CN112745306A - 苯并咪唑类化合物及其制备方法和用途 - Google Patents
苯并咪唑类化合物及其制备方法和用途 Download PDFInfo
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Classifications
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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
- C07D413/10—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 carbon chain containing aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- 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
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于药物化学技术领域,具体公开了一类苯并咪唑类化合物及其制备方法和用途。苯并咪唑类化合物包括阿齐沙坦经修饰后的单体化合物和进一步与芎川嗪或阿魏酸缩合的衍生物,该类化合物在体内迅速释放出川芎嗪和阿魏酸,从而与苯并咪唑类化合物发生有效的协同作用,增强抗高血压疗效,同时又具有降血脂作用,减少不良反应,对患者肝肾具有较理想的保护作用,填补了现有技术中的空白。
Description
技术领域
本发明属于药物化学技术领域,具体涉及一类苯并咪唑类化合物及其制备方法和用途。
背景技术
高血压是常见的一类心脑血管疾病,全球高血压患者已超过10亿人。我国高血压的患病率也呈上升趋势,估计目前全国有2亿高血压患者。在庞大的抗高血压药物市场中,由于非肽类血管紧张素II(AngⅡ)受体抑制剂(ARB,简称“沙坦类”)药物降压平稳、疗效好、作用时间长、患者耐受性好,尤其在预防卒中、延缓糖尿病和非糖尿病肾病的肾功能不全、改善左心室肥厚、对靶器官的保护作用等方面具有优势,且副作用比血管紧张素转换酶抑制剂(ACEI,简称“普利类”)小,血管紧张素II受体拮抗剂(沙坦类)进入我国市场以来,一直保持较高的增长态势,销售金额和销售数量上升迅速。从发展的角度看,随着人们对高血压这一流行病症认识的提高以及收入的增长,沙坦类药物有望成为未来国内抗高血压药物市场的主导者。
阿齐沙坦作为新一代的血管紧缩素II受体抑制剂,与血管紧张素转化酶抑制剂(ACEI)类降压药物相比,单独或联合用药均具有平稳降压、不会引起干咳的优点,平稳持久降血压作用。尽管已上市多个ARBs,但对于许多患者,仅抑制肾素-醛固酮系统(RAS)活性并不足以控制血压和降低心血管疾病及糖尿病的风险,而阿齐沙坦还能通过部分激活过氧化物酶体增殖物激活受体-γ(PPAR-γ)而对糖尿病患者产生潜在的保护作用,相关临床试验结果表明其临床效果要优于现在临床广泛使用的奥美沙坦酯和缬沙坦。
川芎嗪是从伞形科植物川芎中提取的一种生物单体4-甲基吡嗪(tertramethylpyrazine)。药理研究证明,川芎嗪具有改善微循环、扩张血管、增加动脉血流、抑制血小板聚集和降低血小板活性等作用,对心血管疾病有显著疗效。临床上广泛用于脑卒中、哮喘、肺气肿、肺心病、慢性呼吸衰竭、成人呼吸窘迫综合征等疾病治疗。其作用机制主要有清除自由基、抗脂质过氧化、保护冠脉内皮、促进心肌细胞能量代谢、抗纤维化、调控凋亡相关基因c-fos和bc1-2的表达、抗自由基损伤、影响细胞因子、钙拮抗作用、抗心肌缺氧-复氧损伤、抗血管紧张素II致心肌肥大(阻断AT1受体)、扩张血管、抗血小板聚集和血栓形成等。
阿魏酸是从阿魏的树脂中提取的一种酚酸,阿魏为伞形科多年生草本植物,具强烈蒜臭,生于多沙地带,主产于新疆,初生时只有根生叶,至第5年始抽花茎。花茎粗壮,高达2米;春末夏初盛花期至初果期,分次由茎上部往下斜割,收集渗出的乳状树脂,阴干。阿魏含挥发油、树脂及树胶等,油中含多种有机酸化物,如(R)-仲丁基1-丙烯基二硫醚、1(1-甲硫基丙基)1-丙烯基二硫醚、仲丁基3-甲硫基烯丙基二硫醚等。树脂中含阿魏酸及其酯类。阿魏酸能竞争性地抑制肝脏中羟戊酸-5-焦磷酸脱氢酶活性,抑制肝脏合成胆固醇,从而达到降血脂目的。阿魏酸具有抑制血小板凝集,祛痰,抑制结核杆菌等作用。临床上阿魏酸主要用于动脉硬化、冠心病、脑血管、肾小球疾病、肺动脉高压、糖尿病性血管病变、脉管炎等血管性疾病的辅助治疗以及白细胞和血小板减少。
在中国专利(CN105237527B)中公开了一类苯并咪唑衍生物及其制备方法和医药用途,其开发的阿齐沙坦与川芎嗪AT1受体阻断剂(QR01006)与阿齐沙坦比较,降血压作用与阿齐沙坦比较并不明显。在中国专利(CN103254188B)中公开了一种阿奇沙坦衍生物本发明实施例提供的苯并咪唑类衍生物由一个medoxomil 基团和两阿齐沙坦构成,一分子的苯并咪唑类衍生物水解得到两分子的阿齐沙坦,阿齐沙坦分子可在体内发挥药效,可以推断其降压作用应该与阿齐沙坦相当。公开的专利及文献中未见阿齐沙坦与阿魏酸成酯衍生物的报道。
我们在开发苯并咪唑类化合物的过程中意外的发现,阿齐沙坦结构中苯并咪唑环上的乙氧基(-OC2H2CH3)经修饰成环丙氧基或含氟的乙氧基后再与川芎嗪或阿魏酸成酯结合,既可有效增强AT1受体阻断剂抗高血压疗效,亦可达到降血脂,改善血液循环及对肝肾的有效保护作用,同时对其他心血管疾病亦具有潜在的治疗意义。同时结构修饰后的单体化合物与阿齐沙坦相比具有明显的降血压作用。
发明内容
针对现有技术中存在的不足,本发明的目的在于提供了一系列苯并咪唑类化合物,该类化合物在体内迅速释放出川芎嗪或阿魏酸和阿齐沙坦类似物,从而与阿齐沙坦类似物发生有效的协同作用,增强抗高血压疗效,降低血脂,改善血液循环,减少不良反应,对患者肝肾具有较理想的保护作用。
为了实现本发明的目的,本发明采取的技术方案如下:
通式I所示的苯并咪唑衍生物及其异构体和药学上可接受的盐、溶剂合物或多晶型物。
本发明的通式I中具有代表性的化合物如下:
HCP0101: 2-环丙氧基-1-((2'-(5-氧代-2,5-二氢-1,2,4-噁二唑-3-基)-[1,1'-联苯]-4-基)甲基)-1H-苯并咪唑-7-羧酸
HCP0102:2-(2-氟乙氧基)-3-[2'-(5-氧代-2,5-二氢-[1,2,4]恶二唑-3-基)-联苯-4-基甲基]-3H- 苯并咪唑-4-羧酸
HCP0103:2-(2,2-二氟-乙氧基)-3-[2'-(5-氧代-2,5-二氢-[1,2,4]恶二唑-3-基)-联苯-4-基甲基]-3H-苯并咪唑-4-羧酸
HCP0104: 3-[2'-(5-氧代-2,5-二氢-[1,2,4]恶二唑-3-基)-联苯-4-基甲基]-2-(2,2,2-三氟-乙氧基 )-3H-苯并咪唑-4-羧酸
HCP0105: 2-环丙氧基-3-[2'-(5-氧代-2,5-二氢-[1,2,4]恶二唑-3-基)-联苯-4-基甲基]-3H-苯并咪唑-4-羧酸 3,5,6-三甲基吡嗪-2-基甲基酯
HCP0106: 2-(2-氟乙氧基)-3-[2'-(5-氧代-2,5-二氢-[1,2,4]恶二唑-3-基)-联苯-4-基甲基]-3H-苯并咪唑-4-羧酸3,5,6-三甲基-吡嗪-2-基甲基酯
HCP0107: 2-(2,2-二氟-乙氧基)-3-[2'-(5-氧代-2,5-二氢-[1,2,4]恶二唑-3-基)-联苯-4-基甲基]-3H-苯并咪唑-4-羧酸3,5,6-三甲基-吡嗪-2-基甲基酯
HCP0108: 3-[2'-(5-氧代-2,5-二氢-[1,2,4]恶二唑-3-基)-联苯-4-基甲基]-2-(2,2,2-三氟-乙氧基)-3H-苯并咪唑-4-羧酸3,5,6-三甲基吡嗪-2-基甲基酯
HCP0109: 2-环丙氧基-3-[2'-(5-氧代-2,5-二氢-[1,2,4]恶二唑-3-基)-联苯-4-基甲基]-3H-苯并咪唑-4-羧酸4-(2-羧基-乙烯基)-2-甲氧基-苯基酯
HCP0110: 2-(2-氟乙氧基)-3- [2'-(5-氧代-2,5-二氢-[1,2,4]恶二唑-3-基)-联苯-4-基甲基]-3H-苯并咪唑-4-羧酸4-(2-羧基乙烯基)-2-甲氧基-苯基酯
HCP0111: 2-(2,2-二氟-乙氧基)-3-[2'-(5-氧代-2,5-二氢-[1,2,4]恶二唑-3-基)-联苯-4-基甲基]- 3H-苯并咪唑-4-羧酸4-(2-羧基乙烯基)-2-甲氧基-苯基酯
HCP0112: 3-[2'-(5-氧代-2,5-二氢-[1,2,4]恶二唑-3-基)-联苯-4-基甲基]-2-(2,2,2-三氟-乙氧基)-3H-苯并咪唑-4-羧酸4-(2-羧基乙烯基)-2-甲氧基-苯基酯
上述化合物对应的化学结构式如下:
本发明还提供了通式Ⅰ所示的化合物的制备方法:
(1)式IN-01类化合物与羟胺水溶液在有机碱或无机碱碱存在下得化合物IN-02;化合物IN-02与氯甲酸乙酯酯化经闭环后得化合物IN-03;经水解后得通式I-1目标化合物。
(2)通式I-1化合物进一步与相应的醇在缩合剂存在下进行酯化反应即得通式I-2系列目标化合物。
与现有技术相比,本发明技术方案的优点和有益效果在于:
1、本发明公布的苯并咪唑类化合物,主要包括阿齐沙坦的结构修饰后的单体化合物和与川芎嗪、阿魏酸成酯的衍生物。
2、本发明的新的单体化合物进入体内后迅速起到降血压的作用;与川芎嗪、阿魏酸成酯的衍生物进入体内迅速代谢为为苯并咪唑类衍生物以及川芎嗪或阿魏酸,两者协同作用,从而大大增强了苯并咪唑类衍生物抗高血压活性。
具体实施方式
下面申请人将结合具体的实施例对本发明做进一步的详细说明,目的在于使得本领域技术人员更清楚地了解本发明,但以下内容不应以任何方式被理解为对本发明的权利要求书请求保护的范围的限制。若未特别指明,实施例中所用的技术手段均为本领域技术人员所熟知的常规手段。
对比例:依据苯并咪唑衍生物及其制备方法和医药用途专利(CN103709154 B)实施例5的合成方法制备化合物(QR01006),作为对比例。
实施例1:(2-环丙氧基-1-((2'-(5-氧代-2,5-二氢-1,2,4-噁二唑-3-基)-[1,1'-联苯]-4-基)甲基)-1H-苯并咪唑-7-羧酸)(HCP0101)的制备
第一步:中间体IN-02的制备
中间体IN-01(2.0g,4.9mmol)、50%羟胺水溶液(3.4g,49mmol)和三乙胺(0.5g,4.9mmol)加至20ml乙醇中,加热回流。冷却析晶,过滤,柱层析分离纯化,得中间体IN-02。
第二步:中间体IN-03的制备
中间体IN-02(1.7g,3.9mmol)溶于二氯甲烷(10ml)中,加入三乙胺(0.6g,5.9mmol),室温下缓慢滴加含氯甲酸乙酯(0.5g,4.72mmol)的二氯甲烷(10ml)溶液,滴毕,室温反应。用水洗涤,减压浓缩至干,柱层析分离纯化,得中间体IN-03。
第三步:中间体IN-04的制备
中间体IN-03化合物3(12.8g,24.8mmol)于乙醇(50ml)中回流,冷却后过滤,分离纯化,得中间体IN-04。
第四步:化合物HCP0101的制备
中间体IN-04(1.2g,2.55mmol)溶于甲醇(10ml)中,加入10%氢氧化钠水溶液(3ml,7.5mmol),加热回流。搅拌下加入1mol/L盐酸调至PH3.0。过滤,柱层析提纯或溶剂重结晶,得到目标化合物HCP0101。
实施例2-4:参照实施例1的操作,区别在于选用下列起始物料,经一系列反应,分离纯化,得到下述式Ⅰ的化合物。
实施例 | 起始物料 | 产物 |
2 | 3-(2'-氰基-联苯-4-基甲基)-2-(2-氟乙氧基)-3H-苯并咪唑-4-羧酸甲酯 | HCP0102 |
3 | 3-(2'-氰基-联苯-4-基甲基)-2-(2,2-二氟乙氧基)-3H-苯并咪唑-4-羧酸甲酯 | HCP0103 |
4 | 3-(2'-氰基-联苯-4-基甲基)-2-(2,2,2-三氟乙氧基)-3H-苯并咪唑-4-羧酸甲酯 | HCP0104 |
实施例5:(3,5,6-三甲基吡嗪-2-基)甲基2-环丙氧基-1-((2'-(5-氧代-2,5-二氢-1,2,4-噁二唑-3-基)-[1,1'-联苯]-4-基)甲基)-1H-苯并咪唑-7-羧酸酯(HCP0105)的制备
将HCP0101(2.0g,4.4mmol)与(2,4,5-三甲基-苯基)-甲醇(0.7g,4.6mmol)溶解在DMF(30ml)中,降温至5℃,加入碳酸钾(0.7g,4.8mmol),对甲苯磺酰氯(0.9g,4.8mmol),催化剂二甲氨基吡啶,搅拌反应。反应完毕,向反应液中加入水,乙酸乙酯萃取。有机层水洗,饱和食盐水洗涤。干燥浓缩粗品经柱层析纯化得到目标化合物HCP0102。
实施例6-8:参照实施例5的操作,区别在于选用下列起始物料,进一步与(2,4,5-三甲基-苯基)-甲醇缩合,分离纯化,得到下述式Ⅰ的化合物。
实施例9:2-环丙氧基-3-[2'-(5-氧代-2,5-二氢-[1,2,4]恶二唑-3-基)-联苯-4-基甲基]-3H-苯并咪唑-4-羧酸4-(2-羧基-乙烯基)-2-甲氧基-苯基酯(HCP0109)的制备
将HCP0101(2.0g,4.4mmol)与(2,4,5-三甲基-苯基)-甲醇(0.9g,4.6mmol)溶解在DMF(30ml)中,降温至5℃,加入碳酸钾(0.7g,4.8mmol),对甲苯磺酰氯(0.9g,4.8mmol),催化剂二甲氨基吡啶,搅拌反应。反应完毕,向反应液中加入水,乙酸乙酯萃取。有机层水洗,饱和食盐水洗涤。干燥浓缩粗品经柱层析纯化得到目标化合物HCP0109。
实施例10-12:参照实施例9的操作,区别在于选用下列起始物料,进一步与阿魏酸缩合,分离纯化,得到下述式Ⅰ的化合物。
实施例13:
1.口服苯并咪唑化合物单次给药对肾性高血压大鼠的降压作用
Wistar大鼠(由江苏省药物安全性评价中心提供,南京,江苏),雄性,体重,180-200g,随机分成7组,阴性对照组(0.5%CMC-Na)、阳性对照组(以阿齐沙坦为阳性药物,由陕西合成药业股份有限公司研发中心提供)以及受试化合物HCP0101、HCP0102、HCP0105、HCP0109和对比例药物低,中,高三个剂量组(0.5,1.0,2.0mg/kg,所有药物均配制在0.5%CMC-Na中),每组6-8只动物。结扎一侧肾动脉,形成两肾一夹型肾性高血压大鼠(RHR)模型,手术后每周测定一次血压,连续四周,血压稳定升高4kPa的大鼠为造模成功的大鼠。测血压前,大鼠用39℃的循环水浴尾套给鼠尾加温,使尾部血管扩张后,用尾套法(BP98A\BP2010A无创血压计,日本)测定大鼠给药前、灌胃给药后1,3,5,7,10和10h的血压和心率,每个时间点测三次取平均值。最大降血压作用(%)=给药后最大降血压值/给药前血压值×100%。
表1.口服苯并咪唑类化合物HCP0101、HCP0102、HCP0105、HCP0109、对比例药物及阳性药物对肾性高血压大鼠的降压作用
化合物 | 最大降血压作用 | 心率变化 |
阴性对照,0.5%CMC-Na,1.0ml/kg | 3.6±1.5% | -4±3% |
阳性对照,阿奇沙坦,1.0mg/kg | 29±4.1% | -5±4% |
对比例药物 | ||
0.5mg/kg | 14±3.4% | -6±2% |
1.0mg/kg | 18±3.6% | -10±3% |
2.0mg/kg | 24±4.1% | -18±3% |
化合物HCP0101 | ||
0.5mg/kg | 13±3.1% | -9±4% |
1.0mg/kg | 27±4.2% | -15±5% |
2.0mg/kg | 35±5.5% | -20±8% |
化合物HCP0102 | ||
0.5mg/kg | 22±2.8% | -12±4% |
1.0mg/kg | 36±3.2% | -25±6% |
2.0mg/kg | 43±6.7% | -28±4% |
化合物HCP0105 | ||
0.5mg/kg | 30±2.1% | -15±2% |
1.0mg/kg | 45±3.9% | -29±4% |
2.0mg/kg | 51±5.5% | -32±5% |
化合物HCP0109 | ||
0.5mg/kg | 28±2.8% | -13±3% |
1.0mg/kg | 39±3.2% | -26±6% |
2.0mg/kg | 47±6.7% | -35±5% |
结论:在结扎肾动脉大鼠高血压动物模型中,本发明制备的测试化合物均显示有不同程度的降血压作用,本发明所制备的化合物降血压作用强度均明显优于阳性药物阿齐沙坦和对照例药物,降血压作用持续时间比阿齐沙坦及对比药物长。给药后24小时,阳性药阿齐沙坦的降压作用为19%,对照药物为18%,HCP0101为24%, HCP0102为29%, HCP0105为38%,HCP010934%,降压作用优于与阿齐沙坦和对比药物。本发明制备的所有测试化合物对结扎肾动脉大鼠心率有一定的降低作用,表明除显著的降血压作用外,该类化合物尚具有一定程度的降心率作用,且降心率作用优于阿齐沙坦和对比药物。
2.口服苯并咪唑类化合物多次给药对自发性高血压大鼠(SHR)的降压作用
雄性SHR(由江苏省药物安全性评价中心提供,南京,江苏),40周龄,体重250-300克,随机分成7组,阴性对照组(0.5%CMC-Na)、阳性对照组(以阿齐沙坦为阳性药物,由陕西合成药业股份有限公司研发中心提供)以及受试化合物HCP0101、HCP0102、HCP0105、HCP0109和对比例药物低,中,高三个剂量组(所有化合物均配制在0.5%CMC-Na中),每组4-5只动物,每天给药一次,连续给药14天,每次给药1小时后测定血压和心率。测血压前,大鼠用39℃的循环水浴尾套给鼠尾加温,使尾部血管扩张后,用尾套法(BP98A\BP2010A无创血压计,日本)测定大鼠给药前、灌胃给药后的血压和心率,每个时间点测三次取平均值。最大降血压作用(%)=给药后最大降血压值/给药前血压值×100%。
表2.口服苯并咪唑类化合物对自发性高血压大鼠(SHR)的降压作用
结论:在自发性高血压大鼠(SHR)动物模型中,本发明制备的测试化合物显示较强的降血压作用,所有测试的化合物作用强度明显优于阿齐沙坦和对比药物。长期给药后,化合物的降血压作用稳定,动物状态均优于阿齐沙坦给药组和对比药物组。在整个给药过程中,本发明制备的化合物对SHR大鼠心率均显示一定程度的降低作用,表明该类化合物除显著的降压作用,尚具有较佳降心率的作用。
3.口服苯并咪唑类化合物单次给药对正常大鼠血压的影响
Wistar大鼠(由江苏省药物安全性评价中心提供,南京,江苏) ,雄性,体重,200-250g,随机分成7组,阴性对照组(0.5%CMC-Na)、阳性对照组(以阿齐沙坦为阳性药物,由陕西合成药业股份有限公司研发中心提供)以及受试化合物HCP0101、HCP0102、HCP0105、HCP0109和对比例药物低,中,高三个剂量组(0.5,1.0,2.0mg/kg,p.o.,所有药物均配制在0.5%CMC-Na中),每组8-10只动物。测血压前,大鼠用39℃的循环水浴尾套给鼠尾加温,使尾部血管扩张后,用尾套法(BP98A\BP2010A无创血压计,日本)测定大鼠给药前、灌胃给药后0.5,1,2,4,8h的血压和心率,每个时间点测三次取平均值。
结果与结论:本发明制备的受试化合物的三个剂量(0.5,1.0和2.0mg/kg , p.o.,配制在0.5%CMC-Na中)对正常大鼠血压和心率均无显著作用,表明该类化合物对正常血压和心率无显著影响。
Claims (8)
3.权利要求1或2所述的化合物在药学上可接受的盐。
4.一种权利要求1或2所述化合物的制备方法,中间体IN-01类化合物与羟胺水溶液在有机碱或无机碱碱存在下得中间体IN-02;中间体IN-02与氯甲酸乙酯酯化经闭环后得中间体IN-03;经水解后得通式I-1目标化合物。
5.一种权利要求1或4所述化合物的制备方法,通式I-1目标化合物与川芎嗪或阿魏酸缩合,即得通式I-2目标化合物。
6.权利要求1或5所述化合物在制备降血压、降血脂、降心率治疗和预防其他心血管类疾病的药物中的用途。
7.权利要求1-6所述化合物在药学上可接受的盐在制备降血压、降血脂、降心率治疗和预防其他心血管类疾病的药物中的用途。
8.根据权利要求1-7中任一项所述的制备方法制得的化合物在制备降血压、降血脂、降心率治疗和预防其他心血管类疾病的药物中的用途。
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