JP2005023064A - COMPOSITION FOR TREATING OR PREVENTING DISEASE REQUIRING ADMINISTRATION OF ADENOSINE A2a-RECEPTOR AGONIST - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a composition for treating or preventing a disease requiring the administration of an adenosine A2a receptor agonist. <P>SOLUTION: This composition uses a fused heterocyclic compound expressed by formula (1) [wherein, A is N, C-G or the like; R<SP>1</SP>, R<SP>2</SP>are each independently H, a halogen atom, a substitutable alkyl, a substitutable aryl, a substitutable heterocyclic ring or the like; Y, Z are each independently N or C-R<SP>8</SP>, and two R<SP>8</SP>s may be the same or different when the Y and Z are C-R<SP>8</SP>at the same time; X is N or C-R<SP>10</SP>; and further when Y is C-R<SP>8</SP>, X is C-R<SP>10</SP>or Z is C-R<SP>8</SP>, R<SP>8</SP>and R<SP>10</SP>or two R<SP>8</SP>s may join together to form a ring either by containing a hetero atom or not containing the same] or its salt as an active ingredient. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

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

  The adenosine receptor is a seven-transmembrane G protein coupled receptor widely distributed in the living body, and it has been known that there are four subtypes A1, A2a, A2b and A3 so far. A1 and A3 are coupled to adenylate cyclase-inhibited Gi protein, and A2a and A2b are coupled to activated Gs protein, respectively, and play an important role in various physiological functions by regulating cAMP concentration, which is the second messenger. It is considered a thing. A1 and A2a receptors have high affinity for adenosine, while A2b and A3 receptors have low affinity, and their subtypes have different localization and distribution in each tissue in the body. . In addition, stimulation of adenosine A2a receptor by agonists can promote wound healing, sleep, decrease in body temperature, decrease in blood pressure, suppression of immune cell function, suppression of neutrophil function, tumor necrosis factor-α (TNF-α) and interleukin- It has been reported to induce various effects such as suppression of cytokine production such as 2 (IL-2).

  On the other hand, the condensed heterocyclic compound of the following formula (I) 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 agonistic action.

International Publication WO02 / 40485

  The present inventors have found that a specific fused heterocyclic compound or a salt thereof has an adenosine A2a agonistic action, and have proposed the present invention.

  That is, the present invention relates to the formula (I):

[In the formula, A is a nitrogen atom or a CG group {G is CN, NO ₂ , SO ₂ R ³ group (R ³ is an alkyl group that may be substituted, an alkenyl group that may be substituted, An alkynyl group which may be substituted, a cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted, an aryl group which may be substituted or a heterocyclic group which may be substituted), a CO ₂ 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, a substituted An aryl group which may be substituted or a heterocyclic group which may be substituted), CHO, SO ₂ NR ^a R ^b group (R ^a and R ^b are each independently a hydrogen atom, a hydroxyl group, an alkoxy group or a substituted group). Good alkyl group, substitution 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; 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, or a substituted group. An optionally substituted cycloalkenyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, a —B ¹ —R ⁵ group (B ¹ is CO, COO, O, OCO, OSO ₂ , S, SO Or SO ₂ and 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, or optionally substituted. A good cycloalkenyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group, an optionally substituted amino group, or an N = CR ⁶ R ⁷ group (R ⁶ and R ⁷ are each independently , Hydrogen field , 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, and an optionally substituted aryl group Or a heterocyclic group which may be substituted);
Y and Z are each independently a nitrogen atom or a C—R ⁸ group {R ⁸ is a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, or 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 ² -R ⁹ group (B ² is CO, COO , O, OCO, OSO ₂ , S, SO or SO ₂ , R ⁹ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, a substituted An optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group), an optionally substituted amino group, a cyano group or a nitro group. is there , And the two R ⁸ when taking the Y and Z are simultaneously C-R ⁸ groups may be the same or different;
X is a nitrogen atom or a C—R ¹⁰ group {R ¹⁰ is a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, or an optionally substituted group. 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} Is;
Furthermore, when Y is a C—R ⁸ group and X is a C—R ¹⁰ group or Z is a C—R ⁸ group, whether R ⁸ and R ¹⁰ or two R ⁸ together contain a heteroatom A fused heterocyclic compound represented by the following formula: or a salt thereof as an active ingredient, the composition for treating or preventing a disease requiring administration of an adenosine A2a receptor agonist .

  The salt of the condensed heterocyclic compound of the formula (I) may be a pharmaceutically acceptable salt, for example, a mineral salt such as hydrochloride, sulfate, nitrate, etc .; p-toluenesulfonate, propanesulfone Organic salts such as acid salts and methanesulfonates; Alkali metal salts such as potassium salts and sodium salts; Alkaline earth metal salts such as calcium salts; Triethanolamine salts and Tris (hydroxymethyl) aminomethane salts And organic amine salts such as Some of these salts have water of crystallization.

In formula (I), R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^a and R ^b may be substituted. The alkyl part of the alkyl group generally has 1 to 19 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, nonyl, decyl, nonadecyl and the like. They also include those of linear or branched fatty chain structural isomerism.

In formula (I), R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^a and R ^b may be substituted. The alkenyl part of the alkenyl group and the alkynyl part of the alkynyl group which may be substituted generally include those having 2 to 18 carbon atoms, including those having a structural isomer of a linear or branched fatty chain.

In formula (I), R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^a and R ^b may be substituted. The cycloalkyl part of the cycloalkyl group and the cycloalkenyl part of the cycloalkenyl group which may be substituted generally include those having 3 to 10 carbon atoms, such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclohexane group. In addition to monocyclic groups such as a pentenyl group and a cyclohexenyl group, condensed polycyclic groups and bridged polycyclic groups are also included.

Of the optionally substituted aryl group represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ^a and R ^b in formula (I) Examples of the aryl moiety include a phenyl group and a condensed polycyclic group such as a naphthyl group.

An optionally substituted heterocyclic group represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ^a and R ^b in formula (I) As the heterocyclic moiety, pyrrolyl group, pyrrolinyl group, pyrrolidinyl group, furanyl group, dihydrofuranyl group, tetrahydrofuranyl group, thienyl group, dihydrothienyl group, tetrahydrothienyl group, pyrazolyl group, pyrazolinyl group, pyrazolidinyl group, imidazolyl group Imidazolinyl group, imidazolidinyl group, oxazolyl group, oxazolinyl group, oxazolidinyl group, isoxazolyl group, isoxazolinyl group, isoxazolidinyl group, thiazolyl group, thiazolinyl group, thiazolidinyl group, isothiazolyl group, isothiazolidinyl group Group, oxadiazolyl group, oxadiazolinyl group, oxadi Azolidinyl 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, pyridyl group, dihydropyridyl group Group, tetrahydropyridyl group, piperidinyl group, pyrimidyl group, dihydropyrimidyl group, tetrahydropyrimidyl group, hexahydropyrimidyl group, pyridazinyl group, dihydropyridazinyl group, tetrahydropyridazinyl group, hexahydro Pyridazinyl group, pyrazinyl group, dihydropyrazinyl group, tetrahydropyrazinyl group, piperazinyl group, pyranyl group, dihydropyranyl group, tetrahydropyranyl group, dioxinyl group, dioxenyl , Dioxanyl group, dithianyl group, morpholinyl group and the like monocyclic heterocyclic group; thienothienyl group, dihydrocyclopentathienyl group, indolyl group, tetrahydroindolyl group, isoindolyl group, tetrahydroisoindolyl group, benzothienyl group, tetrahydrobenzo group Thienyl group, benzofuranyl group, tetrahydrobenzofuranyl group, benzoxazolyl group, tetrahydrobenzoxazolyl group, benzoisoxazolyl group, tetrahydrobenzoisoxazolyl group, benzothiazolyl group, tetrahydrobenzothiazolyl group, Benzisothiazolyl group, Tetrahydrobenzisothiazolyl group, Benzimidazolyl group, Tetrahydrobenzoimidazolyl group, Benzodioxolyl group, Benzodithiolyl group, Benzodioxanyl group, Benzodithiol Nyl group, quinolinyl group, isoquinolinyl group, quinazolinyl group, quinoxalinyl group, phthalazinyl group, naphthyridinyl group, purinyl group, etc. condensed polycyclic heterocyclic group; bridged polycyclic heterocyclic group such as quinuclidinyl group Etc.

In formula (I), R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^a and R ^b may be substituted. As the secondary substituent of the alkyl group, the optionally substituted alkenyl group and the optionally substituted alkynyl group, a halogen atom, a hydroxyl group, a mercapto group, a substituted alkoxy group, a substituted alkylthio group, a substituted alkenyloxy group, Substituted alkenylthio group, Substitutable alkynyloxy group, Substitutable alkynylthio group, Substitutable cycloalkyl group, Substitutable cycloalkenyl group, Substitutable cycloalkoxy group, Substitutable cycloalkylthio group, Substitutable cycloalkenyloxy group, Substituted Cycloalkenylthio group, Substitutable alkoxycarbonyl group, Substitutable alkylcarbonyl group, Substitutable alkylcarbonyloxy group, Substitutable alkenyloxycal Nyl group, substituted alkenylcarbonyl group, substituted alkenylcarbonyloxy group, substituted alkynyloxycarbonyl group, substituted alkynylcarbonyl group, substituted alkynylcarbonyloxy group, substituted cycloalkoxycarbonyl group, substituted cycloalkylcarbonyl group, Substituted cycloalkylcarbonyloxy group, substituted cycloalkenyloxycarbonyl group, substituted cycloalkenylcarbonyl group, substituted cycloalkenylcarbonyloxy group, substituted aryl group, substituted aryloxy group, substituted arylthio group, substituted aryl Oxycarbonyl group, substituted arylcarbonyl group, substituted arylcarbonyloxy group, substituted heterocyclic group, substituted heterocyclic oxy group, substituted heterocyclic thio group, substituted heterocyclic oxycarbonyl group, substituted heterocyclic Ring carbonyl group, substituted heterocyclic carbonyloxy group, substituted amino group, cyano group, nitro group, carboxyl group, substituted aminocarbonyl group, substituted alkylsulfonyl group, substituted alkenylsulfonyl group, substituted alkynylsulfonyl group, Substitutable cycloalkylsulfonyl group, substituted cycloalkenylsulfonyl group, substituted arylsulfonyl group, substituted heterocyclic sulfonyl group, substituted aminosulfonyl group and the like can be mentioned. Even if the number of these substituents is 1, 2 When the number of substituents is two or more, these substituents may be the same or different.

In formula (I), R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^a and R ^b may be substituted. Examples of the secondary substituent of the cycloalkyl group, the optionally substituted cycloalkenyl group, the optionally substituted aryl group, and the optionally substituted heterocyclic group include a halogen atom, a hydroxyl group, a mercapto group, a substituted alkyl group, Substituted alkenyl group, substituted alkynyl group, substituted alkoxy group, substituted alkylthio group, substituted alkenyloxy group, substituted alkenylthio group, substituted alkynyloxy group, substituted alkynylthio group, substituted cycloalkyl group, Substitutable cycloalkenyl group, Substitutable cycloalkoxy group, Substitutable cycloalkylthio group, Substitutable cycloalkenyloxy group, Substitutable cycloalkenylthio group, Substitutable alkoxycarbonyl Group, substitutable alkylcarbonyl group, substitutable alkylcarbonyloxy group, substitutable alkenyloxycarbonyl group, substitutable alkenylcarbonyl group, substitutable alkenylcarbonyloxy group, substitutable alkynyloxycarbonyl group, substitutable alkynylcarbonyl group, substitutable Alkynylcarbonyloxy group, substituted cycloalkoxycarbonyl group, substituted cycloalkylcarbonyl group, substituted cycloalkylcarbonyloxy group, substituted cycloalkenyloxycarbonyl group, substituted cycloalkenylcarbonyl group, substituted cycloalkenylcarbonyloxy group, Substitutable aryl group, Substitutable aryloxy group, Substitutable arylthio group, Substitutable aryloxycarbonyl group, Substitutable arylcarbonyl group, Substitutable arylcarbonyloxy group, Substitutable Heterocyclic group, substituted heterocyclic 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, substituted aminocarbonyl group, substituted alkylsulfonyl group, substituted alkenylsulfonyl group, substituted alkynylsulfonyl group, substituted cycloalkylsulfonyl group, substituted cycloalkenylsulfonyl group, substituted arylsulfonyl group, substituted A heterocyclic sulfonyl group, a substituted aminosulfonyl group, and the like. The number of these substituents may be one or two or more. When the number of substituents is two or more, These substituents may be the same or different.

Examples of the secondary substituent of the amino group which may be substituted represented by R ¹ , R ² , R ⁸ and R ¹⁰ in formula (I) include a hydroxyl group, a substituted alkyl group, a substituted alkenyl group, a substituted group. Alkynyl group, 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 alkylcarbonyl group, substituted alkenyloxycarbonyl group, substituted alkenylcarbonyl group, substituted alkynyloxycarbonyl group, substituted alkynylcarbonyl group, substituted cycloalkoxycarbonyl group, substituted cycloalkylcarbonyl group, substituted cyclo Alkenyloxycarbonyl group, substituted cycloalkenyl Nyl group, substituted aryl group, substituted aryloxy group, substituted aryloxycarbonyl group, substituted arylcarbonyl group, substituted heterocyclic group, substituted heterocyclic oxy group, substituted heterocyclic oxycarbonyl group, substituted Heterocyclic carbonyl group, substituted aminocarbonyl group, substituted alkylsulfonyl group, substituted alkenylsulfonyl group, substituted alkynylsulfonyl group, substituted cycloalkylsulfonyl group, substituted cycloalkenylsulfonyl group, substituted arylsulfonyl group, substituted Examples thereof include a heterocyclic sulfonyl group and a substituted aminosulfonyl group. The number of secondary substituents may be one or two, and in the case of two, they may be the same. May be different. Two secondary substituents may be combined to form a ring with or without heteroatoms.

  Among the above-mentioned secondary substituents, the tertiary substituents of each substitutable group are halogen atoms, hydroxyl groups, mercapto groups, cyano groups, nitro groups, carboxyl groups, amino groups, alkyl groups, alkenyl groups, alkynyl groups, Cycloalkyl group, cycloalkenyl group, aryl group, heterocyclic group, alkoxy group, alkenyloxy group, alkynyloxy group, cycloalkyloxy group, cycloalkenyloxy group, aryloxy group, heterocyclic oxy group, alkylthio group, alkenylthio Group, alkynylthio group, cycloalkylthio group, cycloalkenylthio group, arylthio group, heterocyclic thio group, alkylsulfonyl group, alkenylsulfonyl group, alkynylsulfonyl group, cycloalkylsulfonyl group, cycloalkenylsulfonyl group, arylsulfonyl group, complex Environment Phonyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl, heterocyclic carbonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, cyclo Alkyloxycarbonyl group, cycloalkenyloxycarbonyl group, aryloxycarbonyl group, heterocyclic oxycarbonyl group, aminocarbonyl group, alkylaminocarbonyl group, dialkylaminocarbonyl group, alkenylaminocarbonyl group, alkynylaminocarbonyl group, cycloalkylaminocarbonyl Group, cycloalkenylaminocarbonyl group, arylaminocarbonyl group, heterocyclic aminocarbonyl group, aminosulfuryl group Nyl group, alkylaminosulfonyl group, dialkylaminosulfonyl group, alkenylaminosulfonyl group, alkynylaminosulfonyl group, cycloalkylaminosulfonyl group, cycloalkenylaminosulfonyl group, arylaminosulfonyl group, heterocyclic aminosulfonyl group, alkylamino group, Dialkylamino group, alkenylamino group, alkynylamino group, cycloalkylamino group, cycloalkenylamino group, arylamino group, heterocyclic amino group, alkylcarbonylamino group, alkenylcarbonylamino group, alkynylcarbonylamino group, cycloalkylcarbonylamino Group, cycloalkenylcarbonylamino group, arylcarbonylamino group, heterocyclic carbonylamino group, alkylsulfonylamino group, alkenylsulfonyl Examples thereof include a phonylamino group, an alkynylsulfonylamino group, a cycloalkylsulfonylamino group, a cycloalkenylsulfonylamino group, an arylsulfonylamino group, a heterocyclic sulfonylamino group, and the number of these tertiary substituents is one or two The number of substituents may be the same or different. Furthermore, when the secondary substituent is an amino group substituted by two tertiary substituents, the tertiary substituents may be combined to contain or not contain a heteroatom to form a ring.

  In addition, the alkyl part, alkenyl part, alkynyl part, cycloalkyl part, cycloalkenyl part, aryl part, and heterocyclic part of these tertiary substituents are further halogen atoms, hydroxyl groups, mercapto groups, cyano groups, nitro groups, carboxyl groups, Amino group, alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, alkylthio group, haloalkylthio group, alkoxycarbonyl group, aminocarbonyl group, alkylaminocarbonyl group, dialkylaminocarbonyl group, aminosulfonyl group, alkylaminosulfonyl group, Substituted with quaternary substituents such as dialkylaminosulfonyl groups, alkylamino groups, dialkylamino groups, alkylcarbonylamino groups, alkylsulfonylamino groups, cycloalkyl groups, aryl groups, heterocyclic groups, etc. The number of the substituents may be one or two or more. When the number of substituents is two or more, the substituents may be the same or different. May be.

  Next, although some desirable embodiments of the present invention are described, the present invention is not limited to these.

(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 as described above) or an amino group which may be substituted, and Y and Z are each independently a nitrogen atom or a C—R ⁸ group {R ⁸ is a hydrogen atom, A good aryl group or a —B ² —R ⁹ group (B ² and R ⁹ are as defined above), and X is a nitrogen atom or a C—R ¹⁰ group (R ¹⁰ is a hydrogen atom or a halogen atom). A condensed heterocyclic compound of the formula (I) or a salt thereof.
(2) G is CN, CO ₂ R ⁴ group (R ⁴ is as described above), SO ₂ NR ^a R ^b group or CONR ^a R ^b group (R ^a and R ^b are as described above). A condensed heterocyclic compound or a salt thereof according to (1).
(3) R ¹ and R ² are each independently a -B ¹ -R ⁵ group (B ¹ and R ⁵ are as described above) or an optionally substituted amino group (1) or (2) A fused heterocyclic compound or a salt thereof.
(4) The condensed heterocyclic compound of (3), wherein R ¹ is a —B ¹ —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 condensed heterocyclic compound or a salt thereof according to (4), wherein B ¹ is S and R ⁵ is an optionally substituted alkyl group.
(6) The fused heterocyclic compound or a salt thereof according to (1), wherein B ² is S and R ⁹ is an optionally substituted alkyl group.
(7) The condensed heterocyclic compound or a salt thereof according to (2), (3), (4) or (5), wherein R ⁴ is a hydrogen atom or an optionally substituted alkyl group.
(8) The fused heterocyclic compound or a salt thereof according to (2), wherein R ^a and R ^b are each independently a hydrogen atom or an optionally substituted alkyl group.
(9) The amino group which may be substituted for R ¹ and R ² is 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 ring. The fused heterocyclic compound of (1) or a salt thereof which is an amino group which may be substituted with a group.
(10) The condensed heterocyclic compound or a salt thereof according to (9), wherein the substituted 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 condensed heterocyclic 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 condensed heterocyclic compound or a salt thereof according to (10), wherein the heterocyclic group is a thienyl group, dioxolanyl group, pyridyl group or dioxanyl group.
(13) The condensed heterocyclic compound or a salt thereof according to (10), wherein the alkoxy group is an alkoxy group which may be substituted with an alkoxy group.
(14) The condensed heterocyclic compound or a salt thereof according to (9), wherein the substitutable alkoxy group is an arylalkoxy group.
(15) The condensed heterocyclic compound or a salt thereof according to (9), wherein the substitutable aryl group is a phenyl group which may be substituted with a halogen atom, a cyano group, a nitro group or an alkyl group.
(16) The condensed heterocyclic compound or a salt thereof according to (9), wherein the substituted heterocyclic group is a benzothiazolyl group or a benzodioxolyl group.

  The compound of the above formula (I) or a salt thereof has an agonistic action on adenosine A2a receptor, promotes wound healing, induces sleep, lowers body temperature, lowers blood pressure, suppresses immune cell function, suppresses neutrophil function , Has a pharmacological action such as suppression of production of cytokines such as TNF-α, IL-2, IL-4, and interferon γ.

  Therefore, the compound of formula (I) or a salt thereof is a skin ulcer, leg ulcer, burn ulcer, frostbite ulcer, traumatic ulcer, pressure ulcer, venous ulcer, arterial ulcer, postherpetic ulcer, radiation ulcer, drug ulcer, Wound healing promoter used for treatment or prevention of diabetic ulcer, postoperative ulcer, etc .; sleep inducer used for treatment or prevention of insomnia, psychotic disease, etc .; used for treatment or prevention of febrile disease Antihypertensive agent; antihypertensive agent used for treatment or prevention of hypertension; therapeutic or preventive agent for diseases associated with abnormally enhanced immune cell function and / or cytokine production; therapeutic agent for diseases associated with abnormally enhanced neutrophil function Or it is useful as active ingredients, such as a preventive agent.

  Examples of the disease accompanied by abnormal increase in immune cell function and / or cytokine production include autoimmune disease, erythema nodosum erythema, Behcet's disease, lupus erythematosis, aphthous ulcer, cachexia in cancer and infection, septic shock , Adult respiratory distress syndrome, osteoarthritis, multiple sclerosis, Crohn's disease, inflammatory bowel disease, multiple organ failure, malaria, meningitis, hepatitis, acquired immune deficiency syndrome, hives, 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 Examples include sclerosis, other organ-specific autoimmune diseases, and rejection associated with organ transplantation.

  Examples of the diseases accompanied by abnormal neutrophil function abnormalities include adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pneumonia, cystic fibrosis, asthma, emphysema, bronchiectasis, Tracheal diseases such as 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 pylori gastritis, non-Helicobacter pylori gastritis, non-steroidal anti-inflammatory drug-induced damage to the gastrointestinal tract.

Specific examples of the use of the compound of the formula (I) or a salt thereof include the following embodiments.
(1) Use of a compound of formula (I) or a salt thereof for the manufacture of a medicament for treating or preventing a disease that requires administration of an adenosine A2a receptor agonist.
(2) Use of a compound of formula (I) or a salt thereof for producing a wound healing promoter.
(3) Use of a compound of formula (I) or a salt thereof for producing a sleep inducer.
(4) Use of a compound of formula (I) or a salt thereof for producing an antipyretic.
(5) Use of a compound of the formula (I) or a salt thereof for producing an antihypertensive agent.
(6) Use of a compound of the formula (I) or a salt thereof for the manufacture of a therapeutic or prophylactic agent for diseases associated with abnormal enhancement of immune cell function and / or cytokine production.
(7) Use of a compound of the formula (I) or a salt thereof for the manufacture of a therapeutic or prophylactic agent for diseases associated with abnormally enhanced 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 a compound of 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 a compound of formula (I) or a salt thereof to a mammal including a human.
(10) A method for treating or preventing sleep disorders, comprising administering an effective amount of a compound of 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 a compound of formula (I) or a salt thereof to a mammal including a human.
(12) A method for treating or preventing hypertension, comprising administering an effective amount of a compound of formula (I) or a salt thereof to a mammal including a human.
(13) A method for treating or preventing a disease associated with abnormal enhancement of immune cell function and / or cytokine production, comprising administering an effective amount of a compound of formula (I) or a salt thereof to a mammal including a human.
(14) A method for treating or preventing a disease associated with abnormally enhanced neutrophil function, comprising administering an effective amount of a compound of formula (I) or a salt thereof to a mammal including a human.

  The compound of the above formula (I) or a salt thereof is usually 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 diluents or excipients such as fillers, extenders, binders, moisturizers, disintegrants, surfactants, lubricants and the like that are usually used. Various forms of pharmaceutical preparations can be selected according to the purpose of treatment. Tablets, pills, powders, powders, granules, capsules, suppositories, solutions, suspensions, emulsions, injections (solutions, suspensions) Etc.), sprays, aerosols, creams, ointments, lotions, transdermal agents (patches, matrix agents, tapes), gels and the like.

  When forming into a tablet form, a wide variety of carriers can be used as carriers, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like. Agent, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dry starch, sodium alginate, agar powder, laminaran powder, Sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose and other disintegrants, sucrose, stearin, cacao butter, hydrogenated oil and other disintegration inhibitors, No. 4 Absorption accelerators such as ammonium base and sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, purified talc, stearate, boric acid powder, polyethylene glycol Examples of such lubricants are as follows. Further, the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets.

  In molding into a pill form, conventionally known carriers can be widely used as carriers, such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc and other excipients, gum arabic powder, Examples thereof include binders such as tragacanth powder, gelatin and ethanol, and disintegrants such as lamina lankanten.

  In molding into a suppository, conventionally known carriers can be widely used, and examples thereof include polyethylene glycol, cacao butter, higher alcohol, esters of higher alcohol, gelatin, semi-synthetic glyceride and the like.

  When prepared as injections, the solutions, emulsions and suspensions are preferably sterilized and isotonic with blood. When forming into these solutions, emulsions and suspensions, diluents Any of those commonly used in this field can be used, such as water, aqueous lactic acid solution, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like. it can. In this case, a sufficient amount of sodium chloride, glucose or glycerin may be contained in the pharmaceutical preparation to prepare an isotonic solution, and a normal solubilizing agent, buffering agent, soothing agent, etc. may be added. May be. Further, if necessary, colorants, preservatives, fragrances, flavors, sweeteners and other pharmaceuticals may be contained in the pharmaceutical preparation.

  The amount of the compound of formula (I) or a salt thereof to be contained in the composition of the present invention is not particularly limited and is appropriately selected within a wide range, but is usually 1 to 70% by weight, preferably 5 It is desirable that the content be ˜50% by weight.

  The administration method of the composition of the present invention is not particularly limited, and it is administered orally or parenterally by a method according to various preparation forms, patient age, sex and other conditions, the degree of disease, and the like. For example, when administered orally, preferred embodiments include tablets, pills, solutions, suspensions, emulsions, granules, capsules and the like. Parenterally, it can be administered in the form of topical administration, injection, transdermal, nasal, pulmonary, suppository, and the like. In the case of an injection, it is preferably administered alone or mixed with a normal fluid such as glucose or amino acid, and intravenously administered, and if necessary, it is preferably administered intramuscularly, intradermally, subcutaneously or intraperitoneally. It is an aspect. In the case of a suppository, it is desirable to administer it rectally. In addition, when using this invention composition as a wound healing agent, it is desirable to administer in the form of a topical administration agent. As a method for administering the topical preparation, for example, in the form of a preparation such as spray, aerosol, cream, ointment, lotion, transdermal agent, gel, or the like, the composition of the present invention is included in various wound dressings to treat the affected area. The method of administering to skin etc. is mentioned. Moreover, the affected part after local administration can also be protected with various wound dressings.

  The dose of the composition of the present invention is appropriately selected depending on the usage, the patient's age, sex and other conditions, the degree of disease, etc. The amount of the compound of the formula (I) or a salt thereof, which is usually the active ingredient, is usually per day. It may be about 0.05 to 50 mg per kg body weight, and can be administered once or divided into several times. In addition, it is desirable that 1 to 1000 mg of the active ingredient is contained in the dosage unit form.

  The composition of the present invention is, for example, an antiviral agent, an antibacterial agent, an antibiotic, an antiparasitic agent, an antifungal agent, an antipruritic agent, an analgesic agent, an anti-inflammatory agent, an antiseptic agent, a proteolytic enzyme agent, a granulation / epidermal formation promoter In addition, at least one of various drugs such as a wound dressing can be included, and a better effect may be exhibited in the treatment or prevention of a disease that requires administration of an adenosine A2a receptor agonist.

  The compound of the above 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. Although the specific example of the compound of Formula (I) is shown in Table 1, the compound of Formula (I) is not necessarily limited to these.

  Next, although the test example concerning this invention is described, this invention is not necessarily limited to these.

Test Example 1 (Wound healing promoting action)
Male ICR mice (body weight 22 ± 2 g) were shaved under shoulder anesthesia with hexobarbital anesthesia (90 mg / kg, intraperitoneal administration), and the skin was removed with 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 skin excision. 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 boundary of the wound. The wound repair speed was evaluated as CT50 (wound half-closure time). CT50 was calculated using Graph-Pad Prism (Graph Pad Software USA). The test was carried out with 5 animals / group, and the difference between the mean values of the test substance-administered group and the solvent control group was tested by Student's t-test. The results are shown in Table 2.

Test Example 2 (Sleep-inducing action)
To male ICR mice (body weight 22 ± 2 g), 150 mg / kg of the test compound suspended in 0.25% CMC-Na is orally administered, and further 1 hour later, 90 mg / kg of hexobarbital sodium is intraperitoneally administered. Thereafter, the sleep time is measured using the recovery of the light reflection reaction as an index. The test is conducted as 3 animals per group. The sleep prolongation rate calculated based on the average sleep time of the group administered with only the solvent instead of the test compound is evaluated as% Prolongation. As a result, it can be seen that the compound of the present invention has a sleep-inducing action.

Test Example 3 (Body temperature lowering action)
Test compounds suspended in 0.25% CMC-Na are orally administered to male ICR mice (body weight 22 ± 2 g), and rectal temperature is measured immediately thereafter (Thermolert, TH-5). Furthermore, body temperature is measured after 30, 60.90, and 120 minutes, and if there is an average variation of 5% or more compared to the body temperature before administration, it is considered that there is a significant variation due to test compound administration. The test is conducted as 3 animals per group. As a result, it can be seen that the compound of the present invention has a body temperature lowering effect.

Test Example 4 (blood pressure lowering effect)
Test compounds suspended in 0.25% CMC-Na were orally administered to male Wistar-Okamoto-derived spontaneously hypertensive (SHR) rats (body weight 250 ± 20 g), and blood pressure was measured by an indirect method immediately thereafter. (Blood-Pressure Indirect Sensors & Model B60, IITC USA). Further, blood pressure is measured after 1, 2 and 4 hours, and if there is an average variation of 10% or more compared to the blood pressure before administration, it is considered that there is a significant variation due to administration of the test compound. The test is conducted as 3 animals per group. As a result, it can be seen that the compound of the present invention has a blood pressure lowering action.

Test Example 5 (Inhibition of cytokine production in human peripheral blood mononuclear cells)
(1) IL-2 production inhibitory effect Human peripheral blood mononuclear cells are stimulated with 20 µg / mL concanavalin A (ConA), and the amount of IL-2 produced after 16 hours of culture in the presence of 10 µM of the test compound is measured by enzyme immunoassay. Measure by the method. As a result, it can be seen that the compound of the present invention has an IL-2 production inhibitory action. In addition, a result is represented by the suppression rate compared with the amount of cytokine of a solvent control group.

(2) IL-4 production inhibitory action
It was carried out based on the basic operation procedure of Code No. 308400 in a consignment test at MDS Pharma Service. That is, human peripheral blood mononuclear cells are stimulated with 20 μg / mL of concanavalin A (ConA), and the amount of IL-4 produced after 16 hours of culture in the presence of 10 μM of the test compound is measured by enzyme immunoassay. As a result, it can be seen that the compound of the present invention has an IL-4 production inhibitory action. In addition, a result is represented by the suppression rate compared with the amount of cytokine of a solvent control group.

(3) Inhibition of INF-γ production Human peripheral blood mononuclear cells are stimulated with 20 µg / mL of concanavalin A (ConA), and the amount of IFN-γ produced after 16 hours of culture in the presence of 10 µM of the test compound is measured by enzyme immunoassay. Measure by the method. As a result, it can be seen that the compound of the present invention has an INF-γ production inhibitory action. In addition, a result is represented by the suppression rate compared with the amount of cytokine of a solvent control group.

(4) TNF-α production inhibitory effect Human peripheral blood mononuclear cells are stimulated with 25 ng / mL of lipopolysaccharide (LPS), and the amount of TNF-α produced after 16 hours of culture in the presence of 10 μM of the test compound is enzymatically immunized. Measure with the measuring method. As a result, it can be seen that the compound of the present invention has a TNF-α production inhibitory action. In addition, a result is represented by the suppression rate compared with the amount of cytokine of a solvent control group.

Test Example 6 (Binding affinity test for adenosine A2a receptor)
Tritium-labeled 50 nM [ ³ H] CGS21680 and 10 μM of the test compound are added to a suspension of human recombinant HEK-293 cells expressing adenosine A2a receptor, which serves as an index of binding affinity to adenosine A2a receptor [ The binding inhibitory activity of [ ³ H] CGS21680 was measured with a liquid scintillation counter. The results are shown in Table 3 as the binding inhibition rate (%).

Test Example 7 (IL-2 production inhibitory action in mouse spleen cells)
The adenosine A2a receptor agonistic 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, cytokine production was induced by treating mouse spleen cells with anti-mouse CD3 antibody and human recombinant IL-2 (Genzyme No. 2202). A test compound was added to this cytokine production system, and its inhibitory action was measured by the following method. Anti-mouse CD3 antibody prepared to 10 to 20 μg / ml with borate buffered saline solution (pH 8.5) was dispensed into a 96-well cell culture plate at 50 μl / well and left at 4 ° C. for 18 hours. After removing the unreacted solution and washing once with Hanks buffer, 50 μl / well of IL-2 prepared to 10 ng / ml with 10% fetal calf serum (FCS) -containing RPMI solution was dispensed. Here, in the negative control group, only the solution was treated except for the anti-CD3 antibody and IL-2. Subsequently, the test compound dilution was dispensed at 50 μl / well (final concentration 10 μM), and 1 × 10 ⁷ cells / ml prepared from the spleen of Balb / c mice (female, 7-10 weeks old). The cell suspension was dispensed at 100 μl / well. After 40 to 48 hours of culture in an incubator (37 ° C., 5% carbon dioxide gas), the culture supernatant was collected, and the amount of cytokine produced was measured by ELISA.

  IL-2 cytokine production was measured by the following methods. That is, the amount of IL-2 produced was quantified by the ELISA method shown below. First, as a primary antibody, rat anti-mouse IL-2 antibody (Pharmingen, Code No. 18161D) was diluted to 1 μg / ml with carbonate buffer (pH 9.5), and 50 μl / well was added to a 96-well plate (IWAKI). , Code No. 3860-096) and coated overnight (16-24 hours) at 4 ° C. Thereafter, the plate was blocked with phosphate buffered saline pH 7.2 (blocking buffer) containing 10% FCS for 2 hours at 37 ° C. (250 μl / well). The plate was washed 4 times with PBS (washing buffer) containing 0.05% Tween 20 (Nacalai Tesque, Code No. 281-51), and 50 μl / well of culture supernatant dilution was plated for 1 hour at room temperature. Incubated. Recombinant mouse IL-2 (R & D Systems, Code No. 402-ML) was used to create a calibration curve. The plate was washed 4 times with a washing buffer, and a biotin-labeled rat anti-mouse IL-2 antibody (Farmingen, Code No. 18172D) was added as a secondary antibody at a concentration of 0.5 μg / blocking in 0.05% Tween20-containing blocking buffer. Diluted in ml was added (50 μl / well) and incubated at room temperature for 1 hour. After washing the plate 4 times with washing buffer, streptavidin-labeled peroxidase (Prozyme, Code No. CJ30H001) diluted 800-fold with a blocking buffer containing 0.05% Tween 20 was added (50 μl / well), and room temperature for 15 minutes. Reacted. The plate was washed 4 times with a washing buffer, and 100 μl / well of TNB substrate solution (Sigma, Code No. T-8665) was added and allowed to develop for 10 to 20 minutes. After stopping the reaction by adding 100 μl / well of 1 M sulfuric acid solution, the absorbance was measured using a microplate reader (Spectramax, Wako Pure Chemical Industries) (wavelength 450 nm).

Each experiment was performed in duplicate, and the average value of each cytokine production was determined. Moreover, the suppression rate (%) was calculated | required by the following formula | equation from this average value.
Inhibition rate (%) = {1− (TN) / (PN)} × 100
Here, T represents the average value of the test compound treatment group, N represents the average value of the negative control group, and P represents the average value of the positive control group. The cytokine production inhibition rates measured in this manner are shown in Table 4.

Claims (10)

Formula (I):

[In the formula, A is a nitrogen atom or a CG group {G is CN, NO ₂ , SO ₂ R ³ group (R ³ is an alkyl group that may be substituted, an alkenyl group that may be substituted, An alkynyl group which may be substituted, a cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted, an aryl group which may be substituted or a heterocyclic group which may be substituted), a CO ₂ 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, a substituted An aryl group which may be substituted or a heterocyclic group which may be substituted), CHO, SO ₂ NR ^a R ^b group (R ^a and R ^b are each independently a hydrogen atom, a hydroxyl group, an alkoxy group or a substituted group). Good alkyl group, substitution 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; 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, or a substituted group. An optionally substituted cycloalkenyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, a —B ¹ —R ⁵ group (B ¹ is CO, COO, O, OCO, OSO ₂ , S, SO Or SO ₂ and 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, or optionally substituted. A good cycloalkenyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group, an optionally substituted amino group, or an N = CR ⁶ R ⁷ group (R ⁶ and R ⁷ are each independently , Hydrogen field , 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, and an optionally substituted aryl group Or a heterocyclic group which may be substituted);
Y and Z are each independently a nitrogen atom or a C—R ⁸ group {R ⁸ is a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, or 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 ² -R ⁹ group (B ² is CO, COO , O, OCO, OSO ₂ , S, SO or SO ₂ , R ⁹ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, a substituted An optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group), an optionally substituted amino group, a cyano group or a nitro group. is there , And the two R ⁸ when taking the Y and Z are simultaneously C-R ⁸ groups may be the same or different;
X is a nitrogen atom or a C—R ¹⁰ group {R ¹⁰ is a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, or an optionally substituted group. 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} Is;
Furthermore, when Y is a C—R ⁸ group and X is a C—R ¹⁰ group or Z is a C—R ⁸ group, whether R ⁸ and R ¹⁰ or two R ⁸ together contain a heteroatom A composition for treating or preventing a disease that requires administration of an adenosine A2a receptor agonist, comprising a fused heterocyclic compound represented by the formula: A wound healing promoter comprising the compound according to claim 1 or a salt thereof as an active ingredient. The wound is a skin ulcer, leg ulcer, burn ulcer, frostbite ulcer, traumatic ulcer, pressure ulcer, venous ulcer, arterial ulcer, postherpetic ulcer, radiation ulcer, drug ulcer, diabetic ulcer or postoperative ulcer 2 wound healing promoters. The sleep inducer which contains the compound or its salt of Claim 1 as an active ingredient. An antipyretic containing the compound according to claim 1 or a salt thereof as an active ingredient. An antihypertensive agent comprising the compound according to claim 1 or a salt thereof as an active ingredient. A therapeutic or prophylactic agent for a disease associated with abnormal enhancement of immune cell function or cytokine production, comprising the compound according to claim 1 or a salt thereof as an active ingredient. Disease is autoimmune disease, erythema nodosum leprosy, Behcet's disease, lupus erythematosis, aphthous ulcer, cachexia in cancer and infection, septic shock, adult respiratory distress syndrome, osteoarthritis, multiple sclerosis, clone Disease, inflammatory bowel disease, multiple organ failure, malaria, meningitis, hepatitis, acquired immune deficiency syndrome, hives, 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 disease and rejection associated with organ transplantation A therapeutic agent for a disease associated with abnormally enhanced immune cell function and / or cytokine production according to claim 7 or at least one selected from Is a preventive drug. A therapeutic or prophylactic agent for a disease associated with abnormally enhanced neutrophil function, comprising the compound according to claim 1 or a salt thereof as an active ingredient. Diseases include tracheal disease, male erectile dysfunction, epilepsy, cerebral ischemia, peripheral vascular disease, post-ischemic reperfusion injury, rheumatoid arthritis, multiple sclerosis, psoriasis, dermatitis, eczema, ulcerative colitis, 10. The neutrophil according to claim 9, which is at least one selected from Crohn's disease, inflammatory bowelitis, Helicobacter pylori gastritis, non-Helicobacter pylori gastritis, and nonsteroidal anti-inflammatory drug-induced damage to the gastrointestinal tract. A therapeutic or prophylactic agent for diseases associated with abnormal function enhancement.