CN107400089A - The preparation method and applications of the twin medicine of aspirin of anti-cerebral apoplexy based on the double target spots of TXA2/ROS - Google Patents
The preparation method and applications of the twin medicine of aspirin of anti-cerebral apoplexy based on the double target spots of TXA2/ROS Download PDFInfo
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- CN107400089A CN107400089A CN201710580467.1A CN201710580467A CN107400089A CN 107400089 A CN107400089 A CN 107400089A CN 201710580467 A CN201710580467 A CN 201710580467A CN 107400089 A CN107400089 A CN 107400089A
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- Prior art keywords
- aspirin
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- medicine
- txa2
- edaravone
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- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 229960001138 acetylsalicylic acid Drugs 0.000 title claims abstract description 36
- 239000003814 drug Substances 0.000 title claims abstract description 31
- 208000006011 Stroke Diseases 0.000 title claims abstract description 27
- 206010008190 Cerebrovascular accident Diseases 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 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 title claims abstract description 10
- QELUYTUMUWHWMC-UHFFFAOYSA-N edaravone Chemical compound O=C1CC(C)=NN1C1=CC=CC=C1 QELUYTUMUWHWMC-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229950009041 edaravone Drugs 0.000 claims abstract description 21
- 230000004112 neuroprotection Effects 0.000 claims abstract description 8
- 208000010110 spontaneous platelet aggregation Diseases 0.000 claims abstract description 7
- 230000002000 scavenging effect Effects 0.000 claims abstract description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 230000002490 cerebral effect Effects 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- 239000008280 blood Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 150000001263 acyl chlorides Chemical class 0.000 claims description 4
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 3
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical group ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 2
- 239000002904 solvent Substances 0.000 claims 2
- 229910019213 POCl3 Inorganic materials 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- 239000005457 ice water Substances 0.000 claims 1
- 150000007530 organic bases Chemical class 0.000 claims 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl chloride Substances ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 11
- 230000003925 brain function Effects 0.000 abstract description 2
- 230000007246 mechanism Effects 0.000 abstract description 2
- 210000003792 cranial nerve Anatomy 0.000 abstract 1
- 238000012827 research and development Methods 0.000 abstract 1
- 206010008118 cerebral infarction Diseases 0.000 description 8
- 208000026106 cerebrovascular disease Diseases 0.000 description 7
- 239000003146 anticoagulant agent Substances 0.000 description 6
- 201000006474 Brain Ischemia Diseases 0.000 description 5
- 206010008120 Cerebral ischaemia Diseases 0.000 description 5
- 230000000702 anti-platelet effect Effects 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 4
- 210000001772 blood platelet Anatomy 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 208000032843 Hemorrhage Diseases 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 230000000302 ischemic effect Effects 0.000 description 3
- 238000005502 peroxidation Methods 0.000 description 3
- 208000019838 Blood disease Diseases 0.000 description 2
- 0 CC(Nc(cccc1)c1C(*)=N)=C Chemical compound CC(Nc(cccc1)c1C(*)=N)=C 0.000 description 2
- 206010008092 Cerebral artery thrombosis Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 206010033799 Paralysis Diseases 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000023555 blood coagulation Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 208000014951 hematologic disease Diseases 0.000 description 2
- 208000018706 hematopoietic system disease Diseases 0.000 description 2
- 230000002008 hemorrhagic effect Effects 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 125000005647 linker group Chemical group 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 208000021090 palsy Diseases 0.000 description 2
- 230000004224 protection Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000000451 tissue damage Effects 0.000 description 2
- 231100000827 tissue damage Toxicity 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- KSPSCHDPAHCVNJ-UHFFFAOYSA-N CC(C=C(CC1)O)=NC1c1ccccc1 Chemical compound CC(C=C(CC1)O)=NC1c1ccccc1 KSPSCHDPAHCVNJ-UHFFFAOYSA-N 0.000 description 1
- AIULFTFDTZPXKS-UHFFFAOYSA-N CC(Oc(cccc1)c1C([O]=C)=N)=O Chemical compound CC(Oc(cccc1)c1C([O]=C)=N)=O AIULFTFDTZPXKS-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010065559 Cerebral arteriosclerosis Diseases 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 208000012671 Gastrointestinal haemorrhages Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 206010003230 arteritis Diseases 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- 201000008247 brain infarction Diseases 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 239000000701 coagulant Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 208000005053 encephalomalacia Diseases 0.000 description 1
- 230000002851 endotheliumprotective effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002085 enols Chemical group 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 201000005851 intracranial arteriosclerosis Diseases 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000012866 low blood pressure Diseases 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000031990 negative regulation of inflammatory response Effects 0.000 description 1
- 230000007971 neurological deficit Effects 0.000 description 1
- 150000002926 oxygen Chemical class 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000003186 pharmaceutical solution Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 208000037922 refractory disease Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium 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
- 239000001509 sodium citrate Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004879 turbidimetry Methods 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/18—One oxygen or sulfur atom
- C07D231/20—One oxygen atom attached in position 3 or 5
- C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of preparation method and applications of the twin medicine of aspirin of the anti-cerebral apoplexy based on the double target spots of TXA2/ROS, and aspirin is connected with Edaravone with ester bond, forms twin medicine, concrete structure such as (I).The twin medicine may have double mechanism; again with stronger ROS scavenging actions while being acted on anti-TXA2; protect cranial nerve and improve the effect of brain function, platelet aggregation-against is organically combined with neuroprotection, new thinking is provided for the research and development of Treatment of Cerebral Stroke medicine.
Description
Technical field
The invention belongs to pharmaceutical field, is related to a kind of twin medicine of aspirin of the anti-cerebral apoplexy based on the double target spots of TXA2/ROS
Preparation method, and the application of the twin medicine as Treatment of Cerebral Stroke medicine.
Background technology
Cerebral apoplexy is also known as apoplexy or cerebrovas-cularaccident (Cerebrovascular accident), is a kind of unexpected onset,
Acute cerebrovascular diseases using focal neurological deficit as common trait, including cerebral hemorrhage, subarachnoid hemorrhage and brain
Infarct.The most common cause of disease is that blood clotting forms clot, plugs cerebral vessels, causes local brain tissue ischemic, anoxic to draw
Cerebromalacia is played, and then is necrosed, is clinical refractory disease.The cause of disease it is most important for high blood pressure, it is cerebral arteriosclerosis, acute
Low blood pressure, arteritis and blood disease, wound etc., but turned to Atherosclerosis with high blood pressure most important.Cerebral apoplexy is people
One of three dead big reasons of class, and cerebral arterial thrombosis accounts for whole cerebral apoplexy 43-65%, its incidence and mortality is far high
In other cerebral apoplexies.What American Stroke association in 2003 proposed《The early stage processing guide of ischemic cerebral stroke patients》, 2004 years
Japan《Treatment of Cerebral Stroke guideline》And by Department of Disease Control of the Ministry of Public Health of China and neurology branch of Chinese Medical Association
Organize what national relevant expert write《Chinese brain blood disease disease guideline of prevention and treatment》Point out：Gathered after cerebral infarction generation using antiplatelet
Collect the drug combination of medicine aspirin+neuroprotection agent Edaravone.
Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is that Japanese Takeda Pharmaceutical Company Limited's exploitation one kind is new certainly
By base scavenger, have the function that to remove free radical and anti-lipid peroxidation, can suppress brain cell (vascular endothelial cell,
Nerve cell) peroxidation and retardance nerve cell death, and brain caused by cerebral ischemia and cerebral ischemia can be mitigated
Oedema and tissue damage, show that there is extraordinary protective effect to cerebral ischemia in various animal cerebral ischemic models, face
It is usually used in cerebral arterial thrombosis treatment on bed, therapeutic dose is 30mg*2 times/d, and Edaravone concrete structure formula is as follows：
During stroke onset, blood platelet plays the effect of key to blood clotting.Aspirin prevents and treats brain
The important mechanisms of palsy are its antiplatelet aggregative activities.Aspirin is combined with cyclooxygenase-l (COX-l) irreversibility, suppression
Thromboxane A2 (TXA2) synthesis processed, then blocks the platelet aggregation of TXA2 mediations, makes the occurrence risk of cardiovascular and cerebrovascular diseases reduce.
Aspirin also has anti-oxidation stress with Endothelium Protective effect, anti-inflammatory response with stablizing patch effect and suppressing blood simultaneously
The effect of pipe reconstruct, but there is increase hemorrhagic apoplexy and the risk of hemorrhage of gastrointestinal tract in aspirin, have research to confirm, Ah Si
Woods adverse reaction and dosage are closely related, and the aspirin dose of recommended by routine is 75~100mg/d at present, and aspirin makes
Use dosage>Hemorrhage of digestive tract events incidence significantly raises during 100mg/d.Aspirin concrete structure formula is as follows：
When being clinically used for treatment of acute stroke (in best 48h), the dosage of aspirin is 150~300mg/d, together
When give the medicine Edaravone with cerebral protection, the prognosis that patient (occurs within 72h) for acute period of cerebral infarction improves, shown
It is shown as effective.By further analysis, it is believed that to morbidity 24h within Cerebral Infarction Patients therapeutic effect it is more notable, according to up to
It is 30mg*2 times/d that dosage is given in drawing, drip-feed.But Edaravone is easy to the side effects such as liver, kidney exception occur.
There is keto-enol tautomeric structure (as follows) in Edaravone structure, patent aspirin of the present invention
Activated carboxylic in molecule is made acyl chlorides and is connected again with the hydroxyl in the enol-type structure of Edaravone with ester bond, forms twin medicine,
Aspirin is fat-soluble to increasing, and reduces the new Treatment of Cerebral Stroke medicine of aspirin dosage.
The content of the invention
Technical problem：
The present invention is proposed for hemorrhagic apoplexy during aspirin for treatment cerebral apoplexy and the risk of hemorrhage of gastrointestinal tract,
Itself and fat-soluble high small molecule neuroprotection agent Edaravone are connected into a molecule with ester bond, there is provided a kind of Ah Si
Twin medicine of woods-Edaravone and preparation method thereof, the twin medicine is while with antiplatelet aggregative activity again with stronger ROS
Remove and the effect of anti-lipid peroxidation, mitigate cerebral ischemia and cerebral ischemia caused by encephaledema and tissue damage, compensate for Ah
The deficiency of a woods clinical treatment is taken charge of, is the combination of platelet aggregation-against and Cerebral protection cerebral apoplexy.
Technical scheme：
The present invention proposes a kind of twin medicine of aspirin with platelet aggregation-against and neuroprotection dual activity, its
Structural formula (I) is：
Active compound aspirin and Edaravone are discharged after the degradation, its linking group is ester bond, susceptible to hydrolysis,
Active compound aspirin and Edaravone are discharged after the degraded of such compound ester bond.
Beneficial effect：
In order to make up aspirin during cerebral apoplexy is treated, dosage is big (150~300mg/d), increases bleeding
Property palsy and hemorrhage of gastrointestinal tract risk the shortcomings that, propose the imagination of aspirin and the twin medicine of Edaravone, gather in antiplatelet
Collect fat-soluble very high, small-molecule drug Edaravone system of the connection with neuroprotection effect on the molecule of medicine aspirin
Into twin medicine, into active compound aspirin and Edaravone is discharged after in vivo, while with antiplatelet aggregative activity again
Removed with stronger ROS, improve brain function effect.The design compensate for the deficiency of aspirin clinical treatment, be that anti-blood is small
Plate assembles the combination with neuroprotection.
The twin medicine of the present invention is using the carboxyl in aspirin molecule as linking group, with enol form in Edaravone molecule
Hydroxyl makes the structure of twin medicine simple, easily prepared and quality control, is easy to apply using the split of covalent bond ester bond as a molecule.
Active compound is connected in the form of ester bond in twin medicine in the present invention, is advantageous to the hydrolysis of twin medicine in vivo.
Embodiment
The following examples can make those skilled in the art that the present invention be more fully understood, but not limit this in any way
Invention.
The synthetic route of the present invention：
Aspirin (35mmol) and thionyl chloride (3ml, 42mmol) are mixed into azeotropic backflow and prepare acetyl salicylic acyl chlorides,
Diluted with dichloromethane (10~20ml) standby；Under preference temperature, appropriate Edaravone (5.5g, 32mmol) is dissolved in two
In chloromethanes (50ml~100ml), triethylamine (5ml, 32mmol) is added dropwise, after stirring 0.5~1h, acetyl salicylic acyl chlorides is dripped
It is added in above-mentioned reaction system, controls temperature of reaction system, stir 1~2h, adds 200~300ml ethyl acetate extraction, water
Wash three times, saturated sodium bicarbonate is washed three times, and saturated nacl aqueous solution is washed three times, anhydrous sodium sulfate drying, is concentrated in vacuo, post layer
Analysis, eluant, eluent is ethyl acetate：Petroleum ether=1:8 (V/V), obtain white powder, yield 87.7%, mp.76~79 DEG C, HR-
MS(ESI)for C19H16N2O4([M+Na]+)calcd：359.3396,found:359.36091HNMR (CDCl3,
300MHz)：2.25 (s, 3H), 2.36 (s, 3H), 6.22 (s, 1H), 7.16 (d, 1H), 7.28-7.35 (m, 2H), 7.39-
7.44 (t, 2H), 7.54-7.55 (d, 2H), 7.60-7.66 (m, 1H), 8.02 (dd, 1H).
External platelet aggregation-against experiment
Take Arteries of Rabbits blood during experiment, and with 3.8% sodium citrate anti-freezing, the ratio of amount for taking blood and anti-coagulants is 9:1(V/
V), it is slowly reverse fully to mix.It is sub-packed in test tube, autobalance centrifuge, 1000r/min centrifugation 10min (4 DEG C), with taking
Sample device, upper liquid, i.e. Platelet-rich plasm (PRP) are carefully drawn, is placed at room temperature standby.By the above-mentioned blood for having drawn PRP
Secondary centrifuging, 3000r/min centrifugations 10min.Sample is taken out after centrifuge stops naturally, the blood plasma of upper strata Platelet poor is
PPP, it is careful to draw upper strata PPP standby (platelet count in control or regulation PRP during as measure).By entering by turbidimetry
The platelet aggregation rate measure of row compound antagonism ADP or AA induction.
The different pharmaceutical solution that precision draws 1 μ L 0.1mM is added in 200 μ L PRP, and blank group adds isometric
DMSO, after 37 DEG C are incubated 5min, are returned to zero with PPP, add ADP (10 μM) or AA (1mM), at 37 DEG C before and after observation medication
Maximum aggregation rates of the PRP in 5min.
Data are expressed as mean ± SD of each group (n=9) .*P<0.05versus ASP+Eda.
The experiment of external scavenging activated oxygen
The culture medium of PC12 cells selects the μ g/ml strepto-s of DMEM in high glucose+10%HS+5%FBS+100U/mL penicillin+100
Element, in 37 DEG C of 5%CO2Incubator culture.The PC12 cells (1000 cells/well) of exponential phase are chosen, are cultivated respectively
96 orifice plates, set per hole sample three it is parallel, pre-process 2h with 10 μM of concentration compounds, add 800 μM of H2O2, change after 2h fresh
Culture medium, add 20 μ L MTT, cell incubation 14h, mtt assay measure cell survival rate.
Results were obtained from independent experiments and were expressed as
Mean ± SD (n=9) .*P<0.01versus ASP+Eda group.
Claims (9)
- A kind of 1. twin medicine of aspirin with ROS scavenging actions again while acted on anti-TXA2, it is characterised in that anti-blood Platelet assembles medicine aspirin and neuroprotection agent Edaravone is formed by connecting through ester bond, the structural formula of compound such as (I) It is described：
- 2. a kind of twin medicine of aspirin of anti-cerebral apoplexy based on the double target spots of TXA2/ROS described in claim 1, its feature exist In medicament for resisting platelet aggregation aspirin and neuroprotection agent Edaravone.
- 3. the preparation method of the twin medicine of aspirin of the anti-cerebral apoplexy based on the double target spots of TXA2/ROS described in claim 1, its Be characterised by that with acylating reagent mixing azeotropic backflow first prepared by aspirin into acetyl salicylic acyl chlorides, in atent solvent again with according to Da Lafeng is condensed into the twin medicine of aspirin-Edaravone.
- 4. according to the preparation method described in claim 3, mol ratio aspirin:Edaravone=1:1.2, the drop of triethylamine Dosage is 3~5ml/ moles of Edaravone.
- 5. according to the preparation method described in claim 3, the acylating agent is oxalyl chloride, thionyl chloride, PCl3, PCl5, POCl3Deng preferably oxalyl chloride or thionyl chloride.
- 6. according to the preparation method described in claim 3, the atent solvent is chloroform, dichloromethane etc..
- 7. according to the preparation method described in claim 3, the organic base is triethylamine, preferably pyridine, triethylamine.
- 8. according to the preparation method described in claim 3, the preference temperature is ice-water bath.
- 9. according to the twin medicine of aspirin of the anti-cerebral apoplexy based on the double target spots of TXA2/ROS described in claim 1, in clinic The application of cerebral apoplexy.
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Cited By (1)
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| CN115991698A (en) * | 2022-11-03 | 2023-04-21 | 广东中科药物研究有限公司 | Heterocyclic compound and preparation method and application thereof |
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|---|---|---|---|---|
| US3976658A (en) * | 1973-07-13 | 1976-08-24 | Sandoz Ltd. | Pyrazole derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US3976658A (en) * | 1973-07-13 | 1976-08-24 | Sandoz Ltd. | Pyrazole derivatives |
Non-Patent Citations (2)
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| 姚书燕，等: "依达拉奉联合阿司匹林治疗进展性脑梗死临床观察", 《深圳中西医结合杂志》 * |
| 王连进: "依达拉奉联合阿司匹林治疗急性脑梗死的系统评价", 《临床医药》 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115991698A (en) * | 2022-11-03 | 2023-04-21 | 广东中科药物研究有限公司 | Heterocyclic compound and preparation method and application thereof |
| CN115991698B (en) * | 2022-11-03 | 2024-03-29 | 广东中科药物研究有限公司 | Heterocyclic compound and preparation method and application thereof |
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