CN108191662B - 一种山竹醇衍生物及应用 - Google Patents
一种山竹醇衍生物及应用 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/12—Acetic acid esters
- C07C69/18—Acetic acid esters of trihydroxylic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
- C07C49/83—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups polycyclic
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
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- C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/12—Acetic acid esters
- C07C69/21—Acetic acid esters of hydroxy compounds with more than three hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
本发明公开了一种山竹醇衍生物或其药学可接受的盐(I),包括其立体异构体或互变异构体。本发明涉及该类化合物的制备方法及在预防和管理心功能不全药物中的用途。
Description
技术领域
本发明涉及山竹醇衍生物及其制备方法与作为预防和管理心功能不全药物的应用。
背景技术
山竹醇是一种聚异戊二烯基二苯甲酮衍生物,是从印度藤黄的干果皮中所提取出来的一种黄色晶体化合物,其化学结构与抗氧化剂姜黄素类似,对口腔癌有明显的化学预防作用,对化疗、药物、疾病或生活方式等引起的心功能不全有好的预防和管理作用,是一个很有前途的天然化学预防药物,但其对粘膜的渗透性、生物利用度不理想,有待于进一步提高。
氟原子通过氢键等作用,对分子的构象、与受体的结合方式,对化合物的生理活性产生较大影响。氟原子与氢原子范德华半径非常接近,氟原子代替分子中的氢原子后,使得原化合物分子体积变化不大,能顺利地代替非氟母体进入生物体的代谢。CF3基团的引入也能显著改变母体分子的脂溶性、代谢稳定性、生物活性。本发明通过引入含氟基团对山竹醇进行化学修饰,以期改善其吸收和渗透性,提高其生物利用度,开发出更有效的、低毒的化学预防药物。
发明内容
本发明的目的在于提供一种山竹醇衍生物,其具有良好的预防和管理心功能不全活性,并且毒性较低。
本发明的另一目的在于提供上述山竹醇衍生物的制备方法。
本发明的再一目的在于提供上述山竹醇衍生物的用途。
以下对本发明进行详细描述。
本发明提供以下通式(I)的山竹醇衍生物或其药学可接受的盐。结构如下式所示:
式中,R1各自独立为F,CF3;R2,R3,R4各自独立为H,OH,OCH3,OAc和其它烷氧基。
本发明通式(I)化合物包括其立体异构体和互变异构体。
所述式(I)化合物的具体实例包括:
本发明还提供了上述通式(I)化合物的制备方法,步骤包括以下步骤:
式中,R1各自独立为F,CF3;R2,R3,R4各自独立为H,OH,OCH3,OAc和其它烷氧基。
本发明的山竹醇衍生物,具有良好的预防和管理心功能不全活性,并且毒性较低。
通过以下实施例进一步举例说明本发明,但应注意本发明的范围并不受这些实施例的任何限制。
具体实施方式
实施例1
取56g(0.5mol)的1,3-环己二酮溶于100ml的水中,冷却至℃,缓慢加入71.5g(0.5mol)的三异丙基胺,再缓慢加82g(0.55mol)3,3-二甲基烯丙基溴,室温搅拌过夜。向反应液加入2NNaOH溶液725mL,分层,水相用300ml乙酸乙酯萃取,水相用冰醋酸酸化至pH3-4,抽滤,干燥,不需要纯化。得到中间体(II),产率60%。ESI-MSm/z:181.0[M+H]。
取35.3g(0.196mol)中间体(II)溶于300ml丙酮中,加入116.6g(0.686mol)异丙基碘和64g(0.784mol)碳酸钾。反应过夜。减圧蒸去丙酮,向残渣中加入400ml水和400ml三氯甲烧,溶解。分层,水相用二氯甲烷萃取(2x300ml),干燥。浓缩,硅胶柱层析纯化(V乙酸乙酯):V石油酸)=1:6),得中间体(Ⅲ),产率93%。ESI-MSm/z: 223.0[M+H]。
取22.3g(0.1mol)中间体(Ⅲ)溶于150ml的THF中,加入32.6g(0.1mol)Cs2CO3,冷却至-10℃,加入34.7g(0.11mol)NFSI,反应过夜,过滤,浓缩,硅胶柱层析纯化,得3-异丙氧基-2-(3-甲基-2-丁烯基)-6-氟环己-2-烯酮(IVa),产率59%。ESI-MSm/z: 241.1[M+H]。
取24g(0.1mol)中间体(IVa),加入250mlTHF,冷至0℃,缓慢加入85mL甲基锂(1.3M的***溶液),室温搅拌30min,将反应液冷至0℃,用稀盐酸调节pH6,再搅拌30min。分层浓缩,水相用乙酸乙酯萃取(3x200ml)。水洗,干燥。浓缩,硅胶柱层析纯化得到中间体(Va),产率72%。
称取0.512g(2.5mmol)溴化亚铜二甲硫醚冷却至-78℃,缓慢加入83.3mI(0.25mmol)甲基溴化镁(3M的***溶液),再缓慢加入17.92g(100mmol)六甲基邻酰三胺,反应20min,缓慢加入含有12.0g(50mmol)中间体Va和10.86g(100mmol)甲基氯硅烷的50mlTHF溶液,保温反应2小时。缓慢的加入1N稀盐酸,调节pH5,再反应30min,升至室温反应10min,反应液分层,减压蒸去THF,水相用乙酸乙酯萃取(3x200ml)。干燥,浓缩,硅胶柱层析纯化,得到中间体VIa,产率87%。
取25.4g(100mmol)中间体VIa加入100mL二氯甲烷,冷却至0℃,加入3.0g(300mmol)三乙胺,0℃反应15min,再缓慢加入26.6g(120mmol)三氟甲磺酸三甲基硅酯,反应过夜,加入300ml石油醚,分层,干燥,浓缩,得VIIa。
取15.98g的VIIa,溶于200ml***中,通氮气,冷却至-20℃,缓慢加入6.7g(47mmol)丙二酰氯,保温反应过夜,再加入10.53g氢氧化钾与70ml水的水溶液,再加入500mg四丁基氯化铵。室温反应5h。加入200ml水和200ml石油醚,加入氢氧化钠溶液调节pH11,分层,水层用石油醚萃取(3x250ml),水相冷至0℃,用稀盐酸酸化,将调节pH2,二氯甲烷萃取(3x300ml),干燥,硅胶柱层析纯化,得到化合物VIIIa,产率19%。
取280mg(1mmol)化合物VIIIa溶于20ml无水THF中,在氮气保护下缓慢加入101mg(1mmol)三乙胺,再加入296mg(1.2mmol)的3,4-二乙酰氧基苯甲酰腈的5ml的THF溶液,温搅拌过夜,加入20ml饱和的氯化铵溶液,减压蒸去THF,乙酸乙酯萃取(3x20ml),干燥。浓缩,硅胶柱层析分离,得到化合物(1),产率70%。ESI-MS m/z: 499.1[M-H]。
实施例2
取22.3g(0.1mol)中间体(Ⅲ)溶于100ml的CHCl3中,加入7.6g(0.004mol)CuI和11.7g(0.11mol)Cs2CO3,冷却至-10℃,加入34.8g(0.11mol)Togni 试剂II,反应24h,过滤,浓缩,硅胶柱层析纯化,得3-异丙氧基-2-(3-甲基-2-丁烯基)-6-三氟甲基环己-2-烯酮(IVb),产率67%。ESI-MSm/z: 291.1[M+H]。
将24g(0.1mol)中间体(IVa)改为29g(0.1mol)中间体(IVb),其它操作同实施例1,得到中间体(Vb),产率71%。
将12.0g(50mmol)中间体Va改为14.5g(50mmol)中间体Vb,其它操作同实施例1,得到中间体VIb,产率84%。
将25.4g(100mmol)中间体VIa改为26.2g(100mmol)中间体VIb,其它操作同实施例1,得到化合物VIIIb,产率20%。
将280mg(1mmol)化合物VIIIa改为330mg(1mmol)化合物VIIIb,将296mg(1.2mmol)3,4-二乙酰氧基苯甲酰腈改为201mg(1.2mmol)3,4-二羟基苯甲酰腈,其它操作同实施例1,得到化合物(2),产率73%。ESI-MS m/z: 465.2[M-H]。
实施例3
将296mg(1.2mmol)3,4-二乙酰氧基苯甲酰腈改为212mg(1.2mmol)3-甲氧基-4-羟基苯甲酰腈,其它操作同实施例2,得到化合物(3),产率75%。ESI-MS m/z: 479.2[M-H]。
实施例4
将296mg(1.2mmol)3,4-二乙酰氧基苯甲酰腈改为366mg(1.2mmol)3,4,5-三乙酰基苯甲酰腈,其它操作同实施例2,得到化合物(4),产率75%。ESI-MS m/z: 607.2[M-H]。
实施例5
取608mg(1.0mmol)化合物(4),加入15mL甲醇,再加入15mL2N的NaOH溶液,室温搅拌5h,稀盐酸调pH3,浓缩,柱层析纯化,制得化合物(5),收率87%。ESI-MS m/z: 481.1[M-H]。
实施例6
将296mg(1.2mmol)3,4-二乙酰氧基苯甲酰腈改为265mg(1.2mmol)3,4,5-三甲氧基苯甲酰腈,其它操作同实施例2,得到化合物(6),产率79%。ESI-MS m/z: 523.2[M-H]。
实施例7
取500mg(1.0mmol)化合物(1)水解,操作同实施例5,制得化合物(7),收率89%。ESI-MS m/z: 415.1[M-H]。
实施例8
山竹醇衍生物对长期阿霉素给药所致的心功能不全和心脏保护作用测试。
以20mg/Kg(口服)剂量的山竹醇衍生物预处理雄性Wistar大鼠30天。在第1, 7,14和28天,将阿霉素以2mg/Kg剂量静脉给药。在第30天,处死动物,对心脏进行组织病理学检查。结果显示,用山竹醇衍生物预处理后,使阿霉素诱致的QT间隔、ST间隔和QTc间隔延长显著的正常化,并能防止心率下降(表1)。
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