TW201932443A - Novel compound - Google Patents

Abstract

The present invention provides a compound represented by general formula (1) or a salt thereof. [In general formula (1), R1 and R2 represent an aldehyde group, a carboxyl group, or a C1-6 alkyl group, and at least one of R1 and R2 is an aldehyde group or a carboxyl group. R3 represents a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C6-10 aryl group, a C7-11 aralkyl group, a C1-6 alkyl carbonyl group, or a C7-11 aralkyl carbonyl group. R4 represents a hydrogen atom or a C1-6 alkyl group.].

Description

Novel compound

This invention relates to a novel compound.

It is known that propolis is a waxy composition obtained by solidifying a resin such as a resin collected from various plants, and has been used as a food or the like since ancient times, and has various physiological activities. For example, Patent Document 1 discloses a leukotriene production or release inhibitor containing propolis or an extract thereof as an active ingredient.
Prior art document patent document

Patent Document 1: Japanese Patent Laid-Open Publication No. 2008-214235

[The problem that the invention wants to solve]

The present inventors have found novel compounds having physiological activities such as inhibition of leukotriene release and inhibition of NF-κB from compounds derived from propolis.

An object of the present invention is to provide a compound which exhibits a leukotriene release inhibitory action and an NF-κB inhibitory activity.
[Technical means to solve the problem]

The present invention relates to a compound or a salt thereof, which is represented by the following formula (1).
[Chemical 1]

[In the general formula (1),
R ¹ and R ² represent an aldehyde group, a carboxyl group or a C _1-6 alkyl group, at least one of which is an aldehyde group or a carboxyl group;
R ³ represents a hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _6-10 aryl group, a C _7-11 aralkyl group, a C _1-6 alkylcarbonyl group, or C _7-11 aralkylcarbonyl;
R ⁴ represents a hydrogen atom or a C _1-6 alkyl group. ]

The compound represented by the above formula (1) exhibits a leukotriene release inhibitory action and an NF-κB inhibitory activity.

In the formula (1), R ¹ may be an aldehyde group or a carboxyl group, and R ² may be a C _1-6 alkyl group.

Further, the present invention relates to a compound or a salt thereof, which is represented by the formula (3).
[Chemical 2]

Further, the present invention relates to a compound or a salt thereof, which is represented by the formula (4).
[Chemical 3]

The present invention relates to a leukotriene releasing inhibitor containing at least one selected from the group consisting of the above compounds and salts thereof as an active ingredient.

Further, the present invention relates to an NF-κB inhibitor comprising at least one selected from the group consisting of the above compounds and salts thereof as an active ingredient.
[Effects of the Invention]

According to the present invention, it is possible to provide a compound which exhibits a leukotriene release inhibitory action and an NF-κB inhibitory activity.

Hereinafter, the form for carrying out the invention will be described in detail. However, the present invention is not limited to the following embodiments. The various substituents defined or exemplified below can be arbitrarily selected and combined.

[This compound]
An embodiment of the present invention is a compound represented by the formula (1) (hereinafter also referred to as "the present compound") or a salt thereof.

[Chemical 4]

In the formula (1), R ¹ and R ² represent an aldehyde group, a carboxyl group or a C _1-6 alkyl group, at least one of which is an aldehyde group or a carboxyl group;
R ³ represents a hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _6-10 aryl group, a C _7-11 aralkyl group, a C _1-6 alkylcarbonyl group, or C _7-11 aralkylcarbonyl;
R ⁴ represents a hydrogen atom or a C _1-6 alkyl group.

In the present specification, the "C _1-6 alkyl group" means a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, a n-propyl group and an isopropyl group. , n-butyl, isobutyl, t-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

In the present specification, the term "C _2-6 alkenyl" means a linear or branched alkenyl group having 2 to 6 carbon atoms. Examples of the C _2-6 alkenyl group include a vinyl group, a propen-1-yl group, a propen-2-yl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, and a 1-methyl group. 1-propenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 5-pentenyl, 1-methyl- 1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 4-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 4-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3 -butenyl, 3-methyl-3-butenyl, 4-methyl-3-butenyl, 1,2-dimethyl-1-propenyl, 1-hexenyl, 2-hexene Alkenyl groups such as 3-hexenyl, 4-hexenyl, 5-hexenyl, 6-hexenyl, and such structural isomers.

In the present specification, the "C _2-6 alkynyl group" means an alkynyl group having 2 to 6 carbon atoms. Examples of the C _2-6 alkynyl group include an ethynyl group, a propargyl group, a butynyl group, a pentynyl group, and a hexynyl group.

In the present specification, the "C _6-10 aryl group" means an aryl group having 6 to 10 carbon atoms. Examples of the C _6-10 aryl group include a phenyl group, a naphthyl group and the like.

In the present specification, the "C _7-11 aralkyl group" refers to an alkyl group having an aryl group having 7 to 11 carbon atoms in total, and examples thereof include a benzyl group, a phenylethyl group, and a naphthylmethyl group.

In the present specification, the "C _1-6 alkylcarbonyl group" means a carbonyl group to which the above-mentioned "C _1-6 alkyl group" is bonded, and examples thereof include an ethyl group, a propyl group, a pentyl group, and a pentamidine group. , Geng Keji and so on.

In the present specification, the "C _7-11 aralkylcarbonyl group" means a carbonyl group bonded to the above-mentioned "C _7-11 aralkyl group".

In the formula (1), R ¹ and R ² represent an aldehyde group, a carboxyl group or a C _1-6 alkyl group, and at least one of them is an aldehyde group or a carboxyl group. One of R ¹ and R ² may represent an aldehyde group or a carboxyl group, and the other represents a C _1-6 alkyl group. That is, the compound of the present invention may be a compound represented by the following formula (2A), (2B), (2C), or (2D).
[Chemical 5]

[Chemical 6]

[Chemistry 7]

[化8]

In the general formulae (2A), (2B), (2C), and (2D), R ³ and R ⁴ are the same as defined above.

The C _1-6 alkyl group in R ¹ and R ² is preferably a C _1-3 alkyl group having 1 to 3 carbon atoms, more preferably a methyl group.

In the formula (1), R ¹ is preferably an aldehyde group or a carboxyl group and R ² is a methyl group, and more preferably R ¹ is an aldehyde group and R ² is a methyl group. The compound represented by the formula (1) is preferably a compound represented by the above formula (2A).

In the formula (1), R ³ is a hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _6-10 aryl group, a C _7-11 aralkyl group, C _1-6 alkylcarbonyl, or C _7-11 aralkylcarbonyl. R ^{3 is} preferably a hydrogen atom.

In the formula (1), R ⁴ is a hydrogen atom or a C _1-6 alkyl group. R ^{4 is} preferably a hydrogen atom.

R ³ and R ^{4 are} preferably at least one of hydrogen atoms, more preferably both of them are hydrogen atoms.

Specific examples of the compound represented by the formula (1) include a compound represented by the following formula (3) (hereinafter also referred to as "compound (3)").
[Chemistry 9]

In addition, as another specific example of the compound represented by the formula (1), a compound represented by the following formula (4) (hereinafter also referred to as "compound (4)")).
[化10]

This compound may also be a salt which is permissible for food or medical use. The salt of the present compound may, for example, be a salt with an alkali metal, an alkaline earth metal, another metal, or ammonium. More specific examples of the salt of the present compound include a potassium salt, a sodium salt, a calcium salt, and a magnesium salt.

The compound of the present invention and a salt thereof can be obtained, for example, from a natural product such as propolis. Specifically, for example, the compound (3) can be obtained from a natural product by the method described in the following examples. Further, the present compound can be obtained by chemical synthesis using a commercially available compound or an extract of a natural product (for example, the compound (3)) as a raw material. Specifically, for example, the phenolic hydroxyl group and/or the carboxyl group of the compound (3) can be obtained by introducing a functional group defined by R ³ and R ⁴ in the above formula (1) by a known method. It is obtained by introducing an aldehyde group by a known method for an extract of a natural product having no aldehyde group.

Among the compounds represented by the formula (1), the compound (3) can be synthesized, for example, in the following manner. Namely, first, the compound (C) is synthesized from the compound (A-1) or the compound (A-2) by the following schemes 1 to 3. Then, the compound (3) can be obtained by deprotecting the protecting group of the compound (C). Further, the compound (A-1) or the compound (A-2) can be synthesized by the following scheme 4.

plan 1
[11]

In the formula, R ^a represents a methyl group (Me), R ^b represents a protecting group of a hydroxyl group such as a mercapto group, an alkyl group or a decyl group, or a hydrogen atom, and R ^c represents an alkyl group or the like. Furthermore, there are a plurality of R ^a representing the same base. Specific examples of the decyl group include a third butyl dimethyl decyl group.

For compound (A-1), by selenium dioxide to make a methyl group (R ^a in the a) oxidized to prepare the compound B (the alcohol B) having hydroxyl groups. Then, the compound (B) is oxidized to prepare a compound (C) having an aldehyde group. The condition for obtaining the compound (C) by oxidizing the compound (B) is preferably mild, and an oxidizing agent such as an organic sulfur reagent or a halogen reagent is used in addition to the metal oxidizing agent such as chromium or manganese. Further, for example, the compound (C) can be obtained from the compound (A-1) by oxidation with selenium dioxide.

Scenario 2
[化12]

In the formula, R ^a represents a methyl group or a hydrogen atom, R ^b represents a protecting group of a hydroxyl group such as a mercapto group, an alkyl group or a decyl group, or a hydrogen atom, and R ^c represents an alkyl group or the like. Furthermore, there are a plurality of R ^a representing the same base.

The compound (D) having an aldehyde group is formed by selectively cleavage of the pentene group of the compound (A-1) or the allylic group of the compound (A-2) by using with 2-(triphenylene) Compound (C) can be obtained by a carbonation reaction of a Wittig reaction of propionaldehyde.

Option 3
[Chemistry 13]

In the formula, R ^a represents a methyl group or a hydrogen atom, R ^b represents a protecting group of a hydroxyl group such as a mercapto group, an alkyl group or a decyl group, or a hydrogen atom, and R ^c represents an alkyl group or the like. Furthermore, there are a plurality of R ^a representing the same base.

Further, the compound (C) can be synthesized by subjecting the compound (A-1) or the compound (A-2) to a cross-metathesis reaction with methacrolein in the presence of a metal catalyst. As a catalyst for the metathesis reaction, Grubbs catalyst, Hoveyda-Grubbs catalyst, etc. are preferable.

The compound (A-1) or the compound (A-2) can be synthesized by the following scheme 4.

Option 4
[Chemistry 14]

In the formula, X represents a halogen atom, R ^a represents a methyl group or a hydrogen atom, R ^b represents a protecting group of a hydroxyl group such as a mercapto group, an alkyl group or a decyl group, or a hydrogen atom, and R ^c represents an alkyl group or the like. Furthermore, there are a plurality of R ^a representing the same base.

The commercially available 4-halophenol (compound (E)) is polyisopylated to give a compound (F-1). As the halogen atom in the compound (E), a bromine atom or an iodine atom is preferred. At this time, a compound (F-2) which is an allyl derivative can be synthesized from a 4-halophenol (compound (E)) using an allyl halide. Compound (F-1) or (F-2), after protecting a hydroxyl group as appropriate, is formed into a compound having a carbon chain by reacting with an acrylate sulphate Mizoroki-Heck in the presence of a palladium catalyst. (A-1) or (A-2). The hydroxyl group in the compound (F-1) or (F-2) may or may not be protected. In the case of protecting a hydroxyl group, the protecting group of the hydroxyl group is preferably a mercapto group, an alkyl group, or a nonyl group. Further, the ester portion of acrylic acid is preferably an ester with an aliphatic alcohol. As the palladium catalyst, a commercially available catalyst such as palladium acetate can be used.

Among the compounds represented by the formula (1), a compound wherein one of R ¹ or R ² is a carboxyl group can be synthesized, for example, according to the following scheme. Specifically, the compound (4) can be synthesized by, for example, Pinnick oxidation of the compound (3) (Drupanal).

Option 5
[化15]

Further, the compound (4) can also be synthesized from Drupinin (raw material) as in Scheme 6. Further, Drupinin can be obtained by the method disclosed in Japanese Laid-Open Patent Publication No. 2008-214235.

Option 6
[Chemistry 16]

In the formula, P represents a protecting group of a functional group. A plurality of Ps may exist in the same or different from each other.

[leukotriene release inhibitor]
This compound and its salt are useful as a leukotriene release inhibitor because they exhibit a leukotriene release inhibitory action. That is, an embodiment of the present invention provides a leukotriene releasing inhibitor containing at least one selected from the group consisting of the compound represented by the above formula (1) and a salt thereof as an active ingredient.

The above leukotriene release inhibitor exhibits anti-allergic action, anti-inflammatory action, anti-hay fever effect, anti-allergic rhinitis effect, anti-atopic dermatitis effect, anti-bronchial asthma effect, etc. through leukotriene release inhibition effect . Therefore, the above leukotriene release inhibitor can also be used as an antiallergic agent, an anti-inflammatory agent, an antifungal agent, an antiallergic rhinitis agent, an anti-atopic dermatitis agent, and an anti-bronchial asthma agent.

The leukotriene release inhibitor of the present embodiment may contain only the above-mentioned active ingredient, and may further contain other components. The other component may, for example, be a pharmaceutically acceptable component (for example, an excipient, a binder, a lubricant, a disintegrant, an emulsifier, a surfactant, a base, a solubilizer, and a suspending agent), as Food-tolerant ingredients (eg, minerals, vitamins, flavonoids, terpenoids, polyphenols, amino acids, nucleic acids, essential fatty acids, cooling agents, binders, sweeteners, disintegrants, lubricants) , coloring materials, perfumes, stabilizers, preservatives, sustained release modifiers, surfactants, solubilizers, and wetting agents).

The leukotriene release inhibitor of the present embodiment may be used in an amount of 0.01 mg or more and 10 g or less per day in an amount of 0.01 kg or more, preferably in an amount of 0.05 mg or more and 8 g or less, in terms of the amount of the active ingredient. More preferably, it is used in an amount of 0.10 mg or more and 3 g or less, more preferably 0.15 mg or more and 1.5 g or less, and more preferably 0.20 mg or more and 1 g or less. It is more preferably used in an amount of 0.22 mg or more and 500 mg or less, and more preferably 0.24 mg or more and 250 mg or less. The amount can be appropriately set within the above range depending on factors such as the state of health of the ingestor, the method of administration, and the combination with other agents.

The leukotriene release inhibitor of the present embodiment can be administered orally (ingested) or administered orally (for example, intranasally). The leukotriene releasing inhibitor of the present embodiment may be administered once a day as long as the amount of the active ingredient per day is within the above range, or may be administered in a plurality of times twice a day or three times a day. Further, the leukotriene releasing inhibitor of the present embodiment is preferably administered continuously. The leukotriene release inhibiting effect is further exerted remarkably by continuous administration.

The leukotriene release inhibitor of the present embodiment may be in any shape such as a solid, a liquid or a paste. The form of the leukotriene release inhibitor of the present embodiment may be, for example, a die, a sugar-coated pellet, a granule, a powder, a tablet, a capsule (hard capsule, soft capsule, and seamless capsule). The leukotriene-releasing inhibitor of the present embodiment can be formed into the above-mentioned dosage form by mixing at least one selected from the group consisting of the above-mentioned compound and a salt thereof as an active ingredient, and other components as necessary. Preparation was carried out.

The leukotriene release inhibitor of the present embodiment can be used as a pharmaceutical, a quasi-drug, and a food composition itself, and can be used by adding it to a pharmaceutical, a quasi-drug, and a food composition. As the food composition, a food that emphasizes the third function of the food (physical condition adjustment function) is preferable. Examples of the food that emphasizes the third function of the food include healthy foods, functional foods, nutritional supplements, supplements, and foods for specific health care.

A pharmaceutical, quasi-drug, or food composition comprising the leukotriene-releasing inhibitor of the present embodiment, or a pharmaceutical, quasi-drug, or food composition containing the leukotriene-releasing inhibitor of the present embodiment may be white For the inhibition of olefin release, and / or anti-allergic, anti-hay fever, anti-allergic rhinitis, anti-atopic dermatitis, anti-bronchial asthma. The above-mentioned preparation consisting of a leukotriene-releasing inhibitor or a leukotriene-releasing inhibitor can be expressed, for example, by suppressing allergy, suppressing allergic symptoms, suppressing hay fever, and suppressing perennial rhinitis. It is intended to suppress the itching or congestion of the eyes, the feeling of discomfort, the purpose of suppressing sneezing or coughing, the purpose of suppressing rhinitis, the purpose of suppressing nasal discharge and nasal congestion, the purpose of inhibiting atopic dermatitis, and the purpose of inhibiting bronchial asthma. The purpose of suppressing dyspnea, suppressing the purpose of urticaria, suppressing erythema, redness, suppressing swelling of the mouth, suppressing the swelling of the eyelids, suppressing the burning sensation, suppressing the meaning of asthma, suppressing nausea, The purpose of suppressing the discomfort of the digestive tract, suppressing vomiting, abdominal pain, and diarrhea, and suppressing headaches.

The content of the leukotriene-releasing inhibitor of the present embodiment in the pharmaceutical, quasi-drug, and food composition is as long as the amount of the active ingredient ingested per day is within the above range, and the pharmaceutical, quasi-drug, and food are considered. The type of the composition or the like may be appropriately set.

When the leukotriene release inhibitor of the present embodiment is used as the food composition itself or when it is added to the food composition, the form of the food composition is not particularly limited, and for example, it may be a beverage (coffee). , refreshing drinks such as juices and tea drinks, milk drinks, lactic acid bacteria drinks, yogurt drinks, carbonated drinks, etc.); West Point Coatings (Custard Cream, etc.), pastes (fruit puree, etc.), Western-style snacks (chocolate, sweet) Circles, pies, puffs, chewing gum, jellies, candies, biscuits, cakes, puddings, etc.); Japanese dim sum (Dafu, rice cake, taro, Nagasaki cake, stuffed honey, lamb, etc.), cold drinks (ice cream, popsicles, Sha Bing, etc.; food (curry, beef rice, vegetable porridge, miso soup, soup, meat sauce, pasta, pickles, jam, etc.); and seasonings (sauce, bibimbap, fresh Agent, soup, etc.).

Using the leukotriene release inhibitor of the present embodiment as a food (for example, a health food, a functional food, a nutritional supplement, a supplement, or a specific health food) that emphasizes the third function of the food itself, or When added to a food that emphasizes the third function of the food, the form of the food that emphasizes the third function of the food may be, for example, a die, a sugar-coated pellet, a granule, a powder, or a lozenge in addition to the form of the food. , capsules (hard capsules, soft capsules, seamless capsules).

When the leukotriene release inhibitor of the present embodiment is used as a pharmaceutical or quasi-drug itself, or when it is added to a pharmaceutical or quasi-drug, the form of the pharmaceutical or quasi-drug is not particularly limited, for example, It can be a bare piece, a sugar-coated pill, a granule, a powder, a tablet, a capsule (hard capsule, soft capsule, seamless capsule).

The method for producing a pharmaceutical product, a quasi drug, or a food composition to which the leukotriene release inhibitor of the present embodiment is added is not particularly limited, and can be appropriately determined according to a known method. For example, a pharmaceutical product, a quasi drug, or a food composition can be obtained by mixing a leukotriene release inhibitor with a semi-finished product or a final product in a manufacturing step of a pharmaceutical, a quasi-drug, or a food composition.

[NF-κB inhibitor]
This compound and its salt are useful as NF-κB inhibitors because they exhibit NF-κB inhibitory activity. That is, an embodiment of the present invention provides an NF-κB inhibitor containing at least one selected from the group consisting of the compound represented by the above formula (1) and a salt thereof as an active ingredient.

The above NF-κB inhibitor exhibits anti-inflammatory action, autoimmune disease-improving effect, arthritis-improving effect, improvement of chronic rheumatoid arthritis, and improvement of deformed rheumatoid arthritis via NF-κB inhibition. Wait. Therefore, the above NF-κB inhibitor can also be used as an anti-inflammatory agent, an autoimmune disease improving agent, an arthritis improving agent, a chronic rheumatoid arthritis improving agent, and a deformable rheumatoid arthritis improving agent.

The NF-κB inhibitor of the present embodiment may contain only the above-mentioned active ingredient, and may further contain other components. Examples of other components include pharmaceutically acceptable components (for example, excipients, binders, lubricants, disintegrators, emulsifiers, surfactants, bases, solubilizers, suspending agents), and foods. Permissible ingredients (for example, minerals, vitamins, flavonoids, terpenoids, polyphenols, amino acids, nucleic acids, essential fatty acids, cooling agents, binding agents, sweeteners, disintegrants, lubricants, coloring) Materials, perfumes, stabilizers, preservatives, slow release modifiers, surfactants, solubilizers, wetting agents).

The NF-κB inhibitor of the present embodiment may be used in an amount of 0.01 mg or more and 10 g or less per day in an amount of 0.01 kg or more, preferably in an amount of 0.05 mg or more and 8 g or less, in terms of the amount of the active ingredient. More preferably, it is used in an amount of 0.10 mg or more and 3 g or less, more preferably 0.15 mg or more and 1.5 g or less, and more preferably 0.20 mg or more and 1 g or less. More preferably, it is used in an amount of 0.22 mg or more and 500 mg or less, and more preferably 0.24 mg or more and 250 mg or less. The amount can be appropriately set within the above range depending on factors such as the state of health of the ingestor, the method of administration, and the combination with other agents.

The NF-κB inhibitor of the present embodiment can be administered orally (ingested) or administered orally (for example, intranasally). The NF-κB inhibitor of the present embodiment may be administered once a day as long as the amount of the active ingredient per day is within the above range, or may be administered in a plurality of times twice a day or three times a day. Further, the NF-κB inhibitor of the present embodiment is preferably administered continuously. The NF-κB inhibitory effect is further exerted remarkably by continuous administration.

The NF-κB inhibitor of the present embodiment may be in any shape such as a solid, a liquid, or a paste. The form of the NF-κB inhibitor of the present embodiment may be, for example, a die, a sugar-coated pellet, a granule, a powder, a tablet, or a capsule (hard capsule, soft capsule, seamless capsule). The NF-κB inhibitor of the present embodiment can be prepared, for example, by mixing at least one selected from the group consisting of the above-mentioned compound and a salt thereof as an active ingredient, and other components as necessary, into the above-mentioned dosage form. .

The NF-κB inhibitor of the present embodiment can be used as a pharmaceutical, a quasi-drug, and a food composition itself, and can be used by adding it to a pharmaceutical, a quasi-drug, and a food composition. As the food composition, a food that emphasizes the third function of the food (physical condition adjustment function) is preferable. Examples of the food that emphasizes the third function of the food include health foods, functional foods, nutritional supplements, supplements, and foods for specific health care.

The pharmaceutical, quasi-drug, or food composition composed of the NF-κB inhibitor of the present embodiment or the pharmaceutical, quasi-drug, or food composition containing the NF-κB inhibitor of the present embodiment may be NF-κB It is used for suppression, anti-inflammatory, autoimmune disease improvement, arthritis improvement, improvement of chronic rheumatoid arthritis, improvement of deformable rheumatoid arthritis, and anticancer. The above-mentioned preparation consisting of an NF-κB inhibitor or an NF-κB inhibitor can be expressed, for example, as follows: inhibition of inflammation, regulation of immune function, prevention of autoimmune diseases, prevention of viral diseases. Intention to relieve the pain of joints, prevent rheumatoid arthritis, prevent the deterioration of atopic dermatitis, prevent Crohn's disease, inflammatory bowel disease, inhibit the occurrence or progress of tumors, Inhibition of cancer occurrence or progression (proliferation, infiltration, metastasis), prevention of sepsis, suppression of proliferation of cytomegalovirus (CMV) or human immunodeficiency virus (HIV), prevention of metabolic syndrome, prevention of movement The meaning of Locomotive Syndrome, the purpose of inhibiting muscle atrophy, the purpose of preventing muscle wasting, the purpose of inhibiting the decline of walking, the purpose of inhibiting the herniated disc, the purpose of suppressing low back pain, the purpose of preventing osteoporosis, and the inhibition of bone aging. The purpose of suppressing the hypertrophy of the epidermis, suppressing the pigmentation, and inhibiting the elasticity of the skin. Low of intention, and the intention to inhibit aging of the skin light and so on.

The content of the NF-κB inhibitor of the present embodiment in the pharmaceutical product, the quasi-drug, and the food composition is regarded as a pharmaceutical product, a quasi drug, and a food combination as long as the amount of the active ingredient ingested per day is within the above range. The type of the object can be appropriately set.

When the NF-κB inhibitor of the present embodiment is used as the food composition itself or when it is added to a food composition, the form of the food composition is not particularly limited, and for example, it can be released from the above leukotriene. The morphology exemplified in the inhibitor is the same.

The NF-κB inhibitor of the present embodiment is used as a food (for example, a health food, a functional food, a nutritional supplement, a supplement, or a specific health food) that emphasizes the third function of the food, or is added thereto. In the case of use in a food that emphasizes the third function of the food, the form of the food that emphasizes the third function of the food may be, for example, a die, a sugar-coated pellet, a granule, a powder, a lozenge, in addition to the form of the food described above. Capsules (hard capsules, soft capsules, seamless capsules).

When the NF-κB inhibitor of the present embodiment is used as a pharmaceutical or quasi-drug itself, or when it is added to a pharmaceutical or quasi-drug, the form of the pharmaceutical or quasi-drug is not particularly limited, for example, It can be a bare piece, a sugar-coated pill, a granule, a powder, a tablet, a capsule (hard capsule, soft capsule, seamless capsule).

The method for producing a pharmaceutical product, a quasi drug, or a food composition to which the NF-κB inhibitor of the present embodiment is added is not particularly limited, and can be appropriately determined according to a known method. For example, a medicinal product, a quasi drug, or a food composition for use in the above-mentioned use can be obtained by mixing an NF-κB inhibitor in a semi-finished product or a final product in a manufacturing step of a pharmaceutical product, a quasi-drug, or a food composition.
Example

Hereinafter, the present invention will be more specifically described based on examples. However, the invention is not limited to the following examples.

[Test Example 1: Purification and Structure Determination of Test Compounds]
[Purification of test compound]
71 g of an 80% ethanol extract (Lot. 451A) of a Brazilian green bee collagen block (manufactured by Minas Gerais, Brazil) was dissolved in 560 mL of ethyl acetate and transferred to a separatory funnel. After adding 700 mL of ultrapure water, the pH was adjusted to 2 by adding 0.1 N hydrochloric acid while confirming with a pH test paper. Liquid-liquid extraction was carried out to recover an ethyl acetate layer. The aqueous layer was extracted twice with an equivalent amount of ethyl acetate. The ethyl acetate layer was concentrated using an evaporator to obtain ethyl acetate extract (38.6 g).

For ethyl acetate extract 726 mg, using column chromatography (type of gel: silicone rubber manufactured by Osaka soda Co., Ltd. (IR-60-40/63, particle size 50 μm, pore size 6 nm, surface area 450 m) ² / g, pore volume 0.70 mL / g, water content less than 2.0%), gel amount: 1000 g, column size: f80 × 630 mm, dissolution conditions: 100% hexane 200 mL, 50% chloroform - 10 L of alkane, 8 L of 70% chloroform-hexane, 5 L of 100% chloroform, 10 L of ethyl acetate-chloroform 5 L, 20% ethyl acetate-chloroform 5 L, and 10 L of methanol), as follows Divided into 13 components.
(1) 100% hexane 200 mL fraction (9.8 mg)
(2) 50% hexane-chloroform 0-10 L component (883.3 mg)
(3) 70% hexane-chloroform 0-7 L component (1967.6 mg)
(4) 70% hexane-chloroform 7-8 L component (6248.7 mg)
(5) 100% chloroform 0-1 L component (6480 mg)
(6) 100% chloroform 1-2 L component (631.6 mg)
(7) 100% chloroform 2-3 L component (1232.78 mg)
(8) 100% chloroform 3-5 L component (2007.1 mg)
(9) 10% ethyl acetate-chloroform 0-2 L component (643.1 mg)
(10) 10% ethyl acetate-chloroform 2-5 L component (3885.9 mg)
(11) 20% ethyl acetate-chloroform 0-3 L component (2197.4 mg)
(12) 20% ethyl acetate-chloroform 3-5 L component (1082.58 mg)
(13) Methanol component (13823.58 mg)

(12) The components (1082.58 mg) of 20% ethyl acetate-chloroform 3 to 5 L were separated by medium pressure column chromatography under the following conditions.
(medium pressure column chromatography conditions)
Use column: ODS-SM 50 μm (gel volume: 110 g, column size: f46 × 130 mm)
Flow rate: 60 mL/min
Differentiate capacity: 100 mL
Dissolution conditions: 40%, 50%, 60%, 70% methanol-0.1% TFA (Trifluoroacetic Acid, trifluoroacetic acid), each recovered for 20 minutes

The components obtained by medium pressure column chromatography are as follows.
・40% MeOH component: component number (Fr.) 1-12
・50% MeOH component: Fr.1-12
・60% MeOH component: Fr.1-12
・70% MeOH component: Fr.1-12

Fr. 3-7 (54.31 mg) of 50% MeOH fraction was subjected to HPLC (High Performance Liquid Chromatography) separation (division conditions: Cosmosil 5C18-AR-II (10 mm × 250 mm) ), 40% methanol - 0.1% TFA).

After the sample obtained by HPLC fractionation was dissolved in ethyl acetate, hexane was added thereto to recrystallize it to obtain a structurally unknown compound.

[Structural determination of test compound]
The obtained compound was analyzed by the following apparatus to determine the structure.
・Quality analysis device: ACQUITY UPLC-Quattro Premier XE manufactured by Waters
・NMR: AVANCE500 type manufactured by Bruker-biospin

LC-MS measurement conditions
(UPLC condition)
Equipment: Waters Acquity
Column: Sunniest C18-HT, 2 μm, 2.1 × 100 mm
Column oven: 40 ° C
Implant quantity: 2 μL
Flow rate: 0.3 mL/min
Solvent: A = 0.1% formic acid water, B = methanol dissolution conditions: B5% (for 2 min), 5-40% (8 min linear gradient), 40-85% (20 min linear gradient), 100 % (for 4 min), 100-5% (2 min linear gradient), 5% (for 4 min) for 40 minutes
(MS/MS conditions)
Equipment: Quattro Premier Mass Spectrometer (Waters)

As a result of MS measurement, it was estimated that the molecular weight of the unknown compound was 246.

NMR measurements were performed on compounds of unknown structure. The data of ¹ H-NMR and ¹³ C-NMR measurement are shown in Table 1.

[Table 1]

According to the measurement results of NMR and MS, the obtained structural unknown compound was identified as (2E)-3-{4-hydroxy-3-[(2E)-3-methyl-4-oxobutene-2- Base] phenyl}-2-acrylic acid and named Drupanal.

[Structural Determination of Synthetic Compounds]
Synthesis of (2E)-3-{4-hydroxy-3-[(2E)-3-methyl-4-oxobuten-2-yl]phenyl} according to the method described in Synthesis Example 1 below 2-acrylic acid (Drupanal). The synthesis compound was subjected to ¹ H-NMR, ¹³ C-NMR, and MS measurement. The measuring device was the same as the device used for the structure determination of Drupanal.

As a result of MS measurement, it was estimated that the molecular weight of the synthetic compound was 246. The data of ¹ H-NMR and ¹³ C-NMR measurement are shown in Table 2.

[Table 2]

[Test Example 2: leukotriene release inhibitory activity]
[Preparation of materials]
First, prepare the following materials.
(1) HL-60 cells
The HL-60 cell line was cultured in RPMI 1640 medium (37 ° C, 5% CO ₂ ) containing 10% FBS, 100 units/ml penicillin, and 100 μg/ml streptomycin.
(2) leukotriene measurement reagent product name: CAST (registered trademark) (cellular antigen stimulation test) - 2000 ELISA (supplier: BUHLMANN)
(3) Other reagents Calcium ionophore A23187 (SIGMA C7522), BSA (SIGMA A8806), DMSO (Nacalai GR13407-45), D-PBS (-) (Nacalai Tesque 14249-95), D-PBS (+) (Nacalai Tesque 14248-05), nitroblue-tetrazole (NBT) (Nacalai Tesque 24720-56), and Phoborl 12-myristate 13-acetate (PMA) (SIGMA P8139) is a commercial item purchased for use.

[Sample Preparation]
Drupanal was dissolved in DMSO in a manner to be 3 mg/ml. After dilution with PBS (+), the test concentration of the target was added to the test system. The preparation was carried out in such a manner that the final concentration of DMSO became 1% (v/v).

[Measurement of leukotriene]
(differentiation of HL-60 cells)
HL-60 cells were cultured in RPMI 1640 (containing 10% FBS, 100 units/ml penicillin, and 100 μg/ml streptomycin) medium and used for the test (37 ° C, 5% CO ₂ ). After the cells were prepared at 5 × 10 ⁵ cells/ml, DMSO was added at 1.25%, cultured at 37 ° C, 5% CO ₂ for 6 days, and induced to differentiate. The determination of the differentiation into the granule cells was carried out by adding an equal amount of 1 mg/ml of NBT and 4 μM of PMA to the cell suspension, and culturing at 37 ° C for 30 minutes. The ratio of positive cells was calculated under a microscope (NBT reduction method).

[Induction of leukotriene production]
Each sample was added to HL-60 cells (suspended in PBS(+)-1% BSA) which was over-differentiated with DMSO, and pre-incubated at 37 ° C for 15 minutes, then 1 μM of A23187 was added at 37 ° C. The cells were cultured for 15 minutes (cell concentration: 1 × 10 ⁶ cells/ml, containing 1% to 2% DMSO). After the production of leukotrienes was induced, the supernatant recovered was used as a measurement sample.

[CysLT amount measurement]
The concentration of leukotrienes in the recovered supernatant was quantified by a CAST ELISA kit (each condition was n=2).

[Calculation of IC ₅₀ ]
The logarithm of the test concentration of each sample was plotted on the horizontal axis, and the leukotriene release inhibition rate was plotted on the vertical axis. The IC _{50 was} calculated by regression calculation software (Kaiki 6) based on the concentration including 50% and its inhibition rate (%), and based on the following calculation formula.
Calculation formula: IC ₅₀ =10 ^{(log[A/B] * [50 - C]/[D - C] + log[B])}
A = higher concentration including 50%
B = lower concentration including 50%
C = inhibition rate under B
D = inhibition rate under A

[test results]
Drupanal of leukotriene inhibition activity IC ₅₀ of 0.90 μg / mL. On the other hand, the IC _{50 of the} leukotriene release inhibitory activity of the cinnamic acid derivatives of Artipillin C and Drupanin disclosed in Japanese Patent Laid-Open Publication No. 2008-214235 is 3.0 μg/mL, respectively. 7.0 μg/mL.

The Brazilian green propolis containing Drupanal itself has an IC ₅₀ of 1.46 μg/mL.

[Test Example 3: NF-κB inhibitory activity]
[material]
Prepare the following materials.
Cell lines: NF-κ reporter (NF-κ Reporter), Luciferase, HEK293 Recombinant Cell Line (BPS Bioscience)
Medium: Dulbecco's Modified Eagle's Medium-low glucose-(Thermo Fisher Scientific)
FBS: Serum, Fetal Bovine, BSE Tested, EC Approved (biowest)
Measuring plate: ViewPlate-384 TC (PerkinElmer)

[test methods]
The cultured cell line (NF-κ reporter gene, luciferase, HEK293 recombinant cell strain) was seeded at a concentration of 10,000 cells/well onto two 384-well culture plates for cell culture. The inoculated cell line was cultured overnight at 37 °C.

The Drupanal was adjusted to a final concentration of 50, 10, 2, 0.4 μg/mL, and 1% DMSO by using dimethyl sulfoxide (DMSO), and added to cells of two culture dishes. The racemization was carried out under conditions of 220 × g and 10 sec. Thereafter, it was cultured at 37 ° C for 1 hour.

TNF-α (R&D Systems) adjusted to a final concentration of 10 ng/mL in DMEM medium was added to the cells of the two plates. The racemization was carried out under conditions of 220 × g and 10 sec. Thereafter, it was cultured at 37 ° C for 5 hours. One of the two identical culture plates was subjected to cell viability measurement, and the other was subjected to luciferase assay. The cell survival number was determined using CellTiter-Glo (registered trademark) Luminescent Cell Viability Assay (Promega).

First, the same amount of CellTiter-Glo reagent as the medium was added to the cells, and the cells were shaken for 2 minutes while being shielded. Then, the cells were incubated at room temperature for 10 minutes, and the fluorescence intensity was measured using EnVision (PerkinElmer). Luciferase Assay using ^{ONE-Glo TM Luciferase Assay System (} Promega). The same amount of ONE-Glo reagent as the medium was added to the cells, and the cells were shaken for 1 minute while being shielded from light. The cells were incubated at room temperature for 3 minutes, and the fluorescence intensity was measured using EnVision (PerkinElmer).

The value of the result of the luciferase assay is divided by the number of cell viability. Further, this value was normalized to a value obtained by setting the fluorescence intensity of the well to which only TNF-α and the solvent were added to 100%, and the hole to which TNF-α was not added to 0%. Based on the results obtained, the statistical software GraphPad Prism 7 was used to calculate the 50% inhibitory concentration.

[test results]
Figure 1 shows the results of NF-κB inhibitory activity of Drupanal. As a result, it was found that the IC ₅₀ of the NF-κB inhibitory activity of Drupanal was 13.4 μg/mL. Furthermore, the IC ₅₀ of Ro106-9920, which is often used as a positive control, was an average of 5.3 μM (= 1.3 μg/mL) (measured value).

[Synthesis Example 1: Chemical Synthesis of Drupanal 1]
The chemical synthesis of Drupanal was carried out according to the following Scheme I.
[化17]

4-Iodophenol (Compound 2), sodium hydride (NaH), and 1-bromo-3-methyl-2-butene were mixed in toluene at 0 ° C, and then stirred at room temperature (rt). The reaction mixture was worked up by a usual method to give Compound 3 in a yield of 62%.

Compound 3 obtained by the above method, tert-butyl acrylate, palladium (II) acetate, tris(o-tolyl)phosphine, tetrabutylammonium chloride, triethylamine, and water in dimethylformamide The reaction was carried out at 35 ° C in (DMF), and the obtained reaction mixture was post-treated by a usual method, whereby Compound 4 was synthesized in a yield of 96%.

Compound 4 was reacted with selenium dioxide in a 95% aqueous solution of ethanol at 60 to 65 ° C, and the obtained reaction mixture was post-treated by a usual method, thereby synthesizing compound 5 (yield 43%) and compound 6 (30%). The yields of the compound 5 and the compound 6 are based on the consumption of the compound 4 as a starting material.

Compound 6 was reacted in dichloromethane and water in the presence of trifluoroacetic acid, and the obtained reaction mixture was post-treated by a usual method, whereby Compound 1 was synthesized in a yield of 94%.

[Synthesis Example 2: Chemical Synthesis of Drupanal 2]
The chemical synthesis of Drupanal was carried out according to Scheme II below.
[化18]

Compound 4 was synthesized from Compound 2 using the same procedure as Scheme I.

Compound 4, tert-butyldimethylchlorodecane (TBSCI), and imidazole were added to dimethylformamide (DMF) at 0 ° C and stirred at room temperature. The obtained reaction mixture was subjected to post treatment by a usual method, whereby Compound 7 was synthesized in a yield of 85%.

Compound 7 was reacted with selenium dioxide in a 95% aqueous solution of ethanol at 60 to 65 ° C, and the obtained reaction mixture was post-treated by a usual method, thereby synthesizing compound 8 (yield 42%) and compound 9 ( twenty two%). Compound 8 was reacted in the presence of manganese dioxide in dichloromethane, and the obtained mixture was post-treated by a usual method to give Compound 9 (yield: 63%).

The obtained compound 9, tributyl dimethyl decyl trifluoromethanesulfonate, and 2,6-lutidine were added to dichloromethane at 0 ° C, and allowed to stand at room temperature. reaction. The obtained reaction mixture was subjected to post treatment, and thereafter, it was reacted in dichloromethane in the presence of 1 mol/l of hydrochloric acid. The reaction mixture thus obtained is subjected to post-treatment by a usual method, and reacted in the presence of tetrabutylammonium fluoride in tetrahydrofuran at room temperature. With respect to the reaction mixture thus obtained, post-treatment was carried out by a usual method to synthesize Compound 1.

It was confirmed that the compound 1 synthesized according to the scheme II and the (2E)-3-{4-hydroxy-3-[(2E)-3-methyl-4-oxobutene-isobutylated from the Brazilian green bee collagen block were isolated. The synthesis data of -2-yl]phenyl}-2-acrylic acid (Drupanal) and the compound 1 synthesized according to the scheme I are the same as those of NMR and MS.

Figure 1 is a graph showing the results of the examples.

Claims (6)

A compound or a salt thereof, which is represented by the following formula (1), [Chemical Formula 1] [In the formula (1), R ¹ and R ² represent an aldehyde group, a carboxyl group or a C _1-6 alkyl group, at least one of which is an aldehyde group or a carboxyl group; and R ³ represents a hydrogen atom, a C _1-6 alkyl group, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _7-11 aralkyl, C _1-6 alkylcarbonyl, or C _7-11 aralkylcarbonyl; R ⁴ represents a hydrogen atom Or C _1-6 alkyl]. The compound of claim 1, wherein R ¹ is an aldehyde group or a carboxyl group, and R ² is a C _1-6 alkyl group, or a salt thereof. A compound or a salt thereof, which is represented by the following formula (3), [Chemical 2] . A compound or a salt thereof, which is represented by the following formula (4), [Chemical 3] . A leukotriene-releasing inhibitor containing at least one selected from the group consisting of a compound according to any one of claims 1 to 4 and a salt thereof as an active ingredient. An NF-κB inhibitor comprising at least one selected from the group consisting of a compound according to any one of claims 1 to 4 and a salt thereof as an active ingredient.