JP2019142779A - Promoter for rise of intracavernous pressure, and pharmaceutical composition and food composition containing the same - Google Patents

Abstract

To provide an active ingredient of a pharmaceutical composition or a food composition for improvement, treatment or prevention of male sexual dysfunction, particularly erectile dysfunction.SOLUTION: The present invention provides a secoiridoid glucoside derivative represented by formula (1) or a pharmacologically acceptable salt thereof, or a hydrolysate thereof (Rand Rindependently represent a C1-4 alkyl group; R-Rindependently represent H, optionally protected two or more hydroxy groups, or a C1-4 alkyl group; m is an integer of 1-3; n is an integer of 1-4).SELECTED DRAWING: None

Description

  The present invention relates to an agent for increasing intracavernous pressure, a pharmaceutical composition for treating and / or preventing male sexual dysfunction containing the same, and a food composition for improving male sexual function.

Male sexual dysfunction is often caused by erectile dysfunction.
on (ED)). Such a pathological condition may be any one of a combination of blockage of cavernous blood inflow due to penile artery contraction due to stress of sympathetic nerves due to stress, reduction of nNOS activity, reduction of guanylate cyclase activity, enhancement of PDE5 activity, etc. As a result, the penis does not erection or does not persist even after erection, and sexual intercourse cannot be performed.
ED is thought to affect more than 150 million men worldwide, and there are predictions that the number will double by 2030.

In recent years, a phosphodiesterase type 5 (PDE5) inhibitor has been found as a compound having an ED improving action, and three kinds of ED therapeutic drugs are on the market in Japan. Specifically, Pfizer Sildenafil (product name: Viagra), Bayer Vardenafil (product name: Levitra), and Eli Lilly's Tadalafil (product name: Cialis). The PDE5 inhibitor inhibits the activity of PDE5, a cGMP-degrading enzyme in the corpus cavernosum, maintains and increases the amount of cGMP in the corpus cavernosum caused by the peripheral nerve of the penis, and increases the intracavernosal pressure (erection) state Sustain and enhance. Although these are orally administered drugs and are widely used, satisfactory efficacy is not always obtained.
In addition, there are ED treatment methods such as cavernous injection of prostaglandin preparations and transplantation to the penile cavernous body of prosthesis such as silicone, but there are problems in terms of invasiveness and risk of infection.

By the way, oleuropein, a secoiloidoid compound, is known as a component that is abundant in olive leaves and oils and produces a characteristic bittersweet aroma. The structural formula of oleuropein is C ₂₅ H ₃₂ O ₁₃ and the molecular weight is 540.514, which is represented by the following chemical formula (2).

It has been reported that oleuropein has physiological activities such as antioxidant, antiviral, antitumor, antibacterial, anti-obesity, and improvement of non-alcoholic fatty liver and hair growth promotion. It is also known that toxicity is not recognized so much that LD ₅₀ cannot be calculated in a safety test such as administration of 1 g / kg body weight of oleuropein to rats for 7 days (Patent Document 1).

Special table 2014-533688 gazette

  An object of the present invention is to provide a new active ingredient of a pharmaceutical composition or a food composition for improving, treating or preventing male sexual dysfunction, particularly ED.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a secoidoid glucoside derivative such as oleuropein has an action of enhancing intracavernous pressure, and completed the present invention. I let you.

  The first aspect of the present invention includes an increase in intracavernous pressure, which contains, as an active ingredient, a secoiridoid glucoside derivative represented by the following general formula (1) or a pharmacologically acceptable salt thereof or a hydrolyzate thereof. Enhancer.

(In the above formula, R ₁ and R ₂ each independently represents an alkyl group having 1 to 4 carbon atoms, and R _{3 to} R ₇ are each independently a hydrogen atom or a hydroxy group optionally protected by a protecting group. Or an alkyl group having 1 to 4 carbon atoms, wherein two or more of R _{3 to} R ₇ may be protected by a protecting group, m is an integer of 1 to 3, and n is 1 to 1 It is an integer of 4.)

In this embodiment, the sequolidoid glucoside derivative is represented by the general formula (1), wherein R ₁ and R ₂ each independently represent an alkyl group having 1 to 2 carbon atoms, and R _{3 to} R ₇ each independently represent hydrogen. It represents a hydroxy group which may be protected by an atom or a protecting group, m is preferably 1 and n is preferably 2, and more preferably a compound represented by the following formula (2). .
Further, the compound represented by the formula (2) is more preferably contained in the enhancer in the form of an olive leaf extract.

Another aspect of the present invention is a pharmaceutical composition for the treatment and / or prevention of male sexual dysfunction comprising the enhancer of intracavernous pressure of the present invention.
In this embodiment, the male sexual dysfunction is preferably erectile dysfunction (ED).

Another aspect of the present invention is a food composition for improving male sexual function, comprising the potentiator for increasing intracavernous pressure of the present invention.
In this embodiment, the male sex function is preferably an erectile function.
The form of this embodiment is preferably a health functional food or supplement, and the health functional food is preferably a functional food.

  The present invention newly provides an effective and safe ingredient that can be contained in a pharmaceutical composition for treating and / or preventing male sexual dysfunction, or a food composition for improving male sexual function.

It is a graph which shows the time-lapse | temporal change of the time after application | coating to electrical stimulation application to the cavernous nerve, and the maximum cavernous body pressure. (Right: experimental group, left: control group).

  Hereinafter, embodiments of the present invention will be described in detail.

<1> Sequolidoid glucoside derivative The enhancer of intracavernous pressure increase according to the present invention comprises a sequolidoid glucoside derivative represented by the following general formula (1), a pharmacologically acceptable salt thereof, or a hydrolyzate thereof. Contains as an active ingredient.

In general formula (1), R ₁ and R ₂ each independently represents an alkyl group having 1 to 4 carbon atoms, preferably an alkyl group having 1 to 2 carbon atoms.
In general formula (1), R _{3 to} R ₇ each independently represents a hydrogen atom, a hydroxy group which may be protected with a protecting group or an alkyl group having 1 to 4 carbon atoms, preferably a hydrogen atom or a protecting group. Represents an optionally protected hydroxy group. Further, two or more of R _{3 to} R ₇ are hydroxy groups which may be protected with a protecting group, preferably two of R _{3 to} R ₇ are hydroxy groups which may be protected with a protecting group, More preferably, two of R ₄ and R ₅ are hydroxy groups optionally protected by a protecting group.
In the general formula (1), m is an integer of 1 to 3, and preferably 1. n is an integer of 1 to 4, preferably 2.

  In this specification, an alkyl group refers to a linear or branched saturated hydrocarbon group.

In the present specification, the protecting group is not particularly limited as long as it can stably protect a hydroxyl group in a chemical reaction process, a preparation process, etc., but preferably it is cleaved in vivo by a biological method such as hydrolysis. Refers to a protecting group that can.
For example, 1- (acyloxy) (C ₁ ~C ₆₎ alkyl group, and specifically, formyl oxy, 1- formyloxyethyl ethyl, 1-formyloxyethyl propyl 1- formyloxy (C ₁ ~ C ₆₎ alkyl group; acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryl oxymethyl, isovaleryloxy oxymethyl, hexanoyloxy methyl, 1-acetoxyethyl, 1-propionyloxy-ethyl 1-butyryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1 -Butyryloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl, 1- 1- (alkylcarbonyloxy) (C ₁ -C ₆ ) alkyl groups such as acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl, 1-pivaloyloxyhexyl; Cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxypropyl, 1-cyclopentyl Carbonyloxy-butyl, 1-cyclohexyl-carbonyloxy butyl 1- ( "cycloalkyl" carbonyloxy) (C ₁ ~C ₆₎ alkyl group; benzoyloxymethyl like 1- ( "arylcarbonyl" aryloxy) (C ₁ ~ C ₆ ) an alkyl group.

Also included are carbonyloxy (C ₁ -C ₆ ) alkyl groups, specifically, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxy Carbonyloxymethyl, pentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxy (cyclohexyl) methyl, 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1 -(Propoxycarbonyloxy) ethyl, 1- (isopropoxycarbonyloxy) ethyl, 1- (butoxycarbonyloxy) ethyl, 1 (Isobutoxycarbonyloxy) ethyl, 1- (t-butoxycarbonyloxy) ethyl, 1- (pentyloxycarbonyloxy) ethyl, 1- (hexyloxycarbonyloxy) ethyl, 1- (cyclopentyloxycarbonyloxy) ethyl, 1 -(Cyclopentyloxycarbonyloxy) propyl, 1- (cyclohexyloxycarbonyloxy) propyl, 1- (cyclopentyloxycarbonyloxy) butyl, 1- (cyclohexyloxycarbonyloxy) butyl, 1- (cyclohexyloxycarbonyloxy) ethyl, 1 -(Ethoxycarbonyloxy) propyl, 1- (methoxycarbonyloxy) propyl, 1- (ethoxycarbonyloxy) propyl, 1- (propoxycarbonyloxy) propyl, 1 (Isopropoxycarbonyloxy) propyl, 1- (butoxycarbonyloxy) propyl, 1- (isobutoxycarbonyloxy) propyl, 1- (pentyloxycarbonyloxy) propyl, 1- (hexyloxycarbonyloxy) propyl, 1- ( Methoxycarbonyloxy) butyl, 1- (ethoxycarbonyloxy) butyl, 1- (propoxycarbonyloxy) butyl, 1- (isopropoxycarbonyloxy) butyl, 1- (butoxycarbonyloxy) butyl, 1- (isobutoxycarbonyloxy) ) Butyl, 1- (methoxycarbonyloxy) pentyl, 1- (ethoxycarbonyloxy) pentyl, 1- (methoxycarbonyloxy) hexyl, 1- (ethoxycarbonyloxy) hexyl and the like (C ₂ -C ₇ ) Lucoxycarbonyloxyalkyl group; (5-phenyl-2-oxo-1,3-dioxolen-4-yl) methyl, [5- (4-methylphenyl) -2-oxo-1,3-dioxolen-4- Yl] methyl, [5- (4-methoxyphenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, [5- (4-fluorophenyl) -2-oxo-1,3-dioxolene 4-yl] methyl, [5- (4-chlorophenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, (2-oxo-1,3-dioxolen-4-yl) methyl, (5 -Methyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-ethyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-propyl-2-oxo-1) , 3-Dioxo N-4-yl) methyl, (5-isopropyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-butyl-2-oxo-1,3-dioxolen-4-yl) methyl and the like Of oxodioxolenylmethyl group.
In addition, phthalidyl groups such as phthalidyl, dimethylphthalidyl and dimethoxyphthalidyl; alkylcarbonyl groups; arylcarbonyl groups such as benzoyl, α-naphthoyl and β-naphthoyl; halogenated arylcarbonyls such as 2-bromobenzoyl and 4-chlorobenzoyl Groups; (C ₁ -C ₆ ) alkylated arylcarbonyl groups such as 2,4,6-trimethylbenzoyl, 4-toluoyl; (C ₁ -C ₆ ) alkoxylated arylcarbonyl groups such as 4-anisoyl; 4-nitro Nitrated arylcarbonyl groups such as benzoyl and 2-nitrobenzoyl; (C ₂ -C ₇ ) alkoxycarbonylated arylcarbonyl groups such as 2- (methoxycarbonyl) benzoyl; arylated arylcarbonyl groups such as 4-phenylbenzoyl; Acid half ester salt residue Phosphate ester salt residue; such amino acid ester forming residues; carbamoyl group; 1 or 2 (C ₁ -C ₆₎ substituted with an alkyl group carbamoyl group; such as pivaloyloxymethyl oxycarbonyl 1- ( Also included are acyloxy) alkyloxycarbonyl groups.

In the present specification, the pharmacologically acceptable salt of the compound represented by the general formula (1) includes inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and carbonate; , Fumarate, oxalate, citrate, lactate, tartrate, methanesulfonate, paratoluenesulfonate, benzenesulfonate, and other organic acid salts; sodium salts, potassium salts, and other alkali metal salts Alkaline earth metal salts such as calcium salt and magnesium salt; organic amine salts such as triethylamine salt, triethanolamine salt, ammonium salt, monoethanolamine salt and piperidine salt, basic amino acid salts such as lysine salt and arginic acid salt And so on.

In the present specification, the hydrolyzate of the compound represented by the general formula (1) is, for example, elenolic acid formed by hydrolysis of the glycosyl group of the compound.
And compounds in which the protective group for the hydroxyl group of R _{3 to} R _{7 in} formula (1) is removed. Elenolic acid is also known to exhibit the same or similar level of biological activity as oleuropein described below (US Pat. Nos. 6,117,844 and 6,455,580).

  The compound represented by the general formula (1) is particularly preferably a compound represented by the following general formula (2) (hereinafter also referred to as “oleopane”).

Oleuropein is contained in leaves, berries, roots, and trunks of plants belonging to the family Oleaceae family, and is particularly contained in a large amount in the leaves.
Therefore, as a sequolidoid glucoside derivative in the present invention, it may be used in the form of an extract of the family Asteraceae as long as it contains the compound.
More than about 600 species of 24 genus are known as such asteraceae plants, and are not particularly limited. For example, olive plant (Olea) plant, Ligustrum plant, Syringa plant, ash genus ( Preferred examples include Fraxinus plants, Jasmin plants, Osmanthus plants and the like, and olive plants are particularly preferable. Furthermore, olive plants include olives (
Olea europaea Linne), Orea Welwitski (Olea we)
lwitschii) and Olea paniculata are preferred.
In a preferred embodiment of the present invention, oleuropein is contained in the enhancer in the form of olive leaf extract.

The extract of the oleaceae plant containing the secoiridoid glucoside derivative can be obtained from the aforementioned oleaceae plant through a normal extraction process. The source of the extraction is preferably a leaf of an Asteraceae plant, more preferably a leaf of the genus Olive, but a stem, a branch, a branch tip, etc. may be included together with the leaf.
Plants such as leaves are subjected to solvent extraction as they are or after being dried and pulverized as necessary.

As an extraction solvent, water, anhydrous or hydrous lower alcohols having 1 to 4 carbon atoms (for example, methanol, ethanol, isopropanol, butanol, etc.), glycols (for example, ethylene glycol, propylene glycol, 1,3-butylene glycol, etc.) , Mixed solvents of the lower alcohol and water, ketones such as glycerin, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, N-methylpyrrolidone, acetonitrile, ethyl acetate, butyl acetate, chloroform, Organic solvents such as hexane can be used alone or in combination of two or more.
Extraction is usually carried out in the temperature range from normal temperature to the boiling point of the solvent under normal pressure, and after extraction, the extract is in the form of a solution, paste, gel, or powder by purification by filtration, evaporation of the solvent, column, etc. It can be. The extraction liquid can be subjected to purification treatment such as deodorization and decolorization.

The extract of the Asteraceae plant may be a fraction obtained by further separating and purifying the extract. For example, fractions obtained by passing an extract of an Asteraceae plant through an ultrafiltration membrane with a certain molecular weight cut-off value, various chromatographies (for separation by size, charge, hydrophobicity or affinity) Fractions obtained by separation according to (prepared one).
In addition, the extract of the Asteraceae plant may be in a powder state by freeze-drying or the like, may be in a concentrated or diluted state, and may be mixed with other components and contained in the enhancer of the present invention. .

  A method for obtaining oleuropein from olive leaf extract is also described in detail in US Patent Application Publication No. 2003-0017217.

  Further, the sequolidoid glucoside derivative can be chemically synthesized. A method for synthesizing a secoiridoid derivative is described in detail in PCT Application Publication No. WO 96/14064.

<2> Agent for increasing intracavernous pressure The mechanism of penile erection will be described below. The “cavernous body” in the penis is surrounded by a fibrous tissue called white membrane. The penile cavernous body has a vein called a cavernous sinus (also called cavernous sinus) in the center. Blood flows into the cavernous sinus from the cavernous artery via the spiral artery existing under the white membrane. The normal cavernous artery is so thin that blood does not flow in so much that blood flows into the cavernous sinus and the blood from the penetrating vein that exists between the expanded cavernous sinus and the white membrane. Since the outflow is balanced as the flow rate, the penis maintains a certain size.

In the present specification, “smooth muscle” means a tissue specialized for contraction, and smooth muscle consists of smooth muscle fibers (cells) present on the wall surface of a hollow internal organ, and is stimulated by autonomic motor neurons. The Smooth muscle means a muscle having a smooth appearance because it does not have a horizontal pattern. Or smooth muscle is also called involuntary muscle. As the Ca ²⁺ concentration increases in the smooth muscle cytosol, contraction occurs as in the striated muscle. However, sarcoplasmic reticulum (Ca ²⁺ reservoir in striated muscle) is poor in smooth muscle. Ca ²⁺ flows from both extracellular fluid and sarcoplasmic reticulum into the smooth muscle cytosol, but smooth muscle fibers do not have transverse tubules, so Ca ²⁺ reaches the filaments at the center of the fibers and contracts. It takes longer to trigger the process. This is partly responsible for slow signs of smooth muscle and persistent contractions.

Various mechanisms regulate smooth muscle cell contraction and relaxation. In one of them,
A regulatory protein called calmodulin binds to Ca ²⁺ in the cytosol. This slows relaxation, in addition to allowing Ca ²⁺ to enter the smooth muscle fibers slowly, as well as causing them to slowly move away from the muscle fibers when the excitation decays. The continued presence of Ca ^{2+ in} the cytosol provides smooth muscle tone and continuous partial contraction. Smooth muscle tissue resides in hollow internal organs such as blood vessels, lung airways, stomach, intestinal gallbladder, bladder, penis and clitoral cavernous walls.

  Penile erections are caused by the enlargement of arteries in the penis through stimulation of the cavernous nerves when the central nervous system is subjected to visual, contact, auditory, olfactory, and / or imaginary stimulation, resulting in large amounts of blood Means the state that flows into the cavernous cave.

  The thickness of the cavernous artery is regulated by the autonomic nerve, and the vascular smooth muscle of the artery wall is normally contracted by the action of the sympathetic nerve, but the contraction is stopped by the stimulation of the parasympathetic nerve at the time of erection. As a result, the artery is believed to dilate.

Neural stimulation from the central nervous system is transmitted to the corpus cavernosum via the cavernous nerve. These non-adrenergic and non-cholinergic nerves end up in the vasculature of the penis where they release nitric oxide. When nitric oxide diffuses into smooth muscle cells of the cavernous artery and increases the production of intracellular cyclic guanosine 3 ′, 5′-monophosphate (cGMP), Ca ²⁺ pump and Ca ²⁺ activity The smooth muscle of the cavernous arteries relaxes by a mechanism presumed to be due to activated K ⁺ channels. As a result, the cavernous artery expands and the helical artery located at the entrance to the cavernous sinus expands, the amount of blood flowing into the cavernous sinus increases rapidly, and the whole tissue expands due to the blood. As a result, the internal pressure of the cavernous body increases. Subsequently, the penetrating vein existing between the expanded cavernous sinus and the white membrane is compressed to suppress the outflow of blood from the cavernous sinus to the outside, and the intracavernous pressure further increases. An increase in the amount of blood flowing into the cavernous sinus and a decrease in the amount of blood flowing out of the cavernous sinus act synergistically, resulting in an erection. On the other hand, when the cavernous artery contracts and the pressure on the vein is reduced, the penis returns to a relaxed state.

In this way, when the cavernous nerve is stimulated, an increase in the amount of blood flowing into the cavernous sinus and a decrease in the amount of outflow occur, and the intracavernous pressure rises (increases). General formula (1) Or a pharmacologically acceptable salt thereof or a hydrolyzate thereof has an action of enhancing such pressor. Here, “the action of increasing the pressure increase” includes an action of increasing the degree of pressure increase and / or an action of maintaining the pressure-boosted state (prolonging the time until returning to the original state).
It can be confirmed, for example, by the measurement system described in International Publication No. 2015/012194 that the cavernous body pressurization is enhanced.
Therefore, the secoiridoid glucoside derivative represented by the general formula (1) or a pharmacologically acceptable salt thereof or a hydrolyzate thereof is an active ingredient of a potentiator for increasing intracavernous pressure. Normally, the cavernous pressure increase that is enhanced is a pressure increase that occurs during the stimulation of the cavernous nerve.

Another aspect of the present invention is the use of a secoiridoid glucoside derivative represented by the general formula (1) or a pharmacologically acceptable salt thereof or a hydrolyzate thereof in the manufacture of an agent for increasing intracavernous pressure. is there.
Another aspect is the use of a sequolidoid glucoside derivative represented by the general formula (1) or a pharmacologically acceptable salt thereof or a hydrolyzate thereof in enhancing the increase in intracavernosal pressure.
Another aspect is the increase in intracavernous pressure containing the sequolidoid glucoside derivative represented by the general formula (1) or a pharmacologically acceptable salt thereof or a hydrolyzate thereof, or an active ingredient thereof. A method of enhancing intracavernous pressure elevation, comprising administering a potentiator to a mammal.

<3> Pharmaceutical composition The intracavernous pressure increase enhancer of the present invention can be incorporated into a pharmaceutical composition, and the pharmaceutical composition is suitable for the treatment and / or prevention of male sexual dysfunction. It is.

  Male sexual dysfunction (SD) is a condition in which sexual intercourse interests or abilities are impaired, primarily due to one or more of the four elements of libido, erection, ejaculation, and orgasm. The treatment of SD is important because it lowers self-esteem and disrupts relationships, causing pain to the person and partner. The causes of SD can be either organic or psychological, and typical organ causes include vascular diseases related to hypertension and diabetes, mental disorders such as depression, and various drugs. . Psychological causes include fear, performance anxiety, and interpersonal conflict.

Among male SDs, erectile dysfunction (ED) is an important treatment because it is highly affected and causes other SD factors.
ED refers to a condition in which an erection sufficient to perform sexual intercourse cannot be achieved or sustained, specifically lack or lack of erection itself, prolonged erection time, erection maintenance sufficient for sexual intercourse Lack or lack.

As described above, the erection is caused by an increase in intracavernous pressure caused by an increase in the amount of blood flowing into the cavernous sinus and a decrease in the amount of outflow. And the secoiridoid glucoside derivative represented by General formula (1), its pharmacologically acceptable salt, or those hydrolysates have the effect | action which strengthens this intracavernosal pressure rise.
Therefore, since the enhancer of intracavernous pressure of the present invention can enhance penile erection, it can be effective for the treatment and / or prevention of ED, and hence the treatment and / or prevention of male SD. Here, “enhancing the erection” means increasing the degree of erection, shortening the time to erection, and / or maintaining the erection state (extending the time to return to the original state). including.

  The subject of administration of the pharmaceutical composition for the treatment and / or prevention of male sexual dysfunction of the present invention is a mammal. For example, in addition to humans, pets such as dogs, cats and rabbits, cows, pigs, sheep And domestic animals such as horses, and the like. Among these, humans are particularly preferable.

Another aspect of the present invention is a secoiridoid glucoside derivative represented by the general formula (1) or a pharmacologically acceptable salt thereof in the manufacture of a pharmaceutical composition for the treatment and / or prevention of male sexual dysfunction. Or the use of hydrolysates thereof.
Another aspect is the use of a sequolidoid glucoside derivative represented by the general formula (1) or a pharmacologically acceptable salt thereof or a hydrolyzate thereof in the treatment and / or prevention of male sexual dysfunction. is there.
Another aspect is the increase in intracavernous pressure containing the sequolidoid glucoside derivative represented by the general formula (1) or a pharmacologically acceptable salt thereof or a hydrolyzate thereof, or an active ingredient thereof. A method for treating and / or preventing male sexual dysfunction comprising administering an enhancer or a pharmaceutical composition for treating and / or preventing male sexual dysfunction to an animal.

  The administration route of the pharmaceutical composition of the present invention may be either oral or parenteral. Parenteral administration includes subcutaneous injection, intravenous injection, rectal administration, inhalation and the like.

  The dosage of the pharmaceutical composition of the present invention may be variously prescribed according to factors such as formulation method, administration mode, administration time, age of the subject, body weight, sex, pathological condition, excretion rate, and response sensitivity. Can do.

The preferable dosage of the pharmaceutical composition of the present invention is preferably 0.01 to 300 mg / kg per day in terms of active ingredient when the subject of administration is an adult from the viewpoint of sufficiently exerting the effect, and further 0 .1 to 250 mg / kg, particularly 1 to 200 mg / kg is preferable. This daily dose can be administered at once or in several divided doses.
The timing of administering the pharmaceutical composition for the treatment and / or prevention of male sexual dysfunction of the present invention is not particularly limited, and examples include one to two hours before sexual intercourse, and any of before meals, after meals, and between meals. But you can. Further, the administration / intake period is not particularly limited.

The pharmaceutical composition of the present invention is formulated into a unit dosage form by using a pharmaceutically acceptable carrier and / or excipient by a method usually performed by a person having ordinary knowledge in the art. Or can be manufactured in a multi-dose container.
The pharmaceutical composition of the present invention can be appropriately formulated into a desired dosage form depending on the administration method. For example, in the case of oral administration, it can be formulated into solid preparations such as powders, granules, tablets and capsules; liquid preparations such as solutions, syrups, suspensions and emulsions. In the case of parenteral administration, it can be formulated into solutions, suppositories, ointments and the like.

The content of the secoiridoid glucoside derivative represented by the general formula (1) or a pharmacologically acceptable salt thereof or a hydrolyzate thereof in the pharmaceutical composition of the present invention is based on the final product of the pharmaceutical composition. The content is preferably at least 0.001% by mass.
In formulation, in addition to the sequolidoid glucoside derivative represented by the general formula (1) or a pharmacologically acceptable salt thereof or a hydrolyzate thereof, an excipient usually used for formulation, Components such as a binder, a disintegrant, a lubricant, a stabilizer, a corrigent, a corrigent, a pH adjuster, and a colorant can be used. It is also possible to use a medicine for treating and / or preventing a known or future disorder or a medicine for treating and / or preventing other diseases in combination.

  Examples of the excipient include sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbit; starch derivatives such as corn starch, potato starch, α-starch, dextrin and carboxymethyl starch; crystalline cellulose, hydroxypropyl cellulose, Cellulose derivatives such as hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium; gum arabic; dextran; pullulan; silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate and magnesium magnesium aluminosilicate; phosphate derivatives such as calcium phosphate; And carbonate derivatives such as calcium; sulfate derivatives such as calcium sulfate and the like.

  Examples of the binder include gelatin, polyvinyl pyrrolidone, macrogol and the like in addition to the above excipients.

  Examples of the disintegrant include, in addition to the above excipients, chemically modified starch or cellulose derivatives such as croscarmellose sodium, carboxymethyl starch sodium, and crosslinked polyvinylpyrrolidone.

  As the lubricant, for example, talc; stearic acid; stearic acid metal salts such as calcium stearate and magnesium stearate; colloidal silica; waxes such as pea gum and geirow; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid Carboxylic acid sodium salts such as sodium benzoate; sulfates such as sodium sulfate; leucine; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as anhydrous silicic acid and silicic acid hydrate; starch derivatives and the like It is done.

  Examples of the stabilizer include paraoxybenzoates such as methyl paraben and propyl paraben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; acetic anhydride; sorbic acid and the like.

Examples of the flavoring agent include sweeteners, acidulants, and fragrances.
In addition, as a support | carrier used in the case of a liquid agent, although it does not specifically limit, solvents, such as water, etc. are mentioned.

<4> Food composition

  The enhancer for increasing intracavernous pressure of the present invention can be in a form to be contained in a food composition, and such food composition is suitable for improving male sexual function.

As described above, the enhancer of intracavernous pressure of the present invention has an action of enhancing the intracavernous pressure, and can thereby enhance the erection of the penis. It can be effective for improvement. Here, `` improvement of male sexual function '' means that male machine performance such as sexual desire, erection, ejaculation, orgasm is reduced or attenuated, returns to a good state or improves / enhances than before. Say. In addition, “improvement of erection function” means that the degree of erection is increased, that the time to erection is shortened, that the erected state is maintained (time until the erection is restored, etc.).
Therefore, the food composition of the present invention is usually taken by males, and more specifically, by males whose male sexual functions including erectile function are reduced or attenuated due to aging or various factors. is there.

  Examples of the food composition for improving masculine function of the present invention include normal foods, beverages, functional display foods, health functional foods such as foods for specified health use, supplements, etc., especially functional display foods Is preferred.

About the usefulness and functionality which the food composition for improving the intracavernous pressure rise of this invention or the male sex function may have, you may attach | subject a label | marker at the time of commercialization.
Such “indication” acts include all acts to inform consumers of the use, and recalls uses such as “for increasing intracavernous pressure” and “for improving male sexual function”. Any expression that can be analogized corresponds to the “display” act of the present invention regardless of the purpose of display, the content of display, the object / medium to be displayed, and the like.
Moreover, it is preferable that the “display” is performed by an expression that allows the consumer to directly recognize the above-described use. Specifically, the act of transferring, displaying, importing, or displaying products for use related to food or drink or products packaging, containers, etc. Displaying or distributing catalogs, pamphlets, POPs, etc. on promotional materials, etc. or transaction documents, displaying or distributing them, or describing the above uses in information containing these contents (such as the Internet) ) Acts provided by the method. In addition, when the food composition of the present invention is approved based on various systems established by the government such as health functional foods and is implemented under the approval, it is preferably displayed in an aspect based on the approval.

  Examples of the “indication” on the food composition for improving male sexual function of the present invention include, for example, “functionality improving male sexual function”, “functionality improving erection function”, “declining male sexual function” , “Functionality that supports the maintenance of male sexual function”, “to those who are concerned about the decline in male sexual function”, “to those who have lost confidence in the function as a man”, etc. Display.

The form of the food composition may be liquid, pasty, solid, powder or the like, and may be tablet confectionery, liquid food, feed or the like.
In making such a form, in addition to the sequolidoid glucoside derivative represented by the general formula (1) or a pharmacologically acceptable salt thereof or a hydrolyzate thereof, ingredients usually added during food production, For example, proteins, carbohydrates, fats, nutrients, seasonings and flavors can be used. Examples of carbohydrates include monosaccharides such as glucose and fructose; disaccharides such as maltose, sucrose, oligosaccharides; and polysaccharides such as normal sugars such as dextrin, cyclodextrin, and xylitol, sorbitol, Examples include sugar alcohols such as erythritol. As the flavoring agent, natural flavoring agents (such as thaumatin and stevia extract) and synthetic flavoring agents (such as saccharin and aspartame) can be used. In addition, additives that are used in the above-described pharmaceutical composition and that are usually added to foods may be used as well.

  In addition, it may be an aspect to be contained in other general foods, for example, bread, macaroni, spaghetti, noodles, cake mix, fried flour, breaded flour product; instant noodles, cup noodles, retort / cooked foods, Canned cooking, microwave food, instant soup and stew, instant miso soup and soup, canned soup, freeze and dried food, etc .; canned food, canned fruits, jams, marmalades, pickles, boiled beans, dried agricultural products, cereals Processed agricultural products such as (grain processed products); Canned fishery products, processed fish products such as fish hams and sausages, marine products, marine delicacies, tsukudani, etc .; Livestock processed products such as livestock canned products and pastes, livestock ham and sausages; Processed milk, milk drinks, yogurts, lactic acid bacteria drinks, cheese, ice cream, prepared milk powder, cream, etc. Milk and dairy products such as products; fats and oils such as butter, margarines, vegetable oils; basic seasonings such as soy sauce, miso, sauces, tomato processed seasonings, mirins, vinegars; cooking mix, curry ingredients, Compound seasonings and foods such as sauces, dressings, noodle soups, spices and other compound seasonings; frozen foods such as frozen foods, semi-cooked frozen foods, cooked frozen foods; caramel, candy, chewing gum, Chocolate, cookies, biscuits, cakes, pies, snacks, crackers, Japanese confectionery, rice confectionery, bean confectionery, dessert confectionery, etc .; carbonated beverages, natural juices, fruit juice beverages, fruit juice soft drinks, fruit meat beverages, fruited fruits Beverages, vegetable drinks, soy milk, soy milk drinks, coffee drinks, tea drinks, powdered drinks, concentrated drinks, sports drinks, nutrition drinks, alcoholic drinks, etc. Postal class; in foods other than the above, the enhancer of the present invention may be added.

The preferred intake of the food composition of the present invention is preferably 0.01 to 300 mg / kg per day in terms of active ingredient when taken by an adult from the viewpoint of sufficiently exerting the effect, and is preferably 0.00. It is preferable to set it as 1-250 mg / kg, especially 1-200 mg / kg. This daily dose can be taken at once or in several divided doses.
Although the timing which ingests the food composition of this invention is not specifically limited, For example, 1 to 2 hours before sexual intercourse is mentioned.

  In the food composition of the present invention, the content of the secoiridoid glucoside derivative represented by the general formula (1) or a pharmacologically acceptable salt thereof or a hydrolyzate thereof is at least with respect to the whole food composition. It is preferable that it is 0.001 mass%.

Another aspect of the present invention is a sequolidoid glucoside derivative represented by the general formula (1) or a pharmacologically acceptable salt thereof or a hydrolyzate thereof in the manufacture of a food composition for improving male sexual function. Is the use of.
Another aspect is the use of a sequolidoid glucoside derivative represented by the general formula (1) or a pharmacologically acceptable salt thereof or a hydrolyzate thereof in improving male sexual function.
Another aspect is the increase in intracavernous pressure containing the sequolidoid glucoside derivative represented by the general formula (1) or a pharmacologically acceptable salt thereof or a hydrolyzate thereof, or an active ingredient thereof. A method of improving male sexual dysfunction comprising ingesting a potentiator or a food composition for improving male sexual function.

  Hereinafter, the present invention will be described in more detail with specific experimental examples. However, the present invention is not limited to the following embodiments.

<Example 1> Cavernous body pressurization enhancing action of oleuropein By the measurement system of the erection level of the corpor cavernous body disclosed in International Publication No. 2015/012194, by oleuropein in the presence of nerve stimulation to the cavernosal nerve The cavernosal pressor potentiating action was examined.
Specifically, sexually matured male rats (11 weeks old, Wistar) were treated with urethane (1 to 1.5 g / kg).
) Was fixed in the supine position, and a catheter for measuring blood pressure and heart rate filled with heparinized physiological saline was inserted into the carotid artery and left in place. In addition, for sample administration, a silicone tube equipped with a syringe was orally inserted into the duodenum and placed. An incision was made in the abdomen to expose the penis from the abdomen, and a bipolar electrode was placed on the cavernous nerve connected to the penis so that it could be stimulated. In addition, stimulation was performed using PowerLab / 4SP of ADInstruments. The intracavernous pressure was measured with a needle inserted into the corpus cavernosum (DTXTM Plus DT-XXAD (Nippon Becton Dickinson), AMPLIFIER CASE (NEC Sanei), PowerLab / 4SP (ADInstruments)).

As an administration sample, olive leaf extract (trade name: Opiace (registered trademark), manufactured by Mitsubishi Chemical Foods Co., Ltd., oleuropein content of 35% by mass or more) or carboxymethylcellulose as a control group was prepared, and the rats were administered (A) oleuropein. The group was divided into two groups (4 mice each): a group (Opiace (registered trademark) as 100 mg / kg, experimental group) and a (B) control group (solvent: carboxymethylcellulose as 100 mg / kg, control group). Samples were administered to each group, and frequency-dependent changes in cavernous pressure were observed before stimulation, 5, 30, 60, 90, and after stimulation for 40 seconds under conditions of 8 Hz and 5 V, respectively. The horizontal axis of the graph in FIG. 1 indicates the elapsed time from administration to stimulation, and the vertical axis indicates the cavernous body pressure. However, since the cavernous body pressure is affected by the blood pressure, the cavernous body pressure / mean blood pressure (corrected cavernous body pressure) is calculated, and the maximum value (maximum cavernous body pressure) during the rising reaction is calculated as the cavernous body pressure (vertical The average value of the maximum cavernous body pressure of 4 animals was plotted.
In the control group, there was no effect on the maximum cavernous pressure due to electrical stimulation, but in the experimental group, it was found that it was significantly enhanced after 90 minutes by administration of oleuropein (FIG. 1).

  ADVANTAGE OF THE INVENTION According to this invention, the effective and safe component which has the effect | action which strengthens the intracavernous pressure rise is newly provided. Since such an ingredient is useful as an active ingredient of a pharmaceutical composition for treating and / or preventing male sexual dysfunction, or a food composition for improving male sexual function, the present invention has industrial applicability. It is expensive.

Claims (10)

Sequoridoid glucoside represented by the following general formula (1)
lucoside) or a pharmacologically acceptable salt thereof or a hydrolyzate thereof as an active ingredient.
(In the above formula, R ₁ and R ₂ each independently represents an alkyl group having 1 to 4 carbon atoms, and R _{3 to} R ₇ are each independently a hydrogen atom or a hydroxy group optionally protected by a protecting group. Or an alkyl group having 1 to 4 carbon atoms, wherein two or more of R _{3 to} R ₇ may be protected by a protecting group, m is an integer of 1 to 3, and n is 1 to 1 It is an integer of 4.) In the secoiridoid glucoside derivative, in the general formula (1), R ₁ and R ₂ each independently represent an alkyl group having 1 to 2 carbon atoms, and R _{3 to} R ₇ each independently represent a hydrogen atom or a protecting group. The enhancer according to claim 1, wherein the enhancer represents a hydroxy group which may be protected with, m is 1, and n is 2. The enhancer according to claim 1 or 2, wherein the secoiridoid glucoside derivative is a compound represented by the following formula (2).
  The enhancer according to claim 3, comprising the compound represented by formula (2) in the form of an olive leaf extract.   A pharmaceutical composition for treating and / or preventing male sexual dysfunction, comprising the enhancer according to any one of claims 1 to 4.   The pharmaceutical composition according to claim 5, wherein the male sexual dysfunction is erectile dysfunction (ED).   The food composition for male function improvement containing the enhancer as described in any one of Claims 1-4.   The food composition according to claim 7, wherein the male sexual function is an erectile function.   The food composition according to claim 7 or 8, which is a health functional food or supplement.   The food composition according to claim 9, wherein the health functional food is a functional label food.