WO2010090300A1

WO2010090300A1 - Diazepinedione derivatives

Info

Publication number: WO2010090300A1
Application number: PCT/JP2010/051740
Authority: WO
Inventors: 佐久間詔悟; 遠藤剛; 高橋俊弘; 今井利安; 津田誠; 井上和秀
Original assignee: 日本ケミファ株式会社
Priority date: 2009-02-03
Filing date: 2010-02-02
Publication date: 2010-08-12
Also published as: JP2012087053A

Abstract

Diazepinedione derivatives represented by general formula (I) or pharmacologically acceptable salts thereof are used as P2X₄ receptor antagonist. In general formula (I), R¹ represents a hydrogen atom, a C1-8 alkyl group, or the like; R² represents a hydrogen atom, a C1-8 alkyl group, a C1-8 alkoxy group, a mono-, di-, or tri-halogenated C1-8 alkyl group, a halogen atom, a hydroxyl group, a nitro group, an amino group, a carboxyl group, a cyano group, or the like; R³ represents a hydrogen atom, a C1-8 alkyl group, or the like; and R⁴ and R⁵ may be the same or different and each represents a hydrogen atom, a C1-8 alkyl group, or the like.

Description

Diazepinedione derivatives

The present invention relates to di-azepine-dione 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 8 types (P2Y _{1, 2, 4, 6} ). _11-14 ) 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: Buell et al. (1996) EMBO J. 15: 55-62; Non-Patent Document 2: Seguela et al. (1996) J. Neurosci. 16: 448-455; (1995) FEBS Lett. 375: 129-133; Non-patent document 4: Soto et al. (1996) Proc Natl. Acad.Sci.USA 93: 3684-3788; Non-patent document 5: Wang et al. (1996) Biochem.Res.Commun. 220: 196-202)
Now, the onset mechanism of intractable pain such as neuropathic pain is not 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, it has announced that through the P2X ₄ receptor expressed in spinal cord microglial cells neuropathic abnormal pain (especially allodynia) is triggered. (Non-patent document 6: M. Tsuda et al. (2003) Nature, 424, 778-783; Non-patent document 7: Jeffrey A. M. Coull et al. (2005) Nature, 438, 1017-1021; Patent document) 1: US Patent Publication 20050074819)
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, Patent Document 2 (WO 2004/085440) includes the following general formula (A),

(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 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.
Further, the present inventors also have the following general formula (B)

(Wherein R ¹¹ represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms, and R ²¹ represents an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or a halogen atom having 1 to 3 carbon atoms) And represents an alkyl group having 1 to 8 carbon atoms or a hydroxyl group substituted with R ³¹ , and R ³¹ represents a hydrogen atom or a halogen atom.)
In represented by 1,4-diazepin-2-one derivatives have filed a patent application found that with a P2X ₄ receptor antagonism. (Patent Document 3: WO 2008/023847)
On the other hand, regarding the 1,5-diazepine derivative, Patent Document 4 (JP-A-2-304437) describes the following formula (C),

The compound represented by these is described.
However, Patent Document 4, there is a description that the compound represented by the above formula (C) is used as the photographic couplers, but no description suggesting the relationship between these drugs and P2X ₄ receptor antagonism .

An object of the present invention is to provide a di-azepine-dione 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),

(Wherein 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 alkyl group having 1 to 8 carbon atoms substituted with a halogen atom having 1 to 3 carbon atoms, or a phenyl group. Represents a substituted alkyl group having 1 to 3 carbon atoms,
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 a halogen atom having 1 to 3 carbon atoms. 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, dialkylamino group having 2 to 8 carbon atoms, and 2 carbon atoms An acylamino group having 8 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkylsulfonylamino group having 1 to 8 carbon atoms, a carboxyl group, an acyl group having 2 to 8 carbon atoms, alkoxycarbonyl Group (the alkoxy moiety has 1 to 8 carbon atoms), a carbamoyl group, an alkylthio group having 1 to 8 carbon atoms, an alkylsulfinyl group having 1 to 8 carbon atoms, an alkylsulfonyl group having 1 to 8 carbon atoms, or a sulfamoyl group It represents,
R ³ 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. Substituted alkoxy group having 1 to 8 carbon atoms, halogen atom, hydroxyl group, nitro group, cyano group, amino group, carboxyl group, acyl group having 2 to 8 carbon atoms, or alkoxycarbonyl group (the carbon number of the alkoxy moiety is 1-8))
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 1 to 3 halogen atoms. )
Or a pharmacologically acceptable salt thereof.
The present invention relates to P2X ₄ receptor antagonist containing acceptable salt compound represented by or its pharmacologically by the general formula (I) as an active ingredient.
Furthermore, this invention relates to the preventive or therapeutic agent of neuropathic pain which contains the compound represented with the said general formula (I), or its pharmacologically acceptable salt as an active ingredient.

Next, the present invention will be described in detail.
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 ¹ , R ² , R ³ , R ⁴ and R ⁵ 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 ¹ include 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.
Examples of the alkyl group having 1 to 8 carbon atoms that is substituted with 1 to 3 halogen atoms of R ¹ , R ² , R ³ , R ^4, and R ⁵ include 1 to 3 fluorine atoms, chlorine atoms, bromine atoms, etc. And a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, or a t-butyl group substituted by a halogen atom, preferably trifluoromethyl group, chloromethyl group, 2-chloroethyl group, 2-bromoethyl. Group or 2-fluoroethyl group.
Examples of the alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms of R ² and R ³ include a methyl group substituted with 1 to 3 halogen atoms such as a fluorine atom, a chlorine atom or a bromine atom , Ethyl group, propyl group, isopropyl group, butyl group or t-butyl group, preferably trifluoromethoxy group, chloromethoxy group, 2-chloroethoxy group, 2-bromoethoxy group or 2-fluoroethoxy group Etc.
Examples of the acyl group for R ² and R ³ include an acetyl group.
Examples of the alkoxycarbonyl group for R ² and R ³ (the alkoxy group having 1 to 8 carbon atoms) include a methoxycarbonyl group and an ethoxycarbonyl group.
Examples of the alkyl group having 1 to 3 carbon atoms substituted by the phenyl group of R ¹ include a benzyl group.
Examples of the alkylamino group having 1 to 8 carbon atoms of R ² include a methylamino group and an ethylamino group.
Further, examples of the dialkylamino group having 1 to 8 carbon atoms of R ² include a dimethylamino group and a diethylamino group.
Examples of the acylamino group having 2 to 8 carbon atoms for R ² include an acetylamino group.
Examples of the acylamino group having 2 to 8 carbon atoms substituted with 1 to 3 halogen atoms of R ² include a trifluoromethylcarbonylamino group.
Examples of the alkylsulfonylamino group having 1 to 8 carbon atoms of R ² include a methylsulfonylamino group.
Examples of the alkylthio group having 1 to 8 carbon atoms of R ² include a methylthio group.
Examples of the alkylsulfinyl group having 1 to 8 carbon atoms of R ² include a methylsulfinyl group.
Examples of the alkylsulfonyl group having 1 to 8 carbon atoms of R ² include a methylsulfonyl group.
In the general formula (I), R ² and R ³ may be present in the same or different benzene rings substituted by R ² and R ³ .
Furthermore, as the compound of the present invention represented by the general formula (I), the following compounds are preferred.
(1)
A diazepinedione derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof, wherein R ¹ is a hydrogen atom or an alkyl group having 1 to 8 carbon atoms.
(2)
A diazepinedione derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof, wherein R ¹ is a hydrogen atom.
(3)
The diazepinedione derivative represented by the above (1), (2) or the above general formula (I) or a pharmacology thereof, wherein R ⁴ is a hydrogen atom and R ⁵ is a hydrogen atom or an alkyl group having 1 to 8 carbon atoms. Acceptable salt.
(4)
The diazepinedione derivative represented by the above (1), (2) or the above general formula (I) or a pharmacologically acceptable salt thereof, wherein R ⁴ and R ⁵ are both hydrogen atoms.
(5)
Any one of the above (1) to (4), wherein R ² is an alkoxy group having 1 to 8 carbon atoms, a hydroxyl group, a carboxyl group, a cyano group or an alkoxycarbonyl group (the alkoxy moiety has 1 to 8 carbon atoms) or the above A diazepinedione derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof.
(6)
Any one of the above (1) to (4), wherein R ² is an alkoxy group having 1 to 8 carbon atoms or a hydroxyl group, or a diazepinedione derivative represented by the above general formula (I) or a pharmacologically acceptable product thereof; Salt.
(7)
A diazepinedione derivative represented by any one of the above (1) to (6) or the general formula (I), wherein R ³ is a hydrogen atom, or a pharmaceutically acceptable salt thereof.
Examples of the pharmacologically acceptable salt of the compound represented by the general formula (I) include hydrochloride and the like when R ² and R ³ are amino groups. Furthermore, when R ² and R ³ are carboxyl groups, alkali metal salts such as sodium, potassium and lithium are exemplified.
The compound of the present invention may have optical isomers such as cis / trans isomers, optically active isomers, and racemates, all of which 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.
(Method 1) When R ¹ = H

(Wherein X represents a halogen atom such as a bromine atom, and R ² , R ³ , R ⁴ and R ⁵ are the same as described above.)
(First step)
The compound represented by the general formula (c) is represented by the general formula (a) using a palladium catalyst or the like in a solvent such as toluene or tert-butanol in the presence of a base such as cesium carbonate or potassium carbonate. It can be obtained by a cross-coupling reaction between the compound represented by formula (b) and the compound represented by formula (b).
(Second step)
The compound represented by the general formula (d) is obtained by converting the compound represented by the general formula (c) into iron, stannous chloride, zinc, or palladium in a solvent that does not participate in the reaction such as THF, methanol, chloroform, and acetic acid. -It can be obtained by reduction by catalytic addition using carbon or the like as a catalyst.
(Third step)
The compound of the present invention represented by the general formula (f) is a compound represented by the general formula (d) and the general formula (d) in a solvent such as toluene and THF in the presence or absence of a base. It can be obtained by reacting the compound represented by e).
(Method 2) When R ¹ ≠ H

(In the formula, X represents a halogen atom such as a bromine atom, a chlorine atom or an iodine atom, a tosyl group or a mesyl group, and R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as described above.)
The compound of the present invention represented by the general formula (h) is synthesized with the compound represented by the general formula (f) and the general formula (f) in a solvent such as dimethyl sulfoxide in the presence of a base such as sodium hydride. It can be obtained by reacting the compound represented by g).
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 to 10.
(1)
A compound represented by the following general formula:

(Wherein R ¹ , R ² , R ⁴ and R ⁵ represent those described in Tables 1 to 4)

(2)
A compound represented by the following general formula:

(Wherein R ¹ , R ² , R ⁴ and R ⁵ represent those described in Tables 5 to 7)

(3)
A compound represented by the following general formula:

(In the formula, R ¹ to R ⁵ are those shown in Tables 8 to 10.)

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.
ATP receptor (human P2X ₄ ) was introduced into 1321N1 cells and used as a stable ATP receptor expression system. Seeded P2X ₄ expressing 1321N1 cells into 96-well plates, 37 ° C., was used for calcium measurements for 24 hours at 5% CO ₂ conditions. Fura-2 AM, which is a calcium fluorescent indicator, was dissolved in an extracellular solution 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. For measurement, a microplate reader Fluostar optima (BMG Labtech) was used. The light emitted from the xenon lamp is transmitted through each of the 340nm and 380nm filters to observe the fluorescence _{F 340} and _{F 380} of 510nm emanating upon irradiating the cells, intracellular calcium changes in ratio value _F 340 _{/ F 380} It was an indicator of change. The measurement was performed by adding each well to an ATP final concentration of 1 μM and observing the ATP-induced Ca ²⁺ response over time. The inhibitory activity of the test substance was measured by pretreating the test substance with ATP for 15 minutes, and was calculated by comparison with the case in the absence of the test substance.
The present invention compounds as is apparent from Example 6 showed a P2X ₄ receptor antagonism excellent.
Thus, salts-diazepine-dione derivative or a pharmacologically acceptable represented by the general formula (I), nociceptive pain from having a P2X ₄ receptor antagonism, inflammatory pain and neuropathic It is considered useful as an agent for preventing or treating pain in pain. 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.
The dose is usually about 0.01 mg to 100 mg of the compound of the present invention, which is an active ingredient in injections, and 1 mg to 2000 mg per day by oral administration in adults, but may 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) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione (1) N- (3-methoxyphenyl) -1- Nitro-2-naphthylamine 1-nitro-2-naphthylamine (565 mg, 3.00 mmol), 3-bromoanisole (374 mg, 2.00 mmol), potassium carbonate (691 mg, 5.00 mmol), tris (dibenzylideneacetone) dipalladium A solution of (18 mg, 0.02 mmol) and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (48 mg, 0.10 mmol) in tert-butanol (4 mL) was stirred at 85 ° C. for 16 hours. After allowing to cool, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10/1) to obtain the title compound (588 mg, yield 99). %).
¹ H NMR (CDCl ₃ , 400 MHz) δ: 3.83 (3H, s), 6.7-6.9 (3H, m), 7.32 (1H, t, J = 8 Hz), 7.3 7.5 (2H, m), 7.63 (1H, ddd, J = 2, 7, 9 Hz), 7.71 (1H, d, J = 7 Hz), 7.75 (1H, d, J = 9 Hz) ), 8.54 (1H, d, J = 8 Hz), 9.48 (1H, s)
(2) N ^2- (3-methoxyphenyl) naphthalene-1,2-diamine N- (3-methoxyphenyl) -1-nitro-2-naphthylamine (7.36 g, 25.01 mmol) in methanol (100 mL) and 10% Palladium-carbon (736 mg) was added to a chloroform (100 mL) solution, and catalytic hydrogenation was performed at room temperature and normal pressure for 16 hours. After the catalyst was filtered off, the solvent was distilled off under reduced pressure. The residue was suspended in ethyl acetate (50 mL) and heated to reflux for 30 minutes. After allowing to cool, the precipitated crystals were collected by filtration and washed with a small amount of ethyl acetate and hexane. The mother liquor and washings were purified by silica gel column chromatography (chloroform / methanol = 25/1). Combined with the above crystals, the title compound was obtained (6.50 g, 98% yield).
¹ H NMR (CDCl ₃ , 400 MHz) δ: 3.52 (3H, s), 6.30 (1H, d, J = 8 Hz), 6.4-6.6 (2H, m), 6.91 ( 1H, t, J = 8 Hz), 7.3-7.4 (2H, m), 7.51 (1H, d, J = 9 Hz), 7.7-7.8 (2H, m), 8. 2-8.3 (1H, m), 10.29 (2H, br s)
(3) 5- (3-methoxyphenyl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione N ^2- (3-methoxyphenyl) naphthalene- 1,2-diamine (2.00 g, 7.57 mmol) was suspended in anhydrous toluene (20 mL), and a solution of malonyl chloride (883 μL, 9.08 mmol) in anhydrous toluene (2 mL) was added dropwise under ice cooling. The reaction mixture was heated to 80 ° C. over 40 minutes and further stirred at 110 ° C. for 20 minutes. After allowing to cool, the solution portion was poured into saturated multistory water, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solid precipitated in the reaction system was dissolved in chloroform, washed with saturated multilayer water and saturated brine, and dried over anhydrous sodium sulfate. The crude products were combined and purified by silica gel chromatography (hexane / ethyl acetate = 55/45) to give the title compound (977 mg, yield 40%).
¹ H NMR (CDCl ₃ , 400 MHz) δ: 3.61 (2H, s), 3.77 (3H, s), 6.8-6.9 (3H, m), 7.07 (1H, d, J = 9 Hz), 7.32 (1H, t, J = 8 Hz), 7.5-7.6 (2H, m), 7.7 (1H, dt, J = 1, 8 Hz), 7.85 ( 1H, d, J = 8 Hz), 8.13 (1H, d, J = 8 Hz), 8.97 (1H, br s)
(4) 5- (3-hydroxyphenyl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione 5- (3-methoxyphenyl) -1H- To a solution of naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione (1.34 g, 4.03 mmol) in dichloromethane (40 mL), 1M boron tribromide-dichloromethane solution (8.1 mL, 8.1 mmol) was added to ice cooling and stirred at room temperature for 5 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, chloroform was added, and the mixture was stirred at room temperature for 10 min. Insoluble crystals were filtered off, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 96/4) together with the above crystals. The obtained crystals were suspended in ethyl acetate (4 mL), heated to reflux for 30 minutes, and stirred at 0 ° C. for 1 hour. The precipitated crystals were collected by filtration to give the title compound as white crystals (963 mg, yield 75%).
mp: 290 ° C (decomposition point)
¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 3.12 (1H, d, J = 12 Hz), 3.68 (1H, d, J = 12 Hz), 6.6-6.7 (2H, m ), 6.74 (1H, d, J = 8 Hz), 7.02 (1H, d, J = 9 Hz), 7.22 (1H, t, J = 8 Hz), 7.59 (1H, t, J = 8 Hz), 7.6-7.7 (2 H, m), 7.91 (1 H, d, J = 8 Hz), 8.23 (1 H, d, J = 8 Hz), 9.64 (1 H, s) ) 10.88 (1H, s)
IR (cm < ^-1 >, KBr): 3205,3126,2943,1684,1637,1597,1512,1458,1431,1398,1371,1311,1279,1238,1178,1151,1003,970,893,860,820 , 783,769,748,708,690,611,567,511,434.

5- (3-carboxyphenyl) -1H-naphtho [1,2-b] [1,4] -diazepine-2,4 (3H, 5H) -dione (1) 3- (1-nitro-2-naphthyl) Amino) ethyl benzoate The title compound was obtained using ethyl 3-bromobenzoate in the same manner as in Example 1 (1).
¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.40 (3H, t, J = 7 Hz), 4.40 (2H, q, J = 7 Hz), 7.33 (1H, d, J = 9 Hz), 7.4-7.6 (3H, m), 7.64 (1H, ddd, J = 1, 7, 9 Hz), 7.73 (1H, d, J = 7 Hz), 7.79 (1H, d , J = 9 Hz), 7.90 (1H, dt, J = 1, 7 Hz), 7.94 (1H, s), 8.49 (1H, d, J = 9 Hz), 9.38 (1H, s) )
(2) Ethyl 3- (1-amino-2-naphthylamino) benzoate The title compound was obtained in the same manner as in Example 1 (2).
¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.36 (3H, t, J = 7 Hz), 4.34 (2H, q, J = 7 Hz), 5.38 (1H, s), 6.7− 6.9 (1H, m), 7.2-7.4 (4H, m), 7.4-7.5 (4H, m), 7.5-7.9 (2H, m)
(3) 5- (3-Ethoxycarbonylphenyl) -1H-naphtho [1,2-b] [1,4] -diazepine-2,4 (3H, 5H) -dione Similar to Example 1 (3) The title compound was obtained using the procedure.
¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.36 (3H, t, J = 7 Hz), 3.63 (2H, s), 4.3-4.4 (2H, m), 6.98 ( 1H, d, J = 9 Hz), 7.4-7.5 (2H, m), 7.5-7.6 (2H, m), 7.71 (1H, dt, J = 1, 7 Hz), 7.85 (1H, d, J = 8 Hz), 7.90 (1 H, s), 8.0-8.1 (1 H, m), 8.10 (1 H, d, J = 9 Hz), 8. 59 (1H, s)
5- (3-carboxyphenyl) -1H-naphtho [1,2-b] [1,4] -diazepine-2,4 (3H, 5H) -dione 5- (3-ethylcarbonylphenyl) -1H-naphtho [1,2-b] [1,4] -diazepine-2,4 (3H, 5H) -dione (70 mg, 0.19 mmol) in ethanol (42 mL) and 1,4-dioxane (1 mL) in 1 M Aqueous sodium hydroxide (0.5 mL, 0.5 mmol) was added and stirred at room temperature for 16 hours. The mixture was neutralized with 1M hydrochloric acid (0.5 mL), poured into a 0.1M aqueous hydrochloric acid solution, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 96/4) to obtain the title compound as a pale brown powder (45 mg, yield). (Rate 69%).
¹ H NMR (DMSO-d ₆ , 400 MHz) δ: 3.17 (1H, d, J = 12 Hz), 3.74 (1H, d, J = 12 Hz), 6.96 (1H, d, J = 9 Hz) ), 7.4-7.7 (6H, m), 7.8-7.9 (2H, m), 8.26 (1H, d, J = 8 Hz), 8.30 (1H, s), 10.91 (1H, s)

5- (3-Cyanophenyl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione (1) 3- (1-nitro-2-naphthylamino ) Benzonitrile 1-nitro-2-naphthylamine (875 mg, 4.65 mmol), 3-bromobenzonitrile (846 mg, 4.65 mmol), cesium carbonate (3.03 g, 9.30 mmol), tris (dibenzylideneacetone) di A solution of palladium (213 mg, 0.23 mmol) and (±) -2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (217 mg, 0.35 mmol) in anhydrous toluene (10 mL) at 110 ° C. Stir for hours. After allowing to cool, the reaction mixture was poured into saturated multistory water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to obtain the title compound (503 mg, yield 37%).
¹ H NMR (CDCl ₃ , 400 MHz) δ: 7.37 (1H, d, J = 9 Hz), 7.4-7.6 (5H, m), 7.66 (1H, t, J = 8 Hz), 7.78 (1H, d, J = 8 Hz), 7.86 (1H, d, J = 9 Hz), 8.38 (1H, d, J = 9 Hz), 8.98 (1H, s)
(2) 3- (1-Amino-2-naphthylamino) benzonitrile The title compound was obtained in the same manner as in Example 1 (2).
¹ H NMR (CDCl ₃ , 400 MHz) δ: 4.38 (2H, br s), 5.45 (1H, br s), 6.87 (2H, s), 7.06 (1H, d, J = 7 Hz), 7.2-7.4 (3H, m), 7.4-7.5 (2H, m), 7.8-7.9 (2H, m)
(3) 5- (3-Cyanophenyl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione In the same manner as in Example 1 (3). The title compound was obtained.
mp: 220-222 ° C
¹ H NMR (CDCl ₃ , 400 MHz) δ: 3.63 (2H, s), 6.93 (1H, d, J = 9 Hz), 7.5-7.7 (6H, m), 7.73 ( 1H, t, J = 7 Hz), 7.89 (1H, d, J = 8 Hz), 8.10 (1H, d, J = 9 Hz), 8.61 (1H, s)
IR (cm ⁻¹ , KBr): 3238, 2931, 2229, 1693, 1628, 1601, 1583, 1512, 1483, 1460, 1423, 1362, 1309, 1263, 1122, 993, 958, 899, 866, 816, 795 769, 708, 679, 604, 565, 523, 492, 476, 432.

5- (3-Cyanophenyl) -1-methyl-1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione and 5- (3-cyanophenyl)- 1,3-dimethyl-1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione 5- (3-cyanophenyl) -1H-naphtho [1,2- b] [1,4] diazepine-2,4 (3H, 5H) -dione (98 mg, 3 mmol) was dissolved in dry dimethyl sulfoxide (1 mL), and 50-72% sodium hydride (12 mg) was added with stirring under water cooling. And stirred at room temperature for 1 hour. To this was added methyl iodide (0.06 mL, 1 mmol), and after stirring at room temperature for 4 hours, 50-72% sodium hydride (6 mg) and methyl iodide (0.03 mL, 0.5 mmol) were added. For 18 hours. Cold water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was washed successively with ethyl acetate and hexane to give 5- (3-cyanophenyl) -1-methyl-1H-naphtho [1,2-b] [1,4] diazepine- 2,4 (3H, 5H) -dione (28 mg, 27% yield) was obtained as pale yellow crystals. The washing solution was concentrated under reduced pressure and then purified by silica gel column chromatography (ethyl acetate / hexane = 1/1) to give 5- (3-cyanophenyl) -1,3-dimethyl-1H-naphtho [1,2 -B] [1,4] diazepine-2,4 (3H, 5H) -dione (9 mg, 8% yield) was obtained as a pale yellow oil.
5- (3-Cyanophenyl) -1-methyl-1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione FAB-MS (m / z): 342 (M + 1)
¹ H NMR (CDCl ₃ , 400 MHz): δ = 3.55 (1H, d, J = 12 Hz), 3.59 (3H, s), 3.65 (1H, d, J = 12 Hz), 6.92 (1H, d, J = 9 Hz), 7.5-7.7 (7H, m), 7.89 (1H, d, J = 8 Hz), 7.95 (1H, d, J = 9 Hz).
5- (3-Cyanophenyl) -1,3-dimethyl-1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione
¹ H NMR (CDCl ₃ , 400 MHz): δ = 0.84 (3H, d, J = 8 Hz), 3.59 (3H, s), 4.10 (1H, q, J = 8 Hz), 6.87 (1H, d, J = 9 Hz), 7.5-7.7 (7H, m), 7.88 (1H, d, J = 8 Hz), 7.94 (1H, d, J = 8 Hz).

5- (4-Cyanophenyl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione (1) 4- (1-nitro-2-naphthylamino ) Benzonitrile The title compound was obtained in the same manner as in Example 3 (1).
¹ H NMR (CDCl ₃ , 400 MHz) δ: 7.25 (2H, d, J = 7 Hz), 7.46-7.53 (2H, m), 7.62-7.70 (3H, m), 7.80 (1H, d, J = 8 Hz), 7.90 (1H, d, J = 9 Hz), 8.28 (1H, d, J = 9 Hz), 8.72 (1H, br s)
(2) 4- (1-Amino-2-naphthylamino) benzonitrile The title compound was obtained in the same manner as in Example 1 (2).
¹ H NMR (CDCl ₃ , 400 MHz) δ: 4.37 (2H, br s), 5.71 (1H, br s), 6.65-6.70 (2H, m), 7.20-7. 30 (1H, m), 7.30-7.40 (1H, m), 7.45-7.55 (4H, m), 7.80-7.90 (2H, m)
(3) 5- (4-Cyanophenyl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione The same procedure as in Example 1 (3). The title compound was obtained using.
mp: 241-243 ° C
¹ H NMR (DNSO-d ₆ , 400 MHz) δ: 3.18 (1H, d, J = 12 Hz), 3.76 (1H, d, J = 12 Hz) 6.93 (1H, d, J = 9 Hz) 7.45 (2H, d, J = 8 Hz), 7.60-7.73 (3H, m), 7.90-7.95 (3H, m), 8.28 (1H, d, J = 8Hz), 10.96 (1H, br s)
IR (cm ⁻¹ , KBr): 3236, 3153, 2929, 2231, 1684, 1664, 1599, 1500, 1471, 1423, 1369, 1313, 1255, 1225, 1201, 1176, 1111, 1018, 982, 920, 849 823,783,748,708,677,555,498,455,428.

(Test method)
The P2X ₄ receptor antagonism of the compounds of the present invention was measured as follows.
ATP receptor (human P2X ₄ ) was introduced into 1321N1 cells and used as a stable ATP receptor expression system. Seeded P2X ₄ expressing 1321N1 cells into 96-well plates, 37 ° C., was used for calcium measurements for 24 hours at 5% CO ₂ conditions. Fura-2 AM, which is a calcium fluorescent indicator, was dissolved in an extracellular solution 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. For measurement, a microplate reader Fluostar optima (BMG Labtech) was used. The light emitted from the xenon lamp is transmitted through each of the 340nm and 380nm filters to observe the fluorescence _{F 340} and _{F 380} of 510nm emanating upon irradiating the cells, intracellular calcium changes in ratio value _F 340 _{/ F 380} It was an indicator of change. The measurement was performed by adding each well to an ATP final concentration of 1 μM and observing the ATP-induced Ca ²⁺ response over time. The inhibitory activity of the test substance was measured by pretreating the test substance with ATP for 15 minutes, and was calculated by comparison with the case in the absence of the test substance.
(Test results)

Thus, as the present invention compounds of Table 11 described, it was found to have excellent P2X ₄ receptor antagonism.

Claims

The following general formula (I),

(Wherein 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 alkyl group having 1 to 8 carbon atoms substituted with a halogen atom having 1 to 3 carbon atoms, or a phenyl group. Represents a substituted alkyl group having 1 to 3 carbon atoms,
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 a halogen atom having 1 to 3 carbon atoms. 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, dialkylamino group having 2 to 8 carbon atoms, and 2 carbon atoms An acylamino group having 8 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkylsulfonylamino group having 1 to 8 carbon atoms, a carboxyl group, an acyl group having 2 to 8 carbon atoms, alkoxycarbonyl Group (the alkoxy moiety has 1 to 8 carbon atoms), a carbamoyl group, an alkylthio group having 1 to 8 carbon atoms, an alkylsulfinyl group having 1 to 8 carbon atoms, an alkylsulfonyl group having 1 to 8 carbon atoms, or a sulfamoyl group It represents,
R 3 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. Substituted alkoxy group having 1 to 8 carbon atoms, halogen atom, hydroxyl group, nitro group, cyano group, amino group, carboxyl group, acyl group having 2 to 8 carbon atoms, or alkoxycarbonyl group (the carbon number of the alkoxy moiety is 1-8))
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 1 to 3 halogen atoms. )
Or a pharmacologically acceptable salt thereof.
The diazepinedione derivative or a pharmacologically acceptable salt thereof according to claim 1 , wherein R 1 is a hydrogen atom or an alkyl group having 1 to 8 carbon atoms.
The diazepinedione derivative or a pharmacologically acceptable salt thereof according to claim 1 , wherein R 1 is a hydrogen atom.
The diazepinedione derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 4 is a hydrogen atom, and R 5 is a hydrogen atom or an alkyl group having 1 to 8 carbon atoms. .
4. The diazepinedione derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 3, wherein R 4 and R 5 are both hydrogen atoms.
The R 2 is an alkoxy group having 1 to 8 carbon atoms, a hydroxyl group, a carboxyl group, a cyano group, or an alkoxycarbonyl group (the carbon number of the alkoxy moiety is 1 to 8). Or a pharmacologically acceptable salt thereof.
6. The diazepinedione derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 5, wherein R 2 is an alkoxy group having 1 to 8 carbon atoms or a hydroxyl group.
The diazepinedione derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 7, wherein R 3 is a hydrogen atom.
-Diazepine Derivatives or P2X 4 receptor antagonist containing a pharmacologically acceptable salt thereof as an active ingredient according to any one of claims 1-8.
A preventive or therapeutic agent for neuropathic pain comprising the diazepinedione derivative according to any one of claims 1 to 8 or a pharmacologically acceptable salt thereof as an active ingredient.