CN112010928A - 乙基pak修饰的双咔啉并哌嗪二酮,其制备,活性和应用 - Google Patents
乙基pak修饰的双咔啉并哌嗪二酮,其制备,活性和应用 Download PDFInfo
- Publication number
- CN112010928A CN112010928A CN201910465459.1A CN201910465459A CN112010928A CN 112010928 A CN112010928 A CN 112010928A CN 201910465459 A CN201910465459 A CN 201910465459A CN 112010928 A CN112010928 A CN 112010928A
- Authority
- CN
- China
- Prior art keywords
- tetrahydro
- ala
- pro
- ethyl
- dione
- 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.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 230000000694 effects Effects 0.000 title claims description 15
- 208000032382 Ischaemic stroke Diseases 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 16
- 230000002785 anti-thrombosis Effects 0.000 claims abstract description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 10
- 230000002537 thrombolytic effect Effects 0.000 claims abstract description 8
- 239000003146 anticoagulant agent Substances 0.000 claims abstract description 4
- -1 1-carbonylmethyl Chemical group 0.000 claims description 20
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 10
- FYQSMXKJYTZYRP-DCAQKATOSA-N Pro-Ala-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 FYQSMXKJYTZYRP-DCAQKATOSA-N 0.000 claims description 9
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 8
- XLSNBAQCWFBMET-ANYOKISRSA-N benzyl (3S)-1-(2,2-dimethoxyethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate Chemical compound COC(CC1N[C@@H](CC2=C1NC1=CC=CC=C21)C(=O)OCC1=CC=CC=C1)OC XLSNBAQCWFBMET-ANYOKISRSA-N 0.000 claims description 6
- NRYLNSILOSCBDD-ABLWVSNPSA-N (3S)-1-(2,2-dimethoxyethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid Chemical compound COC(CC1N[C@@H](CC=2C3=CC=CC=C3NC1=2)C(=O)O)OC NRYLNSILOSCBDD-ABLWVSNPSA-N 0.000 claims description 5
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 4
- 238000004176 ammonification Methods 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000007791 liquid phase Substances 0.000 claims description 2
- 239000003527 fibrinolytic agent Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 37
- 208000007536 Thrombosis Diseases 0.000 abstract description 34
- 229940079593 drug Drugs 0.000 abstract description 8
- 241000700159 Rattus Species 0.000 description 43
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- 239000011780 sodium chloride Substances 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- 239000007787 solid Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 210000001367 artery Anatomy 0.000 description 12
- 239000004698 Polyethylene Substances 0.000 description 11
- 229920000573 polyethylene Polymers 0.000 description 11
- 229920006395 saturated elastomer Polymers 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 10
- 239000002504 physiological saline solution Substances 0.000 description 10
- 210000001168 carotid artery common Anatomy 0.000 description 9
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 9
- 210000003462 vein Anatomy 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 208000032843 Hemorrhage Diseases 0.000 description 5
- 208000034158 bleeding Diseases 0.000 description 5
- 230000000740 bleeding effect Effects 0.000 description 5
- 230000017531 blood circulation Effects 0.000 description 5
- 210000000269 carotid artery external Anatomy 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 4
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 4
- 229960001138 acetylsalicylic acid Drugs 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 210000004004 carotid artery internal Anatomy 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 229920001971 elastomer Polymers 0.000 description 4
- 210000004731 jugular vein Anatomy 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 4
- 229960005356 urokinase Drugs 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007928 intraperitoneal injection Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 230000004580 weight loss Effects 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 210000001715 carotid artery Anatomy 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 2
- 230000007971 neurological deficit Effects 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 210000004761 scalp Anatomy 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000012353 t test Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 210000003437 trachea Anatomy 0.000 description 2
- XHTYQFMRBQUCPX-UHFFFAOYSA-N 1,1,3,3-tetramethoxypropane Chemical compound COC(OC)CC(OC)OC XHTYQFMRBQUCPX-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000004873 anchoring Methods 0.000 description 1
- TYQYRKDGHAPZRF-INIZCTEOSA-N benzyl (2s)-2-amino-3-(1h-indol-3-yl)propanoate Chemical compound O=C([C@H](CC=1C2=CC=CC=C2NC=1)N)OCC1=CC=CC=C1 TYQYRKDGHAPZRF-INIZCTEOSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- RERZNCLIYCABFS-UHFFFAOYSA-N harmaline Chemical compound C1CN=C(C)C2=C1C1=CC=C(OC)C=C1N2 RERZNCLIYCABFS-UHFFFAOYSA-N 0.000 description 1
- 239000002874 hemostatic agent Substances 0.000 description 1
- 230000002439 hemostatic effect Effects 0.000 description 1
- 229960001008 heparin sodium Drugs 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000004804 winding Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
- C07K5/0823—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp and Pro-amino acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明公开了下式的(2’S,5’S)‑四氢吡嗪[1’,2’:1,6]并双[1S,1R‑(1‑乙基‑Pro‑Ala‑Lys)‑2,3,4,9‑四氢‑1H‑吡啶[3,4‑b]并吲哚]‑1’,4’‑二酮,公开了它的制备方法,公开了它的溶血栓活性,公开了它的抗血栓活性以及公开了它对缺血性中风发作24小时仍然有效的特征。因而本发明公开了它在制备溶血栓药物中的应用,公开了它在制备抗血栓药物中的应用,公开了它在制备对缺血性中风发作24小时仍然有效的药物中的应用以及公开了它在制备具有溶血栓,抗血栓及对缺血性中风发作24小时仍然有效的三重作用的药物中的应用。
Description
技术领域
本发明涉及(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-乙基-Pro-Ala-Lys)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮,涉及它的制备方法,涉及它的溶血栓活性,涉及它的抗血栓活性以及涉及它对缺血性中风发作24小时仍然有效的特征。因而本发明涉及它在制备溶血栓药物中的应用,涉及它在制备抗血栓药物中的应用,涉及它在制备缺血性中风发作24小时仍然有效的药物中的应用以及涉及它在制备具有溶血栓,抗血栓及对缺血性中风发作24小时仍然有效的三重作用的药物中的应用。本发明属于生物医药领域。
技术背景
缺血性中风是常见的危害严重的脑血管疾病。缺血性中风以发病率高,致残率高,复发率高和死亡率高为特点,是人类最严重的致死性疾病之一。目前，rtPA是临床公认的治疗缺血性中风的唯一有效药物。然而,rtPA治疗缺血性中风存在两个难以逾越的难题。第一个难题是rtPA对缺血性中风发作4小时以上的患者没有疗效。第二个难题是连续使用rtPA可引起脑,胸腔及腹腔出血。发明对中风发作4小时以上尤其对发作24小时患者有效又无出血副作用的药物是脑血管药物研究的热点与前沿。经过数年探索,发明人发现在双咔啉并哌嗪二酮引入乙基-Pro-Ala-Lys生成的下式的(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-乙基-Pro-Ala-Lys)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮不仅有溶血栓活性,有抗血栓活性,对缺血性中风发作24小时仍有疗效,而且没有出血副作用。根据这些发现，发明人提出了本发明。
发明内容
本发明的第一个内容是提供下式的(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-乙基-Pro-Ala-Lys)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮。
本发明的第二个内容是提供(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-乙基-Pro-Ala-Lys)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮的制备方法，该方法包括以下7个步骤：
(1)制备(3S)-1-(2,2-二甲氧乙-1-基)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯；
(2)制备(3S)-1-(2,2-二甲氧乙-1-基)-2,3,4,9-四氢-β-咔啉-3-羧酸；
(3)制备(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-二甲氧乙-1-基)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮；
(4)制备(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-羰甲基)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮；
(5)采用N,N’-二环己基碳二亚胺为缩合剂,1-羟基苯并三唑为催化剂的液相法合成Pro-Ala-Lys(Cbz)-OBzl；
(6)采用氨化还原法将(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-羰甲基)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮与Pro-Ala-Lys(Cbz)-OBzl反应制备(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-乙基-Pro-Ala-Lys(Cbz)-OBzl)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮；
(7)制备(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-乙基-Pro-Ala-Lys)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮。
本发明的第三个内容是评价(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-乙基-Pro-Ala-Lys)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮的溶血栓活性。
本发明的第四个内容是评价(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-乙基-Pro-Ala-Lys)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮的抗血栓活性。
本发明的第五个内容是评价(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-乙基-Pro-Ala-Lys)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮对缺血性中风发作24小时的大鼠的疗效。
附图说明
图1(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-乙基-Pro-Ala-Lys)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮的合成路线。i)三氟乙酸,二氯甲烷,40℃；ii)NaOH水溶液(2M),丙酮,0℃；iii)2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯,N-甲基吗啉,N,N-二甲基甲酰胺；iv)冰醋酸,水；v)N,N’-二环己基碳二亚胺,1-羟基苯并三唑,N-甲基吗啉,四氢呋喃；vi)NaOH水溶液(2M),甲醇,0℃；vii)氯化氢的乙酸乙酯溶液(4M),0℃；viii)N-甲基吗啉,氰基硼氢化钠,无水硫酸镁,二氯甲烷,甲醇；ix)钯碳(Pd/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(3S)-1-(2,2-二甲氧乙-1-基)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯(1)
于0℃与搅拌下将向150mL二氯甲烷中加入5mL 1,1,3,3-四甲氧基丙烷及3.5mL三氟乙酸，反应40分钟后，加入5g(17.00mmol)Trp-OBzl，于40℃进行反应。反应4小时后，于0℃与搅拌下用浓氨水将反应液pH值调节至7，减压浓缩，残留物用100mL二氯甲烷溶解，依次用饱和碳酸氢钠水溶液洗3次，饱和氯化钠水溶液洗3次，二氯甲烷相用无水硫酸钠干燥12小时，过滤，滤液减压浓缩至干，得到黄色油状物，经硅胶柱层析纯化，得到5.50g(82％)标题化合物，为黄色油状物。ESI-MS(m/e):395[M+H]+。
实施例2制备(3S)-1-(2,2-二甲氧乙-1-基)-2,3,4,9-四氢-β-咔啉-3-羧酸(2)
将5.50g(13.96mmol)(3S)-1-(2,2-二甲氧基乙-1-基)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯(1)溶于50mL丙酮中，于0℃与搅拌下向其中加入NaOH水溶液(2M)，调节溶液pH值为12，反应3小时，保持反应液pH值为12。之后，用饱和硫酸氢钾水溶液调节pH值至中性，减压浓缩。残留物中加入50mL丙酮，过滤除去不溶固体，滤液减压浓缩至干，得到3.63g(86％)标题化合物，为黄色黏状物。ESI-MS(m/e):303[M-H]-。
实施例3制备(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-二甲氧乙-1-基)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮(3)
将3.63g(11.94mmol)(3S)-1-(2,2-二甲氧乙-1-基)-2,3,4,9-四氢-β-咔啉-3-羧酸(2)溶于20mL无水N,N-二甲基甲酰胺中，之后加5.44g(14.32mmol)2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，溶液于0℃与搅拌下用N-甲基吗啉调节溶液pH值至8，室温搅拌16小时后，向反应液中加150mL蒸馏水，之后用二氯甲烷萃取(50mL×3),合并二氯甲烷相,再用饱和氯化钠水溶液洗(50mL×3),二氯甲烷相用无水硫酸钠干燥12小时,过滤,滤液减压浓缩至干,得到的黄色油状物经硅胶柱层析纯化,得到0.73g(21％)标题化合物,为淡黄色固体。ESI-MS(m/e):573[M+H]+。
实施例4制备(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-羰甲基)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮(4)
将0.30g(0.52mmol)(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双{1S,1R-(1-二甲氧乙-1-基)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚}-1’,4’-二酮(3)溶于20mL冰醋酸中，加入2mL蒸馏水，室温搅拌反应48小时后，过滤，滤饼用蒸馏水洗去残留的冰醋酸，晾干，得0.22g(87％)标题化合物，为无色固体。ESI-MS(m/e):479[M-H]-。
实施例5制备Boc-Pro-Ala-OBzl
将5.00g(23.25mmol)Boc-Pro溶于20mL无水四氢呋喃中，于0℃与搅拌下加入2.86g(21.18mmol)1-羟基苯并三唑，5.23g(25.39mmol)N,N’-二环己基碳二亚胺，于0℃与搅拌下搅拌30分钟。之后向其中加入3.79g(21.17mmol)Ala-OBzl，用N-甲基吗啉调节pH值至8，室温搅拌16小时。过滤除去不溶固体，滤液减压浓缩，残留物用100mL乙酸乙酯溶解，过滤除去不溶固体，滤液依次分别用饱和碳酸氢钠水溶液洗(30mL×3)，饱和氯化钠水溶液洗(30mL×3)，5％硫酸氢钾水溶液洗(30mL×3)，饱和氯化钠水溶液洗(30mL×3)，饱和碳酸氢钠水溶液洗(30mL×3)及饱和氯化钠水溶液洗(30mL×3)，乙酸乙酯相用无水硫酸钠干燥12小时，过滤，滤液减压浓缩至干，得6.93g(87％)标题化合物，为无色固体。ESI-MS(m/e):377[M+H]+。
实施例6制备Boc-Pro-Ala
将6.93g(18.43mmol)Boc-Pro-Ala-OBzl溶于30mL甲醇中，于0℃与搅拌下向其中加入NaOH水溶液(2M)，调节pH值为12，搅拌3小时，保持反应液pH值为12。之后用饱和硫酸氢钾水溶液调节pH值至中性，减压浓缩。残留物加入100mL蒸馏水，再用饱和硫酸氢钾水溶液调节pH值至2，用乙酸乙酯萃取(30mL×3)，合并乙酸乙酯相，用饱和氯化钠水溶液洗(30mL×3)，将乙酸乙酯相用无水硫酸钠干燥12小时，过滤，滤液减压浓缩至干，得到4.80g(91％)标题化合物，为无色油状物。ESI-MS(m/e):285[M-H]-。
实施例7制备Boc-Pro-Ala-Lys(Cbz)-OBzl
用实施例5的方法从4.80g(16.78mmol)Boc-Pro-Ala与5.64g(15.24mmol)Lys(Cbz)-OBzl得到7.65g(79％)标题化合物，为无色固体。ESI-MS(m/e):639[M+H]+。
实施例8制备Pro-Ala-Lys(Cbz)-OBzl
于0℃和搅拌下将0.40g(0.63mmol)Boc-Pro-Ala-Lys(Cbz)-OBzl用5mL氯化氢的乙酸乙酯溶液(4M)溶解，之后继续搅拌4小时。将反应液减压浓缩，残留物用5mL无水乙酸乙酯溶解，再减压浓缩。该操作反复3次。得到的无色固体用5mL无水乙醚充分悬浮，洗去游离氯化氢，得到0.33g(97％)标题化合物，为无色固体，直接用于下步反应。
实施例9制备(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-乙基-Pro-Ala-Lys(Cbz)-OBzl)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮(5)
将0.33g(0.61mmol)Pro-Ala-Lys(Cbz)-OBzl溶于5mL二氯甲烷中，用N-甲基吗啉将pH调至8，得到反应液A。将0.10g(0.21mmol)(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-羰甲基)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮(4)悬浮于5mL二氯甲烷，用N-甲基吗啉将pH调至8，得到反应液B。先将反应液B加入到反应液A中，然后依次加50mg无水硫酸镁和2mL甲醇。得到的反应混合物室温搅拌，并每隔30分钟加一次氰基硼氢化钠，共加4次，每次加16mg(0.26mmol)总共加64mg(1.03mmol)。反应混合物室温搅拌16小时。之后，反应混合物减压浓缩，残留物溶解于15mL二氯甲烷中，滤去不溶物，滤液减压浓缩，得到的淡黄色黏状固体经硅胶柱层析纯化，得到0.18g(57％)标题化合物，为无色固体。ESI-MS(m/e):1525[M+H]+.1H NMR(300MHz,DMSO-d6):δ/ppm＝11.24(s,1H),11.09(s,1H),8.44(d,J＝6.9Hz,1H),8.30(d,J＝6.6Hz,2H),7.95(d,J＝7.5Hz,1H),7.46(m,2H),7.35(m,22H),7.22(m,2H),7.07(m,2H),6.99(m,2H),5.81(m,1H),5.23(m,1H),5.10(m,2H),5.08(m,2H),4.99(m,2H),4.98(m,2H),4.45(m,2H),4.25(m,4H),3.55(m,2H),3.48(m,2H),2.89(m,7H),2.77(m,3H),2.27(m,2H),2.07(m,6H),1.75(m,4H),1.60(m,6H),1.31(m,5H),1.23(m,3H),1.16(m,4H),1.09(m,4H).13C NMR(125MHz,DMSO-d6):δ/ppm＝172.9,172.5,172.2,172.1,169.3,164.8,156.5,137.7,136.7,136.6,136.4,136.3,132.8,128.8,128.5,128.3,128.2,126.4,126.2,121.6,119.3,119.1,118.3,118.2,111.8,107.6,105.1,67.7,67.1,66.4,65.6,65.4,57.4,54.4,53.4,52.6,51.3,50.7,48.2,47.6,45.0,32.2,30.8,30.1,29.9,29.5,29.4,29.2,25.4,23.6,23.2,23.0,21.5,19.0,18.8。
实施例10制备(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-乙基-Pro-Ala-Lys)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮(6)
将0.18g(0.12mmol)(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-乙基-Pro-Ala-Lys(Cbz)-OBzl)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮(5)溶于8mL甲醇中。然后依次向内加40mg钯碳(Pd/C)和2滴甲酸。反应混合物室温通氢气并搅拌16小时。之后，滤去Pd/C。滤液减压浓缩，残留物用8mL甲醇溶解。往得到的溶液中再加另外40mg Pd/C和2滴甲酸，然后室温通氢气并搅拌16小时。之后，滤去Pd/C，滤液减压浓缩，得到的无色固体经Sephadex纯化，得到0.10g(77％)标题化合物，为无色固体。Mp 188～189℃；
＝-76.6(c＝0.1,H2O)；ESI-MS(m/e):1077[M+H]+.1H NMR(300MHz,MeOD):δ/ppm＝11.77(s,1H),11.22(s,1H),8.20(m,1H),7.84(m,1H),7.65(m,2H),7.48(m,2H),7.39(m,2H),7.32(m,2H),7.06(m,2H),7.00(m,2H),5.77(m,1H),5.26(m,1H),4.56(m,1H),4.42(m,1H),4.30(m,1H),4.16(m,1H),4.04(m,1H),3.73(m,1H),3.50(m,2H),2.84(m,4H),2.76(m,4H),2.68(m,2H),2.15～2.28(m,10H),1.71(m,3H),1.58(m,9H),1.32(m,3H),1.19(m,11H).13C NMR(125MHz,MeOD):δ/ppm＝177.0,176.7,175.8,175.3,172.6,172.2,169.4,165.4,136.8,136.7,132.7,132.2,129.1,127.8,126.2,126.1,121.4,119.0,118.9,117.5,117.4,111.1,107.7,104.8,68.2,67.4,65.1,57.8,57.3,54.2,54.0,53.4,52.9,52.5,52.3,44.0,41.9,41.8,39.1,38.9,32.5,32.2,32.0,31.9,31.6,29.8,29.5,26.6,25.1,23.2,21.9,20.3,16.8,16.7.IR(cm-1):3415.61,3198.07,3047.73,2879.58,1649.75,1559.44,1428.16,1331.83,1262.91,1070.49,984.26,742.59,612.15。
实验例1评价化合物6的溶血栓活性
将雄性SD大鼠(200±20g)随机分组，每组8只，静息饲养一天。将大鼠用20％乌拉坦的生理盐水溶液腹腔注射麻醉。麻醉大鼠仰卧位固定，分离右颈总动脉，于近心端夹动脉夹，近心端和远心端分别穿入手术线，将远心端的手术线于皮毛用止血钳夹紧，在远心端插管，松开动脉夹，放出约1mL动脉血，装在1mL子弹头中。往垂直固定的橡胶管(长15mm，内径2.5mm，外径5.0mm，管底用胶塞密封，para膜封紧)中注入0.1mL大鼠动脉血液，往管内迅速插入一支不锈钢质料的血栓固定螺栓。该血栓固定螺栓用直径为0.2mm的不锈钢丝绕成，螺旋部分长10mm，含15个螺圈，螺圈的直径为1.0mm，托柄与螺旋相连，长7.0mm，呈问号型。血液凝固40分钟后，从橡胶管中小心取出被血栓包裹的血栓固定螺栓，精确称血栓固定螺栓的起始重量。
旁路插管由三段构成。中段是长60mm内径3.5mm的聚乙烯胶管。两侧段均为长100mm，内径1.0mm，外径2.0mm的聚乙烯管。聚乙烯管的一端拉成长10mm外径1.0mm的尖(用于插入大鼠颈动脉及静脉)，聚乙烯管的另一端的外部套一段长7mm外径3.5mm的聚乙烯管(用于连接中段聚乙烯管)。3段管的内壁均需硅烷化(1％的硅油乙醚溶液)。将精确称重的血栓包裹的血栓固定螺栓置于中段聚乙烯管内。
继续分离麻醉大鼠的气管，并做气管插管。分离大鼠的左颈外静脉，近心端和远心端分别穿入手术线，在暴露的左颈外静脉上小心地剪一斜口。将制好的旁路管道的尖管由斜口插入左颈外静脉开口的近心端，并远离旁路管中段内血栓固定螺旋的托柄。用注射器通过另一端的尖管推入准确量的肝素钠的生理盐水溶液(50IU/kg)，此时注射器不要撤离聚乙烯管。用止血钳夹住注射器与聚乙烯管之间的软管。在右颈总动脉的近心端用动脉夹止血，在离动脉夹不远处将右颈总动脉小心地剪一斜口。从聚乙烯管的尖部拔出注射器，将聚乙烯管的尖部插入动脉斜口的近心端。旁路管道的两端都用4号手术缝线将动静脉固定。
将含生理盐水(3mL/kg)或尿激酶的生理盐水溶液(20000IU/kg)或化合物6的生理盐水溶液(100nmol/kg)的头皮针刺入旁路管中段的远离血栓固定螺旋的近静脉处，打开动脉夹，使血流通过旁路管道从动脉流向静脉。将头皮针中的生理盐水(空白对照)，尿激酶(阳性对照)或化合物6缓慢注入旁路管中段，使之通过血液循环按静脉-心脏-动脉的顺序作用到血栓上。从开始注射时计时，1小时后从旁路管中段取出血栓固定螺栓，精确称血栓固定螺栓的终末重量。血栓固定螺栓的起始重量与终末重量的差即为血栓减重。计算每只大鼠的血栓减重，统计各组大鼠的血栓减重并做t检验。实验数据见表1。可以看到，在100nmol/kg剂量下化合物6治疗的大鼠的血栓减重(28.63±3.41mg)显著大于生理盐水治疗的大鼠的血栓减重(23.18±1.40mg,P<0.01)。此外，在100nmol/kg剂量下化合物6治疗的大鼠的血栓减重与20000IU/kg剂量尿激酶治疗的大鼠的血栓减重(27.61±3.47mg,P>0.05)无显著性差异。化合物6的优秀溶血栓活性说明本发明有突出的技术效果。
表1化合物6的溶血栓活性
a)与生理盐水比P<0.01；b)与生理盐水比P<0.01,与尿激酶比P>0.05；n＝8.
实验例2评价化合物6的抗血栓活性
本实验使用与实验例1相同的旁路插管。将雄性SD大鼠(200±20g)，随机分组，每组10只，饲养1天，停止喂食过夜。灌胃给予化合物6的生理盐水溶液(剂量100nmol/kg)或阿司匹林的生理盐水溶液(剂量167μmol/kg)或生理盐水(剂量3mL/kg)。给药30分钟后，将大鼠用20％乌拉坦的生理盐水溶液腹腔注射麻醉。麻醉后将大鼠固定于大鼠固定板上，分离大鼠的右颈动脉和左颈静脉，将准确称重的丝线置于旁路插管，管的一端插入左静脉，另一端管插入右侧动脉并注射0.2mL肝素钠抗凝。使得血流从右侧动脉流经旁路插管进入左侧静脉，15分钟之后取出附有血栓的丝线称量，计算血液循环前后丝线的重量差。该差值即为血栓重，代表抗血栓活性。统计各组大鼠的血栓重，作t检验。实验数据见表2。可以看出，在100nmol/kg口服剂量下化合物6治疗的大鼠的栓重(17.70±2.63mg)显著小于生理盐水治疗的大鼠的栓重(26.55±4.61mg,P<0.01)。此外，在100nmol/kg口服剂量下化合物6治疗的大鼠的栓重与167μmol/kg口服剂量下阿司匹林治疗的大鼠的栓重(17.08±2.80mg,P>0.05)相比无显著性差异。也就是说，即使剂量低1670倍化合物6的抗动脉血栓活性仍然与阿司匹林相当。化合物6的优秀抗血栓活性说明本发明有突出的技术效果。
表2化合物6的抗血栓活性
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；n＝10.
实验例3评价化合物6对缺血性中风24小时大鼠的治疗作用
雄性SD大鼠(280±20g)用10％水合氯醛(4mL/kg)腹腔注射麻醉。在大鼠的颈部正中部竖直开约2cm长切口，沿胸锁乳突肌内侧缘分离出右颈总动脉,颈外动脉及颈内动脉。用无创动脉夹分别夹闭颈内动脉开口处和颈总动脉近心端,结扎颈外动脉的远心端,在颈外动脉剪一小口,松开颈总动脉近心端的动脉夹,取10μL血入1mL离心管。之后,再用无创动脉夹夹闭颈总动脉的近心端。将离心管中的血常温放置30分钟使凝固，然后-20℃过夜使血块凝结实。取出血液凝块，加入1mL生理盐水，用钢铲把血液凝块捣成大小均一的细小血栓块，制备细小血栓的悬液并转移至1mL注射器内。松开大鼠颈总动脉近心端的动脉夹，将1mL血栓混悬液缓慢从大鼠颈外动脉向近心端经过颈内动脉注入大鼠的大脑，然后结扎颈外动脉近心端，打开颈内动脉和颈总动脉处的动脉夹，恢复血流。等待苏醒。大鼠苏醒24小时后按Zealonga方法评定神经功能缺损程度。0分表示无任何神经功能缺失体征，1分表示未损伤侧前肢不能伸展，2分表示向未损伤侧行走，3分表示向未损伤侧转圈成追尾状行走，4分表示意识障碍无自主行走，5分表示死亡。按照得分将大鼠均匀分组。各组大鼠每天经尾静脉注射1次生理盐水(3mL/kg/d)或rtPA(3mg/kg/d)或化合物6(10nmol/kg/d)。连续注射3天,每天评分。根据评分计算各组大鼠死亡率＝死亡只数/总只数×100％；显效率＝最后一天评分低于给药前评分但不为0的只数/总只数×100％；治愈率＝最后一天评分为0的只数/总只数×100％。数据见表3,表4及表5。结果表明,化合物6治疗的大鼠的死亡率低于生理盐水治疗的大鼠的死亡率而治愈率远远高于生理盐水治疗的治愈率。此外,化合物6治疗大鼠的死亡率低于rtPA治疗大鼠的死亡率而治愈率与rtPA治疗的治愈率持平。rtPA治疗引起大鼠全身出血,化合物6没有出血副作用。可见,本发明有突出的技术效果。
表3生理盐水对缺血性中风发作24小时大鼠神经生物学评分的影响
表4 rtPA对缺血性中风发作24小时大鼠神经生物学评分的影响
表5化合物6对缺血性中风发作24小时大鼠神经生物学评分的影响
Claims (6)
1.结构如下的(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-乙基-Pro-Ala-Lys)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮,
2.权利要求1的(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-乙基-Pro-Ala-Lys)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮的制备方法，该方法包括以下7个步骤：
(1)制备(3S)-1-(2,2-二甲氧乙-1-基)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯；
(2)制备(3S)-1-(2,2-二甲氧乙-1-基)-2,3,4,9-四氢-β-咔啉-3-羧酸；
(3)制备(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-二甲氧乙-1-基)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮；
(4)制备(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-羰甲基)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮；
(5)采用N,N’-二环己基碳二亚胺为缩合剂,1-羟基苯并三唑为催化剂的液相法合成Pro-Ala-Lys(Cbz)-OBzl；
(6)采用氨化还原法将(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-羰甲基)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮与Pro-Ala-Lys(Cbz)-OBzl反应制备(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-乙基-Pro-Ala-Lys(Cbz)-OBzl)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮；
(7)制备(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-乙基-Pro-Ala-Lys)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮。
3.权利要求1的(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-乙基-Pro-Ala-Lys)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮在制备溶血栓药物中的应用。
4.权利要求1的(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-乙基-Pro-Ala-Lys)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮在制备抗血栓药物中的应用。
5.权利要求1的(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-乙基-Pro-Ala-Lys)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮在制备对缺血性中风发作24小时仍然有效的药物中的应用。
6.权利要求1的(2’S,5’S)-四氢吡嗪[1’,2’:1,6]并双[1S,1R-(1-乙基-Pro-Ala-Lys)-2,3,4,9-四氢-1H-吡啶[3,4-b]并吲哚]-1’,4’-二酮在制备具有溶血栓,抗血栓及对缺血性中风发作24小时仍然有效的三重作用的药物中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910465459.1A CN112010928B (zh) | 2019-05-30 | 2019-05-30 | 乙基pak修饰的双咔啉并哌嗪二酮,其制备,活性和应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910465459.1A CN112010928B (zh) | 2019-05-30 | 2019-05-30 | 乙基pak修饰的双咔啉并哌嗪二酮,其制备,活性和应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112010928A true CN112010928A (zh) | 2020-12-01 |
| CN112010928B CN112010928B (zh) | 2022-04-22 |
Family
ID=73500935
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910465459.1A Expired - Fee Related CN112010928B (zh) | 2019-05-30 | 2019-05-30 | 乙基pak修饰的双咔啉并哌嗪二酮,其制备,活性和应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112010928B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114763354A (zh) * | 2021-01-12 | 2022-07-19 | 首都医科大学 | 七环吲哚二酮哌嗪非共价键三聚体,其制备,溶血栓活性及应用 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060142322A1 (en) * | 2004-12-28 | 2006-06-29 | Stuti Gaur | 2-Alkyl/aryl sulphonyl-1,2,3,4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid esters/amides useful as antithrombotic agents |
| US20150290339A1 (en) * | 2012-09-05 | 2015-10-15 | Shanghai Lumosa Therapeutics, Co., Ltd. | Novel compound with effects of thrombolysis, free radical scavenging and thrombus-targeting as well as preparation method and use thereof |
| CN108929372A (zh) * | 2017-05-18 | 2018-12-04 | 首都医科大学 | 1R-甲基-β-四氢咔啉酰-K(GRPAK)-RGDV,其合成,活性和应用 |
| CN108948145A (zh) * | 2017-05-18 | 2018-12-07 | 首都医科大学 | 1R-甲基-β-四氢咔啉酰-K(PAK)-RGDV,其合成,活性和应用 |
-
2019
- 2019-05-30 CN CN201910465459.1A patent/CN112010928B/zh not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060142322A1 (en) * | 2004-12-28 | 2006-06-29 | Stuti Gaur | 2-Alkyl/aryl sulphonyl-1,2,3,4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid esters/amides useful as antithrombotic agents |
| US20150290339A1 (en) * | 2012-09-05 | 2015-10-15 | Shanghai Lumosa Therapeutics, Co., Ltd. | Novel compound with effects of thrombolysis, free radical scavenging and thrombus-targeting as well as preparation method and use thereof |
| CN108929372A (zh) * | 2017-05-18 | 2018-12-04 | 首都医科大学 | 1R-甲基-β-四氢咔啉酰-K(GRPAK)-RGDV,其合成,活性和应用 |
| CN108948145A (zh) * | 2017-05-18 | 2018-12-07 | 首都医科大学 | 1R-甲基-β-四氢咔啉酰-K(PAK)-RGDV,其合成,活性和应用 |
Non-Patent Citations (2)
| Title |
|---|
| HAIMEI ZHU ET. AL: "Docking of THPDTPI: to explore P-selectin as a common target of anti-tumor, anti-thrombotic and anti-inflammatory agent", 《ONCOTARGET》 * |
| 郑佳莉 等: "新型磺酰胺类化合物SZ427的抗血小板聚集作用", 《沈阳药科大学学报》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114763354A (zh) * | 2021-01-12 | 2022-07-19 | 首都医科大学 | 七环吲哚二酮哌嗪非共价键三聚体,其制备,溶血栓活性及应用 |
| CN114763354B (zh) * | 2021-01-12 | 2023-05-05 | 首都医科大学 | 七环吲哚二酮哌嗪非共价键三聚体,其制备,溶血栓活性及应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112010928B (zh) | 2022-04-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112010928B (zh) | 乙基pak修饰的双咔啉并哌嗪二酮,其制备,活性和应用 | |
| CN112094318B (zh) | 乙基rpak修饰的双咔啉并哌嗪二酮,其制备,活性和应用 | |
| CN111995661B (zh) | 乙基arpak修饰的双咔啉并哌嗪二酮,其制备,活性和应用 | |
| CN112010936B (zh) | 乙基grpak修饰的双咔啉并哌嗪二酮,其制备,活性和应用 | |
| CN112175041B (zh) | 乙基qrpak修饰的双咔啉并哌嗪二酮,其制备,活性和应用 | |
| CN106432417B (zh) | 五甲氧色胺基羰丙酰-rpak,其制备,活性和应用 | |
| CN106608905B (zh) | 四氢异喹啉-3-甲酰-k(grpak)rgdv,其合成,活性及应用 | |
| CN110577572B (zh) | 1S-甲基-β-四氢咔啉酰-K(PAK)其合成,活性和应用 | |
| CN111848727B (zh) | 茶氨酰四氢咪唑并吡啶-6-甲酰非极性氨基酸的制备,活性和应用 | |
| CN106699844B (zh) | The-RGDVGRPAK十肽，其制备，活性及应用 | |
| CN106608901B (zh) | 二羟基二甲基四氢异喹啉-3-甲酰-Lys(Lys-Ala),其合成,活性及应用 | |
| CN108948155B (zh) | 1R-甲基-β-四氢咔啉酰-K(QRPAK)-RGDV,其合成,活性和应用 | |
| CN108948145B (zh) | 1R-甲基-β-四氢咔啉酰-K(PAK)-RGDV,其合成,活性和应用 | |
| CN111848730B (zh) | 茶氨酰四氢咪唑并吡啶-6-甲酰极性氨基酸的制备,活性和应用 | |
| CN106432418B (zh) | 五甲氧色胺基羰丙酰-pakpak,其制备,活性和应用 | |
| CN110615828B (zh) | 1S-甲基-β-四氢咔啉酰-K其合成,活性和应用 | |
| CN106432414B (zh) | 五甲氧色胺基-kapkap,其制备,活性和应用 | |
| CN106589059B (zh) | N-(a)-2,3-二羟基异喹啉-7-甲酰-rgdv/f,其合成,活性及应用 | |
| CN111848724B (zh) | 茶氨酰四氢咪唑并吡啶-6-甲酰酸性氨基酸的制备,活性和应用 | |
| CN107698661B (zh) | GRPAKRGDV-The十肽, 其制备, 活性及应用 | |
| CN111848726B (zh) | 茶氨酰四氢咪唑并吡啶-6-甲酰芳香氨基酸的制备,活性和应用 | |
| CN110577578B (zh) | 1S-甲基-β-四氢咔啉酰-K(RPAK)其合成,活性和应用 | |
| CN111848729B (zh) | 茶氨酰四氢咪唑并吡啶-6-甲酰天冬酰胺和谷氨酰胺的制备,活性和应用 | |
| CN110577575B (zh) | 1S-甲基-β-四氢咔啉酰-K(ARPAK)-RGDV,其合成,活性和应用 | |
| CN111848606B (zh) | 茶氨酰四氢咪唑并吡啶-6-甲酰甘氨酸和丙氨酸的制备,活性和应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for 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 | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20220422 |