WO2014192977A1 - Thiazole derivative - Google Patents

Abstract

Provided are: a compound represented by formula (I), which exhibits a superior xanthine oxidase inhibiting activity, or a pharmaceutically acceptable salt thereof; a drug or drug composition including the compound and/or salt thereof as an active ingredient; and a therapeutic or prophylactic drug for diseases mediated by xanthine oxidase, including gout, hyperuricemia, tumor lysis syndrome, urolithiasis, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and cardiac insufficiency, kidney diseases such as diabetic nephropathy, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel disease and autoimmune diseases. (In the formula, A represents a C6-10 aryl group or the like. X, Y and Z each represent CR⁵ or a nitrogen atom, with one variable among X, Y and Z representing a nitrogen atom and the remaining two variables representing a CR⁵ moiety. R¹ represents a hydrogen atom or the like. R⁵ represents a hydrogen atom or the like.)

Description

Thiazole derivative

The present invention relates to a novel compound having xanthine oxidase inhibitory activity, a method for producing the same, and a xanthine oxidase inhibitor containing the compound as an active ingredient. In particular, the present invention includes gout, hyperuricemia, tumor lysis syndrome, urolithiasis, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and heart failure, renal diseases such as diabetic nephropathy, The present invention relates to a thiazole derivative useful as a therapeutic or prophylactic agent for diseases involving xanthine oxidase, such as respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel disease or autoimmune disease.

Xanthine oxidase is an enzyme that catalyzes the conversion of hypoxanthine to xanthine and further to uric acid in nucleic acid metabolism.
In contrast to the action of xanthine oxidase, xanthine oxidase inhibitors reduce uric acid synthesis by inhibiting uric acid synthesis. That is, it is effective in treating hyperuricemia and various diseases caused by it. On the other hand, pathological conditions that occur as a result of persistent hyperuricemia and deposition of urate crystals include gout arthritis called gout and gout nodules. Hyperuricemia is regarded as an important factor in lifestyle-related diseases and metabolic syndrome related to obesity, hypertension, dyslipidemia and diabetes. Recently, epidemiological studies have shown that kidney disorders, urinary calculi, cardiovascular diseases It is being clarified that this is a risk factor for the treatment of hyperuricemia and gout (2nd edition). In addition, xanthine oxidase inhibitors, due to their reactive oxygen species generation inhibitory activity, are useful for treating diseases involving reactive oxygen species, for example, useful for treating cardiovascular diseases through improving vascular function. Expected (Circulation. 2006; 114: 2508-2516).
Clinically, allopurinol and febuxostat are used as therapeutic agents for hyperuricemia, but allopurinol has reported side effects such as Stevens-Johnson syndrome, toxic epidermal necrosis, liver damage, and renal dysfunction. (Nippon Rinsho, 2003; 61, Suppul. 1: 197-201).
Examples of the compound having xanthine oxidase inhibitory activity include 2-phenylthiazole derivatives (Patent Documents 1 to 3), triarylcarboxylic acid derivatives (Patent Documents 4 to 7) and the like, and thiazole derivatives whose central aromatic ring is a benzene ring. Has been reported.
Non-Patent Document 1 and Non-Patent Document 2 report pyrazole carboxylic acid derivatives having a pyridine ring at the center.

International Publication No. 92/09279 JP 2002-105067 A International Publication No. 96/31211 International Publication No. 2007/043457 International Publication No. 2007/099743 International Publication No. 2008/126770 International Publication No. 2008/1267772

Bioorganic Medicinal Chemistry Letters, 2006, 16 (21), p. 5616-5620 Bioorganic Medicinal Chemistry Letters, 2006, 16 (21), p. 5687-5690

The problem to be solved by the present invention is to provide a novel compound having xanthine oxidase inhibitory activity. Furthermore, another object of the present invention is to provide a compound having an excellent uric acid lowering action. Yet another subject of the present invention is gout, hyperuricemia, tumor lysis syndrome, urolithiasis, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and heart failure, diabetic nephropathy To provide a compound useful as a therapeutic or prophylactic agent for diseases involving xanthine oxidase, such as respiratory diseases such as renal diseases such as chronic obstructive pulmonary disease, inflammatory bowel diseases or autoimmune diseases.

で表される化合物、すなわち、３環性のトリアリール構造であり、中央の環に、一つの窒素原子を有するシアノ基で置換されたピリジン環を有するチアゾール誘導体が、キサンチンオキシダーゼ阻害活性を有すること、更には、優れた尿酸低下作用を伴う新規キサンチンオキシダーゼ阻害活性を有すること、更には、特に優れた長時間にわたる尿酸低下作用を可能とする持続的なキサンチンオキシダーゼ阻害活性を有することを見出して本発明を完成させた。更に、このチアゾール誘導体は、痛風、高尿酸血症、腫瘍崩壊症候群、尿路結石、高血圧症、脂質異常症、糖尿病、動脈硬化症や心不全等の心血管疾患、糖尿病性腎症等の腎疾患、慢性閉塞性肺疾患等の呼吸器疾患、炎症性腸疾患または自己免疫性疾患等の良好な治療薬または予防薬になりうることを見出して本発明を完成させた。
　本発明は、以下式（Ｉ）で表される化合物またはその製薬学的に許容される塩である。

［式中、
Ａは、炭素数６~１０のアリール基、またはヘテロアリール基を表し、ここで、アリール基、またはヘテロアリール基は、無置換であるか、または同一もしくは互いに異なって、ハロゲン原子、−ＣＮ、−ＮＯ_２、炭素数１~６のアルキル基、炭素数３~７のシクロアルキル基、炭素数１~６のハロゲノアルキル基、フェニル基、−ＣＨ_２−Ｏ−Ｒ^２、−Ｏ−Ｒ^２、−Ｏ−炭素数１~６のハロゲノアルキル、−Ｏ−ベンジル、−Ｏ−フェニル、−Ｏ−ＣＯ−Ｒ^２、−ＮＲ^３Ｒ^４、−ＮＨ−ＣＯ−Ｒ^２、−ＣＯ_２−Ｒ^２、−ＣＯ−Ｒ^２、−ＣＯ−ＮＲ^３Ｒ^４、−ＮＨ−ＳＯ_２−Ｒ^２、−ＣＯ−アリール、−Ｓ−Ｒ^２、−ＳＯ_２−炭素数１~６のアルキル、および−ＳＯ_２−フェニルからなる群より選択される１~３個の基Ｒで置換されていてもよい。
Ｘ、ＹおよびＺはＣＲ^５または窒素原子を表し、ここで、Ｘ、ＹおよびＺのうち１つは窒素原子を表し、残り２つはＣＲ^５を表す。
Ｒ^１は、水素原子または炭素数１~６のアルキル基を表す。
Ｒ^２は、水素原子または炭素数１~６のアルキル基を表す。
Ｒ^３およびＲ^４は、同一または互いに異なって、水素原子または炭素数１~６のアルキル基であり、ここで、Ｒ^３およびＲ^４は一体となって、これらが結合する窒素原子と共に単環式含窒素飽和複素環を形成してもよい。
Ｒ^５は、水素原子、ハロゲン原子または炭素数１~６のアルキル基を表す。］
　また、本発明は、上記式（Ｉ）で表される化合物またはその製薬学的に許容される塩と、製薬学的に許容される担体とを含む医薬組成物である。
　また、本発明は、上記式（Ｉ）で表される化合物またはその製薬学的に許容される塩を有効成分として含有する、キサンチンオキシダーゼ阻害剤である。
　また、本発明は、上記式（Ｉ）で表される化合物またはその製薬学的に許容される塩を有効成分として含有する、痛風、高尿酸血症、腫瘍崩壊症候群、尿路結石、高血圧症、脂質異常症、糖尿病、動脈硬化症や心不全等の心血管疾患、糖尿病性腎症等の腎疾患、慢性閉塞性肺疾患等の呼吸器疾患、炎症性腸疾患または自己免疫性疾患等、キサンチンオキシダーゼの関与する疾患の治療薬または予防薬である。
　さらに、本発明は、上記式（Ｉ）で表される化合物の製造中間体として用いることができる、以下の式（ＩＩ）で表される化合物である。

［式中、
Ａは、炭素数６~１０のアリール基、またはヘテロアリール基を表し、ここで、アリール基、またはヘテロアリール基は、無置換であるか、または同一もしくは互いに異なって、ハロゲン原子、−ＣＮ、−ＮＯ_２、炭素数１~６のアルキル基、炭素数３~７のシクロアルキル基、炭素数１~６のハロゲノアルキル基、フェニル基、−ＣＨ_２−Ｏ−Ｒ^２、−Ｏ−Ｒ^２、−Ｏ−炭素数１~６のハロゲノアルキル、−Ｏ−ベンジル、−Ｏ−フェニル、−Ｏ−ＣＯ−Ｒ^２、−ＮＲ^３Ｒ^４、−ＮＨ−ＣＯ−Ｒ^２、−ＣＯ_２−Ｒ^２、−ＣＯ−Ｒ^２、−ＣＯ−ＮＲ^３Ｒ^４、−ＮＨ−ＳＯ_２−Ｒ^２、−ＣＯ−アリール、−Ｓ−Ｒ^２、−ＳＯ_２−炭素数１~６のアルキル、および−ＳＯ_２−フェニルからなる群より選択される１~３個の基Ｒで置換されていてもよい。
Ｘ、ＹおよびＺはＣＲ^５または窒素原子を表し、ここで、Ｘ、ＹおよびＺのうち１つは窒素原子を表し、残り２つはＣＲ^５を表す。
Ｒ^１は、水素原子または炭素数１~６のアルキル基を表す。
Ｒ^２は、水素原子または炭素数１~６のアルキル基を表す。
Ｒ^３およびＲ^４は、同一または互いに異なって、水素原子または炭素数１~６のアルキル基であり、ここで、Ｒ^３およびＲ^４は一体となって、これらが結合する窒素原子と共に単環式含窒素飽和複素環を形成してもよい。
Ｒ^５は、水素原子、ハロゲン原子または炭素数１~６のアルキル基を表す。
Ｒ^６は、カルボキシル基の保護基を表す。
Ｗは、ハロゲン原子、メタンスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基またはシアノ基を表す。］
　さらに、本発明は、上記式（Ｉ）で表される化合物の製造中間体として用いることができる、以下の式（ＩＩＩ）で表される化合物である。

［式中、
Ｘ、ＹおよびＺはＣＲ^５または窒素原子を表し、ここで、Ｘ、ＹおよびＺのうち１つは窒素原子を表し、残り２つはＣＲ^５を表す。
Ｒ^１は、水素原子または炭素数１~６のアルキル基を表す。
Ｒ^５は、水素原子、ハロゲン原子または炭素数１~６のアルキル基を表す。
Ｒ^６は、カルボキシル基の保護基を表す。
Ｖは、ハロゲン原子、メタンスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基、水酸基、またはベンジルオキシ基を表す。
Ｗは、ハロゲン原子、メタンスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基またはシアノ基を表す。］ As a result of intensive studies on compounds having xanthine oxidase inhibitory activity, the inventors have found that

A thiazole derivative having a pyridine ring substituted with a cyano group having one nitrogen atom in the central ring, has a xanthine oxidase inhibitory activity. Furthermore, it has been found that it has a novel xanthine oxidase inhibitory activity with an excellent uric acid lowering action, and further has a sustained xanthine oxidase inhibitory activity that enables a particularly excellent long-term uric acid lowering action. Completed the invention. Furthermore, this thiazole derivative is useful for gout, hyperuricemia, tumor lysis syndrome, urolithiasis, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and heart failure, and renal diseases such as diabetic nephropathy. The present invention was completed by finding that it can be a good therapeutic or prophylactic agent for respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel disease or autoimmune disease.
The present invention is a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

[Where:
A represents an aryl group having 6 to 10 carbon atoms or a heteroaryl group, wherein the aryl group or heteroaryl group is unsubstituted or the same or different from each other, and is a halogen atom, -CN, —NO ₂ , an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a phenyl group, —CH ₂ —O—R ² , —O—R ² , halogenoalkyl of 1 to 6 carbon -O- atoms, -O- benzyl, -O- ^{phenyl, -O-CO-R 2,} -NR 3 R 4, -NH-CO-R 2, -CO 2 -R ^{2, -CO-R 2, -CO} -NR 3 R 4, -NH-SO 2 -R 2, -CO- _{^{aryl, -S-R 2, -SO 2}} - alkyl having 1 to 6 carbon atoms, and - It is substituted with 1 to 3 groups R selected from the group consisting of SO ₂ -phenyl. It may be replaced.
X, Y and Z represent CR ⁵ or a nitrogen atom, wherein one of X, Y and Z represents a nitrogen atom and the remaining two represent CR ⁵ .
R ¹ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
R ² represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
R ³ and R ⁴ are the same or different from each other, and are a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, wherein R ³ and R ⁴ are united together with a nitrogen atom to which they are bonded to form a single ring A formula nitrogen-containing saturated heterocycle may be formed.
R ⁵ represents a hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms. ]
The present invention also provides a pharmaceutical composition comprising a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
Moreover, this invention is a xanthine oxidase inhibitor which contains the compound represented by the said Formula (I), or its pharmaceutically acceptable salt as an active ingredient.
The present invention also includes gout, hyperuricemia, tumor lysis syndrome, urinary calculus, hypertension, containing as an active ingredient the compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof. Xanthine, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and heart failure, renal diseases such as diabetic nephropathy, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel disease or autoimmune disease It is a therapeutic or prophylactic agent for diseases involving oxidase.
Furthermore, this invention is a compound represented by the following formula | equation (II) which can be used as a manufacturing intermediate of the compound represented by the said formula (I).

[Where:
A represents an aryl group having 6 to 10 carbon atoms or a heteroaryl group, wherein the aryl group or heteroaryl group is unsubstituted or the same or different from each other, and is a halogen atom, -CN, —NO ₂ , an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a phenyl group, —CH ₂ —O—R ² , —O—R ² , halogenoalkyl of 1 to 6 carbon -O- atoms, -O- benzyl, -O- ^{phenyl, -O-CO-R 2,} -NR 3 R 4, -NH-CO-R 2, -CO 2 -R ^{2, -CO-R 2, -CO} -NR 3 R 4, -NH-SO 2 -R 2, -CO- _{^{aryl, -S-R 2, -SO 2}} - alkyl having 1 to 6 carbon atoms, and - It is substituted with 1 to 3 groups R selected from the group consisting of SO ₂ -phenyl. It may be replaced.
X, Y and Z represent CR ⁵ or a nitrogen atom, wherein one of X, Y and Z represents a nitrogen atom and the remaining two represent CR ⁵ .
R ¹ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
R ² represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
R ³ and R ⁴ are the same or different from each other, and are a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, wherein R ³ and R ⁴ are united together with a nitrogen atom to which they are bonded to form a single ring A formula nitrogen-containing saturated heterocycle may be formed.
R ⁵ represents a hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms.
R ⁶ represents a protecting group for a carboxyl group.
W represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, or a cyano group. ]
Furthermore, this invention is a compound represented by the following formula | equation (III) which can be used as a manufacturing intermediate of the compound represented by the said formula (I).

[Where:
X, Y and Z represent CR ⁵ or a nitrogen atom, wherein one of X, Y and Z represents a nitrogen atom and the remaining two represent CR ⁵ .
R ¹ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
R ⁵ represents a hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms.
R ⁶ represents a protecting group for a carboxyl group.
V represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, a hydroxyl group, or a benzyloxy group.
W represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, or a cyano group. ]

The present invention provides a novel compound having high xanthine oxidase inhibitory activity and a method for producing the same. Furthermore, the compounds of the present invention are particularly useful for gout, hyperuricemia, tumor lysis syndrome, urolithiasis, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and heart failure, kidneys such as diabetic nephropathy, etc. It is useful as a therapeutic or prophylactic agent for diseases involving xanthine oxidase such as diseases, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel diseases or autoimmune diseases.

前記式（Ｉ）中、Ｒ^１は、水素原子または炭素数１~６のアルキル基を表す。「炭素数１~６のアルキル基」の具体例は、前述の定義の通りであるが、好ましい「炭素数１~６のアルキル基」としては、メチル基、エチル基、ｎ−プロピル基、ｎ−ブチル基、ｎ−ペンチル基、ｎ−ヘキシル基、イソプロピル基、イソブチル基、ｓ−ブチル基、ｔ−ブチル基、イソペンチル基、２−メチルブチル基、ネオペンチル基、１−エチルプロピル基、４−メチルペンチル基、３−メチルペンチル基、２−メチルペンチル基、１−メチルペンチル基、３，３−ジメチルブチル基、２，２−ジメチルブチル基、１，１−ジメチルブチル基、１，２−ジメチルブチル基、１，３−ジメチルブチル基、２，３−ジメチルブチル基、１−エチルブチル基、２−エチルブチル基、ｔ−ペンチル基、およびイソヘキシル基等が挙げられ、Ｒ^１は、水素原子、またはメチル基がより好ましく、水素原子が特に好ましい。
　前記式（Ｉ）中、Ｒ^２は、水素原子、または炭素数１~６のアルキル基を表す。「炭素数１~６のアルキル基」の具体例は、前述の定義の通りであるが、好ましい「炭素数１~６のアルキル基」としては、メチル基、エチル基、ｎ−プロピル基、ｎ−ブチル基、ｎ−ペンチル基、ｎ−ヘキシル基、イソプロピル基、イソブチル基、ｓ−ブチル基、ｔ−ブチル基、イソペンチル基、２−メチルブチル基、ネオペンチル基、１−エチルプロピル基、４−メチルペンチル基、３−メチルペンチル基、２−メチルペンチル基、１−メチルペンチル基、３，３−ジメチルブチル基、２，２−ジメチルブチル基、１，１−ジメチルブチル基、１，２−ジメチルブチル基、１，３−ジメチルブチル基、２，３−ジメチルブチル基、１−エチルブチル基、２−エチルブチル基、ｔ−ペンチル基、およびイソヘキシル基等が挙げられ、Ｒ^２は、水素原子、またはメチル基がより好ましく、メチル基が特に好ましい。
　前記式（Ｉ）中、Ｒ^３およびＲ^４は、同一または互いに異なって、水素原子または炭素数１~６のアルキル基であり、ここで、Ｒ^３およびＲ^４は一体となって、これらが結合する窒素原子と共に単環式含窒素飽和複素環を形成してもよい。「炭素数１~６のアルキル基」および「単環式含窒素飽和複素環」は、具体例は、前述の定義の通りであるが、好ましい「炭素数１~６のアルキル基」としては、メチル基、エチル基、ｎ−プロピル基、ｎ−ブチル基、ｎ−ペンチル基、ｎ−ヘキシル基、イソプロピル基、イソブチル基、ｓ−ブチル基、ｔ−ブチル基、イソペンチル基、２−メチルブチル基、ネオペンチル基、１−エチルプロピル基、４−メチルペンチル基、３−メチルペンチル基、２−メチルペンチル基、１−メチルペンチル基、３，３−ジメチルブチル基、２，２−ジメチルブチル基、１，１−ジメチルブチル基、１，２−ジメチルブチル基、１，３−ジメチルブチル基、２，３−ジメチルブチル基、１−エチルブチル基、２−エチルブチル基、ｔ−ペンチル基、およびイソヘキシル基等が挙げられ、好ましい「単環式含窒素飽和複素環」としては、ピロリジン、ピペリジン、ピペラジン、アゼパン、ジアゼパン、アゾカン、モルホリン、チオモルホリン、テトラヒドロピリジン環等が挙げられる。Ｒ^３、Ｒ^４および「単環式含窒素飽和複素環」は、水素原子、メチル基、ピロリジン、ピペリジン、ピペラジンおよびモルホリンがより好ましく、水素原子、メチル基およびモルホリンが特に好ましい。
　前記式（Ｉ）中、Ｘ、ＹおよびＺはＣＲ^５または窒素原子を表し、ここで、Ｘ、ＹおよびＺのうち１つは窒素原子を表し、残り２つはＣＲ^５を表す。Ｘ、Ｙ、Ｚ、それぞれが窒素原子である３例は、以下の構造式で表すことができる。この中で、Ｙが窒素原子であることが好ましい。

　Ｒ^５としては、水素原子、ハロゲン原子または炭素数１~６のアルキル基が挙げられ、水素原子が好ましい。
　前記式（Ｉ）中、Ａ、Ｒ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｘ、ＹおよびＺの組み合わせとしては、それぞれについて上記した好ましい基同士を組み合わせたものが好ましく、好ましい基同士を組み合わせた式（Ｉ）の構造のＡ、Ｒ、Ｒ^１、Ｒ^２をより好ましい基とした組み合わせたがより好ましい。かかるより好ましい式（Ｉ）の組み合わせのＲ^１を、特に好ましい基とした組み合わせが特に好ましい。
　本発明の化合物は優れたキサンチンオキシダーゼ阻害活性を示す化合物である。また、本発明の化合物は、優れた尿酸低下作用を有する。さらに、本発明の化合物は、長時間にわたる持続的な尿酸低下作用を有する。
　好ましい化合物の具体例としては、以下の化合物を挙げることができる。

　このうち、より好ましい化合物は、化合物１、２、３、４、５、６、７、８、９、１０、１１、１２、１３、１４、１５、１６、１７、１８、１９、２０、２１、２２、２４、２６、２７、２８、２９、３０、３２、３３、３４、３５、３６、３８、４０、４１、４２、４３、４４、４５、４７、４９、５０、５１、５２、５３、５４、５５、５６、５７、５８、６２、６３、６４、６５、６６、６７、６８、６９、７０、７１、７２、７３、７４、７５、７６、７７、７８、７９、８０、８２、８３、８４、８５、８７、９３、９４、９５、９６、９７、９９、１００、１０１、１０２、１０３、および１０５であり、さらに好ましくは、化合物１、２、３、４、５、４９、５０、５５および５７であり、特に好ましくは化合物１、２、３および４であり、最も好ましくは化合物１および２である。
　本発明の前記の式（Ｉ）で表される化合物の製造中間体として用いることができる、前記の式（ＩＩ）で表される化合物において、Ａ、Ｒ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｘ、ＹおよびＺは前記の式（Ｉ）における定義と同じである。Ｗは、ハロゲン原子、メタンスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基またはシアノ基を表す。Ｗは、ハロゲン原子、またはシアノ基がより好ましく、シアノ基が特に好ましい。Ｒ^６は、カルボキシル基の保護基を表す。カルボキシル基の保護基の定義は上述の通りであり、好ましくは、メチル基、エチル基、ベンジル基である。
　さらに、本発明の前記の式（Ｉ）で表される化合物の製造中間体として用いることができる、前記の式（ＩＩＩ）で表される化合物において、Ｒ^１、Ｒ^５、Ｘ、ＹおよびＺは前記の式（Ｉ）における定義と同じである。Ｖは、ハロゲン原子、メタンスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基、水酸基、またはベンジルオキシ基を表す。Ｖは、ハロゲン原子、トリフルオロメタンスルホニルオキシ基、水酸基、またはベンジルオキシ基が好ましい。Ｗは、ハロゲン原子、メタンスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基またはシアノ基を表す。Ｗは、ハロゲン原子、またはシアノ基がより好ましく、シアノ基が特に好ましい。Ｒ^６は、カルボキシル基の保護基を表す。カルボキシル基の保護基の定義は上述の通りであり、好ましくは、メチル基、エチル基、ベンジル基である。
＜一般的合成法＞
　本発明の式（Ｉ）の化合物および中間体は、例えば、以下に記載されるような合成法のいずれかに従って合成することができる。なお、各式中、Ａ、Ｒ、およびＲ^１は、式（Ｉ）の定義のとおりである。また、化学式中に記載の条件としての試薬または溶媒などは、本文にも記載のとおり例示にすぎない。各置換基は、必要に応じて、適切な保護基で保護されていてもよく、適切な段階において脱保護を行って良い。なお、適切な保護基およびその除去方法は、この分野で汎用される各置換基の保護基および公知の方法を採用することができ、例えば、ＰＲＯＴＥＣＴＩＶＥ　ＧＲＯＵＰＳ　ｉｎ　ＯＲＧＡＮＩＣ　ＳＹＮＴＨＥＳＩＳ，ＴＨＩＲＤ　ＥＤＩＴＩＯＮ、ＪｏｈｎＷｉｌｅｙ＆Ｓｏｎｓ，Ｉｎｃ．に記載されている。
　また、本文中または表における置換基、試薬、および溶媒の略号を用いている場合は、それぞれ以下のことを表す。
ＤＭＦ：Ｎ，Ｎ‐ジメチルホルムアミド
ＴＨＦ：テトラヒドロフラン
Ｐｈ：フェニル
ＴＦＡ：トリフルオロ酢酸
　合成法（Ａ）
　化合物（Ａ−２）の合成

（式中、Ｘ^１およびＸ^２は脱離基を表す。）Ｘ^１およびＸ^２で示される脱離基としてはハロゲン原子、メタンスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基等が挙げられる。本反応は、化合物（Ａ−１）におけるピリジンの４位を塩基によりリチウム化あるいはナトリウム化させた後に、ホルミル化剤によりホルミル化させることにより、化合物（Ａ−２）を合成する方法である。塩基としては、ジイソプロピルアミンとｎ−ブチルリチウムとから調整されるリチウムジイソプロピルアミン（ＬＤＡ）等が挙げられる。また、ホルミル化剤としては、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、Ｎ−ホルミルモルホリン等が挙げられる。本反応は、−７８℃~０℃下で、反応に不活性な溶媒中、化合物（Ａ−１）に等量、あるいは小過剰に塩基を反応させた後に、等量あるいは過剰量のホルミル化剤を加え、通常０．５~５時間反応させることによって行われる。本反応は窒素等の不活性ガス雰囲気下で行うことが好ましい。ここに、溶媒としては特に限定はされないが、例えばジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４−ジオキサン、１，２−ジメトキシエタン、１，２−ジエトキシエタン等のエーテル類、またはこれらの混合溶媒等が挙げられる。
　化合物（Ａ−４）の合成

（式中、Ｘ^１およびＸ^２は脱離基、Ｙ^１は−Ｂ（ＯＨ）_２または−Ｂ（ＯＲ^７）ＯＲ^８を表す。ここで、Ｒ^７およびＲ^８は同一または互いに異なって炭素数１~６のアルキル基、またはＲ^７およびＲ^８が一体となって炭素数１~６のアルキレン基を表す。）本反応は、化合物（Ａ−２）とボロン酸またはボロン酸エステルである化合物（Ａ−３）とをカップリングさせることにより、化合物（Ａ−４）を合成する方法である。Ｘ^１およびＸ^２で示される脱離基としてはハロゲン原子、メタンスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基等が挙げられる。本反応は、化合物（Ａ−２）と（Ａ−３）を等量、あるいは一方を過剰に用い、反応に不活性な溶媒中、塩基およびパラジウム触媒存在下、室温~加熱還流下で、通常０．５~２日間反応させることによって行われる。本反応は窒素等の不活性ガス雰囲気下で行うことが好ましい。ここに、溶媒としては特に限定はされないが、例えばベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４−ジオキサン、１，２−ジメトキシエタン、１，２−ジエトキシエタン等のエーテル類、ジクロロメタン、１，２−ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、メタノール、エタノール、２−プロパノール、ブタノール等のアルコール類、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、Ｎ−メチルピロリドン、ジメチルスルホキシド（ＤＭＳＯ）、水またはこれらの混合溶媒等が挙げられる。塩基としては、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等の無機塩、リン酸三カリウム、ナトリウムエトキシド、ナトリウムメトキシド等の金属アルコキシド、あるいはこれらの塩基を水等で希釈した溶液等が挙げられる。パラジウム触媒としては、テトラキス（トリフェニルホスフィン）パラジウム、ジクロロビス（トリフェニルホスフィン）パラジウム、塩化パラジウム−１，１’−ビス（ジフェニルホスフィノ）フェロセン等が好ましい。
　化合物（Ａ−５）の合成

（式中、Ｘ^２は脱離基を表す。）Ｘ^２で示される脱離基としてはハロゲン原子、メタンスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基等が挙げられる。本反応は、ホルミル基からシアノ基への変換反応であり、上記式（Ａ−４）で表される芳香族アルデヒド誘導体をヒドロキシルアミンと反応させることにより行われる。ヒドロキシルアミンとしては、その塩酸塩等のその他の塩を用いてもよいが、その場合には適切な塩基性物質を加えることが好ましい。また、無水酢酸、アセチルクロリド及びトリクロロアセチルクロリド等を１．０~３．０当量加えて、反応を加速させることもできる。これらの反応に用いるヒドロキシルアミンまたはその塩の量は、通常１当量以上を用い、好ましくは１．０~２．０当量である。塩基性物質を用いる場合には、ヒドロキシルアミンの塩に対して１．０~３．０当量である。用いる塩基性物質としては、ギ酸ナトリウム、ギ酸カリウム、酢酸ナトリウム等のカルボン酸塩、炭酸カリウム、炭酸ナトリウム、炭酸水素ナトリウム等の炭酸塩、トリエチルアミン、ピリジン、４−アミノピリジン等の有機アミン塩が用いられる。反応は不活性な溶媒中、塩基の存在下、室温~加熱還流下で、通常０．５時間~３日間反応させることによって行なわれる。本反応は窒素等の不活性ガス雰囲気下で行うことが好ましい。これらの反応に用いられる溶媒としては、酢酸、ギ酸、トルエン、ベンゼン、ピリジン、酢酸エチル、ジクロロメタン、１，２−ジクロロエタン、クロロホルム、四塩化炭素、ジエチルエーテル、テトラヒドロフラン、１，４−ジオキサン、１，２−ジメトキシエタン、１，２−ジエトキシエタン、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、Ｎ−メチルピロリドン、ジメチルスルホキシド（ＤＭＳＯ）、メタノール、エタノール、２−プロパノール等の溶媒が挙げられる。
化合物（Ａ−７）の合成

（式中、Ｒ^６はカルボキシル基の保護基、Ｘ^２は脱離基を表す。）本合成法は、化合物（Ａ−５）と（Ａ−６）とをカップリングさせることにより、化合物（Ａ−７）を合成する方法である。Ｘ^２で示される脱離基としてはハロゲン原子、メタンスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基等が挙げられる。本反応は化合物（Ａ−５）と（Ａ−６）を等量、あるいは一方を過剰に用い、反応に不活性な溶媒中、塩基および遷移金属触媒存在下、場合により配位子、カルボン酸および銅（Ｉ価またはＩＩ価）塩を加えて、室温~加熱還流下で、通常０．５~２日間反応させることによって行われる。本反応は窒素等の不活性ガス雰囲気下で行うことが好ましい。ここに、溶媒としては特に限定はされないが、例えばベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４−ジオキサン、１，２−ジメトキシエタン、１，２−ジエトキシエタン等のエーテル類、ジクロロメタン、１，２−ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、メタノール、エタノール、２−プロパノール、ブタノール等のアルコール類、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、Ｎ−メチルピロリドン、ジメチルスルホキシド（ＤＭＳＯ）、水またはこれらの混合溶媒等が挙げられる。塩基としては、水素化リチウム、水素化ナトリウム、水素化カリウム、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、フッ化カリウム、フッ化セシウム、リン酸三カリウム、酢酸ナトリウム、酢酸カリウム等、炭素数１~６のアルコキシドの金属塩（リチウム塩、ナトリウム塩、カリウム塩、マグネシウム塩）、炭素数１~６のアルキルアニオンの金属塩（リチウム塩、ナトリウム塩、カリウム塩、マグネシウム塩）、テトラ（炭素数１~４のアルキル）アンモニウム塩（フッ化塩、塩化塩、臭化塩）、ジイソプロピルエチルアミン、トリブチルアミン、Ｎ−メチルモルホリン、ジアザビシクロウンデセン、ジアザビシクロオクタン、又はイミダゾール等が挙げられる。遷移金属触媒としては、銅、パラジウム、コバルト、鉄、ロジウム、ルテニウム、及びイリジウム等が挙げられる。配位子としては、トリ（ｔ−ブチル）ホスフィン、トリ（シクロヘキシル）ホスフィン、ｔ−ブチルジシクロヘキシルホスフィン、ジ（ｔ−ブチル）シクロヘキシルホスフィン、又はジ（ｔ−ブチル）メチルホスフィン等が挙げられる。銅（Ｉ価またはＩＩ価）塩としては、塩化銅（Ｉ）、臭化銅（Ｉ）、ヨウ化銅（Ｉ）、酢酸銅（Ｉ）、フッ化銅（ＩＩ）、塩化銅（ＩＩ）、臭化銅（ＩＩ）、ヨウ化銅（ＩＩ）、酢酸銅（ＩＩ）及びこれらの水和物、ならびにこれらの混合物等が挙げられる。カルボン酸としては、ギ酸、酢酸、プロピオン酸、ｎ−ブチル酸、イソブチル酸、ペンタン酸、イソペンタン酸、ピバル酸、及びトリフルオロ酢酸等が挙げられる。
　化合物（Ａ−８）の合成

　（式中、Ｒ^６はカルボキシル基の保護基を表す。）本合成法は、化合物（Ａ−７）の保護基Ｒ^６を酸または塩基等により脱保護させることにより、本発明化合物（Ａ−８）を合成する方法である。本反応は、化合物（Ａ−７）に、反応に不活性な溶媒中、酸または塩基を等量、あるいは過剰に用い、室温~加熱還流下で、通常０．５~５日間反応されることによって行なわれる。ここに、溶媒としては特に限定はされないが、例えばベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４−ジオキサン、１，２−ジメトキシエタン、１，２−ジエトキシエタン等のエーテル類、ジクロロメタン、１，２−ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、メタノール、エタノール、２−プロパノール、ブタノール等のアルコール類、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、Ｎ−メチルピロリドン、ジメチルスルホキシド（ＤＭＳＯ）、水またはこれらの混合溶媒等が挙げられる。酸としては、塩化水素、臭化水素、硫酸、硝酸、リン酸等の無機酸、あるいはこれらの酸を水または有機溶媒で希釈した溶液等が挙げられる。塩基としては、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、炭酸ナトリウム、炭酸カリウム等の無機塩、ナトリウムエトキシド、ナトリウムメトキシド等の金属アルコキシド、あるいはこれらの塩基を水等で希釈した溶液等が挙げられる。
　合成法（Ｂ）
　化合物（Ｂ−３）の合成

（式中、Ｘ^４およびＹ^２は脱離基を表す。）本合成法は、化合物（Ｂ−１）と（Ｂ−２）を反応させることにより、化合物（Ｂ−３）を合成する方法である。Ｘ^４で示される脱離基としては、ヨウ素原子、臭素原子、塩素原子が挙げられる。Ｙ^２で示される脱離基としてはハロゲン原子、メタンスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基等が挙げられる。本反応は、化合物（Ｂ−１）と（Ｂ−２）を等量、あるいは一方を過剰に用い、反応に不活性な溶媒中、塩基の存在下、室温~加熱還流下で、通常０．５時間~３日間反応させることによって行なわれる。本反応は窒素等の不活性ガス雰囲気下で行うことが好ましい。ここに、溶媒としては特に限定はされないが、例えばベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４−ジオキサン、１，２−ジメトキシエタン、１，２−ジエトキシエタン等のエーテル類、ジクロロメタン、１，２−ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、Ｎ−メチルピロリドン、ジメチルスルホキシド（ＤＭＳＯ）、ピリジン、酢酸エチルまたはこれらの混合溶媒等が挙げられる。塩基としては、水素化ナトリウム、水素化ナトリウム、水酸化カリウム、水酸化リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等の無機塩、ナトリウムエトキシド、ナトリウムメトキシド等の金属アルコキシド、トリエチルアミン、Ｎ−エチル−Ｎ，Ｎ−ジイソプロピルアミン（ＤＩＰＥＡ）、１，８−ジアザビシクロ［５．４．０］−７−ウンデセン（ＤＢＵ）、ピリジンなどが挙げられる。
化合物（Ｂ−４）の合成

（式中、Ｘ^４は脱離基を表す。）本合成法は、化合物（Ｂ−３）のカルボキシル基の保護基ベンジル基を酸または塩基等により脱保護させることにより、化合物（Ｂ−４）を合成する方法である。本反応は、化合物（Ｂ−３）に、反応に不活性な溶媒中、酸または塩基を等量、あるいは過剰に用い、室温~加熱還流下で、通常０．５~５日間反応されることによって行なわれる。ここに、溶媒としては特に限定はされないが、例えばベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４−ジオキサン、１，２−ジメトキシエタン、１，２−ジエトキシエタン等のエーテル類、ジクロロメタン、１，２−ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、メタノール、エタノール、２−プロパノール、ブタノール等のアルコール類、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、Ｎ−メチルピロリドン、ジメチルスルホキシド（ＤＭＳＯ）、水またはこれらの混合溶媒等が挙げられる。酸としては、塩化水素、臭化水素、硫酸、硝酸、リン酸等の無機酸、あるいはこれらの酸を水または有機溶媒で希釈した溶液等が挙げられる。塩基としては、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、炭酸ナトリウム、炭酸カリウム等の無機塩、ナトリウムエトキシド、ナトリウムメトキシド等の金属アルコキシド、あるいはこれらの塩基を水等で希釈した溶液等が挙げられる。
化合物（Ｂ−５）の合成

（式中、Ｘ^４は脱離基を表す。）本合成法は、化合物（Ｂ−４）のカルボキシル基とアンモニアとを反応させることにより、アミド化合物（Ｂ−５）を合成する方法である。本反応は、文献記載の方法（例えばペプチド合成の基礎と実験、泉屋信夫他、丸善、１９８３年、コンプリヘンシブ　オーガニック　シンセシス（Ｃｏｍｐｒｅｈｅｎｓｉｖｅ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ）、第６巻、Ｐｅｒｇａｍｏｎ　Ｐｒｅｓｓ社、１９９１年、等）、それに準じた方法又はこれらと常法とを組み合わせることにより、通常のアミド形成反応を行えばよく、即ち、当業者に周知の縮合剤を用いて行うか、あるいは、当業者に利用可能なエステル活性化方法、混合酸無水物法、酸クロリド法、カルボジイミド法等により行うことができる。このようなアミド形成試薬としては、例えば塩化チオニル、塩化オキザリル、Ｎ，Ｎ−ジシクロヘキシルカルボジイミド、１−メチル−２−ブロモピリジニウムアイオダイド、Ｎ，Ｎ’−カルボニルジイミダゾール、ジフェニルフォスフォリルクロリド、ジフェニルフォスフォリルアジド、Ｎ，Ｎ’−ジスクシニミジルカルボネート、Ｎ，Ｎ’−ジスクシニミジルオキザレート、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩、ベンゾトリアゾール−１−イルオキシトリス（ピロリジノール）ホスホニウム　ヘキサフルオロフォスフェート、２−（１Ｈ−ベンゾトリアゾール−１−イル）−１，１，３，３−テトラメチルウロニウム　ヘキサフルオロフォスフェート、２−（５−ノルボルネン−２，３−ジカルボキシイミド）−１，１，３，３−テトラメチルウロニウム　テトラフルオロボレート、Ｏ−（Ｎ−サクシニミジル）−１，１，３，３−テトラメチルウロニウム　テトラフルオロボレート、ブロモトリス（ピロリジノ）ホスホニウム　ヘキサフルオロフォスフェート、クロロギ酸エチル、クロロギ酸イソブチル又は２−（７−アザ−１Ｈ−ベンゾトリアゾ−ル−１−イル）−１，１，３，３−テトラメチルウロニウム　ヘキサフルオロフォスフェート等が挙げられ、中でも例えば塩化チオニル、塩化オキサリル、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩又は２−（７−アザ−１Ｈ−ベンゾトリアゾ−ル−１−イル）−１，１，３，３−テトラメチルウロニウム　ヘキサフルオロフォスフェート等が好適である。またアミド形成反応においては、上記アミド形成試薬と共に塩基、縮合補助剤を用いても良い。用いられる縮合補助剤としては、例えばＮ−ヒドロキシベンゾトリアゾール水和物、Ｎ−ヒドロキシスクシンイミド等が挙げられる。
　本反応は、化合物（Ｂ−４）とアンモニアを等量、あるいは一方を過剰に用い、反応に不活性な溶媒中、縮合剤および塩基の存在下、室温~加熱還流下で、通常０．５時間~３日間反応させることによって行なわれる。本反応は窒素等の不活性ガス雰囲気下で行うことが好ましい。ここに、溶媒としては特に限定はされないが、例えばベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４−ジオキサン、１，２−ジメトキシエタン、１，２−ジエトキシエタン等のエーテル類、ジクロロメタン、１，２−ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、Ｎ−メチルピロリドン、ジメチルスルホキシド（ＤＭＳＯ）、ピリジン、酢酸エチルまたはこれらの混合溶媒等が挙げられる。また、用いられる塩基としては、例えばトリメチルアミン、トリエチルアミン、Ｎ，Ｎ−ジイソプロピルエチルアミン、Ｎ−メチルモルホリン、Ｎ−メチルピロリジン、Ｎ−メチルピペリジン、Ｎ，Ｎ−ジメチルアニリン、１，８−ジアザビシクロ［５．４．０］ウンデカ−７−エン、１，５−アザビシクロ［４．３．０］ノナ−５−エン等の第３級脂肪族アミン；ピリジン、４−ジメチルアミノピリジン、ピコリン、ルチジン、キノリン又はイソキノリン等の芳香族アミン等が挙げられ、中でも例えば第３級脂肪族アミン等が好ましく、特にトリエチルアミン又はＮ，Ｎ−ジイソプロピルエチルアミン等が特に好ましい。
化合物（Ｂ−６）の合成

（式中、Ｘ^４は脱離基を表す。）本合成法は、化合物（Ｂ−５）のアミド基を酸により脱水させることにより、化合物（Ｂ−６）を合成する方法である。本反応は、化合物（Ｂ−５）に、反応に不活性な溶媒中、酸を等量、あるいは過剰に用い、室温~加熱還流下で、通常０．５~５日間反応されることによって行なわれる。ここに、溶媒としては特に限定はされないが、例えばベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジクロロメタン、１，２−ジクロロエタン、クロロホルム等のハロゲン化炭化水素類等が挙げられる。酸としては、塩化チオニル、オキザリルクロリド、塩化ホスホリルあるいはフェニルホスホニルジクロリド等が挙げられる。
化合物（Ｂ−７）の合成

（式中、Ｒ^６はカルボキシル基の保護基、Ｘ^４は脱離基を表す。）本合成法は、化合物（Ｂ−６）と（Ａ−６）とをカップリングさせることにより、化合物（Ｂ−７）を合成する方法である。Ｘ^４で示される脱離基としてはハロゲン原子、メタンスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基等が挙げられる。本反応は化合物（Ｂ−６）と（Ａ−６）を等量、あるいは一方を過剰に用い、反応に不活性な溶媒中、塩基および遷移金属触媒存在下、場合により配位子、カルボン酸および銅（Ｉ価またはＩＩ価）塩を加えて、室温~加熱還流下で、通常０．５~２日間反応させることによって行われる。本反応は窒素等の不活性ガス雰囲気下で行うことが好ましい。ここに、溶媒としては特に限定はされないが、例えばベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４−ジオキサン、１，２−ジメトキシエタン、１，２−ジエトキシエタン等のエーテル類、ジクロロメタン、１，２−ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、メタノール、エタノール、２−プロパノール、ブタノール等のアルコール類、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、Ｎ−メチルピロリドン、ジメチルスルホキシド（ＤＭＳＯ）、水またはこれらの混合溶媒等が挙げられる。塩基としては、水素化リチウム、水素化ナトリウム、水素化カリウム、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、フッ化カリウム、フッ化セシウム、リン酸三カリウム、酢酸ナトリウム、酢酸カリウム等、炭素数１~６のアルコキシドの金属塩（リチウム塩、ナトリウム塩、カリウム塩、マグネシウム塩）、炭素数１~６のアルキルアニオンの金属塩（リチウム塩、ナトリウム塩、カリウム塩、マグネシウム塩）、テトラ（炭素数１~４のアルキル）アンモニウム塩（フッ化塩、塩化塩、臭化塩）、ジイソプロピルエチルアミン、トリブチルアミン、Ｎ−メチルモルホリン、ジアザビシクロウンデセン、ジアザビシクロオクタン、又はイミダゾール等が挙げられる。遷移金属触媒としては、銅、パラジウム、コバルト、鉄、ロジウム、ルテニウム、及びイリジウム等が挙げられる。配位子としては、トリ（ｔ−ブチル）ホスフィン、トリ（シクロヘキシル）ホスフィン、ｔ−ブチルジシクロヘキシルホスフィン、ジ（ｔ−ブチル）シクロヘキシルホスフィン、又はジ（ｔ−ブチル）メチルホスフィン等が挙げられる。銅（Ｉ価またはＩＩ価）塩としては、塩化銅（Ｉ）、臭化銅（Ｉ）、ヨウ化銅（Ｉ）、酢酸銅（Ｉ）、フッ化銅（ＩＩ）、塩化銅（ＩＩ）、臭化銅（ＩＩ），ヨウ化銅（ＩＩ）、酢酸銅（ＩＩ）及びこれらの水和物、ならびにこれらの混合物等が挙げられる。カルボン酸としては、ギ酸、酢酸、プロピオン酸、ｎ−ブチル酸、イソブチル酸、ペンタン酸、イソペンタン酸、ピバル酸、及びトリフルオロ酢酸等が挙げられる。
化合物（Ｂ−８）の合成

（式中、Ｒ^６はカルボキシル基の保護基を表す。）本合成法は、化合物（Ｂ−７）の脱ベンジル化を行うことにより、化合物（Ｂ−８）を合成する方法である。本反応は、化合物（Ｂ−７）を反応に不活性な溶媒中、パラジウム触媒存在下、水素ガス雰囲気下、室温~加熱還流下で、通常０．５~２日間反応させることによって行われる。ここに、溶媒としては特に限定はされないが、例えばベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４−ジオキサン、１，２−ジメトキシエタン、１，２−ジエトキシエタン等のエーテル類、ジクロロメタン、１，２−ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、メタノール、エタノール、２−プロパノール、ブタノール等のアルコール類、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、Ｎ−メチルピロリドン、ジメチルスルホキシド（ＤＭＳＯ）、酢酸エチルまたはこれらの混合溶媒等が挙げられる。パラジウム触媒としては、パラジウム−炭素、水酸化パラジウム、パラジウムブラック等が好ましい。
　また、本反応は、化合物（Ｂ−７）に強酸存在下、室温~加熱還流下で、通常０．５~２日間反応させることによっても行われる。用いられる酸としては、トリフルオロ酢酸等が挙げられる。
化合物（Ｂ−１０）の合成

（式中、Ｒ^６はカルボキシル基の保護基を表す。またＲ^９は無置換若しくは置換された炭素数１~９のアルキルスルホニル基、または無置換若しくは置換されたフェニルスルホニル基を表す。またＺ^１は脱離基を表す。）本合成法は、化合物（Ｂ−８）のフェノール性水酸基をスルホニルエステル化することにより、化合物（Ｂ−１０）を合成する方法である。Ｒ^９で示されるスルホニル基としてはメタンスルホニル基、トリフルオロメタンスルホニル基、ｐ−トルエンスルホニル基等が挙げられる。Ｚ^１で示される脱離基としてはハロゲン原子、メタンスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基等が挙げられる。本反応は、化合物（Ｂ−８）と（Ｂ−９）を等量、あるいは一方を過剰に用い、反応に不活性な溶媒中、塩基の存在下、０℃~加熱還流下で、通常０．５時間~３日間反応させることによって行なわれる。本反応は窒素等の不活性ガス雰囲気下で行うことが好ましい。ここに、溶媒としては特に限定はされないが、例えばベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４−ジオキサン、１，２−ジメトキシエタン、１，２−ジエトキシエタン等のエーテル類、ジクロロメタン、１，２−ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、Ｎ−メチルピロリドン、ジメチルスルホキシド（ＤＭＳＯ）、ピリジン、酢酸エチル、またはこれらの混合溶媒等が挙げられる。本反応は不活性ガス雰囲気下で行うことが好ましい。塩基としては、水素化ナトリウム、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、炭酸水素ナトリウム等の無機塩、トリエチルアミン、Ｎ−エチル−Ｎ，Ｎ−ジイソプロピルアミン（ＤＩＰＥＡ）、１，８−ジアザビシクロ［５．４．０］−７−ウンデセン（ＤＢＵ）、ピリジン等が挙げられる。
化合物（Ｂ−１１）の合成

（式中、Ｒ^６はカルボキシル基の保護基を表す。またＲ^９は無置換若しくは置換された炭素数１~９のアルキルスルホニル基、または無置換若しくは置換されたフェニルスルホニル基を表す。またＹ^１は−Ｂ（ＯＨ）_２または−Ｂ（ＯＲ^７）ＯＲ^８を表す。ここで、Ｒ^７およびＲ^８は同一または互いに異なって低級アルキル基、またはＲ^７およびＲ^８が一体となって低級アルキレン基を表す。）本合成法は、化合物（Ｂ−１０）と（Ａ−３）とをカップリングさせることにより、化合物（Ｂ−１１）を合成する方法である。Ｒ^９で示されるスルホニル基としてはメタンスルホニル基、トリフルオロメタンスルホニル基、ｐ−トルエンスルホニル基等が挙げられる。本反応は、化合物（Ｂ−１０）と（Ａ−３）を等量、あるいは一方を過剰に用い、反応に不活性な溶媒中、塩基およびパラジウム触媒存在下、室温~加熱還流下で、通常０．５~２日間反応させることによって行われる。本反応は窒素等の不活性ガス雰囲気下で行うことが好ましい。ここに、溶媒としては特に限定はされないが、例えばベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４−ジオキサン、１，２−ジメトキシエタン、１，２−ジエトキシエタン等のエーテル類、ジクロロメタン、１，２−ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、メタノール、エタノール、２−プロパノール、ブタノール等のアルコール類、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、Ｎ−メチルピロリドン、ジメチルスルホキシド（ＤＭＳＯ）、水またはこれらの混合溶媒等が挙げられる。塩基としては、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、リン酸カリウム等の無機塩、ナトリウムエトキシド、ナトリウムメトキシド等の金属アルコキシド、あるいはこれらの塩基を水等で希釈した溶液等が挙げられる。パラジウム触媒としては、テトラキス（トリフェニルホスフィン）パラジウム、ジクロロビス（トリフェニルホスフィン）パラジウム、塩化パラジウム−１，１’−ビス（ジフェニルホスフィノ）フェロセン等が好ましい。
化合物（Ｂ−１２）の合成

　（式中、Ｒ^６はカルボキシル基の保護基を表す。）本合成法は、化合物（Ｂ−１１）の保護基Ｒ^６を酸または塩基等により脱保護させることにより、本発明化合物（Ｂ−１２）を合成する方法である。本反応は、化合物（Ｂ−１１）に、反応に不活性な溶媒中、酸または塩基を等量、あるいは過剰に用い、室温~加熱還流下で、通常０．５~５日間反応されることによって行なわれる。ここに、溶媒としては特に限定はされないが、例えばベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４−ジオキサン、１，２−ジメトキシエタン、１，２−ジエトキシエタン等のエーテル類、ジクロロメタン、１，２−ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、メタノール、エタノール、２−プロパノール、ブタノール等のアルコール類、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、Ｎ−メチルピロリドン、ジメチルスルホキシド（ＤＭＳＯ）、水またはこれらの混合溶媒等が挙げられる。酸としては、塩化水素、臭化水素、硫酸、硝酸、リン酸等の無機酸、あるいはこれらの酸を水または有機溶媒で希釈した溶液等が挙げられる。塩基としては、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、炭酸ナトリウム、炭酸カリウム等の無機塩、ナトリウムエトキシド、ナトリウムメトキシド等の金属アルコキシド、あるいはこれらの塩基を水等で希釈した溶液等が挙げられる。
　合成法（Ｃ）
　化合物（Ｃ−２）の合成

　（式中、Ｘ^４は脱離基を表す。）本合成法は、化合物（Ｃ−１）をハロゲン化することにより、化合物（Ｃ−２）を合成する方法である。Ｘ^４で示される脱離基としては、ヨウ素原子、臭素原子、塩素原子が挙げられる。本反応は、化合物（Ｃ−１）に、反応に不活性な溶媒中、ハロゲン化剤を等量、あるいは過剰に用い、０℃~加熱還流下で、通常０．５時間~３日間反応させることによって行なわれる。本反応は窒素等の不活性ガス雰囲気下で行うことが好ましい。ここで、溶媒としては特に限定はされないが、例えばベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４−ジオキサン、１，２−ジメトキシエタン、１，２−ジエトキシエタン等のエーテル類、ジクロロメタン、１，２−ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、酢酸エチル、水またはこれらの混合溶媒等が挙げられる。ハロゲン化剤としては、塩素、臭素、Ｎ−クロロスクシンイミド、Ｎ−ブロモスクシンイミド、Ｎ−ヨードスクシンイミド、水またはこれらの混合溶媒等が挙げられる。
化合物（Ｃ−３）の合成

（式中、Ｘ^４およびＹ^２は脱離基を表す。）本合成法は、化合物（Ｃ−２）と（Ｂ−２）を反応させることにより、化合物（Ｃ−３）を合成する方法である。Ｘ^４で示される脱離基としては、ヨウ素原子、臭素原子、塩素原子が挙げられる。Ｙ^２で示される脱離基としてはハロゲン原子、メタンスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基等が挙げられる。本反応は、化合物（Ｃ−２）と（Ｂ−２）を等量、あるいは一方を過剰に用い、反応に不活性な溶媒中、塩基の存在下、室温~加熱還流下で、通常０．５時間~３日間反応させることによって行なわれる。本反応は窒素等の不活性ガス雰囲気下で行うことが好ましい。ここに、溶媒としては特に限定はされないが、例えばベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４−ジオキサン、１，２−ジメトキシエタン、１，２−ジエトキシエタン等のエーテル類、ジクロロメタン、１，２−ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、Ｎ−メチルピロリドン、ジメチルスルホキシド（ＤＭＳＯ）、ピリジン、酢酸エチルまたはこれらの混合溶媒等が挙げられる。塩基としては、水素化ナトリウム、水素化ナトリウム、水酸化カリウム、水酸化リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等の無機塩、ナトリウムエトキシド、ナトリウムメトキシド等の金属アルコキシド、トリエチルアミン、Ｎ‐エチル‐Ｎ，Ｎ‐ジイソプロピルアミン（ＤＩＰＥＡ）、１，８−ジアザビシクロ［５．４．０］−７−ウンデセン（ＤＢＵ）、ピリジンなどが挙げられる。
化合物（Ｃ−４）の合成

　（式中、Ｒ^６はカルボキシル基の保護基、Ｘ^４は脱離基を表す。）本合成法は、化合物（Ｃ−３）と（Ａ−６）とをカップリングさせることにより、化合物（Ｃ−４）を合成する方法である。Ｘ^４で示される脱離基としてはハロゲン原子、メタンスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基等が挙げられる。本反応は化合物（Ｃ−３）と（Ａ−６）を等量、あるいは一方を過剰に用い、反応に不活性な溶媒中、塩基および遷移金属触媒存在下、場合により配位子、カルボン酸および銅（Ｉ価またはＩＩ価）塩を加えて、室温~加熱還流下で、通常０．５~２日間反応させることによって行われる。本反応は窒素等の不活性ガス雰囲気下で行うことが好ましい。ここに、溶媒としては特に限定はされないが、例えばベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４−ジオキサン、１，２−ジメトキシエタン、１，２−ジエトキシエタン等のエーテル類、ジクロロメタン、１，２−ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、メタノール、エタノール、２−プロパノール、ブタノール等のアルコール類、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、Ｎ−メチルピロリドン、ジメチルスルホキシド（ＤＭＳＯ）、水またはこれらの混合溶媒等が挙げられる。塩基としては、水素化リチウム、水素化ナトリウム、水素化カリウム、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、フッ化カリウム、フッ化セシウム、リン酸三カリウム、酢酸ナトリウム、酢酸カリウム等、炭素数１~６のアルコキシドの金属塩（リチウム塩、ナトリウム塩、カリウム塩、マグネシウム塩）、炭素数１~６のアルキルアニオンの金属塩（リチウム塩、ナトリウム塩、カリウム塩、マグネシウム塩）、テトラ（炭素数１~４のアルキル）アンモニウム塩（フッ化塩、塩化塩、臭化塩）、ジイソプロピルエチルアミン、トリブチルアミン、Ｎ−メチルモルホリン、ジアザビシクロウンデセン、ジアザビシクロオクタン、又はイミダゾール等が挙げられる。遷移金属触媒としては、銅、パラジウム、コバルト、鉄、ロジウム、ルテニウム、及びイリジウム等が挙げられる。配位子としては、トリ（ｔ−ブチル）ホスフィン、トリ（シクロヘキシル）ホスフィン、ｔ−ブチルジシクロヘキシルホスフィン、ジ（ｔ−ブチル）シクロヘキシルホスフィン、又はジ（ｔ−ブチル）メチルホスフィン等が挙げられる。銅（Ｉ価またはＩＩ価）塩としては、塩化銅（Ｉ）、臭化銅（Ｉ）、ヨウ化銅（Ｉ）、酢酸銅（Ｉ）、フッ化銅（ＩＩ）、塩化銅（ＩＩ）、臭化銅（ＩＩ），ヨウ化銅（ＩＩ）、酢酸銅（ＩＩ）及びこれらの水和物、ならびにこれらの混合物等が挙げられる。カルボン酸としては、ギ酸、酢酸、プロピオン酸、ｎ−ブチル酸、イソブチル酸、　ペンタン酸、イソペンタン酸、ピバル酸、及びトリフルオロ酢酸等が挙げられる。
化合物（Ｃ−５）の合成

（式中、Ｒ^６はカルボキシル基の保護基を表す。）本合成法は、化合物（Ｃ−４）の脱ベンジル化を行うことにより、化合物（Ｃ−５）を合成する方法である。本反応は、化合物（Ｃ−４）を反応に不活性な溶媒中、パラジウム触媒存在下、水素ガス雰囲気下、室温~加熱還流下で、通常０．５~２日間反応させることによって行われる。ここに、溶媒としては特に限定はされないが、例えばベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４−ジオキサン、１，２−ジメトキシエタン、１，２−ジエトキシエタン等のエーテル類、ジクロロメタン、１，２−ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、メタノール、エタノール、２−プロパノール、ブタノール等のアルコール類、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、Ｎ−メチルピロリドン、ジメチルスルホキシド（ＤＭＳＯ）、酢酸エチルまたはこれらの混合溶媒等が挙げられる。パラジウム触媒としては、パラジウム−炭素、水酸化パラジウム、パラジウムブラック等が好ましい。
　また、本反応は、化合物（Ｃ−４）に強酸存在下、室温~加熱還流下で、通常０．５~２日間反応させることによっても行われる。用いられる酸としては、トリフルオロ酢酸等が挙げられる。
化合物（Ｃ−６）の合成

（式中、Ｒ^６はカルボキシル基の保護基を表す。またＲ^９は無置換若しくは置換された炭素数１~９のアルキルスルホニル基、または無置換若しくは置換されたフェニルスルホニル基を表す。またＺ^１は脱離基を表す。）本合成法は、化合物（Ｃ−５）のフェノール性水酸基をスルホニルエステル化することにより、化合物（Ｃ−６）を合成する方法である。Ｒ^９で示されるスルホニル基としてはメタンスルホニル基、トリフルオロメタンスルホニル基、ｐ−トルエンスルホニル基等が挙げられる。Ｚ^１で示される脱離基としてはハロゲン原子、メタンスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基等が挙げられる。本反応は、化合物（Ｃ−５）と（Ｂ−９）を等量、あるいは一方を過剰に用い、反応に不活性な溶媒中、塩基の存在下、０℃~加熱還流下で、通常０．５時間~３日間反応させることによって行なわれる。本反応は窒素等の不活性ガス雰囲気下で行うことが好ましい。ここに、溶媒としては特に限定はされないが、例えばベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４−ジオキサン、１，２−ジメトキシエタン、１，２−ジエトキシエタン等のエーテル類、ジクロロメタン、１，２−ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、Ｎ−メチルピロリドン、ジメチルスルホキシド（ＤＭＳＯ）、ピリジン、酢酸エチル、またはこれらの混合溶媒等が挙げられる。本反応は不活性ガス雰囲気下で行うことが好ましい。塩基としては、水素化ナトリウム、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、炭酸水素ナトリウム等の無機塩、トリエチルアミン、Ｎ−エチル−Ｎ，Ｎ−ジイソプロピルアミン（ＤＩＰＥＡ）、１，８−ジアザビシクロ［５．４．０］−７−ウンデセン（ＤＢＵ）、ピリジン等が挙げられる。
化合物（Ｃ−７）の合成

（式中、Ｒ^６はカルボキシル基の保護基を表す。またＲ^９は無置換若しくは置換された炭素数１~９のアルキルスルホニル基、または無置換若しくは置換されたフェニルスルホニル基を表す。またＹ^１は−Ｂ（ＯＨ）_２または−Ｂ（ＯＲ^７）ＯＲ^８を表す。ここで、Ｒ^７およびＲ^８は同一または互いに異なって低級アルキル基、またはＲ^７およびＲ^８が一体となって低級アルキレン基を表す。）本合成法は、化合物（Ｃ−６）と（Ａ−３）とをカップリングさせることにより、化合物（Ｃ−７）を合成する方法である。Ｒ^９で示されるスルホニル基としてはメタンスルホニル基、トリフルオロメタンスルホニル基、ｐ−トルエンスルホニル基等が挙げられる。本反応は、化合物（Ｃ−６）と（Ａ−３）を等量、あるいは一方を過剰に用い、反応に不活性な溶媒中、塩基およびパラジウム触媒存在下、室温~加熱還流下で、通常０．５~２日間反応させることによって行われる。本反応は窒素等の不活性ガス雰囲気下で行うことが好ましい。ここに、溶媒としては特に限定はされないが、例えばベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４−ジオキサン、１，２−ジメトキシエタン、１，２−ジエトキシエタン等のエーテル類、ジクロロメタン、１，２−ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、メタノール、エタノール、２−プロパノール、ブタノール等のアルコール類、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、Ｎ−メチルピロリドン、ジメチルスルホキシド（ＤＭＳＯ）、水またはこれらの混合溶媒等が挙げられる。塩基としては、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、リン酸カリウム等の無機塩、ナトリウムエトキシド、ナトリウムメトキシド等の金属アルコキシド、あるいはこれらの塩基を水等で希釈した溶液等が挙げられる。パラジウム触媒としては、テトラキス（トリフェニルホスフィン）パラジウム、ジクロロビス（トリフェニルホスフィン）パラジウム、塩化パラジウム−１，１’−ビス（ジフェニルホスフィノ）フェロセン等が好ましい。
化合物（Ｃ−８）の合成

　（式中、Ｒ^６はカルボキシル基の保護基を表す。）本合成法は、化合物（Ｃ−７）の保護基Ｒ^６を酸または塩基等により脱保護させることにより、本発明化合物（Ｃ−８）を合成する方法である。本反応は、化合物（Ｃ−７）に、反応に不活性な溶媒中、酸または塩基を等量、あるいは過剰に用い、室温~加熱還流下で、通常０．５~５日間反応されることによって行なわれる。ここに、溶媒としては特に限定はされないが、例えばベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４−ジオキサン、１，２−ジメトキシエタン、１，２−ジエトキシエタン等のエーテル類、ジクロロメタン、１，２−ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、メタノール、エタノール、２−プロパノール、ブタノール等のアルコール類、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、Ｎ−メチルピロリドン、ジメチルスルホキシド（ＤＭＳＯ）、水またはこれらの混合溶媒等が挙げられる。酸としては、塩化水素、臭化水素、硫酸、硝酸、リン酸等の無機酸、あるいはこれらの酸を水または有機溶媒で希釈した溶液等が挙げられる。塩基としては、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、炭酸ナトリウム、炭酸カリウム等の無機塩、ナトリウムエトキシド、ナトリウムメトキシド等の金属アルコキシド、あるいはこれらの塩基を水等で希釈した溶液等が挙げられる。
　以下、前記式（Ｉ）で表される化合物のうち、好ましい化合物およびその製薬学的に許容される塩としては、製薬学的に許容される塩であれば特に限定されないが、かかる塩としては、例えば、塩化水素、臭化水素、硫酸、硝酸、リン酸、炭酸などの無機酸との塩；マレイン酸、フマル酸、クエン酸、リンゴ酸、酒石酸、乳酸、コハク酸、安息香酸、シュウ酸、メタンスルホン酸、ベンゼンスルホン酸、ｐ−トルエンスルホン酸、酢酸、トリフルオロ酢酸、ギ酸などの有機酸との塩；グリシン、リジン、アルギニン、ヒスチジン、オルニチン、グルタミン酸、アスパラギン酸などのアミノ酸との塩；ナトリウム、カリウム、リチウムなどのアルカリ金属との塩；カルシウム、マグネシウムなどのアルカリ土類金属との塩；アルミニウム、亜鉛、鉄などの金属との塩；テトラメチルアンモニウム、コリンなどのような有機オニウムとの塩；アンモニア、プロパンジアミン、ピロリジン、ピペリジン、ピリジン、エタノールアミン、Ｎ，Ｎ−ジメチルエタノールアミン、４−ヒドロキシピペリジン、ｔ−オクチルアミン、ジベンジルアミン、モルホリン、グルコサミン、フェニルグリシルアルキルエステル、エチレンジアミン、Ｎ−メチルグルカミン、グアニジン、ジエチルアミン、トリエチルアミン、ジシクロヘキシルアミン、Ｎ，Ｎ’−ジベンジルエチレンジアミン、クロロプロカイン、プロカイン、ジエタノールアミン、Ｎ−ベンジルフェニルアミン、ピペラジン、トリス（ヒドロキシメチル）アミノメタンなどの有機塩基との塩が挙げられる。
　さらに、式（Ｉ）で表される化合物およびその塩には、各種の水和物や溶媒和物が包含される。
　式（Ｉ）で表される化合物の製薬学的に許容される前記各種の塩は、当技術分野の通常の知識に基づいて適宜製造することができる。
　本発明の化合物には、式（Ｉ）で表される化合物の立体異性体、ラセミ体、および可能なすべての光学活性体も含まれる。
　本発明の式（Ｉ）で表される化合物、およびその製薬学的に許容される塩は、特に優れたキサンチンオキシダーゼ阻害活性を有する。その優れたキサンチンオキシダーゼ阻害活性から、本発明の式（Ｉ）で表される化合物、およびその製薬学的に許容される塩は、キサンチンオキシダーゼ阻害剤として有用である。
　本発明の式（Ｉ）で表される化合物、およびその製薬学的に許容される塩は、キサンチンオキシダーゼ阻害剤として臨床で応用可能な、痛風、高尿酸血症、腫瘍崩壊症候群、尿路結石、高血圧症、脂質異常症、糖尿病、動脈硬化症や心不全等の心血管疾患、糖尿病性腎症等の腎疾患、慢性閉塞性肺疾患等の呼吸器疾患、炎症性腸疾患または自己免疫性疾患等、キサンチンオキシダーゼの関与する疾患の治療または予防のための医薬として使用することができる。
　前記式（Ｉ）で表される化合物、その製薬学的に許容される塩は、製薬学的に許容される担体および／または希釈剤とともに、医薬組成物とすることができる。この医薬組成物は種々の剤形に成形して、経口的または非経口的に投与することができる。非経口投与としては、例えば、静脈、皮下、筋肉、経皮、または直腸内への投与が挙げられる。
　本発明の式（Ｉ）で表される化合物またはその塩の１種または２種以上を有効成分として含有する製剤は、通常製剤化に用いられる担体や賦形剤、その他の添加剤を用いて調製される。製剤用の担体や賦形剤としては、固体または液体いずれでも良く、例えば乳糖、ステアリン酸マグネシウム、スターチ、タルク、ゼラチン、寒天、ペクチン、アラビアゴム、オリーブ油、ゴマ油、カカオバター、エチレングリコール等やその他常用のものが挙げられる。投与は錠剤、丸剤、カプセル剤、顆粒剤、散剤、液剤等による経口投与、あるいは静注、筋注等の注射剤、坐剤、経皮等による非経口投与のいずれの形態であってもよい。
　本発明の式（Ｉ）で表される化合物、またはその製薬学的に許容される塩は、疾患の種類、投与経路、患者の症状、年齢、性別、体重等により異なるが、通常成人１日あたり、０．０１~１０００ｍｇの範囲で、１回または数回に分けて、投与することができる。しかし、投与量は種々の条件により変動するため、上記投与量よりも少ない量で十分な場合もあり、また上記の範囲を超える投与量が必要な場合もある。 The terms used alone or in combination in this specification will be described below. Unless otherwise specified, the description of each substituent is common to each site. When any variable is present in any constituent element, its definition is independent in each constituent element. Also, combinations of substituents and variables are permissible as long as such combinations result in chemically stable compounds.
“Xanthine oxidase” is generally used in the broad sense of an enzyme that catalyzes an oxidation reaction from hypoxanthine to xanthine and further to uric acid, and in the narrow sense of an oxidase-type xanthine oxidoreductase that is one of the enzymes that catalyze the reaction. In the present invention, “xanthine oxidase” is a general term for enzymes that catalyze an oxidation reaction from hypoxanthine to xanthine and further to uric acid, unless otherwise specified. There are two types of xanthine oxidoreductase responsible for this reaction, an oxidase type and a dehydrogenase type, both of which are included in the xanthine oxidase of the present invention. In “xanthine oxidase inhibitory activity”, “xanthine oxidase inhibitor” and the like, “xanthine oxidase” has the same meaning as defined above unless otherwise specified.
In the present invention, the “aryl group” means a group generated by leaving one hydrogen atom bonded to an aromatic hydrocarbon ring. Examples of the aryl group having 6 to 10 carbon atoms include a phenyl group, a naphthyl group, an indenyl group, a tetrahydronaphthyl group, an indanyl group, and an azulenyl group.
In the present invention, the “heteroaryl group” refers to a 3- to 10-membered monocyclic or bicyclic aromatic containing 1 to 5 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom. It means a heterocyclic system having a family. “A 3 to 10-membered monocyclic or bicyclic aromatic ring system having an aromatic attribute” means 3 to 5 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom. A monovalent group obtained by removing a hydrogen atom from a 10-membered monocyclic or bicyclic aromatic heterocycle. In the case of a bicyclic heteroaryl group, if one ring is an aromatic ring or an aromatic heterocyclic ring, the other ring may be a non-aromatic ring structure. The number of heteroatoms in the heteroaryl group and the combination thereof are not particularly limited as long as they can form a predetermined number of rings and can exist chemically and stably. Examples of such heteroaryl groups include pyridyl group, pyrazyl group, pyrimidyl group, pyridazinyl group, furyl group, thienyl group, pyrazolyl group, 1,3-dioxaindanyl group, isoxazolyl group, isothiazolyl group, benzofuranyl group, Isobenzofuryl group, benzothienyl group, indolyl group, isoindolyl group, chromanyl group, benzothiazolyl group, benzoimidazolyl group, benzoxazolyl group, pyranyl group, imidazolyl group, oxazolyl group, thiazolyl group, triazinyl group, triazolyl group, furanyl group , Thiadiazolyl group, dihydrobenzofuryl group, dihydroisobenzofuryl group, dihydroquinolyl group, dihydroisoquinolyl group, dihydrobenzoxazolyl group, dihydropteridinyl group, benzoxazolyl group, benzoyl Oxazolyl group, a benzo-di benzoxazolyl group, quinolyl group, isoquinolyl group, benzotriazolyl group, pteridinyl, purinyl, quinoxalinyl group, quinazolinyl group, cinnolinyl group, and tetrazolyl group, and the like.
In the present invention, the “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
In the present invention, the “alkyl group” means a monovalent saturated linear or branched aliphatic hydrocarbon group. Examples of the alkyl group having 1 to 6 carbon atoms include methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, isopropyl group, isobutyl group, and s-butyl group. T-butyl group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3, 3 -Dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, t-pentyl group, isohexyl group and the like can be mentioned.
In the present invention, the “alkylene group” means a divalent saturated linear or branched aliphatic hydrocarbon group having 1 to 6 carbon atoms. Examples of the alkylene group having 1 to 6 carbon atoms include methylene group, ethylene group, n-propylene group, isopropylene group, n-pentylene group, n-hexylene group and the like.
In the present invention, the “cycloalkyl group” means a cyclic saturated hydrocarbon group. Examples of the cycloalkyl group having 3 to 7 carbon atoms include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.
In the present invention, the “halogenoalkyl group” means an alkyl group substituted with one or more halogens. Examples of the halogenoalkyl group having 1 to 6 carbon atoms include a trifluoromethyl group and a difluoromethyl group.
In the present invention, the “monocyclic nitrogen-containing saturated heterocycle” includes one nitrogen atom and may further contain one heteroatom composed of a nitrogen atom, a sulfur atom, and an oxygen atom. Alternatively, it means a partially unsaturated monocyclic heterocycle, and examples thereof include pyrrolidine, piperidine, piperazine, azepan, diazepan, azocan, morpholine, thiomorpholine, tetrahydropyridine ring and the like.
In the “monocyclic nitrogen-containing saturated heterocyclic ring”, a sulfur atom as a ring atom may be oxidized to form an oxide by oxidizing an oxide or a dioxide, or a nitrogen atom.
In the present invention, “carboxyl-protecting group” refers to, for example, PROTECTIVE GROUPS in ORGANIC SYNTHESIS, THIRD EDITION, John Wiley & Sons, Inc. For example, a methyl group, an ethyl group, an isopropyl group, a heptyl group, a t-butyl group, a methoxymethyl group, a methylthiomethyl group, a methoxyethoxymethyl group, a methoxyethyl group, Examples thereof include a benzyl group and a t-butyldimethylsilyl group.
In the formula (I), A represents an aryl group having 6 to 10 carbon atoms or a heteroaryl group, wherein the aryl group or heteroaryl group is unsubstituted or the same or different from each other. , Halogen atom, -CN, -NO ₂ , An alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a phenyl group, -CH ₂ -O-R ² , -O-R ² , -O-halogenoalkyl having 1 to 6 carbon atoms, -O-benzyl, -O-phenyl, -O-CO-R ² , -NR ³ R ⁴ , -NH-CO-R ² , -CO ₂ -R ² , -CO-R ² , -CO-NR ³ R ⁴ , -NH-SO ₂ -R ² , -CO-aryl, -S-R ² , -SO ₂ -C1-C6 alkyl, and -SO ₂ -It may be substituted with 1 to 3 groups R selected from the group consisting of phenyl.
Specific examples of the “aryl group” and the “heteroaryl group” are as defined above, and as the preferable “aryl group” or “heteroaryl group” of A, a phenyl group, a pyridyl group, a pyrazyl group, a pyrimidyl group Group, furyl group, thienyl group, isoxazolyl group, isothiazolyl group, benzofuranyl group, benzothienyl group, benzothiazolyl group, benzoimidazolyl group, benzoxazolyl group, pyranyl group, imidazolyl group, oxazolyl group, thiazolyl group, triazinyl group, triazolyl group , A benzoxazolyl group, a benzoisoxazolyl group, and the like, and a phenyl group is more preferable.
A is unsubstituted or the same or different from each other, and is a halogen atom, -CN, -NO ₂ , An alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a phenyl group, -CH ₂ -O-R ² , -O-R ² , -O-halogenoalkyl having 1 to 6 carbon atoms, -O-benzyl, -O-phenyl, -O-CO-R ² , -NR ³ R ⁴ , -NH-CO-R ² , -CO ₂ -R ² , -CO-R ² , -CO-NR ³ R ⁴ , -NH-SO ₂ -R ² , -CO-aryl, -S-R ² , -SO ₂ -C1-C6 alkyl, and -SO ₂ -It may be substituted with 1 to 3 groups R selected from the group consisting of phenyl. When A is substituted with R, the number of R is preferably 1 or 2. A is unsubstituted or is a halogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a phenyl group, -O-R ² And -O-, preferably substituted with a group R selected from the group consisting of halogenoalkyl having 1 to 6 carbon atoms. More preferably, A is unsubstituted or substituted with a group R selected from the group consisting of a halogen atom, a methyl group, and a methoxy group. As the halogen atom, a fluorine atom is preferable.
More preferable A can be represented by the following structural formula, for example.

In the formula (I), R ¹ Represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. Specific examples of the “alkyl group having 1 to 6 carbon atoms” are as defined above. Preferred “alkyl groups having 1 to 6 carbon atoms” are methyl group, ethyl group, n-propyl group, n -Butyl group, n-pentyl group, n-hexyl group, isopropyl group, isobutyl group, s-butyl group, t-butyl group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, 4-methyl Pentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethyl And butyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, t-pentyl group, and isohexyl group. ¹ Is more preferably a hydrogen atom or a methyl group, and particularly preferably a hydrogen atom.
In the formula (I), R ² Represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. Specific examples of the “alkyl group having 1 to 6 carbon atoms” are as defined above. Preferred “alkyl groups having 1 to 6 carbon atoms” are methyl group, ethyl group, n-propyl group, n -Butyl group, n-pentyl group, n-hexyl group, isopropyl group, isobutyl group, s-butyl group, t-butyl group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, 4-methyl Pentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethyl And butyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, t-pentyl group, and isohexyl group. ² Is more preferably a hydrogen atom or a methyl group, and particularly preferably a methyl group.
In the formula (I), R ³ And R ⁴ Are the same or different and are a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, wherein R is ³ And R ⁴ May be combined to form a monocyclic nitrogen-containing saturated heterocyclic ring together with the nitrogen atom to which they are bonded. Specific examples of the “alkyl group having 1 to 6 carbon atoms” and the “monocyclic nitrogen-containing saturated heterocyclic ring” are as defined above, but preferred “alkyl groups having 1 to 6 carbon atoms” include Methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, isopropyl group, isobutyl group, s-butyl group, t-butyl group, isopentyl group, 2-methylbutyl group, Neopentyl group, 1-ethylpropyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1 , 1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, t-pentyl group, and Hexyl group and the like, preferably a "monocyclic nitrogen-containing saturated heterocyclic ring" include pyrrolidine, piperidine, piperazine, azepane, diazepane, azocane, morpholine, thiomorpholine, tetrahydropyridine ring, and the like. R ³ , R ⁴ The “monocyclic nitrogen-containing saturated heterocyclic ring” is more preferably a hydrogen atom, a methyl group, pyrrolidine, piperidine, piperazine and morpholine, and particularly preferably a hydrogen atom, a methyl group and morpholine.
In the formula (I), X, Y and Z are CR ⁵ Or represents a nitrogen atom, wherein one of X, Y and Z represents a nitrogen atom and the other two represent CR ⁵ Represents. Three examples where X, Y, and Z are each nitrogen atoms can be represented by the following structural formula. Among these, Y is preferably a nitrogen atom.

R ⁵ Examples thereof include a hydrogen atom, a halogen atom, or an alkyl group having 1 to 6 carbon atoms, and a hydrogen atom is preferable.
In the formula (I), A, R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X, Y and Z are preferably combinations of the above-described preferred groups, and A, R, R of the structure of the formula (I) in which preferred groups are combined. ¹ , R ² It is more preferable to combine the groups with more preferable groups. Such a more preferred R of the combination of formula (I) ¹ Particularly preferred are combinations in which are particularly preferred groups.
The compound of the present invention is a compound that exhibits excellent xanthine oxidase inhibitory activity. Further, the compound of the present invention has an excellent uric acid lowering action. Furthermore, the compounds of the present invention have a long-lasting uric acid lowering action.
Specific examples of preferred compounds include the following compounds.

Among these, more preferable compounds are compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21. , 22, 24, 26, 27, 28, 29, 30, 32, 33, 34, 35, 36, 38, 40, 41, 42, 43, 44, 45, 47, 49, 50, 51, 52, 53 , 54, 55, 56, 57, 58, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 82 83, 84, 85, 87, 93, 94, 95, 96, 97, 99, 100, 101, 102, 103, and 105, more preferably compounds 1, 2, 3, 4, 5, 49 , 50, 55 and 57, particularly preferably compounds 1, 2, 3 Preliminary is 4, most preferably the compounds 1 and 2.
In the compound represented by the above formula (II), which can be used as an intermediate for producing the compound represented by the above formula (I) of the present invention, A, R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X, Y and Z are the same as defined in the above formula (I). W represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, or a cyano group. W is more preferably a halogen atom or a cyano group, and particularly preferably a cyano group. R ⁶ Represents a protecting group for a carboxyl group. The definition of the protective group of a carboxyl group is as above-mentioned, Preferably they are a methyl group, an ethyl group, and a benzyl group.
Furthermore, in the compound represented by the above formula (III) which can be used as a production intermediate of the compound represented by the above formula (I) of the present invention, R ¹ , R ⁵ , X, Y and Z are the same as defined in the above formula (I). V represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, a hydroxyl group, or a benzyloxy group. V is preferably a halogen atom, a trifluoromethanesulfonyloxy group, a hydroxyl group, or a benzyloxy group. W represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, or a cyano group. W is more preferably a halogen atom or a cyano group, and particularly preferably a cyano group. R ⁶ Represents a protecting group for a carboxyl group. The definition of the protective group of a carboxyl group is as above-mentioned, Preferably they are a methyl group, an ethyl group, and a benzyl group.
<General synthesis method>
The compounds of formula (I) and intermediates of the present invention can be synthesized, for example, according to any of the synthetic methods as described below. In each formula, A, R, and R ¹ Is as defined in formula (I). Moreover, the reagent or solvent as the condition described in the chemical formula is merely an example as described in the text. Each substituent may be protected with an appropriate protecting group, if necessary, and may be deprotected at an appropriate stage. In addition, as a suitable protecting group and a method for removing the protecting group, a protecting group for each substituent generally used in this field and a known method can be adopted. It is described in.
In addition, when abbreviations of substituents, reagents, and solvents in the text or in the table are used, the following are respectively indicated.
DMF: N, N-dimethylformamide
THF: tetrahydrofuran
Ph: Phenyl
TFA: trifluoroacetic acid
Synthesis method (A)
Synthesis of compound (A-2)

(Where X ¹ And X ² Represents a leaving group. ) X ¹ And X ² Examples of the leaving group represented by the formula include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. This reaction is a method of synthesizing compound (A-2) by lithiating or sodiumating the 4-position of pyridine in compound (A-1) with a base and then formylating with a formylating agent. Examples of the base include lithium diisopropylamine (LDA) prepared from diisopropylamine and n-butyllithium. Examples of the formylating agent include N, N-dimethylformamide (DMF) and N-formylmorpholine. This reaction is carried out at −78 ° C. to 0 ° C. in a solvent inert to the reaction by subjecting compound (A-1) to an equal amount or a small excess of the base, followed by an equal amount or an excess amount of formylation. The reaction is usually carried out by adding an agent and reacting for 0.5 to 5 hours. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, or a mixture thereof. A solvent etc. are mentioned.
Synthesis of compound (A-4)

(Where X ¹ And X ² Is a leaving group, Y ¹ Is -B (OH) ₂ Or -B (OR ⁷ ) OR ⁸ Represents. Where R ⁷ And R ⁸ Are the same or different from each other and are an alkyl group having 1 to 6 carbon atoms, or R ⁷ And R ⁸ Together represent an alkylene group having 1 to 6 carbon atoms. ) This reaction is a method of synthesizing compound (A-4) by coupling compound (A-2) with boronic acid or compound (A-3) which is a boronic ester. X ¹ And X ² Examples of the leaving group represented by the formula include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. In this reaction, compounds (A-2) and (A-3) are used in equal amounts or in excess, and usually in a solvent inert to the reaction in the presence of a base and a palladium catalyst at room temperature to heating under reflux. The reaction is performed for 0.5 to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, metal alkoxides such as tripotassium phosphate, sodium ethoxide and sodium methoxide, or these bases. And a solution obtained by diluting with water or the like. As the palladium catalyst, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride-1,1′-bis (diphenylphosphino) ferrocene and the like are preferable.
Synthesis of compound (A-5)

(Where X ² Represents a leaving group. ) X ² Examples of the leaving group represented by the formula include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. This reaction is a conversion reaction from a formyl group to a cyano group, and is performed by reacting the aromatic aldehyde derivative represented by the above formula (A-4) with hydroxylamine. As hydroxylamine, other salts such as hydrochloride thereof may be used. In that case, it is preferable to add an appropriate basic substance. In addition, the reaction can be accelerated by adding 1.0 to 3.0 equivalents of acetic anhydride, acetyl chloride, trichloroacetyl chloride and the like. The amount of hydroxylamine or a salt thereof used in these reactions is usually 1 equivalent or more, preferably 1.0 to 2.0 equivalents. When a basic substance is used, it is 1.0 to 3.0 equivalents relative to the hydroxylamine salt. As basic substances to be used, carboxylates such as sodium formate, potassium formate and sodium acetate, carbonates such as potassium carbonate, sodium carbonate and sodium bicarbonate, organic amine salts such as triethylamine, pyridine and 4-aminopyridine are used. It is done. The reaction is carried out in an inert solvent in the presence of a base at room temperature to heating under reflux, usually for 0.5 hour to 3 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Solvents used in these reactions include acetic acid, formic acid, toluene, benzene, pyridine, ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1, Examples include 2-dimethoxyethane, 1,2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), methanol, ethanol, 2-propanol and the like.
Synthesis of compound (A-7)

(Wherein R ⁶ Is a protecting group for carboxyl group, X ² Represents a leaving group. ) This synthesis method is a method of synthesizing compound (A-7) by coupling compounds (A-5) and (A-6). X ² Examples of the leaving group represented by the formula include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. In this reaction, the compounds (A-5) and (A-6) are used in an equal amount, or one of them in excess, and in the presence of a base and a transition metal catalyst in a solvent inert to the reaction, optionally a ligand, a carboxylic acid And a copper (I-valent or II-valent) salt, and the reaction is usually carried out at room temperature to heating under reflux for 0.5 to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Bases include lithium hydride, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, cesium fluoride, tripotassium phosphate, sodium acetate, acetic acid Metal salts of alkoxides having 1 to 6 carbon atoms such as potassium (lithium salts, sodium salts, potassium salts, magnesium salts), metal salts of alkyl anions having 1 to 6 carbon atoms (lithium salts, sodium salts, potassium salts, magnesium salts) ), Tetra (alkyl having 1 to 4 carbons) ammonium (fluoride, chloride, bromide), diisopropylethylamine, tributylamine, N-methylmorpholine, diazabicycloundecene, diazabicyclooctane, or Examples include imidazole. Examples of the transition metal catalyst include copper, palladium, cobalt, iron, rhodium, ruthenium, and iridium. Examples of the ligand include tri (t-butyl) phosphine, tri (cyclohexyl) phosphine, t-butyldicyclohexylphosphine, di (t-butyl) cyclohexylphosphine, and di (t-butyl) methylphosphine. Copper (I or II) salts include copper (I) chloride, copper (I) bromide, copper (I) iodide, copper (I) acetate, copper (II) fluoride, copper (II) chloride , Copper (II) bromide, copper (II) iodide, copper (II) acetate and hydrates thereof, and mixtures thereof. Examples of the carboxylic acid include formic acid, acetic acid, propionic acid, n-butyric acid, isobutyric acid, pentanoic acid, isopentanoic acid, pivalic acid, and trifluoroacetic acid.
Synthesis of compound (A-8)

(Wherein R ⁶ Represents a protecting group for a carboxyl group. ) This synthesis method is a protective group R of compound (A-7) ⁶ Is a method of synthesizing the compound (A-8) of the present invention by deprotecting with an acid or a base. In this reaction, compound (A-7) is usually reacted for 0.5 to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done by. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.
Synthesis method (B)
Synthesis of compound (B-3)

(Where X ⁴ And Y ² Represents a leaving group. This synthesis method is a method of synthesizing the compound (B-3) by reacting the compounds (B-1) and (B-2). X ⁴ Examples of the leaving group represented by are an iodine atom, a bromine atom, and a chlorine atom. Y ² Examples of the leaving group represented by the formula include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. In this reaction, the compounds (B-1) and (B-2) are used in an equal amount, or one of them in excess, and in an inert solvent for the reaction, in the presence of a base, at room temperature to heating under reflux, usually 0. It is carried out by reacting for 5 hours to 3 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), pyridine, acetic acid Examples thereof include ethyl or a mixed solvent thereof. Examples of the base include sodium hydride, sodium hydride, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and other inorganic salts, sodium ethoxide, sodium methoxide and other metal alkoxides, triethylamine, N-ethyl -N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), pyridine and the like.
Synthesis of compound (B-4)

(Where X ⁴ Represents a leaving group. ) This synthesis method is a method of synthesizing compound (B-4) by deprotecting the carboxyl-protecting group benzyl group of compound (B-3) with an acid or a base. In this reaction, compound (B-3) is usually reacted for 0.5 to 5 days at room temperature to heating under reflux using an equivalent amount or excess of acid or base in a solvent inert to the reaction. Is done by. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.
Synthesis of compound (B-5)

(Where X ⁴ Represents a leaving group. This synthesis method is a method of synthesizing the amide compound (B-5) by reacting the carboxyl group of the compound (B-4) with ammonia. This reaction is a method described in the literature (eg, peptide synthesis basics and experiments, Nobuo Izumiya et al., Maruzen, 1983, Comprehensive Organic Synthesis, Vol. 6, Pergamon Press, 1991, etc.) The conventional amide formation reaction may be carried out by a method according to the above or a combination thereof with a conventional method, that is, by using a condensing agent well known to those skilled in the art, or an ester available to those skilled in the art. It can be performed by an activation method, a mixed acid anhydride method, an acid chloride method, a carbodiimide method, or the like. Examples of such amide forming reagents include thionyl chloride, oxalyl chloride, N, N-dicyclohexylcarbodiimide, 1-methyl-2-bromopyridinium iodide, N, N′-carbonyldiimidazole, diphenylphosphoryl chloride, diphenyl. Phosphoryl azide, N, N′-disuccinimidyl carbonate, N, N′-disuccinimidyl oxalate, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, benzotriazole- 1-yloxytris (pyrrolidinol) phosphonium hexafluorophosphate, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate, 2- (5-norbornene -2,3-dicarboxyimi ) -1,1,3,3-tetramethyluronium tetrafluoroborate, O- (N-succinimidyl) -1,1,3,3-tetramethyluronium tetrafluoroborate, bromotris (pyrrolidino) phosphonium hexafluorophos Fate, ethyl chloroformate, isobutyl chloroformate or 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate For example, thionyl chloride, oxalyl chloride, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride or 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3,3- Tetramethyluronium hexafluorophosphate and the like are preferable. In the amide forming reaction, a base and a condensation aid may be used together with the amide forming reagent. Examples of the condensation aid used include N-hydroxybenzotriazole hydrate and N-hydroxysuccinimide.
In this reaction, the compound (B-4) and ammonia are used in an equal amount or in excess, and in a solvent inert to the reaction, in the presence of a condensing agent and a base, usually at room temperature to heating under reflux, usually 0.5 It is carried out by reacting for a time to 3 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), pyridine, acetic acid Examples thereof include ethyl or a mixed solvent thereof. Examples of the base used include trimethylamine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N, N-dimethylaniline, and 1,8-diazabicyclo [5. 4.0] tertiary aliphatic amines such as undec-7-ene, 1,5-azabicyclo [4.3.0] non-5-ene; pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline or Examples thereof include aromatic amines such as isoquinoline, among which tertiary aliphatic amines are preferable, and triethylamine or N, N-diisopropylethylamine is particularly preferable.
Synthesis of compound (B-6)

(Where X ⁴ Represents a leaving group. This synthesis method is a method of synthesizing the compound (B-6) by dehydrating the amide group of the compound (B-5) with an acid. This reaction is carried out by reacting compound (B-5) with an acid in an equivalent amount or in excess in a reaction inert solvent at room temperature to heating under reflux, usually for 0.5 to 5 days. It is. Here, the solvent is not particularly limited, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene, and halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform. Examples of the acid include thionyl chloride, oxalyl chloride, phosphoryl chloride, and phenylphosphonyl dichloride.
Synthesis of compound (B-7)

(Wherein R ⁶ Is a protecting group for carboxyl group, X ⁴ Represents a leaving group. ) This synthesis method is a method of synthesizing compound (B-7) by coupling compound (B-6) and (A-6). X ⁴ Examples of the leaving group represented by the formula include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. In this reaction, compounds (B-6) and (A-6) are used in an equal amount or in excess, and in a solvent inert to the reaction, in the presence of a base and a transition metal catalyst, in some cases, a ligand or a carboxylic acid And a copper (I-valent or II-valent) salt, and the reaction is usually carried out at room temperature to heating under reflux for 0.5 to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Bases include lithium hydride, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, cesium fluoride, tripotassium phosphate, sodium acetate, acetic acid Metal salts of alkoxides having 1 to 6 carbon atoms such as potassium (lithium salts, sodium salts, potassium salts, magnesium salts), metal salts of alkyl anions having 1 to 6 carbon atoms (lithium salts, sodium salts, potassium salts, magnesium salts) ), Tetra (alkyl having 1 to 4 carbons) ammonium (fluoride, chloride, bromide), diisopropylethylamine, tributylamine, N-methylmorpholine, diazabicycloundecene, diazabicyclooctane, or Examples include imidazole. Examples of the transition metal catalyst include copper, palladium, cobalt, iron, rhodium, ruthenium, and iridium. Examples of the ligand include tri (t-butyl) phosphine, tri (cyclohexyl) phosphine, t-butyldicyclohexylphosphine, di (t-butyl) cyclohexylphosphine, and di (t-butyl) methylphosphine. Copper (I or II) salts include copper (I) chloride, copper bromide (I), copper iodide (I), copper acetate (I), copper (II) fluoride, copper (II) chloride. , Copper bromide (II), copper (II) iodide, copper (II) acetate and hydrates thereof, and mixtures thereof. Examples of the carboxylic acid include formic acid, acetic acid, propionic acid, n-butyric acid, isobutyric acid, pentanoic acid, isopentanoic acid, pivalic acid, and trifluoroacetic acid.
Synthesis of compound (B-8)

(Wherein R ⁶ Represents a protecting group for a carboxyl group. ) This synthesis method is a method of synthesizing compound (B-8) by debenzylating compound (B-7). This reaction is carried out by reacting compound (B-7) in a solvent inert to the reaction in the presence of a palladium catalyst in a hydrogen gas atmosphere at room temperature to heating under reflux, usually for 0.5 to 2 days. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), ethyl acetate, or a mixed solvent thereof. As the palladium catalyst, palladium-carbon, palladium hydroxide, palladium black and the like are preferable.
This reaction can also be carried out by reacting compound (B-7) in the presence of a strong acid at room temperature to heating under reflux, usually for 0.5 to 2 days. Examples of the acid used include trifluoroacetic acid.
Synthesis of compound (B-10)

(Wherein R ⁶ Represents a protecting group for a carboxyl group. Also R ⁹ Represents an unsubstituted or substituted alkylsulfonyl group having 1 to 9 carbon atoms or an unsubstituted or substituted phenylsulfonyl group. Z ¹ Represents a leaving group. ) This synthesis method is a method of synthesizing compound (B-10) by sulfonyl esterifying the phenolic hydroxyl group of compound (B-8). R ⁹ Examples of the sulfonyl group represented by the formula include a methanesulfonyl group, a trifluoromethanesulfonyl group, and a p-toluenesulfonyl group. Z ¹ Examples of the leaving group represented by the formula include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. In this reaction, the compounds (B-8) and (B-9) are used in an equal amount, or one of them in excess, and in the presence of a base in a solvent inert to the reaction, usually 0 ° C. to heating under reflux. It is carried out by reacting for 5 hours to 3 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), pyridine, acetic acid Examples thereof include ethyl or a mixed solvent thereof. This reaction is preferably performed in an inert gas atmosphere. Examples of the base include sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate and other inorganic salts, triethylamine, N-ethyl-N, N-diisopropylamine ( DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), pyridine and the like.
Synthesis of compound (B-11)

(Wherein R ⁶ Represents a protecting group for a carboxyl group. Also R ⁹ Represents an unsubstituted or substituted alkylsulfonyl group having 1 to 9 carbon atoms or an unsubstituted or substituted phenylsulfonyl group. Y ¹ Is -B (OH) ₂ Or -B (OR ⁷ ) OR ⁸ Represents. Where R ⁷ And R ⁸ Are the same or different from each other and are lower alkyl groups, or R ⁷ And R ⁸ Together represent a lower alkylene group. ) This synthesis method is a method of synthesizing compound (B-11) by coupling compound (B-10) and (A-3). R ⁹ Examples of the sulfonyl group represented by the formula include a methanesulfonyl group, a trifluoromethanesulfonyl group, and a p-toluenesulfonyl group. In this reaction, compounds (B-10) and (A-3) are used in equal amounts or in excess, and usually in a solvent inert to the reaction in the presence of a base and a palladium catalyst at room temperature to heating under reflux. The reaction is performed for 0.5 to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and potassium phosphate, metal alkoxides such as sodium ethoxide and sodium methoxide, or these bases. Examples include a solution diluted with water or the like. As the palladium catalyst, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride-1,1′-bis (diphenylphosphino) ferrocene and the like are preferable.
Synthesis of compound (B-12)

(Wherein R ⁶ Represents a protecting group for a carboxyl group. ) This synthesis method is the protective group R of compound (B-11) ⁶ Is a method of synthesizing the compound (B-12) of the present invention by deprotecting with an acid or a base. In this reaction, compound (B-11) is usually reacted for 0.5 to 5 days at room temperature to heating under reflux using an equal or excess amount of acid or base in a solvent inert to the reaction. Is done by. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.
Synthesis method (C)
Synthesis of compound (C-2)

(Where X ⁴ Represents a leaving group. This synthesis method is a method of synthesizing the compound (C-2) by halogenating the compound (C-1). X ⁴ Examples of the leaving group represented by are an iodine atom, a bromine atom, and a chlorine atom. In this reaction, compound (C-1) is reacted in an solvent inert to the reaction in an equal amount or in excess, and usually at 0 ° C. to heating under reflux, usually for 0.5 hour to 3 days. Is done. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, ethyl acetate, water or a mixed solvent thereof. Examples of the halogenating agent include chlorine, bromine, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, water, or a mixed solvent thereof.
Synthesis of compound (C-3)

(Where X ⁴ And Y ² Represents a leaving group. This synthesis method is a method of synthesizing the compound (C-3) by reacting the compounds (C-2) and (B-2). X ⁴ Examples of the leaving group represented by are an iodine atom, a bromine atom, and a chlorine atom. Y ² Examples of the leaving group represented by the formula include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. In this reaction, the compounds (C-2) and (B-2) are used in an equal amount, or one of them in excess, and in an inert solvent for the reaction, in the presence of a base, at room temperature to heating under reflux, usually 0. The reaction is performed for 5 hours to 3 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), pyridine, acetic acid Examples thereof include ethyl or a mixed solvent thereof. Bases include sodium hydride, sodium hydride, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and other inorganic salts, sodium ethoxide, sodium methoxide and other metal alkoxides, triethylamine, N-ethyl -N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), pyridine and the like.
Synthesis of compound (C-4)

(Wherein R ⁶ Is a protecting group for carboxyl group, X ⁴ Represents a leaving group. This synthesis method is a method of synthesizing the compound (C-4) by coupling the compounds (C-3) and (A-6). X ⁴ Examples of the leaving group represented by the formula include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. In this reaction, compounds (C-3) and (A-6) are used in the same amount or in excess, and in a solvent inert to the reaction, in the presence of a base and a transition metal catalyst, in some cases, a ligand or a carboxylic acid And a copper (I-valent or II-valent) salt, and the reaction is usually carried out at room temperature to heating under reflux for usually 0.5 to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Bases include lithium hydride, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, cesium fluoride, tripotassium phosphate, sodium acetate, acetic acid Metal salts of alkoxides having 1 to 6 carbon atoms such as potassium (lithium salts, sodium salts, potassium salts, magnesium salts), metal salts of alkyl anions having 1 to 6 carbon atoms (lithium salts, sodium salts, potassium salts, magnesium salts) ), Tetra (alkyl having 1 to 4 carbons) ammonium (fluoride, chloride, bromide), diisopropylethylamine, tributylamine, N-methylmorpholine, diazabicycloundecene, diazabicyclooctane, or Examples include imidazole. Examples of the transition metal catalyst include copper, palladium, cobalt, iron, rhodium, ruthenium, and iridium. Examples of the ligand include tri (t-butyl) phosphine, tri (cyclohexyl) phosphine, t-butyldicyclohexylphosphine, di (t-butyl) cyclohexylphosphine, and di (t-butyl) methylphosphine. Copper (I or II) salts include copper (I) chloride, copper bromide (I), copper iodide (I), copper acetate (I), copper (II) fluoride, copper (II) chloride. , Copper bromide (II), copper (II) iodide, copper (II) acetate and hydrates thereof, and mixtures thereof. Examples of the carboxylic acid include formic acid, acetic acid, propionic acid, n-butyric acid, isobutyric acid, pentanoic acid, isopentanoic acid, pivalic acid, and trifluoroacetic acid.
Synthesis of compound (C-5)

(Wherein R ⁶ Represents a protecting group for a carboxyl group. This synthesis method is a method of synthesizing the compound (C-5) by debenzylating the compound (C-4). This reaction is carried out by reacting compound (C-4) in a solvent inert to the reaction in the presence of a palladium catalyst in a hydrogen gas atmosphere at room temperature to heating under reflux, usually for 0.5 to 2 days. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), ethyl acetate, or a mixed solvent thereof. As the palladium catalyst, palladium-carbon, palladium hydroxide, palladium black and the like are preferable.
This reaction can also be carried out by reacting compound (C-4) in the presence of a strong acid at room temperature to heating under reflux, usually for 0.5 to 2 days. Examples of the acid used include trifluoroacetic acid.
Synthesis of compound (C-6)

(Wherein R ⁶ Represents a protecting group for a carboxyl group. Also R ⁹ Represents an unsubstituted or substituted alkylsulfonyl group having 1 to 9 carbon atoms or an unsubstituted or substituted phenylsulfonyl group. Z ¹ Represents a leaving group. ) This synthesis method is a method of synthesizing compound (C-6) by sulfonyl esterifying the phenolic hydroxyl group of compound (C-5). R ⁹ Examples of the sulfonyl group represented by the formula include a methanesulfonyl group, a trifluoromethanesulfonyl group, and a p-toluenesulfonyl group. Z ¹ Examples of the leaving group represented by the formula include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. In this reaction, the compounds (C-5) and (B-9) are used in an equal amount, or one of them in excess, and in an inert solvent for the reaction, in the presence of a base at 0 ° C. to heating under reflux, usually 0 It is carried out by reacting for 5 hours to 3 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), pyridine, acetic acid Examples thereof include ethyl or a mixed solvent thereof. This reaction is preferably performed in an inert gas atmosphere. Examples of the base include sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate and other inorganic salts, triethylamine, N-ethyl-N, N-diisopropylamine ( DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), pyridine and the like.
Synthesis of compound (C-7)

(Wherein R ⁶ Represents a protecting group for a carboxyl group. Also R ⁹ Represents an unsubstituted or substituted alkylsulfonyl group having 1 to 9 carbon atoms or an unsubstituted or substituted phenylsulfonyl group. Y ¹ Is -B (OH) ₂ Or -B (OR ⁷ ) OR ⁸ Represents. Where R ⁷ And R ⁸ Are the same or different from each other and are lower alkyl groups, or R ⁷ And R ⁸ Together represent a lower alkylene group. This synthesis method is a method of synthesizing compound (C-7) by coupling compound (C-6) and (A-3). R ⁹ Examples of the sulfonyl group represented by the formula include a methanesulfonyl group, a trifluoromethanesulfonyl group, and a p-toluenesulfonyl group. In this reaction, compounds (C-6) and (A-3) are used in an equal amount, or in excess, and usually in a solvent inert to the reaction in the presence of a base and a palladium catalyst at room temperature to heating under reflux. The reaction is performed for 0.5 to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and potassium phosphate, metal alkoxides such as sodium ethoxide and sodium methoxide, or these bases. Examples include a solution diluted with water or the like. As the palladium catalyst, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride-1,1′-bis (diphenylphosphino) ferrocene and the like are preferable.
Synthesis of compound (C-8)

(Wherein R ⁶ Represents a protecting group for a carboxyl group. ) This synthesis method is a protective group R of compound (C-7) ⁶ Is a method of synthesizing the compound (C-8) of the present invention by deprotecting with an acid or a base. In this reaction, compound (C-7) is usually reacted for 0.5 to 5 days at room temperature to heating under reflux using an equivalent amount or excess of acid or base in a solvent inert to the reaction. Is done by. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.
Hereinafter, among the compounds represented by the formula (I), preferred compounds and pharmaceutically acceptable salts thereof are not particularly limited as long as they are pharmaceutically acceptable salts. Salts with inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, carbonic acid; maleic acid, fumaric acid, citric acid, malic acid, tartaric acid, lactic acid, succinic acid, benzoic acid, oxalic acid , Salts with organic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, formic acid; salts with amino acids such as glycine, lysine, arginine, histidine, ornithine, glutamic acid, aspartic acid Salts with alkali metals such as sodium, potassium and lithium; salts with alkaline earth metals such as calcium and magnesium; aluminum and zinc Salts with metals such as iron; salts with organic oniums such as tetramethylammonium and choline; ammonia, propanediamine, pyrrolidine, piperidine, pyridine, ethanolamine, N, N-dimethylethanolamine, 4-hydroxypiperidine, t-octylamine, dibenzylamine, morpholine, glucosamine, phenylglycylalkyl ester, ethylenediamine, N-methylglucamine, guanidine, diethylamine, triethylamine, dicyclohexylamine, N, N′-dibenzylethylenediamine, chloroprocaine, procaine, And salts with organic bases such as diethanolamine, N-benzylphenylamine, piperazine, and tris (hydroxymethyl) aminomethane.
Furthermore, the compound represented by the formula (I) and salts thereof include various hydrates and solvates.
The various pharmaceutically acceptable salts of the compound represented by the formula (I) can be appropriately produced based on ordinary knowledge in the art.
The compounds of the present invention also include stereoisomers, racemates, and all possible optically active forms of the compounds of formula (I).
The compound represented by the formula (I) of the present invention and a pharmaceutically acceptable salt thereof have particularly excellent xanthine oxidase inhibitory activity. Due to its excellent xanthine oxidase inhibitory activity, the compounds represented by the formula (I) of the present invention and pharmaceutically acceptable salts thereof are useful as xanthine oxidase inhibitors.
The compound represented by the formula (I) of the present invention and a pharmaceutically acceptable salt thereof are clinically applicable as a xanthine oxidase inhibitor, gout, hyperuricemia, oncolysis syndrome, urolithiasis , Hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and heart failure, kidney diseases such as diabetic nephropathy, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel disease or autoimmune disease Etc., and can be used as a medicament for the treatment or prevention of diseases involving xanthine oxidase.
The compound represented by the above formula (I) and a pharmaceutically acceptable salt thereof can be made into a pharmaceutical composition together with a pharmaceutically acceptable carrier and / or diluent. This pharmaceutical composition can be formed into various dosage forms and administered orally or parenterally. Parenteral administration includes, for example, intravenous, subcutaneous, intramuscular, transdermal, or rectal administration.
Formulations containing one or more of the compounds represented by the formula (I) of the present invention or salts thereof as active ingredients are prepared using carriers, excipients and other additives that are usually used for formulation. Prepared. The carrier or excipient for the preparation may be either solid or liquid, such as lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol, etc. The usual thing is mentioned. Administration may be in any form of oral administration such as tablets, pills, capsules, granules, powders, liquids, or parenteral administration such as injections such as intravenous injection and intramuscular injection, suppositories, and transdermal. Good.
The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof varies depending on the type of disease, administration route, patient symptom, age, sex, body weight, etc. In the range of 0.01 to 1000 mg, it can be administered once or divided into several times. However, since the dose varies depending on various conditions, a dose smaller than the above dose may be sufficient, or a dose exceeding the above range may be required.

［実施例６３］２−（５−シアノ−６−フェニルピリジン−３−イル）−１，３−チアゾール−５−カルボン酸（化合物番号６３）の合成
（１）５−ブロモ−２−ヒドロキシピリジン−３−カルボン酸５．０ｇに炭酸銀１３．９７ｇを加え、トルエン１００ｍＬに懸濁させた。その後にベンジルブロマイド６．０ｍＬを加えて、窒素雰囲気下、７０℃で１４時間、１３０℃で６時間加熱した。反応混合液をセライトろ過して不溶物を取り除き、ろ液に水を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄後、乾燥、減圧濃縮を行った。得られた粗体をシリカゲルカラムクロマトグラフィーで分離精製することで、ベンジル　２−（ベンジルオキシ）−５−ブロモピリジン−３−カルボキシレート６．２６ｇを得た。
（２）上記で得られたベンジル　２−（ベンジルオキシ）−５−ブロモピリジン−３−カルボキシレート１．１６ｇをテトラヒドロフラン４０ｍＬと水５ｍＬに懸濁させ、４Ｍ水酸化リチウム水溶液３．０ｍＬを加え、４５℃で１時間撹拌した。反応混合液に２Ｍ塩酸を加えて中和した後に、ジクロロメタンで抽出し、減圧濃縮を行った。得られた粗体を常法により精製することで、２−（ベンジルオキシ）−５−ブロモピリジン−３−カルボン酸７３０ｍｇを得た。
（３）２−（ベンジルオキシ）−５−ブロモピリジン−３−カルボン酸７３０ｍｇをテトラヒドロフラン２０ｍＬに溶解させた後に、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩１．３６ｇ、Ｎ−ヒドロキシベンゾトリアゾール水和物５４１ｍｇを加えて、窒素雰囲気下、室温で１時間撹拌した。その後に、アンモニア水２ｍＬを加えて、室温で１時間撹拌した。反応混合液に水を加え、ジクロロメタンで抽出した。有機層を食塩水で洗浄後、乾燥、減圧濃縮を行い、２−（ベンジルオキシ）−５−ブロモピリジン−３−カルボキシアミドの粗体を得た。
（４）上記で得られた２−（ベンジルオキシ）−５−ブロモピリジン−３−カルボキシアミドの粗体をトルエン１５ｍＬに懸濁させた後に、フェニルホスホニルジクロリド６６５μＬを加えて、１２０℃で２時間加熱した。反応混合液に炭酸水素ナトリウム水を加えて中和し、ジクロロメタンで抽出した。有機層を食塩水で洗浄後、乾燥、減圧濃縮を行い、２−（ベンジルオキシ）−５−ブロモピリジン−３−カルボニトリルの粗体８２３ｍｇを得た。
（５）上記で得られた２−（ベンジルオキシ）−５−ブロモピリジン−３−カルボニトリルの粗体８２３ｍｇに炭酸水素化カリウム４８９ｍｇ、塩化パラジウム（ＩＩ）２１ｍｇ、臭化銅（Ｉ）９８ｍｇを加え、トルエン１１ｍＬに懸濁させた。その後にエチル１，３−チアゾール−５−カルボキシレート３７２ｍｇ、イソ酪酸４４μＬ及びジ−ｔ−ブチルシクロヘキシルホスフィン１０８ｍｇを加えて、窒素雰囲気下、１２５℃で１４時間加熱した。反応混合液をセライトろ過して不溶物を取り除き、ろ液に水を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄後、乾燥、減圧濃縮した後に常法により精製し、エチル　２−［６−（ベンジルオキシ）−５−シアノピリジン−３−イル］−１，３−チアゾール−５−カルボキシレート３８２ｍｇを得た。
（６）エチル　２−［６−（ベンジルオキシ）−５−シアノピリジン−３−イル］−１，３−チアゾール−５−カルボキシレート２３４ｍｇにトリフルオロ酢酸３ｍＬを加えて、室温で３０分間撹拌した。減圧濃縮した後に常法により精製し、エチル　２−（５−シアノ−６−ヒドロキシピリジン−３−イル）−１，３−チアゾール−５−カルボキシレート１１６ｍｇを得た。
（７）エチル　２−（５−シアノ−６−ヒドロキシピリジン−３−イル）−１，３−チアゾール−５−カルボキシレート３０ｍｇをアセトニトリル１ｍＬに懸濁させ、ピリジン４６μＬを加え、０℃に冷却した後に、トリフルオロメタンスルホン酸無水物８８μＬを加え、窒素雰囲気下、室温で１時間撹拌した。反応混合液に水を加え、ジクロロメタンで抽出した。有機層を食塩水で洗浄後、乾燥、減圧濃縮した後に、常法により精製することで、エチル　２−｛５−シアノ−６−［（トリフルオロメタン）スルホニルオキシ］ピリジン−３−イル｝−１，３−チアゾール−５−カルボキシレート２９ｍｇを得た。
（８）上記で得られたエチル　２−｛５−シアノ−６−［（トリフルオロメタン）スルホニルオキシ］ピリジン−３−イル｝−１，３−チアゾール−５−カルボキシレート２９ｍｇ、炭酸カリウム２０ｍｇ、フェニルボロン酸１３ｍｇおよびテトラキストリフェニルホスフィン１６ｍｇをトルエン１．５ｍＬに懸濁させ、窒素雰囲気下、９０℃で８時間加熱した。反応混合液に水を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄後、乾燥、減圧濃縮した後に、常法により精製し、エチル　２−（５−シアノ−６−フェニルピリジン−３−イル）−１，３−チアゾール−５−カルボキシレート１５ｍｇを得た。
（９）上記のエチル　２−（５−シアノ−６−フェニルピリジン−３−イル）−１，３−チアゾール−５−カルボキシレート１５ｍｇをテトラヒドロフラン２．０ｍＬに懸濁させ、２Ｍ水酸化ナトリウム水溶液０．３０ｍＬを加え、室温で１時間撹拌した。反応混合液に２Ｍ塩酸０．３０ｍＬおよび水２ｍＬを加え、酢酸エチルで抽出、減圧濃縮を行った。得られた粗体を常法により精製することで、２−（５−シアノ−６−フェニルピリジン−３−イル）−１，３−チアゾール−５−カルボン酸８．６ｍｇを得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ‐ｄ_６）δ（ｐｐｍ）：７．６０−７．６１（３Ｈ，ｍ），７．９３−７．９６（２Ｈ，ｍ），８．５５（１Ｈ，ｓ），８．９９（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），９．５１（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ）
ＨＰＬＣ保持時間：１０．２８分
ｏｂｓ　Ｍａｓｓ（Ｍ^＋＋Ｈ）：３０８．０４８５
Ｐｒｅｄ　Ｍａｓｓ（Ｍ^＋＋Ｈ）：３０８．０４８８
Ｆｏｒｍｕｌａ（Ｍ）：Ｃ_１６Ｈ_９Ｎ_３Ｏ_２Ｓ
［実施例６４−８２］
　実施例６３と同様にして、エチル　２−（５−シアノ−６−ヒドロキシピリジン−３−イル）−１，３−チアゾール−５−カルボキシレートを用いて、化合物番号６４~７２を合成した。また、エチル　２−（５−シアノ−６−ヒドロキシピリジン−３−イル）−４−メチル−１，３−チアゾール−５−カルボキシレートを用いて、化合物番号７３~８２を合成した。

［実施例８３］２−（６−シアノ−５−フェニルピリジン−３−イル）−１，３−チアゾール−５−カルボン酸（化合物番号８３）の合成
（１）２−シアノ−３−ヒドロキシピリジン２．７３ｇをアセトリトリル／水＝５／１の混合溶液６０ｍＬに懸濁させ、０℃に冷却させた後に、Ｎ−ブロモスクシンイミド４．８５ｇをゆっくりと加え、窒素雰囲気下、反応溶液を２時間撹拌させた。反応混合物に水を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄後、乾燥、減圧濃縮を行うことにより、６−ブロモ−２−シアノ−３−ヒドロキシピリジンの粗体５．３９ｇを得た。
（２）６−ブロモ−２−シアノ−３−ヒドロキシピリジン５．３９ｇ、炭酸カリウム４．７１ｇをジメチルホルムアミド６０ｍＬに懸濁させ、ベンジルブロマイド４．６６ｇを加え、６０℃で１２時間加熱した。反応混合液を室温まで冷却させた後に水６０ｍＬを加え、常法により精製し、３−ベンジルオキシ−６−ブロモ−２−シアノピリジン４．７３ｇを得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：５．２６（２Ｈ，ｓ），７．２４（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．３６−７．４４（５Ｈ，ｍ），７．５７（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ）
（３）上記で得られた３−ベンジルオキシ−６−ブロモ−２−シアノピリジン２．８９ｇに炭酸水素化カリウム２．１０ｇ、塩化パラジウム（ＩＩ）８８．７ｍｇ、臭化銅（Ｉ）４１１ｍｇを加え、トルエン３０ｍＬに懸濁させた。その後にエチル　１，３−チアゾール−５−カルボキシレート２．３６ｇ、イソ酪酸１８５μＬ及びジ‐ｔ−ブチルシクロヘキシルホスフィン４５７ｍｇを加えて、窒素雰囲気下、１２０℃で１４時間加熱した。反応混合液をセライトろ過して不溶物を取り除き、ろ液に水を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄後、乾燥、減圧濃縮した後に常法により精製し、エチル　２−［５−（ベンジルオキシ）−６−シアノピリジン−２−イル）−１，３−チアゾール−５−カルボキシレート１．７４ｇを得た。
ＥＳＩ／ＭＳ　ｍ／ｅ：３６６．０（Ｍ^＋＋Ｈ，Ｃ_１９Ｈ_１６Ｎ_３Ｏ_３Ｓ）．
（４）エチル　２−［５−（ベンジルオキシ）−６−シアノピリジン−２−イル）−１，３−チアゾール−５−カルボキシレート１．７４ｇをテトラヒドロフラン／エタノール＝１／１の混合溶液３０ｍＬに懸濁させ、パラジウム／炭素（１０％ｗｔ）４０９ｍｇを加えた後に、水素雰囲気下、室温で１時間撹拌した。反応混合液をろ過し、ろ液を減圧濃縮することで、エチル　２−（６−シアノ−５−ヒドロキシピリジン−２−イル）−１，３−チアゾール−５−カルボキシレート１．４４ｇを得た。
（５）エチル　２−（６−シアノ−５−ヒドロキシピリジン−２−イル）−１，３−チアゾール−５−カルボキシレート２７．５ｍｇをジクロロメタン１ｍＬに懸濁させ、Ｎ，Ｎ−ジイソプロピルエチルアミン１９２μＬを加え、０℃に冷却した後に、トリフルオロメタンスルホン酸無水物１８５μＬを加え、窒素雰囲気下、室温で１時間撹拌した。反応混合液に水を加え、ジクロロメタンで抽出した。有機層を食塩水で洗浄後、乾燥、減圧濃縮を行うことで、エチル　２−｛６−シアノ−５−［（トリフルオロメタン）スルホニルオキシ］ピリジン−２−イル｝−１，３−チアゾール−５−カルボキシレートの粗体４０７ｍｇを得た。
（６）エチル　２−｛６−シアノ−５−［（トリフルオロメタン）スルホニルオキシ］ピリジン−２−イル｝−１，３−チアゾール−５−カルボキシレート８１．４ｍｇ、炭酸カリウム５５．３ｍｇ、フェニルボロン酸３６．６ｍｇおよびテトラキストリフェニルホスフィン１１．６ｍｇをトルエン１．０ｍＬに懸濁させ、窒素雰囲気下、９０℃で１４時間加熱した。反応混合液に水を加え、酢酸エチルで抽出した。有機層を食塩水で洗浄後、乾燥、減圧濃縮を行い、エチル　２−（６−シアノ−５−フェニルピリジン−２−イル）−１，３−チアゾール−５−カルボキシレートの粗体を得た。
（７）上記のエチル　２−（６−シアノ−５−フェニルピリジン−２−イル）−１，３−チアゾール−５−カルボキシレートの粗体をテトラヒドロフラン／メタノール＝１／１の混合溶液１．０ｍＬに懸濁させ、２Ｍ水酸化ナトリウム水溶液０．２０ｍＬを加え、室温で４時間撹拌した。反応混合液に２Ｍ塩酸０．２０ｍＬおよび水２ｍＬを加え、酢酸エチルで抽出、減圧濃縮を行った。得られた粗体を常法により精製することで、２−（６−シアノ−５−フェニルピリジン−３−イル）−１，３−チアゾール−５−カルボン酸１９．６ｍｇを得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ‐ｄ_６）δ（ｐｐｍ）：７．５６−７．６３（３Ｈ，ｍ），７．７２−７．７５（２Ｈ，ｍ），８．３２（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），８．４９（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），８．５３（１Ｈ，ｓ）
ＨＰＬＣ保持時間：１１．４２分
ｏｂｓ　Ｍａｓｓ（Ｍ^＋＋Ｈ）：３０８．０４８８
Ｐｒｅｄ　Ｍａｓｓ（Ｍ^＋＋Ｈ）：３０８．０４８８
Ｆｏｒｍｕｌａ（Ｍ）：Ｃ_１６Ｈ_９Ｎ_３Ｏ_２Ｓ
［実施例８４−１０８］
　実施例８３と同様にして、化合物番号８４~９２を合成した。また、化合物番号９３~１０８においては、エチル　４−メチル−１，３−チアゾール−５−カルボキシレートを原料として用いて合成した。

［実施例１０９］
　以上の実施例の方法に従って合成された化合物について、キサンチンオキシダーゼ阻害活性を測定した。
（１）試験化合物の調製
　試験化合物をＤＭＳＯ（シグマ社製）に２０ｍＭの濃度になるように溶解した後、使用時の目的の濃度に調製して用いた。
（２）測定方法
　本発明化合物のキサンチンオキシダーゼ阻害活性評価を文献記載の方法（Ｍｅｔｈｏｄ　Ｅｎｚｙｍａｔｉｃ　Ａｎａｌｙｓｉｓ，１，５２１−５２２，１９７４）を一部改変して実施した。本評価は、オキシダーゼ型のキサンチンオキシドレダクターゼ活性の測定により行われた。すなわち、あらかじめ２０ｍＭ水酸化ナトリウム溶液にて１０ｍＭに調製したキサンチン（シグマ社製）溶掖を１００ｍＭリン酸緩衝液を用いて３０μＭに調製し、９６穴プレートに７５μＬ／穴ずつ加えた。最終濃度の１００倍になるようにＤＭＳＯにて希釈した各試験化合物を１．５μＬ／穴ずつ添加し、ミキシング後にマイクロプレートリーダーＳＰＥＣＴＲＡ　ｍａｘ　Ｐｌｕｓ３８４（モレキュラーデバイス社製）にて２９０ｎｍの吸光度を測定した。続けてオキシダーゼ型キサンチンオキシドレダクターゼ（バターミルク由来、Ｃａｌｂｉｏｃｈｅｍ社製）を１００ｍＭリン酸緩衝液を用いて３０．６ｍＵ／ｍＬに調製し、７３．５μＬ／穴ずつ加えた。ミキシング後速やかに２９０ｎｍにおける吸光度変化を５分間測定した。試験化合物溶液の代わりにＤＭＳＯを添加したときの酵素活性を１００％として試験化合物の阻害率を計算し、用量応答曲線にフィットさせてオキシダーゼ型キサンチンオキシドレダクターゼに対する５０％阻害濃度を計算した。
　この結果を次の表に示す。但し、表中の記号（＋、＋＋、＋＋＋）は以下の通りの阻害活性値を表しているものとする。
　１０．０ｎＭ≦ＩＣ_５０：＋
　５．０ｎＭ≦ＩＣ_５０＜１０．０ｎＭ：＋＋
　１．０ｎＭ≦ＩＣ_５０＜５．０ｎＭ：＋＋＋

［実施例１１０］
血中尿酸低下作用（正常マウス）
　７~８週齢のＣｒｌｊ：ＣＤ１系雄性マウス（日本チャールス・リバー株式会社）に０．５％メチルセルロース液に懸濁した試験化合物を経口ゾンデを用いて強制投与した。投与後６時間、１６時間に心臓より採血した後、血清を分離した。血中尿酸値は尿酸測定キット（オートセラＳＵＡ：積水メディカル）を用いて、ウリカーゼ法にて吸光度計（日立自動分析装置７１８０）にて測定し、尿酸低下率を下式により求めた。
尿酸低下率（％）
＝（対照動物の尿酸値−試験化合物投与動物の尿酸値）ｘ１００／対照動物の尿酸値
　化合物番号１、２、４９、５０、５５および５７の化合物は１ｍｇ／ｋｇの投与後６時間において、尿酸低下率７０％以上を示した。また、化合物番号１、２、３、４、５および５０の化合物は１ｍｇ／ｋｇの投与後１６時間において、尿酸低下率５０％以上を示した。
　以上の結果より、本発明化合物は強力かつ持続的な血中尿酸低下作用を有することが示された。
［実施例１１１］
血中尿酸低下作用（正常ラット）
　８~９週齢のＳｐｒａｇｕｅ−Ｄａｗｌｅｙ系雄性ラット（日本チャールス・リバー株式会社）に０．５％メチルセルロース液に懸濁した試験化合物を経口ゾンデを用いて強制投与した。投与後６時間、２４時間に尾静脈より採血した後、血漿を分離した。血中尿酸値は尿酸測定キット（ＬタイプワコーＵＡ・Ｆ：和光純薬工業）を用いて、ウリカーゼ法にて吸光度計を用いて測定し、尿酸低下率を下式により求めた。
尿酸低下率（％）
＝（対照動物の尿酸値−試験化合物投与動物の尿酸値）ｘ１００／対照動物の尿酸値
　化合物番号１および２の化合物は１ｍｇ／ｋｇの用量で投与後６時間および２４時間において、尿酸低下率７０％以上を示した。また、化合物番号３および４の化合物は１０ｍｇ／ｋｇの用量で投与後６時間および２４時間において、尿酸低下率５０％以上を示した。この結果から、本発明化合物は強力かつ持続的な血中尿酸低下作用を有することが示された。
［実施例１１２］
血中尿酸低下作用（フサオマキザル）
　フサオマキザルに０．５％メチルセルロース液に懸濁した試験化合物をディスポーザブルカテーテルおよび注射筒を用いて鼻腔から胃内に強制投与した。投与後４時間、２４時間に伏在静脈より採血した後、血漿を分離した。血中尿酸値は尿酸測定キット（ＬタイプワコーＵＡ・Ｆ：和光純薬工業）を用いて、ウリカーゼ法にて吸光度計を用いて測定し、尿酸低下率を下式により求めた。
尿酸低下率（％）
＝（対照動物の尿酸値−試験化合物投与動物の尿酸値）ｘ１００／対照動物の尿酸値
　化合物番号１および２の化合物は１ｍｇ／ｋｇの用量で投与後４時間および２４時間において、尿酸低下率５０％以上を示した。
　この結果から、フサオマキザルにおいても、本発明化合物は強力かつ持続的な血中尿酸低下作用を有することが示された。
［実施例１１３］
　血中尿酸低下作用（ビーグル犬）
　化合物番号１および２について、ビーグル犬における血中尿酸低下作用を確認した。ビーグル犬（北山ラベス）に０．５％メチルセルロース液に懸濁した試験化合物を強制経口投与した。投与後１時間および２４時間に橈側皮静脈より採血した後、血漿を分離した。血中尿酸値はＬＣ−ＭＳ／ＭＳ法を用いて測定し、尿酸低下率を下式により求めた。
　尿酸低下率（％）
＝（対照動物の尿酸値−試験化合物投与動物の尿酸値）ｘ１００／対照動物の尿酸値
　化合物番号２の化合物は１ｍｇ／ｋｇの用量で投与後１時間において、尿酸低下率５０％以上を示した。
　化合物番号１は、１０ｍｇ／ｋｇの用量において、投与後２４時間において、尿酸低下率４０％以上を示した。
　この結果から本発明の化合物がイヌにおいて持続的な血中尿酸低下効果を有することが示された。
　以上の結果より、本発明化合物は、１日１回またはそれ以上の間隔で投与しても強力な尿酸低下作用を発揮することが期待できる。また、臨床上、尿酸値を持続的に低下させることは、高尿酸血症およびこれに起因する各種疾患、特に慢性疾患の治療または予防において重要であり、本発明がかかる疾患に対して優れた効果を発揮することが期待できる。 The present invention will be described below based on specific examples. However, the present invention is not limited to these examples.
The structure of the isolated novel compound was confirmed by ¹ H NMR and / or mass spectrometry using a single quadrupole instrument equipped with an electron spray source, and other appropriate analytical methods.
For those measured for ¹ H NMR spectrum (400 MHz, DMSO-d ₆ or CDCl ₃ ), the chemical shift (δ: ppm) and the coupling constant (J: Hz) are shown. About the result of mass spectrometry, the measured value observed as a value which added proton (H ^<+> ) to M ^< + ^> + H, ie, a compound molecular mass (M), is shown. The following abbreviations represent the following.
s = singlet, d = doublet, t = triplet, q = quartet, brs = broad singlet, m = multiplet.
For compounds synthesized according to the methods of the following examples, a high-performance liquid chromatography (HPLC) analysis and a time-of-flight mass spectrometer (TOF-MS) equipped with an electrospray ion source were further analyzed. Analysis was also performed by the mass spectrometry used.
The retention time (unit: minute) of a compound in HPLC analysis under the following analysis conditions is shown as HPLC retention time.
HPLC measurement condition measuring apparatus: Hewlett-Packard 1100 HPLC
Column: Imtakt Cadenza CD-Cl8 100 mm × 4.6 mm 3 μm
UV: PDA detection (254 nm)
Column temperature: 40 degree Gradient condition:
Solvent: A: H ₂ O / acetonitrile = 95/5
0.05% TFA (trifluoroacetic acid)
B: H ₂ O / acetonitrile = 5/95
0.05% TFA (trifluoroacetic acid)
Flow rate: 1.0 mL / min Gradient: 0 to 1 minute, Solvent B: 2% Solvent A: 98%
1-14 minutes, solvent B: 2% → 100% solvent A: 98% → 0%
14-17 minutes, solvent B: 100% solvent A: 0%
17-19 minutes, solvent B: 100% → 2% solvent A: 0% → 98%
As for the results of mass spectrometry, the value of “M ⁺ + H” (Obs. Mass: that is, actual measurement in which proton (H ⁺ ) was added to the molecular mass (M) of the compound, which was observed by the apparatus and analysis conditions described below. Value) and a calculated value of “M ⁺ + H” (Pred. Mass), together with a composition formula (Formula) calculated from the actually measured value of “M ⁺ + H”.
TOF-MS measurement condition mass spectrometer: Shimadzu LCMS-IT-TOF
LC: Prominence
Column: Phenomenex Synergy Hydro-RP 4.0 mm × 20 mm 2.5 μm
UV: PDA detection (254 nm)
Flow rate: 0.6 mL / min Column temperature: 40 degrees Detection voltage: 1.63 kV
Gradient conditions:
Solvent: A: H ₂ O / acetonitrile = 95/5
0.1% HCOOH
B: H ₂ O / acetonitrile = 5/95
0.1% HCOOH
Flow rate: 0.5 mL / min Gradient: 0 to 0.2 minutes, Solvent B: 2% Solvent A: 98%
0.2-2.5 minutes, solvent B: 2% → 100% solvent A: 98% → 0%
2.5-3.8 minutes, solvent B: 100% solvent A: 0%
3.8 to 4.0 minutes, solvent B: 100% → 2% solvent A: 0% → 98%
4.0-5.0 minutes, solvent B: 2% solvent A: 98%
[Reference Example] Synthesis of 5-bromo-2-chloropyridine-4-carbaldehyde (Reference Example Compound) 10.6 mL of diisopropylamine was dissolved in 100 mL of THF and cooled to -78 ° C. 7 mL was slowly added dropwise. After stirring this reaction solution for 1 hour, a solution of 9.7 g of 5-bromo-2-chloropyridine dissolved in 50 mL of THF was slowly added dropwise, and the reaction solution was further stirred for 1 hour. Thereafter, 10 mL of N, N-dimethylformamide (DMF) was added dropwise. After stirring this mixed solution at -78 ° C for 1 hour, 30 mL of 2M hydrochloric acid aqueous solution was added, the temperature was slowly raised to room temperature, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure. To the residue was added 10 mL of dichloromethane to obtain 3.23 g of 5-bromo-2-chloropyridine-4-carbaldehyde. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 9: 1) to obtain 6.34 g of 5-bromo-2-chloropyridine-4-carbaldehyde. It was.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.72 (1H, s), 8.68 (1H, s), 10.30 (1H, s)
Example 1 Synthesis of 2- (5-cyano-6-phenylpyridin-3-yl) -1,3-thiazole-5-carboxylic acid (Compound No. 1 ) (Synthesis Method (A))
(1) Suspend 8.80 g of 5-bromo-2-chloropyridine-4-carbaldehyde, 5.36 g of phenylboronic acid and 11.06 g of potassium carbonate in 100 mL of a mixed solution of 1,4-dioxane / water = 4/1. The mixture was made turbid, tetrakis (triphenylphosphine) palladium (924 mg) was added, and the mixture was heated at 80 ° C. for 5 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure to obtain 10.80 g of 2-chloro-5-phenylpyridine-4-carbaldehyde.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.3-7.42 (2H, m), 7.50-7.60 (3H, m), 7.81 (1H, d, J = 0.6 Hz), 8.61 (1H, d, J = 0.6 Hz), 9.99 (1H, s)
ESI / MS m / e: 218.0, 220.0 (M ⁺ + H, C ₁₂ H ₉ ClNO).
(2) Suspend 10.80 g of 2-chloro-5-phenylpyridine-4-carbaldehyde, 5.56 g of hydroxylamine monohydrochloride and 5.44 g of sodium formate in 100 mL of formic acid, and add 12.2 g of acetic anhydride. The mixture was heated at 100 ° C. for 2 hours in a nitrogen atmosphere. Water (100 mL) was added and the mixture was purified by a conventional method to obtain 6.34 g of 2-chloro-5-phenylpyridine-4-carbonitrile.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.27 (1H, s), 7.5-7.6 (4H, m), 7.67 (1H, s), 8.63 ( 1H, s)
ESI / MS m / e: 215.0, 217.0 (M ⁺ + H, C ₁₂ H ₈ ClN ₂ )
(3) To 3.12 g of 2-chloro-5-phenylpyridine-4-carbonitrile, 3.06 g of potassium bicarbonate, 129 mg of palladium (II) chloride and 598 mg of copper (I) bromide were added, and suspended in 40 mL of toluene. I let you. Thereafter, 3.43 g of ethyl 1,3-thiazole-5-carboxylate, 269 μL of isobutyric acid and 664 mg of di-t-butylcyclohexylphosphine were added and heated at 120 ° C. for 6 hours in a nitrogen atmosphere. The reaction mixture was filtered through Celite to remove insolubles, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried, concentrated under reduced pressure and purified by a conventional method to obtain ethyl 2- (4-cyano-5-phenylpyridin-2-yl) -1,3-thiazole-5-carboxylate 2 .92 g was obtained.
^{ESI / MS m / e: 336.0} (M + + H, C 18 H 14 N 3 O 2 S).
¹ H-NMR (400 MHz, DMSO d6) δ (ppm): 1.33 (3H, t, J = 6.8 Hz), 4.35 (2H, q, J = 6.8 Hz), 7.58-7 .63 (3H, m), 7.73-7.76 (2H, m), 8.60 (1H, s), 8.65 (1H, s), 9.03 (1H, s)
(4) Dissolve 2.92 g of ethyl 2- (4-cyano-5-phenylpyridin-2-yl) -1,3-thiazole-5-carboxylate in 30 mL of a mixed solution of tetrahydrofuran / methanol = 1/1; 9.0 mL of 2M sodium hydroxide aqueous solution was added and stirred at room temperature for 4 hours. To the reaction mixture was added 9.0 mL of a 2M aqueous hydrochloric acid solution, and then purified by a conventional method to obtain 2.57 g of 2- (4-cyano-5-phenylpyridin-2-yl) -1,3-thiazole-5-carboxylic acid. Got.
¹ H-NMR (400 MHz, DMSO d6) δ (ppm): 7.56-7.64 (3H, m), 7.74 (2H, d, J = 8.0 Hz), 8.55 (1H, s ),) 8.58 (1H, s), 9.02 (1H, s), 13.83 (1H, brs)
HPLC retention time: 10.94 minutes ^{Obs Mass (M + + H)} : 308.0488
Pred Mass (M ⁺ + H): 308.0488
Formula (M): C ₁₆ H ₉ N ₃ O ₂ S
[Example 2-62]
Compound Nos. 2 to 62 were synthesized in the same manner as in Example 1 using the above Reference Example compound as a starting material. Compound numbers 49 to 62 were synthesized using ethyl 4-methyl-1,3-thiazole-5-carboxylate as a raw material.

Example 63 Synthesis of 2- (5-cyano-6-phenylpyridin-3-yl) -1,3-thiazole-5-carboxylic acid (Compound No. 63 ) (1) 5-Bromo-2-hydroxypyridine 13.97 g of silver carbonate was added to 5.0 g of -3-carboxylic acid, and suspended in 100 mL of toluene. Thereafter, 6.0 mL of benzyl bromide was added, and the mixture was heated at 70 ° C. for 14 hours and at 130 ° C. for 6 hours under a nitrogen atmosphere. The reaction mixture was filtered through Celite to remove insolubles, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography to obtain 6.26 g of benzyl 2- (benzyloxy) -5-bromopyridine-3-carboxylate.
(2) 1.16 g of benzyl 2- (benzyloxy) -5-bromopyridine-3-carboxylate obtained above is suspended in 40 mL of tetrahydrofuran and 5 mL of water, and 3.0 mL of 4M aqueous lithium hydroxide is added, Stir at 45 ° C. for 1 hour. The reaction mixture was neutralized with 2M hydrochloric acid, extracted with dichloromethane, and concentrated under reduced pressure. The obtained crude product was purified by a conventional method to obtain 730 mg of 2- (benzyloxy) -5-bromopyridine-3-carboxylic acid.
(3) After dissolving 730 mg of 2- (benzyloxy) -5-bromopyridine-3-carboxylic acid in 20 mL of tetrahydrofuran, 1.36 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N -541 mg of -hydroxybenzotriazole hydrate was added, and it stirred at room temperature for 1 hour under nitrogen atmosphere. Thereafter, 2 mL of aqueous ammonia was added and stirred at room temperature for 1 hour. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with brine, dried and concentrated under reduced pressure to obtain a crude 2- (benzyloxy) -5-bromopyridine-3-carboxamide.
(4) After suspending the crude product of 2- (benzyloxy) -5-bromopyridine-3-carboxyamide obtained above in 15 mL of toluene, 665 μL of phenylphosphonyl chloride was added, Heated for hours. The reaction mixture was neutralized with aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with brine, dried and concentrated under reduced pressure to obtain 823 mg of crude 2- (benzyloxy) -5-bromopyridine-3-carbonitrile.
(5) To the crude 823 mg of 2- (benzyloxy) -5-bromopyridine-3-carbonitrile obtained above, 489 mg of potassium bicarbonate, 21 mg of palladium (II) chloride, 98 mg of copper (I) bromide were added. In addition, it was suspended in 11 mL of toluene. Thereafter, 372 mg of ethyl 1,3-thiazole-5-carboxylate, 44 μL of isobutyric acid and 108 mg of di-t-butylcyclohexylphosphine were added, and the mixture was heated at 125 ° C. for 14 hours in a nitrogen atmosphere. The reaction mixture was filtered through Celite to remove insolubles, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried, concentrated under reduced pressure and purified by a conventional method to obtain ethyl 2- [6- (benzyloxy) -5-cyanopyridin-3-yl] -1,3-thiazole-5- 382 mg of carboxylate was obtained.
(6) Ethyl 2- [6- (benzyloxy) -5-cyanopyridin-3-yl] -1,3-thiazole-5-carboxylate (234 mg) was added with 3 mL of trifluoroacetic acid and stirred at room temperature for 30 minutes. . After concentration under reduced pressure, purification was performed by a conventional method to obtain 116 mg of ethyl 2- (5-cyano-6-hydroxypyridin-3-yl) -1,3-thiazole-5-carboxylate.
(7) 30 mg of ethyl 2- (5-cyano-6-hydroxypyridin-3-yl) -1,3-thiazole-5-carboxylate was suspended in 1 mL of acetonitrile, 46 μL of pyridine was added, and the mixture was cooled to 0 ° C. Thereafter, 88 μL of trifluoromethanesulfonic anhydride was added, and the mixture was stirred at room temperature for 1 hour in a nitrogen atmosphere. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer was washed with brine, dried, concentrated under reduced pressure, and purified by a conventional method to obtain ethyl 2- {5-cyano-6-[(trifluoromethane) sulfonyloxy] pyridin-3-yl} -1 , 3-thiazole-5-carboxylate 29 mg was obtained.
(8) Ethyl 2- {5-cyano-6-[(trifluoromethane) sulfonyloxy] pyridin-3-yl} -1,3-thiazole-5-carboxylate 29 mg obtained above, potassium carbonate 20 mg, phenyl Boronic acid (13 mg) and tetrakistriphenylphosphine (16 mg) were suspended in toluene (1.5 mL) and heated at 90 ° C. for 8 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried, concentrated under reduced pressure, purified by a conventional method, and ethyl 2- (5-cyano-6-phenylpyridin-3-yl) -1,3-thiazole-5-carboxylate. 15 mg was obtained.
(9) 15 mg of the above ethyl 2- (5-cyano-6-phenylpyridin-3-yl) -1,3-thiazole-5-carboxylate is suspended in 2.0 mL of tetrahydrofuran, and 2M aqueous sodium hydroxide solution 0 30 mL was added and stirred at room temperature for 1 hour. To the reaction mixture were added 2M hydrochloric acid (0.30 mL) and water (2 mL), and the mixture was extracted with ethyl acetate and concentrated under reduced pressure. The obtained crude product was purified by a conventional method to obtain 8.6 mg of 2- (5-cyano-6-phenylpyridin-3-yl) -1,3-thiazole-5-carboxylic acid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 7.60-7.61 (3H, m), 7.93-7.96 (2H, m), 8.55 (1H, s ), 8.99 (1H, d, J = 2.0 Hz), 9.51 (1H, d, J = 2.4 Hz)
HPLC retention time: 10.28 minutes ^{obs Mass (M + + H)} : 308.0485
Pred Mass (M ⁺ + H): 308.0488
Formula (M): C ₁₆ H ₉ N ₃ O ₂ S
[Examples 64-82]
In the same manner as in Example 63, compound numbers 64-72 were synthesized using ethyl 2- (5-cyano-6-hydroxypyridin-3-yl) -1,3-thiazole-5-carboxylate. Compound numbers 73 to 82 were also synthesized using ethyl 2- (5-cyano-6-hydroxypyridin-3-yl) -4-methyl-1,3-thiazole-5-carboxylate.

Example 83 Synthesis of 2- (6-cyano-5-phenylpyridin-3-yl) -1,3-thiazole-5-carboxylic acid (Compound No. 83 ) (1) 2-Cyano-3-hydroxypyridine 2.73 g was suspended in 60 mL of a mixed solution of acetitolyl / water = 5/1, cooled to 0 ° C., 4.85 g of N-bromosuccinimide was slowly added, and the reaction solution was stirred for 2 hours under a nitrogen atmosphere. I let you. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure to obtain 5.39 g of a crude product of 6-bromo-2-cyano-3-hydroxypyridine.
(2) 6.39 g of 6-bromo-2-cyano-3-hydroxypyridine and 4.71 g of potassium carbonate were suspended in 60 mL of dimethylformamide, 4.66 g of benzyl bromide was added, and the mixture was heated at 60 ° C. for 12 hours. After cooling the reaction mixture to room temperature, 60 mL of water was added and purified by a conventional method to obtain 4.73 g of 3-benzyloxy-6-bromo-2-cyanopyridine.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 5.26 (2H, s), 7.24 (1H, d, J = 8.0 Hz), 7.36-7.44 (5H, m ), 7.57 (1H, d, J = 8.0 Hz)
(3) To 2.89 g of 3-benzyloxy-6-bromo-2-cyanopyridine obtained above, 2.10 g of potassium hydrogen carbonate, 88.7 mg of palladium (II) chloride, and 411 mg of copper (I) bromide were added. In addition, it was suspended in 30 mL of toluene. Thereafter, 2.36 g of ethyl 1,3-thiazole-5-carboxylate, 185 μL of isobutyric acid and 457 mg of di-t-butylcyclohexylphosphine were added and heated at 120 ° C. for 14 hours in a nitrogen atmosphere. The reaction mixture was filtered through Celite to remove insolubles, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried, concentrated under reduced pressure and then purified by a conventional method. Ethyl 2- [5- (benzyloxy) -6-cyanopyridin-2-yl) -1,3-thiazol-5 1.74 g of carboxylate was obtained.
^{ESI / MS m / e: 366.0} (M + + H, C 19 H 16 N 3 O 3 S).
(4) Ethyl 2- [5- (benzyloxy) -6-cyanopyridin-2-yl) -1,3-thiazole-5-carboxylate (1.74 g) was added to 30 mL of a mixed solution of tetrahydrofuran / ethanol = 1/1. After suspending and adding 409 mg of palladium / carbon (10% wt), the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 1.44 g of ethyl 2- (6-cyano-5-hydroxypyridin-2-yl) -1,3-thiazole-5-carboxylate. .
(5) 27.5 mg of ethyl 2- (6-cyano-5-hydroxypyridin-2-yl) -1,3-thiazole-5-carboxylate is suspended in 1 mL of dichloromethane, and 192 μL of N, N-diisopropylethylamine is added. After cooling to 0 ° C., 185 μL of trifluoromethanesulfonic anhydride was added, and the mixture was stirred at room temperature for 1 hour in a nitrogen atmosphere. Water was added to the reaction mixture and extracted with dichloromethane. The organic layer is washed with brine, dried and concentrated under reduced pressure to give ethyl 2- {6-cyano-5-[(trifluoromethane) sulfonyloxy] pyridin-2-yl} -1,3-thiazole-5. -407 mg of crude carboxylate was obtained.
(6) Ethyl 2- {6-cyano-5-[(trifluoromethane) sulfonyloxy] pyridin-2-yl} -1,3-thiazole-5-carboxylate 81.4 mg, potassium carbonate 55.3 mg, phenylboron 36.6 mg of acid and 11.6 mg of tetrakistriphenylphosphine were suspended in 1.0 mL of toluene and heated at 90 ° C. for 14 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure to obtain a crude product of ethyl 2- (6-cyano-5-phenylpyridin-2-yl) -1,3-thiazole-5-carboxylate. .
(7) 1.0 mL of a mixed solution of the above-mentioned ethyl 2- (6-cyano-5-phenylpyridin-2-yl) -1,3-thiazole-5-carboxylate in tetrahydrofuran / methanol = 1/1 2M sodium hydroxide aqueous solution 0.20mL was added, and it stirred at room temperature for 4 hours. To the reaction mixture were added 2M hydrochloric acid 0.20 mL and water 2 mL, extracted with ethyl acetate, and concentrated under reduced pressure. The obtained crude product was purified by a conventional method to obtain 19.6 mg of 2- (6-cyano-5-phenylpyridin-3-yl) -1,3-thiazole-5-carboxylic acid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 7.56-7.63 (3H, m), 7.72-7.75 (2H, m), 8.32 (1H, d , J = 8.0 Hz), 8.49 (1H, d, J = 8.0 Hz), 8.53 (1H, s)
HPLC retention time: 11.42 minutes ^{obs Mass (M + + H)} : 308.0488
Pred Mass (M ⁺ + H): 308.0488
Formula (M): C ₁₆ H ₉ N ₃ O ₂ S
[Examples 84-108]
In the same manner as in Example 83, compound numbers 84 to 92 were synthesized. Compound Nos. 93 to 108 were synthesized using ethyl 4-methyl-1,3-thiazole-5-carboxylate as a raw material.

[Example 109]
About the compound synthesize | combined according to the method of the above Example, the xanthine oxidase inhibitory activity was measured.
(1) Preparation of test compound A test compound was dissolved in DMSO (manufactured by Sigma) so as to have a concentration of 20 mM, and then adjusted to a target concentration at the time of use.
(2) Measurement method The xanthine oxidase inhibitory activity of the compounds of the present invention was evaluated by partially modifying the method described in the literature (Method Enzymatic Analysis, 1,521-522, 1974). This evaluation was performed by measuring oxidase type xanthine oxidoreductase activity. That is, xanthine (manufactured by Sigma) molten iron prepared to 10 mM in a 20 mM sodium hydroxide solution in advance was prepared to 30 μM using a 100 mM phosphate buffer, and 75 μL / well was added to a 96-well plate. Each test compound diluted with DMSO to a final concentration of 100 times was added at 1.5 μL / well, and after mixing, the absorbance at 290 nm was measured with a microplate reader SPECTRA max Plus 384 (manufactured by Molecular Devices). Subsequently, oxidase-type xanthine oxidoreductase (derived from buttermilk, Calbiochem) was prepared to 30.6 mU / mL using 100 mM phosphate buffer, and 73.5 μL / well was added. Immediately after mixing, the change in absorbance at 290 nm was measured for 5 minutes. The inhibition rate of the test compound was calculated by setting the enzyme activity when DMSO was added instead of the test compound solution as 100%, and the 50% inhibitory concentration for the oxidase type xanthine oxidoreductase was calculated by fitting to the dose response curve.
The results are shown in the following table. However, the symbols (+, ++, ++) in the table represent the inhibitory activity values as follows.
10.0 nM ≦ IC ₅₀ : +
5.0 nM ≦ IC ₅₀ <10.0 nM: ++
1.0 nM ≦ IC ₅₀ <5.0 nM: +++

[Example 110]
Blood uric acid lowering effect (normal mouse)
Test compounds suspended in 0.5% methylcellulose solution were forcibly administered to 7 to 8 week-old Crlj: CD1 male mice (Charles River Japan Co., Ltd.) using an oral sonde. Blood was collected from the heart at 6 and 16 hours after administration, and the serum was separated. The blood uric acid level was measured with a uricase method using a uric acid measurement kit (Autocera SUA: Sekisui Medical) with an absorptiometer (Hitachi automatic analyzer 7180), and the uric acid reduction rate was determined by the following equation.
Uric acid reduction rate (%)
= (Uric acid value of control animal−Uric acid value of animal receiving test compound) × 100 / Uric acid value of control animal Compound Nos. 1, 2, 49, 50, 55 and 57 were uric acid at 6 hours after administration of 1 mg / kg. The reduction rate was 70% or more. Moreover, the compounds of Compound Nos. 1, 2, 3, 4, 5 and 50 showed a uric acid reduction rate of 50% or more at 16 hours after administration of 1 mg / kg.
From the above results, it was shown that the compound of the present invention has a strong and continuous blood uric acid lowering action.
[Example 111]
Blood uric acid lowering effect (normal rat)
A test compound suspended in a 0.5% methylcellulose solution was forcibly administered to an 8-9 week old Sprague-Dawley male rat (Charles River Japan Co., Ltd.) using an oral sonde. Blood was collected from the tail vein at 6 and 24 hours after administration, and then plasma was separated. The blood uric acid level was measured using a uric acid measurement kit (L type Wako UA • F: Wako Pure Chemical Industries) with an absorptiometer by the uricase method, and the uric acid reduction rate was determined by the following equation.
Uric acid reduction rate (%)
= (Uric acid value of control animal−Uric acid value of animal receiving test compound) × 100 / Uric acid value of control animal Compound Nos. 1 and 2 were administered at a dose of 1 mg / kg at a dose of 1 mg / kg after 6 hours and 24 hours after uric acid reduction rate of 70 % Or more. In addition, the compounds of Compound Nos. 3 and 4 showed a uric acid reduction rate of 50% or more at 6 and 24 hours after administration at a dose of 10 mg / kg. From these results, it was shown that the compound of the present invention has a strong and sustained blood uric acid lowering action.
[Example 112]
Blood uric acid lowering effect (Fusa capuchin monkey)
Test compounds suspended in 0.5% methylcellulose solution in capuchin monkeys were forcibly administered into the stomach from the nasal cavity using a disposable catheter and syringe. Blood was collected from the saphenous vein at 4 hours and 24 hours after administration, and plasma was separated. The blood uric acid level was measured using a uric acid measurement kit (L type Wako UA • F: Wako Pure Chemical Industries) with an absorptiometer by the uricase method, and the uric acid reduction rate was determined by the following equation.
Uric acid reduction rate (%)
= (Uric acid value of control animals−Uric acid value of animals receiving test compound) × 100 / Uric acid value of control animals Compound Nos. 1 and 2 were administered at a dose of 1 mg / kg at 4 hours and 24 hours after administration, and the uric acid reduction rate was 50. % Or more.
From this result, it was shown that the compound of the present invention has a strong and continuous blood uric acid lowering action even in capuchin monkeys.
[Example 113]
Blood uric acid lowering action (beagle dog)
About the compound numbers 1 and 2, the blood uric acid lowering effect in a beagle dog was confirmed. A test compound suspended in 0.5% methylcellulose solution was orally administered by gavage to a beagle dog (Kitayama Labes). Blood was collected from the cephalic vein at 1 hour and 24 hours after administration, and then plasma was separated. The blood uric acid level was measured using the LC-MS / MS method, and the uric acid reduction rate was determined by the following equation.
Uric acid reduction rate (%)
= (Uric acid value of control animal−Uric acid value of animal receiving test compound) × 100 / Uric acid value of control animal Compound No. 2 showed a uric acid decrease rate of 50% or more at 1 mg / kg after administration for 1 hour. .
Compound No. 1 showed a uric acid reduction rate of 40% or more at a dose of 10 mg / kg at 24 hours after administration.
From these results, it was shown that the compound of the present invention has a sustained blood uric acid lowering effect in dogs.
From the above results, it can be expected that the compound of the present invention exerts a strong uric acid lowering action even if it is administered once a day or more at intervals. In addition, clinically, continuously reducing uric acid levels is important in the treatment or prevention of hyperuricemia and various diseases resulting therefrom, particularly chronic diseases, and the present invention is excellent for such diseases. Expect to be effective.

The compound represented by the above formula (I) of the present invention and a pharmaceutically acceptable salt thereof have xanthine oxidase inhibitory activity and are clinically applicable as xanthine oxidase inhibitors. Respiratory organs such as uricemia, tumor lysis syndrome, urolithiasis, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and heart failure, renal diseases such as diabetic nephropathy, chronic obstructive pulmonary disease It can be used as a therapeutic or prophylactic agent for diseases involving xanthine oxidase such as diseases, inflammatory bowel diseases or autoimmune diseases.

Claims (19)

A compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[Where:
A represents an aryl group having 6 to 10 carbon atoms or a heteroaryl group, wherein the aryl group or heteroaryl group is unsubstituted or the same or different from each other, and is a halogen atom, -CN, —NO ₂ , an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a phenyl group, —CH ₂ —O—R ² , —O—R ² , halogenoalkyl of 1 to 6 carbon -O- atoms, -O- benzyl, -O- ^{phenyl, -O-CO-R 2,} -NR 3 R 4, -NH-CO-R 2, -CO 2 -R ^{2, -CO-R 2, -CO} -NR 3 R 4, -NH-SO 2 -R 2, -CO- _{^{aryl, -S-R 2, -SO 2}} - alkyl having 1 to 6 carbon atoms, and - It is substituted with 1 to 3 groups R selected from the group consisting of SO ₂ -phenyl. It may be replaced.
X, Y, and Z represent CR ⁵ or a nitrogen atom, wherein one of X, Y, and Z represents a nitrogen atom and the remaining two represent CR ⁵ .
R ¹ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
R ² represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
R ³ and R ⁴ are the same or different from each other, and are a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, wherein R ³ and R ⁴ are united together with a nitrogen atom to which they are bonded to form a single ring A formula nitrogen-containing saturated heterocycle may be formed.
R ⁵ represents a hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms. ] The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein X and Z represent CR ⁵ and Y represents a nitrogen atom. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Y and Z represent CR ⁵ and X represents a nitrogen atom. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein X and Y represent CR ⁵ and Z represents a nitrogen atom. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R ⁵ represents a hydrogen atom. 6. The compound according to claim 1, wherein R ¹ represents a hydrogen atom or a methyl group, or a pharmaceutically acceptable salt thereof. A is unsubstituted or the same or different and is a halogen atom, —CN, —NO ₂ , an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or 1 to 6 carbon atoms. halogenoalkyl group, a phenyl ^{_{group, -CH 2 -O-R 2,}} -O-R 2, -O- halogenoalkyl carbon atoms 1 ~ 6, -O- benzyl, -O- phenyl, -O-CO- ^{R 2, -NR 3 R 4,} -NH-CO-R 2, -CO 2 -R 2, -CO-R 2, -CO-NR 3 R 4, -NH-SO 2 -R 2, -CO- 6 carbon atoms that may be substituted with one or two groups R selected from the group consisting of aryl, —S—R ² , —SO ₂ —alkyl having 1 to 6 carbon atoms, and —SO ₂ -phenyl. The compound according to any one of claims 1 to 6, which represents an aryl group of 10 to 10, or a compound thereof A pharmaceutically acceptable salt. A is unsubstituted or the same or different and is a halogen atom, —CN, —NO ₂ , an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or 1 to 6 carbon atoms. halogenoalkyl group, a phenyl ^{_{group, -CH 2 -O-R 2,}} -O-R 2, -O- halogenoalkyl carbon atoms 1 ~ 6, -O- benzyl, -O- phenyl, -O-CO- ^{R 2, -NR 3 R 4,} -NH-CO-R 2, -CO 2 -R 2, -CO-R 2, -CO-NR 3 R 4, -NH-SO 2 -R 2, -CO- A phenyl group which may be substituted with one or two groups R selected from the group consisting of aryl, —S—R ² , —SO ₂ —alkyl having 1 to 6 carbon atoms, and —SO ₂ -phenyl; 8. A compound according to claim 7 or a pharmaceutically acceptable salt thereof. A is unsubstituted or the same or different and is a halogen atom, —CN, —NO ₂ , an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or 1 to 6 carbon atoms. halogenoalkyl group, a phenyl ^{_{group, -CH 2 -O-R 2,}} -O-R 2, -O- halogenoalkyl carbon atoms 1 ~ 6, -O- benzyl, -O- phenyl, -O-CO- ^{R 2, -NR 3 R 4,} -NH-CO-R 2, -CO 2 -R 2, -CO-R 2, -CO-NR 3 R 4, -NH-SO 2 -R 2, -CO- Heteroaryl group optionally substituted with one or two groups R selected from the group consisting of aryl, —S—R ² , —SO ₂ —alkyl having 1 to 6 carbon atoms, and —SO ₂ -phenyl The compound according to any one of claims 1 to 6 or a pharmaceutical product thereof, which represents Acceptable salt thereof. 10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein A is unsubstituted. R represents a halogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a phenyl group, —O—R ² , and —O—carbon number. 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, selected from the group consisting of 1 to 6 halogenoalkyls. 12. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of a halogen atom, a methyl group and a methoxy group. Any compound selected from the following (1) to (108) or a pharmaceutically acceptable salt thereof:
(1) 2- (4-Cyano-5-phenylpyridin-2-yl) -1,3-thiazole-5-carboxylic acid (2) 2- [4-cyano-5- (2-fluorophenyl) pyridine- 2-yl] -1,3-thiazole-5-carboxylic acid (3) 2- [4-cyano-5- (2,4-difluorophenyl) pyridin-2-yl] -1,3-thiazole-5 Carboxylic acid (4) 2- [4-cyano-5- (2-fluoro-4-methylphenyl) pyridin-2-yl] -1,3-thiazole-5-carboxylic acid (5) 2- [4-cyano -5- (2-Fluoro-5-methylphenyl) pyridin-2-yl] -1,3-thiazole-5-carboxylic acid (6) 2- [4-cyano-5- (2,5-difluorophenyl) Pyridin-2-yl] -1,3-thiazole-5-cal Acid (7) 2- [4-Cyano-5- (2,3-difluorophenyl) pyridin-2-yl] -1,3-thiazole-5-carboxylic acid (8) 2- [4-cyano-5 -(4-Fluoro-3-methylphenyl) pyridin-2-yl] -1,3-thiazole-5-carboxylic acid (9) 2- [4-cyano-5- (3-fluoro-4-methylphenyl) Pyridin-2-yl] -1,3-thiazole-5-carboxylic acid (10) 2- [4-cyano-5- (2-fluoro-5-methoxyphenyl) pyridin-2-yl] -1,3- Thiazole-5-carboxylic acid (11) 2- [4-cyano-5- (4-methylphenyl) pyridin-2-yl] -1,3-thiazole-5-carboxylic acid (12) 2- {4-cyano -5- [4- (propan-2-yl) phenyl] pi Gin-2-yl} -1,3-thiazole-5-carboxylic acid (13) 2- [4-cyano-5- (3-ethoxyphenyl) pyridin-2-yl] -1,3-thiazol-5 Carboxylic acid (14) 2- [5- (4-carboxyphenyl) -4-cyanopyridin-2-yl] -1,3-thiazole-5-carboxylic acid (15) 2- [4-cyano-5- ( 3-Fluorophenyl) pyridin-2-yl] -1,3-thiazole-5-carboxylic acid (16) 2- [4-cyano-5- (4-fluorophenyl) pyridin-2-yl] -1,3 -Thiazole-5-carboxylic acid (17) 2- [4-cyano-5- (2-chlorophenyl) pyridin-2-yl] -1,3-thiazole-5-carboxylic acid (18) 2- {4-cyano -5- [4- (trifluoromethyl) fur Enyl] pyridin-2-yl} -1,3-thiazole-5-carboxylic acid (19) 2- [4-cyano-5- (4-methoxyphenyl) pyridin-2-yl] -1,3-thiazole- 5-carboxylic acid (20) 2- {4-cyano-5- [4- (trifluoromethoxy) phenyl] pyridin-2-yl} -1,3-thiazole-5-carboxylic acid (21) 2- [4 -Cyano-5- (thiophen-3-yl) pyridin-2-yl] -1,3-thiazole-5-carboxylic acid (22) 2- [4-cyano-5- (pyridin-3-yl) pyridine- 2-yl] -1,3-thiazole-5-carboxylic acid (23) 2- [4-cyano-5- (4-methoxypyridin-3-yl) pyridin-2-yl] -1,3-thiazole- 5-Carboxylic acid (24) 2- {4-cyano 5- [6- (Dimethylamino) pyridin-3-yl] pyridin-2-yl} -1,3-thiazole-5-carboxylic acid (25) 2- [4-cyano-5- (5-fluoropyridine- 3-yl) pyridin-2-yl] -1,3-thiazole-5-carboxylic acid (26) 2- [5- (1-benzothiophen-3-yl) -4-cyanopyridin-2-yl]- 1,3-thiazole-5-carboxylic acid (27) 2- [4-cyano-5- (3-methylthiophen-2-yl) pyridin-2-yl] -1,3-thiazole-5-carboxylic acid ( 28) 2- [4-Cyano-5- (furan-3-yl) pyridin-2-yl] -1,3-thiazole-5-carboxylic acid (29) 2- {4-cyano-5- [4- (Propan-2-yloxy) phenyl] pyridin-2-yl } -1,3-thiazole-5-carboxylic acid (30) 2- [5- (4-t-butylphenyl) -4-cyanopyridin-2-yl] -1,3-thiazole-5-carboxylic acid ( 31) 2- [4-Cyano-5- (4-phenoxyphenyl) pyridin-2-yl] -1,3-thiazole-5-carboxylic acid (32) 2- {4-cyano-5- [4- ( Methoxymethyl) phenyl] pyridin-2-yl} -1,3-thiazole-5-carboxylic acid (33) 2- {4-cyano-5- [3- (2-methylpropyl) phenyl] pyridin-2-yl } -1,3-thiazole-5-carboxylic acid (34) 2- [4-cyano-5- (naphthalen-2-yl) pyridin-2-yl] -1,3-thiazole-5-carboxylic acid (35 ) 2- {4-Cyano-5- [4- (methyls) Fanyl) phenyl] pyridin-2-yl} -1,3-thiazole-5-carboxylic acid (36) 2- (4-cyano-5- {4-[(morpholin-4-yl) carbonyl] phenyl} pyridine- 2-yl) -1,3-thiazole-5-carboxylic acid (37) 2- (4-cyano-5- {4-[(morpholin-4-yl) carbonyl] phenyl} pyridin-2-yl) -1 , 3-thiazole-5-carboxylic acid (38) 2- {4-cyano-5- [4- (morpholin-4-yl) phenyl] pyridin-2-yl} -1,3-thiazole-5-carboxylic acid (39) 2- [4-Cyano-5- (4-phenylphenyl) pyridin-2-yl] -1,3-thiazole-5-carboxylic acid (40) 2- {4-cyano-5- [3- (Dimethylamino) phenyl] pyrid N-2-yl} -1,3-thiazole-5-carboxylic acid (41) 2- [4-cyano-5- (4-acetamidophenyl) pyridin-2-yl] -1,3-thiazole-5 Carboxylic acid (42) 2- [4-Cyano-5- (4-methanesulfonamidophenyl) pyridin-2-yl] -1,3-thiazole-5-carboxylic acid (43) 2- [5- (4- Acetylphenyl) -4-cyanopyridin-2-yl] -1,3-thiazol-5-carboxylic acid (44) 2- [4-cyano-5- (3-cyanophenyl) pyridin-2-yl] -1 , 3-thiazole-5-carboxylic acid (45) 2- [4-cyano-5- (3-nitrophenyl) pyridin-2-yl] -1,3-thiazole-5-carboxylic acid (46) 2- [ 4-cyano-5- (3-methanesulfonate Phenyl) pyridin-2-yl] -1,3-thiazole-5-carboxylic acid (47) 2- [5- (4-benzoylphenyl) -4-cyanopyridin-2-yl] -1,3-thiazole- 5-carboxylic acid (48) 2- [4-cyano-5- (4-cyclohexylphenyl) pyridin-2-yl] -1,3-thiazole-5-carboxylic acid (49) 2- (4-cyano-5 -Phenylpyridin-2-yl) -4-methyl-1,3-thiazole-5-carboxylic acid (50) 2- (4-cyano-5-phenylpyridin-2-yl) -4-methyl-1,3 -Thiazole-5-carboxylic acid (51) 2- [4-cyano-5- (4-fluorophenyl) pyridin-2-yl] -4-methyl-1,3-thiazole-5-carboxylic acid (52) 2 -[4-cyano-5- ( -Methoxyphenyl) pyridin-2-yl] -4-methyl-1,3-thiazole-5-carboxylic acid (53) 2- [4-cyano-5- (2-fluoro-5-methoxyphenyl) pyridine-2 -Yl] -4-methyl-1,3-thiazole-5-carboxylic acid (54) 2- [4-cyano-5- (2,4-difluoro-5-methoxyphenyl) pyridin-2-yl] -4 -Methyl-1,3-thiazole-5-carboxylic acid (55) 2- [4-cyano-5- (2,4-difluoro-5-methoxyphenyl) pyridin-2-yl] -4-methyl-1, 3-thiazole-5-carboxylic acid (56) 2- [4-cyano-5- (2-fluoro-4-methylphenyl) pyridin-2-yl] -4-methyl-1,3-thiazole-5-carboxylic Acid (57) 2- [4-Si NO-5- (2-Fluoro-5-methylphenyl) pyridin-2-yl] -4-methyl-1,3-thiazole-5-carboxylic acid (58) 2- [4-cyano-5- (3- Fluorophenyl) pyridin-2-yl] -4-methyl-1,3-thiazole-5-carboxylic acid (59) 2- [4-cyano-5- (2-fluoro-3-methylphenyl) pyridine-2- Yl] -4-methyl-1,3-thiazole-5-carboxylic acid (60) 2- [4-cyano-5- (2-fluoro-3-methoxyphenyl) pyridin-2-yl] -4-methyl- 1,3-thiazole-5-carboxylic acid (61) 2- [4-cyano-5- (4-fluoro-3-methylphenyl) pyridin-2-yl] -4-methyl-1,3-thiazole-5 -Carboxylic acid (62) 2- [4-cyano -5- (2-Methylphenyl) pyridin-2-yl] -4-methyl-1,3-thiazole-5-carboxylic acid (63) 2- (5-cyano-6-phenylpyridin-3-yl)- 1,3-thiazole-5-carboxylic acid (64) 2- [5-cyano-6- (2-fluorophenyl) pyridin-3-yl] -1,3-thiazole-5-carboxylic acid (65) 2- [5-Cyano-6- (2-fluoro-4-methylphenyl) pyridin-3-yl] -1,3-thiazole-5-carboxylic acid (66) 2- [5-cyano-6- (2-fluoro -5-methylphenyl) pyridin-3-yl] -1,3-thiazole-5-carboxylic acid (67) 2- [5-cyano-6- (4-fluorophenyl) pyridin-3-yl] -1, 3-Thiazole-5-carboxylic acid (68) -[5-Cyano-6- (2,5-difluorophenyl) pyridin-3-yl] -1,3-thiazole-5-carboxylic acid (69) 2- [5-cyano-6- (2,4- Difluorophenyl) pyridin-3-yl] -1,3-thiazole-5-carboxylic acid (70) 2- [5-cyano-6- (2,4-difluorophenyl) pyridin-3-yl] -1,3 -Thiazole-5-carboxylic acid (71) 2- [5-cyano-6- (2-fluoro-5-methoxyphenyl) pyridin-3-yl] -1,3-thiazole-5-carboxylic acid (72) 2 -[5-Cyano-6- (2,6-difluorophenyl) pyridin-3-yl] -1,3-thiazole-5-carboxylic acid (73) 2- (5-cyano-6-phenylpyridine-3- Yl) -4-methyl-1,3-thia Zole-5-carboxylic acid (74) 2- [5-cyano-6- (2-fluorophenyl) pyridin-3-yl] -4-methyl-1,3-thiazole-5-carboxylic acid (75) 2- [5-Cyano-6- (2-fluoro-5-methylphenyl) pyridin-3-yl] -4-methyl-1,3-thiazole-5-carboxylic acid (76) 2- [5-cyano-6 (2-Fluoro-4-methylphenyl) pyridin-3-yl] -4-methyl-1,3-thiazole-5-carboxylic acid (77) 2- [5-cyano-6- (2,4-difluorophenyl) ) Pyridin-3-yl] -4-methyl-1,3-thiazole-5-carboxylic acid (78) 2- [5-cyano-6- (4-fluorophenyl) pyridin-3-yl] -4-methyl -1,3-thiazole-5-carboxylic acid 79) 2- [5-Cyano-6- (4-fluorophenyl) pyridin-3-yl] -4-methyl-1,3-thiazole-5-carboxylic acid (80) 2- [5-cyano-6- (2,5-difluorophenyl) pyridin-3-yl] -4-methyl-1,3-thiazole-5-carboxylic acid (81) 2- [5-cyano-6- (4-fluoro-3-methylphenyl) ) Pyridin-3-yl] -4-methyl-1,3-thiazole-5-carboxylic acid (82) 2- [5-cyano-6- (2-fluoro-5-methoxyphenyl) pyridin-3-yl] -4-Methyl-1,3-thiazole-5-carboxylic acid (83) 2- (6-cyano-5-phenylpyridin-2-yl) -1,3-thiazole-5-carboxylic acid (84) 2 -[6-Cyano-5- (2-fluorophe Nyl) pyridin-2-yl] -1,3-thiazole-5-carboxylic acid (85) 2- [6-cyano-5- (2-fluoro-5-methylphenyl) pyridin-2-yl] -1, 3-thiazole-5-carboxylic acid (86) 2- [6-cyano-5- (2-fluoro-4-methylphenyl) pyridin-2-yl] -1,3-thiazole-5-carboxylic acid (87) 2- [6-Cyano-5- (2,6-difluorophenyl) pyridin-2-yl] -1,3-thiazole-5-carboxylic acid (88) 2- [6-cyano-5- (4-fluoro) Phenyl) pyridin-2-yl] -1,3-thiazole-5-carboxylic acid (89) 2- [6-cyano-5- (2,4-difluorophenyl) pyridin-2-yl] -1,3- Thiazole-5-carboxylic acid (90) 2- [ -Cyano-5- (2,5-difluorophenyl) pyridin-2-yl] -1,3-thiazole-5-carboxylic acid (91) 2- [6-cyano-5- (4-fluoro-3-methyl) Phenyl) pyridin-2-yl] -1,3-thiazole-5-carboxylic acid (92) 2- [6-cyano-5- (2-fluoro-5-methoxyphenyl) pyridin-2-yl] -1 , 3-thiazole-5-carboxylic acid (93) 2- (6-cyano-5-phenylpyridin-2-yl) -4-methyl-1,3-thiazole-5-carboxylic acid (94) 2- [6 -Cyano-5- (2-fluorophenyl) pyridin-2-yl] -4-methyl-1,3-thiazole-5-carboxylic acid (95) 2- [6-cyano-5- (4-fluorophenyl) Pyridin-2-yl] -4-methyl- 1,3-thiazole-5-carboxylic acid (96) 2- [6-cyano-5- (2,6-difluorophenyl) pyridin-2-yl] -4-methyl-1,3-thiazole-5-carboxylic Acid (97) 2- [6-Cyano-5- (2,4-difluorophenyl) pyridin-2-yl] -4-methyl-1,3-thiazole-5-carboxylic acid (98) 2- [6- Cyano-5- (2,5-difluorophenyl) pyridin-2-yl] -4-methyl-1,3-thiazole-5-carboxylic acid (99) 2- [6-cyano-5- (2-fluoro-) 4-methylphenyl) pyridin-2-yl] -4-methyl-1,3-thiazole-5-carboxylic acid (100) 2- [6-cyano-5- (2-fluoro-5-methylphenyl) pyridine- 2-yl] -4-methyl-1,3- Azol-5-carboxylic acid (101) 2- [6-cyano-5- (4-fluoro-3-methylphenyl) pyridin-2-yl] -4-methyl-1,3-thiazole-5-carboxylic acid ( 102) 2- [6-Cyano-5- (2-fluoro-5-methoxyphenyl) pyridin-2-yl] -4-methyl-1,3-thiazole-5-carboxylic acid (103) 2- [5- (4-Acetylphenyl) -6-cyanopyridin-2-yl] -4-methyl-1,3-thiazole-5-carboxylic acid (104) 2- [5- (4-carboxy-3-fluorophenyl)- 6-Cyanopyridin-2-yl] -4-methyl-1,3-thiazole-5-carboxylic acid (105) 2- [5- (4-carboxyphenyl) -6-cyanopyridin-2-yl] -4 -Methyl-1,3- Azol-5-carboxylic acid (106) 2- [5- (3-acetyl-2-fluorophenyl) -6-cyanopyridin-2-yl] -4-methyl-1,3-thiazole-5-carboxylic acid ( 107) 2- [5- (3-Acetylphenyl) -6-cyanopyridin-2-yl] -4-methyl-1,3-thiazole-5-carboxylic acid (108) 2- [5- (3-carboxyl) Phenyl) -6-cyanopyridin-2-yl] -4-methyl-1,3-thiazole-5-carboxylic acid A pharmaceutical composition comprising the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A xanthine oxidase inhibitor comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof as an active ingredient. Gout, hyperuricemia, tumor lysis syndrome, urolithiasis, hypertension, dyslipidemia containing the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof as an active ingredient Remedies or preventives for cardiovascular diseases such as diabetes, arteriosclerosis and heart failure, kidney diseases such as diabetic nephropathy, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel disease or autoimmune disease . A therapeutic or prophylactic agent for gout or hyperuricemia comprising the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof as an active ingredient. A compound represented by the formula (II).

[Where:
A represents an aryl group having 6 to 10 carbon atoms or a heteroaryl group, wherein the aryl group or heteroaryl group is unsubstituted or the same or different from each other, and is a halogen atom, -CN,- NO ₂ , an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a phenyl group, —CH ₂ —O—R ² , —O—R ² , -O- halogenoalkyl carbon atoms 1 ~ 6, -O- benzyl, -O- ^{phenyl, -O-CO-R 2,} -NR 3 R 4, -NH-CO-R 2, -CO 2 -R 2 ^{, -CO-R 2, -CO-} NR 3 R 4, -NH-SO 2 -R 2, -CO- _{^{aryl, -S-R 2, -SO 2}} - alkyl having 1 to 6 carbon atoms, and -SO Substituted with 1 to 3 groups R selected from the group consisting of ₂ -phenyl May be.
X, Y and Z represent CR ⁵ or a nitrogen atom, wherein one of X, Y and Z represents a nitrogen atom and the remaining two represent CR ⁵ .
R ¹ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
R ² represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
R ³ and R ⁴ are the same or different from each other, and are a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, wherein R ³ and R ⁴ are united together with a nitrogen atom to which they are bonded to form a single ring A formula nitrogen-containing saturated heterocycle may be formed.
R ⁵ represents a hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms.
R ⁶ represents a protecting group for a carboxyl group.
W represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, or a cyano group. ] A compound represented by formula (III).

[Where:
X, Y and Z represent CR ⁵ or a nitrogen atom, one of X, Y and Z represents a nitrogen atom, and the other two represent CR ⁵ .
R ¹ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
R ⁵ represents a hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms.
R ⁶ represents a protecting group for a carboxyl group.
V represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, a hydroxyl group, or a benzyloxy group.
W represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, or a cyano group. ]