JPH11158073A - Adenosine a3 antagonist - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject antagonist which shows excellent adenosine A3 antagonistic activity or the like and is useful as a prophylactic and therapeutic agent for ishemic diseases such as cerebral infarction and myocardial infarction by including a specific monocyclic nitrogen-containing heterocyclic compound thereto. SOLUTION: The objective antagonist is obtained by including a 5-8 membered monocyclic nitrogen-containing heterocyclic compound, preferably a 6 membered ring compound (e.g. pyrimidine, triazine or the like), which is substituted with a (substituted) amino group preferably a group of the formula [R<1> and R<2> are each H, a (substituted) hydroxy, a (substituted) amino or the like]}, possesses 1-3 substituents preferably selected from oxo, thioxo, a halogen, a (substituted) hydroxy, a (substituted) thiol, a (substituted) amino or the like and contains only two or three nitrogen atoms as the ring constructive heteroatom. The content of the compound is 0.1-100 wt.% by weight of the whole preparation in this antagonist. When used orally to an adult, the daily dosage of 10-300 mg is preferably administrated.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an excellent adenosine A
3 antagonism, etc., and is useful as a prophylactic / therapeutic agent (for example, a brain or cardioprotective agent) for various diseases based on the adenosine A3 antagonism (for example, ischemic diseases such as cerebral infarction and myocardial infarction). And an agent comprising a 5- to 8-membered monocyclic nitrogen-containing heterocyclic compound.

[0002]

2. Description of the Related Art Adenosine plays an important role in the expression, maintenance and regulation of various physiological functions inside and outside cells as one of important biological constituents. For example, it exhibits various physiological actions in almost all organs and tissues, such as inhibition of brain function, vasodilation, decrease of cardiac function, renal vasoconstriction, inhibition of platelet aggregation, inhibition of insulin secretion, inhibition of lymphocyte function and inhibition of renin release. These effects are expressed via adenosine receptors (A1, A2a, A2b), which are widely distributed on the cell surface of in vivo tissues [J.
Of Medicinal Chemistry, 25, 197, (19
1982) (JW Daly, J. Med. Chem., 25, 197 (198
2)), M. Williams, Annual Reports Inn
Medicinal Chemistry, Vol. 22, 1 (1987) (M.
Williams, Annu. Rep. Med. Chem., 22, 1 (1987)),
AJ Bridges, Annual Reports in Medicinal Chemistry, 23, 41 (1988) (A.
J. Bridges, Annu.Rep.Med.Chem., 23, 41 (198
8))]. Diseases caused by physiological effects due to abnormal interactions between adenosine and its receptors commonly occur in the neuroendocrine, cardiovascular and gastrointestinal tracts. At this time, the use of adenosine antagonists that inhibit the interaction between adenosine and its receptor is considered to be useful for the treatment and prevention of these diseases [M Williams, Pharmacology Biochemistry and Behavior, 29
Volume, 433 (1988) (M. Williams, Pharm. Biochem.
& Behavior, 29, 433 (1988))]. In recent years, the cloning of the A3 receptor as a new adenosine receptor subtype has been reported [Kew elephant, proceedings
Of the National Academy of Sciences
Of the United States of America, 89
Volume, 7432 (1992) (QY Zhou, Proc. Natl. Aca
d. Sci. USA 89, 7432 (1992)), CA Salvatore, Proceedings of the National Academy of Sciences of the United States of America, 90, 10365 (1993) (C.
A. Salvatore, Proc. Natl. Acad. Sci. USA 90, 10
365 (1993))]. This A3 receptor inhibits adenylate cyclase and activates phospholipase C. It also exhibits physiological effects such as inflammation, hypotension and degranulation of mast cells,
Actions in the central nervous system have also been reported [J. Linden, Trends in Pharmacological Sciences, 15, 298 (1994) (J. Linden, Trends Pharm
acol. Sci., 15, 298 (1994)), JP Hannon,
British Journal of Pharmacology, 1
15, 945 (1995) (JP Hannon, Br. J. Pharma
col., 115, 945 (1995)), JR Fozard, European Journal of Pharmacology, 298, 293 (1996) (JR Fozard, Eur.
J. Pharmacol., 298, 293 (1996)), K. Jacobson, FEBS Letters, 336, 57 (1993) (K.
A. Jacobson, FEBSLett., 336, 57 (1993)]].

On the other hand, the following compounds have been reported as adenosine A3 receptor antagonists.

Embedded image

[0004]

As described above, adenosine exerts various physiological actions through the A3 receptor in the living body as described above. Adenosine A3 that is more satisfactory in terms of action, sustainability, safety, etc. as a therapeutic or prophylactic agent for cardiac ischemia or cerebral ischemia
There is a need for the development of receptor antagonists such as brain and cardioprotective agents.

[0005]

Means for Solving the Problems As a result of various studies, the present inventors have shown that (1) a nitrogen-containing heterocyclic ring containing only two or three nitrogen atoms as ring-constituting heteroatoms. (E.g., a pyrimidine ring, a triazine ring, etc.) and (2) at least one "optionally substituted amino group (preferably, an amino group optionally substituted with one substituent) Group, more preferably a phenylamino group), a compound having a chemical structural characteristic at the place of substitution, that is, a nitrogen atom which is substituted with an optionally substituted amino group and has a ring-forming hetero atom. A 5- to 8-membered monocyclic nitrogen-containing heterocyclic compound containing only 2 or 3 atoms has unexpectedly excellent adenosine A3 antagonism based on its chemical structural characteristics. Based on their excellent adenosine A3 antagonism, these compounds are based on their excellent adenosine A3 antagonism, which suppresses cell death during ischemia, suppresses degranulation of mast cells, activates adenylate cyclase and has excellent durability. Because it shows safety, agents containing these compounds based on these pharmacological actions are used as preventive and therapeutic agents for cerebral infarction, stroke, myocardial infarction, angina pectoris, inflammatory diseases, allergic diseases, etc. It was found to be used, and the present invention was completed. That is, the present invention provides (1)
5- to 8-membered monocyclic nitrogen-containing heterocyclic compounds substituted with an optionally substituted amino group and containing only 2 or 3 nitrogen atoms as ring-constituting heteroatoms (compound [I] and Adenosine A3 antagonists comprising: (2) an oxo group, a thioxo group, a halogen atom, in addition to an amino group which may be substituted with a monocyclic nitrogen-containing heterocyclic ring,
1 selected from a hydroxy group which may be substituted, a thiol group which may be substituted, an amino group which may be substituted, a hydrocarbon group which may be substituted and a heterocyclic group which may be substituted; The agent according to the above (1), which is a monocyclic nitrogen-containing heterocyclic ring which may have 3 to 3 substituents, and (3) the optionally substituted amino group has a formula

Embedded image Wherein R ¹ and R ² are the same or different,
A hydrogen atom, an optionally substituted hydroxy group, an optionally substituted amino group, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group (provided that R ¹ and R ² for either one of hydroxy group which may be substituted or an optionally substituted amino group, the other is an alkyl group which may optionally be a hydrogen atom or a substituent.), R ¹ and R ² are each May form a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom.) (4) R ¹ and The agent according to the above (3), wherein one of R ² is a hydrogen atom,

(5) R ¹ and R ² are the same or different and are each substituted by (i) a hydrogen atom, (ii) an amino group, (iii) a halogen atom, an amino group or a C _1-6 alkoxy group. A C _1-6 alkyl group, (iv) a halogen atom, an amino group, a C _3-6 cycloalkyl group which may be substituted with a C _1-6 alkyl group or a C _1-6 alkoxy group, (v) halogen An atom, an amino group, a C _7-16 aralkyl group which may be substituted by a C _1-6 alkyl group or a C _1-6 alkoxy group, or (vi) a halogen atom,
A C _6-14 aryl group which may be substituted with an amino group, a C _1-6 alkyl group or a C _1-6 alkoxy group (provided that when ^one of R ¹ and R ² is an amino group, _{Represents a} hydrogen atom or a C _1-6 alkyl group.), R ¹ and R ² are a halogen atom, an amino group, a C _1-6 alkyl group or a C _1-6 alkoxy group together with an adjacent nitrogen atom. The agent according to the above (3), which may form a 5- or 6-membered heterocyclic group which may be substituted, (6) ^one of R ¹ and R ² is a hydrogen atom, and the other is ( i) a hydrogen atom, (ii) an amino group, (iii) a halogen atom, an amino group or a C _1-6 alkyl group optionally substituted with a C _1-6 alkoxy group,
(Iv) a C _3-8 cycloalkyl group optionally substituted with a halogen atom, amino group, C _1-6 alkyl group or C _1-6 alkoxy group, (v) a halogen atom, amino group, C _1-6 A C _7-16 aralkyl group optionally substituted with an alkyl group or a C _1-6 alkoxy group or (vi)
C _6-14 optionally substituted with a halogen atom, amino group, C _1-6 alkyl group or C _1-6 alkoxy group
The agent according to the above (3), which represents an aryl group; (7) the agent according to the above (1), wherein the monocyclic nitrogen-containing heterocyclic compound is a 6-membered monocyclic nitrogen-containing heterocyclic compound;

Embedded image [Wherein at least one of R ³ , R ⁴ and R ⁵ is the same or different,

Embedded image (Wherein R ¹ ′ and R ² ′ are the same or different and are each substituted by (i) a hydrogen atom, (ii) an amino group, (iii) a halogen atom, an amino group or a C _1-6 alkoxy group. A C _1-6 alkyl group, (iv) a halogen atom, an amino group, a C _3-6 cycloalkyl group which may be substituted with a C _1-6 alkyl group or a C _1-6 alkoxy group, (v) halogen An atom, an amino group, a C _7-16 aralkyl group which may be substituted by a C _1-6 alkyl group or a C _1-6 alkoxy group, or (vi) a halogen atom,
A C _6-14 aryl group which may be substituted with an amino group, a C _1-6 alkyl group or a C _1-6 alkoxy group (provided that ^one of R ¹ ′ and R ² ′ is an amino group) ,
The other represents a hydrogen atom or a C _1-6 alkyl group. ),
R ¹ ′ and R ² ′ are a 5- or 6-membered heterocyclic ring which may be substituted with a halogen atom, an amino group, a C _1-6 alkyl group or a C _1-6 alkoxy group together with an adjacent nitrogen atom; It may form a group. ), And the other groups are the same or different,
(I) hydrogen atom, (ii) halogen atom, (iii) C _1-6
A hydroxy group which may be substituted with an alkyl group or a C _6-14 aryl group, (iv) a C _6-14 aryl group or (v) a 5- or 6-membered heterocyclic group, and X represents a nitrogen atom or a methine group Is shown. The agent according to the above (1), comprising a compound represented by the formula (I) or a salt thereof:

(9) X represents a nitrogen atom, and R ³ , R ⁴ and R ⁵ are the same or different,

Embedded image (Wherein, R ¹ ′ and R ² ′ have the same meanings as described in the above (8));
X represents a nitrogen atom, and any one of R ³ , R ⁴ and R ⁵
Are the same or different

Embedded image (Wherein, R ¹ ′ and R ² ′ have the same meanings as described in the above (8)), and the others are (i) a halogen atom, (ii) a C _1-6 alkyl group or a C _1-6 alkyl group. _{6-14 a} hydroxy group optionally substituted with an aryl group or (iii)
The agent according to the above (8), which represents a C _6-14 aryl group, (11)
X represents a methine group, and R ³ represents the formula (i)

Embedded image (Wherein R ¹ ′ and R ² ′ have the same meaning as described in the above (8)), (ii) a halogen atom, (iii) C
_A hydroxy group optionally substituted by a _1-6 alkyl group or a C _6-14 aryl group or (iv) a C _6-14 aryl group, wherein one of R ⁴ and R ^{5 is} a group represented by the formula

Embedded image (Wherein R ¹ ′ and R ² ′ have the same meanings as described in the above (8)), and the other is a group represented by the formula (i)

Embedded image (Wherein R ¹ ′ and R ² ′ have the same meaning as described in the above (8)), (ii) a halogen atom, (iii) C
The agent according to the above (8), which represents a hydroxy group optionally substituted with a _1-6 alkyl group or a C _6-14 aryl group or (iv) a C _6-14 aryl group.

Equation (12)

Embedded image [Wherein, R ³ ′ represents (i) a halogen atom, (ii) a hydroxy group optionally substituted with a C _1-6 alkyl group or a C _6-14 aryl group, or (iii) a C _6-14 aryl group. R ⁶ represents (i) a halogen atom, an amino group, C _1-6
An alkyl group or a C _7-16 aralkyl group which may be substituted with a C _1-6 alkoxy group or (ii) a C _1-6 alkyl group substituted with a heterocycle, wherein R ⁴ ′ is a group represented by the formula:

Embedded image (Wherein R ¹ ′ and R ² ′ have the same meanings as described in the above (8)) or the agent according to the above (1) comprising a salt thereof, and (13) brain or The agent according to (1) above, which is a cardioprotective agent.

When the compound [I] or a salt thereof contains an asymmetric carbon in the structure, both the optically active form and the racemic form are included in the scope of the present invention, and the compound [I] or a salt thereof is hydrated. Or anhydrate. The compound [I] is a 5- to 8-membered monocyclic nitrogen-containing heterocyclic ring substituted with an optionally substituted amino group and containing only two or three nitrogen atoms as ring-constituting heteroatoms. Compound ". The “5- to 8-membered monocyclic nitrogen-containing heterocyclic ring which is substituted by an optionally substituted amino group and contains only 2 or 3 nitrogen atoms as a ring-constituting heteroatom” is defined as a “ring At least one substitutable position on the ring of the "5- to 8-membered monocyclic nitrogen-containing heterocycle containing only 2 or 3 nitrogen atoms as constituent heteroatoms",
It preferably has 1 to 3 "amino groups which may be substituted", and further has a substituent at a substitutable position on the ring in addition to the "amino group which may be substituted". 1
Or more, preferably one or two monocyclic nitrogen-containing heterocyclic rings.

As the "5- to 8-membered monocyclic nitrogen-containing heterocyclic compound containing only two or three nitrogen atoms as ring-constituting heteroatoms", a 5- or 6-membered ring compound is preferable, and a 6-membered ring compound is particularly preferable. Ring compounds are preferred. Specifically, for example, (1) a 5- to 8-membered (preferably 5-membered) containing only two or three nitrogen atoms as a ring-constituting heteroatom such as pyrazine, pyrimidine, pyridazine, triazine, imidazole, pyrazole, and triazole ring. Or 6 members,
(More preferably 6-membered) monocyclic aromatic nitrogen-containing heterocyclic compound (preferably a pyrimidine or triazine ring or the like), or (2) dihydropyrazine, tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyridazine, tetrahydropyridazine ,
5 containing only 2 or 3 nitrogen atoms as ring-constituting heteroatoms such as dihydrotriazine, tetrahydrotriazine, hexahydrotriazine, imidazoline, pyrazoline, piperazine, hexahydropyrimidine, hexahydropyridazine, imidazolidine and pyrazolidine ring
And an 8-membered monocyclic non-aromatic nitrogen-containing heterocyclic ring. "Two or three nitrogen atoms as ring-constituting heteroatoms
Examples of the “5- to 8-membered monocyclic nitrogen-containing heterocyclic compound containing only 5 or 8 members” include 5 to 8 members (preferably 5 or 6 members).
And more preferably a 6-membered) monocyclic aromatic nitrogen-containing heterocyclic compound, and particularly preferably a pyrimidine or triazine ring.

The “optionally substituted amino group” in the above compound [I] includes, specifically,

Embedded image Wherein R ¹ and R ² are the same or different,
Hydrogen atom, an optionally substituted hydroxy group, an optionally substituted amino group optionally, optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R ¹
And R ² may be bonded to each other to form a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom (provided that ^one of R ¹ and R ² is substituted) In the case of a hydroxy group which may be substituted or an amino group which may be substituted, the other represents a hydrogen atom or an alkyl group which may be substituted.)]]. As the “substituent” of the “optionally substituted hydroxy group” represented by R ¹ and R ² , for example, a lower alkyl group (for example, methyl, ethyl, n-propyl,
i- propyl, i- butyl, n- butyl, sec- butyl, tert- butyl, n- pentyl, C _1-6 alkyl group such as n- hexyl), aryl group (e.g., phenyl, 2-biphenyl, 3 -Biphenyl, 4-biphenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2
-Anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9
A C _6-14 aryl group such as phenanthryl, preferably a phenyl group), a formyl group or a lower alkyl-carbonyl group (for example, C _6-14 such as acetyl, propionyl and the like);
_And an unsubstituted hydroxy group.

The “substituent” of the “optionally substituted amino group” represented by R ¹ and R ² includes, for example,
(A) a lower alkyl group (for example, methyl, ethyl, n-
Propyl, i-propyl, i-butyl, n-butyl, se
c- butyl, tert- butyl, n- pentyl, n- C _1-6 alkyl group such as hexyl), (b) a lower alkenyl group (e.g., vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl , A C _2-6 alkenyl group such as 3-butenyl), (c) a lower alkynyl group (eg, a C _2-6 alkynyl group such as propargyl, ethynyl, 3-butynyl, 1-hexynyl, etc.), and (d) a lower alkynyl group. cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, C _3-8 cycloalkyl groups such as cyclohexyl), (e) a formyl group, (f) a lower alkyl - group (e.g., acetyl, C, such as propionyl
_1-6 alkyl - carbonyl group), (g) a carboxyl group, (h) lower alkoxy - carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, C _1-6 alkoxy such as butoxycarbonyl - carbonyl group) (I) a carbamoyl group, (j) a mono-lower alkyl-carbamoyl group (for example, a mono-C _1-6 alkyl-carbamoyl group such as methylcarbamoyl, ethylcarbamoyl, etc.), and (k) a di-lower alkyl-carbamoyl group. (For example, dimethylcarbamoyl,
Di-C _1-6 alkylcarbamoyl groups such as diethylcarbamoyl, etc.), (l) aryl-carbamoyl groups (eg, C _6-14 aryl-carbamoyl such as phenylcarbamoyl and naphthylcarbamoyl), (m) sulfo group, n) a lower alkylsulfonyl group (eg, a C _1-6 alkylsulfonyl group such as methylsulfonyl and ethylsulfonyl); (o) an aryl group (eg, a C _6-14 aryl group such as phenyl and naphthyl); ) Thiocarbamoyl group, (q) mono-lower alkyl-thiocarbamoyl group (for example, mono-C _1-6 alkyl-thiocarbamoyl group such as methylthiocarbamoyl, ethylthiocarbamoyl and the like), (r) di-lower alkyl-thio A carbamoyl group (eg, dimethylthiocarbamoyl,
Di-C _1-6 alkyl- such as diethylthiocarbamoyl
Thiocarbamoyl group), (s) aryl-thiocarbamoyl group (eg, C _6-14 aryl-thiocarbamoyl such as phenylthiocarbamoyl, naphthylthiocarbamoyl), (t) aralkyl group (eg, benzyl, phenethyl, - phenylpropyl, etc. C _7-16 aralkyl group such as 2-phenylpropyl), (u) lower alkoxy - carbonyl - lower alkyl group (e.g., methylcarbonyl methyl, C _1-6 alkoxy such as ethyl carbonyl methyl - carbonyl - C _1-6 alkyl group etc.)
Or (v) a carboxyl-lower alkyl group (e.g.,
And carboxyl-C _1-6 alkyl groups such as carboxylmethyl and carboxylethyl).

The "amino group" of the "optionally substituted amino group" represented by R ¹ and R ² may have one or two of the above substituents and the like. Of the “amino groups which may be substituted” represented by R ¹ and R ² , an unsubstituted amino group is preferred. “Optionally substituted hydrocarbon group” represented by R ¹ and R ²
Examples of the “hydrocarbon group” in the above are, for example, groups obtained by removing one hydrogen atom from a hydrocarbon compound, and examples thereof include, for example, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, And a chain or cyclic hydrocarbon group such as a group. this house,
C1 to C16 chain (straight or branched)
Or a cyclic hydrocarbon group or the like, and specifically, a) an alkyl group [preferably, a lower alkyl group (for example, methyl, ethyl, n-propyl, i-propyl, i-
-Butyl, n-butyl, sec-butyl, tert-butyl,
n- pentyl, C _1-6 alkyl group such as n- hexyl)], b) alkenyl groups [preferably, lower alkenyl groups (e.g., vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3 A C _2-6 alkenyl group such as -butenyl)], c) an alkynyl group [preferably, a lower alkynyl group (eg, a C _2-6 alkynyl group such as propargyl, ethynyl, 3-butynyl, 1-hexynyl and the like)] ,

D) Cycloalkyl group [preferably lower cycloalkyl group (for example, cyclopropyl, cyclobutyl, cyclopentyl, 1 to 3 lower alkoxy groups (for example, C _1-6 alkoxy group such as methoxy, etc.))
A C _3-8 cycloalkyl group such as cyclohexyl which may be condensed with a benzene ring which may have a), e) an aryl group (for example, phenyl, 2-biphenyl,
3-biphenyl, 4-biphenyl, 1-naphthyl, 2-
A C _6-14 aryl group such as naphthyl, 1-anthryl, 2-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9-phenanthryl, preferably a phenyl group), f) an aralkyl group [ Preferably, a lower aralkyl group (for example, benzyl, phenethyl, diphenylmethyl, 1-
Naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl,
-C _7-16 aralkyl group such as phenylpentyl, and more preferably benzyl group)]. Preferred examples of the "hydrocarbon group" of the "optionally substituted hydrocarbon group" represented by R ¹ and R ² include a lower alkyl group, a lower cycloalkyl group, a lower aralkyl group, and an aryl group. .

The “substituent” of the “optionally substituted hydrocarbon group” represented by R ¹ and R ² includes, for example,
(I) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.); (ii) a lower alkylenedioxy group (eg, C _1-3 such as methylenedioxy, ethylenedioxy, etc.)
Alkylenedioxy group), (iii) nitro group, (i
v) cyano group, (v) lower alkyl group which may be halogenated, (vi) lower alkenyl group which may be halogenated, (vii) lower alkynyl group which may be halogenated, (viii) Lower cycloalkyl groups (for example,
C _3-8 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (i
x) a lower alkoxy group which may be substituted, (x) a lower alkylthio group which may be halogenated, (xi) a hydroxy group, (xii) an amino group, (xiii) a mono-lower alkylamino group (for example, Mono-C _1-6 alkylamino groups such as methylamino, ethylamino, n-propylamino, i-propylamino, butylamino, etc.), (x
iv) di-lower alkylamino group (for example, di-C _1-6 alkylamino group such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.), (xv) 5
A 6-membered cyclic amino group (eg, morpholino, thiomorpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl, etc.), (xvi) a lower alkyl-carbonyl group (eg, C _1-6 such as acetyl, propionyl, etc.)
(Xvii) carboxyl group, (xviii) lower alkoxy-carbonyl group (for example, C _1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), (xix ) Carbamoyl group, (xx) mono-lower alkyl-carbamoyl group (for example, mono-C _1-6 alkyl-carbamoyl group such as methylcarbamoyl, ethylcarbamoyl and the like), (xxi) di-lower alkyl-carbamoyl group (for example, dimethylcarbamoyl, and di -C _1-6 alkylcarbamoyl group such as diethylcarbamoyl), (xxii) aryl - carbamoyl group (e.g., phenylcarbamoyl, C _6-14 aryl, such naphthylcarbamoyl - carbamoyl, etc.), (xxiii) sulfo Group, (xxiv) low Alkylsulfonyl group (e.g., methylsulfonyl, a C _1-6 alkylsulfonyl group such as ethylsulfonyl), (xxv) aryl groups (e.g., phenyl, C _6-14 aryl groups such as naphthyl), (xxvi) aryloxy Group (for example,
C _6-14 aryloxy groups such as phenoxy, naphthyloxy, etc.), (xxvii) aralkyloxy groups (for example,
Benzyl such as C _7-16 aralkyloxy groups such as oxy), (xxviii) oxo group, (xxix) a thiocarbamoyl group, (xxx) mono- - lower alkyl - thiocarbamoyl group (e.g., mono-, such as methyl thio carbamoyl, ethyl thiocarbamoyl —C _1-6 alkyl-thiocarbamoyl group, etc.), (xxxi) di-lower alkyl-thiocarbamoyl group (eg, di-C _1-6 alkyl-thiocarbamoyl group such as dimethylthiocarbamoyl, diethylthiocarbamoyl, etc.), (Xxxii) aryl-thiocarbamoyl groups (eg, C _6-14 aryl-thiocarbamoyl such as phenylthiocarbamoyl, naphthylthiocarbamoyl, etc.); (xxxiii) aralkyl groups (eg, benzyl, phenethyl, 1-phenylpropyl, 2- such as C _7-16 aralkyl group such as phenylpropyl) (Xxxiv)
A lower alkoxy-carbonyl-lower alkyl group (eg, a C _1-6 alkoxy-carbonyl-C _1-6 alkyl group such as methylcarbonylmethyl, ethylcarbonylmethyl, etc.) or (xxxv) a carboxyl-lower alkyl group (eg, carboxymethyl And carboxyl-C _1-6 alkyl groups such as carboxylethyl). The “substituent” of the “optionally substituted hydrocarbon group” represented by R ¹ and R ² is preferably i)
A halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), (ii) an optionally halogenated lower alkyl group (among which an unsubstituted lower alkyl group (e.g., methyl, ethyl, n-propyl, i- Propyl, i-butyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and other C _1-6 alkyl groups), and (iii) optionally substituted lower alkoxy. Groups (among others, unsubstituted lower alkoxy groups (for example,
Methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, ter
a C _1-6 alkoxy group such as t-butoxy) is preferable) or (iv) an amino group.

The above R¹And R^TwoWith a substituent
Represented as a "substituent" of a "hydrocarbon group which may be
"An optionally halogenated lower alkyl group"
For example, 1 to 3 halogen atoms (for example,
Fluorine, chlorine, bromine, iodine, etc.)
Lower alkyl groups (e.g., methyl, ethyl, n-propyl
, I-propyl, i-butyl, n-butyl, sec-butyl
Tyl, tert-butyl, n-pentyl, n-hexyl, etc.
C_1-6Alkyl group, etc.).
Methyl, chloromethyl, difluoromethyl, tri
Chloromethyl, trifluoromethyl, ethyl, 2-bro
Moethyl, 2,2,2-trifluoroethyl, propyl
3,3,3-trifluoropropyl, i-propyl
, N-butyl, 4,4,4-trifluorobutyl, i
-Butyl, sec-butyl, tert-butyl, n-pliers
Le, i-pentyl, neopentyl, 5,5,5-triff
Luoropentyl, n-hexyl, 6,6,6-trifur
Orohexyl and the like. R above¹And R^TwoIn table
Of the “optionally substituted hydrocarbon group”
“Optionally substituted low halogenated”
Alkenyl groups "and" optionally halogenated "
As the "lower alkynyl group", for example, 1 to 3
Halogen atoms (for example, fluorine, chlorine, bromine, iodine
A lower alkenyl group (for example,
Nil, allyl, 1-propenyl, 1-butenyl, 2-bu
Thenyl, 3-butenyl, 4-pentenyl, 5-hexenyl
C such as _2-6Alkenyl group) and 1 to 3
Halogen atoms (eg, fluorine, chlorine, bromine, iodine
And the like) may have a lower alkynyl group (for example,
Propargyl, ethynyl, 3-butynyl, 1-hexynyl
C such as_2-6Alkynyl group).

The "optionally substituted lower alkoxy group" represented by the "substituent" of the "optionally substituted hydrocarbon group" represented by R ¹ and R ² includes: For example, (i) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), (ii) a mono- or di-lower alkylamino group (eg, mono- or diamino such as methylamino, dimethylamino, ethylamino, diethylamino, etc.) and di -C _1-6 alkylamino group), (iii) lower alkoxy - carbonyl group (e.g., methoxycarbonyl, C _1-6 alkoxy such as ethoxy carbonyl - carbonyl group), (iv) carbamoyl group and (v) A lower alkoxy group optionally having one or two substituents selected from a carboxyl group and the like (for example, methoxy, ethoxy, n-propoxy, i-pro Poxy, n-butoxy,
and C _1-6 alkoxy groups such as i-butoxy, sec-butoxy and tert-butoxy. Examples of the “optionally halogenated lower alkylthio group” represented as the “substituent” of the “optionally substituted hydrocarbon group” represented by R ¹ and R ² include, for example, 1
A lower alkylthio group (eg, methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio) which may have from 3 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) , sec- butylthio, tert- a C _1-6 alkylthio group such as butylthio), and the like. specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, n- propylthio, i- propylthio, butylthio, 4 , 4,4-trifluorobutylthio,
Pentylthio, hexylthio and the like. The “hydrocarbon group” of the “hydrocarbon group optionally having substituent (s)” represented by R ¹ and R ² is 1 to 5 (preferably 1 to 3, preferably 1 to 3, (Preferably 1 or 2).

The "optionally substituted hydrocarbon group" represented by R ¹ and R ² is preferably (1) a halogen atom, an amino group or a C _1-6 alkoxy group (for example, methoxy, ethoxy, n- Propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, t
a C _1-6 alkyl group optionally substituted with ert-butoxy (eg, methyl, ethyl, n-propyl, i-
Propyl, i-butyl, n-butyl, sec-butyl, ter
t-butyl, n-pentyl, n-hexyl, etc.),
(2) halogen atom, amino group, C _1-6 alkyl group (for example, methyl, ethyl, n-propyl, i-propyl, i-butyl, n-butyl, sec-butyl, tert-
Butyl, n-pentyl, n-hexyl, etc.) or C
_1-6 alkoxy group (for example, methoxy, ethoxy, n-
A C _3-8 cycloalkyl group _optionally substituted with propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) , (3) a halogen atom, an amino group,
C _1-6 alkyl group (for example, methyl, ethyl, n-propyl, i-propyl, i-butyl, n-butyl, sec-
Butyl, tert-butyl, n-pentyl, n-hexyl and the like or a C _1-6 alkoxy group (for example, methoxy,
_C7-16 aralkyl groups _optionally substituted by ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy (eg, benzyl, phenethyl, diphenylmethyl, 1-
Naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl,
-Phenylpentyl and the like, more preferably a benzyl group) or (4) a halogen atom, an amino group,
_{A 1-6} alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, i-butyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.) or _C1-6 Alkoxy groups (eg, methoxy,
A C _6-14 aryl group _optionally substituted by ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy (eg, phenyl, 2-biphenyl, -Biphenyl, 4-
Biphenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl, and the like). The “heterocyclic group” of the “optionally substituted heterocyclic group” represented by R ¹ and R ² above may be an arbitrary number (preferably 1 to 5, more preferably (1 to 3) substituents, and when the number of substituents is 2 or more, each substituent may be the same or different, and two adjacent substituents are bonded to each other to form a ring. It may be formed.

The "heterocyclic group" of the "optionally substituted heterocyclic group" represented by R ¹ and R ² includes, for example, (1) a nitrogen atom, a sulfur atom and an oxygen atom other than a carbon atom. A 5- to 9-membered aromatic heterocyclic ring (preferably 5 to 9) containing one or more (for example, 1 to 4, preferably 1 to 3) one or two or more hetero atoms selected from atoms.
Or 6-membered aromatic heterocycle) or (2) one selected from a nitrogen atom, a sulfur atom and an oxygen atom other than a carbon atom
5 to 9 containing one or more (eg, 1 to 4, preferably 1 to 3) hetero atoms or two or more hetero atoms
And a group formed by removing one hydrogen atom from a membered non-aromatic heterocycle (preferably a 5- or 6-membered non-aromatic heterocycle). More specifically, as the "aromatic heterocycle" of the above (1), for example, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, imidazole, pyrazole, triazole, thiophene, furan, thiazole,
In addition to carbon atoms such as isothiazole, oxazole and isoxazole rings, one or three heteroatoms selected from nitrogen, oxygen and sulfur are contained.
And a 9-membered (preferably 5- or 6-membered) aromatic heterocycle. More specifically, as the “non-aromatic heterocycle” of the above (2), for example, tetrahydropyridine,
Dihydropyridine, tetrahydropyrazine, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, pyrroline, imidazoline, pyrazoline, dihydrothiophene, dihydrofuran, dihydrothiazole, dihydroisothiazole, oxazoline, dihydroisoxazole, piperidine, piperazine, hexahydropyrimidine, hexahydropyridazine , Other than carbon atoms such as tetrahydropyran, morpholine, thiomorpholine, pyrrolidine, imidazolidine, pyrazolidine, tetrahydrothiophene, tetrahydrofuran, thiazolidine, tetrahydroisothiazole, oxazolidine, and tetrahydroisoxazole rings, a nitrogen atom, an oxygen atom, and a sulfur atom 5- to 9-membered member containing 1 to 3 selected heteroatoms (preferably Ku is such non-aromatic heterocyclic ring of 5 or 6 membered) and the like.

Examples of the "substituent" of the "optionally substituted heterocyclic group" represented by R ¹ and R ^2, for example, "substituted represented by R ¹ and R ² And the same as the “substituent” of the “optionally substituted hydrocarbon group”. The “alkyl group” of the “optionally substituted alkyl group” represented as the above-mentioned in the case where either one of R ¹ and R ^{2 is} an optionally substituted hydroxy group or an optionally substituted amino group Is preferably a linear or branched lower alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, i-butyl, n-butyl, sec-butyl, tert-butyl, n- And C _1-6 alkyl groups such as -pentyl and n-hexyl). Examples of the substituent of the “alkyl group” include “having a substituent represented by R ¹ and R ² above”. And the like as the substituent of the "optionally substituted hydrocarbon group". The above R ¹ and R ² may be bonded to each other to form a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom, and the `` optionally having a substituent As the "nitrogen-containing heterocyclic group" of the "nitrogen-containing heterocyclic group",
For example, (1) a 5- to 9-membered monocyclic or bicyclic aromatic nitrogen-containing heterocyclic ring (preferably a 5-membered monocyclic aromatic nitrogen-containing heterocyclic ring) composed of a carbon atom and a nitrogen atom, It may contain one or more (for example, 1 to 4, preferably 1 to 3) one or two hetero atoms selected from a sulfur atom and an oxygen atom in addition to the atom and the nitrogen atom. And a group formed by removing one hydrogen atom from a nitrogen atom, such as a 9-membered non-aromatic nitrogen-containing heterocycle (preferably a 5- or 6-membered non-aromatic nitrogen-containing heterocycle). More specifically, as the “aromatic nitrogen-containing heterocycle” of the above (1), for example, pyrrole, imidazole,
And aromatic nitrogen-containing heterocycles such as pyrazole, triazole, indazole and indole rings. More specifically, as the “non-aromatic heterocycle” of the above (2),
For example, tetrahydropyridine, dihydropyridine, tetrahydropyrazine, tetrahydropyrimidine, tetrahydropyridazine, pyrroline, imidazoline, pyrazoline, thiazoline, dihydroisothiazole, oxazoline, dihydroisoxazole, piperidine, piperazine, hexahydropyrimidine, hexahydropyridazine, morpholine, thiomorpholine And non-aromatic nitrogen-containing heterocycles such as pyrrolidine, imidazolidine, pyrazolidine, thiazolidine, tetrahydroisothiazole, oxazolidine and tetrahydroisoxazole rings.

The “substituent” of the “nitrogen-containing heterocyclic group optionally having substituent (s)” includes, for example, the “optionally substituted hydrocarbon” represented by R ¹ and R ² above. And the like as the "substituent" of the "group".
The “nitrogen-containing heterocyclic group optionally having substituent (s)” is preferably a halogen atom, an amino group, a C _1-6
Alkyl groups (e.g., methyl, ethyl, n-propyl,
i-propyl, i-butyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.)
Or a 5- or 6-membered group optionally substituted with a C _1-6 alkoxy group (eg, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy, etc.) And a nitrogen-containing heterocyclic group. The above R ¹ and R ² are preferably (1) a hydrogen atom, (2) an amino group, (3) a halogen atom, an amino group or a C _1-6 alkoxy group (for example, methoxy, ethoxy, n-propoxy, i -Propoxy, n-butoxy, i-butoxy, sec-butoxy, t
a C _1-6 alkyl group optionally substituted with ert-butoxy (eg, methyl, ethyl, n-propyl, i-
Propyl, i-butyl, n-butyl, sec-butyl, ter
t-butyl, n-pentyl, n-hexyl, etc.),
(4) halogen atom, amino group, C _1-6 alkyl group (for example, methyl, ethyl, n-propyl, i-propyl, i-butyl, n-butyl, sec-butyl, tert-
Butyl, n-pentyl, n-hexyl, etc.) or C
_1-6 alkoxy group (for example, methoxy, ethoxy, n-
A C _3-8 cycloalkyl group (eg, cyclopropyl) which may be substituted with a C _1-6 alkoxy group such as propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy, etc. , Cyclobutyl, cyclopentyl, _C3-8 cycloalkyl groups such as cyclohexyl, etc.), (5) halogen atoms, amino groups,
C _1-6 alkyl group (for example, methyl, ethyl, n-propyl, i-propyl, i-butyl, n-butyl, sec-
Butyl, tert-butyl, n-pentyl, n-hexyl and the like or a C _1-6 alkoxy group (for example, methoxy,
_C7-16 aralkyl groups _optionally substituted by ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy (eg, benzyl, phenethyl, diphenylmethyl, 1-
Naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl,
- phenylpentyl) or (6) a halogen atom, an amino group, C _1-6 alkyl group (e.g., methyl, ethyl, n- propyl, i- propyl, i- butyl, n- butyl, sec- butyl, tert- Butyl, n-pentyl, n-hexyl and the like or a C _1-6 alkoxy group (for example, methoxy, ethoxy, n-propoxy, i
A C _6-14 aryl group _optionally substituted with -propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy (eg, phenyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, 1-naphthyl,
2-naphthyl, 1-anthryl, 2-anthryl, 1-
Phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl, etc.). As R ¹ and R ² , one of them is preferably a hydrogen atom, one of R ¹ and R ² is a hydrogen atom, and the other is (1) a hydrogen atom, (2) an amino group, (3) substituted with a halogen atom, amino group or C _1-6 alkoxy group (for example, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy, etc.) An _optionally substituted C _1-6 alkyl group (eg, methyl, ethyl, n-propyl, i-propyl, i-
-Butyl, n-butyl, sec-butyl, tert-butyl,
n-pentyl, n-hexyl, etc.), (4) halogen atom, amino group, C _1-6 alkyl group (for example, methyl, ethyl, n-propyl, i-propyl, i-butyl, n-butyl, sec- Butyl, tert-butyl, n-pentyl, n-hexyl and the like or a C _1-6 alkoxy group (for example, methoxy, ethoxy, n-propoxy, i
A C _3-8 cycloalkyl group _optionally substituted with -propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.),
(5) halogen atom, amino group, C _1-6 alkyl group (for example, methyl, ethyl, n-propyl, i-propyl, i-butyl, n-butyl, sec-butyl, tert-
Butyl, n-pentyl, n-hexyl, etc.) or C
_1-6 alkoxy group (for example, methoxy, ethoxy, n-
A C _7-16 aralkyl group (eg, benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl) which may be substituted by propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy, etc. , 2-naphthylmethyl, 2,2-diphenylethyl,
1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, etc.) or (6) a halogen atom, an amino group, a C _1-6 alkyl group (for example, methyl, ethyl, n
-Propyl, i-propyl, i-butyl, n-butyl,
sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like or a C _1-6 alkoxy group (for example, methoxy, ethoxy, n-propoxy, i-propoxy, n
-Butoxy, i-butoxy, sec-butoxy, tert-butoxy and the like, and a C _6-14 aryl group (for example, phenyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, 1-naphthyl, 2-naphthyl, 1
-Anthryl, 2-anthryl, 1-phenanthryl,
2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9-phenanthryl) is preferred.

"Substituents" other than the "optionally substituted amino group" of the "5- to 8-membered monocyclic nitrogen-containing heterocyclic ring containing only two or three nitrogen atoms as ring-constituting heteroatoms" Examples thereof include (i) an oxo group, (ii) a thioxo group, (iii) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), (iv) an optionally substituted hydroxy group, (v) Examples include an optionally substituted thiol group, (vi) an optionally substituted hydrocarbon group, and (vii) an optionally substituted heterocyclic group. “Substituent” other than “optionally substituted amino group” of “5- to 8-membered monocyclic nitrogen-containing heterocyclic ring containing only two or three nitrogen atoms as ring-constituting heteroatoms” Examples of the “substituent” of the “optionally substituted hydroxy group” or the “optionally substituted thiol group” include the above-mentioned R
^{And the same} as the “substituent” of the “optionally substituted hydrocarbon group” represented by ¹ and R ² , and the like.
Preferably, for example, a lower alkyl group (for example, C ₁ such as methyl, ethyl, n-propyl, i-propyl, i-butyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like) _-6 alkyl group),
Aryl groups (eg, phenyl, 2-biphenyl, 3-
Biphenyl, 4-biphenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4
C such as phenanthryl or 9-phenanthryl
Examples thereof include a _6-14 aryl group and the like, preferably a phenyl group), a formyl group and a lower alkyl group-carbonyl group (for example, a C _1-6 alkyl-carbonyl group such as acetyl and propionyl).

"Substituents" other than "optionally substituted amino group" in "5- to 8-membered monocyclic nitrogen-containing heterocycle containing only 2 or 3 nitrogen atoms as ring-constituting heteroatoms" As the “optionally substituted hydrocarbon group” and the “optionally substituted heterocyclic group”, the “optionally substituted hydrocarbon group” represented by the above R ¹ and R ² And the same as "optionally substituted heterocyclic group". "5-8 containing only 2 or 3 nitrogen atoms as ring-constituting heteroatoms
Examples of the “substituent” other than the “optionally substituted amino group” of the “membered monocyclic nitrogen-containing heterocycle” include (i) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), (ii) hydrocarbon groups, as (iii) such as an optionally substituted hydroxy group or (iv) an optionally substituted heterocyclic group and the like (the "hydrocarbon group", the R ¹
And the same as the “hydrocarbon group” of the “optionally substituted hydrocarbon group” represented by R ² ), and more specifically, for example, (i) a halogen atom (eg, fluorine) , Chlorine, bromine, iodine, etc.), (ii) lower alkyl groups (eg, methyl, ethyl, i-propyl, n
-Propyl, i-butyl, n-butyl, sec-butyl, t
(C _1-6 alkyl groups such as ert-butyl, pentyl, hexyl and the like), (iii) lower alkyl groups (eg, methyl,
Ethyl, i-propyl, n-propyl, i-butyl, n
A C _1-6 alkyl group such as -butyl, sec-butyl, tert-butyl, pentyl, hexyl or the like) or a C _6-14 aryl group (for example, phenyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, 1- Naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-
A hydroxy group optionally substituted with phenanthryl or 9-phenanthryl), (iv) a C _6-14 aryl group (eg, phenyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, 1-naphthyl, 2-naphthyl) , 1
-Anthryl, 2-anthryl, 1-phenanthryl,
2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9-phenanthryl), (v) a 5- or 6-membered heterocyclic group or (vi) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), an amino group A lower alkyl group (e.g., methyl, ethyl, n-propyl, i-
Propyl, i-butyl, n-butyl, sec-butyl, ter
a C _1-6 alkyl group such as t-butyl, n-pentyl, n-hexyl or the like or a lower alkoxy group (eg, methoxy, ethoxy, n-propoxy, i-propoxy, n
Lower aralkyl groups which may be substituted with C _1-6 alkoxy groups such as -butoxy, i-butoxy, sec-butoxy, tert-butoxy and the like (for example, benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, A _C7-16 aralkyl group such as _{-naphthylmethyl} , 2,2-diphenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, and more preferably a benzyl group ) Is a preferred example. "5 containing only two or three nitrogen atoms as ring-constituting heteroatoms
More preferably, the “substituent” other than the “optionally substituted amino group” of the “8-membered monocyclic nitrogen-containing heterocycle” is, for example, (i) a halogen atom (for example, fluorine, chlorine, bromine, (Ii) a lower alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, i
-Butyl, n-butyl, sec-butyl, tert-butyl,
(C _1-6 alkyl groups such as n-pentyl and n-hexyl), (iii) lower alkyl groups (eg, methyl, ethyl, n-propyl, i-propyl, i-butyl, n-butyl, sec-butyl) , Tert-butyl, n-pentyl, n
-C _1-6 alkyl group such as hexyl) or C _6-14
Aryl groups (eg, phenyl, 2-biphenyl, 3-
Biphenyl, 4-biphenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4
Hydroxy group optionally substituted with -phenanthryl or 9-phenanthryl), (iv) a C _6-14 aryl group (for example, phenyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, 1-naphthyl, 2- Naphthyl, 1
-Anthryl, 2-anthryl, 1-phenanthryl,
2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9-phenanthryl) or (v) 5
Or a 6-membered heterocyclic group, and particularly, (i) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), (ii) a lower alkyl group (eg, methyl, ethyl,
n-propyl, i-propyl, i-butyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-
C _1-6 alkyl group such as hexyl), (iii) lower alkyl (e.g., methyl, ethyl, n- propyl, i-
Propyl, i-butyl, n-butyl, sec-butyl, ter
a C _1-6 alkyl group such as t-butyl, n-pentyl, n-hexyl, etc.) or a C _6-14 aryl group (eg, phenyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, 1-naphthyl, 2 -Naphthyl, 1-anthryl, 2
-Anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9
-Phenanthryl or the like, or a hydroxy group optionally substituted with (iv) a C _6-14 aryl group (for example, phenyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, 1-naphthyl, 2-naphthyl, 1- Antril, 2
-Anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9
-Phenanthryl) and the like.

In addition, "substituted amino groups" other than "optionally substituted amino group" in "5- to 8-membered monocyclic nitrogen-containing heterocyclic ring containing only 2 or 3 nitrogen atoms as ring-constituting heteroatoms" When the “group” substitutes for a nitrogen atom of a monocyclic nitrogen-containing heterocyclic ring, particularly a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), an amino group, a lower alkyl group (eg, methyl, ethyl, n - propyl, i- propyl, i- butyl, n- butyl, sec- butyl, tert- butyl, n- pentyl, C _1-6 alkyl group such as n- hexyl) or a lower alkoxy group (e.g., methoxy, ethoxy , N-propoxy, i-propoxy, n-
A lower aralkyl group which may be substituted with a C _1-6 alkoxy group such as butoxy, i-butoxy, sec-butoxy and tert-butoxy (for example, benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2- A _C7-16 aralkyl group such as naphthylmethyl, 2,2-diphenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, and more preferably a benzyl group) And the like are preferred examples.

Preferred examples of the compound [I] include:
For example, the expression

Embedded image (Wherein, R ¹ ′ and R ² ′ are the same or different and are (1) hydrogen atom, (2) amino group, (3) halogen atom, amino group or C _1-6 alkoxy group (for example,
Methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, ter
a C _1-6 alkyl group _optionally substituted with t-butoxy (eg, methyl, ethyl, n-propyl, i-propyl, i-butyl, n-butyl, sec-butyl, tert
-Butyl, n-pentyl, n-hexyl, etc.), (4)
Halogen atom, amino group, C _1-6 alkyl group (for example, methyl, ethyl, n-propyl, i-propyl,
i-butyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.) or C _1-6
C _3-8 cycloalkyl group (eg, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy, etc.) , Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (5) halogen atom, amino group, C
_{A 1-6} alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, i-butyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.) or _C1-6 Alkoxy groups (eg, methoxy,
_C7-16 aralkyl groups _optionally substituted by ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy (eg, benzyl, phenethyl, diphenylmethyl, 1-
Naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl,
- phenylpentyl) or (6) a halogen atom, an amino group, C _1-6 alkyl group (e.g., methyl, ethyl, n- propyl, i- propyl, i- butyl, n- butyl, sec- butyl, tert- Butyl, n-pentyl, n-hexyl and the like or a C _1-6 alkoxy group (for example, methoxy, ethoxy, n-propoxy, i
A C _6-14 aryl group _optionally substituted with -propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy (eg, phenyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, 1-naphthyl,
2-naphthyl, 1-anthryl, 2-anthryl, 1-
Phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl, etc. (provided that ^one of R ¹ ′ and R ² ′ is an amino group, the other is a hydrogen atom or C _1-6) R ¹ ′ and R ² ′ are bonded to each other to form a halogen atom, an amino group, a C _1-6 together with an adjacent nitrogen atom.
Alkyl groups (e.g., methyl, ethyl, n-propyl,
i-propyl, i-butyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.)
Or a 5- or 6-membered group optionally substituted with a C _1-6 alkoxy group (eg, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy, etc.) May form a heterocyclic group. ), And the other groups are the same or different, and each represents (1) a hydrogen atom, (2)
Halogen atom, (3) C _1-6 alkyl group (for example, methyl, ethyl, n-propyl, i-propyl, i-butyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl Or a C _6-14 aryl group (eg, phenyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, 1-naphthyl, 2-naphthyl, 1
-Anthryl, 2-anthryl, 1-phenanthryl,
A hydroxy group which may be substituted with 2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9-phenanthryl, (4) a C _6-14 aryl group (for example, phenyl, 2-biphenyl, 3-biphenyl,
-Biphenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9-phenanthryl) or (5) a 5- or 6-membered complex X represents a ring group, and X represents a nitrogen atom or a methine group. And the like.

In the above compound [II], more preferably, (A) X represents a nitrogen atom, and R ³ , R ^4, and R ⁵ are the same or different from each other.

Embedded image (Wherein R ¹ ′ and R ² ′ are as defined above), (B) X represents a nitrogen atom, and R ³ ,
Any two of R ⁴ and R ⁵ are the same or different

Embedded image (Wherein, R ¹ ′ and R ² ′ have the same meanings as described above), and the others are (1) a halogen atom, (2)
C _1-6 alkyl group (for example, methyl, ethyl, n-propyl, i-propyl, i-butyl, n-butyl, sec-
Butyl, tert-butyl, n-pentyl, n-hexyl and the like or a C _6-14 aryl group (for example, phenyl, 2
-Biphenyl, 3-biphenyl, 4-biphenyl, 1-
Naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 1-phenanthryl, 2-phenanthryl, 3-
A hydroxy group optionally substituted with phenanthryl, 4-phenanthryl or 9-phenanthryl, or (3) a C _6-14 aryl group (for example, phenyl, 2-
Biphenyl, 3-biphenyl, 4-biphenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl, etc.) Or (C) X represents a methine group, and R ³ represents the formula (1)

Embedded image (Wherein R ¹ ′ and R ² ′ are as defined above), (2) halogen atom, (3) C _1-6 alkyl group (for example, methyl, ethyl, n-propyl) , I-propyl, i-butyl, n-butyl, sec-butyl, tert-
Butyl, n-pentyl, n-hexyl, etc.) or C
_6-14 aryl group (for example, phenyl, 2-biphenyl,
3-biphenyl, 4-biphenyl, 1-naphthyl, 2-
A hydroxy group optionally substituted with naphthyl, 1-anthryl, 2-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9-phenanthryl) or (4)
A C _6-14 aryl group (eg, phenyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, 1-naphthyl,
2-naphthyl, 1-anthryl, 2-anthryl, 1-
Phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9-phenanthryl), and one of R ⁴ and R ^{5 is} a group represented by the formula

Embedded image (Wherein R ¹ ′ and R ² ′ are as defined above), and the other is a group represented by the formula (1)

Embedded image (Wherein R ¹ ′ and R ² ′ are as defined above), (2) halogen atom, (3) C _1-6 alkyl group (for example, methyl, ethyl, n-propyl) , I-propyl, i-butyl, n-butyl, sec-butyl, tert-
Butyl, n-pentyl, n-hexyl, etc.) or C
_6-14 aryl group (for example, phenyl, 2-biphenyl,
3-biphenyl, 4-biphenyl, 1-naphthyl, 2-
A hydroxy group optionally substituted with naphthyl, 1-anthryl, 2-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9-phenanthryl) or (4)
A C _6-14 aryl group (eg, phenyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, 1-naphthyl,
2-naphthyl, 1-anthryl, 2-anthryl, 1-
Phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl, etc.).

In the above compound [I], other preferred specific examples include, for example,

Embedded image [Wherein, R ³ ′ is (1) a halogen atom, (2) a C _1-6 alkyl group (eg, methyl, ethyl, n-propyl, i
-Propyl, i-butyl, n-butyl, sec-butyl, t
ert-butyl, n-pentyl, n-hexyl and the like or a C _6-14 aryl group (for example, phenyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, -Anthril,
A hydroxy group which may be substituted with 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl or the like or (3) a C _6-14 aryl group (for example, phenyl, 2-biphenyl, -Biphenyl, 4-biphenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl,
1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl, etc.), and R ⁶ represents (1) a halogen atom, an amino group, a C _1-6 alkyl group (eg, methyl, ethyl, n
-Propyl, i-propyl, i-butyl, n-butyl,
sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like or a C _1-6 alkoxy group (for example, methoxy, ethoxy, n-propoxy, i-propoxy, n
-C _7-16 aralkyl group which may be substituted with -butoxy, i-butoxy, sec-butoxy, tert-butoxy and the like (for example, benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, , 2
-Diphenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, etc.) or (2) a heterocycle (for example, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, imidazole) , Pyrazole, triazole, thiophene, furan, thiazole, isothiazole, oxazole and isoxazole rings and the like (preferably pyridine and the like) (preferably pyridine and the like) substituted C _1-6 alkyl group (eg, methyl, ethyl, n-propyl, i- Propyl, i-butyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.) and R ⁴ ′
Is the expression

Embedded image (Wherein R ¹ ′ and R ² ′ have the same meanings as described above). Specific examples of compound [I] include 2,4-bis (phenylamino) -6- (3,5-dimethylpyrazol-1-yl) -1,3,5-triazine, 4- (3,5- Dimethylpyrazol-1-yl) -6- (4-methoxyphenyl) amino
2-phenylpyrimidine, 2-phenyl-6-phenylamino
-3- (3-picolyl) pyrimidin-4 (3H) -one or a salt thereof. The method for producing the compound [I] is described below. The compound [I] may form a salt or an ester, and may be formed by a method known per se, for example, Journal of American Chemical Society, 73, 2981 (1951) (J. Am. Chem.
Soc., 73, 2981 (1951)), U.S. Pat. No. 4,261,892.
No. (USP-4261892), Journal of Pesticide Science, 13, 13 (1990) (J. Pest
icide Sci., 13, 13 (1990)), The Chemistry
Of the heterocyclic compound `` The Pyrimidines '', pages 162 to 215, pages 227 to 263, published in Interscience Publishers 1962, can be produced by the method described in JP-A-9-227533 or a method analogous thereto, or the like. .

Also, as preferable examples of the compound [I], the above-mentioned compound [II] or a salt thereof and the following compound [II '] can be produced by a method known per se or a method analogous thereto. Specifically, it can be produced by the method shown in the following Scheme 1, or the like.

Embedded image (In the scheme 1, L ¹ to L ³ are a leaving group, and other symbols have the same meanings as described above.) The “leaving groups” represented by L ¹ to L ³ are the same or different and are each a halogen atom. Atoms, especially chlorine or bromine, are mentioned. In addition, compound (VIII) represented by the general formula shown in the following scheme 2 can also be obtained by a method known per se, for example, “The chemistry of heterocyclic compound“ The pyrimidines ”
162 to 215, 227 to 263, 356 to 375, published in Interscience Publishers, 1962 ”or a method analogous thereto. It can be manufactured by the method described above.

Embedded image (Wherein L and Y are each a leaving group, and other symbols have the same meanings as described above) Examples of the leaving group represented by L include a halogen atom, particularly chlorine or bromine;
Examples of the leaving group represented by Y include (1) a halogen atom (for example, chlorine, bromine or iodine), (2)
C optionally substituted with 1 to 3 halogen atoms
_1-6 alkylsulfonyloxy group (e.g., methanesulfonyloxy, trifluoromethane sulfonyloxy), (3) one to four C _1-6 alkyl or optionally C _6-10 arylsulfonyl optionally substituted by a halogen atom An oxy group (for example, p-toluenesulfonyloxy, benzenesulfonyloxy, p-bromobenzenesulfonyloxy, mesitylenesulfonyloxy, etc.); The compound shown in the above scheme includes a case where a salt is formed. As the salt, for example, the compound (I)
And the like as the salt of the above.

Compounds (I), (II), (II ') and (VIII) can be isolated and purified by known means, for example, solvent extraction, liquid conversion, phase transfer, crystallization, recrystallization, chromatography and the like. can do. The starting compounds of the compounds (I), (II), (II ′) and (VIII) or salts thereof can be isolated and purified by the same known means as described above, but without isolation. It may be used as it is as a reaction mixture as a raw material in the next step. Compound (I) or a salt thereof has been confirmed to have a strong antagonistic effect on human adenosine A3 receptor expressed in CHO cells, and inhibition of adenylate cyclase resulting from activation of adenosine A3 receptor. And degranulation of mast cells.
That is, it inhibits the release of inflammatory mediators from mast cells and raises cAMP (cyclic adenosine monophosphate) concentration, suppresses cell death caused by, for example, ischemia, etc. Can be used as a protective agent. Adenosine A comprising the above compound [I] forming a salt and containing the salt
When the 3 antagonist is used as a pharmaceutical, the salt is preferably a pharmaceutically acceptable salt.

Specific examples of the salt of compound [I] include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids. can give. Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and ammonium salt. Preferred examples of the salt with an organic base include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine and the like. Preferable examples of the salt with an inorganic acid include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p -Salts with toluenesulfonic acid and the like. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, and preferred examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Can be For example, when the compound [I] has an acidic functional group, an alkali metal salt (for example, a sodium salt,
Inorganic salts such as potassium salts, alkaline earth metal salts (eg, calcium salts, magnesium salts, barium salts, etc.), ammonium salts, etc., and when the nitrogen-containing heterocyclic compound has a basic functional group, Inorganic salts such as hydrochloride, sulfate, phosphate, hydrobromide, or acetate, maleate, fumarate, succinate, methanesulfonate, p-toluenesulfonate, citric acid Organic salts such as salts and tartrate salts. Compound [I] has low toxicity and is safe. Therefore, an adenosine A3 antagonist containing the compound of the present invention is based on its excellent adenosine A3 antagonism, and is useful for mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human, etc.). It is useful as a safe protective agent for the brain and heart including ischemic diseases (eg, cerebral infarction, myocardial infarction, etc.), and also for inflammatory or allergic diseases (eg, dermatitis (such as atopic dermatitis), psoriasis, It is also useful as a safe preventive and therapeutic agent for asthma, urticaria (such as chronic urticaria), bronchitis, sputum, rhinitis (such as allergic rhinitis), inflammatory bowel disease, and rheumatoid arthritis. Further, the adenosine A3 antagonist containing the compound of the present invention can be formulated according to a method known per se, and by appropriately mixing an appropriate amount of the compound as it is or a pharmacologically acceptable carrier in the formulation step. Pharmaceutical compositions,
For example, tablets (including sugar-coated tablets, film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release preparations, etc., orally or parenterally (eg, topically, Rectally, intravenously, etc.).

The content of the compound in the adenosine A3 antagonist of the present invention is 0.1 to 100% by weight of the whole agent. Although the dose varies depending on the target disease, symptoms, administration target, administration method, etc., for example, when orally administered to an adult (60 kg) patient as a therapeutic agent for ischemic disease such as stroke or cerebral infarction, it is effective per day. The component is about 0.1 to 1000 mg, preferably about 1 to 500 mg, more preferably about 10 to 300 mg, which can be administered once or several times a day. Examples of the pharmacologically acceptable carrier used in the production of the antagonist of the present invention include various organic or inorganic carrier substances commonly used as pharmaceutical materials, for example, excipients in solid formulations,
Lubricants, binders, disintegrants; solvents in liquid preparations, dissolution aids, suspending agents, tonicity agents, buffers, soothing agents and the like. If necessary, additives such as preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like can also be used. Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, and sodium carboxymethylcellulose. Disintegrators include, for example, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, sodium carboxymethyl starch, L-hydroxypropyl cellulose and the like. Examples of the solvent include water for injection, ethanol, propylene glycol, macrogol, sesame oil, corn oil and the like.

Examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol,
Benzyl benzoate, ethanol, trisaminomethane,
Cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like can be mentioned. As a suspending agent, for example, stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride,
A surfactant such as glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose,
Examples include hydrophilic polymers such as hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. As the tonicity agent, for example, glucose, D-sorbitol, sodium chloride, glycerin, D-
Mannitol and the like. Examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Examples of the soothing agent include benzyl alcohol and the like. Examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. As antioxidants,
For example, sulfites, ascorbic acid and the like can be mentioned.

[0033]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention further includes the following reference examples,
The present invention will be described in detail with reference to Examples and Test Examples. However, these Examples are merely examples, do not limit the present invention, and may be changed without departing from the scope of the present invention. The percentages described below mean percent by weight unless otherwise specified. Abbreviations used in other texts have the following meanings. s: singlet d: doublet t: triplet q: quartet m: multiplet br: broad J: coupling constant Hz: hertz ( Hertz) DMSO-d ₆ : Deuterated dimethyl sulfoxide ¹ H-NMR: Proton nuclear magnetic resonance cDNA: Complementary deoxyribonucleic acid DNA: Deoxyribonucleic acid EDTA: Ethylenediaminetetraacetic acid PBS: Phosphate buffer BSA: Bovine serum albumin PMSF: Phenyl fluoride methylsulfonyl HBSS: Hank's solution ^{I-AB-MECA: N 6} - (4- amino-3-iodobenzyl) -5 '- (methyl carboxamide) adenosine NECA: 5' - (ethyl carboxamide) adenosine

[0034]

The compounds of Reference Examples 1 to 53 described below were prepared by a method known per se, for example, Journal of American Chemical Society, 73, 2981 (1951).
(J. Am. Chem. Soc., 73, 2981 (1951)), U.S. Pat. No. 4,261,892 (USP-4261892), Journal of Pesticide Science, 13, 13 (19).
1990) (J. Pesticide Sci., 13, 13 (1990)), "The Chemistry of Heterocyclic Compound," The Pyrimidines ", pp. 162-215, 227-263.
Interscience Publishers 1962, "
It was synthesized by the method described in JP-A-9-227533 or a method analogous thereto.

Reference Example 1 2-chloro-4-ethylamino-6-phenylamino-
1,3,5-triazine Melting point: 210-211 ° C. Reference Example 2 2-chloro-4-isopropylamino-6-phenylamino-1,3,5-triazine Melting point: 115-117 ° C. Reference Example 3 2-chloro- 4-cyclopropylamino-6-phenylamino-1,3,5-triazine Melting point: 190-191 ° C. Reference Example 4 2- (tert-butylamino) -4-chloro-6-phenylamino-1,3,5 -Triazine Melting point: 144-145 ° C Reference example 5 2-Chloro-4-cyclohexylamino-6-phenylamino-1,3,5-triazine Melting point: 201-202 ° C Reference example 6 2,4-bis (phenylamino) -6-chloro-1,
3,5-triazine melting point: 201-202 ° C

Reference Example 7 2-chloro-4- (4-methoxyphenyl) amino-6
-Phenylamino-1,3,5-triazine Melting point: 168-172 ° C Reference Example 8 2,4-bis ((4-methoxyphenyl) amino) -6
-Chloro-1,3,5-triazine melting point: 205-208 ° C. Reference Example 9 2-benzylamino-4-chloro-6-phenylamino-1,3,5-triazine melting point: 178-180 ° C. Reference Example 10 2 -Chloro-4-diethylamino-6-phenylamino-1,3,5-triazine Melting point: 97-100 ° C Reference Example 11 2-Chloro-4-phenylamino-6-piperidino-
1,3,5-triazine Melting point: 137-139 ° C Reference Example 12 2-Chloro-4-morpholino-6-phenylamino-
1,3,5-triazine Melting point: 197-200 ° C Reference Example 13 2-hydrazino-4-methylamino-6-phenylamino-1,3,5-triazine Melting point: 163-166 ° C Reference Example 14 2-hydrazino- 4-isopropylamino-6-phenylamino-1,3,5-triazine melting point: 83-85 ° C

Reference Example 15 2- (tert-butylamino) -4-hydrazino-6
-Phenylamino-1,3,5-triazine melting point: 94-97 ° C. Reference Example 16 2-cyclohexylamino-4-hydrazino-6-phenylamino-1,3,5-triazine melting point: 154-158 ° C. Reference Example 17 2,4-bis (phenylamino) -6-hydrazino-
1,3,5-Triazine Melting point: 189-193 ° C Reference example 18 2-benzylamino-4-hydrazino-6-phenylamino-1,3,5-triazine Melting point: 128-130 ° C Reference example 19 2,4- Bis (phenylamino) -6-methylamino-
1,3,5-triazine melting point: 171-173 ° C

Reference Example 20 2,4-bis (phenylamino) -6-ethylamino-
1,3,5-triazine ¹ H-NMR (DMSO-d ₆ ) δ: 1.15 (3H, t, J = 7.2 Hz), 3.36
(2H, q, J = 7.2Hz), 6.88-7.08 (3H, m), 7.18-7.30 (4
H, m), 7.74-7.86 (4H, m), 8.95 (1H, br s), 9.07 (1
H, brs) Reference Example 21 2,4-bis (phenylamino) -6-cyclohexylamino-1,3,5-triazine Melting point: 198-201 ° C. Reference Example 22 2-benzylamino-4,6-bis ( Phenylamino)
-1,3,5-triazine ¹ H-NMR (DMSO-d ₆ ) δ: 4.55 (2H, d, J = 6.2 Hz), 6.87-
7.01 (2H, m), 7.14-7.31 (5H, m), 7.31-7.44 (4H,
m), 7.58-7.89 (5H, m), 9.05 (1H, br s), 9.09 (1H,
br s) Reference Example 23 2,4-bis (phenylamino) -6- (1-imidazolyl) -1,3,5-triazine Melting point: 268-271 ° C. Reference Example 24 2,4-bis (phenylamino)- 6- (1-Pyrazolyl) -1,3,5-triazine Melting point: 185-187 ° C. Reference Example 25 2- (3,5-dimethylpyrazol-1-yl) -4-
Methylamino-6-phenylamino-1,3,5-triazine Melting point: 187-190 ° C

Reference Example 26 2- (3,5-dimethylpyrazol-1-yl) -4-
Ethylamino-6-phenylamino-1,3,5-triazine Melting point: 149-152 ° C. Reference Example 27 2-Cyclopropylamino-4- (3,5-dimethylpyrazol-1-yl) -6-phenylamino- 1,3,3
5-triazine Melting point: 186-189 ° C Reference Example 28 2- (3,5-dimethylpyrazol-1-yl) -4-
Isopropylamino-6-phenylamino-1,3,5
-Triazine Melting point: 196-199 ° C Reference Example 29 2- (tert-butylamino) -4- (3,5-dimethylpyrazol-1-yl) -6-phenylamino-1,
3,5-Triazine Melting point: 198-200 ° C. Reference Example 30 2-cyclohexylamino-4- (3,5-dimethylpyrazol-1-yl) -6-phenylamino-1,3,3
5-Triazine melting point: 224-226 ° C

Reference Example 31 2,4-bis (phenylamino) -6- (3,5-dimethylpyrazol-1-yl) -1,3,5-triazine Melting point: 238-240 ° C. Reference Example 32 2- ( 3,5-dimethylpyrazol-1-yl) -4-
(4-methoxyphenyl) amino-6-phenylamino-1,3,5-triazine Melting point: 114-116 ° C. Reference Example 33 2,4-bis ((4-methoxyphenyl) amino) -6
-(3,5-dimethylpyrazol-1-yl) -1,
3,5-Triazine melting point: 194-197 ° C. Reference Example 34 2-benzylamino-4- (3,5-dimethylpyrazol-1-yl) -6-phenylamino-1,3,5-triazine melting point: 154- 156 ° C Reference Example 35

2-Diethylamino-4- (3,5-dimethylpyrazol-1-yl) -6-phenylamino-
1,3,5-Triazine Melting point: 144-146 ° C. Reference Example 36 2- (3,5-dimethylpyrazol-1-yl) -4-
Morpholino-6-phenylamino-1,3,5-triazine Melting point: 222-224 ° C. Reference Example 37 2,4-bis (phenylamino) -6- (1-indolyl) -1,3,5-triazine Melting point: 163-166 ° C Reference Example 38 2,4-bis (phenylamino) -6- (2-indazolyl) -1,3,5-triazine Melting point: 196-199 ° C Reference Example 39 2-hydrazino-4,6-diphenyl -1,3,5-Triazine melting point: 188-189 ° C

Reference Example 40 4-Chloro-2-phenyl-6- (phenylamino) pyrimidine Melting point: 137-138 ° C. Reference Example 41 4-Chloro-6- (3,5-dimethylpyrazole-1-)
Il) -2-phenylpyrimidine Melting point: 147-148 ° C Reference Example 42 2,4-bis (benzylamino) -6-chloropyrimidine Melting point: 133-134 ° C Reference Example 43 4-cyclohexylamino-6-hydrazino-2- Phenylpyrimidine Melting point: 128-129 ° C Reference Example 44 4-cyclohexylamino-2-phenyl-6- (phenylamino) pyrimidine Melting point: 139-140 ° C Reference Example 45 2-phenyl-4,6-bis (phenylamino) pyrimidine Melting point: 190-191 ° C Reference Example 46 4-benzylamino-2-phenyl-6- (phenylamino) pyrimidine Melting point: 120-121 ° C

Reference Example 47 4- (3,5-dimethylpyrazol-1-yl) -2-
Phenyl-6- (phenylamino) pyrimidine Melting point: 177-180 ° C Reference Example 48 4- (3,5-dimethylpyrazol-1-yl) -6
(4-methoxyphenyl) amino-2-phenylpyrimidine Melting point: 159-160 ° C Reference Example 49 2,4,6-tris (phenylamino) pyrimidine Melting point: 206-208 ° C Reference Example 50 4-hydrazino-2-phenyl- 6- (Phenyloxy) pyrimidine dihydrochloride Melting point: 170-174 ° C. Reference Example 51 2-phenyl-4-phenylamino-6- (phenyloxy) pyrimidine Melting point: 107-108 ° C. Reference Example 52 4-cyclohexylamino-2 -Phenyl-6- (phenyloxy) pyrimidine hydrochloride Melting point: 138-142 ° C Reference Example 53 2-Phenyl-6-phenylamino-3- (3-picolyl) pyrimidin-4 (3H) -one Melting point: 168-170 C. The chemical structural formulas of the obtained compounds of Reference Examples 1 to 53 are shown below.

[0044]

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[0045]

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[0046]

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Example 1 (1) Reference Example Compound 21 50 mg (2) Lactose 34 mg (3) Corn Starch 10.6 mg (4) Corn Starch (paste) 5 mg (5) Magnesium Stearate 0.4 mg (6) Carboxymethylcellulose calcium 20 mg Total 120 mg The above (1) to (6) were mixed and tabletted with a tablet machine to obtain tablets. Example 2 (1) Reference Example Compound 21 50 mg (2) Fine powdered cellulose 30 mg (3) Lactose 37 mg (4) Magnesium stearate 3 mg Total 120 mg The above (1) to (4) were mixed, and gelatin was mixed. The capsule was filled to obtain a capsule. Example 3 (1) Reference Example Compound 21 50 mg (2) Corn oil 100 mg Total 150 mg The above (1) and (2) were mixed and filled in a soft capsule to obtain a soft capsule.

EXPERIMENTAL EXAMPLE The genetic manipulation method described below is described in
niatis et al., Molecular Cloning, ColdSpringHarbor L
aboratory), 1989) or the protocol described in the attached protocol of the reagent. Cloning of human adenosine A3 receptor Adenosine A3 was obtained from human brain cDNA by PCR method known per se.
Cloning of the three receptor gene was performed. Salvatore et al. Reported using 1 ng of brain cDNA (Toyobo, QUICK-Clone cDNA) as a template (Proceedings
Of the National Academy of Sciences
Of the United States of America, 90
Volume, 10365 pages (1993) (Proc., Natl., Acad., Sci.,
USA, 90, 10365 (1993))) Adenosine A3
Primer set 5′-CGCCTCTAGACAAGATGCC prepared with reference to receptor gene base sequence
CAACAAACAGCACTGC-3 'and 5'-CGG
GGTCGACACTACTCAGAATTCTTCT
CAATGC-3 ′ was added in an amount of 50 pmol each, and TaKaRa LA was added.
Use PCR Kit Ver.2 (Takara Shuzo) to perform PCR
A Thermal cycler 480 (Perkin Elmer) (reaction conditions: 95 ° C for 1 minute, 66 ° C for 1 minute, 75 ° C for 2 minutes)
35 cycles per minute). The PCR product was subjected to agarose gel electrophoresis, and a DNA fragment of 1.0 kb was recovered.
The adenosine A3 receptor gene was cloned using the iginal TA Cloninng Kit (Funakoshi). next,
The resulting plasmid was digested with restriction enzyme XbaI (Takara Shuzo), blunt-ended by T4 DNA polymerase (Takara Shuzo) treatment, and further digested with SalI (Takara Shuzo) to obtain a fragment of adenosine A3 receptor gene.

Preparation of Plasmid for Expression of Human Adenosine A3 Receptor Mouse myeloma FIB1-H01 / × 63 (IFO accession number: 502) described in JP-A-5-076385
57; FFRMBP accession number: 3141).
After digestion with II (Takara Shuzo) and smoothing, EcoRI
(Takara Shuzo) digested pCI vector (Promega) with D
Ligated with NA Ligation kit (Takara Shuzo), pCI-SRα
Was prepared. Next, after digesting this pCI-SRα with ClaI (Takara Shuzo), T4 DNA polymerase (Takara Shuzo)
The ends were blunted by the treatment. On the other hand, pGFP-C
After digesting 1 (Toyobo) with Bsu36I (Daiichi Pure Chemicals), a 1.63 kb DNA fragment whose end was blunted by treatment with T4 DNA polymerase (Takara Shuzo) was obtained.
Ligated with DNA Ligation kit (Takara Shuzo), E. coli JM10
The plasmid pMSRα neo was obtained by transforming 9 competent cells (Takara Shuzo). Next, pMSR
After digesting α neo with EcoRI (Takara Shuzo), T4
The end was blunted by DNA polymerase (Takara Shuzo) treatment, and a 5.4 kb DNA fragment obtained by digestion with SalI (Takara Shuzo) was mixed with the adenosine A3 receptor gene fragment described above, followed by DNA Ligation kit (Takara Shuzo). By ligating and transforming competent cells of E. coli JM109 (Takara Shuzo), plasmid pA3SR was obtained.
α was obtained. CH of plasmid for human adenosine A3 receptor expression
Introduction into O (dhfr-) cells and expression CH grown in 750 ml tissue culture flask (Becton Dickinson) in Ham F12 medium (Nippon Pharmaceutical) containing 10% fetal bovine serum (Lifetech Oriental)
O (dhfr-) cells were treated with 0.5 g / L trypsin-0.2 g / L ED
After peeling with TA (Lifetech Oriental), the cells are washed with PBS (Lifetech Oriental) and centrifuged.
(1000 rpm, 5 minutes) and suspended in PBS. Next, DNA was introduced into the cells using Gene Pulser (Bio-Rad) under the following conditions. That is, 8 × 10 ⁶ cells and 10 μg of human adenosine A3 receptor expression plasmid pA3SRα were added to a 0.4 cm gap cuvette.
Electroporation was performed under a voltage of 0.25 kV and a capacitance of 960 μF. Thereafter, the cells were transferred to Ham's F12 medium containing 10% fetal bovine serum, cultured for 24 hours, the cells were again detached and centrifuged, and then Geneticin (Lifetech Oriental) was added to a concentration of 500 µg / ml.
Suspended in Ham's F12 medium containing 10% fetal bovine serum,
^The cells were diluted to ⁴ cells / ml and seeded on a 96-well plate (Becton Dickinson) to obtain a geneticin-resistant strain. Next, after culturing the obtained geneticin-resistant strain in a 24-well plate (Becton Dickinson),
Adenosine A3 receptor expressing cells were selected from among the resistant strains. That is, assay buffer I (0.1% BSA, 0.25 mM PMSF, 1 μg / ml pepstatin and 50 pM ¹²⁵ I-AB-MECA (Amersham) added as a ligand.
Reaction was performed for 1 hour in HBSS (Wako Pure Chemical Industries, Ltd.) containing 20 μg / ml leupeptin, and washed with assay buffer I.
By measuring the radioactivity with a γ counter, cells to which the ligand specifically bound, the A3AR / CHO strain, were selected.

Preparation of Cell Membrane Fraction of Adenosine A3 Receptor Expressing Cell The A3AR / CHO strain thus obtained was cultured for 2 days in Ham's F12 medium containing 10% fetal bovine serum, and then
Peel off with PBS containing 2% EDTA, collect cells by centrifugation, and assay buffer II (50 mM Tris-HCl (pH
7.5), 1mM EDTA, 10mM magnesium chloride, 0.25mM PM
SF, 1 μg / ml pepstatin, 20 μg / ml leupeptin) and a polytron homogenizer (model PT
-3000, KINEMATICA AG) 2000
The cells were disrupted by treating three times at 0 rpm for 20 seconds. After cell disruption, the mixture was centrifuged at 2000 rpm for 10 minutes to obtain a supernatant containing a membrane fraction. The supernatant was centrifuged at 30,000 rpm for 1 hour in an ultracentrifuge (model L8-70M, rotor 70Ti, Beckman) to obtain a precipitate containing a membrane fraction. Next, remove the precipitate by 2unit /
suspended in assay buffer II containing 0.1 ml adenosine deaminase (Boehringer Mannheim) at 30 ° C.
After treating for 30 minutes, the mixture was centrifuged again in the same manner as above to obtain a precipitate containing a membrane fraction.

Evaluation of Reference Example Compounds In a 96-well microplate, 100 μg / ml of a membrane fraction and 10 nL of [ ³ H] -NECA (Amersham) as a ligand were added to an assay buffer II containing each concentration of a reference example compound.
M, and reacted at room temperature for 1 hour. next,
The membrane fraction was transferred to Unifilter GF / C (Packard) by filtering the reaction solution using a cell harvester (Packard), and cooled in 50 mM Tris buffer (pH 7.5).
Was washed three times. After drying the filter, micro scintillation 0 (Packard) was added to the filter, the radioactivity was measured with a top counter (Packard), and [ ³ H] -NEC was measured.
The concentration (IC ₅₀ ) of the compound required to reduce the amount of A bound to the membrane fraction to 50% was calculated using PRISM 2.01 (Graph Pad Software).

Table 1 shows the IC ₅₀ values of the compounds in antagonizing the adenosine A3 receptor.

[Table 1] These results indicate that the compound [I] of the present invention has an excellent adenosine A3 receptor antagonism.

[0053]

[Sequence list]

Sequence number (SEQ ID NO): 1 Sequence length (SEQUENCE LENGTH): 34 Sequence type (SEQUENCE TYPE): Number of nucleic acid chains (STRANDEDNESS): single Topology (TOPOLOGY): Linear sequence type (MOLECULE TYPE) : Other nucleic acid (s
synthetic DNA) Sequence: CGCCTCTAGA CAAGATGCCC AACAACAGCA CTGC 34 Sequence number (SEQ ID NO): 2 Sequence length (SEQUENCE LENGTH): 34 Sequence type (SEQUENCE TYPE): Number of nucleic acid chains (STRANDEDNESS): single topology (TOPOLOGY) ): Linear sequence type (MOLECULE TYPE): other nucleic acid (s
synthetic DNA) Sequence: CGGGGTCGAC ACTACTCAGA ATTCTTCTCA ATGC 34

[0054]

The compound [I] of the present invention is adenosine A
3 has a strong antagonistic effect on the three receptors, for example,
It is useful as a protective agent for the brain and heart against ischemic diseases.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/00 629 A61K 31/00 629 31/505 31/505 31/53 31/53 // C07D 251/18 C07D 251/18 Z 251/50 251/50 D 251/70 251/70 F 403/04 209 403/04 209 231 231 233 233

Claims (13)

[Claims] 1. A 5- to 8-membered monocyclic nitrogen-containing heterocyclic compound which is substituted with an optionally substituted amino group and contains only 2 or 3 nitrogen atoms as a ring-constituting heteroatom. An adenosine A3 antagonist. 2. A monocyclic nitrogen-containing heterocyclic ring, in addition to an optionally substituted amino group, an oxo group, a thioxo group, a halogen atom, an optionally substituted hydroxy group, an optionally substituted thiol group, An amino group which may be substituted,
2. The monocyclic nitrogen-containing heterocyclic ring which may have 1 to 3 substituents selected from a hydrocarbon group which may be substituted and a heterocyclic group which may be substituted. Agent. (3) the amino group which may be substituted has the formula: Wherein R ¹ and R ² are the same or different,
Hydrogen atom, an optionally substituted hydroxy group, an optionally substituted amino group optionally, optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R ¹
And R ² may be bonded to each other to form a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom (provided that ^one of R ¹ and R ² is substituted) In the case of a hydroxy group which may be substituted or an amino group which may be substituted, the other is a hydrogen atom or an alkyl group which may be substituted.)]]. 4. The agent according to claim 3, wherein one of R ¹ and R ² is a hydrogen atom. 5. The method according to claim 1, wherein R ¹ and R ² are the same or different and each is substituted by (1) a hydrogen atom, (2) an amino group, (3) a halogen atom, an amino group or a C _1-6 alkoxy group. A good C _1-6 alkyl group, (4) a halogen atom, an amino group, a C _3-8 cycloalkyl group optionally substituted with a C _1-6 alkyl group or a C _1-6 alkoxy group, (5) a halogen atom A C _7-16 aralkyl group optionally substituted with an amino group, a C _1-6 alkyl group or a C _1-6 alkoxy group or (6) a halogen atom,
A C _6-14 aryl group which may be substituted with an amino group, a C _1-6 alkyl group or a C _1-6 alkoxy group (provided that when ^one of R ¹ and R ² is an amino group, _{Represents a} hydrogen atom or a C _1-6 alkyl group.), R ¹ and R ² are a halogen atom, an amino group, a C _1-6 alkyl group or a C _1-6 alkoxy group together with an adjacent nitrogen atom. The agent according to claim 3, which may form a 5- or 6-membered heterocyclic group which may be substituted. 6. ^One of R ¹ and R ² is a hydrogen atom, and the other is (1) a hydrogen atom, (2) an amino group, (3) a halogen atom, an amino group or a C _1-6 alkoxy group. An optionally substituted C _1-6 alkyl group, (4) a halogen atom, an amino group, a C _1-6 alkyl group or C _1-6
A C _3-8 cycloalkyl group optionally substituted with an alkoxy group, (5) a halogen atom, an amino group, a C _1-6
A C _7-16 aralkyl group which may be substituted with an alkyl group or a C _1-6 alkoxy group or (6) a halogen atom, an amino group, a C _1-6 alkyl group or a C _1-6 alkoxy group, _4. The agent according to claim 3, which represents a C _6-14 aryl group. 7. The agent according to claim 1, wherein the monocyclic nitrogen-containing heterocyclic compound is a 6-membered monocyclic nitrogen-containing heterocyclic compound. 8. A compound of the formula [Wherein at least one of R ³ , R ⁴ and R ⁵ is the same or different and each has the formula: (Wherein R ¹ ′ and R ² ′ are the same or different and are each substituted with (1) hydrogen atom, (2) amino group, (3) halogen atom, amino group or C _1-6 alkoxy group. also a C _1-6 alkyl group, (4) a halogen atom, an amino group, a C _1-6 alkyl group or C _1-6 alkoxy optionally substituted C _3-8 also be a cycloalkyl group with a group, (5) halogen An atom, an amino group, a C _7-16 aralkyl group which may be substituted by a C _1-6 alkyl group or a C _1-6 alkoxy group, or (6) a halogen atom,
A C _6-14 aryl group optionally substituted with an amino group, a C _1-6 alkyl group or a C _1-6 alkoxy group (provided that ^one of R ¹ ′ and R ² ′ is an amino group) and the other is a hydrogen atom or a C _1-6 alkyl group.), R ¹ 'and R ^2' is a halogen atom together with the adjacent nitrogen atom bonded with each other, an amino group, a C _1-6 alkyl group or a C _{1- It} may form a 5- or 6-membered heterocyclic group which may be substituted with a ₆ alkoxy group. )
And the other groups are the same or different, and each group is represented by (1) a hydrogen atom, (2) a halogen atom, (3)
A hydroxy group which may be substituted with a C _1-6 alkyl group or a C _6-14 aryl group, (4) a C _6-14 aryl group or (5) a 5- or 6-membered heterocyclic group; Indicates an atom or a methine group. The agent according to claim 1, comprising a compound represented by the formula: or a salt thereof. 9. X is a nitrogen atom, and R ³ , R ⁴ and R ⁵
Are the same or different and are of the formula (Wherein R ¹ ′ and R ² ′ are the same as defined in claim 8). 10. X is a nitrogen atom, and R ³ , R ⁴ and R
Any two of the formulas ⁵ are the same or different, (Wherein R ¹ ′ and R ² ′ have the same meanings as in claim 8), and the others are (1) halogen atom, (2) C _1-6 alkyl group or C _{6 A} hydroxy group optionally substituted with a _-14 aryl group or (3) C
_9. The agent according to claim 8, which represents a _6-14 aryl group. 11. X is a methine group, and R ³ is a group represented by the formula (1). Wherein R ¹ ′ and R ² ′ have the same meaning as described in claim 8), (2) a halogen atom, and (3) C
_A hydroxy group or a (4) C _6-14 aryl group which may be substituted with a _1-6 alkyl group or a C _6-14 aryl group, wherein one of R ⁴ and R ^{5 is} a group represented by the formula: (Wherein R ¹ ′ and R ² ′ have the same meanings as defined in claim 8), and the other is a group represented by the formula (1): Wherein R ¹ ′ and R ² ′ have the same meaning as described in claim 8), (2) a halogen atom, and (3) C
The agent according to claim 8, which represents a hydroxy group optionally substituted with a _1-6 alkyl group or a C _6-14 aryl group or (4) a C _6-14 aryl group. 12. A compound of the formula [Wherein, R ³ ′ represents (1) a halogen atom, (2) a hydroxy group optionally substituted by a C _1-6 alkyl group or a C _6-14 aryl group, or (3) a C _6-14 aryl group. R ⁶ represents (1) a halogen atom, an amino group, C _1-6
An alkyl group or a C _1-6 optionally C _7-16 aralkyl group or optionally substituted with alkoxy group (2) C _1-6 alkyl group substituted by heterocycle, R ⁴ 'is the formula: 10] (Wherein R ¹ ′ and R ² ′ are as defined in claim 8) or a salt thereof. 13. The agent according to claim 1, which is a brain or cardioprotective agent.