyl acetate were added to the residue, and the obtained organic layer was washed with water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off. [[2-Amino-1-1- [3- (1,3-dioxolan-1-yl) phenyl] ethyl] thio] methyl] methyl benzoate 91 mg was obtained as a brown oil. Reference Example 46

(S) 1 4-[[[2-Amino 1-1-1 [3- (1,3-dioxolan-1-yl) phenyl] ethyl] thio] methyl] Methyl benzoate 500 mg in dichloroethane 5 ml solution And 0.56 ml of triethylamine under ice-cooling After adding 424 mg of 4-benzene benzenesulfonyl chloride, the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate and chloroform were added to the reaction mixture, and the obtained organic layer was washed with water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane ethyl acetate = 2 1) to give (Sat) 14 [[[2- (4-Cro- mouth phenylsulfonamido). )-368 mg of methyl-1-benzo-3-ethyl-1,3- [1,3-dioxolan-1-yl] phenyl] ethyl] methyl] benzoate was obtained as a pale yellow oil. Reference Example 47

 (Sat) 1 4— [[[2— (4 chlorophenylsulfonamide) 1 1 1

[3- (1,3-Dioxolan-1-yl) phenyl] ethyl] thio] methyl] To a solution of 300 mg of methyl benzoate in 20 ml of tetrahydrofuran was added 2 ml of a 1N aqueous hydrochloric acid solution, and the mixture was stirred at room temperature for 1 hour. Again, 1 ml of a 1 N aqueous hydrochloric acid solution was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was distilled off under reduced pressure, and water and chloroform were added to the obtained residue. The obtained organic layer was washed successively with water and a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off. (Sat) 14-[[[2- (4-cyclophenylphenylsulfone) Amid) — 1— (3-forminorefenyl) ethyl] thio] methyl] methyl benzoate (351 mg) was obtained as a pale yellow oil. Reference Example 48

(Sat) 1-4 — [[[2-Amino 1— (3-hydroxymethyl phenyl) ethyl] thio] methyl] methyl benzoate 2.19 g (6.61 mmol) of acetonitrile in 33 ml and After dissolving in 4.4 ml of distilled water, 2.55 g (6.60 mmol) of (+)-di-p-toluoyl-D-tartaric acid was added, and the mixture was stirred for 1 hour, and the precipitated colorless crude crystals were collected by filtration. The recrystallization (acetonitrile distilled water) was repeated, and (+) — 4 — [[[2-amino-1- (3-hydroxymethylphenyl) ethyl] thio] methyl] benzoic acid Methyl. (+) 289 mg (0.403 mmol) of di-p-toluoyl-D-tartrate were obtained as colorless crystals. Reference 49

In the same manner as in Reference Example 48, (-) — 4— [[[2-amino 1- (3-hydroxymethyl phenyl) ethyl] thio] methyl] benzoic acid methyl ester (1) di- _p — Toluoyl-tartrate was obtained as colorless crystals. Reference example 50

To a solution of 3.56 g of 3- (1,3-dioxolan-1-yl) benzaldehyde in 50 ml of benzene was added 2.92 g of n-butylamine, and the mixture was refluxed for 1 hour while distilling off the generated water. The reaction mixture was concentrated under reduced pressure, and 50 ml of acetic acid and 2.44 g of nitromethane were added to the residue. After stirring under heating at C for 3 hours, 3.64 g of 4-methylcaptomethyl benzoate was added, and the mixture was heated and stirred at 60 ° C for 12 hours and at 80 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure, benzene was added to the residue, and concentrated under reduced pressure twice. Saturated aqueous sodium bicarbonate and ethyl acetate were added to the residue, and the resulting organic layer was washed with water and saturated saline in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off. 8.71 g of methyl [[[[1-1] [3- (1,3-dioxolane-2-yl) phenyl] —2-2 ditroethyl] thio] methyl] benzoate was obtained as a brown oil. The resulting 4-[[[[[1- [1- (1,3-dioxolan-1-2-yl) phenyl] -1-2-troethyl] thio] methyl] methyl benzoate 8.71 g in methanol 100 ml, After adding 20 ml of acetic acid and adding 13.08 g of zinc under ice-cooling, the mixture was stirred at 50 ° C for 2 hours and at room temperature for 15 hours. The insoluble material of the reaction mixture was separated by filtration through celite, washed with methanol, the obtained filtrate was concentrated under reduced pressure, benzene was added to the residue, and the operation of reducing the pressure under reduced pressure was performed twice. To the residue was added a saturated aqueous sodium bicarbonate solution and chloroform, and the resulting organic layer was washed with water and saturated saline. After washing successively with, dry over anhydrous sodium sulfate and distill off the solvent to remove (+ or 1) 1-4 [[[[2-amino 1-1 [3-(1,3-dioxolane) 1.2-yl) phenyl] ethyl] thio] methyl] 8.92 g of methyl benzoate was obtained as a pale yellow oil. Obtained (+ or one) —4 — [[[2-amino-11- [3- (1,3-dioxolan-2-yl) phenyl] ethyl] thio] methyl] benzoic acid 45 ml of 1,4-dioxane, 16.2 g of (+)-toluoyltartaric acid monohydrate was added to methyl and dissolved by heating. The mixture was stirred at room temperature for 8 hours, and the precipitated crystals were collected by filtration. After washing with ethanol and drying, 3.59 g of colorless crystals were obtained. To 3.50 g of the obtained crystals, 17.5 ml of 1,4-dioxanoethanol = 1/1 solution was added and dissolved by heating. The mixture was allowed to stand at room temperature for 12 hours, and the precipitated crystals were collected by filtration. The solution was washed successively with 1-dioxane / ethanol = 1Z1 solution and ether to give 2.47 g of colorless crystals. To 2.40 g of the obtained crystals, 12 ml of a 1,4-dioxane / ethanol = 1Z1 solution was added, and the mixture was dissolved by heating. The mixture was allowed to stand at room temperature for 12 hours, and the precipitated crystals were collected by filtration to give 1,4-dioxane ethanol. = 1 1 Wash with solution and ether sequentially. (+ Or 1) 1 4 1 [[[2—amino 1 1— [3— (1,3-dioxolan 1-2-yl) phenyl] ethyl] 1.96 g of [thio] methyl] methyl benzoate · 1-(+) toluoyl tartrate were obtained as colorless crystals. Reference Example 51

(+ Or one) —4-1 [[[2-amino-1 ([3- (1,3-dioxolan-1-2-yl) fu Xnil] ethyl] thio] methyl] methyl benzoate A saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to 1.80 g of toluene (+) toluene oil tartrate, and the obtained organic layer was washed with water and saturated saline solution in that order, and then washed with sodium sulfate anhydride. To a solution of the residue in 10 ml of dichloroethane were added 0.66 ml of triethylamine and 600 mg of 4-phenylphenylsulfonyl chloride under ice-cooling, followed by stirring at room temperature for 20 minutes. 10 ml of hydrochloric acid was added, and the mixture was stirred at room temperature for 30 minutes. In addition, the obtained organic layer was washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off (+ or 1). 1.50 g of methyl 1- (3-formylphenyl) ethyl] thio] methyl] benzoate was obtained as a pale yellow oil. Reference Example 52

 Dissolve 407 mg (1.45 mmol) of 3- [2- (7- (2-chloro-2-quinolyl) vinyl] aniline in 8.0 ml of ethane dichloride and 8001 of acetic acid, and add 3- (ethoxycarbonyl) under ice-cooling. (Methoxy) Benzaldehyde (302 mg, 1.45 mmol) and triacetoxyborohydride sodium (461 mg, 2.18 mmol) were added, and the mixture was stirred at room temperature for 3 hours. Distilled water was added to the reaction solution, and extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel force chromatography (n-hexane: ethyl acetate -2: 1) and purified by 3-[[3- [2- (7-chloro-2-quinolyl) vinyl] phenyl. Nyl] aminomethyl] phenyl ethyl acetate (471 mg, 0.996 mmol) was obtained as a pale yellow oil. Reference Example 53

Dissolve 365 mg (1.46 mmol) of 2- (4-chlorobenzenesulfonylamino) acetic acid in 5.0 ml of dichloroethane, add 1.8 ml of thionyl chloride and a catalytic amount of dimethylformamide, and separate at 60 ° C for 1 hour. After stirring, the reaction solution was concentrated under reduced pressure (toluene azeotrope). The residue was dissolved in 15 ml of dichloroethane, and 461 mg of 3- [N- [3- [2- (7-chloro-1-2-quinolyl) vinyl] phenyl] aminomethyl] phenoxydipate was added. 0.975 mmol) and 2.0 ml of pyridine were added and stirred at room temperature for 150 minutes. Distilled water was added to the reaction solution, and the mixture was separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Remaining The residue is purified by silica gel gel chromatography (n-hexane: ethyl acetate = 2: 1: 2: 3), and purified by 3- [N-[(4-cyclobenzenebenzenesulfonylamino). ) Acethyl] -N- [3- [2- (7-chloro-2-quinolyl) vinyl] phenyl] aminomethyl] phenyloxyacetate 550 mg (0.781 mmol) as a pale yellow solid I got it. Reference example 54

 By performing the same operation as in Reference Example 52, 3 — [[3 -— [2- (7-Cross_2—quinolyl) vinyl] phenyl] aminomethyl] phenyl Methyl acetate was obtained. Reference Example 55

 By performing the same operation as in Reference Example 53, 3- [N-[(4-chlorobenzenesulfonylamino) acetyl] —N— [3- [2- (7-chloro-2-quinolyl)] [Vinyl] phenyl] aminomethyl] phenyl methyl acetate was obtained. Reference Example 56

3— [4— (tert-Butoxycarbonylamino) phenyl] Ethyl propionate (22.3 g, 76.0 mmol) is dissolved in tetrahydrofuran (220 ml), and sodium borohydride is added to 3.45 g Ol. lmmol), the temperature was raised to 60 ° C, and 9.0 ml of methanol was added dropwise over 2 hours. After stirring for 2 hours after completion of the dropwise addition, 5.00 g (132 mmol) of sodium borohydride was added, and 10 ml of methanol was added dropwise over 2 hours, followed by stirring at 60 ° for 12 hours. The reaction solution was concentrated under reduced pressure, distilled water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and concentrated under reduced pressure. Dissolve 18. lg of the residue in 150 ml of dichloroethane, add 12.1 ml (86.8 mmol) of triethylamine and 6.13 m of methanesulfonyl chloride (79.2 mmol) under ice-cooling, and keep at that temperature for 30 minutes. Stirred. Reaction liquid Distilled water was added to the mixture, and the mixture was separated. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. 20.6 g of the residue was dissolved in 200 ml of dimethylformamide, and 18.7 g (124.8 mmol) of sodium iodide was added. The mixture was stirred at 60 ° C for 2 hours. Further, 13.0 g (65.5 mmol) of sodium 41-chlorosulfinate was added, and the mixture was stirred at 60 ° C for 1 day. Distilled water and ethyl acetate were added to the reaction solution, and the mixture was separated and extracted with ethyl acetate. N-Hexane was added to the organic layer, and the precipitate was collected by filtration. [4- [3- (4-Clo-phenylphenylsulfonyl) propyl] phenyl] carbamic acid tert-butyl ester 15.6 g (38.1 mmol) ) Was obtained as a brown solid. Reference Example 57

 [4- [3- (4-chlorophenylsulfonyl) propyl] phenyl] carno, tert-butyl ester of phosphoric acid 3.06 g (7.46 mmol) was dissolved in 30 ml of dimethylformamide, and the solution was cooled on ice. In the above, 358 mg (8.95 mmol) of 60% sodium hydride was added, and the mixture was stirred for 10 minutes. Ethyl bromoacetate 993/1 (8.95 mmol) was further added, and the mixture was stirred at room temperature for 2 hours. Distilled water and ethyl acetate were added to the reaction solution, and the mixture was separated and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 3: 1 → 2: 3), and [N- (tert-butoxycarbonyl) -N— [4-[3 — (4.1-Crophenylphenylsulfonyl) propyl] phenyl] amino] ethyl acetate 3.01 g (6.07 mmol) was obtained as a colorless oil. Reference Example 58

[N- (tert-butoxycarbonyl) —N— [4- (3- (4-chlorophenylsulfonyl) propyl] phenyl] amino] ethyl acetate 3.00 g (6.05 mmol) of ethyl acetate Dissolve 30ml in ice-cooled Then, 10 ml of a 4N hydrochloric acid-ethyl acetate solution was added, and the mixture was stirred at 50 ° C. for 5 hours. Getyl ether was added to the reaction mixture, and the mixture was stirred. The precipitated solid was collected by filtration, and [[4- [3- (4-cyclophenylphenylsulfonyl) propyl] phenyl] amino] ethyl acetate · hydrochloride 2.41 g (5.57 mmol) were obtained as a pale orange solid. Reference example 59

 [[4- [3- (4-Monophenylphenylsulfonyl) propyl] phenyl] amino] Ethyl acetate hydrochloride 500 mg (1.16 mmol) was desalted, and the obtained compound (405 mg) was added. It was dissolved in 8.0 ml of tetrahydrofuran and 4.0 ml of methanol, and 1N aqueous sodium hydroxide solution 905 ^ 1 was added under ice-cooling, followed by stirring at room temperature for 30 minutes. 40 ml of a 10% aqueous solution of citric acid was added to the reaction solution, and the mixture was stirred. The precipitated solid was collected by filtration, and [[4- [3- (4-chlorophenylsulfonyl) propyl] phenyl] amino] acetic acid was added. 295 mg (0.802 mmol) were obtained as a colorless solid. Example 1

(Sat) 1-[[3- (4-chlorophenylsulfonylamino)-1- [3- (2-quinolylmethoxy) phenyl] propyl] thio] 0.17 g of methyl propionate Dissolve it in 0.5 ml of methanol, tetrahydrofuran lm], add 0.4 ml of 1N aqueous sodium hydroxide solution to the solution, react at room temperature for 3 hours, and add 0.5 ml of 1N aqueous sodium hydroxide solution to the solution. Was added and reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, water and a 10% aqueous solution of citric acid were added to the residue, and the precipitated solid was collected by filtration. The obtained solid was purified by silica gel column chromatography (nomethanol formate Z-form: 0.1 / 1/20), and the obtained residue was crystallized from ethanol-water to give (Sat) 1-3 [[3- (4-Cross-phenylphenylsulfonylamino) 1-1- [3- (2-quinolinolemethoxy) phenyl] propyl] thio] 0.08β propionic acid was obtained. The compound of Example 2 was obtained in the same manner as in Example 1.

Example 2

 3-[[2- (4-chlorophenylsulfonylamino)-(1RS) -1-1 [3- (2-quinolylmethoxy) phenyl] ethyl] thio]-(2RS) Enenylpropionic acid Example 3

 (Sat) 1 4 — [[[2— (4—Chlorophenylsulfonylamino) 1 1 1 1 3 — [(E) —2— (7—Chloro-2-quinolyl) Vinyl [Phenyl] ethyl] thio] methyl] 0.77 g (1.2 mmol) of methyl benzoate is dissolved in 8 ml of methanol and 8 ml of tetrahydrofuran, and 1N sodium hydroxide is added to the solution. 3.73 ml (3.7 mmol) of an aqueous solution was added and reacted at 60 ° C for 3 hours. After ice and a 10% aqueous solution of citric acid were added to the reaction mixture, the precipitated solid was collected by filtration. The obtained solid was crystallized from acetonitrile to give (Sat) 14-[[[2- (4-crophenylphenylsulfonylamino) 1-1- [3-[(E) -2 -(7-Chlorol 2-quinolyl) vinyl] phenyl] ethyl] thio] methyl] benzoic acid 0.68 g was obtained. The compounds of Examples 4 to 19 were obtained in the same manner as in Example 3.

Example 4

 (Sat) 1 4 1 [[[2-(4-Cross phenylsulfonylamino) 1 1-[3— [(E) — 2— (7—Cross 1 2-quinolinyl) Vinyl] phenyl] ethyl] thio] methyl] phenylacetic acid Example 5

(Person) 1 4 1 [[[2- (4-chlorophenylsulfonylamino)] 1 1 1 [3 — [(E) 1 2— (7-chloro 2-quinolyl) vinyl] [Phenyl] ethyl] thio] methyl] — 2-methoxybenzoic acid Example 6

 (Sat) I 4 — [[2 (4-chloro-2-ylenoylamino)-[3-[(E) -2] (7-chloro 2-quinoline) vinyl] full] ethyl] Thio] 3,3-Dimethylbutanoic acid Example 7

 (S) 1 1 — [[[2- (4-chlorophenylsulfonylamino)) 1 1 1 [3 — [(E) -2- (7-chloro-2-quinolyl) vinyl] phenyl ] Ethyl] thio] methyl] — 1-cyclopropaneacetic acid Example 8

 (S) 1 4 1 [[[2-(4 Chlorophenylsulfonylamino) 1 1 1 1 [3-[(E)-2-(7-Chloro 2-Quinolyl) Bull] Enthyl] ethyl] thio] methyl] -1-fluorobenzoic acid Example 9

 (Sat) 1—4— [2 — [[2- (4-Chlorophenylsulfonylamino) 1—1 1—3 — [(E) —2— (7—1—2-quinolyl) vinyl] [Phenyl] ethyl] thio] ethyl] benzoic acid Example 10

 (Sat) 1—4 [[[[1-[3— [(E) 1—2— (7—Chlorol 2—quinolyl) vinyl] phenyl] —1 2— (4—Trifluoromethylphenyl) Sulfonylamino) ethyl] thio] methyl] benzoic acid Example 11

(Sat) — 4 — [[[[1— [3 — [(E) 2— (7—Cro-1-2-quinolyl) vinyl] phenyl] -12— (Fenylsulfonylamino) ethyl ] Thio] methyl] benzoic acid 卖 Example 12

 (Sat) — 4-[[[[2- (4-promophenylsulfonylamino)] 1-11- [3-[(E) -2- (7-chloro-2-quinolyl) vinyl] phenyl [Ethyl] thio] methyl] benzoic acid Example 13

 (Sat) 1-41 [[[1-[3— [(E) -12- (7-Cross—2-Quinolyl) vinyl] vinyl] —2- (4-Nitrophenylsulfonyl Amino) ethyl] thio] methyl] benzoic acid Example 14

 (Sat) 14-[[[1-1-1 [3-[(E) -12- (7-chloro-2-quinolyl) vinyl] phenyl] —2- (4-Fluorophenylsulfonylamino) Ethyl] thio] methyl] benzoic acid Example 15

 (Sat) 14 1 [[[1 1 [3 — [(E) 1 2— (7-Cross 1—2-quinolyl) vinyl] vinyl] —2— (4-Methoxyphenylsulfonyl Amino) ethyl] thio] methyl] benzoic acid Example 16

 (Earth) 1 4 — [[[1— [3-[(E) —2— (7—Cross 1—2-quinolyl) vinyl] phenyl] 1—2— (4-Methylphenylsulfonyluna [Mino] ethyl] thio] methyl] benzoic acid Example 17

(Sat) 1-3-Bromo4-1-1 [[[2- (4-chlorophenylsulfonylamino) 1 1— [3 — [(E) —2— (7—Cross 1-2-quinolyl ) Vinyl] fuunil] ethyl] thio] methyl] benzoic acid Example 18

 (Sat) 1 4 1 [[2- (4-chlorophenylsulfonylamino) 1 1 — [3 — [(E) 1 2— (7-chloro 2-quinolyl) vinyl] [Ethyl] thio] propionic acid Example 19

 (Sat) 1-41 [[[2- (4-chlorophenylsulfonylamino)] 1-11 [3 — [(E) —2— (7-chloro2-quinolinyl) vinyl] [Phenyl] ethyl] thio] methyl] 1-3-methoxybenzoic acid Example 20

 (±) — 4-1 [[3— (4-chlorophenylsulfonylamino)] – 1 [3 — [(E) -2- (7-chloro-2-quinolyl) vinyl] phenyl [Propyl] thio] methyl propionate (0.30 g, 0.49 mmol) was dissolved in tetrahydrofuran (6 ml) and methanol (3 ml), and 1N sodium hydroxide aqueous solution (1.22 ml, 1.22 ml) was added to the solution. mmol) was added. After reacting at room temperature for 12 hours, ice and a 10% aqueous solution of quinic acid were added to the reaction solution, and the product was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel gel chromatography (ethyl acetate / hexane = 3/7), the obtained residue was powdered with hexane, and the solid was collected by filtration. 1) 4-[[3- (4-chlorophenylsulfonylamino)] 1-11-[(E) -12- (7-chloro-2-quinolyl) vinyl] phenyl] propyl] thio] propionic acid 0.08 g was obtained as a pale yellow solid. The compounds of Examples 21 to 35 were obtained in the same manner as in Example 20.

Example 21

(Sat) 1 4— [[[[3— (4-chlorophenylsulfonylamino) 1- [3-[(E) -12- (7-Cro 1-2-quinolyl) vinyl] phenyl] propyl] thio] methyl] phenylacetic acid Example 22

 (Sat) 1 4-[[[[3- (4-chlorophenylsulfonylamino)] 1 1 1 [3 — [(E) 1 2— (7-chloro-2-quinolyl) vinyl] [Phenyl] propyl] thio] methyl] benzoic acid Example 23

 (Sat) — 1 — [[[[3— (4-Cross phenylsulfonylamino) 1 1— [3 — [(E) 1 2— (7—Cross 1 2—quinolyl) Vinyl] phenyl] propyl] thio] methyl] 1-1-cyclopropaneacetic acid Example 24

 (Sat) 1 4 — [[3— (4—Cross-phenylphenylsulfonylamino) —1—1—3 — [(E) —2— (7—Chlorol 2-quinolyl) vinyl] [Propyl] thio] — 2-methylpropionic acid Example 25

 (Sat) 1 4— [[3— (4 1-channel phenylsulfonylamino) 1 1

-[3 — [(E) —2— (7-chloro-2-2-quinolyl) vinyl] phenyl] propyl] thio] —3,3-dimethylbutanoic acid Example 26

4-[[IRS) — 1— [[3 -— (4-chlorophenylsulfonylamino) 1 (1RS)-1-[3— [(E) 1 2— (7—kuroro 2— Quinolyl) vinyl] phenyl] propyl] thio] ethyl] benzoic acid Example 27

 (Sat) 1-41 [[3- (4-chlorophenylsulfonylamino) -1- [3-[(E) -2- (7-chloro-2-quinolyl) vinyl] full 1 propyl ] Chio] Acetic acid Example 28

 (Sat) 1-3-Promo 4-1 [[[3-(4-Cross phenylsulfonylamino) 1-1 [3-[(E)-2-(7-Chloro 2-Quinolyl) Vinyl] [vinyl] propyl] thio] methyl] benzoic acid Example 29

 (1R or 1S) — 4 — [[3-14-chloroninolesnolehoninoleamino) 1 1 1 [3 — [(E) —2— (7-chloro-2-quinolyl) vinyl] [Phenyl] propyl] thio]--3,3 -dimethylbutanoic acid Example 30

 (1R or 1S) — 4-[[3 (4-Cross-Phenylsnorehonylamino)] 1-11-[(E) -2- (7-Chloro-2-quinolyl) vinyl] Enyl] propyl] thio] -3,3-dimethylbutanoic acid Example 31

 4 1 [2— [[3-(4 1-channel phenylsulfonylamino) 1 1 1

[3 -— [(E) -12- (7-chloro-2-quinolyl) vinyl] phenyl] propyl] thio] ethyl] benzoic acid Example 32

(Sat) One 4 — [[[[3- (4-Chlorophenylsulfonylamino)] One-One [3 — [(E) One Two— (7-Chloror-2-quinolyl) vinyl] Nyl] propyl] thio] methyl] 1-3-methoxybenzoic acid Example 33

 (±) — 4— [[[3-(4 Chlorophenylsulfonylamino) 1 1 1 1 [3— [(E) — 2— (7—Cro mouth 1 2—Quinolyl) Vinyl] phenyl] propyl] thio] methyl] —3-benzoic benzoic acid Example 34

 (Sat) 1-41 [[[3- (4-chlorophenylsulfonylamino) 1-1] [3-([(E) -2] (7-chloro 1-2-2-quinolyl) vinyl] [Phenyl] propyl] thio] methyl] 1-2-methoxybenzoic acid Example 35

 (Sat) 1 4— [[3— (4 1-channel phenylsulfonylamino) 1 1

— [3 — [(E) —2— (7-chloro-2-quinolyl) vinyl] phenyl] propyl] thio] butanoic acid Example 36

(Sat) 1-3-[[2- (4-Cross-phenylphenylsulfonylamino)] 1-11- [3- (2-Quinolylmethoxy) phenyl] ethyl] thio] methyl propionate 0.12g Was dissolved in 1 ml of methanol and 2 ml of tetrahydrofuran, and 1 ml of a 1N aqueous solution of sodium hydroxide was added to the solution, and the mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, water and a 10% aqueous solution of citric acid were added to the residue, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate, washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel gel chromatography (hexane Z-ethyl acetate = 1/1), and the obtained residue was crystallized from ethanol to give (Sat) — 3— [[2-— (4-1) 0.07 g of 1- [3- (2-quinolylmethoxy) phenyl] ethyl] thio] propionic acid were obtained. The compounds of Examples 37 to 57 were obtained in the same manner as in Example 36.

Example 37

 3-[[2- (4-chlorophenylsulfonylamino) 1 (1RS)-1- [3- (2-quinolylmethoxy) phenyl] ethyl] thio] 1 (2RS)-2-methyl Cylpropionic acid Example 38

 (Sat) 1 3— [[[2— (4—Cross phenylsulfonylamino) 1

1 — [3- (2-Quinolylmethoxy) phenyl] ethyl] thio] methyl] benzoic acid Example 39

 (Sat) 1 3 — [[2- (4-chlorophenylsulfonylamino) 1 1 1 1 [3— (2-quinolylmethoxy) phenyl] ethyl] thio] —2,

2-Dimethylpropionic acid Example 40

 (Sat) 1-41 [[2- (4-chlorophenylsulfonylamino) -1-1 [3- (2-quinolylmethoxy) phenyl] ethyl] thio] phenylacetic acid Example 41

 3-[[2-((4-chlorophenylphenylsulfonylamino)]-(1RS)-1- [3- (2-quinolylmethoxy) phenyl] ethyl] thio] -1- (2RS) -1-2-ethylpropion Acid Example 42

(2RS) — 2-benzyl-1 3 -— [[2- (4-chlorophenylsulfonylamino) -1 (IRS) 1 — [3 -— (2-quinolylmethoxy) phene [Ethyl] thio] propionic acid Example 43

 (Sat) 1-41 [[2- (4-Chlorophenylsulfonylamino)] 1-1 1 [3- (2-Quinolylmethoxy) phenyl] ethyl] thio] — 3,3-dimension Tilbutanoic acid Example 44

 (Sat) 1 1 — [[2- (4-Chlorophenylsulfonylamino) 1 1 1 [3-(2-Quinolylmethoxy) phenyl] ethyl] thio] methyl] 1 1—Six Lopropaneacetic acid Example 45

 3 — [[2- (4-Chlorophenylsulfonylamino) 1 (1RS) —1–1 [3— (2-Quinolylmethoxy) fuynyl] ethyl] Cho] 1 (2RS) 1 2—A Sopropylpropionic acid Example 46

 3-[[2- (4-Chlorophenylsulfonylamino) 1 (1RS)-1-1 [3-(2-quinolylmethoxy) phenyl] ethyl] thio]-(2RS) 1 -2-Propylpropion Acid Example 47

 (Sat) 1-41 [[[2- (4-chlorophenylsulfonylamino) 1-1-1] [3- (2-quinolylmethoxy) phenyl] ethyl] thio] methyl] phenylacetic acid Example 48

(Sat) 1 4 1 [[2-(4-chlorophenylsulfonylamino) 1 1 I [3- (2-Quinolylmethoxy) phenyl] ethyl] thio] benzoic acid Example 49

 3-[[2-((4-chlorophenylsulfonylamino)]-(1RS) -1-1 [3- (2-quinolylmethoxy) phenyl] ethyl] thio] -1- (3RS) Cylpropionic acid Example 50

 3-[[2- (4-chlorophenylsulfonylamino) 1 (1RS)-1-[3- (2-quinolylmethoxy) phenyl] ethyl] thio] 1 (2RS) 1 2— Enenylpropionic acid Example 51

 (Sat) 14-[[2- (4-chlorophenylsulfonylamino) 1-11] [3- (2-quinolylmethoxy) phenyl] ethyl] thio] butanoic acid Example 52

 (Earth) 1 3— [4 — [[2- (4-Cross phenylsulfonylamino)] 1—11 [3— (2-Quinolylmethoxy) phenyl] ethyl] thio] phenyl] propion Acid Example 53

3-[[2- (4-Cross phenylsulfonylamino) 1 (1R or 1S) —1 1 [3-(2-Quinolylmethoxy) phenyl] ethyl] thio] 1 (3R or 3S) — 2-Phenylpropionic acid Example 54

 3-[[2- (4-Cross-phenylphenylsulfonylamino) 1 (1R or 1S) 1-11] [3- (2-Quinolylmethoxy) phenyl] ethyl] thio] ― (3R or 3S) — 2-Phenylpropionic acid Example 55

 (Sat) 1—4 [[[2- (4-Cross-phenylsnorehonylamino) 1-1- [3- (2-Quinolylmethoxy) phenyl] ethyl] thio] methyl] Benzoic acid Example 56

 (Sat)-3-[[2-(4-Chloronylsnorehonylamino) 1-1-[3-(2-quinolinolemethoxy) phenyl] ethyl] Thio]-1, 3, 3-dimethylpropion Acid Example 57

(Sat) Single 4- [2 - [[2- (4 one chlorophyll _t Nino less Honoré e Nino Rare Mi Roh) Single 1 one [3- (2-quinolinone Rirume butoxy) Tilia sulfonyl] Echiru] Chio] E chill] benzoic Acid Example 58

(Sat) 1 (E) — 4-chloro π— N— [2— [3— (7-chloro-2-quinolyl) vinyl] phenyl] 1—2 — [(4-cyanobenzyl) thio] ethyl] benzene To a solution of 0.20 g of sulfonamide in 4 ml of 1-methylbiperidone was added 63 mg of sodium azide and 67 mg of triethylamine hydrochloride. The reaction solution was stirred at 100 ° C for 1 hour and at 150 ° C for 2 hours under an argon atmosphere. The reaction solution was cooled to room temperature, added with a 10% aqueous solution of citric acid, and extracted three times with 50 ml of ethyl acetate. The obtained organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain The residue obtained was purified by silica gel chromatography (hexane / ethyl acetate = 11) and washed with ether to give (Sat)-(E) 141 — [2-[3— [(E) -1-2- (7-Cro-1-2-quinolyl) vinyl] phenyl] —2 -— [[4- (1H—Tetrazol 5-yl) benzyl) [Chi] ethyl] benzenesulfonamide (45 mg) was obtained as a yellow amorphous. Example 59

 (Sat) 1-4 — [[[2 -— (4-chlorophenylsulfonylamino) 1-1- [3-((E) -2- (7-chloro-2-quinolyl) vinyl] [Nyl] ethyl] thio] methyl] benzoic acid (0.45 g) was added with ethanol (18 ml) and hydrazine monohydrate (0.9 ml), and the mixture was heated under reflux for 8 hours. Ice and a 10% aqueous solution of quinic acid were added to the reaction solution, and the product was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl hexanoacetate = 1Z1), and the obtained residue was crystallized from ethanol-hexane to give (Sat) 1-4 — [[[2- (4-chlorophenylsulfonylamino) 1-11 [3-[(E) -2- (7-chloro-2-quinolyl) ethyl] phenyl] ethyl] thio] methyl] benzoic acid 0.26 g I got The compound of Example 60 was obtained in the same manner as in Example 59.

Example 60

 (±) — 1 [[[2- (4-chlorophenylsulfonylamino)] 1 1 1 [3 — [(E) 1 2— (7-chloro2-quinolinyl) ethyl] phenyl [Ethyl] thio] methyl] 1-1-cyclopropaneacetic acid Example 61

(Sat) 1 4 1 [[[3— (4 chlorophenylsulfonyl) 1 1— [3 1-((E) 1-2- (7-Chloro-2-quinolyl) vinyl] phenyl] propyl] thio] methyl] methyl benzoate (501 mg, 0.756 mmol) in 5.0 ml of tetrahydrofuran Dissolved in 5.0 ml of methanol, added 1.13 ml of 1N aqueous sodium hydroxide solution, and stirred at 50 ° C for 4 hours. A 10% aqueous solution of citrate was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. Acetonitrile methanol was added to the residue, and the precipitated solid was collected by filtration. (Sat) 4-1 [[[[3- (4-Cro- mouth phenylsulfonyl) 1-1- [3 [ 319 mg (0.491 mmol) of (E) — 2— (7-chloro-2-quinolyl) vinyl] phenyl] propylpyro [thio] methyl] benzoic acid was obtained as a pale yellow solid. The compounds of Examples 62 to 66 were obtained in the same manner as in Example 61.

Example 62

 (Sat) 1-[[3- (4-chlorophenylphenylsulfonyl)] 1-11-[(E) _2— (7-chloro2-quinolyl) vinyl] phenyl] pill ] Thio] — 3,3-dimethylbutanoic acid Example 63

 (Sat) 1-11 [[[3- (4-Chlorophenylsulfonyl) 1 1- [3 ― [(E) —2— (7-Cro 1-2-1quinolyl) vinyl] phenyl [Pipyl] thio] methyl] 1-1-cyclopropaneacetic acid Example 64

(Sat) 1 4 1 [2 — [[3— (4—chlorophenylsulfonyl) 1 1 1 [3 — [(E) 1 2— (7—chloro 2—quinolyl) Nyl] Propyl] Cho] Ethyl] Benzoic acid Example 65

 (Sat) 1 3 — [[3-(4 Chlorofluorophenylsulfonyl) 1 1 — [31 [(E) — 2— (7-Chloro 1-2-quinolyl) vinyl] phenyl] [Cho] propionic acid Example 66

 (Earth) — 4 [[[3 — (4—Chlorophenylsulfonyl) 1 1 1 [3 1 [(E) 1 2— (7-Chlorol 2-quinolyl) vinyl] phenyl] Mouth pill] thio] methyl] phenylacetic acid Example 67

 (Sat) 1 5 — [3— (4 chlorophenylsulfonyl) 1 1 — [3 — [(E) 1 2— (7-chloro 2—quinolyl) vinyl] fuunyl] propoxy] penta Dissolve 359 mg (0.573 mmol) of ethyl ester in 5.0 ml of tetrahydrofuran and 5.0 ml of methanol, add 859 μl of 1N aqueous sodium hydroxide solution, and add it at 50 ° C for 100 minutes. Stirred. A 10% aqueous solution of citrate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane Z ethyl acetate = 1/1 → 1/2). (Sat) 1-5— [3— (4—Chlorophenylphenylsulfonyl) 1 1 1 [ 212 mg (0.354 mmol) of 3-[(E) -2- (7-chloro-2-quinolyl) vinyl] phenyl] propoxy] pentanoic acid were obtained as a pale yellow foam. The compound of Example 68 was obtained in the same manner as in Example 67.

Example 68

(Sat) 1 4 — [[3— (4 chlorophenylsulfonyl) 1 1 1 3 1 [3 — [(E) -2- (7-chloro-1-2-quinolyl) vinyl] phenyl] propyloxy ] Methyl] benzoic acid Example 69

 (±) — 3 — [[3- (4-Cross-mouth fuynylsulfonyl) 1-1— [3- (2-quinolylmethoxy) phenyl] propyl] thio] methyl propionate 154 mg (0.270 mmol Was dissolved in 2.0 ml of tetrahydrofuran and 1.0 ml of methanol, and 2.0 ml of 1N aqueous sodium hydroxide solution was added thereto, followed by stirring at room temperature for 2 hours. A 10% aqueous solution of citrate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 15/1) and purified by (Sat) 13-[[3- (4-chlorophenylsulfonyl) 93 mg (0.167 mmol) of -1-[3- (2-quinolylmethoxy) phenyl] propyl] thio] propionic acid was obtained as a white solid. The compounds of Examples 70 to 72 were obtained in the same manner as in Example 69.

Example 70

 (Sat) 1-3-[[3- (4-Chlorophenylsulfonyl) -1-]-[3- (2-quinolylmethoxy) phenyl] propyl] thio] 2-methylpropionic acid Example 71

 (Sat) 1-41 [[3- (4-chlorophenylsulfonyl) 1- [31- (2-quinolylmethoxy) phenyl] propyl] thio] 3,3-dimethylbutanoic acid 72

(Sat) 1-[[3- (4-Chlorophenylsulfonyl)-1- [3- (2-quinolylmethoxy) phenyl] propyl] thio] 2-phenylpropionic acid Example 73

 (+) — 4 — [[[2-Amino 1— (3—hydroxymethyl-phenyl) ethyl] thio] methyl] Methyl benzoate (+) — G p-toluoyl D -Tartrate is suspended in ethyl acetate, 1N aqueous sodium hydroxide solution is added to extract the solution, and the mixture is extracted. The organic layer is washed with saturated saline and dried over magnesium sulfate. Thereafter, the mixture was concentrated under reduced pressure, and the obtained compound was treated in the same manner as in Reference Example 42 and Reference Example 43 to give (+) 1-41 [[[2- (4-chlorophenylsulfonylamino) 1-1] — [3 — [(E) -1-2- (7-chloro-2-quinolyl) vinyl] fuunyl] ethyl] thio] methyl] methyl benzoate was obtained. Further, the same operation as in Example 3 was performed to obtain (+)-4-1 [[[2- (4-chlorophenylsulfonylamino) 1-1- [3 — [(E) —2— (7— Chloro-2-quinolyl) vinyl] phenyl] ethyl] thio] methyl] benzoic acid was obtained. Example 74

 The same operation as in Example 73 was carried out, and (-) 1-4 [[[2-(4-chlorophenylsulfonylamino)-1-1 [3-[(E)-2-(7- Mouth-2-quinolyl) vinyl] phenyl] ethyl] thio] methyl] benzoic acid was obtained. Example 75

(+) — 4 — [[[2- (4-chlorophenylsulfonylamino) 1 1-[3 — [(E) 1 2— (7-chloro-2-quinolyl) vinyl] [Phenyl] ethyl] thio] methyl] benzoic acid (500 mg, 0.770 mmol) was suspended in ethanol (5 ml), 1N aqueous sodium hydroxide solution 770β1 (0.770 mmol) was added, and ethanol (5 ml) was further added. The mixture was stirred at room temperature for 1 晚. The precipitated crystals are collected by filtration, and purified by filtration with 4-[[[2- (4-chlorophenylsulfonylamino) 1-111 [3-[(E) 12-2- (7-chloro-2-quinolyl) vinyl] vinyl] ] Ethyl] thio] methyl] sodium benzoate 463 mg (0.671 mmol) of tritium 'monohydrate was obtained as colorless crystals. Example 76

 3- [N-[(4-cyclobenzene-1-sulfonylamino) acetyl] -1-N— [3 -— [2- (7-cyclo1-2-quinolyl) vinyl] phenyl] amino Dissolve 550 mg (0.781 mmol) of ethyl butyl acetate in 5.5 ml of tetrahydrofuran and 5.5 ml of methanol, and add 1.95 ml of 1 N aqueous sodium hydroxide solution under ice-cooling. Was added and stirred for 1 hour. To the reaction solution, 20 ml of a 10% aqueous solution of citric acid and 10 ml of distilled water were added, and the precipitated crystals were collected by filtration. 3- [N-[(4-cyclobenzenebenzenesulfonylamino) acetyl] -N- [3- [2- (7-Cro-1-2-quinolyl) vinyl] phenyl] aminomethyl] phenoxyacetic acid / 1 tetrahydrofuranate 529 mg (0.707 mmol) obtained as pale yellow crystals Was. Example 77

 By performing the same operation as in Example 76, 3- [N-[(4-cyclobenzenebenzenesulfonylamino) acetyl] -1-N— [3-[2- (7-cyclo1-2-quino) Ryl) vinyl] phenyl] aminomethyl] phenyl acetic acid / 1Z dihydrate was obtained. Example 78

Dissolve 205 mg (0.699 mmol) of 3- (2-quinolylmethoxy) phenylacetic acid in 2 ml of tetrahydrofuran and, at 150 ° C, add N-methylmorpholine 77/1 (0.700 mmol) and ethyl ethyl chloroformate at 150 ° C. 67 1 (0.701 mmol) was added. The mixture was stirred for 5 minutes and [[4- [3- (4-cyclophenylphenylsulfonyl) propyl] phenyl] amino] acetic acid 257 mg (0.699 mmol) of dimethylformamide (2 ml ) The solution was added dropwise, left at room temperature, and stirred for 1 hour. To the reaction solution was added 20 ml of a 10% aqueous solution of citric acid, and the mixture was extracted with ethyl acetate. The organic layer is washed with a saturated saline solution and magnesium sulfate. After drying in a vacuum, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1), and [[4- [3- (4-chlorophenylsulfonyl) propyl] phenyl] was purified. 1-[[3- (2-Quinolylmethoxy) phenyl] acetyl] amino] acetic acid 343 mg (0.533 mmol) was obtained as a pale orange solid.

 The physicochemical properties of the reference compound are shown in Tables 3 to 8, and the structural formulas and physicochemical properties of the compounds of Examples 1 to 2, 36 to 57 and 69 to 72 are shown in Table 9. 35. The structural formulas and physicochemical properties of the compounds of 58, 61-68 and 73-75 are shown in Table 10, the structural formulas and physicochemical properties of the compounds of Examples 59 and 60 are shown in Table 11, and Examples 76-78. Table 12 shows the structural formulas and physicochemical properties of the compounds of Table 1.

 The symbols in the table have the following meaning.

Rex .: Reference example number

Ex .: Example number

DATA: Physicochemical properties

mp .: melting point

Anal .: Elemental analysis value

calcd .: theoretical value

found .: Experimental value

NMR: Nuclear magnetic resonance spectrum

MS: mass spectrometry value (mZz)

zi8 OA o / 6V £ 6sfc.6fcAl: £-.

6zicfev:> d iso / 86 o

Dimension

/ U 6dK71: £ i oo / 86

Transfer:

 C) 6 挲

68

t ^ Z0 / ^ 6dfX3d Table 9 (continued)

s/卜 6 oio/86 OAfcVAL3J.

s / u 6 oio / 86 OAfcVAL3J.

05

CO

Table 10

Table 10 (continued) F (¾)) Br (X)

too

(C) 0 I¾ 0 (continued)

 p) O

86

6Z0 / .6df / XDd 0Z880 / 86 ΟΛ

 () 0

66

fe6ZO / 6JT / 3 <I 0880/86 OAV

0 (continued)

εοτ mu 6dfAl «I The compounds whose chemical structural formulas are listed in Table 13 below can be prepared in substantially the same manner as described in the above Examples or Preparations, or by applying some modifications obvious to those skilled in the art. , Can be easily manufactured.

 The symbols in the table have the following meanings.

Co .: Compound number

 Ph: Phenyl group

Phe phenylene group

Tet 5—tetrazolyl group

MM one CH CH ₂ —

VI:-CH = CH-MO one CH-one

OM one 0— CH

 6,7-CI: 6-CI and 7—CI Table 13

表 1 3 (つづき）

Table 13 (continued)

1 3 (つづき）

1 3 (continued)

3 (つづき） 0. t 一 Y— A 1— (ΥΛ 1，一 A 2- m n Ka

3 (continued) 0. t one Y— A 1— (ΥΛ 1, one A 2- mn Ka

157 7-CI MO — S— CH2 one U, 4— Pne one 2 one CH2 one COOH 204-CI

158 7-CI MO — S— CH2 one (Ι, ο— Pne) one ϋ— CH2— Tet 2 0 4 One CI

159 7-CI MO — ϋ 一 CH2― U4one Pne; ― CH2one Tet 2 0 4— CI

160 7-CI MO — ϋ 一 H2— (1,4-Pne; one LH2- Tet 2 1 4 CI

161 7-CI MO — 0-CH2 1,4-- Phe) CH2- Tet 1 1 4-CI

162 7-CI MO — 0-CH2 1,3-Phe)-CH2 Tet 2 0 4 CI

163 7-CI MO — 0— CH2— (13-Phe) — CH2 One Tet 2 1 4-CI

164 7-CI MO 1 0-CH2-(1,3 1 Phe)-CH2 1 Tet 1 1 4 1 CI

165 7-CI MO 1 0-CH2 1 (1,3 1 Phe) 1 CH2 1 COOH 2 0 4-CI

166 7-CI MO 1 0-CH2-(ι, 3 1 Phe) 1 CH2-COOH 2 1 4-CI

167 7-CI MO 1 0-CH2 1 (1,3-Phe) 1 CH2 1 COOH 1 1 4 1 CI

168 7-CI OM one 0-CH2- (1,4-Phe)-COOH 204-CI

169 7-CI O 1 0-CH2-(1,4— Phe)-COOH 2 1 4 — CI

170 7-CI OM 0-CH2 1,4 Phe) COOH 1 1 4-CI

171 7-CI OM 1 0-CH2 1,4-Phe)-CH2 1 COOH 2 0 4-CI

172 7-CI OM one 0-CH2 one (1,4 one Phe) one CH2 one COOH 2 1 4 one CI

173 7-CI OM — 0-CH2- (1,4-Phe) — CH2-COOH 1 1 4-I CI

174 7-CI MM S— CH2 1,4- Phe) COOH 1 1 H

175 7-CI MM — S-CH2— (1,4— Phe)-COOH 1 1 4— CH3

176 7 -CI Customer -S-CH2- (1.4-Phe) -COOH 1 1 4 1 Br

177 7-CI MM one S—CH2— (1 »4 one Phe one Tet 1 1 H

178 7-CI MM — S— CH2 one (1,4 one Phe) one Tet 1 1 4 one CH3 one 1 MM — — ί! 2— 14— rile) ― Tet 1 1 4— br loU — I I MM — b—H2A then Η3 ·) 2-shi Η2-COOH 1 1 4 i lol 7—1 MM — — HI H2-—H2 one COO "H 1 4 1

182 7 -CI Hire Tet 2 1 4 One CI

 . -S-CH2AI CH2-

183 6,7-CI MM COOH 2 1 4 1 CI

 -S-CH2 V CH2-

184 7-CI O-S CH2C (CH3) 2 -CH2- Tet 2 1 4 1 CI

185 7-CI MM-0-CH2C (CH3) 2 -CH2-COOH 2 1 4— CI

186 7 -CI O-0-CH2C (CH3) 2 -CH2- Tet 2 1 4 1 CI

187 7 -CI MM-S— CH2C (C2H5) 2 -CH2-COOH 2 1 4 1 CI

188 7 -CI MM one S-CH2-C1.3-Phe) -CH2-COOH 1 1 4 One CI

189 7-CI MM-S-CH2-(1,3-Phe)-CH2-Tet 1 1 4 -CI

190 7— CI MM one S-CH2-(1,4 one Phe) one 0-CH2-COOH 1 1 4 -CI

13- ^ 0 ζ -mo-1 0-1 (aqd--mo-1 s-face Ό-1 OOZ

I ー ー 0 ζ HOOD -mo 一 0-(3Md-ε'ΐ) -m — s-Marauder D-Z 66 T

ID-f 0 ζ HOOD -mo-1 0--mo-1 s-Simple Ό- L 861

. -ζ -mo-0-(aqd― ε'υ — s-Customer D-Z L61

D-f ζ HOOD-o1 0-(3Md-ευ -mo -s- Ό L- L 96T

Ό 一 ζ 13 丄 '-o 一 0-(aqd-I) -mo — s-marauder Ό- L 261

D-ζ HOOD -mo 〇-(aqd--mo _s-丽 Ό-L V61

Ό-Ρ ΐ -mo 一 0-(3¾1— ε'υ -mo — s--L E6I

10-ΐ HOOD -mo-1 0-(a¾d-ε'ΐ) -mo-1 s-顺 Ό-ί ZGl

1-ι -mo-1 0-d- VI) -mo-1 s--ί-Ό 161 u UI a τν- -x- Z

 (,) Ε i

801

 Pi6ZQIL6d £ llDd

Claims

 The scope of the claims 1. A benzene sulfone compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof.

(The symbols in the formula have the following meanings.  B: quinolyl group which may be substituted, D: a phenyl group which may be substituted; E: a group represented by the formula:

A ¹ , A ² : one of them is an optionally substituted methylene group or an optionally substituted ethylene group, and the other is a single bond, an optionally substituted methylene group or an optionally substituted methylene group. A good ethylene group, provided that when 1 is 1 and Y is a phenylene group which may be substituted, both A ¹ and "may be a single bond;  X: oxygen or sulfur atom,  Y: an optionally substituted phenylene group, an optionally substituted phenyleneoxy group or an optionally substituted spirocyclopropynyl group, Z: a group represented by the formula: CH = CH—, the formula — CH ₀ -CH ₉ —, the formula _ CH ₂₀ — or the formula — 0—CH ₂ — R: carboxyl group or tetrazolyl group which may be substituted with an ester residue, 1, n, p, q: same or different 0 or 1, m: 1, 2 or 3) Strength, halogen atom, hydroxyl group, lower alkoxy group, cyano group, amino group, mono- or di-lower alkylamino group, nitro group and lower alkyl group (the lower alkyl group is a halogen atom, a hydroxyl group, Lower alkoxy group, cyano group, amino group, mono- or di-lower alkylamino group, nitro group, aryloxy group and aralkyloxy group. A quinolyl group which may be substituted, and which has a D-force; a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group, a mono- or di-lower alkylamino group, a nitro group and a lower alkyl group; Group (the lower alkyl group includes a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group, a mono- or di-lower alkyl group). A phenyl group which may be substituted with a group selected from the group consisting of a quinamino group, a nitro group, an aryloxy group and an aralkyloxy group. A phenylene group, a phenylenequine group which may be substituted or a spirocyclopropyl group which may be substituted may be a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group, a mono- or di-lower group, respectively. Alkylamino group, nitro group and lower alkyl group (the lower alkyl group is a halogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group, a mono- or di-lower alkylamino group, a nitro group) , An aryloxy group and an aralkyloxy group may be substituted). Group optionally substituted off Weniren group, a full Wenire Nokishi group or spiro cyclopropyl group, and, Alpha Alpha definitive ^2, ethylene but it may also have been the good methylene group or a substituted also be substituted Groups represented by a halogen atom, a hydroxyl group, a lower alkoxy group, an aryl group and a lower alcohol group, respectively (the lower alkyl group is a halogen atom, a hydroxyl group, a lower alkoxy group, an amino group, a mono- or di- A methylene group or an ethylene group which may be substituted with one or more groups selected from a lower alkylamino group, an aryloxy group and an aryl group. 3. The benzene sulfone compound according to item 1, or a pharmaceutically acceptable salt thereof. B is a 2-quinolyl group optionally substituted with a halogen atom, and D is selected from a halogen atom, a lower alkoxy group, a nitro group and a lower alkyl group optionally substituted with a halogen atom. Y is a phenylene group, a phenyleneoxy group or a spirocyclopropyl group, which may be substituted with a group selected from a halogen atom and a lower alkoxy group; A ¹ or A ² is a methylene group, one of which may be substituted with a group selected from a lower alkyl group, an aryl group and an aralkyl group, or a lower alkyl group, an aryl group and an aralkyl group. Is an ethylene group which may be substituted by a group selected from the group; the other is a single bond, a methylene group or an ethylene group, provided that 1 is 1 and Y is phenylene; When it may be A ¹ and A ² are both single bonds, Z is the formula - CH = CH -, wherein - CH o-CH. - or a group of the formula one CH ₂ 0-, p is 0, q is is 1, and, benzenesulfonic compound of R is according to claim 2, wherein a carboxyl group or fruit Torazoriru group or a Pharmaceutically acceptable salts. 3. The benzenesulfone compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein X-.E is a group represented by the formula ——CH 2. 5. The benzene sulfone compound or a pharmaceutically acceptable salt thereof according to claim 4, wherein X is a sulfur atom. 3. The benzenesulfone compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein Z is a group represented by the formula: CH = CH—. 7. The benzenesulfone compound or the pharmaceutically acceptable salt thereof according to claim 2, wherein the scale is a carboxyl group. 8. The benzene sulfone compound according to claim 2, wherein n is 1, or a pharmaceutically acceptable salt thereof. 9. The method according to claim 1, wherein 1 is 1, Y is a phenylene group which may be substituted with a group selected from a halogen atom and a lower alkoxy group, A ¹ is a methylene group and A ² is a single bond. The benzenesulfon compound or the pharmaceutically acceptable salt thereof according to range 2. 10. 3 — [[3 -— (4-Chlorophenylsulfonylamino) 111] [31- (2-quinolylmethoxy) phenyl] propyl] thio] propionic acid, 4 — [[[ 2- (4-chlorophenylsulfonylamino) -1 [3- [2- (7-chloro-2-quinolyl) vinyl] phenyl] ethyl] thio] methyl] benzoic acid, 4-[[[[1-[3-[2— (7-cyclo-1-2-quinolyl) vinyl] phenyl] -12- (4-methoxyphenylsulfonylamino) ethyl] thio] methyl ] Benzoic acid, 4-[[[[1- [3-—2- (7-chloro-1-2-quinolyl) vinyl] phenyl] -1-2- (4-methylphenylphenylsulfonylamino) ethyl] [Thio] methyl] benzoic acid, or a pharmaceutically acceptable salt thereof. 11. A medicament comprising the benzenesulfone compound described in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 12. Preparative port Nbokisan A ₂ and leuco preparative Lien range 11 medicament according claims are both antagonists. 13. The medicament according to claim 12, which is a therapeutic agent for bronchial asthma.