Functional protective agent for organs or tissues

Abstract

The present invention addresses the problem of providing a low-molecular-weight compound which is highly safe when ingested and which has an effect of preventing or ameliorating organ or tissue dysfunction. A prophylactic or ameliorating agent for organ or tissue dysfunction is used, said prophylactic or ameliorating agent comprising one or more compounds selected from the group consisting of compounds represented by formula (I) and physiologically acceptable salts thereof. In the formula, each of R and R independently represents H or a C1-C6 alkyl group; r and R each independently represent: H; alternatively, a C1-C6 alkyl group may have at least one group selected from the group consisting of a hydroxyl group, a phenyl group, a hydroxyphenyl group, an S-CH group, an NHgroup, a carboxyl group, a carbamoyl group, a guanidyl group, and a nitrogen-containing heteroaryl group; r and R may form a ring via a C2-C4 alkylene group which may have a hydroxyl group; and R and R may form a ring via a C2-C4 alkylene group which may have a hydroxyl group.

Description

TECHNICAL FIELD

[0001] The present application relates to a prophylactic or improving agent for a functional decline of an organ or a tissue (hereinafter, sometimes referred to as "organ or the like"), and the like, which contains a specific 2,5-diketopiperazine or a derivative thereof (hereinafter, sometimes referred to as "diketopiperazine compound of the present application") as an effective ingredient. BACKGROUND

[0002] The kidney is an extremely important organ that maintains homeostasis of the organism by regulating the concentration of body fluid components through excretion and reabsorption, and also has a function as an endocrine organ that produces and secretes physiologically active substances such as active vitamin D, erythropoietin, and renin. If the function of the kidney, which bears such an important role, is impaired, it is in a state of functional decline, and various disorders are induced, resulting in a variety of kidney diseases. Among these kidney diseases, there are also kidney diseases closely related to diabetes, obesity, and abnormal lipid metabolism, and in particular, diabetic nephropathy, which is a kidney disease that occurs as a complication of diabetes, is difficult to stop even if diabetes is strictly controlled after being diagnosed as a kidney disease, and many cases of renal failure are trapped, and the number of patients is not small.

[0003] 2,5-diketopiperazine (also referred to as "cyclic dipeptide") is a dipeptide having a cyclic structure generated by dehydration condensation of amino and carboxyl groups present at the terminal of a straight-chain dipeptide, and in recent years, various physiological activities thereof have been attracting attention. For example, it has been reported that a specific diketopiperazine has an effect of improving the moisturizing function of the skin (Patent Literature 1), has an effect of activating or inhibiting sympathetic nerve activity in the skin (Patent Literature 2), and has an effect of dilating blood vessels (Patent Literature 3). However, it has not been known until now that 2,5-diketopiperazine is effective against a functional decline of an organ or the like.

[0004] [Patent Literature]

[0005] [Patent Literature]

[0006] [Patent Literature 1] International Publication No. 2016 / 063901 pamphlet

[0007] [Patent Literature 2] Japanese Patent Application Publication No. 2022-48337

[0008] [Patent Literature 3] Japanese Patent Application Publication No. 2018-16612 SUMMARY

[0009] [Problems to be Solved by the Invention]

[0010] The present application relates to a prophylactic or improving agent for a functional decline of an organ or a tissue (hereinafter, sometimes referred to as "organ or the like"), and the like, which contains a specific 2,5-diketopiperazine or a derivative thereof (hereinafter, sometimes referred to as "diketopiperazine compound of the present application") as an effective ingredient.

[0011] [Problems to be Solved by the Invention]

[0012] The present inventors have conducted intensive studies in order to solve the above-described problems. In the course of the studies, it has been found that a specific 2, 5-diketopiperazine has an effect of improving a low function of an organ or the like due to renal failure, diabetes, or the like, and thus the present application has been completed.

[0013] That is, the present application is as described below.

[0014] [1] A prophylactic or improving agent for a low function of an organ or tissue, comprising one or two or more compounds selected from the group consisting of a compound represented by the following formula (I) and a physiologically tolerated salt thereof.

[0015] [Chemical Formula 1]

[0016]

[0017] In the formula (I), R 1 and R 2 each independently represent H or C1-C6 alkyl;

[0018] R 3 and R 4 each independently represent H; or C1-C6 alkyl which can have at least one group selected from the group consisting of a hydroxyl group, a phenyl group, a hydroxyphenyl group, an S-CH3 group, an NH2 group, a carboxyl group, a carbamoyl group, a guanidino group, and a nitrogen-containing heteroaryl group;

[0019] R 1 and R 3 may form a ring via a C2-C4 alkylene group which can have a hydroxyl group;

[0020] R 2 and R 4 may form a ring via a C2-C4 alkylene group which can have a hydroxyl group.

[0021] [2] The prophylactic or improving agent according to the above [1], the compound represented by the formula (I) being a compound represented by the following formula (I-1).

[0022] [Chemical Formula 2]

[0023]

[0024] [3] The prophylactic or improving agent according to the above [1] or [2], the organ being a kidney or a liver.

[0025] [4] The prophylactic or improving agent according to any one of the above [1] to [3], for preventing or improving a low function of an organ or tissue of a mammal suffering from renal failure or diabetes.

[0026] [5] The preventive or improving agent as described in any one of [1] to [4] above is a medicine, pet food or food.

[0027] Furthermore, as other embodiments of the present invention, examples include: a method for preventing or improving (treating) organ dysfunction, including the step of ingesting (applying) the diketopiramate compound of the present invention to a mammal requiring prevention or improvement (treatment) of organ dysfunction; the diketopiramate compound of the present invention used in the prevention or improvement (treatment) of organ dysfunction; and the use of the diketopiramate compound of the present invention in the manufacture of an agent for the prevention or improvement (treatment) of organ dysfunction.

[0028] [Invention Effects]

[0029] The diketopiperazine compounds in this case have the effect of improving organ dysfunction caused by diseases such as renal failure and diabetes. Furthermore, because these diketopiperazine compounds include 2,5-diketopiperazines derived from food, their safety upon ingestion is relatively high. Therefore, ingestion of these diketopiperazine compounds can protect organ function, prevent or treat diseases such as renal failure and diabetes, or reduce the risk of these diseases becoming severe. Attached Figure Description

[0030] [ Figure 1 The figure [] shows the results (mean ± standard deviation) of the measurement of uremic substance (creatinine) concentration in plasma samples taken at week 2 post-feeding in Example 1 for three groups (normal feeding group [“Control” in the figure], adenine-fed control group [“RF” in the figure], and adenine-fed cGP group [“RF-c(GP)” in the figure]). “*” and “**” in the figure indicate statistically significant differences according to Dunnett’s test (p < 0.05 and p < 0.01, respectively).

[0031] [ Figure 2 [Figure 1] shows the results of the analysis of kidney tissue from the above three groups after 2 weeks of feeding in Example 1. Figure 2 Figure A shows the results of the analysis of the percentage of renal tubules in the renal cortex (mean ± standard deviation). "**" in the figure indicates a statistically significant difference according to the Dunnett test (p < 0.01). Figure 2 B is Figure 2 A representative example of the renal tissue images used in analysis A. Darker areas represent normal renal parenchyma, while lighter areas represent fibrotic regions.

[0032] [ Figure 3ALT (alanine aminotransferase) concentration (A) and total cholesterol concentration (B) in the "plasma sample at 2 weeks after feeding" of the 3 groups (normal feeding group ["Ctrl" in the figure], adenine feeding control group ["RF" in the figure], and adenine feeding cGP group ["RF-c(GP)" in the figure]) in Example 1. The results (average ± standard deviation) of measurement of the concentrations of ALT and total cholesterol are shown. "*" in the figure indicates a statistically significant difference (p<0.05) by Dunnett's test. Figure 3 A) and total cholesterol concentration (B) in the "plasma sample at 2 weeks after feeding" of the 3 groups (normal feeding group ["Ctrl" in the figure], adenine feeding control group ["RF" in the figure], and adenine feeding cGP group ["RF-c(GP)" in the figure]) in Example 1. The results (average ± standard deviation) of measurement of the concentrations of ALT and total cholesterol are shown. "*" in the figure indicates a statistically significant difference (p<0.05) by Dunnett's test. Figure 3 B) and total cholesterol concentration (B) in the "plasma sample at 2 weeks after feeding" of the 3 groups (normal feeding group ["Ctrl" in the figure], adenine feeding control group ["RF" in the figure], and adenine feeding cGP group ["RF-c(GP)" in the figure]) in Example 1. The results (average ± standard deviation) of measurement of the concentrations of ALT and total cholesterol are shown. "*" in the figure indicates a statistically significant difference (p<0.05) by Dunnett's test.

[0033] [ Figure 4 ] is a graph showing the results of analysis of liver tissues of the 2 groups (diabetes model normal feeding group ["dbdb" in the figure] and diabetes model cGP group ["dbdb-c(GP)" in the figure]) after 6 weeks of feeding using hematoxylin-eosin staining (HE) method in Example 2. Fat droplets appear as white, patchy within the tissues.

[0034] [ Figure 5 ] is a graph showing the results of measurement of creatinine concentration in the "plasma sample at 6 weeks after feeding" of the 4 groups (wild type normal feeding group ["Normal" in the figure], wild type cGP group ["Normal-c(GP)" in the figure], diabetes model normal feeding group ["dbdb" in the figure], and diabetes model cGP group ["dbdb-c(GP)" in the figure]) in Example 2. "*", "**", and "***" in the figure indicate statistically significant differences (p<0.05, p<0.01, and p<0.001) by Dunnett's test, respectively.

[0035] [ Figure 6 ] is a graph showing the results of measurement of the concentrations of 3 substances (creatinine [A], phenyl sulfate [B], and Ac6Lys [C]) in the "plasma sample at 0 weeks after feeding" ( "0 weeks" in the figure) and the "plasma sample at 6 weeks after feeding" ( "6 weeks" in the figure) of the diabetes model cGP group in Example 2. "*" in the figure indicates a statistically significant difference (p<0.05) by paired t-test. Figure 6 A], phenyl sulfate [B], and Ac6Lys [C]) in the "plasma sample at 0 weeks after feeding" ( "0 weeks" in the figure) and the "plasma sample at 6 weeks after feeding" ( "6 weeks" in the figure) of the diabetes model cGP group in Example 2. "*" in the figure indicates a statistically significant difference (p<0.05) by paired t-test. Figure 6 B], and Ac6Lys [C]) in the "plasma sample at 0 weeks after feeding" ( "0 weeks" in the figure) and the "plasma sample at 6 weeks after feeding" ( "6 weeks" in the figure) of the diabetes model cGP group in Example 2. "*" in the figure indicates a statistically significant difference (p<0.05) by paired t-test. Figure 6 C], and Ac6Lys [C]) in the "plasma sample at 0 weeks after feeding" ( "0 weeks" in the figure) and the "plasma sample at 6 weeks after feeding" ( "6 weeks" in the figure) of the diabetes model cGP group in Example 2. "*" in the figure indicates a statistically significant difference (p<0.05) by paired t-test.

[0036] [ Figure 7 ] is a graph showing the results of measurement of 2 uremic substances (1-methyladenosine [m1A] [A] and indoxyl sulfate [B]) in the plasma sample of the 2 groups (diabetes model normal feeding group ["dbdb" in the figure] and diabetes model cGP group ["dbdb-c(GP)" in the figure]) after 5 weeks of feeding in Example 3. "*" in the figure indicates a statistically significant difference (p<0.05) by Dunnett's test. Figure 7A] and trimethylamine oxide [TMAO] [B] Figure 7 B) are shown. In the figure, "**" indicates a statistically significant difference (p<0.01) by an unpaired t-test. DETAILED DESCRIPTION

[0037] The prophylactic or ameliorative agent of the present application is an agent (hereinafter, sometimes referred to as "the prophylactic / ameliorative agent of the present application") which contains one or two or more compounds selected from the diketopiperazine compounds of the present application, i.e., compounds of the following formula (I) and physiologically tolerated salts thereof, and is limited to an agent for preventing or ameliorating a functional insufficiency of an organ or tissue.

[0038] [Chemical Formula 3]

[0039]

[0040] In formula (I),

[0041] R 1 and R 2 each independently represents H or C1-C6 alkyl;

[0042] R 3 and R 4 each independently represents H; or C1-C6 alkyl which can also have at least one group selected from the group consisting of a hydroxyl group, a phenyl group, a hydroxyphenyl group, an S-CH3 group, an NH2 group, a carboxyl group, a carbamoyl group, a guanidino group, and a nitrogen-containing heteroaryl group (i.e., C1-C6 alkyl; or C1-C6 alkyl having at least one group selected from the group consisting of a hydroxyl group, a phenyl group, a hydroxyphenyl group, an S-CH3 group, an NH2 group, a carboxyl group, a carbamoyl group, a guanidino group, and a nitrogen-containing heteroaryl group);

[0043] R 1 and R 3 may form a ring via a C2-C4 alkylene group which can also have a hydroxyl group;

[0044] R 2 and R 4 may form a ring via a C2-C4 alkylene group which can also have a hydroxyl group.

[0045] In formula (I), as the C1-C6 alkyl group of R 1 to R 4 or the C1-C6 alkyl group of R 2 , for example, there can be mentioned a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, an n-butyl group, a sec-butyl group, an iso-butyl group, a t-butyl group, an n-pentyl group, an n-hexyl group, and the like.

[0046] In formula (I), as R 3 and R4 A nitrogen-containing heteroaromatic group having one of the substituents of C1-C6 alkyl groups, includes a 5- to 7-membered monocyclic or polycyclic aromatic heterocycle having 1 to 4 nitrogen atoms as heteroatoms, and a condensed ring formed by condensation of a benzene ring and a 5- to 7-membered heterocycle having 1 to 4 nitrogen atoms as heteroatoms. For example, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, pyrrolyl, quinolyl, indolyl, benzimidazolyl, pyridazinyl, triazinyl, and the like can be given.

[0047] The diketopiperazine compound of the present application includes stereoisomers (enantiomers, etc.), tautomers, solvates, hydrates, and the like, and mixtures thereof.

[0048] As the physiologically acceptable salt of the compound represented by the above formula (I), for example, inorganic salts such as sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, and the like; organic salts such as acetate, propionate, decanoate, octanoate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, fumarate, maleate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfonate, xylene sulfonate, phenylacetic acid, phenylpropionic acid, phenylbutyric acid, citrate, lactate, hydroxybutyric acid, glycolate, malate, tartarate, and the like; alkali metal salts such as sodium salt, potassium salt, and the like; alkaline earth metal salts such as calcium salt, magnesium salt, and the like; ammonium salt; and the like can be given.

[0049] As the diketopiperazine compound of the present application, specifically, a compound represented by the following formula (I-1) (cGP [cyclo(glycyl-proline)]), a compound represented by formula (I-2) (cGS [cyclo(glycyl-serine)]), a compound represented by formula (I-3) (cGL [cyclo(glycyl-leucine)]), a compound represented by formula (I-4) (cGE [cyclo(glycyl-glutamic acid)]), a compound represented by formula (I-5) (cGA [cyclo(glycyl-alanine)]), or a compound represented by formula (I-6) (cGF [cyclo(glycyl-phenylalanine)]), since the effects thereof are confirmed in the following Examples, a compound represented by the following formula (I-1) is preferable.

[0050] [Chemical 4]

[0051]

[0052] [Chemical 5]

[0053]

[0054] [Chemical Formula 6]

[0055]

[0056] [Chemical Formula 7]

[0057]

[0058] [Chemical Formula 8]

[0059]

[0060] [Chemical Formula 9]

[0061]

[0062] The diketopiperazine compound of the present application can be used either as a commercially available product or as a substance synthesized by a publicly known method.

[0063] As a method for synthesizing the diketopiperazine compound of the present application by a publicly known method, for example, there can be mentioned a method in which a dipeptide represented by the following formula (II) is heated in an organic solvent while removing water by distillation.

[0064] [Chemical Formula 10]

[0065]

[0066] In formula (II), R 1 ~ R 4 have the meanings of R 1 ~ R 4 in formula (I), respectively.

[0067] As the above organic solvent, there can be mentioned, for example, acetonitrile, allyl alcohol, benzene, benzyl alcohol, n-butanol, 2-butanol, t-butanol, butyl acetate, carbon tetrachloride, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethane, diethyl acetal, dimethyl acetal, ethyl acetate, heptane, methyl isobutyl ketone, 3-pentanol, toluene, xylene and the like, as long as it forms a low-boiling azeotrope with water.

[0068] The temperature at the time of the reaction is usually from 50 to 200°C, and preferably from 80 to 150°C. As the pH at which the cyclization is performed, there can be mentioned usually from 2 to 9, and preferably from 3 to 7.

[0069] The dipeptide represented by formula (II) can be obtained, for example, by a dehydration condensation reaction of glycine with another amino acid or a derivative thereof.

[0070] Further, according to the method described in Japanese Patent No. 5456876, by heating an aqueous solution containing a linear dipeptide or a linear tripeptide at 70 to 100°C under a pressure of 0.5 MPa or less, it is also possible to produce.

[0071] It is known that 2,5-diketopiperazines are contained in processed products related to fruits, fermentation processes, or heating processes such as blackcurrants, cordyceps, cheese, stewed beef, chicken essence, and can be obtained as a part of an extract or a concentrate from food.

[0072] In the present specification, as mammals, there can be mentioned humans, non-human mammals (for example, monkeys; mice; rats; pets such as dogs, cats, etc.; domestic animals such as rabbits, pigs, horses, cows, sheep, goats, deer, etc.), and the like.

[0073] In the case where a non-human mammal ingests or a non-human mammal is administered the preventive / improving agent of the present application, the diketopiperazine compound of the present application can be used alone as a feed for non-human mammals, or an additive can be further mixed to be used in the form of a composition (i.e., a feed composition for non-human mammals). Further, in the case where a non-human mammal or a human ingests or is administered the preventive / improving agent of the present application, the diketopiperazine compound of the present application can be used alone as a diet or a pharmaceutical (preparation), or an additive can be further mixed to be used in the form of a composition (a diet composition or a pharmaceutical composition). As the diet, there can be mentioned, for example, health foods (functional foods, nutritional supplementary foods, health supplementary foods, nutritionally enhanced foods, nutritionally adjusted foods, supplements, etc.), health function foods (specific health foods, nutrition function foods, functional labeled foods, etc.), Chinese medicines. As the preventive / improving agent of the present application, a pharmaceutical, a pet feed, or a diet is preferred.

[0074] In the present specification, as "organs or tissues", there can be mentioned, for example, large intestines (colon or rectum), stomach, liver, heart, brain, spinal cord, lung, esophagus, duodenum, small intestine, skin, prostate, bladder, uterus, kidney, pancreas, spleen, trachea, bronchus, gall bladder, bile duct, bone, gum, adrenal gland, thyroid, blood vessels, and the like, and since the effects thereof are confirmed in the following embodiments, kidney, liver can be preferably exemplified.

[0075] In the present specification, "deterioration of function of an organ or tissue" means a state in which the function of an organ or tissue is lower than normal due to a disease or the like, for example, a state in which a test value obtained by health diagnosis (for example, the blood concentration of uremic substances [for example, creatinine, phenyl sulfate, 1-methyladenosine, oxidized trimethylamine-N-oxide (TMAO), indoxyl sulfate, blood urea nitrogen (BUN)], the blood concentration of a factor that causes renal failure in a patient with type 1 diabetes [for example, Ac6Lys], the estimated glomerular filtration rate (eGFR), the urine concentration of protein, the blood concentration of a marker of liver function [for example, AST [aspartate aminotransferase], ALT, ALP [alkaline phosphatase], γGTP, and the like], the blood concentration of a lipid [for example, triglyceride (TG), total cholesterol]) shows an abnormality (for example, a state in which the blood concentration of uremic substances increases, the blood concentration of a factor that causes renal failure in a patient with type 1 diabetes increases, eGFR decreases, the urine concentration of protein increases [proteinuria is positive], the blood concentration of a marker of liver function increases, the blood concentration of a lipid increases, and the like). As the above disease, for example, oral inflammation, intestinal inflammation, and the like, abnormality of the digestive system; multiple neuritis, (developmental) dyskinesia, and the like, abnormality of the nervous system; arteriosclerosis, anemia, dyserythropoiesis, hypertension, ischemic heart disease, pericarditis, myocarditis, (blood) coagulation abnormality, heart failure, cardiovascular disorder, and the like, abnormality of the circulatory system; pigmentation, pruritus, psoriasis, atopic dermatitis, alopecia, and the like, abnormality (disease) of the skin; albuminuria, renal failure (acute renal failure or chronic renal failure), acute renal tubular necrosis, renal anemia, renal tubulointerstitial damage, acute nephritis, chronic nephritis, nephrotic syndrome, diabetic nephropathy, arteriosclerotic nephropathy, renal osteopathy (for example, renal osteodystrophy), edema, and the like, renal dysfunction; dyslipidemia (hyperlipidemia); diabetes; cerebral stroke; myocardial infarction; cancer; autism; immunodeficiency; bone abnormality; hyperparathyroidism; insulin resistance; malnutrition; inflammation (for example, chronic inflammation); cell damage; tremor; and the like can be given. Furthermore, among the above diseases, symptoms or diseases caused by LPS (lipopolysaccharide) such as IgA nephropathy, polycystic kidney, liver dysfunction (for example, fulminant hepatitis, fatty liver, NASH, NAFLD), cancer (for example, cholecarcinogenesis), inflammatory bowel disease such as ulcerative colitis and Crohn's disease, arteriosclerosis-related diseases, autoimmune diseases such as lupus, scleroderma, and rheumatism, autism, Parkinson's disease, Alzheimer's disease, and sarcopenia are also included. In addition, in the present specification, "uremic substances" mean substances (metabolic waste, toxins, and the like) that are excreted by a normal kidney, and substances that increase (accumulate) in the blood when the excretion function decreases due to renal dysfunction or the like.The intake (administration) subject of the prophylactic / improver of the present case is not particularly limited as long as it is a mammal, and is usually a mammal in which the function of an organ or the like is to be prevented or improved (treated), and more specifically, a mammal in which the state of the function of an organ or tissue is low due to the above-mentioned disease or the like as a cause, and since the effect thereof is confirmed in the following-described embodiment, a mammal suffering from renal failure or diabetes can be preferably exemplified. If the diketopiperazine compound of the present case contained in the prophylactic / improver of the present case is ingested, the examination value obtained by health examination is improved, the function of an organ or tissue is protected, and in addition to the prevention or treatment of the above-mentioned disease, it is also useful for reducing the risk of exacerbation, and therefore, the prophylactic / improver of the present case can be used for: improving the examination value obtained by health examination; protecting the function of an organ or tissue; preventing or treating the above-mentioned disease; or reducing the risk of exacerbation of the above-mentioned disease.

[0076] As the administration form of the prophylactic / improver of the present case, oral administration in which the prophylactic / improver is ingested (administered) in a dosage form such as a powder, granules, tablets, capsules, syrup, jelly, gum, lozenge, soft candy, film, and the like, and non-oral administration in which the prophylactic / improver is ingested (administered) in a dosage form such as a skin external preparation, transdermal preparation, transmucosal preparation, transnasal preparation, transenteral preparation, injection, suppository, inhalant, patch, and the like can be exemplified. In the non-oral administration, administration in a dosage form such as a liquid, semi-solid preparation, or the like through a stoma in a gastrostomy or the like, or through a tube for tube feeding such as a nasogastric tube is included.

[0077] The prophylactic / improver of the present case for oral intake (administration) can be prepared as a sustained-release agent or an enteric agent. The enteric agent can be obtained, for example, by filling granules containing the diketopiperazine compound of the present case as an effective ingredient in an enteric coating (i.e., a coating in which a matrix [enteric component] having resistance to gastric juice and dissolving in the small intestine is the main component), or by coating a lozenge obtained by adding a lubricant to granules containing the diketopiperazine compound of the present case as an effective ingredient and tabletting.

[0078] As a method for obtaining the prophylactic / improver of the present case in the form of a tablet, for example, a method in which the diketopiperazine compound of the present case as an effective ingredient is mixed with an arbitrary ingredient (additive) blended as necessary, and the mixture is compression-molded to obtain a tablet can be exemplified, a method in which the tablet obtained after compression-molding is further coated with an enteric component (a method for preparing an enteric agent) or the like is preferred.

[0079] As the above-mentioned enteric component, for example, shellac, zein, hydroxymethylcellulose phthalate, carboxymethylcellulose, carboxymethylethylcellulose, cellulose acetate phthalate, methacrylic acid copolymer, water-insoluble ethylcellulose, methacrylic acid amine alkyl ester copolymer, beer yeast cell wall (for example, trade name Yeast Wrap and the like), tapioca starch, gelatin, pectin and the like can be mentioned, of which shellac is preferred. In addition, whether or not it is an enteric agent can be confirmed by the disintegration test method of the 14th edition of the Japanese Pharmacopoeia.

[0080] The intake amount of the diketopiperazine compound of the present application contained in the preventive / improving agent of the present application is, for example, in the range of 0.1 μg to 200 mg per kg (body weight) per day in terms of the concentration of the diketopiperazine compound of the present application, and is appropriately determined in accordance with the age, body weight, sex, symptoms, drug sensitivity, biological species and the like of the mammal to be the intake (administration) subject. In addition, the preventive / improving agent of the present application can be ingested once a day or in divided doses (for example, 2 to 4 times) per day.

[0081] In the present specification, as the "additive", a conventional carrier, binding agent, stabilizer, excipient, diluent, pH buffer, disintegrant, isotonic agent, coating agent, solubilizer, lubricant, flow aid, solubilizer, slip agent, flavoring agent, sweetening agent, solvent, gelling agent, nutrient, various oil agent, surfactant, preservative, antioxidant, dispersant, chelating agent, thickening agent, ultraviolet absorber, emulsion stabilizer, pH adjustor, pigment, perfume and the like can be mentioned. As the additive, water, physiological saline, animal fat and oil, vegetable oil, lactose, starch, gelatin, crystalline cellulose, gum, talc, magnesium stearate, hydroxypropyl cellulose, polyalkylene glycol, polyvinyl alcohol, glycerin, vitamin, mineral, lactic acid bacteria, protein, collagen can be specifically exemplified.

[0082] As the preventive / improving agent of the present application, a component other than the diketopiperazine compound of the present application can be contained as a component for preventing or improving the functional decline of organs and the like, but since the diketopiperazine compound of the present application alone also exerts an excellent inhibitory effect, the above-mentioned component (for example, protein, amino acid, DNA, RNA, polymer and the like; extract from plant origin [for example, sesamin compound]) other than the diketopiperazine compound of the present application can not be contained.

[0083] Hereinafter, the present application will be more specifically described by way of Examples, but the technical scope of the present application is not limited to these examples.

[0084] [Example 1]

[0085] 1. Confirmation that the compound of the present application can protect the renal function and liver function of a renal failure model

[0086] Using 2,5-diketopiperazine (cGP; see Table 1) contained in the compound of the present case, in order to confirm that the compound of the present case has an effect of protecting the renal function and the liver function in a model of renal failure, cGP was administered to model mice (hereinafter referred to as "adenine-fed renal failure model mice") that had suffered from chronic renal failure by ingesting adenine, and the blood concentration of a uremic substance (creatinine) as an index of renal function and the ratio of renal tubules were analyzed, and the blood concentrations of 3 liver function markers (ALT, AST, and γGTP) and 2 kinds of lipids (total cholesterol and TG) were analyzed. In addition, the adenine-fed renal failure model mice are mice in which renal damage is caused by crystallization of ingested adenine into insoluble 2,8-dihydroxyadenine in the renal tubules (Cozzolino, M. et al. Kidney Int. 64, 441-450 (2003), Tamagaki, K. et al. Nephrol. Dial. Transplant 21, 651-659 (2006)).

[0087] 1-1 Method

[0088] The analysis using the adenine-fed renal failure model mice was performed according to the following steps [1] to [5].

[0089] [1] Eight-week-old male C57BL / 6 mice (purchased from CLEA Japan, Inc.) were divided into a normal feeding group (n = 6) fed with a regular feed (CE-2, manufactured by CLEA Japan, Inc.) and an adenine-fed feeding group (n = 12) fed with a regular feed containing 0.2% adenine (manufactured by Wako Pure Chemical Industries, Ltd.).

[0090] [2] After 6 weeks of feeding, the adenine-fed feeding group was divided into an adenine-fed feeding control group (n = 6) fed with a regular feed and an adenine-fed feeding cGP group (n = 6) fed with a regular feed containing cGP. In addition, the regular feed containing cGP was prepared by mixing cGP (manufactured by Bachem) into the regular feed so that the final concentration was 0.0025%.

[0091] [3] After 2 weeks of feeding, blood samples were collected from each of the 3 groups (the normal feeding group, the adenine-fed feeding control group, and the adenine-fed feeding cGP group), and plasma samples (referred to as "plasma samples at 2 weeks after feeding") were prepared according to a conventional method.

[0092] [4] After 1 more week of feeding (3 weeks in total), blood samples were collected from each of the 3 groups, and plasma samples (referred to as "plasma samples at 3 weeks after feeding") were prepared according to a conventional method, and then renal tissues were collected, fixed with 10% neutral buffered formalin, and subjected to paraffin embedding, and then paraffin-embedded renal tissue sections were cut to prepare renal tissue sections.

[0093] [5] The blood concentration of uremic substance (creatinine) as an index of renal function was measured using a mass spectrometry method using a liquid chromatograph tandem mass spectrometer (LC-MS / MS) (manufactured by Shimadzu Corporation) with respect to "the blood plasma sample at 2 weeks after the feeding" (see Figure 1 ), and the blood concentrations of 3 kinds of liver function markers (ALT [see Figure 3 A], AST, and γGTP) and 2 kinds of lipids (total cholesterol [see Figure 3 B], and TG) were measured using 10 μL of "the blood plasma sample at 2 weeks after the feeding" and "the blood plasma sample at 3 weeks after the feeding" by DRI-CHEM 7000V (manufactured by Fuji Photo Film Co., Ltd.), respectively. In addition, analysis based on the Masson's trichrome staining (MTS) method was performed according to a conventional method with respect to the above-mentioned kidney tissue sections prepared (see Figure 2 ).

[0094] 1-2 Results

[0095] The creatinine concentration in the "blood plasma sample at 2 weeks after the feeding" of the adenine feeding control group showed a significant increase compared to the creatinine concentration in the "blood plasma sample at 2 weeks after the feeding" of the normal feeding group (see Figure 1 ). In addition, the proportion of renal tubules in the adenine feeding control group showed a significant decrease compared to the proportion of renal tubules in the normal feeding group (see Figure 2 A). These results indicate that, in the adenine feeding control group (i.e., the adenine-fed renal failure model mouse), the result of the decrease in renal function accompanying renal failure resulted in an increase in the blood concentration of uremic substance (creatinine).

[0096] On the other hand, the creatinine concentration in the "blood plasma sample at 2 weeks after the feeding" of the adenine feeding cGP group showed a significant decrease compared to the creatinine concentration in the "blood plasma sample at 2 weeks after the feeding" of the adenine feeding control group (see Figure 1 ). In addition, it was shown that the proportion of renal tubules in the adenine feeding cGP group showed a significant increase compared to the proportion of renal tubules in the adenine feeding control group (see Figure 2 A). These results indicate that, if the compound group (cGP) of the present application is administered to the adenine-fed renal failure model mouse, the decreased renal function is improved, resulting in a decrease in the increased blood concentration of uremic substance (creatinine).

[0097] Furthermore, the ALT concentration in the "blood plasma sample at 2 weeks after the feeding" of the adenine feeding cGP group showed a significant decrease compared to the ALT concentration in the "blood plasma sample at 2 weeks after the feeding" of the adenine feeding control group (see Figure 3A). In addition, the total cholesterol concentration in the "plasma sample at 2 weeks after feeding" of the cGP group fed with adenine was shown to be decreased compared to the total cholesterol concentration in the "plasma sample at 2 weeks after feeding" of the control group fed with adenine (see Figure 3 B). These results indicate that if the present compounds (cGP) are administered to adenine-fed kidney failure model mice, liver function is improved, and lipid abnormalities are improved.

[0098] [Table 1]

[0099]

[0100] [Example 2]

[0101] 2. Confirmation that the present compounds protect kidney function and liver function in a diabetes model

[0102] Next, in order to confirm that the present compounds protect kidney function and liver function in a diabetes model, cGP was administered to diabetes model mice (db / db mice), and the blood concentrations of 2 uremic substances (creatinine and phenyl sulfate) and a factor that leads to kidney failure in type 1 diabetes patients (N6-acetyl lysine [Ac6Lys]) were analyzed, and the pathological tissue of the liver and the blood concentrations of 3 liver function markers (ALT, AST, and γGTP) and 2 lipids (total cholesterol and TG) were analyzed.

[0103] 2-1 Method

[0104] The analysis using diabetes model mice was performed in accordance with the following steps [1] to [3].

[0105] [1] Wild-type mice (BKS-m+ / m+ mice; purchased from CLEA Japan, Inc.) fed with ordinary feed (CE-2, manufactured by CLEA Japan, Inc.) were divided into a wild-type normal feeding group (n = 5) fed with ordinary feed and a wild-type cGP group (n = 4) fed with ordinary feed containing cGP. In addition, diabetes model mice (BKS-db / db mice; purchased from CLEA Japan, Inc.) fed with ordinary feed were divided into a diabetes model normal feeding group (n = 4) fed with ordinary feed and a diabetes model cGP group (n = 4) fed with ordinary feed containing cGP. Blood samples were collected from the diabetes model cGP group, and plasma samples (referred to as "plasma samples at 0 weeks after feeding") were prepared in accordance with a conventional method.

[0106] [2] After 6 weeks of feeding, blood samples were collected from the above-mentioned 4 groups (wild type normal feeding group, wild type cGP group, diabetic model normal feeding group, and diabetic model cGP group), plasma samples (referred to as "plasma samples after 6 weeks of feeding") were prepared according to a conventional method, and liver tissues were collected, fixed with 10% neutral buffered formalin, and embedded in paraffin. Then, paraffin-embedded liver tissue sections were cut, and liver tissue sections were prepared.

[0107] [3] Using the "plasma samples after 0 weeks of feeding" and the "plasma samples after 6 weeks of feeding", the blood concentrations of 3 substances (creatinine, phenyl sulfate, and Ac6Lys) were measured by mass spectrometry using LC-MS / MS (manufactured by Shimadzu Corporation) (see Figure 5 and Figure 6 ), and the blood concentrations of 3 liver function markers (ALT, AST, and γGTP) and 2 lipids (total cholesterol and TG) were measured. In addition, using the above-mentioned liver tissue sections prepared, analysis based on hematoxylin-eosin staining (HE) was performed according to a conventional method (see Figure 4 ).

[0108] 2-2 Results

[0109] The fat droplets in the liver of the diabetic model cGP group were reduced compared to the fat droplets in the liver of the diabetic model normal feeding group (see Figure 4 ). This result indicates that if the compound group (cGP) of the present case is administered to a diabetic model mouse, fatty liver is improved.

[0110] In addition, the creatinine concentration in the "plasma samples after 6 weeks of feeding" of the diabetic model normal feeding group was significantly increased compared to the creatinine concentration in the "plasma samples after 6 weeks of feeding" of the wild type normal feeding group or the wild type cGP group (see Figure 5 ). This result indicates that in the diabetic model normal feeding group, the result of reduced kidney function accompanying diabetes leads to an increase in the blood concentration of uremic substances (creatinine).

[0111] On the other hand, the creatinine concentration in the "plasma samples after 6 weeks of feeding" of the diabetic model cGP group was significantly reduced compared to the creatinine concentration in the "plasma samples after 6 weeks of feeding" of the diabetic model normal feeding group (see Figure 5 ). This result indicates that if the compound group (cGP) of the present case is administered to a diabetic model mouse, the reduced kidney function is improved, and the reduced blood concentration of uremic substances (creatinine) is increased.

[0112] Further, using the "plasma sample at 0 weeks after feeding" and the "plasma sample at 6 weeks after feeding" of the cGP group of the diabetes model, the blood concentration of the three substances (creatinine, phenyl sulfate, and Ac6Lys) was measured, and as a result, the blood concentration of any of the substances showed a significant decrease at 6 weeks after feeding compared to 0 weeks after feeding (see Table 1 Figure 6 ). This result indicates that if the compound group (cGP) of the present case is administered to a diabetes model mouse, the low kidney function is improved, the risk of kidney failure is reduced, as a result, the blood concentration of uremic substances (creatinine and phenyl sulfate) is reduced, and the blood concentration of a factor that causes kidney failure in type 1 diabetes patients (Ac6Lys) is reduced.

[0113] [Example 3]

[0114] 3. Confirmation that the compound of the present case can reduce chronic inflammation of a diabetes model and cell damage caused thereby and prevent vascular complications

[0115] Next, in order to confirm that the compound of the present case can reduce chronic inflammation of a diabetes model and cell damage caused thereby and prevent vascular complications, the cGP was administered to a diabetes model mouse (db / db mouse), and the blood concentration of two uremic substances (1-methyladenosine [m1A] and trimethylamine N-oxide [TMAO]) was analyzed.

[0116] 3-1 Method

[0117] The analysis using a diabetes model mouse was performed according to the following steps [1] to [3].

[0118] [1] Diabetes model mice (BKS-db / db mice; purchased from CLEA Japan, Inc.) fed with a regular feed (CE-2, manufactured by CLEA Japan, Inc.) were divided into a diabetes model normal feeding group (n = 10) fed with a regular feed and a diabetes model cGP group (n = 10) fed with a regular feed containing cGP.

[0119] [2] After 5 weeks of feeding, blood samples were collected from the above two groups (diabetes model normal feeding group and diabetes model cGP group), and plasma samples were prepared according to a conventional method.

[0120] [3] Using the prepared plasma samples, the blood concentration of the two uremic substances (m1A and TMAO) was measured by mass spectrometry using LC-MS / MS (manufactured by Shimadzu Corporation) (see Table 1 Figure 7 ).

[0121] 3-2 Results

[0122] The concentration of mlA in the plasma sample of the diabetic model cGP group showed a significant decrease compared to the concentration of mlA in the plasma sample of the diabetic model normal feeding group (see Figure 7 A). Since mlA is known to be an early marker that rises upon cell damage, this indicates that if the present group of compounds (cGP) is administered to a diabetic model mouse, chronic inflammation and cell damage caused thereby can be reduced.

[0123] In addition, the concentration of TMAO in the plasma sample of the diabetic model cGP group showed a significant decrease compared to the concentration of TMAO in the plasma sample of the diabetic model normal feeding group (see Figure 7 B). Since TMAO is known to be a promoting factor of arteriosclerosis, and it is also reported to be associated with cardiovascular events or life prognosis, this indicates that if the present group of compounds (cGP) is administered to a diabetic model mouse, vascular complications, which are one of the major complications of diabetes, can be prevented.

[0124] [Industrial applicability]

[0125] The present application is useful for the prevention and treatment of diseases such as renal failure, diabetes, and the reduction of the risk of exacerbation of the disease.

Claims

1. A prophylactic or improving agent for a dysfunction of an organ or tissue, comprising one or two or more compounds selected from the group consisting of a compound represented by the following formula (I) and a physiologically tolerated salt thereof; [Chem. 1] ， In the formula, R 1 and R 2 each independently represents H or C1-C6alkyl; R 3 and R 4 each independently represents: H, or a C1-C6 alkyl group which can also have at least one group selected from the group consisting of a hydroxyl group, a phenyl group, a hydroxyphenyl group, an S-CH3 group, an NH2 group, a carboxyl group, a carbamoyl group, a guanidino group, and a nitrogen-containing heteroaryl group; R 1 and R 3 may form a ring through a C2-C4alkylene group which can have a hydroxyl group; R 2 and R 4 The ring can be formed by a C2-C4alkylene group which can have a hydroxyl group.

2. The prophylactic or improving agent according to claim 1, wherein the compound represented by formula (I) is a compound represented by the following formula (I-1), [Chem. 2] 。 3. The prophylactic or improving agent according to claim 1, wherein the organ is a kidney or a liver.

4. The prophylactic or improving agent according to claim 1, which is used for preventing or improving a dysfunction of an organ or tissue in a mammal suffering from renal failure or diabetes.

5. The prophylactic or improving agent according to any one of claims 1 to 4, which is a pharmaceutical product, a pet feed or a diet.

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