Agent for preventing or ameliorating renal function decline and composition for preventing or ameliorating renal function decline; agent for preventing or ameliorating decreased waste excretion into urine and composition for preventing or ameliorating decreased waste excretion into urine; agent for preventing or ameliorating at least one state selected from group consisting of fatigue, lethargy, and anemia, and composition for preventing or ameliorating at least one state selected from group consisting of fatigue, lethargy, and anemia; agent for preventing or ameliorating nephritis and composition for preventing or ameliorating nephritis; agent for preventing or ameliorating tissue fibrosis and composition for preventing or ameliorating tissue fibrosis; agent for preventing or ameliorating decline in urine concentration ability and composition for preventing or ameliorating decline in urine concentration ability; and agent for preventing or ameliorating nocturnal polyuria and composition for preventing or ameliorating nocturnal polyuria

Abstract

Provided is an agent for preventing or ameliorating renal function decline, the agent containing a compound represented by structural formula (1).

Description

Agent for preventing or improving renal function decline and composition for preventing or improving renal function decline, agent for preventing or improving reduced urinary waste excretion and composition for preventing or improving reduced urinary waste excretion, agent for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy and anemia and composition for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy and anemia, agent for preventing or improving nephritis and composition for preventing or improving nephritis, agent for preventing or improving tissue fibrosis and composition for preventing or improving tissue fibrosis, agent for preventing or improving reduced urinary concentrating ability and composition for preventing or improving reduced urinary concentrating ability, and agent for preventing or improving nocturnal polyuria and composition for preventing or improving nocturnal polyuria

[0001] The present invention relates to an agent for preventing or ameliorating renal function decline and a composition for preventing or ameliorating renal function decline, an agent for preventing or ameliorating reduced urinary waste excretion and a composition for preventing or ameliorating reduced urinary waste excretion, an agent for preventing or ameliorating at least one condition selected from the group consisting of fatigue, lethargy, and anemia and a composition for preventing or ameliorating at least one condition selected from the group consisting of fatigue, lethargy, and anemia, an agent for preventing or ameliorating nephritis and a composition for preventing or ameliorating nephritis, an agent for preventing or ameliorating tissue fibrosis and a composition for preventing or ameliorating tissue fibrosis, an agent for preventing or ameliorating reduced urinary concentrating ability and a composition for preventing or ameliorating reduced urinary concentrating ability, and an agent for preventing or ameliorating nocturnal polyuria and a composition for preventing or ameliorating nocturnal polyuria.

[0002] Kidney disease, excluding acute nephritis, is a lifelong illness that can eventually lead to end-stage renal failure, which requires dialysis therapy. As the number of elderly people increases in the future, it is expected that the number of elderly people with declining kidney function and suffering from nephritis will also increase.

[0003] The kidneys are organs that excrete metabolic products and waste products produced in the body and maintain extracellular fluid homeostasis. Therefore, a decline in renal function leads to a decrease in the secretion of erythropoietin, which is produced by tubulointerstitial cells. Because erythropoietin is a hormone that promotes red blood cell production, a decline in renal function can lead to conditions such as fatigue, lethargy, and anemia.

[0004] Furthermore, fibrosis of tissues such as the kidneys is known to lead to various diseases. For example, when kidney fibrosis progresses, it can lead to renal failure in the worst case scenario. Furthermore, as kidney fibrosis progresses, the ability to concentrate urine decreases, leading to polyuria (nocturnal polyuria).

[0005] To date, compositions for preventing or ameliorating renal dysfunction, which contain Bifidobacterium breve as an active ingredient, have been proposed (see, for example, Patent Document 1).

[0006] Furthermore, a tissue fibrosis inhibitor containing bofutsushosan extract, boiogito extract and / or daishaikoto extract has been proposed as a tissue fibrosis inhibitor (see, for example, Patent Document 2).

[0007] However, there remains a strong demand for new materials that have the effect of preventing or improving renal function decline, preventing or improving reduced urinary excretion of waste products, preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, preventing or improving nephritis, preventing or improving tissue fibrosis, preventing or improving reduced urinary concentrating ability, or preventing or improving nocturnal polyuria, and that are highly safe and therefore can be widely used as ingredients in foods and beverages, pharmaceuticals, research reagents, and the like, and the current situation is that there is a strong demand for such materials to be developed quickly.

[0008] JP 2023-126304 A JP 2021-104952 A

[0009] The present invention aims to solve the above-mentioned conventional problems and achieve the following objectives. Specifically, it is an object of the present invention to provide an agent for preventing or improving renal function decline, and a composition for preventing or improving renal function decline, which have an excellent effect of preventing or improving renal function decline and are highly safe. Another object of the present invention is to provide an agent for preventing or improving reduced urinary waste excretion, and a composition for preventing or improving reduced urinary waste excretion, which have an excellent effect of preventing or improving reduced urinary waste excretion and are highly safe. Another object of the present invention is to provide an agent for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, and a composition for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, which have an excellent effect of preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, and are highly safe. Another object of the present invention is to provide an agent for preventing or improving nephritis, and a composition for preventing or improving nephritis, which have an excellent effect of preventing or improving nephritis and are highly safe. Another object of the present invention is to provide an agent for preventing or ameliorating tissue fibrosis and a composition for preventing or ameliorating tissue fibrosis, which have an excellent effect of preventing or ameliorating tissue fibrosis and are highly safe.Another object of the present invention is to provide an agent for preventing or ameliorating a decrease in urinary concentrating ability and a composition for preventing or ameliorating a decrease in urinary concentrating ability, which have an excellent effect of preventing or ameliorating nocturnal polyuria and are highly safe.Another object of the present invention is to provide an agent for preventing or ameliorating nocturnal polyuria and a composition for preventing or ameliorating nocturnal polyuria, which have an excellent effect of preventing or ameliorating nocturnal polyuria and are highly safe.

[0010] As a result of intensive research conducted by the present inventors to solve the above problems, it has been found that a compound represented by the following structural formula (1) has an excellent effect of preventing or improving renal function decline, preventing or improving reduced urinary excretion of waste products, preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, preventing or improving nephritis, preventing or improving tissue fibrosis, preventing or improving reduced urinary concentrating ability, or preventing or improving nocturnal polyuria, is highly safe, and is useful for preventing or improving renal function decline, preventing or improving reduced urinary excretion of waste products, preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, preventing or improving nephritis, preventing or improving tissue fibrosis, preventing or improving reduced urinary concentrating ability, or preventing or improving nocturnal polyuria.

[0011] The present invention is based on the above-mentioned findings of the present inventors, and provides the following means for solving the above-mentioned problems: <1> An agent for preventing or ameliorating renal dysfunction, comprising a compound represented by the following structural formula (1): <2> An agent for preventing or improving decreased excretion of waste products into urine, the agent comprising a compound represented by the following structural formula (1): <3> An agent for preventing or improving at least one condition selected from the group consisting of fatigue, listlessness, and anemia, the agent comprising a compound represented by the following structural formula (1): <4> A prophylactic or ameliorating agent for nephritis, comprising a compound represented by the following structural formula (1): <5> An agent for preventing or ameliorating tissue fibrosis, comprising a compound represented by the following structural formula (1): <6> The agent for preventing or ameliorating tissue fibrosis according to <5>, wherein the tissue is kidney tissue. <7> An agent for preventing or ameliorating a decrease in urine concentrating ability, the agent comprising a compound represented by the following structural formula (1): <8> An agent for preventing or ameliorating nocturnal polyuria, comprising a compound represented by the following structural formula (1): <9> A composition for preventing or improving renal function decline, comprising the agent for preventing or improving renal function decline described in <1>. <10> A composition for preventing or improving reduced urinary waste excretion, comprising the agent for preventing or improving reduced urinary waste excretion described in <2>. <11> A composition for preventing or improving at least one condition selected from the group consisting of fatigue, fatigue, and anemia, comprising the agent for preventing or improving at least one condition selected from the group consisting of fatigue, fatigue, and anemia described in <3>. <12> A composition for preventing or improving nephritis, comprising the agent for preventing or improving nephritis described in <4>. <13> A composition for preventing or improving tissue fibrosis, comprising the agent for preventing or improving tissue fibrosis described in <5> or <6>. <14> A composition for preventing or improving reduced urinary concentrating ability, comprising the agent for preventing or improving urinary concentrating ability described in <7>. <15> A composition for preventing or ameliorating nocturnal polyuria, comprising the agent for preventing or ameliorating nocturnal polyuria according to <8>.

[0012] The agent for preventing or ameliorating renal function decline and composition for preventing or ameliorating renal function decline of the present invention can solve the above-mentioned conventional problems and achieve the above-mentioned object, and it is possible to provide an agent for preventing or ameliorating renal function decline and composition for preventing or ameliorating renal function decline that has an excellent effect of preventing or ameliorating renal function decline and is highly safe.The agent for preventing or ameliorating reduced urinary waste excretion and composition for preventing or ameliorating reduced urinary waste excretion of the present invention can solve the above-mentioned conventional problems and achieve the above-mentioned object, and it is possible to provide an agent for preventing or ameliorating reduced urinary waste excretion and composition for preventing or ameliorating reduced urinary waste excretion that has an excellent effect of preventing or ameliorating reduced urinary waste excretion and is highly safe. The agent for preventing or ameliorating at least one condition selected from the group consisting of fatigue, fatigue, and anemia, and the composition for preventing or ameliorating at least one condition selected from the group consisting of fatigue, fatigue, and anemia of the present invention can solve the above-mentioned conventional problems and achieve the above-mentioned object, and it is possible to provide an agent for preventing or ameliorating at least one condition selected from the group consisting of fatigue, fatigue, and anemia, and a composition for preventing or ameliorating at least one condition selected from the group consisting of fatigue, fatigue, and anemia, which have an excellent effect of preventing or ameliorating at least one condition selected from the group consisting of fatigue, fatigue, and anemia, and which are highly safe.The agent for preventing or ameliorating nephritis and the composition for preventing or ameliorating nephritis of the present invention can solve the above-mentioned conventional problems and achieve the above-mentioned object, and it is possible to provide an agent for preventing or ameliorating nephritis and a composition for preventing or ameliorating nephritis, which have an excellent effect of preventing or ameliorating nephritis, and which are highly safe. The agent for preventing or ameliorating tissue fibrosis and composition for preventing or ameliorating tissue fibrosis of the present invention can solve the above-mentioned conventional problems and achieve the above-mentioned object, and can provide an agent for preventing or ameliorating tissue fibrosis and composition for preventing or ameliorating tissue fibrosis that have excellent tissue fibrosis prevention or amelioration effects and are highly safe.The agent for preventing or ameliorating a decline in urinary concentrating ability and the composition for preventing or ameliorating a decline in urinary concentrating ability of the present invention can solve the above-mentioned conventional problems and achieve the above-mentioned object, and it is possible to provide an agent for preventing or ameliorating a decline in urinary concentrating ability and a composition for preventing or ameliorating a decline in urinary concentrating ability that has an excellent effect of preventing or ameliorating a decline in urinary concentrating ability and is highly safe.The agent for preventing or ameliorating nocturnal polyuria and the composition for preventing or ameliorating nocturnal polyuria of the present invention can solve the above-mentioned conventional problems and achieve the above-mentioned object, and it is possible to provide an agent for preventing or ameliorating nocturnal polyuria and a composition for preventing or ameliorating nocturnal polyuria that has an excellent effect of preventing or ameliorating nocturnal polyuria and is highly safe.

[0013] FIG. 1 is a diagram showing the results of analyzing the expression level of Fn1 mRNA in Test Example 1. FIG. 2 is a diagram showing the results of analyzing the expression level of coll1a1 mRNA in Test Example 1. FIG. 3 is a diagram showing the results of analyzing the expression level of coll3a1 mRNA in Test Example 1. FIG. 4 is a diagram showing the results of analyzing the concentration of urea nitrogen in serum in Test Example 2. FIG. 5 is a diagram showing the results of analyzing the concentration of creatinine in serum in Test Example 2. FIG. 6 is a diagram showing the results of analyzing the expression level of Fn1 mRNA in Test Example 2. FIG. 7 is a diagram showing the results of analyzing the expression level of coll1a1 mRNA in Test Example 2. FIG. 8 is a diagram showing the results of analyzing the expression level of ccl2 mRNA in Test Example 2. FIG. 9 is a diagram showing the results of analyzing the expression level of coll3a1 mRNA in Test Example 2. FIG. 10 is a diagram showing the results of analyzing the expression level of Saa3 mRNA in Test Example 2. Fig. 11 is a diagram showing the results of analyzing the expression level of Emr1 mRNA in Test Example 2. Fig. 12 is Fig. 1 showing the results of Azan-Mallory staining in Test Example 2. Fig. 13 is Fig. 2 showing the results of Azan-Mallory staining in Test Example 2.

[0014] (Agent for preventing or improving renal function decline, agent for preventing or improving reduced urinary waste excretion, agent for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, agent for preventing or improving nephritis, agent for preventing or improving tissue fibrosis, agent for preventing or improving reduced urinary concentrating ability, agent for preventing or improving nocturnal polyuria) The agent for preventing or improving renal function decline of the present invention comprises a compound represented by the following structural formula (1) as an active ingredient, and further comprises other ingredients as needed. The agent for preventing or improving reduced urinary waste excretion of the present invention comprises a compound represented by the following structural formula (1) as an active ingredient, and further comprises other ingredients as needed. The agent for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia of the present invention comprises a compound represented by the following structural formula (1) as an active ingredient, and further comprises other ingredients as needed. The agent for preventing or improving nephritis of the present invention comprises a compound represented by the following structural formula (1) as an active ingredient, and further comprises other ingredients as needed. The agent for preventing or ameliorating tissue fibrosis of the present invention contains a compound represented by the following structural formula (1) as an active ingredient, and further contains other ingredients as needed. The agent for preventing or ameliorating a decrease in urinary concentrating ability of the present invention contains a compound represented by the following structural formula (1) as an active ingredient, and further contains other ingredients as needed. The agent for preventing or ameliorating nocturnal polyuria of the present invention contains a compound represented by the following structural formula (1) as an active ingredient, and further contains other ingredients as needed.

[0015] As used herein, "reduced renal function" refers to a state in which renal function is reduced compared to a normal state. The degree of renal function reduction is not particularly limited, and may be a state in which a patient is suffering from a renal disease, or a state in which the patient has not yet developed renal disease. The type of renal disease is not particularly limited, and examples include glomerular disease, renal tubulointerstitial disease, renal failure, kidney stones, and urinary stones.

[0016] As used herein, "preventing renal function decline" refers to maintaining normal renal function or inhibiting decline in renal function. Prevention of renal function decline also includes inhibiting further decline in renal function after decline. Improvement of renal function decline refers to restoring declined renal function to a normal state or to a state approaching the normal state.

[0017] The method for checking the state of renal function is not particularly limited and can be appropriately selected depending on the purpose. For example, the blood urea nitrogen concentration, creatinine concentration, etc. can be used as an indicator.

[0018] As used herein, "decreased excretion of waste products into urine" refers to a state in which the amount of waste products excreted into urine is reduced compared to normal. The degree of reduction in the amount of waste products excreted into urine is not particularly limited. The type of waste product is not particularly limited, and examples thereof include uric acid, creatinine, urea, xanthine, and urea nitrogen.

[0019] As used herein, "preventing a decrease in urinary waste excretion" refers to maintaining a normal level of urinary waste excretion or inhibiting a decrease in urinary waste excretion. Preventing a decrease in urinary waste excretion also includes inhibiting a further decrease in an already decreased level of urinary waste excretion. Furthermore, improving a decrease in urinary waste excretion refers to restoring a decreased level of urinary waste excretion to a normal level or approaching a normal level.

[0020] As used herein, "preventing at least one condition selected from the group consisting of fatigue, fatigue, and anemia" refers to preventing at least one condition selected from the group consisting of fatigue, fatigue, and anemia from occurring. Prevention of at least one condition selected from the group consisting of fatigue, fatigue, and anemia also includes preventing at least one condition selected from the group consisting of fatigue, fatigue, and anemia from worsening. Furthermore, "improving at least one condition selected from the group consisting of fatigue, fatigue, and anemia" refers to alleviating at least one condition selected from the group consisting of fatigue, fatigue, and anemia. The alleviation may be complete or partial relief of the condition.

[0021] The type of nephritis is not particularly limited, and may be acute nephritis or chronic nephritis.

[0022] As used herein, "prevention of nephritis" refers to preventing the onset of nephritis. Prevention of nephritis also includes suppressing further deterioration of nephritis. Improvement of nephritis refers to restoring the kidney to a normal state or approaching a normal state.

[0023] The tissue involved in the fibrosis is not particularly limited and can be appropriately selected, and examples thereof include kidney tissue, lung tissue, heart tissue, liver tissue, and pancreatic tissue.

[0024] As used herein, "preventing tissue fibrosis" refers to inhibiting the occurrence of fibrosis. Prevention of tissue fibrosis also includes inhibiting further deterioration of fibrosis. Improvement of tissue fibrosis refers to restoring tissue to a normal state or approaching a normal state.

[0025] As used herein, "a decrease in urine concentrating ability" refers to a state in which the urine concentrating ability is decreased compared to a normal state. There are no particular limitations on the degree of decrease in urine concentrating ability.

[0026] As used herein, "preventing a decline in urinary concentrating ability" refers to maintaining a normal state of urinary concentrating ability or inhibiting a decline in urinary concentrating ability. Preventing a decline in urinary concentrating ability also includes inhibiting a further decline in an already-decreased urinary concentrating ability. Furthermore, "ameliorating a decline in urinary concentrating ability" refers to restoring a decreased urinary concentrating ability to a normal state or approaching a normal state.

[0027] As used herein, nocturnal polyuria refers to an increase in the amount of urine produced only at night. There are no particular limitations on the degree of nocturnal polyuria.

[0028] As used herein, "preventing nocturnal polyuria" refers to maintaining a normal nighttime urinary volume or inhibiting an increase in nighttime urinary volume. Prevention of nocturnal polyuria also includes inhibiting further deterioration of the nocturnal polyuria condition. Improvement of nocturnal polyuria refers to restoring or approaching a normal nighttime urinary volume.

[0029] The compound represented by the structural formula (1) has excellent effects of preventing or improving renal function decline, preventing or improving reduced urinary excretion of waste products, preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, preventing or improving nephritis, preventing or improving tissue fibrosis, preventing or improving reduced urinary concentrating ability, or preventing or improving nocturnal polyuria, and is useful as an agent for preventing or improving renal function decline, preventing or improving reduced urinary excretion of waste products, preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, preventing or improving nephritis, preventing or improving tissue fibrosis, preventing or improving reduced urinary concentrating ability, or preventing or improving nocturnal polyuria, which was not previously known and is a new finding by the present inventors.

[0030] <Compound Represented by Structural Formula (1)> The name of the compound represented by the following structural formula (1) is 3-(4-hydroxy-3-methoxyphenyl)propionic acid (hereinafter, may be referred to as "HMPA").

[0031] The compound represented by the structural formula (1) is a known compound, and a commercially available product may be used, or one produced by a known method may be used.

[0032] The content of the compound represented by structural formula (1) in the agent for preventing or improving renal function decline, agent for preventing or improving reduced urinary waste excretion, agent for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, agent for preventing or improving nephritis, agent for preventing or improving tissue fibrosis, agent for preventing or improving reduced urinary concentrating ability, or agent for preventing or improving nocturnal polyuria of the present invention is not particularly limited and can be appropriately selected depending on the purpose. The agent for preventing or improving renal function decline, agent for preventing or improving reduced urinary waste excretion, agent for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, agent for preventing or improving nephritis, agent for preventing or improving tissue fibrosis, agent for preventing or improving reduced urinary concentrating ability, or agent for preventing or improving nocturnal polyuria may consist solely of the compound represented by structural formula (1).

[0033] <Other Components> The other components are not particularly limited as long as they do not impair the effects of the present invention, and can be appropriately selected depending on the usage form of the agent for preventing or improving renal function decline, agent for preventing or improving reduced urinary waste excretion, agent for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, agent for preventing or improving nephritis, agent for preventing or improving tissue fibrosis, agent for preventing or improving reduced urinary concentrating ability, or agent for preventing or improving nocturnal polyuria, and examples thereof include excipients, moisture-proofing agents, preservatives, strengthening agents, thickeners, emulsifiers, antioxidants, sweeteners, acidulants, seasonings, colorants, fragrances, whitening agents, moisturizers, oily components, UV absorbers, surfactants, thickeners, alcohols, powder components, colorants, aqueous components, water, skin nutrients, etc. These may be used alone or in combination of two or more.

[0034] The content of the other ingredients in the agent for preventing or improving renal function decline, the agent for preventing or improving reduced excretion of waste products into urine, the agent for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, the agent for preventing or improving nephritis, the agent for preventing or improving tissue fibrosis, the agent for preventing or improving reduced urine concentrating ability, or the agent for preventing or improving nocturnal polyuria is not particularly limited and can be selected appropriately depending on the purpose.

[0035] <Uses> The uses of the agent for preventing or improving renal function decline, agent for preventing or improving decline in excretion of waste products into urine, agent for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, agent for preventing or improving nephritis, agent for preventing or improving tissue fibrosis, agent for preventing or improving decline in urine concentrating ability, or agent for preventing or improving nocturnal polyuria are not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include pharmaceuticals, quasi-drugs, foods and beverages, etc.

[0036] The agent for preventing or improving renal function decline has an excellent effect of preventing or improving renal function decline and is highly safe, and therefore can be suitably used, for example, as an active ingredient in a composition for preventing or improving renal function decline, which will be described later.

[0037] The agent for preventing or improving reduced urinary waste excretion has an excellent effect of preventing or improving reduced urinary waste excretion and is highly safe, and therefore can be suitably used, for example, as an active ingredient in a composition for preventing or improving reduced urinary waste excretion, as described below.

[0038] The agent for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia has an excellent effect of preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, and is highly safe, and therefore can be suitably used, for example, as an active ingredient in a composition for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, which will be described later.

[0039] The agent for preventing or ameliorating nephritis has an excellent effect of preventing or ameliorating nephritis and is highly safe, and therefore can be suitably used, for example, as an active ingredient of a composition for preventing or ameliorating nephritis, which will be described later.

[0040] The agent for preventing or improving tissue fibrosis has an excellent effect of preventing or improving tissue fibrosis and is highly safe, and therefore can be suitably used, for example, as an active ingredient in a composition for preventing or improving tissue fibrosis, which will be described later.

[0041] The agent for preventing or improving a decrease in urine concentration ability has an excellent effect of preventing or improving a decrease in urine concentration ability and is highly safe, and therefore can be suitably used, for example, as an active ingredient in a composition for preventing or improving a decrease in urine concentration ability described below.

[0042] The agent for preventing or improving nocturnal polyuria has an excellent effect of preventing or improving nocturnal polyuria and is highly safe, and therefore can be suitably used, for example, as an active ingredient in a composition for preventing or improving nocturnal polyuria, which will be described later.

[0043] The agent for preventing or improving renal function decline, agent for preventing or improving reduced excretion of waste products into urine, agent for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy and anemia, agent for preventing or improving nephritis, agent for preventing or improving tissue fibrosis, agent for preventing or improving reduced urine concentrating ability, or agent for preventing or improving nocturnal polyuria of the present invention is preferably applied to humans, but can also be applied to animals other than humans (e.g., mice, rats, hamsters, dogs, cats, cows, pigs, monkeys, etc.) as long as its functional effects are achieved.

[0044] The method of use of the agent for preventing or improving renal function decline, agent for preventing or improving reduced excretion of waste products into urine, agent for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, agent for preventing or improving nephritis, agent for preventing or improving tissue fibrosis, agent for preventing or improving reduced urine concentrating ability, or agent for preventing or improving nocturnal polyuria is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include oral, parenteral, and topical use.

[0045] The application site, method of use, and dosage form of the agent for preventing or improving renal function decline, agent for preventing or improving reduced excretion of waste products into urine, agent for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, agent for preventing or improving nephritis, agent for preventing or improving tissue fibrosis, agent for preventing or improving reduced urine concentrating ability, or agent for preventing or improving nocturnal polyuria can be selected appropriately depending on the purpose of use.

[0046] The agent for preventing or improving renal function decline, agent for preventing or improving reduced urinary waste excretion, agent for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, agent for preventing or improving nephritis, agent for preventing or improving tissue fibrosis, agent for preventing or improving reduced urinary concentrating ability, or agent for preventing or improving nocturnal polyuria can be formulated into any dosage form such as powder, granules, tablets, or liquid using a pharmaceutically acceptable carrier such as dextrin, cyclodextrin, or any other auxiliary agent according to a conventional method. In this case, examples of the auxiliary agent that can be used include excipients, binders, disintegrants, lubricants, stabilizers, flavorings, and odor masking agents. The agent for preventing or improving renal function decline, agent for preventing or improving reduced urinary waste excretion, agent for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, agent for preventing or improving nephritis, agent for preventing or improving tissue fibrosis, agent for preventing or improving reduced urinary concentrating ability, or agent for preventing or improving nocturnal polyuria can be used by being incorporated into other compositions (for example, the below-mentioned composition for preventing or improving renal function decline, composition for preventing or improving reduced urinary waste excretion, composition for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, composition for preventing or improving nephritis, composition for preventing or improving tissue fibrosis, composition for preventing or improving reduced urinary concentrating ability, or composition for preventing or improving nocturnal polyuria), and can also be used as parenteral administration agents such as injections, infusions, and suppositories, ointments, eye drops, external liquid preparations, patches, etc.

[0047] The method of use, such as the amount to be used, the period of use, and the interval between uses, of the agent for preventing or improving renal function decline, the agent for preventing or improving reduced excretion of waste products into urine, the agent for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, the agent for preventing or improving nephritis, the agent for preventing or improving tissue fibrosis, the agent for preventing or improving reduced urine concentrating ability, or the agent for preventing or improving nocturnal polyuria are not particularly limited and can be selected appropriately depending on the purpose.

[0048] Furthermore, the agent for preventing or improving renal function decline of the present invention has a preventive or improving effect on renal function decline, the agent for preventing or improving reduced urinary waste excretion of the present invention has a preventive or improving effect on reduced urinary waste excretion, the agent for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia has a preventive or improving effect on at least one condition selected from the group consisting of fatigue, lethargy, and anemia, the agent for preventing or improving nephritis of the present invention has a preventive or improving effect on nephritis, the agent for preventing or improving tissue fibrosis of the present invention has a preventive or improving effect on tissue fibrosis, the agent for preventing or improving reduced urinary concentrating ability of the present invention has a preventive or improving effect on reduced urinary concentrating ability, and the agent for preventing or improving nocturnal polyuria of the present invention can also be used as a reagent for research into the mechanism of action of preventing or improving nocturnal polyuria.

[0049] (Composition for preventing or ameliorating renal function decline, composition for preventing or ameliorating reduced urinary waste excretion, composition for preventing or ameliorating at least one condition selected from the group consisting of fatigue, lethargy, and anemia, composition for preventing or ameliorating nephritis, composition for preventing or ameliorating tissue fibrosis, composition for preventing or ameliorating reduced urinary concentrating ability, composition for preventing or ameliorating nocturnal polyuria) The composition for preventing or ameliorating renal function decline of the present invention comprises the agent for preventing or ameliorating renal function decline of the present invention, and further comprises other ingredients as necessary. The composition for preventing or ameliorating reduced urinary waste excretion of the present invention comprises the agent for preventing or ameliorating reduced urinary waste excretion of the present invention, and further comprises other ingredients as necessary. The composition for preventing or ameliorating at least one condition selected from the group consisting of fatigue, lethargy, and anemia of the present invention comprises the agent for preventing or ameliorating at least one condition selected from the group consisting of fatigue, lethargy, and anemia of the present invention, and further comprises other ingredients as necessary. The composition for preventing or ameliorating nephritis of the present invention comprises the agent for preventing or ameliorating nephritis of the present invention, and further comprises other ingredients as necessary. The composition for preventing or ameliorating tissue fibrosis of the present invention comprises the agent for preventing or ameliorating tissue fibrosis of the present invention, and further comprises other ingredients as necessary.The composition for preventing or ameliorating a decrease in urinary concentrating ability of the present invention comprises the agent for preventing or ameliorating a decrease in urinary concentrating ability of the present invention, and further comprises other ingredients as necessary.The composition for preventing or ameliorating nocturnal polyuria of the present invention comprises the agent for preventing or ameliorating nocturnal polyuria of the present invention, and further comprises other ingredients as necessary.

[0050] <Agent for preventing or improving renal function decline, agent for preventing or improving reduced urinary waste excretion, agent for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, agent for preventing or improving nephritis, agent for preventing or improving tissue fibrosis, agent for preventing or improving reduced urinary concentrating ability, and agent for preventing or improving nocturnal polyuria> The agent for preventing or improving renal function decline is the agent for preventing or improving renal function decline of the present invention described above. The agent for preventing or improving reduced urinary waste excretion is the agent for preventing or improving reduced urinary waste excretion of the present invention described above. The agent for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia is the agent for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia described above. The agent for preventing or improving nephritis is the agent for preventing or improving nephritis of the present invention described above. The agent for preventing or improving tissue fibrosis is the agent for preventing or improving tissue fibrosis of the present invention described above. The agent for preventing or ameliorating a decrease in urinary concentrating ability is the agent for preventing or ameliorating a decrease in urinary concentrating ability of the present invention described above. The agent for preventing or ameliorating nocturnal polyuria is the agent for preventing or ameliorating nocturnal polyuria of the present invention described above.

[0051] The content of the agent for preventing or ameliorating renal function decline in the composition for preventing or ameliorating renal function decline is not particularly limited and can be appropriately adjusted depending on the form of the composition for preventing or ameliorating renal function decline, but is preferably 0.0001% by mass to 50% by mass, and more preferably 0.0001% by mass to 30% by mass, calculated as the amount of the compound represented by structural formula (1). The composition for preventing or ameliorating renal function decline may consist solely of the agent for preventing or ameliorating renal function decline.

[0052] The content of the agent for preventing or improving reduced urinary waste excretion in the composition for preventing or improving reduced urinary waste excretion is not particularly limited and can be appropriately adjusted depending on the form of the composition for preventing or improving reduced urinary waste excretion, but is preferably 0.0001% by mass to 50% by mass, and more preferably 0.0001% by mass to 30% by mass, calculated as the amount of the compound represented by structural formula (1). The composition for preventing or improving reduced urinary waste excretion may consist solely of the agent for preventing or improving reduced urinary waste excretion.

[0053] The content of the agent for preventing or improving at least one condition selected from the group consisting of fatigue, fatigue, and anemia in the composition for preventing or improving at least one condition selected from the group consisting of fatigue, fatigue, and anemia is not particularly limited and can be appropriately adjusted depending on the form of the composition for preventing or improving at least one condition selected from the group consisting of fatigue, fatigue, and anemia, but is preferably 0.0001% by mass to 50% by mass, and more preferably 0.0001% by mass to 30% by mass, converted into the amount of the compound represented by structural formula (1). The composition for preventing or improving at least one condition selected from the group consisting of fatigue, fatigue, and anemia may consist solely of the agent for preventing or improving at least one condition selected from the group consisting of fatigue, fatigue, and anemia.

[0054] The content of the agent for preventing or ameliorating nephritis in the composition for preventing or ameliorating nephritis is not particularly limited and can be appropriately adjusted depending on the form of the composition for preventing or ameliorating nephritis, but is preferably 0.0001% by mass to 50% by mass, and more preferably 0.0001% by mass to 30% by mass, calculated as the amount of the compound represented by structural formula (1). The composition for preventing or ameliorating nephritis may consist solely of the agent for preventing or ameliorating nephritis.

[0055] The content of the agent for preventing or ameliorating tissue fibrosis in the composition for preventing or ameliorating tissue fibrosis is not particularly limited and can be appropriately adjusted depending on the form of the composition for preventing or ameliorating tissue fibrosis, but is preferably 0.0001% by mass to 50% by mass, and more preferably 0.0001% by mass to 30% by mass, calculated as the amount of the compound represented by structural formula (1). The composition for preventing or ameliorating tissue fibrosis may consist solely of the agent for preventing or ameliorating tissue fibrosis.

[0056] The content of the agent for preventing or improving a decline in urine concentrating ability in the composition for preventing or improving a decline in urine concentrating ability is not particularly limited and can be appropriately adjusted depending on the form of the composition for preventing or improving a decline in urine concentrating ability, but is preferably 0.0001% by mass to 50% by mass, and more preferably 0.0001% by mass to 30% by mass, converted into the amount of the compound represented by structural formula (1). The composition for preventing or improving a decline in urine concentrating ability may consist solely of the agent for preventing or improving a decline in urine concentrating ability.

[0057] The content of the agent for preventing or ameliorating nocturnal polyuria in the composition for preventing or ameliorating nocturnal polyuria is not particularly limited and can be appropriately adjusted depending on the form of the composition for preventing or ameliorating nocturnal polyuria, but is preferably 0.0001% by mass to 50% by mass, and more preferably 0.0001% by mass to 30% by mass, converted into the amount of the compound represented by structural formula (1). The composition for preventing or ameliorating nocturnal polyuria may consist solely of the agent for preventing or ameliorating nocturnal polyuria.

[0058] <Other Components> Other components in the composition for preventing or improving renal function decline, composition for preventing or improving reduced urinary waste excretion, composition for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, composition for preventing or improving nephritis, composition for preventing or improving tissue fibrosis, composition for preventing or improving reduced urinary concentrating ability, or composition for preventing or improving nocturnal polyuria are not particularly limited, and may be used for preventing or improving at least one condition selected from the group consisting of the composition for preventing or improving renal function decline, composition for preventing or improving reduced urinary waste excretion, fatigue, lethargy, and anemia. The composition for preventing or improving renal function decline, the composition for preventing or improving tissue fibrosis, the composition for preventing or improving decreased urinary concentrating ability, or the composition for preventing or improving nocturnal polyuria can be appropriately selected depending on the form of use, and examples thereof include the same as the other ingredients described in the above-mentioned items for the agent for preventing or improving renal function decline, the agent for preventing or improving decreased urinary waste excretion, the agent for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, the agent for preventing or improving nephritis, the agent for preventing or improving tissue fibrosis, the agent for preventing or improving decreased urinary concentrating ability, and the agent for preventing or improving nocturnal polyuria. These may be used alone or in combination of two or more.

[0059] The content of the other ingredients in the composition for preventing or improving renal function decline, the composition for preventing or improving reduced excretion of waste products into urine, the composition for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, the composition for preventing or improving nephritis, the composition for preventing or improving tissue fibrosis, the composition for preventing or improving reduced urine concentrating ability, or the composition for preventing or improving nocturnal polyuria is not particularly limited and can be selected appropriately depending on the purpose.

[0060] <Aspects> The aspect of the composition for preventing or ameliorating renal function decline, composition for preventing or ameliorating reduced excretion of waste products into urine, composition for preventing or ameliorating at least one condition selected from the group consisting of fatigue, lethargy, and anemia, composition for preventing or ameliorating nephritis, composition for preventing or ameliorating tissue fibrosis, composition for preventing or ameliorating reduced urine concentrating ability, or composition for preventing or ameliorating nocturnal polyuria is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include pharmaceuticals, quasi-drugs, foods and beverages, etc. The composition for preventing or ameliorating renal function decline, the composition for preventing or ameliorating reduced urinary waste excretion, the composition for preventing or ameliorating at least one condition selected from the group consisting of fatigue, lethargy, and anemia, the composition for preventing or ameliorating nephritis, the composition for preventing or ameliorating tissue fibrosis, the composition for preventing or ameliorating reduced urinary concentrating ability, and the composition for preventing or ameliorating nocturnal polyuria of the present invention can be used daily, and by the action of the compound represented by structural formula (1) as the active ingredient, can extremely effectively exert various physiological activities including the effect of preventing or ameliorating renal function decline, the effect of preventing or ameliorating reduced urinary waste excretion, the effect of preventing or ameliorating at least one condition selected from the group consisting of fatigue, lethargy, and anemia, the effect of preventing or ameliorating nephritis, the effect of preventing or ameliorating tissue fibrosis, the effect of preventing or ameliorating reduced urinary concentrating ability, and the effect of preventing or ameliorating nocturnal polyuria.

[0061] The composition of the present invention for preventing or improving renal function decline, composition for preventing or improving reduced waste excretion into urine, composition for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, composition for preventing or improving nephritis, composition for preventing or improving tissue fibrosis, composition for preventing or improving reduced urine concentrating ability, and composition for preventing or improving nocturnal polyuria are preferably applied to humans, but can also be applied to animals other than humans (e.g., mice, rats, hamsters, dogs, cats, cows, pigs, monkeys, etc.) as long as their respective functional effects are achieved.

[0062] The method of use of the composition of the present invention for preventing or improving renal function decline, composition for preventing or improving reduced excretion of waste products into urine, composition for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, composition for preventing or improving nephritis, composition for preventing or improving tissue fibrosis, composition for preventing or improving reduced urine concentrating ability, or composition for preventing or improving nocturnal polyuria is not particularly limited and can be selected appropriately depending on the purpose, and examples include oral, parenteral, and topical administration, with oral administration being preferred.

[0063] Examples of the oral composition include the above-mentioned orally administered agents and foods and beverages. Here, foods and beverages refer to those that are unlikely to be harmful to human health and are taken orally or by administration through the digestive tract in normal social life, and are not limited to administrative classifications such as foods, medicines, and quasi-drugs. Therefore, the foods and beverages refer to a wide range of foods and beverages that are taken orally, such as general foods, health foods (functional foods and beverages), health functional foods (foods for specified health uses, foods with nutrient functions, and foods with functional claims), quasi-drugs, and medicines.

[0064] The type of the oral composition is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include beverages such as tea drinks, soft drinks, carbonated drinks, nutritional drinks, fruit drinks, lactic acid drinks, alcoholic drinks, coffee drinks, and coffee-containing soft drinks (including concentrated liquids and powders for adjusting these beverages); frozen desserts such as ice cream, ice sherbet, and shaved ice; noodles such as soba noodles, udon noodles, vermicelli, gyoza wrappers, shumai wrappers, Chinese noodles, and instant noodles; confectioneries such as candy, gummy candy, gummies, chocolate, candy tablets, snacks, biscuits, cookies, jelly, jam, cream, baked goods, and bread; seafood such as crab, salmon, clams, tuna, sardines, shrimp, bonito, mackerel, whale, oysters, saury, squid, ark shells, scallops, abalone, sea urchin, salmon roe, and tokobushi sea bream; processed seafood and livestock foods such as maboko, ham, and sausage; dairy products such as processed milk and fermented milk; oils and fats and oil-processed foods such as salad oil, tempura oil, margarine, mayonnaise, shortening, whipped cream, and dressing; condiments such as sauces and dressings; soups such as curry, stew, oyakodon (chicken and egg rice bowl), rice porridge, porridge, Chinese rice bowl, katsudon (pork cutlet bowl), tendon (tempura bowl), unadon (grilled eel bowl), hayashi rice, oden, mabo dolph, beef bowl, meat sauce, and egg soup, and retort pouch foods such as omelet rice, gyoza (dumplings), shumai (steamed dumplings), hamburger steak, and meatballs; prepared dishes such as salads and pickles; health, beauty, and nutritional supplements in various forms; pharmaceuticals and quasi-drugs such as tablets, powders, capsules, granules, extracts, syrups, drinks, lozenges, and mouthwash; and oral fresheners and toothpastes used in the mouth.

[0065] The method for producing the composition for preventing or ameliorating renal function decline, composition for preventing or ameliorating reduced urinary waste excretion, composition for preventing or ameliorating at least one condition selected from the group consisting of fatigue, lethargy, and anemia, composition for preventing or ameliorating nephritis, composition for preventing or ameliorating tissue fibrosis, composition for preventing or ameliorating reduced urinary concentrating ability, or composition for preventing or ameliorating nocturnal polyuria is not particularly limited, and can be appropriately selected depending on the form in which the composition for preventing or ameliorating renal function decline, composition for preventing or ameliorating reduced urinary waste excretion, composition for preventing or ameliorating at least one condition selected from the group consisting of fatigue, lethargy, and anemia, composition for preventing or ameliorating nephritis, composition for preventing or ameliorating tissue fibrosis, composition for preventing or ameliorating reduced urinary concentrating ability, or composition for preventing or ameliorating nocturnal polyuria is to be used.

[0066] The amount, period of use, interval of use, etc. of the composition for preventing or improving renal function decline, composition for preventing or improving reduced excretion of waste products into urine, composition for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, composition for preventing or improving nephritis, composition for preventing or improving tissue fibrosis, composition for preventing or improving reduced urine concentrating ability, or composition for preventing or improving nocturnal polyuria are not particularly limited and can be selected appropriately depending on the purpose.

[0067] As described above, the agent for preventing or ameliorating renal function decline and the composition for preventing or ameliorating renal function decline of the present invention have excellent preventive or ameliorating effects on renal function decline. Therefore, the present invention also relates to a method for preventing or ameliorating renal function decline, which comprises administering to an individual at least one selected from the group consisting of the agent for preventing or ameliorating renal function decline and the composition for preventing or ameliorating renal function decline. The present invention also relates to the use of a compound represented by structural formula (1) for use in preventing or ameliorating renal function decline.

[0068] As described above, the agent for preventing or improving reduced urinary waste excretion and the composition for preventing or improving reduced urinary waste excretion of the present invention have excellent effects of preventing or improving reduced urinary waste excretion. Therefore, the present invention also relates to a method for preventing or improving reduced urinary waste excretion, comprising administering to an individual at least one selected from the group consisting of the agent for preventing or improving reduced urinary waste excretion and the composition for preventing or improving reduced urinary waste excretion. The present invention also relates to the use of a compound represented by structural formula (1) for preventing or improving reduced urinary waste excretion.

[0069] As described above, the agent for preventing or improving at least one condition selected from the group consisting of fatigue, fatigue, and anemia and the composition for preventing or improving at least one condition selected from the group consisting of fatigue, fatigue, and anemia of the present invention have excellent effects of preventing or improving at least one condition selected from the group consisting of fatigue, fatigue, and anemia. Therefore, the present invention also relates to a method for preventing or improving at least one condition selected from the group consisting of the agent for preventing or improving at least one condition selected from the group consisting of fatigue, fatigue, and anemia and the composition for preventing or improving at least one condition selected from the group consisting of fatigue, fatigue, and anemia to an individual. The present invention also relates to the use of a compound represented by structural formula (1) for use in preventing or improving at least one condition selected from the group consisting of fatigue, fatigue, and anemia.

[0070] As described above, the agent for preventing or ameliorating nephritis and the composition for preventing or ameliorating nephritis of the present invention have excellent nephritis prevention or amelioration effects. Therefore, the present invention also relates to a method for preventing or ameliorating nephritis, which comprises administering to an individual at least one selected from the group consisting of the agent for preventing or ameliorating nephritis and the composition for preventing or ameliorating nephritis. The present invention also relates to the use of a compound represented by the structural formula (1) for use in preventing or ameliorating nephritis.

[0071] As described above, the tissue fibrosis prevention or amelioration agent and composition for preventing or ameliorating tissue fibrosis of the present invention have excellent tissue fibrosis prevention or amelioration effects. Therefore, the present invention also relates to a method for preventing or ameliorating tissue fibrosis, comprising administering to an individual at least one selected from the group consisting of the tissue fibrosis prevention or amelioration agent and composition for preventing or ameliorating tissue fibrosis. The present invention also relates to the use of a compound represented by structural formula (1) for use in preventing or ameliorating tissue fibrosis.

[0072] As described above, the agent for preventing or ameliorating a decline in urinary concentrating ability and the composition for preventing or ameliorating a decline in urinary concentrating ability of the present invention have excellent effects of preventing or ameliorating a decline in urinary concentrating ability. Therefore, the present invention also relates to a method for preventing or ameliorating a decline in urinary concentrating ability, which comprises administering to an individual at least one selected from the group consisting of the agent for preventing or ameliorating a decline in urinary concentrating ability and the composition for preventing or ameliorating a decline in urinary concentrating ability. The present invention also relates to the use of a compound represented by structural formula (1) for preventing or ameliorating a decline in urinary concentrating ability.

[0073] As described above, the agent for preventing or ameliorating nocturnal polyuria and the composition for preventing or ameliorating nocturnal polyuria of the present invention have excellent effects in preventing or ameliorating nocturnal polyuria. Therefore, the present invention also relates to a method for preventing or ameliorating nocturnal polyuria, which comprises administering to an individual at least one selected from the group consisting of the agent for preventing or ameliorating nocturnal polyuria and the composition for preventing or ameliorating nocturnal polyuria. The present invention also relates to the use of a compound represented by structural formula (1) for use in preventing or ameliorating nocturnal polyuria.

[0074] Test examples and formulation examples of the present invention will be explained below, but the present invention is not limited to these test examples and formulation examples.

[0075] Test Example 1 Aristolochic acid (hereinafter, sometimes referred to as "AA") was administered to mice to induce aristolochic acid nephropathy (hereinafter, sometimes referred to as "AA model"), and the effect of ingestion of the compound represented by the above-mentioned structural formula (1) was investigated.

[0076] <Preparation of AA model> AA (2.5 mg / kg) was intraperitoneally administered to 8-week-old male C57BL / 6J mice (Charles River Japan) once every 3 days for 3 weeks. After that, 4 weeks were allowed to pass to allow kidney tissue fibrosis to progress. AA was dissolved in dimethyl sulfoxide, and then saline was added before intraperitoneal administration.

[0077] The test was conducted in the following three groups. - AA group: A normal diet prepared according to AIN93G was administered starting two days before AA administration. - Compound represented by structural formula (1) group: The normal diet used in AA group was replaced with a compound represented by structural formula (1) diet containing 1% by mass of the compound represented by structural formula (1). - Control group: The same as AA group except that AA was not administered.

[0078] <Gene Expression Analysis> Gene expression analysis in the kidneys of the mice subjected to the above test was performed as follows. Total RNA was prepared from the collected kidneys using an RNeasy lipid tissue mini kit (Qiagen). Mouse kidneys were excised and homogenized with Qiazol (Qiagen). 200 μL of chloroform was added, vortexed for 20 seconds, and then left at room temperature for 3 minutes and centrifuged (12,000 G, 4°C, 15 minutes). 300 μL of the supernatant was collected, an equal volume of 70% ethanol was added, and the mixture was mixed by inversion. The entire volume was then transferred to a spin column and centrifuged (12,000 G, 4°C, 15 seconds), and the flow-through fraction was removed. 700 μL of buffer RW was added and centrifuged (12,000 G, 4°C, 15 seconds) to remove the flow-through fraction. Next, 500 μL of buffer RPE, to which ethanol had been added, was added to the column and centrifuged (12,000 G, 4°C, 15 seconds) to remove the flow-through fraction. RNase-free water was then added dropwise and centrifuged (12,000 G, 4°C, 1 minute) to recover the RNA.

[0079] The concentration of the recovered total RNA was measured using Nanodrop 2000 (Thermo), and reverse transcription was carried out using RevaTra Ace RT (TOYOBO). ２ THUNDERBIRD after dilution with O ＴＭ Gene expression analysis was performed using SYBR (registered trademark) qPCR Mix (TOYOBO Corporation).

[0080] Figures 1 to 3 show the results of gene expression analysis. Figure 1 shows the results of analyzing the expression level of the mRNA of the FN1 gene encoding fibronectin (hereinafter, sometimes referred to as "Fn1 mRNA"). Figure 2 shows the results of analyzing the expression level of the mRNA of the COL1A1 gene encoding the pro-α1 chain of type I collagen (hereinafter, sometimes referred to as "coll1a1 mRNA"). Figure 3 shows the results of analyzing the expression level of the mRNA of the COL3A1 gene encoding the α1 chain of type III collagen (hereinafter, sometimes referred to as "coll3a1 mRNA"). In Figures 1 to 3, (I) shows the results for the control group, (II) shows the results for the AA group, and (III) shows the results for the group of compounds represented by structural formula (1).

[0081] In a model in which aristolochic acid induces chronic interstitial nephritis and toxic renal damage, administration of a compound represented by structural formula (1) was confirmed to suppress the increased expression of collagen and fibronectin, markers of fibrosis. Increased expression of type I or type III collagen has been observed in many fibrotic conditions, such as liver and kidney fibrosis and systemic sclerosis. Fibronectin is known to promote cell differentiation as a cell adhesion molecule and to have many functions for maintaining normal vital functions, such as adhesion to the extracellular matrix, formation and maintenance of connective tissue, and wound healing. Furthermore, it is known that renal tissue containing fibroblasts with elevated fibronectin expression exhibits severe fibrosis and impaired renal function.

[0082] (Test Example 2) Adenine was administered to mice to induce adenine-induced nephropathy (hereinafter, sometimes referred to as "adenine nephritis model"), and the effect of ingestion of the compound represented by the above structural formula (1) was investigated.

[0083] <Preparation of an adenine nephritis model> Seven-week-old male ICR mice (Charles River Japan) were used. To induce adenine-induced nephropathy, a diet consisting of a normal diet based on AIN93G and adenine (Wako) mixed at 0.2% by weight (hereinafter sometimes referred to as the "adenine diet") was used. Renal damage was induced by loading the mice with the adenine diet for two weeks, and the mice were subjected to various analyses.

[0084] The test was conducted in the following three groups. Adenine group: Subjects were given the above-mentioned adenine diet for two weeks. Compound represented by structural formula (1) group: Subjects were given a diet containing the above-mentioned adenine diet plus the compound represented by structural formula (1) at 1% by mass for two weeks. Control group: Subjects were given a normal diet similar to AIN93G for two weeks.

[0085] <Serum Analysis> The mice subjected to the above test were dissected, and blood was collected from a vein, and the urea nitrogen concentration and creatinine concentration were measured using an automatic serum chemistry analyzer (manufactured by Beckman Coulter).

[0086] The results of serum analysis are shown in Figures 4 and 5. Figure 4 shows the analysis results of urea nitrogen concentration, and Figure 5 shows the analysis results of creatinine concentration. In Figures 4 and 5, (i) shows the results for the control group, (ii) shows the results for the adenine group, and (iii) shows the results for the compound group represented by structural formula (1).

[0087] <Gene Expression Analysis> In the same manner as in Test Example 1, gene expression analysis was carried out in the kidneys of the mice subjected to the above test.

[0088]

[0049] Figures 6 to 11 show the results of gene expression analysis. Figure 6 shows the results of analyzing the expression level of Fn1 mRNA, Figure 7 shows the results of analyzing the expression level of coll1a1 mRNA, Figure 8 shows the results of analyzing the expression level of CCL2 gene mRNA (hereinafter, sometimes referred to as "ccl2 mRNA"), Figure 9 shows the results of analyzing the expression level of coll3a1 mRNA, Figure 10 shows the results of analyzing the expression level of Saa3 gene mRNA (hereinafter, sometimes referred to as "Saa3 mRNA"), and Figure 11 shows the results of analyzing the expression level of EMR1 gene mRNA (hereinafter, sometimes referred to as "Emr1 mRNA"). In Figures 6 to 11, (i) shows the results for the control group, (ii) shows the results for the adenine group, and (iii) shows the results for the compound group represented by structural formula (1).

[0089] Azan-Mallory staining. Kidney tissue was removed by dissection and fixed overnight in 4% paraformaldehyde. After fixation, the tissue was transferred to a dehydration cassette and washed with water for 40 minutes. Then, dehydration was initiated by immersion in 70% ethanol for over 24 hours. The tissue was then dehydrated using 80-100% ethanol, and then infiltrated with xylene and paraffin. After paraffin substitution, the tissue was embedded in paraffin. Kidney paraffin sections prepared using a microtome were immersed in three baths of 100% xylene for 10 minutes each, dehydrated with 100% ethanol through 70% ethanol, and then rinsed in running water for 10 minutes. After immersion in 0.5% Orange G solution for 15 minutes, the sections were rinsed in tap water for 6 seconds. The sections were then immersed in two baths of distilled water for 6 seconds each, followed by immersion in Azocarmine G solution (Muto Chemicals) at 60°C for 45 minutes. After immersion in 45°C tap water for 5 minutes, the specimen was immersed in 35°C tap water for 3 minutes and then rinsed. After immersion in a 5% aqueous phosphotungstic acid solution for 60 minutes, the specimen was rinsed with tap water and then immersed in aniline blue dye solution for 10 minutes. The specimen was immersed in three tanks of 100% ethanol for 3 seconds each, and then in three tanks of 100% xylene for 10 minutes each, followed by microscopic observation. A 0.5% Orange G solution was prepared by adding one drop of Orange G (Fujifilm Wako Pure Chemical Industries) to 50 mL of acetic acid. A 5% aqueous phosphotungstic acid solution was prepared by diluting phosphotungstic acid hydrate (MP Biomedicals). The aniline blue staining solution was prepared by mixing 0.4 g of Aniline Blue Water Soluble (Fujifilm Wako Pure Chemical Industries, Ltd.), 100 mL of deionized water, and 8 mL of acetic acid, and then boiling the mixture in a water bath for 20 to 30 minutes.

[0090] The results of Azan-Mallory staining are shown in Figures 12 and 13. Figure 12 shows the results for the whole kidney, and Figure 13 shows an enlarged view of the results of Figure 12 (upper row (HE): HE staining, lower row (AZM): Azan-Mallory staining). In Figures 12 and 13, (i) shows the results for the control group, (ii) for the adenine group, and (iii) for the group of the compound represented by structural formula (1).

[0091] In a model in which an adenine diet produces excess purines, resulting in renal damage due to urinary tract obstruction caused by urinary stones, administration of the compound represented by structural formula (1) was confirmed to suppress increases in urea nitrogen and creatinine, which are renal function markers, as well as increases in the expression of collagen and fibronectin, which are fibrosis markers, and increases in the expression of CCL2, Saa3, and EMR1, which are inflammatory markers.

[0092] As shown in the above test examples, the compound represented by structural formula (1) is useful for preventing or ameliorating nephritis.

[0093] Furthermore, the ingestion of the compound represented by structural formula (1) inhibited increases in urea nitrogen and creatinine, which are markers of renal function, confirming that the compound represented by structural formula (1) is useful for preventing or ameliorating decline in renal function. Furthermore, since the compound represented by structural formula (1) can prevent or ameliorate decline in renal function, it is also useful for preventing or ameliorating decline in urinary excretion of waste products and for preventing or ameliorating at least one condition selected from the group consisting of fatigue, lethargy, and anemia.

[0094] Furthermore, ingestion of the compound represented by structural formula (1) inhibited the increase in expression of factors involved in fibrosis not only in the kidney but also in other tissues, such as collagen and fibronectin, demonstrating that the compound represented by structural formula (1) is useful for preventing or ameliorating tissue fibrosis. Furthermore, because the compound represented by structural formula (1) can prevent or ameliorate tissue fibrosis, it is also useful for preventing or ameliorating a decrease in urine concentrating ability and nocturnal polyuria.

[0095] Formulation Example 1 Tablets having the following composition were produced by a conventional method: Compound represented by the structural formula (1) 5.0 mg Dolomite 83.4 mg (containing 20% ​​calcium and 10% magnesium) Casein phosphopeptide 16.7 mg Vitamin C 33.4 mg Maltitol 136.8 mg Collagen 12.7 mg Sucrose fatty acid ester 12.0 mg

[0096] Formulation Example 2 An oral liquid formulation having the following composition was produced by a conventional method. <Composition in 1 ampoule (100 mL per ampoule)> Compound represented by the structural formula (1) 0.3% by mass Sorbitol 12.0% by mass Sodium benzoate 0.1% by mass Flavoring 1.0% by mass Calcium sulfate 0.5% by mass Purified water Balance

[0097] (Formulation Example 3) A coffee drink having the following composition was produced by a conventional method: 0.1% by mass of the compound represented by the structural formula (1) 40.0% by mass of coffee extract (L (lightness) = 20, Brix = 3) 2.0% by mass of maltitol an appropriate amount of flavoring, and the balance water.

[0098] Formulation Example 4 Capsules having the following composition were produced by a conventional method. No. 1 hard gelatin capsules were used. <Composition per capsule> Compound represented by the structural formula (1) 30.0 mg Corn starch 70.0 mg Lactose 80.0 mg Calcium lactate 10.0 mg Hydroxypropyl cellulose (HPC-L) 10.0 mg

[0099] This application claims priority based on Japanese Patent Application No. 2024-037372, filed on March 11, 2024, the entire contents of which are incorporated herein by reference.

Claims

1. An agent for preventing or ameliorating renal dysfunction, comprising a compound represented by the following structural formula (1):

2. An agent for preventing or improving decreased excretion of waste products into urine, characterized by containing a compound represented by the following structural formula (1):

3. An agent for preventing or improving at least one condition selected from the group consisting of fatigue, lethargy, and anemia, characterized by containing a compound represented by the following structural formula (1):

4. A preventive or ameliorating agent for nephritis, comprising a compound represented by the following structural formula (1):

5. An agent for preventing or ameliorating tissue fibrosis, comprising a compound represented by the following structural formula (1):

6. The agent for preventing or ameliorating tissue fibrosis according to claim 5, wherein the tissue is kidney tissue.

7. An agent for preventing or improving a decrease in urine concentrating ability, characterized by containing a compound represented by the following structural formula (1):

8. A preventive or ameliorating agent for nocturnal polyuria, comprising a compound represented by the following structural formula (1):

9. A composition for preventing or improving renal function decline, comprising the agent for preventing or improving renal function decline described in claim 1.

10. A composition for preventing or improving decreased urinary waste excretion, comprising the agent for preventing or improving decreased urinary waste excretion as described in claim 2.

11. A composition for preventing or improving at least one condition selected from the group consisting of fatigue, fatigue, and anemia, characterized by comprising the agent for preventing or improving at least one condition selected from the group consisting of fatigue, fatigue, and anemia described in claim 3.

12. A composition for preventing or ameliorating nephritis, comprising the agent for preventing or ameliorating nephritis described in claim 4.

13. A composition for preventing or ameliorating tissue fibrosis, comprising the agent for preventing or ameliorating tissue fibrosis according to claim 5 or 6.

14. A composition for preventing or improving a decrease in urine concentrating ability, comprising the agent for preventing or improving a decrease in urine concentrating ability described in claim 7.

15. A composition for preventing or ameliorating nocturnal polyuria, comprising the agent for preventing or ameliorating nocturnal polyuria described in claim 8.

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