CN105796551A - Ace抑制剂木脂内酯组合物及其制备方法与应用 - Google Patents

Ace抑制剂木脂内酯组合物及其制备方法与应用 Download PDF

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CN105796551A
CN105796551A CN201510987617.1A CN201510987617A CN105796551A CN 105796551 A CN105796551 A CN 105796551A CN 201510987617 A CN201510987617 A CN 201510987617A CN 105796551 A CN105796551 A CN 105796551A
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neolignan
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ace
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韩梅
蔡恩博
贾彩霞
张羽
赵岩
王冉秀
何忠梅
郜玉刚
张永刚
郑小曼
夏靖
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Jilin Agricultural University
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

本发明涉及一种ACE抑制剂木脂内酯组合物及其制备方法与作为ACE活性抑制剂，用于降血压的应用。其结构通式如式I所示，R为Boc‑L‑Met,Boc‑L‑Try,Boc‑L‑Pro,Boc‑L‑Phe,Boc‑L‑Thr氨基酸侧链。

Description

ACE抑制剂木脂内酯组合物及其制备方法与应用
技术领域
本发明属于医药技术领域，尤其涉及ACE抑制剂——木脂内酯组合物及其制备方法与作为ACE活性抑制剂的用途，以及应用于降血压。
背景技术
高血压是以体循环动脉压增高为主要表现的临床综合征，是最常见的心血管疾病。原发性高血压的发病因素主要有两大类，一类是内因，如遗传；另一类是外因，如精神紧张、食盐过多、吸烟、肥胖、酗酒、缺乏运动等。长期高血压可影响到心、脑、肾等器官的功能，最终导致这些器官功能的衰竭。高血压属多发病，上世纪80年代，中国高血压发病率为7.7%；到了本世纪初，迅速上升到18.8%；而近10年，高血压的患病率增长了31%。目前，我国高血压病人估计已超过2亿，而且这一趋势仍会继续延续，短时期内不太可能出现逆转。如果再不加以控制，在今后的15年中将增长50%。降压药物种类主要包括利尿药、β受体阻滞剂、钙通道阻滞剂、血管紧张素转换酶抑制剂、血管紧张素II受体阻滞剂。这些药物具有一定的副作用，如心脏抑制、代谢异常、肾脏损害等。且具有我国自主知识产权的降血压药物较少。
牛蒡子苷元（ARG），一种木脂内酯化合物，是菊科(Compositae)植物牛蒡(ArctiumIappaL.)的干燥成熟果实牛蒡子（FructusArctii）的主要活性成分，具有抗肿瘤、抗糖尿病等药理活性。但其口服生物利用度低，严重制约了在临床上的应用。本发明将氨基酸引入到药物分子中，形成木脂内酯组合物，研究发现其具有较好的抑制ACE活性。
发明内容
本发明涉及具有ACE抑制活性的木脂内酯组合物的制备。
具体而言，本发明内容如下：本发明提供了组合物，见通式I
通式I
其中，通式I中的R为Boc-L-Met,Boc-L-Try,Boc-L-Pro,Boc-L-Phe,Boc-L-Thr氨基酸侧链。
具体实施方式
下面的实施例可以对本发明进一步的描述，然而，这些实施例不应该作为对本发明的范围的限制。
下述制备实施例中，NMR（核磁共振）用BrukerAvance-300M仪器测定。
实施例14-(4-(3,4-二甲氧苯甲基)-2-羰基)四氢呋喃甲基-2-甲氧基苯酚2-(N-叔丁氧羰基)氨基-4-甲硫基丁酸酯(ARG1)的合成。
称取0.20g(0.54mmol)牛蒡子苷元,0.27g(1.08mmol)BOC-L-蛋氨酸,0.21g(1.08mmol)1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCI)，0.03g(0.27mmol)4-二甲氨基吡啶（DMAP）置于100ml旋瓶中，加入10ml乙腈溶液，冰水浴下搅拌溶解，再室温反应1-2小时，TLC检测反应至反应完毕，减压蒸去溶剂，得到浅黄色粘稠物。将粘稠物用YMC反相填料进行柱层析分离，用乙腈/水(55:45)混合溶剂洗脱，收集所需组分，减压蒸去有机溶剂，冷冻干燥，得白色粉末状化合物ARG1。
白色固体，产率82%。1H-NMR(CDCl3,300MHz),δppm:6.99(1H,d,8.1HZ,C6 H 5),6.79(1H,d,7.8HZ,C6 H 5),6.76(1H,d,2.1HZ,C6 H 5),6.70(1H,dd,1.8HZ,8.1HZ,C6 H 5),6.56(1H,dd,1.8HZ,7.8HZ,C6 H 5),6.51(1H,d,1.8HZ,C6 H 5),5.24(1H,m,NH),4.73(m,-NH-CH-COO-),3.94,4.21(m,-COOCH 2-),3.76(3H,s,OCH 3),3.86(3H,s,OCH 3),3.83(3H,s,OCH 3),2.97,3.03(m,CH 2),2.70(m,CH),2.38,2.63(m,CH 2),2.54(1H,m,CH),2.50(2H,m,CH 2S-),2.15(3H,s,CH 3),2.01(2H,m,CH 2),1.51(3H,s,CH 3),1.47(3H,s,CH 3),1.46(3H,s,CH 3)。
实施例24-(4-(3,4-二甲氧苯甲基)-2-羰基)四氢呋喃甲基-2-甲氧基苯酚-2-(N-叔丁氧羰基)氨基-3-(2-吲哚基)丙酸酯(ARG2)的合成。
制备方法同实施例1，所不同用Boc-色氨酸，得到化合物ARG2。
白色固体，产率72%。1H-NMR(CDCl3,300MHz)δppm:7.68(1H,d,7.8HZ,C6 H 5),7.39(1H,dd,0.9,8.4HZ,C6 H 5),7.25(1H,dd,0.9,7.2HZ,C6 H 5),7.20(1H,dd,0.9,7.2HZ,C6 H 5),7.14(1H,dd,0.9,8.4HZ,C6 H 5),6.80(1H,d,8.1HZ,C6 H 5),6.64(1H,dd,1.8,8.1HZ,C6 H 5),6.75(1H,d,3.9HZ,C6 H 5),6.84(1H,d,8.1HZ,C6 H 5),6.56(1H,dd,2.1HZ,8.4HZ,C6 H 5),6.51(1H,d,3.9HZ,C6 H 5),5.16(NH),4.97(m,-NH-CH-COO-),3.93,4.22(m,-COOCH 2-),3.87(3H,s,OCH 3),3.82(3H,s,OCH 3),3.73(3H,s,OCH 3),3.56,3.45(m,CH 2),2.963.03(m,CH 2),2.70(m,CH),2.54,2.63(m,CH 2),2.48(m,CH),1.44(3H,s,CH 3)。
实施例34-(4-(3,4-二甲氧苯甲基)-2-羰基)四氢呋喃甲基-2-甲氧基苯酚-N-叔丁氧羰基2-四氢吡咯甲酸酯(ARG3)的合成。
制备方法同实施例1，所不同用Boc-L-脯氨酸，得到化合物ARG3。
白色固体，产率65%。1H-NMR(CDCl3,300MHz)δppm:7.04(1H,d,8.1HZ,C6 H 5),6.94(1H,d,7.8HZ,C6 H 5),6.77(1H,d,2.1HZ,C6 H 5),6.70(1H,dd,1.8HZ,8.1HZ,C6 H 5),6.59(1H,dd,1.2HZ,8.4HZ,C6 H 5),6.51(1H,d,2.1HZ,C6 H 5),4.52(m,-NH-CH-COO-),3.93,4.16(m,-COOCH 2-),3.87(3H,s,OCH 3),3.84(3H,s,OCH 3),3.77(3H,s,OCH 3),3.523.67(m,CH 2 ),2.973.00(m,CH 2),2.70(m,CH),2.342.69(m,CH 2),2.30(m,CH),2.16(m,CH 2 ),1.52,1.64(m,CH 2 ),1.49(3H,s,CH 3)。
实施例44-(4-(3,4-二甲氧苯甲基)-2-羰基)四氢呋喃甲基-2-甲氧基苯酚-2-(N-叔丁氧羰基)氨基-苯丙酸酯(ARG4)的合成。
制备方法同实施例1，所不同用Boc-L-苯丙氨酸，得到化合物ARG4。
白色固体，产率78%。1H-NMR(CDCl3,300MHz)δppm:7.25-7.35(m,C6 H 5),6.91(1H,d,7.8HZ,C6 H 5),6.78(1H,d,8.4HZ,C6 H 5),6.75(1H,d,2.1HZ,C6 H 5),6.69(1H,dd,2.1HZ,7.8HZ,C6 H 5),6.55(1H,dd,2.1HZ,8.4HZ,C6 H 5),6.50(1H,d,2.1HZ,C6 H 5),4.86(m,-NH-CH-COO-),3.90,4.20(m,-COOCH 2-),3.85(3H,s,OCH 3),3.81(3H,s,OCH 3),3.76(3H,s,OCH 3),3.00,3.23(m,CH 2),2.69,3.36(m,CH 2),2.62(m,CH),2.47(m,CH),2.532.57(m,CH 2),1.42(3H,s,CH 3)。
实施例54-(4-(3,4-二甲氧苯甲基)-2-羰基)四氢呋喃甲基-2-甲氧基苯酚-2-(N-叔丁氧羰基)氨基-3-羟基丁酸酯(ARG5)的合成。
制备方法同实施例1，所不同用Boc-L-苏氨酸，得到化合物ARG5。
白色固体，产率61%。1H-NMR(CDCl3,300MHz)δppm:6.98(1H,d,8.1HZ,C6 H 5),6.96(1H,d,8.4HZ,C6 H 5),6.74(1H,d,2.1HZ,C6 H 5),6.67(1H,dd,1.8HZ,8.1HZ,C6 H 5),6.47(1H,dd,1.2HZ,8.4HZ,C6 H 5),6.49(1H,d,2.1HZ,C6 H 5),5.5(NH),4.48(m,-NH-CH-COO-),4.51(m,CH)3.894.14(m,-COOCH 2-),3.81(3H,s,OCH 3),3.77(3H,s,OCH 3),3.72(3H,s,OCH 3),2.91,3.00(m,CH 2),2.65(m,CH),2.45,2.55(m,CH 2),2.55(m,CH),2.65(m,CH),1.43(3H,s,CH 3),1.29(3H,d,CH 3)3.68(OH)。
实施例6ACE抑制活性测试
（1）ACE的制备
将新鲜的猪肺用遇冷的0.9%NaCL溶液冲洗干净，洗去气管、脂肪，切成小块，去一定量的猪肺组织，用遇冷的含PH8.3、0.1mol/L硼酸盐缓冲液5倍体积进行匀浆，将匀浆液置于冰箱中浸提5小时。4℃下离心（8000rmp）离心15min，得粗提液（上清液）。冷冻干燥待用。
（2）实验方法
取样品配制成4mg/ml的提取物溶液。分别向样品管和空白管加入硼酸盐缓冲液85μL，10μLHHL溶液，向样品管加入10μL提取物溶液，空白管加入10μL硼酸盐缓冲液，37℃温育5min后，向样品管和空白管各加入5μLACE溶液，在37℃条件下反应30min，再向样品管和空白管各加入300μL1.0mol/LHCl中止反应,10000r/min离心10min,吸取上清作为供试品溶液，0.45μm过滤后用于HPLC分析。色谱条件：ThermoBDSHYPERSILC18（250mm*4.6mm，5um），流动相甲醇：0.01%三氟乙酸水溶液（40:60），检测波长228nm，流速0.8mL/min，柱温25℃，进样量20μL。ACE抑制率计算公式如下：R=(A-B)/A×100%，式中，A和B分别为空白组和样品组马尿酸的峰面积。抑制率结果见表1。
结果与分析
通过以上实验，测定的苯丙二苄基丁内酯组合物对ACE抑制活性较原药高。

Claims (2)

1.一种ACE抑制剂，具有降血压的作用，其特征在于：该抑制剂为具有通式I结构的化合物，
通式I
其中，式I中的R为Boc-L-Met,Boc-L-Try,Boc-L-Pro,Boc-L-Phe,Boc-L-Thr氨基酸侧链。
2.权利要求1所述的抑制剂具有明显的抑制ACE活性的作用。
CN201510987617.1A 2015-12-24 2015-12-24 Ace抑制剂木脂内酯组合物及其制备方法与应用 Pending CN105796551A (zh)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105541764A (zh) * 2015-12-24 2016-05-04 吉林农业大学 乙酰胆碱酯酶抑制剂木脂内酯组合物及其制备方法与应用
CN105541764B (zh) * 2015-12-24 2017-12-01 吉林农业大学 乙酰胆碱酯酶抑制剂木脂内酯组合物及其制备方法与应用

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