JP5707063B2 - Novel catechol derivatives, pharmaceutical compositions containing them, and uses thereof - Google Patents

Description

  The present invention relates to a novel catechol derivative having a catechol-O-methyltransferase inhibitory action, a pharmaceutical composition containing it, and uses 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.

（式中、Ｒ^Ａは水素であり、Ｒ^Ｂは芳香族複素環式基である）で表される化合物を開示している。 Patent Document 1 has a general formula having a COMT inhibitory action:

(Wherein R ^A is hydrogen and R ^B is an aromatic heterocyclic group).

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

  The object of the present invention is to provide a novel compound having a strong COMT inhibitory action and preferably having a 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^１およびＲ^２は、それぞれ独立して、水素原子、低級アシル基、低級アルコキシカルボニル基、アラルキルカルボニル基または−Ｃ（Ｏ）ＮＲ^１１Ｒ^１２を表すか、あるいはＲ^１およびＲ^２が一緒になって−Ｃ（Ｏ）−または低級アルキレン基を形成し；
Ｒ^３は、以下のａ）〜ｓ）：
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）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アリールスルホニル基、
ｒ）−ＳＯ_２ＮＲ^１１Ｒ^１２、または
ｓ）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、非置換もしくは以下からなる群：
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、および
ｈ）ヒドロキシ低級アルキル基、
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、但し、該ヘテロアリール基は[１，２，４]オキサジアゾール−３−イルでなく；
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に関する。 That is, the present invention relates to the general formula (I):

[Where,
R ¹ and R ² each independently represent a hydrogen atom, a lower acyl group, a lower alkoxycarbonyl group, an aralkylcarbonyl group, or —C (O) NR ¹¹ R ¹² , or R ¹ and R ² together Forming a -C (O)-or lower alkylene group;
R ³ represents the following a) to s):
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) An unsubstituted or group consisting of: an arylsulfonyl 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;
r) —SO ₂ NR ¹¹ R ¹² , or s) Unsubstituted or the group consisting of: 1 to 3 groups independently selected from 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 is unsubstituted or a group consisting of:
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, and h) a hydroxy lower alkyl group,
A heteroaryl group wherein the ring is substituted with 1 to 3 groups independently selected from: provided that the heteroaryl group is not [1,2,4] oxadiazol-3-yl;
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 pharmaceutically acceptable salt thereof.

  The present invention also relates to a pharmaceutical composition comprising a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.

  The present invention also relates to a catechol-O-methyltransferase inhibitor comprising as an active ingredient the compound described in general formula (I) or a pharmacologically acceptable salt thereof.

  The present invention also provides a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof and at least one selected from L-dopa and an aromatic L-amino acid decarboxylase inhibitor. The present invention relates to a combined medicine.

  The present invention also relates to a therapeutic or prophylactic agent for Parkinson's disease, depression or hypertension, comprising as an active ingredient the compound described in general formula (I) or a pharmacologically acceptable salt thereof.

  The compound of the present invention has a strong COMT inhibitory action. In addition, the compound of the present invention has a slight effect on the liver and has high safety. Therefore, the compound of the present invention is useful as a therapeutic or prophylactic agent for Parkinson's disease, depression, and hypertension. In particular, by using the compound of the present invention in combination with L-dopa, Since the bioavailability 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 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-oxadiazol-5-yl, 1,3,4-oxadiazole Examples include 2-yl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidyl and pyridazinyl, and preferably oxazolyl, isoxazolyl, thiazolyl or 1,2,4-oxadiazole. -5-yl, 1,3,4-oxadiazol-2-yl. Examples of the bicyclic aromatic heterocycle include indolyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, quinolyl, isoquinolyl, phthalazinyl, benzimidazolyl, benzoxazolyl, and preferably benzothiazolyl. 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.

  "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.

The “arylsulfonyl group” means a group represented by aryl-SO ₂ —, and examples thereof include a phenylsulfonyl group.

  “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.

The “lower alkylene group” means a divalent linear or branched C _1-6 saturated hydrocarbon chain. Specific examples of the lower alkylene group, _{e.g., -CH 2 -, - CH 2} CH 2 -, - CH (CH 3) -, - CH (CH 3) CH 2 -, - CH 2 CH (CH 3) - , —C (CH ₃ ) ₂ — and the like, and —CH (CH ₃ ) — or —C (CH ₃ ) ₂ — is preferable.

  When one or more asymmetric carbon atoms are present in the compound represented by the general formula (I) of the present invention, 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 those combinations of compounds are 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) of the present invention, the present invention includes any of the geometric isomers. When the atropisomer is present in the compound represented by the general formula (I) of the present invention, the present invention includes any of the atropisomers. Furthermore, the compound represented by the general formula (I) of the present invention includes solvates with pharmaceutically acceptable solvents such as hydrates and ethanol.

  The compound represented by the general formula (I) of the present invention 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) of the present invention,
R ¹ and R ² are preferably hydrogen atoms; or R ³ is preferably a) to c) below:
a) 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,
b) a lower alkoxycarbonyl group, or c) a group consisting of 1 to 3 groups independently selected from the group consisting of unsubstituted or the following: halogen atom, lower alkyl group, halo lower alkyl group, and lower alkoxy group A substituted arylsulfonyl group.

In a preferred embodiment of the invention,
R ¹ and R ² are preferably a hydrogen atom.

In a further preferred embodiment of the invention,
R ¹ and R ² are preferably hydrogen atoms,
R ³ is the following a) to c):
a) 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,
b) a lower alkoxycarbonyl group, or c) a group consisting of 1 to 3 groups independently selected from the group consisting of unsubstituted or the following: halogen atom, lower alkyl group, halo lower alkyl group, and lower alkoxy group A substituted arylsulfonyl group.

Specific examples of preferred embodiments of the present invention are compounds selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
Methyl 6-benzothiazol-2-yl-3,4-dihydroxy-2-nitrobenzoate;
Methyl 3,4-dihydroxy-6- (3-methylisoxazol-5-yl) -2-nitrobenzoate;
Methyl 3,4-dihydroxy-6- (5-methyloxazol-2-yl) -2-nitrobenzoate;
Methyl 3,4-dihydroxy-2-nitro-6-thiazol-2-ylbenzoate;
Methyl 3,4-dihydroxy-2-nitro-6-oxazol-2-ylbenzoate;
(6-benzothiazol-2-yl-3,4-dihydroxy-2-nitrophenyl) phenylmethanone;
1- (6-benzothiazol-2-yl-3,4-dihydroxy-2-nitrophenyl) ethanone; and 3,4-dihydroxy-6- (3-methyl- [1,2,4] oxadiazole- 5-yl) -2-nitrobenzoic acid methyl ester.

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

（式中、Ｒ^３、Ｒ^４は前記と同義であり、Ｌ^１は臭素原子、ヨウ素原子、塩素原子、トリフルオロメタンスルホニルオキシ基などの脱離基を表し、Ｒ^１０は低級アシル基、低級アルコキシカルボニル基または−ＣＯＮＲ^１１Ｒ^１２を表し、Ｂｎはベンジル基を表す。）

Wherein R ³ and R ⁴ are as defined above, L ¹ represents a leaving group such as a bromine atom, an iodine atom, a chlorine atom or a trifluoromethanesulfonyloxy group, and R ¹⁰ represents a lower acyl group or a lower alkoxy group. Represents a carbonyl group or —CONR ¹¹ R ¹² , and Bn represents a benzyl group.)

Step 1-1
Compound (XII) is obtained by condensing compound (X) and tributyltin derivative (XI) in the presence of a metal catalyst in an inert solvent. Examples of the inert solvent used in this reaction include 1,4-dioxane, N, N-dimethylformamide, 1,2-dimethoxyethane, toluene and the like. Examples of the metal catalyst include palladium acetate, tris (dibenzylideneacetone) dipalladium (0), bis (triphenylphosphine) palladium (II), tetrakis (triphenylphosphine) palladium (0), and the like. The reaction temperature is usually from 80 ° C. to 200 ° C., and the reaction time is usually from 5 minutes to 24 hours, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.

Step 1-2
The benzyl group of compound (XII) is removed in an inert solvent (eg, ethanol, N, N-dimethylformamide, tetrahydrofuran, etc.) in the presence of a metal catalyst (eg, palladium carbon, platinum oxide, etc.) in a hydrogen atmosphere. By doing so, a phenol derivative (XIII) is obtained. 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 is carried out by using compound (XII) with an acid or a Lewis acid (eg, hydrogen bromide, aluminum chloride, titanium tetrachloride, etc.) in an inert solvent (eg, methylene chloride, toluene, etc.). It can also be done by processing. 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 1-3
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 1-4
The compound (Ia) 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.

Step 1-5
Compound (Ib) is obtained by acylating compound (Ia) with an acylating agent. Such acylation is well known to those skilled in the art and can be performed, for example, according to the methods described in TWGreene and PGHWuts, “Protective Groups in Organic Synthesis”, 4th edition.

（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
The aldehyde derivative (XVI) is obtained by reacting the compound (XV) with an organomagnesium reagent in an inert solvent and then reacting with N, N-dimethylformamide (DMF). 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 2-2
The benzyl alcohol derivative (XIX) is obtained by reacting the aldehyde derivative (XVI) with an organic magnesium reagent (XVII) or an organic lithium reagent (XVIII) 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 2-3
Compound (XV) is reacted with an organomagnesium reagent in an inert solvent, and then reacted with aldehyde (XX) to give benzyl alcohol derivative (XIX). 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 2-4
The ketone derivative (XXI) is obtained by oxidizing the benzyl alcohol derivative (XIX) 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.

Step 2-5
The compound (XV) is reacted with an organomagnesium reagent in an inert solvent, and then reacted with an acid anhydride (XXII), or an acid halide or N-methoxy-N-methylamide (XXIII) to give a ketone derivative (XXI ) 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.

  Hereinafter, compound (Ic) can be synthesized from ketone derivative (XXI) in the same manner as in step 1-2 to step 1-4 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 (XXIII) is obtained by condensing the compound (XV) and the alcohol (XXII) 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
The carboxylic acid derivative (XXIV) is obtained by oxidizing the aldehyde derivative (XVI) 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 (XXIII) is obtained by reacting the carboxylic acid derivative (XXIV) with an alkyl halide (XXV) 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.
The ester derivative (XXIII) is a carboxylic acid derivative (XXIV) and an alcohol (XXVI) in an inert solvent (eg, methylene chloride, N, N-dimethylformamide, etc.), a condensing agent (eg, 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 (XXIV) is converted into a condensing agent (for example, dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3- in an inert solvent (for example, methylene chloride, N, N-dimethylformamide, tetrahydrofuran, etc.). Condensation with amine (XXVII) in the presence of ethyl carbodiimide hydrochloride, diethyl cyanophosphate, diphenylphosphoryl azide, etc.) gives amide derivative (XXVIII). 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 (XXIII) in the same manner as in step 1-2 to step 1-4 of Scheme 1. Similarly, compound (Ie) can be synthesized from compound (XXVIII).

（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 (XV) and triisopropylsilanethiol (XXIX) in the presence of a base, a palladium catalyst and a phosphorus ligand in an inert solvent, triisopropylsilylphenylthioether derivative (XXX) 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 (XXX) in an inert solvent (for example, 1,4-dioxane, N, N-dimethylformamide, 1,2-dimethoxyethane, tetrahydrofuran, etc.), alkyl halide (XXV), 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 (XXXI) is obtained by oxidizing the alkylphenyl thioether 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 the triisopropylsilylphenylthioether derivative (XXX) 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 (XXVII) in an inert solvent (eg, tetrahydrofuran, N, N-dimethylformamide, ethyl acetate, methylene chloride, etc.) in the presence of a base (eg, triethylamine, N, N-diisopropylethylamine, etc.). To give a sulfonamide derivative (XXXII). 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.

  Thereafter, compound (If) can be synthesized from compound (XXXI) in the same manner as in step 1-2 to step 1-4 of Scheme 1. Similarly, compound (Ig) can be synthesized from compound (XXXII).

（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 (XXXIV) is obtained by condensing the aldehyde derivative (XVI) with isocyanide (XXXIII) 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 (XXXIV) in a suitable solvent (eg, tetrahydrofuran, methanol, ethanol, water, etc.) in the presence of a base (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.) The alcohol derivative (XXXV) 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 (XXXVI) is obtained by oxidizing the alcohol derivative (XXXV) in the same manner as in Step 2-4.

  Hereinafter, in the same manner as in Step 1-2 to Step 1-4 in Scheme 1, compound (Ih) can be synthesized from compound (XXXVI).

  The schemes shown above are several examples of methods for preparing the compounds of the present invention or their 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) of the present invention and the intermediate used for producing the compound are isolation / purification means well known to those skilled in the art, if necessary. Isolation and purification can be performed by performing operations such as solvent extraction, crystallization, recrystallization, chromatography, preparative high performance liquid chromatography and the like.

The compound of the present invention thus produced has an excellent COMT inhibitory action and thus is useful as a therapeutic or prophylactic agent for Parkinson's disease, and is preferably used in combination with L-dopa. Further, the compound of the present invention 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 compounds of the present invention are also useful as therapeutic or prophylactic agents for depression. The compound of the present invention is also useful as a therapeutic agent for hypertension because it has an action of promoting urinary sodium excretion.

  The pharmaceutical composition containing the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof as an active ingredient is used in various dosage forms 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.

  The dose of the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof is appropriately determined depending on the age, sex, weight, disease, degree of treatment, etc. of the patient. In the case of parenteral administration in the range of about 10 mg to about 3000 mg per day for an adult, it can be appropriately administered once or divided into several times within the range of about 5 mg to about 1000 mg per day for an adult.

  A combination of the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof and at least one selected from L-dopa and an aromatic L-amino acid decarboxylase inhibitor. The resulting medicament can be administered as a formulation containing these active ingredients together 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.

  A combination of the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof and at least one selected from L-dopa and an aromatic L-amino acid decarboxylase inhibitor. In such a medicament, the compounding ratio of the drugs can be appropriately selected depending on the age, sex and weight of the patient, symptoms, administration time, dosage form, administration method, combination of drugs, and the like.

  The contents of the present invention will be described in more detail with reference to the following reference examples, examples and test 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 2-1
4-Benzyloxy-2-iodo-5-methoxybenzoic acid 4-Benzyloxy-2-iodo-5-methoxybenzaldehyde (Reference Example 1-1) (20 g), dimethyl sulfoxide (19 mL), concentrated sulfuric acid (3 mL), To a mixture of water (30 mL) and acetonitrile (181 mL) was added a mixture of sodium chlorite (9.8 g) and water (30 mL). After stirring at room temperature for 30 minutes, water was added to the mixture. The insoluble material was collected by filtration to give the title compound (20.3 g).
¹ H-NMR (CDCl ₃ ) δ ppm: 3.88 (3H, s), 5.15 (2H, s), 7.31-7.46 (6H, m), 7.56 (1H, s)

Reference Example 3-1
4-Benzyloxy-2-iodo-5-methoxy-N- (2-oxopropyl) benzamide 4-Benzyloxy-N- (2-hydroxypropyl) -2-iodo-5-methoxybenzamide (Reference Example 5-2) ) (1.15 g), triethylamine (0.9 mL) and dimethyl sulfoxide (12 mL) were added with a mixture of sulfatrioxide pyridine complex (621 mg) and dimethyl sulfoxide (12 mL) under ice-cooling. After stirring at room temperature for 2 hours, water and ethyl acetate were added to the mixture. The separated organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with hexane / ethyl acetate to give the title compound (596 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 2.28 (3H, s), 3.87 (3H, s), 4.35 (2H, d, J = 4.3 Hz), 5.13 (2H, s), 6.55-6.70 (1H, m), 7.03 (1H, s), 7.25-7.50 (7H, m)

Reference Example 4-1
2- (4-Benzyloxy-2-iodo-5-methoxyphenyl) -5-methyloxazole 4-Benzyloxy-2-iodo-5-methoxy-N- (2-oxopropyl) benzamide (Reference Example 3-1) ) (572 mg), toluene (13 mL) and phosphorus oxychloride (0.364 mL) were stirred under reflux for 5 hours. After cooling to room temperature, the mixture was poured into ice water. The mixture was extracted with ethyl acetate. The separated organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0% -20% ethyl acetate / hexane, gradient elution) to give the title compound (114 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 2.35-2.45 (3H, m), 3.91 (3H, s), 5.15 (2H, s), 6.85-6.95 (1H, m), 7.30-7.50 (7H, m )

Reference Example 5-1
N ′-[(4-Benzyloxy-3-methoxy-5-iodobenzoyl) oxy] acetamidine 4-benzyloxy-2-iodo-5-methoxybenzoic acid (870 mg) and N, N-dimethylformamide (5 mL) 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (518 mg) and 1-hydroxybenzotriazole (420 mg) were added to the mixture at room temperature. After stirring for 15 minutes, N-hydroxyacetamidine (839 mg) and triethylamine (0.95 mL) were added to the mixture. After stirring for 3 hours, water was added to the mixture. The insoluble material was collected by filtration to give the title compound (961 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 1.81 (3H, s), 3.82 (3H, s), 5.17 (2H, s), 6.40 (2H, brs), 7.30-7.50 (6H, m), 7.50- 7.55 (1H, m)

Reference Example 5-2
4-Benzyloxy-N- (2-hydroxypropyl) -2-iodo-5-methoxybenzamide 1-amino-2-propanol was used instead of N-hydroxyacetamidine in the same manner as in Reference Example 5-1, The title compound was synthesized.
¹ H-NMR (CDCl ₃ ) δ ppm: 1.28 (3H, d, J = 6.3 Hz), 3.24-3.31 (1H, m), 3.62-3.69 (1H, m), 3.86 (3H, s), 4.06- 4.14 (1H, m), 5.11 (2H, s), 7.01 (1H, s), 7.29-7.46 (6H, m)

Reference Example 5-3
2-Benzenesulfinyl-4-benzyloxy-5-methoxybenzoic acid N′-acetylhydrazide Instead of 4-benzyloxy-2-iodo-5-methoxybenzoic acid and N-hydroxyacetamidine, 2-benzenesulfinyl-4- The title compound was synthesized in the same manner as in Reference Example 5-1, using benzyloxy-5-methoxybenzoic acid (Reference Example 11-4) and acetic hydrazide.

Reference Example 6-1
5- (4-Benzyloxy-2-iodo-5-methoxyphenyl) -3-methyl [1,2,4] oxadiazole N ′-[(4-benzyloxy-3-methoxy-5-iodobenzoyl) Tetrabutylammonium fluoride (1 mol / L, tetrahydrofuran solution, 6.6 mL) was added to a mixture of oxy] acetamidine (Reference Example 5-1) (961 mg) and tetrahydrofuran (4 mL) at room temperature. After stirring for 3 days, water was added to the mixture. The insoluble material was collected by filtration to give the title compound (480 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 2.49 (3H, s), 3.92 (3H, s), 5.17 (2H, s), 7.30-7.30 (7H, m)

Reference Example 7-1
5- (4-Benzyloxy-2-iodo-5-methoxyphenyl) -3-methylisoxazole A mixture of acetone oxime (302 mg) and tetrahydrofuran (20 mL) was mixed with n-butyllithium (1.65 mol) under ice conditions in an argon atmosphere. / L hexane solution, 5 mL) was added. After stirring at room temperature for 30 minutes, methyl 4-benzyloxy-2-iodo-5-methoxybenzoate (Reference Example 12-3) (1.075 g) was added to the mixture. After stirring at 60 ° C. for 2 hours, concentrated sulfuric acid (2.15 mL) was added to the mixture under ice cooling. After stirring at room temperature for 15 minutes, 5 mol / L aqueous sodium hydroxide solution (10 mL) was added to the mixture. The mixture was stirred for 1 hour. 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: 5% -50% ethyl acetate / hexane, gradient elution) to give the title compound (414 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 2.38 (3H, s), 3.90 (3H, s), 5.15 (2H, s), 6.72 (1H, s), 7.25-7.50 (7H, m)

Reference Example 8-1
2- (4-Benzyloxy-2-iodo-5-methoxyphenyl) benzthiazole 4-Benzyloxy-2-iodo-5-methoxybenzoic acid (Reference Example 2-1) (0.5 g), thionyl chloride (3.8 mL) ) And N, N-dimethylformamide (1 drop) were stirred at 80 ° C. for 2 hours. The mixture was concentrated under reduced pressure to obtain crude 4-benzyloxy-2-iodo-5-methoxybenzoyl chloride.
A mixture of crude 4-benzyloxy-2-iodo-5-methoxybenzoyl chloride, 2-aminothiophenol (0.15 mL) and N-methylpyrrolidinone (10 mL) was stirred at 100 ° C. for 4 hours. After cooling to room temperature, 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 purified by silica gel column chromatography (eluent: 0% -50% ethyl acetate / hexane, gradient elution) to give the title compound (375 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 3.93 (3H, s), 5.18 (2H, s), 7.30-7.60 (9H, m), 7.93 (1H, d, J = 7.8 Hz), 8.12 (1H, d, J = 8.1Hz)

Reference Example 9-1
5-Benzyloxy-4-methoxy-2- (3-methylisoxazol-5-yl) benzaldehyde 5- (4-Benzyloxy-2-iodo-5-methoxyphenyl) -3-methylisoxazole (reference) Example 7-1) To a mixture of (410 mg) and tetrahydrofuran (5 mL) was added isopropylmagnesium chloride (2.0 mol / L tetrahydrofuran solution, 0.6 mL) under an ice salt bath argon atmosphere. After stirring at 0 ° C. for 1 hour, N, N-dimethylformamide (0.485 mL) was added. After stirring at room temperature for 7 hours, water and ethyl acetate were 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 ethyl acetate and hexane to give the title compound (310 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 2.39 (3H, s), 4.00 (3H, s), 5.24 (2H, s), 6.29 (1H, s), 7.10-7.20 (1H, m), 7.25- 7.50 (5H, m), 7.60-7.64 (1H, m), 10.17 (1H, s)

  5- (4-benzyloxy-2-iodo-5-methoxyphenyl) -3-methylisoxazole and N, N-dimethylformamide instead of the corresponding iodobenzene and N, N-dimethylformamide, acid anhydrides, Reference Example 9-2 to Reference Example 9-5 were synthesized in the same manner as Reference Example 9-1 using acid chloride or N-methoxy-N-methylamide. These are shown in Table 1.

  The physical property values of Reference Example 9-2 to Reference Example 9-5 are shown below.

Reference Example 9-2
¹ H-NMR (CDCl ₃ ) δ ppm: 4.03 (3H, s), 5.28 (2H, s), 7.27 (1H, s), 7.31-7.58 (7H, m), 7.69 (1H, s), 7.95 ( 1H, d, J = 8.0Hz), 8.11 (1H, d, J = 8.0Hz), 10.51 (1H, s)

Reference Example 9-3
¹ H-NMR (CDCl ₃ ) δ ppm: 2.25 (3H, s), 3.99 (3H, s), 5.24 (2H, s), 7.17 (1H, s), 7.20 (1H, s), 7.30-7.54 ( 7H, m), 7.92 (1H, d, J = 8.0Hz), 8.05 (1H, d, J = 8.0Hz)

Reference Example 9-4
¹ H-NMR (CDCl ₃ ) δ ppm: 4.04 (3H, s), 5.21 (2H, s), 7.11 (1H, s), 7.20-7.51 (11H, m), 7.67-7.71 (2H, m), 7.74 (1H, d, J = 8.0Hz), 7.82 (1H, d, J = 8.0Hz)

Reference Example 9-5
¹ H-NMR (CDCl ₃ ) δ ppm: 2.50 (3H, s), 4.03 (3H, s), 5.27 (2H, s), 7.30-7.50 (5H, m), 7.55-7.60 (1H, m), 7.65-7.70 (1H, m), 10.80 (1H, s)

Reference Example 10-1
Methyl 5-benzyloxy-4-methoxy-2-thiazol-2-ylbenzoate Methyl 5-benzyloxy-2-bromo-4-methoxybenzoate (Reference Example 12-2) (1.2 g), 2-tributyl ester A mixture of nilthiazole (1.53 g), dichlorobis (triphenylphosphine) palladium (II) (479 mg) and toluene (10 mL) was irradiated with microwaves and heated at 210 ° C. for 10 minutes. The mixture 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 (910 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 3.71 (3H, s), 3.95 (3H, s), 5.22 (2H, s), 7.10 (1H, s), 7.30-7.49 (7H, m), 7.85 ( (1H, d, J = 3.3Hz)

Reference Example 10-2
Methyl 5-benzyloxy-4-methoxy-2-oxazol-2-ylbenzoate The title compound was synthesized in the same manner as in Reference Example 10-1 using 2-tributyltin oxazole instead of 2-tributyltin thiazole.
¹ H-NMR (CDCl ₃ ) δ ppm: 3.79 (3H, s), 3.96 (3H, s), 5.21 (2H, s), 7.24 (1H, d, J = 0.8 Hz), 7.29 (1H, s) , 7.30-7.49 (6H, m), 7.71 (1H, d, J = 0.8Hz)

Reference Example 11-1
2-Benzothiazol-2-yl-5-benzyloxy-4-methoxybenzoic acid 2-Benzothiazol-2-yl-5-benzyloxy-4-methoxybenzaldehyde (Reference Example 9-2) (297 mg), phosphoric acid To a mixture of sodium dihydrogen dihydrate (494 mg), acetonitrile (7.5 mL) and water (1.5 mL), 30% aqueous hydrogen peroxide (0.358 mL) and sodium chlorite (286 mg) were sequentially added at 0 ° C. . After stirring at room temperature for 5 hours, 1 mol / L hydrochloric acid was added to the mixture. The insoluble material was collected by filtration to give the title compound (251 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 4.03 (3H, s), 5.30 (2H, s), 7.20-7.65 (8H, m), 7.85-8.00 (1H, m), 8.00-8.10 (1H, m ), 8.17 (1H, s)

  Reference Example 11-1 using the corresponding aldehyde (Reference Example 9-1, Reference Example 9-5, Reference Example 16-1) instead of 2-benzothiazol-2-yl-5-benzyloxy-4-methoxybenzaldehyde Reference Example 11-2 to Reference Example 11-4 were synthesized in the same manner as above. These are shown in Table 2.

  The physical property values of Reference Example 11-2 to Reference Example 11-4 are shown below.

Reference Example 11-2
¹ H-NMR (CDCl ₃ ) δ ppm: 2.36 (3H, s), 3.95 (3H, s), 5.22 (2H, s), 6.30 (1H, s), 7.05-7.10 (1H, m), 7.25- 7.50 (6H, m), 7.55-7.65 (1H, m)

Reference Example 11-3
¹ H-NMR (CDCl ₃ ) δ ppm: 2.53 (3H, s), 4.01 (3H, s), 5.28 (2H, s), 7.30-7.50 (6H, m), 7.95-8.05 (1H, m)
7.05-7.10 (1H, m), 7.25-7.50 (6H, m), 7.55-7.65 (1H, m)

Reference Example 11-4
¹ H-NMR (DMSO-d ₆ ) δ ppm: 3.86 (3H, s), 5.30-5.40 (2H, m), 7.00-8.50 (12H, m), 13.47 (1H, brs)

Reference Example 12-1
2-Benzothiazol-2-yl-5-benzyloxy-4-methoxybenzoate methyl 2-benzothiazol-2-yl-5-benzyloxy-4-methoxybenzoate (Reference Example 11-1) (251 mg) and To a mixture of N, N-dimethylformamide (3 mL) was added iodomethane (0.06 mL) and potassium carbonate (133 mg) at room temperature. After stirring for 1 hour, water and ethyl acetate were added to the mixture. The separated organic layer was washed successively with water and brine, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0% -30% ethyl acetate / hexane, gradient elution) to give the title compound (196 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 3.69 (3H, s), 3.96 (3H, s), 5.24 (2H, s), 7.17 (1H, s), 7.30-7.60 (8H, m), 7.85- 7.95 (1H, m), 8.00-8.15 (1H, m)

  Reference Example 12-2 to Reference Example 12-5 were prepared in the same manner as Reference Example 12-1, using the corresponding carboxylic acid instead of 2-benzothiazol-2-yl-5-benzyloxy-4-methoxybenzoic acid. Was synthesized. These are shown in Table 3.

  The physical property values of Reference Example 12-2 to Reference Example 12-5 are shown below.

Reference Example 12-2
¹ H-NMR (CDCl ₃ ) δ ppm: 3.89 (3H, s), 3.91 (3H, s), 5.13 (2H, s), 7.12 (1H, s), 7.30-7.46 (5H, m), 7.49 ( 1H, s)

Reference Example 12-3
¹ H-NMR (CDCl ₃ ) δ ppm: 3.89 (3H, s), 3.91 (3H, s), 5.15 (2H, s), 7.32-7.46 (7H, m)

Reference Example 12-4
¹ H-NMR (CDCl ₃ ) δ ppm: 2.36 (3H, s), 3.79 (3H, s), 3.94 (3H, s), 5.21 (2H, s), 6.24 (1H, s), 7.05-7.10 ( 1H, m), 7.25-7.50 (6H, m)

Reference Example 12-5
¹ H-NMR (CDCl ₃ ) δ ppm: 2.48 (3H, s), 3.81 (3H, s), 3.96 (3H, s), 5.23 (2H, s), 7.20-7.25 (1H, m), 7.30- 7.50 (6H, m)

Reference Example 13-1
Methyl 5-benzyloxy-4-methoxy-2- (5-methyloxazol-2-yl) benzoate Tris (dibenzylideneacetone) dipalladium (0) (54 mg), 1,1′-bis (diphenylphosphino) A mixture of ferrocene (66 mg) and N, N-dimethylformamide (7 mL) was stirred under an argon atmosphere for 20 minutes. To the mixture, 2- (4-benzyloxy-2-iodo-5-methoxyphenyl) -5-methyloxazole (Reference Example 4-1) (250 mg), methanol (3 mL) and triethylamine (0.248 mL) were added. After displacement under a carbon monoxide atmosphere, the mixture was stirred at 90 ° C. overnight. After cooling to room temperature, ethyl acetate and silica gel were added to the mixture. The mixture was passed through a Celite® layer. The filtrate was washed successively with 1 mol / L hydrochloric acid, water and brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0% -40% ethyl acetate / hexane, gradient elution) to give the title compound (114 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 2.36 (3H, d, J = 1.0 Hz), 3.79 (3H, s), 3.96 (3H, s), 5.20 (2H, s), 6.80-6.90 (1H, m), 7.26 (1H, s), 7.30-7.55 (6H, m)

Reference Example 14-1
Methyl 6-benzothiazol-2-yl-5-hydroxy-4-methoxybenzoate methyl 2-benzothiazol-2-yl-5-benzyloxy-4-methoxybenzoate (Reference Example 12-1) (196 mg) and To a mixture of methylene chloride (5 mL) was added titanium tetrachloride (0.107 mL) at room temperature. After stirring for 15 minutes, 1 mol / L hydrochloric acid and ethyl acetate were added to the mixture. The separated organic layer was washed successively with 1 mol / L hydrochloric acid and brine, and then concentrated under reduced pressure. The residue was triturated with hexane-ethyl acetate to give the title compound (147 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 3.73 (3H, s), 3.99 (3H, s), 5.84 (1H, s), 7.17 (1H, s), 7.35-7.55 (3H, m), 7.85- 7.95 (1H, m), 8.00-8.10 (1H, m)

  Reference Example 14-2 to Reference Example 14- were carried out in the same manner as Reference Example 14-1, using the corresponding benzyl ether instead of methyl 2-benzothiazol-2-yl-5-benzyloxy-4-methoxybenzoate. 9 was synthesized. These are shown in Table 4.

  The physical property values of Reference Example 14-2 to Reference Example 14-8 are shown below.

Reference Example 14-2
¹ H-NMR (CDCl ₃ ) δ ppm: 2.35 (3H, s), 3.81 (3H, s), 3.97 (3H, s), 5.91 (1H, s), 6.24 (1H, s), 7.05-7.10 ( 1H, m), 7.40-7.50 (1H, m)

Reference Example 14-3
¹ H-NMR (CDCl ₃ ) δ ppm: 2.35 (3H, d, J = 1.0 Hz), 3.81 (3H, s), 3.98 (3H, s), 5.83 (1H, s), 6.80-6.85 (1H, m), 7.29 (1H, s), 7.32 (1H, s)

Reference Example 14-4
¹ H-NMR (CDCl ₃ ) δ ppm: 3.73 (3H, s), 3.96 (3H, s), 7.09 (1H, s), 7.40 (1H, d, J = 3.4 Hz), 7.42 (1H, s) , 7.84 (1H, d, J = 3.4Hz)

Reference Example 14-5
¹ H-NMR (CDCl ₃ ) δ ppm: 3.81 (3H, s), 3.98 (3H, s), 7.23 (1H, d, J = 0.8 Hz), 7.29 (1H, s), 7.37 (1H, s) , 7.71 (1H, d, J = 0.8Hz)

Reference Example 14-6
¹ H-NMR (CDCl ₃ ) δ ppm: 4.06 (3H, s), 7.11 (1H, s), 7.25-7.31 (3H, m), 7.33-7.40 (2H, m), 7.41 (1H, s), 7.72-7.84 (4H, m)

Reference Example 14-7
¹ H-NMR (CDCl ₃ ) δ ppm: 2.36 (3H, s), 4.00 (3H, s), 7.18 (1H, s), 7.19 (1H, s), 7.37-7.53 (3H, m), 7.90 ( 1H, d, J = 7.9Hz), 8.04 (1H, d, J = 7.9Hz)

Reference Example 14-8
¹ H-NMR (CDCl ₃ ) δ ppm: 2.47 (3H, s), 3.83 (3H, s), 3.99 (3H, s), 6.00 (1H, s), 7.25-7.30 (1H, m), 7.40- 7.45 (1H, m)

Reference Example 15-1
Methyl 6-benzothiazol-2-yl-3-hydroxy-4-methoxy-2-nitrobenzoate Methyl 6-benzothiazol-2-yl-5-hydroxy-4-methoxybenzoate (Reference Example 14-1) 147 mg) and methylene chloride (35 mL) were added fuming nitric acid (0.031 mL) at room temperature. After stirring for 15 minutes, 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 and ethyl acetate to give the title compound (129 mg).
¹ H-NMR (DMSO-d ₆ ) δ ppm: 3.66 (3H, s), 4.05 (3H, s), 7.40-7.65 (3H, m), 8.00-8.10 (1H, m), 8.10-8.25 (1H , m), 11.00-12.00 (1H, br)

  Reference Example 15-2 to Reference Example 15-9 were prepared in the same manner as Reference Example 15-1 using the corresponding phenol instead of methyl 6-benzothiazol-2-yl-5-hydroxy-4-methoxybenzoate. Synthesized. These are shown in Table 5.

  The physical property values of Reference Example 15-2 to Reference Example 15-8 are shown below.

Reference Example 15-2
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.35 (3H, s), 3.93 (3H, s), 4.03 (3H, s), 6.30 (1H, s), 7.48 (1H, s), 10.60 ( 1H, s)

Reference Example 15-3
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.36 (3H, d, J = 1.4 Hz), 3.73 (3H, s), 4.00 (3H, s), 6.95-7.05 (1H, m), 7.54 ( 1H, s), 11.30-11.60 (1H, br)

Reference Example 15-4
¹ H-NMR (CDCl ₃ ) δ ppm: 3.91 (3H, s), 4.04 (3H, s), 7.44 (1H, d, J = 3.3 Hz), 7.53 (1H, s), 7.89 (1H, d, J = 3.3Hz), 10.50 (1H, s)

Reference Example 15-5
¹ H-NMR (CDCl ₃ ) δ ppm: 4.00 (3H, s), 4.06 (3H, s), 7.25-7.27 (1H, m), 7.73 (1H, d, J = 0.8 Hz), 7.79 (1H, s)

Reference Example 15-6
¹ H-NMR (CDCl ₃ ) δ ppm: 4.12 (3H, s), 7.30-7.50 (5H, m), 7.73 (1H, s), 7.75-7.87 (4H, m)

Reference Example 15-7
¹ H-NMR (CDCl ₃ ) δ ppm: 2.23 (3H, s), 4.06 (3H, s), 7.50-7.60 (3H, m), 8.02 (1H, d, J = 7.9 Hz), 8.22 (1H, d, J = 7.9Hz), 11.54 (1H, br)

Reference Example 15-8
¹ H-NMR (CDCl ₃ ) δ ppm: 2.46 (3H, s), 4.01 (3H, s), 4.07 (3H, s), 7.77 (1H, s), 10.75 (1H, s)

Reference Example 16-1
4-Benzyloxy-5-methoxy-2-phenylsulfanylbenzaldehyde Tris (dibenzylideneacetone) dipalladium (0) (12 mg), (oxydi-2,1-phenylene) bis (diphenylphosphine) (15 mg) and toluene (1.2 mg) mL) was stirred for 10 minutes under an argon atmosphere. 4-Benzyloxy-2-iodo-5-methoxybenzaldehyde (Reference Example 1-1) (0.1 g), thiophenol (33 mg) and N, N-diisopropylethylamine (0.093 mL) were sequentially added to the mixture. The mixture was stirred at 80 ° C. for 1 hour. After cooling to room temperature, toluene and Florisil (registered trademark) were added to the mixture. After stirring for 1 hour, the mixture was passed through a Celite® layer. The filtrate was concentrated under reduced pressure. The residue was triturated with methanol to give the title compound (50 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 3.95 (3H, s), 5.09 (2H, s), 6.86 (1H, s), 7.00-7.40 (10H, m), 7.47 (1H, s), 10.40 ( 1H, s)

Reference Example 17-1
2- (2-Benzenesulfinyl-4-benzyloxy-5-methoxyphenyl) -5-methyl- [1,3,4] oxadiazole triphenylphosphine (561 mg), carbon tetrachloride (1.05 g) and methylene chloride (8.6 mL) of the mixture was stirred at room temperature for 20 minutes. Triethylamine (0.477 mL) and 2-benzenesulfinyl-4-benzyloxy-5-methoxybenzoic acid N′-acetylhydrazide (Reference Example 5-3) (376 mg) were added and the mixture was stirred for 18 hours. Ethyl acetate and 2 mol / L hydrochloric acid were added to the mixture. The separated organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 50% -66% ethyl acetate / hexane, gradient elution) to give the title compound (400 mg).

Reference Example 18-1
2- (2-Benzenesulfonyl-4-benzyloxy-5-methoxyphenyl) -5-methyl- [1,3,4] oxadiazole 2- (2-benzenesulfinyl-4-benzyloxy-5-methoxyphenyl) ) -5-Methyl- [1,3,4] oxadiazole (Reference Example 17-1) (400 mg) and methylene chloride (9.6 mL) were mixed with m-chloroperbenzoic acid (382 mg) under water-cooling and stirring. And stirred at the same temperature for 3 hours. Ethyl acetate and a 1 mol / L sodium thiosulfate aqueous solution were added to the mixture. The separated organic layer was washed successively with 2 mol / L aqueous sodium hydroxide solution and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 50% -66% ethyl acetate / hexane, gradient elution) to give the title compound (250 mg).
¹ H-NMR (CDCl ₃ ) δ ppm: 2.58 (3H, s), 3.94 (3H, s), 5.33 (2H, s), 7.15 (1H, s), 7.30-7.70 (10H, m), 7.76 ( 1H, s)

Example 1-1
Methyl 6-benzothiazol-2-yl-3,4-dihydroxy-2-nitrobenzoate (Compound 1-1)
To a mixture of methyl 6-benzothiazol-2-yl-3-hydroxy-4-methoxy-2-nitrobenzoate (Reference Example 15-1) (128 mg) and ethyl acetate (6 mL) was added aluminum chloride (149 mg) and pyridine ( 0.3 mL) was added. After stirring under reflux for 1.5 hours, the mixture was cooled to room temperature, and 1 mol / L hydrochloric acid and ethyl acetate were added to the mixture. The separated organic layer was washed successively with 1 mol / L hydrochloric acid, water and brine, and concentrated under reduced pressure to obtain the title compound (100 mg).
¹ H-NMR (DMSO-d ₆ ) δ ppm: 3.66 (3H, s), 7.41 (1H, s), 7.45-7.60 (2H, m), 7.95-8.05 (1H, m), 8.10-8.20 (1H , m)

  Similar to Example 1-1, using the corresponding 3-nitrobenzene-1-methoxy-2-ol instead of methyl 6-benzothiazol-2-yl-3-hydroxy-4-methoxy-2-nitrobenzoate By the method, compound 1-2 to compound 1-9 were synthesized. These are shown in Table 6.

The physical property values of Compound 1-2 to Compound 1-9 are shown below.

Compound 1-2
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.27 (3H, s), 3.69 (3H, s), 6.54 (1H, s), 7.21 (1H, s), 11.31 (1H, brs)

Compound 1-3
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.30-2.40 (3H, m), 3.71 (3H, s), 6.90-7.05 (1H, m), 7.44 (1H, s)

Compound 1-4
¹ H-NMR (DMSO-d ₆ ) δ ppm: 3.62 (3H, s), 7.32 (1H, s), 7.83 (1H, d, J = 3.2 Hz), 7.89 (1H, d, J = 3.2 Hz) , 11.27 (1H, br)

Compound 1-5
¹ H-NMR (DMSO-d ₆ ) δ ppm: 3.71 (3H, s), 7.37 (1H, d, J = 0.8 Hz), 7.47 (1H, s), 8.22 (1H, d, J = 0.8 Hz) , 11.31 (1H, br)

Compound 1-6
¹ H-NMR (DMSO-d ₆ ) δ ppm: 7.25-7.43 (5H, m), 7.51 (1H, s), 7.60-7.70 (3H, m), 8.00 (1H, d, J = 7.8 Hz)

Compound 1-7
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.25 (3H, s), 7.44 (1H, s), 7.48-7.60 (2H, m), 8.00 (1H, d, J = 8.1 Hz), 8.18 ( 1H, d, J = 8.1Hz), 11.22 (1H, br)

Compound 1-8
¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.40 (3H, s), 3.73 (3H, s), 7.50 (1H, s), 11.60 (1H, brs)

Compound 1-9
¹ H-NMR (MeOH-d ₄ ) δ ppm: 2.55 (3H, s), 7.08 (1H, s), 7.30-7.80 (3H, m), 7.80-8.00 (2H, m)

Test 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 and entacapone were similarly tested. These results are shown in Table 7.

Test example 2
Measurement of uncoupling activity 1) Preparation of rat liver-derived mitochondrial fraction Rat liver-derived mitochondrial fraction was obtained according to the method of Nissinen et al. (Eur. J. Pharmacol., 1997, 340, P. 287-294). It was. That is, the liver is 4 volumes of ice-cold buffer A (0.25 mol / L sucrose, 2 mmol / L trishydroxymethylaminomethane-hydrochloric acid (pH 6.8) and 0.1 mmol / L disodium ethylenediaminetetraacetate (EDTA) ) Was homogenized. The crude mitochondrial fraction was obtained as a supernatant after centrifugation at 1000 × g for 10 minutes at 4 ° C. This fraction was precipitated by centrifugation at 8200 × g for 10 minutes at 4 ° C., dispersed again in the same amount of buffer A, and centrifuged under the same conditions. The resulting precipitate was resuspended in buffer A to 10 mg protein / mL to obtain a mitochondrial fraction.
2) Measurement of uncoupling activity Measurement of uncoupling activity was carried out by modifying Haasio et al.'S method (Eur. J. Pharmacol., 2002, volume 453, pages 21-26). Buffer B (0.22 mol / L mannitol, 0.05 mol / L sucrose, 5 mmol / L potassium hydrochloride, 5 mmol / L potassium dihydrogen phosphate, 1 mmol / L EDTA, 3 mmol / L magnesium chloride, and 0.01 mol / L 3-morpholine Adjust the pH of the linopropane sulfonic acid mixture to 7.4 with potassium hydroxide), mix 150 μL with 20 μL of 0.3 mmol / L 2,8-dimethylphenosafranine (dissolved in safranin O, buffer B) and 8 μL of mitochondrial fraction. And allowed to stand at room temperature in the dark for 20 minutes. After standing, fluorescence (excitation wavelength: 520 nm and fluorescence wavelength: 570 nm) was measured with a microplate reader to obtain the basal membrane potential. 20 μL of 0.1 mol / L sodium succinate dibasic hexahydrate (dissolved in buffer B) was added, and fluorescence was measured after 6 minutes to obtain the maximum membrane potential. Thereafter, 2 μL each of the test compound and dimethyl sulfoxide mixture was added and immediately mixed to start fluorescence measurement. The final fluorescence measurement was performed 10 minutes after the addition of the test compound. When basement membrane potential dimethylsulfoxide only and the maximum difference was set to 100%, showing the concentration which reduced 50% as EC _50. These results are shown in Table 8.

  As a result of these tests, it was suggested that the compounds of the present invention show very little hepatotoxicity compared with tolcapone or entacapone.

  Since the compound 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, when the compound of the present invention and L-dopa are used in combination, 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 (5)

Formula (I):

R ¹ and R ² are each independently a hydrogen atom, (C _1-6 alkyl) -CO— , (C _1-6 alkoxy) -C (O) — , an aralkylcarbonyl group, or —C (O) NR ¹¹ R ¹² or R ¹ and R ² together form a —C (O) — or C _1-6 alkylene group;
R ³ represents the following a) to s):
a) a halo C _1-6 alkyl group,
b) (C _1-6 alkyl) -CO—
c) (HaloC _1-6 alkyl) -C (O)-
d) a cycloalkylcarbonyl group,
e) unsubstituted or group consisting of: halogen atom, C _1-6 alkyl group, halo C _1-6 alkyl group, C _1-6 alkoxy group, cycloalkyl C _1-6 alkoxy group, hydroxyl group, (C _{1- 6-} alkoxy) -C (O)- , -C (O) NR ¹¹ R ¹² and an arylcarbonyl group in which the ring is substituted with 1 to 5 groups independently selected from a cyano group,
f) unsubstituted or group consisting of: a ring with 1 to 3 groups independently selected from a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, and a C _1-6 alkoxy group A heteroarylcarbonyl group substituted with
g) unsubstituted or group consisting of: a ring with 1 to 5 groups independently selected from a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, and a C _1-6 alkoxy group An aralkylcarbonyl group in which is substituted,
h) unsubstituted or group consisting of: a ring with 1 to 5 groups independently selected from a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, and a C _1-6 alkoxy group (AryloxyC _1-6 alkyl) -C (O) -substituted with
i) (C _1-6 alkoxy) -C (O)-
j) a cycloalkyloxycarbonyl group,
k) (C _1-6 alkoxyC _1-6 alkoxy) -C (O)-
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) ( C _1-6 alkyl) -SO _2- ,
q) unsubstituted or group consisting of: a ring of 1 to 3 groups independently selected from a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, and a C _1-6 alkoxy group An arylsulfonyl group substituted with
r) —SO ₂ NR ¹¹ R ¹² , or s) unsubstituted or independently of the group consisting of: a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, and a C _1-6 alkoxy group. A heteroaryl group wherein the ring is substituted with 1 to 3 groups selected;
R ⁴ is unsubstituted or a group consisting of:
a) a C _1-6 alkyl group,
b) a halo C _1-6 alkyl group,
c) a cycloalkyl group,
d) a heterocycloalkyl group,
e) a C _1-6 alkoxy C _1-6 alkyl group,
f) aryloxy C _1-6 alkyl group,
g) (C _1-6 alkoxy) -C (O) -C _1-6 alkyl, and h) a hydroxy C _1-6 alkyl group,
A heteroaryl group wherein the ring is substituted with 1 to 3 groups independently selected from: provided that the heteroaryl group is not [1,2,4] oxadiazol-3-yl;
R ¹¹ and R ¹² each independently represent a hydrogen atom, a C _1-6 alkyl group, a cycloalkyl group, a bridged cyclic hydrocarbon group, a phenyl group or an aralkyl group, or R ¹¹ and R ¹² are Together with the nitrogen atom to which they are attached, forms a cyclic amino group)
Or a pharmacologically acceptable salt thereof. The compound or pharmacologically acceptable salt thereof according to claim 1, wherein R ¹ and R ² are hydrogen atoms. R ³ is the following a) to c):
a) unsubstituted or group consisting of: a ring with 1 to 5 groups independently selected from a halogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, and a C _1-6 alkoxy group An arylcarbonyl group substituted with
b) (C _1-6 alkoxy) -C (O)- , or c) the group consisting of unsubstituted or the following: halogen atom, C _1-6 alkyl group, halo C _1-6 alkyl group, and C _1-6 The compound or pharmacologically acceptable salt thereof according to claim 2, which is an arylsulfonyl group in which the ring is substituted with 1 to 3 groups independently selected from an alkoxy group. The pharmaceutical composition which contains the compound as described in any one of Claims 1-3, or its salt accept | permitted pharmacologically as an active ingredient. A combination of the compound according to any one of claims 1 to 3 or a pharmacologically acceptable salt thereof and at least one selected from L-dopa and an aromatic L-amino acid decarboxylase inhibitor. The medicine which becomes.