JP2017206443A - Combination of substituted biaryl compound and another medicine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition useful as a therapeutic and/or preventive agent of a respiratory disease such as asthma, the pharmaceutical composition to be administered in combined with another medicine such as a phosphodiesterase 4 inhibitor.SOLUTION: The present invention provides a pharmaceutical composition containing a substituted biaryl compound represented by formula (I), or a pharmacologically acceptable salt thereof [Ris a carboxyl group, which may be protected; W is nitrogen or a -CH= group; Ris an ethoxy group, a 1-propenyl group or a 1-propynyl group; Z is a phenyl group, a 3-fluorophenyl group, a pyridine-2-yl group, a pyridine-3-yl group, a thiophene-2-yl group, or a thiophene-3-yl group].SELECTED DRAWING: None

Description

  The present invention relates to a pharmaceutical composition comprising a specific substituted biaryl compound or a pharmacologically acceptable salt thereof, wherein the pharmaceutical composition is administered in combination with another pharmaceutical agent, and a therapeutically effective amount of the pharmaceutical composition. The present invention relates to a method for treating a respiratory disease, which comprises administering a specific substituted biaryl compound or a pharmacologically acceptable salt thereof and a therapeutically effective amount of another pharmaceutical agent to a warm-blooded animal in combination.

  There are many types of respiratory diseases such as asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis, pulmonary hypertension, etc. Some diseases are chronic, and others are chronic and have no effective treatment. Among them, chronic obstructive pulmonary disease, which is an airway obstructive disease, is characterized by chronic bronchitis and irreversible and persistent airway obstruction, resulting in inflamed bronchial inflammation and alveolar destruction caused by smoking. It is a sex disorder. As a therapeutic agent for chronic obstructive pulmonary disease, a safe and established therapeutic agent has not yet been found. For example, roflumilast, which is a phosphodiesterase 4 (hereinafter abbreviated as PDE4) inhibitor, has been clinically applied as a therapeutic agent for chronic obstructive pulmonary disease due to excellent medicinal effects such as suppression of inflammatory cell function and bronchial smooth muscle relaxation. Clinical utility is limited due to vomiting and nausea as side effects. In addition, interstitial pneumonia and pulmonary fibrosis, which are diffuse lung diseases, are also designated as specific diseases in Japan, and the prognosis after onset is poor, and symptomatic treatment with administration of steroids or pirfenidone with strong side effects has been made Yes. On the other hand, asthma, which is an allergic lung disease, is a disease that exhibits chronic airway inflammation. Currently, there are a plurality of effective therapeutic agents that can control seizures, and treatment methods are almost established. However, there are also severe asthma that becomes intractable even by administration of inhaled steroids.

Prostaglandin E ₂ (hereinafter abbreviated as PGE ₂ ) has a wide range of physiological activities as a metabolite in the arachidonic acid cascade, and acts as an agonist for four receptors EP1, EP2, EP3 and EP4. . PGE ₂ is involved in many inflammatory reactions and has inflammatory effects such as vascular permeability enhancing action, release of various inflammatory mediators, induction of inflammatory cells and immune cells, angiogenic action, etc. Have been reported to exhibit an anti-inflammatory action via EP2 and / or EP4 receptors (see Non-Patent Document 1).

  So far, non-plastanoid compounds having EP2 agonistic activity have been known (see Patent Documents 1 to 8), and various diseases listed as pharmaceutical uses of the compounds described in Patent Documents 1 to 8 are known. Respiratory diseases including chronic obstructive pulmonary disease, pulmonary fibrosis and asthma are included. Furthermore, a combination of a specific compound having an EP2 agonistic action and another pharmaceutical (for example, a corticosteroid, an anticholinergic agent, a β2-receptor agonist, a PDE4 inhibitor, etc.) is disclosed (for example, patent document) 9).

International Publication No. 2009/113600 Pamphlet International Publication No. 2011/030864 Pamphlet International Publication No. 2011/030865 Pamphlet International Publication No. 2011/030868 Pamphlet International Publication No. 2011/030871 Pamphlet International Publication No. 2011/030872 Pamphlet International Publication No. 2011/030873 Pamphlet International Publication No. 2011/0708303 Pamphlet International Publication No. 2013/164326 Pamphlet

British Journal of Pharmacology, 122, 149 (1997)

However, in any of the above prior art documents, a sulfonamide compound having a biaryl group substituted with a specific substituent at a specific site as a partial structure has a strong EP2 agonistic action and anti-inflammatory action, and other Useful for prevention and / or treatment of respiratory diseases such as asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis and pulmonary hypertension in combination with medicine It is neither described nor suggested.
The present inventors have provided a pharmaceutical composition comprising a specific substituted biaryl compound or a pharmacologically acceptable salt thereof, wherein the pharmaceutical composition is administered in combination with other pharmaceuticals, and has an anti-inflammatory effect. Treatment of respiratory diseases such as asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis and pulmonary hypertension and / Or it discovered that it had the outstanding effect in prevention, and completed this invention.

The present invention is a pharmaceutical composition comprising a compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof, wherein the pharmaceutical composition is administered in combination with other pharmaceuticals, And a therapeutically effective amount of a compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof and a therapeutically effective amount of another pharmaceutical agent in combination with a warm-blooded animal: A method of treating a disease is provided.
The present invention provides the following from one aspect.

(1) General formula (I):

(Where
R ¹ represents an optionally protected carboxy group,
W represents a nitrogen atom or a group —CH═;
R ² represents an ethoxy group, a 1-propenyl group or a 1-propynyl group,
Z represents a phenyl group, a 3-fluorophenyl group, a pyridin-2-yl group, a pyridin-3-yl group, a thiophen-2-yl group, or a thiophen-3-yl group)
A pharmaceutical composition comprising a compound represented by: or a pharmacologically acceptable salt thereof,
Other drugs (the other drugs are PDE4 inhibitor, PDE5 inhibitor, corticosteroid, anticholinergic agent, β2-receptor agonist, H1-histamine receptor antagonist, leukotriene receptor antagonist, endothelin receptor One or more drugs selected from the group consisting of antagonists, PGI2 receptor agonists, theophylline, and pirfenidone)
A pharmaceutical composition, wherein the pharmaceutical composition is administered in combination.

(2) A pharmaceutical composition comprising a compound represented by the general formula (I) or a salt thereof and another pharmaceutical agent are administered as different formulations at the same time or at different times, The pharmaceutical composition according to 1).

(3) The pharmaceutical composition according to (1), wherein the pharmaceutical composition comprising the compound represented by the general formula (I) or a salt thereof and another pharmaceutical agent are administered as a single preparation. object.

(4) The pharmaceutical composition according to any one of (1) to (3), wherein R ¹ represents a carboxy group or a C ₁ -C ₆ alkoxycarbonyl group.

(5) The pharmaceutical composition according to any one of (1) to (3), wherein R ¹ represents a carboxy group, an ethoxycarbonyl group, an isopropoxycarbonyl group, or a hexyloxycarbonyl group.

(6) R ¹ represents a carboxy group, an ethoxycarbonyl group, an isopropoxycarbonyl group or a hexyloxycarbonyl group,
W represents a nitrogen atom or a group —CH═;
R ² represents a 1-propenyl group or a 1-propynyl group,
(1) to (3), wherein Z represents a phenyl group, a 3-fluorophenyl group, a pyridin-2-yl group, a pyridin-3-yl group, a thiophen-2-yl group, or a thiophen-3-yl group. A pharmaceutical composition according to any one of the above.

(7) The compound represented by the general formula (I) is
(6-{[3 ′-(1-propenyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{[3 ′-(1-propenyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
{6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid,
{6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetate hexyl,
{6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid,
{6-[(benzenesulfonyl) (3′-ethoxybiphenyl-4-ylmethyl) aminomethyl] pyridin-2-ylamino} acetic acid,
{6-[(3′-ethoxybiphenyl-4-ylmethyl) (thiophen-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid,
(6-{[4- (6-Ethoxypyridin-2-yl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{(benzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{(benzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{(3-Fluorobenzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-ylamino) acetic acid, or (6-{[3 ′-(1-propynyl) The pharmaceutical composition according to any one of (1) to (3), which is)) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) isopropyl acetate.

(8) The other drug is one or more drugs selected from the group consisting of a PDE4 inhibitor, a corticosteroid, an anticholinergic drug, a β2-receptor agonist, and pirfenidone, (1) to (7) A pharmaceutical composition according to any one of the above.

(9) The pharmaceutical composition according to any one of (1) to (7), wherein the other medicament is a PDE4 inhibitor, a corticosteroid, or pirfenidone.

(10) The pharmaceutical composition according to any one of (1) to (7), wherein the other medicament is roflumilast, fluticasone, or pirfenidone.

(11) (1) to (10) for treating or preventing asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis or pulmonary hypertension A pharmaceutical composition according to any one of the above.

(12) The pharmaceutical composition according to any one of (1) to (10), for treating or preventing asthma, chronic obstructive pulmonary disease or pulmonary fibrosis.

(13) (i) Therapeutically effective amount of general formula (I):

(Where
R ¹ represents an optionally protected carboxy group,
W represents a nitrogen atom or a group —CH═;
R ² represents an ethoxy group, a 1-propenyl group or a 1-propynyl group,
Z represents a phenyl group, a 3-fluorophenyl group, a pyridin-2-yl group, a pyridin-3-yl group, a thiophen-2-yl group, or a thiophen-3-yl group)
Or a pharmacologically acceptable salt thereof, and
(Ii) Other medicaments having therapeutically effective amounts (the other medicaments are PDE4 inhibitor, PDE5 inhibitor, corticosteroid, anticholinergic agent, β2-receptor agonist, H1-histamine receptor antagonist, leukotriene receptor) One or more drugs selected from the group consisting of a body antagonist, an endothelin receptor antagonist, a PGI2 receptor agonist, theophylline, and pirfenidone.)
A method for treating a disease, which comprises administering to a warm-blooded animal in combination.

(14) The method according to (13), wherein the compound represented by the general formula (I) or a salt thereof and another pharmaceutical agent are administered as different formulations at the same time or at different times. .

(15) The method according to (13), wherein both the compound represented by the general formula (I) or a salt thereof and another pharmaceutical agent are administered as a single preparation.

(16) The method according to any one of (13) to (15), wherein R ¹ represents a carboxy group or a C ₁ -C ₆ alkoxycarbonyl group.

(17) The method according to any one of (13) to (15), wherein R ¹ represents a carboxy group, an ethoxycarbonyl group, an isopropoxycarbonyl group, or a hexyloxycarbonyl group.

(18) R ¹ represents a carboxy group, an ethoxycarbonyl group, an isopropoxycarbonyl group or a hexyloxycarbonyl group,
W represents a nitrogen atom or a group —CH═;
R ² represents a 1-propenyl group or a 1-propynyl group,
(13) to (15), wherein Z represents a phenyl group, a 3-fluorophenyl group, a pyridin-2-yl group, a pyridin-3-yl group, a thiophen-2-yl group, or a thiophen-3-yl group. The method according to any one.

(19) The compound represented by the general formula (I) is
(6-{[3 ′-(1-propenyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{[3 ′-(1-propenyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
{6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid,
{6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetate hexyl,
{6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid,
{6-[(benzenesulfonyl) (3′-ethoxybiphenyl-4-ylmethyl) aminomethyl] pyridin-2-ylamino} acetic acid,
{6-[(3′-ethoxybiphenyl-4-ylmethyl) (thiophen-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid,
(6-{[4- (6-Ethoxypyridin-2-yl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{(benzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{(benzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{(3-Fluorobenzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-ylamino) acetic acid, or (6-{[3 ′-(1-propynyl) ) Biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) isopropyl acetate (13) to (15).

(20) The other medicament is one or more medicaments selected from the group consisting of a PDE4 inhibitor, a corticosteroid, an anticholinergic agent, a β2-receptor agonist and pirfenidone, (13) to (19) The method in any one of.

(21) The method according to any one of (13) to (19), wherein the other medicament is a PDE4 inhibitor, a corticosteroid, or pirfenidone.

(22) The method according to any one of (13) to (19), wherein the other medicament is roflumilast, fluticasone, or pirfenidone.

(23) Any of (13) to (22), wherein the disease is asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis or pulmonary hypertension The method described in.

(23) The method according to any one of (13) to (22), wherein the disease is asthma, chronic obstructive pulmonary disease or pulmonary fibrosis.

(25) The method according to any one of (13) to (24), wherein the warm-blooded animal is a human.

In the pharmaceutical composition of the present invention, the pharmacological effect of the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof is added to the pharmacological effect of another pharmaceutical, and the dosage of the other pharmaceutical is reduced. This is useful in that the side effects of other drugs can be reduced. The pharmaceutical composition is a respiratory disease, preferably asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis or pulmonary hypertension, more preferably asthma , A pharmaceutical composition for the treatment and / or prevention of chronic obstructive pulmonary disease or pulmonary fibrosis, and is useful as a pharmaceutical for warm-blooded animals (particularly for humans).
The treatment method of the present invention is useful as a treatment method for the above-mentioned diseases, and is also useful as a treatment method for warm-blooded animals (particularly for humans).

  In the compound represented by the general formula (I), preferred forms of each substituent are shown below.

The optionally protected carboxy group represented by R ^{1 in the} general formula (I) means a carboxy group or a carboxy group protected by a protecting group, and examples of such protecting groups include ester-type protecting groups. be able to. Examples of the partial structure of the ester-type protecting group include methyl group, ethyl group, propyl group, isopropyl group, 1-ethylpropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, 3,3- Dimethylbutyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1-ethylbutyl group, 2 - ethylbutyl group, heptyl group, octyl group, nonyl group, decyl group, C ₁ -C ₁₂ alkyl groups such as undecyl group or dodecyl group; a benzyl group, phenethyl group, phenylpropyl group, phenylbutyl group, phenylpentyl group, Phenylhexyl group, phenylheptyl group, phenyloctyl group, phenylnonyl Group, a phenyl decyl group, C ₇ -C ₁₈ aralkyl groups such as undecyl group or phenyl dodecyl group; acetoxymethyl group, 1-acetoxyethyl group, 1-acetoxy propyl, 1-acetoxy-butyl group, propanoyloxy Methyl group, 1-propanoyloxyethyl group, butanoyloxymethyl group, 1-butanoyloxyethyl group, pivaloyloxymethyl group, 1-pivaloyloxyethyl group, 1-pivaloyloxypropyl group or 1-pivaloyl C ₁ -C ₄ alkyl group substituted by a C ₂ -C ₅ alkanoyloxy groups as oxy butyl; methoxycarbonyloxymethyl group, methoxycarbonyloxyethyl group, ethoxycarbonyloxymethyl group 1-ethoxycarbonyloxyethyl group, propoxy Carbonyloxymethyl group, 1-propoxycarbonyloxyethyl group, isopropoxycarbonyloxymethyl group, 1-isopropoxycarbonyloxyethyl group, butoxycarbonyloxymethyl group, 1-butoxycarbonyloxyethyl group, tert-butoxycarbonyloxymethyl group Or a C ₁ -C ₄ alkyl group substituted with a (C ₁ -C ₄ alkoxy) carbonyloxy group such as a 1-tert-butoxycarbonyloxyethyl group; an N, N-dimethylaminocarbonylmethyl group or N, N— N, N-dialkylaminocarbonylalkyl group such as diethylaminocarbonylmethyl group; 2- (N, N, such as 2- (N, N-dimethylamino) ethyl group or 2- (N, N-diethylamino) ethyl group -Dialkyla Mino) ethyl group; 1 or 2 heteroatoms selected from N, O and S such as 2- (morpholin-4-yl) ethyl group, 2-piperidinoethyl group or 2- (4-methylpiperidino) ethyl group _C 1 -C ₄ alkyl group substituted with 5- or 6-membered heterocyclic saturated monocyclic ring containing; or (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group or (5-phenyl And 2-oxo-1,3-dioxolen-4-yl) methyl group and the like groups that can be easily deprotected and converted into a carboxy group in vivo, preferably a C ₁ -C ₁₂ alkyl group, C ₇ -C ₁₈ aralkyl _group, C 2 -C ₅ alkanoyloxy _C 1 -C ₂ alkyl group substituted by a _{group, (C} 1 -C ₄ alkoxy) _C 1 -C ₂ substituted with a carbonyl group Alkyl group, N, N-dimethylaminocarbonylmethyl group, 2- (morpholin-4-yl) ethyl group, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group or (5- phenyl-2-oxo-1,3-dioxolen-4-yl) methyl group, more _preferably a C 1 -C ₆ alkyl group, particularly preferably an ethyl group, an isopropyl group or hexyl group.

Therefore, in the general formula (I), R ¹ is preferably a carboxy group or a C ₁ -C ₆ alkoxycarbonyl group. In certain embodiments of general formula (I), R ¹ is a carboxy group, an ethoxycarbonyl group, an isopropoxycarbonyl group or a hexyloxycarbonyl group.

  In the general formula (I), W is a nitrogen atom or a group —CH═. That is, in the general formula (I), the aromatic ring containing W is a pyridine ring or a benzene ring. In certain embodiments of general formula (I), W is a group -CH =. In another particular embodiment of general formula (I), W is a nitrogen atom.

In general formula (I), ^{R 2} is an ethoxy group, a 1-propenyl group or a 1-propynyl group. In certain embodiments of general formula (I), R ² is an ethoxy group. In another particular embodiment of general formula (I), R ² is a 1-propenyl group or a 1-propynyl group.

  In general formula (I), Z is a phenyl group, 3-fluorophenyl group, pyridin-2-yl group, pyridin-3-yl group, thiophen-2-yl group or thiophen-3-yl group. In certain embodiments of general formula (I), Z is a phenyl group, a 3-fluorophenyl group, a pyridin-2-yl group or a pyridin-3-yl group, preferably a phenyl group or pyridin-2-yl group. An yl group or a pyridin-3-yl group. In another particular embodiment of general formula (I), Z is a thiophen-2-yl group or a thiophen-3-yl group, preferably a thiophen-2-yl group.

  When geometric isomers or rotational isomers exist in the compound represented by the general formula (I), these isomers are also included in the scope of the present invention, and when proton tautomerism exists, These tautomers are also included in the scope of the compounds represented by the general formula (I) according to the present invention.

  The compound represented by the general formula (I) 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.

  The compound represented by the general formula (I) is 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 toluenesulfonate, glutamate or aspartate.

When R ¹ is a carboxy group, the compound represented by the general formula (I) is converted to a pharmacologically acceptable basic salt by treating with a base. Examples of such salts include metal salts such as sodium salt, potassium salt, calcium salt or magnesium salt; inorganic salts such as ammonium salt; or organic amine salts such as triethylamine salt or guanidine salt.

Compound represented by the general formula (I), when R ¹ is a carboxy group protected by a protecting group, when administered in vivo (in vivo test, etc.), biochemical reactions in vivo (e.g. It can be easily hydrolyzed by esterase etc. and converted to a pharmacologically active form in which R ¹ is a carboxy group.

  Although the typical manufacturing method of the compound represented with general formula (I) is shown below, each specific manufacturing method is demonstrated in detail by the below-mentioned Example.

〔式中、Ｒ^２、Ｗ及びＺは、前記と同意義を示し、Ｒ^１’は、カルボキシ基の保護基を示し、Ｒ^３は、ｔｅｒｔ−ブトキシカルボニル基又は水素原子を示し、Ｘは、ヒドロキシ基、クロロ基、ブロモ基、ヨード基、メタンスルホニルオキシ基、ベンゼンスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基又はトリフルオロメタンスルホニルオキシ基を示し、Ｘ’は、クロロ基、ブロモ基又はヨード基を示す。〕

[Wherein R ² , W and Z are as defined above, R ¹ ′ represents a protecting group for a carboxy group, R ³ represents a tert-butoxycarbonyl group or a hydrogen atom, and X represents A hydroxy group, a chloro group, a bromo group, an iodo group, a methanesulfonyloxy group, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group, and X ′ represents a chloro group, a bromo group or an iodo group. Show. ]

The compound represented by the general formula (I) is obtained by any one of the synthesis routes 1 to 5, wherein R ¹ is a carboxy group, and R ³ is a hydrogen atom as the compound (Ia) or R ¹ Can be obtained as compound (I ′) in which R ³ is a hydrogen atom.

[Synthesis route 1]
In the compound (a), when X is a hydroxy group, the compound (a) and the compound (b) are reacted in an inert organic solvent in the presence of an azo compound-based condensing agent and a phosphine reagent. Compound (I ′) can be obtained.
The inert organic solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the raw material to some extent. For example, aromatic hydrocarbons such as benzene, toluene or xylene; diethyl ether, tetrahydrofuran , Ethers such as 1,4-dioxane or 1,2-dimethoxyethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide or N-methylpyrrolidone; nitriles such as acetonitrile or propionitrile An ester such as methyl acetate, ethyl acetate or isopropyl acetate; or any mixed solvent thereof, and the like, preferably tetrahydrofuran, N, N-dimethylformamide, acetonitrile or a mixed solvent thereof.
Examples of the azo compound-based condensing agent to be used include diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), N, N, N ′, N′-tetraisopropyl azodicarboxamide (TIPA). 1,1 ′-(azodicarbonyl) dipiperidine (ADDP), N, N, N ′, N′-tetramethylazodicarboxamide (TMAD) or 1,6-dimethyl-1,5,7-hexahydro-1 , 4,6,7-tetrazocine-2,5-dione (DHTD), etc., preferably diethyl azodicarboxylate (DEAD) or N, N, N ′, N′-tetramethylazodicarboxamide ( TMAD). The amount of the azo compound-based condensing agent to be used is generally 0.9 to 10-fold mol amount, preferably 1 to 5-fold mol amount based on 1 mol of Compound (b).
Examples of the phosphine reagent used include trimethylphosphine, triethylphosphine, tri-n-butylphosphine, triphenylphosphine, and the like, and tri-n-butylphosphine or triphenylphosphine is preferable. The amount of the phosphine compound to be used is generally 0.9 to 10-fold mol amount, preferably 1 to 5-fold mol amount based on 1 mol of Compound (b).
The amount of compound (a) to be used is generally 0.8 to 2-fold mol amount, preferably 0.9 to 1.5-fold mol amount based on 1 mol of Compound (b).
The reaction temperature varies depending on the kind of raw material, solvent, etc., the amount used, etc., but is usually −20 ° C. to 100 ° C., preferably −5 ° C. to 50 ° C.
The reaction time varies depending on the reaction temperature and the like, but is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.

In the compound (a), when X is a chloro group, bromo group, iodo group, methanesulfonyloxy group, benzenesulfonyloxy group, p-toluenesulfonyloxy group or trifluoromethanesulfonyloxy group, the compound (a) and the compound Compound (I ′) can be obtained by reacting (b) with an inert organic solvent in the presence of a base.
The inert solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the raw material to some extent. For example, ethers such as tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane Halogenated aliphatic hydrocarbons such as methylene chloride, chloroform or 1,2-dichloroethane; nitriles such as acetonitrile or propionitrile; esters such as methyl formate, ethyl formate, methyl acetate or ethyl acetate; benzene or toluene Aromatic hydrocarbons such as N; N-dimethylformamide, amides such as N, N-dimethylacetamide or N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide; or any mixed solvent thereof. Preferably, tetrahydrofuran, , N- dimethylformamide, methylene chloride or 1,2-dichloroethane.
Examples of the base used include alkali metal hydrides such as sodium hydride or potassium hydride; alkali metal amides such as lithium amide, sodium amide, lithium diisopropylamide or lithium bistrimethylsilylamide; sodium methoxide, sodium ethoxide Alkali metal alkoxides such as sodium tert-butoxide or potassium tert-butoxide; alkali metal carbonates such as sodium carbonate or potassium carbonate; or triethylamine, tributylamine, diisopropylethylamine, pyridine, picoline, 2,6-lutidine or 4- Examples include amines such as dimethylaminopyridine, and preferably sodium hydride, potassium carbonate, triethylamine or diisopropylethyl. It is an amine. However, when the inert solvent used is an ester, nitrile or halogenated aliphatic hydrocarbon, the base is preferably triethylamine or diisopropylethylamine.
The amount of the base to be used is generally 1 to 5-fold mol amount, preferably 1 to 2.5-fold mol amount based on 1 mol of Compound (b).
The amount of compound (a) to be used is generally 0.5 to 3-fold mol amount, preferably 0.5 to 1.5-fold mol amount based on 1 mol of Compound (b).
The reaction temperature varies depending on the type of raw material, solvent, etc., the amount used, etc., but is usually −80 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
The reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to 48 hours, preferably 1 hour to 24 hours.

[Synthesis route 2]
In the compound (d), when X is a hydroxy group, the compound (c) and the compound (d) are reacted in an inert organic solvent in the presence of an azo compound-based condensing agent and a phosphine reagent. Compound (I ′) can be obtained. In this step, X in the compound (a) is a hydroxy group in the above [Synthesis route 1] except that the compound (d) is used instead of the compound (a) and the compound (c) is used instead of the compound (b). It is done according to the case.
In the compound (d), when X is a chloro group, a bromo group, an iodo group, a methanesulfonyloxy group, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group, the compound (c) and the compound Compound (I ′) can be obtained by reacting (d) with an inert organic solvent in the presence of a base. In this step, X in the compound (a) is a chloro group in the above [Synthesis route 1] except that the compound (d) is used instead of the compound (a) and the compound (c) is used instead of the compound (b). , A bromo group, an iodo group, a methanesulfonyloxy group, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, or a trifluoromethanesulfonyloxy group.

[Synthesis route 3]
Synthesis route 3-1 is a step of obtaining compound (f) by reacting compound (c) with compound (e) in the presence of a base in an inert organic solvent. In this step, X of compound (a) is a chloro group in the above [Synthesis route 1] except that compound (e) is used instead of compound (a), and compound (c) is used instead of compound (b). , A bromo group, an iodo group, a methanesulfonyloxy group, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, or a trifluoromethanesulfonyloxy group.
In the synthesis route 3-2, the compound (f) and the compound (g) obtained in the synthesis route 3-1 are mixed in an inert solvent under an inert gas atmosphere, in the presence of either a base or a fluoride and a palladium catalyst. To give compound (I ′).
The inert solvent used is not particularly limited as long as it is a solvent that does not inhibit the reaction and dissolves raw materials, catalysts, and bases (or fluorides) to some extent. For example, an aromatic hydrocarbon such as benzene or toluene. Ethers such as tetrahydrofuran, 1,2-dimethoxyethane or 1,4-dioxane; alcohols such as methanol, ethanol, propanol or isopropanol; esters such as methyl acetate or ethyl acetate; N, N-dimethylformamide; Examples thereof include amides such as N, N-dimethylacetamide or N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide; nitriles such as acetonitrile; water; or any mixed solvent thereof, preferably toluene, toluene- Ethanol-water mixed solvent or Toluene - is water mixed solvent.
Examples of the inert gas used include nitrogen, helium, and argon.
Examples of the palladium catalyst used include palladium-activated carbon or palladium metal such as palladium black; tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium, 1,1′-bis (diphenylphosphine chloride). Phino) ferrocene palladium or an organic palladium complex such as tris (dibenzylideneacetone) dipalladium; or palladium salts such as palladium chloride or palladium acetate; and tetrakis (triphenylphosphine) palladium or palladium acetate is preferable. The amount of palladium used as the catalyst is usually 0.0001 to 1-fold mol amount, preferably 0.005 to 0.3-fold mol amount based on 1 mol of Compound (f).
When tris (dibenzylideneacetone) dipalladium, palladium chloride or palladium acetate is used as the catalyst, it is preferable to coexist an organic phosphine compound. Examples of the organic phosphine compound used include tri-n-butylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, butyldi-1-adamantylphosphine, triphenylphosphine, tri (o-tolyl) phosphine, 2- Dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, 1,1′-bis (diphenylphosphino) ferrocene or 1,2,3,4,5-pentaphenyl-1 ′-(di-tert-butylphosphino ) Ferrocene and the like, and preferred are tricyclohexylphosphine, butyldi-1-adamantylphosphine, triphenylphosphine or 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl. The amount of the organic phosphine compound used is usually 1 to 5 times the molar amount, preferably 1.5 to 2.5 times the molar amount per 1 mol of palladium.
Examples of the base or fluoride used include alkali metal acetates such as sodium acetate or potassium acetate; alkali metal carbonates such as sodium carbonate, potassium carbonate or cesium carbonate; trisodium phosphate or tripotassium phosphate Alkali metal phosphates; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; quaternary ammonium hydroxides such as tetramethylammonium hydroxide, tetraethylammonium hydroxide or tetrabutylammonium hydroxide; Alternatively, fluorides such as cesium fluoride, tetramethylammonium fluoride, tetraethylammonium fluoride, and tetrabutylammonium fluoride can be used, and sodium carbonate or tripotassium phosphate is preferable. The amount of the base or fluoride to be used is generally 1 to 10-fold mol amount, preferably 1.5 to 5-fold mol amount based on 1 mol of Compound (f).
The amount of compound (g) to be used is generally 1 to 3-fold mol amount, preferably 1 to 2-fold mol amount based on 1 mol of Compound (f).
The reaction temperature varies depending on the type of raw material, solvent, etc., the amount used, etc., but is usually 0 ° C. to 200 ° C., preferably 50 ° C. to 150 ° C.
The reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to 120 hours, preferably 1 hour to 48 hours.

[Synthesis route 4]
Compound (I ′) can be obtained by reacting compound (h) with compound (i) in an inert organic solvent in the presence or absence (preferably in the presence) of a base.
The inert organic solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the raw material to some extent. For example, aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform Or halogenated aliphatic hydrocarbons such as 1,2-dichloroethane; ethers such as 1,4-dioxane, tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane; N, N-dimethylformamide, N, N-dimethyl Amides such as acetamide or N-methylpyrrolidone; Nitriles such as acetonitrile or propionitrile; or any mixed solvent thereof is preferable, preferably methylene chloride, 1,2-dichloroethane, N, N-dimethyl Formamide, acetonitrile or a mixture thereof It is a solvent.
Examples of the base to be used include organic bases such as triethylamine or diisopropylethylamine; or inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate or potassium carbonate, preferably triethylamine or diisopropylethylamine. . The amount of the base to be used is generally 0.9 to 20-fold mol amount, preferably 1 to 10-fold mol amount based on 1 mol of Compound (i).
The amount of compound (h) to be used is generally 0.7 to 5-fold mol amount, preferably 0.8 to 1.5-fold mol amount based on 1 mol of Compound (i).
The reaction temperature varies depending on the kind of raw material, solvent, etc., the amount used, etc., but is usually −20 ° C. to 100 ° C., preferably −5 ° C. to 50 ° C.
The reaction time varies depending on the reaction temperature and the like, but is usually 1 minute to 36 hours, preferably 1 hour to 18 hours.

[Synthesis route 5]
In the compound (I ′), when R ³ is a tert-butoxycarbonyl group, the compound (I ′) is deprotected by acid treatment, whereby R ¹ is protected by an ester-type protecting group. A compound represented by the general formula (I) can be obtained. However, 'in, ^{R 1} Compound (I)' is the tert- butyl group, and if ^{R 3} is tert- butoxycarbonyl group, hydrochloric, deprotection by acid treatment, such as trifluoroacetic acid, ^{R 1} A compound represented by the general formula (I) in which is a carboxy group can be obtained. Similarly, in the compound (I ′), when R ³ is a hydrogen atom, R ¹ is a carboxy group by subjecting the compound (I ′) to appropriate deprotection by alkali hydrolysis or the like. The compound represented by (I) can be obtained.

The substituent R ² may have a desired substituent introduced from the beginning, and after producing the basic skeleton by the above method, oxidation, reduction, alkylation, esterification, amidation, dehydration reaction, A desired substituent may be introduced using a deprotection reaction, hydrolysis, coupling reaction, cyclization reaction, and / or a commonly used synthetic method combining these reactions.
The starting compound of the compound represented by formula (I) is commercially available or can be produced by a production method known to those skilled in the art. The starting compound of the compound represented by the general formula (I) and the production method of the intermediate compound will be described in detail in Reference Examples described later.

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, then an organic solvent such as ethyl acetate that is immiscible with water is added, and after washing with water, the organic layer containing the target compound is removed. 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 separated and purified by a suitable 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) or a pharmacologically acceptable salt thereof can exist as a hydrate or a solvate.

A pharmaceutical composition containing a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof is characterized by being administered in combination with other pharmaceuticals. In the present invention, “administered in combination” refers to a pharmaceutical composition containing a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof within a certain period, and other subjects (particularly humans) Means to take the medicine of the body into the body. Therefore, the pharmaceutical composition is
(A) A pharmaceutical composition containing a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof and another pharmaceutical agent are administered as different preparations at the same time or at different times. Or a pharmaceutical composition; or
(B) A pharmaceutical composition comprising a pharmaceutical composition comprising a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof and another pharmaceutical agent as a single preparation (compound) It can be a composition, and is preferably the pharmaceutical composition of (a) above.

  In the pharmaceutical composition of the above (a), there is no limitation on the administration time of the preparation containing the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof and the preparation containing another medicine. The formulations can be administered simultaneously, at different times (separately) or on different days. There is no limitation on the order, frequency, route and dose of administration of the above two preparations, and the frequency, route and dose of administration can be different. Further, there is no limitation on the period from administration of one of the above two preparations to administration of the other, and a certain period during which one pharmacological effect remains (for example, 1 week, preferably 2 or 3 days, more preferably May be administered within one day, more preferably within 1 to 8 hours). As long as the desired effect is exhibited, the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof and other medicines do not have to be present in the blood at a certain concentration at the same time, and one of them is administered. Sometimes the other may disappear from the blood.

The dosage form of the pharmaceutical composition of the present invention is, for example, as follows.
(A) a preparation containing a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof and a preparation containing other medicaments (two different preparations) are administered simultaneously;
(B) a preparation containing the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof and a preparation containing other medicaments (two different preparations) are administered separately over a period of time;
(C) A single preparation containing both the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof and other pharmaceuticals is administered.

  Other medicaments in the pharmaceutical composition of the present invention are not limited as long as they exhibit a desired effect (preferably, an anti-inflammatory effect, an anti-fibrosis, or a bronchodilation effect by suppressing production of inflammatory mediators, etc.). For example, PDE4 inhibitor, PDE5 inhibitor, corticosteroid, anticholinergic agent, β2-receptor agonist, H1-histamine receptor antagonist, leukotriene receptor antagonist, endothelin receptor antagonist, PGI2 receptor agonist It may be one or more drugs selected from the group consisting of drugs, theophylline and pirfenidone, preferably selected from the group consisting of PDE4 inhibitors, corticosteroids, anticholinergics, β2-receptor agonists and pirfenidone One or more drugs, more preferably a PDE4 inhibitor, a corticosteroid or pirfenidone, most preferably Preferably, it is roflumilast, fluticasone or pirfenidone.

  In the present invention, examples of the PDE4 inhibitor in other medicaments include silomilast, roflumilast, tetomilast, tofimilast, filaminast, picramilast, or lilimilast, and are preferably siromilast or roflumilast, and more preferably roflumilast.

  In the present invention, examples of the PDE5 inhibitor in other pharmaceuticals include sildenafil, vardenafil, tadalafil, udenafil, or avanafil.

  In the present invention, examples of corticosteroids in other pharmaceuticals include prednisone, prednisolone, methylprednisolone, cortisone, hydrocortisone, fludrocortisone, dexamethasone, betamethasone, budesonide, fluticasone, beclomethasone, mometasone, triamcinolone or ciclesonide.

  In the present invention, examples of the anticholinergic agent in other pharmaceuticals include glycopyrronium bromide, acridinium bromide, tiotropium bromide, ipratropium bromide, and the like.

  In the present invention, β2-receptor agonists in other pharmaceuticals include, for example, salbutamol, milveterol, indacaterol, carmoterol, salmeterol or formoterol.

  In the present invention, examples of the H1-histamine receptor antagonist in other pharmaceuticals include azelastine, olopatadine, loratadine, desloratadine, and cetirizine.

  In the present invention, examples of the leukotriene receptor antagonist in other pharmaceuticals include montelukast, pranlukast, zafirlukast, and the like.

  In the present invention, examples of endothelin receptor antagonists in other pharmaceuticals include bosentan, ambrisentan, atrasentan, darsentan, clazosentan, and avosentan.

  In the present invention, examples of the PGI2 receptor agonist in other medicaments include beraprost and epoprestenol.

  These other pharmaceuticals, including theophylline and pirfenidone, are commercially available or can be manufactured by manufacturing methods known to those skilled in the art.

The pharmaceutical composition (formulation) containing the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof and other pharmaceuticals (formulation) can be administered per se (as is). Or tablets, capsules, powders, syrups, granules, fine granules, pills, suspensions, emulsions manufactured by mixing with appropriate pharmacologically acceptable excipients, diluents, etc. Oral or parenteral (intravenous administration, intramuscular administration, intraperitoneal administration, transdermal administration, nasal administration) in the form of preparations such as transdermal absorption agents, suppositories, ointments, lotions, inhalants or injections , Transrespiratory administration, transpulmonary administration, intradermal administration, subcutaneous administration, etc.). The pharmaceutical composition containing the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof and the other medicament may be different formulations, respectively, and the compound represented by the general formula (I) or the The pharmaceutical composition containing a pharmacologically acceptable salt may be a single preparation further containing another pharmaceutical agent.
These preparations are produced by well-known methods using additives such as excipients, lubricants, binders, disintegrants, emulsifiers, stabilizers, flavoring agents, and diluents.

  Examples of the excipient include organic excipients and 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 etc. are 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 and the like.

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

  Diluents are compounds that are usually used as diluents, such as lactose, mannitol, glucose, sucrose, calcium sulfate, hydroxypropylcellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, Examples thereof include starch, polyvinyl pyrrolidone, and mixtures thereof.

  In addition, an appropriate additive can be used according to a dosage form. For example, when the active ingredient of the pharmaceutical composition of the present invention is an aerosol for nasal administration or respiratory tract administration, chlorofluorocarbons (CFCs) such as dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane are used. Alternatively, carbon dioxide or the like can be used as a propellant.

  In the pharmaceutical composition of the present invention, the dose of the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof may vary depending on conditions such as the patient's symptoms, age, weight, etc. In the case of parenteral administration, 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). A lower limit of 0.0001 mg / 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 the symptoms.

  In the pharmaceutical composition of the present invention, the dosage of other pharmaceuticals may vary depending on other pharmaceutical types, patient symptoms, age, body weight and other conditions. In the case of parenteral administration, the lower limit is 0.001 mg / Kg (preferably 0.01 mg / Kg) and the upper limit is 500 mg / Kg (preferably 50 mg / Kg). Is 0.0005 mg / Kg), and an upper limit of 50 mg / Kg (preferably 5 mg / Kg) can be administered to adults 1 to 6 times per day depending on the 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.

[Example 1]
(6-{[3 ′-(1-propenyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate

To a solution of 3 ′-(1-propenyl) biphenyl-4-ylmethanol 205 mg (0.913 mmol) obtained in Reference Example 3- (b) in 9.4 mL of tetrahydrofuran, the same method as in Reference Example 1- (g) {6-[(Pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} ethyl acetate 320 mg (0.913 mmol), tri-n-butylphosphine 570 μL (2.31 mmol) and N, N , N ′, N′-Tetramethylazodicarboxamide (236 mg, 1.37 mmol) was added, and the mixture was stirred at room temperature for 5 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 = 2: 3 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 510 mg of the title compound as a pale yellow oil. Obtained as a thing. (quantitative)
Mass spectrum (FAB, m / z): 557 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.62 (ddd, J = 4.7, 1.8, 1.0 Hz, 1H), 7.83 (ddd, J = 7.8, 1.0, 1.0 Hz, 1H), 7.75 (ddd, J = 7.8, 7.6, 1.8 Hz, 1H), 7.52-7.43 (m, 3H), 7.41-7.30 (m, 6H), 7.27-7.20 (m, 1H), 6.51 (d, J = 7.3 Hz, 1H), 6.50 -6.42 (m, 1H), 6.38-6.26 (m, 1H), 6.23 (d, J = 8.3 Hz, 1H), 4.80 (s, 2H), 4.70 (t, J = 5.4 Hz, 0.9H), 4.42 (s, 2H), 4.22 (q, J = 7.1 Hz, 2H), 3.96 (d, J = 5.4 Hz, 2H), 1.91 (dd, J = 6.3, 1.5 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H).

[Example 2]
(6-{[3 ′-(1-propenyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid

220 mg (0.395 mmol) of ethyl acetate (6-{[3 ′-(1-propenyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) obtained in Example 1 1) 1.98 mL (1.98 mmol) of 1 mol / L sodium hydroxide aqueous solution was added to ethanol 2.0 mL solution, and the mixture was stirred at room temperature for 2.5 hours. After completion of the reaction, water was added to the reaction solution, and then adjusted to pH 4.5 with 1 mol / L hydrochloric acid. The precipitated solid was collected by filtration and dried under reduced pressure to give 146 mg of the title compound as a white solid. (Yield 70%)
Mass spectrum (FAB, m / z): 529 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 8.64 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 7.95 (ddd, J = 7.7, 7.7, 1.7 Hz, 1H), 7.80 (ddd, J = 7.7, 1.0, 0.9 Hz, 1H), 7.61-7.56 (m, 4H), 7.48-7.44 (m, 1H), 7.39-7.37 (m, 2H), 7.35-7.32 (m, 2H), 7.19 ( dd, J = 8.3, 7.2 Hz, 1H), 6.61 (brs, 0.8H), 6.52-6.47 (m, 1H), 6.44-6.37 (m, 1H), 6.33 (d, J = 8.3 Hz, 1H), 6.28 (d, J = 7.2 Hz, 1H), 4.74 (s, 2H), 4.24 (s, 2H), 3.76 (d, J = 4.0 Hz, 2H), 1.87 (dd, J = 6.2, 1.5 Hz, 3H ).

[Example 3]
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate

To a 4.0 mL tetrahydrofuran solution of 200 mg (0.900 mmol) of 3 ′-(1-propynyl) biphenyl-4-ylmethanol obtained in Reference Example 4- (b), the same method as in Reference Example 1- (g) {6-[(Pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} ethyl acetate 315 mg (0.900 mmol), 450 μL (1.82 mmol) tri-n-butylphosphine and N, N , N ′, N′-Tetramethylazodicarboxamide (310 mg, 1.80 mmol) was added, and the mixture was stirred at room temperature for 3 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 = 3: 2 → 2: 3 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 483 mg of the title compound. Was obtained as a white foam. (Yield 97%)
Mass spectrum (FAB, m / z): 555 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.62 (ddd, J = 4.6, 1.7, 1.0 Hz, 1H), 7.83 (ddd, J = 7.7, 1.3, 1.0 Hz, 1H), 7.75 (ddd, J = 7.7, 7.7, 1.7 Hz, 1H), 7.59-7.58 (m, 1H), 7.47-7.43 (m, 3H), 7.41-7.31 (m, 5H), 7.23 (dd, J = 8.2, 7.1 Hz, 1H) , 6.51 (d, J = 7.1 Hz, 1H), 6.23 (d, J = 8.2 Hz, 1H), 4.79 (s, 2H), 4.70 (t, J = 5.4 Hz, 1H), 4.42 (s, 2H) , 4.22 (q, J = 7.1 Hz, 2H), 3.96 (d, J = 5.4 Hz, 2H), 2.08 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H).

[Example 4]
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid

476 mg (0.858 mmol) of ethyl acetate (6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) obtained in Example 3 ) In ethanol (3.0 mL) was added 1 mol / L aqueous sodium hydroxide solution (3.43 mL, 3.43 mmol), and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, water was added to the reaction solution, adjusted to pH 4.5 with 1 mol / L 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; methylene chloride: methanol = 15: 1 → 10: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 444 mg of the title compound in white. Obtained as a foam. (Yield 98%)
Mass spectrum (FAB, m / z): 527 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 12.42 (brs, 0.6H), 8.64 (ddd, J = 4.7, 1.8, 1.0 Hz, 1H), 7.95 (ddd, J = 7.8, 7.7, 1.8 Hz) , 1H), 7.80 (ddd, J = 7.8, 1.0, 1.0 Hz, 1H), 7.63-7.56 (m, 5H), 7.43 (dd, J = 7.9, 7.9 Hz, 1H), 7.37 (ddd, J = 7.9 , 1.7, 0.9 Hz, 1H), 7.35-7.32 (m, 2H), 7.19 (dd, J = 8.4, 7.0 Hz, 1H), 6.75 (t, J = 5.9 Hz, 1H), 6.34 (d, J = 8.4 Hz, 1H), 6.28 (d, J = 7.0 Hz, 1H), 4.74 (s, 2H), 4.24 (s, 2H), 3.82 (d, J = 5.9 Hz, 2H), 2.07 (s, 3H) .

[Example 5]
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate

To a 4.0 mL tetrahydrofuran solution of 178 mg (0.800 mmol) of 3 ′-(1-propynyl) biphenyl-4-ylmethanol obtained in the same manner as in Reference Example 4- (b), Reference Example 2- (b) 280 mg (0.800 mmol) of ethyl {6-[(pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} obtained by the same method as above, 395 μL (1.60 mmol) of tri-n-butylphosphine And 276 mg (1.60 mmol) of N, N, N ′, N′-tetramethylazodicarboxamide were added and stirred at room temperature for 3 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 = 3: 7 → 0: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 400 mg of the title compound. Was obtained as a slightly yellow oil. (Yield 90%)
Mass spectrum (ESI ⁺ , m / z): 555 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.97 (dd, J = 2.3, 0.7 Hz, 1H), 8.69 (dd, J = 4.9, 1.7 Hz, 1H), 7.92 (ddd, J = 8.0, 2.3, 1.7 Hz, 1H), 7.61-7.60 (m, 1H), 7.52-7.49 (m, 2H), 7.48-7.46 (m, 1H), 7.38-7.35 (m, 4H), 7.32-7.27 (m, 2H) , 6.46 (d, J = 7.0 Hz, 1H), 6.28 (d, J = 8.2 Hz, 1H), 4.74 (t, J = 5.4 Hz, 1H), 4.66 (s, 2H), 4.34 (s, 2H) , 4.22 (q, J = 7.2 Hz, 2H), 3.87 (d, J = 5.4 Hz, 2H), 2.08 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H).

[Example 6]
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid

395 mg (0.712 mmol) ethyl (6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetate obtained in Example 5 ) In ethanol (3.0 mL) was added 1 mol / L aqueous sodium hydroxide solution (3.0 mL, 3.0 mmol), and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, water was added to the reaction solution, adjusted to pH 4.5 with 1 mol / L hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the residue, 10 mL of tert-butyl methyl ether and 0.5 mL of methanol were added, and the solid precipitated by ultrasonication was collected by filtration and dried under reduced pressure to obtain 340 mg of the title compound as a white solid. (Yield 91%)
Mass spectrum (ESI ⁺ , m / z): 527 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 12.42 (brs, 0.6H), 8.83 (dd, J = 2.4, 0.6 Hz, 1H), 8.72 (dd, J = 4.8, 1.6 Hz, 1H), 8.02 (ddd, J = 8.1, 2.4, 1.6 Hz, 1H), 7.65-7.61 (m, 4H), 7.47 (ddd, J = 8.1, 4.8, 0.6 Hz, 1H), 7.44 (dd, J = 7.9, 7.9 Hz, 1H), 7.39-7.36 (m, 3H), 7.24 (dd, J = 8.3, 7.1 Hz, 1H), 6.78 (t, J = 5.9 Hz, 1H), 6.37 (d, J = 8.3 Hz, 1H ), 6.33 (d, J = 7.1 Hz, 1H), 4.71 (s, 2H), 4.21 (s, 2H), 3.71 (d, J = 5.9 Hz, 2H), 2.07 (s, 3H).

[Example 7]
{6-[(3′-Ethoxybiphenyl-4-ylmethyl) (pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid

7- (a): (tert-Butoxycarbonyl {6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate Reference To a 4.0 mL tetrahydrofuran solution of 183 mg (0.800 mmol) of 3′-ethoxybiphenyl-4-ylmethanol obtained in Example 5, (tert-butoxycarbonyl) was obtained in the same manner as in Reference Example 1- (f). {6-[(Pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate 422 mg (0.880 mmol), 395 μL (1.60 mmol) tri-n-butylphosphine and N, N , N ′, N′-tetramethylazodicarboxamide 276 mg (1.60 mmol) was added. And stirred at room temperature for 3 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; toluene: ethyl acetate = 8: 1 → 6: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 537 mg of the title compound as white. Obtained as a foam. (Yield 98%)
Mass spectrum (FAB, m / z): 689 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.60 (ddd, J = 4.6, 1.8, 1.0 Hz, 1H), 7.82 (ddd, J = 7.7, 1.0, 1.0 Hz, 1H), 7.77 (ddd, J = 7.7, 7.6, 1.8 Hz, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.48-7.26 (m, 7H), 7.11 (ddd, J = 7.9, 1.7, 0.9 Hz, 1H), 7.07 (dd , J = 2.3, 1.7 Hz, 1H), 6.91 (d, J = 7.3 Hz, 1H), 6.88 (ddd, J = 7.9, 2.3, 0.9 Hz, 1H), 4.74 (s, 2H), 4.51 (s, 2H), 4.46 (s, 2H), 4.10 (q, J = 6.9 Hz, 2H), 1.52 (s, 9H), 1.45 (t, J = 6.9 Hz, 3H), 1.42 (s, 9H).

7- (b): {6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid obtained in Example 7- (a) (Tert-Butoxycarbonyl {6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate (525 mg, 0.762 mmol) To a 4.0 mL solution of 1,4-dioxane, 3.2 mL (19.2 mmol) of 6 mol / L hydrochloric acid and 0.8 mL of water were added, and the mixture was heated and stirred at 70 ° C. for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, then water was added, the pH was adjusted to 4.4 with a 1 mol / L 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; methylene chloride: methanol = 15: 1 → 10: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 369 mg of the title compound as white. Obtained as a foam. (Yield 91%)
Mass spectrum (FAB, m / z): 533 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 12.41 (brs, 0.4H), 8.64 (ddd, J = 4.6, 1.8, 0.9 Hz, 1H), 7.95 (ddd, J = 7.8, 7.8, 1.8 Hz) , 1H), 7.80 (ddd, J = 7.8, 1.0, 0.9 Hz, 1H), 7.59-7.56 (m, 3H), 7.36 (dd, J = 8.1, 8.1 Hz, 1H), 7.33-7.31 (m, 2H ), 7.20 (dd, J = 8.2, 7.1 Hz, 1H), 7.18 (ddd, J = 8.1, 1.8, 0.8 Hz, 1H), 7.14 (dd, J = 2.3, 1.8 Hz, 1H), 6.92 (ddd, J = 8.1, 2.3, 0.8 Hz, 1H), 6.75 (t, J = 5.9 Hz, 1H), 6.34 (d, J = 8.2 Hz, 1H), 6.28 (d, J = 7.1 Hz, 1H), 4.74 ( s, 2H), 4.24 (s, 2H), 4.10 (q, J = 7.0 Hz, 2H), 3.82 (d, J = 5.9 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H).

[Example 8]
{6-[(3′-Ethoxybiphenyl-4-ylmethyl) (pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetate hexyl

To a 4.0 mL tetrahydrofuran solution of 171 mg (0.750 mmol) of 3′-ethoxybiphenyl-4-ylmethanol obtained in Reference Example 5 was added {6-[(pyridin-2-ylsulfonyl) obtained in Reference Example 6. Aminomethyl] pyridin-2-ylamino} acetyl 305 mg (0.750 mmol), tri-n-butylphosphine 280 μL (1.14 mmol) and N, N, N ′, N′-tetramethylazodicarboxamide 196 mg (1. 14 mmol) and stirred at room temperature for 16 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 = 3: 2 → 2: 3 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 429 mg of the title compound. Was obtained as a colorless oil. (Yield 93%)
Mass spectrum (FAB, m / z): 617 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.61 (ddd, J = 4.7, 1.7, 1.0 Hz, 1H), 7.82 (ddd, J = 7.7, 1.1, 1.0 Hz, 1H), 7.75 (ddd, J = 7.7, 7.7, 1.7 Hz, 1H), 7.47-7.45 (m, 2H), 7.38 (ddd, J = 7.7, 4.7, 1.1 Hz, 1H), 7.35-7.31 (m, 3H), 7.23 (dd, J = 8.4, 7.3 Hz, 1H), 7.12 (ddd, J = 8.1, 1.8, 1.0 Hz, 1H), 7.08 (dd, J = 2.4, 1.8 Hz, 1H), 6.88 (ddd, J = 8.1, 2.4, 1.0 Hz , 1H), 6.51 (d, J = 7.3 Hz, 1H), 6.23 (d, J = 8.4 Hz, 1H), 4.79 (s, 2H), 4.70 (t, J = 5.3 Hz, 1H), 4.42 (s , 2H), 4.15 (t, J = 6.8 Hz, 2H), 4.10 (q, J = 7.0 Hz, 2H), 3.96 (d, J = 5.3 Hz, 2H), 1.66-1.60 (m, 2H), 1.45 (t, J = 7.0 Hz, 3H), 1.34-1.25 (m, 6H), 0.87 (t, J = 7.0 Hz, 3H).

[Example 9]
{6-[(3′-Ethoxybiphenyl-4-ylmethyl) (pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid

9- (a): (tert-Butoxycarbonyl {6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate Reference To a 4.0 mL tetrahydrofuran solution of 183 mg (0.800 mmol) of 3′-ethoxybiphenyl-4-ylmethanol obtained in Example 5, (tert-butoxycarbonyl) was obtained in the same manner as in Reference Example 2- (a). {6-[(Pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate 422 mg (0.880 mmol), tri-n-butylphosphine 395 μL (1.60 mmol) and N, N , N ′, N′-tetramethylazodicarboxamide 276 mg (1.60 mmol) was added. And stirred at room temperature for 3 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 = 7: 3 → 1: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 550 mg of the title compound. Was obtained as a white foam. (quantitative)
Mass spectrum (FAB, m / z): 689 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.96 (dd, J = 2.4, 0.7 Hz, 1H), 8.71 (dd, J = 4.8, 1.6 Hz, 1H), 7.87 (ddd, J = 7.9, 2.4, 1.6 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.54-7.47 (m, 3H), 7.36-7.26 (m, 4H), 7.13 (ddd, J = 7.9, 1.9, 1.0 Hz, 1H ), 7.08 (dd, J = 2.3, 1.9 Hz, 1H), 6.89 (ddd, J = 8.3, 2.3, 1.0 Hz, 1H), 6.87 (d, J = 7.3 Hz, 1H), 4.62 (s, 2H) , 4.42 (s, 2H), 4.37 (s, 2H), 4.10 (q, J = 7.0 Hz, 2H), 1.52 (s, 9H), 1.45 (t, J = 7.0 Hz, 3H), 1.42 (s, 9H).

9- (b): {6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid obtained in Example 9- (a) (Tert-Butoxycarbonyl {6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate 540 mg (0.784 mmol) To 4.0 mL solution of 1,4-dioxane, 3.3 mL (20 mmol) of 6 mol / L hydrochloric acid and 1.0 mL of water were added, and the mixture was heated and stirred at 70 ° C. for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, then water was added, the pH was adjusted to 4.4 with a 1 mol / L 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; methylene chloride: methanol = 15: 1 → 10: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. 2 mL of ethyl acetate and 8 mL of n-hexane were added to the concentrate, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 388 mg of the title compound as a white solid. (Yield 93%)
Mass spectrum (FAB, m / z): 533 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 12.43 (brs, 0.4H), 8.83 (dd, J = 2.4, 0.7 Hz, 1H), 8.72 (dd, J = 4.8, 1.7 Hz, 1H), 8.02 (ddd, J = 8.0, 2.4, 1.7 Hz, 1H), 7.64-7.61 (m, 2H), 7.47 (ddd, J = 8.0, 4.8, 0.7 Hz, 1H), 7.38-7.34 (m, 3H), 7.24 (dd, J = 8.3, 7.2 Hz, 1H), 7.20 (ddd, J = 7.8, 1.7, 0.9 Hz, 1H), 7.16 (dd, J = 2.3, 1.7 Hz, 1H), 6.92 (ddd, J = 8.2, 2.3, 0.9 Hz, 1H), 6.78 (t, J = 5.9 Hz, 1H), 6.37 (d, J = 8.3 Hz, 1H), 6.33 (d, J = 7.2 Hz, 1H), 4.70 (s, 2H), 4.21 (s, 2H), 4.10 (q, J = 7.0 Hz, 2H), 3.71 (d, J = 5.9 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H).

[Example 10]
{6-[(Benzenesulfonyl) (3′-ethoxybiphenyl-4-ylmethyl) aminomethyl] pyridin-2-ylamino} acetic acid

10- (a) ({6-[(Benzenesulfonyl) (3′-ethoxybiphenyl-4-ylmethyl) aminomethyl] pyridin-2-yl} tert-butoxycarbonylamino) tert-butyl acetate Reference Example 7- (b ) (Tert-butoxycarbonyl {6-[(3′-ethoxybiphenyl-4-ylmethyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate 350 mg (0.639 mmol) of methylene chloride 1 To the 8 mL solution, 178 μL (1.28 mmol) of triethylamine and 98 μL (0.77 mmol) of benzenesulfonyl chloride were added under ice cooling, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, subject the reaction solution to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 4: 1 → 7: 3 (V / V)), and concentrate the fraction containing the desired product under reduced pressure. Gave 392 mg of the title compound as a white foam. (Yield 89%)
Mass spectrum (CI, m / z): 688 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.77-7.73 (m, 2H), 7.67 (d, J = 8.3 Hz, 1H), 7.56-7.41 (m, 6H), 7.33 (dd, J = 7.9, 7.7 Hz, 1H), 7.24-7.19 (m, 2H), 7.11 (ddd, J = 7.7, 1.7, 0.9 Hz, 1H), 7.07 (dd, J = 2.3, 1.7 Hz, 1H), 6.88 (ddd, J = 7.9, 2.3, 0.9 Hz, 1H), 6.86 (d, J = 7.5 Hz, 1H), 4.54 (s, 2H), 4.39 (s, 2H), 4.35 (s, 2H), 4.09 (q, J = 7.1 Hz, 2H), 1.51 (s, 9H), 1.44 (t, J = 7.1 Hz, 3H), 1.41 (s, 9H).

10- (b): {6-[(Benzenesulfonyl) (3′-ethoxybiphenyl-4-ylmethyl) aminomethyl] pyridin-2-ylamino} acetic acid obtained in Example 10- (a) ({6- To a solution of 389 mg (0.566 mmol) tert-butyl [(benzenesulfonyl) (3′-ethoxybiphenyl-4-ylmethyl) aminomethyl] pyridin-2-yl} tert-butoxycarbonylamino) methylene chloride in 5.8 mL At room temperature, 5.8 mL (76 mmol) of trifluoroacetic acid was added and allowed to stand for 3.5 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, then water was added, the pH was adjusted to 4.4 with a saturated aqueous sodium hydrogen carbonate solution and 1 mol / L hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 3.9 mL of diisopropyl ether was added to the concentrate, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 293 mg of the title compound as a white solid. (Yield 97%)
Mass spectrum (FAB, m / z): 532 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 12.41 (brs, 0.8H), 7.74-7.72 (m, 2H), 7.61-7.59 (m, 3H), 7.52-7.48 (m, 2H), 7.35 (dd, J = 7.8, 7.8 Hz, 1H), 7.31-7.29 (m, 2H), 7.23 (dd, J = 8.4, 7.2 Hz, 1H), 7.19 (ddd, J = 7.8, 1.7, 0.9 Hz, 1H ), 7.14 (dd, J = 2.3, 1.7 Hz, 1H), 6.91 (ddd, J = 7.8, 2.3, 0.9 Hz, 1H), 6.76 (t, J = 5.9 Hz, 1H), 6.37 (d, J = 8.4 Hz, 1H), 6.29 (d, J = 7.2 Hz, 1H), 4.59 (s, 2H), 4.16 (s, 2H), 4.10 (q, J = 7.0 Hz, 2H), 3.77 (d, J = 5.9 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H).

[Example 11]
{6-[(3′-Ethoxybiphenyl-4-ylmethyl) (thiophen-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid

11- (a) (tert-Butoxycarbonyl {6-[(3′-ethoxybiphenyl-4-ylmethyl) (thiophen-2-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate reference example 350 mg (0.639 mmol) of tert-butyl acetate (tert-butoxycarbonyl {6-[(3′-ethoxybiphenyl-4-ylmethyl) aminomethyl] pyridin-2-yl} amino) obtained in 7- (b) To a 1.8 mL solution of methylene chloride was added a solution of triethylamine 178 μL (1.28 mmol) and 2-thiophenesulfonyl chloride 141 mg (0.772 mmol) in methylene chloride 0.3 mL at room temperature. Stir for hours. After completion of the reaction, subject the reaction solution to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 9: 1 → 3: 2 (V / V)), and concentrate the fraction containing the desired product under reduced pressure. Gave 376 mg of the title compound as a white foam. (Yield 85%)
Mass spectrum (CI, m / z): 694 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.70 (d, J = 8.5 Hz, 1H), 7.54-7.42 (m, 5H), 7.33 (dd, J = 8.0, 7.8 Hz, 1H), 7.27-7.23 (m, 2H), 7.12 (ddd, J = 7.7, 1.7, 0.9 Hz, 1H), 7.08 (dd, J = 2.4, 1.7 Hz, 1H), 7.02 (dd, J = 5.1, 3.7 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.88 (ddd, J = 8.0, 2.4, 0.9 Hz, 1H), 4.56 (s, 2H), 4.43 (s, 2H), 4.39 (s, 2H), 4.10 (q, J = 7.0 Hz, 2H), 1.52 (s, 9H), 1.44 (t, J = 7.0 Hz, 3H), 1.42 (s, 9H).

11- (b) {6-[(3′-ethoxybiphenyl-4-ylmethyl) (thiophen-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid obtained in Example 11- (a) ( tert-Butoxycarbonyl {6-[(3′-ethoxybiphenyl-4-ylmethyl) (thiophen-2-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate 374 mg (0.538 mmol) chloride To a 5.6 mL methylene solution, 5.6 mL (73 mmol) trifluoroacetic acid was added at room temperature, and the mixture was allowed to stand for 3.5 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, then water was added, the pH was adjusted to 4.4 with a saturated aqueous sodium hydrogen carbonate solution and 1 mol / L hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the concentrate was added 3.7 mL of tert-butyl methyl ether, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 272 mg of the title compound as a white solid. (Yield 94%)
Mass spectrum (FAB, m / z): 538 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 12.42 (brs, 0.7H), 7.91 (dd, J = 5.1, 1.4 Hz, 1H), 7.61-7.58 (m, 2H), 7.54 (dd, J = 3.7, 1.4 Hz, 1H), 7.35 (dd, J = 7.9, 7.8 Hz, 1H), 7.34-7.31 (m, 2H), 7.27 (dd, J = 8.4, 7.2 Hz, 1H), 7.19 (ddd, J = 7.8, 1.7, 0.9 Hz, 1H), 7.15 (dd, J = 2.3, 1.7 Hz, 1H), 7.13 (dd, J = 5.1, 3.7 Hz, 1H), 6.91 (ddd, J = 7.9, 2.3, 0.9 Hz, 1H), 6.79 (t, J = 5.8 Hz, 1H), 6.41 (d, J = 8.4 Hz, 1H), 6.35 (d, J = 7.2 Hz, 1H), 4.58 (s, 2H), 4.17 (s, 2H), 4.10 (q, J = 7.0 Hz, 2H), 3.83 (d, J = 5.8 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H).

[Example 12]
(6-{[4- (6-Ethoxypyridin-2-yl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid

12- (a): [tert-Butoxycarbonyl (6-{[4- (6-ethoxypyridin-2-yl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-yl) amino] acetic acid To a solution of 267 mg (1.16 mmol) of 4- (6-ethoxypyridin-2-yl) phenylmethanol obtained in tert-butyl Reference Example 8 in 11 mL of tetrahydrofuran was obtained in the same manner as in Reference Example 1- (f). (Tert-Butoxycarbonyl {6-[(pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate 560 mg (1.17 mmol), tri-n-butylphosphine 724 μL (2. 90 mmol) and N, N, N ′, N′-tetramethylazodicarboxamide 300 mg (1.7 mmol), and the mixture was stirred for 1.5 hours at room temperature. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 3: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 606 mg of the title compound as a white foam. Obtained as a thing. (Yield 76%)
Mass spectrum (CI, m / z): 690 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.60 (ddd, J = 4.7, 1.8, 1.1 Hz, 1H), 7.92-7.88 (m, 2H), 7.82 (ddd, J = 7.7, 1.3, 1.1 Hz, 1H), 7.76 (ddd, J = 7.7, 7.5, 1.8 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.61 (dd, J = 8.2, 7.5 Hz, 1H), 7.45 (dd, J = 8.3, 7.5 Hz, 1H), 7.38 (ddd, J = 7.5, 4.7, 1.3 Hz, 1H), 7.34-7.30 (m, 2H), 7.28 (dd, J = 7.5, 0.6 Hz, 1H), 6.90 ( d, J = 7.5 Hz, 1H), 6.66 (dd, J = 8.3, 0.6 Hz, 1H), 4.76 (s, 2H), 4.49 (s, 2H), 4.48 (q, J = 7.1 Hz, 2H), 4.46 (s, 2H), 1.52 (s, 9H), 1.44 (t, J = 7.1 Hz, 3H), 1.42 (s, 9H).

12- (b) (6-{[4- (6-Ethoxypyridin-2-yl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid in Example 12- (a) The resulting [tert-butoxycarbonyl (6-{[4- (6-ethoxypyridin-2-yl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-yl) amino] tert-butyl acetate To a solution of 590 mg (0.855 mmol) in methylene chloride (8.6 mL) was added trifluoroacetic acid (8.6 mL, 112 mmol) at room temperature, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, then water was added, the pH was adjusted to 4.5 with a 2 mol / L aqueous sodium hydroxide solution and dilute hydrochloric acid, 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 to obtain 357 mg of the title compound as a white foam. (Yield 78%)
Mass spectrum (FAB, m / z): 534 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 12.59 (brs, 0.5H), 8.67 (d, J = 4.7 Hz, 1H), 8.01-7.95 (m, 3H), 7.85 (d, J = 7.7 Hz, 1H), 7.76 (dd, J = 8.4, 7.5 Hz, 1H), 7.61 (dd, J = 7.2, 4.7 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.36-7.27 (m , 3H), 6.75 (d, J = 8.4 Hz, 1H), 6.44 (s, 1H), 6.37 (s, 1H), 4.72 (s, 2H), 4.42 (q, J = 7.1 Hz, 2H), 4.33 (s, 2H), 3.87 (s, 2H), 1.37 (t, J = 7.1 Hz, 3H).

[Example 13]
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate

To a 8.0 mL tetrahydrofuran solution of 533 mg (1.50 mmol) of ethyl {6-[(thiophen-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetate obtained in Reference Example 9- (b), 3 ′-(1-propynyl) biphenyl-4-ylmethanol 333 mg (1.50 mmol), tri-n-butylphosphine 740 μL (3.00 mmol) and N, N, N ′, 517 mg (3.00 mmol) of N′-tetramethylazodicarboxamide was added and stirred at room temperature for 7 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 = 1: 0 → 1: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 806 mg of the title compound. Was obtained as a colorless oil. (Yield 96%)
Mass spectrum (CI, m / z): 560 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.60-7.59 (m, 1H), 7.51 (dd, J = 5.0, 1.3 Hz, 1H), 7.48-7.43 (m, 4H), 7.36-7.27 (m, 5H), 7.01 (dd, J = 5.0, 3.8 Hz, 1H), 6.54 (d, J = 6.9 Hz, 1H), 6.29 (d, J = 8.0 Hz, 1H), 4.78 (t, J = 5.4 Hz, 1H), 4.60 (s, 2H), 4.33 (s, 2H), 4.21 (q, J = 7.1 Hz, 2H), 3.99 (d, J = 5.4 Hz, 2H), 2.07 (s, 3H), 1.27 ( t, J = 7.1 Hz, 3H).

[Example 14]
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid

800 mg (1.43 mmol) ethyl (6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetate obtained in Example 13 ) In ethanol (6.0 mL) was added 1 mol / L aqueous sodium hydroxide solution (6.0 mL, 6.0 mmol), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, water was added to the reaction solution, adjusted to pH 4.5 with 1 mol / L hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was dissolved in 10 mL of ethyl acetate, and 10 mL of n-hexane was added at 50 ° C., followed by stirring to room temperature over 1.5 hours. The precipitated solid was collected by filtration and dried under reduced pressure to give 620 mg of the title compound as a white solid. (Yield 82%)
Mass spectrum (ESI ⁺ , m / z): 532 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 12.39 (brs, 0.9H), 7.91 (dd, J = 5.0, 1.3 Hz, 1H), 7.64-7.59 (m, 4H), 7.54 (dd, J = 3.8, 1.3 Hz, 1H), 7.43 (dd, J = 7.7, 7.7 Hz, 1H), 7.38-7.32 (m, 3H), 7.26 (dd, J = 8.3, 7.2 Hz, 1H), 7.13 (dd, J = 5.0, 3.8 Hz, 1H), 6.80 (t, J = 5.8 Hz, 1H), 6.41 (d, J = 8.3 Hz, 1H), 6.35 (d, J = 7.2 Hz, 1H), 4.59 (s, 2H), 4.18 (s, 2H), 3.84 (d, J = 5.8 Hz, 2H), 2.07 (s, 3H).

[Example 15]
(6-{(Benzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-ylamino) ethyl acetate

In a solution of 524 mg (1.50 mmol) of ethyl {6-[(benzenesulfonyl) aminomethyl] pyridin-2-ylamino} acetate obtained in Reference Example 10- (b) in 8.0 mL of tetrahydrofuran, the same as in Reference Example 13 333 mg (1.50 mmol) of 3 ′-(1-propynyl) biphenyl-4-ylmethanol obtained by the method, 740 μL (3.00 mmol) of tri-n-butylphosphine and N, N, N ′, N′-tetra 517 mg (3.00 mmol) of methyl azodicarboxamide was added and 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 = 3: 1 → 1: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 809 mg of the title compound. Was obtained as a colorless oil. (Yield 97%)
Mass spectrum (CI, m / z): 554 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.78-7.75 (m, 2H), 7.59-7.58 (m, 1H), 7.53-7.40 (m, 6H), 7.37-7.25 (m, 5H), 6.48 ( d, J = 7.0 Hz, 1H), 6.27 (d, J = 8.0 Hz, 1H), 4.74 (t, J = 5.2 Hz, 1H), 4.58 (s, 2H), 4.32 (s, 2H), 4.21 ( q, J = 7.2 Hz, 2H), 3.90 (d, J = 5.2 Hz, 2H), 2.07 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H).

[Example 16]
(6-{(Benzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-ylamino) acetic acid

804 mg (1.45 mmol) of ethyl 6- (6-{(benzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-ylamino) acetate obtained in Example 15 To the 0.0 mL solution, 6.0 mL (6.0 mmol) of 1 mol / L sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, water was added to the reaction solution, adjusted to pH 4.5 with 1 mol / L hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was dissolved in 10 mL of ethyl acetate, and 10 mL of n-hexane was added at 50 ° C., followed by stirring to room temperature over 2 hours. The precipitated solid was collected by filtration and dried under reduced pressure to give 724 mg of the title compound as a white solid. (Yield 95%)
Mass spectrum (ESI ⁺ , m / z): 526 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 12.40 (brs, 0.6H), 7.75-7.72 (m, 2H), 7.63-7.58 (m, 5H), 7.53-7.48 (m, 2H), 7.43 (dd, J = 7.7, 7.7 Hz, 1H), 7.37 (ddd, J = 7.7, 1.4, 1.4 Hz, 1H), 7.33-7.30 (m, 2H), 7.23 (dd, J = 8.3, 7.2 Hz, 1H ), 6.75 (t, J = 5.6 Hz, 1H), 6.37 (d, J = 8.3 Hz, 1H), 6.29 (d, J = 7.2 Hz, 1H), 4.59 (s, 2H), 4.17 (s, 2H ), 3.77 (d, J = 5.6 Hz, 2H), 2.07 (s, 3H).

[Example 17]
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate obtained in Reference Example 11- (b) { 6-[(Thiophen-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} ethyl acetate in a solution of 284 mg (0.800 mmol) in tetrahydrofuran (4.0 mL) was obtained in the same manner as in Reference Example 13 and 3′- 178 mg (0.800 mmol) of (1-propynyl) biphenyl-4-ylmethanol, 395 μL (1.60 mmol) of tri-n-butylphosphine and 276 mg of N, N, N ′, N′-tetramethylazodicarboxamide (1. 60 mmol) was added and stirred at room temperature for 3 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 432 mg of the title compound. Was obtained as colorless candy. (Yield 97%)
Mass spectrum (CI, m / z): 560 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.80 (dd, J = 3.1, 1.3 Hz, 1H), 7.60-7.59 (m, 1H), 7.50-7.45 (m, 3H), 7.36-7.28 (m, 6H), 7.17 (dd, J = 5.1, 1.3 Hz, 1H), 6.52 (d, J = 7.2 Hz, 1H), 6.31 (d, J = 8.0 Hz, 1H), 4.80 (t, J = 5.4 Hz, 1H), 4.61 (s, 2H), 4.32 (s, 2H), 4.21 (q, J = 7.2 Hz, 2H), 3.99 (d, J = 5.4 Hz, 2H), 2.08 (s, 3H), 1.27 ( t, J = 7.2 Hz, 3H).

[Example 18]
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid obtained in Example 17 (6-{[3 '-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate (426 mg, 0.762 mmol) in ethanol (3.5 mL) Sodium hydroxide aqueous solution 3.5mL (3.5mmol) was added, and it stirred at room temperature for 16 hours. After completion of the reaction, water was added to the reaction solution, adjusted to pH 4.4 with 1 mol / L hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the concentrate, 5 mL of ethyl acetate and 5 mL of n-hexane were added and heated to 50 ° C., and then stirred for 2 hours to room temperature. The precipitated solid was collected by filtration and dried under reduced pressure to give 390 mg of the title compound as a white solid. (Yield 96%)
Mass spectrum (CI, m / z): 532 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 12.46 (brs, 0.6H), 8.14 (dd, J = 3.0, 1.4 Hz, 1H), 7.66 (dd, J = 5.1, 3.0 Hz, 1H), 7.64-7.59 (m, 4H), 7.45-7.24 (m, 6H), 6.81 (t, J = 5.5 Hz, 1H), 6.40 (d, J = 8.2 Hz, 1H), 6.33 (d, J = 7.0 Hz , 1H), 4.58 (s, 2H), 4.16 (s, 2H), 3.84 (d, J = 5.5 Hz, 2H), 2.07 (s, 3H).

[Example 19]
(6-{(3-Fluorobenzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-ylamino) acetic acid

19- (a) [tert-butoxycarbonyl (6-{(3-fluorobenzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-yl) amino] acetic acid tert- [Tert-Butoxycarbonyl (6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-yl) amino] acetic acid tert-obtained in butyl reference example 12- (c) To a solution of 542 mg (1.00 mmol) of butyl in 3.5 mL of methylene chloride was added 280 μL (2.01 mmol) of triethylamine and 150 μL (1.13 mmol) of 3-fluorobenzenesulfonyl chloride under ice-cooling, and the mixture was stirred at room temperature for 2 hours. 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. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 9: 1 → 7: 3 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 673 mg of the title compound. Was obtained as a white foam. (Yield 96%)
Mass spectrum (CI, m / z): 700 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.70 (d, J = 8.1 Hz, 1H), 7.59-7.58 (m, 1H), 7.53-7.32 (m, 9H), 7.27-7.19 (m, 3H) , 6.87 (d, J = 7.3 Hz, 1H), 4.57 (s, 2H), 4.39 (s, 2H), 4.37 (s, 2H), 2.08 (s, 3H), 1.52 (s, 9H), 1.42 ( s, 9H).

19- (b) (6-{(3-Fluorobenzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-ylamino) acetic acid obtained in Example 19- (a) [Tert-Butoxycarbonyl (6-{(3-fluorobenzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-yl) amino] acetic acid tert-butyl 595 mg To a 5.0 mL solution of 0.850 mmol) in tetrahydrofuran was added 5.0 mL (20 mmol) of 4 mol / L hydrochloric acid, and the mixture was heated and stirred at 70 ° C. for 5 hours. After completion of the reaction, the pH was adjusted to 4.5 with a 1 mol / L sodium hydroxide aqueous solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the concentrate, 10 mL of ethyl acetate and 5 mL of n-hexane were added and heated to 50 ° C., and then stirred for 2 hours to room temperature. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 429 mg of the title compound as a white solid. (Yield 93%)
Mass spectrum (ESI ⁺ , m / z): 544 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 12.41 (brs, 0.9H), 7.65-7.60 (m, 4H), 7.58-7.50 (m, 2H), 7.46-7.34 (m, 6H), 7.25 (dd, J = 8.3, 7.2 Hz, 1H), 6.79 (t, J = 5.7 Hz, 1H), 6.38 (d, J = 8.3 Hz, 1H), 6.32 (d, J = 7.2 Hz, 1H), 4.67 (s, 2H), 4.19 (s, 2H), 3.74 (d, J = 5.7 Hz, 2H), 2.07 (s, 3H).

[Example 20]
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) isopropyl acetate

To a solution of 1.05-g (2.88 mmol) of {6-[(pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetate obtained in Reference Example 14 in 15.0 mL of tetrahydrofuran, Reference Example 13 and 640 mg (2.88 mmol) of 3 ′-(1-propynyl) biphenyl-4-ylmethanol obtained in the same manner, 1.42 mL (5.76 mmol) of tri-n-butylphosphine and N, N, N ′, N'-tetramethylazodicarboxamide 992 mg (5.76 mmol) was added, and the mixture was stirred at room temperature for 3 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 = 3: 2 → 2: 3 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound 1 .59 g was obtained as colorless candy. (Yield 97%)
Mass spectrum (CI, m / z): 569 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.62 (ddd, J = 4.7, 1.7, 1.0 Hz, 1H), 7.83 (ddd, J = 7.7, 1.0, 1.0 Hz, 1H), 7.76 (ddd, J = 7.7, 7.7, 1.7 Hz, 1H), 7.60-7.58 (m, 1H), 7.47-7.43 (m, 3H), 7.38 (ddd, J = 7.7, 4.7, 1.0 Hz, 1H), 7.36-7.32 (m, 4H), 7.23 (dd, J = 8.2, 7.3 Hz, 1H), 6.50 (d, J = 7.3 Hz, 1H), 6.22 (d, J = 8.2 Hz, 1H), 5.09 (sep, J = 6.3 Hz, 1H), 4.79 (s, 2H), 4.70 (t, J = 5.3 Hz, 1H), 4.42 (s, 2H), 3.92 (d, J = 5.3 Hz, 2H), 2.08 (s, 3H), 1.26 ( d, J = 6.3 Hz, 6H).

  The compounds used in the examples were synthesized as follows.

[Reference Example 1]
{6-[(Pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} ethyl acetate

1- (a): [tert-Butoxycarbonyl (6-ethoxycarbonylpyridin-2-yl) amino] tert-butyl sodium hydride acetate (55 wt% mineral oil dispersion) 15.7 g (0.360 mol) N , N-dimethylformamide in a solution of 362 mL of ethyl 6-tert-butoxycarbonylaminopyridine-2-carboxylate (see WO 2006/074884 pamphlet) 81.2 g (0.305 mol) of N, N-dimethylformamide 300 mL The solution was added dropwise over 20 minutes under ice-cooling in an argon atmosphere and 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, and the mixture was 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 = 9: 1 → 4: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 108 g of the title compound. Was 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, calcium chloride 34.6 g (0.312 mol) in ethanol 195 mL was added dropwise over 20 minutes under ice cooling. did. After completion of the dropwise addition, 105 mL (0.315 mol) of a 3 mol / L 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 a mixed solution of 17.8 mL of acetic acid and 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 saturated aqueous sodium chloride solution, and concentrated under reduced pressure. The 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 to give 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 of Martin reagent 12.9 g (30.4 mmol), Reference Example 1 A solution of [tert-butoxycarbonyl (6-hydroxymethylpyridin-2-yl) amino] tert-butyl acetate 10.0 g (29.6 mmol) obtained in (b) in 50 mL of methylene chloride was cooled with ice 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 wt% aqueous sodium thiosulfate solution was added to the reaction solution, and extracted with methylene chloride. The organic layer was washed successively with 0.5 mol / L aqueous sodium hydroxide solution and 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) 2-yl) amino] To a solution of 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 wt% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and 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 2.76 g of the title compound as colorless. Obtained as an 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-butyl acetate [tert-butoxycarbonyl (6-hydroxyiminomethyl) obtained in Reference Example 1- (d) Pyridin-2-yl) amino] 0.98 g of 10% by weight palladium-activated carbon (containing 50% by weight water) was added to a solution of 2.75 g (7.83 mmol) of tert-butyl acetate in ethanol (49 mL) under a 1 atmosphere hydrogen atmosphere. And stirred at room temperature for 1 hour. After completion of the reaction, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 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-2- ylsulfonyl ) aminomethyl] pyridin-2-yl} amino) tert-butyl 2-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 A solution of 2.24 mL (16.2 mmol) of triethylamine in 12 mL of methylene chloride was added, and the mixture was stirred at room temperature for 0.5 hour. After completion of the reaction, a 5 wt% aqueous potassium hydrogen sulfate solution was added to the reaction solution, and the mixture was extracted with methylene chloride. The organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and 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: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 1.46 g of the title compound in white. Obtained as a 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).

1- (g): {6-[(Pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} ethyl acetate (tert-butoxycarbonyl {) obtained in the same manner as in Reference Example 1- (f) 6-[(Pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate 3.59 g (7.50 mmol) was added to a 2 mol / L hydrogen chloride / ethanol solution 37.5 mL (75 0.0 mmol) was added, and the mixture was stirred for 3 hours under heating to reflux. After completion of the reaction, water was added to the reaction solution, neutralized with a 1 mol / L sodium hydroxide aqueous 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 give 2.17 g of the title compound as a brown oil. (Yield 83%)
Mass spectrum (CI, m / z): 351 (M ⁺ +1).
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 8.71 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 8.18 (brs, 0.1H), 8.05 (ddd, J = 7.8, 7.6, 1.8 Hz) , 1H), 7.91 (ddd, J = 7.8, 1.0, 0.8 Hz, 1H), 7.64 (ddd, J = 7.6, 4.6, 1.0 Hz, 1H), 7.33 (dd, J = 8.1, 7.2 Hz, 1H), 6.86 (t, J = 6.1 Hz, 0.2H), 6.52 (d, J = 7.2 Hz, 1H), 6.39 (d, J = 8.1 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H), 4.01 (s, 2H), 3.95 (s, 2H), 1.16 (t, J = 7.1 Hz, 3H).

[Reference Example 2]
{6-[(Pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} ethyl acetate

2- (a): (tert-Butoxycarbonyl {6-[(pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate In the same manner as in Reference Example 1- (e) The obtained [(6-aminomethylpyridin-2-yl) tert-butoxycarbonylamino] tert-butyl acetate 1.20 g (3.56 mmol) was used, and 3-pyridylsulfonyl chloride was used instead of 2-pyridylsulfonyl chloride. Except for using 640 mg (3.60 mmol), the reaction and post-treatment were performed according to Reference Example 1- (f) to obtain 1.45 g of the title compound 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).

2- (b): {6-[(Pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} ethyl acetate (tert-butoxycarbonyl {6-[(pyridin-2-ylsulfonyl) aminomethyl] pyridine (Tert-Butoxycarbonyl {6-[(pyridin-3-ylsulfonyl) aminomethyl] obtained in the same manner as in Reference Example 2- (a) instead of tert-butyl acetate Reference Example 1 except that 1.00 g (2.09 mmol) of tert-butyl acetate was used and 10.4 mL (20.8 mmol) of a 2 mol / L hydrogen chloride / ethanol solution was used. -Reaction and post-treatment were performed according to (g) to obtain 686 mg of the title compound as a brown oil. (Yield 94%)
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 9.06 (dd, J = 2.3, 0.7 Hz, 1H), 8.71 (dd, J = 4.9, 1.6 Hz, 1H), 8.09 (ddd, J = 8.0, 2.3, 1.6 Hz, 1H), 7.35 (ddd, J = 8.0, 4.9, 0.7 Hz, 1H), 7.28 (dd, J = 8.3, 7.3 Hz, 1H), 6.38 (d, J = 7.3 Hz, 1H), 6.29 ( d, J = 8.3 Hz, 1H), 5.95 (t, J = 5.4 Hz, 1H), 4.96 (t, J = 5.4 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 4.14 (d, J = 5.4 Hz, 2H), 4.03 (d, J = 5.4 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H).

[Reference Example 3]
3 ′-(1-propenyl) biphenyl-4-ylmethanol

3- (a): 3 ′-(1-propenyl) biphenyl-4-ylcarbaldehyde 3′-bromobiphenyl-4-ylcarbaldehyde (see Journal of Organic Chemistry, 68, 247 (2003)) 500 mg (1. 91 mmol), 27.5 mL of toluene and 1.65 mL of water were added, followed by the addition of 1.63 g (7.68 mmol) of tripotassium phosphate and 656 mg (7.64 mmol) of 1-propenylboric acid, and then under a nitrogen gas atmosphere. did. Further, 6.2 mg (0.028 mmol) of palladium acetate and 20.2 mg (0.0563 mmol) of butyldi-1-adamantylphosphine were added, and the mixture was stirred at 100 ° C. for 4.5 hours in a nitrogen gas atmosphere. 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 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 420 mg of the title compound as a pale yellow oil. Obtained as a thing. (Yield 99%)
Mass spectrum (CI, m / z): 223 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 10.06 (s, 1H), 7.98-7.92 (m, 2H), 7.79-7.72 (m, 2H), 7.59-7.55 (m, 1H), 7.49-7.42 ( m, 1H), 7.41-7.37 (m, 2H), 6.48 (dd, J = 15.9, 1.5 Hz, 1H), 6.33 (dq, J = 15.9, 6.3 Hz, 1H), 1.92 (dd, J = 6.3, 1.5 Hz, 3H).

3- (b): 3 ′-(1-propenyl) biphenyl-4-ylmethanol Reference Example 3- (a) 3 ′-(1-propenyl) biphenyl-4-ylcarbaldehyde 417 mg (1. 88 mmol) in 4.6 mL of ethanol was added 35.6 mg (0.941 mmol) of sodium borohydride at room temperature, and the mixture was stirred at the same temperature for 45 minutes. After completion of the reaction, 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 401 mg of the title compound as a white solid. Obtained. (Yield 95%)
Mass spectrum (EI, m / z): 224 (M ⁺ ).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.63-7.56 (m, 2H), 7.55-7.52 (m, 1H), 7.47-7.29 (m, 5H), 6.47 (dd, J = 15.9, 1.5 Hz, 1H), 6.31 (dq, J = 15.9, 6.6 Hz, 1H), 4.74 (d, J = 5.7 Hz, 2H), 1.91 (dd, J = 6.6, 1.5 Hz, 3H), 1.70 (t, J = 5.7 Hz, 1H).

[Reference Example 4]
3 ′-(1-propynyl) biphenyl-4-ylmethanol

4- (a): 3 ′-(1-propynyl) biphenyl-4- ylcarbaldehyde 3′-bromobiphenyl-4-ylcarbaldehyde 1.04 g (3.98 mmol) in 10 mL of toluene was degassed under reduced pressure. The gas was replaced with argon gas. Subsequently, 231 mg (0.200 mmol) of tetrakistriphenylphosphine palladium and 1.46 mL (4.80 mmol) of tributyl (1-propynyl) tin were added, and the mixture was stirred at 110 ° C. for 7 hours in an argon gas atmosphere. After completion of the reaction, 60 mL of 0.8 mol / L potassium fluoride aqueous solution was added to the reaction 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 = 1: 0 → 4: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 660 mg of the title compound. Was obtained as a pale yellow solid. (Yield 75%)
Mass spectrum (CI, m / z): 221 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 10.06 (s, 1H), 7.97-7.93 (m, 2H), 7.76-7.72 (m, 2H), 7.68-7.67 (m, 1H), 7.55-7.52 ( m, 1H), 7.45-7.37 (m, 2H), 2.08 (s, 3H).

4- (b): 3 ′-(1-propynyl) biphenyl-4-ylmethanol 3 ′-(1-propenyl) biphenyl-4-ylcarbaldehyde instead of Reference Example 4- (a) Reference Example 3 except that 723 mg (3.28 mmol) of 3 ′-(1-propynyl) biphenyl-4-ylcarbaldehyde obtained in 1 was used and 62.2 mg (1.64 mmol) of sodium borohydride was used. -Reaction and post-treatment were performed according to (b) to obtain 588 mg of the title compound as a pale yellowish white solid. (Yield 81%)
Mass spectrum (EI, m / z): 222 (M ⁺ ).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.63-7.62 (m, 1H), 7.60-7.56 (m, 2H), 7.51-7.47 (m, 1H), 7.46-7.42 (m, 2H), 7.38- 7.32 (m, 2H), 4.75 (d, J = 6.0 Hz, 2H), 2.07 (s, 3H), 1.68 (t, J = 6.0 Hz, 1H).

[Reference Example 5]
To 1.21 g (6.02 mmol) of 3′- ethoxybiphenyl- 4-ylmethanol 3-bromophenetole, 15 mL of toluene, 15 mL of ethanol, and 4.5 mL (9.0 mmol) of a 2 mol / L aqueous sodium carbonate solution were added, followed by depressurization. After the gas was replaced with argon gas. Subsequently, 1.37 g (9.02 mmol) of 4- (hydroxymethyl) phenylboric acid and 347 mg (0.300 mmol) of tetrakistriphenylphosphine palladium were added, and the mixture was stirred at 100 ° C. for 4 hours in an argon gas atmosphere. 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 → 7: 3 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound 1 .23 g was obtained as a pale yellow oil. (Yield 90%)
Mass spectrum (CI, m / z): 229 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.61-7.56 (m, 2H), 7.46-7.41 (m, 2H), 7.34 (dd, J = 8.0, 8.0 Hz, 1H,), 7.18-7.11 (m , 2H), 6.91-6.87 (m, 1H), 4.74 (d, J = 5.9 Hz, 2H), 4.10 (q, J = 7.0 Hz, 2H), 1.67 (t, J = 5.9 Hz, 1H), 1.45 (t, J = 7.0 Hz, 3H).

[Reference Example 6]
{6-[(Pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} hexyl acetate Reference Example 1- (f) (tert-butoxycarbonyl {6-[(pyridine- To a 6.0 mL n-hexanol solution of 957 mg (2.00 mmol) tert-butyl acetate of 2-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) acetate, 0.56 mL (10 mmol) of concentrated sulfuric acid was added at 100 ° C. Stir for 8 hours. After completion of the reaction, the reaction solution was poured into 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 = 1: 1 → 3: 7 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give 658 mg of the title compound. Was obtained as a slightly yellow oil. (Yield 81%)
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.62 (ddd, J = 4.6, 1.8, 1.0 Hz, 1H), 7.97 (ddd, J = 7.7, 1.2, 1.0 Hz, 1H), 7.84 (ddd, J = 7.7, 7.7, 1.8 Hz, 1H), 7.41 (ddd, J = 7.7, 4.6, 1.2 Hz, 1H), 7.29 (dd, J = 8.4, 7.4 Hz, 1H), 6.44 (d, J = 7.4 Hz, 1H ), 6.28 (d, J = 8.4 Hz, 1H), 6.02 (t, J = 5.3 Hz, 1H), 4.92 (t, J = 5.3 Hz, 1H), 4.25 (d, J = 5.3 Hz, 2H), 4.18 (t, J = 6.7 Hz, 2H), 4.08 (d, J = 5.3 Hz, 2H), 1.71-1.61 (m, 2H), 1.39-1.26 (m, 6H), 0.91-0.87 (m, 3H) .

[Reference Example 7]
(Tert-Butoxycarbonyl {6-[(3′-ethoxybiphenyl-4-ylmethyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate

7- (a): 3' -ethoxybiphenyl-4-ylcarbaldehyde 4.20 g (22.7 mmol) of 4-bromobenzaldehyde instead of 3-bromophenetole, 3 instead of 4- (hydroxymethyl) phenylboric acid -3.13 g (18.9 mmol) of ethoxyphenylboric acid was used, respectively, 28.4 ml (56.8 mmol) of 2 mol / L aqueous sodium carbonate solution and 2.18 g (1.89 mmol) of tetrakistriphenylphosphine palladium were used. Except for the above, the reaction and post-treatment were carried out according to Reference Example 5 to obtain 4.08 g of the title compound as a colorless oil. (Yield 95%)
Mass spectrum (CI, m / z): 227 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 10.06 (s, 1H), 7.97-7.93 (m, 2H), 7.76-7.73 (m, 2H), 7.38 (dd, J = 8.1, 7.9 Hz, 1H) , 7.21 (ddd, J = 7.9, 2.0, 0.9 Hz, 1H), 7.16 (dd, J = 2.3, 2.0 Hz, 1H), 6.95 (ddd, J = 8.1, 2.3, 0.9 Hz, 1H), 4.11 (q , J = 6.9 Hz, 2H), 1.46 (t, J = 6.9 Hz, 3H).

7- (b): (tert-Butoxycarbonyl {6-[(3′-ethoxybiphenyl-4-ylmethyl) aminomethyl] pyridin-2-yl} amino) similar to tert-butyl acetate reference example 1- (e) Reference Example 7- (a) was added to a solution of [(6-aminomethylpyridin-2-yl) tert-butoxycarbonylamino] tert-butyl acetate 4.02 g (11.9 mmol) obtained in the above method in 12 mL of methylene chloride. 2.46 g (10.9 mmol) of 3′-ethoxybiphenyl-4-ylcarbaldehyde obtained in 1 above was added and stirred at room temperature for 30 minutes. Next, 3.25 g (15.3 mmol) of sodium triacetoxyborohydride was added under ice cooling, and the mixture was stirred at the same temperature for 3.5 hours. After completion of the reaction, an aqueous sodium hydrogen carbonate 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 potassium carbonate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 3: 2 → 0: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound 3 Obtained .68 g as a pale yellow oil. (Yield 62%)
Mass spectrum (CI, m / z): 548 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.69 (d, J = 8.2 Hz, 1H), 7.59 (dd, J = 8.2, 7.3 Hz, 1H), 7.57-7.53 (m, 2H), 7.43-7.39 (m, 2H), 7.33 (dd, J = 7.9, 7.7 Hz, 1H), 7.16 (ddd, J = 7.7, 1.7, 0.9 Hz, 1H), 7.12 (dd, J = 2.3, 1.7 Hz, 1H), 6.97 (d, J = 7.3 Hz, 1H), 6.87 (ddd, J = 7.9, 2.3, 1.0 Hz, 1H), 4.57 (s, 2H), 4.10 (q, J = 7.1 Hz, 2H), 3.84 (s , 2H), 3.83 (s, 2H), 1.53 (s, 9H), 1.44 (t, J = 7.1 Hz, 3H), 1.42 (s, 9H).

[Reference Example 8]
Instead of 4- (6 -ethoxypyridin-2- yl) phenylmethanol 3-bromophenetole, 0.49 g (2.4 mmol) of 2-bromo-6-ethoxypyridine (see US 2003/199440) was used, Except for using 0.59 g (3.9 mmol) of 4- (hydroxymethyl) phenylboric acid, 1.7 ml (3.4 mmol) of 2 mol / L sodium carbonate aqueous solution and 138 mg (0.119 mmol) of tetrakistriphenylphosphine palladium, The reaction and post-treatment were performed according to Reference Example 5 to obtain 284 mg of the title compound as a white solid. (Yield 51%)
Mass spectrum (CI, m / z): 230 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.05-8.01 (m, 2H), 7.62 (dd, J = 8.2, 7.4 Hz, 1H), 7.47-7.43 (m, 2H), 7.32 (dd, J = 7.4, 0.6 Hz, 1H), 6.67 (dd, J = 8.2, 0.6 Hz, 1H), 4.75 (d, J = 6.0 Hz, 2H), 4.49 (q, J = 7.1 Hz, 2H), 1.67 (t, J = 6.0 Hz, 1H), 1.44 (t, J = 7.1 Hz, 3H).

[Reference Example 9]
{6-[(thiophen-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} ethyl acetate

9- (a): (tert-Butoxycarbonyl {6-[(thiophen-2-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate In the same manner as in Reference Example 1- (e) Using 1.35 g (4.00 mmol) of tert-butyl acetate obtained ([6-aminomethylpyridin-2-yl) tert-butoxycarbonylamino] acetate, 2-thiophenesulfonyl chloride instead of 2-pyridylsulfonyl chloride Except for using 731 mg (4.00 mmol), the reaction and post-treatment were performed according to Reference Example 1- (f), to give 1.61 g of the title compound as a white solid. (Yield 84%)
Mass spectrum (CI, m / z): 484 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.71 (d, J = 8.4 Hz, 1H), 7.57 (dd, J = 3.8, 1.3 Hz, 1H), 7.56 (dd, J = 8.4, 7.4 Hz, 1H) ), 7.50 (dd, J = 5.0, 1.3 Hz, 1H), 7.01 (dd, J = 5.0, 3.8 Hz, 1H), 6.83 (d, J = 7.4 Hz, 1H), 5.67 (t, J = 5.3 Hz , 1H), 4.45 (s, 2H), 4.27 (d, J = 5.3 Hz, 2H), 1.53 (s, 9H), 1.47 (s, 9H).

9- (b): { tert-Butoxycarbonyl {6-[() obtained in {6-[(thiophen-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} ethyl acetate Reference Example 9- (a) To 1.60 g (3.31 mmol) of thiophen-2-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate, 20 mL (40 mmol) of a 2 mol / L hydrogen chloride / ethanol solution was added and heated to reflux. Stir for 3 hours under. After completion of the reaction, the reaction solution was concentrated under reduced pressure, neutralized with 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 = 7: 3 → 1: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound 1 .10 g was obtained as a colorless oil. (Yield 93%)
Mass spectrum (CI, m / z): 356 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.57 (dd, J = 3.8, 1.3 Hz, 1H), 7.51 (dd, J = 5.0, 1.3 Hz, 1H), 7.32 (dd, J = 8.3, 7.3 Hz) , 1H), 7.01 (dd, J = 5.0, 3.8 Hz, 1H), 6.44 (dd, J = 7.3, 0.6 Hz, 1H), 6.32 (dd, J = 8.3, 0.6 Hz, 1H), 5.86 (t, J = 4.9 Hz, 1H), 4.96 (t, J = 5.3 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 4.18 (d, J = 4.9 Hz, 2H), 4.06 (d, J = 5.3 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H).

[Reference Example 10]
{6-[(Benzenesulfonyl) aminomethyl] pyridin-2-ylamino} ethyl acetate

10- (a): ({6-[(Benzenesulfonyl) aminomethyl] pyridin-2-yl} tert-butoxycarbonylamino) tert-butyl acetate Obtained in the same manner as in Reference Example 1- (e) [ (6-Aminomethylpyridin-2-yl) tert-butoxycarbonylamino] tert-butyl acetate 1.35 g (4.00 mmol) was used, and benzenesulfonyl chloride 707 mg (4.00 mmol) instead of 2-pyridylsulfonyl chloride The reaction and post-treatment were performed according to Reference Example 1- (f) except that was used to obtain 1.71 g of the title compound as a slightly beige solid. (Yield 89%)
Mass spectrum (CI, m / z): 478 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.86-7.83 (m, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.53-7.48 (m, 2H), 7.45-7.41 (m, 2H) , 6.78 (dd, J = 7.4, 0.6 Hz, 1H), 5.56 (t, J = 5.4 Hz, 1H), 4.41 (s, 2H), 4.19 (d, J = 5.4 Hz, 2H), 1.53 (s, 9H), 1.46 (s, 9H).

10- (b): {6-[(Benzenesulfonyl) aminomethyl] pyridin-2-ylamino} ethyl acetate (tert-butoxycarbonyl {6-[(thiophen-2-ylsulfonyl) aminomethyl] pyridin-2-yl } Amino) tert-butyl acetate ({6-[(benzenesulfonyl) aminomethyl] pyridin-2-yl} tert-butoxycarbonylamino) obtained in Reference Example 10- (a) instead of tert-butyl acetate The title compound was subjected to reaction and post-treatment according to Reference Example 9- (b) except that 1.70 g (3.56 mmol) was used and 20 mL (40 mmol) of 2 mol / L hydrogen chloride / ethanol solution was used. 1.13 g was obtained as a white solid. (Yield 91%)
Mass spectrum (CI, m / z): 350 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.87-7.84 (m, 2H), 7.53-7.42 (m, 3H), 7.28 (dd, J = 8.3, 7.3 Hz, 1H), 6.39 (dd, J = 7.3, 0.6 Hz, 1H), 6.30 (dd, J = 8.3, 0.6 Hz, 1H), 5.73 (t, J = 4.9 Hz, 1H), 4.92 (t, J = 5.2 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 4.09 (d, J = 4.9 Hz, 2H), 4.04 (d, J = 5.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H).

[Reference Example 11]
{6-[(thiophen-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} ethyl acetate

11- (a): (tert-Butoxycarbonyl {6-[(thiophen-3-ylsulfonyl) aminomethyl] pyridin-2-yl} amino) tert-butyl acetate In the same manner as in Reference Example 1- (e) Using 1.35 g (4.00 mmol) of tert-butyl acetate obtained ([6-aminomethylpyridin-2-yl) tert-butoxycarbonylamino] acetate, 3-thiophenesulfonyl chloride instead of 2-pyridylsulfonyl chloride Except for using 731 mg (4.00 mmol), the reaction and post-treatment were performed in accordance with Reference Example 1- (f) to obtain 1.64 g of the title compound as a slightly yellowish white solid. (Yield 85%)
Mass spectrum (CI, m / z): 484 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.93 (dd, J = 2.9, 1.4 Hz, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.54 (dd, J = 8.3, 7.4 Hz, 1H) ), 7.30 (dd, J = 5.1, 2.9 Hz, 1H), 7.28 (dd, J = 5.1, 1.4 Hz, 1H), 6.80 (dd, J = 7.4, 0.6 Hz, 1H), 5.59 (t, J = 5.4 Hz, 1H), 4.43 (s, 2H), 4.23 (d, J = 5.4 Hz, 2H), 1.53 (s, 9H), 1.47 (s, 9H).

11- (b): {6-[(thiophen-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} ethyl acetate (tert-butoxycarbonyl {6-[(thiophen-2-ylsulfonyl) aminomethyl] pyridine (2-yl} amino) (tert-butoxycarbonyl {6-[(thiophen-3-ylsulfonyl) aminomethyl] pyridine-2-yl) obtained in Reference Example 11- (a) instead of tert-butyl acetate Il} amino) Reference Example 9- (b) except that 1.63 g (3.37 mmol) of tert-butyl acetate was used and 17.5 mL (35.0 mmol) of a 2 mol / L hydrogen chloride / ethanol solution was used. The reaction and post-treatment were performed according to the above. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 7: 3 → 1: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The obtained crude product was recrystallized from 5 mL of ethyl acetate to obtain 731 mg of the title compound as a white solid. (Yield 61%)
Mass spectrum (CI, m / z): 356 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.93 (dd, J = 3.0, 1.4 Hz, 1H), 7.33-7.28 (m, 3H), 6.40 (dd, J = 7.3, 0.6 Hz, 1H), 6.32 (dd, J = 8.3, 0.6 Hz, 1H), 5.76 (t, J = 5.1 Hz, 1H), 4.95 (t, J = 5.4 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 4.13 (d, J = 5.1 Hz, 2H), 4.06 (d, J = 5.4 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H).

[Reference Example 12]
[Tert-Butoxycarbonyl (6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-yl) amino] tert-butyl acetate

12- (a): 1-Bromo-3- (1-propynyl) benzene 1-Bromo-3-iodobenzene 7.07 g (25.0 mmol) in 50 mL of toluene was added 1.43 g of copper (I) iodide ( 7.51 mmol) and 1.45 g (1.25 mmol) of tetrakistriphenylphosphine palladium were added, degassed under reduced pressure, and then purged with argon gas. Next, 2.81 g (25.0 mmol) of 1-trimethylsilyl-1-propyne, 11.5 ml (82.5 mmol) of triethylamine and 25.0 mL (25.0 mmol) of a 1 mol / L tetrafluoroammonium fluoride / tetrahydrofuran solution were added. The mixture was stirred at room temperature for 17 hours under an argon gas atmosphere. After completion of the reaction, water and t-butyl methyl ether were added to the reaction solution, and insolubles were separated by filtration through Celite (trade name). The separated 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), and the fraction containing the desired product was concentrated under reduced pressure to give 4.22 g of the title compound as a colorless oil. (Yield 86%)
Mass spectrum (CI, m / z): 195, 197 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.53 (dd, J = 1.7, 1.7 Hz, 1H), 7.39 (ddd, J = 8.0, 1.7, 1.0 Hz, 1H), 7.31-7.29 (m, 1H) , 7.14 (dd, J = 8.0, 8.0 Hz, 1H), 2.04 (s, 3H).

12- (b): 3 ′-(1-propynyl) biphenyl-4 -ylcarbaldehyde 1-bromo-3-obtained in the same manner as in Reference Example 12- (a) instead of 3-bromophenetole Using 2.93 g (15.0 mmol) of (1-propynyl) benzene and 3.37 g (37.5 mmol) of 4-formylphenylboric acid instead of 4- (hydroxymethyl) phenylboric acid, 2 mol / L of carbonic acid was used. Except for using 11.3 ml (22.6 mmol) of an aqueous sodium solution and 867 mg (0.750 mmol) of tetrakistriphenylphosphine palladium, the reaction and post-treatment were carried out according to Reference Example 5, and 3.31 g of the title compound was pale yellowish white Obtained as a solid. (quantitative)
The NMR spectrum of the compound obtained in Reference Example 12- (b) was the same as the NMR spectrum of the compound obtained in Reference Example 4- (a).

12- (c): [tert-Butoxycarbonyl (6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-yl) amino] acetic acid tert-butyl Reference Example 1- ( 5.57 g (16.5 mmol) of tert-butyl [(6-aminomethylpyridin-2-yl) tert-butoxycarbonylamino] acetate obtained in the same manner as in e), and 3′-ethoxybiphenyl-4- Instead of ylcarbaldehyde, 3.30 g (15.0 mmol) of 3 ′-(1-propynyl) biphenyl-4-ylcarbaldehyde obtained in Reference Example 12- (b) was used, and triacetoxyborohydride The reaction was conducted according to Reference Example 7- (b) except that 4.45 g (21.0 mmol) of sodium was used, and the title compound 6 .48 g was obtained as a pale yellow oil. (Yield 80%)
Mass spectrum (CI, m / z): 542 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 7.70 (d, J = 8.2 Hz, 1H), 7.63-7.62 (m, 1H), 7.59 (dd, J = 8.2, 7.4 Hz, 1H), 7.55-7.52 (m, 2H), 7.50-7.47 (m, 1H), 7.43-7.40 (m, 2H), 7.37-7.32 (m, 2H), 6.97 (d, J = 7.4 Hz, 1H), 4.57 (s, 2H ), 3.85 (s, 2H), 3.83 (s, 2H), 2.07 (s, 3H), 1.53 (s, 9H), 1.41 (s, 9H).

[Reference Example 13]
1-bromo-3- (1-propynyl) benzene 3 obtained in the same manner as in Reference Example 12- (a) instead of 3 ′-(1-propynyl) biphenyl-4-ylmethanol 3-bromophenetole .90 g (20.0 mmol) was used, 4.56 g (30.0 mmol) of 4- (hydroxymethyl) phenylboric acid, 15 ml (30 mmol) of 2 mol / L sodium carbonate aqueous solution and 1.16 g of tetrakistriphenylphosphine palladium (1 (.00 mmol) was used, and the reaction was carried out according to Reference Example 5. 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. The obtained crude product was stirred in 45 mL of a mixed solvent (ethyl acetate: n-hexane = 1: 10 (V / V)) for 1 hour, and the precipitated solid was collected by filtration and dried under reduced pressure to give the title compound 3 Obtained .85 g as a white solid. (Yield 87%)
The NMR spectrum of the compound obtained in Reference Example 13 was the same as the NMR spectrum of the compound obtained in Reference Example 4- (b).

[Reference Example 14]
{6-[(Pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} isopropyl acetate (tert-butoxycarbonyl {6-[(thiophen-2-ylsulfonyl) aminomethyl] pyridin-2-yl} amino ) (Tert-Butoxycarbonyl {6-[(pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-yl} obtained in the same manner as in Reference Example 1- (f) instead of tert-butyl acetate Amino) 1.44 g (3.01 mmol) of tert-butyl acetate was used, and 16.0 mL (32.0 mmol) of 2 mol / L hydrogen chloride / isopropanol solution was used instead of 2 mol / L hydrogen chloride / ethanol solution. The reaction and post-treatment were performed according to Reference Example 9- (b), except that 1.05 g of the title compound was white. It was obtained as a body. (Yield 96%)
Mass spectrum (CI, m / z): 365 (M ⁺ +1).
¹ H-NMR spectrum (CDCl ₃ , δ ppm): 8.63 (ddd, J = 4.7, 1.7, 1.0 Hz, 1H), 7.97 (ddd, J = 7.7, 1.0, 1.0 Hz, 1H), 7.84 (ddd, J = 7.7, 7.7, 1.7 Hz, 1H), 7.41 (ddd, J = 7.7, 4.7, 1.0 Hz, 1H), 7.29 (dd, J = 8.2, 7.3 Hz, 1H), 6.44 (d, J = 7.3 Hz, 1H ), 6.28 (d, J = 8.2 Hz, 1H), 6.04 (t, J = 5.4 Hz, 1H), 5.10 (sep, J = 6.3 Hz, 1H), 4.93 (t, J = 5.4 Hz, 1H), 4.25 (d, J = 5.4 Hz, 2H), 4.04 (d, J = 5.4 Hz, 2H), 1.28 (d, J = 6.3 Hz, 6H).

[Test Example 1]
Measurement of EP2 receptor binding action The EP2 receptor binding action was measured according to the method of Abramovitz et al. (Biochimica et Biophysica Acta, 1483, 285 (2000)). Buffer solution (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 ), A test compound dissolved in dimethyl sulfoxide (final concentration 1.0 (V / V)%) and [ ³ H] prostaglandin E ₂ (NET-428, manufactured by PerkinElmer) (final concentration 10 nM) are added, Incubated for 60 minutes at 30 ° C. Using a cell harvester (M30R, manufactured by Brandel), the membrane fraction was collected on a glass fiber filter paper (GF / B, manufactured by 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 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 formula.
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 represented by the general formula (I) showed an excellent EP2 receptor binding action.

[Test Example 2]
LPS-induced TNFα production inhibition test using human peripheral blood mononuclear cells Peripheral blood collected from healthy individuals in the presence of heparin was diluted 2-fold with PBS containing 2 (V / V)% FBS. A blood cell separation solution (Ficoll Paque ^™ PLUS, manufactured by GE Healthcare Bioscience) was added to SepMate ^™ -50 (manufactured by STEMCELL), and then the diluted blood was overlaid. A peripheral blood mononuclear cell (hereinafter abbreviated as PBMC) layer was recovered by centrifugation at 20 ° C. and 1200 × g for 10 minutes. The obtained PBMC were further centrifuged and washed twice, suspended in RPMI 1640 medium containing 1 (V / V)% FBS, and used for the following tests.

The LPS-induced TNFα production inhibition test was performed by partially modifying the method of Mary et al. (Journal of Pharmacology and Experimental Therapeutics, 284, 420 (1998)). 185 μL of PBMC suspension prepared to a final concentration of 5 × 10 ⁵ cells / mL was added to a 96-well plate, and then RPMI1640 medium containing 1 (V / V)% DMSO containing the test compound was added to each well. 10 μL each was added (DMSO final concentration was 0.05 (V / V)%). RPMI1640 medium containing 1 (V / V)% DMSO was similarly added to wells to which no test compound was added. After incubating in a carbon dioxide incubator for 1 hour, 5 μL of LPS (L2880-500MG, manufactured by SIGMA) prepared in RPMI 1640 medium was added to each well (the final concentration of LPS was 100 ng / mL). To wells not stimulated with LPS, 5 μL of RPMI1640 medium was added. After culturing for about 18 hours in a carbon dioxide incubator, the culture supernatant was recovered. The collected culture supernatant was stored at −20 ° C. until TNFα content measurement.

A sandwich ELISA kit (Quantikine DTA00c, manufactured by R & D Systems) was used for measuring the TNFα content. The TNFα content of each sample was calculated from a standard curve of E. coli-derived human recombinant TNFα included in the kit. The amount of TNFα produced by LPS when only DMSO was added was taken as 100%, and the TNFα production inhibition rate at each concentration of the test compound was calculated. From the relationship between the concentration of the added test compound and the inhibition rate of TNFα production of the test compound, the concentration of the test compound that inhibits TNFα production by 50% was calculated as an IC ₅₀ value (nM).
The test results are shown in Table 2.

  In this test, the compound represented by the general formula (I) showed an excellent TNFα production inhibitory action.

[Test Example 3]
LPS-induced TNFα production suppression test using human peripheral blood mononuclear cells for confirmation of combined effect This test was performed according to [Test Example 2].
In order to evaluate the single action of each of the test compound and roflumilast and the combined action of the test compound and roflumilast, 175 μL of PBMC suspension prepared to a final concentration of 5 × 10 5 cells / mL was added to a 96-well plate, and then 10 μL of 1 (V / V)% DMSO-containing RPMI1640 medium in which roflumilast was dissolved was added to each well. To wells to which roflumilast was not added, RPMI1640 medium containing 1 (V / V)% DMSO was similarly added. After incubation for 30 minutes in a carbon dioxide incubator, 10 μL of 1 (V / V)% DMSO-containing RPMI1640 medium in which the test compound was dissolved was added to each well (the final DMSO concentration per well was 0.1 (V / V). V)%). RPMI1640 medium containing 1 (V / V)% DMSO was similarly added to wells to which no test compound was added. After incubating for 30 minutes in a carbon dioxide incubator, 5 μL of LPS (L2880-500MG, manufactured by SIGMA) prepared in RPMI 1640 medium was added to each well (the final concentration of LPS was 100 ng / mL). To wells not stimulated with LPS, 5 μL of RPMI1640 medium was added. After culturing for about 16 to 18 hours in a carbon dioxide incubator, the culture supernatant was recovered. The collected culture supernatant was stored at −20 ° C. until TNFα content measurement.

A sandwich ELISA kit (Quantikine DTA00c, manufactured by R & D Systems) was used for measuring the TNFα content. The TNFα content of each sample was calculated from a standard curve of E. coli-derived human recombinant TNFα included in the kit. The amount of TNFα produced by LPS when only DMSO was added was taken as 100%, and the inhibition rate of TNFα production at each concentration of the test compound and roflumilast was calculated. At the same time, the TNFα production inhibition rate at each concentration of the combination of the test compound and roflumilast was calculated, and the effect of the test compound alone and the effect of the combined use with roflumilast were compared.
The test results are shown in Tables 3 and 4.

  In this test, when the compound represented by the general formula (I) is used in combination with roflumilast, the pharmacological effect of the compound represented by the general formula (I) is added to the pharmacological effect of roflumilast, and the TNFα production inhibitory action is more excellent. showed that.

[Test Example 4]
Inhibition of rat lung neutrophil infiltration About 16 hours SD rats (male, 7-8 weeks old, body weight 240g-270g (average about 250g), supplied by Charles River Japan, Inc.) under isoflurane inhalation anesthesia, LPS A physiological saline solution (concentration 0.04 mg / mL) of L2880-500MG (manufactured by SIGMA) was administered into the trachea 25 μL (about 4 μg / Kg). For intratracheal administration, MicroSprayer ^™ (IA-1C-M, manufactured by PennCentury) was used.

  The administration solution of roflumilast was prepared by pulverizing roflumilast with agate for 2-3 minutes, and then suspending roflumilast in 0.5% methylcellulose solution (final concentration of roflumilast 0.01 mg / mL). The roflumilast solution prepared in this manner was orally administered at 10 mL / kg (0.1 mg / Kg) 1 hour before LPS administration. A 0.5% methylcellulose solution was administered to the control group. The test compound administration solution was prepared by dissolving the test compound in a 0.1 mol / L or 1 mol / L sodium hydroxide aqueous solution and neutralizing it by adding a medium (the final concentration of the test compound was 0.1 mg / L). mL). PBS or phosphate buffer (20 mM, pH = 7.4) was used as the medium. The test compound solution thus prepared was intratracheally administered 25 μL (about 0.01 mg / Kg) in the same manner as LPS administration 10 minutes after administration of roflumilast. The control group received vehicle. In addition, 5 rats were used for the test compound administration group and the control group, respectively.

  Four hours after LPS administration, bronchoalveolar lavage was performed as described below, and leukocytes in the lung were collected. SD rats were anesthetized by intraperitoneal administration of somnopentyl (1 mL / kg) and then exsanguinated by inferior vena cava incision. After exposing the trachea and inserting an oral sonde for mice (Fujigami Instrument Co., Ltd.) connected to a disposable syringe (5 mL, manufactured by Terumo Corporation), the trachea was ligated and fixed. A physiological saline solution (4 mL) containing BSA (final concentration 1%) and heparin (final concentration 1 U / mL) was injected, and immediately recovered to obtain a bronchoalveolar lavage fluid (hereinafter abbreviated as BALF). The BALF obtained by repeating this operation two more times was centrifuged (420 × g, 10 minutes, 4 ° C.), then the supernatant was removed until the liquid volume reached 1.5 ml, the precipitated cells were suspended, and the BALF cell suspension was suspended. A turbid liquid was obtained. The white blood cell count and neutrophil count of the BALF cell suspension were measured by either of the following (Method 1) or (Method 2).

(Method 1)
The white blood cell count of the BALF cell suspension was measured using a multi-item automatic blood cell counter (KX-21, manufactured by Sysmex Corporation). Next, the white blood cell count was diluted to 10 ⁶ cells / mL, and 100 μL of this cell suspension was applied to a slide glass to prepare a single-layer smear. Next, after cell staining using a Diff-Quik staining kit (catalog number 16920, manufactured by Sysmex), the number of neutrophils in 300 leukocytes was measured under an optical microscope (BH-2, manufactured by Olympus) to obtain leukocytes. The ratio of neutrophils in the middle (NR = number of neutrophils in 300 leukocytes / 300) was calculated. The inhibition rate of neutrophil infiltration in test compound administration was calculated from the following formula.
Inhibition rate (%) = 100 − [(WBCc × NRc) / (WBCv × NRv)] × 100
WBCv: White blood cell count in BALF cell suspension of control group WBCc: White blood cell count in BALF cell suspension of test compound administration group NRv: Proportion of neutrophils in leukocytes of control group NRc: Test compound administration group Proportion of neutrophils in white blood cells

(Method 2)
The neutrophil count of the BALF cell suspension was measured using a multi-item automatic blood cell counter (XT-2000iV, manufactured by Sysmex Corporation). The inhibition rate of neutrophil infiltration in test compound administration was calculated from the following formula.
Inhibition rate (%) = 100 − [(NEUTc) / (NEUTv)] × 100
NEUTv: number of neutrophils in BALF cell suspension of control group NEUTc: number of neutrophils in suspension of BALF cell of test compound administration group

  In this test, the compound represented by the general formula (I) is used in combination with roflumilast, so that the pharmacological effect of the compound represented by the general formula (I) is added to the pharmacological effect of roflumilast. Infiltration suppression effect was shown. For example, the inhibition rate of lung neutrophil infiltration with the compound of Example 4 and roflumilast alone was 51% and 10%, respectively, but when the compound of Example 4 and roflumilast were used in combination, 64% The inhibition rate of neutrophil infiltration was shown.

  In the pharmaceutical composition of the present invention, the pharmacological effect of the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof is added to the pharmacological effect of another pharmaceutical, and the dosage of the other pharmaceutical is reduced. This is useful in that the side effects of other drugs can be reduced. The pharmaceutical composition is a respiratory disease, preferably asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis or pulmonary hypertension, more preferably asthma , A pharmaceutical composition for the treatment and / or prevention of chronic obstructive pulmonary disease or pulmonary fibrosis, and is useful as a pharmaceutical for warm-blooded animals (particularly for humans).

Claims (12)

Formula (I):

(Where
R ¹ represents an optionally protected carboxy group,
W represents a nitrogen atom or a group —CH═;
R ² represents an ethoxy group, a 1-propenyl group or a 1-propynyl group,
Z represents a phenyl group, a 3-fluorophenyl group, a pyridin-2-yl group, a pyridin-3-yl group, a thiophen-2-yl group, or a thiophen-3-yl group)
A pharmaceutical composition comprising a compound represented by: or a pharmacologically acceptable salt thereof,
Other drugs (the other drugs are PDE4 inhibitor, PDE5 inhibitor, corticosteroid, anticholinergic agent, β2-receptor agonist, H1-histamine receptor antagonist, leukotriene receptor antagonist, endothelin receptor It is one or more medicines selected from the group consisting of antagonists, PGI2 receptor agonists, theophylline and pirfenidone)
A pharmaceutical composition, wherein the pharmaceutical composition is administered in combination.   The pharmaceutical composition comprising the compound represented by the general formula (I) or a salt thereof and the other medicament are administered as different preparations at the same time or at different times, respectively. The pharmaceutical composition as described.   The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprising the compound represented by the general formula (I) or a salt thereof and the other pharmaceutical agent are administered as a single preparation. The pharmaceutical composition according to any one of claims 1 to 3, wherein R ¹ represents a carboxy group or a C ₁ -C ₆ alkoxycarbonyl group. The pharmaceutical composition according to any one of claims 1 to 3, wherein R ¹ represents a carboxy group, an ethoxycarbonyl group, an isopropoxycarbonyl group or a hexyloxycarbonyl group. R ¹ represents a carboxy group, an ethoxycarbonyl group, an isopropoxycarbonyl group or a hexyloxycarbonyl group,
W represents a nitrogen atom or a group —CH═;
R ² represents a 1-propenyl group or a 1-propynyl group,
Any one of claims 1 to 3, wherein Z represents a phenyl group, a 3-fluorophenyl group, a pyridin-2-yl group, a pyridin-3-yl group, a thiophen-2-yl group, or a thiophen-3-yl group. A pharmaceutical composition according to 1. The compound represented by the general formula (I) is:
(6-{[3 ′-(1-propenyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{[3 ′-(1-propenyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
{6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid,
{6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetate hexyl,
{6-[(3′-ethoxybiphenyl-4-ylmethyl) (pyridin-3-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid,
{6-[(benzenesulfonyl) (3′-ethoxybiphenyl-4-ylmethyl) aminomethyl] pyridin-2-ylamino} acetic acid,
{6-[(3′-ethoxybiphenyl-4-ylmethyl) (thiophen-2-ylsulfonyl) aminomethyl] pyridin-2-ylamino} acetic acid,
(6-{[4- (6-Ethoxypyridin-2-yl) benzyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{(benzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{(benzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) ethyl acetate,
(6-{[3 ′-(1-propynyl) biphenyl-4-ylmethyl] (thiophen-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid,
(6-{(3-Fluorobenzenesulfonyl) [3 ′-(1-propynyl) biphenyl-4-ylmethyl] aminomethyl} pyridin-2-ylamino) acetic acid, or (6-{[3 ′-(1-propynyl) 4. The pharmaceutical composition according to any one of claims 1 to 3, which is) biphenyl-4-ylmethyl] (pyridin-2-ylsulfonyl) aminomethyl} pyridin-2-ylamino) isopropyl acetate.   The other medicament is one or more medicaments selected from the group consisting of a PDE4 inhibitor, a corticosteroid, an anticholinergic agent, a β2-receptor agonist, and pirfenidone. Pharmaceutical composition.   The pharmaceutical composition according to any one of claims 1 to 7, wherein the other medicament is a PDE4 inhibitor, a corticosteroid, or pirfenidone.   The pharmaceutical composition according to any one of claims 1 to 7, wherein the other medicament is roflumilast, fluticasone or pirfenidone.   11. The treatment according to any one of claims 1 to 10, for the treatment or prevention of asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis or pulmonary hypertension. Pharmaceutical composition.   The pharmaceutical composition according to any one of claims 1 to 10, for treating or preventing asthma, chronic obstructive pulmonary disease or pulmonary fibrosis.