JP2005325103A - Pharmaceutical composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain an excellent high-conductance type calcium-sensitive K-channel opening drug. <P>SOLUTION: For producing the high-conductance type calcium-sensitive K-channel opening drug, a five-membered heterocyclic compound of formula(II) or a pharmacologically acceptable salt thereof is used. In formula(II), ring A is a ring represented by either of formula A; R<SP>1</SP>is a substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted heterocyclic group-substituted carbonyl; R<SP>2</SP>is a substituted alkyl; R<SP>3</SP>is a substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted alkyl; and R<SP>4</SP>is H or a substituted or unsubstituted alkyl; wherein, when R<SP>1</SP>and R<SP>3</SP>are each phenyl, R<SP>2</SP>is neither carboxymethyl nor ethoxycarbonylmethyl. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to an excellent high-conductance calcium-sensitive K channel opener comprising a 5-membered heterocyclic compound as an active ingredient, which is useful for the treatment of diseases such as frequent urination, urinary incontinence, cerebral infarction and subarachnoid hemorrhage.

Potassium is the most abundant cation in the cell and is very important for maintaining physiological homeostasis. Potassium channels are found in almost all vertebrate cells, and potassium influx from these channels is essential for maintaining the resting membrane potential of hyperpolarized cells.
High conductance calcium-sensitive potassium channels (also referred to as BK channels or maxi-K channels) are expressed specifically in neurons and smooth muscle cells. Since the maxi-K channel is activated by an increase in intracellular calcium concentration and membrane depolarization, it has been considered to play an extremely important role in controlling calcium influx depending on the potential. Increases in intracellular calcium levels mediate many processes such as neurotransmitter release, smooth muscle contraction, cell proliferation and cell death. In fact, the opening of the maxi-K channel causes strong membrane hyperpolarization, thereby suppressing these calcium-induced reactions. Therefore, a substance having an action of opening a maxi-K channel suppresses physiological reactions mediated by various depolarizations, thereby treating diseases such as cerebral infarction, subarachnoid hemorrhage, frequent urination and urinary incontinence. Potential as an agent is expected.

  Various reports have been made on high conductance calcium sensitive potassium channel openers. For example, WO 96/40634 and WO 99/36069 describe pyrrole derivatives, JP 2000-351773 describes furan derivatives, and WO 98/04135 describes nitrogen-containing nitrogen atoms substituted with phenyl or benzyl groups. 5-membered ring derivatives are described.

  The present invention provides an excellent high-conductance calcium-sensitive K-channel opener comprising a 5-membered heterocyclic compound as an active ingredient, which is useful for the treatment of diseases such as frequent urination, urinary incontinence, cerebral infarction, and subarachnoid hemorrhage. Is.

  In order to solve the problem, the present inventors have found that certain 5-membered heterocyclic compounds have excellent high conductance calcium-sensitive K channel opening action as a result of intensive studies, and have completed the present invention.

［式中、環Ａは、以下の式のいずれかで示される環を表す。

Ｒ^１は、置換もしくは非置換のアリール、置換もしくは非置換の複素環式基または置換もしくは非置換の複素環式基置換カルボニルを表す。
Ｒ^２は、水素原子、ハロゲン原子、カルボキシ、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、アルコキシカルボニル、置換もしくは非置換のアルケニルまたはシクロアルキルを表す。
Ｒ^３は、置換もしくは非置換のアリール、置換もしくは非置換の複素環式基または置換もしくは非置換のアルキルを表す。
Ｒ^４は、水素原子または置換もしくは非置換のアルキルを表す。］
で示される５員複素環化合物またはその薬理的に許容し得る塩を有効成分として含有する高コンダクタンス型カルシウム感受性Ｋチャネル開口薬。 That is, the present invention is as follows.
[1] Formula (1)

[Wherein, ring A represents a ring represented by any of the following formulae.

R ¹ represents substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group or substituted or unsubstituted heterocyclic group-substituted carbonyl.
R ² represents a hydrogen atom, a halogen atom, carboxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, alkoxycarbonyl, substituted or unsubstituted alkenyl or cycloalkyl.
R ³ represents a substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted alkyl.
R ⁴ represents a hydrogen atom or substituted or unsubstituted alkyl. ]
A high-conductance calcium-sensitive K-channel opener comprising a 5-membered heterocyclic compound represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

[2] R ¹ is (1) nitro, amino, hydroxyl, carbamoyl, cyano, carboxy, trifluoromethyl, alkoxycarbonyl, halogen atom, alkyl, hydroxyalkyl, alkoxy, alkoxyalkoxy, mono or dialkylamino, mono or di Aryl optionally substituted with a group selected from alkanoylamino, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfamoyl, mono- or dialkylsulfamoyl, alkylsulfonylamino and phenylalkoxy, (2) nitro, hydroxyl, formyl, carbamoyl, cyano Amino, carboxy, alkoxycarbonyl, halogen atom, alkyl, hydroxyalkyl, alkoxy, mono- or dialkylamino, mono- or dialka A heterocyclic group optionally substituted with a group selected from ylamino, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfamoyl and mono- or dialkylsulfamoyl, or (3) nitro, hydroxyl, carbamoyl, cyano, carboxy, alkoxycarbonyl, Heteroaryl optionally substituted by a group selected from halogen atom, alkyl, hydroxyalkyl, alkoxy, alkanoyl, mono or dialkylamino, mono or dialkanoylamino, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfamoyl and mono or dialkylsulfamoyl A cyclic group-substituted carbonyl,
R ² is amino optionally substituted with a group selected from (1) a hydrogen atom, (2) a halogen atom, (3) carboxy, (4) formyl, alkyl, alkanoyl, alkylsulfonyl and alkoxycarbonyl, (5) Halogen atom, hydroxyl group, cyano, carboxy, carbamoyl, amino, aminosulfonyl, amidinothio, mono or dialkylamino, alkanoylamino, alkylsulfonylamino, hydroxyamino, mono or dialkylcarbamoyl, trifluoromethyl, alkoxy, alkylthio, alkylsulfinyl, alkyl Sulfonyl, alkylsulfonylamino, hydroxycarbamoyl, hydroxycarbamoyl substituted with 1 or 2 alkyls, alkylsulfonylcarbamoyl, sulfamoyl, mono Or alkyl optionally substituted with a group selected from dialkylsulfamoyl, alkoxycarbonyl, heterocyclic group, heterocyclic group-substituted carbamoyl, heterocyclic group-substituted alkylcarbamoyl and heterocyclic group-substituted sulfonylcarbamoyl, (6 ) Alkoxycarbonyl, (7) alkenyl optionally substituted with carboxy or alkoxycarbonyl, or (8) cycloalkyl,
R ³ is (1) cyano, nitro, amino, halogen atom, trifluoromethyl, carboxy, hydroxyl group, carbamoyl, mono or dialkylamino, aminoalkyl, mono or dialkylaminoalkyl, mono or dialkylcarbamoyl, alkyl, hydroxyalkyl, Aryl optionally substituted with a group selected from alkoxy, alkoxycarbonyl, alkanoyl, alkanoyloxy, alkanoyloxyalkyl, sulfo, alkylthio, alkylthioalkyl, alkylsulfonyl, sulfamoyl, mono- or dialkylsulfamoyl and alkylsulfinyl, (2) Oxo, cyano, nitro, amino, halogen atom, carboxy, hydroxyl group, formyl, carbamoyl, mono- or dialkylamino, N- Alkyl-N-cycloalkylamino, aminoalkyl, mono- or dialkylaminoalkyl, mono- or dialkylcarbamoyl, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkanoyl, sulfo, alkylthio, alkylsulfonyl, sulfamoyl, mono- or dialkylsulfo A heterocyclic group optionally substituted with a group selected from famoyl, alkylsulfinyl and heterocyclic groups, or (3) hydroxyl, cyano, carboxy, carbamoyl, amino, mono- or dialkylamino, alkanoylamino, alkylsulfonylamino , Hydroxyamino, mono- or dialkylcarbamoyl, trifluoromethyl, halogen atom, alkoxy, alkylthio, alkylsulfur Sulfonyl, alkylsulfonyl, sulfamoyl, a mono or dialkyl sulfamoyl, alkoxycarbonyl and alkyl which may be substituted by a group selected from a heterocyclic group,
R ⁴ is (1) a hydrogen atom, or (2) alkyl optionally substituted with mono- or dialkylamino.
[1] The high conductance calcium-sensitive K channel opener according to [1].

[3] R ¹ is a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group,
R ² is carboxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, alkoxycarbonyl or substituted or unsubstituted alkenyl.
R ³ is a substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic group,
The high conductance calcium-sensitive K channel opener according to [1] or [2].

[4] R ¹ is (1) aryl which may be substituted with 1 or 2 halogen atoms, or (2) a heterocyclic group which may be substituted with halogen atoms or alkyl,
R ² may be substituted with a group selected from carboxy, carbamoyl, mono- or dialkylcarbamoyl, hydroxycarbamoyl, hydroxycarbamoyl substituted with 1 or 2 alkyls, alkoxycarbonyl, alkylsulfonylcarbamoyl and heterocyclic groups Alkyl,
R ³ is (1) a heterocyclic group which may be substituted with one or two groups selected from amino, halogen atom, alkyl, alkoxy, mono- or dialkylamino and alkylthio, or (2) amino, halogen atom , Aryl optionally substituted with a group selected from alkyl, alkylthio, alkoxy and mono- or dialkylamino,
R ⁴ is a hydrogen atom or alkyl,
[1] The high conductance calcium-sensitive K channel opener according to [1].

[5] R ¹ is (1) aryl optionally substituted with 1 or 2 halogen atoms, (2) thienyl optionally substituted with halogen atoms, or (3) pyridyl optionally substituted with alkyl And
R ² is (1) carboxyalkyl, (2) carbamoylalkyl, (3) mono- or dialkylcarbamoylalkyl, (4) alkoxycarbonylalkyl, (5) alkylsulfonylcarbamoylalkyl, or (6) tetrazolylalkyl ,
R ³ is (1) phenyl optionally substituted with a halogen atom, (2) phenyl optionally substituted with a group selected from a halogen atom, alkylthio, alkyl, alkoxy and dialkylamino, (3) alkyl, alkoxy And pyridinyl optionally substituted with a group selected from dialkylamino, (4) pyrimidinyl optionally substituted with alkoxy, alkyl, dialkylamino or alkylthio, (5) thienyl optionally substituted with 1 or 2 alkyls , (6) thieno [3,2-b] pyridyl, (7) benzofuryl, (8) dihydrobenzofuryl, or (9) indolyl optionally substituted with alkyl,
R ⁴ is a hydrogen atom or alkyl,
[1] The high conductance calcium-sensitive K channel opener according to [1].

[6] R ¹ is (1) aryl which may be substituted with 1 or 2 halogen atoms, or (2) thienyl which may be substituted with halogen atoms,
R ² is (1) carboxyalkyl, (2) carbamoylalkyl, (3) mono- or dialkylcarbamoylalkyl, or (4) alkoxycarbonylalkyl,
R ³ is (1) phenyl optionally substituted with a halogen atom, (2) phenyl optionally substituted with a group selected from a halogen atom, alkylthio, alkyl, alkoxy and dialkylamino, (3) alkyl, alkoxy And pyridinyl optionally substituted with a group selected from dialkylamino, (4) pyrimidinyl optionally substituted with alkoxy or dialkylamino, (5) thienyl optionally substituted with 1 or 2 alkyls, (6) An indolyl optionally substituted with thieno [3,2-b] pyridyl, (7) benzofuryl, (8) dihydrobenzofuryl, or (9) alkyl;
R ⁴ is a hydrogen atom or alkyl,
[1] The high conductance calcium-sensitive K channel opener according to [1].

[7] R ¹ is (1) aryl optionally substituted with 1 or 2 halogen atoms, or (2) thienyl optionally substituted with halogen atoms,
R ² is (1) carboxyalkyl or (2) alkoxycarbonylalkyl;
R ³ is (1) benzothienyl optionally substituted with a halogen atom, (2) phenyl optionally substituted with a group selected from a halogen atom, alkylthio, alkoxy and dialkylamino, (3) alkoxy or dialkylamino Optionally substituted pyridyl, (4) pyrimidinyl optionally substituted with dialkylamino, (5) thienyl optionally substituted with 1 or 2 alkyls, (6) thieno [3,2-b] pyridyl, Or (7) indolyl optionally substituted with alkyl,
R ⁴ is a hydrogen atom or alkyl,
[1] The high conductance calcium-sensitive K channel opener according to [1].

[8] The high conductance calcium-sensitive K channel opener according to any one of [1] to [6], wherein R ² is carboxymethyl or alkoxycarbonylmethyl.

[9] The high conductance calcium-sensitive K channel opener according to any one of [1] to [8], wherein Ring A is a ring represented by any of the following formulae.

［式中、環Ａは、以下の式のいずれかで示される環を表す。

Ｒ^１は、置換もしくは非置換のアリール、置換もしくは非置換の複素環式基または置換もしくは非置換の複素環式基置換カルボニルを表す。
Ｒ^２は、置換アルキルを表す。
Ｒ^３は、置換もしくは非置換のアリール、置換もしくは非置換の複素環式基または置換もしくは非置換のアルキルを表す。
Ｒ^４は、水素原子または置換もしくは非置換のアルキルを表す。
ただし、Ｒ¹およびＲ^３がフェニルの時、Ｒ^２はカルボキシメチルまたはエトキシカルボニルメチルではない。］
で示される５員複素環化合物またはその薬理的に許容し得る塩。 [10] Formula (II)

[Wherein, ring A represents a ring represented by any of the following formulae.

R ¹ represents substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group or substituted or unsubstituted heterocyclic group-substituted carbonyl.
R ² represents substituted alkyl.
R ³ represents a substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted alkyl.
R ⁴ represents a hydrogen atom or substituted or unsubstituted alkyl.
However, when R ¹ and R ³ are phenyl, R ² is not carboxymethyl or ethoxycarbonylmethyl. ]
Or a pharmacologically acceptable salt thereof.

[11] R ¹ is a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted heterocyclic group-substituted carbonyl, or aryl substituted with two halogens;
[10] The 5-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to [10].

[12] R ¹ is (1) nitro, amino, hydroxyl, carbamoyl, cyano, carboxy, trifluoromethyl, alkoxycarbonyl, halogen atom, alkyl, hydroxyalkyl, alkoxy, alkoxyalkoxy, mono or dialkylamino, mono or di Aryl optionally substituted with a group selected from alkanoylamino, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfamoyl, mono- or dialkylsulfamoyl, alkylsulfonylamino and phenylalkoxy, (2) nitro, hydroxyl, formyl, carbamoyl, cyano Amino, carboxy, alkoxycarbonyl, halogen atom, alkyl, hydroxyalkyl, alkoxy, mono- or dialkylamino, mono- or dialkano A heterocyclic group optionally substituted with a group selected from ylamino, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfamoyl and mono- or dialkylsulfamoyl, or (3) nitro, hydroxyl, carbamoyl, cyano, carboxy, alkoxycarbonyl, Heteroaryl optionally substituted by a group selected from a halogen atom, alkyl, hydroxyalkyl, alkoxy, alkanoyl, mono- or dialkylamino, mono- or dialkanoylamino, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfamoyl and mono- or dialkylsulfamoyl A cyclic group-substituted carbonyl,
R ² is halogen atom, hydroxyl group, cyano, carboxy, carbamoyl, amino, aminosulfonyl, amidinothio, mono or dialkylamino, alkanoylamino, alkylsulfonylamino, hydroxyamino, mono or dialkylcarbamoyl, trifluoromethyl, alkoxy, alkylthio, Alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, hydroxycarbamoyl, hydroxycarbamoyl substituted with 1 or 2 alkyls, alkylsulfonylcarbamoyl, sulfamoyl, mono- or dialkylsulfamoyl, alkoxycarbonyl, heterocyclic group, heterocyclic Selected from group-substituted carbamoyl, heterocyclic group-substituted alkylcarbamoyl and heterocyclic group-substituted sulfonylcarbamoyl An alkyl optionally substituted with a group,
R ³ is (1) cyano, nitro, amino, halogen atom, trifluoromethyl, carboxy, hydroxyl group, carbamoyl, mono or dialkylamino, aminoalkyl, mono or dialkylaminoalkyl, mono or dialkylcarbamoyl, alkyl, hydroxyalkyl, Aryl optionally substituted with a group selected from alkoxy, alkoxycarbonyl, alkanoyl, alkanoyloxy, alkanoyloxyalkyl, sulfo, alkylthio, alkylthioalkyl, alkylsulfonyl, sulfamoyl, mono- or dialkylsulfamoyl and alkylsulfinyl, (2) Oxo, cyano, nitro, amino, halogen atom, carboxy, hydroxyl group, formyl, carbamoyl, mono- or dialkylamino, N- Alkyl-N-cycloalkylamino, aminoalkyl, mono- or dialkylaminoalkyl, mono- or dialkylcarbamoyl, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkanoyl, sulfo, alkylthio, alkylsulfonyl, sulfamoyl, mono- or dialkylsulfo A heterocyclic group optionally substituted with a group selected from famoyl, alkylsulfinyl and heterocyclic groups, or (3) hydroxyl, cyano, carboxy, carbamoyl, amino, mono- or dialkylamino, alkanoylamino, alkylsulfonylamino , Hydroxyamino, mono- or dialkylcarbamoyl, trifluoromethyl, halogen atom, alkoxy, alkylthio, alkylsulfur Sulfonyl, alkylsulfonyl, sulfamoyl, a mono or dialkyl sulfamoyl, alkoxycarbonyl and alkyl which may be substituted by a group selected from a heterocyclic group,
R ⁴ is (1) a hydrogen atom, or (2) alkyl optionally substituted with mono- or dialkylamino.
[10] The 5-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to [11].

[13] R ¹ is (1) aryl which may be substituted with 1 or 2 halogen atoms, or (2) a heterocyclic group which may be substituted with halogen atoms or alkyl,
R ² may be substituted with a group selected from carboxy, carbamoyl, mono- or dialkylcarbamoyl, hydroxycarbamoyl, hydroxycarbamoyl substituted with 1 or 2 alkyls, alkoxycarbonyl, alkylsulfonylcarbamoyl and heterocyclic groups Alkyl,
R ³ is (1) a heterocyclic group which may be substituted with one or two groups selected from amino, halogen atom, alkyl, alkoxy, mono- or dialkylamino and alkylthio, or (2) amino, halogen atom , Aryl optionally substituted with a group selected from alkyl, alkylthio, alkoxy and mono- or dialkylamino,
R ⁴ is a hydrogen atom or alkyl,
The 5-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to [10] or [11].

［式中、環Ａは、以下の式のいずれかで示される環を表す。

Ｒ^１は、置換もしくは非置換のチエニル、または２個のハロゲン原子で置換されたアリールを表す。
Ｒ^２は、置換アルキルを表す。
Ｒ^３は、置換もしくは非置換のアリール、置換もしくは非置換の複素環式基または置換もしくは非置換のアルキルを表す。
Ｒ^４は、水素原子または置換もしくは非置換のアルキルを表す。
ただし、Ｒ^１が２−チエニルの時、Ｒ^３は２−チエニルではない。］
で示される５員複素環化合物またはその薬理的に許容し得る塩。 [14] Formula (III)

[Wherein, ring A represents a ring represented by any of the following formulae.

R ¹ represents substituted or unsubstituted thienyl, or aryl substituted with two halogen atoms.
R ² represents substituted alkyl.
R ³ represents a substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted alkyl.
R ⁴ represents a hydrogen atom or substituted or unsubstituted alkyl.
However, when R ¹ is 2-thienyl, R ³ is not 2-thienyl. ]
Or a pharmacologically acceptable salt thereof.

[15] R ² is a halogen atom, hydroxyl group, cyano, carboxy, carbamoyl, amino, aminosulfonyl, amidinothio, mono- or dialkylamino, alkanoylamino, alkylsulfonylamino, hydroxyamino, mono- or dialkylcarbamoyl, trifluoromethyl, alkoxy Alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, hydroxycarbamoyl, hydroxycarbamoyl substituted with 1 or 2 alkyls, alkylsulfonylcarbamoyl, sulfamoyl, mono- or dialkylsulfamoyl, alkoxycarbonyl, heterocyclic group, Select from heterocyclic group-substituted carbamoyl, heterocyclic group-substituted alkylcarbamoyl and heterocyclic group-substituted sulfonylcarbamoyl An alkyl which may be substituted with a group
R ³ is (1) cyano, nitro, amino, halogen atom, trifluoromethyl, carboxy, hydroxyl group, carbamoyl, mono or dialkylamino, aminoalkyl, mono or dialkylaminoalkyl, mono or dialkylcarbamoyl, alkyl, hydroxyalkyl, Aryl optionally substituted with a group selected from alkoxy, alkoxycarbonyl, alkanoyl, alkanoyloxy, alkanoyloxyalkyl, sulfo, alkylthio, alkylthioalkyl, alkylsulfonyl, sulfamoyl, mono- or dialkylsulfamoyl and alkylsulfinyl, (2) Oxo, cyano, nitro, amino, halogen atom, carboxy, hydroxyl group, formyl, carbamoyl, mono- or dialkylamino, N- Alkyl-N-cycloalkylamino, aminoalkyl, mono- or dialkylaminoalkyl, mono- or dialkylcarbamoyl, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkanoyl, sulfo, alkylthio, alkylsulfonyl, sulfamoyl, mono- or dialkylsulfo A heterocyclic group optionally substituted with a group selected from famoyl, alkylsulfinyl and heterocyclic groups, or (3) hydroxyl, cyano, carboxy, carbamoyl, amino, mono- or dialkylamino, alkanoylamino, alkylsulfonylamino , Hydroxyamino, mono- or dialkylcarbamoyl, trifluoromethyl, halogen atom, alkoxy, alkylthio, alkylsulfur Sulfonyl, alkylsulfonyl, sulfamoyl, a mono or dialkyl sulfamoyl, alkoxycarbonyl and alkyl which may be substituted by a group selected from a heterocyclic group,
R ⁴ is (1) a hydrogen atom, or (2) alkyl optionally substituted with mono- or dialkylamino.
[14] The 5-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to [14].

[16] R ² is substituted with a group selected from carboxy, carbamoyl, mono- or dialkylcarbamoyl, hydroxycarbamoyl, hydroxycarbamoyl substituted with 1 or 2 alkyls, alkoxycarbonyl, alkylsulfonylcarbamoyl and heterocyclic groups Which may be alkyl,
R ³ is (1) a heterocyclic group which may be substituted with one or two groups selected from amino, halogen atom, alkyl, alkoxy, mono- or dialkylamino and alkylthio, or (2) amino, halogen atom , Aryl optionally substituted with a group selected from alkyl, alkylthio, alkoxy and mono- or dialkylamino,
R ⁴ is a hydrogen atom or alkyl,
[14] The 5-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to [14].

[17] R ¹ is thienyl optionally substituted with a halogen atom;
R ² is (1) carboxyalkyl, (2) carbamoylalkyl, (3) mono- or dialkylcarbamoylalkyl, (4) alkoxycarbonylalkyl, (5) alkylsulfonylcarbamoylalkyl, or (6) tetrazolylalkyl ,
R ³ is (1) phenyl optionally substituted with a halogen atom, (2) phenyl optionally substituted with a group selected from a halogen atom, alkylthio, alkyl, alkoxy and dialkylamino, (3) alkyl, alkoxy And pyridinyl optionally substituted with a group selected from dialkylamino, (4) pyrimidinyl optionally substituted with alkoxy, alkyl, dialkylamino or alkylthio, (5) thienyl optionally substituted with 1 or 2 alkyls , (6) thieno [3,2-b] pyridyl, (7) benzofuryl, (8) dihydrobenzofuryl, or (9) indolyl optionally substituted with alkyl,
R ⁴ is a hydrogen atom or alkyl,
[5] The 5-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to [10] or [14].

[18] R ² is (1) carboxyalkyl, (2) carbamoylalkyl, (3) mono- or dialkylcarbamoylalkyl, or (4) alkoxycarbonylalkyl,
R ³ is (1) phenyl optionally substituted with a halogen atom, (2) phenyl optionally substituted with a group selected from a halogen atom, alkylthio, alkyl, alkoxy and dialkylamino, (3) alkyl, alkoxy And pyridinyl optionally substituted with a group selected from dialkylamino, (4) pyrimidinyl optionally substituted with alkoxy or dialkylamino, (5) thienyl optionally substituted with 1 or 2 alkyls, (6) Thieno [3,2-b] pyridyl, (7) benzofuryl, (8) dihydrobenzofuryl, or (9) an indolyl optionally substituted with alkyl,
[17] The 5-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to [17].

[19] R ² is a carboxyalkyl or alkoxycarbonylalkyl,
R ³ is (1) benzothienyl optionally substituted with a halogen atom, (2) phenyl optionally substituted with a group selected from a halogen atom, alkylthio, alkoxy and dialkylamino, (3) alkyl, alkoxy or dialkyl Pyridyl optionally substituted with amino, (4) pyrimidinyl optionally substituted with dialkylamino, (5) thienyl optionally substituted with 1 or 2 alkyls, (6) thieno [3,2-b] Pyridyl, or (7) indolyl optionally substituted with alkyl,
[17] The 5-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to [17].

[20] The 5-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of [17] to [19], wherein R ² is carboxymethyl or alkoxycarbonylmethyl.
[21] The 5-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of [17] to [20], wherein ring A is furan or thiophene.
[22] A compound selected from the examples and preferred examples in the specification, or a pharmaceutically acceptable salt thereof.
[23] A medicament comprising the 5-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of [10] to [22].
[24] A high conductance calcium-sensitive K channel opener containing the 5-membered heterocyclic compound or the pharmaceutically acceptable salt thereof according to any one of [10] to [22] as an active ingredient.
[25] The high conductance calcium-sensitive K channel opener according to any one of [1] to [9] and [24], which is a preventive or therapeutic agent for frequent urination or urinary incontinence.

［式中、環Ａは、以下の式のいずれかで示される環を表す。

Ｒ^１は、置換もしくは非置換のアリール、置換もしくは非置換の複素環式基または置換もしくは非置換の複素環式基置換カルボニルを表す。
Ｒ^２は、水素原子、ハロゲン原子、カルボキシ、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、アルコキシカルボニル、置換もしくは非置換のアルケニルまたはシクロアルキルを表す。
Ｒ^３は、置換もしくは非置換のアリール、置換もしくは非置換の複素環式基または置換もしくは非置換のアルキルを表す。
Ｒ^４は、水素原子または置換もしくは非置換のアルキルを表す。］
で示される５員複素環化合物またはその薬理的に許容し得る塩。 [26] Formula (I)

[Wherein, ring A represents a ring represented by any of the following formulae.

R ¹ represents substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group or substituted or unsubstituted heterocyclic group-substituted carbonyl.
R ² represents a hydrogen atom, a halogen atom, carboxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, alkoxycarbonyl, substituted or unsubstituted alkenyl or cycloalkyl.
R ³ represents a substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted alkyl.
R ⁴ represents a hydrogen atom or substituted or unsubstituted alkyl. ]
Or a pharmacologically acceptable salt thereof.

[27] R ¹ is (1) nitro, amino, hydroxyl, carbamoyl, cyano, carboxy, trifluoromethyl, alkoxycarbonyl, halogen atom, alkyl, hydroxyalkyl, alkoxy, alkoxyalkoxy, mono or dialkylamino, mono or di Aryl optionally substituted with a group selected from alkanoylamino, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfamoyl, mono- or dialkylsulfamoyl, alkylsulfonylamino and phenylalkoxy, (2) nitro, hydroxyl, formyl, carbamoyl, cyano Amino, carboxy, alkoxycarbonyl, halogen atom, alkyl, hydroxyalkyl, alkoxy, mono- or dialkylamino, mono- or dialkano A heterocyclic group optionally substituted with a group selected from ylamino, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfamoyl and mono- or dialkylsulfamoyl, or (3) nitro, hydroxyl, carbamoyl, cyano, carboxy, alkoxycarbonyl, Heteroaryl optionally substituted by a group selected from a halogen atom, alkyl, hydroxyalkyl, alkoxy, alkanoyl, mono- or dialkylamino, mono- or dialkanoylamino, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfamoyl and mono- or dialkylsulfamoyl A cyclic group-substituted carbonyl,
R ² is amino optionally substituted with a group selected from (1) a hydrogen atom, (2) a halogen atom, (3) carboxy, (4) formyl, alkyl, alkanoyl, alkylsulfonyl and alkoxycarbonyl, (5) Halogen atom, hydroxyl group, cyano, carboxy, carbamoyl, amino, aminosulfonyl, amidinothio, mono or dialkylamino, alkanoylamino, alkylsulfonylamino, hydroxyamino, mono or dialkylcarbamoyl, trifluoromethyl, alkoxy, alkylthio, alkylsulfinyl, alkyl Sulfonyl, alkylsulfonylamino, hydroxycarbamoyl, hydroxycarbamoyl substituted with 1 or 2 alkyls, alkylsulfonylcarbamoyl, sulfamoyl, mono Or alkyl optionally substituted with a group selected from dialkylsulfamoyl, alkoxycarbonyl, heterocyclic group, heterocyclic group-substituted carbamoyl, heterocyclic group-substituted alkylcarbamoyl and heterocyclic group-substituted sulfonylcarbamoyl, (6 ) Alkoxycarbonyl, (7) alkenyl optionally substituted with carboxy or alkoxycarbonyl, or (8) cycloalkyl,
R ³ is (1) cyano, nitro, amino, halogen atom, trifluoromethyl, carboxy, hydroxyl group, carbamoyl, mono or dialkylamino, aminoalkyl, mono or dialkylaminoalkyl, mono or dialkylcarbamoyl, alkyl, hydroxyalkyl, Aryl optionally substituted with a group selected from alkoxy, alkoxycarbonyl, alkanoyl, alkanoyloxy, alkanoyloxyalkyl, sulfo, alkylthio, alkylthioalkyl, alkylsulfonyl, sulfamoyl, mono- or dialkylsulfamoyl and alkylsulfinyl, (2) Oxo, cyano, nitro, amino, halogen atom, carboxy, hydroxyl group, formyl, carbamoyl, mono- or dialkylamino, N- Alkyl-N-cycloalkylamino, aminoalkyl, mono- or dialkylaminoalkyl, mono- or dialkylcarbamoyl, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkanoyl, sulfo, alkylthio, alkylsulfonyl, sulfamoyl, mono- or dialkylsulfo A heterocyclic group optionally substituted with a group selected from famoyl, alkylsulfinyl and heterocyclic groups, or (3) hydroxyl, cyano, carboxy, carbamoyl, amino, mono- or dialkylamino, alkanoylamino, alkylsulfonylamino , Hydroxyamino, mono- or dialkylcarbamoyl, trifluoromethyl, halogen atom, alkoxy, alkylthio, alkylsulfur Sulfonyl, alkylsulfonyl, sulfamoyl, a mono or dialkyl sulfamoyl, alkoxycarbonyl and alkyl which may be substituted by a group selected from a heterocyclic group,
R ⁴ is (1) a hydrogen atom, or (2) alkyl optionally substituted with mono- or dialkylamino.
[26] The 5-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to [26].
[28] A pharmaceutical composition for opening a high-conductance calcium-sensitive K channel comprising the compound according to any one of 1 to 27 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier

Examples of the alkyl in “alkyl” and “alkylthio”, “alkylsulfinyl” and “alkylsulfonyl” include linear or branched C ₁ -C ₆ alkyl, specifically, methyl, ethyl, propyl, Examples include isopropyl, butyl, isobutyl, pentyl, hexyl and the like. _Preferably, it includes C 1 -C ₄ alkyl.
Examples of the alkoxy in “alkoxy” and “alkoxycarbonyl” include linear or branched C ₁ -C ₆ alkoxy, specifically methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy. Hexoxy and the like. _Preferably, it includes C 1 -C ₄ alkoxy.
Examples of “alkenyl” include linear or branched C ₂ -C ₇ alkenyl, and specific examples include vinyl, allyl, 3-butenyl, 2-pentenyl, 3-hexenyl and the like. With preference given to _C 2 -C ₅ alkenyl.
Examples of “alkanoyl” include linear or branched C ₂ -C ₇ alkanoyl, and specific examples include acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl and the like. With preference given to _C 2 -C ₅ alkanoyl.
“Cycloalkyl” includes, for example, C ₃ -C ₈ cycloalkyl, preferably C ₃ -C ₆ cycloalkyl.
Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, preferably a fluorine atom and a chlorine atom.
“Aryl” includes, for example, monocyclic, bicyclic or tricyclic C ₆ -C ₁₄ aryl, and specific examples include phenyl, naphthyl, phenanthryl, anthryl and the like. Of these, phenyl and naphthyl are preferred.

Examples of the heterocyclic group in the “heterocyclic group” and the “heterocyclic group-substituted carbonyl” include 1 to 3 selected from a nitrogen atom, an oxygen atom, and a sulfur atom, which may be partially or fully saturated. Examples thereof include a monocyclic, bicyclic or tricyclic heterocyclic group having 5 to 14 members as a whole, which contains 4 hetero atoms.
The monocyclic heterocyclic group may contain 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and a part or all of 5 to 7 members as a whole may be saturated. Heterocyclic groups are mentioned as preferred examples, and specific examples include furyl, thienyl, thiazolyl, thiazolidinyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyranyl, pyridyl, pyrazinyl, pyrimidinyl, Examples include triazinyl, piperidyl, piperazinyl, morpholyl and the like.
The bicyclic heterocyclic group includes a bicyclic heterocyclic group obtained by condensing two monocyclic heterocyclic groups which are the same or different, or a condensed monocyclic heterocyclic group and a benzene ring. Preferred examples of the bicyclic heterocyclic group include indolyl, dihydroindolyl, isoindolyl, quinolyl, tetrahydroquinolyl, isoquinolyl, naphthyridyl, quinoxalyl, dihydroquinoxalyl, phthalazinyl, quinazolinyl, quinolinyl. , Dihydroquinolinyl, benzofuryl, isobenzofuryl, dihydrobenzofuryl, benzothienyl, benzodioxanyl, chromenyl, indolizinyl, purinyl, quinuclidinyl, trihydrocyclopentathienyl, benzothianyl, benzothiazolyl, imidazopyridyl, indolinyl, chromanyl, Ofenopirijiru, Furanopirijiru, dihydrobenzopyranyl, 3,4-methylenedioxyphenyl and the like.
Examples of the tricyclic heterocyclic group include a tricyclic heterocyclic group obtained by condensation of the monocyclic heterocyclic group and the bicyclic heterocyclic group, or the monocyclic heterocyclic group and benzene. Preferred examples include tricyclic heterocyclic groups fused with two rings, and specific examples include carbazolyl, carbolinyl, xanthenyl, phenanthridinyl, acridinyl, peridinyl, phenazinyl, phenoxazinyl and the like.

Preferred examples of the heterocyclic group include heterocyclic groups having at least one aromatic ring. Preferred examples include furyl, thienyl, thiazolyl, isoxazolyl, pyrrolidinyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, tetrazolyl, indolyl, quinolyl, isoquinolyl, benzofuryl, benzothienyl, dihydrobenzofuryl, thienopyridyl, benzodioxanyl and the like. It is done. Preferred heterocyclic groups for R ¹ include, for example, thienyl, pyridyl and the like. Preferred heterocyclic groups for R ³ include, for example, benzothienyl, pyridyl, pyrimidinyl, thienyl, thieno [3.2-b] pyridyl, indolyl, benzofuryl, dihydrobenzofuryl and the like, particularly preferably benzo [b] Examples include thienyl, pyridyl, pyrimidinyl, thienyl, thieno [3.2-b] pyridyl, indolyl and the like.

Examples of the substituent of “substituted aryl” in R ¹ include nitro, amino, hydroxyl group, carbamoyl, cyano, carboxy, trifluoromethyl, alkoxycarbonyl, halogen atom, alkyl, hydroxyalkyl, alkoxy, alkoxyalkoxy, mono or dialkylamino. Mono or dialkanoylamino, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfamoyl, mono or dialkylsulfamoyl, alkylsulfonylamino, phenylalkoxy and the like. Aryl may be substituted with 1 to 3 of the above or different substituents. Preferred examples of the substituent include halogen atoms such as chlorine atom and fluorine atom.

Examples of the substituent of the “substituted heterocyclic group” in R ¹ include nitro, hydroxyl group, formyl, carbamoyl, cyano, amino, carboxy, alkoxycarbonyl, halogen atom, alkyl, hydroxyalkyl, alkoxy, mono or dialkylamino, mono Alternatively, dialkanoylamino, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfamoyl, mono- or dialkylsulfamoyl and the like can be mentioned. The heterocyclic group may be substituted with 1 to 3 of the above or different substituents. Preferred examples of the substituent include halogen atoms such as chlorine atom and fluorine atom, and alkyl.

Examples of the substituent on the heterocyclic group of “substituted heterocyclic group-substituted carbonyl” in R ¹ include nitro, hydroxyl group, formyl, carbamoyl, cyano, amino, carboxy, alkoxycarbonyl, halogen atom, alkyl, hydroxyalkyl, Examples include alkoxy, alkanoyl, mono- or dialkylamino, mono- or dialkanoylamino, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfamoyl, mono- or dialkylsulfamoyl and the like. The heterocyclic group-substituted carbonyl may be substituted with 1 to 3 of the above or different substituents. Preferred examples of the substituent include halogen atoms such as chlorine atom and fluorine atom.

Examples of the substituent of “substituted amino” in R ² include formyl, alkyl, alkanoyl, alkylsulfonyl, alkoxycarbonyl and the like. Amino may be substituted with the same or different 1 or 2 of each of the above substituents.

Examples of the substituent of “substituted alkyl” and “substituted alkenyl” in R ² include halogen atom, hydroxyl group, cyano, carboxy, carbamoyl, amino, aminosulfonyl, amidinothio, mono- or dialkylamino, alkanoylamino, alkylsulfonylamino, hydroxy Amino, mono or dialkylcarbamoyl, trifluoromethyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, hydroxycarbamoyl, hydroxycarbamoyl, alkylsulfonylcarbamoyl, sulfamoyl, mono or dialkyl substituted with 1 or 2 alkyls Sulfamoyl, alkoxycarbonyl, heterocyclic group, heterocyclic group-substituted carbamoyl, heterocyclic group-substituted alkylcal Examples include vamoyl, heterocyclic group-substituted sulfonylcarbamoyl and the like. Particularly preferred substituents include carboxy, alkoxycarbonyl, carbamoyl, mono- or dialkylcarbamoyl, tetrazolyl and the like. Alkyl and alkenyl may each be substituted with 1 to 3 of the same or different substituents. Particularly preferred examples of “substituted alkyl” for R ² include carboxymethyl, alkoxycarbonylmethyl, carbamoylmethyl, mono- or dialkylcarbamoylmethyl, and tetrazolylmethyl.

Examples of the substituent of “substituted aryl” in R ³ include cyano, nitro, amino, halogen atom, trifluoromethyl, carboxy, hydroxyl group, carbamoyl, mono- or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, mono- or dialkyl Carbamoyl, alkyl, hydroxyalkyl, alkoxy, alkoxycarbonyl, alkanoyl, alkanoloxy, alkanoyloxyalkyl, sulfo, alkylthio, alkylthioalkyl, alkylsulfonyl, sulfamoyl, mono- or dialkylsulfamoyl, alkylsulfinyl, trimethylene, tetramethylene, etc. Can be mentioned. Aryl may be substituted with 1 to 3 of the above or different substituents. Preferable substituents include amino, halogen atom, alkyl, alkylthio, alkoxy, mono or dialkylamino, and particularly preferably include halogen atom, alkylthio, alkoxy, dialkylamino and the like. When R ³ is substituted phenyl, preferred substitution positions for the substituent include para and meta positions. For example, the above two or more substituents may be substituted at the para position and the meta position, and a divalent group (alkylene such as trimethylene and tetramethylene) may be substituted at the para position and the meta position.

Examples of the substituent of the “substituted heterocyclic group” in R ³ include oxo, cyano, nitro, amino, halogen atom, carboxy, hydroxyl group, formyl, carbamoyl, mono- or dialkylamino, N-alkyl-N-cycloalkylamino. Aminoalkyl, mono or dialkylaminoalkyl, mono or dialkylcarbamoyl, alkyl, hydroxyalkyl, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkanoyl, sulfo, alkylthio, alkylsulfonyl, sulfamoyl, mono or dialkylsulfamoyl, alkylsulfinyl, hetero A cyclic group, trimethylene, tetramethylene and the like can be mentioned. The heterocyclic group may be substituted with 1 to 3 of the above or different substituents. Preferred substituents include amino, halogen atom, alkyl, alkylthio, alkoxy, mono or dialkylamino and the like. Preferred substitution positions of the substituents in the substituted heterocyclic group are the β-position and γ-position (the second or third position from the bonding position) with respect to the bonding position with the 5-membered heterocyclic ring of the formula (1). Is mentioned. For example, the above two or more substituents may be substituted at the β-position and γ-position, and a divalent group (alkylene such as trimethylene and tetramethylene) may be substituted at the para-position and meta-position.

Examples of the substituent of “substituted alkyl” in R ³ include a hydroxyl group, cyano, carboxy, carbamoyl, amino, mono- or dialkylamino, alkanoylamino, alkylsulfonylamino, hydroxyamino, mono- or dialkylcarbamoyl, trifluoromethyl, halogen atom , Alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, sulfamoyl, mono- or dialkylsulfamoyl, alkoxycarbonyl, heterocyclic group and the like. Alkyl may be substituted with 1 to 3 of the above or different substituents.
Examples of the substituent of “substituted alkyl” in R ⁴ include mono- or dialkylamino. Alkyl may be substituted with one or two of the above or different substituents.

  In the 5-membered heterocyclic compound (1) of the present invention, there may exist optical isomers and tautomers based on asymmetric carbons depending on the type of the substituent, but these optical isomers, Both tautomers and mixtures thereof are included.

The 5-membered heterocyclic compound (1) of the present invention or a pharmacologically acceptable salt thereof can be used for the pharmaceutical use in a free form or a pharmacologically acceptable salt form. Examples of the pharmacologically acceptable salt of compound (1) include inorganic acid salts such as hydrochloride, sulfate, phosphate, and hydrobromide, acetate, fumarate, oxalate, and citric acid. Examples thereof include organic salts such as salts, methanesulfonate, benzenesulfonate, tosylate and maleate. In addition, when it has an acidic group such as carboxy, a salt with a base (for example, an alkali metal salt such as sodium salt or potassium salt, an alkaline earth metal salt such as calcium salt, an organic base salt such as triethylamine salt, a lysine salt, etc. And amino acid salts thereof.
The 5-membered heterocyclic compound (1) of the present invention or a pharmacologically acceptable salt thereof includes any solvate such as an inner salt or hydrate thereof.

The 5-membered heterocyclic compound (1) of the present invention or a pharmacologically acceptable salt thereof can be administered orally or parenterally, and together with a pharmaceutically acceptable carrier or diluent, a tablet , Granules, capsules, powders, injections, inhalants and the like can be used as conventional pharmaceutical preparations.
Examples of pharmaceutical carriers for such oral preparations include binders (syrup, gum arabic, gelatin, sorbit, tragacanth, polyvinylpyrrolidone, etc.), excipients (lactose, sugar, corn starch, potassium phosphate, sorbit, glycine). Etc.), lubricants (magnesium stearate, talc, polyethylene glycol, silica, etc.), disintegrating agents (potato starch, etc.) and wetting agents (anhydrous sodium lauryl sulfate, etc.).
On the other hand, when the active ingredient of the present invention is administered parenterally, for example, it can be used as an injection, a drip infusion, a suppository, etc. using distilled water for injection, physiological saline, aqueous glucose solution and the like. .
The dose of the 5-membered heterocyclic compound (1) of the present invention or a pharmacologically acceptable salt thereof varies depending on the administration method, patient age, body weight, condition or disease type / degree, but usually 1 About 0.1 to 50 mg / kg per day, especially about 0.3 to 30 mg / kg is preferable.

  The 5-membered heterocyclic compound (1) of the present invention or a pharmacologically acceptable salt thereof has an excellent high conductance calcium-sensitive K channel opening action and hyperpolarizes the cell's membrane electric potential. Premature birth, irritable bowel syndrome, chronic heart failure, angina, myocardial infarction, cerebral infarction, subarachnoid hemorrhage, cerebrovascular spasm, cerebral hypoxia, peripheral vascular disorder, anxiety, male baldness, erectile dysfunction, diabetes, Diabetic peripheral neuropathy, other diabetic complications, infertility, urolithiasis and associated pain, frequent urination, urinary incontinence, nocturnal enuresis, asthma, chronic obstructive pulmonary disease (COPD), asthma or chronic obstructive pulmonary disease It is useful as a preventive, alleviating and / or therapeutic agent for cough, stroke, cerebral ischemia, traumatic brain injury and the like associated with (COPD).

（式中、Ｘは反応性残基を表す。Ｚは−Ｂ(ＯＲ)_２、−Ｂ(ＯＨ)_２または−Ｓｎ(Ｒ)_３を表す。Ｒはアルキルを表す。環Ａ、Ｒ^１、Ｒ^２およびＲ^３は前記と同一意味を有する。）
化合物（２）と化合物（３）をパラジウム系触媒の存在下反応させることで、化合物（１）を製造することができる。パラジウム系触媒としては、例えばテトラキス（トリフェニルホスフィン）パラジウム（０）、ビス（トリフェニルホスフィン）パラジウム（II）クロリド、パラジウム（II）アセテート等の０価または２価のパラジウム系触媒があげられ、これらを好適に用いることができる。Ｚが−Ｂ(ＯＲ)_２または−Ｂ(ＯＨ)_２である化合物（３）を用いて反応する場合は、塩基を存在させるのが好ましい。塩基としては、例えば炭酸アルカリ金属、水酸化アルカリ金属、リン酸アルカリ金属、フッ化アルカリ金属等の無機塩基やトリエチルアミン等の有機塩基等があげられ、これらを好適に用いることができる。本反応は、適当な溶媒中または無溶媒で実施することができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えばジメトキシエタン、テトラヒドロフラン、ジメチルホルムアミド、メタノール、エタノール、トルエン、ベンゼン、クロロホルムまたはこれらの混合溶媒があげられ、これらを適宜用いることができる。本反応は、６０〜１５０℃、とりわけ８０〜１２０℃で好適に進行する。Ｘにおける反応性残基としては、例えば、ハロゲン原子等が好適に挙げられる。 The 5-membered heterocyclic compound (1) of the present invention can be produced, for example, by the following [Method A] to [Method G].
[Method A]

(Wherein X represents a reactive residue; Z represents —B (OR) ₂ , —B (OH) ₂ or —Sn (R) ₃ ; R represents alkyl; ring A, R ¹ , R ² and R ³ have the same meaning as above.)
Compound (1) can be produced by reacting compound (2) and compound (3) in the presence of a palladium-based catalyst. Examples of the palladium-based catalyst include zero-valent or divalent palladium-based catalysts such as tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, palladium (II) acetate, and the like. These can be used suitably. When the reaction is carried out using the compound (3) in which Z is —B (OR) ₂ or —B (OH) _2, it is preferable that a base is present. Examples of the base include inorganic bases such as alkali metal carbonates, alkali metal hydroxides, alkali metal phosphates, and alkali metal fluorides, and organic bases such as triethylamine, and these can be suitably used. This reaction can be carried out in a suitable solvent or without solvent. The solvent may be any solvent that does not adversely influence the reaction. Examples thereof include dimethoxyethane, tetrahydrofuran, dimethylformamide, methanol, ethanol, toluene, benzene, chloroform, and mixed solvents thereof, and these can be used as appropriate. . This reaction suitably proceeds at 60 to 150 ° C, particularly 80 to 120 ° C. Preferable examples of the reactive residue in X include a halogen atom.

（式中、環Ａ、Ｘ、Ｚ、Ｒ^１およびＲ^２は前記と同一意味を有する。）
化合物（４）と化合物（５）とを、上記の[Ａ法]と同様に反応させることで、化合物（６）を製造することができる。なお、Ｘが−Ｂ(ＯＲ)_２、−Ｂ(ＯＨ)_２または−Ｓｎ(Ｒ)_３である化合物（４）を、Ｚが反応性残基である化合物（５）と反応させることにより、化合物（６）を得ることもできる。
続いて、化合物（６）をハロゲン化剤を用いて、常法により、ハロゲン化等をすることで化合物（２）を製造することができる。ハロゲン化剤としては、臭素、塩素、ヨウ素、[ビス（トリフルオロアセトキシ）ヨード]ベンゼン、Ｎ−ブロモコハク酸イミド等があげられ、これらを好適に用いることができる。本反応は、常法により、０℃〜３０℃で好適に進行する。
なお、本[Ａ法]においては、Ｒ^２が導入された環Ａに、Ｒ^１、Ｒ^３の順で導入する方法として説明したが、Ｒ^３、Ｒ^１の順で導入することも、Ｒ^２の位置に別の置換基を入れておいて最後にＲ^２に変換することもできる。
この[Ａ法]は、化合物（１）の中でも特に環Ａがフラン環およびチオフェン環である場合に好適に適用することができる。 The raw material compound (2) can be produced, for example, as follows.

(In the formula, ring A, X, Z, R ¹ and R ² have the same meaning as described above.)
Compound (6) can be produced by reacting compound (4) and compound (5) in the same manner as in the above [Method A]. In addition, by reacting the compound (4) in which X is —B (OR) ₂ , —B (OH) ₂ or —Sn (R) ₃ with the compound (5) in which Z is a reactive residue, Compound (6) can also be obtained.
Subsequently, compound (2) can be produced by halogenating compound (6) by a conventional method using a halogenating agent. Examples of the halogenating agent include bromine, chlorine, iodine, [bis (trifluoroacetoxy) iodo] benzene, N-bromosuccinimide, and the like, which can be preferably used. This reaction suitably proceeds at 0 ° C. to 30 ° C. by a conventional method.
In addition, in this [Method A], it has been described as a method of introducing R ¹ and R ³ in this order into ring A into which R ² has been introduced, but it is also possible to introduce R ³ and R ¹ in this order. Finally it can be converted to R ² keep putting another substituent at the ^2-position.
This [Method A] can be suitably applied particularly when the ring A is a furan ring or a thiophene ring among the compounds (1).

（式中、Ｒ、Ｒ^１、Ｒ^２およびＲ^３は前記と同一意味を有する。）
環Ａがフラン環である化合物（１ａ）は、化合物（７）を酸で処理することで製造することができる。酸としては、塩酸、硫酸、硝酸、リン酸、メタンスルホン酸、トリフルオロ酢酸等が挙げられる。反応溶媒としては、反応に悪影響を及ぼさないものであれば、いかなるものでも使用しうるが、例えば化合物（７）および上記酸を溶解しうる溶媒が使用でき、具体的には酢酸等が好適に使用できる。反応温度としては、室温から溶媒の沸点までの範囲が挙げられる。また、上記製法ではＲ^１およびＲ^２が上記の通りの配置を有する反応を図示しているが、Ｒ^１およびＲ^２の結合位置が逆の化合物も上記と同様の方法で製造することができる。 [Method B]

(In the formula, R, R ¹ , R ² and R ³ have the same meaning as described above.)
Compound (1a) in which ring A is a furan ring can be produced by treating compound (7) with an acid. Examples of the acid include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, trifluoroacetic acid and the like. As the reaction solvent, any solvent can be used as long as it does not adversely influence the reaction. For example, a solvent capable of dissolving the compound (7) and the above acid can be used, and specifically, acetic acid or the like is preferable. Can be used. Examples of the reaction temperature include a range from room temperature to the boiling point of the solvent. Further, in the above production method, a reaction in which R ¹ and R ² have the above-described arrangement is illustrated, but a compound in which the bonding positions of R ¹ and R ² are reversed can be produced by the same method as described above. .

（式中、Ｘ、Ｒ、Ｒ^１、Ｒ^２およびＲ^３は前記と同一意味を有する。）
化合物（８）を常法に従って塩基存在下、化合物（９）と反応させることで、化合物（１０）が製造できる。続いて、化合物（１０）を常法に従って塩基存在下、化合物（１１）と反応させることで、原料化合物（７）が製造できる。なお、本反応では先に化合物（１１）を化合物（８）に反応させ、続いて化合物（９）を反応させることもできる。 The starting compound (7) can be produced, for example, as follows.

(In the formula, X, R, R ¹ , R ² and R ³ have the same meaning as described above.)
Compound (10) can be produced by reacting compound (8) with compound (9) in the presence of a base according to a conventional method. Subsequently, the starting compound (7) can be produced by reacting the compound (10) with the compound (11) in the presence of a base according to a conventional method. In this reaction, compound (11) can be reacted with compound (8) first, and then compound (9) can be reacted.

（式中、Ｒ^１、Ｒ^２およびＲ^３は前記と同一意味を有する。Ｔｓはp-トルエンスルホニルを表す。）
環Ａがフラン環である化合物（１ａ）は、化合物（１２）を常法に従い、酸で処理することでも製造することができる(”Comprehensive Heterocyclic Chemistry” Vol. 4, A. Katritzky他, Pergamon Press Ltd., 1984, p.661-662)。また、上記製法ではＲ^１およびＲ^２が上記の通りの配置を有する反応を図示しているが、Ｒ^１およびＲ^２の結合位置が逆の化合物も上記と同様の方法で製造することができる。 [Method C]

(In the formula, R ¹ , R ² and R ³ have the same meaning as described above. Ts represents p-toluenesulfonyl.)
Compound (1a) in which ring A is a furan ring can also be produced by treating compound (12) with an acid according to a conventional method ("Comprehensive Heterocyclic Chemistry" Vol. 4, A. Katritzky et al., Pergamon Press). Ltd., 1984, p.661-662). Further, in the above production method, a reaction in which R ¹ and R ² have the above-described arrangement is illustrated, but a compound in which the bonding positions of R ¹ and R ² are reversed can be produced by the same method as described above. .

（式中、Ｒ^１、Ｒ^２、Ｒ^３、ＸおよびＴｓは前記と同一意味を有する。）
原料化合物（１２）は、化合物（１３）を常法に従い、塩基存在下、Ｒ^２−ＸおよびＲ^１−ＣＨＯを順に反応させることで製造することができる(”Comprehensive Heterocyclic Chemistry” Vol. 4, A. Katritzky他, Pergamon Press Ltd., 1984, p.661-662)。

(In the formula, R ¹ , R ² , R ³ , X and Ts have the same meaning as described above.)
The starting compound (12) can be produced by reacting the compound (13) with R ² -X and R ¹ -CHO in the presence of a base in the usual manner ("Comprehensive Heterocyclic Chemistry" Vol. 4, A. Katritzky et al., Pergamon Press Ltd., 1984, p.661-662).

（式中、Ｒ、Ｒ^１、Ｒ^２およびＲ^３は前記と同一意味を有する。）
環Ａがチオフェン環である化合物（１ｂ）は、常法に従い、化合物（１４）に硫化剤を反応させることで製造することができる(”Comprehensive Heterocyclic Chemistry” Vol. 4, A. Katritzky他, Pergamon Press Ltd., 1984, p.885-887)。硫化剤としては硫化水素、三硫化リン、ローソン試薬（２，４−ビス（４−メトキシフェニル）−１，３−ジチア−２，４−ジフォスフェタン−２，４−ジスルフィド）などがあげられ、これらを好適に用いられる。化合物（１４）は、例えば[Ｂ法]の原料化合物（７）から導くこともできる。また、上記製法ではＲ^１およびＲ^２が上記の通りの配置を有する反応を図示しているが、Ｒ^１およびＲ^２の結合位置が逆の化合物も上記と同様の方法で製造することができる。 [Method D]

(In the formula, R, R ¹ , R ² and R ³ have the same meaning as described above.)
Compound (1b) in which ring A is a thiophene ring can be produced by reacting compound (14) with a sulfurizing agent according to a conventional method ("Comprehensive Heterocyclic Chemistry" Vol. 4, A. Katritzky et al., Pergamon). Press Ltd., 1984, p.885-887). Examples of the sulfurizing agent include hydrogen sulfide, phosphorus trisulfide, Lawesson's reagent (2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide), and the like. Are preferably used. Compound (14) can also be derived from, for example, starting compound (7) of [Method B]. Further, in the above production method, a reaction in which R ¹ and R ² have the above-described arrangement is illustrated, but a compound in which the bonding positions of R ¹ and R ² are reversed can be produced by the same method as described above. .

（式中、Ｒ、Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４は前記と同一意味を有する。）
環Ａがピロール環である化合物（１ｂ）は、常法に従い、化合物（１４）にＲ^４ＮＨ_２またはその塩を反応させることで製造することができる(”Comprehensive Heterocyclic Chemistry” Vol. 4, A. Katritzky他, Pergamon Press Ltd., 1984, p.329-330)。Ｒ^４ＮＨ_２またはその塩としては、アンモニア、炭酸アンモニウム、酢酸アンモニウム、モノアルキルアミン等があげられ、これらを使用することができる。Ｒ^４ＮＨ_２の代わりに、常法に従い、酢酸アミドなどのアミド誘導体や、スルホンアミド誘導体などを用いて反応させ、後に加水分解することにより、Ｒ^４が水素原子である化合物（１ｂ）を製造することもできる。また、上記製法ではＲ^１およびＲ^２が上記の通りの配置を有する反応を図示しているが、Ｒ^１およびＲ^２の結合位置が逆の化合物も上記と同様の方法で製造することができる。 [E method]

(In the formula, R, R ¹ , R ² , R ³ and R ⁴ have the same meaning as described above.)
Compound (1b) in which ring A is a pyrrole ring can be produced by reacting compound (14) with R ⁴ NH ₂ or a salt thereof according to a conventional method (“Comprehensive Heterocyclic Chemistry” Vol. 4, A Katritzky et al., Pergamon Press Ltd., 1984, p.329-330). Examples of R ⁴ NH ₂ or a salt thereof include ammonia, ammonium carbonate, ammonium acetate, monoalkylamine, and the like, and these can be used. A compound (1b) in which R ⁴ is a hydrogen atom is produced by reacting with an amide derivative such as acetic acid amide or a sulfonamide derivative according to a conventional method instead of R ⁴ NH ₂ , followed by hydrolysis. You can also Further, in the above production method, a reaction in which R ¹ and R ² have the above-described arrangement is illustrated, but a compound in which the bonding positions of R ¹ and R ² are reversed can be produced by the same method as described above. .

（式中、Ｒ^１、Ｒ^２およびＲ^３は前記と同一意味を有する。）
環Ａがピロール環である化合物（１ｃ）は、常法に従い、化合物（１５）に還元剤を反応させることで製造することができる。還元剤としては、例えば、ジフェニルジスルフィド等のジスルフィドとトリn-ブチルホスフィン等のホスフィンがあげられ、これらを組み合わせて使用することができる。反応温度としては、還元剤の種類により変化するが、例えば０℃から溶媒の沸点の範囲が挙げられる。また、上記製法ではＲ^１およびＲ^２が上記の通りの配置を有する反応を図示しているが、Ｒ^１およびＲ^２の結合位置が逆の化合物も上記と同様の方法で製造することができる。 [F method]

(Wherein R ¹ , R ² and R ³ have the same meaning as described above.)
Compound (1c) in which ring A is a pyrrole ring can be produced by reacting compound (15) with a reducing agent according to a conventional method. Examples of the reducing agent include disulfides such as diphenyl disulfide and phosphines such as tri-n-butylphosphine, and these can be used in combination. The reaction temperature varies depending on the type of the reducing agent, and examples include a range from 0 ° C. to the boiling point of the solvent. Further, in the above production method, a reaction in which R ¹ and R ² have the above-described arrangement is illustrated, but a compound in which the bonding positions of R ¹ and R ² are reversed can be produced by the same method as described above. .

（式中、Ｒ^１、Ｒ^２およびＲ^３は前記と同一意味を有する。）
環Ａがピロール環である化合物（１ｃ）は、化合物（１６）にパラジウム触媒を作用することでも製造することができる(”Comprehensive Heterocyclic Chemistry” Vol. 4, A. Katritzky他, Pergamon Press Ltd., 1984, p.321)。また、上記製法ではＲ^１およびＲ^２が上記の通りの配置を有する反応を図示しているが、Ｒ^１およびＲ^２の結合位置が逆の化合物も上記と同様の方法で製造することができる。 [G method]

(Wherein R ¹ , R ² and R ³ have the same meaning as described above.)
Compound (1c) in which ring A is a pyrrole ring can also be produced by reacting compound (16) with a palladium catalyst ("Comprehensive Heterocyclic Chemistry" Vol. 4, A. Katritzky et al., Pergamon Press Ltd., 1984, p.321). Further, in the above production method, a reaction in which R ¹ and R ² have the above-described arrangement is illustrated, but a compound in which the bonding positions of R ¹ and R ² are reversed can be produced by the same method as described above. .

  In the 5-membered heterocyclic compound (1) produced by the above production method, the functional group can be converted to another functional group as necessary. Conversion between functional groups can be carried out according to a conventional method, for example, “Comprehensive Organic Tranformations” Richard C. Larock, VCH Pubishers Inc., 1989, “Comprehensive Organic Synthesis” Vol. 1-9, Barry M. Trost In addition, the method described in Pergamon Press Ltd., 1991, “Organic Reactions” John Wiley & Sons Ltd., 1963- can be used. Conversion from carboxy to hydroxy, Curtius rearrangement from carboxy to amino, conversion from carboxy to amide, condensation of amide with Grignard reagent, Friedel-Crafts reaction, Vilsmeier reaction, etc., and more specific methods include Examples include the following methods (a) to (u).

(A) Law:
The compound (1) in which R ² is a halogen atom can be produced by reacting a corresponding compound in which R ² is a hydrogen atom with a halogenating agent. Examples of the halogenating agent include bromine, chlorine, iodine, [bis (trifluoroacetoxy) iodo] benzene, N-bromosuccinimide, and the like, which can be preferably used. This reaction suitably proceeds at 0 ° C to 30 ° C.
(B) Law:
Compound R ¹ is aryl optionally substituted or optionally substituted heterocyclic group (1) is a compound corresponding R ¹ is a halogen atom, it is also aryl or substituted substituted It can be produced by reacting a trialkyltin compound having a good heterocyclic group in the presence of a catalyst. Examples of the catalyst include zero-valent or divalent palladium-based catalysts such as bis (triphenylphosphine) palladium (II) chloride, palladium (II) acetate, and tetrakis (triphenylphosphine) palladium (0). Can be used. In addition, this reaction proceeds more suitably when a zinc salt such as zinc chloride, zinc bromide, zinc iodide or the like is added. This reaction suitably proceeds at 50 ° C to 120 ° C.
This reaction can also be carried out in the presence of a base using a boric acid compound or a boric acid ester compound instead of the trialkyltin compound. Examples of the palladium-based catalyst and the base include any of those described in the above-mentioned method A, and these can be suitably used. This reaction suitably proceeds at 60 ° C to 120 ° C.

(C) Law:
The compound (1) in which R ⁴ is an optionally substituted alkyl is a compound in which the corresponding R ⁴ is a hydrogen atom in the presence of a base, an alkyl halide (alkyl iodide, alkyl chloride, alkyl bromide) that may be substituted. Etc.) or an alkyl sulfonate (alkyl trifluoromethane sulfonate, alkyl methane sulfonate, etc.). Examples of the base include alkali metal hydride, alkali metal carbonate, alkoxy alkali metal, alkali metal hydroxide, and the like, and these can be preferably used. This reaction suitably proceeds at 30 ° C to 80 ° C.
(D) Method:
The compound (1) in which R ² is formylamino or N-alkyl-N-formylamino is obtained by combining a corresponding compound in which R ² is amino or N-alkylamino with a formic acid alkyl ester (methyl ester, ethyl ester, etc.) It can be made to react. This reaction suitably proceeds at 60 ° C to 100 ° C.

(E) Law:
The compound (1) in which R ² is N-methylamino, N-alkyl-N-methylamino or N-ethylamino is a compound in which the corresponding R ² is formylamino, N-alkyl-N-formylamino or N-acetylamino In the presence of a reducing agent.
Examples of the reducing agent include borane complexes (for example, borane / dimethyl sulfide complex) and lithium aluminum hydride, and these can be preferably used. This reaction suitably proceeds at 0 ° C to 60 ° C.
(F) Method:
R ² is alkoxycarbonyl amino compound (1) can be accommodated in R ² is manufactured a compound with an alkoxycarbonyl halide is amino is reacted in the presence of a base. Examples of the base include pyridine, triethylamine, alkali metal carbonate, alkoxy alkali metal, alkali metal hydride, and the like, and these can be preferably used. This reaction suitably proceeds at 0 ° C to 50 ° C.

(G) Method:
The compound (1) in which R ² is hydroxyalkyl can be produced by reacting a corresponding compound in which R ² is a hydrogen atom with formaldehyde in the presence of a base. Examples of the base include alkali metal carbonate, alkoxy alkali metal, triethylamine, and the like, and these can be used preferably. This reaction suitably proceeds at 60 ° C to 120 ° C.
(H) Law:
The compound (1) in which R ² is halogenoalkyl can be produced by reacting the corresponding compound in which R ² is hydroxyalkyl with a halogenating agent. Examples of the halogenating agent include thionyl chloride and thionyl bromide, and these can be preferably used. This reaction suitably proceeds at 0 ° C to 50 ° C.

(I) Law:
The compound (1) in which R ² is alkoxyalkyl can be produced by reacting a compound in which the corresponding R ² is halogenoalkyl with an alkanol. Examples of the alkanol include methanol, ethanol and the like, and these can be preferably used. This reaction suitably proceeds at 30 ° C to 80 ° C.
(J) Law:
The compound (1) in which R ² is alkylthioalkyl can be produced by reacting a compound in which the corresponding R ² is halogenoalkyl with an alkyl sulfide salt. Examples of the alkyl sulfide salt include alkali metal salts such as sodium methyl sulfide, and these can be suitably used. This reaction is preferably performed in the presence of a base. Examples of the base include triethylamine, pyridine, alkali metal carbonate, alkali metal hydroxide, alkoxyalkali metal, and the like, and these can be preferably used. This reaction suitably proceeds at 0 ° C to 60 ° C.

(K) Method:
The compound (1) in which R ² is alkylsulfinylalkyl or alkylsulfonylalkyl can be produced by reacting a compound in which the corresponding R ² is alkylthioalkyl with an oxidizing agent. Examples of the oxidizing agent include metachloroperbenzoic acid, aqueous hydrogen peroxide, and the like, and these can be suitably used. This reaction suitably proceeds at −20 ° C. to 30 ° C.
(L) Method:
The compound (1) in which R ² is carboxyalkyl can be produced by hydrolyzing a compound in which the corresponding R ² is alkoxycarbonylalkyl in the presence of a base. Examples of the base include alkali metal hydroxides, and these can be preferably used. This reaction suitably proceeds at 30 ° C to 60 ° C.

(M) Method:
In the compound (1) in which R ³ is a heterocyclic group substituted with sulfo, the corresponding R ³ is an unsubstituted heterocyclic group (however, other positions other than those where the sulfo group on the heterocyclic ring is bonded) And a halogenosulfonic acid (such as chlorosulfonic acid), and then treating the resulting compound with a basic aqueous solution (such as aqueous ammonia). . This reaction suitably proceeds at 0 ° C to 50 ° C.
(N) Method:
Compound (1) in which R ³ is a heterocyclic group substituted with sulfamoyl is obtained by treating a compound in which R ³ is a heterocyclic group substituted with chlorosulfonyl obtained by the above method (n) with ammonia. Can be manufactured. This reaction suitably proceeds at 0 ° C to 60 ° C.

(O) Law:
In the compound (1) in which R ¹ or R ³ is a heterocyclic group substituted with hydroxyalkyl, the corresponding compound in which R ¹ or R ³ is a heterocyclic group substituted with alkoxycarbonyl is treated with a reducing agent. Can be manufactured. Examples of the reducing agent include lithium aluminum hydride, lithium boron hydride, borane complex (for example, borane / dimethyl sulfide complex) and the like, and these can be preferably used. This reaction suitably proceeds at 0 ° C to 60 ° C.
(P) Method:
Pyridyl R ³ is substituted by a mono- or dialkylamino, or compounds which are mono- or pyrazinyl substituted with dialkylamino, (1) is a compound which is compatible R ³ is halogenopyridyl or halogeno-pyrazinyl, corresponding It can be produced by reacting with a mono- or dialkylamine. This reaction suitably proceeds at 30 ° C to 120 ° C.

(Q) Method:
R ³ is pyrimidinyl substituted with a mono- or dialkylamino (1), the corresponding R ³ is alkyl thio pyrimidinyl compound is oxidized with an oxidizing agent, followed by produced by reacting a mono- or dialkylamine be able to. Examples of the oxidizing agent include m-chloroperbenzoic acid and hydrogen peroxide, and these are preferably used. This reaction suitably proceeds at 30 ° C to 120 ° C.
(R) Method:
Compound (1) in which R ² is optionally substituted carbamoylalkyl is obtained by reacting the corresponding R ² in carboxyalkyl with a corresponding optionally substituted amine in the presence of a condensing agent. Can be manufactured. Examples of the condensing agent include 3-ethyl-1- (3-dimethylaminopropyl) carbodiimide hydrochloride, diethyl cyanophosphate, and the like, which are preferably used. This reaction suitably proceeds at 0 ° C to 50 ° C.

(S) Method:
The compound (1) in which R ² is cyanoalkyl can be produced by reacting a compound in which the corresponding R ² is carbamoylalkyl with a dehydrating agent. Examples of the dehydrating agent include phosphorus oxychloride, acetic anhydride, thionyl chloride, and the like, which are preferably used. This reaction suitably proceeds at 50 ° C to 100 ° C.
(T) Method:
The compound (1) in which R ² is tetrazolylalkyl can be produced by reacting a compound in which the corresponding R ² is cyanoalkyl with an azide compound. Examples of the azide compound include sodium azide, trialkyltin azide, trialkylsilicon azide and the like, and these are preferably used. This reaction suitably proceeds at 80 ° C to 120 ° C.

(U) Method:
The compound (1) in which R ² is alkoxycarbonylmethyl can be synthesized by a one-carbon carbon addition reaction of a compound in which the corresponding R ² is formyl. Examples of the one-carbon increasing reagent include methyl (methylsulfinylmethyl) sulfide, tosylmethyl isocyanate, diethylphosphonodithiane, diethyl 1-piperidinomethylphosphonate, and the like are preferably used. After the reaction with these reagents in the presence of a base, the resulting compound is reacted with an alcohol in the presence of an acid to obtain an alkoxycarbonylmethyl compound.
The reactions described in the above methods (a) to (u) can be carried out in a solvent inert to the reaction or without solvent. The solvent is not particularly limited, and examples thereof include methylene chloride, chloroform, tetrahydrofuran, methanol, ethanol, isopropanol, dimethylformamide, dimethyl sulfoxide, water, ethyl acetate, dimethoxyethane, toluene, benzene, and the like, or a mixed solvent thereof.

In the above production, the functional group can be protected and deprotected as necessary. As the protecting group for the functional group, those used in ordinary organic synthetic chemistry can be used. For example, “Protective Groups in Organic Synthesis” TW Greene, PM Wuts, John Wiley and sons 1991, etc. The thing of description is mentioned. Examples of conditions for introducing and deprotecting a protecting group include the methods described in the same document.
In the above production, each produced compound and each intermediate can be purified by a usual method such as column chromatography, recrystallization and the like. Examples of the recrystallization solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic solvents such as toluene, ketone solvents such as acetone, and hydrocarbons such as hexane. A solvent, water, etc., or these mixed solvents are mentioned. In addition, the compound (1) of the present invention can be converted into a pharmaceutically acceptable salt according to a conventional method, followed by recrystallization and the like.

Hereinafter, the present invention will be described in more detail with reference to examples, reference examples, and test examples. However, these examples do not limit the present invention in any way.
The following abbreviations used in this specification have the following meanings, respectively.
Me: methyl Et: ethyl Ph: phenyl THF: tetrahydrofuran DMF: N, N-dimethylformamide DME: dimethoxyethane

（１） 化合物１(0.5 g, 3.6 mmol)、２−ブロモ−５−クロロチオフェン(0.6 ml, 5.5 mmol)、PdCl₂(PPh₃)₂ (250 mg, 0.36 mmol)のＤＭＦ(17 ml)溶液に２Ｎ炭酸ナトリウム水溶液(5.5 ml)を加えた。３時間加熱還流後、セライトろ過をした。濾液を酢酸エチル抽出し、水洗、飽和食塩水で洗浄し、芒硝乾燥した後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン/ 酢酸エチル＝ 20/ 1）で精製し、化合物２(215 mg, 28.2％)を粉末として得た。
MS・APCI(m/z): 227/229 ([M+H+MeOH-H₂O]⁺)
（２） 化合物２(200 mg, 0.94 mmol)のＴＨＦ(5 ml)溶液にメチル（メチルスルフィニルメチル）スルフィド(0.3 ml, 2.9 mmol)とTriton B(0.22 ml, 0.5 mmol, 40％メタノール溶液)を加え４時間加熱還流した。反応液を０.５Ｎ塩酸に注いだ後、酢酸エチル抽出した。抽出液を飽和食塩水で洗浄し芒硝乾燥した後、減圧濃縮した。残渣を０.５Ｎ塩酸−エタノール溶液(5 ml)に溶解し、1.5時間加熱還流した。溶媒を減圧留去後、酢酸エチル抽出した。抽出液を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した後、減圧濃縮した。残渣をシリカゲルカラムクロマログラフィー（ヘキサン/ 酢酸エチル＝ 20/ 1）で精製し、化合物３(148 mg, 58.1％)を油状物質として得た。
MS・APCI(m/z): 271/273 ([M+H]⁺)
（３） 化合物３(68 mg, 0.25 mmol)のクロロホルム(5 ml)溶液に臭素(40 mg, 0.25 mmol)のクロロホルム(1 ml)溶液を氷冷下滴下した。反応液に飽和炭酸水素ナトリウム水溶液を加えた後、酢酸エチル抽出をした。抽出液を15％チオ硫酸ナトリウム水溶液、次いで飽和食塩水で洗浄後、芒硝乾燥し、減圧濃縮し、粗化合物４(0.1 g)を得た。
（４） 得られた化合物４および４-メチルチオフェニルボロン酸(75 mg, 45 mmol)のＤＭＥ溶液にPdCl₂(PPh₃)₂ (60 mg, 0.029 mmol)と２Ｎ炭酸ナトリウム溶液(0.86 ml, 1.8 mmol)を加えた。反応液を３時間加熱還流した後、セライトろ過をした。濾液を酢酸エチル抽出し、水洗、飽和食塩水で洗浄し、芒硝乾燥した後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン/ 酢酸エチル＝ 20/ 1）で精製し、化合物５(57 mg, 57.9％)を粉末として得た。
MS・APCI(m/z): 393/395 ([M+H]⁺)
（５） 得られた化合物５(52 mg, 0.13 mmol)のエタノール(5 ml)溶液に２Ｎ水酸化ナトリウム水溶液を加えて室温で一晩攪拌した。反応液に１Ｎ塩酸を加えて酢酸エチル抽出した。有機層を飽和食塩水で洗浄し、芒硝乾燥した後、濾過し、濾液を減圧濃縮した。残渣を分取用ＨＰＬＣで精製し、対応のカルボン酸 (34 mg, 71 %)を得た。
MS・ESI(m/z): 363/365 ([M-H]⁺)
得られたカルボン酸(31 mg, 0.085 mmol)をメタノール(1.5 mmol)に溶解し、0.5Ｎナトリウムメトキシド(メタノール溶液, 0.165 ml, 0.083 mmol)を加えた。溶媒を留去し、化合物６（35 mg）を得た。
MS・ESI(m/z): 363/365 ([M-Na]^-) Example 1

(1) DMF (17 ml) solution of compound 1 (0.5 g, 3.6 mmol), 2-bromo-5-chlorothiophene (0.6 ml, 5.5 mmol), PdCl ₂ (PPh ₃ ) ₂ (250 mg, 0.36 mmol) 2N aqueous sodium carbonate solution (5.5 ml) was added. The mixture was refluxed for 3 hours and then filtered through Celite. The filtrate was extracted with ethyl acetate, washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 20/1) to obtain Compound 2 (215 mg, 28.2%) as a powder.
MS ・ APCI (m / z): 227/229 ([M + H + MeOH-H ₂ O] ⁺ )
(2) Methyl (methylsulfinylmethyl) sulfide (0.3 ml, 2.9 mmol) and Triton B (0.22 ml, 0.5 mmol, 40% methanol solution) were added to a solution of compound 2 (200 mg, 0.94 mmol) in THF (5 ml). The mixture was heated to reflux for 4 hours. The reaction mixture was poured into 0.5N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in 0.5N hydrochloric acid-ethanol solution (5 ml) and heated to reflux for 1.5 hours. The solvent was distilled off under reduced pressure, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 20/1) to obtain Compound 3 (148 mg, 58.1%) as an oily substance.
MS ・ APCI (m / z): 271/273 ([M + H] ⁺ )
(3) A solution of bromine (40 mg, 0.25 mmol) in chloroform (1 ml) was added dropwise to a solution of compound 3 (68 mg, 0.25 mmol) in chloroform (5 ml) under ice cooling. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 15% aqueous sodium thiosulfate solution and then with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give crude compound 4 (0.1 g).
(4) To a DME solution of the obtained compound 4 and 4-methylthiophenylboronic acid (75 mg, 45 mmol), PdCl ₂ (PPh ₃ ) ₂ (60 mg, 0.029 mmol) and 2N sodium carbonate solution (0.86 ml, 1.8 mmol) was added. The reaction solution was heated to reflux for 3 hours and then filtered through celite. The filtrate was extracted with ethyl acetate, washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 20/1) to obtain Compound 5 (57 mg, 57.9%) as a powder.
MS ・ APCI (m / z): 393/395 ([M + H] ⁺ )
(5) 2N sodium hydroxide aqueous solution was added to the ethanol (5 ml) solution of the obtained compound 5 (52 mg, 0.13 mmol), and it stirred at room temperature overnight. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the corresponding carboxylic acid (34 mg, 71%).
MS ・ ESI (m / z): 363/365 ([MH] ⁺ )
The obtained carboxylic acid (31 mg, 0.085 mmol) was dissolved in methanol (1.5 mmol), and 0.5N sodium methoxide (methanol solution, 0.165 ml, 0.083 mmol) was added. The solvent was distilled off to obtain compound 6 (35 mg).
MS ・ ESI (m / z): 363/365 ([M-Na] ^- )

（１） 化合物１(875 mg, 5 mmol：Helvetica Chimica Acta, 60, 2085 (1977))を用いて、実施例１の化合物３の製造と同様に反応することで、化合物２(664 mg, 57.0％)を油状物質として得た。
MS・APCI(m/z): 250/252 ([M+NH₄]⁺)
（２） 化合物２(650 mg, 2.8 mmol)、５−クロロ−２−チエニル（トリブチル）スズ (1.71 g, 4.18 mmol)、PdCl₂(PPh₃)₂ (98 mg, 0.14 mmol)のトルエン(10 ml)溶液を４時間加熱還流した。反応液にフッ化カリウム水溶液（40%, 10 ml）、エタノール（5 ml）を加えて30分攪拌した。反応液に水とイソプロピルエーテルを加え、セライト濾過した。濾液の有機層を飽和食塩水で洗浄し、芒硝乾燥した後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン/ 酢酸エチル＝ 30/ 1）で精製し、化合物３ (154 mg, 20.4％)を粉末として得た。
MS・APCI(m/z): 288/290 ([M+NH₄]⁺)
（３） 化合物３(145 mg, 0.54 mmol)のクロロホルム(5 ml)溶液に臭素(86 mg，0.54mmol)のクロロホルム(1 ml)溶液を氷冷下滴下した。1時間後、反応液に飽和炭酸水素ナトリウム水溶液および15％チオ硫酸ナトリウム水溶液を加え、ヘキサンで抽出した。有機層を飽和食塩水で洗浄後、芒硝乾燥し減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン/ 酢酸エチル＝ 50/ 1）で精製し、化合物４ (47 mg, 25.1％)を油状物質として得た。
MS・ESI(m/z): 349/351 ([M+H]⁺)
（４） フェニルボロン酸(21 mg, 0.17 mmol)および化合物４ (40 mg, 0.11 mmol)を用いて、実施例１の化合物５の製造と同様に反応することで、化合物５ (32 mg, 80.0％)を油状物質として得た。
MS・ESI(m/z): 347/349 ([M+H]⁺)
（５） 化合物５(28 mg, 0.08 mmol)を用いて、実施例１の化合物６の製造と同様に反応することで、カルボン酸(20 mg, 77 %)を得、カルボン酸（16 mg, 0.05 mmol）をナトリウム塩とすることで、化合物６(17 mg, 99 %)を得た。
MS・ESI(m/z): 317/319 ([M-Na]⁺) Example 2

(1) Using compound 1 (875 mg, 5 mmol: Helvetica Chimica Acta, 60, 2085 (1977)) and reacting in the same manner as in the production of compound 3 of Example 1, compound 2 (664 mg, 57.0 %) As an oil.
MS ・ APCI (m / z): 250/252 ([M + NH ₄ ] ⁺ )
(2) Compound 2 (650 mg, 2.8 mmol), 5-chloro-2-thienyl (tributyl) tin (1.71 g, 4.18 mmol), PdCl ₂ (PPh ₃ ) ₂ (98 mg, 0.14 mmol) in toluene (10 ml) The solution was heated to reflux for 4 hours. An aqueous potassium fluoride solution (40%, 10 ml) and ethanol (5 ml) were added to the reaction solution, and the mixture was stirred for 30 minutes. Water and isopropyl ether were added to the reaction mixture, and the mixture was filtered through celite. The organic layer of the filtrate was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 30/1) to obtain Compound 3 (154 mg, 20.4%) as a powder.
MS ・ APCI (m / z): 288/290 ([M + NH ₄ ] ⁺ )
(3) A solution of bromine (86 mg, 0.54 mmol) in chloroform (1 ml) was added dropwise to a solution of compound 3 (145 mg, 0.54 mmol) in chloroform (5 ml) under ice cooling. After 1 hour, a saturated aqueous sodium bicarbonate solution and a 15% aqueous sodium thiosulfate solution were added to the reaction solution, and the mixture was extracted with hexane. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 50/1) to obtain Compound 4 (47 mg, 25.1%) as an oily substance.
MS ・ ESI (m / z): 349/351 ([M + H] ⁺ )
(4) By using phenylboronic acid (21 mg, 0.17 mmol) and compound 4 (40 mg, 0.11 mmol) in the same manner as in the production of compound 5 of Example 1, compound 5 (32 mg, 80.0 %) As an oil.
MS ・ ESI (m / z): 347/349 ([M + H] ⁺ )
(5) Carboxylic acid (20 mg, 77%) was obtained by reacting in the same manner as in the production of compound 6 of Example 1 using compound 5 (28 mg, 0.08 mmol), and carboxylic acid (16 mg, 0.05 mmol) was converted to a sodium salt to obtain Compound 6 (17 mg, 99%).
MS ・ ESI (m / z): 317/319 ([M-Na] ⁺ )

（１） 化合物１(5 g, 26.17 mmol)を用いて、実施例２の化合物１の製造と同様に反応することで化合物２(4.58 g, 70.2 %)を油状物質として得た。
MS・APCI(m/z): 266/268 ([M+NH₄]⁺)
（２） 化合物２(3.74 g, 15 mmol)、５−クロロ−２−チエニルボロン酸 (3.17 g, 19.5 mmol)を用いて、実施例２の化合物５の製造と同様に反応することで、粗化合物３(3.35 g)を油状物質として得た。
MS・APCI(m/z): 304/306 ([M+NH₄]⁺)
（３） 得られた粗化合物３(574 mg, 2.22 mmol)および臭素(384 mg)を用いて、実施例２の化合物４の製造と同様に反応することで、化合物４(80 mg, 9 % (2工程))を油状物質として得た。
MS・APCI(m/z): 382/384 ([M+NH₄]⁺)
（４） フェニルボロン酸(366 mg, 3 mmol)および化合物４(731 mg, 2 mmol)を用いて、実施例２の化合物５の製造と同様に反応することで、化合物５(552 mg, 72.9 %)を油状物質として得た。
MS・APCI(m/z): 363/365 ([M+H]⁺)
（５） 化合物５(470 mg, 1.24 mmol)を用いて、実施例１の化合物６の製造と同様に反応することで化合物６（91 mg, 20.5 %）を得た。
MS・ESI(m/z): 333/335 ([M-Na]⁺) Example 3

(1) Compound 2 (4.58 g, 70.2%) was obtained as an oily substance by reacting in the same manner as in the production of Compound 1 of Example 2 using Compound 1 (5 g, 26.17 mmol).
MS ・ APCI (m / z): 266/268 ([M + NH ₄ ] ⁺ )
(2) By using Compound 2 (3.74 g, 15 mmol) and 5-chloro-2-thienylboronic acid (3.17 g, 19.5 mmol) in the same manner as in the preparation of Compound 5 of Example 2, Compound 3 (3.35 g) was obtained as an oily substance.
MS ・ APCI (m / z): 304/306 ([M + NH ₄ ] ⁺ )
(3) By using the obtained crude compound 3 (574 mg, 2.22 mmol) and bromine (384 mg) and reacting in the same manner as in the production of compound 4 of Example 2, compound 4 (80 mg, 9% (2 steps)) was obtained as an oil.
MS ・ APCI (m / z): 382/384 ([M + NH ₄ ] ⁺ )
(4) By using phenylboronic acid (366 mg, 3 mmol) and compound 4 (731 mg, 2 mmol) and reacting in the same manner as in the preparation of compound 5 of Example 2, compound 5 (552 mg, 72.9 %) Was obtained as an oil.
MS ・ APCI (m / z): 363/365 ([M + H] ⁺ )
(5) Compound 6 (91 mg, 20.5%) was obtained by reacting in the same manner as in the production of compound 6 of Example 1 using compound 5 (470 mg, 1.24 mmol).
MS ・ ESI (m / z): 333/335 ([M-Na] ⁺ )

（１） 化合物１（25.6 g, 116 mmol：Tetrahedron, 2000, 56, 7205）、ヨードメタン(11.0 ml, 0.177 mmol)、炭酸カリウム(24.0 g, 0.174 mmol)の懸濁液を室温で一晩攪拌した。反応液を水に注ぎ酢酸エチル抽出し、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥し濾過した。濾液を濃縮し、シリカゲルカラムクロマトグラフィー(ヘキサン/ 酢酸エチル = 20 / 1)で精製することで化合物２(23.17 g, 85.1 %)を油状物質として得た。
MS・APCI(m/z): 252/254 ([M+NH₄]⁺)
（２） 化合物２(3.0 g, 12.8 mmol)および５−クロロ−２−チエニル（トリブチル）スズ (7.80 g, 19.1 mmol)を用いて、実施例２の化合物３の製造と同様に反応することで、化合物３(3.09 g, 88.8 %)を油状物質として得た。
MS・APCI(m/z): 273/275 ([M+H]⁺)
（３） 化合物３(3.0 g, 0.011 mmol)および臭素(0.57 ml, 0.011 mmol)を用いて、実施例２の化合物４の製造と同様に反応することで、化合物４(3.62 g, 93.6 %)を油状物質として得た。
MS・APCI(m/z): 352/354 ([M+H]⁺)
（４） ４−メトキシフェニルボロン酸(325 mg, 2.1 mmol)および化合物４(500 mg, 1.4 mmol)を用いて、実施例２の化合物５の製造と同様に反応することで、化合物５(405 mg, 75.1 %)を油状物質として得た。
MS・APCI(m/z): 379/381 ([M+H]⁺)
（５） 化合物５(345 mg, 0.91 mmol)を用いて、実施例１の化合物６の製造と同様に反応することで化合物６（239 mg）を得た。
MS・ESI(m/z): 363/365 ([M-Na]⁺) Example 4

(1) A suspension of Compound 1 (25.6 g, 116 mmol: Tetrahedron, 2000, 56, 7205), iodomethane (11.0 ml, 0.177 mmol) and potassium carbonate (24.0 g, 0.174 mmol) was stirred overnight at room temperature. . The reaction mixture was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (hexane / ethyl acetate = 20/1) to give compound 2 (23.17 g, 85.1%) as an oily substance.
MS ・ APCI (m / z): 252/254 ([M + NH ₄ ] ⁺ )
(2) Using compound 2 (3.0 g, 12.8 mmol) and 5-chloro-2-thienyl (tributyl) tin (7.80 g, 19.1 mmol), reacting in the same manner as in the production of compound 3 of Example 2. Compound 3 (3.09 g, 88.8%) was obtained as an oily substance.
MS ・ APCI (m / z): 273/275 ([M + H] ⁺ )
(3) Using compound 3 (3.0 g, 0.011 mmol) and bromine (0.57 ml, 0.011 mmol) and reacting in the same manner as in the production of compound 4 of Example 2, compound 4 (3.62 g, 93.6%) Was obtained as an oil.
MS ・ APCI (m / z): 352/354 ([M + H] ⁺ )
(4) Using 4-methoxyphenylboronic acid (325 mg, 2.1 mmol) and compound 4 (500 mg, 1.4 mmol) and reacting in the same manner as in the preparation of compound 5 of Example 2, compound 5 (405 mg, 75.1%) was obtained as an oily substance.
MS ・ APCI (m / z): 379/381 ([M + H] ⁺ )
(5) Compound 6 (239 mg) was obtained by reacting in the same manner as in the production of Compound 6 of Example 1 using Compound 5 (345 mg, 0.91 mmol).
MS ・ ESI (m / z): 363/365 ([M-Na] ⁺ )

実施例２と同様にして、上記のエチルエステルおよびカルボン酸ナトリウム塩を合成した。
実施例５の化合物(Ｙ＝エチル)：MS・APCI(m/z): 403/405 ([M+H]⁺)
実施例６の化合物(Ｙ＝Ｎa) ：MS・ESI(m/z): 373/375 ([M-Na]⁺) Examples 5 and 6

In the same manner as in Example 2, the above ethyl ester and carboxylic acid sodium salt were synthesized.
Compound of Example 5 (Y = ethyl): MS · APCI (m / z): 403/405 ([M + H] ⁺ )
Compound of Example 6 (Y = Na): MS · ESI (m / z): 373/375 ([M-Na] ⁺ )

実施例２と同様にして、上記のエチルエステルおよびカルボン酸ナトリウム塩を合成した。
実施例７の化合物(Ｙ＝エチル)：MS・APCI(m/z): 403/405 ([M+H]⁺)
実施例８の化合物(Ｙ＝Ｎa) ：MS・ESI(m/z): 329/331 ([M-Na-CO₂]⁺) Examples 7 and 8

In the same manner as in Example 2, the above ethyl ester and carboxylic acid sodium salt were synthesized.
Compound of Example 7 (Y = ethyl): MS · APCI (m / z): 403/405 ([M + H] ⁺ )
Compound of Example 8 (Y = Na): MS · ESI (m / z): 329/331 ([M-Na-CO ₂ ] ⁺ )

Examples 9-16
In the same manner as in Example 3, the compounds of Examples 9 to 16 were synthesized.

Examples 17-26
In the same manner as in Example 4, the compounds of Examples 17 to 26 were synthesized.

（１） 化合物１(1.76 g, 12 mmol)と化合物２(1.76 g, 10 mmol)のエタノール(20 ml)溶液に、水酸化カリウム(1.12 g, 20 mmol)の水溶液(1.1 ml)を加えた。反応液を室温で一晩攪拌後、水を加え析出物を濾取した。析出物を水洗し、酢酸エチル−ＴＨＦに溶解し、硫酸マグネシウムで乾燥した。抽出液に活性炭を加えて濾過し、濾液を濃縮した。残渣を酢酸エチル−イソプロピルエーテルより粉末化することで、化合物３（2.36ｇ, 77 %）を得た。
MS・APCI(m/z): 305/307 ([M+H]⁺)
（２） カリウム ｔ−ブトキシド（22 mg, 0.2 mmol）、３−ニトロアクリル酸メチル（200 mg, 1.5 mmol：A. Rodriguez et al., Tetrahedron Lett., 39, 8563 (1998)）および化合物３（305 mｇ, 1 mmol）のＴＨＦ（10 ml）溶液を室温で一晩攪拌した。反応液に１０％塩酸を加え、酢酸エチル抽出をした。有機層を飽和食塩水で洗浄し、芒硝で乾燥した後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/ 酢酸エチル＝ 50/ 1）で精製することで、化合物４ (312 mg, 71.2 %)を粉末として得た。
MS・APCI(m/z): 438/440 ([M+H]⁺)
（３） 化合物４(700 mg, 1.6 mmol)とジフェニルジスルフィド（1.05 g, 4.81 mmol）のＴＨＦ溶液に室温でトリn-ブチルホスフィン（2.4 ml, 9.64 mmol）を加えた後、2時間加熱還流した。反応液を濃縮し、シリカゲルカラムクロマトグラフィー（クロロホルム/ ヘキサン＝１/１→ ９/１）で精製することで、化合物５（340 mg, 55 %）を得た。
MS・APCI(m/z): 388/390 ([M+H]⁺)
（４） 化合物５を用いて、実施例１の化合物６の製造と同様に反応することで、化合物６を得た。
MS・ESI(m/z): 372/374 ([M-Na]⁺) Example 27

(1) An aqueous solution (1.1 ml) of potassium hydroxide (1.12 g, 20 mmol) was added to an ethanol (20 ml) solution of compound 1 (1.76 g, 12 mmol) and compound 2 (1.76 g, 10 mmol). . The reaction mixture was stirred at room temperature overnight, water was added, and the precipitate was collected by filtration. The precipitate was washed with water, dissolved in ethyl acetate-THF, and dried over magnesium sulfate. Activated carbon was added to the extract and filtered, and the filtrate was concentrated. The residue was pulverized from ethyl acetate-isopropyl ether to obtain Compound 3 (2.36 g, 77%).
MS ・ APCI (m / z): 305/307 ([M + H] ⁺ )
(2) Potassium t-butoxide (22 mg, 0.2 mmol), methyl 3-nitroacrylate (200 mg, 1.5 mmol: A. Rodriguez et al., Tetrahedron Lett., 39, 8563 (1998)) and compound 3 ( (305 mg, 1 mmol) in THF (10 ml) was stirred overnight at room temperature. 10% hydrochloric acid was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate = 50/1) to give Compound 4 (312 mg, 71.2%) as a powder.
MS ・ APCI (m / z): 438/440 ([M + H] ⁺ )
(3) To a THF solution of compound 4 (700 mg, 1.6 mmol) and diphenyl disulfide (1.05 g, 4.81 mmol) was added tri-n-butylphosphine (2.4 ml, 9.64 mmol) at room temperature, and the mixture was heated to reflux for 2 hours. . The reaction solution was concentrated and purified by silica gel column chromatography (chloroform / hexane = 1/1 → 9/1) to obtain Compound 5 (340 mg, 55%).
MS ・ APCI (m / z): 388/390 ([M + H] ⁺ )
(4) Compound 6 was obtained by reacting compound 5 in the same manner as in the production of compound 6 of Example 1.
MS ・ ESI (m / z): 372/374 ([M-Na] ⁺ )

（１） ジイソプロピルアミン（13.68 g, 135 mmol）のＴＨＦ（600 ml）溶液にｎ−ブチルリチウム(1.56 M in Hexane, 85 ml, 135 mmol)をドライアイス−アセトン冷却下加え、化合物１ (38 g, 134 mmol)のＴＨＦ(50 ml)溶液を加えた。同温で２５分攪拌後、化合物２(17 ml)のＴＨＦ(20 ml)溶液を加えた。反応液を室温に戻して3.5時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加えた後、酢酸エチル抽出した。有機層を芒硝乾燥し、濾過して濃縮した。残渣をＴＨＦ(750 ml)に溶解し、１Ｎテトラブチルアンモニウムフロリド（ＴＨＦ溶液, 130 ml）を加え１時間攪拌した。反応液に飽和重曹水を加え、酢酸エチル抽出し、芒硝乾燥した。濾過後、濾液を濃縮し、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/ 酢酸エチル＝ 5/ 1)で精製することで、化合物３ (18.53 g, 48 %)を得た。
MS・APCI(m/z): 308/310 ([M+NH₄]⁺)
（２） 化合物３(148 mg, 0.51 mmol)をアセトン（5 ml）に溶解し、炭酸カリウム（106 mg, 0.77 mmol）と４−フルオロフェナシルブロミド(260 mg, 2.4 mmol)を加え一晩攪拌した。反応液を濃縮後、水を加えて酢酸エチル抽出した。抽出液を飽和食塩水で洗浄し、芒硝で乾燥した。濾過後、濾液を濃縮し、残渣をシリカゲルカラムクロマトグラフィーで精製することで、化合物４ (163 mg, 75％)を得た。
MS・APCI(m/z): 427/429 ([M+H]⁺)
（３） 化合物４ (83.1 mg, 0.195 mmol)を酢酸（2 ml）に溶解して、濃塩酸(0.5 ml)、水(0.5 ml)を加えた。反応液を6時間加熱還流後、水を加え酢酸エチルで抽出した。有機層を飽和食塩水で洗浄をし、芒硝乾燥した。抽出液に活性炭を加え濾過をし、濾液を濃縮することで、化合物５（48 mg, 73 %）を得た。
MS・ESI(m/z): 335/337 （［M-H］^-） Example 28

(1) To a solution of diisopropylamine (13.68 g, 135 mmol) in THF (600 ml), n-butyllithium (1.56 M in Hexane, 85 ml, 135 mmol) was added while cooling with dry ice-acetone, and compound 1 (38 g , 134 mmol) in THF (50 ml) was added. After stirring at the same temperature for 25 minutes, a solution of compound 2 (17 ml) in THF (20 ml) was added. The reaction solution was returned to room temperature and stirred for 3.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried with sodium sulfate, filtered and concentrated. The residue was dissolved in THF (750 ml), 1N tetrabutylammonium fluoride (THF solution, 130 ml) was added, and the mixture was stirred for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, followed by extraction with ethyl acetate and drying with sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to give Compound 3 (18.53 g, 48%).
MS ・ APCI (m / z): 308/310 ([M + NH ₄ ] ⁺ )
(2) Compound 3 (148 mg, 0.51 mmol) is dissolved in acetone (5 ml), potassium carbonate (106 mg, 0.77 mmol) and 4-fluorophenacyl bromide (260 mg, 2.4 mmol) are added and stirred overnight. did. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain compound 4 (163 mg, 75%).
MS ・ APCI (m / z): 427/429 ([M + H] ⁺ )
(3) Compound 4 (83.1 mg, 0.195 mmol) was dissolved in acetic acid (2 ml), and concentrated hydrochloric acid (0.5 ml) and water (0.5 ml) were added. The reaction mixture was heated to reflux for 6 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with sodium sulfate. Activated carbon was added to the extract and filtered, and the filtrate was concentrated to obtain Compound 5 (48 mg, 73%).
MS ・ ESI (m / z): 335/337 ([MH] ^- )

In the same manner as in the above examples, the compounds of Examples 29 to 62 were synthesized.

（１） 実施例２８の化合物２の代わりにマロン酸ジアリルエステルを用いて実施例２８と同様に合成した化合物１を用いて、化合物１(48 mg, 0.10 mmol)のTHF（2 ml）溶液にテトラキス（トリフェニルホスフィン）パラジウム（12 mg, 0.01 mmol）およびモルホリン（0.026 ml）を加え、アルゴン雰囲気下、室温で一晩攪拌した。反応液にクエン酸水溶液を加え、酢酸エチルで抽出後、有機層を飽和食塩水で洗浄し、芒硝で乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝100:0 → 95:5）で精製することにより化合物２（35 mg, 99 %）を得た。
MS・ESI(m/z)：353/355 (M-H)
（２） 化合物２（209 mg, 0.59 mmol）と酢酸アンモニウム（910 mg, 12 mmol）の混合物を120℃で30分加熱攪拌した。反応液を冷却後、残渣に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、芒硝で乾燥後、活性炭処理を行った。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィ（クロロホルム）で精製することにより、化合物３（104 mg, 53%）を得た。
MS・ESI(m/z)：334/336 (M-H)
化合物３を実施例１（５）の方法と同様にナトリウムメトキシドと処理することにより、対応のナトリウム塩を得た。
MS・ESI(m/z)：334 [M-Na]^- Example 63

(1) Using Compound 1 synthesized in the same manner as Example 28 using malonic acid diallyl ester instead of Compound 2 of Example 28, a THF (2 ml) solution of Compound 1 (48 mg, 0.10 mmol) was used. Tetrakis (triphenylphosphine) palladium (12 mg, 0.01 mmol) and morpholine (0.026 ml) were added, and the mixture was stirred overnight at room temperature under an argon atmosphere. An aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 → 95: 5) to give compound 2 (35 mg, 99%).
MS ・ ESI (m / z) ： 353/355 (MH)
(2) A mixture of compound 2 (209 mg, 0.59 mmol) and ammonium acetate (910 mg, 12 mmol) was stirred with heating at 120 ° C. for 30 minutes. The reaction mixture was cooled, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and then treated with activated carbon. After the solvent was distilled off, the residue was purified by silica gel column chromatography (chloroform) to obtain Compound 3 (104 mg, 53%).
MS ・ ESI (m / z) ： 334/336 (MH)
Compound 3 was treated with sodium methoxide in the same manner as in Example 1 (5) to give the corresponding sodium salt.
MS · ESI (m / z): 334 [M-Na] ^-

実施例６３（２）において、酢酸アンモニウムの代わりにメチルアミンのメタノール溶液を用いて、同様に反応・処理することにより、化合物２を得た。
MS・ESI(m/z)：348/350（M-H）
化合物２を実施例１（５）の方法と同様にナトリウムメトキシドと処理することにより、対応のナトリウム塩を得た。
MS・ESI(m/z)：348/350 [M-Na]^- Example 64

In Example 63 (2), Compound 2 was obtained by reacting and treating in the same manner using a methanol solution of methylamine instead of ammonium acetate.
MS / ESI (m / z): 348/350 (MH)
Compound 2 was treated with sodium methoxide in the same manner as in Example 1 (5) to give the corresponding sodium salt.
MS · ESI (m / z): 348/350 [M-Na] ^-

In the same manner as in the above examples, the compounds of Examples 65 and 66 were synthesized.

5-ブロモ-2-ジメチルアミノピリミジン(2.0 g, 9.9 mmol：Bull. Chem. Soc. Jpn., 72, 2523 (1999))のＴＨＦ（25 ml）溶液に1.56 M n-ブチルリチウム(ヘキサン溶液, 7.0 ml, 10.9 mmol)をドライアイス−アセトン浴で冷却下加えた。40分攪拌の後、反応液にトリイソプロピルボロン酸エステル (3.5 ml, 0.15 ml)のＴＨＦ溶液（6 ml）を加えた。室温に昇温し、塩酸を加えて後、溶媒を留去した。残渣をメタノール−ジエチルエーテルで粉末化すると2-ジメチルアミノ-5-ピリミジニル硼酸 塩酸塩（2.26 g）を得た。
参考例１で得られた化合物は、実施例２１、２２の化合物の製造において使用した。 Reference example 1

To a solution of 5-bromo-2-dimethylaminopyrimidine (2.0 g, 9.9 mmol: Bull. Chem. Soc. Jpn., 72, 2523 (1999)) in THF (25 ml) was added 1.56 M n-butyllithium (hexane solution, 7.0 ml, 10.9 mmol) was added with cooling in a dry ice-acetone bath. After stirring for 40 minutes, a THF solution (6 ml) of triisopropylboronic acid ester (3.5 ml, 0.15 ml) was added to the reaction solution. The temperature was raised to room temperature, hydrochloric acid was added, and then the solvent was distilled off. The residue was triturated with methanol-diethyl ether to give 2-dimethylamino-5-pyrimidinyl boric acid hydrochloride (2.26 g).
The compound obtained in Reference Example 1 was used in the production of the compounds of Examples 21 and 22.

The following compounds are further synthesized in the same manner as in the above Examples and Reference Examples.

Experimental example 1
[Relaxation of potassium-induced contraction in rabbit isolated bladder specimens]
Were excised bladders from male NZW rabbits (2.0 to 3.5 kg), ice-cold Krebs - bicarbonate solution (Unit mM: 118 NaCl, 4.7 KCl, 2.55 CaCl 2, 1.18 MgSO 4, 1.18 KH 2 PO 4, 24.88 NaHCO 3 And 11.1 glucose). The bladder was cut after removing the membranous tissue of the lumen, and was cut into a strip in the longitudinal direction (total length: 5 mm, width: 3 to 4 mm).
The specimen was immersed in an organ bath filled with 10 ml of Krebs solution heated to 37 ° C. and aerated with a mixed gas of 95% O ₂ /5% CO ₂ . The specimen was stretched so that the static tension was 2.0 ± 1.0 g, and the change in isometric contraction was measured with a force-displacement transducer. Change the organ bath solution to Krebs solution (unit mM: 118 NaCl, 4.7 KCl, 2.55 CaCl ₂ , 1.18 MgSO ₄ , 1.18 KH ₂ PO ₄ , 24.88 NaHCO ₃ and 11.1 glucose) in high concentration potassium ion (30 mM). Pre-shrink.
After showing stable contraction, the test compound was cumulatively added to the organ bath (10 ⁻⁸ M−10 ⁻⁴ M). The effect of the test compound was expressed as a percentage with the maximum relaxation caused by the addition of 10 ⁻⁴ M papaverine as 100%. The concentration at which the relaxation rate was 50% (IC ₅₀ ) was calculated, and the IC ₅₀ value range (μM) of the selected compound of the present invention was shown in the following Table 1 by the rank of A, B or C. These ranges are as follows.
3 μM ≧ C> 1 μM ≧ B> 0.5 μM ≧ A

Table 1
Example IC ₅₀ value range
2 (Compound 6) A
3 (Compound 6) B
6 A
8 A
10 A
14 B
16 C
26 A

Experimental example 2
[Inhibitory action against Substance P-induced rhythmic bladder contraction in anesthetized rats]
In the experiment, female Sprague-Dawley rats (9-12 weeks old) weighing 200 to 300 g were used. After urethane anesthesia (1.2 g / kg, subcutaneous administration), the left and right femoral veins were cannulated. One catheter was used for intravenous administration of the test compound, and the other catheter was used for injection of Substance P (0.33 μg / kg / min). A catheter was also inserted into the ureter to secure the urinary tract. A polyethylene catheter was inserted into the carotid artery for continuous measurement of arterial pressure and heart rate. For continuous infusion, a transurethral bladder catheter was inserted into the bladder from the urethra and fixed with a ligature around the urethral closure. One end of the catheter was connected to a pressure transducer for measurement of intravesical pressure. The other end of the catheter was used to inject saline into the bladder. After the blood pressure and heart rate were stabilized and the bladder was emptied, about 0.6 ml of physiological saline was slowly loaded to measure the intravesical pressure. Approximately 10 minutes later, continuous infusion of Substance P into the vein (0.33 μg / kg / min) was started to stabilize the bladder contraction. After confirming that the onset of rhythmic contraction lasted for about 15 minutes, the test compound was administered. All test compounds were dissolved or suspended in saline containing 0.5% Tween 80 and administered intravenously (0.1 ml / kg). Rhythmic bladder contractions and intravesical pressure were observed up to 35 minutes after test compound administration.
As a result, the compound of the present invention suppressed the development of rhythmic bladder contraction without affecting the bladder contractile force. In addition, the time (min) at which the frequency of rhythmic contraction was completely suppressed by administration of 0.25 mg / kg of the test compound was determined. Table 2 shows the 100% inhibition time (minutes) of selected compounds in the present invention.

Table 2
Example 100% suppression time (minutes)
2 (Compound 6) 13.1
3 (Compound 6) 27.1
6 16.8
18 12.5
36 15.3
58 23.8

The active ingredient of the present invention exhibited a relaxing action on specimens contracted with 20 mM potassium ions, and the action was inhibited by iberiotoxin, which is a selective high conductance calcium-sensitive K channel blocker.
Furthermore, in an in vivo experiment, the pre-administration of iberiotoxin (0.15 mg / kg, intravenous administration) reduced the rhythmic bladder contraction suppression effect of the active ingredient of the present invention. As a result, it was shown that the active ingredient of the present invention has a bladder smooth muscle relaxing action through a high conductance calcium sensitive K channel opening action.
Therefore, it was shown that the compound which is an active ingredient of the present invention is useful as a prophylactic / therapeutic agent for diseases such as frequent urination and urinary incontinence through a high conductance type calcium sensitive K channel opening action.

The 5-membered heterocyclic compound (1) or a pharmacologically acceptable salt thereof, which is an active ingredient of the present invention, has an excellent high conductance calcium-sensitive K channel opening action and hyperpolarizes the membrane electrical potential of cells. For example, hypertension, premature birth, irritable bowel syndrome, chronic heart failure, angina, myocardial infarction, cerebral infarction, subarachnoid hemorrhage, cerebrovascular spasm, cerebral hypoxia, peripheral vascular disorder, anxiety, male baldness, Erectile dysfunction, diabetes, diabetic peripheral neuropathy, other diabetic complications, infertility, urolithiasis and associated pain, frequent urination, urinary incontinence, nocturnal enuresis, asthma, chronic obstructive pulmonary disease (COPD), asthma or It is useful as a preventive, alleviating and / or therapeutic agent for cough, stroke, cerebral ischemia, traumatic brain injury and the like associated with chronic obstructive pulmonary disease (COPD).
Further, the 5-membered heterocyclic compound (1) of the present invention or a pharmacologically acceptable salt thereof has low toxicity and high safety as a medicine.

Claims (13)

Formula (II) for manufacturing high conductance calcium-sensitive potassium channel openers

[Wherein, ring A represents a ring represented by any of the following formulae.

R ¹ represents substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group or substituted or unsubstituted heterocyclic group-substituted carbonyl.
R ² represents substituted alkyl.
R ³ represents a substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted alkyl.
R ⁴ represents a hydrogen atom or substituted or unsubstituted alkyl.
However, when R ¹ and R ³ are phenyl, R ² is not carboxymethyl or ethoxycarbonylmethyl. ]
Or a pharmacologically acceptable salt thereof. R ¹ is a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted heterocyclic group-substituted carbonyl, or aryl substituted with two halogens;
Use according to claim 1. R ¹ is (1) nitro, amino, hydroxyl group, carbamoyl, cyano, carboxy, trifluoromethyl, alkoxycarbonyl, halogen atom, alkyl, hydroxyalkyl, alkoxy, alkoxyalkoxy, mono- or dialkylamino, mono- or dialkanoylamino, Aryl optionally substituted with a group selected from alkylthio, alkylsulfonyl, alkylsulfinyl, sulfamoyl, mono- or dialkylsulfamoyl, alkylsulfonylamino and phenylalkoxy, (2) nitro, hydroxyl, formyl, carbamoyl, cyano, amino, Carboxy, alkoxycarbonyl, halogen atom, alkyl, hydroxyalkyl, alkoxy, mono- or dialkylamino, mono- or dialkanoyl A heterocyclic group optionally substituted with a group selected from mino, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfamoyl and mono- or dialkylsulfamoyl, or (3) nitro, hydroxyl, carbamoyl, cyano, carboxy, alkoxycarbonyl, Heteroaryl optionally substituted by a group selected from a halogen atom, alkyl, hydroxyalkyl, alkoxy, alkanoyl, mono- or dialkylamino, mono- or dialkanoylamino, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfamoyl and mono- or dialkylsulfamoyl A cyclic group-substituted carbonyl,
R ² is halogen atom, hydroxyl group, cyano, carboxy, carbamoyl, amino, aminosulfonyl, amidinothio, mono or dialkylamino, alkanoylamino, alkylsulfonylamino, hydroxyamino, mono or dialkylcarbamoyl, trifluoromethyl, alkoxy, alkylthio, Alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, hydroxycarbamoyl, hydroxycarbamoyl substituted with 1 or 2 alkyls, alkylsulfonylcarbamoyl, sulfamoyl, mono- or dialkylsulfamoyl, alkoxycarbonyl, heterocyclic group, heterocyclic Selected from group-substituted carbamoyl, heterocyclic group-substituted alkylcarbamoyl and heterocyclic group-substituted sulfonylcarbamoyl An alkyl optionally substituted with a group,
R ³ is (1) cyano, nitro, amino, halogen atom, trifluoromethyl, carboxy, hydroxyl group, carbamoyl, mono or dialkylamino, aminoalkyl, mono or dialkylaminoalkyl, mono or dialkylcarbamoyl, alkyl, hydroxyalkyl, Aryl optionally substituted with a group selected from alkoxy, alkoxycarbonyl, alkanoyl, alkanoyloxy, alkanoyloxyalkyl, sulfo, alkylthio, alkylthioalkyl, alkylsulfonyl, sulfamoyl, mono- or dialkylsulfamoyl and alkylsulfinyl, (2) Oxo, cyano, nitro, amino, halogen atom, carboxy, hydroxyl group, formyl, carbamoyl, mono- or dialkylamino, N- Alkyl-N-cycloalkylamino, aminoalkyl, mono- or dialkylaminoalkyl, mono- or dialkylcarbamoyl, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkanoyl, sulfo, alkylthio, alkylsulfonyl, sulfamoyl, mono- or dialkylsulfo A heterocyclic group optionally substituted with a group selected from famoyl, alkylsulfinyl and heterocyclic groups, or (3) hydroxyl, cyano, carboxy, carbamoyl, amino, mono- or dialkylamino, alkanoylamino, alkylsulfonylamino , Hydroxyamino, mono- or dialkylcarbamoyl, trifluoromethyl, halogen atom, alkoxy, alkylthio, alkylsulfur Sulfonyl, alkylsulfonyl, sulfamoyl, a mono or dialkyl sulfamoyl, alkoxycarbonyl and alkyl which may be substituted by a group selected from a heterocyclic group,
R ⁴ is (1) a hydrogen atom, or (2) alkyl optionally substituted with mono- or dialkylamino.
Use according to claim 1 or 2. R ¹ is (1) aryl optionally substituted with 1 or 2 halogen atoms, or (2) heterocyclic group optionally substituted with halogen atoms or alkyl,
R ² may be substituted with a group selected from carboxy, carbamoyl, mono- or dialkylcarbamoyl, hydroxycarbamoyl, hydroxycarbamoyl substituted with 1 or 2 alkyls, alkoxycarbonyl, alkylsulfonylcarbamoyl and heterocyclic groups Alkyl,
R ³ is (1) a heterocyclic group which may be substituted with one or two groups selected from amino, halogen atom, alkyl, alkoxy, mono- or dialkylamino and alkylthio, or (2) amino, halogen atom , Aryl optionally substituted with a group selected from alkyl, alkylthio, alkoxy and mono- or dialkylamino,
R ⁴ is a hydrogen atom or alkyl,
Use according to claim 1 or 2. Formula (III) for manufacturing high conductance calcium-sensitive potassium channel openers

[Wherein, ring A represents a ring represented by any of the following formulae.

R ¹ represents substituted or unsubstituted thienyl, or aryl substituted with two halogen atoms.
R ² represents substituted alkyl.
R ³ represents a substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted alkyl.
R ⁴ represents a hydrogen atom or substituted or unsubstituted alkyl.
However, when R ¹ is 2-thienyl, R ³ is not 2-thienyl. ]
Or a pharmacologically acceptable salt thereof. R ² is halogen atom, hydroxyl group, cyano, carboxy, carbamoyl, amino, aminosulfonyl, amidinothio, mono or dialkylamino, alkanoylamino, alkylsulfonylamino, hydroxyamino, mono or dialkylcarbamoyl, trifluoromethyl, alkoxy, alkylthio, Alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, hydroxycarbamoyl, hydroxycarbamoyl substituted with 1 or 2 alkyls, alkylsulfonylcarbamoyl, sulfamoyl, mono- or dialkylsulfamoyl, alkoxycarbonyl, heterocyclic group, heterocyclic Selected from group-substituted carbamoyl, heterocyclic group-substituted alkylcarbamoyl and heterocyclic group-substituted sulfonylcarbamoyl An alkyl optionally substituted with a group,
R ³ is (1) cyano, nitro, amino, halogen atom, trifluoromethyl, carboxy, hydroxyl group, carbamoyl, mono or dialkylamino, aminoalkyl, mono or dialkylaminoalkyl, mono or dialkylcarbamoyl, alkyl, hydroxyalkyl, Aryl optionally substituted with a group selected from alkoxy, alkoxycarbonyl, alkanoyl, alkanoyloxy, alkanoyloxyalkyl, sulfo, alkylthio, alkylthioalkyl, alkylsulfonyl, sulfamoyl, mono- or dialkylsulfamoyl and alkylsulfinyl, (2) Oxo, cyano, nitro, amino, halogen atom, carboxy, hydroxyl group, formyl, carbamoyl, mono- or dialkylamino, N- Alkyl-N-cycloalkylamino, aminoalkyl, mono- or dialkylaminoalkyl, mono- or dialkylcarbamoyl, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkanoyl, sulfo, alkylthio, alkylsulfonyl, sulfamoyl, mono- or dialkylsulfo A heterocyclic group optionally substituted with a group selected from famoyl, alkylsulfinyl and heterocyclic groups, or (3) hydroxyl, cyano, carboxy, carbamoyl, amino, mono- or dialkylamino, alkanoylamino, alkylsulfonylamino , Hydroxyamino, mono- or dialkylcarbamoyl, trifluoromethyl, halogen atom, alkoxy, alkylthio, alkylsulfur Sulfonyl, alkylsulfonyl, sulfamoyl, a mono or dialkyl sulfamoyl, alkoxycarbonyl and alkyl which may be substituted by a group selected from a heterocyclic group,
R ⁴ is (1) a hydrogen atom, or (2) alkyl optionally substituted with mono- or dialkylamino.
Use according to claim 5. R ² may be substituted with a group selected from carboxy, carbamoyl, mono- or dialkylcarbamoyl, hydroxycarbamoyl, hydroxycarbamoyl substituted with 1 or 2 alkyls, alkoxycarbonyl, alkylsulfonylcarbamoyl and heterocyclic groups Alkyl,
R ³ is (1) a heterocyclic group which may be substituted with one or two groups selected from amino, halogen atom, alkyl, alkoxy, mono- or dialkylamino and alkylthio, or (2) amino, halogen atom , Aryl optionally substituted with a group selected from alkyl, alkylthio, alkoxy and mono- or dialkylamino,
R ⁴ is a hydrogen atom or alkyl,
Use according to claim 5. R ¹ is thienyl which may be substituted with a halogen atom;
R ² is (1) carboxyalkyl, (2) carbamoylalkyl, (3) mono- or dialkylcarbamoylalkyl, (4) alkoxycarbonylalkyl, (5) alkylsulfonylcarbamoylalkyl, or (6) tetrazolylalkyl ,
R ³ is (1) phenyl optionally substituted with a halogen atom, (2) phenyl optionally substituted with a group selected from a halogen atom, alkylthio, alkyl, alkoxy and dialkylamino, (3) alkyl, alkoxy And pyridinyl optionally substituted with a group selected from dialkylamino, (4) pyrimidinyl optionally substituted with alkoxy, alkyl, dialkylamino or alkylthio, (5) thienyl optionally substituted with 1 or 2 alkyls , (6) thieno [3,2-b] pyridyl, (7) benzofuryl, (8) dihydrobenzofuryl, or (9) indolyl optionally substituted with alkyl,
R ⁴ is a hydrogen atom or alkyl,
Use according to claim 1 or 5. R ² is (1) carboxyalkyl, (2) carbamoylalkyl, (3) mono- or dialkylcarbamoylalkyl, or (4) alkoxycarbonylalkyl,
R ³ is (1) phenyl optionally substituted with a halogen atom, (2) phenyl optionally substituted with a group selected from a halogen atom, alkylthio, alkyl, alkoxy and dialkylamino, (3) alkyl, alkoxy And pyridinyl optionally substituted with a group selected from dialkylamino, (4) pyrimidinyl optionally substituted with alkoxy or dialkylamino, (5) thienyl optionally substituted with 1 or 2 alkyls, (6) Thieno [3,2-b] pyridyl, (7) benzofuryl, (8) dihydrobenzofuryl, or (9) an indolyl optionally substituted with alkyl,
Use according to claim 8. R ² is carboxyalkyl or alkoxycarbonylalkyl;
R ³ is (1) benzothienyl optionally substituted with a halogen atom, (2) phenyl optionally substituted with a group selected from a halogen atom, alkylthio, alkoxy and dialkylamino, (3) alkyl, alkoxy or dialkyl Pyridyl optionally substituted with amino, (4) pyrimidinyl optionally substituted with dialkylamino, (5) thienyl optionally substituted with 1 or 2 alkyls, (6) thieno [3,2-b] Pyridyl, or (7) indolyl optionally substituted with alkyl,
Use according to claim 8. Use according to any of claims 8 to 10, wherein R ² is carboxymethyl or alkoxycarbonylmethyl.   The use according to any of claims 8 to 11, wherein ring A is furan or thiophene. Use of a compound selected from the examples and preferred examples in the specification or a pharmacologically acceptable salt thereof for producing a high conductance calcium-sensitive potassium channel opener.