JP2020158391A - Novel nitrocatechol derivative - Google Patents

Abstract

To provide a novel nitrocatechol derivative or a salt thereof that has catechol-O-methyltransferase inhibitory action and dopa decarboxylase inhibitory action and to provide a pharmaceutical composition containing the same derivative or the salt thereof.SOLUTION: A compound represented by formula (1) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition including the same compound or the salt thereof are provided. [A ring A represents 3 to 6 heterocyclic compounds represented by oxadiazole or the like; Q1 to Q6 are each independently C, N, S or O; X, Y and Z are each independently a single bond, C, O, N or S; R1, R2 and R11 are each independently H or alkylcarbonyl; R3 is H, halogen or haloalkyl; R4 is H, halogen or alkyl; R5 to R10 are each independently H, halogen, alkyl or cyano; and n is an integer of 0 to 3.]SELECTED DRAWING: None

Description

The present invention presents a novel nitrocatechol derivative or a salt thereof having a catechol-O-methyltransferase (COMT) inhibitory action and a dopa decarboxylase (DDC) inhibitory action, and salts thereof. Regarding the pharmaceutical composition contained.

Parkinson's disease is caused by degeneration of dopaminergic nerves in the black muscle rigidity and ventral cover area of the brain, resulting in a decrease in the neurotransmitter dopamine, resulting in akinesia / behavior, resting tremor, and postural instability. , A progressive neurodegenerative disease characterized by akinesia due to muscle rigidity.

In recent years, with the aging of the population in Japan, the prevalence rate is increasing, with 100 to 150 out of 100,000 and 150 to 200 in Europe and the United States. The onset is more common in middle-aged and elderly people, and the incidence rate tends to increase as the elderly age. In addition, there is a case called juvenile Parkinson's disease that develops before the age of 40, and in some cases, a genetic abnormality has been clarified.

Treatment of Parkinson's disease includes surgical and drug therapy. Surgical treatment includes, for example, deep brain electrical stimulation therapy by stereotactic brain surgery, but it requires electrode attachment to the brain and implantation of a chest stimulator, which is a heavy burden on the elderly and is affected by the high magnetic field of the device. There is a high risk of intracerebral hemorrhage.

Drug therapies include dopamine receptor stimulants, monoamine oxidase B inhibitors, and adenosine A2a receptor antagonists as drugs with new mechanisms, but even today, dopamine replacement therapy with L-dopa is the most effective. Treatment method. L-dopa is a precursor of dopamine, and after translocating into the brain, it is metabolized to dopamine and exerts its action. However, when L-dopa enters the body, it is rapidly metabolized by peripheral COMT and DDC, and has a short half-life in blood. Therefore, each inhibitor is administered at the same time to halve L-dopa in blood. Prolonging the period and increasing the amount of L-dopa transferred into the brain and the amount of dopamine produced in the brain are effective means for improving motor symptoms (Non-Patent Document 1).

DDC inhibitors include carbidopa ((-)-L-α-hydrazino-α-methyl-β- (3,4-dihydroxybenzene) propionic acid monohydrate), and L-dopa as a mixture. Although it is used in combination, the duration of the effect is shortened as the disease progresses, and diurnal fluctuations in motor symptoms called the wear-off phenomenon are observed. Therefore, it is necessary to further improve the symptom by increasing the blood L-dopa concentration in combination with a COMT inhibitor (Non-Patent Document 2).

Many catechol compounds have been developed as COMT inhibitors (for example, Non-Patent Documents 3 and 1 to 8), among which entacapone ((E) -2-cyano-N, N-diethyl-3-3). (3,4-Dihydroxy-5-nitrophenyl) acrylamide) is used in many patients, but has a problem of weak action and lack of sustainability (Non-Patent Document 4). In addition, tolcapone (3,4-dihydroxy-4'-methyl-5-nitrobenzophenone) has been reported to have hepatic dysfunction (Non-Patent Document 5). More recently, a more potent and persistent COMT inhibitor, opicapon (5- [3- (2,5-dichloro-4,6-dimethyl-1-oxy-pyridine-3-yl) -1,2,4). −Oxadiazole-5-yl] -3-nitrobenzene-1,2-diol) has been developed (Non-Patent Document 6).

However, when a COMT inhibitor and a DDC inhibitor are used in combination, it is difficult to regulate the blood L-dopa concentration because the onset time and duration of the action are different for each drug, which is as expected. Problems such as ineffectiveness or excessive effect may cause side effects such as dyskinesia.

Therefore, it is considered that a pharmaceutical compound having two actions, COMT inhibition and DDC inhibition, can easily regulate L-dopa by equally expressing both actions, and patient convenience and medication compliance. From the aspect as well, the development of new dual inhibitors is desired.

JP-A-2008-308495 JP 2009-508902 Special table 2009-533423 Special table 2009-544571 JP 2011-21010 JP 2011-146657 JP 2011-021009 JP 2012-51884

Ｋｉｓｓ ＬＥ ａｎｄ Ｓｏａｒｅｓ−ｄａ−Ｓｉｌｖａ Ｐ．，Ｊ Ｍｅｄ Ｃｈｅｍ．２０１４，５７，８６９２−８７１７．

Ｂｅｎａｂｏｕ Ｒ ａｎｄ Ｗａｔｅｒｓ Ｃ．，Ｅｘｐｅｒｔ Ｏｐｉｎ Ｄｒｕｇ Ｓａｆ．２００３，２，２６３−２６７． Ｒｏｃｈａ ＪＦ ｅｔ ａｌ．，Ｂｒ Ｊ Ｃｌｉｎ Ｐｈａｒｍａｃｏｌ．２０１７，８３，５４０−５５３．

Kiss LE and Soares-da-Silva P.M. , J Med Chem. 2014, 57,8692-8717.

Benabou Rand Waters C.I. , Expert Opine Drug Saf. 2003, 2, 263-267. Rocha JF et al. , Br J Clin Pharmacol. 2017, 83, 540-553.

An object of the present invention is to provide a novel nitrocatechol derivative having a COMT inhibitory action and a DDC inhibitory action or a salt thereof, and a pharmaceutical composition containing them.

As a result of diligent studies to solve the above problems, the present inventors have found a novel nitrocatechol derivative having a dual inhibitory action of COMT and DDC represented by the formula (1).

［式中、
Ｒ^１〜Ｒ^２は、水素原子、置換されていてもよいＣ_１−Ｃ_６アルキルカルボニル基、置換されていてもよいＣ_１−Ｃ_６アルコキシカルボニル基、置換されていてもよいＣ_１−Ｃ_６アルキルアミノカルボニル基を示し、
Ｒ^３は、水素原子、ハロゲン原子、ハロアルキル基、シアノ基、カルボキシ基を示し；
Ｒ^４は、水素原子、ハロゲン原子、置換されていてもよいＣ_１−Ｃ_６アルキル基、ハロアルキル基、シアノ基、カルボン酸、アミノカルボニル基、置換されていてもよいＣ_１−Ｃ_６アルキルスルファニル基、ハロアルキルスルファニル基、置換されていてもよいアリールスルファニル基、置換されていてもよいヘテロアリールスルファニル基、置換されていてもよいＣ_１−Ｃ_６アルコキシ基、置換されていてもよいアリールオキシ基、置換されていてもよいヘテロアリールオキシ基、置換されていてもよいＣ_１−Ｃ_６アルコキシカルボニル基、置換されていてもよいＣ_１−Ｃ_６アルキルカルボニル基、置換されていてもよいアリールカルボニル基、置換されていてもよいヘテロアリールカルボニル基、置換されていてもよいＣ_１−Ｃ_６のアルキルスルホニル基、置換されていてもよいアリールスルホニル基、置換されていてもよいヘテロアリールスルホニル基、置換されていてもよいＣ_１−Ｃ_６のアルキルスルフィニル基、置換されていてもよいアリールスルフィニル基、置換されていてもよいヘテロアリールスルフィニル基、置換されていてもよいＣ_１−Ｃ_６のアルキルアミノカルボニル基、置換されていてもよいアミノスルホニル基、置換されていてもよいヘテロシクロアルキルカルボニル基、置換されていてもよいベンゾフラン、置換されていてもよい２，３−ジヒドロフラン、置換されていてもよいクロマン環、置換されていてもよい２−クロマノン環、置換されていてもよい３−クロマノン環、置換されていてもよい４−クロマノン環、置換されていてもよいクマリン環、置換されていてもよいクロモン環、置換されていてもよい２−クマラノン環、置換されていてもよいインデン環、置換されていてもよいインデノン環、置換されていてもよいフタリド環を示し、
Ｒ^５〜Ｒ^１０は、それぞれ独立に水素原子、ハロゲン原子、Ｃ_１−Ｃ_６アルキル基、シアノ基、隣接するお互いでカルボニル基を形成し、若しくは隣接するお互いでシクロアルキル基を形成してもよく；
Ｒ^１１は、水素原子、置換されていてもよいＣ_１−Ｃ_６アルキルカルボニル基、置換されていてもよいＣ_１−Ｃ_６アルコキシカルボニル基、置換されていてもよいＣ_１−Ｃ_６アルキルアミノカルボニル基を示し、
Ｘ、Ｙ、Ｚは、それぞれ単結合、炭素原子、酸素原子、窒素原子、硫黄原子を示し；

Ｑ^１〜Ｑ^６は、炭素原子（各々の炭素原子は、水素原子、置換されていてもよいＣ_１−Ｃ_６アルキル基、置換されていてもよいＣ_１−Ｃ_６アルキルスルファニル基、置換されていてもよいＣ_１−Ｃ_６アルキルスルホニル基、置換されていてもよいＣ_１−Ｃ_６アルコキシ基、ハロゲン原子、水酸基、ニトロ基、トリフルオロメチル基、シアノ基、カルボキシ基で置換でされていてもよい、又は炭素原子もしくはヘテロ原子を介して環を形成していてもよい）、窒素原子、又は、隣接するお互いで環を形成してもよく、若しくはＱ^２とＱ^３は一緒で硫黄原子、又は酸素原子を示し；
ｎは、０〜３を示し（但し、Ｑ^２〜Ｑ^６のうち１つが窒素原子で残りが炭素原子の場合の時は、ｎは１〜３を示す）；
環Ａは、３〜６の複素環式化合物を示す。］That is, the present invention
[1] A compound represented by the following general formula (1), a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing these.

[During the ceremony,
R ^{1 to} R ² are a hydrogen atom, a C _1- C ₆ alkylcarbonyl group which may be substituted, a C _1- C ₆ alkoxycarbonyl group which may be substituted, and a C _1- C which may be substituted. Shows ₆ alkylaminocarbonyl groups,
R ³ represents a hydrogen atom, a halogen atom, a haloalkyl group, a cyano group, a carboxy group;
R ⁴ is a hydrogen atom, a halogen atom, an optionally substituted C _1- C ₆ alkyl group, a haloalkyl group, a cyano group, a carboxylic acid, an aminocarbonyl group, and an optionally substituted C _1- C ₆ alkyl sulfanyl. group, halo alkylsulfanyl group, optionally substituted arylsulfanyl group, optionally substituted heteroaryl sulfanyl groups, optionally substituted C ₁ -C ₆ alkoxy group, an optionally substituted aryloxy group , optionally substituted heteroaryloxy group, an optionally substituted C ₁ -C ₆ alkoxycarbonyl group, an optionally substituted C ₁ -C ₆ alkylcarbonyl group, an arylcarbonyl substituted group, optionally substituted heteroarylcarbonyl group, an alkylsulfonyl group optionally C ₁ -C ₆ optionally substituted, may be substituted arylsulfonyl group, optionally substituted heteroarylsulfonyl group, alkylsulfinyl group optionally C ₁ -C ₆ optionally substituted, an optionally substituted arylsulfinyl group, optionally substituted heteroaryl arylsulfinyl group, alkyl optionally C ₁ -C ₆ substituted Aminocarbonyl groups, optionally substituted aminosulfonyl groups, optionally substituted heterocycloalkylcarbonyl groups, optionally substituted benzofurans, optionally substituted 2,3-dihydrofurans, substituted May be chroman ring, optionally substituted 2-chromanone ring, optionally substituted 3-chromanone ring, optionally substituted 4-chromanone ring, optionally substituted coumarin ring, substituted A chromon ring which may be substituted, a 2-cumalanone ring which may be substituted, an inden ring which may be substituted, an indenone ring which may be substituted, and a phthalide ring which may be substituted are shown.
R ⁵ to R ¹⁰ each independently represent a hydrogen atom, a halogen atom, C ₁ -C ₆ alkyl, cyano group, form a carbonyl group with each other adjacent, or even to form a cycloalkyl group with the adjacent one another Often;
R ¹¹ represents a hydrogen atom, an optionally substituted _C 1 -C ₆ alkylcarbonyl group, an optionally substituted _C 1 -C ₆ alkoxycarbonyl group, an optionally substituted _C 1 -C ₆ alkylamino Shows a carbonyl group,
X, Y and Z represent single bonds, carbon atoms, oxygen atoms, nitrogen atoms and sulfur atoms, respectively;

Q ¹ to Q ⁶ is a carbon atom (each carbon atom is hydrogen atom, optionally substituted _C 1 -C ₆ alkyl group, optionally substituted _C 1 -C ₆ alkylsulfanyl group, substituted It is substituted with a C _1- C ₆ alkylsulfonyl group which may be present, a C _1- C ₆ alkoxy group which may be substituted, a halogen atom, a hydroxyl group, a nitro group, a trifluoromethyl group, a cyano group, and a carboxy group. may be, or a carbon atom or may form a ring through a hetero atom), a nitrogen atom, or may form a ring with each other adjacent, or Q ² and Q ³ are sulfur together Indicates an atom or an oxygen atom;
n represents 0 to 3 (provided ^that when the rest is in the case of carbon atoms in one of the nitrogen atoms of the Q 2 to Q ^6, n represents 1 to 3);
Ring A represents 3 to 6 heterocyclic compounds. ]

（式中、
Ｒ^１２は、水素原子、置換されていてもよいＣ_１−Ｃ_６アルキル基、カルボキシ基、置換されていてもよいＣ_１−Ｃ_６アルコキシカルボニル基、置換されていてもよいアミノカルボニル基、シアノ基を示し、
Ｒ^１３は、水素原子、Ｃ_１−Ｃ_６アルキル基を示す）である、［１］記載の化合物、又はその医薬上許容される塩、及びこれらを含んでなる医薬組成物。
［３］Ｒ^１およびＲ^２が、水素原子である、［１］、又は［２］記載の化合物、又はその医薬上許容される塩、及びこれらを含んでなる医薬組成物。
［４］Ｒ^１１が、水素原子である［３］記載の化合物、又はその医薬上許容される塩、及びこれらを含んでなる医薬組成物。
［５］Ｑ^１〜Ｑ^６は、炭素原子（各々の炭素原子は、水素原子、ハロゲン原子で置換でされていてもよい）を示し；
ｎは、１〜３を示す［４］記載の化合物、又はその医薬上許容される塩、及びこれらを含んでなる医薬組成物に関する。[2] The heterocyclic compound of ring A is

(During the ceremony
R ¹² is a hydrogen atom, an optionally substituted C ₁ -C ₆ alkyl group, a carboxy group, an optionally substituted C ₁ -C ₆ alkoxycarbonyl group, an optionally substituted amino group, a cyano Show the group,
R ¹³ is a hydrogen atom, a a C ₁ -C ₆ alkyl group), [1] the compounds described, or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions comprising these.
[3] A compound according to [1] or [2], wherein R ¹ and R ² are hydrogen atoms, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing these.
[4] A compound according to [3], wherein R ¹¹ is a hydrogen atom, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing these.
[5] Q ¹ ~Q ⁶ is a carbon atom (the carbon atoms of each of a hydrogen atom, may also optionally be substituted by a halogen atom) indicates;
n relates to the compound according to [4] showing 1-3, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing these.

The novel nitrocatechol compound of the present invention or a salt thereof is highly safe, has an excellent COMT inhibitory action and a DDC inhibitory action, and is useful for the treatment of Parkinson's disease.

Hereinafter, the present invention will be specifically described.

As described herein, "may be substituted" means that it is unsubstituted or has 1 to 5 substituents, and when it has a plurality of substituents, those substituents are used. They may be the same or different from each other.

Examples of the "halogen atom" in the present specification include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

The "C _1- C ₆ alkyl group" means a hydrocarbon chain which may be linear, branched chain, cyclic, or a combination thereof. For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, t-butyl group, n-pentyl group, n-hexyl group, cyclopropyl group, cyclobutyl group. , Cyclopentyl group, cyclohexyl group and the like.

“Haloalkyl group” means a C1-6 alkyl group substituted with 1 to 3 homologous or dissimilar halogen atoms, for example, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a pentafluoroethyl group. And so on.

Examples of the "C _1- C ₆ alkyl sulfanyl group" include methyl sulfanyl group, ethyl sulfanyl group, n-propyl sulfanyl group, isopropyl sulfanyl group, cyclopropyl sulfanyl group, cyclopentyl sulfanyl group and the like.

Examples of the "haloalkylsulfanil group" include a trifluoromethylsulfanil group and the like.

Examples of the "arylsulfanil group" include a phenylsulfanil group and a naphthylsulfanil group.

Examples of the "C _1- C ₆ alkoxy group" include a methoxy group, an ethoxy group, an isopropoxy group, a t-butoxy group, a cyclopropoxy group, a cyclobutyloxy group, a cyclopentyloxy group and the like.

Examples of the "aryloxy group" include a phenoxy group and a naphthyloxy group, and examples of the "heteroaryloxy group" include a pyridyloxy group and a thiophenoxy group.

Examples of the "alkoxycarbonyl group of C _1- C ₆ " include a methoxycarbonyl group, an ethoxycarbonyl group, a t-butoxycarbonyl group and the like.

Examples of the "C _1- C ₆ alkylcarbonyl group" include a methylcarbonyl group, an ethylcarbonyl group, an isobutylcarbonyl group, a cyclopropylcarbonyl group, a cyclohexylcarbonyl group and the like.

Examples of the "arylcarbonyl group" include a phenylcarbonyl group and the like, and examples of the "heteroarylcarbonyl group" include a pyridinylcarbonyl group, a thienylcarbonyl group, a thiazolocarbonyl group and the like.

The "C ₁ -C ₆ alkylsulfonyl group", for example, methanesulfonyl group, isopropylsulfonyl group, cyclopentylsulfonyl group, and the like.

Examples of the "arylsulfonyl group" include a phenylsulfonyl group and the like.

The "heteroarylsulfonyl group" is a monocyclic or bicyclic heterocycle containing 1 to 4 heteroatoms selected from the group consisting of 1 to 5 carbon atoms and oxygen, nitrogen and sulfur atoms. It has a sulfonyl group having a ring, and examples thereof include a pyridylsulfonyl group and a thienylsulfonyl group.

The "C ₁ -C ₆ alkylsulfinyl group", for example, methylsulfinyl group, isopropyl sulfinyl group, a cycloalkyl pentylsulfamoyl sulfinyl group and the like.

Examples of the "arylsulfinyl group" include a phenylsulfinyl group.

The "heteroarylsulfinyl group" is a monocyclic or bicyclic heterocycle containing 1 to 5 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms. It has a ring-bearing sulfinyl group, and examples thereof include pyridylsulfinyl groups and thienylsulfinyl groups.

The "C ₁ -C ₆ alkylaminocarbonyl group", for example, methylaminocarbonyl group, ethylaminocarbonyl group, cyclopropylamino group, and the like cyclohexylamino carbonyl group.

Examples of the "aminosulfonyl group" include a methylaminosulfonyl group and the like.

The "heterocycloalkylcarbonyl group" represents a carbonyl compound having a saturated heterocycle having a 4- to 7-membered ring containing a nitrogen atom, an oxygen atom, and a sulfur atom in the ring and bonded via a carbon atom. For example, tetrahydrofuryl Examples thereof include a carbonyl group, a tetrahydrothienyl carbonyl group, a pyrrolidinyl carbonyl group, and a piperidinyl carbonyl group.

The "heterocyclic compound" is a 5- or 6-membered saturated compound or an unsaturated ring compound containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in a ring, for example. The 5-membered ring heterocycles include pyrrolidine, pyrrol, pyrrolin, pyrazole, pyrazoline, pyrazolidine, imidazole, imidazoline, triazole, triazoline, tetrazole, furan, dihydrofuran, dioxolan, thiophene, dihydrothiophene, thiazole, thiadiazol, isothiazole, isothiazoline. , Oxadiazole, isoxazole, oxadiazole, dihydroisoxazole, diazoline, oxadiazolin, isooxazoline, dioxazoline and the like, and examples of the 6-membered ring heterocycle include piperidine, pyridine, pyridazine, pyrimidine, tetrahydropyran, Examples thereof include dioxane, morpholin, thiomorpholin, and ditian. Further, the positions of the heteroatoms in these heterocycles and the positions of the substituents of the heterocycle which may be substituted are not particularly limited as long as they are chemically acceptable positions.

Ｑ^１〜Ｑ^６は、炭素原子（各々の炭素原子は、水素原子、置換されていてもよいＣ_１−Ｃ_６アルキル基、置換されていてもよいＣ_１−Ｃ_６アルキルチオ基、置換されていてもよいＣ_１−Ｃ_６アルコキシ基、ハロゲン原子、ニトロ基、トリフルオロメチル基、シアノ基、カルボン酸で置換でされていてもよい）、窒素原子、又は、隣接するお互いで環を形成してもよく、若しくはＱ^２とＱ^３は一緒で硫黄原子、又は酸素原子を示し；
ｎは、０〜３を示し（但し、Ｑ^２〜Ｑ^６のうち１つが窒素原子で残りが炭素原子の場合の時は、ｎは１〜３を示す）である。In a preferred embodiment of the present invention, the heterocyclic compound of the general formula (1) ring A is a triazole, tetrazole, oxazole, oxadiazole, dihydroisoxazole ring, thiazole ring, thiadiazole ring;
R ¹ and R ² are hydrogen atoms;
R ³ represents a hydrogen atom, a halogen atom, a haloalkyl group, a cyano group, a carboxy group;
R ⁴ is a hydrogen atom, a halogen atom, an optionally substituted C _1- C ₆ alkyl group, a haloalkyl group, a cyano group, a carboxy group, an aminocarbonyl group, and an optionally substituted C _1- C ₆ alkyl sulfanyl. group, halo alkylsulfanyl group, optionally substituted arylsulfanyl group, optionally substituted heteroaryl sulfanyl groups, optionally substituted C ₁ -C ₆ alkoxy group, an optionally substituted aryloxy group , optionally substituted heteroaryloxy group, an optionally substituted C ₁ -C ₆ alkoxycarbonyl group, an optionally substituted C ₁ -C ₆ alkylcarbonyl group, an arylcarbonyl substituted group, optionally substituted heteroarylcarbonyl group, an alkylsulfonyl group optionally C ₁ -C ₆ optionally substituted, may be substituted arylsulfonyl group, optionally substituted heteroarylsulfonyl group, alkylsulfinyl group optionally C ₁ -C ₆ optionally substituted, an optionally substituted arylsulfinyl group, optionally substituted heteroaryl arylsulfinyl group, alkyl optionally C ₁ -C ₆ substituted Shows aminocarbonyl groups, optionally substituted aminosulfonyl groups, optionally substituted heterocycloalkylcarbonyl groups, phthalide rings;
R ^{5 to} R ¹⁰ independently represent a hydrogen atom and a halogen atom, respectively;
R ¹¹ represents a hydrogen atom;
X, Y and Z represent single bonds, carbon atoms, oxygen atoms, nitrogen atoms and sulfur atoms, respectively;

Q ¹ to Q ⁶ is a carbon atom (each carbon atom is hydrogen atom, optionally substituted _C 1 -C ₆ alkyl group, optionally substituted _C 1 -C ₆ alkylthio group, substituted good C ₁ -C ₆ alkoxy group, a halogen atom, a nitro group, a trifluoromethyl group, a cyano group, may be substituted with a carboxylic acid), nitrogen atom, or form a ring with each other adjacent and it may be, or Q ² and Q ³ are a sulfur atom, or oxygen atom in together;
n represents 0 to 3 (provided ^that when the rest is in the case of carbon atoms in one of the nitrogen atoms of the Q 2 to Q ^6, n represents 1 to 3) is.

^Further, a preferred embodiment of the ^{Q 1 ~Q 6, Q 1 ~Q} 6 carbon atoms carbon atoms (each a hydrogen atom, an optionally substituted _C 1 -C ₆ alkyl group, optionally substituted good C ₁ -C ₆ alkylthio group, an optionally substituted C ₁ -C ₆ alkoxy group, a halogen atom, a nitro group, a trifluoromethyl group, a cyano group, may be substituted with a carboxy group), a nitrogen atom, or may form a ring with each other adjacent, or Q ² and Q ³ are include the group represents a sulfur atom, or oxygen atom in together, for example, groups shown below.

A preferred embodiment of the general formula (1) is a compound composed of a combination of each of the preferred groups described above. For example, the compounds described in Examples, pharmaceutically acceptable salts thereof, or hydrates thereof, or a solvent thereof. Japanese products can be mentioned.

The compound of the present invention or a pharmaceutically acceptable salt, hydrate, or solvate thereof represented by the general formula (1) is a geometric isomer or tautomer based on a double bond depending on the type of substituent. May be present, or due to the presence of asymmetric carbon atoms, optical isomers and diastereomers may be present. The present invention includes all isolated or mixtures of these isomers.

The salt of the compound of the present invention is a pharmaceutically acceptable salt of the compound of the general formula (1), and can be produced by treating the compound of the general formula (1) with a desired base in a solvent. .. Examples of such a salt form include a lithium salt, a potassium salt, a sodium salt and the like, and a sodium salt is preferable. The compounds of the present invention also include compounds labeled with various radioactive or non-radioactive isotopes.

The compound of the present invention represented by the general formula (1) may exist as an isomer, for example, a geometric isomer, an optical isomer or a diastereo isomer may exist. In the present invention, isolated isomers, arbitrary mixtures, racemates and the like are all included.

The compound of the present invention represented by the general formula (1), or a pharmaceutically acceptable salt thereof, includes a prodrug as an equivalent compound thereof within the scope of the present invention. A "prodrug" is a compound that is converted into a compound of the general formula (1) by a metabolic mechanism in the living body, that is, enzymatically oxidized, reduced, hydrolyzed, or hydrolyzed by gastric acid in the living body. A compound that changes to the compound of the general formula (1). Examples of the prodrug of the compound of the general formula (1) include compounds in which a phosphate group and a hydroxyl group are modified to an acyl group, an alkyl group, or the like, for example, a compound in which acetylation, pivaloylation, or pivaloyloxymethylation is performed. Can be mentioned. These compounds can be synthesized from the compound of the general formula (1) by a known method. Further, these prodrugs are changed to the compound of the general formula (1) under the conditions described in, for example, "The Organic chemistry of drug design and drug action (second edition)" chapter 8 p497-557. There may be.

The method for producing the compound of the present invention is not particularly limited, and for example, it can be produced according to the following steps. In addition, various radioactive or non-radioactive isotope-labeled compounds included in the present invention can also be produced by the isotope substitution raw material in the same manner as in the following production method.

Hereinafter, a typical method for producing a novel nitrocatechol compound will be described.

（式中、Ｒ^９はメチル基、ベンジル基等、Ｒ^１０はメトキシメチル基、メチル基等の水酸基の保護基であり、他の記号は前記と同義である）

(In the formula, R ⁹ is a methyl group, a benzyl group, etc., R ¹⁰ is a hydroxyl protecting group such as a methoxymethyl group, a methyl group, etc., and other symbols have the same meanings as described above)

First step: Compound (3) can be produced by reacting compound (2) with lithium chloride in N, N-dimethylformamide, N-methylpyrrolidone or N-methylmorpholine solvent under warming conditions. it can.

Second step: Compound (4) is treated with aluminum chloride in a solvent, in the presence of a base, or in an acetic acid solvent or in the absence of a solvent under hydrobromic acid at room temperature or under warming conditions. ) Can be manufactured. Examples of the solvent include 1,2-dichloroethane, pyridine and the like. Examples of the base include triethylamine, diisopropylethylamine, pyridine and the like.

Third step: To produce compound (1) by treating compound (4) with hydrochloric acid, boron tribromide, or hydrobromic acid solution in a dichloromethane solvent or without a solvent under room temperature to warming conditions. Can be done.

When the ring A is a 1,2,4-oxadiazole ring, the compound (2-A-1) used in the first step is produced as described in Chemical formula 4 by performing the following normal reaction operation. be able to.

Fourth step: The carboxylic acid intermediate (7) is subjected to a base acid chloride using thionyl chloride, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, oxalyl chloride, etc. under warming conditions from room temperature in an organic solvent. In the presence, mixed acid anhydrides can be produced using ethyl chloroformate, isobutyl chloroformate and the like. The acid chloride and mixed acid anhydride are used as the acylating agent (8) in the sixth step. Examples of the solvent include dichloromethane, tetrahydrofuran, ethyl acetate and the like. Examples of the base include triethylamine, diisopropylethylamine, morpholine and the like.

Fifth step: The cyano compound (5) is made into the compound (6) by reacting it with hydroxylamine in a solvent under room temperature to warming conditions. Examples of the solvent include methanol, ethanol, tetrahydrofuran and the like, and ethanol is preferable.

Sixth step: The acylating agent (8) obtained in the fourth step and the compound (6) obtained in the fifth step are reacted in a solvent in the presence of a base at −20 ° C. to warming conditions. Examples of the solvent include dichloromethane, ethyl acetate, tetrahydrafuran, N, N-dimethylformamide and the like, and examples of the base include triethylamine, diisopropylethylamine, diazabicycloundecene and the like.

Seventh step: The compound (2-A-1) can be produced by adding a catalyst to the compound obtained in the sixth step in a solvent and reacting the compound under room temperature or warming conditions. Examples of the solvent include N, N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran and the like. Examples of the catalyst include p-toluenesulfonic acid, camphorsulfonic acid, tetrabutylammonium fluoride and the like.

The scheme shown above is an example of a method for producing the compounds of the present invention and can be modified in various ways.

The compound (7) in which R ¹ or R ² is substituted can be produced according to, for example, the methods of JP-A-2011-148782, JP-A-2012-51884, etc., or modified.

The method for producing a compound of the present invention can also be produced by desorption of an appropriate protecting group when it has a functional group at the stage of a raw material or an intermediate. Examples of such a functional group include an amino group, a hydroxy group, a carboxy group and the like, and examples of the type of protecting group and the method of desorption are described in, for example, "Protective Groups in Organic Synthesis (Fourth Edition)" (Greene, Wuts). The method and the like can be mentioned.

The compound of the general formula (1) synthesized as described above can be extracted, concentrated, distilled, crystallized, filtered, recrystallized, various chromatographies, etc., which are usual chemical operations, in the free state or as a salt thereof. Can be isolated and purified. When an optical isomer, a stereoisomer, or a positional isomer is contained, each can be isolated by a fractional recrystallization method, a chiral column method, a diastereomer method, or the like.

Since the compound of the present invention has excellent COMT and DDC inhibitory effects, it is useful as a therapeutic or prophylactic agent for Parkinson's disease, and is preferably used in combination with L-dopa. In addition, the compound of the present invention and L-dopa may be used in combination with a DDC inhibitor. Examples of the DDC inhibitor that can be used in combination with the present invention include carbidopa, benserazide and the like. In addition, examples of COMT inhibitors that can be used in combination with the present invention include entacapone, tolcapone, and opicapon.

Compounds of the present invention also include therapeutic or prophylactic agents other than Parkinson's disease, such as depression, dementia with Lewy bodies, juvenile dementia, Alzheimer's disease, and schizophrenia.

The compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof may be used as it is, but a drug containing one or more pharmaceutically acceptable carriers, for example, a pharmaceutical additive. It may be used as a composition. The pharmaceutical composition may be used in any dosage form, such as tablets, pills, capsules, powders, fine granules, granules, liquids, suspensions, syrups, injections, external preparations, suppositories and the like. Can be applied as.

The type of pharmaceutical additive used in a pharmaceutical composition containing the compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient is not particularly limited, but for example, the Pharmaceutical Additives Dictionary (2007). Bases, excipients, lubricants, coating agents, sugar coating agents, wetting agents, binders, disintegrants, solvents, solubilizers, solubilizers, solubilizers, suspending agents, etc. Dispersants, emulsifiers, surfactants, tonicity agents, buffers, pH adjusters, soothing agents, preservatives, preservatives, stabilizers, antioxidants, colorants, sweeteners, etc. alone or in combination as appropriate Can be used.

The compound of the present invention can be used in combination with other therapeutic agents or preventive agents for diseases for which the compound of the present invention is considered to be effective. The combination means administration at the same time, individually, continuously, or at desired time intervals. The co-administration preparation may be a combination preparation or a kit preparation.

In the case of oral administration, the single dose of the compound of the present invention or a salt thereof is about 1 to 100 mg / kg per body weight, and this is administered once a day or 1 to 3 times a week. When administered intravenously, a single dose of about 0.1 to 10 mg / kg per body weight is appropriate, and the dose is administered once a day or once to several times a month. The dose is appropriately determined according to each individual case in consideration of symptoms, age, gender and the like.

Hereinafter, the present invention will be specifically described with reference to Examples, but the present invention is not limited to the following Examples.

The meanings of the abbreviations in the examples are as follows.
¹ H-NMR: Proton Nuclear Magnetic Resonance Spectrum, CDCl ₃ : Deuterated chloroform, DMSO-d ₆ : Deuterated Dimethyl Sulfoxide, D ₂ O: Heavy Water, Hz: Hertz, J: Coupling Constant, m: Multiplet , Sept: Septet, quint: Quintet, q: Quartet, dt: Double triplet, dd: Double doublet, ddd: Double double doublet, t: Triplet, d: Doublet, s: Singlet, br: Broad, M: Molar concentration. MS showed mass spectrometry and was measured by dissolving Example compounds in 0.1% aqueous formic acid solution-acetonitrile using an instrument whose ionization method is ESI (electrospray ionization).

Reference Example 1: (E) -3- [3,4-bis (methoxymethoxy) phenyl] acrylonitrile

To a solution of diethyl cyanomethylphosphonate (1.85 mL) in tetrahydrofuran (20.0 mL) was added 60% sodium hydride (480 mg) under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. A solution of 3,4-bis (methoxymethoxy) benzaldehyde (2.26 g) in tetrahydrofuran (5.0 mL) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (2.43 g).
^{1 1} H-NMR (CDCl ₃ ) δ: 3.50 (3H, s), 3.52 (3H, s), 5.24 (2H, s), 5.26 (2H, s), 5.73 ( 1H, d, J = 16.4Hz), 7.05 (1H, dd, J = 2.4,8.8Hz), 7.16 (1H, d, J = 8.0Hz), 7.22-7 .33 (2H, m).

Reference example 2: 3- [3,4-bis (methoxymethoxy) phenyl] propanenitrile

5% palladium activated carbon (60 mg) was added to a solution of (E) -3- [3,4-bis (methoxymethoxy) phenyl] acrylonitrile (624 mg) prepared in Reference Example 1 in tetrahydrofuran (5.0 mL), and hydrogen was added. The mixture was stirred at room temperature for 5 hours in an atmosphere. After removing the insoluble material, the solvent was evaporated under reduced pressure to give the title compound (250 mg).
^{1 1} H-NMR (CDCl ₃ ) δ: 2.60 (2H, t, J = 10.8Hz), 2.90 (2H, dd, J = 10.8, 11.2Hz), 3.52 (3H, s), 3.53 (3H, s), 5.22 (2H, s), 5.24 (2H, s), 6.83 (1H, dd, J = 3.2, 12.0Hz), 7 .04 (1H, d, J = 3.2Hz), 7.12 (1H, d, J = 12.8Hz).

Reference Example 3: 2-Ethylhexyl propionate 3-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanil}

Tris (dibenzylideneacetone) dipalladium (676 mg), 4,5- in a solution of 4-bromo-1-fluoro-2- (methoxymethoxy) benzene (7.97 g) in 1,4-dioxanthene (50.0 mL). Bis (diphenylphosphino) -9,9-dimethylxanthene (1.46 g) was added 2-ethylhexyl 3-sulfanylpropionate (7.05 g), and the mixture was stirred at 105 ° C. for 11 hours under a nitrogen atmosphere. The solvent was evaporated under reduced pressure, an aqueous citric acid solution and ethyl acetate (60.0 mL) were added to the residue to remove insoluble matters, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (11.2 g).
^{1 1} H-NMR (CDCl ₃ ): δ: 0.85-0.92 (6H, m), 1.25-1.40 (8H, m), 2.60 (2H, t, J = 7.2Hz) ), 3.11 (2H, t, J = 7.2Hz), 3.52 (3H, s), 4.01 (2H, dd, J = 5.6, 2.6Hz), 5.20 (2H) , S), 7.00-7.30 (2H, m), 7.25 (1H, dd, J = 7.6, 1.6Hz).

Reference Example 4: 2,2-Difluoro-2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanil} methyl acetate

参考例３で製造した３−｛［４−フルオロ−３−（メトキシメトキシ）フェニル］スルファニル｝プロピオン酸２−エチルヘキシル（１．００ｇ）のテトラヒドロフラン（３．０ｍＬ）溶液を氷冷し、窒素雰囲気下、１Ｍカリウムｔｅｒｔ−ブトキシドテトラヒドロフラン溶液（３．０ｍＬ）を滴下し、室温で２．５時間撹拌後、５０℃で２０分間撹拌した。氷冷下、ブロモジフルオロ酢酸メチル（５２１ｍｇ）のテトラヒドロフラン（１．０ｍＬ）溶液を滴下し、室温で１．５時間撹拌した。溶媒を減圧留去し、表題化合物を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：３．５３（３Ｈ，ｓ），３．８５（３Ｈ，ｓ），５．２２（２Ｈ，ｓ），７．１２（１Ｈ，ｄｄ，Ｊ＝１０．８，８．４Ｈｚ），７．２４（１Ｈ，ｄｄｄ，Ｊ＝８．４，４．４，２．４Ｈｚ），７．４６（１Ｈ，ｄｄ，Ｊ＝８．４，２．４Ｈｚ）．

A solution of 3-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanyl} propionate 2-ethylhexyl (1.00 g) in tetrahydrofuran (3.0 mL) prepared in Reference Example 3 was ice-cooled and placed in a nitrogen atmosphere. A 1 M potassium tert-butoxide tetrahydrofuran solution (3.0 mL) was added dropwise, and the mixture was stirred at room temperature for 2.5 hours and then at 50 ° C. for 20 minutes. A solution of methyl bromodifluoroacetate (521 mg) in tetrahydrofuran (1.0 mL) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated under reduced pressure to give the title compound.
^{1 1} H-NMR (CDCl ₃ ) δ: 3.53 (3H, s), 3.85 (3H, s), 5.22 (2H, s), 7.12 (1H, dd, J = 10.8) , 8.4Hz), 7.24 (1H, ddd, J = 8.4, 4.4, 2.4Hz), 7.46 (1H, dd, J = 8.4, 2.4Hz).

Reference Example 5: 2,2-Difluoro-2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanil} acetamide

Methyl 2,2-difluoro-2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanyl} prepared in Reference Example 4 and 2M ammonia ethanol solution (5.0 mL) under ice-cooling were added dropwise. The mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (400 mg) as slightly yellow crystals.
^{1 1} H-NMR (CDCl ₃ ) δ: 3.52 (3H, s), 5.23 (2H, s), 7.12 (1H, dd, J = 10.4, 8.8Hz), 7.28 (1H, ddd, J = 8.8, 4.4, 2.4 Hz), 7.50 (1H, dd, J = 8.8, 2.4 Hz).

Reference Example 6: 2,2-Difluoro-2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanil} acetonitrile

In a pyridine (22.0 mL) solution of 2,2-difluoro-2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanyl} acetamide (2.20 g) prepared in Reference Example 5, under ice-cooling, Trifluoromethanesulfonic anhydride (4.40 g) was added dropwise, and the mixture was stirred at room temperature for 10 hours. The solvent was evaporated under reduced pressure, an aqueous citric acid solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (2.10 g) as a slightly yellow oil.
^{1 1} H-NMR (CDCl ₃ ) δ: 3.53 (3H, s), 5.25 (2H, s), 7.19 (1H, dd, J = 10.4, 8.4Hz), 7.33 (1H, ddd, J = 8.4, 4.4, 2.0 Hz), 7.56 (1H, dd, J = 8.4, 2.0 Hz).

Reference Example 7: 2,2-Difluoro-2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanil} -N-hydroxyacetimideamide

In an ethanol (21.0 mL) solution of 2,2-difluoro-2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanyl} acetonitrile (2.10 g) prepared in Reference Example 6, under an ice bath, A 50% hydroxylamine ethanol solution (8.0 mL) was added dropwise, and the mixture was stirred at room temperature for 40 minutes. The solvent was evaporated under reduced pressure to give the title compound (2.45 g) as a slightly yellow oil.
^{1 1} H-NMR (CDCl ₃ ) δ: 3.52 (3H, s), 5.22 (2H, s), 7.11 (1H, dd, J = 10.8, 8.8Hz), 7.27 (1H, ddd, J = 8.8, 4.4, 2.0 Hz), 7.56 (1H, dd, J = 8.8, 2.0 Hz).

Reference Example 8: [4-Fluoro-3- (methoxymethoxy) phenyl] Methanethiol

A solution of 4- (chloromethyl) -1-fluoro-2- (methoxymethoxy) benzene (1.62 g) in N, N-dimethylformamide (9.0 mL) was ice-cooled, and potassium thioacetate (996 mg) was cooled in a nitrogen atmosphere. ) Was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was ice-cooled, lithium hydroxide (819 mg), methanol (3.0 mL) and water (1.5 mL) were added, and the mixture was stirred at room temperature for 45 minutes. An aqueous citric acid solution was added to the reaction solution, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (1.60 g) as a colorless oil.

Reference Example 9: 2,2-difluoro-2-({[4-fluoro-3- (methoxymethoxy) phenyl] methyl} sulfanil) acetamide

A solution of [4-fluoro-3- (methoxymethoxy) phenyl] methanethiol (1.60 g) prepared in Reference Example 8 in tetrahydrofuran (16.0 mL) was ice-cooled, and under a nitrogen atmosphere, methyl bromodifluoroacetate (1.60 g). ), Diazabicycloundecene (1.44 g) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, an aqueous citric acid solution was added, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was ice-cooled, a 4% ammonia-methanol solution (30.0 mL) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (1.85 g) as a white solid.

Reference Example 10: 2,2-Difluoro-2-({[4-fluoro-3- (methoxymethoxy) phenyl] methyl} sulfanil) acetonitrile

Ice in a pyridine (7.0 mL) solution of 2,2-difluoro-2-({[4-fluoro-3- (methoxymethoxy) phenyl] methyl} sulfanyl) acetamide (1.60 g) prepared in Reference Example 9. Under cooling, trifluoromethanesulfonic anhydride (1.90 g) was added dropwise, and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, an aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.75 g) as a slightly yellow oil.

Reference Example 11: 2,2-Difluoro-2-({[4-fluoro-3- (methoxymethoxy) phenyl] methyl} sulfanil) -N-hydroxyacetimideamide

Ice in a solution of 2,2-difluoro-2- ({[4-fluoro-3- (methoxymethoxy) phenyl] methyl} sulfanyl) acetonitrile (0.75 g) prepared in Reference Example 10 in ethanol (7.0 mL). Under cooling, a 50% hydroxylamine ethanol solution (0.20 mL) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure to give the title compound (0.84 g) as a slightly yellow oil.
^{1 1} H-NMR (CDCl ₃ ) δ: 3.52 (3Hs), 4.04 (2H, s), 5.17 (2H, s), 4.90 (2H, bs), 6.94 (1H, 1H, ddd, J = 84,4,5,2.4 Hz), 7.01 (1H, dd, J = 10.8,8.4 Hz), 7.19 (1H, dd, J = 8.4,2) .4Hz).

Reference Example 12: 5- (3,4-dimethoxy-5-nitrophenyl) -3-[(3-methoxyphenyl) methyl] -1,2,4-oxadiazole

(A): A 50% aqueous hydroxyamine solution (2.0 mL) is added to a solution of 2- (3-methoxyphenyl) acetonitrile (588 mg) in ethanol (10.0 mL), the mixture is stirred at 80 ° C. for 6 hours, and the solvent is reduced in pressure. Distilled away.
(B): N, N-dimethylformamide (6.0 mL), 3,4-dimethoxy-5-nitrobenzoyl chloride (736 mg) and diisopropylethylamine (0.60 mL) were added to (a), and the mixture was stirred at room temperature for 15 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure.
(C): N, N-dimethylformamide (6.0 mL) and camphorsulfonic acid (350 mg) were added to (b), and the mixture was stirred at 100 ° C. for 2 hours. Water was added and the precipitated crystals were collected by filtration to give the title compound (524 mg).
^{1 1} H-NMR (CDCl ₃ ) δ: 3.79 (3H, s), 4.00 (3H, s), 4.05 (3H, s), 4.10 (2H, s), 6.72- 6.84 (3H, m), 7.26 (1H, dd, J = 6.4,9.2Hz), 7.76 (1H, d, J = 2.0Hz), 7.80 (1H, d) , J = 2.0Hz).

Reference Example 13: 2-Methoxy-4- {3-[(3-methoxyphenyl) methyl] -1,2,4-oxadiazole-5-yl} -6-nitrophenol

参考例１２で製造した５−（３，４−ジメトキシ−５−ニトロフェニル）−３−［（３−メトキシフェニル）メチル］−１，２，４−オキサジアゾール（５２４ｍｇ）のＮ−メチルモルホリン（５．０ｍＬ）溶液に、塩化リチウム（２４５ｍｇ）を加え、１３０℃で３時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、表題化合物（４５０ｍｇ）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：３．７０（３Ｈ，ｓ），３．９５（３Ｈ，ｓ），４．０９（２Ｈ，ｓ），６．７４−６．９１（３Ｈ，ｍ），７．２２（１Ｈ，ｄｄ，Ｊ＝７．６，８．０Ｈｚ），８．０９（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），８．８４（１Ｈ，ｓ）．

N-methylmorpholine of 5- (3,4-dimethoxy-5-nitrophenyl) -3-[(3-methoxyphenyl) methyl] -1,2,4-oxadiazole (524 mg) prepared in Reference Example 12 Lithium chloride (245 mg) was added to the (5.0 mL) solution, and the mixture was stirred at 130 ° C. for 3 hours. Water was added to the reaction solution, the mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (450 mg).
^{1 1} H-NMR (CDCl ₃ ) δ: 3.70 (3H, s), 3.95 (3H, s), 4.09 (2H, s), 6.74-6.91 (3H, m), 7.22 (1H, dd, J = 7.6, 8.0Hz), 8.09 (1H, d, J = 2.0Hz), 8.84 (1H, s).

Example 1: 5- {3-[(3-Methoxyphenyl) methyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol

1,2-Methoxy-4- {3-[(3-methoxyphenyl) methyl] -1,2,4-oxadiazole-5-yl} -6-nitrophenol (450 mg) produced in Reference Example 13 1, Pyridine (0.54 mL) and aluminum chloride (372 mg) were added to a solution of 2-dichloroethane (5.0 mL), and the mixture was stirred at 55 ° C. for 5 hours. 1M Hydrochloric acid solution was added to the reaction mixture, the mixture was stirred at room temperature for 30 minutes, and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the precipitated crystals were washed with diethyl ether: n-hexane (10: 1) to give the title compound (295 mg).

Example 2: 5- {3-[(3-Hydroxyphenyl) methyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol

Dichloromethane of 5- {3-[(3-methoxyphenyl) methyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol (275 mg) produced in Example 1. A 1M boron tribromide dichloromethane solution (2.4 mL) was added to the (5.0 mL) solution, and the mixture was stirred at room temperature for 15 hours. 1M hydrochloric acid water was added to the reaction mixture, the mixture was stirred at room temperature for 30 minutes, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified on an ODS flash column to give the title compound (80 mg).

Reference Example 14: Methyl 4- (benzyloxy) -5-methoxy-2- (trifluoromethyl) benzoate

2,2-Difluoro-2- (fluorosulfonyl) acetate in a solution of methyl 4- (benzyloxy) -2-iodo-5-methoxybenzoate (3.00 g) in N, N-dimethylformamide (10.0 mL) Methyl (7.2 g) and copper (I) iodide (1.72 g) were added, and the mixture was stirred at 100 ° C. for 20 hours. Ethyl acetate was added to the reaction mixture to remove insoluble matters, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (1.02 g).
^{1 1} H-NMR (CDCl ₃ ) δ: 3.90 (3H, s), 3.94 (3H, s), 5.21 (2H, s), 7.18-7.50 (7H, m).

Reference Example 15: 4- (benzyloxy) -5-methoxy-2- (trifluoromethyl) benzoic acid

Methyl 4- (benzyloxy) -5-methoxy-2- (trifluoromethyl) benzoate (1.02 g) prepared in Reference Example 14 was mixed with tetrahydrofuran: methanol: water (1: 2: 1) (20.0 mL). Lithium hydroxide monohydrate (504 mg) was added, and the mixture was stirred at room temperature for 15 hours. 1M hydrochloric acid water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (1.01 g).
^{1 1} H-NMR (CDCl ₃ ) δ: 3.96 (3H, s), 5.21 (2H, s), 7.28 (1H, s), 7.29-7.46 (5H, m), 7.51 (1H, s).

Reference Example 16: 4- {3- [4-Fluoro-3- (methoxymethoxy) phenyl] -1,2,4-oxadiazole-5-yl} -2-methoxy-5- (trifluoromethyl) phenol

(A): 4- (benzyloxy) -5-methoxy-2- (trifluoromethyl) benzoic acid (440 mg) prepared in Reference Example 15 was dissolved in toluene: tetrahydrofuran (4: 1) (5.0 mL). , Thionyl chloride (0.50 mL) was added, and the mixture was stirred at 65 ° C. for 5 hours. The solvent was evaporated under reduced pressure and azeotropically distilled with toluene.
(B): N, N-dimethylformamide (5.0 mL), diisopropylethylamine (0.30 mL), 4-fluoro-N-hydroxy-3- (methoxymethoxy) benzimideamide (535 mg) were added to (a). , Stirred at room temperature for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
(C): Tetrahydrofuran (15.0 mL) and 1M tetrabutylammonium fluoride tetrahydrofuran solution (3.0 mL) were added to (b), and the mixture was stirred at room temperature for 15 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography.
(D): N, N-dimethylformamide (5.0 mL), acetic acid (1.0 mL) and 5% palladium activated carbon (600 mg) were added to (c), and the mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. After removing the insoluble material, the solvent was evaporated under reduced pressure to give the title compound (200 mg).
^{1 1} H-NMR (CDCl ₃ ) δ: 3.55 (3H, s), 4.05 (3H, s), 5.30 (2H, s), 7.17-7.22 (1H, m), 7.41 (1H, s), 7.55 (1H, s), 7.80-7.91 (1H, m), 8.02-8.12 (1H, m).

Reference Example 17: 4- {3- [4-Fluoro-3- (methoxymethoxy) phenyl] -1,2,4-oxazole-5-yl} -6-methoxy-2-nitro-3- (trifluoromethyl) ) Phenol

4- {3- [4-Fluoro-3- (methoxymethoxy) phenyl] -1,2,4-oxadiazole-5-yl} -2-methoxy-5- (trifluoromethyl) produced in Reference Example 16. ) Phenol (200 mg) was dissolved in acetic acid (2.0 mL), 60% nitrate (40 μL) was added under water cooling, and the mixture was stirred at room temperature for 1.5 hours. Water was added and the precipitated crystals were collected by filtration to give the title compound (170 mg).
^{1 1} H-NMR (CDCl ₃ ) δ: 3.55 (3H, s), 4.10 (3H, s), 5.30 (2H, s), 7.15-7.32 (1H, m), 7.43 (1H, s), 7.72-7.86 (1H, m), 7.94-8.08 (1H, m).

Example 3: 5- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitro-4- (trifluoromethyl) benzene-1, 2-diol

(A): 4- {3- [4-Fluoro-3- (methoxymethoxy) phenyl] -1,2,4-oxazole-5-yl} -6-methoxy-2-nitro-produced in Reference Example 17 Pyridine (0.54 mL) and aluminum chloride (372 mg) were added to a solution of 3- (trifluoromethyl) phenol (170 mg) in 1,2-dichloroethane (5.0 mL), and the mixture was stirred at 55 ° C. for 5 hours. After adding 1M hydrochloric acid water and stirring for 30 minutes, the mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the precipitated crystals were washed with diethyl ether: n-hexane (10: 1).
(B): A 4M hydrochloric acid 1,4-dioxane solution (5.0 mL) was added to (a), and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated under reduced pressure to give the title compound (100 mg).

Reference Example 18: 5- (benzyloxy) -4-methoxy-2-{3- [3- (methoxymethoxy) phenyl] -1,2,4-oxadiazole-5-yl} benzonitrile

(A): 4- (benzyloxy) -2-cyano-5-methoxybenzoic acid (566 mg) synthesized from 5- (benzyloxy) -2-formyl-4-methoxybenzonitrile in the same manner as in Reference Example 23. N-Hydroxy-3- (methoxymethoxy) benzimideamide (490 mg), triethylamine (0.83 mL), 50% 2,4,6-tripropyl 1,3,5, in a solution of ethyl acetate (10.0 mL). A solution of 2,4,6-trioxatriphosphorinan-2,4,6-trioxide ethyl acetate (1.80 mL) was added, and the mixture was stirred at room temperature for 19 hours. Ethyl acetate was added to the reaction mixture, the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
(B): Tetrahydrofuran (20.0 mL) and 1 M tetrabutylammonium fluoride tetrahydrofuran solution (4.0 mL) were added to (a), and the mixture was stirred at room temperature for 15 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (220 mg).
^{1 1} H-NMR (CDCl ₃ ) δ: 3.50 (3H, s), 4.05 (3H, s), 5.24 (2H, s), 5.25 (2H, s), 7.17- 7.22 (1H, m), 7.29 (1H, s), 7.31-7.48 (6H, m), 7.72 (1H, s), 7.81-7.89 (2H, s) m).

Reference Example 19: 5-Hydroxy-4-methoxy-2-{3- [3- (methoxymethoxy) phenyl] -1,2,4-oxadiazole-5-yl} benzonitrile

5- (Benzyloxy) -4-methoxy-2-{3- [3- (methoxymethoxy) phenyl] -1,2,4-oxadiazole-5-yl} benzonitrile (220 mg) prepared in Reference Example 18 ) Was dissolved in methanol: tetrahydrofuran (2: 3) (5.0 mL), 5% palladium activated charcoal (600 mg) was added, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The insoluble material was removed, ethyl acetate was added, the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (178 mg).
^{1 1} H-NMR (CDCl ₃ ) δ: 3.50 (3H, s), 4.09 (3H, s), 5.25 (2H, s), 7.16-7.23 (1H, m), 7.38 (1H, s), 7.42 (1H, dd, J = 8.0, 8.4Hz), 7.72 (1H, d, 0.8Hz), 7.81-7.87 (2H) , M).

Example 4: 3,4-dihydroxy-6- [3- (3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -2-nitrobenzonitrile

Performed from 5-hydroxy-4-methoxy-2-{3- [3- (methoxymethoxy) phenyl] -1,2,4-oxadiazole-5-yl} benzonitrile (178 mg) produced in Reference Example 19. It was produced in the same manner as in Example 3 to obtain the title compound (110 mg).

Example 5: 3,4-dihydroxy-6- [3- (3-hydroxyphenyl) -1,2,4-oxadiazolo-5-yl] -2-nitrobenzoic acid

Ethanol of 3,4-dihydroxy-6- [3- (3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -2-nitrobenzonitrile (90 mg) prepared in Example 4 ( To the 2.0 mL) solution was added a 4 M aqueous sodium hydroxide solution (1.0 mL), and the mixture was stirred at 80 ° C. for 15 hours. 4M hydrochloric acid water was added, the mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by an ODS flash column to give the title compound (10 mg).

Reference Example 20: 2- [4-Fluoro-3- (methoxymethoxy) phenoxy] acetonitrile

To a solution of 4-fluoro-3- (methoxymethoxy) phenol (130 mg) in N, N-dimethylformamide (3.0 mL) was added 60% sodium hydride (45 mg) under ice-cooling, and the mixture was stirred for 10 minutes. Bromoacetonitrile (137 mg) was added and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (148 mg).
^{1 1} H-NMR (CDCl ₃ ) δ: 3.51 (3H, s), 4.72 (2H, s), 5.21 (2H, s), 6.51-6.62 (1H, m), 6.86-6.92 (1H, m), 7.01-7.12 (1H, m).

Reference Example 21: 5- [4- (benzyloxy) -2-iodo-5-methoxyphenyl] -3- [4-fluoro-3- (methoxyphenyl)] -1,2,4-oxadiazole

It was produced in the same manner as in Reference Example 12 using 4- (benzyloxy) -5-methoxy-2-iodobenzoic acid (766 mg) and 4-fluoro-N-hydroxy-3-methoxybenzimideamide (552 mg). Compound (380 mg) was obtained.
^{1 1} H-NMR (CDCl ₃ ) δ: 3.95 (3H, s), 3.99 (2H, s), 5.19 (2H, s), 7.16-7.24 (1H, m), 7.32-7.58 (5H, m), 7.53 (2H, d, J = 4.0Hz), 7.72-7.84 (2H, m).

Reference Example 22: 5- [4- (benzyloxy) -5-methoxy-2-phenoxyphenyl] 3- (4-fluoro-3-methoxyphenyl) -1,2,4-oxadiazole

5- [4- (benzyloxy) -2-iodo-5-methoxyphenyl] -3- [4-fluoro-3- (methoxyphenyl)] -1,2,4-oxadiazole produced in Reference Example 21 Copper (I) iodide (214 mg), 1,10-phenylanthroline (205 mg), cesium carbonate (513 mg) and phenol (141 mg) were added to a solution of (532 mg) in N, N-dimethylformamide (5.0 mL). The mixture was stirred at 110 ° C. for 3 hours. Ethyl acetate was added to the reaction mixture, the insoluble material was removed by filtration, the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (300 mg).
^{1 1} H-NMR (CDCl ₃ ) δ: 3.94 (3H, s), 4.01 (3H, s), 5.11 (2H, s), 6.67 (1H, s) 6.84-6 .95 (1H, m), 7.28-7.34 (5H, m), 7.62-7.72 (3H, m).

Reference Example 23: 2-chloro-3,4-dimethoxy-5-nitrobenzoic acid

2-Chloro-3,4-dimethoxy-5-nitrobenzaldehyde (2.80 g) was dissolved in tetrahydrofuran: water (1: 1) (48.0 mL), and under ice-cooling, 2-methyl-2-butene (2). .1 mL), sodium chlorite (1.35 g) and citric acid (1.60 g) were added, and the mixture was stirred at room temperature for 30 minutes. A 10% aqueous sodium nitrite solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the precipitated crystals were washed with chloroform / n-hexane to give the title compound (1.90 g).
^{1 1} H-NMR (DMSO-d ₆ ) δ: 3.90 (3H, s), 4.01 (3H, s), 8.12 (2H, s)

Reference Example 24: 2-chloro-4,5-dimethoxy-3-nitrobenzoic acid

To a solution of ethyl 4- (benzyloxy) -3-methoxybenzoate (5.90 g) in N, N-dimethylformamide (100 mL), add imide N-chlorosuccinate (4.43 g) and stir at 70 ° C. for 7 hours. did. Water was added to the reaction solution, the mixture was extracted with diethyl ether, the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain ethyl 4- (benzyloxy) -2-chloro-5-methoxybenzoate (6.16 g). The title compound was obtained according to Reference Example 19, Reference Example 17, Reference Example 48, and Example 5.
^{1 1} H-NMR (CDCl ₃ ) δ: 3.96 (3H, s), 4.02 (3H, s), 7.68 (1H, s).

Reference Example 25: 4,5-dimethoxy-3-nitro-2- (phenylsulfanil) benzoic acid

(A): Methyl 4- (benzyloxy) -2-iodo-5-methoxybenzoate (735 mg) was dissolved in 1,4-dioxanthene (6.0 mL), and diisopropylethylamine (0.63 mL) and benzenethiol (benzenethiol) ( 0.25 mL), tris (dibenzylideneacetone) dipalladium (63 mg), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (81 mg), sodium hydroxymethanesulfinate dihydrate (287 mg) Was added, and the mixture was stirred at 100 ° C. for 26 hours. Ethyl acetate was added, the insoluble material was removed, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain methyl 4- (benzyloxy) -5-methoxy-2- (phenylsulfanil) benzoate (488 mg).
(B): Dichloromethane (5.0 mL) and titanium tetrachloride (0.18 mL) were added to (a), and the mixture was stirred at room temperature for 1 hour. 10% hydrochloric acid water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain methyl 4-hydroxy-5-methoxy-2- (phenylsulfanyl) benzoate (0.30 g) as light brown crystals. The title compound was obtained according to Reference Examples 17, 48 and Example 5.
^{1 1} H-NMR (CDCl ₃ ) δ: 3.99 (3H, s), 4.01 (3H, s), 7.15-7.26 (5H, m), 7.63 (1H, s).

Reference Example 26: 4,5-dimethoxy-3-nitro-2- (phenylsulfonyl) benzoic acid

To a solution of methyl 4- (benzyloxy) -5-methoxy-2- (phenylsulfanyl) benzoate (2.03 g) in ethyl acetate (30.0 mL), m-chloroperbenzoic acid (2.83 g) was added. The mixture was stirred at room temperature for 1 hour. Under ice-cooling, an aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with ethyl acetate, the organic layer was washed with an aqueous sodium hydroxide solution, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. .. N-Hexane: ethyl acetate (1: 1) was added to the residue, and the precipitated crystals were collected by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography and combined with crystals to obtain methyl 4- (benzyloxy) -5-methoxy-2-phenylsulfonyl benzoate (1.43 g). The title compound was obtained in the same manner as in Reference Example 25.
^{1 1} H-NMR (DMSO-d ₆ ) δ: 3.85 (3H, s), 4.02 (3H, s), 7.54 (1H, s), 7.67 (2H, dt, J = 1) .6Hz, 7.2Hz), 7.75 (1H, tt, J = 1.6Hz, 7.2Hz), 7.99 (2H, dd, J = 1.6Hz, 7.2Hz).

Reference Example 27: 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzoic acid

(A): Copper (I) iodide (954 mg), 2, in a solution of ethyl 4-acetoxy-2-iodo-5-methoxybenzoate (1.22 g) in N, N-dimethylformamide (20.0 mL). Methyl 2-difluoro-2- (fluorosulfonyl) acetate (1.30 mL) was added, and the mixture was stirred at 80 ° C. for 5 hours. Water was added to the reaction solution to remove insoluble matters, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain ethyl 4-acetoxy-5-methoxy-2- (trifluoromethyl) benzoate (1.37 g).
(B): Dissolved in (a) in ethanol (15.0 mL), added potassium carbonate (1.86 g), and stirred at room temperature for 8 hours. 1M hydrochloric acid water was added to the reaction solution, the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain ethyl 4-hydroxy-5-methoxy-2- (trifluoromethyl) benzoate (1.07 g).
(C): Acetic acid (5.0 mL) and 60% nitric acid (0.40 mL) were added to (b), and the mixture was stirred at room temperature for 5 minutes. Water was added and the precipitated crystals were collected by filtration.
(D): Tetrahydrofuran (10.0 mL), methanol (0.20 mL), triphenylphosphine (1.55 g) and diisopropylazodicarboxylate (1.00 mL) were added to (c), and the mixture was stirred at room temperature for 1 hour. .. Ethyl acetate was added, the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
(E): Methanol (10.0 mL), tetrahydrofuran (10.0 mL) and 2M aqueous sodium hydroxide solution (20.0 mL) were added to (d), and the mixture was stirred at room temperature for 4.5 hours. 1M hydrochloric acid water was added to the reaction solution, the mixture was extracted with ethyl acetate, and then extracted with saturated aqueous sodium hydrogen carbonate solution. 1M hydrochloric acid water was added to the aqueous layer, and the precipitated crystals were collected by filtration. The crystals were washed 3 times with water to give the title compound (595 mg).
^{1 1} H-NMR (DMSO-d ₆ ) δ: 3.91 (3H, s), 4.03 (3H, s), 7.61 (1H, s), 14.26 (1H, brs).

Reference Example 28: 4,5-dimethoxy-2- (methylsulfanil) -3-nitrobenzoic acid

Sodium thiomethoxydo (0.12 g) was added to a solution of methyl 2-fluoro-4,5-dimethoxy-3-nitrobenzoate (0.60 g) in N, N-dimethylformamide (4.0 mL) at room temperature. Stirred for 1.5 hours. 1M hydrochloric acid water was added to the reaction solution, the mixture was extracted with ethyl acetate, washed with water and saturated brine, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain methyl 4,5-dimethoxy-2-methylthio-3-nitrobenzoate. The title compound was obtained as a colorless solid (0.38 g) according to Example 5.
^{1 1} H-NMR (CDCl ₃ ) δ: 2.47 (3H, s), 3.98 (3H, s), 3.99 (3H, s), 7.77 (1H, s).

Reference Example 29: 3- [4- (benzyloxy) -3-methoxy-5-nitrophenyl] -5-methyl-5-phenyl-4,5-dihydroisoxazole

(A): N-Chlorosuccinate imide (240 mg) was added to a solution of 4- (benzyloxy) -3-methoxy-5-nitrobenzaldehyde oxime (500 mg) in dichloromethane (5.0 mL), and the mixture was stirred at room temperature for 30 minutes. .. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
(B): Dichloromethane (5.0 mL), 1-methylstyrene (0.28 mL) and triethylamine (1.50 mL) were added to (a), and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (447 mg).
^{1 1} H-NMR (CDCl ₃ ) δ: 1.82 (3H, s), 3.44 (1H, d, J = 16.5Hz), 3.53 (1H, d, J = 16.5Hz), 3 .98 (3H, s), 5.20 (2H, s), 7.25-7.58 (11H, m), 7.69 (1H, d, J = 1.9Hz).

Reference Example 30: 3,4-dimethoxy-5-nitrobenzamide

Thionyl chloride (0.60 mL) was added to a solution of 3,4-dimethoxy-5-nitrobenzoic acid (0.50 g) in ethyl acetate (5.0 mL), and the mixture was refluxed for 1 hour. The solvent was evaporated under reduced pressure, azeotropically distilled with toluene, a 2M ammonia-methanol solution (20.0 mL) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, water was added to the residue, and the precipitated crystals were filtered to give the title compound (0.45 g) as pale yellow crystals.
^{1 1} H-NMR (CDCl ₃ ) δ: 3.99 (3H, s), 4.04 (3H, s), 7.68 (1H, d, J = 2Hz), 7.71 (1H, d, J) = 2Hz).

Reference Example 31: 3,4-Dimethotoxi-5-nitrobenzothioamide

Lawesson's reagent (0.89 g) was added to a solution of 3,4-dimethoxy-5-nitrobenzamide (0.45 g) in toluene (10.0 mL), and the mixture was stirred at 80 ° C. for 2 hours. Water was added to the reaction solution, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.53 g) as yellow crystals.
^{1 1} H-NMR (CDCl ₃ ) δ: 3.99 (3H, s), 4.03 (3H, s), 7.68 (1H, d, J = 2Hz), 7.85 (1H, d, J) = 2Hz).

Reference Example 32: 2- (3,4-dimethoxy-5-nitrophenyl) -4-phenylthiazole-5-carbonitrile

(A): N, N-dimethylbenzamide dimethyl acetal (1.30 g) and 3,4-dimethoxy-5-nitrobenzothioamide (0.40 g) were mixed and stirred at 60 ° C. for 1 hour. Purification by silica gel column chromatography gave N-[(dimethylamino) (phenyl) methylene] -3,4-dimethoxy-5-nitrobenzothioamide as a reddish brown oil.
(B): Bromoacetonitrile (0.13 g) was added to the acetone (5.0 mL) solution of (a), and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure, acetic acid (5.0 mL) was added to the residue, and the mixture was refluxed for 1 hour. Water was added, and the precipitated crystals were collected by filtration and washed with diisopropyl ether to give the title compound (0.19 g) as pale yellow crystals.
^{1 1} H-NMR (CDCl) δ: 4.06 (6H, s), 7.51-7.58 (3H, m), 7.77 (1H, d, J = 2Hz), 7.95 (1H, 1H, d, J = 2Hz), 8.15-8.24 (2H, m).

Reference Example 33: 5- (3,4-dimethoxy-5-nitrophenyl) -3-phenyl-1,2,4-thiadiazole

N-[(dimethylamino) (phenyl) methylene] -3,4-dimethoxy-5-nitrobenzothioamide (0.34 g) in a solution of methanol (4.0 mL), pyridine (0.13 g), hydroxyamine-O -Sulfonic acid (0.14 g) was added, and the mixture was stirred at room temperature for 1 hour. 10% hydrochloric acid water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (0.15 g) as yellow-green crystals.
^{1 1} H-NMR (CDCl ₃ ) δ: 4.08 (6H, s), 7.49-7.56 (3H, m), 7.79 (1H, d, J = 2Hz), 7.98 (1H) , D, J = 2Hz), 8.34-8.43 (2H, m).

Reference Example 34: (E) -1- [4- (benzyloxy) -3-methoxy-5-nitrophenyl] -3-phenylprop-2-ene-1-one

Piperidine (0.38 mL) was added to a solution of benzaldehyde (0.41 mL) in methanol (5.0 mL), and the mixture was stirred at 60 ° C. for 1 hour to 1- [4- (benzyloxy) -3-methoxy-5-nitro. Phenyl] ethane-1-one (602 mg) was added, and the mixture was stirred for 15 hours. Water citrate was added, the mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (600 mg).
^{1 1} H-NMR (CDCl ₃ ) δ: 4.05 (3H, s), 5.29 (2H, s), 7.28-7.56 (9H, m), 7.62-7.78 (2H) , M), 7.80-7.95 (2H, m), 8.00 (1H, d, J = 1.9Hz).

Reference Example 35: 3- [4- (benzyloxy) -3-methoxy-5-nitrophenyl] -5-phenyl-1H-pyrazole

1,4- of (E) -1- [4- (benzyloxy) -3-methoxy-5-nitrophenyl] -3-phenylprop-2-ene-1-one (100 mg) produced in Reference Example 34 Hydrazine monohydrate (20 μL) was added to a dioxane (2.0 mL) solution, and the mixture was stirred at room temperature for 2 hours. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (100 mg) was added to the reaction mixture, and the mixture was stirred for 1 hour. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (31 mg).
^{1 1} H-NMR (CDCl ₃ ) δ: 3.99 (3H, s), 5.21 (2H, s), 6.84 (1H, s), 7.28-7.62 (8H, m), 7.66-7.72 (3H, m), 7.72 (1H, d, J = 1.9Hz).

Reference Example 36: 3,4-dimethoxy-5-nitro-N- (2-oxo-2-phenylethyl) benzamide

2-Amino-1-phenylethane-1-one (400 mg), 1-hydroxybenzotriazole in a solution of 3,4-dimethoxy-5-nitrobenzoic acid (340 mg) in N, N-dimethylformamide (3.0 mL). (245 mg), triethylamine (0.25 mL) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (352 mg) were added, and the mixture was stirred at room temperature for 15 hours. Water (6.0 mL) and saturated aqueous sodium hydrogen carbonate solution (3.0 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (510 mg).
^{1 1} H-NMR (CDCl ₃ ) δ: 4.00 (3H, s), 4.04 (3H, s), 4.95 (2H, d, J = 4.3Hz), 7.39-7.73 (4H, m), 7.80 (1H, d, J = 2.4Hz), 8.00-8.13 (2H, m), 9.09 (1H, s).

Reference Example 37: 2- (3,4-dimethoxy-5-nitrophenyl) -4-phenyl-1H-imidazole

参考例３６で製造した３，４−ジメトキシ−５−ニトロ−Ｎ−（２−オキソ−２−フェニルエチル）ベンズアミド（５００ｍｇ）の酢酸（５．０ｍＬ）溶液に、酢酸アンモニウム（２８０ｍｇ）を加え、１１０℃で５時間撹拌した。反応液に１Ｍ水酸化ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物（２５３ｍｇ）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：４．００（３Ｈ，ｓ），４．０２（３Ｈ，ｓ），７．２２−７．４９（５Ｈ，ｍ），７．６６（１Ｈ，ｄ，Ｊ＝１．９Ｈｚ），７．６２−７．８９（１Ｈ，ｍ），７．８５（１Ｈ，ｄ，Ｊ＝１．９Ｈｚ）．

Ammonium acetate (280 mg) was added to a solution of 3,4-dimethoxy-5-nitro-N- (2-oxo-2-phenylethyl) benzamide (500 mg) prepared in Reference Example 36 in acetic acid (5.0 mL). The mixture was stirred at 110 ° C. for 5 hours. A 1M aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (253 mg).
^{1 1} H-NMR (CDCl ₃ ) δ: 4.00 (3H, s), 4.02 (3H, s), 7.22-7.49 (5H, m), 7.66 (1H, d, J) = 1.9Hz), 7.62-7.89 (1H, m), 7.85 (1H, d, J = 1.9Hz).

Reference Example 38: 2- (3,4-dimethoxy-5-nitrophenyl) -5-phenyl-1,3-oxazole

Concentrated sulfuric acid (3.0 mL) was added to 2- (3,4-dimethoxy-5-nitrophenyl) -4-phenyl-1H-imidazole (350 mg) produced in Reference Example 37, and the mixture was stirred at 80 ° C. for 3 hours. did. A 1M aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (253 mg).
^{1 1} H-NMR (CDCl ₃ ) δ: 4.04 (3H, s), 4.05 (3, s), 7.32-7.53 (4H, m), 7.73 (1H, d, J) = 7.0Hz), 7.83 (1H, d, J = 1.6Hz), 8.05 (1H, d, J = 1.9Hz).

Reference Example 39: 5- [4- (4-Hydroxyphenyl) thiazole-2-yl] -3-nitrobenzene-1,2-diol

(A): 1- [4- (benzyloxy) phenyl] -2-bromoethane-1-one (250 mg) in a solution of 3,4-dimethoxy-5-nitrobenzothioamide (200 mg) in methanol (1.0 mL). Was added, and the mixture was stirred at 120 ° C. for 15 hours, and the solvent was distilled off under reduced pressure.
(B): N-methylmorpholine (5.0 mL) and lithium chloride (120 mg) were added to (a), and the mixture was stirred at 130 ° C. for 5 hours. A 10% aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
(C): 1,2-Dichloroethane (5.0 mL), pyridine (0.43 mL) and aluminum chloride (287 mg) were added to (b), and the mixture was stirred at 50 ° C. for 15 hours. After adding 1M hydrochloric acid water and stirring for 30 minutes, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
(D): Trifluoroacetic acid (2.0 mL) and thioanisole (0.03 mL) were added to (c), and the mixture was stirred at 70 ° C. for 15 hours. The solvent was evaporated under reduced pressure, and the obtained residue was purified on an ODS flash column to give the title compound (50 mg).
^{1 1} H-NMR (DMSO-d ₆ ) δ: 6.79-6.94 (2H, m), 7.58-7.88 (4H, m), 8.11 (1H, s).

Reference Example 40: 4- [5- (3,4-dimethoxy-5-nitrophenyl) -1H-1,2,4-triazole-3-yl] pyridazine

Pyridazine-4-carbohydrazide hydrochloride (146 mg) was added to a solution of ethyl 3,4-dimethoxy-5-nitrobenzimidate (225 mg) in N, N-dimethylformamide (5.0 mL) at 100 ° C. for 15 hours. Stirred. Water was added to the reaction solution, and the precipitated crystals were collected by filtration and washed with water (5.0 mL) three times with ethyl acetate (5.0 mL) to give the title compound (197 mg).
^{1 1} H-NMR (DMSO-d ₆ ) δ: 3.96 (3H, s), 4.04 (3H, s), 8.01 (1H, d, J = 2.8Hz), 8.12 (1H) , D, J = 2.4Hz), 8.22 (1H, dd, J = 3.6, 8.0Hz), 9.40 (1H, d, J = 8.0Hz), 9.83 (1H, 1H, s)

Reference Example 41: 2- (3,4-dimethoxy-5-nitrophenyl) -5- [2- (3,4-dimethoxyphenyl) ethyl] -1,3,4-oxadiazole

(A): 3- (3,4-dimethoxyphenyl) propylcarbohydrazide hydrochloride (108 mg) in a solution of 3,4-dimethoxy-5-nitrobenzoic acid (225 mg) in N, N-dimethylformamide (5.0 mL). ), Triethylamine (0.7 mL) and 50% propylphosphonic acid anhydride ethyl acetate solution (0.60 mL) were added, and the mixture was stirred at room temperature for 1.5 hours. Water citrate was added to the reaction solution, the mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography.
(B): Triphenylphosphine oxide (425 mg) was dissolved in dichloromethane (10.0 mL), trifluoromethanesulfonic anhydride (0.13 mL) was added under ice-cooling, and the mixture was stirred for 5 minutes. (A) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, the mixture was extracted with chloroform, the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by NH silica gel column chromatography to give the title compound (66 mg) as a yellow amorphous substance.
^{1 1} H-NMR (CDCl ₃ ) δ: 3.13 (2H, t, J = 6.8Hz), 3.21-3.28 (2H, m), 3.87 (3H, s), 4.02 (3H, s), 4.06 (3H, s), 6.74-6.84 (3H, m), 7.79 (1H, d, J = 2.0Hz), 7.90 (1H, d) , J = 2.0Hz).

Reference Example 42: 5-ethynyl-1,2-dimethoxy-3-nitrobenzene

（ａ）：３，４−ジヒドロキシ−５−ニトロベンズアルデヒド（５．４７ｇ）のＮ，Ｎ−ジメチルホルムアミド（５５．０ｍＬ）溶液に、炭酸カリウム（６，４０ｇ）、ジメチル硫酸（２．２ｍＬ）を加え、６０℃で撹拌後、反応液に６０％水素化ナトリウム（８８ｍｇ）を加え、６時間撹拌した。析出した結晶をろ取した。
（ｂ）：（ａ）に、テトラヒドロフラン（１１．０ｍＬ）、トリフェニルホスフィン（１．７０ｇ）、メタノール（０．３３ｍＬ）、アゾジカルボン酸ジイソプロピル（１．２７ｍＬ）を加え、１５時間撹拌した。溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィーで精製した。
（ｃ）：（ｂ）にメタノール（１３．０ｍＬ）、炭酸カリウム（６３４ｍｇ）、１−ジアゾアセトニルホスホン酸ジメチル（８８４ｍｇ）を加え，室温で３時間撹拌した。反応液に酢酸エチルを加え、有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、表題化合物（８５０ｍｇ）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：３．１３（１Ｈ，ｓ），３．９３（３Ｈ，ｓ），３．９９（１Ｈ，ｓ），７．１８（１Ｈ，ｄ，Ｊ＝１．９Ｈｚ），７．４７（１Ｈ，ｄ，Ｊ＝１．９Ｈｚ）

(A): Potashium carbonate (6,40 g) and dimethyl sulfate (2.2 mL) were added to a solution of 3,4-dihydroxy-5-nitrobenzaldehyde (5.47 g) in N, N-dimethylformamide (55.0 mL). In addition, after stirring at 60 ° C., 60% sodium hydride (88 mg) was added to the reaction solution, and the mixture was stirred for 6 hours. The precipitated crystals were collected by filtration.
(B): Tetrahydrofuran (11.0 mL), triphenylphosphine (1.70 g), methanol (0.33 mL) and diisopropyl azodicarboxylate (1.27 mL) were added to (a), and the mixture was stirred for 15 hours. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography.
(C): Methanol (13.0 mL), potassium carbonate (634 mg), and dimethyl 1-diazoacetonylphosphonate (884 mg) were added to (b), and the mixture was stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (850 mg).
^{1 1} H-NMR (CDCl ₃ ) δ: 3.13 (1H, s), 3.93 (3H, s), 3.99 (1H, s), 7.18 (1H, d, J = 1.9Hz) ), 7.47 (1H, d, J = 1.9Hz)

Reference Example 43: 4- (3,4-dimethoxy-5-nitrophenyl) -1- (4-fluoro-3-methoxyphenyl) -1H-1,2,3-triazole

Sodium azide (163 mg) and copper acetate (22 mg) were added to a solution of 4-fluoro-3-methoxyphenylboronic acid (400 mg) in methanol (10.0 mL), and the mixture was stirred at 60 ° C. for 1 hour. A solution of 5-ethynyl-1,2-dimethoxy-3-nitrobenzene (497 mg) prepared in Reference Example 42 in acetonitrile (10.0 mL) and copper (I) iodide (17 mg) were added to the reaction solution, and 1 at 85 ° C. Stirred for hours. Hydrochloric acid solution was added to the reaction solution, and the precipitated crystals were collected by filtration to give the title compound (410 mg).
^{1 1} H-NMR (DMSO-d ₆ ) δ: 3.92 (3H, s), 3.99 (3H, s), 4.03 (3H, s), 7.47-7.56 (2H, m) ), 7.73 (1H, dd, J = 2.0Hz, 8.4Hz), 7.89 (1H, d, J = 1.6Hz), 7.94 (1H, d, J = 1.6Hz) , 9.45 (1H, s).

Reference Example 44: 3- (4-Hydroxy-3-methoxyphenyl) ethynylbenzonitrile

2-Methoxy-4-[(trimethylsilyl) ethynyl] phenol (800 mg) in triethylamine (4.0 mL) solution, 3-iodobenzonitrile (916 mg), 1M tetrabutylammonium fluoride tetrahydrofuran solution (4.4 mL), iodine Copper (6.9 mg) and tetrakis (triphenylphosphine) palladium (42 mg) were added, and the mixture was stirred at 50 ° C. for 15 hours. 1M hydrochloric acid water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound (551 mg).

Reference Example 45: 3- [4- (4-Hydroxy-3-methoxyphenyl) -4,5-dihydro-1H-1,2,3-triazole-5-yl] benzonitrile

Sodium azide (256 mg) was added to a solution of 3- (4-hydroxy-3-methoxyphenyl) ethynylbenzonitrile (491 mg) in dimethyl sulfoxide (5.0 mL) prepared in Reference Example 44, and the mixture was stirred at 95 ° C. Ethyl acetate was added to the reaction mixture, the mixture was washed with saturated aqueous citric acid, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (565 mg).
δ: ¹ H-NMR (CDCl ₃ ) δ: 4.00 (3H, s), 6.19 (1H, brs), 7.06 (1H, d, J = 7.8Hz), 7.31-7 .43 (4H, m), 7.44-7.56 (2H, m).

Reference Example 46: 3- [4- (4-Hydroxy-3-methoxy-5-nitrophenyl) -1H-1,2,3-triazole-5-yl] benzonitrile

Acetic acid (565 mg) of 3- [4- (4-hydroxy-3-methoxyphenyl) -4,5-dihydro-1H-1,2,3-triazol-5-yl] benzonitrile (565 mg) prepared in Reference Example 45. 60% nitric acid (81 μL) was added dropwise to the 2.8 mL) solution under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to ice water and extracted with chloroform. The organic layer is washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate to give the title compound (465 mg).

Reference Example 47: Synthesis of 4-hydroxy-3-methoxy-5-nitrobenzonitrile

60% nitric acid (3.1 mL) was added to a solution of 4-hydroxy-3-methoxybenzonitrile (10.0 g) in acetic acid (35.0 mL) under ice-cooling, and the mixture was stirred for 1 hour. N-Hexane was added to the reaction solution, and the precipitated crystals were collected by filtration to give the title compound (7.80 g).

Reference Example 48: Synthesis of 3,4-dihydroxy-5-nitrobenzonitrile

Methanol (1.9 mL) and triphenylphosphine (9.70 g) were added to a solution of 4-hydroxy-3-methoxy-5-nitrobenzonitrile (6.10 g) prepared in Reference Example 47 in tetrahydrofuran (60.0 mL). And diisopropyl azodicarboxylate (7.3 mL) was added, and the mixture was stirred for 15 hours. Ethyl acetate was added to the reaction mixture, the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with ethyl acetate / n-hexane to obtain a crude product (5.40 g) containing the title compound.

Reference Example 49: 5- (3,4-dimethoxy-5-nitrophenyl) -2H-tetrazole

In a solution of 3,4-dihydroxy-5-nitrobenzonitrile (4.80 g) prepared in Reference Example 48 in N, N-dimethylformamide (24.0 mL), sodium azide (2.30 g) and water (24. 0 mL) and zinc bromide (5.70 g) were added, and the mixture was stirred at 120 ° C. for 2 hours. 2M hydrochloric acid water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with 2-propanol / n-hexane to give the title compound (2.30 g).

Reference Example 50: 2-Benzyl-5- (3,4-dimethoxy-5-nitrophenyl) -2H-tetrazole

Potassium carbonate (828 mg), benzyl bromide (0.26 mL) in an acetone (5.0 mL) solution of 5- (3,4-dimethoxy-5-nitrophenyl) -2H-tetrazole (500 mg) prepared in Reference Example 49. Was added, and the mixture was stirred at 60 ° C. for 15 hours. 1M hydrochloric acid water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (507 mg).
^{1 1} H-NMR (CDCl ₃ ) δ: 4.01 (3H, s), 4.03 (3H, s), 5.81 (2H, s), 7.34-7.47 (5H, m), 7.88 (1H, d, J = 1.9Hz), 8.10 (1H, d, J = 1.9Hz).

Reference Example 51: 5- (3,4-dimethoxy-5-nitrophenyl) -2-phenyl-2H-tetrazole

Phenylboronic acid (205 mg) and copper iodide (I) were added to a solution of 5- (3,4-dimethoxy-5-nitrophenyl) -2H-tetrazole (212 mg) prepared in Reference Example 49 in dimethyl sulfoxide (4.0 mL). ) (8.0 mg) was added, and the mixture was stirred at 100 ° C. for 1.5 hours under an oxygen atmosphere. 1M hydrochloric acid water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude product (220 mg) containing the title compound.
^{1 1} H-NMR (CDCl ₃ ) δ: 4.07 (6H, s), 7.51-7.64 (3Hm), 8.00 (1H, d, J = 1.9Hz), 8.19-8 .24 (3H, m).

Reference Example 52: 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) aniline

(A): Diphenylphosphoryl azide (1.20 g) and diisopropylethylamine in a toluene (10.0 mL) solution of 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzoic acid (1.00 g). (1.8 mL) and t-butanol (1.3 mL) were added, and the mixture was stirred at 60 ° C. for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
(B): A 4M ethyl acetate solution (12.0 mL) and a 4M hydrochloric acid 1,4-dioxane solution (60.0 mL) were added to (a), and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, chloroform (5.0 mL) was added to the residue, the insoluble material was filtered off, and the solvent was evaporated under reduced pressure to give the title compound (0.92 g).

Reference Example 53: 1-Azide-4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzene

To the solution of 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) aniline (0.50 g) prepared in Reference Example 52 in dimethyl sulfoxide (8.0 mL), 2M hydrochloric acid water (2.0 mL) was added. , A solution of sodium nitrate (0.20 g) in water (0.5 mL) was added dropwise under ice-cooling, and the mixture was stirred for 15 minutes. A solution of sodium azide (0.20 g) in water (0.5 mL) was added dropwise under ice-cooling. Water was added to the reaction solution, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.90 g).

Reference Example 54: 1- [4,5-dimethoxy-3-nitro-2- (trifluoromethyl) phenyl] -4- (4-fluoro-3-methoxyphenyl) -1H-1,2,3-triazole

Water (15.0 mL) was added to a t-butanol (40.0 mL) solution of 1-azido-4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzene (0.80 g) prepared in Reference Example 53. ), 4-Ethynyl-1-fluoro-2-methoxybenzene (0.40 g), copper (I) iodide (149 mg), tris [(1-benzyl-1H-1,2,3-triazol-yl) methyl ] Amine (138 mg) was added and refluxed for 15 hours. The insoluble material was removed, and the solvent was distilled off under reduced pressure. Water was added, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.37 g).

Example 6: 4- [5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazole-3-yl] benzoic acid

The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 3 using methyl 4-cyanobenzoate.

Example 7: 5- [3- (Phenylmethyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 1 using 2-phenylacetonitrile.

Example 8: 3-Nitro-5-[3- (1-phenylethyl) -1,2,4-oxazole-5-yl] benzene-1,2-diol

The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 1 using 2-phenylpropionitrile.

Example 9: 3-Nitro-5-[3- (1-phenylpropyl) -1,2,4-oxadiazole-5-yl] benzene1,2-diol

The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 1 using 2-phenylbutanenitrile.

Example 10: 3-Nitro-5-[3- (2-phenylethyl) -1,2,4-oxazole-5-yl] benzene-1,2-diol

The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 1 using 3-phenylpropionitrile.

Example 11: 5- [3- (2-Cyclohexylethyl) -1,2,4-oxazole-5-yl] benzene-1,2-diol

The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 1 using 3-cyclohexylpropionitrile.

Example 12: 5- [3- (2,3-dimethylphenyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 1 using 2,3-dimethylbenzonitrile.

Example 13: 3-Nitro-5-[3- (2,3,4,5-tetrafluorophenyl) -1,2,4-oxazole-5-yl] benzene-1,2-diol

The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 1 using 2,3,4,5-tetrafluorobenzonitrile.

Example 14: 3- [5- (3,4-hydroxy-5-nitrophenol) -1,2,4-oxadiazole-3-yl] benzoic acid

Using 3-cyanobenzoic acid, the title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 15: 5- {3- [2- (4-Hydroxyphenyl) ethyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol

Using 3- (4-methoxyphenyl) propanenitrile, the title compound was obtained in the same manner as in Reference Examples 12 and 13, Examples 1 and 2.

Example 16: 5- {3- [2- (3-Hydroxyphenyl) ethyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol

Using 3- (3-methoxyphenyl) propanenitrile, the title compound was obtained in the same manner as in Reference Examples 12 and 13, Examples 1 and 2.

Example 17: 5- {3- [2- (3,4-dihydroxyphenyl) ethyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol

Using 3- (3,4-dimethoxyphenyl) propanenitrile, the title compound was obtained in the same manner as in Reference Examples 12 and 13, Examples 1 and 2.

Example 18: 5- {3- [2- (2,3-dihydroxyphenyl) ethyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol

Using 3- (2,3-dimethoxyphenyl) propanenitrile, the title compound (yield 23%) was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.

Example 19: 5- {3-[(4-Hydroxyphenyl) methyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol

Using 2- (4-methoxyphenyl) acetonitrile, the title compound (yield 2%) was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.

Example 20: 5- [3- (3-Hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

Using 3-methoxybenzonitrile, the title compound was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.

Example 21: 5- {2- [5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazole-3-yl] ethyl} benzene-1,2,3-triol

Using 3- (2,3,4-trimethoxyphenyl) propanenitrile, the title compound (yield 19%) was obtained in 4 steps in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.

Example 22: 4-Bromo-5-{2- [5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazole-3-yl] ethyl} benzene-1,2 ， 3-Triol

The title compound (yield 21%) was obtained as a by-product of Example 22.

Example 23: 5-{[5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazole-3-yl] methyl} benzene-1,2,3-triol

Using 2- (3,4,5-trimethoxyphenyl) acetonitrile, the title compound (yield 38%) was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.

Example 24: 5- {3- [2- (3,5-dihydroxyphenyl) ethyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol

Using 3- [3,5-bis (methoxyethoxy) phenyl] propanenitrile, the title compound (yield 3%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 25: 5- {3- [3- (3-Hydroxyphenyl) propyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol

Using 4- (3-methoxyphenyl) butanenitrile, the title compound was obtained in the same manner as in Reference Examples 12 and 13, Examples 1 and 2.

Example 26: 5- {3- [2- (2,5-dihydroxyphenyl) ethyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol

Using 3- [2,5-bis (methoxymethoxy) phenyl] propanenitrile, the title compound (yield 11%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 27: 5-{[(2-Hydroxyphenyl) methyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol

Using 2- (3-methoxyphenyl) acetonitrile, the title compound (yield 2%) was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.

Example 28: 5- {3- [3- (4-Hydroxyphenyl) propyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol

Using 4- (4-methoxyphenyl) butanenitrile, the title compound (yield 48%) was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.

Example 29: 5- {3- [3- (3,4-dihydroxyphenyl) propyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol 4- ( Using 3,4-dimethoxyphenyl) butanenitrile, the title compound was obtained in the same manner as in Reference Examples 12 and 13, Examples 1 and 2.

Example 30: 5-{[3- (3,4-dimethoxyphenyl) methyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol

The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 1 using 2- (3,4-dimethoxyphenyl) acetonitrile.

Example 31: 5- {3-[(3,4-dihydroxyphenyl) methyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol

5-{3-[(3,4-dimethoxyphenyl) methyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol was used in the same manner as in Example 2. The title compound was obtained.

Example 32: 5- {3- [2- (2,4-dihydroxyphenyl) ethyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol

Using 3- (2,4-dimethoxyphenyl) propionitrile, the title compound (yield 21%) was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.

Example 33: 5- {3-[(4-Bromo-3-hydroxyphenyl) methyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol

The title compound was obtained as a by-product of Example 2.

Example 34: 5- {3- [3- (2-Hydroxyphenyl) propyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol

Using 4- (2-methoxyphenyl) butanenitrile, the title compound (yield 22%) was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.

Example 35: 5- [3- (3,4-dihydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

Using 3,4-dimethoxybenzonitrile, the title compound was obtained in the same manner as in Reference Examples 12 and 13, Examples 1 and 2.

Example 36: 5- {3- [2- (2-Hydroxyphenyl) ethyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol

Using 3- (2-methoxyphenyl) propanenitrile, the title compound (yield 7%) was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.

Example 37: 5- {3-[(2,3-dihydroxyphenyl) methyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol

Using 2- [2,3-bis (methoxymethoxy) phenyl] acetonitrile, the title compound (yield 48%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 38: 3- {2- [5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazole-3-yl] ethyl} benzo [b] thiophene-5,6 -Diol

Using 3- (5,6-dimethoxybenzo [b] thiophene-3-yl) propanenitrile, the title compound (yield 27%) was obtained in the same manner as in Reference Examples 12 and 13, Examples 1 and 2. ..

Example 39: 5- [3- (2,3-dihydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

Using 2,3-bis (methoxymethoxy) benzonitrile, the title compound (yield 3%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 40: 4- {2- [5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazole-3-yl] ethyl} benzene-1,2,3-triol

Using 3- [2,3,4-tris (methoxymethoxy) phenyl] propanenitrile, the title compound (yield 61%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 41: 5- [5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazole-3-yl] -1,3-dihydro-2H-benzo [d] imidazole -2-on

Using 2-oxo-2,3-dihydro-1H-benzo [d] imidazole-5-carbonitrile, the title compound (yield 58%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 1.

Example 42: 3-Chloro-4- {2- [5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazole-3-yl] ethyl} benzene-1,2 -Diol

Using 3- (2-chloro-3,4-dimethoxyphenyl) propanenitrile, the title compound (yield 4%) was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.

Example 43: 4- {2- [5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazole-3-yl] ethyl} -3-methylbenzene-1,2 -Diol

Using 3- [3,4-bis (methoxymethoxy) -2-methylphenyl] propanenitrile, the title compound (34%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 44: 5- {3- [2- (2,6-dimethoxyphenyl) ethyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol

Using 3- (2,6-dimethoxyphenyl) propanenitrile, the title compound (yield 83%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 1.

Example 45: 5- {3- [2- (2,6-dihydroxyphenyl) ethyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol

Example 2 with 5-{3- [2- (2,6-dimethoxyphenyl) ethyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol. The title compound (yield 44%) was obtained in the same manner as above.

Example 46: 5- [3- (4-Hydroxy-3-methoxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

Using 3-methoxy-4- (methoxymethoxy) benzonitrile, the title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 47: (E) -5-{3- [2- (3,4-dihydroxyphenyl) ethen-1-yl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene- 1,2-diol

Using (E) -3- [3,4-bis (methoxymethoxy) phenyl] acrylonitrile, the title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 48: 5- {3- [2- (3-fluoro-2-hydroxyphenyl) ethyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol

Using 3- [3-fluoro-2- (methoxymethoxy) phenyl] propanenitrile, the title compound (yield 41%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 49: 3- [5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazole-3-yl] -1- (3-hydroxythiophen-2-yl) propane -1-On

Using 4- (3-methoxythiophene-2-yl) -4-oxobutanenitrile, the title compound (yield 52%) was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.

Example 50: 5- {3- [2- (3,4-dihydroxy-5-methylphenyl) ethyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2- Diol

Using 3- [3,4-bis (methoxymethoxy) -5-methylphenyl] propanenitrile, the title compound (yield 5%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 51: 5- {3- [2- (3-bromo-2,6-dihydrophenyl) ethyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2- Diol

The title compound (yield 17%) was obtained as a by-product of Example 45.

Example 52: 5- [3- (2-Hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

Using 2- (methoxymethoxy) benzonitrile, the title compound (yield 14%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 53: 5- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 3 using 4-fluoro-3- (methoxymethoxy) benzonitrile.

Example 54: 5- [3- (3-Hydroxy-4-methylphenyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

Using 3- (methoxymethoxy) -4-methylbenzonitrile, the title compound was obtained in the same manner as in Reference Examples 12, 13 and Example 3.

Example 55: 5- [3- (2,6-dihydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

Using 2,6-bis (methoxymethoxy) benzonitrile, the title compound (yield 21%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 56: 5- {3- [2- (4-chloro-2,3-dihydroxyphenyl) ethyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2- Diol

Using 3- (4-chloro-2,3-dimethoxyphenyl) propanenitrile, the title compound (yield 43%) was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.

Example 57: 5- {3- [2- (2-fluoro-3-hydroxyphenyl) ethyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol

Using 3- (2-fluoro-3-methoxyphenyl) propanenitrile, the title compound (yield 60%) was obtained in 4 steps in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.

Example 58: 5- {3- [2- (4-fluoro-3-hydroxyphenyl) ethyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol

Using 3- (4-fluoro-3-methoxyphenyl) propanenitrile, the title compound (yield 52%) was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.

Example 59: 5- [3- (3-Hydroxy-4-methoxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 3 using 4-methoxy-3- (methoxymethoxy) benzonitrile.

Example 60: 5- [3- (2-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 3 using 2-fluoro-3- (methoxymethoxy) benzonitrile.

Example 61: 3-Nitro-5-{3- [2- (2,4,5-trifluoro-3-hydroxyphenyl) ethyl] -1,2,4-oxadiazole-5-yl} benzene- 1,2-diol

Using 3- (2,4,5-trifluoro-3-methoxyphenyl) propanenitrile, the title compound (yield 45%) was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.

Example 62: 5- {3- [2- (3-Fluoro-4-hydroxyphenyl) ethyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol

Using 3- (3-fluoro-4-methoxyphenyl) propanenitrile, the title compound (57%) was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.

Example 63: 5- [3- (4-Chloro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 3 using 4-chloro-3- (methoxymethoxy) benzonitrile.

Example 64: 5- [3- (4-fluoro-3-methoxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

Using 4-fluoro-3-methoxybenzonitrile, the title compound was obtained in the same manner as in Reference Examples 12, 13 and Example 1.

Example 65: 5- [3- (2,4-difluoro-5-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

Using 2,4-difluoro-5- (methoxymethoxy) benzonitrile, the title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 66: 3-Chloro-4- [3- (3-Hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -6-nitrobenzene-1,2-diol

The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 3 using 3- (methoxymethoxy) benzonitrile and 2-chloro-3,4-dimethoxy-5-nitrobenzoyl chloride.

Example 67: 4- [5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazole-3-yl] -2-hydroxybenzonitrile

(A): 5- (3,4-dimethoxy-5-nitrophenyl) -3- (4-iodo-3-methoxyphenyl) using 4-iodo-3-methoxybenzonitrile in the same manner as in Reference Example 12. ) -1,2,4-oxadiazole was obtained.
(B): (a) is reacted with copper (I) cyanide to 4- [5- (3,4-dimethoxy-5-nitrophenyl) -1,2,4-oxadiazole-3-yl]. Using -2-methoxybenzonitrile, the title compound (yield 7%) was obtained in the same manner as in Reference Example 13 and Examples 1 and 2.

Example 68: 4- [5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazole-3-yl] -3-fluorobenzene-1,2-diol

Using 2-fluoro-3,4-dimethoxybenzonitrile, the title compound (yield 15%) was obtained in the same manner as in Reference Examples 12 and 13, Examples 1 and 2.

Example 69: 5- {3- [2- (4-Hydroxybenzo [d] oxazole-7-yl) ethyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1, 2-diol

Using 3- [4- (methoxymethoxy) benzo [d] oxazole-7-yl] propanenitrile, the title compound (8%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 70: 5- [3- (2,4-difluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

Using 2,4-difluoro-3- (methoxymethoxy) benzonitrile, the title compound (yield 23%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 71: 5-{[3- (4-fluoro-3-hydroxyphenyl) methyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol

Using 2- [4-fluoro-3- (methoxymethoxy) phenyl] acetonitrile, the title compound (yield 39%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 72: 5- {3- [2- (2,4-difluoro-5-hydroxyphenyl) ethyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2- Diol

Using 3- [2,4-difluoro-5- (methoxymethoxy) phenyl] propanenitrile, the title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 73: 5-({3-[(3,4-dihydroxyphenyl) sulfanil] methyl} -1,2,4-oxadiazole-5-yl) -3-nitrobenzene-1,2-diol

Using 2-[(3,4-dimethoxyphenyl) sulfanil] acetonitrile, the title compound (yield 19%) was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.

Example 74: 5- {3- [3- (4-fluoro-3-hydroxyphenyl) propyl] -1,2,4-oxazole-5-yl} -3-nitrobenzene-1,2-diol

Using 4- [4-fluoro-3- (methoxymethoxy) phenyl] butanenitrile, the title compound (yield 28%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 75: 5- [3- (2-fluoro-5-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

Using 2-fluoro-5-methoxybenzonitrile, the title compound (yield 40%) was obtained in the same manner as in Reference Examples 12 and 13, Examples 1 and 2.

Example 76: 5- [3- (2-Chloro-5-Hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

Using 2-chloro-5-methoxybenzonitrile, the title compound (yield 12%) was obtained in the same manner as in Reference Examples 12 and 13, Examples 1 and 2.

Example 77: 5- [3- (3,4-difluoro-5-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

Using 3,4-difluoro-5- (methoxymethoxy) benzonitrile, the title compound (yield 36%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 78: 5- [3- (4-Hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

Using 4-methoxybenzonitrile, the title compound (yield 13%) was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.

Example 79: 5- [3- (4-fluoro-2,3-dihydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

Using 4-fluoro-2,3-dimethoxybenzonitrile, the title compound (yield 16%) was obtained in the same manner as in Reference Examples 12 and 13, Examples 1 and 2.

Example 80: 3-Chloro-4- {3- [2- (4-fluoro-3-hydroxyphenyl) ethyl] -1,2,4-oxadiazole-5-yl} -6-nitrobenzene-1, 2-diol

Using 3- [4-fluoro-3- (methoxymethoxy) phenyl] propanenitrile and 2-chloro-3,4-dimethoxy-5-nitrobenzoyl chloride in the same manner as in Reference Examples 12 and 13, the title is the same as in Example 3. A compound (yield 9%) was obtained.

Example 81: 4- {2- [5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazole-3-yl] ethyl} -3-fluorobenzene-1,2 -Diol

Using 3- (2-fluoro-3,4-dimethoxyphenyl) propanenitrile, the title compound (yield 7%) was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.

Example 82: 3-Chloro-4- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -6-nitrobenzene-1,2-diol

The title compound (yield 17) was used in the same manner as in Reference Examples 12 and 13 and Example 3 using 4-fluoro-3- (methoxymethoxy) benzonitrile and 2-chloro-3,4-dimethoxy-5-nitrobenzoyl chloride. %) Was obtained.

Example 83: 3-Chloro-4- {3- [2- (2,4-difluoro-5-hydroxyphenyl) ethyl] -1,2,4-oxadiazole-5-yl} -6-nitrobenzene- 1,2-diol

Using 3- [2,4-difluoro-5- (methoxymethoxy) phenyl] propanenitrile and 2-chloro-3,4-dimethoxy-5-nitrobenzoyl chloride in the same manner as in Reference Examples 12 and 13 and Example 3. The title compound (yield 31%) was obtained.

Example 84: 5-({3-[(4-fluoro-3-hydroxyphenyl) sulfanil] methyl} -1,2,4-oxadiazole-5-yl) -3-nitrobenzene-1,2-diol

The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 3 using 2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanil} acetonitrile.

Example 85: 2,3-Dihydroxy-6- [3- (3-Hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -4-nitrobenzonitrile

Using 2- (methoxymethoxy) benzonitrile and 2-cyano-3,4-dimethoxy-5-nitrobenzoyl chloride, the title compound (yield 30%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3. It was.

Example 86: 5- {3-[(1R ^* , 2R ^* ) -2- (2,4-difluoro-5-hydroxyphenyl) cyclopropyl] -1,2,4-oxadiazole-5-yl} -3-Nitrobenzene-1,2-diol

(1R ^* , 2R ^* ) -2- [2,4-difluoro-5- (methoxymethoxy) phenyl] cyclopropane-1-carbonitrile was used, and the title compound was used in the same manner as in Reference Examples 12 and 13 and Example 3. (Yield 59%) was obtained.

Example 87: 5- {3-[(1R ^* , 2S ^* ) -2- (2,4-difluoro-5-hydroxyphenyl) cyclopropyl] -1,2,4-oxadiazole-5-yl} -3-Nitrobenzene-1,2-diol

(1R ^* , 2S ^* ) -2- [2,4-difluoro-5- (methoxymethoxy) phenyl] cyclopropane-1-carbonitrile was used, and the title compound was used in the same manner as in Reference Examples 12 and 13 and Example 3. (Yield 41%) was obtained.

Example 88: 5- [3- (5-Hydroxypyridin-3-yl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

Using 3-cyano-5- (methoxymethoxy) pyridine, the title compound (yield 8%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 89: 5- [3- (4-Hydroxypyridin-2-yl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

Using 2-cyano-4-methoxypyridine, the title compound (yield 17%) was obtained in the same manner as in Reference Examples 12 and 13, Examples 1 and 2.

Example 90: 4-({[5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazole-3-yl] methyl} sulfanil) -2-hydroxybenzonitrile

Using 4- (cyanomethyl) sulfanil-2- (methoxymethoxy) benzonitrile, the title compound (yield 11%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 91: 5-(3-{[(4-fluoro-3-hydroxyphenyl) sulfonyl] methyl} -1,2,4-oxadiazole-5-yl) -3-nitrobenzene-1,2-diol

Using 2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfonyl} acetonitrile, the title compound (yield 11%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 92: 5- [3- (6-hydroxypyridin-2-yl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

Using 2-cyano-6-methoxypyridine, the title compound (yield 41%) was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.

Example 93: 4-Fluoro-5- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

The title compound (yield) in the same manner as in Reference Examples 12 and 13 and Example 3 using 2-fluoro-4,5-dimethoxy-3-nitrobenzoyl chloride and 4-fluoro-3- (methoxymethoxy) benzonitrile. 28%) was obtained.

Example 94: 6- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3,4-dihydroxy-2-nitrobenzonitrile

The title compound (yield) was used in the same manner as in Reference Examples 12 and 13 and Example 3 using 2-cyano-4,5-dimethoxy-3-nitrobenzoyl chloride and 4-fluoro-3- (methoxymethoxy) benzonitrile. 14%) was obtained.

Example 95: 3-Chloro-4- (3-{[(4-fluoro-3-hydroxyphenyl) sulfanil] methyl} -1,2,4-oxadiazole-5-yl) -6-nitrobenzene-1 , 2-diol

Using 2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanil} acetonitrile and 2-chloro-3,4-dimethoxy-5-nitrobenzoyl chloride in the same manner as in Reference Examples 12, 13 and 3. The title compound (yield 35%) was obtained.

Example 96: 4-Chloro-5- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

2-Chloro-4,5-dimethoxy-3-nitrobenzoic acid produced in Reference Example 24 was converted to 2-chloro-4,5-dimethoxy-3-nitrobenzoyl chloride with thionyl chloride, and then 2-fluoro-3-3. Using (methoxymethoxy) benzonitrile, the title compound (yield 60%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 97: 3-Chloro-4- {3-[(1R ^* , 2R ^* ) -2- (4-fluoro-3-hydroxyphenyl) cyclopropyl] -1,2,4-oxadiazole-5- Il} -6-nitrobenzene-1,2-diol

(1R ^* , 2R ^* ) -2- [4-fluoro-3- (methoxymethoxy) phenyl] cyclopropane-1-carbonitrile and 2-chloro-3,4-dimethoxy-5-nitrobenzoyl chloride are used for reference. The title compound (yield 9%) was obtained in the same manner as in Examples 12 and 13 and Example 3.

Example 98: 4-Chloro-5-{3-[(3-Hydroxyphenyl) methyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1,2-diol

The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 3 using 2- [3- (methoxymethoxy) phenyl] acetonitrile and 2-chloro-4,5-dimethoxy-3-nitrobenzoyl chloride. ..

Example 99: 4- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -6-nitro-3- (trifluoromethyl) benzene-1, 2-diol

Using 3,4-dimethoxy-5-nitro-2- (trifluoromethyl) benzoyl chloride and 4-fluoro-3- (methoxymethoxy) benzonitrile, the title is the same as in Reference Examples 12 and 13 and Example 3. A compound (yield 17%) was obtained.

Example 100: 4-Chloro-5- [3- (3-Hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

The title compound (72%) using 2- [3- (methoxymethoxy) phenyl] acetonitrile and 2-chloro-4,5-dimethoxy-3-nitrobenzoyl chloride in the same manner as in Reference Examples 12 and 13 and Example 3. ) Was obtained.

Example 101: 3-Chloro-4- (3- {difluoro-[(4-fluoro-3-hydroxyphenyl) sulfanil] methyl} -1,2,4-oxadiazole-5-yl) -6-nitrobenzene -1,2-diol

2,2-Difluoro-2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanil} -N-hydroxyacetimideamide and 2-chloro-3,4-dimethoxy-5-produced in Reference Example 7 Using nitrobenzoyl chloride, the title compound (yield 38%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 102: 5- [3- (3-Hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitro-4- (trifluoromethyl) benzene-1,2-diol

Using 4- (benzyloxy) -5-methoxy-2- (trifluoromethyl) benzoic acid and 3- (methoxymethoxy) benzonitrile prepared in Reference Example 15, the same procedure as in Reference Examples 16 and 17 and Example 3 was carried out. The title compound was obtained.

Example 103: 4- [5- (2-chloro-3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazole-3-yl] -2-hydroxybenzonitrile

(A): Using 4-iodo-3-methoxybenzonitrile and 2-chloro-3,4-dimethoxy-5-nitrobenzoyl chloride in the same manner as in Reference Example 12, 5- (2-chloro-3,4) -Dimethoxy-5-nitrophenyl) -3- (4-iodo-3-methoxyphenyl) -1,2,4-oxadiazole was obtained.
(B): (a) is reacted with copper (I) cyanide to 4- [5- (2-chloro-3,4-dimethoxy-5-nitrophenyl) -1,2,4-oxadiazole- 3-Il] -2-methoxybenzonitrile was used, and the title compound was obtained in the same manner as in Reference Example 13 and Examples 1 and 2.

Example 104: 6- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -2,3-dihydroxy-4-nitrobenzonitrile

The title compound (yield) was used in the same manner as in Reference Examples 12 and 13 and Example 3 using 2-cyano-3,4-dimethoxy-5-nitrobenzoyl chloride and 4-fluoro-3- (methoxymethoxy) benzonitrile. 26%) was obtained.

Example 105: 6- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3,4-dihydroxy-2-nitrobenzoic acid

The 6- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3,4-dihydroxy-2-nitrobenzonitrile produced in Example 94 was carried out. It was obtained in the same manner as in Example 5 (yield 4%).

Example 106: 3-Fluoro-4- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -6-nitrobenzene-1,2-diol

The title compound (yield) was used in the same manner as in Reference Examples 12 and 13 and Example 3 using 2-fluoro-3,4-dihydroxy-5-nitrobenzoyl chloride and 4-fluoro-3- (methoxymethoxy) benzonitrile. 38%) was obtained.

Example 107: 6- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -2,3-dihydroxy-4-nitrobenzoic acid

The 6- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -2,3-dihydroxy-4-nitrobenzonitrile produced in Example 104 was carried out. The title compound (yield 2%) was obtained in the same manner as in Example 5.

Example 108: 5- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitro-4- (phenylsulfanil) benzene-1,2 -Diol

After the 4,5-dimethoxy-3-nitro-2- (phenylsulfanyl) benzoic acid produced in Reference Example 25 was converted to 4,5-dimethoxy-3-nitro-2- (phenylsulfanyl) benzoyl chloride with thionyl chloride, Using 4-fluoro-3- (methoxymethoxy) benzonitrile, the title compound (yield 58%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 109: 5- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitro-4- (phenylsulfonyl) benzene-1,2 -Diol

After the 4,5-dimethoxy-3-nitro-2- (phenylsulfonyl) benzoic acid produced in Reference Example 26 was converted to 4,5-dimethoxy-3-nitro-2- (phenylsulfonyl) benzoyl chloride with thionyl chloride, Using 4-fluoro-3- (methoxymethoxy) benzonitrile, the title compound (yield 26%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 110: 5-({3-[(4-fluoro-3-hydroxyphenyl) methyl] amino} -1,2,4-oxadiazole-5-yl) -3-nitrobenzene-1,2-diol

(A): 4,5-dimethoxy-5-nitrobenzoyl chloride and 1-tert-butoxycarbonylguanidine are reacted in pyridine to cause N- (tert-butoxycarbamidrill) -3,4-dimethoxy-5-nitrobenzamide. Got
(B): (a) and iodobenzenediasetate are reacted in an N, N-dimethylformamide solution and tert-butyl [5- (3,4-dimethoxy-5-nitrophenyl) -1,2,4. -Oxadiazole-3-yl] carbamate was obtained.
(C): Trifluoroacetic acid was reacted with the dichloromethane solution of (b) to obtain 3-amino-5- (3,4-dimethoxy-5-nitrophenyl) -1,2,4-oxadiazole. ..
(D): Lithium bis (trimethylsilyl) amide and trifluoroacetic anhydride were reacted with the tetrahydrofuran solution of (c), and N- [5- (3,4-dimethoxy-5-nitrophenyl) -1,2, 4-Oxadiazole-3-yl] -2,2,2-trifluoroacetamide was obtained.
(E): [4-Fluoro-3- (methoxymethoxy) phenyl] methanol, triphenylphosphine, and bis (2-methoxyethyl) azodicarboxylate were reacted with the tetrahydrofuran solution of (d) to N- [5-( 3,4-Dimethoxy-5-nitrophenyl) -1,2,4-oxadiazole-3-yl] -2,2,2-trifluoro-N- [4-fluoro-3- (methoxymethoxy) benzyl ] Acetamide was obtained. The title compound (3 steps: yield 0.5%) was obtained in the same manner as in Reference Example 13 and Example 3.

Example 111: 3-Chloro-4- {3- [3-hydroxy-4- (trifluoromethyl) phenyl] -1,2,4-oxadiazole-5-yl} -6-nitrobenzene-1,2 -Diol

Using 3- (methoxymethoxy) -4- (trifluoromethyl) benzonitrile and 2-chloro-3,4-dimethoxy-5-nitrobenzoyl chloride in the same manner as in Reference Examples 12 and 13, the title is the same as in Example 3. The compound was obtained.

Example 112: 5- {3-[(1R ^* , 2R ^* ) -2- (4-fluoro-3-hydroxyphenyl) cyclopropyl] -1,2,4-oxadiazole-5-yl} -3 -Nitro-4- (trifluoromethyl) benzene-1,2-diol

The 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzoic acid produced in Reference Example 27 was converted to 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzoyl chloride with thionyl chloride. Later, using (1R ^* , 2R ^* ) -2- [4-fluoro-3- (methoxymethoxy) phenyl] cyclopropan-1-carbonitrile, the title was the same as in Reference Examples 12 and 13 and Example 3. A compound (yield 17%) was obtained.

Example 113: 4-Chloro-5 {-3- [3- (4-fluoro-3-hydroxyphenyl) propyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene-1, 2-diol

2-Chloro-4,5-dimethoxy-3-nitrobenzoic acid produced in Reference Example 23 was converted to 2-chloro-4,5-dimethoxy-3-nitrobenzoyl chloride with thionyl chloride, and then 4- [4-fluoro. The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 3 using -3- (methoxymethoxy) phenyl] butanenitrile.

Example 114: 4-Chloro-5-{3-[(1R ^* , 2R ^* ) -2- (4-fluoro-3-hydroxyphenyl) cyclopropyl] -1,2,4-oxadiazole-5- Il} -3-nitrobenzene-1,2-diol

After the 2-chloro-4,5-dimethoxy-3-nitrobenzoic acid produced in Reference Example 24 was converted to 2-chloro-4,5-dimethoxy-3-nitrobenzoyl chloride with thionyl chloride, (1R ^* , 2R ^*). ) -2- [4-Fluoro-3- (methoxymethoxy) phenyl] cyclopropan-1-carbonitrile was used to obtain the title compound (62%) in the same manner as in Reference Examples 12 and 13 and Example 3. ..

Example 115: 5- {3- [2- (4-fluoro-3-hydroxyphenyl) ethyl] -1,2,4-oxadiazole-5-yl} -3-nitro-4- (trifluoromethyl) ) Benzene-1,2-diol

The 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzoic acid produced in Reference Example 27 was converted to 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzoyl chloride with thionyl chloride. After that, 3- [4-fluoro-3- (methoxymethoxy) phenyl] propanenitrile was used to obtain the title compound (yield 14%) in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 116: (E) -4-chloro-5-{3-[(4-fluoro-3-hydroxyphenyl) ethen-2-yl} -1,2,4-oxadiazole-5-yl]- 3-Nitrobenzene-1,2-diol

After the 2-chloro-4,5-dimethoxy-3-nitrobenzoic acid produced in Reference Example 24 was converted to 2-chloro-4,5-dimethoxy-3-nitrobenzoyl chloride with thionyl chloride, (E) -3- [4-Fluoro-3- (methoxymethoxy) phenyl] Using acrylonitrile, the title compound (yield 15%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 117: (E) -5-{[3- (4-fluoro-3-hydroxyphenyl) ethen-2-yl] -1,2,4-oxadiazole-5-yl} -3-nitro- 4- (Trifluoromethyl) benzene-1,2-diol

The 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzoic acid produced in Reference Example 27 was converted to 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzoyl chloride with thionyl chloride. Later, using (E) -3- [4-fluoro-3- (methoxymethoxy) phenyl] acrylonitrile, the title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 118: 5- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitro-4-phenoxybenzene-1,2-diol

Refer to 5- [4- (benzyloxy) -5-methoxy-2-phenoxyphenyl] -3- (4-fluoro-3-methoxyphenyl) -1,2,4-oxadiazole produced in Reference Example 22. After the same procedure as in Example 19, the title compound was obtained in the same manner as in Reference Example 17 and Example 3.

Example 119: 4-Chloro-5-({3-[(4-fluoro-3-hydroxyphenyl) oxy] methyl} -1,2,4-oxadiazole-5-yl) -3-nitrobenzene-1 , 2-diol

The 2-chloro-4,5-dimethoxy-3-nitrobenzoic acid produced in Reference Example 24 was converted to 2-chloro-4,5-dimethoxy-3-nitrobenzoyl chloride with thionyl chloride, and then obtained in Reference Example 20. The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 3 using 2-{[4-fluoro-3- (methoxymethoxy) phenyl] oxy} acetonitrile.

Example 120: 5- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -4- (methylsulfanil) -3-nitrobenzene-1,2- Diol

After the 4,5-dimethoxy-2- (methylsulfanyl) -3-nitrobenzoic acid produced in Reference Example 28 was converted to 4,5-dimethoxy-2- (methylsulfanyl) -3-nitrobenzoyl chloride with thionyl chloride, Using 4-fluoro-3- (methoxymethoxy) benzonitrile, the title compound (yield 75%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 121: 5- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -4- (methylsulfonyl) -3-nitrobenzene-1,2- Diol

(A): 5- [4,5-dimethoxy-2- (methylsulfanyl) -3-nitrophenyl] -3- [4-fluoro-3- (methoxymethoxy) phenyl] -1,2,4-oxadi 3-Chloroperbenzoic acid (300 mg) was added to a solution of azole (0.26 g) in ethyl acetate (5.0 mL), and the mixture was stirred at room temperature for 18 hours. A 1M aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and 5- [4,5-dimethoxy-2- (methylsulfonyl) -3-nitrophenyl] -3- [4-fluoro-3- (methoxymethoxy) phenyl] -1,2,4 -Oxadiazole (0.21 g) was obtained as a light brown solid.
(B): The title compound (63%) was obtained in the same manner as in Reference Example 13 and Example 3 in (a).

Example 122: 5- (3- {difluoro [(4-fluoro-3-hydroxyphenyl) sulfanil] methyl} -1,2,4-oxadiazole-5-yl) -4- (methylsulfanil) -3 -Nitrobenzene-1,2-diol

After the 4,5-dimethoxy-2- (methylsulfanyl) -3-nitrobenzoic acid produced in Reference Example 28 was converted to 4,5-dimethoxy-2- (methylsulfanyl) -3-nitrobenzoyl chloride with thionyl chloride, Using 2,2-difluoro-2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanyl} -N-hydroxyacetimideamide obtained in Reference Example 7, Reference Examples 12, 13, and Example 3 Similarly, the title compound (yield 17%) was obtained.

Example 123: 5- (3,4-dihydroxy-5-nitrophenyl) -N- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-3-carboxamide

(A): Methyl cyanoformate was used to obtain methyl 5- (3,4-dimethoxy-5-nitrophenyl) -1,2,4-oxadiazole-3-carboxylate in the same manner as in Reference Example 12. It was.
(B): 5- (3,4-dimethoxy-5-nitrophenyl) -1,2,4-oxadiazole-3-carboxylic acid was obtained by alkaline hydrolysis of (a).
(C): (b) was reacted with oxalyl chloride to obtain 5- (3,4-dimethoxy-5-nitrophenyl) -1,2,4-oxadiazole-3-benzoyl chloride.
(D) (c) is reacted with 4-fluoro-3- (methoxymethoxy) aniline to form 5- (3,4-dimethoxy-5-nitrophenyl) -N- [4-fluoro-3- (methoxymethoxy). Phenyl] 1,2,4-oxadiazole-3-carboxamide was used, and the title compound (yield 28%) was obtained in the same manner as in Reference Example 13 and Example 3.

Example 124: 5- [3- (4-fluoro-2,3-dihydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitro-4- (trifluoromethyl) benzene- 1,2-diol

The 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzoic acid produced in Reference Example 27 was converted to 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzoyl chloride with thionyl chloride. After that, 4-fluoro-2,3-bis (methoxymethoxy) benzonitrile was used to obtain the title compound (yield 26%) in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 125: 5- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -4-iodo-3-nitrobenzene-1,2-diol

2-Iodo-4,5-dimethoxy-3-nitrobenzoic acid was converted to 2-iodo-4,5-dimethoxy-3-nitrobenzoyl chloride with thionyl chloride, and then 4-fluoro-3- (methoxymethoxy) benzo. Using nitrile, the title compound (yield 31%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 126: Cyclohexyl {6- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3,4-dihydroxy-2-nitrophenyl} metanone

(A): Methyl 4- (benzyloxy) -2- (cyclohexylcarbonyl) -5-methoxybenzoate was synthesized according to the method described in JP-A-2011-148782, and the same operation as in Reference Examples 19, 17, and 27 was performed. After that, alkali hydrolysis was carried out to obtain 2- (cyclohexylcarbonyl) -4,5-dimethoxy-3-nitrobenzoic acid.
(B): After converting (a) to 2- (cyclohexylcarbonyl) -4,5-dimethoxy-3-nitrobenzoyl chloride with thionyl chloride, 4-fluoro-3- (methoxymethoxy) benzonitrile was used as a reference example. The title compound (yield 33%) was obtained in the same manner as in Examples 12 and 13.

Example 127: 2,2,2-trifluoro-1- {6- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3,4 -Dihydroxy-2-nitrophenyl} ethane-1-one

(A): Ethyl 4- (benzyloxy) -5-methoxy-2- (2,2,2-trifluoroacetyl) benzoate was synthesized according to the method described in JP-A-2011-148782, and Reference Example 19, Alkaline hydrolysis was carried out in sequence on 17 and 27 to obtain 4,5-dimethoxy-3-nitro-2- (2,2,2-trifluoroacetyl) benzoic acid.
(B): After (a) was converted to 4,5-dimethoxy-3-nitro-2- (2,2,2-trifluoroacetyl) benzoyl chloride with thionyl chloride, 4-fluoro-3- (methoxymethoxy) Using benzonitrile, the title compound (yield 20%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 128: 4- {5- [4,5-dihydroxy-3-nitro-2- (trifluoromethyl) phenyl] -1,2,4-oxadiazole-3-yl} -2-hydroxybenzonitrile

(A): 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzoic acid produced in Reference Example 27 with thionyl chloride, 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) Benzoyl chloride was used.
(B): Using (a) and 4-iodo-3- (methoxymethoxy) benzonitrile, 5- [4,5-dimethoxy-3-nitro-2- (trifluoromethyl)) as in Reference Example 12. Phenyl] -3- (4-iodo-3-methoxyphenyl) -1,2,4-oxadiazole was obtained.
(C): 4- {5- [4,5-dimethoxy-3-nitro-2- (trifluoromethyl) phenyl] -1,2, obtained by the reaction of (b) and copper (I) cyanide. The title compound (yield 11%) was obtained in the same manner as in Reference Example 13 and Examples 1 and 2 using 4-oxadiazole-3-yl} -2- (methoxymethoxy) benzonitrile.

Example 129: 5- (3,4-dihydroxy-5-nitrophenyl) -N-ethyl-N- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-3-carboxamide

5- (3,4-dimethoxy-5-nitrophenyl) -N-[(4-fluoro-3-methoxymethoxy) phenyl] -1,2,4-oxadiazole-3-carboxamide prepared in Example 123 5- (3,4-dimethoxy-5-nitrophenyl) -N-ethyl-N-[(4-fluoro-3-methoxymethoxy) phenyl] -1,2 by reacting sodium hydride and ethyl iodide. , 4-Oxadiazole-3-carboxamide was used, and the title compound (yield 13%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 130: 4- (cyclopentylsulfanil) -5- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2- Diol

Reference Example 22 using 5- [4- (benzyloxy) -2-iodo-5-methoxyphenyl] -3,4-fluoro-3- (methoxyphenyl-1,2,4-oxadiazol and cyclopentylthiol) In the same manner as in 5- [4- (benzyloxy) -2- (cyclopentylsulfanyl) -5-methoxyphenyl] -3- (4-fluoro-3-methoxyphenyl) -1,2,4-oxadiazol. The title compound was obtained in the same manner as in Reference Examples 19 and 17 and Examples 1 and 2.

Example 131: 4-Chloro-5- [3- (3,4-difluorophenyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

2-Chloro-4,5-dimethoxy-3-nitrobenzoic acid produced in Reference Example 24 was converted to 2-chloro-4,5-dimethoxy-3-nitrobenzoyl chloride with thionyl chloride, and then 3,4-difluorobenzo. Using nitrile, the title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 1.

Example 132: 4- (cyclopentylsulfonyl) -5- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2- Diol

5- [2- (cyclopentylsulfanyl) -4,5-dimethoxy-3-nitrophenyl] -3- (4-fluoro-3-methoxyphenyl) -1,2,4-oxa, which is an intermediate of Example 130 Diazole was oxidized with 3-chloroperbenzoic acid, and 5- [2- (cyclopentylsulfonyl) -4,5-dimethoxy-3-nitrophenyl] -3- (4-fluoro-3-methoxyphenyl) -1, The title compound was 2,4-oxadiazole, and the title compound was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.

Example 133: 3-Nitro-5-[3- (2,3,4,5-tetrafluorophenyl) -1,2,4-oxadiazole-5-yl] -4- (trifluoromethyl) benzene -1,2-diol

The 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzoic acid produced in Reference Example 27 was converted to 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzoyl chloride with thionyl chloride. After that, using 2,3,4,5-tetrafluorobenzonitrile, the title compound (yield 7%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 1.

Example 134: 5- [3- (4-fluorophenyl) -1,2,4-oxadiazole-5-yl] -3-nitro-4- (trifluoromethyl) benzene-1,2-diol

The 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzoic acid produced in Reference Example 27 was converted to 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzoyl chloride with thionyl chloride. After that, 4-fluorobenzonitrile was used to obtain the title compound (yield 7%) in the same manner as in Reference Examples 12 and 13 and Example 1.

Example 135: 3-Nitro-4- (trifluoromethyl) -5- [3- (3,4,5-trifluorophenyl) -1,2,4-oxadiazole-5-yl] benzene-1 , 2-diol

The 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzoic acid produced in Reference Example 27 was converted to 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzoyl chloride with thionyl chloride. Then, using 3,4,5-trifluorobenzonitrile, the title compound (yield 21%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 1.

Example 136: 5- (3- {difluoro [(4-fluoro-3-hydroxyphenyl) sulfanil] methyl} -1,2,4-oxadiazole-5-yl) -3-nitro-4- (phenyl) Sulfonyl) benzene-1,2-diol

After the 4,5-dimethoxy-3-nitro-2- (phenylsulfonyl) benzoic acid produced in Reference Example 26 was converted to 4,5-dimethoxy-3-nitro-2- (phenylsulfonyl) benzoyl chloride with thionyl chloride. , Reference Examples 12 and 13, Examples using 2,2-difluoro-2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanyl} -N-hydroxyacetimideamide produced in Reference Example 7. The title compound (yield 40%) was obtained in the same manner as in 3.

Example 137: {6- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3,4-dihydroxy-2-nitrophenyl} (phenyl) Metanon

(A): Ethyl 2-benzoyl-4- (benzyloxy) -5-methoxybenzoate was synthesized according to the method described in JP-A-2011-148782, and the same reaction as in Reference Examples 19, 17, and 27 was carried out. After that, alkali hydrolysis was carried out to obtain 2-benzoyl-4,5-dimethoxy-3-nitrobenzoic acid.
(B): (a) was converted to 2-benzoyl-4,5-dimethoxy-3-nitrobenzoyl chloride with thionyl chloride, and 4-fluoro-3- (methoxymethoxy) benzonitrile was used, and Reference Examples 12 and 13 were carried out. The title compound (yield 70%) was obtained in the same manner as in Example 3.

Example 138: 5- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -4-[(propan-2-yl) oxy] -3- Nitrobenzene-1,2-diol

To 3-fluoro-4- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -6-methoxy-2-nitrophenol produced in Example 93 Reacting sodium hydride and 2-propanol, 4- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-[(propane-2-) Il) Oxy] -6-methoxy-2-nitrophenol was used, and the title compound (yield 11%) was obtained in the same manner as in Example 1.

Example 139: 4-bromo-5-[3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

2-Bromo-4,5-dimethoxy-3-nitrobenzoic acid is converted to 2-bromo-4,5-dimethoxy-3-nitrobenzoyl chloride with thionyl chloride, and then 4-fluoro-3- (methoxymethoxy) benzonitrile. The title compound (yield 42%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 140: [6- (3- {difluoro [(4-fluoro-3-hydroxyphenyl) sulfanil] methyl} -1,2,4-oxadiazole-5-yl) -3,4-dihydroxy-2 -Nitrophenyl] (Phenyl) Metanon

2-Benzoyl-4,5-dimethoxy-3-nitrobenzoyl chloride, which is an intermediate of Example 139, and 2,2-difluoro-2-{[4-fluoro-3- (methoxymethoxy)) prepared in Reference Example 7. Using phenyl] sulfanyl} -N-hydroxyacetimideamide, the title compound (yield 40%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.

Examples 141: 5- {3- [1,1-difluoro-2- (4-fluoro-3-hydroxyphenyl) ethyl] -1,2,4-oxadiazole-5-yl} -3-nitrobenzene- 1,2-diol

Using 2,2-difluoro-3- [4-fluoro-3- (methoxymethoxy) phenyl] propanenitrile, the title compound (yield 57%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3. ..

Example 142: 5- (3- {difluoro [(4-fluoro-3-hydroxyphenyl) sulfanil] methyl} -1,2,4-oxadiazole-5-yl) -3-nitrobenzene-1,2- Diol

Using 2,2-difluoro-2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanil} -N-hydroxyacetimideamide produced in Reference Example 7, Reference Examples 12 and 13, Example 3 The title compound (yield 39%) was obtained in the same manner as above.

Example 143: 4-Chloro-5- (3- {difluoro [(4-fluoro-3-hydroxyphenyl) sulfanil] methyl} -1,2,4-oxadiazole-5-yl) -3-nitrobenzene- 1,2-diol

2-Chloro-4,5-dimethoxy-3-nitrobenzoic acid produced in Reference Example 24 was converted to 2-chloro-4,5-dimethoxy-3-nitrobenzoyl chloride with thionyl chloride, and then produced in Reference Example 7. The title compound in the same manner as in Reference Examples 12 and 13 and Example 3 using 2,2-difluoro-2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanyl} -N-hydroxyacetimideamide. (Yield 25%) was obtained.

Example 144: 4-[(Butane-1-yl) Oxygen] -5- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3- Nitrobenzene-1,2-diol

3-Fluoro-4- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -6-methoxy-2-nitro, which is an intermediate of Example 94 Phenol is reacted with sodium hydride and 1-butanol, and 3-[(butane-1-yl) oxy] -4- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadi Azol-5-yl] -6-methoxy-2-nitrophenol was used, and the title compound (yield 21%) was obtained in the same manner as in Example 1.

Example 145: 4-Cyclopentyl-5-[3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2-diol

(A): 1-Cyclopentenylboronic acid, tetrakis (triphenylphosphine) palladium and cesium carbonate are added to ethyl 2-iodo-5-methoxy-4- (methoxymethoxy) benzoate, and 1,4-dioxane and water are added. As a solvent, the mixture was stirred at 100 ° C. for 15 hours to obtain ethyl 2- (cyclopentene-1-yl) -5-methoxy-4- (methoxymethoxy) benzoate.
(B): After catalytic reduction of (a), 2-cyclopentyl-4,5-dimethoxy-3-nitrobenzoic acid was obtained in the same manner as in Reference Example 27.
(C): After converting (b) to thionyl chloride to acid chloride, 4-fluoro-3- (methoxymethoxy) benzonitrile was used, and the title compound (yield) was used in the same manner as in Reference Examples 12 and 13 and Example 3. 46%) was obtained.

Example 146: 5- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -4-[(propan-2-yl) sulfonyl] -3- Nitrobenzene-1,2-diol

As in Reference Example 26, 2-[(propan-2-yl) sulfonyl] -4,5-dimethoxy-3-nitrobenzoic acid was synthesized, and 2-[(propan-2-yl) sulfonyl] was synthesized with thionyl chloride. After -4,5-dimethoxy-3-nitrobenzoyl chloride, 4-fluoro-3- (methoxymethoxy) benzonitrile was used, and the title compound (yield 21) was used in the same manner as in Reference Examples 12 and 13 and Example 3. %) Was obtained.

Example 147: 4- (cyclopentyloxy) -5- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3-nitrobenzene-1,2- Diol

3-Fluoro-4- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -6-methoxy-2-nitro, which is an intermediate of Example 93 Sodium hydride and cyclopentanol were reacted with phenol to obtain the title compound (yield 27%) in the same manner as in Example 1.

Example 148: 5- (3- {difluoro-[(4-fluoro-3-hydroxyphenyl) sulfanil] methyl} -1,2,4-oxadiazole-5-yl) -3-nitro-4- [ (Trifluoromethyl) sulfanil] Benzene-1,2-diol

4,5-Dimethoxy-3-nitro-2-[(trifluoromethyl) sulfanilic acid] Benzoic acid and 2,2-difluoro-2-{[4-fluoro-3- (methoxymethoxy) phenyl) prepared in Reference Example 7 ] Sulfanilic} -N-hydroxyacetimideamide was used to give the title compound (20%) in the same manner as in Reference Examples 12 and 13 and Example 3.

Example 149: 5- (3- {2-[(4-fluoro-3-hydroxyphenyl) sulfanil] propan-2-yl} -1,2,4-oxadiazole-5-yl) -3-nitrobenzene -1,2-diol

Reference Example 12 using 2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanyl} -2-methylpropanenitrile and 3,4-dimethoxy-5-nitrobenzoyl chloride produced in the same manner as in Reference Example 6. , 13, The title compound (yield 3%) was obtained in the same manner as in Example 3.

Example 150: 5- (5-Methyl-5-Phenyl-4,5-dihydroisoxazole-3-yl) -3-nitrobenzene-1,2-diol

Using 3- [4- (benzyloxy) -3-methoxy-5-nitrophenyl] -5-methyl-5-phenyl-4,5-dihydroisoxazole produced in Reference Example 29, Reference Example 13, The title compound was obtained in the same manner as in Example 1.

Example 151: 3- (3,4-dihydroxy-5-nitrophenyl) -5-methyl-4,5-dihydroisoxazole-5-carboxylic acid benzyl

The title compound was obtained in the same manner as in Reference Examples 29 and 13 and Example 1 using 4- (benzyloxy) -3-methoxy-5-nitrobenzaldehyde oxime and benzyl methacrylate.

Example 152: 3- (3,4-dihydroxy-5-nitrophenyl) -5-methyl-4,5-dihydroisoxazole-5-carboxylic acid

The title compound was obtained in the same manner as in Reference Examples 29 and 13 and Examples 1 and 5 using 4- (benzyloxy) -3-methoxy-5-nitrobenzaldehyde oxime and methacrylic acid.

Example 153: 5- (5-ethyl-5-phenyl-4,5-dihydroisoxazole-3-yl) -3-nitrobenzene-1,2-diol

The title compound was obtained in the same manner as in Reference Examples 29 and 13 and Example 1 using 4- (benzyloxy) -3-methoxy-5-nitrobenzaldehyde oxime and 1-ethylstyrene.

Example 154: 5- [5- (4-chlorophenyl) -4,5-dihydroisoxazole-3-yl] -3-nitrobenzene-1,2-diol

The title compound was obtained in the same manner as in Reference Examples 29 and 13 and Example 1 using 4- (benzyloxy) -3-methoxy-5-nitrobenzaldehyde oxime and 1-chloro-4-vinylbenzene.

Example 155: 5- [5- (4-Methoxyphenyl) -5-methyl-4,5-dihydroisoxazole-3-yl] -3-nitrobenzene-1,2-diol

Similar to Reference Examples 29 and 13 and Example 1 using 4- (benzyloxy) -3-methoxy-5-nitrobenzaldehyde oxime and 1-methoxy-4- (propa-1-en-2-yl) benzene. The title compound was obtained.

Example 156: 3-Nitro-5- (5-Phenyl-4,5-dihydroisoxazole) Benzene-1,2-diol

The title compound was obtained in the same manner as in Reference Examples 29 and 13 and Example 1 using 4- (benzyloxy) -3-methoxy-5-nitrobenzaldehyde oxime and styrene.

Example 157: 5- (5-benzyl-4,5-dihydroisoxazole-3-yl) -3-nitrobenzene-1,2-diol

The title compound was obtained in the same manner as in Reference Examples 29 and 13 and Example 1 using 4- (benzyloxy) -3-methoxy-5-nitrobenzaldehyde oxime and allylbenzene.

Example 158: 5- {5- [4- (hydroxymethyl) phenyl] -5-methyl-4,5-dihydroisoxazole-3-yl} -3-nitrobenzene-1,2-diol

[4- (Propa-1-en-2-yl) phenyl] Methanol was used to obtain the title compound in the same manner as in Reference Examples 29 and 13 and Example 1.

Example 159: 4- [3- (3,4-dihydroxy-5-nitrophenyl) -5-methyl-4,5-dihydroisoxazole-5-yl] benzoic acid

Similar to Reference Examples 29 and 13 and Examples 1 and 5 using 4- (benzyloxy) -3-methoxy-5-nitrobenzaldehyde oxime and methyl 4- (propa-1-en-2-yl) benzoate. The title compound was obtained.

Example 160: 2- (3,4-dihydroxy-5-nitrophenyl) -4-phenylthiazole-5-carbonitrile

The title compound (yield 72) was used in the same manner as in Reference Example 13 and Example 1 using 2- (3,4-dimethoxy-5-nitrophenyl) -4-phenylthiazole-5-carbonitrile produced in Reference Example 32. %) Was obtained.

Examples 161: 3-Nitro-5- (3-Phenyl-1,2,4-Thiadiazole-5-yl) Benzene-1,2-diol

The title compound (3,4-dimethoxy-5-nitrophenyl) -3-phenyl-1,2,4-thiadiazole prepared in Reference Example 33 was used in the same manner as in Reference Example 13 and Example 1. Yield 51%) was obtained.

Example 162: 2- (3,4-dihydroxy-5-nitrophenyl) -4-phenylthiazole-5-carboxylic acid

Using N, N-dimethylbenzamide dimethyl acetal, the title compound (yield 89%) was obtained in the same manner as in Reference Examples 32 and 13 and Examples 1 and 5.

Example 163- [5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-thiadiazole-3-yl] benzoic acid

4- [N'-(3,4-dimethoxy-5-nitrophenylcarbonotioil) -N, N-dimethylcarbimideyl] Methyl benzoate was used in the same manner as in Examples 1 and 5 of Reference Examples 33 and 13. The title compound (yield 12%) was obtained.

Examples 164: 2- (3,4-dihydroxy-5-nitrophenyl) -4-{[(3-hydroxyphenyl) methyl] oxy} thiazole-5-carboxylate methyl

Example 165: tert-butyl 2- [2- (3,4-dihydroxy-5-nitrophenyl) -4-phenylthiazole-5-carbonyl] hydrazine-1-carboxylate

Example 166: 2- (3,4-dihydroxy-5-nitrophenyl) -4-phenylthiazole-5-carbohydrazide hydrochloride

Example 167: 3-Nitro-5- (5-phenylthiazole-2-yl) Benzene-1,2-diol

Using 3- [4- (benzyloxy) -3-methoxy-5-nitrophenyl] -5-phenyl-1H-thiazole produced in Reference Example 35, the title compound was used in the same manner as in Reference Example 13 and Example 1. Got

Example 168: 3-Nitro-5- (3-Phenyl-1H-Pyrazole-5-yl) Benzene-1,2-diol

The title compound was obtained in the same manner as in Reference Examples 34, 35, 13 and Example 1 using 1- [4- (benzyloxy) -3-methoxy-5-nitrophenyl] ethane-1-one.

Example 169: 3-Nitro-5- (4-Phenyl-1H-imidazol-2-yl) Benzene-1,2-diol

The title compound was obtained in the same manner as in Reference Example 13 and Example 1 using 2- (3,4-dimethoxy-5-nitrophenyl) -4-phenyl-1H-imidazole prepared in Reference Example 37.

Example 170: 3-Nitro-5- (4-Phenyloxazole-2-yl) Benzene-1,2-diol

Using 2- (3,4-dimethoxy-5-nitrophenyl) -5-phenyl-1,3-oxazole prepared in Reference Example 38, the title compound was obtained in the same manner as in Reference Example 13 and Example 1. It was.

Example 171: 3-Nitro-5-[3- (pyridazine-4-yl) -1H-1,2,4-triazole-5-yl] benzene-1,2-diol

Reference Example 13, Example 1 using 4- [5- (3,4-dimethoxy-5-nitrophenyl) -1H-1,2,4-triazole-3-yl] pyridazine produced in Reference Example 40. The title compound (yield 12%) was obtained in the same manner as above.

Example 172: 4- [5- (3,4-dihydroxy-5-nitrophenyl) -1H-1,2,4-triazole-3-yl) pyridin-2-carbonitrile

The title compound (yield 40%) in the same manner as in Reference Examples 40 and 13 and Example 1 using 2-cyanopyridin-4-carbohydrazide hydrochloride and ethyl 3,4-dimethoxy-5-nitrobenzimidate. Got

Example 173: 3-Nitro-5- (3-Phenyl-1H-1,2,4-Triazole-5-yl) Benzene-1,2-diol

Using benzohydrazide hydrochloride and ethyl 3,4-dimethoxy-5-nitrobenzimidate, the title compound (yield 38%) was obtained in the same manner as in Reference Examples 40 and 13 and Example 1.

Example 174: 3- [5- (3,4-dihydroxy-5-nitrophenyl) -1H-1,2,4-triazole-3-yl] benzonitrile

Using 3-cyanobenzohydrazide hydrochloride and ethyl 3,4-dimethoxy-5-nitrobenzimidate, the title compound (yield 65%) was obtained in the same manner as in Reference Examples 40 and 13 and Example 1.

Example 175: 5- [3- (2-chloropyridin-4-yl) -1H-1,2,4-triazole-5-yl] -3-nitrobenzene-1,2-diol

The title compound (yield 48%) was used in the same manner as in Reference Examples 40 and 13 and Example 1 using 2-chloropyridin-4-carbohydrazide hydrochloride and ethyl 3,4-dimethoxy-5-nitrobenzimidate. Got

Example 176: 5- {3- [3,5-bis (trifluoromethyl) phenyl] -1H-1,2,4-triazole-5-yl} -3-nitrobenzene-1,2-diol

The title compound (yield) using 3,5-bis (trifluoromethyl) benzohydrazide hydrochloride and ethyl 3,4-dimethoxy-5-nitrobenzimidate in the same manner as in Reference Examples 40 and 13 and Example 1. 38%) was obtained.

Example 177: 3-Nitro-5-{3- [4- (trifluoromethyl) phenyl] -1H-1,2,4-triazole-5-yl} benzene-1,2-diol

The title compound (yield 9%) in the same manner as in Reference Examples 40 and 13 and Example 1 using 4- (trifluoromethyl) benzohydrazide hydrochloride and ethyl 3,4-dimethoxy-5-nitrobenzimidate. Got

Example 178: 5- [3- (2,5-dichlorothiophene-3-yl) -1H-1,2,4-triazole-5-yl] -3-nitrobenzene-1,2-diol

The title compound (yield 13) was used in the same manner as in Reference Examples 40 and 13 and Example 1 using 2,5-dichlorothiophene-3-carbohydrazide hydrochloride and ethyl 3,4-dimethoxy-5-nitrobenzimidate. %) Was obtained.

Example 179: 5- [3- (4-fluoro-3-hydroxyphenyl) -1H-1,2,4-triazole-5-yl] -3-nitrobenzene-1,2-diol

The title compound (yield 10) was used in the same manner as in Reference Examples 40 and 13 and Examples 1 and 2 using 4-fluoro-3-methoxybenzohydrazide hydrochloride and ethyl 3,4-dimethoxy-5-nitrobenzimidate. %) Was obtained.

Example 180: 3- [3- (3,4-dihydroxy-5-nitrophenyl) -1-methyl-1H-1,2,4-triazole-5-yl] benzonitrile

(A): Sodium ethoxide (42 mg) was added to a solution of 3,4-bis (3,3-dimethoxypropoxy) -5-nitrobenzonitrile (300 mg) in methanol (3.0 mL), and the mixture was stirred at room temperature for 10 minutes. did. 3-Cyano-N-methylbenzohydrazide (164 mg) was added to the reaction mixture, and the mixture was stirred at 60 ° C. for 15 hours. Water citrate was added, the mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography.
(B): Water (1.0 mL) and p-toluenesulfonic acid monohydrate (30 mg) were added to the acetone (2.0 mL) solution of (a), and the mixture was stirred at 60 ° C. for 15 hours. The solvent was evaporated under reduced pressure, aqueous citric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (yield 27%).

Examples 181: 5- (1-methyl-3-phenyl-1H-1,2,4-triazole-5-yl) -3-nitrobenzene-1,2-diol

Methylbenzimidethioate hydrogen iodide in a solution of 3,4-bis (3,3-dimethoxypropoxy) -N'-methyl-5-nitrobenzohydrazide (280 mg) in N, N-dimethylformamide (5.0 mL). The acid salt (417 mg) was added, and the mixture was stirred at 120 ° C. for 3 hours. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography. Diisopropyl ether (5.0 mL) was added and the slurry was washed to obtain the title compound (yield 6%).

Example 182: 5- [5- (4-chlorophenyl) -1,3,4-oxadiazole-2-yl] -3-nitrobenzene-1,2-diol

The title compound (yield 28%) was obtained in the same manner as in Reference Examples 41 and 13 and Example 1 using 4-chlorobenzohydrazide hydrochloride and ethyl 3,4-dimethoxy-5-nitrobenzoic acid.

Example 183: 3- [5- (3,4-dihydroxy-5-nitrophenyl) -1,3,4-oxadiazole-2-yl] benzonitrile

The title compound (yield 6%) was obtained in the same manner as in Reference Examples 41 and 13 and Example 1 using 3-cyanobenzohydrazide hydrochloride and ethyl 3,4-dimethoxy-5-nitrobenzoic acid.

Example 184: 3-Cyclohexyl-2- [5- (3,4-dihydroxy-5-nitrophenyl) -1,3,4-oxadiazole-2-yl] propanenitrile

The title compound (yield 4%) in the same manner as in Reference Examples 41 and 13 and Example 1 using 2-cyano-3-cyclohexylpropanecarbohydrazide hydrochloride and ethyl 3,4-dimethoxy-5-nitrobenzoic acid. Got

Example 185: 5-(5-[(3,4-dihydroxyphenyl) methyl] sulfanil} -1,3,4-oxadiazole-2-yl) -3-nitrobenzene-1,2-diol

(A): 3,4-Dimethoxybenzoyl chloride was reacted with hydrazine monohydrate to obtain 3,4-dimethoki-5-nitrobenzohydrazide.
(B): (a) is reacted with carbon disulfide, lithium hydroxide, and ethanol, and then 4- (2-bromoethyl) -1,2-dimethoxybenzene is reacted, as in Reference Example 13 and Example 1. The title compound was obtained.

Example 186: 5- [5- (4-fluoro-3-hydroxyphenyl) -1,3,4-oxadiazole-2-yl] -3-nitrobenzene-1,2-diol

The title compound (yield 16%) was used in the same manner as in Reference Examples 41 and 13 and Examples 1 and 2 using 4-fluoro-3-methoxybenzohydrazide hydrochloride and ethyl 3,4-dimethoxy-5-nitrobenzoic acid. ) Was obtained.

Example 187: 5- {5- [2- (3,4-dihydroxyphenyl) ethyl] -1,3,4-oxadiazole-2-yl} -3-nitrobenzene-1,2-diol

The title compound (3,4-dimethoxyphenylethyl) propanehydrazide hydrochloride and ethyl 3,4-dimethoxy-5-nitrobenzoic acid were used in the same manner as in Reference Examples 41 and 13, Examples 1 and 2. Yield 5%) was obtained.

Example 188: 3- [4- (3,4-dihydroxy-5-nitrophenyl) -1H-1,2,3-triazole-5-yl] benzonitrile

Using the 3- [4- (4-hydroxy-3-methoxy-5-nitrophenyl) -1H-1,2,3-triazole-5-yl] benzonitrile produced in Reference Example 46 with Example 1. The title compound (yield 11%) was obtained in the same manner.

Example 189: 5- (1-benzyl-1H-1,2,3-triazole-4-yl) -3-nitrobenzene-1,2-diol

Using benzylboronic acid, the title compound (yield 17%) was obtained in the same manner as in Reference Examples 43 and 13 and Example 1.

Example 190: 5- {1- [2- (2-bromo-4,5-dihydroxyphenyl) ethyl] -1H-1,2,3-triazole-4-yl} -3-nitrobenzene-1,2- Diol

It was obtained as a by-product of Example 191 (yield 16%).

Examples 191: 5- {1- [2- (3,4-dihydroxyphenyl) ethyl] -1H-1,2,3-triazole-4-yl} -3-nitrobenzene-1,2-diol

The title compound (yield) was used in the same manner as in Reference Example 54, Reference Example 13, and Examples 1 and 2 using 2- (3,4-dimethoxyphenyl) ethyl azide and 5-ethynyl-1,2-dimethoxy-3-nitrobenzene. The rate was 23%).

Example 192: 5- [1- (4-fluoro-3-hydroxyphenyl) -1H-1,2,3-triazole-4-yl] -3-nitrobenzene-1,2-diol

Using 4-fluoro-3-methoxyphenylboronic acid, the title compound (yield 6%) was obtained in the same manner as in Reference Examples 43 and 13 and Examples 1 and 2.

Example 193: 4-Chloro-5- [1- (4-fluoro-3-hydroxyphenyl) -1H-1,2,3-triazole-4-yl] -3-nitrobenzene-1,2-diol

The title compound (yield) was used in the same manner as in Reference Examples 42, 43, 13 and Examples 1 and 2 using 4-fluoro-3-methoxyphenylboronic acid and 2-chloro-4,5-dimethoxy-3-nitrobenzaldehyde. 15%) was obtained.

Example 194: 5- [1- (4-fluoro-3-hydroxyphenyl) -1H-1,2,3-triazole-4-yl] -3-nitro-4- (trifluoromethyl) benzene-1, 2-diol

Using 4-fluoro-3-methoxyphenylboronic acid and 2-trifluoromethyl-4,5-dimethoxy-3-nitrobenzaldehyde in the same manner as in Reference Examples 42, 43, 13 Examples 1 and 2, the title compound (yield). The rate was 19%).

Example 195: 3,5-dichloro-4- [1- (4-fluoro-3-hydroxyphenyl) -1H-1,2,3-triazole-4-yl] -6-nitrobenzene-1,2-diol

The title compound (yield) using 4-fluoro-3-methoxyphenylboronic acid and 2,6-dichloro-4,5-dimethoxy3-nitrobenzaldehyde in the same manner as in Examples 1 and 2 of Reference Examples 42, 43 and 13. Rate 2%) was obtained.

Example 196: 3-Nitro-5-[2- (2-phenylpropan-2-yl) -2H-tetrazol-5-yl] benzene-1,2-diol

(A): Trifluoroacetic acid (914 mg) and 2- in an acetone (5.0 mL) solution of 5- (3,4-dimethoxy-5-nitrophenyl) -2H-tetrazole (500 mg) prepared in Reference Example 49. Phenyl-1-propene (0.52 mL) was added, and the mixture was stirred at room temperature for 4 hours. A 1M aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled under reduced pressure.
(B): N, N-dimethylformamide (3.8 mL) and lithium chloride (169 mg) were added to (a), and the mixture was stirred at 120 ° C. for 2 hours and then at room temperature for 15 hours. 2M hydrochloric acid water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled under reduced pressure, 2-propanol and n-hexane were added to the residue, and the precipitated crystals (243 mg) were collected by filtration.
(C): Pyridine (2.4 mL) and aluminum chloride (272 mg) were added to (b), and the mixture was stirred at room temperature for 6 hours. 2M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled under reduced pressure. 2-Propanol and n-hexane were added to the residue, and the precipitated crystals were collected by filtration to give the title compound (221 mg).
^{1 1} H-NMR (CDCl3) δ: 2.22 (6H, s), 6.16 (1H, brs), 7.12-7.24 (2H, m), 7.26-7.52 (3H, 3H,) m), 8.03 (1H, d, J = 2.3Hz), 8.46 (1H, d, J = 2.3Hz), 10.76 (1H, brs).

Example 197: 3-Nitro-5-{[2- (pyridin-4-yl) methyl] -2H-tetrazol-5-yl} benzene-1,2-diol

Using (4-bromomethyl) pyridine and 5- (3,4-dimethoxy-5-nitrophenyl) -2H-tetrazole obtained in Reference Example 49, the title compound was used in the same manner as in Reference Examples 50, 13 and Example 1. (Yield 4%) was obtained.

Example 198: 3-Nitro-5-{2- [2- (piperidine-1-yl) ethyl] -2H-tetrazole-5-yl} benzene-1,2-diol

Using 1- (2-bromoethyl) piperidine and 5- (3,4-dimethoxy-5-nitrophenyl) -2H-tetrazole obtained in Reference Example 49, in the same manner as in Reference Examples 50, 13 and Example 1. The title compound was obtained.

Example 199: 5- {2-[(3,5-dimethoxyphenyl) methyl] -2H-tetrazol-5-yl} -3-nitrobenzene-1,2-diol

Using 1-chloromethyl- (3,5-dimethoxy) benzene and 5- (3,4-dimethoxy-5-nitrophenyl) -2H-tetrazole obtained in Reference Example 49, Reference Examples 50 and 13, Examples. The title compound (yield 34%) was obtained in the same manner as in 1.

Example 200: 3-Nitro-5- (2-Phenyl-2H-Tetrazole-5-yl) Benzene-1,2-diol

The 5- (3,4-dimethoxy-5-nitrophenyl) -2-phenyl-2H-tetrazole produced in Reference Example 51 was used in the same manner as in Example 1 to obtain the title compound (yield 34%). ..

Example 201: 5- [5- (3,4-dihydroxy-5-nitrophenyl) -2H-tetrazol-2-yl] -2-fluoromethylbenzoate

Using 4-fluoro-3- (methoxycarbonyl) phenylboronic acid and 5- (3,4-dimethoxy-5-nitrophenyl) -2H-tetrazole obtained in Reference Example 49, Reference Examples 51 and 13, Examples. The title compound (yield 34%) was obtained in the same manner as in 1.

Example 202: 5- [5- (3,4-dihydroxy-5-nitrophenyl) -2H-tetrazole-2-yl] -2-fluorobenzoic acid

Reference Examples 51 and 13, Examples using 4-fluoro-3- (methoxycarbonyl) phenylboronic acid and 5- (3,4-dimethoxy-5-nitrophenyl) -2H-tetrazole produced in Reference Example 49. The title compound (17%) was obtained in the same manner as in 1 and 5.

Example 203: 5- [2- (4-Hydroxyphenyl) -2H-tetrazol-5-yl] -3-nitrobenzene-1,2-diol

Using 4-methoxyphenylboronic acid and 5- (3,4-dimethoxy-5-nitrophenyl) -2H-tetrazole prepared in Reference Example 49, in the same manner as in Reference Examples 51 and 13, Examples 1 and 2. The title compound (yield 3%) was obtained.

Example 204: 5- [2- (3-Hydroxyphenyl) -2H-tetrazol-5-yl] -3-nitrobenzene-1,2-diol

Using 3-methoxyphenylboronic acid and 5- (3,4-dimethoxy-5-nitrophenyl) -2H-tetrazole prepared in Reference Example 49, in the same manner as in Reference Examples 51 and 13, Examples 1 and 2. The title compound (yield 2%) was obtained.

Example 205: 5- {2- [3,4- (methylenedioxy) phenyl] -2H-tetrazol-5-yl} -3-nitrobenzene-1,2-diol

Reference Examples 51 and 13, Example 1 using 3,4- (methylenedioxy) phenylboronic acid and 5- (3,4-dimethoxy-5-nitrophenyl) -2H-tetrazole produced in Reference Example 49. The title compound (yield 4%) was obtained in the same manner as above.

Example 206: 5- [2- (3,4-dihydroxyphenyl) -2H-tetrazol-5-yl] -3-nitrobenzene-1,2-diol

Examples 1, 51, and 13 Examples using 3,4- (methylenedioxy) phenylboronic acid and 5- (3,4-dimethoxy-5-nitrophenyl) -2H-tetrazole produced in Reference Example 49. The title compound (yield 4%) was obtained in the same manner as in 1 and 2.

Example 207: 4-Chloro-5- [4- (4-fluoro-3-hydroxyphenyl) -1H-1,2,3-triazole-1-yl] -3-nitrobenzene-1,2-diol

Using 4-ethynyl-1-fluoro-2-methoxybenzene and 4,5-dimethoxy-3-nitro-2-chlorobenzoic acid, the title is the same as in Reference Examples 52, 53, 54, 13 and Example 3. A compound (yield 22%) was obtained.

Example 208: 5- [4- (4-fluoro-3-hydrophenyl) -1H-1,2,3-triazole-1-yl] -3-nitro-4- (trifluoromethyl) benzene-1, 2-diol

Reference Examples 52, 53, 54, 13, using 4-ethynyl-1-fluoro-2-methoxybenzene and 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzoic acid, Example 1, The title compound (yield 13%) was obtained in the same manner as in 2.

Example 209: 3- {6- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-5-yl] -3,4-dihydroxy-2-nitrophenyl} iso Benzofuran-1 (3H) -on

(A): 5- [4- (benzyloxy) -2-iodo-5-methoxyphenyl] -3- [4-fluoro-3- (methoxyphenyl)] -1,2,4 produced in Reference Example 21. -Oxadiazole is reacted with n-butyllithium, N, N-dimethylformamide, and 5- (benzyloxy) -2-{3- [4-fluoro-3- (methoxymethoxy) phenyl] -1,2, 4-Oxadiazole-5-yl} -4-methoxybenzaldehyde was obtained.
(B): (a) is reacted with 2- (methoxycarbonyl) phenylmagnesium iodide and 3- [5- (benzyloxy) -2-{(3- [4-fluoro-3- (methoxymethoxy) phenyl). ] -1,2,4-oxadiazole-5-yl} -4-methoxyphenyl] Isobenzofuran-1 (3H) -one was obtained.
(C): Using (b), the title compound was obtained in the same manner as in Reference Examples 19 and 17 and Example 3.

The chemical structure and equipment data of Examples are shown below.

Rat liver COMT and DDC inhibition test (enzyme preparation method): Liver of a rat that had been bleeding and lethal under isoflurane anesthesia was removed, and 4 times the amount of ice-cooled homogenate buffer (0.135 mol / L KCl) was contained in the liver weight. 10 mM mmol / L sodium phosphate buffer, pH 8.0) was added and homogenized. The homogenate solution was centrifuged (20,000 × g, 4 ° C., 10 minutes), the supernatant was collected, and the supernatant was centrifuged again (20,000 × g, 4 ° C., 30 minutes) to obtain the final supernatant. 400 μL of the obtained supernatant was added to a gel filtration column, and about 800 μL of the eluate was used as an enzyme solution.

Test Example 1 (Measurement of rat COMT inhibitory effect): 91 μL of 10 mmol / L sodium phosphate buffer (pH 7.8), ₂ μL of 500 mmol / L MgCl ₂ and 2 μL of 200 μmol / L esculetin in each well of a 96-well plate. 2 μL of 30 mmol / L AdoMet and 1 μL of each test substance solution were added and mixed. A sample to which 30 mmol / L AdoMet was not added was used as the blank. 2 μL of the prepared enzyme solution was added, and the fluorescence intensity (excitation wavelength 390 nm, fluorescence wavelength 465 nm, 37 ° C., 60 minutes) was measured with a microplate reader. The COMT activity was calculated as the amount of increase per second in the steady state of the fluorescence intensity increase reaction. The IC ₅₀ value represents the concentration which gave 50% inhibition of enzyme activity.

Test Example 2 (Measurement of rat DDC inhibitory action): 186 μL of 30 mmol / L potassium phosphate buffer (pH 6.8), 2 μL of 100 mmol / L L-Dopa, 2 μL of 7 mmol / L pyridoxal phosphate, and each test substance. 2 μL of the solution was added and mixed. 8 μL of the prepared enzyme solution was added and incubated (37 ° C., 15 minutes). A sample at 0 minutes of incubation was used for the blank. Then, it was boiled at 100 ° C. for 3 minutes, cooled on ice for 2 minutes, and then centrifuged (4 ° C., 10000 rpm, 10 minutes). The supernatant was collected after adding 400μL of distilled water dilution, it was added the total amount to Amberlite CG50 _(NH ^{4 +)} column and washed twice with distilled water 0.3mL and 1.5 mL. Then, dopamine was eluted with 1.2 mL of 2N acetic acid, and the absorbance (wavelength 279 nm) was measured with a spectrophotometer, and this value was taken as the enzyme activity. The IC ₅₀ value represents the concentration which gave 50% inhibition of enzyme activity. As a comparative example, tolcapone and entacapone were tested in the same manner.

The results of Test Example 1 and Test Example 2 are shown in Tables 22 and 23.

Rat mitochondrial toxicity test (preparation method of rat heart mitochondrial solution): The heart of a rat that was lethal and lethal under isoflurane anesthesia was removed, and 8 times the amount of ice-cooled homogenate buffer (210 mmol / L mannitol, 70 mmol) based on the heart weight. / L sucrose, 5 mmol / L HEPES, a buffer solution consisting of 1 mmol / L EGTA, pH 7.2) was added and homogenized. The homogenate solution was centrifuged (500 × g, 4 ° C., 10 minutes), the supernatant was collected, and the supernatant was centrifuged again (10000 × g, 4 ° C., 10 minutes). The obtained precipitate was suspended in 8 times the amount of homogenate buffer, and then centrifuged (10000 × g, 4 ° C., 10 minutes). After repeating the same operation once, the obtained precipitate was suspended in 0.25 mL of homogenate buffer per 1 g of heart weight to prepare a mitochondrial solution.

Test Example 3 (Measurement of rat heart mitochondrial inhibitory action): The oxygen consumption of mitochondria at 30 ° C. was measured using an oxygen consumption measurement system (NeoFox, FOL / C1T500P, Instech). Reaction solution (220 mmol / L mannitol, 70 mmol / L sucrose, 2 mmol / L HEPES, 1 mmol / L EGTA, 10 mmol / L potassium dihydrogen phosphate, 5 mmol / L magnesium chloride buffer, pH 7.2) in the measurement chamber. 485 μL, 5.2 μL of each test substance solution, and 15 μL of mitochondrial solution were added and mixed. After sealing the chamber, the temperature was equilibrated for 1 minute. 6.7 μL of a substrate solution consisting of 750 mmol / L sodium malate and 750 mmol / L sodium pyruvate was added, and the oxygen consumption for 1 minute was measured (State 4). Subsequently, 6.7 μL of 50 mmol / L ADP was added, and the oxygen consumption for 1 minute was measured (State 3). The respiratory regulation rate (State 3 / State 4) is calculated from the measurement result of each test substance addition, and the reduction rate with respect to the control (without test substance addition) is obtained. Incidentally, _{IC 50} value indicates the concentration that reduces the respiratory control ratio of 50%.

The results of Test Example 3 are shown in Table 24.

Formulation Example 1 (tablet): Granules were prepared by a wet granulation method using crystalline cellulose, D-mannitol, hydroxypropyl cellulose, and sodium carmellose as additives in Example 53, and magnesium stearate was added to the conventional method. Manufactured by.

Formulation Example 2 (Injection): In Example 53, D-mannitol and sodium citrate are used as additives and dissolved in purified water to prepare an injection by a conventional method.

The compound of the present invention has a COMT inhibitory action and a DDC inhibitory action, and is useful for the treatment of Parkinson's disease.

Claims (5)

A compound represented by the following general formula (1), a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing these.

[During the ceremony,
R ^{1 to} R ² are a hydrogen atom, a C _1- C ₆ alkylcarbonyl group which may be substituted, a C _1- C ₆ alkoxycarbonyl group which may be substituted, and a C _1- C which may be substituted. Shows ₆ alkylaminocarbonyl groups,
R ³ represents a hydrogen atom, a halogen atom, a haloalkyl group, a cyano group, a carboxy group;
R ⁴ is a hydrogen atom, a halogen atom, an optionally substituted C _1- C ₆ alkyl group, a haloalkyl group, a cyano group, a carboxy group, an aminocarbonyl group, and an optionally substituted C _1- C ₆ alkyl sulfanyl. group, halo alkylsulfanyl group, optionally substituted arylsulfanyl group, optionally substituted heteroaryl sulfanyl groups, optionally substituted C ₁ -C ₆ alkoxy group, an optionally substituted aryloxy group , optionally substituted heteroaryloxy group, an optionally substituted C ₁ -C ₆ alkoxycarbonyl group, an optionally substituted C ₁ -C ₆ alkylcarbonyl group, an arylcarbonyl substituted group, optionally substituted heteroarylcarbonyl group, an alkylsulfonyl group optionally C ₁ -C ₆ substituted, alkylsulfinyl group optionally C ₁ -C ₆ substituted, it may be substituted an arylsulfonyl group, an optionally substituted heteroarylsulfonyl group, an optionally substituted arylsulfinyl group, optionally substituted heteroaryl arylsulfinyl group, alkyl optionally C ₁ -C ₆ substituted Aminocarbonyl groups, optionally substituted aminosulfonyl groups, optionally substituted heterocycloalkylcarbonyl groups, optionally substituted benzofurans, optionally substituted 2,3-dihydrofurans, substituted May be chroman ring, optionally substituted 2-chromanone ring, optionally substituted 3-chromanone ring, optionally substituted 4-chromanone ring, optionally substituted coumarin ring, substituted A chromon ring which may be substituted, a 2-cumalanone ring which may be substituted, an inden ring which may be substituted, an indenone ring which may be substituted, and a phthalide ring which may be substituted are shown;
R ⁵ to R ¹⁰ each independently represent a hydrogen atom, a halogen atom, C ₁ -C ₆ alkyl, cyano group, form a carbonyl group with each other adjacent, or even to form a cycloalkyl group with the adjacent one another Often;
R ¹¹ represents a hydrogen atom, an optionally substituted _C 1 -C ₆ alkylcarbonyl group, an optionally substituted _C 1 -C ₆ alkoxycarbonyl group, an optionally substituted _C 1 -C ₆ alkylamino Shows a carbonyl group;
X, Y and Z represent single bonds, carbon atoms, oxygen atoms, nitrogen atoms and sulfur atoms, respectively;

Q ¹ to Q ⁶ is a carbon atom (each carbon atom is hydrogen atom, optionally substituted _C 1 -C ₆ alkyl group, optionally substituted _C 1 -C ₆ alkylthio group, substituted good C ₁ -C ₆ alkoxy group, a halogen atom, a nitro group, a trifluoromethyl group, a cyano group, a carboxy group may be substituted, or through a carbon atom or hetero atom to form a ring it may also be), nitrogen atom, or may form a ring with each other adjacent, or Q ² and Q ³ are a sulfur atom, or oxygen atom in together;
n represents 0 to 3 (provided ^that when the rest is in the case of carbon atoms in one of the nitrogen atoms of the Q 2 to Q ^6, n represents 1 to 3);
Ring A represents 3 to 6 heterocyclic compounds. ] The heterocyclic compound of ring A is

(During the ceremony
R ¹² is a hydrogen atom, an optionally substituted C ₁ -C ₆ alkyl group, a carboxy group, an optionally substituted C ₁ -C ₆ alkoxycarbonyl group, an optionally substituted amino group, a cyano Show the group,
R ¹³ is a hydrogen atom, a a C ₁ -C ₆ alkyl group), a compound of claim 1, or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions comprising these. A pharmaceutical composition comprising the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are hydrogen atoms. The compound according to claim 3, wherein R ¹¹ is a hydrogen atom, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing these. Q ¹ to Q ⁶ is a carbon atom (the carbon atoms of each of a hydrogen atom, may also optionally be substituted by a halogen atom) indicates;
n is the compound according to claim 4 showing 1-3, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing these.