WO2015012194A1

WO2015012194A1 - Male function-improving effect of helipyrone a

Info

Publication number: WO2015012194A1
Application number: PCT/JP2014/069040
Authority: WO
Inventors: 折戸謙介; 小菅直哉
Original assignee: 学校法人麻布獣医学園
Priority date: 2013-07-22
Filing date: 2014-07-17
Publication date: 2015-01-29
Also published as: JPWO2015012194A1

Abstract

The present invention addresses the problem of newly finding a compound that has no effect other than an effect of increasing cavernous pressure, different from conventional medicinal compositions for treating or ameliorating erectile dysfunction. The present inventors examined various substances derived from natural products with respect to the presence or absence of a male function-improving effect. As a result, they found that the administration of helipyrone A (3,3'-methylenebis(6-ethyl-4-hydroxy-5-methyl-2H-pyran-2-one)), which is a component derived from curry plant belonging to the genus Helichrysum of the family Asteraceae, enhances an cavernous nerve stimulation-induced cavernous pressure increasing effect in the corpus cavernosum of the penis, and thus completed the present invention.

Description

Hepirone A improves male sexual function

The present invention relates to providing a compound having a male sexual function improving action.

Male sexual dysfunction often occurs as erectile dysfunction (erectile dysfunction, erectile dysfunction or erectile dysfunction; referred to as ED, etc.). Such a pathological condition may be one of a combination of blockage of cavernous blood inflow due to penile artery contraction due to sympathetic nerve tension 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, making it impossible to have sexual intercourse.
Erectile dysfunction (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, PDE5 inhibitors have been found as compounds having such an effect of improving erectile dysfunction in men, and ED treatment has greatly advanced. This 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 NO nerve of the penis, and maintains the increased penile intracavernosal pressure (erection) state -It is to be strengthened (see Figure 2).
In Japan, three types of erectile dysfunction drugs have been marketed so far. Specifically, Viagra (Sildenafil), launched in 1999 from Pfizer, Levitra (Vardenafil), launched from Bayer in 2004, and Cialis (Tadalafil), launched from Eli Lilly in 2007. is there. All of these components are identical in that the mechanism of action is a PDE5 inhibitor.
Because of such a background, in this field, it is required to newly find other compounds having a cavernous body pressurization enhancing action.

Therefore, the inventors have been researching and developing with particular attention to hepyrone A (Non-patent Document 1) in developing ED therapeutic agents. So far, helipilon A has been used as a singlet oxygen scavenger, skin aging improver, wrinkle improver, sagging improver, skin moisture content improver, whitening agent, melanin inhibitor, nitric oxide scavenger, antioxidant. (Patent Document 1), utilization as an adiponectin production promoter (Patent Document 2), utilization as a tissue fibrosis inhibitor (Patent Document 3), but report on utilization as an ED therapeutic agent Does not exist.

WO2007 / 125832 JP2013-060383 JP2004-175780

In the present invention, unlike a conventional pharmaceutical composition for treating or improving penile erection dysfunction, it is an object to find another compound that does not have another action other than the cavernosal pressor enhancing action. did.

The inventors of the present invention have examined whether various sexually derived substances have an effect of improving male sexual function, and as a result, hepyrone A (3, 3), a component derived from a curry plant of the asteraceae Helixam plant. Cavernosal pressurization caused by stimulation of cavernous nerves in the penile cavernosa when 3'-methylenebis (6-ethyl-4-hydroxy-5-methyl-2H-pyran-2-one)) is administered Since the enhancement of the action was observed, the present invention was completed.

Accordingly, the present invention provides the following formula (I)

Wherein R ¹ and R ² are each independently a hydrogen atom or a hydroxyl-protecting group, or a male sexual function comprising a compound or a pharmaceutically acceptable ester or prodrug thereof Pharmaceutical compositions are provided for treating disorders, particularly erectile dysfunction (ED).

An example of the active ingredient of the pharmaceutical composition according to the present invention is the following formula (II):

Or hepropyrone A (3,3′-methylene bis (6-ethyl-4-hydroxy-5-methyl-2H-pyran-2-one)), or a prodrug.

The above-mentioned pharmaceutical composition of the present invention was found to be effective for the treatment of male sexual dysfunction (especially erectile dysfunction (ED)) even when orally administered. The pharmaceutical composition is orally administered.

Furthermore, the present invention relates to male sex comprising administering a compound represented by the above formula (I) or formula (II) or a pharmaceutically acceptable ester or prodrug thereof to a patient with male sexual dysfunction. Provide a method for treating dysfunction, particularly erectile dysfunction (ED).

Until now, only three male sexual dysfunction drugs have been marketed in Japan, but helipon A can be used to treat male sexual dysfunction (especially erectile dysfunction (ED)). Since it became clear, it can be developed as a new drug. In addition, because the structure of the compound is different from conventional male sexual function-improving drugs, to provide a drug for the treatment of male sexual dysfunction (especially erectile dysfunction (ED)) with a different mechanism of action. There is a high possibility that

FIG. 1 is a diagram showing a cross-sectional schematic view of the corpus cavernosum during normal (A) and erection (B). FIG. 2 is a diagram showing a molecular cascade from sexual arousal in the brain to erection of the cavernous corpus cavernosum. FIG. 3 is a diagram showing an outline of a measurement system for the erection level of the cavernous corpus cavernosum. The upper row schematically shows the incision site of the rat, the arrangement of tubes and electrodes for measurement, and the like when measuring using a rat. The lower part shows an outline of data such as voltage, blood pressure, and cavernous pressure applied to the cavernous nerve by the measurement system. Fig. 4 shows that the system for measuring the erection level of the corporal cavernous body of the present invention was able to stably measure the application of electrical stimulation and the coronary body pressurizing action in response to the application of electrical stimulation over a long period (90 minutes) under anesthesia conditions. FIG. FIG. 5 shows a measurement system of penile cavernous body erection level according to the present invention, under the condition of applying electrical stimulation to the cavernous nerve, carboxymethylcellulose (CMC, solvent control group) (A) or hepyrone A (30 It is the figure which showed the cavernosal pressor action before administration and 90 minutes after administration of mg / kg (experimental group) (B). FIG. 6 shows a measurement system of the erection level of the corpor cavernosa of the present invention, under the condition of applying electrical stimulation to the cavernous nerve, and compared with carboxymethylcellulose (CMC, solvent control group) It is the figure which showed that cavernosal pressor action by electrical stimulation was significantly enhanced by administration of 30 mg / kg, experimental group). FIG. 7 is a diagram for explaining the “maximum cavernous body pressure” and “cavernous body pressure half-life” shown in this example. In this example, “maximum cavernous body pressure”, which is the maximum value of “cavernous body pressure for average blood pressure”, and a time that indicates a value of one half of the maximum cavernous body pressure from the end of electrical stimulation. Was evaluated as “cavernous body pressure half-life”. FIG. 8 shows the results of studying the effects of sildenafil and helipyrone A (HA) on blood pressure using the penile cavernous body erection level measurement system of the present invention. Numbers in parentheses indicate the number of animals used in the experiment. FIG. 9 shows the results of examining the effect of sildenafil on the increase in cavernosal pressure caused by electrical stimulation using the system for measuring the erection level of the penile cavernous body of the present invention. Numbers in parentheses indicate the number of animals used in the experiment. FIG. 10 shows the results of examining the effect of helipyrone A (HA) on the increase in corpus cavernosum caused by electrical stimulation, using the penile cavernous body erection level measurement system of the present invention. Numbers in parentheses indicate the number of animals used in the experiment. FIG. 11 is a diagram of the organ bus apparatus used in the example of the present invention. FIG. 12 shows the results of investigating the relaxing action of helipyrone A and sildenafil on the isolated corpus cavernosum using an organ bath apparatus. Figure 13 shows that helipyrone A (HA) potentiates the electrical stimulation-induced relaxation in isolated corpus cavernosum, which L-NAME suppresses this effect, and that the inhibitory effect of L-NAME is restored by L-arginine. FIG. The upper figure shows the contraction-relaxation profile of the isolated corpus cavernosum, and the arrowheads indicate the time point when hepyrone A, L-NAME and L-arginine were added. The lower graph is a graph showing the extension of the cavernous relaxation half-life due to the addition of heliciron A, L-NAME and L-arginine. As a control, a solvent (CMC) was added.

I. Active ingredient As described above, the present invention comprises the following formula (I):

In the present invention, the hydroxyl-protecting group is not particularly limited as long as it can stably protect the hydroxyl group during the reaction, and specifically, a biological method such as hydrolysis in vivo. Or a protecting group that can be cleaved by chemical methods such as hydrogenolysis, hydrolysis, electrolysis and photolysis, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl , Pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexa Decanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, 1 Alkylcarbonyl groups such as 3,13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, eicosanoyl and heinacosanoyl, carboxy such as succinoyl, glutaroyl, adipoyl Alkylcarbonyl groups, halogeno lower alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, lower alkoxy lower alkylcarbonyl groups such as methoxyacetyl, (E) -2-methyl-2-butenoyl “Aliphatic acyl groups” such as unsaturated alkylcarbonyl groups; arylcarbonyl groups such as benzoyl, α-naphthoyl, β-naphthoyl, halogenoary such as 2-bromobenzoyl, 4-chlorobenzoyl Carbonyl group, 2,4,6-trimethylbenzoyl, lower alkylated arylcarbonyl group such as 4-toluoyl, lower alkoxylated arylcarbonyl group such as 4-anisoyl, 2-carboxybenzoyl, 3-carboxybenzoyl, 4 -Carboxylated arylcarbonyl groups such as carboxybenzoyl, nitrated arylcarbonyl groups such as 4-nitrobenzoyl, 2-nitrobenzoyl, lower alkoxycarbonylated arylcarbonyl groups such as 2- (methoxycarbonyl) benzoyl, 4- An “aromatic acyl group” such as an arylated arylcarbonyl group such as phenylbenzoyl; an acyloxyalkyl group such as ethylcarbonyloxymethyl, pivaloyloxymethyl, dimethylaminoacetyloxymethyl, 1-acetoxyethyl; Methoxycarbo Loxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, ethoxycarbonyloxymethyl, 1- (isopropoxycarbonyloxy) ethyl, 1- (t-butoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) propyl, 1- 1- (alkoxycarbonyloxy) alkyl groups such as (cyclohexyloxycarbonyloxy) ethyl; phthalidyl groups; 4-methyl-oxodioxorenylmethyl, 4-phenyl-oxodioxorenylmethyl, oxodioxorenyl “Carbonyloxyalkyl groups” such as oxodioxorenylmethyl groups such as methyl; “half ester salt residues of succinic acid”; “phosphate ester salt residues”; “ester forming residues such as amino acids”; carbamoyl Group; a carbamoyl group substituted with one or two lower alkyl groups; pivalloy "Alkylcarbonyloxy alkyloxycarbonyl group" such as oxymethyl oxycarbonyl; and a like "silyl group". Among these, a group that forms a pharmacologically acceptable ester such as “aliphatic acyl group” and “aromatic acyl group” or “silyl group” is preferable, and acetyl, propionyl are more preferable. , “C ₁ -C ₆ alkanoyl groups” such as butyryl, isobutyryl, pentanoyl and pivaloyl; or “silyl groups” such as t-butyldimethylsilyl group and t-butyldiphenylsilyl group, particularly preferably Acetyl group, t-butyldimethylsilyl group or t-butyldiphenylsilyl group.

A protective group for a hydroxyl group, which is a “protecting group that can be cleaved in vivo by a biological method such as hydrolysis” refers to a free acid or its acid that is cleaved by a biological method such as hydrolysis in the human body. A protective group that forms a salt. Whether it is such a derivative or not is determined by administering it intravenously to a laboratory animal such as a rat or mouse, examining the body fluid of the animal, and then examining the original compound or its pharmacological agent. It can be determined by the ability to detect acceptable salts.

As the protecting group for a hydroxyl group, which is a “protecting group that can be cleaved by a biological method such as hydrolysis in vivo”, preferably formyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, Pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1-pivalo Yloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1-butyryloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropi 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxy 1-formyloxy “C ₁ -C ₆ alkyl group” or 1-(“alkylcarbonyl” oxy) “C ₁ -C ₆ alkyl” such as pentyl, 1-pivaloyloxypentyl, 1-pivaloyloxyhexyl Group '', cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxypropyl, 1-cyclopentylcarbonyloxybutyl, 1- Cyclohexylcarbonyloxy Such as butyl 1- ( "cycloalkyl" carbonyloxy) "C ₁ -C ₆ alkyl group", such as benzoyloxy methyl 1- ( "arylcarbonyl" oxy) such as "C ₁ -C ₆ alkyl group" 1- (acyloxy) “C ₁ -C ₆ alkyl group”; methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, pentyloxycarbonyl Oxymethyl, hexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxy (cyclohexyl) methyl, 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1- ( (Ropoxycarbonyloxy) 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- (d Xoxycarbonyloxy) propyl, 1- (propoxycarbonyloxy) propyl, 1- (isopropoxycarbonyloxy) propyl, 1- (butoxycarbonyloxy) propyl, 1- (isobutoxycarbonyloxy) propyl, 1- (pentyloxycarbonyl) Oxy) 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- ( Ethoxycarboni Yloxy) such as hexyl (C ₂ -C ₇ alkoxycarbonyloxy) alkyl 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-4-yl) methyl "Carbonyloxy C ₁ -C ₆ alkyl group" such as; oxodioxolenyl methyl group such as phthalidyl, dimethyl-phthalidyl, "phthalidyl group" such as dimethoxy phthalidyl; "alkylcarbonyl group"; benzoyl, alpha -Arylcarbonyl groups such as naphthoyl, β-naphthoyl, halogenated arylcarbonyl groups such as 2-bromobenzoyl, 4-chlorobenzoyl, C ₁ -C such as 2,4,6-trimethylbenzoyl, 4-toluoyl ₆ alkylated arylcarbonyl groups, C ₁ -C ₆ alkoxylated arylcarbonyl groups such as 4-anisoyl, 4-nitrobenzoyl, nitrated arylcarbonyl groups such as 2-nitrobenzoyl, 2- (methoxycarbonyl) benzoyl C ₂ -C ₇ alkoxycarbonyl arylcarbonyl group such as, ants such as 4-phenylbenzoyl Arylcarbonyl groups such as aryl carbonyl groups; “half-ester salt residues of succinic acid”; “phosphate ester salt residues”; “ester-forming residues such as amino acids”; carbamoyl groups; A carbamoyl group substituted with a C ₁ -C ₆ alkyl group; and a “1- (acyloxy) alkyloxycarbonyl group” such as pivaloyloxymethyloxycarbonyl.

Methods for selecting and producing “esters of hydroxy groups” having “protecting groups that can be cleaved by biological methods such as hydrolysis in vivo” are described in, for example, “Design of Prodrugs, Elsevier, Amsterdam” 1985, Pharmaceuticals Development Volume 7 Molecular Design 廣 gawa Shoten 1990 published. Examples of this compound include acetate, pivaloate, benzoate and the like.

Examples of the ester of the compound of the present invention include esters formed from alkyl groups having 1 to 6 carbon atoms. Examples of such esters include methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, s-butyl ester, t-butyl ester, pentyl ester, isopentyl ester, neopentyl ester, etc. can do.

Helipiron A
An example of an active ingredient according to the present invention that can be used in the treatment of male sexual dysfunction, particularly erectile dysfunction (ED), is the following formula (II):

Or hepropyrone A (3,3′-methylene bis (6-ethyl-4-hydroxy-5-methyl-2H-pyran-2-one)), or a prodrug.
The active ingredient contained in this pharmaceutical composition and heliponone A having the structure of the above formula (I) is described in Esahak Ali et al. (Esahak A., et al., Phytochemistry, 1982, 21, 243-244). As described above, it is a component contained in various plants, for example, a curry plant (Helichrysum italicum) of the Asteraceae Heliksum family, and originally obtained as a component derived from a natural product.

When helipyrone A is used as cosmetics or foods, it can be expected to suppress wrinkles, improve skin aging, photoaging, whitening agents, melanin production, antioxidant, and singlet oxygen elimination, resulting in skin aging improving agents and photoaging. It has been known that it can be used as an inhibitor, a whitening agent, a melanin production inhibitor, an antioxidant, a singlet oxygen scavenger, and a nitric oxide scavenger (WO2007 / 125832 or JP2013-060383).

Heripiron A used in the present invention can be extracted from a plant (for example, a curry plant of the genus Helixamaceae) or chemically synthesized. In the present invention, helipyrone A was provided by FANCL Corporation.

Heliponone A can be chemically synthesized at present and can be performed based on the literature of Esahak Ali et al. Specifically, a method for chemically synthesizing helipyrone A is known (for example, WO2007 / 125832 or JP2013-060383), and the synthesis method is outlined below.

In the presence of titanium tetrachloride, 172 g of compound 1 (diethyl ketone (3-pentanone)) and compound 2 (terahydro-1,4-oxazine (morpholine) in 400 mL of hexane solvent )) 1,000 g was reacted at 4 ℃ for 3 hours and purified by distillation. Compound 3 ((N-isopropenyl) -tetrahydro-1,4-oxazine ((N-isopropenyl) -terahydro-1,4- oxazine)) 503.57 g (yield 81.1%).

Using 200 mL of toluene solvent, 167 g of compound 3 ((N-isopropenyl) -tetrahydro-1,4-oxazine) was converted to compound 4 (ethylmalonyl). The compound 5 represented by the following formula (III) was synthesized by reacting 81 g of ethyl malonyl chloride with methanol-ice cooling (-17 ° C to -11 ° C).

The reaction between Compound 3 and Compound 4 was terminated by adding 2N hydrochloric acid, and extracted with chloroform, followed by magnesium sulfate drying treatment. Next, 200 mL of toluene and 400 mL of 25% hydrochloric acid were sequentially added to the reaction solution, and the toluene layer was recovered by liquid-liquid partition. The toluene layer was washed with 400 mL of 0.1N hydrochloric acid, and after drying with magnesium sulfate, toluene was removed with a vacuum evaporator to obtain an orange oily solution. 1 kg of PPA (polyphosphoric acid) was added to this solution and cyclized at 110 ° C to 118 ° C to synthesize Compound 5. Compound 5 was cooled to room temperature, recovered by extraction with chloroform, and chloroform was removed by a vacuum evaporator after magnesium sulfate drying treatment. The solid was subjected to silica gel chromatography (chloroform: methanol = 50: 1 (v / v)) to obtain orange solid compound 5.

Compound 6 (Helipyrone A) was chemically synthesized by subjecting Compound 5 to polymerization reaction of formaldehyde in the presence of 1 N hydrochloric acid. 45.7 g of Compound 5 was dissolved in 460 mL of ethanol, and 247.81 g of formaldehyde (37%) was refluxed at 79 ° C. in the presence of 2.5 mL of concentrated hydrochloric acid to precipitate crystals. The crystals are washed with ethanol to give white crystals as the following formula (II): Helipyrone A

Got.

Prodrug The active ingredient may be derived from a prodrug. Examples of prodrugs have specific protecting groups and have no pharmacological activity per se, but for example when administered orally or parenterally they are subsequently metabolized in the body and become pharmacological. An object in which an active substance is formed.
All protected derivatives and prodrugs of compounds of the invention are included within the scope of the invention.

II. Mechanism of penile erection The cavernous body of the cavernous penis is surrounded by a fibrous tissue called white membrane. The corpus cavernosum (corpora cavernosa penis) has a vein called the cavernous sinus (or 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 cavernous arteries are usually thin and do not allow much blood to flow in. As a result, 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, it maintains a constant size (see Figure 1A).

Smooth muscle The term “smooth muscle” used in the present invention means a tissue specialized for contraction, and smooth muscle consists of smooth muscle fibers (cells) existing on the wall of a hollow internal organ, and is an autonomic motor neuron. Stimulated by. The term “smooth muscle” means a muscle that has a smooth appearance because it has no striated pattern. Or smooth muscle is also called involuntary muscle. Increased Ca ²⁺ concentration in the smooth muscle cytosol causes contraction similar to 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 to 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.

Contraction and relaxation A number of mechanisms regulate the contraction and relaxation of smooth muscle cells. In one, 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 erection Penile erection causes the arteries in the penis to expand through stimulation of the cavernous nerves when the central nervous system is subjected to visual, contact, auditory, olfactory stimulation, or imaginary stimulation, It means a state where a large amount of blood flows into the cavernous sinus.

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.

When the nerve stimulation from the central nervous system is transmitted to the cavernous body via the cavernous nerve, the smooth muscle of the cavernous body relaxes. 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, subsequently, the penetrating vein existing between the expanded cavernous sinus and the white membrane is compressed, and the outflow of blood from the cavernous sinus to the outside is suppressed. An increase in the amount of blood flowing into the cavernous sinus and a decrease in the outflow of blood from the cavernous sinus work synergistically to produce an erection (see FIG. 1B). On the other hand, when the cavernous artery contracts and the pressure on the vein is reduced, the penis returns to a relaxed state.

The molecular mechanism of action of changes that occur during the erection process is complex (see Figure 2). Body smooth muscle is regulated by noradrenergic innervation of the sympathetic nervous system through active compounds of the postsynaptic α ₁ adrenergic receptor. Male erectile dysfunction may be associated with increased endogenous smooth muscle tone in the corpus cavernosum. However, the process of relaxation of the body's smooth muscle is mediated in part by nonadrenergic, noncholinergic (NANC) neurotransmission. There are many other NANC neurotransmitters found in penis other than NO, such as calcitonin hereditary related peptide (CGRP) and vasoactive intestinal peptide (VIP). The main relaxing factor involved in mediating this relaxation is nitric oxide (NO), which is synthesized from L-arginine by nitric oxide synthase (NOS) (Taub et al., 1993 Urology, 42, 698-704). . It is thought that the decrease in the smooth muscle tone of the body can assist the induction of cavernous relaxation by NO. During sexual arousal in males, NO is released from neurons and endothelium and binds to and activates soluble guanylate cyclase (sGC) localized in smooth muscle cells and endothelium, resulting in intracellular cyclic guanosine 3 ′, Leads to increased 5'-monophosphate (cGMP) levels. This increase in cGMP decreases intracellular calcium concentration ([Ca ²⁺ ] _i ) via an unknown mechanism (possibly due to Ca ²⁺ pumps and Ca ²⁺ activated K ⁺ channels) thought to be associated with protein kinase G activation Leads to dilatation of the cavernous artery.

Treatment target When this hepyrone A is administered, the cavernous pressor action caused when the cavernous nerve is stimulated in the cavernous corpus cavernosum is enhanced. Specifically, in rats under anesthesia, hepatic nerve was stimulated while administering hepirone A into the gastrointestinal tract.

Sexual dysfunction (SD) refers to a serious clinical problem that can generally affect both men and women. The cause of SD is thought to be both organic and psychological. The organizational aspects of SD are typically due to vascular disease, eg, vascular disease associated with hypertension or diabetes, prescription drugs, and / or mental illness such as depression. Physiological factors include fear, performance anxiety and interpersonal conflict. SD causes personal pain because it impairs sexual function, reduces self-esteem, and disrupts personal relationships.

Erectile dysfunction (ED)
Among the sexual dysfunctions described above, the present invention is particularly directed to male sexual dysfunction, and in particular, penile erectile dysfunction (lack of erection itself, longer time to erection, or sexual intercourse). Such as lack of erection maintenance for a sufficiently long time).

III. Pharmaceutical Compositions Composition of Pharmaceutical Compositions The present invention also provides a therapeutically effective amount of a pharmaceutically effective carrier of hepyrone A or an active derivative or prodrug thereof, and a pharmaceutically acceptable carrier. A pharmaceutical composition comprising a diluent or additive (including combinations thereof). This pharmaceutical composition is for use in treating male sexual dysfunction, in particular erectile dysfunction (ED).

Preservatives, stabilizers, pigments, and flavoring agents may also be included in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid, and p-hydroxybenzoic acid esters. Antioxidants and suspending agents can also be used.

Since heliciron A, which is an active ingredient of the present invention, is a component derived from a natural product (Asteraceae genus plant, curry plant), there is a high possibility that side effects are unlikely to occur even when administered orally. Further, it has been clarified that the pharmaceutical composition of the present invention is effective for the treatment of male sexual dysfunction (especially erectile dysfunction (ED)) even when orally administered. Therefore, the pharmaceutical composition of the present invention can be formulated in a dosage form suitable for oral administration and is orally administered.

The active ingredient of the present invention can be administered alone, but in general, it may be mixed with, for example, a pharmacologically acceptable carrier, diluent or additive. For example, the active ingredient can be administered orally in the form of tablets, capsules, suppositories, elixirs, solutions or suspensions. When preparing a solution or suspension, a solubilizing agent that assists in dissolving the fat-soluble substance, for example, methyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, or the like may be used.

For example, the tablet may contain additives such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine, disintegrants such as starch (preferably corn starch, potato starch or tapioca starch), sodium starch glycolate, Croscarmellose sodium and certain complex silicates and granulating binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and gum arabic can be included. In addition, lubricants such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.

A similar type of solid composition can also be used as a filler in gelatin capsules. Preferred additives in this regard include lactose, starch, cellulose, lactose or high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the active ingredients are various sweeteners or flavoring agents, coloring substances or pigments, emulsifiers and / or suspending agents, and diluents such as water, ethanol, propylene glycol, etc. And glycerin and combinations thereof.

Dosage level The dosage level and frequency of administration of the active ingredients of the present invention for oral administration typically can be determined by a physician. However, this dose level and frequency of administration may vary depending on a wide variety of factors such as the activity of the particular compound used, metabolic stability, and the length, age, weight, general health, sex, diet, Depending on the mode of administration and time, the rate of elimination, the combination of drugs, the severity of the particular condition, and the treatment the individual receives). For example, the active ingredient and / or pharmaceutical composition of the present invention can be administered according to a schedule of 1 to 10 times a day, for example, once or twice a day.

For oral administration to humans, the daily dose of the active ingredient may be administered once or divided. The daily oral dose can be, for example, 20 to 1000 mg, preferably 50 to 300 mg, and for example, an appropriate dose can be an amount that is effective for treating male sexual dysfunction.

If necessary, the active ingredient can be administered at a dose of 0.01 to 30 mg / kg body weight, for example, 0.1 to 10 mg / kg, more preferably 0.1 to 1 mg / kg body weight. Of course, the dosages mentioned in the present invention are typical of the average case. There are, of course, individual instances where higher or lower dosage ranges are beneficial.

Preferably, if necessary, the active ingredient can be administered at 0.01 to 10 mg / dose, for example, 0.1 to 5 mg / dose, more preferably 1 to 3 mg / dose. Of course, the dosages mentioned in the present invention are typical of the average case. There are, of course, individual instances where higher or lower dosage ranges are beneficial. As a guide, pramipexole is administered at about 0.125-0.25 mg / dose and apomorphine is administered at about 2-3 mg / dose.

Formulation The active ingredients of the present invention can be formulated into pharmaceutical compositions using techniques known in the art, for example, by mixing with one or more suitable carriers, diluents or additives.

IV. Treatment Method Furthermore, the present invention provides a method for treating male sexual dysfunction, particularly erectile dysfunction (ED), by administering the pharmaceutical composition or prodrug of the present invention to a patient or the like.
“Treatment” as used herein means preventing or alleviating the progression and worsening of the disease state in a mammal suffering from male sexual dysfunction, particularly erectile dysfunction (ED), thereby causing progression of the disease. And treatment aimed at preventing or mitigating exacerbations.
The “mammal” as a target of the treatment method of the present invention means any animal classified as a mammal, and is not particularly limited. For example, in addition to humans, pet animals such as dogs, cats, rabbits, and cattle , Livestock animals such as pigs, sheep and horses. Particularly preferred “mammals” are humans.

Example 1: Construction of measurement system for erection level of penile cavernous body In this example, development was carried out for the purpose of constructing a measurement system for erection level of penile cavernous body.
As animals, 11-week-old adult Wistar rats (male) were used. The rat was anesthetized by intraperitoneal administration of urethane (1-1.5 g / kg), and a catheter for blood pressure and heart rate measurement was inserted into the carotid artery. On the other hand, a tube for intraduodenal administration was inserted from the mouth to the duodenum. 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 Corporation), AMPLIFIER CASE (NEC Sanei Co., Ltd.), PowerLab / 4SP (ADInstruments)) (Figure 3A) See).

FIG. 3B shows the result in this example obtained using this animal. When stimulation is applied to the cavernous nerve from data such as voltage, blood pressure, and cavernous body pressure applied to the cavernous nerve by the measurement system shown in FIG. 3B, the systemic blood pressure also rises in conjunction with the rise. It was revealed that the cavernous body pressure may also increase. As a result, in order to clarify the rise in cavernous pressure more accurately, it is clear that it is most reasonable to examine the ratio of cavernous pressure to mean blood pressure (ie, cavernous pressure / mean blood pressure). became.

Example 2: Measurement of the cavernous body pressurizing action by the measurement system of the erection level of the corporal cavernous body of the present invention The present invention was caused when the cavernous nerve was electrically stimulated using the measurement system constructed in Example 1. An experiment was conducted with the aim of confirming that the cavernosal pressor action can be measured.
In Wistar rats (male) with catheters and electrodes set in the same manner as in Example 1, blood pressure, mean blood pressure, and heart rate were measured, and before the start of the experiment and 5, 30, 60, 90 minutes after the start of the experiment. Changes in cavernosal pressure were observed after stimulation for 40 seconds under conditions of 2, 4, 8 Hz, and 5 V, respectively. Since the cavernous body pressure is affected by the blood pressure, as shown in Example 1, the cavernous body pressure / average blood pressure was used as an index.
The results in this example are shown in FIG. The system for measuring the erection level of the corporal corpus cavernosum of the present invention shows that the application of electrical stimulation and the corpus cavernopressor action in response to the stimulation can be stably measured over a long period (90 minutes) under anesthesia conditions. Yes. Therefore, it was shown that the model animal system presented in this example is an experimental model that can be used in experiments over a long period of time.

Example 3: Enhancement of cavernosal pressurization of helipyrone A This example confirms whether helipyrone A has a cavernosal pressurization enhancing action when nerve stimulation to the cavernous cavernous nerve is present. An experiment was conducted for the purpose.
In this example, blood pressure, mean blood pressure, and heart rate were measured in Wistar rats (male) in which catheters and electrodes were set in the same manner as in Example 1, and carboxymethylcellulose (CMC, solvent control group) ( A) or cavernosal pressure when stimulated for 40 seconds under conditions of 4 Hz and 5 V before administration of Hepirone A (30 mg / kg, experimental group) (B) and 5, 30, 60, and 90 minutes after administration Changes were observed. Since the cavernous body pressure is affected by the blood pressure, as shown in Example 1, the cavernous body pressure / average blood pressure was used as an index.
In this example, the results of observing the cavernous body pressure when stimulated for 40 seconds under the conditions of 4 Hz and 5 V before administration and 90 minutes after administration are shown in FIG. Intraduodenal administration of CMC had no effect on the cavernosal pressor action by electrical stimulation, but hepirone A (30 mg / kg) enhanced intracavernosal pressor action by electrical stimulation.

Carboxymethylcellulose (CMC, solvent control group) (A) or hepyrone A (30 mg / kg, experimental group) (B) before administration and at 5, 30, 60, and 90 minutes after administration at 4 Hz and 5 V, respectively The results of observing changes in cavernous pressure when stimulated for 40 seconds are shown in FIG. In this experiment, under the condition of applying electrical stimulation to the corpus cavernosum, compared with carboxymethylcellulose (CMC, solvent control group), administration of hepyrone A (30 mg / kg, experimental group) significantly increased the cavernous pressure. It was shown that the effect was enhanced.

In an anesthetized rat experiment, it was reported that the cavernosal pressor-potentiating effect when sildenafil (viagra) was used was enhanced only 3 minutes after administration, and the degree of enhancement was about 23% ( Eur Urol 44 731-36, 2003). On the other hand, in the present invention, hepirone A action time was 90 minutes, which increased cavernous pressor action by cavernous nerve stimulation by about 40%. From these results, it is highly possible that the drug for human beings is highly durable and powerful even when compared with conventional male sexual function improving drugs.

Example 4: Effect of hepyrone A on the cavernosal pressure increase response by cavernosal nerve stimulation in rats Using rat, the effect of hepyrone A on the cavernous pressure etc. by cavernous nerve stimulation and the effect of sildenafil We examined while comparing.
Sexually matured male rats were fixed in a supine position under urethane anesthesia, and a blood pressure / heart rate measuring catheter filled with heparinized physiological saline was inserted into the carotid artery and placed. A silicone tube equipped with a material administration syringe was orally inserted into the duodenum and left in place. After laparotomy, electrodes were placed on the cavernous nerve running on the prostate, and frequency-dependent cavernosal pressure increase response was observed by electrical stimulation at 4, 8 Hz and 5 V for 40 seconds (see Figure 3). )
This electrical stimulation was performed before material administration and 5, 30, 60, 90, 120 minutes after administration. The cavernous body pressure was measured with a needle inserted into the cavernous body, and the cavernous body pressure / mean blood pressure (corrected cavernous body pressure) was calculated considering the effect of blood pressure. In addition, the maximum value of the corrected cavernous body pressure rise reaction induced by electrical stimulation is the maximum cavernous body pressure, and the time until the corrected cavernous body pressure recovers to half from the end of the electrical stimulation is the time of the cavernous body pressure half-life. Evaluation was made (Figure 7).

First, FIG. 8 shows the results of examining the effects of sildenafil and helipyrone A on blood pressure.
With regard to sildenafil, the blood pressure decreased significantly from 5 minutes after administration at 1 mg / kg, which is a dose at which the effect of electrical stimulation on the increase in cavernous pressure was observed. On the other hand, no change in blood pressure was observed for helipyrone A. Neither sildenafil nor helipiron A affected the heart rate (data not shown).

Next, the effects of sildenafil and helipyrone A on the increase in cavernous pressure caused by electrical stimulation were examined.
FIG. 9 shows the effect of sildenafil. FIG. 9 is a graph comparing the effect of sildenafil on the increase in cavernous pressure caused by electrical stimulation with distilled water as a solvent. The horizontal axis of the graph represents the time after administration.
First, there was no change in “maximum cavernous body pressure” in both 4 Hz and 8 Hz (upper and lower graphs in FIG. 9).
On the other hand, it was found that the “cavernous pressure half-life” was significantly extended from 5 minutes to 1.5 hours after administration at 8 Hz.
FIG. 10 shows the results for helipyrone A. For helipyrone A, “maximum cavernous pressure” significantly increased from 1 hour to 1.5 hours after administration at 4 Hz. On the other hand, there was no significant change in “cavernous body pressure half-life”.

The above results are summarized in Table 1.

Helipyrone A did not affect blood pressure or heart rate, but the maximum cavernosal pressure obtained by electrical stimulation (4 Hz) was significantly increased 60-90 minutes after administration. On the other hand, sildenafil, a conventional drug for erectile dysfunction, did not affect the maximum cavernous body pressure at any electrical stimulation frequency, but the cavernous body pressure half-life at the time of electrical stimulation (8 Hz) was 5- Significantly extended at 90 minutes. It also affected blood pressure, with a significant decrease in blood pressure 5-90 minutes after administration.
From this, it is considered that helipyrone A promotes the cavernous body pressure increasing action by an action qualitatively different from sildenafil.

Example 5: Examination of relaxation effect of heliciron A on isolated corpus cavernosum using organ bath The organ bath is to measure the contraction / relaxation response of tissues such as rat, mouse or human bladder or urethra. And a small bus to hang the tissue in (see Figure 11).
The isolated cancellous body vertically divided was suspended in an organ bath filled with Krebs solution (97% O ₂ + 3% CO ₂ , 37 ° C.), and after stabilization, contracted with phenylephrine. This specimen was used to elucidate the relaxation profiles of helipiron A and sildenafil.
The isolated caverns suspended in the organ bath were contracted with phenylephrine and then heripilone A was added, but even the highest concentration of 10 ^-4 M did not cause relaxation. Sildenafil, on the other hand, caused relaxation from 10 ^-7 M (Figure 12). From these results, it was suggested that sildenafil has a direct vasorelaxant effect but helipon A does not have a vasorelaxant effect.

A transient relaxation reaction is observed when the isolated cavernous body contracted with phenylephrine is electrically stimulated. When helipyrone A (10 ⁻⁴ M) was added 20 minutes after the start of the measurement, the half-life for recovering from the relaxation reaction was significantly prolonged (FIG. 13). 1 hour later, NO inhibitor L-NAME (N-omega-nitro-L-arginine methyl ester) (10 ^-4 M) was added. The effect of extending the half-life by was significantly suppressed. Furthermore, it was found that the addition of L-arginine (5 × 10 ⁻⁴ M), which is a NO supply substance, restores the half-life extending action suppressed by L-NAME.
From the above results, it was suggested that NO is involved in the prolongation effect of hemipyrone A on the cavernous relaxation reaction.

Until now, only three male sexual dysfunction drugs have been marketed in Japan, but helipon A can be used to treat male sexual dysfunction (especially erectile dysfunction (ED)). As a result, it can be developed as a new drug, and a new drug for male sexual dysfunction (especially erectile dysfunction (ED)) can be provided. In addition, because the structure of the compound is different from conventional male sexual function improving drugs, male sexual dysfunctions (especially erections) differ in the mechanism of action and side effects from those of conventional male sexual function improving drugs. It may be possible to provide a medicament for the treatment of dysfunction (ED).

Claims

The following formula (I)

Formula (I)
Wherein R 1 and R 2 are each independently a hydrogen atom or a hydroxyl-protecting group, or a male sexual function comprising a compound or a pharmaceutically acceptable ester or prodrug thereof A pharmaceutical composition for the treatment of disorders, in particular erectile dysfunction (ED).
The compound has the following formula (II)

The pharmaceutical composition according to claim 1, which is heliponone A (3,3′-methylene bis (6-ethyl-4-hydroxy-5-methyl-2H-pyran-2-one)) represented by the formula: object.
The pharmaceutical composition according to claim 1 or 2, wherein the male sexual dysfunction is erectile dysfunction (ED).
The pharmaceutical composition according to any one of claims 1 to 3, which is orally administered.
The pharmaceutical composition according to any one of claims 1 to 4, which enhances the cavernosal pressurizing action by cavernous nerve stimulation.
6. The pharmaceutical composition according to any one of claims 1 to 5, wherein helipiron A is derived from a natural product.