CN116970032A - 2-Trp-AA-tetrahydrocarboline-3-carboxylic acid AA inhibitor and antithrombotic application thereof - Google Patents
2-Trp-AA-tetrahydrocarboline-3-carboxylic acid AA inhibitor and antithrombotic application thereof Download PDFInfo
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- CN116970032A CN116970032A CN202310960632.1A CN202310960632A CN116970032A CN 116970032 A CN116970032 A CN 116970032A CN 202310960632 A CN202310960632 A CN 202310960632A CN 116970032 A CN116970032 A CN 116970032A
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- 239000003146 anticoagulant agent Substances 0.000 title description 4
- 230000002785 anti-thrombosis Effects 0.000 title description 2
- 239000003112 inhibitor Substances 0.000 title description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 claims abstract description 58
- 229940114079 arachidonic acid Drugs 0.000 claims abstract description 29
- 235000021342 arachidonic acid Nutrition 0.000 claims abstract description 29
- 238000002360 preparation method Methods 0.000 claims abstract description 15
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical group OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims abstract description 10
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical group OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims abstract description 10
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical group CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims abstract description 10
- 125000000267 glycino group Chemical group [H]N([*])C([H])([H])C(=O)O[H] 0.000 claims abstract description 9
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 7
- 150000001413 amino acids Chemical class 0.000 claims abstract description 3
- 208000010110 spontaneous platelet aggregation Diseases 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 4
- 230000001732 thrombotic effect Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 229940122902 Arachidonic acid inhibitor Drugs 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 206010003178 Arterial thrombosis Diseases 0.000 abstract description 15
- 150000001875 compounds Chemical class 0.000 abstract description 14
- 208000007536 Thrombosis Diseases 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 7
- 229940124639 Selective inhibitor Drugs 0.000 abstract description 4
- 238000002474 experimental method Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 238000000034 method Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
- 241000700159 Rattus Species 0.000 description 9
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 9
- 239000002504 physiological saline solution Substances 0.000 description 8
- 239000000843 powder Substances 0.000 description 7
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 6
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 6
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 108010003541 Platelet Activating Factor Proteins 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 108090000190 Thrombin Proteins 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 229960004072 thrombin Drugs 0.000 description 6
- 210000001367 artery Anatomy 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 210000004623 platelet-rich plasma Anatomy 0.000 description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- 238000004252 FT/ICR mass spectrometry Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000000411 inducer Substances 0.000 description 4
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical group CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 3
- 206010003658 Atrial Fibrillation Diseases 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 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 3
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004220 aggregation Methods 0.000 description 3
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- 238000005520 cutting process Methods 0.000 description 3
- 229960002897 heparin Drugs 0.000 description 3
- 229920000669 heparin Polymers 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
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- 238000004809 thin layer chromatography Methods 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 230000000702 anti-platelet effect Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 210000001715 carotid artery Anatomy 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 230000004087 circulation Effects 0.000 description 2
- 230000001143 conditioned effect Effects 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 210000004731 jugular vein Anatomy 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- -1 polyethylene Polymers 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000002627 tracheal intubation Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- WXYGVKADAIJGHB-ZDUSSCGKSA-N (2s)-3-(1h-indol-2-yl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound C1=CC=C2NC(C[C@H](NC(=O)OC(C)(C)C)C(O)=O)=CC2=C1 WXYGVKADAIJGHB-ZDUSSCGKSA-N 0.000 description 1
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010002388 Angina unstable Diseases 0.000 description 1
- 208000003343 Antiphospholipid Syndrome Diseases 0.000 description 1
- 206010014513 Embolism arterial Diseases 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical group NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 208000032109 Transient ischaemic attack Diseases 0.000 description 1
- GRQCSEWEPIHLBI-JQWIXIFHSA-N Trp-Asn Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(O)=O)=CNC2=C1 GRQCSEWEPIHLBI-JQWIXIFHSA-N 0.000 description 1
- UYKREHOKELZSPB-JTQLQIEISA-N Trp-Gly Chemical compound C1=CC=C2C(C[C@H](N)C(=O)NCC(O)=O)=CNC2=C1 UYKREHOKELZSPB-JTQLQIEISA-N 0.000 description 1
- PITVQFJBUFDJDD-XEGUGMAKSA-N Trp-Ile Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O)=CNC2=C1 PITVQFJBUFDJDD-XEGUGMAKSA-N 0.000 description 1
- MYVYPSWUSKCCHG-JQWIXIFHSA-N Trp-Ser Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CO)C(O)=O)=CNC2=C1 MYVYPSWUSKCCHG-JQWIXIFHSA-N 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 206010000891 acute myocardial infarction Diseases 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000001168 carotid artery common Anatomy 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 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
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 210000003709 heart valve Anatomy 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000013146 percutaneous coronary intervention Methods 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 108010038745 tryptophylglycine Proteins 0.000 description 1
Classifications
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- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Biophysics (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a 2-Trp-AA-tetrahydrocarboline-3-carboxylic acid compound with the structure for selectively inhibiting Arachidonic Acid (AA), wherein the amino acid represented by AA is L-Ser residue, L-Asn residue, L-Ile residue and Gly residue, and further discloses a preparation method of the compound and application of the compound in treating arterial thrombotic diseases. Experiments prove that the AA selective inhibitor has good anti-arterial thrombosis effect. Therefore, the invention provides an effective technical means for resisting arterial thrombosis.
Description
Technical Field
The invention relates to Arachidonic Acid (AA) selective inhibitors with the following structures (wherein AA is L-Ser residue, L-Asn residue, L-Ile residue and Gly residue), a preparation method thereof and application thereof in treating arterial thrombotic diseases. The invention belongs to the field of biological medicine.
Background
Arterial embolism has become one of the diseases with high morbidity and mortality. Arterial thrombosis is responsible for transient ischemic attacks, acute coronary syndromes, myocardial infarction and atrial fibrillation. Between 18% and 47% of patients with atrial fibrillation suffer from coronary artery disease, and about 20% of patients with atrial fibrillation associated with coronary artery disease receive percutaneous coronary intervention. Arterial thrombosis is also responsible for prosthetic heart valves, arteriovenous fistulae and other post-operative arterial thrombosis and unstable angina. For example, following liver transplant surgery, the patient is at risk of arterial thrombosis of the liver. In addition, patients with antiphospholipid syndrome are also at risk of arterial thrombosis. Arterial thrombosis is associated with platelet aggregation. Inducers that generally induce platelet aggregation include Platelet Activating Factor (PAF), adenosine Diphosphate (ADP), thrombin (TH), and Arachidonic Acid (AA). And the selective inhibitor of arachidonic acid is found to be an important direction for the research of anti-arterial thrombosis medicines. The inventor screens four types of 2-Boc-Trp-AA-3S-tetrahydro-beta-carboline-3-carboxylic acid in long-term research, and can effectively and selectively inhibit platelet aggregation induced by Arachidonic Acid (AA).
4 2-Boc-Trp-AA-3S-tetrahydro-beta-carboline-3-carboxylic acid showed excellent anti-arterial thrombosis activity on rat silk-process arterial thrombosis model. Based on these studies and findings, the present inventors have proposed the present invention.
Disclosure of Invention
The invention aims to provide four types of 2-Boc-Trp-AA-3S-tetrahydro-beta-carboline-3-carboxylic acid compounds for selectively inhibiting Arachidonic Acid (AA). Experiments prove that the 2-Boc-Trp-AA-3S-tetrahydro-beta-carboline-3-carboxylic acid compound prepared by the invention has excellent anti-arterial thrombosis effect. In order to achieve the technical effects, the invention adopts the following five technical means.
The first technical means is to confirm four types of 2-Boc-Trp-AA-3S-tetrahydro-beta-carboline-3-carboxylic acid compounds, wherein the structural formula of the compounds is as follows:
wherein the amino acid represented by AA is L-Ser residue, L-Asn residue, L-Ile residue or Gly residue respectively.
The second technical means is to provide a method for preparing the 2-Boc-Trp-AA-3S-tetrahydro-beta-carboline-3-carboxylic acid, which comprises the following steps:
1) Preparing 3S-tetrahydro-beta-carboline-3-carboxylic acid;
2) Preparing Boc-Trp-AA, wherein AA is L-Ser residue, L-Asn residue, L-Ile residue and Gly residue;
3) Preparing 2-Boc-Trp-AA-3S-tetrahydro-beta-carboline-3-carboxylic acid, wherein AA is L-Ser residue, L-Asn residue, L-Ile residue and Gly residue;
4) Preparing 2-Trp-AA-3S-tetrahydro-beta-carboline-3-carboxylic acid, wherein AA is L-Ser residue, L-Asn residue, L-Ile residue and Gly residue.
The third technical means is to confirm the application of the 2-Trp-AA-3S-tetrahydro-beta-carboline-3-carboxylic acid in preparing a medicament for selectively inhibiting Arachidonic Acid (AA).
The fourth technical means is to confirm the selective inhibition of AA-induced platelet aggregation by the 2-Trp-AA-3S-tetrahydro- β -carboline-3-carboxylic acid.
The fifth technical means is to confirm the excellent inhibitory effect of the 2-Trp-AA-3S-tetrahydro-beta-carboline-3-carboxylic acid on arterial thrombosis.
Drawings
FIG. 1 is a synthetic scheme for 2-Trp-AA-3S-tetrahydro-beta-carboline-3-carboxylic acid i) CH 2 O,H 2 SO 4 The method comprises the steps of carrying out a first treatment on the surface of the ii) DCC, HOBt, N-methylmorpholine, boc-Trp-AA; iii) Ethyl acetate solution of hydrogen chloride 4N.
Detailed Description
To further illustrate the invention, a series of examples are given below. These examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention.
Example 1 preparation of 3S-tetrahydro-beta-carboline-3-carboxylic acid (1)
To 400mL of water was slowly added 0.2mL of concentrated sulfuric acid. To the resulting aqueous dilute sulfuric acid solution was added 5.0g (24.5 mmol) of L-Trp, and the solution was sonicated until the L-Trp was completely dissolved. To the resulting solution was added 10mL of a 35% strength aqueous formaldehyde solution. The reaction mixture was stirred at room temperature for 6 hours, and the disappearance of L-Trp was monitored by thin layer chromatography (ethyl acetate/diethyl ether, 20/1) to terminate the reaction. Concentrated ammonia water is slowly added dropwise into the reaction solution, the pH is adjusted to 6, and the reaction solution is kept stand for 30 minutes. The precipitate formed was filtered off and washed with water, and the colorless solid filtered off was spread on a petri dish and dried in air to give 5.05g (95%) of the title compound as a colorless solid. ESI-MS (m/e): 217[ M+H ]] + 。
EXAMPLE 2 preparation of Boc-Trp-AA
By conventional DCC method, from Boc-Trp and Ser-O-CH 3 ,Asn-O-CH 3 ,Ile-O-CH 3 Gly-O-CH 3 Preparation of Boc-Trp-Ser-O-CH 3 ,Boc-Trp-Asn-O-CH 3 ,Boc-Trp-Ile-O-CH 3 Boc-Trp-Gly-O-CH 3 . Boc-Trp-Ser-O-CH at 0 DEG C 3 ,Boc-Trp-Asn-O-CH 3 ,Boc-Trp-Ile-O-CH 3 Boc-Trp-Gly-O-CH 3 Saponification in 2N aqueous sodium hydroxide solution gives Boc-Trp-Ser, ESI-MS:392[ M+H ]] + ；Boc-Trp-Asn,ESI-MS:419[M+H] + ；Boc-Trp-Ile,ESI-MS:418[M+H] + And Boc-Trp-Gly, ESI-MS:362[ M+H ]] + . They are all 91% pure and are known compounds which are used directly in the subsequent synthesis without detection.
Example 3 preparation of 3S- [2- (Boc-Trp-Ser) ] -tetrahydro-beta-carboline-3-carboxylic acid (2 a)
To a solution of 3.03g (14 mmol) of 3S-tetrahydro-beta-carboline-3-carboxylic acid and 5.47g (14 mmol) of Boc-Trp-Ser and 150mL of anhydrous tetrahydrofuran was added 2.0g (14.8 mmol) of N-hydroxybenzotriazole (HOBt), 3.1g (14.8 mmol) of Dicyclohexylcarbodiimide (DCC) at 0 ℃. The reaction mixture was stirred for 30 minutes at 0 ℃. The pH was then adjusted to 8 with N-methylmorpholine (NMM). The reaction mixture was stirred for 6 hours at 0deg.C, and the disappearance of 3S-tetrahydro-beta-carboline-3-carboxylic acid was monitored by thin layer chromatography (ethyl acetate/methanol, 20/1) to terminate the reaction. The reaction mixture was filtered, the filtrate concentrated to dryness under reduced pressure, and the residue was taken up in 200mL of ethyl acetateThe ester is dissolved. The resulting solution was washed with 5% aqueous sodium hydrogencarbonate (30 mL. Times.3), saturated aqueous sodium chloride (30 mL. Times.3), 5% aqueous hydrochloric acid (30 mL. Times.3) and saturated aqueous sodium chloride (30 mL. Times.3) in this order. The ethyl acetate layer was separated, dried over anhydrous sodium sulfate for 12 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to give 7.67g (93%) of the title compound as a colorless powder. ESI-MS 590[ M+H ]] + ； 1 H NMR(300MHz,DMSO-d 6 ):δ/ppm＝12.881(s,1H),11.665(s,1H),10.789(s,1H),8.321(s,1H),7.583(d,J＝7.6Hz,1H),7.351(d,J＝7.7Hz,1H),7.396(s,1H),7.331(d,J＝7.9Hz,1H),7.212(d,J＝7.9Hz,1H),7.210(s,1H),7.065(t,J＝7.2Hz,1H),6.982(t,J＝7.2Hz,1H),6.932(t,J＝7.2Hz,1H),6.913(t,J＝7.2Hz,1H),4.937(s,1H),4.924(t,J＝5.6Hz,1H),4.855(t,J 1 ＝6.1Hz,1H),4.557(t,J 1 ＝6.1Hz,1H),4.552(s,2H),4.167(d,J 1 ＝6.1Hz,2H),3.311(d,J＝5.6Hz,2H),3.043(d,J＝6.1Hz,2H),1.426(s,9H)； 13 C NMR(75MHz,DMSO-d 6 ):δ/ppm＝171.90,171.72,170.12,161.22,136.52,136.19,130.42,127.46,127.32,123.13,121.79,121.73,119.85,119.82,118.84,118.76,111.15,111.14,109.88,104.79,79.68,67.82,62.93,60.99,59.53,38.16,31.63,28.44,28.43,28.42,27.82,22.66。
Example 4 preparation of 3S- [2- (Trp-Ser) ] -tetrahydro-beta-carboline-3-carboxylic acid (3 a)
5.9g (10 mmol) of 3S- [2- (Boc-Trp-Ser)]-tetrahydro- β -carboline-3-carboxylic acid in 50mL of ethyl acetate solution of hydrogen chloride (4N) and the reaction mixture was stirred at room temperature for 60 minutes. Thin layer chromatography (ethyl acetate/methanol, 20/1) monitored 3S- [2- (Boc-Trp-Ser)]-tetrahydro- β -carboline-3-carboxylic acid disappears, terminating the reaction. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 50mL of ethyl acetate and concentrated under reduced pressure. This operation was repeated 5 times to obtain 4.9g (98%) of the title compound as a colorless powder. FT-ICR-MS 490.2090[ M+H ]] + ； 1 H NMR(300MHz,DMSO-d 6 ):δ/ppm＝12.891(s,1H),11.661(s,1H),10.779(s,1H),8.851(s,2H),8.323(s,1H),7.581(d,J＝7.6Hz,1H),7.356(d,J＝7.7Hz,1H),7.354(d,J＝7.9Hz,1H),7.214(d,J＝7.9Hz,1H),7.211(s,1H),7.066(t,J＝7.2Hz,1H),6.983(t,J＝7.2Hz,1H),6.933(t,J＝7.2Hz,1H),6.914(t,J＝7.2Hz,1H),4.947(s,1H),4.851(t,J 1 ＝6.1Hz,1H),4.552(s,2H),4.542(t,J 1 ＝6.1Hz,1H),4.163(d,J 1 ＝6.1Hz,2H),3.951(t,J＝5.6Hz,1H),3.331(d,J＝5.6Hz,2H),3.042(d,J＝6.1Hz,2H)； 13 C NMR(75MHz,DMSO-d 6 ):δ/ppm＝171.92,171.742,170.02,161.22,136.54,136.29,130.32,127.43,127.36,123.03,121.77,121.75,119.83,119.81,118.82,118.79,111.16,111.15,106.88,104.19,67.85,63.13,61.19,56.73,38.11,27.42,22.63。
Example 5 preparation of 3S- [2- (Boc-Trp-Asn) ] -tetrahydro-beta-carboline-3-carboxylic acid (2 b)
Using the procedure of example 3 from 3.03g (14 mmol) of 3S-tetrahydro- β -carboline-3-carboxylic acid and 6.05g (14 mmol) of Boc-Trp-Asn gave 7.8g (90%) of the title compound as colorless powder. ESI-MS 617[ M+H ]] + ； 1 H NMR(300MHz,DMSO-d 6 ):δ/ppm＝12.883(s,1H),11.667(s,1H),10.787(s,1H),8.322(s,1H),7.585(d,J＝7.6Hz,1H),7.395(s,1H),7.353(d,J＝7.9Hz,1H),7.333(d,J＝7.9Hz,1H),7.232(s,1H),7.212(d,J＝7.9Hz,1H),7.032(s,2H),7.066(t,J＝7.2Hz,1H),6.983(t,J＝7.2Hz,1H),6.933(t,J＝7.2Hz,1H),6.915(t,J＝7.2Hz,1H),4.926(t,J＝5.6Hz,1H),4.845(t,J 1 ＝6.1Hz,1H),4.857(t,J 1 ＝6.1Hz,1H),4.555(s,2H),3.313(d,J＝5.6Hz,2H),3.046(d,J＝6.1Hz,2H),2.815(d,J 1 ＝6.1Hz,2H),1.425(s,9H)； 13 C NMR(75MHz,DMSO-d 6 ):δ/ppm＝172.62,171.92,171.75,170.02,155.99,136.54,136.21,130.43,127.43,127.33,123.05,121.75,121.74,119.86,119.84,118.85,118.79,111.14,111.13,109.80,104.89,79.58,67.85,59.54,53.53,38.18,37.56,28.45,28.44,28.43,27.83,22.68。
Example 6 preparation of 3S- [2- (Trp-Asn) ] -tetrahydro-beta-carboline-3-carboxylic acid (3 b)
Using the procedure of example 4, from 5.6g (9.1 mmol) of 3S- [2- (Boc-Trp-Asn)]-tetrahydro- β -carboline-3-carboxylic acid gives 4.4g (93%) of the title compound as colorless powder. FT-ICR-MS 517.2199[ M+H ]] + ； 1 H NMR(300MHz,DMSO-d 6 ):δ/ppm＝12.889(s,1H),11.666(s,1H),10.789(s,1H),8.855(s,2H),8.832(s,1H),7.583(d,J＝7.6Hz,1H),7.355(d,J＝7.9Hz,1H),7.335(d,J＝7.9Hz,1H),7.212(d,J＝7.9Hz,1H),7.202(s,1H),7.033(s,2H),7.067(t,J＝7.2Hz,1H),6.985(t,J＝7.2Hz,1H),6.934(t,J＝7.2Hz,1H),6.913(t,J＝7.2Hz,1H),4.857(t,J 1 ＝6.1Hz,1H),4.843(t,J 1 ＝6.1Hz,1H),4.553(s,2H),3.9455(d,J＝5.6Hz,1H),3.315(d,J＝5.6Hz,2H),3.045(d,J＝6.1Hz,2H),2.816(d,J 1 ＝6.1Hz,2H)； 13 C NMR(75MHz,DMSO-d 6 ):δ/ppm＝172.32,171.94,171.73,170.06,136.55,136.23,130.45,127.45,127.34,123.03,121.73,121.71,119.85,119.83,118.84,118.76,111.15,111.14,107.10,104.86,67.83,56.73,53.53,38.16,37.46,27.44,22.64。
Example 7 preparation of 3S- [2- (Boc-Trp-Ile) ] -tetrahydro-beta-carboline-3-carboxylic acid (2 c)
Using the procedure of example 3 from 3.03g (14 mmol) of 3S-tetrahydro- β -carboline-3-carboxylic acid and 5.84g (14 mmol) of Boc-Trp-Leu gave 7.7g (90%) of the title compound as colorless powder. ESI-MS 616[ M+H ]] + ； 1 H NMR(300MHz,DMSO-d 6 ):δ/ppm＝12.892(s,1H),11.664(s,1H),10.788(s,1H),8.322(s,1H),7.583(d,J＝7.6Hz,1H),7.391(s,1H),7.353(d,J＝7.9Hz,1H),7.333(d,J＝7.9Hz,1H),7.211(s,1H),7.212(d,J＝7.9Hz,1H),7.065(t,J＝7.2Hz,1H),6.982(t,J＝7.2Hz,1H),6.930(t,J＝7.2Hz,1H),6.912(t,J＝7.2Hz,1H),4.920(t,J＝5.6Hz,1H),4.853(t,J 1 ＝6.1Hz,1H),4.345(t,J 1 ＝6.1Hz,1H),4.552(s,2H),3.312(d,J 1 ＝5.9Hz,2H),3.043(d,J 1 ＝6.1Hz,2H),2.481(m,J 1 ＝6.1Hz,1H),1.552(m,J 1 ＝6.1Hz,2H),1.431(s,9H),1.112(d,J 1 ＝6.1Hz,3H),0.993(t,J 1 ＝6.1Hz,3H)； 13 CNMR(75MHz,DMSO-d 6 ):δ/ppm＝171.95,171.73,169.35,155.92,136.53,136.22,130.43,127.45,127.33,123.31,121.72,121.69,119.85,119.81,118.81,118.78,111.14,111.13,109.71,104.91,79.46,67.85,59.52,57.72,37.21,38.04,28.37,28.36,28.35,27.83,24.67,22.61,14.62,10.90。
Example 8 preparation of 3S- [2- (Trp-Ile) ] -tetrahydro-beta-carboline-3-carboxylic acid (3 c)
Using the procedure of example 4, from 5.6g (9.1 mmol) of 3S- [2- (Boc-Trp-Leu)]-tetrahydro- β -carboline-3-carboxylic acid gives 4.2g (90%) of the title compound as colorless powder. FT-ICR-MS:516.2611[ M+H ]] + ； 1 H NMR(300MHz,DMSO-d 6 ):δ/ppm＝12.891(s,1H),11.665(s,1H),10.791(s,1H),8.862(s,2H),8.323(s,1H),7.583(d,J＝7.6Hz,1H),7.354(d,J＝7.9Hz,1H),7.334(d,J＝7.9Hz,1H),7.213(d,J＝7.9Hz,1H),7.201(s,1H),7.062(t,J＝7.2Hz,1H),6.984(t,J＝7.2Hz,1H),6.933(t,J＝7.2Hz,1H),6.914(t,J＝7.2Hz,1H),4.852(t,J 1 ＝6.1Hz,1H),4.552(s,2H),4.341(t,J＝7.2Hz,1H),3.953(t,J 1 ＝5.6Hz,1H),3.313(d,J 1 ＝5.6Hz,2H),3.093(t,J＝5.6Hz,2H),3.041(d,J 1 ＝6.1Hz,2H),2.483(m,J＝7.2Hz,1H),1.556(m,J＝7.2Hz,2H),1.113(d,J＝7.2Hz,3H),0.992(d,J＝7.2Hz,3H)； 13 CNMR(75MHz,DMSO-d 6 ):δ/ppm＝171.95,171.76,169.32,136.53,136.23,130.42,127.44,127.35,123.04,121.75,121.73,119.84,119.82,118.84,118.83,111.15,111.14,107.11,104.91,67.83,57.76,56.73,52.60,41.15,38.12,37.23,27.43,24.75,22.64,14.59,11.05。
Example 9 preparation of 3S- [2- (Boc-Trp-Gly) ] -tetrahydro-beta-carboline-3-carboxylic acid (2 d)
Using the procedure of example 3 from 3.03g (14 mmol) of 3S-tetrahydro- β -carboline-3-carboxylic acid and 5.25g (14 mmol) of Boc-Trp-Gly gave 7.04g (90%) of the title compound as colorless powder. ESI-MS 560[ M+H ]] + ； 1 H NMR(300MHz,DMSO-d 6 ):δ/ppm＝12.890(s,1H),11.671(s,1H),10.791(s,1H),9.041(s,1H),7.581(d,J＝7.6Hz,1H),7.391(s,1H),7.352(d,J＝7.9Hz,1H),7.331(d,J＝7.9Hz,1H),7.214(d,J＝7.9Hz,1H),7.203(s,1H),7.062(t,J＝7.2Hz,1H),6.981(t,J＝7.2Hz,1H),6.932(t,J＝7.2Hz,1H),6.911(t,J＝7.2Hz,1H),4.921(t,J＝5.6Hz,1H),4.851(t,J 1 ＝6.1Hz,1H),4.455(s,2H),4.092(s,2H),3.331(d,J 1 ＝5.6Hz,2H),3.041(d,J 1 ＝6.1Hz,2H),1.416(s,9H)； 13 CNMR(75MHz,DMSO-d 6 ):δ/ppm＝171.93,172.02,164.54,155.87,136.51,136.24,130.42,127.42,127.32,123.03,121.74,121.67,119.83,119.76,118.84,118.77,111.15,111.13,109.72,104.92,79.53,67.33,59.22,42.62,37.71,28.38,28.37,28.36,27.81,22.65。
Example 10 preparation of 3S- [2- (Trp-Gly) ] -tetrahydro-beta-carboline-3-carboxylic acid (3 d)
Using the procedure of example 4, from 5.6g (10 mmol) of 3S- [2- (Boc-Trp-Gl)y)]-tetrahydro- β -carboline-3-carboxylic acid gives 4.18g (91%) of the title compound as a colorless solid. FT-ICR-MS 460.1985[ M+H ]] + ； 1 H NMR(300MHz,DMSO-d 6 ):δ/ppm＝12.891(s,1H),11.666(s,1H),10.792(s,1H),9.041(s,1H),8.861(s,2H),7.581(d,J＝7.6Hz,1H),7.355(d,J＝7.9Hz,1H),7.332(d,J＝7.9Hz,1H),7.211(s,1H),7.213(d,J＝7.9Hz,1H),7.063(t,J＝7.2Hz,1H),6.982(t,J＝7.2Hz,1H),6.933(t,J＝7.2Hz,1H),6.912(t,J＝7.2Hz,1H),4.852(t,J 1 ＝6.1Hz,1H),4.543(s,2H),4.093(s,2H),3.951(t,J 1 ＝5.6Hz,1H),3.313(d,J＝5.6Hz,2H),3.043(d,J 1 ＝6.1Hz,2H)； 13 CNMR(75MHz,DMSO-d 6 ):δ/ppm＝171.85,171.66,169.30,136.54,136.22,130.41,127.43,127.35,123.16,121.74,121.71,119.85,119.82,118.84,118.78,111.14,111.11,107.12,104.91,67.83,57.75,56.71,38.14,27.43,22.62。
Example 11 evaluation of anti-platelet aggregation Activity
Fresh pig carotid blood was anticoagulated with 3.8% sodium citrate (1/9 by volume). Platelet Rich Plasma (PRP) was obtained by centrifugation at 1000g for 10 min, and Platelet Poor Plasma (PPP) was obtained by centrifugation at 3000g for 10 min. Platelet rich plasma is conditioned with platelet poor plasma to adapt the number of platelets in the platelet rich plasma to determine anti-platelet aggregation activity. 3a-d are dissolved in physiological saline. To the turbidimetric tube was added 0.24mL of conditioned platelet rich plasma, followed by 5. Mu.L of physiological saline solution or 3a-d of physiological saline solution (5. Mu.L, concentration 0.1. Mu.M, 10. Mu.M, 15. Mu.M, 20. Mu.M). The absorbance baseline was adjusted, and 5. Mu.L of physiological saline solution of four inducers was added to observe the maximum aggregation rate (Am) of platelets within 5 minutes. The four inducers were platelet activating factor (PAF, final concentration 50. Mu.M), adenosine diphosphate (ADP, final concentration 500. Mu.M), thrombin (TH, final concentration 50 IU/L) and arachidonic acid (AA, final concentration 7.5 mg/mL). The maximum aggregation rate is a value corresponding to the peak of the aggregation curve. Each concentration was measured in parallel 6 times to form a platelet aggregation curve. IC for 3a-d inhibition of platelet-activating factor, adenosine diphosphate, thrombin and arachidonic acid-induced platelet aggregation, as determined by platelet aggregation curves 50 (see Table 1). The data in Table 1 show that 3a-d inhibits AA-induced platelet aggregation in IC 50 Minimum value of3a-d are selective inhibitors of AA.
TABLE 1 3a-d IC inhibiting 4 inducer-induced platelet aggregation 50 (mean.+ -. SD, μM)
| Compounds of formula (I) | ADP | PAF | TH | AA |
| 3a | 26.24±0.32 | 22.30±0.28 | 20.55±0.25 | 1.58±0.11 |
| 3b | 27.96±0.33 | 23.41±0.29 | 19.96±0.24 | 1.38±0.10 |
| 3c | 25.13±0.29 | 24.22±0.27 | 18.46±0.20 | 1.32±0.09 |
| 3d | 22.31±0.21 | 25.34±0.31 | 19.41±0.23 | 1.48±0.13 |
n＝6
Example 12 evaluation of anti-arterial thrombotic Activity
1) Drawing a polyethylene tube into a thin tube with one end being a bevel, wherein the fixed length is 10.0cm, and the thin tube is respectively used for inserting a right jugular vein (with thicker tube diameter) and a left carotid artery (with thinner tube diameter); the length of the middle polyethylene tube is 8.0cm, the thrombus line is pressed in the carotid artery intubation direction, and heparin is filled in the tube before intubation.
2) Male SD rats weighing 200+ -20 g were acclimatized and fasted for one day prior to surgery. The animals were randomized into physiological saline groups (blank control, oral dose of 0.3mL/100g,10 rats), aspirin groups (positive control, oral dose of 167. Mu. Mol/kg,10 rats), and physiological saline solution groups of 3a-d (oral dose of 0.1. Mu. Mol/kg,10 rats). After 30 minutes of oral administration, the rats were anesthetized with 20% uratam solution (7 mL/kg) and surgery was started after 2 minutes. The method comprises the steps of lying a rat on the back on a fixed plate in an operation, cutting neck skin, separating a right common carotid artery and a left jugular vein, pressing down a wire for accurate weighing by a blood vessel, ligating a distal end, cutting a small opening at the distal end of the vein, inserting a cannula into the vein end, injecting heparin, then taking down a syringe for injecting heparin, tying a wire for fixing, clamping an artery proximal end by an artery clamp, cutting a small opening at the distal end of the artery, ligating the artery end, loosening the artery clamp after the tying is fixed, and establishing an extracorporeal circulation bypass. After 15 minutes of circulation, veins are cut off to observe whether blood circulation is normal, if blood circulation is normal, a silk thread with thrombus is taken out from an arterial end, non-coagulated blood is sucked by filter paper, the silk thread with thrombus is accurately weighed, the weight of the silk thread with thrombus is subtracted from the weight of the silk thread, and the weight of thrombus is obtained, and data are listed in Table 2. The thrombus weights in the table indicate that 3a-d are effective in inhibiting arterial thrombosis in rats at an oral dose of 0.1. Mu. Mol/kg (p <0.01 to normal saline and aspirin ratio at 16.7. Mu. Mol/kg). This is an unexpected technical effect.
TABLE 2 influence of 3a-d on arterial thrombosis in rats
a) The ratio p of aspirin to physiological saline and oral dosage of 16.7 mu mol/kg is less than 0.01; b) The ratio p with physiological saline is more than 0.05; n=10.
Claims (5)
1. The 2-Trp-AA-3S-tetrahydro-beta-carboline-3-carboxylic acid compound with the structural formula is characterized in that the amino acid represented by AA in the structural formula is respectively selected from L-Ser residue, L-Asn residue, L-Ile residue or Gly residue,
2. the 2-Trp-AA-3S-tetrahydro- β -carboline-3-carboxylic acid compound of claim 1, wherein the process for preparing the 2-Trp-AA-3S-tetrahydro- β -carboline-3-carboxylic acid compound comprises the steps of:
1) Preparing 3S-tetrahydro-beta-carboline-3-carboxylic acid;
2) Preparing Boc-Trp-AA, wherein AA is L-Ser residue, L-Asn residue, L-Ile residue and Gly residue;
3) Preparing 2-Boc-Trp-AA-3S-tetrahydro-beta-carboline-3-carboxylic acid, wherein AA is L-Ser residue, L-Asn residue, L-Ile residue and Gly residue;
4) Preparing 2-Trp-AA-3S-tetrahydro-beta-carboline-3-carboxylic acid, wherein AA is L-Ser residue, L-Asn residue, L-Ile residue and Gly residue.
3. Use of a 2-Trp-AA-3S-tetrahydro-beta-carboline-3-carboxylic acid compound according to claim 1 or 2 in the preparation of an arachidonic acid inhibitor.
4. The use of claim 3, wherein the use of a 2-Trp-AA-3S-tetrahydro- β -carboline-3-carboxylic acid compound in the manufacture of a medicament for selectively inhibiting arachidonic acid-induced platelet aggregation.
5. Use of a 2-Trp-AA-3S-tetrahydro-beta-carboline-3-carboxylic acid compound according to claim 1 or 2 in the preparation of an anti-arterial thrombotic agent.
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