WO1994026737A1 - Imidazolylquinoxalinedione derivative and pharmaceutical composition thereof - Google Patents

Abstract

An imidazolylquinoxalinedione derivative, represented by general formula (I), useful as a glutamate receptor antagonist, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same as the active ingredient, wherein R1 represents hydrogen or lower alkyl; R2 represents hydrogen or hydroxy; X represents -O-, -NR4- or -S(O)¿n-; R?4 represents hydrogen or lower alkyl; n represents 0, 1 or 2; A represents a direct bond or lower alkylene; and R3 represents (1) lower alkyl, (2) carboxy, or (3) phenyl, cycloalkyl or mono- or bicyclic heterocyclic group wherein the heteroatom(s) is(are) N and/or S, each of which may be substituted.

Description

 TECHNICAL FIELD The present invention relates to imidazolylquinoxalinedione derivatives and pharmaceutical compositions thereof.

 The present invention relates to an imidazolylquinoxalinedione derivative having a glutamate receptor antagonistic action, in particular, an anti-kainic acid neurocytotoxic action, an audiogenic seizure inhibitory action and a neuroprotective action, and a pharmaceutically acceptable salt thereof. And a pharmaceutical composition containing them. Background of the Invention

 Amino acids such as L-glutamic acid and L-aspartic acid are known to be mediators of the central nervous system. If these excitatory amino acids accumulate extracellularly and continue to stimulate the nerves excessively, Huntington's chorea, Parkinson's disease, epilepsy, Alzheimer's disease, senile dementia, and cerebral ischemia, hypoxia, low It is said to lead to neurodegeneration or mental and motor dysfunction observed after blood sugar status

 Therefore, drugs capable of regulating the abnormal action of these excitatory amino acids have been considered to be useful for treating neurodegenerative and psychiatric disorders.

The action of excitatory amino acids is exerted via specific receptors located at postsynaptic or presynaptic sites. Such receptors are currently classified into three groups based on electrophysiological and neurochemical evidence. 1) NMD A (N-methyl-D-aspartate) receptor

2) n 0 n—NMD A receptor

 a) AMP A [2-amino-3- (3-hydroxy-15-methyl-4-isoxazole) propionic acid] / kainic acid receptor

 b) Kainate receptor

 3) Metabotropic glumate receptor

 L-glutamate and L-aspartate activate the above receptors and transmit excitement. NMDA, AMP A. Nerve damage occurs when an excessive amount of kainate is applied to nerves. 2-amino-5-phosphonovaleric acid or 2-amino-7-phosphonoheptanoic acid, a selective antagonist of the NMD A receptor, has been tested in NMD A-induced neuropathy, epilepsy and cerebral ischemia It has been reported to be effective in animal models (J. Pharmacology and Experimental Therapeutics, 250, 100 (1989): J. Pharmacology and Experimental Therapeutics, 240, 737 (1987): Science, 226, 850 (1984)).

 The NMD A receptor has been reported to work in an allosteric manner via the glycine receptor (EJP, -126, 303 (1986)), and HA-966, an antagonist of the glycine receptor, is still present. It has been reported to be effective in experimental animal models of cerebral ischemia (American Neuroscience Society 1989).

NBQX (6-nitro7-sulfamoylbenzo [f] quinoxaline), a selective AMP A receptor antagonist, has also been reported to be effective in experimental animal models of cerebral ischemia. (Science, 247, 571 (1990)). On the other hand, no selective antagonists of kainate receptor and metabotropic glutamate receptor have been reported so far. Disclosure of the invention

An object of the present invention is to provide a compound having a diketoquinoxaline-based glutamate receptor antagonistic action, and particularly having an anti-kainic acid neurotoxicity action, an audiogenic spasm inhibitory action, and a neuroprotective action. Is what you do. Several diketoquinoxaline derivatives having NMDA-glycine receptor antagonistic activity and / or AMP A receptor antagonistic activity have been reported (JP-A-63-83074, No. 6 3−2 5 8 4 6 6; Japanese Unexamined Patent Application Publication No. HEI 1—15 3680; Japanese Unexamined Patent Application Publication No. HEI 2—4 857 8 No. 2-222124 and WO 92/07847 pamphlet), the compound of the present invention is imidazolyl via a linking group of 0, S and N heteroatoms. The structure of the quinoxalinedione skeleton connected to a substituted or unsubstituted hydrocarbon chain represented by R ³ —A—, a substituted or unsubstituted carbocyclic ring, or a substituted or unsubstituted heterocyclic ring It is a novel compound having even better pharmacological activity.

 That is, the present invention provides a compound represented by the general formula (I):

(The symbols in the formula represent the following meanings c

R ¹ hydrogen atom or lower alkyl group,

R ² hydrogen atom or hydroxyl group,

X group — 0—, — NR ⁴ — or —S (0) R ⁴ : a hydrogen atom or a lower alkyl group,

 n: 0, 1 or 2,

 A: bond or lower alkylene group,

R ³ : 1) a lower alkyl group,

 2) a carboxy group, or

 3) A phenyl group, a cycloalkyl group, or a monocyclic or bicyclic heterocyclic group having N and / or S as a hetero atom, each of which may be substituted. )

The present invention relates to an imidazolylquinoxalinedione derivative represented by the formula or a pharmaceutically acceptable salt thereof.

 The present invention also relates to a pharmaceutical composition comprising an imidazolyl quinoxalindione derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

 Hereinafter, the compound of the present invention will be described in detail.

 In the definition of the general formula herein, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified.o

Accordingly, as the “lower alkyl group”, specifically, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group , Neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3- Dimethylbuty 1-ethylbutyl group, 2-ethylbutyl group, 1,2,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1— Ethyl-2-methylpropyl group.

 The “lower alkylene group” represented by A includes methylene group, ethylene group, methylmethylene group, trimethylene group, 1-methylethylene group, 2-methylethylene group, tetramethylene group, 1-methyltrimethylene group, 2-methyl Trimethylene group, 3-methyltrimethylene group, 1-ethylethylene group, 2_ethylethylene group, 1,2-dimethylethylene group, propylmethylene group, pentamethylene group, 1-methyltetramethylene group, 2-methyltetramethylene group, 3-methyltetramethylene group, 4-methyltetramethylene group, 1-ethyltrimethylene group, 2-ethylethylmethylene group, 3-ethyltrimethylene group, 1,1-dimethyltrimethylene group, 2,2- Dimethyltrimethylene group, 3,3-dimethyltrimethylene group, hexamethylene group, 1-methylpentame Carbon atoms such as styrene, 2-methylpentamethylene, 3-methylpentamethylene, 4-methylpentamethylene, 5-methylpentamethylene, 1,1-dimethyltetramethylene, and 4,4-dimethyltetramethylene; Examples include 1 to 6 linear or branched alkylene groups.

In R ^3, the `` optionally substituted phenyl group, cycloalkyl group, or monocyclic or bicyclic heterocyclic group having N and / or S as a hetero atom '' is a phenyl group, a substituted phenyl group. Group, cycloalkyl group, substituted cycloalkyl group, monocyclic or bicyclic heterocyclic group having N and S or S as a hetero atom, monocyclic or bicyclic heterocyclic group having substituted N and / or S as a hetero atom Cyclic heterocyclic group means all Among them, the cycloalkyl group is preferably a cycloalkyl group having 3 to 8 carbon atoms, specifically, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group Groups.

 Specific examples of the monocyclic or bicyclic heterocyclic group having N and Z or S as a hetero atom include, for example, a pyrrolyl group, a pyrrolinyl group, an imidazolyl group, an imidazolinyl group, a virazolyl group, a virazolinyl group, and a triazolyl group. Group, tetrazolyl group, pyridyl group, dihydropyridyl group, pyrimidinyl group, virazinyl group, pyridazinyl group, triazinyl group, etc. 5- or 6-membered monocyclic heterocyclic group containing only 1 to 4 nitrogen atoms, thiazolyl group A 5- to 6-membered monocyclic heterocyclic group containing 1 to 4 nitrogen and sulfur atoms such as isothiazolyl group, thiadiazolyl group, dithiazolyl group, dithiazolinyl group, thiazinyl group, thiadiazinyl group, dithiazinyl group, chenyl group , Dithiolyl, thiopyranyl, dichenyl, trithenyl, etc. 5- or 6-membered monocyclic heterocyclic group containing only 1 to 3 carbon atoms, indolyl group, isoindolyl group, imidazolyl group, benzimidazolyl group, quinolyl group, isoquinolyl group, phthalazinyl group, cinnolinyl group, quinazo Preferred are nitrogen-containing bicyclic heterocyclic rings such as a linyl group and a quinoxalinyl group. Among them, an imidazolyl group, a tetrazolyl group, a pyridyl group, a thiadiazolyl group, and an indolyl group are preferred.

The above-mentioned phenyl ring, cycloalkyl ring, monocyclic or bicyclic heterocycle having N and S or hetero atoms as hetero atoms may have one or more substituents at any positions. Examples of such a substituent include a phenyl ring, a cycloalkyl ring and a heterocyclic ring in the art. Any known substituents on the mouth ring may be used, and in particular, halogen atoms; lower alkyl groups, halogeno lower alkyl groups, carboxy lower alkyl groups, lower alkoxy groups, lower alkoxy groups, lower alkyl groups, and lower amino alkyl groups. Substituted or unsubstituted lower alkyl groups such as mono- or di-lower alkylamino lower alkyl groups; substituents of hydroxyl groups such as hydroxyl group and lower alkoxy group; substitution of carboxy groups such as carboxy group and lower alkoxycarbonyl group Group; a cyano group; a nitro group; a substituent of an amino group such as an amino group, a mono- or di-lower alkylamino group; or a monocyclic or bicyclic heterocyclic group having N as a hetero atom is preferable. Examples thereof include a substituent.

 Here, the “halogen atom” includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and the “lower alkyl group” includes the specific groups described above.

 "Halogeno lower alkyl group" means a group in which any one or two or more hydrogen atoms of the lower alkyl group are substituted with a halogen atom. When a halogen atom is exemplified by a fluorine atom, a fluoromethyl group, a difluoromethyl group Trifluoromethyl group, 2,2,2-trifluoroethyl group and the like. -

The "lower alkoxy group" includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyl (amyl) oxy, isopentyl And the like. A “lower alkoxycarbonyl group” is a group in which these “lower alkoxy groups” are esterified by replacing OH of a carboxy group (eg, a methoxycarbonyl group, an ethoxycarbonyl group). Etc.).

“Mono or di-lower alkylamino group” is one of the amino groups or A group in which two hydrogen atoms are mono- or di-substituted with a specific group of the lower alkyl group, specifically, for example, a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, Mono-lower alkylamino such as isobutylamino, sec-butylamino, tert-butylamino, pentylamino, isopentylamino, hexylamino, isohexylamino, dimethylamino, getylamino, dipropylamino And asymmetric di-lower alkylamino groups such as a symmetric di-lower alkylamino group such as a group, disopropylamino group and dibutylamino group, an ethylmethylamino group, a methylpropylamino group and an ethylpropylamino group.

“Carboxy lower alkyl group”, “lower alkoxycarbonyl lower alkyl group”, “amino lower alkyl group”, “mono or di lower alkylamino lower alkyl group” means that any hydrogen atom of the lower alkyl group is carboxy. A lower alkoxycarboxy group, an amino group, or a group substituted with the mono- or di-lower alkylamino group.A typical example is `` carboxy lower alkyl group '' such as carboxymethyl group, Examples of the `` lower alkoxycarbonyl lower alkyl group '' include carboxyethyl, carboxypropyl, carboxybutyl, and the like, and methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylethyl, Methoxycarbonyl A propyl group, an ethoxycarbonylpropyl group, a methoxycarbonylbutyl group, an ethoxycarbonylbutyl group, and the like, and the “amino lower alkyl group” are an aminomethyl group, an aminoethyl group, an aminopropyl group, an aminobutyl group, and the like. Lower alkylamino lower alkyl group "and Examples include methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, ethylaminomethyl, methylaminoethyl, ethylaminoethyl, dimethylaminoethyl, and dimethylaminoethyl. And methylaminopropyl group, ethylaminopropyl group, propylaminopropyl group, dimethylaminopropyl group, getylaminopropyl group, dipropylaminopropyl group and the like.

 Examples of the “monocyclic or bicyclic heterocyclic group having N as a heteroatom” include all the heterocyclic groups having only a nitrogen atom among the above-mentioned heterocyclic groups, and particularly, an imidazolyl group and a triazolyl group. And a tetrazolyl group.

The “monocyclic or bicyclic heterocyclic group having N as a hetero atom” as a substituent is particularly preferably a group bonded via a ring carbon atom. The compound (I) of the present invention forms a salt with an acid. Further, depending on the type of the substituent, a salt with a base may be formed. The present invention also includes pharmaceutically acceptable salts of compound (I), and examples of such salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid. Formic acid, acetic acid, propionic acid, succinic acid, valeric acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid Acid addition salts with organic acids such as ethanesulfonic acid, glutamic acid, and aspartic acid; and inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum, such as methylamine, ethylamine, dimethylamine, getylamine, Trimethylamine, triethylamine, monoethanolamine, diethanolamine, triethanolamine, cyclohexylamine And salts with organic bases such as lysine and lysine, and ammonium salts. The compound of the present invention has a tautomer based on a diketoquinoxaline structure. Also, depending on the type of the substituent, there are optical isomers (optically active isomers, diastereomers, etc.). The present invention includes a separated form of these isomers and a mixture thereof.

 Further, the compound of the present invention may be isolated as various solvates such as hydrates and ethanol solvates and crystalline polymorphic substances, and the present invention includes all of these substances.

Among the compounds of the present invention, particularly preferred are compounds in which X is -0-, and in particular, R ³ is a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a carboxy lower alkyl group, a lower alcohol, Oxycarbonyl lower alkyl group, amino lower alkyl group, mono or di lower alkyl amino lower alkyl group, hydroxyl group, lower alkoxy group, carboxy group, lower alkoxycarbonyl group, cyano group, nitro group, amino group, A phenyl group which may be substituted with one or more substituents selected from the group consisting of a mono- or di-lower alkylamino group, and a monocyclic or bicyclic heterocyclic group having N as a hetero atom Compounds. Among them, preferred compounds include the compounds described in Examples, and particularly preferred examples include the following.

(1) 4-[[6-(1 H—Imidazol— 1 —Ill) 1 2, 3 (1

H, 4H) Monoquinoxalinedione-7-yl] oxy] benzoic acid or a pharmaceutically acceptable salt thereof

(2) 4-[[4-hydroxy-17- (1H-imidazole-1-yl) -12,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-yl] oxymethyl ] Benzoic acid or a pharmaceutically acceptable salt thereof (3) 6— (1H-imidazole-1-yl) — 7— [4- (1H-tetrazole-5-yl) phenoxy] one, 2,3 (1H, 4H) —quinoxalinedione or its pharmaceuticals Chemically acceptable salts

 (4) 6— (1 H—imidazole—1—yl) 1—1-hydroxyl 7—1 (4—1 (1H—imidazole—5—yl) phenoxy) — 2,

3 (1H, 4H) monoquinoxalinedion or its pharmaceutically acceptable salt

 (5) 4-[[4-hydroxy-7- (1H-imidazole-1-yl)]-1,2,3-dioxo-1,2,3,4-tetrahydroquinoxaxin-6-yl] oxymethyl] benzoic acid Or a pharmaceutically acceptable salt thereof.

 (6) 4-[[2,3-Dioxo-1-hydroxy-1- 7- (4-methyl-1H-imidazole-1-yl)] 1,2,3,4-tetrahydroquinoxaline 6-yl] oxy] benzoic acid or a pharmaceutically acceptable salt thereof.

 (Manufacturing method)

 The compound of the present invention can be produced by a method represented by the following reaction formula.

First manufacturing method

(In the formula, R ¹ , R ² , R ³ , X and A have the above-mentioned meaning, and Y means a halogen atom.)

 The compound (I) of the present invention can be obtained by reacting a halogen compound (Π) in an amount corresponding to the reaction with an imidazole compound (ΠΙ) while stirring. Although the reaction proceeds without solvent, it is usually heated in a solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrile, acetone, tetrahydrofuran (THF) or the like. Done. To promote the reaction, a base such as caustic soda, caustic potash, potassium carbonate or a copper salt may be added.

 Second manufacturing method

(Wherein, R ¹ , R ³ , X and A have the above-mentioned meanings.)

The compound of the general formula (la) in the compound of the present invention is obtained by reacting the diamino compound (W) with an equivalent to excess amount of oxalic acid or a reactive derivative (V) thereof at room temperature to under heating, preferably under heating to reflux. Can be reacted. Examples of the reactive derivative of oxalic acid include salts, esters, hydrates, anhydrides, and acid halides. This reaction is usually performed in water or an alcohol solvent. To promote the reaction, it is preferred to add an acid such as hydrochloric acid. Third manufacturing method

0 0

(In the formula, R ¹ , R ³ , X and A have the above-mentioned meanings, and t Bu means a tert-butyl group.)

 This production method is an alternative to the second production method, and comprises adding a tert-butylamine compound (VI) and an equivalent or excess amount of oxalic acid or a reactive derivative thereof in water or an alcohol solvent under an acidic condition from room temperature to a heated condition. The reaction can be carried out while stirring.

 The reactive derivative of oxalic acid is as described above.

 4th manufacturing method

0

0

(In the formula, R ¹ , R ³ , X and A have the above-mentioned meaning, and R ⁵ represents an ester-forming group.)

The compound (Ia) of the present invention is a lower alkoxalylamino compound (W) Can be produced by reductive cyclization of Is not particularly limited as long as herein ester forming group for R ⁵ is an ester-forming group that does not inhibit the cyclization by reaction, typically a methyl group, those lower alkyl groups such as Echiru group used. The reaction can be carried out, for example, by a conventional catalytic reduction method in which hydrogen gas is used at least three times the amount of the compound (W) in the presence of a catalyst such as Raney nickel or palladium-carbon (Pd-C), such as iron chloride or activated carbon. The reaction can be carried out by a reduction method using hydrazine or a hydrate thereof in the presence of a catalyst prepared from Raney nickel or the like. Fifth manufacturing method

(Wherein, R ¹ and R ³ are as described above.)

Present compound (lb) is a lower alkoxy hexa Lil amino compound (W) palladium one-carbon, platinum oxide (P t 0 _2), Irijiumu - carbon

(Ir-C) can be obtained by a conventional catalytic reduction method in which twice the amount of hydrogen gas is allowed to act in the presence of a catalyst such as (Ir-C). It can also be added. Sixth production method (hydrolysis)

(Wherein, R ¹ , R ² , X and A have the above-mentioned meanings, and B is a bond or an optionally substituted phenylene group, cycloalkanediyl group, or N and or S is a heteroatom Represents a monocyclic or bicyclic heterocyclic divalent group represented by the following formula, and ^Re represents an ester-forming group.) The compound (Ic) of the present invention having at least one carboxy group as a substituent is a corresponding ester It can be produced by hydrolyzing compound (H). Here, the ester-forming group of R ⁶ is not particularly limited as long as it forms an ester as well as the lower alkyl group constituting the compound of the present invention and gives the corresponding carboxylic acid by this hydrolysis. Hydrolysis may be carried out by any of acid hydrolysis in the presence of an acid such as hydrochloric acid and alkylation in the presence of a base such as sodium hydroxide. Can be.

7th manufacturing method

(I e) (wherein, R ¹ , R ² , X, A and B have the above-mentioned meanings, and M represents a hydrogen atom or a metal atom.)

 The compound (I e) having at least one tetrazolyl group in the compound of the present invention, when the corresponding nitrile compound (I d) is used as a raw material, may be used in an amount corresponding to the reaction or an excess amount of hydrogen azide or azide. It can be produced by reacting a metal azide, such as sodium azide, tin azide compound, gayzide azide compound and aluminum azide compound, usually under heating. The reaction is usually carried out in an organic solvent such as DMF.However, N-methylpyrrolidone is used as a solubilizing agent, or an amine such as ammonium chloride such as ammonium chloride or trimethylamine or triethylamine, or an amine or a salt thereof is added. Solubility can also be improved.

 (Other manufacturing methods)

 The compound of the present invention can also be produced by applying various conventional methods, particularly the methods described in Reference Examples and modifications thereof in consideration of the features of the structure in addition to the above-mentioned production methods.

For example, a compound in which X is -0- or _S- is a compound in which the corresponding halide is replaced with a hydroxy or mercapto compound, such as sodium hydride. The reaction can be carried out at room temperature or under heating in the presence of a base by conventional etherification or thioetherification. Further, the compound in which X is -N- is used to convert the corresponding amine and the corresponding halide or sulfonate from room temperature to heating in the presence of a base such as potassium carbonate or triethylamine, if necessary. It can be produced by applying a so-called N-alkylation ordinary method for reacting with the above. Compounds having a mono- or di-lower alkylamino group or a mono- or di-lower alkylamino lower alkyl group as a substituent can be produced by the same N-alkylation using the corresponding primary or secondary amino compound as a raw material.

Further, compounds in which X is —SO— or 1 S 0 ₂ — can be used to convert the corresponding sulfide (—S—) or sulfonyl (—SO—) compound into an organic peracid such as m-chloroperbenzoic acid. It can be produced by conventional oxidation by treating with an oxidizing agent such as hydrogen peroxide or nitric acid.

 Compounds having a lower alkoxycarbonyl group as a substituent can be prepared by reacting a reactive derivative thereof such as a corresponding carboxylic acid diacid halide with a reactive derivative thereof such as a lower alkanol or a lower alkyl halide. Can be produced by esterification of

 The compound of the present invention thus produced is isolated and purified as a free compound, a salt thereof, a hydrate, various solvates and the like. The pharmaceutically acceptable salt of the compound (I) of the present invention can also be produced by subjecting the compound to a conventional salt formation reaction.

Isolation and purification are performed by applying ordinary chemical operations such as extraction, fractional crystallization, and various types of fractional chromatography. The optical isomer can be obtained by selecting an appropriate starting compound or by a racemic resolution method of a racemic compound (for example, a method of leading to a diastereomer salt with a general optically active base and performing optical fractionation). Can lead to stereochemically pure isomers. Industrial applicability

 The compound of the present invention has an affinity for AMPA receptor, but has a strong anti-kainic acid neurotoxicity in rat fetal hippocampal neuronal primary culture system regardless of the degree of affinity for AMPA receptor. Showed an effect. In rat fetal hippocampus primary cultures, the kainate-binding site of the AMPA kainate receptor is thought to play an important role in inducing neuronal necrosis [J. Neuroscience, 10, 693 (1990)]. Furthermore, the compound of the present invention strongly suppressed late neuronal necrosis in the hippocampus of murine rats. In addition, the platform of the present invention also showed strong suppression of audiogenic convulsions in DBAZ2 mice.

 Therefore, the compound of the present invention is effective for hunting-ton's chorea, Parkinson's disease, epilepsy, Alzheimer's disease, senile dementia, cerebral ischemia, cerebral ischemia, and oxygen deficiency based on these effects, particularly the potent anti-kainic acid neurocytotoxic effect It is a particularly useful drug for protecting cells during temporary cardiac arrest, preventing hypoglycemia and post-convulsive neurodegeneration or mental and motor dysfunction.

[ ³ H] AMPA binding inhibitory activity, anti-kainic acid neurocytotoxic activity, audiogenic seizure inhibitory activity and neuronal protective activity of the compound of the present invention were confirmed as follows. 1) Measurement of [ ³ H] AM PA binding activity

About 45 nM of [ ³ H] AMP A [2-amino-3_ (3-hydroxy-5-methyl-4-isoxazolyl) propionic acid] and about 30 Omg of rat cerebral membrane specimen A total of 0.5 of the reaction solution containing the test compound was reacted in ice water for 45 minutes. The amount of [ ³ H] AMP A bound to the quisqualate receptor was measured by a filtration method. The specific binding amount was the portion of the total binding amount that was replaced by 10 M quisqualic acid. The test compounds were evaluated by determining the rate of binding inhibition on specific binding.

 As a result, the activity of the compound of the present invention for inhibiting the binding to the AMP A receptor was expressed at a concentration of 10 nM to 100 M.

 2) Anti-kainic acid neurotoxicity test

 Cells in which AMP A receptor is present show only weak cytotoxicity by AMP A itself, but show strong cytotoxicity by kainate (KA). The effect of the compound of the present invention on kainate neuronal toxicity was examined using a rat fetal hippocampal neuronal primary culture system.

 ① Culture conditions

The hippocampus was excised from the rat brain on days 18-20 of the embryo and treated with papain and DNase I to disperse the cells. The cells were suspended in MEM containing 10% serum, and seeded on a 48-well plate previously treated with poly-1-Lysine at a concentration of 4 × 10 ⁵ cellZcnf. After 24 hours, the medium was replaced with a serum-free medium. The medium was exchanged twice / week. Cells cultured for 6 days or more were subjected to the following experiment.

 ② Kainic acid neurotoxicity

Neurotoxicity was expressed as the activity of lactate dehydratase released into the culture medium due to cell death. 300; in a serum-free medium containing kainic acid Using the compound exposed for 24 hours as a control, each compound was allowed to act on nerve cells for 24 hours simultaneously with 300 β カ イ of kainate, and the inhibitory effect of each compound on nerve cell death caused by kainate was evaluated.

As a result, the compound of Example 37 had an IC ₅ . The value of 0.20 / Μ showed an excellent effect.

 3) Measurement of audiogenic spasm and seizure inhibitory effects in DBA / 2 mice

 21 1-28-day-old male mice (10 mice) were placed in a soundproof box, and 1 2 kHz,

A 12 OdB sound stimulus was applied for 1 minute or until the mouse developed rigid convulsions. The test compound was suspended in a 0.5% methylcellulose solution or dissolved in saline, and administered intraperitoneally 15 minutes before sound stimulation. The efficacy was evaluated based on the presence or absence of seizures, and the minimum effective dose (MED) was determined.

 As a result, the compound of Example 3 suppressed the convulsive seizure by 0.3 呢 1¾.

 4) Neuroprotective effect in hippocampus

'The protective effect of neuronal necrosis caused by cerebral ischemia was tested using a murine bilateral common carotid artery occlusion model.

 ① Operation

 The rats were allowed to recover from anesthesia by occlusion of the bilateral common carotid artery for 5 minutes under a mouth-to-mouth anesthesia while the sand rats (n = 6) were kept warm to avoid hypothermia. Four days later, the brain was removed and sectioned, and the degree of neuronal damage in hippocampal CA was examined histologically.

 ② Administration method

The test drug was suspended in 0.5% methylcellulose solution or dissolved in physiological saline and administered intraperitoneally. At 60 minutes, 70 minutes, and 85 minutes after reopening, administration of 3 OmgZkg was performed once. ③ Evaluation method

 Histological examination was performed under a light microscope. The degree of neuronal damage in the hippocampal C A i area was assessed on a four-point scale: no damage, mild necrosis, moderate necrosis, and complete necrosis.

 As a result, the compound of Example 23 of the present invention had a score of 1 in the degree of damage.

0, indicating a neuroprotective effect of 100%.

 Pharmaceutical compositions containing one or more of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient can be used as a carrier for commonly used pharmaceutical preparations. Tablets, powders, fine granules, granules, capsules, pills, liquids, injections, suppositories, etc., and orally or parenterally. .

 The dosage is determined as appropriate depending on the individual case, taking into account the symptoms, age of the subject to be administered, gender, body weight, etc., but it is usually l-1000 mg, preferably 50-200 mg per adult daily. Orally once or several times daily in the range of lmg to 50 mg / day for adults, once or several times daily, or It is continuously administered intravenously for 1 hour to 24 hours a day. Of course, as described above, the dose varies under various conditions, so that a dose smaller than the above dose range may be sufficient.

As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, the one or more active substances include at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone. The metasilicate is mixed with magnesium aluminate. The composition is prepared according to the usual methods, using additives other than inert diluents, such as magnesium stearate. Lubricants, disintegrants such as calcium cellulose glycolate, stabilizers such as lactose, and solubilizing or solubilizing agents such as glutamate or aspartic acid. Is also good. Tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, or hydroxypropylmethylcellulose phthalate, if necessary.

 Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as purified water , Including ethanol. This composition may contain, in addition to the inert diluent, solubilizing or dissolving aids, auxiliary agents such as wetting agents and suspending agents, sweeteners, flavoring agents, fragrances, and preservatives. .

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of aqueous diluents and suspension diluents include distilled water for injection and physiological saline. As diluents for non-water-soluble solutions and suspensions, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80 (trade name) And so on. Such compositions may further comprise additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing aids. Good. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. These can also be used by preparing a sterile solid composition and dissolving it in sterile water or a sterile injection solvent before use. BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in more detail with reference to Examples. It goes without saying that the present invention is not limited to only the examples. The starting compounds of the present invention also include novel substances. Reference examples are given and their production methods are shown.

Reference example 1

a) 2-Chloro-4-nitrophenol 8.59 g, methyl iodide 4. Ίm £, lium carbonate 10.3 g, tetra-n-butylammonium hydroxide 100 mg, 2-butanone The mixture of 507 ^ was heated to reflux for 3 hours to react. After cooling, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with water and saturated saline, the organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was recrystallized from ether hexane to obtain 8.56 g of 2-chloro-4--2-troisanol.

 Mass spec (m / z): 18 7 (M +)

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard)

 δ: 4.02 (3Η, s), 7.01 (1H, d, J = 9.3), 8.17 (1H, q, J-2. 4, 9.3), 8.29 (1H , d, J = 2.4)

b) 2-Black mouth-4 12 troisole 4 83 g, concentrated hydrochloric acid 3.5 ml £, platinum oxide 150 mg, methanol 10 mixture at room temperature under normal pressure hydrogen atmosphere for 8 hours Stir and react. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and dried. Acetic anhydride (3.0 mL) and chloroform (50) were added to the residue, and triethylamine (7.9) was added dropwise over 5 minutes while stirring at room temperature.

The mixture was further stirred for 2 hours. Dilute the reaction mixture with ethyl acetate and sequentially add water, saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and saturated saline. Washed. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from ether to give 4-chloro-4-methoxyacetanilide (470 g).

 Mass spec (m / z): 199 (M +)

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard)

 δ: 2.02 (3H, s), 3.8K3H, s), 7.08 (1H, d, J = 8.8), 7.40 (1H, q, J = 0.8,8.8), 7.77 (1H, d, J-0.8)

 c) 2.5 nitric acid (d = 1.4) 2.5 Under ice-cooling, 1.0 g of 3____________________ 4 Methoxyacetanilide was added with stirring. The reaction mixture was stirred and reacted for 2 hours while being heated to room temperature. The reaction mixture was added to ice water, and the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain 1.1 g of 5-chloro-4-methoxy1-2-nitroacetoanilide. Mass spec (m / z): 2 4 4 (M +)

Nuclear magnetic resonance spectra (C DC 1 _3, TMS internal standard)

 δ: 2.34 (3H, s), 3.97 (3H, s), 7.73 (lH, s), 8.80 (lH, s)

d) Hydroxidizing room 20

To the mixture of imidazole 347 and 5-Ogone-4-methoxy-2-nitroacetoanilide (50 mg) was added, and the mixture was stirred and reacted at 90 ° C for 1.5 hours. Water was added to the reaction mixture, and the precipitated insoluble material was collected by filtration. Ethyl acetate was added to the filtrate for extraction, and the organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue and the insoluble material collected by filtration were combined, mixed with 5 Q methanol and concentrated hydrochloric acid 3 and heated under reflux for 2 hours.

The reaction mixture was concentrated under reduced pressure, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue is silica Purify by gel column chromatography (elution solvent; black form: methanol: ammonia water = 50: 1: 0.1), and purify 5- (1H-midazo 1-yl) 1 223 mg of 4-methoxy-2-nitroaniline was obtained.

 Mass spec (m / z): 2 3 4 (M +)

Nuclear magnetic resonance spectrum (DMS 0- d _6, TMS internal standard) δ: 3.81 (3H, s ), 7.10 (1H, s), 7.12 (1H, s), 7.47 (lH, s), 7.64 (1 H , S), 8. OKlH.s)

 Reference example 2

 After washing sodium hydride 68 Omg (17.0 mraol) with hexane,

DMF 10 m was suspended and 3.6 g (17.0 mmol) of dimethyl 4-hydroxyphthalate was added. After 10 minutes, add 5-g-fluoro-4-1- (1H-imidazole-1 _yl) -1.5 g (5.6-8 marlol) of 2-nitroacetanilide and stir at 100 ° C for 1 hour. did. After concentrating the reaction solution ', water was added to obtain a powder, which was filtered. The obtained solid was purified by silica gel column chromatography (elution solvent; chloroform: methanol: concentrated ammonia water = 1100: 1: 0.1) to give 4- [2- (1H-imidazole-1). 4-yl-5-acetanilide] Dimethyl oxyphthalate (1.63 g, 63%) was obtained.

 Mass spec (mZz): 4 5 4 (M +)

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard)

δ: 2.27 (3H, s, CH ₃ C0), 3.90 (6H, s.COOMe), 7.19-7.32 (4H, m), 7.81-7.86 (2Η, πι), 8.36 (lH, s), 8.59 (lH, s), 10.52 (lH, s)

 Reference example 3

Sodium hydride 127 mg, DMF Zm £, THF 12, 4-hydroxymethyl benzoate 4 84 mg, 5-fluoro-4 _ (1 H When the reaction was carried out in the same manner as in Reference Example 2 using 70 mg of midazole (1 -yl)-2 -nitroacetanilide, deacetylation also proceeded.

 There was obtained 76 Omg (81%) of methyl [2-(1H-imidazole-1-yl) -4-212throw 5-anilino] oxybenzoate.

Mass spectrometry value (mZz): 3 5 5 ( M + + 1)

Nuclear magnetic resonance spectrum (DMS 0- d _6, TMS internal standard) δ: 3.86 (3H, s , C00Me), 6.53 (lH, s), 7.00 (lH, s), 7.31 (2H, d, J = 8.8 Hz), 7.45 (1H, s), 7.63 (2H, s), 7.91 (1H, s), 8.03 (2H, d, J = 8.8Hz), 8.12 (lH, s)

Reference example 4

 Sodium hydride 1 2 1mg, DMF 8m £, THF 8m £, 3-dimethylaminophenol 4 15mg, 5-fluoro-4-((1H-imidazole-1yl) 1-2-2-nitroacetanilide When 800 mg was used and the reaction was carried out in the same manner as in Reference Example 2, 5- (3-dimethylaminofurinoxy) — 4- (1H-imidazoyl-1-1-yl) —2-acetate 982 mg (85%) of trianilide was obtained.

 Mass spec (mZz): 3 8 2 (M ++ 1)

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard)

δ: 2.23 (3H, s, C0CH 3), 2 · 96 (6H, s, negation _{e 2), 6.37-6.40 (2H,} m), 6. 58-6.62 (1H, m), 7.22 (lH, s ), 7.24-7.33 (1H, m), 7.32-7.33 (lH, m), 7.92 (1H, m), 8.32 (lH, s), 8.49 (lH, s), 10.55 (1H, s, NH)

Reference example 5

Sodium hydride 12 lmg, ethanol 5, THF 5W, 3-hydroxypyridine 288 mg, 5-fluoro-1-4- (1H-imidazole-1-yl) — 2-nitroacetanilide 800 When the reaction was carried out using mg in the same manner as in Reference Example 2, deacetylation also progressed and 4 _ (1 H-imidazoyl 1 _yl) — 5— (3-pyridyloxy) — 2 400 mg (44%) of nitroaniline was obtained.

Mass analysis (m / z): 2 9 8 (M + + 1)

Nuclear magnetic resonance scan Bae-vector (CDC 1 _3, TMS internal standard) δ: 6.17 (lH, s ), 7.17 (1H, s), 7.19 (1H, s), 7.36-7.43 (2H, m), 7

.75 (lH, s), 8.25 (lH, s), 8.43-8.45 (1H, m), 8.52-8.54 (1H, m) Reference example 6

 Sodium hydride 12 1 mg, DMF 10 THF 15, 4- (2-benzyloxycarbonylamidoethyl) phenol 82 2 mg, 5-fluoro-4- (1H-imidazoyl 1-yl) — 2— Nitroacetanilide Using 80 Omg, the reaction was carried out in the same manner as in Reference Example 2 to give 5— [4- (2-benzyloxycarbonylamidoethyl) phenoxy] — 4 -— (1H-imidazole _______________________________________________________ 1.56-g (100%) of 1-2-nitroacetanilide was obtained.

Mass spectrometry value (mZz): 5 1 6 ( M + + 1)

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard) δ: 2.18 (3H, s , C0CH 3), 2.84-2.88 (2H, m), 3.44-3.50 (2H, m), 5. 10 (2H, s), 7.00 (lH, s), 7.02 (1H, s), 7.24-7.34 (9H, m), 7.89 (lH, s), 8.32 (lH, s), 8.40 (lH, s)

Reference example Ί

Sodium hydride 1 2 1 mg, DMF 2 ml, THF 8, 2-Methoxyxycarbonyldithiol phenol 4 16 mg, 5-Fluoro-4- (1 H-Imidazol- 1-yl) _ 2-Ditroacetanilide 80 When 0 mg was used and the reaction was carried out in the same manner as in Reference Example 2, deacetylation also proceeded, and 2 _ [2— (1H—imidazo-1-ru 1-yl) —4-122tro 5-anilino] Methyl thiobenzoate 8 13 mg (72%) was obtained. Mass spec (mZz): 370 (M ⁺ )

Nuclear magnetic resonance spectrum (DMSO- d _6, TMS internal standard) δ: 3.80 (3H, s , COOMe), 6.93 (lH, s), 7.00 (lH, s), 7.22 (lH, s),

7.27-7.30 (lH, m), 7.40-7.45 (lH, ra), 7.51-7.56 (lH, m), 7.65 (1H, s), 7.84-7.88 (lH, m), 7.97 (1H, s)

Reference Example 8

 Sodium hydride 12 1 mg, DMF 6, THF 10, 2-hydroxymethyl benzoate 393 mg, 5-fluoro-4- (1H-imidazole-1-yl) 1-2-2-troacetanilide 800 mg Then, the reaction was carried out in the same manner as in Reference Example 2 to give 2- [2- (1H-imidazo-1-yl-11-yl) -1-4-nitro-5-acetoanilide] methyl benzoate 1.19 g (100 %).

 Mass spec (mZz): 397 (M ++ 1)

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard) δ: 2.20 (3H, s , COCH3), 3.79 (3H, s.COOMe), 7.16-7.18 (2H, ra), 7

.22 (lH, s), 7.41-7.46 (2H, ra), 7.66-7.71 (lH, m), 8.06 (lH, s), 8.12-8.15 (lH, ra), 8.22 (lH, s), 8.3F (lH, s), 10.60 (lH, s)

Reference Example 9

After washing 95 mg (2.37 marl ol) of sodium hydride with hexane, the suspension was suspended in DMF5, and the ice-cooled 4- [5-amino-2- (1H-imidazole-1-y) obtained in Reference Example 3 was obtained. M)-(4- (12-trophenyl) methyl) oxybenzoate (0.65 mg) was added. After 15 minutes, the mixture was added with 0.4 ml of getyloxalate, slowly heated to room temperature, and stirred overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated to dryness. The obtained residue is purified by silica gel column chromatography (solvent). Solvent: Purified with chloroform; 4- [2- (1H-imidazo-nor-1--1-yl)-4--2-tro-5-ethylethyloxalyl anilide] methyl benzoate 5 0 mg (60% was obtained.

 Mass analysis value (m / z): 4 5 5 (M ++ 1)

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard)

 δ: 1.42 (3H, t), 3.93 (3H, s, C00Me), 4.44 (2H, q), 7.15 (lH, d, J = 6.8Hz), 7.23C1H, s), 7.3K1H, s), 7.9 K1H, s), 8.14 (lH, d, J = 6.8Hz), 8.43 (lH, s), 8.53 (lH, s), 12.09 (lH, s)

Reference example 10

At room temperature under argon stream, 121 mg (3.03 ramol) of sodium hydride was suspended in 10 ml of THF, and 46 mg of methyl m-hydroxybenzoate (3.03 related) and DMF 6n ^ were added. added. After 5 minutes, add 5-mg-fluoro-4- (1H-imidazo-1-yl) -1-2-2-troacetanilide 800 mg (3.0 3 ramol), and heat at the same temperature for 30 minutes at 60 ° C. For 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate and water. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; chloroform: methanol: concentrated aqueous ammonia = 100: 1: 0.1) to give 3-[[5-acetamino-2- (1 H-imidazoyl (11-yl)-4- 12-nitrophenyl] oxy] methyl benzoate 1.20 g (100%) was obtained. Mass spec (mZz): 396 (M ⁺ )

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard)

δ: 2.24 (3H, s), 3.92 (3H, s), 7.22 (1H, s), 7.30-7.33 (2H, ra), 7.54 (1H, t, J = 7.8Hz), 7.80 (1H, t, J = 2.4Hz), 7.89 (lH, s), 7.97 (lH, d, J = 7.8Hz), 8.36 (lH, s), 8.48 (lH, s), 10.58 (lH, s) Reference example 1 1

 Sodium hydride 12 lmg, THF 10, DMF34-Methyl mercaptobenzoate 509 mg, 5-Fluoro-4— (1H—Midazo 1-yl-1—yl) 1-2—Nitro The reaction was carried out in the same manner as in Reference Example 10 using 80 mg of cetanilide, and 4-[[5-acetoamino-2- (1H-imidazo-l-l-yl)-4-nitrophenyl] thio] 963 mg (77%) of methyl benzoate was obtained.

Mass analysis (m / z): 4 1 3 (M + + 1)

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard) δ: 2.22 (3H, s ), 3.94 (3H, s), 7.14 (1H, s), 7.23 (lH, s), 7.54 (2

H, d, J = 8.8Hz), 7.67 (1H, s), 8.11 (2H, d, J = 8.8Hz), 8.17 (1H, s), 8.56 (lH, s), 10.43 (lH, s )

Reference example 1 2

 Sodium hydride 1 2 1 mg, THF 10? ^, DMF 4 i, 2-mercaptoimidazole 303 mg, 5-fluoro-4-(1 H-imidazo 1 -yl)-2-nitroacetanilide 80 mg The reaction was carried out in the same manner as in Reference Example 10. The reaction was carried out in the same manner as in Reference Example 10; 4— (1H—imidazo—11—yl) —5 — [(1H—imidazo—2—yl) thio] —2—Nitroacetanilide 737 mg (71%) were obtained.

Mass spec (mZz): 4 4 4 (M ⁺ )

Nuclear magnetic resonance spectrum (DMS 0_ d _6, TMS internal standard) δ: 2.01 (3H, s ), 7.03 (lH, s), 7.17 (lH, s), 7.24 (1H, s), 7.50 (1 H, s), 7.51 (lH, s), 7.96 (lH, s), 8.01 (lH, s), 10.43 (lH, s), 13.04 (1H, s)

Reference Example 1 3

THF 1 m £ ^ DMF 4 5-Mercapto-1 1-Methyltetra Sodium sodium monohydrate 4 19 mg, 5-fluoro-4- (1H-imidazole-11-yl) 12-2-nitroacetanilide Using 80 Om, as in Reference Example 10 The reaction was carried out and 4— (1H—imidazole—11-yl) 1—5 — [(1-methyltetrazol-5-yl) thio] —2-nitroacetoanilide 34 Omg (31 %).

 Mass spectrometry (m / z): 360 (M +)

Nuclear magnetic resonance spectrum (DMS 0- d _6, TMS internal standard) δ: 2.06 (3H, s ), 3.94 (3H, s), 7.13 (1H, s), 7.46-7.48 (1H, m), 7. 51 (lH, s), 7.97 (lH, s), 8.ll (lH, s), 10.44 (1H, s)

Reference example 1 4

 Sodium hydride 121 mg, THF 15 m, DMF 1 rd ^ 3-mercapto-5-methyl_1,3,4-thiadiazole 400 mg, 5-fluoro-41 (1H-imidazolu-l The reaction was carried out in the same manner as in Reference Example 10 using 80 mg of 12-nitroacetanilide, and 4- (1H-imidazoyl-1-yl) 1-5- [(5-Methyl-1,

3,4-thiadiazol-2-yl) thio] —2-nitroacetanilide 1.055 g (93%) was obtained.

Mass spec (mZz): 3 76 (M ⁺ )

Nuclear magnetic resonance scan Bae-vector (CDC 1 _3, TMS internal standard)

 δ: 2.29 (3H, s), 2.82 (3H, s), 7.12 (1H, s), 7.21 (1H, s), 7.64 (1

H, s), 8.22 (1H, s), 8.98 (lH, s), 10.40 (lH, s)

Reference example 1 5

At room temperature under a stream of argon, 121 mg (3.0 3 mmol) of sodium hydride was suspended in THF 1, and 285 mg (3.0 3 cited ol) of phenol and DMF 6 were added. After 5 minutes, 5-fluoro-41 (1H-imidazo-l-yl) 1-2-nitroacetanilide 80 Omg (3.0 3 mmol) and stirred at 60 ° C for 1 hour. The reaction solution was concentrated under reduced pressure, 3N hydrochloric acid 3 ^ and methanol 3 were added to the residue, and the mixture was refluxed under heating for 2.5 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the obtained residue was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with chloroform. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: solvent: methanol: concentrated aqueous ammonia = 100: 1.5: 0.15) to give 4- (1H-imidazole-1-yl) — 2-— 88.8 mg (9.9%) of 2-nitro-5-phenoxyaniline were obtained. Mass spec (mZz): 296 (M ⁺ )

Nuclear magnetic resonance spectrum (DMSO_d _6, TMS internal standard) δ: 6.37 (lH, s ), 7.04 (1H, s), 7.24 (1H, s), 7.25 (2H, d, J = 0.9Hz), 7.32 ( 2H, t, J-lOHz), 7.50 (2H, dt, J-0.9, 10Hz), 7.62 (2H, bs), 7.96 (lH, s), 8.0K1H, s)

Reference Example 1 6

 a) Under ice-cooling, 3.30 g (11.6 mmol) of methyl 4-[(4-acetoamino-2-fluorophenyl) oxy] valerate was added to 60% nitric acid with stirring. The internal temperature of the reaction mixture was raised to room temperature and stirred for 10 minutes. The reaction mixture was poured into ice-water and extracted with black form. The organic layer was separated, washed successively with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent; hexane: drunk acid = 5: 1) to give 4-[(4-acetoamino-2-fluoro-5-nitrophenyl) oxy. 3.21 g (86%) of methyl valerate was obtained.

Mass spec (mZz): 3 2 8 (M ⁺ ) Nuclear magnetic resonance spectrum (CDC 13, TMS internal standard)

 δ: 1.83-1.92 (4H, m), 2.28 (3H, s), 2.42 (2H, t, d = 6.8Hz), 3.69 (3H, s), 4.08 (2H, t, J = 5.8Hz), 7.79 (1H, d, J-4.6Hz), 8.66 (lH, d, J = l 3.2Hz), 10.38 (lH, s)

b) A mixture of 1.97 g (6.0 關 ol) of methyl valerate, imidazole (14.4 ol) and benzene 20 W of 4-[(4-acetamino- 12_fluoro-5-nitrophenyl) oxy] The mixture was heated under reflux for 20 hours. After cooling, the reaction mixture was diluted with chloroform, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent; chloroform: methanol: concentrated aqueous ammonia = 100: 2: 0.2), and 4 _ [[4-acetamino-2- (1 There were obtained 2.22 g (98%) of methyl H-imidazole-11-yl-5-nitrophenyl] oxy] valerate.

 Mass spec (mZz): 3 7 6 (M +)

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard)

 δ: 1.74-1.81 (2H, m), 1.85-1.92 (2H, m), 2.33 (3H, s), 2.38 (2H, t, d = 7.4Hz), 4.12 (2H, t, d = 4.3Hz) , 7.19 (lH, s), 7.36 (1H, s), 7.85 (lH, s), 8.02 (1H, s), 8.89 (lH, s), 10.29 (lH, s)

REFERENCE EXAMPLE 1 7'a) A mixture of 60% nitric acid 2Qi and black mouth form 20m £ was stirred at an internal temperature of 5 ° C or less while stirring N- [3-fluoro-41-[(4-methoxycarbonitrile). To the mixture was added 2.01 g (5.34 ol) of the mixture, and the mixture was stirred at the same temperature for 10 minutes and at 10 ° C or lower for 1 hour. The reaction mixture was poured into ice water and extracted with black-mouthed form. The organic layer was separated, washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated saline, and It was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (elution solvent; black form: methanol: concentrated aqueous ammonia = 100: 0.5: 0.05) to give N- [5-fluoro-41-[(4 -Methoxycarbonylphenyl) methoxy] —2-ditrophenyl] ethyl oxamate 2.0 5 g

(9 1%).

Mass spectrometry value (mZz): 4 2 1 ( M + + 1)

Nuclear magnetic resonance scan Bae-vector (CDC 1 _3, TMS internal standard)

 δ: 1.45 (3H, t, J = 6.8Ηζ), 3.93 (3H, s), 4.41 (2H, q, J = 6.8Hz), 5.26 (2H, s), 7.53 (1H, d, J = 7.8Hz), 7.93 (1H, d, J = 8.3Hz), 8.08 (2H, d, J = 8.3Hz), 8.72 (2H, d, J = 8.3Hz), 11.93 (lH, s)

b) N- [5-Fluoro-4-[(4-methoxycarbonylphenyl) methoxy] —2-ditrophenyl] oxaminate 2.03 g (4.83 mmol), imidazole 6.58 mg (9.6 7 mmol) and benzene 45, and N- [51- (1H-imidazole-11-yl) 1-41-[(4 1.83 g (81%) of —methoxy-2-carbonyl) methoxy] —2-ditrophenyl] oxamate was obtained.

 Mass spec (mZz): 4 6 8 (M +)

Nuclear magnetic resonance scan Bae-vector (CDC 1 _3, TMS internal standard)

 δ: 1.46 (3H, t, J-6.8Hz), 3.93 (3H, s), 4.47 (2H, q, J = 6.8Hz), 5.29 (2H, s), 7.22 (1H, s), 7.38 (1H, s), 7.42 (1H, s), 7.44 (lH, s), 8.04 (2H, d, J = 8.5Hz), 8.06 (2H, d, J = 8.6Hz), 8.97 (1H, s), 11.87 (lH, s) Reference example 1 8

a) 2-[(4-acetamino-2-fluorophenyl) oxy] ethyl acetate 2.25 g (8.81 ol), 60% nitric acid 1 Using the same method as in item a) of Example 16, 2.40 g (91%) of 2-[(4-acetoamino-2-fluoro-5-nitrophenyl) oxy] ethyl acetate was obtained.

Mass spec (m / z): 300 (M ⁺ )

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard)

 <5: 1.32 (3H, t, J = 15Hz), 2.29 (3H, s), 2.29 (2H, t, d = 15Hz), 4.73 (2H, s), 7.82 (1H, d, J-8.3Hz) , 8.71 (lH, d, J = 13.2 Hz), 10.40 (lH, s) b) 2-[(4-acetamino- 12-fluoro-5-nitrophenyl) oxy] ethyl acetate 2.40 g (7.9 9 mmol), Using imidazole 1.20 g (17.6 marl ol) and benzene 4, in the same manner as in item b) of Reference Example 16, 2 — [(4-acetoamino-2- (1H-imidazole-11-yl) — 5- (2-trifluorophenyl) oxy] ethyl acetate (2.69 g, 97%) was obtained.

 Mass spec (mZz): 348 (M +)

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard) δ: 1.32 (3H, t , J = 7.3Hz), 2.31 (3H, s), 4.29 (2H, q, J = 7.3Hz), 4. 76 (2H, s), 7.2K1H, s), 7.46 (1H, s), 7.80 (lH, s), 8.12 (1H, s), 8.95 (lH, s), 10.32 (1H, s)

Reference Example 1 9

a) A method similar to item a) in Reference Example 16 using 3.11 g (11.0 mmol) of 4-[(4-aminophenyl-2-fluorophenyl) oxybutyrate and 60% nitric acid 2 Then, 3.25 g (90%) of ethyl 4-([4-acetoamino-2-fluoro-5-nitrophenyl) oxy] butyrate was obtained.

Mass spectrometry value (mZz): 32 9 (M + + 1)

Nuclear magnetic resonance spectrum (CDC13, TMS internal standard) δ: 1.27 (3H, t, J = 7.1Hz), 2.17 (2H, dt, J = 6.6, 7.0Hz), 2.25 (3H, s), 2.55 (2H, t, J = 7.0Hz), 4.10-4.19 (4H, m), 7.80 (1H, d, J = 8.3Hz), 8.65 (lH, d, J = 13.2Hz), 10.37 (lH, s)

b) 4 — [(4-Acetamino-2-fluoro-5-nitrophenyl) oxy] ethyl butyrate 2.30 g (7.0 lmmol), imidazole

1. Using 16 g (17 marl ol) and benzene 30 in the same manner as in item b) of Reference Example 16, 4 — [(4-acetoamino-2— (1H—imidazole-1 —Yl) —5-nitrophenyl) oxy] ethyl ethyl butyrate (2.03 g, 77%) was obtained.

 Mass spec (mZz): 3 7 6 (M +)

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard)

 δ: 1.26 (3H, t, J = 7.2Hz), 2.16 (2Η, dt, J-6.8, 7.1Hz), 2.03 (3H, s), 2.46 (2H, t, J-7.1Hz), 4.11-4.19 (4H, m), 7.20 (1H, s), 7.35 (1H, s), 7.88 (lH, s), 8.00 (lH, s), 8.90 (lH, s), 10.30 (lH, s) Reference example 2 0

a) In an ice-methanol bath, add concentrated sulfuric acid 15 i to N- [3-fluoro-4-[(4-methoxycarbonylcarbonyl) thio] phenyl] ethyl ethyl oxamate 1.0 g (2. 6 5 marauder ol) was added. Under stirring, fuming nitric acid 0.4 was added dropwise. After stirring at the same temperature for 1 hour, the reaction mixture was poured into ice-water and extracted with black hole form. The organic layer was separated, washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; black form: methanol: aqueous ammonia = 1100: 0.25: 0.025) to give N— [5-fluoro-4-. [977] (977 mg, 84%) of [(4-Methoxycarbonyl) sulfenyl] -2-ditrophenyl] oxamate was obtained. Mass analysis (m / z): 4 3 9 (M + + 1)

Nuclear magnetic resonance scan Bae-vector (CDC 1 _3, TMS internal standard)

 δ: 1.45 (3H, t, J = 7.1Hz), 3.93 (3H, s), 4.47 (2H, q, J = 7.1Hz), 7.

83 (2H, d, J = 13.3Hz), 8.15-8.18 (1H, m), 8.70 (lH, d, J = 9.2Hz), 8.87 (lH, d, J = 7.1Hz), 12.15 (lH, s )

b) N- [5-Fluoro-4-[(4-methoxycarbonylphenyl) sulfenyl] -12-nitrophenyl] oxamate

Using 94.7 mg (2.16 rec. Ol), imidazole 29.4 mg (432 mmol), and benzene 3, N- [5- (1H— There was obtained 580 mg (55%) of imidazo 1-yl) 1-4-[(4-methoxycarbonyldiphenyl) sulfanyl] -12-nitrophenyl] oxoxamate.

 Mass spec (mZz): 487 (M ++ 1)

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard)

 δ 1.45 (3H, t, J = 6.9Hz), 3.90 (3H, s), 4.47 (2Η, q, J = 6.9Hz), 7.

09-7.13 (2H, m), 7.31 (lH, s), 7.64 (lH, s), 7.98 (1H, dd, J = l.9, 6.8Hz), 8.86 (1H, s), 9.13 (lH , S), 12.10 (lH, s)

Reference Example 2 1

a) A mixture of 2.0 g (5.5 4 mmol) of N- [3-fluoro-41-[(4-methoxycarbonylphenyl) oxy] phenyl] oxamate and the form 3 of ethyl acetate was added under cooling with ice to a mixture of 60 g. % Nitric acid 157 ^ was added and stirred. The reaction mixture was warmed to room temperature, fuming nitric acid 0.3 / ^ was added dropwise, and stirred for 1.5 hours. The reaction mixture was poured into ice water and extracted with black-mouthed form. The organic layer was separated, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue is subjected to silica gel column chromatography (elution solvent: Loroform: Methanol: Ammonia water = 100: 0.5: 0.05) Purified with N- [3-Fluoro-4-[(4-Methoxycarbonylphenyl) oxy] 16-Nitrophenyl] oxami 1.72 g (77%) of ethyl ester were obtained.

Mass spectrometry value (mZz): 4 0 7 ( M + + 1)

Nuclear magnetic resonance scan Bae-vector (C DC 1 _3, TMS internal standard)

 δ: 1.7 (3H, t, J-7.9Hz), 3.92 (3H, s), 4.48 (2H, q, J-7.9Hz), 7.02 (2H, dt, J = 2.5, 10Hz), 8.06 (2H, dt, J = 2.5, 10Hz), 8.11 (1H, d, J = ll .8Hz), 8.83 (1H, d, J-12.7Hz), 12.01 (2H, s)

b) N- [3-Fluoro-41-((4-methoxycarbonylphenyl) oxy] -16-2-trophenyl] oxamic acid ethyl 1.70 g (4.18 mmol), imidazole 627 mg (9.20 mmol) and benzene 25 »^ in the same manner as in item b) of Reference Example 16 to obtain N— [5— (1H—imidazo-1-ru 1-yl) —4— [ This yielded 1.69 g (89%) of (4-Methoxycarbonyl) oxy]-[2-nitrophenyl] oxamic acid ethyl ester.

Mass spec (m / z): 4 5 4 (M ⁺ )

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard)

 δ 1.47 (3H, t, J = 7.1Hz), 3.92 (3H, s), 4.49 (2H, q, J = 7.1Hz), 6.99- 7.03 (2H, in), 7.19 (lH, s), 7.37 (1H, d, J = 6.9Hz), 8.02 (lH, s), 8.06 (lH, s), 8.07 (lH, d, J = 10Hz), 9.10 (1H, s), 11.95 (lH, s) Reference example 2 2

Under a stream of argon, to a mixture of 75 mg (1.87 mmol) of sodium hydride and ethanol 1 of THF was added ethyl mercaptoacetate 205/1 (1.87 mmol) under ice-cooling, followed by stirring. After 5 minutes, 5—Fluoro 4- (1H—imidazole—11-yl) -12-Nitroacetate Add 449 mg (1.70 ol) of anilide and stir at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and ethyl acetate and water were added to the residue to separate the extracted organic layer _{c. The} organic layer was washed with saturated aqueous ammonium chloride and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. . The obtained residue was purified by silica gel column chromatography (elution solvent; black form: methanol: concentrated aqueous ammonia = 75: 1: 0.1) to give 2 — [[5-acetamino-2 -— (1 H- imidazole - 1-I le) one 4 two Torofuweniru] Chio] acetate Echiru 5 4 0 mg (8 8% ) c mass spectrometry value was obtained (m / z): 3 6 5 (M + + 1)

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard)

 δ: 1.30 (3H, t, J = 7Hz), 2.34 (3H, s), 3.78 (2H, s), 4.25 (2H, q, J = 7Hz), 7.13 (1H, s), 7.24 (1H, s) ), 7.66 (lH, s), 8.13 (1H, s), 8.97 (1H, s), 10.61 (lH, s)

Reference Example 2 3

 Sodium hydride 227 mg, THF 10, ethanol 1 Qm £, cyclopentenethiol 638 £, 5-fluoro-4- (1 H-imidazole-1-yl)-2-nitroacetanilide 1.5 Using 0 g, the reaction was carried out in the same manner as in Reference Example 10 to obtain 4- (1H-imidazole-1-1-yl) -15- (cyclopentyl) thio-12-nitroaniline 1.643 g ( 95%).

Mass spectrometry value (m / z): 304 ( ⁺ )

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard)

δ: 1.56-1.68 (4H, m), 1.70-1.76 (2H, m), 2.11-2.17 (2H, m), 3.4 9-3.55 (1H, m), 6.40 (2H, bs), 6.67 (lH, s), 7.03 (lH, s), 7.19 (lH, s), 7.57 (lH, s), 8.01 (lH, s) Reference example 2 4

a) Under ice-cooling, 1.27 g (4.89 marl ol) of 3-fluoro-4-benzyloxycetanilide was added to 7% of 60% nitric acid and stirred. The reaction mixture was warmed to room temperature and stirred for 10 minutes. The reaction mixture was poured into ice water and extracted with black-mouthed form. The organic layer was separated, washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl form: ethyl acetate = 3: 1: 1), and 5-fluoro-4-benzyloxy1-2-2-troacetanilide 1.37 g ( 9 2%).

Mass spec (mZz): 304 (M ⁺ )

 Nuclear magnetic resonance spectrum (CDC13, TMS internal standard)

 δ: 2.30 (3Η, s), 5.17 (2H, s), 7.33-7.45 (5H, m), 7.87 (lH, d, J = 8 Hz), 8.68 (lH, d, J = 14 Hz), 10.37 ( 1H, s)

b) Using 1.33 g (4.37 mmol) of 5-fluoro-4-benzyloxy-2-nitroacetoanilide, 5.55 mg (9.6 1 mmol) of imidazole, and benzene 2, paragraph b) of Reference Example 16 In the same manner as in the above, 1.19 g (84%) of 5- (1H-imidazo-l-l-yl) -14-benziloxy-l-2-nitroacetanilide was obtained.

 Mass spectrometry value (mZ z): 3 5 3 (M ++ 1)

Nuclear magnetic resonance scan Bae-vector (DMSO- d _6, TMS internal standard) δ: 2.06 (3H, s ), 5.30 (2H, s), 7.09 (1H, d, J = l.5Hz), 7.32-7.45 ( 5H, m), 7.57 (1H, t, J = l.5Hz), 7.69 (1H, d, J = 5.3Hz), 7.91 (lH, s), 8.06 (lH, s), 10.23 (1H, s)

Reference Example 2 5

Sodium hydride 0.46 g (60%, 1 2 After washing the thigh ol) with hexane, a mixture of DMF 2 Οτ ^ was added, and with stirring, 1.93 g (9.84 bandol ol) of 4-hydroxy-3-methoxybenzoic acid ethyl was added. After the generation of hydrogen gas ceased, under ice-cooling, add 4-g (4.5-bandol ol) of 4- (1H-imidazo-1-yl) -5-fluoro-2-nitroacetanilide The temperature was gradually raised to room temperature.

After 1 hour, the reaction mixture is concentrated under reduced pressure, water is added to the obtained residue, and the obtained residue is washed with water to give 4-[[5-acetoamino-2- (1H-imidazole-11-yl). 1.52 g (80%) of ethyl 4-ethyl] benzoate-3- (3-methoxybenzoate) was obtained.

 Mass spectrometry value (mZz): 440 (M +)

Nuclear magnetic resonance spectrum (DMS 0_ d _6, TMS internal standard)

 <5: 1.34 (3H, t), 2.02 (3H, s), 3.83 (3H, s), 4.35 (2H, q), 7.11 (1H, s), 7.18 (lH, s), 7.46 (1H, d), 7.46-7.71 (3H, m), 8.ll (lH, s), 8.21 (lH, s), 10.29 (1H, s)

Reference Example 2 6

Under an argon stream at room temperature, 0.46 g (60%, 12 mmol) of sodium hydride was washed with hexane, and then a mixture of DMF 2 was added. The mixture was stirred while stirring. 1.58 g (9.86 mmol) of phenol was added. After hydrogen gas generation ceased, 2.0 g (7.5 7 mmol) of 4- (1-H-imidazole-11-yl) -5-fluoro-2-nitroacetanilide was added under ice-cooling, and the temperature was gradually raised to room temperature. Temperature. One hour later, water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate 5. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; solvent: chloroform: methanol: 28% ammonia = 25: 1: 0.1) to give 5- [4- (1H-imidazole-1). Ill) Huenoki シ] — 4_ (1 H—imidazo-1-yl) — 2-nitroacetanilide 2.7 g (88%). This was made into 1N hydrochloric acid 5 solution and refluxed for 2 hours. The reaction mixture was cooled on ice and the resulting crystals were collected by filtration to give 5- [4- (1H-imidazole-1-yl) phenoxy] —4- (1H-imidazole-1-yl) -12-nitroaniline · 2 2.7 g (93%) of the hydrochloride were obtained.

 Mass spec (mZz): 362 (M +)

Nuclear magnetic resonance spectrum (DMSO- d _6, TMS internal standard) δ: 6.54 (lH, s ), 7.58-7.61 (2H, m), 7.87 (3H, m), 7.95 (lH, s), 8 .01 (lH, t), 8.04 (lH, t), 8.12 (lH, t), 8.35 (lH, d), 8.51 (lH, s), 9.6K1H, s), 9.86 (lH, s)

Reference Example 27

 0.57 g (60%, 143 mmol) of sodium hydride was used as a mixture of 10 mL of THF and DMF 2, and 2.70 g (13.5 related ol) of 4-hydroxy-2-chloroethyl benzoate was added with stirring. After the generation of hydrogen gas ceased, 4.00 g (11.4 t ol) of 4- (1H-imidazole-1-11) -15-fluoro-2-nitroacetanilide was added, and the temperature was raised to 60 ° C. . After 2 hours and 30 minutes, the reaction mixture is concentrated under reduced pressure, water is added to the obtained residue, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography, and purified with 4-[[5-acetamino-2- (1H-imidazole-11-yl)-4-nitrophenyl]. 1.10 g (22%) of ethyl 2-benzoate.

 Mass spec (mZz): 445 (M ++ 1)

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard) δ: 1.40 (3H, t), 2.29 (3H, s), 4.39 (2H, q), 7.02 (lH, dd), 7.14 (lH, d), 7.20-7.27 (2H, m), 7.83 (1H, s), 7.96 (1H, d), 8.37 (lH, s), 8.63 (lH, s), 10.55 (lH, s)

Reference Example 2 8

 Sodium hydride 1 2 1 mg, THF 10, DMF Z i, 4-hydroxybenzonitrinole 36 1 nig, 5-fluo-41- (1H-midazo-l-yl) The reaction was carried out in the same manner as in Reference Example 15 using 800 mg of 1,2-nitroacetanilide, and 4-[[5_amino-2-((1H_imidazoyl 1-yl)) — 4— Nitrophenyl] oxy] benzonitrile 875 mg (90%) was obtained.

 Mass spec (mZz): 3 2 1 (M +)

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard)

 δ: 6.54 (lH, s), 6.70 (1H, s), 7.40 (2H, dt, J-2.0, 9.0Hz), 7.45 (1H, s), 7.67 (2H, s), 7.90 (1H, s) , 7.95 (2H, dt, J = 2.0, 9.0Hz), 8.12 (lH, s) ,.

Reference Example 2 9

 Sodium hydride 8 1 mg, THF 3 Ora. DMF 155 -Hydroxyindole-2-methyl carboxylate 386 mg, 5-Fluoro 41 (1 H-imidazo 1-yl)-2 The reaction was carried out in the same manner as in Reference Example 2 using 53.4 mg of 2-nitroacetanilide, and 5 — [[5-acetamino-2— (1H—imidazo-1-ru 1-yl) —4—2 trophenyl [Doxy] indole-1-2-methyl ribonate 88.8 mg (100%) was obtained.

 Mass spec (m / z): 4 3 5 (M +)

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard)

δ: 2.19 (3H, s), 3.95 (3H, s), 7.07 (1H, dd, J = l.9, 8.0Hz), 7.19 (lH, s), 7.67 (2H, s), 7.90 (1H, s), 7.24-7.27 (2H, m), 7.36 (lH, s), 7.41 (lH, d, J = l.9Hz), 7.48 (lH, d, J = 8.8Hz), 7.96 (lH, s), 8.34 (1H, s), 8.43 (lH, s), 9.24 (1H, s), 10.58 (1H, s),.

Reference example 30

a) 60% nitric acid 15m, fuming nitric acid 0.5, black form 70, N- [3-fluoro-41- (4-cyanoenoxy) phenyl] ethyl ethyl oxamate 2.5 35 g (7.7 2 bandol ol ), And in the same manner as in item a) of Reference Example 17, N- [5-fluoro-4- (4-cyanophenoxy)-2-ditrophenyl] oxethylate 2.29 g (79% ).

 Mass spec (mZz): 3 7 3 (M +)

Nuclear magnetic resonance scan Bae-vector (CDC 1 _3, TMS internal standard) δ: 1. 7 (3H, t, J = 7.3Hz), 4.49 (2Η, q, J = 7.3Hz), 7.06 (2H, d, J = 9.1 1Hz), 7.68 (2H, d, J = 9.1Hz), 8.16 (1H, d, 1 = 1.1Hz), 8.86 (1H, d, J = 12.2Hz), 7.41 (lH, d, J = l.9Hz), 7.48 (lH, d, J-8.8Hz), 7.96 (lH, s), 8.34 (1H, s), 12.02 (1H, s) ,.

b) N— [5-Fluoro 4- (4-cyanophenoxy) 1-2-2-trophenyl] oxaminate 2.29 g (6.12 ol), imidazole 920 mg, toluene 2 Using 5 ml, in the same manner as in item b) of Reference Example 16, N— [5— (1H—imidazole—11-yl) —4 -— (4-cyanophenoxy) 1.62 g (63%) of 2-ethyl [2-nitrophenyl] oxamate was obtained.

Mass spectrometry value (mZz): 4 2 2 ( M + + 1)

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard) δ: 1.47 (3H, t , J = l.7Hz), 4.48 (2H, q, J = l.7Hz), 7.04 (2H, d, J = 9.

2Hz), 7.18 (1H, s), 7.34 (1H, s), 7.66 (2H, d, J = 9.2Hz), 7.97 (1H, s) , 8.13 (lH, s), 9.13 (1H, s), 12.00 (lH, s) ,.

Reference example 3 1

a) Using 60% nitric acid 20m £, fuming nitric acid 0.5 black form 60, N- [3-fluoro-4-benzyloxyphenyl] oxamic acid 41177 g (13.Ommol) In the same manner as in item a) of Reference Example 17, 448 g (95%) of ethyl N- [5-fluoro-4-benzyloxy-2-nitrophenyl] oxaminate was obtained.

 Mass spec (m / z): 36 2 (M +)

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard)

 δ: 1.45 (3H, t, J = 7.0Hz), 4.47 (2Η, q, J = 7.0Hz), 5.20 (2H, s), 7.

33-7.45 (5H, m), 7.95 (1H, d, J = 8.0Hz), 8.68 (1H, d, J = ll.8Hz), 11.9 l (lH, s) ,.

b) Using 1.28 g (3.5 3 mmol) of N- [5-fluoro-4-1-benzyloxy-2-nitrophenyl] oxaminate, 3.55 mmol of imidazole and toluene 2 to obtain b) of b) of Reference Example 16 In the same manner as described in the section, 8-18 mg (57%) of N- [5- (1H-imidazole-1-yl) -4-benzyloxy-2-ditrophenyl] oxaminate was obtained. .

Mass spectrometry value (m / z): 410 (M ⁺ )

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard)

 δ: 1.46 (3H, t, J-7.0Hz), 4.47 (2H, q, J = 7.OHz), 5.24 (2H, s), 7.18 (lH, s), 7.34-7.42 (6H, m ), 8.056 (1H, s), 8.061 (lH, s), 8.95 (1H, s), 12.13 (1H, s) ,.

Reference example 3 2

0.34 g (60%, 8.5 mmol) of sodium hydride was made into a suspension of THF 10 W, and 4-hydroxy-3-methylbenzoic acid was added with stirring. 1.55 g (8.5fflmol) of ethyl ester in DMF solution 3 was added. After the generation of hydrogen gas ceased, 2.00 g (7.6 related ol) of 4- (1H-imidazole-1-11) -15-fluoro-2-nitroacetanilide was added, and 80 The temperature was raised to ° C. After 40 minutes, the reaction mixture is concentrated under reduced pressure, water is added to the obtained residue, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by silica gel column chromatography, and the residue is purified with 4-[[5-acetoamino-2- (1H-imidazole_1-yl) -14-nitrophenyl] oxy. 3.4 g (100%) of ethyl 3-methylbenzoate was obtained.

Mass spectrometry value (mZz): 4 2 5 ( M + + 1)

 Nuclear magnetic resonance spectrum (CDC13, TMS internal standard)

δ: 1.40 (3H, t,

, 2.23 (3H, s), 2.24 (3H, s), 4.37 (2H, q, J = 7.1Hz), 7.03 (1H, d, J = 8.3Hz), 7.24-7.30 (2H, m), 7.90 ( lH, s), 7.95-7.97 (1H, m), 8.02 (1H, s), 8.37 (2H, m), 10.57 (lH, s).

Reference example 3 3

0.34 g (60%, 8.5 mmol) of sodium hydride was made into a suspension of 10 mL of THF, and while stirring, DMF of 1.70 g (8.5 mmol) of 4-hydroxy-3-cycloethyl benzoate was added. Solution 3 was added. After the generation of hydrogen gas has ceased, add 2.0 g (7.6 mmol) of 4- (1H-imidazo-1-yl) -5-fluoro-2-nitroacetanilide, and add 80 ° C. The temperature rose. After 40 minutes, the reaction mixture is concentrated under reduced pressure, water is added to the obtained residue, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography, and purified by silica gel chromatography [4-acetoamino-21- (1H-imidazole-11-yl) -4-nitrophenyl] oxo. 3.3-g (9.9%) of ethyl benzoate was obtained. Mass spectrometry value (mZ z): 444 (M + + 1)

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard)

 δ: 1.41 (3H, t, J = 7.1Hz), 2.25 (3H, s), 4.40 (2H, q, J-7.1Hz), 7.

22 (1H, d, J = 8.8Hz), 7.23 (1H, s), 7.36 (1H, s), 7.95 (lH, s), 8.05 (1H, dd, J = 2.0, 8.8Hz), 8.22 ( lH, d, J-2.0Hz), 8.37 (lH, s), 8.39 (lH, s

), 10.60 (lH, s).

Reference example 34

 A suspension of 0.25 g of sodium hydride (60%, 6.3 liters) in THF was added to a DMF solution 2 of 1.14 g (8.5 mniol) of methyl 4-hydroxy-2-methoxybenzoate while stirring. After hydrogen gas generation stops, add 4_ (1H-imidazole-1-yl) -5-fluoro-2-nitroacetanilide 1.50 g (5.7 bandol) and raise the temperature to 80 ° C did. After 40 minutes, the reaction mixture is concentrated under reduced pressure, water is added to the obtained residue, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography, and purified by silica gel column chromatography [4- [5-acetamino-121- (1H-imidazole-1-1-yl)-4-nitrophenyl] olefin. 3.4 g (62%) of methyl 3-methoxybenzoate was obtained.

 Mass spec (mZz): 427 (M ++ 1)

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard)

 δ: 2.26 (3H, s), 3.88 (3H, s), 3.89 (3H, s), 6.65 (lH, dd, J = l.8, 8.5Hz), 6.7K1H, d, J = l.8Hz ), 7.21 (lH, s), 7.26 (1H, s), 7.86 (lH, s), 7.91 (lH, d, J = 8.5 Hz), 8.35 (lH, s), 8.60 (lH, s), 10.51 (lH, s). Reference Example 35

N- [5-Fluoro-4 -— [(4-ethoxycarbonylphenyl) oxy] —2-ditrophenyl] oxamic acid 2.00 g (4.5 mmol) and 0.80 g (0.98 mraol) of 4-methylimidazole were heated under reflux for 3 hours. After cooling, the reaction mixture was diluted with chloroform, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and N- [5- (4-methyl-1H-imidazole-1-1yl) -14-[(4-ethoxycarbonylphenyl) oxy] There was obtained 1.20 g (53%) of ethyl 2- (2-trophenyl) oxaminate.

Mass spectrometry value (mZz): 4 8 3 ( M + + 1)

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard)

δ: 1.40 (3H, t,

, 2.25 (3H, s), 4.38 (2H, q, J = 7.1Hz), 4.49 (lH, q, J = 7.1Hz), 7.01 (2H, d, J = 9.0Hz), 7.03 ( lH, s), 7.95 (1H, s), 8.02 (1H, s), 8.07 (2H, d, J = 9.0Hz), 9.06 (1H, s).

Reference Example 3 6

 a) In a bath of ice-methanol, a solution of 1.29 g (3.2 mmol) of N- [3-fluoro-4-[[(4-methoxycarbonylcarbonyl) sulfonyl] phenyl] oxamate in concentrated sulfuric acid at 20 ml. 0.5 f of fuming nitric acid was added dropwise. After stirring for 30 minutes, the reaction mixture was poured into iced water and extracted with black hole form. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 0.90 g (63%) of N- [5-fluoro-4-[(4-methoxycarbonyldiphenyl) sulfonyl] phenyl] oxaminate ethyl ester. .

Mass spectrometry value (mZz): 4 5 5 ( M + + 1)

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard) δ: 1.45C3H, t, J = 7.0Hz), 3.96 (3H, s), 4.47 (2H, q, J-7.0Hz), 8.ll (2H, d, J = 8.0Hz), 8.23 (2H, d, J = 8.0Hz), 8.74 (1H, d, J = ll.7Hz), 9.10C1H, d, 7.8Hz), 12.23 (111, s).

b) N- [5-Fluoro-4-[(4-methoxycarbonylphenyl) sulfonyl] phenyl] ethyl oxamate 0.87 g (1.9 ol) imidazole 260 mg DMF solution 30 The mixture was heated and stirred at 100 ° C. overnight. After cooling, the reaction mixture is concentrated under reduced pressure, water is added to the obtained residue, extracted with chloroform, washed with brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give N— [5- (1H-imidazoyl-1-1yl) —4 -— ((4-methoxycarbonyl) 650 mg (68%) of ethyl) sulfonyl] phenyl] oxamate.

 Mass spec (mZz): 503 (M +)

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard) δ: 1.46 (3Η, t , J-7.0Hz), 3.94 (3H, s), 4.47 (2H, q, J = 7.0Hz), 5. 24 (2H, s), 7.18 (lH, s), 7.34-7.42 (6H, m), 8.056 (1H, s), 8.06K1H, s), 8.95 (lH, s), 12.13 (1H, s).

Reference Example 3 7

N- [3-Fluoro-4-[(4-methoxycarbonyl-2-pyridyl) oxy] phenyl] ethyl oxamate 0.77 g (2.1 mmol) in concentrated sulfuric acid in an ice-methanol bath 1 Q 0.3 ml of fuming nitric acid was added dropwise to the ml. After stirring for 30 minutes, the reaction mixture was poured into ice water, and the precipitate was filtered. To the precipitate was added a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with black hole form. The organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and concentrated under reduced pressure to give N- [5-fluoro-4-1 [(4-methoxycarbonyl). There was obtained 0.79 g (91%) of ethyl 2-ethylpyridyl) oxy] phenylsuccinate.

 Mass spec (m / z): 408 (M ++ 1)

Nuclear magnetic resonance spectrum (CDC 1 _3, TMS internal standard)

 δ: 1.47 (3H, t, J = 7. OHz), 3.89 (3H, s), 4.50 (2H, q, J = 7.0Hz), 6.

67 (1H, d, J-9.8Hz), 7.97 (1H, dd, J = 2.4, 9.8Hz), 8.13 (1H, d, J-2.4Hz)

), 8.45 (1H, d, J-8.3Hz), 8.91 (1H, d, J = 12.2Hz), 12.23 (lH, s).

Example 1

 5— (1 H—imidazole — 1 —yl) — 4 — Methoxy — 2 —ditroaniline 5 26 mg, concentrated hydrochloric acid 3, platinum oxide 120 mg, and a mixture of methanol 5 The mixture was stirred at room temperature under a normal pressure hydrogen atmosphere for 2.5 hours to be reacted. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure.

 Oxalic acid (404 mg) and 3 N hydrochloric acid (10 mL) were added to the obtained residue, and the mixture was heated under reflux for 20 minutes. After cooling, the resulting crystals were collected by filtration, washed with 3N hydrochloric acid, water and methanol in that order, and dried under reduced pressure to give 6- (1H-imidazole-

1 1) 17-Methoxyxinoxaline 1,2,3 (1H, 4H) -dion.hydrochloride 34.3 mg was obtained.

Example 2

 To a mixture of 5-66-mg of 5-fluoro- (1H-imidazole-l-yl) 1-26-nitroacetanilide and DMF was added an aqueous solution of sodium methylmercaptan (30%) at room temperature. The mixture was stirred for 60 hours, and further stirred at 60 ° C for 1 hour to react. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with a mixed solvent of ethyl acetate-dichloromethane.

The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. In the residue, THF 1 Qm £, ethanol 3 Qm £, Concentrated hydrochloric acid (10%) and palladium carbon (20 Omg) were added, and the mixture was stirred and reacted at room temperature under a normal pressure hydrogen atmosphere for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To the residue, oxalic acid (385 mg) and 3 N hydrochloric acid (4 m) were added, and the mixture was heated under reflux for 30 minutes. After cooling, the precipitated crystals were collected by filtration, washed with 3N hydrochloric acid, water and methanol, dried under reduced pressure, and dried with 6- (1H-imidazoyl 1-yl) -7-methylthioquinoxaline_2,3 (1H, 4H) -dione hydrochloride (390 mg) was obtained.

Example 3

 A mixture of 5-fluoro-41 (1H-imidazole-1-yl) -2-2-nitroacetanilide 65 mg and methylamine 40% methanol solution 1 was heated to reflux for 2 hours. After cooling, the reaction mixture was concentrated under reduced pressure. To the obtained residue, 12 of 3N hydrochloric acid was added, and the mixture was heated under reflux for 30 minutes. After cooling, the mixture was concentrated under reduced pressure.

 To the obtained residue were added concentrated hydrochloric acid (lm), methanol (6 Qm), and platinum oxide (100 mg), and the mixture was stirred at room temperature under a normal pressure hydrogen atmosphere for 8 hours to be reacted. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To the obtained residue, 567 mg of oxalic acid and 12 m of 3N hydrochloric acid were added, and the mixture was heated under reflux for 20 minutes. After cooling, the precipitated crystals are collected by filtration, washed with 3N hydrochloric acid, water, and methanol, dried under reduced pressure, and dried with 6- (1H-imidazo-1-yl) -7-N-methylaminoquinoxaline There was obtained 19 mg of 1,2,3 (1H, 4H) dione hydrochloride.

Example 4

4- [2- (1H-imidazole-1-yl) -14-nitro-15-acetanilide] Dimethyl oxyphthalate 62 Omg was dissolved in 4N hydrochloric acid 6W and stirred at 100 ° C overnight. . After concentrating the reaction mixture, it was dissolved in methanol-water (50%, & m £) and added with 10% palladium-carbon 130 mg. Then, hydrogenation was performed at normal pressure and normal temperature. After concentrating the reaction solution, it was dissolved in 4N hydrochloric acid 5 and 24 Omg of oxalic acid was added, followed by refluxing for 3 hours. The reaction mixture was concentrated, purified with HP-20 resin, and purified with 4- [6— (1H-imidazole-1-11) -12,3 (1H, 4H) -quinoxalinedione-7- Oxyphthalic acid 36 Omg (64%) was obtained.

Example 5

 4- [2- (1H-Imidazol-1-yl) _4-nitro-5-anilino] methyl benzoate 742 mg, concentrated hydrochloric acid 1, methanol 15, 10% palladium carbon 10 Hydrogenation was carried out at normal pressure and normal temperature in the same manner as in Example 4 using 0 rag. After concentrating the reaction mixture, treatment was carried out in the same manner as in Example 4 using 31 ^ hydrochloric acid 10 ^ and oxalic acid 30 Omg to give 4- [1- (1H-imidazole-11-yl) -2,3 (1 (H, 4H) monoquinoxalinedione-7-yl] oxybenzoic acid (47 2 mg, 62%) was obtained. Example 6

 5-(3-Dimethylaminophenoxy) 1-4-(1H-imidazole-11-yl)-2-nitroacetanilide 960 mg, 3N hydrochloric acid 5m £, methanol 3W Then, the reaction mixture was deacetylated and subsequently hydrogenated under normal pressure and normal temperature in the same manner as in Example 4 using 100% palladium carbon (200 mg), 3N hydrochloric acid (5 W) and methanol (4). After concentrating the reaction mixture, the reaction mixture was treated with 3N hydrochloric acid 5; ^ and oxalic acid 4

There were obtained 994 mg (89%) of (3-dimethylaminophenoxy) -17- (1H-imidazole-1-yl) -2,3 (1H, 4H) -quinoxalinedione.

Example 7

4-(1H-imidazole-1-yl) 1-5-(3-pyridyloxy)-2-di-acetoanilide 380 mg, 3N hydrochloric acid 3m £, meta In the same manner as in Example 4, hydrogenation was carried out under normal pressure and normal temperature using 40% phenol and 10% Omg of palladium carbon. After concentrating the reaction mixture, it was treated in the same manner as in Example 4 using 3N hydrochloric acid (10 w £) and oxalic acid (23 O mg) to give 6 — (1 H-imidazo 1-1-yl) — 7 — ( 3-Pyridyloxy) 1,2,3 (1H, 4H) -quinoxalinedione (409 mg, 72%) was obtained.

Example 8

 5-[4-(2-benzyloxycarbonylamidoethyl) phenoxy]-4-(1 H-imidazole-1-yl)-2-nitroacetanilide 1.56 g, 3 N-hydrochloric acid 6 and methanol 1 were used to deacetylate, and then hydrogen was added at normal pressure and room temperature in the same manner as in Example 4 using 10% palladium carbon 250 mg, 3N hydrochloric acid 8 and methanol 6. . After concentrating the reaction mixture, the mixture was treated in the same manner as in Example 4 using 10 mL of 3 N hydrochloric acid and 550 mg of oxalic acid to give 6- [4- (2-aminoethyl) phenoxy] —7— (1H —Imidazolone 1 _yl) —2,3 (1 H, 4 H) —Quinoxalinedione 1.20 g (87%) was obtained.

Example 9

2- [2- (1H-imidazole-1-yl) -1-4-nitro-5-anilino] methyl thiobenzoate 800 mg, 3 37 ^ hydrochloric acid, methanol 40m £, 10% palladium carbon 15 Hydrogenation was carried out at normal pressure and normal temperature in the same manner as in Example 4 using Omg. After concentrating the reaction mixture, treatment with 3 N hydrochloric acid 4 ^ and oxalic acid 50 Omg was carried out in the same manner as in Example 4 to give 2— [6- (1H-imidazole-11-yl) 1-2,3 (1H , 4H) 1-quinoxalindione-17-yl] thioxybenzoic acid 52 mg (56%) _c Example 10

 2-[2-(1 H—imidazole-1 —yl) 1-412

—Acetanilide] Methyl oxybenzoate 1.19 g, 3N hydrochloric acid 8, Deacetylation was carried out using 5j ^ of methanol, followed by hydrogenation at normal pressure and room temperature in the same manner as in Example 4 using 3N hydrochloric acid 3, methanol 40W, and 10% palladium carbon 12 Omg. After concentrating the reaction mixture, treatment with 3 N hydrochloric acid 6 and oxalic acid 540 mg was carried out in the same manner as in Example 4 to give 2- [6- (1H-imidazole-1-yl) -2,3 (1H, 4H 8) 62 mg (58%) of monoquinoxa lindion-7-yl] oxybenzoic acid were obtained. Example 1 1

 4- [2- (1H-imidazo-l-ul-l-yl)-4-12-toro-5-ethylethyloxalyl anilide] obtained in Reference Example 9 methyl benzoate 0.48 g (1.2 Was dissolved in DMF, and 12 Omg of 5% iridium carbon was added, followed by hydrogenation at normal pressure and normal temperature. The reaction solution was filtered, washed with DMF and concentrated. The obtained residue was recrystallized from ethanol-water to give 4- [4-hydroxy-6- (1H-imidazole-11yl) -2,3 (1H, 4H) -quinoxalinedione. There was obtained 34 Omg of methyl 7-yloxybenzoate.

Example 1 2

 4-[4-Hydroxy-1-6- (1H-imidazole_1-yl) -2,3 (1H, 4H) -quinoxalinedione-1-7-yl] Methoxy benzoate 0.34 g (1.2 (5 mmol) was dissolved in 8 m of 4 N hydrochloric acid and refluxed for 3 hours. The resulting crystals were filtered to obtain 4- [4-hydroxy-

6- (1H-imidazole-1_yl) -1,2,3 (1H, 4H) -quinoxalinedione-7-yl] oxybenzoic acid was obtained in an amount of 295 mg (93%).

Example 13

3-[[acetamino _ 2— (1H—imidazo-1-yl 1-yl) 1-412 trophenyl] oxy] Methyl benzoate 1.20 g, 3N salt A mixture of acid 5 and methanol 3 was heated and refluxed for 2 hours under an argon stream. After cooling, the reaction mixture was concentrated under reduced pressure. To the obtained residue, methanol 40, 3N hydrochloric acid 4, 10% palladium carbon 12 Omg were added, and hydrogenation was performed at room temperature under normal pressure. After the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To the obtained residue, 3N hydrochloric acid 5 ^ and oxalic acid 540 mg were added, and the mixture was heated under reflux for 4 hours. After cooling, crystals precipitated from the reaction mixture were collected by filtration, washed sequentially with 3N hydrochloric acid, water and methanol, and dried under reduced pressure. To the obtained compound, a 1 N aqueous solution of sodium hydroxide 7 was added, and the mixture was stirred at 60 ° C for 1 hour. After the reaction, 3 N hydrochloric acid was added to make the reaction solution acidic, and the precipitated crystals were collected by filtration, washed sequentially with 3 N hydrochloric acid, water and methanol, dried under reduced pressure, and dried under reduced pressure. Dioxo 7- (1H-imidazo-l-l-yl) 1-1,2,3,4-tetrahydronoquinoxaline-1 6-yl] oxy] benzoic acid · hydrochloride 800 mg (61 %).

Example 14

 4-[[5-acetamino-2- (1H-imidazo-l-l-yl) -4-12-trophenyl] thio] methyl benzoate 933 mg, 3N hydrochloric acid 4mi, methanol 3W Deacetylation was carried out, and hydrogenation was carried out at normal pressure and normal temperature in the same manner as in Example 13 using 100% palladium carbon (400 mg) and methanol (150 j ^). The reaction mixture was filtered, concentrated under reduced pressure, and treated in the same manner as in Example 13 with 3N hydrochloric acid 5 ^ and oxalic acid 45 Omg, to give 4-[[7- (1H-imidazole-11i). 1) 1,2,3-Dioxo-1,2,3,4-tetrahydroquinoxaline-16-yl] thio] benzoic acid hydrochloride 655.3 mg (65%).

Example 15

4-(1 H—imidazole— 1 yl) 1 5— [(1 H—imidazole Zoyl 2-yl) thio] — 2-Nitroacetanilide 710 mg, 3N hydrochloric acid 3 and methanol 2 were used to deacetylate, and 10% palladium carbon 25 Om and methanol 5 were converted. As in Example 13, hydrogenation was performed at normal pressure and normal temperature. The reaction mixture was filtered and concentrated under reduced pressure. Then, using 31 ^ hydrochloric acid 3 ^ and oxalic acid 40 Omg, 6- (1H-imidazolone 1 1-yl) — 7 1 [(1H-imidazo-l- 2-yl) thio] _ 2,3 (1H, 4H) monoquinoxalinedione ♦ dihydrochloride 5 76 mg (65%) Obtained. Example 16

 4 _ (1 H-imidazole-1-yl) — 5— [(1-methyltetrazol-5-yl) thio] 1-2-2-nitroacetoanilide 32 3 mg, 31 ^ HCl 2 ^, methanol 5 Then, hydrogenation was carried out at normal pressure and normal temperature in the same manner as in Example 13 using 150 mg of 10% palladium carbon and 100 mL of methanol. The reaction mixture was filtered, concentrated under reduced pressure, and subjected to a ring closure reaction using 3N hydrochloric acid 3 ^ and oxalic acid 162 mg. The reaction mixture was concentrated under reduced pressure, and the obtained residue was diluted with water, purified with HP-20 (Mitsubishi Kasei), and purified with 6- (1H-imidazole-11-yl) -17- [1-methyl). Tetrazole-5-yl) thio] —2,3 (1 H, 4 H) monoquinoxalinedione (183 mg, 59%) was obtained.

Example 17

4- (1H-imidazole-1yl) 1-5-[(5-methyl-1,3,4-thiadiazol-2-yl) thio] 1-2-2-troacetanilide 9 3 lmg, 3N hydrochloric acid 2 The mixture was deacetylated using methanol 3 and hydrogenated under normal pressure and normal temperature in the same manner as in Example 13 using 10% palladium carbon 40 Omg. The reaction mixture was filtered, concentrated under reduced pressure, and closed with 3 N hydrochloric acid 3 and oxalic acid 162 mg. The reaction was performed. The reaction mixture was concentrated under reduced pressure, and the obtained residue was diluted with water, purified with HP-20 (Mitsubishi Chemical), and purified with 6- (1H-imidazolone 1-yl) 17-[(5-methyl- 1,3,4-Thiadiazol-2-yl) thio] —2,3 (1H, 4H) —quinoxalinedion 2 15 mg (24%) was obtained.

Example 18

 -(1 H—imidazole— 1—yl) —2-nitro—5-phenoxyaniline 862 mg, methanol 4 Qm £, 3 N hydrochloric acid 4J ^, 10% palladium carbon 12 O m At room temperature, normal pressure hydrogenation was performed. After the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To the obtained residue, 3] ^ hydrochloric acid (5 <1 £) and oxalic acid (54 Omg) were added, and the mixture was heated under reflux for 1.5 hours. After cooling, the crystals precipitated from the reaction mixture were collected by filtration, washed successively with 3N hydrochloric acid, water and methanol, dried under reduced pressure, and dried under reduced pressure to give 6- (1H-imidazole). There were obtained 877 mg (78%) of 1,2 (1H, 4H) monoquinoxaline hydrochloride.

Example 19

At room temperature under a stream of argon, 1333 nig (3.33 mmol) of sodium hydride was suspended in THF, and 554 mg (3.33 mmol) of methyl p-hydroxyfuranate was added to DM F 6 was added. Five minutes later, 80-mg (3.03 mmol) of 5-fluoro-4- (1H-imidazole-1-yl) -2-nitroacetanilide was added, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was extracted with saturated aqueous ammonium chloride and ethyl persulfate. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the obtained residue, 3N hydrochloric acid & m £ and methanol 5m £ were added, and the mixture was heated under reflux for 2 hours. After cooling, the reaction mixture was concentrated under reduced pressure. 3N Hydrochloric acid 2 and 10% palladium carbon 20 Omg were added, and the mixture was hydrogenated under normal pressure at room temperature. The reaction mixture was filtered, and the obtained filtrate was concentrated under reduced pressure. To the residue, 3N hydrochloric acid 5 ^ and oxalic acid 545 mg were added, and the mixture was heated under reflux. After cooling, the precipitated crystals were collected by filtration, washed with 3 N hydrochloric acid, water and methanol in that order, and dried under reduced pressure. To the obtained compound was added 10% aqueous hydroxide water 5 and the mixture was stirred at 60 ° C. After adding 3N hydrochloric acid to the reaction mixture to make the solution acidic, the precipitated crystals are collected by filtration, washed with 3N hydrochloric acid, water and methanol in that order, and dried under reduced pressure. 2,3-Dioxo-1- (1H-imidazole-1-yl) — 1,2,3,4-tetrahydroquinoxaline-6-yl] oxy] phenyl] acetic acid hydrochloride 8 8 5 nig (7 0%).

Example 20

 The same reaction as in Example 19 was carried out using 121 mg of sodium hydride, 52 mg of 4-ethoxycarbonylimidazolone 2-thiol, 22 mg of THF, and 10 m of DMF, and purified with HP-20. 2 — [[2,3-Dioxo—7— (1H—imidazo-1-yl) —1,2,3,4-tetrahydro-6_quinoxalinyl] thio] —1H—imidazole-4 There were obtained 25.2 mg (19%) of the acid hydrochloride. Example 2 1

At room temperature under an argon stream, 121 mg (3.03 mraol) of sodium hydride was suspended in 10 THF, and 646 mg (3.33 mmol) of p-nitrophenol and DMF 6 were added. Five minutes later, 800 mg (3.03 mmol) of 5-fluoro-41- (1H-imidazole-11-yl) -2--2-acetoanilide was added, and the mixture was stirred at the same temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with saturated aqueous ammonium chloride and ethyl acetate. The organic layer is separated, washed with saturated saline, and anhydrous sodium sulfate. And concentrated under reduced pressure. To the obtained residue, 3N hydrochloric acid 3 and methanol 5 were added, and the mixture was heated under reflux for 2 hours. Filtration After cooling, to the residue and the reaction mixture was concentrated under the reduced pressure, methanol 4 0, 3 ^ hydrochloride 5 ^, 1 0% palladium-carbon 2 5 Omg was added, at room temperature, the _c reaction mixture was added atmospheric pressure of hydrogen The obtained filtrate was concentrated under reduced pressure. 3N hydrochloric acid 3 ^ and oxalic acid 55 Omg were added to the residue, and the mixture was heated under reflux. After cooling, the precipitated crystals were collected by filtration, washed with 3N hydrochloric acid, water and methanol in that order, dried under reduced pressure, and dried under reduced pressure to give 6- (4-aminophenyl)-7- (1H-imidazolu (1) One, two, three (1H, 4H) -quinoxalinedione dihydrochloride (698 mg, 56%) was obtained.

Example 22

 4-[(4-acetamino _ 2-(1 H-imidazo-l-l-yl) -l-2-trophenyl) -oxy] Methyl valerate 2.20 g, 3 N hydrochloric acid 5, methanol 2 m £ The catalyst was hydrogenated at normal pressure and normal temperature in the same manner as in Example 13 using 100% palladium carbon (200 mg) and methanol (150). The reaction mixture was filtered, concentrated under reduced pressure, treated with 5N 3N hydrochloric acid and 1.05 g of oxalic acid, and treated in the same manner as in Example 13 to give 5-[[7- (1H-imidazole-11-yl). 1.37 g (49%) of 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-16-yl] oxy] valerate acid hydrochloride was obtained.

Example 23

N- [5— (1H—imidazo-1-yl) 1-4-1 [(4-methoxycarbonyldiphenyl) methoxy] 1-2-2-trophenyl] ethyl ethyl oxamate 1.07 g (2.28 ol), methanol (500 mL), dichloromethane (100 mL), and platinum oxide (200 mg) were hydrogenated at normal pressure under ice cooling. After the reaction, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. 50% methanol was added to the obtained residue, and the mixture was heated under reflux for 1 hour under an argon stream. After cooling, the crystals precipitated in the reaction mixture were collected by filtration, washed with methanol and dichloromethane, and dried under reduced pressure. To the obtained product, 2 N aqueous sodium hydroxide solution 6 I ^ was added, and the mixture was heated and refluxed for 1 hour and a half.c. 3 N hydrochloric acid was added to this mixture to adjust the pH to about 2 or more, and the precipitated crystals were collected by filtration. , 3N hydrochloric acid, water, and methanol in that order, and dried under reduced pressure. 4-[[4-Hydroxy-7- (1H-imidazole-1-yl) 1-2,3-dioxo-1,2] There was obtained 708 mg (72%) of 3,3,4-tetrahydroquinoxaline-16- [yl] oxymethyl] benzoic acid · hydrochloride.

Example 2 4

 2 — [(4-acetamino—2— (1H—imidazole-1-yl) —5-ditrophenyl) oxy] ethyl acetate 2.50 g, 3N hydrochloric acid 4, methanol 4 W Hydrogenation was carried out at normal pressure and normal temperature in the same manner as in Example 13 using 10% palladium carbon (200 mg) and methanol (200). The reaction mixture was filtered, concentrated under reduced pressure, and treated in the same manner as in Example 13 using 5N hydrochloric acid 5 and 1.29 g of oxalic acid to give 2-[[7- (1H-imidazole-1-yl). 1.83 g (74%) of 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-16-yl] oxy] acetic acid · hydrochloride was obtained.

Example 2 5

4 - [[4- § Se Bok Amino - 2-(1 H- imidazol-1-I le) Single ₅ twelve Torofuweniru] Okishi] butyric Echiru 2.0 g, 3 N hydrochloric acid 5 m £, de Asechiru by using methanol Hydrogenation was carried out at normal pressure and normal temperature in the same manner as in Example 13 using 10% palladium carbon 27 Omg, methanol 150 mL, and ethyl acetate 100 mi. Filtering the reaction mixture, After concentration under reduced pressure, the same treatment as in Example 13 was carried out using 5 ^ 31 hydrochloric acid 5 and 0.95 g of oxalic acid, followed by treatment with 4-[[7- (1H-imidazoyl-1-yl)]. 1.27 g (65%) of 1,2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-yl] oxy] butyric acid hydrochloride was obtained. Example 26

 N— [5-(1 H—imidazoyl— 1 —yl) — 4 — [(4—Methoxycarbonyl) sulfinyl] — 2-dinitrophenyl] Ethyl oxamate 580 mg (1. A mixture of 19 mmol), 50 mL of ethyl acetate, 2 mL of methanol, 40 mg of platinum oxide, and 55.8 mg of DMS was hydrogenated at room temperature under normal pressure. After the reaction, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Methanol 2 was added to the obtained residue, and the mixture was heated under reflux. After cooling, the precipitate was collected by filtration, washed with methanol, and dried under reduced pressure. To the obtained compound was added 1N aqueous sodium hydroxide solution of 5; ^, and the mixture was stirred in an oil bath at 80 ° C for 2 hours. To the reaction mixture was added 3N hydrochloric acid, the pH was adjusted to 2 or more, and the precipitated crystals were collected by filtration, washed successively with 3N hydrochloric acid, water and methanol, dried under reduced pressure, and dried under reduced pressure. Droxy—7— (1H—imidazole-1-yl) —2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-16-yl] sulfenyl] benzoic acid hydrochloride 36 2 mg (63 %).

Example 2 7

N- [5- (1H-imidazo-l-l-yl) _ 4-[(4-methoxycarbonyldiphenyl) oxy] -l2-nitrophenyl] oxaethylate 1.65 g (3 6 33 mmol), ethyl acetate 50 ^, methanol 100 ^, platinum oxide 123 mg, and DMS O 16 mg in the same manner as in Example 26 to give 4 -— [[4-hydroxy — Ί 1 (1 H—Midazo 1—1) — 2, 3 —Zoxor 1, 2, 3, 4—T Trahydroquinoxaline-16-yl] oxy] benzoic acid was obtained in an amount of 89.4 mg (61%).

Example 2 8

 2-[[5-acetoamino-2- (1H-imidazo-l-u-i-l-yl) -l-412-trophenyl] thio] ethyl acetate 5 36 mg, 3N hydrochloric acid

Deacetylation was performed using 2i-ethanol, and hydrogenation was performed under normal pressure and normal temperature using 10% palladium-carbon 200 mg and ethanol 3. The reaction mixture was filtered, concentrated under reduced pressure, reacted in the same manner as in Example 13 using 3N hydrochloric acid (10πέ) and oxalic acid (300 mg), purified with HP-20, and purified using 2 _ [[7— (1 H—imidazole-1 —yl) — 2, 3 —dioxo—

There were obtained 22 mg (46%) of 1,2,3,4-tetrahydroquinoxaline-16-yl] thio] acetic acid.

Example 2 9

 4-(1 H—imidazole-1 —yl) — 5— (cyclopentyl) thio-2-nitroaniline 700 mg, methanol 40? ^, 3 N hydrochloric acid

6- (cyclopentyl) thio 7 _ (1 H-imidazole) 1, 2, 3 (1) in the same manner as in Example 18 using 3 mL and 10% palladium carbon 200 mg. (H, 4H) monoquinoxalinedione hydrochloride (429 mg, 50%) was obtained.

Example 30

5-(1 H—imidazole— 1 —yl) — 4 —benzyloxy-2-nitroacetanilide 55 3 mg (1.78 mmol), benzene 30 m £, methanol 30 n £, oxidation A mixture of 100 mg of platinum was hydrogenated under normal pressure at room temperature. After the reaction, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Oxalic acid (40 Omg. IN hydrochloric acid) (10) was added to the obtained residue, and the mixture was refluxed for 3 hours under an argon stream. After the reaction, the precipitated crystals are collected by filtration, and 1 Wash with N hydrochloric acid, water and methanol sequentially, and dry under reduced pressure. 6-Benzyroxy 7- (1H-imidazo-1-yl) 1-2,3 (1H, 4H) -quinoxalinedione There were obtained 467 mg (68%) of the hydrochloride.

Example 3 1

 4-[[5-acetamino-2_ (1H-imidazoyl-1-yl)-4-12-trophenyl] oxy]-3-methylethoxybenzoate 1.58 g A mixture of 30 N aqueous hydrochloric acid was heated to reflux for 2 hours. After cooling, the reaction mixture was filtered and evaporated under reduced pressure. To the residue were added 1N aqueous hydrochloric acid (30) and ethanol (3), 10% palladium on carbon (30 Omg), and hydrogenation at room temperature under normal pressure. After the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To the obtained residue, 4 N hydrochloric acid (2 Qm £) and oxalic acid (500 mg) were added, and the mixture was heated under reflux for 15 minutes. After cooling, the precipitated crystals were collected by filtration, washed successively with water and methanol, dried under reduced pressure, and dried under reduced pressure to give 4-[[2,3-dioxo-7- (1H-imidazo-l-yl) -1]. There was obtained 62 mg (40%) of 1,2,3,4-tetrahydroquinoxaline-16-yl] oxy] —3-methoxybenzoic acid '^ -acid salt.

Example 3 2

5-[4-(1 H-imidazo 1-yl) phenoxy]-4- (1 H-imidazo 1-1 -yl)-2-ditroaniline dihydrochloride 2.7 g, Hydrogenation was carried out at normal pressure and normal temperature in the same manner as in Example 31 using 1N hydrochloric acid 5 and 400 mg of 10% palladium carbon. The reaction mixture was filtered and concentrated under reduced pressure, and then treated with 20 mL of 4 N hydrochloric acid and 840 _{mg of} oxalic acid in the same manner as in Example 31 to obtain 6— (1H-imidazolone 1 _). Yl)-7-[4-(1 H—imidazole-1 1 yl) phenoxy] — 2,

3 (1H, 4H)-quinoxalinedione hydrochloride 1.8 g (63%) I got

Example 3 3

 4-[[5-acetamino-2- (1H-imidazole-1-yl)-4-nitrophenyl] oxy]-mixture of 1.00 g of ethyl 2-ethyl benzoate and 80 j ^ of 3N aqueous hydrochloric acid Was heated to reflux for 30 minutes. After evaporating the solvent under reduced pressure, 1N aqueous hydrochloric acid (30τ ^), ethanol (30 ^), and 10% palladium carbon (30Omg) were added, and the mixture was hydrogenated at room temperature under normal pressure. After the reaction, the solvent was distilled off under reduced pressure. To the obtained residue, 30 mL of 3 N hydrochloric acid and 42 Omg of oxalic acid were added, and the mixture was heated under reflux for 2 hours. After cooling, the precipitate formed was collected by filtration, washed sequentially with water and methanol, dried under reduced pressure, and dried under reduced pressure. [4, [2,3-Dioxo 7- (1H-imidazo-l-l-yl)] ― 1,2,3,4-tetrahydroquinoxaline-16-yl] oxy] -12-chlorobenzoic acid hydrochloride 67 Omg (68%) was obtained.

Example 3 4

 4-[[5-Amino-2- (1H-imidazole-1-1-yl) -412-trophenyl] oxy] benzonitrile 85Omg, 3N HCl 2n £ ^ Methanol 50W, 10% palladium on carbon Using 25 Omg, hydrogenation was carried out at normal pressure in the same manner as in Example 18. The reaction mixture was filtered, concentrated under reduced pressure, and subjected to a ring closure reaction using 3N hydrochloric acid (10R) and oxalic acid (50Omg). After cooling, the precipitated product was collected by filtration, washed successively with 3N hydrochloric acid, water and methanol, dried under reduced pressure, and 6- (1H-imidazole-11-yl) -17- (4-cyanophenoxy) -12 , 3 (1 H, 4 H) monoquinoxalinedione hydrochloride (530 mg).

Example 3 5

6-(1 H—imidazo 1-yl) 1 7— (4—cyanophenoxy) 1—2, 3 (1 H, 4 H) —quinoxalinedione hydrochloride A mixture of 465 mg (1.04 marl ol), DMF 2 Or, sodium azide 678 mg, and ammonium chloride 556 mg was stirred for 5 hours on a 120 ° C. oil bath. After cooling, the reaction mixture was diluted with water, the pH was adjusted to 2 by adding 3N hydrochloric acid, and the precipitated compound was collected by filtration. The residue was washed with 3N hydrochloric acid, water and methanol in that order, dried under reduced pressure, and dried with 6- (1H-imidazole-1-yl)-7- [4- (1H-tetrazol-5-y). Phenoxy] — 2,3 (1H, 4H) monoquinoxalinedione hydrochloride (393 mg, 79, 9%).

Example 3 6

 N- [5-(1 H-imidazo 1-1-yl)-4-1 (4-cyanophenoxy) 1-2-2-phenyl] oxamic acid 1.013 g (2.40 mmol), ethyl ethyl sulphonate Using the same operation as in Example 26 using 2 Qm £, methanol 50m £, platinum oxide 700mg, and DMS 06mg, 6- (4-cyanophenoxy) 1-1-hydroxy-6_ (1H— Imidazolone 1-yl) — 2, 3 (1 H, 4 H) — quinoxaline dione (627 mg, 72%) was obtained.

Example 3 7

6— (4-cyanophenoxy) 1-1-hydroxy-5- (1H-imidazole-11-yl) 1-2,3 (1H, 4H) -quinoxalinedione 4 2 1 mg (1.17 marl ol) 6_ (1H-imidazole-1-yl) in the same manner as in Example 35 using 22 mg of sodium azide, 10 ^ of N-methylpyrrolidone 10 ^ and 24 lmg of triethylamine hydrochloride. — 1-Hydroxy-7— [4- (1 H-tetrazole-5-yl) phenoxy] — 2,3 (1 H, 4 H) —Quinoxalinedione 2 4 7 mg (46%, purity 95%) I got Example 3 8

 N- [5-(1H-imidazole-1-1yl)-4-[(4-methoxycarbonylphenyl) methoxy]-2-ditrophenyl] ethyl ethyl oxamate 6 45 mg (1. A mixture of 38 mraol), THF 60, methanol 120 ^, 3 lmg of iron chloride (BI), 1 drop of water and 53 mg of activated carbon was refluxed under heating for 30 minutes. To this mixture, hydrazine monohydrate 0.6 was added dropwise, and the mixture was refluxed for 20 hours while heating. After cooling, the reaction mixture was filtered and concentrated under reduced pressure. To the obtained residue, 3 N hydrochloric acid (2Qr) and oxalic acid (248 mg) were added, and the mixture was heated under reflux for 2 hours. After cooling, the precipitated crystals were collected by filtration and washed sequentially with 3N hydrochloric acid, water and methanol. To the obtained compound was added 3N aqueous sodium hydroxide 1 and the mixture was refluxed for 1 hour under heating. 3 N hydrochloric acid was added dropwise to the reaction mixture to adjust the pH to 3, and the precipitated crystals were collected by filtration, washed successively with 3 N hydrochloric acid, water and methanol, dried under reduced pressure, and dried under reduced pressure to give 4-([2,3-dioxo-7-). (1H-imidazoyl-1-yl) 1,1,2,3,4-tetrahydroquinoxaline-16-yl] oxymethyl] benzoic acid hydrochloride (325 mg, 50%) was obtained.

Example 3 9

 N— [5— (1H—imidazole-11-yl) —4—benzyloxy_2-2-nitrophenyl) oxamic acid ethyl 800 mg, platinum oxide 3 mg, methanol 100 W, acetic acid Ethyl 2 Qm £ ヽ THF 20,

In the same manner as in Example 26 using DMS 0 1 Omg, 7-benzyloxy 1-hydroxyl-6- (1H-imidazole-1yl) -2,3 (1H, 4 H) -Quinoxalinedione 647 mg (95%) was obtained.

Example 40

5 — [[5—acetamino-2— (1H—imidazole-1 1) 4-nitrophenyl] oxy] indole methyl 2-carboxylate 8776 mg, 3N hydrochloric acid 5 and methanol 5 were used to deacetylate 100% palladium on carbon 100 mg and methanol 10 Omi And hydrogenation was carried out in the same manner as in Example 13. The reaction mixture was filtered and concentrated under reduced pressure. To the obtained residue, 3N hydrochloric acid 5 ^ and oxalic acid 362 mg were added, and the mixture was heated under reflux for 3 hours. After cooling, the precipitated product was collected by filtration and washed sequentially with 3N hydrochloric acid, water and methanol. To this product was added 1N aqueous sodium hydroxide 5 and the mixture was heated to reflux. After cooling, 1N hydrochloric acid was added dropwise to the reaction mixture to adjust the pH to 6, and the precipitated crystals were collected by filtration, washed with water and methanol in that order, dried under reduced pressure, and dried under reduced pressure to give 5-([2,3-dioxo-7-). (1 H-Midazo-1-yl) 1,1,2,3,4-tetrahydroquinoxaline-6-yl] oxy] Indole-2-carboxylic acid hydrochloride

46 2 mg (50%) were obtained.

Example 4 1

 4-[[5-acetamino-2— (1H—imidazo-1-yl) -1-4-nitrophenyl] oxy] 3.4-ethyl 3-methylbenzoate 3.4 g, 3 N hydrochloric acid 200 W, methanol 10 0 Was heated to reflux for 30 minutes. After cooling, the reaction mixture was concentrated under reduced pressure. To the obtained residue were added ethanol 100, 1 ^^ hydrochloric acid 100 ^, 10% palladium on carbon 10 Omg, and hydrogenated at room temperature under normal pressure. After the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. 3 N hydrochloric acid was added to the obtained residue.

5 Qm £ and 1.40 g of oxalic acid were added, and the mixture was heated under reflux for 2 hours. After cooling, the crystals precipitated from the reaction mixture were collected by filtration, washed successively with 1N hydrochloric acid, water and methanol, dried under reduced pressure, and dried under reduced pressure to give a solution of 4-[[2,3-dioxo 7- (1H-imidazole-1). 1-yl) 1,2,3,4-tetrahydroquinoxaline-16-yl] oxy] -13-methylbenzoic acid hydrochloride 1.10 g (36%) were obtained.

Example 4 2

 4-[[5-acetamino-2- (1-H-imidazo-l-l-yl) -l-412-trophenyl] oxy] -1-3-cycloethyl benzoate 2.0 g, 3N hydrochloric acid 16 A mixed solution of 0-3 and methanol 3 was heated to reflux for 30 minutes. After cooling, the reaction mixture was concentrated under reduced pressure. Ethanol 50, 丄! ^ Hydrochloric acid, 10% palladium carbon 10 Omg, and normal pressure hydrogenation at room temperature. After the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To the obtained residue, 40 mi of 3 N hydrochloric acid and 84 mg of oxalic acid were added, and the mixture was heated under reflux for 2 hours. After cooling, the crystals precipitated from the reaction mixture were collected by filtration, washed successively with 1N hydrochloric acid, water, and methanol, dried under reduced pressure, and dried under reduced pressure to give 4-[[2,3-dioxo-7- (1H-imidazole- 1 yl) — 1,2,3,4-tetrahydroquinoxalin 1-6 —yl] oxy] — 3-chlorobenzoic acid hydrochloride 1.08 g (54%) .

Example 4 3

4-[[5-Acetamino-2-(1 H-imidazole-1 -yl) 1 -412 trophenyl] oxy]-1-2-methyl benzoate 1.45 g, 3 N hydrochloric acid 8 Q i The mixed solution of methanol and methanol was heated to reflux overnight. After cooling, the reaction mixture was concentrated under reduced pressure. To the obtained residue were added 30% of methanol, 30% of 1 ^^ hydrochloric acid, and 20 Omg of 10% palladium carbon, and hydrogenation was performed at room temperature under normal pressure. After the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To the obtained residue, 3 N hydrochloric acid 4 and oxalic acid 61 Omg were added, and the mixture was heated under reflux for 2 hours. After cooling, the crystals precipitated from the reaction mixture were collected by filtration, washed successively with 1 N hydrochloric acid, water and methanol, dried under reduced pressure, and dried under reduced pressure. H—imidazoyl 1-yl) — 1,2,3,4-tetrahydroquinoxaline—6-yl] oxy] 12-methoxybenzoic acid · hydrochloride 0.5 1 g (3 1 %).

Example 4 4

 N-[3-(4 —methyl-1 H—imidazole— 1 —yl) — 4

-[(4-Ethoxycarbonyldiphenyl) oxy] 1-6-ditrophenyl] oxamic acid ethyl ester 60 Omg in ethanol solution 50 ^ ^ Add 10% palladium on carbon 8 Omg, hydrogen at room temperature and atmospheric pressure hydrogen Was added. After the reaction, the precipitate was filtered, ethanol 5 was added, and the mixture was heated under reflux for 30 minutes. After the solvent was distilled off, 1 N sodium hydroxide 5 was added to the obtained residue, and the mixture was heated under reflux for 30 minutes. The reaction mixture is filtered, and the obtained filtrate is neutralized with hydrochloric acid. Crystals precipitated from the reaction mixture are collected by filtration, washed with water and methanol in that order, dried under reduced pressure, and dried under reduced pressure to give 4-[[2,3-dioxo-4-hydroxy-7- (4-methyl-1H-imidazole-1 1 1,2,3,4 -tetrahydroquinoxaline 16 -yl] oxy] benzoic acid 0.26 g (50%) was obtained.

Example 4 5

N— [3-(1H—imidazole-1—yl) — 4 — [(2—Methoxy—4-ethoxycarbonyldiphenyl) oxy] —6—Nitrophenyl] ethyl ethyl oxamate 1.12 g ethanol 1 O mg of DMSO and 50 mg of platinum oxide were added to 5 Qn of the solution, and hydrogenated at normal pressure at room temperature. After the reaction, the precipitate was filtered, ethanol 3 was added, and the mixture was refluxed for 30 minutes. After evaporating the solvent, 1 N sodium hydroxide 1 is added to the obtained residue, and the mixture is refluxed for 30 minutes. The reaction mixture is filtered, and the obtained filtrate is neutralized with hydrochloric acid. The crystals precipitated from the reaction mixture are collected by filtration, washed successively with water and methanol, dried under reduced pressure, and dried under reduced pressure. Kiso 4-Hydroxy 1 7 — (1 H—Imidazo 1-yl 1 —yl) 1,1,2,3,4-tetrahydroquinoxaline 1 6 —yl] oxy] — 3 —Methoxybenzoic acid hydrochloride 2 95 mg (28%) were obtained.

Example 4 6

 N-[3 — (1 H—imidazoyl— 1 —yl) — 4 — [(4 —methoxycarbonyldiphenyl) sulfonyl] — 6-ditrophinyl] ethyl oxamate 6 5 O mg. Ethanol 2 O 1 O mg of DMS 0 and 4 O mg of platinum oxide were added to a mixed solution of ^ ethyl ethyl 307 ^ and hydrogenated at room temperature under normal pressure. After the reaction, the precipitate was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. Then, to the residue were added ethanol 2Qi and chloroform 2 and the mixture was heated under reflux for 30 minutes. The precipitate is filtered, 5 N of 1 N sodium hydroxide is added, the mixture is heated under reflux for 30 minutes, and neutralized with hydrochloric acid. The crystals precipitated from the reaction mixture are collected by filtration, washed successively with water and methanol, dried under reduced pressure, and dried under reduced pressure to give 4 — [[2,3-dioxo-1-hydroxy-1- 7— (1H-imidazole). 11-yl) 1,1,2,3,4-tetrahydroquinoxaline-6-yl] sulfonyl] benzoic acid 28 O mg (45%) was obtained.

Example 4 7

N- [3- (1H-imidazole-1_yl) _4-1 [(3-trifluoromethyl-4-methoxycarbonylphenyl) oxy] 16-12-phenylphenyl] oxazin 1 O mg of DMS 0 and 30 mg of platinum oxide were added to 297 mg of ethanol solution of ethanol solution 15 and hydrogenated under normal pressure at room temperature. After the reaction, the precipitate was filtered, and the filtrate was heated under reflux for 30 minutes. After filtering the precipitate, adding 31 ^ hydrochloric acid 5 ^ and dioxane 5 and heating and refluxing for 2 hours, the crystals precipitated from the reaction mixture were collected by filtration, washed with water, dried under reduced pressure, and dried under reduced pressure. , 3—Jokiso 4—Hydro Xy—7— (1H—imidazoyl 1—yl) —1,2,3,4—tetrahydrodroquinoxaline—6-yl] oxy—1—3—trifluo Methyl benzoate hydrochloride 6 0 mg (22%) was obtained.

Example 4 8

a) N- [5-monofluoro-4 — [(4-methoxycarbonyl-2—pyridyl) oxy]] ethyl oxamate 0.79 g (1.9 related), imidazole 28 O mg benzene after _c cooled was heated to reflux overnight the solution 3, the reaction mixture was concentrated under reduced pressure, water to the resulting residue was added, followed by extraction with chloroform, washed with saturated brine, dried over anhydrous sodium sulphate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography, and N- [5- (1H-imidazo-lu-111)-4-[(4-methoxycarbonylcarbonyl) [Sulfonyl] phenyl] oxamate 65 O mg was obtained. To a mixed solution of 560 mg of this compound, 5 Ol of ethyl acetate and ethanol 2 was added 1 O mg of DMS 0 and 38 mg of platinum oxide, and hydrogenated at room temperature under normal pressure. After the reaction, the precipitate was filtered, 3 methanol was added, and the mixture was heated under reflux for 30 minutes. The precipitate was filtered, 15 mi of 3 N hydrochloric acid was added, and the mixture was heated under reflux for 2 hours. After distilling off the solvent, 2 — [[2,3-dioxo-4—hydroxy-7— (1H—imidazol— 1 —yl) 1,1,2,3,4 —Tetrahydroquinoxaline 16 —yl] oxy] _5 —Hydrochloride of pyridincarboxylic acid 6 O mg (10%) was obtained.

Table 1 below shows the structures and physicochemical properties of the compounds obtained in the examples. table 1

o

,

s)

For example,

hand)

An example

s) s),)

For example,

 β

)

Example:

In addition to the exemplified compounds described above, the following compounds can be synthesized without the need for special experiments according to the methods described in the above-mentioned Production Methods and Examples or modifications thereof, or production methods or modifications thereof known to those skilled in the art. (Table 2 (Examples B-1 to 60)).

Table 2

(Note) Me methyl group

E tethyl group

Example Imidazolyl X and its

R ¹ AR ³ R ² ports

 -i Possible position position

 Seven

 B-1 4 '-Me 6-1 0 -COOH H

2 2 '-Me 〃 〃 〃 〃 〃

3 5 '-Me 〃 〃 〃 〃

4 4 '-Et 〃 〃 / ノ 〃

5 2 '-Et 〃 〃 〃

6 5 '-Et 〃 〃 〃 〃 〃

7 2 *, 5 '-Me ₂ 〃 〃 〃 〃

8 4 '-Me 〃 〃 〃 0 H

9 2 '-Me 〃 〃 〃 〃 〃

Example Imidazolyl X and its

R ¹ AR ⁸ R ² ports

Position

4 1 H 6 7 1 0 CH ₂ H

4 2 〃 〃 〃 〃 0 H

4 3 〃 〃 〃 〃 H

4 4 〃 〃 〃 〃 〃 0 H

4 5 〃 〃 〃-C H 〃 H

4 6 〃 〃 〃 〃 II 1 11 〃 0 H

4 7 4 *-M e 〃 〃 C H 〃 0 H

4 8 4 '-E t 〃 〃 〃 〃

4 9 2 '-M e 〃 〃 〃 〃 〃

5 0 H 〃 〃 CH ₂ H

Prescription example

Lyophilized formulation

 In one vial

 50 mg of the compound of the present invention (0.5%:

■ Cuenoic acid 210 mg (2.1%:

 Take D-mannitol 100 (1.0%: water 800 ??), add 5 g of the compound of the present invention, 21 g of citrate and 10 g of D-mannitol in order, and dissolve. This solution was aseptically filtered, filled into brown vials at 1 Oral at a time, and lyophilized to give a ready-to-use solution.

Claims

Range of

1. An imidazolylquinoxalinedione derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

Contract

Request

(The symbols in the formula represent the following meanings.

R ^{1 is a} hydrogen atom or a lower alkyl group,

R ² : a hydrogen atom or a hydroxyl group,

X: a group represented by the formula — 0—, — NR ⁴ — or — S (0) _n ; R ⁴ : a hydrogen atom or a lower alkyl group;

 n: 0, 1 or 2,

 A: bond or lower alkylene group,

R ³ : 1) a lower alkyl group,

 2) carboxy group, or

 3) An optionally substituted phenyl group, cycloalkyl group, or monocyclic or bicyclic heterocyclic group having N and / or S as a hetero atom. )

2. When R ³ is substituted, the substituent is a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, an amino lower alkyl group, a mono- or di-lower alkylamino lower alkyl group , Hydroxyl, low Group consisting of a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, a cyano group, a nitro group, an amino group, a mono- or di-lower alkylamino group, and a monocyclic or bicyclic heterocyclic group having N as a hetero atom. 2. The compound according to claim 1, which is one or more substituents selected from the group consisting of:

3. The compound _{c according to} claim 1, wherein X is a group represented by the formula —0—

4. R ³ is a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, an amino lower alkyl group, a mono- or di-lower alkylamino lower alkyl group, a hydroxyl group, a lower alkoxy group, A group consisting of a carboxyl group, a lower alkoxycarbonyl group, a cyano group, a nitro group, an amino group, a mono- or di-lower alkylamino group, and a monocyclic or bicyclic heterocyclic group having N as a hetero atom. 4. The compound according to claim 3, which is a fuunyl group optionally substituted with one or more selected substituents.

 5. 4-[[6— (1H—imidazoyl 1-yl) 1-2,3 (1H, 4H) —quinoxalinedione—7-yl] oxy] benzoic acid or its pharmaceutically Acceptable salt.

 6.4-[[4-Hydroxy-1- 7- (1H-imidazo-1-yl) -1-2,3-dioxo-1,2,3,4-tetrahydroxyquinoxalin-6-yl] oxymethyl ] Benzoic acid or a pharmaceutically acceptable salt thereof.

 7. 6— (1H-Imidazole-1-yl) — 7— [4- (1H-Tetrazol-5-yl) phenoxy] —2,3 (1H, 4H) —Quinoxalinedione or Its pharmaceutically acceptable salts.

8. 6— ((1 H—Imidazole-1-yl) — 1-Hydroxy— 7- [4- (1H-imidazole-5-yl) phenoxy] 12,3 (1H, 4H) -quinoxalinedione or a pharmaceutically acceptable salt thereof.

 9. 4-[[4-hydroxy-7- (1H-imidazo-1-yl-1) -1,2,3-dioxo-1,2,3,4-tetrahydroxyquinoxaline-6-yl] oxymethyl] Benzoic acid or a pharmaceutically acceptable salt thereof.

 10. 4-[[2,3-Dioxo-1-4-hydroxy 7- (4-methyl-1 H-imidazoyl-1-yl) -1 1,2,3,4-tetrahydroquinoxaline _ 6_yl] oxy] benzoic acid or a pharmaceutically acceptable salt thereof.

 11. A pharmaceutical composition comprising an imidazolylquinoxalinedione derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

 X- A-R

(The symbols in the formula represent the following meanings.

 R hydrogen atom or lower alkyl group,

 R hydrogen atom or hydroxyl group,

X Formula —0—, — NR ⁴ — or — S (0) 基 Group represented by R, R hydrogen atom or lower alkyl group,

n 0, 1 or 2, A: bond or lower alkylene group,

R ³ : 1) a lower alkyl group,

 2) a carboxy group, or

 3) An optionally substituted phenyl group, cycloalkyl group, or monocyclic or bicyclic heterocyclic group having N and / or S as a hetero atom. )

 12. The pharmaceutical composition c according to claim 11, which is a glutamate receptor antagonist.

13. The pharmaceutical composition according to claim 12, which is a psychotropic drug.

 14. The pharmaceutical composition according to claim 11, which is a nerve cell protective agent.

 15. The pharmaceutical composition according to claim 14, which is an anti-ischemic drug.