2H-BENZOTRIAZOLE DERIVATIVES, PREPARATION METHOD THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abstract

The present invention provides 2H-benzotriazole derivatives, methods for preparing them, and pharmaceutical compositions containing them. The present invention relates to the pharmaceutical technical field, particularly to a 2H-benzotriazole derivative represented by formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing them, as well as their use in the manufacture of a medicament for the treatment and / or prevention of premature ejaculation. In vivo activity studies have shown that the 2H-benzotriazole derivatives of the present invention exhibit significantly higher premature ejaculation prevention effects than the only clinically approved drug, the commercially available drug dapoxetine, and thus possess therapeutically important features and represent a substantial technological advance. The 2H-benzotriazole derivatives of the present invention, or their pharmaceutically acceptable salts, have great potential for research and application as therapeutic agents for premature ejaculation. [Formula 1] JPEG2025531344000040.jpg28170

Description

[Technical Field]

[0001] The present invention relates to the technical field of pharmacy, in particular to novel 2H-benzotriazole derivatives, their preparation methods and pharmaceutical compositions containing them. [Background technology]

[0002] Premature ejaculation (premature ejaculation) is one of the most common male sexual dysfunctions, with an incidence rate of 20% to 30%. The International Society of Sexual Medicine defines premature ejaculation as follows: ejaculation often or always occurs before or within approximately one minute after vaginal penetration at the onset of sexual activity (primary premature ejaculation); or a significantly shortened intravaginal ejaculatory latency time (IELT), typically less than three minutes (secondary premature ejaculation); or ejaculation is never or rarely controlled or delayed, accompanied by adverse physical and psychological effects such as distress, anxiety, depression, and avoidance of sexual contact. The causes of premature ejaculation are complex and include disorders of central 5-hydroxytryptamine and dopamine neurotransmitters, hypersensitivity of the penile head, genetic mutations, psychological factors such as tension and / or anxiety, erectile dysfunction, chronic prostatitis, thyroid disease, and medications. Premature ejaculation is a psychological and physical disorder. According to the holistic concept of traditional Chinese medicine, this disorder is a localized symptom of systemic maladaptation. The new goal of premature ejaculation treatment is psychological and physical joint adjustment, and holistic and local joint treatment. The purpose of treatment is to improve the patient's ejaculation control, improve sexual satisfaction for both spouses, and prolong ejaculation time. Based on a clear diagnosis and classification, doctors should discuss treatment needs with the patient and their partner and jointly formulate treatment goals and guidelines.

[0003] Dapoxetine hydrochloride is a selective 5-hydroxytryptamine reuptake inhibitor. It is the only drug marketed worldwide for the treatment of premature ejaculation. It is currently approved as a long-awaited treatment for premature ejaculation in over 50 countries and regions, including the EU and China. Research has shown that taking 30 mg or 60 mg of dapoxetine hydrochloride 1 to 2 hours before sexual activity increases IELT by 2.5 and 3.0 times, respectively, compared with placebo, improving ejaculation control, reducing patient discomfort, and improving sexual satisfaction. Dapoxetine hydrochloride has similar therapeutic effects for primary and secondary premature ejaculation, with dose-dependent treatment-related side effects such as nausea, diarrhea, headache, and dizziness. The initial recommended dose of dapoxetine hydrochloride for treatment is 30 mg. It is usually evaluated after six doses within four weeks, and if efficacy is poor, the dose can be increased to 60 mg. However, the clinical discontinuation rate is very high, increasing over time and reaching over 90% two years after the start of treatment. Reasons for discontinuation include high cost (29.9%), disappointment with refractory premature ejaculation, and dependence on on-demand administration (25.0%). The low bioavailability of dapoxetine is an important reason for its poor therapeutic efficacy and low patient satisfaction, resulting in a high clinical discontinuation rate. Therefore, the development of new drugs for the treatment of premature ejaculation is of clinical significance. Summary of the Invention [Problem to be solved by the invention]

[0004] The primary object of the present invention is to provide 2H-benzotriazole derivatives having medicinal properties, methods for preparing the same, and pharmaceutical compositions containing the derivatives.

[0005] A second object of the present invention is to provide the use of 2H-benzotriazole derivatives and pharmaceutical compositions containing said derivatives in the manufacture of medicaments for treating and / or preventing premature ejaculation. [Means for solving the problem]

[0006] The 2H-benzotriazole derivative disclosed in the present invention is a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, and the salt includes hydrochloride, hydrobromide, sulfate, trifluoroacetate, methanesulfonate, tartrate, malate, citrate, succinate, etc., and the salt may contain 0.5 to 3 molecules of water of crystallization.

[0007] [ka]

[0008] In formula (I), X represents C3-C4-alkyl or C3-C4-alkoxy, Y represents CH or N; Z represents O or S; R represents an optional substitution of a hydrogen atom with 1 to 3 halogen atoms selected from the group consisting of fluorine, chlorine, and bromine.

[0009] Preferably, the 2H-benzotriazole derivative is any one of the following compounds: A001: 1-(4-(4-benzisoxazolyl)piperazin-1-yl)butyl-2H-benzotriazole, A002: 1-(3-(4-(3-(6-fluorobenzisoxazolyl))piperidin-1-yl)propyl-2H-benzotriazole, A003: 1-(4-(4-(3-(6-fluorobenzisoxazolyl))piperidin-1-yl)butyl-2H-benzotriazole, A004: 1-(3-(4-benzisothiazolyl)piperazin-1-yl)propyl-2H-benzotriazole, A005: 1-(3-(4-(3-(6-fluorobenzisoxazolyl))piperazin-1-yl)propyl-2H-benzotriazole, or A006: 1-(4-(4-(3-(6-fluorobenzisoxazolyl))piperazin-1-yl)butyl-2H-benzotriazole

[0010] Specific chemical structural formulas are shown in the table below.

[0011] [Table 1A]

[0012] A general synthetic scheme is shown below.

[0013] [ka]

[0014] where X, Y, Z and R are defined as above.

[0015] Taking compound A001 as an example, substituted 1H-benzotriazole is used as the starting material, and the resulting product is subjected to a substitution reaction with 1-bromo-4-chlorobutane in aqueous sodium hydroxide to prepare 1-(4-chlorobutyl)-1H-benzotriazole (yield: approximately 70%) and 1-(4-chlorobutyl)-2H-benzotriazole (yield: approximately 30%). The resulting mixture is purified by silica gel column chromatography to obtain 1-(4-chlorobutyl)-2H-substituted benzotriazole (purity: >95%), which is then reacted with benzisoxazolepiperazine via a condensation reaction to prepare compound A001. Compound A001 can finally be converted to the corresponding salt by acidification. Compounds A002 to A006 and their salts can be prepared by the above method.

[0016] Also provided is a pharmaceutical composition comprising one or more of the 2H-benzotriazole derivatives or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier. The carrier refers to a conventional carrier in the pharmaceutical field, including diluents; excipients such as water; binders such as cellulose derivatives, gelatin, and polyvinylpyrrolidone; fillers such as starch; disintegrants such as calcium carbonate and sodium bicarbonate; and lubricants such as calcium stearate or magnesium stearate. Furthermore, other adjuvants, such as flavorings and sweeteners, can also be added to the pharmaceutical composition. For oral administration, the pharmaceutical composition can be prepared as a conventional solid formulation, such as a tablet, powder, or capsule, or as an injectable solution.

[0017] Various dosage forms of the pharmaceutical composition according to the present invention are prepared according to conventional methods in the art, and contain 0.1% to 99.5% (mass %) of the active ingredient.

[0018] Also provided is the use of a 2H-benzotriazole derivative according to the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing said derivative, in the manufacture of a medicament for treating and / or preventing premature ejaculation. [Effects of the Invention]

[0019] The 2H-benzotriazole derivatives of the present invention exhibit significant effects in inhibiting premature ejaculation, and have significant therapeutic features and significant technological advances compared with dapoxetine, the only clinically approved drug. Their therapeutic features and advantages are as follows:

[0020] The 2H-benzotriazole derivatives or pharmaceutically acceptable salts thereof of the present invention are a group of 2H-benzotriazole derivatives with a novel structure. In vivo experimental studies have shown that the premature ejaculation inhibitory effect of these compounds is significantly higher than that of the commercially available drug dapoxetine. The 2H-benzotriazole derivatives or pharmaceutically acceptable salts thereof of the present invention have great potential for research and application as therapeutic agents for premature ejaculation. [Brief explanation of the drawings]

[0021] [Figure 1] Histogram of total ejaculation frequency in Wistar rats within 30 minutes after PCA induction, One-way ANOVA, Dunnett post hoc, *** indicates P<0.001, compared with the PE model group, N=5. [Figure 2] Histogram of the first ejaculation latency of Wistar rats within 30 minutes after PCA induction, One-way ANOVA, Dunnett post hoc, *: P<0.05, **: P<0.01, ***: P<0.001, compared with the PE model group, N=5. [Figure 3] Histogram of the number of seminal vesicle contractions in Wistar rats within 30 minutes after PCA induction. One-way ANOVA, Dunnett post hoc. *** indicates P<0.001, compared with the PE model group. N=5. [Figure 4] Histogram of the latency period of the first seminal vesicle contraction in Wistar rats within 30 min after PCA induction. One-way ANOVA, Dunnett post hoc, **: P<0.01, ***: P<0.001, compared with the PE model group, N=5. [Figure 5] Histogram of seminal vesicle basal pressure in Wistar rats within 30 minutes after PCA induction. One-way ANOVA, Dunnett post hoc. *** indicates P<0.001, compared with the PE model group. N=5. [Figure 6] Histogram of seminal vesicle peak pressure in Wistar rats within 30 minutes after PCA induction. One-way ANOVA, Dunnett post hoc. *** indicates P<0.001, compared with the PE model group. N=5. DETAILED DESCRIPTION OF THE INVENTION

[0022] Reagents and solvents were purchased from Sigma-Aldrich or Fisher Scientific and used without further purification. All reactions were subjected to thin-layer chromatography (silica gel GF-254 thin-layer plates) and monitored by LC-MS. Column chromatography purification was performed on 300-400 mesh silica gel (Qingdao Ocean Chemical Co., Ltd.). 1 H and 13 C NMR spectra were obtained using a Bruker AV-400 nuclear magnetic resonance spectrometer with TMS as the internal standard. The purity of the compounds, as determined by LC-MS analysis, was greater than 95%. LC-MS analysis was also used to record MS spectra of the compounds, and was performed using a Shimadzu LCMS-2020.

[0023] General Synthesis Process (1) Preparation of Key Intermediate: 1-(4-chlorobutyl)-2H-benzotriazole (A1)

[0024] [ka]

[0025] 30.0 g (251 mmol) of benzotriazole, 39.3 g (229 mmol) of 1-bromo-4-chlorobutane, 1.85 g (6 mmol) of tetrabutylammonium bromide, and 240 g (20%) of aqueous sodium hydroxide solution were placed in a 500 mL single-neck flask and stirred thoroughly until completely dissolved. The temperature was raised to 60 °C, and the reaction was continued for 2 hours while stirring and monitoring by TLC. After completion of the reaction, the reaction mixture was extracted with dichloromethane (240 mL x 3), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Purification by silica gel column chromatography yielded 10.23 g of a pale yellow oily liquid (yield 19.44%).

[0026] (2) Preparation of Key Intermediate: 1-(3-chloropropyl)-2H-benzotriazole (A2)

[0027] [ka]

[0028] 36.0 g (302 mmol) of benzotriazole, 47.5 g (302 mmol) of 1-bromo-3-chlorobutane, 2.22 g (6.8 mmol) of tetrabutylammonium bromide, and 240 g (20%) of aqueous sodium hydroxide solution were placed in a 500 mL single-neck flask and stirred thoroughly until completely dissolved. The temperature was raised to 60 °C, and the reaction was continued for 2 hours while stirring and monitoring by TLC. After completion of the reaction, the reaction mixture was extracted with dichloromethane (240 mL x 3), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The product was purified by silica gel column chromatography to obtain 11.71 g of a pale yellow oily liquid (yield 19.82%).

[0029] (3) Preparation of 6-fluoro-3-(piperazin-1-yl)benzisoxazole (A3)

[0030] [ka]

[0031] A 100 mL single-neck flask was charged with 1.58 g (10 mmol) of 2-chloro-4-fluorobenzaldehyde, 0.84 g (10 mmol) of hydroxylamine hydrochloride, 1.64 g (20 mmol) of sodium acetate, 30 mL of ethanol, and 10 mL of water, and the mixture was reacted for 2 hours. The reaction was monitored by TLC. After completion of the reaction, the ethanol was removed by vacuum distillation, and the mixture was suction filtered. The filter cake was washed with purified water to obtain 1.65 g (95% yield) of (E)-2-chloro-4-fluorobenzaldehyde oxime. A 50 mL single-neck flask was charged with 1.73 g (10 mmol) of (E)-2-chloro-4-fluorobenzaldehyde oxime and 15 mL of N,N-dimethylformamide, and 1.47 g (11 mmol) of N-chlorosuccinimide. The reaction was carried out at room temperature for 1 hour while monitoring by TLC. After the reaction was complete, the reaction mixture was added dropwise to 300 mL of purified water and stirred. After suction filtration, 1.85 g of (Z)-2-chloro-4-fluorochlorohydroxyimine benzyl was obtained (yield: 89%). 1.04 g (5 mmol) of (Z)-2-chloro-4-fluorochlorohydroxyimine benzyl, 3.44 g (40 mmol) of anhydrous piperazine, and 1.01 g (10 mmol) of trimethylamine were dissolved in 30 mL of dichloromethane in a 100 mL one-neck flask. The reaction was carried out for 2 hours while monitoring by TLC. After the reaction was complete, saturated aqueous copper sulfate solution was added to the reaction mixture with stirring until no blue flocculent precipitate was formed. The reaction mixture was suction filtered, washed with saturated brine, extracted with dichloromethane, and the solvent was evaporated to obtain 0.79 g of (Z)-(2-chloro-4-fluorophenyl)-1-piperazinylmethanone oxime (yield: 61%). 0.65 g (5 mmol) of (Z)-(2-chloro-4-fluorophenyl)-1-piperazinylmethanone oxime, 0.56 g (5 mmol) of potassium tert-butoxide, and 10 mL of 1,4-dioxane were placed in a 50 mL single-neck flask and reacted at 100 °C for 12 hours. The reaction was monitored by TLC. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain a yellow oil. The product was purified by silica gel column chromatography to obtain 0.282 mg of 6-fluoro-3-(piperazin-1-yl)benzisoxazole as a white powdery solid (yield: 51%).

[0032] (4) General preparation method of target compound (A004 as an example) A 50 mL single-neck flask was charged with 1.88 g of 3-(1-piperazinyl)-1,2-benzisothiazole, 3.3 g of triethylamine, 1.4 g of potassium iodide, and 15 mL of acetonitrile and stirred thoroughly until the starting materials were completely dissolved. Intermediate A2 (1.8 g) was added and heated under reflux at 81 °C for 18 hours. After the reaction was terminated based on TLC analysis, the reaction mixture was cooled to room temperature, suction filtered, and the filtrate was distilled under reduced pressure to remove the solvent, yielding a yellow oil. The residue was washed with saturated brine, extracted with dichloromethane, and distilled under reduced pressure to remove the solvent, yielding an oil. This oil was dissolved in absolute ethanol and adjusted to pH 1 by adding a solution of hydrochloric acid in ethanol. After the dropwise addition, the mixture was stirred at room temperature for 1 hour to precipitate a solid, which was then filtered. The filter cake was recrystallized from absolute ethanol to obtain the final product.

[0033] Example 1 Preparation of 1-(4-(4-benzisoxazolyl)piperazin-1-yl)butyl-2H-benzotriazole

[0034] [ka]

[0035] The synthesis was carried out according to the general preparation method, and recrystallization from absolute ethanol gave 1.12 g of a white powdery solid (42% yield). 1 H NMR(300MHz,DMSO-d6)δ8.04-7.85(m,3H), 7.58(d,J=3.9Hz,2H), 7.51-7.40(m,2H), 7.29(dt,J=8.0,4.0Hz,1H), 4.80(t,J=6.9 Hz,2H), 3.46(t,J=4.9Hz,4H), 2.51(dq,J=5.6,3.5,2.6Hz,4H), 2.37(t,J=7.1Hz,2H), 2.17-1.98(m,2H), 1.47(p,J=7.3Hz,2H);13 C NMR(100MHz,DMSO-d6)δ163.64, 161.29, 144.10, 130.39, 126.68, 123.42, 123.10, 118 .24, 116.04, 110.53, 57.44, 56.32, 52.48, 48.15, 27.84, 23.57;HR-MS(ESI)m / z:calcd for C 21 H 25 NO [M+H] + 377.2084 found 377.2089.

[0036] Example 2 Preparation of 1-(3-(4-(3-(6-fluorobenzisoxazolyl))piperidin-1-yl)propyl-2H-benzotriazole hydrochloride

[0037] [ka]

[0038] The synthesis was carried out according to the general preparation method. Recrystallization from ethyl acetate gave 1.36 g of a white powdery solid (42% yield). 1 H NMR(400MHz,DMSO-d6)δ11.16(s,1H), 8.22(dd,J=8.8,5.2Hz,1H), 7.94(dd,J =6.5,3.1Hz,2H), 7.71(dd,J=9.1,2.2Hz,1H), 7.46(dd,J=6.5,3.1Hz,2H), 7. 32(td,J=9.1,2.2Hz,1H), 4.93(t,J=6.8Hz,2H), 3.55-3.43(m,1H), 3.30-2.9 5(m,5H), 2.74-2.58(m,2H), 2.40(dd,J=13.3,3.5Hz,1H), 2.29-2.11(m,2H): 13C NMR(100MHz,DMSO-d6)δ165.43, 163.78, 163.64, 162.97, 160.54, 144.23, 126.97, 124.39, 124.28, 118.32 , 117.13, 113.34, 113.09, 98.12, 97.85, 53.92, 53.87, 51.84, 31.60, 27.31, 24.31;LC-MS(ESI)m / z:380.17 [M+1] + .

[0039] Example 3 Preparation of 1-(4-(4-(3-(6-fluorobenzisoxazolyl))piperidin-1-yl)butyl-2H-benzotriazole hydrochloride

[0040] [ka]

[0041] The synthesis was carried out according to the general preparation method. Recrystallization from absolute ethanol gave 1.72 g of a white powdery solid (51% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.24 (dd, J = 8.8, 5.3 Hz, 1H), 7.99-7.87 (m, 2H), 7.71 (dd, J = 9.1, 2.2 Hz, 1H), 7.44 (dp, J = 5.9, 2.9 Hz, 2H), 7.33 (td, J = 9.1, 2. 2Hz,1H), 4.83(t,J=6.8Hz,2H), 3.57(d,J=12.0Hz,2H), 3.52-3.42(m,1H), 3.23- 3.02(m,4H), 2.40(qd,J=13.2,3.8Hz,2H), 2.29-2.03(m,4H), 1.90-1.69(m,2H); 13C NMR(100MHz,DMSO-d6)δ165.44, 163.78, 163.64, 162.97, 160.58, 144.17, 126.82, 124.38(d,J=11.2Hz), 118.27(d,J=3.2Hz), 117.14 , 113.33, 113.08, 98.12, 97.85, 55.76(d, J=13.5Hz), 51.70, 48.98, 31.65, 27.19(d,J=7.3Hz), 24.54, 20.93;LC-MS(ESI)m / z:394.21 [M+1] + .

[0042] Example 4 Preparation of 1-(3-(4-benzisothiazolyl)piperazin-1-yl)propyl-2H-benzotriazole hydrochloride

[0043] [ka]

[0044] The synthesis was carried out according to the general preparation method, and recrystallization from absolute ethanol gave 1.21 g of a white powdery solid (44% yield). 1 H NMR(300MHz,DMSO-d6)δ11.66(s,1H), 8.17-8.05(m,3H), 8.01(d,J=8.4Hz,1H), 7.67-7.55(m,2H), 7.45(q,J=7.7Hz,2H) , 4.91(t,J=6.9Hz,2H), 4.05(d,J=13.6Hz,2H), 3.58(q,J=12.9,11.8Hz,4H), 3.29(d,J=10.3Hz,4H), 2.67-2.33(m,2H); 13 C-NMR (100MHz,DMSO-d6)δ162.65, 152.58, 145.66, 133.28, 128.58, 127.80, 127.43, 125.08, 124.5 3, 124.47, 121.66, 119.64, 111.14, 53.59, 51.09, 46.80, 45.50, 24.17;HR-MS(ESI)m / z:calcd for C 20 H 23 N6S [M+H] +379.1699 found 379.1701.

[0045] Example 5 Preparation of 1-(3-(4-(3-(6-fluorobenzisoxazolyl))piperazin-1-yl)propyl-2H-benzotriazole hydrochloride

[0046] [ka]

[0047] The synthesis was carried out according to the general preparation method, and recrystallization from absolute ethanol gave 165 mg of a white powdery solid (yield 51%). 1 H NMR(400MHz,DMSO-d6)δ11.67(s,1H), 8.09(dd,J=8.9,5.2Hz,1H), 7.94(dd,J=6.6,3.1Hz,2H), 7.59(dd,J=9.1,2.3Hz,1H), 7.46(dd,J=6.6,3.1Hz ,2H), 7.24(td,J=9.1,2.3Hz,1H), 4.92(t,J=6.8Hz,2H), 4.09(d,J=13.5 Hz,2H), 3.61(d,J=12.2Hz,4H), 3.26(t,J=8.2Hz,4H), 2.66-2.54(m,2H); 13 C NMR(100MHz,DMSO-d6)δ165.22, 164.69, 164.55, 162.75, 160.25, 144.23, 126.95, 124.85, 124.74, 118 .33, 112.49, 112.40, 112.16, 98.26, 97.99, 53.89, 53.51, 50.47, 45.11, 24.14;LC-MS(ESI)m / z:381.15 [M+1] + .

[0048] Example 6 Preparation of 1-(4-(4-(3-(6-fluorobenzisoxazolyl))piperazin-1-yl)butyl-2H-benzotriazole hydrochloride

[0049] [ka]

[0050] The synthesis was carried out according to the general preparation method. Recrystallization from absolute ethanol gave 182 mg of a white powdery solid (yield 54%). NMR(400MHz,DMSO-d6)δ11.29(s,1H), 8.09(dd,J=8.9,5.2Hz,1H), 7.93(dd,J= 6.5,3.1Hz,2H), 7.60(dd,J=9.1,2.3Hz,1H), 7.51-7.40(m,2H), 7.24(td,J=9. 1,2.3Hz,1H), 4.82(t,J=6.8Hz,2H), 4.08(d,J=13.2Hz,2H), 3.54(d,J=12.5Hz ,4H), 3.21(t,J=8.2Hz,4H), 2.12(t,J=7.5Hz,2H), 1.79(dd,J=8.0,3.6Hz,2H); 13 C NMR(100MHz,DMSO-d6)δ166.82-162.55(m), 160.28, 144.16, 126.84, 124.85, 124.74, 118.29, 1 12.49, 112.18, 98.29, 98.02, 55.80, 55.35, 50.46, 45.10, 27.06, 20.87;LC-MS(ESI)m / z:395.18 [M+1] + .

[0051] Example 7 In vivo activity study of compounds A001-A006 in a premature ejaculation model

[0052] 7.1 Materials and Methods

[0053] 7.1.1 Compound information

[0054] [Table 1B]

[0055] 7.2 Experimental scheme

[0056] 7.2.1 Animal information

[0057] [Table 1C]

[0058] 7.2.2 Animal adaptation After the animals arrived at the animal facility, they were acclimated to the feeding program for at least one week. During this time, the animals were monitored for their health and for any physiological or behavioral abnormalities, and any animals exhibiting abnormalities were excluded from the study.

[0059] 7.2.3 Rearing environment The animal enclosure was maintained at a temperature of 18-26°C, humidity of 30-70%, and a 12-hour light / 12-hour dark cycle, which was temporarily suspended depending on the research plan.

[0060] 7.2.4 Feed and water The rats' maintenance diet (provided by Jiangsu Xitong Pharmaceutical Bioengineering Co., Ltd.) and reverse osmosis water were available at all times during the study period.

[0061] 7.2.5 Animal selection and fasting The animals used in this study were selected based on their health status and adaptability to cage culture. Animals were not fasted or deprived of water prior to the experiment.

[0062] 7.2.6 Animal Grouping Before the experiment, the animals were weighed and randomly divided into groups according to their weight as follows:

[0063] [Table 1D]

[0064] NOTE: po indicates oral administration, ip indicates intraperitoneal injection, and PCA indicates p-chloramphetamine hydrochloride.

[0065] 7.2.7 Experimental Procedure Male Wistar rats weighing approximately 300 g were acclimated for one week before the experiment. On the day of the experiment, the animals were anesthetized with 20 mg / kg zoletil 50 (ip) and 8 mg / kg xylazine (ip), and body temperature was maintained at 37°C using a heating blanket. The exposed common carotid artery was intubated using a PE50 tube to monitor arterial pressure (systolic, diastolic, and mean arterial pressure) in real time. The seminal vesicles and corpus cavernosum muscle of the animals were then exposed. Stable baseline seminal vesicle pressure and cavernous electromyograms were recorded for 10 minutes. Subsequently, the dapoxetine group received a drug via the tail vein, while the test compound group received an oral dose of the test compound (the drug was replaced with vehicle in the PE model group). One minute later, 5 mg / kg PCA was injected intraperitoneally to induce the PE model, and the seminal vesicle pressure curve and cavernous electromyogram were continuously recorded for 30 minutes.

[0066] Experimental endpoints A. The actual number of ejaculations by the animal within 30 minutes and the latency of the first ejaculation. B. Number of seminal vesicle contractions within 30 minutes, latency of the first contraction, basal pressure and peak pressure.

[0067] 7.2.8 Data analysis Experimental data were expressed as mean ± SEM, and statistical analysis was performed using GraphPad Prism 7.0 software. One-way ANOVA was used for comparisons between multiple groups, and Dunnett's t-test was used for post hoc statistical analysis. Student's t-test was used for comparisons between two groups. P < 0.05 was considered significant.

[0068] 7.3 Results Table 1. List of original data for various premature ejaculation indices in Wistar rats within 30 min after PCA induction

[0069] [Table 1-1]

[0070]

Table 1-2

[0071]

Table 1-3

[0072]

Table 1-4

[0073]

Table 1-5

[0074]

Table 1-6

[0075]

Table 1-7

[0076]

Table 1-8

[0077]

Table 1-9

[0078]

Table 1-10

[0079]

Table 1-11

[0080]

Table 1-12

[0081]

Table 1-13

[0082]

Table 1-14

[0083]

Table 1-15

[0084]

Table 1-16

[0085]

Table 1-17

[0086]

Table 1-18

[0087]

Table 1-19

[0088]

Table 1-20

[0089]

Table 1-21

[0090] In this study, the ejaculation frequency of Wistar rats was basically maintained at approximately 18 times within 30 minutes after PCA induction, and a highly significant decrease in the number of ejaculations was observed in all groups compared with the PE model group (all achieved P<0.05). The average number of ejaculations in 30 minutes was 5 or less (see Figure 1). At a dose of 2 mg / kg, the efficacy of each of compounds A001 to A006 was superior to that of dapoxetine hydrochloride.

[0091] The results of the initial ejaculatory latency period showed a significantly prolonged period in each group compared with the PE model group (see Figure 2). Furthermore, the number of seminal vesicle contractions within 30 minutes after PCA induction was approximately 22.4 in the PE model group, compared with less than six in the other groups, indicating a significantly decreased number of seminal vesicle contractions compared with the PE model group (all P<0.05) (see Figure 3). Furthermore, the initial seminal vesicle contraction latency period was significantly prolonged in the sham group, dapoxetine group, A001 medium-dose group, A001 high-dose group, A002 medium-dose group, and A002 high-dose group compared with the PE model group (P<0.001, P<0.001, P<0.01, P<0.001, respectively). The remaining groups (A001 low-dose group and A002 low-dose group) showed some delay, but the difference was not statistically significant compared to the PE model group (all P>0.05, see Figure 4). Seminal vesicle basal pressure monitoring data showed that all groups were able to effectively reduce PCA-induced seminal vesicle basal pressure (all groups achieved P<0.001, see Figure 5). Similarly, seminal vesicle peak pressure monitoring data showed that all groups were able to highly effectively reduce PCA-induced seminal vesicle peak pressure (all groups achieved P<0.001, see Figure 6). At oral administration of 2 mg / kg, the efficacy of each of compounds A001 to A006 was superior to that of dapoxetine hydrochloride administered by injection at 2 mg / kg.

[0092] 7.4 Conclusion The potential effects of different doses of the test drugs A001-A006 and dapoxetine were monitored in a PCA-induced Wistar rat premature ejaculation model. Statistical analysis of relevant indicators, including ejaculation frequency, initial ejaculation latency, seminal vesicle pressure, and corpus cavernosum muscle contractions, revealed that medium and high doses of dapoxetine and A001-A006 effectively prolonged ejaculation latency, significantly reduced ejaculation frequency, seminal vesicle pressure, and corpus cavernosum muscle contractions. Compared with the efficacy of dapoxetine in treating premature ejaculation, the efficacy of A001-A006 at 2 mg / kg oral administration was superior to that of dapoxetine hydrochloride at 2 mg / kg injection. Considering the bioavailability of dapoxetine hydrochloride (control) at 42%, the compounds of the present invention are significantly superior to dapoxetine hydrochloride.

Claims

1. A 2H-benzotriazole derivative or a pharmaceutically acceptable salt thereof, The derivative has a structure represented by the following formula (I): 【Chemical 1】 In formula (I), X is C ３ -C ４ - alkyl or C ３ -C ４ represents alkoxy, Y represents CH or N; Z represents O or S; A 2H-benzotriazole derivative or a pharmaceutically acceptable salt thereof, wherein R represents any substitution of a hydrogen atom with 1 to 3 halogen atoms selected from the group consisting of fluorine, chlorine, and bromine.

2. 2. The 2H-benzotriazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the 2H-benzotriazole alkyl derivative is any one of the following compounds: A001: 1-(4-(4-benzisoxazolyl)piperazin-1-yl)butyl-2H-benzotriazole, A002: 1-(3-(4-(3-(6-fluorobenzisoxazolyl))piperidin-1-yl)propyl-2H-benzotriazole, A003: 1-(4-(4-(3-(6-fluorobenzisoxazolyl))piperidin-1-yl)butyl-2H-benzotriazole, A004: 1-(3-(4-benzisothiazolyl)piperazin-1-yl)propyl-2H-benzotriazole, A005: 1-(3-(4-(3-(6-fluorobenzisoxazolyl))piperazin-1-yl)propyl-2H-benzotriazole, or A006: 1-(4-(4-(3-(6-fluorobenzisoxazolyl))piperazin-1-yl)butyl-2H-benzotriazole

3. 1. A pharmaceutical composition comprising:

3. A pharmaceutical composition comprising one or more of the 2H-benzotriazole derivatives or pharmaceutically acceptable salts thereof according to claim 1 or 2, and a pharmaceutically acceptable carrier.

4. The dosage form of the pharmaceutical composition is selected from a tablet, a spray, an oral dissolvable film, a powder, a capsule, and an injection; The pharmaceutical composition according to claim 3, wherein the content of the active ingredient in the dosage form is 0.1% to 99.5%.

5. 3. Use of the 2H-benzotriazole derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2 in the manufacture of a medicament for treating and / or preventing premature ejaculation.

6. 5. Use of the pharmaceutical composition according to claim 3 or 4 in the manufacture of a medicament for treating and / or preventing premature ejaculation.

7. A method for preparing the 2H-benzotriazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, comprising: A method for preparing a 2H-benzotriazole derivative or a pharmaceutically acceptable salt thereof, comprising the following synthesis scheme: 【Chemistry 2】

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