KR101082802B1 - Pharmaceutical composition for preventing or treating premature ejaculation comprising 8-hydroxyclomipramine or its salt - Google Patents

Abstract

PURPOSE: A pharmaceutical composition containing 8-hydroxyclomipramine or pharmaceutically acceptable salt thereof is provided to delay ejaculation. CONSTITUTION: A pharmaceutical composition for preventing or treating premature ejaculation contains a compound of chemical formula 1 or pharmaceutically acceptable salt thereof as an active ingredient. The composition is used for oral administration. The composition is manufactured in the form of powder, granules, tablets, capsules, pills, liquid, suspension, emulsion, and syrup. The daily dose of the compound or salt is 0.1-10 mg/kg.

Description

Pharmaceutical composition for preventing or treating premature ejaculation comprising 8-hydroxyclomipramine or its salt}

The present invention relates to a pharmaceutical composition for preventing or treating premature ejaculation, comprising a specific metabolite of clomipramine, that is, 8-hydroxycyclomipramine or a pharmaceutically acceptable salt thereof as an active ingredient.

Premature ejaculation is one of the male sexual dysfunctions, and WHO says premature ejaculation is "unable to control the situation at will, or reach extremes immediately after intravaginal insertion or with minimal stimulation, to satisfy sexual intercourse". It is defined. The treatment of premature ejaculation can be divided into behavioral therapy, surgical treatment, and drug treatment. Among them, a topical therapeutic agent using a local anesthetic such as lidocaine is typically used.

As a drug therapy, it has been reported in a number of documents that selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCA) can be used for the prevention or treatment of premature ejaculation in men. For example, clomipramine, a tricyclic antidepressant, has been reported to have better ejaculation delaying effects than other drugs or SSRIs in daily and on-demand doses (Korean Journal of Urology, Vol. 49, No. 9). 2008). In addition, US Pat. No. 6,495,154 discloses a rapid release formulation comprising clomipramine that can be conveniently taken on demand of a patient, and US Patent Publication No. 2007-0043030 discloses clomipramine. Lung-suction compositions have been disclosed.

However, clomipramine and its active metabolite, desmethylclomipramine, have been reported to have a combination of anti-cholinergic, anti-muscarin side effects such as drowsiness, dry mouth, nausea and vomiting (The Journal of Urology, 1998, (159): 425-427). Clomipramine is derived from desmethyl-clomipramine, 8-hydroxy-clomipramine, 8-hydroxydesmethyl-clomipramine, clomipramine-N-oxide, 2-hydrate in vivo. It is metabolized into a variety of metabolites such as Roxy-clomipramine, of which desmethyl-clomipramine is known as the main active metabolite. Nunez R et al. Reported that 8-hydroxycyclomipramine among the metabolites of clomipramine has lower anti-muscarin side effects than clomipramine and its main metabolite, desmethylclomipramine (Psychopharmacol Bull. 1995; 31 (2): 217-21), no pharmacological activity, especially ejaculation delay activity, of other metabolites, including 8-hydroxycyclomipramine, has been reported.

The present inventors conducted various studies to develop a compound having an excellent rate of absorption of the drug upon oral administration, which can express a fast medicinal effect, and also have an excellent ejaculation delay activity. As a result, when a compound having a hydroxyl group at the 8 position of clomipramine (i.e., 8-hydroxycyclomipramine) is designed and orally administered, it is rapidly absorbed by the gastrointestinal tract and shows strong ejaculation delay activity. Rather, it was found that 8-hydroxycyclomipramine glucuronide conjugates, which were rapidly converted through liver-metabolic enzyme reactions, showed ejaculation delay activity.

Accordingly, an object of the present invention is to provide a pharmaceutical composition for preventing or treating premature ejaculation in men, comprising the 8-hydroxycyclomipramine or a pharmaceutically acceptable salt thereof as an active ingredient.

According to one aspect of the invention, there is provided a pharmaceutical composition for preventing or treating premature ejaculation, comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

<Formula 1>

The composition may preferably be formulated as a composition for oral administration.

It has been found by the present invention that certain metabolites of clomipramine, i.e., 8-hydroxycyclomipramine or salts thereof, exhibit much stronger ejaculation delay activity than clomipramine. In particular, the compound of Formula 1 or a pharmaceutically acceptable salt thereof is rapidly converted to the glucuronide form through rapid liver-metabolism enzyme reaction upon oral administration, thereby glucuronide conjugate of 8-hydroxycyclomipramine It has been found by the present invention that the gate exhibits ejaculation delay activity. In addition, oral administration of a compound of Formula 1 or a salt thereof may fundamentally avoid the formation of desmethylclomipramine, which is known to be a major cause of the anti-muscarin side effects of clomipramine. Minimize side effects when

Figure 1 shows the plasma concentration profile of 8-hydroxycyclomipramine obtained by intravenous injection of 8-hydroxycyclomipramine. In Fig. 1,-▽-is the result of analyzing the blood sample by enzyme treatment, and-●-is the result of analyzing the blood sample without enzyme treatment.
Figure 2 shows the plasma concentration profile of 8-hydroxycyclomipramine obtained by oral administration of 8-hydroxycyclomipramine. In Fig. 2,-▽-is the result of analyzing the blood sample by enzyme treatment, and-●-is the result of analyzing the blood sample without treating the enzyme.

The present invention provides a pharmaceutical composition for preventing or treating premature ejaculation, comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

<Formula 1>

It has been found that certain metabolites of clomipramine, the compounds of formula (I) or their pharmaceutically acceptable salts, exhibit much more potent delay activity than clomipramine. In particular, the compound of Formula 1 or a pharmaceutically acceptable salt thereof is rapidly converted into glucuronide form (ie, glucuronide conjugate form) through rapid liver-metabolic enzyme reaction upon oral administration. It has been found by the present invention that the glucuronide conjugate of 8-hydroxycyclomipramine exhibits ejaculation delay activity. In addition, oral administration of a compound of Formula 1 or a salt thereof may fundamentally avoid the formation of desmethylclomipramine, which is known to be a major cause of the anti-muscarin side effects of clomipramine. Minimize side effects when

The pharmaceutical compositions according to the invention may be formulated in intravenous or oral administration, more preferably in various forms, including powders (powders), granules, tablets, capsules, pills, solutions, suspensions, emulsions, syrups and the like. It may be formulated in an oral dosage form of. Particularly preferably the pharmaceutical composition according to the invention may be in the form of oral administration in the form of tablets or strips (oral dissolution film formulations).

The pharmaceutical composition according to the present invention includes the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, and may also include a pharmaceutically acceptable carrier. For example, the pharmaceutically acceptable carrier is lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl Cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil and the like. Oral solid preparations such as powders, granules, tablets, capsules, pills, and the like may include, for example, starch, calcium carbonate, sucrose or lactose, gelatin, and the like. Lubricants such as magnesium stearate, talc and the like. Oral liquid preparations such as suspending agents, solvents, emulsions, and syrups may include, for example, water, diluents such as liquid paraffin, wetting agents, sweetening agents, fragrances, preservatives, and the like.

The dosage of the compound of formula 1 or a pharmaceutically acceptable salt thereof contained in the pharmaceutical composition of the present invention depends on the condition and weight of the premature ejaculation patient, the extent of the disease, the form of the drug, the route of administration, and the duration thereof, and is appropriate for the skilled person. Can be chosen. For example, the compound of Formula 1 or a pharmaceutically acceptable salt thereof may be administered at a dose of 0.1 to 10 mg / kg, preferably 0.1 to 2 mg / kg.

Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are for illustrating the present invention, and the scope of the present invention is not limited to these examples.

Example  1.8- Hydrocyclocyclomipramine  Preparation of Hydrochloride

Step 1: Preparation of Iminoquinone Compound (Compound of Formula 3)

The starting compound of formula 2 (3-chloro-10,11-dihydro-5H-dibenzo [b, f] azepine, CAS No .: 32943-25-2) is known from US Pat. No. 3,056,776. It was disclosed and purchased from Taicang Hengyi Medical & Chemical Material Factory (China). After dissolving 3 g of the compound of formula 2 in 300 ml of acetone, a solution of 10 g of potassium nitrosodisulphonate (Fremy's salt) and 6 g of disodium phosphate 12 hydrate in 100 ml of water was added dropwise over 30 minutes. The reaction solution was filtered through a filter previously filled with Celite 545, and the filtrate was distilled under reduced pressure to remove acetone. The precipitated solid was separated by filtration and dried in vacuo to give 1.7 g of a dark brown solid. The obtained solid was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1, v / v) to obtain 0.42 g of an orange iminoquinone compound (compound of formula 3).

¹ H-NMR (400 MHz, CDCl ₃ ) d 2.80 (m, 2H) 2.90 (m, 2H) 6.28 (d, J = 1.6 Hz, 1H) 6.61 (dd, J = 8.0, 1.6 Hz, 1H) 7.10 (d , J = 6.4 Hz, 1H) 7.21 (dd, J = 6.4, 1.6 Hz, 1H) 7.25 (d, J = 8.0 Hz, 1H) 7.61 (d, J = 1.6 Hz, 1H)

Step 2: Preparation of an Aminophenol Compound (Compound of Formula 4)

0.42 g of compound of formula 3 was dissolved in 35 ml of methylene chloride, a solution of 2 g of sodium hydrosulphite dissolved in 10 ml of water was added, followed by vigorous stirring for 10 minutes. The organic layer was separated and water was removed with anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in 1 ml of methylene chloride, 5 ml of n-hexane was added, and then left in a refrigerator. The resulting crystals were filtered off and dried in vacuo to yield 0.38 g of a white aminophenol compound (Compound 5).

Step 3: introduce the saver

After dissolving 0.38 g of the compound of Formula 5 in 5 ml of diethylamine under a nitrogen atmosphere, 0.5 g of tert-butyldimethylsilyl chloride (TBDMS-Cl) was added and stirred at room temperature for 18 hours. 10 ml of diisopropyl ether was added to the reaction mixture to precipitate diethylamine hydrochloride. The precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-nucleic acid: ethyl acetate = 20: 1, v / v). The obtained solution was concentrated under reduced pressure, and the obtained residue was dried in vacuo to obtain 0.52 g of the compound of formula (5).

Step 4: N-alkylation reaction

0.52 g of a compound of Formula 5 and 100 mg of sodium amide (NaNH ₂ ) were added to 10 ml of anhydrous toluene, followed by 1 ml of 3-dimethylaminopropyl chloride, followed by heating to reflux for 2 hours. 10 ml of toluene was added to the reaction mixture, which was then filtered through Celite 545 to obtain a pale yellow solution. The filtrate was concentrated under reduced pressure and dried in vacuo to yield 0.63 g of a compound of formula 6 in oil form.

Step 5: Deprotection Reaction

0.63 g of the compound of formula 6 was dissolved in 30 ml of anhydrous ethanol, and then 1 ml of 3N-hydrochloric acid solution was added and stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure to remove ethanol and water, and the obtained residue was vacuum dried at 60 ° C. for 24 hours to obtain 0.51 g of a hydrochloride salt of the compound of formula 1.

¹ H-NMR (400 MHz, D ₂ O) d 1.89 (m, 2H) 2.71 (s, 6H) 2.96-3.06 (m, 2H + 4H) 3.66 (t, J = 6.4 Hz, 2H) 6.69 (dd, J = 8.4, 3.2 Hz, 1H) 6.75 (d, J = 3.2 Hz, 1H) 6.92 (dd, J = 8.0, 2.0 Hz, 1H) 6.97 (d, J = 2.0 Hz, 1H) 7.02 (d, J = 8.0 Hz, 1H) 7.11 (d, J = 2.0 Hz, 1H)

Example  2. Animal Evaluation

Drug efficacy was assessed using a premature ejaculation animal efficacy test model, Para-chloroamphetamine-induced ejaculation model. Male rats 8 to 10 weeks of fertility were divided into 4 groups of 10 rats per group. The first group (negative control group) was administered 0.9% saline, the second group (positive control group) orally administered clomipramine hydrochloride at a dose of 10 mg / kg, and the third group (positive control group) was dapoxetine Hydrochloride was orally administered at a dose of 10 mg / kg, and the fourth group (test group) orally administered the hydrochloride of the compound of Formula 1 prepared in Example 1 at a dose of 10 mg / kg. Oral administration of the second to fourth groups was administered orally by dissolving each test substance in purified water. After 30 minutes of administration, p-chloroamphetamine, an ejaculator, was dissolved in water and intraperitoneally injected at a dose of 5 mg / kg, and the ejaculation time was observed. The results are shown in Table 1 below.

Test group Medication Average cumshot time (seconds) Change rate ^* p-value ^** First group Negative Control 0.9% saline 546.0 ± 246 2nd group Positive control group Clomipramine 654.6 ± 366 19.9 0.48 Third group Positive control group Dapoxetine 881.4 ± 366 61.4 0.03 4th group Test group 8-hydroxycyclomipramine 925.2 ± 273 69.5 0.01

*: Change rate compared to negative control

**: p value compared to negative control (paired T-test)

As can be seen from the results of Table 1, the statistical significance was analyzed using a paired T-test, and in the 95% confidence interval, the positive control group dapoxetine and the test group 8-hydroxycyclomifra in the 95% confidence interval. You can check the effect of the delay of the people. Clomipramine did not show an ejaculatory effect compared to the negative control group, which may be due to the fact that the effective blood concentration of clomipramine has not been reached 30 minutes after drug administration.

Example  3. Pharmacokinetics ( Pharmacokinetics ) exam

Male rats (weight: approximately 250 g) of 8 weeks or older were divided into two groups of three, fasted for 24 hours, and used for testing. In the first group, 8-hydroxycyclomipramine hydrochloride was dissolved in 0.9% physiological saline, and administered once through the tail vein at a dose of 10 mg / kg, followed by 1, 5, 10, About 30 uL was drawn from the tail vein after 30, 60, 90, 120, 180, 240, 360, 480, 720 minutes. In the second group, 8-hydroxycyclomipramine hydrochloride was dissolved in purified water and orally administered in a single dose of 10 mg / kg, followed by 0, 10, 20, 30, 60, 90 using a 24-gauge catheter. After about 120, 360, 480, 600 and 720 minutes, about 200 uL was collected from the tail vein. The collected blood is centrifuged at 10,000 rpm for 1 minute to separate the plasma, and then divided into 50uL of each obtained plasma, one of which is not treated with enzyme and the other is beta-glucuronidase (beta). After treatment with -glucuronidase, the concentration of 8-hydroxycyclomipramine in plasma was analyzed by high performance liquid chromatography (HPLC). When beta-glucuronidase is treated with plasma samples, the 8-hydroxycyclomipramine glucuronide metabolite is hydrolyzed to favor 8-hydroxycyclomipramine. The HPLC analysis conditions are as follows:

<HPLC Analysis Conditions>

Column: column equivalent to INNO C18 (4.6 x 150 mm, 5um)

Mobile phase: Acetonitrile: buffer (31: 69, v / v)

Buffer: The 5 mM potassium phosphate buffer is adjusted to pH 2.5 with phosphoric acid.

Flow rate: 1mL / min

Detector: UV-visible spectrophotometer (wavelength 215 nm)

Injection volume: 20uL

Pharmacokinetic Parameters According to Intravenous Injection (iv bolus) Enzyme Treatment (-▽-) Enzyme untreated (-●-) Tmax (min) 1.0 1.0 Cmax (ng / mL) 103.9 55.8 AUC _last (ng * min / mL) 8040.1 404.0

Pharmacokinetic Parameters Following Oral Administration Enzyme Treatment (-▽-) Enzyme untreated (-●-) Tmax (min) 43.3 Not detected Cmax (ng / mL) 18.5 Not detected AUC _last (ng * min / mL) 6110 Not detected

As can be seen from the results of FIG. 1 and Table 2, plasma treated after intravenous treatment with beta-glucuronidase showed significantly higher AUC values compared to the enzyme-untreated samples. In addition, as can be seen from the results of FIG. 2 and Table 3, when the plasma collected after oral administration was treated with beta-glucuronidase, 8-hydroxycyclomipramine was detected, whereas enzyme-treated No 8-hydroxycyclomipramine was detected in the sample. From these results, it can be seen that 8-hydroxycyclomipramine is rapidly converted into the glucuronide form, ie, the glucuronide conjugate form through liver-metabolase enzyme reaction. It can be seen that the metabolite in the form of a conjugated conjugate exhibits ejaculation delay activity.

Claims (2)

A pharmaceutical composition for preventing or treating premature ejaculation comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
<Formula 1>

The pharmaceutical composition of claim 1, wherein the composition is for oral administration.

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