JP2009057281A - P2X4 receptor antagonist - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a P2X<SB>4</SB>receptor antagonist. <P>SOLUTION: This P2X<SB>4</SB>receptor antagonist uses a compound represented by general formula (I) (wherein, X is S or CH<SB>2</SB>; Y is O, S or NH; R<SP>1</SP>is H, a 1-8C alkyl group, or the like; R<SP>2</SP>and R<SP>3</SP>are each H, a 1-8C alkyl group, a 1-8C alkoxy group, a halogen, OH, or the like; R<SP>4</SP>and R<SP>5</SP>are each H, a 1-8C alkyl group, or the like; and the double line comprising a broken line and a solid line is a single bond or a double bond) or its salt. <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, Patent Document 1) Accordingly, substances which inhibit the action of P2X ₄ receptors is expected as a prophylactic agent or therapeutic agent for pain in nociceptive pain, inflammatory pain and neuropathic pain.
On the other hand, in Patent Document 2, the following general formula (A),

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）、

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７には、一般式（Ｄ）、

It is described that the compound represented by these is used as a raw material.
Non-Patent Document 7 includes general formula (D),

で表される化合物が記載されている。

The compound represented by these is described.

The compound of the present invention, which will be described later, and the compound represented by the above general formula (A) are such that the compound of the present invention is condensed with benzothiophene and the like at positions 6 and 7 of 1,4-diazepin-2-one. The compound represented by the general formula (A) is different in that benzofuran is condensed.
Similarly, the compound of the present invention and the compound represented by the above general formula (B) are represented by the above general formula (B) while the 2-position of 1,4-diazepine is a carbonyl group or the like. that compound is dihydro, or hydroxyl group, its use in anti-ulcer activity, no description of P2X ₄ antagonism according to the present invention. Moreover, there is no description of a specific Example etc. about the compound represented by general formula (C).
On the other hand, the compound of the present invention described later and the compound represented by the above general formula (D) are that the compound of the present invention is condensed with benzothiophene or the like at positions 6 and 7 of 1,4-diazepin-2-one. respect, compounds represented by the general formula (D) has a difference that indole is condensed, also no description regarding P2X ₄ receptor antagonism according to the present invention.

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 Journal of Heterocyclic Chemistry (1973), 10 (1), 51-53.

An object of the present invention is to provide a 1,4-diazepin-2-one derivative represented by the following general formula with a P2X ₄ receptor antagonism (I).

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

（式中、ＸはＳ又はＣＨ_２を表し、
ＹはＯ、Ｓ又はＮＨを表し、
Ｒ^１は、水素原子、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のアルキル基、アラルキル基（アルキル部分の炭素数が１〜６で、アリ−ル部分の炭素数が６〜１０）、炭素数２〜８のアルケニル基、カルボキシメチル基又はアルコキシカルボニルメチル基（アルコキシ部分の炭素数は１〜８）を表し、
Ｒ^２及びＲ^３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、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、ハロゲン原子で置換された炭素数１〜８のアルコキシ基、ハロゲン原子、アミノ基、カルボキシル基、水酸基、ニトロ基、シアノ基、炭素数２〜８のアシル基、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^４及びＲ^５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、破線と実線からなる二重線は単結合又は二重結合を表す。）
で表される化合物又はその塩に関する。
また、本発明は上記一般式（Ｉ）で表される化合物又はその塩を有効成分として含有するＰ２Ｘ_４受容体拮抗剤に関する。
さらにまた、本発明は上記一般式（Ｉ）で表される化合物又はその塩を有効成分として含有する神経因性疼痛の予防又は治療剤に関する。

(Wherein X represents S or CH ₂ ;
Y represents O, S or NH;
R ¹ is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, an aralkyl group (the alkyl portion has 1 to 6 carbon atoms, A carbon number of 6 to 10), an alkenyl group having 2 to 8 carbon atoms, a carboxymethyl group or an alkoxycarbonylmethyl group (the carbon number of the alkoxy moiety is 1 to 8);
R ² and R ³ may be the same or different and may be 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, halogen An alkoxy group having 1 to 8 carbon atoms substituted with an atom, a halogen atom, an amino group, a carboxyl group, a hydroxyl group, a nitro group, a cyano group, an acyl group having 2 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, or Represents a 5- or 6-membered heterocyclic group,
R ⁴ and R ⁵ 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;
A double line composed of a broken line and a solid line represents a single bond or a double bond. )
Or a salt thereof.
The present invention relates to P2X ₄ receptor antagonist containing a compound or a salt thereof as an active ingredient represented by the general formula (I).
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) as an active ingredient.

Next, the present invention will be described in detail.
In the general formula (I), the alkyl group having 1 to 8 carbon atoms of R ¹ , R ² , R ³ , R ⁴ and R ⁵ includes a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, i -A butyl group, a t-butyl group, a pentyl group, a hexyl group, etc. are mentioned.
Examples of the alkenyl group having 2 to 8 carbon atoms for R ¹ include a vinyl group and an allyl group.
Examples of the alkoxy group having 1 to 8 carbon atoms of R ² and R ³ include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, i-butoxy group, t-butoxy group, pentyloxy group or hexyloxy group Etc.
Examples of the halogen atom for R ² and R ³ include a fluorine atom, a chlorine atom, or a bromine atom.
The alkyl group having 1 to 8 carbon atoms substituted by the halogen atoms of R ¹ , R ² , R ³ , R ⁴ and R ^{5 is} a halogen atom such as 1 to 3 fluorine atoms, chlorine atoms or bromine atoms. Examples thereof include a substituted methyl group, ethyl group, propyl group, isopropyl group, butyl group or t-butyl group, preferably trifluoromethyl group, chloromethyl group, 2-chloroethyl group, 2-bromoethyl group or 2- A fluoroethyl group etc. are mentioned.
Examples of the alkoxy group having 1 to 8 carbon atoms substituted with a halogen atom of R ² and R ³ include a methoxy group, an ethoxy group, and a propoxy group substituted with a halogen atom such as 1 to 3 fluorine atoms, chlorine atoms, or bromine atoms. Group, isopropyloxy group, butyloxy group or t-butyloxy group, etc., preferably trifluoromethyloxy group, chloromethyloxy group, 2-chloroethyloxy group, 2-bromoethyloxy group or 2-fluoroethyloxy group Groups and the like.
Examples of the acyl group having 2 to 8 carbon atoms of R ² and R ³ include an acetyl group and a propionyl group.
The aryl group of R ² and carbon atoms of ^{R 3} 6 to 10, a phenyl group.
Examples of the 5- or 6-membered heterocyclic group of R ² and R ³ include a pyridyl group.
Examples of the aralkyl group for R ¹ (the alkyl moiety has 1 to 6 carbon atoms and the aryl moiety has 6 to 10 carbon atoms) include a benzyl group and a phenethyl group.
Examples of the alkoxycarbonylmethyl group of R ¹ (the alkoxy moiety has 1 to 8 carbon atoms) include a methoxycarbonylmethyl group and an ethoxycarbonylmethyl group.

In addition, as for R < ² > and R < ³ > in the said general formula (I), 1-3 same or different things may exist in the benzene ring which R < ² >, R < ³ > substituted.

Furthermore, as the compound of the present invention, the following compounds are preferred.

(1) The compound or its salt as described in the said general formula (I) whose X is S.
(2) The compound or salt thereof according to the above general formula (I) or (1), wherein Y is O.
(3) The compound or a salt thereof according to the above general formula (I), the above (1) or (2), wherein R ¹ is a hydrogen atom or an alkyl group having 1 to 8 carbon atoms.
(4) R ² and R ³ may be the same or different, hydrogen atom, alkyl group having 1 to 8 carbon atoms, alkoxy group having 1 to 8 carbon atoms, alkyl having 1 to 8 carbon atoms substituted with a halogen atom Group, the above general formula (I) or (1) to (3), which is a C 1-8 alkoxy group substituted with a halogen atom, a halogen atom, an amino group, a carboxyl group, a hydroxyl group, a nitro group or a cyano group Or a salt thereof.
(5) The compound or a salt thereof according to the above general formula (I) or the above (1) to (3), wherein R ³ is a hydrogen atom and R ² is a halogen atom or a hydroxyl group.
(6) The compound or a salt thereof according to the above general formula (I) or the above (1) to (5), wherein R ² is substituted at the meta position.
(7) The compound or a salt thereof according to the above general formula (I) or the above (1) to (6), wherein R ⁴ and R ⁵ are hydrogen atoms.
(8) The compound or a salt thereof according to the above general formula (I) or the above (1) to (7), wherein a double line consisting of a broken line and a solid line is a double bond.

The compound represented by the general formula (I) may be a pharmacologically acceptable salt, 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 formula (I) is shown below.
(1) In the above general formula (I), Y = O, R ¹ = R ⁴ = R ⁵ = H, and a double line consisting of a broken line and a solid line is a double bond

（式中、Ｚ^１及びＺ^２はハロゲン原子を表し、そしてＸ、Ｒ^２及びＲ^３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等の塩基の存在下、ジクロロメタン等の溶媒中、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させた後、モレキュラーシーブスの存在下、加熱還流することで得ることができる。
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 X, R ² and R ³ are the same as 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 in the presence of a base such as triethylamine, the compound represented by the general formula (c) is represented. To obtain the compound. The compound of the present invention represented by the general formula (d) can be obtained by allowing ammonia to act on the compound represented by the general formula (c) and then heating to reflux in the presence of molecular sieves.
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^２及びＲ^３は前記と同じ）

（２）上記一般式（Ｉ）で、Ｒ ^１ がアルキルの場合

(Wherein Z ³ represents a halogen atom, and R ² and R ³ are the same as above)

(2) In the above general formula (I), when R ¹ is alkyl

（式中、Ｚ^４はハロゲン原子を表し、そしてＸ、Ｙ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５及び破線と実線からなる二重線は前記と同じ）

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（Ｉ）で、破線と実線からなる二重線が単結合の場合

(In the formula, Z ⁴ represents a halogen atom, and X, Y, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and a double line consisting of a broken line and a solid line 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 above general formula (I), a double line consisting of a broken line and a solid line is a single bond

（式中、Ｘ、Ｙ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４及びＲ^５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, Y, R ¹ , R ² , R ³ , R ⁴ and R ⁵ 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.

Moreover, this invention compound represented by the said general formula (I) can also be manufactured with reference to the said patent document and well-known literature other than the Example of a postscript.

Examples of the compound of the present invention thus obtained are shown in Tables 1-19.

(1-1)
The following general formula:

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４及びＲ^５は表１〜３記載のもの）
で表される化合物。

(Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are those described in Tables 1 to 3)
A compound represented by

（１−２）
次の一般式、

(1-2)
The following general formula:

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４及びＲ^５は表４及び５記載のもの）
で表される化合物。

(Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are those described in Tables 4 and 5)
A compound represented by

（２−１）
次の一般式、

(2-1)
The following general formula:

（式中、Ｒ^２及びＲ^３は表６及び７記載のもの）
で表される化合物。

(Wherein R ² and R ³ are those described in Tables 6 and 7)
A compound represented by

（２−２）
次の一般式、

(2-2)
The following general formula:

（式中、Ｒ^２、Ｒ^３及びＹは表８〜１０記載のもの）
で表される化合物。

(Wherein R ² , R ³ and Y are those described in Tables 8 to 10)
A compound represented by

（３−１）
次の一般式、

(3-1)
The following general formula:

（式中、Ｙ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４及びＲ^５は表１１〜１３記載のもの）
で表される化合物。

(Wherein Y, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are those described in Tables 11-13)
A compound represented by

（１−２）
次の一般式、

(1-2)
The following general formula:

（式中、Ｙ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４及びＲ^５は表１４〜１６記載のもの）
で表される化合物。

(Wherein Y, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are those described in Tables 14-16)
A compound represented by

（１−２）
次の一般式、

(1-2)
The following general formula:

（式中、Ｙ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４及びＲ^５は表１７〜１９記載のもの）
で表される化合物。

(Wherein Y, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are those described in Tables 17-19)
A compound represented by

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.

Example Table 20 As is clear 1 compounds of the present invention described showed P2X ₄ receptor antagonism excellent.
Thus, the compound represented by the general formula (I) of the present invention is useful as a preventive or therapeutic agent for pain in nociceptive pain, inflammatory pain and neuropathic pain have a P2X ₄ receptor antagonism It is believed that there is. 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-Bromophenyl) -1,3-dihydro-2H-benzothieno [3,2-e] -1,4-diazepin-2-one

(1) 3-amino-2- (3-bromobenzoyl) benzo [b] thiophene To a solution of 2-mercaptobenzonitrile (135 mg, 1.00 mmol) in anhydrous N, N-dimethylformamide (3 mL), triethylamine (0. 15 mL, 1.10 mmol) and 3-bromophenacyl bromide (278 mg, 1.00 mmol) were added, and the mixture was stirred at 70 ° C. for 2.5 hours. The reaction mixture was poured into water, 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 / hexane = 3/1) to obtain the title compound as yellow crystals (312 mg, yield 94%).
¹ H NMR (CDCl ₃ , 400 MHz) δ: 7.03 (2H, br s), 7.36 (1H, t, J = 8 Hz), 7.3-7.5 (1H, m), 7.5 -7.6 (1H, m), 7.6-7.7 (1H, m), 7.7-7.8 (2H, m), 7.8-7.9 (1H, m), 8 .02 (1H, t, J = 2Hz)

(2) 2-bromo-N- [2- (3-bromobenzoyl) benzo [b] thiophen-3-yl] acetamide 3-amino-2- (3-bromobenzoyl) benzo [b] thiophene (308 mg) , 0.927 mmol) in anhydrous dichloromethane (3 mL) were added triethylamine (0.16 mL, 1.11 mmol) and bromoacetyl bromide (97 μL, 1.11 mmol) under ice cooling, and the mixture was stirred overnight at room temperature. Triethylamine (0.08 mL) and bromoacetyl bromide (50 μL) were further added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / hexane = 4/1) to give the title compound as brown crystals. (315 mg, 75% yield).
¹ H NMR (CDCl ₃ , 400 MHz) δ: 4.10 (2H, s), 7.40 (1H, t, J = 8 Hz), 7.4-7.6 (2H, m), 7.7− 7.8 (1H, m), 7.80 (1 H, d, J = 8 Hz), 7.8-8.0 (1 H, m), 8.0-8.2 (2H, m), 10. 77 (1H, s)

(3) 5- (3-Bromophenyl) -1,3-dihydro-2H-benzothieno [3,2-e] -1,4-diazepin-2-one The above 2-bromo-N- [2- ( A saturated ammonia ethanol solution (5 mL) was added to 3-bromobenzoyl) benzo [b] thiophen-3-yl] acetamide (315 mg, 0.695 mmol), and the mixture was stirred at room temperature for 22 hours. The reaction mixture was evaporated under reduced pressure, molecular sieves 3A (200 mg) and ethanol (5 mL) were added, and the mixture was heated to reflux for 6.5 hr. After returning to room temperature, chloroform (5 mL) was added, insolubles were filtered off, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / ethyl acetate = 9/1). The obtained crystals were suspended in ethyl acetate (1.8 mL), heated to reflux for 30 minutes, and stirred at 0 ° C. for 2 hours. The precipitated crystals were collected by filtration to give the title compound as pale yellow crystals (161 mg, yield 62%).
mp: 250 ° C or higher
¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 4.38 (2H, s), 7.44 (1H, t, J = 8 Hz), 7.5-7.7 (2H, m), 7. 7-7.8 (2H, m), 7.87 (1H, t, J = 2Hz), 8.02 (1H, d, J = 2Hz), 8.18 (1H, d, J = 8Hz), 11.44 (1H, s)
IR (cm ⁻¹ , KBr): 1695, 1581, 1554, 1525, 1502, 1421, 1412, 1356, 1294, 1255, 1068, 1012, 947, 895, 785, 735, 685, 521, 422.

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

5- (3-Bromophenyl) -1,3-dihydro-2H-benzothieno [3,2-e] -1,4-diazepin-2-one (49 mg, 0.132 mmol) in anhydrous N, N-dimethylformamide To the (1 mL) solution, 55% sodium hydride (8 mg, 0.183 mmol) was added and stirred at room temperature for 15 minutes. Further, methyl iodide (13 μL, 0.209 mmol) was added and stirred at room temperature for 30 minutes. The reaction mixture was poured into water, 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 = 30/1) to give the title compound as yellow crystals (25 mg, yield 49%).
mp: 211-213 ° C
¹ H NMR (CDCl ₃ , 400 MHz) δ: 3.59 (3H, s), 3.96 (1H, d, J = 10 Hz), 5.05 (1H, d, J = 10 Hz), 7.32 ( 1H, m), 7.5-7.6 (2H, m), 7.63 (1H, d, J = 8 Hz), 7.79 (1H, d, J = 8 Hz), 7.8-7. 9 (1H, m), 7.9-8.0 (1 H, m), 8.01 (1 H, t, J = 2 Hz)
IR (cm ⁻¹ , KBr): 1680, 1583, 1554, 1518, 1473, 1416, 1389, 1333, 1292, 1255, 1194, 1032, 1022, 1005, 762, 735, 714.

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

5- (3-Bromophenyl) -1,3-dihydro-2H-benzothieno [3,2-e] -1,4-diazepin-2-one (160 mg, 0.432 mmol) in N, N-dimethylformamide ( To a 1 mL) -methanol (0.1 mL) solution was added sodium borohydride (29 mg, 0.767 mmol), and the mixture was stirred at room temperature for 14.5 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform, 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 / acetone = 20/1) to obtain the title compound as white crystals (30 mg, yield 19%).
mp: 188-190 ° C
¹ H NMR (CDCl ₃ , 400 MHz) δ: 2.34 (1H, brs), 3.78 (1H, d, J = 15 Hz), 3.86 (1H, d, J = 15 Hz), 5.46 ( 1H, s), 7.2-7.3 (1H, m), 7.32 (1H, d, J = 8 Hz), 7.37 (1H, m), 7.4-7.5 (2H, m), 7.55 (1H, s), 7.59 (1H, d, J = 8 Hz), 7.69 (1H, d, J = 8 Hz), 7.82 (1H, brs)
IR (cm ⁻¹ , KBr): 1670, 1635, 1591, 1560, 1497, 1456, 1454, 1412, 1387, 1335, 1302, 1263, 1257, 1068, 804, 789, 752, 731, 692, 671.

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２０から明らかなように実施例１記載の化合物は優れたＰ２Ｘ_４受容体拮抗作用を示した。

Example Table 20 As is clear 1 compounds described showed P2X ₄ receptor antagonism excellent.

Claims (11)

The following general formula (I),

(Wherein X represents S or CH ₂ ;
Y represents O, S or NH;
R ¹ is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, an aralkyl group (the alkyl portion has 1 to 6 carbon atoms, A carbon number of 6 to 10), an alkenyl group having 2 to 8 carbon atoms, a carboxymethyl group or an alkoxycarbonylmethyl group (the carbon number of the alkoxy moiety is 1 to 8);
R ² and R ³ may be the same or different and may be 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, halogen C1-C8 alkoxy group substituted with atoms, halogen atom, amino group, carboxyl group, hydroxyl group, nitro group, cyano group, C2-C8 acyl group, C6-C10 aryl group or 5 Or a 6-membered heterocyclic group,
R ⁴ and R ⁵ 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;
A double line composed of a broken line and a solid line represents a single bond or a double bond. )
Or a salt thereof.   The compound or a salt thereof according to claim 1, wherein X is S.   The compound or salt thereof according to claim 1 or 2, wherein Y is O. The compound or a salt thereof according to any one of claims 1 to 3 R ¹ is a hydrogen atom or an alkyl group having 1 to 8 carbon atoms. R ² and R ³ may be the same or different, and may be 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, halogen The compound or a salt thereof according to any one of claims 1 to 4, which is an alkoxy group having 1 to 8 carbon atoms substituted by an atom, a halogen atom, an amino group, a carboxyl group, a hydroxyl group, a nitro group or a cyano group. The compound according to any one of claims 1 to 4, or a salt thereof, wherein R ³ is a hydrogen atom, and R ² is a halogen atom or a hydroxyl group. Compound or salt thereof according to any one of claims 1 to 6 substitution position of R ² is meta-position. The compound or a salt thereof according to any one of claims 1 to 7 R ⁴ and R ⁵ are hydrogen atoms.   The compound or a salt thereof according to any one of claims 1 to 8, wherein a double line consisting of a broken line and a solid line is a double bond. Compound or P2X ₄ receptor antagonist containing a salt thereof as an active ingredient according to any one of claims 1 to 9. A preventive or therapeutic agent for neuropathic pain comprising the compound or salt thereof according to any one of claims 1 to 9 as an active ingredient.