JP2013234159A - Synergic antidiabetic therapeutic agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an antidiabetic therapeutic agent excellent in controlling blood sugar of diabetic patients, and capable of suppressing adverse effects and reducing a dose.SOLUTION: There is provided an insulin secretion promoting agent comprising a compound expressed by general formula (I) or pharmaceutically acceptable salts or solvates thereof, and a sugar nucleotide or glucosamine as active ingredients. (In the formula, Rrepresents H, -COORor the like; Rrepresents H, 1-6C alkyl or 2-6C alkenyl both of which may be substituted, or the like).

Description

  The present invention relates to a novel antidiabetic therapeutic agent that combines two kinds of compounds. More specifically, the present invention relates to an insulin secretagogue comprising baccarines and sugar nucleotides or glucosamine as active ingredients.

  Diabetes mellitus is a disease with a persistent hyperglycemic state and is said to result from the action of a wide variety of environmental and genetic factors. It is known that insulin is a major regulator of blood glucose, and hyperglycemia is caused by insulin deficiency or excessive factors that inhibit its action (eg, genetic predisposition, lack of exercise, obesity, stress, etc.). It has been. Diabetes is mainly caused by type 1 diabetes caused by a decrease in pancreatic insulin secretion function due to autoimmune diseases and the like, and a decrease in pancreatic insulin secretion function and insulin resistance due to pancreatic exhaustion associated with continuous high insulin secretion 2 Classified as type 2 diabetes. In Japan, diabetes is a modern national disease, and more than 95% of diabetic patients (predicted to exceed 20 million including the reserve army) are said to be non-insulin dependent diabetes mellitus. As the lifestyle changes, the increase in the number of patients has become a problem. The global level is estimated to be about 200 million (Non-patent Document 1), and the global market for anti-diabetic drugs is about 1 trillion yen in 2006. This is almost first in both market and population.

  In the treatment of diabetes, diet therapy, exercise therapy, obesity improvement, etc. are mainly carried out in mild cases, and when further progressed, oral diabetes drugs (insulin secretion promoters) are administered. In severe cases, insulin preparations are administered. Has been done. As insulin secretagogues (or insulin secretagogues), in addition to glucose, amino acids (particularly arginine), β receptor stimulants, α receptor blockers, sulfonylurea agents and the like are known. Among them, the sulfonylurea agent stimulates pancreatic β cells and promotes endogenous insulin secretion, but the timing and amount of insulin secretion are determined by the administration timing and dose of the drug regardless of the blood glucose level. For this reason, hypoglycemia resulting from sustained action of the drug may be exhibited as a side effect (Non-patent Document 2). Thus, conventionally used insulin secretion promoters and insulin preparations have the above-mentioned problems. Therefore, a drug capable of controlling blood glucose at a higher level, that is, a drug capable of controlling blood sugar within a normal range, is not desired, but a drug that simply lowers blood sugar.

  In addition, L-arginine, which is one of amino acids, has many actions in vivo, and is involved in, for example, regulation of immune function, wound healing, hormone secretion, vascular tone, endothelial function, and insulin secretion (non- Patent Document 3). L-arginine is a biologically active food compound that mediates numerous physiological activities, either directly or through metabolites. In this connection, a metabolic enzyme that uses L-arginine as a substrate is the well-known L-arginine targeting factor (AIF). However, little is known about AIF that directly mediates the physiological effects of L-arginine. So far, the present inventors have succeeded in purification and identification of AIF using magnetic nanobeads on which L-arginine methyl ester (AME) has been developed (Non-patent Document 4). AME, like arginine, promotes insulin secretion as an agonist of arginine, while AME, like L-NAME (nitro-L-arginine-methyl ester), NOS (nitrogen monoxide) as an antagonist of arginine. Synthase). With this AME-immobilized magnetic nanobead, PFK (phosphofructokinase), RBL2 (RuvB-like 2), and RBL1 (RuvB-like 1) were identified as AIF (Non-patent Document 4).

  Until now, the present inventors have newly identified an insulin secretion control factor and developed a screening method for an antidiabetic drug using the factor (Patent Document 1). Furthermore, it was verified by the above screening method that baccarin can be used as an anti-diabetic drug by using buccalin having an activity of promoting insulin secretion (Patent Document 1).

WO2012 / 029958

Stumvol. M.M. Lancet, 365, 1333-1346 (2005). McCrimmon, R.M. J. et al. Et al., Diabete. Metab. , 20, 503-512 (1994) Weinhaus, A.M. J. et al. Et al., Diabetologia, 40, 374-382 (1997). Hiramoto et al., Biomed. Chromatogr. , 24, 606-612 (2010)

  An object of the present invention is to provide an anti-diabetic therapeutic agent that is excellent in controlling blood sugar in diabetic patients, suppresses side effects, and can reduce the dose.

  As described above, a plurality of substances are known as substances that promote insulin secretion. However, as a result of searching for an insulin secretion-promoting substance using a novel anti-diabetic drug screening method that has been developed previously, The present inventors have found that a combination of a saccharide and a sugar nucleotide promotes insulin secretion very remarkably, thereby completing the present invention.

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

(Where
R ₁ is a hydrogen atom, halogen, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, —OR ₃ , —CH ₂ OR ₄ , —COOR. ₅ , —COR ₆ , or —CON (R ₇ ) R ₈ , wherein R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R ₈ may be the same or different and are independent. And R ₂ is selected from the group consisting of a hydrogen atom, C _1-6 alkyl, and C _3-6 cycloalkyl; and R ₂ is a hydrogen atom, halogen, nitro, cyano, —OR ₉ (where R ₉ is Selected from the group consisting of a hydrogen atom, C _1-6 alkyl, and C _3-6 cycloalkyl), C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, or C _2-6 alkynyl Where C _1-6 Alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, and C _2-6 alkynyl contain at least one heteroatom selected from halogen; hydroxyl group; nitro; cyano; oxygen, nitrogen, and sulfur. And may have one or more substituents selected from the group consisting of phenyl, tolyl, naphthyl, pyridyl, thiazolyl, furyl, or thienyl; and alkoxycarbonyl)
Or a pharmaceutically acceptable salt or solvate thereof; and an insulin secretagogue comprising a sugar nucleotide or glucosamine as an active ingredient.

[2] The insulin secretion promoter according to [1] above, wherein R ₁ is a hydroxyl group; and R ₂ is hydrogen or C _2-6 alkenyl.

[3] The compound represented by the general formula (I) is:
(E) -3- [3- (3-Methylbut-2-en-1-yl) -4-{(3-phenylpropanoyl) oxy} phenyl] acrylic acid; or (E) -3- [4- The insulin secretion promoter according to [1] or [2] above, which is {(3-phenylpropanoyl) oxy} phenyl] acrylic acid.

[4] The insulin secretion promoter according to any one of the above [1] to [3], wherein the sugar nucleotide is selected from the group consisting of UDP glucose, ADP glucose, GDP glucose, and UDP glucuronic acid.

[5] The insulin secretion promoter according to any one of [1] to [3] above, wherein the glucosamine is N-acetyl-D-glucosamine.

[6] General formula (I):

(Where
R ₁ is a hydrogen atom, halogen, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, —OR ₃ , —CH ₂ OR ₄ , —COOR. ₅ , —COR ₆ , or —CON (R ₇ ) R ₈ , wherein R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R ₈ may be the same or different and are independent. And R ₂ is selected from the group consisting of a hydrogen atom, C _1-6 alkyl, and C _3-6 cycloalkyl; and R ₂ is a hydrogen atom, halogen, nitro, cyano, —OR ₉ (where R ₉ is Selected from the group consisting of a hydrogen atom, C _1-6 alkyl, and C _3-6 cycloalkyl), C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, or C _2-6 alkynyl Where C _1-6 Alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, and C _2-6 alkynyl contain at least one heteroatom selected from halogen; hydroxyl group; nitro; cyano; oxygen, nitrogen, and sulfur. And may have one or more substituents selected from the group consisting of phenyl, tolyl, naphthyl, pyridyl, thiazolyl, furyl, or thienyl; and alkoxycarbonyl)
Or a pharmaceutically acceptable salt or solvate thereof;
A pharmaceutical composition for preventing and / or treating diabetes comprising a sugar nucleotide or glucosamine; and a pharmaceutically acceptable carrier.

[7] General formula (I):

(Where
R ₁ is a hydrogen atom, halogen, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, —OR ₃ , —CH ₂ OR ₄ , —COOR. ₅ , —COR ₆ , or —CON (R ₇ ) R ₈ , wherein R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R ₈ may be the same or different and are independent. And R ₂ is selected from the group consisting of a hydrogen atom, C _1-6 alkyl, and C _3-6 cycloalkyl; and R ₂ is a hydrogen atom, halogen, nitro, cyano, —OR ₉ (where R ₉ is Selected from the group consisting of a hydrogen atom, C _1-6 alkyl, and C _3-6 cycloalkyl), C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, or C _2-6 alkynyl Where C _1-6 Alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, and C _2-6 alkynyl contain at least one heteroatom selected from halogen; hydroxyl group; nitro; cyano; oxygen, nitrogen, and sulfur. And may have one or more substituents selected from the group consisting of phenyl, tolyl, naphthyl, pyridyl, thiazolyl, furyl, or thienyl; and alkoxycarbonyl)
Or a pharmaceutically acceptable salt or solvate thereof; and a food composition having an insulin secretion-promoting action, comprising a sugar nucleotide or glucosamine.

[8] General formula (I):

(Where
R ₁ is a hydrogen atom, halogen, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, —OR ₃ , —CH ₂ OR ₄ , —COOR. ₅ , —COR ₆ , or —CON (R ₇ ) R ₈ , wherein R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R ₈ may be the same or different and are independent. And R ₂ is selected from the group consisting of a hydrogen atom, C _1-6 alkyl, and C _3-6 cycloalkyl; and R ₂ is a hydrogen atom, halogen, nitro, cyano, —OR ₉ (where R ₉ is Selected from the group consisting of a hydrogen atom, C _1-6 alkyl, and C _3-6 cycloalkyl), C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, or C _2-6 alkynyl Where C _1-6 Alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, and C _2-6 alkynyl contain at least one heteroatom selected from halogen; hydroxyl group; nitro; cyano; oxygen, nitrogen, and sulfur. And may have one or more substituents selected from the group consisting of phenyl, tolyl, naphthyl, pyridyl, thiazolyl, furyl, or thienyl; and alkoxycarbonyl)
Or a pharmaceutically acceptable salt or solvate thereof; and a functional food having an insulin secretion-promoting action, comprising a sugar nucleotide or glucosamine.

[9] General formula (I):

(Where
R ₁ is a hydrogen atom, halogen, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, —OR ₃ , —CH ₂ OR ₄ , —COOR. ₅ , —COR ₆ , or —CON (R ₇ ) R ₈ , wherein R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R ₈ may be the same or different and are independent. And R ₂ is selected from the group consisting of a hydrogen atom, C _1-6 alkyl, and C _3-6 cycloalkyl; and R ₂ is a hydrogen atom, halogen, nitro, cyano, —OR ₉ (where R ₉ is Selected from the group consisting of a hydrogen atom, C _1-6 alkyl, and C _3-6 cycloalkyl), C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, or C _2-6 alkynyl Where C _1-6 Alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, and C _2-6 alkynyl contain at least one heteroatom selected from halogen; hydroxyl group; nitro; cyano; oxygen, nitrogen, and sulfur. And may have one or more substituents selected from the group consisting of phenyl, tolyl, naphthyl, pyridyl, thiazolyl, furyl, or thienyl; and alkoxycarbonyl)
And a food containing a pharmaceutically acceptable salt or solvate thereof; and a food containing a sugar nucleotide or glucosamine.

[10] General formula (I):

(Where
R ₁ is a hydrogen atom, halogen, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, —OR ₃ , —CH ₂ OR ₄ , —COOR. ₅ , —COR ₆ , or —CON (R ₇ ) R ₈ , wherein R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R ₈ may be the same or different and are independent. And R ₂ is selected from the group consisting of a hydrogen atom, C _1-6 alkyl, and C _3-6 cycloalkyl; and R ₂ is a hydrogen atom, halogen, nitro, cyano, —OR ₉ (where R ₉ is Selected from the group consisting of a hydrogen atom, C _1-6 alkyl, and C _3-6 cycloalkyl), C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, or C _2-6 alkynyl Where C _1-6 Alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, and C _2-6 alkynyl contain at least one heteroatom selected from halogen; hydroxyl group; nitro; cyano; oxygen, nitrogen, and sulfur. And may have one or more substituents selected from the group consisting of phenyl, tolyl, naphthyl, pyridyl, thiazolyl, furyl, or thienyl; and alkoxycarbonyl)
Or a pharmaceutically acceptable salt or solvate thereof; and a method for preventing and / or treating diabetes, comprising administering an effective amount of a sugar nucleotide or glucosamine.

  The combination of the baccalins represented by the above formula (I) and the sugar nucleotide or glucosamine of the present invention exhibits a very high insulin secretion promoting activity due to their synergistic effect. Therefore, by using the insulin secretagogue of the present invention, the dose can be reduced and side effects can be suppressed as compared with existing diabetes drugs.

The result of having measured the amount of insulin secretion after the addition of baccharin (Bac) and UDP-glucose in NIT-1 cells forcibly expressing an insulin secretion promoting factor is shown.

1. Insulin secretion promoter The insulin secretion promoter of the present invention contains, as an active ingredient, the following general formula (I):

Or a pharmaceutically acceptable salt or solvate thereof; and a sugar nucleotide or glucosamine.

In the above formula,
R ₁ is a hydrogen atom, halogen, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, —OR ₃ , —CH ₂ OR ₄ , —COOR. ₅ , —COR ₆ , or —CON (R ₇ ) R ₈ , where R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R ₈ may be the same or different. , Independently, may be selected from the group consisting of a hydrogen atom, C _1-6 alkyl, and C _3-6 cycloalkyl; and R ₂ is a hydrogen atom, halogen, nitro, cyano, —OR ₉ (where R ₉ may be selected from the group consisting of a hydrogen atom, C _1-6 alkyl, and C _3-6 cycloalkyl), C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6. alkenyl, or _{C 2-6} alkynyl der And may, where said _{C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6} alkenyl, and _{C 2-6} alkynyl, halogen, hydroxyl, nitro, cyano, oxygen, nitrogen, and sulfur One or more substituents selected from the group consisting of phenyl, tolyl, naphthyl, pyridyl, thiazolyl, furyl, or thienyl, which may contain at least one selected heteroatom; and alkoxycarbonyl .

Here, definitions of terms in the present invention are as follows.
As used herein, “C _1-6 alkyl” means a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Examples of “C _1-6 alkyl” include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group, 2-methylbutyl group, 2 , 2-dimethylpropyl group, n-hexyl group and the like.

As used herein, “C _3-6 cycloalkyl” means a monocyclic saturated hydrocarbon group having 3 to 6 carbon atoms. Examples of “C _3-6 cycloalkyl” include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

As used herein, “C _2-6 alkenyl” means a straight or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms, and is an ethynyl group, prop-1-ene-1- Yl group, prop-2-en-1-yl group, but-1-en-1-yl group, but-3-en-1-yl group, 1-methylprop-2-en-1-yl group, 3 -Methylbut-2-en-1-yl group, penta-1-en-1-yl group, penta-4-en-1-yl group, hexa-1-en-1-yl, hexa-5-ene- A 1-yl group is mentioned. As the “C _2-6 alkenyl”, a 3-methylbut-2-en-1-yl group is preferable.

As used herein, “C _2-6 alkynyl” means a linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms, such as a prop-1-in-1-yl group, Prop-2-yn-1-yl group, but-1-yn-1-yl group, but-3-yn-1-yl group, 1-methylprop-2-yn-1-yl group, penta-1- Examples include in-1-yl group, penta-4-in-1-yl group, hexa-1-in-1-yl group, and hexa-5-in-1-yl group.

As used herein, “alkoxycarbonyl” means a group in which an alkoxy group is substituted on a carbonyl group, and the alkoxy group refers to a group in which the above “alkyl” is substituted on an oxygen atom. “Alkoxycarbonyl” includes methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, i-butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, n-pentyloxycarbonyl, n -Hexyloxycarbonyl, n-heptyloxycarbonyl, n-octyloxycarbonyl are mentioned.
In addition, about a group whose definition is not described in this specification, a normal definition is followed.

  Specific examples of the compound represented by the general formula (I) of the present invention include the following compounds.

  The compound represented by the general formula (I) of the present invention, or a salt thereof, or a solvate thereof includes not only the compound of the present invention but also a pharmaceutically acceptable salt thereof, various hydrates thereof, It includes solvates, or crystalline polymorphs thereof, or substances that are prodrugs of these substances.

  As the pharmaceutically acceptable salt of the compound represented by the general formula (I) of the present invention, specifically, when the compound is treated as a basic compound, an inorganic acid (for example, hydrochloric acid, hydrobromic acid, Hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) and organic acids (eg formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid Acid addition salts with methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, etc.), and when the compound is treated as an acidic compound, an inorganic salt (for example, sodium salt, potassium salt) Salts, lithium salts, barium salts, calcium salts, magnesium salts, etc.) and organic salts (eg, pyridinium salts, picolinium salts, triethylammonium salts, etc.).

  As the solvate of the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof, a hydrate or various solvates (for example, a solvate with an alcohol such as ethanol). Is mentioned.

  The compound represented by the general formula (I) of the present invention can be produced with reference to a known method or a method analogous thereto. Although an example of a manufacturing method is shown below, the manufacturing method of the compound represented by general formula (I) of this invention is not limited to this.

（式中、Ｒ_１及びＲ_２は、前記と同じものを示し、Ｒは、−ＣＯ（ＣＨ_２）_２Ｐｈである）

(Wherein R ₁ and R ₂ are the same as described above, and R is —CO (CH ₂ ) ₂ Ph)

  Compounds (II) to (III), which are starting materials in reaction step i in Scheme 1 above, can be prepared from Bates, R. et al. W, et al. Tetrahedron, Vol. 51, no. 30, p. 8199-8212 (1995). Furthermore, compound (III) to compound (IV) (reaction step ii) are described in Tani, H .; , Et al. Bioorg. Med. Chem. , Vol. 18, p. 151-158 (2010). Further, the final compound (I) (reaction step iii) can be synthesized from the compound (IV) by the Mizoroki-Herk reaction.

For the purpose of avoiding side reactions, the substituents R ₁ and R ₂ of the compound (I) are protected with an appropriate protecting group, and the compound (I) is produced by deprotecting after completion of the reaction step. You can also. As the protection and deprotection conditions for the substituent, a generally used method (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.) can be used as a reference.

  Intermediates and target products obtained in the above reactions are necessary for purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, etc. Can be isolated and purified. In addition, the intermediate can be subjected to the next reaction without any particular purification.

  Furthermore, various isomers can be isolated by a conventional method utilizing the difference in physicochemical properties between isomers. For example, a racemic mixture is optically resolved by a general racemic resolution method such as a method of optical resolution by introducing a diastereomeric salt with a general optically active acid such as tartaric acid or a method using optically active column chromatography. To the pure isomer. Further, the diastereomeric mixture can be divided by, for example, fractional crystallization or various chromatography. An optically active compound can also be produced by using an appropriate optically active raw material.

Compound 1 listed in Table 1 above is a compound in which R ₁ = —COOH and R ₂ = 3-methylbut-2-en-1-yl group, and compound 2 is R ₁ = —COOH, and R _A compound in which ₂ = H. Here, the compound 1 is generally a compound called baccaroin and can be chemically synthesized based on the scheme 1 as described above, but can also be extracted from natural propolis.

  Propolis is a mixture of plant shoots and exudates collected by bees, tree sap, pollen, beeswax, and the like, and is a resinous solid mass. Propolis is composed of a wide variety of natural ingredients such as flavonoids, terpenoids, organic acids, amino acids, polysaccharides and minerals. So far, propolis has been reported to have various biological activities such as antibacterial activity, anti-inflammatory activity, analgesic activity, antipruritic activity, immunostimulatory activity, antitumor activity, and antioxidant activity (for example, JP 2003-55297), further research is being conducted on its components and biological activity. Baccharin is known as the main component of Brazilian propolis (Tani, H., et al., Inhibitory activity of Brazilian green proliferative components and their derivatives on the M. biotechnology. 18: 151-157, 2010). On the other hand, it is known that propolis extract has an action to improve insulin-dependent diabetes (type 1 diabetes) (for example, JP 2010-37211 A). As described above, the present inventors have verified that baccarin can be used as an antidiabetic drug by using a buccalin having an activity of promoting insulin secretion by a screening method developed by the present inventors (WO2012 / 029958 (Patent Document 1)).

  The insulin secretion promoter of the present invention can synergistically promote insulin secretion by combining the compound represented by the above general formula (I) with a sugar nucleotide or glucosamine. Here, the sugar nucleotide and glucosamine used in the insulin secretagogue of the present invention are technical terms well known to those skilled in the art. As used herein, “sugar nucleotide” means a nucleotide to which a sugar residue is bound, and may also be referred to as “nucleotide sugar”. Sugar nucleotides include, but are not limited to, uridine-5′-diphosphate glucose (“UDP-glucose”), adenosine-5′-diphosphate glucose (“ADP-glucose”), guanosine-5′-diphosphate. Acid glucose ("GDP-glucose"), cytidine-5'-diphosphate glucose ("CDP-glucose), uridine-5'-diphosphate glucuronic acid (" UDP-glucuronic acid "), uridine-5'- Diphosphate galactose (“UDP-galactose:”), uridine-5′-diphosphate-N-acetylglucosamine (“UDP-N-acetylglucosamine”), uridine-5′-diphosphate-N-acetylgalactosamine ("UDP-N-acetylgalactosamine"), uridine-5'-diphosphate xylose ("UDP-xylo ), Guanosine-5′-diphosphate fucose (“GDP-fucose”), guanosine-5′-diphosphate mannose (“GDP-mannose”), cytidine-5′-monophosphate-N-acetylneuramin Acid ("CDP-N-acetylneuraminic acid"), and salts thereof. In the present invention, it is not limited as long as it is a sugar nucleotide having an action of synergistically promoting insulin secretion when used together with the compound represented by the general formula (I), but preferably UDP-glucose, ADP-glucose, GDP-glucose and UDP-glucuronic acid.

  In the present invention, glucosamine can be used in place of “sugar nucleotide”. As used herein, “glucosamine” refers to an amino sugar also called 2-amino-2-deoxyglucose or chitosamine, and may be any of D-form, L-form, and DL-form. As glucosamine, N-acetyl-D-glucosamine is preferable. In this invention, it can be used with the compound and sugar nucleotide which are represented with general formula (I).

  The molar ratio of the compound represented by formula (I) and the sugar nucleotide or glucosamine used in the insulin secretagogue in the present invention is not limited, but is 1: 1 to 1: 1000, preferably 1: 2 to 1: 500, more preferably 1:10 to 1: 200. As will be described later, Example 1 shows the result of synergistically promoting insulin secretion when baccarain and UDP-glucose were used at various molar ratios (see FIG. 1).

  The insulin secretagogue of the present invention contains a compound represented by the general formula (I), a salt thereof or a solvate thereof, and a sugar nucleotide or glucosamine as active ingredients, and is used as a pharmaceutical composition. can do. According to the present invention, only these active ingredients may be used, but usually they are used in combination with a pharmaceutically acceptable carrier and / or diluent. In this case, the amount of the active ingredient added in the pharmaceutical composition of the present invention should be appropriately selected according to the specific form and purpose of the pharmaceutical composition, and is not limited. It is at least 0.01% by weight based on the total composition. Preferably it is 0.1 to 50% by weight, more preferably 0.5 to 30% by weight, even more preferably 1.0 to 10% by weight. In addition, when using the compound represented with general formula (I), sugar nucleotide, or glucosamine in a pharmaceutical composition, the molar ratio of each component is the same as that of the said insulin secretion promoter.

  The administration route is not particularly limited, but can be appropriately selected depending on the purpose of treatment. For example, any of oral preparations, injections, suppositories, inhalants and the like may be used. Pharmaceutical compositions suitable for these dosage forms can be produced by utilizing known preparation methods.

  When preparing an oral solid preparation, the compound represented by the general formula (I) and the sugar nucleotide or glucosamine are pharmaceutically acceptable excipients, and if necessary, a binder, a disintegrant, a lubricant, After adding a coloring agent, a flavoring agent, a flavoring agent and the like, tablets, coated tablets, granules, powders, capsules and the like can be produced by utilizing conventional methods. Additives may be those commonly used in the art. Examples of excipients include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid and the like. Examples of the binder include water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, and polyvinylpyrrolidone. Examples of the disintegrant include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose. Examples of the lubricant include purified talc, stearate, borax, and polyethylene glycol. Examples of the corrigent include sucrose, orange peel, citric acid, tartaric acid and the like.

  When preparing an oral liquid preparation, an oral solution is prepared by adding a corrigent, a buffer, a stabilizer, a corrigent and the like to the compound represented by the general formula (I) and the sugar nucleotide or glucosamine. Syrups, elixirs and the like can be produced. As the corrigent, those mentioned above may be used. Examples of the buffer include sodium citrate, and examples of the stabilizer include tragacanth, gum arabic, and gelatin.

  When preparing an injection, a pH adjuster, buffer, stabilizer, isotonic agent, local anesthetic, etc. are added to the compound represented by the general formula (I) and sugar nucleotide or glucosamine. Can be used to produce subcutaneous, intramuscular and intravenous injections. Examples of the pH adjuster and buffer include sodium citrate, sodium acetate, sodium phosphate and the like. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like. Examples of local anesthetics include procaine hydrochloride and lidocaine hydrochloride. Examples of isotonic agents include sodium chloride and glucose.

When preparing a suppository, a compound represented by the general formula (I) and a carrier for suppositories known to sugar nucleotides or glucosamine, such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride, etc., if necessary After adding a surfactant (for example, Tween (registered trademark)) or the like, it can be produced using a conventional method.
In addition to the above, it is possible to appropriately prepare a preferable preparation using a conventional method.

  The dose of the compound represented by the general formula (I) of the present invention and the sugar nucleotide or glucosamine varies depending on the age, body weight, symptom, dosage form and frequency of administration of the subject to be administered, but usually for adults. It is preferable that 1 mg to 1000 mg per day as the compound represented by the general formula (I) and sugar nucleotide or glucosamine is orally or parenterally administered once or several times.

  As shown in Example 1, which will be described later, in the NIT-1 cells in which insulin secretion is negatively controlled by expressing an insulin secretion regulator, insulin secretion is significantly increased by the addition of the insulin secretion promoter of the present invention. Will be increased. Therefore, the insulin secretagogue and pharmaceutical composition of the present invention can be used as an insulin alternative medicine and an alternative medicine for the purpose of preventing and / or treating diabetes.

2. According to the present invention, the use of a combination of the compound represented by the general formula (I) and the sugar nucleotide or glucosamine is limited to pharmaceuticals. However, it can also be given in various forms, for example, in the form of food or drink as a food composition or health food (preferably a functional food) or feed when used as a food additive. Here, food includes (1) a function as a nutrient (primary function), (2) a function that appeals to the human senses (secondary function), and (3) human health, physical ability, or psychology. Functions that have a positive effect on the condition (tertiary function), for example, to maintain the health and restore the health by regulating the physiological system such as digestive system, circulatory system, endocrine system, immune system, or nervous system It is known to have a positive effect. In the present specification, the “food composition or health food” means a food that has some effect on health or can be expected to have an effect. Furthermore, the “functional food” refers to the various bioregulatory functions (namely, digestive system, circulatory system, endocrine system, immune system, or nervous system such as nervous system) among the above “health food”. It means food that has been designed and processed so that it can fully express its regulatory function. In the present invention, a combination of a compound represented by the general formula (I) and a sugar nucleotide or glucosamine can be used as a functional food.

  The addition amount of the compound represented by the general formula (I) and the sugar nucleotide or glucosamine in the food composition of the present invention should be appropriately selected according to the specific form and purpose of the food composition of the present invention. Although it is not limited, the addition amount is about 1/1000 to 1/100 of the addition amount in the pharmaceutical composition as compared with the pharmaceutical composition, for example, 0.001 to 0.00 with respect to the whole composition. It may be 5% by mass, preferably 0.005 to 0.3% by mass. Moreover, in the functional food of the present invention, although not limited, the addition amount is about 1/100 to 1/10 of the addition amount in the pharmaceutical composition as compared with the pharmaceutical composition. It is 0.01-5 mass% with respect to it, Preferably it is 0.05-3 mass%. In addition, when using the compound represented with general formula (I), sugar nucleotide, or glucosamine in a food composition or a functional food, the molar ratio of each component is the same as that of the said insulin secretion promoter.

  According to one aspect of the present invention, a functional food comprising a combination of a food containing a compound represented by the general formula (I) or a pharmaceutically acceptable salt or solvate thereof and a food containing a sugar nucleotide or glucosamine. Can be provided. Here, the baccalin mentioned as a typical example of the compound represented by the general formula (I) is contained in Brazilian propolis. Propolis itself is marketed as health food or functional food. On the other hand, it is known that many sugar nucleotides are contained in, for example, yeast and bovine liver. Examples of foods or foods rich in glucosamine include shellfish such as shrimps and crabs, yams, eels, shark fins and the like.

  The following examples further illustrate the present invention, but the present invention is not limited to these examples.

Example 1: NIT-1 cells expressing insulin secretory insulin secretion regulators by a combination of buccalin and UDP-glucose in NIT-1 cells forcibly expressing insulin secretion regulators are disclosed in Japanese Patent Application Laid-Open No. 2010-2010. 196952. Baccharin (“Bac”) (0, 1.5, and 3 mM) and UDP-glucose (10, 30, 100, and 300 mM) were added in combination to the transformed NIT-1 cell culture system, Incubated for 10 minutes. As a control, a system in which no UDP-glucose was added and a system in which glucose (“Glc”) (2.8 mM and 22.2 mM) was added instead of UDP-glucose were used. Then, each culture medium was collect | recovered and the amount of insulin secretion per one minute (arbitrary unit) secreted from 1 cell was measured with the ELISA kit for Shibayagi Levis insulin measurement.

  The result of insulin secretion is shown in FIG. In the system to which Glc of Bac (3 mM) and Glc (22.2 mM (high concentration)) was added, a system having no additive other than Bac (indicated as “(−)”), and Glc of 2.8 mM Insulin secretion was noticeable (over about 100) compared to the system added at (low concentration). This was the same as the results previously disclosed by the present inventors (see JP 2010-196952). Next, in the system to which Bac and UDP-glucose were added, insulin secretion was as low as that of the control when UDP-glucose was 10 mM. On the other hand, in the system in which high concentration (30, 100, and 300 mM) UDP-glucose was added to Bac, very high insulin secretion was observed compared to the system in which Glc (high concentration) was added. It was done. In the system in which UDP-glucose exceeds 100 mM, remarkable insulin secretion was measured 100 to 1000 times higher than that of a single use system and more than 10 to 100 times higher than that of a Glc added system. From these results, it can be said that such high insulin secretion activity is due to a synergistic effect of each combination as compared with the case where Bac and UDP-glucose are used alone.

  The present invention can remarkably promote insulin secretion based on a synergistic effect by simultaneous use of buccalin and UDP-glucose, as compared with the conventionally reported single use of insulin secretion promoting factors such as buccalin. Therefore, it is possible to provide an antidiabetic therapeutic agent that is excellent in controlling blood sugar of diabetic patients, suppresses side effects, and reduces the dose.

  All publications and patent documents cited herein are hereby incorporated by reference in their entirety. While specific embodiments of the invention have been described herein for purposes of illustration, it will be apparent to those skilled in the art that various modifications may be made without departing from the spirit and scope of the invention. It will be easily understood.

Claims (10)

Formula (I):

(Where
R ₁ is a hydrogen atom, halogen, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, —OR ₃ , —CH ₂ OR ₄ , —COOR. ₅ , —COR ₆ , or —CON (R ₇ ) R ₈ , wherein R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R ₈ may be the same or different and are independent. And R ₂ is selected from the group consisting of a hydrogen atom, C _1-6 alkyl, and C _3-6 cycloalkyl; and R ₂ is a hydrogen atom, halogen, nitro, cyano, —OR ₉ (where R ₉ is Selected from the group consisting of a hydrogen atom, C _1-6 alkyl, and C _3-6 cycloalkyl), C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, or C _2-6 alkynyl Where C _1-6 Alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, and C _2-6 alkynyl contain at least one heteroatom selected from halogen; hydroxyl group; nitro; cyano; oxygen, nitrogen, and sulfur. And may have one or more substituents selected from the group consisting of phenyl, tolyl, naphthyl, pyridyl, thiazolyl, furyl, or thienyl; and alkoxycarbonyl)
Or a pharmaceutically acceptable salt or solvate thereof; and an insulin secretagogue comprising a sugar nucleotide or glucosamine as an active ingredient. The insulin secretion promoter according to claim 1, wherein R ₁ is a hydroxyl group; and R ₂ is hydrogen or C _2-6 alkenyl. The compound represented by the general formula (I) is:
(E) -3- [3- (3-Methylbut-2-en-1-yl) -4-{(3-phenylpropanoyl) oxy} phenyl] acrylic acid; or (E) -3- [4- The insulin secretion promoter according to claim 1 or 2, which is {(3-phenylpropanoyl) oxy} phenyl] acrylic acid.   The insulin secretion promoter according to any one of claims 1 to 3, wherein the sugar nucleotide is selected from the group consisting of UDP glucose, ADP glucose, GDP glucose, and UDP glucuronic acid.   The insulin secretion promoter according to any one of claims 1 to 3, wherein the glucosamine is N-acetyl-D-glucosamine. Formula (I):

(Where
R ₁ is a hydrogen atom, halogen, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, —OR ₃ , —CH ₂ OR ₄ , —COOR. ₅ , —COR ₆ , or —CON (R ₇ ) R ₈ , wherein R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R ₈ may be the same or different and are independent. And R ₂ is selected from the group consisting of a hydrogen atom, C _1-6 alkyl, and C _3-6 cycloalkyl; and R ₂ is a hydrogen atom, halogen, nitro, cyano, —OR ₉ (where R ₉ is Selected from the group consisting of a hydrogen atom, C _1-6 alkyl, and C _3-6 cycloalkyl), C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, or C _2-6 alkynyl Where C _1-6 Alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, and C _2-6 alkynyl contain at least one heteroatom selected from halogen; hydroxyl group; nitro; cyano; oxygen, nitrogen, and sulfur. And may have one or more substituents selected from the group consisting of phenyl, tolyl, naphthyl, pyridyl, thiazolyl, furyl, or thienyl; and alkoxycarbonyl)
Or a pharmaceutically acceptable salt or solvate thereof;
A pharmaceutical composition for preventing and / or treating diabetes comprising a sugar nucleotide or glucosamine; and a pharmaceutically acceptable carrier. Formula (I):

(Where
R ₁ is a hydrogen atom, halogen, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, —OR ₃ , —CH ₂ OR ₄ , —COOR. ₅ , —COR ₆ , or —CON (R ₇ ) R ₈ , wherein R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R ₈ may be the same or different and are independent. And R ₂ is selected from the group consisting of a hydrogen atom, C _1-6 alkyl, and C _3-6 cycloalkyl; and R ₂ is a hydrogen atom, halogen, nitro, cyano, —OR ₉ (where R ₉ is Selected from the group consisting of a hydrogen atom, C _1-6 alkyl, and C _3-6 cycloalkyl), C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, or C _2-6 alkynyl Where C _1-6 Alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, and C _2-6 alkynyl contain at least one heteroatom selected from halogen; hydroxyl group; nitro; cyano; oxygen, nitrogen, and sulfur. And may have one or more substituents selected from the group consisting of phenyl, tolyl, naphthyl, pyridyl, thiazolyl, furyl, or thienyl; and alkoxycarbonyl)
Or a pharmaceutically acceptable salt or solvate thereof; and a food composition having an insulin secretion-promoting action, comprising a sugar nucleotide or glucosamine. Formula (I):

(Where
R ₁ is a hydrogen atom, halogen, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, —OR ₃ , —CH ₂ OR ₄ , —COOR. ₅ , —COR ₆ , or —CON (R ₇ ) R ₈ , wherein R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R ₈ may be the same or different and are independent. And R ₂ is selected from the group consisting of a hydrogen atom, C _1-6 alkyl, and C _3-6 cycloalkyl; and R ₂ is a hydrogen atom, halogen, nitro, cyano, —OR ₉ (where R ₉ is Selected from the group consisting of a hydrogen atom, C _1-6 alkyl, and C _3-6 cycloalkyl), C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, or C _2-6 alkynyl Where C _1-6 Alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, and C _2-6 alkynyl contain at least one heteroatom selected from halogen; hydroxyl group; nitro; cyano; oxygen, nitrogen, and sulfur. And may have one or more substituents selected from the group consisting of phenyl, tolyl, naphthyl, pyridyl, thiazolyl, furyl, or thienyl; and alkoxycarbonyl)
Or a pharmaceutically acceptable salt or solvate thereof; and a functional food having an insulin secretion-promoting action, comprising a sugar nucleotide or glucosamine. Formula (I):

(Where
R ₁ is a hydrogen atom, halogen, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, —OR ₃ , —CH ₂ OR ₄ , —COOR. ₅ , —COR ₆ , or —CON (R ₇ ) R ₈ , wherein R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R ₈ may be the same or different and are independent. And R ₂ is selected from the group consisting of a hydrogen atom, C _1-6 alkyl, and C _3-6 cycloalkyl; and R ₂ is a hydrogen atom, halogen, nitro, cyano, —OR ₉ (where R ₉ is Selected from the group consisting of a hydrogen atom, C _1-6 alkyl, and C _3-6 cycloalkyl), C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, or C _2-6 alkynyl Where C _1-6 Alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, and C _2-6 alkynyl contain at least one heteroatom selected from halogen; hydroxyl group; nitro; cyano; oxygen, nitrogen, and sulfur. And may have one or more substituents selected from the group consisting of phenyl, tolyl, naphthyl, pyridyl, thiazolyl, furyl, or thienyl; and alkoxycarbonyl)
And a food containing a pharmaceutically acceptable salt or solvate thereof; and a food containing a sugar nucleotide or glucosamine. Formula (I):

(Where
R ₁ is a hydrogen atom, halogen, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, —OR ₃ , —CH ₂ OR ₄ , —COOR. ₅ , —COR ₆ , or —CON (R ₇ ) R ₈ , wherein R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R ₈ may be the same or different and are independent. And R ₂ is selected from the group consisting of a hydrogen atom, C _1-6 alkyl, and C _3-6 cycloalkyl; and R ₂ is a hydrogen atom, halogen, nitro, cyano, —OR ₉ (where R ₉ is Selected from the group consisting of a hydrogen atom, C _1-6 alkyl, and C _3-6 cycloalkyl), C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, or C _2-6 alkynyl Where C _1-6 Alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, and C _2-6 alkynyl contain at least one heteroatom selected from halogen; hydroxyl group; nitro; cyano; oxygen, nitrogen, and sulfur. And may have one or more substituents selected from the group consisting of phenyl, tolyl, naphthyl, pyridyl, thiazolyl, furyl, or thienyl; and alkoxycarbonyl)
Or a pharmaceutically acceptable salt or solvate thereof; and a method for preventing and / or treating diabetes, comprising administering an effective amount of a sugar nucleotide or glucosamine.

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