WO2011030873A1 - Benzyl compounds - Google Patents

Abstract

Provided are novel benzyl compounds represented by general formula (I), which exhibit excellent bronchodilating effect that relies on potent EP2 agonist activity; or salts thereof.

Description

Benzyl compounds

The present invention relates to a novel benzyl compound useful as a medicine or a pharmacologically acceptable salt thereof. More specifically, since the benzyl compound according to the present invention has an EP2 agonistic action, for example, a therapeutic and / or prophylactic agent for respiratory diseases such as asthma and chronic obstructive pulmonary disease (hereinafter abbreviated as COPD). Useful as.

In asthmatic patients, it has been reported that prostaglandin E ₂ (hereinafter abbreviated as PGE ₂ ) administered by inhalation suppresses immediate and delayed asthmatic reactions (see Non-Patent Document 1). In addition, PGE ₂ is known to act as an agonist for receptors such as EP1, EP2, EP3, and EP4, and among them, the agonistic action for EP2 receptor is deeply involved in the bronchodilating action. Has been suggested (see Non-Patent Document 2).

So far, it is known that sulfonamide compounds having a structure similar to the compound of the present invention have EP2 agonistic activity (see Patent Documents 1 to 4). Among them, the compound described as Example 14e in Patent Document 2 has an effect of accelerating the healing of fractures by increasing the concentration of cyclic adenosine monophosphate (hereinafter abbreviated as cAMP) by the EP2 agonist action. Has been reported (see Non-Patent Document 3). However, it is not specifically described that the compounds described in Patent Documents 1 to 4 have a bronchodilator action due to EP2 agonistic action. Further, none of the above-mentioned documents relates to the compound of the present invention. There is no specific disclosure of a phenyl group having a specific substituent and a sulfonamide compound having pyridylaminoacetic acid and its ester as a partial structure.

WO 98/28264 WO99 / 19300 WO2004 / 078169 WO2008 / 015517

As a result of intensive studies on various sulfonamide compounds with the aim of developing an excellent therapeutic or preventive agent for respiratory diseases, the present inventors have found that a novel benzyl compound having a specific structure is a powerful EP2 Has excellent bronchodilator action based on agonistic action, and further, tissue transferability, bioavailability (BA), rapid onset of drug effect, sustained drug effect, solubility, physical stability, drug interaction In addition, since it has excellent properties such as toxicity, it has been found that it is particularly useful as a therapeutic agent and / or preventive agent (preferably a therapeutic agent) for respiratory diseases such as asthma and COPD. completed.
The present invention has a novel bronchodilator action based on a strong EP2 agonist action, and is particularly useful as a therapeutic agent and / or preventive agent (preferably a therapeutic agent) for respiratory diseases such as asthma and COPD. Provided is a benzyl compound or a pharmacologically acceptable salt thereof.

The “benzyl compound” in the present invention means a compound represented by the following general formula (I).

[Where:
R ¹ represents a hydrogen atom or a C ₁ -C ₆ alkyl group which may be substituted with a halogeno group;
R ² and R ³ each independently represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
A represents an aryl group, heteroaryl group or heterocyclic group which may be substituted with the same or different 1 to 3 groups selected from the substituent group α,
Y is a C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group which may be substituted with the same or different 1 to 3 groups selected from the substituent group α C ₃ -C ₈ cycloalkyl group, C ₅ -C ₈ cycloalkenyl group, aryl group, heteroaryl group or heterocyclic group,
Z is a C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group which may be substituted with the same or different 1 to 3 groups selected from the substituent group α C ₃ -C ₈ cycloalkyl group, C ₅ -C ₈ cycloalkenyl group, aryl group, heteroaryl group or heterocyclic group,
Substituents included in the substituent group α are hydroxy group, oxo group, halogeno group, cyano group, nitro group, formyl group, C ₁ -C ₆ alkyl group, C ₇ -C ₁₂ aralkyl group, C ₂ -C _6. Alkenyl group, C ₂ -C ₆ alkynyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl group, C ₇ -C ₁₂ aralkyloxy group, C ₃ -C ₈ cycloalkyl Group, C ₃ -C ₈ cycloalkyl-C ₁ -C ₆ alkyl group, C ₅ -C ₈ cycloalkenyl group, C ₂ -C ₆ alkanoyl group, C ₃ -C ₈ cycloalkyl-C ₂ -C ₆ alkanoyl group C ₂ -C ₆ alkanoyl-C ₁ -C ₆ alkyl group, arylcarbonyl group, heteroarylcarbonyl group, carboxy group, C ₁ -C ₆ alkoxycarbonyl group, C ₁ -C ₆ alkylthio group, arylthio group, heteroarylthio group, C ₁ -C ₆ alkylsulfinyl group, arylsulfinyl group, heteroarylsulfinyl group, C ₁ -C ₆ alkylsulfonyl group, arylsulfonyl group, heteroarylsulfonyl group, aminosulfonyl Group, C ₁ -C ₆ alkylaminosulfonyl group, di- (C ₁ -C ₆ alkyl) aminosulfonyl group (two alkyl groups may form a 4- to 8-membered ring together), aryl Aminosulfonyl group, heteroarylaminosulfonyl group, amino group, C ₁ -C ₆ alkylamino group, di- (C ₁ -C ₆ alkyl) amino group (two alkyl groups together to form a 4- to 8-membered ring A tri- (C ₁ -C ₆ alkyl) ammonium group (of 3 alkyl groups) Two of them may form a 4- to 8-membered ring together), C ₂ -C ₆ alkenylamino group, C ₂ -C ₆ alkynylamino group, C ₃ -C ₈ cycloalkylamino group, aryl Amino group, heteroarylamino group, C ₁ -C ₆ alkylsulfonylamino group, arylsulfonylamino group, heteroarylsulfonylamino group, aminosulfonylamino group, C ₁ -C ₆ alkylaminosulfonylamino group, di- (C ₁ -C ₆ alkyl) aminosulfonylamino group (two alkyl groups may form a 4- to 8-membered ring together), arylaminosulfonylamino group, heteroarylaminosulfonylamino group, C ₂ -C ₆ alkanoylamino group, an arylcarbonylamino group, heteroarylcarbonyl group, Aminoka Boniruamino group, C ₁ -C ₆ alkylamino carbonyl amino group, di - (C ₁ -C ₆ alkyl) aminocarbonylamino group (two alkyl groups may form a 4 to 8-membered ring together ), Arylaminocarbonylamino group, heteroarylaminocarbonylamino group, C ₁ -C ₆ alkoxycarbonylamino group, aryloxycarbonylamino group, heteroaryloxycarbonylamino group, carbamoyl group, C ₁ -C ₆ alkylcarbamoyl group, Di- (C ₁ -C ₆ alkyl) carbamoyl group (two alkyl groups may form a 4- to 8-membered ring together), arylcarbamoyl group, heteroarylcarbamoyl group, aryl group, heteroaryl Group, aryloxy group, heteroaryloxy group and heterocyclic group Ri,
When the substituent of the substituent group α includes an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, an aryl group, a heteroaryl group, or a heterocyclic group, further selected from the substituent group α The same or different 1 to 3 substituents may be substituted. ]
Or a pharmacologically acceptable salt thereof.

The benzyl compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof exhibits an excellent bronchodilator action based on a strong EP2 agonist action, and further, tissue transferability, bioavailability; (BA), rapid onset of drug efficacy, sustained efficacy, solubility, physical stability, drug interaction, toxicity, etc., together with the present invention, respiratory disease (for example, asthma) , COPD, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome (ARDS), cystic fibrosis, pulmonary hypertension, etc.) We were able to. Further, the compound represented by the general formula (1) of the present invention is also useful as a therapeutic and / or prophylactic agent for diseases (for example, bone diseases, gastric ulcers, hypertension, glaucoma, etc.) for which EP2 agonist action is considered useful. It is.

The “C ₁ -C ₆ alkyl group” represented by each substituent and the “C ₁ -C ₆ alkyl group” portion in each substituent each mean a “C ₁ -C ₆ alkyl group” having the same meaning. Examples of such “C ₁ -C ₆ alkyl group” include, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, Isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1-ethylpropyl group, 1,2-dimethylpropyl group, hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group 1,3-dimethylbutyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group A straight-chain or branched C ₁ -C ₆ alkyl group such as a 1,1,2-trimethylpropyl group or a 1,2,2-trimethylpropyl group, preferably a C ₁ -C ₄ alkyl group And more preferably a methyl group, an ethyl group, a propyl group, an isopropyl group or a tert-butyl group, and particularly preferably a methyl group or an ethyl group.

The “C ₂ -C ₆ alkenyl group” represented by each substituent means a “C ₂ -C ₆ alkenyl group” having the same meaning, and as such a “C ₂ -C ₆ alkenyl group”, For example, vinyl group, 1-propenyl group, 2-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-1-propenyl group, 2-methyl-1- Propenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 1-ethylvinyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-methyl- 1-butenyl group, 2-methyl-1-butenyl group, 3-methyl-1-butenyl group, 1-methyl-2-butenyl group, 2-methyl-2-butenyl group, 3-methyl-2-butenyl group, 1-methyl -3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1,1-dimethyl-2- Propenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 1-methyl-1-pentenyl group, 2-methyl-1-pentenyl group, 3-methyl- 1-pentenyl group, 4-methyl-1-pentenyl group, 1-methyl-2-pentenyl group, 2-methyl-2-pentenyl group, 3-methyl-2-pentenyl group, 4-methyl-2-pentenyl group, 1-methyl-3-pentenyl group, 2-methyl-3-pentenyl group, 3-methyl-3-pentenyl group, 4-methyl-3-pentenyl group, 1-methyl-4-pentenyl group, 2-methyl-4 Pentenyl group, 3-methyl-4-pentenyl group, 4-methyl-4-pentenyl group, 1-ethyl-1-butenyl group, 2-ethyl-1-butenyl group, 1-ethyl-2-butenyl group, 2- Straight chain such as ethyl-2-butenyl group, 1-ethyl-3-butenyl group, 2-ethyl-3-butenyl group, 1,1-dimethyl-2-butenyl group or 1,1-dimethyl-3-butenyl group Or a branched C ₂ -C ₆ alkenyl group, preferably a C ₃ -C ₅ alkenyl group, more preferably a 1-propenyl group, a 2-propenyl group, an isopropenyl group, or a 1-butenyl group. Group, 2-butenyl group, 3-butenyl group or 2-methyl-1-propenyl group, particularly preferably 1-propenyl group, 1-butenyl group or 2-methyl-1-propenyl group.

The “C ₂ -C ₆ alkynyl group” represented by each substituent means a “C ₂ -C ₆ alkynyl group” having the same meaning, and as such a “C ₂ -C ₆ alkynyl group”, For example, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 3-methyl-1-butynyl group, 1-methyl-2-butynyl group, 1-methyl-3-butynyl group, 2-methyl-3-butynyl group, 1-ethyl- 2-propynyl group, 1-hexynyl group, 2-hexynyl group, 3-hexynyl group, 4-hexynyl group, 5-hexynyl group, 3-methyl-1-pentynyl group, 4-methyl-1-pentynyl group, 1- Methyl 2-pentynyl group, 4-methyl-2-pentynyl group, 1-methyl-3-pentynyl group, 2-methyl-3-pentynyl group, 1-methyl-4-pentynyl group, 2-methyl-4-pentynyl group, 3-methyl-4-pentynyl group, 3,3-dimethyl-1-butynyl group, 1,1-dimethyl-2-butynyl group, 1-ethyl-2-butynyl group, 1,1-dimethyl-3-butynyl group 1,2-dimethyl-3-butynyl group, 2,2-dimethyl-3-butynyl group, 1-ethyl-3-butynyl group, 2-ethyl-3-butynyl group, 1-propyl-2-propynyl group, Examples thereof include linear or branched C ₂ -C ₆ alkynyl groups such as 1-isopropyl-2-propynyl group or 1-ethyl-1-methyl-2-propynyl group, preferably C ₃ -C ₅ alkynyl. Base More preferred is a 2-propynyl group, 2-butynyl group, 3-butynyl group, 2-pentynyl group, 3-pentynyl group or 4-pentynyl group, and particularly preferred is a 2-propynyl group or 2-butynyl group. is there.

And _"C 3 -C ₈ cycloalkyl group" indicated by each substituent, _"C 3 -C ₈ cycloalkyl group" moiety in each substituent both have the same meaning _"C 3 -C ₈ cycloalkyl group means ", such as" C ₃ -C ₈ cycloalkyl group ", for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, C ₃ -C _8, such as a cyclohexyl group, cycloheptyl group or cyclooctyl group Examples thereof include a cycloalkyl group, preferably a C ₃ -C ₆ cycloalkyl group, more preferably a cyclopropyl group, a cyclobutyl group or a cyclopentyl group, and particularly preferably a cyclopropyl group or a cyclobutyl group.

The “C ₅ -C ₈ cycloalkenyl group” represented by each substituent means a “C ₅ -C ₈ cycloalkenyl group” having the same meaning, and such a “C ₅ -C ₈ cycloalkenyl group”. Are, for example, cyclopentenyl, cyclopenten-3-yl, cyclohexenyl, cyclohexen-3-yl, cyclohexen-4-yl, cycloheptenyl, cyclohepten-3-yl, cyclohepten-4-yl Group, cyclohepten-5-yl group, cyclooctenyl group, cycloocten-3-yl group, cycloocten-4-yl group, cycloocten-5-yl group and the like, and preferred are C ₅ -C ₈ cycloalkenyl groups. _is a C 5 -C ₆ cycloalkenyl group, more preferably, cyclopentenyl group, cyclopentene -3 A yl group or a cyclohexenyl group, particularly preferably a cyclopentenyl group or cyclohexenyl group.

_"C 1 -C ₆ alkoxy group" or _"C 1 -C ₆ alkoxy group" moiety in the substituent group α are both mean _"C 1 -C ₆ alkoxy group" having the same significance, such Examples of the “C ₁ -C ₆ alkoxy group” include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy Group, neopentyloxy group, tert-pentyloxy group, 1-methylbutoxy group, 2-methylbutoxy group, 1-ethylpropoxy group, 1,2-dimethylpropoxy group, hexyloxy group, 1-methylpentyloxy group, 2-methylpentyloxy group, 3-methylpentyloxy group, 4-methylpentyloxy group, 1-ethylbutoxy 2-ethylbutoxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 1,3-dimethylbutoxy group, 2,2-dimethylbutoxy group, 2,3-dimethylbutoxy group, 3,3 -Linear or branched such as dimethylbutoxy group, 1-ethyl-1-methylpropoxy group, 1-ethyl-2-methylpropoxy group, 1,1,2-trimethylpropoxy group or 1,2,2-trimethylpropoxy group A C ₁ -C ₆ alkoxy group, preferably a C ₁ -C ₄ alkoxy group, more preferably a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group, particularly preferably a methoxy group It is a group.

_"C 2 -C ₆ alkanoyl group" and _"C 2 -C ₆ alkanoyl group" moiety in the substituent group α are all means _"C 2 -C ₆ alkanoyl group" having the same significance, such Examples of the “C ₂ -C ₆ alkanoyl group” include acetyl group, propanoyl group, butanoyl group, 2-methylpropanoyl group, pentanoyl group, 2-methylbutanoyl group, 3-methylbutanoyl group, 2,2 -Dimethylpropanoyl group, hexanoyl group, 2-methylpentanoyl group, 3-methylpentanoyl group, 4-methylpentanoyl group, 2-ethylbutanoyl group, 2,2-dimethylbutanoyl group, 2,3- Examples thereof include a linear or branched C ₂ -C ₆ alkanoyl group such as a dimethylbutanoyl group or a 3,3-dimethylbutanoyl group, preferably a C ₂ -C ₄ alkanoyl group, more preferably acetyl group, propanoyl group or butanoyl group, particularly preferably acetyl group or propanoyl group.

Examples of the “C ₇ -C ₁₂ aralkyl group” in the substituent group α include, for example, benzyl group, 1-phenylethyl group, 2-phenylethyl group, 1-phenylpropyl group, 2-phenylpropyl group, 3-phenylpropyl group. Group, phenylbutyl group, phenylpentyl group, phenylhexyl group, naphthalen-1-ylmethyl group, naphthalen-2-ylmethyl group, 1- (naphthalen-1-yl) ethyl group, 2- (naphthalen-1-yl) ethyl Group, 1- (naphthalen-2-yl) ethyl group, 2- (naphthalen-2-yl) ethyl group and the like, preferably benzyl group, 1-phenylethyl group, 2-phenylethyl group or 1- A methyl-2-phenylethyl group, more preferably a benzyl group, a 1-phenylethyl group or a 2-phenylethyl group. Particularly preferred is benzyl or 2-phenylethyl.

Examples of the “C ₇ -C ₁₂ aralkyloxy group” in the substituent group α include, for example, benzyloxy group, 1-phenylethyloxy group, 2-phenylethyloxy group, 1-phenylpropyloxy group, 2-phenylpropyloxy group Group, 3-phenylpropyloxy group, phenylbutyloxy group, phenylpentyloxy group, phenylhexyloxy group, naphthalen-1-ylmethyloxy group, naphthalen-2-ylmethyloxy group, 1- (naphthalen-1-yl) ) Ethyloxy group, 2- (naphthalen-1-yl) ethyloxy group, 1- (naphthalen-2-yl) ethyloxy group, 2- (naphthalen-2-yl) ethyloxy group, etc., preferably benzyloxy Group, 1-phenylethyloxy group, 2-phenylethyloxy group or 1 A methyl-2-phenylethyloxy group, more preferably a benzyloxy group, a 1-phenylethyloxy group or a 2-phenylethyloxy group, and particularly preferably a benzyloxy group or a 1-phenylethyloxy group. is there.

The “aryl group” represented by each substituent and the “aryl group” portion in each substituent all mean an “aryl group” having the same significance. Examples of such an “aryl group” include phenyl Group or naphthyl group.

The “heteroaryl group” represented by each substituent and the “heteroaryl group” part in each substituent all mean a “heteroaryl group” having the same significance, and as such a “heteroaryl group”, For example, pyrrolyl group, furyl group, thienyl group, pyrazolyl group, imidazolyl group, oxazolyl group, thiazolyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, benzofuryl group, benzothienyl group, benzoxazolyl group, benzothiazolyl Group, isoindolyl group, indolyl group, indazolyl group, benzimidazolyl group, isoquinolyl group or quinolyl group, and the like, preferably thienyl group, pyrazolyl group, imidazolyl group, thiazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, benzofuryl group , Benzothie A group or quinolyl group, more preferably a thienyl group, a pyrazolyl group, a thiazolyl group, a pyridyl group, a benzofuryl group or a benzothienyl group, particularly preferably a thienyl or pyridyl group.

The “heterocyclic group” represented by each substituent means a “heterocyclic group” having the same significance, and such a “heterocyclic group” is a group consisting of an oxygen atom, a nitrogen atom and a sulfur atom. Means a partially unsaturated or fully saturated monocyclic or bicyclic group containing 1 to 4 heteroatoms (in each case, independently of each other) selected from As the partially unsaturated heterocyclic group, for example, 4,5-dihydro-1H-imidazolyl group, 4,5-dihydrooxazolyl group, 4,5-dihydrothiazolyl group, 1,4,5, Examples include a 6-tetrahydropyrimidinyl group, a 5,6-dihydro-4H-1,3-oxazinyl group, or a 5,6-dihydro-4H-1,3-thiazinyl group. Examples of the fully saturated heterocyclic group include Pyrrolidinyl group, tetrahydrofuryl group, 1,3- Oxolanyl group, a piperidinyl group, tetrahydropyranyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, and 1,3-dioxanyl group or a 1,4-dioxanyl group. The “heterocyclic group” represented by each substituent is preferably a 4,5-dihydro-1H-imidazolyl group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, or a thiomorpholinyl group, and more preferably , Azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group or morpholinyl group, particularly preferably pyrrolidinyl group or piperidinyl group.

The “halogeno group” represented by each substituent means a “halogeno group” having the same significance. Examples of such a “halogeno group” include a fluoro group, a chloro group, a bromo group, and an iodo group. Preferably, it is a fluoro group, a chloro group or a bromo group.

When the substituent of the substituent group α is further substituted with a substituent selected from the substituent group α, the preferred substituent is a combination of the respective preferred substituents. Examples of such a substituent include a halogeno C ₁ -C ₄ alkyl group, a halogeno C ₁ -C ₄ alkoxy group, or a C ₁ -C ₄ alkylamino-C ₁ -C ₄ alkyl group.

R ¹ is preferably a hydrogen atom or a C ₁ -C ₄ alkyl group, more preferably a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, or a tert-butyl group, and particularly preferably , Hydrogen atom, methyl group, ethyl group or isopropyl group.

R ² is preferably a hydrogen atom or a C ₁ -C ₄ alkyl group, more preferably a hydrogen atom or a methyl group, and particularly preferably a hydrogen atom.

R ³ is preferably a hydrogen atom or a C ₁ -C ₄ alkyl group, more preferably a hydrogen atom or a methyl group, and particularly preferably a hydrogen atom.

A is preferably a hydroxy group, a halogeno group, a cyano group, a C ₁ -C ₄ alkyl group, a halogeno C ₁ -C ₄ alkyl group, a C ₇ -C ₁₂ aralkyl group, a C ₃ -C ₅ alkenyl group, C _3- C ₅ alkynyl group, C ₁ -C ₄ alkoxy group, C ₇ -C ₁₂ aralkyloxy group, C ₃ -C ₆ cycloalkyl group, C ₅ -C ₆ cycloalkenyl group, arylcarbonyl group, C ₁ -C ₄ alkoxycarbonyl group, C ₁ -C ₄ alkylthio group, C ₁ -C ₄ alkylsulfinyl group, C ₁ -C ₄ alkylsulfonyl group, C ₁ -C ₄ alkylamino group, di- (C ₁ -C ₄ alkyl) amino group, an arylamino _group, C 2 -C ₄ alkanoylamino _group, C 1 -C ₄ alkoxycarbonylamino group, an aryl group, a heteroaryl group, Lille group and fully saturated groups selected from the group consisting of heterocyclic group may be substituted, an aryl group, a heteroaryl group or a heterocyclic group, more preferably, fluoro, chloro groups, C ₁ -C ₄ alkyl group, a trifluoromethyl group, a benzyl group, 1-propenyl, 1-butenyl, 2-propynyl, 2-butynyl group, methoxy group, benzyloxy group, cyclopropyl group, cyclopentenyl group, It may be substituted with a group selected from the group consisting of benzoyl group, methoxycarbonyl group, methylthio group, methylamino group, dimethylamino group, anilino group, acetylamino group, methoxycarbonylamino group, pyrrolidinyl group and piperidinyl group. Phenyl group, naphthyl group, thienyl group, pyrazolyl group, thiazolyl group, pyridyl group, Nzofuryl group or benzothienyl group, and still more preferably, phenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 4-methylphenyl group, 4-trifluoromethylphenyl group, 4- (1-propenyl) phenyl group, 4-methoxyphenyl group, 4-cyclopropylphenyl group, 4-methoxycarbonylphenyl group, 4-methylthiophenyl group, 4-dimethylaminophenyl group, 4- (pyrrolidin-1-yl) Phenyl group, naphthalen-1-yl group, naphthalen-2-yl group, thiophen-2-yl group, thiazol-2-yl group, thiazol-4-yl group, pyridin-3-yl group or pyridin-4-yl Particularly preferably a phenyl group, a 4-fluorophenyl group, a naphthalen-2-yl group, a thiol group. It is E emission-2-yl group or pyridine-4-yl group.

Y is preferably a halogeno group, a C ₁ -C ₄ alkoxy group, a C ₃ -C ₆ cycloalkyl group, a C ₁ -C ₄ alkoxycarbonyl group, a C ₁ -C ₄ alkylthio group, or a C ₁ -C ₄ alkyl group. Sulfinyl group, C ₁ -C ₄ alkylsulfonyl group, C ₁ -C ₄ alkylamino group, di- (C ₁ -C ₄ alkyl) amino group, C ₂ -C ₄ alkanoylamino group, C ₁ -C ₄ alkoxycarbonyl C ₁ -C ₄ alkyl group, C ₃ -C ₅ alkenyl group, C _3- which may be substituted with a group selected from the group consisting of an amino group, an aryl group, a heteroaryl group and a fully saturated heterocyclic group C ₅ alkynyl _group, C 3 -C ₆ cycloalkyl _group, C 5 -C ₆ cycloalkenyl group, or a halogeno group, a cyano group, a nitro group, formyl _groups, C 1 -C Alkyl _group, C 7 _{-C 12} aralkyl _group, C 7 _{-C 12} aralkyloxy _group, C 3 -C ₆ cycloalkyl _groups, C 1 -C ₄ alkoxycarbonyl _groups, C 1 -C ₄ alkylthio _groups, C 1 -C _4- alkylamino group, di- (C ₁ -C ₄ alkyl) amino group, arylamino group, C ₂ -C ₄ alkanoylamino group, C ₁ -C ₄ alkoxycarbonylamino group, aryl group, heteroaryl group, aryloxy A phenyl group or heteroaryl group which may be substituted with a group selected from the group consisting of a group and a fully saturated heterocyclic group, or a fully saturated heterocyclic group, more preferably C ₁ -C _4. Alkyl group, trifluoromethyl group, methoxymethyl group, cyclopropylmethyl group, 2-methylaminoethyl group, 2-dimethylaminoethyl Group, 2- (pyrrolidin-1-yl) ethyl group, 1-propenyl group, 1-butenyl group, 2-propynyl group, 2-butynyl group, cyclopropyl group, cyclopentenyl group, [fluoro group, chloro group, cyano group Group, methyl group, ethyl group, benzyl group, benzyloxy group, cyclopropyl group, methoxycarbonyl group, methylthio group, methylamino group, dimethylamino group, anilino group, acetylamino group, methoxycarbonylamino group, phenyl group, pyrrolidinyl A phenyl group, a thienyl group, a pyrazolyl group, a thiazolyl group, a pyridyl group, a benzofuryl group, a benzothienyl group, a pyrrolidinyl group, or a piperazinyl group, which may be substituted with a group selected from the group consisting of: Even more preferably, methyl, ethyl, propyl, trif Oromethyl group, phenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 4-methylphenyl group, 4-cyclopropylphenyl group, thiophen-2-yl group, thiazol-2-yl group, A thiazol-4-yl group, a pyridin-3-yl group, a pyridin-4-yl group, a pyrrolidin-1-yl group or a piperidin-1-yl group, particularly preferably a methyl group, an ethyl group, a phenyl group, 4-fluorophenyl group, thiophen-2-yl group or pyridin-4-yl group.

Z is preferably a halogeno group, a C ₇ -C ₁₂ aralkyl group, a C ₁ -C ₄ alkoxy group, a C ₇ -C ₁₂ aralkyloxy group, a C ₃ -C ₆ cycloalkyl group, or a C ₅ -C ₆ cyclo group. Alkenyl group, arylcarbonyl group, C ₁ -C ₄ alkylamino group, di- (C ₁ -C ₄ alkyl) amino group, arylamino group, aryl group, heteroaryl group, aryloxy group and fully saturated heterocyclic group A C ₁ -C ₄ alkyl group, a C ₃ -C ₆ cycloalkyl group, a C ₅ -C ₆ cycloalkenyl group, a C ₃ -C ₅ alkenyl group, C, which may be substituted with a group selected from the group consisting of ₃ -C ₅ alkynyl group, fully saturated heterocyclic group, or a halogeno group, a cyano group, a nitro group, formyl _group, C 1 -C ₄ alkyl group, halogeno _C 1 -C ₄ a Kill _group, C 7 _{-C 12} aralkyl _group, C 7 _{-C 12} aralkyloxy _group, C 3 -C ₆ cycloalkyl _groups, C 1 -C ₄ alkoxy _groups, C 1 -C ₄ alkoxycarbonyl _groups, C 1 -C ₄ alkylthio group, C ₁ -C ₄ alkylamino group, di- (C ₁ -C ₄ alkyl) amino group, arylamino group, C ₂ -C ₄ alkanoylamino group, C ₁ -C ₄ alkoxycarbonylamino group, aryl A phenyl group or a heteroaryl group which may be substituted with a group selected from the group consisting of a group, a heteroaryl group, an aryloxy group and a fully saturated heterocyclic group, more preferably a [fluoro group, a chloro group , Benzyl, methoxy, benzyloxy, cyclopropyl, cyclopentenyl, benzoyl, methylamino, dimethyl Amino group, an anilino group, a phenyl group, a thienyl group, a pyridyl group, a phenoxy group, a pyrrolidinyl group and a piperidinyl group] may be substituted with a group selected from the group consisting of C ₁ -C ₄ alkyl group, 2-propynyl Group, 2-butynyl group, cyclopropyl group, cyclobutyl group, cyclopentenyl group, [fluoro group, chloro group, cyano group, nitro group, methyl group, ethyl group, trifluoromethyl group, benzyl group, benzyloxy group, cyclo Propyl group, methoxy group, methoxycarbonyl group, methylthio group, methylamino group, dimethylamino group, anilino group, acetylamino group, methoxycarbonylamino group, phenyl group, phenoxy group, azetidinyl group, pyrrolidinyl group and piperidinyl group] Fe optionally substituted with a group selected from the group Nyl group, thienyl group, pyrazolyl group, thiazolyl group or pyridyl group, more preferably methyl group, ethyl group, trifluoromethyl group, 2-phenylethyl group, cyclopropyl group, phenyl group, 2-fluorophenyl Group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 4-cyanophenyl group, 4-cyclopropylphenyl group, 4-methoxyphenyl group, thiophene- 2-yl group, thiophen-3-yl group, pyridin-2-yl group, pyridin-3-yl group or pyridin-4-yl group, particularly preferably phenyl group, 4-fluorophenyl group, pyridin-2 -Yl group or pyridin-3-yl group.

When the compound represented by the general formula (I) of the present invention has optical isomers, geometric isomers or rotational isomers, these isomers are also included in the scope of the present invention, and proton tautomerism exists. In that case, those tautomers are also included in the scope of the present invention.

The compound represented by the general formula (I) of the present invention is easily converted into a pharmacologically acceptable acid addition salt by treating with an acid. Examples of such salts include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or phosphate; or acetate, trifluoroacetate, benzoate Oxalate, malonate, succinate, maleate, fumarate, tartrate, citrate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p -Organic acid salts such as toluene sulfonate, glutamate or aspartate.

When R ¹ is a hydrogen atom, the compound represented by the general formula (I) of the present invention is easily converted into a pharmacologically acceptable basic salt by treatment with a base. Examples of such salts include metal salts such as sodium salts, potassium salts, calcium salts, and magnesium salts; inorganic salts such as ammonium salts; and organic amine salts such as triethylamine salts and guanidine salts.

Furthermore, the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof can exist as a hydrate or a solvate, and these are also included in the present invention.

In the compound represented by the general formula (I) of the present invention, preferably,
(1) a compound in which R ¹ is a hydrogen atom or a C ₁ -C ₄ alkyl group,
(2) Compound wherein R ¹ is a hydrogen atom, methyl group, ethyl group, propyl group, isopropyl group or tert-butyl group (3) Compound wherein R ¹ is a hydrogen atom, methyl group, ethyl group or isopropyl group,
(4) the compound wherein R ² and R ³ are each independently a hydrogen atom or a C ₁ -C ₄ alkyl group,
(5) A compound in which R ² and R ³ are each independently a hydrogen atom or a methyl group,
(6) A compound in which R ² and R ³ are both hydrogen atoms,
(7) A is a hydroxy group, halogeno group, cyano group, C ₁ -C ₄ alkyl group, halogeno C ₁ -C ₄ alkyl group, C ₇ -C ₁₂ aralkyl group, C ₃ -C ₅ alkenyl group, C ₃ —C ₅ alkynyl group, C ₁ -C ₄ alkoxy group, C ₇ -C ₁₂ aralkyloxy group, C ₃ -C ₆ cycloalkyl group, C ₅ -C ₆ cycloalkenyl group, arylcarbonyl group, C ₁ -C ₄ Alkoxycarbonyl group, C ₁ -C ₄ alkylthio group, C ₁ -C ₄ alkylsulfinyl group, C ₁ -C ₄ alkylsulfonyl group, C ₁ -C ₄ alkylamino group, di- (C ₁ -C ₄ alkyl) amino group, an arylamino _group, C 2 -C ₄ alkanoylamino _group, C 1 -C ₄ alkoxycarbonylamino group, an aryl group, a heteroaryl group, Ariruoki May be substituted with a group selected from the group consisting of heterocyclic groups groups and fully saturated, aryl group, the compound is a heteroaryl group or a heterocyclic group,
(8) A is a fluoro group, chloro group, C ₁ -C ₄ alkyl group, trifluoromethyl group, benzyl group, 1-propenyl group, 1-butenyl group, 2-propynyl group, 2-butynyl group, methoxy group Benzyloxy group, cyclopropyl group, cyclopentenyl group, benzoyl group, methoxycarbonyl group, methylthio group, methylamino group, dimethylamino group, anilino group, acetylamino group, methoxycarbonylamino group, pyrrolidinyl group and piperidinyl group A compound which is a phenyl group, a naphthyl group, a thienyl group, a pyrazolyl group, a thiazolyl group, a pyridyl group, a benzofuryl group or a benzothienyl group, which may be substituted with a group selected from the group;
(9) A is a phenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group, a 4-chlorophenyl group, a 4-methylphenyl group, a 4-trifluoromethylphenyl group, a 4- (1-propenyl) phenyl group, 4-methoxyphenyl group, 4-cyclopropylphenyl group, 4-methoxycarbonylphenyl group, 4-methylthiophenyl group, 4-dimethylaminophenyl group, 4- (pyrrolidin-1-yl) phenyl group, naphthalen-1-yl A compound which is a group, naphthalen-2-yl group, thiophen-2-yl group, thiazol-2-yl group, thiazol-4-yl group, pyridin-3-yl group or pyridin-4-yl group,
(10) A compound wherein A is a phenyl group, a 4-fluorophenyl group, a naphthalen-2-yl group, a thiophen-2-yl group or a pyridin-4-yl group,
(11) Y represents a halogeno group, a C ₁ -C ₄ alkoxy group, a C ₃ -C ₆ cycloalkyl group, a C ₁ -C ₄ alkoxycarbonyl group, a C ₁ -C ₄ alkylthio group, a C ₁ -C ₄ alkylsulfinyl group Group, C ₁ -C ₄ alkylsulfonyl group, C ₁ -C ₄ alkylamino group, di- (C ₁ -C ₄ alkyl) amino group, C ₂ -C ₄ alkanoylamino group, C ₁ -C ₄ alkoxycarbonylamino A C ₁ -C ₄ alkyl group, a C ₃ -C ₅ alkenyl group, a C ₃ -C optionally substituted with a group selected from the group consisting of a group, an aryl group, a heteroaryl group and a fully saturated heterocyclic group _{5 alkynyl,} C 3 -C ₆ cycloalkyl _group, C 5 -C ₆ cycloalkenyl group, or a halogeno group, a cyano group, a nitro group, formyl _group, C 1 -C ₄ alkyl , _C 7 _{-C 12} aralkyl _group, C 7 _{-C 12} aralkyloxy _group, C 3 -C ₆ cycloalkyl _group, C 1 -C ₄ alkoxycarbonyl _group, C 1 -C ₄ alkylthio _group, C 1 -C ₄ alkyl Amino group, di- (C ₁ -C ₄ alkyl) amino group, arylamino group, C ₂ -C ₄ alkanoylamino group, C ₁ -C ₄ alkoxycarbonylamino group, aryl group, heteroaryl group, aryloxy group and A compound which is a phenyl group or heteroaryl group which may be substituted with a group selected from the group consisting of a fully saturated heterocyclic group, or a fully saturated heterocyclic group,
(12) Y is a C ₁ -C ₄ alkyl group, trifluoromethyl group, methoxymethyl group, cyclopropylmethyl group, 2-methylaminoethyl group, 2-dimethylaminoethyl group, 2- (pyrrolidin-1-yl) ) Ethyl group, 1-propenyl group, 1-butenyl group, 2-propynyl group, 2-butynyl group, cyclopropyl group, cyclopentenyl group, [fluoro group, chloro group, cyano group, methyl group, ethyl group, benzyl group Benzyloxy group, cyclopropyl group, methoxycarbonyl group, methylthio group, methylamino group, dimethylamino group, anilino group, acetylamino group, methoxycarbonylamino group, phenyl group, pyrrolidinyl group and piperidinyl group] Phenyl group, thienyl group, pyrazolyl group, thia Lil group, a pyridyl group, benzofuryl group, benzothienyl group, compound is a pyrrolidinyl group or piperazinyl group,
(13) Y is methyl, ethyl, propyl, trifluoromethyl, phenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-cyclopropyl Phenyl group, thiophen-2-yl group, thiazol-2-yl group, thiazol-4-yl group, pyridin-3-yl group, pyridin-4-yl group, pyrrolidin-1-yl group or piperidin-1-yl A compound that is a group,
(14) A compound wherein Y is a methyl group, an ethyl group, a phenyl group, a 4-fluorophenyl group, a thiophen-2-yl group or a pyridin-4-yl group,
(15) Z is a halogeno group, a C ₇ -C ₁₂ aralkyl group, a C ₁ -C ₄ alkoxy group, a C ₇ -C ₁₂ aralkyloxy group, a C ₃ -C ₆ cycloalkyl group, a C ₅ -C ₆ cycloalkenyl group A group, an arylcarbonyl group, a C ₁ -C ₄ alkylamino group, a di- (C ₁ -C ₄ alkyl) amino group, an arylamino group, an aryl group, a heteroaryl group, an aryloxy group and a fully saturated heterocyclic group A C ₁ -C ₄ alkyl group, a C ₃ -C ₆ cycloalkyl group, a C ₅ -C ₆ cycloalkenyl group, a C ₃ -C ₅ alkenyl group, a C ₃ optionally substituted with a group selected from the group consisting of -C ₅ alkynyl group, fully saturated heterocyclic group, or a halogeno group, a cyano group, a nitro group, formyl _group, C 1 -C ₄ alkyl group, halogeno _C 1 -C ₄ alkyl group, ₇ -C ₁₂ aralkyl _group, C 7 _{-C 12} aralkyloxy _group, C 3 -C ₆ cycloalkyl _group, C 1 -C ₄ alkoxy _groups, C 1 -C ₄ alkoxycarbonyl _group, C 1 -C ₄ alkylthio group, C ₁ -C ₄ alkylamino group, di- (C ₁ -C ₄ alkyl) amino group, arylamino group, C ₂ -C ₄ alkanoylamino group, C ₁ -C ₄ alkoxycarbonylamino group, aryl group, heteroaryl A compound which is a phenyl group or a heteroaryl group optionally substituted with a group selected from the group consisting of a group, an aryloxy group and a fully saturated heterocyclic group,
(16) Z is [fluoro group, chloro group, benzyl group, methoxy group, benzyloxy group, cyclopropyl group, cyclopentenyl group, benzoyl group, methylamino group, dimethylamino group, anilino group, phenyl group, thienyl group. A C ₁ -C ₄ alkyl group, a 2-propynyl group, a 2-butynyl group, a cyclopropyl group, which may be substituted with a group selected from the group consisting of a pyridyl group, a phenoxy group, a pyrrolidinyl group and a piperidinyl group], Cyclobutyl group, cyclopentenyl group, [fluoro group, chloro group, cyano group, nitro group, methyl group, ethyl group, trifluoromethyl group, benzyl group, benzyloxy group, cyclopropyl group, methoxy group, methoxycarbonyl group, methylthio Group, methylamino group, dimethylamino group, anilino group, acetylamino group A methoxycarbonylamino group, a phenyl group, a phenoxy group, an azetidinyl group, a pyrrolidinyl group, and a piperidinyl group], which may be substituted with a phenyl group, a thienyl group, a pyrazolyl group, a thiazolyl group, or a pyridyl group. A compound,
(17) Z is a methyl group, an ethyl group, a trifluoromethyl group, a 2-phenylethyl group, a cyclopropyl group, a phenyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group, 2- Chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 4-cyanophenyl group, 4-cyclopropylphenyl group, 4-methoxyphenyl group, thiophen-2-yl group, thiophen-3-yl group, pyridine-2- A compound which is an yl group, a pyridin-3-yl group or a pyridin-4-yl group,
(18) A compound wherein Z is a phenyl group, a 4-fluorophenyl group, a pyridin-2-yl group or a pyridin-3-yl group.

In the groups (1)-(3), (4)-(6), (7)-(10), (11)-(14), (15)-(18), the number is As the compound size increases, more preferable compounds are shown. R ¹ is from groups (1) to (3), R ² and R ³ are from groups (4) to (6), and A is from groups (7) to (10). , Y is arbitrarily selected from groups (11)-(14), Z is arbitrarily selected from groups (15)-(18), and compounds obtained by arbitrarily combining these are also preferred compounds.
Such compounds are
(19) R ¹ is a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group or a tert-butyl group,
R ² and R ³ are each independently a hydrogen atom or a methyl group,
A is a hydroxy group, halogeno group, cyano group, C ₁ -C ₄ alkyl group, halogeno C ₁ -C ₄ alkyl group, C ₇ -C ₁₂ aralkyl group, C ₃ -C ₅ alkenyl group, C ₃ -C ₅ Alkynyl group, C ₁ -C ₄ alkoxy group, C ₇ -C ₁₂ aralkyloxy group, C ₃ -C ₆ cycloalkyl group, C ₅ -C ₆ cycloalkenyl group, arylcarbonyl group, C ₁ -C ₄ alkoxycarbonyl group C ₁ -C ₄ alkylthio group, C ₁ -C ₄ alkylsulfinyl group, C ₁ -C ₄ alkylsulfonyl group, C ₁ -C ₄ alkylamino group, di- (C ₁ -C ₄ alkyl) amino group, aryl amino _group, C 2 -C ₄ alkanoylamino _group, C 1 -C ₄ alkoxycarbonylamino group, an aryl group, heteroaryl group, aryloxy Moto及Fully saturated group selected from the group consisting of heterocyclic group may be substituted, an aryl group, a heteroaryl group or a heterocyclic group,
Y represents a halogeno group, a C ₁ -C ₄ alkoxy group, a C ₃ -C ₆ cycloalkyl group, a C ₁ -C ₄ alkoxycarbonyl group, a C ₁ -C ₄ alkylthio group, a C ₁ -C ₄ alkylsulfinyl group, C _1- C ₄ alkylsulfonyl group, C ₁ -C ₄ alkylamino group, di- (C ₁ -C ₄ alkyl) amino group, C ₂ -C ₄ alkanoylamino group, C ₁ -C ₄ alkoxycarbonylamino group, aryl A C ₁ -C ₄ alkyl group, a C ₃ -C ₅ alkenyl group, a C ₃ -C ₅ alkynyl group optionally substituted by a group selected from the group consisting of a group, a heteroaryl group and a fully saturated heterocyclic group C ₃ -C ₆ cycloalkyl group, C ₅ -C ₆ cycloalkenyl group, or halogeno group, cyano group, nitro group, formyl group, C ₁ -C ₄ alkyl group, C ₇ -C ₁₂ aralkyl _group, C 7 _{-C 12} aralkyloxy _group, C 3 -C ₆ cycloalkyl _group, C 1 -C ₄ alkoxycarbonyl _group, C 1 -C ₄ alkylthio _group, C 1 -C ₄ alkylamino group, Di- (C ₁ -C ₄ alkyl) amino group, arylamino group, C ₂ -C ₄ alkanoylamino group, C ₁ -C ₄ alkoxycarbonylamino group, aryl group, heteroaryl group, aryloxy group and fully saturated A phenyl group or heteroaryl group optionally substituted with a group selected from the group consisting of heterocyclic groups, or a fully saturated heterocyclic group,
Z is a halogeno group, a C ₇ -C ₁₂ aralkyl group, a C ₁ -C ₄ alkoxy group, a C ₇ -C ₁₂ aralkyloxy group, a C ₃ -C ₆ cycloalkyl group, a C ₅ -C ₆ cycloalkenyl group, an aryl From the group consisting of a carbonyl group, a C ₁ -C ₄ alkylamino group, a di- (C ₁ -C ₄ alkyl) amino group, an arylamino group, an aryl group, a heteroaryl group, an aryloxy group, and a fully saturated heterocyclic group C ₁ -C ₄ alkyl group, C ₃ -C ₆ cycloalkyl group, C ₅ -C ₆ cycloalkenyl group, C ₃ -C ₅ alkenyl group, C ₃ -C ₅ optionally substituted with a selected group alkynyl group, fully saturated heterocyclic group, or a halogeno group, a cyano group, a nitro group, formyl _group, C 1 -C ₄ alkyl group, halogeno _C 1 -C ₄ alkyl groups, _{C 7} - ₁₂ aralkyl _group, C 7 _{-C 12} aralkyloxy _group, C 3 -C ₆ cycloalkyl _group, C 1 -C ₄ alkoxy _groups, C 1 -C ₄ alkoxycarbonyl _group, C 1 -C ₄ alkylthio group, _{C 1} - C ₄ alkylamino group, di- (C ₁ -C ₄ alkyl) amino group, arylamino group, C ₂ -C ₄ alkanoylamino group, C ₁ -C ₄ alkoxycarbonylamino group, aryl group, heteroaryl group, aryl A compound which is a phenyl group or a heteroaryl group optionally substituted with a group selected from the group consisting of an oxy group and a fully saturated heterocyclic group,
(20) R ¹ is a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, or a tert-butyl group,
R ² and R ³ are each independently a hydrogen atom or a methyl group,
A is a fluoro group, chloro group, C ₁ -C ₄ alkyl group, trifluoromethyl group, benzyl group, 1-propenyl group, 1-butenyl group, 2-propynyl group, 2-butynyl group, methoxy group, benzyloxy Selected from the group consisting of a group, a cyclopropyl group, a cyclopentenyl group, a benzoyl group, a methoxycarbonyl group, a methylthio group, a methylamino group, a dimethylamino group, an anilino group, an acetylamino group, a methoxycarbonylamino group, a pyrrolidinyl group, and a piperidinyl group A phenyl group, a naphthyl group, a thienyl group, a pyrazolyl group, a thiazolyl group, a pyridyl group, a benzofuryl group, or a benzothienyl group, which may be substituted with
Y is a C ₁ -C ₄ alkyl group, trifluoromethyl group, methoxymethyl group, cyclopropylmethyl group, 2-methylaminoethyl group, 2-dimethylaminoethyl group, 2- (pyrrolidin-1-yl) ethyl group 1-propenyl group, 1-butenyl group, 2-propynyl group, 2-butynyl group, cyclopropyl group, cyclopentenyl group, [fluoro group, chloro group, cyano group, methyl group, ethyl group, benzyl group, benzyloxy Group selected from the group consisting of a group, cyclopropyl group, methoxycarbonyl group, methylthio group, methylamino group, dimethylamino group, anilino group, acetylamino group, methoxycarbonylamino group, phenyl group, pyrrolidinyl group and piperidinyl group] Phenyl group, thienyl group, pyrazolyl group, thiazolyl group optionally substituted by Pyridyl, benzofuryl group, benzothienyl group, pyrrolidinyl group or piperazinyl group,
Z is [fluoro group, chloro group, benzyl group, methoxy group, benzyloxy group, cyclopropyl group, cyclopentenyl group, benzoyl group, methylamino group, dimethylamino group, anilino group, phenyl group, thienyl group, pyridyl group , A phenoxy group, a pyrrolidinyl group, and a piperidinyl group], which may be substituted with a group selected from the group consisting of a C ₁ -C ₄ alkyl group, a 2-propynyl group, a 2-butynyl group, a cyclopropyl group, a cyclobutyl group, Cyclopentenyl, [fluoro, chloro, cyano, nitro, methyl, ethyl, trifluoromethyl, benzyl, benzyloxy, cyclopropyl, methoxy, methoxycarbonyl, methylthio, methyl Amino group, dimethylamino group, anilino group, acetylamino group, methoxy A carbonylamino group, a phenyl group, a phenoxy group, an azetidinyl group, a pyrrolidinyl group, and a piperidinyl group] which may be substituted with a group selected from the group consisting of a phenyl group, a thienyl group, a pyrazolyl group, a thiazolyl group, and a pyridyl group. Compound,
(21) R ¹ is a hydrogen atom, a methyl group, an ethyl group or an isopropyl group,
R ² and R ³ are both hydrogen atoms,
A is a phenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 4-methylphenyl group, 4-trifluoromethylphenyl group, 4- (1-propenyl) phenyl group, 4-methoxy Phenyl group, 4-cyclopropylphenyl group, 4-methoxycarbonylphenyl group, 4-methylthiophenyl group, 4-dimethylaminophenyl group, 4- (pyrrolidin-1-yl) phenyl group, naphthalen-1-yl group, naphthalene A -2-yl group, a thiophen-2-yl group, a thiazol-2-yl group, a thiazol-4-yl group, a pyridin-3-yl group or a pyridin-4-yl group;
Y is a methyl group, ethyl group, propyl group, trifluoromethyl group, phenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 4-methylphenyl group, 4-cyclopropylphenyl group, A thiophen-2-yl group, a thiazol-2-yl group, a thiazol-4-yl group, a pyridin-3-yl group, a pyridin-4-yl group, a pyrrolidin-1-yl group, or a piperidin-1-yl group ,
Z is a methyl group, ethyl group, trifluoromethyl group, 2-phenylethyl group, cyclopropyl group, phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 4-cyanophenyl group, 4-cyclopropylphenyl group, 4-methoxyphenyl group, thiophen-2-yl group, thiophen-3-yl group, pyridin-2-yl group, A compound that is a pyridin-3-yl group or a pyridin-4-yl group, or
(22) R ¹ is a hydrogen atom, a methyl group, an ethyl group or an isopropyl group,
R ² and R ³ are both hydrogen atoms,
A is a phenyl group, a 4-fluorophenyl group, a naphthalen-2-yl group, a thiophen-2-yl group or a pyridin-4-yl group;
Y is a methyl group, an ethyl group, a phenyl group, a 4-fluorophenyl group, a thiophen-2-yl group or a pyridin-4-yl group;
A compound in which Z is a phenyl group, a 4-fluorophenyl group, a pyridin-2-yl group or a pyridin-3-yl group.
(23) As a benzyl compound, preferably
[6-({4- [bis (4-fluorophenyl) methyl] benzyl} (pyridin-3-ylsulfonyl) aminomethyl) pyridin-2-ylamino] acetic acid,
[6-({4- [1- (Naphthalen-2-yl) ethyl] benzyl} (pyridin-3-ylsulfonyl) aminomethyl) pyridin-2-ylamino] acetic acid, or [6-({4- [phenyl And compounds such as (pyridin-4-yl) methyl] benzyl} (pyridin-3-ylsulfonyl) aminomethyl) pyridin-2-ylamino] acetic acid.

In the present invention,
(24) A pharmaceutical composition comprising as an active ingredient the compound represented by the above general formula (I), the sulfonamide compound according to any one of (1) to (23) or a pharmacologically acceptable salt thereof And (25) the pharmaceutical composition according to (24) for the prevention or treatment of respiratory diseases.

A typical production method of the compound of the present invention is shown below. In addition, each specific manufacturing method of this invention compound is demonstrated in detail by the below-mentioned Example.

[Wherein R ² , R ³ , A, Y and Z are as defined above, and X is a hydroxy group, a chloro group, a bromo group, an iodo group, a methanesulfonyloxy group, a benzenesulfonyloxy group, p - indicates toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group, Boc represents a tert- butoxycarbonyl group, Bu ^t represents a tert- butyl group. ]

Synthetic pathways 1 to 3: Compound A and Compound B, or Compound C and Compound D, or Compound E and Compound F are reacted in an organic solvent in the presence of a condensing agent or a base. Compound (I ′) which is a precursor can be obtained.
Compounds of the invention wherein R ¹ is a hydrogen atom (Ia) may be a precursor compound of the Boc group and Bu ^t group (I ') obtained by deprotection by acid treatment.
As the substituent on the substituent A, the substituent Y and / or the substituent Z, a desired substituent may be introduced from the beginning, and after the basic skeleton is produced by the above method, oxidation, reduction , Alkylation, esterification, amidation, dehydration reaction, deprotection reaction, acetylation, hydrolysis, coupling reaction, cyclization reaction and / or using synthetic methods that combine these reactions, A desired substituent may be introduced into the skeleton.
The method for producing the synthetic intermediate of the compound of the present invention will be described in detail in the Examples below.

The target compound produced in each reaction can be obtained from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, and then an organic solvent such as ethyl acetate that is immiscible with water is added. It isolate | separates and it obtains by distilling a solvent off after drying with desiccants, such as anhydrous magnesium sulfate or anhydrous sodium sulfate.
If necessary, the obtained target compound can be obtained by a conventional method such as recrystallization; reprecipitation; or a method commonly used for separation and purification of organic compounds (for example, adsorption column chromatography using a carrier such as silica gel or alumina). Can be combined and separated and purified as appropriate by a combination of a chromatography method; an ion exchange chromatography method; or a normal phase / reverse phase column chromatography method (preferably high performance liquid chromatography) using silica gel or alkylated silica gel. .

The compound represented by the general formula (I) of the present invention can be converted into a pharmacologically acceptable salt according to a conventional method, if necessary, but can also be separated directly from the reaction mixture as a salt.

When the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is used as a medicine, it can be administered as it is (as it is in the bulk) or an appropriate pharmacology. Tablets, capsules, powders, syrups, granules, fine granules, pills, suspensions, emulsions, percutaneous absorptions, manufactured by mixing with pharmaceutically acceptable excipients, diluents, etc. Oral or parenteral (intravenous, intramuscular, intraperitoneal, transdermal, transrespiratory, intradermal, or subcutaneous) in the form of suppositories, ointments, lotions, inhalants or injections Etc.).
These preparations are produced by well-known methods using additives such as excipients, lubricants, binders, disintegrants, emulsifiers, stabilizers, flavoring agents or diluting seats.

Excipients include, for example, organic excipients or inorganic excipients. Examples of the organic excipient include sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, α-starch or dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; Dextran; or pullulan and the like. Examples of inorganic excipients include light anhydrous silicic acid; or sulfates such as calcium sulfate.

Lubricants include, for example, stearic acid; stearic acid metal salts such as calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as beeswax or gallow; boric acid; adipic acid; sulfate such as sodium sulfate; glycol Fumaric acid; sodium benzoate; D, L-leucine; sodium lauryl sulfate; silicic acids such as anhydrous silicic acid or silicic acid hydrate; or starch derivatives in the above-mentioned excipients.

Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and compounds represented by the above excipients.

Disintegrants include, for example, cellulose derivatives such as low substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium or internally crosslinked carboxymethylcellulose calcium; crosslinked polyvinylpyrrolidone; or chemically modified starch such as carboxymethyl starch or sodium carboxymethyl starch Or a cellulose derivative is mentioned.

The emulsifier is, for example, colloidal clay such as bentonite or bee gum; an anionic surfactant such as sodium lauryl sulfate; a cationic surfactant such as benzalkonium chloride; or polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester Or nonionic surfactants, such as sucrose fatty acid ester, etc. are mentioned.

Stabilizers include, for example, parahydroxybenzoates such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; acetic anhydride Or sorbic acid.

Examples of the flavoring agent include sweeteners such as saccharin sodium or aspartame; acidulants such as citric acid, malic acid or tartaric acid; or flavors such as menthol, lemon extract or orange extract.

Diluents are compounds that are commonly used as diluents, such as lactose, mannitol, glucose, sucrose, calcium sulfate, hydroxypropylcellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, starch , Polyvinylpyrrolidone or a mixture thereof.

The dose of the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof can vary depending on conditions such as the patient's symptoms, age, body weight, etc. The lower limit is 0.001 mg / Kg (preferably 0.01 mg / Kg) and the upper limit is 20 mg / Kg (preferably 10 mg / Kg) per dose. In the case of parenteral administration, the lower limit is 0.0001 mg per dose. / Kg (preferably 0.0005 mg / Kg) and an upper limit of 10 mg / Kg (preferably 5 mg / Kg) can be administered to adults 1 to 6 times per day depending on symptoms.

The present invention will be described in more detail with reference to Examples, Reference Examples, and Test Examples below, but the scope of the present invention is not limited to these. Incidentally, the Rf values in the examples, thin layer chromatography is a value measured using a (Merck, TLC plate silica gel 60F 254 _(trade name)), is described in parentheses represent the developing solvent (volume ratio) .

[Example 1]
[6-({4- [Bis (4-fluorophenyl) methyl] benzyl} (pyridin-3-ylsulfonyl) aminomethyl) pyridin-2-ylamino] acetic acid hydrochloride

1- (a): {tert-butoxycarbonyl [6-({4- [bis (4-fluorophenyl) methyl] benzyl} (pyridin-3-ylsulfonyl) aminomethyl) pyridin-2-yl] amino} acetic acid was obtained in a similar manner to tert- butyl reference example 1-(f) (tert- butoxycarbonyl {6 - [(pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) acetate tert- butyl To a solution of 163 mg (0.341 mmol) in tetrahydrofuran (3.2 ml) was added 101 mg (0.325 mmol) of 4- [bis (4-fluorophenyl) methyl] benzyl alcohol obtained in Reference Example 2- (c), tri-n- Butylphosphine 122 μl (0.488 mmol) and N, N, N ′, N′-tetramethylazodicarboxa De 83.9mg of (0.488 mmol) was added and stirred for 16 hours at room temperature. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 5: 1 → 1: 1 (V / V)), and further reverse phase C18 column chromatography (elution solvent; water: acetonitrile = 7: 3 → 0: 1 (V / V)) to obtain 172 mg of the title compound as a white foam. (Yield 75%)
Mass spectrum (CI, m / z): 771 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.92 (dd, J = 2.4, 0.8 Hz, 1H), 8.69 (dd, J = 4.9, 1.7 Hz, 1H), 7.86 (ddd, J = 8.1, 2.4, 1.7 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.48 (dd, J = 8.2, 7.2 Hz, 1H), 7.29 (ddd, J = 8.1, 4.9, 0.8 Hz, 1H), 7.19- 7.12 (m, 2H), 7.04-6.93 (m, 10H), 6.85 (d, J = 7.2 Hz, 1H), 5.45 (s, 1H), 4.54 (s, 2H), 4.38 (s, 2H), 4.35 (s, 2H), 1.52 (s, 9H), 1.40 (s, 9H).

1- (b): [6-({4- [Bis (4-fluorophenyl) methyl] benzyl} (pyridin-3-ylsulfonyl) aminomethyl) pyridin-2-ylamino] acetic acid hydrochloride Example 1- ( {tert-Butoxycarbonyl [6-({4- [bis (4-fluorophenyl) methyl] benzyl} (pyridin-3-ylsulfonyl) aminomethyl) pyridin-2-yl] amino} acetic acid obtained in a) To a solution of 151 mg (0.195 mmol) of tert-butyl in 2 ml of methylene chloride was added 2.0 ml (8.0 mmol) of 4N hydrogen chloride / 1,4-dioxane solution, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, 2 ml of acetone was added to the resulting residue, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure to give 106 mg of the title compound as a white solid. (79% yield as dihydrochloride)
Mass spectrum (FAB, m / z): 615 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 8.94 (brs, 1H), 8.81 (brs, 1H), 8.17 (brs, 1H), 7.58 (brs, 1H), 7.49 (brs, 1H), 7.22 -7.18 (m, 2H), 7.18-7.12 (m, 4H), 7.09-7.03 (m, 4H), 6.98 (d, J = 8.1 Hz, 2H), 6.66 (brs, 1H), 6.44 (brs, 1H ), 5.60 (s, 1H), 4.53 (s, 2H), 4.40 (brs, 2H).
Rf value: 0.75 (n-butanol: acetic acid: water = 3: 1: 1).

[Example 2]
[6-({4- [1- (Naphthalen-2-yl) ethyl] benzyl} (pyridin-3-ylsulfonyl) aminomethyl) pyridin-2-ylamino] acetic acid

2- (a): {tert-butoxycarbonyl [6-({4- [1- (naphthalen-2-yl) ethyl] benzyl} (pyridin-3-ylsulfonyl) aminomethyl) pyridin-2-yl] amino } (Tert-Butoxycarbonyl {6-[(pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-acetate obtained in the same manner as in tert-butyl acetate Reference Example 1- (f) -To a solution of 192 mg (0.401 mmol) of butyl in 3.8 ml of tetrahydrofuran, 100 mg (0.381 mmol) of 4- [1- (naphthalen-2-yl) ethyl] benzyl alcohol obtained in Reference Example 3- (c), 143 μl (0.572 mmol) of tri-n-butylphosphine and N, N, N ′, N′-tetramethylazodicarboxa De 98.6mg of (0.572 mmol) was added and stirred for 1.5 hours at room temperature. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 4: 1 → 2: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 256 mg of the title compound. Was obtained as a white foam. (Yield 93%)
Mass spectrum (FAB, m / z): 723 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 8.87 (dd, J = 2.4, 0.7 Hz, 1H), 8.74 (dd, J = 4.9, 1.7 Hz, 1H), 8.07 (ddd, J = 8.1, 2.4, 1.7 Hz, 1H), 7.89-7.76 (m, 4H), 7.62-7.41 (m, 5H), 7.32 (dd, J = 8.4, 1.8 Hz, 1H), 7.22-7.15 (m, 2H), 7.11 -7.04 (m, 2H), 6.88 (dd, J = 6.6, 1.5 Hz, 1H), 4.47 (s, 2H), 4.35 (s, 2H), 4.32-4.22 (m, 3H), 1.63 (d, J = 7.3 Hz, 3H), 1.45 (s, 9H), 1.32 (s, 9H).

2- (b): [6-({4- [1- (Naphthalen-2-yl) ethyl] benzyl} (pyridin-3-ylsulfonyl) aminomethyl) pyridin-2-ylamino] acetic acid Example 2- ( {tert-Butoxycarbonyl [6-({4- [1- (naphthalen-2-yl) ethyl] benzyl} (pyridin-3-ylsulfonyl) aminomethyl) pyridin-2-yl] amino obtained in a) } To a solution of tert-butyl acetate 253 mg (0.349 mmol) in methylene chloride 3.5 ml was added 4N hydrogen chloride / 1,4-dioxane solution 3.5 ml (14 mmol), and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, 3.5 ml of acetone and 3.5 ml of water were added to the resulting residue, and the pH was adjusted to 4.5 with 1N aqueous sodium hydroxide solution. Subsequently, acetone was distilled off under reduced pressure, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 189 mg of the title compound as a white solid. (Yield 95%)
Mass spectrum (FAB, m / z): 567 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 12.40 (s, 0.6H), 8.78 (dd, J = 2.4, 0.7 Hz, 1H), 8.67 (dd, J = 4.8, 1.6 Hz, 1H), 7.96 (ddd, J = 8.1, 2.4, 1.5 Hz, 1H), 7.89-7.78 (m, 4H), 7.51-7.43 (m, 2H), 7.41 (ddd, J = 8.1, 4.8, 0.8 Hz, 1H), 7.36 (dd, J = 8.6, 1.8 Hz, 1H), 7.27-7.23 (m, 2H), 7.21-7.17 (m, 2H), 7.21 (dd, J = 8.3, 7.1 Hz, 1H), 6.75-6.68 ( m, 1H), 6.34 (d, J = 8.3 Hz, 1H), 6.29 (d, J = 7.1 Hz, 1H), 4.61 (s, 2H), 4.31 (q, J = 7.2 Hz, 1H), 4.15 ( s, 2H), 3.67 (d, J = 5.5 Hz, 2H), 1.66 (d, J = 7.2 Hz, 3H).
Rf value: 0.73 (n-butanol: acetic acid: water = 3: 1: 1).

[Example 3]
[6-({4- [Phenyl (pyridin-4-yl) methyl] benzyl} (pyridin-3-ylsulfonyl) aminomethyl) pyridin-2-ylamino] acetic acid hydrochloride

3- (a): {tert-butoxycarbonyl [6-({4- [phenyl (pyridin-4-yl) methyl] benzyl} (pyridin-3-ylsulfonyl) aminomethyl) pyridin-2-yl] amino} (Tert-Butoxycarbonyl {6-[(pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) acetic acid tert-butyl ester obtained in the same manner as in tert-butyl acetate reference example 1- (f) To a solution of 384 mg (0.795 mmol) of butyl in 5 ml of tetrahydrofuran was added 230 mg (0.795 mmol) of 4- [phenyl (pyridin-4-yl) methyl] benzyl alcohol obtained in Reference Example 4- (c), tri-n- Butylphosphine 300 μl (1.22 mmol) and N, N, N ′, N′-tetramethylazodicarboxami 205mg of (1.22 mmol) was added and stirred for 3 hours at room temperature. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 3: 1 → 1: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 440 mg of the title compound. Was obtained as a white foam. (Yield 75%)
Mass spectrum (FAB, m / z): 736 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.92 (dd, J = 2.3, 0.7 Hz, 1H), 8.69 (dd, J = 4.9, 1.7 Hz, 1H), 8.52 (dd, J = 4.6, 1.2 Hz) , 2H), 7.86 (ddd, J = 8.1, 2.3, 1.7 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.48 (dd, J = 8.4, 7.4 Hz, 1H), 7.38-6.95 ( m, 12H), 6.85 (d, J = 7.4 Hz, 1H), 5.45 (s, 1H), 4.55 (s, 2H), 4.39 (s, 2H), 4.35 (s, 2H), 1.52 (s, 9H ), 1.40 (s, 9H).

3- (b): [6-({4- [Phenyl (pyridin-4-yl) methyl] benzyl} (pyridin-3-ylsulfonyl) aminomethyl) pyridin-2-ylamino] acetic acid hydrochloride Example 3- {Tert-Butoxycarbonyl [6-({4- [phenyl (pyridin-4-yl) methyl] benzyl} (pyridin-3-ylsulfonyl) aminomethyl) pyridin-2-yl] amino obtained in (a) } To a solution of 401 mg (0.544 mmol) of tert-butyl acetate in 5 ml of methylene chloride was added 2.7 ml (11 mmol) of 4N hydrogen chloride / 1,4-dioxane solution, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, 5 ml of tetrahydrofuran was added to the resulting residue, and the mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 281 mg of the title compound as a white solid. (Yield 75% as trihydrochloride)
Mass spectrum (FAB, m / z): 580 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 8.90 (brs, 1H), 8.87-8.74 (m, 3H), 8.19-8.07 (m, 1H), 7.87-7.02 (m, 13H), 6.58 ( brs, 1H), 6.42 (d, J = 7.6 Hz, 1H), 5.96 (s, 1H), 4.58 (s, 2H), 4.36 (brs, 2H).
Rf value: 0.56 (n-butanol: acetic acid: water = 3: 1: 1).

The compounds used in the examples were synthesized as follows.

[Reference Example 1]
(Tert-Butoxycarbonyl {6-[(pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate

1- (a): [tert-butoxycarbonyl (6-ethoxycarbonylpyridin-2-yl) amino] acetic acid sodium tert-butyl hydride (55% mineral oil dispersion) 15.7 g (0.360 mol) N, To a 362 ml solution of N-dimethylformamide was added a solution of 81.2 g (0.305 mol) of ethyl 6-tert-butoxycarbonylaminopyridine-2-carboxylate (see WO 2006/074884) in 300 ml of N, N-dimethylformamide. In the atmosphere, it was added dropwise over 20 minutes under ice cooling, and the mixture was stirred at room temperature for 1 hour. Next, 54.0 ml (0.366 mol) of tert-butyl bromoacetate was added dropwise over 10 minutes under ice cooling, and the mixture was further stirred at room temperature for 1 hour. After completion of the reaction, an aqueous solution in which 1.77 g (33.0 mmol) of ammonium chloride was dissolved in 300 ml of water was added to the reaction solution, followed by extraction with toluene. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 9: 1 → 4: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. 108 g of the title compound were obtained as a pale yellow oil. (Yield 93%)
Mass spectrum (CI, m / z): 381 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.04 (d, J = 7.8 Hz, 1H), 7.81 (dd, J = 7.6, 1.5 Hz, 1H), 7.76 (dd, J = 7.8, 7.6 Hz, 1H) ), 4.67 (s, 2H), 4.40 (q, J = 7.1 Hz, 2H), 1.52 (s, 9H), 1.45 (s, 9H), 1.40 (t, J = 7.1 Hz, 3H).

1- (b): [tert-Butoxycarbonyl (6-hydroxymethylpyridin-2-yl) amino] [tert-Butoxycarbonyl (6-ethoxycarbonylpyridine) obtained in tert-butyl acetate Reference Example 1- (a) -2-yl) amino] tert-butyl acetate 98.8 g (0.260 mol) in ethanol (195 ml) was added dropwise with calcium chloride (34.6 g, 0.312 mol) in ethanol (195 ml) over 20 minutes under ice cooling. did. After completion of the dropwise addition, 105 ml (0.315 mol) of 3M sodium borohydride / tetraethylene glycol dimethyl ether solution was added dropwise at 35 ° C. or lower over 20 minutes, and further stirred at room temperature for 15 minutes. After completion of the reaction, the reaction solution was added dropwise to an aqueous solution of 17.8 ml of acetic acid in 195 ml of water over 10 minutes under ice-cooling, and stirred at room temperature for 1 hour. Subsequently, 315 ml of water was added and extracted with toluene. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and then saturated aqueous sodium chloride solution and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 4: 1 → 3: 2 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The title compound (81.1 g) was obtained as a pale yellow oil. (Yield 92%)
Mass spectrum (CI, m / z): 339 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.74 (d, J = 8.2 Hz, 1H), 7.63 (dd, J = 8.2, 7.4 Hz, 1H), 6.93-6.98 (m, 1H), 4.68-4.65 (m, 2H), 4.54 (s, 2H), 3.39 (t, J = 5.3 Hz, 1H), 1.54 (s, 9H), 1.46 (s, 9H).

1- (c): [tert- butoxycarbonyl (6-formyl-2-yl) amino] acetate tert- butyl des - methylene chloride 130ml solution Martin reagent 12.9 g (30.4 mmol), Reference Example 1 A solution of 10.0 g (29.6 mmol) of [tert-butoxycarbonyl (6-hydroxymethylpyridin-2-yl) amino] acetate obtained in (b) in 50 ml of methylene chloride was ice-cooled in an argon atmosphere. Added dropwise over 20 minutes. After completion of dropping, the mixture was stirred at room temperature for 2 hours. After completion of the reaction, 305 ml of 0.1% aqueous sodium thiosulfate solution was added to the reaction solution, and extracted with methylene chloride. The organic layer was washed successively with 0.5N aqueous sodium hydroxide solution and then with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to almost quantitatively give 9.61 g of the title compound as a pale yellow oil. I got it.
Mass spectrum (EI, m / z): 336 (M ⁺ ).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 9.82 (s, 1H), 8.11-7.99 (m, 2H), 7.68 (dd, J = 6.6, 1.5 Hz, 1H), 4.58 (s, 2H) , 1.48 (s, 9H), 1.42 (s, 9H).

1- (d): [tert-Butoxycarbonyl (6-hydroxyiminomethylpyridin-2-yl) amino] [tert-butoxycarbonyl (6-formylpyridine) obtained in tert-butyl acetate Reference Example 1- (c) To a solution of -2-yl) amino] tert-butyl acetate (2.88 g, 8.56 mmol) in methanol (29 ml) was added hydroxylammonium chloride (0.650 g, 9.35 mmol) and pyridine (3.5 ml, 43 mmol). Stir for hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, and the mixture was washed successively with 5% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and then saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 3: 2 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound 2. 76 g was obtained as a colorless oil. (Yield 92%)
Mass spectrum (EI, m / z): 351 (M ⁺ ).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.06 (s, 1H), 7.91 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.65 (dd, J = 8.2, 7.6 Hz, 1H ), 7.47 (dd, J = 7.6, 0.7 Hz, 1H), 4.59 (s, 2H), 1.53 (s, 9H), 1.45 (s, 9H).

1- (e): [(6-Aminomethylpyridin-2-yl) tert-butoxycarbonylamino] [tert-butoxycarbonyl (6-hydroxyiminomethyl) obtained in tert-butyl acetate Reference Example 1- (d) Pyridin-2-yl) amino] 0.98 g of 10% palladium-activated carbon (containing 50% water) was added to a solution of 2.75 g (7.83 mmol) of tert-butyl acetate in 49 ml of ethanol at room temperature under 1 atm hydrogen atmosphere. For 1 hour. After completion of the reaction, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give 2.48 g of the title compound as a colorless oil. (Yield 94%)
Mass spectrum (CI, m / z): 338 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.68 (d, J = 8.3 Hz, 1H), 7.58 (dd, J = 8.3, 7.4 Hz, 1H), 6.91 (d, J = 7.4 Hz, 1H), 4.57 (s, 2H), 3.85 (s, 2H), 1.53 (s, 9H), 1.46 (s, 9H).

1- (f): (tert-butoxycarbonyl {6-[(pyridin-3- ylsulfonyl ) aminomethyl] pyridin-2-yl} amino) tert-butyl 3-pyridylsulfonyl chloride 0.640 g (3.60 mmol) ) In methylene chloride (14 ml), [(6-aminomethylpyridin-2-yl) tert-butoxycarbonylamino] acetic acid tert-butyl 1.20 g (3.56 mmol) obtained in Reference Example 1- (e) and 2.24 ml (16.2 mmol) of triethylamine was added and stirred at room temperature for 1 hour. After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and then with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 1: 1 → 1: 2 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The title compound (1.45 g) was obtained as a colorless oil. (Yield 85%)
Mass spectrum (CI, m / z): 479 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 9.06 (d, J = 2.2 Hz, 1H), 8.71 (dd, J = 4.6, 1.5 Hz, 1H), 8.13-8.08 (m, 1H), 7.68 (d , J = 8.2 Hz, 1H), 7.52 (dd, J = 8.2, 7.4 Hz, 1H), 7.38-7.32 (m, 1H), 6.77 (d, J = 7.4 Hz, 1H), 5.80 (t, J = 5.1 Hz, 1H), 4.40 (s, 2H), 4.24 (d, J = 5.1 Hz, 2H), 1.53 (s, 9H), 1.46 (s, 9H).

[Reference Example 2]
4- [bis (4-fluorophenyl) methyl] benzyl alcohol 2- (a): 4- [bis (4-fluorophenyl) (hydroxy) methyl] benzoic acid 4-bromobenzoic acid 2.00 g (9.95 mmol) 17 ml (30 mmol) of a 1.76 M tert-butyllithium / pentane solution was added dropwise to a 40 ml tetrahydrofuran solution at −70 ° C. in an argon atmosphere over 15 minutes, and the mixture was stirred at the same temperature for 1 hour. Next, a solution of 3.26 g (14.9 mmol) of 4,4′-difluorobenzophenone in 10 ml of tetrahydrofuran was added dropwise over 10 minutes. After completion of dropping, the mixture was gradually heated to room temperature and stirred. After completion of the reaction, a saturated ammonium chloride solution was added dropwise to the reaction solution under ice cooling. After adding water, the mixture was separated, and the aqueous layer was adjusted to pH 3.0 and extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 4: 1 → 1: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound 1 .17 g was obtained as a slightly yellow foam. (Yield 35%)
Mass spectrum (CI, m / z): 341 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.10-8.03 (m, 2H), 7.45-7.38 (m, 2H), 7.28-7.18 (m, 4H), 7.07-6.97 (m, 4H).

2- (b): 4- [bis (4-fluorophenyl) methyl] benzoic acid 4- [bis (4-fluorophenyl) (hydroxy) methyl] benzoic acid obtained in Reference Example 2- (a) To a solution of 18 g (3.47 mmol) in 16 ml of methylene chloride, 2.55 ml (15.9 mmol) of triethylsilane and 5 ml of methylene chloride in 0.36 ml (4.8 mmol) of trifluoroacetic acid were added under ice cooling. Stir for hours. Furthermore, 0.51 ml (3.2 mmol) of triethylsilane and 0.12 ml (1.6 mmol) of trifluoroacetic acid were added and stirred for 3.5 hours. After completion of the reaction, water was added to the reaction solution and extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 3: 1 → 0: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound 1 0.08 g was obtained as a colorless oil. (Yield 96%)
Mass spectrum (CI, m / z): 325 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.07-8.00 (m, 2H), 7.22-7.15 (m, 2H), 7.10-6.95 (m, 8H), 5.57 (s, 1H).

2- (c): 4- [bis (4-fluorophenyl) methyl] benzyl alcohol A solution of 381 mg (10.0 mmol) of lithium aluminum hydride in 15 ml of tetrahydrofuran was added at 40 ° C. under argon atmosphere at Reference Example 2- (b A solution of 1.08 g (3.33 mmol) of 4- [bis (4-fluorophenyl) methyl] benzoic acid obtained in 1) in tetrahydrofuran was added dropwise over 20 minutes. The mixture was further stirred at the same temperature for 2 hours. After completion of the reaction, 345 μl of water, 345 μl of a 15% aqueous sodium hydroxide solution and 1.04 ml of water were sequentially added to the reaction solution under ice cooling, followed by stirring at room temperature for 1 hour. The insoluble material was then filtered off and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 1: 0 → 1: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 707 mg of the title compound. Was obtained as a slightly yellow oil. (Yield 68%)
Mass spectrum (EI, m / z): 310 (M ⁺ ).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.40-6.92 (m, 12H), 5.50 (s, 1H), 4.68 (d, J = 5.7, 2H), 1.62 (t, J = 5.7, 1H).

[Reference Example 3]
4- [1- (Naphthalen-2-yl) ethyl] benzyl alcohol 3- (a): 4- [1-hydroxy-1- (naphthalen-2-yl) ethyl] benzoic acid 4,4′-difluorobenzophenone Instead, the reaction and post-treatment were performed in accordance with Reference Example 2- (a) except that 2.54 g (14.9 mmol) of 2′-acetonaphthone was used to obtain 967 mg of the title compound as a pale yellow foam. . (Yield 33%)
Mass spectrum (CI, m / z): 293 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 8.05-8.01 (m, 1H), 7.95-7.76 (m, 5H), 7.62-7.55 (m, 2H), 7.54-7.43 (m, 3H), 6.01 (s, 1H), 1.96 (s, 3H).

3- (b): 4- [1- (Naphthalen-2-yl) ethyl] benzoic acid 4- [1-hydroxy-1- (naphthalen-2-yl) ethyl obtained in Reference Example 3- (a) ] To a solution of 963 mg (3.29 mmol) of benzoic acid in 5.3 ml of methylene chloride was added 5.25 ml (32.9 mmol) of triethylsilane and 0.50 ml (3.9 mmol) of boron trifluoride-ethyl ether complex under ice-cooling. Methylene chloride 2.5 ml solution was added and stirred at room temperature for 30 minutes. Further, a solution of 0.33 ml (2.6 mmol) of boron trifluoride / tetrahydrofuran complex in 2.5 ml of methylene chloride was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the precipitated solid was collected by filtration and dried under reduced pressure to obtain 298 mg of the title compound as a white solid. (Yield 33%)
Mass spectrum (CI, m / z): 277 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 7.90-7.79 (m, 6H), 7.53-7.35 (m, 5H), 4.42 (q, J = 7.3 Hz, 1H), 1.70 (d, J = 7.3 Hz, 3H).

3- (c): 4- [1- (naphthalen-2-yl) ethyl] benzyl alcohol Instead of 4- [bis (4-fluorophenyl) methyl] benzoic acid, obtained in Reference Example 3- (b) Reference Example 2- (c) except that 294 mg (1.06 mmol) of 4- [1- (naphthalen-2-yl) ethyl] benzoic acid was used and 247 mg (6.52 mmol) of lithium aluminum hydride was used. The reaction and post-treatment were carried out according to, and 278 mg of the title compound was quantitatively obtained as a pale yellow oil.
Mass spectrum (EI, m / z): 262 (M ⁺ ).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 7.90-7.77 (m, 4H), 7.52-7.40 (m, 2H), 7.40-7.33 (m, 1H), 7.29-7.19 (m, 4H), 5.07 (t, J = 5.7 Hz, 1H), 4.43 (d, J = 5.7 Hz, 2H), 4.31 (q, J = 7.1 Hz, 1H), 1.66 (d, J = 7.1 Hz, 3H).

[Reference Example 4]
4- [Phenyl (pyridin-4-yl) methyl] benzyl alcohol 4- (a): Instead of 4,4′-difluorobenzophenone 4- [hydroxy (phenyl) (pyridin-4-yl) methyl] benzoate Except for using 2.73 g (14.9 mmol) of 4-benzoylpyridine, the reaction and post-treatment were performed according to Reference Example 2- (a) to obtain 871 mg of the title compound as a slightly yellow foam. (Yield 29%)
Mass spectrum (CI, m / z): 306 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.64-8.57 (m, 2H), 8.10-8.03 (m, 2H), 7.46-7.16 (m, 9H).

4- (b): 4- [ Hydroxy (phenyl) (pyridin-4-yl) methyl] benzoic acid obtained in 4- [phenyl (pyridin-4-yl) methyl] benzoic acid Reference Example 4- (a) To 855 mg (2.80 mmol), 9.0 ml (56 mmol) of triethylsilane and 6.5 ml (84 mmol) of trifluoroacetic acid were added and stirred at 70 ° C. for 9 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. Next, water was added to the residue, and the mixture was adjusted to pH 4.0 with 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; ethyl acetate), and the fraction containing the desired product was concentrated under reduced pressure to obtain 646 mg of the title compound as a pale yellow foam. (Yield 80%)
Mass spectrum (CI, m / z): 290 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.60-8.54 (m, 2H), 8.10-8.02 (m, 2H), 7.38-7.17 (m, 5H), 7.14-7.05 (m, 4H), 5.58 ( s, 1H), 3.13 (brs, 0.4H).

4- (c): Obtained instead of 4- [phenyl (pyridin-4-yl) methyl] benzyl alcohol 4- [bis (4-fluorophenyl) methyl] benzoic acid in Reference Example 4- (b) Reference Example except that 565 mg (1.95 mmol) of 4- [phenyl (pyridin-4-yl) methyl] benzoic acid was used and 1.5 ml (3.0 mmol) of 2M lithium aluminum hydride / tetrahydrofuran solution The reaction and post-treatment were performed according to 2- (c) to obtain 234 mg of the title compound as a pale yellow oil. (Yield 44%)
Mass spectrum (CI, m / z): 276 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.52-8.43 (m, 2H), 7.37-7.21 (m, 5H), 7.14-7.05 (m, 6H), 5.50 (s, 1H), 4.34 (s, 2H).

[Test Example 1]
Measurement of EP2 receptor binding action The measurement of EP2 receptor binding action was carried out according to the method of Abramovitz et al. (Biochimica et Biophysica Acta, 1483, 285 (2000)). A buffer (10 mM MES-KOH (pH 6.0), 10 mM MgCl ₂ , 1 mM EDTA) in which 10 μg of a membrane fraction (ES-562-M, manufactured by Euroscreen) of HEK293 cells expressing human EP2 receptor was suspended. The test compound dissolved in dimethyl sulfoxide and [ ³ H] prostaglandin E ₂ (NET-428, manufactured by PerkinElmer) (final concentration: 10 nM) were added, and incubated at 30 ° C. for 60 minutes. Using a cell harvester (M30R, Brandel), the membrane fraction was collected on glass fiber filter paper (GF / B, Whatman) and buffered (10 mM MES-KOH (pH 6.0), 10 mM MgCl ₂ ). ), And the radioactivity was measured with a liquid scintillation analyzer (2000 CA, manufactured by Packard). EXSAS (version 7.1.6, manufactured by Arm Systex) is the concentration of the test compound (IC ₅₀ value) required to replace 50% of [ ³ H] prostaglandin E ₂ bound to the receptor. The inhibition constant (Ki value) was determined from the following equation.
Ki = IC ₅₀ / (1 + ([ ³ H] prostaglandin E ₂ concentration / Kd))
The dissociation constant (Kd value) was calculated by Scatchard analysis.

In this test, the compound of the present invention showed an excellent EP2 receptor binding action.

[Test Example 2]
Measurement of EP2 agonist activity EP2 agonist activity was measured according to the method of Wilson et al. (European Journal of Pharmacology, 501, 49 (2004)). HEK293 cells (ES-562-C, manufactured by Euroscreen) expressing human EP2 receptor were cultured in MEM medium containing 10% FBS, and 2 × 10 ⁴ cells were seeded in 96-well plates. The next day, the medium was replaced with a serum-free MEM medium containing 3-isobutyl-1-methylxanthine (final concentration 500 μM) and incubated for 30 minutes, and then the test compound dissolved in dimethyl sulfoxide was added and left in a carbon dioxide incubator. After 30 minutes, the amount of intracellular cAMP was measured with a cAMP Biotrak EIA System kit (GE Healthcare Bioscience). The concentration (EC ₅₀ value) of the test compound required to raise cAMP to 50% of the maximum increase amount was calculated using EXSAS by nonlinear regression between the test compound concentration and the cAMP amount.

In this test, the compound of the present invention showed excellent EP2 agonist activity.

[Test Example 3]
Guinea pig excision tracheal relaxation test Trachea was excised from a guinea pig (Hartley male, 7-9 weeks old, supplied by SLC Japan). An annular section containing cartilage was prepared and used as a trachea specimen. A trachea sample was suspended in a Krebs nutrient solution supplemented with 3 μM indomethacin under a load of 1.0 g, and the change in tension was measured via an FD pickup (TB-611T, manufactured by Nihon Kohden Co., Ltd.). The trachea specimen was kept at 37 ° C., and a mixed gas consisting of 95% oxygen gas and 5% carbon dioxide gas was stabilized by aeration, and used for the test. The tracheal specimen was stimulated and contracted with an electric stimulator (SEN-3401, manufactured by Nihon Kohden Co., Ltd.), and after the contraction reaction was stabilized, the test compound (concentration 10 μM) dissolved in dimethyl sulfoxide was added to relax the tracheal specimen. . The inhibition rate for the contraction reaction before the compound addition was calculated.
The test results are shown in Table 1.

In this test, the compound of the present invention exhibited an excellent tracheal contraction inhibitory action.

Formulation Example (Formulation Example 1) (Hard Capsule)
50 mg of the powdered compound of Example 7, 128.7 mg of lactose, 70 mg of cellulose and 1.3 mg of magnesium stearate were mixed, passed through a 60 mesh sieve, and 250 mg of this powder was put into a No. 3 gelatin capsule. Into capsules.

(Formulation Example 2) (Tablet)
50 mg of the compound of Example 7, 124 mg of lactose, 25 mg of cellulose and 1 mg of magnesium stearate are mixed, and tableted by a tableting machine to make one tablet of 200 mg. This tablet can be sugar-coated if necessary.

The benzyl compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof exhibits an excellent bronchodilator action based on a strong EP2 agonist action, and further, tissue transferability, bioavailability; BA), the rapid onset of drug efficacy, sustained drug efficacy, solubility, physical stability, drug interaction, toxicity, etc. Useful as a medicament for the treatment and / or prevention of respiratory diseases (eg, asthma, COPD, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome (ARDS), cystic fibrosis, pulmonary hypertension, etc.) Furthermore, for the treatment and / or prevention of diseases (for example, bone diseases, gastric ulcers, hypertension, glaucoma, etc.) for which EP2 agonist action seems to be useful. Also useful as a pharmaceutical.

Claims (21)

1. Formula (I):
   

   

   [Where:
   R ¹ represents a hydrogen atom or a C ₁ -C ₆ alkyl group which may be substituted with a halogeno group;
   R ² and R ³ each independently represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
   A represents an aryl group, heteroaryl group or heterocyclic group which may be substituted with the same or different 1 to 3 groups selected from the substituent group α,
   Y is a C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group which may be substituted with the same or different 1 to 3 groups selected from the substituent group α C ₃ -C ₈ cycloalkyl group, C ₅ -C ₈ cycloalkenyl group, aryl group, heteroaryl group or heterocyclic group,
   Z is a C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group which may be substituted with the same or different 1 to 3 groups selected from the substituent group α C ₃ -C ₈ cycloalkyl group, C ₅ -C ₈ cycloalkenyl group, aryl group, heteroaryl group or heterocyclic group,
   Substituents included in the substituent group α are hydroxy group, oxo group, halogeno group, cyano group, nitro group, formyl group, C ₁ -C ₆ alkyl group, C ₇ -C ₁₂ aralkyl group, C ₂ -C _6. Alkenyl group, C ₂ -C ₆ alkynyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl group, C ₇ -C ₁₂ aralkyloxy group, C ₃ -C ₈ cycloalkyl Group, C ₃ -C ₈ cycloalkyl-C ₁ -C ₆ alkyl group, C ₅ -C ₈ cycloalkenyl group, C ₂ -C ₆ alkanoyl group, C ₃ -C ₈ cycloalkyl-C ₂ -C ₆ alkanoyl group C ₂ -C ₆ alkanoyl-C ₁ -C ₆ alkyl group, arylcarbonyl group, heteroarylcarbonyl group, carboxy group, C ₁ -C ₆ alkoxycarbonyl group, C ₁ -C ₆ alkylthio group, arylthio group, heteroarylthio group, C ₁ -C ₆ alkylsulfinyl group, arylsulfinyl group, heteroarylsulfinyl group, C ₁ -C ₆ alkylsulfonyl group, arylsulfonyl group, heteroarylsulfonyl group, aminosulfonyl Group, C ₁ -C ₆ alkylaminosulfonyl group, di- (C ₁ -C ₆ alkyl) aminosulfonyl group (two alkyl groups may form a 4- to 8-membered ring together), aryl Aminosulfonyl group, heteroarylaminosulfonyl group, amino group, C ₁ -C ₆ alkylamino group, di- (C ₁ -C ₆ alkyl) amino group (two alkyl groups together to form a 4- to 8-membered ring A tri- (C ₁ -C ₆ alkyl) ammonium group (of 3 alkyl groups) Two of them may form a 4- to 8-membered ring together), C ₂ -C ₆ alkenylamino group, C ₂ -C ₆ alkynylamino group, C ₃ -C ₈ cycloalkylamino group, aryl Amino group, heteroarylamino group, C ₁ -C ₆ alkylsulfonylamino group, arylsulfonylamino group, heteroarylsulfonylamino group, aminosulfonylamino group, C ₁ -C ₆ alkylaminosulfonylamino group, di- (C ₁ -C ₆ alkyl) aminosulfonylamino group (two alkyl groups may form a 4- to 8-membered ring together), arylaminosulfonylamino group, heteroarylaminosulfonylamino group, C ₂ -C ₆ alkanoylamino group, an arylcarbonylamino group, heteroarylcarbonyl group, Aminoka Boniruamino group, C ₁ -C ₆ alkylamino carbonyl amino group, di - (C ₁ -C ₆ alkyl) aminocarbonylamino group (two alkyl groups may form a 4 to 8-membered ring together ), Arylaminocarbonylamino group, heteroarylaminocarbonylamino group, C ₁ -C ₆ alkoxycarbonylamino group, aryloxycarbonylamino group, heteroaryloxycarbonylamino group, carbamoyl group, C ₁ -C ₆ alkylcarbamoyl group, Di- (C ₁ -C ₆ alkyl) carbamoyl group (two alkyl groups may form a 4- to 8-membered ring together), arylcarbamoyl group, heteroarylcarbamoyl group, aryl group, heteroaryl Group, aryloxy group, heteroaryloxy group and heterocyclic group Ri,
   When the substituent of the substituent group α includes an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, an aryl group, a heteroaryl group, or a heterocyclic group, further selected from the substituent group α The same or different 1 to 3 substituents may be substituted. ]
   Or a pharmacologically acceptable salt thereof.
2. The benzyl compound or a pharmacologically acceptable salt thereof according to claim ₁ , wherein R ² and R ³ each independently represent a hydrogen atom or a C ₁ -C ₄ alkyl group.
3. A is a hydroxy group, halogeno group, cyano group, C ₁ -C ₄ alkyl group, halogeno C ₁ -C ₄ alkyl group, C ₇ -C ₁₂ aralkyl group, C ₃ -C ₅ alkenyl group, C ₃ -C ₅ Alkynyl group, C ₁ -C ₄ alkoxy group, C ₇ -C ₁₂ aralkyloxy group, C ₃ -C ₆ cycloalkyl group, C ₅ -C ₆ cycloalkenyl group, arylcarbonyl group, C ₁ -C ₄ alkoxycarbonyl group C ₁ -C ₄ alkylthio group, C ₁ -C ₄ alkylsulfinyl group, C ₁ -C ₄ alkylsulfonyl group, C ₁ -C ₄ alkylamino group, di- (C ₁ -C ₄ alkyl) amino group, aryl amino _group, C 2 -C ₄ alkanoylamino _group, C 1 -C ₄ alkoxycarbonylamino group, an aryl group, heteroaryl group, aryloxy Moto及The benzyl compound according to claim 1 or 2, or a compound thereof, which represents an aryl group, heteroaryl group or heterocyclic group optionally substituted with a group selected from the group consisting of fully saturated heterocyclic groups Pharmacologically acceptable salt.
4. Y represents a halogeno group, a C ₁ -C ₄ alkoxy group, a C ₃ -C ₆ cycloalkyl group, a C ₁ -C ₄ alkoxycarbonyl group, a C ₁ -C ₄ alkylthio group, a C ₁ -C ₄ alkylsulfinyl group, C _1- C ₄ alkylsulfonyl group, C ₁ -C ₄ alkylamino group, di- (C ₁ -C ₄ alkyl) amino group, C ₂ -C ₄ alkanoylamino group, C ₁ -C ₄ alkoxycarbonylamino group, aryl A C ₁ -C ₄ alkyl group, a C ₃ -C ₅ alkenyl group, a C ₃ -C ₅ alkynyl group optionally substituted by a group selected from the group consisting of a group, a heteroaryl group and a fully saturated heterocyclic group C ₃ -C ₆ cycloalkyl group, C ₅ -C ₆ cycloalkenyl group, or halogeno group, cyano group, nitro group, formyl group, C ₁ -C ₄ alkyl group, C ₇ -C ₁₂ aralkyl _group, C 7 _{-C 12} aralkyloxy _group, C 3 -C ₆ cycloalkyl _group, C 1 -C ₄ alkoxycarbonyl _group, C 1 -C ₄ alkylthio _group, C 1 -C ₄ alkylamino group, Di- (C ₁ -C ₄ alkyl) amino group, arylamino group, C ₂ -C ₄ alkanoylamino group, C ₁ -C ₄ alkoxycarbonylamino group, aryl group, heteroaryl group, aryloxy group and fully saturated 4. The compound according to claim 1, wherein the compound is a phenyl group or heteroaryl group which may be substituted with a group selected from the group consisting of heterocyclic groups, or a fully saturated heterocyclic group. 5. A benzyl compound or a pharmacologically acceptable salt thereof.
5. Z is a halogeno group, a C ₇ -C ₁₂ aralkyl group, a C ₁ -C ₄ alkoxy group, a C ₇ -C ₁₂ aralkyloxy group, a C ₃ -C ₆ cycloalkyl group, a C ₅ -C ₆ cycloalkenyl group, an aryl From the group consisting of a carbonyl group, a C ₁ -C ₄ alkylamino group, a di- (C ₁ -C ₄ alkyl) amino group, an arylamino group, an aryl group, a heteroaryl group, an aryloxy group, and a fully saturated heterocyclic group C ₁ -C ₄ alkyl group, C ₃ -C ₆ cycloalkyl group, C ₅ -C ₆ cycloalkenyl group, C ₃ -C ₅ alkenyl group, C ₃ -C ₅ optionally substituted with a selected group alkynyl group, fully saturated heterocyclic group, or a halogeno group, a cyano group, a nitro group, formyl _group, C 1 -C ₄ alkyl group, halogeno _C 1 -C ₄ alkyl groups, _{C 7} - ₁₂ aralkyl _group, C 7 _{-C 12} aralkyloxy _group, C 3 -C ₆ cycloalkyl _group, C 1 -C ₄ alkoxy _groups, C 1 -C ₄ alkoxycarbonyl _group, C 1 -C ₄ alkylthio group, _{C 1} - C ₄ alkylamino group, di- (C ₁ -C ₄ alkyl) amino group, arylamino group, C ₂ -C ₄ alkanoylamino group, C ₁ -C ₄ alkoxycarbonylamino group, aryl group, heteroaryl group, aryl The benzyl compound according to any one of claims 1 to 4, which represents a compound which is a phenyl group or a heteroaryl group optionally substituted with a group selected from the group consisting of an oxy group and a fully saturated heterocyclic group Its pharmacologically acceptable salt.
6. A is a fluoro group, chloro group, C ₁ -C ₄ alkyl group, trifluoromethyl group, benzyl group, 1-propenyl group, 1-butenyl group, 2-propynyl group, 2-butynyl group, methoxy group, benzyloxy Selected from the group consisting of a group, cyclopropyl group, cyclopentenyl group, benzoyl group, methoxycarbonyl group, methylthio group, methylamino group, dimethylamino group, anilino group, acetylamino group, methoxycarbonylamino group, pyrrolidinyl group and piperidinyl group A benzyl compound according to any one of claims 1 to 5, which represents a phenyl group, a naphthyl group, a thienyl group, a pyrazolyl group, a thiazolyl group, a pyridyl group, a benzofuryl group or a benzothienyl group, which may be substituted with a group represented by Or a pharmacologically acceptable salt thereof.
7. A is a phenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 4-methylphenyl group, 4-trifluoromethylphenyl group, 4- (1-propenyl) phenyl group, 4-methoxy Phenyl group, 4-cyclopropylphenyl group, 4-methoxycarbonylphenyl group, 4-methylthiophenyl group, 4-dimethylaminophenyl group, 4- (pyrrolidin-1-yl) phenyl group, naphthalen-1-yl group, naphthalene The benzyl according to claim 6, which represents a -2-yl group, a thiophen-2-yl group, a thiazol-2-yl group, a thiazol-4-yl group, a pyridin-3-yl group or a pyridin-4-yl group Compound or pharmacologically acceptable salt thereof.
8. The benzyl compound or pharmacologically acceptable thereof according to claim 6, wherein A represents a phenyl group, a 4-fluorophenyl group, a naphthalen-2-yl group, a thiophen-2-yl group or a pyridin-4-yl group. salt.
9. Y is a C ₁ -C ₄ alkyl group, trifluoromethyl group, methoxymethyl group, cyclopropylmethyl group, 2-methylaminoethyl group, 2-dimethylaminoethyl group, 2- (pyrrolidin-1-yl) ethyl group 1-propenyl group, 1-butenyl group, 2-propynyl group, 2-butynyl group, cyclopropyl group, cyclopentenyl group, [fluoro group, chloro group, cyano group, methyl group, ethyl group, benzyl group, benzyloxy Group selected from the group consisting of a group, cyclopropyl group, methoxycarbonyl group, methylthio group, methylamino group, dimethylamino group, anilino group, acetylamino group, methoxycarbonylamino group, phenyl group, pyrrolidinyl group and piperidinyl group] Phenyl group, thienyl group, pyrazolyl group, thiazolyl group optionally substituted by Pyridyl, benzofuryl group, a benzothienyl group, a pyrrolidinyl group or a piperazinyl group, a benzyl compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 5.
10. Y is a methyl group, ethyl group, propyl group, trifluoromethyl group, phenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 4-methylphenyl group, 4-cyclopropylphenyl group, Represents thiophen-2-yl group, thiazol-2-yl group, thiazol-4-yl group, pyridin-3-yl group, pyridin-4-yl group, pyrrolidin-1-yl group or piperidin-1-yl group The benzyl compound according to claim 9 or a pharmacologically acceptable salt thereof.
11. The benzyl compound or a pharmaceutically acceptable salt thereof according to claim 9, wherein Y represents a methyl group, an ethyl group, a phenyl group, a 4-fluorophenyl group, a thiophen-2-yl group or a pyridin-4-yl group. .
12. Z is [fluoro group, chloro group, benzyl group, methoxy group, benzyloxy group, cyclopropyl group, cyclopentenyl group, benzoyl group, methylamino group, dimethylamino group, anilino group, phenyl group, thienyl group, pyridyl group , A phenoxy group, a pyrrolidinyl group, and a piperidinyl group], which may be substituted with a group selected from the group consisting of a C ₁ -C ₄ alkyl group, a 2-propynyl group, a 2-butynyl group, a cyclopropyl group, a cyclobutyl group, Cyclopentenyl, [fluoro, chloro, cyano, nitro, methyl, ethyl, trifluoromethyl, benzyl, benzyloxy, cyclopropyl, methoxy, methoxycarbonyl, methylthio, methyl Amino group, dimethylamino group, anilino group, acetylamino group, methoxy A carbonylamino group, a phenyl group, a phenoxy group, an azetidinyl group, a pyrrolidinyl group and a piperidinyl group], which represents a phenyl group, a thienyl group, a pyrazolyl group, a thiazolyl group or a pyridyl group, which may be substituted with a group selected from the group consisting of The benzyl compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 5.
13. Z is a methyl group, ethyl group, trifluoromethyl group, 2-phenylethyl group, cyclopropyl group, phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 4-cyanophenyl group, 4-cyclopropylphenyl group, 4-methoxyphenyl group, thiophen-2-yl group, thiophen-3-yl group, pyridin-2-yl group, The benzyl compound or a pharmacologically acceptable salt thereof according to claim 12, which represents a pyridin-3-yl group or a pyridin-4-yl group.
14. The benzyl compound or pharmacologically acceptable salt thereof according to claim 12, wherein Z represents a phenyl group, a 4-fluorophenyl group, a pyridin-2-yl group or a pyridin-3-yl group.
15. R ¹ is a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group or a tert-butyl group;
    R ² and R ³ are each independently a hydrogen atom or a methyl group,
    A is a hydroxy group, halogeno group, cyano group, C ₁ -C ₄ alkyl group, halogeno C ₁ -C ₄ alkyl group, C ₇ -C ₁₂ aralkyl group, C ₃ -C ₅ alkenyl group, C ₃ -C ₅ Alkynyl group, C ₁ -C ₄ alkoxy group, C ₇ -C ₁₂ aralkyloxy group, C ₃ -C ₆ cycloalkyl group, C ₅ -C ₆ cycloalkenyl group, arylcarbonyl group, C ₁ -C ₄ alkoxycarbonyl group C ₁ -C ₄ alkylthio group, C ₁ -C ₄ alkylsulfinyl group, C ₁ -C ₄ alkylsulfonyl group, C ₁ -C ₄ alkylamino group, di- (C ₁ -C ₄ alkyl) amino group, aryl amino _group, C 2 -C ₄ alkanoylamino _group, C 1 -C ₄ alkoxycarbonylamino group, an aryl group, heteroaryl group, aryloxy Moto及Fully saturated group selected from the group consisting of heterocyclic group may be substituted, an aryl group, a heteroaryl group or a heterocyclic group,
    Y represents a halogeno group, a C ₁ -C ₄ alkoxy group, a C ₃ -C ₆ cycloalkyl group, a C ₁ -C ₄ alkoxycarbonyl group, a C ₁ -C ₄ alkylthio group, a C ₁ -C ₄ alkylsulfinyl group, C _1- C ₄ alkylsulfonyl group, C ₁ -C ₄ alkylamino group, di- (C ₁ -C ₄ alkyl) amino group, C ₂ -C ₄ alkanoylamino group, C ₁ -C ₄ alkoxycarbonylamino group, aryl A C ₁ -C ₄ alkyl group, a C ₃ -C ₅ alkenyl group, a C ₃ -C ₅ alkynyl group optionally substituted by a group selected from the group consisting of a group, a heteroaryl group and a fully saturated heterocyclic group C ₃ -C ₆ cycloalkyl group, C ₅ -C ₆ cycloalkenyl group, or halogeno group, cyano group, nitro group, formyl group, C ₁ -C ₄ alkyl group, C ₇ -C ₁₂ aralkyl _group, C 7 _{-C 12} aralkyloxy _group, C 3 -C ₆ cycloalkyl _group, C 1 -C ₄ alkoxycarbonyl _group, C 1 -C ₄ alkylthio _group, C 1 -C ₄ alkylamino group, Di- (C ₁ -C ₄ alkyl) amino group, arylamino group, C ₂ -C ₄ alkanoylamino group, C ₁ -C ₄ alkoxycarbonylamino group, aryl group, heteroaryl group, aryloxy group and fully saturated A phenyl group or heteroaryl group optionally substituted with a group selected from the group consisting of heterocyclic groups, or a fully saturated heterocyclic group,
    Z is a halogeno group, a C ₇ -C ₁₂ aralkyl group, a C ₁ -C ₄ alkoxy group, a C ₇ -C ₁₂ aralkyloxy group, a C ₃ -C ₆ cycloalkyl group, a C ₅ -C ₆ cycloalkenyl group, an aryl From the group consisting of a carbonyl group, a C ₁ -C ₄ alkylamino group, a di- (C ₁ -C ₄ alkyl) amino group, an arylamino group, an aryl group, a heteroaryl group, an aryloxy group, and a fully saturated heterocyclic group C ₁ -C ₄ alkyl group, C ₃ -C ₆ cycloalkyl group, C ₅ -C ₆ cycloalkenyl group, C ₃ -C ₅ alkenyl group, C ₃ -C ₅ optionally substituted with a selected group alkynyl group, fully saturated heterocyclic group, or a halogeno group, a cyano group, a nitro group, formyl _group, C 1 -C ₄ alkyl group, halogeno _C 1 -C ₄ alkyl groups, _{C 7} - ₁₂ aralkyl _group, C 7 _{-C 12} aralkyloxy _group, C 3 -C ₆ cycloalkyl _group, C 1 -C ₄ alkoxy _groups, C 1 -C ₄ alkoxycarbonyl _group, C 1 -C ₄ alkylthio group, _{C 1} - C ₄ alkylamino group, di- (C ₁ -C ₄ alkyl) amino group, arylamino group, C ₂ -C ₄ alkanoylamino group, C ₁ -C ₄ alkoxycarbonylamino group, aryl group, heteroaryl group, aryl The benzyl compound or pharmacologically acceptable salt thereof according to claim 1, which represents a phenyl group or a heteroaryl group which may be substituted with a group selected from the group consisting of an oxy group and a fully saturated heterocyclic group.
16. R ¹ is a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group or a tert-butyl group;
    R ² and R ³ are each independently a hydrogen atom or a methyl group,
    A is a fluoro group, chloro group, C ₁ -C ₄ alkyl group, trifluoromethyl group, benzyl group, 1-propenyl group, 1-butenyl group, 2-propynyl group, 2-butynyl group, methoxy group, benzyloxy Selected from the group consisting of a group, a cyclopropyl group, a cyclopentenyl group, a benzoyl group, a methoxycarbonyl group, a methylthio group, a methylamino group, a dimethylamino group, an anilino group, an acetylamino group, a methoxycarbonylamino group, a pyrrolidinyl group, and a piperidinyl group A phenyl group, a naphthyl group, a thienyl group, a pyrazolyl group, a thiazolyl group, a pyridyl group, a benzofuryl group, or a benzothienyl group, which may be substituted with
    Y is a C ₁ -C ₄ alkyl group, trifluoromethyl group, methoxymethyl group, cyclopropylmethyl group, 2-methylaminoethyl group, 2-dimethylaminoethyl group, 2- (pyrrolidin-1-yl) ethyl group 1-propenyl group, 1-butenyl group, 2-propynyl group, 2-butynyl group, cyclopropyl group, cyclopentenyl group, [fluoro group, chloro group, cyano group, methyl group, ethyl group, benzyl group, benzyloxy Group selected from the group consisting of a group, cyclopropyl group, methoxycarbonyl group, methylthio group, methylamino group, dimethylamino group, anilino group, acetylamino group, methoxycarbonylamino group, phenyl group, pyrrolidinyl group and piperidinyl group] Phenyl group, thienyl group, pyrazolyl group, thiazolyl group optionally substituted by Pyridyl, benzofuryl group, benzothienyl group, pyrrolidinyl group or piperazinyl group,
    Z is [fluoro group, chloro group, benzyl group, methoxy group, benzyloxy group, cyclopropyl group, cyclopentenyl group, benzoyl group, methylamino group, dimethylamino group, anilino group, phenyl group, thienyl group, pyridyl group , A phenoxy group, a pyrrolidinyl group, and a piperidinyl group], which may be substituted with a group selected from the group consisting of a C ₁ -C ₄ alkyl group, a 2-propynyl group, a 2-butynyl group, a cyclopropyl group, a cyclobutyl group, Cyclopentenyl, [fluoro, chloro, cyano, nitro, methyl, ethyl, trifluoromethyl, benzyl, benzyloxy, cyclopropyl, methoxy, methoxycarbonyl, methylthio, methyl Amino group, dimethylamino group, anilino group, acetylamino group, methoxy A carbonylamino group, a phenyl group, a phenoxy group, an azetidinyl group, a pyrrolidinyl group and a piperidinyl group; The benzyl compound according to claim 1 or a pharmacologically acceptable salt thereof.
17. R ¹ is a hydrogen atom, a methyl group, an ethyl group or an isopropyl group;
    R ² and R ³ are both hydrogen atoms,
    A is a phenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 4-methylphenyl group, 4-trifluoromethylphenyl group, 4- (1-propenyl) phenyl group, 4-methoxy Phenyl group, 4-cyclopropylphenyl group, 4-methoxycarbonylphenyl group, 4-methylthiophenyl group, 4-dimethylaminophenyl group, 4- (pyrrolidin-1-yl) phenyl group, naphthalen-1-yl group, naphthalene A -2-yl group, a thiophen-2-yl group, a thiazol-2-yl group, a thiazol-4-yl group, a pyridin-3-yl group or a pyridin-4-yl group;
    Y is a methyl group, ethyl group, propyl group, trifluoromethyl group, phenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 4-methylphenyl group, 4-cyclopropylphenyl group, A thiophen-2-yl group, a thiazol-2-yl group, a thiazol-4-yl group, a pyridin-3-yl group, a pyridin-4-yl group, a pyrrolidin-1-yl group, or a piperidin-1-yl group ,
    Z is a methyl group, ethyl group, trifluoromethyl group, 2-phenylethyl group, cyclopropyl group, phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 4-cyanophenyl group, 4-cyclopropylphenyl group, 4-methoxyphenyl group, thiophen-2-yl group, thiophen-3-yl group, pyridin-2-yl group, The benzyl compound or pharmacologically acceptable salt thereof according to claim 1, which represents a pyridin-3-yl group or a pyridin-4-yl group.
18. R ¹ is a hydrogen atom, a methyl group, an ethyl group or an isopropyl group;
    R ² and R ³ are both hydrogen atoms,
    A is a phenyl group, a 4-fluorophenyl group, a naphthalen-2-yl group, a thiophen-2-yl group or a pyridin-4-yl group;
    Y is a methyl group, an ethyl group, a phenyl group, a 4-fluorophenyl group, a thiophen-2-yl group or a pyridin-4-yl group;
    The benzyl compound or a pharmacologically acceptable salt thereof according to claim 1, wherein Z represents a phenyl group, a 4-fluorophenyl group, a pyridin-2-yl group or a pyridin-3-yl group.
19. Benzyl compounds
    [6-({4- [bis (4-fluorophenyl) methyl] benzyl} (pyridin-3-ylsulfonyl) aminomethyl) pyridin-2-ylamino] acetic acid,
    [6-({4- [1- (Naphthalen-2-yl) ethyl] benzyl} (pyridin-3-ylsulfonyl) aminomethyl) pyridin-2-ylamino] acetic acid, or [6-({4- [phenyl The benzyl compound or a pharmacologically acceptable salt thereof according to claim 1, which is (pyridin-4-yl) methyl] benzyl} (pyridin-3-ylsulfonyl) aminomethyl) pyridin-2-ylamino] acetic acid.
20. A pharmaceutical composition comprising the benzyl compound according to any one of claims 1 to 19 or a pharmacologically acceptable salt thereof as an active ingredient.
21. 21. A pharmaceutical composition according to claim 20 for the prevention or treatment of respiratory diseases.