WO2011030865A1 - Substituted zenzyl compounds - Google Patents

Abstract

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

Description

Substituted benzyl compounds

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

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 substituted benzyl compound having a specific structure is a powerful compound. It has excellent bronchodilating action based on EP2 agonistic action, and further, tissue transferability, bioavailability (BA), rapid onset of drug effect, sustained drug effect, solubility, physical stability, drug interaction Since it has excellent properties in terms of action and toxicity, it has been found that it is particularly useful as a therapeutic and / or preventive agent (preferably a therapeutic agent) for respiratory diseases such as asthma and COPD. Was completed.
The present invention has a novel bronchodilator action based on a strong EP2 agonistic 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. A substituted benzyl compound or a pharmacologically acceptable salt thereof is provided.

In the present invention, the “substituted benzyl compound” 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,
Y is a C ₁ -C ₁₂ alkyl group substituted with the same or different 1 to 3 groups selected from the substituent group α (provided that a halogeno group, a C ₁ -C ₆ alkyl group and a C ₂ -C ₆ alkenyl groups are excluded, and aryl groups, heteroaryl groups and heterocyclic groups are excluded as substituents at the 1-position), C ₂ -C ₆ alkenyl groups (provided that C ₁ -C ₆ alkyl groups are substituted) Groups, and aryl groups, heteroaryl groups and heterocyclic groups are excluded as substituents at the 1-position) or C ₁ -C ₆ alkoxy groups (however, halogeno groups are excluded as substituents), or substituents A C ₂ -C ₆ alkynyl group optionally substituted by the same or different 1 to 3 groups selected from group α,
n represents an integer of 1 to 3,
when n is 2 or 3, Y may be the same as or different from each other;
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 substituted 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 (bioavailability). BA), rapid onset of drug efficacy, sustained drug efficacy, solubility, physical stability, drug interaction, toxicity, etc., together with the present invention, respiratory disease (for example, A novel compound having excellent properties as a therapeutic and / or prophylactic agent for asthma, COPD, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome (ARDS), cystic fibrosis, pulmonary hypertension, etc.) Could be provided. 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.

In the compound represented by the general formula (I), the “C ₁ -C ₆ alkyl group” represented by each substituent and the “C ₁ -C ₆ alkyl group” moiety in each substituent have the same significance. Having a “C ₁ -C ₆ alkyl group”, such a “C ₁ -C ₆ alkyl group” includes, 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- Methylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethyl-1-methyl And linear or branched C ₁ -C ₆ alkyl groups such as propyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group or 1,2,2-trimethylpropyl group. Preferably a C ₁ -C ₄ alkyl group, 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.

Examples of the “C ₁ -C ₁₂ alkyl group” represented by Y include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, and an isopentyl group. Neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, 1-ethylpropyl 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, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group, 1,3-dimethylbutyl Group, 2,3-dimethylbutyl group, heptyl group, 1-methylhexyl group, 2-methylhexyl group, 3-methylhexyl group 4-methylhexyl group, 5-methylhexyl group, 1-ethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, 1,2-dimethylpentyl group, 1,3-dimethylpentyl group, 1,4- Dimethylpentyl group, 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 3,4-dimethylpentyl group, 1,1-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group Group, 4,4-dimethylpentyl group, 1-methyl-2-ethylbutyl group, octyl group, 1-methylheptyl group, 2-methylheptyl group, 3-methylheptyl group, 4-methylheptyl group, 5-methylheptyl group Group, 6-methylheptyl group, 1-ethylhexyl group, 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 1,1-di- Tilhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, 5,5-dimethylhexyl group, 1-propylpentyl group, 2-propylpentyl group, nonyl group, 1-methyloctyl group, 2-methyloctyl group, 3-methyloctyl group, 4-methyloctyl group, 5-methyloctyl group, 6-methyloctyl group, 7-methyloctyl group, 1-ethylheptyl group, 2- Ethyl heptyl group, 3-ethylheptyl group, 4-ethylheptyl group, 5-ethylheptyl group, 1,1-dimethylheptyl group, 2,2-dimethylheptyl group, 3,3-dimethylheptyl group, 4,4- Dimethylheptyl group, 5,5-dimethylheptyl group, 1-propylhexyl group, 2-propylhexyl group, 3-propylhexyl group, 2, 2,4,4-tetramethylpentyl group, decyl group, 1-methylnonyl group, 2-methylnonyl group, 3-methylnonyl group, 4-methylnonyl group, 5-methylnonyl group, 6-methylnonyl group, 7-methylnonyl group, 8 -Methylnonyl group, 1,1-dimethyloctyl group, 2,2-dimethyloctyl group, 3,3-dimethyloctyl group, 4,4-dimethyloctyl group, 5,5-dimethyloctyl group, 6,6-dimethyloctyl Group, 1-ethyloctyl group, 2-ethyloctyl group, 3-ethyloctyl group, 4-ethyloctyl group, 5-ethyloctyl group, 6-ethyloctyl group, 1-propylheptyl group, 2-propylheptyl group, 3-propylheptyl group, 4-propylheptyl group, undecyl group, 1-methyldecyl group, 2-methyldecyl group, 3-methyl Sil group, 4-methyldecyl group, 5-methyldecyl group, 6-methyldecyl group, 7-methyldecyl group, 8-methyldecyl group, 9-methyldecyl group, 1,1-dimethylnonyl group, 2,2-dimethylnonyl group, 3 , 3-dimethylnonyl group, 4,4-dimethylnonyl group, 5,5-dimethylnonyl group, 6,6-dimethylnonyl group, 7,7-dimethylnonyl group, 8,8-dimethylnonyl group, 1-ethylnonyl Group, 2-ethylnonyl group, 3-ethylnonyl group, 4-ethylnonyl group, 5-ethylnonyl group, 6-ethylnonyl group, 7-ethylnonyl group, 1-propyloctyl group, 2-propyloctyl group, 3-propyloctyl group, 4-propyloctyl group, 5-propyloctyl group, dodecyl group, 1-methylundecyl group, 2-methylundecyl group, 3-methyl Undecyl group, 4-methylundecyl group, 5-methylundecyl group, 6-methylundecyl group, 7-methylundecyl group, 8-methylundecyl group, 9-methylundecyl group, 10-methylundecyl group Group, 1,1-dimethyldecyl group, 2,2-dimethyldecyl group, 3,3-dimethyldecyl group, 4,4-dimethyldecyl group, 5,5-dimethyldecyl group, 6,6-dimethyldecyl group, 7,7-dimethyldecyl group, 8,8-dimethyldecyl group, 9,9-dimethyldecyl group, 1-ethyldecyl group, 2-ethyldecyl group, 3-ethyldecyl group, 4-ethyldecyl group, 5-ethyldecyl group, 6 -Ethyldecyl group, 7-ethyldecyl group, 8-ethyldecyl group, 1-propylnonyl group, 2-propylnonyl group, 3-propylnonyl group, 4-propylnonyl group, And a linear or branched C ₁ -C ₁₂ alkyl group such as a 5-propylnonyl group or a 6-propylnonyl group, preferably a C ₁ -C ₉ alkyl group, more preferably a methyl group, An ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a hexyl group, or a 2,2,4,4-tetramethylpentyl group, particularly preferably A methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group or a 2,2,4,4-tetramethylpentyl 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 cyclohexyl group, and particularly preferably a cyclopropyl group or a cyclohexyl 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.

The “C ₁ -C ₆ alkoxy group” represented by each substituent and the “C ₁ -C ₆ alkoxy group” part in each substituent each mean a “C ₁ -C ₆ alkoxy group” having the same meaning. Examples of such “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- Tylbutoxy group, 2-ethylbutoxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 1,3-dimethylbutoxy group, 2,2-dimethylbutoxy group, 2,3-dimethylbutoxy group, 3 Linear chain such as 1,3-dimethylbutoxy group, 1-ethyl-1-methylpropoxy group, 1-ethyl-2-methylpropoxy group, 1,1,2-trimethylpropoxy group, 1,2,2-trimethylpropoxy group Or a branched C ₁ -C ₆ alkoxy group, preferably a 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 or hexyloxy group, Are preferably a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a pentyloxy group or a hexyloxy group, and particularly preferably a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentyloxy group or Hexyloxy 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, pivaloyl group, Hexanoyl group, 2-methylpentanoyl group, 3-methylpentanoyl group, 4-methylpentanoyl group, 2-ethylbutanoyl group, 2,2-dimethylbutanoyl group, 2,3-dimethylbutanoyl group or 3 , 3-dimethyl-pig linear or branched _C 2 -C ₆ alkanoyl group such as alkanoyl group, and _preferably, C 2 -C ₄ alkanoyl group There, more preferably, an acetyl group, a propanoyl group or a butanoyl group, particularly preferably an 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 or 2- (naphthalen-2-yl) ethyloxy group, preferably benzyloxy group 1-phenylethyloxy group, 2-phenylethyloxy group or 1-phenylethyloxy group, A til-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 2-phenylethyloxy group. .

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, a naphthyl group, etc. are mentioned, Preferably it is a phenyl 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, 1,3-dioxanyl group or a 1,4-dioxanyl group and the like. 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 tetrahydropyranyl group, a piperazinyl group, a morpholinyl group or a thiomorpholinyl group. More preferably a pyrrolidinyl group, a piperidinyl group, a tetrahydropyranyl group, a piperazinyl group or a morpholinyl group, and particularly preferably a pyrrolidinyl group, a tetrahydropyranyl group or a 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.

n represents an integer of 1 to 3,
When n is 2 or 3, Ys may be the same as or different from each other.

A C ₁ -C ₁₂ alkyl group substituted with the same or different 1 to 3 groups selected from the substituent group α represented by Y (provided that a halogeno group, a C ₁ -C ₆ alkyl group and C ₂ -C ₆ alkenyl group is excluded, and aryl group, heteroaryl group and heterocyclic group are excluded as a substituent at the 1-position), C ₂ -C ₆ alkenyl group (provided that C ₁ -C _{6 is} substituted as a substituent) Except for alkyl groups, and aryl groups, heteroaryl groups and heterocyclic groups as substituents at the 1-position), C ₁ -C ₆ alkoxy groups (however, halogeno groups are excluded as substituents), and substitution A C ₂ -C ₆ alkynyl group which may be substituted by the same or different 1 to 3 groups selected from the group α, and the same or different 1 to 3 selected from the substituent group α shown by Z Substituted with _There, C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl _group, C 2 -C ₆ alkynyl _group, C 3 -C ₈ cycloalkyl _group, C 5 -C ₈ cycloalkenyl group, an aryl group, heteroaryl group The number of substituents in the heterocyclic group is preferably 1 to 2.

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.

Y is preferably a hydroxy group, a C ₇ -C ₁₂ aralkyl group, a C ₁ -C ₆ alkoxy group, a C ₇ -C ₁₂ aralkyloxy group, a C ₃ -C ₆ cycloalkyl group, or a C ₂ -C ₄ alkanoyl. 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, Substituted with di- (C ₁ -C ₄ alkyl) amino group, tri- (C ₁ -C ₄ alkyl) ammonium group, C ₂ -C ₄ alkanoylamino group, C ₁ -C ₄ alkoxycarbonylamino group, methoxy group Optionally substituted with a group selected from the group consisting of an aryl group, a heteroaryl group, an aryloxy group and a fully saturated heterocyclic group. C ₁ -C ₉ alkyl group (provided that 1-position substituent as optionally substituted aryl group with a methoxy group, excluding heterocyclic group heteroaryl group and completely saturated), or, C ₇ -C ₁₂ aralkyl Group, C ₁ -C ₆ alkoxy group, C ₇ -C ₁₂ aralkyloxy group, C ₃ -C ₆ cycloalkyl group, C ₂ -C ₄ alkanoyl group, C ₁ -C ₄ alkoxycarbonyl group, C ₁ -C ₄ A C ₃ -C ₅ alkenyl group substituted with a group selected from the group consisting of an alkylthio group, a C ₁ -C ₄ alkylsulfinyl group, a C ₁ -C ₄ alkylsulfonyl group, an aryl group and a fully saturated heterocyclic group ( However, the 1-position of excluding heterocyclic group of aryl and fully saturated as substituents) or _C 1 -C ₄ alkoxy groups, _or, C 7 _{-C 12} aralkyl _groups, C 1 -C Selected from the group consisting of ₆ alkoxy groups, C ₇ -C ₁₂ aralkyloxy groups, C ₃ -C ₆ cycloalkyl groups, C ₂ -C ₄ alkanoyl groups, aryl groups, heteroaryl groups and fully saturated heterocyclic groups A C ₃ -C ₅ alkynyl group optionally substituted with a group, more preferably a hydroxy group, a benzyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a pentyloxy group, a hexyloxy group Group, benzyloxy group, 1-phenylethyloxy group, 2-phenylethyloxy group, cyclopropyl group, cyclohexyl group, acetyl group, propanoyl group, benzoyl group, methoxycarbonyl group, methylthio group, methylsulfinyl group, methylsulfonyl group , Methylamino group, dimethylamino group, trimethylammoni Substituted with a group selected from the group consisting of a phenyl group, a thienyl group, a pyridyl group, a pyrrolidinyl group, a tetrahydropyranyl group, and a piperidinyl group, which may be substituted with an um group, an acetylamino group, a methoxycarbonylamino group, and a methoxy group A C ₁ -C ₉ alkyl group (excluding a phenyl group, a thienyl group, a pyridyl group, a pyrrolidinyl group, a tetrahydropyranyl group and a piperidinyl group which may be substituted with a methoxy group as a substituent at the 1-position), Or benzyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, pentyloxy group, hexyloxy group, benzyloxy group, 1-phenylethyloxy group, 2-phenylethyloxy group, cyclopropyl group Cyclohexyl group, phenyl group, pyrrolidinyl group, tetrahy Ropiraniru groups and has been C ₃ -C ₅ alkenyl group substituted with a group selected from the group consisting of piperidinyl group (provided that the phenyl group as the 1-position of the substituent, a pyrrolidinyl group, a tetrahydropyranyl group and a piperidinyl group are excluded) or C ₁ -C ₄ alkoxy group, or benzyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, pentyloxy group, hexyloxy group, benzyloxy group, 1-phenylethyloxy group, 2- C ₃ -C which may be substituted with a group selected from the group consisting of phenylethyloxy group, cyclopropyl group, cyclohexyl group, phenyl group, thienyl group, pyridyl group, pyrrolidinyl group, tetrahydropyranyl group and piperidinyl group ₅ alkynyl group, still more preferably, hydroxy Til group, hydroxyethyl group, 3-hydroxy-2,2,4,4-tetramethylpentan-3-yl group, 1,1-dimethyl-3-phenylpropyl group, 2-methoxy-1,1-dimethylethyl Group, 2-ethoxy-1,1-dimethylethyl group, 1,1-dimethyl-2-propoxyethyl group, 2-butoxy-1,1-dimethylethyl group, 1,1-dimethyl-2-pentyloxyethyl group 2-hexyloxy-1,1-dimethylethyl group, 2-benzyloxy-1,1-dimethylethyl group, 2- (1-phenylethyloxy) -1,1-dimethylethyl group, 2- (2- Phenylethyloxy) -1,1-dimethylethyl group, 1-cyclopropylethyl group, 2-cyclopropylethyl group, 1-cyclohexylethyl group, 2-cyclohexylethyl group, -Cyclohexylpropyl group, 4-cyclohexylbutyl group, (trimethylammonio) methyl group, (triethylammonio) methyl group, 1- (4-methoxybenzyl) -1-methylethyl group, 1- (3-methoxybenzyl) -1-methylethyl group, 1- (2-methoxybenzyl) -1-methylethyl group, phenoxymethyl group, 3-phenoxypropyl group, benzyloxymethyl group, 2-benzyloxyethyl group, 1,1-dimethyl- 2- (tetrahydro-2H-pyran-4-yl) ethyl group, 3-cyclopropyl-1-propenyl group, 3-cyclohexyl-1-propenyl group, 4-cyclopropyl-1-butenyl group, 4-cyclohexyl-1 -Butenyl group, 3-phenyl-1-propenyl group, benzyloxy group, 2-phenoxy group, 2 A methoxyethoxy group, 2-phenoxyethoxy group, 2-propynyl group, 3-phenyl-2-propynyl group or 2-butynyl group, particularly preferably a hydroxymethyl group, 3-hydroxy-2,2,4,4 -Tetramethylpentan-3-yl group, 1,1-dimethyl-3-phenylpropyl group, 2-methoxy-1,1-dimethylethyl group, 2-ethoxy-1,1-dimethylethyl group, 2-butoxy- 1,1-dimethylethyl group, 1,1-dimethyl-2-pentyloxyethyl group, 2-hexyloxy-1,1-dimethylethyl group, 2-benzyloxy-1,1-dimethylethyl group, 1-cyclohexyl Ethyl group, (trimethylammonio) methyl group, 1- (4-methoxybenzyl) -1-methylethyl group, 1- (2-methoxybenzyl) -1 A methylethyl group, a phenoxymethyl group, a 3-phenoxypropyl group or a 1,1-dimethyl-2- (tetrahydro-2H-pyran-4-yl) ethyl 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, dimethyla Amino group, an anilino group, a phenyl group, a thienyl group, a pyridyl group, a phenoxy group, a pyrrolidinyl group, and optionally C ₁ -C ₄ alkyl group optionally substituted with a group selected from the group consisting of piperidinyl, 2-propynyl group 2-butynyl group, cyclopropyl group, cyclobutyl group, cyclopentenyl group, or fluoro group, chloro group, cyano group, nitro group, methyl group, ethyl group, trifluoromethyl group, benzyl group, benzyloxy group, cyclo Group consisting of 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 which may be substituted with a group selected from 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) Y is a hydroxy group, a C ₇ -C ₁₂ aralkyl group, a C ₁ -C ₆ alkoxy group, a C ₇ -C ₁₂ aralkyloxy group, a C ₃ -C ₆ cycloalkyl group, a C ₂ -C ₄ alkanoyl 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, tri- (C ₁ -C ₄ alkyl) ammonium group, C ₂ -C ₄ alkanoylamino group, C ₁ -C ₄ alkoxycarbonylamino group, substituted with methoxy group It is aryl group, heteroaryl groups, C ₁ -C substituted with a group selected from the group consisting of heterocyclic group aryloxy group and completely saturated Alkyl group (provided that 1-position substituent as an aryl group which may be substituted by a methoxy group, excluding heterocyclic group heteroaryl group and completely saturated), or, C ₇ -C ₁₂ aralkyl group, C ₁ - C ₆ alkoxy group, C ₇ -C ₁₂ aralkyloxy group, C ₃ -C ₆ cycloalkyl group, C ₂ -C ₄ alkanoyl group, C ₁ -C ₄ alkoxycarbonyl group, C ₁ -C ₄ alkylthio group, C ₁ A C ₃ -C ₅ alkenyl group substituted with a group selected from the group consisting of —C ₄ alkylsulfinyl group, C ₁ -C ₄ alkylsulfonyl group, aryl group and fully saturated heterocyclic group (provided that the aryl group and completely saturated as substituents heterocyclic group is excluded) or a _C 1 -C ₄ alkoxy groups, _or, C 7 _{-C 12} aralkyl _group, C 1 -C ₆ alkoxy _Group, C 7 _{-C 12} aralkyloxy _group, C 3 -C ₆ cycloalkyl _group, C 2 -C ₄ alkanoyl group, an aryl group, a group selected from the group consisting of heterocyclic group heteroaryl group and completely saturated A compound that is an optionally substituted C ₃ -C ₅ alkynyl group,
(8) Y is hydroxy group, benzyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, pentyloxy group, hexyloxy group, benzyloxy group, 1-phenylethyloxy group, 2-phenyl Ethyloxy, cyclopropyl, cyclohexyl, acetyl, propanoyl, benzoyl, methoxycarbonyl, methylthio, methylsulfinyl, methylsulfonyl, methylamino, dimethylamino, trimethylammonium, acetylamino , Substituted with a group selected from the group consisting of a methoxycarbonylamino group, a phenyl group optionally substituted with a methoxy group, a thienyl group, a pyridyl group, a phenoxy group, a pyrrolidinyl group, a tetrahydropyranyl group, and a piperidinyl group ₁ -C ₉ Rualkyl group (however, phenyl group, thienyl group, pyridyl group, pyrrolidinyl group, tetrahydropyranyl group and piperidinyl group which may be substituted with methoxy group as a substituent at the 1-position), benzyl group, methoxy group Ethoxy group, propoxy group, isopropoxy group, butoxy group, pentyloxy group, hexyloxy group, benzyloxy group, 1-phenylethyloxy group, 2-phenylethyloxy group, cyclopropyl group, cyclohexyl group, phenyl group, A C ₃ -C ₅ alkenyl group substituted with a group selected from the group consisting of a pyrrolidinyl group, a tetrahydropyranyl group and a piperidinyl group (provided that a phenyl group, a pyrrolidinyl group, a tetrahydropyranyl group and a piperidinyl group are substituted at the 1-position) group are excluded) or _C 1 -C ₄ alkoxy group Alternatively, benzyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, pentyloxy group, hexyloxy group, benzyloxy group, 1-phenylethyloxy group, 2-phenylethyloxy group, cyclopropyl group A compound that is a C ₃ -C ₅ alkynyl group optionally substituted with a group selected from the group consisting of a cyclohexyl group, a phenyl group, a thienyl group, a pyridyl group, a pyrrolidinyl group, a tetrahydropyranyl group, and a piperidinyl group,
(9) Y is a hydroxymethyl group, hydroxyethyl group, 3-hydroxy-2,2,4,4-tetramethylpentan-3-yl group, 1,1-dimethyl-3-phenylpropyl group, 2-methoxy 1,1-dimethylethyl group, 2-ethoxy-1,1-dimethylethyl group, 1,1-dimethyl-2-propoxyethyl group, 2-butoxy-1,1-dimethylethyl group, 1,1-dimethyl -2-pentyloxyethyl group, 2-hexyloxy-1,1-dimethylethyl group, 2-benzyloxy-1,1-dimethylethyl group, 2- (1-phenylethyloxy) -1,1-dimethylethyl 2- (2-phenylethyloxy) -1,1-dimethylethyl group, 1-cyclopropylethyl group, 2-cyclopropylethyl group, 1-cyclohexylethyl group, 2- Chloroethyl group, 3-cyclohexylpropyl group, 4-cyclohexylbutyl group, (trimethylammonio) methyl group, (triethylammonio) methyl group, 1- (4-methoxybenzyl) -1-methylethyl group, 1- (3-methoxybenzyl) -1-methylethyl group, 1- (2-methoxybenzyl) -1-methylethyl group, phenoxymethyl group, 3-phenoxypropyl group, benzyloxymethyl group, 2-benzyloxyethyl group, 1,1-dimethyl-2- (tetrahydro-2H-pyran-4-yl) ethyl group, 3-cyclopropyl-1-propenyl group, 3-cyclohexyl-1-propenyl group, 4-cyclopropyl-1-butenyl group 4-cyclohexyl-1-butenyl group, 3-phenyl-1-propenyl group, benzyloxy group, A compound which is a 2-phenoxy group, a 2-methoxyethoxy group, a 2-phenoxyethoxy group, a 2-propynyl group, a 3-phenyl-2-propynyl group or a 2-butynyl group,
(10) Y is hydroxymethyl group, 3-hydroxy-2,2,4,4-tetramethylpentan-3-yl group, 1,1-dimethyl-3-phenylpropyl group, 2-methoxy-1,1 -Dimethylethyl group, 2-ethoxy-1,1-dimethylethyl group, 2-butoxy-1,1-dimethylethyl group, 1,1-dimethyl-2-pentyloxyethyl group, 2-hexyloxy-1,1 -Dimethylethyl group, 2-benzyloxy-1,1-dimethylethyl group, 1-cyclohexylethyl group, (trimethylammonio) methyl group, 1- (4-methoxybenzyl) -1-methylethyl group, 1- ( 2-methoxybenzyl) -1-methylethyl, phenoxymethyl, 3-phenoxypropyl or 1,1-dimethyl-2- (tetrahydro-2H-pyran-4- Le) compound is an ethyl group,
(11) 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,
(12) Z is a 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, C ₁ -C ₄ alkyl group, 2-propynyl group, 2-butynyl group, cyclopropyl group, cyclobutyl group optionally substituted with a group selected from the group consisting of pyridyl group, phenoxy group, pyrrolidinyl group and piperidinyl group , Cyclopentenyl group, or 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 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 a methoxycarbonylamino group, a phenyl group, a phenoxy group, an azetidinyl group, a pyrrolidinyl group, and a piperidinyl group. A compound,
(13) Z is methyl, ethyl, trifluoromethyl, 2-phenylethyl, cyclopropyl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 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,
(14) 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), more preferable compounds are used as the number increases. R ¹ from group (1)-(3), R ² and R ³ from group (4)-(6), R ⁴ from group (7)-(10), and Z from group (11). A compound obtained by arbitrarily selecting from-(14) and combining them arbitrarily is also a preferred compound.
Such compounds are
(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,
Y represents a hydroxy group, a C ₇ -C ₁₂ aralkyl group, a C ₁ -C ₆ alkoxy group, a C ₇ -C ₁₂ aralkyloxy group, a C ₃ -C ₆ cycloalkyl group, a C ₂ -C ₄ alkanoyl group, an 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, tri- (C ₁ -C ₄ alkyl) ammonium group, C ₂ -C ₄ alkanoylamino group, C ₁ -C ₄ alkoxycarbonylamino group, optionally substituted by methoxy group aryl, heteroaryl, C ₁ -C ₉ aralkyl which is substituted by a group selected from the group consisting of heterocyclic group aryloxy group and completely saturated Le group (provided that 1-position substituent as optionally substituted aryl group with a methoxy group, excluding heterocyclic group heteroaryl group and completely saturated), or, C ₇ -C ₁₂ aralkyl group, C ₁ - C ₆ alkoxy group, C ₇ -C ₁₂ aralkyloxy group, C ₃ -C ₆ cycloalkyl group, C ₂ -C ₄ alkanoyl group, C ₁ -C ₄ alkoxycarbonyl group, C ₁ -C ₄ alkylthio group, C ₁ A C ₃ -C ₅ alkenyl group substituted with a group selected from the group consisting of —C ₄ alkylsulfinyl group, C ₁ -C ₄ alkylsulfonyl group, aryl group and fully saturated heterocyclic group (provided that the aryl group and completely saturated as substituents heterocyclic group is excluded) or a _C 1 -C ₄ alkoxy groups, _or, C 7 _{-C 12} aralkyl _group, C 1 -C ₆ alkoxy group, ₇ -C ₁₂ aralkyloxy _group, C 3 -C ₆ cycloalkyl _group, C 2 -C ₄ alkanoyl group, an aryl group, optionally substituted by a group selected from the group consisting of heterocyclic group heteroaryl group and completely saturated An optionally substituted C ₃ -C ₅ alkynyl 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,
(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,
Y is hydroxy group, benzyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, pentyloxy group, hexyloxy group, benzyloxy group, 1-phenylethyloxy group, 2-phenylethyloxy group , Cyclopropyl group, cyclohexyl group, acetyl group, propanoyl group, benzoyl group, methoxycarbonyl group, methylthio group, methylsulfinyl group, methylsulfonyl group, methylamino group, dimethylamino group, trimethylammonium group, acetylamino group, methoxycarbonyl C ₁ -C substituted with a group selected from the group consisting of phenyl, thienyl, pyridyl, phenoxy, pyrrolidinyl, tetrahydropyranyl and piperidinyl optionally substituted with amino, methoxy ₉ alkylene A group (excluding a phenyl group, a thienyl group, a pyridyl group, a pyrrolidinyl group, a tetrahydropyranyl group and a piperidinyl group, which may be substituted with a methoxy group as a substituent at the 1-position), or a benzyl group, a methoxy group, Ethoxy group, propoxy group, isopropoxy group, butoxy group, pentyloxy group, hexyloxy group, benzyloxy group, 1-phenylethyloxy group, 2-phenylethyloxy group, cyclopropyl group, cyclohexyl group, phenyl group, pyrrolidinyl A C ₃ -C ₅ alkenyl group substituted with a group selected from the group consisting of a group, a tetrahydropyranyl group and a piperidinyl group (provided that a phenyl group, a pyrrolidinyl group, a tetrahydropyranyl group and a piperidinyl group are substituted at the 1-position) They are excluded) or _C 1 -C ₄ alkoxy group, walk Benzyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, pentyloxy group, hexyloxy group, benzyloxy group, 1-phenylethyloxy group, 2-phenylethyloxy group, cyclopropyl group, A C ₃ -C ₅ alkynyl group optionally substituted with a group selected from the group consisting of a cyclohexyl group, a phenyl group, a thienyl group, a pyridyl group, a pyrrolidinyl group, a tetrahydropyranyl group and a piperidinyl group,
Z is fluoro, chloro, benzyl, methoxy, benzyloxy, cyclopropyl, cyclopentenyl, benzoyl, methylamino, dimethylamino, anilino, phenyl, thienyl, pyridyl, C ₁ -C ₄ alkyl group, 2-propynyl group, 2-butynyl group, cyclopropyl group, cyclobutyl group, cyclopentenyl which may be substituted with a group selected from the group consisting of phenoxy group, pyrrolidinyl group and piperidinyl group Group, or fluoro, chloro, cyano, nitro, methyl, ethyl, trifluoromethyl, benzyl, benzyloxy, cyclopropyl, methoxy, methoxycarbonyl, methylthio, methylamino Group, dimethylamino group, anilino group, acetylamino group, metho 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 a sicarbonylamino group, a phenyl group, a phenoxy group, an azetidinyl group, a pyrrolidinyl group, and a piperidinyl group Compound,
(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,
Y is hydroxymethyl group, hydroxyethyl group, 3-hydroxy-2,2,4,4-tetramethylpentan-3-yl group, 1,1-dimethyl-3-phenylpropyl group, 2-methoxy-1, 1-dimethylethyl group, 2-ethoxy-1,1-dimethylethyl group, 1,1-dimethyl-2-propoxyethyl group, 2-butoxy-1,1-dimethylethyl group, 1,1-dimethyl-2- Pentyloxyethyl group, 2-hexyloxy-1,1-dimethylethyl group, 2-benzyloxy-1,1-dimethylethyl group, 2- (1-phenylethyloxy) -1,1-dimethylethyl group, 2 -(2-phenylethyloxy) -1,1-dimethylethyl group, 1-cyclopropylethyl group, 2-cyclopropylethyl group, 1-cyclohexylethyl group, 2-cyclo Xylethyl group, 3-cyclohexylpropyl group, 4-cyclohexylbutyl group, (trimethylammonio) methyl group, (triethylammonio) methyl group, 1- (4-methoxybenzyl) -1-methylethyl group, 1- (3 -Methoxybenzyl) -1-methylethyl group, 1- (2-methoxybenzyl) -1-methylethyl group, phenoxymethyl group, 3-phenoxypropyl group, benzyloxymethyl group, 2-benzyloxyethyl group, 1, 1-dimethyl-2- (tetrahydro-2H-pyran-4-yl) ethyl group, 3-cyclopropyl-1-propenyl group, 3-cyclohexyl-1-propenyl group, 4-cyclopropyl-1-butenyl group, 4 -Cyclohexyl-1-butenyl group, 3-phenyl-1-propenyl group, benzyloxy group, 2-phenyl An ethenyloxy group, a 2-methoxyethoxy group, a 2-phenoxyethoxy group, a 2-propynyl group, a 3-phenyl-2-propynyl group or a 2-butynyl 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
(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,
Y is hydroxymethyl group, 3-hydroxy-2,2,4,4-tetramethylpentan-3-yl group, 1,1-dimethyl-3-phenylpropyl group, 2-methoxy-1,1-dimethylethyl Group, 2-ethoxy-1,1-dimethylethyl group, 2-butoxy-1,1-dimethylethyl group, 1,1-dimethyl-2-pentyloxyethyl group, 2-hexyloxy-1,1-dimethylethyl Group, 2-benzyloxy-1,1-dimethylethyl group, 1-cyclohexylethyl group, (trimethylammonio) methyl group, 1- (4-methoxybenzyl) -1-methylethyl group, 1- (2-methoxy) Benzyl) -1-methylethyl, phenoxymethyl, 3-phenoxypropyl or 1,1-dimethyl-2- (tetrahydro-2H-pyran-4-yl) Is a 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.
(19) As a substituted benzyl compound, preferably
(6-{[4- (1-cyclohexylethyl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
{6-[(4-hydroxymethylbenzyl) (pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid,
(6-{[4- (3-hydroxy-2,2,4,4-tetramethylpentan-3-yl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
2- {6-[(N- {4-[(trimethylammonio) methyl] benzyl} pyridine-3-sulfonamido) methyl] pyridin-2-ylamino} acetate,
{6-[(4-phenoxymethylbenzyl) (pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid,
(6-{[4- (3-phenoxypropyl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
[6-({4- [1- (4-methoxybenzyl) -1-methylethyl] benzyl} (pyridin-2-ylsulfonyl) aminomethyl) pyridin-2-ylamino] acetic acid,
[6-({4- [1- (2-methoxybenzyl) -1-methylethyl] benzyl} (pyridin-2-ylsulfonyl) aminomethyl) pyridin-2-ylamino] acetic acid,
(6-{[4- (1,1-dimethyl-3-phenylpropyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
[6-({4- [1,1-dimethyl-2- (tetrahydro-2H-pyran-4-yl) ethyl] benzyl} (pyridin-2-ylsulfonyl) aminomethyl) pyridin-2-ylamino] acetic acid,
(6-{[4- (2-methoxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{[4- (2-ethoxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{[4- (2-butoxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{[4- (1,1-dimethyl-2-pentyloxyethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{[4- (2-hexyloxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid, or (6-{[4- ( And 2-benzyloxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid.

In the present invention,
(20) A pharmaceutical composition comprising as an active ingredient the compound represented by the above general formula (I), the substituted benzyl compound according to any one of (1) to (19) or a pharmacologically acceptable salt thereof And (21) the pharmaceutical composition according to (20) 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 , Y, Z and n 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 of the present invention by reacting compound A and compound B, or compound C and compound D, or compound E and compound F in an organic solvent in the presence of a condensing agent or a base, respectively. Compound (I ′) which is a precursor of
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.
The substituent on the substituent Y and / or the substituent Z may have a desired substituent 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 a general synthetic method combining these reactions can be used as desired for the basic skeleton. Substituents may be introduced.
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 the following examples, reference examples, and test examples, but the scope of the present invention is not limited thereto. 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- (1-cyclohexylethyl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid

1- (a): [tert-Butoxycarbonyl (6-{[4- (1-cyclohexylethyl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-yl) amino] tert-butyl acetate Reference Example 1 (tert-Butoxycarbonyl {6-[(pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate 210 mg (0.439 mmol) of tetrahydrofuran obtained in Example 1- (f) In a 4 ml solution, 90.6 mg (0.415 mmol) of 4- (1-cyclohexylethyl) benzyl alcohol obtained in Reference Example 2- (c), 155 μl (0.621 mmol) of tri-n-butylphosphine and N, N , N ′, N′-Tetramethylazodicarboxamide 107 mg (0.621 mmol) And the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was 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 → 1: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 274 mg of the title compound. Was obtained as a white foam. (Yield 97%)
Mass spectrum (FAB, m / z): 679 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.95 (dd, J = 2.4, 0.8 Hz, 1H), 8.69 (dd, J = 4.9, 1.6 Hz, 1H), 7.85 (ddd, J = 8.1, 2.4, 1.6 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.50 (dd, J = 8.5, 7.3 Hz, 1H), 7.29 (ddd, J = 8.1, 4.9, 0.8 Hz, 1H), 7.14- 7.07 (m, 2H), 7.05-6.99 (m, 2H), 6.87 (d, J = 7.3 Hz, 1H), 4.53 (s, 2H), 4.39 (s, 4H), 2.45-2.33 (m, 1H) 1.89-0.67 (m, 14H), 1.52 (s, 9H), 1.43 (s, 9H).

1- (b): (6-{[4- (1-cyclohexylethyl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid obtained in Example 1- (a) [Tert-Butoxycarbonyl (6-{[4- (1-cyclohexylethyl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-yl) amino] tert-butyl acetate 270 mg (0.416 mmol) To a 4.2 ml solution of methylene chloride was added 4.2 ml (17 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, 3.5 ml of water was added to the resulting residue, and the pH was adjusted to 4.5 with 1N hydrochloric acid. The precipitated solid was collected by filtration and stirred in 1 ml of a mixed solvent (acetone: diisopropyl ether = 1: 1 (V / V)) for 2 hours. The precipitated solid was collected by filtration and dried under reduced pressure to give 170 mg of the title compound as a light brown solid. (Yield 78%)
Mass spectrum (FAB, m / z): 523 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 8.80 (dd, J = 2.4, 0.8 Hz, 1H), 8.70 (dd, J = 4.8, 1.6 Hz, 1H), 8.00 (ddd, J = 8.0, 2.4, 1.6 Hz, 1H), 7.45 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 7.21 (dd, J = 8.3, 7.1 Hz, 1H), 7.19-7.15 (m, 2H), 7.10-7.06 (m, 2H), 6.61 (brs, 1H), 6.34 (d, J = 8.3 Hz, 1H), 6.29 (d, J = 7.1 Hz, 1H), 4.60 (s, 2H), 4.17 (s, 2H) , 3.65 (d, J = 4.2 Hz, 2H), 2.45-2.37 (m, 1H), 1.85-1.66 (m, 2H), 1.63-1.52 (m, 2H), 1.40-0.66 (m, 10H).
Rf value: 0.74 (n-butanol: acetic acid: water = 3: 1: 1).

[Example 2]
{6-[(4-Hydroxymethylbenzyl) (pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid

2- (a): (tert-Butoxycarbonyl {6-[(4-hydroxymethylbenzyl) (pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate Reference Example 1- ( f) (tert-butoxycarbonyl {6-[(pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate 383 mg (0.800 mmol) of N, N-dimethyl To a 3 ml formamide solution were added 221 mg (1.60 mmol) potassium carbonate and 188 mg (1.20 mmol) (4-hydroxymethyl) benzyl chloride, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, water was added to the reaction solution and extracted with toluene. The organic layer was washed successively with water and then 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 = 2: 1 → 0: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 340 mg of the title compound. Was obtained as a white foam. (Yield 71%)
Mass spectrum (FAB, m / z): 599 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.91 (dd, J = 2.4, 0.7 Hz, 1H), 8.72 (dd, J = 4.9, 1.7 Hz, 1H), 7.91 (ddd, J = 8.1, 2.4, 1.7 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.50 (dd, J = 8.3, 7.4 Hz, 1H), 7.34 (ddd, J = 8.1, 4.9, 0.7 Hz, 1H), 7.28- 7.22 (m, 2H), 7.21-7.16 (m, 2H), 6.89 (d, J = 7.4 Hz, 1H), 4.64 (d, J = 6.0 Hz, 2H), 4.55 (s, 2H), 4.36 (s , 2H), 4.34 (s, 2H), 1.99 (t, J = 6.0 Hz, 1H), 1.52 (s, 9H), 1.41 (s, 9H).

2- (b): {6-[(4-Hydroxymethylbenzyl) (pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid (tert-butoxy obtained in Example 2- (a) To a solution of carbonyl {6-[(4-hydroxymethylbenzyl) (pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate 30 mg (0.050 mmol) in tetrahydrofuran 50 μl And 100 microliters of water was added and it stirred at 60 degreeC for 2 hours. After completion of the reaction, water was added to the reaction solution, adjusted to pH 4.4 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. To the obtained residue, 2 ml of a mixed solvent (ethyl acetate: n-hexane = 1: 3 (V / V)) was added, and sonication was performed. The precipitated solid was collected by filtration and dried under reduced pressure to give 17 mg of the title compound as a white solid. (Yield 78%)
Mass spectrum (FAB, m / z): 443 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 8.81 (d, J = 2.0 Hz, 1H), 8.71 (dd, J = 4.8, 1.8 Hz, 1H), 8.00 (ddd, J = 8.1, 2.0, 1.8 Hz, 1H), 7.46 (dd, J = 8.1, 4.8 Hz, 1H), 7.31-7.19 (m, 5H), 6.75 (t, J = 5.7 Hz, 1H), 6.36 (d, J = 8.3 Hz, 1H), 6.31 (d, J = 7.1 Hz, 1H), 4.65 (s, 2H), 4.48 (s, 2H), 4.14 (s, 2H), 3.69 (d, J = 5.7 Hz, 2H).
Rf value: 0.55 (n-butanol: acetic acid: water = 3: 1: 1).

[Example 3]
(6-{[4- (3-Hydroxy-2,2,4,4-tetramethylpentan-3-yl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid

3- (a): [tert-butoxycarbonyl (6-{[4- (3-hydroxy-2,2,4,4-tetramethylpentan-3-yl) benzyl] (pyridin-3-ylsulfonyl) amino (Methyl} pyridin-2-yl) amino] tert-butyl acetate (tert-butoxycarbonyl {6-[(pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-yl obtained in Reference Example 1- (f) } 4- (3-Hydroxy-2,2,4,4-tetramethylpentane-3) obtained in Reference Example 3- (b) was added to a solution of 288 mg (0.600 mmol) of tert-butyl acetate in 4 ml of tetrahydrofuran. -Yl) benzyl alcohol 151 mg (0.601 mmol), tri-n-butylphosphine 222 μl (0.900 mmol) and N, N N ', N'-tetramethyl azodicarboxamide 155mg of (0.900 mmol) was added and stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was 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; toluene: ethyl acetate = 4: 1 → 3: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 282 mg of the title compound as white. Obtained as a foam. (Yield 66%)
Mass spectrum (FAB, m / z): 711 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.97 (d, J = 2.0 Hz, 1H), 8.70 (dd, J = 4.8, 1.7 Hz, 1H), 7.87 (ddd, J = 8.1, 2.0, 1.7 Hz) , 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.49-7.41 (m, 2H), 7.48 (dd, J = 8.3, 7.3 Hz, 1H), 7.31 (dd, J = 8.1, 4.8 Hz, 1H), 7.15-7.07 (m, 2H), 6.86 (d, J = 7.3 Hz, 1H), 4.54 (s, 2H), 4.40 (s, 2H), 4.39 (s, 2H), 1.90 (s, 1H ), 1.52 (s, 9H), 1.42 (s, 9H), 1.05 (s, 18H).

3- (b): (6-{[4- (3-hydroxy-2,2,4,4-tetramethylpentan-3-yl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridine-2 -Ylamino) acetic acid [tert-Butoxycarbonyl (6-{[4- (3-hydroxy-2,2,4,4-tetramethylpentan-3-yl) benzyl] obtained in Example 3- (a) (Pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-yl) amino] tert-butyl acetate 279 mg (0.392 mmol) in tetrahydrofuran 1.3 ml was added concentrated hydrochloric acid 325 μl and water 1 ml. Stir for hours. After completion of the reaction, water was added to the reaction solution, adjusted to pH 4.4 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. Subsequently, it was dried under reduced pressure to obtain 214 mg of the title compound as a white foam. (Yield 98%)
Mass spectrum (FAB, m / z): 555 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 8.82 (dd, J = 2.4, 0.8 Hz, 1H), 8.70 (dd, J = 4.8, 1.5 Hz, 1H), 8.01 (ddd, J = 8.1, 2.4, 1.5 Hz, 1H), 7.63-7.55 (m, 1H), 7.50-7.42 (m, 1H), 7.46 (ddd, J = 8.1, 4.8, 0.8 Hz, 1H), 7.20 (dd, J = 8.4, 7.0 Hz, 1H), 7.19-7.10 (m, 2H), 6.73 (t, J = 5.8 Hz, 1H), 6.34 (d, J = 8.4 Hz, 1H), 6.29 (d, J = 7.0 Hz, 1H) , 4.62 (s, 2H), 4.23 (s, 1H), 4.17 (s, 2H), 3.71 (d, J = 5.8 Hz, 2H), 1.00 (s, 18H).
Rf value: 0.71 (n-butanol: acetic acid: water = 3: 1: 1).

[Example 4]
2- {6-[(N- {4-[(trimethylammonio) methyl] benzyl} pyridine-3-sulfonamido) methyl] pyridin-2-ylamino} acetate

4- (a): 1- (4-{[N-({6-[(2-tert-butoxy-2-oxoethyl) (tert-butoxycarbonyl) amino] pyridin-2-yl} methyl) pyridine-3 -Sulfonamido] methyl} phenyl) -N, N, N-trimethylmethanaminium iodide (tert-butoxycarbonyl {6-[(pyridin-3-ylsulfonyl) aminomethyl] obtained in Reference Example 1- (f) ] 1-[(4-hydroxymethyl) phenyl] -N, N, obtained in Reference Example 4 was added to a solution of 184 mg (0.385 mmol) tert-butyl acetate in tetrahydrofuran 1.8 ml. N-trimethylmethanaminium iodide 130 mg (0.423 mmol), tri-n-butylphosphine 290 μl (1.16 m ol) and N, N, N ', N'- tetramethyl azodicarboxamide 200mg of (1.16 mmol) was added and stirred for 15 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; chloroform: methanol: 28% aqueous ammonia = 90: 10: 1 (V / V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give the title 127 mg of compound was obtained as a white foam. (Yield 43%)
Mass spectrum (FAB, m / z): 640 (M ⁺ ).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 8.92 (dd, J = 2.3, 0.6 Hz, 1H), 8.81 (dd, J = 4.8, 1.6 Hz, 1H), 8.19 (ddd, J = 8.1, 2.3, 1.6 Hz, 1H), 7.62-7.56 (m, 3H), 7.39-7.34 (m, 2H), 7.32-7.27 (m, 2H), 6.91 (dd, J = 4.6, 3.7 Hz, 1H), 4.56 (s, 2H), 4.44 (s, 2H), 4.42 (s, 2H), 4.34 (s, 2H), 2.95 (s, 9H), 1.45 (s, 9H), 1.40 (s, 9H).

4- (b): 2- {6-[(N- {4-[(trimethylammonio) methyl] benzyl} pyridine-3-sulfonamido) methyl] pyridin-2-ylamino} acetate Example 4- (a 1- (4-{[N-({6-[(2-tert-butoxy-2-oxoethyl) (tert-butoxycarbonyl) amino] pyridin-2-yl} methyl) pyridine-3- To a solution of 124 mg (0.162 mmol) of sulfonamide] methyl} phenyl) -N, N, N-trimethylmethanaminium iodide in 0.65 ml of tetrahydrofuran was added 139 μl of concentrated hydrochloric acid and stirred at room temperature for 19 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was subjected to reverse phase C18 column chromatography (elution solvent; water: acetonitrile = 1: 0 → 1: 1 (V / V)). The fraction containing the desired product was concentrated under reduced pressure to obtain 30 mg of the title compound as a white solid. (Yield 38%)
Mass spectrum (FAB, m / z): 484 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 8.87 (dd, J = 2.4, 0.7 Hz, 1H), 8.76 (dd, J = 4.8, 1.6 Hz, 1H), 8.18 (ddd, J = 8.1, 2.4, 1.6 Hz, 1H), 7.56 (ddd, J = 8.1, 4.8, 0.7 Hz, 1H), 7.45-7.41 (m, 2H), 7.41-7.38 (m, 2H), 7.17 (dd, J = 8.3, 7.1 Hz, 1H), 6.25 (d, J = 7.1 Hz, 1H), 6.21 (d, J = 8.3 Hz, 1H), 5.73 (brs, 1H), 4.65 (s, 2H), 4.46 (s, 2H) , 4.22 (s, 2H), 3.19 (d, J = 3.9 Hz, 2H), 2.98 (s, 9H).
Rf value: 0.06 (n-butanol: acetic acid: water = 3: 1: 1).

[Example 5]
{6-[(4-Phenoxymethylbenzyl) (pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid

5- (a): (tert-Butoxycarbonyl {6-[(4-phenoxymethylbenzyl) (pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate Reference Example 1- ( To a solution of tert-butyl (tert-butoxycarbonyl {6-[(pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate obtained in f) in 3 ml of tetrahydrofuran, 108 mg (0.500 mmol) of 4-phenoxybenzyl alcohol (see WO2003 / 106403), 247 μl (1.00 mmol) of tri-n-butylphosphine and 173 mg of N, N, N ′, N′-tetramethylazodicarboxamide ( 1.00 mmol) at room temperature for 16:00 It stirred. After completion of the reaction, the reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was 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; toluene: ethyl acetate = 4: 1 → 3: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 271 mg of the title compound as white. Obtained as a foam. (Yield 80%)
Mass spectrum (FAB, m / z): 675 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.94 (dd, J = 2.1, 0.6 Hz, 1H), 8.69 (dd, J = 4.8, 1.8 Hz, 1H), 7.85 (ddd, J = 8.3, 2.1, 1.8 Hz, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.50 (dd, J = 8.3, 7.3 Hz, 1H), 7.38-7.22 (m, 7H), 7.01-6.93 (m, 3H), 6.85 (d, J = 7.3 Hz, 1H), 5.03 (s, 2H), 4.59 (s, 2H), 4.38 (s, 2H), 4.36 (s, 2H), 1.53 (s, 9H), 1.42 (s , 9H).

5- (b): {6-[(4-phenoxymethylbenzyl) (pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid (tert-butoxy obtained in Example 5- (a) To a solution of 266 mg (0.395 mmol) of tert-butyl carbonyl {6-[(4-phenoxymethylbenzyl) (pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) acetate in 0.50 ml of tetrahydrofuran, Hydrochloric acid 0.33 ml and water 0.70 ml were added and stirred at 60 ° C. for 1 hour. After completion of the reaction, water was added to the reaction solution, adjusted to pH 4.4 with 1N aqueous sodium hydroxide solution, and extracted with a mixed solvent of ethyl acetate and tetrahydrofuran. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the obtained residue, 5 ml of a mixed solvent (ethyl acetate: n-hexane = 1: 1 (V / V)) was added, and sonication was performed. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 184 mg of the title compound as a white solid. (Yield 90%)
Mass spectrum (FAB, m / z): 519 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 8.81 (d, J = 2.0 Hz, 1H), 8.71 (dd, J = 4.9, 1.8 Hz, 1H), 8.00 (ddd, J = 8.3, 2.0, 1.8 Hz, 1H), 7.45 (ddd, J = 8.3, 4.9 Hz, 1H), 7.44-7.38 (m, 2H), 7.34-7.25 (m, 4H), 7.23 (dd, J = 8.3, 7.1 Hz, 1H ), 7.04-6.91 (m, 3H), 6.74 (brs, 1H), 6.36 (d, J = 8.3 Hz, 1H), 6.31 (d, J = 7.1 Hz, 1H), 5.08 (s, 2H), 4.67 (s, 2H), 4.17 (s, 2H), 3.68 (d, J = 5.6 Hz, 2H).
Rf value: 0.69 (n-butanol: acetic acid: water = 3: 1: 1).

[Example 6]
(6-{[4- (3-phenoxypropyl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid

6- (a): [tert-Butoxycarbonyl (6-{[4- (3-hydroxypropyl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-yl) amino] tert-butyl acetate Reference Example 1 (tert-Butoxycarbonyl {6-[(pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) 120 mg (0. 251 mmol) in acetonitrile (1.0 ml) was added 60 mg (0.26 mmol) of 4- (3-hydroxypropyl) benzyl bromide (see Journal of Medicinal Chemistry, 35, 1702 (1992)) and 69 mg (0.50 mmol) of potassium carbonate. The mixture was further stirred at room temperature for 2 hours. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic phase was 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 = 1: 1 → 1: 2 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 150 mg of the title compound. Was obtained as a white foam. (Yield 95%)
Mass spectrum (FAB, m / z): 627 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.91 (dd, J = 2.3, 0.8 Hz, 1H), 8.70 (dd, J = 4.8, 1.7 Hz, 1H), 7.89 (ddd, J = 8.0, 2.3, 1.7 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.50 (dd, J = 8.4, 7.4 Hz, 1H), 7.32 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 7.16- 7.05 (m, 4H), 6.87 (d, J = 7.4 Hz, 1H), 4.52 (s, 2H), 4.38 (s, 2H), 4.37 (s, 2H), 3.62 (dd, J = 11.4, 6.5 Hz , 2H), 2.66 (t, J = 7.4 Hz, 2H), 1.92-1.79 (m, 2H), 1.52 (s, 9H), 1.43 (s, 9H), 1.26 (t, J = 7.4 Hz, 1H) .

6- (b) [tert-Butoxycarbonyl (6-{[4- (3-phenoxypropyl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-yl) amino] acetate acetate [Tert-Butoxycarbonyl (6-{[4- (3-hydroxypropyl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-yl) amino] acetic acid tert obtained in 6- (a) -To a solution of 63 mg (0.10 mmol) of butyl in 1.0 ml of tetrahydrofuran, 9 mg (0.1 mmol) of phenol, 37 μl (0.15 mmol) of tri-n-butylphosphine and N, N, N ′, N′-tetramethylazo Dicarboxamide 26 mg (0.15 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was 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 the title compound. 63 mg was obtained as a colorless oil (yield 90%).
Mass spectrum (FAB, m / z): 703 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.93 (dd, J = 2.4, 0.7 Hz, 1H), 8.68 (dd, J = 4.9, 1.6 Hz, 1H), 7.85 (ddd, J = 8.1, 2.4, 1.6 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.50 (dd, J = 8.4, 7.4 Hz, 1H), 7.31-7.25 (m, 3H), 7.17-7.08 (m, 4H), 6.98-6.87 (m, 3H), 6.85 (d, J = 7.4 Hz, 1H), 4.54 (s, 2H), 4.37 (s, 4H), 3.95 (t, J = 6.3 Hz, 2H), 2.78 (t , J = 7.7 Hz, 2H), 2.13-2.02 (m, 2H), 1.52 (s, 9H), 1.42 (s, 9H).

6- (c) (6-{[4- (3-phenoxypropyl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid obtained in Example 6- (b) [ tert-Butoxycarbonyl (6-{[4- (3-phenoxypropyl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-yl) amino] tert-butyl acetate 60 mg (0.085 mmol) chloride To a 1.0 ml solution of methylene, 0.43 ml (1.7 mmol) of 4N hydrogen chloride / 1,4-dioxane solution was added and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, water was added to the resulting residue, the pH was adjusted to 4.4 with a 0.1 N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then dried under reduced pressure to obtain 45 mg of the title compound as a white foam. (Yield 97%)
Mass spectrum (FAB, m / z): 547 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 8.79 (dd, J = 2.4, 0.7 Hz, 1H), 8.69 (dd, J = 4.9, 1.5 Hz, 1H), 7.99 (ddd, J = 8.1, 2.4, 1.5 Hz, 1H), 7.45 (ddd, J = 8.1, 4.9, 0.7 Hz, 1H), 7.33-7.12 (m, 7H), 6.97-6.88 (m, 3H), 6.74 (t, J = 5.7 Hz , 1H), 6.35 (d, J = 8.1 Hz, 1H), 6.30 (d, J = 7.1 Hz, 1H), 4.62 (s, 2H), 4.16 (s, 2H), 3.95 (t, J = 6.3 Hz , 2H), 3.69 (d, J = 5.7 Hz, 2H), 2.72 (t, J = 7.7 Hz, 2H), 2.07-1.93 (m, 2H).
Rf value: 0.73 (n-butanol: acetic acid: water = 3: 1: 1).

[Example 7]
[6-({4- [1- (4-methoxybenzyl) -1-methylethyl] benzyl} (pyridin-2-ylsulfonyl) aminomethyl) pyridin-2-ylamino] acetic acid

7- (a): {tert-butoxycarbonyl [6-({4- [1- (4-methoxybenzyl) -1-methylethyl] benzyl} (pyridin-2-ylsulfonyl) aminomethyl) pyridine-2- (Tert-Butoxycarbonyl {6-[(pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert -butyl acetate obtained in the same manner as in Reference Example 5 To a 1.0 ml tetrahydrofuran solution of 86 mg (0.18 mmol) of butyl, 48 mg (0.18 mmol) of 4- [1- (4-methoxybenzyl) -1-methylethyl] benzyl alcohol obtained in Reference Example 6- (e). ), 112 μl (0.454 mmol) of tri-n-butylphosphine and N, N, N ′, N′-tetramethylazodica Bokisamido 77mg of (0.45 mmol) was added, and stirred at room temperature for 7 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was 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 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 105 mg of the title compound as a colorless oil. Got as. (Yield 80%)
Mass spectrum (FAB, m / z): 731 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.59 (ddd, J = 4.7, 1.6, 1.1 Hz, 1H), 7.82 (ddd, J = 7.8, 1.3, 1.1 Hz, 1H), 7.76 (ddd, J = 7.8, 7.5, 1.6 Hz, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.45 (dd, J = 8.3, 7.4 Hz, 1H), 7.37 (ddd, J = 7.5, 4.7, 1.3 Hz, 1H ), 7.13 (s, 4H), 6.90 (d, J = 7.4 Hz, 1H), 6.73-6.63 (m, 4H), 4.67 (s, 2H), 4.48 (s, 2H), 4.47 (s, 2H) , 3.74 (s, 3H), 2.75 (s, 2H), 1.52 (s, 9H), 1.43 (s, 9H), 1.25 (s, 6H).

7- (b): [6-({4- [1- (4-methoxybenzyl) -1-methylethyl] benzyl} (pyridin-2-ylsulfonyl) aminomethyl) pyridin-2-ylamino] acetic acid {Tert-Butoxycarbonyl [6-({4- [1- (4-methoxybenzyl) -1-methylethyl] benzyl} (pyridin-2-ylsulfonyl) aminomethyl) pyridine obtained in 7- (a) -2-yl] amino} acetic acid tert-butyl (102 mg, 0.140 mmol) in methylene chloride (2.1 ml) was added dropwise trifluoroacetic acid (0.54 ml, 7.1 mmol) under ice-cooling, and the mixture was stirred at room temperature for 18 hours. did. After completion of the reaction, the reaction solution was concentrated under reduced pressure, 2 ml of water was added to the residue, and the pH was adjusted to 4.2 with 1N aqueous sodium hydroxide solution and 0.2N hydrochloric acid. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 71 mg of the title compound as a white solid. (Yield 88%)
Mass spectrum (FAB, m / z): 575 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 8.62 (ddd, J = 4.6, 1.6, 0.9 Hz, 1H), 7.94 (ddd, J = 7.8, 7.6, 1.6 Hz, 1H), 7.79 (ddd, J = 7.8, 1.1, 0.9 Hz, 1H), 7.57 (ddd, J = 7.6, 4.6, 1.1 Hz, 1H), 7.25-7.11 (m, 5H), 6.76-6.63 (m, 5H), 6.34 (dd, J = 8.3 Hz, 1H), 6.28 (dd, J = 7.1 Hz, 1H), 4.65 (s, 2H), 4.20 (s, 2H), 3.80 (d, J = 4.9 Hz, 2H), 3.67 (s, 3H), 2.75 (s, 2H), 1.25 (s, 6H).
Rf value: 0.71 (n-butanol: acetic acid: water = 3: 1: 1).

[Example 8]
[6-({4- [1- (2-methoxybenzyl) -1-methylethyl] benzyl} (pyridin-2-ylsulfonyl) aminomethyl) pyridin-2-ylamino] acetic acid

8- (a): {tert-butoxycarbonyl [6-({4- [1- (2-methoxybenzyl) -1-methylethyl] benzyl} (pyridin-2-ylsulfonyl) aminomethyl) pyridine-2- yl] amino} obtained in the same manner as acetate tert- butyl reference example 5 (tert- butoxycarbonyl {6 - [(pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) acetic acid tert- To a 2.0 ml tetrahydrofuran solution of 196 mg (0.410 mmol) of butyl, 92 mg (0.34 mmol) of 4- [1- (2-methoxybenzyl) -1-methylethyl] benzyl alcohol obtained in Reference Example 8- (g) ), 128 μl (0.512 mmol) of tri-n-butylphosphine and N, N, N ′, N′-tetramethylazo Carboxamide 88mg of (0.51 mmol) was added and stirred at room temperature for 4 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; toluene: ethyl acetate = 9: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 117 mg of the title compound as a colorless oil. It was. (Yield 47%)
Mass spectrum (FAB, m / z): 731 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.58 (ddd, J = 4.7, 1.6, 0.9 Hz, 1H), 7.81 (ddd, J = 7.7, 1.2, 0.9 Hz, 1H), 7.75 (ddd, J = 7.7, 7.4, 1.6 Hz, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.45 (dd, J = 8.3, 7.4 Hz, 1H), 7.37 (ddd, J = 7.4, 4.7, 1.2 Hz, 1H ), 7.21-7.09 (m, 5H), 6.91 (d, J = 7.4 Hz, 1H), 6.78 (dd, J = 8.1, 0.7 Hz, 1H), 6.75-6.64 (m, 2H), 4.67 (s, 2H), 4.49 (s, 2H), 4.47 (s, 2H), 3.67 (s, 3H), 2.86 (s, 2H), 1.52 (s, 9H), 1.43 (s, 9H), 1.25 (s, 6H ).

8- (b): [6-({4- [1- (2-methoxybenzyl) -1-methylethyl] benzyl} (pyridin-2-ylsulfonyl) aminomethyl) pyridin-2-ylamino] acetic acid Examples {Tert-Butoxycarbonyl [6-({4- [1- (2-methoxybenzyl) -1-methylethyl] benzyl} (pyridin-2-ylsulfonyl) aminomethyl) pyridine obtained in 8- (a) To a solution of tert-butyl -2-yl] amino} acetate 115 mg (0.157 mmol) in methylene chloride, 0.60 ml (7.8 mmol) of trifluoroacetic acid was added dropwise over 1 minute under ice-cooling. Stir at room temperature for 21 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, water was added to the residue, pH was adjusted to 4.2 with 1N aqueous sodium hydroxide solution and 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; ethyl acetate: acetic acid = 50: 1 (V / V)) and then reverse phase C18 column chromatography (elution solvent; acetonitrile: 0.05 vol% aqueous trifluoroacetic acid = 1: 4). → 3: 2 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The pH was adjusted to 4.2 with 1N aqueous sodium hydroxide solution and 1N hydrochloric acid, and the precipitated solid was collected by filtration and dried under reduced pressure to give 28 mg of the title compound as a white solid. (Yield 31%)
Mass spectrum (FAB, m / z): 575 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 8.64-8.60 (m, 1H), 7.94 (ddd, J = 7.8, 7.7, 1.6 Hz, 1H), 7.78 (ddd, J = 7.8, 1.0, 1.0 Hz, 1H), 7.56 (ddd, J = 7.7, 4.6, 1.0 Hz, 1H), 7.26-7.08 (m, 6H), 6.88 (d, J = 8.3 Hz, 1H), 6.76-6.64 (m, 3H) , 6.34 (d, J = 8.3 Hz, 1H), 6.28 (d, J = 7.1 Hz, 1H), 4.66 (s, 2H), 4.20 (s, 2H), 3.81 (d, J = 5.1 Hz, 2H) , 3.63 (s, 3H), 2.82 (s, 2H), 1.20 (s, 6H).
Rf value: 0.71 (n-butanol: acetic acid: water = 3: 1: 1).

[Example 9]
(6-{[4- (1,1-dimethyl-3-phenylpropyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid

9- (a): [tert-butoxycarbonyl (6-{[4- (1,1-dimethyl-3-phenylpropyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-yl) amino Tert-Butyl acetate (tert-Butoxycarbonyl {6-[(pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) 215 mg 0.449 mmol) in tetrahydrofuran (5 ml) was mixed with 114 mg (0.448 mmol) of 4- (1,1-dimethyl-3-phenylpropyl) benzyl alcohol obtained in Reference Example 9- (b), 260 μl (1.04 mmol) and N, N, N ′, N′-tetramethylazodicarboxamide 1 6mg of (0.674mmol) was added and stirred at room temperature for 5 hours. After completion of the reaction, a saturated aqueous sodium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was 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 = 9: 1 → 1: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 293 mg of the title compound. Was obtained as a colorless oil. (Yield 91%)
Mass spectrum (CI, m / z): 715 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.59-8.55 (m, 1H), 7.82 (ddd, J = 7.7, 1.1, 1.0 Hz, 1H), 7.75 (ddd, J = 7.7, 7.5, 1.8 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.43 (dd, J = 8.2, 7.4 Hz, 1H), 7.34 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 7.28-7.11 (m , 7H), 7.10-7.05 (m, 2H), 6.91 (d, J = 7.4 Hz, 1H), 4.67 (s, 2H), 4.51 (s, 2H), 4.47 (s, 2H), 2.34-2.24 ( m, 2H), 1.93-1.83 (m, 2H), 1.52 (s, 9H), 1.43 (s, 9H), 1.32 (s, 6H).

9- (b): (6-{[4- (1,1-dimethyl-3-phenylpropyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid Example 9- ( [tert-Butoxycarbonyl (6-{[4- (1,1-dimethyl-3-phenylpropyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-yl) amino obtained in a) To a solution of 292 mg (0.408 mmol) of tert-butyl acetate in 4 ml of methylene chloride was added 4 ml (16 mmol) of 4N hydrogen chloride / 1,4-dioxane solution, and the mixture was stirred at room temperature for 21 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, water was added to the resulting residue, the pH was adjusted to 4.5 with 1N aqueous sodium hydroxide solution and 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; ethyl acetate: acetic acid = 40: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 206 mg of the title compound as a pale brown foam. Got as. (Yield 90%)
Mass spectrum (FAB, m / z): 559 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 8.61 (ddd, J = 4.7, 1.6, 0.8 Hz, 1H), 7.93 (ddd, J = 7.8, 7.7, 1.6 Hz, 1H), 7.80-7.77 ( m, 1H), 7.54 (ddd, J = 7.7, 4.7, 1.0 Hz, 1H), 7.32-7.06 (m, 10H), 6.72 (brs, 1H), 6.32 (d, J = 8.1 Hz, 1H), 6.27 (d, J = 7.0 Hz, 1H), 4.66 (s, 2H), 4.23 (s, 2H), 3.82 (d, J = 5.5 Hz, 2H), 2.28-2.21 (m, 2H), 1.88-1.80 ( m, 2H), 1.30 (s, 6H).
Rf value: 0.71 (n-butanol: acetic acid: water = 3: 1: 1).

[Example 10]
[6-({4- [1,1-Dimethyl-2- (tetrahydro-2H-pyran-4-yl) ethyl] benzyl} (pyridin-2-ylsulfonyl) aminomethyl) pyridin-2-ylamino] acetic acid

10- (a): (tert-Butoxycarbonyl [6-({4- [1,1-dimethyl-2- (tetrahydro-2H-pyran-4-yl) ethyl] benzyl} (pyridin-2-ylsulfonyl) (Aminomethyl) pyridin-2-yl] amino) (tert-butoxycarbonyl {6-[((pyridin-2-ylsulfonyl) aminomethyl] pyridine-2-) obtained by a method similar to that of tert-butyl acetate Reference Example 5 Yl} amino) 4- [1,1-dimethyl-2- (tetrahydro-2H-pyran) obtained in Reference Example 10- (d) in a solution of 256 mg (0.535 mmol) of tert-butyl acetate in 6.1 ml of tetrahydrofuran. -4-yl) ethyl] benzyl alcohol 133 mg (0.536 mmol), tri-n-butylphosphine 253 μl (1.0 mmol) and N, N, N ', N'- tetramethyl azodicarboxamide 145mg of (0.842 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 = 3: 2 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 123 mg of the title compound as a white foam. Obtained as a thing. (Yield 32%)
Mass spectrum (FAB, m / z): 709 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.58 (ddd, J = 4.7, 1.6, 1.1 Hz, 1H), 7.81 (ddd, J = 7.7, 1.4, 1.1 Hz, 1H), 7.76 (ddd, J = 7.7, 7.4, 1.6 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.43 (dd, J = 8.1, 7.4 Hz, 1H), 7.37 (ddd, J = 7.4, 4.7, 1.4 Hz, 1H ), 7.23-7.17 (m, 2H), 7.17-7.11 (m, 2H), 6.87 (d, J = 7.4 Hz, 1H), 4.67 (s, 2H), 4.46 (s, 4H), 3.82-3.70 ( m, 2H), 3.28-3.14 (m, 2H), 1.60-1.06 (m, 7H), 1.52 (s, 9H), 1.43 (s, 9H), 1.28 (s, 6H).

10- (b): [6-({4- [1,1-dimethyl-2- (tetrahydro-2H-pyran-4-yl) ethyl] benzyl} (pyridin-2-ylsulfonyl) aminomethyl) pyridine- 2-ylamino] acetic acid (tert-butoxycarbonyl [6-({4- [1,1-dimethyl-2- (tetrahydro-2H-pyran-4-yl) ethyl]) obtained in Example 10- (a) Benzyl} (pyridin-2-ylsulfonyl) aminomethyl) pyridin-2-yl] amino) tert-butyl acetate 122 mg (0.172 mmol) in methylene chloride 1.0 ml was added 4N hydrogen chloride / 1,4- Dioxane solution 0.84 ml (3.3 mmol) was added and stirred at room temperature for 16.5 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, water was added to the resulting residue, and the pH was adjusted to 4.5 with 1N aqueous sodium hydroxide and 1N hydrochloric acid. The precipitated solid was collected by filtration and dried under reduced pressure to give 56 mg of the title compound as a white solid. (Yield 59%)
Mass spectrum (FAB, m / z): 553 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 8.64-8.60 (m, 1H), 7.94 (ddd, J = 7.8, 7.7, 1.7 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H) , 7.57 (ddd, J = 7.7, 4.6, 1.1 Hz, 1H), 7.27-7.23 (m, 2H), 7.18 (dd, J = 8.3, 7.2 Hz, 1H), 7.16-7.12 (m, 2H), 6.76 -6.66 (m, 0.9H), 6.33 (d, J = 8.3 Hz, 1H), 6.26 (d, J = 7.2 Hz, 1H), 4.63 (s, 2H), 4.18 (s, 2H), 3.81 (d , J = 5.5 Hz, 1H), 3.66-3.59 (m, 2H), 3.13-3.05 (m, 2H), 1.54 (d, J = 5.3 Hz, 2H), 1.40-1.29 (m, 1H), 1.25 ( s, 6H), 1.22-1.14 (m, 2H), 1.05-0.94 (m, 2H).
Rf value: 0.68 (n-butanol: acetic acid: water = 3: 1: 1).

[Example 11]
(6-{[4- (2-methoxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid

11- (a): (tert-butoxycarbonyl [6-({4- [2- (4-methoxybenzyloxy) -1,1-dimethylethyl] benzyl} (pyridin-2-ylsulfonyl) aminomethyl) pyridine -2-yl] amino) (tert-Butoxycarbonyl {6-[(pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) obtained by a method similar to that of Reference Example 5 4- [2- (4-methoxybenzyloxy) -1,1-dimethylethyl] benzyl obtained in Reference Example 11- (b) was added to a solution of 5.56 g (11.8 mmol) of tert-butyl acetate in 70 ml of tetrahydrofuran. 3.90 g (13.0 mmol) of alcohol, 4.4 ml (18 mmol) of tri-n-butylphosphine and N, N, N ′, '- tetramethyl azodicarboxamide 4.57g of (26.5 mmol) was added and stirred for 2 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 the title compound 6 Obtained .83 g as an oil. (Yield 76%)
Mass spectrum (CI, m / z): 761 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 8.62 (ddd, J = 4.6, 1.8, 0.9 Hz, 1H), 7.98 (ddd, J = 7.7, 7.7, 1.8 Hz, 1H), 7.83 (ddd, J = 7.7, 1.0, 0.9 Hz, 1H), 7.62-7.53 (m, 3H), 7.25-7.18 (m, 2H), 7.18-7.12 (m, 2H), 7.11-7.03 (m, 2H), 6.91- 6.83 (m, 3H), 4.57 (s, 2H), 4.40 (s, 2H), 4.37 (s, 2H), 4.35 (s, 2H), 3.73 (s, 3H), 3.36 (s, 2H), 1.45 (s, 9H), 1.37 (s, 9H), 1.22 (s, 6H).

11- (b): [tert-Butoxycarbonyl (6-{[4- (2-hydroxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-yl) amino Tert-Butyl acetate (tert-Butoxycarbonyl [6-({4- [2- (4-methoxybenzyloxy) -1,1-dimethylethyl] benzyl} (pyridine) obtained in Example 11- (a) -2-ylsulfonyl) aminomethyl) pyridin-2-yl] amino) tert-butyl acetate 6.80 g (8.94 mmol) in methylene chloride 180 ml was added 2,3-dichloro-5,6-dicyano-1, 4-Benzoquinone (3.04 g, 13.4 mmol) and water (10 ml) were added, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was 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 = 4: 1 → 1: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound 3 Obtained .81 g as an oil. (Yield 67%)
Mass spectrum (CI, m / z): 641 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.60 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 7.87-7.74 (m, 2H), 7.62 (d, J = 8.5 Hz, 1H), 7.48 -7.35 (m, 2H), 7.25-7.20 (m, 2H), 7.20-7.15 (m, 2H), 6.90 (d, J = 7.6 Hz, 1H), 4.65 (s, 2H), 4.48 (s, 2H ), 4.45 (s, 2H), 3.60-3.54 (m, 2H), 1.52 (s, 9H), 1.43 (s, 9H), 1.29 (s, 6H).

11- (c): [tert-butoxycarbonyl (6-{[4- (2-methoxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-yl) amino [Tert-Butyl acetate] [tert-Butoxycarbonyl (6-{[4- (2-hydroxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl)] obtained in Example 11- (b) 196 mg (4.5 mmol) of sodium hydride (55% mineral oil dispersion) was added to a solution of 1.92 g (3.00 mmol) of tert-butyl acetate in aminomethyl} pyridin-2-yl) amino] acetate in 20 ml of tetrahydrofuran. For 1.5 hours. Next, 280 μl (4.50 mmol) of iodomethane and 893 μl (4.51 mmol) of 15-crown-5 were added and stirred at room temperature for 24 hours. 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 → 1: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound 0. .38 g was obtained as an oil. (Yield 19%)
Mass spectrum (CI, m / z): 655 (M ⁺ +1).
¹ H-NMR spectrum (CD ₃ OD, δ ppm): 8.60 (ddd, J = 4.8, 1.7, 1.0 Hz, 1H), 7.93 (ddd, J = 7.8, 7.7, 1.7 Hz, 1H), 7.84 (ddd, J = 7.8, 1.0, 1.0 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.56-7.48 (m, 2H), 7.26-7.20 (m, 2H), 7.16-7.08 (m, 2H), 6.95-6.98 (m, 1H), 4.62 (s, 2H), 4.46 (s, 2H), 4.43 (s, 2H), 3.36 (s, 2H), 3.27 (s, 3H), 1.52 (s, 9H) , 1.44 (s, 9H), 1.25 (s, 6H).

11- (d): (6-{[4- (2-methoxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid Example 11- ( [tert-Butoxycarbonyl (6-{[4- (2-methoxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-yl) amino obtained in c) To a solution of 0.38 g (0.58 mmol) of tert-butyl acetate in 30 ml of methylene chloride was added 4.33 ml (17.3 mmol) of 4N hydrogen chloride / 1,4-dioxane solution, and the mixture was stirred at room temperature for 32 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent; ethyl acetate: methanol = 9: 1), and the fraction containing the desired product was concentrated under reduced pressure. -Hexane was added, and the precipitated solid was collected by filtration and dried under reduced pressure to give 0.22 g of the title compound as a white solid (yield 76%).
Mass spectrum (FAB, m / z): 499 (M ⁺ +1).
¹ H-NMR spectrum (CD ₃ OD, δ ppm): 8.75 (ddd, J = 4.6, 1.7, 1.0 Hz, 1H), 8.15-8.00 (m, 2H), 7.73-7.63 (m, 2H), 7.26-7.20 (m, 2H), 7.17-7.10 (m, 2H), 6.80 (d, J = 9.0 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 4.71 (s, 2H), 4.49 (s, 2H), 4.15 (s, 2H), 3.35 (s, 2H), 3.28 (s, 3H), 1.22 (s, 6H).
Rf value: 0.63 (n-butanol: acetic acid: water = 3: 1: 1).

[Example 12]
(6-{[4- (2-Ethoxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid

12- (a): [tert-butoxycarbonyl (6-{[4- (2-ethoxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-yl) amino [Tert-Butyl acetate] [tert-Butoxycarbonyl (6-{[4- (2-hydroxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl)] obtained in Example 11- (b) Aminomethyl} pyridin-2-yl) amino] tert-butyl acetate 0.26 g (0.41 mmol) in tetrahydrofuran 3 ml was added sodium hydride (mineral oil 55% dispersion) 21 mg (0.48 mmol) at room temperature. For 30 minutes. Next, 49 μl (0.61 mmol) of iodoethane and 97 μl (0.49 mmol) of 15-crown-5 were added and stirred at room temperature for 24 hours. 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 → 1: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 43 mg of the title compound. Was obtained as an oil. (Yield 16%)
Mass spectrum (CI, m / z): 669 (M ⁺ +1).
¹ H-NMR spectrum (CD ₃ OD, δ ppm): 8.60 (ddd, J = 4.6, 1.8, 1.0 Hz, 1H), 7.93 (ddd, J = 7.8, 7.8, 1.8 Hz, 1H), 7.84 (ddd, J = 7.8, 1.0, 1.0 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.56-7.48 (m, 2H), 7.26-7.20 (m, 2H), 7.15-7.07 (m, 2H), 6.94-6.89 (m, 1H), 4.62 (s, 2H), 4.46 (s, 2H), 4.43 (s, 2H), 3.47-7.37 (m, 4H), 1.52 (s, 9H), 1.44 (s, 9H), 1.26 (s, 6H), 1.12 (t, J = 7.0 Hz, 3H).

12- (b): (6-{[4- (2-Ethoxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid Example 12- ( [tert-Butoxycarbonyl (6-{[4- (2-ethoxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-yl) amino obtained in a) ] To a solution of 40 mg (0.060 mmol) of tert-butyl acetate in 3 ml of methylene chloride was added 0.30 ml (1.2 mmol) of 4N hydrogen chloride / 1,4-dioxane solution, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent; ethyl acetate: methanol = 9: 1). Obtained as a white foam (52% yield).
Mass spectrum (FAB, m / z): 513 (M ⁺ +1).
¹ H-NMR spectrum (CD ₃ OD, δ ppm): 8.80-8.70 (m, 1H), 8.18-7.98 (m, 2H), 7.76-7.58 (m, 2H), 7.28-7.19 (m, 2H), 7.19 -7.10 (m, 2H), 6.80 (d, J = 9.0 Hz, 1H), 6.62 (d, J = 7.3 Hz, 1H), 4.70 (s, 2H), 4.50 (s, 2H), 4.15 (s, 2H), 3.43 (q, J = 7.0 Hz, 2H), 3.37 (s, 2H), 1.23 (s, 6H), 1.12 (t, J = 7.0 Hz, 3H).
Rf value: 0.65 (n-butanol: acetic acid: water = 3: 1: 1).

[Example 13]
(6-{[4- (2-Butoxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid

13- (a): [(6-{[4- (2-butoxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-yl) tert-butoxycarbonylamino [Tert-Butyl acetate] [tert-Butoxycarbonyl (6-{[4- (2-hydroxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl)] obtained in Example 11- (b) Aminomethyl} pyridin-2-yl) amino] tert-butyl acetate 0.26 g (0.41 mmol) in tetrahydrofuran 3 ml was added sodium hydride (mineral oil 55% dispersion) 21 mg (0.48 mmol) at room temperature. For 30 minutes. Subsequently, 60 μl (0.53 mmol) of 1-iodobutane and 97 μl (0.49 mmol) of 15-crown-5 were added and stirred at room temperature for 24 hours. 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 → 1: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 22 mg of the title compound. Was obtained as an oil. (Yield 7.7%)
Mass spectrum (CI, m / z): 697 (M ⁺ +1).
¹ H-NMR spectrum (CD ₃ OD, δ ppm): 8.60 (ddd, J = 4.8, 1.7, 1.0 Hz, 1H), 7.93 (ddd, J = 7.8, 7.7, 1.7 Hz, 1H), 7.84 (ddd, J = 7.8, 1.0, 1.0 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.56-7.48 (m, 2H), 7.27-7.20 (m, 2H), 7.15-7.07 (m, 2H), 6.94-6.89 (m, 1H), 4.62 (s, 2H), 4.45 (s, 2H), 4.43 (s, 2H), 3.40-3.33 (m, 4H), 1.58-1.20 (m, 4H), 1.52 ( s, 9H), 1.44 (s, 9H), 1.26 (s, 6H), 0.88 (t, J = 7.3 Hz, 3H).

13- (b): (6-{[4- (2-Butoxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid Example 13- ( [tert-Butoxycarbonyl (6-{[4- (2-butoxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-yl) amino obtained in a) To a solution of tert-butyl acetate 21 mg (0.030 mmol) in 5 ml of methylene chloride was added 0.15 ml (0.60 mmol) of 4N hydrogen chloride / 1,4-dioxane solution, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent; ethyl acetate: methanol = 9: 1), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound 7. 8 mg was obtained as a white foam (48% yield).
Mass spectrum (FAB, m / z): 541 (M ⁺ +1).
¹ H-NMR spectrum (CD ₃ OD, δ ppm): 8.80-8.68 (m, 1H), 8.20-7.90 (m, 2H), 7.78-7.54 (m, 2H), 7.32-7.19 (m, 2H), 7.19 -7.10 (m, 2H), 6.77 (d, J = 8.8 Hz, 1H), 6.61 (d, J = 7.3 Hz, 1H), 4.68 (s, 2H), 4.51 (s, 2H), 4.14 (s, 2H), 3.42-3.33 (m, 4H), 1.56-1.42 (m, 2H), 1.40-1.26 (m, 2H), 1.23 (s, 6H), 0.89 (t, J = 7.3 Hz, 3H).
Rf value: 0.68 (n-butanol: acetic acid: water = 3: 1: 1).

[Example 14]
(6-{[4- (1,1-Dimethyl-2-pentyloxyethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid

14- (a): [tert-butoxycarbonyl (6-{[4- (1,1-dimethyl-2-pentyloxyethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-yl) [Amino] tert-butyl acetate [tert-Butoxycarbonyl (6-{[4- (2-hydroxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) obtained in Example 11- (b) To a solution of) aminomethyl} pyridin-2-yl) amino] tert-butyl acetate 0.27 g (0.42 mmol) in tetrahydrofuran 3 ml was added sodium hydride (55% mineral oil dispersion) 28 mg (0.64 mmol), Stir at room temperature for 30 minutes. Next, 82 μl (0.63 mmol) of 1-iodopentane and 121 μl (0.611 mmol) of 15-crown-5 were added and stirred at room temperature for 24 hours. 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 → 1: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 39 mg of the title compound. Was obtained as an oil. (Yield 13%)
Mass spectrum (CI, m / z): 711 (M ⁺ +1).
¹ H-NMR spectrum (CD ₃ OD, δ ppm): 8.60 (ddd, J = 4.8, 1.7, 1.0 Hz, 1H), 7.93 (ddd, J = 7.8, 7.7, 1.7 Hz, 1H), 7.84 (ddd, J = 7.8, 1.0, 0.9 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.57-7.47 (m, 2H), 7.27-7.20 (m, 2H), 7.15-7.07 (m, 2H), 6.95-6.88 (m, 1H), 4.62 (s, 2H), 4.45 (s, 2H), 4.43 (s, 2H), 3.40-3.32 (m, 4H), 1.57-1.37 (m, 6H), 1.52 ( s, 9H), 1.44 (s, 9H), 1.26 (s, 6H), 0.87 (t, J = 6.8 Hz, 3H).

14- (b): (6-{[4- (1,1-dimethyl-2-pentyloxyethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid Example 14- [Tert-Butoxycarbonyl (6-{[4- (1,1-dimethyl-2-pentyloxyethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-yl obtained in (a) ) A solution of tert-butyl acetate 35 mg (0.049 mmol) in 3 ml of methylene chloride was added 0.25 ml (1.0 mmol) of 4N hydrogen chloride / 1,4-dioxane solution and stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent; ethyl acetate: methanol = 9: 1), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound 8. 3 mg was obtained as a white foam (yield 31%).
Mass spectrum (FAB, m / z): 555 (M ⁺ +1).
¹ H-NMR spectrum (CD ₃ OD, δ ppm): 8.82-8.68 (m, 1H), 8.15-7.95 (m, 2H), 7.70-7.55 (m, 2H), 7.30-7.19 (m, 2H), 7.19 -7.10 (m, 2H), 6.74 (d, J = 8.3 Hz, 1H), 6.58 (d, J = 7.3 Hz, 1H), 4.65 (s, 2H), 4.53 (s, 2H), 4.12 (s, 2H), 3.42-3.33 (m, 4H), 1.58-1.42 (m, 2H), 1.38-1.16 (m, 4H), 1.23 (s, 6H), 0.88 (t, J = 6.7 Hz, 3H).
Rf value: 0.70 (n-butanol: acetic acid: water = 3: 1: 1).

[Example 15]
(6-{[4- (2-Hexyloxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid

15- (a): [tert-butoxycarbonyl (6-{[4- (2-hexyloxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-yl) [Amino] tert-butyl acetate [tert-Butoxycarbonyl (6-{[4- (2-hydroxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) obtained in Example 11- (b) 16 mg (0.37 mmol) of sodium hydride (55% mineral oil dispersion) was added to a solution of 0.20 g (0.31 mmol) of tert-butyl acetate) in 3 ml of tetrahydrofuran. Stir at room temperature for 30 minutes. Subsequently, 60 μl (0.41 mmol) of 1-iodohexane and 74 μl (0.37 mmol) of 15-crown-5 were added and stirred at room temperature for 24 hours. 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 → 1: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 18 mg of the title compound. Was obtained as an oil. (Yield 8.0%)
Mass spectrum (CI, m / z): 725 (M ⁺ +1).
¹ H-NMR spectrum (CD ₃ OD, δ ppm): 8.59 (ddd, J = 4.8, 1.7, 1.0 Hz, 1H), 7.93 (ddd, J = 7.8, 7.7, 1.7 Hz, 1H), 7.84 (ddd, J = 7.7, 1.0, 1.0 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.56-7.47 (m, 2H), 7.28-7.20 (m, 2H), 7.15-7.07 (m, 2H), 6.95-6.88 (m, 1H), 4.62 (s, 2H), 4.45 (s, 2H), 4.43 (s, 2H), 3.40-3.32 (m, 4H), 1.57-1.18 (m, 8H), 1.52 ( s, 9H), 1.44 (s, 9H), 1.26 (s, 6H), 0.87 (t, J = 6.7 Hz, 3H).

15- (b): (6-{[4- (2-Hexyloxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid Example 15- [Tert-Butoxycarbonyl (6-{[4- (2-hexyloxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-yl obtained in (a) ) Amino] 0.12 ml (0.48 mmol) of 4N hydrogen chloride / 1,4-dioxane solution was added to a solution of 18 mg (0.025 mmol) of tert-butyl acetate in 5 ml of methylene chloride, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent; ethyl acetate: methanol = 9: 1), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound 5. 1 mg was obtained as a white foam (yield 36%).
Mass spectrum (FAB, m / z): 569 (M ⁺ +1).
¹ H-NMR spectrum (CD ₃ OD, δ ppm): 8.80-8.65 (m, 1H), 8.20-7.90 (m, 2H), 7.76-7.50 (m, 2H), 7.30-7.20 (m, 2H), 7.20 -7.06 (m, 2H), 6.74 (d, J = 8.5 Hz, 1H), 6.59 (d, J = 7.1 Hz, 1H), 4.65 (s, 2H), 4.53 (s, 2H), 4.12 (s, 2H), 3.40-3.33 (m, 4H), 1.58-1.42 (m, 2H), 1.38-1.18 (m, 6H), 1.23 (s, 6H), 0.88 (t, J = 6.5 Hz, 3H).

[Example 16]
(6-{[4- (2-Benzyloxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid

16- (a): [(6-{[4- (2-benzyloxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-yl) tert-butoxycarbonyl [Amino] tert-butyl acetate [tert-Butoxycarbonyl (6-{[4- (2-hydroxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) obtained in Example 11- (b) To a solution of) aminomethyl} pyridin-2-yl) amino] tert-butyl acetate 113 mg (0.176 mmol) in tetrahydrofuran 1 ml was added sodium hydride (mineral oil 55% dispersion) 7.7 mg (0.18 mmol), Stir at room temperature for 1 hour. Subsequently, 23 μl (0.19 mmol) of benzyl bromide and 35 μl (0.18 mmol) of 15-crown-5 were added and stirred at room temperature for 24 hours. 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 → 1: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 29 mg of the title compound. Was obtained as an oil. (Yield 23%)
Mass spectrum (CI, m / z): 731 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.56 (ddd, J = 4.6, 1.7, 1.1 Hz, 1H), 7.79 (ddd, J = 7.7, 1.2, 1.1 Hz, 1H), 7.72 (ddd, J = 7.7, 7.7, 1.7 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.43 (dd, J = 8.7, 7.6 Hz, 1H), 7.39-7.18 (m, 8H), 7.18-7.11 (m , 2H), 6.89 (d, J = 7.6 Hz, 1H), 4.66 (s, 2H), 4.48 (s, 2H), 4.47 (s, 2H), 4.46 (s, 2H), 3.41 (s, 2H) , 1.52 (s, 9H), 1.42 (s, 9H), 1.30 (s, 6H).

16- (b): (6-{[4- (2-Benzyloxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid Example 16- [(6-{[4- (2-Benzyloxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-yl) tert-butoxy obtained in (a) Carbonylamino] tert-butyl acetate 25 mg (0.034 mmol) in tetrahydrofuran 1 ml solution was added concentrated hydrochloric acid 57 μl (0.68 mmol) and water 1 ml, and the mixture was stirred at 60 ° C. for 8 hours. After completion of the reaction, the pH was adjusted to 5 with 1N aqueous sodium hydroxide solution, and the mixture was 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: methanol = 9: 1), and the fraction containing the desired product was concentrated under reduced pressure to obtain 12 mg of the title compound as a white foam (yield). 61%)
Mass spectrum (FAB, m / z): 575 (M ⁺ +1).
¹ H-NMR spectrum (CD ₃ OD, δ ppm): 8.55 (ddd, J = 4.8, 1.7, 1.0 Hz, 1H), 7.85 (ddd, J = 7.8, 7.6, 1.7 Hz, 1H), 7.76 (ddd, J = 7.8, 1.2, 1.0 Hz, 1H), 7.46 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.33-7.17 (m, 10H), 6.40 (d, J = 7.1 Hz, 1H), 6.31 ( d, J = 8.1 Hz, 1H), 4.72 (s, 2H), 4.44 (s, 2H), 4.32 (s, 2H), 3.88 (s, 2H), 3.45 (s, 2H), 1.30 (s, 6H ).
Rf value: 0.69 (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- (1-cyclohexylethyl) benzyl alcohol 2- (a): 4- (1-cyclohexyl-1-hydroxyethyl) benzoic acid 4-bromobenzoic acid 1.00 g (4.97 mmol) in 20 ml of tetrahydrofuran was added argon. Under an atmosphere, 10.8 ml (15.8 mmol) of a 1.46 M tert-butyllithium / pentane solution was added dropwise at −70 ° C. over 15 minutes, and the mixture was stirred at the same temperature for 30 minutes. Subsequently, 1.1 ml (8.0 mmol) of cyclohexyl methyl ketone was added dropwise over 5 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 1.7 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 365 mg of the title compound. Was obtained as a slightly yellow foam. (Yield 30%)
Mass spectrum (CI, m / z): 249 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 7.90-7.82 (m, 2H), 7.53-7.45 (m, 2H), 4.82 (s, 1H), 1.75-0.80 (m, 11H), 1.41 ( s, 3H).

2- (b): 4- (1-cyclohexylethyl) benzoic acid Reference Example 2- (a) 4- (1-cyclohexyl-1-hydroxyethyl) benzoic acid 361 mg (1.45 mmol) in methylene chloride To a 2.3 ml solution, 2.35 ml (14.5 mmol) of triethylsilane and 365 μl (2.91 mmol) of boron trifluoride / ethyl ether complex in 1 ml of methylene chloride were added under ice cooling, followed by stirring at room temperature for 15 hours. 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 = 10: 1 → 2: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 325 mg of the title compound. Was obtained as a white solid. (Yield 96%)
Mass spectrum (CI, m / z): 233 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.05-7.98 (m, 2H), 7.27-7.20 (m, 2H), 2.53 (dq, J = 7.3, 7.1, 1H), 1.95-0.70 (m, 11H ), 1.25 (d, J = 7.1, 3H).

2- (c): Obtained in a solution of 4- (1-cyclohexylethyl) benzyl alcohol lithium aluminum hydride (158 mg, 4.17 mmol) in tetrahydrofuran (4 ml) at 40 ° C. under argon gas atmosphere in Reference Example 2- (b) A solution of 321 mg (1.38 mmol) of 4- (1-cyclohexylethyl) benzoic acid in 9 ml of tetrahydrofuran was added dropwise over 10 minutes. After stirring at the same temperature for 1.5 hours, 53.3 mg (1.38 mmol) of lithium aluminum hydride was further added, and the mixture was further stirred for 1 hour. After completion of the reaction, 212 μl of water, 212 μl of 15% aqueous sodium hydroxide solution and 636 μl of water were sequentially added to the reaction solution under ice cooling. The insoluble material was then removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 1: 0 → 0: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 273 mg of the title compound. Was obtained as a slightly yellow oil. (Yield 91%)
Mass spectrum (EI, m / z): 218 (M ⁺ ).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.31-7.24 (m, 2H), 7.17-7.11 (m, 2H), 4.66 (d, J = 5.9, 2H), 2.45 (dq, J = 7.3, 7.1 , 1H), 1.95-0.70 (m, 12H), 1.22 (d, J = 7.1, 3H).

[Reference Example 3]
4- (3-hydroxy-2,2,4,4-tetramethylpentan-3-yl) benzyl alcohol 3- (a): 4- (3-hydroxy-2,2,4,4-tetramethylpentane- 3-yl) benzoic acid 12 ml (21 mmol) of a 1.76 M tert-butyllithium / pentane solution was added to a solution of 1.40 g (6.96 mmol) of 4-bromobenzoic acid in 28 ml of tetrahydrofuran at −70 ° C. in an argon atmosphere. The solution was added dropwise over 10 minutes and stirred at the same temperature for 1 hour. Then, a solution of 2,2,4,4-tetramethyl-3-pentanone (1.00 g, 7.03 mmol) in tetrahydrofuran (7 ml) was added dropwise over 5 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. Water was added, the aqueous layer was adjusted to pH 2.8, 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 = 2: 1 → 0: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 593 mg of the title compound. (Purity 81%) was obtained as a white solid. (Yield 26%)
Mass spectrum (CI, m / z): 265 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.06 (dd, J = 8.4, 1.7, 1H), 7.98 (dd, J = 8.4, 1.7, 1H), 7.85 (dd, J = 8.4, 1.8, 1H) , 7.68 (dd, J = 8.4, 1.8, 1H), 2.05 (s, 1H), 1.10 (s, 18H).

3- (b): 4- (3-Hydroxy-2,2,4,4-tetramethylpentan-3-yl) benzyl alcohol obtained in Reference Example 3- (a) , 2,4,4-Tetramethylpentan-3-yl) benzoic acid 502 mg (1.54 mmol as 81% purity) in tetrahydrofuran 5 ml solution at room temperature at 0.99 M borane-tetrahydrofuran complex / tetrahydrofuran solution 6 ml (7.5 mmol) was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 2 hours. 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 → 3: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to obtain 339 mg of a crude product. Got. To the crude product, 6 ml of n-hexane was added and stirred for 1 hour under ice cooling. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 154 mg of the title compound as a white solid. (Yield 40%)
Mass spectrum (CI, m / z): 233 (M ⁺ -17).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.68 (dd, J = 8.2, 2.1, 1H), 7.55 (dd, J = 8.2, 2.1, 1H), 7.35-7.20 (m, 2H), 4.69 (d , J = 6.0, 2H), 1.93 (s, 1H), 1.61 (t, J = 6.0 Hz, 1H), 1.09 (s, 18H).

[Reference Example 4]
1- (4-Hydroxymethylphenyl) -N, N, N-trimethylmethanaminium iodide 4-aminomethylbenzyl alcohol 100 mg (0.729 mmol) in N, N-dimethylformamide 320 μl in ice-cooled tributylamine 348 μl (1.46 mmol) and 227 μl (3.65 mmol) of methyl iodide were sequentially added and stirred at room temperature for 25 hours. After completion of the reaction, the reaction solution was poured into 30 ml of ethyl acetate and stirred for 1.5 hours. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 134 mg of the title compound as a pale yellow solid. (Yield 60%)
Mass spectrum (CI, m / z): 180 (M ⁺ ).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 7.52-7.42 (m, 4H), 5.33 (t, J = 5.6 Hz, 1H), 4.56 (d, J = 5.6 Hz, 2H), 4.49 (s , 2H), 3.01 (s, 9H).

[Reference Example 5]
(Tert-Butoxycarbonyl {6-[(pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate [(6-aminomethylpyridine) obtained in Reference Example 1- (e) -2-yl) tert-butoxycarbonylamino] tert-butyl acetate 1.20 g (3.56 mmol) was used, but 2-pyridylsulfonyl chloride 640 mg (3.60 mmol) was used instead of 3-pyridylsulfonyl chloride Were reacted and worked up according to Reference Example 1- (f) to give 1.46 g of the title compound as a white solid. (Yield 86%)
Mass spectrum (APCI, m / z): 479 (M + +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.56 (ddd, J = 4.7, 1.7, 0.9 Hz, 1H), 7.97 (ddd, J = 7.8, 1.1, 0.9 Hz, 1H), 7.84 (ddd, J = 7.8, 7.7, 1.7 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.52 (dd, J = 8.4, 7.4 Hz, 1H), 7.40 (ddd, J = 7.7, 4.7, 1.1 Hz, 1H ), 6.84 (dd, J = 7.4, 0.5 Hz, 1H), 5.86 (t, J = 5.6 Hz, 1H), 4.48 (s, 2H), 4.36 (d, J = 5.6 Hz, 2H), 1.53 (s , 9H), 1.45 (s, 9H).

[Reference Example 6]
4- [1- (4-methoxybenzyl) -1-methylethyl] benzyl alcohol 6- (a): 2- {4-[(tert-butyldimethylsilyloxy) methyl] phenyl} -1- (4-methoxy Phenyl) propan- 1 -one 1- (4-methoxyphenyl) propan-1-one 1.64 g (9.99 mmol) in 7 ml of tetrahydrofuran was added to (4-bromobenzyloxy) (tert-butyl) dimethylsilane (Journal). of the American Chemical Society, 117, 704 (1995)) 3.01 g (9.99 mmol), sodium tert-butoxide 1.06 g (11.0 mmol) and 1,1′-bis (di-tert-butylphosphine chloride) Fino) ferrocene palladium 460 mg (0. 706 mmol) and stirred at room temperature for 8 hours. 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 = 19: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 2.10 g of the title compound orange. Obtained as an oil. (Yield 55%)
Mass spectrum (CI, m / z): 385 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.97-7.90 (m, 2H), 7.24 (s, 4H), 6.88-6.81 (m, 2H), 4.67 (s, 2H), 4.62 (q, J = 6.9 Hz, 1H), 3.81 (s, 3H), 1.50 (d, J = 6.9 Hz, 3H), 0.92 (s, 9H), 0.07 (s, 6H).

6- (b): 2- {4-[(tert-butyldimethylsilyloxy) methyl] phenyl} -1- (4-methoxyphenyl) -2-methylpropan-1-one In Example 6- (a) 2.07 g (5.38 mmol) of N, N-dimethylformamide obtained 2- {4-[(tert-butyldimethylsilyloxy) methyl] phenyl} -1- (4-methoxyphenyl) propan-1-one To the 16 ml solution, 281 mg (6.4 mmol) of sodium hydride (55% mineral oil dispersion) was added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes and further at room temperature for 13 hours. Then, 575 μl (9.24 mmol) of iodomethane was added dropwise over 1 minute under ice cooling, and the mixture was stirred at the same temperature for 15 minutes. After completion of the reaction, the reaction solution was added to a saturated aqueous ammonium chloride solution and extracted 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 residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 40: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 1.12 g of the title compound colorless. Obtained as an oil. (Yield 52%)
Mass spectrum (CI, m / z): 399 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.58-7.51 (m, 2H), 7.32-7.23 (m, 4H), 6.73-6.66 (m, 2H), 4.73 (s, 2H), 3.77 (s, 3H), 1.59 (s, 6H), 0.94 (s, 9H), 0.09 (s, 6H).

6- (c): 2- {4-[(tert-butyldimethylsilyloxy) methyl] phenyl} -1- (4-methoxyphenyl) -2-methylpropan-1-ol In Example 6- (b) To a solution of the obtained 2- {4-[(tert-butyldimethylsilyloxy) methyl] phenyl} -1- (4-methoxyphenyl) -2-methylpropan-1-one in 717 mg (1.80 mmol) in 9 ml of ethanol. , 82 mg (2.2 mmol) of sodium borohydride was added, and the mixture was stirred at room temperature for 1 hour and further at 45 ° C. for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was 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 = 9: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 599 mg of the title compound as a colorless oil. Got as. (Yield 83%)
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.38-7.32 (m, 2H), 7.31-7.25 (m, 2H), 7.08-7.01 (m, 2H), 6.81-6.75 (m, 2H), 4.74 ( s, 2H), 4.71 (d, J = 2.8 Hz, 1H), 3.79 (s, 3H), 1.68 (d, J = 2.8 Hz, 1H), 1.29 (s, 3H), 1.26 (s, 3H), 0.95 (s, 9H), 0.11 (s, 6H).

6- (d): 2- {2- {2- [2-chloro-2- (4-methoxyphenyl) -1,1-dimethylethyl] benzyloxy} dimethylsilane obtained from 6- (c) 4-[(tert-Butyldimethylsilyloxy) methyl] phenyl} -1- (4-methoxyphenyl) -2-methylpropan-1-ol 301 mg (0.751 mmol) and triethylamine 628 μl (4.51 mmol) in methylene chloride To the 8 ml solution, 174 μl (2.25 mmol) of methanesulfonyl chloride was added dropwise over 1 minute under ice cooling, followed by stirring at the same temperature for 40 minutes and further at room temperature 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 to obtain 398 mg of the title compound as a yellow oil almost quantitatively.
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.22 (s, 4H), 6.99-6.92 (m, 2H), 6.73-6.66 (m, 2H), 5.05 (s, 1H), 4.73 (s, 2H) , 3.77 (s, 3H), 1.49 (s, 3H), 1.37 (s, 3H), 0.94 (s, 9H), 0.10 (s, 6H).

6- (e): 4- [1- (4-methoxybenzyl) -1-methylethyl] benzyl alcohol obtained in the same manner as 6- (d) tert-butyl {4- [2-chloro-2 To a 12 ml tetrahydrofuran solution of 567 mg (1.35 mmol) of-(4-methoxyphenyl) -1,1-dimethylethyl] benzyloxy} dimethylsilane was added 2.7 ml (2.7 mmol) of a 2M lithium aluminum hydride / tetrahydrofuran solution. The mixture was added dropwise over 3 minutes under ice cooling, and stirred for 3 hours under reflux. After completion of the reaction, water was added to the reaction solution under sodium chloride / ice cooling, followed by extraction 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 = 25: 1 → 3: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 145 mg of the title compound. Was obtained as a colorless oil. (Yield 40%)
Mass spectrum (EI, m / z): 270 (M ⁺ ).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.29 (s, 4H), 6.77-6.71 (m, 2H), 6.71-6.65 (m, 2H), 4.68 (d, J = 5.1 Hz, 2H), 3.75 (s, 3H), 2.81 (s, 2H), 1.59 (brs, 1H), 1.30 (s, 6H).

[Reference Example 7]
2,4,6-Trimethylbenzoic acid [4- (1-chloro-1-methylethyl) benzyl]
7- (a): 2,4,6-trimethylbenzoic acid [4- (methoxycarbonyl) benzyl]
To a solution of methyl 4- (hydroxymethyl) benzoate 4.99 g (30.0 mmol), pyridine 4.83 ml (60.0 mmol) and 4-dimethylaminopyridine 73 mg (0.60 mmol) in 140 ml of methylene chloride, A solution of 6.03 g (33.0 mmol) of 6-trimethylbenzoic acid chloride in 10 ml of methylene chloride was added dropwise over 20 minutes under sodium chloride / ice cooling, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was added to a saturated aqueous ammonium chloride 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 = 19: 1 → 9: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound 8 0.02 g was obtained as a slightly pink oil. (Yield 86%)
Mass spectrum (CI, m / z): 313 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.07-8.01 (m, 2H), 7.53-7.47 (m, 2H), 6.85 (s, 2H), 5.39 (s, 2H), 3.92 (s, 3H) , 2.27 (s, 3H), 2.25 (s, 6H).

7- (b): 2,4,6-trimethylbenzoic acid [4- (1-hydroxy-1-methylethyl) benzyl]
To a solution of 6.71 g (21.5 mmol) of 2,4,6-trimethylbenzoic acid [4- (methoxycarbonyl) benzyl] obtained in 7- (a) in 86 ml of tetrahydrofuran was added 1.4 M methylmagnesium bromide / toluene. —33.8 ml (47.3 mmol) of a tetrahydrofuran mixed solution was added dropwise at −6 ° C. over 30 minutes, followed by stirring at the same temperature for 30 minutes and further at room temperature for 16 hours. After completion of the reaction, the reaction solution was added to a saturated aqueous ammonium chloride 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 = 17: 3 → 4: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound 4 .11 g was obtained as a colorless oil. (Yield 61%)
Mass spectrum (EI, m / z): 312 (M ⁺ ).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.53-7.45 (m, 2H), 7.45-7.35 (m, 2H), 6.83 (s, 2H), 5.33 (s, 2H), 2.26 (s, 9H) , 1.72 (s, 1H), 1.58 (s, 6H).

7- (c): 2,4,6-trimethylbenzoic acid [4- (1-chloro-1-methylethyl) benzyl]
To a solution of 2,4,6-trimethylbenzoic acid [4- (1-hydroxy-1-methylethyl) benzyl] 1.09 g (3.49 mmol) obtained in 7- (b) in 3 ml of methylene chloride was added concentrated hydrochloric acid. 1.1 ml (12 mmol) was added dropwise over 2 minutes under ice cooling, and the mixture was stirred at the same temperature for 2 hours and further at room temperature for 7 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 to give 1.07 g of the title compound as a yellow oil. (Yield 93%)
Mass spectrum (CI, m / z): 331 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.62-7.55 (m, 2H), 7.44-7.37 (m, 2H), 6.84 (s, 2H), 5.33 (s, 2H), 2.26 (s, 9H) , 1.98 (s, 6H).

[Reference Example 8]
4- [1- (2-methoxybenzyl) -1-methylethyl] benzyl alcohol 8- (a): 2- (tert-butyldimethylsilyloxy) -2- (2-methoxyphenyl) acetonitrile 2-methoxybenzaldehyde 4 0.08 g (30.0 mmol) in 25 ml of acetonitrile were added 8.00 g (123 mmol) of potassium cyanide, 200 mg (0.627 mmol) of zinc iodide and 5.50 g (36.5 mmol) of tert-butyldimethylsilyl chloride. And stirred for 25.5 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and 150 ml of diethyl ether was added to the residue and filtered. 100 ml of ethyl acetate was added to the filtrate, washed with a saturated aqueous sodium carbonate solution and a saturated aqueous sodium chloride solution in that order, 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 = 19: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 7.20 g of the title compound colorless. Obtained as an oil. (Yield 87%)
Mass spectrum (CI, m / z): 278 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.59 (dd, J = 7.6, 1.7 Hz, 1H), 7.35 (ddd, J = 8.1, 7.8, 1.7 Hz, 1H), 7.02 (ddd, J = 7.8, 7.6, 1.0 Hz, 1H), 6.90 (dd, J = 8.1, 1.0 Hz, 1H), 5.78 (s, 1H), 3.88 (s, 3H), 0.94 (s, 9H), 0.23 (s, 3H), 0.13 (s, 3H).

8- (b): 2,4,6-trimethylbenzoic acid {4- [2- (tert-butyldimethylsilyloxy) -2-cyano-2- (2-methoxyphenyl) -1,1-dimethylethyl] Benzyl}
To a solution of 1.19 g (4.29 mmol) of 2- (tert-butyldimethylsilyloxy) -2- (2-methoxyphenyl) acetonitrile obtained in 8- (a) in 8 ml of tetrahydrofuran was added 1.14 M lithium diisopropylamide. /4.2 ml (4.8 mmol) of tetrahydrofuran solution was added dropwise at −61 ° C. over 10 minutes and stirred at the same temperature for 1 hour. Subsequently, 1.44 g (4.29 mmol) of 2,4,6-trimethylbenzoic acid [4- (1-chloro-1-methylethyl) benzyl] obtained in the same manner as in Reference Example 7- (c) was obtained. Tetrahydrofuran 4 ml solution was added dropwise at the same temperature over 10 minutes and stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was added to a saturated aqueous ammonium chloride 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 = 40: 1 → 20: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 917 mg of the title compound. Was obtained as a colorless oil. (Yield 37%)
Mass spectrum (EI, m / z): 571 (M ⁺ ).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.29-7.19 (m, 5H), 6.96-6.69 (m, 5H), 5.31 (s, 2H), 3.61 (s, 3H), 2.27 (s, 9H) , 1.55 (s, 6H), 0.97 (s, 9H), 0.11 (s, 3H), -0.18 (s, 3H).

8- (c): 2,4,6-trimethylbenzoic acid {4- [2- (2-methoxyphenyl) -1,1-dimethyl-2-oxoethyl] benzyl}
2,4,6-Trimethylbenzoic acid {4- [2- (tert-butyldimethylsilyloxy) -2-cyano-2- (2-methoxyphenyl) -1,1-] obtained in 8- (b) To a 13 ml tetrahydrofuran solution of dimethylethyl] benzyl} 912 mg (1.59 mmol), 1.6 ml (1.6 mmol) of 1M tetrabutylammonium fluoride / tetrahydrofuran solution was added dropwise over 5 minutes under cooling with sodium chloride / ice. The mixture was stirred at the same temperature for 30 minutes. After completion of the reaction, the reaction solution was added to a saturated aqueous sodium hydrogen carbonate 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 = 19: 1 → 9: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 656 mg of the title compound. Was obtained as a white solid. (Yield 96%)
Mass spectrum (CI, m / z): 431 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.42-7.34 (m, 4H), 7.29-7.15 (m, 1H), 6.84 (s, 2H), 6.81 (d, J = 8.5 Hz, 1H), 6.68 (ddd, J = 7.5, 7.5, 0.7 Hz, 1H), 6.39 (dd, J = 7.5, 1.7 Hz, 1H), 5.34 (s, 2H), 3.69 (s, 3H), 2.27 (s, 3H), 2.25 (s, 6H), 1.57 (s, 6H).

8- (d): 2,4,6-trimethylbenzoic acid {4- [2-hydroxy-2- (2-methoxyphenyl) -1,1-dimethylethyl] benzyl}
2,4-6-Trimethylbenzoic acid {4- [2- (2-methoxyphenyl) -1,1-dimethyl-2-oxoethyl] benzyl} 642 mg (1.49 mmol) obtained in Example 8- (c) ) In ethanol (10 ml) was added sodium borohydride (135 mg, 3.57 mmol), and the mixture was stirred at 50 ° C. for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was 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 = 9: 1 → 4: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 558 mg of the title compound. Was obtained as a colorless oil. (Yield 87%)
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.36 (s, 4H), 7.24-7.17 (m, 1H), 7.02 (dd, J = 7.6, 1.7 Hz, 1H), 6.88-6.82 (m, 3H) , 6.78 (dd, J = 8.3, 0.7 Hz, 1H), 5.33 (s, 2H), 5.09 (d, J = 5.9 Hz, 1H), 3.62 (s, 3H), 2.47 (d, J = 5.9 Hz, 1H), 2.27 (s, 9H), 1.33 (s, 6H).

8- (e): 2,4,6-trimethylbenzoic acid {4- [2-chloro-2- (2-methoxyphenyl) -1,1-dimethylethyl] benzyl}
2,4,6-Trimethylbenzoic acid {4- [2-hydroxy-2- (2-methoxyphenyl) -1,1-dimethylethyl] benzyl} obtained in 8- (d) 553 mg (1.28 mmol) 297 μl (3.84 mmol) of methanesulfonyl chloride was added dropwise to a solution of 1.07 ml (7.68 mmol) of triethylamine in 7 ml of methylene chloride over 1 minute under ice-cooling, 30 minutes at the same temperature, and 3 hours at room temperature. Stir. 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. After adding 5 ml of toluene to the residue and filtering, the filtrate was concentrated under reduced pressure to obtain 589 mg of the title compound as a yellow oil almost quantitatively.
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.37-7.30 (m, 4H), 7.30-7.14 (m, 2H), 6.88 (t, J = 7.6 Hz, 1H), 6.83 (s, 2H), 6.74 (d, J = 7.8 Hz, 1H), 5.78 (s, 1H), 5.32 (s, 2H), 3.67 (s, 3H), 2.27 (s, 3H), 2.26 (s, 6H), 1.49 (s, 3H), 1.36 (s, 3H).

8- (f): 2,4,6-trimethylbenzoic acid {4- [1- (2-methoxybenzyl) -1-methylethyl] benzyl}
2,4,6-Trimethylbenzoic acid {4- [2-chloro-2- (2-methoxyphenyl) -1,1-dimethylethyl] benzyl} obtained in 8- (e) 528 mg (1.17 mmol) To a 6 ml toluene solution were added 614 μl (2.34 mmol) tributyltin hydride and 29 mg (0.18 mmol) azobisisobutyronitrile, and the mixture was stirred under reflux for 3 hours. After completion of the reaction, the reaction solution is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 30: 1 → 20: 1 (V / V)), and the fraction containing the target product is concentrated under reduced pressure. Gave 398 mg of the title compound as a colorless oil. (Yield 82%)
Mass spectrum (FAB, m / z): 417 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.37-7.28 (m, 4H), 7.17-7.09 (m, 1H), 6.83 (s, 2H), 6.78 (d, J = 8.1 Hz, 1H), 6.74 -6.63 (m, 2H), 5.32 (s, 2H), 3.66 (s, 3H), 2.91 (s, 2H), 2.27 (s, 9H), 1.30 (s, 6H).

8- (g): 2,4,6-Trimethylbenzoic acid {4- [1-(-) obtained with 4- [1- (2-methoxybenzyl) -1-methylethyl] benzyl alcohol 8- (f) To a solution of 167 mg (0.401 mmol) of 2-methoxybenzyl) -1-methylethyl] benzyl} in 1.6 ml of tetrahydrofuran was added 0.88 ml (0.88 mmol) of a 1M lithium aluminum hydride / tetrahydrofuran solution at room temperature. Stir at 0 ° C. for 2 hours. After completion of the reaction, the reaction solution was added dropwise to ice water 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 = 9: 1 → 4: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 97 mg of the title compound. Was obtained as a colorless oil. (Yield 89%)
Mass spectrum (EI, m / z): 270 (M ⁺ ).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.37-7.24 (m, 4H), 7.17-7.10 (m, 1H), 6.89-6.68 (m, 3H), 4.67 (s, 2H), 3.68 (s, 3H), 2.92 (s, 2H), 2.39 (s, 1H), 1.30 (s, 6H).

[Reference Example 9]
4- (1,1-dimethyl-3-phenylpropyl) benzyl alcohol 9- (a): 4- (1,1-dimethyl-3-phenylpropyl) benzaldehyde 1-bromo-4- (1,1-dimethyl- 3-phenylpropyl) benzene (see WO2004 / 67992) 300 mg (0.989 mmol) in tetrahydrofuran 3 ml was added 1.67 M n-butyllithium / tetrahydrofuran solution 0.60 ml (1.0 mmol) at −70 ° C. And stirred at the same temperature for 30 minutes. Next, 300 μl of N, N-dimethylformamide was added dropwise at the same temperature. After completion of the dropwise addition, the mixture was gradually warmed to room temperature and stirred. After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction solution under ice cooling, and the mixture was 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 = 1: 0 → 1: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 175 mg of the title compound. Was obtained as a colorless oil. (Yield 70%)
Mass spectrum (CI, m / z): 253 (M ⁺⁺ 1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 10.01 (s, 1H), 7.89-7.83 (m, 2H), 7.59-7.54 (m, 2H), 7.25-7.21 (m, 2H), 7.18-7.13 ( m, 1H), 7.09-7.04 (m, 2H), 2.38-2.30 (m, 2H), 2.02-1.92 (m, 2H), 1.41 (s, 6H).

9- (b): 168 mg of 4- (1,1-dimethyl-3-phenylpropyl) benzaldehyde obtained with 4- (1,1-dimethyl-3 -phenylpropyl) benzyl alcohol 9- (a) (0. 666 mmol) in ethanol (2 ml) was added with sodium borohydride (22 mg, 0.58 mmol) and stirred at room temperature for 2 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was 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 = 9: 1 → 1: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 116 mg of the title compound. Was obtained as a colorless oil. (Yield 68%)
Mass spectrum (EI, m / z): 254 (M ⁺ )
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.43-7.31 (m, 4H), 7.25-7.19 (m, 2H), 7.17-7.12 (m, 1H), 7.11-7.06 (m, 2H), 4.69 ( d, J = 5.9 Hz, 2H), 2.40-2.31 (m, 2H), 1.98-1.88 (m, 2H), 1.66-1.57 (m, 1H), 1.37 (s, 6H).

[Reference Example 10]
4- [1,1-dimethyl-2- (tetrahydro-2H-pyran-4-yl) ethyl] benzyl alcohol 10- (a): 1- (4-bromophenyl) -2- (tetrahydro-2H-pyran- 4-yl) ethanone 2- (tetrahydro-2H-pyran-4-yl) acetyl chloride (see WO2005 / 103038) 4.16 g (25.6 mmol) in 1,2-dichloroethane 20.8 ml was cooled with ice. Below, 7.50 g (56.2 mmol) of aluminum chloride was added, and then a solution of 4.02 g (25.6 mmol) of bromobenzene in 5.9 ml of 1,2-dichloroethane was added dropwise and stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was added to ice water 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: 2 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 3.73 g of the title compound. Obtained as a yellow solid. (Yield 52%)
Macrospectrum (CI, m / z): 283 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.85-7.78 (m, 2H), 7.64-7.58 (m, 2H), 4.00-3.91 (m, 2H), 3.49-3.39 (m, 2H), 2.86 ( d, J = 6.6 Hz, 2H), 2.32-2.15 (m, 1H), 1.71-1.63 (m, 2H), 1.46-1.30 (m, 2H).

10- (b): 4- [2- (4-Bromophenyl) -2-methylpropyl] tetrahydro-2H-pyran titanium tetrachloride 4.5 ml (41 mmol) in methylene chloride 158 ml solution with 2M dimethylzinc / toluene 20.3 ml (40.6 mmol) of the solution was added dropwise at −50 ° C. and stirred at the same temperature for 15 minutes. Next, a solution of 3.72 g (13.1 mmol) of 1- (4-bromophenyl) -2- (tetrahydro-2H-pyran-4-yl) ethanone obtained in 10- (a) in 40 ml of methylene chloride was used. The solution was added dropwise at a temperature over 40 minutes. After completion of the dropping, the mixture was gradually heated to room temperature and then stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was added to ice water and extracted with methylene chloride. The organic layer was washed with 1N hydrochloric acid and saturated sodium chloride in this order, 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 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 2.08 g of the title compound in white. Obtained as a solid. (Yield 53%)
Mass spectrum (CI, m / z): 297 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.43-7.37 (m, 2H), 7.24-7.18 (m, 2H), 3.82-3.74 (m, 2H), 3.27-3.16 (m, 2H), 1.59 ( d, J = 5.6 Hz, 2H), 1.45-1.32 (m, 1H), 1.31-1.07 (m, 4H), 1.29 (s, 6H).

10- (c): 4- [2- (4-Bromophenyl) obtained with 4- [1,1-dimethyl-2- (tetrahydro-2H-pyran-4-yl) ethyl] benzaldehyde 10- (b) ) -2-methylpropyl] tetrahydro-2H-pyran 1.90 g (6.39 mmol) in 78 ml of tetrahydrofuran was added 4.08 ml (6.41 mmol) of 1.57 M n-butyllithium / tetrahydrofuran solution at −70 ° C. And stirred at the same temperature for 30 minutes. Next, 1.49 ml of N, N-dimethylformamide was added dropwise at the same temperature. After completion of the addition, the mixture was gradually heated to room temperature and stirred. After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was 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 = 7: 3 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 864 mg of the title compound as a colorless oil. Got as. (Yield 55%)
Mass spectrum (CI, m / z): 247 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 10.06 (s, 1H), 7.97-7.92 (m, 2H), 7.78-7.73 (m, 2H), 2.68 (t, J = 7.8 Hz, 2H), 1.75 -1.61 (m, 2H), 1.59-1.51 (m, 1H), 1.42-1.30 (m, 4H), 0.97-0.84 (m, 2H), 0.91 (s, 6H).

10- (d): 4- [1,1-dimethyl-2- (tetrahydro-2H-pyran-4-yl) ethyl] benzyl alcohol 10- (c) To a 7.0 ml ethanol solution of 863 mg (3.50 mmol) 2- (tetrahydro-2H-pyran-4-yl) ethyl] benzaldehyde was added 66 mg (1.74 mmol) sodium borohydride, and the mixture was stirred at room temperature for 1 hour. 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: 2 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 134 mg of the title compound as a colorless oil. Got as. (Yield 15%)
Mass spectrum (EI, m / z): 248 (M ⁺ ).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.34-7.29 (m, 4H), 4.67 (d, J = 5.6 Hz, 2H), 3.81-3.71 (m, 2H), 3.28-3.15 (m, 2H) , 1.62 (d, J = 5.4 Hz, 2H), 1.47-1.33 (m, 1H), 1.32 (s, 6H), 1.30-1.08 (m, 4H).

[Reference Example 11]
4- [2- (4-methoxybenzyloxy) -1,1-dimethylethyl] benzyl alcohol 11- (a): 4- [2- (4-methoxybenzyloxy) -1,1-dimethylethyl] benzaldehyde 1 -To a solution of 8.10 g (23.2 mmol) of bromo-4- [2- (4-methoxybenzyloxy) -1,1-dimethylethyl] benzene in 80 ml of tetrahydrofuran, 1.6 M n-butyllithium / tetrahydrofuran solution 21 0.7 ml (35 mmol) was added dropwise at −70 ° C., and the mixture was stirred at the same temperature for 1 hour. Next, 5.7 ml of N, N-dimethylformamide was added dropwise at the same temperature. After completion of the dropwise addition, the mixture was gradually heated to -10 ° C and stirred. After completion of the reaction, the reaction solution was added to a saturated aqueous ammonium chloride 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 = 9: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 5.11 g of the title compound as an oil. Obtained as a thing. (Yield 74%)
Mass spectrum (CI, m / z): 299 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 9.97 (s, 1H), 7.86-7.80 (m, 2H), 7.62-7.57 (m, 2H), 7.19-7.10 (m, 2H), 6.90-6.83 ( m, 2H), 4.36 (s, 2H), 3.73 (s, 3H), 3.48 (s, 2H), 1.29 (s, 6H).

11- (b): 4- [2- (4-Methoxybenzyloxy)-obtained with 4- [2- (4-methoxybenzyloxy) -1,1-dimethylethyl] benzyl alcohol 11- (a) To a solution of 5.1 g (17 mmol) of 1,1-dimethylethyl] benzaldehyde in 50 ml of ethanol was added 0.71 g (19 mmol) of sodium borohydride, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was added to 1N hydrochloric acid 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 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 3.91 g of the title compound as an oil. Obtained as a thing. (Yield 77%)
Mass spectrum (EI, m / z): 300 (M ⁺ ).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.33-7.27 (m, 2H), 7.25-7.20 (m, 2H), 7.19-7.13 (m, 2H), 6.91-6.84 (m, 2H), 5.07 ( t, J = 5.5 Hz, 1H), 4.45 (d, J = 5.5 Hz, 2H), 4.36 (s, 2H), 3.73 (s, 3H), 3.40 (s, 2H), 1.25 (s, 6H).

[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.
The test results are shown in Table 1.

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.
The test results are shown in Table 2.

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, a test compound 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 3.

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 12, 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 12, 124 mg of lactose, 25 mg of cellulose and 1 mg of magnesium stearate are mixed, and tableted with a tableting machine to make one tablet of 200 mg. This tablet can be sugar-coated if necessary.

The substituted benzyl compound represented by the general formula (1) 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 (bioavailability). BA), rapid onset of drug efficacy, sustained drug efficacy, solubility, physical stability, drug interaction, toxicity, etc., and also has excellent properties as a pharmaceutical compound. 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.) Treatment and / or prevention of diseases that are useful and that EP2 agonist activity is likely to be useful (for example, bone diseases, gastric ulcers, hypertension, glaucoma, etc.) Even a medicament for useful.

Claims (14)

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,
   Y is a C ₁ -C ₁₂ alkyl group substituted with the same or different 1 to 3 groups selected from the substituent group α (provided that a halogeno group, a C ₁ -C ₆ alkyl group and a C ₂ -C ₆ alkenyl groups are excluded, and aryl groups, heteroaryl groups and heterocyclic groups are excluded as substituents at the 1-position), C ₂ -C ₆ alkenyl groups (provided that C ₁ -C ₆ alkyl groups are substituted) Groups, and aryl groups, heteroaryl groups and heterocyclic groups are excluded as substituents at the 1-position) or C ₁ -C ₆ alkoxy groups (however, halogeno groups are excluded as substituents), or substituents A C ₂ -C ₆ alkynyl group optionally substituted by the same or different 1 to 3 groups selected from group α,
   n represents an integer of 1 to 3,
   when n is 2 or 3, Y may be the same or different from each other;
   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 substituted 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. Y represents a hydroxy group, a C ₇ -C ₁₂ aralkyl group, a C ₁ -C ₆ alkoxy group, a C ₇ -C ₁₂ aralkyloxy group, a C ₃ -C ₆ cycloalkyl group, a C ₂ -C ₄ alkanoyl group, an 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, tri- (C ₁ -C ₄ alkyl) ammonium group, C ₂ -C ₄ alkanoylamino group, C ₁ -C ₄ alkoxycarbonylamino group, optionally substituted by methoxy group aryl, heteroaryl, C ₁ -C ₉ aralkyl which is substituted by a group selected from the group consisting of heterocyclic group aryloxy group and completely saturated Le group (provided that 1-position substituent as optionally substituted aryl group with a methoxy group, excluding heterocyclic group heteroaryl group and completely saturated), or, C ₇ -C ₁₂ aralkyl group, C ₁ - C ₆ alkoxy group, C ₇ -C ₁₂ aralkyloxy group, C ₃ -C ₆ cycloalkyl group, C ₂ -C ₄ alkanoyl group, C ₁ -C ₄ alkoxycarbonyl group, C ₁ -C ₄ alkylthio group, C ₁ A C ₃ -C ₅ alkenyl group substituted with a group selected from the group consisting of —C ₄ alkylsulfinyl group, C ₁ -C ₄ alkylsulfonyl group, aryl group and fully saturated heterocyclic group (provided that the aryl group and completely saturated as substituents heterocyclic group is excluded) or a _C 1 -C ₄ alkoxy groups, _or, C 7 _{-C 12} aralkyl _group, C 1 -C ₆ alkoxy group, ₇ -C ₁₂ aralkyloxy _group, C 3 -C ₆ cycloalkyl _group, C 2 -C ₄ alkanoyl group, an aryl group, optionally substituted by a group selected from the group consisting of heterocyclic group heteroaryl group and completely saturated The substituted benzyl compound or a pharmacologically acceptable salt thereof according to claim 1 or 2, which represents an optionally substituted C ₃ -C ₅ alkynyl group.
4. 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 substituted benzyl compound or the pharmacology thereof according to any one of claims 1 to 3, 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 Top acceptable salt.
5. Y is hydroxy group, benzyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, pentyloxy group, hexyloxy group, benzyloxy group, 1-phenylethyloxy group, 2-phenylethyloxy group , Cyclopropyl group, cyclohexyl group, acetyl group, propanoyl group, benzoyl group, methoxycarbonyl group, methylthio group, methylsulfinyl group, methylsulfonyl group, methylamino group, dimethylamino group, trimethylammonium group, acetylamino group, methoxycarbonyl A C ₁ -C ₉ alkyl group substituted with a group selected from the group consisting of an amino group, a phenyl group optionally substituted with a methoxy group, a thienyl group, a pyridyl group, a pyrrolidinyl group, a tetrahydropyranyl group and a piperidinyl group; (However, 1 A phenyl group, a thienyl group, a pyridyl group, a pyrrolidinyl group, a tetrahydropyranyl group, and a piperidinyl group, which may be substituted with a methoxy group as a substituent, or a benzyl group, methoxy group, ethoxy group, propoxy group, Isopropoxy group, butoxy group, pentyloxy group, hexyloxy group, benzyloxy group, 1-phenylethyloxy group, 2-phenylethyloxy group, cyclopropyl group, cyclohexyl group, phenyl group, pyrrolidinyl group, tetrahydropyranyl group And a C ₃ -C ₅ alkenyl group substituted with a group selected from the group consisting of a piperidinyl group (excluding a phenyl group, a pyrrolidinyl group, a tetrahydropyranyl group and a piperidinyl group as a substituent at the 1-position) or C ₁ -C ₄ alkoxy group, or a benzyl group Methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, pentyloxy group, hexyloxy group, benzyloxy group, 1-phenylethyloxy group, 2-phenylethyloxy group, cyclopropyl group, cyclohexyl group, phenyl The substitution according to claim 3, which represents a C ₃ -C ₅ alkynyl group optionally substituted with a group selected from the group consisting of a group, a thienyl group, a pyridyl group, a pyrrolidinyl group, a tetrahydropyranyl group and a piperidinyl group. A benzyl compound or a pharmacologically acceptable salt thereof.
6. Y is hydroxymethyl group, hydroxyethyl group, 3-hydroxy-2,2,4,4-tetramethylpentan-3-yl group, 1,1-dimethyl-3-phenylpropyl group, 2-methoxy-1, 1-dimethylethyl group, 2-ethoxy-1,1-dimethylethyl group, 1,1-dimethyl-2-propoxyethyl group, 2-butoxy-1,1-dimethylethyl group, 1,1-dimethyl-2- Pentyloxyethyl group, 2-hexyloxy-1,1-dimethylethyl group, 2-benzyloxy-1,1-dimethylethyl group, 2- (1-phenylethyloxy) -1,1-dimethylethyl group, 2 -(2-phenylethyloxy) -1,1-dimethylethyl group, 1-cyclopropylethyl group, 2-cyclopropylethyl group, 1-cyclohexylethyl group, 2-cyclyl Hexylethyl group, 3-cyclohexylpropyl group, 4-cyclohexylbutyl group, (trimethylammonio) methyl group, (triethylammonio) methyl group, 1- (4-methoxybenzyl) -1-methylethyl group, 1- ( 3-methoxybenzyl) -1-methylethyl group, 1- (2-methoxybenzyl) -1-methylethyl group, phenoxymethyl group, 3-phenoxypropyl group, benzyloxymethyl group, 2-benzyloxyethyl group, 1 , 1-dimethyl-2- (tetrahydro-2H-pyran-4-yl) ethyl group, 3-cyclopropyl-1-propenyl group, 3-cyclohexyl-1-propenyl group, 4-cyclopropyl-1-butenyl group, 4-cyclohexyl-1-butenyl group, 3-phenyl-1-propenyl group, benzyloxy group, 2- The substituted benzyl compound according to claim 3, which represents a phenetoxy group, 2-methoxyethoxy group, 2-phenoxyethoxy group, 2-propynyl group, 3-phenyl-2-propynyl group or 2-butynyl group, or a pharmacologically acceptable salt thereof. Salt.
7. Z is fluoro, chloro, benzyl, methoxy, benzyloxy, cyclopropyl, cyclopentenyl, benzoyl, methylamino, dimethylamino, anilino, phenyl, thienyl, pyridyl, C ₁ -C ₄ alkyl group, 2-propynyl group, 2-butynyl group, cyclopropyl group, cyclobutyl group, cyclopentenyl which may be substituted with a group selected from the group consisting of phenoxy group, pyrrolidinyl group and piperidinyl group Group, or fluoro, chloro, cyano, nitro, methyl, ethyl, trifluoromethyl, benzyl, benzyloxy, cyclopropyl, methoxy, methoxycarbonyl, methylthio, methylamino Group, dimethylamino group, anilino group, acetylamino group, metho 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 a sicarbonylamino group, a phenyl group, a phenoxy group, an azetidinyl group, a pyrrolidinyl group and a piperidinyl group The substituted benzyl compound according to claim 4 or a pharmacologically acceptable salt thereof.
8. 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,
   Y represents a hydroxy group, a C ₇ -C ₁₂ aralkyl group, a C ₁ -C ₆ alkoxy group, a C ₇ -C ₁₂ aralkyloxy group, a C ₃ -C ₆ cycloalkyl group, a C ₂ -C ₄ alkanoyl group, an 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, tri- (C ₁ -C ₄ alkyl) ammonium group, C ₂ -C ₄ alkanoylamino group, C ₁ -C ₄ alkoxycarbonylamino group, optionally substituted by methoxy group aryl, heteroaryl, C ₁ -C ₉ aralkyl which is substituted by a group selected from the group consisting of heterocyclic group aryloxy group and completely saturated Le group (provided that 1-position substituent as optionally substituted aryl group with a methoxy group, excluding heterocyclic group heteroaryl group and completely saturated), or, C ₇ -C ₁₂ aralkyl group, C ₁ - C ₆ alkoxy group, C ₇ -C ₁₂ aralkyloxy group, C ₃ -C ₆ cycloalkyl group, C ₂ -C ₄ alkanoyl group, C ₁ -C ₄ alkoxycarbonyl group, C ₁ -C ₄ alkylthio group, C ₁ A C ₃ -C ₅ alkenyl group substituted with a group selected from the group consisting of —C ₄ alkylsulfinyl group, C ₁ -C ₄ alkylsulfonyl group, aryl group and fully saturated heterocyclic group (provided that the aryl group and completely saturated as substituents heterocyclic group is excluded) or a _C 1 -C ₄ alkoxy groups, _or, C 7 _{-C 12} aralkyl _group, C 1 -C ₆ alkoxy group, ₇ -C ₁₂ aralkyloxy _group, C 3 -C ₆ cycloalkyl _group, C 2 -C ₄ alkanoyl group, an aryl group, optionally substituted by a group selected from the group consisting of heterocyclic group heteroaryl group and completely saturated An optionally substituted C ₃ -C ₅ alkynyl 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 substituted benzyl compound or a 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. .
9. 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,
   Y is hydroxy group, benzyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, pentyloxy group, hexyloxy group, benzyloxy group, 1-phenylethyloxy group, 2-phenylethyloxy group , Cyclopropyl group, cyclohexyl group, acetyl group, propanoyl group, benzoyl group, methoxycarbonyl group, methylthio group, methylsulfinyl group, methylsulfonyl group, methylamino group, dimethylamino group, trimethylammonium group, acetylamino group, methoxycarbonyl A C ₁ -C ₉ alkyl group substituted with a group selected from the group consisting of an amino group, a phenyl group optionally substituted with a methoxy group, a thienyl group, a pyridyl group, a pyrrolidinyl group, a tetrahydropyranyl group and a piperidinyl group; (However, 1 A phenyl group, a thienyl group, a pyridyl group, a pyrrolidinyl group, a tetrahydropyranyl group, and a piperidinyl group, which may be substituted with a methoxy group as a substituent, or a benzyl group, methoxy group, ethoxy group, propoxy group, Isopropoxy group, butoxy group, pentyloxy group, hexyloxy group, benzyloxy group, 1-phenylethyloxy group, 2-phenylethyloxy group, cyclopropyl group, cyclohexyl group, phenyl group, pyrrolidinyl group, tetrahydropyranyl group And a C ₃ -C ₅ alkenyl group substituted with a group selected from the group consisting of a piperidinyl group (excluding a phenyl group, a pyrrolidinyl group, a tetrahydropyranyl group and a piperidinyl group as a substituent at the 1-position) or C ₁ -C ₄ alkoxy group, or a benzyl group Methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, pentyloxy group, hexyloxy group, benzyloxy group, 1-phenylethyloxy group, 2-phenylethyloxy group, cyclopropyl group, cyclohexyl group, phenyl A C ₃ -C ₅ alkynyl group optionally substituted with a group selected from the group consisting of a group, a thienyl group, a pyridyl group, a pyrrolidinyl group, a tetrahydropyranyl group and a piperidinyl group,
   Z is fluoro, chloro, benzyl, methoxy, benzyloxy, cyclopropyl, cyclopentenyl, benzoyl, methylamino, dimethylamino, anilino, phenyl, thienyl, pyridyl, C ₁ -C ₄ alkyl group, 2-propynyl group, 2-butynyl group, cyclopropyl group, cyclobutyl group, cyclopentenyl which may be substituted with a group selected from the group consisting of phenoxy group, pyrrolidinyl group and piperidinyl group Group, or fluoro, chloro, cyano, nitro, methyl, ethyl, trifluoromethyl, benzyl, benzyloxy, cyclopropyl, methoxy, methoxycarbonyl, methylthio, methylamino Group, dimethylamino group, anilino group, acetylamino group, metho 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 a sicarbonylamino group, a phenyl group, a phenoxy group, an azetidinyl group, a pyrrolidinyl group and a piperidinyl group The substituted benzyl compound according to claim 1, or a pharmacologically acceptable salt thereof.
10. 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,
    Y is hydroxymethyl group, hydroxyethyl group, 3-hydroxy-2,2,4,4-tetramethylpentan-3-yl group, 1,1-dimethyl-3-phenylpropyl group, 2-methoxy-1, 1-dimethylethyl group, 2-ethoxy-1,1-dimethylethyl group, 1,1-dimethyl-2-propoxyethyl group, 2-butoxy-1,1-dimethylethyl group, 1,1-dimethyl-2- Pentyloxyethyl group, 2-hexyloxy-1,1-dimethylethyl group, 2-benzyloxy-1,1-dimethylethyl group, 2- (1-phenylethyloxy) -1,1-dimethylethyl group, 2 -(2-phenylethyloxy) -1,1-dimethylethyl group, 1-cyclopropylethyl group, 2-cyclopropylethyl group, 1-cyclohexylethyl group, 2-cyclo Xylethyl group, 3-cyclohexylpropyl group, 4-cyclohexylbutyl group, (trimethylammonio) methyl group, (triethylammonio) methyl group, 1- (4-methoxybenzyl) -1-methylethyl group, 1- (3 -Methoxybenzyl) -1-methylethyl group, 1- (2-methoxybenzyl) -1-methylethyl group, phenoxymethyl group, 3-phenoxypropyl group, benzyloxymethyl group, 2-benzyloxyethyl group, 1, 1-dimethyl-2- (tetrahydro-2H-pyran-4-yl) ethyl group, 3-cyclopropyl-1-propenyl group, 3-cyclohexyl-1-propenyl group, 4-cyclopropyl-1-butenyl group, 4 -Cyclohexyl-1-butenyl group, 2-methyl-1-propenyl group, 3-phenyl-1-propenyl group Group, benzyloxy group, 2-phenoxy group, 2-methoxyethoxy group, 2-phenoxyethoxy group, 2-propynyl group, 3-phenyl-2-propynyl group or 2-butynyl 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 substituted benzyl compound or a pharmacologically acceptable salt thereof according to claim 1, which represents a pyridin-3-yl group or a pyridin-4-yl group.
11. 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,
    Y is hydroxymethyl group, 3-hydroxy-2,2,4,4-tetramethylpentan-3-yl group, 1,1-dimethyl-3-phenylpropyl group, 2-methoxy-1,1-dimethylethyl Group, 2-ethoxy-1,1-dimethylethyl group, 2-butoxy-1,1-dimethylethyl group, 1,1-dimethyl-2-pentyloxyethyl group, 2-hexyloxy-1,1-dimethylethyl Group, 2-benzyloxy-1,1-dimethylethyl group, 1-cyclohexylethyl group, (trimethylammonio) methyl group, 1- (4-methoxybenzyl) -1-methylethyl group, 1- (2-methoxy) Benzyl) -1-methylethyl, phenoxymethyl, 3-phenoxypropyl or 1,1-dimethyl-2- (tetrahydro-2H-pyran-4-yl) Is a group,
    The substituted 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.
12. Substituted benzyl compounds are
    (6-{[4- (1-cyclohexylethyl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
    {6-[(4-hydroxymethylbenzyl) (pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid,
    (6-{[4- (3-hydroxy-2,2,4,4-tetramethylpentan-3-yl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
    2- {6-[(N- {4-[(trimethylammonio) methyl] benzyl} pyridine-3-sulfonamido) methyl] pyridin-2-ylamino} acetate,
    {6-[(4-phenoxymethylbenzyl) (pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid,
    (6-{[4- (3-phenoxypropyl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
    [6-({4- [1- (4-methoxybenzyl) -1-methylethyl] benzyl} (pyridin-2-ylsulfonyl) aminomethyl) pyridin-2-ylamino] acetic acid,
    [6-({4- [1- (2-methoxybenzyl) -1-methylethyl] benzyl} (pyridin-2-ylsulfonyl) aminomethyl) pyridin-2-ylamino] acetic acid,
    (6-{[4- (1,1-dimethyl-3-phenylpropyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
    [6-({4- [1,1-dimethyl-2- (tetrahydro-2H-pyran-4-yl) ethyl] benzyl} (pyridin-2-ylsulfonyl) aminomethyl) pyridin-2-ylamino] acetic acid,
    (6-{[4- (2-methoxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
    (6-{[4- (2-ethoxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
    (6-{[4- (2-butoxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
    (6-{[4- (1,1-dimethyl-2-pentyloxyethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
    (6-{[4- (2-hexyloxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid, or (6-{[4- ( The substituted benzyl compound according to claim 1, which is 2-benzyloxy-1,1-dimethylethyl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid, or a pharmaceutically acceptable salt thereof. Salt.
13. A pharmaceutical composition comprising the substituted benzyl compound according to any one of claims 1 to 12 or a pharmacologically acceptable salt thereof as an active ingredient.
14. The pharmaceutical composition according to claim 13 for the prevention or treatment of respiratory diseases.