WO2014157635A1 - Sulfamoylbenzene derivative and drug application - Google Patents

Abstract

The purpose of the present invention is to provide a drug that demonstrates a pharmaceutical effect by having high mobility to the mid-brain and converting to bumetanide in the mid-brain, which is the primary site of epilepsy. The present invention provides a sulfamoylbenzene derivative expressed by general formula (1), or a pharmacologically permissible salt thereof.

Description

Sulfamoylbenzene derivative and its pharmaceutical use

The present invention relates to a sulfamoylbenzene derivative and its pharmaceutical use.

Epilepsy is a disease or symptom that causes seizures (epileptic seizures) due to excessive excitement that occurs in nerve cells such as the cerebrum and hippocampus and abnormal neural activity that spreads the excitement (epilepsy discharge). At present, as a therapeutic agent for epilepsy, a drug having an inhibitory action on sodium channel or calcium channel or a drug having an enhancing action on γ-aminobutyric acid (GABA) receptor for controlling inhibitory neurotransmission is generally used. Yes.

Bumetanide, has been widely used as a diuretic, sodium ion - potassium ions - chloride cotransporter ^{(Na + -K + -Cl - cotransporter} ; hereinafter, NKCC) activity inhibiting NKCC1 isoform of Therefore, the possibility of having a therapeutic effect on epilepsy has been suggested (Non-patent Documents 1 and 2).

On the other hand, as one means for enhancing the utility of a compound having a certain pharmacological activity as a pharmaceutical, the formation of a drug as a prodrug is known. A prodrug is a compound in which a drug is chemically modified for the purpose of improving stability, solubility, absorbability or transferability, etc., and after administration, the active substance (drug ) And is designed to exert its pharmacological action.

For example, as a prodrug obtained by esterifying carboxylic acid with ethyl ester, enalapril as an antihypertensive agent, as a prodrug obtained by esterifying alcohol as pivalic acid ester, as dipivefrin as an agent for treating open-angle glaucoma, as a prodrug obtained by esterifying alcohol as an amino acid ester Are known as herpesvirus infection therapeutic agent herpesbaracyclovir, acetaminophen derivative (Patent Document 1) and the like as prodrugs obtained by glycosyl etherification of acetaminophen.

Patent Document 2 discloses prodrugs in which bumetanide is esterified or amidated, and these prodrugs are suggested to have an antiepileptic effect when administered to rats.

US Patent Application Publication No. 2012/0022012 US Patent Application Publication No. 2012/0004225

Koyama et al., Nature Medicine, 2012, Vol. 18, p. 1271-1278 Eftekhari et al., Epilepsia, 2013, 54, e9-e12 Loscher et al., Neuropharmacology, 2012, p. 1-13, printing, online version released on June 13, 2012

However, currently used epilepsy treatment agents are commonly associated with central side effects such as sleepiness, dizziness, lightheadedness, headache, malaise, epilepsy hate, ataxia, speech disturbance or vomiting and are not necessarily At present, it is impossible to administer doses that show epileptic action.

In addition, bumetanide, which has been suggested to have pharmacological activity against epilepsy, has a short plasma half-life of about 120 minutes and is known to hardly migrate into the brain where epilepsy develops. Therefore, it was necessary to administer a dose higher than the dose that can be safely used as a diuretic or to administer it frequently (Non-patent Document 3).

In addition, prodrugs esterified or amidated with bumetanide have been suggested to be effective in humans based on rat experiments. However, the persistence of brain concentrations of bumetanide when these prodrugs are administered Was low to exert a sufficient antiepileptic effect.

Therefore, an object of the present invention is to provide a medicament that exhibits high pharmacological action by being converted into bumetanide in the brain, which is the site of epilepsy, and has high transferability into the brain.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a novel sulfamoylbenzene derivative or a pharmaceutically acceptable salt thereof has a high ability to migrate into the brain and has a pharmacological activity to bumetanide. It was found that the concentration of bumetanide in the brain and the converted concentration of bumetanide persist, and the present invention was completed.

［式中、Ｒ^１は、水素原子、あるいは、アミノ酸の部分構造からなる下記Ａ群から選択される基、又は、６位の水酸基の水素原子がアセチル基、ベンゾイル基若しくはピバロイル基で置換されていてもよい糖の部分構造からなる下記Ｂ群から選択される基、を表し、Ｘは、酸素原子又はＮＨを表し、Ｒ^２は、Ｘが酸素原子である場合に、水素原子、エチル基、ブチル基、ヘキシル基、ベンジル基、シクロヘキシルカルボニルオキシメチル基、イソブチリルオキシメチル基若しくはピバロイルオキシメチル基又はアミノ酸の部分構造からなる下記Ｃ群から選択される基を表し、ＸがＮＨである場合に、水酸基の水素原子がメチル基で置換されていてもよい糖の部分構造からなる下記Ｄ群から選択される基を表すが、Ｒ^１が水素原子である場合に水素原子又はエチル基を表すことはない。
Ａ群：

（＊は、Ｒ^１が結合する窒素原子との結合位置を表す。）
Ｂ群：

（＊は、Ｒ^１が結合する窒素原子との結合位置を表す。）
Ｃ群：

（＊は、Ｒ^２が結合する酸素原子との結合位置を表す。）
Ｄ群：

（＊は、Ｒ^２が結合する窒素原子との結合位置を表す。］ That is, the present invention provides a sulfamoylbenzene derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

[Wherein R ¹ is a hydrogen atom or a group selected from the following group A consisting of a partial structure of an amino acid, or a hydrogen atom of the hydroxyl group at the 6-position is substituted with an acetyl group, a benzoyl group or a pivaloyl group. Represents a group selected from the following group B consisting of a partial structure of sugar, X represents an oxygen atom or NH, and R ² represents a hydrogen atom, an ethyl group, when X is an oxygen atom, A group selected from the following group C consisting of a butyl group, a hexyl group, a benzyl group, a cyclohexylcarbonyloxymethyl group, an isobutyryloxymethyl group, a pivaloyloxymethyl group or a partial structure of an amino acid, and X is NH in some cases, represents a group wherein a hydrogen atom of a hydroxyl group is selected from the following group D consisting of partial structures of good sugar may be substituted with a methyl group, R ¹ is a hydrogen atom It does not represent a hydrogen atom or an ethyl group.
Group A:

(* Represents the bonding position with the nitrogen atom to which R ¹ is bonded.)
Group B:

(* Represents the bonding position with the nitrogen atom to which R ¹ is bonded.)
Group C:

(* Represents the bonding position with the oxygen atom to which R ² is bonded.)
Group D:

(* Represents the bonding position with the nitrogen atom to which R ² is bonded.]

であるか、Ｒ^１が、

であり、Ｘが、酸素原子であり、かつ、Ｒ^２が、水素原子であるか、又は、Ｒ^１が、

であり、Ｘが、酸素原子であり、かつ、Ｒ^２が、エチル基であることが好ましい。 In the above sulfamoylbenzene derivative, R ¹ is a hydrogen atom, X is an oxygen atom, and R ² is

Or R ¹ is

And X is an oxygen atom and R ² is a hydrogen atom or R ¹ is

X is an oxygen atom, and R ² is preferably an ethyl group.

By adding these limitations, bumetanide transferability in the brain and sustainability in the brain compared to when bumetanide itself is administered are further improved.

The present invention also provides a medicament comprising as an active ingredient a sulfamoylbenzene derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof. This medicament is preferably a therapeutic or prophylactic agent for epilepsy.

The sulfamoylbenzene derivative of the present invention or a pharmaceutically acceptable salt thereof is converted to bumetanide having high pharmacological activity in the brain, and further, the brain concentration of the converted bumetanide is further converted. Can be used as a prodrug of bumetanide, particularly as a therapeutic or prophylactic agent for epilepsy.

It is a figure which shows the plasma concentration and brain concentration of bumetanide when bumetanide is orally administered to rats (20 μmol / kg). It is a figure which shows the plasma concentration and brain concentration of the compound of Example 1 and the converted bumetanide when the compound of Example 1 is orally administered to rats (20 μmol / kg). It is a figure which shows the plasma concentration and brain concentration of the compound of Example 2 and the converted bumetanide when the compound of Example 2 is orally administered to rats (20 μmol / kg). It is a figure which shows the plasma concentration and brain concentration of the compound of Example 3 and the converted bumetanide when the compound of Example 3 is orally administered to rats (20 μmol / kg). It is a figure which shows the plasma concentration and brain concentration of the compound of Example 4 and the converted bumetanide when the compound of Example 4 is orally administered to rats (20 μmol / kg). It is a figure which shows the plasma concentration and brain concentration of the compound of Example 5 and the converted bumetanide when the compound of Example 5 is orally administered to rats (20 μmol / kg). It is a figure which shows the plasma concentration and brain concentration of the compound of Example 6 and the converted bumetanide when the compound of Example 6 is orally administered to rats (20 μmol / kg). It is a figure which shows the plasma concentration and brain concentration of the compound of Example 7 and the converted bumetanide when the compound of Example 7 is orally administered to rats (20 μmol / kg). It is a figure which shows the plasma concentration and brain concentration of the compound of Example 8 and the converted bumetanide when the compound of Example 8 is orally administered to rats (20 μmol / kg). It is a figure which shows the plasma concentration and brain concentration of the compound of Example 9 and the converted bumetanide when the compound of Example 9 is orally administered to rats (20 μmol / kg). It is a figure which shows the plasma concentration and brain concentration of the compound of Example 10 and the converted bumetanide when the compound of Example 10 is orally administered to rats (20 μmol / kg). It is a figure which shows the plasma concentration and brain concentration of the compound of Example 11 and the converted bumetanide when the compound of Example 11 is orally administered to rats (20 μmol / kg). It is a figure which shows the plasma concentration and brain concentration of the compound of Example 12 and the converted bumetanide when the compound of Example 12 is orally administered to rats (20 μmol / kg). It is a figure which shows the plasma concentration and brain concentration of the compound of Example 13 and the converted bumetanide when the compound of Example 13 is orally administered to rats (20 μmol / kg). It is a figure which shows the plasma concentration and the brain concentration of the compound of the comparative example 1 and the converted bumetanide when the compound of the comparative example 1 is orally administered (20 micromol / kg) to a rat. It is a figure which shows the plasma concentration and brain concentration of the compound of the comparative example 2 and the converted bumetanide when the compound of the comparative example 2 is orally administered to a rat (20 micromol / kg). It is a figure which shows the plasma concentration and brain concentration of the compound of the comparative example 3 and the converted bumetanide when the compound of the comparative example 3 is orally administered to a rat (20 micromol / kg). It is a figure which shows the plasma concentration and brain concentration of the compound of the comparative example 4 and the converted bumetanide when the compound of the comparative example 4 is orally administered to a rat (20 micromol / kg). It is a figure which shows the plasma concentration and cerebrospinal fluid concentration of bumetanide when bumetanide is orally administered to cynomolgus monkeys (3 mg / kg). It is a figure which shows the plasma concentration and cerebrospinal fluid concentration of the compound of Example 3 and the converted bumetanide when the compound of Example 3 was orally administered (3 mg / kg) to cynomolgus monkeys. It is a figure which shows the plasma concentration and cerebrospinal fluid concentration of the compound of Example 14 and converted bumetanide when the compound of Example 14 is orally administered (3 mg / kg) to cynomolgus monkeys.

［式中、Ｒ^１は、水素原子、あるいは、アミノ酸の部分構造からなる下記Ａ群から選択される基、又は、６位の水酸基の水素原子がアセチル基、ベンゾイル基若しくはピバロイル基で置換されていてもよい糖の部分構造からなる下記Ｂ群から選択される基、を表し、Ｘは、酸素原子又はＮＨを表し、Ｒ^２は、Ｘが酸素原子である場合に、水素原子、エチル基、ブチル基、ヘキシル基、ベンジル基、シクロヘキシルカルボニルオキシメチル基、イソブチリルオキシメチル基若しくはピバロイルオキシメチル基又はアミノ酸の部分構造からなる下記Ｃ群から選択される基を表し、ＸがＮＨである場合に、水酸基の水素原子がメチル基で置換されていてもよい糖の部分構造からなる下記Ｄ群から選択される基を表すが、Ｒ^１が水素原子である場合に水素原子又はエチル基を表すことはない。
Ａ群：

（＊は、Ｒ^１が結合する窒素原子との結合位置を表す。）
Ｂ群：

（＊は、Ｒ^１が結合する窒素原子との結合位置を表す。）
Ｃ群：

（＊は、Ｒ^２が結合する酸素原子との結合位置を表す。）
Ｄ群：

（＊は、Ｒ^２が結合する窒素原子との結合位置を表す。）］ The sulfamoylbenzene derivative of the present invention is characterized by being represented by the following general formula (I).

[Wherein R ¹ is a hydrogen atom or a group selected from the following group A consisting of a partial structure of an amino acid, or a hydrogen atom of the hydroxyl group at the 6-position is substituted with an acetyl group, a benzoyl group or a pivaloyl group. Represents a group selected from the following group B consisting of a partial structure of sugar, X represents an oxygen atom or NH, and R ² represents a hydrogen atom, an ethyl group, when X is an oxygen atom, A group selected from the following group C consisting of a butyl group, a hexyl group, a benzyl group, a cyclohexylcarbonyloxymethyl group, an isobutyryloxymethyl group, a pivaloyloxymethyl group or a partial structure of an amino acid, and X is NH in some cases, represents a group wherein a hydrogen atom of a hydroxyl group is selected from the following group D consisting of partial structures of good sugar may be substituted with a methyl group, R ¹ is a hydrogen atom It does not represent a hydrogen atom or an ethyl group.
Group A:

(* Represents the bonding position with the nitrogen atom to which R ¹ is bonded.)
Group B:

(* Represents the bonding position with the nitrogen atom to which R ¹ is bonded.)
Group C:

(* Represents the bonding position with the oxygen atom to which R ² is bonded.)
Group D:

(* Represents the bonding position with the nitrogen atom to which R ² is bonded.)]

The following terms used in this specification are as defined below unless otherwise specified.

“Amino acid” means a compound having both an amino group and a carboxyl group in the same molecule, and examples thereof include α-amino acids such as glycine, valine, threonine or serine. When the molecule has an asymmetric carbon, each optical isomer and a mixture thereof are also included in the “amino acid”.

から選択される一の基が挙げられる。 The “group consisting of a partial structure of an amino acid” means a free radical obtained by removing a hydrogen atom or a hydroxyl group from the molecule of the above “amino acid”.

One group selected from is mentioned.

“Sugar” means a monosaccharide having a chain structure or a cyclic structure, and examples thereof include monosaccharides such as glucopyranose, mannopyranose and galactopyranose, and deoxysugars such as 2-deoxyglucopyranose. Monosaccharides include α and β isomers based on tautomerization of molecules, and D and L isomers based on asymmetric carbon in the molecule. , Each isomer and mixtures thereof.

から選択される一の基が挙げられる。 The “group consisting of a sugar partial structure” means a free radical obtained by removing a hydrogen atom or a hydroxyl group from the above-mentioned “sugar” molecule.

One group selected from is mentioned.

から選択される一の基が挙げられる。 The “group consisting of a sugar partial structure in which the hydrogen atom of the hydroxyl group may be substituted with a methyl group” means that the hydrogen atom of the hydroxyl group of the “group consisting of a sugar partial structure” is substituted with a methyl group Means a good group, for example

One group selected from is mentioned.

から選択される一の基が挙げられる。 The “group consisting of a sugar partial structure in which the hydrogen atom of the hydroxyl group at the 6-position may be substituted with an acetyl group, a benzoyl group or a pivaloyl group” means the hydroxyl group at the 6-position of the above “group consisting of a sugar partial structure” Means a group in which the hydrogen atom may be substituted with an acetyl group, a benzoyl group or a pivaloyl group.

One group selected from is mentioned.

であるか、
　Ｒ^１が、

であり、Ｘが、酸素原子であり、かつ、Ｒ^２が、水素原子であるか、又は、
　Ｒ^１が、

であり、Ｘが、酸素原子であり、かつ、Ｒ^２が、エチル基であることが好ましい。 In the above sulfamoylbenzene derivative, R ¹ is a hydrogen atom, X is an oxygen atom, and R ² is

Or
R ¹ is

Or X is an oxygen atom and R ² is a hydrogen atom, or
R ¹ is

X is an oxygen atom, and R ² is preferably an ethyl group.

“Prodrug” refers to a drug precursor and a substance that are converted into a compound having pharmacological activity (ie, a drug) by being converted enzymatically or non-enzymatically after reaching the living body or the site of action. In a broad sense, it also includes substances whose physical properties change in vivo to change stability, absorbability, distribution, or the like.

The “double prodrug” is a prodrug having two sites that undergo enzymatic or non-enzymatic conversion after reaching the living body or site of action.

“Triple prodrug” refers to a prodrug having three sites that undergo enzymatic or non-enzymatic conversion after reaching the living body or site of action.

The sulfamoylbenzene derivative represented by the general formula (I) (hereinafter referred to as sulfamoylbenzene derivative (I)) may contain an asymmetric carbon atom depending on the type of the substituent. Can exist. The present invention also includes each optical isomer and a mixture thereof.

The sulfamoylbenzene derivative (I) may form a salt and is included in the present invention as long as the salt is pharmaceutically acceptable. Examples of the pharmaceutically acceptable salt include inorganic base salts such as sodium salt, potassium salt, calcium salt or magnesium salt, organic base salts such as tromethamine [tris (hydroxylmethyl) methylamine] salt, ethanolamine salt, Organic amine salts such as trimethylamine salt, triethylamine salt, tert-butylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, dicyclohexylamine salt or N, N-dibenzylethylenediamine salt, arginine salt, lysine salt or ornithine salt, etc. Basic amine salt or ammonia salt, or inorganic acid salt such as hydrochloride, sulfate, hydrobromide, hydroiodide or phosphate, acetate, lactate, citrate, Oxalate, citrate, glutarate, malic acid , Organic carboxylates such as tartrate, fumarate, mandelate, maleate, benzoate or phthalic acid, or methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfone And organic sulfonates such as acid salts and camphorsulfonate.

The sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof includes hydrates and solvates thereof and crystal polymorphs.

Preferred specific examples of the sulfamoylbenzene derivative (I) are shown in Table 1-1 and Table 1-2.

The sulfamoylbenzene derivative (I) can be produced by, for example, the following method or a method analogous thereto. The starting materials and reagents used in this production are generally available or can be produced by known methods.

The sulfamoylbenzene derivative (I) and intermediates and starting materials used for the production thereof can be isolated and purified by known means. Known means for isolation and purification include, for example, solvent extraction, recrystallization or chromatography.

When the sulfamoylbenzene derivative (I) contains an optical isomer or a stereoisomer, each isomer can be obtained as a single compound by a known method. Known methods include, for example, crystallization, enzyme resolution, or chiral chromatography.

Specific examples of the method for producing the sulfamoylbenzene derivative (I) include the methods described in the following production methods 1 to 8.

［式中、Ｒ^３－ＯＨは、アミノ基がｔｅｒｔ－ブトキシカルボニル基で保護されたアミノ酸誘導体を表し、Ｒ^４は、アミノ酸の部分構造からなる下記Ｅ群から選択される一の基を表す。
Ｅ群：

（＊は、Ｒ^４が結合する窒素原子との結合位置を表す。）］ [Production method 1]
In the sulfamoylbenzene derivative (I), R ¹ is one group selected from the following group E consisting of an amino acid partial structure, X is an oxygen atom, and R ² is a hydrogen atom. For example, as shown in Scheme 1, the sulfamoylbenzene derivative (Ia) is prepared by reacting the carboxyl group of bumetanide with paramethoxybenzyl chloride in the presence of a base (step 1-1), followed by a condensing agent. In the presence of an activating agent, the ester derivative (II) obtained in Step 1-1 is condensed with an amino acid derivative (R ³ —OH) in which the amino group is protected with a tert-butoxycarbonyl group (Step 1- 2) Subsequently, it can be produced by deprotection reaction (step 1-3) of the ester derivative (III) obtained in step 1-2 in the presence of an acid.

[Wherein R ³ —OH represents an amino acid derivative in which an amino group is protected with a tert-butoxycarbonyl group, and R ⁴ represents one group selected from the following group E consisting of a partial structure of an amino acid.
Group E:

(* Represents the bonding position with the nitrogen atom to which R ⁴ is bonded.)]

[Step 1-1]
Bumetanide, which is a starting material for the protection reaction, can be obtained by purchasing a commercially available product, or producing it by a known method (for example, US Pat. No. 3,806,534) or a method analogous thereto.

Examples of the base used for the protection reaction include basic inorganic salts such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, and triethylamine. Examples include tertiary organic amines such as butylamine, N-methylpiperidine, N-methylpiperidone or N-methylmorpholine, or metal amides such as lithium diisopropylamide or lithium hexamethyldisilazide, but triethylamine or N, N-diisopropylethylamine is preferred.

The amount of the base used for the protection reaction is preferably 1 to 6 moles, more preferably 1 to 3 moles per mole of bumetanide.

The amount of paramethoxybenzyl chloride used for the protection reaction is preferably 1 to 6 mol per 1 mol of bumetanide.

The reaction solvent used for the protection reaction is usually appropriately selected from solvents that do not inhibit the reaction. For example, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbons such as toluene or xylene, diethyl ether, Examples include ether solvents such as tetrahydrofuran or dioxane, N, N-dimethylformamide, and acetonitrile, and halogen solvents are preferable.

The concentration of bumetanide used for the protective reaction at the start of the reaction is preferably 0.01 to 10 mol / L, more preferably 0.05 to 1 mol / L.

The reaction temperature of the protective reaction is preferably −20 ° C. to 120 ° C., more preferably 15 to 80 ° C.

The reaction time for the protection reaction is appropriately selected according to the reaction temperature and other conditions, but is preferably 30 minutes to 24 hours.

[Step 1-2]
Examples of the condensing agent used in the condensation reaction include carbodiimide-based reagents such as N, N′-dicyclohexylcarbodiimide (hereinafter referred to as DCC) or 1-ethyl-3- (3-dimethylaminopropylcarbodiimide (hereinafter referred to as EDCI), N , N′-carbodiimidazole, (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate or (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate and other phosphonium salt reagents, Examples include 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride or diphenylphosphoryl azide, with DCC being preferred.

The amount of the condensing agent used in the condensation reaction is preferably 1 to 10 mol, more preferably 1 to 3 mol, relative to 1 mol of the ester derivative (II).

As the activator used in the condensation reaction, 4-amino-N, N-dimethyl-pyridine (hereinafter referred to as DMAP) is preferable.

The amount of the activator used in the condensation reaction is preferably 0.001 to 3 mol, more preferably 1 to 3 mol, relative to 1 mol of the ester derivative (II).

R ³ —OH used for the condensation reaction can be obtained by purchasing a commercially available product or by producing it by a known method or a method analogous thereto.

The amount of R ³ —OH used for the condensation reaction is preferably 1 to 10 moles, more preferably 1 to 3 moles per mole of ester derivative (II).

The reaction solvent used for the condensation reaction is appropriately selected from solvents that do not normally inhibit the reaction. For example, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbons such as toluene or xylene, diethyl ether, Examples include ether solvents such as tetrahydrofuran or dioxane, N, N-dimethylformamide, and acetonitrile, with dichloromethane being preferred.

The concentration of the ester derivative (II) used for the condensation reaction at the start of the reaction is preferably 0.01 to 10 mol / L, and more preferably 0.05 to 1 mol / L.

The reaction temperature of the condensation reaction is preferably −20 ° C. to 120 ° C., more preferably 15 to 80 ° C.

The reaction time of the condensation reaction is appropriately selected according to the reaction temperature and other conditions, but is preferably 30 minutes to 24 hours, more preferably 1 to 12 hours.

[Step 1-3]
Examples of the acid used for the deprotection reaction include organic acids such as formic acid, trichloroacetic acid or trifluoroacetic acid, or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride or hydrogen bromide. Trifluoroacetic acid is preferred.

The amount of the acid used for the deprotection reaction is preferably 1 to 300 mol, more preferably 1 to 10 mol, relative to 1 mol of the ester derivative (III).

Examples of the additive used for the deprotection reaction include thiophenol and anisole, and anisole is preferable.

The amount of the additive used for the deprotection reaction is preferably 0.001 to 20 mol, more preferably 0.01 to 5 mol, relative to 1 mol of the ester derivative (III).

The reaction solvent used for the deprotection reaction is appropriately selected from solvents that do not normally inhibit the reaction. For example, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, ether solvents such as diethyl ether, tetrahydrofuran or dioxane, N , N-dimethylformamide or acetonitrile, with dichloromethane being preferred. Further, the acid itself may be used as a reaction solvent.

The concentration of the ester derivative (III) used for the deprotection reaction at the start of the reaction is preferably 0.01 to 100 mol / L.

The reaction temperature of the deprotection reaction is preferably −20 ° C. to 100 ° C., more preferably 15 to 60 ° C.

The reaction time for the deprotection reaction is appropriately selected according to the reaction temperature and other conditions, but preferably 30 minutes to 24 hours.

［式中、Ｒ^５－ＯＡｃは、全ての水酸基がアセチル基で保護された糖誘導体を表し、Ｒ^６は、糖の部分構造からなる下記Ｆ群から選択される一の基を表す。
Ｆ群：

（＊は、Ｒ^６が結合する窒素原子との結合位置を表す。）］ [Production method 2]
In the sulfamoylbenzene derivative (I), R ¹ is one group selected from the following group F consisting of a sugar partial structure, X is an oxygen atom, and R ² is a hydrogen atom. For example, as shown in Scheme 2, the sulfamoylbenzene derivative (Ib) is protected in the presence of a base in the presence of a base using benzyl chloride to protect the carboxyl group of bumetanide (step 2-1), followed by the presence of a Lewis acid. Glycosylation of the ester derivative (IV) obtained in Step 2-1 with a sugar derivative (R ⁵ -OAc) in which all hydroxyl groups are protected with acetyl groups (Step 2-2), followed by hydrogenation A hydrogenolysis reaction of the ester derivative (V) obtained in step 2-2 in an atmosphere and in the presence of a metal catalyst, and a solvolysis reaction of a compound obtained in the hydrogenolysis reaction in the presence of a base. Deprotection reaction 2-3) by can be produced.

[Wherein R ⁵ -OAc represents a sugar derivative in which all hydroxyl groups are protected with an acetyl group, and R ⁶ represents one group selected from the following group F consisting of a sugar partial structure.
Group F:

(* Represents the bonding position with the nitrogen atom to which R ⁶ is bonded.)]

[Step 2-1]
Examples of the base used for the protection reaction include basic inorganic salts such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, and triethylamine. Examples include tertiary organic amines such as butylamine, N-methylpiperidine, N-methylpiperidone or N-methylmorpholine, or metal amides such as lithium diisopropylamide or lithium hexamethyldisilazide. N-diisopropylethylamine is preferred.

The amount of the base used for the protection reaction is preferably 1 to 6 moles, more preferably 1 to 3 moles per mole of bumetanide.

The amount of benzyl chloride used for the protection reaction is preferably 1 to 6 mol per 1 mol of bumetanide.

The reaction solvent used for the protection reaction is usually appropriately selected from solvents that do not inhibit the reaction. For example, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbons such as toluene or xylene, diethyl ether, Examples include ether solvents such as tetrahydrofuran or dioxane, N, N-dimethylformamide, and acetonitrile, with N, N-dimethylformamide being preferred.

The concentration of bumetanide used for the protective reaction at the start of the reaction is preferably 0.01 to 10 mol / L, more preferably 0.05 to 1 mol / L.

The reaction temperature of the protective reaction is preferably −20 ° C. to 120 ° C., more preferably 15 to 80 ° C.

The reaction time for the protection reaction is appropriately selected according to the reaction temperature and other conditions, but is preferably 30 minutes to 24 hours.

[Step 2-2]

Examples of Lewis acids used in the glycosylation reaction include boron trifluoride ether complexes, halides such as tin (IV) tetrachloride or titanium (IV) tetrachloride, or ytterbium (III) trifluoromethanesulfonate, trifluoromethane. Examples of the organic sulfonate include yttrium (III) sulfonate and trimethylsilyl trifluoromethanesulfonate, and boron trifluoride ether complex is preferable.

The amount of Lewis acid used in the glycosylation reaction is preferably 0.01 to 30 mol, more preferably 0.05 to 10 mol, per 1 mol of the ester derivative (IV).

R ⁵ -OAc used in the glycosylation reaction can be obtained by purchasing a commercially available product, or by producing it by a known method or a method analogous thereto.

The amount of R ⁵ —OAc used in the glycosylation reaction is preferably 1 to 10 mol, more preferably 1 to 2 mol, relative to 1 mol of the ester derivative (IV).

The reaction solvent used for the glycosylation reaction is appropriately selected from solvents that do not normally inhibit the reaction. For example, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbons such as toluene or xylene, diethyl ether, and the like. , Ether solvents such as tetrahydrofuran or dioxane, N, N-dimethylformamide, and acetonitrile are preferable, but acetonitrile is preferable.

The concentration of the ester derivative (IV) used for the glycosylation reaction at the start of the reaction is preferably 0.01 to 5 mol / L, more preferably 0.05 to 2 mol / L.

The reaction temperature of the glycosylation reaction is preferably −78 ° C. to 170 ° C., more preferably 15 to 120 ° C.

The reaction time of the glycosylation reaction is appropriately selected according to the reaction temperature and other conditions, but preferably 30 minutes to 24 hours.

[Step 2-3]
The hydrogen pressure in the hydrocracking reaction of the deprotection reaction is preferably 1 to 100 atm, and more preferably 1 to 5 atm.

Examples of the metal catalyst used in the hydrogenolysis reaction of the deprotection reaction include platinum oxide, palladium hydroxide, and palladium-carbon, and palladium hydroxide or palladium-carbon is preferable.

The amount of the metal catalyst used in the hydrocracking reaction of the deprotection reaction is preferably 1 to 100% by weight, more preferably 5 to 20% by weight, based on the ester derivative (V).

The reaction solvent used for the hydrogenolysis reaction of the deprotection reaction is appropriately selected from solvents that do not normally inhibit the reaction. For example, an alcohol solvent such as methanol or ethanol, or an alcohol solvent and water, N, N-dimethyl Although a mixed solvent with formamide or acetonitrile is mentioned, methanol is preferable.

The concentration of the ester derivative (V) used for the hydrogenolysis reaction of the deprotection reaction is preferably 0.001 to 10 mol / L, more preferably 0.01 to 1 mol / L.

The reaction temperature of the hydrocracking reaction of the deprotection reaction is preferably 5 to 80 ° C, more preferably 15 to 40 ° C.

The reaction time for the hydrocracking reaction of the deprotection reaction is appropriately selected according to conditions such as the reaction temperature, but is preferably 1 to 24 hours.

Examples of the base used for the solvolysis reaction of the deprotection reaction include basic inorganic salts such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate, and potassium carbonate is preferable.

The amount of the base used for the solvolysis reaction of the deprotection reaction is preferably 0.1 to 30 mol, more preferably 1 to 10 mol, relative to 1 mol of the ester derivative (V).

The reaction solvent used for the solvolysis reaction of the deprotection reaction is appropriately selected from solvents that do not normally inhibit the reaction. For example, an alcohol solvent such as methanol or ethanol, or an alcohol solvent and water, N, N-dimethyl Although a mixed solvent with formamide or acetonitrile is mentioned, methanol is preferable.

The reaction temperature for the solvolysis reaction of the deprotection reaction is preferably −20 ° C. to 100 ° C., more preferably 15 to 40 ° C.

The reaction time for the solvolysis reaction of the deprotection reaction is appropriately selected according to the conditions such as the reaction temperature, but is preferably 30 minutes to 24 hours.

The hydrogenolysis reaction and solvolysis reaction of the deprotection reaction may be carried out continuously by a one-pot reaction. For example, after removing the compound obtained by the hydrogenolysis reaction, it is used for the solvolysis reaction. You may do it by the method.

［式中、Ｒ^７－ＯＨは、アミノ基がｔｅｒｔ－ブトキシカルボニル基で保護され、カルボキシル基がパラメトキシベンジル基又はｔｅｒｔ－ブチル基で保護されたアミノ酸誘導体を表し、Ｒ^８は、アミノ酸の部分構造からなる上記Ｃ群から選択される一の基を表す。］ [Production method 3]
Among the sulfamoylbenzene derivatives (I), R ¹ is a hydrogen atom, X is an oxygen atom, and R ² is one group selected from the group C consisting of a partial structure of an amino acid. In the presence of a condensing agent and an activator, for example, as shown in Scheme 3, the sulfamoylbenzene derivative (Ic) is protected with a tert-butoxycarbonyl group in the presence of bumetanide, and the carboxyl group is a paramethoxybenzyl group. Or a condensation reaction with an amino acid derivative (R ⁷ —OH) protected with a tert-butyl group (step 3-1), followed by the ester derivative obtained in step 3-1 in a hydrogen atmosphere and in the presence of a metal catalyst It can be produced by a deprotection reaction (step 3-2) comprising a hydrogenolysis reaction of (VI) and a solvolysis reaction of the compound obtained by the hydrogenolysis reaction in the presence of an acid.

[Wherein R ⁷ -OH represents an amino acid derivative in which an amino group is protected with a tert-butoxycarbonyl group and a carboxyl group is protected with a paramethoxybenzyl group or a tert-butyl group, and R ⁸ represents an amino acid moiety. It represents one group selected from the group C consisting of the structure. ]

[Step 3-1]
Examples of the condensing agent used in the condensation reaction include carbodiimide reagents such as DCC or EDCI, N, N′-carbodiimidazole, (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate, or (benzotriazole- 1-yloxy) tris (dimethylamino) phosphonium phosphonium salt reagents such as hexafluorophosphate, 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride Or, diphenylphosphoryl azide is exemplified, and EDCI is preferable.

The amount of the condensing agent used in the condensation reaction is preferably 1 to 10 moles per mole of bumetanide.

The activator used in the condensation reaction is preferably DMAP or 1-hydroxybenzotriazole.

The amount of activator used in the condensation reaction is preferably 0.001 to 3 moles per mole of bumetanide.

R ⁷ —OH used for the condensation reaction can be obtained by purchasing a commercially available product or by producing it by a known method or a method analogous thereto.

The amount of R ⁷ —OH used in the condensation reaction is preferably 1 to 10 moles per mole of bumetanide.

The reaction solvent used for the condensation reaction is appropriately selected from solvents that do not normally inhibit the reaction. For example, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbons such as toluene or xylene, diethyl ether, Examples include ether solvents such as tetrahydrofuran or dioxane, N, N-dimethylformamide, and acetonitrile, with N, N-dimethylformamide being preferred.

The concentration of bumetanide used for the condensation reaction at the start of the reaction is preferably 0.01 to 10 mol / L, and more preferably 0.05 to 1 mol / L.

The reaction temperature of the condensation reaction is preferably −20 ° C. to 120 ° C., more preferably 15 to 60 ° C.

The reaction time of the condensation reaction is appropriately selected according to the reaction temperature and other conditions, but is preferably 30 minutes to 24 hours, more preferably 1 to 12 hours.

[Step 3-2]
The hydrogen pressure in the hydrocracking reaction of the deprotection reaction is preferably 1 to 100 atm, and more preferably 1 to 5 atm.

Examples of the metal catalyst used in the hydrogenolysis reaction of the deprotection reaction include platinum oxide, palladium hydroxide, and palladium-carbon, and palladium hydroxide or palladium-carbon is preferable.

The amount of the metal catalyst used in the hydrogenolysis reaction of the deprotection reaction is preferably 1 to 100% by weight, more preferably 5 to 20% by weight, based on the ester derivative (VI).

The reaction solvent used for the hydrogenolysis reaction of the deprotection reaction is appropriately selected from solvents that do not normally inhibit the reaction. For example, an alcohol solvent such as methanol or ethanol, or an alcohol solvent and water, N, N-dimethyl Although a mixed solvent with formamide or acetonitrile is mentioned, methanol is preferable.

The concentration of the ester derivative (VI) used for the hydrogenolysis reaction of the deprotection reaction is preferably 0.001 to 10 mol / L, more preferably 0.01 to 1 mol / L.

The reaction temperature of the hydrocracking reaction of the deprotection reaction is preferably 5 to 80 ° C, more preferably 15 to 40 ° C.

The reaction time for the hydrocracking reaction of the deprotection reaction is appropriately selected according to conditions such as the reaction temperature, but is preferably 1 to 24 hours.

Examples of the acid used for the solvolysis reaction of the deprotection reaction include organic acids such as formic acid, acetic acid, trichloroacetic acid or trifluoroacetic acid, or hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride or hydrogen bromide. Inorganic acids are mentioned, but trifluoroacetic acid is preferred.

The amount of acid used for the solvolysis reaction of the deprotection reaction is preferably 0.1 to 30 mol, more preferably 1 to 10 mol, relative to 1 mol of the ester derivative (VI).

The reaction solvent used for the solvolysis reaction of the deprotection reaction is usually appropriately selected from solvents that do not inhibit the reaction. Examples include ether solvents, N, N-dimethylformamide, and acetonitrile, with dichloromethane being preferred. Further, the acid itself may be used as a reaction solvent.

The reaction temperature for the solvolysis reaction of the deprotection reaction is preferably −20 ° C. to 100 ° C., more preferably 15 to 40 ° C.

The reaction time of the solvolysis reaction of the deprotection reaction is appropriately selected according to the conditions such as the reaction temperature, but is preferably 1 to 24 hours.

The hydrogenolysis reaction and solvolysis reaction of the deprotection reaction may be carried out continuously by a one-pot reaction, or the compound obtained by the hydrogenolysis reaction is once taken out and then used in the solvolysis reaction. You can go.

［式中、Ｒ^９－ＮＨ_２は、水酸基の１つがアミノ基で置換された糖誘導体を表し、Ｒ^９は、水酸基の水素原子がメチル基で置換されていてもよい糖の部分構造からなる上記Ｄ群から選択される一の基を表す。］ [Production Method 4]
Among the sulfamoylbenzene derivatives (I), R ¹ is a hydrogen atom, X is NH, and R ² is a sugar partial structure in which a hydrogen atom of a hydroxyl group may be substituted with a methyl group. The sulfamoylbenzene derivative (Id) which is one group selected from the group D is, for example, as shown in Scheme 4, in the presence of a condensing agent and an activator, one of the hydroxyl groups of bumetanide is an amino group. It can be produced by a condensation reaction with a sugar derivative (R ⁹ -NH ₂ ) substituted with (Step 4-1).

[Wherein R ⁹ —NH ₂ represents a sugar derivative in which one of the hydroxyl groups is substituted with an amino group, and R ⁹ consists of a sugar partial structure in which the hydrogen atom of the hydroxyl group may be substituted with a methyl group. 1 group selected from the said D group is represented. ]

[Step 4-1]
Examples of the condensing agent used in the condensation reaction include carbodiimide reagents such as DCC or EDCI, N, N′-carbodiimidazole, (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate, or (benzotriazole- 1-yloxy) tris (dimethylamino) phosphonium phosphonium salt reagents such as hexafluorophosphate, 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride Or diphenyl phosphoryl azide is mentioned, but EDCI is preferable.

The amount of the condensing agent used in the condensation reaction is preferably 1 to 10 mol per 1 mol of bumetanide.

The activator used in the condensation reaction is preferably 1-hydroxybenzotriazole.

The amount of activator used in the condensation reaction is preferably 0.001 to 3 moles per mole of bumetanide.

R ⁹ —NH ₂ used for the condensation reaction may be purchased commercially or by a known method (eg, Pedersen et al., European Journal of Chemistry, 2011, Vol. 17, p. 7080-7086, or Ahuja). Et al., 2007, Vol. 72, p. 3430-3442) or a method based thereon.

The amount of R ⁹ —NH ₂ used in the condensation reaction is preferably 1 to 10 moles per mole of bumetanide.

The reaction solvent used for the condensation reaction is appropriately selected from solvents that do not normally inhibit the reaction. For example, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbons such as toluene or xylene, diethyl ether, Examples include ether solvents such as tetrahydrofuran or dioxane, N, N-dimethylformamide, and acetonitrile, with N, N-dimethylformamide being preferred.

The concentration of bumetanide used for the condensation reaction at the start of the reaction is preferably 0.01 to 10 mol / L, and more preferably 0.05 to 1 mol / L.

The reaction temperature of the condensation reaction is preferably −20 ° C. to 120 ° C., more preferably 15 to 80 ° C.

The reaction time of the condensation reaction is appropriately selected according to the reaction temperature and other conditions, but is preferably 30 minutes to 24 hours, more preferably 1 to 12 hours.

［式中、Ｒ^１０－ＯＨは、アルコールを表し、Ｒ^１０は、エチル基、ブチル基又はヘキシル基を表し、Ｒ^１１は、エチル基、ブチル基、ヘキシル基又はベンジル基を表し、Ｒ^５－ＯＡｃ及びＲ^６は、上記定義と同義である。］ [Production Method 5]
In the sulfamoylbenzene derivative (I), R ¹ is one group selected from the group F consisting of a sugar partial structure, X is an oxygen atom, R ² is an ethyl group, butyl The sulfamoylbenzene derivative (Ie), which is a hexyl group, hexyl group or benzyl group, for example, as shown in Scheme 5, is a condensation reaction of bumetanide with an alcohol (R ¹⁰ —OH) in the presence of an acid (step 5- 1) Subsequently, in the presence of a Lewis acid, the ester derivative (VII) obtained in Step 5-1 or the sugar derivative (all R ^5- above) in which all the hydroxyl groups of the ester body (IV) are protected with an acetyl group. Glycosylation with OAc) (step 5-2), followed by deprotection reaction (step 5-3) of the ester derivative (VIII) obtained in step 5-2 in the presence of a base.

[Wherein R ¹⁰ —OH represents an alcohol, R ¹⁰ represents an ethyl group, a butyl group or a hexyl group, R ¹¹ represents an ethyl group, a butyl group, a hexyl group or a benzyl group, and R ⁵ — OAc and R ⁶ are as defined above. ]

[Step 5-1] Examples of the acid used in the condensation reaction include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and p-toluenesulfonic acid, with sulfuric acid or p-toluenesulfonic acid being preferred.

The amount of acid used in the condensation reaction is preferably 0.001 to 20 mol, more preferably 0.01 to 5 mol, per mol of bumetanide.

The amount of R ¹⁰ —OH used for the condensation reaction is preferably such that the concentration of bumetanide used for the condensation reaction is 0.01 to 10 mol / L, more preferably 0.1 to 1 mol / L. .

The reaction temperature of the condensation reaction is preferably 50 to 150 ° C, more preferably 70 to 100 ° C.

The reaction time for the condensation reaction is appropriately selected according to the reaction temperature and other conditions, but preferably 30 minutes to 24 hours.

[Step 5-2]
Examples of Lewis acids used in the glycosylation reaction include boron trifluoride ether complexes, halides such as tin (IV) tetrachloride or titanium (IV) tetrachloride, or ytterbium (III) trifluoromethanesulfonate, trifluoromethane. Examples of the organic sulfonate include yttrium (III) sulfonate and trimethylsilyl trifluoromethanesulfonate, and boron trifluoride ether complex is preferable.

The amount of Lewis acid used in the glycosylation reaction is preferably 0.01 to 30 mol, more preferably 0.05 to 10 mol, per 1 mol of the ester (IV) or ester derivative derivative (VII).

The amount of R ⁵ -OAc used in the glycosylation reaction is preferably 1 to 10 mol, more preferably 1 to 2 mol, relative to 1 mol of the ester (IV) or ester derivative derivative (VII).

The reaction solvent used for the glycosylation reaction is appropriately selected from solvents that do not normally inhibit the reaction. For example, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbons such as toluene or xylene, diethyl ether, and the like. , Ether solvents such as tetrahydrofuran or dioxane, N, N-dimethylformamide, and acetonitrile are preferable, but acetonitrile is preferable.

The concentration at the start of the reaction of the ester (IV) or ester derivative derivative (VII) used for the glycosylation reaction is preferably 0.01 to 5 mol / L, more preferably 0.05 to 2 mol / L.

The reaction temperature of the glycosylation reaction is preferably −78 ° C. to 170 ° C., more preferably 15 to 120 ° C.

The reaction time of the glycosylation reaction is appropriately selected according to the reaction temperature and other conditions, but preferably 30 minutes to 24 hours.

[Step 5-3]
Examples of the base used in the deprotection reaction include basic inorganic salts such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate, and potassium carbonate is preferred.

The amount of the base used for the deprotection reaction is preferably 0.1 to 30 mol, more preferably 1 to 10 mol, relative to 1 mol of the ester derivative (VIII).

The reaction solvent used for the deprotection reaction is appropriately selected from solvents that do not normally inhibit the reaction. For example, an alcohol solvent such as methanol or ethanol, or an alcohol solvent and water, N, N-dimethylformamide, acetonitrile, or the like. In this case, methanol is preferable.

The concentration of the ester derivative (VIII) used for the deprotection reaction at the start of the reaction is preferably 0.001 to 10 mol / L, and more preferably 0.01 to 1 mol / L.

The reaction temperature for the deprotection reaction is preferably −20 ° C. to 100 ° C., more preferably 15 to 40 ° C.

The reaction time for the deprotection reaction is appropriately selected according to the reaction temperature and other conditions, but preferably 30 minutes to 24 hours.

［式中、Ｒ^１２－Ｃｌは、クロロメチルアルキルカルボキシレートを表し、Ｒ^１２は、シクロヘキシルカルボニルオキシメチル基、イソブチリルオキシメチル基又はピバロイルオキシメチル基を表し、Ｒ^６は、上記定義と同義である。］ [Production Method 6]
In the sulfamoylbenzene derivative (I), R ¹ is one group selected from the group F consisting of a sugar partial structure, X is an oxygen atom, and R ² is cyclohexylcarbonyloxymethyl. The sulfamoylbenzene derivative (If) which is a group, an isobutyryloxymethyl group or a pivaloyloxymethyl group is, for example, as shown in Scheme 6 in the presence of a base in the presence of a base. And a condensation reaction with chloromethylalkylcarboxylate (R ¹² -Cl) (step 6-1).

[Wherein R ¹² -Cl represents a chloromethylalkylcarboxylate, R ¹² represents a cyclohexylcarbonyloxymethyl group, an isobutyryloxymethyl group or a pivaloyloxymethyl group, and R ⁶ represents the above definition. It is synonymous with. ]

[Step 6-1]
Examples of the base used for the condensation reaction include basic inorganic salts such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or cesium carbonate, and potassium carbonate is preferable.

The amount of the base used for the condensation reaction is preferably 1 to 10 mol per 1 mol of the sulfamoylbenzene derivative (1b).

The amount of R ¹² -Cl used for the condensation reaction is preferably 1 to 10 mol per 1 mol of the sulfamoylbenzene derivative (1b).

The reaction solvent used for the condensation reaction is appropriately selected from solvents that do not normally inhibit the reaction. For example, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbons such as toluene or xylene, diethyl ether, Examples include ether solvents such as tetrahydrofuran or dioxane, N, N-dimethylformamide, and acetonitrile, with N, N-dimethylformamide being preferred.

The concentration of the sulfamoylbenzene derivative (1b) used for the condensation reaction at the start of the reaction is preferably 0.001 to 10 mol / L, more preferably 0.01 to 1 mol / L.

The reaction temperature of the condensation reaction is preferably −20 ° C. to 100 ° C., more preferably 15 to 70 ° C.

The reaction time of the condensation reaction is appropriately selected according to the reaction temperature and other conditions, but is preferably 1 to 24 hours.

［式中、Ｒ^１３－Ｃｌは、酸塩化物を表し、Ｒ^１３は、アセチル基、ベンゾイル基又はピバロイル基を表し、Ｒ^１４は、６位の水酸基の水素原子がアセチル基、ベンゾイル基又はピバロイル基で置換された糖の部分構造からなる下記Ｇ群から選択される一の基を表し、Ｒ^５及びＲ^６は上記定義と同義である。
Ｇ群：

（＊は、Ｒ^１４が結合する窒素原子との結合位置を表す。）] [Production method 7]
Among the sulfamoylbenzene derivatives (I), R ¹ is one selected from the following G group consisting of a sugar partial structure in which the hydrogen atom of the 6-position hydroxyl group is substituted with an acetyl group, a benzoyl group or a pivaloyl group A sulfamoylbenzene derivative (Ig) in which X is an oxygen atom and R ² is a hydrogen atom, for example, a sodium alkoxide prepared from metallic sodium and benzyl alcohol as shown in Scheme 7 Deprotection reaction of the ester derivative (V) using (Step 7-1), followed by acid chloride (R ¹³ − of the alcohol derivative (IX) obtained in Step 7-1 in the presence of a base. Cl) with a condensation reaction (Step 7-2), followed by a deprotection reaction (Step 7-3) of the ester derivative (X) obtained in Step 7-2 in a hydrogen atmosphere and in the presence of a metal catalyst. I can build it.

[Wherein, R ¹³ -Cl represents an acid chloride, R ¹³ represents an acetyl group, a benzoyl group or a pivaloyl group, and R ¹⁴ represents an acetyl group, a benzoyl group or a pivaloyl group in which the hydrogen atom of the 6-position hydroxyl group is It represents one group selected from the following group G consisting of a sugar partial structure substituted with a group, and R ⁵ and R ⁶ have the same definitions as above.
Group G:

(* Represents the bonding position with the nitrogen atom to which R ¹⁴ is bonded.)]

[Step 7-1]
The amount of sodium alkoxide prepared from metallic sodium and benzyl alcohol used for the deprotection reaction is preferably such that the concentration of the ester derivative (V) used for the deprotection reaction is 0.01 to 10 mol / L at the start of the reaction. An amount of 0.1-1 mol / L is more preferable.

The reaction temperature for the deprotection reaction is preferably −20 ° C. to 100 ° C., more preferably 15 to 40 ° C.

The reaction time for the deprotection reaction is appropriately selected according to the reaction temperature and other conditions, but preferably 30 minutes to 24 hours.

[Step 7-2]
Examples of the base used in the condensation reaction include basic inorganic salts such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate, aromatic amines such as pyridine, lutidine or 2,4,6-trimethylpyridine. , Tertiary organic amines such as triethylamine, tripropylamine, tributylamine, N-methylpiperidine, N-methylpiperidone or N-methylmorpholine, or metal amides such as lithium diisopropylamide or lithium hexamethyldisilazide Among them, pyridine, lutidine or 2,4,6-trimethylpyridine is preferable.

The amount of the base used for the condensation reaction is preferably 1 to 10 mol per 1 mol of the alcohol derivative (IX).

R ¹³ -Cl used for the condensation reaction can be obtained by purchasing a commercially available product or by producing it by a known method or a method analogous thereto.
The amount of R ¹³ —Cl used in the condensation reaction is preferably 1 to 10 moles per mole of the alcohol derivative (IX).

The reaction solvent used in the condensation reaction is appropriately selected from solvents that do not normally inhibit the reaction. For example, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbons such as toluene or xylene, or diethyl Examples include ether solvents such as ether, tetrahydrofuran, and dioxane, with dichloromethane being preferred.

The concentration of the alcohol derivative (IX) used for the condensation reaction at the start of the reaction is preferably 0.001 to 10 mol / L, more preferably 0.01 to 1 mol / L.

The reaction temperature of the condensation reaction is preferably −20 ° C. to 100 ° C., more preferably 15 to 40 ° C.

The reaction time for the condensation reaction is appropriately selected according to the reaction temperature and other conditions, but preferably 30 minutes to 24 hours.

[Step 7-3]
The hydrogen pressure for the deprotection reaction is preferably 1 to 100 atm, and more preferably 1 to 5 atm.

Examples of the metal catalyst used in the deprotection reaction include platinum oxide, palladium hydroxide, and palladium-carbon, with palladium hydroxide or palladium-carbon being preferred.

The amount of the metal catalyst used in the deprotection reaction is preferably 1 to 100% by weight, more preferably 5 to 20% by weight, based on the ester derivative (X).

The reaction solvent used for the deprotection reaction is appropriately selected from solvents that do not normally inhibit the reaction. For example, an alcohol solvent such as methanol or ethanol, or an alcohol solvent and water, N, N-dimethylformamide, acetonitrile, or the like. In this case, methanol is preferable.

The concentration of the ester derivative (X) used for the deprotection reaction at the start of the reaction is preferably 0.001 to 10 mol / L, and more preferably 0.01 to 1 mol / L.

The reaction temperature of the deprotection reaction is preferably 5 to 80 ° C, more preferably 15 to 40 ° C.

The reaction time of the deprotection reaction is appropriately selected according to the reaction temperature and other conditions, but is preferably 1 to 24 hours.

［式中、Ｒ^1１は、上記定義と同義である。］ [Production method 8]
In the sulfamoylbenzene derivative (I), R ¹ is a group consisting of a sugar partial structure in which the hydrogen atom of the 6-position hydroxyl group is substituted with an acetyl group, X is an oxygen atom, and R ² is Sulfamoylbenzene derivative (Ih), which is an ethyl group, butyl group, hexyl group or benzyl group, for example, as shown in Scheme 8, condensation reaction of alcohol derivative (XI) with acetyl chloride in the presence of a base It can be manufactured by (Step 8-1).

[Wherein R ¹¹ has the same definition as above. ]

[Step 8-1]
Examples of the base used in the condensation reaction include basic inorganic salts such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate, aromatic amines such as pyridine, lutidine or 2,4,6-trimethylpyridine. , Tertiary organic amines such as triethylamine, tripropylamine, tributylamine, N-methylpiperidine, N-methylpiperidone or N-methylmorpholine, or metal amides such as lithium diisopropylamide or lithium hexamethyldisilazide Among them, pyridine, lutidine or 2,4,6-trimethylpyridine is preferable.

The amount of the base used for the condensation reaction is preferably 1 to 10 mol per 1 mol of the alcohol derivative (XI).

The amount of acetyl chloride used in the condensation reaction is preferably 1 to 10 moles per mole of alcohol derivative (XI).

The reaction solvent used in the condensation reaction is appropriately selected from solvents that do not normally inhibit the reaction. For example, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbons such as toluene or xylene, or diethyl Examples include ether solvents such as ether, tetrahydrofuran, and dioxane, with dichloromethane being preferred.

The concentration of the alcohol derivative (XI) used for the condensation reaction at the start of the reaction is preferably 0.001 to 10 mol / L, and more preferably 0.01 to 1 mol / L.

The reaction temperature of the condensation reaction is preferably −20 ° C. to 100 ° C., more preferably 15 to 40 ° C.

The reaction time for the condensation reaction is appropriately selected according to the reaction temperature and other conditions, but preferably 30 minutes to 24 hours.

［式中、Ｒ^１５は、アミノ基がｔｅｒｔ－ブトキシカルボニル基で保護されたアミノ酸誘導体を表し、Ｒ^１６は、アミノ酸の部分構造からなる下記Ｈ群から選択される一の基を表す。
Ｈ群：

（＊は、Ｒ^１６が結合する窒素原子との結合位置を表す。）] [Production Method 9]
In the sulfamoylbenzene derivative (I), R ¹ is one group selected from the following group H consisting of an amino acid partial structure, X is an oxygen atom, and R ² is an ethyl group. For example, as shown in Scheme 9, the sulfamoylbenzene derivative (Ii) can be amidated by reacting the ester derivative (VII) with a succinic anhydride derivative (XII) in the presence of a base (Step 9-1). Followed by deprotection of the amide derivative (XIII) obtained in Step 9-1 in the presence of an acid (Step 9-2).

[Wherein R ¹⁵ represents an amino acid derivative in which an amino group is protected with a tert-butoxycarbonyl group, and R ¹⁶ represents one group selected from the following group H consisting of a partial structure of an amino acid.
Group H:

(* Represents the bonding position with the nitrogen atom to which R ¹⁶ is bonded.)]

[Step 9-1]
Examples of the base used in the amidation reaction include inorganic substances such as lithium hydride, sodium hydride, potassium hydride, cesium carbonate, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, and potassium fluoride. Although a base is mentioned, sodium hydride is preferable.

The amount of the base used for the amidation reaction is preferably 1 to 10 mol per 1 mol of the ester derivative (VII).

The succinic anhydride derivative (XII) used for the amidation reaction can be obtained by producing L-aspartic acid as a starting material by a known method or a method analogous thereto.

The amount of the succinic anhydride derivative (XII) used for the amidation reaction is preferably 1 to 10 moles per mole of the ester derivative (VII).

The reaction solvent used for the amidation reaction is usually appropriately selected from solvents that do not inhibit the reaction. For example, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aromatic hydrocarbons such as toluene or xylene, diethyl ether, and the like. An ether solvent such as tetrahydrofuran or dioxane, N, N-dimethylformamide, or acetonitrile is preferable, and N, N-dimethylformamide is preferable.

The concentration of the ester derivative (VII) used for the amidation reaction at the start of the reaction is preferably 0.001 to 10 mol / L, and more preferably 0.01 to 1 mol / L.

The reaction temperature of the amidation reaction is preferably −20 ° C. to 120 ° C., more preferably 15 to 60 ° C.

The reaction time of the amidation reaction is appropriately selected according to the reaction temperature and other conditions, but preferably 30 minutes to 24 hours.

[Step 9-2]
Examples of the acid used for the deprotection reaction include organic acids such as formic acid, acetic acid, trichloroacetic acid, and trifluoroacetic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, and hydrogen bromide. However, trifluoroacetic acid is preferred.

The amount of the acid used for the deprotection reaction is preferably 0.01 to 20 mol with respect to 1 mol of the amide derivative (XIII).

The reaction solvent used for the deprotection reaction is appropriately selected from solvents that do not normally inhibit the reaction. For example, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, ether solvents such as diethyl ether, tetrahydrofuran or dioxane, N , N-dimethylformamide or acetonitrile, with dichloromethane being preferred. Further, the acid itself may be used as a reaction solvent.

The concentration of the amide derivative (XIII) used for the deprotection reaction at the start of the reaction is preferably 0.01 to 100 mol / L.

The reaction temperature of the deprotection reaction is preferably −20 ° C. to 100 ° C., more preferably 15 to 60 ° C.

The reaction time for the deprotection reaction is appropriately selected according to the reaction temperature and other conditions, but preferably 30 minutes to 24 hours.

The medicament of the present invention and the therapeutic and prophylactic agent for epilepsy are characterized by containing a sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

The sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof is converted into bumetanide having high translocation into the brain and having pharmacological activity, and further, the brain of the converted bumetanide. Since the medium concentration persists, it can be used in medicine as a prodrug of bumetanide.

The sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof is a prodrug of bumetanide obtained by chemically modifying the carboxyl group, amino group, or both groups (carboxyl group and amino group) of bumetanide. . Among them, a prodrug having two sites that are converted enzymatically or non-enzymatically after reaching the living body or the site of action is called a double prodrug of bumetanide, and a prodrug having three sites to be converted Is called the triple prodrug of bumetanide. Examples of double prodrugs of bumetanide include prodrugs in which both the carboxyl group and amino group of bumetanide are chemically modified, and prodrugs that have been chemically modified so that the amino group of bumetanide undergoes transformation in two steps. Can be mentioned. Examples of triple prodrugs of bumetanide include prodrugs that are chemically modified so that the amino group of bumetanide undergoes transformation in two steps in addition to the chemical modification of the carboxyl group of bumetanide. Examples of the double prodrug of bumetanide include the compounds of Examples 14 to 24 and 26. Examples of the triple prodrug of bumetanide include the compounds of Examples 25, 27 and 28. The compounds of Examples 14-28 are finally converted to bumetanide, which is the active body (drug).

Bumetanide inhibits NKCC1 and NKCC2, which are involved in transcellular ion transport that takes sodium ion (Na ⁺ ), potassium ion (K ⁺ ), or chloride ion (Cl ⁻ ) into the cell, and the cell volume regulation mechanism that accompanies these transports In addition, the sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof has excellent ability to migrate into the brain and sustain the concentration of bumetanide in the brain after conversion. Therefore, the sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof can be used as a therapeutic or prophylactic agent for diseases involving NKCC1 and NKCC2 in the center. Examples of such diseases include epilepsy which is a disease in which NKCC1 is involved. Preferably, the sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof is a therapeutic or prophylactic agent for epilepsy. Can be used as More preferably, the sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof is brain or head trauma, encephalitis, hypoxia or trauma at birth, stroke (cerebral hemorrhage or cerebral infarction), brain tumor, brain It can be used as a therapeutic and prophylactic agent for epilepsy caused by vascular disorders, brain infections, brain development abnormalities, high fever, alcohol abuse, drug abuse.

The therapeutic effect and preventive effect on epilepsy of the sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof can be measured, for example, using a method described in Patent Document 2 or Non-Patent Document 3 at a predetermined time. A decrease in epileptic seizures in rats can be confirmed as an index.

In order to maintain the antiepileptic action of the sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof, bumetanide converted from the sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof However, it is important to remain in the brain for a long time and inhibit NKCC1. Therefore, the antiepileptic action of the sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof is maintained, for example, when the sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof is administered to a rat. Rise and persistence in the brain concentration of bumetanide converted from the sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof, and the brain concentration / plasma concentration of the converted bumetanide This can be confirmed by evaluating the percentage (%). Further, for example, sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof is administered to cynomolgus monkey, and bumetanide converted from sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof It can be confirmed by evaluating the rise and persistence of cerebrospinal fluid concentration, and the percentage of cerebrospinal fluid concentration / plasma concentration of converted bumetanide. In addition, although drugs in cerebrospinal fluid exist in a protein non-binding state (Lange, Journal of Pharmacokinetics and Pharmacodynamics 2013, 40, p.315-326), 95% of bumetanide in plasma is in plasma protein. (Pentikainen et al., British Journal of Clinical Pharmacology, 1977, Vol. 4, p. 39-44), and the effect of drugs is influenced by the ease of binding to plasma proteins. Confirmed by evaluating the percentage of cerebrospinal fluid concentration / plasma concentration of non-protein bound bumetanide calculated as a value closer to the substance as an indicator of brain migration of bumetanide with pharmacological activity it can.

Since the sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof has excellent ability to migrate into the brain and the percentage of the converted bumetanide in the brain / plasma concentration is high, The diuretic effect of bumetanide inhibiting NKCC2 present in the ascending limb of kidney henle is reduced, and it can be preferably used as a therapeutic or prophylactic agent for epilepsy.

The brain translocation of the sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof uses, for example, a BBB kit (Pharmacocell Co., Ltd.) marketed as a blood brain barrier remodeling model as a simple method. Can be predicted. BBB kit is composed of three types of cells: brain capillary endothelial cells, pericytes (perisite) and astrocytes (astrocytes), which are constituent cells of the blood-brain barrier. These physiological BBB characteristics are maintained.

When the sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof is used by oral administration, it is also important that oral absorbability is excellent in order to enhance brain migration. The oral absorbability of the sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof can be predicted, for example, by using Caco-2 cell monolayer culture as a simple method. Caco-2 cells are cells isolated from human colon malignancies and form a monolayer when cultured on a filter. On the surface of the monolayer, there are brush borders with microvillous processes, and there are cohesive bands between cells, which have the same morphology as epithelial cells of the small intestine. It has been reported that the absorptivity when a drug is orally administered and the permeability of a Caco-2 cell culture membrane show a good correlation, and as an intestinal epithelial cell model for more easily predicting in vivo absorption. (Arthursson P, et al., Adv Drug Deliv Rev, 2001, 46, p. 27-43).

When the sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof is used as a medicine, it can be used as it is or as a pharmaceutical composition in an appropriate dosage form as a mammal (eg, mouse, rat, hamster, Rabbit, dog, monkey, cow, sheep or human).

The above medicaments are usually prepared using one or more of the sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier, excipient or other additive usually used for formulation. It can be prepared according to the method. Administration is oral by tablet, pill, capsule, granule, powder or liquid, or parenteral administration by injection or suppository such as intravenous or intramuscular injection, nasal, transmucosal or transdermal. Either form may be sufficient. When the sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof is a double prodrug or triple prodrug, it is preferably used as an orally-administered drug because of its particularly excellent oral absorbability.

As a solid composition for oral administration of the above-mentioned medicine, tablets, powders, granules, or the like can be used. In such a solid composition, one or more sulfamoylbenzene derivatives (I) or a pharmaceutically acceptable salt thereof is at least one inert diluent (eg lactose, mannitol, glucose, Hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone or magnesium aluminate metasilicate). The composition contains additives other than inert diluents (for example, lubricants such as magnesium stearate, disintegrating agents such as calcium calcium glycolate, stabilizers or solubilizers) according to a conventional method. It may be. Tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropylcellulose or hydroxypropylmethylcellulose phthalate, or a gastric or enteric film, if necessary.

Liquid compositions for oral administration of the above pharmaceuticals include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs, and generally used inert diluents ( For example, it may contain purified water or ethanol). In addition to the inert diluent, the composition may contain an adjuvant such as a wetting agent or a suspending agent, a sweetening agent, a flavoring agent, a fragrance, or a preservative.

The above-mentioned injection for parenteral administration of a medicine may contain a sterile aqueous or non-aqueous solution, suspension or emulsion. Examples of the aqueous solution or suspension include distilled water for injection or physiological saline. Examples of the non-aqueous solution or suspension include vegetable oils such as propylene glycol, polyethylene glycol or olive oil, alcohols such as ethanol, or polysorbate 80 (Pharmacopoeia name). Such a composition may further contain adjuvants such as preservatives, wetting agents, emulsifiers, dispersants, stabilizers or solubilizers. The injection can be sterilized in the course of manufacture, for example, by filtration through a bacteria-retaining filter, or by adding a germicide or irradiation. Moreover, the said injection is manufactured as a sterilized solid composition, and can also be melt | dissolved and used for the sterilized water or the sterilized solvent for injection before use.

The above medicament preferably contains 0.001 to 99% by weight, more preferably 0.01 to 99% by weight, of the sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof. . The effective dosage and frequency of administration of the sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof varies depending on the dosage form, the age, weight of the patient, or the nature or severity of the condition to be treated. When administered intravenously, the daily dose is usually about 0.0001 to 100 mg / kg per body weight, preferably about 0.001 to 10 mg / kg, once a day or divided into multiple doses. In the case of oral administration, the daily dose is usually about 0.01 to 1000 mg / kg, preferably 0.1 to 100 mg / kg per body weight once or several times a day. Can be administered separately.

The above medicines may be administered alone, but may be combined with other drugs or used in combination with other drugs in order to supplement or enhance the preventive or therapeutic effect of the disease or reduce the dose. Can also be used.

Examples of other drugs that can be combined or used together (hereinafter referred to as combined drugs) include, for example, preventive or therapeutic agents for epilepsy.

When using the above medicines in combination with a concomitant drug, the administration time of the above medicine and the concomitant drug is not particularly limited, and these may be administered simultaneously to the administration subject, with a time difference. May be administered. The dose of the concomitant drug can be appropriately selected based on the clinically used dose.

The compounding ratio of the above medicine and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination of the above medicine and concomitant drug, and the like. For example, when the administration subject is a human, the concomitant drug may be used at a compounding ratio of 0.01 to 99.99 with respect to the sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof.

Examples of the epilepsy therapeutic or prophylactic agent used in combination with the above-mentioned medicine include phenobarbital, primidone, metalbital, ethoin, phenytoin, ethosuximide, acetazolamide, sultiam, zonisamide, clonazepam, diazepam, nitrazepam, midazolam, clobazam, valproic acid Sodium, carbamazepine, gabapentin, topiramate or lamotrigine levetiracetam.

Hereinafter, the present invention will be specifically described by way of examples, but the present invention is not limited to these examples.

The 600 MHz NMR spectrum was measured using an apparatus manufactured by Bruker BioSpin Corporation. The chemical shift is represented by δ (unit: ppm) based on tetramethylsilane, and the signals are represented by s (single line), d (double line), t (triple line), and br (wide), respectively.

The ESI-MS spectrum was measured using a quadrupole LC / MS system manufactured by Agilent Technologies.

All commercially available reaction solvents were used.

The compound was purified by column chromatography, and silica gel was used unless otherwise specified.

In addition, Daisogel (trademark registration; 250 × 20 mm, C18, 10 μm) was used as the column when the compound was purified by HPLC fractionation.

For the compounds used in the Reference Example compounds, for which no synthesis method is described, commercially available compounds were used.

　室温下、ブメタニド（１．２８ｇ、３．５ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（１０ｍＬ）溶液に、トリエチルアミン（０．４８８ｍＬ、３．５ｍｍｏｌ）、パラメトキシベンジルクロリド（０．７１ｇ、４．５５ｍｍｏｌ）を順次加え、７０℃で一晩撹拌した。反応混合物を室温に冷却し、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を水、１ｍｏｌ／Ｌの水酸化ナトリウム水溶液で順次洗浄し、無水硫酸ナトリウムで乾燥し、濃縮した。残渣を酢酸エチル（１０ｍＬ／ｇ）で１５分間洗浄し、ろ過する作業を４回繰り返し、参考例１の化合物を１．２２ｇ（７２％）得た。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＣＤＣｌ_３）　
δ：０．８０（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），１．１１－１．１５（２Ｈ，ｍ），１．３８－１．４１（２Ｈ，ｍ），３．０８（２Ｈ，ｔ，Ｊ＝６．６Ｈｚ），３．８２（３Ｈ，ｓ），４．８８（２Ｈ，ｓ），５．３１（２Ｈ，ｓ），６．９１（４Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．０９（１Ｈ，ｔ，Ｊ＝７．２Ｈｚ），７．３０（２Ｈ，ｔ，Ｊ＝７．２Ｈｚ），７．３９（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．５８（１Ｈ，ｓ），７．９６（１Ｈ，ｓ）． (Example 1)
Synthesis of 3- (N- (2-aminoacetyl) sulfamoyl) -5- (butylamino) -4-phenoxybenzoic acid (hereinafter, the compound of Example 1):
[Step 1]
Synthesis of 4-methoxybenzyl 3- (butylamino) -4-phenoxy-5-sulfamoylbenzoate (hereinafter, the compound of Reference Example 1):

At room temperature, a solution of bumetanide (1.28 g, 3.5 mmol) in N, N-dimethylformamide (10 mL) was added to triethylamine (0.488 mL, 3.5 mmol), paramethoxybenzyl chloride (0.71 g, 4.55 mmol). Were sequentially added and stirred at 70 ° C. overnight. The reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and 1 mol / L aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate, and concentrated. The residue was washed with ethyl acetate (10 mL / g) for 15 minutes and filtered four times to obtain 1.22 g (72%) of the compound of Reference Example 1.
¹ H-NMR (600 MHz, CDCl ₃ )
δ: 0.80 (3H, t, J = 7.2 Hz), 1.11-1.15 (2H, m), 1.38-1.41 (2H, m), 3.08 (2H, t , J = 6.6 Hz), 3.82 (3H, s), 4.88 (2H, s), 5.31 (2H, s), 6.91 (4H, d, J = 7.8 Hz), 7.09 (1H, t, J = 7.2 Hz), 7.30 (2H, t, J = 7.2 Hz), 7.39 (2H, d, J = 8.4 Hz), 7.58 (1H , S), 7.96 (1H, s).

　室温下、参考例１の化合物（０．４８５ｇ、１ｍｍｏｌ）とＮ―（ｔｅｒｔ―ブトキシカルボニル)グリシン（０．２６３ｇ、１．５ｍｍｏｌ）のジクロロメタン（１０ｍＬ）溶液に、ＤＣＣ（０．４１２ｇ、２ｍｍｏｌ）、ＤＭＡＰ（０．０１２ｇ、０．１ｍｍｏｌ）を順次加え、室温で一晩撹拌した。反応混合物に水を加え、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、濃縮した。残渣をカラムクロマトグラフィー（石油エーテル／酢酸エチル＝６７／３３）で精製し、４－メトキシベンジル　３－（Ｎ－（２－（（ｔｅｒｔ―ブトキシカルボニル）アミノ）アセチル）スルファモイル）－５－（ブチルアミノ）－４－フェノキシベンゾエートを０．３１３ｇ（４９％）得た。得られた化合物（０．３１３ｇ、０．４８３ｍｍｏｌ）のトリフルオロ酢酸（５ｍＬ）溶液に、アニソールを２滴加え、室温で３０分間撹拌し、反応混合物を濃縮した。残渣をカラムクロマトグラフィー（オクタデシルシリル化シリカゲルを使用　メタノール／０．１％ギ酸水溶液＝６５／３５）で精製し、実施例１の化合物を０．１４１ｇ（７０％）得た。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＣＤ_３ＯＤ）
δ：０．８４（３Ｈ，ｔ，Ｊ＝６．６Ｈｚ），１．１５－１．２０（２Ｈ，ｍ），１．３１－１．４８（２Ｈ，ｍ），３．１３（２Ｈ，ｔ，Ｊ＝６．６Ｈｚ），３．２０（２Ｈ，ｓ），６．９３（２Ｈ，ｄ，Ｊ＝７．２Ｈｚ），７．１１（１Ｈ，ｔ，Ｊ＝６．６Ｈｚ），７．３５（２Ｈ，ｔ，Ｊ＝６．０Ｈｚ），７．６５（１Ｈ，ｓ），８．０３（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）：（［Ｍ－Ｈ］^－）４２０． [Step 2]
Synthesis of the compound of Example 1:

At room temperature, DCC (0.412 g, 2 mmol) was added to a solution of the compound of Reference Example 1 (0.485 g, 1 mmol) and N- (tert-butoxycarbonyl) glycine (0.263 g, 1.5 mmol) in dichloromethane (10 mL). , DMAP (0.012 g, 0.1 mmol) was sequentially added and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 67/33) and 4-methoxybenzyl 3- (N- (2-((tert-butoxycarbonyl) amino) acetyl) sulfamoyl) -5- (butyl 0.313 g (49%) of amino) -4-phenoxybenzoate was obtained. Two drops of anisole were added to a solution of the obtained compound (0.313 g, 0.483 mmol) in trifluoroacetic acid (5 mL), the mixture was stirred at room temperature for 30 minutes, and the reaction mixture was concentrated. The residue was purified by column chromatography (using octadecylsilylated silica gel, methanol / 0.1% aqueous formic acid = 65/35) to obtain 0.141 g (70%) of the compound of Example 1.
¹ H-NMR (600 MHz, CD ₃ OD)
δ: 0.84 (3H, t, J = 6.6 Hz), 1.15-1.20 (2H, m), 1.31-1.48 (2H, m), 3.13 (2H, t , J = 6.6 Hz), 3.20 (2H, s), 6.93 (2H, d, J = 7.2 Hz), 7.11 (1H, t, J = 6.6 Hz), 7.35. (2H, t, J = 6.0 Hz), 7.65 (1H, s), 8.03 (1H, s).
MS (ESI): ([M−H] ⁻ ) 420.

　参考例１の化合物とＮ―（ｔｅｒｔ―ブトキシカルボニル）バリンを用いて、実施例１と同様の手順により、実施例２の化合物を合成した。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＤＭＳＯ－ｄ_６）
δ：０．７７（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），０．８１（３Ｈ，ｄ，Ｊ＝７．２Ｈｚ），０．９２（３Ｈ，ｄ，Ｊ＝７．２Ｈｚ），１．０７－１．１１（２Ｈ，ｍ），１．３１－１．３８（２Ｈ，ｍ），２．１５－２．２５（１Ｈ，ｍ），３．０２－３．１８（３Ｈ，ｍ），４．８６（１Ｈ，ｂｒｓ），６．８０（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．０２（１Ｈ，ｔ，Ｊ＝８．４Ｈｚ），７．２８（２Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．４１（１Ｈ，ｓ），７．８１（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）：（［Ｍ－Ｈ］^－）４６２． (Example 2)
Synthesis of (S) -3- (N- (2-amino-3-methylbutanoyl) sulfamoyl) -5- (butylamino) -4-phenoxybenzoic acid (hereinafter, the compound of Example 2):

Using the compound of Reference Example 1 and N- (tert-butoxycarbonyl) valine, the compound of Example 2 was synthesized by the same procedure as Example 1.
¹ H-NMR (600 MHz, DMSO-d ₆ )
δ: 0.77 (3H, t, J = 7.2 Hz), 0.81 (3H, d, J = 7.2 Hz), 0.92 (3H, d, J = 7.2 Hz), 1.07 -1.11 (2H, m), 1.31-1.38 (2H, m), 2.15-2.25 (1H, m), 3.02-3.18 (3H, m), 4 .86 (1H, brs), 6.80 (2H, d, J = 8.4 Hz), 7.02 (1H, t, J = 8.4 Hz), 7.28 (2H, t, J = 7. 8 Hz), 7.41 (1H, s), 7.81 (1H, s).
MS (ESI): ([M−H] ⁻ ) 462.

　室温下、ブメタニド（０．３６４ｇ、１ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（５ｍＬ）溶液に、トリエチルアミン（０．１１ｇ、１．１ｍｍｏｌ）、ベンジルクロリド（０．１３９ｇ、１．１ｍｍｏｌ）を順次加え、７０℃で８時間撹拌した。反応混合物を室温に冷却し、冷水を加え、酢酸エチルで抽出した。有機層を塩化アンモニウム水溶液、炭酸カリウム水溶液、水で順次洗浄し、無水硫酸ナトリウムで乾燥し、濃縮し、参考例２の化合物を０．３８０ｇ（８４％）得た。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＣＤＣｌ_３）
δ：０．８１（３Ｈ，ｔ，Ｊ＝６．６Ｈｚ），１．１４（２Ｈ，ｍ），１．４０（２Ｈ，ｍ），３．０９（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ），４．９１（２Ｈ，ｓ），５．３８（２Ｈ，ｓ），６．９１（２Ｈ，ｄ，Ｊ＝７．２Ｈｚ），７．１０（１Ｈ，ｔ，Ｊ＝８．４Ｈｚ），７．３０（２Ｈ，ｔ，Ｊ＝８．４Ｈｚ），７．３５（１Ｈ，ｄ，Ｊ＝７．２Ｈｚ），７．３９（２Ｈ，ｔ，Ｊ＝７．２Ｈｚ），７．４５（２Ｈ，ｄ，Ｊ＝１２Ｈｚ），７．５９（１Ｈ，ｓ），７．９８（１Ｈ，ｄ，Ｊ＝７．２Ｈｚ）． (Example 3)
3- (Butylamino) -4-phenoxy-5- (N-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-2- Yl) sulfamoyl) benzoic acid (hereinafter the compound of Example 3):
[Step 1]
Synthesis of benzyl 3- (butylamino) -4-phenoxy-5-sulfamoylbenzoate (hereinafter, the compound of Reference Example 2):

Triethylamine (0.11 g, 1.1 mmol) and benzyl chloride (0.139 g, 1.1 mmol) were sequentially added to a solution of bumetanide (0.364 g, 1 mmol) in N, N-dimethylformamide (5 mL) at room temperature, Stir at 70 ° C. for 8 hours. The reaction mixture was cooled to room temperature, cold water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with an aqueous ammonium chloride solution, an aqueous potassium carbonate solution and water, dried over anhydrous sodium sulfate and concentrated to obtain 0.380 g (84%) of the compound of Reference Example 2.
¹ H-NMR (600 MHz, CDCl ₃ )
δ: 0.81 (3H, t, J = 6.6 Hz), 1.14 (2H, m), 1.40 (2H, m), 3.09 (2H, t, J = 6.8 Hz), 4.91 (2H, s), 5.38 (2H, s), 6.91 (2H, d, J = 7.2 Hz), 7.10 (1H, t, J = 8.4 Hz), 7. 30 (2H, t, J = 8.4 Hz), 7.35 (1H, d, J = 7.2 Hz), 7.39 (2H, t, J = 7.2 Hz), 7.45 (2H, d , J = 12 Hz), 7.59 (1H, s), 7.98 (1H, d, J = 7.2 Hz).

　参考例２の化合物（０．４５４ｇ、１ｍｍｏｌ）と１，２，３，４，６－ペンタ－Ｏ－アセチル－Ｄ－グルコピラノース（０．３９０ｇ、１ｍｍｏｌ）のトルエン（４０ｍＬ）溶液に、室温下、三フッ化ホウ素エーテル錯体（０．５ｍＬ）を加え、９０℃で２時間撹拌した。反応混合物を室温に冷却し、冷水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥し、濃縮した。残渣をカラムクロマトグラフィー（石油エーテル／酢酸エチル＝７５／２５）で精製し、（２Ｒ，３Ｒ，４Ｓ，５Ｒ）－２－（アセトキシメチル）－６－（５－（（ベンジルオキシ）カルボニル）－３－（ブチルアミノ）－２－フェノキシフェニルスルホンアミド）テトラヒドロ－２Ｈ－ピラン－３，４，５－トリイル　トリアセテートを０．０９１ｇ（１２％）得た。得られた化合物（０．０７８ｇ、０．１ｍｍｏｌ）のメタノール（１０ｍＬ）溶液に、１０重量％パラジウム／炭素（０．０１ｇ）を加え、水素雰囲気下、室温で一晩撹拌した。反応混合物をセライトろ過し、メタノールで洗浄した。ろ液に炭酸カリウム（０．１３８ｇ、１ｍｍｏｌ）を加え、室温で２時間撹拌した。反応混合物に水（５ｍＬ）を加え、カラムクロマトグラフィー（オクタデシルシリル化シリカゲルを使用　メタノール／水＝６０／４０）で精製し、実施例３の化合物を０．０３４ｇ（６５％）得た。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＣＤ_３ＯＤ）
δ：０．８５（３Ｈ，ｔ，７．４Ｈｚ），１．１６－１．２５（２Ｈ，ｍ），１．４２－１．５０（２Ｈ，ｍ），３．１３（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ），３．１９－３．２６（２Ｈ，ｍ），３．２８－３．４３（２Ｈ，ｍ），３．５７（２Ｈ，ｄｄ，Ｊ＝３．６Ｈｚ，２０．０Ｈｚ），４．５６（１Ｈ，ｄ，Ｊ＝８．９Ｈｚ），６．９３（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．０７（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．３１（２Ｈ，ｔ，Ｊ＝８．０Ｈｚ），７．６０（１Ｈ，ｓ），７．９９（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）：（［Ｍ－Ｈ］^－）５２５． [Step 2]
Synthesis of the compound of Example 3:

To a solution of the compound of Reference Example 2 (0.454 g, 1 mmol) and 1,2,3,4,6-penta-O-acetyl-D-glucopyranose (0.390 g, 1 mmol) in toluene (40 mL) at room temperature. , Boron trifluoride ether complex (0.5 mL) was added, and the mixture was stirred at 90 ° C. for 2 hours. The reaction mixture was cooled to room temperature, cold water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 75/25) and (2R, 3R, 4S, 5R) -2- (acetoxymethyl) -6- (5-((benzyloxy) carbonyl)- 0.091 g (12%) of 3- (butylamino) -2-phenoxyphenylsulfonamido) tetrahydro-2H-pyran-3,4,5-triyl triacetate was obtained. To a solution of the obtained compound (0.078 g, 0.1 mmol) in methanol (10 mL) was added 10 wt% palladium / carbon (0.01 g), and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. The reaction mixture was filtered through celite and washed with methanol. To the filtrate was added potassium carbonate (0.138 g, 1 mmol), and the mixture was stirred at room temperature for 2 hours. Water (5 mL) was added to the reaction mixture, which was purified by column chromatography (using octadecylsilylated silica gel, methanol / water = 60/40) to obtain 0.034 g (65%) of the compound of Example 3.
¹ H-NMR (600 MHz, CD ₃ OD)
δ: 0.85 (3H, t, 7.4 Hz), 1.16-1.25 (2H, m), 1.42-1.50 (2H, m), 3.13 (2H, t, J = 6.8 Hz), 3.19-3.26 (2H, m), 3.28-3.43 (2H, m), 3.57 (2H, dd, J = 3.6 Hz, 20.0 Hz) , 4.56 (1H, d, J = 8.9 Hz), 6.93 (2H, d, J = 7.9 Hz), 7.07 (1H, t, J = 7.4 Hz), 7.31 ( 2H, t, J = 8.0 Hz), 7.60 (1H, s), 7.99 (1H, s).
MS (ESI): ([M−H] ⁻ ) 525.

　参考例２の化合物と１，２，３，４，６－ペンタ－Ｏ－アセチル－Ｄ－ガラクトピラノースを用いて、実施例３と同様の手順により、実施例４の化合物を合成した。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＣＤ_３ＯＤ）
δ：０．８５（３Ｈ，ｔ，Ｊ＝７．４Ｈｚ），１．１６－１．２２（２Ｈ，ｍ），１．４２－１．５０（２Ｈ，ｍ），３．１１－３．１８（２Ｈ，ｍ），３．２８－３．３８（２Ｈ，ｍ），３．４２－３．４７（１Ｈ，ｍ），３．４９－３．５５（２Ｈ，ｍ），３．７８－３．９５（１Ｈ，ｍ），４．５１（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），６．９４（２Ｈ，ｄ，Ｊ＝７．７Ｈｚ），７．０７（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．３１（２Ｈ，ｔ，Ｊ＝８．０Ｈｚ），７．５９（１Ｈ，ｓ），７．９６（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）：（［Ｍ－Ｈ］^－）５２５． Example 4
3- (Butylamino) -4-phenoxy-5- (N-((3R, 4S, 5R, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-2- Yl) sulfamoyl) benzoic acid (hereinafter the compound of Example 4):

The compound of Example 4 was synthesized by the same procedure as Example 3 using the compound of Reference Example 2 and 1,2,3,4,6-penta-O-acetyl-D-galactopyranose.
¹ H-NMR (600 MHz, CD ₃ OD)
δ: 0.85 (3H, t, J = 7.4 Hz), 1.16-1.22 (2H, m), 1.42-1.50 (2H, m), 3.11-3.18 (2H, m), 3.28-3.38 (2H, m), 3.42-3.47 (1H, m), 3.49-3.55 (2H, m), 3.78-3 .95 (1H, m), 4.51 (1H, d, J = 8.5 Hz), 6.94 (2H, d, J = 7.7 Hz), 7.07 (1H, t, J = 7. 3 Hz), 7.31 (2H, t, J = 8.0 Hz), 7.59 (1 H, s), 7.96 (1 H, s).
MS (ESI): ([M−H] ⁻ ) 525.

　参考例２の化合物と１，２，３，４，６－ペンタ－Ｏ－アセチル－Ｄ－マンノピラノースを用いて、実施例３と同様の手順により、実施例５の化合物を合成した。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＣＤ_３ＯＤ）
δ：０．８５（３Ｈ，ｔ，Ｊ＝７．４Ｈｚ），１．１６－１．２５（２Ｈ，ｍ），１．４２－１．５０（２Ｈ，ｍ），３．１３（３Ｈ，ｔ，Ｊ＝６．８Ｈｚ），３．４７－３．５１（１Ｈ，ｍ），３．５３－３．６８（３Ｈ，ｍ），３．７２－３．７６（１Ｈ，ｍ），４．８２－４．８８（１Ｈ，ｍ），６．９２（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ），７．０９（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．３２（２Ｈ，ｔ，Ｊ＝８．０Ｈｚ），７．６１（１Ｈ，ｓ），７．９３　（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）：（［Ｍ－Ｈ］^－）５２５． (Example 5)
3- (Butylamino) -4-phenoxy-5- (N-((3S, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-2- Yl) sulfamoyl) benzoic acid (hereinafter the compound of Example 5):

The compound of Example 5 was synthesized by the same procedure as in Example 3 using the compound of Reference Example 2 and 1,2,3,4,6-penta-O-acetyl-D-mannopyranose.
¹ H-NMR (600 MHz, CD ₃ OD)
δ: 0.85 (3H, t, J = 7.4 Hz), 1.16-1.25 (2H, m), 1.42-1.50 (2H, m), 3.13 (3H, t , J = 6.8 Hz), 3.47-3.51 (1H, m), 3.53-3.68 (3H, m), 3.72-3.76 (1H, m), 4.82 -4.88 (1H, m), 6.92 (2H, d, J = 7.9 Hz), 7.09 (1H, t, J = 7.3 Hz), 7.32 (2H, t, J = 8.0 Hz), 7.61 (1H, s), 7.93 (1H, s).
MS (ESI): ([M−H] ⁻ ) 525.

　参考例２の化合物と１，３，４，６－テトラ－Ｏ－アセチル－２－デオキシ－Ｄ－グルコピラノースを用いて、実施例３と同様の手順により、実施例６の化合物を合成した。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＤＭＳＯ－ｄ_６）
δ：０．７１（３Ｈ，ｔ，Ｊ＝７．０Ｈｚ），１．００－１．０８（２Ｈ，ｍ），１．２７－１．３６（２Ｈ，ｍ），１．４０－１．５０（１Ｈ，ｍ），１．７５－１．８２（１Ｈ，ｍ），２．９５－３．０５（４Ｈ，ｍ），３．１２－３．２０（１Ｈ，ｍ），３．３６－３．４５（２Ｈ，ｍ），４．５９（１Ｈ，ｄ，Ｊ＝１０．８Ｈｚ），６．７９（２Ｈ，ｄ，Ｊ＝７．７Ｈｚ），７．０２（１Ｈ，ｔ，Ｊ＝７．１Ｈｚ），７．２７（２Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．４１（１Ｈ，ｓ），７．７０（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）：（［Ｍ－Ｈ］^－）５０９． (Example 6)
3- (Butylamino) -5- (N-((4R, 5S, 6R) -4,5-dihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-2-yl) sulfamoyl) -4-phenoxybenzoic acid Synthesis of acid (hereinafter, compound of Example 6):

The compound of Example 6 was synthesized by the same procedure as Example 3 using the compound of Reference Example 2 and 1,3,4,6-tetra-O-acetyl-2-deoxy-D-glucopyranose.
¹ H-NMR (600 MHz, DMSO-d ₆ )
δ: 0.71 (3H, t, J = 7.0 Hz), 1.00-1.08 (2H, m), 1.27-1.36 (2H, m), 1.40-1.50 (1H, m), 1.75-1.82 (1H, m), 2.95-3.05 (4H, m), 3.12-3.20 (1H, m), 3.36-3 .45 (2H, m), 4.59 (1H, d, J = 10.8 Hz), 6.79 (2H, d, J = 7.7 Hz), 7.02 (1H, t, J = 7. 1 Hz), 7.27 (2H, t, J = 7.4 Hz), 7.41 (1 H, s), 7.70 (1 H, s).
MS (ESI): ([M−H] ⁻ ) 509.

　ブメタニド（０．３６４ｇ、１ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（５ｍＬ）溶液に、ＥＤＣＩ（０．２３０ｇ、１．２ｍｍｏｌ）、１－ヒドロキシベンゾトリアゾール（０．１６２ｇ、１．２ｍｍｏｌ）を順次加え、０℃で１時間撹拌した。反応混合物に、メチル－６－アミノ－６－デオキシ－Ｄ－マンノピラノシド（０．１９３ｇ、１ｍｍｏｌ）の水溶液（２ｍＬ）を加え、室温で４時間撹拌し、濃縮した。残渣をカラムクロマトグラフィー（オクダデシルシリル化シリカゲルを使用　メタノール／水＝６０／４０）で精製し、実施例７の化合物を０．２８ｇ（５２％）得た。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＣＤＣｌ_３）
δ：０．７６（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），１．０４－１．１２（２Ｈ，ｍ），１．３０－１．４０（２Ｈ，ｍ），３．０３（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ），３．２７（３Ｈ，ｓ），３．４０－３．５０（１Ｈ，ｍ），３．６０－３．６８（２Ｈ，ｍ），３．７２－３．９０（２Ｈ，ｍ），３．９４－４．０２（１Ｈ，ｍ），４．５９（１Ｈ，ｄ，Ｊ＝３．６Ｈｚ），５．７２（２Ｈ，ｂｒｓ），６．８６（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．０３（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．２３（２Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．３６（１Ｈ，ｓ），７．６１（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）：（［Ｍ＋Ｈ］^＋）５４０． (Example 7)
3- (Butylamino) -4-phenoxy-5-sulfamoyl-N-(((2R, 3S, 4S, 5S) -3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl ) Synthesis of methyl) benzamide (hereinafter the compound of Example 7):

To a solution of bumetanide (0.364 g, 1 mmol) in N, N-dimethylformamide (5 mL), EDCI (0.230 g, 1.2 mmol) and 1-hydroxybenzotriazole (0.162 g, 1.2 mmol) were sequentially added. Stir at 0 ° C. for 1 hour. To the reaction mixture was added an aqueous solution (2 mL) of methyl-6-amino-6-deoxy-D-mannopyranoside (0.193 g, 1 mmol), and the mixture was stirred at room temperature for 4 hours and concentrated. The residue was purified by column chromatography (using okdadecyl silylated silica gel, methanol / water = 60/40) to obtain 0.28 g (52%) of the compound of Example 7.
¹ H-NMR (600 MHz, CDCl ₃ )
δ: 0.76 (3H, t, J = 7.3 Hz), 1.04-1.12 (2H, m), 1.30-1.40 (2H, m), 3.03 (2H, t , J = 6.8 Hz), 3.27 (3H, s), 3.40-3.50 (1H, m), 3.60-3.68 (2H, m), 3.72-3.90. (2H, m), 3.94-4.02 (1H, m), 4.59 (1H, d, J = 3.6 Hz), 5.72 (2H, brs), 6.86 (2H, d , J = 8.0 Hz), 7.03 (1H, t, J = 7.4 Hz), 7.23 (2H, t, J = 7.8 Hz), 7.36 (1H, s), 7.61 (1H, s).
MS (ESI): ([M + H] ^< +>) 540.

　ブメタニドと２－アミノ－２－デオキシ－Ｄ－グルコピラノースを用いて、実施例７と同様の手順により、実施例８の化合物を合成した。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＤＭＳＯ－ｄ_６）
δ：０．７２（３Ｈ，ｔ，Ｊ＝６．６Ｈｚ），０．９８－１．１０（２Ｈ，ｍ），１．２８－１．４２（２Ｈ，ｍ），３．０４（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ），３．１２－３．３８（１Ｈ，ｍ），３．５０－３．６０（１Ｈ，ｍ），３．６０－３．７５（２Ｈ，ｍ），３．７５－３．９０（２Ｈ，ｍ），５．０５－５．２０（１Ｈ，ｍ），６．８２（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．０１（１Ｈ，ｔ，Ｊ＝７．４Ｈｚ），７．２５（２Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．４０（１Ｈ，ｓ），７．５８（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）：（［Ｍ＋Ｈ］^＋）５２６． (Example 8)
3- (Butylamino) -4-phenoxy-5-sulfamoyl-N-((3R, 4R, 5S, 6R) -2,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-3 Synthesis of -yl) benzamide (hereinafter the compound of Example 8):

The compound of Example 8 was synthesized by the same procedure as Example 7 using bumetanide and 2-amino-2-deoxy-D-glucopyranose.
¹ H-NMR (600 MHz, DMSO-d ₆ )
δ: 0.72 (3H, t, J = 6.6 Hz), 0.98-1.10 (2H, m), 1.28-1.42 (2H, m), 3.04 (2H, t , J = 6.8 Hz), 3.12-3.38 (1H, m), 3.50-3.60 (1H, m), 3.60-3.75 (2H, m), 3.75 -3.90 (2H, m), 5.05-5.20 (1H, m), 6.82 (2H, d, J = 8.0 Hz), 7.01 (1H, t, J = 7. 4 Hz), 7.25 (2H, t, J = 7.8 Hz), 7.40 (1 H, s), 7.58 (1 H, s).
MS (ESI): ([M + H] ⁺ ) 526.

　ブメタニドとメチル－６－アミノ－６－デオキシ－Ｄ－グルコピラノシドを用いて、実施例７と同様の手順により、実施例９の化合物を合成した。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＤＭＳＯ－ｄ_６）
δ：０．７７（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），１．０６－１．２０（２Ｈ，ｍ），１．３０－１．４０（２Ｈ，ｍ），２．９８（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ），３．０５－３．１２（２Ｈ，ｍ），３．１８－３．２５（１Ｈ，ｍ），３．３０－３．４０（１Ｈ，ｍ），３．３９（３Ｈ，ｓ），３．５２－３．６０（１Ｈ，ｍ），３．７０－３．８２（１Ｈ，ｍ），４．５５（１Ｈ，ｄ，Ｊ＝３．６Ｈｚ），６．８４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．００（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．２６（２Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．３９（１Ｈ，ｓ），７．６１（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）：（［Ｍ＋Ｈ］^＋）５４０． Example 9
3- (Butylamino) -4-phenoxy-5-sulfamoyl-N-(((2R, 3S, 4S, 5R) -3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl ) Synthesis of methyl) benzamide (hereinafter the compound of Example 9):

The compound of Example 9 was synthesized by the same procedure as Example 7 using bumetanide and methyl-6-amino-6-deoxy-D-glucopyranoside.
¹ H-NMR (600 MHz, DMSO-d ₆ )
δ: 0.77 (3H, t, J = 7.3 Hz), 1.06-1.20 (2H, m), 1.30-1.40 (2H, m), 2.98 (2H, t , J = 6.8 Hz), 3.05-3.12 (2H, m), 3.18-3.25 (1H, m), 3.30-3.40 (1H, m), 3.39. (3H, s), 3.52-3.60 (1H, m), 3.70-3.82 (1H, m), 4.55 (1H, d, J = 3.6 Hz), 6.84 (2H, d, J = 7.8 Hz), 7.00 (1H, t, J = 7.3 Hz), 7.26 (2H, t, J = 7.8 Hz), 7.39 (1H, s) , 7.61 (1H, s).
MS (ESI): ([M + H] ^< +>) 540.

　ブメタニドとメチル－６－アミノ－６－デオキシ－Ｄ－ガラクトピラノシドを用いて、実施例７と同様の手順により、実施例１０の化合物を合成した。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＤＭＳＯ－ｄ_６）
δ：０．７３（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），１．０２－１．１１（２Ｈ，ｍ），１．２８－１．３７（２Ｈ，ｍ），３．０３（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ），３．２５（３Ｈ，ｓ），３．３８－３．４８（２Ｈ，ｍ），３．５７（２Ｈ，ｄｄ，Ｊ＝３．４Ｈｚ，Ｊ＝２８．７Ｈｚ），３．６５－３．７２（１Ｈ，ｍ），３．７８－３．８５（１Ｈ，ｍ），４．５７（１Ｈ，ｄ，Ｊ＝３．６Ｈｚ），６．８１（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．００（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．２５（２Ｈ，ｔ，Ｊ＝７．９Ｈｚ），７．３４（１Ｈ，ｓ），７．５５（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）：（［Ｍ＋Ｈ］^＋）５４０． (Example 10)
3- (Butylamino) -4-phenoxy-5-sulfamoyl-N-(((2R, 3R, 4S, 5R) -3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl ) Synthesis of methyl) benzamide (hereinafter the compound of Example 10):

The compound of Example 10 was synthesized by the same procedure as Example 7 using bumetanide and methyl-6-amino-6-deoxy-D-galactopyranoside.
¹ H-NMR (600 MHz, DMSO-d ₆ )
δ: 0.73 (3H, t, J = 7.3 Hz), 1.02-1.11 (2H, m), 1.28-1.37 (2H, m), 3.03 (2H, t , J = 6.8 Hz), 3.25 (3H, s), 3.38-3.48 (2H, m), 3.57 (2H, dd, J = 3.4 Hz, J = 28.7 Hz) , 3.65-3.72 (1H, m), 3.78-3.85 (1H, m), 4.57 (1H, d, J = 3.6 Hz), 6.81 (2H, d, J = 7.8 Hz), 7.00 (1 H, t, J = 7.3 Hz), 7.25 (2 H, t, J = 7.9 Hz), 7.34 (1 H, s), 7.55 ( 1H, s).
MS (ESI): ([M + H] ^< +>) 540.

　ブメタニドと１－アミノ－１－デオキシ－Ｄ－ガラクトピラノシドを用いて、実施例７と同様の手順により、実施例１１の化合物を合成した。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＣＤ_３ＯＤ）
δ：０．７３（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），１．０３－１．１６（２Ｈ，ｍ），１．３０－１．３７（２Ｈ，ｍ），３．０２－３．１２（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ），３．４８－３．５５（１Ｈ，ｍ），３．５７－３．７３（４Ｈ，ｍ），３．８０－３．８８（１Ｈ，ｍ），５．０３（１Ｈ，ｄ，Ｊ＝９．１Ｈｚ），６．８３（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），６．９７（１Ｈ，ｔ，Ｊ＝７．０Ｈｚ），７．２０（２Ｈ，ｔ，Ｊ＝７．７Ｈｚ），７．５９（１Ｈ，ｓ），７．６６（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）：（［Ｍ－Ｈ］^－）５２４． (Example 11)
3- (Butylamino) -4-phenoxy-5-sulfamoyl-N-((3R, 4S, 5R, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-2 -Il) Synthesis of benzamide (hereinafter the compound of Example 11):

The compound of Example 11 was synthesized by the same procedure as Example 7 using bumetanide and 1-amino-1-deoxy-D-galactopyranoside.
¹ H-NMR (600 MHz, CD ₃ OD)
δ: 0.73 (3H, t, J = 7.3 Hz), 1.03-1.16 (2H, m), 1.30-1.37 (2H, m), 3.02-3.12 (2H, t, J = 6.8 Hz), 3.48-3.55 (1H, m), 3.57-3.73 (4H, m), 3.80-3.88 (1H, m) , 5.03 (1H, d, J = 9.1 Hz), 6.83 (2H, d, J = 8.5 Hz), 6.97 (1H, t, J = 7.0 Hz), 7.20 ( 2H, t, J = 7.7 Hz), 7.59 (1H, s), 7.66 (1H, s).
MS (ESI): ([M−H] ⁻ ) 524.

　Ｎ―（ｔｅｒｔ―ブトキシカルボニル)スレオニン（１．６６ｇ、７．５７ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（１５ｍＬ）溶液に、室温下、炭酸カリウム（１．１４ｇ、８．３ｍｍｏｌ）、パラメトキシベンジルクロリド（１．３１ｇ、８．３ｍｍｏｌ）、ヨウ化ナトリウム（１．２６ｇ、８．３ｍｍｏｌ）を順次加え、室温で一晩撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥し、濃縮した。残渣をカラムクロマトグラフィー（石油エーテル／酢酸エチル＝７５／２５）で精製し、参考例３の化合物を１．６２ｇ（６３％）得た。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＣＤＣｌ_３）
δ：１．２１（３Ｈ，ｄ，Ｊ＝６．６Ｈｚ），１．４４（９Ｈ，ｓ），３．８０（３Ｈ，ｍ），　４．２４－４．３０（２Ｈ，ｍ），５．１０－５．１７（２Ｈ，ｄｄ，Ｊ＝１２．０Ｈｚ），５．３３（１Ｈ，ｄ，Ｊ＝７．２Ｈｚ），６．８７（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．２８（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ）． Example 12
Synthesis of (2S, 3S) -2-amino-3-((3- (butylamino) -4-phenoxy-5-sulfamoylbenzoyl) oxy) butanoic acid (hereinafter the compound of Example 12):
[Step 1]
Synthesis of N- (tert-butoxycarbonyl) threonine-4-methoxybenzyl ester (hereinafter referred to as compound of Reference Example 3)

To a solution of N- (tert-butoxycarbonyl) threonine (1.66 g, 7.57 mmol) in N, N-dimethylformamide (15 mL) at room temperature, potassium carbonate (1.14 g, 8.3 mmol), paramethoxybenzyl chloride. (1.31 g, 8.3 mmol) and sodium iodide (1.26 g, 8.3 mmol) were sequentially added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 75/25) to obtain 1.62 g (63%) of the compound of Reference Example 3.
¹ H-NMR (600 MHz, CDCl ₃ )
δ: 1.21 (3H, d, J = 6.6 Hz), 1.44 (9H, s), 3.80 (3H, m), 4.24-4.30 (2H, m), 5. 10-5.17 (2H, dd, J = 12.0 Hz), 5.33 (1H, d, J = 7.2 Hz), 6.87 (2H, d, J = 8.4 Hz), 7.28 (2H, d, J = 8.4 Hz).

　ブメタニド（０．３８３ｇ、１．０５ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（５ｍＬ）溶液に、室温下、ＥＤＣＩ（０．２０２ｇ、１．０５ｍｍｏｌ）、ＤＭＡＰ（０．２５６ｇ、２．１ｍｍｏｌ）を順次加え、室温で１５分間撹拌した。反応混合物に、参考例３の化合物（０．３２６ｇ、０．９６ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（５ｍＬ）溶液、１－ヒドロキシベンゾトリアゾール（０．１４２ｇ、１．０５ｍｍｏｌ）を順次加え、室温で一晩撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥し、濃縮した。残渣をカラムクロマトグラフィー（石油エーテル／酢酸エチル＝６７／３３）で精製し、（２Ｓ，３Ｓ）－３－（（ｔｅｒｔ―ブトキシカルボニル）アミノ）－４－（（４－メトキシベンジル）オキシ）－４－オキソブタン－２－イル　３－（ブチルアミノ）－４－フェノキシ－５－スルファモイルベンゾエートを０．３３６ｇ（５１％）得た。得られた化合物（０．３５ｇ、０．５１ｍｍｏＬ）のメタノール（５ｍＬ）溶液に、１０重量％パラジウム／炭素（０．０１ｇ）を加え、水素雰囲気下、室温で一晩撹拌した。反応混合物をセライトろ過し、ろ液を濃縮した。残渣のジクロロメタン（２ｍＬ）溶液に、氷冷下、トリフルオロ酢酸（０．５ｍＬ）のジクロロメタン（３ｍＬ）溶液を加え、室温で１時間撹拌し、反応混合物を濃縮した。残渣をカラムクロマトグラフィー（オクタデシルシリル化シリカゲルを使用　メタノール／０．１％ギ酸水溶液＝６５／３５）で精製し、実施例１２の化合物を０．１９６ｇ（８０％）得た。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＤＭＳＯ－ｄ_６）
δ：０．７０（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），１．００－１．０６（２Ｈ，ｍ），１．２７－１．３２（２Ｈ，ｍ），１．３４（３Ｈ，ｄ，Ｊ＝５．４Ｈｚ），３．００－３．０３（２Ｈ，ｍ），３．４６－３．５５（１Ｈ，ｍ），４．９２（１Ｈ，ｔ，Ｊ＝５．４Ｈｚ），５．３７－５．４１（１Ｈ，ｍ），６．７７（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），６．９４（１Ｈ，ｔ，Ｊ＝７．２Ｈｚ），７．１９（２Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．２７（２Ｈ，ｂｒｓ），７．４２（１Ｈ，ｓ），７．６６（１Ｈ，ｄ，Ｊ＝１．２Ｈｚ）．
ＭＳ（ＥＳＩ）：（［Ｍ＋Ｈ］^＋）４６６． [Step 2]
Synthesis of the compound of Example 12:

EDCI (0.202 g, 1.05 mmol) and DMAP (0.256 g, 2.1 mmol) were sequentially added to a solution of bumetanide (0.383 g, 1.05 mmol) in N, N-dimethylformamide (5 mL) at room temperature. And stirred at room temperature for 15 minutes. To the reaction mixture, a solution of the compound of Reference Example 3 (0.326 g, 0.96 mmol) in N, N-dimethylformamide (5 mL) and 1-hydroxybenzotriazole (0.142 g, 1.05 mmol) were successively added at room temperature. Stir overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 67/33) and (2S, 3S) -3-((tert-butoxycarbonyl) amino) -4-((4-methoxybenzyl) oxy)- 0.336 g (51%) of 4-oxobutan-2-yl 3- (butylamino) -4-phenoxy-5-sulfamoylbenzoate was obtained. To a solution of the obtained compound (0.35 g, 0.51 mmol) in methanol (5 mL) was added 10 wt% palladium / carbon (0.01 g), and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated. To a dichloromethane (2 mL) solution of the residue was added a solution of trifluoroacetic acid (0.5 mL) in dichloromethane (3 mL) under ice cooling, and the mixture was stirred at room temperature for 1 hour, and the reaction mixture was concentrated. The residue was purified by column chromatography (using octadecylsilylated silica gel, methanol / 0.1% aqueous formic acid = 65/35) to obtain 0.196 g (80%) of the compound of Example 12.
¹ H-NMR (600 MHz, DMSO-d ₆ )
δ: 0.70 (3H, t, J = 7.2 Hz), 1.00-1.06 (2H, m), 1.27-1.32 (2H, m), 1.34 (3H, d , J = 5.4 Hz), 3.00-3.03 (2H, m), 3.46-3.55 (1H, m), 4.92 (1H, t, J = 5.4 Hz), 5 .37-5.41 (1H, m), 6.77 (2H, d, J = 8.4 Hz), 6.94 (1H, t, J = 7.2 Hz), 7.19 (2H, t, J = 7.8 Hz), 7.27 (2H, brs), 7.42 (1 H, s), 7.66 (1 H, d, J = 1.2 Hz).
MS (ESI): ([M + H] ⁺ ) 466.

　ブメタニドとＮ―（ｔｅｒｔ―ブトキシカルボニル)セリン－４－メトキシベンジルエステルを用いて、実施例１２と同様の手順により、実施例１３の化合物を合成した。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＤＭＳＯ－ｄ_６）
δ：０．７７（３Ｈ，ｔ，Ｊ＝６．８Ｈｚ），１．０５－１．１８（２Ｈ，ｍ），１．３２－１．４３（２Ｈ，ｍ），３．０５－３．１２（２Ｈ，ｍ），３．７４－３．８０（１Ｈ，ｍ），４．４３－４．４８（１Ｈ，ｍ），４．６８－４．７４（１Ｈ，ｍ），５．０１－５．０７（１Ｈ，ｍ），６．８５（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．０１（１Ｈ，ｔ，Ｊ＝７．２Ｈｚ），７．２６（２Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．５０（１Ｈ，ｓ），７．７５（１Ｈ，ｄ，Ｊ＝１．２Ｈｚ）．
ＭＳ（ＥＳＩ）：（［Ｍ－Ｈ］^－）４５０． (Example 13)
Synthesis of (S) -2-amino-3-((3- (butylamino) -4-phenoxy-5-sulfamoylbenzoyl) oxy) propanoic acid (hereinafter the compound of Example 13):

The compound of Example 13 was synthesized by the same procedure as Example 12 using bumetanide and N- (tert-butoxycarbonyl) serine-4-methoxybenzyl ester.
¹ H-NMR (600 MHz, DMSO-d ₆ )
δ: 0.77 (3H, t, J = 6.8 Hz), 1.05-1.18 (2H, m), 1.32-1.43 (2H, m), 3.05-3.12. (2H, m), 3.74-3.80 (1H, m), 4.43-4.48 (1H, m), 4.68-4.74 (1H, m), 5.01-5 .07 (1H, m), 6.85 (2H, d, J = 8.4 Hz), 7.01 (1H, t, J = 7.2 Hz), 7.26 (2H, t, J = 7. 8 Hz), 7.50 (1 H, s), 7.75 (1 H, d, J = 1.2 Hz).
MS (ESI): ([M−H] ⁻ ) 450.

　参考例１の化合物とＮ―（ｔｅｒｔ―ブトキシカルボニル）イソロイシンを用いて、上記実施例１と同様の手順により、比較例１の化合物を合成した。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＤＭＳＯ－ｄ_６）
δ：０．７０－０．９０（９Ｈ，ｍ），１．０４－１．５０（６Ｈ，ｍ），１．７５－１．８６（１Ｈ，ｍ），２．８８－３．１０（３Ｈ，ｍ），４．５０（１Ｈ，ｂｒｓ），６．７５（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），６．９６（１Ｈ，ｔ，Ｊ＝７．２Ｈｚ），７．２５（３Ｈ，ｍ），７．５０（２Ｈ，ｂｒｓ），７．８２（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）：（［Ｍ－Ｈ］－）４７６． (Comparative Example 1)
Synthesis of 3- (N-((2S, 3S) -2-amino-3-methylpentanoyl) sulfamoyl) -5- (butylamino) -4-phenoxybenzoic acid (hereinafter, compound of Comparative Example 1):

Using the compound of Reference Example 1 and N- (tert-butoxycarbonyl) isoleucine, the compound of Comparative Example 1 was synthesized by the same procedure as in Example 1 above.
¹ H-NMR (600 MHz, DMSO-d ₆ )
δ: 0.70-0.90 (9H, m), 1.04-1.50 (6H, m), 1.75-1.86 (1H, m), 2.88-3.10 (3H , M), 4.50 (1H, brs), 6.75 (2H, d, J = 8.4 Hz), 6.96 (1H, t, J = 7.2 Hz), 7.25 (3H, m ), 7.50 (2H, brs), 7.82 (1H, s).
MS (ESI): ([MH]-) 476.

　参考例１の化合物とＮ―（ｔｅｒｔ―ブトキシカルボニル)プロリンを用いて、実施例１と同様の手順により、比較例２の化合物を合成した。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＤＭＳＯ－ｄ_６）
δ：０．７６（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），１．０６－１．１５（２Ｈ，ｍ），１．３０－１．４０（２Ｈ，ｍ），１．６２－１．８０（３Ｈ，ｍ），２．００－２．１０（１Ｈ，ｍ），３．００－３．２０（４Ｈ，ｍ），３．５０－３．７０（１Ｈ，ｍ），４．８２（１Ｈ，ｂｒｓ），６．７７（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．０１（１Ｈ，ｔ，Ｊ＝７．２Ｈｚ），７．２７（２Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．３７（１Ｈ，ｓ），７．８０（１Ｈ，ｓ），８．３０（１Ｈ，ｂｒｓ），８．９５（１Ｈ，ｂｒｓ）．
ＭＳ（ＥＳＩ）：（［Ｍ－Ｈ］－）４６０． (Comparative Example 2)
Synthesis of (S) -3- (butylamino) -4-phenoxy-5- (N- (pyrrolidine-2-carbonyl) sulfamoyl) benzoic acid (hereinafter, compound of Comparative Example 2):

The compound of Comparative Example 2 was synthesized by the same procedure as Example 1 using the compound of Reference Example 1 and N- (tert-butoxycarbonyl) proline.
¹ H-NMR (600 MHz, DMSO-d ₆ )
δ: 0.76 (3H, t, J = 7.2 Hz), 1.06-1.15 (2H, m), 1.30-1.40 (2H, m), 1.62-1.80 (3H, m), 2.00-2.10 (1H, m), 3.00-3.20 (4H, m), 3.50-3.70 (1H, m), 4.82 (1H , Brs), 6.77 (2H, d, J = 8.4 Hz), 7.01 (1H, t, J = 7.2 Hz), 7.27 (2H, t, J = 7.8 Hz), 7 .37 (1H, s), 7.80 (1H, s), 8.30 (1H, brs), 8.95 (1H, brs).
MS (ESI): ([M−H] −) 460.

　参考例２の化合物（０．４５４ｇ、１ｍｍｏｌ）と１，２，３，４，６－ペンタ－Ｏ－アセチル－Ｄ－グルコピラノース（０．３９０ｇ、１ｍｍｏｌ）のトルエン（４０ｍＬ）溶液に、室温下、三フッ化ホウ素エーテル錯体（０．５ｍＬ）を加え、９０℃で２時間撹拌した。反応混合物を室温に冷却し、冷水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥し、濃縮した。残渣をカラムクロマトグラフィー（石油エーテル／酢酸エチル＝７５／２５）で精製し、（２Ｒ，３Ｒ，４Ｓ，５Ｒ）－２－（アセトキシメチル）－６－（５－（（ベンジルオキシ）カルボニル）－３－（ブチルアミノ）－２－フェノキシフェニルスルホンアミド）テトラヒドロ－２Ｈ－ピラン－３，４，５－トリイル　トリアセテートを０．０９１ｇ（１２％）得た。得られた化合物（０．０７８ｇ、０．１ｍｍｏｌ）のメタノール（１０ｍＬ）溶液に、１０重量％パラジウム／炭素（０．０１ｇ）を加え、水素雰囲気下、室温で一晩撹拌した。反応混合物をセライトろ過し、ろ液を濃縮した。残渣をカラムクロマトグラフィー（オクタデシルシリル化シリカゲルを使用　メタノール／０．１％ギ酸水溶液＝８５／１５）で精製し、比較例３の化合物を０．０４５ｇ（６５％）得た。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＣＤＣｌ_３）
δ：０．８２（３Ｈ，ｔ，Ｊ＝７．４Ｈｚ），１．１０－１．２０（２Ｈ，ｍ），１．３８－１．４６（２Ｈ，ｍ），１．９０－２．２０（１２Ｈ，ｍ），３．１３（２Ｈ，ｔ，Ｊ＝６．４Ｈｚ），３．６０－３．７０（１Ｈ，ｍ），３．７４－３．８１（１Ｈ，ｍ），４．００－４．１２（１Ｈ，ｍ），４．７０－４．８０（２Ｈ，ｍ），４．９０－５．１２（１Ｈ，ｍ），５．２０－５．２５（１Ｈ，ｍ），６．９６（２Ｈ，ｄ，Ｊ＝８．１Ｈｚ），７．１４（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．３０－７．４０（２Ｈ，ｍ），７．６０（１Ｈ，ｓ），８．００（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）：（［Ｍ－Ｈ］－）６９３． (Comparative Example 3)
3- (Butylamino) -4-phenoxy-5- (N-((3R, 4S, 5R, 6R) -3,4,5-triacetoxy-6- (acetoxymethyl) tetrahydro-2H-pyran-2- Yl) sulfamoyl) benzoic acid (compound of Comparative Example 3):

To a solution of the compound of Reference Example 2 (0.454 g, 1 mmol) and 1,2,3,4,6-penta-O-acetyl-D-glucopyranose (0.390 g, 1 mmol) in toluene (40 mL) at room temperature. , Boron trifluoride ether complex (0.5 mL) was added, and the mixture was stirred at 90 ° C. for 2 hours. The reaction mixture was cooled to room temperature, cold water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 75/25) and (2R, 3R, 4S, 5R) -2- (acetoxymethyl) -6- (5-((benzyloxy) carbonyl)- 0.091 g (12%) of 3- (butylamino) -2-phenoxyphenylsulfonamido) tetrahydro-2H-pyran-3,4,5-triyl triacetate was obtained. To a solution of the obtained compound (0.078 g, 0.1 mmol) in methanol (10 mL) was added 10 wt% palladium / carbon (0.01 g), and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated. The residue was purified by column chromatography (using octadecylsilyl silica gel, methanol / 0.1% aqueous formic acid solution = 85/15) to obtain 0.045 g (65%) of the compound of Comparative Example 3.
¹ H-NMR (600 MHz, CDCl ₃ )
δ: 0.82 (3H, t, J = 7.4 Hz), 1.10-1.20 (2H, m), 1.38-1.46 (2H, m), 1.90-2.20 (12H, m), 3.13 (2H, t, J = 6.4 Hz), 3.60-3.70 (1H, m), 3.74-3.81 (1H, m), 4.00 -4.12 (1H, m), 4.70-4.80 (2H, m), 4.90-5.12 (1H, m), 5.20-5.25 (1H, m), 6 .96 (2H, d, J = 8.1 Hz), 7.14 (1H, t, J = 7.3 Hz), 7.30-7.40 (2H, m), 7.60 (1H, s) , 8.00 (1H, s).
MS (ESI): ([MH]-) 693.

　ブメタニド（０．３６４ｇ、１ｍｍｏｌ）のエタノール（５ｍＬ）溶液に、室温下、濃硫酸（０．１ｍＬ）を加え、７０℃で８時間撹拌した。反応混合物を室温に冷却し、フィルターろ過し、得られた固体をエタノールで洗浄し、エチル　３－（ブチルアミノ）－４－フェノキシ－５－スルファモイルベンゾエート（以下、参考例４の化合物）を０．３５１ｇ（９０％）得た。参考例４の化合物（０．３９２ｇ、１ｍｍｏｌ）と１，２，３，４，６－ペンタ－Ｏ－アセチル－Ｄ－グルコピラノース（０．３９０ｇ、１ｍｍｏｌ）のトルエン（４０ｍＬ）溶液に、室温下、三フッ化ホウ素エーテル錯体（０．５ｍＬ）を加え、９０℃で２時間撹拌した。反応混合物を室温に冷却し、冷水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥し、濃縮した。残渣をカラムクロマトグラフィー（石油エーテル／酢酸エチル＝７５／２５）で精製し、比較例４の化合物を０．０８３ｇ（１２％）得た。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＣＤＣｌ_３）
δ：０．８２（３Ｈ，ｔ，Ｊ＝７．０Ｈｚ），１．１０－１．２０（２Ｈ，ｍ），１．３５－１．４８（５Ｈ，ｍ），１．９０－２．２０（１２Ｈ，ｍ），３．０９（２Ｈ，ｔ，Ｊ＝６．４Ｈｚ），３．５９（１Ｈ，ｄ，Ｊ＝９．２Ｈｚ），３．７４（１Ｈ，ｄ，Ｊ＝１２．１Ｈｚ），４．０５（１Ｈ，ｄ，Ｊ＝９．４Ｈｚ），４．４０（２Ｈ，ｔ，Ｊ＝６．４Ｈｚ），４．７０－４．８０（１Ｈ，ｍ），４．９４（１Ｈ，ｔ，Ｊ＝９．４Ｈｚ），５．２０（１Ｈ，ｔ，Ｊ＝９．２Ｈｚ），５．６４（１Ｈ，ｄ，Ｊ＝９．４Ｈｚ），６．９４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．１３（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．３３（２Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．５５（１Ｈ，ｓ），７．９１（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）：（［Ｍ－Ｈ］^－）７２１． (Comparative Example 4)
(2R, 3R, 4S, 5R) -2- (acetoxymethyl) -6- (3- (butylamino) -5- (ethoxycarbonyl) -2-phenoxyphenylsulfonamido) tetrahydro-2H-pyran-3,4 , 5-Triyl triacetate (Compound of Comparative Example 4):

Concentrated sulfuric acid (0.1 mL) was added to a solution of bumetanide (0.364 g, 1 mmol) in ethanol (5 mL) at room temperature, and the mixture was stirred at 70 ° C. for 8 hours. The reaction mixture was cooled to room temperature, filtered, and the resulting solid was washed with ethanol, and ethyl 3- (butylamino) -4-phenoxy-5-sulfamoylbenzoate (hereinafter referred to as the compound of Reference Example 4) was added. 0.351 g (90%) was obtained. To a solution of the compound of Reference Example 4 (0.392 g, 1 mmol) and 1,2,3,4,6-penta-O-acetyl-D-glucopyranose (0.390 g, 1 mmol) in toluene (40 mL) at room temperature. , Boron trifluoride ether complex (0.5 mL) was added, and the mixture was stirred at 90 ° C. for 2 hours. The reaction mixture was cooled to room temperature, cold water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 75/25) to obtain 0.083 g (12%) of the compound of Comparative Example 4.
¹ H-NMR (600 MHz, CDCl ₃ )
δ: 0.82 (3H, t, J = 7.0 Hz), 1.10-1.20 (2H, m), 1.35-1.48 (5H, m), 1.90-2.20 (12H, m), 3.09 (2H, t, J = 6.4 Hz), 3.59 (1H, d, J = 9.2 Hz), 3.74 (1H, d, J = 12.1 Hz) , 4.05 (1H, d, J = 9.4 Hz), 4.40 (2H, t, J = 6.4 Hz), 4.70-4.80 (1H, m), 4.94 (1H, t, J = 9.4 Hz), 5.20 (1H, t, J = 9.2 Hz), 5.64 (1H, d, J = 9.4 Hz), 6.94 (2H, d, J = 7) .8 Hz), 7.13 (1 H, t, J = 7.3 Hz), 7.33 (2 H, t, J = 7.8 Hz), 7.55 (1 H, s), 7.91 (1 H, s) ).
MS (ESI): ([M−H] ⁻ ) 721.

　室温下、ブメタニド（１．０９ｇ、３ｍｍｏｌ）のエタノール（１５ｍＬ）溶液に、硫酸（０．５ｍＬ）を加え、１０時間還流した。反応混合物を室温に冷却し、濃縮した。残渣に飽和炭酸ナトリウム水溶液（１００ｍＬ）を加え、酢酸エチル（１２０ｍＬ）で抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、濃縮し、参考例４の化合物を１．１２ｇ（９５％）得た。
ＭＳ（ＥＳＩ）：（［Ｍ＋Ｈ］^＋）３９３． (Example 14)
Ethyl 3- (butylamino) -4-phenoxy-5- (N-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-2 Synthesis of -yl) sulfamoyl) benzoate (compound of Example 14 hereinafter):
[Step 1]
Synthesis of the compound of Reference Example 4:

Sulfuric acid (0.5 mL) was added to a solution of bumetanide (1.09 g, 3 mmol) in ethanol (15 mL) at room temperature and refluxed for 10 hours. The reaction mixture was cooled to room temperature and concentrated. A saturated aqueous sodium carbonate solution (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate (120 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 1.12 g (95%) of the compound of Reference Example 4.
MS (ESI): ([M + H] ^< +>) 393.

　室温下、参考例４の化合物（０．３９２ｇ、１ｍｍｏｌ）と（３Ｒ，４Ｓ，５Ｒ，６Ｒ）－６－（アセトキシメチル）テトラヒドロ－２Ｈ－ピラン－２，３，４，５－テトライル　テトラアセテート（０．３９０ｇ、１ｍｍｏｌ）のトルエン（４０ｍＬ）溶液に、三フッ化ホウ素エーテル錯体（０．５ｍＬ）を加え、９０℃で２時間撹拌した。反応混合物を室温に冷却し、冷水（３０ｍＬ）を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液（３０ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥し、濃縮した。残渣をカラムクロマトグラフィー（石油エーテル／酢酸エチル＝８０／２０）で精製し、比較例４の化合物を０．１２２ｇ（１７％）得た。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＣＤＣｌ_３）
δ：０．８２（３Ｈ，ｔ，Ｊ＝７．０Ｈｚ），１．１０－１．２０（２Ｈ，ｍ），１．３５－１．４８（５Ｈ，ｍ），１．９０－２．２０（１２Ｈ，ｍ），３．０９（２Ｈ，ｔ，Ｊ＝６．４Ｈｚ），３．５９（１Ｈ，ｄ，Ｊ＝９．２Ｈｚ），３．７４（１Ｈ，ｄ，Ｊ＝１２．１Ｈｚ），４．０５（１Ｈ，ｄ，Ｊ＝９．４Ｈｚ），４．４０（２Ｈ，ｔ，Ｊ＝６．４Ｈｚ），４．７０－４．８０（１Ｈ，ｍ），４．９４（１Ｈ，ｔ，Ｊ＝９．４Ｈｚ），５．２０（１Ｈ，ｔ，Ｊ＝９．２Ｈｚ），５．６４（１Ｈ，ｄ，Ｊ＝９．４Ｈｚ），６．９４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．１３（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．３３（２Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．５５（１Ｈ，ｓ），７．９１（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）：（［Ｍ－Ｈ］^－）７２１． [Step 2]
Synthesis of the compound of Comparative Example 4:

At room temperature, the compound of Reference Example 4 (0.392 g, 1 mmol) and (3R, 4S, 5R, 6R) -6- (acetoxymethyl) tetrahydro-2H-pyran-2,3,4,5-tetrayl tetraacetate ( Boron trifluoride ether complex (0.5 mL) was added to a toluene (40 mL) solution of 0.390 g, 1 mmol), and the mixture was stirred at 90 ° C. for 2 hours. The reaction mixture was cooled to room temperature, cold water (30 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 80/20) to obtain 0.122 g (17%) of the compound of Comparative Example 4.
¹ H-NMR (600 MHz, CDCl ₃ )
δ: 0.82 (3H, t, J = 7.0 Hz), 1.10-1.20 (2H, m), 1.35-1.48 (5H, m), 1.90-2.20 (12H, m), 3.09 (2H, t, J = 6.4 Hz), 3.59 (1H, d, J = 9.2 Hz), 3.74 (1H, d, J = 12.1 Hz) , 4.05 (1H, d, J = 9.4 Hz), 4.40 (2H, t, J = 6.4 Hz), 4.70-4.80 (1H, m), 4.94 (1H, t, J = 9.4 Hz), 5.20 (1H, t, J = 9.2 Hz), 5.64 (1H, d, J = 9.4 Hz), 6.94 (2H, d, J = 7) .8 Hz), 7.13 (1 H, t, J = 7.3 Hz), 7.33 (2 H, t, J = 7.8 Hz), 7.55 (1 H, s), 7.91 (1 H, s) ).
MS (ESI): ([M−H] ⁻ ) 721.

比較例４の化合物（０．０７２ｇ、０．１ｍｍｏｌ）のメタノール（１ｍＬ）溶液に、炭酸カリウム（０．０６９ｇ、０．５ｍｍｏｌ）を加え、室温で１時間撹拌した。ＨＰＬＣ（カラム：ダイソーゲル（商標登録）、２５０×２０ｍｍ、Ｃ１８、１０μｍ；　溶出液：７５％メタノール、２５％蒸留水、０．１ｖ％ギ酸；　流速：２０ｍＬ／ｍｉｎ、室温）で分取し、実施例１４の化合物を０．０４８ｇ（８７％）得た。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＣＤＣｌ_３）
δ：０．７７（３Ｈ，ｔ，Ｊ＝１０．８Ｈｚ），１．０４－１．１２（２Ｈ，ｍ），１．３３－１．３６（５Ｈ，ｍ），３．０１－３．０４（３Ｈ，ｍ），３．３３－３．５２（５Ｈ，ｍ），４．３１－４．３６（２Ｈ，ｍ），４．５３（１Ｈ，ｔ，Ｊ＝１３．８Ｈｚ），６．８６（２Ｈ，ｄ，Ｊ＝１１．４Ｈｚ），６．９６（１Ｈ，ｔ，Ｊ＝１０．８Ｈｚ），７．１７（２Ｈ，ｔ，Ｊ＝５．４Ｈｚ），７．５１（１Ｈ，ｓ），７．９５（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）：（［Ｍ－Ｈ］^－）５５３． [Step 3]
Synthesis of the compound of Example 14:

To a solution of the compound of Comparative Example 4 (0.072 g, 0.1 mmol) in methanol (1 mL) was added potassium carbonate (0.069 g, 0.5 mmol), and the mixture was stirred at room temperature for 1 hour. Fractionated by HPLC (column: Daiso Gel (registered trademark), 250 × 20 mm, C18, 10 μm; eluent: 75% methanol, 25% distilled water, 0.1 v% formic acid; flow rate: 20 mL / min, room temperature) 0.048 g (87%) of the compound of Example 14 was obtained.
¹ H-NMR (600 MHz, CDCl ₃ )
δ: 0.77 (3H, t, J = 10.8 Hz), 1.04-1.12 (2H, m), 1.33-1.36 (5H, m), 3.01-3.04 (3H, m), 3.33-3.52 (5H, m), 4.31-4.36 (2H, m), 4.53 (1H, t, J = 13.8 Hz), 6.86 (2H, d, J = 11.4 Hz), 6.96 (1H, t, J = 10.8 Hz), 7.17 (2H, t, J = 5.4 Hz), 7.51 (1H, s) , 7.95 (1H, s).
MS (ESI): ([M−H] ⁻ ) 553.

　参考例４の化合物と（３Ｓ，４Ｓ，５Ｒ，６Ｒ）－６－（アセトキシメチル）テトラヒドロ－２Ｈ－ピラン－２，３，４，５－テトライル　テトラアセテートを用いて、実施例１４と同様の手順により、実施例１５の化合物を合成した。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＣＤＣｌ_３）
δ：０．７７（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），１．０５－１．１２（２Ｈ，ｍ），１．３５－１．３７（５Ｈ，ｍ），３．０４－３．０５（２Ｈ，ｍ），３．４４－３．４７（３Ｈ，ｍ），３．６４－３．８０（３Ｈ，ｍ），４．３３－４．３６（２Ｈ，ｍ），４．７５（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），６．８５－６．８９（２Ｈ，ｍ），７．００－７．０３（１Ｈ，ｍ），７．２１－７．２４（２Ｈ，ｍ），７．５１（１Ｈ，ｓ），７．９２（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）：（［Ｍ－Ｈ］^－）５５３． (Example 15)
Ethyl 3- (butylamino) -4-phenoxy-5- (N-((3S, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-2 Synthesis of -yl) sulfamoyl) benzoate (compound of Example 15 hereinafter):

Procedures similar to those in Example 14 using the compound of Reference Example 4 and (3S, 4S, 5R, 6R) -6- (acetoxymethyl) tetrahydro-2H-pyran-2,3,4,5-tetrayl tetraacetate Thus, the compound of Example 15 was synthesized.
¹ H-NMR (600 MHz, CDCl ₃ )
δ: 0.77 (3H, t, J = 7.2 Hz), 1.05-1.12 (2H, m), 1.35-1.37 (5H, m), 3.04-3.05 (2H, m), 3.44-3.47 (3H, m), 3.64-3.80 (3H, m), 4.33-4.36 (2H, m), 4.75 (1H , D, J = 9.0 Hz), 6.85-6.89 (2H, m), 7.00-7.03 (1H, m), 7.21-7.24 (2H, m), 7 .51 (1H, s), 7.92 (1H, s).
MS (ESI): ([M−H] ⁻ ) 553.

　参考例４の化合物と（３Ｒ，４Ｓ，５Ｓ，６Ｒ）－６－（アセトキシメチル）テトラヒドロ－２Ｈ－ピラン－２，３，４，５－テトライル　テトラアセテートを用いて、実施例１４と同様の手順により、実施例１６の化合物を合成した。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＣＤ_３ＯＤ）
δ：０．８３－０．８５（３Ｈ，ｍ），１．１８－１．１９（２Ｈ，ｍ），１．４３－１．４４（５Ｈ，ｍ），３．１２－３．３１（２Ｈ，ｍ），３．４３－３．４４（１Ｈ，ｍ），３．５０－３．５１（２Ｈ，ｍ），３．８８－３．９７（１Ｈ，ｍ），４．４１－４．４２（２Ｈ，ｍ），４．４９－４．５０（１Ｈ，ｍ），６．９３－６．９４（２Ｈ，ｍ），７．０７－７．０８（１Ｈ，ｍ），７．３１－７．３２（２Ｈ，ｍ），７．５６－７．５９（１Ｈ，ｍ），７．８７－７．９３（１Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：（［Ｍ－Ｈ］^－）５５３． (Example 16)
Ethyl 3- (butylamino) -4-phenoxy-5- (N-((3R, 4S, 5R, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-2 Synthesis of -yl) sulfamoyl) benzoate (compound of Example 16 hereinafter):

Procedures similar to those of Example 14 using the compound of Reference Example 4 and (3R, 4S, 5S, 6R) -6- (acetoxymethyl) tetrahydro-2H-pyran-2,3,4,5-tetrayl tetraacetate Thus, the compound of Example 16 was synthesized.
¹ H-NMR (600 MHz, CD ₃ OD)
δ: 0.83-0.85 (3H, m), 1.18-1.19 (2H, m), 1.43-1.44 (5H, m), 3.12-3.31 (2H M), 3.43-3.44 (1H, m), 3.50-3.51 (2H, m), 3.88-3.97 (1H, m), 4.41-4.42. (2H, m), 4.49-4.50 (1H, m), 6.93-6.94 (2H, m), 7.07-7.08 (1H, m), 7.31-7 .32 (2H, m), 7.56-7.59 (1H, m), 7.87-7.93 (1H, m).
MS (ESI): ([M−H] ⁻ ) 553.

　０℃下、（Ｓ）－２－（（ｔｅｒｔ－ブトキシカルボニル）アミノ）スクシニック酸（０．６９９ｇ，３ｍｍｏｌ）の酢酸エチル（１０ｍＬ）溶液に、ＤＣＣ（０．６１８ｇ，３ｍｍｏｌ）を加え、１時間撹拌した。室温まで昇温し、１時間撹拌した。反応混合物をろ過し、ろ液を濃縮し、参考例６の化合物を０．６００ｇ（９３％）得た。 (Example 17)
Synthesis of (S) -2-amino-4- (3- (butylamino) -5- (ethoxycarbonyl) -2-phenoxyphenylsulfonamido) -4-oxobutanoic acid (hereinafter the compound of Example 17):
[Step 1]
Synthesis of (S) -tert-butyl (2,5-dioxotetrahydrofuran-3-yl) -carbamate (hereinafter referred to as compound of Reference Example 6):

DCC (0.618 g, 3 mmol) was added to a solution of (S) -2-((tert-butoxycarbonyl) amino) succinic acid (0.699 g, 3 mmol) in ethyl acetate (10 mL) at 0 ° C. for 1 hour. Stir. The mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated to obtain 0.600 g (93%) of the compound of Reference Example 6.

　室温下、参考例４の化合物（０．３９２ｇ，１ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（５ｍＬ）溶液に、水素化ナトリウム（４０ｍｇ，１ｍｍｏｌ，６０％オイルディスパージョン）を加え、１．５時間撹拌した。反応混合物に参考例６の化合物（０．２１５ｇ，１ｍｍｏｌ）を加え、一晩撹拌した。反応混合物に水（２０ｍＬ）を加え、酢酸エチル（２０ｍＬ）で抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、濃縮した。０℃下、残渣（０．６０７ｇ，１ｍｍｏｌ）のジクロロメタン（１５ｍＬ）溶液に、トリフルオロ酢酸（２ｍＬ）をゆっくりと加え、室温で３０分間撹拌した。反応混合物を濃縮し、ＨＰＬＣ（カラム：ダイソーゲル（商標登録）、２５０×２０ｍｍ、Ｃ１８、１０μｍ；　溶出液：７５％メタノール、２５％蒸留水、０．１ｖ％ギ酸；　流速：２０ｍＬ／ｍｉｎ、室温）で分取し、実施例１７の化合物を０．３００ｇ（６６％）得た。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＤＭＳＯ－ｄ_６）
δ：０．７６（３Ｈ，ｔ，Ｊ＝７．８Ｈｚ），１．０７－１．１１（２Ｈ，ｍ），１．３３－１．３７（５Ｈ，ｍ），２．１５－２．２１（２Ｈ，ｍ），３．０１－３．０４（２Ｈ，ｍ），３．４６－３．４８（１Ｈ，ｍ），４．３３－４．３６（２Ｈ，ｍ），４．６８－４．７２（１Ｈ，ｍ），６．７０－６．８５（２Ｈ，ｍ），６．９０－７．０５（１Ｈ，ｍ），７．２２－７．２５（２Ｈ，ｍ），７．３３（１Ｈ，ｓ），７．７８（１Ｈ，ｓ）.
ＭＳ（ＥＳＩ）：（［Ｍ－Ｈ］^－）５０６． [Step 2]
Synthesis of the compound of Example 17:

Sodium hydride (40 mg, 1 mmol, 60% oil dispersion) was added to a solution of the compound of Reference Example 4 (0.392 g, 1 mmol) in N, N-dimethylformamide (5 mL) at room temperature, and the mixture was stirred for 1.5 hours. did. The compound of Reference Example 6 (0.215 g, 1 mmol) was added to the reaction mixture, and the mixture was stirred overnight. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. At 0 ° C., trifluoroacetic acid (2 mL) was slowly added to a solution of the residue (0.607 g, 1 mmol) in dichloromethane (15 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and HPLC (column: Daisogel ™, 250 × 20 mm, C18, 10 μm; eluent: 75% methanol, 25% distilled water, 0.1 v% formic acid; flow rate: 20 mL / min, room temperature ) To obtain 0.300 g (66%) of the compound of Example 17.
¹ H-NMR (600 MHz, DMSO-d ₆ )
δ: 0.76 (3H, t, J = 7.8 Hz), 1.07-1.11 (2H, m), 1.33-1.37 (5H, m), 2.15-2.21 (2H, m), 3.01-3.04 (2H, m), 3.46-3.48 (1H, m), 4.33-4.36 (2H, m), 4.68-4 .72 (1H, m), 6.70-6.85 (2H, m), 6.90-7.05 (1H, m), 7.22-7.25 (2H, m), 7.33 (1H, s), 7.78 (1H, s).
MS (ESI): ([M−H] ⁻ ) 506.

　実施例１７と同様の手順により、実施例１８の化合物を合成した。ＨＰＬＣで分取する際、実施例１７の化合物と分離して、実施例１８の化合物を０．２００ｇ（３３％）得た。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＤＭＳＯ－ｄ_６）
δ：０．７７（３Ｈ，ｔ，Ｊ＝７．８Ｈｚ），１．０５－１．１２（２Ｈ，ｍ），１．３２－１．３６（５Ｈ，ｍ），２．３１－２．３５（１Ｈ，ｍ），２．６８－２．７１（１Ｈ，ｍ），３．００－３．０２（２Ｈ，ｍ），３．１５－３．２０（１Ｈ，ｍ），４．３２－４．３６（２Ｈ，ｍ），４．７０－４．７２（１Ｈ，ｍ），６．７３－６．８０（２Ｈ，ｍ），６．９０－７．０５（１Ｈ，ｍ），７．２２－７．２５（２Ｈ，ｍ），７．２８（１Ｈ，ｓ），７．８１（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）：（［Ｍ－Ｈ］^－）５０６． (Example 18)
Synthesis of (S) -3-amino-4- (3- (butylamino) -5- (ethoxycarbonyl) -2-phenoxyphenylsulfonamido) -4-oxobutanoic acid (hereinafter the compound of Example 18):

The compound of Example 18 was synthesized according to the same procedure as Example 17. When fractionated by HPLC, it separated from the compound of Example 17 to obtain 0.200 g (33%) of the compound of Example 18.
¹ H-NMR (600 MHz, DMSO-d ₆ )
δ: 0.77 (3H, t, J = 7.8 Hz), 1.05-1.12 (2H, m), 1.32-1.36 (5H, m), 2.31-2.35 (1H, m), 2.68-2.71 (1H, m), 3.00-3.02 (2H, m), 3.15-3.20 (1H, m), 4.32-4 .36 (2H, m), 4.70-4.72 (1H, m), 6.73-6.80 (2H, m), 6.90-7.05 (1H, m), 7.22 -7.25 (2H, m), 7.28 (1H, s), 7.81 (1H, s).
MS (ESI): ([M−H] ⁻ ) 506.

　実施例３の化合物（０．０５３ｇ、０．１ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（１ｍＬ）溶液に、炭酸カリウム（０．０２８ｇ、０．２ｍｍｏｌ）、ヨウ化カリウム（０．０３３ｇ、０．２ｍｍｏｌ）、クロロメチルシクロヘキサンカルボキシレート（０．０３６ｍｇ、０．２ｍｍｏｌ）を順次加え、５０℃で４時間撹拌した。反応混合物を室温に冷却し、飽和塩化アンモニウム水溶液（２０ｍＬ）を加え、酢酸エチル（１０ｍＬ）で抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、濃縮し、ＨＰＬＣ（カラム：ダイソーゲル（商標登録）、２５０×２０ｍｍ、Ｃ１８、１０μｍ；　溶出液：７５％メタノール、２５％蒸留水、０．１ｖ％ギ酸；　流速：２０ｍＬ／ｍｉｎ、室温）で分取し、実施例１９の化合物を０．０３４ｇ（５０％）得た。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＣＤＣｌ_３）
δ：０．７７（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），１．０６－１．１１（２Ｈ，ｍ），１．１９－１．２８（３Ｈ，ｍ），１．３４－１．３７（２Ｈ，ｍ），１．４１－１．４６（２Ｈ，ｍ），１．６２（１Ｈ，ｄ，Ｊ＝１０．２Ｈｚ），１．７１－１．７３（２Ｈ，ｍ），１．９０（２Ｈ，ｄ，Ｊ＝１０．８Ｈｚ），２．２４（１Ｈ，ｔ，Ｊ＝１２．０Ｈｚ），３．０１－３．０３（２Ｈ，ｍ），３．０８（１Ｈ，ｓ），３．３６－３．５２（４Ｈ，ｍ），４．０３（１Ｈ，ｓ），４．５３（１Ｈ，ｓ），５．９３（２Ｈ，ｓ），６．８６（２Ｈ，ｄ，Ｊ＝７．２Ｈｚ），６．９７（１Ｈ，ｔ，Ｊ＝６．６Ｈｚ），７．１８－７．１９（２Ｈ，ｍ），７．４９（１Ｈ，ｓ），７．９６（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）：（［Ｍ＋Ｎａ］^＋）６８９． (Example 19)
((Cyclohexanecarbonyl) oxy) methyl 3- (butylamino) -4-phenoxy-5- (N-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) Synthesis of tetrahydro-2H-pyran-2-yl) sulfamoyl) benzoate (hereinafter the compound of Example 19):

To a solution of the compound of Example 3 (0.053 g, 0.1 mmol) in N, N-dimethylformamide (1 mL) was added potassium carbonate (0.028 g, 0.2 mmol), potassium iodide (0.033 g, 0.2 mmol). ) And chloromethylcyclohexanecarboxylate (0.036 mg, 0.2 mmol) were sequentially added, and the mixture was stirred at 50 ° C. for 4 hours. The reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution (20 mL) was added, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and HPLC (column: Daiso Gel (registered trademark), 250 × 20 mm, C18, 10 μm; eluent: 75% methanol, 25% distilled water). 0.1 v% formic acid; flow rate: 20 mL / min, room temperature) to obtain 0.034 g (50%) of the compound of Example 19.
¹ H-NMR (600 MHz, CDCl ₃ )
δ: 0.77 (3H, t, J = 7.2 Hz), 1.06-1.11 (2H, m), 1.19-1.28 (3H, m), 1.34-1.37 (2H, m), 1.41-1.46 (2H, m), 1.62 (1H, d, J = 10.2 Hz), 1.71-1.73 (2H, m), 1.90 (2H, d, J = 10.8 Hz), 2.24 (1H, t, J = 12.0 Hz), 3.01-3.03 (2H, m), 3.08 (1H, s), 3 .36-3.52 (4H, m), 4.03 (1H, s), 4.53 (1H, s), 5.93 (2H, s), 6.86 (2H, d, J = 7) .2 Hz), 6.97 (1 H, t, J = 6.6 Hz), 7.18-7.19 (2 H, m), 7.49 (1 H, s), 7.96 (1 H, s).
MS (ESI): ([M + Na] ^< +>) 689.

　実施例３の化合物とクロロメチルピバレートを用いて、実施例１９と同様の手順により、実施例２０の化合物を合成した。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＣＤＣｌ_３）
δ：０．７７（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），１．０６－１．１１（２Ｈ，ｍ），１．２１（９Ｈ，ｓ），１．３１－１．３６（２Ｈ，ｍ），３．０１－３．０３（２Ｈ，ｍ），３．０７（１Ｈ，ｓ），３．３８－３．５１（５Ｈ，ｍ），４．５２－４．５３（１Ｈ，ｍ），５．９４（２Ｈ，ｓ），６．８７（２Ｈ，ｄ，Ｊ＝６．６Ｈｚ），６．９８（１Ｈ，ｔ，Ｊ＝７．２Ｈｚ），７．１８（２Ｈ，ｔ，Ｊ＝７．２Ｈｚ），７．５１　（１Ｈ，ｓ），７．９８（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）：（［Ｍ－Ｈ］^－）６３９． (Example 20)
(Pivaloyloxy) methyl 3- (butylamino) -4-phenoxy-5- (N-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H- Synthesis of pyran-2-yl) sulfamoyl) benzoate (hereinafter the compound of Example 20):

The compound of Example 20 was synthesized by the same procedure as in Example 19 using the compound of Example 3 and chloromethyl pivalate.
¹ H-NMR (600 MHz, CDCl ₃ )
δ: 0.77 (3H, t, J = 7.2 Hz), 1.06-1.11 (2H, m), 1.21 (9H, s), 1.31-1.36 (2H, m ), 3.01-3.03 (2H, m), 3.07 (1H, s), 3.38-3.51 (5H, m), 4.52-4.53 (1H, m), 5.94 (2H, s), 6.87 (2H, d, J = 6.6 Hz), 6.98 (1H, t, J = 7.2 Hz), 7.18 (2H, t, J = 7) .2 Hz), 7.51 (1H, s), 7.98 (1H, s).
MS (ESI): ([M−H] ⁻ ) 639.

　実施例３の化合物とクロロメチルイソブチレートを用いて、実施例１９と同様の手順により、実施例２１の化合物を合成した。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＣＤＣｌ_３）
δ：０．７６（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），１．０８－１．１０（２Ｈ，ｍ），１．１７（６Ｈ，ｄ，Ｊ＝６．６Ｈｚ），１．３２－１．３６（２Ｈ，ｍ），２．５８－２．６０（１Ｈ，ｍ），３．０１－３．０２（２Ｈ，ｍ），３．１０（１Ｈ，ｓ），３．３６－３．５３（５Ｈ，ｍ），４．５２－４．５３（１Ｈ，ｍ），５．９４（２Ｈ，ｓ），６．８７（２Ｈ，ｍ），６．９７（１Ｈ，ｍ），７．１８（２Ｈ，ｍ），７．５３（１Ｈ，ｓ），７．９８（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）：（［Ｍ＋Ｎａ］^＋）６４９． (Example 21)
(Isobutyryloxy) methyl 3- (butylamino) -4-phenoxy-5- (N-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro Synthesis of -2H-pyran-2-yl) sulfamoyl) benzoate (hereinafter the compound of Example 21):

The compound of Example 21 was synthesized by the same procedure as in Example 19 using the compound of Example 3 and chloromethyl isobutyrate.
¹ H-NMR (600 MHz, CDCl ₃ )
δ: 0.76 (3H, t, J = 7.2 Hz), 1.08-1.10 (2H, m), 1.17 (6H, d, J = 6.6 Hz), 1.32-1 .36 (2H, m), 2.58-2.60 (1H, m), 3.01-3.02 (2H, m), 3.10 (1H, s), 3.36-3.53 (5H, m), 4.52-4.53 (1H, m), 5.94 (2H, s), 6.87 (2H, m), 6.97 (1H, m), 7.18 ( 2H, m), 7.53 (1H, s), 7.98 (1H, s).
MS (ESI): ([M + Na] ⁺ ) 649.

　０℃、アルゴン雰囲気下、（２Ｒ，３Ｒ，４Ｓ，５Ｒ）－２－（アセトキシメチル）－６－（５－（（ベンジルオキシ）カルボニル）－３－（ブチルアミノ）－２－フェノキシフェニルスルホンアミド）テトラヒドロ－２Ｈ－ピラン－３，４，５－トリイル　トリアセテート（０．７２６ｇ、０．９２６ｍｍｏｌ）のベンジルアルコール（３ｍＬ）溶液に金属ナトリウム（０．１０７ｇ、４．６３ｍｍｏｌ）をゆっくりと加え、室温で１時間撹拌した。反応混合物に飽和塩化アンモニウム水溶液（１５ｍＬ）を加え、酢酸エチル（１５ｍＬ）で抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、濃縮した。残渣をカラムクロマトグラフィー（ジクロロメタン／メタノール＝９７／３）で精製し、参考例５の化合物を０．２９９ｇ（５３％）得た。
^１Ｈ－ＮＭＲ（６００　ＭＨｚ，ＣＤＣｌ_３）
δ：０．７２（３Ｈ，ｔ，Ｊ＝１０．８Ｈｚ），０．９９－１．０８（２Ｈ，ｍ），１．２４－１．３２（２Ｈ，ｍ），２．９５（２Ｈ，ｔ，Ｊ＝１０．２Ｈｚ），３．０４－３．０５（１Ｈ，ｍ），３．２９－３．４７（５Ｈ，ｍ），４．５３（１Ｈ，ｔ，Ｊ＝１３．２Ｈｚ），５．２８（２Ｈ，ｓ），６．８４（２Ｈ，ｄ，Ｊ＝１２．０Ｈｚ），６．９０（１Ｈ，ｔ，Ｊ＝１０．８Ｈｚ），７．１２（２Ｈ，ｔ，Ｊ＝１０．８Ｈｚ），７．２８－７．３３（３Ｈ，ｍ），７．３８（２Ｈ，ｄ，Ｊ＝１０．２Ｈｚ），７．５１（１Ｈ，ｓ），８．００（１Ｈ，ｓ）． (Example 22)
3- (N-((3R, 4S, 5S, 6R) -6- (acetoxymethyl) -3,4,5-trihydroxytetrahydro-2H-pyran-2-yl) sulfamoyl) -5- (butylamino) Synthesis of -4-phenoxybenzoic acid (hereinafter the compound of Example 22):
[Step 1]
Benzyl 3- (butylamino) -4-phenoxy-5- (N-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-2 Synthesis of -yl) sulfamoyl) benzoate (hereinafter the compound of Reference Example 5):

(2R, 3R, 4S, 5R) -2- (acetoxymethyl) -6- (5-((benzyloxy) carbonyl) -3- (butylamino) -2-phenoxyphenylsulfonamide at 0 ° C. under argon atmosphere ) Tetrahydro-2H-pyran-3,4,5-triyl triacetate (0.726 g, 0.926 mmol) in benzyl alcohol (3 mL) was added slowly with sodium metal (0.107 g, 4.63 mmol) at room temperature. Stir for 1 hour. Saturated aqueous ammonium chloride solution (15 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (dichloromethane / methanol = 97/3) to obtain 0.299 g (53%) of the compound of Reference Example 5.
¹ H-NMR (600 MHz, CDCl ₃ )
δ: 0.72 (3H, t, J = 10.8 Hz), 0.99-1.08 (2H, m), 1.24-1.32 (2H, m), 2.95 (2H, t , J = 10.2 Hz), 3.04-3.05 (1 H, m), 3.29-3.47 (5 H, m), 4.53 (1 H, t, J = 13.2 Hz), 5 .28 (2H, s), 6.84 (2H, d, J = 12.0 Hz), 6.90 (1H, t, J = 10.8 Hz), 7.12 (2H, t, J = 10. 8 Hz), 7.28-7.33 (3 H, m), 7.38 (2 H, d, J = 10.2 Hz), 7.51 (1 H, s), 8.00 (1 H, s).

　－３０℃下、参考例５の化合物（０．１２３ｇ、０．２ｍｍｏｌ）のジクロロメタン（１ｍＬ）溶液に、２，４，６－トリメチルピリジン（０．０８６ｇ、０．８ｍｍｏｌ）、アセチルクロリド（０．０１９ｇ、０．２４ｍｍｏｌ）を順次加え、室温で２時間撹拌した。反応混合物に酢酸エチル（１５ｍＬ）を加え希釈し、有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥し、濃縮した。アルゴン雰囲気下、残渣のメタノール（５ｍＬ）溶液に、１０重量％パラジウム／炭素（０．０１０ｇ）を加え、水素雰囲気下になるように３回置換した後、室温で２時間撹拌した。アルゴン雰囲気下、反応混合物をろ過し、メタノールで洗浄し、ろ液を濃縮した。ＨＰＬＣ（カラム：ダイソーゲル（商標登録）、２５０×２０ｍｍ、Ｃ１８、１０μｍ；　溶出液：４５％メタノール、５５％蒸留水、０．１ｖ％ギ酸；　流速：２０ｍＬ／ｍｉｎ、室温）で分取し、実施例２２の化合物を０．０５２ｇ（４７％）得た。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＣＤ_３ＯＤ）
δ：０．８２－０．８５（３Ｈ，ｍ），１．１４－１．２０（２Ｈ，ｍ），１．４１－１．４６（２Ｈ，ｍ），１．９１（３Ｈ，ｓ），３．１１（２Ｈ，ｔ，Ｊ＝７．２Ｈｚ），３．１４－３．１７（１Ｈ，ｍ），３．２４－３．３３（１Ｈ，ｍ），３．３３－３．３９（２Ｈ，ｍ），４．００（２Ｈ，ｄ，Ｊ＝３．６Ｈｚ），４．５３（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），６．９６－６．９８（２Ｈ，ｍ），７．０８（１Ｈ，ｔ，Ｊ＝７．２Ｈｚ），７．３０－７．３３（２Ｈ，ｍ），７．５７（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），７．９４（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ）．
ＭＳ（ＥＳＩ）：（［Ｍ－Ｈ］^－）５６７． [Step 2]
Synthesis of the compound of Example 22:

At −30 ° C., a solution of the compound of Reference Example 5 (0.123 g, 0.2 mmol) in dichloromethane (1 mL) was added to 2,4,6-trimethylpyridine (0.086 g, 0.8 mmol), acetyl chloride (0. 019 g, 0.24 mmol) was added sequentially, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate (15 mL) was added to the reaction mixture for dilution, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated. Under an argon atmosphere, 10% by weight palladium / carbon (0.010 g) was added to a methanol (5 mL) solution of the residue, and the mixture was replaced three times so as to be in a hydrogen atmosphere, followed by stirring at room temperature for 2 hours. The reaction mixture was filtered under an argon atmosphere, washed with methanol, and the filtrate was concentrated. Fractionation by HPLC (column: Daiso Gel (registered trademark), 250 × 20 mm, C18, 10 μm; eluent: 45% methanol, 55% distilled water, 0.1 v% formic acid; flow rate: 20 mL / min, room temperature) 0.052 g (47%) of the compound of Example 22 was obtained.
¹ H-NMR (600 MHz, CD ₃ OD)
δ: 0.82-0.85 (3H, m), 1.14-1.20 (2H, m), 1.41-1.46 (2H, m), 1.91 (3H, s), 3.11 (2H, t, J = 7.2 Hz), 3.14-3.17 (1H, m), 3.24-3.33 (1H, m), 3.33-3.39 (2H M), 4.00 (2H, d, J = 3.6 Hz), 4.53 (1H, d, J = 9.0 Hz), 6.96-6.98 (2H, m), 7.08 (1H, t, J = 7.2 Hz), 7.30-7.33 (2H, m), 7.57 (1H, d, J = 1.8 Hz), 7.94 (1H, d, J = 1.8 Hz).
MS (ESI): ([M−H] ⁻ ) 567.

　参考例５の化合物とベンゾイルクロリドを用いて、実施例２２と同様の手順により、実施例２３の化合物を合成した。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＣＤ_３ＯＤ）
δ：０．７７（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），１．０４－１．１０（２Ｈ，ｍ），１．２３－１．２８（２Ｈ，ｍ），２．８０－２．９３（２Ｈ，ｍ），３．２３－３．２６（１Ｈ，ｍ），３．４２－３．４６（３Ｈ，ｍ），４．１８－４．２０（１Ｈ，ｍ），４．２８－４．３０（１Ｈ，ｍ），４．５９（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），６．９１－６．９２（２Ｈ，ｍ），７．０４－７．０７（１Ｈ，ｍ），７．２７－７．３０（２Ｈ，ｍ），７．３８（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），７．４３－７．４６（２Ｈ，ｍ），７．５８－７．６０（１Ｈ，ｍ），７．８９－７．９１（２Ｈ，ｍ），７．９５（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ）．
ＭＳ（ＥＳＩ）：（［Ｍ－Ｈ］^－）６２９． (Example 23)
3- (N-((3R, 4S, 5S, 6R) -6-((benzoyloxy) methyl) -3,4,5-trihydroxytetrahydro-2H-pyran-2-yl) sulfamoyl) -5- ( Synthesis of Butylamino) -4-phenoxybenzoic acid (hereinafter referred to as the compound of Example 23):

The compound of Example 23 was synthesized by the same procedure as Example 22 using the compound of Reference Example 5 and benzoyl chloride.
¹ H-NMR (600 MHz, CD ₃ OD)
δ: 0.77 (3H, t, J = 7.2 Hz), 1.04-1.10 (2H, m), 1.23-1.28 (2H, m), 2.80-2.93 (2H, m), 3.23-3.26 (1H, m), 3.42-3.46 (3H, m), 4.18-4.20 (1H, m), 4.28-4 .30 (1H, m), 4.59 (1H, d, J = 9.0 Hz), 6.91-6.92 (2H, m), 7.04-7.07 (1H, m), 7 .27-7.30 (2H, m), 7.38 (1H, d, J = 1.8 Hz), 7.43-7.46 (2H, m), 7.58-7.60 (1H, m), 7.89-7.91 (2H, m), 7.95 (1H, d, J = 1.8 Hz).
MS (ESI): ([M−H] ⁻ ) 629.

　参考例５の化合物とピバロイルクロリドを用いて、実施例２２と同様の手順により、実施例２４の化合物を合成した。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＣＤＣｌ_３）
δ：０．７７（３Ｈ，ｔ，Ｊ＝１０．２Ｈｚ），１．００（９Ｈ，ｓ），１．０８－１．１２（２Ｈ，ｍ），１．３４－１．３８（２Ｈ，ｍ），２．９９－３．００（２Ｈ，ｍ），３．４４－３．４９（４Ｈ，ｍ），４．１０－４．１３（２Ｈ，ｍ），４．６３－４．６４（１Ｈ，ｍ），６．８８－６．８９（２Ｈ，ｍ），６．９９－７．０１（１Ｈ，ｍ），７．１９－７．２２（２Ｈ，ｍ），７．４８（１Ｈ，ｓ），８．０３（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）：（［Ｍ－Ｈ］^－）６０９． (Example 24)
3- (Butylamino) -4-phenoxy-5- (N-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6-((pivaloyloxy) methyl) tetrahydro-2H-pyran- Synthesis of 2-yl) sulfamoyl) benzoic acid (hereinafter the compound of Example 24):

The compound of Example 24 was synthesized by the same procedure as in Example 22 using the compound of Reference Example 5 and pivaloyl chloride.
¹ H-NMR (600 MHz, CDCl ₃ )
δ: 0.77 (3H, t, J = 10.2 Hz), 1.00 (9H, s), 1.08-1.12 (2H, m), 1.34-1.38 (2H, m ), 2.99-3.00 (2H, m), 3.44-3.49 (4H, m), 4.10-4.13 (2H, m), 4.63-4.64 (1H) , M), 6.88-6.89 (2H, m), 699-7.01 (1H, m), 7.19-7.22 (2H, m), 7.48 (1H, s) ), 8.03 (1H, s).
MS (ESI): ([M−H] ⁻ ) 609.

　９０℃下、参考例２の化合物（０．４５４ｇ、１．０ｍｍｏｌ）と１，２，３，４，６－ペンタ－Ｏ－アセチル－Ｄ－グルコピラノース（０．３９０ｇ、１．０ｍｍｏｌ）のトルエン（４０ｍＬ）溶液に、三フッ化ホウ素エーテル錯体（０．５ｍＬ）を加え、９０℃で２時間撹拌した。反応混合物を室温に冷却し、冷水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次で洗浄し、無水硫酸ナトリウムで乾燥し、濃縮した。残渣をカラムクロマトグラフィー（石油エーテル／酢酸エチル＝５／１）で精製し、参考例７の化合物を０．０９１ｇ（１２％）得た。
ＭＳ（ＥＳＩ）：（［Ｍ＋Ｈ］^＋）７８５． (Example 25)
Benzyl 3- (N-((3R, 4S, 5S, 6R) -6- (acetoxymethyl) -3,4,5-trihydroxytetrahydro-2H-pyran-2-yl) sulfamoyl) -5- (butylamino ) Synthesis of 4-phenoxybenzoate (hereinafter, the compound of Example 25):
[Step 1]
(2R, 3R, 4S, 5R) -2- (acetoxymethyl) -6- (5-((benzyloxy) carbonyl) -3- (butylamino) -2-phenoxyphenylsulfonamido) tetrahydro-2H-pyran- Synthesis of 3,4,5-triyl triacetate (hereinafter, compound of Reference Example 7):

Under 90 ° C., the compound of Reference Example 2 (0.454 g, 1.0 mmol) and 1,2,3,4,6-penta-O-acetyl-D-glucopyranose (0.390 g, 1.0 mmol) in toluene To the (40 mL) solution, boron trifluoride ether complex (0.5 mL) was added and stirred at 90 ° C. for 2 hours. The reaction mixture was cooled to room temperature, cold water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5/1) to obtain 0.091 g (12%) of the compound of Reference Example 7.
MS (ESI): ([M + H] ^< +>) 785.

　０℃、アルゴン雰囲気下、参考例７の化合物（０．７２６ｇ、０．９３ｍｍｏｌ）のブタノール（３ｍＬ）溶液に、金属ナトリウム（０．１０７ｇ、４．６３ｍｍｏｌ）をゆっくりと加え、室温で１時間撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、濃縮した。残渣をカラムクロマトグラフィー（ジクロロメタン／メタノール＝２０／１）で精製し、参考例８の化合物を０．２９９ｇ（５３％）得た。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＣＤＣｌ_３）
δ：０．７２（３Ｈ，ｔ，Ｊ＝１０．８Ｈｚ），０．９９－１．０８（２Ｈ，ｍ），１．２４－１．３２（２Ｈ，ｍ），２．９５（２Ｈ，ｔ，Ｊ＝１０．２Ｈｚ），３．０４－３．０５（１Ｈ，ｍ），３．２９－３．４７（５Ｈ，ｍ），４．５３（１Ｈ，ｔ，Ｊ＝１３．２Ｈｚ），５．２８（２Ｈ，ｓ），６．８３－６．８５（２Ｈ，ｍ），６．９０（１Ｈ，ｔ，Ｊ＝１０．８Ｈｚ），７．１２（２Ｈ，ｔ，Ｊ＝１０．８Ｈｚ），７．２８－７．３３（３Ｈ，ｍ），７．３７－７．３９（２Ｈ，ｍ），７．５１（１Ｈ，ｓ），８．００（１Ｈ，ｓ）． [Step 2]
Benzyl 3- (butylamino) -4-phenoxy-5- (N-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-2 Synthesis of -yl) sulfamoyl) benzoate (hereinafter the compound of Reference Example 8):

Metallic sodium (0.107 g, 4.63 mmol) was slowly added to a solution of the compound of Reference Example 7 (0.726 g, 0.93 mmol) in butanol (3 mL) at 0 ° C. under an argon atmosphere, and the mixture was stirred at room temperature for 1 hour. did. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (dichloromethane / methanol = 20/1) to obtain 0.299 g (53%) of the compound of Reference Example 8.
¹ H-NMR (600 MHz, CDCl ₃ )
δ: 0.72 (3H, t, J = 10.8 Hz), 0.99-1.08 (2H, m), 1.24-1.32 (2H, m), 2.95 (2H, t , J = 10.2 Hz), 3.04-3.05 (1 H, m), 3.29-3.47 (5 H, m), 4.53 (1 H, t, J = 13.2 Hz), 5 .28 (2H, s), 6.83-6.85 (2H, m), 6.90 (1H, t, J = 10.8 Hz), 7.12 (2H, t, J = 10.8 Hz) 7.28-7.33 (3H, m), 7.37-7.39 (2H, m), 7.51 (1H, s), 8.00 (1H, s).

　参考例８の化合物とアセチルクロリドを用いて、実施例２２と同様の手順により、実施例２５の化合物を合成した。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＣＤ_３ＯＤ）
δ：０．７３（３Ｈ，ｔ、Ｊ＝１０．８Ｈｚ），０．９９－１．０８（２Ｈ，ｍ），１．２４－１．３５（２Ｈ，ｍ），１．７４（３Ｈ，ｓ），２．９５（２Ｈ，ｔ，Ｊ＝１０．２Ｈｚ），３．０４－３．２５（４Ｈ，ｍ），３．８６－３．８７（２Ｈ，ｍ），４．４３（１Ｈ，ｄ，Ｊ＝１３．２Ｈｚ），５．３２（２Ｈ，ｓ），６．８６－６．８７（２Ｈ，ｍ），６．９９（１Ｈ，ｔ，Ｊ＝１０．８Ｈｚ），７．２１－７．３２（７Ｈ，ｍ），７．４１（１Ｈ，ｓ），７．８５（１Ｈ，ｓ）． [Step 3]
Synthesis of the compound of Example 25:

Using the compound of Reference Example 8 and acetyl chloride, the compound of Example 25 was synthesized by the same procedure as Example 22.
¹ H-NMR (600 MHz, CD ₃ OD)
δ: 0.73 (3H, t, J = 10.8 Hz), 0.99-1.08 (2H, m), 1.24-1.35 (2H, m), 1.74 (3H, s) ), 2.95 (2H, t, J = 10.2 Hz), 3.04-3.25 (4H, m), 3.86-3.87 (2H, m), 4.43 (1H, d) , J = 13.2 Hz), 5.32 (2H, s), 6.86-6.87 (2H, m), 6.99 (1H, t, J = 10.8 Hz), 7.21-7 .32 (7H, m), 7.41 (1H, s), 7.85 (1H, s).

　１００℃下、ブメタニド（０．３６４ｇ、１．０ｍｍｏｌ）とブタノール（０．２７ｍＬ、３．０ｍｍｏｌ）のトルエン（８ｍＬ）溶液に、硫酸（０．１３５ｍＬ）を加え、１００℃で６時間撹拌した。反応混合物を室温に冷却し、冷水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、水で順次洗浄し、無水硫酸ナトリウムで乾燥し、濃縮し、参考例９の化合物を０．３６０ｇ（８６％）得た。
ＭＳ（ＥＳＩ）：（［Ｍ＋Ｈ］^＋）４２１． (Example 26)
Butyl 3- (butylamino) -4-phenoxy-5- (N-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-2 Synthesis of yl) sulfamoyl) benzoate (hereinafter the compound of Example 26):
[Step 1]
Synthesis of butyl 3- (butylamino) -4-phenoxy-5-sulfamoylbenzoate (hereinafter referred to as the compound of Reference Example 9):

Sulfuric acid (0.135 mL) was added to a toluene (8 mL) solution of bumetanide (0.364 g, 1.0 mmol) and butanol (0.27 mL, 3.0 mmol) at 100 ° C., and the mixture was stirred at 100 ° C. for 6 hours. The reaction mixture was cooled to room temperature, cold water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and concentrated to obtain 0.360 g (86%) of the compound of Reference Example 9.
MS (ESI): ([M + H] ^< +>) 421.

　９０℃下、参考例９の化合物（０．３６０ｇ、０．８５ｍｍｏｌ）と（３Ｒ，４Ｓ，５Ｒ，６Ｒ）－６－（アセトキシメチル）テトラヒドロ－２Ｈ－ピラン－２，３，４，５－テトライル　テトラアセテート（０．３３１ｇ、０．８５ｍｍｏｌ）のトルエン（１８ｍＬ）溶液に、三フッ化ホウ素エーテル錯体（０．４２ｍＬ）を加え、９０℃で１．５時間撹拌した。反応混合物を室温に冷却し、冷水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥し、濃縮した。残渣をカラムクロマトグラフィー（石油エーテル／酢酸エチル＝５／１）で精製し、参考例１０の化合物を０．０７５ｇ（１２％）得た。
ＭＳ（ＥＳＩ）：（［Ｍ＋Ｈ］^＋）７５１． [Step 2]
(2R, 3R, 4S, 5R) -2- (acetoxymethyl) -6- (5- (butoxycarbonyl) -3- (butylamino) -2-phenoxyphenylsulfonamido) tetrahydro-2H-pyran-3,4 , 5-Triyl triacetate (hereinafter referred to as compound of Reference Example 10):

Under 90 ° C., the compound of Reference Example 9 (0.360 g, 0.85 mmol) and (3R, 4S, 5R, 6R) -6- (acetoxymethyl) tetrahydro-2H-pyran-2,3,4,5-tetrayl Boron trifluoride ether complex (0.42 mL) was added to a solution of tetraacetate (0.331 g, 0.85 mmol) in toluene (18 mL), and the mixture was stirred at 90 ° C. for 1.5 hours. The reaction mixture was cooled to room temperature, cold water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5/1) to obtain 0.075 g (12%) of the compound of Reference Example 10.
MS (ESI): ([M + H] ^< +>) 751.

　０℃、アルゴン雰囲気下、参考例１０の化合物（０．０７４５ｇ、０．０９９ｍｍｏｌ）のブタノール（０．１８ｍＬ）溶液に金属ナトリウム（０．０２０ｇ）をゆっくりと加え、室温で１．５時間撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和塩化アンモニウム水溶液、水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥し、濃縮した。残渣をカラムクロマトグラフィー（ジクロロメタン／メタノール＝３０／１）で精製し、実施例２６の化合物を０．０３０ｇ（５３％）得た。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＣＤＣｌ_３）
δ：０．７７（３Ｈ，ｍ），０．９５（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），１．０８（２Ｈ，ｂｒｓ），１．４２（２Ｈ，ｂｒｓ），１．４３（２Ｈ，ｂｒｓ），１．７１（２Ｈ，ｂｒｓ），３．０２（３Ｈ，ｂｒｓ），３．２０－３．６０（５Ｈ，ｍ），４．２８（２Ｈ，ｂｒｓ），４．５２（１Ｈ，ｔ，Ｊ＝１３．８Ｈｚ），６．８７（２Ｈ，ｄ，Ｊ＝１１．４Ｈｚ），６．９７（１Ｈ，ｔ，Ｊ＝１０．８Ｈｚ），７．１７（２Ｈ，ｔ，Ｊ＝５．４Ｈｚ），７．５１（１Ｈ，ｓ），７．９５（１Ｈ，ｓ）． [Step 3]
Synthesis of the compound of Example 26:

Metallic sodium (0.020 g) was slowly added to a solution of the compound of Reference Example 10 (0.0745 g, 0.099 mmol) in butanol (0.18 mL) under an argon atmosphere at 0 ° C., and the mixture was stirred at room temperature for 1.5 hours. . A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous ammonium chloride solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (dichloromethane / methanol = 30/1) to obtain 0.030 g (53%) of the compound of Example 26.
¹ H-NMR (600 MHz, CDCl ₃ )
δ: 0.77 (3H, m), 0.95 (3H, t, J = 7.2 Hz), 1.08 (2H, brs), 1.42 (2H, brs), 1.43 (2H, brs), 1.71 (2H, brs), 3.02 (3H, brs), 3.20-3.60 (5H, m), 4.28 (2H, brs), 4.52 (1H, t , J = 13.8 Hz), 6.87 (2H, d, J = 11.4 Hz), 6.97 (1H, t, J = 10.8 Hz), 7.17 (2H, t, J = 5. 4 Hz), 7.51 (1H, s), 7.95 (1H, s).

　実施例２６の化合物とアセチルクロリドを用いて、実施例２２と同様の手順により、実施例２７の化合物を合成した。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＣＤ_３ＯＤ）
δ：０．８３（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），１．０５（３Ｈ，ｂｒｓ），１．１０－１．２５（２Ｈ，ｍ），１．３５－１．５５（４Ｈ，ｍ），１．６５－１．７５（２Ｈ，ｍ），１．７９（３Ｈ，ｍ），２．９０－３．２０（３Ｈ，ｍ），３．２０－３．５０（２Ｈ，ｍ），３．９０－４．００（２Ｈ，ｍ），４．３６（２Ｈ，ｄ，Ｊ＝３．６Ｈｚ），４．５４（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），６．９０－６．９５（２Ｈ，ｍ），６．９２－７．００（２Ｈ，ｍ），７．２０－７．３５（２Ｈ，ｍ），７．５３（１Ｈ，ｓ），７．９０（１Ｈ，ｓ）． (Example 27)
Butyl 3- (N-((3R, 4S, 5S, 6R) -6- (acetoxymethyl) -3,4,5-trihydroxytetrahydro-2H-pyran-2-yl) sulfamoyl) -5- (butylamino ) Synthesis of 4-phenoxybenzoate (compound of Example 27):

The compound of Example 27 was synthesized in the same manner as in Example 22 using the compound of Example 26 and acetyl chloride.
¹ H-NMR (600 MHz, CD ₃ OD)
δ: 0.83 (3H, t, J = 7.2 Hz), 1.05 (3H, brs), 1.10-1.25 (2H, m), 1.35 to 1.55 (4H, m ), 1.65-1.75 (2H, m), 1.79 (3H, m), 2.90-3.20 (3H, m), 3.20-3.50 (2H, m), 3.90-4.00 (2H, m), 4.36 (2H, d, J = 3.6 Hz), 4.54 (1H, d, J = 9.0 Hz), 6.90-6.95 (2H, m), 6.92-7.00 (2H, m), 7.20-7.35 (2H, m), 7.53 (1H, s), 7.90 (1H, s).

　室温下、ブメタニド（０．３６４ｇ、１．０ｍｍｏｌ）とヘキサノール（０．１６７ｍＬ、１．３ｍｍｏｌ）のトルエン（１７ｍＬ）溶液に、硫酸（０．５ｍＬ）を加え、１００℃で５時間撹拌した。反応混合物を室温に冷却し、冷水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、水で順次洗浄し、無水硫酸ナトリウムで乾燥し、濃縮し、参考例１１の化合物を０．３７５ｇ（８４％）得た。
ＭＳ（ＥＳＩ）：（［Ｍ＋Ｈ］^＋）４４９． (Example 28)
Hexyl 3- (N-((3R, 4S, 5S, 6R) -6- (acetoxymethyl) -3,4,5-trihydroxytetrahydro-2H-pyran-2-yl) sulfamoyl) -5- (butylamino ) Synthesis of 4-phenoxybenzoate (compound of Example 28):
[Step 1]
Synthesis of hexyl 3- (butylamino) -4-phenoxy-5-sulfamoylbenzoate (hereinafter referred to as the compound of Reference Example 11):

Sulfuric acid (0.5 mL) was added to a toluene (17 mL) solution of bumetanide (0.364 g, 1.0 mmol) and hexanol (0.167 mL, 1.3 mmol) at room temperature, and the mixture was stirred at 100 ° C. for 5 hours. The reaction mixture was cooled to room temperature, cold water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and concentrated to obtain 0.375 g (84%) of the compound of Reference Example 11.
MS (ESI): ([M + H] ⁺ ) 449.

　参考例１１の化合物（０．４４９ｇ、１．０ｍｍｏｌ）と（３Ｒ，４Ｓ，５Ｒ，６Ｒ）－６－（アセトキシメチル）テトラヒドロ－２Ｈ－ピラン－２，３，４，５－テトライル　テトラアセテート（０．３９０ｇ、１．０ｍｍｏｌ）のトルエン（４０ｍＬ）溶液に、三フッ化ホウ素エーテル錯体（０．５ｍＬ）を加え、９０℃で２時間撹拌した。反応混合物を室温に冷却し、冷水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥し、濃縮した。残渣をカラムクロマトグラフィー（石油エーテル／酢酸エチル＝５／１）で精製し、参考例１２の化合物を０．２０９ｇ（２７％）得た。
ＭＳ（ＥＳＩ）：（［Ｍ＋Ｈ］^＋）７７９．８６ [Step 2]
(2R, 3R, 4S, 5R) -2- (acetoxymethyl) -6- (3- (butylamino) -5-((hexyloxy) carbonyl) -2-phenoxyphenylsulfonamido) tetrahydro-2H-pyran- Synthesis of 3,4,5-triyl triacetate (hereinafter, compound of Reference Example 12):

The compound of Reference Example 11 (0.449 g, 1.0 mmol) and (3R, 4S, 5R, 6R) -6- (acetoxymethyl) tetrahydro-2H-pyran-2,3,4,5-tetrayl tetraacetate (0 Boron trifluoride ether complex (0.5 mL) was added to a solution of .390 g (1.0 mmol) in toluene (40 mL), and the mixture was stirred at 90 ° C. for 2 hours. The reaction mixture was cooled to room temperature, cold water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5/1) to obtain 0.209 g (27%) of the compound of Reference Example 12.
MS (ESI): ([M + H] ⁺ ) 779.86

　０℃、アルゴン雰囲気下、ヘキサノール（３ｍＬ）に金属ナトリウム（０．０３１ｇ、１．３４ｍｍｏｌ）を加えて得られた溶液を、参考例１２の化合物（０．２０９ｇ、０．２７ｍｍｏｌ）のトルエン（１５ｍＬ）溶液にゆっくりと加え、室温で１時間撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、濃縮した。残渣をカラムクロマトグラフィー（ジクロロメタン／メタノール＝４０／１）で精製し、参考例１３の化合物を０．０６０ｇ（３６％）得た。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＣＤＣｌ_３）
δ：０．５０－０．９０（３Ｈ，ｍ），０．８８（３Ｈ，ｂｒｓ）、１．００－１．１５（２Ｈ，ｍ），１．２０－１．４０（８Ｈ，ｍ），１．６０－１．７５（２Ｈ，ｍ），２．８０－３．１０（３Ｈ，ｍ），３．２０－３．６０（５Ｈ，ｍ），４．００（１Ｈ，ｂｒｓ），４．０６－４．３５（２Ｈ，ｍ），４．５２（１Ｈ，ｔ，Ｊ＝１３．８Ｈｚ），６．８５－６．８７（２Ｈ，ｍ），６．９６（１Ｈ，ｔ，Ｊ＝１０．８Ｈｚ），７．１７（２Ｈ，ｔ，Ｊ＝５．４Ｈｚ），７．５０（１Ｈ，ｓ），７．９５（１Ｈ，ｓ）． [Step 3]
Hexyl 3- (butylamino) -4-phenoxy-5- (N-((3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-2 Synthesis of -yl) sulfamoyl) benzoate (compound of Reference Example 13 hereinafter):

A solution obtained by adding metallic sodium (0.031 g, 1.34 mmol) to hexanol (3 mL) under an argon atmosphere at 0 ° C. was dissolved in toluene (15 mL) of the compound of Reference Example 12 (0.209 g, 0.27 mmol). ) Slowly added to the solution and stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (dichloromethane / methanol = 40/1) to obtain 0.060 g (36%) of the compound of Reference Example 13.
¹ H-NMR (600 MHz, CDCl ₃ )
δ: 0.50-0.90 (3H, m), 0.88 (3H, brs), 1.00-1.15 (2H, m), 1.20-1.40 (8H, m), 1.60-1.75 (2H, m), 2.80-3.10 (3H, m), 3.20-3.60 (5H, m), 4.00 (1H, brs), 4. 06-4.35 (2H, m), 4.52 (1H, t, J = 13.8 Hz), 6.85-6.87 (2H, m), 6.96 (1H, t, J = 10) .8 Hz), 7.17 (2H, t, J = 5.4 Hz), 7.50 (1H, s), 7.95 (1H, s).

　参考例１３の化合物とアセチルクロリドを用いて、実施例２２と同様の手順により、実施例２８の化合物を合成した。
^１Ｈ－ＮＭＲ（６００ＭＨｚ，ＣＤ_３ＯＤ）
δ：０．７１（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），０．７２（３Ｈ，ｂｒｓ），０．９０－１．１０（２Ｈ，ｍ），１．２８（６Ｈ，ｂｒｓ），１．３８（２Ｈ，ｂｒｓ），１．６０－１．７０（２Ｈ，ｍ），１．７５（３Ｈ，ｓ），２．９０－３．１０（３Ｈ，ｍ），３．１０－３．５０（２Ｈ，ｍ），３．７５－３．９０（２Ｈ，ｍ），４．２５（２Ｈ，ｄ，Ｊ＝３．６Ｈｚ），４．３９（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），６．８０－６．９５（２Ｈ，ｍ），６．９２－７．００（２Ｈ，ｍ），７．１０－７．２０（２Ｈ，ｍ），７．４０（１Ｈ，ｓ），７．７７（１Ｈ，ｓ）． [Step 4]
Synthesis of the compound of Example 28:

The compound of Example 28 was synthesized by the same procedure as in Example 22 using the compound of Reference Example 13 and acetyl chloride.
¹ H-NMR (600 MHz, CD ₃ OD)
δ: 0.71 (3H, t, J = 7.2 Hz), 0.72 (3H, brs), 0.90-1.10 (2H, m), 1.28 (6H, brs), 1. 38 (2H, brs), 1.60-1.70 (2H, m), 1.75 (3H, s), 2.90-3.10 (3H, m), 3.10-3.50 ( 2H, m), 3.75-3.90 (2H, m), 4.25 (2H, d, J = 3.6 Hz), 4.39 (1H, d, J = 9.0 Hz), 6. 80-6.95 (2H, m), 6.92-7.00 (2H, m), 7.10-7.20 (2H, m), 7.40 (1H, s), 7.77 ( 1H, s).

(Example 29)
Pharmacokinetics in rats of sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof:
After the oral administration of the compounds of Examples 1 to 13 and the compounds of Comparative Examples 1 to 4 to male rats, the plasma concentration and brain concentration of converted bumetanide were measured. Comparison was made with plasma and brain concentrations.

In the experiment, 6-8 week old Rcc: Han Wistar male rats (Nippon Medical and Animal Research Laboratories) were allowed to freely ingest solid feed (Oriental Yeast Co., Ltd.) and tap water before compound administration. Used after fasting for about 16 hours. Feeding was resumed after about 4 hours had elapsed after administration.

The compounds of Examples 1 to 13, the compounds of Comparative Examples 1 to 4 and bumetanide were each orally administered to a rat at a dose of 20 μmol / kg. The administration solutions of the compounds of Examples 1 to 13, the compounds of Comparative Examples 1 to 4 and bumetanide were prepared by dissolving or suspending in 0.5% methylcellulose aqueous solution, respectively. Oral administration of the administration solution was forcibly performed into the stomach at a volume of 5 mL / kg using a syringe equipped with an oral sonde without anesthesia.

At 30 minutes after oral administration and at 1, 2, 6 hours, blood was collected from rat jugular vein or heart under isoflurane light anesthesia. Each compound was administered to 6 rats, of which 3 were collected at 30 minutes and 1 hour after oral administration, and the remaining 3 were collected at 2 and 6 hours after oral administration. Blood was collected. In addition, brains were collected from rats that had finished blood collection for 1 and 6 hours after oral administration. In addition, blank blood and brain were collected from rats not receiving the compound.

The collected blood was centrifuged at 4 ° C. and 15000 rpm for 10 minutes (Hitachi Koki CT15RE) to separate plasma, and the obtained plasma was stored at −20 ° C. until the preparation of the sample for analysis. In addition, the collected brain is added with distilled water twice as much as the brain weight to grind the tissue until it becomes uniform (Biomedical Science, Inc., Shake Master Neo), and the obtained brain homogenized solution is used when preparing the sample for analysis. Until -20 ° C. The plasma and brain homogenized solution obtained from the rat administered with the compound are referred to as the rat plasma sample and the rat brain sample, respectively, and the plasma and brain homogenized solution obtained from the rat not administered with the compound are respectively referred to as the blank plasma. This is called a blank brain.

To a rat plasma sample or rat plasma sample diluted appropriately with blank plasma, 50 μL of an internal standard solution and 120 μL of methanol were added, stirred, and then cooled at 4 ° C. for 10 minutes. In addition, 20 μL of an internal standard solution and 120 μL of acetonitrile or methanol / acetonitrile = 1/1 (V / V) were added to 50 μL of a rat brain sample or a rat plasma sample appropriately diluted with a blank brain, and then stirred. Cool at 10 ° C. for 10 minutes. A calibration curve sample was prepared by treating a blank plasma and a blank brain to which a standard curve standard solution was added in the same manner.

Each sample after cooling is centrifuged for 10 minutes at 4 ° C. and 3000 rpm (Hitachi Koki Himac CF7D2), and the supernatant is added onto a 0.2 μm filter plate (Whatman) and further centrifuged at 4 ° C. and 2000 rpm for 5 minutes ( Hitachi Koki Himac CF7D2), and distilled water (50 μL) was added to the obtained filtrate to prepare a sample for analysis.

The obtained analytical sample was subjected to LC / MS / MS analysis. The analysis was performed under the conditions shown in Table 2 or 3 or a method according thereto.

From the results of LC / MS / MS analysis, a calibration curve was prepared using Analyst 1.4 (Applied Biosystems), and the administered compound (the compounds of Examples 1 to 13 and Comparative Examples 1 to 4) in the sample for analysis. And bumetanide after conversion (when the compounds of Examples 1 to 13 and the compounds of Comparative Examples 1 to 4 were administered) were calculated. For each compound, the plasma concentration and brain concentration (average value ± standard deviation, N = 3 (partially, N = 2)) of the administered compound and bumetanide after conversion were calculated for each time point of blood collection and brain collection. . Further, the percentage of brain concentration (nmol / kg tissue) / plasma concentration (nmol / L) of bumetanide (converted bumetanide when administered with the compounds of Examples 1 to 13 and Comparative Examples 1 to 4) (%) Was calculated. In calculating the percentage (%) of brain concentration (nmol / kg tissue) / plasma concentration (nmol / L), the mean value of brain concentration and plasma at each time point of blood collection and brain collection for each compound The average value of medium concentration was used.

The results are shown in FIGS. 1 to 18 and Tables 4 to 39.

1 and Tables 4 and 5 show the results when bumetanide was orally administered (20 μmol / kg) to rats. Table 4 shows the plasma concentration (nmol / L) and brain concentration (nmol / kg tissue) of bumetanide at each time (each time point) after bumetanide administration, and FIG. 1 shows the plasma concentration and brain concentration in the vertical axis. The values in Table 4 are plotted with the concentration as the horizontal axis and the time from the administration of bumetanide (mean value ± standard deviation, N = 3). Table 5 shows the percentage (%) of bumetanide brain concentration (nmol / kg tissue) / plasma concentration (nmol / L) 1 and 6 hours after administration of bumetanide.

The results of oral administration (20 μmol / kg) of the compounds of Examples 1 to 13 to rats are shown in FIGS. 2 to 14 and Tables 6 to 31, respectively.

Table 6 shows the plasma concentration of the compound of Example 1 and bumetanide converted from the compound of Example 1 (nmol / m) at each time (each time point) after administration of the compound of Example 1 (20 μmol / kg). L) and brain concentration (nmol / kg tissue), FIG. 2 plots the values in Table 6 with the vertical axis representing plasma concentration and brain concentration, and the horizontal axis representing time from administration of the compound of Example 1. (Mean ± standard deviation, N = 3). Table 7 also shows the percentage (%) of converted bumetanide brain concentration (nmol / kg tissue) / plasma concentration (nmol / L) 1 and 6 hours after administration of the compound of Example 1.

Table 8 shows the plasma concentration of the compound of Example 2 and bumetanide converted from the compound of Example 2 (nmol / mg) at each time (each time point) after administration of the compound of Example 2 (20 μmol / kg). L) and brain concentration (nmol / kg tissue), FIG. 3 plots the values in Table 8 with the vertical axis representing plasma concentration and brain concentration, and the horizontal axis representing time from administration of the compound of Example 2. (Mean ± standard deviation, N = 3). Table 9 shows the percentage (%) of converted bumetanide brain concentration (nmol / kg tissue) / plasma concentration (nmol / L) 1 and 6 hours after administration of the compound of Example 2.

Table 10 shows the plasma concentration of the compound of Example 3 and bumetanide converted from the compound of Example 3 (nmol / mg) at each time (each time point) after administration of the compound of Example 3 (20 μmol / kg). L) and brain concentration (nmol / kg tissue), FIG. 4 plots the values in Table 10 with the vertical axis representing plasma concentration and brain concentration, and the horizontal axis representing time from administration of the compound of Example 3. (Mean ± standard deviation, N = 3). Table 11 shows the percentage (%) of converted bumetanide brain concentration (nmol / kg tissue) / plasma concentration (nmol / L) 1 and 6 hours after administration of the compound of Example 3.

Table 12 shows the plasma concentration (nmol / mg) of the compound of Example 4 and bumetanide converted from the compound of Example 4 at each time (each time point) after administration of the compound of Example 4 (20 μmol / kg). L) and brain concentration (nmol / kg tissue), FIG. 5 plots the values in Table 12 with the vertical axis representing plasma concentration and brain concentration, and the horizontal axis representing time from administration of the compound of Example 4. (Mean ± standard deviation, N = 3). Table 13 shows the percentage (%) of converted bumetanide brain concentration (nmol / kg tissue) / plasma concentration (nmol / L) 1 and 6 hours after administration of the compound of Example 4.

Table 14 shows the plasma concentration (nmol / mg) of the compound of Example 5 and bumetanide converted from the compound of Example 5 at each time (each time point) after administration of the compound of Example 5 (20 μmol / kg). L) and brain concentration (nmol / kg tissue), FIG. 6 plots the values in Table 14 with the vertical axis representing plasma concentration and brain concentration, and the horizontal axis representing time from administration of the compound of Example 5. (Mean ± standard deviation, N = 3). Table 15 shows the percentage (%) of converted bumetanide brain concentration (nmol / kg tissue) / plasma concentration (nmol / L) 1 and 6 hours after administration of the compound of Example 5.

Table 16 shows the plasma concentration of the compound of Example 6 and bumetanide converted from the compound of Example 6 (nmol / mg) at each time (each time point) after administration of the compound of Example 6 (20 μmol / kg). L) and brain concentration (nmol / kg tissue), FIG. 7 plots the values in Table 16 with the vertical axis representing plasma concentration and brain concentration, and the horizontal axis representing time from administration of the compound of Example 6. (Mean ± standard deviation, N = 3). Table 17 shows the percentage (%) of converted bumetanide brain concentration (nmol / kg tissue) / plasma concentration (nmol / L) 1 and 6 hours after administration of the compound of Example 6.

Table 18 shows the plasma concentration of the compound of Example 7 and bumetanide converted from the compound of Example 7 (nmol / m) at each time (each time point) after administration of the compound of Example 7 (20 μmol / kg). L) and brain concentration (nmol / kg tissue), FIG. 8 plots the values in Table 18 with the vertical axis representing plasma concentration and brain concentration, and the horizontal axis representing time from administration of the compound of Example 7. (Mean ± standard deviation, N = 3). Table 19 shows the percentage (%) of converted bumetanide brain concentration (nmol / kg tissue) / plasma concentration (nmol / L) 1 and 6 hours after administration of the compound of Example 7. The percentage (%) of the converted bumetanide brain concentration (nmol / kg tissue) / plasma concentration (nmol / L) at 1 and 6 hours after administration is the plasma concentration at 1 and 6 hours after administration. Since it was 0 nmol / L, calculation was impossible.

Table 20 shows the plasma concentration of the compound of Example 8 and bumetanide converted from the compound of Example 8 (nmol / mg) at each time (each time point) after administration of the compound of Example 8 (20 μmol / kg). L) and brain concentration (nmol / kg tissue), FIG. 9 plots the values in Table 20 with the vertical axis representing plasma concentration and brain concentration, and the horizontal axis representing time from administration of the compound of Example 8. (Mean ± standard deviation, N = 3). Table 21 also shows the percentage (%) of converted bumetanide brain concentration (nmol / kg tissue) / plasma concentration (nmol / L) 1 and 6 hours after administration of the compound of Example 8.

Table 22 shows the plasma concentration (nmol / mol) of the compound of Example 9 and bumetanide converted from the compound of Example 9 at each time (each time point) after administration of the compound of Example 9 (20 μmol / kg). L) and brain concentration (nmol / kg tissue), FIG. 10 plots the values in Table 22 with the vertical axis representing plasma concentration and brain concentration, and the horizontal axis representing time from administration of the compound of Example 9. (Mean ± standard deviation, N = 3). Table 23 also shows the percentage (%) of converted bumetanide brain concentration (nmol / kg tissue) / plasma concentration (nmol / L) 1 and 6 hours after administration of the compound of Example 9. The percentage (%) of the converted bumetanide brain concentration (nmol / kg tissue) / plasma concentration (nmol / L) 6 hours after administration was such that the plasma concentration 6 hours after administration was 0 nmol / L. Therefore, calculation was impossible.

Table 24 shows the plasma concentration (nmol / mg) of the compound of Example 10 and bumetanide converted from the compound of Example 10 at each time (each time point) after administration of the compound of Example 10 (20 μmol / kg). L) and brain concentration (nmol / kg tissue), FIG. 11 plots the values in Table 24, with the vertical axis representing plasma concentration and brain concentration, and the horizontal axis representing time from administration of the compound of Example 10. (Mean ± standard deviation, N = 3). Table 25 also shows the percentage (%) of converted bumetanide brain concentration (nmol / kg tissue) / plasma concentration (nmol / L) 1 and 6 hours after administration of the compound of Example 10. The percentage (%) of the converted bumetanide brain concentration (nmol / kg tissue) / plasma concentration (nmol / L) 1 and 6 hours after administration is the plasma concentration 1 and 6 hours after administration. Since it was 0 nmol / L, calculation was impossible.

Table 26 shows the plasma concentration of the compound of Example 11 and bumetanide converted from the compound of Example 11 (nmol / mol) at each time (each time point) after administration of the compound of Example 11 (20 μmol / kg). L) and brain concentration (nmol / kg tissue), FIG. 12 plots the values in Table 26, with the vertical axis representing plasma concentration and brain concentration, and the horizontal axis representing time from administration of the compound of Example 11. (Mean ± standard deviation, N = 3). Table 27 also shows the percentage (%) of converted bumetanide brain concentration (nmol / kg tissue) / plasma concentration (nmol / L) 1 and 6 hours after administration of the compound of Example 11.

Table 28 shows the plasma concentration of the compound of Example 12 and bumetanide converted from the compound of Example 12 (nmol / mg) at each time (each time point) after administration of the compound of Example 12 (20 μmol / kg). L) and brain concentration (nmol / kg tissue), FIG. 13 plots the values in Table 28 with the vertical axis representing plasma concentration and brain concentration, and the horizontal axis representing time from administration of the compound of Example 12. (Mean ± standard deviation, N = 3). Table 29 also shows the percentage (%) of converted bumetanide brain concentration (nmol / kg tissue) / plasma concentration (nmol / L) 1 and 6 hours after administration of the compound of Example 12.

Table 30 shows the plasma concentration of the compound of Example 13 and bumetanide converted from the compound of Example 13 (nmol / mg) at each time (each time point) after administration of the compound of Example 13 (20 μmol / kg). L) and brain concentration (nmol / kg tissue), FIG. 14 plots the values in Table 30 with the vertical axis representing plasma concentration and brain concentration, and the horizontal axis representing time from administration of the compound of Example 13. (Mean ± standard deviation, N = 3). Table 31 shows the percentage (%) of converted bumetanide brain concentration (nmol / kg tissue) / plasma concentration (nmol / L) 1 and 6 hours after administration of the compound of Example 13.

The results of oral administration (20 μmol / kg) of the compounds of Comparative Examples 1 to 4 to rats are shown in FIGS. 15 to 18 and Tables 32 to 39, respectively.

Table 32 shows the plasma concentration of the compound of Comparative Example 1 and bumetanide converted from the compound of Comparative Example 1 at each time (each time point) after administration of the compound of Comparative Example 1 (20 μmol / kg) (nmol / L) and brain concentration (nmol / kg tissue), FIG. 15 plots the values in Table 32 with the vertical axis representing plasma concentration and brain concentration, and the horizontal axis representing time from administration of the compound of Comparative Example 1. (Mean ± standard deviation, N = 2 or 3). The values indicated by * in Table 32 are values calculated with N = 2 (other values were calculated with N = 3). Table 33 shows the percentage (%) of converted bumetanide brain concentration (nmol / kg tissue) / plasma concentration (nmol / L) 1 and 6 hours after administration of the compound of Comparative Example 1.

Table 34 shows the plasma concentration of the compound of Comparative Example 2 and bumetanide converted from the compound of Comparative Example 2 at each time (each time point) after administration of the compound of Comparative Example 2 (20 μmol / kg) (nmol / L) and brain concentration (nmol / kg tissue), FIG. 16 plots the values in Table 34, with the vertical axis representing plasma concentration and brain concentration, and the horizontal axis representing time from administration of the compound of Comparative Example 2. (Mean ± standard deviation, N = 2 or 3). In Table 34, the value indicated by * indicates a value calculated with N = 2 (other values were calculated with N = 3). Table 35 shows the percentage (%) of converted bumetanide brain concentration (nmol / kg tissue) / plasma concentration (nmol / L) 1 and 6 hours after administration of the compound of Comparative Example 2.

Table 36 shows the plasma concentration of the compound of Comparative Example 3 and bumetanide converted from the compound of Comparative Example 3 at each time (each time point) after administration of the compound of Comparative Example 3 (20 μmol / kg) (nmol / L) and brain concentration (nmol / kg tissue), FIG. 17 plots the values in Table 36 with the vertical axis representing plasma concentration and brain concentration, and the horizontal axis representing time from administration of the compound of Comparative Example 3. (Mean ± standard deviation, N = 3). Table 37 shows the percentage (%) of converted bumetanide brain concentration (nmol / kg tissue) / plasma concentration (nmol / L) 1 and 6 hours after administration of the compound of Comparative Example 3.

Table 38 shows the plasma concentration (nmol / mol) of the compound of Comparative Example 4 and bumetanide converted from the compound of Comparative Example 4 at each time (each time point) after administration of the compound of Comparative Example 4 (20 μmol / kg). L) and brain concentration (nmol / kg tissue), and FIG. 18 plots the values in Table 38, with the vertical axis representing plasma concentration and brain concentration, and the horizontal axis representing time from administration of the compound of Comparative Example 4. (Mean ± standard deviation, N = 3). Table 39 shows the percentage (%) of converted bumetanide brain concentration (nmol / kg tissue) / plasma concentration (nmol / L) 1 and 6 hours after administration of the compound of Comparative Example 4.

The brain concentration when bumetanide was orally administered to rats (20 μmol / kg) was 11.0 ± 15.5 nmol / kg tissue 1 hour after administration, but 1.39 ± 1. It was 00 nmol / kg tissue, and the brain concentration rapidly decreased and did not persist at all (FIG. 1 and Table 4). On the other hand, when the compounds of Examples 1 to 13 were orally administered to rats (20 μmol / kg), the converted bumetanide concentration in the brain was 1 hour after administration when bumetanide was orally administered to rats (20 μmol / kg). However, at 6 hours after administration, the brain concentration at 1 hour after administration continued or increased.

In addition, the concentration of bumetanide in the brain / plasma concentration (%) at 1 and 6 hours after administration of bumetanide was 2.12% and 0.68%, respectively. The medium concentration (%) was extremely low. On the other hand, the brain concentration / plasma concentration (%) of the converted bumetanide when the compounds of Examples 1 to 13 were administered were higher than those when bumetanide was orally administered. From this, it was shown that the compounds of Examples 1 to 13 have high transferability into the brain and are converted into bumetanide having pharmacological activity in the brain.

On the other hand, when the compounds of Comparative Examples 1 to 4 were orally administered to rats (20 μmol / kg), no converted bumetanide was detected in the brain.

Therefore, the sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof can be converted into bumetanide having high transferability into the brain and having pharmacological activity, and further converted bumetanide. It was shown that the brain concentration of was sustained.

(Example 30)
Evaluation of blood-brain barrier permeability coefficient by blood-brain barrier remodeling model of sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof:
Using the blood brain barrier remodeling model, the blood brain barrier permeability coefficient as an index of brain migration was evaluated, and the blood brain barrier permeability coefficient of the compounds of Examples 3 and 14 to 28 and the blood brain barrier permeability coefficient of bumetanide Compared.

In the experiment, a monkey-type BBB kit (MBT-24H; Pharmacocell Co., Ltd.) commercially available as a blood-brain barrier reconstruction model was used.

With the BBB kit frozen, the attached medium was added to the brain and blood compartments and thawed, and culture was started in a 37 ° C. incubator containing 5% carbon dioxide in the air. The medium was changed 3 hours after the start of culture and the next day, and then used for the following experiments 4 to 5 days after the start of culture.

The media of the BBB kit brain side and blood side compartments were removed. 200 μL of 1 μmol / L compound (dissolved in Dulbecco's phosphate buffered saline containing 25 mmol / L sucrose) is added to the blood side compartment, and Dulbeccolic acid containing 25 mmol / L sucrose is added to the brain side compartment 900 μL of buffered saline was added and held in a 37 ° C. incubator for 30 minutes with shaking at 50 times / minute. Brain and blood compartment solutions were collected and used as samples for analysis.

The obtained analytical sample was subjected to LC / MS / MS analysis. The analysis was performed under the conditions shown in Table 2 or 3 or a method according thereto.

From the results of LC / MS / MS analysis, the compound concentration of the brain side compartment solution when the compound concentration of the blood side compartment solution was 1 μmol / L was calculated using Analyst 1.4 (Applied Biosystems).

From the compound concentration obtained, the blood brain barrier permeability coefficient was calculated using the following formula 1.
Formula 1: Blood-brain barrier permeability coefficient = compound concentration of brain compartment solution × volume of brain compartment solution ÷ (test time × membrane area × compound concentration of blood compartment solution)

Table 40 shows the blood brain barrier permeability coefficient (× 10 ⁻⁷ cm / sec) of bumetanide and the compounds of Examples 3, 14-28, and the compounds of Examples 3, 14-28 against the blood brain barrier permeability coefficient of bumetanide. The ratio of blood-brain barrier permeability coefficient (vsumetanide ratio) is shown.

Since the compound of Example 3 exhibited a blood-brain barrier permeability coefficient 4.08 times higher than that of bumetanide, it is predicted that the compound has a higher brain transferability than bumetanide. The compounds of Examples 14 to 24 and 26, which are double prodrugs of bumetanide, and the compounds of Examples 25, 27 and 28, which are triple prodrugs of bumetanide, all showed higher blood brain barrier permeability coefficients than bumetanide. . Among them, the compounds of Examples 14 to 16 and 22 showed higher blood-brain barrier permeability coefficient than the compound of Example 3, so that the brain transferability is improved as compared with the case of administering the compound of Example 3. Was suggested.

(Example 31)
Evaluation of permeability coefficient of Caco-2 cell monolayer culture of sulfamoylbenzene derivative (I) or pharmaceutically acceptable salt thereof:
Caco-2 cells were used to evaluate the permeability coefficient of Caco-2 cell monolayer culture membranes, and using the predicted oral absorption rate calculated from this value, the compounds of Examples 3, 14, 19 to 28 and bumetanide Oral absorbability was compared.

In the experiment, Caco-2 cells (American Type Culture Collection) and Millicell 96 Cell Culture Plate (Nippon Millipore) were used.

Caco-2 cells were cultured at 9 × 10 ⁵ cells / mL using medium (Dulbecco's modified Eagle medium (Sigma Aldrich Japan) containing 15% fetal bovine serum, 1% non-essential amino acid solution (GIBCO) and 50 nmol / L vinblastine). 75 microliters seeded on an insert of Millicell 96 Cell Culture Plate coated with collagen (Japan BD Bioscience). 250 μL of the above medium was added to the receiver of the Millicell 96 Cell Culture Plate. Millicell 96 Cell Culture Plate seeded with Caco-2 cells was cultured for 4 days in a 37 ° C. incubator containing 5% carbon dioxide in air.

The insert and receiver medium was replaced with a medium in which 50 nmol / L vinblastine was added to Entero-STIM intestinal epithelial cell differentiation medium (Japan BD Bioscience) containing MITO + and further cultured for 3 days in the following experiment. used.

The medium of the insert and receiver was removed. 75 μL of 1 μmol / L compound (dissolved in Hanks physiological buffer salt solution containing Ca and Mg) is added to the insert, and 250 μL of Hanks physiological buffer salt solution containing Ca and Mg is added to the receiver at 37 ° C. In an incubator for 60 minutes with shaking at 50 times / min. The solution in the insert and receiver was collected and used as a sample for analysis.

The obtained analytical sample was subjected to LC / MS / MS analysis. The analysis was performed under the conditions shown in Table 2 or 3 or a method according thereto.

From the results of LC / MS / MS analysis, the compound concentration in the receiver when the compound concentration in the insert was 1 μmol / L was calculated using Analyst 1.4 (Applied Biosystems).

From the obtained compound concentration, the Caco-2 cell monolayer culture membrane permeability coefficient was calculated using the following formula 2.
Formula 2: Caco-2 cell monolayer culture membrane permeability coefficient = compound concentration in receiver × receiver volume ÷ (test time × membrane area × compound concentration in insert)

In addition, the permeability coefficient of Caco-2 cell monolayer culture membranes of standard compounds with known oral absorption rates (propranolol (oral absorption rate 90%), cimetidine (oral absorption rate 62%), caffeine (oral absorption rate 100%)) Was measured simultaneously, and the predicted oral absorption rate (%) of each compound was determined based on the correlation between the measured Caco-2 cell monolayer culture membrane permeability coefficient and the oral absorption rate of the standard compound.

Tables 41 and 42, Caco-2 cell monolayer membrane permeability coefficient of standard compounds (× 10 ⁻⁶ cm / sec) and oral absorption rate (%), bumetanide and Caco of compounds of Examples 3, 14, 19-28 -2 shows a cell monolayer culture membrane permeability coefficient (× 10 ^-6 cm / sec) and predicted oral absorption rate (%).

The compound of Example 3 showed a predicted oral absorption rate lower than that of bumetanide, and a decrease in oral absorption was predicted compared to bumetanide. On the other hand, the compounds of Examples 14, 19 to 21 and 26 which are double prodrugs of bumetanide (the compound of Example 3 is obtained when only the chemical modification of the carboxyl group of the two sites undergoing conversion undergoes conversion) And the compounds of Examples 22 and 23 (the compound of Example 3 is obtained when only the acyl group part of the sugar partial structure is subjected to conversion in the two sites undergoing conversion) and the triple prodrug of bumetanide Since the compounds of Examples 25, 27 and 28 showed a higher predicted oral absorption rate than the compound of Example 3, when these compounds were orally administered, the compounds of Example 3 were administered orally. It was also suggested that oral absorption is improved. Furthermore, the compounds of Examples 14, 19 to 21 and 26 and the compounds of Examples 25, 27 and 28 showed higher predicted oral absorption rates than bumetanide. Therefore, when these compounds were administered orally, It was suggested that oral absorption is improved. Therefore, from the results of Examples 30 and 31, the double prodrug and triple prodrug of bumetanide according to the present invention are particularly useful when administered orally because they have excellent brain migration and oral absorption. It was shown that.

(Example 32)
Pharmacokinetics in cynomolgus monkeys of the sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof:
After the oral administration of the compounds of Examples 3 and 14, respectively, to male cynomolgus monkeys, the plasma concentration and cerebrospinal fluid concentration of converted bumetanide were measured. It was compared with the concentration in the liquid.

In the experiment, male cynomolgus monkeys (New Nihon Kagaku Co., Ltd.) aged 4 to 6 years with free access to solid feed (Purina Mills, LLC) and tap water were fasted for about 14 hours before compound administration. did. Feeding was resumed after about 4 hours had elapsed after administration.

The compounds of Examples 3 and 14 and bumetanide were each orally administered to cynomolgus monkeys at a dose of 3 mg / kg. The administration solutions of the compounds of Examples 3 and 14 and bumetanide were prepared by dissolving or suspending each in Dulbecco's phosphate buffered saline. Oral administration of the administration liquid was performed in the stomach through the nasal cavity using a disposable catheter (Nipro Corporation) and a syringe (Nipro Corporation) without anesthesia, and about 5 mL of drinking water was injected after the administration.

At 30, 45, 45 minutes and 1, 2, 4, 6, 8 hours after oral administration, heparin sodium injection cylinder from cynomolgus monkey femoral vein (heparin sodium added to 10 units / mL with respect to the amount of blood collected) ). Cerebrospinal fluid was collected from the subarachnoid space under combined anesthesia with medetomidine hydrochloride and ketamine hydrochloride 15 minutes after oral administration. In addition, blank blood and cerebrospinal fluid were collected from cynomolgus monkeys not receiving the compound.

The collected blood was centrifuged at 4 ° C. and 1710 × g for 15 minutes (Kubota Co., Ltd., compact high-speed cooling centrifuge 6930) to separate plasma, and the obtained plasma was −70 ° C. until the preparation of the sample for analysis. Stored in. The collected cerebrospinal fluid was centrifuged at 4 ° C. and 1710 × g for 15 minutes (Kubota Co., Ltd., compact high-speed cooling centrifuge 6930) to separate and remove blood cells and the like at −70 ° C. until the preparation of the sample for analysis. Stored. The plasma and cerebrospinal fluid obtained from the cynomolgus monkey administered with the compound are referred to as cynomolgus monkey plasma sample and cynomolgus monkey cerebral spinal fluid sample, respectively. It is called blank plasma or blank cerebrospinal fluid.

The internal standard solution 20 μL and methanol 120 μL were added to a cynomolgus monkey plasma sample or 50 μL of a cynomolgus monkey plasma sample appropriately diluted with blank plasma, stirred, and then cooled at 4 ° C. for 10 minutes. Further, 20 μL of an internal standard solution and 120 μL of methanol were added to 50 μL of a cynomolgus monkey cerebrospinal fluid sample, stirred, and then cooled at 4 ° C. for 10 minutes. A calibration curve sample was prepared by treating a blank plasma or blank cerebrospinal fluid with a standard curve standard solution in the same manner.

Each sample after cooling is centrifuged for 10 minutes at 4 ° C. and 3000 rpm (Hitachi Koki Himac CF7D2), and the supernatant is added onto a 0.2 μm filter plate (Whatman) and further centrifuged at 4 ° C. and 2000 rpm for 5 minutes ( Hitachi Koki Himac CF7D2), and distilled water (50 μL) was added to the obtained filtrate to prepare a sample for analysis.

The obtained analytical sample was subjected to LC / MS / MS analysis. The analysis was performed under the conditions shown in Table 2 or 3 or a method according thereto.

From the results of LC / MS / MS analysis, a calibration curve was prepared using Analyst 1.4 (Applied Biosystems), and the administered compound (the compound of Examples 3 and 14 and bumetanide) in the sample for analysis, and The concentration of bumetanide after conversion (when the compounds of Examples 3 and 14 were administered) was calculated. For each time point of blood collection and cerebrospinal fluid collection for each compound, the plasma concentration and cerebrospinal fluid concentration (mean value ± standard deviation, N = 3) of the administered compound and bumetanide after conversion were calculated. Also, the percentage (%) of cerebrospinal fluid concentration (ng / mL) / plasma concentration (ng / mL) of bumetanide (bumetanide after conversion when the compounds of Examples 3 and 14 were administered) for each individual. Calculated and expressed as mean ± standard deviation (N = 3). Since there is almost no protein in cerebrospinal fluid, the drug exists in a protein-unbound state. Therefore, the drug concentration in the cerebrospinal fluid can be regarded as a protein non-binding drug concentration (Lange, Journal of Pharmacokinetics and Pharmacodynamics 2013, 40, p. 315-326). On the other hand, since there is a protein typified by albumin in plasma, that is, plasma protein, 95% of bumetanide in plasma is bound to plasma protein, and bumetanide unbound to plasma protein is 5%. (Pentikainen et al., British Journal of Clinical Pharmacology, 1977, Vol. 4, p. 39-44). Therefore, with the intention of comparing both the concentration of bumetanide in cerebrospinal fluid and plasma in the protein non-binding state, which is substantially closer to the value as an indicator of brain translocation of bumetanide having pharmacological activity, By using the value obtained by converting the plasma concentration to the plasma concentration of non-protein bound bumetanide, that is, the value obtained by multiplying the plasma concentration of bumetanide by the plasma protein non-binding rate of plasma bumetanide (0.05), The percentage (%) of cerebrospinal fluid concentration (ng / mL) / plasma concentration (ng / mL) of non-protein bound bumetanide was calculated and expressed as the mean ± standard deviation (N = 3).

The results are shown in FIGS. 19 to 21 and Tables 43 to 48.

FIG. 19, Tables 43 and 44 show the results when bumetanide was orally administered to cynomolgus monkeys (3 mg / kg). Table 43 shows the plasma concentration (ng / mL) and cerebrospinal fluid concentration (ng / mL) of bumetanide at each time (each time point) after administration of bumetanide, and FIG. The values in Table 43 are plotted with the concentration in the spinal fluid and the horizontal axis as the time since bumetanide administration (mean ± standard deviation, N = 3). Table 44 also shows the percentage of bumetanide cerebrospinal fluid concentration (ng / mL) / plasma concentration (ng / mL) (%) 15 minutes after administration of bumetanide and cerebrospinal fluid of protein-bound bumetanide It represents the percentage (%) of medium concentration (ng / mL) / plasma concentration (ng / mL).

Tables 45 to 48 and FIGS. 20 to 21 show the results of oral administration (3 mg / kg) of the compounds of Examples 3 and 14 to cynomolgus monkeys, respectively.

Table 45 shows the plasma concentration (ng / ng) of the compound of Example 3 and bumetanide converted from the compound of Example 3 at each time (each time point) after administration of the compound of Example 3 (3 mg / kg). 20) and cerebrospinal fluid concentration (ng / mL). FIG. 20 shows the concentration in plasma and cerebrospinal fluid on the vertical axis, and the time from administration of the compound of Example 3 on the horizontal axis. Values are plotted (mean ± standard deviation, N = 3). Table 46 also shows the percentage (%) of the converted cerebrospinal fluid concentration (ng / mL) / plasma concentration (ng / mL) of bumetanide 15 minutes after administration of the compound of Example 3, and the protein non- It represents the percentage (%) of cerebrospinal fluid concentration (ng / mL) / plasma concentration (ng / mL) of bound bumetanide (converted).

Table 47 shows the plasma concentration (ng / mg) of the compound of Example 14 and bumetanide converted from the compound of Example 14 at each time (each time point) after administration of the compound of Example 14 (3 mg / kg). mL) and cerebrospinal fluid concentration (ng / mL). FIG. 21 shows the concentration in plasma and cerebrospinal fluid on the vertical axis, and the time from administration of the compound of Example 14 on the horizontal axis. Values are plotted (mean ± standard deviation, N = 3). Table 48 also shows the percentage of converted bumetanide cerebrospinal fluid concentration (ng / mL) / plasma concentration (ng / mL) 15 minutes after administration of the compound of Example 14 and protein non- It represents the percentage (%) of cerebrospinal fluid concentration (ng / mL) / plasma concentration (ng / mL) of bound bumetanide (converted).

When bumetanide was orally administered to cynomolgus monkeys (3 mg / kg), the cerebrospinal fluid concentration was 0.048 ± 0.019 ng / mL at 15 minutes after administration, and bumetanide cerebrospinal fluid concentration / plasma concentration The percentage (%) was 0.035 ± 0.033%. Further, the percentage (%) of cerebrospinal fluid concentration / plasma concentration of protein-unbound bumetanide calculated as a value closer to the substance as an index indicating the brain transferability of bumetanide having pharmacological activity is 0.700 ± 0.660%. (FIG. 19 and Tables 43 and 44). On the other hand, when the compounds of Examples 3 and 14 were orally administered to cynomolgus monkeys (3 mg / kg), the concentration of converted bumetanide in the cerebrospinal fluid was 0.041 ± 0.011 ng / mL, 15 minutes after administration, 0.035 ± 0.003 ng / mL, converted bumetanide cerebrospinal fluid concentration / percentage of plasma concentration (%) is 0.698 ± 0.403%, 1.045 ± 0.496%, protein, respectively The percentage of cerebrospinal fluid concentration / plasma concentration of unbound bumetanide (converted) was 13.9 ± 8.06% and 20.9 ± 9.9%, respectively, and bumetanide was orally administered Compared with the case, the high value was shown (FIGS. 20, 21 and Tables 45 to 48). From this, it was shown that the compounds of Examples 3 and 14 have high transferability into the brain and are converted into bumetanide having pharmacological activity in the brain.

Therefore, this result also shows that the sulfamoylbenzene derivative (I) or a pharmaceutically acceptable salt thereof is highly transferred to the brain and converted into bumetanide having pharmacological activity in the brain. It was done.

Industrial applicability

The sulfamoylbenzene derivative (I) of the present invention or a pharmaceutically acceptable salt thereof is converted into bumetanide having a high transferability into the brain and having pharmacological activity, and further converted bumetanide. Since the concentration in the brain persists, it can be used as a prodrug of bumetanide, and in particular, can be used as a therapeutic or prophylactic agent for epilepsy.

Claims (6)

A sulfamoylbenzene derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

[Wherein R ¹ is a hydrogen atom or a group selected from the following group A consisting of a partial structure of an amino acid, or a hydrogen atom of the hydroxyl group at the 6-position is substituted with an acetyl group, a benzoyl group or a pivaloyl group. Represents a group selected from the following group B consisting of a partial structure of sugar,
X represents an oxygen atom or NH;
R ² represents a hydrogen atom, an ethyl group, a butyl group, a hexyl group, a benzyl group, a cyclohexylcarbonyloxymethyl group, an isobutyryloxymethyl group, a pivaloyloxymethyl group, or an amino acid when X is an oxygen atom. Represents a group selected from the following group C consisting of a partial structure, and when X is NH, selected from the following group D consisting of a sugar partial structure in which the hydrogen atom of the hydroxyl group may be substituted with a methyl group Represents a group, but when R ¹ is a hydrogen atom, it does not represent a hydrogen atom or an ethyl group.
Group A:

(* Represents the bonding position with the nitrogen atom to which R ¹ is bonded.)
Group B:

(* Represents the bonding position with the nitrogen atom to which R ¹ is bonded.)
Group C:

(* Represents the bonding position with the oxygen atom to which R ² is bonded.)
Group D:

(* Represents the bonding position with the nitrogen atom to which R ² is bonded.)] R ¹ is a hydrogen atom, X is an oxygen atom, R ² is

The sulfamoylbenzene derivative according to claim 1 or a pharmaceutically acceptable salt thereof. R ¹ is

The sulfamoylbenzene derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein X is an oxygen atom and R ² is a hydrogen atom. R ¹ is

The sulfamoylbenzene derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein X is an oxygen atom, and R ² is an ethyl group. A pharmaceutical comprising the sulfamoylbenzene derivative according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient. A therapeutic or prophylactic agent for epilepsy comprising the sulfamoylbenzene derivative according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient.

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