JP2007176933A - Medicinal composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine consisting of a compound useful as a high conductance type calcium sensitive K channel-opening medicine useful for the treatment of pollaki-uria, urinary incontinence, etc., or its pharmaceutically acceptable salt. <P>SOLUTION: This medicine consists of a bicyclic compound expressed by the formula of the figure [wherein, a ring Q is pyridine or pyrimidine; ring A is benzene or a heterocyclic ring; G is a ring B which may have a substituent R<SP>3</SP>or an amino which may be substituted by an alkyl or the like; the ring B is benzene, a heterocyclic ring, a cycloalkane or a cycloalkene; R<SP>1</SP>is amide, hydrazide, hydroxamic acid, an ester group, etc.; R<SP>2</SP>, R<SP>3</SP>are each the same or different and are each cyano, nitro or the like; (m), (n) are each the same or different and are each 0, 1 or 2; R<SP>4</SP>is H, a halogen or the like; and R<SP>5</SP>, R<SP>6</SP>are each the same or different and are each H, an alkyl which may be substituted or the like] or its pharmaceutically acceptable salt. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a high conductance calcium sensitive K channel opener useful for the treatment of diseases such as frequent urination, urinary incontinence, asthma, chronic obstructive pulmonary disease (COPD), cerebral infarction, subarachnoid hemorrhage and the like.

Ion channels, including potassium channels, are found in all mammalian cells and are involved in the regulation of various physiological processes and normal cellular homeostasis. Potassium channels generally control the resting membrane potential of cells, and the outward flow of potassium ions repolarizes the plasma membrane after cell depolarization.
There are many subtypes of potassium channels. From a physiological point of view, the maxi-K channel is one of the important subtypes, which are defined as high conductance calcium sensitive potassium channels (BK channels) and are present in neural tissue and smooth muscle. Intracellular calcium concentration and membrane potential control these high conductance calcium sensitive potassium channels. For example, high conductance-type calcium-sensitive potassium channels are opened to allow outward efflux of potassium ions by increasing intracellular calcium concentration or membrane depolarization (change in potential), membrane depolarization and It acts to suppress the increase in intracellular calcium concentration. Increases in intracellular calcium concentration are required for processes such as neurotransmitter release, smooth muscle contraction, and proliferation of certain cell types. Therefore, the drug having the action of opening the maxi-K channel attenuates the excitability of nerve cells, suppresses the release of transmitter substances from nerve endings, suppresses the contraction of smooth muscle, It is effective in treating diseases such as subarachnoid hemorrhage, frequent urination and urinary incontinence.

It has been reported that a drug that opens a BK channel has an action of suppressing airway contraction of a guinea pig airway specimen by electronic stimulation (Non-patent Document 1). Therefore, it is effective for the treatment of asthma, COPD, etc., for example. Further, it has been suggested that a drug that opens a BK channel can be a therapeutic drug for sexual dysfunction such as erectile dysfunction (Patent Document 1).
Examples of the high conductance calcium-sensitive K channel opener include a pyrrole derivative (Patent Document 2), a furan derivative (Patent Document 3), and a nitrogen-containing 5-membered ring derivative in which a nitrogen atom is substituted with a phenyl group or a benzyl group ( Various reports such as Patent Document 4), diphenyltriazole derivatives (Non-Patent Document 2), celecoxib derivatives (Patent Document 5) and the like have been reported.
A method for synthesizing pyrimidine derivatives such as 4-amino-5- (4-cyanophenyl) pyrimidine is reported in Non-Patent Document 3.
Patent Document 6 reports that 2- (4-fluorophenyl) -3- (4-pyrimidyl) pyridine derivatives are effective for the treatment of diseases involving CSBP / RK / p38 kinase.
WO 00/34244 WO 96/40634 JP2000-351773 WO 98/04135 EP 1400243 WO 00/40243 J. Pharmacol. Exp. Ther., (1998) 286: 952-958 J. Med. Chem., Vol. 45, p.2942-2952 (2002) Anales de la Asociacion Quimica Argentina, 56 (1-2), 73 (1968)

  The present invention has an excellent high conductance calcium-sensitive K channel opening action with few side effects, and is a compound useful for the treatment of diseases such as frequent urination, urinary incontinence, asthma, COPD, cerebral infarction, subarachnoid hemorrhage or the like The object is to provide a medicament comprising a pharmaceutically acceptable salt.

［式中、環Ｑはピリジンまたはピリミジンを表す。
環Ａはベンゼンまたは複素芳香環を表す。
Ｇは

またはアルキル、アラルキル及びシクロアルキルからそれぞれ選ばれる１若しくは２の置換基によって置換されていてもよいアミノを表す。
環Ｂはベンゼン、複素環、シクロアルカンまたはシクロアルケンを表す。
Ｒ^１は下式から選ばれる基を表す。

Ｒ^２およびＲ^３は同一または異なって、それぞれシアノ、ニトロ、水酸基、アルコキシ、ハロゲン、カルボキシ、アルコキシカルボニル、置換されていてもよいカルバモイル、置換されていてもよいアミノまたは置換されていてもよいアルキルを表す。但し、ｍが２の時、２つのＲ^２は同一または異なっていてもよく、ｎが２の時、２つのＲ^３は同一または異なっていてもよい。
ｍおよびｎは、同一または異なって、それぞれ０、１または２を表す。
Ｒ^４は、水素原子、ハロゲン、シアノ、アルコキシ、水酸基、カルバモイル、置換されていてもよいアミノ、置換されていてもよいアルキル、置換されていてもよいアリールオキシ、シクロアルキルオキシまたは置換されていてもよい複素環式基を表す。
Ｒ^５およびＲ^６は同一または異なって、それぞれ水素原子、置換されていてもよいアルキル、置換されていてもよいシクロアルキル(該シクロアルキルはアリールと縮合されていてもよい)、置換されていてもよいアリール、置換されていてもよい複素環式基、もしくはアルコキシカルボニルを表すか、またはＲ^５およびＲ^６が一緒になって、それらが結合している原子と共に、置換されていてもよい複素環を形成してもよい。但し、４‐アミノ−５‐（４−シアノフェニル）ピリミジンを除く。］
で表される二環化合物またはその薬学上許容される塩。
［２］ 式１ａ：

［式中、環Ｑ、環Ａ、環Ｂ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、ｍおよびｎは、[１]記載における意義と同義である。］
で表される［１］記載の二環化合物またはその薬学上許容される塩。
［３］ 環Ｑがピリジンである［１］または［２］記載の二環化合物またはその薬学上許容される塩。
［４］ 式１b：

［式中、ＸおよびＹは一方が窒素原子を表し、他方がメチンを表す。
環Ａ、環Ｂ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、ｍおよびｎは、前記と同義である。］
で表される［２］記載の二環化合物またはその薬学上許容される塩。
［５］ 環Ａが５又は６員環である［１］〜［４］のいずれか記載の二環化合物またはその薬学上許容される塩。 As a result of diligent research, the present inventors have found that the bicyclic compound represented by the following formula has an excellent high conductance calcium-sensitive K channel opening action, and completed the present invention.
That is, the present invention is as follows.
[1] Formula 1:

[Wherein, ring Q represents pyridine or pyrimidine.
Ring A represents benzene or a heteroaromatic ring.
G is

Alternatively, it represents amino optionally substituted by 1 or 2 substituents selected from alkyl, aralkyl and cycloalkyl, respectively.
Ring B represents benzene, heterocycle, cycloalkane or cycloalkene.
R ¹ represents a group selected from the following formulae.

R ² and R ³ are the same or different and are each cyano, nitro, hydroxyl group, alkoxy, halogen, carboxy, alkoxycarbonyl, optionally substituted carbamoyl, optionally substituted amino, or optionally substituted alkyl Represents. However, when m is 2, two R ² may be the same or different, and when n is 2, two R ³ may be the same or different.
m and n are the same or different and each represents 0, 1 or 2.
R ⁴ is a hydrogen atom, halogen, cyano, alkoxy, hydroxyl group, carbamoyl, optionally substituted amino, optionally substituted alkyl, optionally substituted aryloxy, cycloalkyloxy or substituted. Represents a good heterocyclic group.
R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, an optionally substituted alkyl, an optionally substituted cycloalkyl (the cycloalkyl may be condensed with an aryl), a substituted Represents an optionally substituted aryl, an optionally substituted heterocyclic group, or alkoxycarbonyl, or R ⁵ and R ⁶ together, together with the atom to which they are attached, optionally substituted heterocycle A ring may be formed. However, 4-amino-5- (4-cyanophenyl) pyrimidine is excluded. ]
Or a pharmaceutically acceptable salt thereof.
[2] Formula 1a:

[Wherein, ring Q, ring A, ring B, R ¹ , R ² , R ³ , R ⁴ , m and n are as defined in [1]. ]
Or a pharmaceutically acceptable salt thereof.
[3] The bicyclic compound or the pharmaceutically acceptable salt thereof according to [1] or [2], wherein ring Q is pyridine.
[4] Formula 1b:

[Wherein, one of X and Y represents a nitrogen atom and the other represents methine.
Ring A, ring B, R ¹ , R ² , R ³ , R ⁴ , m and n are as defined above. ]
Or a pharmaceutically acceptable salt thereof.
[5] The bicyclic compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [4], wherein ring A is a 5- or 6-membered ring.

[6] The bicyclic compound or the pharmaceutically acceptable salt thereof according to any one of [1] to [4], wherein Ring A is benzene, pyridine, pyrimidine, or thiophene.
[7] The bicyclic compound or the pharmaceutically acceptable salt thereof according to any one of [1] to [4], wherein ring A is benzene.
[8] The bicyclic compound according to any one of [1] to [7], wherein ring A is a 6-membered ring and R ¹ is substituted at the para position with respect to ring Q, or a pharmaceutically acceptable salt thereof salt.
[9] The bicyclic compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein the ring B is benzene, pyridine, pyrimidine, thiophene, piperidine, morpholine, cyclohexane, cyclohexene, pyrrolidine or pyrrole.
[10] The bicyclic compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [9], wherein R ¹ is a group selected from the following formulae.

［式中、Ｒ^７は（１）水素原子、（２）置換されていてもよいアリールもしくは置換されていてもよい複素環式基で置換されていてもよいアルキル、（３）ヒドロキシアルキル、（４）アルコキシアルキルまたは（５）置換されていてもよい複素環式基を表す。
Ｒ^８およびＲ^９は同一または異なって、それぞれ（１）水素原子、（２）置換されていてもよいアリールもしくは置換されていてもよい複素環式基で置換されていてもよいアルキル、（３）ヒドロキシアルキル、（４）アルコキシアルキル、（５）アルコキシカルボニル、（６）置換されていてもよい複素環式基または（７）置換されていてもよいアリールを表すか、または（８）Ｒ^８およびＲ^９が一緒になって、それらが結合している原子と共に、置換されていてもよい複素環を形成してもよい。
Ｒ^１０およびＲ^１１は、同一または異なって、それぞれ（１）水素原子、（２）置換されていてもよいアリールもしくは置換されていてもよい複素環式基で置換されていてもよいアルキル、（３）ヒドロキシアルキル、（４）アルコキシアルキル、（５）アルカノイル、（６）アルキルスルホニル、（７）アルコキシカルボニルまたは（８）置換されていてもよい複素環式基を表す。］
［１２］ Ｒ^５の置換アルキルの置換基が下式から選ばれる１〜３個の基である［１１］記載の二環化合物またはその薬学上許容される塩。

［式中、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０およびＲ^１１は前記と同義である。］ [11] R ⁵ is a hydrogen atom, an optionally substituted alkyl (the substituent of the substituted alkyl is 1 to 3 groups selected from the following formula), an optionally substituted cycloalkyl (the cyclo Alkyl may be condensed with aryl), optionally substituted aryl, or optionally substituted heterocyclic group, wherein R ⁶ is substituted with a hydrogen atom, alkoxycarbonyl, or a hydroxyl group or alkoxy. The bicyclic ring according to [10], wherein R ⁵ and R ⁶ may be taken together to form an optionally substituted heterocycle together with the atoms to which they are attached. A compound or a pharmaceutically acceptable salt thereof.

[Wherein R ⁷ is (1) a hydrogen atom, (2) an aryl which may be substituted or an alkyl which may be substituted with an optionally substituted heterocyclic group, (3) a hydroxyalkyl, ( 4) represents an alkoxyalkyl or (5) an optionally substituted heterocyclic group.
R ⁸ and R ⁹ are the same or different and are each (1) a hydrogen atom, (2) an optionally substituted aryl or an optionally substituted heterocyclic group, (3 Represents a) hydroxyalkyl, (4) alkoxyalkyl, (5) alkoxycarbonyl, (6) an optionally substituted heterocyclic group or (7) an optionally substituted aryl, or (8) R ⁸ And R ⁹ together can form an optionally substituted heterocycle with the atoms to which they are attached.
R ¹⁰ and R ¹¹ are the same or different and are each (1) a hydrogen atom, (2) an optionally substituted aryl or an optionally substituted heterocyclic group, ( 3) represents hydroxyalkyl, (4) alkoxyalkyl, (5) alkanoyl, (6) alkylsulfonyl, (7) alkoxycarbonyl, or (8) an optionally substituted heterocyclic group. ]
[12] The bicyclic compound or a pharmaceutically acceptable salt thereof according to [11], wherein the substituted alkyl substituent of R ⁵ is 1 to 3 groups selected from the following formula:

[Wherein, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ have the same meanings as described above. ]

［式中、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０およびＲ^１１は前記と同義である。］
［１４］ 環Ｑがピリミジンであり、Ｒ^１が下式から選ばれる基である［１］〜［１３］のいずれか記載の二環化合物またはその薬学上許容される塩。

［式中、Ｒ^５およびＲ^６は［１］における意義と同義であり、Ｒ^５１は下式から選ばれる１〜３個の基で置換されたアルキルを表す。

［式中、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０およびＲ^１１は［１１］における意義と同義である。］
［１５］ ｍおよびｎが同一または異なって、それぞれ０または１である［１］〜［１４］のいずれか記載の二環化合物またはその薬学上許容される塩。
［１６］ Ｒ^２およびＲ^３が同一または異なって、それぞれシアノ、水酸基、アルコキシ、ハロゲンまたは置換されていてもよいアルキルである［１］〜［１５］のいずれか記載の二環化合物またはその薬学上許容される塩。 [13] The bicyclic compound or a pharmaceutically acceptable salt thereof according to [11], wherein the substituted alkyl substituent of R ⁵ is 1 to 3 groups selected from the following formulae.

[Wherein, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ have the same meanings as described above. ]
[14] The bicyclic compound or the pharmaceutically acceptable salt thereof according to any one of [1] to [13], wherein ring Q is pyrimidine and R ¹ is a group selected from the following formulae.

[Wherein, R ⁵ and R ⁶ have the same meanings as in [1], and R ⁵¹ represents alkyl substituted with 1 to 3 groups selected from the following formula.

[Wherein, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ have the same meaning as in [11]. ]
[15] The bicyclic compound or the pharmaceutically acceptable salt thereof according to any one of [1] to [14], wherein m and n are the same or different and each is 0 or 1.
[16] The bicyclic compound according to any one of [1] to [15], wherein R ² and R ³ are the same or different and each is cyano, hydroxyl group, alkoxy, halogen, or optionally substituted alkyl, or a pharmacy thereof Top acceptable salt.

であり、環Ｂが

でも

でもない［１］〜［１７］のいずれか記載の二環化合物またはその薬学上許容される塩。 [17] The bicyclic compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [16], wherein R ⁴ is a hydrogen atom, halogen, or optionally substituted alkyl.
[18] A medicament comprising the bicyclic compound according to any one of [1] to [17] or a pharmaceutically acceptable salt thereof.
[19] The medicament according to [18], which is a high conductance calcium-sensitive K channel opener.
[20] The medicament according to [18], which is an agent for preventing and / or treating frequent urination, urinary incontinence, asthma or chronic obstructive pulmonary disease.
[21] The medicament according to [20], which is a preventive and / or therapeutic agent for frequent urination, urinary incontinence or chronic obstructive pulmonary disease.
[22] Ring Q is

And ring B is

But

However, the bicyclic compound or pharmaceutically acceptable salt thereof according to any one of [1] to [17].

Hereinafter, groups represented by symbols in this specification will be described.
The alkyl in “alkyl”, “alkoxyalkyl” and “alkylsulfonyl” includes, for example, C _1-6 , preferably C _1-4 linear or branched alkyl, specifically, methyl, Examples include ethyl, propyl, isopropyl, butyl, isobutyl, 1-methylpropyl, pentyl, hexyl and the like.
“Hydroxyalkyl” includes, for example, C _1-6 , preferably C _1-4 linear or branched alkyl substituted with a hydroxyl group, specifically hydroxymethyl, 2-hydroxyethyl , 3-hydroxypropyl, 2-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl and the like.
The alkoxy in “alkoxy”, “alkoxyalkyl” and “alkoxycarbonyl” includes, for example, C _1-6 , preferably C _1-4 linear or branched alkoxy, specifically, methoxy, Examples include ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy and the like.
“Halogen” includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
Examples of the “alkanoyl” include C _1-6 , preferably C _1-4 linear or branched alkanoyl, and specifically include formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl and the like. It is done.

“Haloalkyl” includes, for example, C _1-6 , preferably C _1-4 linear or branched alkyl substituted with halogen, specifically chloromethyl, dichloromethyl, fluoromethyl, Examples include difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3-chloropropyl, 3-fluoropropyl, 4-chlorobutyl, 4-fluorobutyl and the like.
“Haloalkoxy” includes, for example, C _1-6 , preferably C _1-4 linear or branched alkoxy substituted with halogen, specifically chloromethoxy, dichloromethoxy, fluoromethoxy. , Difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, 3-chloropropoxy, 3-fluoropropoxy, 4-chlorobutoxy, 4-fluorobutoxy and the like.
“Alkenyl” includes, for example, C _2-6 , preferably C _2-4 linear or branched alkenyl, specifically vinyl, allyl, 1-methyl-2-propenyl, 3-butenyl. , 2-pentenyl, 3-hexenyl and the like.

The aryl in “aryl” and “aryloxy” includes, for example, C _6-14 , preferably C _6-10 monocyclic, bicyclic or tricyclic aryl, specifically phenyl, Naphthyl, phenanthryl, anthryl and the like can be mentioned, and phenyl and naphthyl are particularly preferable.
The “aralkyl” is, for example, C _1-6 , preferably C _1-4 linear or branched alkyl substituted with aryl, specifically, benzyl, 2-phenylethyl, Examples thereof include 1-phenylethyl and 3-phenylpropyl, and among them, benzyl is particularly preferable.

Examples of cycloalkyl in “cycloalkyl” and “cycloalkyloxy” include C _3-8 , preferably C _3-6 cycloalkyl, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. . The “cycloalkyl condensed with aryl” includes cycloalkyl in which C _3-8 , preferably C _3-6 cycloalkyl is condensed with aryl (preferably phenyl), specifically indanyl, tetralinyl and the like. Can be mentioned. The “cycloalkyl” and “cycloalkyl condensed with aryl” may be substituted, and examples of the substituent include a hydroxyl group, halogen, C _1-4 alkyl, C _1-4 alkoxy, and the like. Can be mentioned. Specific examples of the substituted aryl-fused cycloalkyl include 2-hydroxyindan-1-yl.
Examples of the “cycloalkane” include C _3-8 , preferably C _3-6 cycloalkane, and specifically include cyclopropane, cyclobutane, cyclopentane, cyclohexane and the like.
Examples of “cycloalkene” include C _3-8 , preferably C _3-6 cycloalkene, and specific examples include cyclopropene, cyclobutene, cyclopentene, and cyclohexene.

As the “heterocyclic group”, for example, it contains 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and a part or all of 5 to 10 members as a whole may be saturated. Monocyclic or bicyclic heterocyclic groups may be mentioned. In the case of a monocyclic or bicyclic heterocyclic group which may be partially or fully saturated, the heterocyclic group may be substituted with oxo.
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 preferred examples. Specific examples include oxazolyl, pyrrolidinyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, tetrazolyl, thiazolyl, piperidyl, piperazinyl, morpholyl, tetrahydropyranyl, tetrahydrofuryl, imidazolidinyl, oxazolidinyl and the like.
The bicyclic heterocyclic group includes a bicyclic heterocyclic group obtained by condensing two identical or different monocyclic heterocyclic groups or a condensed benzene ring with the monocyclic heterocyclic group. Bicyclic heterocyclic groups are preferred examples. Specific examples include dihydroindolyl, tetrahydroquinolyl and the like.

As long as G and ring A can be substituted in ring Q, the nitrogen atom on ring Q may be present at any position, and is preferably as shown below.

  The “heteroaromatic ring” in ring A is, for example, a monocyclic or bicyclic heterocycle having 5 to 10 members as a whole, containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. An aromatic ring is mentioned, Preferably a 5 or 6 membered aromatic heterocyclic ring is mentioned. Specific examples include thiophene, furan, pyrrole, pyridine, pyrimidine, pyrazine, benzo [b] thiophene, oxazole, isoxazole, thiazole, benzo [b] furan, and quinoline, preferably pyridine, pyrimidine, and thiophene. Particularly preferred is pyridine.

The “heterocycle” in ring B includes, for example, 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom. Good monocyclic or bicyclic heterocycles are preferable, preferably 5-membered heterocycles and 6-membered heterocycles not having two or more nitrogen atoms, particularly preferably 6-membered aromatic heterocycles. . Specifically, thiophene, furan, pyrrole, pyridine, pyrimidine, pyrazine, piperidine, piperazine, pyrrolidine, tetrahydropyran, benzo [b] thiophene, oxazole, isoxazole, thiazole, benzo [b] furan, 2,3-dihydroindole 2,3-dihydrobenzo [b] furan, 1,4-benzodioxane, quinoline, pyrrolidine, morpholine, thiomorpholine, homopiperidine and 1,5-benzodioxepin, preferably pyridine, pyrimidine, thiophene Particularly preferred is pyridine in which the ring Q may be in any position, and preferred positions of the ring Q include an ortho position and a meta position with respect to the nitrogen atom.
“R ⁵ and R ⁶ together to form a heterocycle with the atoms to which they are attached” and “R ⁸ and R ⁹ together to form a heterocycle with the atoms to which they are attached. "Includes a saturated 5- to 8-membered monocyclic heterocycle containing 1 or 2 heteroatoms (nitrogen, oxygen, sulfur, etc.), specifically, pyrrolidine, piperidine, Examples include piperazine, morpholine, thiomorpholine, and homopiperidine.

  The heterocyclic ring may be substituted, and the substituents are (1) (i) halogen, (ii) hydroxyl group, (iii) haloalkoxy, (iv) halogen, alkyl, phenyl, etc. May be alkoxy, (v) carbamoyl optionally substituted with alkyl, (vi) cyano, (vii) alkoxycarbonyl, (viii) carboxy, (ix) alkyl, amino optionally substituted with phenyl, (x) alkoxy, hydroxyl group and the like, and (xi) alkyl optionally substituted with a group selected from an imino optionally substituted with a heterocyclic group, (2) cyano, (3) halogen, (4 ) Amino optionally substituted by alkyl, alkanoyl, cycloalkyl, etc., (5) alkenyl, (6) imino optionally substituted by alkoxy, hydroxyl group, etc., (7) alkyl, Carbamoyl which may be substituted by such aralkyl, (8) alkoxycarbonyl, (9) a heterocyclic group, and (10) oxo. Preferred examples of the substituent include alkyl optionally substituted with a hydroxyl group, and a 5- or 6-membered monocyclic heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Particularly preferred are hydroxymethyl and pyrimidyl.

Preferred examples of the “heterocyclic group” in R ⁵ to R ^{11 and} the “heterocyclic group” in the substituent of the substituted alkyl in R ⁵ to R ¹¹ include pyridyl, pyrazolyl, pyrazyl, pyrimidinyl, tetrazolyl, tetrahydropyranyl , Thiazolyl, piperidyl, morpholinyl, oxazolyl, piperazinyl and the like. Examples of the substituent of the heterocyclic group include alkyl, haloalkyl, hydroxyl group, and alkoxy, preferably methyl, trifluoromethyl, hydroxyl group, and methoxy. More specific examples of the heterocyclic group for R ⁷ include pyrimidyl and tetrahydropyranyl. More specific examples of the heterocyclic group for R ¹⁰ and R ¹¹ include pyridyl.

［式中、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０およびＲ^１１は前記と同義である。］
これら基のうち、好ましくは

等が挙げられ、さらに好ましくは、

等が挙げられる。
Ｒ^５またはＲ^６における置換アルキルの具体例には下式から選ばれる基が含まれる。

［式中、Ｒ^１２、Ｒ^１３、Ｒ^１４およびＲ^１５はそれぞれ同一または異なってもよく、それぞれは水素又はアルキル等を示す。］ Examples of the substituent of the substituted alkyl in R ⁵ and R ⁶ include a group selected from the following formulas, and the same or different 1 to 3 groups can be substituted with alkyl.

[Wherein, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ have the same meanings as described above. ]
Of these groups, preferably

And more preferably,

Etc.
Specific examples of the substituted alkyl in R ⁵ or R ⁶ include a group selected from the following formulae.

[Wherein R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ may be the same or different, and each represents hydrogen, alkyl or the like. ]

Examples of the substituent of substituted aryl in R ^{5 to} R ¹¹ include halogen, hydroxyl group, alkoxy, alkyl, haloalkyl and the like.
Examples of the substituent of the substituted carbamoyl in R ² and R ³ include alkyl optionally substituted by halogen, hydroxyl group, alkoxy, amino, mono or dialkylamino, and the like.
The alkyl of “amino optionally substituted by 1 or 2 substituents each selected from alkyl, aralkyl and cycloalkyl” in G is, for example, a C _1-6 linear or branched, preferably C 1 _1-4 branched chain alkyl may be mentioned, and specific examples include isopropyl, isobutyl, 1-methylpropyl, isoamyl and the like. More preferred is isopropyl.
Examples of the substituent of substituted amino in R ² , R ³ and R ⁴ include alkyl optionally substituted by halogen, hydroxyl group, alkoxy, amino, mono or dialkylamino, and the like.

Examples of the substituent of the substituted alkyl in R ² , R ³ and R ⁴ include a hydroxyl group, alkoxy, halogen and the like. Specific examples of the substituted alkyl include hydroxymethyl, 2-hydroxyethyl, methoxymethyl, trifluoromethyl. Etc.
Specific examples of R ¹ to R ¹³ , G, ring A and ring B include groups corresponding to the compounds described in the examples.

Examples of the pharmaceutically acceptable salt of the bicyclic compound (1) of the present invention include inorganic acid salts such as hydrochloride, sulfate, phosphate and hydrobromide, acetate, fumarate and oxalic acid. Examples thereof include organic acid salts such as salts, citrates, methanesulfonates, benzenesulfonates, tosylates and maleates. 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 bicyclic compound (1) or a pharmacologically acceptable salt thereof includes any of its internal salts and solvates such as hydrates thereof.

  When an asymmetric carbon or the like is present in the bicyclic compound (1), optical isomers exist, but the bicyclic compound (1) includes any of these isomers and mixtures thereof. Furthermore, when the bicyclic compound (1) has a double bond or cycloalkanediyl, cis- and trans-isomers exist, and when the bicyclic compound (1) has an unsaturated bond such as carbonyl, tautomerism The bicyclic compound (1) includes any isomers and mixtures thereof.

［式中、Ｚ^１は塩素原子、臭素原子、アルキルスルホニルオキシまたはトリフルオロメタンスルホニルオキシを表し、Ｚ²は保護基を有してもよい水酸基またはアミノ基を表し、Ｌは−Ｂ(ＯＨ)_２、−Ｂ(ＯＲ)_２または−Ｓｎ(Ｒ)_３を表し、Ｒはアルキルを表し、その他の記号は前記と同義である。］ The bicyclic compound (1) can be produced by the following method.
Manufacturing method 1

[Wherein, Z ¹ represents a chlorine atom, a bromine atom, alkylsulfonyloxy or trifluoromethanesulfonyloxy, Z ² represents a hydroxyl group or an amino group which may have a protecting group, and L represents —B (OH) _2. , -B (OR) ₂ or -Sn (R) ₃ , R represents alkyl, and the other symbols are as defined above. ]

This production method can be carried out with reference to Bioorg. Med. Chem. Lett., 1998, 8, 2777 and WO 98/03484.
Compound (4) can be synthesized by reacting compound (2) with compound (3) in the presence of a palladium catalyst. Examples of the palladium catalyst include zero-valent or divalent palladium catalysts such as tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, and palladium (II) acetate. When reacting with the compound (3) in which L is —B (OH) ₂ or —B (OR) _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. Any solvent may be used as long as it does not adversely influence the reaction. For example, dimethoxyethane (DME), tetrahydrofuran (THF), dioxane, dimethylformamide (DMF), dimethylacetamide (DMA), toluene, benzene or these. Of the mixture. The reaction temperature is usually 60 to 150 ° C, preferably 80 to 120 ° C, and the reaction time is usually 1 to 24 hours.

Z ² of compound (4) is converted to Z ¹ according to a conventional method, and subsequently reacted in the same manner in the presence of compound (5) and a palladium catalyst, whereby compound (1a) can be produced.
In addition, compound (2) is reacted with compound (5) first, and in the same manner, even if Z ² is reacted with compound (3) after conversion, two kinds of halogens having different reactivity are introduced as in Example 20. The bicyclic compound (1a) can also be preferably produced using the prepared compound.

［式中、記号は前記と同義である。］
本製法は、Org. Lett., 2001, 3, 835を参考にして実施することができる。なお、ここではピリジンの窒素原子が上記化学式の位置であるピリジン(1c)および(1d)で説明するが、環Ａと環Ｂの導入順序を変えることで、その位置異性体の二環化合物も同様に製造することができる。 Manufacturing method 2

[Wherein the symbols are as defined above. ]
This production method can be carried out with reference to Org. Lett., 2001, 3, 835. Here, pyridine (1c) and (1d), in which the nitrogen atom of pyridine is the position of the above chemical formula, will be described, but by changing the introduction order of ring A and ring B, the bicyclic compound of the position isomer can also be It can be manufactured similarly.

  The compound (6) or compound (9) is treated with an organolithium reagent (lithium diisopropylamide, etc.) to give a pyridine lithium salt, followed by the action of zinc chloride to give a pyridine zinc salt. Compound (8) or (10) can be produced by reacting with compound (7) in the presence of. The reaction solvent for conversion to pyridine lithium salt and pyridine zinc salt may be any solvent as long as it does not adversely influence the reaction, and examples thereof include dimethoxyethane, THF, dioxane, toluene, benzene, and mixtures thereof. The reaction temperature is usually −110 to −50 ° C. Production of compound (1c) or (1d) from compound (8) or (10) can be carried out in the same manner as in Production Method 1.

［式中、各記号は前記と同義である。］ Manufacturing method 3
The compound (1e) represented by the following formula can be produced, for example, in the same manner as in Production Method 1, and can also be produced as follows.

[Wherein the symbols are as defined above. ]

Pyridine (1e) substituted with R ⁴ at the β-position can be produced with reference to Org. Lett., 2000, 15, p.2339, and the starting compounds (11) and (12) Can be produced with reference to J. Org. Chem., 2000, 65, p. 8415 and J. Org. Chem., 2000, 65, p. 4571, respectively. Here, pyridine (1e) in which the nitrogen atom of pyridine is the position of the above chemical formula will be described, but the same can be applied to pyridine in which ring A is substituted at the 2-position and ring B is substituted at the 3-position. .

  The ketone (11) is treated with an alkali alkoxide such as tert-butoxy potassium in an ether such as THF, diethyl ether, ethylene glycol dimethyl ether or dioxane at a temperature of 0 ° C. to 40 ° C. Then, the obtained reaction solution is dropped into a mixed acid of acetic acid and trifluoroacetic acid, and finally, the compound (1e) is produced by heating and ring closure with ammonia such as aqueous ammonia at a temperature from 50 ° C. to the boiling point of the solvent. can do.

[式中、Ｚ^３はＺｎ-ＺまたはＭｇ-Ｚを表し、Ｚは塩素原子、臭素原子またはヨウ素原子を表し、Ｐは水酸基の保護基(ベンジル基など)を表し、その他の記号は前記と同義である。] Manufacturing method 4

[Wherein Z ³ represents Zn-Z or Mg-Z, Z represents a chlorine atom, a bromine atom or an iodine atom, P represents a protecting group for a hydroxyl group (such as a benzyl group), and other symbols are as defined above. It is synonymous. ]

Compound (15) can be produced from compound (13) with reference to J. Org. Chem., 62, 503 (1997), and then compound (15) is obtained from compound (15) in the same manner as in Production Method 1. Can be manufactured.
Here, pyridine in which the nitrogen atom of pyridine is the position of the above chemical formula will be described, but a pyridine derivative in which ring A is substituted at the 3-position and ring B is substituted at the 4-position can be similarly produced.

[式中、Ｇ¹は置換されてもよいアミノを表し、その他の記号は前記と同義である。] Manufacturing method 5

[Wherein G ¹ represents an optionally substituted amino, and other symbols are as defined above. ]

In Formula 1, a compound in which G ¹ is unsubstituted amino can be produced according to Production Method 1. In addition, compound (1f) in which G ¹ is substituted amino can be produced by reacting compound (16), which can be produced according to Production Method 1, with amine G ¹ -H.

When the substitution position of Z ¹ is located next to N, it can be produced with reference to Example 83. Any solvent may be used as long as it does not adversely influence the reaction, and examples thereof include dichloromethane, chloroform, THF, dioxane, DMF, DMA, toluene, and mixtures thereof. The reaction temperature is usually 0 ° C. to 150 ° C., preferably room temperature to the solvent boiling point used. The reaction time is usually 1 hour to 3 days. In addition, you may make it react in base presence suitably. Examples of the base include an inorganic base such as an alkali metal carbonate and an organic base such as triethylamine.
When the substitution position of Z ¹ is not adjacent to N, palladium is referred to Acc. Chem. Res. 31 (1998), 805 or Angew. Chem., Int. Ed. 37 (1998), 2046. It can be produced by an amination reaction using a catalyst.

［式中、各記号は前記と同義である。］ Manufacturing method 6
Carboxylic acid (1i) can be produced as follows from compound (1g) contained in compound (1) that can be produced by referring to the above production methods and examples.

[Wherein the symbols are as defined above. ]

  The compound (1 g) is reacted with a cyanating agent (sodium cyanide, cuprous cyanide, etc.) in a solvent (acetonitrile, dimethyl sulfoxide, DMF, a mixture thereof, etc.) at room temperature to 100 ° C. for 1-24 hours. (1h) can be synthesized. In addition, a cyanating agent such as zinc cyanide or potassium cyanide can be reacted in the presence of a tetrakis (triphenylphosphine) palladium catalyst or the like.

Nitrile (1h) in a solvent (water, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, ethylene glycol, diethylene glycol, mixtures thereof, etc.), acid (hydrochloric acid, sulfuric acid, etc.) or base (sodium hydroxide, potassium hydroxide) Etc.) can be used to produce carboxylic acid (1i). The reaction temperature is usually −20 to 150 ° C., and the reaction time is usually 30 minutes to 48 hours.
Compound (1h) can also be produced by the same method as Production Method 1.
The nitrile (1h) is hydrolyzed with an alkali hydroxide (sodium hydroxide, potassium hydroxide, etc.) in a solvent (water, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, ethylene glycol, diethylene glycol, a mixture thereof, etc.). By decomposing, compound (1j) -1 in which R ⁵ and R ⁶ are hydrogen atoms can also be produced directly.

［式中、Ａｒは化合物(1i)の残基を表し、その他の記号は前記と同義である。］ Manufacturing method 7
The following bicyclic compounds (1j) to (1s) can be produced by reacting the carboxylic acid (1i) with a corresponding compound according to a conventional method.
Specifically, for example, it can be carried out as follows.

[In the formula, Ar represents a residue of the compound (1i), and other symbols are as defined above. ]

The compounds (1j), (1k), (1m) and (1n) contained in the bicyclic compound (1) can be produced by any of the following methods.
(A) Carboxylic acid (1i) is converted to an acid halide by treatment with a halogenating agent (thionyl chloride, etc.), and each reagent and base (sodium hydrogen carbonate, potassium carbonate, triethylamine, pyridine) described in the reaction formula Etc.), the compounds (1j), (1k), (1m) and (1n) can be produced by reacting at −78 ° C. to room temperature for 30 minutes to 24 hours.
(B) Condensing agent (1,3-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, carbonyldiimidazole, cyanoline in carboxylic acid (1i) in a solvent (DMF, THF, dioxane, etc.) Compounds (1j), (1k), (1m) and (1n) can be produced by condensation with the respective reagents described in the reaction formula in the presence of diethyl acid or the like. The reaction temperature is usually from 0 ° C. to 100 ° C., and the reaction time is usually from 30 minutes to 24 hours. In addition, in reaction using a condensing agent, it can also carry out in presence of 1-hydroxy benztriazole, N-hydroxysuccinimide, etc. as needed.
(C) Convert the carboxylic acid (1i) to a mixed acid anhydride with a monoalkyl ester carbonate such as methyl carbonate or isobutyl carbonate, or a mixed acid anhydride with an organic acid such as pivalic acid or isovaleric acid. In a solvent (THF, toluene, nitrobenzene, mixed solvent thereof, etc.), in the presence of a base (triethylamine, pyridine, etc.), -20 ° C. to room temperature for 1 to 24 hours with each reagent described in the reaction formula Thus, compounds (1j), (1k), (1m) and (1n) can be produced.

［式中、各記号は前記と同義である。］

[Wherein the symbols are as defined above. ]

  The compound (1q) contained in the bicyclic compound (1) can be produced by the following method. To aldehyde (1p) that can be derived from carboxylic acid (1i) according to a conventional method, Grignard reagent in a solvent (THF, diethyl ether, ethylene glycol dimethyl ether, benzene, toluene, xylene, dioxane, etc.) at −20 to 100 ° C. Alcohol (17) is produced by reacting for 30 minutes to 24 hours. Subsequently, the compound (1q) can be produced by reacting the alcohol (17) with an oxidizing agent at −78 to 100 ° C. for 30 minutes to 24 hours. As oxidizing agents, chromic acid-sulfuric acid, chromium oxide (VI) -sulfuric acid-acetone (Jones reagent), chromium oxide (VI) -pyridine complex (Collins reagent), dichromate (sodium dichromate, dichromic acid) Potassium etc.)-Sulfuric acid, pyridinium chlorochromate (PCC), manganese dioxide, dimethyl sulfoxide-electrophilic activator (dicyclohexylcarbodiimide, acetic anhydride, phosphorus pentoxide, sulfur trioxide-pyridine complex, trifluoroacetic anhydride, oxalyl chloride Halogen), sodium hypochlorite, potassium hypochlorite, sodium bromate and the like.

［式中、各記号は前記と同義である。］

[Wherein the symbols are as defined above. ]

  The compounds (1r) and (1s) contained in the bicyclic compound (1) can be produced by the following method. Compound (1j) -1 contained in compound (1j) is converted to the acid halide described in the above reaction formula in the presence of a base (sodium hydrogen carbonate, potassium carbonate, triethylamine, pyridine, etc.) at -20 ° C. to room temperature for 30 minutes to 24 minutes. By reacting for a period of time, compounds (1r) and (1s) can be produced.

  In the above method, when the bicyclic compound, intermediate compound, raw material compound or the like of the present invention has a functional group (hydroxyl group, amino, carboxy, etc.), the reaction is carried out by protecting with a protective group usually used in organic synthetic chemistry. After the reaction, the target compound can be obtained by removing the protecting group. Examples of the hydroxyl protecting group include tetrahydropyranyl, trimethylsilyl, and benzyl. Examples of the amino protecting group include tert-butoxycarbonyl and benzyloxycarbonyl. Examples of the carboxyl protecting group include Examples thereof include alkyl such as methyl and ethyl, benzyl and the like.

In addition, after the bicyclic compound and intermediate compound of the present invention are produced according to the above method, the functional group can be converted or modified according to a conventional method. Specifically, the following methods are mentioned.
(1) Modification of amino After protecting amino as necessary, (i) reaction with alkyl halide in the presence of a base (sodium hydride, triethylamine, sodium carbonate, potassium carbonate, etc.) or (ii ) Alcohol or the like can be derived into mono- or dialkylamino by subjecting it to Mitsunobu reaction using dialkylazodicarboxylate and triphenylphosphine, and deprotecting as necessary.
(2) Conversion of amino to amide Amino can be reacted with an acyl halide to convert to the corresponding amide.
(3) Conversion of carboxy to carbamoyl The amine can be reacted with carboxy to convert it to the corresponding carbamoyl.

(4) Hydrogenation of CC double bond CC double bond can be converted to the corresponding single bond by catalytic hydrogen reduction using a transition metal (platinum, palladium, rhodium, ruthenium, nickel, etc.) catalyst. it can.
(5) Hydrolysis of ester The ester can be converted to the corresponding carboxy by hydrolysis with an alkali (sodium hydroxide, potassium hydroxide, etc.).
(6) Conversion of carbamoyl to nitrile Carbamoyl can be converted to the corresponding nitrile by reacting with trifluoroacetic anhydride.

(7) Conversion of carboxy to 4,5-dihydrooxazol-2-yl Carboxy is reacted with 2-haloethylamine in the presence of a condensing agent to give the corresponding 4,5-dihydrooxazol-2-yl. Can be converted.
(8) Halogenation and alkylation of hydroxyl group The hydroxyl group can be converted into a corresponding halide by reacting with a halogenating agent. Alternatively, the halide can be converted to the corresponding alkoxy by reacting with an alcohol.
(9) Reduction of ester The ester can be converted to the corresponding hydroxyl group by reducing with a reducing agent (metal reducing reagents such as lithium aluminum hydride, sodium borohydride, lithium borohydride, diborane, etc.). it can.

(10) Oxidation of hydroxyl group Oxidized hydroxyl group can be converted into aldehyde, ketone, or carboxy.
(11) Amination of ketone or aldehyde A mono- or di-substituted aminomethyl is obtained by performing a reductive amination reaction of a ketone or aldehyde in the presence of an amine and a reducing agent (sodium borohydride, sodium cyanoborohydride, etc.). Can be converted to
(12) Conversion of ketone or aldehyde to double bond A ketone or aldehyde can be converted to a double bond by subjecting it to a Wittig reaction.
(13) Conversion of sulfonamide to salt By treating sulfonamide with sodium hydroxide, potassium hydroxide, etc. in alcohol (methanol, ethanol, etc.), the corresponding sulfonamide salt (sodium salt, potassium salt, etc.) Can be converted to

(14) Conversion of aldehyde to oxime, etc. By reacting aldehyde with hydroxylamine or O-alkylhydroxylamine in alcohol (methanol, ethanol, etc.) in the presence of a base (sodium hydrogencarbonate, etc.), the corresponding oxime, etc. Can be converted to
(15) Conversion of halide to nitrile The halide can be converted to the corresponding nitrile by reacting with a cyanating agent.
(16) Amination of halide
It can be converted to the corresponding amine by reacting a halide according to the method described in Tetrahedron, 2002, p.2041.
(17) Conversion of Carboxylic Acid to Carbamoyl and Hydroxymethyl After the carboxylic acid is condensed with N-hydroxysuccinimide to form a succinimide ester, it can be converted to the corresponding carbamoyl by reacting with an amine. Further, the succinimide ester can be converted to the corresponding hydroxymethyl by treating with a reducing agent (such as sodium borohydride).

(18) Dehalogenation A halogen-substituted aromatic ring can be dehalogenated by a catalytic hydrogenation reaction. Further, it can be dehalogenated by reacting with potassium methoxide in the presence of a palladium catalyst according to the method described in Organometallics 2001, 20, 3607 and Example 4.
(19) Conversion of aryl halide According to production method 5, nucleophile (primary amine, secondary amine, alcohol, phenol, etc.) is reacted with aryl halide or heteroaryl halide to give the corresponding amino, Can be converted to alkoxy or aryloxy.
(20) Alkylation of heteroaryl halide
Chem. Commun., 1996, 2719, J. Chem. Soc., Chem. Commun., 1988, 638, or Tetrahedron Lett., 37, 1309 (1996) can be used to convert halogen to alkyl. it can.

  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 bicyclic compound of the present invention can be converted into a pharmaceutically acceptable salt according to a conventional method, followed by recrystallization and the like.

  The bicyclic compound (1) or a pharmacologically acceptable salt thereof can be formulated into a pharmaceutical composition comprising a therapeutically effective amount of the compound and a pharmacologically acceptable carrier. As pharmacologically acceptable carriers, diluents, binders (syrup, gum arabic, gelatin, sorbit, tragacanth, polyvinylpyrrolidone, etc.), excipients (lactose, sucrose, corn starch, potassium phosphate, sorbit, Glycine, etc.), lubricants (magnesium stearate, talc, polyethylene glycol, silica, etc.), disintegrating agents (potato starch, etc.) and wetting agents (sodium lauryl sulfate).

  The bicyclic compound (1) or a pharmaceutically acceptable salt thereof can be administered orally or parenterally and can be used as an appropriate pharmaceutical preparation. Examples of suitable pharmaceutical preparations for oral administration include solid preparations such as tablets, granules, capsules and powders, solution preparations, suspension preparations and emulsion preparations. Appropriate pharmaceutical preparations for parenteral administration include suppositories, injections or infusion preparations using distilled water for injection, physiological saline or aqueous glucose solution, or inhalants.

  The dose of the bicyclic compound (1) or a pharmacologically acceptable salt thereof varies depending on the administration method, patient age, body weight, condition or type / degree of disease, but is usually about 0.1 to 50 per day. mg / kg, more preferably about 0.1-30 mg / kg.

  The bicyclic 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 membrane electrical potential of the cell. 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, urinary stones and associated pain, frequent urination, urinary incontinence, nocturnal enuresis, asthma, chronic obstructive pulmonary disease (COPD), cough associated with asthma or COPD, stroke, It is useful as an agent for preventing, reducing and / or treating cerebral ischemia, traumatic brain injury and the like.

  EXAMPLES Hereinafter, although an Example and a reference example demonstrate this invention in detail, this invention is not limited at all by these.

(1) 化合物Ａ(12.0 g, 41.4 mmol)をＴＨＦ(200 ml)に溶解し、アルゴン気流下０℃でtert-ブトキシカリウム(6.09 g, 54.3 mmol)のＴＨＦ(50 ml)溶液を３０分間かけて滴下した。滴下後、室温で１時間撹拌した後、化合物Ｂ(12.7 g, 41.4 mmol)を一気に加えた。４５分間撹拌後、反応液をアルゴン気流下、カニューレを通してトリフルオロ酢酸(3.19 ml, 41.4 mmol)と酢酸(20.7 ml, 362 mmol)の混合液中に室温で滴下する。室温で１時間撹拌後、28%アンモニア水溶液(250 ml)を加え、一晩加熱還流する。反応液を室温まで戻した後、約半分量まで減圧濃縮し、酢酸エチル(400 ml)にて抽出後、抽出液を水で洗浄し、無水硫酸マグネシウムで乾燥し濃縮した。残渣をＮＨ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＝9:1→1:1）で精製することにより、化合物Ｃ(12.42 g, 88%)を固体として得た。
MS: 359/361[M+H]⁺, APCI(MeOH)
(2) 化合物Ｃ(4.00 g, 11.1 mmol)、シアン化亜鉛(1.306 g, 11.1 mmol)、テトラキス（トリフェニルホスフィン）パラジウム(1.285 g, 1.1 mmol)のＤＭＦ(50 ml)懸濁液を８０℃に加熱して１時間撹拌した。懸濁液を酢酸エチル／水に注ぎ、有機層を飽和食塩水で洗浄後、芒硝で乾燥し、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＝6:1）で精製し、化合物Ｄ(2.79 g, 82%)を粉末として得た。
MS: 306/308[M+H]⁺, APCI(MeOH)
(3) 化合物Ｄ(100 mg, 0.327 mmol)のtert-ブタノール溶液(5.0 ml)に、粉末水酸化カリウム(165 mg, 2.94 mmol)を加え、攪拌しながら２時間加熱還流した。反応液を冷却後、飽和食塩水を加え、酢酸エチルで抽出した。有機層を芒硝で乾燥し、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（クロロホルム:メタノール＝100:0→90:10）で精製し、化合物Ｅ(102 mg, 96%)を固体として得た。
MS: 324/326[M+H]⁺, APCI(MeOH) Example 1

(1) Compound A (12.0 g, 41.4 mmol) was dissolved in THF (200 ml), and a solution of tert-butoxypotassium (6.09 g, 54.3 mmol) in THF (50 ml) was added at 0 ° C under an argon stream for 30 minutes. And dripped. After dropping, the mixture was stirred at room temperature for 1 hour, and then Compound B (12.7 g, 41.4 mmol) was added all at once. After stirring for 45 minutes, the reaction solution is added dropwise at room temperature to a mixture of trifluoroacetic acid (3.19 ml, 41.4 mmol) and acetic acid (20.7 ml, 362 mmol) through a cannula under a stream of argon. After stirring at room temperature for 1 hour, 28% aqueous ammonia solution (250 ml) is added and heated to reflux overnight. After returning the reaction solution to room temperature, the reaction solution was concentrated to about half volume under reduced pressure and extracted with ethyl acetate (400 ml). The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by NH silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 1: 1) to give compound C (12.42 g, 88%) as a solid.
MS: 359/361 [M + H] ⁺ , APCI (MeOH)
(2) A suspension of compound C (4.00 g, 11.1 mmol), zinc cyanide (1.306 g, 11.1 mmol), tetrakis (triphenylphosphine) palladium (1.285 g, 1.1 mmol) in DMF (50 ml) at 80 ° C. And stirred for 1 hour. The suspension was poured into ethyl acetate / water, and 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 = 6: 1) to obtain Compound D (2.79 g, 82%) as a powder.
MS: 306/308 [M + H] ⁺ , APCI (MeOH)
(3) To a tert-butanol solution (5.0 ml) of compound D (100 mg, 0.327 mmol), powdered potassium hydroxide (165 mg, 2.94 mmol) was added, and the mixture was heated to reflux for 2 hours with stirring. The reaction mixture was cooled, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 → 90: 10) to obtain Compound E (102 mg, 96%) as a solid.
MS: 324/326 [M + H] ⁺ , APCI (MeOH)

実施例１で得られた化合物Ｄ(2.69 g, 8.80 mmol)に、6N塩酸(50 ml)を加え、攪拌しながら４時間加熱還流した。反応液を濃縮後、残渣をエタノール−エーテルにて懸濁洗浄し、化合物Ｆ(3.34 g, 100%)を固体として得た。
MS: 323/325[M-H]^-, ESI(MeOH) Example 2

6N hydrochloric acid (50 ml) was added to the compound D (2.69 g, 8.80 mmol) obtained in Example 1, and the mixture was heated to reflux for 4 hours with stirring. The reaction mixture was concentrated, and the residue was suspended and washed with ethanol-ether to give compound F (3.34 g, 100%) as a solid.
MS: 323/325 [MH] ^- , ESI (MeOH)

実施例２で得られた化合物Ｆ(76 mg, 0.20 mmol)に、塩化チオニル(0.5 ml)を加え、攪拌しながら１時間加熱還流した。反応液を濃縮後、ジクロロメタンに懸濁させ、氷冷したエタノールアミン(24 mg, 0.40 mmol)およびトリエチルアミン(112μl, 0.80 mmol)のジクロロメタン(2 ml)溶液に加えた。室温で一晩撹拌後、反応液を濃縮し、酢酸エチル加え有機層を水で洗浄後、減圧濃縮した。残渣を高速液体クロマトグラフィー（メタノール−水）で精製し、化合物Ｇ(25.2 mg, 34%)を固体として得た。
MS: 368/370[M+H]⁺, ESI(MeOH) Example 3

To the compound F (76 mg, 0.20 mmol) obtained in Example 2, thionyl chloride (0.5 ml) was added and heated to reflux for 1 hour with stirring. The reaction mixture was concentrated, suspended in dichloromethane, and added to ice-cooled ethanolamine (24 mg, 0.40 mmol) and triethylamine (112 μl, 0.80 mmol) in dichloromethane (2 ml). After stirring at room temperature overnight, the reaction mixture was concentrated, ethyl acetate was added, the organic layer was washed with water, and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (methanol-water) to obtain Compound G (25.2 mg, 34%) as a solid.
MS: 368/370 [M + H] ⁺ , ESI (MeOH)

後記実施例１１の化合物(60 mg, 0.15 mmol)、（ジベンジリデンアセトン）パラジウム(9 mg, 16μmol)、１，３−ビス（２，４，６−トリメチルフェニル）イミダゾリウム クロリド(5 mg, 15μmol)、カリウムメトキシド(21 mg, 0.30 mmol)をジオキサン(10ml)に懸濁させ、アルゴン気流下100℃で2時間撹拌した。不溶物を濾別後、反応液を濃縮し、残渣をシリカゲルクロマトグラフィー（クロロホルム：メタノール＝90:10）で精製し、Ｎ−（２−ヒドロキシプロピル）−４−（２−フェニルピリジン−３−イル）ベンズアミド(3.6 mg, 7%)を固体として得た。
MS: 333[M+H]⁺,APCI(MeOH) Example 4

The compound of Example 11 described later (60 mg, 0.15 mmol), (dibenzylideneacetone) palladium (9 mg, 16 μmol), 1,3-bis (2,4,6-trimethylphenyl) imidazolium chloride (5 mg, 15 μmol) ), Potassium methoxide (21 mg, 0.30 mmol) was suspended in dioxane (10 ml) and stirred at 100 ° C. for 2 hours under an argon stream. The insoluble material was filtered off, the reaction mixture was concentrated, the residue was purified by silica gel chromatography (chloroform: methanol = 90: 10), and N- (2-hydroxypropyl) -4- (2-phenylpyridine-3- Yl) benzamide (3.6 mg, 7%) was obtained as a solid.
MS: 333 [M + H] ⁺ , APCI (MeOH)

Examples 5-8
The following compounds were obtained by reacting in the same manner as in Examples 1 and 2.

Examples 9-19
By reacting in the same manner as in Example 3, the following compounds were obtained.

(1) 化合物Ａ(10.95 g, 48 mmol: J.Chem.Soc., 1646(1953))、トリn-ブチルフェニルチン(20.0 g, 0.54 mol)、二塩化ビス(トリフェニルホスフィン)パラジウム(II)(1.01 g, 1.4 mmol)をＤＭＦ(100 ml)中、18時間70℃で加熱した。放冷後、酢酸エチルと20％フッ化カリウム水溶液を加えて攪拌した。析出した沈殿を濾過して除いた後、酢酸エチルで抽出した。有機層を水で洗浄し、芒硝で乾燥し、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＝97:3)で精製し、化合物Ｂ(6.82 g, 53％)を固体として得た。
MS: 269/271[M+H]⁺, APCI
(2) 化合物Ｂ(0.45 g, 1.67 mmol)、ジメチルアミン塩酸塩(0.54 g, 6.62 mmol)、トリエチルアミン(1.39 ml, 9.97 mmol)をエタノール(15 ml)に溶解し、15時間加熱還流した。溶媒を減圧溜去、得られた残渣を水で希釈し、酢酸エチルで抽出した。有機層を水で洗浄し、芒硝で乾燥し、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Ｃ(0.38 g, 82％)を固体として得た。
MS: 278/280[M+H]⁺, APCI
(3) 化合物Ｃ(1 g, 3.60 mmol)、４‐カルボキフェニルホウ酸（656 mg, 3.95 mmol）、二塩化ビス（トリフェニルホスフィン）パラジウム(II)(252 mg, 0.36 mmol)、及び2N炭酸ナトリウム水溶液(7.2 ml)をＤＭＥ(7.2 ml)中、マイクロウェーブ照射下、100℃で1時間加熱した。冷却後、反応液に水、エーテルを加えた。水層を分取し、ｐＨ４になるまで酢酸を加えた後、酢酸エチルで抽出した。有機層を水洗、芒硝で乾燥し、減圧濃縮し、粗化合物Ｄを固体として得た。得られた化合物ＤとＮ−ヒドキシスクシンイミド(0.497 g, 4.32 mmol)をＤＭＦ(5 ml)に溶解し、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩(0.754 g, 3.95 mmol)を氷冷下加え、室温で3日間攪拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水で洗浄し、芒硝で乾燥し、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＝90:10→1:1)で精製し、化合物Ｅ(869 mg, 58％)を固体として得た。
MS: 417[M+H]⁺, APCI
(4) 化合物Ｅ(75 mg, 0.18 mmol)、２−アミノ―１，３−プロパンジオール(33 mg, 0.36 mmol)、ピリジン(0.05 ml)をＴＨＦ(5 ml)、ＤＭＦ(5 ml)に溶解し50℃で3時間攪拌した。反応液を冷却し、水で希釈し、酢酸エチルで抽出した。有機層を水で洗浄し、芒硝で乾燥し、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(クロロホルム：メタノール＝100:0→90:10)で精製し、化合物Ｆ(20mg, 28％)を固体として得た。
MS: 393[M+H]⁺, APCI Example 20

(1) Compound A (10.95 g, 48 mmol: J. Chem. Soc., 1646 (1953)), tri-n-butylphenyltin (20.0 g, 0.54 mol), bis (triphenylphosphine) palladium dichloride (II ) (1.01 g, 1.4 mmol) was heated in DMF (100 ml) at 70 ° C. for 18 hours. After allowing to cool, ethyl acetate and 20% aqueous potassium fluoride solution were added and stirred. The deposited precipitate was filtered off and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 97: 3) to obtain Compound B (6.82 g, 53%) as a solid.
MS: 269/271 [M + H] ⁺ , APCI
(2) Compound B (0.45 g, 1.67 mmol), dimethylamine hydrochloride (0.54 g, 6.62 mmol) and triethylamine (1.39 ml, 9.97 mmol) were dissolved in ethanol (15 ml) and heated to reflux for 15 hours. The solvent was distilled off under reduced pressure, and the resulting residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, 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 C (0.38 g, 82%) as a solid.
MS: 278/280 [M + H] ⁺ , APCI
(3) Compound C (1 g, 3.60 mmol), 4-carboxyphenylboric acid (656 mg, 3.95 mmol), bis (triphenylphosphine) palladium (II) dichloride (252 mg, 0.36 mmol), and 2N carbonic acid Aqueous sodium solution (7.2 ml) was heated in DME (7.2 ml) at 100 ° C. for 1 hour under microwave irradiation. After cooling, water and ether were added to the reaction solution. The aqueous layer was separated, acetic acid was added until the pH reached 4, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to obtain crude compound D as a solid. The obtained compound D and N-hydroxysuccinimide (0.497 g, 4.32 mmol) were dissolved in DMF (5 ml), and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.754 g, 3.95 mmol) was dissolved. ) Was added under ice-cooling, and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90: 10 → 1: 1) to obtain Compound E (869 mg, 58%) as a solid.
MS: 417 [M + H] ⁺ , APCI
(4) Compound E (75 mg, 0.18 mmol), 2-amino-1,3-propanediol (33 mg, 0.36 mmol), pyridine (0.05 ml) dissolved in THF (5 ml) and DMF (5 ml) And stirred at 50 ° C. for 3 hours. The reaction was cooled, diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 → 90: 10) to obtain Compound F (20 mg, 28%) as a solid.
MS: 393 [M + H] ⁺ , APCI

実施例１２４記載の化合物Ａ（100 mg，0.32 mmol）、トリメチルアルミニウム（1.0Mヘキサン溶液 0.97 ml，0.97 mmol）、テトラキス（トリフェニルホスフィン）パラジウム（74 mg，64μmol）のジオキサン（3 ml）懸濁液をアルゴン気流下70℃に加熱して9時間撹拌した。反応液を0℃に冷却した後、飽和K₂CO₃水溶液を添加した。酢酸エチルにて抽出後、芒硝で乾燥し、減圧濃縮した。残渣をシリカゲルクロマトグラフィー（クロロホルム：メタノール＝95：5→88：12）で精製することにより、化合物Ｂ（64 mg，0.22 mmol，68%）を粉末として得た。
MS：290 [M+H]⁺，APCI (MeOH) Example 21

Suspension of Compound A (100 mg, 0.32 mmol) described in Example 124, trimethylaluminum (1.0 M hexane solution 0.97 ml, 0.97 mmol), tetrakis (triphenylphosphine) palladium (74 mg, 64 μmol) in dioxane (3 ml). The solution was heated to 70 ° C. under an argon stream and stirred for 9 hours. After the reaction solution was cooled to 0 ° C., saturated aqueous K ₂ CO ₃ solution was added. After extraction with ethyl acetate, it was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: methanol = 95: 5 → 88: 12) to give compound B (64 mg, 0.22 mmol, 68%) as a powder.
MS: 290 [M + H] ⁺ , APCI (MeOH)

化合物Ａ（500 mg，1.61 mmol）のジクロロメタン（3 ml）懸濁液に、氷冷下で濃ヨウ化水素水（3 ml，12.9 mmol）を加え、その温度で8時間撹拌した。K₂CO₃で中和した後、１０％NaHSO₃水溶液でヨウ素を還元した。不溶物を濾取し、水、ヘキサンで洗浄して粗２−ヨードピリミジン（225 mg）を得た。得られた粗２−ヨードピリミジンは精製せずに次の反応に用いた。粗２−ヨードピリミジン（175 mg）、銅粉末（333 mg，5.24 mmol）、ジブロモジフルオロカーボン（0.16 ml，1.75 mmol）のＤＭＡ（6 ml）懸濁液を、アルゴン気流下100 ℃で6時間加熱撹拌した。放冷後、反応液を酢酸エチルで希釈し、水で洗浄した。有機層を芒硝で乾燥し、減圧濃縮した。残渣を高速液体クロマトグラフィー（メタノール−水）で精製することにより、化合物Ｂ（9 mg，2%）を粉末として得た。
MS：344 [M+H]⁺，APCI (MeOH) Example 22

Concentrated aqueous hydrogen iodide (3 ml, 12.9 mmol) was added to a suspension of compound A (500 mg, 1.61 mmol) in dichloromethane (3 ml) under ice cooling, and the mixture was stirred at that temperature for 8 hours. After neutralization with K ₂ CO ₃ , iodine was reduced with a 10% aqueous NaHSO ₃ solution. The insoluble material was collected by filtration and washed with water and hexane to obtain crude 2-iodopyrimidine (225 mg). The obtained crude 2-iodopyrimidine was used in the next reaction without purification. A suspension of crude 2-iodopyrimidine (175 mg), copper powder (333 mg, 5.24 mmol) and dibromodifluorocarbon (0.16 ml, 1.75 mmol) in DMA (6 ml) was heated at 100 ° C. for 6 hours under an argon stream. Stir. After allowing to cool, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (methanol-water) to give Compound B (9 mg, 2%) as a powder.
MS: 344 [M + H] ⁺ , APCI (MeOH)

Examples 23-66
The following compounds were obtained according to the methods and examples described in the present specification and the methods described in known literature.

MS 360[M+H]+, APCI Example 30

MS 360 [M + H] +, APCI

MS 333[M+H]+, APCI Example 31

MS 333 [M + H] +, APCI

60％NaH（25 mg，0.65 mmol）のＤＭＦ（3 ml）懸濁液に、氷冷下シクロヘキシルアルコール（0.17 ml，1.6 mmol）を滴下した。反応液を室温で30分間撹拌した後、化合物Ａ （10 mg，0.32 mmol）を加え、80℃で2時間30分間撹拌した。放冷後、水を加え、酢酸エチルで抽出した。有機層を芒硝で乾燥し、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＝3：2→酢酸エチル）で精製することにより、化合物Ｂ（41 mg，0.11 mmol，34%）を粉末として得た。
MS：374 [M+H]⁺, APCI (MeOH) Example 67

Cyclohexyl alcohol (0.17 ml, 1.6 mmol) was added dropwise to a suspension of 60% NaH (25 mg, 0.65 mmol) in DMF (3 ml) under ice cooling. The reaction mixture was stirred at room temperature for 30 min, compound A (10 mg, 0.32 mmol) was added, and the mixture was stirred at 80 ° C. for 2 hr 30 min. After allowing to cool, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2 → ethyl acetate) to give Compound B (41 mg, 0.11 mmol, 34%) as a powder.
MS: 374 [M + H] ⁺ , APCI (MeOH)

Examples 68-82
The following compounds were obtained according to the methods and examples described in the present specification and the methods described in known literature.

（１）化合物Ａ（5.2 g, 29.9 mmol）、及び化合物Ｂ（5.4 g， 35.6 mmol）のＤＭＥ（50 ml）溶液と、２Ｍ炭酸ナトリウム水溶液（30 ml）による懸濁液を、減圧下超音波により脱気し、アルゴン置換した。その混合液に二塩化ビス（トリフェニルフォスフィン）パラジウム（II）（2.1 g，2.9 mmol）を加え、アルゴン雰囲気下１６時間加熱還流した。反応液を室温まで戻した後、酢酸エチル（300 ml）、水（50 ml）を加え、ラヂオライトにてろ過し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、ケムエルート5 mlを用いて乾燥し減圧下濃縮した。得られた結晶性残渣を酢酸エチルで懸濁洗浄することにより、化合物Ｃ（2.65 g，45%）を固体として得た。
MS：197[M+H]⁺，APCI (MeOH)
（２）化合物Ｃ（2.65 g，13.5 mmol）のピリジン（40 ml）溶液に、氷冷下トリフルオロメタンスルホン酸無水物（6.8 ml, 40.4 mmol）を10分間で滴下した。反応液を室温まで上昇させ、16時間攪拌した後減圧下濃縮し、酢酸エチル、水を加えた。酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、ケムエルート5 mlを用いて乾燥し、減圧下濃縮した。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＝5：1→3：1）で精製し、更に得られた結晶性残渣をヘキサンで懸濁洗浄することにより、化合物Ｄ（3.9 g，88%）を固体として得た。
MS：329[M+H]⁺，APCI (MeOH)
（３）化合物Ｅ（98 mg，0.30 mmol）、ピペリジン（90μｌ，0.91 mmol）のＴＨＦ（3 ml）溶液を、24時間加熱還流した後、ピペリジン（90μｌ，0.91 mmol）、ＴＨＦ（3 ml）を追加し、さらに24時間加熱還流した。反応液を室温まで冷却後、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＝90：10→70：30）で精製することにより、化合物Ｅ（27.4 mg，35%）を粉末として得た。
MS：264 [M+H]⁺，APCI (MeOH) Example 83

(1) A suspension of Compound A (5.2 g, 29.9 mmol) and Compound B (5.4 g, 35.6 mmol) in DME (50 ml) and 2M aqueous sodium carbonate solution (30 ml) was subjected to ultrasonication under reduced pressure. And then purged with argon. Bis (triphenylphosphine) palladium (II) (2.1 g, 2.9 mmol) was added to the mixture, and the mixture was heated to reflux for 16 hours under an argon atmosphere. After returning the reaction solution to room temperature, ethyl acetate (300 ml) and water (50 ml) were added, and the mixture was filtered through radiolite and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried using 5 ml of Chem Elut and concentrated under reduced pressure. The obtained crystalline residue was suspended and washed with ethyl acetate to give Compound C (2.65 g, 45%) as a solid.
MS: 197 [M + H] ⁺ , APCI (MeOH)
(2) To a solution of compound C (2.65 g, 13.5 mmol) in pyridine (40 ml), trifluoromethanesulfonic anhydride (6.8 ml, 40.4 mmol) was added dropwise over 10 minutes under ice cooling. The reaction mixture was allowed to rise to room temperature, stirred for 16 hours, concentrated under reduced pressure, and ethyl acetate and water were added. Extracted with ethyl acetate. The organic layer was washed with saturated brine, dried using 5 ml of Chem Elut, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 → 3: 1), and the obtained crystalline residue was suspended and washed with hexane to give compound D (3.9 g, 88%). Was obtained as a solid.
MS: 329 [M + H] ⁺ , APCI (MeOH)
(3) A solution of compound E (98 mg, 0.30 mmol) and piperidine (90 μl, 0.91 mmol) in THF (3 ml) was heated under reflux for 24 hours, and then piperidine (90 μl, 0.91 mmol) and THF (3 ml) were added. Further, the mixture was further heated under reflux for 24 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90: 10 → 70: 30) to give Compound E (27.4 mg, 35%) as a powder.
MS: 264 [M + H] ⁺ , APCI (MeOH)

（１）60% NaH（4.42 g，111 mmol）を化合物Ａ（10.0 g，105 mmol）のＤＭＦ(100 ml)溶液に0℃で加え、つづいて臭化ベンジル（13.7 ml, 115 mmol）を加えた。その後、室温で一晩撹拌した。反応液を氷水に注ぎ、ジエチルエーテルにて抽出を行った。抽出液を水で洗浄した後、芒硝で乾燥し、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＝97：3→50：50）で精製することにより、化合物Ｂ（16.3 g，84%）を液体として得た。
MS：186 [M+H]⁺，APCI (MeOH)
（２）クロルギ酸フェニル（3.45 ml，27.5 mmol）のＴＨＦ（20 ml）溶液を化合物Ｂ（4.63 g，25.0 ml）、塩化リチウム（0.21 g，5.0 mmol）、ヨウ化銅(I)（0.476 g，2.5 mmol）のＴＨＦ（500 ml）溶液に−23℃で滴下した。滴下終了から20分後、化合物Ｃ（0.5Ｍ ＴＨＦ溶液、50 ml，25.0 mmol）を−23℃で滴下した。滴下終了から20分後、反応液温度を徐々に室温に戻した。20％塩化アンモニウム水溶液（100 ml）、及び5％アンモニア水（20 ml）を加えた後、ＴＨＦを減圧留去した。ジエチルエーテルを加え、水で洗浄、芒硝で乾燥し、減圧濃縮した。残渣にトルエン（200 ml）を加え、ｏ−クロラニル（6.15 g，25.0 mmol）のトルエン（50 ml）溶液を0 ℃で滴下した。滴下後、室温にて一晩撹拌した。ジエチルエーテルを加え、10％水酸化ナトリウム水溶液、水にて洗浄し、芒硝で乾燥し、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＝95：5→50：50）で精製することにより、化合物Ｄ（2.61 g，31%）を粉末として得た。
MS：334 [M+H]⁺，APCI (MeOH)
（３）化合物Ｄ（2.61 g，7.83 mmol）及び、10％パラジウム炭素（0.26 g）をメタノール（40 ml）に懸濁させ、水素雰囲気下、室温にて一晩撹拌した。不溶物を濾別した後、濾液を減圧濃縮した。残渣をＮＨ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＝95：5→75：25）で精製することにより、化合物Ｅ(1.87 g, 91%)を粉末として得た。
MS：244 [M+H]⁺，APCI (MeOH)
（４）化合物Ｅを実施例８３（２）に従いトリフルオロメタンスルホニル化したのち、製法１に従いフェニル基を導入後、常法に従い、エステル基を加水分解し、続いて製法７（B）の手法を用い化合物Ｆを得た。
MS：275[M+H]⁺，APCI (MeOH) Example 84

(1) 60% NaH (4.42 g, 111 mmol) was added to a DMF (100 ml) solution of compound A (10.0 g, 105 mmol) at 0 ° C., followed by benzyl bromide (13.7 ml, 115 mmol). It was. Then, it stirred at room temperature overnight. The reaction solution was poured into ice water and extracted with diethyl ether. The extract was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 97: 3 → 50: 50) to give Compound B (16.3 g, 84%) as a liquid.
MS: 186 [M + H] ⁺ , APCI (MeOH)
(2) A solution of phenyl chloroformate (3.45 ml, 27.5 mmol) in THF (20 ml) was added compound B (4.63 g, 25.0 ml), lithium chloride (0.21 g, 5.0 mmol), copper (I) iodide (0.476 g). , 2.5 mmol) in THF (500 ml) was added dropwise at -23 ° C. 20 minutes after the completion of dropping, Compound C (0.5 M THF solution, 50 ml, 25.0 mmol) was added dropwise at -23 ° C. 20 minutes after the completion of dropping, the reaction solution temperature was gradually returned to room temperature. After adding 20% aqueous ammonium chloride solution (100 ml) and 5% aqueous ammonia (20 ml), THF was distilled off under reduced pressure. Diethyl ether was added, washed with water, dried over sodium sulfate, and concentrated under reduced pressure. Toluene (200 ml) was added to the residue, and a toluene (50 ml) solution of o-chloranil (6.15 g, 25.0 mmol) was added dropwise at 0 ° C. After dropping, the mixture was stirred overnight at room temperature. Diethyl ether was added, washed with a 10% aqueous sodium hydroxide solution and water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5 → 50: 50) to give Compound D (2.61 g, 31%) as a powder.
MS: 334 [M + H] ⁺ , APCI (MeOH)
(3) Compound D (2.61 g, 7.83 mmol) and 10% palladium carbon (0.26 g) were suspended in methanol (40 ml) and stirred overnight at room temperature in a hydrogen atmosphere. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane: ethyl acetate = 95: 5 → 75: 25) to give compound E (1.87 g, 91%) as a powder.
MS: 244 [M + H] ⁺ , APCI (MeOH)
(4) After trifluoromethanesulfonylation of Compound E according to Example 83 (2), the phenyl group was introduced according to Production Method 1, and then the ester group was hydrolyzed according to a conventional method, followed by the method of Production Method 7 (B). The compound F used was obtained.
MS: 275 [M + H] ⁺ , APCI (MeOH)

Examples 85-126
The following compounds were obtained according to the methods and examples described in the present specification and the methods described in known literature.

MS: 274[M-H]^-,ESI Example 100

MS: 274 [MH] ^- , ESI

Example 101

MS: 271 [M + H] ⁺ , APCI

MS: 304[M+H]⁺,APCI Example 106

MS: 304 [M + H] ⁺ , APCI

MS: 347 [M+H]⁺, APCI Example 133

MS: 347 [M + H] ⁺ , APCI

化合物Ａ(32 mg, 0.102 mmol)と10％パラジウム−炭素（6 mg）をメタノール（2 ml）溶液を、水素雰囲気下、室温で１日攪拌した。パラジウム触媒を濾別し、濾液を減圧濃縮した。残渣を分取用薄層クロマトグラフィー（ＮＨシリカゲル クロロホルム：メタノール＝20：1）で精製後、塩化水素で処理し、化合物Ｂ(22 mg, 68%)を粉末として得た。
MS: 281 [M+H]⁺, APCI Example 134

A solution of compound A (32 mg, 0.102 mmol) and 10% palladium-carbon (6 mg) in methanol (2 ml) was stirred at room temperature for 1 day in a hydrogen atmosphere. The palladium catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (NH silica gel, chloroform: methanol = 20: 1) and then treated with hydrogen chloride to obtain Compound B (22 mg, 68%) as a powder.
MS: 281 [M + H] ⁺ , APCI

（１）化合物Ａ（1.50 g, 5.14 mmol）の塩化メチレン(20 ml)溶液に55％ヨウ化水素水溶液(15 ml, 107 mmol)を、アルゴン雰囲気下、0℃で15分以上かけて滴下した。滴下後、反応液を同温で30分間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液と10％亜硫酸ナトリウム水溶液を続け様に加えた。反応液をクロロホルムで抽出し、有機層を芒硝で乾燥し、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＝90：10→80：20）で精製することにより、化合物Ａと化合物Ｂの混合物（1.16 g，モル比B：A = 87:13）を粉末として得た。
（２）得られた化合物Ａと化合物Ｂの混合物（1.16 g，モル比B：A = 87:13）、ジフルオロ（フルオロスルホニル）酢酸メチル（775 μl, 6.09 mmol）、及び臭化（I）銅（87 mg, 0.61 mmol）をＮ−メチルピペリドン（30 ml）中で、アルゴン雰囲気下120℃で3時間攪拌した。反応液を冷却した後、酢酸エチルを加え、有機層を水、及び飽和食塩水で洗浄し、芒硝で乾燥し、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＝90：10）で精製することにより、化合物Ｃ（0.744 g， 2工程で収率44％）を粉末として得た。
MS: 326 [M+H]⁺, APCI (MeOH)
（３）化合物Ｃ（0.449 g, 1.38 mmol）を48％臭化水素水溶液（15 ml）に加え、その懸濁液をアルゴン雰囲気下8時間加熱還流した。反応液を冷却した後、ジエチルエーテルを加え、有機層より２Ｍ水酸化ナトリウム水溶液で抽出した。水層に36％塩酸を加えてｐＨを1に調節した後、その水層をクロロホルム−メタノール（9：1）で抽出した。有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮することにより、化合物Ｄ（0.478 g, 100％）を固体として得た。
MS: 343 [M-H]^-, ESI (MeOH)
（４）化合物Ｄ（80 mg, 0.232 mmol）のクロロホルム（5.0 ml）懸濁液に塩化オキザリル（61 μl, 0.699 mmol）とＮ,Ｎ−ジメチルホルムアミド（1滴）を加え、室温下30分間攪拌した。反応液を減圧濃縮し、得られた酸クロリドのクロロホルム（3.0 ml）懸濁液を0℃で3分間以上かけて28％アンモニア水溶液（3.0 ml, 49 mmol）に滴下した。滴下後反応液を同温で30分間攪拌した。水を加え、反応液をクロロホルム−メタノール（9：1）で抽出した。有機層を芒硝で乾燥し、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（クロロホルム：メタノール＝100：1→90：10）で精製することにより、化合物Ｅ（45 mg， 57％）を粉末として得た。
MS: 344 [M+H]⁺, APCI (MeOH) Example 135
The compound of Example 22 could be obtained in good yield by the following procedure.

(1) 55% aqueous solution of hydrogen iodide (15 ml, 107 mmol) was added dropwise to a solution of compound A (1.50 g, 5.14 mmol) in methylene chloride (20 ml) at 0 ° C. over 15 minutes in an argon atmosphere. . After dropping, the reaction solution was stirred at the same temperature for 30 minutes. A saturated aqueous sodium bicarbonate solution and a 10% aqueous sodium sulfite solution were successively added to the reaction solution. The reaction solution was extracted with chloroform, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90: 10 → 80: 20) to give a mixture of compound A and compound B (1.16 g, molar ratio B: A = 87: 13) as a powder Obtained.
(2) A mixture of the obtained compound A and compound B (1.16 g, molar ratio B: A = 87: 13), methyl difluoro (fluorosulfonyl) acetate (775 μl, 6.09 mmol), and copper (I) bromide (87 mg, 0.61 mmol) was stirred in N-methylpiperidone (30 ml) at 120 ° C. for 3 hours under an argon atmosphere. After cooling the reaction solution, ethyl acetate was added, and the organic layer was 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 = 90: 10) to give Compound C (0.744 g, yield 44% over 2 steps) as a powder.
MS: 326 [M + H] ⁺ , APCI (MeOH)
(3) Compound C (0.449 g, 1.38 mmol) was added to 48% aqueous hydrogen bromide solution (15 ml), and the suspension was heated to reflux for 8 hours under an argon atmosphere. After cooling the reaction solution, diethyl ether was added, and the organic layer was extracted with 2M aqueous sodium hydroxide solution. 36% hydrochloric acid was added to the aqueous layer to adjust the pH to 1, and the aqueous layer was extracted with chloroform-methanol (9: 1). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain Compound D (0.478 g, 100%) as a solid.
MS: 343 [MH] ^- , ESI (MeOH)
(4) Oxalyl chloride (61 μl, 0.699 mmol) and N, N-dimethylformamide (1 drop) were added to a suspension of compound D (80 mg, 0.232 mmol) in chloroform (5.0 ml) and stirred at room temperature for 30 minutes. did. The reaction mixture was concentrated under reduced pressure, and the resulting suspension of acid chloride in chloroform (3.0 ml) was added dropwise to a 28% aqueous ammonia solution (3.0 ml, 49 mmol) at 0 ° C. over 3 minutes. After dropping, the reaction solution was stirred at the same temperature for 30 minutes. Water was added and the reaction solution was extracted with chloroform-methanol (9: 1). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1 → 90: 10) to give Compound E (45 mg, 57%) as a powder.
MS: 344 [M + H] ⁺ , APCI (MeOH)

Reference Examples 1-4
The following compounds were obtained as synthetic intermediates according to the methods and examples described in this specification and the methods described in known literature.

Test example 1
[Relaxing effect in rabbit isolated bladder specimen]
A Krebs nutrient solution (118 mM NaCl, 4.7 mM KCl, 2.55 mM CaCl ₂ , 1.18 mM MgSO ₄ , 1.18 mM KH ₂ PO ₄ , 24.88 mM NaHCO ₃ ) immediately cooled on ice from a rabbit (body weight 2.0 kg to 3.5 kg) was immediately cooled on ice. And 11.1 mM glucose) to remove surrounding connective tissue. After removing the membranous tissue of the lumen, the bladder was cut into a width of 3 to 4 mm in the longitudinal direction with respect to the urinary tract, and a strip having a total length of about 5 mm in the longitudinal muscle direction.
Fill the organ bath with 95% O ₂ -5% CO ₂ gas mixture warmed to 37 ° C and fully aerated Krebs nutrient solution, tie cotton thread to the upper and lower ends of the specimen, and attach one end to the lower end of the organ bath. One was fixed to a strain gauge transducer. The tension generated from the specimen is measured isometrically and continuously recorded on a pen recorder. The specimen was stretched so that the static tension was 2.0 g. When the static tension was stabilized, a KCl solution was added to the organ bath so that the potassium ion concentration was 30 mM, and the specimen was contracted.
The test drug was cumulatively added to the organ bath at a common ratio of 10 to a specimen showing stable contraction, and a dose-response curve was obtained. The generated tension immediately before the start of drug addition was relaxed by 0%. After the cumulative addition was completed, the tension generated when 10 ^-4 M papaverine was added to the nutrient solution was defined as 100% relaxation. The effect of the test drug is expressed as a dose (IC ₅₀ ) (μM) at which the relaxation rate is 50%, and the IC ₅₀ value range (μM) of the Example compound is shown in Table 1. The ranges of A, B, and C are as follows. 3 μM ≧ C> 1 μM ≧ B> 0.5 μM ≧ A

Test example 2
[Effects on SP-induced rhythmic contraction in urethane anesthetized rats]
In the experiment, SD female rats (9-12 weeks old) weighing 200-300 g were used. After urethane anesthesia (1.2 g / kg, subcutaneous administration), a cannula was inserted into the bladder through both ureters and the external urethral orifice under spontaneous breathing. The other end was connected to a pressure transducer and an infusion pump via a three-way stopcock. Further, a blood pressure measuring cannula was inserted into the left carotid artery from the neck. A cannula was inserted into the left femoral vein for intravenous administration of the drug solution and further into the right femoral vein for continuous infusion of Substance P. After blood pressure, heart rate, and intravesical pressure were stabilized, approximately 0.6 ml of saline was loaded through the bladder cannula. About 10 minutes later, continuous injection of Substance P into the vein (0.33 μg / kg / min) was started using a microinjector. Stable rhythmic contractions were induced by increasing or decreasing the amount of saline in the bladder as needed. Changes in intravesical pressure, blood pressure, and heart rate were continuously recorded on a recorder. After confirming that the onset of constant contraction lasted for about 15 minutes, the test compound suspended in a 0.5% Tween 80 aqueous solution was administered via an intravenous administration cannula. Evaluation items were rhythmic bladder contraction suppression time and bladder contraction force, and were observed up to 35 minutes after administration of the test compound.

  As a result, the active ingredient compound of the present invention suppressed the development of rhythmic bladder contraction without affecting the bladder contractile force. Table 2 shows the time (minutes) in which the onset of rhythmic contraction was suppressed 100% upon intravenous administration of the drug 0.25 mg / kg.

  Further, pre-administration of iberiotoxin (0.15 mg / kg, intravenous administration), which is a specific inhibitor of high conductance type calcium sensitive K channel, attenuated the rhythmic bladder contraction expression inhibitory effect of the compound of the present invention. Therefore, it was shown that the bicyclic compound of the present invention is useful as a prophylactic / therapeutic agent for frequent urination, urinary incontinence, etc. via a high conductance calcium sensitive K channel opening action.

  Since the bicyclic compound of the present invention has an excellent high conductance calcium-sensitive K channel opening action, it is useful as a preventive, alleviating and / or therapeutic agent for pollakiuria, urinary incontinence, asthma and COPD.

Claims (20)

Formula 1:

[Wherein, ring Q represents pyridine or pyrimidine.
Ring A represents benzene or a heteroaromatic ring.
G is

Alternatively, it represents amino optionally substituted by 1 or 2 substituents selected from alkyl, aralkyl and cycloalkyl, respectively.
Ring B represents benzene, heterocycle, cycloalkane or cycloalkene.
R ¹ represents a group selected from the following formulae.

R ² and R ³ are the same or different and are each cyano, nitro, hydroxyl group, alkoxy, halogen, carboxy, alkoxycarbonyl, optionally substituted carbamoyl, optionally substituted amino, or optionally substituted alkyl Represents. However, when m is 2, two R ² may be the same or different, and when n is 2, two R ³ may be the same or different.
m and n are the same or different and each represents 0, 1 or 2.
R ⁴ is a hydrogen atom, halogen, cyano, alkoxy, hydroxyl group, carbamoyl, optionally substituted amino, optionally substituted alkyl, optionally substituted aryloxy, cycloalkyloxy or substituted. Represents a good heterocyclic group.
R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, an optionally substituted alkyl, an optionally substituted cycloalkyl (the cycloalkyl may be condensed with an aryl), a substituted Represents an optionally substituted aryl, an optionally substituted heterocyclic group, or alkoxycarbonyl, or R ⁵ and R ⁶ together, together with the atom to which they are attached, optionally substituted heterocycle A ring may be formed. However, 4-amino-5- (4-cyanophenyl) pyrimidine is excluded. ]
Or a pharmaceutically acceptable salt thereof. Formula 1a:

[Wherein, ring Q, ring A, ring B, R ¹ , R ² , R ³ , R ⁴ , m and n are as defined in claim 1. ]
The pharmaceutical of Claim 1 represented by these. The pharmaceutical according to claim 1 or 2, wherein ring Q is pyridine. Formula 1b:

[Wherein, one of X and Y represents a nitrogen atom and the other represents methine.
Ring A, ring B, R ¹ , R ² , R ³ , R ⁴ , m and n are as defined in claim 1. ]
The pharmaceutical of Claim 1 represented by these. The medicine according to any one of claims 1 to 4, wherein ring A is a 5- or 6-membered ring. The pharmaceutical according to any one of claims 1 to 4, wherein ring A is benzene, pyridine, pyrimidine, or thiophene. Ring A is benzene, The pharmaceutical in any one of Claims 1-4. The pharmaceutical according to any one of claims 1 to 7, wherein ring A is a 6-membered ring and R ¹ is substituted at the para position with respect to ring Q. The pharmaceutical according to any one of claims 1 to 8, wherein the ring B is benzene, pyridine, pyrimidine, thiophene, piperidine, morpholine, cyclohexane, cyclohexene, pyrrolidine or pyrrole. The pharmaceutical according to any one of claims 1 to 9, wherein R ¹ is a group selected from the following formulae.

R ⁵ is a hydrogen atom, optionally substituted alkyl (the substituent of the substituted alkyl is 1 to 3 groups selected from the following formula), optionally substituted cycloalkyl (the cycloalkyl is aryl) Optionally substituted aryl), an optionally substituted aryl, or an optionally substituted heterocyclic group, wherein R ⁶ may be substituted with a hydrogen atom, alkoxycarbonyl, or a hydroxyl group or alkoxy. alkyl either, or R ⁵ and R ⁶ taken together along with the atoms to which they are attached, a substituted may form a heterocyclic ring which may have claim 10 a medicament according.

[Wherein R ⁷ is (1) a hydrogen atom, (2) an aryl which may be substituted or an alkyl which may be substituted with an optionally substituted heterocyclic group, (3) a hydroxyalkyl, ( 4) represents an alkoxyalkyl or (5) an optionally substituted heterocyclic group.
R ⁸ and R ⁹ are the same or different and are each (1) a hydrogen atom, (2) an optionally substituted aryl or an optionally substituted heterocyclic group, (3 Represents a) hydroxyalkyl, (4) alkoxyalkyl, (5) alkoxycarbonyl, (6) an optionally substituted heterocyclic group or (7) an optionally substituted aryl, or (8) R ⁸ And R ⁹ together can form an optionally substituted heterocycle with the atoms to which they are attached.
R ¹⁰ and R ¹¹ are the same or different and are each (1) a hydrogen atom, (2) an optionally substituted aryl or an optionally substituted heterocyclic group, ( 3) represents hydroxyalkyl, (4) alkoxyalkyl, (5) alkanoyl, (6) alkylsulfonyl, (7) alkoxycarbonyl, or (8) an optionally substituted heterocyclic group. ] The pharmaceutical according to claim 11 wherein the substituent of substituted alkyl R ⁵ is 1 to 3 groups selected from the following formulas.

[Wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ have the same meanings as defined in claim 11. ] The pharmaceutical according to claim 11 wherein the substituent of substituted alkyl R ⁵ is 1 to 3 groups selected from the following formulas.

[Wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ have the same meanings as defined in claim 11. ] The pharmaceutical according to any one of claims 1 to 13, wherein ring Q is pyrimidine and R ¹ is a group selected from the following formulae.

[Wherein, R ⁵ and R ⁶ have the same meaning as in claim 1, and R ⁵¹ represents an alkyl substituted with 1 to 3 groups selected from the following formulae.

[Wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ have the same meanings as defined in claim 11. ] The medicament according to any one of claims 1 to 14, wherein m and n are the same or different and each is 0 or 1. The pharmaceutical according to any one of claims 1 to 15, wherein R ² and R ³ are the same or different and each is cyano, hydroxyl group, alkoxy, halogen, or optionally substituted alkyl. The pharmaceutical according to any one of claims 1 to 16, wherein R ⁴ is a hydrogen atom, a halogen, or an optionally substituted alkyl. The medicament according to any one of claims 1 to 17, which is a high conductance calcium-sensitive K channel opener. The medicament according to any one of claims 1 to 17, which is a preventive and / or therapeutic agent for pollakiuria, urinary incontinence, asthma or chronic obstructive pulmonary disease. The medicament according to claim 19, which is a preventive and / or therapeutic agent for frequent urination, urinary incontinence or chronic obstructive pulmonary disease.