JP5529639B2 - Novel catechol-O-methyltransferase inhibitor - Google Patents

Description

  The present invention relates to a novel catechol-O-methyltransferase inhibitor and use thereof.

  Parkinson's disease is a progressive neurodegenerative disease that frequently occurs in middle-aged and elderly people, and the number of patients is increasing with the progress of an aging society. Parkinson's disease is a disease whose main symptoms are coordinated motor dysfunction such as resting tremor, rigidity, ataxia, and postural reflex disorder, and its etiology is striae due to degeneration of midbrain dopaminergic neurons. It is believed to be due to a lack of body dopamine. For this reason, L-dopa and dopamine receptor stimulants are used as therapeutic agents for Parkinson's disease.

  L-dopa is a precursor of dopamine and is a drug that is metabolized to dopamine in the brain and has an effect, but has a drawback that its blood half-life is very short. Therefore, L-dopa is commonly used with peripheral aromatic L-amino acid decarboxylase inhibitors and / or catechol-O-methyltransferase inhibitors, which are L-dopa metabolic enzyme inhibitors. Catechol-O-methyltransferase (hereinafter referred to as COMT) is an enzyme that catalyzes the transfer of a methyl group from its coenzyme S-adenosyl-L-methionine to a catechol substrate, and by inhibiting this enzyme Metabolism of L-dopa to 3-O-methyl-L-dopa is inhibited, the blood half-life of L-dopa increases, and the amount of L-dopa penetrating the blood brain barrier increases. It is known to do. Thus, it is known that a COMT inhibitor increases the bioavailability of L-dopa and prolongs its action time when administered together with L-dopa (for example, non-patented). Reference 1).

  A COMT inhibitor is also expected to be useful as a therapeutic agent for hypertension because it has an action of promoting urinary sodium excretion (see, for example, Non-Patent Document 2). COMT inhibitors are also expected to be useful as therapeutic agents for depression (see, for example, Non-Patent Document 3).

  In recent years, various COMT inhibitors have been reported. The most potent COMT inhibitors known to date are tolcapone (3,4-dihydroxy-4′-methyl-5-nitrobenzophenone, see US Pat. No. 6,057,049) and entacapone ((E) -2-cyano-N, N-diethyl-3- (3,4-dihydroxy-5-nitrophenyl) acrylamide, see Patent Document 2), and these two agents are used in Parkinson's disease patients. However, since tolcapone has been observed to have severe liver dysfunction, it needs to be administered under strict monitoring of liver function (for example, see Non-Patent Document 4). In addition, entacapone has a problem that its effect is weaker than that of tolcapone and has a short action duration (for example, see Non-Patent Document 5). Therefore, a novel COMT inhibitor having high safety and a strong COMT inhibitory action is desired.

  Patent Document 1 discloses 5- [3-methyl-1,2,4-oxadiazol-5-yl) -3-nitropyrocatechol as a [1,2,4] oxadiazole derivative having a COMT inhibitory action. (See Example 75 of Patent Document 1). However, the compound and the compound represented by the general formula (I) contained as an active ingredient in the pharmaceutical composition of the present invention are the bonding position of the nitrocatechol group bonded to the 1,2,4-oxadiazole ring. Is different.

European Patent Application No. 237929 British Patent Application No. 2200109

Nutt J.G. et al., “Lancet”, 1998, 351, 9111, p.1221-1222 Eklof A.C. et al., `` Kidney Int. '', 1997, 52, 3, p.742-747 Moreau J.L., et al., "Behav. Pharmacol.", 1994, 5 (3), p.344-350 Benabou R. et al., "Expert Opin. Drug Saf.", 2003, Vol. 2, No. 3, p.263-267 Forsberg M. et al., "J. Pharmacol. Exp. Ther.", 2003, 304, 2, 498-506 Koga K. et al., “Eur. J. Pharmacol.” 2000, 408, 249-255.

  An object of the present invention is to provide a novel pharmaceutical composition having a strong COMT inhibitory action and preferably having high safety.

  As a result of intensive studies to solve the above problems, the present inventors have found that the catechol derivative represented by the general formula (I) has an excellent COMT inhibitory action and further has high safety. The headline and the present invention were completed.

〔式中、Ｒ^３は、以下のａ）〜ｒ）：
ａ）ハロ低級アルキル基、
ｂ）低級アシル基、
ｃ）ハロ低級アルキルカルボニル基、
ｄ）シクロアルキルカルボニル基、
ｅ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、低級アルコキシ基、シクロアルキル低級アルコキシ基、水酸基、低級アルコキシカルボニル基、−Ｃ（Ｏ）ＮＲ^１１Ｒ^１２およびシアノ基から独立して選択される１〜５個の基で環が置換されるアリールカルボニル基、
ｆ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、および低級アルコキシ基から独立して選択される１〜３個の基で環が置換されるヘテロアリールカルボニル基、
ｇ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、および低級アルコキシ基から独立して選択される１〜５個の基で環が置換されるアラルキルカルボニル基、
ｈ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、および低級アルコキシ基から独立して選択される１〜５個の基で環が置換されるアリールオキシ低級アルキルカルボニル基、
ｉ）低級アルコキシカルボニル基、
ｊ）シクロアルキルオキシカルボニル基、
ｋ）低級アルコキシ低級アルコキシカルボニル基、
ｌ）カルボキシ基、
ｍ）シアノ基、
ｎ）−Ｃ（Ｏ）ＮＲ^１１Ｒ^１２、
ｏ）−Ｃ（Ｏ）Ｃ（Ｏ）ＮＲ^１１Ｒ^１２、
ｐ）低級アルキルスルホニル基、
ｑ）−ＳＯ_２ＮＲ^１１Ｒ^１２、または
ｒ）非置換もしくは以下からなる群：ハロゲン原子、低級アルキル基、ハロ低級アルキル基、および低級アルコキシ基から独立して選択される１〜３個の基で環が置換されるヘテロアリール基であり；
Ｒ^４は、以下のａ）〜ｈ）：
ａ）低級アルキル基、
ｂ）ハロ低級アルキル基、
ｃ）シクロアルキル基、
ｄ）ヘテロシクロアルキル基、
ｅ）低級アルコキシ低級アルキル基、
ｆ）アリールオキシ低級アルキル基、
ｇ）低級アルコキシカルボニル低級アルキル基、または
ｈ）ヒドロキシ低級アルキル基であり；
Ｒ^１１およびＲ^１２は、それぞれ独立して、水素原子、低級アルキル基、シクロアルキル基、橋かけ環状炭化水素基、フェニル基またはアラルキル基を表すか、あるいはＲ^１１およびＲ^１２が、それらが結合している窒素原子と一緒になって、環状アミノ基を形成する〕
で表される化合物またはその薬理学的に許容される塩を有効成分として含有する医薬組成物に関する。 That is, the present invention relates to the general formula (I):

[Wherein R ³ represents the following a) to r):
a) a halo lower alkyl group,
b) a lower acyl group,
c) a halo lower alkylcarbonyl group,
d) a cycloalkylcarbonyl group,
e) Unsubstituted or group consisting of: halogen atom, lower alkyl group, halo lower alkyl group, lower alkoxy group, cycloalkyl lower alkoxy group, hydroxyl group, lower alkoxycarbonyl group, —C (O) NR ¹¹ R ¹² and cyano An arylcarbonyl group wherein the ring is substituted with 1 to 5 groups independently selected from the group;
f) Unsubstituted or the group consisting of the following: a heteroarylcarbonyl group in which the ring is substituted with 1 to 3 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, and a lower alkoxy group,
g) An unsubstituted or group consisting of the following: an aralkylcarbonyl group in which the ring is substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, and a lower alkoxy group,
h) unsubstituted or aryloxy lower alkylcarbonyl in which the ring is substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, and a lower alkoxy group Group,
i) a lower alkoxycarbonyl group,
j) a cycloalkyloxycarbonyl group,
k) a lower alkoxy lower alkoxycarbonyl group,
l) a carboxy group,
m) a cyano group,
n) —C (O) NR ¹¹ R ¹² ,
o) -C (O) C (O) NR < ¹¹ > R < ¹² >,
p) a lower alkylsulfonyl group,
q) —SO ₂ NR ¹¹ R ¹² , or r) unsubstituted or 1 to 3 groups independently selected from the group consisting of: a halogen atom, a lower alkyl group, a halo lower alkyl group, and a lower alkoxy group A heteroaryl group wherein the ring is substituted with:
R ⁴ represents the following a) to h):
a) a lower alkyl group,
b) a halo lower alkyl group,
c) a cycloalkyl group,
d) a heterocycloalkyl group,
e) a lower alkoxy lower alkyl group,
f) an aryloxy lower alkyl group,
g) a lower alkoxycarbonyl lower alkyl group, or h) a hydroxy lower alkyl group;
R ¹¹ and R ¹² each independently represent a hydrogen atom, a lower alkyl group, a cycloalkyl group, a bridged cyclic hydrocarbon group, a phenyl group or an aralkyl group, or R ¹¹ and R ¹² are bonded to each other. Together with the nitrogen atom that forms a cyclic amino group)
Or a pharmacologically acceptable salt thereof as an active ingredient.

  The present invention relates to a pharmaceutical composition for treating or preventing Parkinson's disease, depression or hypertension, which contains a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient. .

  The present invention also provides a pharmaceutical composition containing a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient, and L-DOPA and aromatic L-amino acid decarboxylase inhibition. The present invention relates to a pharmaceutical comprising a combination of at least one selected from agents.

  The present invention also provides a pharmaceutical composition containing a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient, and L-DOPA and aromatic L-amino acid decarboxylase inhibition. The present invention relates to a medicament for treating or preventing Parkinson's disease, which is combined with at least one selected from agents.

  The pharmaceutical composition of the present invention has a strong COMT inhibitory effect, has a slight effect on the liver, and has high safety. Therefore, the pharmaceutical composition of the present invention is useful as a therapeutic or prophylactic agent for Parkinson's disease, depression and hypertension. In particular, by using the pharmaceutical composition of the present invention in combination with L-dopa, -Since the bioavailability of dopa can be increased, it is suitable for the treatment or prevention of Parkinson's disease.

  In the compound represented by the general formula (I), the following terms have the following meanings unless otherwise specified.

  In this specification, the term “lower” means having 1 to 6 carbon atoms unless otherwise specified.

  The “halogen atom” represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The “lower alkyl group” means a linear or branched C _1-6 alkyl group, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, Examples thereof include tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group and the like. In R ⁴ , R ¹¹ and R ¹² , C _1-4 alkyl is preferable, and a methyl group is more preferable.

The “halo lower alkyl group” means a C _1-6 alkyl group substituted with 1 to 3 of the same or different halogen atoms, and examples thereof include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, 2 , 2,2-trifluoroethyl group and the like, preferably a difluoromethyl group or a trifluoromethyl group.

“Hydroxy lower alkyl group” means a hydroxy-C _1-6 alkyl group, for example, a hydroxymethyl group, a 1-hydroxyethyl group, a 1-hydroxy-1,1-dimethylmethyl group, a 2-hydroxyethyl group. , 2-hydroxy-2-methylpropyl group, 3-hydroxypropyl group and the like.

“Lower alkoxy group” means a linear or branched C _1-6 alkoxy group, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group. Tert-butoxy group, pentyloxy group, hexyloxy group and the like.

  The “cycloalkyl group” means a 3 to 7-membered saturated cyclic hydrocarbon, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.

  “Heterocycloalkyl group” means a 4 to 7-membered saturated heterocyclic group containing —NH—, —O— or —S— in the ring and bonded via a carbon atom. Examples include a furyl group, a tetrahydrothienyl group, a tetrahydropyranyl group, a pyrrolidin-2-yl group, a pyrrolidin-3-yl group, a piperidin-2-yl group, a piperidin-3-yl group, and a piperidin-4-yl group. .

  “Bridged cyclic hydrocarbon group” means a bridged saturated cyclic hydrocarbon having 7 to 10 carbon atoms and having a 5- to 7-membered ring. For example, bicyclo [2.2.1] heptane- A 2-yl group, an adamantane-1-yl group, etc. are mentioned.

The “aryl group” means a C _6-10 aromatic hydrocarbon, and includes a phenyl group, a 1-naphthyl group, and a 2-naphthyl group, and is preferably a phenyl group.

The “aralkyl group” means an aryl-C _1-6 alkyl group, and examples thereof include a benzyl group, a phenethyl group, a 1-phenylethyl group, a 3-phenylpropyl group, a 4-phenylbutyl group, and a naphthylmethyl group. .

The “cycloalkyl lower alkoxy group” means a cycloalkyl-C _1-6 alkoxy group, and examples thereof include a cyclopropylmethoxy group, a cyclopentylmethoxy group, a cyclohexylmethoxy group, and the like.

  A “heteroaryl group” is a 5-6 membered monocyclic containing 1 to 5 carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of O, N and S atoms An aromatic heterocycle or an 8-10 membered bicyclic aromatic containing 1-9 carbon atoms and 1-4 heteroatoms independently selected from the group consisting of O, N and S atoms Means a heterocycle, provided that these rings do not contain adjacent oxygen and / or sulfur atoms. Examples of the monocyclic aromatic heterocycle include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, triazolyl, Examples thereof include pyridyl, pyrazinyl, pyrimidyl and pyridazinyl, and pyridyl, thiazolyl or 1,2,4-oxadiazolyl is preferable. Examples of the bicyclic aromatic heterocycle include indolyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, quinolyl, isoquinolyl, phthalazinyl, benzimidazolyl, benzoxazolyl and the like. All positional isomers of these heterocycles are contemplated (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl, etc.).

The “lower alkoxy lower alkyl group” means a C _1-6 alkoxy-C _1-6 alkyl group, and examples thereof include a methoxymethyl group, a 2-methoxyethyl group, an ethoxymethyl group, and a 2-ethoxyethyl group. And preferably a methoxymethyl group or a 2-ethoxyethyl group.

“Aryloxy lower alkyl group” means an aryloxy-C _1-6 alkyl group, for example, phenoxymethyl group, 1-phenoxyethyl group, 2-phenoxyethyl group, 1-methyl-1-phenoxyethyl group , 3-phenoxypropyl group, naphthyloxymethyl group and the like.

The “lower acyl group” means a group represented by (C _1-6 alkyl) -C (O) —, for example, acetyl group, propionyl group, butyryl group, isobutyryl group, pivaloyl group, valeryl group, And isovaleryl group.

The “halo lower alkylcarbonyl group” means a group represented by (haloC _1-6 alkyl) -C (O) —, and examples thereof include a trifluoroacetyl group and a trichloroacetyl group.

  "Cycloalkylcarbonyl group" means a group represented by (cycloalkyl) -C (O)-, for example, cyclopropylcarbonyl group, cyclobutylcarbonyl group, cyclopentylcarbonyl group, cyclohexylcarbonyl group, etc. Means.

The “arylcarbonyl group” means a group represented by (aryl) -C (O) —, and examples thereof include a benzoyl group.
In R ³ , “unsubstituted or group consisting of: halogen atom, lower alkyl group, halo lower alkyl group, lower alkoxy group, cycloalkyl lower alkoxy group, hydroxyl group, lower alkoxycarbonyl group, —C (O) NR ¹¹ R ¹² And an arylcarbonyl group whose ring is substituted with 1 to 5 groups independently selected from cyano group include, for example, benzoyl group, 2-fluorobenzoyl group, 3-fluorobenzoyl group, 4-fluorobenzoyl Group, 2,4-difluorobenzoyl group, 4-chlorobenzoyl group, 2-methylbenzoyl group, 3-methylbenzoyl group, 4-methylbenzoyl group, 2-methoxybenzoyl group, 3-methoxybenzoyl group, 4-methoxybenzoyl group Group, 4-hydroxybenzoyl group, 4-cyanobenzoyl group, 4-methyl And the like. Toxicarbonylbenzoyl group, 4-ethoxycarbonylbenzoyl group, 4-cyclopropylmethoxybenzoyl group and the like are mentioned, preferably benzoyl group, 2-fluorobenzoyl group or 4-hydroxybenzoyl group, more preferably benzoyl group. .

  "Heteroarylcarbonyl group" means a group represented by (heteroaryl) -C (O)-, for example, 2-furylcarbonyl group, 2-thienylcarbonyl group, 2-oxazolylcarbonyl group, Examples include 2-thiazolylcarbonyl group, 5-isoxazolylcarbonyl group, 2-pyridylcarbonyl group, 3-pyridylcarbonyl group, 4-pyridylcarbonyl group and the like.

  The “aralkylcarbonyl group” means a group represented by (aralkyl) -C (O) —, and examples thereof include a benzylcarbonyl group and a 2-phenylethylcarbonyl group.

The “aryloxy lower alkylcarbonyl group” means a group represented by ( _{aryloxyC 1-6} alkyl) -C (O) —, and examples thereof include a phenoxymethylcarbonyl group.

“Lower alkoxycarbonyl group” means a group represented by (C _1-6 alkoxy) -C (O) —, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, Examples include butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, hexyloxycarbonyl group and the like.

  The “cycloalkyloxycarbonyl group” means a group represented by (cycloalkyl) -O—C (O) —, and means, for example, a cyclopentyloxycarbonyl group, a cyclohexyloxycarbonyl group or the like.

The “lower alkoxy lower alkoxycarbonyl group” means a group represented by (C _1-6 alkoxyC _1-6 alkoxy) -C (O) —, and includes 2-methoxyethoxycarbonyl group, 2-ethoxyethoxycarbonyl group. Group, 3-methoxypropoxycarbonyl group and the like.

The “lower alkoxycarbonyl lower alkyl group” means a group represented by (C _1-6 alkoxy) -C (O) —C _1-6 alkyl, and examples thereof include a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, Examples include 2- (ethoxycarbonyl) ethyl group.

The “lower alkylsulfonyl group” means a group represented by (C _1-6 alkyl) -SO ₂ —, for example, a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group, a butanesulfonyl group, a pentanesulfonyl group. And a hexanesulfonyl group, and a methanesulfonyl group is preferred.

  “Cyclic amino group” means a 5- to 7-membered saturated cyclic amine which may contain —NH—, —O— or —S— in the ring. For example, 1-pyrrolidyl group, piperidino group, piperazino Group, morpholino group, thiomorpholino group and the like. The cyclic amino group may be optionally substituted with 1 to 2 lower alkyl groups.

  When one or more asymmetric carbon atoms are present in the compound represented by the general formula (I), the present invention relates to a compound in which each asymmetric carbon atom is in the R configuration, a compound in the S configuration, and any of them. Any combination of these compounds is included. Also included within the scope of the present invention are those racemates, racemic mixtures, single enantiomers and diastereomeric mixtures. When geometric isomerism exists in the compound represented by the general formula (I), the present invention encompasses any of the geometric isomers. When atropisomers exist in the compound represented by the general formula (I), the present invention includes any of the atropisomers. Furthermore, the compound represented by the general formula (I) includes solvates with pharmaceutically acceptable solvents such as hydrates and ethanol.

  The compound represented by the general formula (I) can exist in the form of a salt. Such salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid Acid with organic acids such as p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid Examples thereof include salts with inorganic bases such as addition salts, lithium salts, sodium salts, potassium salts, calcium salts, and magnesium salts, and salts with organic bases such as triethylamine, piperidine, morpholine, and lysine.

In one embodiment of the compound represented by the general formula (I):
R ³ is preferably the following a) to h):
a) a lower acyl group,
b) a cycloalkylcarbonyl group,
c) An unsubstituted or group consisting of: an arylcarbonyl group in which the ring is substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, and a lower alkoxy group;
d) Unsubstituted or the group consisting of the following: a heteroarylcarbonyl group in which the ring is substituted with 1 to 3 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, and a lower alkoxy group,
e) An unsubstituted or group consisting of the following: an aralkylcarbonyl group in which the ring is substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, and a lower alkoxy group,
f) Unsubstituted or the group consisting of: aryloxy lower alkylcarbonyl in which the ring is substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, and a lower alkoxy group Group,
g) a lower alkoxycarbonyl group, or h) —C (O) C (O) NR ¹¹ R ¹² ,
More preferably R ³ is a) to e):
a) a lower acyl group,
b) a cycloalkylcarbonyl group,
c) An unsubstituted or group consisting of: an arylcarbonyl group in which the ring is substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, and a lower alkoxy group;
d) a lower alkoxycarbonyl group, or e) —C (O) C (O) NR ¹¹ R ¹² ;
R ⁴ is preferably the following a) to d):
a) a lower alkyl group,
b) a lower alkoxy lower alkyl group,
c) an aryloxy lower alkyl group, or d) a lower alkoxycarbonyl lower alkyl group,
More preferably, R ⁴ is a lower alkyl group or a lower alkoxy lower alkyl group; or R ¹¹ and R ¹² are preferably each independently a hydrogen atom, a lower alkyl group, a cycloalkyl group, a bridged cyclic hydrocarbon. Group or phenyl group.

In a preferred embodiment of the invention,
R ³ represents the following a) to h):
a) a lower acyl group,
b) a cycloalkylcarbonyl group,
c) An unsubstituted or group consisting of: an arylcarbonyl group in which the ring is substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, and a lower alkoxy group;
d) Unsubstituted or the group consisting of the following: a heteroarylcarbonyl group in which the ring is substituted with 1 to 3 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, and a lower alkoxy group,
e) An unsubstituted or group consisting of the following: an aralkylcarbonyl group in which the ring is substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, and a lower alkoxy group,
f) Unsubstituted or the group consisting of: aryloxy lower alkylcarbonyl in which the ring is substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, and a lower alkoxy group Group,
g) a lower alkoxycarbonyl group, or h) —C (O) C (O) NR ¹¹ R ¹² ;
R ⁴ represents the following a) to d):
a) a lower alkyl group,
b) a lower alkoxy lower alkyl group,
c) an aryloxy lower alkyl group, or d) a lower alkoxycarbonyl lower alkyl group;
R ¹¹ and R ¹² each independently represent a hydrogen atom, a lower alkyl group, a cycloalkyl group, a bridged cyclic hydrocarbon group, a phenyl group or an aralkyl group, or R ¹¹ and R ¹² are bonded to each other. Together with the nitrogen atom, a cyclic amino group is formed.

In a further preferred embodiment of the invention R ³ is a) to e):
a) a lower acyl group,
b) a cycloalkylcarbonyl group,
c) An unsubstituted or group consisting of: an arylcarbonyl group in which the ring is substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, and a lower alkoxy group;
d) a lower alkoxycarbonyl group, or e) —C (O) C (O) NR ¹¹ R ¹² ;
R ⁴ represents the following a) to d):
a) a lower alkyl group,
b) a lower alkoxy lower alkyl group,
c) an aryloxy lower alkyl group, or d) a lower alkoxycarbonyl lower alkyl group;
R ¹¹ and R ¹² each independently represent a hydrogen atom, a lower alkyl group, a cycloalkyl group, a bridged cyclic hydrocarbon group, a phenyl group or an aralkyl group, or R ¹¹ and R ¹² are bonded to each other. Together with the nitrogen atom, a cyclic amino group is formed.

In a still further preferred embodiment of the invention,
R ³ represents the following a) to e):
a) a lower acyl group,
b) a cycloalkylcarbonyl group,
c) An unsubstituted or group consisting of: an arylcarbonyl group in which the ring is substituted with 1 to 5 groups independently selected from a halogen atom, a lower alkyl group, a halo lower alkyl group, and a lower alkoxy group;
d) a lower alkoxycarbonyl group, or e) —C (O) C (O) NR ¹¹ R ¹² ;
R ⁴ is a lower alkyl group or a lower alkoxy lower alkyl group;
R ¹¹ and R ¹² each independently represent a hydrogen atom, a lower alkyl group, a cycloalkyl group, a bridged cyclic hydrocarbon group, a phenyl group or an aralkyl group, or R ¹¹ and R ¹² are bonded to each other. Together with the nitrogen atom, a cyclic amino group is formed.

A specific example of a preferred embodiment of the present invention is a pharmaceutical composition comprising as an active ingredient a compound selected from the group consisting of the following or a pharmacologically acceptable salt thereof:
[3,4-dihydroxy-6- (5-methyl- [1,2,4] oxadiazol-3-yl) -2-nitrophenyl] phenylmethanone;
1- [3,4-dihydroxy-6- (5-methyl- [1,2,4] oxadiazol-3-yl) -2-nitrophenyl] ethanone;
Methyl 3,4-dihydroxy-6- (5-methyl- [1,2,4] oxadiazol-3-yl) -2-nitrobenzoate;
N-cyclohexyl-2- [3,4-dihydroxy-6- (5-methyl- [1,2,4] oxadiazol-3-yl) -2-nitrophenyl] -2-oxoacetamide;
N-cyclohexyl-2- [3,4-dihydroxy-6- (5-methyl- [1,2,4] oxadiazol-3-yl) -2-nitrophenyl] -N-methyl-2-oxoacetamide ;
1- {6- [5- (2-ethoxyethyl)-[1,2,4] oxadiazol-3-yl] -3,4-dihydroxy-2-nitrophenyl} ethanone; and cyclohexyl- [3, 4-dihydroxy-6- (5-methyl- [1,2,4] oxadiazol-3-yl) -2-nitrophenyl] methanone.

  The compound represented by the general formula (I) can be produced by the methods shown in Schemes 1 to 5.

（式中、Ｒ^３、Ｒ^４は前記と同義である。）

(In the formula, R ³ and R ⁴ are as defined above.)

Step 1-1
An amidoxime (X) is prepared in an inert solvent (eg, tetrahydrofuran, methylene chloride, etc.) or a base (eg, triethylamine, pyridine, N, N-diisopropylethylamine, etc.) as an acylating agent (eg, acid halide, acid). Anhydrides, mixed acid anhydrides, benzotriazol-1-yl esters, 4-nitrophenyl esters, 2,5-dioxapyrrolidine esters, etc.) and bases (eg, triethylamine, pyridine, N, N-diisopropylethylamine, etc.) Acylation in the presence gives acylamidoxime derivative (XI). The temperature of this acylation reaction is usually from −20 ° C. to the reflux temperature, and the reaction time is usually from 15 minutes to 24 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.
The acylamidoxime derivative (XI) is prepared by reacting a carboxylic acid and amidoxime (X) in an inert solvent (eg, N, N-dimethylformamide, methylene chloride, etc.) with a condensing agent (eg, dicyclohexylcarbodiimide, 1- (3 -Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, diethyl cyanophosphate, diphenylphosphoryl azide, etc.). This condensation reaction is usually from −20 ° C. to reflux temperature, and the reaction time is usually from 15 minutes to 24 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.

Step 1-2
Cyclization of the acylamidoxime derivative (XI) in an inert solvent (eg, tetrahydrofuran) in the presence of a base (eg, pyridine, tetrabutylammonium fluoride, etc.) provides an oxadiazole derivative (XII) . The reaction temperature is usually from 0 ° C. to 120 ° C., and the reaction time is usually from 15 minutes to 12 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.
The oxadiazole derivative (XII) can also be obtained by cyclizing the acylamidoxime derivative (XI) in a base (for example, pyridine). This cyclization is usually from 20 ° C. to reflux temperature, and the reaction time is usually from 15 minutes to 24 hours, although it varies depending on the raw materials and solvents used, the reaction temperature and the like.

Step 1-3
Presence of a metal catalyst (eg, palladium carbon, platinum oxide, etc.) in a hydrogen atmosphere in an inert solvent (eg, ethanol, N, N-dimethylformamide, tetrahydrofuran, etc.) for the benzyl group of the oxadiazole derivative (XII) The phenol derivative (XIII) is obtained by removing below. The reaction temperature is usually from room temperature to 80 ° C., and the reaction time is usually from 30 minutes to 12 hours, although it varies depending on the raw material and solvent used, the reaction temperature, and the like.
In addition, this debenzylation can be performed by reacting the oxadiazole derivative (XII) with an acid or Lewis acid (for example, hydrogen bromide, aluminum chloride, titanium tetrachloride) in an inert solvent (for example, methylene chloride, toluene, etc.). It can also be performed by processing using The reaction temperature is usually from 0 ° C. to 80 ° C., and the reaction time is usually from 15 minutes to 24 hours, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.

Step 1-4
Nitrophenol derivative (XIV) is obtained by nitration of phenol derivative (XIII) in an inert solvent using a nitrating agent. Examples of the inert solvent used in this reaction include methylene chloride, 1,2-dichloroethane, ethyl acetate, acetic acid, tetrahydrofuran, acetic anhydride and the like. Examples of the nitrating agent include nitric acid, fuming nitric acid, nitronium tetrafluoroborate, and the like. The reaction temperature is usually from −40 ° C. to 80 ° C., and the reaction time is usually from 5 minutes to 12 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like. Moreover, you may perform this reaction by adding additives, such as a sulfuric acid, as needed.

Step 1-5
The compound (I) is obtained by demethylating the nitrophenol derivative (XIV) in an inert solvent using a demethylating agent. Examples of the inert solvent used in this reaction include ethyl acetate, pyridine, 1,4-dioxane and the like. Examples of the demethylating agent include aluminum chloride-pyridine and boron tribromide. The reaction temperature is usually from −20 ° C. to 120 ° C., and the reaction time is usually from 1 hour to 24 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.
This demethylation can also be carried out by treating the nitrophenol derivative (XIV) with hydrobromic acid or hydroiodic acid in an acetic acid solvent. The reaction temperature is usually 20 ° C. to reflux temperature, and the reaction time is usually 1 hour to 24 hours, although it varies depending on the raw material used, the reaction temperature and the like.

（式中、Ｒ^４、Ｂｎは前記と同義であり、Ｒ^２０はアリール、低級アルキル、ハロ低級アルキル、シクロアルキル、へテロアリールまたはアラルキルを表し、Ｘは塩素、臭素または−N（ＣＨ_３）ＯＣＨ_３を表す。）

Wherein R ⁴ and Bn are as defined above, R ²⁰ represents aryl, lower alkyl, halo-lower alkyl, cycloalkyl, heteroaryl or aralkyl, and X is chlorine, bromine or —N (CH ₃ ) OCH ₃ )

Step 2-1
Iodine is obtained by iodination of an aldehyde derivative (XV) in an inert solvent (eg, methylene chloride, methanol, acetic acid, etc.) and in the presence of an iodinating agent (eg, iodine, N-iodosuccinimide, iodine monochloride). Benzaldehyde (XVI) is obtained. The reaction temperature is usually 20 ° C. to reflux temperature, and the reaction time is usually 15 minutes to 24 hours, although it varies depending on the raw material used, the reaction temperature, and the like. Further, this reaction may be carried out by adding an additive such as trifluoroacetic acid or silver trifluoroacetate, if necessary.

Step 2-2
Oxime derivative (XVII) is obtained by oximation of iodobenzaldehyde (XVI) in an inert solvent (for example, ethanol, N, N-dimethylformamide, tetrahydrofuran, etc.) in the presence of hydroxylamine. The reaction temperature is usually 20 ° C. to reflux temperature, and the reaction time is usually 15 minutes to 24 hours, although it varies depending on the raw material used, the reaction temperature, and the like. Moreover, you may perform this reaction by adding additives, such as sodium acetate and sodium hydroxide, as needed.

Step 2-3
N-hydroxybenzimidoyl is obtained by chlorinating the oxime derivative (XVII) in an inert solvent (for example, N, N-dimethylformamide, tetrahydrofuran, etc.) in the presence of a chlorinating agent (N-chlorosuccinimide, etc.). A chloride derivative is obtained. The reaction temperature is 0 ° C. to 80 ° C., and the reaction time is usually 5 minutes to 24 hours, although it varies depending on the raw material used, the reaction temperature, and the like.
The amidoxime derivative (XVIII) is obtained by reacting the N-hydroxybenzimidoyl chloride derivative with an aminating agent (eg, aqueous ammonia) in an inert solvent (eg, N, N-dimethylformamide, tetrahydrofuran, etc.). It is done. The reaction temperature is 0 ° C. to 30 ° C., and the reaction time is usually 15 minutes to 24 hours, although it varies depending on the raw material used, the reaction temperature, and the like.

Step 2-4
The acylamide amidoxime derivative (XIX) is obtained by acylating the amidoxime derivative (XVIII) in the same manner as in Step 1-1.

Step 2-5
The oxadiazole derivative (XX) is obtained by cyclizing the acylamidoxime derivative (XIX) in the same manner as in Step 1-2.

Step 2-6
A benzyl alcohol derivative (XXII) is obtained by reacting the oxadiazole derivative (XX) with an organomagnesium reagent in an inert solvent and then reacting with an aldehyde (XXI). Examples of the inert solvent used in this reaction include tetrahydrofuran. Examples of the organic magnesium reagent include isopropyl magnesium chloride. The reaction temperature is usually −78 ° C. to 10 ° C., and the reaction time is usually 15 minutes to 2 hours, although it varies depending on the raw material and solvent used, the reaction temperature, and the like.

Step 2-7
The oxadiazole derivative (XX) is reacted with an organomagnesium reagent in an inert solvent and then reacted with N, N-dimethylformamide (DMF) to obtain the aldehyde derivative (XXIII). Examples of the inert solvent used in this reaction include tetrahydrofuran. Examples of the organic magnesium reagent include isopropyl magnesium chloride. The reaction temperature is usually −78 ° C. to 10 ° C., and the reaction time is usually 15 minutes to 2 hours, although it varies depending on the raw material and solvent used, the reaction temperature, and the like.

Step 2-8
The benzyl alcohol derivative (XXII) is obtained by reacting the aldehyde derivative (XXIII) with an organic magnesium reagent (XXIV) or an organic lithium reagent (XXV) in an inert solvent (such as tetrahydrofuran). The reaction temperature is usually −78 ° C. to 10 ° C., and the reaction time is usually 15 minutes to 2 hours, although it varies depending on the raw material and solvent used, the reaction temperature, and the like.

Step 2-9
Reaction of the oxadiazole derivative (XX) with an organomagnesium reagent in an inert solvent followed by reaction with an acid anhydride (XXVI), or an acid halide or N-methoxy-N-methylamide (XXVII) Derivative (XXVIII) is obtained. Examples of the inert solvent used in this reaction include tetrahydrofuran. Examples of the organic magnesium reagent include isopropyl magnesium chloride. The reaction temperature is usually from −78 ° C. to 50 ° C., and the reaction time is usually from 15 minutes to 2 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.

Step 2-10
The ketone derivative (XXVIII) is obtained by oxidizing the benzyl alcohol derivative (XXII) in an appropriate solvent using an oxidizing agent. Examples of the solvent used in this reaction include methylene chloride and acetonitrile. Examples of the oxidizing agent include manganese dioxide, sulfur trioxide pyridine complex-dimethyl sulfoxide, 4-methylmorpholine-N-oxide, and the like. The reaction temperature is usually 0 ° C. to 30 ° C., and the reaction time is usually 15 minutes to 3 days, although it varies depending on the raw material, solvent, oxidant, and reaction temperature used.

  Hereafter, compound (Ic) can be synthesized from ketone derivative (XXVIII) in the same manner as in step 1-3 to step 1-5 of Scheme 1.

（式中、Ｒ^４、Ｒ^１１、Ｒ^１２、Ｂｎは前記と同義であり、Ｒ^３０は低級アルキル、シクロアルキルまたは低級アルコキシ低級アルキルを表す。）

(Wherein R ⁴ , R ¹¹ , R ¹² and Bn are as defined above, and R ³⁰ represents lower alkyl, cycloalkyl or lower alkoxy lower alkyl.)

Step 3-1
The ester derivative (XXX) is obtained by condensing the compound (XX) and the alcohol (XXIX) in an inert solvent under a carbon monoxide atmosphere in the presence of a base, a palladium catalyst and a phosphorus ligand. Examples of the inert solvent used in this reaction include N, N-dimethylformamide, 1,4-dioxane, 1,2-dimethoxyethane, tetrahydrofuran, toluene and the like. Examples of the base include triethylamine and N, N-diisopropylethylamine. Examples of the palladium catalyst include tris (dibenzylideneacetone) dipalladium (0), palladium acetate, and the like. Examples of the ligand include 1,1′-bis (diphenylphosphino) ferrocene and triphenylphosphine. The reaction temperature is usually from 80 ° C. to 110 ° C., and the reaction time is usually from 1 hour to 24 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.

Step 3-2
Carboxylic acid derivative (XXXII) is obtained by oxidizing aldehyde derivative (XXIII) in an inert solvent using an oxidizing agent. Examples of the solvent used in this reaction include methylene chloride, acetonitrile, water, methanol and the like. Examples of the oxidizing agent include potassium permanganate, manganese dioxide, sodium chlorite-hydrogen peroxide, sodium chlorite-dimethyl sulfoxide and the like. The reaction temperature is usually 0 ° C. to 80 ° C., and the reaction time is usually 15 minutes to 3 days, although it varies depending on the raw material, solvent, oxidant, and reaction temperature used. Moreover, you may perform this reaction by adding additives, such as sodium hydrogenphosphate and a sulfuric acid, as needed.

Step 3-3
The ester derivative (XXX) is obtained by reacting the carboxylic acid derivative (XXXII) with an alkyl halide (XXXI) in the presence of a base in an inert solvent. Examples of the inert solvent used in this reaction include 1,4-dioxane, N, N-dimethylformamide, 1,2-dimethoxyethane, tetrahydrofuran and the like. Examples of the base include sodium tert-butoxide, potassium tert-butoxide, potassium carbonate and the like. The reaction temperature is usually from 0 ° C. to 100 ° C., and the reaction time is usually from 5 minutes to 24 hours, although it varies depending on the raw material used, solvent, reaction temperature, and the like.
Further, the ester derivative (XXX) is obtained by reacting the carboxylic acid derivative (XXXII) and the alcohol (XXIX) in an inert solvent (for example, methylene chloride, N, N-dimethylformamide, etc.), a condensing agent (for example, dicyclohexylcarbodiimide, 1 It can also be obtained by condensation in the presence of-(3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, diethyl cyanophosphate, diphenylphosphoryl azide and the like. Moreover, you may perform this reaction by adding bases, such as a triethylamine, as needed.

Step 3-4
Carboxylic acid derivative (XXXII) is converted into an inert solvent (for example, methylene chloride, N, N-dimethylformamide, tetrahydrofuran, etc.), a condensing agent (for example, dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3- Condensation with an amine (XXXIII) in the presence of ethyl carbodiimide hydrochloride, diethyl cyanophosphate, diphenylphosphoryl azide, etc.) gives an amide derivative (XXXIV). The reaction temperature is usually from −20 ° C. to the reflux temperature, and the reaction time is usually from 15 minutes to 24 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like. Moreover, you may perform this reaction by adding additives, such as a triethylamine, as needed.

  Hereafter, compound (Id) can be synthesized from compound (XXX) in the same manner as in step 1-3 to step 1-5 of Scheme 1. Similarly, compound (Ie) can be synthesized from compound (XXXIV).

（式中、Ｒ^４、Ｒ^１１、Ｒ^１２、Ｒ^３０およびＢｎは前記と同義である。）

(In the formula, R ⁴ , R ¹¹ , R ¹² , R ³⁰ and Bn are as defined above.)

Step 4-1
By condensing compound (XX) and triisopropylsilanethiol (XXXV) in the presence of a base, a palladium catalyst and a phosphorus ligand in an inert solvent, triisopropylsilylphenylthioether derivative (XXXVI) is obtained. Examples of the inert solvent used in this reaction include toluene, N, N-dimethylformamide, 1,4-dioxane, 1,2-dimethoxymethane, and the like. Examples of the base include sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium tert-butoxide and the like. Examples of the palladium catalyst include tris (dibenzylideneacetone) dipalladium (0), tetrakistriphenylphosphine palladium (0), palladium acetate, and the like. Examples of the ligand include (oxydi-2,1-phenylene) bis (diphenylphosphine). The reaction temperature is usually from 60 ° C. to 110 ° C., and the reaction time is usually from 1 hour to 24 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.

Step 4-2
Triisopropylsilylphenyl thioether derivative (XXXVI) in an inert solvent (for example, 1,4-dioxane, N, N-dimethylformamide, 1,2-dimethoxyethane, tetrahydrofuran, etc.), alkyl halide (XXXI), base (for example, In the presence of cesium fluoride, tetrabutylammonium fluoride, etc.), an alkylphenylthioether derivative can be obtained by converting a triisopropylsilyl group to an alkyl group (R ³⁰ ). The reaction temperature is usually from 0 ° C. to 100 ° C., and the reaction time is usually from 5 minutes to 24 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.
The sulfone derivative (XXXVII) is obtained by oxidizing the alkylphenylthioether derivative with an oxidizing agent in an appropriate solvent. Examples of the solvent used in this reaction include methylene chloride, acetone, acetic acid, water, and the like. Examples of the oxidizing agent include m-chloroperbenzoic acid, oxone (registered trademark), hydrogen peroxide solution, sodium perborate and the like. The reaction temperature is usually from 0 ° C. to 80 ° C., and the reaction time is usually from 5 minutes to 24 hours, although it varies depending on the raw material used, solvent, reaction temperature, and the like.

Step 4-3
Reacting a triisopropylsilylphenylthioether derivative (XXXVI) in an inert solvent (eg acetonitrile, N, N-dimethylformamide, etc.) in the presence of sulfuryl chloride and nitrate (eg potassium nitrate, sodium nitrate, silver nitrate, etc.) Gives a sulfonyl chloride derivative. The reaction temperature is usually from 0 ° C. to 40 ° C., and the reaction time is usually from 5 minutes to 5 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.
The sulfonyl chloride derivative is converted to an amine (XXXIII) in the presence of a base (eg, triethylamine, N, N-diisopropylethylamine, etc.) in an inert solvent (eg, tetrahydrofuran, N, N-dimethylformamide, ethyl acetate, methylene chloride, etc.). To give a sulfonamide derivative (XXXVIII). The reaction temperature is usually from 0 ° C. to 40 ° C., and the reaction time is usually from 5 minutes to 5 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.

  Hereafter, compound (If) can be synthesized from compound (XXXVII) in the same manner as in step 1-3 to step 1-5 of Scheme 1. Similarly, compound (Ig) can be synthesized from compound (XXXVIII).

（式中、Ｒ^４、Ｒ^１１、Ｒ^１２、Ｂｎは前記と同義であり、Ｒ^３１は低級アルキル、シクロアルキルを表す。）

(In the formula, R ⁴ , R ¹¹ , R ¹² , and Bn are as defined above, and R ³¹ represents lower alkyl or cycloalkyl.)

Step 5-1
The ester derivative (XL) is obtained by condensing the aldehyde derivative (XXIII) with isocyanide (XXXIX) in the presence of acetic acid in an inert solvent (for example, acetonitrile, methylene chloride, diethyl ether, etc.). The reaction temperature is usually 20 ° C. to 100 ° C., and the reaction time is usually 5 minutes to 24 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like. Moreover, you may perform this reaction by adding additives, such as titanium tetrachloride, as needed.

Step 5-2
By hydrolyzing the ester derivative (XL) in a suitable solvent (eg, tetrahydrofuran, methanol, ethanol, water, etc.) in the presence of a base (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), An alcohol derivative (XLI) is obtained. The reaction temperature is usually 20 ° C. to 100 ° C., and the reaction time is usually 5 minutes to 24 hours, although it varies depending on the raw material used, solvent, reaction temperature and the like.

Step 5-3
The ketone derivative (XLII) is obtained by oxidizing the alcohol derivative (XLI) in the same manner as in Step 2-10.

  Hereafter, compound (Ih) can be synthesized from compound (XLII) in the same manner as in step 1-3 to step 1-5 of Scheme 1.

  The schemes shown above are some examples of methods for preparing compound (I) or its intermediates, and various modifications of these schemes are possible as will be readily understood by those skilled in the art. It is.

  The compound represented by the general formula (I) and the intermediate used for producing the compound are, as necessary, solvent extraction, which is an isolation and purification means well known to those skilled in the art, It can be isolated and purified by performing operations such as crystallization, recrystallization, chromatography, preparative high performance liquid chromatography and the like.

The compound (I) produced in this manner has an excellent COMT inhibitory action and is therefore useful as a therapeutic or prophylactic agent for Parkinson's disease, and is preferably used in combination with L-dopa. In addition, compound (I) and L-dopa may be used in combination with an aromatic L-amino acid decarboxylase inhibitor. Examples of the aromatic L-amino acid decarboxylase inhibitor that can be used in combination with the COMT inhibitor of the present invention include carbidopa and benserazide.
Further, if necessary, a Parkinson therapeutic agent other than the COMT inhibitor and L-DOPA may be used in combination. Examples of such Parkinson's disease therapeutic agents include droxidopa, melevodopa, throdops; dopamine D ₂ receptor agonists (eg cabergoline, bromocriptine mesylate, terguride, talipexol hydrochloride, ropinirole mesilate, pergolide mesylate, pramipexole hydrochloride, rotigotine, etc. ); Anticholinergic agents (eg, prophenamine, trihexyphenidyl hydrochloride, masaticol hydrochloride, piperidene, pyroheptin hydrochloride, methixene hydrochloride, etc.); adenosine A _2A antagonists (eg, istradefylline); Monodioxidase B inhibitors (for example, selegiline hydrochloride, rasagiline mesylate, safinamide mesylate, etc.); zonisamide; amantadine hydrochloride, etc.

  The pharmaceutical composition of the present invention is also useful as a therapeutic or prophylactic agent for depression. The pharmaceutical composition of the present invention is also useful as a therapeutic agent for hypertension because it has an action of promoting urinary sodium excretion.

  For the pharmaceutical composition of the present invention, various dosage forms are used depending on the usage. Examples of such dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, solutions, ointments, suppositories, patches and the like, orally or parenterally. Administered.

  These pharmaceutical compositions are prepared according to pharmacologically known methods depending on the dosage form, using appropriate excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives. It can be prepared by mixing or diluting / dissolving appropriately with pharmaceutical additives such as wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents.

A therapeutically or prophylactically effective amount of the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof contained in the pharmaceutical composition of the present invention is administered.
The dose of the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof contained as an active ingredient in the pharmaceutical composition of the present invention depends on the age, sex, weight, disease and treatment of the patient. The dose is appropriately determined depending on the degree, etc. In the case of oral administration, it is in the range of about 10 mg to about 3000 mg per day for adults, and in the case of parenteral administration, it is in the range of about 5 mg to about 1000 mg per day for adults, once or several times. It can be divided and administered as appropriate.

  A pharmaceutical composition such as a preventive or therapeutic agent for Parkinson's disease comprising a combination of the pharmaceutical composition of the present invention and at least one selected from L-dopa and an aromatic L-amino acid decarboxylase inhibitor is an active ingredient thereof. Can be administered as a formulation containing each of these, or as a formulation in which each of these active ingredients is formulated separately. When formulated separately, the formulations can be administered separately or simultaneously. Moreover, when it formulates separately, those formulations can be mixed using a diluent etc. at the time of use, and can be administered simultaneously.

  In a pharmaceutical composition such as a preventive or therapeutic agent for Parkinson's disease comprising a combination of the pharmaceutical composition of the present invention and at least one selected from L-dopa and an aromatic L-amino acid decarboxylase inhibitor, Can be appropriately selected depending on the age, sex, and weight of the patient, symptoms, administration time, dosage form, administration method, drug combination, and the like.

  The contents of the present invention will be described in more detail with reference to the following Reference Examples, Production Examples and Examples, but the present invention is not limited to these contents.

Reference Example 1-1
4-Benzyloxy-2-iodo-5-methoxybenzaldehyde 4-Benzyloxy-3-methoxybenzaldehyde (10 g), silver trifluoroacetate (11.4 g) and methylene chloride (105 mL) were mixed with iodine (13.1 g) at room temperature. Added below. After stirring for 2 hours, the mixture was filtered through a Celite® layer. The filtrate was washed successively with aqueous sodium hydrogen sulfite solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with methanol: water = 4: 1 to give the title compound (13.2 g).
¹ H-NMR (CDCl ₃ ) δ ppm: 3.91 (3H, s), 5.19 (2H, s), 7.30-7.50 (7H, m), 9.86 (1H, s)

Reference Example 1-2
5-Benzyloxy-2-iodo-4-methoxybenzaldehyde The title compound was synthesized in the same manner as in Reference Example 1-1 using 3-benzyloxy-4-methoxybenzaldehyde instead of 4-benzyloxy-3-methoxybenzaldehyde. did.
¹ H-NMR (CDCl ₃ ) δ ppm: 3.95 (3H, s), 5.16 (2H, s), 7.29-7.47 (6H, m), 7.48 (1H, s), 9.84 (1H, s)

Reference Example 2-1
4-Benzyloxy-2-iodo-5-methoxybenzaldehyde oxime 4-Benzyloxy-2-iodo-5-methoxybenzaldehyde (Reference Example 1-1) (12.2 g), hydroxylamine hydrochloride (2.54 g), sodium acetate ( A mixture of 6 g) and ethanol (170 mL) was stirred at 70 ° C. for 1.5 hours. The mixture was concentrated under reduced pressure. Water was added to the residue and the mixture was stirred at room temperature for 30 minutes. The solid was collected by filtration to give the title compound (12.8 g).
¹ H-NMR (CDCl ₃ ) δ ppm: 3.88 (3H, s), 5.13 (2H, s), 7.19 (1H, s), 7.29 (1H, s), 7.30-7.50 (6H, m), 8.30 ( 1H, s)

  Reference Example 2-2 to Reference Example 2-3 were synthesized in the same manner as in Reference Example 2-1, using the corresponding aldehyde instead of 4-benzyloxy-2-iodo-5-methoxybenzaldehyde. These are shown in Table 1.

  The physical property values of Reference Example 2-3 are shown below.

Reference Example 2-3
¹ H-NMR (CDCl ₃ ) δ ppm: 3.88 (3H, s), 5.13 (2H, s), 7.25 (1H, s), 7.29-7.45 (6H, m), 8.28 (1H, s)

Reference Example 3-1
4-Benzyloxy-N-hydroxy-2-iodo-5-methoxybenzamidine 4-Benzyloxy-2-iodo-5-methoxybenzaldehyde oxime (Reference Example 2-1) (12.8 g) and N, N-dimethylformamide N-chlorosuccinimide (4.9 g) was added to a mixture of (110 mL) at room temperature. After stirring at room temperature for 20 minutes, water and ethyl acetate were added to the mixture under ice cooling. The separated organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 4-benzyloxy-N-hydroxy-2-iodo-5-methoxybenzimidoyl chloride.
To a mixture of 4-benzyloxy-N-hydroxy-2-iodo-5-methoxybenzimidoyl chloride and N, N-dimethylformamide (110 mL) was added 28% aqueous ammonia (12 mL) under ice cooling. After stirring for 3 hours under ice cooling, water and ethyl acetate were added to the mixture. The separated organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with hexane: diethyl ether = 1: 4 to give the title compound (9.3 g).
¹ H-NMR (DMSO-d ₆ ) δ ppm: 3.77 (3H, s), 5.12 (2H, s), 5.65 (2H, br s), 6.91 (1H, s), 7.30-7.50 (6H, m) , 9.35 (1H, s)

  Reference Example 3-2 to Reference Example 3-3 were synthesized in the same manner as in Reference Example 3-1, using the corresponding oxime instead of 4-benzyloxy-2-iodo-5-methoxybenzaldehyde oxime. These are shown in Table 2.

  The physical property values of Reference Example 3-3 are shown below.

Reference Example 3-3
¹ H-NMR (CDCl ₃ ) δ ppm: 3.87 (3H, s), 5.09 (2H, s), 7.00 (1H, s), 7.27-7.50 (5H, m)

Reference Example 4-1
3- (4-Benzyloxy-2-iodo-5-methoxyphenyl) -5-methyl- [1,2,4] oxadiazole 4-Benzyloxy-N-hydroxy-2-iodo-5-methoxybenzamidine (Reference Example 3-1) To a mixture of (35 g), triethylamine (31 mL) and tetrahydrofuran (300 mL) was added acetyl chloride (8.2 mL) under ice cooling. The mixture was stirred at the same temperature for 1 hour. Insoluble material was removed by filtration. Tetrabutylammonium fluoride (1 mol / L, tetrahydrofuran solution, 89 mL) was added to the filtrate under an argon atmosphere. After stirring at the same temperature for 2 hours, water and ethyl acetate were added to the mixture. The separated organic layer was washed successively with 1 mol / L hydrochloric acid, 1 mol / L sodium hydroxide aqueous solution, sodium hydrogen carbonate aqueous solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with methanol to give the title compound (31.5 g).
¹ H-NMR (CDCl ₃ ) δ ppm: 2.67 (3H, s), 3.90 (3H, s), 5.16 (2H, s), 7.28 (1H, s), 7.30-7.50 (6H, m)

Reference Example 4-2
3- (5-Benzyloxy-2-iodo-4-methoxyphenyl) -5-methyl- [1,2,4] oxadiazole 5-benzyloxy-N-hydroxy-2-iodo-4-methoxybenzamidine Reference Example 3-3 To a mixture of (20 g) and pyridine (115 mL) was added acetyl chloride (3.8 mL) under ice cooling. After stirring at the same temperature for 3 hours, the mixture was heated and stirred at 120 ° C. for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. Ethyl acetate and 2 mol / L hydrochloric acid were added to the residue. The separated organic layer was washed successively with 2 mol / L hydrochloric acid and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 15% -50% ethyl acetate / hexane, gradient elution) to give the title compound (17.0 g).
¹ H-NMR (CDCl ₃ ) δ ppm: 2.66 (3H, s), 3.91 (3H, s), 5.14 (2H, s), 7.25-7.50 (7H, m)

  4-Benzyloxy-N-hydroxy-2-iodo-5-methoxybenzamidine and the corresponding amidine and acid chloride or anhydride instead of acetyl chloride were used in the same manner as in Reference Example 4-1, Example 4-3 Reference Example 4-13 was synthesized. These are shown in Table 3.

  The physical property values of Reference Example 4-3 and Reference Example 4-13 are shown below.

Reference Example 4-3
¹ H-NMR (CDCl ₃ ) δ ppm: 2.59 (3H, s), 2.60 (3H, s), 3.97 (3H, s), 5.22 (2H, s), 7.25-7.50 (7H, m)

Reference Example 4-4
¹ H-NMR (CDCl ₃ ) δ ppm: 1.23-1.28 (2H, m), 1.30-1.34 (2H, m), 2.24-2.30 (1H, m), 3.89 (3H, s), 5.15 (2H, s ), 7.25 (1H, s), 7.31-7.45 (6H, m)

Reference Example 4-5
¹ H-NMR (CDCl ₃ ) δ ppm: 3.57 (3H, s), 3.90 (3H, s), 4.77 (2H, s), 5.17 (2H, s), 7.32 (1H, s), 7.33-7.46 ( 5H, m), 7.47 (1H, s)

Reference Example 4-6
¹ H-NMR (CDCl ₃ ) δ ppm: 1.51 (9H, s), 3.91 (3H, s), 5.16 (2H, s), 7.29 (1H, s), 7.31-7.45 (6H, m)

Reference Example 4-7
¹ H-NMR (CDCl ₃ ) δ ppm: 3.90 (3H, s), 5.17 (2H, s), 5.37 (2H, s), 7.00-7.10 (3H, m), 7.25-7.50 (9H, m)

Reference Example 4-8
¹ H-NMR (CDCl ₃ ) δ ppm: 1.40-1.50 (6H, m), 3.20-3.40 (1H, m), 3.90 (3H, s), 5.16 (2H, s), 7.29 (1H, s), 7.30-7.50 (6H, m)

Reference Example 4-9
¹ H-NMR (CDCl3) δ ppm: 1.00-1.10 (3H, m), 1.80-2.00 (2H, m), 2.90-3.00 (2H, m), 3.90 (3H, s), 5.16 (2H, s) , 7.28 (1H, s), 7.30-7.50 (6H, m)

Reference Example 4-10
¹ H-NMR (CDCl ₃ ) δ ppm: 1.27 (3H, t, J = 7.2Hz), 2.94 (2H, t, J = 7.4Hz), 3.28 (2H, t, J = 7.4Hz), 3.90 (3H , s), 4.19 (2H, q, J = 7.2Hz), 5.16 (2H, s), 7.20-7.50 (7H, m)

Reference Example 4-11
¹ H-NMR (CDCl 3) δ ppm: 3.92 (3H, s), 5.18 (2H, s), 7.33-7.46 (6H, m), 7.50 (1H, s)

Reference Example 4-12
¹ H-NMR (CDCl ₃ ) δ ppm: 2.05-2.15 (4H, m), 3.24-3.34 (1H, m), 3.54-3.64 (2H, m), 3.90 (3H, s), 4.03-4.10 (2H , m), 5.16 (2H, s), 7.30 (1H, s), 7.31-7.48 (6H, m)

Reference Example 4-13
¹ H-NMR (CDCl ₃ ) δ ppm: 1.20 (3H, t, J = 6.8 Hz), 3.24 (2H, t, J = 6.7 Hz), 3.56 (2H, q, J = 6.8 Hz), 3.85-4.00 (5H, m), 5.16 (2H, s), 7.30 (1H, s), 7.30-7.50 (6H, m)

Reference Example 5-1
5-Benzyloxy-4-methoxy-2- (5-methyl- [1,2,4] oxadiazol-3-yl) benzoic acid 5-benzyloxy-4-methoxy-2- (5-methyl- [ 1,2,4] oxadiazol-3-yl) benzaldehyde (Reference Example 15-1) (5.38 g), dimethyl sulfoxide (5.89 mL), concentrated sulfuric acid (0.506 mL), water (8 mL) and acetonitrile (41 mL) To this mixture was added a mixture of sodium chlorite (2.25 g) and water (10 mL). After stirring at room temperature for 30 minutes, water was added to the mixture. The solid was collected by filtration to give the title compound (3.58 g).
¹ H-NMR (CDCl ₃ ) δ ppm: 2.67 (3H, s), 3.95 (3H, s), 5.23 (2H, s), 7.19 (1H, s), 7.30-7.50 (5H, m), 7.68 ( 1H, s)

Reference Example 6-1
[5-Benzyloxy-4-methoxy-2- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] phenylmethanol 5-benzyloxy-4-methoxy-2- (5- Methyl- [1,2,4] oxadiazol-3-yl) benzaldehyde (Reference Example 15-1) (450 mg) and tetrahydrofuran (5.6 mL) were mixed with phenylmagnesium bromide (1.08 mol / L in an ice-salt bath). , Tetrahydrofuran solution, 1.4 mL) was added dropwise. After stirring at the same temperature for 30 minutes, an aqueous ammonium chloride solution, ethyl acetate and 2 mol / L hydrochloric acid were added to the mixture. The separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (564 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 2.64 (3H, s), 3.94 (3H, s), 4.60-4.70 (1H, m), 4.90-5.10 (2H, m), 6.10-6.20 (1H, m ), 6.72 (1H, s), 7.20-7.40 (10H, m), 7.49 (1H, s)

  Reference Example 6 using 5-benzyloxy-4-methoxy-2- (5-methyl- [1,2,4] oxadiazol-3-yl) benzaldehyde and phenylmagnesium bromide instead of the corresponding aldehyde and organomagnesium Reference Example 6-2 to Reference Example 6-7 were synthesized by the same method as -1. These are shown in Table 4.

  The physical property values of Reference Example 6-2 to Reference Example 6-4 and Reference Example 6-6 to Reference Example 6-7 are shown below.

Reference Example 6-2
¹ H-NMR (CDCl ₃ ) δ ppm: 1.40-1.50 (3H, m), 2.67 (3H, s), 3.76 (1H, br s), 3.94 (3H, s), 5.20-5.30 (3H, m) , 7.20 (1H, s), 7.30-7.50 (6H, m)

Reference Example 6-3
¹ H-NMR (CDCl ₃ ) δ ppm: 2.35 (3H, s), 2.63 (3H, s), 3.94 (3H, s), 4.50-4.60 (1H, m), 4.90-5.10 (2H, m), 6.10-6.20 (1H, m), 6.76 (1H, s), 7.00-7.30 (9H, m), 7.48 (1H, br s)

Reference Example 6-4
¹ H-NMR (CDCl ₃ ) δ ppm: 0.76-1.18 (7H, m), 1.51-1.72 (3H, m), 1.95-1.99 (1H, m), 2.65 (3H, s), 3.20 (1H, d , J = 5.5Hz), 3.94 (3H, s), 4.76-5.81 (1H, m), 5.20-5.30 (2H, m), 7.07 (1H, s), 7.27-7.45 (6H, m)

Reference Example 6-6
¹ H-NMR (CDCl ₃ ) δ ppm: 1.40-1.50 (9H, m), 3.20-3.40 (1H, m), 3.94 (3H, s), 3.95-4.10 (1H, m), 5.00-5.20 (1H , m), 5.20-5.30 (2H, m), 7.19 (1H, s), 7.30-7.50 (6H, m)

Reference Example 6-7
¹ H-NMR (CDCl ₃ ) δ ppm: 1.00-1.10 (3H, m), 1.40-1.50 (3H, m), 1.80-2.00 (2H, m), 2.90-3.00 (2H, m), 3.90-4.00 (4H, m), 5.10-5.30 (3H, m), 7.19 (1H, s), 7.20-7.50 (6H, m)

Reference Example 7-1
1- [5-Benzyloxy-4-methoxy-2- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-methylpropan-1-ol 3- (4- Benzyloxy-2-iodo-5-methoxyphenyl) -5-methyl- [1,2,4] oxadiazole (Reference Example 4-1) (844 mg) and tetrahydrofuran (6 mL) were mixed with ice salt under argon atmosphere. After cooling in a bath, isopropylmagnesium chloride (2.0 mol / L, tetrahydrofuran solution, 1.2 mL) was added, and the mixture was stirred in an ice-salt bath for 10 minutes. Isobutyraldehyde (0.55 mL) was added and the mixture was stirred in an ice-salt bath for 10 minutes and at room temperature for 30 minutes. Water and 2 mol / L hydrochloric acid were added to the mixture, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 10% -35% ethyl acetate / hexane, gradient elution) to give the title compound (533 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 0.63 (3H, d, J = 6.7 Hz), 0.98 (3H, d, J = 6.7 Hz), 1.87-1.96 (1H, m), 2.66 (3H, s) , 3.36 (1H, d, J = 5.5Hz), 3.94 (3H, s), 4.69-4.72 (1H, m), 5.21 (1H, d, J = 12.3Hz), 5.27 (1H, d, J = 12.3 Hz), 7.10 (1H, s), 7.28-7.39 (3H, m), 7.44-7.46 (3H, m)

  Instead of 3- (4-benzyloxy-2-iodo-5-methoxyphenyl) -5-methyl- [1,2,4] oxadiazole and isobutyraldehyde the corresponding iodobenzene and aldehyde or N, N-dimethyl Reference Example 7-2 to Reference Example 7-8 were synthesized by the same method as Reference Example 7-1 using formamide. These are shown in Table 5.

  The physical property values of Reference Example 7-2 to Reference Example 7-3 and Reference Example 7-5 to Reference Example 7-8 are shown below.

Reference Example 7-2
¹ H-NMR (CDCl ₃ ) δ ppm: 2.66 (3H, s), 3.93 (3H, s), 4.95-5.15 (2H, m), 5.60 (1H, d, J = 4.4 Hz), 6.50-6.60 ( 1H, m), 6.79 (1H, s), 7.10-7.40 (7H, m), 7.47 (1H, s), 7.50-7.65 (1H, m), 8.45-8.55 (1H, m)

Reference Example 7-3
MS (ESI, m / z): 391 (M + Na) +

Reference Example 7-5
¹ H-NMR (CDCl ₃ ) δ ppm: 1.92-2.01 (1H, m), 2.07-2.17 (1H, m), 2.57-2.66 (4H, m), 2.73-2.81 (1H, m), 3.68 (1H , d, J = 5.0Hz), 3.94 (3H, s), 5.01-5.06 (1H, m), 5.17-5.26 (2H, m), 7.12-7.46 (12H, m)

Reference Example 7-6
¹ H-NMR (CDCl ₃ ) δ ppm: 0.73 (9H, s), 2.25 (1H, bs), 2.64 (3H, s), 3.94 (3H, s), 5.21 (1H, d, J = 12.6 Hz) , 5.29 (1H, d, J = 12.6Hz), 5.45 (1H, bs), 7.21 (1H, s), 7.28-7.31 (1H, m), 7.33-7.38 (3H, m), 7.44-7.46 (2H , m)

Reference Example 7-7
¹ H-NMR (CDCl ₃ ) δ ppm: 2.61 (3H, s), 3.93 (3H, s), 4.57 (1H, d, J = 5.2 Hz), 4.99-5.10 (4H, m), 6.13 (1H, d, J = 5.2Hz), 6.77 (1H, s), 6.88 (2H, d, J = 8.7Hz), 7.18 (2H, d, J = 8.7Hz), 7.23-7.47 (10H, m), 7.48 ( 1H, s)

Reference Example 7-8
¹ H-NMR (CDCl ₃ ) δ ppm: 0.33-0.39 (2H, m), 0.62-0.69 (2H, m), 1.22-1.35 (1H, m), 2.64 (3H, s), 3.80 (2H, d , J = 7.0Hz), 3.94 (3H, s), 4.56 (1H, d, J = 5.5Hz), 4.99-5.11 (2H, m), 6.11 (1H, d, J = 5.5Hz), 6.77 (1H , s), 6.81 (2H, d, J = 8.6Hz), 7.16 (2H, d, J = 8.6Hz), 7.25-7.34 (5H, m), 7.48 (1H, s)

Reference Example 8-1
5-Benzyloxy-4-methoxy-2- (5-methyl- [1,2,4] oxadiazol-3-yl) benzonitrile 3- (4-benzyloxy-2-iodo-5-methoxyphenyl) -5-methyl- [1,2,4] oxadiazole (Reference Example 4-1) (500 mg), cuprous cyanide (424 mg), tris (dibenzylideneacetone) dipalladium (0) (271 mg), A mixture of tetraethylammonium cyanide (222 mg), 1,1′-bis (diphenylphosphino) ferrocene (525 mg) and 1,4-dioxane (12 mL) was stirred at 105 ° C. for 2.5 hours under an argon atmosphere. The mixture was cooled to room temperature, the mixture was filtered through a Celite (registered trademark) layer, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 25% -50% ethyl acetate / hexane, gradient elution) to give the title compound (231 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 2.69 (3H, s), 4.01 (3H, s), 5.21 (2H, s), 7.24 (1H, s), 7.30-7.50 (5H, m), 7.57 ( 1H, s)

Reference Example 9-1
1- [5-Benzyloxy-4-methoxy-2- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -2-phenylethanone 5-Benzyloxy-4-methoxy -2- (5-Methyl- [1,2,4] oxadiazol-3-yl) benzoic acid (Reference Example 5-1) (817 mg), thionyl chloride (0.53 mL), N, N-dimethylformamide ( 1 drop) and toluene (10 mL) were stirred at 80 ° C. for 30 min. The mixture was concentrated under reduced pressure, toluene was added to the residue, concentrated under reduced pressure, and 5-benzyloxy-4-methoxy-2- (5-methyl- [1,2,4] oxadiazol-3-yl) benzoyl. Chloride was obtained.
5-benzyloxy-4-methoxy-2- (5-methyl- [1,2,4] oxadiazol-3-yl) benzoyl chloride, benzylzinc bromide (0.5 mol / L, tetrahydrofuran solution, 4.4 mL), A mixture of dichlorobis (triphenylphosphine) palladium (II) (153 mg) and toluene (6 mL) was stirred at room temperature for 5 hours under an argon atmosphere. Ethyl acetate and 2 mol / L hydrochloric acid were added to the mixture. The separated organic layer was washed successively with water, aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 5% -20% ethyl acetate / hexane, gradient elution) to give the title compound (307 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 1.84 (3H, s), 3.29 (1H, d, J = 14.2 Hz), 3.42 (1H, d, J = 14.2 Hz), 3.91 (3H, s), 5.19 -5.25 (2H, m), 7.11 (1H, s), 7.15-7.20 (3H, m), 7.26-7.28 (2H, m), 7.30 (1H, s), 7.32-7.45 (5H, m)

Reference Example 10-1
5-Benzyloxy-4-methoxy-2- (5-methyl- [1,2,4] oxadiazol-3-yl) -N-phenylbenzamide 5-benzyloxy-4-methoxy-2- (5- Methyl- [1,2,4] oxadiazol-3-yl) benzoic acid (Reference Example 5-1) (500 mg), hexafluorophosphoric acid benzotriazol-1-yloxytripyrrolidinephosphonium (1.15 g), 1 To a mixture of -hydroxybenzotriazole (20 mg), methylene chloride (3 mL) and N, N-dimethylformamide (3 mL) was added aniline (0.2 mL) and triethylamine (0.62 mL). After stirring at room temperature for 4 hours, ethyl acetate and 2 mol / L hydrochloric acid were added to the mixture. The separated organic layer was washed successively with 2 mol / L aqueous sodium hydroxide solution, aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with methanol to give the title compound (449 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 2.58 (3H, s), 3.96 (3H, s), 5.22 (2H, s), 7.11-7.14 (1H, m), 7.31-7.56 (11H, m), 8.03 (1H, br)

  Reference Example 10-2 to Reference Example 10-4 were synthesized in the same manner as in Reference Example 10-1, using the corresponding amine or alcohol instead of aniline. These are shown in Table 6.

  The physical property values of Reference Example 10-2 and Reference Example 10-4 are shown below.

Reference Example 10-2
¹ H-NMR (CDCl ₃ ) δ ppm: 1.70 (6H, br s), 2.00-2.20 (9H, m), 2.63 (3H, s), 3.93 (3H, s), 5.20 (2H, s), 5.53 (1H, br s), 7.14 (1H, br s), 7.28 (1H, br s), 7.30-7.50 (5H, m)

Reference Example 10-4
¹ H-NMR (CDCl ₃ ) δ ppm: 2.63 (3H, s), 3.32 (3H, s), 3.50-3.60 (2H, m), 3.94 (3H, s), 4.20-4.40 (2H, m), 5.22 (2H, s), 7.14 (1H, s), 7.30-7.50 (6H, m)

Reference Example 11-1
5-Benzyloxy-4-methoxy-2- (5-methyl- [1,2,4] oxadiazol-3-yl) isopropyl benzoate 5-benzyloxy-4-methoxy-2- (5-methyl-) [1,2,4] oxadiazol-3-yl) benzoic acid (Reference Example 5-1) (308 mg), 2-iodopropane (0.225 mL), potassium carbonate (312 mg) and N, N-dimethylformamide ( 2.6 mL) was stirred at 60 ° C. for 2.5 hours. After cooling to room temperature, water and ethyl acetate were added to the mixture. The separated organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (342 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 1.10-1.25 (6H, m), 2.64 (3H, s), 3.93 (3H, s), 5.00-5.20 (1H, m), 5.23 (2H, s), 7.10 (1H, s), 7.33-7.50 (6H, m)

Reference Example 11-2
Ethyl 5-benzyloxy-4-methoxy-2- (5-methyl- [1,2,4] oxadiazol-3-yl) benzoate Reference Example 11-1 substituting iodoethane for 2-iodopropane The title compound was synthesized by the same method.
¹ H-NMR (CDCl ₃ ) δ ppm: 1.10-1.30 (3H, m), 2.64 (3H, s), 3.94 (3H, s), 4.20-4.30 (2H, m), 5.22 (2H, s), 7.13 (1H, s), 7.30-7.50 (6H, m)

Reference Example 12-1
Acetic acid [5-benzyloxy-4-methoxy-2- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] tert-butylcarbamoylmethyl 5-benzyloxy-4-methoxy-2 -(5-Methyl- [1,2,4] oxadiazol-3-yl) benzaldehyde (Reference Example 15-1) (453 mg), tert-butylisocyanide (465 mg), acetic acid (0.32 mL) and acetonitrile (8 mL ) Was stirred at 70 ° C. for 13 hours. Cool to room temperature and add ethyl acetate and water to the mixture. The separated organic layer was washed successively with water, aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 15-50% ethyl acetate / hexane, gradient elution) to give the title compound (604 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 1.26 (9H, s), 2.06 (3H, s), 2.69 (3H, s), 3.95 (3H, s), 5.21-5.30 (2H, m), 6.38 ( 1H, s), 7.27-7.50 (8H, m)

Reference Example 12-2
[5-Benzyloxy-4-methoxy-2- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] acetic acid cyclohexyl isocyanide instead of tert-butyl isocyanide The title compound was synthesized in the same manner as in Example 12-1.
¹ H-NMR (CDCl ₃ ) δ ppm: 0.95-1.43 (5H, m), 1.48-1.71 (4H, m), 1.93-1.99 (1H, m), 2.07 (3H, s), 2.70 (3H, s ), 3.67-3.76 (1H, m), 3.94 (3H, s), 5.20-5.30 (2H, m), 6.48 (1H, s), 7.28-7.50 (8H, m)

Reference Example 13-1
2- [5-Benzyloxy-4-methoxy-2- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] N-tert-butyl-2-hydroxyacetamide acetic acid [5- Benzyloxy-4-methoxy-2- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] tert-butylcarbamoylmethyl (Reference Example 12-1) (604 mg), 5 mol / L A mixture of aqueous sodium hydroxide (1 mL) and methanol (8 mL) was stirred at room temperature for 1.5 hours. To the mixture was added ethyl acetate and water. The separated organic layer was washed successively with water and aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (552 mg).
MS (ESI, m / z): 426 (M + 1)

Reference Example 13-2
2- [5-Benzyloxy-4-methoxy-2- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] N-cyclohexyl-2-hydroxyacetamidoacetic acid [5-benzyloxy [4-Benzyloxy-4-methoxy-2-acetate instead of -4-methoxy-2- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] tert-butylcarbamoylmethyl The title compound was synthesized in the same manner as in Reference Example 13-1 using (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] cyclohexylcarbamoylmethyl (Reference Example 12-2).
¹ H-NMR (CDCl ₃ ) δ ppm: 0.97-1.48 (5H, m), 1.54-1.95 (5H, m), 2.69 (3H, s), 3.71-3.80 (1H, m), 3.93 (3H, s ), 4.84 (1H, d, J = 5.5Hz), 5.18 (2H, s), 5.51 (1H, d, J = 5.5Hz), 7.16 (1H, s), 7.29-7.47 (6H, m), 7.67 (1H, d, J = 7.6Hz)

Reference Example 14-1
[5-Benzyloxy-4-methoxy-2- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] phenylmethanone [5-benzyloxy-4-methoxy-2- ( A mixture of 5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] phenylmethanol (Reference Example 6-1) (526 mg), manganese dioxide (1.18 g) and methylene chloride (6.8 mL). Stir at room temperature overnight. Manganese dioxide (1.18 g) was added and the mixture was stirred for 7.5 hours, manganese dioxide (0.59 g) was added overnight. The mixture was passed through a Celite® layer. The filtrate was concentrated under reduced pressure to obtain the title compound (526 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 2.42 (3H, s), 4.01 (3H, s), 5.18 (2H, s), 7.06 (1H, s), 7.30-7.50 (9H, m), 7.60- 7.70 (2H, m)

Reference Example 14-2
1- [5-Benzyloxy-4-methoxy-2- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] ethanone 1- [5-Benzyloxy-4-methoxy-2 -(5-Methyl- [1,2,4] oxadiazol-3-yl) phenyl] ethanol (Reference Example 6-2) (467 mg), triethylamine (0.956 mL) and dimethyl sulfoxide (6 mL) A mixture of sulfur oxide pyridine complex (655 mg) and dimethyl sulfoxide (2 mL) was added. After stirring at room temperature for 2 hours, water and ethyl acetate were added to the mixture. The separated organic layer was washed successively with 2 mol / L hydrochloric acid and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 25% -34% ethyl acetate / hexane, gradient elution) to give the title compound (365 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 2.38 (3H, s), 2.64 (3H, s), 3.96 (3H, s), 5.22 (2H, s), 7.13 (1H, s), 7.28 (1H, s), 7.30-7.50 (5H, m)

  [5-Benzyloxy-4-methoxy-2- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] phenylmethanol or 1- [5-benzyloxy-4-methoxy-2 -(5-Methyl- [1,2,4] oxadiazol-3-yl) phenyl] Reference is made in the same manner as in Reference Example 14-1 or Reference Example 14-2 using the corresponding alcohol instead of ethanol. Example 14-3 to Reference Example 14-17 were synthesized. These are shown in Table 7.

  The physical property values of Reference Example 14-3 to Reference Example 14-17 are shown below.

Reference Example 14-3
¹ H-NMR (CDCl ₃ ) δ ppm: 1.06 (6H, d, J = 6.8 Hz), 2.62 (3H, s), 2.79-2.86 (1H, m), 3.97 (3H, s), 5.22 (2H, s), 6.92 (1H, s), 7.29-7.44 (6H, m)

Reference Example 14-4
¹ H-NMR (CDCl ₃ ) δ ppm: 1.32 (9H, s), 2.60 (3H, s), 3.99 (3H, s), 5.19 (2H, s), 6.94 (1H, br), 7.18 (1H, s), 7.31-7.47 (6H, m)

Reference Example 14-5
¹ H-NMR (CDCl ₃ ) δ ppm: 2.37 (3H, s), 2.44 (3H, s), 4.01 (3H, s), 5.30 (2H, s), 7.03 (1H, s), 7.10-7.70 ( 10H, m)

Reference Example 14-6
¹ H-NMR (CDCl ₃ ) δ ppm: 2.38 (3H, s), 4.01 (3H, s), 5.21 (2H, s), 7.20-7.55 (8H, m), 7.75-7.85 (1H, m), 8.05-8.20 (1H, m), 8.35-8.50 (1H, m)

Reference Example 14-7
MS (ESI, m / z): 407 (M + 1)

Reference Example 14-8
¹ H-NMR (CDCl ₃ ) δ ppm: 0.89-0.93 (2H, m), 1.18-1.22 (2H, m), 2.00-2.06 (1H, m), 2.63 (3H, s), 3.96 (3H, s ), 5.22 (2H, s), 7.19 (1H, s), 7.29 (1H, s), 7.30-7.47 (5H, m)

Reference Example 14-9
¹ H-NMR (CDCl ₃ ) δ ppm: 2.45 (3H, s), 3.99 (3H, s), 5.18 (2H, s), 6.96-7.01 (1H, m), 7.08-7.12 (1H, m), 7.14 (1H, s), 7.31-7.45 (7H, m), 7.52-7.57 (1H, m)

Reference Example 14-10
¹ H-NMR (CDCl ₃ ) δ ppm: 2.45 (3H, s), 4.01 (3H, s), 5.22 (2H, s), 7.25-7.50 (6H, m), 7.51 (1H, s), 7.55- 7.65 (1H, m), 7.75-7.85 (1H, m)

Reference Example 14-11
¹ H-NMR (CDCl ₃ ) δ ppm: 2.62 (3H, s), 2.93-3.02 (4H, m), 3.95 (3H, s), 5.14 (2H, s), 6.92 (1H, s), 7.13- 7.44 (11H, m)

Reference Example 14-12
¹ H-NMR (CDCl ₃ ) δ ppm: 1.11 (9H, s), 2.59 (3H, s), 3.98 (3H, s), 5.22 (2H, s), 6.67 (1H, s), 7.28-7.43 ( 5H, m), 7.54 (1H, s)

Reference Example 14-13
¹ H-NMR (CDCl ₃ ) δ ppm: 1.40-1.50 (6H, m), 2.36 (3H, s), 3.20-3.40 (1H, m), 3.97 (3H, s), 5.22 (2H, s), 7.13 (1H, s), 7.29 (1H, s), 7.30-7.50 (5H, m)

Reference Example 14-14
¹ H-NMR (CDCl ₃ ) δ ppm: 1.00-1.10 (3H, m), 1.80-2.00 (2H, m), 2.36 (3H, s), 2.80-3.00 (2H, m), 3.96 (3H, s ), 5.22 (2H, s), 7.13 (1H, s), 7.29 (1H, s), 7.30-7.50 (5H, m)

Reference Example 14-15
¹ H-NMR (CDCl ₃ ) δ ppm: 1.15-1.41 (5H, m), 1.60-1.88 (5H, m), 2.60 (3H, s), 3.58-3.67 (1H, m), 4.00 (3H, s ), 5.19 (2H, s), 6.95 (1H, d, J = 8.6Hz), 7.21 (1H, s), 7.30-7.48 (6H, m)

Reference Example 14-16
¹ H-NMR (CDCl ₃ ) δ ppm: 2.44 (3H, s), 4.00 (3H, s), 5.10 (2H, s), 5.17 (2H, s), 6.89 (2H, d, J = 9.0 Hz) , 7.01 (1H, s), 7.27-7.44 (10H, m), 7.48 (1H, s), 7.66 (2H, d, J = 9.0Hz)

Reference Example 14-17
¹ H-NMR (CDCl ₃ ) δ ppm: 0.33-0.39 (2H, m), 0.62-0.70 (2H, m), 1.22-1.33 (1H, m), 2.46 (3H, s), 3.83 (2H, d , J = 6.9Hz), 4.01 (3H, s), 5.17 (2H, s), 6.81 (2H, d, J = 9.0Hz), 7.02 (1H, s), 7.28-7.44 (5H, m), 7.49 (1H, s), 7.66 (2H, d, J = 9.0Hz)

Reference Example 15-1
5-Benzyloxy-4-methoxy-2- (5-methyl- [1,2,4] oxadiazol-3-yl) benzaldehyde 3- (4-benzyloxy-2-iodo-5-methoxyphenyl)- A mixture of 5-methyl- [1,2,4] oxadiazole (Reference Example 4-1) (3.52 g) and tetrahydrofuran (35 mL) was cooled in an ice-salt bath under an argon atmosphere, and isopropylmagnesium chloride (2.0 mol / mol) was cooled. L, tetrahydrofuran solution, 5 mL) was added. After stirring for 1 hour under ice cooling, N, N-dimethylformamide (1.28 mL) was added to the mixture. After stirring overnight at room temperature, water, 2 mol / L hydrochloric acid and ethyl acetate were sequentially added to the mixture. The separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 25% -34% ethyl acetate / hexane, gradient elution) to give the title compound (1.83 g).
¹ H-NMR (CDCl ₃ ) δ ppm: 2.69 (3H, s), 4.02 (3H, s), 5.25 (2H, s), 7.30-7.50 (6H, m), 7.67 (1H, s), 10.58 ( 1H, s)

  Instead of 3- (4-benzyloxy-2-iodo-5-methoxyphenyl) -5-methyl- [1,2,4] oxadiazole and N, N-dimethylformamide, the corresponding halobenzene and N, N- Reference Example 15-2 to Reference Example 15-14 were synthesized in the same manner as Reference Example 15-1 using dimethylformamide, acid anhydride, acid chloride, or N-methoxy-N-methylamide. These are shown in Table 8.

  The physical property values of Reference Example 15-2 to Reference Example 15-14 are shown below.

Reference Example 15-2
¹ H-NMR (CDCl ₃ ) δ ppm: 2.68 (3H, s), 3.99 (3H, s), 2.27 (2H, s), 7.30-7.50 (5H, m), 7.56 (1H, s), 7.62 ( 1H, s), 10.61 (1H, s)

Reference Example 15-3
¹ H-NMR (CDCl ₃ ) δ ppm: 2.50 (3H, s), 4.03 (3H, s), 5.23 (2H, s), 6.67 (1H, d, J = 1.7Hz), 7.21 (1H, s) , 7.30-7.50 (5H, m), 7.51 (1H, s), 8.23 (1H, d, J = 1.7Hz)

Reference Example 15-4
¹ H-NMR (CDCl ₃ ) δ ppm: 2.63 (3H, s), 4.00 (3H, s), 5.21 (2H, s), 7.12 (1H, s), 7.25-7.55 (6H, m)

Reference Example 15-5
MS (ESI, m / z): 431 (M + 1)

Reference Example 15-6
¹ H-NMR (CDCl ₃ ) δ ppm: 2.35 (3H, s), 3.96 (3H, s), 5.23 (2H, s), 5.34 (2H, s), 6.95-7.10 (3H, m), 7.14 ( 1H, s), 7.20-7.60 (8H, m)

Reference Example 15-7
¹ H-NMR (CDCl ₃ ) δ ppm: 1.40-1.50 (6H, m), 3.20-3.40 (1H, m), 4.02 (3H, s), 5.25 (2H, s), 7.30-7.50 (6H, m ), 7.67 (1H, s), 10.59 (1H, s)

Reference Example 15-8
¹ H-NMR (CDCl ₃ ) δ ppm: 1.00-1.10 (3H, m), 1.90-2.00 (2H, m), 2.90-3.00 (2H, m), 4.02 (3H, s), 5.25 (2H, s ), 7.30-7.50 (6H, m), 7.67 (1H, s), 10.59 (1H, s)

Reference Example 15-9
¹ H-NMR (CDCl ₃ ) δ ppm: 1.27 (3H, t, J = 7.1 Hz), 2.35 (3H, s), 2.90 (2H, t, J = 7.2 Hz), 3.24 (2H, t, J = 7.2Hz), 3.96 (3H, s), 4.18 (2H, q, J = 7.1Hz), 5.21 (2H, s), 7.11 (1H, s), 7.29 (1H, s), 7.25-7.50 (5H, m)

Reference Example 15-10
¹ H-NMR (CDCl ₃ ) δ ppm: 2.44 (3H, s), 3.98 (3H, s), 5.25 (2H, s), 7.21 (1H, s), 7.25 (1H, s), 7.30-7.50 ( 5H, m)

Reference Example 15-11
¹ H-NMR (CDCl ₃ ) δ ppm: 1.95-2.15 (4H, m), 2.37 (3H, s), 3.19-3.30 (1H, m), 3.52-3.62 (2H, m), 3.97 (3H, s ), 4.00-4.08 (2H, m), 5.22 (2H, s), 7.13 (1H, s), 7.29 (1H, s), 7.30-7.50 (5H, m)

Reference Example 15-12
¹ H-NMR (CDCl ₃ ) δ ppm: 1.19 (3H, d, J = 7.0 Hz), 2.36 (3H, s), 3.21 (2H, t, J = 6.6 Hz), 3.54 (2H, q, J = 7.0Hz), 3.89 (2H, t, J = 6.6Hz), 3.96 (3H, s), 5.22 (2H, s), 7.13 (1H, s), 7.29 (1H, s), 7.30-7.50 (5H, m)

Reference Example 15-13
¹ H-NMR (CDCl ₃ ) δ ppm: 2.42 (3H, s), 3.93 (3H, s), 4.02 (3H, s), 5.19 (2H, s), 7.06 (1H, s), 7.30-7.44 ( 5H, m), 7.49 (1H, s), 7.71 (2H, d, J = 8.6Hz), 7.98 (2H, d, J = 8.6Hz)

Reference Example 15-14
¹ H-NMR (CDCl ₃ ) δ ppm: 2.44 (3H, s), 4.02 (3H, s), 5.20 (2H, s), 7.04 (1H, s), 7.30-7.46 (5H, m), 7.50 ( 1H, s), 7.61 (2H, d, J = 8.8Hz), 7.73 (2H, d, J = 8.8Hz)

Reference Example 16-1
5-Benzyloxy-4-methoxy-2- (5-methyl- [1,2,4] oxadiazol-3-yl) benzoic acid methyl tris (dibenzylideneacetone) dipalladium (0) (163 mg), 1 , 1′-bis (diphenylphosphino) ferrocene (394 mg) and N, N-dimethylformamide (10 mL) were stirred under an argon atmosphere for 10 minutes. To the mixture was added 3- (4-benzyloxy-2-iodo-5-methoxyphenyl) -5-methyl- [1,2,4] oxadiazole (Reference Example 4-1) (1.5 g), methanol (15 mL). And triethylamine (1.5 mL) was added. After displacement under a carbon monoxide atmosphere, the mixture was stirred at 90 ° C. for 16 hours. After cooling to room temperature, ethyl acetate and 2 mol / L hydrochloric acid were added to the mixture. The separated organic layer was washed successively with water, 2 mol / L aqueous sodium hydroxide solution, aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 15% -30% ethyl acetate / hexane, gradient elution) to give the title compound (1.1 g).
¹ H-NMR (CDCl ₃ ) δ ppm: 2.65 (3H, s), 3.77 (3H, s), 3.94 (3H, s), 5.21 (2H, s), 7.16 (1H, s), 7.31-7.47 ( 6H, m)

  3- (4-Benzyloxy-2-iodo-5-methoxyphenyl) -5-methyl- [1,2,4] oxadiazole, instead of the corresponding iodobenzene, the same method as in Reference Example 16-1 Thus, Reference Example 16-2 to Reference Example 16-4 were synthesized. These are shown in Table 9.

  The physical property values of Reference Example 16-2 to Reference Example 16-4 are shown below.

Reference Example 16-2
¹ H-NMR (CDCl ₃ ) δ ppm: 1.22-1.30 (4H, m), 2.21-2.27 (1H, m), 3.76 (3H, s), 3.94 (3H, s), 5.21 (2H, s), 7.15 (1H, s), 7.31-7.46 (6H, m)

Reference Example 16-3
¹ H-NMR (CDCl ₃ ) δ ppm: 3.56 (3H, s), 3.77 (3H, s), 3.95 (3H, s), 4.76 (2H, s), 5.22 (2H, s), 7.17 (1H, s), 7.32-7.47 (5H, m), 7.49 (1H, s)

Reference Example 16-4
¹ H-NMR (CDCl ₃ ) δ ppm: 1.49 (9H, s), 3.73 (3H, s), 3.95 (3H, s), 5.21 (2H, s), 7.18 (1H, s), 7.30-7.46 ( 6H, m)

Reference Example 17-1
3- (4-Benzyloxy-5-methoxy-2-trifluoromethylphenyl) -5-methyl- [1,2,4] oxadiazole 3- (4-Benzyloxy-2-iodo-5-methoxyphenyl) ) -5-methyl- [1,2,4] oxadiazole (Reference Example 4-1) (650 mg), methyl fluorosulfonyldifluoroacetate (0.59 mL), cuprous iodide (88 mg) and N, N- A mixture of dimethylformamide (8 mL) was stirred at 90 ° C. for 3.5 hours. Cool to room temperature and add ethyl acetate to the mixture. The mixture was passed through a Celite® layer. The filtrate was washed successively with aqueous sodium hydroxide solution, aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 10-40% ethyl acetate / hexane, gradient elution) to give the title compound (522 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 2.67 (3H, s), 3.95 (3H, s), 5.22 (2H, s), 7.25 (1H, s), 7.31 (1H, s), 7.32-7.47 ( 5H, m)

Reference Example 18-1
2- [5-Benzyloxy-4-methoxy-2- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] N-cyclohexyl-N-methyl-2-oxoacetamide 2- [5-Benzyloxy-4-methoxy-2- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] N-cyclohexyl-2-oxoacetamide (Reference Example 14-15) ( 860 mg) and N, N-dimethylformamide (6 mL) was added sodium hydride (60%, 92 mg). After stirring at room temperature for 20 minutes, iodomethane (0.48 mL) was added to the mixture. After stirring at room temperature for 8 hours, the mixture was poured into a mixture of 2 mol / L hydrochloric acid and ice water. Ethyl acetate was added to the mixture. The separated organic layer was washed successively with water, aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0% -50% ethyl acetate / hexane gradient elution) to give the title compound (605 mg).
MS (ESI, m / z): 464 (M + 1)

Reference Example 19-1
5-Methanesulfonyl-2-methoxy-4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenol 3- (4-benzyloxy-2-iodo-5-methoxyphenyl)- 5-methyl- [1,2,4] oxadiazole (Reference Example 4-1) (0.7 g), triisopropylsilanethiol (0.391 mL), tris (dibenzylideneacetone) dipalladium (0) (152 mg), A mixture of (oxydi-2,1-phenylene) bis (diphenylphosphine) (90 mg), sodium hexamethyldisilazide (1.0 mol / L, tetrahydrofuran solution, 0.39 mL) and toluene (20 mL) at 80 ° C. under an argon atmosphere. Stir for 2 hours. After cooling to room temperature, Florisil® (1 g) was added to the mixture. After stirring for 10 minutes, the mixture was passed through a Celite (registered trademark) layer, and the filtrate was concentrated under reduced pressure to give 3- (4-benzyloxy-5-methoxy-2-triisopropylsilanylsulfanylphenyl) -5-methyl- [1,2,4] Oxadiazole was obtained.
3- (4-Benzyloxy-5-methoxy-2-triisopropylsilanylsulfanylphenyl) -5-methyl- [1,2,4] oxadiazole, iodomethane (0.155 mL), cesium fluoride (756 mg) and A mixture of N, N-dimethylformamide (20 mL) was stirred at room temperature for 30 minutes. Water and ethyl acetate were added to the mixture. The separated organic layer was washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and 3- (4-benzyloxy-5-methoxy-2-methylsulfanylphenyl) -5-methyl- [1, 2,4] oxadiazole was obtained.
3- (4-Benzyloxy-5-methoxy-2-methylsulfanylphenyl) -5-methyl- [1,2,4] oxadiazole, m-chloroperbenzoic acid (60%, 1.43 g) and methylene chloride (30 mL) of the mixture was stirred overnight. To the mixture was added aqueous sodium bisulfite solution and methylene chloride. The separated organic layer was washed successively with 2 mol / L aqueous sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 3- (4-benzyloxy-2-methanesulfonyl-5-methoxy). Phenyl) -5-methyl- [1,2,4] oxadiazole was obtained.
To a mixture of 3- (4-benzyloxy-2-methanesulfonyl-5-methoxyphenyl) -5-methyl- [1,2,4] oxadiazole and methylene chloride (20 mL) was added titanium tetrachloride (0.472 g). added. After stirring at room temperature for 15 minutes, 2 mol / L hydrochloric acid and methylene chloride were added to the mixture. The separated organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 10% -100% ethyl acetate / hexane gradient elution) to give the title compound (112 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 2.67 (3H, s), 3.42 (3H, s), 3.99 (3H, s), 7.18 (1H, s), 7.76 (1H, s)

Reference Example 20-1
5-hydroxy-4-methoxy-N, N-dimethyl-2- (5-methyl- [1,2,4] oxadiazol-3-yl) benzenesulfonamide 3- (4-benzyloxy-2-iodo) -5-Methoxyphenyl) -5-methyl- [1,2,4] oxadiazole (Reference Example 4-1) (0.7 g), triisopropylsilanethiol (0.391 mL), tris (dibenzylideneacetone) dipalladium (0) (152 mg), (oxydi-2,1-phenylene) bis (diphenylphosphine) (90 mg), sodium hexamethyldisilazide (1.0 mol / L, tetrahydrofuran solution, 0.39 mL) and toluene (20 mL) mixture Was stirred at 80 ° C. for 2 hours under an argon atmosphere. After cooling to room temperature, Florisil® (1 g) was added to the mixture. After stirring for 10 minutes, the mixture was passed through a Celite (registered trademark) layer, and the filtrate was concentrated under reduced pressure to give 3- (4-benzyloxy-5-methoxy-2-triisopropylsilanylsulfanylphenyl) -5-methyl- [1,2,4] Oxadiazole was obtained.
To a mixture of 3- (4-benzyloxy-5-methoxy-2-triisopropylsilanylsulfanylphenyl) -5-methyl- [1,2,4] oxadiazole, sodium nitrate (352 mg) and acetonitrile (16 mL) Sulfuryl chloride (0.336 mL) was added under ice cooling. After stirring for 1 hour at room temperature, the mixture was poured into ice water. Ethyl acetate was added to the mixture. The separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-benzyloxy-4-methoxy-2- (5-methyl- [1,2,4] oxadiazol-3-yl). Benzenesulfonyl chloride was obtained.
To a mixture of 5-benzyloxy-4-methoxy-2- (5-methyl- [1,2,4] oxadiazol-3-yl) benzenesulfonyl chloride, dimethylamine hydrochloride (203 mg) and tetrahydrofuran (20 mL) Triethylamine (0.693 mL) was added under ice cooling. After stirring overnight at room temperature, 2 mol / L hydrochloric acid was added to the mixture. The separated organic layer was washed successively with 2 mol / L hydrochloric acid and brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and 5-benzyloxy-4-methoxy-N, N-dimethyl-2- (5 -Methyl- [1,2,4] oxadiazol-3-yl) benzenesulfonamide was obtained.
To a mixture of 5-benzyloxy-4-methoxy-N, N-dimethyl-2- (5-methyl- [1,2,4] oxadiazol-3-yl) benzenesulfonamide and methylene chloride (20 mL) Titanium chloride (0.472 g) was added under ice cooling. After stirring at room temperature overnight, 2 mol / L hydrochloric acid and methylene chloride were added to the mixture. The separated organic layer was washed successively with 2 mol / L hydrochloric acid and brine, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: 10% -100% ethyl acetate / hexane gradient elution) to obtain the title compound (121 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 2.66 (3H, s), 2.78 (6H, s), 3.95 (3H, s), 6.95 (1H, s), 7.50 (1H, s)

Reference Example 21-1
[5-Hydroxy-4-methoxy-2- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] phenylmethanone [5-benzyloxy-4-methoxy-2- (5 -Methyl- [1,2,4] oxadiazol-3-yl) phenyl] phenylmethanone (Reference Example 14-1) (526 mg) and methylene chloride (22 mL) were mixed with titanium tetrachloride (0.288 mL). Added at room temperature. After stirring for 30 minutes, 2 mol / L hydrochloric acid and ethyl acetate were added to the mixture. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 50-67% ethyl acetate / hexane, gradient elution) to give the title compound (383 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 2.44 (3H, s), 4.03 (3H, s), 5.93 (1H, s), 7.07 (1H, s), 7.30-7.80 (6H, m)

  [5-Benzyloxy-4-methoxy-2- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] phenyl methanone instead of the corresponding benzyl ether Reference Example 21- In the same manner as in Example 1, Reference Examples 21-2 to 21-45 were synthesized. These are shown in Table 10.

  The physical property values of Reference Example 21-2 to Reference Example 21-35 and Reference Example 21-37 to Reference Example 21-45 are shown below.

Reference Example 21-2
¹ H-NMR (CDCl3) δ ppm: 2.48 (3H, s), 2.63 (3H, s), 3.98 (3H, s), 5.90 (1H, s), 7.17 (1H, s)

Reference Example 21-3
¹ H-NMR (CDCl ₃ ) δ ppm: 1.16 (6H, d, J = 7.0 Hz), 2.62 (3H, s), 2.90-3.00 (1H, m), 3.99 (3H, s), 5.91 (1H, s), 7.01 (1H, s), 7.38 (1H, s)

Reference Example 21-4
¹ H-NMR (CDCl ₃ ) δ ppm: 2.67 (3H, s), 3.98 (3H, s), 5.90 (1H, s), 7.24 (1H, s), 7.36 (1H, s)

Reference Example 21-5
¹ H-NMR (CDCl ₃ ) δ ppm: 2.64 (3H, s), 3.80 (3H, s), 3.97 (3H, s), 5.85 (1H, s), 7.17 (1H, s), 7.44 (1H, s)

Reference Example 21-6
¹ H-NMR (CDCl ₃ ) δ ppm: 2.59 (3H, s), 2.60 (3H, s), 4.00 (3H, s), 5.88 (1H, s), 7.34 (1H, s), 7.39 (1H, s)

Reference Example 21-7
¹ H-NMR (CDCl ₃ ) δ ppm: 1.21-1.29 (4H, m), 2.21-2.27 (1H, m), 3.78 (3H, s), 3.96 (3H, s), 5.83 (1H, s), 7.16 (1H, s), 7.42 (1H, s)

Reference Example 21-8
¹ H-NMR (CDCl ₃ ) δ ppm: 2.69 (3H, s), 4.04 (3H, s), 5.96 (1H, s), 7.33 (1H, s), 7.57 (1H, s)

Reference Example 21-9
¹ H-NMR (CDCl ₃ ) δ ppm: 3.55 (3H, s), 3.79 (3H, s), 3.97 (3H, s), 4.74 (2H, s), 5.87 (1H, s), 7.18 (1H, s), 7.46 (1H, s)

Reference Example 21-10
¹ H-NMR (CDCl ₃ ) δ ppm: 1.49 (9H, s), 3.76 (3H, s), 3.98 (3H, s), 5.84 (1H, s), 7.19 (1H, s), 7.42 (1H, s)

Reference Example 21-11
¹ H-NMR (CDCl ₃ ) δ ppm: 1.20-1.26 (6H, m), 2.64 (3H, s), 3.96 (3H, s), 5.00-5.20 (1H, m), 5.86 (1H, s), 7.11 (1H, s), 7.46 (1H, s)

Reference Example 21-12
¹ H-NMR (CDCl ₃ ) δ ppm: 1.30-1.90 (10H, m), 2.63 (3H, s), 3.96 (3H, s), 4.80-5.00 (1H, m), 5.83 (1H, s), 7.10 (1H, s), 7.48 (1H, s)

Reference Example 21-13
¹ H-NMR (CDCl ₃ ) δ ppm: 2.63 (3H, s), 3.35 (3H, s), 3.50-3.60 (2H, m), 3.96 (3H, s), 4.30-4.40 (2H, m), 5.89 (1H, s), 7.14 (1H, s), 7.48 (1H, s)

Reference Example 21-14
¹ H-NMR (CDCl ₃ ) δ ppm: 1.20-1.30 (3H, m), 2.64 (3H, s), 3.96 (3H, s), 4.20-4.30 (2H, m), 5.84 (1H, s), 7.14 (1H, s), 7.47 (1H, s)

Reference Example 21-15
¹ H-NMR (CDCl ₃ ) δ ppm: 1.21 (9H, s), 2.60 (3H, s), 3.90 (3H, s), 7.04 (1H, s), 7.30 (1H, s), 7.98 (1H, br), 10.10 (1H, s)

Reference Example 21-16
MS (ESI, m / z): 249 (M-1)

Reference Example 21-17
¹ H-NMR (CDCl ₃ ) δ ppm: 2.39 (3H, s), 2.47 (3H, s), 4.08 (3H, s), 7.10-7.30 (2H, m), 7.60-7.70 (2H, m), 7.79 (1H, s), 10.70 (1H, br s)

Reference Example 21-18
¹ H-NMR (CDCl ₃ ) δ ppm: 2.57 (3H, s), 3.87 (3H, s), 7.02 (1H, s), 7.04-7.07 (1H, m), 7.28-7.32 (2H, m), 7.35 (1H, s), 7.61-7.63 (2H, m), 10.01 (1H, s), 10.23 (1H, br)

Reference Example 21-19
¹ H-NMR (CDCl ₃ ) δ ppm: 2.39 (3H, s), 4.03 (3H, s), 5.94 (1H, brs), 7.12 (1H, s), 7.25-7.40 (1H, m), 7.49 ( 1H, s), 7.75-7.90 (1H, m), 8.10-8.20 (1H, m), 8.40-8.55 (1H, m)

Reference Example 21-20
¹ H-NMR (CDCl ₃ ) δ ppm: 1.16-1.24 (3H, m), 1.40-1.48 (2H, m), 1.63-1.93 (5H, m), 2.61 (3H, s), 2.63-2.71 (1H , m), 3.98 (3H, s), 5.88 (1H, s), 7.00 (1H, s), 7.38 (1H, s)

Reference Example 21-21
¹ H-NMR (CDCl ₃ ) δ ppm: 1.11-1.14 (2H, m), 1.43-1.46 (2H, m), 2.09-2.15 (1H, m), 2.64 (3H, s), 4.04 (3H, s ), 7.64 (1H, s), 10.26 (1H, s)

Reference Example 21-22
¹ H-NMR (CDCl ₃ ) δ ppm: 2.47 (3H, s), 4.02 (3H, s), 5.90 (1H, s), 7.00-7.05 (1H, m), 7.12 (1H, s), 7.12- 7.17 (1H, m), 7.39 (1H, s), 7.42-7.48 (1H, m), 7.63-7.67 (1H, m)

Reference Example 21-23
¹ H-NMR (CDCl ₃ ) δ ppm: 2.45 (3H, s), 4.03 (3H, s), 5.94 (1H, s), 7.31 (1H, s), 7.51 (1H, s), 7.62 (1H, d, J = 3.0Hz), 7.84 (1H, d, J = 3.0Hz)

Reference Example 21-24
¹ H-NMR (CDCl ₃ ) δ ppm: 2.50 (3H, s), 4.05 (3H, s), 5.99 (1H, brs), 6.80 (1H, d, J = 2.0 Hz), 7.22 (1H, s) , 7.52 (1H, s), 8.26 (1H, d, J = 2.0Hz)

Reference Example 21-25
¹ H-NMR (CDCl ₃ ) δ ppm: 1.85 (3H, s), 3.28 (1H, d, J = 14.2 Hz), 3.43 (1H, d, J = 14.2 Hz), 3.95 (3H, s), 6.07 (1H, s), 7.10 (1H, s), 7.13-7.21 (3H, m), 7.26-7.29 (2H, m), 7.32 (1H, s)

Reference Example 21-26
¹ H-NMR (CDCl ₃ ) δ ppm: 2.61 (3H, s), 3.02-3.08 (4H, m), 3.98 (3H, s), 5.88 (1H, s), 7.03 (1H, s), 7.16- 7.20 (3H, m), 7.25-7.29 (2H, m), 7.33 (1H, s)

Reference Example 21-27
¹ H-NMR (CDCl ₃ ) δ ppm: 1.25 (9H, s), 2.60 (3H, s), 3.98 (3H, s), 5.93 (1H, s), 6.82 (1H, s), 7.53 (1H, s)

Reference Example 21-28
¹ H-NMR (CDCl ₃ ) δ ppm: 2.62 (3H, s), 4.03 (3H, s), 5.99 (1H, s), 7.15-7.20 (1H, m), 7.47 (1H, s)

Reference Example 21-29
¹ H-NMR (CDCl3) δ ppm: 1.70 (6H, br s), 2.08 (9H, br s), 2.62 (3H, s), 3.95 (3H, s), 5.53 (1H, br s), 7.10 ( 1H, br s), 7.29 (1H, br s)

Reference Example 21-30
¹ H-NMR (CDCl ₃ ) δ ppm: 2.50 (3H, s), 4.00 (3H, s), 4.96 (2H, s), 5.92 (1H, s), 6.83-6.96 (3H, m), 7.12 ( 1H, s), 7.21-7.26 (2H, m), 7.41 (1H, s)

Reference Example 21-31
¹ H-NMR (CDCl ₃ ) δ ppm: 2.46 (3H, s), 3.98 (3H, s), 5.33 (2H, s), 5.91 (1H, s), 6.95-7.10 (3H, m), 7.19 ( 1H, s), 7.27 (1H, s), 7.25-7.40 (2H, m)

Reference Example 21-32
¹ H-NMR (CDCl ₃ ) δ ppm: 1.40-1.50 (6H, m), 2.46 (3H, s), 3.20-3.40 (1H, m), 3.98 (3H, s), 5.93 (1H, s), 7.15 (1H, s), 7.28 (1H, s)

Reference Example 21-33
¹ H-NMR (CDCl ₃ ) δ ppm: 1.00-1.10 (3H, m), 1.80-2.00 (2H, m), 2.46 (3H, s), 2.80-3.00 (2H, m), 3.98 (3H, s ), 5.92 (1H, s), 7.16 (1H, s), 7.27 (1H, s)

Reference Example 21-34
¹ H-NMR (CDCl ₃ ) δ ppm: 1.27 (3H, t, J = 7.2 Hz), 2.45 (3H, s), 2.90 (2H, t, J = 7.4 Hz), 3.24 (2H, t, J = 7.4Hz), 3.98 (3H, s), 4.18 (2H, q, J = 7.2Hz), 5.89 (1H, s), 7.14 (1H, s), 7.27 (1H, s)

Reference Example 21-35
¹ H-NMR (CDCl ₃ ) δ ppm: 2.54 (3H, s), 4.00 (3H, s), 5.97 (1H, s), 7.23 (1H, s), 7.29 (1H, s)

Reference Example 21-37
¹ H-NMR (CDCl ₃ ) δ ppm: 1.19 (3H, t, J = 7.0 Hz), 2.45 (3H, s), 3.20 (2H, t. J = 6.7 Hz), 3.54 (2H, q, J = 7.0Hz), 3.89 (2H, t, J = 6.7Hz), 3.98 (3H, s), 5.91 (1H, s), 7.16 (1H, s), 7.28 (1H, s)

Reference Example 21-38
¹ H-NMR (CDCl ₃ ) δ ppm: 2.66 (3H, s), 2.78 (6H, s), 3.95 (3H, s), 6.95 (1H, s), 7.50 (1H, s)

Reference Example 21-39
¹ H-NMR (CDCl ₃ ) δ ppm: 2.67 (3H, s), 3.42 (3H, s), 3.99 (3H, s), 7.18 (1H, s), 7.76 (1H, s)

Reference Example 21-40
¹ H-NMR (CDCl ₃ ) δ ppm: 1.17-1.41 (5H, m), 1.59-1.91 (5H, m), 2.59 (3H, s), 3.59-3.68 (1H, m), 4.02 (3H, s ), 5.94 (1H, br), 6.97 (1H, d, J = 8.3Hz), 7.16 (1H, s), 7.48 (1H, s)

Reference Example 21-41
MS (ESI, m / z): 372 (M-1)

Reference Example 21-42
¹ H-NMR (CDCl ₃ ) δ ppm: 2.45 (3H, s), 4.01 (3H, s), 5.09 (2H, s), 6.13 (1H, s), 6.92 (2H, d, J = 8.9 Hz) , 7.02 (1H, s), 7.30-7.43 (5H, m), 7.47 (1H, s), 7.74 (2H, d, J = 8.9Hz)

Reference Example 21-43
¹ H-NMR (CDCl ₃ ) δ ppm: 0.31-0.39 (2H, m), 0.61-0.69 (2H, m), 1.21-1.31 (1H, m), 2.46 (3H, s), 3.83 (2H, d , J = 6.9Hz), 4.01 (3H, s), 6.11 (1H, s), 6.84 (2H, d, J = 8.8Hz), 7.02 (1H, s), 7.48 (1H, s), 7.73 (2H , d, J = 8.9Hz)

Reference Example 21-44
¹ H-NMR (CDCl ₃ ) δ ppm: 2.42 (3H, s), 3.93 (3H, s), 4.04 (3H, s), 7.07 (1H, s), 7.49 (1H, s), 7.80 (2H, d, J = 8.5Hz), 8.02 (2H, d, J = 8.5Hz)

Reference Example 21-45
¹ H-NMR (CDCl ₃ ) δ ppm: 2.45 (3H, s), 3.93 (3H, s), 6.95 (1H, s), 7.45 (1H, s), 7.73 (2H, d, J = 8.4 Hz) , 7.91 (2H, d, J = 8.4Hz)

Reference Example 22-1
[3-Hydroxy-4-methoxy-6- (5-methyl- [1,2,4] oxadiazol-3-yl) -2-nitrophenyl] phenylmethanone [5-hydroxy-4-methoxy-2 -(5-Methyl- [1,2,4] oxadiazol-3-yl) phenyl] phenylmethanone (Reference Example 21-1) (383 mg) and methylene chloride (10 mL) in a mixture of fuming nitric acid (68 μL) At room temperature and the mixture was stirred for 20 minutes. The separated organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was triturated with hexane: methylene chloride = 4: 1 to give the title compound (377 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 2.46 (3H, s), 4.09 (3H, s), 7.30-7.90 (6H, m), 10.72 (1H, s)

  [5-hydroxy-4-methoxy-2- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] similar to Reference Example 22-1 using the corresponding phenol instead of phenylmethanone By the method of Reference Example 22-2 to Reference Example 22-45 were synthesized. These are shown in Table 11.

  Physical property values of Reference Example 22-2 to Reference Example 22-20, Reference Example 22-22 to Reference Example 22-32, Reference Example 22-34, Reference Example 22-35, Reference Example 22-37 to Reference Example 22-45 Is shown below.

Reference Example 22-2
¹ H-NMR (CDCl ₃ ) δ ppm: 2.64 (3H, s), 2.68 (3H, s), 4.04 (3H, s), 7.75 (1H, s)

Reference Example 22-3
¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.01 (6H, d, J = 6.8 Hz), 2.57-2.64 (1H, m), 2.67 (3H, s), 4.00 (3H, s), 7.54 ( 1H, s), 11.47 (1H, br s)

Reference Example 22-4
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.70 (3H, s), 3.99 (3H, s), 7.43 (1H, s), 11.82 (1H, br)

Reference Example 22-5
MS (ESI, m / z): 308 (M-1)

Reference Example 22-6
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.59 (3H, s), 2.62 (3H, s), 4.03 (3H, s), 7.62 (1H, s)

Reference Example 22-7
¹ H-NMR (CDCl ₃ ) δ ppm: 1.12-1.15 (2H, m), 1.28-1.32 (2H, m), 2.38-2.43 (1H, m), 3.68 (3H, s), 3.99 (3H, s ), 7.50 (1H, s), 11.54 (1H, br)

Reference Example 22-8
¹ H-NMR (CDCl ₃ ) δ ppm: 2.72 (3H, s), 4.10 (3H, s), 7.67 (1H, s), 9.99 (1H, br s)

Reference Example 22-9
¹ H-NMR (DMSO-d ₆ ) δ ppm: 3.42 (3H, s), 3.69 (3H, s), 4.01 (3H, s), 4.83 (2H, s), 7.55 (1H, s), 11.66 ( 1H, br)

Reference Example 22-10
¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.42 (9H, s), 3.68 (3H, s), 4.00 (3H, s), 7.51 (1H, s), 11.58 (1H, br)

Reference Example 22-11
¹ H-NMR (CDCl ₃ ) δ ppm: 1.30-1.40 (6H, m), 2.64 (3H, s), 4.04 (3H, s), 5.30-5.40 (1H, m), 7.71 (1H, s), 10.54 (1H, s)

Reference Example 22-12
¹ H-NMR (CDCl ₃ ) δ ppm: 1.00-2.10 (10H, m), 2.63 (3H, s), 4.03 (3H, s), 5.10-5.20 (1H, m), 7.71 (1H, s), 10.51 (1H, br s)

Reference Example 22-13
¹ H-NMR (CDCl ₃ ) δ ppm: 2.64 (3H, s), 3.38 (3H, s), 3.70-3.80 (2H, m), 4.04 (3H, s), 4.50-4.60 (2H, s), 7.74 (1H, s), 10.65 (1H, br s)

Reference Example 22-14
¹ H-NMR (CDCl ₃ ) δ ppm: 1.30-1.40 (3H, m), 2.64 (3H, s), 4.04 (3H, s), 4.40-4.50 (2H, m), 7.73 (1H, s), 10.58 (1H, s)

Reference Example 22-15
¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.25 (9H, s), 2.62 (3H, s), 4.02 (3H, s), 7.59 (1H, s), 8.00 (1H, br), 11.53 ( 1H, br)

Reference Example 22-16
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.66 (3H, s), 3.97 (3H, s), 7.43 (1H, s)

Reference Example 22-18
MS (ESI, m / z): 369 (M-1)

Reference Example 22-19
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.45 (3H, s), 4.03 (3H, s), 7.50-7.70 (2H, m), 7.95-8.15 (2H, m), 8.40-8.50 (1H , m), 11.00-11.70 (1H, br)

Reference Example 22-20
MS (ESI, m / z): 362 (M + 1)

Reference Example 22-22
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.48 (3H, s), 4.03 (3H, s), 7.20-7.28 (2H, m), 7.60 (1H, s), 7.61-7.65 (2H, m ), 11.59 (1H, br s)

Reference Example 22-23
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.49 (3H, s), 4.05 (3H, s), 7.65 (1H, s), 7.94 (1H, d, J = 3.0 Hz), 8.22 (1H, d, J = 3.0Hz), 11.00-12.00 (1H, br)

Reference Example 22-24
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.53 (3H, s), 4.05 (3H, s), 7.16 (1H, d, J = 2.2 Hz), 7.68 (1H, s), 8.76 (1H, d, J = 2.2Hz)

Reference Example 22-25
¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.77 (3H, s), 3.97 (3H, s), 7.16-7.24 (5H, m), 7.57 (1H, s), 11.67 (1H, br)

Reference Example 22-26
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.66 (3H, s), 2.88-2.95 (4H, m), 3.97 (3H, s), 7.15-7.28 (5H, m), 7.61 (1H, s ), 11.56 (1H, br)

Reference Example 22-27
¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.00 (9H, s), 2.67 (3H, s), 3.99 (3H, s), 7.54 (1H, s), 11.49 (1H, brs)

Reference Example 22-28
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.68 (3H, s), 4.06 (3H, s), 7.68 (1H, s)

Reference Example 22-29
¹ H-NMR (CDCl3) δ ppm: 1.70 (6H, br s), 2.05-2.20 (9H, m), 2.65 (3H, s), 4.01 (3H, s), 5.39 (1H, br s), 7.53 (1H, s), 9.86 (1H, br s)

Reference Example 22-30
¹ H-NMR (CDCl ₃ ) δ ppm: 2.58 (3H, s), 4.06 (3H, s), 5.10 (2H, s), 6.78-6.81 (2H, m), 6.93-6.97 (1H, m), 7.21-7.25 (2H, m), 7.76 (1H, s), 10.85 (1H, s)

Reference Example 22-31
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.30 (3H, s), 4.00 (3H, s), 5.60 (2H, s), 6.95-7.15 (3H, m), 7.25-7.40 (2H, m ), 7.60 (1H, s)

Reference Example 22-32
¹ H-NMR (CDCl ₃ ) δ ppm: 1.40-1.50 (6H, m), 2.70 (3H, s), 3.20-3.30 (1H, m), 4.05 (3H, s), 7.77 (1H, s), 10.73 (1H, br s)

Reference Example 22-34
¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.18 (3H, t, J = 7.1 Hz), 2.32 (3H, s), 2.88 (2H, t, J = 6.8 Hz), 3.24 (2H, t, J = 6.8Hz), 3.99 (3H, s), 4.08 (2H, q, J = 7.1Hz), 7.56 (1H, s), 11.00-12.00 (1H, br)

Reference Example 22-35
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.43 (3H, s), 4.01 (3H, s), 7.62 (1H, s), 11.05-12.50 (1H, br)

Reference Example 22-37
¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.07 (3H, t, J = 7.0 Hz), 2.34 (3H, s), 3.25 (2H, t, J = 6.1 Hz), 3.46 (2H, q, J = 7.0Hz), 3.80 (2H, t, J = 6.1Hz), 3.99 (3H, s), 7.57 (1H, s), 11.40-11.70 (1H, br)

Reference Example 22-38
¹ H-NMR (CDCl ₃ ) δ ppm: 2.69 (3H, s), 2.81 (6H, s), 3.99 (3H, s), 6.96 (1H, s)

Reference Example 22-39
¹ H-NMR (CDCl ₃ ) δ ppm: 2.69 (3H, s), 3.55 (3H, s), 4.04 (3H, s), 7.15 (1H, s)

Reference Example 22-40
¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.03-1.73 (10H, m), 2.61 (3H, s), 3.39-3.50 (1H, m), 4.03 (3H, s), 7.59 (1H, s ), 8.66 (1H, d, J = 8.6Hz), 11.56 (1H, br)

Reference Example 22-41
¹ H-NMR (CDCl ₃ ) δ ppm: 1.07-2.01 (10H, m), 2.59-2.60 (3H, m), 2.94-3.36 (3H, m), 4.03-4.04 (3H, m), 4.25-4.80 (1H, m), 7.75-7.80 (1H, m), 10.87 (1H, br)

Reference Example 22-42
¹ H-NMR (CDCl ₃ ) δ ppm: 2.48 (3H, s), 4.08 (3H, s), 5.09 (2H, s), 6.95 (2H, d, J = 9.0 Hz), 7.31-7.44 (5H, m), 7.63-7.80 (3H, m)

Reference Example 22-43
¹ H-NMR (CDCl ₃ ) δ ppm: 0.32-0.39 (2H, m), 0.63-0.71 (2H, m), 1.22-1.32 (1H, m), 2.48 (3H, s), 3.84 (2H, d , J = 6.9Hz), 4.08 (3H, s), 6.86 (2H, d, J = 9.1Hz), 7.60-7.79 (3H, m)

Reference Example 22-44
¹ H-NMR (CDCl ₃ ) δ ppm: 2.45 (3H, s), 3.93 (3H, s), 4.10 (3H, s), 7.82-7.88 (3H, m), 8.07 (2H, d, J = 8.8 Hz)

Reference Example 22-45
¹ H-NMR (CDCl ₃ ) δ ppm: 2.47 (3H, s), 4.09 (3H, s), 7.69-7.95 (5H, m)

Reference Example 23-1
[3-Hydroxy-4-methoxy-6- (5-methyl- [1,2,4] oxadiazol-3-yl) -2-nitrophenyl]-(4-hydroxyphenyl) methanone (4-benzyloxy Phenyl)-[3-hydroxy-4-methoxy-6- (5-methyl- [1,2,4] oxadiazol-3-yl) -2-nitrophenyl] methanone (Reference Example 22-42) (395 mg ) And a 25% hydrobromic acid-acetic acid solution (10 mL) were stirred at 45 ° C. for 2 hours. The mixture was concentrated under reduced pressure to obtain the title compound (310 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 2.48 (3H, s), 4.06 (3H, s), 6.81 (2H, d, J = 8.8 Hz), 7.53-7.68 (2H, m), 7.71 (1H, s)

Production Example 1-1
[3,4-Dihydroxy-6- (5-methyl- [1,2,4] oxadiazol-3-yl) -2-nitrophenyl] phenylmethanone (Compound 1-1)
[3-Hydroxy-4-methoxy-6- (5-methyl- [1,2,4] oxadiazol-3-yl) -2-nitrophenyl] phenylmethanone (Reference Example 22-1) (377 mg) Aluminum chloride (361 mg) and pyridine (0.387 mL) were added to a mixture of and ethyl acetate (10.6 mL). The mixture was heated to reflux for 2.5 hours. After cooling to room temperature, 1 mol / L hydrochloric acid was added to the mixture. The separated organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with hexane: methylene chloride = 4: 1 to give the title compound (317 mg) as amorphous.
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.43 (3H, s), 7.40-7.70 (6H, m), 11.28 (2H, brs)
MS (ESI, m / z): 342 (M + 1)

  Instead of [3-hydroxy-4-methoxy-6- (5-methyl- [1,2,4] oxadiazol-3-yl) -2-nitrophenyl] phenylmethanone, the corresponding 3-nitrobenzene-1 Compound 1-2 to compound 1-45 were synthesized in the same manner as in Production Example 1-1 using -methoxy-2-ol. These are shown in Table 12.

  The physical property values of Compound 1-2 to Compound 1-45 are shown below.

Compound 1-2
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.34 (3H, s), 2.65 (3H, s), 7.52 (1H, s), 11.17 (1H, br s)

Compound 1-3
¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.00 (6H, d, J = 6.8 Hz), 2.56-2.63 (1H, m), 2.64 (3H, s), 7.46 (1H, s), 11.18 ( 2H, br s)

Compound 1-4
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.68 (3H, s), 7.21 (1H, s), 11.57 (2H, br)

Compound 1-5
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.64 (3H, s), 3.67 (3H, s), 7.42 (1H, s), 11.29 (2H, br)

Compound 1-6
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.56 (3H, s), 2.61 (3H, s), 7.54 (1H, s), 11.38 (2H, br s)

Compound 1-7
¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.10-1.14 (2H, m), 1.26-1.31 (2H, m), 2.35-2.42 (1H, m), 3.66 (3H, s), 7.40 (1H , s), 11.27 (2H, br)

Compound 1-8
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.70 (3H, s), 7.61 (1H, s)

Compound 1-9
¹ H-NMR (DMSO-d ₆ ) δ ppm: 3.41 (3H, s), 3.67 (3H, s), 4.81 (2H, s), 7.44 (1H, s), 11.38 (2H, br)

Compound 1-10
¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.41 (9H, s), 3.67 (3H, s), 7.45 (1H, s), 11.33 (2H, br)

Compound 1-11
¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.10-1.20 (6H, m), 2.63 (3H, s), 4.90-5.00 (1H, m), 7.63 (1H, s), 11.27 (2H, br s)

Compound 1-12
¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.20-1.80 (10H, m), 2.62 (3H, s), 4.70-4.80 (1H, m), 7.36 (1H, s), 11.26 (2H, br s)

Compound 1-13
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.62 (3H, s), 3.18 (3H, s), 3.40-3.50 (2H, m), 4.10-4.20 (2H, m), 7.38 (1H, s ), 11.16 (1H, br s)

Compound 1-14
¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.00-1.20 (3H, m), 2.64 (3H, s), 4.10-4.20 (2H, m), 7.38 (1H, s), 11.25 (1H, br s)

Compound 1-15
¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.24 (9H, s), 2.60 (3H, s), 7.50 (1H, s), 7.97 (1H, br), 11.32 (2H, br)

Compound 1-16
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.63 (3H, s), 7.31 (1H, s)

Compound 1-17
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.33 (3H, s), 2.45 (3H, s), 7.20-7.30 (2H, m), 7.50-7.60 (3H, m), 11.22 (1H, br s)

Compound 1-18
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.55 (3H, s), 7.05-7.10 (1H, m), 7.27-7.32 (2H, m), 7.46-7.49 (2H, m), 7.55 (1H , s), 10.41 (1H, s), 10.98 (1H, br), 11.08 (1H, br)

Compound 1-19
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.42 (3H, s), 7.50-7.65 (2H, m), 7.95-8.15 (2H, m), 8.40-8.50 (1H, m), 10.50-11.50 (2H, m)

Compound 1-20
¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.02-1.78 (10H, m), 2.22-2.30 (1H, m), 2.65 (3H, s), 7.46 (1H, s), 11.11 (1H, br )

Compound 1-21
¹ H-NMR (DMSO-d ₆ ) δ ppm: 0.91-0.99 (4H, m), 1.91-1.98 (1H, m), 2.64 (3H, s), 7.43 (1H, s), 11.18 (2H, br )

Compound 1-22
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.45 (3H, s), 7.19-7.27 (2H, m), 7.51 (1H, s), 7.58-7.64 (2H, m), 11.27 (1H, br s)

Compound 1-23
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.46 (3H, s), 7.56 (1H, s), 7.93 (1H, d, J = 3.0 Hz), 8.20 (1H, d, J = 3.0 Hz) , 10.50-12.00 (2H, br)

Compound 1-24
¹ H-NMR (DMSO-d ₆ ) δ ppm: 7.13 (1H, d, J = 2.0 Hz), 7.62 (1H, s), 8.74 (1H, d, J = 2.0 Hz)

Compound 1-25
¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.75 (3H, s), 3.25-3.33 (2H, m), 7.13 (1H, s), 7.14-7.23 (5H, m), 11.52 (1H, br )

Compound 1-26
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.64 (3H, s), 2.87-2.93 (4H, m), 7.14-7.28 (5H, m), 7.55 (1H, s), 11.17 (2H, br )

Compound 1-27
¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.00 (9H, s), 2.65 (3H, s), 7.47 (1H, s), 11.11 (2H, br s)

Compound 1-28
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.66 (3H, s), 7.59 (1H, s)

Compound 1-29
¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.60 (6H, br s), 1.89 (6H, br s), 1.99 (3H, br s), 2.62 (3H, s), 7.40 (1H, s) , 7.81 (1H, s), 10.69 (1H, br s), 10.81 (1H, br s)

Compound 1-30
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.56 (3H, s), 4.94 (2H, s), 6.84-6.96 (3H, m), 7.23-7.27 (2H, m), 7.58 (1H, s ), 11.30 (2H, br)

Compound 1-31
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.29 (3H, s), 5.59 (2H, s), 6.95-7.15 (3H, m), 7.30-7.40 (2H, m), 7.54 (1H, s ), 10.00-12.00 (2H, br)

Compound 1-32
¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.30-1.40 (6H, m), 2.35 (3H, s), 7.56 (1H, s), 11.17 (2H, br s)

Compound 1-33
¹ H-NMR (DMSO-d ₆ ) δ ppm: 0.90-1.00 (3H, m), 1.70-1.90 (2H, m), 2.34 (3H, s), 2.90-3.00 (2H, m), 7.54 (1H , s), 11.18 (2H, br s)

Compound 1-34
¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.10-1.25 (3H, m), 2.31 (3H, s), 2.86 (2H, t, J = 6.8 Hz), 3.22 (2H, t, J = 6.8 Hz), 4.00-4.15 (2H, m), 7.50 (1H, s), 10.50-11.50 (2H, br)

Compound 1-35
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.41 (3H, s), 7.57 (1H, s), 10.50-12.00 (2H, br)

Compound 1-36
MS (ESI, m / z): 348 (M-1)

Compound 1-37
¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.07 (3H, t, J = 7.0 Hz), 2.33 (3H, s), 3.23 (2H, t, J = 6.2 Hz), 3.45 (2H, q, J = 7.0Hz), 3.79 (2H, t, J = 6.2Hz), 7.52 (1H, s), 10.80-11.80 (2H, br)

Compound 1-38
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.63 (6H, s), 6.95 (1H, s)

Compound 1-39
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.68 (3H, s), 3.46 (3H, s), 7.11 (1H, s)

Compound 1-40
¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.02-1.72 (10H, m), 2.59 (3H, s), 3.37-3.48 (1H, m), 7.51 (1H, s), 8.61 (1H, d , J = 8.5Hz), 11.32 (2H, br)

Compound 1-41
¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.03-1.89 (10H, m), 2.60-2.65 (3H, m), 2.60-3.05 (3H, m), 3.83-3.94 (1H, m), 7.40 -7.45 (1H, m), 11.30 (2H, br)

Compound 1-42
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.47 (3H, s), 6.74 (2H, d, J = 9.1 Hz), 7.48 (2H, d, J = 8.2 Hz), 7.54 (1H, s)

Compound 1-43
¹ H-NMR (DMSO-d ₆ ) δ ppm: 0.29-0.38 (2H, m), 0.53-0.63 (2H, m), 1.19-1.29 (1H, m), 2.47 (3H, s), 3.86-3.92 (2H, m), 6.90-6.97 (3H, m), 7.51 (2H, d, J = 8.8Hz)

Compound 1-44
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.43 (3H, s), 3.86 (3H, s), 7.60 (1H, s), 7.76 (2H, d, J = 8.7 Hz), 7.99 (2H, d, J = 8.7Hz)

Compound 1-45
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.44 (3H, s), 7.60 (1H, s), 7.81 (2H, d, J = 8.6 Hz), 7.92 (2H, d, J = 8.6 Hz)

Production Example 2-1
Monopotassium salt of [3,4-dihydroxy-6- (5-methyl- [1,2,4] oxadiazol-3-yl) -2-nitrophenyl] phenylmethanone (Compound 2-1)
[3,4-Dihydroxy-6- (5-methyl- [1,2,4] oxadiazol-3-yl) -2-nitrophenyl] phenylmethanone (Compound 1-1) (100 mg), water ( To a mixture of 2.5 mL) and tert-butanol (2.5 mL) was added 1 mol / L aqueous potassium hydroxide solution (0.292 mL). The mixture was concentrated under reduced pressure to give the title compound (103 mg) as amorphous.
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.38 (3H, s), 6.94 (1H, s), 7.35-7.41 (2H, m), 7.45-7.51 (1H, m), 7.63-7.68 (2H , m)

  Instead of [3,4-dihydroxy-6- (5-methyl- [1,2,4] oxadiazol-3-yl) -2-nitrophenyl] phenylmethanone and aqueous potassium hydroxide, the corresponding 3- Compounds 2-2 to 2-6 were synthesized in the same manner as in Production Example 2-1, using nitrobenzene-1,2-diol and aqueous sodium hydroxide or potassium hydroxide.

Compound 2-2
Monosodium salt of [3,4-dihydroxy-6- (5-methyl- [1,2,4] oxadiazol-3-yl) -2-nitrophenyl] phenylmethanone
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.38 (3H, s), 6.93 (1H, s), 7.34-7.41 (2H, m), 7.44-7.51 (1H, m), 7.62-7.68 (2H , m)

Compound 2-3
Monopotassium salt of methyl 3,4-dihydroxy-6- (5-methyl- [1,2,4] oxadiazol-3-yl) -2-nitrobenzoate
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.56 (3H, s), 3.60 (3H, s), 6.72 (1H, s)

Compound 2-4
Monosodium salt of methyl 3,4-dihydroxy-6- (5-methyl- [1,2,4] oxadiazol-3-yl) -2-nitrobenzoate
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.56 (3H, s), 3.59 (3H, s), 6.68 (1H, s)

Compound 2-5
1- [3,4-dihydroxy-6- (5-methyl- [1,2,4] oxadiazol-3-yl) -2-nitrophenyl] -2-methylpropan-1-one monopotassium salt
¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.04 (6H, d, J = 7.0 Hz), 2.55 (3H, s), 2.59-2.72 (1H, m), 6.84 (1H, s)

Compound 2-6
1- [3,4-dihydroxy-6- (5-methyl- [1,2,4] oxadiazol-3-yl) -2-nitrophenyl] -2-methylpropan-1-one monosodium salt
¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.03 (6H, d, J = 6.8 Hz), 2.55 (3H, s), 2.59-2.70 (1H, m), 6.81 (1H, s)

Example 1
Human COMT Inhibitory Activity 1) Preparation of Recombinant Human COMT (1) Preparation of Recombinant Human Catechol-O-Methyltransferase NCBI (National Center for NC) encoding full-length human catechol-O-methyltransferase (hereinafter referred to as COMT) Based on the DNA sequence of Accession No. BC011935 registered on Biotechnology Information), two oligonucleotide primers were designed to amplify the DNA sequence encoding the recombinant human COMT described in SEQ ID NO: 1. The sequence of the 5 ′ primer is shown in SEQ ID NO: 3, and the sequence of the 3 ′ primer is shown in SEQ ID NO: 4. These primers contain a restriction enzyme site (BamH I on the 5 ′ side and EcoR I on the 3 ′ side) to facilitate insertion of the PCR product into the desired vector.
Each of the 5 ′ primer described in SEQ ID NO: 3 and the 3 ′ primer described in SEQ ID NO: 4 was diluted with TE buffer to obtain a 15 pmol / μL solution. H ₂ O (for PCR, 34.8 μL), 25 mmol / L MgSO ₄ (2.0 μL), 2 mmol / L dNTPs (5.0 μL), 10-fold concentrated DNA polymerase KOD plus buffer (5.0 μL, Toyobo) were mixed, A PCR reaction mixture was prepared. Then human liver cDNA (5.0 μL, Clontech) and each primer pair (1 μL, 15 pmol) were added to the above mixture, and finally 1.0 μL of KOD plus (Toyobo) was added. Thereafter, a PCR reaction was performed. The PCR reaction was carried out at 94 ° C. for 2 minutes, followed by 40 cycles of 94 ° C. for 15 seconds, 59 ° C. for 30 seconds, and 68 ° C. for 1 minute. Subsequently, it was completed at 68 ° C. for 5 minutes and at 4 ° C. for 10 minutes.
The PCR product was purified with QIAquick PCR Purification Kit (QIAGEN). The desired insert DNA was eluted with EB buffer (30 μL) of the same kit.

(2) Double digestion of recombinant human COMT insert DNA and pGEX-2T vector To recombinant human COMT insert DNA (1.5 μg), 10-fold concentrated EcoR I buffer (3.0 μL, New England Biolab), H ₂ O (11.1 μL), BamH I (1.5 μL, 15 U, 10 U / μL) and EcoR I (1.0 μL, 15 U, 10 U / μL) were added and mixed. The mixed solution was heated at 37 ° C. for 1.5 hours. Further, a 10-fold concentrated loading buffer was added to the solution. The mixed solution was separated by electrophoresis, and the gel portion containing the DNA having the digested fragment was excised and purified using MinElute Gel Extraction Kit (QIAGEN). pGEX-2T vector DNA (1.5 μg, Amersham) was similarly purified by double digestion.

(3) Ligation and transformation of E. coli JM109 Double-digested pGEX-2T vector (2.0 μL, 50 ng) and insert DNA (1.24 μL, 33.4 ng) were added to 2-fold concentrated ligation buffer (3.24 μL, Promega). Added and mixed. T4 ligase (1.0 μL, 3 U / μL, Promega) was then added to the mixed solution and the mixture was incubated at 25 ° C. for 1 hour. Next, E. coli JM109 (100 μL) was dissolved at 0 ° C., and the above mixed solution (5 μL) reacted with ligase was added to the JM109 suspension, gently mixed, and allowed to stand at 0 ° C. for 30 minutes. The mixture was heat shocked at 42 ° C. for 40 seconds without vigorous shaking and cooled at 0 ° C. for 10 minutes. Next, 450 μL of the SOC solution was added to the solution after the heat shock and shaken at 37 ° C. for 1 hour. After shaking, 50 μL and 200 μL of the mixed solution were respectively seeded on a plate of LB-ampicillin medium (diameter 9 cm, ampicillin concentration 100 μg / mL), and static culture was performed at 37 ° C. for 16 hours. As a result, colonies appeared on the plate.

(4) Colony Selection after JM109 Transformation with GST-Fused Recombinant Human COMT Plasmid An appropriate number of colonies are selected from the plate after stationary culture as described above, and the LB-ampicillin liquid medium (2 mL each, Ampicillin concentration 100 μg / mL), and cultured with shaking at 37 ° C. for 16 hours. 200 μL of each was dispensed into 1.5 mL microtubes, and the plasmid was extracted by the phenol extraction method. The extracted plasmid was redissolved in TE buffer and subjected to electrophoresis. A detected band having a migration position close to that of the pGEX-2T vector having no insert DNA was determined as a primary positive colony, and reconfirmation was performed by the following restriction enzyme double digestion.
The DNA solution derived from the primary positive colonies (7 μL each) was mixed with 10-fold concentrated EcoR I buffer (0.9 μL, New England Biolab), then BamHI (0.5 μL, 10 U / μL) and EcoR I ( 0.5 μL, 15 U / μL) was added. The solution was heated at 37 ° C. for 1 hour and then subjected to electrophoresis. A colony from which a sample in which a band was detected at a position of about 670 bp was determined as a secondary positive colony.

(5) Extraction and purification of GST fusion recombinant human COMT plasmid from Escherichia coli JM109 A part of the culture solution of JM109 transformed with GST fusion recombinant human COMT plasmid, which was determined as a secondary positive colony in (4), was partially (100 μL) was used as a glycerol stock, and the remaining culture was centrifuged at 12000 rpm for 10 minutes to obtain an E. coli pellet. Plasmid DNA was purified from the resulting E. coli pellet using QIAGEN Plasmid mini kit (QIAGEN). Its concentration was determined by OD260nm and was 247ng / μL. When the sequence was confirmed according to a conventional method, the DNA sequence of SEQ ID NO: 2 was inserted at the desired position.

(6) Transformation of GST-fused recombinant human COMT plasmid DNA into E. coli BL21 CODEN PLUS (DE3) RP GST-fused recombinant human COMT plasmid DNA 1 μL (1 ng / μL) purified in (5) and sequence confirmed In addition to 50 μL of E. coli BL21 CODEN PLUS (DE3) RP cell suspension thawed at 0 ° C., transformation was performed in the same manner as in (3), and plate culture was performed.

(7) Expression of GST-fused recombinant human COMT Colonies were picked up from the transformed E. coli BL21 CODON PLUS (DE3) RP plate, put into 5 mL of LB-ampicillin medium (ampicillin concentration 100 μg / mL), and 37 ° C. For 15 hours. A 50 μL portion of the culture was used as a glycerol stock and stored at −80 ° C. At the time of use, a part of this glycerol stock was inoculated into 150 mL of LB-ampicillin medium (ampicillin concentration 100 μg / mL) and cultured at 37 ° C. for 16 hours with shaking. This culture solution was diluted with seven LB-ampicillin media (ampicillin concentration 100 μg / mL) at 500 mL each, followed by shaking culture at 20 ° C. for 4.5 hours. After confirming that the absorbance at 600 nm of the culture solution was 0.44, 50 μL of isopropyl-β-D-thiogalactopyranoside (1 mol / L) was added, and shaking culture was performed at 20 ° C. for 18 hours. Went. The culture broth was centrifuged at 9000 rpm for 20 minutes to recover the E. coli pellet, divided into 4 pieces of 4 g each, and stored frozen at −80 ° C. until use.

(8) Thrombin treatment of GST-fused recombinant human COMT To the E. coli pellet obtained from (7), 40 mL of BugBuster solution (Novagen), 30 μL of Benzonase (Novagen) and 1 μL of rLysozyme (Novagen) were added, and room temperature for 15 minutes Treated with gentle agitation. The obtained lysate was centrifuged at 12000 rpm, 4 ° C. for 20 minutes, and the supernatant was recovered. Next, 20 mL of glutathione 4B Sepharose (resin bed volume 10 mL), which had been equilibrated in advance with D-PBS (Dulbecco's Phosphate Buffered Saline) and resuspended to 50% with D-PBS, was added to the supernatant solution to obtain The mixture was shaken at 4 ° C. for 1 hour. The mixture after shaking was separated into a resin and a filtrate by a filter. The obtained resin was washed 5 times with 30 mL of D-PBS, and 30 mL of thrombin treatment buffer (150 mmol / L NaCl, 50 mmol / L Tris-HCl, pH 8.0, 10% glycerol, 2.5 mmol / L CaCl _2). , 0.5% β-octyl-D-glucopyranoside). Next, thrombin treatment buffer was added to the resin to make 30 mL, and 30 units of thrombin (Amersham Biosciences) were added. After the resin mixture was gently stirred at 4 ° C. for 15 hours, the resin was filtered, and the resulting recombinant human COMT solution was stored at −80 ° C. until use.

2) Measurement of human COMT inhibitory action Human COMT inhibitory action was measured by partially modifying the method of Zurcher G et al. (J. Neurochem., 1982, 38, P.191-195). Recombinant human COMT (about 1 mg / mL) 0.25 μL prepared in 1), potassium phosphate buffer (500 mmol / L, pH 7.6) 40 μL, magnesium chloride (100 mmol / L) 10 μL, dithiothreitol (62.5 mmol / L) A mixture of 10 μL, adenosine deaminase (2550 units / mL) 0.5 μL and the test compound was preincubated at 37 ° C. for 5 minutes. A control sample was prepared in a similar manner, but dimethyl sulfoxide (5 μL) was added instead of the test compound. After adding [ ³ H] -S-adenosyl-L-methionine (12.5 mmol / L, 1.2 Ci / mol; Amersham Biosciences) 20 μL, the reaction was started by adding 25 μL of catechol substrate (7 mmol / L) . The reaction mixture (final volume 0.25 mL) was incubated at 37 ° C. for 30 minutes. The reaction was stopped by adding ice-cooled 1 mol / L hydrochloric acid (0.25 mL) containing 0.1 g / L guaiacol. Add 2.5 mL of scintillator (Optiflow (registered trademark) 0; Packard), shake vigorously for 1 minute, and then directly count the radioactivity present in the organic layer with a Packard liquid scintillation counter (TRICARB 1900CA) did. Blanks were incubated in the absence of catechol substrate (substrate was added after the reaction was stopped). IC ₅₀ values indicate the concentration required to inhibit enzyme activity by 50%. As comparative examples, tolcapone, entacapone and 5- (3-methyl- [1,2,4] oxadiazol-5-yl) -3-nitrobenzene-1,2-described in Example 75 of Patent Document 1 were used. The diol was similarly tested as Comparative Example 1. These results are shown in Table 13.

Example 2
Rat hepatotoxicity
Rat frozen hepatocytes 3 × 10 ⁻⁶ cells / vial stored at −150 ° C. were warmed to 37 ° C., added to a glucose-containing thawing medium (10 mL), mixed, and then centrifuged at 1000 rpm for 1 minute. After removing the supernatant, the cell pellet was suspended in Williams E. medium (15 mL). Drugs were prepared to 45, 15, 4.5, 1.5, and 0.45 mmol / L using dimethyl sulfoxide, and each drug solution and control (dimethyl sulfoxide) were dispensed in 2.0 μL aliquots into the test tube. The suspension (300 μL) was dispensed and mixed. Each suspension was dispensed at 100 μL into a 96-well plate and incubated at 37 ° C. for 4 hours in a CO ₂ incubator. ATP activity was measured according to Cell Viability Assay method of Promega. The concentration showing 50% ATP activity of the control was expressed as an EC ₅₀ value. These results are shown in Table 14.

  As a result of these tests, it was suggested that the compound contained as an active ingredient in the pharmaceutical composition of the present invention showed very slight hepatotoxicity compared with Tolcapone, Entacapone or Comparative Example 1.

Example 3
Evaluation of plasma L-DOPA concentration (1) Dosing and plasma sampling Male Sprague-Dawley rats (Charles River Japan) 6 weeks old (body weight 170 g to 190 g) were fasted overnight. A suspension of the test compound (0.6 mg / mL) and a mixed suspension of L-dopa (1 mg / mL) and carbidopa (6 mg / mL) were prepared using a mortar using 0.5% aqueous methylcellulose as a medium. . A mixed suspension of L-dopa (5 mg / kg) and carbidopa (30 mg / kg) was orally administered 4 hours or 6 hours after the oral administration (3 mg / kg) of the test compound. Two hours after administration of the mixed suspension of L-dopa and carbidopa, blood was collected, and the obtained blood was transferred to a tube containing sodium heparin, glycol ether diamine tetraacetic acid and reduced glutathione, and stored on ice. Plasma samples for L-dopa concentration measurement were obtained by centrifugation.

(2) Measurement of L-DOPA concentration After adding 0.01 mL of 100 μg / mL aqueous solution of metformin hydrochloride as an internal standard substance to 0.05 mL of the plasma obtained in (1) according to a conventional method, disodium ethylenediaminetetraacetate (250 mmol / L, 0.5 mol / L perchloric acid aqueous solution, 0.05 mL) was added for deproteinization. After centrifugation, 0.002 mL of the supernatant was injected into LC-MS / MS. Plasma L-dopa concentration was measured by the LC-MS / MS method under the following conditions. The L-dopa concentration is shown in Table 15 with the L-dopa concentration of the control group without administration of the test compound as 100%.
LC
Equipment: Agilent 1100
Column: Capcellpak C18 MGIII 5μm 4.6x50mm
Mobile phase: 0.5% heptafluorobutyric acid aqueous solution / acetonitrile column temperature: 40 ° C
Flow rate: 0.5mL / min

MS / MS
Device: API-4000
Ionization method: ESI (Turbo Ion Spray)

  From the results of these tests, the effect of increasing L-dopa concentration in plasma when L-dopa and carbidopa and a compound contained as an active ingredient in the pharmaceutical composition of the present invention are administered in combination is As compared with the case where pa, carbidopa, and comparative example 1 were administered, it became clear that it was more durable.

Example 4
L-dopa efficacy enhancing action in unilateral Parkinson's disease rats with unilateral 6-hydroxydopamine injury (1) Drugs The following drugs were used:
6-hydroxydopamine hydrochloride (6-OHDA, sigma); desipramine hydrochloride (desipramine, sigma); L-ascorbic acid (sigma); pentobarbital sodium (Nembutal Note, Sumitomo Dainippon Pharma); apomorphine hydrochloride 1/2 Hydrates (apomorphine, sigma); dihydroxyphenylalanine (L-dopa, sigma); carbidopa monohydrate (carbidopa, kenprotech); 0.5% methylcellulose (Wako Pure Chemical Industries).
6-OHDA was dissolved at 2 mg / mL in physiological saline containing 0.2% L-ascorbic acid. Desipramine was dissolved at 10 mg / mL in distilled water in a warm water bath. Apomorphine was dissolved at 0.1 mg / mL in physiological saline. L-dopa / carbidopa was suspended in a 0.5% aqueous methylcellulose solution. The test compound was dissolved in a solution containing 0.5% dimethyl sulfoxide, 20% polyethylene glycol and 79.5% 0.1 mol / L arginine aqueous solution.

(2) Creation of 6-OHDA damage model 6-OHDA damage model was created by partially modifying the method of Non-Patent Document 6. Male Sprague-Dawley rats (6 weeks old, Nippon Charles River) were anesthetized by intraperitoneal administration of sodium pentobarbital (45 mg / kg) and fixed in a stereotaxic frame (Narishige, Tokyo, Japan). In order to prevent damage of noradrenaline neurons by 6-OHDA, intraperitoneal desipramine injection (25 mg / kg) was given 30 minutes prior to 6-OHDA injection. After identifying the bregma via a mid-top incision, a hole was drilled in the skull using a dental drill at the 6-OHDA injection site. Injury is caused by injecting 6-OHDA (8 μg in 4 μL at a rate of 1 μL per minute) into the left inner forebrain bundle using an injection cannula (30 gauge needle) connected to a microsyringe (Hamilton). Performed (coordinates of the damaged site; from the Bregma point and the skull surface, anteroposterior −2.5 mm, left and right −1.8 mm, depth −8.0 mm). The cannula was left at the injury site for 5 minutes and then carefully removed from the animal. The hole in the skull was supplemented with dental cement, and after disinfection, the incision site of the scalp was surgically sutured. Animals that recovered from anesthesia were bred as usual until the experimental day.

(3) Evaluation of rotational behavior Rats were tested based on contralateral rotation in response to 0.1 mg / kg apomorphine administered subcutaneously (one rotation is defined as 360 ° rotation) 3 weeks after injury. When observing the behavior, the rat was placed in a plastic cylinder having a radius of 20 centimeters, and the rotational behavior was video-recorded and quantified by a rat rotational motion automatic measuring device R-RACS (Kissey Welcom). Animals that rotated more than 100 counts per hour were used for further experiments. On the experimental day, the animals were fasted for 10 hours from 9 am and the test compound was orally administered at a dose of 10 mg / kg, while L-dopa 5 mg / kg and carbidopa 30 mg / kg were orally administered. The strength of the medicinal effect was measured as the contralateral rotation speed, and the duration of the medicinal effect was defined as the time until the time when the rotation speed per 10 minutes was 10 counts or less lasted for 60 minutes. Table 16 shows the total number of rotations and the duration of drug efficacy. Similarly, a group containing only L-dopa and carbidopa was shown as a control.

  As a result of these tests, the compound contained as an active ingredient in the pharmaceutical composition of the present invention and L-dopa / carbidopa were significantly used in combination as compared with the L-dopa / carbidopa-only control. A significant increase in drug efficacy was observed.

  Since the pharmaceutical composition of the present invention has an excellent COMT inhibitory action, it is useful as a therapeutic or prophylactic agent for Parkinson's disease, depression, and hypertension. In particular, by using the pharmaceutical composition of the present invention in combination with L-dopa, the bioavailability of L-dopa can be increased, which is suitable for the treatment and prevention of Parkinson's disease.

<SEQ ID NO: 1>
SEQ ID NO: 1 is the sequence of recombinant human catechol-O-methyltransferase.
<SEQ ID NO: 2>
SEQ ID NO: 2 is a DNA sequence amplified using the primers of SEQ ID NOs: 3 and 4 to express the recombinant human catechol-O-methyltransferase of SEQ ID NO: 1.
<SEQ ID NO: 3>
SEQ ID NO: 3 is the sequence of the 5 ′ primer used to amplify the DNA of SEQ ID NO: 2.
<SEQ ID NO: 4>
SEQ ID NO: 4 is the sequence of the 3 ′ primer used to amplify the DNA of SEQ ID NO: 2.

Claims (7)

Formula (I):

[Where,
R ³ represents the following a) to i):
a) (C _1-6 alkyl) -C (O)-,
b) (HaloC _1-6 alkyl) -C (O)-,
c) a cycloalkylcarbonyl group,
d) An unsubstituted or group consisting of: an arylcarbonyl group whose ring is substituted with 1 to 5 groups independently selected from a halogen atom and a cyano group;
e) a heteroarylcarbonyl group,
f) an aralkylcarbonyl group,
g) (Aryloxy C _1-6 alkyl) -C (O)-,
h) (C _1-6 alkoxy) -C (O) —, or i) —C (O) C (O) NR ¹¹ R ¹² ;
R ⁴ represents the following a) to d):
a) a C _1-6 alkyl group,
b) a C _1-6 alkoxy-C _1-6 alkyl group,
c) an aryloxy-C _1-6 alkyl group, or d) a (C _1-6 alkoxy) -C (O) -C _1-6 alkyl group;
R ¹¹ and R ¹² are each independently a hydrogen atom, a C _1-6 alkyl group or a cycloalkyl group.
Or a pharmacologically acceptable salt thereof as an active ingredient. R ³ is a) to h) below:
a) (C _1-6 alkyl) -C (O)-,
b) a cycloalkylcarbonyl group,
c) an arylcarbonyl group which is unsubstituted or substituted on the ring by 1 to 5 halogen atoms,
d) a heteroarylcarbonyl group,
e) an aralkylcarbonyl group,
f) (AryloxyC _1-6 alkyl) -C (O)-,
2. The pharmaceutical composition according to claim 1, which is g) ( _C1-6 alkoxy) -C (O)-, or h) -C (O) C (O) NR < ¹¹ > R < ¹² >. R ³ is the following a) to e):
a) (C _1-6 alkyl) -C (O)-,
b) a cycloalkylcarbonyl group,
c) an arylcarbonyl group,
d) (C _1-6 alkoxy) -C (O) —, or e) —C (O) C (O) NR ¹¹ R ¹² ,
The pharmaceutical composition according to claim 2, wherein R ⁴ is a C _1-6 alkyl group or a C _1-6 alkoxy-C _1-6 alkyl group. The group consisting of:
[3,4-dihydroxy-6- (5-methyl- [1,2,4] oxadiazol-3-yl) -2-nitrophenyl] phenylmethanone;
1- [3,4-dihydroxy-6- (5-methyl- [1,2,4] oxadiazol-3-yl) -2-nitrophenyl] ethanone;
Methyl 3,4-dihydroxy-6- (5-methyl- [1,2,4] oxadiazol-3-yl) -2-nitrobenzoate;
N-cyclohexyl-2- [3,4-dihydroxy-6- (5-methyl- [1,2,4] oxadiazol-3-yl) -2-nitrophenyl] -2-oxoacetamide;
N-cyclohexyl-2- [3,4-dihydroxy-6- (5-methyl- [1,2,4] oxadiazol-3-yl) -2-nitrophenyl] -N-methyl-2-oxoacetamide ;
1- {6- [5- (2-ethoxyethyl)-[1,2,4] oxadiazol-3-yl] -3,4-dihydroxy-2-nitrophenyl} ethanone; and cyclohexyl- [3, 4-dihydroxy-6- (5-methyl- [1,2,4] oxadiazol-3-yl) -2-nitrophenyl] methanone,
Or a pharmacologically acceptable salt thereof as an active ingredient.   The pharmaceutical composition according to any one of claims 1 to 4, which is used for treatment or prevention of Parkinson's disease.   The pharmaceutical which combines the pharmaceutical composition as described in any one of Claims 1-4, and at least 1 sort (s) selected from L-dopa and an aromatic L-amino acid decarboxylase inhibitor. The medicament according to claim 6 , which is used for treatment or prevention of Parkinson's disease.