TW201617076A - Substituted biaryl compound and combination with other medicaments - Google Patents

Abstract

The present invention provides a pharmaceutical composition administered in combination with other medicaments. The pharmaceutical composition contains a specific substituted biaryl compound or a pharmacologically acceptable salt thereof. The pharmaceutical composition of the present invention is useful as a treating drug and/or a preventing drug for respirator disease such as asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome, Cystic Fibrosis and pulmonary hypertension.

Description

Substituted biaryl compound and other pharmaceutical combinations

The present invention relates to a pharmaceutical composition comprising a specific substituted biaryl compound or a pharmacologically acceptable salt thereof, and a method for treating a respiratory disease, which is administered in combination with other medicines. The method of treating a respiratory disease is administered to a warm-blooded animal by administering a therapeutically effective amount of a particular substituted aryl compound or a pharmacologically acceptable salt thereof, and a therapeutically effective amount of another pharmaceutical 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. The disease also has chronic diseases without effective treatment. Among them, chronic obstructive pulmonary disease, which is a respiratory obstructive disease, is a refractory disease characterized by chronic bronchitis and irreversible and persistent airway obstruction, which causes inflammation of the bronchus or rupture of the lungs by smoking or the like. . In the case of therapeutic drugs for chronic obstructive pulmonary disease, no safe and established therapeutic agents have been found. For example, roflumilast, which is a phosphodiesterase 4 (hereinafter, abbreviated as PDE4) inhibitor, is due to inflammation. It is clinically useful as a therapeutic drug for chronic obstructive pulmonary disease, and is clinically useful because of vomiting and vomiting of side effects, but it is clinically useful as a therapeutic drug for chronic obstructive pulmonary disease. In addition, interstitial pneumonia/pulmonary fibrosis, which is a diffuse lung disease, is also designated as a specific disease in Japan, and the prognosis after the onset is not good. There are steroids or pirfenidone (Pirfenidone) with strong side effects. Symptomatic therapy. On the other hand, asthma, which is an allergic lung disease, is a disease that exhibits chronic airway inflammation, but there are now a number of effective therapeutic drugs that can control seizures, and treatment methods have been generally established. However, there are also severe asthma that can be difficult to treat even if the inhaled steroid agent is administered.

Prostaglandin E ₂ (prostaglandin E _2, hereinafter abbreviated as PGE ₂₎ is used as peanut oil acid cascade metabolites (arachidonic acid cascade) while in a wide range of physiological activity, EP1, EP2, EP3 and EP4 4 The receptor acts as an agonist. PGE _{2 is} involved in a variety of inflammatory reactions, including: vascular penetrating hyperactivity, release of various inflammatory mediators, induction of inflammatory cells/immune cells, and angiogenesis. It has been reported that an anti-inflammatory action is exhibited via the EP2 and/or EP4 receptor (see Non-Patent Document 1).

In the past, a non-prastanoid-based sulfonamide compound having an action of an EP2 agonist (see Patent Documents 1 to 8) is known as a pharmaceutical use of the compound described in the above Patent Documents 1 to 8. Among the various diseases listed, include respiratory diseases including chronic obstructive pulmonary disease, pulmonary fibrosis, and asthma. Furthermore, specific compounds with the action of EP2 agonists have been disclosed with other medicines (eg, cortex) A combination of a steroid, an anticholinergic agent, a β2-receptor agonist, a PDE4 inhibitor, and the like (for example, Patent Document 9).

[Previous Technical Literature] [Patent Literature]

[Patent Document 1] International Publication No. 2009/113600

[Patent Document 2] International Publication No. 2011/030864

[Patent Document 3] International Publication No. 2011/030865

[Patent Document 4] International Publication No. 2011/030868

[Patent Document 5] International Publication No. 2011/030871

[Patent Document 6] International Publication No. 2011/030872

[Patent Document 7] International Publication No. 2011/030873

[Patent Document 8] International Publication No. 2011/078303

[Patent Document 9] International Publication No. 2013/164326

[Non-patent literature]

[Non-Patent Document 1] British Journal of Pharmacology, 122, 149 (1997)

However, any of the above prior art documents does not disclose or suggest that a biarylamine compound having a specific substituent substituted at a specific site as a partial structure has a strong EP2 agonist action and an anti-inflammatory action. And combined with other medicines for asthma, chronic obstruction It is useful for the prevention and/or treatment of respiratory diseases such as pulmonary diseases, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis and pulmonary hypertension.

The present inventors have found that a pharmaceutical composition containing a specific substituted biaryl compound or a pharmacologically acceptable salt thereof and administered in combination with other medicines is due to an anti-inflammatory action, an anti-fibrotic action, and a bronchodilating action. Excellent in the treatment and/or prevention of respiratory diseases such as asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis and pulmonary hypertension. The effect is completed and the present invention is completed.

The present invention provides a pharmaceutical composition comprising a compound represented by the following formula (I) or a pharmacologically acceptable salt thereof, which is administered in combination with other pharmaceuticals, and a method for treating a respiratory disease. The method for treating a respiratory disease is administered to a warm-blooded animal by combining a therapeutically effective amount of a compound represented by the following formula (I) or a pharmacologically acceptable salt thereof with a therapeutically effective amount of another pharmaceutical agent. .

The present invention is provided by one side thereof as described below.

(1) A pharmaceutical composition comprising a compound of the formula (I) or a pharmacologically acceptable salt thereof: (wherein R ¹ represents a protected carboxyl group, W represents a nitrogen atom or a -CH= group, R ² represents an ethoxy group, a 1-propenyl group or a 1-propynyl group, and Z represents a phenyl group, 3-fluorophenyl, pyridin-2-yl, pyridin-3-yl, thiophen-2-yl or thiophen-3-yl); and with PDE4 inhibitor, PDE5 inhibitor, corticosteroid, anticholinergic, β 2- Receptor agonists, H1-histamine receptor antagonists, leukotriene receptor antagonists, endothelin receptor antagonists, PGI2 receptor agonists, theophylline and pyridin One or more pharmaceutical combinations selected from the group consisting of fenidone are administered.

(2) The pharmaceutical composition according to (1), wherein the pharmaceutical composition containing the compound of the formula (I) or a salt thereof and the other pharmaceuticals are separately prepared as different preparations at the same time or at different times Cast.

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

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

(6) The pharmaceutical composition according to any one of (1) to (3) wherein R ¹ represents a carboxyl group, an ethoxycarbonyl group, an isopropoxycarbonyl group or a hexyloxycarbonyl group, and W represents a nitrogen atom. Atom or -CH= group, R ² represents 1-propenyl or 1-propynyl, and Z represents phenyl, 3-fluorophenyl, pyridin-2-yl, pyridin-3-yl, thiophene-2- Or thiophen-3-yl.

(7) The pharmaceutical composition according to any one of (1) to (3) wherein the compound of the formula (I) is: (6-{[3'-(1-propenyl)) Ethyl phenyl-4-ylmethyl](pyridin-2-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate, (6-{[3'-(1-propenyl)) Benzyl-4-ylmethyl](pyridin-2-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetic acid, (6-{[3'-(1-propynyl)biphenyl) Ethyl -4-ylmethyl](pyridin-2-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate, (6-{[3'-(1-propynyl)) Benzyl-4-ylmethyl](pyridin-2-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetic acid, (6-{[3'-(1-propynyl)biphenyl) Ethyl -4-ylmethyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate, (6-{[3'-(1-propynyl)) Benz-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}hexyl acetate, {6-[(3'- Ethoxybiphenyl-4-ylmethyl)(pyridin-3-ylsulfonyl)aminomethyl]pyridin-2-ylamino}acetic acid, {6-[(phenylsulfonyl) (3' -Ethoxybiphenyl-4-ylmethyl)aminomethyl]pyridin-2-ylamino}acetic acid, {6-[(3'-ethoxybiphenyl-4-ylmethyl) (thiophene) -2-ylsulfonyl)aminomethyl]pyridin-2-ylamino}acetic acid, (6-{[4-(6-ethoxypyridin-2-yl)benzyl](pyridine-2- (6-{[3'-(1-propynyl)biphenyl-4-ylmethyl](thiophen-2-yl), sulfamoyl)aminomethyl}pyridin-2-ylamino)acetic acid Ethyl sulfonyl)aminomethyl}pyridin-2-ylamino)acetate, (6-{[3'-(1-propynyl)biphenyl-4-ylmethyl](thiophene-2- Alkylsulfonyl)aminomethyl}pyridin-2-ylamino)acetic acid, (6-{(phenylsulfonyl)[3'-(1-propynyl)biphenyl-4-ylmethyl] Ethylmethyl}pyridin-2-ylamino)acetate, (6-{(phenylsulfonyl)[3'-(1-propynyl)biphenyl-4-ylmethyl]amine A base} Pyridin-2-ylamino)acetic acid, (6-{[3'-(1-propynyl)biphenyl-4-ylmethyl](thiophen-3-ylsulfonyl)aminomethyl}pyridine Ethyl-2-ylamino)acetate, (6-{[3'-(1-propynyl)biphenyl-4-ylmethyl](thiophen-3-ylsulfonyl)aminomethyl} Pyridin-2-ylamino)acetic acid, (6-{(3-Fluorophenylsulfonyl)[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)acetic acid isopropyl ester .

(8) The pharmaceutical composition according to any one of (1) to (7), wherein the other medicine is a PDE4 inhibitor, a corticosteroid, an anticholinergic, a β2-receptor agonist, and a pirfenibine One or more medicines selected from the group consisting of ketones.

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

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

(11) The pharmaceutical composition according to any one of (1) to (10) for use in the treatment or prevention of asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pulmonary fibrosis, acute respiration Distress syndrome, cystic fibrosis or pulmonary hypertension.

(12) The pharmaceutical composition according to any one of (1) to (10) for use in the treatment or prevention of asthma, chronic obstructive pulmonary disease or pulmonary fibrosis.

(13) A method for treating a disease by administering the following (i) and (ii) to a warm-blooded animal. (i) a therapeutically effective amount of a compound of the formula (I) or a pharmacologically acceptable salt thereof: (wherein R ¹ represents a protected carboxyl group, W represents a nitrogen atom or a -CH= group, R ² represents an ethoxy group, a 1-propenyl group or a 1-propynyl group, and Z represents a phenyl group, 3-fluorophenyl, pyridin-2-yl, pyridin-3-yl, thiophen-2-yl or thiophen-3-yl) (ii) therapeutically effective amount of other medicines (this other medicine is a PDE4 inhibitor , PDE5 inhibitors, corticosteroids, anticholinergics, β2-receptor agonists, H1-histamine receptor antagonists, leukotriene receptor antagonists, endothelin receptor antagonists, PGI2 receptor agonists, More than one medicine selected from the group consisting of theophylline and pirfenidone)

(14) The method according to (13), wherein the compound of the formula (I) or a salt thereof and the other pharmaceuticals are administered as separate preparations at the same time or at different times.

(15) The method according to (13), wherein the compound represented by the formula (I) or a salt thereof and the other pharmaceuticals are administered as a single preparation.

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

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

(19) The method according to any one of (13) to (15), wherein the compound of the formula (I) is: (6-{[3'-(1-propenyl)biphenyl- 4-ethylmethyl](pyridin-2-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate, (6-{[3'-(1-propenyl)biphenyl- 4-ylmethyl](pyridin-2-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetic acid, (6-{[3'-(1-propynyl)biphenyl-4 Ethylmethyl](pyridin-2-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate, (6-{[3'-(1-propynyl)biphenyl- 4-ylmethyl](pyridin-2-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetic acid, (6-{[3'-(1-propynyl)biphenyl-4 Ethylmethyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate, (6-{[3'-(1-propynyl)biphenyl- 4-ylmethyl](pyridin-3-ylsulfonyl)amine Methyl}pyridin-2-ylamino)acetic acid, {6-[(3'-ethoxybiphenyl-4-ylmethyl)(pyridin-2-ylsulfonyl)aminomethyl]pyridine- 2-ylamino}acetic acid, {6-[(3'-ethoxybiphenyl-4-ylmethyl)(pyridin-2-ylsulfonyl)aminomethyl]pyridin-2-ylamino }Hexyl acetate, {6-[(3'-ethoxybiphenyl-4-ylmethyl)(pyridin-3-ylsulfonyl)aminomethyl]pyridin-2-ylamino}acetic acid, {6-[(phenylsulfonyl)(3'-ethoxybiphenyl-4-ylmethyl)aminomethyl]pyridin-2-ylamino}acetic acid, {6-[(3'-B) Oxybiphenyl-4-ylmethyl)(thiophen-2-ylsulfonyl)aminomethyl]pyridin-2-ylamino}acetic acid, (6-{[4-(6-ethoxypyridine) -2-yl)benzyl](pyridin-2-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetic acid, (6-{[3'-(1-propynyl)biphenyl) Ethyl -4-ylmethyl](thiophen-2-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate, (6-{[3'-(1-propynyl)) Benz-4-ylmethyl](thiophen-2-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetic acid, (6-{(phenylsulfonyl)[3'-(1- Acetyl)biphenyl-4-ylmethyl]aminomethyl}pyridin-2-ylamino)acetate, (6-{(phenylsulfonyl)[3'-(1-propyne) Biphenyl-4-ylmethyl]aminomethyl}pyridin-2-ylamino)acetic acid, (6-{[3'-(1-propynyl)biphenyl-4-ylmethyl]( Ethyl thiophen-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate, (6-{[3'-(1-propynyl)biphenyl-4-ylmethyl] (thiophen-3-ylsulfonyl)amino group Methyl}pyridin-2-ylamino)acetic acid, (6-{(3-fluorophenylsulfonyl)[3'-(1-propynyl)biphenyl-4-ylmethyl]aminomethyl }pyridin-2-ylamino)acetic acid, or (6-{[3'-(1-propynyl)biphenyl-4-ylmethyl](pyridin-2-ylsulfonyl)aminomethyl Pyridine-2-ylamino)acetate.

(20) The method according to any one of (13) to (19), wherein the other medicine is a PDE4 inhibitor, a corticosteroid, an anticholinergic, a β2-receptor agonist, and pirfenidone. More than one type of medicine selected by the group.

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

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

(23) The method according to any one of (13) to (22) wherein the disease is asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pulmonary fibrosis, acute respiratory distress syndrome, cysticity Fibrosis or pulmonary hypertension.

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

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

The pharmaceutical composition of the present invention is obtained by adding a compound represented by the formula (I) or pharmacologically thereto to the pharmacological effects of other drugs. The pharmacological effect of the permissible salt is useful in reducing the amount of other medicines and reducing the side effects of other medicines. The above pharmaceutical composition is a pharmaceutical composition for treating and/or preventing respiratory diseases, and is ideal for treating and/or preventing asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pulmonary fibrosis, acute respiration A pharmaceutical composition for stress syndrome, cystic fibrosis or pulmonary hypertension, preferably a medical composition for treating and/or preventing asthma, chronic obstructive pulmonary disease or pulmonary fibrosis, and as a warm-blooded animal It is useful with medicine (especially for human use).

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 (especially for human use).

In the compound represented by the above formula (I), a preferred form of each substituent is as follows.

The protected carboxyl group represented by R ^{1 of the} formula (I) is a carboxyl group which is protected by a carboxyl group or a protective group, and examples of such a protecting group include a protecting group of an ester type. Examples of the partial configuration of the ester type protecting group include methyl group, ethyl group, propyl group, isopropyl group, 1-ethylpropyl group, butyl group, isobutyl group, secondary butyl group, and tertiary butyl group. , 3,3-dimethylbutyl, pentyl, isopentyl, neopentyl, tertiary pentyl, 1-methylbutyl, hexyl, 1-methylpentyl, 2-methylpentyl , C ₁ -C ₁₂ alkane such as 3-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, heptyl, octyl, decyl, decyl, undecyl or dodecyl Base; benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, phenylheptyl, phenyloctyl, benzoyl, phenylhydrazine, phenylundecyl or phenyldodecane C ₇ -C ₁₈ aralkyl group; ethoxymethyl, 1-ethyloxyethyl, 1-ethyloxypropyl, 1-ethyloxybutyl, propyloxy , 1-propoxycarbonylethyl, butyloxymethyl, 1-butoxycarbonylethyl, trimethylethoxymethyloxy, 1-trimethylethenyloxyethyl, 1 a C ₁ -C ₄ alkyl group substituted by a C ₂ -C ₅ alkoxy group such as trimethylacetoxypropyl or 1-trimethylethoxycarbonyl; methoxycarbonyloxymethyl 1-methoxycarbonyloxy Ethyl ethyl, ethoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl, propoxycarbonyloxymethyl, 1-propoxycarbonyloxyethyl, isopropoxycarbonyloxy Methyl, 1-isopropoxycarbonyloxyethyl, butoxycarbonyloxymethyl, 1-butoxycarbonyloxyethyl, tert-butoxycarbonyloxymethyl or 1-tri level butoxycarbonyloxy ethyl and the like by (C ₁ -C ₄ alkoxy) carbonyl group substituted by C ₁ -C ₄ alkyl; N, N- dimethylamino-carbonyl group or N, N N,N-dialkylaminocarbonylalkyl such as diethylaminocarbonylmethyl; 2-(N,N-dimethylamino)ethyl or 2-(N,N-diethylamine 2-(N,N-dialkylamino)ethyl; ethyl 2-(morpholin-4-yl)ethyl, 2-piperidinylethyl or 2-(4-methylpiperidyl) a 5- or 6-membered heterosaturated monocyclic C ₁ -C ₄ alkyl group substituted with 1 or 2 heteroatoms selected from N, O and S; or (5-methyl) -2-Sideoxy-1,3-dioxolene-4-yl)methyl or (5-phenyl-2-oxo-1,3-dioxolene a group such as a methyl group or the like which is easily deprotected in a living body and which can be converted into a carboxyl group, and is preferably a C ₁ -C ₁₂ alkyl group, a C ₇ -C ₁₈ aralkyl group, a C ₂ -C ₅ alkane group. oxygen Substituted C ₁ -C ₂ alkyl, (C ₁ -C ₄ alkoxy) carbonyl group substituted by C ₁ -C ₂ alkyl, N, N- dimethylamino-carbonyl-methyl, 2- ( Morpholin-4-yl)ethyl, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl or (5-phenyl-2-oxooxy) The benzyl-1,3-dioxol-4-yl)methyl group is more preferably a C ₁ -C ₆ alkyl group, and particularly preferably an ethyl group, an isopropyl group or a hexyl group.

Therefore, in the formula (I), R ^{1 is} desirably a carboxyl group or a C ₁ -C ₆ alkoxycarbonyl group. Specific embodiments aspects of formula (I) of, R ¹ is carboxyl, ethoxycarbonyl, isopropoxycarbonyl or hexyloxycarbonyl.

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

In the formula (I), R ² is an ethoxy group, a 1-propenyl group or a 1-propynyl group. In a particular embodiment of formula (I), R ² is ethoxy. In another specific embodiment of formula (I), R ² is 1-propenyl or 1-propynyl.

In the formula (I), Z is 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. In a particular embodiment of formula (I), Z is phenyl, 3-fluorophenyl, pyridin-2-yl or pyridin-3-yl, preferably phenyl or pyridin-2-yl or pyridine-3 -base. In other specific embodiments of formula (I), Z is thiophen-2-yl or thiophen-3-yl, preferably thiophen-2-yl.

When a compound represented by the formula (I) is present as a geometric isomer or a rotamer, such isomers are also included in the scope of the present invention, and in the presence of a proton tautomer, such The tautomer is also included in the scope of the compound of the formula (I) of the present invention.

The compound of the formula (I) can be converted into a pharmacologically acceptable salt according to a usual method, but it can also be obtained from the reaction mixture. Separated directly as a salt.

The compound of the formula (I) is converted to a pharmacologically acceptable acid addition salt by treatment with an acid. Examples of such a salt include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or phosphate; or acetate, trifluoroacetate and benzylate. , oxalate, malonate, succinate, maleate, fumarate, tartrate, citrate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate An acid salt such as a salt, a besylate, a p-toluenesulfonate, a glutamate or an aspartate.

The compound represented by the formula (I), when R ¹ is a carboxyl group, is converted into a pharmacologically acceptable basic salt by treatment with a base. The salt may, for example, be a metal salt such as a sodium salt, a potassium salt, a calcium salt or a magnesium salt; an inorganic salt such as an ammonium salt; or an organic amine salt such as a triethylamine salt or a phosphonium salt.

A compound represented by the formula (I), when R ¹ is a carboxyl group protected by a protective group, is administered to a living body (in vivo test, etc.), and is easily biochemically reacted in a living body (for example, an esterase or the like). Hydrolysis can be converted into a pharmacologically active substance in which R ¹ is a carboxyl group.

A representative production method of the compound represented by the general formula (I) is shown below, and an individual specific production method will be described in detail in the examples described later.

Wherein R ² , W and Z represent the same meaning as defined above, R ¹ 'is a protecting group representing a carboxyl group, R ³ represents a tertiary butoxycarbonyl group or a hydrogen atom, and X represents a hydroxyl group, a chlorine group, a bromine group. Base, iodine, methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy or trifluoromethanesulfonyloxy, X' represents a chloro, bromo or iodo group]

The compound of the formula (I) can be obtained by the method of any one of the synthetic routes 1 to 5, wherein the compound wherein R ¹ is a carboxyl group is obtained as the compound (Ia) wherein R ³ is a hydrogen atom, and R ¹ is a carboxyl group by a protecting group R ³ as compound (I ') is obtained by a hydrogen atom.

[synthetic path 1]

In the compound (a), when X is a hydroxyl 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 to obtain a compound. (I').

The inert organic solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the raw material substance to some extent, and examples thereof include aromatic hydrocarbons such as benzene, toluene or xylene; and diethyl ether and tetrahydrofuran. 1,4-two An ether such as an alkane or a 1,2-dimethoxyethane; an amide such as N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone; a nitrile such as acetonitrile or propionitrile; an ester such as methyl acetate, ethyl acetate or isopropyl acetate; or any mixed solvent of the above, preferably tetrahydrofuran, N,N-dimethylformamide, acetonitrile Or such mixed solvents.

The azo compound-based condensing agent used may, for example, be diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), N, N, N', N'- Tetraisopropyl azomethanamine (TIPA), 1,1'-(azodicarbonyl)dipiperidine (ADDP), N,N,N',N'-tetramethylazodiazepine Amine (TMAD) or 1,6-dimethyl-1,5,7-hexahydro-1,4,6,7-tetraazacyclotetradecene-2,5-dione (DHTD), etc., ideal It is diethyl azodicarboxylate (DEAD) or N,N,N',N'-tetramethylazolylamine (TMAD). The amount of the azo compound-based condensing agent to be used is usually 0.9 to 10 moles, preferably 1 to 5 moles, per mole of the compound (b).

The phosphine reagent to be used may, for example, be trimethylphosphine, triethylphosphine, tri-n-butylphosphine or triphenylphosphine, and is preferably tri-n-butylphosphine or triphenylphosphine. The amount of the phosphine compound used is usually 0.9 to 10 times the molar amount, and preferably 1 to 5 times the molar amount, relative to the compound (b) 1 mole.

The amount of the compound (a) to be used is usually 0.8 to 2 times the molar amount, and preferably 0.9 to 1.5 times the molar amount, relative to the compound (b) 1 mole.

The reaction temperature varies depending on the kind of the raw material, the solvent, and the like, the amount used, and the like, 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 from 30 minutes to 48 hours, preferably from 1 hour to 24 hours.

In the compound (a), 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 (by Compound (I') can be obtained by reacting a) and compound (b) in an inert organic solvent in the presence of a base.

The inert solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the raw material to some extent, and examples thereof include tetrahydrofuran and 1,4-diene. An ether such as an alkane or a 1,2-dimethoxyethane; a halogenated aliphatic hydrocarbon such as dichloromethane, chloroform or 1,2-dichloroethane; a nitrile such as acetonitrile or propionitrile; and methyl formate An ester such as ethyl formate, methyl acetate or ethyl acetate; an aromatic hydrocarbon such as benzene or toluene; N,N-dimethylformamide, N,N-dimethylacetamide or N-A a guanamine such as a pyrrolidone; an anthracene such as dimethyl hydrazine; or an arbitrary mixed solvent of the above, preferably tetrahydrofuran, N,N-dimethylformamide, dichloromethane or 1, 2-Dichloroethane.

Examples of the base to be used include alkali metal hydrides such as sodium hydride or potassium hydride; lithium amide, sodium amide, lithium diisopropylamide or Alkali metal amines such as lithium bis(trimethylsilyl)amide; alkanol bases such as sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium butoxide An alkali metal carbonate such as sodium carbonate or potassium carbonate; or triethylamine, tributylamine, diisopropylethylamine, pyridine, picoline, 2,6-lutidine or 4-di An amine or the like such as methylaminopyridine is preferably sodium hydride, potassium carbonate, triethylamine or diisopropylethylamine. but When the inert solvent to be used is an ester, a nitrile or a halogenated aliphatic hydrocarbon, it is preferred that the base be triethylamine or diisopropylethylamine.

The amount of the base to be used is usually 1 to 5 times the molar amount, and preferably 1 to 2.5 times the molar amount, relative to the compound (b) 1 mole.

The amount of the compound (a) to be used is usually 0.5 to 3 times the molar amount, and preferably 0.5 to 1.5 times the molar amount, relative to the compound (b) 1 mole.

The reaction temperature varies depending on the kind of the raw material, the solvent, and the like, the amount used, and the like, and 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, and is usually from 10 minutes to 48 hours, preferably from 1 hour to 24 hours.

[synthetic path 2]

In the compound (d), when X is a hydroxyl 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 to obtain a compound ( I'). This process is carried out except that the compound (d) is used instead of the compound (a), and the compound (c) is used instead of the compound (b), and the compound (a) in the above [Synthesis Route 1] is a hydroxyl group. .

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 (by Compound (I') is obtained by reacting c) with compound (d) in an inert organic solvent in the presence of a base. In the present process, except that the compound (d) is used instead of the compound (a), and the compound (c) is used instead of the compound (b), the X of the compound (a) in the above [Synthesis Route 1] is a chlorine group or a bromine group. Iodine, methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy or three It is carried out in the case of fluoromethanesulfonyloxy.

[synthetic path 3]

The synthesis route 3-1 is a process for obtaining a compound (f) by reacting the compound (c) and the compound (e) in an inert organic solvent in the presence of a base. In the present process, except that the compound (e) is used instead of the compound (a), and the compound (c) is used instead of the compound (b), the X of the compound (a) according to the above [Synthesis Route 1] is a chlorine group or a bromine group. In the case of iodine, methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy or trifluoromethanesulfonyloxy.

Synthetic route 3-2 is obtained by reacting compound (f) and compound (g) obtained in synthesis route 3-1 in an inert solvent in an inert gas atmosphere, in one of alkali or fluoride and palladium The reaction is carried out in the presence of a medium to obtain the compound (I').

The inert solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the solvent of the raw material, the catalyst, and the alkali (or fluoride) to some extent. For example, an aromatic hydrocarbon such as benzene or toluene may be mentioned. Hydrocarbons; tetrahydrofuran, 1,2-dimethoxyethane or 1,4-two Ethers such as alkanes; alcohols such as methanol, ethanol, propanol or isopropanol; esters such as methyl acetate or ethyl acetate; N,N-dimethylformamide, N,N-dimethylacetamidine a guanamine such as an amine or N-methylpyrrolidone; an anthracene such as dimethyl hydrazine; a nitrile such as acetonitrile; water; or any mixed solvent such as toluene, toluene-ethanol-water. Mixed solvent or toluene-water mixed solvent.

Examples of the inert gas to be used include nitrogen, helium or argon.

Examples of the palladium catalyst to be used include metal palladium such as palladium-activated carbon or palladium black; tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium chloride, and chlorination. An organic palladium complex such as 1,1'-bis(diphenylphosphino)pyrene palladium or tris(dibenzylideneacetone)dipalladium; or a palladium salt such as palladium chloride or palladium acetate; (triphenylphosphine) palladium or palladium acetate. The amount of palladium used as a catalyst is usually 0.0001 to 1 mol, and preferably 0.005 to 0.3 mol, relative to 1 mol of the compound (f).

When tris(dibenzylideneacetone)dipalladium, palladium chloride or palladium acetate is used as a catalyst, it is preferably coexisted with an organic phosphine compound. Examples of the organic phosphine compound to be used include tri-n-butylphosphine, tri-tertiary butylphosphine, tricyclohexylphosphine, butyldi-1-adamantylphosphine, triphenylphosphine, and tri O-tolyl)phosphine, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 1,1'-bis(diphenylphosphino)iron or 1,2,3,4 , 5-pentaphenyl-1 '-(di-tertiary butylphosphino)iron ruthenium, etc., ideally tricyclohexylphosphine, butyl di-1-adamantylphosphine, triphenylphosphine or 2-di Cyclohexylphosphino-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, relative to the palladium 1 mole.

Examples of the base or fluoride to be used include an alkali metal acetate such as sodium acetate or potassium acetate; an alkali metal carbonate such as sodium carbonate, potassium carbonate or cesium carbonate; and an alkali metal phosphate such as trisodium phosphate or tripotassium phosphate. An alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide; tetramethylammonium hydroxide, tetraethylammonium hydroxide or tetrabutylammonium hydroxide; or fluorinated Fluoride such as hydrazine, tetramethylammonium fluoride, tetraethylammonium fluoride or tetrabutylammonium fluoride, etc., is preferably sodium carbonate or tripotassium phosphate. The amount of the base or fluoride to be used is usually from 1 to 10 moles, preferably from 1.5 to 5 moles, per mole of the compound (f).

The amount of the compound (g) to be used is usually 1 to 3 times the molar amount, and preferably 1 to 2 times the molar amount, relative to the compound (f) 1 mole.

The reaction temperature varies depending on the kind of the raw material, the solvent, and the like, the amount used, and the like, and is usually from 0 ° C to 200 ° C, preferably from 50 ° C to 150 ° C.

The reaction time varies depending on the reaction temperature and the like, and is usually from 10 minutes to 120 hours, preferably from 1 hour to 48 hours.

[synthetic path 4]

The compound (I') can be obtained by reacting the compound (h) and the compound (i) in an inert organic solvent in the presence or absence of a base (preferably in the presence).

The inert organic solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the raw material to some extent, and examples thereof include aromatic hydrocarbons such as benzene, toluene or xylene; and dichloromethane and trichlorobenzene. Halogenated aliphatic hydrocarbons such as methane or 1,2-dichloroethane; 1,4-two An ether such as an alkane, tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane; N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone Isoguanamines; nitriles such as acetonitrile or propionitrile; or any of these mixed solvents, etc., preferably dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, acetonitrile Or such mixed solvents.

Examples of the base to be used include an organic base such as triethylamine or diisopropylethylamine; or an inorganic base such as sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate or potassium carbonate; Alkylamine or diisopropylethylamine. The amount of the base to be used is usually 0.9 to 20 times the molar amount, and preferably 1 to 10 times the molar amount, relative to the compound (i) 1 mole.

The amount of the compound (h) to be used is usually 0.7 to 5 times the molar amount, and preferably 0.8 to 1.5 times the molar amount, relative to the compound (i) 1 mole.

The reaction temperature varies depending on the kind of the raw material, the solvent, and the like, the amount used, and the like, and 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, and is usually from 1 minute to 36 hours, preferably from 1 hour to 18 hours.

[synthetic path 5]

In the compound (I'), when R ³ is a tertiary butoxycarbonyl group, R ¹ is protected by an ester type protecting group by subjecting the compound (I') to deprotection by an acid treatment. A compound of the formula (I) which has a carboxyl group. However, in the compound (I'), R ¹ 'is a tertiary butyl group, and when R ³ is a tertiary butyloxycarbonyl group, it can be obtained by deprotection by an acid treatment such as hydrochloric acid or trifluoroacetic acid. A compound represented by the formula (I) wherein R ¹ is a carboxyl group. Similarly, in the case of the compound (I'), when R ³ is a hydrogen atom, the compound (I') is subjected to an appropriate deprotection by alkali hydrolysis or the like, and the formula (I) wherein R ¹ is a carboxyl group can be obtained. The compound shown.

The substituent R ² may be introduced with a desired substituent from the beginning, or may be subjected to oxidation, reduction, alkylation, esterification, amide amination, dehydration, or removal after the basic skeleton is produced by the above method. A synthetic method widely used for protecting a reaction, hydrolysis, coupling reaction, cyclization reaction, and/or a combination of these reactions, and introducing a desired substituent.

The starting compound of the compound of the formula (I) is commercially available or can be produced by a production method known to those skilled in the art. The method for producing the starting compound and the intermediate compound of the compound represented by the formula (I) will be described in detail in the reference examples described later.

The target compound produced in each reaction is obtained from the reaction mixture in accordance with a usual method. For example, when the reaction mixture is appropriately neutralized or in the presence of insoluble matter, it is removed by filtration, and an organic solvent such as ethyl acetate which is not mixed with water is added, and after washing with water, the organic layer containing the target compound is separated. After drying with a desiccant such as anhydrous magnesium sulfate or anhydrous sodium sulfate, the solvent is distilled off.

The obtained target compound may be subjected to a usual method, for example, recrystallization, reprecipitation, or a method conventionally used for separation and purification of an organic compound (for example, an adsorption column layer using a carrier such as ruthenium gel or alumina). Analytical method; ion exchange chromatography; or cis phase/reverse phase column chromatography (suitable for high-speed liquid chromatography) of ruthenium gel or alkyl ruthenium gel, suitably combined, separated and refined .

The compound represented by the formula (I) or a pharmacologically acceptable salt thereof can be present as a hydrate or a solvent.

A pharmaceutical composition containing a compound represented by the formula (I) or a pharmacologically acceptable salt thereof is characterized by being administered in combination with other pharmaceuticals. The term "administered in combination" in the present invention means a pharmaceutical composition which will be administered to a subject (especially a human) to contain a compound of the formula (I) or a pharmacologically acceptable salt thereof for a certain period of time. And other medicines are ingested in the body. Therefore, the pharmaceutical composition may be: (a) a pharmaceutical composition in which a pharmaceutical composition containing a compound represented by the formula (I) or a pharmacologically acceptable salt thereof and other pharmaceuticals are respectively different a formulation, administered at the same time or at different times; or (b) a pharmaceutical composition comprising a compound of the formula (I) or The pharmacologically acceptable salt pharmaceutical composition and other pharmaceuticals are administered as a single preparation (mixture); and the pharmaceutical composition of the above (a) is preferred.

In the pharmaceutical composition of the above (a), the preparation period containing the compound represented by the formula (I) or a pharmacologically acceptable salt thereof and the preparation containing the other medicine are not limited, and the above two preparations may be used. In the same time, at different times (respectively) or on different days. The order, number, route and amount of administration of the above two preparations are not limited, and the number, route and amount of administration may be different. Further, the period from the administration of one of the above two preparations to the administration of the other is not limited, as long as the pharmacological effect of one of them remains for a certain period of time (for example, one week, preferably two or three days, It is desirable to vote for the other one on the 1st, more preferably 1 to 8 hours. The compound represented by the formula (I) or a pharmacologically acceptable salt thereof and other pharmaceuticals need not be present in the blood at a certain concentration or more, as long as it exhibits the desired effect, and may be administered in the blood. The other one has disappeared from the blood.

The administration form of the pharmaceutical composition of the present invention is, for example, as described below. (A) a preparation containing a compound represented by the formula (I) or a pharmacologically acceptable salt thereof, and a preparation containing two other pharmaceuticals (two different preparations); (B) containing a formula ( A formulation of the compound shown in I) or a pharmacologically acceptable salt thereof and a preparation containing other pharmaceuticals (two different preparations) are administered separately for a certain period of time; (C) administration of the compound of the formula (I) a compound or a pharmacologically acceptable salt thereof And a single preparation of both other medicines.

The other medicine in the pharmaceutical composition of the present invention is not limited as long as it exhibits a desired effect (ideally, an anti-inflammatory effect, an anti-fibrosis or a bronchodilator effect due to suppression of the production of an inflammatory mediator, etc.), for example, It may be a PDE4 inhibitor, a PDE5 inhibitor, a corticosteroid, an anticholinergic, a β2-receptor agonist, an H1-histamine receptor antagonist, a leukotriene receptor antagonist, an endothelin receptor antagonist, One or more medicines selected from the group consisting of PGI2 receptor agonist, theophylline and pirfenidone, preferably PDE4 inhibitor, corticosteroid, anticholinergic, β2-receptor agonist and pirfenib One or more kinds of medicines selected from the group consisting of ketones are preferably PDE4 inhibitors, corticosteroids or pirfenidone, and most preferably roflumilast, fluticasone or pirfenidone.

In the present invention, other PDE4 inhibitors in medicine include, for example, cilomilast, roflumilast, tetomilast, tofimilast, and non-Minist ( Filaminast), Piclamilast, or Lirimilast, etc., ideally cilostatin or roflumilast, more preferably roflumilast.

In the present invention, other PDE5 inhibitors in medicine include, for example, sildenafil, vardenafil, tadalafil, Udenafil, or Avanafil et al.

In the present invention, corticosteroids in other medicines include, for example, prednisone, prednisolone, methylpresusol, cortisone, and hydrocortisone. (hydrocortisone), fludrocortisone, dexamethasone, betamethasone, Budesonide, fluticasone, beclometasone, mometasone, koji Triamcinolone or ciclesonide, etc., ideally budesonide, fluticasone, beclomethasone, mometasone or ciclesonide, preferably fluticasone.

In the present invention, other anticholinergic drugs in medicine include, for example, Glycopyrronium bromide, Aclidinium Bromide, Tiotropium bromide or Ipratropium bromide. )Wait.

In the present invention, examples of the β2-receptor agonist in other medicines include, for example, salbutamol, milveterol, Indacaterol, and carmoterol ( Carmoterol), salmeterol (Salmeterol) or formoterol (formoterol).

In the present invention, H1-histamine receptor antagonists in other medicines include, for example, azelastine, olopatadine, loratadine, and deslorata. Desloratadine or cetirizine, etc.

In the present invention, other leukotriene receptor antagonists in medicine include, for example, Montelukast, Pranlukast, or zafirlukast.

In the present invention, other endothelin receptor antagonists in medicine include, for example, Bosentan and Abesentan. (Ambrisentan), Atrasentan, darusentan, clazosentan or avosentan.

In the present invention, examples of the PGI2 receptor agonist in other medicines include beraprost or epoprostenol.

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

A pharmaceutical composition (formulation) containing a compound represented by the formula (I) or a pharmacologically acceptable salt thereof, and other pharmaceuticals (formulations) may be administered per se (maintaining the state of the raw material powder), or may be suitable Tablets, capsules, powders, syrups, granules, fine granules, pills, suspensions, emulsions, percutaneous absorption agents, suppositories, and the like, which are prepared by mixing pharmacologically acceptable excipients, diluents, and the like. Forms of preparations such as ointments, lotions, inhalants or injections, by oral or parenteral (intravenous administration, intramuscular administration, intraperitoneal administration, transdermal administration, nasal administration, etc.) It is administered via the respiratory tract, administered via the lung, intradermally or subcutaneously, etc.). The pharmaceutical composition containing the compound represented by the formula (I) or a pharmacologically acceptable salt thereof and the other pharmaceuticals may be different preparations, or may be a compound represented by the formula (I) or a pharmacological agent thereof. The pharmaceutical composition of the above-mentioned permissible salt further contains a single preparation of another pharmaceutical.

These preparations are produced by a known method using additives such as an excipient, a lubricant, a binder, a disintegrant, an emulsifier, a stabilizer, a flavoring agent, and a diluent.

Examples of the excipients include organic excipients or inorganic excipients. Examples of the organic excipients include sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, α-starch or dextrin; and fibers such as crystalline cellulose. a derivative; gum arabic; dextran; or polytriglucose (pullulan) and the like. Examples of the inorganic excipients include light anhydrous citric acid; sulfates such as calcium sulfate; and the like.

The lubricant may, for example, be stearic acid; a metal stearate such as calcium stearate or magnesium stearate; talc; colloidal silica; a wax such as beeswax or cetyl wax; boric acid; adipic acid. Sulfate such as sodium sulfate; diol; fumaric acid; sodium benzylate; D,L-leucine; sodium lauryl sulfate; citric acid such as anhydrous citric acid or citric acid hydrate; or the above-mentioned excipients Starch derivatives and the like.

Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinylgol or a compound represented by the above-mentioned excipients.

Examples of the disintegrator include cellulose derivatives such as low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium or internal cross-linked carboxymethylcellulose calcium; crosslinked polyvinylpyrrole a chemically modified starch or a cellulose derivative such as carboxymethyl starch or sodium carboxymethyl starch.

Examples of the emulsifier include colloidal clay such as bentonite or Veegum; an anionic surfactant such as sodium lauryl sulfate; a cationic surfactant such as benzalkonium chloride; or polyoxyethylene. A nonionic surfactant such as an alkyl ether, a polyoxyethylene sorbitan fatty acid ester or a sucrose fatty acid ester.

As the stabilizer, for example, p-hydroxybenzyl esters such as methyl paraben or propyl p-hydroxybenzoate; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; Phenols such as phenol or cresol; thimerosal; acetic anhydride; or sorbic acid.

The flavoring agent may, for example, be a sweetener such as sodium saccharin or aspartame; a sour material such as citric acid, malic acid or tartaric acid; or a flavor such as menthol, lemon extract or orange extract.

The diluent is a compound which is usually used as a diluent, and examples thereof include lactose, mannitol, glucose, sucrose, calcium sulfate, hydroxypropylcellulose, microcrystalline cellulose, water, ethanol, and polyethylene glycol. , propylene glycol, glycerin, starch, polyvinylpyrrolidone or a mixture of these, and the like.

Alternatively, appropriate additives may be used depending on the form of administration. For example, when the active ingredient of the pharmaceutical composition of the present invention is used as a nasal spray or a nasal spray, for example, dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethylene can be used. A chlorofluorocarbon (CFC) such as ethane or carbon dioxide or the like is used as a propellant.

In the pharmaceutical composition of the present invention, the administration amount of the compound represented by the formula (I) or a pharmacologically acceptable salt thereof may vary depending on the symptoms, age, body weight and the like of the patient, and may be adult depending on the symptoms. 1 to 6 times a day, when administered orally, the lower limit of each dose is 0.001mg/Kg (ideally 0.01mg/Kg), and the upper limit is 20mg/Kg (ideally 10mg/Kg). At the time of administration, the lower limit of each injection is 0.0001 mg/Kg (ideally 0.0005 mg/Kg), upper limit 10 mg/Kg (ideally 5 mg/Kg).

In the pharmaceutical composition of the present invention, the dosage of other medicines may vary depending on the type of other medicine, the symptoms of the patient, the age, the body weight, and the like, and may be administered to the adult 1 to 6 times per day depending on the symptoms. When administered orally, the lower limit of each dose is 0.001 mg/Kg (preferably 0.01 mg/Kg), and the upper limit is 500 mg/Kg (ideally 50 mg/Kg), and each time it is administered orally, each time The lower limit of administration is 0.0001 mg/kg (preferably 0.0005 mg/kg), and the upper limit is 50 mg/kg (preferably 5 mg/kg).

[Examples]

The present invention will be described in more detail below with reference to examples, reference examples, and test examples, but the scope of the invention is not limited thereto.

[Example 1]

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

In a solution of 205 mg (0.913 mmol) of tetrahydrofuran in 3'-(1-propenyl)biphenyl-4-ylmethanol obtained in Reference Example 3-(b), 9.4 mL was added in the same manner as in Reference Example 1-(g). The obtained {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'-tetramethylazolylamine 236 mg (1.37 mmol) was stirred at room temperature for 5 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous The residue was subjected to hydrazine gel column chromatography (dissolved solvent; n-hexane: ethyl acetate = 2:3 (V/V)), and the fractions containing the target substance were concentrated under reduced pressure to give a yellowish color. The title compound of the oil was 510 mg. (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=8.3Hz,1H), 4.80(s,2H), 4.70(t,J=5.4Hz,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).

[Embodiment 2]

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

(6-{[3'-(1-Propyl)biphenyl-4-ylmethyl](pyridin-2-ylsulfonyl)aminomethyl}pyridin-2-ylamine obtained in Example 1 To a solution of ethyl acetate 220 mg (0.395 mmol) in ethanol (2.0 mL), 1.89 mL (1.98 mmol) of a 1 mol/L aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 2.5 hours. After the completion of the reaction, water was added to the reaction solution, followed by adjustment to pH 4.5 with 1 mol/L hydrochloric acid. The precipitated solid was filtered, dried, evaporated, evaporated (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

In a solution of 4'-(1-propynyl)biphenyl-4-ylmethanol 200 mg (0.900 mmol) in tetrahydrofuran (4.0 mL) obtained in Reference Example 4-(b), was added in the same manner as in Reference Example 1-(g) Ethyl acetate {6-[(pyridin-2-ylsulfonyl)aminomethyl]pyridin-2-ylamino}}ethyl acetate 315 mg (0.900 mmol), tri-n-butylphosphine 450 μL (1.82 mmol) And N,N,N',N'-tetramethylazolylamine 310 mg (1.80 mmol), and stirred at room temperature for 3 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous The residue was subjected to hydrazine gel column chromatography (dissolved solvent; n-hexane: ethyl acetate = 3:2→2:3 (V/V)), and the fractions containing the target substance were concentrated under reduced pressure to give white foam. The title compound was 483 mg. (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

(6-{[3'-(1-propynyl)biphenyl-4-ylmethyl](pyridin-2-ylsulfonyl)aminomethyl}pyridin-2-yl obtained in Example 3 To a solution of 476 mg (0.858 mmol) of ethyl acetate in 3.0 mL of ethanol, 3.43 mL (3.43 mmol) of a 1 mol/L aqueous sodium hydroxide solution 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 the mixture was adjusted to pH 4.5 with 1 mol/L hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous The residue was subjected to hydrazine gel column chromatography (dissolved solvent; dichloromethane: methanol = 15:1 → 10:1 (V/V)), and the fraction containing the target substance was concentrated under reduced pressure to give a white foam. The title compound was 444 mg. (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

In a solution of 178 mg (0.800 mmol) of tetrahydrofuran in a solution of 3'-(1-propynyl)biphenyl-4-ylmethanol obtained in the same manner as in Reference Example 4-(b), was added to Reference Example 2 - (b) ethoxylate (6-[(pyridin-3-ylsulfonyl)aminomethyl]pyridin-2-ylamino} ethyl acetate 280 mg (0.800 mmol), tri-n-butylphosphine 395 μL (1.60 mmol) and 276 mg (1.60 mmol) of N,N,N',N'-tetramethylazolylamine were stirred at room temperature for 3 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous The residue was subjected to hydrazine gel column chromatography (dissolved solvent; n-hexane: ethyl acetate = 3:7 → 0:1 (V/V)), and the fractions containing the target substance were concentrated under reduced pressure to give a yellowish color. The title compound of the oil was 400 mg. (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).

[Embodiment 6]

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

(6-{[3'-(1-propynyl)biphenyl-4-ylmethyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-yl obtained in Example 5 To a solution of 395 mg (0.712 mmol) of ethyl acetate in 3.0 mL of ethanol, 3.0 mL (3.0 mmol) of a 1 mol/L aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was adjusted to pH 4.5 with 1 mol/L hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous To the residue, 10 mL of butyl dimethyl ether and 0.5 mL of methanol were added, and the solid which was precipitated by ultrasonication was filtered, and dried under reduced pressure to give 340 mg of the title compound. (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).

[Embodiment 7]

{6-[(3'-ethoxybiphenyl-4-ylmethyl)(pyridin-2-ylsulfonyl)aminomethyl]pyridin-2-ylamino}acetic acid

7-(a): (tertiary butoxycarbonyl {6-[(3'-ethoxybiphenyl-4-ylmethyl)(pyridin-2-ylsulfonyl)aminomethyl]pyridine- 3-benzyl}amino)acetic acid tert-butyl acrylate

In a solution of 183 mg (0.800 mmol) of tetrahydrofuran (4.0 mL) of 3'-ethoxybiphenyl-4-ylmethanol obtained in Reference Example 5, a solution obtained in the same manner as in Reference Example 1-(f) was added. Oxycarbonyl {6-[(pyridin-2-ylsulfonyl)aminomethyl]pyridin-2-yl}amino)acetic acid tert-butyl 422 mg (0.880 mmol), tri-n-butylphosphine 395 μL (1.60 Methyl) 276 mg (1.60 mmol) of N,N,N',N'-tetramethylazolylamine was stirred at room temperature for 3 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous The residue was subjected to hydrazine gel column chromatography (dissolved solvent; toluene: ethyl acetate = 8:1 → 6:1 (V/V)), and the fractions containing the target substance were concentrated under reduced pressure to give a white foam. The title compound was 537 mg. (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

(Tri-tert-butoxycarbonyl {6-[(3'-ethoxybiphenyl-4-ylmethyl)(pyridin-2-ylsulfonyl))carbamate obtained in Example 7-(a) Benzyl-2-pyridin-2-yl}amino)acetic acid tert-butyl 525 mg (0.762 mmol) of 1,4-di To a solution of 4.0 mL of alkane, 3.2 mL (19.2 mmol) of 6 mol/L hydrochloric acid and 0.8 mL of water were added, and the mixture was stirred under heating at 70 ° C for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and then water was added, and the mixture was adjusted to pH 4.4 with a 1 mol/L aqueous sodium hydroxide solution, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous The residue was subjected to hydrazine gel column chromatography (dissolved solvent; dichloromethane: methanol = 15:1 → 10:1 (V/V)), and the fraction containing the target substance was concentrated under reduced pressure to give a white foam. The title compound was 369 mg. (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).

[Embodiment 8]

{6-[(3'-ethoxybiphenyl-4-ylmethyl)(pyridin-2-ylsulfonyl)aminomethyl]pyridin-2-ylamino}hexyl acetate

In a solution of 171 mg (0.750 mmol) of tetrahydrofuran in 4 mL of 3'-ethoxybiphenyl-4-ylmethanol obtained in Reference Example 5, the 6-[(pyridin-2-ylsulfonyl) group obtained in Reference Example 6 was added. Aminomethyl]pyridin-2-ylamino}hexyl acetate 305 mg (0.750 mmol), tri-n-butylphosphine 280 μL (1.14 mmol) and N,N,N',N'-tetramethylazo Methionamine 196 mg (1.14 mmol) was stirred at room temperature for 16 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous The residue was subjected to hydrazine gel column chromatography (dissolved solvent; n-hexane: ethyl acetate = 3:2 → 2:3 (V/V)), and the fractions containing the target were concentrated under reduced pressure to give a colorless oil. The title compound was 429 mg. (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).

[Embodiment 9]

{6-[(3'-ethoxybiphenyl-4-ylmethyl)(pyridin-3-ylsulfonyl)aminomethyl] Pyridin-2-ylamino}acetic acid

9-(a): (tertiary butoxycarbonyl {6-[(3'-ethoxybiphenyl-4-ylmethyl)(pyridin-3-ylsulfonyl)aminomethyl]pyridine- 3-benzyl}amino)acetic acid tert-butyl acrylate

In a solution of 183 mg (0.800 mmol) of tetrahydrofuran in 4 mL of 3'-ethoxybiphenyl-4-ylmethanol obtained in Reference Example 5, a solution obtained in the same manner as in Reference Example 2-(a) was added. Oxycarbonyl {6-[(pyridin-3-ylsulfonyl)aminomethyl]pyridin-2-yl}amino)acetic acid tert-butyl 422 mg (0.880 mmol), tri-n-butylphosphine 395 μL (1.60 Methyl) 276 mg (1.60 mmol) of N,N,N',N'-tetramethylazolylamine was stirred at room temperature for 3 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous The residue was subjected to hydrazine gel column chromatography (dissolved solvent; n-hexane: ethyl acetate = 7:3 → 1:1 (V/V)), and the fraction containing the target substance was concentrated under reduced pressure to give a white foam. The title compound was 550 mg. (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

(Tri-tert-butoxycarbonyl {6-[(3'-ethoxybiphenyl-4-ylmethyl)(pyridin-3-ylsulfonyl))carbamate obtained in Example 9-(a) Benzyl-2-pyridin-2-yl}amino)acetic acid tert-butyl 540 mg (0.784 mmol) of 1,4-di To a solution of 4.0 mL of alkane, 3.3 mL (20 mmol) of 6 mol/L hydrochloric acid and 1.0 mL of water were added, and the mixture was stirred under heating at 70 ° C for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and then water was added, and the mixture was adjusted to pH 4.4 with a 1 mol/L aqueous sodium hydroxide solution, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous The residue was subjected to hydrazine gel column chromatography (dissolved solvent; dichloromethane: methanol = 15:1 → 10:1 (V/V)), and the fractions containing the target were 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 filtered. (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).

[Embodiment 10]

{6-[(phenylsulfonyl)(3'-ethoxybiphenyl-4-ylmethyl)aminomethyl]pyridin-2-ylamino}acetic acid

10-(a)({6-[(phenylsulfonyl)(3'-ethoxybiphenyl-4-ylmethyl)aminomethyl]pyridin-2-yl}tertiary butoxycarbonylamine Tertiary butyl acetate

(Tertiary butoxycarbonyl {6-[(3'-ethoxybiphenyl-4-ylmethyl)aminomethyl]pyridin-2-yl}amino group obtained in Reference Example 7-(b) A solution of 350 mg (0.639 mmol) of tributyl acetate in 1.8 mL of dichloromethane, 178 μL (1.28 mmol) of triethylamine and 98 μL (0.77 mmol) of phenylsulfonium chloride were added under ice cooling, and stirred at room temperature. hour. After completion of the reaction, the reaction solution was subjected to hydrazine gel column chromatography (dissolved solvent; n-hexane: ethyl acetate = 4:1 → 7:3 (V/V)), and the fractions containing the target substance were concentrated under reduced pressure. The title compound was 392 mg of 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-[(phenylsulfonyl)(3'-ethoxybiphenyl-4-ylmethyl)aminomethyl]pyridin-2-ylamino}acetic acid

({6-[(Benzenesulfonyl)(3'-ethoxybiphenyl-4-ylmethyl)aminomethyl]pyridin-2-yl}) obtained in Example 10-(a) To a solution of 389 mg (0.566 mmol) of butyloxycarbonylamino)acetic acid tert-butyl acetate in 5.8 mL of dichloromethane, 5.8 mL (76 mmol) of trifluoroacetic acid was added at room temperature, and allowed to stand for 3.5 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and water was added, and the mixture was adjusted to pH 4.4 with a saturated aqueous sodium hydrogen carbonate solution and 1 mol/L hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous To the concentrate, 3.9 mL of diisopropyl ether was added, and the precipitated solid was filtered and dried under reduced pressure to yield 293 mg of the title compound. (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) (tertiary butoxycarbonyl {6-[(3'-ethoxybiphenyl-4-ylmethyl)(thiophen-2-ylsulfonyl)aminomethyl]pyridine-2 -amino}amino) Butyl tertiary butyl ester

(Tertiary butoxycarbonyl {6-[(3'-ethoxybiphenyl-4-ylmethyl)aminomethyl]pyridin-2-yl}amino group obtained in Reference Example 7-(b) To a solution of 350 mg (0.639 mmol) of tributyl acetate in 1.8 mL of dichloromethane, 178 μL (1.28 mmol) of triethylamine and 141 mg (0.772 mmol) of 2-thiophenesulfonium chloride were added to the mixture under ice cooling. 0.3 mL of the solution was stirred at room temperature for 1.5 hours. After the completion of the reaction, the reaction solution was subjected to a gel column chromatography (dissolved solvent; n-hexane: ethyl acetate = 9:1 → 3:2 (V/V)), and the fractions containing the target were concentrated under reduced pressure. The title compound 376 mg was obtained as 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

(Tertiary butoxycarbonyl {6-[(3'-ethoxybiphenyl-4-ylmethyl)(thiophen-2-ylsulfonyl))carbamate obtained in Example 11-(a) a solution of 374 mg (0.538 mmol) of methylene chloride of pyridin-2-yl}amino)acetic acid in 5.6 mL of dichloromethane, 5.6 mL (73 mmol) of trifluoroacetic acid was added at room temperature, and stood still 3.5 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and water was added, and the mixture was adjusted to pH 4.4 with a saturated aqueous sodium hydrogen carbonate solution and 1 mol/L hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous 3.7 mL of a ternary butyl methyl ether was added to the concentrate, and the precipitated solid was filtered and dried under reduced pressure to give 272mg of the title compound. (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).

[Embodiment 12]

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

12-(a): [tertiary butoxycarbonyl (6-{[4-(6-ethoxypyridin-2-yl)benzyl](pyridin-2-ylsulfonyl)aminomethyl} Pyridin-2-yl)amino]acetic acid tert-butyl acrylate

In a solution of 267 mg (1.16 mmol) of 4-(6-ethoxypyridin-2-yl)phenylmethanol obtained in Reference Example 8 in tetrahydrofuran (11 mL), Example 1-(f) obtained by the same method (tertiary butoxycarbonyl {6-[(pyridin-2-ylsulfonyl)aminomethyl]pyridin-2-yl}amino)acetic acid tert-butyl The ester was 560 mg (1.17 mmol), 724 μL (2.90 mmol) of tri-n-butylphosphine, and 300 mg (1.74 mmol) of N,N,N',N'-tetramethylazolylamine, and stirred at room temperature for 1.5 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous The residue was subjected to hydrazine gel column chromatography (eluent solvent; n-hexane: ethyl acetate = 3:1 (V/V)), and the fractions containing the target substance were concentrated under reduced pressure to give white powder of the title compound 606 mg. Shape. (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

[Tri-tert-butoxycarbonyl (6-{[4-(6-ethoxypyridin-2-yl)benzyl](pyridin-2-ylsulfonyl)amine obtained in Example 12-(a) Benzylmethyl}pyridin-2-yl)amino]acetic acid tert-butyl 590mg (0.855mmol) dissolved in dichloromethane 8.6mL 8.6 mL (112 mmol) of trifluoroacetic acid was added to the solution 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, and then water was added, and the mixture was adjusted to pH 4.5 with a 2 mol/L aqueous sodium hydroxide solution and diluted hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc. (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

Illustrator 9-(b) obtained {6-[(thiophen-2-ylsulfonyl)aminomethyl]pyridin-2-ylamino} ethyl acetate 533 mg (1.50 mmol) in tetrahydrofuran 8.0 mL solution 3'-(1-propynyl)biphenyl-4-ylmethanol 333 mg (1.50 mmol), tri-n-butylphosphine 740 μL (3.00 mmol) and N, N obtained in the same manner as in Reference Example 13 N, N'-tetramethylazolylamine 517 mg (3.00 mmol) was stirred at room temperature for 7 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous Residue The residue containing the target substance was concentrated under reduced pressure by a gel column chromatography (solvent solvent; n-hexane: ethyl acetate = 1:0 to 1:1 (V/V)) to give a colorless oil. The title compound was 806 mg. (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).

[Embodiment 14]

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

(6-{[3'-(1-propynyl)biphenyl-4-ylmethyl](thiophen-2-ylsulfonyl)aminomethyl}pyridin-2-yl obtained in Example 13 To a solution of 800 mg (1.43 mmol) of ethyl acetate in 6.0 ml of ethanol, 6.0 mL (6.0 mmol) of a 1 mol/L aqueous sodium hydroxide 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, and the mixture was adjusted to pH 4.5 with 1 mol/L hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous The concentrate was dissolved in 10 mL of ethyl acetate, and 10 mL of n-hexane was added thereto at 50 ° C, and the mixture was stirred to room temperature over 1.5 hours. The precipitated solid was filtered and dried under reduced pressure toield, m. (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 acetate of {6-[(phenylsulfonyl)aminomethyl]pyridin-2-ylamino} obtained in Reference Example 10-(b), 8.0 mL of THF 3'-(1-propynyl)biphenyl-4-ylmethanol 333 mg (1.50 mmol), tri-n-butylphosphine 740 μL (3.00 mmol) and N,N,N', obtained in the same manner as in Reference Example 13. N'-tetramethylazolylamine 517 mg (3.00 mmol) was stirred at room temperature for 2 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous The residue was subjected to hydrazine gel column chromatography (dissolved solvent; n-hexane: ethyl acetate = 3:1 → 1:1 (V/V)), and the fractions containing the target substance were concentrated under reduced pressure to give a colorless oil. The title compound was 809 mg. (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-{(phenylsulfonyl)[3'-(1-propynyl)biphenyl-4-ylmethyl]aminomethyl}pyridin-2-ylamino)acetic acid

(6-{(Benzenesulfonyl)[3'-(1-propynyl)biphenyl-4-ylmethyl]aminomethyl}pyridin-2-ylamino)acetic acid obtained in Example 15 To a solution of 804 mg (1.45 mmol) of ethyl acetate in 6.0 mL of ethanol, 6.0 mL (6.0 mmol) of a 1 mol/L aqueous sodium hydroxide 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, and the mixture was adjusted to pH 4.5 with 1 mol/L hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous The concentrate was dissolved in 10 mL of ethyl acetate, and 10 mL of n-hexane was added thereto at 50 ° C, and the mixture was stirred to room temperature over 2 hours. The precipitated solid was filtered and dried under reduced pressure toieldieldiel (yield 95%)

Mass Spectrum (ESI ⁺ , m/z): 564 (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

Ethyl acetate {6-[(thiophen-3-ylsulfonyl)aminomethyl]pyridin-2-ylamino} ethyl acetate 284 mg (0.800 mmol) in tetrahydrofuran 4.0 mL solution obtained in Reference Example 11-(b) In the same manner as in Reference Example 13, 3'-(1-propynyl)biphenyl-4-ylmethanol 178 mg (0.800 mmol), tri-n-butylphosphine 395 μL (1.60 mmol) and N, N were added. 276 mg (1.60 mmol) of N',N'-tetramethylazolylamine was stirred at room temperature for 3 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous The residue was subjected to hydrazine gel column chromatography (dissolved solvent; n-hexane: ethyl acetate = 4:1 → 1:1 (V/V)), and the fractions containing the target substance were concentrated under reduced pressure to give a colorless mixture. The title compound was 432 mg. (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).

[Embodiment 18]

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

(6-{[3'-(1-propynyl)biphenyl-4-ylmethyl](thiophen-3-ylsulfonyl)aminomethyl}pyridin-2-yl obtained in Example 17 To a solution of 426 mg (0.762 mmol) of ethyl acetate in 3.5 mL of ethanol, 3.5 mL (3.5 mmol) of a 1 mol/L aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was adjusted to pH 4.4 with 1 mol/L hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous 5 mL of ethyl acetate and 5 mL of n-hexane were added to the concentrate and heated to 50 ° C, followed by stirring to room temperature over 2 hours. The precipitated solid was filtered and dried under reduced pressure to yield 390 mg of Compound (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).

[Embodiment 19]

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

19-(a) [tertiary butoxycarbonyl (6-{(3-fluorophenylsulfonyl)[3'-(1-propynyl)biphenyl-4-ylmethyl]aminomethyl} Pyridin-2-yl)amino]acetic acid tert-butyl acrylate

[Tertiary butoxycarbonyl (6-{[3'-(1-propynyl)biphenyl-4-ylmethyl]aminomethyl}pyridine-2- obtained in Reference Example 12-(c) Amino]acetic acid To a solution of 542 mg (1.00 mmol) of butyl ester in 3.5 mL of dichloromethane, 280 μL (2.01 mmol) of triethylamine and 150 μL (1.13 mmol) of 3-fluorobenzenesulfonyl chloride were added under ice cooling, and stirred at room temperature for 2 hours. . After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous The residue was subjected to hydrazine gel column chromatography (solvent solvent; n-hexane: ethyl acetate = 9:1 to 7:3 (V/V)), and the fractions containing the target substance were concentrated under reduced pressure to give the title compound. 673 mg of 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-Fluorophenylsulfonyl)[3'-(1-propynyl)biphenyl-4-ylmethyl]aminomethyl}pyridin-2-ylamino Acetic acid

[Tertiary butoxycarbonyl (6-{(3-fluorophenylsulfonyl)[3'-(1-propynyl)biphenyl-4-ylmethyl] obtained in Example 19-(a) Add a solution of 595 mg (0.850 mmol) of aminomethyl}pyridin-2-yl)amino]acetic acid tert-butyl acetate to a solution of 595 mg (0.850 mmol) in tetrahydrofuran (5.0 mL), add 4 mL/L hydrochloric acid 5.0 mL (20 mmol), and stir at 70 ° C for 5 hours. . After completion of the reaction, the mixture was adjusted to pH 4.5 with a 1 mol/L aqueous sodium hydroxide solution, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous Ethyl acetate 10 mL and n-hexane 5 mL were added to the concentrate and heated to 50 ° C, and then stirred for 2 hours to room temperature. The precipitated solid is filtered and dried under reduced pressure, and The title compound was obtained as a white solid 429 mg. (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)acetic acid isopropyl ester

In a solution of 1.06 g (2.88 mmol) of tetrahydrofuran in 15.0 mL of isopropyl p-{6-[(pyridin-2-ylsulfonyl)aminomethyl]pyridin-2-ylamino}acetate obtained in Reference Example 14 3'-(1-propynyl)biphenyl-4-ylmethanol 640 mg (2.88 mmol), tri-n-butylphosphine 1.42 mL (5.76 mmol), and N,N, obtained in the same manner as in Reference Example 13. 992 mg (5.76 mmol) of N',N'-tetramethylazolylamine was stirred at room temperature for 3 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous The residue was subjected to hydrazine gel column chromatography (dissolved solvent; n-hexane: ethyl acetate = 3:2 → 2:3 (V/V)), and the fractions containing the target substance were concentrated under reduced pressure to give a colorless mixture. The title compound was 1.59 g. (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 compound used in the examples was synthesized in the following manner.

[Reference Example 1]

{6-[(pyridin-2-ylsulfonyl)aminomethyl]pyridin-2-ylamino}ethyl acetate

1-(a): [tertiary butyloxycarbonyl (6-ethoxycarbonylpyridin-2-yl)amino]acetic acid tert-butyl acrylate

Ethyl 6-tertiary butoxycarbonylaminopyridine-2-carboxylate (refer to International Publication No. 2006/074884) 81.2 g (0.305 mol) of N,N-dimethylformamide 300 mL solution In an argon atmosphere, it was added to a solution of 15.7 g (0.360 mol) of N,N-dimethylformamide in 362 mL of sodium hydride (mineral oil 55 wt% dispersion) under ice cooling for 20 minutes, and stirred at room temperature. hour. Then, 54.0 mL (0.366 mol) of butyl bromoacetate was added dropwise under ice cooling for 10 minutes, and further stirred at room temperature for 1 hour. After completion of the reaction, an aqueous solution in which 1.77 g (33.0 mmol) of ammonium chloride was dissolved in 300 mL of water was added to the reaction solution, followed by extraction with toluene. The organic layer was washed with a saturated aqueous The residue was subjected to a gel column chromatography (dissolved solvent; n-hexane: ethyl acetate = 9:1 → 4:1 (V/V)), and the fractions containing the target were concentrated under reduced pressure to give a pale yellow. The title compound 108g was obtained as a coloured 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): [tertiary butyloxycarbonyl (6-hydroxymethylpyridin-2-yl)amino]acetic acid tert-butyl acrylate

A solution of 34.6 g (0.312 mol) of calcium chloride in 195 mL of ethanol was added dropwise to the [tertiary butoxycarbonyl group (6-ethoxycarbonylpyridine-2) obtained in Reference Example 1-(a) under ice cooling for 20 minutes. A solution of 98.8 g (0.260 mol) of ethanol in a 195 mL solution of 3-aminobutyl acetate. After the 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 for 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 under ice cooling for 10 minutes, and stirred at room temperature for 1 hour. Then, 315 mL of water was added, and the mixture was extracted with toluene. The organic layer was washed successively with a saturated aqueous The residue was subjected to hydrazine gel column chromatography (dissolved solvent; n-hexane: ethyl acetate = 4:1 → 3:2 (V/V)), and the fractions containing the target substance were concentrated under reduced pressure to give a pale yellow color. The title compound of the oil was 81.1 g. (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): [tertiary butyloxycarbonyl (6-methylpyridin-2-yl)amino]acetic acid tert-butyl acrylate

A solution of 10.0 g (29.6 mmol) of [tertiary butyloxycarbonyl (6-hydroxymethylpyridin-2-yl)amino]acetic acid tert-butyl ester obtained in Example 1-(b) in 50 mL of dichloromethane was obtained. In an argon atmosphere, it was added to a solution of 12.9 g (30.4 mmol) of dichloromethane in 130 mL of Dess Martin reagent under ice cooling for 20 minutes. After the completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. After completion of the reaction, 305 mL of a 0.1% by weight aqueous sodium thiosulfate solution was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with aq. aq.

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): [tertiary butyloxycarbonyl (6-hydroxyiminomethylpyridin-2-yl)amino]acetic acid tert-butyl acrylate

In a solution of 2.88 g (8.56 mmol) of methanol as a tertiary butyl 3-butoxycarbonyl (6-methylpyridylpyridin-2-yl)amino]acetate obtained in Reference Example 1-(c), a solution of 29 mL was added. Hydroxylamine hydrochloride 0.650 g (9.35 mmol) and pyridine 3.5 mL (43 mmol) were stirred at room temperature for 1 hour. After the reaction is over, the reaction solution is Concentrate under reduced pressure. Ethyl acetate was added to the obtained residue, and the mixture was washed with EtOAc EtOAc EtOAc EtOAc. The residue was subjected to hydrazine gel column chromatography (solvent solvent; n-hexane: ethyl acetate = 3:2 (V/V)), and the fractions containing the target substance were concentrated under reduced pressure to give the title of colorless oil. Compound 2.76 g. (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)tris-butoxycarbonylamino]acetic acid tert-butyl acrylate

A solution of 2.75 g (7.83 mmol) of ethanol as a tertiary ester of [tertiary butoxycarbonyl (6-hydroxyiminomethylpyridin-2-yl)amino]acetic acid, obtained in Reference Example 1-(d), 49 mL Into, 108% by weight of palladium-activated carbon (50% by weight aqueous) of 0.98 g was added, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere of 1 atm. After the reaction was completed, the title compound was obtained. (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): (tertiary butyloxycarbonyl {6-[(pyridin-2-ylsulfonyl)aminomethyl]pyridin-2-yl}amino)acetic acid tert-butyl acrylate

In a solution of 0.64 g (3.60 mmol) of 2-pyridylsulfonyl chloride in 14 mL of dichloromethane, the [(6-aminomethylpyridin-2-yl)trioxane obtained in Reference Example 1-(e) was added. A solution of 1.20 g (3.56 mmol) of benzylamino]acetic acid tert-butyl acetate and 2.24 mL (16.2 mmol) of triethylamine in dichloromethane was stirred at room temperature for 0.5 hr. After completion of the reaction, a 5 wt% aqueous potassium hydrogensulfate solution was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen sulfate and saturated aqueous The residue was subjected to hydrazine gel column chromatography (eluent solvent: n-hexane: ethyl acetate = 1:1 (V/V)). g. (yield 86%)

Mass Spectrum (APCI, m/z): 495 (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

(Tri-tert-butoxycarbonyl {6-[(pyridin-2-ylsulfonyl)aminomethyl]pyridin-2-yl}amino) obtained in the same manner as in Reference Example 1-(f) To 3.59 g (7.50 mmol) of tributyl acetate, 37.5 mL (75.0 mmol) of a 2 mol/L hydrogen chloride/ethanol solution was added, and the mixture was stirred under heating and reflux for 3 hours. After the reaction is completed, water is added to the reaction solution to a 1 mol/L aqueous sodium hydroxide solution. After neutralization, it was extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc. (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): (tertiary butyloxycarbonyl {6-[(pyridin-3-ylsulfonyl)aminomethyl]pyridin-2-yl}amino)acetic acid tert-butyl acrylate

1.20 g (3.56 mmol) of [(6-aminomethylpyridin-2-yl)tris-butoxycarbonylamino]acetic acid tert-butyl acetate obtained in the same manner as in Reference Example 1-(e). The title compound 1.45 was obtained as a colorless oil, m. m. m. g. (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

A (tertiary butoxycarbonyl {6-[(pyridin-3-ylsulfonyl)aminomethyl]pyridin-2-yl}amino group obtained by the same method as in Reference Example 2-(a) was used. 1.00 g (2.09 mmol) of tertiary butyl acetate was replaced by (tertiary butoxycarbonyl {6-[(pyridin-2-ylsulfonyl)aminomethyl]pyridin-2-yl}amino)acetic acid The title compound 686 mg of the title compound was obtained 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-ylformaldehyde

To 500 mg (1.91 mmol) of 3'-bromobiphenyl-4-ylformaldehyde (refer to Journal of Organic Chemistry, 68, 247 (2003)), 27.5 mL of toluene and 1.65 mL of water were added, followed by the addition of 1.35 g of tripotassium phosphate (7.68 mmol). ) After 656 mg (7.64 mmol) of 1-propenylboronic acid, it was set to the nitrogen atmosphere. 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 under a nitrogen atmosphere. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous The residue was subjected to hydrazine gel column chromatography (dissolving solvent; n-hexane: ethyl acetate = 4:1 (V/V)), and the fractions containing the target substance were concentrated under reduced pressure to give a yellowish oil. The title compound was 420 mg. (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) , 1.5Hz, 3H).

3-(b): 3'-(1-propenyl)biphenyl-4-ylmethanol

In a 4.6 mL solution of 3'-(1-propenyl)biphenyl-4-ylformaldehyde 417 mg (1.88 mmol) obtained in Reference Example 3-(a), sodium borohydride 35.6 mg (0.941) was added at room temperature. Mmmol), stirred at the same temperature for 45 minutes. After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous The residue was subjected to hydrazine gel column chromatography (solvent solvent: n-hexane: ethyl acetate = 7:3 (V/V)). . (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-ylformaldehyde

A 10 mL solution of 3'-bromobiphenyl-4-ylcarboxaldehyde 1.04 g (3.98 mmol) in toluene was deaerated under reduced pressure and then replaced with argon gas. Then, 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 under an argon atmosphere. After completion of the reaction, 60 mL of a 0.8 mol/L potassium fluoride aqueous solution was added to the reaction solution, followed by extraction with toluene. The organic layer was washed with a saturated aqueous The residue was subjected to hydrazine gel column chromatography (dissolved solvent; n-hexane: ethyl acetate = 1:0 → 4:1 (V/V)), and the fractions containing the target substance were concentrated under reduced pressure to give a pale yellow color. The title compound of the solid was 660 mg. (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

In place of 3'-(1-propenyl)biphenyl, 3'-(1-propynyl)biphenyl-4-ylformaldehyde 723 mg (3.28 mmol) obtained by the same method as Reference Example 4-(a) was used. 4-ylformaldehyde, and using sodium borohydride 62.2 mg (1.64 mmol), The title compound (588 mg) was obtained as a 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]

3'-ethoxybiphenyl-4-ylmethanol

To 1.21 g (6.02 mmol) of 3-bromoethoxybenzene, 15 mL of toluene, 15 mL of ethanol, and 4.5 ml (9.0 mmol) of a 2 mol/L sodium carbonate aqueous solution were added, and the mixture was degassed under reduced pressure, and then replaced with argon gas. Then, 1.37 g (9.02 mmol) of 4-(hydroxymethyl)phenylboronic acid and 347 mg (0.300 mmol) of tetrakistriphenylphosphine palladium were added, and the mixture was stirred at 100 ° C for 4 hours under an argon atmosphere. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and water was evaporated. The organic layer was washed with a saturated aqueous The residue was subjected to a gel column chromatography (dissolved solvent; n-hexane: ethyl acetate = 9:1 → 7:3 (V/V)), and the fractions containing the target were concentrated under reduced pressure to give a pale yellow. The title compound of the oil was 1.23 g. (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

(Tri-tert-butoxycarbonyl {6-[(pyridin-2-ylsulfonyl)aminomethyl]pyridin-2-yl}amino) obtained in the same manner as in Reference Example 1-(f) To a solution of 957 mg (2.00 mmol) of n-butyl acetate in 6.0 mL of n-hexanol, 0.56 mL (10 mmol) of concentrated sulfuric acid was added, and the mixture was stirred at 100 ° C for 8 hours. After completion of the reaction, the reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous The residue was subjected to hydrazine gel column chromatography (dissolved solvent; n-hexane: ethyl acetate = 1:1 → 3:7 (V/V)), and the fractions containing the target substance were concentrated under reduced pressure to give a yellowish color. The title compound of the oil was 658 mg. (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]

(Tri-tert-butyloxycarbonyl {6-[(3'-ethoxybiphenyl-4-ylmethyl)aminomethyl]pyridin-2-yl}amino)acetic acid tert-butyl acrylate

7-(a): 3'-ethoxybiphenyl-4-ylformaldehyde

In addition to using 4-bromobenzaldehyde 4.20 g (22.7 mmol) instead of 3-bromoethoxy Benzene, using 3.13 g (18.9 mmol) of 3-ethoxyphenylboronic acid instead of 4-(hydroxymethyl)phenylboronic acid, using 2 mol/L sodium carbonate aqueous solution 28.4 ml (56.8 mmol) and tetrakistriphenylphosphine palladium 2.18 g (1.89 mmol), the title compound was obtained 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): (tertiary butoxycarbonyl {6-[(3'-ethoxybiphenyl-4-ylmethyl)aminomethyl]pyridin-2-yl}amino)acetic acid tertiary Butyl ester

[(6-Aminomethylpyridin-2-yl)tris-butoxycarbonylamino]acetic acid tert-butyl acrylate 4.02 g (11.9 mmol) obtained in the same manner as in Reference Example 1-(e) To a solution of 12 mL of dichloromethane, 2.46 g (10.9 mmol) of 3'-ethoxybiphenyl-4-ylaldehyde obtained in Reference Example 7-(a) was added, and stirred at room temperature for 30 minutes. Then, 3.25 g (15.3 mmol) of sodium triethoxysulfonate hydride 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 hydrogencarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous The residue was subjected to hydrazine gel column chromatography (dissolved solvent; n-hexane: ethyl acetate = 3:2 → 0:1 (V/V)), and the fractions containing the target substance were concentrated under reduced pressure to give a pale yellow color. The title compound of the oil was 3.68 g. (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]

4-(6-ethoxypyridin-2-yl)phenylmethanol

In place of 2-bromo-6-ethoxypyridine (refer to US 2003/199440) 0.49 g (2.4 mmol) in place of 3-bromoethoxybenzene, and using 4-(hydroxymethyl)phenylboronic acid 0.59 g ( 3.9 mmol), 1.7 ml (3.4 mmol) of a 2 mol/L aqueous sodium carbonate solution, and 138 mg (0.119 mmol) of tetratriphenylphosphine palladium were reacted in the same manner as in Reference Example 5 to give 284 mg of the title compound. (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-[(Thien-2-ylsulfonyl)aminomethyl]pyridin-2-ylamino}ethyl acetate

9-(a): (tertiary butyloxycarbonyl {6-[(thiophen-2-ylsulfonyl)aminomethyl]pyridin-2-yl}amino)acetic acid tert-butyl acrylate

1.35 g (4.00 mmol) of [(6-aminomethylpyridin-2-yl)tris-butoxycarbonylamino]acetic acid tert-butyl acrylate obtained by the same method as in Reference Example 1-(e). The reaction was carried out in the same manner as in the title compound (1). (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): {6-[(thiophen-2-ylsulfonyl)aminomethyl]pyridin-2-ylamino} ethyl acetate

Tertiary butyl ester of (tertiary butoxycarbonyl {6-[(thiophen-2-ylsulfonyl)aminomethyl]pyridin-2-yl}amino)acetic acid obtained in Reference Example 9-(a) To 1.60 g (3.31 mmol), 20 mL (40 mmol) of a 2 mol/L hydrogen chloride/ethanol solution was added, and the mixture was stirred under heating under reflux for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The organic layer was washed with a saturated aqueous The residue was subjected to hydrazine gel column chromatography (dissolved solvent; n-hexane: ethyl acetate = 7:3 → 1:1 (V/V)), and the fractions containing the target substance were concentrated under reduced pressure to give a colorless oil. The title compound 1.10 g. (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-[(phenylsulfonyl)aminomethyl]pyridin-2-ylamino} ethyl acetate

10-(a): (6-[(phenylsulfonyl)aminomethyl]pyridin-2-yl}tertiary butoxycarbonylamino)acetic acid tert-butyl acrylate

1.35 g (4.00 mmol) of [(6-aminomethylpyridin-2-yl)tris-butoxycarbonylamino]acetic acid tert-butyl acrylate obtained by the same method as in Reference Example 1-(e). The reaction product and the post-treatment were carried out to give the title compound 1.71 g of the title compound (yield). (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-[(phenylsulfonyl)aminomethyl]pyridin-2-ylamino} ethyl acetate

In addition to the use of ({6-[(phenylsulfonyl)aminomethyl]pyridin-2-yl}tertiarybutoxycarbonyl) acetic acid tert-butyl acetate 1.70 g (Reference Example 10-(a)) 3.56 mmol) instead of (tertiary butyloxycarbonyl {6-[(thiophen-2-ylsulfonyl)aminomethyl]pyridin-2-yl}amino)acetic acid tert-butyl butyl ester, and using 2 mol/L The title compound (1.13 g) was obtained as white crystals. (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-[(Thien-3-ylsulfonyl)aminomethyl]pyridin-2-ylamino}ethyl acetate

11-(a): (tertiary butyloxycarbonyl {6-[(thiophen-3-ylsulfonyl)aminomethyl]pyridin-2-yl}amino)acetic acid tert-butyl acrylate

1.35 g (4.00 mmol) of [(6-aminomethylpyridin-2-yl)tris-butoxycarbonylamino]acetic acid tert-butyl acrylate obtained by the same method as in Reference Example 1-(e). The reaction was carried out in the same manner as in the title compound (1). (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

In addition to the use of Reference Example 11-(a), (tertiary butoxycarbonyl {6-[(thiophen-3-ylsulfonyl)aminomethyl]pyridin-2-yl}amino)acetic acid tert-butyl 1.63 g (3.37 mmol) of ester instead of (tertiary butyloxycarbonyl {6-[(thiophen-2-ylsulfonyl)aminomethyl]pyridin-2-yl}amino)acetic acid tert-butyl acrylate, and The reaction and post treatment were carried out in accordance with Reference Example 9-(b), except that 17.5 mL (35.0 mmol) of a 2 mol/L hydrogen chloride/ethanol solution was used. The residue was subjected to hydrazine gel column chromatography (solvent solvent; n-hexane: ethyl acetate = 7:3 to 1:1 (V/V)), and the fractions containing the target substance were concentrated under reduced pressure. The obtained crude product was recrystallized from ethyl acetate (5 mL) toield (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]

[Tri-tert-butoxycarbonyl (6-{[3'-(1-propynyl)biphenyl-4-ylmethyl]aminomethyl}pyridin-2-yl)amino]acetic acid tert-butyl acrylate

12-(a): 1-bromo-3-(1-propynyl)benzene

To a solution of 7.07 g (25.0 mmol) of 1-bromo-3-iodobenzene in 50 mL of toluene, 1.43 g (7.51 mmol) of copper iodide (I) and 1.45 g (1.25 mmol) of tetrakistriphenylphosphine palladium were added. After degassing, it was replaced with argon. Then, 2.81 g (25.0 mmol) of 1-trimethyldecyl-1-propyne, 11.5 ml (82.5 mmol) of triethylamine, and 15.0 mL of a tetrafluoroammonium fluoride/tetrahydrofuran solution of 1 mol/L were added (25.0 mmol). The mixture was stirred at room temperature for 17 hours under an argon atmosphere. After completion of the reaction, water and tertiary butyl methyl ether were added to the reaction solution, and filtered by Celite (trade name) to filter insoluble matter. The organic layer after separation was dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to hydrazine gel column chromatography (eluent solvent: n-hexane). (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-ylformaldehyde

4-methyl hydrazine was used in place of 3-bromoethoxybenzene except that 1-bromo-3-(1-propynyl)benzene obtained in the same manner as in Reference Example 12-(a) was used instead of 3-bromoethoxybenzene. 3.37 g (37.5 mmol) of phenylboronic acid in place of 4-(hydroxymethyl)phenylboronic acid, using 11.3 ml (22.6 mmol) of a 2 mol/L sodium carbonate aqueous solution and 867 mg (0.750 mmol) of tetrakistriphenylphosphine palladium. The reaction was carried out in the same manner as in Reference Example 5 to give the title compound 3.31 g. (quantitative)

NMR spectrum and reference examples of the compound obtained in Reference Example 12-(b) The NMR spectrum of the compound obtained in 4-(a) was the same.

12-(c): [tertiary butoxycarbonyl (6-{[3'-(1-propynyl)biphenyl-4-ylmethyl]aminomethyl}pyridin-2-yl)amino group Tributyl acetate

5.7 g (16.5 mmol) of [(6-aminomethylpyridin-2-yl)tris-butoxycarbonylamino]acetic acid tert-butyl acrylate obtained by the same method as Reference Example 1-(e). And using 3'-(1-propynyl)biphenyl-4-ylformaldehyde 3.30 g (15.0 mmol) obtained in Reference Example 12-(b) in place of 3'-ethoxybiphenyl-4-ylformaldehyde, The title compound (6.48 g, m. m. (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]

3'-(1-propynyl)biphenyl-4-ylmethanol

Except that 3-bromo-3-(1-propynyl)benzene 3.90 g (20.0 mmol) obtained in the same manner as in Reference Example 12-(a) was used instead of 3-bromoethoxybenzene, 4-(hydroxyl) was used. The reaction was carried out in accordance with Reference Example 5 except that 4.56 g (30.0 mmol) of methylphenylboronic acid, 15 ml (30 mmol) of a 2 mol/L sodium carbonate aqueous solution, and 1.16 g (1.00 mmol) of tetrakistriphenylphosphine palladium were used. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer is saturated with sodium chloride solution After washing, it was dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to hydrazine gel column chromatography (dissolving solvent; n-hexane: ethyl acetate = 4:1 to 1:1 (V/V)), and the fractions containing the target substance were concentrated under reduced pressure. The obtained crude product was stirred for 45 hours in 45 mL of a mixed solvent (ethyl acetate: n-hexane = 1:10 (V/V)), and the precipitated solid was filtered and dried under reduced pressure to give the title compound as a white solid. 3.85g. (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

Except that the same procedure as in Reference Example 1-(f) was used (tris-butoxycarbonyl {6-[(pyridin-2-ylsulfonyl)aminomethyl]pyridin-2-yl}amino group Substituting 1.44 g (3.01 mmol) of tertiary butyl acetate to replace (tertiary butoxycarbonyl {6-[(thiophen-2-ylsulfonyl)aminomethyl]pyridin-2-yl}amino)acetic acid Butyl ester, using 2 mol/L hydrogen chloride/isopropanol solution 16.0 mL (32.0 mmol) instead of 2 mol/L hydrogen chloride/ethanol solution, followed by the reaction and post-treatment according to Reference Example 9-(b) to obtain a white solid. The title compound was 1.05 g. (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]

Determination of EP2 receptor binding

The determination of EP2 receptor binding was carried out in accordance with the method of Abramovitz et al. (Biochimica et Biophysica Acta, 1483, 285 (2000)). Addition of 10 μg of buffer (10 mM MES-KOH (pH 6.0), 10 mM MgCl ₂ , 1 mM EDTA) to HEK293 cells expressing human EP2 receptor (ES-562-M, manufactured by Eurocscreen) 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) at 30 ° C Cultivate for 60 minutes. The membrane was collected and recovered into a glass fiber filter paper (GF/B, manufactured by Whatman) using a cell harvester (M30R, manufactured by Brandel Co., Ltd.) as a buffer (10 mM MES-KOH (pH 6.0), 10 mM MgCl). ₂ ) After washing, the radioactivity was measured with a liquid scintillation analyzer (2000CA, manufactured by Packard). The concentration (IC ₅₀ value) of the test compound required to replace 50% of the [ ³ H]prostaglandin E ₂ of the receptor was calculated using EXSAS (version 7.1.6, manufactured by ArmSystex Co., Ltd.), and the following The formula determines the inhibition constant (Ki value).

Ki=IC ₅₀ /(1+([ ³ H] prostaglandin E ₂ concentration/Kd))

Further, the dissociation constant (Kd value) is calculated by Scatchard analysis.

The test results are shown in Table 1.

In the present test, the compound represented by the formula (I) showed excellent EP2 receptor binding.

[Test Example 2]

Inhibition of LPS-induced TNF-α production using human peripheral blood mononuclear cells

The peripheral blood collected from a healthy person in the presence of heparin was diluted twice with PBS containing 2 (V/V)% FBS. Add blood cell separation medium ^{(Ficoll Paque TM PLUS, GE Healthcare} Bioscience Corporation) in SepMate ^TM -50 (STEMCELL Co., Ltd.), followed by the diluted blood overlap. The peripheral blood mononuclear cells (hereinafter abbreviated as PBMC) layer was collected by centrifugation at 1200 x g for 10 minutes at 20 °C. The obtained PBMC was further centrifuged and washed twice, and suspended in RPMI1640 medium containing 1 (V/V)% FBS, and the following test was used.

The inhibition of LPS-induced TNFα production assay was carried out by changing the method of Mary et al. (Journal of Pharmacology and Experimental Therapeutics, 284, 420 (1998)). 185 μL of a PBMC suspension prepared in such a manner that the final concentration became 5 × 10 ⁵ cells/mL was added to a 96-well culture plate, followed by RPMI1640 medium containing 1 (V/V)% DMSO in which the test compound was dissolved. 10 μL (the final concentration of DMSO was 0.05 (V/V)%) was added to each well. RPMI1640 medium containing 1 (V/V)% DMSO was similarly added to the wells to which the test compound was not added. After culturing for 1 hour in a carbon dioxide incubator, LPS (L2880-500MG, manufactured by SIGMA) prepared in RPMI1640 medium was added to each well to 5 μL (the final concentration of LPS was 100 ng/mL). In the well without LPS stimulation, 5 μL of RPMI1640 medium was added. After culturing for about 18 hours in a carbon dioxide incubator, the culture supernatant was recovered. The recovered culture supernatant was stored at -20 ° C before the TNF α content was measured.

The TNF α content was measured using a Sandwich ELISA kit (Quantikine DTA00c, manufactured by R&D Systems, Inc.). The TNFα content of each sample was calculated from the standard curve of human recombinant TNFα derived from Escherichia coli attached to the kit. The amount of TNF α production by LPS only when DMSO was added was taken as 100%, and the TNF α production inhibition rate of each concentration of the test compound was calculated. From the relationship between the concentration of the test compound to be added and the inhibition rate of TNFα production of the test compound, the concentration of the test compound which inhibited the production of TNFα by 50% was calculated as the IC ₅₀ value (nM).

The test results are shown in Table 2.

In the present test, the compound represented by the formula (I) showed an excellent effect of inhibiting the production of TNF?.

[Test Example 3]

Inhibition of LPS-induced TNF-α production using human peripheral blood mononuclear cells to confirm the combined effect

This test was carried out in accordance with the aforementioned [Test Example 2].

In order to evaluate the respective effects of the test compound and roflumilast, and the combined effect of the test compound and roflumilast, it was added in a 96-well culture plate to adjust the final concentration to 5 × 10 ⁵ cells/mL. 175 μL of a PBMC suspension, followed by RPMI1640 medium containing 1 (V/V)% DMSO in which roflumilast was dissolved, and 10 μL of each was added to each well. RPMI1640 medium containing 1 (V/V)% DMSO was similarly added to the well without the addition of roflumilast. After culturing for 30 minutes in a carbon dioxide incubator, RPMI1640 medium containing 1 (V/V)% DMSO in which the test compound was dissolved was added to each well by 10 μL (the final concentration of DMSO per well was set to 0.1 (V/V). )%). RPMI1640 medium containing 1 (V/V)% DMSO was similarly added to the wells to which the test compound was not added. After culturing for 30 minutes in a carbon dioxide incubator, LPS (L2880-500MG, manufactured by SIGMA) prepared in RPMI1640 medium was added to each well to 5 μL (the final concentration of LPS was 100 ng/mL). In the well without LPS stimulation, 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 recovered culture supernatant was stored at -20 ° C before the TNF α content was measured.

The TNF α content was measured using a Sandwich ELISA kit (Quantikine DTA00c, manufactured by R&D Systems, Inc.). The TNFα content of each sample was calculated from the standard curve of human recombinant TNFα derived from Escherichia coli attached to the kit. The amount of TNF α production by LPS only when DMSO was added was taken as 100%, and the inhibition ratio of TNF α production of each of the test compound and roflumilast was calculated. At the same time, the inhibition rate of TNFα production at each concentration in the combination of the test compound and roflumilast was calculated, and the effects of the test compound alone and the effect of the combination of roflumilast were compared.

The test results are shown in Tables 3 and 4.

In the test, the compound represented by the formula (I) is used in combination with roflumilast to increase the pharmacological effect of the compound represented by the formula (I) on the pharmacological effect of roflumilast, and exhibits superiority. Inhibits the action of TNFα production.

[Test Example 4]

Inhibition of pulmonary neutrophil infiltration in rats

SD rats with a hunger strike for about 16 hours (male, 7 to 8 weeks old, body weight 240 g to 270 g (average about 250 g), supplied by Charles River, Japan), intratracheal administration under inhalation anesthesia with isoflurane 25 μL (about 4 μg/Kg) of a physiological saline solution (concentration: 0.04 mg/mL) of LPS (L2880-500MG, manufactured by SIGMA) was added. MicroSprayerTM (IA-1C-M, manufactured by Penn Century ⁾ was used for intratracheal administration.

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

After 4 hours of LPS administration, bronchoalveolar lavage was performed as follows to recover white blood cells in the lungs. SD rats were anesthetized by intraperitoneal administration of somnopentyl (1 mL/kg), followed by exsanguination by incision of the great venous incision. The trachea was exposed, and a mouse connected to a disposable syringe (5 mL, manufactured by Terumo) was inserted with a feeding needle (manufactured by Fuchigami Instruments Co., Ltd.), and the trachea was ligated and fixed. 4 mL of a physiological saline solution containing BSA (final concentration: 1%) and heparin (final concentration: 1 U/mL) was injected, and immediately recovered to obtain a bronchopulmonary cell washing solution (hereinafter abbreviated as BALF). After centrifugation (420 x g, 10 minutes, 4 ° C) of BALF obtained by further repeating this operation twice, the supernatant was removed until the amount of liquid became 1.5 ml. The precipitated cells were suspended to obtain a BALF cell suspension. The measurement of the number of white blood cells and the number of neutrophils in the BALF cell suspension is carried out in accordance with the method of any of the following (Method 1) or (Method 2).

(method 1)

The number of white blood cells of the BALF cell suspension was measured using a multi-project automatic blood cell measuring device (KX-21, manufactured by Sysmex Corporation). Next, the white blood cell count was diluted to 10 ⁶ cells/mL, and 100 μL of the cell suspension was applied onto a glass slide to prepare a single-layer smear sample. Then, the cells were stained with a Diff-Quik staining kit (model number 16920, manufactured by Sysmex), and the number of neutrophils in 300 white blood cells was measured under an optical microscope (BH-2, manufactured by Olympus) to calculate white blood cells. The ratio of neutrophils in the NR (NR = number of neutrophils in 300 white blood cells / 300). The neutrophil infiltration inhibition rate in the administration of the test compound was calculated by the following formula.

Inhibition rate (%) = 100 - [(WBCc × NRc) / (WBCv × NRv)] × 100

WBCv: number of white blood cells in BALF cell suspension of control group

WBCc: the number of white blood cells in the BALF cell suspension of the test compound administered to the group

NRv: ratio of neutrophils in white blood cells of the control group

NRc: the ratio of neutrophils in the white blood cells of the test compound administered to the group

(Method 2)

The number of neutrophils in the BALF cell suspension was measured using a multi-item automatic blood cell measuring device (XT-2000iV, manufactured by Sysmex). The neutrophil infiltration inhibition rate in the administration of the test compound was calculated by the following formula.

Inhibition rate (%) = 100 - [(NEUTc) / (NEUTv)] × 100

NEUTv: number of neutrophils in the BALF cell suspension of the control group

NEUTc: the number of neutrophils in the BALF cell suspension of the test compound administered to the group

In the test, the compound represented by the formula (I) is used in combination with roflumilast to increase the pharmacological effect of the compound represented by the formula (I) on the pharmacological effect of roflumilast, and exhibits superiority. Inhibits the role of pulmonary neutrophil infiltration. For example, the compound of Example 4 alone and roflumilast alone had a lung neutrophil infiltration inhibition rate of 51% and 10%, respectively, but the compound of Example 4 showed 64% of the lung when used in combination with roflumilast. Neutrophil infiltration inhibition rate.

[Industry use possibility]

In the pharmaceutical composition of the present invention, the pharmacological effect of the compound represented by the formula (I) or a pharmacologically acceptable salt thereof is added to the pharmacological effects of other drugs, and the amount of other drugs can be reduced to reduce the amount of the drug. It is useful for the point of side effects of other medicines. The above pharmaceutical composition is a pharmaceutical composition for treating and/or preventing respiratory diseases, and is ideal for treating and/or preventing asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pulmonary fibrosis, acute respiration A pharmaceutical composition for stress syndrome, cystic fibrosis or pulmonary hypertension, preferably a medical composition for treating and/or preventing asthma, chronic obstructive pulmonary disease or pulmonary fibrosis, and as a warm-blooded animal It is useful with medicine (especially for human use).

Claims (12)

A pharmaceutical composition comprising a compound of the formula (I) or a pharmacologically acceptable salt thereof: Wherein R ¹ represents a protected carboxyl group, W represents a nitrogen atom or a -CH= group, R ² represents an ethoxy group, a 1-propenyl group or a 1-propynyl group, and Z represents a phenyl group, 3 -fluorophenyl, pyridin-2-yl, pyridin-3-yl, thiophen-2-yl or thiophen-3-yl; and the pharmaceutical composition is composed of a PDE4 inhibitor, a PDE5 inhibitor, a corticosteroid, an anticholinergic, 2-2-receptor agonist, H1-histamine receptor antagonist, leukotriene receptor antagonist, endothelin receptor antagonist, PGI2 receptor agonist, theophylline and pirfenidone One or more pharmaceutical combinations selected by the group are administered. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition containing the compound represented by the formula (I) or a salt thereof and the other pharmaceuticals are respectively used as different preparations at the same time or at different times. Cast. The pharmaceutical composition as described in claim 1 of the patent application, wherein A pharmaceutical composition having a compound represented by the formula (I) or a salt thereof and other pharmaceuticals are administered as a single preparation. The pharmaceutical composition according to any one of claims 1 to 3, wherein R ¹ represents a carboxyl 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 carboxyl group, an ethoxycarbonyl group, an isopropoxycarbonyl group or a hexyloxycarbonyl group. The pharmaceutical composition according to any one of claims 1 to 3, wherein R ¹ represents a carboxyl group, an ethoxycarbonyl group, an isopropoxycarbonyl group or a hexyloxycarbonyl group, and W represents a nitrogen atom. Atom or -CH= group, R ² represents 1-propenyl or 1-propynyl, and Z represents phenyl, 3-fluorophenyl, pyridin-2-yl, pyridin-3-yl, thiophene-2- Or thiophen-3-yl. The pharmaceutical composition according to any one of claims 1 to 3, wherein the compound represented by the formula (I) is: (6-{[3'-(1-propenyl)) Ethyl phenyl-4-ylmethyl](pyridin-2-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate, (6-{[3'-(1-propenyl)) Benzyl-4-ylmethyl](pyridin-2-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetic acid, (6-{[3'-(1-propynyl)biphenyl) Ethyl -4-ylmethyl](pyridin-2-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate, (6-{[3'-(1-propynyl)) Benz-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}hexyl acetate, {6-[(3'- Ethoxybiphenyl-4-ylmethyl)(pyridin-3-ylsulfonyl)aminomethyl]pyridin-2-ylamino}acetic acid, {6-[(phenylsulfonyl) (3' -Ethoxybiphenyl-4-ylmethyl)aminomethyl]pyridin-2-ylamino}acetic acid, {6-[(3'-ethoxybiphenyl-4-ylmethyl) (thiophene) -2-ylsulfonyl)aminomethyl]pyridin-2-ylamino}acetic acid, (6-{[4-(6-ethoxypyridin-2-yl)benzyl](pyridine-2- (6-{[3'-(1-propynyl)biphenyl-4-ylmethyl](thiophen-2-yl), sulfamoyl)aminomethyl}pyridin-2-ylamino)acetic acid Ethyl sulfonyl)aminomethyl}pyridin-2-ylamino)acetate, (6-{[3'-(1-propynyl)biphenyl-4-ylmethyl](thiophene-2- Base (amino)methyl}pyridin-2-ylamino)acetic acid, (6-{(phenylsulfonyl)[3'-(1-propynyl)biphenyl-4-ylmethyl]amine Ethyl acetate, pyridyl-2-ylamino)(6-{(phenylsulfonyl)[3'-(1-propynyl)biphenyl-4-ylmethyl]aminomethyl}pyridine -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-Fluorophenylsulfonyl)[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)acetic acid isopropyl ester . The pharmaceutical composition according to any one of claims 1 to 7, wherein the other medicine is a PDE4 inhibitor, a corticosteroid, an anticholinergic, a β2-receptor agonist, and a pirfenibine. One or more medicines selected from the group consisting of ketones. The pharmaceutical composition according to any one of claims 1 to 7, wherein the other medicine is a PDE4 inhibitor, a corticosteroid or pirfenidone. The pharmaceutical composition according to any one of claims 1 to 7, wherein the other medicine is roflumilast, fluticasone or pirfenidone. The pharmaceutical composition according to any one of claims 1 to 10, which is for treating or preventing asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pulmonary fibrosis, acute respiration Distress syndrome, cystic fibrosis or pulmonary hypertension. The pharmaceutical composition according to any one of claims 1 to 10, which is for treating or preventing asthma, chronic obstructive pulmonary disease Disease or pulmonary fibrosis.