WO2024060912A1 - 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 - Google Patents

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 Download PDF

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WO2024060912A1
WO2024060912A1 PCT/CN2023/114340 CN2023114340W WO2024060912A1 WO 2024060912 A1 WO2024060912 A1 WO 2024060912A1 CN 2023114340 W CN2023114340 W CN 2023114340W WO 2024060912 A1 WO2024060912 A1 WO 2024060912A1
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benzotriazole
benzotriazole derivative
preparation
pharmaceutical composition
pharmaceutically acceptable
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French (fr)
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王朋
赵余庆
周延
张丽荣
周杰
周欣
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原研药港生命科学研究(辽宁)有限公司
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Publication of WO2024060912A1 publication Critical patent/WO2024060912A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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

Definitions

  • the invention belongs to the field of medical technology, and specifically relates to a new 2H-benzotriazole derivative, its preparation method and pharmaceutical compositions containing them.
  • 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 starting from the first sexual intercourse, ejaculation often or always occurs within about 1 minute before or after vaginal insertion (primary premature ejaculation); or intra-vaginal ejaculation latency (Intra-vaginal ejaculation).
  • Ejaculation latency time (IELT) is significantly shortened, usually less than 3 minutes (secondary premature ejaculation); always or almost unable to control and delay ejaculation; negative physical and mental effects, such as distress, worry, depression, avoidance of sexual contact, etc.
  • the causes of premature ejaculation are complex, including central serotonin and dopamine system neurotransmitter disorders, excessive sensitivity of the glans penis, genetic variation, stress and/or anxiety and other mental and psychological factors, erectile dysfunction, chronic prostatitis, thyroid disease, and drug factors. wait.
  • Premature ejaculation is a psychosomatic disease. According to the holistic concept of traditional Chinese medicine, the disease is a local symptom of an overall disorder.
  • the new goal of premature ejaculation treatment is to harmonize the mind and body, and treat the whole and the parts at the same time.
  • the purpose of treatment is to improve the patient's ejaculation control, improve the couple's sexual life satisfaction, and prolong ejaculation time.
  • doctors should discuss treatment expectations with patients and their partners, and jointly develop treatment goals and treatment plans with patients and partners.
  • Dapoxetine hydrochloride is a selective serotonin reuptake inhibitor. It is the only drug marketed as a treatment for premature ejaculation in the world. It has been approved for premature ejaculation in more than 50 countries or regions around the world, including the European Union and China. of on-demand treatment. Studies have shown that taking dapoxetine hydrochloride 30 mg or 60 mg 1 to 2 hours before sexual intercourse is more effective than placebo, increasing IELT by 2.5 times and 3.0 times respectively, improving ejaculation control, reducing patient pain, and improving sexual life satisfaction. Spend.
  • the drug has similar efficacy in primary premature ejaculation and secondary premature ejaculation, with treatment-related side effects that are dose-dependent and include nausea, diarrhea, headache and dizziness.
  • the recommended initial dose of dapoxetine hydrochloride treatment is 30 mg. Generally, if the effect is not good after 6 uses within 4 weeks, the dose can be increased to 60 mg. However, the clinical discontinuation rate is very high. The cumulative discontinuation rate increases over time and reaches more than 90% 2 years after starting treatment. The reasons for discontinuation include high cost (29.9%), disappointment that premature ejaculation cannot be cured, and lack of medication. (25.0%), etc.
  • dapoxetine The poor bioavailability of dapoxetine is an important reason for the poor efficacy of dapoxetine and low patient satisfaction, which leads to a high rate of clinical discontinuation. Therefore, it is of clinical significance to study new drugs for treating premature ejaculation.
  • the primary purpose of the present invention is to disclose a 2H-benzotriazole derivative with medicinal value and a preparation method thereof, as well as a pharmaceutical composition containing the derivative.
  • a secondary purpose of the present invention is to disclose the use of the 2H-benzotriazole derivatives and pharmaceutical compositions containing the derivatives in the preparation of drugs for the treatment and/or prevention of premature ejaculation.
  • the 2H-benzotriazole derivative disclosed in the present invention is a compound represented by formula (I) or a pharmaceutically acceptable salt of the compound.
  • the salts include hydrochloride, hydrobromide, sulfate, Trifluoroacetate, methanesulfonate, tartrate, malate, citrate, succinate, the salts thereof may contain 0.5-3 molecules of crystal water:
  • X represents: C 3 -C 4 alkyl group or C 3 -C 4 alkoxy group
  • Y represents: CH or N
  • Z stands for: O or S
  • R represents: the hydrogen atom may be optionally replaced by 1 to 3 halogen atoms, and the halogen element is selected from fluorine, chlorine and bromine.
  • the 2H-benzotriazole derivative is any one of the following compounds:
  • A002 1-(3-(4-(3-(6-fluorobenzisoxazolyl))piperidin-1-yl)propyl-2H-benzotriazole
  • A005 1-(3-(4-(3-(6-fluorobenzisoxazolyl))piperazin-1-yl)propyl-2H-benzotriazole
  • X, Y, Z and R are defined as above.
  • substituted 1H-benzotriazole is used as raw material, and a substitution reaction is carried out with 1-bromo-4-chlorobutane in an aqueous sodium hydroxide solution to prepare 1-(4-chlorobutyl)- 1H-benzotriazole (yield about 70%) and 1-(4-chlorobutyl)-2H-benzotriazole (yield about 30%) were purified by silica gel column chromatography to obtain 1-( 4-Chlorobutyl)-2H-substituted benzene triazole (purity >95%); then perform a condensation reaction with benzisoxazole-piperazine to prepare compound A001, and finally undergo acidification to form a salt to prepare the corresponding salt.
  • Compounds A002 to A006 and their salts can be prepared using the above method.
  • a pharmaceutical composition comprising any one or more of the 2H-benzotriazole derivatives, or a pharmaceutically acceptable salt of the derivative and a pharmaceutically acceptable carrier.
  • the carrier refers to a conventional carrier in the pharmaceutical field, including diluents and excipients such as water; binders such as cellulose derivatives, gelatin, and polyvinylpyrrolidone; fillers such as starch; disintegrating agents such as calcium carbonate and sodium bicarbonate; Lubricant such as calcium stearate or magnesium stearate.
  • other adjuvants such as flavoring agents and sweetening agents can also be added to the pharmaceutical compositions.
  • 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).
  • the 2H-benzotriazole derivative of the present invention has significant anti-premature ejaculation effect, and has significant therapeutic characteristics and substantial technological progress compared with dapoxetine, the only clinically approved drug currently on the market. Its treatment features and advantages are as follows:
  • the 2H-benzotriazole derivative or its pharmaceutically acceptable salt according to the present invention is a type of 2H-benzotriazole derivative with a completely new structure. According to in vivo activity tests, the anti-premature ejaculation activity of this type of compound is significantly stronger than that of the drug dapoxetine on the market.
  • the 2H-benzotriazole derivative of the present invention or its pharmaceutically acceptable salt has broad research and application prospects as a drug for treating premature ejaculation.
  • 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 animal room environment is controlled at a temperature of 18-26°C, a humidity of 30-70%, and a 12-h light/12-h dark cycle.
  • the 12-h dark cycle may be temporarily interrupted to accommodate the research protocol.
  • Rat maintenance feed (provided by Jiangsu Collaborative 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 not deprived of food or water.
  • mice were weighed before the experiment and randomly divided into groups according to their body weight, as follows: Note: po means oral administration; ip means intraperitoneal injection; PCA means parachloroamphetamine hydrochloride.
  • 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 minute later, and the seminal vesicle pressure map and bulbosponge were continued to be recorded. Body muscle EMG changes for 30 minutes.
  • the experimental data were expressed as mean ⁇ S.E.M., and statistical analysis was performed using GraphPad Prism 7.0 software. One-way ANOVA was used for comparison among multiple groups, and Dunnett’s t-test was used for post hoc test; Student’s t-test was used for comparison between two groups. P ⁇ 0.05 was considered to be significantly different.
  • Table 1 Original data table of various premature ejaculation indicators in Wistar rats within 30 minutes after PCA induction
  • each group showed a very significant extension in the first ejaculation latency time compared with the PE model group ( Figure 2).
  • the number of contractions of the seminal vesicles of rats in the PE model group was approximately 22.4 times, and the number of contractions of the seminal vesicles in each group was less than 6 times.
  • All groups had a higher number of contractions of the seminal vesicles than the PE model group. showed an extremely significant decrease (all P ⁇ 0.05) ( Figure 3).
  • the Wistar rat premature ejaculation model was induced by PCA to monitor the potential effects of the test drugs A001 to A006 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 dapoxetine and A001 to A006 at medium and high doses can effectively prolong the ejaculation latency, and significantly reduce the number of ejaculation, Reduce seminal vesicle pressure and cavernous muscle contraction times.
  • A001 to A006 are all better than the injected dapoxetine hydrochloride 2 mg/kg.
  • the bioavailability is 42%, and the series of compounds of the present invention are significantly better than dapoxetine hydrochloride.

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Abstract

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，属于医药技术领域，具体涉及一种如式(I)所示的2H-苯并三氮唑衍生物或其在药学上可接受的盐、或包含其的药物组合物，以及其在制备治疗和/或预防早泄药物中的应用。经体内活性试验研究，本发明所述2H-苯并三氮唑衍生物具有显著的抗早泄作用，其与临床现有唯一批准上市药物达泊西汀相比，明显强于在售药物达泊西汀，具有显著的治疗特点和实质性的技术进步。本发明所述2H-苯并三氮唑衍生物或其药学上可接受的盐在作为早泄治疗药物方面具有广泛的研究应用前景。

Description

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 技术领域
本发明属于医药技术领域，具体涉及一种新的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。
背景技术
早泄(Premature ejaculation，早泄)是最常见的男性性功能障碍之一，发病率为20％～30％。国际性医学会定义为，早泄是指从初次性生活开始，射精往往或总是在插入阴道前或插入阴道后大约1分钟以内发生(原发性早泄)；或阴道内射精潜伏期(Intra-vaginal ejaculation latency time，IELT)显著缩短，通常小于3分钟(继发性早泄)；总是或几乎不能控制和延迟射精；消极的身心影响，如苦恼、忧虑、沮丧，避免性接触等。早泄病因复杂，包括中枢5-羟色胺和多巴胺系统神经递质紊乱、阴茎头敏感性过高、遗传变异、紧张和/或焦虑等精神心理因素、勃起功能障碍、慢性前列腺炎、甲状腺疾病、药物因素等。早泄是心身疾病，根据中医整体观念，本病是整体失调下的局部症状，早泄治疗的新目标是心身同调，整体与局部同治。治疗目的是提高患者射精控制力，改善夫妻双方性生活满意度，延长射精时间。在明确诊断与分类的基础上，医生应当与患者和其伴侣讨论治疗预期，与患者及伴侣共同制定治疗目标及治疗方案。
盐酸达泊西汀是一种选择性5-羟色胺再摄取抑制剂，是全世界唯一作为早泄治疗药物上市的药品，目前已在欧盟、中国等全球五十多个国家或地区获批用于早泄的按需治疗。研究表明，性交前1～2小时服用盐酸达泊西汀30mg或60mg比安慰剂更有效，分别将IELT提高2.5倍和3.0倍，并且提高了射精控制，减少了患者痛苦，提高了性生活满意度。该药在原发性早泄和继发性早泄中疗效相似，治疗相关的副作用，呈剂量依赖性，包括恶心、腹泻、头痛和头晕。盐酸达泊西汀治疗初始剂量建议为30mg，一般4周内6次使用后评价，效果不佳，可增加剂量到60mg。但临床停用率很高，累计停用率随时间增加，且在开始治疗2年后达到90％以上，停药的原因包括成本高(29.9％)、对早泄无法治愈的失望和药物的按需性(25.0％)等，达泊西汀的生物利用度差是达泊西汀疗效差和患者满意度低进而导致临床停用率高的重要原因。因此研究新的治疗早泄药具有临床意义。
发明内容
本发明的首要目的是公开一种具有药用价值的2H-苯并三氮唑衍生物及其制备方法，还公开含有该衍生物的药物组合物。
本发明的次要目的是公开所述2H-苯并三氮唑衍生物和包含该衍生物的药物组合物在制备治疗和/或预防早泄药物中的应用。
本发明公开的2H-苯并三氮唑衍生物为式(I)所示的化合物或该化合物在药学上可接受的盐，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，其所述的盐可含有0.5-3分子的结晶水：
其中：
X代表：C3-C4的烷基或C3-C4的烷氧基；
Y代表：CH或N；
Z代表：O或S；
R代表：氢原子可以任选被1-3个卤原子取代，所述卤族元素选自氟、氯、溴。
优选地，所述的2H-苯并三氮唑衍生物为如下所示化合物中任一个：
A001：1-(4-(4-苯并异噁唑基)哌嗪-1-基)丁基-2H-苯并三氮唑
A002：1-(3-(4-(3-(6-氟苯并异噁唑基))哌啶-1-基)丙基-2H-苯并三氮唑
A003：1-(4-(4-(3-(6-氟苯并异噁唑基))哌啶-1-基)丁基-2H-苯并三氮唑
A004：1-(3-(4-苯并异噻唑基)哌嗪-1-基)丙基-2H-苯并三氮唑
A005：1-(3-(4-(3-(6-氟苯并异噁唑基))哌嗪-1-基)丙基-2H-苯并三氮唑
A006：1-(4-(4-(3-(6-氟苯并异噁唑基))哌嗪-1-基)丁基-2H-苯并三氮唑
具体化学结构式如下表所示：

合成路线通式：
其中，X、Y、Z和R如上所述定义。
以化合物A001为例，以取代1H-苯并三氮唑为原料，在氢氧化钠水溶液中，与1-溴-4-氯丁烷进行取代反应，制备1-(4-氯丁基)-1H-苯并三氮唑(收率约70％)和1-(4-氯丁基)-2H-苯并三氮唑(收率约30％)，经硅胶柱层析纯化得到1-(4-氯丁基)-2H-取代苯三氮唑(纯度＞95％)；再与苯并异噁唑哌嗪进行缩合反应，制备化合物A001，最后经酸化成盐制备相应的盐。采用上述方法可制备化合物A002～A006及其盐。
一种药物组合物，包含所述2H-苯并三氮唑衍生物中任一种或多种，或所述衍生物在药学上可接受的盐及药学上可接受的载体。所述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、粉剂或胶囊；用于注射时，可将其制备成注射液。
本发明所述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2H-苯并三氮唑衍生物，或其在药学上可接受的盐，或包含所述衍生物的药物组合物在制备治疗和/或预防早泄药物中的应用。
本发明的有益效果：
本发明所述2H-苯并三氮唑衍生物具有显著的抗早泄作用，其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。其治疗特点和优势如下：
本发明所述2H-苯并三氮唑衍生物或其药学上可接受的盐，为一类全新结构的2H-苯并三氮唑衍生物。经体内活性试验研究，该类化合物的抗早泄活性明显强于在售药物达泊西汀。本发明所述2H-苯并三氮唑衍生物或其药学上可接受的盐在作为早泄治疗药物方面具有广泛的研究应用前景。
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：图为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。
合成通法：
(1)关键中间体：1-(4-氯丁基)-2H-苯并三氮唑(A1)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)关键中间体：1-(3-氯丙基)-2H-苯并三氮唑(A2)的制备
苯并三氮唑36.0g(302mmol)、1-溴-3-氯丁烷47.5g(302mmol)、四丁基溴化铵2.22g(6.8mmol)、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11.71g(产率19.82％)。
(3)6-氟-3-(哌嗪-1-基)苯并异噁唑(A3)的制备
将2-氯-4-氟苯甲醛1.58g(10mmol)、盐酸羟胺0.84g(10mmol)，乙酸钠1.64g(20mmol)、30mL乙醇和10mL水置于100mL单口瓶中反应2h，TLC监测反应进程。反应完毕后，减压蒸馏除去乙醇，抽滤，滤饼经纯化水洗涤后得到(E)-2-氯-4-氟-苯甲醛肟1.65g(产率95％)。将(E)-2-氯-4-氟-苯甲醛肟1.73g(10mmol)、N,N-二甲基甲酰胺15mL置于50mL单口瓶中，加入N-氯代丁二酰亚胺1.47g(11mmol)，常温反应1h，TLC监测反应进程。反应完毕后，将反应液滴入300mL纯化水中，搅拌，抽滤后得到(Z)-2-氯-4-氟-氯代羟亚胺苄1.85g(产率89％)。将(Z)-2-氯-4-氟-氯代羟亚胺苄1.04g(5mmol)、无水哌嗪3.44g(40mmol)、三乙胺1.01g(10mmol)溶于30mL二氯甲烷于100mL单口瓶中，反应2h，TLC检测反应进程。反应完毕后，搅拌下向反应液加入硫酸铜饱和溶液至不再产生蓝色絮状沉淀，抽滤，饱和食盐 水洗涤，二氯甲烷萃取，蒸除溶剂得到(Z)-(2-氯代-4-氟苯基)-1-哌嗪基甲酮肟0.79g(产率61％)。将(Z)-(2-氯代-4-氟苯基)-1-哌嗪基甲酮肟0.65g(5mmol)、叔丁醇钾0.56g(5mmol)、1,4-二氧六环10mL置于50mL单口瓶中100℃反应12h，TLC监测反应进程。反应完毕后，减压蒸馏除去溶剂，得到黄色油状物。经硅胶层析柱分离纯化得到6-氟-3-(哌嗪-1-基)苯并异噁唑白色粉末状固体0.282mg(产率51％)。
(4)目标化合物的制备通法(以A004为例)
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。加入中间体A2(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1小时，析出固体，过滤。滤饼经无水乙醇重结晶得到终产物。
实施例1
1-(4-(4-苯并异噁唑基)哌嗪-1-基)丁基-2H-苯并三氮唑的制备
合成遵循制备通法。经无水乙醇重结晶，得到1.12g白色粉末状固体(产率42％)。1H 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＝6.9Hz,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)；13C 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 C21H25N6O[M+H]+377.2084 found 377.2089。
实施例2
1-(3-(4-(3-(6-氟苯并异噁唑基))哌啶-1-基)丙基-2H-苯并三氮唑盐酸盐的制备
合成遵循制备通法，经乙酸乙酯重结晶，得到1.36g白色粉末状固体(收率42％)。1H 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),3.30–2.95(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]+。
实施例3
1-(4-(4-(3-(6-氟苯并异噁唑基))哌啶-1-基)丁基-2H-苯并三氮唑盐酸盐的制备
合成遵循制备通法。经无水乙醇重结晶，得到1.72g白色粉末状固体(产率51％)。1H NMR(400MHz,DMSO-d6)δ11.01(s,1H),8.24(dd,J＝8.8,5.3Hz,1H),7.99–7.87(m,2H),7.71(dd,J＝9.1,2.2Hz,1H),7.44(dp,J＝5.9,2.9Hz,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]+。
实施例4
1-(3-(4-苯并异噻唑基)哌嗪-1-基)丙基-2H-苯并三氮唑盐酸盐的制备
合成遵循制备通法。经无水乙醇重结晶，得到1.21g白色粉末状固体(产率44％)。1H 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)；13C NMR(100MHz,DMSO-d6)δ162.65,152.58,145.66,133.28,128.58,127.80,127.43,125.08,124.53,124.47,121.66,119.64,111.14,53.59,51.09,46.80,45.50,24.17；HR-MS(ESI)m/z:calcd for C20H23N6S[M+H]+379.1699found 379.1701。
实施例5
1-(3-(4-(3-(6-氟苯并异噁唑基))哌嗪-1-基)丙基-2H-苯并三氮唑盐酸盐的制备
合成遵循制备通法，经无水乙醇重结晶，得到165mg白色粉末状固体(收率51％)。1H 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＝13.5Hz,2H),3.61(d,J＝12.2Hz,4H),3.26(t,J＝8.2Hz,4H),2.66–2.54(m,2H).13C 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]+。
实施例6
1-(4-(4-(3-(6-氟苯并异噁唑基))哌嗪-1-基)丁基-2H-苯并三氮唑盐酸盐的制备
合成遵循制备通法，经无水乙醇重结晶，得到182mg白色粉末状固体(收率54％)。1H 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).13C NMR(100MHz,DMSO-d6)δ166.82–162.55(m),160.28,144.16,126.84,124.85,124.74,118.29,112.49,112.18,98.29,98.02,55.80,55.35,50.46,45.10,27.06,20.87.LC-MS(ESI)m/z:395.18[M+1]+。
实施例7
化合物A001～A006对早泄模型的体内活性研究
7.1材料与方法
7.1.1化合物信息

7.2实验方案
7.2.1动物信息
7.2.2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。
7.2.3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。
7.2.4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。
7.2.5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。
7.2.6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。
7.2.7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PCA 5mg/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。
7.2.8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。
7.3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)。30min平均射精次数均处于5次及以下(图1)。2mg/kg剂量下，A001～A006均优于盐酸达泊西汀。
从初次射精潜伏期结果可得，各组别均较PE model组在初次射精潜伏期时间上呈现极为显著的延长(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，各组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)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、A001中剂量组、A001高剂量组、A002中剂量组、A002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<0.001，P<0.001，P<0.01，P<0.001)，其余组别(A001低剂量组、A002低剂量组较PE model组虽有一定程度延缓但并无统计学上的显著性差异(均P>0.05，图4)。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)。2mg/kg口服剂量下，A001～A006均优于注射2mg/kg盐酸达泊西汀。
7.4结论
通过PCA诱导Wistar大鼠早泄模型，监测不同剂量下的受试药物A001～A006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，揭示达泊西汀和中高剂量下的A001～A006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，2mg/kg口服剂量下，A001～A006均优于注射2mg/kg盐酸达泊西汀。结合对照药盐酸达泊西汀生物利用度为42％，本发明系列化合物显著优于盐酸达泊西汀。

Claims (7)

  1. 一种2H-苯并三氮唑衍生物或其在药学上可接受的盐，其特征在于，所述衍生物结构如式(I)所示；
    其中：
    X代表：C3-C4的烷基或C3-C4的烷氧基；
    Y代表：CH或N；
    Z代表：O或S；
    R代表：氢原子可以任选被1-3个卤原子取代，所述卤族元素选自氟、氯、溴。
  2. 根据权利要求1所述的2H-苯并三氮唑衍生物或其在药学上可接受的盐，其特征在于，所述的2H-苯并三氮唑烷基衍生物为如下所示化合物中任一个：
    A001：1-(4-(4-苯并异噁唑基)哌嗪-1-基)丁基-2H-苯并三氮唑
    A002：1-(3-(4-(3-(6-氟苯并异噁唑基))哌啶-1-基)丙基-2H-苯并三氮唑
    A003：1-(4-(4-(3-(6-氟苯并异噁唑基))哌啶-1-基)丁基-2H-苯并三氮唑
    A004：1-(3-(4-苯并异噻唑基)哌嗪-1-基)丙基-2H-苯并三氮唑
    A005：1-(3-(4-(3-(6-氟苯并异噁唑基))哌嗪-1-基)丙基-2H-苯并三氮唑
    A006：1-(4-(4-(3-(6-氟苯并异噁唑基))哌嗪-1-基)丁基-2H-苯并三氮唑。
  3. 一种药物组合物，其特征在于，包含权利要求1或2所述的2H-苯并三氮唑衍生物及其在药学上可接受的盐中任一种或多种，以及药学上可接受的载体。
  4. 根据权利要求3所述的药物组合物，其特征在于，所述的药物组合物剂型选自片剂、喷雾剂、口溶膜剂、粉剂、胶囊、注射液；所述剂型中活性成分的含量为0.1％～99.5％。
  5. 权利要求1或2所述的2H-苯并三氮唑衍生物或其在药学上可接受的盐在制备治疗和/或预防早泄药物中的应用。
  6. 权利要求3或4所述的药物组合物在制备治疗和/或预防早泄药物中的应用。
  7. 一种权利要求1所述的2H-苯并三氮唑衍生物或其药学上的盐的制备方法，其特征在于，包括如下合成路线：
PCT/CN2023/114340 2022-09-19 2023-08-23 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 WO2024060912A1 (zh)

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CN115304593B (zh) * 2022-09-19 2024-02-23 皮摩尔新药(辽宁)有限公司 苯并异噻唑化合物及其药物组合物和应用

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