JP2019214546A - Advanced glycation end product production inhibitor and pharmaceutical composition - Google Patents

Abstract

An object of the present invention is to provide a terminal saccharified product production inhibitor capable of suppressing the production of advanced saccharified products.
The present invention relates to an advanced saccharified product production inhibitor comprising a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. In the formula, n represents an integer of 0 to 4. The compound represented by the formula (1) or a pharmaceutically acceptable salt thereof can significantly suppress an increase in the HbA1c value.

[Selection diagram] FIG.

Description

  TECHNICAL FIELD The present invention relates to an advanced glycation end product formation inhibitor and a pharmaceutical composition.

  The phenomenon of browning when a mixture of amino acids and reducing sugars is heated is generally called the Maillard reaction. Glycosyl hemoglobin (HbA1c) was identified in vivo, and it was revealed that the glycation reaction of protein progresses in vivo with the progression of diabetes, aging and the like. Such advanced glycation end products (hereinafter also referred to as “AGEs”) in the saccharification reaction of proteins have been reported to be involved in the development of lifestyle-related diseases such as diabetic complications and arteriosclerosis, progression of aging, and the like. ing. The accumulation of these AGEs in the body is caused not only by diabetic complications such as renal glomerular tissue sclerosis and renal arteriosclerosis, but also by neurodegenerative diseases such as Alzheimer's disease, skin aging such as decreased skin elasticity and yellowing, and It has been reported that it is deeply involved in aging, ocular aging, and aging of albumin protein.

  For example, Patent Literature 1 describes a Maillard reaction inhibitor containing a compound such as aminoguanidine. Aminoguanidine is a substance showing an anti-glycation effect, but has not been put to practical use due to side effects such as liver damage. Patent Document 2 describes an advanced saccharified product formation inhibitor containing a quercetin derivative as an active ingredient. On the other hand, Patent Literature 3 discloses a method for alleviating the accumulation of unnecessary nitrogen in humans using 4-phenylbutyric acid or the like.

Japanese Patent Publication No. 6-67827 JP 2017-66052 A International Publication No. 1985/04805

  An object of the present invention is to provide a terminal saccharified product production inhibitor capable of suppressing the production of a terminal saccharified product.

A first aspect is an advanced saccharified product formation inhibitor comprising a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. In the formula, n represents an integer of 0 to 4.

  The second aspect is a method for treating at least one selected from a group of diseases derived from the production or accumulation of advanced glycation end products, which comprises a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. A pharmaceutical composition.

  A third aspect is at least one method of treatment selected from the group of diseases derived from the production or accumulation of advanced glycation end products, which comprises administering the pharmaceutical composition to a subject.

  Further, the present invention provides a use of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof in the production of the aforementioned terminal glycation end product formation inhibitor or the pharmaceutical composition, and a compound represented by the formula (1). Or use of a pharmaceutically acceptable salt thereof, which is used in at least one kind of treatment selected from the group of diseases derived from the production or accumulation of advanced glycation end products, and diseases caused by production or accumulation of advanced glycation end products. A compound represented by the formula (1) or a pharmaceutically acceptable salt thereof, a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof used in at least one treatment selected from the group: Also included is a method of inhibiting the production or accumulation of advanced glycation end products, which comprises administering a salt to a subject.

  ADVANTAGE OF THE INVENTION According to this invention, the end-glycation-product production inhibitor which can suppress generation of an end-glycation product can be provided.

It is a graph which shows the result of an albumin saccharification experiment. It is a graph which shows the result of a collagen saccharification experiment. It is a graph which shows the weight change of a mouse. It is a graph which shows the blood glucose level change of a mouse. It is a graph which shows the change of the total cholesterol level of a mouse. It is a graph which shows the change of the triglyceride value of a mouse. It is a graph which shows the change of HbA1c value of a mouse. It is a graph which shows the weight change of a mouse. It is a graph which shows the result of the oral glucose tolerance test with respect to a mouse.

  In the present specification, the content of each component in the composition, if there are a plurality of substances corresponding to each component in the composition, unless otherwise specified, the total amount of the plurality of substances present in the composition Means Hereinafter, embodiments of the present invention will be described in detail. However, the embodiments described below are for exemplifying the terminal glycation product production inhibitor and the like for embodying the technical concept of the present invention, and the present invention is directed to the terminal glycation product generation inhibitor and the like shown below. It is not limited to.

  The advanced glycation end product formation inhibitor and the pharmaceutical composition contain at least one compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition is used for treating at least one selected from a group of diseases derived from the production or accumulation of advanced glycation end products.

  In the formula, n represents an integer of 0 to 4, and is preferably 1.

  The compound represented by the formula (1) can suppress the production of advanced glycation end products in vivo. Therefore, a pharmaceutical composition containing the compound represented by the formula (1) is administered to a subject to treat at least one selected from a group of diseases derived from the production or accumulation of advanced glycation end products in the subject. can do. In addition, by administering to healthy individuals, it is possible to prevent diseases caused by the production or accumulation of advanced glycation end products.

  Among the compounds represented by the formula (1), sodium salt of 4-phenylbutyric acid where n is 1 is a drug which has been approved for urea cycle abnormality. Sodium 4-phenylbutyrate is called a prodrug of phenylacetic acid, and is converted to phenylacetic acid by β-oxidation in vivo. It is said that phenylacetic acid binds to glutamine to produce phenylacetylglutamine and is excreted in urine from the kidney. This phenylacetic acid excretion pathway is said to be an alternative route to the ammonia elimination pathway by the urea cycle, and administration of sodium phenylbutyrate using this pathway is a standard treatment for long-term treatment management of urea cycle disorders. It recognized. The details of the mechanism by which the compound represented by the formula (1) suppresses the production of advanced glycation end products in a living body are not yet known.

  The compound represented by the formula (1) or a pharmaceutically acceptable salt thereof can be produced by a known method. Moreover, it can also be suitably selected from commercially available products.

  The advanced glycation end product formation inhibitor or the pharmaceutical composition may contain the compound represented by the formula (1) as a pharmaceutically acceptable salt. Examples of the salt of the compound represented by the formula (1) include an alkali metal salt, an alkaline earth metal salt, an ammonium salt, and a substituted ammonium salt, and are at least one selected from the group consisting of these. And more preferably at least one selected from alkali metal salts. Examples of the alkali metal salt include a lithium salt, a sodium salt, a potassium salt, a cesium salt and the like. Examples of the alkaline earth metal salt include a magnesium salt and a calcium salt. Examples of the substituted ammonium salt include tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and trishydroxymethylaminomethane (Tris). No.

  The advanced glycation end product formation inhibitor or the pharmaceutical composition may contain the compound represented by the formula (1) in the form of a prodrug. A prodrug is, for example, a compound that can be converted in vivo into a compound represented by formula (1) by hydrolysis.

  The pharmaceutical composition is used, for example, for treating at least one selected from a group of diseases derived from the production or accumulation of advanced glycation end products (hereinafter, also referred to as “specific diseases”). Specific diseases include, for example, arteriosclerosis including atherosclerosis, hyperlipidemia, cardiovascular disease, cerebrovascular disease, hypertension, renal disorder, chronic renal failure, dementia, Alzheimer's disease and Parkinson's disease. Neurodegenerative diseases, cataracts, glaucoma, sarcopenia, etc., and at least one selected from the group consisting of these is preferable. Further, the specific disease may include a diabetic complication. Examples of diabetic complications include diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, and diabetic vascular complications, and at least one selected from the group consisting of these is preferred. Here, the “treatment” used in the present specification may be any treatment performed for a disease, and examples thereof include treatment, improvement, suppression of progression (prevention of deterioration), and the like.

  The pharmaceutical composition may contain a pharmaceutically acceptable carrier in addition to the compound represented by the formula (1). Pharmaceutically acceptable carriers include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc .; starch, gelatin, carboxymethyl cellulose, shellac, methyl cellulose, Binders such as potassium phosphate and polyvinylpyrrolidone; dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch, lactose, etc. Disintegrators; disintegrators such as sucrose, stearin, cocoa butter, and hydrogenated oil; absorption promoters such as quaternary ammonium bases and sodium lauryl sulfate; humectants such as glycerin and starch; starch, lactose, kaolin; Adsorbents such as tonite and colloidal silicic acid; lubricating agents such as purified talc, stearates, powdered boric acid, and polyethylene glycol; buffers; flavoring agents; suspending agents; emulsifiers; Is mentioned.

  When the pharmaceutical composition is a liquid preparation, the pharmaceutical composition contains, in addition to the active ingredient, a solvent, a solubilizer, a suspending agent, an isotonic agent, a buffer, a pH adjuster, a soothing agent, and the like. It may be. Examples of the solvent in the liquid preparation include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like. Examples of the solubilizer include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate and the like. Examples of the suspending agent include benzalkonium chloride, carmellose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose, glyceryl monostearate and the like. Examples of the tonicity agent include glucose, D-sorbitol, sodium chloride, D-mannitol and the like. Examples of the buffer or the pH adjuster include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate and the like. Examples of the soothing agent include benzyl alcohol and the like.

  The pharmaceutical composition may further contain a known diabetic drug, another drug having an AGEs production inhibitory effect, and the like. Examples of other drugs include insulin sensitizers, drugs for treating dyslipidemia, angiotensin II type 1 receptor antagonists, angiotensin converting enzyme inhibitors, metformin and the like.

  As the dosage form of the pharmaceutical composition, tablets such as orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and dissolving tablets; capsules; granules such as effervescent granules; powders; elixirs, suspensions, and emulsions , Syrup (agent for syrup); oral jelly; lozenges, sublingual tablets, buccal tablets, adhesive tablets, gums and other oral tablets; oral sprays; oral semisolids Injections such as infusions, implants, continuous injections, etc .; Dialysis agents such as peritoneal dialysis agents, hemodialysis agents, etc .; Inhalants such as inhalation powders, inhalation solutions, inhalation aerosols, etc. Suppositories; Rectal semisolids; Enemas; Eye drops; Eye ointments; Ear drops; Nasal drops such as nasal powders, nasal drops; Vaginal tablets; Vaginal suppositories; (External powder); External liquid such as liniment, lotion, etc .; External aerosol, pump spray Sprays; ointments; creams; gels; tape agents, and patches such as a poultice. Among them, tablets, capsules, granules, powders, oral liquids, syrups, oral jellies, oral tablets, oral sprays, oral semi-solids, and mouthwashes in terms of ease of oral administration. And tablets, capsules, granules and powders are more preferable in that they are easily absorbed into the living body.

  In addition, the pharmaceutical composition comprises a compound represented by the formula (1) in a herbal medicine-related preparation such as an extract, a pill, an alcoholic beverage, an infusion, a decoction, a tea, a tincture, a fragrance, a fluid extract, etc. It can also be used in an added dosage form. These dosage forms are appropriately selected according to conditions such as the degree of specific diseases such as diabetes and diabetic complications, the degree of other diseases, age, sex, and the like.

  The dose of the pharmaceutical composition is appropriately selected depending on the degree of a disease derived from the production or accumulation of advanced glycation end products, the degree of other diseases, age, sex, and the like. For example, the compound represented by the formula (1) in an amount capable of suppressing the generation of AGEs (hereinafter, also referred to as an “effective amount of suppressing the generation of AGEs”) may be administered. The effective amount of AGEs production suppression can be appropriately determined using a method well-known to those skilled in the art, including at least one of various non-clinical and clinical tests.

  The pharmaceutical composition may be one that administers an effective amount of the compound represented by the formula (1) at the time of inhibiting the generation of AGEs, or may be one that is divided and administered at intervals. When dividedly administered, the total amount of the compound represented by the formula (1) administered per day may be an effective amount for suppressing the generation of AGEs. For example, the compound may be administered according to the number of meals. Is also good.

  The pharmaceutical composition can be administered to either a subject or a healthy subject suffering from a disease resulting from the production or accumulation of advanced glycation end products. It is preferably administered to a subject suffering from a specific disease such as diabetes, which is highly associated with AGEs. For example, a subject suffering from diabetes refers to a subject having a hemoglobin A1c (HbA1c) of 6.1% (JDS value) or more and falling under any of the following (1) to (3): ( 1) Fasting blood glucose level is 126 mg / dL or more, (2) occasional blood glucose level (whether fasting or after eating) is 200 mg / dL or more, and (3) 2 hours after glucose loading is 200 mg / dL or more. Details of the Diabetes Diagnostic Criteria are described in “A Committee Report on Diabetes Classification and Diagnosis Criteria” by the Japanese Diabetes Society (available from the website of the society).

Method of Treatment A method of treatment is a method of treating a disease resulting from the production or accumulation of advanced glycation end products, comprising administering to a subject an effective amount of the pharmaceutical composition. In particular, treatment methods include atherosclerosis, including atherosclerosis, hyperlipidemia, cardiovascular disease, cerebrovascular disease, hypertension, nephropathy, chronic renal failure, dementia, neurology including Alzheimer's disease and Parkinson's disease. A method for treating at least one specific disease selected from the group consisting of a degenerative disease, cataract, glaucoma, and sarcopenia. Details of the pharmaceutical composition and the method of administration are as described above. The subject to be treated is, for example, a mammal, wherein the mammal includes a human.

  EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

Example 1
Albumin Saccharification Experiment The final concentration of α-glucose (manufactured by Nacalai Tesque) in Dulbecco's phosphate buffered saline (containing no Ca and Mg) (DPBS: manufactured by Nacalai Tesque) was 0.2 mol / L, and human albumin ( The concentration was adjusted to an Eppendorf tube (750 μl / tube) so that the final concentration of SIGMA (8 g / ml) was 8 mg / ml. An appropriate amount of sodium 4-phenylbutyrate (PBA; manufactured by LKT Laboratories, Inc.) was added to each tube to a predetermined final concentration, followed by incubation at 60 ° C. for 40 hours. The production level of glycated albumin (AGEs) after incubation was evaluated by measuring the fluorescence intensity (excitation wavelength 370 nm, detection wavelength 440 nm) using a microplate reader (TECAN). In addition, instead of PBA, aminoguanidine (AG; manufactured by Wako Pure Chemical Industries, Ltd.) was used as a positive control, and the generation level of AGEs was similarly evaluated. The results are shown in FIG. FIG. 1 also shows the suppression rate when the control is set to 100%. Table 1 shows the relative fluorescence intensity when the control using water was set to 100.

  From FIG. 1 and Table 1, it was confirmed that sodium 4-phenylbutyrate has a dose-dependent saccharification inhibitory effect on albumin.

Example 2
Collagen Saccharification Experiment The ability of sodium 4-phenylbutyrate (PBA) to inhibit collagen saccharification was evaluated using a collagen anti-saccharification assay kit (glyceraldehyde) (manufactured by Cosmo Bio). Aminoguanidine attached to the kit was used as a positive control. The assay was performed according to the instructions attached to the kit, and the incubation was performed at 37 ° C. for 24 hours. The results are shown in FIG. FIG. 2 also shows the suppression rate when the control is set to 100%. Note that a numerical value with “+” means that the generation level has been increased. Table 2 shows the relative fluorescence intensity when the control using water was set to 100.

  From FIG. 2 and Table 2, it was confirmed that sodium 4-phenylbutyrate has a dose-dependent inhibitory effect on saccharification of collagen.

Example 3
KK / Ta Jcl mice (10-week-old, male, n = 2 in each group) which are type 2 diabetes model mice are bred on a normal diet (CE-2), and sodium 4-phenylbutyrate is used as a test substance for 12 weeks. (PBA) was orally administered, and changes in blood sugar level, total cholesterol level (T-cho), triglyceride (TG), urinary sugar, and urine volume were examined. Specifically, a solution prepared by dissolving 20 mg of sodium 4-phenylbutyrate in 200 μL of distilled water was orally administered once daily using an oral sonde for mice. Controls received water only. From 10 weeks to 14 weeks of age, blood glucose level, total cholesterol level and triglyceride were measured by blood sampling at any time, and urinary glucose was measured from urination at any time. After 15 weeks of age, blood was collected every week after a 12-hour fast, and fasting blood glucose (FBS), total cholesterol, and triglyceride were measured. During fasting, urine was collected in a metabolic cage, and urine volume and urine sugar were measured. The body weight was measured immediately before fasting. HbA1c was measured at the end of the 22-week-old experiment.

  Blood glucose was measured using a glutest sensor chip. The total cholesterol value and triglyceride were measured using a chip for T-cho and a chip for TG (manufactured by Fuji Dry Chem Co., Ltd.), respectively. Urine sugar was measured using urine sugar test paper (New Uriace Ga). HbA1c was measured using a DCA Vantage HbA1c cartridge (manufactured by Siemens Healthcare).

  Table 3 shows the measurement results of HbA1c as average values. FIG. 3 shows changes in body weight and urinary sugar, FIG. 4 shows changes in blood glucose, FIG. 5 shows changes in total cholesterol (T-cho), and FIG. 6 shows changes in triglyceride (TG).

  As shown in FIG. 3, in the group to which the test substance was administered, the increase in body weight was more gradual, and urinary glucose conversion was delayed as compared with the control. Further, the HbA1c value was lower in the test substance administration group than in the control.

(Example 4)
KK / Ta Jcl mice (10-week-old, male, n = 5 in each group) which are type 2 diabetes model mice are bred on a normal diet (CE-2), and sodium 4-phenylbutyrate is used as a test substance for 6 weeks. (PBA) was orally administered at 5 mg / day or 20 mg / day, and changes in body weight, urinary sugar, and HbA1c were examined. Specifically, a solution prepared by dissolving 5 mg or 20 mg of sodium 4-phenylbutyrate in 200 μL of distilled water was orally administered once daily using an oral sonde for mice. Controls received water only. Blood was collected weekly after a 12-hour fast, and fasting blood glucose was measured. In addition, blood was collected again 2 hours after free feeding after a 12-hour fast, and blood glucose levels were measured. HbA1c was measured every two weeks. Further, an oral glucose tolerance test was performed on the 13th week. The oral glucose tolerance test was performed by orally administering 1.5 g / kg of glucose, collecting blood every 60 minutes, and measuring the blood glucose level. The results are shown in Table 4, FIG. 7, FIG. 8 and FIG. FIG. 7 is a graph showing changes in HbA1c, and Table 4 shows the measurement results of HbA1c as average values. FIG. 8 is a graph showing the results of weight change and urine sugar test, and FIG. 9 is a graph showing the results of oral glucose tolerance test.

  7 and Table 4, HbA1c was lower in the group to which the test substance was administered than in the control. As shown in FIG. 8, the test substance alleviated the weight gain in the type 2 diabetes model mouse compared to the control.

  From the above, it was shown that the compound represented by the formula (1) can suppress the generation of AGEs in a living body in a dose-dependent manner. Further, it was shown that the compound represented by the formula (1) can induce a low level of HbA1c in a type 2 diabetes model mouse. In addition, it was shown to alleviate weight gain in model mice and to delay urine sugar positivity.

Claims (7)

A terminal glycation end product formation inhibitor comprising a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

(Where n represents an integer of 0 to 4)   The compound according to claim 1, wherein the compound represented by the formula (1) contains 4-phenylbutyric acid. Pharmaceutical composition for treating at least one selected from a group of diseases derived from the production or accumulation of advanced glycation end products, comprising a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. object.

(Where n represents an integer of 0 to 4)   The pharmaceutical composition according to claim 3, wherein the compound represented by the formula (1) contains 4-phenylbutyric acid.   Diseases resulting from the production or accumulation of advanced glycation end products are arteriosclerosis including atherosclerosis, hyperlipidemia, cardiovascular disease, cerebrovascular disorder, hypertension, renal disorder, chronic renal failure, dementia, The pharmaceutical composition according to claim 3 or 4, comprising at least one selected from the group consisting of neurodegenerative diseases including Alzheimer's disease and Parkinson's disease, cataract, glaucoma, and sarcopenia.   Tablets, capsules, granules, powders, oral solutions, syrups, oral jellies, oral tablets, oral sprays, oral semisolids, gargles, injections and inhalants The pharmaceutical composition according to any one of claims 3 to 5, which is in the form.   7. A method for treating at least one selected from a group of diseases derived from the production or accumulation of advanced glycation end products, which comprises administering the pharmaceutical composition according to any one of claims 3 to 6 to a subject. .