CN106317176B - 双吲哚-三肽衍生物,其合成,抗血栓活性和制备抗血栓剂的应用 - Google Patents
双吲哚-三肽衍生物,其合成,抗血栓活性和制备抗血栓剂的应用 Download PDFInfo
- Publication number
- CN106317176B CN106317176B CN201510351798.9A CN201510351798A CN106317176B CN 106317176 B CN106317176 B CN 106317176B CN 201510351798 A CN201510351798 A CN 201510351798A CN 106317176 B CN106317176 B CN 106317176B
- Authority
- CN
- China
- Prior art keywords
- asp
- val
- leu
- hydroxyl
- bis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 239000003146 anticoagulant agent Substances 0.000 title claims abstract description 11
- 230000002785 anti-thrombosis Effects 0.000 title claims abstract description 10
- 230000015572 biosynthetic process Effects 0.000 title abstract description 5
- 238000003786 synthesis reaction Methods 0.000 title abstract description 5
- 229960004676 antithrombotic agent Drugs 0.000 title description 2
- QCSFMCFHVGTLFF-NHCYSSNCSA-N Leu-Asp-Val Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O QCSFMCFHVGTLFF-NHCYSSNCSA-N 0.000 claims abstract description 5
- 108010083708 leucyl-aspartyl-valine Proteins 0.000 claims abstract description 5
- SEOVTRFCIGRIMH-UHFFFAOYSA-N indole-3-acetic acid Chemical compound C1=CC=C2C(CC(=O)O)=CNC2=C1 SEOVTRFCIGRIMH-UHFFFAOYSA-N 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- JVTZFYYHCGSXJV-UHFFFAOYSA-N isovanillin Chemical compound COC1=CC=C(C=O)C=C1O JVTZFYYHCGSXJV-UHFFFAOYSA-N 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 3
- 238000006929 Pictet-Spengler synthesis reaction Methods 0.000 claims description 2
- 238000007171 acid catalysis Methods 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 2
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 2
- 238000007127 saponification reaction Methods 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- MSHFRERJPWKJFX-UHFFFAOYSA-N 4-Methoxybenzyl alcohol Chemical compound COC1=CC=C(CO)C=C1 MSHFRERJPWKJFX-UHFFFAOYSA-N 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 abstract description 12
- 238000012986 modification Methods 0.000 abstract description 3
- 230000004048 modification Effects 0.000 abstract description 3
- 239000003112 inhibitor Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 19
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 10
- -1 3- hydroxyl -4- methoxyphenyl Chemical group 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000011780 sodium chloride Substances 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000007832 Na2SO4 Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 210000003462 vein Anatomy 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- HUDBDWIQSIGUDI-UHFFFAOYSA-N Ethyl 3-indoleacetate Chemical compound C1=CC=C2C(CC(=O)OCC)=CNC2=C1 HUDBDWIQSIGUDI-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 description 4
- 210000001367 artery Anatomy 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 4
- 239000004698 Polyethylene Substances 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 3
- 239000004519 grease Substances 0.000 description 3
- 229920000573 polyethylene Polymers 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000003292 diminished effect Effects 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 229960000905 indomethacin Drugs 0.000 description 2
- DVCSNHXRZUVYAM-BQBZGAKWSA-N leu-asp Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(O)=O)CC(O)=O DVCSNHXRZUVYAM-BQBZGAKWSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000002627 tracheal intubation Methods 0.000 description 2
- SOHLZANWVLCPHK-LBPRGKRZSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-oxo-4-phenylmethoxybutanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC(=O)OCC1=CC=CC=C1 SOHLZANWVLCPHK-LBPRGKRZSA-N 0.000 description 1
- IFNDEOYXGHGERA-UHFFFAOYSA-N 2-methoxy-5-methylphenol Chemical compound COC1=CC=C(C)C=C1O IFNDEOYXGHGERA-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- MDXGYYOJGPFFJL-QMMMGPOBSA-N N(alpha)-t-butoxycarbonyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)OC(C)(C)C MDXGYYOJGPFFJL-QMMMGPOBSA-N 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000001168 carotid artery common Anatomy 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 238000002788 crimping Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000003617 indole-3-acetic acid Substances 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
- DSNBHJFQCNUKMA-SCKDECHMSA-N thromboxane A2 Chemical compound OC(=O)CCC\C=C/C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCC)O[C@@H]2O[C@H]1C2 DSNBHJFQCNUKMA-SCKDECHMSA-N 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Indole Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
本发明公开了下式Leu‑Asp‑Val修饰的双吲哚乙酸，即2，2’‑双(1H‑吲哚‑3‑乙酰‑Leu‑Asp‑ValA‑2‑基)‑(3‑羟基‑4‑甲氧基苯基)‑甲烷，公开了它的合成，公开了它的抗血栓活性，因而本发明公开了它作为抗血栓抑制剂的临床应用前景。
Description
发明领域
本发明涉及Leu-Asp-Val修饰的双吲哚乙酸,即2,2’-双(1H-吲哚-3-乙酰-Leu-Asp-ValA-2-基)-(3-羟基-4-甲氧基苯基)-甲烷,涉及它的合成,涉及它的抗血栓活性,因而本发明涉及它作为抗血栓抑制剂的临床应用前景。本发明属于生物医药领域。
背景技术
吲哚乙酸的衍生物吲哚美辛(Indomethacin)除具有抗炎以及解热镇痛作用外，还可以通过抑制血栓素TXA2的合成而抑制血小板的聚集。我们的前期发明披露，通式II的双吲哚衍生物(式中AA为氨基酸残基)在1nml/kg口服剂量下具有抗血栓活性。在急性毒性研究中，发明人发现剂量通式II的双吲哚衍生物的不能溶解。在通式II的双吲哚衍生物的代谢研究中，发明人发现大鼠的粪便中含较高量通式II的双吲哚衍生物。这些发现使发明人认识到，提高双吲哚衍生物的生物利用度至关重要。
经过3年摸索，终于发现将通式II的乙基用3-羟基-4-甲氧基苯基代替，乙酰-AA用乙酰-Leu-Asp-Val替代可以达到改善生物利用度的目标。于是，发明人提出来本发明。
发明内容
本发明的第一个内容是提供下式Leu-Asp-Val修饰的双吲哚乙酸,即2,2’-双(1H-吲哚-3-乙酰-Leu-Asp-Val-2-基)-(3-羟基-4-甲氧基苯基)-甲烷。
本发明的第二个内容是提供2,2’-双(1H-吲哚-3-乙酰-Leu-Asp-Val-2-基)-(3-羟基-4-甲氧基苯基)-甲烷的合成方法，该方法包括：
(1)吲哚乙酸在乙醇中经浓硫酸催化，与异香草醛进行Pictet-Spengler缩合，生成2,2’-双(1H-吲哚-3-乙酸乙酯-2-基)-(3-羟基-4-甲氧基苯基)-甲烷；
(2)2,2’-双(1H-吲哚-3-乙酸乙酯-2-基)-(3-羟基-4-甲氧基苯基)-甲烷在NaOH溶液(4N)中皂化反应生成2,2’-双(1H-吲哚-3-乙酸-2-基)-(3-羟基-4-甲氧基苯基)-甲烷；
(3)按照标准接肽方法制备Leu-Asp(OBzl)-Val-OBzl；
(4)2,2’-双(1H-吲哚-3-乙酸-2-基)-(3-羟基-4-甲氧基苯基)-甲烷与Leu-Asp(OBzl)-Val-OBzl偶联得到2,2’-双(1H-吲哚-3-乙酰-Leu-Asp(OBzl)-Val-OBzl-2-基)-(3-羟基-4-甲氧基苯基)-甲烷；
(5)2,2’-双(1H-吲哚-3-乙酰-Leu-Asp(OBzl)-Val-OBzl-2-基)-(3-羟基-4-甲氧基苯基)-甲烷在甲醇中Pd/C催化氢解生成2,2’-双(1H-吲哚-3-乙酰-Leu-Asp-Val-2-基)-(3-羟基-4-甲氧基苯基)-甲烷。
本发明的第三个内容是评价2,2’-双(1H-吲哚-3-乙酰-Leu-Asp-Val-2-基)-(3-羟基-4-甲氧基苯基)-甲烷的抗栓活性。
附图说明
图1 2,2’-双(1H-吲哚-3-乙酰-Leu-Asp-Val-2-基)-(3-羟基-4-甲氧基苯基)-甲烷的合成路线.i)乙醇,浓硫酸,3-羟基4-甲氧基苯基醛；ii)丙酮,NaOH；iii)HOBt,DCC,NMM；iv)4N氯化氢-乙酸乙酯溶液；v)Pb/c,H2,甲醇。
具体实施方式
为了进一步阐述本发明，下面给出一系列实施例。这些实施例完全是例证性的，它们仅用来对本发明进行具体描述，不应当理解为对本发明的限制。
实施例1制备2,2’-双(1H-吲哚-3-乙酸乙酯-2-基)-(3-羟基-4-甲氧基苯基)-甲烷(1)
1g(5.71mmol)吲哚-3-乙酸溶于40ml无水乙醇，滴加1ml浓硫酸，活化20min。加500mg(3.29mmol)3-羟基4-甲氧基苯基醛，室温反应6h，减压浓缩至干。柱层析纯化(石油醚/丙酮＝9/1-5/1)，得到870mg(57％)标题化合物，为淡黄色糖浆。ESI/MS(m/e):541[M+H]+；1HNMR(300MHz,CDCl3):δ＝8.40(s,2H),7.55(m,2H),7.34(m,2H),7.13(m,4H),6.78(m,3H),6.15(m,1H),4.18(m,4H),3.83(s,3H),3.56(m,4H),1.30(m,6H)。
实施例2制备2,2’-双(1H-吲哚-3-乙酸-2-基)-(3-羟基-4-甲氧基苯基)-甲烷(2)
200mg(0.37mmol)2,2’-双(1H-吲哚-3-乙酸乙酯-2-基)-(3-羟基-4-甲氧基苯基)-甲烷(1)溶于5ml丙酮，4N NaOH调pH＝12。室温反应6h。冰浴下用饱和KHSO4调pH＝7，减压浓缩除去丙酮后，用饱和KHSO4调pH＝2，水层用50ml乙酸乙酯萃取3遍，合并乙酸乙酯层，用饱和NaCl洗至中性，无水Na2SO4干燥。减压过滤，滤液减压浓缩至干，得到172mg(98％)标题化合物，为紫色粉末。ESI/MS(m/e):483[M-H]-；1HNMR(300MHz,DMSO-d6):δ＝8.40(s,2H),7.55(m,2H),7.34(m,2H),7.13(m,4H),6.78(m,3H),6.15(m,1H),3.83(s,3H),3.56(m,4H)。
实施例3制备Boc-Asp(OBzl)-Val-OBzl
将808mg(2.5mmol)Boc-Asp(OBzl)溶于20ml无水THF中，冰浴下加入338mg(2.5mmol)HOBt和619mg(3mmol)DCC,活化30min。往里加558mg(2.3mmol)HCl·Val-Obzl,用N-甲基吗啉调节反应液pH至9,室温反应8h,原料点消失。滤除DCU，减压浓缩得到的油状物用乙酸乙酯溶解，依次用40ml饱和NaHCO3溶液洗3次,40ml饱和NaCl溶液洗3次,40ml饱和KHSO4洗3次,40ml饱和NaCl溶液洗3次,40ml饱和NaHCO3洗3次,40ml饱和NaCl溶液洗3次,乙酸乙酯层用Na2SO4干燥12h，滤除Na2SO4,滤液减压浓缩,得到1.12g(93％)标题化合物,为无色油状液体。ESI-MS(m/z):512.4[M+H]+。
实施例4制备HCl·Asp(OBzl)-Val-OBzl
将1.28g(2.5mmol)Boc-Asp(OBzl)-Val-OBzl溶于少量的干燥乙酸乙酯中,冰浴下加入15ml氯化氢-乙酸乙酯溶液(4N)搅拌3h,原料点消失后减压浓缩,残留物用无水乙醚析晶,得到的目标化合物化合物直接用于下步反应。
实施例5制备Boc-Leu-Asp(OBzl)-Val-OBzl
将575mg(2.5mmol)Boc-Leu溶于20mL无水THF中，冰浴下加入338mg(2.5mmol)HOBt和619mg(3mmol)DCC,反应液活化30min。往里加入1.03g(2.3mmol)HCl·Asp(OBzl)-Val-OBzl，用N-甲基吗啉调反应液pH至9，室温搅拌8h。原料点消失后滤除DCU，减压浓缩得到的油状物用100mL乙酸乙酯溶解，依次用40ml饱和NaHCO3洗3次，40ml饱和NaCl溶液洗3次，40ml饱和KHSO4洗3次，40ml饱和NaCl溶液洗3次，40ml饱和NaHCO3洗3次，40ml饱和NaCl溶液洗3次，乙酸乙酯层用Na2SO4干燥12h。滤除Na2SO4，滤液减压浓缩得到1.24g(83％)标题化合物，为无色固体。ESI-MS(m/z):626[M+H]+。
实施例6制备HCl·Leu-Asp(OBzl)-Val-OBzl
将1.56g(2.5mmol)Boc-Leu-Asp(OBzl)-Val-OBzl溶于少量无水乙酸乙酯中，冰浴下加入20ml氯化氢-乙酸乙酯溶液(4N)搅拌3h,原料点消失后减压浓缩,残留物用无水乙醚析晶,得到的目标化合物化合物直接用于下步反应。
实施例7制备2,2’-双(1H-吲哚-3-乙酰-Leu-Asp(OBzl)-Val-OBzl-2-基)-(3-羟基-4-甲氧基苯基)-甲烷(3)
将1g(2.07mmol)2,2’-双(1H-吲哚-3-乙酸-2-基)-(3-羟基-4-甲氧基苯基)-甲烷(2)溶于50ml无水THF中,冰浴下加入586mg(4.35mmol)HOBt和937mg(4.55mmol)DCC,反应液活化30min。往里加2.38g(4.55mmol)HCl·Leu-Asp(OBzl)-Val-OBzl,用N-甲基吗啉调反应液pH至9,室温搅拌反应8h。原料点消失后滤除DCU，减压浓缩,得到的油状物用100ml乙酸乙酯溶解。溶液依次用40ml饱和NaHCO3洗3次,40ml饱和NaCl溶液洗3次,40ml饱和KHSO4洗3次,40mL饱和NaCl溶液洗3次,40ml饱和NaHCO3洗3次,40mL饱和NaCl溶液洗3次,乙酸乙酯层用Na2SO4干燥12h。滤除Na2SO4,滤液减压浓缩，得到1.70g(55％)标题化合物,为无色固体。ESI-MS(m/z):1499[M+H]+；Mp 121-122℃； 1HNMR(300MHz,CDCl3):δ＝10.6(s,1H),10.09(s,1H),7.39(m,26H),7.12(m,6H),6.58(m,2H),6.25(m,1H),6.23(m,2H),5.96(s,1H),5.79(s,1H),5.10(m,8H),4.89(m,1H),4.79(m,1H),4.49(m,4H),3.85(s,3H),3.55(m,3H),3.18(m,1H),2.88(m,4H),2.15(m,2H),1.59(m,6H),0.83(m,24H)。
实施例8制备2,2’-双(1H-吲哚-3-乙酰-Leu-Asp-Val-2-基)-(3-羟基-4-甲氧基苯基)-甲烷(4)
将50mg(0.03mmol)2,2’-双(1H-吲哚-3-乙酰-Leu-Asp(OBzl)-Val-OBzl-2-基)-(3-羟基-4-甲氧基苯基)-甲烷(3)溶于20ml甲醇,加10mg Pd/C,通入氢气。TLC(石油醚:丙酮1.5:1)检测原料点消失,减压过滤,浓缩至干,得到30mg(79％)标题化合物,为紫色粉末。ESI-MS(m/z):1138[M+H]+；Mp 176-177℃； 1HNMR(300MHz,DMSO-d6):δ＝12.49(s,2H),11.57(s,1H),10.90(m,1H),8.49(m,2H),8.42(m,2H),7.59(m,4H),7.29(m,1H),7.20(s,1H),6.99(s,2H),6.93(m,2H),6.79(m,1H),6.59(s,1H),6.42(m,1H),6.19(s,1H),4.63(m,2H),4.40(m,2H),4.13(m,2H),3.72(s,3H),3.56(m,4H),3.13(m,2H),2.73(dd,J＝16.5,6Hz,2H),2.04(m,2H),1.54(m,2H),1.44(m,4H),0.79(m,24H)。
实施例9评价4d1抗血栓活性
1)聚乙烯管的组装：将聚乙烯管拉成一端为斜口的细管，定长为10.0cm，分别为右经静脉(管径较粗)及左颈动脉(管径较细)插管；中段聚乙烯管定长为8.0cm，血栓线压在颈动脉插管方向，插管前需在管中充满肝素。
2)SD大鼠以0.1nmol/kg剂量4灌胃，30分钟后腹腔注射20％的乌拉坦进行麻醉。仰卧位将大鼠固定于鼠板上，剪开颈部皮肤，分离右颈总动脉及左颈静脉，血管下压线，结扎远心端，静脉靠远心端处剪一小口，进行静脉端插管，注射肝素，系线固定，再用动脉夹夹住动脉近心端，靠近远心端方向剪一小口，进行动脉端结扎，系线固定后松开动脉夹，建立体外循环旁路。循环15分钟后先剪断静脉端观察血液循环是否正常，若正常从动脉端取出血栓线，在纸上沾干浮血后称量并记录其湿重，大鼠断颈处死。每组大鼠10只，最后进行数据统计并评价化合物活性。以栓重表示化合物的活性。表1的数据表明，4具有优秀的抗血栓活性，有效剂量低达0.1nmol/kg，比发明人先前公开的双吲哚化合物的有效剂量低10倍，获得了显著的技术效果。此外，4的有效剂量是阿司匹林的1/1670000。
表1化合物4对SD大鼠栓重的影响
n＝10；a)与生理盐水比,p<0.01；b)与生理盐水比p<0.01,与阿司匹林比,p>0.05。
Claims (3)
1.下式的Leu-Asp-Val修饰的双吲哚乙酸,即2,2’-双-1H-吲哚-3-乙酰-Leu-Asp-Val-2-基-3-羟基-4-甲氧基苯基-甲烷
2.权利要求1的Leu-Asp-Val修饰的双吲哚乙酸,即2,2’-双-1H-吲哚-3-乙酰-Leu-Asp-Val-2-基-3-羟基-4-甲氧基苯基-甲烷的制备方法，该方法包括：
(1)吲哚乙酸在乙醇中经浓硫酸催化，与异香草醛进行Pictet-Spengler缩合，生成2,2’-双-1H-吲哚-3-乙酸乙酯-2-基-3-羟基-4-甲氧基苯基-甲烷；
(2)2,2’-双-1H-吲哚-3-乙酸乙酯-2-基-3-羟基-4-甲氧基苯基-甲烷在4 NNaOH溶液中皂化反应生成2,2’-双-1H-吲哚-3-乙酸-2-基-3-羟基-4-甲氧基苯基-甲烷；
(3)按照标准接肽方法制备Leu-β-羧基-OBzl-Asp-Val-OBzl；
(4)2,2’-双-1H-吲哚-3-乙酸-2-基-3-羟基-4-甲氧基苯基-甲烷与Leu-β-羧基-OBzl-Asp-Val-OBzl偶联得到2,2’-双-1H-吲哚-3-乙酰-Leu-β-羧基-OBzl-Asp-Val-OBzl-2-基-3-羟基-4-甲氧基苯基-甲烷；
(5)2,2’-双-1H-吲哚-3-乙酰-Leu-β-羧基-OBzl-Asp-Val-OBzl-2-基-3-羟基-4-甲氧基苯基-甲烷在甲醇中Pd/C催化氢解生成2,2’-双-1H-吲哚-3-乙酰-Leu-Asp-Val-2-基-3-羟基-4-甲氧基苯基-甲烷。
3.权利要求1的2,2’-双-1H-吲哚-3-乙酰-Leu-Asp-Val-2-基-3-羟基-4-甲氧基苯基-甲烷在制备抗血栓药物中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510351798.9A CN106317176B (zh) | 2015-06-23 | 2015-06-23 | 双吲哚-三肽衍生物,其合成,抗血栓活性和制备抗血栓剂的应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510351798.9A CN106317176B (zh) | 2015-06-23 | 2015-06-23 | 双吲哚-三肽衍生物,其合成,抗血栓活性和制备抗血栓剂的应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106317176A CN106317176A (zh) | 2017-01-11 |
| CN106317176B true CN106317176B (zh) | 2019-07-26 |
Family
ID=57727774
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510351798.9A Expired - Fee Related CN106317176B (zh) | 2015-06-23 | 2015-06-23 | 双吲哚-三肽衍生物,其合成,抗血栓活性和制备抗血栓剂的应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106317176B (zh) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0537532B1 (en) * | 1991-10-07 | 1996-11-27 | Nisshin Flour Milling Co., Ltd. | 2,2'-Alkylenediindole derivatives, process for their production, medicines containing them and their use as anti-ulcer agents |
| CN103450067A (zh) * | 2012-05-29 | 2013-12-18 | 首都医科大学 | 乙基连接的双吲哚-3-基-乙酰氨基酸、其制备、抗血栓作用和应用 |
| CN103539722A (zh) * | 2012-07-10 | 2014-01-29 | 永光制药有限公司 | 芳基取代甲基连接的双吲哚乙酸衍生物及其制备方法和应用 |
-
2015
- 2015-06-23 CN CN201510351798.9A patent/CN106317176B/zh not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0537532B1 (en) * | 1991-10-07 | 1996-11-27 | Nisshin Flour Milling Co., Ltd. | 2,2'-Alkylenediindole derivatives, process for their production, medicines containing them and their use as anti-ulcer agents |
| CN103450067A (zh) * | 2012-05-29 | 2013-12-18 | 首都医科大学 | 乙基连接的双吲哚-3-基-乙酰氨基酸、其制备、抗血栓作用和应用 |
| CN103539722A (zh) * | 2012-07-10 | 2014-01-29 | 永光制药有限公司 | 芳基取代甲基连接的双吲哚乙酸衍生物及其制备方法和应用 |
Non-Patent Citations (1)
| Title |
|---|
| Nitro-substituted 3,3"-bis(indolyl)methane derivatives as anion receptors: electron-withdrawing effect and tunability of anion binding properties.;Wang L, et al.;《Spectrochimica Acta Part A》;20110228;第78卷(第2期);全文 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106317176A (zh) | 2017-01-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Dakin et al. | A general reaction of amino acids | |
| Westall | The amino acids and other ampholytes of urine. 2. The isolation of a new sulphur-containing amino acid from cat urine | |
| CN109912597A (zh) | 七环醛,其合成,抗栓活性和应用 | |
| CN111793067B (zh) | 二羟甲基四氢咔啉-3-甲酰-The其合成, 活性和应用 | |
| EP4269407A1 (en) | Near-infrared fluorescent probe specifically targeting tumor, synthesis method therefor, and use thereof | |
| CN106866572B (zh) | 一氧化氮供体型β‑榄香烯衍生物及其制备方法和用途 | |
| BR112020023269A2 (pt) | inibidores de metaloproteinases de matriz (mmps) e métodos de uso do mesmo | |
| CN106317176B (zh) | 双吲哚-三肽衍生物,其合成,抗血栓活性和制备抗血栓剂的应用 | |
| US2460708A (en) | Process for making acetamido dimethylacrylic acid | |
| Cook et al. | 50. Studies in the azole series. Part III. The interaction of aminoacetonitrile and carbon disulphide | |
| CN106317169B (zh) | 双吲哚-二肽衍生物,其合成,抗血栓活性和制备抗血栓剂的应用 | |
| Hill et al. | A new synthesis of methionine and a scheme relating certain α-amino-acids | |
| CN106316918B (zh) | 氨基酸修饰的双吲哚,其合成,抗血栓活性和制备抗血栓剂的应用 | |
| Bickel | The addition of malonic esters to an acetylenic ketone | |
| Harington et al. | Synthesis of the d-and l-3: 4-dihydroxyphenylalanines | |
| Leaf et al. | The preparation of homogentisic acid and of 2: 5-dihydroxyphenylethylamine | |
| Pryde et al. | The biochemistry and physiology of glucuronic acid: The structure of glucuronic acid of animal origin | |
| Benoiton et al. | AN IMPROVED SYNTHESIS OF ϵ-N-ACETYL-l-LYSINE AND SIMILAR COMPOUNDS | |
| Tryding et al. | Synthesis and metabolism of 2, 2-dimethylnonadecanoic acid | |
| Balajthy | An improved preparation of N-benzyloxycarbonyl-L-lysine methyl ester hydrochloride | |
| Lawson et al. | Synthesis of the Sulfur Analogs of Batyl and Chimyl Alcohols | |
| CN101723848B (zh) | 新型18f标记间硝基苯甲酰基氨基酸、制备方法和在肿瘤显像中的应用 | |
| BARNES et al. | Bicyclic ortho esters by direct esterification | |
| CN101906097B (zh) | 1,3-二氧六环类化合物及其合成方法和在医学中应用 | |
| FR2555577A1 (fr) | Nouveaux derives de peptides, leur procede de preparation et leur emploi comme reactif biologique |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20190726 |