KR20210065748A - Composition for preventing, improving or treating erectile dysfunction comprising phenylcyclohexanecarboxamide compound - Google Patents

Abstract

The present invention relates to the use of a phenylcyclohexanecarboxamide compound for the prevention, alleviation or treatment of erectile dysfunction. The compound of the present invention can be usefully used as a pharmaceutical composition for treating erectile dysfunction. The present invention is a pharmaceutical composition for preventing or treating erectile dysfunction comprising a compound of chemical formula 1 or 2, or a pharmaceutically acceptable salt thereof, as an active component.

Description

TECHNICAL FIELD [0001] Composition for preventing, improving or treating erectile dysfunction comprising phenylcyclohexanecarboxamide compound

The present invention relates to the use of a phenylcyclohexanecarboxamide compound for the prevention, improvement or treatment of erectile dysfunction.

Erectile dysfunction (ED) is a chronic disease that cannot initiate or maintain an erection sufficient for satisfactory sexual function, and is mainly caused by vascular, neurological and endocrine factors and damage, surgery and aging. Erectile dysfunction is not a life-threatening disease, but it is a factor that has a great influence in determining the quality of life.

The erectile response is a phenomenon in which the cavernous corpus expands and the penis hardens as blood fills. When a sexual stimulus is transmitted to the cavernous nerve, nitric oxide (NO) is generated at the nerve endings, and the generated nitric oxide is involved in the expansion of blood vessels composed of smooth muscle, thereby promoting the inflow of blood into the cavernous body. Nitric oxide increases the concentration of cGMP in signaling molecules activate sGC (soluble guanylate cyclase) to cells and reduces the concentration of intracellular Ca ^{2 +} ions induces relaxation of smooth muscle. Since increased cGMP in cells is degraded by phosphodiesterase (PDE), PDE is recognized as a major target for erectile dysfunction treatment.

Erectile dysfunction treatment includes oral administration of erection-inducing drugs (oral), intracavernosal injection (intracavernosal), and urethral injection (intraurethral). Among them, oral administration is the most preferred and effective treatment for patients.

All erectile dysfunction drugs (sildenafil, tadalafil, vardenafil, udenafil, and mirodenafil) developed so far are phosphodiesterase type 5 (PDE5) inhibitors. However, PDE5 inhibitors are not fundamental therapeutic agents, and there is a problem of discontinuation of drug administration due to side effects such as headache, flushing, increased blood pressure, and visual disturbances, as well as a problem of ineffective patient groups of about 40%.

Therefore, there is a need to develop new therapeutic agents for patients who are non-responsive to PDE5 inhibitors and patients who cannot be used (eg, patients with angina pectoris, myocardial infarction, stroke, patients with cardiovascular disease or severe liver failure, and patients with retinitis pigmentosa).

Republic of Korea Patent Publication No. 10-2003-0077542

Accordingly, the present inventors found that the phenylcyclohexanecarboxamide compound named URO-K10 _{can effectively treat erectile dysfunction by activating the K v} 7 potassium ion channel of the cavernous smooth muscle cells of the penis to induce relaxation of the cavernous smooth muscle of the penis. By confirming, the present invention was completed.

Accordingly, an object of the present invention is to provide a pharmaceutical composition for preventing or treating erectile dysfunction comprising a compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof, as an active ingredient.

Another object of the present invention is (a) a compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof; And (b) to provide a pharmaceutical composition for preventing or treating erectile dysfunction comprising a PDE5 (phosphodiesterase 5) inhibitor as an active ingredient.

Another object of the present invention is to provide a quasi-drug composition for preventing or improving erectile dysfunction comprising a compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof, as an active ingredient.

Another object of the present invention is to provide a food composition for preventing or improving erectile dysfunction comprising a compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof, as an active ingredient.

However, the technical task to be achieved by the present invention is not limited to the tasks mentioned above, and other tasks not mentioned can be clearly understood by those of ordinary skill in the art to which the present invention belongs from the following description. will be.

In order to achieve the object of the present invention, the present invention provides a pharmaceutical composition for preventing or treating erectile dysfunction comprising a compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof, as an active ingredient.

Formula 1

Formula 2

Furthermore, the present invention provides a method for treating erectile dysfunction comprising administering to a subject a compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides the use of the compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof, for preventing, improving or treating erectile dysfunction.

In addition, the present invention provides (a) a compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof; And (b) provides a pharmaceutical composition for preventing or treating erectile dysfunction comprising a PDE5 inhibitor as an active ingredient.

Furthermore, the present invention relates to a compound comprising (a) a compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof; and (b) administering a PDE5 inhibitor to the subject.

In addition, the present invention relates to (a) a compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof; And (b) provides a use for preventing, improving or treating erectile dysfunction of a composition comprising a PDE5 inhibitor as an active ingredient.

In addition, the present invention provides a quasi-drug composition for preventing or improving erectile dysfunction comprising a compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof, as an active ingredient.

In addition, the present invention provides a food composition for preventing or improving erectile dysfunction comprising a compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof, as an active ingredient.

In one embodiment of the present invention, the compound or a pharmaceutically acceptable salt thereof may relax the smooth muscle of the cavernous body of the penis, but is not limited thereto.

In another embodiment of the present invention, the compound or a pharmaceutically acceptable salt thereof may _{activate the K v} 7 potassium ion channel of the corpus cavernosum smooth muscle cells, but is not limited thereto.

In another embodiment of the present invention, the K _v 7 potassium ion channel may be a K _v 7.4 potassium ion channel subunit, but is not limited thereto.

In another embodiment of the present invention, the PDE5 inhibitor is composed of sildenafil, tadalafil, vardenafil, udenafil, mirodenafil, and combinations thereof. It may be selected from the group, but is not limited thereto.

In another embodiment of the present invention, the component (a) may be administered simultaneously, separately or sequentially with the PDE5 inhibitor (component (b)), but is not limited thereto. .

In another embodiment of the present invention, the food composition may be a health functional food, but is not limited thereto.

The phenylcyclohexanecarboxamide compound of the present invention has an excellent effect of relaxing the smooth muscle of the cavernous body of the penis, and the relaxation effect of the smooth muscle is not affected by the presence or absence of vascular endothelial cells.

In addition, the phenylcyclohexanecarboxamide compound of the present invention exhibits a synergistic effect when administered in combination with a PDE5 inhibitor, which is a conventional treatment for erectile dysfunction.

In particular, the phenylcyclohexanecarboxamide compound of the present invention _{activates the K v} 7 potassium ion channel of the corpus cavernosum smooth muscle cells to relax the corpus cavernosum smooth muscle, and the K _v 7 potassium ion channel subunit (K _v 7.1-K _v 7.5) is characterized by tissue- and cell-specific expression, and among them, the K _v 7.4 potassium ion channel subunit, which is the main target of the compound of the present invention, has very low expression in cardiac tissue, It has the advantage of fewer systemic side effects, such as lowering of blood pressure, which is a major side effect.

Accordingly, the compound of the present invention is expected to be usefully used as a pharmaceutical composition for treating erectile dysfunction.

1 is a view showing a synthesis reaction scheme of the compounds of Formulas 1 and 2.
2 is a diagram showing that the URO-K10 compound induces relaxation of the corpus cavernosum smooth muscle in a concentration-dependent manner.
endothelium-intact: vascular endothelial cell maintenance group
endothelium-denuded: vascular endothelial cell removal group
3 is a diagram showing that the URO-K10 compound induces a relaxation response through activation of _{the K v 7 potassium ion channel present in the corpus cavernosum smooth muscle cells.}
XE991: K _v 7 potassium ion channel inhibitor
4-AP: membrane voltage-dependent potassium channel inhibitor
TEA: nonselective potassium channel inhibitor
IbTX: BKCa pathway inhibitor
4 is a diagram showing the results of measuring the change in tension of the cavernous smooth muscle of the penile corpus cavernosum in rabbit penile corpus cavernosum after treatment with URO-K10 compound alone, sildenafil alone, and URO-K10 compound and sildenafil combination, respectively, using the organ bath method.
^* p<0.05 vs. URO-K10, ^§ p<0.05 vs. Sildenafil
_{5 is a diagram showing the K v} 7 potassium ion channel activation effect of the URO-K10 compound in human penile corpus cavernosum smooth muscle cells.
_{Figures 5a and 5b measure the effect on the K v} 7 potassium ion channel of human penile corpus cavernosum smooth muscle cells using the amphotericin-B perforated patch-clamp method, and the cell membrane voltage is - It is a diagram showing the result of recording the change in current after treatment with URO-K10 (10 μM) in the perfusion solution in the state fixed at 10 mV, depolarization to +40 mV.
Figure 5c is a diagram showing _{the EC 50} of the URO-K10 compound at -10 mV and +40 mV.
Figure 5d is a diagram showing that the outward current increased by the URO-K10 compound _{was reduced to the control level by the K v} 7 potassium ion channel inhibitor XE991 (10 μM).
6 is a diagram showing the results of measuring the current magnitude according to the voltage change by giving electrical stimulation by increasing the voltage by +10 mV from -80 mV to +40 mV to obtain a current-voltage curve.
Figure 7 shows the stabilizing membrane voltage regulation effect of the URO-K10 compound in human penile corpus cavernosum smooth muscle cells. Using the amphotericin-B perforated patch clamp method, 1 μM URO- in the current-clamp mode It is a diagram showing the result of measuring the change in membrane voltage after treatment with the K10 compound in the perfusion solution.
Figures 8a and 8b are diagrams showing the effect of improving the erectile function of the URO-K10 compound in a diabetic erectile dysfunction rat model.
Max ICP: Maximum penile cavernous pressure
MAP: mean arterial blood pressure

The present invention provides a pharmaceutical composition for preventing or treating erectile dysfunction comprising a compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof, as an active ingredient.

Formula 1

Formula 2

As used herein, the term "pharmaceutically acceptable" means that the benefit/risk ratio is reasonable without undue toxicity, irritation, allergic reaction, or other problems or complications, so that it is suitable for use in contact with the tissues of a subject (eg, a human). suitable and means a compound or composition that is within the scope of sound medical judgment.

The compound of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid may be useful.

Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. It is obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids.

Such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, ioda. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate , sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Toxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycol lactate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound of Formula 1 or 2 in an aqueous acid solution, and dissolving the salt in a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation using It can also be prepared by evaporating the solvent or excess acid from the mixture and drying the mixture, or by suction filtration of the precipitated salt.

In addition, a pharmaceutically acceptable metal salt may be prepared using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound of the formula (1) or (2) in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, it may be pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt. The corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg silver nitrate).

The scope of the compound of the present invention may include all isomers, hydrates and solvates that can be prepared by conventional methods as well as pharmaceutically acceptable salts.

In the present invention, the pharmaceutical composition of the present invention is the compound of Formula 1 ((1S,2S)-5,5-difluoro-N-((R)-2-hydroxy-1-(3-(trifluoromethyl)pheny) )ethyl)-2-phenylcyclohexanecarboxamide) or a pharmaceutically acceptable salt thereof, but is not limited thereto.

As used herein, the term “prevention” refers to any action that blocks erectile dysfunction symptoms or suppresses or delays erectile dysfunction symptoms by administering the composition according to the present invention.

As used herein, the term “treatment” refers to any action in which erectile dysfunction symptoms are improved or beneficially changed by administration of the composition according to the present invention.

As used herein, the term "Erectile Dysfunction" refers to a state in which an inability to obtain or maintain an erection sufficient to enjoy a satisfactory sex life continues, and includes psychogenic erectile dysfunction, vascular erectile dysfunction (e.g., arterial erectile dysfunction, venous obstructive impotence), neurogenic erectile dysfunction, endocrine impotence, erectile dysfunction due to metabolic syndrome, erectile dysfunction due to drug side effects, and erectile dysfunction due to iatrogenic and other causes.

In the present invention, the compound of the present invention or a pharmaceutically acceptable salt thereof may relax the smooth muscle of the cavernous body of the penis, but is not limited thereto.

As used herein, the term "corpus cavernosum" is the erectile tissue constituting the main body of the penis or clitoris of mammals, and is surrounded by a thick and strong connective tissue membrane containing elastic fibers, and this membrane enters into the spongy small make up a room Inside the penis of men, there are two corpus cavernosums on the left and one urethral corpus cavernosum below it. The cavernous smooth muscle and blood vessels of the penis are normally in a contracted state by adrenergic sympathetic nerves, and after an erectile response due to relaxation, they return to a contracted state by stimulation of the adrenergic sympathetic nervous system. As such, the erectile tissue normally maintains a contracted state, but during sexual arousal, the erectile tissue relaxes, begins an erection, and an erection begins, due to signals from the brain center, stimulation of the nervous system, and various neurotransmitters and hormones in the body and erectile tissues. maintain. After the erection reaction is over, the erectile tissue is again maintained in a contracted state.

In the present invention, the compound of the present invention or a pharmaceutically acceptable salt thereof may _{activate the K v} 7 (KCNQ) potassium ion channel in the corpus cavernosum smooth muscle cells, but is not limited thereto.

In the present invention, the K _v 7 potassium ion channel may be a K _v 7.4 potassium ion channel subunit (voltage-gated potassium channel subunit K _v 7.4), but is not limited thereto.

In an embodiment of the present invention, it was confirmed that the compound of Formula 1 has an excellent effect in relaxing the smooth muscle of the cavernous body of the penis, and this smooth muscle relaxation effect is not affected by the presence or absence of vascular endothelial cells (see Example 1). .

In addition, in one embodiment of the present invention, it was confirmed that when the compound of Formula 1 and sildenafil were used in combination, the effect of relaxing the corpus cavernosum smooth muscle was significantly increased (see Example 2), and the compound of Formula 1 showed the K of the corpus cavernosum smooth muscle cells. _{It was confirmed that the v} 7 potassium ion channel was activated (see Example 3) and hyperpolarized the cell stable membrane voltage (see Example 4).

In addition, in one embodiment of the present invention, it was confirmed that the compound of Formula 1 exhibits an excellent erectile effect in a rat model of diabetic erectile dysfunction (see Example 5).

On the other hand, the pharmaceutical composition according to the present invention may further include an appropriate carrier, excipient and/or diluent commonly used to prepare a pharmaceutical composition in addition to the active ingredient. In addition, according to a conventional method, it can be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, and sterile injection solutions.

Carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose , microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate, and mineral oil. When formulating the composition, it can be prepared using a diluent or excipient such as a filler, extender, binder, wetting agent, disintegrant, surfactant, etc. commonly used.

The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is the type, severity, and drug activity of the patient. , sensitivity to drug, administration time, administration route and excretion rate, treatment period, factors including concurrent drugs, and other factors well known in the medical field.

As a specific example, the pharmaceutical composition is 0.001 to 1000 mg/kg, 0.003 to 200 mg/kg, 0.003 to 100 mg/kg, 0.003 to 50 mg/kg, 0.003 to 10 mg/kg or 0.003 to 1 mg/kg of The amount can be administered in divided doses from once to several times a day, and as a weight-based dose as well as a flat-dose, for example, 0.1 to 100 mg, 0.1 to 80 mg, If necessary, it may be administered once in a dose of 0.1 to 50 mg, 0.1 to 30 mg, 0.1 to 10 mg, 0.1 to 1 mg, or 0.1 to 0.5 mg. The above dosage is an exemplary dosage of the composition of the present invention, and a preferred dosage may be selected according to the condition and weight of the individual, the degree of disease, the drug form, the route of administration, and the duration.

In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be determined by a person skilled in the art. Specifically, the effective amount of the pharmaceutical composition according to the present invention may vary depending on the patient's age, sex, condition, weight, absorption of the active ingredient in the body, inactivation rate and excretion rate, disease type, and drugs used in combination.

The pharmaceutical composition of the present invention may be administered to an individual by various routes. All modes of administration can be envisaged, for example, by oral administration, intrapenis administration, intranasal administration, transbronchial administration, arterial injection, intravenous injection, subcutaneous injection, intramuscular injection or intraperitoneal injection. . The daily dosage may be administered once or divided into several times a day.

In another aspect of the present invention, the present invention provides (a) a compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof; And (b) it provides a pharmaceutical composition for preventing or treating erectile dysfunction comprising a PDE5 (phosphodiesterase 5) inhibitor as an active ingredient.

Since the combination composition (formulation) includes component (a) as an active ingredient, the description of the above-described pharmaceutical composition is also applied to the combination composition as it is, and overlapping descriptions thereof will be omitted.

As used herein, the term “phosphodiesterase 5 (PDE5) inhibitor” refers to inhibiting the degradation of cGMP-specific phosphodiesterase type 5 in vascular smooth muscle cells that supply blood to the cavernous body of the penis. means a substance that

In the present invention, the PDE5 inhibitor may be selected from the group consisting of sildenafil, tadalafil, vardenafil, udenafil, mirodenafil, and combinations thereof. However, the present invention is not limited thereto.

In the present invention, the PDE5 inhibitor may be silderafil, but is not limited thereto.

In the present invention, the component (a) may be administered simultaneously with the PDE5 inhibitor (simultaneous), separately (separate) or sequentially (sequential), may be administered single or multiple.

As another aspect of the present invention, the present invention provides a quasi-drug composition for preventing or improving erectile dysfunction comprising the compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof, as an active ingredient.

As used herein, the term "improvement" refers to any action of reducing the parameters associated with erectile dysfunction, for example, the severity of symptoms by administration of the composition according to the present invention.

As used herein, the term "quasi-drug" refers to articles with a milder action than pharmaceuticals among articles used for the purpose of treating, improving, alleviating, treating or preventing diseases of humans or animals. For example, quasi-drugs according to the Pharmaceutical Affairs Act exclude products used for pharmaceutical purposes, and include products used for the treatment or prevention of human/animal diseases, and products with minor or no direct action on the human body.

When the composition of the present invention is used as a quasi-drug composition, the active ingredient may be added as it is or used together with other quasi-drug ingredients, and may be appropriately used according to a conventional method. The mixing amount of the active ingredient may be appropriately determined depending on the purpose of use (prophylactic, health or therapeutic treatment).

As another aspect of the present invention, the present invention provides a food composition for preventing or improving erectile dysfunction comprising a compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof, as an active ingredient.

In the present invention, the food composition may be a health functional food, but is not limited thereto.

As used herein, the term "health functional food" refers to food having biological control functions such as prevention and improvement of diseases, biological defense, immunity, recovery from disease, and suppression of aging, and should be harmless to the human body when taken for a long time. do.

The compound of the present invention or a pharmaceutically acceptable salt thereof may be added to food (eg, health functional food) for the purpose of improving erectile dysfunction. For example, when the compound of the present invention or a pharmaceutically acceptable salt thereof is used as an additive (active ingredient) of a health functional food, it can be added as it is, or used with other foods, food ingredients, or dry liver functional drugs. , can be appropriately used according to a conventional method. The mixed amount of the active ingredient may be appropriately determined according to the purpose of use (prevention, health or therapeutic treatment).

There is no particular limitation on the type of the food, for example, there are drinks, vitamin complexes, nutritional supplements, and the like, and includes all health functional foods in a conventional sense.

As another aspect of the present invention, the present invention provides a method for treating erectile dysfunction comprising administering to an individual a compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof.

Further, as another aspect of the present invention, the present invention provides (a) a compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof; and (b) administering a PDE5 inhibitor to the subject.

As used herein, the term "subject" refers to a subject in need of prevention, treatment, treatment enhancement, or resistance suppression of a disease. For example, the subject may be a human, or a mammal, including non-human primates, mice, dogs, cats, horses, sheep and cattle.

Hereinafter, preferred examples are presented to help the understanding of the present invention. However, the following examples are only provided for easier understanding of the present invention, and the contents of the present invention are not limited by the following examples.

[ Example ]

manufacturing example . Preparation of compounds of formulas 1 and 2

According to the synthesis scheme shown in FIG. 1, compounds of Formulas 1 and 2 were prepared in the following manner. ¹ H NMR spectrum analysis was performed using a Varian Mercury 400 MHz, and TMS was used as an internal standard.

LCMS is a quadrupole Mass Spectrometer of Agilent LC/MSD 1200 Series (Column: Ultimate XB-C18 (50 Х 4.6 mm, 5 μm) operating in ES (+) or (-) ionization mode; T = 30℃; flow rate = 1.5 mL/min; detected wavelengths: 214 nm and 254 nm) were used.

One. methyl 5,5- difluoro -2- Oxocyclohexanecarboxylate ( methyl 5,5-difluoro-2-oxocyclohexanecarboxylate) ( 2 ) synthesis

A mixture of compound No. 1 (10 g, 74.62 mmol) was placed in DMF (100 mL), then NaH (3.6 g, 60%, 89.55 mmol) was added at 0 °C, and dimethyl carbonate (8.1 g, 89.55 mmol) was added. did. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was cooled with ice and extracted with EA. The combined organic layer was washed with brine _{, dried over Na 2} SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (PE/EA = 7:1) to obtain compound 2 (8.2 g, 57% yield) as a colorless oil.

2. methyl 5,5- difluoro -2-((( trifluoromethyl ) sulfonyl ) oxy ) cyclohex -1-enecarboxylate (methyl 5,5- difluoro -2-((( trifluoromethyl ) sulfonyl ) oxy ) cyc lohex-1-enecarboxylate) ( 3 ) synthesis

Compound No. 2 solution (8.2 g, 42.7 mmol) was placed in THF (100 mL), and then NaH (3.07 g, 60%, 51.2 mmol) was added at 0°C. The reaction mixture was stirred at 0° C. for 0.5 h. Then, Commin's reagent (20.1 g, 51.2 mmol) was added, and the reaction was stirred at room temperature for 16 hours. The reaction mixture was cooled with ice and extracted with EA. The mixed organic layer was washed with brine, _{dried over Na 2} SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (PE/EA = 30/1) to obtain compound No. 3 (12.4 g, 89% yield) as a colorless oil.

3. methyl 4,4- difluoro -3,4,5,6- tetrahydro -[1,1'- biphenyl ]-2- carboxylate (methyl 4,4- difluoro -3,4,5,6- tetrahydro -[1,1'- biphenyl ]-2- carboxyla te)( 4 ) synthesis

A mixture of compound 3 (12.4 g, 38.27 mmol) was added to toluene (100 mL), followed by phenylboronic acid (9.3 g, 76.5 mmol), Pd(dppf)Cl ₂ (2.8 g, 3.83 mmol), Na ₂ CO ₃ (8.1 g, 76.5 mmol), EtOH (50 mL) and water (20 mL) were added under _{N 2 .} The reaction mixture was stirred at 90° C. for 16 hours, then the mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (PE/EA = 30/1) to obtain compound No. 4 (8.2 g, 85% yield) as a colorless oil.

4. ( sheath )- methyl 5,5- difluoro -2- Phenylcyclohexanecarboxylate ((cis) -methyl 5,5- difluoro -2-phenylcyclohexanecarboxylate) ( 5 )of synthesis

A mixture of compound No. 4 (8.2 g, 32.5 mmol) was placed in MeOH (100 mL), and then Pd/C (4.1 g, 10% Pd, 50% H ₂ O) was added under _{H 2 balloon.} The reaction mixture was stirred at room temperature overnight, then the mixture was filtered and washed with MeOH. The filtrate was concentrated to obtain compound No. 5 (7.8 g, 94% yield) as an off-white solid.

5. (trans)-5,5- difluoro -2- Phenylcyclohexanecarboxylic acid ((trans) -5,5- difl uoro-2-phenylcyclohexanecarboxylic acid )( 6 )of synthesis

To a mixture of compound No. 5 (3.8 g, 14.4 mmol) was added EtONa (20 mL, 21% in EtOH) under _{N 2 .} The reaction mixture was stirred at 90° C. overnight. The mixture was concentrated and dissolved in water, acidified with 1N HCl (pH = 3-4) and extracted with EA. The mixed organic layer was washed with brine, _{dried over Na 2} SO ₄ , filtered and concentrated to obtain compound No. 6 (1.65 g, 42% yield) as an off-white solid.

6. 5,5- difluoro -N-((R)-2- hydroxy -1-(3-( trifluoromethyl )phenyl)ethyl)-2-phenylcyclohexanecarboxamide (5,5-difluoro-N-((R)-2-hydroxy-1-(3-(trIf luoromethyl)phenyl)ethyl)-2-phenylcyclohexanecarboxamide) ( UC191687 ) synthesis

A mixture of compound 6 (3.3 g, 13.76 mmol) was placed in DMF (60 mL), and compound 7 (2.82 g, 13.76 mmol), HATU (5.74 g, 15.12 mmol) and DIEA (3.56 g, 27.52 mmol) were added. added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (100 mL) and extracted with EA. The mixed organic layer was washed with brine, _{dried over Na 2} SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (PE/EA = 3/1) to obtain the compound UC191687 (4.8 g, 80% yield) as an off-white solid.

MS (ESI) m / z : 428.2 ([M ⁺ H] ⁺ ).

7. ( 1S, 2S )-5,5- difluoro -N-((R)-2- hydroxy -1-(3-( trifluoromethyl )phenyl)ethyl)-2-phenylcyclohexanecarboxamide ((1S,2S)-5,5-difluoro-N-((R)-2-hyd roxy-1-(3-(trifluoromethyl)phenyl)ethyl )-2-phenylcyclohexanecarboxamide) ( UC191687A ) and ( 1R, 2R )-5,5- difluoro -N-((R)-2- hydroxy -1-(3-( trifluoromethyl )phenyl)ethyl)-2-phenylcyclohexanecarboxamide ((1R,2R)-5,5-difluoro-N-((R)-2-hydroxy-1-(3-(trifluoromethyl)phenyl)ethyl) -2-phenylcyclohexanecarboxami de) ( UC191687B ) synthesis

UC191687 compound (4.8 g) was purified by chiral-HPLC to UC191687A compound (compound of formula 1, named 'URO-K10' in the following examples; column: Chiralpak OJ-H 5 μm 4.6 * 250 mm; mobile phase: Hex: EtOH = 95:5 at 1.0 mL/min; Temperature: 30 °C; Wavelength: 214 nm, RT = 6.29 min, 1.45 g) and compound UC191687B (Compound of Formula 2; Column: Chiralpak OJ-H 5 μm 4.6 * 250 mm ; mobile phase: Hex:EtOH = 95:5 at 1.0 mL/min; temperature: 30 °C; wavelength: 214 nm, RT = 15.29 min, 1.47 g) as a white solid.

UC191687A (Formula 1, URO- K10) :

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.29 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.38 (s, 1H), 7.22-7.11 (m, 6H), 6.68 (d, J = 7.6 Hz, 1H), 4.87 (br s, 1H), 4.72-4.68 (m, 1H), 3.46-3.46 (m, 2H), 3.05-2.98 (m, 1H), 2.86-2.79 (m, 1H), 2.26-2.21 (m, 1H), 2.10-1.98 (m, 3H), 1.83-1.80 (m, 1H) , 1.71-1.60 (m, 1H).

LCMS [mobile phase: from 95% water (0.02 % NH ₄ OAc) and 5% CH ₃ CN to 5% water (0.02 % NH ₄ OAc) and 95% CH ₃ CN in 10 min, finally under these conditions for 0.5 min .] purity > 95%, Rt = 4.18 min; MS Calcd.: 427.2; MS (ESI) m/z : 428.1 ([M+H] ⁺ ).

UC191687B (Formula 2) :

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.20 (d, J = 8.0 Hz, 1H), 7.57-7.45 (m, 4H), 7.30-7.28 (m, 2H), 7.22-7.18 (m, 3H) ), 6.61-4.58 (m, 2H), 3.08-3.02 (m, 2H), 2.95-2.83 (m, 2H), 2.09-1.95 (m, 4H), 1.88-1.82 (m, 1H), 1.75-1.64 (m, 1H).

LCMS [mobile phase: from 80% water (0.02 % NH ₄ OAc) and 20% CH ₃ CN to 5% water (0.02 % NH ₄ OAc) and 95% CH ₃ CN in 10 min, finally under these conditions for 0.5 min .] purity > 95%, Rt = 4.19 min; MS Calcd.: 427.2; MS (ESI) m/z : 428.2 ([M+H] ⁺ ).

Example One. URO -The relaxing effect of K10 on rabbit penile corpus cavernosum smooth muscle

Tension changes in the corpus cavernosum smooth muscle of rabbits were measured using the organ bath method. As a result, as shown in FIG. 2, it induced a smooth muscle relaxation response in a concentration-dependent manner of URO-K10 (expressed as endothelium-intact in FIG. 2; 0.1 μM: 7.4±1.2%, 1 μM: 20.4±2.6%, 3 μM: 47.3±4.6%, 10 μM: 84.0±3.3%, 30 μM: 102.1±3.3%, 100 μM: 109.0±3.6%, n=14), even when vascular endothelial cells were removed, there was no effect on relaxation ability ( endothelium-denuded in Fig. 2).

Additionally, in order to confirm the mechanism of action on the smooth muscle relaxation effect of URO-K10, the effect of URO-K10 on the smooth muscle relaxation effect was observed after each pretreatment with a potassium ion channel inhibitor.

As a result, as shown in FIG. 3 , the smooth muscle relaxation effect of URO-K10 was determined by the non-selective potassium channel inhibitor tetraethylammonium (TEA) and the membrane voltage-dependent potassium channel inhibitor 4-aminopyridine (4-aminopyridine, 4- AP) and the BKCa channel inhibitor iberiotoxin (IbTX), the relaxation response by URO-K10 was completely inhibited by the _{K v 7 potassium ion channel inhibitor XE991 (n=6).} -14).

These results show that URO-K10 induces a relaxation response through the activation of _{K v} 7 potassium ion channels present in the corpus cavernosum smooth muscle cells in an endothelial cell-independent manner.

Example 2. PDE5 Synergistic relaxation with inhibitors

URO-K10 alone, sildenafil alone, and URO-K10 + sildenafil combination were respectively treated in the corpus cavernosum in rabbits, and the change in tension of the cavernous smooth muscle of the penis was measured using the organ bath method.

As a result, as shown in FIG. 4, when 3 X 10 ^-6 M URO-K10 and PDE5 inhibitor sildenafil 1 X 10 ^-7 M were simultaneously treated, a synergistic effect of relaxation was observed compared to treatment alone. (n=8, 3 X 10 ^-6 M URO-K10: 49.4±5.0%, 1 X 10 ^-7 M Sildenafil: 33.8±3.1%, 3 X 10 ^-6 M URO-K10 + 1 X 10 ^-7 M Sildenafil : 84.8±3.2%).

Example 3. In Human Penile Cavernous Smooth Muscle Cells URO -K10's K _v 7 potassium ion channel activation effect

_{The effect on the K v} 7 potassium ion channel of human penile corpus cavernosum smooth muscle cells was observed using the amphotericin-B perforated patch-clamp method. URO-K10 (10 μM) was treated with the perfusion solution while the cell membrane voltage was fixed at -10 mV, and the current change was recorded after depolarization to +40 mV. As shown in FIGS. 5a and 5b, URO-K10 There was a significant increase in outward current in a concentration-dependent manner (at -10 mV, 0 µM: 0.81 ± 0.12 pA/pF, 0.03 µM: 0.80 ± 0.15 pA/pF, 0.1 µM: 1.18 ± 0.19 pA/pF, 0.3 µM: 1.37 ±0.24 pA/pF, 1 μM: 1.53±0.24, 3 μM: 1.56±0.29, 10 μM: 1.74±0.33, n=14).

_{The EC 50} of URO-K10 was measured to be 82.1 nM at -10 mV and 160.1 nM at +40 mV ( FIG. 5c ).

The outward current increased by URO-K10 was reduced to control levels by XE991 (10 μM), a _{K v 7 potassium ion channel inhibitor (Fig. 5d).}

To obtain a current-voltage curve, electrical stimulation was applied by increasing the voltage by +10 mV from -80 mV to +40 mV, and the magnitude of the current according to the voltage change was measured. As a result, as shown in FIG. 6 , when URO-K10 was treated, the outward current was significantly increased at a voltage of -30 mV or higher (n=7), and the activated current was completely reduced by XE991 (10 μM). .

Through the above experiment, it was recorded K _v 7 currents activated by URO-K10 in corpus cavernosum smooth muscle cells.

Example 4. In Human Penile Cavernous Smooth Muscle Cells URO -K10's stable film voltage conditioning effect

Using the amphotericin-B puncture patch clamp method, 1 μM of URO-K10 was treated in the perfusion solution in current-clamp mode, and then the change in membrane voltage was measured.

As a result, as shown in FIG. 7 , the stable membrane voltage before drug treatment in penile cavernous smooth muscle cells was measured to be -41.6±4.0 mV, and when treated with URO-K10, it was hyperpolarized by -14 mV to -55.67±4.57 mV ( n=12, p<0.05 vs. control). When the same cells were _{treated with the K v} 7 potassium ion channel inhibitor XE991, the effect of URO-K10 was inhibited (URO-K10 + XE991: -48.46±4.97 mV, n=9, p<0.05 vs. URO-K10). ), when URO-K10 was removed from the perfusion solution, the membrane voltage was restored to the level before drug treatment.

Example 5. Diabetic Erectile Dysfunction rat in the model URO -K10 in erectile function impact

For 8-week-old male Sprague-Dawley rats (Orient Bio), streptozotocin (65 mg/kg body weight) dissolved in 5 mM citrate buffer (pH 4.5) was injected into the abdominal cavity of the rat once. Diabetes was induced by injection. After 48 hours, blood was collected from the tail vein to test for blood sugar, and only mice with a blood sugar level of 250 mg/dL or higher were selected as the diabetes-induced group. Blood glucose and body weight were checked every 4 weeks, and only when it maintained 250 mg/dL or more, it was used as a diabetes model. After 12 weeks of diabetes-induced white paper, after ketamine anesthesia, the pelvic ganglion on the outside of the right prostate was dissected and exposed in the pelvis through an abdominal midsection. After finding the main pelvic ganglion located on the posterior wall of the prostate, the branches of the pelvic nerve and the cavernous nerve were separated, and platinum electrodes were installed on the cavernous nerve of the penis and connected to an electric stimulator.

To measure the intracavernosal pressure (ICP), the penile foreskin was incised to expose the corpus cavernosum, and then a 23 G needle connected to a polyethylene tube (PE-50) was placed in the corpus cavernosum. During the experiment, to determine the state of systemic blood flow following electrical stimulation or drug injection, the right internal carotid artery was dissected and a polyethylene tube (PE-50) was inserted, and then the mean arterial pressure (MAP) was continuously measured. The cavernous pressure was measured by checking the major pelvic ganglion and then stimulating the cavernous nerve at 12 Hz, 5 ms, 2.5 V, or 5 V for 60 seconds. For the evaluation of erectile function in the white paper, the maximum penile cavernous pressure (ICP), the maximum penile cavernous pressure/mean arterial pressure (ICP/MAP) ratio, and AUC (area under the curve) were compared and analyzed.

As a result, as shown in Figures 8a and 8b, the diabetic group significantly decreased erectile function compared to the normal control group. Under the 2.5 V electrical stimulation condition, the ICP/BP ratios of the normal group and the diabetic group were 65.3±3.6 and 40.6±1.6, respectively. Under the 5 V electrical stimulation condition, the ICP/BP ratios of the normal group and the diabetic group were 79.8±3.7 and 58.2± was measured to be 2.5 (Fig. 8 and Table 1).

In the group injected with URO-K10 in the same way, there was little change in blood pressure, but the cavernous pressure was significantly increased, and the 20 μg/kg injection group was more effective than the 10 μg/kg injection group (Fig. 8 and Table). One).

Max ICP (intracavernosal pressure): maximum penile cavernosal pressure

MAP (mean arterial pressure): mean arterial blood pressure

The above description of the present invention is for illustration, and those of ordinary skill in the art to which the present invention pertains can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.

Claims (10)

A pharmaceutical composition for preventing or treating erectile dysfunction comprising a compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof, as an active ingredient.
Formula 1

Formula 2

According to claim 1,
The compound or a pharmaceutically acceptable salt thereof is characterized in that it relaxes the smooth muscle of the cavernous body of the penis, a pharmaceutical composition.
According to claim 1,
The compound or a pharmaceutically acceptable salt thereof is characterized in that it activates the _{K v 7 potassium ion channel of the cavernous smooth muscle cells of the penis, a pharmaceutical composition.}
4. The method of claim 3,
The K _v 7 potassium ion channel is a K _v 7.4 potassium ion channel subunit, characterized in that, the pharmaceutical composition.
(a) a compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof; And (b) a pharmaceutical composition for preventing or treating erectile dysfunction comprising a PDE5 (phosphodiesterase 5) inhibitor as an active ingredient.
Formula 1

Formula 2

6. The method of claim 5,
The PDE5 inhibitor is a pharmaceutical, characterized in that selected from the group consisting of sildenafil, tadalafil, vardenafil, udenafil, mirodenafil, and combinations thereof. composition.
6. The method of claim 5,
The component (a) is characterized in that the PDE5 inhibitor is administered simultaneously (simultaneous), separately (separate) or sequentially (sequential), the pharmaceutical composition.
A quasi-drug composition for preventing or improving erectile dysfunction comprising a compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof, as an active ingredient.
Formula 1

Formula 2

A food composition for preventing or improving erectile dysfunction comprising a compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof, as an active ingredient.
Formula 1

Formula 2

10. The method of claim 9,
The food composition is a health functional food, characterized in that the food composition.

Images