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WO2024060911A1 - 苯并异噻唑化合物及其药物组合物和应用 - Google Patents

苯并异噻唑化合物及其药物组合物和应用 Download PDF

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Publication number
WO2024060911A1
WO2024060911A1 PCT/CN2023/114338 CN2023114338W WO2024060911A1 WO 2024060911 A1 WO2024060911 A1 WO 2024060911A1 CN 2023114338 W CN2023114338 W CN 2023114338W WO 2024060911 A1 WO2024060911 A1 WO 2024060911A1
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compound
pharmaceutical composition
premature ejaculation
pharmaceutically acceptable
dapoxetine
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French (fr)
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王朋
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Picomole New Drugs Liaoning Co Ltd
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Picomole New Drugs Liaoning Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence

Definitions

  • the invention belongs to the field of medical technology, and specifically relates to a benzisothiazole compound and its pharmaceutical composition and application.
  • Premature ejaculation is one of the most commonly reported male sexual dysfunctions.
  • the global incidence rate of premature ejaculation in adult men is 20% to 30%, which seriously affects the relationship between husband and wife and family harmony.
  • the International Society for Sexual Medicine (ISSM) proposed the first comprehensive, evidence-based definition of primary premature ejaculation.
  • the drugs currently used in clinical applications are mainly dapoxetine, local anesthetics, etc., which have opened up a new path for the drug treatment of premature ejaculation.
  • these drugs have problems such as poor efficacy, many adverse reactions, and high discontinuation rates.
  • Dapoxetine is currently the only drug on the market for the treatment of premature ejaculation in the world.
  • Dapoxetine has a high clinical discontinuation rate, and the cumulative discontinuation rate increases over time.
  • Local anesthetics can delay ejaculation by reducing the sensitivity of the glans penis, but common side effects include impotence and poor sexual satisfaction.
  • SSRIs 5-HT reuptake inhibitors
  • the present invention discloses a novel 2H-benzotriazole substituted benzisothiazole compound, a pharmaceutical composition comprising the compound and the use of the compound in preparing a drug for treating or preventing premature ejaculation.
  • the invention discloses benzisothiazole compounds represented by formula (I) and pharmaceutically acceptable salts thereof.
  • the salts include hydrochloride, hydrobromide, sulfate, trifluoroacetate, methanesulfonate Acid, tartrate, malate, citrate, succinate, etc., their salts can contain 0.5-3 molecules of crystal water:
  • a pharmaceutical composition comprising the benzisothiazole compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier;
  • the carrier refers to a conventional carrier in the pharmaceutical field, including: diluent , excipients such as water; binders such as cellulose derivatives, gelatin, polyvinylpyrrolidone; fillers such as starch; disintegrating agents such as calcium carbonate, sodium bicarbonate; lubricants such as calcium stearate or magnesium stearate.
  • other auxiliary agents such as flavoring agents can also be added to the pharmaceutical composition. and sweeteners.
  • the pharmaceutical composition when used for oral administration, it can be prepared into conventional solid preparations such as tablets, powders, orally dissolvable films or capsules; when used for external use, it can be prepared into sprays, liniments, and ointments; When used for injection, it can be prepared into an injection solution.
  • compositions of the present invention are prepared according to conventional methods in the art, and the content of the active ingredients is 0.1% to 99.5% (weight ratio).
  • benzisothiazole compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound in the preparation of a medicament for treating and/or preventing premature ejaculation.
  • the compound of the present invention has a significant anti-premature ejaculation effect. Compared with dapoxetine, the only clinically approved drug currently on the market, the product has significant therapeutic characteristics and substantial technical progress.
  • the compound of the present invention or its pharmaceutically acceptable salt is a type of 2H-benzotriazole-substituted benzisothiazole compound with a completely new structure. According to in vivo activity tests, the anti-premature ejaculation activity of this compound is significantly stronger than that of the drug dapoxetine on the market.
  • Reagents and solvents were purchased from Sigma-Aldrich or Fisher Scientific and used without further purification. All reactions were analyzed by thin layer chromatography (silica gel GF-254 thin layer plates) and monitored by LC-MS. Column chromatography purification used 300-400 mesh silica gel (Qingdao Ocean Chemical Co., Ltd.). 1 H and 13 C NMR spectra were recorded on a Bruker AV-400 nuclear magnetic resonance instrument, with TMS as the internal standard. The purity of the compound was determined to be greater than 95% by LC-MS analysis and was simultaneously used to record the MS spectrum of the compound. LC-MS analysis was performed using Shimadzu LCMS-2020.
  • Animals are acclimated to feeding for at least one week after arrival at the animal facility. During this period, the health of the animals and any physiological and behavioral abnormalities were monitored, and all animals with abnormalities were removed from the study.
  • the environment of the animal room is controlled at a temperature of 18-26°C, a humidity of 30-70%, and a 12h light/12h dark cycle.
  • the 12h dark cycle may be temporarily interrupted to accommodate research protocols.
  • Rat maintenance feed (provided by Jiangsu Synergy Pharmaceutical Bioengineering Co., Ltd.) and reverse osmosis water were readily available during the study.
  • the animals used in this study were selected based on their health status and adaptability to cage housing. Before the experiment, the animals were deprived of food and water.
  • mice were weighed and randomly divided into groups according to their weight, as follows: Note: po means oral administration; ip means intraperitoneal injection; PCA means parachloramphetamine hydrochloride.
  • mice Male Wistar rats, weighing about 300g, started the experiment after one week of adaptation. On the day of the experiment, animals were anesthetized with Serta 50 20 mg/kg i.p. combined with thioperazine 8 mg/kg i.p., and a thermal blanket was used to maintain the body temperature at 37°C.
  • the common carotid artery was exposed and cannulated with a PE50 to monitor real-time arterial pressure (systolic, diastolic, and mean arterial pressure). Expose the animal's seminal vesicles and cavernous muscles. The pressure of the seminal vesicles and the stable baseline of cavernosal electromyography were recorded for 10 min.
  • the dapoxetine group was given the drug through the tail vein, and the test compound group was given the test compound orally (the PE model group was replaced by vehicle).
  • PCA 5mg/kg was injected intraperitoneally when inducing PE modeling 1 min later, and the seminal vesicle pressure map and bulbospongiosum were continued to be recorded. Muscle EMG changes for 30 minutes.
  • Table 1 Original data table of various premature ejaculation indicators in Wistar rats within 30 minutes after PCA induction
  • the first ejaculation latency time was extremely significantly longer than that of the PE model group (P ⁇ 0.05, P ⁇ 0.01, P ⁇ 0.001 respectively) ( Figure 2).
  • the number of contractions of the seminal vesicles of the rats in the PE model group was approximately 22.4 times, and the number of contractions of the seminal vesicles was less than 6 times. All groups showed an extremely high number of contractions of the seminal vesicles compared with the PE model group. Significant decreases (all P ⁇ 0.05) ( Figure 3) were superior to dapoxetine at the dose of 2 mg/kg.
  • the Wistar rat premature ejaculation model was induced by PCA to monitor the potential effects of the patented test drug and dapoxetine at different doses.
  • Statistical analysis of related indicators such as the number of ejaculation times, first ejaculation latency, seminal vesicle pressure, and cavernous muscle contraction in rats revealed that both dapoxetine and this compound can effectively prolong the ejaculation latency, significantly reduce the number of ejaculations, seminal vesicle pressure, and The number of cavernous muscle contractions.
  • the oral dose of 2 mg/kg of this compound is better than the intravenous dose of dapoxetine hydrochloride at 2 mg/kg.
  • the anti-premature ejaculation activity of this compound is significantly better than that of dapoxetine.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Gynecology & Obstetrics (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

苯并异噻唑化合物及其药物组合物和应用，属于医药技术领域，具体涉及一种式(I)所示的新型结构2H-苯并三氮唑取代的苯并异噻唑化合物，以及包含该化合物的药物组合物和其在制备治疗和/或预防早泄药物中的应用。经体内活性试验研究，该化合物的抗早泄活性明显强于在售药物达泊西汀。

Description

苯并异噻唑化合物及其药物组合物和应用 技术领域
本发明属于医药技术领域，具体涉及一种苯并异噻唑化合物及其药物组合物和应用。
背景技术
早泄(Premature ejaculation，早泄)是最常报告的男性性功能障碍之一，全球成年男性早泄发病率为20％～30％，严重影响夫妻感情和家庭和谐。2014年，国际性医学会(The International Society for Sexual Medicine,ISSM)提出了第一个基于证据的原发性早泄的全面定义。目前临床应用的药物主要为达泊西汀、局部麻醉药等，已为早泄的药物治疗开辟了新的道路。但是这些药物存在疗效差、不良反应多、停药率高等问题。达泊西汀是目前全球唯一上市治疗早泄的药物，临床常见不良反应包括恶心、腹泻、头痛、失眠等，也有极低的严重不良反应，如晕厥。达泊西汀临床停药率很高，累积停用率随时间增加。局部麻醉药可通过降低阴茎头的敏感性延迟射精时间，但常见不良反应是可引起阳痿，性满意度较差。
临床医生经常超适应症的使用5-HT再摄取抑制剂(SSRIs)药物，但患者不能突然停药，需在2～3月内逐渐减量，防止SSRIs停药综合征，因此临床使用受限，依从性很低。长期应用精神类药物，患者本身接受性较差。因此研究新的治疗早泄药具有临床意义。
发明内容
针对上述问题，本发明公开一种新型结构2H-苯并三氮唑取代的苯并异噻唑化合物，以及包含该化合物的药物组合物和其在制备治疗或预防早泄药物中的应用。
本发明公开的式(I)所示的苯并异噻唑化合物及其药学上可接受的盐，所述的盐包括盐酸盐、溴氢酸盐、硫酸盐、三氟醋酸盐、甲磺酸盐、酒石酸盐、苹果酸盐、枸橼酸盐、琥珀酸盐等，其盐可含有0.5-3分子的结晶水：
一种药物组合物，包含所述的苯并异噻唑化合物或其在药学上可接受的盐，以及药学上可接受的载体；所述及的载体是指药学领域常规的载体，包括：稀释剂、赋形剂如水；粘合剂如纤维素衍生物、明胶、聚乙烯吡咯烷酮；填充剂如淀粉；崩裂剂如碳酸钙、碳酸氢钠；润滑剂如硬脂酸钙或硬脂酸镁。另外，还可以在所述药物组合物中加入其他辅助剂如香味剂 和甜味剂。所述药物组合物在用于口服时，可将其制备成常规的固体制剂如片剂、粉剂、口溶膜剂或胶囊；用于外用时，将其制备成喷雾剂、擦剂、膏剂；用于注射时，可将其制备成注射液。
本发明所述的药物组合物的各种剂型依据本领域常规的方法进行制备，其中活性成分的含量为0.1％～99.5％(重量比)。
本发明所述的苯并异噻唑化合物，或其药学上可接受的盐，或包含所述化合物的药物组合物在制备治疗和/或预防早泄的药物中的应用。
本发明的有益效果：
本发明所述化合物具有显著的抗早泄作用，本品与临床现有唯一批准上市药物达泊西汀相比，具有显著的治疗特点和实质性的技术进步。
本发明所述化合物或其药学上可接受的盐，为一类全新结构的2H-苯并三氮唑取代的苯并异噻唑化合物。经体内活性试验研究，该化合物的抗早泄活性明显强于在售药物达泊西汀。
附图说明
图1：PCA诱导后30min内Wistar大鼠射精总次数柱状图，One-way ANOVA，Dunnett post hoc，***P<0.001，与PE model组比较，N＝5。
图2：PCA诱导后30min内Wistar大鼠初次射精潜伏期柱状图，One-way ANOVA，Dunnett post hoc，*P<0.05，**P<0.01，***P<0.001，与PE model组比较，N＝5。
图3：PCA诱导后30min内Wistar大鼠储精囊收缩次数柱状图，One-way ANOVA，Dunnett post hoc，***P<0.001，与PE model组比较，N＝5。
图4：PCA诱导后30min内Wistar大鼠初次储精囊收缩潜伏期柱状图，One-way ANOVA，Dunnett post hoc，**P<0.01，***P<0.001，与PE model组比较，N＝5。
图5：PCA诱导后30min内Wistar大鼠储精囊基础压力柱状图，One-way ANOVA，Dunnett post hoc，***P<0.001，与PE model组比较，N＝5。
图6：PCA诱导后30min内Wistar大鼠储精囊压力峰值柱状图，One-way ANOVA，Dunnett post hoc，***P<0.001，与PE model组比较，N＝5。
具体实施方式
试剂和溶剂购自Sigma-Aldrich或Fisher Scientific，无需进一步纯化即可使用。所有反应进行薄层色谱分析(硅胶GF-254薄层板)和LC-MS监测。柱层析纯化使用300-400目硅胶(青岛海洋化工有限公司)。1H和13C NMR光谱记录在Bruker AV-400核磁共振仪测定，以TMS作为内标。通过LC-MS分析确定的化合物纯度大于95％，并同时用于记录化合物的MS光谱。LC-MS分析使用Shimadzu LCMS-2020。
实施例1
(1)关键中间体：1-(4-氯丁基)-2H-苯并三氮唑的制备
苯并三氮唑30.0g(251mmol)、1-溴-4-氯丁烷39.3g(229mmol)、四丁基溴化铵1.85g(6mmol)、氢氧化钠水溶液240g(20％)置于500mL单口瓶中，充分搅拌至物料完全溶解。升温至60℃，搅拌反应2h，TLC监控反应进程。反应完毕后，二氯甲烷240mL×3萃取，无水硫酸钠干燥后减压蒸馏除去溶剂，经硅胶层析柱分离纯化得淡黄色油状液体10.23g(产率19.44％)。
(2)目标化合物的制备
将3-(1-哌嗪基)-1，2-苯并异噻唑1.88g，三乙胺(3.3g)、碘化钾(1.4g)、乙腈15mL加入到50mL单口瓶中，充分搅拌至原料完全溶解。加入1-(4-氯丁基)-2H-苯并三氮唑(1.8g)并升温至81℃回流反应18h。经TLC检测反应结束后，将反应液冷却至室温，抽滤，滤液经减压蒸馏除去溶剂得到黄色油状物。饱和食盐水洗涤，二氯甲烷萃取，减压蒸馏除去溶剂得到油状物，油状物用无水乙醇溶解，加盐酸乙醇溶液调节pH＝1，滴毕，室温搅拌1h，析出固体，过滤。滤饼经无水乙醇重结晶得到终产物，记为A001。
经无水乙醇重结晶，得到1.64g白色粉末状固体(产率49％)。1H NMR(400MHz,DMSO-d6)δ10.62(s,1H),8.12(dd,J＝11.4,8.2Hz,2H),7.94(dd,J＝6.6,3.1Hz,2H),7.63–7.54(m,1H),7.50–7.37(m,3H),4.84(t,J＝6.8Hz,2H),4.06(d,J＝13.6Hz,2H),3.57(d,J＝12.0Hz,2H),3.50–3.39(m,2H),3.32–3.19(m,4H),2.19–2.06(m,2H),1.77(tt,J＝6.6,2.5Hz,2H).13C NMR(100MHz,DMSO-d6)δ162.11,152.06,143.63,128.09,126.89,126.31,124.58,123.96,121.14,117.75,55.27,54.86,50.57,46.36,26.50,20.43.LC-MS(ESI)m/z:393.15[M+1]+。
实施例2
化合物A001对早泄模型的体内活性研究
2.1材料与方法
2.1.1化合物信息
2.2实验方案
2.2.1动物信息
2.2.2动物适应
动物到达动物设施后，至少适应性喂养一周。在此期间，对动物健康和是否有任何生理、行为异常进行监测，并将所有出现异常的动物从研究中移除。
2.2.3饲养环境
动物房的环境控制在温度18-26℃，湿度30-70％，并给予12h光照/12h黑暗循环。12h的黑暗周期可能会被暂时中断，以适应研究方案。
2.2.4食物和水
大鼠维持饲料(由江苏省协同医药生物工程有限责任公司提供)以及反渗透水在研究过程中都是随时可用的。
2.2.5动物选择和禁食
本研究中使用的动物是根据动物的健康状况和对笼养的适应能力选择的。实验前，动物不禁食不禁水。
2.2.6动物分组
实验前对动物称取体重，并根据体重进行随机分组，具体如下：


注：p.o.表示口服；i.p.表示腹腔注射；PCA表示对氯苯丙胺盐酸盐。
2.2.7实验步骤：
雄性Wistar大鼠，体重300g左右，适应一周后开始实验。实验当天，使用舒泰50 20mg/kg i.p.联合噻拉嗪8mg/kg i.p.麻醉动物后，用保温毯维持体温37℃。暴露颈总动脉用PE50插管以监测实时动脉压力(收缩压、舒张压以及平均动脉压)。暴露动物储精囊及海绵体肌。记录储精囊的压力和海绵体肌电稳定基线10min。达泊西汀组尾静脉给予药物，待测化合物组口服给予待测化合物(PE model组用溶媒代替)，1min后诱导PE造模时腹腔注射PCA5mg/kg，继续记录精囊压力图和球海绵体肌EMG变化30min。
实验终点：
A.30min内，动物实际射精次数及第一次射精潜伏期
B.30min内，储精囊收缩的次数，第一次收缩潜伏期，基础压力及峰值压力
2.2.8数据分析
实验数据采用mean±S.E.M.表示，GraphPad Prism 7.0软件进行统计分析。多组间比较采用单因素方差分析(One-way ANOVA)，Post hoc test采用Dunnett’t-test进行统计分析；两组间比较采用Student's t-test进行统计分析。P＜0.05为具有显著性差异。
2.3结果
表1 PCA诱导后30min内Wistar大鼠各项早泄指标原始数据表

从本研究中得出，Wistar大鼠在PCA诱导后30min内射精次数基本维持约18次，所有剂量组别均较PE model组在射精次数上呈现极为显著的下降(均P<0.05)。低、中、高剂量均优于达泊西汀。(图1)
从初次射精潜伏期结果可得，均较PE model组在初次射精潜伏期时间上呈现极为显著的延长(分别P<0.05,P<0.01,P<0.001)(图2)。此外，PCA诱导后30min内，PE model组大鼠的储精囊收缩次数约为22.4次，储精囊的收缩次数均在6次以下，所有组别均较PE model组在储精囊收缩次数上呈现极为显著的下降(均P<0.05)(图3)2mg/kg剂量下优于达泊西汀。
同时，观察大鼠储精囊初次收缩潜伏期可得，Sham组、达泊西汀组、中剂量组、高剂量组均在初次储精囊收缩潜伏期上较PE model组存在显著的上升(分别P<0.01，P<0.001)(图4)。并且，根据储精囊基础压力监测的数据表明，所有组别均能有效降低PCA诱导后引起 的基础储精囊压力(均P<0.001)(图5)。相似的是，储精囊峰值压力监测的数据表明，所有组别均能极为有效降低PCA诱导后引起的峰值储精囊压力(均P<0.001)(图6)。
2.4结论
通过PCA诱导Wistar大鼠早泄模型，监测不同剂量下的本专利受试药物和达泊西汀的潜在效果。从大鼠射精次数、初次射精潜伏期、储精囊压力、海绵体肌肉收缩等相关指标统计分析，揭示达泊西汀和本化合物均能够有效延长射精潜伏期，并且大幅减少射精次数、降低储精囊压力和海绵体肌肉收缩次数。与达泊西汀治疗PE的药效相比，本化合物口服2mg/kg剂量优于盐酸达泊西汀静脉注射剂量2mg/kg。参照达泊西汀生物利用度42％，在相同剂量下，本化合物抗早泄活性显著优于达泊西汀。

Claims (6)

  1. 一种苯并异噻唑化合物或其药学上可接受的盐，其特征在于，所述化合物结构式如下：
  2. 一种药物组合物，其特征在于，包含权利要求1所述的苯并异噻唑化合物或其在药学上可接受的盐，以及药学上可接受的载体。
  3. 根据权利要求2所述的药物组合物，其特征在于，在用于口服时，制剂选自片剂、口溶膜剂、粉剂、胶囊；用于外用时，将其制备成喷雾剂、擦剂、膏剂；用于注射时，将其制备成注射液。
  4. 根据权利要求2所述的药物组合物，其特征在于，所述的药物组合物的各种剂型中活性成分的含量为0.1％～99.5％。
  5. 权利要求1所述的苯并异噻唑化合物或其药学上可接受的盐在制备治疗和/或预防早泄的药物中的应用。
  6. 权利要求2所述的药物组合物在制备治疗和/或预防早泄的药物中的应用。
PCT/CN2023/114338 2022-09-19 2023-08-23 苯并异噻唑化合物及其药物组合物和应用 Ceased WO2024060911A1 (zh)

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CN115304590B (zh) * 2022-09-19 2024-05-28 皮摩尔新药(辽宁)有限公司 2h-苯并三氮唑衍生物及其制备方法及含有它们的药物组合物

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