JP2011032267A - 11 beta hsd1 inhibitor and application thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an 11βHSD1 inhibitor containing a benzofuran derivative as an effective component. <P>SOLUTION: This 11βHSD1 inhibitor contains a compound expressed by general formula (1) or a salt thereof as an effective component, where in the formula, X is a hydroxy group, alkoxy group, amino group or trifluoromethyl group; Y is a hydrogen atom or halogen atom; and Z is a hydroxy group or alkoxy group. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to an 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) inhibitor and use thereof. More specifically, the present invention relates to an 11βHSD1 inhibitor containing a benzofuran derivative as an active ingredient, foods and medicines containing the 11βHSD1 inhibitor, and the like.

  Metabolic syndrome (MS) is a pathological condition in which metabolic abnormalities such as insulin resistance, impaired glucose tolerance, lipid metabolism, and hypertension accumulate, mainly in visceral fat obesity, and is a fatal event represented by myocardial infarction or stroke It is known to become the basis of the onset of the disease.

  In recent years, it has become clear that abnormal activation of glucocorticoid (GC) in adipocytes is involved in the development of MS from approaches focusing on adipose tissue function. The enzyme that converts inactive GC into active GC in the cell is 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1). In humans and rodents, 11βHSD1 shows higher enzyme activity and gene expression level in visceral adipose tissue than subcutaneous adipose tissue, and has a strong correlation with obesity and insulin resistance index.

  There are two types of 11βHSD, 11βHSD1 and 11βHSD2, as described below.

  Specifically, 11βHSD1 is highly expressed in GC target tissues such as liver and lung in addition to adipose tissue. 11βHSD1 is from 11-dehydrocorticosterone (11-dehydrocorticosterone (inactive)) to corticosterone (active) in rodents and from cortisone (inactive) in humans, It is converted into cortisol (cortisol (active form)) and activated. In 11βHSD1 systemic knockout mice, it is proved that 11βHSD1 is the only intracellular GC-activating enzyme in the living body because the administered inactive GC cannot be converted into active GC.

  On the other hand, 11βHSD2 is highly expressed in tissues such as kidney, large intestine, and placenta, and is responsible for the reverse reaction (converting activated GC to inactive GC) with 11β-HSD1.

  11βHSD1 is localized in the endoplasmic reticulum and requires NADPH as a coenzyme, and hexose-6-phosphate dehydrogenase (H6PDH) supplies this NADPH. H6PDH is also localized in the endoplasmic reticulum like 11β-HSD1. Glucose-6-phosphate (G6P) present in the cytoplasm flows into the endoplasmic reticulum via the G6P transporter (G6TP) and is converted to 6-phosphogluconic acid (6PG) by H6PDH, and simultaneously NADPH from NADP Generate. 11βHSD1 converts inactive GC to active GC using the produced NADPH as a coenzyme. In the cytoplasm, glucose-6-phosphate dehydrogenase (G6PDH) that performs the same reaction as H6PDH exists. However, since 11βHSD1 activity is not observed in H6PDH knockout mice, it is considered that 11βHSD1 activity is dependent on H6PDH.

  GC plays an important role in the differentiation and proliferation of adipocytes and inhibits glucose and lipid metabolism by insulin as a typical insulin antagonist hormone. In addition, blood pressure is increased through induction of angiotensinogen production and enhancement of angiotensin II receptor (ATI) expression. Furthermore, it has been suggested to cause overeating and obesity as a powerful leptin antagonist hormone. Therefore, GC is considered to be involved in the pathology of MS, and 11βHSD1 that activates GC is attracting attention as a molecular basis for the onset of MS.

  In recent years, the possibility of involvement of 11βHSD1 in MS has been verified in model mice in which 11βHSD1 has been genetically manipulated. That is, 11βHSD1 knockout mice show increased insulin sensitivity and improved glucose tolerance, suppressed visceral fat accumulation due to high-fat diet load, and are resistant to the onset and progression of MS.

  On the other hand, transgenic mice that overexpress 11βHSD1 in adipocytes express major signs of MS such as visceral fat accumulation, insulin resistance, lipid metabolism abnormality, hypertension, and fatty liver. What should be noted in this model mouse is that no increase in the blood GC concentration in the whole body is observed, but the GC concentration in the adipose tissue is 2 to 3 times higher than in the wild type, and it is transferred to the liver via the portal vein. The inflowing GC was also increasing. Furthermore, it has been reported that transgenic mice in which 11βHSD1 is overexpressed specifically in the liver in order to examine the effect of excessive GC on the liver exhibit hypertension and non-obese hyperinsulinemia. In addition, it has been reported that the signs of MS are improved by administration of an 11βHSD1 inhibitor to various MS pathological model mice. That is, in mice that are induced with obesity by loading with a high fat diet, suppression of weight gain, reduction of fat accumulation, and improvement of insulin resistance are observed by administration of the 11βHSD1 inhibitor. Furthermore, improvement in insulin resistance is observed in type 2 diabetes model mice, and blood lipids are decreased in arteriosclerosis model mice.

  Cushing's syndrome is a pathological condition that is highly suggestive in considering the onset mechanism of MS. This syndrome is characterized as hypercortisolemia and is accompanied by visceral fat obesity, insulin resistance, diabetes, dyslipidemia and hypertension. As an important difference between MS and Cushing's syndrome, it is noted that blood cortisol levels in most MS patients are at normal levels. This contrast suggests that blood cortisol levels do not necessarily determine the onset of MS pathology.

  From the above, the key to the prevention and treatment of visceral fat obesity and MS is to suppress (inhibit) 11βHSD1 activity that leads to excessive GC activation in the visceral adipose tissue.

  In addition, active glucocorticoids (cortisol in humans) have physiological functions such as gluconeogenesis, glucose uptake and glycolysis inhibition by insulin, adipose differentiation, angiotensinogen production or bone formation inhibition, and play an important role in vivo. Is responsible. However, excessive cortisol causes various diseases caused by impaired glucose tolerance, abnormal lipid metabolism, inhibition of bone formation, excessive secretion of adipocyte-derived physiologically active substances, and the like.

  For example, diseases caused by excessive production of cortisol include type 2 diabetes, impaired glucose tolerance, insulin resistance, dyslipidemia, hyperlipidemia, hypertriglyceridemia, obesity (especially visceral fat obesity), atheromatous arteries Examples include sclerosis, Cushing's syndrome, hypertension, cognitive impairment, memory impairment, depression, anxiety, dementia, Alzheimer's disease, osteoporosis and the like.

  Therefore, the 11βHSD1 inhibitor is effective for the treatment or prevention of such diseases.

  For example, Non-Patent Document 1 describes various 11βHSD1 inhibitors including carbenoxolone, compound 544, BVT2733.

  On the other hand, Patent Document 1 discloses that a 2- (4-hydroxyl) benzofuran derivative has a remarkable affinity for an estradiol receptor and exhibits a strong antiestrogenic action.

  In addition, the inventors of the present application show that 4- (2-benzofuranyl) phenol (KNPNP17) and 4- (3-methyl-benzofuranyl) phenol (KNPP20), which are benzofuran derivatives, exhibit 11βHSD1 inhibitory activity in adipose tissue. (Non-patent Document 2).

  In addition, the present inventors have revealed that 4- (2-benzofuranyl) phenol (KNPNP17) and Stemofuran A (KNPP25), which are benzofuran derivatives, show 11βHSD1 inhibitory activity in brain tissue (non-patented). Reference 3).

JP-T 6-507615 (published on September 1, 1994)

Drug Discovery Today, Volume 12, No.13 / 14 July 2007 pp 504-520. 13th International Congress of Endocrinology Nov.8-12 (2008) Rio de Janeiro. Abstracts of the 128th Annual Meeting of the Japanese Pharmaceutical Society Presentation Number: 27PW-pm014, March 2008 J. Org. Chem. Volume 70, 2005 pp 10292-10296

  It is an object of the present invention to provide an 11βHSD1 inhibitor containing a benzofuran derivative having a chemical structure different from that of the above-mentioned known compound as an active ingredient, and its use (utilization method).

  The present inventors have found that a specific benzofuran derivative significantly inhibits 11βHSD1 activity, and found a remarkable biological activity that a hydroxybenzofuran derivative selectively inhibits 11βHSD1 activity, thereby completing the present invention. I came to let you.

  That is, in order to solve the above problems, the 11βHSD1 inhibitor of the present invention has the following general formula (1) (wherein X is a hydroxyl group, an alkoxyl group, an amino group, or a trifluoromethyl group, and Y is a hydrogen atom) An atom or a halogen atom, and Z is a hydroxyl group or an alkoxyl group) or a salt thereof as an active ingredient.

  In the 11βHSD1 inhibitor of the present invention, the substituent X of the compound represented by the general formula (1) is preferably a hydroxyl group or an alkoxyl group bonded to the 5- or 6-position carbon of the benzofuran ring.

The 11βHSD1 inhibitor of the present invention is a compound represented by the above general formula (1),
3-iodo-6-methoxy-2- (4-methoxyphenyl) -benzofuran,
3-iodo-5-methoxy-2- (4-methoxyphenyl) -benzofuran,
6-methoxy-2- (4-methoxyphenyl) -benzofuran,
5-methoxy-2- (4-methoxyphenyl) -benzofuran,
2- (4-hydroxyphenyl) -6-benzofuranol, or
2- (4-Hydroxyphenyl) -5-benzofuranol is preferred.

  In the 11βHSD1 inhibitor of the present invention, it is preferable that the substituents X and Z of the compound represented by the general formula (1) are both hydroxyl groups.

The 11βHSD1 inhibitor of the present invention is a compound represented by the above general formula (1),
2- (4-hydroxyphenyl) -6-benzofuranol, or
Particularly preferred is 2- (4-hydroxyphenyl) -5-benzofuranol.

  The food of the present invention is characterized by containing any one of the above 11βHSD1 inhibitors.

  The medicament of the present invention is characterized by containing any one of the 11βHSD1 inhibitors.

  The medicament of the present invention is preferably a therapeutic or prophylactic agent for diseases involving glucocorticoids.

  In the medicament of the present invention, the above-mentioned diseases involving glucocorticoids include, for example, diabetes (particularly type 2 diabetes), diabetic complications, impaired glucose tolerance, insulin resistance, lipid metabolism abnormality, hyperlipidemia, hypertriglyceridemia , Obesity (especially visceral fat obesity), fatty liver, metabolic syndrome, atherosclerosis, fatal vascular events including myocardial infarction or stroke, Cushing syndrome, hypertension, cognitive impairment, memory impairment, depression, mania, anxiety Dementia, Alzheimer's disease, osteoporosis and the like.

  In the medicament of the present invention, it is more preferable that the disease involving the glucocorticoid is visceral fat obesity.

  In the medicament of the present invention, the disease associated with the glucocorticoid is more preferably metabolic syndrome.

  ADVANTAGE OF THE INVENTION According to this invention, the 11 (beta) HSD1 inhibitor which uses as an active ingredient the benzofuran derivative (benzofuran derivative shown by General formula (1)) from which a chemical structure differs from the well-known compound which shows 11 (beta) HSD1 inhibitory activity is realizable. In addition, according to the present invention, the 11βHSD1 inhibitor can be used as a food or pharmaceutical use for preventing or treating diseases caused by glucocorticoids.

  As described above, the present invention uses the benzofuran derivative represented by the general formula (1) or a salt thereof as an active ingredient. Therefore, the 11βHSD1 inhibitory activity has the effect of preventing or treating diseases caused by glucocorticoids.

It is a graph which shows the time-dependent inhibitory effect of KPNP9 with respect to 11 (beta) HSD1 of a mesenteric adipose tissue. It is a graph which shows the time-dependent inhibitory effect of KPNP13 with respect to 11 (beta) HSD1 of a mesenteric adipose tissue. It is a graph which shows the density | concentration dependence inhibitory effect of KPNP9 with respect to 11 (beta) HSD1 of a mesenteric adipose tissue. It is a graph which shows the density | concentration dependence inhibitory effect of KPNP13 with respect to 11 (beta) HSD1 of a mesenteric adipose tissue. It is a graph which shows the inhibitory activity with respect to 11 (beta) HSD1 of the mesenteric adipose tissue of KPNP9,13 and 17,25. It is a graph which shows the inhibitory effect with respect to 11 (beta) HSD1 of the mesentery adipose tissue of KPNP7,8,9,11,12,13. It is a graph which shows the inhibitory reaction form of KPNP9 with respect to 11 (beta) HSD1 of a mesenteric adipose tissue. It is a graph which shows the inhibitory reaction form of KPNP13 with respect to 11 (beta) HSD1 of a mesenteric adipose tissue. It is a graph which shows the concentration-dependent inhibitory effect of KPNP9 with respect to 11 (beta) HSD2 of a kidney. It is a graph which shows the density | concentration dependence inhibitory effect of KPNP13 with respect to 11 (beta) HSD2 of a kidney. 6 is a graph showing the weight of a mouse in Example 3. 6 is a graph showing the food intake of mice in Example 3. 6 is a graph showing the systolic blood pressure of mice in Example 3. It is a graph which shows 11 (beta) HSD1 activity in a brain tissue. It is a graph which shows the time-dependent inhibitory effect of KPNP9,13 with respect to 11 (beta) HSD1 of a cerebral cortex. It is a graph which shows the inhibitory effect of KPNP9,13 with respect to 11 (beta) HSD1 of a cerebral cortex. It is a graph which shows the density | concentration dependence inhibitory effect of KPNP9 with respect to 11 (beta) HSD1 of a cerebral cortex. It is a graph which shows the inhibition reaction form of KPNP9 with respect to 11 (beta) HSD1 of a cerebral cortex. It is a graph which shows the inhibitory reaction pattern of KPNP13 with respect to 11 (beta) HSD1 of a cerebral cortex. 10 is a graph showing the weight of a mouse in Example 5. It is a graph which shows the food intake of the mouse | mouth in Example 5. 6 is a graph showing the adipose tissue weight of a mouse in Example 5. 10 is a graph showing average blood pressure of mice in Example 5. 10 is a graph showing the systolic blood pressure of mice in Example 5.

  Hereinafter, an embodiment of the present invention will be described in detail with reference to FIGS. The present invention is based on the finding that a benzofuran derivative significantly inhibits the activity of 11βHSD1, which is the only intracellular GC activating enzyme in the living body.

1. 11βHSD1 Inhibitor of the Present Invention The 11βHSD1 inhibitor of the present invention comprises a compound represented by the following general formula (1) (hereinafter also referred to as “benzofuran derivative”) or a salt thereof as an active ingredient.

  The benzofuran derivative has a substituent X in the benzene portion of the benzofuran ring, a phenyl group having a substituent Y and a substituent Z at the 4-position in the furan portion.

  Here, the “substituent X” is bonded to any carbon at the 4th to 7th positions of the benzofuran ring. Specifically, the “substituent X” represents a hydroxyl group (—OH), an alkoxyl group (—OR; R is a hydrocarbon group), an amino group, or a trifluoromethyl group. That is, the “substituent X” can be rephrased as a polar group.

  In addition, an alkoxyl group shows a C1-C12 linear, branched, or cyclic alkoxy group. The alkoxyl group is preferably a linear or branched lower alkoxyl group having 1 to 6 carbon atoms, and more preferably a linear alkoxyl group having 1 to 6 carbon atoms. Specifically, the alkoxyl group includes methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, pentyloxy, 2,2-dimethylpropoxy and the like. Can be mentioned.

The amino group is a primary amino group represented by —NH ₂ , a secondary amino group in which one hydrogen of the primary amino group is substituted, or a tertiary amino in which any hydrogen of the primary amino group is substituted. Any of the groups may be used. Examples of the secondary amino group include an alkylamino group in which one hydrogen atom is substituted with an alkyl group. Examples of the tertiary amino group include a dialkylamino group in which any hydrogen is substituted with an alkyl group.

  On the other hand, the “substituent Y” is bonded to the 3-position carbon of the benzofuran ring. Specifically, the “substituent Y” is a hydrogen atom or a halogen atom (iodine, bromine, chlorine, fluorine atoms).

  Further, the phenyl group having a substituent Z at the 4-position is bonded to the 2-position carbon of the benzofuran ring. Specifically, the phenyl group having a substituent Z at the 4-position is a hydroxyphenyl group or a phenoxyl group. That is, the “substituent Z” is a hydroxyl group (—OH) or an alkoxyl group (similar to the alkoxyl group of the “substituent X”). For example, a 4-hydroxyphenyl group or a 4-alkoxyphenyl group is bonded to the carbon at the 2-position of the benzofuran ring as a phenyl group having a substituent Z at the 4-position.

As a specific example of such a benzofuran derivative, as shown below,
3-iodo-6-methoxy-2- (4-methoxyphenyl) -benzofuran (KNPNP7),
3-iodo-5-methoxy-2- (4-methoxyphenyl) -benzofuran (KNPNP11),
6-methoxy-2- (4-methoxyphenyl) -benzofuran (KNPP8),
5-methoxy-2- (4-methoxyphenyl) -benzofuran (KNPP12),
2- (4-hydroxyphenyl) -6-benzofuranol (KNPP9),
2- (4-Hydroxyphenyl) -5-benzofuranol (KNPP13) and the like can be mentioned.

  In addition, the “substituent X” of the benzofuran derivative is bonded to any of the carbons at the 4th to 7th positions of the benzofuran ring, but is bonded to the 5th or 6th carbon of the benzofuran ring. It is more preferable that it is bonded to carbon at the 6-position. Thereby, this invention 11 (beta) HSD1 inhibitor shows higher 11 (beta) HSD1 inhibitory activity.

  Moreover, the benzofuran derivative which the hydroxyl group couple | bonded with the benzofuran ring exists in the tendency which shows high 11 (beta) HSD1 inhibitory activity. Therefore, the “substituent X” is particularly preferably a hydroxyl group.

  A benzofuran derivative in which a 2- (4-hydroxy) phenyl group is bonded to the carbon at the 2-position of the benzofuran ring tends to exhibit high 11βHSD1 inhibitory activity. Therefore, the “substituent Z” is preferably a hydroxyl group.

  Thus, as a preferable combination of the benzofuran derivatives, “substituent X” and “substituent Z” are preferably both hydroxyl groups, and “substituent X” is the 5-position or 6-position of the benzofuran ring. More preferably, it is bonded to carbon. That is, among the above-exemplified compounds, 2- (4-hydroxyphenyl) -6-benzofuranol (KNPNP9) or 2- (4-hydroxyphenyl) -5-benzofuranol (KNPP13) is preferable. -(4-Hydroxyphenyl) -6-benzofuranol (KNPP9) is particularly preferred.

  In particular, a benzofuran derivative in which “substituent X” and “substituent Z” are both hydroxyl groups has a remarkable pharmacological activity that not only inhibits the activity of 11βHSD1, but also does not inhibit the activity of 11βHSD2. Therefore, the benzofuran derivative can be used as a selective 11βHSD1 inhibitor. In particular, as in Examples described later, 2- (4-hydroxyphenyl) -6-benzofuranol (KNPNP9) and 2- (4-hydroxyphenyl) -5-benzofuranol (KNPP13) are selectively used. It has been demonstrated to inhibit 11βHSD1.

  In the benzofuran derivative, hydrogen atoms other than “Substituent X”, “Substituent Y”, and “Substituent Z” are substituted with an arbitrary substituent as long as they do not affect 11βHSD1 inhibitory activity. May be. As an arbitrary substituent, a halogen atom, an alkyl group, an aryl group, a hydroxyl group, an amino group, an alkoxyl group etc. can be mentioned, for example.

  The benzofuran derivative is a known compound and can be manufactured based on the method described in Patent Document 1 or Non-Patent Document 4, for example, and thus the description of the manufacturing method is omitted.

  The benzofuran derivative may be in the form of any salt. These salts include all non-toxic salts, pharmacologically acceptable salts, prodrugs and the like. For example, the benzofuran derivative may have a hydroxyl group or an amino group in the molecule. Therefore, the salt of the said benzofuran derivative can be comprised using a hydroxyl group and an amino group. The salts of the benzofuran derivative are preferably non-toxic pharmacologically acceptable salts and water-soluble.

  Specifically, examples of the salts of the benzofuran derivative include metal salts, salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, and the like.

  Examples of the metal salt include salts of alkali metals (potassium, sodium, lithium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.); aluminum salts and the like.

  Examples of the salt with an inorganic acid include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, and the like.

  Examples of salts with organic acids include formate, acetate, trifluoroacetate, lactate, tartrate, oxalate, phthalate, fumarate, maleate, benzoate, citrate Methanesulfonate, succinate, malate, benzenesulfonate, p-toluenesulfonate, glucuronate, gluconate and the like.

  Note that a salt with an inorganic acid and a salt with an organic acid are also referred to as an acid adduct salt.

  Examples of the salt with an inorganic base include ammonium salts such as tetramethylammonium salt and tetrabutylammonium salt.

  Salts with organic bases include triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) methylamine, lysine, arginine, N-methyl-D- Examples include salts of organic amines such as glucamine.

  The salts of the benzofuran derivative also include solvates or solvates of the metal salts, ammonium salts, organic amine salts, and acid adduct salts of the benzofuran derivatives. The solvate is preferably non-toxic and water-soluble. Examples of suitable solvates include solvates such as water and alcohol solvents (ethanol and the like). The benzofuran derivative can be converted into a non-toxic salt or a pharmacologically acceptable salt by a known method.

  The salts of the benzofuran derivative include N-oxide in which the nitrogen atom of the amino group is oxidized.

  On the other hand, the prodrug of the benzofuran derivative indicates a compound that is converted into the benzofuran derivative by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo. That is, a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. to change to the above benzofuran derivative, a compound that is hydrolyzed, etc., by gastric acid, etc., to the above benzofuran derivative, and the like are shown.

  For example, when the compound represented by the general formula (1) has an amino group, as a prodrug of the benzofuran derivative, a compound in which the amino group is acylated, alkylated or phosphorylated (for example, the amino group is acetylated). , Eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethyl , Acetoxymethylated, tert-butylated compounds, etc.).

  On the other hand, when the compound represented by the general formula (1) has a hydroxyl group, as a prodrug of the benzofuran derivative, a compound in which the hydroxyl group is acylated, alkylated, phosphorylated or borated (the hydroxyl group is acetylated, palmitoyl). , Propanoylation, pivaloylation, succinylation, fumarylation, alanylation, dimethylaminomethylcarbonylated compounds, etc.).

  Such prodrugs of benzofuran derivatives can be produced by a method known per se. The prodrug may be either a hydrate or a non-hydrate. Further, the prodrug may be an oligomer or polymer in which a plurality of the benzofuran derivatives are polymerized. Also in this case, it is decomposed enzymatically or chemically in the living body to become the benzofuran derivative.

  Such salts of benzofuran derivatives (especially prodrugs) are excellent in sustaining action, gastrointestinal stability, oral absorption, and side effects, and can achieve low doses by improving bioavailability.

The benzofuran derivative and salts thereof may be labeled with a radioisotope (for example, ³ H, ¹⁴ C) or the like. Moreover, when various isomers exist in the benzofuran derivative and salts thereof, the 11βHSD1 inhibitor of the present invention may be a mixture of the isomers.

  In addition, the 11βHSD1 inhibitor of the present invention may contain one compound selected from the above-mentioned benzofuran derivatives or salts thereof as an active ingredient, or a mixture of a plurality of compounds as an active ingredient. May be.

  The 11βHSD1 inhibitor of the present invention may be in a solid form, a liquid form, or a semi-solid form. For example, when the 11βHSD1 inhibitor of the present invention is a single component of the benzofuran derivative or a salt thereof, it is in a solid form. The 11βHSD1 inhibitor of the present invention can be prepared in the form of tablets, capsules and the like preferred for oral administration. Moreover, if the said benzofuran derivative or its salt is melt | dissolved in a suitable solvent, it will become a semi-solid form (cream etc.), if it melt | dissolves a part with a liquid form. For example, the 11βHSD1 inhibitor of the present invention may be a solution or suspension obtained by dissolving or suspending the above benzofuran derivative or a salt thereof in distilled water for injection or physiological saline.

  Thus, the 11βHSD1 inhibitor of the present invention may be composed of the benzofuran derivative or a salt thereof, and in addition to the benzofuran derivative or a salt thereof, such as water, physiological saline, glycerol, or ethanol. One or more ingredients may be included. Further, the 11βHSD1 inhibitor of the present invention may contain auxiliary substances such as a wetting or emulsifying agent, a pH buffering substance, a stabilizing agent and an antioxidant.

  The 11βHSD1 inhibitor of the present invention as described above inhibits the activity of 11βHSD1, which is the only intracellular GC activating enzyme in the living body. Therefore, 11βHSD1 activity can be suppressed by administering an effective amount of the 11βHSD1 inhibitor of the present invention to a mammal. Mammals are not limited to humans, and examples include mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, and the like.

  Furthermore, a part of the 11βHSD1 inhibitor of the present invention can be used as a selective 11βHSD1 inhibitor that inhibits the activity of 11βHSD1 but does not inhibit the activity of 11βHSD2.

  Here, the inhibitory activity of 11βHSD1 is, for example, in the case of rats, 11-dehydrocorticosterone (inactive type) as a substrate and NADPH as a coenzyme are added to the microsomal fraction of cells expressing 11βHSD1 and incubated. The produced corticosterone (active form) can be measured by quantification by HPLC or the like. According to the present invention, in this assay, the amount of corticosterone produced is less than that of the control (solvent control) (ie, 11βHSD1 activity is reduced), preferably statistically relative to the amount of corticosterone produced in the control. A benzofuran derivative having a P value of 0.05 or less, more preferably a benzofuran derivative having a P value of 0.01 or less, is evaluated as “having 11βHSD1 inhibitory activity”.

On the other hand, the inhibitory activity of 11βHSD2 was generated by, for example, incubating by adding corticosterone (active form) as a substrate and NAD ⁺ as a coenzyme to the microsomal fraction of cells expressing 11βHSD2. 11-dehydrocorticosterone (inactive form) can be measured by quantifying with GC-MS or the like. In the present invention, in this assay, a benzofuran derivative having a statistically significant P value of 0.05 or more with respect to the amount of 11-dehydrocorticosterone produced as a control (solvent control) is expressed as “11βHSD2 inhibitory activity”. “None”.

2. Use of the 11βHSD1 Inhibitor of the Present Invention The 11βHSD1 inhibitor of the present invention exhibits an inhibitory action on the activity of 11βHSD1. Therefore, the 11βHSD1 inhibitor of the present invention can be used to treat diseases caused by glucocorticoids produced by 11βHSD1. For example, the 11βHSD1 inhibitor of the present invention can be used in the form of foods, pharmaceuticals, quasi drugs, cosmetics and the like as a composition containing the same. The content of the 11βHSD1 inhibitor in each composition is not particularly limited, but is preferably 0.001 to 99.999% by weight, more preferably 0.01 to 99.9% by weight based on the weight of the composition. It is.

  Note that “treating a disease” means reducing or eliminating symptoms of a disease involving glucocorticoids, either prophylactically (before onset) or therapeutically (after onset). “Treatment” includes not only the meaning of a general treatment that leads the pathology of a disease in the direction of healing, but also the meaning of suppressing the deterioration of the pathological condition (meaning the progress inhibitor that stops the progression of the pathological condition).

(1) Foodstuff of this invention The foodstuff of this invention is a thing (edible composition) formed by containing, adding or diluting the 11 (beta) HSD1 inhibitor of this invention. The food of the present invention includes beverages and feeds. The food of the present invention suppresses 11βHSD1 inhibitor.

  The method for producing the food of the present invention is not particularly limited, and examples thereof include cooking, processing, and production by a generally used method for producing foods. The produced food or beverage can contain the 11βHSD1 inhibitor of the present invention. May be contained, added and / or diluted.

  Although it does not specifically limit as the foodstuff of this invention, For example, confectionery, dairy products (for example, yogurt), health food (for example, a capsule, a tablet, powder), a drink (for example, soft drink, milk drink, Vegetable drinks) and drinks. Confectionery is preferable from the viewpoint of carrying convenience, and dairy products are more preferable from the viewpoint of having a large intake per time compared to confectionery and being easily consumed every day.

  The content of the 11βHSD1 inhibitor in the food according to the present invention is not particularly limited, and can be appropriately selected from the viewpoint of its function and expression of action.

  The shape of the food of the present invention is not particularly limited as long as the 11βHSD1 inhibitor of the present invention is contained, added and / or diluted, and contains an effective amount for expressing its physiological action. . The food of the present invention can be in any form of liquid or solid. For example, the food of the present invention may be in the form of tablets, granules, capsules, liquids, etc. that can be taken orally. When the food of the present invention is in a capsule form, it can be a soft capsule encapsulated by gelatin or the like. The capsule is made of, for example, a gelatin film prepared by adding water to raw material gelatin and dissolving it, and adding a plasticizer (glycerin, D-sorbitol, etc.) thereto.

  Since the food of the present invention contains an 11βHSD1 inhibitor, it has an 11βHSD1 inhibitory action. For this reason, if the foodstuff of this invention is ingested on a daily basis, 11 (beta) HSD1 inhibitory activity will be exhibited continuously. Therefore, the food of the present invention is suitable as a functional food (a food for specified health use) and a health food for preventing a disease involving glucocorticoid (particularly a disease caused by excessive production of glucocorticoid). In particular, the functional foods (such as foods for specified health use) of the present invention are suitable for use in the fields of health foods and preventive medicines for preventing diseases involving glucocorticoids. Diseases involving glucocorticoid will be described later.

  In addition to the 11βHSD1 inhibitor, which is an essential component, vitamins, carbohydrates, pigments, and fragrances that are usually added to foods can be appropriately added to the food of the present invention as optional components.

(2) Medicament of the Present Invention The medicament of the present invention contains the 11βHSD1 inhibitor of the present invention as an active ingredient. As described above, the medicament of the present invention may contain the above-described benzofuran derivative as a salt form such as a prodrug.

  The use of the medicament of the present invention is not particularly limited, but is suitable for treating diseases involving active glucocorticoids (particularly diseases involving excessive production of cortisol) in order to inhibit 11βHSD1. is there.

  Specifically, 11βHSD1 is an enzyme that converts inactive glucocorticoid (cortisone in humans) to active glucocorticoid (cortisol in humans). Cortisol has a physiological role such as gluconeogenesis, inhibition of sugar uptake and glycolysis by insulin, adipose differentiation, angiotensinogen production or bone formation inhibition, and plays an important role in vivo. However, excessive cortisol is known to cause various pathologies caused by abnormal glucose tolerance, abnormal lipid metabolism, inhibition of bone formation, excessive secretion of adipocyte-derived physiologically active substances, and the like.

  Therefore, the medicament of the present invention can be suitably used for the treatment or prevention of diseases caused by cortisol overproduction.

  Diseases caused by excessive production of cortisol include various metabolic diseases such as metabolic syndrome, fatal events based on metabolic syndrome, neurodegenerative diseases, emotional disorders, schizophrenia, and neurological dysfunction diseases including increased appetite And immune diseases.

  Specifically, diseases caused by excessive production of cortisol include, for example, diabetes (particularly type 2 diabetes), diabetic complications, impaired glucose tolerance, insulin resistance, lipid metabolism abnormality, hyperlipidemia, hypertriglyceridemia , Obesity (especially visceral fat obesity), fatty liver, metabolic syndrome, atherosclerosis, fatal vascular events including myocardial infarction or stroke, Cushing syndrome, hypertension, cognitive impairment, memory impairment, depression, mania, anxiety Dementia, Alzheimer's disease, osteoporosis and the like.

  It is preferable to administer the medicament of the present invention to a patient who has developed or is likely to develop such a disease. In particular, it is more preferable to administer to a patient who has developed or is likely to develop visceral fat-type obesity or metabolic syndrome. Thereby, the inhibitory action of 11 (beta) HSD1 activity is shown in the living body, and the preventive or therapeutic effect of cortisol overproduction is acquired.

  Here, the medicament of the present invention is only required to have at least 11βHSD1 inhibitory activity, but preferably does not have 11βHSD2 inhibitory activity. If the medicament of the present invention also shows 11βHSD2 inhibitory activity in addition to 11βHSD1 inhibitory activity, cortisol (active form) cannot be converted to cortisone (inactive form). As a result, cortisol that is not converted to cortisone accumulates, and the accumulated cortisol exhibits various pharmacological actions.

  For example, 11βHSD2 is mainly present in kidney tissue. For this reason, if 11βHSD1 inhibitor inhibits the activity of 11βHSD2 in kidney tissue, cortisol is not inactivated. As a result, accumulation of the accumulated cortisol may cause side effects such as hypertension.

  Accordingly, the medicament of the present invention preferably inhibits 11βHSD1 activity but does not inhibit 11βHSD2 activity. That is, the 11βHSD1 inhibitor preferably contains an 11βHSD1 inhibitor that selectively inhibits 11βHSD1 activity. Thereby, 11 (beta) HSD2 activity is inhibited and the side effect by accumulation | storage of cortisol can be reduced or prevented.

  In addition, the side effect by accumulation | storage of cortisol can also be reduced or prevented by administering the pharmaceutical of this invention specifically to a target site | part by techniques, such as local administration or DDS.

  The medicament of the present invention has low toxicity, and the medicament of the present invention is used as it is or mixed with a pharmacologically acceptable carrier according to a means known per se that is generally used as a method for producing a pharmaceutical preparation. Tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release pharmaceutical preparations, etc., orally or parenterally ( (Eg, topical, rectal, intravenous administration, etc.).

  The content of the active ingredient present in the medicament of the present invention is such that the benzofuran derivative or a salt thereof can be administered within the dosage range described below using the medicament in consideration of the administration form, administration method and the like. If there is no particular limitation. For example, the content can be about 0.01 to about 100% by weight of the total pharmaceutical formulation.

  The dosage of the medicament of the present invention is appropriately set according to the preparation form, administration subject, administration route, disease, age, weight, symptom of the subject patient, benzofuran derivative as the active ingredient, etc., and is not constant. In general, the dose of the active ingredient contained in the preparation is preferably 0.01 to 1000 mg / kg, more preferably 0.1 to 200 mg / kg per day for an adult. Of course, since the dosage varies depending on various conditions, an amount smaller than the above dosage may be sufficient or may be necessary beyond the range.

  In addition, in order to selectively inhibit 11βHSD1 activity, this dose may be reduced as compared with the case of non-selectively inhibiting 11βHSD1 activity. However, the Example (Example 3) described below does not show 11βHSD2 inhibitory activity even at a relatively high dose. Therefore, the dose may be the same for selectively inhibiting 11βHSD1 activity and for nonselectively inhibiting 11βHSD1 activity.

  Administration may be carried out in a single dose or divided into several doses within a desired dose range. In addition, when the medicament of the present invention is applied as an infusion preparation, for example, it can be continuously administered intravenously. In this case, for example, several hundred mg to several hundred g of the active ingredient may be added to a 500 mL solution. Moreover, the medicament of the present invention can be administered orally or parenterally as it is, or can be added to any food or drink and taken on a daily basis.

  Examples of the pharmacologically acceptable carrier that may be used in the production of the medicament of the present invention include various organic or inorganic carrier substances that are conventionally used as a preparation material. For example, excipients, lubricants in solid preparations, Examples include binders and disintegrants, or solvents, solubilizers, suspending agents, isotonic agents, buffers, stabilizers and soothing agents in liquid preparations. Further, if necessary, additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.

  In particular, when the medicament of the present invention is used as an injection or infusion preparation, it is preferable to make the medicament into a kit (kit preparation). The kit preparation indicates a package including a container (for example, a bottle, a plate, a tube, a dish, etc.) containing a specific material, and includes a vial used for an injection. The kit preparation may be in the form of a vial preparation containing the benzofuran derivative or a salt thereof, or a kit preparation comprising the benzofuran derivative or a salt thereof and an aqueous solvent.

  When the medicament of the present invention is a vial preparation, the size of the vial is appropriately selected according to the purpose of use. For example, when an injection solution prepared by injecting an aqueous solvent into the vial and dissolving the benzofuran derivative or a salt thereof is used by inhaling the syringe, the size of the vial is about 1 to about 50 mL. . Also, for example, when used for infusions where a larger volume of injectable solution needs to be prepared at once, the vial size is about 50 to about 300 mL.

  When the medicine of the present invention is a kit preparation, the kit preparation is integrally molded, and the above-mentioned benzofuran derivative or a salt thereof is sealed in one room of a bag consisting of a plurality of rooms partitioned by a partition wall and dissolved in another room. A physiological saline solution or a glucose solution as a liquid is sealed, and the partition walls in both chambers can be easily opened at the time of use, and both can be mixed and dissolved at the time of use. The kit preparation may have a configuration in which the medicine of the present invention is added from the beginning to a single bag that is not partitioned into a plurality of rooms as described above.

  Although the time which administers the pharmaceutical of this invention is not specifically limited, When expecting the preventive effect, it is preferable to administer on a daily basis before onset of the above-mentioned disease. Moreover, what is necessary is just to administer the pharmaceutical of this invention after onset of the above-mentioned disease, when expecting a therapeutic effect. When both effects are expected, administration may be started on a daily basis and continued after treatment of the above-mentioned diseases.

  The medicament of the present invention can be used in combination with a drug (concomitant drug) other than the medicament of the present invention.

  Examples of drugs that can be used in combination with the medicament of the present invention include α-glucosidase inhibitors.

  Furthermore, the medicament of the present invention can be used in combination with a drug (see Non-Patent Document 1) that has been observed to inhibit 11βHSD1 activity or to selectively inhibit 11βHSD1 activity in animal models or clinically.

Thus, the following excellent effects can be obtained by combining the medicament of the present invention and the concomitant drug.
(I) The dosage can be reduced as compared with the case where the pharmaceutical or concomitant drug of the present invention is administered alone.
(Ii) A drug to be used in combination with the medicament of the present invention can be selected according to the patient's symptoms (mild, severe, etc.).
(Iii) By selecting a concomitant drug having a different mechanism of action from the medicament of the present invention, the treatment period can be set short.
(Iv) By selecting a concomitant drug having a different mechanism of action from the medicament of the present invention, the therapeutic effect can be sustained.
(V) A synergistic effect can be obtained by using the drug of the present invention and the concomitant drug in combination.

  When the drug of the present invention and the concomitant drug are used in combination, the administration timing of the drug of the present invention and the concomitant drug is not limited, and the drug of the present invention and the concomitant drug may be administered simultaneously to the administration subject. However, it may be administered with a time difference. The dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.

Examples of the dosage form of the medicament of the present invention and the concomitant drug include,
-Administration of a single preparation obtained by simultaneously formulating the medicament of the present invention and a concomitant drug;
-Simultaneous administration by the same administration route of two kinds of preparations obtained by separately formulating the medicament of the present invention and the concomitant drug;
・ Administration of two kinds of preparations obtained by separately formulating the medicine of the present invention and the concomitant drug at a time difference in the same administration route ・ obtained by formulating the medicine of the present invention and the concomitant drug separately Simultaneous administration of two preparations by different administration routes-Administration of two preparations obtained by separately formulating the pharmaceutical of the present invention and a concomitant drug separately at different time intervals in different administration routes (for example, the present invention Administration of drugs, concomitant drugs in reverse order, or reverse order)
Etc.

  As described above, according to the present invention, a disease caused by excessive production of cortisol can be prevented or treated by the inhibitory effect of 11βHSD1 activity possessed by a benzofuran derivative. Moreover, according to this invention, the foodstuff and pharmaceutical which have the inhibitory effect of 11 (beta) HSD1 can be provided. Therefore, according to the present invention, an effective prophylactic method and / or therapeutic method for a disease caused by cortisol overproduction can be established.

  The present invention is not limited to the above-described embodiments, and various modifications can be made within the scope shown in the claims. That is, embodiments obtained by combining technical means appropriately modified within the scope of the claims are also included in the technical scope of the present invention.

In Examples 1, 2 and 4 below, male Wistar rats, 10 weeks old (body weight: 240 to 260 g) were used as experimental animals after breeding for 1 week. Moreover, the numerical value in a figure represents an average value +/- standard error (mean +/- SE) or an average value (mean). The number of specimens in each group was n = 3 to 5, and the significant difference test was performed using the Dunnett test for comparison with the control (vehicle) group. “**” in each figure indicates that p <0.01 and “*” is p <0.05 in Dunnett's test. Moreover, the correspondence between the number of the benzofuran derivative used in the examples (KNPP) and the compound name is as follows.
KNPP7: 3-iodo-6-methoxy-2- (4-methoxyphenyl) -benzofuran KSNP8: 6-methoxy-2- (4-methoxyphenyl) -benzofuran NPNP9: 2- (4-hydroxyphenyl) -6-benzo Furanol NPNP11: 3-iodo-5-methoxy-2- (4-methoxyphenyl) -benzofuran KSNP12: 5-methoxy-2- (4-methoxyphenyl) -benzofuran QPNP13: 2- (4-hydroxyphenyl) -5 Benzofuranol NPNP17: 4- (2-benzofuranyl) phenol KSNP25: Stemofuran A.

[Example 1] 11βHSD1 inhibitory activity in rat mesenteric adipose tissue (1) Time-dependent inhibitory action Microsomes prepared from rat mesenteric adipose tissue were added to incubation buffer (pH 7.0) at 37 ° C. After incubation, the resulting corticosterone was quantified by HPLC. The incubation buffer is a 20 mM MOPS buffer containing 1-M of 11-dehydrocorticosterone (substrate), β-NADP ⁺ 1 mM, G6P6 mM, and 25 μM of a benzofuran derivative (KNPNP9,13). 14 μL of 25 unit / mL G6PDH was added to 1 mL of this incubation buffer (final G6PDH concentration: 0.35 unit / mL), and preincubated for 5 minutes in a 37 ° C. water bath. Next, 10 μL of microsome was added (final microsomal protein concentration: 40 μg / mL) to start the reaction. After incubation for 40 minutes, 2.0 mL of dichloromethane was added to stop the reaction. Centrifugation was performed, and the dichloromethane layer was separated. To the remaining aqueous layer, 2.0 mL of dichloromethane was again added, followed by centrifugal separation. The dichloromethane layer was combined with the dichloromethane layer collected for the first time. After the dichloromethane layer was dried under reduced pressure, the concentration of produced corticosterone was quantified by HPLC to determine 11βHSD1 activity.

  For the determination of corticosterone, NANOSPACE SI-1 semi-micro HPLC system (SHISEIDO) equipped with UV detector and autosampler was used. Capcellpak C18 MGII type (3 μm), 250 mm × 2 mm ID was used as the analytical column. It was used. The measurement conditions were as follows: the flow rate was 0.1 mL / min, the mobile phase solvent was water-methanol (45:55, v / v), the column temperature was 40 ° C., the detection wavelength was 240 nm, the sample injection amount was 20 μL, and the analysis time. Was 12 minutes. And corticosterone was quantified from the calibration curve prepared beforehand.

  FIG. 1 is a graph showing the time-dependent inhibitory effect of KPNP9 on 11βHSD1. FIG. 2 is a graph showing the time-dependent inhibitory effect of KPNP13 on 11βHSD1.

  As a result, as shown in FIGS. 1 and 2, the 11βHSD1 activity in rat adipose tissue microsomes was suppressed over time by the addition of a benzofuran derivative. In addition, as shown in the figure, since the graph shows linearity, it was confirmed that the benzofuran derivative itself inhibited 11βHSD1, and its metabolite did not inhibit 11βHSD1. In the figure, the black circles indicate the results of the control, and the black triangles indicate the results of adding the benzofuran derivative.

(2) Concentration-dependent inhibitory action Prepared from rat mesenteric adipose tissue in 20 mM MOPS buffer containing 11-dehydrocorticosterone (1 μM), NADPH (1 mM), benzofuran derivative (KNPNP9, 13: 1 to 50 μM) The microsomes (final microsomal protein concentration: 40 μg / mL) were added and incubated at 37 ° C. for 40 minutes, and the produced corticosterone was quantified by HPLC.

  FIG. 3 is a graph showing the concentration-dependent inhibitory action of KPNP9 on 11βHSD1. FIG. 4 is a graph showing the concentration-dependent inhibitory effect of KPNP13 on 11βHSD1.

  As a result, as shown in FIGS. 3 and 4, the 11βHSD1 activity in rat adipose tissue microsomes was significantly suppressed in a dose-dependent manner by the addition of a benzofuran derivative. In particular, as shown in FIG. 3, the addition of 5 μM or more of KPNP9 showed a strong inhibitory activity of 60% or more. In the figure, “CBX” indicates the result of carbenoxolone (50 μM) used as a positive control. Further, the IC50 of KPNP9 obtained from the figure is 4.5 μM, and the IC50 of KPNP13 is 10 μM.

  On the other hand, FIG. 5 is a diagram comparing the inhibitory activities of KPNP9,13 and 17,25 against 11βHSD1. As shown in the figure, any of the benzofuran derivatives showed significantly 11βHSD1 inhibitory activity relative to the control. In particular, KPNP9 showed strong inhibitory activity.

  Similarly, 11βHSD1 inhibitory activity of KPNP7, 8, 11, 12 was confirmed. FIG. 6 is a graph showing the inhibitory action of KPNP7, 8, 9, 11, 12, 13 on 11βHSD1. As shown in the figure, it was confirmed that any of the benzofuran derivatives had 11βHSD1 activity lower than that of the control and exhibited 11βHSD1 inhibitory activity.

(3) Inhibition reaction pattern Lineweaver-Burk plot was created in the same manner as in (2) above, and the inhibition reaction form was examined (final microsomal protein concentration: 2.8 mg / mL). FIG. 7 is a graph showing the inhibition reaction pattern of KPNP9 against 11βHSD1. FIG. 8 is a graph showing the inhibition reaction pattern of KPNP13 against 11βHSD1.

  As a result, as shown in FIG. 7 and FIG. 8, the inhibition reaction mode of the 11βHSD1 activity in rat adipose tissue microsomes by the benzofuran derivative was non-antagonistic. That is, it was confirmed that the binding sites of KPNP9 and KPNP13 to 11βHSD1 are different from the binding site of dehydrocorticosterone as a substrate. Also, the Km value for 11βHSD1 obtained from the same figure was 0.6 μM to 1.3 μM, which was almost consistent with previous reports. Furthermore, the inhibition constant Ki value for 11βHSD1 of KPNP9 obtained from Dixon plot was 1 μM, and the Ki value of KPNP13 was 8 μM.

[Example 2] 11βHSD2 inhibitory activity in rat kidney Microsomes were prepared from rat kidney, incubated at 37 ° C. in addition to incubation buffer (pH 7.4), and the resulting 11-dehydrocorticosterone was produced by GC-MS method. Quantified with. The incubation buffer is a 5 mM MOPS buffer containing 1 μM corticosterone (substrate), β-NAD ⁺ 2 mM, and 50 μM benzofuran derivative (KNPNP9,13). 1 mL of this incubation buffer was preincubated for 5 minutes in a 37 ° C. water bath. Next, 10 μL of microsome was added (final microsomal protein concentration: 2.26 mg / mL) to start the reaction. After incubation for 30 minutes, 2.0 mL of dichloromethane was added to stop the reaction. Centrifugation was performed, and the dichloromethane layer was separated. To the remaining aqueous layer, 2.0 mL of dichloromethane was again added, followed by centrifugal separation. The dichloromethane layer was combined with the dichloromethane layer collected for the first time. After the dichloromethane layer was dried under reduced pressure, the produced 11-dehydrocorticosterone was extracted. The extracted 11-dehydrocorticosterone is dissolved in 0.1 mL of methanol, 50 μL of pentafluoropropionic anhydride (PFPA) is added as a GC / MS derivatizing agent, and reacted at 70 ° C. for 60 minutes. Next, 0.1 mL of androstenediol-containing dichloromethane solution (200 ng / mL) as an internal standard substance was added to the residue after drying under reduced pressure, and further 0.1 mL of dichloromethane was added to make the total volume 0.2 mL. A sample of MS was used.

  For quantification of 11-dehydrocorticosterone, a Hewlett-Packard mass spectrometer (Model 5973) and a Hewlett-Packard gas chromatography (Model 6890) were used, and J & W DB-1 column (length) was used. 15 m, 0.25 mm ID, film thickness 0.1 μm). The measurement conditions were an ionization voltage of 70 eV, a helium gas flow rate of 1 mL / min, an injector temperature of 300 ° C., an interface temperature of 290 ° C., a column oven temperature of 50 ° C. at the initial stage (1.5 min), The temperature was raised at 30 ° C./min, and the final temperature was 300 ° C. (2 min). And 11-dehydrocorticosterone was quantified from the calibration curve prepared beforehand.

  FIG. 9 is a graph showing the concentration-dependent inhibitory action of KPNP9 on 11βHSD2. FIG. 10 is a graph showing the concentration-dependent inhibitory effect of KPNP13 on 11βHSD2.

  As a result, as shown in FIGS. 9 and 10, neither KPNP9 nor KPNP13 inhibited 11βHSD2 activity. On the other hand, as shown in FIG. 10, CBX (carbenoxolone), which is a positive control, significantly suppressed the activity of 11βHSD2.

[Example 3] Animal experiment-1
Male 5-week-old C57BL / 6J mice (weight: 18.1 to 21.5 g) were purchased, and 6-week-old mice fed with a normal diet for 1 week were used as experimental animals. In the benzofuran derivative administration group, 170 mg / kg / day of KPNP9 was mixed with olive oil, and 0.1 mL / kg / day was orally administered. On the other hand, olive oil 0.1 mL / kg / day was administered to the control group. In addition, the diet during the test was changed from a normal diet to a high fat diet (60 kcal% lard). And the body weight before and after the test, food intake, and blood pressure were compared. FIG. 11 is a graph showing the weight of a mouse. FIG. 12 is a graph showing the food intake of mice. FIG. 13 is a graph showing the systolic blood pressure of mice.

  As shown in FIG. 11, the body weight after 14 days was significantly reduced in the benzofuran derivative-administered group compared to the control group. However, as shown in FIG. 12, there is no difference in food intake between the two groups. Thus, administration of KPNP9 inhibited 11βHSD1 and significantly reduced body weight.

  In addition, as shown in FIG. 13, no difference in systolic blood pressure was observed between the two groups. That is, administration of KPNP9 did not show side effects of hypertension due to inhibition of 11βHSD2. Therefore, it was confirmed that KPNP9 selectively inhibits 11βHSD1.

[Example 4] 11βHSD1 inhibitory activity in rat brain tissue Microsomes were prepared from brain tissue (cerebral cortex, hippocampus, hypothalamus, and cerebellum), and in the same manner as in Example 1, in each part in the absence of a benzofuran derivative. 11βHSD1 activity and 11βHSD1 activity when a benzofuran derivative (KNPP9, 13) was added were measured.

  FIG. 14 is a graph showing 11βHSD1 activity in rat brain tissue. As shown in FIG. 13, 11βHSD1 activity was confirmed in all of the cerebral cortex, hippocampus, hypothalamus and cerebellum. In particular, in the hippocampus and cerebellum, 11βHSD1 activity is higher compared to other sites. In addition, the result of each site | part in FIG. 14 performed the significant difference test by the Turkey method.

  On the other hand, FIG. 15 is a graph showing the time-dependent inhibitory action of KPNP9, 13 on 11βHSD1 in the cerebral cortex. As shown in FIG. 15, the 11βHSD1 activity in rat cerebral cortex microsomes was suppressed over time by the addition of a benzofuran derivative. In addition, as shown in the figure, since the graph shows linearity, it was confirmed that the benzofuran derivative itself inhibited 11βHSD1, and its metabolite did not inhibit 11βHSD1.

  FIG. 16 is a graph showing the inhibitory action of KPNP9,13 on 11βHSD1 in the cerebral cortex. FIG. 17 is a graph showing the concentration-dependent inhibitory effect of KPNP9 on 11βHSD1 in the cerebral cortex. As shown in FIG. 16, 11βHSD1 activity in rat cerebral cortical microsomes was significantly suppressed by the addition of KPNP9,13. In particular, as shown in FIG. 17, the addition of 10 μM or more of KPNP9 showed a strong inhibitory activity of 40% or more. Further, the IC50 of KPNP9 obtained from the figure is 8.5 μM.

  On the other hand, FIG. 18 is a graph showing the inhibition reaction form of KPNP9 against 11βHSD1. FIG. 19 is a graph showing the inhibition reaction pattern of KPNP13 against 11βHSD1.

  As shown in FIG. 18 and FIG. 19, the inhibition reaction mode of the 11βHSD1 activity in the rat cerebral cortical microsomes by the benzofuran derivative was non-antagonistic. That is, it was confirmed that the binding sites of KPNP9 and KPNP13 to 11βHSD1 are different from the binding site of dehydrocorticosterone as a substrate. Also, the Km value for 11βHSD1 obtained from the same figure was 2 μM, which was almost consistent with previous reports. Furthermore, the inhibition constant Ki value for 11βHSD1 of KPNP9 obtained from Dixon plot was 1 μM, and the Ki value of KPNP13 was 10 μM.

[Example 5] Animal experiment-2
Male 3-year-old C57BL / 6J mice (weight: 18.1 to 21.5 g) were purchased, and 5-week-old mice fed with a normal diet for 2 weeks were used as experimental animals. The test groups were: normal food intake + benzofuran derivative non-administration group (control (−)), normal food intake + benzofuran derivative administration group (control (+)), high fat food intake + benzofuran derivative non-administration group (HF (−)) ), High fat diet intake + benzofuran derivative administration group (HF (+)), and the number of specimens in each group was n = 13-15. In the benzofuran derivative administration group, 100 mg / kg / day of KPNP9, which is less than in Example 3, was mixed with olive oil, and 0.1 mL / kg / day was orally administered. On the other hand, olive oil 0.1 mL / kg / day was administered to the benzofuran derivative non-administered group. Then, the body weight during the test period, food intake, adipose tissue weight, blood pressure, and adipose tissue weight after completion of the test were compared. FIG. 20 is a graph showing the weight of the mouse. FIG. 21 is a graph showing the food intake of mice. FIG. 22 is a graph showing the adipose tissue weight of a mouse. FIG. 23 is a graph showing average blood pressure of mice. FIG. 24 is a graph showing the systolic blood pressure of mice.

  The enlarged graph in FIG. 20 shows the weight on the 21st to 30th days. As shown in FIG. 20, significant weight loss was observed in the HF (+) group as compared with the HF (−) group from the 28th day to the 30th day after the start of administration of the benzofuran derivative. During the test period, there was no significant difference in body weight between the control (-) group and the control (+) group, suggesting that the body weight-suppressing effect by administration of KPNP9 is not due to cytotoxicity. . Moreover, although there was no significant difference, since the weight increase tendency was seen in the HF (-) group compared with the control (-) group, it is thought that obesity is induced by HF. In the significant difference test in FIG. 20, comparison with the HF (−) group is performed using the Dunnett test, “**” is p <0.01, and “*” is p <0.05. Indicates. Moreover, as shown in FIG. 21, there was no difference between the groups in the amount of food intake during the test period. Thus, KPNP9 inhibited 11βHSD1 and significantly suppressed weight gain.

  In addition, the tissue weights of subcutaneous fat, mesenteric fat, testicular fat, brown fat, liver, and kidney were measured in each group after the end of the test period (day 30 after administration of benzofuran derivative: 10 weeks old). As a result, as shown in FIG. 22, the tissue weights of subcutaneous fat, mesenteric fat, and testicular fat in the HF (−) group were significantly increased compared to the control (−) group. Furthermore, the tissue weights of subcutaneous fat, mesenteric fat, and testicular fat were significantly reduced in the HF (+) group as compared to the HF (−) group. Since no significant difference in tissue weight was observed between the control (−) group and the control (+) group, it was suggested that the decrease in tissue weight due to administration of KPNP9 was not due to cytotoxicity. The significant difference test in FIG. 22 is performed using a Tukey test, where “**” indicates p <0.01 and “*” indicates p <0.05. Thus, KPNP9 inhibited 11βHSD1 and significantly reduced the tissue weight of subcutaneous fat, mesenteric fat, and testicular fat closely related to metabolic syndrome (MS).

  Moreover, the blood pressure of each group was measured before the start of benzofuran derivative administration (3 weeks of age), 16 days (5 weeks of age) and 32 days (10 weeks of age) after the start of administration. The blood pressure was measured by the tail cuff method using a non-invasive automatic blood pressure measuring device (Softtron BP-98A-L). As a result, as shown in FIGS. 23 and 24, no difference was observed between the groups in the mean blood pressure and the systolic blood pressure at any measurement. That is, it was confirmed that both the high fat diet and KPNP9 do not affect blood pressure. Thus, it was confirmed that KPNP9 does not show the side effect of hypertension due to inhibition of 11βHSD2, but selectively inhibits 11βHSD1.

  According to the present invention, a disease involving cortisol can be prevented or treated by the inhibitory effect of 11βHSD1 activity possessed by a benzofuran derivative. Moreover, according to this invention, the foodstuff and pharmaceutical which have the inhibitory effect of 11 (beta) HSD1 can be provided. Therefore, according to the present invention, an effective prophylactic method and / or therapeutic method for a disease caused by cortisol overproduction can be established.

Claims (11)

The following general formula (1)

(In the formula, X is a hydroxyl group, an alkoxyl group, an amino group, or a trifluoromethyl group, Y is a hydrogen atom or a halogen atom, and Z is a hydroxyl group or an alkoxyl group)
An 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) inhibitor comprising the compound represented by the formula (1) or a salt thereof as an active ingredient.   The 11βHSD1 inhibitor according to claim 1, wherein the substituent X of the compound represented by the general formula (1) is a hydroxyl group or an alkoxyl group bonded to the carbon at the 5th or 6th position of the benzofuran ring. The compound represented by the general formula (1) is
3-iodo-6-methoxy-2- (4-methoxyphenyl) -benzofuran,
3-iodo-5-methoxy-2- (4-methoxyphenyl) -benzofuran,
6-methoxy-2- (4-methoxyphenyl) -benzofuran,
5-methoxy-2- (4-methoxyphenyl) -benzofuran,
2- (4-hydroxyphenyl) -6-benzofuranol, or
The 11βHSD1 inhibitor according to claim 1 or 2, which is 2- (4-hydroxyphenyl) -5-benzofuranol.   The 11βHSD1 inhibitor according to any one of claims 1 to 3, wherein the substituents X and Z of the compound represented by the general formula (1) are both hydroxyl groups. The compound represented by the general formula (1) is
2- (4-hydroxyphenyl) -6-benzofuranol, or
The 11βHSD1 inhibitor according to claim 1, which is 2- (4-hydroxyphenyl) -5-benzofuranol.   A food comprising the 11βHSD1 inhibitor according to any one of claims 1 to 5.   A medicament comprising the 11βHSD1 inhibitor according to any one of claims 1 to 5.   The medicament according to claim 7, which is a therapeutic or prophylactic agent for a disease involving glucocorticoid.   The above-mentioned diseases involving glucocorticoids are diabetes, diabetic complications, impaired glucose tolerance, insulin resistance, abnormal lipid metabolism, hyperlipidemia, hypertriglyceridemia, obesity, fatty liver, metabolic syndrome, atherosclerosis 9. Fatal vascular events including myocardial infarction or stroke, Cushing syndrome, hypertension, cognitive impairment, memory impairment, depression, mania, anxiety, dementia, Alzheimer's disease, or osteoporosis Medicines.   The medicine according to claim 9, wherein the disease involving glucocorticoid is visceral fat obesity.   The medicament according to claim 9, wherein the disease involving glucocorticoid is metabolic syndrome.

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