Benzisothiazole compounds, pharmaceutical compositions thereof and uses thereof

Abstract

The present invention belongs to the field of pharmaceutical technology and provides a benzisothiazole compound, its pharmaceutical composition and use. Specifically, the present invention relates to a benzisothiazole compound substituted with 2H-benzotriazole having a novel structure represented by formula (I), as well as a pharmaceutical composition containing the compound and its use in the manufacture of a drug for the treatment and / or prevention of premature ejaculation. In vivo activity studies show that the anti-premature ejaculation activity of the compound is significantly stronger than that of the commercially available drug dapoxetine.

Description

[Technical Field]

[0001] The present invention belongs to the field of pharmaceutical technology, and more particularly relates to a benzisothiazole compound, its pharmaceutical composition and its use. [Background technology]

[0002] Premature ejaculation (PE) is one of the most commonly reported male sexual dysfunctions. The prevalence of premature ejaculation among adult men worldwide is 20% to 30%, severely impacting marital and family harmony. In 2014, the International Society for Sexual Medicine (ISSM) proposed the first comprehensive evidence-based definition of primary premature ejaculation. Currently, clinically used medications, primarily dapoxetine and local anesthetics, have paved the way for new approaches to the pharmacological treatment of premature ejaculation. However, these medications have problems such as low efficacy, frequent side effects, and high discontinuation rates. Dapoxetine is currently the only approved medication for premature ejaculation worldwide, but common clinical side effects include nausea, diarrhea, headache, and insomnia. Serious side effects such as fainting have also been reported in rare cases. The discontinuation rate for dapoxetine in clinical trials is very high, and the cumulative discontinuation rate increases over time. Local anesthetics can prolong ejaculation time by reducing the sensitivity of the glans penis, but common side effects include erectile dysfunction and reduced sexual satisfaction.

[0003] Clinicians frequently use 5-HT reuptake inhibitors (SSRIs) off-label, but their clinical use is limited because patients cannot suddenly discontinue the medication and must gradually taper over 2–3 months to prevent SSRI withdrawal syndrome. Patients also have low tolerance for long-term psychotropic medication use. Therefore, research into new drugs for the treatment of premature ejaculation is clinically relevant. Cardiovascular drugs often have diverse clinical uses. For example, sildenafil is used clinically to treat male erectile dysfunction and pulmonary arterial hypertension. Therefore, research into male medications often examines multiple indications for cardiovascular disease. Summary of the Invention

[0004] In response to the above-mentioned problems, the present invention discloses a 2H-benzotriazole-substituted benzisothiazole compound having a novel chemical structure, as well as a pharmaceutical composition containing the compound and its use in the manufacture of a medicament for the treatment or prevention of premature ejaculation.

[0005] The present invention discloses a benzisothiazole compound represented by formula (I) and pharmaceutically acceptable salts thereof. The salts include hydrochloride, hydrobromide, sulfate, trifluoroacetate, methanesulfonate, tartrate, malate, citrate, succinate, etc., and may contain 0.5 to 3 molecules of water of crystallization. JPEG2026504208000002.jpg2267(I)

[0006] The present invention provides a pharmaceutical composition containing the benzisothiazole compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The carrier refers to a carrier commonly used in the pharmaceutical field and may contain a diluent, an excipient such as water, a binder such as a cellulose derivative, gelatin, or polyvinylpyrrolidone, a filler such as starch, a disintegrant such as calcium carbonate or sodium bicarbonate, or a lubricant such as calcium stearate or magnesium stearate. Other adjuvants such as flavoring agents and sweeteners may also be added to the pharmaceutical composition. For oral administration, the pharmaceutical composition may be formulated into a conventional solid formulation such as a tablet, powder, orally disintegrating film, or capsule. For external use, the pharmaceutical composition may be formulated into a spray, rub, or ointment. For injection, the pharmaceutical composition may be formulated into an injectable solution.

[0007] The various dosage forms of the pharmaceutical composition of the present invention are prepared by conventional methods in the art, and the content of the active ingredient therein is 0.1% to 99.5% (by weight).

[0008] Use of the benzisothiazole compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound in the manufacture of a medicament for treating and / or preventing premature ejaculation. [Effects of the Invention]

[0009] The compound of the present invention has a significant anti-premature ejaculation effect and has significant therapeutic features and substantial technological advances compared to dapoxetine, the only drug currently approved and commercially available in clinical practice.

[0010] The compound of the present invention or its pharmaceutically acceptable salt is a novel 2H-benzotriazole-substituted benzisothiazole compound.In vivo activity test shows that the anti-premature ejaculation activity of this compound is significantly stronger than that of the commercially available drug dapoxetine.

[0011] Use of the compound of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing cardiovascular disease. [Brief explanation of the drawings]

[0012] [Figure 1] This is a bar graph showing the total number of ejaculations in Wistar rats within 30 minutes after PCA induction (One-way ANOVA, Dunnett post hoc, ***P<0.001, compared with the PE model group, N=5). [Figure 2] This is a bar graph showing the latency to first ejaculation in 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] This is a bar graph showing the number of seminal vesicle contractions in Wistar rats within 30 minutes after PCA induction (One-way ANOVA, Dunnett post hoc, ***P<0.001, compared with the PE model group, N=5). [Figure 4] This is a bar graph showing the latency of the first seminal vesicle contraction in Wistar rats within 30 minutes 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] 1 is a bar graph showing the basal seminal vesicle pressure of Wistar rats within 30 minutes after PCA induction (One-way ANOVA, Dunnett post hoc, ***P<0.001, compared with the PE model group, N=5). [Figure 6] 1 is a bar graph showing peak seminal vesicle pressure in Wistar rats within 30 minutes after PCA induction (One-way ANOVA, Dunnett post hoc, ***P<0.001, compared with the PE model group, N=5). DETAILED DESCRIPTION OF THE INVENTION

[0013] Reagents and solvents were purchased from Sigma-Aldrich or Fisher Scientific and used without further purification. All reactions were monitored by thin-layer chromatography (silica gel GF-254 thin-layer plates) and LC-MS. Column chromatography purification was performed using 300-400 mesh silica gel (Qingdao Ocean Chemical Co., Ltd.). 1 H and 13 C NMR spectra were measured on a Bruker AV-400 nuclear magnetic resonance spectrometer, with TMS used as the internal standard. The purity of the compound determined by LC-MS analysis was greater than 95%, and MS spectra of the compound were also recorded. A Shimadzu LCMS-2020 was used for LC-MS analysis.

[0014] Example 1 (1) Preparation of Key Intermediate: 1-(4-chlorobutyl)-2H-benzotriazole 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 were placed in a 500 mL single-neck flask and stirred thoroughly until the materials were completely dissolved. The mixture was heated to 60 °C and stirred for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, the mixture was extracted with 240 mL of dichloromethane (3 x 240 mL). After drying over anhydrous sodium sulfate, the solvent was removed by vacuum distillation. The product was purified by silica gel column chromatography to obtain 10.23 g of a pale yellow oily liquid (19.44% yield).

[0015] (2) Preparation of target compound 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 were added to a 50 mL single-neck flask and stirred thoroughly until the raw materials were completely dissolved. 1.8 g of 1-(4-chlorobutyl)-2H-benzotriazole was added, and the mixture was heated to 81°C and refluxed for 18 hours. After confirming the completion of the reaction by TLC, the reaction mixture was cooled to room temperature and suction filtered. The filtrate was distilled under reduced pressure to remove the solvent, yielding a yellow oil. This was washed with saturated brine, extracted with dichloromethane, and the solvent was distilled under reduced pressure to obtain an oil. The oil was dissolved in absolute ethanol, adjusted to pH 1 with the addition of hydrochloric acid in ethanol, and stirred at room temperature for 1 hour. A solid precipitated and was filtered. The filter cake was recrystallized from absolute ethanol to obtain the final product, designated A001.

[0016] Recrystallization from absolute ethanol gave 1.64 g of a white powdery solid (yield 49%). 1 H NMR (400 MHz, DMSO-d6δ 10.62 (s, 1H), 8.12 (dd, J = 11.4, 8.2 Hz,2H), 7.94 (dd, J = 6.6, 3.1 Hz,2H), 7.63 - 7.54 (m, 1H), 7.50 - 7.37 (m, 3H), 4.84 (t, J = 6.8 Hz,2H), 4.06 (d, J = 13.6 Hz,2H), 3.57 (d, J = 12.0 Hz,2H), 3.50 - 3.39 (m,2H), 3.32 - 3.19 (m, 4H), 2.19 - 2.06 (m,2H), 1.77 (tt, J = 6.6, 2.5 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 162.11, 152.06, 143.63, 128.09, 126.89, 126.31, 124.58, 123.96, 121.14, 117.75, 55.27, 54.86, 50.57, 46.36, 26.50, 20.43. LC-MS (ESI) m / z: 393.15 [M+1] +.

[0017] Example 2 In vivo activity study of compound A001 in a premature ejaculation model 2.1 Materials and Methods 2.1.1 Compound information JPEG2026504208000004.jpg35158

[0018] 2.2 Experimental design 2.2.1 Animal information JPEG2026504208000005.jpg61147

[0019] 2.2.2 Animal Acclimatization After arrival at the animal facility, animals were allowed to acclimate for at least one week. During this period, animals were monitored for health and physiological or behavioral abnormalities, and any animals exhibiting abnormalities were excluded from the study.

[0020] 2.2.3 Rearing environment The animal room environment was controlled at a temperature of 18–26°C and humidity of 30–70%, and a 12-hour light / 12-hour dark cycle was maintained. The 12-hour dark period could be temporarily interrupted to accommodate research protocols.

[0021] 2.2.4 Feed and water Rat maintenance diet (provided by Jiangsu Cooperative Pharmaceutical and Bioengineering Co., Ltd.) and reverse osmosis water were available at all times throughout the study period.

[0022] 2.2.5 Animal selection and fasting The animals used in this study were selected based on their health and ability to adapt to caged conditions. Animals were not fasted or deprived of water before the experiment.

[0023] 2.2.6 Animal Grouping Before the experiment, the animals were weighed and randomly assigned to groups based on their weight, as detailed below. JPEG2026504208000006.jpg99155Note: po indicates oral administration; ip indicates intraperitoneal injection; PCA indicates parachloroamphetamine hydrochloride.

[0024] 2.2.7 Experimental Procedure: Male Wistar rats weighing approximately 300 g were anesthetized for one week after acclimation. On the day of the experiment, animals were anesthetized with a combination of Zoletil 50 20 mg / kg ip and xylazine 8 mg / kg ip, and body temperature was maintained at 37°C using a heating blanket. The common carotid artery was exposed and cannulated with PE50 tubing to monitor real-time arterial pressure (systolic, diastolic, and mean arterial pressure). The seminal vesicles and corpus cavernosum muscles of the animals were then exposed. Seminal vesicle pressure and stable baseline corpus cavernosum electromyograms were recorded for 10 minutes. The dapoxetine group received drug administration via the tail vein, while the test compound group received oral administration of the test compound (vehicle was substituted for the PE model group). One minute later, PCA 5 mg / kg was injected intraperitoneally to create the PE model. Subsequently, seminal vesicle pressure graphs and bulbocavernosus muscle EMG changes were recorded for 30 minutes.

[0025] Experimental Endpoints: A. The actual number of ejaculations and first ejaculation latency of the animal within 30 minutes B. Number of seminal vesicle contractions, first contraction latency, basal pressure, and peak pressure within 30 minutes

[0026] 2.2.8 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 tests. Student's t-test was used for comparisons between two groups. P < 0.05 was considered significant.

[0027] 2.3 Results Table 1. Raw data table of various premature ejaculation indices in Wistar rats within 30 minutes after PCA induction JPEG2026504208000007.jpg227162JPEG2026504208000008.jpg86162

[0028] In this study, the number of ejaculations in Wistar rats within 30 minutes after PCA induction was maintained at approximately 18, and the number of ejaculations was significantly reduced in all dose groups compared to the PE model group (all P<0.05). The low, medium, and high dose groups were all superior to dapoxetine (Fig. 1).

[0029] The results of the first ejaculation latency showed that all groups had significantly prolonged first ejaculation latency compared with the PE model group (P<0.05, P<0.01, P<0.001, respectively) (Fig. 2). Furthermore, within 30 minutes after PCA induction, the number of seminal vesicle contractions in the PE model group was approximately 22.4, whereas the number of seminal vesicle contractions in all treatment groups was 6 or less, a significantly reduced number compared with the PE model group (all P<0.05) (Fig. 3). At a dose of 2 mg / kg, zaprole was superior to dapoxetine.

[0030] At the same time, when the latency to the first seminal vesicle contraction was observed in the rats, the sham group, dapoxetine group, medium-dose group, and high-dose group all had significantly increased latency compared to the PE model group (P<0.01, P<0.001, respectively) (Fig. 4). Furthermore, monitoring data for seminal vesicle basal pressure showed that all treatment groups effectively inhibited the PCA-induced increase in seminal vesicle basal pressure (all P<0.001) (Fig. 5). Similarly, monitoring data for seminal vesicle peak pressure showed that all treatment groups effectively inhibited the PCA-induced increase in seminal vesicle peak pressure (all P<0.001) (Fig. 6).

[0031] 2.4 Conclusion The potential effects of different doses of the test drug and dapoxetine were monitored using a Wistar rat premature ejaculation model using PCA. Statistical analysis of relevant indicators, such as the rats' ejaculation frequency, first ejaculation latency, seminal vesicle pressure, and corpus cavernosum muscle contractions, revealed that both dapoxetine and this compound effectively prolonged ejaculation latency and significantly reduced ejaculation frequency, seminal vesicle pressure, and corpus cavernosum muscle contractions. Compared with the efficacy of dapoxetine in treating PE, oral administration of this compound at a dose of 2 mg / kg was superior to intravenous administration of 2 mg / kg of dapoxetine hydrochloride. Given the bioavailability of dapoxetine (42%), the anti-premature ejaculation activity of this compound at the same dose was significantly superior to that of dapoxetine.

Claims

1. A benzisothiazole compound or a pharmaceutically acceptable salt thereof, characterized in that it has a structure represented by formula (I): (I)

2. A pharmaceutical composition comprising the benzisothiazole compound or a pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable carrier.

3. The pharmaceutical composition according to claim 2, characterized in that when used for oral administration, the dosage form is selected from tablets, orally disintegrating films, powders, and capsules; when used for external administration, the dosage form is prepared into sprays, rubs, and ointments; and when used for injection, the dosage form is prepared into an injection solution.

4. 3. The pharmaceutical composition according to claim 2, wherein the content of the active ingredient in each dosage form of the pharmaceutical composition is 0.1% to 99.5%.

5. 10. The benzisothiazole compound or a pharmaceutically acceptable salt thereof according to claim 1 for the treatment and / or prevention of premature ejaculation.

6. The pharmaceutical composition according to claim 2 for the treatment and / or prevention of cardiovascular diseases.

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