JP7193150B2 - New compound - Google Patents

Description

The present invention relates to novel compounds.

Propolis is a wax-like composition obtained by solidifying resins and the like collected from various plants by insects belonging to the family Apiaceae. It has been used as a food and the like for a long time, and is known to have various physiological activities. For example, Patent Document 1 discloses a leukotriene production or release inhibitor containing propolis or its extract as an active ingredient.

JP 2008-214235 A

The inventors of the present invention have discovered, among compounds derived from propolis, novel compounds having physiological activities such as inhibition of leukotriene release and inhibition of NF-κB.

An object of the present invention is to provide compounds exhibiting leukotriene release inhibitory activity and NF-κB inhibitory activity.

［一般式（１）中、
Ｒ^１及びＲ^２は、アルデヒド基、カルボキシル基又はＣ_１－６アルキル基を示し、但し、少なくとも一方がアルデヒド基又はカルボキシル基であり、
Ｒ^３は、水素原子、Ｃ_１－６アルキル基、Ｃ_２－６アルケニル基、Ｃ_２－６アルキニル基、Ｃ_６－１０アリール基、Ｃ_７―１１アラルキル基、Ｃ_１－６アルキルカルボニル基、又はＣ_７―１１アラルキルカルボニル基を示し、
Ｒ^４は、水素原子、又はＣ_１－６アルキル基を示す。］The present invention relates to a compound represented by the following general formula (1) or a salt thereof.

[In general formula (1),
R ¹ and R ² represent an aldehyde group, a carboxyl group or a C _1-6 alkyl group, provided that at least one is an aldehyde group or a carboxyl group;
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, a C _1-6 alkylcarbonyl group, or C _7-11 aralkylcarbonyl group,
R ⁴ represents a hydrogen atom or a C _1-6 alkyl group. ]

The compound represented by the general formula (1) exhibits leukotriene release inhibitory activity and NF-κB inhibitory activity.

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

The present invention also relates to a compound represented by formula (3) or a salt thereof.

The present invention also relates to a compound represented by formula (4) or a salt thereof.

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

The present invention also relates to an NF-κB inhibitor containing as an active ingredient at least one selected from the group consisting of the above compounds and salts thereof.

ADVANTAGE OF THE INVENTION According to this invention, it becomes possible to provide the compound which shows a leukotriene release inhibitory effect and NF-(kappa)B inhibitory activity.

It is a graph which shows the result of an Example.

DETAILED DESCRIPTION OF THE INVENTION Embodiments for carrying out the present invention will be described in detail below. However, the present invention is not limited to the following embodiments. Various substituents defined or exemplified below can be arbitrarily selected and combined.

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

In general formula (1), R ¹ and R ² represent an aldehyde group, a carboxyl group or a C _1-6 alkyl group, provided that at least one is an aldehyde group or a carboxyl group,
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, a C _1-6 alkylcarbonyl group, or C _7-11 aralkylcarbonyl group,
R ⁴ represents a hydrogen atom or a C _1-6 alkyl group.

As used herein, "C _1-6 alkyl group" means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group and the like.

As used herein, a “C _2-6 alkenyl group” means a linear or branched alkenyl group having 2 to 6 carbon atoms. C _2-6 alkenyl groups include, for example, vinyl group, propen-1-yl group, propen-2-yl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-1-propenyl group, 2-methyl-1-propenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 5-pentenyl group, 1-methyl-1-butenyl group, 2-methyl-1 -butenyl group, 3-methyl-1-butenyl group, 4-methyl-1-butenyl group, 1-methyl-2-butenyl group, 2-methyl-2-butenyl group, 3-methyl-2-butenyl group, 4 -methyl-2-butenyl group, 1-methyl-3-butenyl group, 2-methyl-3-butenyl group, 3-methyl-3-butenyl group, 4-methyl-3-butenyl group, 1,2-dimethyl- Examples include alkenyl groups such as 1-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 6-hexenyl and structural isomers thereof.

As used herein, “C _2-6 alkynyl group” means an alkynyl group having 2 to 6 carbon atoms. Examples of C _2-6 alkynyl groups include ethynyl, propargyl, butynyl, pentynyl and hexynyl groups.

As used herein, “C _6-10 aryl group” means an aryl group having 6 to 10 carbon atoms. The C _6-10 aryl group includes, for example, a phenyl group, a naphthyl group and the like.

As used herein, a “C _7-11 aralkyl group” means an alkyl group having a total of 7 to 11 carbon atoms and having an aryl group, such as a benzyl group, a phenylethyl group and a naphthylmethyl group.

As used herein, "C _1-6 alkylcarbonyl group" means a carbonyl group to which the above "C _1-6 alkyl group" is bonded, such as acetyl group, propanoyl group, pentanoyl group, pivaloyl group, heptanoyl and the like.

As used herein, "C _7-11 aralkylcarbonyl group" means a carbonyl group bonded to the above "C _7-11 aralkyl group".

In general formula (1), represents an aldehyde group, a carboxyl group or a C _1-6 alkyl group, provided that at least one 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 a C _1-6 alkyl group. That is, the subject compound may be a compound represented by the following general formula (2A), (2B), (2C), or (2D).

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

The C _1-6 alkyl group for 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 general formula (1), R ¹ is preferably an aldehyde group or a carboxyl group and R ² is a methyl group, more preferably R ¹ is an aldehyde group and R ² is a methyl group. The compound represented by general formula (1) is preferably the compound represented by general formula (2A) above.

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

In general formula (1), R ⁴ is a hydrogen atom or a C _1-6 alkyl group. ^R4 is preferably a hydrogen atom.

At least one of R ³ and R ⁴ is preferably a hydrogen atom, more preferably both are hydrogen atoms.

A specific example of the compound represented by the general formula (1) is a compound represented by the following formula (3) (hereinafter also referred to as "compound (3)").

Further, another specific example of the compound represented by general formula (1) is a compound represented by the following formula (4) (hereinafter also referred to as "compound (4)").

The present compound may be a salt acceptable for food use or pharmaceutical use. Salts of the present compound include, for example, salts with alkali metals, alkaline earth metals, other metals, ammonium, and the like. More specific examples of the salt of the present compound include potassium salt, sodium salt, calcium salt and magnesium salt.

The present compound and its salt may be obtained by purifying a natural product such as propolis. Specifically, for example, compound (3) can be obtained from a natural product by the method described in Examples below. The present compound can also be obtained by chemical synthesis using commercially available compounds or extracts of natural products (for example, compound (3)) as raw materials. Specifically, for example, a functional group defined by R ³ and R ⁴ in the general formula (1) is introduced by a known method to the phenolic hydroxyl group and/or carboxyl group of compound (3). Alternatively, it may be obtained by introducing an aldehyde group into an extract of a natural product having no aldehyde group by a known method.

Among the compounds represented by general formula (1), compound (3) can be synthesized, for example, as follows. That is, first, compound (C) is synthesized from compound (A-1) or compound (A-2) according to Schemes 1 to 3 below. Then, compound (3) can be obtained by deprotecting the protecting group of compound (C). Compound (A-1) or compound (A-2) can be synthesized according to Scheme 4 described below.

式中、Ｒ^ａは、メチル基（Ｍｅ）を示し、Ｒ^ｂは、アシル基、アルキル基、若しくはシリル基等の水酸基の保護基、又は水素原子を示し、Ｒ^ｃは、アルキル基等を示す。なお、複数存在するＲ^ａは同一の基を示す。シリル基の具体例としては、例えば、ｔｅｒｔ－ブチルジメチルシリル基が挙げられる。Scheme 1

In the formula, R ^a represents a methyl group (Me), R ^b represents a hydroxyl-protecting group such as an acyl group, an alkyl group, or a silyl group, or a hydrogen atom, and R ^c represents an alkyl group or the like. . In addition, multiple R ^a 's represent the same group. A specific example of the silyl group is a tert-butyldimethylsilyl group.

One of the methyl groups (one of R ^a ) of the compound (A-1) is oxidized with selenium dioxide to obtain a compound B having a hydroxyl group (alcohol B). Subsequently, compound (B) is oxidized to form compound (C) having an aldehyde group. The conditions for oxidizing compound (B) to obtain compound (C) are desirably mild conditions, and metal oxidizing agents such as chromium and manganese, as well as oxidizing agents such as organic sulfur reagents and halogen reagents are used. Further, for example, compound (C) can be obtained from compound (A-1) by oxidation with selenium dioxide.

式中、Ｒ^ａは、メチル基又は水素原子を示し、Ｒ^ｂは、アシル基、アルキル基、若しくはシリル基等の水酸基の保護基、又は水素原子を示し、Ｒ^ｃは、アルキル基等を示す。なお、複数存在するＲ^ａは同一の基を示す。Scheme 2

In the formula, R ^a represents a methyl group or a hydrogen atom, R ^b represents a hydroxyl-protecting group such as an acyl group, an alkyl group, or a silyl group, or a hydrogen atom, and R ^c represents an alkyl group or the like. . In addition, multiple R ^a 's represent the same group.

A compound (D) having an aldehyde group is obtained by selectively oxidatively cleaving the prenyl group of the compound (A-1) or the allyl group of the compound (A-2) to give 2-(triphenylphosphoranylidene)propion. A compound (C) can be obtained by a carburizing reaction by a Wittig reaction with an aldehyde.

式中、Ｒ^ａは、メチル基又は水素原子を示し、Ｒ^ｂは、アシル基、アルキル基、若しくはシリル基等の水酸基の保護基、又は水素原子を示し、Ｒ^ｃは、アルキル基等を示す。なお、複数存在するＲ^ａは同一の基を示す。Scheme 3

In the formula, R ^a represents a methyl group or a hydrogen atom, R ^b represents a hydroxyl-protecting group such as an acyl group, an alkyl group, or a silyl group, or a hydrogen atom, and R ^c represents an alkyl group or the like. . In addition, multiple R ^a 's represent the same group.

Compound (C) can also be synthesized by subjecting compound (A-1) or compound (A-2) to a cross-metathesis reaction with methacrolein in the presence of a metal catalyst. Grubbs catalyst, Hoveyda-Grubbs catalyst and the like are suitable as the catalyst used in the metathesis reaction.

Compound (A-1) or compound (A-2) can be synthesized according to Scheme 4 below.

式中、Ｘは、ハロゲン原子を示し、Ｒ^ａは、メチル基又は水素原子を示し、Ｒ^ｂは、アシル基、アルキル基、若しくはシリル基等の水酸基の保護基、又は水素原子を示し、Ｒ^ｃは、アルキル基等を示す。なお、複数存在するＲ^ａは同一の基を示す。Scheme 4

In the formula, X represents a halogen atom, R ^a represents a methyl group or a hydrogen atom, R ^b represents a hydroxyl-protecting group such as an acyl group, an alkyl group, or a silyl group, or a hydrogen atom, and R ^c represents an alkyl group or the like. In addition, multiple R ^a 's represent the same group.

A commercially available 4-halophenol (compound (E)) is prenylated to give compound (F-1). A bromine atom or an iodine atom is suitable as the halogen atom in the compound (E). In this case, allyl halide can be used to synthesize compound (F-2), which is an allyl derivative, from 4-halophenol (compound (E)). Compound (F-1) or (F-2), after optionally protecting the hydroxyl group, is subjected to a Mizoroki-Heck reaction with an acrylic ester in the presence of a palladium catalyst to give compound (A-1) or (A-1) having an extended carbon chain. Let (A-2) be. The hydroxyl group in compound (F-1) or (F-2) may or may not be protected. When protecting a hydroxyl group, the protecting group for the hydroxyl group is preferably an acyl group, an alkyl group, a silyl group, or the like. Moreover, the ester portion of acrylic acid is desirably an ester with an aliphatic alcohol. A commercially available catalyst such as palladium acetate can be used as the palladium catalyst.

A compound represented by general formula (1) in which one of R ¹ and R ² is a carboxyl group can be synthesized, for example, according to the following scheme. Specifically, compound (4) can be synthesized, for example, by Pinnick oxidation of compound (3) (dorpanal).

scheme 5

Compound (4) can also be synthesized from dorpanin (raw material) as shown in Scheme 6. Drupanin can be obtained by the method disclosed in JP-A-2008-214235.

式中、Ｐは、官能基の保護基を意味する。一分子内に複数存在するＰは、互いに同一であっても異なっていてもよい。Scheme 6

In the formula, P means a functional group-protecting group. A plurality of P's present in one molecule may be the same or different.

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

The above leukotriene release inhibitor exhibits antiallergic action, antiinflammatory action, antihay fever action, antiallergic rhinitis action, anti-atopic dermatitis action, antibronchial asthma action, etc. through the leukotriene release inhibitory action. Therefore, the leukotriene release inhibitor can also be used as an anti-allergic agent, anti-inflammatory agent, anti-pollinosis agent, anti-allergic rhinitis agent, anti-atopic dermatitis agent, anti-bronchial asthma agent and the like.

The leukotriene release inhibitor of the present embodiment may contain only the above active ingredients, or may further contain other ingredients. Other ingredients include, for example, pharmaceutically acceptable ingredients (e.g., excipients, binders, lubricants, disintegrants, emulsifiers, surfactants, bases, solubilizers, suspending agents). , Food acceptable ingredients (e.g., minerals, vitamins, flavonoids, quinones, polyphenols, amino acids, nucleic acids, essential fatty acids, cooling agents, binders, sweeteners, disintegrants, lubricants, coloring agents , fragrances, stabilizers, preservatives, sustained release modifiers, surfactants, solubilizers, wetting agents).

The leukotriene release inhibitor of the present embodiment can be used at a dose of 0.01 mg or more and 10 g or less per day for an adult with a body weight of 60 kg in terms of the amount of active ingredient, and is preferably used at a dose of 0.05 mg or more and 8 g or less. , more preferably 0.10 mg or more and 3 g or less, more preferably 0.15 mg or more and 1.5 g or less, even more preferably 0.20 mg or more and 1 g or less, and 0 It is even more preferred to use a dose of 0.22 mg to 500 mg, particularly preferably 0.24 mg to 250 mg. The dose can be appropriately set within the above range depending on factors such as the health condition of the person taking the drug, administration method, and combination with other agents.

The leukotriene release inhibitor of this embodiment may be orally administered (ingested) or parenterally administered (for example, intranasally administered). The leukotriene release inhibitor of the present embodiment may be administered once a day as long as the amount of active ingredient per day is within the range described above, or may be administered multiple times such as twice a day, three times a day, etc. May be administered separately. Moreover, the leukotriene release inhibitor of the present embodiment is preferably administered continuously. By continuously administering, the leukotriene release inhibitory effect is exhibited more remarkably.

The leukotriene release inhibitor of this embodiment may be in any form such as solid, liquid or paste. The form of the leukotriene release inhibitor of the present embodiment may be, for example, an uncoated tablet, sugar-coated tablet, granule, powder, tablet, capsule (hard capsule, soft capsule, seamless capsule). The leukotriene release inhibitor of the present embodiment is, for example, at least one selected from the group consisting of the above compounds and salts thereof, which are active ingredients, and if necessary, other ingredients are mixed and molded into the above dosage form. It can be prepared by

The leukotriene release inhibitor of the present embodiment can be used as a pharmaceutical, quasi-drug, or food composition itself, or added to a pharmaceutical, quasi-drug, or food composition. The food composition is preferably a food in which the tertiary function of food (physical conditioning function) is emphasized. Examples of foods in which the tertiary functions of foods are emphasized include health foods, foods with function claims, dietary supplements, supplements, and foods for specified health uses.

A pharmaceutical, quasi-drug or food composition comprising the leukotriene release inhibitor of the present embodiment, or a pharmaceutical, quasi-drug or food composition comprising the leukotriene release inhibitor of the present embodiment is for leukotriene release suppression, and / Or anti-allergy, anti-hay fever, anti-allergic rhinitis, anti-atopic dermatitis, anti-bronchial asthma. The above products consisting of or containing a leukotriene release inhibitor are, for example, suppressing allergies, suppressing anaphylactic symptoms, suppressing hay fever, suppressing perennial rhinitis, itching of the eyes, and Suppressing hyperemia and discomfort Suppressing sneezing and coughing Suppressing rhinitis Suppressing runny nose and stuffy nose Suppressing atopic dermatitis Suppressing bronchial asthma Suppressing dyspnea Suppressing hives Suppresses erythema/redness Suppresses oral swelling Suppresses eyelid swelling Suppresses burning sensation Suppresses shortness of breath Suppresses nausea Suppresses discomfort in the digestive tract Vomiting/abdominal pain/ It may be accompanied by a label indicating that it suppresses diarrhea, that it suppresses headache, or the like.

The content of the leukotriene release inhibitor of the present embodiment in the pharmaceutical, quasi-drug, and food composition is such that the amount of active ingredient taken per day is within the above-described range. It may be appropriately set according to the type of object.

When the leukotriene release inhibitor of the present embodiment is used as the food composition itself or added to the food composition, the form of the food composition is not particularly limited, for example, beverages (coffee, juice, tea beverages, etc. Soft drinks, milk drinks, lactic acid drinks, yogurt drinks, carbonated drinks, etc.); Spreads (custard cream, etc.); Pastes (fruit paste, etc.); , cookies, cakes, puddings, etc.); Japanese sweets (daifuku, mochi, steamed buns, castella, anmitsu, yokan, etc.); ice desserts (ice cream, popsicles, sherbet, etc.); , soup, meat sauce, pasta, pickles, jam, etc.);

The leukotriene release inhibitor of the present embodiment is used as a food in which the tertiary function of food is emphasized (for example, health food, food with functional claims, dietary supplement, supplement or food for specified health use) itself, or the tertiary function of food When used by being added to a food in which the tertiary function of the food is emphasized, the form of the food in which the tertiary function of the food is emphasized is, in addition to the forms of the food described above, for example, uncoated tablets, sugar-coated tablets, granules, powders, tablets, capsules (Hard capsule, soft capsule, seamless capsule).

When the leukotriene release inhibitor of the present embodiment is used as a drug or quasi-drug itself, or added to a drug or quasi-drug, the form of the drug or quasi-drug is not particularly limited. Tablets, sugar-coated tablets, granules, powders, tablets, capsules (hard capsules, soft capsules, seamless capsules) may be used.

The method for producing a pharmaceutical, quasi-drug, or food composition to which the leukotriene release inhibitor of the present embodiment is added is not particularly limited, and can be appropriately followed by a known method. For example, by mixing a leukotriene release inhibitor with an intermediate product or final product in the manufacturing process of pharmaceuticals, quasi-drugs, or food compositions, pharmaceuticals, quasi-drugs, or food compositions used for the above purposes Obtainable.

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

The above NF-κB inhibitor exhibits anti-inflammatory action, autoimmune disease improving action, arthritis improving action, chronic rheumatoid arthritis improving action, rheumatoid arthritis improving action and the like through the NF-κB inhibitory action. Therefore, the above NF-κB inhibitors can also be used as anti-inflammatory agents, autoimmune disease improving agents, arthritis improving agents, chronic rheumatoid arthritis improving agents, rheumatoid arthritis improving agents, and the like.

The NF-κB inhibitor of this embodiment may contain only the above active ingredients, or may further contain other ingredients. Other ingredients include, for example, pharmaceutically acceptable ingredients (e.g., excipients, binders, lubricants, disintegrants, emulsifiers, surfactants, bases, solubilizers, suspending agents). , Food acceptable ingredients (e.g., minerals, vitamins, flavonoids, quinones, polyphenols, amino acids, nucleic acids, essential fatty acids, cooling agents, binders, sweeteners, disintegrants, lubricants, coloring agents , fragrances, stabilizers, preservatives, sustained release modifiers, surfactants, solubilizers, wetting agents).

The NF-κB inhibitor of the present embodiment can be used at a dose of 0.01 mg or more and 10 g or less per day for an adult with a body weight of 60 kg, and can be used at a dose of 0.05 mg or more and 8 g or less in terms of the amount of active ingredient. Preferably, it is used at a dose of 0.10 mg or more and 3 g or less, more preferably at a dose of 0.15 mg or more and 1.5 g or less, and even more preferably at a dose of 0.20 mg or more and 1 g or less, It is even more preferred to use a dose of 0.22 mg or more and 500 mg or less, and it is particularly preferred to use a dose of 0.24 mg or more and 250 mg or less. The dose can be appropriately set within the above range depending on factors such as the health condition of the person taking the drug, administration method, and combination with other agents.

The NF-κB inhibitor of this embodiment may be administered orally (ingested) or parenterally (eg, intranasally administered). The NF-κB inhibitor of this embodiment may be administered once a day, or multiple times such as twice a day, three times a day, etc., as long as the amount of active ingredient per day is within the range described above. may be administered in separate doses. In addition, the NF-κB inhibitor of this embodiment is preferably administered continuously. By continuous administration, the NF-κB inhibitory effect is exhibited more remarkably.

The NF-κB inhibitor of this embodiment may be in any form such as solid, liquid or paste. The form of the NF-κB inhibitor of this embodiment may be, for example, plain tablet, sugar-coated tablet, granule, powder, tablet, capsule (hard capsule, soft capsule, seamless capsule). The NF-κB inhibitor of the present embodiment is prepared, for example, in the above dosage form by mixing at least one selected from the group consisting of the above compounds and salts thereof as active ingredients and, if necessary, other ingredients. It can be prepared by molding.

The NF-κB inhibitor of this embodiment can be used as a pharmaceutical, quasi-drug, or food composition itself, or added to a pharmaceutical, quasi-drug, or food composition. The food composition is preferably a food in which the tertiary function of food (physical conditioning function) is emphasized. Examples of foods in which the tertiary functions of foods are emphasized include health foods, foods with function claims, dietary supplements, supplements, and foods for specified health uses.

A pharmaceutical, quasi-drug, or food composition comprising the NF-κB inhibitor of the present embodiment, or a pharmaceutical, quasi-drug, or food composition comprising the NF-κB inhibitor of the present embodiment is an NF-κB inhibitor anti-inflammatory, autoimmune disease ameliorating, arthritis ameliorating, rheumatoid arthritis ameliorating, rheumatoid arthritis osteoarthritis improving, and anti-cancer. The above products consisting of or containing an NF-κB inhibitor are, for example, anti-inflammatory, modulate immune function, prevent autoimmune diseases, prevent viral diseases. to relieve joint pain, to prevent rheumatoid arthritis, to prevent exacerbation of atopic dermatitis, to prevent Crohn's disease and inflammatory bowel disease, to suppress the occurrence and progression of tumors, and to cancer prevention of sepsis; inhibition of proliferation of cytomegalovirus (CMV) and human immunodeficiency virus (HIV); prevention of metabolic syndrome; To prevent locomotive syndrome, to suppress muscle atrophy, to prevent sarcopenia, to suppress decline in walking, to suppress intervertebral disc herniation, to suppress back pain, to prevent osteoporosis, to prevent bone aging. It may be indicated that it suppresses, that it suppresses thickening of the epidermis, that it suppresses pigmentation, that it suppresses a decrease in skin elasticity, that it suppresses photoaging of the skin, or the like.

The content of the NF-κB inhibitor of this embodiment in the pharmaceutical, quasi-drug, and food composition is such that the amount of active ingredient taken per day is within the above-described range. It may be appropriately set according to the type of composition and the like.

When the NF-κB inhibitor of the present embodiment is used as a food composition itself or added to a food composition, the form of the food composition is not particularly limited, for example, those exemplified for the above leukotriene release inhibitor may be similar to

The NF-κB inhibitor of the present embodiment is a food that emphasizes the tertiary function of food (for example, health food, food with functional claims, dietary supplement, supplement or food for specified health use) itself, or the tertiary function of food When used by adding to a food whose function is emphasized, the form of the food whose tertiary function is emphasized is, in addition to the above-described food forms, for example, uncoated tablets, sugar-coated tablets, granules, powders, tablets, It may be a capsule (hard capsule, soft capsule, seamless capsule).

When the NF-κB inhibitor of the present embodiment is used as a drug or quasi-drug itself, or added to a drug or quasi-drug, the form of the drug or quasi-drug is not particularly limited. Uncoated tablets, sugar-coated tablets, granules, powders, tablets, capsules (hard capsules, soft capsules, seamless capsules) may be used.

A method for producing a pharmaceutical, quasi-drug, or food composition to which the NF-κB inhibitor of the present embodiment is added is not particularly limited, and can be appropriately followed by a known method. For example, pharmaceuticals, quasi-drugs, or food compositions used for the above applications by mixing NF-κB inhibitors with intermediate products or final products in the manufacturing process of pharmaceuticals, quasi-drugs, or food compositions. can be obtained.

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

[Test Example 1: Purification and structure determination of test compound]
[Purification of test compound]
71 g of an 80% ethanol extract (Lot. 451A) of alecrine propolis mass (from Minas Gerais) was dissolved in 560 mL of ethyl acetate and transferred to a separatory funnel. 700 mL of ultrapure water was added, and the pH was adjusted to 2 by adding 0.1N hydrochloric acid while checking with pH test paper. After liquid-liquid extraction, the ethyl acetate layer was recovered. The aqueous layer was further extracted twice with the same amount of ethyl acetate. The ethyl acetate layer was concentrated by an evaporator to obtain 38.6 g of ethyl acetate extract.

726 mg of the ethyl acetate extract was subjected to column chromatography (type of gel: silica gel 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, moisture content 2.0% or less), gel amount: 1000 g, column size: φ80 × 630 mm, elution conditions: 200 mL of 100% hexane, 10 L of 50% chloroform-hexane, 8 L of 70% chloroform-hexane, 100% 5 L of chloroform, 5 L of 10% ethyl acetate-chloroform, 5 L of 20% ethyl acetate-chloroform, and 10 L of methanol were flowed to divide into 13 fractions as follows.
(1) 100% hexane 200 mL fraction (9.8 mg)
(2) 50% hexane-chloroform 0-10L fraction (883.3 mg)
(3) 70% hexane-chloroform 0-7L fraction (1967.6 mg)
(4) 70% hexane-chloroform 7-8L fraction (6248.7 mg)
(5) 100% chloroform 0-1L fraction (6480 mg)
(6) 100% chloroform 1-2L fraction (631.6 mg)
(7) 100% chloroform 2-3L fraction (1232.78 mg)
(8) 100% chloroform 3-5L fraction (2007.1 mg)
(9) 10% ethyl acetate-chloroform 0-2L fraction (643.1 mg)
(10) 10% ethyl acetate-chloroform 2-5 Lth fraction (3885.9 mg)
(11) 20% ethyl acetate-chloroform 0-3 Lth fraction (2197.4 mg)
(12) 20% ethyl acetate-chloroform 3-5 Lth fraction (1082.58 mg)
(13) Methanol fraction (13823.58 mg)

(12) 20% ethyl acetate-chloroform The 3rd to 5th L fractions (1082.58 mg) were fractionated by medium pressure column chromatography under the following conditions.
(Medium pressure column chromatography conditions)
Column used: ODS-SM 50 μm (gel amount: 110 g, column size: φ46×130 mm)
Flow rate: 60mL/min
Fractionation volume: 100 mL
Elution conditions: 40%, 50%, 60%, 70% methanol-0.1% TFA, each 20 minutes recovery

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

Fr. of 50% MeOH fraction. 3-7 (54.31 mg) was collected by HPLC (collection conditions: Cosmosil 5C18-AR-II (10 mm×250 mm), 40% methanol-0.1% TFA).

A sample obtained by HPLC fractionation was dissolved in ethyl acetate and then recrystallized by adding hexane to obtain a compound of unknown structure.

[Structure Determination of Test Compound]
The obtained compound was analyzed with the following equipment to determine the structure.
- Mass spectrometer: Waters ACQUITY UPLC-Quattro Premier XE
・ NMR: AVANCE 500 type manufactured by Bruker Biospin

LC-MS measurement conditions (UPLC conditions)
Equipment: Waters Acquity
Column: Sunnyst C18-HT, 2 μm, 2.1×100 mm
Column oven: 40°C
Implantation amount: 2 μL
Flow rate: 0.3mL/min
Solvent: A = 0.1% aqueous formic acid, B = methanol Elution conditions: B 5% (2min hold), 5-40% (8min linear gradient), 40-85% (20min linear gradient), 100% (4 min hold), 100-5% (2 min linear gradient), 5% (4 min hold) total 40 min (MS/MS conditions)
Instrument: Quattro Premier Mass Spectrometer (Waters)

As a result of MS measurement, the molecular weight of the compound of unknown structure was estimated to be 246.

NMR measurements were performed on compounds with unknown structures. Table 1 shows ¹ H-NMR and ¹³ C-NMR measurement data.

From the results of NMR and MS measurements, the obtained compound of unknown structure was identified as (2E)-3-{4-hydroxy-3-[(2E)-3-methyl-4-oxobuten-2-yl]phenyl}-2- It was determined to be propenoic acid and named Dorpanal.

[Structure Determination of Synthetic Compound]
(2E)-3-{4-Hydroxy-3-[(2E)-3-methyl-4-oxobuten-2-yl]phenyl}-2-propenoic acid (dorpanal) by the method described in Synthesis Example 1 below. Synthesized according to ¹ H-NMR, ¹³ C-NMR and MS measurements were carried out on the synthesized compounds. The same measuring device as that used for determining the structure of Dorpanal was used.

As a result of MS measurement, the molecular weight of the synthesized compound was estimated to be 246. Table 2 shows ¹ H-NMR and ¹³ C-NMR measurement data.

[Test Example 2: Leukotriene release inhibitory activity]
[Preparation of materials]
First, the following materials were prepared.
(1) HL-60 Cells HL-60 cells were cultured in RPMI 1640 medium containing 10% FBS, 100 units/ml penicillin and 100 μg/ml streptomycin (37° C., 5% CO ₂ ).
(2) Reagent for measuring leukotriene 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), nitro blue tetrazolium (NBT) (Nacalai Tesque 24720-56), and Phorborl 12-myristate 13-acetate (PMA) (SIGMA P8139) were purchased and used on the market.

[Sample preparation]
Dorpanal was dissolved in DMSO to 3 mg/ml. After dilution with PBS(+), it was added to the test system according to the desired test concentration. The final concentration of DMSO was adjusted to 1% (v/v).

[Leukotriene measurement]
(Differentiation of HL-60 cells)
HL-60 cells were cultured in RPMI1640 (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 adjusted to 5×10 ⁵ cells/ml, 1.25% DMSO was added and incubated at 37° C., 5% CO ₂ for 6 days to induce differentiation. To determine differentiation into granulocyte-like cells, add equal amounts of 1 mg/ml NBT and 4 μM PMA to the cell suspension, incubate at 37° C. for 30 minutes, and then calculate the percentage of positive cells under a microscope. (NBT reduction method).

[Leukotriene production induction]
Each sample was added to DMSO-differentiated HL-60 cells (suspended in PBS(+)-1% BSA) and preincubated at 37°C for 15 minutes, then 1 µM A23187 was added and incubated at 37°C for 15 minutes. (Cell concentration 1×10 ⁶ cells/ml, containing 1% to 2% DMSO). After inducing the production of reutokoriene, the recovered supernatant was used as a measurement sample.

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

[Calculation of _IC50 ]
The logarithm of the concentration tested for each sample was plotted on the horizontal axis, and the percent leukotriene release inhibition was plotted on the vertical axis. _IC50 was calculated based on the following formula using regression calculation software (Kaiki 6) from two concentrations sandwiching 50% and their inhibition rate (%).
Formula: IC ₅₀ = 10 ^{(log[A/B]*[50-C]/[D-C]+log[B])}
A = higher concentrations between 50% B = lower concentrations between 50% C = percent inhibition at B D = percent inhibition at A

〔Test results〕
The _IC50 of leukotriene release inhibitory activity of drupanal was 0.90 μg/mL. On the other hand, the _IC50 of leukotriene release inhibitory activity of artepillin C and durpanin, which are cinnamic acid derivatives disclosed in JP-A-2008-214235, were 3.0 μg/mL and 7.0 μg/mL, respectively.

Brazilian green propolis itself containing drupanal had an _IC50 of 1.46 μg/mL.

[Test Example 3: NF-κB inhibitory activity]
〔material〕
The following materials were prepared.
Cell line: 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)
Measurement plate: ViewPlate-384 TC (PerkinElmer)

〔Measuring method〕
The cultured cell lines (NF-κ Reporter, Luciferase, HEK293 Recombinant Cell Line) were seeded in two 384-well plates for cell culture at a concentration of 10,000 cells/well. The seeded cells were incubated overnight at 37°C.

Dorpanal was adjusted with dimethyl sulfoxide (DMSO) to final concentrations of 50, 10, 2 and 0.4 μg/mL and 1% DMSO, and added to two plates of cells. It was spun down under conditions of 220×g and 10 sec. After that, it was incubated 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 two plates of cells. It was spun down under conditions of 220×g and 10 sec. After that, it was incubated at 37°C for 5 hours. Of the two identical plates, one was subjected to cell viability measurements and the other to the luciferase assay. CellTiter-Glo® Luminescent Cell Viability Assay (Promega) was used for cell viability measurement.

First, CellTiter-Glo reagent in an amount equal to the medium was added to the cells and shaken for 2 minutes while shielding from light. After incubation at room temperature for 10 minutes, fluorescence intensity was measured with EnVision (PerkinElmer). The ONE-Glo ^™ Luciferase Assay System (Promega) was used for the luciferase assay. A volume of ONE-Glo reagent equal to the medium was added to the cells and shaken for 1 minute while shielded from light. After incubation at room temperature for 3 minutes, fluorescence intensity was measured with EnVision (PerkinElmer).

Values resulting from luciferase assays are divided by cell viability. Furthermore, the values were standardized to the values where the fluorescence intensity of the wells to which only TNF-α and solvent were added was taken as 100%, and the fluorescence intensity of the wells to which no TNF-α was added was taken as 0%. From the results obtained, the 50% inhibitory concentration was calculated using the statistical software GraphPad Prism 7.

〔Test results〕
FIG. 1 shows the results of the NF-κB inhibitory activity of dorpanal. As a result, the IC ₅₀ of dorpanal's NF-κB inhibitory activity was found to be 13.4 μg/mL. The average IC ₅₀ of Ro106-9920, which is often used as a positive control, is 5.3 μM (=1.3 μg/mL) (actual value).

[Synthesis Example 1: Chemical Synthesis 1 of Dorpanal]
The chemical synthesis of drupanal was carried out according to Scheme I below.

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 post-treated by a usual method to synthesize compound 3 with a yield of 62%.

Compound 3 obtained by the above method, t-butyl acrylate, palladium(II) acetate, tri(o-tolyl)phosphine, tetrabutylammonium chloride, triethylamine and water were reacted in dimethylformamide (DMF) at 35°C. The compound 4 was synthesized with a yield of 96% by post-treating the resulting reaction mixture by a conventional method.

Compound 4 was reacted with selenium dioxide in a 95% ethanol aqueous solution at 60-65°C, and the resulting reaction mixture was worked up by a conventional method to give compound 5 (43% yield) and compound 6 (30% yield). %) were synthesized. The yields of compound 5 and compound 6 are yields based on the consumption of compound 4 as a starting material.

Compound 6 was reacted in dichloromethane and water in the presence of trifluoroacetic acid, and the resulting reaction mixture was post-treated by a conventional method to synthesize compound 1 with a yield of 94%.

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

Compound 4 was synthesized from compound 2 in the same manner as in Scheme I.

Compound 4, tert-butyldimethylsilyl chloride (TBSCl), and imidazole were added in dimethylformamide (DMF) at 0° C. and stirred at room temperature. Compound 7 was synthesized with a yield of 85% by post-treating the resulting reaction mixture by a conventional method.

Compound 7 was reacted with selenium dioxide in a 95% ethanol aqueous solution at 60-65° C., and the resulting reaction mixture was worked up by a conventional method to give compound 8 (yield 42%) and compound 9 (22 %) were synthesized. Compound 8 was reacted in dichloromethane in the presence of manganese dioxide and the resulting mixture was worked up to compound 9 (63% yield) by conventional methods.

The obtained compound 9, tert-butyldimethylsilyl triflate and 2,6-lutidine were added to dichloromethane at 0° C. and reacted at room temperature. The resulting reaction mixture was worked up and then reacted in dichloromethane in the presence of 1 mol/l hydrochloric acid. The resulting reaction mixture was worked up in the usual manner and reacted at room temperature in tetrahydrofuran in the presence of tetrabutylammonium fluoride. The resulting reaction mixture was post-treated by a conventional method to synthesize compound 1.

Compound 1, synthesized according to Scheme II, was (2E)-3-{4-hydroxy-3-[(2E)-3-methyl-4-oxobute-2-yl]phenyl}- isolated from alecrin propolis bulk. It was confirmed that 2-propenoic acid (dorpanal) and Compound 1 synthesized according to Scheme I were in agreement with the NMR and MS measurement data.

Claims (6)

A compound represented by the following general formula (1) or a salt thereof.

[In general formula (1),
R ¹ and R ² represent an aldehyde group, a carboxyl group or a C _1-6 alkyl group, provided that at least one is an aldehyde group or a carboxyl group;
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, a C _1-6 alkylcarbonyl group, or C _7-11 aralkylcarbonyl group,
R ⁴ represents a hydrogen atom or a C _1-6 alkyl group. ] The compound or salt thereof according to claim 1, wherein said R ¹ is an aldehyde group or a carboxyl group and said R ² is a C _1-6 alkyl group. A compound represented by the following formula (3) or a salt thereof.

A compound represented by the following formula (4) or a salt thereof.

A leukotriene release inhibitor containing, as an active ingredient, at least one selected from the group consisting of the compound according to any one of claims 1 to 4 and salts thereof. An NF-κB inhibitor containing, as an active ingredient, at least one selected from the group consisting of the compound according to any one of claims 1 to 4 and salts thereof.

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