WO2020194531A1

WO2020194531A1 - Agent for reducing blood uremic substance

Info

Publication number: WO2020194531A1
Application number: PCT/JP2019/012952
Authority: WO
Inventors: 阿部　高明
Original assignee: 国立大学法人東北大学
Priority date: 2019-03-26
Filing date: 2019-03-26
Publication date: 2020-10-01
Also published as: JP7256540B2; JPWO2020194531A1

Abstract

The present invention addresses the problem of providing a substance that has: an effect of effectively reducing (decreasing) the amount of a uremic substance present in the blood; an effect of effectively preventing or ameliorating uremia; and an effect of effectively preventing or ameliorating renal dysfunction.　By administering a compound represented by formula (I), etc. by, for example, oral administration, the amount of a uremic substance present in the blood is decreased and uremia and renal dysfunction are ameliorated.

Description

Agent for reducing blood uremic substances

The present invention is an agent for reducing the amount of uremic substance present in blood (in other words, the concentration of uremic substance in blood); an agent for preventing or ameliorating uremic disease; and preventing renal dysfunction. Or an agent for improvement;

The kidney is an organ that regulates homeostasis (balance) in the body. As one of the renal functions, it has the action of taking in waste products and toxins (uremic substances) in the blood, sending them out into the urine, and excreting them outside the body. When such renal function is reduced, uremic substances that should be excreted by the kidney are likely to be accumulated in the body, causing symptoms such as nausea and loss of appetite, as well as damage to cells in the kidney and further deterioration of renal function. It is also known that those with impaired renal function have a higher risk of suffering from stroke or myocardial infarction than healthy subjects. Therefore, prevention or treatment of symptoms and diseases (uremia) caused by the accumulation of such uremic substances not only treats symptoms such as nausea and loss of appetite, but also exacerbation of renal disorders, such as stroke and It is also necessary from the viewpoint of preventing heart disease.

Dialysis is considered to be the most effective treatment for uremia. In fact, if uremic substances are excreted from the body by dialysis therapy, even if renal function is abolished, the death of the patient due to the uremic substances can be avoided. However, long-term dialysis has created new problems with complications such as anemia, renal osteodystrophy, renal cancer, epicarditis, aluminum osteopathy, amyloidosis, crystalline arthritis, and polycystic kidney disease. .. In addition, there are medical economic problems such as a decrease in QOL (quality of life) of patients who frequently go to dialysis facilities in terms of social life and high costs.

The present inventor has reported that lubiprostone (trade name: Amitiza [registered trademark]), which is a chloride channel activator, has a preventive or ameliorating effect on renal dysfunction (Patent Document 1). In addition, the present inventor has reported that linaclotide (trade name: Lindes [registered trademark]), which is a guanylate cyclase C receptor agonist, has a preventive or therapeutic effect on uremia (Patent Document 2). However, elobixibat hydrate (trade name: Goofis [registered trademark]), which is a bile acid transporter inhibitor, has an effect of reducing blood uremic substances and an effect of improving uremia or renal dysfunction. Until now, it was not known to have.

International Publication No. 2015/0498776 Pamphlet JP-A-2018-127435

The subject of the present invention is an action of effectively reducing (reducing) the amount of a uremic substance present in blood; an action of effectively preventing or ameliorating uremia; and an action of effectively preventing or ameliorating renal dysfunction. The purpose is to provide a substance having an action.

The present inventor is continuing diligent research to solve the above problems. In the process, it was found that the compound group shown below has an action of effectively reducing the concentration of the elevated blood uremic substance and an action of effectively improving the decreased renal function, and the present invention was developed. It came to be completed.

[During the ceremony,
R ¹ and R ² may be the same or different, respectively; hydrogen atom; substituted or unsubstituted linear or branched alkyl group having 1 to 10 carbon atoms; substituted or substituted, respectively. Alkoxy group of linear or branched chain having 1 to 10 carbon atoms; substituted or unsubstituted alkylcarbonyl group of linear or branched chain having 1 to 10 carbon atoms; substituted or substituted A cycloalkyl group having 3 to 10 carbon atoms in a non-ring; a cycloalkyloxy group having 3 to 10 carbon atoms substituted or not substituted; a linear or fraction having 2 to 10 carbon atoms substituted or not substituted Branch chain alkoxy groups; substituted or unsubstituted linear or branched alkoxyoxy groups having 2 to 10 carbon atoms; substituted or unsubstituted aryl groups having 6 to 14 carbon atoms; or An substituted or unsubstituted aralkyl group having 7 to 18 carbon atoms;
R ³ is a substituted or unsubstituted linear or branched alkyl group having 1 to 10 carbon atoms; substituted or unsubstituted linear or branched alkoxy having 1 to 10 carbon atoms. Group; Substituent or unsubstituted linear or branched alkylcarbonyl group having 1 to 10 carbon atoms; Substituted or unsubstituted ring having 3 to 10 carbon atoms; Substituted Or an unsubstituted cycloalkyloxy group having 3 to 10 carbon atoms; a linear or branched alkenyl group having 2 to 10 carbon atoms substituted or not substituted; substituted or unsubstituted carbon number 2-10 linear or branched alkenyloxy groups; substituted or unsubstituted aryl groups with 6-14 carbon atoms; or substituted or unsubstituted aralkyl groups with 7-18 carbon atoms ; And
R ⁴ is a hydrogen atom; a linear or branched substituted or 1-10 carbon atoms non-substituted; substituted or a lower alkyl group of straight or branched chain having 1 to 10 carbon atoms and being substituted Alkyl carbonyl group of branched chain; substituted or unsubstituted cycloalkyl group having 3 to 10 carbon atoms; substituted or unsubstituted linear or branched lower alkenyl group having 2 to 10 carbon atoms; An aryl group having 6 to 14 carbon atoms substituted or not substituted; or an aralkyl group having 7 to 18 carbon atoms substituted or not substituted;
R ⁵ is a hydrogen atom; a linear or branched lower alkyl group having 1 to 10 carbon atoms substituted or unsubstituted; a linear or fractionated linear or fractionated chain having 1 to 10 carbon atoms substituted or unsubstituted. Alkoxy group of branched chain; alkylcarbonyl group of linear or branched chain having 1 to 10 carbon atoms substituted or unsubstituted; cycloalkyl group having 3 to 10 carbon atoms of substituted or unsubstituted ring Substituted or unsubstituted cycloalkyloxy groups with 3 to 10 carbon atoms; substituted or unsubstituted linear or branched lower alkoxy groups with 2 to 10 carbon atoms; substituted or substituted Non-substituted linear or branched alkoxyoxy group with 2-10 carbon atoms; substituted or unsubstituted aryl group with 6-14 carbon atoms; or substituted or unsubstituted carbon number 7 ~ 18 Alkoxy groups;
X is S, SO, or SO ₂ ,
Y is O or S,
Z is O, S, SO, or SO ₂ ], from pharmaceutically acceptable salts of the compounds, pharmaceutically acceptable esters of the compounds, and hydrates of the compounds. Group (hereinafter, these may be collectively referred to as the "Compound Group").

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

[During the ceremony,
R ¹ and R ² may be the same or different, respectively; hydrogen atom; substituted or unsubstituted linear or branched alkyl group having 1 to 10 carbon atoms; substituted or substituted, respectively. Alkoxy group of linear or branched chain having 1 to 10 carbon atoms; substituted or unsubstituted alkylcarbonyl group of linear or branched chain having 1 to 10 carbon atoms; substituted or substituted A cycloalkyl group having 3 to 10 carbon atoms in a non-ring; a cycloalkyloxy group having 3 to 10 carbon atoms substituted or not substituted; a linear or fraction having 2 to 10 carbon atoms substituted or not substituted Branch chain alkoxy groups; substituted or unsubstituted linear or branched alkoxyoxy groups having 2 to 10 carbon atoms; substituted or unsubstituted aryl groups having 6 to 14 carbon atoms; or An substituted or unsubstituted aralkyl group having 7 to 18 carbon atoms;
R ³ is a substituted or unsubstituted linear or branched alkyl group having 1 to 10 carbon atoms; substituted or unsubstituted linear or branched alkoxy having 1 to 10 carbon atoms. Group; Substituent or unsubstituted linear or branched alkylcarbonyl group having 1 to 10 carbon atoms; Substituted or unsubstituted ring having 3 to 10 carbon atoms; Substituted Or an unsubstituted cycloalkyloxy group having 3 to 10 carbon atoms; a linear or branched alkenyl group having 2 to 10 carbon atoms substituted or not substituted; substituted or unsubstituted carbon number 2-10 linear or branched alkenyloxy groups; substituted or unsubstituted aryl groups with 6-14 carbon atoms; or substituted or unsubstituted aralkyl groups with 7-18 carbon atoms ; And
R ⁴ is a hydrogen atom; a linear or branched substituted or 1-10 carbon atoms non-substituted; substituted or a lower alkyl group of straight or branched chain having 1 to 10 carbon atoms and being substituted Alkyl carbonyl group of branched chain; substituted or unsubstituted cycloalkyl group having 3 to 10 carbon atoms; substituted or unsubstituted linear or branched lower alkenyl group having 2 to 10 carbon atoms; An aryl group having 6 to 14 carbon atoms substituted or not substituted; or an aralkyl group having 7 to 18 carbon atoms substituted or not substituted;
R ⁵ is a hydrogen atom; a linear or branched lower alkyl group having 1 to 10 carbon atoms substituted or unsubstituted; a linear or fractionated linear or fractionated chain having 1 to 10 carbon atoms substituted or unsubstituted. Alkoxy group of branched chain; alkylcarbonyl group of linear or branched chain having 1 to 10 carbon atoms substituted or unsubstituted; cycloalkyl group having 3 to 10 carbon atoms of substituted or unsubstituted ring Substituted or unsubstituted cycloalkyloxy groups with 3 to 10 carbon atoms; substituted or unsubstituted linear or branched lower alkoxy groups with 2 to 10 carbon atoms; substituted or substituted Non-substituted linear or branched alkoxyoxy group with 2-10 carbon atoms; substituted or unsubstituted aryl group with 6-14 carbon atoms; or substituted or unsubstituted carbon number 7 ~ 18 Alkoxy groups;
X is S, SO, or SO ₂ ,
Y is O or S,
Z is O, S, SO, or SO ₂ ], from a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable ester of the compound, and a hydrate of the compound. An agent for reducing a blood uremic substance, which comprises one or more compounds selected from the above group as an active ingredient.
[2] The reducing agent according to the above [1], which is characterized by oral administration.
[3] The reducing agent according to the above [1] or [2], wherein the compound is a compound represented by the following formula.

[4] The uremic substance is one or more substances selected from phenyl sulfate, creatinine, 1-methyladenosine, urea nitrogen, trimethylamine-N-oxide, indoxyl sulfate, phenol, and indole. The reducing agent according to any one of the above [1] to [3].
[5] The following formula (I);

[During the ceremony,
R ¹ and R ² may be the same or different, respectively; hydrogen atom; substituted or unsubstituted linear or branched alkyl group having 1 to 10 carbon atoms; substituted or substituted, respectively. Alkoxy group of linear or branched chain having 1 to 10 carbon atoms; substituted or unsubstituted alkylcarbonyl group of linear or branched chain having 1 to 10 carbon atoms; substituted or substituted A cycloalkyl group having 3 to 10 carbon atoms in a non-ring; a cycloalkyloxy group having 3 to 10 carbon atoms substituted or not substituted; a linear or fraction having 2 to 10 carbon atoms substituted or not substituted Branch chain alkoxy groups; substituted or unsubstituted linear or branched alkoxyoxy groups having 2 to 10 carbon atoms; substituted or unsubstituted aryl groups having 6 to 14 carbon atoms; or An substituted or unsubstituted aralkyl group having 7 to 18 carbon atoms;
R ³ is a substituted or unsubstituted linear or branched alkyl group having 1 to 10 carbon atoms; substituted or unsubstituted linear or branched alkoxy having 1 to 10 carbon atoms. Group; Substituent or unsubstituted linear or branched alkylcarbonyl group having 1 to 10 carbon atoms; Substituted or unsubstituted ring having 3 to 10 carbon atoms; Substituted Or an unsubstituted cycloalkyloxy group having 3 to 10 carbon atoms; a linear or branched alkenyl group having 2 to 10 carbon atoms substituted or not substituted; substituted or unsubstituted carbon number 2-10 linear or branched alkenyloxy groups; substituted or unsubstituted aryl groups with 6-14 carbon atoms; or substituted or unsubstituted aralkyl groups with 7-18 carbon atoms ; And
R ⁴ is a hydrogen atom; a linear or branched substituted or 1-10 carbon atoms non-substituted; substituted or a lower alkyl group of straight or branched chain having 1 to 10 carbon atoms and being substituted Alkyl carbonyl group of branched chain; substituted or unsubstituted cycloalkyl group having 3 to 10 carbon atoms; substituted or unsubstituted linear or branched lower alkenyl group having 2 to 10 carbon atoms; An aryl group having 6 to 14 carbon atoms substituted or not substituted; or an aralkyl group having 7 to 18 carbon atoms substituted or not substituted;
R ⁵ is a hydrogen atom; a linear or branched lower alkyl group having 1 to 10 carbon atoms substituted or unsubstituted; a linear or fractionated linear or fractionated chain having 1 to 10 carbon atoms substituted or unsubstituted. Alkoxy group of branched chain; alkylcarbonyl group of linear or branched chain having 1 to 10 carbon atoms substituted or unsubstituted; cycloalkyl group having 3 to 10 carbon atoms of substituted or unsubstituted ring Substituted or unsubstituted cycloalkyloxy groups with 3 to 10 carbon atoms; substituted or unsubstituted linear or branched lower alkoxy groups with 2 to 10 carbon atoms; substituted or substituted Non-substituted linear or branched alkoxyoxy group with 2-10 carbon atoms; substituted or unsubstituted aryl group with 6-14 carbon atoms; or substituted or unsubstituted carbon number 7 ~ 18 Alkoxy groups;
X is S, SO, or SO ₂ ,
Y is O or S,
Z is O, S, SO, or SO ₂ ], from a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable ester of the compound, and a hydrate of the compound. A preventive or ameliorating agent for uremia, which comprises one or more compounds selected from the above group as an active ingredient.
[6] The preventive or ameliorating agent according to the above [5], which is characterized by oral administration.
[7] The prophylactic or ameliorating agent according to the above [5] or [6], wherein the uremia is diabetic nephropathy, nephrotic syndrome, or chronic nephritis syndrome.
[8] The preventive or ameliorating agent according to any one of the above [5] to [7], wherein the compound is a compound represented by the following formula.

[9] The following formula (I);

[During the ceremony,
R ¹ and R ² may be the same or different, respectively; hydrogen atom; substituted or unsubstituted linear or branched alkyl group having 1 to 10 carbon atoms; substituted or substituted, respectively. Alkoxy group of linear or branched chain having 1 to 10 carbon atoms; substituted or unsubstituted alkylcarbonyl group of linear or branched chain having 1 to 10 carbon atoms; substituted or substituted A cycloalkyl group having 3 to 10 carbon atoms in a non-ring; a cycloalkyloxy group having 3 to 10 carbon atoms substituted or not substituted; a linear or fraction having 2 to 10 carbon atoms substituted or not substituted Branch chain alkoxy groups; substituted or unsubstituted linear or branched alkoxyoxy groups having 2 to 10 carbon atoms; substituted or unsubstituted aryl groups having 6 to 14 carbon atoms; or An substituted or unsubstituted aralkyl group having 7 to 18 carbon atoms;
R ³ is a substituted or unsubstituted linear or branched alkyl group having 1 to 10 carbon atoms; substituted or unsubstituted linear or branched alkoxy having 1 to 10 carbon atoms. Group; Substituent or unsubstituted linear or branched alkylcarbonyl group having 1 to 10 carbon atoms; Substituted or unsubstituted ring having 3 to 10 carbon atoms; Substituted Or an unsubstituted cycloalkyloxy group having 3 to 10 carbon atoms; a linear or branched alkenyl group having 2 to 10 carbon atoms substituted or not substituted; substituted or unsubstituted carbon number 2-10 linear or branched alkenyloxy groups; substituted or unsubstituted aryl groups with 6-14 carbon atoms; or substituted or unsubstituted aralkyl groups with 7-18 carbon atoms ; And
R ⁴ is a hydrogen atom; a linear or branched substituted or 1-10 carbon atoms non-substituted; substituted or a lower alkyl group of straight or branched chain having 1 to 10 carbon atoms and being substituted Alkyl carbonyl group of branched chain; substituted or unsubstituted cycloalkyl group having 3 to 10 carbon atoms; substituted or unsubstituted linear or branched lower alkenyl group having 2 to 10 carbon atoms; An aryl group having 6 to 14 carbon atoms substituted or not substituted; or an aralkyl group having 7 to 18 carbon atoms substituted or not substituted;
R ⁵ is a hydrogen atom; a linear or branched lower alkyl group having 1 to 10 carbon atoms substituted or unsubstituted; a linear or fractionated linear or fractionated chain having 1 to 10 carbon atoms substituted or unsubstituted. Alkoxy group of branched chain; alkylcarbonyl group of linear or branched chain having 1 to 10 carbon atoms substituted or unsubstituted; cycloalkyl group having 3 to 10 carbon atoms of substituted or unsubstituted ring Substituted or unsubstituted cycloalkyloxy groups with 3 to 10 carbon atoms; substituted or unsubstituted linear or branched lower alkoxy groups with 2 to 10 carbon atoms; substituted or substituted Non-substituted linear or branched alkoxyoxy group with 2-10 carbon atoms; substituted or unsubstituted aryl group with 6-14 carbon atoms; or substituted or unsubstituted carbon number 7 ~ 18 Alkoxy groups;
X is S, SO, or SO ₂ ,
Y is O or S,
Z is O, S, SO, or SO ₂ ], from pharmaceutically acceptable salts of the compound, pharmaceutically acceptable esters of the compound, and hydrates of the compound. A preventive or ameliorating agent for renal dysfunction, which comprises one or more compounds selected from the above group as an active ingredient.
[10] The preventive or ameliorating agent according to the above [9], which is characterized by oral administration.
[11] The preventive or ameliorating agent according to the above [9] or [10], wherein the compound is a compound represented by the following formula.

[12] The preventive or ameliorating agent according to any one of the above [9] to [11], wherein the renal dysfunction is renal failure.

Further, as another embodiment of the present invention, blood uremia is caused by administering one or more compounds selected from the present compound group to a patient who needs reduction of blood uremia substances. One or more compounds selected from the present compound group for use as a method for reducing substances or as a reducing agent for blood uremic substances, or for use in reducing blood uremic substances. , Use of one or more compounds selected from the present compound group, or one or more compounds selected from the present compound group for producing a reducing agent for blood uremia substances. Can be mentioned.

Further, as another embodiment of the present invention, uremia is caused by administering one or more compounds selected from the present compound group to a patient who needs prevention or amelioration (treatment) of uremia. One or more compounds selected from the present compound group for use as a method for preventing or ameliorating (treating) uremia, or as a preventive or ameliorating (treating) agent for uremia, and prevention or amelioration of uremia. One or more compounds selected from the present compound group for use in (treatment), and one selected from the present compound group for producing a preventive or ameliorating (therapeutic) agent for uremia 1 The use of a species or two or more compounds can be mentioned.

In addition, as another embodiment of the present invention, by administering one or more compounds selected from the present compound group to a patient in need of prevention or improvement (treatment) of renal dysfunction, the kidneys One or more compounds selected from the present compound group for use as a method for preventing or ameliorating (treating) dysfunction or as a preventive or ameliorating (treating) agent for renal dysfunction, or renal dysfunction. One or more compounds selected from the present compound group for use in the prevention or improvement (treatment) of, or the present compound group for producing a preventive or ameliorating (therapeutic) agent for renal dysfunction. The use of one or more compounds selected from the above can be mentioned.

Since the compound group has an effect of reducing the elevated concentration of uremic substances in blood, the concentration of uremic substances in blood can be adjusted to a normal value, which is useful for prevention or amelioration of uremia. .. In addition, since the compound group has an action of improving renal dysfunction such as reduction of renal tubules, it is also useful for prevention or improvement of renal dysfunction.

In Example 1, the concentrations of three uremic substances (phenyl sulfate, creatinine, and 1-methyladenosine) in blood were measured in three groups (normal breeding group, placebo group, and elobixibat group). It is a figure which shows the result (mean value ± standard deviation). “#” And “####” in the figure indicate that there is a statistically significant difference (P <0.05 and P <0.001) between the placebo group and the placebo group by Dunnett's test, respectively. .. In Example 1, the results of analysis of renal tissues in three types of groups (normal breeding group, placebo group [“P group” in the figure], and elobixibat group [“E group” in the figure)) are shown. It is a figure. FIG. 2A shows the result (mean ± standard deviation) of analysis of the ratio (%) of renal tubules in the renal cortex, and FIG. 2B is a histological image of renal tissue used for the analysis. “***” in the figure indicates that there is a statistically significant difference (P <0.001) from the placebo group (P group) by Dunnett's test. In Example 2, two types of uremia in blood in three types of groups (normal breeding group, placebo group [“P group” in the figure], and erobixibat group [“E group” in the figure)). It is a figure which shows the result (average value ± standard deviation) of measuring the concentration of a substance (urea nitrogen [BUN] and creatinine). “**” and “***” in the figure indicate that there is a statistically significant difference (P <0.01 and P <0.001) by Dunnett's test, respectively. In Example 2, four types of uremia in blood in three types of groups (normal breeding group, placebo group [“P group” in the figure], and erobixibat group [“E group” in the figure)). It is a figure which shows the result (average value ± standard deviation) of measuring the concentration of a substance (phenyl sulfate, creatinine, trimethylamine-N-oxide [TMAO], and indoxyl sulfate). "#" And "####" in the figure are statistically significant differences (P <0.05 and P <0.001) between the placebo group (P group) and the placebo group (P group) by Dunnett's test, respectively. Indicates that there is. FIG. 5A shows phenyl sulfate in blood in two groups of db / db mice (normal breeding group [“C group” in the figure] and phenyl sulfate group [“PS group” in the figure]) in Example 3. It is a figure which shows the result of having measured the density | concentration of | The size bar in the PAS image of FIG. 5B shows 80 μm, and the size bar in the electron microscope image shows 1 μm. FIG. 5C shows two groups of KKAY mice (HFD-KKAY mice) bred on a high-fat feed [HFD] in Example 3 (normal breeding group [“C group” in the figure] and phenyl sulfate group [in the figure]. It is a figure which shows the result of having measured the concentration of phenyl sulfate in blood in "PS group"]), and FIG. 5D is a figure which shows the result of having analyzed the renal tissue in these two kinds of groups. The size bar in the PAS image of FIG. 5D shows 200 μm, the size bar in the electron microscope image shows 1 μm, and the size bars in the Elastica Masson image and the F4 / 80 image each show 80 μm. “*” In FIGS. 5A and 5 indicates that there is a statistically significant difference (P <0.05) by Student's test.

The present invention has been specified for the purpose of reducing the blood uremic substance reducing agent of the present invention for "to reduce the uremic substance in blood (more specifically, the amount of uremic substance present in blood)". An agent containing one or more compounds selected from the compound group (hereinafter, may be referred to as "reducing agent"), and the preventive or ameliorating agent for uremia of the present invention is "uremia". An agent containing one or more compounds selected from the present compound group, which is specified for the purpose of "preventing or ameliorating uremia" (hereinafter, may be referred to as "the present uremia preventive / ameliorating agent"). ), And the preventive or ameliorating agent for renal dysfunction of the present invention is one or more selected from the present compound group specified for the purpose of "preventing or ameliorating renal dysfunction". It is an agent containing the above compound (hereinafter, may be referred to as "the present agent for preventing / ameliorating renal dysfunction") (these agents may be collectively referred to as "the present agent"). The present agent may use the present compound group as an active ingredient alone as a food or drink or a pharmaceutical product (formulation), or may be further mixed with an additive to form a composition (food or drink composition or pharmaceutical composition). ) May be used. Such foods and drinks include, for example, health foods (functional foods, nutritional supplements, health supplements, nutritionally fortified foods, nutritionally adjusted foods, supplements, etc.), health functional foods (foods for specified health use, nutritional functional foods, functional foods, etc.). Labeled foods, etc.) can be mentioned.

In the present specification, the "uremic substance (also referred to as" uremic toxin ")" is a substance (waste products, toxins, etc.) excreted by the normal kidney, and is caused by some cause such as decreased renal function. It means a substance that increases (accumulates) in the blood and causes uremia symptoms or diseases when the excretory function declines. "Uremic substances" are usually classified into three types: water-soluble low-molecular-weight substances (500 daltons or less), medium-molecular-weight substances (more than 500 daltons), and protein-binding substances (Reference "Vanholder, R. , Et al: Kidney Int., 63 (5): 1934-1943, 2003 ”).

Specific examples of the water-soluble low molecular weight substance include 1-methyladenosine, 1-methylguanosine, 1-methylinosine, and ADMA (Asymmetric dimethylarginine). α-keto-δ-guanidinovaleric acid, α-N-acetylarginine, Arabitol, Argininic acid, benzyl alcohol (Benzylalcohol) ), Β-guanidinopropionic acid, β-lipotropin, Createine, Creatinine, Cytidine, Dimethylglycine, Erythritol, γ -Guanidinobutyric acid, Guaniidine, Guanidinoacetic acid, Guanidonosuccinic acid, Hypoxanthine, Malondialdehyde, Mannitol, Methylguanitol (Methylguanidine), myo-inositol ^{^{(myoinositol), N 2, N}} 2 - dimethyl-guanosine ^{^{(N 2, N 2 -dimethylguanosine)}} , N 4 - acetyl cytidine ^{^{(N 4 -acetylcytidine), N 6}} - methyl adenosine (N ⁶ -methyladenosine ), ^{N 6} - threonyl carbamoyl adenosine (N ⁶ -threonylcarbamoyladenosine), orotic acid (orotic acid), orotidine (orotidine), oxalate (oxalate), phenylacetylglutamine (phenylacetylglutamine), pseudouridine (pseudouridine), SDMA (Symmetric dimethylarginine), sol Sorbitol, Taurocyamine, Threitol, Thymine, Uracil, Urea, Uric acid, Uridine, Xanthine, Xanthosine ), Trimethylamine-N-oxide (TMAO) and the like.

Specific examples of the medium-molecular-weight substance include adrenomedullin, atrial natriuretic peptide (ANP), β _2- microglobulin (β _2- microglobulin), and β-endolphin (β-). endorphin, Cholecystokinin, CC16 (Clara cell protein), Complement factor D, Cystatin C, Degranulation inhibiting protein 1, Delta sleep-inducing protein (Delta-sleep inducing protein), Endothelin, Hyaluronic acid, Interleukin-1β, Interleukin-6, κ-Ig light chain (κ-Ig light) Chain), λ-Ig light chain, λ-Ig light chain, Leptin, Methionine-enkephalin, Neuropeptide, Parathyroid hormone, Retinol- Binding protein), tumor necrosis factor (TNF) -α (Tumor necrosis factor-α) and the like can be mentioned.

Specific examples of the protein-binding substance include 2-methoxyresorcinol, 3-deoxyglucosone, and CMPF (3-Carboxy-4-methyl-5-propyl-2-furanpropionate). ), Fructoselysine, Glyoxal, Hippuric acid, Homocysteine, Hydroquinone, Indole-3-acetic acid, Indoxyl sulfate or its precursor (Indole), Kinurenine, Kynurenic acid, Leptin, Melatonin, Methylglyoxal, N-carboxymethyllyxine (N-( carboxymethyl) lysine), p-Cresyl sulfate or its precursor (p-Cresol), Pentosidine, Phenyl sulfate or its precursor (phenol [Phenol]) ), P-OH-horseuric acid (P-OHhippuric axid), putrescine, quinolinic acid, Retinol-binding protein, spermidine, spermine, etc. Can be done.
In addition, the uremic substance also includes urea nitrogen (BUN), which has been specifically confirmed to have a reducing effect in the examples of the present specification.

The uremic substance in the present invention includes one or more selected from phenyl sulfate, creatinine, 1-methyladenosine, urea nitrogen, TMAO, indoxyl sulfate, and precursors thereof (eg, phenol, indole). The substance is preferred.

In the present specification, "reduction of blood uremic substance" means an action such as suppression of production (production) of uremic substance or its precursor and promotion of excretion of uremic substance or its precursor to the outside of the body. It means that the concentration of uremic substances contained in blood is reduced (decreased).

The targets for prevention or improvement of the present uremic disease preventive / ameliorating agent are uremic diseases, that is, the above-mentioned uremic substances (preferably phenyl sulfate, creatinine, 1-methyladenosine, urea nitrogen, TMAO, indoxyl sulfate, and these. Symptoms or diseases caused by one or more substances selected from precursors [eg, phenol, indol]) are not particularly limited, and such symptoms or diseases include, for example, loss of appetite, nausea, and the like. Gastrointestinal abnormalities such as vomiting, mouth odor, stomatitis, enteritis; nervous system abnormalities such as selflessness, indifference, decreased memory, depression, leaning, coma, polyneuritis, (developmental) coordination disorder, loss of appetite Cardiovascular abnormalities such as arteriosclerosis, anemia, erythroid hematopoietic disorders, hypertension, ischemic heart disease, peritonitis, myocarditis, (blood) coagulation disorders, heart failure, cardiovascular disorders; pigmentation, itching (feeling), Skin abnormalities (diseases) such as subcutaneous bleeding, skin atrophy, infection, atopy, hair loss; albuminuria, acute renal failure, acute uremic nephropathy, renal anemia, chronic renal failure, uremic interstitial disorder, acute nephritis, chronic nephritis , Acute nephritis syndrome, chronic nephritis syndrome, nephropathy syndrome, diabetic nephropathy, arteriosclerotic nephropathy, renal osteodystrophy (eg, renal osteodystrophy), renal dysfunction such as flooding; stroke; myocardial infarction Cancer; autism; immunodeficiency; bone abnormalities; hyperparathyroidism; insulin resistance; malnutrition; inflammation; quake; etc., among these, diabetic nephropathy, nephropathy syndrome, chronic Nephritis syndrome can be preferably exemplified. In addition, LPS (Lipopolysaccharide) such as IgA nephropathy, cystic kidney, liver dysfunction (for example, fulminant hepatitis, fatty liver, NASH, NAFLD) and cancer (for example, bile carcinogenesis, liver cancer) are included in the above urinary diseases. )-Involved symptoms or diseases; inflammatory bowel diseases such as ulcerative colitis and Crohn's disease; arteriosclerosis-related diseases; autoimmune diseases such as lupus, fatty liver disease and rheumatism; obesity; metabolic syndrome; diabetes; autism Parkinson's disease; Alzheimer's disease; Sarcopenia is also included.

The target for prevention or improvement of the renal dysfunction prevention / ameliorating agent is not particularly limited as long as renal dysfunction, that is, a state in which some abnormality occurs due to a disease or trauma to the kidney and renal function is impaired. For example, acute glomerulonephritis, microvariant nephritis, chronic glomerulonephritis, nephrosclerosis, membranous proliferative nephritis, mesangium proliferative glomerulonephritis, membranous proliferative glomerulonephritis, crescentic nephritis, rapid progression Nephritis such as gonad nephritis, membranous glomerulonephritis, tubulointerstitial nephritis, acute nephritis, chronic nephritis, intraductal proliferative nephritis, lupus nephritis, acute nephritis, chronic nephritis, acute nephritis syndrome, chronic nephritis syndrome, etc. Acute renal failure, renal failure such as chronic renal failure; amyloid kidney; membranous nephropathy; focal glomerulosclerosis; IgA nephropathy; acute tubule necrosis; nephrosis syndrome; diabetic nephropathy; gout kidney; renal Emulsion; renal tumor; renal ischemic disorder; renal ischemic reperfusion disorder; etc. can be mentioned, and among these, renal failure can be preferably exemplified.

In the present invention, the compound selected from the present compound group includes a compound represented by the following formula (I), a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable ester of the compound, and Means the hydrate of the compound.

During the ceremony
R ¹ and R ² may be the same or different, respectively; hydrogen atom; substituted or unsubstituted linear or branched alkyl group having 1 to 10 carbon atoms; substituted or substituted, respectively. Alkoxy group of linear or branched chain having 1 to 10 carbon atoms; substituted or unsubstituted alkylcarbonyl group of linear or branched chain having 1 to 10 carbon atoms; substituted or substituted A cycloalkyl group having 3 to 10 carbon atoms in a non-ring; a cycloalkyloxy group having 3 to 10 carbon atoms substituted or not substituted; a linear or fraction having 2 to 10 carbon atoms substituted or not substituted Branch chain alkoxy groups; substituted or unsubstituted linear or branched alkoxyoxy groups having 2 to 10 carbon atoms; substituted or unsubstituted aryl groups having 6 to 14 carbon atoms; or An substituted or unsubstituted aralkyl group having 7 to 18 carbon atoms;
R ³ is a substituted or unsubstituted linear or branched alkyl group having 1 to 10 carbon atoms; substituted or unsubstituted linear or branched alkoxy having 1 to 10 carbon atoms. Group; Substituent or unsubstituted linear or branched alkylcarbonyl group having 1 to 10 carbon atoms; Substituted or unsubstituted ring having 3 to 10 carbon atoms; Substituted Or an unsubstituted cycloalkyloxy group having 3 to 10 carbon atoms; a linear or branched alkenyl group having 2 to 10 carbon atoms substituted or not substituted; substituted or unsubstituted carbon number 2-10 linear or branched alkenyloxy groups; substituted or unsubstituted aryl groups with 6-14 carbon atoms; or substituted or unsubstituted aralkyl groups with 7-18 carbon atoms ; And
R ⁴ is a hydrogen atom; a linear or branched substituted or 1-10 carbon atoms non-substituted; substituted or a lower alkyl group of straight or branched chain having 1 to 10 carbon atoms and being substituted Alkyl carbonyl group of branched chain; substituted or unsubstituted cycloalkyl group having 3 to 10 carbon atoms; substituted or unsubstituted linear or branched lower alkenyl group having 2 to 10 carbon atoms; An aryl group having 6 to 14 carbon atoms substituted or not substituted; or an aralkyl group having 7 to 18 carbon atoms substituted or not substituted;
R ⁵ is a hydrogen atom; a linear or branched lower alkyl group having 1 to 10 carbon atoms substituted or unsubstituted; a linear or fractionated linear or fractionated chain having 1 to 10 carbon atoms substituted or unsubstituted. Alkoxy group of branched chain; alkylcarbonyl group of linear or branched chain having 1 to 10 carbon atoms substituted or unsubstituted; cycloalkyl group having 3 to 10 carbon atoms of substituted or unsubstituted ring Substituted or unsubstituted cycloalkyloxy groups with 3 to 10 carbon atoms; substituted or unsubstituted linear or branched lower alkoxy groups with 2 to 10 carbon atoms; substituted or substituted Non-substituted linear or branched alkoxyoxy group with 2-10 carbon atoms; substituted or unsubstituted aryl group with 6-14 carbon atoms; or substituted or unsubstituted carbon number 7 ~ 18 Alkoxy groups;
X is S, SO, or SO ₂ ,
Y is O or S,
Z is O, S, SO, or SO ₂ .

As used herein, the term "alkyl group" refers to one hydrogen atom from any carbon atom of an alkane (aliphatic saturated hydrocarbon) represented by the general formula C _n H _{2n + 2} (n is a positive integer). Means the remaining hydrocarbon groups excluding. The alkyl group in the present invention has 1 to 10 carbon atoms. In one aspect of the present invention, the alkyl group has 1 to 10 carbon atoms. In one aspect of the present invention, the alkyl group is an alkyl group having 1 to 10 carbon atoms. In one aspect of the present invention, the alkyl group is an alkyl group having 1 to 8 carbon atoms. In one aspect of the present invention, the alkyl group is an alkyl group having 1 to 6 carbon atoms. In one aspect of the present invention, the alkyl group is an alkyl group having 1 to 4 carbon atoms.

Examples of the above "alkyl group" include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group and 1-methylbutyl group. , 2-Methylbutyl group, 3-Methylbutyl group, 1-ethylpropyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, n-hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-Methylpentyl group, 4-Methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl Group, 3,3-dimethylbutyl group, 1,1,2-trimethylpropyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group, n-Hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethyl Butyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1,1,2-trimethylpropyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1-ethyl -1-Methylpropyl group, 1-ethyl-2-methylpropyl group, n-heptyl group, 1-methylhexyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl Groups, 1-ethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, 4,4-dimethylpentyl group, 1-propylbutyl group, n-octyl group and the like can be mentioned.

The term "alkoxy group" as used herein means a group represented by an "-O-alkyl group". The "alkyl group" is as defined above. As used herein, the term "substituted or unsubstituted linear or branched alkoxy group" refers to "-O-substituted or unsubstituted linear or branched alkyl. It means "group". The alkyl group of the alkoxy group in the present invention has 1 to 10 carbon atoms. In one aspect of the present invention, the alkyl group of the alkoxy group is an alkyl group having 1 to 10 carbon atoms. In one aspect of the present invention, the alkyl group of the alkoxy group is an alkyl group having 1 to 8 carbon atoms. In one aspect of the present invention, the alkyl group of the alkoxy group is an alkyl group having 1 to 6 carbon atoms. In one aspect of the present invention, the alkyl group of the alkoxy group is an alkyl group having 1 to 4 carbon atoms.

Examples of the above "alkoxy group" include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, n-pentoxy group, 1-methyl. Butoxy group, 2-methylbutoxy group, 3-methylbutoxy group, 1-ethylpropoxy group, 1,1-dimethylpropoxy group, 1,2-dimethylpropoxy group, 2,2-dimethylpropoxyl group, n-hexyloxy Group, 1-methylpentyloxy group, 2-methylpentyloxy group, 3-methylpentyloxy group, 4-methylpentyloxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 1,3- Dimethylbutoxy group, 2,2-dimethylbutoxy group, 2,3-dimethylbutoxy group, 3,3-dimethylbutoxy group, 1,1,2-trimethylpropoxy group, 1-ethylbutoxy group, 2-ethylbutoxy group, 1-Ethyl-1-methylpropoxy group, 1-ethyl-2-methylpropoxy group, n-heptyloxy group, 1-methylhexyloxy group, 2-methylhexyloxy group, 3-methylhexyloxy group, 4-methyl Hexyloxy group, 5-methylhexyloxy group, 1-ethylpentyloxy group, 2-ethylpentyloxy group, 3-ethylpentyloxy group, 4,4-dimerpentyloxy group, 1-propylbutoxy group, n- Examples thereof include an octyloxy group.

The term "alkylcarbonyl group" as used herein means a group represented by "-CO-alkyl group". The "alkyl group" is as defined above. As used herein, the term "substituted or unsubstituted linear or branched alkylcarbonyl group with 1-10 carbon atoms" is referred to as "-CO-substituted or unsubstituted direct." It means "alkyl group of chain or branched chain". The alkyl group of the alkylcarbonyl group in the present invention has 1 to 10 carbon atoms. Therefore, the "carbonyl group 1 to 10" in the "linear or branched alkyl carbonyl group having 1 to 10 carbon atoms substituted or not substituted" does not include the carbon of the carbonyl group. In one aspect of the present invention, the alkyl group of the alkylcarbonyl group is an alkyl group having 1 to 10 carbon atoms. In one aspect of the present invention, the alkyl group of the alkylcarbonyl group is an alkyl group having 1 to 8 carbon atoms. In one aspect of the present invention, the alkyl group of the alkylcarbonyl group is an alkyl group having 1 to 6 carbon atoms. In one aspect of the present invention, the alkyl group of the alkylcarbonyl group is an alkyl group having 1 to 4 carbon atoms.

Examples of the above "alkylcarbonyl group" include an acetyl group (ethanoyl group), an n-propionyl group (n-propanoyl group), an isopropionyl group (isopropanoyl group), an n-butylcarbonyl group, an isobutylcarbonyl group, and sec-. Butylcarbonyl group, tert-butylcarbonyl group, n-pentylcarbonyl group, 1-methylbutylcarbonyl group, 2-methylbutylcarbonyl group, 3-methylbutylcarbonyl group, 1-ethylpropylcarbonyl group, 1,1-dimethylpropyl Carbonyl group, 1,2-dimethylpropylcarbonyl group, 2,2-dimethylpropylcarbonyl group, n-hexylcarbonyl group, 1-methylpentylcarbonyl group, 2-methylpentylcarbonyl group, 3-methylpentylcarbonyl group, 4- Methylpentylcarbonyl group, 1,1-dimethylbutylcarbonyl group, 1,2-dimethylbutylcarbonyl group, 1,3-dimethylbutylcarbonyl group, 2,2-dimethylbutylcarbonyl group, 2,3-dimethylbutylcarbonyl group, 3,3-Dimethylbutylcarbonyl group, 1,1,2-trimethylpropylcarbonyl group, 1-ethylbutylcarbonyl group, 2-ethylbutylcarbonyl group, 1-ethyl-1-methylpropylcarbonyl group, 1-ethyl-2 -Methylpropylcarbonyl group, n-heptylcarbonyl group, 1-methylhexylcarbonyl group, 2-methylhexylcarbonyl group, 3-methylhexylcarbonyl group, 4-methylhexylcarbonyl group, 5-methylhexylcarbonyl group, 1-ethyl Examples thereof include a pentylcarbonyl group, a 2-ethylpentylcarbonyl group, a 3-ethylpentylcarbonyl group, a 4,4-dimerpentylcarbonyl group, a 1-propylbutylcarbonyl group, an n-octylcarbonyl group and the like.

As used herein, the term "alkenyl group" has only one carbon-carbon double bond in the molecule and is represented by the general formula C _n H _2n (n is a positive integer greater than or equal to 2 or 3). It means the remaining hydrocarbon group obtained by removing one hydrogen atom from an arbitrary carbon atom of an alkene (olefin hydrocarbon). The alkenyl group in the present invention has 2 to 10 carbon atoms. In one aspect of the present invention, the alkenyl group is an alkenyl group having 2 to 10 carbon atoms. In one aspect of the present invention, the alkenyl group is an alkenyl group having 2 to 8 carbon atoms. In one aspect of the present invention, the alkenyl group is an alkenyl group having 2 to 6 carbon atoms. In one aspect of the present invention, the alkenyl group is an alkenyl group having 2 to 4 carbon atoms.

Examples of the above "alkenyl group" include ethenyl group (vinyl group), 1-propenyl group, 2-propenyl group (allyl group), 1-butenyl group, 2-butenyl group, 3-butenyl group, isobutenyl group, 1- Penthenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 1-octenyl group, 2-octenyl group, 3-octenyl group, 4- Examples thereof include an octenyl group.

As used herein, the term "alkenyloxy group" means a group represented by "-O-alkenyl group". The "alkenyl group" is as defined above. As used herein, the term "substituted or unsubstituted straight chain or branched chain alkenyl group" refers to "-O-substituted or unsubstituted linear or branched chain alkenyl group". means. The alkenyl group of the alkenyloxy group in the present invention has 2 to 10 carbon atoms. In one aspect of the present invention, the alkenyl group of the alkenyloxy group is an alkenyl group having 2 to 10 carbon atoms. In one aspect of the present invention, the alkenyl group of the alkenyloxy group is an alkenyl group having 2 to 8 carbon atoms. In one aspect of the present invention, the alkenyl group of the alkenyloxy group is an alkenyl group having 2 to 6 carbon atoms. In one aspect of the present invention, the alkenyl group of the alkenyloxy group is an alkenyl group having 2 to 4 carbon atoms.

Examples of the above "alkenyloxy group" include ethenyloxy group (vinyloxy group), 1-propenyloxy group, 2-propenyl group oxy (allyloxy group), 1-butenyloxy group, 2-butenyloxy group, 3-butenyloxy group, isobu. Tenyloxy group, 1-pentenyloxy group, 2-pentenyloxy group, 3-pentenyloxy group, 4-pentenyloxy group, 1-hexenyloxy group, 2-hexenyloxy group, 3-hexenyloxy group, 1-octenyl Examples thereof include an oxy group, a 2-octenyloxy group, a 3-octenyloxy group, a 4-octenyloxy group and the like.

As used herein, the term "cycloalkyl group" is derived from any carbon atom of a cycloalkane (cyclic saturated hydrocarbon) represented by the general formula C _n H _2n (n is a positive integer greater than or equal to 3). It means the remaining hydrocarbon groups excluding one hydrogen atom. The "cycloalkyl group" of the present invention has 3 to 10 carbon atoms. In one aspect of the present invention, the cycloalkyl group is a cycloalkyl group having 3 to 10 carbon atoms. In one embodiment of the present invention, the cycloalkyl group is a cycloalkyl group having 3 to 8 carbon atoms. In one aspect of the present invention, the cycloalkyl group is a cycloalkyl group having 3 to 6 carbon atoms. In one aspect of the present invention, the cycloalkyl group is a cycloalkyl group having 3 to 4 carbon atoms.

Examples of the above-mentioned "cycloalkyl group" include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, cyclodecyl group and the like.

The term "cycloalkyloxy group" as used herein means a group represented by "-O-cycloalkyl group". The "cycloalkyl group" is as defined above. As used herein, the term "substituted or unsubstituted cycloalkyloxy group" means "-O-substituted or unsubstituted cycloalkyloxy group". The "cycloalkyloxy group" of the present invention has 3 to 10 carbon atoms. In one aspect of the present invention, the cycloalkyloxy group is a cycloalkyloxy group having 3 to 10 carbon atoms. In one aspect of the present invention, the cycloalkyloxy group is a cycloalkyloxy group having 3 to 8 carbon atoms. In one aspect of the present invention, the cycloalkyloxy group is a cycloalkyloxy group having 3 to 6 carbon atoms. In one aspect of the present invention, the cycloalkyloxy group is a cycloalkyloxy group having 3 to 4 carbon atoms.

Examples of the above "cycloalkyloxy group" include cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group, cycloheptyloxy group, cyclooctyloxy group, cyclononyloxy group, cyclodecyloxy group and the like. Can be mentioned.

As used herein, the term "aryl group" refers to a compound having an aromatic ring, i.e., the remaining hydrocarbons except for one hydrogen atom attached to the ring atom of the aromatic ring of an aromatic hydrocarbon. It means a hydrogen group. Here, the term "aromatic ring" means a cyclic structure having a delocalized π-electron orbital or a compound having the cyclic structure, which constitutes a single ring or a plurality of rings only with hydrocarbons. When the aromatic ring constitutes a plurality of rings, the aromatic ring may be a fused ring or a non-condensed ring (for example, biphenyl). The aryl group in the present invention has 6 to 14 carbon atoms. In one aspect of the invention, the aryl group is an aryl group having 6 to 14 carbon atoms in the ring. In one aspect of the invention, the aryl group is an aryl group having 6 to 10 carbon atoms in the ring. In one aspect of the present invention, the aryl group is an aryl group (phenyl group) having 6 carbon atoms in the ring.

Examples of the above "aryl group" include phenyl group, o-tolyl group, m-tolyl group, p-tolyl group, o-xylyl group, m-xylyl group, p-xylsilyl group, 1-naphthyl group and 2-naphthyl. The groups can be mentioned.

The term "aralkyl group" used in the present specification, one of the hydrogen atoms of the alkyl group (C n _H 2n _{+ 1)} refers to an alkyl group substituted with an aryl group. In one aspect of the present invention, the aralkyl group is an aralkyl group having 7 to 18 carbon atoms (including 6 to 14 carbon atoms in the ring). In one aspect of the present invention, the aralkyl group is an aralkyl group having 7 to 18 carbon atoms (including 6 to 14 carbon atoms in the ring). In one aspect of the present invention, the aralkyl group is an aralkyl group having 7 to 15 carbon atoms (including 6 to 14 carbon atoms in the ring). In one aspect of the present invention, the aralkyl group is an aralkyl group having 7 to 14 carbon atoms (including 6 to 10 carbon atoms in the ring). In one aspect of the present invention, the aralkyl group is an aralkyl group having 7 to 12 carbon atoms in the ring (of which the carbon number of the ring is & 10). In one aspect of the present invention, the aralkyl group is an aralkyl group having 7 to 8 carbon atoms in the ring (including 6 carbon atoms in the ring).

Examples of the above-mentioned "aralkyl group" include a benzyl group (phenylmethyl group), a phenethyl group (phenylethyl group) and the like.

In the term "substituted or not substituted" as used herein, "substituted" means having one or more substituents, and "unsubstituted" means a substituent. Means that there is no. Examples of substituents are halogen atoms (fluorine atom (fluoro group), chlorine atom (chloro group), bromine atom (bromo group), and iodine atom (iodo group)), alkyl groups having a prime number of 1 to 4, and a prime number of 1. Aalkoxy group, hydroxy group, amino group, mono (C1-C4) alkylamino group, di (C1-C4) alkylamino group, acetyl group, carboxyl group, nitro group, cyano group, methoxy group, ethoxy group, Examples thereof include a trifluoromethyl group, a pentafluoroethyl group and a phenyl group. When having two or more substituents, each substituent is independently selected and may be the same or different. In addition. "(C1-C4)" means 1 to 4 carbon atoms.

The term "linear" used in the present specification means a structure in which atoms other than hydrogen atoms are connected in a straight line without branching.

As used herein, the term "branched chain" means a structure in which one or more arbitrary carbon atoms are bonded to two or more other carbon atoms.

As used herein, the term "pharmaceutically acceptable salt" is, within reasonable medical judgment, excessively toxic, to be used in contact with human or non-human mammalian tissues. Means those compounds, substances, compositions, and / or dosage forms that are suitable for a reasonable benefit / risk ratio without irritation, allergic response, and / or complications.

The pharmaceutically acceptable salt in the present compound group includes a base salt. Such base salts include ammonium salts; alkali metal salts such as sodium salts, lithium salts and potassium salts; alkaline earth metal salts such as aluminum salts, calcium salts and magnesium salts; dicyclohexylamine salts and N-methyl-D-glucamine. Salts with organic bases such as; salts with amino acids such as arginine, lysine, ornithine; and the like.

The present compound group includes various isomers of the compound of the present invention represented by the formula (I) (for example, optical isomers, positional isomers, tautomers, etc.), solvent products such as hydrates, and the like. Crystal polymorphs and esters (eg, compounds of the invention represented by formula (I) with methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, or tert-butanol. Esther,) is included.

In addition, a compound in which one or more atoms constituting the compound of the present invention represented by the formula (I) are isotopes, a pharmaceutically acceptable salt of the compound, and a pharmaceutically acceptable salt of the compound. Esters to be produced, hydrates of the compounds, and optical isomers thereof are also included in the present invention. Examples of isotopes contained in the present compounds, hydrogen, carbon, nitrogen, oxygen, fluorine, bromine, and chlorine, such ^{^{^{^{as, 2 H, 3 H, 11}}}} C, 13 C, 14 C, 13 N , ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ¹⁸ F, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ⁸² Br, ³⁷ Cl and the like.

Examples of the compound of the present invention represented by the formula (I) include the following compound Nos. 1 to 20 can be preferably exemplified.

"COOH · H ₂ O" in the table means monohydrate.

The compound of the present invention represented by the formula (I) can be synthesized by appropriately combining known reactions. The raw material can be obtained by purchasing a commercially available product (for example, Goofis [elobixibat hydrate] manufactured by EA Pharma) or by synthesizing the commercially available product by adding a general protecting group or the like. .. The reduction of the carbonyl group and the halogenation of the alcohol group can be synthesized by using a reducing agent or a halogenating reagent used in general organic chemistry. In addition, any process can be applied to purification by protection / deprotection, which is widely used in organic chemistry.

The agent may be a pharmaceutically acceptable conventional carrier, binder, stabilizer, excipient, diluent, pH buffer, disintegrant, isotonic agent, additive, coating agent, as required. It may further contain additives such as solubilizers, lubricants, gliding agents, solubilizing agents, lubricants, flavoring agents, sweeteners, solvents, gelling agents, and nutrients. Specific examples of such additives 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.

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, sensitivity to the drug, etc., and is, for example, in the range of 0.1 μg to 200 mg / kg (body body) / day. In this example, which will be described later, the dose of elobixibat hydrate of 10 to 30 mg / kg body weight / day is specifically shown by an experiment using a model mouse. Such a dose is a dose to humans based on the human equivalent dose (HED) 12.3 in mice (see the document “Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers”). When converted to, it is 0.81 to 2.4 mg / kg body weight / day. Therefore, the dose of the present drug is preferably 0.01 to 100 mg / kg body weight / day, more preferably 0.03 to 60 mg / kg body weight / day, and further preferably 0.06 to 30 mg / kg body weight / day. Preferably, 0.1 to 10 mg / kg body weight / day is even more preferable, and 0.6 to 4.0 mg / kg body weight / day is most preferable. The drug may be administered once or in multiple doses (for example, 2 to 4 doses) per day.

The administration target of the reducing agent is not particularly limited, but usually, a person who needs to reduce the blood uremic substance, specifically, the concentration of the uremic substance in the blood increases (increases) for some reason. ). The target of administration of the uremia preventive / ameliorating agent is not particularly limited, but usually a person who needs prevention or amelioration (treatment) of uremia, specifically, a uremic substance in the body for some reason. Those who have accumulated uremia, or who have developed uremia, or who are at risk of developing uremia, or who are at risk of developing uremia. In addition, the administration target of the renal dysfunction preventive / ameliorating agent is not particularly limited, but usually a person who needs prevention or improvement (treatment) of renal dysfunction, specifically, renal function due to some cause. Those who have decreased and suffered from renal dysfunction, those who have developed renal dysfunction, those who may suffer from renal dysfunction, or those who may develop renal dysfunction.

The reducing agent may contain a component that reduces blood uremic substances other than the compound group, but the compound group alone can effectively reduce blood uremic substances. Therefore, it is preferable that the compound does not contain any reducing action component (for example, protein, DNA, RNA, plant-derived extract, polymer) of a blood uremic substance other than the present compound group. In addition, the uremia preventive / ameliorating agent may contain a component for preventing or improving uremia other than the present compound group, but the present compound group alone effectively prevents or ameliorate uremia. Therefore, it is preferable that the compounds do not contain components for preventing or improving uremia (for example, proteins, DNA, RNA, plant-derived extracts, polymers) other than the present compound group. In addition, the present renal dysfunction preventive / ameliorating agent may contain a component for preventing or improving renal dysfunction other than the present compound group, but the present compound group alone can effectively prevent renal dysfunction. Since it can be prevented or ameliorated, those containing no components for preventing or improving renal dysfunction (for example, protein, DNA, RNA, plant-derived extract, polymer) other than the present compound group are preferable.

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.

1. 1. Measurement of blood uremic substance concentration using renal failure model and analysis of renal tissue Chronic kidney by feeding Adenin to confirm that this compound group has an improving effect on renal dysfunction Erobixibat hydrate was administered to a model mouse that developed insufficiency (hereinafter referred to as "adenine dietary renal failure model mouse"), and the concentration of blood uremic substance was analyzed. The adenine-phagocytic model mouse is a mouse in which the fed adenine crystallizes as insoluble 2,8-dihydroxyadenine in the renal tubule, resulting in renal damage (Cozzolino, M. et al. Kidney Int). . 64, 441-450 (2003), Tamagi, K. et al. Nephrol. Dial. Transplant 21, 651-659 (2006)).

1-1 Method According to the following procedures [1] to [6], analysis was performed using adenine dietary renal failure model mice.
[1] Male C57BL / 6 mice (purchased from Japan CLEA Co., Ltd.) were bred with normal feed (CE-2, manufactured by Japan CLEA Co., Ltd.) until 6 weeks of age.
[2] At 7 weeks of age, a normal breeding group (n = 6) fed with a normal diet and an adenine diet breeding group (n = 12) fed with a normal feed containing 2% adenine (manufactured by Wako). Divided into.
[3] After breeding for 6 weeks, the adenine diet-fed group was orally administered with a suspension containing 10 (mg / kg body weight) of goofis and a placebo group (n = 6) to ingest distilled water once a day. It was divided into the Elobixibat group (n = 6). The suspension containing Goofis was prepared by suspending Goofis (elobixibat hydrate) (manufactured by EA Pharma) in distilled water.
[4] After breeding for 1 week, blood samples were collected from each of the 3 groups (normal breeding group, placebo group, and elobixibat group), plasma was prepared according to a conventional method, and "plasma sample after 1 week". Got
[5] The placebo group and the elobixibat group were returned to the normal diet, and the animals were bred for another week while continuing the administration. Then, blood samples were collected from each group, plasma was prepared according to a conventional method, and "2. After a week, a plasma sample was obtained. In addition, renal tissue was collected from the placebo group and the elobixibat group, fixed with 10% neutral buffered formalin, paraffin-embedded, and then the paraffin-embedded renal tissue was sliced to prepare a renal tissue section. ..
[6] Three types of uremia in blood by mass spectrometry using a liquid chromatograph-tandem mass spectrometer (LC-MS / MS) (manufactured by Shimadzu Corporation) using the obtained plasma sample. The concentrations of the substances (phenyl sulfate, creatinine, and 1-methyladenosine) were measured (see FIG. 1). In addition, the prepared renal tissue section was used for analysis by Masson's trichrome staining (MTS) method (see FIG. 2).

1-2 Results It was shown that the concentrations of the three uremic substances (phenyl sulfate, creatinine, and 1-methyladenosine) in the blood were higher in the placebo group than in the normal breeding group ( (See FIG. 1). It was also shown that the proportion of renal tubules was lower in the placebo group than in the normal breeding group (see FIG. 2). These results indicate that in the placebo group (ie, adenine dietary renal failure model mice), renal function declines and blood levels of uremic substances increase.

On the other hand, it was shown that the concentrations of the three types of uremic substances in blood in the elobixibat group were lower than those in the placebo group (see FIG. 1). It was also shown that the proportion of renal tubules in the elobixibat group was higher than in the placebo group (see FIG. 2). These results show that administration of the compound group (elobixibat hydrate) to adenine-phagocytic model mice can improve the decreased renal function and further reduce the increased concentration of blood uremic substances. It shows that it can be done.

2. 2. Measurement of Concentration of Blood Uremia Substance Using Renal Failure Model The amount of elobixibat hydrate administered to Adenine dietary renal failure model mice was increased 3-fold, and the blood uremic substance was obtained in the same manner as in Example 1. The concentration of was analyzed.

2-1 Method Analysis was performed using adenine dietary renal failure model mice according to the following procedures [1] to [6].
[1] Male C57BL / 6 mice (purchased from Japan CLEA Co., Ltd.) were bred with normal feed (CE-2, manufactured by Japan CLEA Co., Ltd.) until 6 weeks of age.
[2] At 7 weeks of age, a normal breeding group (n = 6) fed with a normal diet and an adenine diet breeding group (n = 12) fed with a normal feed containing 2% adenine (manufactured by Wako). Divided into.
[3] After breeding for 6 weeks, the adenine diet-fed group was orally administered once a day with a placebo group (n = 6) to ingest distilled water and a suspension containing 30 (mg / kg body weight) of goofis. It was divided into the Elobixibat group (n = 6). The suspension containing Goofis was prepared by suspending Goofis (elobixibat hydrate) (manufactured by EA Pharma) in distilled water.
[4] After breeding for 1 week, blood samples were collected from each of the 3 groups (normal breeding group, placebo group, and elobixibat group), plasma was prepared according to a conventional method, and "plasma sample after 1 week". Got
[5] The placebo group and the elobixibat group were returned to the normal diet, and the animals were bred for another week while continuing the administration. Then, blood samples were collected from each group, plasma was prepared according to a conventional method, and "2. After a week, a plasma sample was obtained.
[6] Using the obtained "plasma sample after 2 weeks", the concentrations of two types of uremic substances (BUN and creatinine) in blood were measured by a blood analyzer (i-STAT) (manufactured by Abbott) (BUN and creatinine). (See FIG. 3). In addition, four types of uremic substances (phenyl sulfate, creatinine, TMAO) in blood were measured by mass spectrometry using LC-MS / MS (manufactured by Shimadzu Corporation) using the obtained "plasma sample after 2 weeks". , And indoxyl sulfate) (see FIG. 4).

2-2 Results When the amount of elobixibat hydrate administered to Adenine dietary renal failure model mice was increased by 3 times, the increased blood uremic substances (phenyl sulfate, creatinine, BUN, TMAO, and India) were also increased. It was shown that the concentration of (xyl sulfate) decreased (see FIGS. 3 and 4). These results support the results of Example 1 and show that similar effects can be obtained when an amount of elobixibat hydrate different from the dose of Example 1 is administered. ..

3. 3. Analysis of renal tissue in a diabetic model administered with phenyl sulfate When glomerular podocytes (podocytes) in the renal tissue are damaged, proteinuria occurs, resulting in diabetic nephropathy, nephrotic syndrome, chronic nephritis syndrome, etc. (Reference "Brinkkoetter PT, Ising C, Benzing T. Nature reviews Nephrology 9: 328-336, 2013", Reference "Journal of the Japanese Society of Internal Medicine Vol. 101, No. 4, April 10, 2012" See "day"). Therefore, the effect of phenyl sulfate, which is one of the uremic substances, on podocytes was investigated. Specifically, the analysis was performed according to the following methods (1) and (2).

3-1 Method (1)
[1] 11-week-old diabetic model mice (db / db mice; purchased from Japan CLEA Co., Ltd.) bred on ordinary feed were fed with distilled water in a normal breeding group (n = 5) and 50 (mg / kg). Distilled water containing phenyl sulfate (manufactured by Sundia MediTech) (by body weight) was divided into a phenyl sulfate group (n = 6) to be orally administered once a day.
[2] After breeding for 6 weeks, blood samples were collected from each of the above two groups (normal breeding group and phenyl sulfate group), plasma was prepared according to a conventional method, and LC-MS / MS (manufactured by Shimadzu Corporation). The concentration of phenyl sulfate in blood was measured by mass spectrometry using (see FIG. 5A). In addition, renal tissue was collected, fixed with 10% neutral buffered formalin, and embedded in paraffin. Paraffin-embedded renal tissue is sliced to prepare renal tissue sections, and analysis using an electron microscope and analysis according to the method described in the document "Matsuhashi, T., et al: EBioMedicine 20: 27-38, 2017" Analysis using the periodic acid-Schiff (PAS) staining method was performed (see FIG. 5B).

3-2 Method (2)
[1] Six-week-old diabetic model mice (KKAY mice; purchased from Japan CLEA Co., Ltd.) bred in HFD were divided into a normal breeding group (n = 3) ingesting distilled water and 50 (mg / kg body weight). Distilled water containing phenyl sulfate (manufactured by Sundia MediTech) was orally administered once a day to the phenyl sulfate group (n = 4).
[2] After breeding for 6 weeks, blood samples were collected from each of the above two groups (normal breeding group and phenyl sulfate group), plasma was prepared according to a conventional method, and LC-MS / MS (manufactured by Shimadzu Corporation). The concentration of phenyl sulfate in blood was measured by mass spectrometry using. In addition, renal tissue was collected, fixed with 10% neutral buffered formalin, and embedded in paraffin. Paraffin-embedded renal tissue is sliced to prepare renal tissue sections, and analysis using an electron microscope and analysis according to the method described in the document "Matsuhashi, T., et al: EBioMedicine 20: 27-38, 2017" Analysis using the Elastica Masson staining method and analysis using the DAB staining method using an anti-F4 / 80 antibody were performed.

3-3 Results The blood phenyl sulfate concentrations in the phenyl sulfate group of the two diabetes model mice (db / db mice and HFD-KKAY mice) were 27.3 ± 9.17 μM and 6.09 ± 3.18 μM, respectively. It was confirmed that there was a significant increase in the blood phenyl sulfate concentration (3.06 ± 2.63 μM and 1.48 ± 0.85 μM, respectively) in the normal breeding group (see FIGS. 5A and 5C). In addition, the mesangial region of the glomerulus in the phenyl sulfate group of db / db mice expanded, and the disappearance of the glomerular podocytes (podocytes) increased (see the arrow in FIG. 5B), and the glomerular basement membrane (see the arrow in FIG. 5B). GBM) thickened (see arrowhead in FIG. 5B). Similarly, in HFD-KKAY mice, the disappearance of podocyte foot processes in the phenyl sulfate group increased (see the arrow in the electron microscope image of FIG. 5D), and the GBM became thickened (see the arrowhead in the electron microscope image of FIG. 5D). ). In addition, perivascular fibrotic regions were found in the podocytes of the HFD-KKAY mouse phenyl sulfate group (see arrowheads in the Elastica Masson and F4 / 80 images in FIG. 5D).

These results indicate that phenyl sulfate damages the podocytes that make up the glomerulus in diabetic model mice. On the other hand, as mentioned above, considering that diabetic nephropathy, nephrotic syndrome, chronic nephritis syndrome, etc. occur when podocytes are injured, when the phenyl sulfate concentration in the blood of diabetic patients increases, diabetic nephropathy, It shows that the risk of developing nephrotic syndrome, chronic nephritis syndrome, etc. increases. Then, in consideration of the contents of Examples 1 and 2, the compound group of the present invention such as erobixibat hydrate reduces the concentration of the elevated blood uremic substance (for example, phenyl sulfate), and diabetic nephropathy. It has been shown to be effective in preventing or ameliorating uremia such as nephrotic syndrome and chronic nephritis syndrome.

The present invention contributes to the medical treatment of uremia and renal dysfunction.

Claims

The following formula (I);

[During the ceremony,
R 1 and R 2 may be the same or different, respectively; hydrogen atom; substituted or unsubstituted linear or branched alkyl group having 1 to 10 carbon atoms; substituted or substituted, respectively. Alkoxy group of linear or branched chain having 1 to 10 carbon atoms; substituted or unsubstituted alkylcarbonyl group of linear or branched chain having 1 to 10 carbon atoms; substituted or substituted A cycloalkyl group having 3 to 10 carbon atoms in a non-ring; a cycloalkyloxy group having 3 to 10 carbon atoms substituted or not substituted; a linear or fraction having 2 to 10 carbon atoms substituted or not substituted Branch chain alkoxy groups; substituted or unsubstituted linear or branched alkoxyoxy groups having 2 to 10 carbon atoms; substituted or unsubstituted aryl groups having 6 to 14 carbon atoms; or An substituted or unsubstituted aralkyl group having 7 to 18 carbon atoms;
R 3 is a substituted or unsubstituted linear or branched alkyl group having 1 to 10 carbon atoms; substituted or unsubstituted linear or branched alkoxy having 1 to 10 carbon atoms. Group; Substituent or unsubstituted linear or branched alkylcarbonyl group having 1 to 10 carbon atoms; Substituted or unsubstituted ring having 3 to 10 carbon atoms; Substituted Or an unsubstituted cycloalkyloxy group having 3 to 10 carbon atoms; a linear or branched alkenyl group having 2 to 10 carbon atoms substituted or not substituted; substituted or unsubstituted carbon number 2-10 linear or branched alkenyloxy groups; substituted or unsubstituted aryl groups with 6-14 carbon atoms; or substituted or unsubstituted aralkyl groups with 7-18 carbon atoms ; And
R 4 is a hydrogen atom; a linear or branched substituted or 1-10 carbon atoms non-substituted; substituted or a lower alkyl group of straight or branched chain having 1 to 10 carbon atoms and being substituted Alkyl carbonyl group of branched chain; substituted or unsubstituted cycloalkyl group having 3 to 10 carbon atoms; substituted or unsubstituted linear or branched lower alkenyl group having 2 to 10 carbon atoms; An aryl group having 6 to 14 carbon atoms substituted or not substituted; or an aralkyl group having 7 to 18 carbon atoms substituted or not substituted;
R 5 is a hydrogen atom; a linear or branched lower alkyl group having 1 to 10 carbon atoms substituted or unsubstituted; a linear or fractionated linear or fractionated chain having 1 to 10 carbon atoms substituted or unsubstituted. Alkoxy group of branched chain; alkylcarbonyl group of linear or branched chain having 1 to 10 carbon atoms substituted or unsubstituted; cycloalkyl group having 3 to 10 carbon atoms of substituted or unsubstituted ring Substituted or unsubstituted cycloalkyloxy groups with 3 to 10 carbon atoms; substituted or unsubstituted linear or branched lower alkoxy groups with 2 to 10 carbon atoms; substituted or substituted Non-substituted linear or branched alkoxyoxy group with 2-10 carbon atoms; substituted or unsubstituted aryl group with 6-14 carbon atoms; or substituted or unsubstituted carbon number 7 ~ 18 Alkoxy groups;
X is S, SO, or SO 2 ,
Y is O or S,
Z is O, S, SO, or SO 2 ], from a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable ester of the compound, and a hydrate of the compound. An agent for reducing a blood uremic substance, which comprises one or more compounds selected from the above group as an active ingredient.
The reducing agent according to claim 1, which is orally administered.
The reducing agent according to claim 1 or 2, wherein the compound is a compound represented by the following formula.
The uremic substance is one or more substances selected from phenyl sulfate, creatinine, 1-methyladenosine, urea nitrogen, trimethylamine-N-oxide, indoxyl sulfate, phenol, and indole. The reducing agent according to any one of claims 1 to 3.
The following formula (I);

[During the ceremony,
R 1 and R 2 may be the same or different, respectively; hydrogen atom; substituted or unsubstituted linear or branched alkyl group having 1 to 10 carbon atoms; substituted or substituted, respectively. Alkoxy group of linear or branched chain having 1 to 10 carbon atoms; substituted or unsubstituted alkylcarbonyl group of linear or branched chain having 1 to 10 carbon atoms; substituted or substituted A cycloalkyl group having 3 to 10 carbon atoms in a non-ring; a cycloalkyloxy group having 3 to 10 carbon atoms substituted or not substituted; a linear or fraction having 2 to 10 carbon atoms substituted or not substituted Branch chain alkoxy groups; substituted or unsubstituted linear or branched alkoxyoxy groups having 2 to 10 carbon atoms; substituted or unsubstituted aryl groups having 6 to 14 carbon atoms; or An substituted or unsubstituted aralkyl group having 7 to 18 carbon atoms;
R 3 is a substituted or unsubstituted linear or branched alkyl group having 1 to 10 carbon atoms; substituted or unsubstituted linear or branched alkoxy having 1 to 10 carbon atoms. Group; Substituent or unsubstituted linear or branched alkylcarbonyl group having 1 to 10 carbon atoms; Substituted or unsubstituted ring having 3 to 10 carbon atoms; Substituted Or an unsubstituted cycloalkyloxy group having 3 to 10 carbon atoms; a linear or branched alkenyl group having 2 to 10 carbon atoms substituted or not substituted; substituted or unsubstituted carbon number 2-10 linear or branched alkenyloxy groups; substituted or unsubstituted aryl groups with 6-14 carbon atoms; or substituted or unsubstituted aralkyl groups with 7-18 carbon atoms ; And
R 4 is a hydrogen atom; a linear or branched substituted or 1-10 carbon atoms non-substituted; substituted or a lower alkyl group of straight or branched chain having 1 to 10 carbon atoms and being substituted Alkyl carbonyl group of branched chain; substituted or unsubstituted cycloalkyl group having 3 to 10 carbon atoms; substituted or unsubstituted linear or branched lower alkenyl group having 2 to 10 carbon atoms; An aryl group having 6 to 14 carbon atoms substituted or not substituted; or an aralkyl group having 7 to 18 carbon atoms substituted or not substituted;
R 5 is a hydrogen atom; a linear or branched lower alkyl group having 1 to 10 carbon atoms substituted or unsubstituted; a linear or fractionated linear or fractionated chain having 1 to 10 carbon atoms substituted or unsubstituted. Alkoxy group of branched chain; alkylcarbonyl group of linear or branched chain having 1 to 10 carbon atoms substituted or unsubstituted; cycloalkyl group having 3 to 10 carbon atoms of substituted or unsubstituted ring Substituted or unsubstituted cycloalkyloxy groups with 3 to 10 carbon atoms; substituted or unsubstituted linear or branched lower alkoxy groups with 2 to 10 carbon atoms; substituted or substituted Non-substituted linear or branched alkoxyoxy group with 2-10 carbon atoms; substituted or unsubstituted aryl group with 6-14 carbon atoms; or substituted or unsubstituted carbon number 7 ~ 18 Alkoxy groups;
X is S, SO, or SO 2 ,
Y is O or S,
Z is O, S, SO, or SO 2 ], from a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable ester of the compound, and a hydrate of the compound. A preventive or ameliorating agent for uremia, which comprises one or more compounds selected from the above group as an active ingredient.
The preventive or ameliorating agent according to claim 5, which is orally administered.
The preventive or ameliorating agent according to claim 5 or 6, wherein the uremia is diabetic nephropathy, nephrotic syndrome, or chronic nephritis syndrome.
The preventive or ameliorating agent according to any one of claims 5 to 7, wherein the compound is a compound represented by the following formula.
The following formula (I);

[During the ceremony,
R 1 and R 2 may be the same or different, respectively; hydrogen atom; substituted or unsubstituted linear or branched alkyl group having 1 to 10 carbon atoms; substituted or substituted, respectively. Alkoxy group of linear or branched chain having 1 to 10 carbon atoms; substituted or unsubstituted alkylcarbonyl group of linear or branched chain having 1 to 10 carbon atoms; substituted or substituted A cycloalkyl group having 3 to 10 carbon atoms in a non-ring; a cycloalkyloxy group having 3 to 10 carbon atoms substituted or not substituted; a linear or fraction having 2 to 10 carbon atoms substituted or not substituted Branch chain alkoxy groups; substituted or unsubstituted linear or branched alkoxyoxy groups having 2 to 10 carbon atoms; substituted or unsubstituted aryl groups having 6 to 14 carbon atoms; or An substituted or unsubstituted aralkyl group having 7 to 18 carbon atoms;
R 3 is a substituted or unsubstituted linear or branched alkyl group having 1 to 10 carbon atoms; substituted or unsubstituted linear or branched alkoxy having 1 to 10 carbon atoms. Group; Substituent or unsubstituted linear or branched alkylcarbonyl group having 1 to 10 carbon atoms; Substituted or unsubstituted ring having 3 to 10 carbon atoms; Substituted Alternatively, a cycloalkyloxy group having 3 to 10 carbon atoms which has not been substituted; a linear or branched alkenyl group having 2 to 10 carbon atoms which has been substituted or not substituted; an alkenyl group having substituted or unsubstituted carbon number. 2-10 linear or branched alkenyloxy groups; substituted or unsubstituted aryl groups with 6-14 carbon atoms; or substituted or unsubstituted aralkyl groups with 7-18 carbon atoms ; And
R 4 is a hydrogen atom; a linear or branched substituted or 1-10 carbon atoms non-substituted; substituted or a lower alkyl group of straight or branched chain having 1 to 10 carbon atoms and being substituted Alkyl carbonyl group of branched chain; substituted or unsubstituted cycloalkyl group having 3 to 10 carbon atoms; substituted or unsubstituted linear or branched lower alkenyl group having 2 to 10 carbon atoms; An aryl group having 6 to 14 carbon atoms substituted or not substituted; or an aralkyl group having 7 to 18 carbon atoms substituted or not substituted;
R 5 is a hydrogen atom; a linear or branched lower alkyl group having 1 to 10 carbon atoms substituted or unsubstituted; a linear or fractionated linear or fractionated chain having 1 to 10 carbon atoms substituted or unsubstituted. Alkoxy group of branched chain; alkylcarbonyl group of linear or branched chain having 1 to 10 carbon atoms substituted or unsubstituted; cycloalkyl group having 3 to 10 carbon atoms of substituted or unsubstituted ring Substituted or unsubstituted cycloalkyloxy groups with 3 to 10 carbon atoms; substituted or unsubstituted linear or branched lower alkoxy groups with 2 to 10 carbon atoms; substituted or substituted Non-substituted linear or branched alkoxyoxy group with 2-10 carbon atoms; substituted or unsubstituted aryl group with 6-14 carbon atoms; or substituted or unsubstituted carbon number 7 ~ 18 Alkoxy groups;
X is S, SO, or SO 2 ,
Y is O or S,
Z is O, S, SO, or SO 2 ], from pharmaceutically acceptable salts of the compound, pharmaceutically acceptable esters of the compound, and hydrates of the compound. A preventive or ameliorating agent for renal dysfunction, which comprises one or more compounds selected from the above group as an active ingredient.
The preventive or ameliorating agent according to claim 9, which is orally administered.
The preventive or ameliorating agent according to claim 9 or 10, wherein the compound is a compound represented by the following formula.
The preventive or ameliorating agent according to any one of claims 9 to 11, wherein the renal dysfunction is renal failure.