WO2021049628A1 - P2x4 receptor antagonist - Google Patents

Abstract

[Problem] To provide a novel diazepine derivative having a P2X4 receptor antagonizing action. [Solution] The present invention pertains to: a compound represented by general formula (I) (in the formula, R1 and R2 may be the same or different, and represent a hydrogen atom, a C1-8 alkyl group, a C2-8 alkenyl group, a C1-8 alkoxy group, a C1-8 alkyl group substituted by 1 to 3 halogen atoms, a C1-8 alkoxy group substituted by 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, a C1-8 alkylamino group, a C2-8 dialkylamino group, a C2-8 acylamino group, a C2-8 acylamino group substituted by 1 to 3 halogen atoms, a C1-8 alkylsulfonylamino group, a carboxyl group, a C2-8 acyl group, an alkoxycarbonyl group (where the number of carbon atoms in the alkoxy moiety is 1-8), a carbamoyl group, a C1-8 alkylthio group, a C1-8 alkylsulfinyl group, a C1-8 alkylsulfonyl group, or a sulfamoyl group; and R3 represents an optionally substituted 5- or 6-membered ring heterocycle including 1 to 4 nitrogen atoms as a ring constituent element); a tautomer, stereoisomer, or pharmacologically acceptable salt of the compound; or a hydrate or solvate thereof.

Description

P2X4 receptor antagonist

The present invention relates to diazepine derivatives having P2X4 receptor antagonistic activity.
The present application claims priority based on Japanese Patent Application No. 2019-166974 filed in Japan on September 13, 2019, the contents of which are incorporated herein by reference.

ATP receptors are roughly divided into the P2X family of ion channel type receptors and the P2Y family of G protein-conjugated receptors, and up to now, 7 types (P2X _1-7 ) and 8 types (P2Y _{1, 2, 4, 6), respectively. , 11-14} ) subtypes have been reported.
It has been reported that the P2X4 receptor (Genebank No. X87763), which is a subtype of the P2X family, is 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).
The mechanism of onset of intractable pain such as neuropathic pain has not been clarified accurately, and there is no cure if non-steroidal anti-inflammatory drugs (NSAIDs) and morphine do not work. Therefore, the burden on the patient and those around him is extremely heavy. Neuropathic pain is often caused by damage to the peripheral or central nerves, such as sequelae of surgery, cancer, spinal cord injury, herpes zoster, diabetic neuritis, and trigeminal neuralgia.

Inoue et al. Examined the involvement of P2X receptors in neuropathic pain using an animal model with injured spinal nerves that can detect allodynia. Then, it has been announced that neuropathic abnormal pain (particularly allodynia) is induced through P2X4 receptors expressed in microglial cells of the spinal cord (Non-Patent Document 6, Non-Patent Document 7, Patent Document 1). ..
Therefore, substances that inhibit the action of P2X4 receptors are expected as prophylactic or therapeutic agents for pain in nociceptive pain, inflammatory pain and neuropathic pain.

In Patent Document 2, the following general formula (A),

(In the formula, 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 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. )
It has been reported that the benzoflo-1,4-diazepine-2-one derivative represented by (2) has a P2X4 receptor antagonism.

In Patent Document 3, the following general formula (B),

(In the formula, A is ^{selected from N, N-oxide and CR 2 , L 1} is selected from the binder, an alkyl group having 1 to 6 carbon atoms and a haloalkyl group having 1 to 6 carbon atoms, and R ¹ is arbitrary. in one or more substituents R ⁶ is a cycloalkyl group carbon number of 3 to 8 substituted, aryl of 6 to 14-membered ring, 5-10 membered ring heteroaryl and 3-10 membered heterocyclyl groups of ring Yes, R ³ is a halogen, CN, OR ¹¹ , NR ¹² R ¹³ , with 1 or more substituents R ¹⁴ substituted independently, haloalkyl groups with 1 to 6 carbon atoms, and 1 to 6 carbon atoms. R ⁴ and R ⁵ are independently hydrogen, OH, NH ₂ , alkyl groups having 1 to 6 carbon atoms, haloalkyl groups having 1 to 6 carbon atoms, and alkoxy groups having 1 to 6 carbon atoms. , Selected from cycloalkyl groups with 3-8 carbon atoms and heterocyclyl groups with 3-10 membered rings, where n is 0, 1, 2, 3 or 4).
However, it has been reported that it has a P2X4 receptor antagonistic effect.

It has also been reported that paroxetine, an antidepressant, also has a P2X4 receptor antagonism. (Non-Patent Document 8)

On the other hand, the present inventors also have the following formula (C),

We have found that the naphtho [1,2-e] -1,4-diazepine-2-one derivative and its related compounds represented by (Patent Documents 3 to 3) have a P2X4 receptor antagonism. 12).
Of these, Patent Document 4, Patent Document 11, Patent Document 12, and Patent Document 13 describe naphtho [1,2-e] -1,4-diazepine-2-one derivatives.
In the compound described in Patent Document 4 and the compound of the present invention represented by the general formula (I) described later, the former has a hydroxy group, a halogen atom, and 1 to 8 carbon atoms as the substituent of the phenyl group at the 5-position. Whereas the latter is an alkyl group or the like, the ^{heterocycle represented by R 3} is a tetrazole ring, a triazole ring, an imidazole ring or the like. If heterocyclic ring herein general formula (I) represented by R ³ is a tetrazole ring, but Patent Document 4 may be included in the compounds of general formula (I) according to Patent Document 4, 5-position of the phenyl group There is no description of a specific compound when the substituent is only a hydroxy group, a methoxy group, a methoxyphenyl group, a hydroxyphenyl group, etc. and the substituent is a tetrazolyl group.
Further, the compound described in Patent Document 11 and the compound of the present invention represented by the general formula (I) described later are NHC (= O) in which the former is represented by G and the phenyl group or heterocycle is represented by B. , NHC (= O) NH, NHS (O) ₂ is different.
Further, the compound described in Patent Document 13 and the compound of the present invention represented by the general formula (I) described later have an NHC phenyl group or heterocycle represented by A in the former, as in Patent Document 11. The difference is that they are connected via (= O).
Further, the compound described in Patent Document 12 and the compound of the present invention represented by the general formula (I) described later are used even when B represents a bond and D represents a tetrazole ring or the like. , G-represented phenyl group, pyridyl group and the like are bonded via an ethyl group and the like represented by E.
On the other hand, in Patent Document 4, Patent Document 11, Patent Document 12, and Patent Document 13, substances that inhibit the action of P2X4 receptors are agents for preventing or treating pain in nociceptive pain, inflammatory pain, and neuropathic pain. It is disclosed that it is useful as.
Further, in Patent Document 14, the following equation (D),

Naft [1,2-b] -1,4-diazepine-4-one derivatives represented by are described.
However, although Patent Document 14 describes that the compound represented by the above formula (D) is used as a photographic coupler, there is no description suggesting a relationship between these drugs and P2X4 receptor antagonism. ..
On the other hand, Patent Document 15 describes the formula (E), which has a phosphodiasterase 2 inhibitory action.

Although the 1,4-benzodiazepine derivative represented by is described, there is no description in this document that the compound of the formula (E) has a P2X4 inhibitory effect.

Patent Document 1: U.S. Patent Publication 20050074819
Patent Document 2: WO 2004/0854440
Patent Document 3: WO 2015/088565
Patent Document 4: WO 2008/023847
Patent Document 5: WO 2010/093061
Patent Document 6: WO 2010/090300
Patent Document 7: WO 2012/008478
Patent Document 8: WO 2012/011549
Patent Document 9: WO 2012/014910
Patent Document 10: WO 2012/017876
Patent Document 11: WO 2013/105608
Patent Document 12: WO 2015/005468
Patent Document 13: WO 2015/005467
Patent Document 14: Japanese Patent Application Laid-Open No. 2-304437
Patent Document 15: WO 2004/041258

Non-Patent Document 1: Buell et al. (1996) EMBO J. 15: 55-62
Non-Patent Document 2: Seguela et al. (1996) J.M. Neurosci. 16: 448-455
Non-Patent Document 3: Bo et al. (1995) FEBS Lett. 375: 129-133
Non-Patent Document 4: Soto et al. (1996) Proc Natl. Acad. Sci. USA 93: 3864-3788
Non-Patent Document 5: Wang et al. (1996) Biochem. Res. Commun. 220: 196-202
Non-Patent Document 6: M. Tsuda et al. (2003) Nature, 424, 778-783
Non-Patent Document 7: Jeffrey A. M. Cool et al. (2005) Nature, 438, 1017-1021
Non-Patent Document 8: Abstract of the 49th Annual Meeting of the Japanese Neurochemistry Conference (2006) Program Lecture P3-N-114

An object of the present invention is to provide a diazepine derivative represented by the following general formula (I) having a P2X4 receptor antagonism.

That is, the present invention relates to a compound represented by the following general formula (I), a tautomer of the compound, a stereoisomer or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. ..
In particular, the present invention relates to a compound represented by the following general formula (I), or a pharmaceutically acceptable salt thereof.

（式中、Ｒ^１及びＲ^２は同一又は異なっていてもよく水素原子、炭素数１～８のアルキル基、炭素数２～８のアルケニル基、炭素数１～８のアルコキシ基、１～３のハロゲン原子で置換された炭素数１～８のアルキル基、１～３の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、ヒドロキシル基、ニトロ基、シアノ基、アミノ基、炭素数１～８のアルキルアミノ基、炭素数２～８のジアルキルアミノ基、炭素数２～８のアシルアミノ基、１～３のハロゲン原子で置換された炭素数２～８のアシルアミノ基、炭素数１～８のアルキルスルホニルアミノ基、カルボキシル基、炭素数２～８のアシル基、アルコキシカルボニル基（アルコキシ部分の炭素数は１～８。）、カルバモイル基、炭素数１～８のアルキルチオ基、炭素数１～８のアルキルスルフィニル基、炭素数１～８のアルキルスルホニル基又はスルファモイル基を表し、
　Ｒ^３は、置換基を有していても良い環構成元素として窒素原子を１～４個含む５又は６員環の複素環を表す。）
で表される化合物、前記化合物の互変異性体、立体異性体、若しくはその薬学的に許容される塩又はその水和物若しくは溶媒和物。 (1) The following general formula (I):

(In the formula, R ¹ and R ² may be the same or different, hydrogen atom, alkyl group having 1 to 8 carbon atoms, alkoxy group having 2 to 8 carbon atoms, alkoxy group having 1 to 8 carbon atoms, 1 to 3 carbon atoms. Alkyl group having 1 to 8 carbon atoms substituted with halogen atom, alkoxy group having 1 to 8 carbon atoms substituted with halogen atom 1 to 3, halogen atom, hydroxyl group, nitro group, cyano group, amino group, Alkylamino group with 1 to 8 carbon atoms, dialkylamino group with 2 to 8 carbon atoms, acylamino group with 2 to 8 carbon atoms, acylamino group with 2 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and carbon number of carbon atoms. Alkylsulfonylamino group of 1 to 8, carboxyl group, acyl group of 2 to 8 carbon atoms, alkoxycarbonyl group (alkoxy portion has 1 to 8 carbon atoms), carbamoyl group, alkylthio group of 1 to 8 carbon atoms, carbon Represents an alkylsulfinyl group having a number of 1 to 8, an alkylsulfonyl group having a carbon number of 1 to 8, or a sulfamoyl group.
R ³ represents a 5- or 6-membered heterocycle containing 1 to 4 nitrogen atoms as a ring-constituting element which may have a substituent. )
A compound represented by, a tautomer of the compound, a stereoisomer, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

The active ingredient of the present invention is a compound represented by the above general formula (I), a tautomer of the compound, a stereoisomer, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. With respect to the P2X4 receptor antagonist contained as.
Further, the present invention comprises a compound represented by the above general formula (I), a tautomer of the compound, a steric isomer, a pharmaceutically acceptable salt thereof, or a hydrate or a solvent thereof as an active ingredient. Containing as a medicament for the prevention or treatment of nociceptive pain, inflammatory pain, or neuropathic pain.

Next, the present invention will be described in detail.
In the present specification, examples of the alkyl group having 1 to 8 carbon atoms 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, a hexyl group and the like. ..
Examples of the alkoxy group having 1 to 8 carbon atoms 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, a hexyloxy group and the like.
Examples of the alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms include a methyl group, an ethyl group, and a propyl group substituted with 1 to 3 fluorine atoms, chlorine atoms, bromine atoms, and other halogen atoms. , An isopropyl group, a butyl group, a t-butyl group and the like, and preferably a trifluoromethyl group, a chloromethyl group, a 2-chloroethyl group, a 2-bromoethyl group, a 2-fluoroethyl group and the like.
Examples of the alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms include a methoxy group, an ethoxy group, and a propoxy group substituted with 1 to 3 halogen atoms such as a fluorine atom, a chlorine atom, or a bromine atom. , Isopropoxy group, butoxy group, t-butoxy group and the like, preferably trifluoromethoxy group, chloromethoxy group, 2-chloroethoxy group, 2-bromoethoxy group, 2-fluoroethoxy group and the like.
Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and the like.
Examples of the alkylamino group having 1 to 8 carbon atoms include a methylamino group and an ethylamino group.
Examples of the dialkylamino group having 2 to 8 carbon atoms include a dimethylamino group and a diethylamino group.
Examples of the acylamino group having 2 to 8 carbon atoms include an acetylamino group.
Examples of the acyl group having 2 to 8 carbon atoms include an acetyl group.
Examples of the alkoxycarbonyl group (the number of carbon atoms in the alkoxy moiety is 1 to 8) include a methoxycarbonyl group and the like.

As the compound of the present invention represented by the general formula (I), the following compounds are preferable.
(2) R ³ is an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, and an alkyl having 1 to 8 carbon atoms substituted with halogen atoms of 1 to 3 carbon atoms. Group, alkoxy group with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atom, hydroxyl group, nitro group, cyano group, amino group, alkylamino group with 1 to 8 carbon atoms, 2 to 2 carbon atoms A pyridine ring, a pyrazine ring, a pyrimidine ring, a pyridazine ring, a tetrazole ring, which may have 1 to 4 substituents which may be the same or different and selected from the dialkylamino group, the oxo group and the thioxo group of 8. It is a triazole ring, an imidazole ring, an imidazoline ring, a pyrazole ring, a pyrrole ring, a pyrrolidine ring, an oxazole ring, an isoxazole ring, a thiazole ring, an isothiazole ring, an oxaziazole ring, an oxathiazol ring, a piperazine ring or a piperidine ring (1). The compound according to the above, a homovariant of the compound, a steric isomer, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate thereof.
(3) R ³ is 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 1 to 3 halogen atoms, and a halogen atom having 1 to 3 carbon atoms. It is selected from the substituted alkoxy group having 1 to 8 carbon atoms, halogen atom, hydroxyl group, nitro group, cyano group, amino group, alkylamino group having 1 to 8 carbon atoms or dialkylamino group having 2 to 8 carbon atoms. Tetrazole ring, triazole ring, imidazole ring, imidazoline ring, pyrazole ring, pyrrol ring, pyrrolidine ring, oxazole ring, isoxazole ring, thiazole ring, which may have 1 to 4 substituents which may be the same or different. The compound according to any one of (1) or (2), which is an isothiazole ring or an oxadiazol ring, a homovariant of the compound, a steric isomer, or a pharmaceutically acceptable salt thereof or hydration thereof. A compound or a mixture of solvents.

(4) R ³ is 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 1 to 3 halogen atoms, and a halogen atom having 1 to 3 carbon atoms. It is selected from substituted alkoxy groups having 1 to 8 carbon atoms, halogen atoms, hydroxyl groups, nitro groups, cyano groups, amino groups, alkylamino groups having 1 to 8 carbon atoms or dialkylamino groups having 2 to 8 carbon atoms. Any of (1) to (3), which is a tetrazole ring, a triazole ring, an imidazole ring, an imidazoline ring, a pyrazole ring or an oxadiazole ring which may have 1 to 4 substituents which may be the same or different. The compound described in the above, a homovariant of the compound, a steric isomer, a pharmaceutically acceptable salt thereof, or a hydrate or a solvent product thereof.
(5) R ³ is 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 1 to 3 halogen atoms, and a halogen atom having 1 to 3 carbon atoms. It is selected from the substituted alkoxy group having 1 to 8 carbon atoms, halogen atom, hydroxyl group, nitro group, cyano group, amino group, alkylamino group having 1 to 8 carbon atoms or dialkylamino group having 2 to 8 carbon atoms. The compound according to any one of (1) to (4), which is a tetrazole ring, a triazole ring or an imidazole ring which may have 1 to 4 substituents which may be the same or different, and a mutual variation of the compound. A sex form, a steric isomer, or a pharmaceutically acceptable salt thereof, or a hydrate or a solvate thereof.
(6) A compound according to any one of the R ³ has a cyano group as the tetrazole ring or substituent is 1,2,3-triazole ring (1) to (5), tautomers of the compounds, stereoisomers An isomer, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

(7) R ¹ is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, and 1 to 3 carbon atoms substituted with halogen atoms of 1 to 3 carbon atoms. Alkoxy group with 8 alkyl groups, alkoxy group with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atom, hydroxyl group, nitro group, cyano group, amino group, carboxyl group, acyl group with 2 to 8 carbon atoms Alternatively, the compound according to any one of (1) to (6), which is an alkoxycarbonyl group (the number of carbon atoms in the alkoxy moiety is 1 to 8), a homovariant of the compound, a steric isomer, or a pharmaceutical thereof. Acceptable salts or hydrates or solvates thereof.
(8) R ¹ 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 1 to 3 halogen atoms, and 1 to 3 carbon atoms. The compound according to any one of (1) to (7), which is an alkoxy group having 1 to 8 carbon atoms or a halogen atom substituted with a halogen atom, a homovariant of the compound, a steric isomer, or a pharmaceutical drug thereof. Tolerable salts or hydrates or solvates thereof.
(9) ^{The compound according to any one of (1) to (8) in which R 1} is a hydrogen atom, a tautomer of the compound, a stereoisomer, or a pharmaceutically acceptable salt thereof or hydration thereof. Compound or solvate.

(10) R ² is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, and 1 to 3 carbon atoms substituted with halogen atoms of 1 to 3 carbon atoms. Alkoxy group with 8 alkyl groups, alkoxy group with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atom, hydroxyl group, nitro group, cyano group, amino group, carboxyl group, acyl group with 2 to 8 carbon atoms Alternatively, the compound according to any one of (1) to (9), which is an alkoxycarbonyl group (the number of carbon atoms in the alkoxy moiety is 1 to 8), a homovariant of the compound, a steric isomer, or a pharmaceutical thereof. Acceptable salts or hydrates or solvates thereof.
(11) R ² 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 1 to 3 halogen atoms, and 1 to 3 carbon atoms. The compound according to any one of (1) to (10), which is an alkoxy group having 1 to 8 carbon atoms or a halogen atom substituted with a halogen atom, a homovariant of the compound, a steric isomer, or a pharmaceutical drug thereof. Tolerable salts or hydrates or solvates thereof.
(12) ^{The compound according to any one of (1) to (11) in which R 2} is a hydrogen atom, a tautomer of the compound, a stereoisomer, or a pharmaceutically acceptable salt thereof or hydration thereof. Compound or solvate.
(13) R ¹ and R ² may be the same or different, and have 1 carbon atom substituted with a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, and a halogen atom having 1 to 3 carbon atoms. It is an alkoxy group or a halogen atom having 1 to 8 carbon atoms substituted with an alkyl group of ~ 8 and a halogen atom of 1 to 3.
R ³ was substituted with 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 1 to 3 halogen atoms, and a halogen atom having 1 to 3 carbon atoms. The same or different selected from an alkoxy group having 1 to 8 carbon atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms or a dialkylamino group having 2 to 8 carbon atoms. The compound according to (1), which is a tetrazole ring, a triazole ring, an imidazole ring, an imidazoline ring, a pyrazole ring or an oxadiazol ring which may have 1 to 4 substituents which may be present, and the compounds of the above compounds. Variants, steric isomers, or pharmaceutically acceptable salts thereof, or hydrates or solvates thereof.
(14) R ¹ and R ² are hydrogen atoms,
The compound according to (1) or (13), wherein R ³ is a tetrazole ring or a 1,2,3-triazole ring having a cyano group as a substituent, a tautomer of the compound, a steric isomer, or a pharmaceutical drug thereof. Tolerable salt or hydrate or solvate thereof.

(15) Any of the compounds shown below, tautomers, stereoisomers of the compounds, or pharmaceutically acceptable salts thereof, or hydrates or solvates thereof:
5- [3- (1H-tetrazol-5-yl) phenyl] -1,3-dihydro-2H-naphtho [1,2-e] [1,4] diazepine-2-one;
5- [4- (1H-tetrazol-5-yl) phenyl] -1,3-dihydro-2H-naphtho [1,2-e] [1,4] diazepine-2-one;
5- [3- (5-Cyano-1H-1,2,3-triazole-4-yl) phenyl] -1,3-dihydro-2H-naphtho [1,2-e] [1,4] diazepine- 2-on.
(16) The pharmaceutically acceptable salt is a sodium salt. A pharmaceutically acceptable salt of the compound according to (1) to (15).

The compound according to any one of (1) to (16), a tautomer of the compound, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is next. It can be used as an active ingredient of the indicated drug or pharmaceutical.
(17) The compound according to any one of (1) to (16), a tautomer of the compound, a stereoisomer, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is effective. A P2X4 receptor antagonist contained as an ingredient.
(18) The compound according to any one of (1) to (18), a tautomer of the compound, a steric isomer, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is effective. A drug for the prevention or treatment of nociceptive pain, inflammatory pain or neuropathic pain contained as an ingredient.

In the above general formula (I), R ³ is preferably at the meta or para position with the phenyl group at the 5-position of the general formula (I), and more preferably at the para position.
Pharmaceutically acceptable salts of the compound represented by the above general formula (I) include hydrochloride, hydrobromide, maleate, mesylate, phosphate, sulfate, tartrate, and the like. Examples thereof include alkali metal salts such as sodium, potassium and lithium.

The compound represented by the general formula (I) may have a tautomer, but the tautomer exhibits the same activity as the compound and is included in the present invention.

The compound represented by the above general formula (I) may have cis-trans isomers, optically active isomers, racemic isomers and other steric isomers, all of which are included in the present invention.

The compound represented by the above general formula (I) may have one or two or more asymmetric carbons depending on the type of the substituent, and any optical isomer based on these asymmetric carbons, The present invention also includes any mixture of optical isomers, racemates, diastereoisomers based on two or more asymmetric carbons, any mixture of diastereoisomers, and the like. Geometric isomers may be present when the compound represented by the above general formula (I) contains a double bond or a cyclic structure, but in addition to the pure form geometric isomers, any ratio thereof. Mixtures of are also included in the present invention.

The compound represented by the general formula (I) may include a pharmaceutically acceptable solvate of the compound of the present invention or a pharmaceutically acceptable salt thereof, all of which are included in the present invention. .. The solvate also includes a hydrate.

In the present specification, the compound represented by the above general formula (I) is a homovariant of the compound, a stereoisomer such as a cis-trans isomer, an optically active substance, or a racemate, unless otherwise specified. , Any optical isomers based on asymmetric carbons, racemates, diastereoisomers based on two or more asymmetric carbons, and mixtures thereof.

In the present specification, neuropathic pain includes neuropathic pain.

  Next, the synthesis scheme of the compound of the present invention represented by the above general formula (I) is shown below.
(First step)

(In the equation, X represents a halogen atom such as a bromine atom, and R ¹ is the same as above.)
The compound represented by the general formula (a) and the iodobenzonitrile compound represented by the general formula (b) are reacted in a solvent such as THF in the presence of bis (2-dimethylaminoethyl) ether and isopropylmagnesium chloride. By doing so, a compound represented by the general formula (c) can be obtained. The obtained compound represented by the general formula (c) is represented by the general formula (d) by oxidizing a hydroxyl group to a carbonyl group in a solvent such as dichloromethane in the presence of an oxidizing agent such as pyridinium dichromate. The compound is obtained.

Next, the compound represented by the general formula (d) is represented by the general formula (e) by reducing the nitro group to an amino group in a solvent such as acetic acid or ethanol in the presence of a reducing agent such as iron powder. The compound is obtained.

The compound of the general formula (f) can be obtained by reacting the compound represented by the general formula (e) with bromoacetyl bromide using sodium hydrogen carbonate or the like as a base in the presence of a solvent such as dichloromethane.

The compound represented by the general formula (g) can be obtained by allowing the compound represented by the general formula (f) to act on a saturated ethanol / ammonium solution at room temperature.

Oxidation of the compound of the general formula (c) to the compound of the general formula (d) is carried out by an oxidizing agent such as pyridinium chlorochromate, pyridinium dichromate, manganese dioxide or the like in a solvent not involved in the reaction such as dichloromethane or chloroform. ..

The reduction of the compound of the general formula (d) to the compound of the general formula (e) is carried out by a reducing agent such as iron or zinc in a solvent such as acetic acid, methanol, ethanol or water which is not involved in the reaction. Alternatively, it can be obtained by catalytic hydrogenation using palladium-carbon or the like as a catalyst in a solvent such as methanol or ethanol that does not participate in the reaction.

(Second step)

The compound of the general formula (g), by the action of a reagent capable of converting the Hajime Tamaki represented by R ³ (tetrazole ring and a triazole ring), to give compounds of the general formula (h) .. An example is as follows.

Compound (h) can be produced by reacting (g) with tri-n-butyltin azide when R ^{3 is a tetrazole-5-yl group and then treating with an acid.}

When R ³ is a (1,2,3-triazole) -4-yl group (g) is a methylphenyl sulfone derivative under basic conditions after converting the cyano group to a formyl group using a nickel-aluminum alloy in a formic acid solution. The compound (h) can be produced by condensing the above and reacting the resulting product (vinyl sulfone derivative) with sodium azide.

The compound of the present invention represented by the general formula (I) can be produced by referring to the above-mentioned patent documents, publicly known documents and the like, in addition to the above-mentioned synthesis method and the examples described later.
Examples of the representative compounds of the present invention thus obtained are shown below.

　（式中、Ｒ^３並びにＲ^３の置換位置は表１に記載のとおり）
　表１において、Ｒ^３の置換位置は、ベンゼン環上の置換位置を示す。すなわち、表中の３位及び４位は、代表化合物１の式中の３’位及び４’位にそれぞれ対応する。 (Representative compound example 1)

(In the formula, the replacement positions of R ^{3 and R 3} are as shown in Table 1).
In Table 1, ^{the substitution position of R 3} indicates the substitution position on the benzene ring. That is, the 3rd and 4th positions in the table correspond to the 3'position and the 4'position in the formula of the representative compound 1, respectively.

Next, the pharmacological effect of the present invention will be described.
The P2X4 receptor antagonism of the compound of the present invention was measured as follows.
ATP receptor (human P2X4) was introduced into 1321N1 cells and used as a stable ATP receptor expression system. P2X4-expressing 1321N1 cells were seeded on a 96-well plate, _{cultured at 37 ° C. under 5% CO 2} conditions for 24 hours, and used for calcium measurement. Fura-2 AM, which is a calcium fluorescence indicator, was dissolved in extracellular fluid for calcium imaging, treated on the seeded cells, and allowed to stand at room temperature for 45 minutes to incorporate fura-2 AM into the cells. A microplate reader, Fluostar optima (BMG Labtech), was used for the measurement. The light emitted from the xenon lamp is transmitted through the filters of 340 nm and 380 nm, respectively, and the fluorescence F340 and F380 of 510 nm emitted when the cells are irradiated are observed, and the change of the ratio value F340 / F380 is used as an index of the intracellular calcium change. did. The measurement was performed by adding to each well so that the final concentration of ATP was 1 μM, and observing the ATP-induced Ca2 + response over time. The inhibitory activity of the test substance was measured by pretreating the test substance for 15 minutes with the addition of ATP, and was calculated by comparison with the case in the absence of the test substance. As is clear from Example 6, the compound of the present invention showed excellent P2X4 receptor antagonism (Table 2).

Next, the medicament of the present invention will be described.
The compound represented by the general formula (I), a tautomer of the compound, a steric isomer or a pharmaceutically acceptable salt thereof, or a hydrate or a solvent thereof thereof is used for nociceptive pain and inflammation. It is useful as a medicine for the prevention or treatment of pain in sexual pain and neuropathic pain. However, the application target of the drug is not limited to these.

In addition, the prophylaxis for the prevention or treatment of the present invention may be used in combination with other drugs as needed, for example, opioid analgesics (morphine, fentanyl), sodium channel blockers (novocaine, lidocaine), NSAIDs (aspirin). , Ibuprofen), etc. When used for cancer pain, it may be used in combination with an anticancer agent such as a chemotherapeutic agent.

In addition to the above-mentioned compound, any solvate of a compound in the free form of the compound or a compound in the form of a salt is used as the active ingredient of the medicine containing the compound represented by the general formula (I) as an active ingredient. You may use it.

The compound of the present invention can be appropriately administered to humans by parenteral administration such as oral administration, intravenous administration, intrathecal administration and the like.
In order to formulate, it can be produced into a dosage form such as tablets, granules, powders, capsules, suspensions, injections and suppositories by a usual method in the technical field of formulation.

For these preparations, for example, in the case of tablets, pharmaceutically acceptable additives such as ordinary excipients, disintegrants, binders, lubricants and pigments are used. Here, as an excipient, lactose, D-mannitol, crystalline cellulose, glucose and the like are used, starch, carboxymethyl cellulose calcium (CMC-Ca) and the like are used as a disintegrant, and magnesium stearate is used as a lubricant. Examples of the binder include talc and the like, such as hydroxypropyl cellulose (HPC), gelatin, polyvinylpyrrolidone (PVP) and the like.

Pharmaceutically acceptable additives such as solvents, stabilizers, solubilizers, suspensions, emulsifiers, soothing agents, buffers and preservatives are used to prepare the injection.
That is, the compound of the present invention, the tautomer of the compound, the steric isomer or a pharmaceutically acceptable salt thereof, or the hydrate or solvate thereof is the tautomer of the compound of the present invention and the compound. It may be provided as a pharmaceutical composition containing an active ingredient which is a compound, a steric isomer or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, and a pharmaceutically acceptable additive thereof.

The dose is usually about 0.01 mg to 100 mg of the compound of the present invention, which is the active ingredient in an injection, and 1 mg to 2000 mg of the oral administration per day in adults, but the dose is not limited to the above. It can be increased or decreased depending on age, symptoms, etc.

Among the compounds of the present invention, there is an excellent P2X4 receptor antagonist that can be easily taken as an orally administered preparation. It is also useful as a medicine for the prevention and treatment of nociceptive pain, inflammatory pain, or neuropathic pain.

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

　（１）３－［ヒドロキシ（１－ニトロナフタレン－２－イル）メチル］ベンゾニトリル
ビス（２－ジメチルアミノエチル）エーテル（５．６２ｍＬ，２９．８ｍｍｏｌ）の乾燥テトラヒドロフラン（１２５ｍＬ）溶液に窒素雰囲気下２Ｍイソプロピルマグネシウムクロリド　テトラヒドロフラン溶液（１４．９ｍＬ，２９．８ｍｍｏｌ）を室温で滴下し、２０分間撹拌した。さらに３－ヨードベンゾニトリル（５．６９ｇ，２４．９ｍｍｏｌ）を加え３０分間撹拌した。さらに氷冷下１－ニトロ－２－ナフトアルデヒドを加え室温で１時間撹拌した。この反応混合物に１Ｍ　塩酸水溶液を注ぎ酢酸エチルで抽出した。有機層を水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下に溶媒留去し、残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝４／１）に処し、橙緑色油状物として表題化合物（７．３７ｇ，収率９７％）を得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）δ：２．７５（１Ｈ，ｄ，Ｊ＝４Ｈｚ），６．１２（１Ｈ，ｄ，Ｊ＝４Ｈｚ），７．４－７．５（２Ｈ，ｍ），７．５９（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．６－７．７（３Ｈ，ｍ），７．７－７．８（２Ｈ，ｍ），７．９２（１Ｈ，ｄ，Ｊ＝９Ｈｚ），８．０２（１Ｈ，ｄ，Ｊ＝１２Ｈｚ）．
　（２）３－（１－ニトロ－２－ナフトイル）ベンゾニトリル
３－［ヒドロキシ（１－ニトロナフタレン－２－イル）メチル］ベンゾニトリル（７．３７ｇ，２４．２ｍｍｏｌ）を乾燥ジクロロメタン（７０ｍＬ）に溶解し、シリカゲル（３０ｇ）を加えた。さらにジクロム酸ピリジニウム（１３．７ｇ，３６．３ｍｍｏｌ）を加え１８時間撹拌した。得られた反応混合物をセライトろ過し、ろ物をクロロホルムで洗浄した。ろ液を減圧下に溶媒留去し、得られた粗体を酢酸エチルで再結晶しヘキサンで洗浄後、乾燥して淡黄色結晶として表題化合物（６．３２ｇ，収率８６％）を得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）δ：７．５２（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．６４（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．７－７．９（２Ｈ，ｍ），７．９０（１Ｈ，ｄｔ，Ｊ＝１Ｈｚ，７Ｈｚ），８．０－８．１（３Ｈ，ｍ），８．１－８．３（２Ｈ，ｍ）．
　（３）３－（１－アミノ－２－ナフトイル）ベンゾニトリル
３－（１－ニトロ－２－ナフトイル）ベンゾニトリル（６．２２ｇ，２０．６ｍｍｏｌ）を酢酸（１５０ｍＬ）、エタノール（１５０ｍＬ）および水（１５ｍＬ）に６５℃で加熱溶解した。室温まで放冷後、鉄粉（６．６７ｇ，１１９ｍｍｏｌ）を加え、再度６５℃で１時間撹拌した。放冷後、シリカゲル（１００ｇ）を加えセライトろ過し、ろ物を酢酸エチルで洗浄した。得られたろ液を減圧下に溶媒留去した後、残渣を酢酸エチルに溶解し飽和重層水および飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した。減圧下に溶媒留去し、残留物をシリカゲルカラムクロマトグラフィー（クロロホルム）に処し、黄色結晶として表題化合物（５．４０ｇ，収率９６％）を得た。
^１Ｈ　ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）δ：７．００（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．３０（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．５－７．７（５Ｈ，ｍ），７．７６（１Ｈ，ｄ，Ｊ＝７Ｈｚ），７．８０（１Ｈ，ｄｔ，Ｊ＝１Ｈｚ，９Ｈｚ），７．８－７．９（１Ｈ，ｍ），７．９－８．０（１Ｈ，ｍ），７．９８（１Ｈ，ｄ，Ｊ＝８Ｈｚ）．  5- [3- (1H-tetrazol-5-yl) phenyl] -1,3-dihydro-2H-naphtho [1,2-e] [1,4] diazepine-2-one

(1) A dry tetrahydrofuran (125 mL) solution of 3- [hydroxy (1-nitronaphthalene-2-yl) methyl] benzonitrile bis (2-dimethylaminoethyl) ether (5.62 mL, 29.8 mmol). A 2M isopropylmagnesium chloride tetrahydrofuran solution (14.9 mL, 29.8 mmol) was added dropwise at room temperature under a nitrogen atmosphere, and the mixture was stirred for 20 minutes. Further, 3-iodobenzonitrile (5.69 g, 24.9 mmol) was added, and the mixture was stirred for 30 minutes. Further, 1-nitro-2-naphthaldehyde was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. A 1M aqueous hydrochloric acid solution was poured into this reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 4/1) to obtain the title compound (7.37 g, yield 97%) as an orange-green oil.
^{1 1} H NMR (CDCl ₃ , 400 MHz) δ: 2.75 (1H, d, J = 4 Hz), 6.12 (1H, d, J = 4 Hz), 7.4-7.5 (2H, m), 7.59 (1H, d, J = 8Hz), 7.6-7.7 (3H, m), 7.7-7.8 (2H, m), 7.92 (1H, d, J = 9Hz) ), 8.02 (1H, d, J = 12Hz).
(2) 3- (1-Nitro-2 -naphthal) benzonitrile 3- [hydroxy (1-nitronaphthalene-2-yl) methyl] benzonitrile (7.37 g, 24.2 mmol) is added to dry dichloromethane (70 mL). It was dissolved and silica gel (30 g) was added. Further, pyridinium dichromate (13.7 g, 36.3 mmol) was added, and the mixture was stirred for 18 hours. The resulting reaction mixture was filtered through Celite and the filtrate was washed with chloroform. The filtrate was evaporated under reduced pressure, the obtained crude product was recrystallized from ethyl acetate, washed with hexane, and dried to give the title compound (6.32 g, yield 86%) as pale yellow crystals. ..
^{1 1} H NMR (CDCl ₃ , 400 MHz) δ: 7.52 (1H, d, J = 8 Hz), 7.64 (1H, t, J = 8 Hz), 7.7-7.9 (2H, m), 7.90 (1H, dt, J = 1Hz, 7Hz), 8.0-8.1 (3H, m), 8.1-8.3 (2H, m).
(3) 3- (1-Amino-2-naphthoyl) benzonitrile 3- (1-nitro-2-naphthoyl) benzonitrile (6.22 g, 20.6 mmol) in acetic acid (150 mL), ethanol (150 mL) and water. It was dissolved by heating in (15 mL) at 65 ° C. After allowing to cool to room temperature, iron powder (6.67 g, 119 mmol) was added, and the mixture was stirred again at 65 ° C. for 1 hour. After allowing to cool, silica gel (100 g) was added, the mixture was filtered through Celite, and the filtrate was washed with ethyl acetate. After distilling off the solvent under reduced pressure, the obtained filtrate was dissolved in ethyl acetate, washed with saturated aqueous stratified water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform) to obtain the title compound (5.40 g, yield 96%) as yellow crystals.
^{1 1} H NMR (CDCl ₃ , 400 MHz) δ: 7.00 (1H, d, J = 9 Hz), 7.30 (1H, d, J = 9 Hz), 7.5-7.7 (5H, m), 7.76 (1H, d, J = 7Hz), 7.80 (1H, dt, J = 1Hz, 9Hz), 7.8-7.9 (1H, m), 7.9-8.0 (1H) , M), 7.98 (1H, d, J = 8Hz).

(4) 2-Bromo-N- [2- (3-cyanobenzoyl) naphthalene-1-yl] acetamide The above 3- (1-amino-2-naphthoyl) benzonitrile (2.36 g, 8) To a solution of .67 mmol) in chloroform (60 mL) was added sodium hydrogen carbonate (7.28 g, 86.7 mmol) and bromoacetyl bromide (1.51 mL, 17.33 mmol) under ice-cooling, and the mixture was stirred for 30 minutes. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, the obtained crude crystals were suspended in toluene (30 mL), and the mixture was stirred overnight. The crystals were collected by filtration, washed with toluene and hexane, and air-dried overnight to give the title compound as grayish white crystals (3.41 g, quantitative yield).
^{1 1} H NMR (CDCl ₃ , 400 MHz) δ: 3.97 (2H, s), 7.1-7.2 (1H, m), 7.3-7.5 (3H, m), 7.44 ( 1H, d, J = 8Hz), 7.5-7.7 (2H, m), 7.84 (1H, d, J = 8Hz), 7.8-8.0 (2H, m), 9. 09 (1H, br s)
(5) 3- (2-oxo-2,3-dihydro-1H-naphtho [1,2-e] [1,4] diazepine-5-yl) benznitrile The above 2-bromo-N- [2- (3-Cyanobenzoyl) Naphthalene-1-yl] After adding dry dioxane (75 mL) to acetamide (5.55 g, 4.11 mmol), add 10 to 15% ammonia ethanol solution (75 mL), and in a sealed tube. The mixture was stirred at 65 ° C. overnight. After returning to room temperature, the reaction mixture was distilled off under reduced pressure, a small amount of ethyl acetate and methanol were added to the residue, and the mixture was heated under reflux for 30 minutes. After returning to room temperature, the crystals were collected by filtration, washed with ethyl acetate and hexane, and air-dried overnight to give the title compound as pale yellow crystals (4.30 g, yield 98%).
^{1 1} H NMR (DMSO-d ₆ , 400 MHz) δ: 3.7-3.9 (1 H, m), 4.5-4.7 (1 H, m), 7.28 (1 H, d, J = 8 Hz) ), 7.6-7.8 (4H, m), 7.85 (1H, d, J = 8Hz), 7.9-8.1 (3H, m), 8.18 (1H, d, J) = 8Hz), 10.84 (1H, brs)
(6) 5- [3- (1H-tetrazol-5-yl) phenyl] -1,3-dihydro-2H-naphtho [1,2-e] [1,4] diazepine-2-one
3- (2-oxo-2,3-dihydro-1H-naphtho [1,2-e] [1,4] diazepine-5-yl) benznitrile (100 mg, 0.321 mmol) in toluene (1.5 mL) To a mixed solution of anhydrous DMF (1.5 mL) was added tri-n-butyltin azide (312 μL, 1.13 mmol), and the mixture was heated and stirred overnight. After allowing to cool, chloroform was added to the reaction solution, and the mixture was further poured into a saturated aqueous sodium hydrogen carbonate solution to separate the aqueous layer. Subsequently, a 2M aqueous hydrochloric acid solution was added to the aqueous layer to make it acidic, and then the precipitated solid was filtered off. The solid was heated under reflux with a mixed solvent of methanol and chloroform, filtered, washed with chloroform, and dried to give the title compound (35 mg, yield 31%) as yellow crystals.
^{1 1} H NMR (DMSO-d ₆ , 400 MHz) δ: 3.87 (1 H, d, J = 9 Hz), 4.65 (1 H, d, J = 9 Hz), 7.31 (1 H, d, J = 8 Hz) ), 7.4-7.8 (5H, m), 8.0-8.3 (3H, m), 8.3-8.5 (1H, m), 10.92 (1H, br s)

5- [3- (1H-tetrazol-5-yl) phenyl] -1,3-dihydro-2H-naphtho [1,2-e] [1,4] diazepine-2-one sodium salt 5- [3-] (1H-tetrazol-5-yl) phenyl] -1,3-dihydro-2H-naphtho [1,2-e] [1,4] diazepine-2-one (35 mg, 0.099 mmol) in ethanol (2. Sodium hydrogen carbonate (8.3 mg, 0.099 mmol) was added to the suspension of 5 mL) and water (0.5 mL), and the mixture was stirred at room temperature for 60 minutes. After concentration under reduced pressure, the mixture was azeotropically boiled with water several times to give the title compound (37 mg, 99% yield) as a slightly yellow amorphous residue.
^{1 1} H NMR (DMSO-d ₆ , 400 MHz) δ: 3.81 (1H, d, J = 9 Hz), 4.64 (1 H, d, J = 9 Hz), 7.21 (1 H, d, J = 8 Hz) ), 7.4-7.5 (2H, m), 7.6-7.8 (3H, m), 7.9-8.2 (3H, m), 8.3-8.5 (1H) , M), 10.85 (1H, br s)

5- [4- (1H-tetrazol-5-yl) phenyl] -1,3-dihydro-2H-naphtho [1,2-e] [1,4] diazepine-2-one sodium salt 4-iodobenzonitrile And 1-nitro-2-naphthaldehyde was used, and the title compound was obtained as a slightly yellow amorphous by referring to the methods described in Examples 1 and 2.
^{1 1} H NMR (DMSO-d ₆ , 400 MHz) δ: 3.78 (1 H, d, J = 9 Hz), 4.58 (1 H, d, J = 9 Hz), 7.34 (1 H, d, J = 8 Hz) ), 7.56 (2H, d, J = 8Hz), 7.6-7.8 (3H, m), 7.9-8.1 (3H, m), 8.39 (1H, d, J) = 8Hz), 10.89 (1H, br s)

　（１）３－（２－オキソ－２，３－ジヒドロ－１Ｈ－ナフト［１，２－e］［１，４］ジアゼピン－５－イル）ベンズアルデヒド
　３－（２－オキソ－２，３－ジヒドロ－１Ｈ－ナフト［１，２－e］［１，４］ジアゼピン－５－イル）ベンズニトリル（４００ｍｇ，１．２８５ｍｍｏｌ）の７５％ギ酸（１０ｍＬ）溶液に、ニッケル・アルミニウム合金（４００ｍｇ）を加え６０℃で３時間加熱した。室温まで放冷後、ろ過し濃縮した。得られた残渣に酢酸エチルと炭酸水素ナトリウム水溶液を加た。酢酸エチル層を分取後、水で洗浄、無水硫酸ナトリウムでした。減圧下に溶媒留去し、得られた残渣をジエチルエーテルで洗浄・ろ過する事で黄色粉末の表題化合物を（２５８ｍｇ，収率６４％）を得た。
^１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ_６，４００ＭＨｚ）δ：  ３．８－３．９（１Ｈ，ｍ），４．７－４．８（１Ｈ，ｍ），７．２９（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．６－７．８（４Ｈ，ｍ），７．９０（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．０－８．２（３Ｈ，ｍ），８．３９（１Ｈ，ｄ，Ｊ＝８Ｈｚ），１０．１０（１Ｈ，ｓ），１０．９０（１Ｈ，ｂｒ　ｓ）
　（２）５－［３－（５－シアノ－１Ｈ－１，２，３－トリアゾール－４－イル）フェニル］－１，３－ジヒドロ－２Ｈ－ナフト［１，２－e］［１，４］ジアゼピン－２－オン　
３－（２－オキソ－２，３－ジヒドロ－１Ｈ－ナフト［１，２－e］［１，４］ジアゼピン－５－イル）ベンズアルデヒド（１２６ｍｇ，０．４００ｍｍｏｌ）のＤＭＦ（４ｍＬ）溶液に、２－（フェニルスルフォニル）アセトニトリル（７２ｍｇ，０．４００ｍｍｏｌ）、ピぺリジン（１０μＬ）およびベンゼン（１５ｍＬ）を順次加えた後にディーン・ スターク・トラップ装置を使用し一晩加熱還流した。室温まで放冷後、反応液に水と酢酸エチルを加え、酢酸エチル層を分取後、水で洗浄し無水硫酸ナトリウムで乾燥した。減圧下に溶媒留去し、残留物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝２００／１）に処し、黄色粉末である３－［３－（２－オキソ－２，３－ジヒドロ－１Ｈ－ナフト［１，２－e］［１，４］ジアゼピン－５－イル）フェニル］－２－（フェニルスルフォニル）アクリロニトリルの粗体（７４ｍｇ）を得た。続いて粗体（７４ｍｇ）をＤＭＦ（３ｍＬ）に溶解後、アジ化ナトリウム（１０ｍｇ，０．１５４ｍｍｏｌ）を加え１００℃で３０分間加熱した。室温まで放冷後、反応液に水と酢酸エチルを加え、酢酸エチル層を分取後、水で洗浄し無水硫酸ナトリウムで乾燥した。減圧下に溶媒留去し、得られた残渣をジエチルエーテルで洗浄・ろ過する事で微褐色粉末の表題化合物を（３５ｍｇ，２工程収率２３％）を得た。
^１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ_６，４００ＭＨｚ）δ：  ３．８－３．９（１Ｈ，ｍ），４．６－４．７（１Ｈ，ｍ），７．３２（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．６－７．８（５Ｈ，ｍ），８．０－８．１（２Ｈ，ｍ），８．１１（１Ｈ，ｓ），８．３－８．４（１Ｈ，ｍ），１０．９０（１Ｈ，ｂｒ　ｓ） 5- [3- (5-Cyano-1H-1,2,3-triazole-4-yl) phenyl] -1,3-dihydro-2H-naphtho [1,2-e] [1,4] diazepine- 2-on

(1) 3- (2-oxo-2,3-dihydro-1H-naphtho [1,2-e] [1,4] diazepine-5-yl) benzaldehyde 3- (2-oxo-2,3-dihydro) Add nickel-aluminum alloy (400 mg) to a 75% formic acid (10 mL) solution of -1H-naphtho [1,2-e] [1,4] diazepine-5-yl) benznitrile (400 mg, 1.285 mmol). It was heated at 60 ° C. for 3 hours. After allowing to cool to room temperature, it was filtered and concentrated. Ethyl acetate and an aqueous sodium hydrogen carbonate solution were added to the obtained residue. After separating the ethyl acetate layer, it was washed with water and made over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was washed with diethyl ether and filtered to obtain the title compound of yellow powder (258 mg, yield 64%).
^{1 1} H NMR (DMSO-d ₆ , 400 MHz) δ: 3.8-3.9 (1 H, m), 4.7-4.8 (1 H, m), 7.29 (1 H, d, J = 8 Hz) ), 7.6-7.8 (4H, m), 7.90 (1H, d, J = 8Hz), 8.0-8.2 (3H, m), 8.39 (1H, d, J) = 8Hz), 10.10 (1H, s), 10.90 (1H, br s)
(2) 5- [3- (5-Cyano-1H-1,2,3-triazole-4-yl) phenyl] -1,3-dihydro-2H-naphtho [1,2-e] [1,4 ] Diazepine-2-on
In a DMF (4 mL) solution of 3- (2-oxo-2,3-dihydro-1H-naphtho [1,2-e] [1,4] diazepine-5-yl) benzaldehyde (126 mg, 0.400 mmol). 2- (Phenylsulfonyl) acetonitrile (72 mg, 0.400 mmol), piperidine (10 μL) and benzene (15 mL) were added sequentially and then heated to reflux using a Dean-Stark trap device overnight. After allowing to cool to room temperature, water and ethyl acetate were added to the reaction solution, the ethyl acetate layer was separated, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform / methanol = 200/1), and the yellow powder was 3- [3- (2-oxo-2,3-dihydro-1H-naphtho). A crude (74 mg) of [1,2-e] [1,4] diazepine-5-yl) phenyl] -2- (phenylsulfonyl) acrylonitrile was obtained. Subsequently, the crude product (74 mg) was dissolved in DMF (3 mL), sodium azide (10 mg, 0.154 mmol) was added, and the mixture was heated at 100 ° C. for 30 minutes. After allowing to cool to room temperature, water and ethyl acetate were added to the reaction solution, the ethyl acetate layer was separated, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was washed with diethyl ether and filtered to obtain the title compound of a light brown powder (35 mg, yield of 2 steps: 23%).
^{1 1} H NMR (DMSO-d ₆ , 400 MHz) δ: 3.8-3.9 (1 H, m), 4.6-4.7 (1 H, m), 7.32 (1 H, d, J = 8 Hz) ), 7.6-7.8 (5H, m), 8.0-8.1 (2H, m), 8.11 (1H, s), 8.3-8.4 (1H, m), 10.90 (1H, br s)

5- [3- (5-Cyano-1H-1,2,3-triazole-4-yl) phenyl] -1,3-dihydro-2H-naphtho [1,2-e] [1,4] diazepine- 2-one sodium salt 5- [3- (5-cyano-1H-1,2,3-triazole-4-yl) phenyl] -1,3-dihydro-2H-naphtho [1,2-e] [1 , 4] Add 0.1 mol / L sodium hydroxide aqueous solution (870 μL, 0.087 mmol) to a suspension of diazepine-2-one (33 mg, 0.087 mmol) in methanol (10 mL) and water (1 mL). It was. After 15 minutes, the mixture was concentrated under reduced pressure and azeotropically boiled with water several times to give the title compound (36 mg, quantitative yield) as a brown amorphous residue.
^{1 1} H NMR (DMSO-d ₆ , 400 MHz) δ: 3.83 (1H, d, J = 10 Hz), 4.61 (1 H, d, J = 10 Hz), 7.33 (1 H, d, J = 8 Hz) ), 7.4-7.6 (2H, m), 7.7-7.8 (3H, m), 7.9-8.1 (2H, m), 8.06 (1H, s), 8.2-8.4 (1H, m), 10.89 (1H, br s)

　表２の記載から明らかなように実施例記載の本発明化合物は、優れたＰ２Ｘ４受容体拮抗作用を有することが判明した。

  (P2X4 receptor antagonistic action)
(Test method)
The P2X4 receptor antagonism of the compound of the present invention was measured as follows.
ATP receptor (human P2X4) was introduced into 1321N1 cells and used as a stable ATP receptor expression system. P2X4-expressing 1321N1 cells were seeded on a 96-well plate, cultured at 37 ° C. under 5% CO2 conditions for 24 hours, and used for calcium measurement. Fura-2 AM, which is a calcium fluorescence indicator, was dissolved in extracellular fluid for calcium imaging, treated on the seeded cells, and allowed to stand at room temperature for 45 minutes to incorporate fura-2 AM into the cells. A microplate reader, Fluostar optima (BMG Labtech), was used for the measurement. The light emitted from the xenon lamp is transmitted through the filters of 340 nm and 380 nm, respectively, and the fluorescence F340 and F380 of 510 nm emitted when the cells are irradiated are observed, and the change of the ratio value F340 / F380 is used as an index of the intracellular calcium change. did. The measurement was performed by adding to each well so that the final concentration of ATP was 1 μM, and observing the ATP-induced Ca2 + response over time. The inhibitory activity of the test substance was measured by pretreating the test substance for 15 minutes with the addition of ATP, and was calculated by comparison with the case in the absence of the test substance.
The test results are shown in Table 2.
As a reference example, 5- (3-hydroxyphenyl) -1,3-dihydro-2H-naphtho [1,2-e] -1,4-diazepine-2-one was used. The compound of the reference example is disclosed in International Publication 2008/023487, and can be easily obtained by referring to this international publication.
(Test results)

As is clear from the description in Table 2, the compounds of the present invention described in Examples were found to have excellent P2X4 receptor antagonistic activity.

Claims (18)

The following general formula (I),

(In the formula, R ¹ and R ² may be the same or different, hydrogen atom, alkyl group having 1 to 8 carbon atoms, alkoxy group having 2 to 8 carbon atoms, alkoxy group having 1 to 8 carbon atoms, 1 to 3 carbon atoms. Alkyl group having 1 to 8 carbon atoms substituted with halogen atom, alkoxy group having 1 to 8 carbon atoms substituted with halogen atom 1 to 3, halogen atom, hydroxyl group, nitro group, cyano group, amino group, Alkylamino group with 1 to 8 carbon atoms, dialkylamino group with 2 to 8 carbon atoms, acylamino group with 2 to 8 carbon atoms, acylamino group with 2 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and carbon number of carbon atoms. Alkylsulfonylamino group of 1 to 8, carboxyl group, acyl group of 2 to 8 carbon atoms, alkoxycarbonyl group (alkoxy portion has 1 to 8 carbon atoms), carbamoyl group, alkylthio group of 1 to 8 carbon atoms, carbon Represents an alkylsulfinyl group having a number of 1 to 8, an alkylsulfonyl group having a carbon number of 1 to 8, or a sulfamoyl group.
R ³ represents a 5- or 6-membered heterocycle containing 1 to 4 nitrogen atoms as a ring-constituting element which may have a substituent. ), Or a pharmaceutically acceptable salt thereof. R ³ is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, and an alkyl having 1 to 8 carbon atoms substituted with halogen atoms of 1 to 3 carbon atoms. Group, alkoxy group with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atom, hydroxyl group, nitro group, cyano group, amino group, alkylamino group with 1 to 8 carbon atoms, 2 to 2 carbon atoms A pyridine ring, a pyrazine ring, a pyrimidine ring, a pyridazine ring, a tetrazole ring, which may have 1 to 4 substituents which may be the same or different and selected from the dialkylamino group, the oxo group or the thioxo group of 8. Claim 1 which is a triazole ring, an imidazole ring, an imidazoline ring, a pyrazole ring, a pyrrole ring, a pyrrolidine ring, an oxazole ring, an isoxazole ring, a thiazole ring, an isothiazole ring, an oxadiazole ring, an oxathiazol ring, a piperazine ring or a piperidine ring. The compound described in the above, or a pharmaceutically acceptable salt thereof. R ³ was substituted with 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 1 to 3 halogen atoms, and a halogen atom having 1 to 3 carbon atoms. The same or different selected from an alkoxy group having 1 to 8 carbon atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms or a dialkylamino group having 2 to 8 carbon atoms. It may have 1 to 4 substituents, tetrazole ring, triazole ring, imidazole ring, imidazoline ring, pyrazole ring, pyrrole ring, pyrrolidine ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring. Alternatively, the compound according to any one of claims 1 or 2, which is an oxadiazole ring, or a pharmaceutically acceptable salt thereof. R ³ was substituted with 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 1 to 3 halogen atoms, and a halogen atom having 1 to 3 carbon atoms. The same or different selected from an alkoxy group having 1 to 8 carbon atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms or a dialkylamino group having 2 to 8 carbon atoms. The claim 1 to any one of claims 1 to 3, which is a tetrazole ring, a triazole ring, an imidazole ring, an imidazoline ring, a pyrazole ring or an oxaziazole ring which may have 1 to 4 substituents which may be present. The compound described, or a pharmaceutically acceptable salt thereof. R ³ was substituted with 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 1 to 3 halogen atoms, and a halogen atom having 1 to 3 carbon atoms. The same or different selected from an alkoxy group having 1 to 8 carbon atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms or a dialkylamino group having 2 to 8 carbon atoms. The compound according to any one of claims 1 to 4, which is a tetrazole ring, a triazole ring or an imidazole ring which may have 1 to 4 substituents which may be present, or pharmaceutically acceptable thereof. Salt. Salts R ³ is a compound or a pharmaceutically acceptable according to any one of claims 1 to 5, which is a 1,2,3-triazole ring having a cyano group as the tetrazole ring or a substituent. R ¹ is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, and an alkyl having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms. Group, alkoxy group with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atom, hydroxyl group, nitro group, cyano group, amino group, carboxyl group, acyl group with 2 to 8 carbon atoms or alkoxycarbonyl The compound according to any one of claims 1 to 6, which is a group (the number of carbon atoms in the alkoxy moiety is 1 to 8), or a pharmaceutically acceptable salt thereof. R ¹ 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 1 to 3 halogen atoms, and a halogen atom having 1 to 3 carbon atoms. The compound according to any one of claims 1 to 7, which is a substituted alkoxy group having 1 to 8 carbon atoms or a halogen atom, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 8, wherein R ^{1 is a hydrogen atom, or a pharmaceutically acceptable salt thereof.} R ² is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, alkyl of 1 1 carbon atoms which is substituted with a halogen atom ~ 3-8 Group, alkoxy group with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atom, hydroxyl group, nitro group, cyano group, amino group, carboxyl group, acyl group with 2 to 8 carbon atoms or alkoxycarbonyl The compound according to any one of claims 1 to 9, which is a group (the number of carbon atoms in the alkoxy moiety is 1 to 8), or a pharmaceutically acceptable salt thereof. R ² is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, 1 to 3 alkyl groups having 1 to 8 carbon atoms substituted with a halogen atom, with 1 to 3 halogen atoms The compound according to any one of claims 1 to 10, which is a substituted alkoxy group having 1 to 8 carbon atoms or a halogen atom, or a pharmaceutically acceptable salt thereof. A compound according to any one of claims 1 to 11 R ² is a hydrogen atom, or a pharmaceutically acceptable salt thereof. R ¹ and R ² may be the same or different, and have hydrogen atoms, alkyl groups having 1 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, and halogen atoms having 1 to 3 carbon atoms substituted with 1 to 8 carbon atoms. It is an alkyl group, an alkoxy group having 1 to 8 carbon atoms or a halogen atom substituted with 1 to 3 halogen atoms, or a halogen atom.
R ³ was substituted with 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 1 to 3 halogen atoms, and a halogen atom having 1 to 3 carbon atoms. The same or different selected from an alkoxy group having 1 to 8 carbon atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms or a dialkylamino group having 2 to 8 carbon atoms. The compound according to claim 1, which is a tetrazole ring, a triazole ring, an imidazole ring, an imidazoline ring, a pyrazole ring or an oxadiazol ring which may have 1 to 4 substituents which may be present, or a pharmaceutical compound thereof. Tolerant salt. R ¹ and R ² are hydrogen atoms,
Compound or a pharmaceutically acceptable salt thereof according to claim 1 or 13, which is a 1,2,3-triazole ring R ³ has a cyano group as the tetrazole ring or a substituent. Any of the compounds listed below, or pharmaceutically acceptable salts thereof:
5- [3- (1H-tetrazol-5-yl) phenyl] -1,3-dihydro-2H-naphtho [1,2-e] [1,4] diazepine-2-one;
5- [4- (1H-tetrazol-5-yl) phenyl] -1,3-dihydro-2H-naphtho [1,2-e] [1,4] diazepine-2-one;
5- [3- (5-Cyano-1H-1,2,3-triazole-4-yl) phenyl] -1,3-dihydro-2H-naphtho [1,2-e] [1,4] diazepine- 2-on. A pharmaceutically acceptable salt of the compound according to any one of claims 1 to 15, wherein the pharmaceutically acceptable salt is a sodium salt. A P2X4 receptor antagonist containing the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof as an active ingredient. For the prevention or treatment of nociceptive pain, inflammatory pain or neuropathic pain containing the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof as an active ingredient. Medicine.