JP2009062278A - P2x4 receptor antagonist - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a P2X<SB>4</SB>receptor antagonist. <P>SOLUTION: A compound represented by general formula (I) or a salt thereof is used as a P2X<SB>4</SB>receptor antagonist. In the formula, X<SP>a</SP>is O, S or the like; R<SP>1a</SP>is a hydroxy group, an amino group, a 1-8C alkylamino group, a dialkylamino group, a 1-8C alkyl group substituted with a halogen atom, a phenyl group or the like; R<SP>2a</SP>and R<SP>3a</SP>are each a hydrogen atom, a 1-8C alkyl group or the like; and R<SP>4a</SP>is a hydrogen atom or the like. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

The present invention relates to 1,4-diazepin-2-one derivatives having a P2X ₄ receptor antagonism.

ATP receptors are broadly classified into the P2X family of ion channel receptors and the P2Y family of G protein-coupled receptors. Up to now, there are 7 types (P2X _1-7 ) and 9 types (P2Y 1, 2, ₄ , 11). _-15 ) subtypes have been reported.
The P2X ₄ receptor (Genebank No. X87763), a subtype of the P2X family, has been reported to be widely expressed in the central nervous system and the like. (Non-patent document 1, Non-patent document 2, Non-patent document 3, Non-patent document 4, Non-patent document 5)
Now, the onset mechanism of intractable pain such as neuropathic pain has not been accurately understood, and there is no treatment if non-steroidal anti-inflammatory drugs (NSAIDs) or morphine do not work. Therefore, the burden on the mind and body of the patient and the surrounding people is very heavy. Neuropathic pain is often caused by damage to the peripheral nerve or central nerve, and is caused by, for example, sequelae of surgery, cancer, spinal cord injury, herpes zoster, diabetic neuritis, trigeminal neuralgia.
Recently, Inoue et al. Examined the involvement of the P2X receptor in neuropathic pain using an animal model that damaged spinal nerves that could detect allodynia. Then, via a P2X ₄ receptor expressed in spinal cord microglial cells neuropathic abnormal pain (peripheral neuropathy pain, particularly Arodeinia) has announced that is induced. (Non-Patent Document 6, Non-Patent Document 7, Patent Document 1) Accordingly, P2X ₄ substances that inhibit the action of receptors, nociceptive pain, pain in inflammatory pain and neuropathic pain prophylactic or therapeutic agents As expected.
On the other hand, in Patent Document 2, the following general formula (A),

（式中、Ｒ_１がハロゲンで、かつＲ_２が水素、ハロゲン、ニトロ、シアノ、Ｃ（Ｏ）−ＯＲ_３，Ｃ（Ｏ）−ＮＲ_４Ｒ_５，ＳＯ_２−ＯＲ_３，ＳＯ_２−ＮＲ_４Ｒ_５であるか、
又はＲ_１が水素で、かつＲ_２がハロゲン、ニトロ、シアノ、Ｃ（Ｏ）−ＯＲ_３，Ｃ（Ｏ）−ＮＲ_４Ｒ_５，ＳＯ_２−ＯＲ_３，ＳＯ_２−ＮＲ_４Ｒ_５である。）

で表されるベンゾフロ−１，４−ジアゼピン−２−オン誘導体が、Ｐ２Ｘ_４受容体拮抗作用を有する旨の報告がなされている。
後述する本発明化合物と類似構造を有すると考えられる化合物として、
次の一般式（Ｂ）、

(Wherein R ₁ is halogen and R ₂ is hydrogen, halogen, nitro, cyano, C (O) —OR ₃ , C (O) —NR ₄ R ₅ , SO ₂ —OR ₃ , SO ₂ —NR ₄ R ₅ or
Or R ₁ is hydrogen and R ₂ is halogen, nitro, cyano, C (O) —OR ₃ , C (O) —NR ₄ R ₅ , SO ₂ —OR ₃ , SO ₂ —NR ₄ R ₅ . . )

In benzofuro diazepin-2-one derivative represented by the, it reported that with a P2X ₄ receptor antagonism have been made.
As a compound considered to have a similar structure to the compound of the present invention described later,
The following general formula (B),

で表される化合物が特許文献３に記載され、この特許文献３には、次の一般式（Ｃ）、

Is described in Patent Document 3, which includes the following general formula (C),

で表される化合物を原料とすることが記載されている。
また、非特許文献８には、一般式（Ｄ）、

It is described that the compound represented by these is used as a raw material.
Non-Patent Document 8 includes general formula (D),

（式中、（１）Ｙ_１＝Ｈ、Ｙ_２＝Ｈ，Ｙ_３＝Ｈ、Ｙ_４＝Ｏ、
（２）Ｙ_１＝ＣＨ_３，Ｙ_２＝Ｈ，Ｙ_３＝Ｈ、Ｙ_４＝Ｏ、
（３）Ｙ_１＝Ｈ、Ｙ_２＝Ｃｌ，Ｙ_３＝Ｈ、Ｙ_４＝Ｏ、
（４）Ｙ_１＝ＣＨ_３，Ｙ_２＝Ｃｌ、Ｙ_３＝Ｈ、Ｙ_４＝Ｏ、
（５）Ｙ_１＝ＣＨ_３，Ｙ_２＝Ｈ、Ｙ_３＝ＣＨ_３、Ｙ_４＝Ｏ、
（６）Ｙ_１＝Ｈ、Ｙ_２＝Ｈ、Ｙ_３＝Ｈ、Ｙ_４＝Ｓ）

で表される化合物が記載されている。

また、試薬リスト（非特許文献９）には次の化合物（Ｅ）が掲載されている。

(Where, (1) Y ₁ = H, Y ₂ = H, Y ₃ = H, Y ₄ = O,
(2) Y ₁ = CH ₃ , Y ₂ = H, Y ₃ = H, Y ₄ = O,
(3) Y ₁ = H, Y ₂ = Cl, Y ₃ = H, Y ₄ = O,
(4) Y ₁ = CH ₃ , Y ₂ = Cl, Y ₃ = H, Y ₄ = O,
(5) Y ₁ = CH ₃ , Y ₂ = H, Y ₃ = CH ₃ , Y ₄ = O,
(6) Y ₁ = H, Y ₂ = H, Y ₃ = H, Y ₄ = S)

The compound represented by these is described.

Moreover, the following compound (E) is published by the reagent list (nonpatent literature 9).

上記一般式（Ａ）で表される化合物と後記一般式（Ｉ）で表される本発明化合物とは、ベンゾフラン環の置換基と１，４−ジアゼピンの５位に結合しているフェニル基の置換基の組み合わせが異なる。また、上記一般式（Ａ）で表される化合物と後記一般式（ＩＩ）で表される本発明化合物とは、前者は１，４−ジアゼピンの１位が水素原子であるのに対し、後者はアルキル基が結合している相違がある。また、上記一般式（Ａ）で表される化合物と後記一般式（III）で表される本発明化合物とは、前者は１，４−ジアゼピンの４位が二重結合であるのに対し、後者は単結合との相違がある。
一方、上記一般式（Ｂ）、（Ｃ）、（Ｄ）及び（Ｅ）で表される化合物と後記一般式（Ｉ）、（ＩＩ）及び（III）で表される本発明化合物とは、構造上の違いの他、これらの文献にはＰ２Ｘ_４受容体拮抗作用に関する記載はない。

The compound represented by the above general formula (A) and the compound of the present invention represented by the following general formula (I) are a benzofuran ring substituent and a phenyl group bonded to the 5-position of 1,4-diazepine. The combination of substituents is different. In addition, the compound represented by the above general formula (A) and the compound of the present invention represented by the following general formula (II), the former is a hydrogen atom at the 1-position of 1,4-diazepine, while the latter Is different in that an alkyl group is bonded. In addition, the compound represented by the above general formula (A) and the compound of the present invention represented by the following general formula (III) have a double bond at the 4-position of 1,4-diazepine, The latter is different from a single bond.
On the other hand, the compounds represented by the general formulas (B), (C), (D) and (E) and the compounds of the present invention represented by the following general formulas (I), (II) and (III) are: another structural difference, there is no description about the P2X ₄ receptor antagonism in these documents.

US Patent Publication 20050074819 WO 2004/085440 JP-A-2-59582 Buell et al. (1996) EMBO J. et al. 15: 55-62 Seguela et al. (1996) J. MoI. Neurosci. 16: 448-455 Bo et al. (1995) FEBS Lett. 375: 129-133 Soto et al. (1996) Proc Natl. Acad. Sci. USA 93: 3684-3788 Wang et al. (1996) Biochem. Res. Commun. 220: 196-202 M.M. Tsuda et al. (2003) Nature, 424, 778-783 Jeffrey A. M.M. Coull et al. (2005) Nature, 438, 1017-1021. Journal of Heterocyclic Chemistry (1979), 16, 189-191 Accession No. 2001: 1432209 CHEMCATS Catalog Name: Screening Collection Publication Date: 11 Aug 2003 Order Number: A2222 / 0093564

Following general formulas purpose with P2X ₄ receptor antagonism of the present invention (I), is to provide a 1,4-diazepin-2-one derivative of formula (II) and (III).

  That is, the present invention provides the following general formula (I),

（式中、Ｘ^ａは、Ｏ、Ｓ又はＮＨを表し、
Ｒ^１ａは、水酸基、テトラゾリル基、Ｎ（Ｒ^５ａ）（Ｒ^６ａ）、炭素数２〜８のアルケニル基、炭素数２〜８のアルキニル基、ハロゲン原子で置換された炭素数１〜８のアルキル基、ハロゲン原子で置換された炭素数１〜８のアルコキシ基又は炭素数６〜１０個のアリール基を表し、
ここで、Ｒ^５ａは、水素原子又は炭素１〜８のアルキル基を表し、Ｒ^６ａは、水素原子、炭素１〜８のアルキル基又は炭素数２〜８のアシル基を表し、
Ｒ^２ａ及びＲ^３ａは、同一又は異なっていても良く水素原子、炭素数１〜８のアルキル基又はハロゲン原子で置換された炭素数１〜８のアルキル基を表し、
そして、Ｒ^４ａは、水素原子、炭素数１〜８のアルキル基、炭素数１〜８のアルコキシ基、ハロゲン原子で置換された炭素数１〜８のアルキル基、ハロゲン原子、水酸基、ニトロ基、アミノ基、カルボキシル基、テトラゾリル基、シアノ基、炭素数６〜１０のアリール基、又は５若しくは６員環の複素環基を表す。）
で表される化合物又はその塩に関する。

また、本発明は、次の一般式（ＩＩ）、

Wherein X ^a represents O, S or NH;
R ^1a is a hydroxyl group, a tetrazolyl group, N (R ^5a ) (R ^6a ), an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, or an alkyl having 1 to 8 carbon atoms substituted with a halogen atom. Group, a C1-C8 alkoxy group substituted with a halogen atom or a C6-C10 aryl group,
Here, R ^5a represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms, R ^6a represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an acyl group having 2 to 8 carbon atoms,
R ^2a and R ^3a may be the same or different and each represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom;
R ^4a is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, a halogen atom, a hydroxyl group, a nitro group, It represents an amino group, a carboxyl group, a tetrazolyl group, a cyano group, an aryl group having 6 to 10 carbon atoms, or a 5- or 6-membered heterocyclic group. )
Or a salt thereof.

Further, the present invention provides the following general formula (II),

（式中、Ｘ^ｂは、Ｏ、Ｓ又はＮＨを表し、
Ｒ^１ｂは、ハロゲン原子、水酸基、テトラゾリル基、Ｎ（Ｒ^５ｂ）（Ｒ^６ｂ）、炭素数２〜８のアルケニル基、炭素数２〜８のアルキニル基、ハロゲン原子で置換された炭素数１〜８のアルキル基、ハロゲン原子で置換された炭素数１〜８のアルコキシ基又は炭素数６〜１０個のアリール基を表し、
ここで、Ｒ^５ｂは、水素原子又は炭素１〜８のアルキル基を表し、Ｒ^６ｂは、水素原子、炭素１〜８のアルキル基又は炭素数２〜８のアシル基を表し、
Ｒ^２ｂ及びＲ^３ｂは、同一又は異なっていても良く水素原子、炭素数１〜８のアルキル基又はハロゲン原子で置換された炭素数１〜８のアルキル基を表し、
Ｒ^４ｂは、水素原子、炭素数１〜８のアルキル基、アルコキシ基、ハロゲン原子で置換された炭素数１〜８のアルキル基、ハロゲン原子、水酸基、ニトロ基、アミノ基、カルボキシル基、テトラゾリル基、シアノ基、炭素数６〜１０のアリール基、又は５若しくは６員環の複素環基を表し、
そして、Ｒ^７ｂは炭素数１〜８のアルキル基を表す。）
で表される化合物又はその塩に関する。

また、本発明は、次の一般式（III）、

^Wherein X ^b represents O, S or NH;
R ^1b is a halogen atom, a hydroxyl group, a tetrazolyl group, N (R ^5b ) (R ^6b ), an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, or a carbon number 1 to 1 substituted with a halogen atom. 8 represents an alkyl group, an alkoxy group having 1 to 8 carbon atoms substituted with a halogen atom, or an aryl group having 6 to 10 carbon atoms,
Here, R ^5b represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms, R ^6b represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an acyl group having 2 to 8 carbon atoms,
R ^2b and R ^3b may be the same or different and each represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom,
R ^4b is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, a halogen atom, a hydroxyl group, a nitro group, an amino group, a carboxyl group, or a tetrazolyl group. , A cyano group, an aryl group having 6 to 10 carbon atoms, or a 5- or 6-membered heterocyclic group,
R ^7b represents an alkyl group having 1 to 8 carbon atoms. )
Or a salt thereof.

Further, the present invention provides the following general formula (III),

（式中、Ｘ^ｃは、Ｏ、Ｓ又はＮＨを表し、
Ｒ^１ｃは、水素原子、ハロゲン原子、炭素数１〜８のアルキル基、炭素数１〜８のアルコキシ基、水酸基、テトラゾリル基、Ｎ（Ｒ^５ｃ）（Ｒ^６ｃ）、炭素数２〜８のアルケニル基、炭素数２〜８のアルキニル基、ハロゲン原子で置換された炭素数１〜８のアルキル基、ハロゲン原子で置換された炭素数１〜８のアルコキシ基又は炭素数６〜１０個のアリール基を表し、
ここで、Ｒ^５ｃは、水素原子又は炭素１〜８のアルキル基を表し、Ｒ^６ｃは、水素原子、炭素１〜８のアルキル基又は炭素数２〜８のアシル基を表し、
Ｒ^２ｃ及びＲ^３ｃは、同一又は異なっていても良く水素原子、炭素数１〜８のアルキル基又はハロゲン原子で置換された炭素数１〜８のアルキル基を表し、
Ｒ^４ｃは、水素原子、炭素数１〜８のアルキル基、アルコキシ基、ハロゲン原子で置換された炭素数１〜８のアルキル基、ハロゲン原子、水酸基、ニトロ基、アミノ基、カルボキシル基、テトラゾリル基、シアノ基、炭素数６〜１０のアリール基、又は５若しくは６員環の複素環基を表し、
Ｒ^７ｃは、水素原子又は炭素数１〜８のアルキル基を表し、
そして、Ｒ^８ｃは、水素原子、炭素数１〜８のアルキル基又は炭素数２〜８のアシル基を表す。）
で表される化合物又はその塩に関する。

^Wherein X ^c represents O, S or NH;
R ^1c is a hydrogen atom, a halogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a hydroxyl group, a tetrazolyl group, N (R ^5c ) (R ^6c ), or an alkenyl having 2 to 8 carbon atoms. Group, an alkynyl group having 2 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, an alkoxy group having 1 to 8 carbon atoms substituted with a halogen atom, or an aryl group having 6 to 10 carbon atoms Represents
Here, R ^5c represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms, R ^6c represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an acyl group having 2 to 8 carbon atoms,
R ^2c and R ^3c may be the same or different and each represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom,
R ^4c is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, a halogen atom, a hydroxyl group, a nitro group, an amino group, a carboxyl group, or a tetrazolyl group. , A cyano group, an aryl group having 6 to 10 carbon atoms, or a 5- or 6-membered heterocyclic group,
R ^7c represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms,
R ^8c represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an acyl group having 2 to 8 carbon atoms. )
Or a salt thereof.

Further, the present invention is the above formula (I), about P2X ₄ receptor antagonist containing a compound or a salt thereof as an active ingredient represented by the general formula (II) or (III).
Furthermore, this invention relates to the preventive or therapeutic agent of neuropathic pain which contains the compound or its salt represented by the said general formula (I), (II) or (III) as an active ingredient.

Next, the present invention will be described in detail.
(A)
In the compound of the present invention represented by the above general formula (I), the alkyl group having 1 to 8 carbon atoms of R ^2a , R ^3a , R ^4a , R ^5a and R ^6a includes a methyl group, an ethyl group, a propyl group, Examples include isopropyl group, butyl group, i-butyl group, t-butyl group, pentyl group, hexyl group and the like.

Examples of the alkenyl group having 2 to 8 carbon atoms of R ^1a include a vinyl group and an allyl group.
Examples of the alkynyl group having 2 to 8 carbon atoms of R ^1a include ethynyl and 2-propynyl.

Examples of the alkoxy group having 1 to 8 carbon atoms of R ^4a include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an i-butoxy group, a t-butoxy group, a pentyloxy group, and a hexyloxy group. It is done.
Examples of the halogen atom for R ^4a include a fluorine atom, a chlorine atom, or a bromine atom.
The alkyl group having 1 to 8 carbon atoms substituted with the halogen atoms of R ^1a , R ^2a , R ^3a and R ^4a is substituted with 1 to 3 fluorine atoms, chlorine atoms, bromine atoms or other halogen atoms. Examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group or a t-butyl group, preferably a trifluoromethyl group, a chloromethyl group, a 2-chloroethyl group, a 2-bromoethyl group or a 2-fluoroethyl group. Etc.
Examples of the alkoxy group having 1 to 8 carbon atoms substituted with a halogen atom of R ^1a include a methoxy group, an ethoxy group, a propoxy group, and an isopropyl group substituted with a halogen atom such as 1 to 3 fluorine atoms, chlorine atoms, or bromine atoms. An oxy group, a butyloxy group, a t-butyloxy group, etc. are mentioned, Preferably a trifluoromethyloxy group, a chloromethyloxy group, a 2-chloroethyloxy group, a 2-bromoethyloxy group, a 2-fluoroethyloxy group, or the like. Can be mentioned.

Examples of the acyl group having 2 to 8 carbon atoms of R ^6a include an acetyl group and a propionyl group.
Examples of the aryl group having 6 to 10 carbon atoms of R ^1a and R ^4a include a phenyl group.
^Examples of the 5- or 6-membered heterocyclic group of R ^4a include a pyridyl group.

In addition, as for R ^1a and R ^4a in the above general formula (I), 1 to 3 identical or different benzene rings substituted by R ^1a and R ^4a may be present.

Furthermore, as the compound of the present invention represented by the general formula (I), the following compounds are preferred.

(1) The compound or a salt thereof according to the general formula X ^a is O (I).
(2) R ^1a is a hydroxyl group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 12 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, or a phenyl group. The compound or its salt as described in the above general formula (I) or (1).
(3) The compound or a salt thereof according to the above general formula (I) or the above (1) or (2), wherein the substitution position of R ^1a is a meta position.
(4) The compound or a salt thereof according to the above general formula (I) or the above (1) to (3), wherein R ^2a and R ^3a are hydrogen atoms.
(5) The compound or a salt thereof according to the above general formula (I) or the above (1) to (4), wherein R ^4a is a hydrogen atom.

(B)
In this invention compound represented by the said general formula (II), as a C1-C8 alkyl group of R ^{< 2b>} , R ^<3b> , R ^<4b> , R ^<5b> , R ^<6b> and R ^<7b >, a methyl group, an ethyl group, A propyl group, an isopropyl group, a butyl group, an i-butyl group, a t-butyl group, a pentyl group, a hexyl group, and the like can be given.

Examples of the alkenyl group having 2 to 8 carbon atoms for R ^1b include a vinyl group and an allyl group.
Examples of the alkynyl group having 2 to 8 carbon atoms of R ^1b include ethynyl and 2-propynyl.

Examples of the alkoxy group having 1 to 8 carbon atoms of R ^4b include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, i-butoxy group, t-butoxy group, pentyloxy group, and hexyloxy group. It is done.
Examples of the halogen atom for R ^1b and R ^4b include a fluorine atom, a chlorine atom, or a bromine atom.
The alkyl group having 1 to 8 carbon atoms substituted by the halogen atom of R ^1b , R ^2b , R ^3b and R ^4b is substituted with a halogen atom such as 1 to 3 fluorine atoms, chlorine atoms or bromine atoms. Examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group or a t-butyl group, preferably a trifluoromethyl group, a chloromethyl group, a 2-chloroethyl group, a 2-bromoethyl group or a 2-fluoroethyl group. Etc.
The alkoxy group having 1 to 8 carbon atoms substituted by the halogen atom of R ^1b includes a methoxy group, an ethoxy group, a propoxy group, and an isopropyl group substituted by a halogen atom such as 1 to 3 fluorine atoms, chlorine atoms or bromine atoms. An oxy group, a butyloxy group, a t-butyloxy group, etc. are mentioned, Preferably a trifluoromethyloxy group, a chloromethyloxy group, a 2-chloroethyloxy group, a 2-bromoethyloxy group, a 2-fluoroethyloxy group, or the like. Can be mentioned.

Examples of the acyl group having 2 to 8 carbon atoms of R ^6b include an acetyl group and a propionyl group.
A phenyl group etc. are mentioned as a C6-C10 aryl group of R ^{< 1b>} and R ^<4b >.
^Examples of the 5- or 6-membered heterocyclic group of R ^4b include a pyridyl group.
In addition, as for R ^<1b> and R ^{<4b >} in the said general formula (II), 1-3 same or different thing may exist in the benzene ring which R ^{< 1b>} , R ^<4b> has substituted.

Furthermore, as the compound of the present invention represented by the general formula (II), the following compounds are preferred.
(6) The compound or its salt as described in the said general formula (II) whose ^Xb is O.
(7) R ^1b is a halogen atom, a hydroxyl group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 12 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, or phenyl The compound or a salt thereof according to the above general formula (II) or (6), which is a group.
(8) The compound or a salt thereof according to the above general formula (II), the above (6) or (7), wherein R ^1b is substituted at the meta position.
(9) The compound or a salt thereof according to the general formula (II) or the above (6) to (8), wherein R ^2b and R ^3b are hydrogen atoms.
(10) The compound or a salt thereof according to the above general formula (II) or the above (6) to (9), wherein R ^4b is a hydrogen atom.

(C)
In the compound of the present invention represented by the above general formula (III), R ^1c , R ^2c , R ^3c , R ^4c , R ^5c , R ^6c , R ^7c, and R ^8c as the alkyl group having 1 to 8 carbon atoms include Examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an i-butyl group, a t-butyl group, a pentyl group, and a hexyl group.

Examples of the alkenyl group having 2 to 8 carbon atoms of R ^1c include a vinyl group and an allyl group.
Examples of the alkynyl group having 2 to 8 carbon atoms of R ^1c include ethynyl and 2-propynyl.

Examples of the alkoxy group having 1 to 8 carbon atoms of R ^1c and R ^4c include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an i-butoxy group, a t-butoxy group, a pentyloxy group, or a hexyloxy group. Etc.
Examples of the halogen atom for R ^1c and R ^4c include a fluorine atom, a chlorine atom, or a bromine atom.
The alkyl group having 1 to 8 carbon atoms substituted by the halogen atom of R ^1c , R ^2c , R ^3c and R ^4c is substituted with a halogen atom such as 1 to 3 fluorine atoms, chlorine atom or bromine atom Examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group or a t-butyl group, preferably a trifluoromethyl group, a chloromethyl group, a 2-chloroethyl group, a 2-bromoethyl group or a 2-fluoroethyl group. Etc.
Examples of the alkoxy group having 1 to 8 carbon atoms substituted by the halogen atom of R ^1c include a methoxy group, an ethoxy group, a propoxy group, and an isopropyl group substituted by a halogen atom such as 1 to 3 fluorine atoms, chlorine atoms, or bromine atoms. An oxy group, a butyloxy group, a t-butyloxy group, etc. are mentioned, Preferably a trifluoromethyloxy group, a chloromethyloxy group, a 2-chloroethyloxy group, a 2-bromoethyloxy group, a 2-fluoroethyloxy group, or the like. Can be mentioned.

Examples of the acyl group having 2 to 8 carbon atoms of R ^6c and R ^8c include an acetyl group and a propionyl group.
A phenyl group etc. are mentioned as a C6-C10 aryl group of R ^{< 1c>} and R ^<4c >.
^Examples of the 5- or 6-membered heterocyclic group of R ^4c include a pyridyl group.
In addition, as for R ^<1c> and R ^{<4c >} in the said general formula (I), 1-3 same or different thing may exist in the benzene ring which R ^{< 1c>} , R ^<4c> substituted.

Furthermore, as the compound of the present invention represented by the general formula (III), the following compounds are preferred.
(11) The compound or its salt as described in the said general formula (III) whose ^Xc is O.
(12) R ^1c is a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 12 carbon atoms, or an alkyl having 1 to 8 carbon atoms substituted with a halogen atom. Or a salt thereof according to the above general formula (III) or (11), which is a group or a phenyl group.
(13) The compound or a salt thereof according to the above general formula (III), the above (11) or (12), wherein R ^1c is substituted at the meta position.
(14) The compound or a salt thereof according to the above general formula (III) or the above (11) to (1), wherein R ^2c and R ^3c are hydrogen atoms.
(15) The compound or a salt thereof according to the above general formula (III) or the above (11) to (14), wherein R ^4c is a hydrogen atom or a halogen atom.
(16) The compound or a salt thereof according to the above general formula (III) or the above (11) to (15), wherein R ^7c is a hydrogen atom.
(17) The compound or a salt thereof according to the above general formula (III) or the above (11) to (16), wherein R ^8c is a hydrogen atom.

The compounds represented by the general formulas (I), (II) and (III) may be pharmacologically acceptable salts, and examples thereof include alkali metal salts such as sodium, potassium and lithium.
The compound of the present invention may have optical isomers such as an optically active substance and a racemate, and all of them are included in the present invention.

Next, a synthesis scheme of the compound of the present invention represented by the above general formulas (I), (II) and (III) is shown below.
(1) In the above general formula (I), when X ^a = O, R ^2a = R ^3a = H

（式中、Ｚ^１及びＺ^２はハロゲン原子を表し、そしてＲ^１ａ及びＲ^４ａは前記と同じ。）

一般式（ａ）で表される化合物にトリエチルアミン、炭酸水素ナトリウム等の塩基の存在下、ジクロロメタン、クロロホルム等の溶媒中、一般式（ｂ）で表されるアシル化剤を作用させることで、一般式（ｃ）で表される化合物を得る。一般式（ｄ）で表される本発明化合物は上記一般式（ｃ）で表される化合物にアンモニアを作用し、加熱する（閉環）ことで得ることができる。なお、一般式（ｄ）で表される本発明化合物で、Ｒ^１ａが水酸基のものは、一般式（ｃ）で表される化合物で、Ｒ^１ａに対応するものが、例えばアセチルオキシであるものを使用すると、閉環と共に脱アセチル化することで得られる。
なお、上記一般式（ａ）で表される化合物は例えば以下に示す方法等により得ることができる。

(Wherein Z ¹ and Z ² represent a halogen atom, and R ^1a and R ^4a are the same as described above.)

By reacting the compound represented by the general formula (a) with the acylating agent represented by the general formula (b) in a solvent such as dichloromethane or chloroform in the presence of a base such as triethylamine or sodium hydrogen carbonate, A compound represented by the formula (c) is obtained. The compound of the present invention represented by the general formula (d) can be obtained by acting ammonia on the compound represented by the general formula (c) and heating (ring closure). The compound of the present invention represented by the general formula (d) wherein R ^1a is a hydroxyl group is a compound represented by the general formula (c), and the one corresponding to R ^1a is, for example, acetyloxy Can be obtained by deacetylation with ring closure.
In addition, the compound represented by the said general formula (a) can be obtained by the method etc. which are shown below, for example.

（式中、Ｚ^３はハロゲン原子を表し、そしてＲ^１ａ及びＲ^４ａは前記と同じ。）

（２）上記一般式（ＩＩ）の場合

(Wherein Z ³ represents a halogen atom, and R ^1a and R ^4a are the same as described above.)

(2) In the case of the above general formula (II)

（式中、Ｚ^４はハロゲン原子を表し、そしてＸ^ｂ、Ｒ^１ｂ、Ｒ^２ｂ、Ｒ^３ｂ、Ｒ^４ｂ及びＲ^７ｂは前記と同じ）

一般式（ｆ）で表される本発明化合物は一般式（ｅ）で表される化合物をＤＭＦ等の溶媒中、水素化ナトリウム等の塩基の存在下、ヨウ化アルキル等のアルキル化剤等を作用させることで得ることができる。

（３）上記一般式（III）で、Ｒ ^８ ＝Ｈの場合

(Wherein Z ⁴ represents a halogen atom, and X ^b , R ^1b , R ^2b , R ^3b , R ^4b and R ^7b are the same as above)

The compound of the present invention represented by the general formula (f) is obtained by subjecting the compound represented by the general formula (e) to an alkylating agent such as alkyl iodide in a solvent such as DMF in the presence of a base such as sodium hydride. It can be obtained by acting.

(3) In the general formula (III), when R ⁸ = H

（式中、Ｘ^ｃ、Ｒ^１ｃ、Ｒ^２ｃ、Ｒ^３ｃ、Ｒ^４ｃ、及びＲ^７ｃは前記と同じ）
一般式（ｈ）で表される本発明化合物は一般式（ｇ）で表される化合物をＤＭＦ、メタノール等の溶媒中、水素化ホウ素ナトリウム等の還元剤を作用させることで得ることができる。

(Wherein, X ^c , R ^1c , R ^2c , R ^3c , R ^4c , and R ^7c are the same as above)
The compound of the present invention represented by the general formula (h) can be obtained by reacting the compound represented by the general formula (g) with a reducing agent such as sodium borohydride in a solvent such as DMF or methanol.

The compounds of the present invention represented by the above general formulas (I), (II) and (III) can also be produced with reference to the above-mentioned patent documents and publicly known documents in addition to the examples described later.

Examples of the compound of the present invention thus obtained are shown in Tables 1-12.

(A-1)
The following general formula:

で表される化合物。（式中、Ｒ^１ａ，Ｒ^２ａ，Ｒ^３ａ及びＸ^ａは表１及び２記載のとおり。）

A compound represented by (Wherein, R ^1a , R ^2a , R ^3a and X ^a are as described in Tables 1 and 2.)

（Ａ−２）
次の一般式、

(A-2)
The following general formula:

で表される化合物。（式中、Ｒ^１ａ、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４ａ及びＸ^ａは表３〜５記載のとおり。）

A compound represented by ^{(Wherein, R 1a, R 2a, R} 3a, R 4a and ^{X a} are shown in Table 3-5 described.)

（Ｂ）
次の一般式、

(B)
The following general formula:

で表される化合物。（式中、Ｒ^１ｂ、Ｒ^２ｂ、Ｒ^３ｂ、Ｒ^４ｂ、Ｒ^７ｂ及びＸ^ｂは表６〜８記載のとおり。）

A compound represented by (In the formula, R ^1b , R ^2b , R ^3b , R ^4b , R ^7b and X ^b are as described in Tables 6-8.)

（Ｃ）
次の一般式、

(C)
The following general formula:

で表される化合物。（式中、Ｒ^１ｃ、Ｒ^２ｃ、Ｒ^３ｃ、Ｒ^４ｃ、Ｒ^７ｃ、Ｒ^８ｃ及びＸ^ｃは表９〜１２記載のとおり。）

A compound represented by (In the formula, R ^1c , R ^2c , R ^3c , R ^4c , R ^7c , R ^8c and X ^c are as described in Tables 9-12.)

Next, the pharmacological effect of the present invention will be described.
The P2X ₄ receptor antagonism of the compounds of the present invention was measured as follows.
After the 1321N1 cells P2X ₄ receptor expression plasmid was gene introduced using transfection reagent FuGENE 6 a (Roche), and cultured for one week. Ca fluorescent dye Fura2-AM (SIGMA) was introduced into 1321N1 cells, and Ca ion fluorescence intensity was measured using Aqua-Cosmos (Hamamatsu Photonics). The rate of increase in fluorescence intensity due to ATP in the presence of each concentration of the test substance was calculated, and the inhibition rate was determined, assuming that the rate of increase in Ca ²⁺ fluorescence intensity in 1321N1 cells due to ATP (3 μM) was 100%. The test substance was treated from 10 minutes before ATP stimulation until the end of stimulation.

The present invention compounds of Examples 1, 6 and 7, wherein As is apparent from Table 13 showed P2X ₄ receptor antagonism excellent.
Accordingly, the compounds of general formula (I), a compound represented by (II) and (III), pain in nociceptive pain, inflammatory pain and neuropathic pain have a P2X ₄ receptor antagonism It is considered useful as a preventive or therapeutic agent. That is, it is useful as a prophylactic or therapeutic agent for various cancer pains, pain associated with neuropathy of diabetes, pain associated with viral diseases such as herpes, osteoarthritis and the like. In addition, the preventive or therapeutic agent of the present invention may be used in combination with other drugs as necessary, for example, opioid analgesics (morphine, fentanyl), sodium channel blockers (novocaine, lidocaine), NSAIDs (aspirin, ibuprofen) Etc. are used together. Moreover, when using for cancer pain, combined use with anticancer agents, such as a chemotherapeutic agent, is mentioned.

The compound of the present invention can be administered to humans by an appropriate administration method such as oral administration or parenteral administration.
For formulation, it can be produced into a dosage form such as a tablet, granule, powder, capsule, suspension, injection, suppository and the like by a conventional method in the technical field of formulation.
For these preparations, for example, in the case of tablets, usual excipients, disintegrants, binders, lubricants, pigments and the like are used. Here, as the excipient, lactose, D-mannitol, crystalline cellulose, glucose and the like, as the disintegrant, starch, carboxymethylcellulose calcium (CMC-Ca), etc., as the lubricant, magnesium stearate, Examples of binders include talc and the like, and hydroxypropylcellulose (HPC), gelatin, polyvinylpyrrolidone (PVP), and the like. Solvents, stabilizers, solubilizers, suspending agents, emulsifiers, soothing agents, buffers, preservatives and the like are used for the preparation of injections.

In general, for adults, the compound of the present invention, which is an active ingredient in injections, is about 0.01 mg to 100 mg per day, and 1 mg to 2000 mg per day by oral administration, but can be increased or decreased depending on age, symptoms, etc. .

Next, although an Example is given and this invention is demonstrated further in detail, this invention is not limited to these.

5- (3-Hydroxyphenyl) -1,3-dihydro-2H-benzofuro [3,2-e] -1,4-diazepin-2-one

(1) A suspension of 3′-acetoxy-2-bromoacetophenone 3′-acetoxyacetophenone (2.62 g, 14.7 mmol) and sodium hydrogen carbonate (2.52 g, 30.0 mmol) in chloroform (10 mL) at 0 ° C. Then, a solution of bromine (0.76 mL, 14.8 mmol) in chloroform (5 mL) was added dropwise over 30 minutes. After stirring at 0 ° C. to room temperature for 16 hours, cis 2-butene-1,4-diol (0.2 mL) was added. Toluene was added to the reaction mixture, washed successively with water and saturated aqueous sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a mixture of the title compound and 3′-acetoxyacetophenone of about 4: 1 as yellow crystals (3.52 g).
¹ H NMR (CDCl ₃ , 500 MHz) δ: 2.34 (3H, s), 4.43 (2H, s), 7.37 (1H, m), 7.52 (1H, t, J = 8 Hz) 7.72 (1 H, t, J = 2 Hz), 7.85 (1 H, d, J = 8 Hz)

(2) 2- (3-acetoxybenzoyl) -3-amino-benzo [b] furan solution of the above mixture and 2-hydroxybenzonitrile (1.75 g, 14.7 mmol) in N, N-dimethylformamide (10 mL) Was added triethylamine (2.05 mL, 14.7 mmol), and the mixture was stirred at room temperature for 20 minutes. Further, 1,8-diazabicyclo [5.4.0] undec-5-ene (0.44 mL, 2.94 mmol) was added and stirred at 70 ° C. for 17 hours. The reaction mixture was extracted with toluene, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (toluene / ethyl acetate = 50/1 to 20/1 to 10/1) to give the title compound as yellow crystals (1.52 g, Yield 44%).
¹ H NMR (CDCl ₃ , 500 MHz) δ: 2.35 (3H, s), 6.05 (2H, brs), 7.2-7.3 (2H, m), 7.47 (1H, d, J = 8 Hz), 7.5-7.6 (2H, m), 7.64 (1H, d, J = 7 Hz), 7.97 (1H, t, J = 2 Hz), 8.16 (1H, d, J = 8Hz)

(3) 2- (3-acetoxybenzoyl) -3- (chloroacetamido) benzo [b] furan The above 2- (3-acetoxybenzoyl) -3-amino-benzo [b] furan (546 mg, 1.85 mmol) And chloroacetyl chloride (150 μL, 75 μL, 75 μL, 3.70 mmol) were added dropwise in three portions to a suspension of sodium bicarbonate (1.55 g, 18.5 mmol) in chloroform (5 mL) under ice cooling. The reaction mixture was stirred for 30 minutes under ice cooling, and the solvent was distilled off under reduced pressure. Water was added to the residue, and the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to give the title compound as yellow crystals (662 mg, yield 96%).
¹ H NMR (CDCl ₃ , 500 MHz) δ: 2.36 (3H, s), 4.32 (2H, s), 7.3-7.4 (2H, m), 7.5-7.6 ( 3H, m), 7.99 (1H, t, J = 2 Hz), 8.18 (1H, d, J = 8 Hz), 8.55 (1H, d, J = 8 Hz), 11.56 (1H, brs)

(4) 5- (3-hydroxyphenyl) -1,3-dihydro-2H-benzofuro [3,2-e] -1,4-diazepin-2-one The above 2- (3-acetoxybenzoyl) -3 To (chloroacetamido) benzo [b] furan (639 mg, 1.72 mmol) was added dimethyl sulfoxide (10 mL) and 1,4-dioxane solution (0.9 mol / L, 25 mL, 22.5 mmol) of ammonia at 80 ° C. For 45 hours. The reaction mixture was evaporated under reduced pressure, ethyl acetate was added, the insoluble material was filtered off, the filtrate was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, toluene was added to the residue and the precipitated crystals were collected by filtration to give the title compound as pale yellow crystals (330 mg, yield 66%).
mp: 268-269 ° C
¹ H NMR (DMSO-d ₆ , 500 MHz) δ: 4.47 (2H, brs), 6.99 (1H, d, J = 8 Hz), 7.20 (2H, m), 7.33 (1H, m), 7.48 (1H, t, J = 8 Hz), 7.63 (1H, t, J = 8 Hz), 7.75 (1H, d, J = 8 Hz), 8.04 (1H, d, J = 8 Hz), 9.70 (1H, brs), 11.55 (1H, brs)
IR (cm ⁻¹ , KBr): 1739, 1681, 1608, 1579, 1552, 1484, 1396, 1353, 1313, 1309, 1288, 1184, 1037, 1018, 867, 794, 792, 754, 730.

Using the same method as in Example 1, the following Examples 2 to 5 were obtained.

5- (3-Trifluoromethylphenyl) -1,3-dihydro-2H-benzofuro [3,2-e] -1,4-diazepin-2-one

¹ H NMR (CDCl ₃ , 500 MHz) δ: 4.66 (2H, s), 7.44 (1H, m), 7.5-7.6 (3H, m), 7.76 (1H, d, J = 8 Hz), 7.81 (1H, d, J = 8 Hz), 8.00 (1H, d, J = 8 Hz), 8.13 (1H, brs), 9.70 (1H, brs)

5- (3-Biphenyl) -1,3-dihydro-2H-benzofuro [3,2-e] -1,4-diazepin-2-one

¹ H NMR (CDCl ₃ , 500 MHz) δ: 4.66 (2H, brs), 7.37 (1H, m), 7.4-7.5 (3H, m), 7.5-7.6 ( 3H, m), 7.6-7.7 (2H, m), 7.7-7.8 (3H, m), 8.02 (1H, brs), 9.19 (1H, brs)

5- (3-Aminophenyl) -1,3-dihydro-2H-benzofuro [3,2-e] -1,4-diazepin-2-one

¹ H NMR (CD ₃ OD, 500 MHz) δ: 3.34 (1H, s), 4.52 (2H, brs), 7.1-7.2 (3H, m), 7.44 (1H, m ), 7.54 (1H, m), 7.69 (1H, brd, J = 9 Hz), 7.80 (1H, m), 8.10 (1H, d, J = 9 Hz)

5- (3-Dimethylaminophenyl) -1,3-dihydro-2H-benzofuro [3,2-e] -1,4-diazepin-2-one

¹ H NMR (CDCl ₃ , 500 MHz) δ: 2.98 (6H, s), 4.61 (2H, brs), 6.89 (1H, m), 7.05 (1H, brd, J = 7 Hz) 7.16 (1H, brs), 7.30 (1H, t, J = 5 Hz), 7.41 (1H, m), 7.52 (2H, m), 7.83 (1H, d, J = 7 Hz), 10.20 (1 H, brs)

5- (3-Bromophenyl) -1,3-dihydro-1-methyl-2H-benzofuro [3,2-e] -1,4-diazepin-2-one

5- (3-Bromophenyl) -1,3-dihydro-2H-benzofuro [3,2-e] -1,4-diazepin-2-one (52 mg, 0.146 mmol) in anhydrous N, N-dimethylformamide To the (1 mL) solution, 55% sodium hydride (7 mg, 0.156 mmol) was added and stirred at room temperature for 15 minutes. Further, methyl iodide (18 μL, 0.282 mmol) was added and stirred at room temperature for 30 minutes. The reaction mixture was poured into water, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, hexane was added to the resulting crystals and filtered to give the title compound as yellow crystals (29 mg, 54% yield).
mp: 159-161 ° C.
¹ H NMR (CDCl ₃ , 400 MHz) δ: 3.65 (3H, s), 4.57 (2H, s), 7.34 (1H, t, J = 8 Hz), 7.41 (1H, m) 7.5-7.7 (3H, m), 7.7-7.9 (2H, m), 8.01 (1H, s)
IR (cm ⁻¹ , KBr): 1686, 1601, 1599, 1551, 1491, 1425, 1350, 1315, 1263, 1232, 1178, 1124, 1065, 1032, 997, 874, 750, 723, 714.

5- (3-Bromophenyl) -1,3,4,5-tetrahydro-2H-benzofuro [3,2-e] -1,4-diazepin-2-one

5- (3-Bromophenyl) -1,3-dihydro-2H-benzofuro [3,2-e] -1,4-diazepin-2-one (108 mg, 0.303 mmol) in N, N-dimethylformamide ( To a 3 mL) -methanol (0.3 mL) solution was added sodium borohydride (16 mg, 0.423 mmol), and the mixture was stirred at room temperature for 2 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform / ethyl acetate = 10/1) to give the title compound as white crystals (27 mg, yield 25%).
mp: 208-210 ° C
¹ H NMR (CDCl ₃ , 400 MHz) δ: 2.27 (1H, brs), 3.74 (1H, d, J = 16 Hz), 3.80 (1H, d, J = 16 Hz), 5.38 ( 1H, s), 7.2-7.4 (5H, m), 7.47 (1H, m), 7.50 (1H, m), 7.64 (1H, m), 8.45 (1H , Brs)
IR (cm ⁻¹ , KBr): 1662, 1591, 1568, 1543, 1522, 1458, 1425, 1400, 1356, 1319, 1265, 1232, 1178, 1128, 1107, 1068, 1014, 835, 793, 754, 752 750, 723, 696.

P2X ₄ receptor antagonism of the compounds of the present invention was measured as follows.
After the 1321N1 cells P2X ₄ receptor expression plasmid was gene introduced using transfection reagent FuGENE 6 a (Roche), and cultured for one week. Ca fluorescent dye Fura2-AM (SIGMA) was introduced into 1321N1 cells, and Ca ion fluorescence intensity was measured using Aqua-Cosmos (Hamamatsu Photonics). The rate of increase in fluorescence intensity due to ATP in the presence of each concentration of the test substance was calculated, and the inhibition rate was determined, assuming that the rate of increase in Ca ²⁺ fluorescence intensity in 1321N1 cells due to ATP (3 μM) was 100%. The test substance was treated from 10 minutes before ATP stimulation until the end of stimulation.
(Test results)

表１３から明らかなように実施例１、６、７記載の化合物は優れたＰ２Ｘ_４受容体拮抗作用を示した。

The compounds of Examples 1, 6 and 7, wherein As is apparent from Table 13 showed P2X ₄ receptor antagonism excellent.

Claims (22)

The following general formula (I),

Wherein X ^a represents O, S or NH;
R ^1a is a hydroxyl group, a tetrazolyl group, N (R ^5a ) (R ^6a ), an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, or an alkyl having 1 to 8 carbon atoms substituted with a halogen atom. Group, a C1-C8 alkoxy group substituted with a halogen atom or a C6-C10 aryl group,
Here, R ^5a represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms, R ^6a represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an acyl group having 2 to 8 carbon atoms,
R ^2a and R ^3a may be the same or different and each represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom;
R ^4a is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, a halogen atom, a hydroxyl group, a nitro group, It represents an amino group, a carboxyl group, a tetrazolyl group, a cyano group, an aryl group having 6 to 10 carbon atoms, or a 5- or 6-membered heterocyclic group. )
Or a salt thereof. The compound or a salt thereof according to claim 1, wherein ^Xa is O. R ^1a is a hydroxyl group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 12 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, or a phenyl group. Or the compound or its salt as described in any one of 2 paragraphs. The compound or a salt thereof according to any one of claims 1 to 3, wherein the substitution position of R ^1a is a meta position. ^R2a and ^R3a are hydrogen atoms, The compound or its salt as described in any one of Claims 1-4. ^R4a is a hydrogen atom, The compound or its salt as described in any one of Claims 1-5. The following general formula (II),

^Wherein X ^b represents O, S or NH;
R ^1b is a halogen atom, a hydroxyl group, a tetrazolyl group, N (R ^5b ) (R ^6b ), an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, or a carbon number 1 to 1 substituted with a halogen atom. 8 represents an alkyl group, an alkoxy group having 1 to 8 carbon atoms substituted with a halogen atom, or an aryl group having 6 to 10 carbon atoms,
Here, R ^5b represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms, R ^6b represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an acyl group having 2 to 8 carbon atoms,
R ^2b and R ^3b may be the same or different and each represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom,
R ^4b is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, a halogen atom, a hydroxyl group, a nitro group, an amino group, a carboxyl group, or a tetrazolyl group. , A cyano group, an aryl group having 6 to 10 carbon atoms, or a 5- or 6-membered heterocyclic group,
R ^7b represents an alkyl group having 1 to 8 carbon atoms. )
Or a salt thereof. The compound or a salt thereof according to claim 7, wherein ^Xb is O. ^9. R ^1b is a halogen atom, a hydroxyl group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, or a phenyl group. The compound or salt thereof according to any one of the items. The compound or a salt thereof according to any one of claims 7 to 9, wherein the substitution position of R ^1b is a meta position. ^R2b and ^R3b are hydrogen atoms, The compound or its salt in any one of Claims 7-10. ^R4b is a hydrogen atom, The compound or its salt in any one of Claims 7-11. The following general formula (III),

^Wherein X ^c represents O, S or NH;
R ^1c is a hydrogen atom, a halogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a hydroxyl group, a tetrazolyl group, N (R ^5c ) (R ^6c ), or an alkenyl having 2 to 8 carbon atoms. Group, an alkynyl group having 2 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, an alkoxy group having 1 to 8 carbon atoms substituted with a halogen atom, or an aryl group having 6 to 10 carbon atoms Represents
Here, R ^5c represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms, R ^6c represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an acyl group having 2 to 8 carbon atoms,
R ^2c and R ^3c may be the same or different and each represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom,
R ^4c is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, a halogen atom, a hydroxyl group, a nitro group, an amino group, a carboxyl group, or a tetrazolyl group. , A cyano group, an aryl group having 6 to 10 carbon atoms, or a 5- or 6-membered heterocyclic group,
R ^7c represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms,
R ^8c represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an acyl group having 2 to 8 carbon atoms. )
Or a salt thereof. The compound or a salt thereof according to claim 13, wherein ^Xc is O. R ^1c is a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, or a phenyl group. Or the compound according to any one of 14 or a salt thereof. The compound or a salt thereof according to any one of claims 13 to 15, wherein the substitution position of R ^1c is a meta position. ^R2c and ^R3c are hydrogen atoms, The compound or its salt in any one of Claims 13-16. The compound or a salt thereof according to any one of claims 13 to 17 R ^4c is hydrogen atom or a halogen atom. The compound or a salt thereof according to any one of claims 13 to 18, wherein R ^7c is a hydrogen atom. The compound or a salt thereof according to any one of claims 13 to 19, wherein R ^8c is a hydrogen atom. Compound or P2X ₄ receptor antagonist containing a salt thereof as an active ingredient according to any one of claims 1 to 20. A preventive or therapeutic agent for neuropathic pain comprising the compound according to any one of claims 1 to 20 or a salt thereof as an active ingredient.