JP6952350B2 - Insulin secretagogue or insulin sensitizer - Google Patents

Description

The present invention is one selected from a compound represented by the formula (I) described later and a pharmacologically acceptable salt thereof (hereinafter, these may be collectively referred to as "the present insulin compounds"). Alternatively, an agent for promoting insulin secretion or an agent for improving insulin resistance, which contains two or more compounds as an active ingredient, or one or more compounds selected from the Sulfate compounds as an active ingredient. It is regulated by GATA, which contains, as an active ingredient, a prophylactic or ameliorating agent for a disease caused by decreased insulin secretion or insulin resistance, and one or more compounds selected from the Sulfate compounds of the present case. Insulin activator.

Diabetes is a disease associated with persistent hyperglycemia. According to the World Health Organization (WHO), the number of diabetic patients in the world is increasing year by year, reaching 422 million as of 2014, according to the research results. With the increase in the number of diabetic patients, the market size of diabetes treatment drugs is expanding, and the market size of diabetes treatment drugs in Japan, the United States, and Europe has exceeded 3.5 trillion yen as of 2014.

Insulin is a type of hormone secreted from the pancreas into the body and has the effect of lowering the blood sugar level. Persistent hyperglycemia in diabetes is known to result from insulin deficiency or inhibition of its action due to genetic or environmental factors.

In the case of mild diabetes, diabetes is mainly treated by diet therapy, exercise therapy, and improvement of constitution such as obesity. When the symptom progresses further, a drug therapy for controlling the blood glucose level is performed by injecting insulin, a substance having an insulin secretagogue action, or a substance having an action of improving insulin resistance. As a substance having an insulin secretion promoting action, for example, a pyrrolizidine compound (Patent Document 1), a polyglycerin fatty acid ester (Patent Document 2), a rosmarinic acid (Patent Document 3) and the like have been reported. Further, as substances having an action of improving insulin resistance, for example, apple fruit squeezed residue and rosemary extract (Patent Document 4), tranilast (N- (3,4-dimethoxycinnamoyl) anthranilic acid) (Patent Document 5). ), Adiponectin (Patent Document 6) and the like have been reported. However, the relationship between the sulfuric acid compounds and the insulin secretagogue action and the insulin resistance improving action has not been known so far.

Japanese Unexamined Patent Publication No. 2016-34929 Japanese Unexamined Patent Publication No. 2012-140406 Japanese Unexamined Patent Publication No. 2005-139136 Japanese Unexamined Patent Publication No. 2016-000707 JP-A-2009-120607 International Publication 2003/6389 Pamphlet

An object of the present invention is an insulin secretagogue having an action of effectively promoting insulin secretion, an insulin sensitizer having an action of effectively improving insulin resistance, and an insulin sensitizer that effectively promotes insulin secretion. Or, a preventive or ameliorating agent for diseases caused by decreased insulin secretion or insulin resistance, which has an effect of effectively promoting hypoglycemia by effectively improving insulin resistance, and transcription regulated by GATA. The purpose is to provide an activator having an action of increasing the level.

The present inventor is continuing diligent research to solve the above problems. In the process, the sulfuric acid compounds have the effect of effectively promoting insulin secretion, the effect of effectively improving insulin resistance, and the effect of effectively promoting hypoglycemic lowering. , And it happened to have the effect of increasing the transcriptional level regulated by GATA, and completed the present invention.

（式中、Ａは、置換若しくは無置換のアルキル基、置換若しくは無置換のアルキルカルボニル基、置換若しくは無置換のシクロアルキル基、置換若しくは無置換のアリール基、置換若しくは無置換のキノリニル基、置換若しくは無置換のウンベリフェリル基、又は置換若しくは無置換のステロイド残基を表し、上記各基が置換基を有する場合、当該置換基は、Ｃ_１−６アルキル基、フェニル基、置換フェニル基、Ｃ_１−６アルコキシ基、ハロゲン原子、ニトロ基、アミノ基、ヒドロキシ基、カルボキシ基、アルデヒド基、アセチル基、カルボキシ−Ｃ_１−６アルキル基、ヒドロキシ−Ｃ_１−６アルキル基、ジヒドロキシ−Ｃ_１−６アルキル基、カルバモイル−Ｃ_１−６アルキル基、並びに末端の炭素原子がカルボキシ及びアミノによって置換されたＣ_１−６アルキル基からなる群より選択される１若しくは２以上の基を意味する）
で表される化合物及びその薬理学的に許容される塩から選択される１種又は２種以上の化合物を有効成分として含有することを特徴とするインスリン分泌促進剤又はインスリン抵抗性改善剤。
〔２〕化合物が、下記のいずれかの化合物であることを特徴とする上記〔１〕に記載のインスリン分泌促進剤又はインスリン抵抗性改善剤。

〔３〕経口投与することを特徴とする上記〔１〕又は〔２〕に記載のインスリン分泌促進剤又はインスリン抵抗性改善剤。
〔４〕下記式（Ｉ）

（式中、Ａは、置換若しくは無置換のアルキル基、置換若しくは無置換のアルキルカルボニル基、置換若しくは無置換のシクロアルキル基、置換若しくは無置換のアリール基、置換若しくは無置換のキノリニル基、置換若しくは無置換のウンベリフェリル基、又は置換若しくは無置換のステロイド残基を表し、上記各基が置換基を有する場合、当該置換基は、Ｃ_１−６アルキル基、フェニル基、置換フェニル基、Ｃ_１−６アルコキシ基、ハロゲン原子、ニトロ基、アミノ基、ヒドロキシ基、カルボキシ基、アルデヒド基、アセチル基、カルボキシ−Ｃ_１−６アルキル基、ヒドロキシ−Ｃ_１−６アルキル基、ジヒドロキシ−Ｃ_１−６アルキル基、カルバモイル−Ｃ_１−６アルキル基、並びに末端の炭素原子がカルボキシ及びアミノによって置換されたＣ_１−６アルキル基からなる群より選択される１若しくは２以上の基を意味する）
で表される化合物及びその薬理学的に許容される塩から選択される１種又は２種以上の化合物を有効成分として含有することを特徴とする、インスリン分泌低下又はインスリン抵抗性に起因する疾患の予防又は改善剤。
〔５〕化合物が、下記のいずれかの化合物であることを特徴とする上記〔４〕に記載の予防又は改善剤。

〔６〕経口投与することを特徴とする上記〔４〕又は〔５〕に記載の予防又は改善剤。
〔７〕インスリン分泌低下又はインスリン抵抗性に起因する疾患が、糖尿病であることを特徴とする上記〔４〕〜〔６〕のいずれかに記載の予防又は改善剤。
〔８〕下記式（Ｉ）

（式中、Ａは、置換若しくは無置換のアルキル基、置換若しくは無置換のアルキルカルボニル基、置換若しくは無置換のシクロアルキル基、置換若しくは無置換のアリール基、置換若しくは無置換のキノリニル基、置換若しくは無置換のウンベリフェリル基、又は置換若しくは無置換のステロイド残基を表し、上記各基が置換基を有する場合、当該置換基は、Ｃ_１−６アルキル基、フェニル基、置換フェニル基、Ｃ_１−６アルコキシ基、ハロゲン原子、ニトロ基、アミノ基、ヒドロキシ基、カルボキシ基、アルデヒド基、アセチル基、カルボキシ−Ｃ_１−６アルキル基、ヒドロキシ−Ｃ_１−６アルキル基、ジヒドロキシ−Ｃ_１−６アルキル基、カルバモイル−Ｃ_１−６アルキル基、並びに末端の炭素原子がカルボキシ及びアミノによって置換されたＣ_１−６アルキル基からなる群より選択される１若しくは２以上の基を意味する）
で表される化合物及びその薬理学的に許容される塩から選択される１種又は２種以上の化合物を有効成分として含有することを特徴とする、ＧＡＴＡにより調節される転写の活性化剤。
〔９〕化合物が、下記の化合物であることを特徴とする上記〔８〕に記載の活性化剤。

That is, the present invention is as follows.
[1] The following formula (I)

(In the formula, A is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkylcarbonyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted quinolinyl group, a substituent. Alternatively, it represents an unsubstituted umbelliferyl group or a substituted or unsubstituted steroid residue, and when each of the above groups has a substituent, the substituent is a C _1-6 alkyl group, a phenyl group, a substituted phenyl group, C _1-6 alkoxy group, halogen atom, nitro group, amino group, hydroxy group, carboxy group, aldehyde group, acetyl group, carboxy-C _1-6 alkyl group, hydroxy-C _1-6 alkyl group, dihydroxy-C ₁ It means one or more groups selected from the group consisting of a _-6 alkyl group, a carbamoyl-C _{1-6 alkyl group, and a C 1-6} alkyl group in which the terminal carbon atom is substituted with carboxy and amino).
An insulin secretagogue or an insulin sensitizer, which comprises, as an active ingredient, one or more compounds selected from the compound represented by the above and a pharmacologically acceptable salt thereof.
[2] The insulin secretagogue or insulin resistance improving agent according to the above [1], wherein the compound is any of the following compounds.

[3] The insulin secretagogue or insulin sensitizer according to the above [1] or [2], which is orally administered.
[4] The following formula (I)

(In the formula, A is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkylcarbonyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted quinolinyl group, a substituent. Alternatively, it represents an unsubstituted umbelliferyl group or a substituted or unsubstituted steroid residue, and when each of the above groups has a substituent, the substituent is a C _1-6 alkyl group, a phenyl group, a substituted phenyl group, C _1-6 alkoxy group, halogen atom, nitro group, amino group, hydroxy group, carboxy group, aldehyde group, acetyl group, carboxy-C _1-6 alkyl group, hydroxy-C _1-6 alkyl group, dihydroxy-C ₁ It means one or more groups selected from the group consisting of a _-6 alkyl group, a carbamoyl-C _{1-6 alkyl group, and a C 1-6} alkyl group in which the terminal carbon atom is substituted with carboxy and amino).
A disease caused by decreased insulin secretion or insulin resistance, which comprises containing one or more compounds selected from the compound represented by the above and a pharmacologically acceptable salt thereof as an active ingredient. Preventive or ameliorating agent.
[5] The preventive or ameliorating agent according to the above [4], wherein the compound is any of the following compounds.

[6] The preventive or ameliorating agent according to the above [4] or [5], which is characterized by oral administration.
[7] The preventive or ameliorating agent according to any one of the above [4] to [6], wherein the disease caused by decreased insulin secretion or insulin resistance is diabetes.
[8] The following formula (I)

(In the formula, A is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkylcarbonyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted quinolinyl group, a substituent. Alternatively, it represents an unsubstituted umbelliferyl group or a substituted or unsubstituted steroid residue, and when each of the above groups has a substituent, the substituent is a C _1-6 alkyl group, a phenyl group, a substituted phenyl group, C _1-6 alkoxy group, halogen atom, nitro group, amino group, hydroxy group, carboxy group, aldehyde group, acetyl group, carboxy-C _1-6 alkyl group, hydroxy-C _1-6 alkyl group, dihydroxy-C ₁ It means one or more groups selected from the group consisting of a _-6 alkyl group, a carbamoyl-C _{1-6 alkyl group, and a C 1-6} alkyl group in which the terminal carbon atom is substituted with carboxy and amino).
A GATA-regulated transcriptional activator, which comprises, as an active ingredient, one or more compounds selected from the compound represented by and the pharmacologically acceptable salt thereof.
[9] The activator according to the above [8], wherein the compound is the following compound.

In addition, as another embodiment of the present invention, one or more compounds selected from the present sulfuric acid compounds are applied to patients who require a preventive or ameliorating (therapeutic) agent for a disease caused by decreased insulin secretion. Select from the Sulfate compounds for use as a method for preventing or ameliorating (treating) a disease caused by decreased insulin secretion or as a preventive or ameliorating (therapeutic) agent for a disease caused by decreased insulin secretion by administration. One or more compounds selected from the Sulfate Compounds for use in the prevention or amelioration (treatment) of diseases caused by decreased insulin secretion, or one or more compounds selected from the Sulfate Compounds. Examples thereof include the use of one or more compounds selected from the present sulfuric acid compounds for producing a preventive or ameliorating (therapeutic) agent for a disease caused by decreased insulin secretion.

Further, as another embodiment of the present invention, one or more compounds selected from the present sulfuric acid compounds are administered to a patient who needs prevention or amelioration (treatment) of a disease caused by insulin resistance. By doing so, it is selected from the Sulfate compounds for use as a method for preventing or ameliorating (treating) a disease caused by insulin resistance or as a preventive or ameliorating (therapeutic) agent for a disease caused by insulin resistance. One or more compounds, one or more compounds selected from the Sulfate compounds for use in the prevention or amelioration (treatment) of diseases caused by insulin resistance, and insulin. Examples thereof include the use of one or more compounds selected from the Sulfate compounds for producing a preventive or ameliorating (therapeutic) agent for a disease caused by resistance.

Further, as another embodiment of the present invention, one or more compounds selected from the present sulfuric acid compounds are used to prevent or ameliorate (treat) a disease caused by a decrease in transcription level regulated by GATA. A method of preventing or ameliorating (treating) a disease caused by a decrease in the transcription level regulated by GATA, or prevention or prevention of a disease caused by a decrease in the transcription level regulated by GATA, by administering to a patient in need. In the prevention or amelioration (treatment) of one or more compounds selected from the Sulfate compounds for use as an ameliorating (therapeutic) agent, and diseases caused by a decrease in transcription level regulated by GATA. For producing one or more compounds selected from the Sulfate Compounds for use, or a preventive or ameliorating (therapeutic) agent for a disease caused by a decrease in transcription level regulated by GATA. The use of one or more compounds selected from the Sulfate compounds can be mentioned.

According to the present invention, insulin by effectively promoting insulin secretion, effectively improving insulin resistance, effectively promoting hypoglycemic depression, and activating transcription regulated by GATA. Because it can suppress or prevent decreased secretion, decreased insulin sensitivity, hyperglycemia, and / or decreased transcription levels regulated by GATA, and normally regulate insulin secretion, sensitivity to insulin, and / or blood glucose levels. It is useful for the prevention or amelioration (treatment) of diseases caused by decreased insulin secretion or insulin resistance and diseases caused by decreased transcription level regulated by GATA.

Glucose-stimulated cell line INS-1e derived from rat Langerhans islets (also referred to as "La islets", "pancreatic islets", and "pancreatic islets") was used in the presence of the sulfuric acid compounds (sodium phenyl sulfate [PS]). or is a diagram showing the results of measurement of the absence (deionized water solvent [H 2 _O] presence) insulin concentrations when cultured in (secretion amount). “*” In the figure indicates that there is a statistically significant difference (p <0.05). Amount of insulin secreted when glucose-stimulated mouse pancreatic island La is cultured in the presence or absence of the Sulfate compounds (sodium phenyl sulfate [100 μM PS]) or in the absence (in the presence of deionized water [Control] of the solvent). (Fig. 2A), insulin secretion amount corrected by protein amount (Fig. 2B), total insulin content in the mouse pancreatic island of La (Fig. 2C), and insulin secretion rate (ratio of secreted insulin to total insulin amount) (Fig. 2A). It is a figure which shows the result of having measured 2D). “*” In the figure indicates that there is a statistically significant difference (p <0.05). FIG. 3A shows eight types of the present sulfate compounds (sodium sulphate phenyl [PS], potassium sulfate p-cresol [# 1], potassium sulfate p-chlorophenol [# 8], and INS-1e cells stimulated with glucose. Potassium sulphate p-nitrophenol [# 11], potassium sulphate o-cresol [# 14], potassium sulphate quinolinol [# 21], potassium sulphate 1-naphthol [# 22], and potassium sulphate dihydroferric acid [# 24] ]) It is a figure which shows the result of having measured the insulin secretion amount corrected by the amount of protein at the time of culturing in the presence or absence (in the presence of deionized water [dH2O] of a solvent). FIG. 3B shows nine types of Sulfate compounds (potassium 2-naphthol sulfate [# 20], potassium androsterone sulfate [# 23], potassium cyclohexanol sulfate [# 34], and INS-1e cells stimulated with glucose. Potassium Sulfate Testosterone [# 35], Potassium Sulfate 2- (4-Hydroxyphenyl) Acetamide [# 37], Potassium Sulfate o-methoxyphenyl [# 42], Potassium Sulfate 4-Ethylphenyl [# 48], Potassium Sulfate Vanillin [# 48] The results of measuring the amount of insulin secreted corrected by the amount of protein when cultured in the presence or absence of (# 50] and potassium tyrosine sulfate [# 69]) (in the presence of the solvent dimethylsulfoxide [DMSO]) are shown. It is a figure which shows. “*” And “**” in the figure have statistically significant differences (p <0.05 and p <0.01) with respect to the control solvent (deionized water or DMSO), respectively. Indicates that. Diabetes model mice (KK-Ay mice) administered with sodium phenyl sulfate (“PS” in the figure) or KK-Ay mice not administered with sodium phenyl sulfate (administered with deionized water as a solvent) (“water” in the figure). ) Was subjected to a glucose tolerance test (GTT; Glucose Tolerance Test), and the blood insulin concentration was measured. The horizontal axis shows the elapsed time (minutes) after glucose loading. In addition, "*" in the figure indicates that there is a statistically significant difference (p <0.05). KK-Ay mice administered with sodium sulphate (“PS” in the figure) or KK-Ay mice not administered with sodium sulphate (administered with deionized water as a solvent) (“water” in the figure) were loaded with insulin. It is a figure which shows the result of having measured the blood glucose level by the test (IPTT; Insulin Tolerance Test). The horizontal axis shows the elapsed time (minutes) after insulin loading. The “blood glucose level” on the vertical axis is shown as a relative value when the blood glucose level immediately after insulin loading (0 minutes) is set to 1. In addition, "*" in the figure indicates that there is a statistically significant difference (p <0.05). Kidney-derived erythropoietin-producing cell (REP cells) strains in the presence or absence of the Sulfate Compounds (Sodium Sulfate [PS]) (in the presence of solvent deionized water [H ₂ O]) It is a figure which shows the result of having measured the transfer activation level by GATA when cultivated in.

The insulin secretagogue of the present invention is an agent containing one or more compounds selected from the Sulfate Compounds as an active ingredient, for which the purpose of "promoting insulin secretion" is limited (hereinafter, The insulin secretagogue (sometimes referred to as the "insulin secretion promoter"), and the insulin resistance improver of the present invention is selected from the sulfate compounds for which the use "to improve insulin resistance" is limited. It is an agent containing one or more compounds as an active ingredient (hereinafter, may be referred to as "the Insulin Resistance Improving Agent"), and is caused by a decrease in insulin secretion or insulin resistance of the present invention. The disease preventive or ameliorating agent is one or more compounds selected from the Sulfate Compounds for which the use is limited to "to prevent or ameliorate a disease caused by decreased insulin secretion or insulin resistance". Is an agent containing insulin as an active ingredient (hereinafter, may be referred to as "the Prophylactic / Improving Agent"), and the insulin activator regulated by GATA of the present invention is "GATA-regulated transcription. An agent containing one or more compounds selected from the insulin compounds as an active ingredient, for which the purpose of "to activate" is limited (hereinafter, may be referred to as "the transcription activator"). (These agents are collectively referred to as the "Insulin"). This drug is regulated by pharmaceutical products (preparation for promoting insulin secretion, preparation for improving [treatment] of insulin resistance, preparation for preventing or improving [treatment] of diseases caused by decreased insulin secretion or insulin resistance, GATA. In addition to (preparations for activating transcription), there are also pharmaceutical-like (food) compositions and functional foods that have specific functions such as health supplements, health functional foods, and supplements and are eaten for the purpose of maintaining health. included.

In the present invention, "promoting insulin secretion" means that the amount of insulin secreted from islet-derived cells (β cells, etc.) (for example, the amount of insulin secreted as the blood glucose concentration increases) increases. Means that. The presence or absence of "promotion of insulin secretion" can be confirmed and evaluated by performing a glucose tolerance test (GTT; Glucose Tolerance Test) and measuring the insulin concentration.

In the present invention, "insulin resistance" means a state in which insulin sensitivity, more specifically, the action and effect of insulin is reduced (worsened). "Insulin resistance" is caused by a decrease in the number of insulin receptors, an increase in insulin antagonists, a decrease in the level of intracellular signal transduction via the insulin receptor, and the like. The presence or absence of "insulin resistance" can be confirmed and evaluated by conducting an insulin tolerance test (IPTT) and measuring the blood glucose level.

In the present invention, "gATA-regulated transcriptional activation" refers to the transcriptional (mRNA expression) level of a gene regulated by at least one GATA protein, which is a transcription factor, in mammalian (eg, human) cells. Means that it is activated (increased). Specific examples of such GATA proteins include GATA-1, GATA-2, GATA-3, GATA-4, GATA-5 and GATA-6 proteins.

（式中、Ａは、置換若しくは無置換のアルキル基、置換若しくは無置換のアルキルカルボニル基、置換若しくは無置換のシクロアルキル基、置換若しくは無置換のアリール基、置換若しくは無置換のキノリニル基、置換若しくは無置換のウンベリフェリル基、又は置換若しくは無置換のステロイド残基を表し、上記各基が置換基を有する場合、当該置換基は、Ｃ_１−６アルキル基、フェニル基、置換フェニル基、Ｃ_１−６アルコキシ基、ハロゲン原子、ニトロ基、アミノ基、ヒドロキシ基、カルボキシ基、アルデヒド基、アセチル基、カルボキシ−Ｃ_１−６アルキル基、ヒドロキシ−Ｃ_１−６アルキル基、ジヒドロキシ−Ｃ_１−６アルキル基、カルバモイル−Ｃ_１−６アルキル基、並びに末端の炭素原子がカルボキシ及びアミノによって置換されたＣ_１−６アルキル基からなる群より選択される１若しくは２以上の基を意味する）
以下、置換若しくは無置換のアルキル基、置換若しくは無置換のアルキルカルボニル基、置換若しくは無置換のシクロアルキル基、置換若しくは無置換のアリール基、置換若しくは無置換のキノリニル基、置換若しくは無置換のウンベリフェリル基、及び置換若しくは無置換のステロイド残基の各々を官能基ということがある。The compound used in the present invention is one or more compounds selected from the compound represented by the following formula (I) and a pharmacologically acceptable salt thereof.

(In the formula, A is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkylcarbonyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted quinolinyl group, a substituent. Alternatively, it represents an unsubstituted umbelliferyl group or a substituted or unsubstituted steroid residue, and when each of the above groups has a substituent, the substituent is a C _1-6 alkyl group, a phenyl group, a substituted phenyl group, C _1-6 alkoxy group, halogen atom, nitro group, amino group, hydroxy group, carboxy group, aldehyde group, acetyl group, carboxy-C _1-6 alkyl group, hydroxy-C _1-6 alkyl group, dihydroxy-C ₁ It means one or more groups selected from the group consisting of a _-6 alkyl group, a carbamoyl-C _{1-6 alkyl group, and a C 1-6} alkyl group in which the terminal carbon atom is substituted with carboxy and amino).
Hereinafter, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkylcarbonyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted quinolinyl group, a substituted or unsubstituted ung Each of the beryferyl group and the substituted or unsubstituted steroid residue may be referred to as a functional group.

In addition to the above, in another aspect of the invention, A is a substituted or unsubstituted C _1-6 alkyl group, a substituted or unsubstituted C _1-6 alkylcarbonyl group, a substituted or unsubstituted C _3-8. Cycloalkyl group, substituted or unsubstituted phenyl group, substituted or unsubstituted naphthyl group, substituted or unsubstituted phenyl C _1-6 alkyl group, substituted or unsubstituted quinolinyl group, substituted or unsubstituted umbelliferyl group , Substituent or unsubstituted androsterone residue, substituted or unsubstituted dehydroepiandrosterone residue, substituted or unsubstituted testosterone residue, substituted or unsubstituted dihydrotestosterone residue, substituted or unsubstituted estron residue. , Substituted or unsubstituted estradiol residue, or substituted or unsubstituted estriol residue, and when each of the above groups has a substituent, the substituent is a C _1-6 alkyl group, a phenyl group, a substituted phenyl. Group, C _1-6 alkoxy group, halogen atom, nitro group, amino group, hydroxy group, carboxy group, aldehyde group, acetyl group, carboxy-C _1-6 alkyl group, hydroxy-C _1-6 alkyl group, dihydroxy- C _1-6 alkyl group, a carbamoyl -C _1-6 alkyl group, and the terminal carbon atoms means 1 or more groups selected from the group consisting of C _1-6 alkyl group substituted by carboxy and amino do.

In yet another embodiment of the present invention, A is a substituted or unsubstituted C _1-4 alkyl group, a substituted or unsubstituted C _1-4 alkylcarbonyl group, an unsubstituted C _5-6 cycloalkyl group, a substituted or unsubstituted group. Unsubstituted phenyl group, substituted or unsubstituted naphthyl group, substituted or unsubstituted quinolinyl group, substituted or unsubstituted umbelliferyl group, substituted or unsubstituted androsterone residue, or substituted or unsubstituted testosterone residue. Representing a group, when each of the above groups has a substituent, the substituent is a C _1-4 alkyl group, a phenyl group, a C _1-4 alkoxy-substituted phenyl group, a C _1-4 alkoxy group, a halogen atom, a nitro group. , Amino group, hydroxy group, carboxy group, aldehyde group, acetyl group, carboxy-C _1-4 alkyl group, hydroxy-C _1-4 alkyl group, dihydroxy-C _1-4 alkyl group, carbamoyl-C _1-4 alkyl It means a group and one or more groups selected from the group consisting of _{C 1-4} alkyl groups in which the terminal carbon atom is substituted with carboxy and amino.

In yet another embodiment of the present invention, A is a methoxyphenyl substituted C _1-4 alkyl group, a phenyl substituted C _1-4 alkylcarbonyl group, an unsubstituted C _5-6 cycloalkyl group, a substituted or unsubstituted phenyl group. (If it has a substituent, the substituent is a C _1-4 alkyl group, a nitro group, a halogen atom, a C _1-4 alkoxy group, a carboxy-C _1-4 alkyl group, a carbamoyl-C _1-4 alkyl group, Hydroxyl group, dihydroxy-C _1-4 alkyl group, carboxy-C _1-4 alkyl group, carboxy group, hydroxy-C _1-4 alkyl group, acetyl group, and C with terminal carbon atoms substituted with carboxy and amino. _{One or more groups selected from the group consisting of 1-4} alkyl groups), unsubstituted naphthyl group, unsubstituted quinolinyl group, substituted or unsubstituted umbelliferyl group (if it has a substituent). The substituent represents a C _1-4 alkyl group), an unsubstituted androsterone residue, or an unsubstituted testosterone residue.

The pharmacologically acceptable salts of the compound represented by the above formula (I) include salts with alkali metals such as ammonium salt, sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; aluminum. Metal salts such as salts, zinc salts, iron salts; salts with organic amines such as triethylamine, ethanolamine, morpholine, piperidine, dicyclohexylamine; salts with basic amino acids such as arginine, lysine, etc. Specific examples of the salt include sodium sulphate, potassium sulphate, calcium sulphate, magnesium sulphate, ammonium sulphate, tetramethylammonium sulphate, aluminum sulphate, zinc sulphate, triethylamine sulphate, and piperidine sulphate. , And potassium sulphate phenyl, potassium sulphate o-cresol, potassium sulphate p-nitrophenol, potassium sulphate p-chlorophenol, potassium sulphate quinolinol, potassium sulphate 1-naphthol, potassium sulphate 2-naphthol, potassium sulphate 4-methylumbelliferyl , Potassium sulphate androsterone, potassium sulphate p-cresol, potassium sulphate vanillin, potassium sulphate tyrosine, 4-potassium potassium dihydroferric acid, potassium sulphate 2- (4-hydroxyphenyl) acetamide, potassium sulphate cyclohexanol, potassium sulphate 4-ethyl Phenyl, potassium sulphate testosterone, potassium sulphate o-methoxyphenyl, potassium sulphate 4-hydroxy-3-methoxyphenyl glycol, potassium sulphate homovanillin, 4-hydroxybenzoic acid-4-O-potassium sulphate, potassium tyrosol sulphate, potassium sulphate Umberiferyl, Potassium Sulfate 4-methoxyphenyl Ethanol, Potassium Sulfate Catecol, Potassium Sulfate p-Hydroxyphenol, 4-Hydroxybutanoic acid-O-Potassium Sulfate, 2,4-Dihydroxyacetophenone 2-Potassium Sulfate, and 3,4- Dihydroxyphenyl glycol O-potassium sulfate can be mentioned.

In the present invention, the "alkyl group" means _{a linear or branched monovalent group represented by −C n} H _{2n + 1} (where n is a natural number). For example, an alkyl group having 1 to 20 carbon atoms (C _1-20 alkyl group), an _{alkyl group having 1 to 16 carbon atoms (C 1-16} alkyl group), and an alkyl group having 1 to 12 carbon atoms (C _1-12 alkyl group). Group), alkyl group with 1 to 8 carbon atoms (C _1-8 alkyl group), alkyl group with 1 to 6 carbon atoms (C _1-6 alkyl group), alkyl group with 1 to 4 carbon atoms (C _1-4) Alkyl group) and the like. Specific alkyl groups include methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, isobutyl group, tert-butyl group (t-butyl group), pentyl group, and isopentyl group (3-methylbutyl). Group), sec-pentyl group (1-methylbutyl group), 3-pentyl group (1-ethylpropyl group), tert-pentyl group (1,1-dimethylpropyl group), hexyl group, 2-methylpentyl group, 3 -Methylpentyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, octyl group, isooctyl group, 1-methylheptyl group and the like are exemplified.

In the present invention, the "alkylcarbonyl group" is a monovalent group in which a carbonyl group is bonded to the alkyl group, that is, a monovalent group represented by -CO-C _n H _{2n + 1} (where n is a natural number in the formula). Means the group of. For example, an alkylcarbonyl group having 1 to 20 carbon atoms (C _1-20 alkylcarbonyl group) in the alkyl group portion, an alkylcarbonyl group having 1 to 16 carbon atoms in the alkyl group portion (C _1-16 alkylcarbonyl group), An alkylcarbonyl group having 1 to 12 carbon atoms (C _1-12 alkylcarbonyl group) in the alkyl group portion, an alkylcarbonyl group having 1 to 8 carbon atoms in the alkyl group portion (C _1-8 alkylcarbonyl group), and an alkyl group. An alkylcarbonyl group having 1 to 6 carbon atoms (C _1-6 alkylcarbonyl group), an alkylcarbonyl group having 1 to 4 carbon atoms in the alkyl group portion (C _1-4 alkylcarbonyl group), and the like can be mentioned. can. Specific alkyl groups include acetyl group, propionyl group, butanoyl group (butyryl group), sec-butylcarbonyl group, isobutylcarbonyl group, tert-butylcarbonyl group (t-butylcarbonyl group), pentanoyl group, and isopentylcarbonyl group. (3-Methylbutylcarbonyl group), sec-pentylcarbonyl group (1-methylbutylcarbonyl group), 3-pentylcarbonyl group (1-ethylpropylcarbonyl group), tert-pentylcarbonyl group (1,1-dimethylpropylcarbonyl) Group), hexanoyl group, 2-methylpentylcarbonyl group, 3-methylpentylcarbonyl group, 2,2-dimethylbutylcarbonyl group, 2,3-dimethylbutylcarbonyl group, octanoyl group, isooctylcarbonyl group, and 1-methyl Heptylcarbonyl groups and the like are exemplified.

In the present invention, the "cycloalkyl group" is a monovalent group obtained by removing one hydrogen atom from any ring carbon atom of a cycloalkane (saturated monocyclic hydrocarbon). That is, _{it means a monovalent group of cyclic alkanes represented by C n} H _2n-1- (in the formula, n is a natural number of 3 or more). For example, a cycloalkyl group having 3 to 20 carbon atoms (C _3-20 cycloalkyl group), a cycloalkyl group _{having 3 to 16} carbon atoms (C 3-16 cycloalkyl group), and a cycloalkyl group having 3 to 12 carbon atoms (C 3-12 cycloalkyl group). C _3-12 cycloalkyl group), cycloalkyl group with 3 to 8 carbon atoms (C _3-8 cycloalkyl group), cycloalkyl group with 3 to 6 carbon atoms (C _3-6 cycloalkyl group), carbon number 5 Alkyl groups of ~ 6 ( _C5-6 alkyl groups) and the like can be mentioned. Specific examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group and the like.

In the present invention, the "aryl group" means a monovalent group obtained by removing one hydrogen atom from any ring carbon atom of a monocyclic or polycyclic aromatic hydrocarbon. Specific aryl groups include a phenyl group, a tolyl group, a 1-naphthyl group, a 2-naphthyl group, a 1-anthrasenyl group, a 2-anthrasenyl group, a 1-phenanthrenyl group, a 2-phenanthrenyl group, a 1-pyrenyl group, and 2 -Pyrenyl groups and the like are exemplified.

In the present invention, the "quinolinyl group" means a monovalent group obtained by removing one hydrogen atom of any ring carbon atom of quinoline. For example, 2-quinolinyl group, 3-quinolinyl group, 4-quinolinyl group, 5-quinolinyl group, 6-quinolinyl group, 7-quinolinyl group and 8-quinolinyl group can be mentioned.

In the present invention, "umberiferyl group" is synonymous with 7-cuminyl group.

In the present invention, the "steroid residue" is one from a steroid compound having at least one hydroxy group in the ring structure of the steroid skeleton, for example, a steroid compound having a hydroxy group at at least one of the 3-position and the 17-position. It means a monovalent group obtained by removing a hydroxy group. Examples of such steroid compounds include androsterone, cholesterol, cholic acid, esterone, dehydroepiandsterone, estradiol, estriol, testosterone, dihydrotestosterone and the like.

In the present invention, "alkoxy group" means a group represented by "-O-alkyl group". The alkyl group has the meaning as described above. For example, an alkoxy group having 1 to 20 carbon atoms (C _1-20 alkoxy group), an alkoxy group having 1 to 16 carbon atoms (C _1-16 alkoxy group), and an alkoxy group having 1 to 12 carbon atoms (C _1-12 alkoxy group). Group), alkoxy group with 1 to 8 carbon atoms (C _1-8 alkoxy group), alkoxy group with 1 to 6 carbon atoms (C _1-6 alkoxy group), alkoxy group with 1 to 4 carbon atoms (C _1-4) Alkoxy group) and the like. Specific alkoxy groups include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a sec-butoxy group, an isobutoxy group, a tert-butoxy group (t-butoxy group), a pentoxy group, and an isopentoxy group (3-). Methylbutoxy group), sec-pentoxy group (1-methylbutoxy group), 3-pentoxy group (1-ethylpropoxy group), tert-pentoxy group (1,1-dimethylpropoxy group), hexoxy group, 2-methylpen Examples thereof include a toxi group, a 3-methylpentoxy group, a 2,2-dimethylbutoxy group, a 2,3-dimethylbutoxy group, an octoxy group, an isooctoxy group, a 1-methylheptoxy group and the like.

In the present invention, the "halogen atom" means any of a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

In the present invention, the "carboxyalkyl group" means a group in which one hydrogen atom bonded to an arbitrary carbon atom of an alkyl group is replaced with one carboxy group. The alkyl group has the meaning as described above. Examples of such a carboxyalkyl group include a carboxy-C _1-12 alkyl group, a carboxy-C _1-8 alkyl group, a carboxy-C _1-6 alkyl group, and a carboxy-C _1-4 alkyl group. Carboxyalkyl groups in which carboxy is attached to the carbon atom at the end of the alkyl group, such as -CH _2- COOH, -CH _2- CH _2- COOH, and -CH _2- CH _2- CH _2- COOH, are preferred. .. The H of carboxy in the carboxyalkyl group may be replaced by a metal atom such as Na, K, Mg, Ca, Zn, Fe (for example, -COOK and -COONa).

In the present invention, the "hydroxyalkyl group" means a group in which one hydrogen atom bonded to an arbitrary carbon atom of an alkyl group is replaced with one hydroxy group. The alkyl group has the meaning as described above. Examples of such a hydroxyalkyl group include a hydroxy-C _1-12 alkyl group, a hydroxy-C _1-8 alkyl group, a hydroxy-C _1-6 alkyl group, and a hydroxy-C _1-4 alkyl group. Hydroxyalkyl groups in which hydroxy is attached to the carbon atom at the end of the alkyl group, such as -CH _2- OH, -CH _2- CH _2- OH, and -CH _2- CH _2- CH _2- OH, are preferred. ..

In the present invention, the "dihydroxyalkyl group" means a group in which two hydrogen atoms bonded to an arbitrary carbon atom of an alkyl group are replaced with two hydroxy groups. The two hydrogen atoms may be the same carbon atom or different carbon atoms. The alkyl group has the meaning as described above. Examples of such a dihydroxyalkyl group include a dihydroxy-C _1-12 alkyl group, a dihydroxy-C _1-8 alkyl group, a dihydroxy-C _1-6 alkyl group, and a dihydroxy-C _1-4 alkyl group. Examples of such dihydroxyalkyl groups include -CH (OH) -CH _2- OH, -CH (OH) -CH _2- CH _2- OH, and -CH (CH _2- OH) -CH _2- OH. Can be done.

In the present invention, the "carbamoyl alkyl group" means a group in which one hydrogen atom bonded to an arbitrary carbon atom of the alkyl group is replaced with _{one carbamoyl (-CONH 2) group.} The alkyl group has the meaning as described above. Examples of such a carbamoylalkyl group include a carbamoyl-C _1-12 alkyl group, a carbamoyl-C _1-8 alkyl group, a carbamoyl-C _1-6 alkyl group, and a carbamoyl-C _1-4 alkyl group. Carbamoyl alkyl groups in which carbamoyl is attached to the carbon atom at the end of the alkyl group, such as -CH _2- CONH ₂ , -CH _2- CH _2- CONH ₂ , and -CH _2- CH _2- CH _2- CONH ₂ , Are preferred.

In the present invention, "alkyl group in which the terminal carbon atom is substituted with carboxy and amino" means an alkyl group in which the terminal carbon atom of the alkyl group is substituted with carboxy group and amino group. The alkyl group has the meaning as described above. As the alkyl group in which the terminal carbon atom is substituted with carboxy and amino, the C _1-12 alkyl group in which the terminal carbon atom is substituted with carboxy and amino, and C _{1 in which the terminal carbon atom is substituted with carboxy and amino. Examples} thereof include a −8 alkyl group, a C _1-6 alkyl group in which the terminal carbon atom is substituted with carboxy and amino, and a C _1-4 alkyl group in which the terminal carbon atom is substituted with carboxy and amino. The H of carboxy in the alkyl group in which the carbon atom at the terminal of calcium is substituted with carboxy and amino may be replaced by a metal atom such as Na, K, Mg, Ca, Zn, Fe (for example, -COOK, And -COONa).

In the present invention, when a functional group is referred to as "substituted or unsubstituted", it means that the functional group may have no substituent or may have one or more substituents. When a functional group has a substituent, the number, position, and type of the substituent to be bonded are not particularly limited. If a functional group has two or more substituents, they may be the same or different. In the present invention, when a functional group has a substituent, examples of the substituent include an alkyl group, an aryl group, a substituted aryl group, an alkoxy group, a halogen atom, a nitro group, an amino group, a hydroxy group, a carboxy group and an aldehyde. Examples thereof include a group, an acetyl group, a carboxyalkyl group, a hydroxyalkyl group, a dihydroxyalkyl group, a carbamoylalkyl group, and an alkyl group in which a terminal carbon atom is substituted with carboxy and amino. These substituents have the meanings as described above.

Further, in the present invention, when a functional group has a substituent, examples of the substituent include a C _1-6 alkyl group, a phenyl group, a substituted phenyl group, a C _1-6 alkoxy group, a halogen atom and a nitro group. Amino group, hydroxy group, carboxy group, aldehyde group, acetyl group, carboxy-C _1-6 alkyl group, hydroxy-C _1-6 alkyl group, dihydroxy-C _1-6 alkyl group, carbamoyl-C _1-6 alkyl group _{, And a C 1-6} alkyl group in which the terminal carbon atom is substituted with carboxy and amino.

Furthermore, in the present invention, when a functional group has a substituent, examples of the substituent include a C _1-4 alkyl group, a phenyl group, a C _1-4 alkoxy-substituted phenyl group, a C _1-4 alkoxy group, and a halogen. Atomic, nitro group, amino group, hydroxy group, carboxy group, aldehyde group, acetyl group, carboxy-C _1-4 alkyl group, hydroxy-C _1-4 alkyl group, dihydroxy-C _1-4 alkyl group, carbamoyl-C _{Examples thereof include a 1-4 alkyl group and a C 1-4} alkyl group in which the terminal carbon atom is substituted with carboxy and amino.

Furthermore, in the present invention, when a functional group has a substituent, examples of the substituent include a methoxyphenyl group as a substituent _{of a C 1-4 alkyl group and a substituent of a C 1-4} alkyl carbonyl group. _{C 1-4} alkyl group, nitro group, halogen atom, C _1-4 alkoxy group, carboxy-C _1-4 alkyl group, carbamoyl-C _1-4 alkyl group, hydroxy group as substituents of phenyl group and phenyl group, Dihydroxy-C _1-4 alkyl group, carboxy-C _1-4 alkyl group, carboxy group, hydroxy-C _{1-4 alkyl group, acetyl group, and C 1-4} in which terminal carbon atoms are substituted with carboxy and amino. One or more groups selected from the group consisting of _{alkyl groups, and C 1-4} alkyl groups can be mentioned as substituents for the umbelliferyl group.

If a stereoisomer such as a geometric isomer or an optical isomer is present in the compound represented by the formula (I) used in the present invention and the pharmacologically acceptable salt thereof, the isomer, All compounds such as isomers are included in the scope of the compounds of the present invention.

Specific examples of the compound of the present invention represented by the formula (I) are shown below.

The agent may be a pharmaceutically acceptable conventional carrier, binder, stabilizer, excipient, diluent, pH buffer, disintegrant, isotonic agent, additive, coating agent, as required. Examples thereof include those to which a compounding component such as a solubilizer, a lubricant, a gliding agent, a solubilizing agent, a lubricant, a flavoring agent, a sweetening agent, a solvent, a gelling agent, and a nutritional agent is further added. Specific examples of such compounding ingredients include water, physiological saline, animal fats and oils, vegetable oils, lactose, starch, gelatin, crystalline cellulose, gum, talc, magnesium stearate, hydroxypropyl cellulose, and polyalkylene glycol. Polyvinyl alcohol and glycerin can be exemplified.

Diseases caused by decreased insulin secretion or insulin resistance, which are the diseases to be prevented or improved by the preventive / improving agent, include decreased insulin secretion produced from the pancreas and diseases caused by insulin resistance. For example, obesity, glucose resistance, hyperlipidemia, diabetes (eg, type 1 diabetes, type 2 diabetes, pancreatic diabetes), hyperglycemia, hypertension, diabetic neuropathy, diabetic nephropathy, diabetic retina. Disease, edema, unstable diabetes, fat atrophy, insulin allergy, and insulinoma can be mentioned, and among these, diabetes is preferable.

The above-mentioned sulfuric acid compounds have an action of effectively promoting insulin secretion, particularly insulin secretion by glucose stimulation, an action of effectively improving insulin resistance, and an action of effectively promoting hypoglycemic decrease. Therefore, the Insulin Secretagogue or the Insulin Resistance Improver, which contains the Sulfate Compounds as an active ingredient, is advantageously applied to the above-mentioned preventive or ameliorating agents for diseases caused by decreased insulin secretion or insulin resistance. can do. When the Insulin secretion promoter, the insulin resistance improver, or the preventive / improver is used, insulin secretion, decreased sensitivity to insulin (deterioration), and / or hyperglycemia are suppressed or prevented, and insulin secretion, insulin Sensitivity to and / or blood glucose levels can be regulated normally.

In addition, the above-mentioned sulfuric acid compounds have an action of activating transcription regulated by GATA. Therefore, the transcription activator containing the sulfuric acid compounds as an active ingredient can be advantageously applied as a preventive or ameliorating agent for diseases caused by a decrease in transcription level regulated by GATA. In the present specification, "disease caused by a decrease in transcription level regulated by GATA" is caused by a mutation in the GATA protein, a mutation in the binding sequence of the GATA protein (GATA sequence), or the like, and is downstream of the GATA sequence. Any disease caused by a decrease in the transcription (expression of mRNA) level of the located gene may be used. Specifically, among the above-mentioned specific diseases caused by decreased insulin secretion or insulin resistance, GATA causes Diseases caused by decreased levels of regulated transcription, as well as GATA (preferably GATA2 or GATA-3) haploinsufficiency (eg, hypoparathyroidism, sensory deafness, renal hypoplasia, etc.) be able to.

The administration form of the present drug includes oral administration in which the dosage form is powder, granules, tablets, capsules, syrup, suspension, etc., or injection or spray in the dosage form such as solution, emulsion, suspension, etc. Parenteral administration, which is administered intranasally, can be mentioned as a dosage form, and oral administration is preferable.

The dose of the drug is appropriately determined according to age, body weight, gender, symptoms, susceptibility to the drug, and the like. Usually in the range of doses of 1 μg to 200 mg / day, preferably in the range of doses of 2 μg to 2000 μg / day, more preferably in the range of doses of 3 to 200 μg / day, still more preferably 4 to 20 μg / day. Within the range of the dose of day, it is administered once or in a plurality of times (for example, 2 to 4 times) per day, but the dose may be adjusted according to the situation of improvement of symptoms.

The sulfuric acid compounds can be produced by any known method such as chemical synthesis, production by microorganisms, production by enzymes, etc., but commercially available products can also be used. For example, when potassium phenyl sulfate is used as the sulfate compounds, the "Simplified Method for the Preparation of Aromatic Sulfuric" described in the literature (J. Feigenbaum and CANeuberg J Am Chem Soc., 63, p.3529-3530 (1941)) It can be produced according to "Acid Esters (simple synthesis method of aromatic sulfate esters)". _{That is, sulfonic acid chloride (HSO 3} Cl) is added dropwise to an ice-cooled solution of phenol in dimethylaniline with uniform stirring. Next, an equal amount of a strongly alkaline aqueous potassium hydroxide solution is added to prepare an alkaline solution, and then the solid portion is filtered off by suction and sufficiently washed with ether. The ester salt is extracted from the residue with hot alcohol (95%), the alcohol solution is filtered through a heated funnel, and the crystals obtained by allowing to cool are collected by filtration and washed with cold alcohol. It can be recrystallized from a minimum amount of hot water to obtain a pure white object (potassium phenyl sulfate). When sodium phenyl sulfate is used as the sulfuric acid compounds, the method of using an aqueous sodium hydroxide solution instead of the aqueous solution of potassium hydroxide in the above-mentioned simple synthesis method of aromatic sulfate ester, or the synthesis method described in this example. Can be manufactured according to.

１）Ｘ＝２，４−ジニトロ
２）Ｘ＝２，５−ジニトロ
３）Ｘ＝２，３，４，５，６−ペンタフルオロ
４）Ｘ＝４−ニトロ
５）Ｘ＝２−ニトロ
６）Ｘ＝３−ニトロ
７）Ｘ＝３−クロロ
８）Ｘ＝４−クロロ
９）Ｘ＝２，４−ジメチル
また、目的とするアルキルサルフェートに対応するアルコールを出発原料として、前記製造方法と同様にして、下記の硫酸アルキル類を製造することができる。

１０）Ｘ＝−ＣＨ_２Ｃ（ＣＨ_３）_３
１１）Ｘ＝−ＣＨ_２（ＣＨ_２）_３ＣＨ_３
更に、式（Ｉ）におけるＡがフェニル基及びアルキル基以外の官能基の場合についても、目的とする本件硫酸化合物類に対応する、ヒドロキシ基を有する化合物を用いて、式（Ｉ）におけるＡがフェニル基及びアルキル基以外の官能基を有する本件硫酸化合物類を製造することができる。以下に製造された本件硫酸化合物類を記載する。

By the above-mentioned production method, the following compounds can be produced using a phenol compound corresponding to the target sulfuric acid compounds as a starting material.

1) X = 2,4-dinitro 2) X = 2,5-dinitro 3) X = 2,3,4,5,6-pentafluoro 4) X = 4-nitro 5) X = 2-nitro 6) X = 3-nitro 7) X = 3-chloro 8) X = 4-chloro 9) X = 2,4-dimethyl Further, using an alcohol corresponding to the target alkyl sulfate as a starting material, the same as the above-mentioned production method is applied. The following alkyl sulfates can be produced.

10) X = -CH ₂ C (CH ₃ ) ₃
11) X = -CH ₂ (CH ₂ ) ₃ CH ₃
Further, even when A in the formula (I) is a functional group other than a phenyl group and an alkyl group, A in the formula (I) can be obtained by using a compound having a hydroxy group corresponding to the target sulfuric acid compounds of the present invention. The Sulfate compounds having a functional group other than a phenyl group and an alkyl group can be produced. The sulfuric acid compounds produced are described below.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the technical scope of the present invention is not limited to these examples.

[material]
1. 1. Sodium sulphate phenyl Sodium sulphate phenyl was produced according to the procedure shown in the following [1] to [4] and was obtained from Namki Shoji Co., Ltd.

〔１〕イソブチルアルコール（１）に塩化スルフリル(ＳＯ_２Ｃｌ_２)を添加して、イソブチルクロロサルフェート（２）を得た。
〔２〕ヘキサメチルジシラザンナトリウム（ＮａＨＭＤＳ）のテトラヒドロフラン（ＴＨＦ）溶液にフェノールを溶解したものに、−７８℃に冷却下で、撹拌しながらイソブチルクロロサルフェート（２）を滴加して、フェニルイソブチルサルフェート（３）を含む反応混合液を得た。
〔３〕フェニルイソブチルサルフェート（３）を含む反応混合液を徐々に室温に戻し、撹拌しながら、ナトリウムメトキシド（ＮａＯＭｅ）のメタノール溶液を添加した。
〔４〕減圧下で溶媒を除去し、残留物をエタノールで再結晶し、白色結晶として硫酸ナトリウムフェニル（４）を得た。

[1] Sulfuryl chloride (SO ₂ Cl ₂ ) was added to isobutyl alcohol (1) to obtain isobutyl chlorosulfate (2).
[2] Isobutylchlorosulfate (2) is added dropwise to a solution of hexamethyldisilazane sodium (NaHMDS) in tetrahydrofuran (THF) in tetrahydrofuran (THF) at −78 ° C. with stirring. A reaction mixture containing sulfate (3) was obtained.
[3] The reaction mixture containing phenylisobutyl sulfate (3) was gradually returned to room temperature, and a methanol solution of sodium methoxide (NaOMe) was added with stirring.
[4] The solvent was removed under reduced pressure, and the residue was recrystallized from ethanol to obtain sodium phenyl sulfate (4) as white crystals.

2. Method for Synthesizing Phenyl Sulfate Analogs The method for synthesizing o-cresol sulfate potassium is shown below as a typical example. For the synthesis of other sulfates, the desired sulfates can be obtained by using phenols (or alcohols) corresponding to the synthetic raw materials as the synthetic raw materials. In addition, synthetic raw materials and reaction reagents used for synthesis are general commercial products.

ネジ付試験管（２５φｘ１５０ｍｍ）に撹拌子を入れ、ｏ−クレゾール（１０ｍｍｏｌ)と三酸化硫黄-ピリジン錯体（１１ｍｍｏｌ）とピリジン（５ｍＬ）を混合し、キャップで封管し、４５℃で２時間撹拌した。室温に戻し、氷冷下にて反応液を水酸化カリウム水溶液（１Ｍ、５０ｍＬ）中にゆっくり滴下した。次に、イソプロパノールを約２００ｍＬ加えて冷蔵庫に終夜静置した。析出物を桐山ロートで濾取し、イソプロパノールで洗浄した。得られた固体を２００ｍＬフラスコに移し、エタノール:水＝３:１の溶液を約１００ｍＬ加え、超音波照射及び湯浴（＞８０℃）による十分な加熱溶解を行った。不溶物を濾過し、濾液を冷蔵庫に終夜静置した。析出物を濾取し、前述の溶解・沈殿操作を繰り返すことにより目的のｏ−クレゾールサルフェートカリウムを得た（白色粉末、収率：２１％）。生成物は^１Ｈ−ＮＭＲ、元素分析により同定した。（参考文献： Edwards, D. R.; Lohman, D. C.; Wolfenden, R. J. Am. Chem. Soc. 2012, 134, 525.）
元素分析（Ｃ_７Ｈ_７ＫＯ_４Ｓ）
計算値：Ｃ，３７．１５；Ｈ，３．１２．
実測値：Ｃ，３７．０４；Ｈ，３．１１．
^１Ｈ−ＮＭＲ（６００ＭＨｚ，Ｄ_２Ｏ）d：７．３６（ｄｄ，２Ｈ，Ｊ＝８．２Ｈｚ），７．２９（ｔ，１Ｈ，Ｊ＝８．２，７．６Ｈｚ），７．２５（ｔ，１Ｈ，Ｊ＝８．２，７．６Ｈｚ），２．３３（ｓ，３Ｈ） Synthesis of o-cresol sulfate potassium

A stir bar is placed in a screwed test tube (25φ x 150 mm), o-cresol (10 mmol), sulfur trioxide-pyridine complex (11 mmol) and pyridine (5 mL) are mixed, sealed with a cap, and stirred at 45 ° C. for 2 hours. bottom. The temperature was returned to room temperature, and the reaction solution was slowly added dropwise to an aqueous potassium hydroxide solution (1M, 50 mL) under ice-cooling. Next, about 200 mL of isopropanol was added and the mixture was allowed to stand in the refrigerator overnight. The precipitate was collected by filtration with a Kiriyama funnel and washed with isopropanol. The obtained solid was transferred to a 200 mL flask, about 100 mL of a solution of ethanol: water = 3: 1 was added, and sufficient heat dissolution was carried out by ultrasonic irradiation and a hot water bath (> 80 ° C.). The insoluble material was filtered and the filtrate was left in the refrigerator overnight. The precipitate was collected by filtration, and the above-mentioned dissolution / precipitation operation was repeated to obtain the desired potassium o-cresol sulfate (white powder, yield: 21%). The product was ^{identified by 1 1} H-NMR, elemental analysis. (References: Edwards, DR; Lohman, DC; Wolfenden, RJ Am. Chem. Soc. 2012, 134, 525.)
Elemental analysis (C ₇ H ₇ KO ₄ S)
Calculated values: C, 37.15; H, 3.12.
Measured value: C, 37.04; H, 3.11.
_{^{1 H-NMR (600MHz, D}} 2 O) d: 7.36 (dd, 2H, J = 8.2Hz), 7.29 (t, 1H, J = 8.2,7.6Hz), 7.25 (T, 1H, J = 8.2,7.6Hz), 2.33 (s, 3H)

3. 3. La islet-derived cell line and La's island, and kidney-derived cell line Rat Langerhans's islet (La's islets, pancreatic islets) -derived cell line INS-1e are 1 mM sodium pyruvate, 10 mM HEEPS, 2 mM glutamine, 50 μM β-mercapto. RPMI1640 (GIBCO) containing ethanol (all manufactured by Sigma-Aldrich), 100 U / mL penicillin (GIBCO), 100 μg / mL streptomycin (GIBCO), and 10% deactivated FBS (GIBCO). Manufactured) The cells were cultured and maintained under the conditions of _{5% CO 2} /20% O _{2 and 37 ° C. in the culture solution.} RPMI 1640 containing 5.5 mM glucose, 0.5% BSA (bovine serum albumin), 100 μg / mL streptomycin (GIBCO), and 10% immobilized FBS (GIBCO). The cells were cultured and maintained in a culture solution (manufactured by GIBCO) _{under the conditions of 5% CO 2} /20% O ₂ , humidity 95%, and 37 ° C. The REP cell line is a DMEM (GIBCO) culture medium containing 100 U / mL penicillin (manufactured by GIBCO), 100 μg / mL streptomycin (manufactured by GIBCO), and 10% immobilized FBS (manufactured by GIBCO). _{Hereinafter, the cells were cultured and maintained under the conditions of 5% CO 2} /20% O ₂ , humidity 95%, and 37 ° C. in (hereinafter simply referred to as "10% FBS / DMEM culture solution").

[Example 1]
1. 1. Confirmation that the sulfuric acid compounds have an insulin secretagogue action 1
In order to confirm that the sulfuric acid compounds have an insulin secretagogue action, INS-1e cells and mouse pancreatic La's island were used for analysis.

1-1 Method 1-1-1 Analysis using INS-1e cells Glucose-stimulated insulin secretion is described in the literature (Santini, E. et al., Diabetes 53 Suppl. 3: S79-S83, 2004). I went according to. That is, 100,000 INS-1e cells were sprinkled on a 12-well plate and cultured for 48 hours, then sodium phenyl sulfate was added to the culture solution to a final concentration of 100 μM, and the cells were further cultured for 24 hours. Then, the cells were subjected to KRB (Krebs Ringer bicarbonate) buffer (135 mM sodium chloride, 3.6 mM potassium chloride, 5 mM sodium hydrogen carbonate, 0.5 mM sodium dihydrogen phosphate, 0.5 mM magnesium chloride, 1.5 mM calcium chloride, 10 mM. After culturing in HEPES [pH 7.4], and 0.1% BSA) for 1 hour, the cells were washed twice with fresh KRB buffer and cultured in KRB buffer containing 11 mM glucose for an additional hour. Then, the culture supernatant (KRB buffer) was collected, and the insulin concentration in the culture supernatant was measured using a rat insulin ELISA kit (manufactured by Mercodia). Distilled water was used as a control instead of sodium phenyl sulfate.

1-1-2 Analysis using mouse pancreatic la's island 30 mouse pancreatic la's islands were collected from 11-week-old C57BL / 6J mice in the literature (Takahashi, I. et al., J Diabetes Investig. 3 (4). ): 362-370, 2012), the cells were isolated, sodium phenyl sulfate was added to the culture solution to a final concentration of 100 μM, and the cells were cultured for 48 hours. Then, the island of La was cultured in KRB buffer containing 2.8 mM glucose for 1 hour, replaced with a new KRB buffer containing 11 mM glucose, and then cultured for another 1 hour. Then, the insulin concentration in the culture supernatant was measured using a rat insulin ELISA kit (manufactured by Mercodia). The total amount of protein in the culture supernatant was measured using a reagent for quantifying BCA protein (Micro-BCA Protein Assay Reagent, manufactured by PIERCE). Distilled water was used as a control instead of sodium phenyl sulfate.

1-2 Results It was shown that when glucose-stimulated INS-1e cells were cultured in the presence of sodium phenyl sulfate, the amount of insulin secreted was increased as compared with the case of culturing in the absence of sodium phenyl sulfate ( (See FIG. 1). It was also shown that the amount of insulin secreted increased when glucose-stimulated mouse pancreatic La's island was cultured in the presence of sodium phenyl sulfate (see FIG. 2).

[Example 2]
2. Confirmation that the sulfuric acid compounds have an insulin secretagogue action 2
In order to confirm that the Sulfate Compounds other than phenyl sulfate also have the effect of increasing insulin secretion by glucose stimulation, 16 kinds of Sulfate Compounds (potassium sulfate p-cresol, potassium sulfate p-chlorophenol, etc.) Potassium sulphate p-nitrophenol, potassium sulphate o-cresol, potassium sulphate quinolinol, potassium sulphate 1-naphthol, potassium sulphate dihydroferric acid, potassium sulphate 2-naphthol, potassium sulphate androsterone, potassium sulphate cyclohexanol, potassium sulphate testosterone , Potassium sulphate 2- (4-hydroxyphenyl) acetamido, potassium sulphate o-methoxyphenyl, potassium sulphate 4-ethylphenyl, potassium sulphate vanillin, and potassium sulphate tyrosine), and the above "1-1-1" of Example 1 was used. The analysis was performed according to the method described in the item.
As a result, when INS-1e cells stimulated with glucose were cultured in the presence of the above 16 types of the present sulfuric acid compounds, the amount of insulin secreted was compared with the case of culturing in the absence of the above 16 types of the present sulfuric acid compounds. Was shown to increase (see Figure 3).
The above results show the present sulfuric acid compounds (for example, phenyl sulfate, p-cresol sulfate, p-chlorophenol sulfate, p-nitrophenol sulfate, o-cresol sulfate, quinolinol sulfate, 1-naphthol sulfate, 4-dihydroferla sulfate. Acid, 2-naphthol sulfate, androsterone sulfate, cyclohexanol sulfate, testosterone sulfate, 2- (4-hydroxyphenyl) acetate, o-methoxyphenyl sulfate, 4-ethylphenyl sulfate, vanillin sulfate, tyrosine sulfate, etc.) It has been shown that it has an effect of increasing insulin secretion by stimulation of sulfuric acid on the island of La.

[Example 3]
3. 3. Confirmation that the Sulfate Compounds are useful for diseases caused by decreased insulin secretion and insulin resistance To confirm that the Sulfate compounds are useful for diseases caused by decreased insulin secretion and insulin resistance. Among the sulfuric acid compounds specifically shown to have an action of increasing insulin secretion in Examples 1 and 2, sodium phenyl sulfate was used as a representative example, and a diabetes model mouse (KK-Ay mouse) was used. And analyzed.

3-1 Method 3-1-1 Glucose load test (GTT)
KK-Ay mice 6 weeks old (CLEA Japan, Inc) were given water containing 0.1% sodium sulphate or water free of sodium sulphate in a water bottle, and after 5 weeks, GTT (2 g glucose) was given according to a conventional method. / Mouse body weight [kg]) and blood insulin concentration were measured.

3-1-2 Insulin tolerance test (IPTT)
KK-Ay mice 6 weeks old (CLEA Japan, Inc) were given water containing 0.1% sodium sulphate or water free of sodium sulphate in a water bottle, and after 5 weeks, IPTT (1U insulin) was given according to a conventional method. / Mouse body weight [kg]) and blood glucose level were measured.

3-2 Results When KK-Ay mice administered with sodium sulphate were loaded with glucose, the blood insulin concentration was increased as compared with the case where KK-Ay mice not administered with sodium phenyl sulfate were loaded with glucose. Shown (see Figure 4).
From this result, it was shown that phenyl sulfate has an action of increasing insulin secretion by glucose stimulation in vivo (diabetes model KK-Ay mouse).

In addition, it was shown that when KK-Ay mice administered with sodium sulphate were loaded with insulin, the blood glucose level was lowered as compared with the case where KK-Ay mice not administered with sodium phenyl sulfate were loaded with insulin. (See FIG. 5).
This result indicates that phenyl sulfate has an effect of improving insulin resistance in vivo (diabetes model KK-Ay mouse).

Summarizing the results of Examples 1 to 3, it is considered that the sulfuric acid compounds promote blood glucose lowering by promoting insulin secretion in La's Island and improving insulin resistance.

[Example 4]
4. Confirmation that the Sulfuric Acid Compounds have the effect of promoting transcriptional activation by GATA In order to analyze the mechanism by which the Sulfuric Acid Compounds promote insulin secretion or improve insulin resistance, Changes in mRNA expression levels due to 45 transcription factors were analyzed using sulfuric acid compounds.

4-1 Method The procedure was as follows [1] to [7].
[1] Two types of Opti-MEM I (manufactured by GIBCO) per well are added to the Cignal transduction 45 pathways plate (manufactured by QIAGEN) and lightly moved back and forth to adhere to the surface of each well in a dry state. Luciferase reporter vector (firefly [firefly] luciferase reporter vector expressed in response to 45 kinds of transcription factors, and sea pansy [renilla] luciferase reporter vector expressed constitutively) was lysed.
[2] Add 0.6 μL of Lipofectamin 2000 (manufactured by Invitrogen) to 50 μL of Opti-MEM I, incubate at room temperature for 5 minutes, and then prepare such Lipofectamin 2000 / Opti-MEM I solution in [1] above. 50 μL was added to each well, and the mixture was incubated at room temperature for 20 minutes.
[3] REP cells were suspended in 10% FBS / DMEM culture medium free of antibiotics (penicillin and streptomycin) so as to have a concentration of ^{3 × 10 4 cells / 50 μL, and 50 μL was seeded in each well.} , 24 hours culture.
[4] The culture broth in each well was replaced with 100 μL of 0.5% FBS / DMEM culture broth containing 100 μM sodium sulphate, or 100 μL of 10% FBS / DMEM culture broth free of sodium sulphate as a control. Incubated for hours.
[5] The culture medium was removed, and the cells were washed with 100 μL of PBS.
[6] PLB (Passive Lysis Buffer), which is a reagent for cell lysis, was added to each well in a 1-fold amount and incubated at room temperature for 15 minutes.
[7] A luciferase reporter assay was performed using the Dual Luciferase Reporter Assay System (manufactured by Promega), and the amounts of luciferase in Fire fly and Renilla were measured using a luminometer Lumat LB9507 (manufactured by NERTHOLD TECHNOLOGIES). The transcriptional activation level was calculated by dividing the amount of Firefly luciferase by the amount of Renilla luciferase, which is an internal control (see the vertical axis in FIG. 6).

4-2 Results It was shown that culturing REP cells in the presence of sodium sulphate increased the expression level of mRNA regulated by GATA compared to culturing in the absence of sodium sulphate (Fig. 6). reference).
This result indicates that the present sulfuric acid compounds such as phenyl sulfate have an action of activating transcription regulated by GATA.
In addition, when the results of Examples 1 to 3 are combined, it is presumed that the sulfuric acid compounds activated the transcription regulated by GATA, and as a result, promoted insulin secretion in Ujishima and improved insulin resistance. NS.

The present invention contributes to the prevention or amelioration (treatment) of a disease caused by decreased insulin secretion or insulin resistance, or a disease caused by a decrease in transcription level regulated by GATA.

Claims (9)

The following formula (I)

(In the formula, A, substitution or unsubstituted cycloalkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted quinolinyl group, or a substituted or unsubstituted steroid residue Representing a group, when each of the above groups has a substituent, the substituent is a C _1-6 alkyl group, a phenyl group , a C _1-6 alkoxy group, a halogen atom, a nitro group, an amino group, a hydroxy group, or a carboxy group. , Alaldehyde group, acetyl group, carboxy-C _1-6 alkyl group, hydroxy-C _1-6 alkyl group, dihydroxy-C _1-6 alkyl group, carbamoyl-C _1-6 alkyl group, and terminal carbon atom is carboxy And one or more groups selected from the group consisting of _{C 1-6} alkyl groups substituted with amino)
An insulin secretagogue or an insulin sensitizer, which comprises, as an active ingredient, one or more compounds selected from the compound represented by the above and a pharmacologically acceptable salt thereof. The insulin secretagogue or insulin sensitizer according to claim 1, wherein the compound is any of the following compounds.

The insulin secretagogue or insulin sensitizer according to claim 1 or 2, which is orally administered. The following formula (I)

(In the formula, A, substitution or unsubstituted cycloalkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted quinolinyl group, or a substituted or unsubstituted steroid residue Representing a group, when each of the above groups has a substituent, the substituent is a C _1-6 alkyl group, a phenyl group , a C _1-6 alkoxy group, a halogen atom, a nitro group, an amino group, a hydroxy group, or a carboxy group. , Alaldehyde group, acetyl group, carboxy-C _1-6 alkyl group, hydroxy-C _1-6 alkyl group, dihydroxy-C _1-6 alkyl group, carbamoyl-C _1-6 alkyl group, and terminal carbon atom is carboxy And one or more groups selected from the group consisting of _{C 1-6} alkyl groups substituted with amino)
A disease caused by decreased insulin secretion or insulin resistance, which comprises containing one or more compounds selected from the compound represented by the above and a pharmacologically acceptable salt thereof as an active ingredient. Preventive or ameliorating agent. The preventive or ameliorating agent according to claim 4, wherein the compound is any of the following compounds.

The preventive or ameliorating agent according to claim 4 or 5, which is orally administered. The preventive or ameliorating agent according to any one of claims 4 to 6, wherein the disease caused by decreased insulin secretion or insulin resistance is diabetes. The following formula (I)

(In the formula, A, substitution or unsubstituted cycloalkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted quinolinyl group, or a substituted or unsubstituted steroid residue Representing a group, when each of the above groups has a substituent, the substituent is a C _1-6 alkyl group, a phenyl group , a C _1-6 alkoxy group, a halogen atom, a nitro group, an amino group, a hydroxy group, or a carboxy group. , Alaldehyde group, acetyl group, carboxy-C _1-6 alkyl group, hydroxy-C _1-6 alkyl group, dihydroxy-C _1-6 alkyl group, carbamoyl-C _1-6 alkyl group, and terminal carbon atom is carboxy And one or more groups selected from the group consisting of _{C 1-6} alkyl groups substituted with amino)
A GATA-regulated transcriptional activator, which comprises, as an active ingredient, one or more compounds selected from the compound represented by and the pharmacologically acceptable salt thereof. The activator according to claim 8, wherein the compound is the following compound.

Images