WO2004110454A1 - COMPOSITION FOR TREATMENT FOR OR PREVENTION OF DISEASE NECESSITATING ADMINISTRATION OF ADENOSINE A2a RECEPTOR AGONIST - Google Patents

Abstract

A composition for treatments for or prevention of diseases which necessitate the administration of an adenosine A2a receptor agonist. The composition contains as an active ingredient either a fused heterocyclic compound represented by the formula (I): (I) (wherein A is nitrogen, C-G, etc.; R1 and R2 each independently is hydrogen, halogeno, optionally substituted alkyl, optionally substituted aryl, an optionally substituted heterocyclic group, etc.; Y and Z each independently is nitrogen or C-R8 and when both of Y and Z are C-R8, then the two R8's may be the same or different; X is nitrogen or C-R10; and when Y is C-R8 and either X is C-R10 or Z is C-R8, then either R8 and R10 or the two R8's may be bonded to each other to form a ring optionally containing one or more heteroatoms) or a salt of the compound.

Description

 Specification

 Thread composition for treating or preventing diseases requiring administration of adenosine A2a receptor agonist

 Technical field

 The present invention relates to a composition for treating or preventing a disease requiring administration of an adenosine A2a receptor agonist, and is useful as a medicament such as a wound healing promoter.

 Background art

 [0002] Adenosine receptor is a seven-transmembrane G protein-coupled receptor widely distributed in vivo, and it has been known that there are four subtypes of Al, A2a, A2b and A3 so far. I have. A1 and A3 are coupled to adenylate cyclase-inhibited Gi protein, and A2a and A2b are coupled to activated Gs protein, respectively, and play important roles in various physiological functions by regulating the concentration of cAMP, a second messenger It is considered. The A1 and A2a receptors have high affinity for adenosine, whereas the A2b and A3 receptors have low affinity, and their subtypes have different localization and distribution in tissues in vivo. I have. Stimulation of adenosine A2a receptors by agonists is also associated with promotion of wound healing, sleep, hypothermia, hypotension, suppression of immune cell function, suppression of neutrophil function, tumor necrosis factor-H (TNF-a) and interleukin-1. It has been reported to induce various actions such as suppression of production of cytokins such as 2 (IL-2).

 [0003] On the other hand, the condensed heterocyclic compound of the formula (I) described below is a compound described in WO02 / 40485 as an active ingredient of a preventive or therapeutic agent for diabetes. However, it is not known that these compounds have an adenosine A2a receptor agonist action.

 Patent Document 1: International Publication WO02 / 40485

 Disclosure of the invention

 Problems the invention is trying to solve

[0004] The present inventors have found that a specific fused heterocyclic compound or a salt thereof has an adenosine A2a agonist action, and have accomplished the present invention.

Means for solving the problem That is, the present invention provides a compound represented by the formula (I)

[0006] [Formula 1]

[Wherein, A is a nitrogen atom or a CG group {G is CN, NO, SOR ³ group (R ³ is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, substitution which may be a cycloalkyl group, an optionally substituted cycloalkenyl group, a substituted by Moyoi Ariru group or an optionally substituted heterocyclic group), CO R ⁴ group (R ⁴ is , Hydrogen atom

An optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group or is an optionally substituted heterocyclic group), CH_〇, the SO NR¾ ^b group (R ^a and R ^b are each independently a hydrogen atom, a hydroxyl group, an alkoxy group, an optionally substituted alkyl group, a substituted Alkenyl group which may be substituted, alkynyl group which may be substituted, cycloalkyl group which may be substituted, cycloalkenyl group which may be substituted, aryl group which may be substituted or heterocyclic ring which may be substituted R ^a and R ^b together form a ring) or a CONR ^a R ^b group (where R ^a and R ^b are as defined above)};

R ¹ and R ² are each independently a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, An optionally substituted cycloalkenyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, a -B ^ R ⁵ group (B ¹ is C〇, COO, 0, 〇CO, OSO,

S, SO or SO, wherein R ⁵ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, Optionally substituted cycloalkenyl group, optionally substituted aryl group or substituted An optionally substituted amino group or N = CR ⁶ R ⁷ group (R ⁶ and R ⁷ are each independently a hydrogen atom, an optionally substituted alkyl group, An optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group. There is);

Y and Z are each independently a nitrogen atom or C - R ⁸ group {R ⁸ is a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, § optionally substituted Norekiniru Group, optionally substituted cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted aryl group, optionally substituted heterocyclic group, —B ² —R ⁹ group (B ² is , CO〇, 0, OCO, OSO, S, SO or SO, wherein R ⁹ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, A cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted, an aryl group which may be substituted, an aryl group or a heterocyclic group which may be substituted), Group, a cyano group or a nitro group}, Y and Z Well-, it is two R ⁸ when taking a C one R ⁸ groups simultaneously be the same or different;

X is a nitrogen atom or a CR ^1Q group (R ^1Q is a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted A cycloalkyl group, an optionally substituted cycloalkenyl group, one B ² —R ⁹ group (B ² and R ⁹ are as defined above), an optionally substituted amino group, a cyano group or a nitro group };

Furthermore Y is C one R ⁸ groups, if X is C one R ^1Q group or Z is a C one R ⁸ groups, R ⁸ and R ^1Q there have two R ⁸ are hetero atoms together such connexion A ring may be formed with or without the adenosine A2a receptor agonist containing, as an active ingredient, a fused heterocyclic compound represented by the formula (1) or a salt thereof. Composition. The salt of the fused heterocyclic compound of the formula (I) may be a pharmaceutically acceptable salt, for example, a mineral acid salt such as hydrochloride, sulfate, nitrate, etc .; ρ_toluenesulfonate, propane Organic acid salts such as sulfonates and methanesulfonates; alkali metal salts such as potassium salts and sodium salts; alkaline earth metal salts such as calcium salts; triethanolamine salts; Organic amine salts such as ris (hydroxymethyl) aminomethane salt and the like can be mentioned. Some of these salts have water of crystallization.

R^1Q、 R^a及び R^bで表される置換され てもよいアルキル基のアルキル部分としては、一般に炭素数 1一 19のもの、例えばメ チノレ基、ェチル基、プロピル基、ブチル基、ペンチル基、へキシル基、ォクチル基、ノ ニル基、デシル基、ノナデシル基などが挙げられ、それらは直鎖又は枝分かれ脂肪 鎖の構造異性のものも含む。 [0008] In the formula (I), R ² , R ³ ,

The alkyl moiety of the alkyl group which may be substituted represented by R ^1Q , ^Ra and R ^b generally has a carbon number of 119, for example, a methynole group, an ethyl group, a propyl group, a butyl group, a pentyl group Hexyl group, octyl group, nonyl group, decyl group, nonadecyl group and the like, and these also include those having linear or branched structural aliphatic isomers.

R^a及び R^bで表される置換され てもよレ、アルケニル基のアルケニル部分、また置換されてもょレ、アルキニル基のアル キニル部分としては、一般に炭素数 2— 18のものが挙げられ、それらは直鎖又は枝 分かれ脂肪鎖の構造異性のものも含む。 [0009] In formula (I), R ¹ R ² , R ³ ,

The substituted or unsubstituted alkenyl moiety of the alkenyl group or the alkynyl moiety of the alkynyl group represented by R ^{a or} R ^b generally has 2 to 18 carbon atoms. They also include those having structural isomers of linear or branched fatty chains.

R^1Q、 R^a及び R^bで表される置換され てもよぃシクロアルキル基のシクロアルキル部分、また置換されてもよいシクロアルケ ニル基のシクロアルケニル部分としては、一般に炭素数 3— 10のものが挙げられ、シ クロプロピル基、シクロブチル基、シクロペンチル基、シクロへキシル基、シクロペンテ ニル基、シクロへキセニル基などの単環式基の他、縮合型多環式基、架橋型多環式 基なども挙げられる。 [0010] In the formula (I), R ² , R ³ , R ⁴ , R ⁵ , R ⁶ ,

The cycloalkyl portion of the substituted or unsubstituted cycloalkyl group represented by R ^1Q , R ^a and R ^b and the cycloalkenyl portion of the optionally substituted cycloalkenyl group generally have 3 to 10 carbon atoms. Monocyclic groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclopentenyl group and cyclohexenyl group, condensed polycyclic groups and crosslinked polycyclic groups. And the like.

R⁵、 R⁶、 R⁷、 R⁸、 R⁹、 R^a及び R^bで表される置換されてもよ ぃァリール基のァリール部分としては、フエニル基の他、ナフチル基のような縮合型 多環式基が挙げられる。 [0011] In the formula (I)

The aryl group of the aryl group which may be substituted represented by R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ^a and R ^b may be a phenyl group or a condensed type such as a naphthyl group. And polycyclic groups.

R⁴、 R⁵、 R⁶、 R⁷、 R⁸、 R⁹、 R^a及び R^bで表される置換されてもよ い複素環基の複素環部分としては、ピロリル基、ピロリニル基、ピロリジニル基、フラニ ル基、ジヒドロフラニル基、テトラヒドロフラニル基、チェニル基、ジヒドロチェニル基、 テトラヒドロチェニル基、ピラゾリル基、ピラゾリニル基、ピラゾリジニル基、イミダゾリル 基、イミダゾリニル基、イミダゾリジニル基、ォキサゾリル基、ォキサゾリニル基、ォキサ ゾリジニル基、イソォキサゾリル基、イソォキサゾリニル基、イソォキサゾリジニル基、チ ァゾリル基、チアゾリニル基、チアゾリジニル基、イソチアゾリル基、イソチアゾリニル基[0012] In the formula (I)

The heterocyclic moiety of the optionally substituted heterocyclic group represented by R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ^a and R ^b includes a pyrrolyl group, a pyrrolinyl group, a pyrrolidinyl Group, furanyl group, dihydrofuranyl group, tetrahydrofuranyl group, phenyl group, dihydrophenyl group, tetrahydrophenyl group, pyrazolyl group, pyrazolinyl group, pyrazolidinyl group, imidazolyl group, imidazolinyl group, imidazolidinyl group, oxazolyl group, oxazolinyl group Group, oxazolidinyl group, isoxazolyl group, isoxazolinyl group, isoxazolidinyl group, thiazolyl group, thiazolinyl group, thiazolidinyl group, isothiazolyl group, isothiazolinyl group

, Isothiazolidinyl, oxadiazolyl, oxadiazolinyl, oxadiazolyl Zinyl group, thiadiazolyl group, thiadiazolinyl group, thiadiazolidinyl group, triazolyl group, triazolinyl group, triazolidinyl group, tetrazolyl group, tetrazolinyl group, tetrazolidinyl group, dioxolyl group, dioxolanyl group, dithiolyl group, dithiolanyl group, pyridinole group , Dihydropyridinole, tetrahydropyridyl, piperidinyl, pyrimidyl, dihydropyrimidinole, tetrahydropyrimidinole, hexahydropyrimidyl, pyridazinyl, dihydropyridazinyl, tetrahydropyridinyl Dazinyl group, hexahydropyridazinyl group, pyrazul group, dihydropyrazul group, tetrahydropyrazul group, piperazinyl group, pyranyl group, dihydroviranyl group, tetrahydropyranyl group, dioxyl group, dioxyl group Monocyclic heterocyclic groups such as phenyl, dioxanyl, dithianyl, and morpholinyl; thienoenyl, dihydrocyclopentaphenyl, indolinole, tetrahydroindolyl, isoindolyl, tetrahydroisoindolyl Benzobenzoyl group, tetrahydrobenzozoenyl group, benzofuranyl group, tetrahydrobenzozofuranyl group, benzoxazolyl group, tetrahydrobenzozoxazolyl group, benzoisoxazolyl group, tetrahydrobenzozoisoxazolyl group, benzothiazolyl group , Tetrahydrobenzothiazolyl, benzoisothiazolyl, tetrahydrobenzoisothiazolyl, benzoimidazolyl, tetrahydrobenzoimidazolyl, benzodioxolyl, benzodithiolyl, benzodioxanyl Condensed polycyclic heterocyclic groups such as benzodithianyl group, quinolinyl group, isoquinolinyl group, quinazolinyl group, quinoxalinyl group, phthalazinyl group, naphthyridinyl group, and purinyl group; cross-linked polycyclic heterocyclic groups such as quinutalidinyl group And a ring group.

R^1Q、 R^a及び R^bで表される置換され てもよレ、アルキル基、置換されてもょレ、アルケニル基及び置換されてもょレ、アルキニ ル基の二次置換基としては、ハロゲン原子、水酸基、メルカプト基、置換可アルコキ シ基、置換可アルキルチオ基、置換可アルケニルォキシ基、置換可ァルケ二ルチオ 基、置換可アルキニルォキシ基、置換可アルキニルチオ基、置換可シクロアルキル 基、置換可シクロアルケニル基、置換可シクロアルコキシ基、置換可シクロアルキル チォ基、置換可シクロアルケニルォキシ基、置換可シクロアルケ二ルチオ基、置換可 アルコキシカルボニル基、置換可アルキルカルボニル基、置換可アルキルカルボ二 ルォキシ基、置換可アルケニルォキシカルボニル基、置換可アルケニルカルボニル 基、置換可アルケニルカルボニルォキシ基、置換可アルキニルォキシカルボニル基 、置換可アルキニルカルボニル基、置換可アルキニルカルボニルォキシ基、置換可 シクロアルコキシカルボニル基、置換可シクロアルキルカルボニル基、置換可シクロ アルキルカルボニルォキシ基、置換可シクロアルケニルォキシカルボニル基、置換可 シクロアルケニルカルボニル基、置換可シクロアルケニルカルボニルォキシ基、置換 可ァリール基、置換可ァリールォキシ基、置換可ァリールチオ基、置換可ァリールォ キシカルボニル基、置換可ァリールカルボニル基、置換可ァリールカルボニルォキシ 基、置換可複素環基、置換可複素環ォキシ基、置換可複素環チォ基、置換可複素 環ォキシカルボニル基、置換可複素環カルボニル基、置換可複素環カルボ二ルォキ シ基、置換可ァミノ基、シァノ基、ニトロ基、カルボキシル基、置換可ァミノカルボニル 基、置換可アルキルスルホニル基、置換可ァルケニルスルホニル基、置換可アルキ ニルスルホニル基、置換可シクロアルキルスルホニル基、置換可シクロアルケニルス ルホニル基、置換可ァリールスルホニル基、置換可複素環スルホニル基、置換可アミ ノスルホニル基などが挙げられ、それら置換基の数は 1個であっても 2個以上であつ てもよく、置換基の数が 2個以上の場合には、それらの置換基は同一であっても異な つていてもよい。 In the formula (I), R ² , R ³ ,

The secondary substituents of the substituted or unsubstituted, alkyl, substituted or alkenyl, substituted or unsubstituted or alkynyl groups represented by R ^1Q , ^Ra and R ^b include: Halogen atom, hydroxyl group, mercapto group, substitutable alkoxy group, substitutable alkylthio group, substitutable alkenyloxy group, substitutable alkenylthio group, substitutable alkynyloxy group, substitutable alkynylthio group, substitutable cycloalkyl Group, substitutable cycloalkenyl group, substitutable cycloalkoxy group, substitutable cycloalkylthio group, substitutable cycloalkenyloxy group, substitutable cycloalkenylthio group, substitutable alkoxycarbonyl group, substitutable alkylcarbonyl group, substitutable Alkyl carboxy alkoxy, substituted alkenyloxycarbonyl, substituted alkenylcarbonyl Group, substituted alkenylcarbonyloxy group, substituted alkynyloxycarbonyl group, substituted alkynylcarbonyl group, substituted alkynylcarbonyloxy group, substituted cycloalkoxycarbonyl group, substituted cycloalkylcarbonyl group, substituted cycloalkyl Carbonyloxy group, substituted cycloalkenyloxycarbonyl group, substituted cycloalkenylcarbonyl group, substituted cycloalkenylcarbonyloxy group, substituted aryl group, substituted aryloxy group, substituted arylaryl group, substituted aryloxycarbonyl group Group, substituted arylcarbonyl group, substituted arylcarbonyl group, substituted heterocyclic group, substituted heterocyclic oxy group, substituted heterocyclic thio group, substituted heterocyclic oxycarbonyl group, substituted heterocyclic group Ring carbonyl group, Substitutable heterocyclic ring Carbonyl group, substituted amino group, cyano group, nitro group, carboxyl group, substituted aminocarbonyl group, substituted alkylsulfonyl group, substituted alkenylsulfonyl group, substituted alkynylsulfonyl group, substituted A cycloalkylsulfonyl group, a substituted cycloalkenylsulfonyl group, a substituted arylarylsulfonyl group, a substituted heterocyclic sulfonyl group, a substituted aminosulfonyl group, and the like. It may be two or more, and when the number of substituents is two or more, those substituents may be the same or different.

R^1Q、 R^a及び R^bで表される置換され てもよぃシクロアルキル基、置換されてもよいシクロアルケニル基、置換されてもよい ァリール基及び置換されてもよい複素環基の二次置換基としては、ハロゲン原子、水 酸基、メルカプト基、置換可アルキル基、置換可アルケニル基、置換可アルキニル基 、置換可アルコキシ基、置換可アルキルチオ基、置換可アルケニルォキシ基、置換 可ァルケ二ルチオ基、置換可アルキニルォキシ基、置換可アルキニルチオ基、置換 可シクロアルキル基、置換可シクロアルケニル基、置換可シクロアルコキシ基、置換 可シクロアルキルチオ基、置換可シクロアルケニルォキシ基、置換可シクロアルケ二 ルチオ基、置換可アルコキシカルボニル基、置換可アルキルカルボニル基、置換可 アルキルカルボニルォキシ基、置換可アルケニルォキシカルボニル基、置換可アル ケニルカルボニル基、置換可アルケニルカルボニルォキシ基、置換可アルキニルォ キシカルボニル基、置換可アルキニルカルボニル基、置換可アルキニルカルボニル ォキシ基、置換可シクロアルコキシカルボニル基、置換可シクロアルキルカルボニル 基、置換可シクロアルキルカルボニルォキシ基、置換可シクロアルケニルォキシカル ボニル基、置換可シクロアルケニルカルボニル基、置換可シクロアルケニルカルボ二 ルォキシ基、置換可ァリール基、置換可ァリールォキシ基、置換可ァリールチオ基、 置換可ァリールォキシカルボニル基、置換可ァリールカルボニル基、置換可ァリール カルボニルォキシ基、置換可複素環基、置換可複素環ォキシ基、置換可複素環チ ォ基、置換可複素環ォキシカルボニル基、置換可複素環カルボニル基、置換可複 素環カルボニルォキシ基、置換可ァミノ基、シァノ基、ニトロ基、カルボキシル基、置 換可ァミノカルボニル基、置換可アルキルスルホニル基、置換可ァルケニルスルホニ ル基、置換可アルキニルスルホニル基、置換可シクロアルキルスルホニル基、置換可 シクロアルケニルスルホニル基、置換可ァリールスルホニル基、置換可複素環スルホ ニル基、置換可アミノスルホニル基などが挙げられ、それら置換基の数は 1個であつ ても 2個以上であってもよぐ置換基の数が 2個以上の場合には、それらの置換基は 同一であっても異なってレ、てもよレ、。 In the formula (I), R ² , R ³ ,

Secondary of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted aryl group and a substituted or unsubstituted heterocyclic group represented by R ^1Q , R ^a and R ^b Examples of the substituent include a halogen atom, a hydroxyl group, a mercapto group, a substituted alkyl group, a substituted alkenyl group, a substituted alkynyl group, a substituted alkoxy group, a substituted alkylthio group, a substituted alkenyloxy group, a substituted alkenyl group. Dilthio, substituted alkynyloxy, substituted alkynylthio, substituted cycloalkyl, substituted cycloalkenyl, substituted cycloalkoxy, substituted cycloalkylthio, substituted cycloalkenyloxy, substituted Cycloalkenylthio group, substituted alkoxycarbonyl group, substituted alkylcarbonyl group, substituted alkylcarbonyloxy group Group, substituted alkenyloxycarbonyl group, substituted alkenylcarbonyl group, substituted alkenylcarbonyloxy group, substituted alkynyloxycarbonyl group, substituted alkynylcarbonyl group, substituted alkynylcarbonyl group Oxy, substituted cycloalkoxycarbonyl, substituted cycloalkylcarbonyl, substituted cycloalkylcarbonyl, substituted cycloalkenyloxycarbonyl, substituted cycloalkenylcarbonyl, substituted cycloalkenylcarbonyl Group, substituted aryl group, substituted aryl thio group, substituted aryl carbonyl group, substituted aryl carbonyl group, substituted aryl carbonyl group, substituted hetero ring group, substituted hetero ring group Cyclic oxy group, substituted heterocyclic thio group, substituted heterocyclic oxycarbonyl group, substituted heterocyclic carbonyl group, substituted heterocyclic carbonyloxy group, substituted amino group, cyano group, nitro group, carboxyl group Group, replaceable aminocarbonyl group, replaceable alkylsulfonyl group, replaceable Alkenylsulfonyl group, substituted alkynylsulfonyl group, substituted cycloalkylsulfonyl group, substituted cycloalkenylsulfonyl group, substituted arylarylsulfonyl group, substituted heterocyclic sulfonyl group, substituted aminosulfonyl group, and the like. The number of substituents may be 1 or 2 or more.If the number of substituents is 2 or more, those substituents may be the same or different. Les ,.

R⁸及び R^1Qで表される置換されてもょレ、ァミノ基の二次置換基とし ては、水酸基、置換可アルキル基、置換可アルケニル基、置換可アルキニル基、置 換可アルコキシ基、置換可アルケニルォキシ基、置換可アルキニルォキシ基、置換 可シクロアルキル基、置換可シクロアルケニル基、置換可シクロアルコキシ基、置換 可シクロアルケニルォキシ基、置換可アルコキシカルボニル基、置換可アルキルカル ボニル基、置換可アルケニルォキシカルボニル基、置換可アルケニルカルボニル基 、置換可アルキニルォキシカルボニル基、置換可アルキニルカルボニル基、置換可 シクロアルコキシカルボニル基、置換可シクロアルキルカルボニル基、置換可シクロ アルケニルォキシカルボニル基、置換可シクロアルケニルカルボニル基、置換可ァリ ール基、置換可ァリールォキシ基、置換可ァリールォキシカルボニル基、置換可ァリ ールカルボニル基、置換可複素環基、置換可複素環ォキシ基、置換可複素環ォキ シカルボニル基、置換可複素環カルボニル基、置換可ァミノカルボニル基、置換可 アルキルスルホニル基、置換可ァルケニルスルホニル基、置換可アルキニルスルホ 二ノレ基、置換可シクロアルキルスルホニル基、置換可シクロアルケニルスルホニル基 、置換可ァリールスルホニル基、置換可複素環スルホニル基、置換可アミノスルホニ ル基などが挙げられ、それら二次置換基の数は 1個であっても 2個であってもよぐ 2 個の場合、それらは同一であっても異なっていてもよい。また、 2個の二次置換基が 一緒になつてへテロ原子を含むか含まずして環を形成してもよい。 Formula (I)

Examples of the substituted substituent of the substituted or unsubstituted amino group represented by R ⁸ and R ^1Q include a hydroxyl group, a substituted alkyl group, a substituted alkenyl group, a substituted alkynyl group, a substituted alkoxy group, Substituted alkenyloxy group, substituted alkynyloxy group, substituted cycloalkyl group, substituted cycloalkenyl group, substituted cycloalkoxy group, substituted cycloalkenyloxy group, substituted alkoxycarbonyl group, substituted alkylcal Bonyl group, substituted alkenyloxycarbonyl group, substituted alkenylcarbonyl group, substituted alkynyloxycarbonyl group, substituted alkynylcarbonyl group, substituted cycloalkoxycarbonyl group, substituted cycloalkylcarbonyl group, substituted cycloalkenyl group Xycarbonyl group, substituted cycloalkenylcarbonyl group, substituted aryl Aryl group, substituted aryloxy carbonyl group, substituted aryl carbonyl group, substituted heteroaryl group, substituted heterocyclic oxy group, substituted heterocyclic oxycarbonyl group, substituted Heterocyclic carbonyl group, substituted aminocarbonyl group, substituted alkylsulfonyl group, substituted alkenylsulfonyl group, substituted alkynylsulfoninole group, substituted cycloalkylsulfonyl group, substituted cycloalkenylsulfonyl group , A substituted arylsulfonyl group, a substituted heterocyclic sulfonyl group, a substituted aminosulfonyl group, etc., and the number of the secondary substituents may be one or two. If so, they can be the same or different. Also, two secondary substituents may be joined together to form a ring with or without a heteroatom.

Among the above secondary substituents, the tertiary substituent of each substitutable group includes a halogen atom, a hydroxyl group, a mercapto group, a cyano group, a nitro group, a carboxy group, an amino group, an alkyl group, an alkenyl group, and an alkynyl group. , Cycloalkyl group, cycloalkenyl group, aryl group, complex ring group, alkoxy group, alkenyloxy group, alkynyloxy group, cycloalkyloxy group, cycloalkenyloxy group, aryloxy group, heterocyclic oxy group, alkyl Thio, alkenylthio, alkynylthio, cycloalkylthio, cycloalkenylthio, arylthio, heterocyclic thio, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl , Arylsulfonyl group, multiple Ring sulfonyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl, heterocyclic carbonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynylo Xylation carbonyl, cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl, aryloxycarbonyl, heterocyclic oxycarbonyl, amino, alkylaminocarbonyl, dialkylaminocarbonyl, Alkenylamino force carbonyl group, alkynylaminocarbonyl group, cycloalkylaminocarbonyl group, cycloalkenylaminocarbonyl group, arylaminocarbonyl group, heterocyclic aminocarbonyl group, Aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkenylaminosulfonyl, alkynylaminosulfonyl, cycloalkylaminosulfonyl, cycloalkenylaminosulfonyl, arylaminosulfonyl, heterocyclic aminosulfonyl Group, anolequinoleamino group, dialkylamino group, alkenylamino group, alkynylamino group, cycloalkylamino group, cycloalkenylamino group, arylamino group, heterocyclic amino group, alkylcarbonylamino group, Alkenylcarbonyl amino, alkynylcarbonylamino, cycloalkylcarbonylamino, cyclo Alkenylcarbonylamino group, arylcarbonylamino group, heterocyclic carbonylamino group, alkylsulfonylamino group, alkenylsulfonylamino group, alkynylsulfonylamino group, cycloalkylsulfonylamino group, cycloalkenylsulfonylam Amino group, arylsulfonylamino group, heterocyclic sulfonylamino group and the like.The number of tertiary substituents may be one or two or more. The substitution groups may be the same or different. Further, when the secondary substituent is an amino group substituted by two tertiary substituents, the tertiary substituents may form a ring together with or without a hetero atom-containing force. Les ,.

[0017] Further, the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclic moieties of these tertiary substituents further include a halogen atom, a hydroxyl group, a mercapto group, a cyano group, a nitro group, Carboxyl group, amino group, alkynole group, haloalkyl group, alkoxy group, haloalkoxy group, alkylthio group, noroanokelthio group, alkoxycarbonyl group, aminocarbonyl group, alkylaminocarboxy group, dialkylaminocarbonyl group, amino Quaternary groups such as sulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, anoalkylamino, dialkylamino, alkylcarbonylamino, alkylsulfonylamino, cycloalkyl, aryl, and heterocyclic groups When the number of the substituents which may be substituted by the substituent is 1 or 2 or more, the number of the substituents is 2 or more. Even if one is different, it may be different.

 BEST MODE FOR CARRYING OUT THE INVENTION

Next, some preferred embodiments of the present invention will be described, but the present invention is not limited thereto.

(1) A is a CG group (G is as described above); R ¹ and R ² are each independently a hydrogen atom, an optionally substituted alkyl group, a —B ¹ —R ⁵ group (B ¹ And R ⁵ are the same as described above) or an optionally substituted amino group, and Y and Z are each independently a nitrogen atom or a CR ⁸ group (where R ⁸ is a hydrogen atom, And X is a nitrogen atom or a C_R ^1Q group (R ^1Q is a hydrogen atom or a halogen atom), or a —B ² —R ⁹ group (B ² and R ⁹ are as described above). Or a fused heterocyclic compound of the formula (I) or a salt thereof. (2) 0 is 〇CO R ⁴ group (R ⁴ is as described above), SO NR ^a R ^b group or CONR ^a R ^b group (R ^a and R ^b are as described above) (1 )) Or a salt thereof.

(3 ¹ and R ² are each independently a condensation of (1) or (2) which is a B ^ R ⁵ group (B ¹ and R ⁵ are as defined above) or an amino group which may be substituted. A heterocyclic compound or a salt thereof.

(4) the fused heterocyclic compound of (3), wherein R ¹ is a —B ^ R ⁵ group (B ¹ and R ⁵ are as described above), and R ² is an amino group which may be substituted; Its salt.

(5) The fused heterocyclic compound of (4) or a salt thereof, wherein B ¹ is S, and R ⁵ is an optionally substituted alkyl group.

(6) The fused heterocyclic compound of (1) or a salt thereof, wherein B ² is S and R ⁹ is an optionally substituted alkyl group.

(7) The fused heterocyclic compound of (2), (3), (4) or (5), wherein R ⁴ is a hydrogen atom or an alkyl group which may be substituted, or a salt thereof.

(8) The fused heterocyclic compound of (2) or a salt thereof, wherein ^Ra and ^Rb are each independently a hydrogen atom or an optionally substituted alkyl group.

(9) R ¹ and R ² may have an amino group which may be substituted.A hydroxyl group, a substituted alkyl group, a substituted alkynyl group, a substituted alkoxy group, a substituted aryl group, a substituted aryloxy group or a substituted heterocyclic group The fused heterocyclic compound of (1) which is an amino group which may be substituted with or a salt thereof.

 (10) The fused heterocyclic compound of (9) or a salt thereof, wherein the substitutable alkyl group is an alkyl group which may be substituted with an aryl group, a heterocyclic group, an alkoxy group, an aryloxy group or an alkyloxycarbonyl group.

 (11) The fused complex ring compound or a salt thereof according to (10), wherein the aryl group is a phenyl group which may be substituted with a halogen atom.

 (12) The fused heterocyclic compound of (10) or a salt thereof, wherein the heterocyclic group is a chenyl group, a dioxolanyl group, a pyridinole group or a dioxanyl group.

 (13) The condensed heterocyclic compound of (10) or a salt thereof, wherein the alkoxy group is an alkoxy group which may be substituted with an alkoxy group.

(14) The fused heterocyclic compound of (9), wherein the substitutable alkoxy group is an arylalkoxy group, or Is its salt.

 (15) The fused heterocyclic compound of (9) or a salt thereof, wherein the substituted aryl group may be substituted with a halogen atom, a cyano group, a nitro group or an alkyl group, or a phenyl group.

 (16) The fused heterocyclic compound of (9), wherein the substituted heterocyclic group is a benzothiazolyl group or a benzodioxolyl group, or a salt thereof.

 The compound of the formula (I) or a salt thereof has an agonist action on adenosine A2a receptor, promotes wound healing, induces sleep, lowers body temperature, lowers blood pressure, suppresses immune cell function, and suppresses neutrophils. It has pharmacological effects such as suppression of function and suppression of production of cytokins such as TNF-, IL_2, IL_4, and interferon-γ.

 [0020] Therefore, the compound of the formula (I) or a salt thereof is used for skin ulcer, leg ulcer, burn ulcer, frostbite ulcer, traumatic ulcer, pressure ulcer, venous ulcer, arterial ulcer, post-herpetic ulcer, radiation ulcer Wound healing promoter used for treatment or prevention of drug ulcer, diabetic ulcer, postoperative ulcer, etc .; Sleep inducer used for treatment or prevention of insomnia, psychiatric disease, etc .; Treatment of febrile illness Antipyretics used for the prevention or prevention of blood pressure; antihypertensives used for the treatment or prevention of hypertension; drugs for the treatment or prevention of diseases associated with abnormally enhanced immune cell function and / or production of cytodynamics; abnormal neutrophil function It is useful as an active ingredient such as a therapeutic or prophylactic agent for a disease associated with hypertension.

 [0021] The above-mentioned diseases accompanied by abnormally enhanced immune cell function and / or cytodynamic production include autoimmune diseases, erythema nodosum leprosum, Behcet's disease, lupus erythematosus, aphthous ulcers, cancer and infectious diseases in infectious diseases. Fluid quality, septic shock, adult respiratory distress syndrome, osteoarthritis, multiple sclerosis, Crohn's disease, inflammatory bowel disease, multiple organ failure, malaria, meningitis, hepatitis, acquired immunodeficiency syndrome, junction measles, Food allergy, anaphylactic shock, eosinophilia syndrome, asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, other allergic diseases, systemic lupus erythematosus, rheumatoid arthritis, type I diabetes, Hashimoto's thyroiditis, severe Examples include myasthenia, multiple sclerosis, other organ-specific autoimmune diseases, and rejection associated with organ transplantation.

 [0022] Examples of the disease associated with abnormally enhanced neutrophil function include adult respiratory distress syndrome (

ARDS), bronchitis, chronic bronchitis, chronic obstructive pneumonia, cystic fibrosis, asthma, emphysema, Tracheal diseases such as bronchiectasis, chronic sinusitis and rhinitis, male erectile dysfunction, epilepsy, cerebral ischemia, peripheral vascular disease, post-ischemic reperfusion injury, rheumatoid arthritis, multiple sclerosis, psoriasis, Dermatitis, eczema, ulcerative colitis, Crohn's disease, inflammatory bowel disease, Helicobacter 'Heriobacter pylori' gastritis, non-Helicobacter 'H. pylori' gastritis, non-steroidal anti-inflammatory drug-induced damage to the gastrointestinal tract No.

 With respect to the use of the compound of the formula (I) or a salt thereof, there are specifically the following embodiments.

 (1) Use of a compound of the formula (I) or a salt thereof for producing a medicament for treating or preventing a disease requiring administration of an adenosine A2a receptor agonist.

 (2) Use of the compound of the formula (I) or a salt thereof for producing a wound healing promoter.

 (3) Use of the compound of the formula (I) or a salt thereof for producing a sleep inducer.

 (4) Use of the compound of the formula (I) or a salt thereof for producing an antipyretic agent.

 (5) Use of a compound of the formula (I) or a salt thereof for producing a hypotensive agent.

 (6) Use of the compound of the formula (I) or a salt thereof for the manufacture of a therapeutic or prophylactic agent for a disease associated with abnormally enhanced immune cell function and / or cytokin production.

 (7) Use of the compound of the formula (I) or a salt thereof for producing a therapeutic or prophylactic agent for a disease associated with abnormally increased neutrophil function.

 (8) A method for treating or preventing a disease requiring administration of an adenosine A2a receptor agonist, comprising administering an effective amount of the compound of the formula (I) or a salt thereof to a mammal including a human.

 (9) A method for treating or preventing a wound comprising administering an effective amount of the compound of the formula (I) or a salt thereof to a mammal including a human.

 (10) A method for treating or preventing a sleep disorder, which comprises administering an effective amount of the compound of the formula (I) or a salt thereof to a mammal including a human.

 (11) A method for treating or preventing a febrile disease, comprising administering an effective amount of the compound of the formula (I) or a salt thereof to a mammal including a human.

 (12) A method for treating or preventing hypertension, which comprises administering an effective amount of the compound of the formula (I) or a salt thereof to a mammal including a human.

(13) Treating or preventing a disease associated with abnormally enhanced immune cell function and / or cytodynamic production, which comprises administering an effective amount of the compound of the formula (I) or a salt thereof to mammals including humans. how to.

 (14) A method for treating or preventing a disease associated with abnormally enhanced neutrophil function, comprising administering an effective amount of the compound of the formula (I) or a salt thereof to a mammal including a human.

 [0024] The compound of the formula (I) or a salt thereof is generally used in the form of a general pharmaceutical preparation (for example, a method prescribed in the 14th revised Japanese Pharmacopoeia). This pharmaceutical preparation is prepared using commonly used diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants and lubricants. Various forms of pharmaceutical preparations can be selected according to the purpose of treatment, such as tablets, pills, powders, powders, granules, capsules, suppositories, solutions, suspensions, emulsions, injections (solutions, suspensions). Agents), sprays, aerosols, creams, ointments, lotions, transdermal agents (patches, matrices, tapes), gels and the like.

 [0025] In the form of a tablet, a wide variety of carriers known in the art can be widely used, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and caic acid. Excipients such as water, ethanol, propanol, single syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.IJ, dry starch, sodium alginate , Agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, disintegrants such as monoglyceride stearate, starch, lactose, sucrose, stearin, cocoa butter, hydrogenated oil, etc. Collapse Antibiotics, quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, and colloidal keic acid, purified talc, stearate , Boric acid powder, and lubricants such as polyethylene dalicol. Further, the tablet can be made into a tablet coated with a usual coating, if necessary, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an S-coated tablet, a film-coated tablet, a double tablet, or a multilayer tablet.

[0026] In molding into a pill form, a wide variety of carriers known in the art can be widely used as a carrier, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, and the like. Examples thereof include a gum arabic powder, a tragacanth powder, a binder such as gelatin and ethanol, and a disintegrant such as laminaran agar. [0027] In molding into a suppository form, conventionally known carriers can be widely used, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides. Can be.

 [0028] When prepared as an injection, the liquid preparation, emulsion and suspension are sterilized, and when formed into the form of these liquid preparations, emulsions and suspensions, which are preferably isotonic with blood and blood. As the diluent, any one commonly used in this field can be used as a diluent, for example, water, aqueous solution of lactate, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid Esters and the like can be mentioned. In this case, a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution may be included in the pharmaceutical preparation, and ordinary solubilizers, buffers, and soothing agents are added. May be. Further, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent or the like and other pharmaceuticals may be incorporated into the pharmaceutical preparation, if necessary.

 [0029] The amount of the compound of the formula (I) or a salt thereof to be contained in the composition of the present invention is not particularly limited and may be appropriately selected over a wide range. In a preferred embodiment, the content is preferably 5 to 50% by weight.

[0030] The administration method of the composition of the present invention is orally or parenterally administered according to a method depending on various formulation forms, patient age, sex and other conditions, degree of disease, etc., which are not particularly limited. For example, when administered orally, tablets, pills, solutions, suspensions, emulsions, granules, capsules and the like are mentioned as desirable embodiments. Parenterally, it can be administered in the form of topical administration, injection, transdermal, nasal, pulmonary, suppository, etc. In the case of injections, they are administered intravenously, alone or mixed with normal replenishers such as glucose and amino acids, and if necessary, intramuscularly, intradermally, subcutaneously, or intraperitoneally. This is a desirable mode. In the case of suppositories, it is a desirable embodiment to administer rectally. When the composition of the present invention is used as a wound healing agent, it is desirable to administer the composition in the form of a topical administration agent. As a method for administering a topically administered agent, for example, a spray, an aerosol, a cream, an ointment, a lotion, a transdermal agent, a gel or the like, or a composition of the present invention contained in various kinds of wound dressings, To the skin and the like. In addition, The affected area after administration can be protected with various wound dressings.

 [0031] The dose of the composition of the present invention is appropriately selected depending on the usage, the age of the patient, gender and other conditions, the degree of the disease, and the like. Can be administered at a dose of about 0.05 to 50 mg per kg of body weight per day. In addition, it is a desirable embodiment that the active ingredient is contained in the dosage unit form in an amount of 110 mg.

 [0032] The composition of the present invention includes, for example, antiviral drugs, antibacterial drugs, antibiotics, antiparasitic drugs, antifungal drugs, antipruritics, analgesics, anti-inflammatory drugs, disinfectants, proteolytic enzymes, granulation and epidermis Formation promoter

And at least one of various agents such as a wound covering agent, and may exhibit more excellent effects in treating or preventing a disease requiring administration of adenosine A2a receptor agonist.

 [0033] The compound of the formula (I) or a salt thereof can be produced by a known method or a method analogous thereto, for example, a method described in WO02 / 40485. Table 1 shows specific examples of the compound of the formula (I), but the compound of the formula (I) is not limited thereto.

[0034] [Table 1]

Table 1

2] 第 1表つづき

2] Table 1 continued

3] 第 1表つづき

3] Table 1 continued

Example

 Next, the ability to describe test examples according to the present invention The present invention is not limited to these.

 Test Example 1 (Wound healing promoting action)

A male ICR mouse (body weight: 22 soil, 2 g) was anesthetized with hexobarbital (90 mg / kg, intraperitoneal administration), and the skin of the shoulder and back was removed by a sharp punch with a diameter of 12 mm. Immediately thereafter, 30 μg / 20 μL of the test compound suspended in 1.5% CMC-Na was applied to the cut skin. Thereafter, the test compound was applied once a day every day, and the wound area was measured 1, 3, 5, 7, 9 and 11 days later. The wound area was measured with an image analyzer (Life Science Resources Vista, Version 3.0) after placing a transparent plastic sheet on the wound and tracing the wound boundary. The rate of wound repair was evaluated as CT50 (wound half-closure time). CT50 was calculated using Graph-Pad Prism (Graph Pad Software USA). The test was performed with 5 animals / group, and the difference between the mean values of the test substance administration group and the vehicle control group was tested by the Student's t test. The results are shown in Table 2. [Table 4] Table 2

Test Example 2 (Sleep-inducing effect)

A test compound suspended in 0.25% CMC_Na is orally administered to a male ICR mouse (body weight 22 ± 2 g) at 150 mg / kg, and one hour later, 90 mg / kg of hexobarbital sodium is intraperitoneally administered. Then, the sleep time is measured using the recovery of the light reflection reaction as an index. The test is performed as 3 animals per group. Only evaluate the average sleep during sleep extension time rate calculated based on between group administered%? As ^ 10 _{1¾ &} 110 _{1 1} solvent instead of the test compound. As a result, it is found that the compound of the present invention has a sleep-inducing effect.

 Test Example 3 (body temperature lowering effect)

 A test compound suspended in 0.25% CMC_Na is orally administered to a male ICR mouse (body weight: 22 ± 2 g) at 150 mg / kg, and rectal temperature is measured immediately thereafter (Thermolert, TH_5). Further, the body temperature is measured at 30, 60, 90 and 120 minutes later. If there is an average change of 5% or more compared to the body temperature before administration, it is considered that there is a significant change due to administration of the test compound. The test is performed as 3 animals per group. As a result, it is found that the compound of the present invention has a body temperature lowering effect.

Test Example 4 (blood pressure lowering effect)

 To a male Wistar-Okamoto-derived spontaneously hypertensive (SHR) rat (body weight 250 ± 20 g), a test compound suspended in 0.25% CMC_Na was orally administered at 150 mg / kg, and immediately thereafter, blood pressure was increased by an indirect method. Measure (Blood-Pressure Indirect Sensors & Model B60, IITC USA). Further, blood pressure is measured at 1, 2 and 4 hours later. If the blood pressure changes by an average of 10% or more compared to the blood pressure before administration, it is considered that there is a significant change due to the administration of the test compound. The test is performed as 3 animals per group. As a result, it is found that the compound of the present invention has a blood pressure lowering effect.

Test Example 5 (Inhibition of cytoforce-in production in human peripheral blood mononuclear cells) (1) IL-2 production inhibitory action

Human peripheral blood mononuclear cells were stimulated with 20 μg / mL concanapalin A (ConA), and the amount of IL-2 produced after 16 hours of culture in the presence of the test compound at _{10 /} iM was measured by enzyme immunoassay. Measure. As a result, it is found that the compound of the present invention has an IL-2 production inhibitory action. The results are expressed as the inhibition rate compared with the amount of site force in the solvent control group.

 (2) IL-4 production inhibitory action

 In a commissioned test at MDS Pharma Service, it was performed based on the basic operating procedures of Code No.308400. That is, human peripheral blood mononuclear cells were stimulated with 20 μg / mL concanapalin A (ConA), and the amount of IL-4 produced after 16 hours of culture was measured by enzyme immunoassay in the presence of 10 μM of the test compound. Measure. As a result, it is found that the compound of the present invention has an IL-4 production inhibitory action. In addition, the result is represented by the inhibition rate in comparison with the amount of site force in the solvent control group.

 (3) INF-y production inhibitory action

Human peripheral blood mononuclear cells were stimulated with 20 μg / mL concanapalin A (ConA), and the amount of IFN-γ production after 16 hours of culture in the presence of the test compound at _{10 /} iM was measured by enzyme immunoassay. Measure. As a result, it is found that the compound of the present invention has an INF-γ production inhibitory action. The results are expressed as the inhibition rate compared with the amount of site force in the solvent control group.

 (4) TNF_ct production inhibitory action

Human peripheral blood mononuclear cells are stimulated with 25 ng / mL lipopolysaccharide (LPS), and the amount of TNF-a production after 16 hours of culture in the presence of ₁₀ M of the test compound is measured by enzyme immunoassay. As a result, it is found that the compound of the present invention has a TNF-ct production inhibitory action. The results are expressed as the inhibition rate compared to the amount of site force in the solvent control group.

 Test Example 6 (Test for binding affinity to adenosine A2a receptor)

The ^[3 H] CGS 21680 and the test compound 10 mu Micromax adenosine A2a human recombinant receptor was expressed HEK-293 cell suspension Torichi © beam labeled 50nM added, the binding affinity to the adenosine A2a receptor The binding inhibitory activity of [3H] CGS21680 as an index was measured using a liquid scintillation counter. The results are shown in Table 3 as the binding inhibition rate (%).

[Table 5] Table 3

Test Example 7 (IL-2 production inhibitory action in mouse spleen cells)

The adenosine A2a receptor agonist action of the test compound was evaluated using the IL-2 production inhibitory activity induced by T cell receptor stimulation as an index. That is, the treatment of mouse spleen cells with anti-mouse CD3 antibody and human recombinant IL_2 (Genzym No. 2202) induced cytodynamic force-in production. A test compound was added to the cytoforce-in producing system, and its production was measured by the following method. Anti-mouse CD3 antibody prepared at 10-20 μg / ml with borate buffered saline (PH8.5) was dispensed into a 96-well cell culture plate at 50 _β1 / well and incubated at 4 ° C for 18 hours. Left for hours. After removing the unreacted solution and washing once with Hank's buffer, IL-2 adjusted to 10 ng / ml with RPMI solution containing 10% fetal calf serum (FCS) was dispensed at 50 _β 1 / well. Here, in the negative control group, the anti-CD3 antibody and IL-12 were removed, and only the solution was processed. Subsequently, the test compound dilution was dispensed in 50 μl / well portions (final concentration: 10 μΜ), and 1 × 10 5 prepared from the spleen of Balb / c mouse (female, 7-10 weeks old). ^Seven cell suspensions / ml were dispensed at 100 μl / well. After culturing for 40-48 hours in an incubator (37 ° C, 5% CO2), the culture supernatant was collected and the amount of cytodynamic force produced was measured by ELISA.

[0047] The amount of IL-12 cytoplasm produced was measured by the following method. That is, IL-12 production The amount was quantified by the following ELISA method. First, as a primary antibody, rat anti-mouse IL-2 antibody (Pharmingin, Code No. 18161D) was diluted 1 / ig / ml with a carbonate buffer (ρΗ9.5) to form a 50 / well 96-well plate. (IWAKI, Code No. 3860-096), and coated at 4 ° C for 16 hours. Then the plate is 10. Blocking was performed at 37 ° C for 2 hours in phosphate buffered saline containing 7.2 g / oFCS (blocking buffer) (250 µl / well). The plate is washed four times with PBS (washing buffer) containing 0.05% Tween20 (Nacalai Tester, Code No. 281-51), and the culture supernatant diluent is spread at 50 μl / well at room temperature. And incubated for 1 hour. Recombinant mouse IL_2 (R & D Systems, Code No. 402—ML) was used to create a calibration curve. The plate is washed four times using a washing buffer, and a biotin-labeled rat anti-mouse IL-12 antibody (Pharmingen, Code No. 18172D) is used as a secondary antibody in a blocking buffer containing 0.05% Tween 20 at 0.5 μl. The solution diluted in gZml was added (50 μl 1-well), and incubated at room temperature for 1 hour. After washing the plate four times with the washing buffer, add streptavidin-labeled peroxidase (Prozyme, Code No. CJ30H001) diluted 800-fold with a blocking buffer containing 0.05% Tween20 (50 / il / well). The reaction was performed at room temperature for 15 minutes. The plate was washed four times with a washing buffer, and 100 µl / well of a TNB substrate solution (Sigma, Code No. T-8665) was added for color development for 10-20 minutes. After stopping the reaction by adding 100 μl / well of 1 M sulfuric acid solution, the absorbance was measured (wavelength 450 nm) using a microplate reader (Spectramax, Wako Pure Chemical Industries, Ltd.).

[0048] Each experiment was performed in duplicate, and the average value of the amount of cytodynamic force produced was determined. From the average value, the inhibition rate (%) was determined by the following equation.

 Suppression rate (%) = {l- (T-N) / (P-N)} X 100

 Here, T represents the average value of the test compound treated group, N represents the average value of the negative control group, and P represents the average value of the positive control group. Table 4 shows the inhibitory rates of production of each site force in this manner.

[Table 6] Table 4

Compound IL-2 Compound IL-2 Compound IL-2 Compound IL-2

No. Inhibition rate% No. Inhibition rate% No. Inhibition rate% No. Inhibition rate%

1 98 10 60 29 96 43 94

2 95 1 1 93 30 87 44 99

3 98 13 63 31 72 46 85

4 98 20 75 32 58 47 86

5 94 21 99 33 82 48 97

6 80 24 81 35 83 50 97

7 98 25 97 38 94 51 99

8 98 26 91 41 98 52 73

9 66 28 37 42 97

Claims

[In the formula, A nitrogen atom or C-G group {G is CN, NO, SO R ³ group (R ³ is an alkyl group but it may also be substituted, an optionally substituted alkenyl group, optionally substituted A good alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group), a C〇R ⁴ group ( R ⁴ is a hydrogen atom An optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group or is an optionally substituted heterocyclic group), CH_〇, SO NR ^b group (Ra and Rb are each independently a hydrogen atom, a hydroxyl group, an alkoxy group, an optionally substituted alkyl group, optionally substituted Or an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group. Or R ^a and R ^b together form a ring) or a CONR ^a R ^b group (R ^a and R ^b are as defined above)}; R ¹ and R ² are each independently a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, Optionally substituted cycloalkenyl group, optionally substituted aryl group, optionally substituted heterocyclic group, —B ^ R ⁵ group (B ¹ is C ¹ , COO, 0, 〇CO, OSO, S, SO or SO, wherein R ⁵ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl An optionally substituted cycloalkenyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group), an optionally substituted amino group or an N = CR ⁷ group (R ⁶ and R ⁷ is each independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkyl group; An alkenyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group); Y and Z are each independently a nitrogen atom or C - R ⁸ group {R ⁸ is a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, § optionally substituted Norekiniru Group, optionally substituted cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted aryl group, optionally substituted heterocyclic group, —B ² —R ⁹ group (B ² is , CO〇, 0, OCO, OSO, S, SO or SO, wherein R ⁹ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, A cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted, an aryl group which may be substituted, an aryl group or a heterocyclic group which may be substituted), Group, a cyano group or a nitro group}, Y and Z Well-, it is two R ⁸ when taking a CR ⁸ group simultaneously be the same or different; X is a nitrogen atom or a CR ^1Q group (R ^1Q is a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted A cycloalkyl group, an optionally substituted cycloalkenyl group, a B ² —R ⁹ group (B ² and R ⁹ are as defined above), an optionally substituted amino group, a cyano group or a nitro group} And; Furthermore Y is C one R ⁸ groups, if X is C one R ^1Q group or Z is a C one R ⁸ groups, R ⁸ and R ^1Q there have two R ⁸ are hetero atoms together such connexion A ring may be formed with or without the adenosine A2a receptor agonist containing, as an active ingredient, a fused heterocyclic compound represented by the formula (1) or a salt thereof. Composition.  [2] A wound healing promoter comprising the compound according to claim 1 or a salt thereof as an active ingredient. [3] Wounds are skin ulcers, leg ulcers, burn ulcers, frostbite ulcers, traumatic ulcers, pressure ulcers, venous ulcers, arterial ulcers, post-herpetic ulcers, radiation ulcers, drug ulcers, diabetic ulcers or surgery 3. The wound healing promoter according to claim 2, which is a post-ulcer. [4] A sleep inducer comprising the compound according to claim 1 or a salt thereof as an active ingredient. [5] An antipyretic agent comprising the compound according to claim 1 or a salt thereof as an active ingredient. [6] A blood pressure lowering agent comprising the compound according to claim 1 or a salt thereof as an active ingredient. [7] A therapeutic or prophylactic agent for a disease associated with abnormally enhanced immune cell function or cytodynamic production, comprising the compound according to claim 1 or a salt thereof as an active ingredient. [8] Diseases include autoimmune disease, erythema nodosum leprosum, Behcet's disease, lupus erythema, aphthous ulcer, cachexia in cancer and infectious diseases, septic shock, adult respiratory distress syndrome, osteoarthritis, multiple occurrence Sclerosis, Crohn's disease, inflammatory bowel disease, multiple organ failure, malaria, meningitis, hepatitis, acquired immunodeficiency syndrome, juniper measles, food allergy, anaphylactic shock, eosinophilia syndrome, asthma, allergic rhinitis , Allergic conjunctivitis, atopic dermatitis, other allergic diseases, systemic lupus erythematosus, rheumatoid arthritis, type I diabetes, Hashimoto's thyroiditis, myasthenia gravis, multiple sclerosis, organ-specific autoimmune diseases and 9. A method for treating a disease associated with abnormally enhanced immune cell function and / or cytodynamic in production according to claim 7, which is at least one selected from rejection reactions associated with organ transplantation. Medicinal or prophylactic drugs [9] A therapeutic or prophylactic agent for a disease associated with abnormally increased neutrophil function, comprising the compound according to claim 1 or a salt thereof as an active ingredient.  [10] The disease is tracheal disease, male erectile dysfunction, epilepsy, cerebral ischemia, peripheral vascular disease, recurrent injury after ischemia, rheumatoid arthritis, multiple sclerosis, psoriasis, dermatitis, eczema, ulcer At least one selected from ulcerative colitis, Crohn's disease, inflammatory bowel disease, Helicobacter pylori gastritis, non-Helicobacter pylori gastritis, and nonsteroidal anti-inflammatory drug-induced damage to the gastrointestinal tract. Therapeutic agent or prevention of a disease associated with abnormally enhanced neutrophil function according to 9