JP7047440B2 - An agent for increasing the pressure inside the sponge, and a pharmaceutical composition and a food composition containing the agent. - Google Patents

Description

The present invention relates to an agent for enhancing the pressure in the sponge, a pharmaceutical composition for treating and / or preventing masculine dysfunction containing the same, and a food composition for improving masculine dysfunction.

Male sexual dysfunction is often erectile dysfuncti
Occurs as on (ED)). Such pathological conditions include blocking of corpus cavernosum blood inflow due to penile artery contraction due to sympathetic tone due to stress, decrease in nNOS activity, decrease in guanylate cyclase activity, increase in PDE5 activity, etc., or a combination thereof. As a result, the penis does not erect, or even if it erects, it does not last, making it impossible to have sexual intercourse.
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 effect, and three types of ED therapeutic agents have been put on the market in Japan. Specifically, Pfizer's Sildenafil (product name: Viagra), Bayer's Vardenafil (product name: Levitra), and Eli Lilly's Tadalafil (product name: Cialis). The PDE5 inhibitor inhibits the activity of PDE5, which is a cGMP-degrading enzyme in the corpus cavernosum penis, maintains and increases the amount of cGMP in the corpus cavernosum penis brought about by the peripheral nerves of the penis, and causes an increase in pressure (erection) in the corpus cavernosum penis. It is intended to sustain and enhance. Although these are orally administered drugs and are widely used, they do not always provide satisfactory efficacy.
In addition, there are ED treatment methods such as spongy injection of prostaglandin preparations and transplantation surgery of prostaglandin such as silicone into the corpus cavernosum, but there are problems in terms of invasiveness and risk of infection.

By the way, oleuropein, a secoiridoid compound, is known as a component that is abundantly contained in olive leaves and oils and produces a characteristic bittersweet scent. 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).

Oleuropein has been reported to have physiological activities such as antioxidant, antiviral, antitumor, antibacterial, antiobesity, and improvement of non-alcoholic fatty liver and promotion of hair growth. It is also known that even in a safety test such as administration of 1 g / kg body weight oleuropein to rats for 7 days, no toxicity is observed so that LD ₅₀ cannot be calculated (Patent Document 1).

Japanese Patent Publication No. 2014-533688

It is an object of the present invention 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 diligent studies to solve the above problems, the present inventors have found that a secoiridoid glucoside derivative such as oleuropein has an action of enhancing an increase in intraspinal pressure, and completed the present invention. I let you.

The first aspect of the present invention is to increase the pressure in the sponge containing a secoylidoid glucoside derivative represented by the following general formula (1), a pharmacologically acceptable salt thereof, or a hydrolyzate thereof as an active ingredient. It is an enhancer of.

（前記式中、Ｒ₁及びＲ₂はそれぞれ独立して炭素数１～４のアルキル基を表し、Ｒ₃～Ｒ₇はそれぞれ独立して水素原子、保護基で保護されていてもよいヒドロキシ基又は炭素数１～４のアルキル基を表し、Ｒ₃～Ｒ₇の２つ以上が保護基で保護されていてもよいヒドロキシ基であり、ｍは１～３の整数であり、ｎは１～４の整数である。）

(In the above formula, R ₁ and R ₂ each independently represent an alkyl group having 1 to 4 carbon atoms, and R ₃ to R ₇ are independently protected by a hydrogen atom and a protecting group, respectively. Alternatively, it represents an alkyl group having 1 to 4 carbon atoms, and 2 or more of R ₃ to R ₇ are hydroxy groups which 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, in the secoilidoid 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 independently represent hydrogen. It represents a hydroxy group which may be protected by an atom or a protecting group, and m is preferably 1 and n is preferably a compound of 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, which comprises the agent for enhancing the pressure increase in the spongy body 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 masculine function, which comprises the agent for enhancing the pressure in the sponge of the present invention.
In this embodiment, the masculine function is preferably an erectile function.
As the form of this embodiment, foods with health claims or supplements are preferable, and foods with functional claims are preferable as foods with health claims.

INDUSTRIAL APPLICABILITY The present invention provides a new effective and safe ingredient that can be contained in a pharmaceutical composition for treating and / or preventing masculine dysfunction, or a food composition for improving masculine dysfunction.

It is a graph which shows the elapsed time until the electric stimulus is applied to the corpus cavernosum nerve after administration, and the time-dependent change of the maximum corpus cavernosum pressure. (Right: experimental group, left: control group).

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

<1> Seco-iridoid glucoside derivative The agent for enhancing the pressure increase in the canal of the present invention is a seco-iridoid glucoside derivative represented by the following general formula (1), a pharmacologically acceptable salt thereof, or a hydrolyzate thereof. Contains as an active ingredient.

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

As used herein, 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 the hydroxyl group in a chemical reaction step, a formulation step, or the like, but it is preferably cleaved by a biological method such as hydrolysis in vivo. Refers to a possible protecting group.
For example, 1- (acyloxy) (C ₁ to C ₆ ) alkyl groups can be mentioned, and specific examples thereof include 1-formyloxy (C ₁ to C 6) such as formyloxymethyl, 1-formyloxyethyl and 1-formyloxypropyl. C ₆ ) Alkyl group; acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-acetoxyethyl, 1-propionyloxyethyl , 1-butyryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1 -Butylyloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-buchi 1- (Lyloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl, 1-pivaloyloxyhexyl, etc. Alkylcarbonyloxy) (C ₁ to C ₆ ) Alkyl group; cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxy 1- (“Cycloalkyl” carbonyloxy) (C ₁ to C ₆ ) alkyl groups such as propyl, 1-cyclopentylcarbonyloxybutyl, 1-cyclohexylcarbonyloxybutyl, etc .; 1- (“arylcarbonyl” oxy) such as benzoyloxymethyl ) (C ₁ to C ₆ ) Alkyl groups can be mentioned.

In addition, carbonyloxy (C ₁ to C ₆ ) alkyl groups are also mentioned, and 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- (ethoxy) Carbonyloxy) 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- (ethoxy) (C ₂ ) such as carbonyloxy) hexyl ~ C ₇ ) alkoxycarbonyloxyalkyl 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 -Dioxolen-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-dioxolen-4-yl) methyl, (5-isopropyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-butyl-2-oxo-1,3-dioxolen-) Examples thereof include oxodioxorenylmethyl groups such as 4-yl) methyl.
Further, a phthalidyl group such as phthalidyl, dimethylphthalidyl and dimethoxyphthalidyl; an alkylcarbonyl group; an arylcarbonyl group such as benzoyl, α-naphthoyl and β-naphthoyl; an arylcarbonyl group halide such as 2-bromobenzoyl and 4-chlorobenzoyl. Group; (C ₁ to C ₆ ) alkylated arylcarbonyl group such as 2,4,6-trimethylbenzoyl, 4-toluoil; (C ₁ to C ₆ ) alkoxylated arylcarbonyl group such as 4-anisoil; 4-nitro Nitrylated arylcarbonyl groups such as benzoyl and 2-nitrobenzoyl; (C ₂ to C ₇ ) alkoxycarbonylated arylcarbonyl groups such as 2- (methoxycarbonyl) benzoyl; arylated arylcarbonyl groups such as 4-phenylbenzoyl; Half-ester salt residue of acid; Phosphate ester salt residue; Ester-forming residue such as amino acid; Carbamoyl group; Carbamoyl group substituted with one or two (C ₁ to C ₆ ) alkyl groups; Pivaloyloxy Also mentioned are 1- (acyloxy) alkyloxycarbonyl groups such as methyloxycarbonyl.

In the present specification, the pharmacologically acceptable salt of the compound represented by the general formula (1) is an inorganic salt such as a hydrochloride, a sulfate, a nitrate, a phosphate, a carbonate, etc .; a maleate. , Fumarate, oxalate, citrate, lactate, tartrate, methanesulfonate, paratoluenesulfonate, benzenesulfonate and other organic acid salts; sodium salt, potassium salt 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, and basic amino acid salts such as lysine salt and arginate 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 hydrolyzing the glycosyl group of the compound.
Examples thereof include compounds from which the protecting group for the hydroxyl groups of R ₃ to R ₇ of the general formula (1) has been removed. Elenolic acid is also known to exhibit the same or similar levels of biological activity as oleuropein described below (US Pat. Nos. 6,117,844 and 6,455,580).

As the compound represented by the general formula (1), the compound represented by the following general formula (2) (hereinafter, also referred to as “oleuropein”) is particularly preferable.

Oleuropein is contained in the leaves, fruits, roots and trunks of plants belonging to the family Oleaceae family, and is particularly abundant in the leaves.
Therefore, the secoyridoid glucoside derivative in the present invention may be used in the form of an extract of an Oleaceae plant as long as the compound is contained.
More than about 600 species of 24 genera are known as such plants of the family Mokusei, and are not particularly limited. Fraxinus plants, Jasminum plants, Osmanthus plants and the like are preferable, and olive plants are particularly preferable. Furthermore, as an olive plant, olive (
Olivea europaea Linne), Olive Welwitzski (Olea we)
lwitzchii), Olea paniculata and the like are preferably mentioned.
In a preferred embodiment of the invention, oleuropein is contained in the enhancer in the form of an olive leaf extract.

The extract of the Oleaceae plant containing the secoyridoid glucoside derivative can be obtained from the above-mentioned Oleaceae plant by a normal extraction step. The extraction source is preferably leaves of Oleaceae plants, more preferably olive genus plants, but stems, branches, branch tips and the like may be contained together with the leaves.
Plants such as leaves are subjected to solvent extraction as they are or after being dried and pulverized as needed.

Extraction solvents include water, anhydrous or hydrous lower alcohols having 1 to 4 carbon atoms (eg, methanol, ethanol, isopropanol, butanol, etc.), glycols (eg, ethylene glycol, propylene glycol, 1,3-butylene glycol, etc.). , The mixed solvent 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 under normal pressure in the temperature range from room temperature to the boiling point of the solvent, and after extraction, the extract is purified by filtration, distillation of solvent, column, etc. to obtain a solution, paste, gel, or powder. Can be. Purification treatments such as deodorization and decolorization can also be performed on the extract.

The extract of the Oleaceae plant may be a fraction obtained by further separating and purifying the extract. For example, fractions obtained by passing an Oleaceae plant extract through an ultrafiltration membrane with a constant molecular weight cutoff value, for various chromatographies (separation by size, charge, hydrophobicity or affinity). Examples thereof include fractions obtained by separation according to the produced product).
Further, the extract of the Oleaceae plant may be in a powder state by freeze-drying or the like, may be in a concentrated or diluted state, or may be mixed with other components and contained in the enhancer of the present invention. ..

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

In addition, the secoyridoid glucoside derivative can be chemically synthesized. The method for synthesizing the secoyridoid derivative is described in detail in PCT Application Publication No. WO 96/14064.

<2> Agent for increasing pressure in sponge The mechanism of penile erection will be described below. The body of the "corpora cavernosa" on the penis is surrounded by a fibrous tissue called the tunica albugi. In the corpus cavernosum, there is a vein called the cavernous sinus (also called the cavernous sinus) in the center. Blood flows into this corpus cavernosum sinus from the corpus cavernosum artery via the helicine artery existing under the tunica albugi. Since the corpus cavernosum artery is thin in normal times, blood does not flow much, and as a result, blood flows into the corpus cavernosum sinus and blood from the penetrating vein existing between the inflated corpus cavernosum sinus and the tunica albugi. The penis maintains a constant size because the outflow is balanced as a flow rate.

In the detailed text of the present invention, "smooth muscle" means a tissue specialized for contraction, and smooth muscle consists of smooth muscle fibers (cells) existing on the wall surface of a hollow internal organ and is stimulated by autonomic neuromotor neurons. To. Smooth muscle means muscle that has a smooth appearance because it does not have striated muscles. Alternatively, smooth muscle is also referred to as involuntary muscle. Increased Ca ²⁺ concentration in smooth muscle cytosol causes contraction similar to striated muscle. However, the sarcoplasmic reticulum (the reservoir of Ca ²⁺ in striated muscle) is poor in smooth muscle. Ca ²⁺ flows from both extracellular fluid and sarcoplasmic reticulum into the smooth muscle cytosol, but because smooth muscle fibers do not have tubules, Ca ²⁺ reaches the filament in the center of the fiber and is contractile. It takes longer to trigger the process. This partially causes slow signs of smooth muscle and persistent contractions.

Various mechanisms regulate the contraction and relaxation of smooth muscle cells. In one of them
A regulatory protein called calmodulin binds to Ca ²⁺ in the cytosol. This delays relaxation by slowly allowing Ca ²⁺ to enter the smooth muscle fibers and slowly moving them out of the muscle fibers when the excitation diminishes. The continuous presence of Ca ²⁺ in the cytosol provides smooth muscle tone, continuous partial contraction. Smooth muscle tissue is present on the walls of the corpus cavernosum of hollow internal organs such as blood vessels, airways to the lungs, stomach, intestinal gallbladder, bladder, penis and clitoris.

An erection of the penis is a large amount of blood that dilates the arteries in the penis through stimulation of the corpus cavernosum nerve when the central nervous system is stimulated by visual, contact, auditory, olfactory, and / or imagination. Means the condition of flowing into the corpus cavernosum.

The thickness of the corpus cavernosum artery is regulated by the autonomic nerve, and the vascular smooth muscle of the arterial wall normally contracts by the function of the sympathetic nerve, but the contraction stops by the stimulation of the parasympathetic nerve at the time of erection. As a result, it is believed that the arteries dilate.

Nerve stimulation from the central nervous system is transmitted to the corpus cavernosum via the corpus cavernosum nerve. These non-adrenergic, non-cholinergic nerves originate in the vascular structure of the penis, where they release nitric oxide. Nitric oxide diffuses into the smooth muscle cells of the corpus cavernosum artery to increase the production of intracellular cyclic guanosine 3', 5'-monophosphate (cGMP), resulting in Ca ²⁺ pump and Ca ²⁺ activity. The smooth muscle of the corpus cavernosum artery is relaxed by a mechanism presumed to be due to the K ⁺ channel. As a result, the corpus cavernosum artery dilates and the helicine artery located at the entrance to the corpus cavernosum sinus also dilates, the inflow of blood into the corpus cavernosum rapidly increases, and the blood causes the entire tissue to expand. As a result, the internal pressure of the corpus cavernosum rises. Subsequently, the penetrating vein existing between the swollen corpus cavernosum sinus and the tunica albugi is compressed to suppress the outflow of blood from the corpus cavernosum sinus to the outside, and the intracavernosal pressure further increases. An increase in the inflow of blood into the cavernous sinus and a decrease in the outflow of blood from the cavernous sinus act synergistically to cause an erection. On the other hand, when the corpus cavernosum artery contracts and the pressure on the vein is relieved, the penis returns to a relaxed state.

In this way, when the corpus cavernosum nerve is stimulated, the inflow of blood into the corpus cavernosum sinus increases and the outflow of blood decreases, and the intracavernosal pressure rises (pressurizes). The secoiridoid glucoside derivative represented by, or a pharmacologically acceptable salt thereof or a hydrolyzate thereof has an action of enhancing such pressurization. Here, the "action of enhancing the pressurization" includes an action of enhancing the degree of pressurization and / or an action of maintaining the boosted state (prolonging the time until the original state is restored).
The enhancement of corpus cavernosum pressurization can be confirmed, for example, by the measurement system described in International Publication No. 2015/012194.
Therefore, the seco-iridoid glucoside derivative represented by the general formula (1), a pharmacologically acceptable salt thereof, or a hydrolyzate thereof is an active ingredient of the agent for increasing the pressure in the sponge. Normally, the corpus cavernosum pressurization to be enhanced is a pressurization that occurs when the corpus cavernosum nerve is stimulated.

Another aspect of the present invention is the use of a secoyridoid glucoside derivative represented by the general formula (1) or a pharmacologically acceptable salt thereof or a hydrolyzate thereof in the production of an agent for enhancing the pressure increase in spongy body. be.
Another aspect is the use of a secoylidoid glucoside derivative represented by the general formula (1) or a pharmacologically acceptable salt thereof or a hydrolyzate thereof in enhancing the increase in spongy body pressure.
Another aspect is the increase in the pressure inside the sponge containing the secoiridoid glucoside derivative represented by the general formula (1), a pharmacologically acceptable salt thereof or a hydrolyzate thereof, or a hydrolyzate thereof as an active ingredient. A method of enhancing an increase in spongy pressure, including administration of a enhancer to a mammal.

<3> Pharmaceutical composition The agent for enhancing the pressure in the sponge of the present invention can be contained in the pharmaceutical composition, and the pharmaceutical composition is suitable for the treatment and / or prevention of male sexual dysfunction. Is.

Male sexual dysfunction (SD) is a condition in which sexual interest or ability is impaired, primarily due to problems with one or more of the four components of libido, erection, ejaculation, and orgasm. Treatment is important because SD causes pain to the person and partner by reducing self-esteem and disrupting relationships. The causes of SD include organ and psychological ones, and typical organ causes include vascular diseases related to hypertension and diabetes, psychiatric diseases such as depression, and various drugs. .. Psychological causes include fear, anxiety about performance, and interpersonal conflict.

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

As mentioned above, an erection is caused by an increase in intracavernosal pressure caused by an increase in blood influx into the cavernous sinus and a decrease in outflow. The seco-iridoid glucoside derivative represented by the general formula (1), a pharmacologically acceptable salt thereof, or a hydrolyzate thereof has an action of enhancing the increase in the pressure inside the sponge.
Therefore, since the agent for enhancing the pressure in the sponge of the present invention can enhance the erection of the penis, it may be effective for the treatment and / or prevention of ED, and thus for the treatment and / or prevention of SD in men. Here, "enhancing erection" means increasing the degree of erection, shortening the time to erection, and / or maintaining the erection state (prolonging the time to return to the original state). including.

The subject of administration of the pharmaceutical composition for treating and / or preventing male sexual dysfunction of the present invention is a mammal, for example, in addition to humans, pet animals such as dogs, cats and rabbits, cows, pigs and sheep. , Horses and other livestock animals, and among these, humans are particularly preferable.

Another aspect of the present invention is the seco-iridoid glucoside derivative represented by the general formula (1) or a pharmacologically acceptable salt thereof in the production of a pharmaceutical composition for the treatment and / or prevention of male sexual dysfunction. Or the use of those hydrolysates.
Another aspect is the use of a secoylidoid 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. be.
Another aspect is the increase in the pressure inside the spongy skin containing the secoylidoid glucoside derivative represented by the general formula (1), a pharmacologically acceptable salt thereof or a hydrolyzate thereof, or a hydrolyzate thereof as an active ingredient. A method of treating and / or preventing masculine dysfunction, which comprises administering to an animal a pharmaceutical composition for the treatment and / or prevention of an enhancer or masculine dysfunction.

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

The dose of the pharmaceutical composition of the present invention is variously prescribed depending on factors such as the formulation method, administration method, administration time, age, body weight, sex, pathological condition, excretion rate, and reaction sensitivity. Can be done.

When the subject to be administered is an adult, the preferable dose of the pharmaceutical composition of the present invention is preferably 0.01 to 300 mg / kg per day in terms of the active ingredient, from the viewpoint of sufficiently exerting the effect, and further 0. .1 to 250 mg / kg, particularly preferably 1 to 200 mg / kg. This daily dose can be administered at one time or in several divided doses.
The timing of administration of the pharmaceutical composition for treating and / or preventing male sexual dysfunction of the present invention is not particularly limited, and examples thereof include 1 to 2 hours before sexual intercourse, and any of pre-meal, post-meal, and inter-meal. But it may be. The administration / ingestion period is not particularly limited.

The pharmaceutical composition of the present invention is formulated in a unit dose form using a pharmaceutically acceptable carrier and / or excipient by a method usually carried out by a person having ordinary knowledge in the art. It can be manufactured in the same way, or it can be manufactured by injecting it into 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 a solid preparation such as a powder, a granule, a tablet or a capsule; a liquid preparation such as a solution, a syrup, a suspension or an emulsion. In the case of parenteral administration, it can be formulated into a liquid, a suppository, an ointment, or the like.

The content of the secoyridoid glucoside derivative represented by the general formula (1), 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. , It is preferably at least 0.001% by mass.
In the formulation, in addition to the secoylidoid glucoside derivative represented by the general formula (1) or a pharmacologically acceptable salt thereof or a hydrolyzate thereof, an excipient usually used for the formulation, Ingredients such as binders, disintegrants, lubricants, stabilizers, flavoring agents, odorants, pH adjusters, and colorants can be used. It is also possible to use a drug for treating and / or preventing a disorder known or found in the future, a drug for treating and / or preventing other diseases, and the like in combination.

Examples of excipients include sugar derivatives such as lactose, sucrose, glucose, mannit, and sorbit; starch derivatives such as corn starch, horse bell starch, α-starch, dextrin, and carboxymethyl starch; crystalline cellulose, hydroxypropyl cellulose, and the like. Cellulose derivatives such as hydroxypropylmethyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium; Arabic rubber; Dextran; Plulan; Silate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminometasilicate; Phosphate derivatives such as calcium phosphate; Carbonated Carbonated carbonate derivatives such as calcium; sulfate derivatives such as calcium sulfate can be mentioned.

Examples of the binder include gelatin; polyvinylpyrrolidone; macrogol and the like in addition to the above-mentioned excipients.

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

Examples of the lubricant include talc; stearic acid; metal stearate salts such as calcium stearate and magnesium stearate; colloidal silica; waxes such as pea gum and gay wax; 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. Be done.

Examples of the stabilizer include paraoxybenzoic acid esters such as methylparaben and propylparaben; 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.
The carrier used in the case of a liquid preparation is not particularly limited, and examples thereof include a solvent such as water.

<4> Food composition

The agent for increasing the pressure in the sponge of the present invention can be contained in a food composition, and the food composition is suitable for improving masculine function.

As described above, the agent for enhancing the increase in spongy body pressure of the present invention has an action of enhancing the increase in sponge body pressure, and thereby can enhance the erection of the penis, thereby improving male sexual function, particularly erection function. Can be effective in improving. Here, "improvement of male sexual function" means that the condition in which the performance of male genitalia such as sexual desire, erection, ejaculation, orgasm is deteriorated or weakened returns to a good condition or is improved or enhanced more than before. say. Further, "improvement of erection function" means that the degree of erection is enhanced, the time to erection is shortened, the erection state is maintained (the time to return to the original state is extended), and the like.
Therefore, it is usually males who ingest the food composition of the present invention, and more specifically, males whose masculine functions including erectile function are deteriorated or diminished due to aging or various factors. be.

Examples of the aspect of the food composition for improving masculine function of the present invention include ordinary foods, beverages, foods with functional claims, foods with health claims such as foods for specified health use, supplements, etc., and foods with functional claims in particular. Is preferable.

The usefulness and functionality of the agent for increasing the pressure in the sponge of the present invention or the food composition for improving masculine function may be labeled at the time of commercialization.
Such "display" actions include all actions for informing consumers of the above-mentioned uses, and recall uses such as "for enhancing increase in spongy body pressure" and "for improving masculine function". Any expression that can be inferred falls under the "display" act of the present invention regardless of the purpose of the display, the content of the display, the object / medium to be displayed, and the like.
Further, it is preferable that the "display" is performed by an expression that allows the consumer to directly recognize the above-mentioned use. Specifically, the act of transferring, delivering, transferring or displaying for delivery, importing, advertising, price list, etc. of products related to food and drink, packaging, containers, etc. Advertisements, etc. at sales sites such as catalogs, pamphlets, POPs, etc., or transaction documents that describe the above-mentioned uses, are exhibited or distributed, or the above-mentioned uses are described in the information containing these, and are electromagnetic (Internet, etc.) ) The act of providing by the method can be mentioned. When the food composition of the present invention is approved based on various systems established by the government such as foods with health claims and is implemented under the approval, it is preferable to label the food composition based on the approval.

The "labeling" on the food composition for improving masculine function of the present invention includes, for example, "functionality for improving masculine function", "functionality for improving erectile function", and "decline of masculine function". "Functionality to suppress masculine function", "Functionality to support maintenance of masculine function", "For those who are worried about deterioration of masculine function", "For those who are not confident in their function as a man", etc. The display is mentioned.

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

In addition, it may be contained in other general foods, for example, bread, macaroni, spaghetti, noodles, cake mix, fried flour, bread flour flour products; instant noodles, cup noodles, retort / cooked foods, etc. Instant foods such as canned cooked foods, microwave foods, instant soups / stews, instant miso soups / soups, canned soups, frozen / dried foods; canned agricultural products, canned fruits, jams and marmalades, pickles, boiled beans, dried agricultural products, serials. Processed agricultural products such as (processed grain products); Processed marine products such as canned fish, fish hams and sausages, paste products, marine delicacies, and boiled Tsukuda; Canned livestock and pastes, processed livestock products such as meat hams and sausages; Milk and dairy products such as processed milk, dairy beverages, yogurts, lactic acid bacteria beverages, cheese, ice creams, prepared milk powders, creams, and other dairy products; butter, margarines, vegetable oils and other fats and oils; soy sauce, miso , Sauces, processed tomato seasonings, mirins, vinegars, and other basic seasonings;・ Foods; 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 sweets, rice sweets, bean sweets, Confectionery such as dessert confectionery; carbonated beverages, natural fruit juices, fruit juice beverages, refreshing beverages containing fruit juices, fruit meat beverages, fruit beverages containing fruit grains, vegetable beverages, soymilk, soymilk beverages, coffee beverages, tea beverages, powdered beverages, concentrated beverages , Sports beverages, nutritional beverages, alcoholic beverages and other beverages; the enhancer of the present invention may be added to other foods and the like.

When the food composition of the present invention is ingested by an adult, it is preferably 0.01 to 300 mg / kg per day in terms of active ingredient, from the viewpoint of sufficiently exerting the effect, and further 0. It is preferably 1 to 250 mg / kg, particularly preferably 1 to 200 mg / kg. This daily dose can be taken at one time or in several divided doses.
The timing of ingesting the food composition of the present invention is not particularly limited, and examples thereof include 1 to 2 hours before sexual intercourse.

The content of the secoyridoid glucoside derivative represented by the general formula (1), a pharmacologically acceptable salt thereof, or a hydrolyzate thereof in the food composition of the present invention is at least the content of the whole food composition. It is preferably 0.001% by mass.

Another aspect of the present invention is a secoyridoid glucoside derivative represented by the general formula (1) in the production of a food composition for improving masculine function, a pharmacologically acceptable salt thereof, or a hydrolyzate thereof. Is the use of.
Another aspect is the use of a secoylidoid glucoside derivative represented by the general formula (1) or a pharmacologically acceptable salt thereof or a hydrolyzate thereof in improving masculine function.
In addition, another aspect is the increase in the pressure inside the spongy skin containing the secoiridoid glucoside derivative represented by the general formula (1), a pharmacologically acceptable salt thereof or a hydrolyzate thereof, or a hydrolyzate thereof as an active ingredient. A method of ameliorating masculine dysfunction, including ingesting a enhancer or a food composition for improving masculine function.

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

<Example 1> Corpus cavernosum boosting effect of oleuropain Using the system for measuring the erection level of the corpus cavernosum disclosed in International Publication No. 2015/012194, oleuropain is used when nerve stimulation to the corpus cavernosum nerve is present. The effect of enhancing corpus cavernosum pressurization was investigated.
Specifically, sexually mature male rats (11 weeks old, Wistar type) are subjected to urethane (1 to 1.5 g / kg).
) Was anesthetized by intraperitoneal administration, fixed in the supine position, and a catheter for measuring blood pressure and heart rate filled with heparinized saline was inserted into the carotid artery and indwelled. In addition, for sample administration, a silicone tube with a syringe was orally inserted and indwelled up to the duodenum. An incision was made in the abdomen to expose the penis from the abdomen to the outside, and bipolar electrodes were placed on the corpus cavernosum nerve connecting to the penis so that it could be stimulated. The stimulation was performed using PowerLab / 4SP of AD Instruments. The intracavernosal pressure was measured with a needle inserted into the corpus cavernosum (DTXTM Plus DT-XXAD (Nippon Becton Dickinson Co., Ltd.), AMPLIFIER CASE (NEC Sanei Co., Ltd.), PowerLab / 4SP (ADInstruments)).

Olive leaf extract (trade name: Opiece (registered trademark), manufactured by Mitsubishi Chemical Foods Co., Ltd., oleuropein content of 35% by mass or more) or carboxymethyl cellulose was prepared as a control group, and the rat was administered with (A) oleuropein. They were divided into two groups (4 animals in each group): a group (100 mg / kg as oleuropein (registered trademark), experimental group) and a control group (B) control group (solvent: 100 mg / kg as carboxymethyl cellulose, control group). Samples were administered to each group, and frequency-dependent changes in corpus cavernosum pressure were observed before, after, and after administration at 8 Hz and 5 V for 40 seconds. The horizontal axis of the graph in FIG. 1 shows the elapsed time from administration to stimulation, and the vertical axis shows the cavernous body pressure. However, since the corpus cavernosum pressure is affected by blood pressure, the corpus cavernosum pressure / mean blood pressure (corrected corpus cavernosum pressure) is calculated, and the maximum value (maximum corpus cavernosum pressure) at the time of the increase reaction is the corpus cavernosum pressure (vertical graph). (Axis), the average value of the maximum corpus cavernosum pressure of 4 animals was plotted.
In the control group, there was no effect on the maximum corpus cavernosum pressure due to electrical stimulation, but in the experimental group, it was found that the administration of oleuropein significantly increased it after 90 minutes (Fig. 1).

INDUSTRIAL APPLICABILITY According to the present invention, an effective and safe ingredient having an action of enhancing an increase in spongy body pressure is newly provided. Since such an ingredient is useful as an active ingredient of a pharmaceutical composition for treating and / or preventing masculine dysfunction, or a food composition for improving masculine dysfunction, the present invention has industrial applicability. It is expensive.

Claims (7)

Contains olive leaf extract as an active ingredient,
The olive leaf extract contains a compound represented by the following formula (2) or a pharmacologically acceptable salt thereof, and is an enhancer for increasing the pressure in the sponge.

A pharmaceutical composition for treating and / or preventing male sexual dysfunction, which comprises the enhancer according to claim 1 . The pharmaceutical composition according to claim 2 , wherein the male sexual dysfunction is erectile dysfunction (ED). A food composition for improving masculine function containing the enhancer according to claim 1 . The food composition according to claim 4 , wherein the masculine function is an erectile function. The food composition according to claim 4 or 5 , which is a food with health claims or a supplement. The food composition according to claim 6 , wherein the food with health claims is a food with functional claims.

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