CN106608849B - 2- (substituted-phenyl) -4,4,5,5- tetramethyl -1- hydroxyl-imidazoline, synthesis, activity and application - Google Patents
2- (substituted-phenyl) -4,4,5,5- tetramethyl -1- hydroxyl-imidazoline, synthesis, activity and application Download PDFInfo
- Publication number
- CN106608849B CN106608849B CN201510689618.8A CN201510689618A CN106608849B CN 106608849 B CN106608849 B CN 106608849B CN 201510689618 A CN201510689618 A CN 201510689618A CN 106608849 B CN106608849 B CN 106608849B
- Authority
- CN
- China
- Prior art keywords
- tetramethyl
- phenyl
- gly
- formyl
- hydroxyl
- 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.)
- Active
Links
- -1 2- (substituted-phenyl) -4,4,5,5- tetramethyl -1- hydroxyl-imidazoline Chemical class 0.000 title claims description 22
- 230000000694 effects Effects 0.000 title abstract description 15
- 230000015572 biosynthetic process Effects 0.000 title 1
- 238000003786 synthesis reaction Methods 0.000 title 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 27
- 239000001301 oxygen Substances 0.000 claims abstract description 23
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 23
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000003146 anticoagulant agent Substances 0.000 claims abstract description 11
- 230000002785 anti-thrombosis Effects 0.000 claims abstract description 10
- 229940079593 drug Drugs 0.000 claims abstract description 5
- 239000003814 drug Substances 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 3
- 239000003527 fibrinolytic agent Substances 0.000 claims abstract description 3
- 229960000103 thrombolytic agent Drugs 0.000 claims abstract description 3
- 241000790917 Dioxys <bee> Species 0.000 claims description 17
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 claims description 9
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 claims description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- KUSCJQLNEHUVIP-UHFFFAOYSA-N 5-(1,3-dihydroxy-4,4,5,5-tetramethylimidazolidin-2-yl)-2-hydroxybenzoic acid Chemical compound C(=O)(O)C=1C=C(C=CC=1O)C1N(C(C(N1O)(C)C)(C)C)O KUSCJQLNEHUVIP-UHFFFAOYSA-N 0.000 claims description 4
- 239000001273 butane Substances 0.000 claims description 4
- DWCLXOREGBLXTD-UHFFFAOYSA-N dmdnb Chemical compound [O-][N+](=O)C(C)(C)C(C)(C)[N+]([O-])=O DWCLXOREGBLXTD-UHFFFAOYSA-N 0.000 claims description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 4
- 206010008092 Cerebral artery thrombosis Diseases 0.000 claims 1
- 208000007536 Thrombosis Diseases 0.000 abstract description 26
- 241000700159 Rattus Species 0.000 abstract description 21
- 208000006011 Stroke Diseases 0.000 abstract description 9
- 201000006474 Brain Ischemia Diseases 0.000 abstract description 7
- 206010008120 Cerebral ischaemia Diseases 0.000 abstract description 5
- 206010008118 cerebral infarction Diseases 0.000 abstract description 5
- 239000000243 solution Substances 0.000 description 24
- 150000001875 compounds Chemical class 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 210000001367 artery Anatomy 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000004698 Polyethylene Substances 0.000 description 8
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 8
- 229920000573 polyethylene Polymers 0.000 description 8
- 210000003462 vein Anatomy 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 7
- 230000017531 blood circulation Effects 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 101800004637 Communis Proteins 0.000 description 5
- 230000023555 blood coagulation Effects 0.000 description 5
- 210000000269 carotid artery external Anatomy 0.000 description 5
- 229920001971 elastomer Polymers 0.000 description 5
- 238000011156 evaluation Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- QEWYKACRFQMRMB-UHFFFAOYSA-N monofluoroacetic acid Natural products OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 description 5
- 206010008190 Cerebrovascular accident Diseases 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 210000001168 carotid artery common Anatomy 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- 238000002627 tracheal intubation Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- 229920000669 heparin Polymers 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- UTCFOFWMEPQCSR-UHFFFAOYSA-N 5-formylsalicylic acid Chemical compound OC(=O)C1=CC(C=O)=CC=C1O UTCFOFWMEPQCSR-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 2
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000010612 desalination reaction Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 235000019441 ethanol Nutrition 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
- 229960001008 heparin sodium Drugs 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- YADSGOSSYOOKMP-UHFFFAOYSA-N lead dioxide Inorganic materials O=[Pb]=O YADSGOSSYOOKMP-UHFFFAOYSA-N 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 2
- 229960005356 urokinase Drugs 0.000 description 2
- WFIYPADYPQQLNN-UHFFFAOYSA-N 2-[2-(4-bromopyrazol-1-yl)ethyl]isoindole-1,3-dione Chemical compound C1=C(Br)C=NN1CCN1C(=O)C2=CC=CC=C2C1=O WFIYPADYPQQLNN-UHFFFAOYSA-N 0.000 description 1
- FGLBSLMDCBOPQK-UHFFFAOYSA-N 2-nitropropane Chemical compound CC(C)[N+]([O-])=O FGLBSLMDCBOPQK-UHFFFAOYSA-N 0.000 description 1
- GNCJRTJOPHONBZ-UHFFFAOYSA-N 4,4,5,5-tetramethyl-1h-imidazole Chemical compound CC1(C)NC=NC1(C)C GNCJRTJOPHONBZ-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 238000004252 FT/ICR mass spectrometry Methods 0.000 description 1
- SCCPDJAQCXWPTF-VKHMYHEASA-N Gly-Asp Chemical compound NCC(=O)N[C@H](C(O)=O)CC(O)=O SCCPDJAQCXWPTF-VKHMYHEASA-N 0.000 description 1
- 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 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 238000001467 acupuncture Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- CKSRFHWWBKRUKA-UHFFFAOYSA-N ethyl 2-ethoxyacetate Chemical compound CCOCC(=O)OCC CKSRFHWWBKRUKA-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000007971 neurological deficit Effects 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- WYWIFABBXFUGLM-UHFFFAOYSA-N oxymetazoline Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C)=C1CC1=NCCN1 WYWIFABBXFUGLM-UHFFFAOYSA-N 0.000 description 1
- 125000001151 peptidyl group Chemical group 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000004761 scalp Anatomy 0.000 description 1
- 238000002444 silanisation 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
- 239000006228 supernatant Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D233/26—Radicals substituted by carbon atoms having three bonds to hetero atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention discloses 1- hydroxyl -2- [3- (formyl-Gly) -4- (oxygen acetyl-Ala) phenyl] -4,4,5,5- tetramethyl imidazoline, discloses its preparation method, discloses its antithrombotic acitivity, disclose its thrombus dissolving activity, the effect that it treats rats with cerebral ischemia is disclosed, thus is preparing antithrombotic reagent the invention discloses it, the application in thrombolytic agent and treatment ishemic stroke drug.
Description
Technical field
The present invention relates to 1- hydroxyl -2- [3- (formyl-Gly) -4- (oxygen acetyl-Ala) phenyl] -4,4,5,5- tetramethyl miaows
Oxazoline is related to its preparation method, is related to its antithrombotic acitivity, is related to its thrombus dissolving activity, is related to it and treats cerebral ischemia
The effect of rat, thus antithrombotic reagent is being prepared the present invention relates to it, in thrombolytic agent and treatment ishemic stroke drug
Application.
Background technique
Ishemic stroke be it is a kind of more typically and the serious cranial vascular disease of harm, feature be disease incidence is high, case fatality rate is high,
Disability rate height and high recurrence rate.Clinical treatment ishemic stroke faces the reality of not active drug, especially apoplexy face 4h at present
Above patient is non-extremely i.e. residual.Invention is clinical important need to the effective drug of patient of apoplexy face 4h or more.Inventor
The imidazolinium compounds of Formula II was once disclosed on the ischemia/reperfusion in rats apoplexy model for 24 hours of apoplexy face, shows outstanding curative effect.Connect
The imidazolinium compounds of 6 days Formula II of continuous intravenous injection, 1 time a day, initial dose are 5 μm of ol/kg, and rear 5 dosage is 2 μ
Mol/kg has outstanding curative effect.Aa in formula1And aa2It can be to exist simultaneously, aa1In the presence of but aa2It is not present, or is not present simultaneously;When
aa1And aa2When existing simultaneously, aa1For R (Arg), and aa2For G (Gly), A (Ala) or Q (Gln);Work as aa1In the presence of but aa2It does not deposit
When, aa1For R (Arg);aa3It can be S (Ser), V (Val) or F (Phe).The position 2- of the imidazolinium compounds of Formula II is 4- oxygen second
Acyl-Lys.And the side-chain amino group and main-chain carboxylic group of the Lys is connected with RGD antithrombotic tetrapeptide and ARPAK thrombolysis peptide respectively, structure ratio
It is more complex to need to simplify.It needs to stabilize in addition, bis- Sinerol of 1,3- is unstable.
Inventor passes through 5 years experimental studies, finds to use 1- hydroxyl -2- (3- formoxyl -4- oxygen acetylphenyl) -4,4,5,
5- tetramethyl imidazoline replaces 2- (4- oxygen acetylphenyl) -1,3- dioxy -4,4,5,5- tetramethyl imidazoline of II formula, uses
Ala and Gly replaces the long peptidyl of II formula can obtain structure simple, stability height and eutherapeutic triple unexpected technologies
Effect.According to this discovery, the present invention is inventors herein proposed.
Summary of the invention
1. 1- hydroxyl -2- [3- (formyl-Gly) -4- (oxygen acetyl-Ala) benzene that one of contents of the present invention are to provide following formula
Base] -4,4,5,5- tetramethyl imidazoline
2. the two of the contents of the present invention are to provide 1- hydroxyl -2- [3- (formyl-Gly) -4- (oxygen acetyl-Ala) phenyl] -4,
The preparation method of 4,5,5- tetramethyl imidazoline, this method are made of following methods:
(1) 2,3- dimethyl -2,3- dinitrobutane is prepared;
(2) 2,3- dimethyl -2,3- dihydroxy amido butane is prepared;
(3) 2- (3- carboxyl -4- hydroxy phenyl) -1,3- dihydroxy -4,4,5,5- tetramethyl imidazoles is prepared;
(4) 2- (3- carboxyl -4- hydroxy phenyl) -1,3- dioxy -4,4,5,5- tetramethyl imidazoline is prepared;
(5) 2- [3- (formyl-Gly-OtBu) -4- hydroxy phenyl] -1,3- dioxy -4,4,5,5- tetramethyl imidazoles is prepared
Quinoline;
(6) 2- [3- (formyl-Gly-OtBu) -4- (ethoxycarbonylmethoxy) phenyl] -1,3- dioxy -4,4,5,5- is prepared
Tetramethyl imidazoline;
(7) 2- [3- (formyl-Gly-OtBu) -4- (carboxymethoxyl) phenyl] -1,3- dioxy -4,4,5,5- tetramethyl is prepared
Imidazoline;
(8) 2- [3- (formyl-Gly-OtBu) -4- (oxygen acetyl-Ala-OtBu) phenyl] -4,4,5,5- tetramethyl-is prepared
Bis- Sinerol of 1,3-;
(9) 1- hydroxyl -2- [3- (formyl-Gly) -4- (oxygen acetyl-Ala) phenyl] -4,4,5,5- tetramethyl imidazoles is prepared
Quinoline.
3. the contents of the present invention third is that evaluation 1- hydroxyl -2- [3- (formyl-Gly) -4- (oxygen acetyl-Ala) phenyl] -4,
The antithrombotic acitivity of 4,5,5- tetramethyl imidazoline.
4. the contents of the present invention fourth is that evaluation 1- hydroxyl -2- [3- (formyl-Gly) -4- (oxygen acetyl-Ala) phenyl] -4,
The thrombus dissolving activity of 4,5,5- tetramethyl imidazoline.
5. the contents of the present invention fifth is that evaluation 1- hydroxyl -2- [3- (formyl-Gly) -4- (oxygen acetyl-Ala) phenyl] -4,
4,5,5- tetramethyl imidazoline treats the activity of cerebral ischemia in cerebral ischemia afterwards for 24 hours.
Detailed description of the invention
Fig. 1 1- hydroxyl -2- [3- (formyl-Gly) -4- (oxygen acetyl-Ala) phenyl] -4,4,5,5- tetramethyl imidazoline
Synthetic route i) Br2,6N NaOH;ii)Zn,NH4Cl, 50% ethyl alcohol;Iii) 5- formylsalicylic acid, CH3OH;iv)PbO2,
CH3OH;v)DCC/HOBt,HCl·Ala-OtBu;vi)Br CH2CO2C2H5;vii)2N NaOH,CH3OH;viii)DCC/
HOBt,Arg(NO2)Gly-Asp(OBzl)-AA-OBz;ix)TFA/TFMSA,NaNO2。
Specific embodiment
In order to which the present invention is further explained, a series of embodiments are given below.These embodiments be entirely it is illustrative, it
Only be used to the present invention is specifically described, be not construed as limitation of the present invention.
Embodiment 1 prepares 2,3- dimethyl -2,3- dinitrobutane
Successively add 130mL 6N NaOH solution in ice bath and lower past 69.0g (0.78mol, 70mL) the 2- nitropropane of stirring,
20mL (0.38mol is slowly added dropwise, and drips in 1 hour) Br2With 240mL ethyl alcohol.90 DEG C of compound of reaction are flowed back 3 hours, the phase
Between there is flaky precipitate.Reaction solution is poured into while hot in 800mL ice water, 49.0g (73%) title compound is filtered to obtain, for no color chips
Shape crystallization.ESI-MS(m/e):177[M+H]+。
Embodiment 2 prepares 2,3- dimethyl -2,3- dihydroxy amido butane
By 7.00g (40mmol) 2,3- dimethyl -2,3- dinitrobutane and 4.00g NH4Cl is dissolved in 80mL 50%
Ethanol water in, stirred under ice bath, 16.00g zinc powder be added portionwise within 3 hours.After zinc powder adds, reaction mixture room
Temperature stirring 3h, filters, filter cake is washed repeatedly with 50% ethanol water.Merging filtrate and cleaning solution are 2 with concentrated hydrochloric acid tune pH,
Slurry is concentrated under reduced pressure to obtain.A small amount of 50% ethanol water of slurry is dissolved, adds appropriate potassium carbonate, after mixing thoroughly
It is packed into cable type extractor according, makees extractant, 60 DEG C of extraction 6h with methylene chloride, extracting solution is concentrated under reduced pressure, and residue is ground with petroleum ether
Mill obtains 2.07g (35%) title compound, is colourless powder.ESI-MS(m/e):149[M+H]+。
Embodiment 3 prepares 2- (3- carboxyl -4- hydroxy phenyl) -1,3- dihydroxy -4,4,5,5- tetramethyl imidazoles
The a small amount of methanol of 1.48g (10mmol) 2,3- dimethyl -2,3- dihydroxy amido butane is dissolved at room temperature, is added
2.0g (12mmol) 3- carboxyl -4- hydroxy benzaldehyde reacts 12 hours, 2.07g (70%) title compound is obtained by filtration, and is nothing
Color powder.ESI-MS(m/e):298[M+H]+。
Embodiment 4 prepares 2- (3- carboxyl -4- hydroxy phenyl) -1,3- dioxy -4,4,5,5- tetramethyl base imidazoline
By 1.00g (3.38mmol) 2- (3- carboxyl -4- hydroxy phenyl) -1,3- dihydroxy -4,4,5,5- tetramethyl imidazoles
After the dissolution of 100mL methanol, pH to 7 is adjusted with 1N NaOH, 6.77g PbO is added2.After TLC display reaction terminates, filter
Remove PbO2, filtrate with 1N HCl adjust pH to 7, be concentrated under reduced pressure.The a small amount of acetone solution of residue filters desalination, obtains
693mg (70%) title compound is blue powder.ESI-MS(m/e):292[M-H]-。
Embodiment 5 prepares 2- [3- (formyl-Gly-OtBu) -4- hydroxy phenyl] -1,3- dioxy -4,4,5,5- tetramethyl miaow
Oxazoline
300mg (1mmol) 2- (3- carboxyl -4- hydroxy phenyl) -1,3- dioxy -4,4,5,5- tetramethyl base imidazoline is molten
In the anhydrous THF of 20mL, 135mg (1mmol) HOBt and 268mg (1.2mmol) DCC is added under ice bath, adds after activation 30min
Enter 174mg (1.2mmol) HClGly-OtBu, 8h is stirred at room temperature in reaction solution NMM tune pH to 9.Reaction was completed, filters out DCU,
It is concentrated under reduced pressure, residue column chromatographs (chloroform/methanol, 10/1) and purifies, and 204mg (68%) title compound is obtained, for blue
Powder.ESI-MS(m/e):406[M+H]+。
Embodiment 6 prepares 2- [3- (formyl-Gly-OtBu) -4- (fluoroacetic acid ethyl ester) phenyl] -1,3- dioxy -4,4,5,5-
Tetramethyl imidazoline
By 406mg (1mmol) 2- [3- (formyl-Gly-OtBu) -4- hydroxy phenyl] -1,3- dioxy -4,4,5,5- tetramethyl
Base imidazoline is dissolved in the anhydrous THF of 20mL.Add 72mg (3mmol) NaH and 0.5mL (3mmol) BrCH into solution2CO2C2H5,60
DEG C reaction 5h, TLC detection reaction display raw material point disappear.Filtering, filtrate decompression concentration, residue is through dry column column chromatographic purifying
(chloroform/methanol, 10/1) obtains 410mg (83%) title compound, is blue powder.ESI-MS(m/e):493[M-H]-。
Embodiment 7 prepares 2- [3- (formyl-Gly-OtBu) -4- (fluoroacetic acid) phenyl] -1,3- dioxy -4,4,5,5- tetramethyl
Base imidazoline
By 492mg (1mmol) 2- [3- (formyl-Gly-OtBu)-4- (ethoxyacetic acid ethyl ester) phenyl] dioxy-4-1,3-,
4,5,5- tetramethyl imidazolines are dissolved in 30mL methanol, and 2N NaOH tune reaction solution pH to 12 is used under ice bath, react 2h, TLC (chloroform/
Methanol, 10/1) display raw material point disappearance.Reaction solution subtracts concentration, and 2mL is added and is saturated NaCl solution, with 1N hydrochloric acid tune pH to 3.It is mixed
It closes solution to be extracted with ethyl acetate 3 times, the combined ethyl acetate phase dry 12h of anhydrous sodium sulfate, filtering, filtrate decompression is dense
Contracting, obtains 420mg (90%) title compound, is blue powder.EI-MS(m/z):463[M-H]-。
Embodiment 8 prepares 2- [3- (formyl-Gly-OtBu) -4- (oxygen acetyl-Ala-OtBu) phenyl] -4,4,5,5- tetramethyl
Two Sinerol of base -1,3-
By 464mg (1mmol) 2- [3- (formyl-Gly-OtBu) -4- (fluoroacetic acid) phenyl] -1,3- dioxy -4,4,5,5-
Tetramethyl imidazoline is dissolved in the anhydrous THF of 20mL, and 135mg (1mmol) HOBt and 268mg (1.2mmol) DCC is added under ice bath,
180mg (1.2mmol) HClAla-OtBu is added after activation 30min, 8h is stirred at room temperature in reaction solution NMM tune pH to 9.Knot
Shu Fanying filters out DCU, is concentrated under reduced pressure, and residue column chromatographs (petrol ether/ethyl acetate, 1/1) and purifies, and obtains 450mg
(76%) title compound is blue powder.ESI-MS(m/e):592[M+H]+。
Embodiment 9 prepares 1- hydroxyl -2- [3- (formyl-Gly) -4- (oxygen acetyl-Ala) phenyl] -4,4,5,5- tetramethyl
Imidazoline (7)
By 50mg (85 μm of ol) 2- [3- (formyl-Gly-OtBu) -4- (oxygen acetyl-Ala-OtBu) phenyl] -1 under ice bath,
3- dioxy -4,4,5,5- tetramethyl imidazolines are mixed with 1mL TFA and 0.3mL TFMSA, stir 15min, and reaction mixture is used
Anhydrous ether dilution, stands, topples over supernatant, residue is diluted with anhydrous ether again, residue is drained, with 5mL distilled water
50mg NaNO is added in dissolution2, reaction solution color has blue to gradually become colourless (30min), and the pH of solution is adjusted to 7, is used
Sephadex G10 desalination, freeze-drying, obtains 20mg white solid powder .ESI-MS (m/e): 465 [M+H]+;FT-MS:
465.19712。
The antithrombotic acitivity of the evaluation compound 7 of experimental example 1
It is random to be grouped by male SD rat (200 ± 20g), it every group 10, raises 1 day, stops feeding and stay overnight.Stomach-filling is given
Give compound 7 normal saline solution (dosage 100nmol/kg) or aspirin normal saline solution (dosage be 167 μ
Mol/kg) or after physiological saline (dosage 10mL/kg) 30min, the normal saline solution of 20% Ethylurethanm of rat is anaesthetized,
It performs the operation later.The silk thread of correct amount is placed in bypass intubation by the right carotid and left neck vein for separating rat, and one end of pipe is inserted
Enter left vein, another end pipe is inserted into right artrial and to inject 0.2mL heparin sodium anticoagulant.So that blood flow flows through bypass from right artrial
Intubation enters left side vein, and the silk thread with thrombus is taken out after 15min and is weighed, the weight of silk thread before and after blood circulation is calculated,
Obtained thrombus weight indicates and represents antithrombotic acitivity with mean value ± SD mg, makees t inspection.Data are included in table 1.The result shows that mouth
Thrombosis can be effectively inhibited by taking 1nmol/kg compound 7.Illustrate that present invention obtains unexpected technical effects.
The antithrombotic acitivity of 1 100nmol/kg compound 7 of table
N=10;A) p < 0.01 compared with physiological saline.
The thrombus dissolving activity of the evaluation compound 7 of experimental example 2
SD rat (male, 200 ± 20g) is carried out by the dosage intraperitoneal injection urethane normal saline solution of 1200mg/kg
Anesthesia.Its dorsal position is fixed after anesthetized rat, its right common carotid artery is separated, clamps artery clamp at proximal part, by proximal part and
Distal end respectively penetrates surgical thread, the surgical thread ligation of distal end, and artery clamp is unclamped, takes out about 1mL artery by distal end intubation
Blood is placed in 1mL centrifuge tube.Toward vertically fixed rubber tube, (long 15mm, internal diameter 2.5mm, outer diameter 5.0mm, tube bottom rubber plug are close
Envelope, para film is tamping) in inject 0.1mL rat artery blood, the thrombus of a stainless steel material is then rapidly inserted into pipe
Fixing bolt (the fixed spiral of thrombus is coiled into the stainless steel wire that diameter is 0.2mm, and the long 10mm of spiral part includes 15 bung flanges,
The diameter of bung flange is that 1.0mm asks handle to be connected with spiral, is about 7.0mm, is in question mark type).After blood clotting 45min, from glass tube
In carefully take out the fixed spiral of the thrombus wrapped up by thrombus, accurately claim its weight.
Bypass intubation is made of three parts, and interlude is long 60.0mm, the polyethylene rubber tube of internal diameter 3.5mm;Both ends are
The identical polyethylene pipe of long 100.0mm, internal diameter 1.0mm, outer diameter 2.0mm, the pipe one end pull into spike tube, are about 10.0mm and (use
In insertion rat carotid artery and vein), outer diameter 1.0mm, one section of length of outer cover of the other end is 7.0mm, outer diameter 3.5mm
Polyethylene pipe (for being inserted into the polyethylene rubber tube in middle section), the inner wall of 3 sections of pipes is required to silanization (1% silicone oil ether
Solution).The fixed spiral of the thrombus of thrombus package is placed in the polyethylene rubber tube of middle section, the other both ends of sebific duct are poly- with two respectively
The overstriking end of ethylene is nested, and guarantees that blood will not be leaked during circulation.With syringe heparin will be filled by spike tube end in pipe
Normal saline solution (50IU/kg) excludes bubble, spare.
The left vena jugularis externa of rat is separated, proximal part and distal end respectively penetrate surgical thread, ligature the blood vessel of distal end,
An osculum is cut on exposed left vena jugularis externa, the above-mentioned bypass duct spike tube prepared is inserted into left vena jugularis externa by osculum and is open
Place, while far from shunt valve middle section (the fixed spiral of the thrombus containing accurate weighing) the interior fixed spiral of thrombus.Passed through with syringe another
The normal saline solution (50IU/kg) of the heparin sodium of the spike tube injection correct amount of one end, syringe not withdraw polyethylene at this time
Pipe, the hose between syringe and polyethylene pipe is clamped with artery clamp.Stop blooding in the proximal part artery clamp of right common carotid artery, ties
Distal end is pricked, right common carotid artery is nearby being cut into an osculum from artery clamp, syringe is extracted from the tip of polyethylene pipe, will gather
The proximal part of the tip insertion artery angle of ethylene tube.Arteriovenous is fixed with No. 4 sutures in the both ends of bypass duct.
With scalp acupuncture by the normal saline solution (dosage 20000IU/kg) of physiological saline (3mL/kg) or urokinase or
The normal saline solution (dosage 100nmol/kg) of compound 7 by the middle section of shunt valve, (fix by the thrombus containing accurate weighing
Spiral), the nearly vein end far from the fixed spiral of thrombus is penetrated, artery clamp is unclamped, flows to blood flow from artery by bypass duct
Vein.Solution in syringe is slowly injected into blood, by blood circulation, by vein-heart-artery sequential action in spiral shell
On the thrombus of rotation.After blood circulation 1h, the spiral of fixed thrombus, accurate weighing are taken out from bypass duct.It calculates every big
The weight difference that the spiral blood circulation front and back thrombus of thrombus is fixed in mouse bypass duct, is indicated and is represented molten with mean value ± SD mg
Thrombus activity, makees t inspection.Data are included in table 2.The result shows that 100nmol/kg compound 7 can effectively lysigenous thrombus.
Illustrate that present invention obtains unexpected technical effects.
The thrombus dissolving activity of 2 1nmol/kg compound 7 of table
N=10;And physiological saline ratio p<0.01, a) p>0.05 compared with urokinase.
Experimental example 3 evaluates therapeutic effect of the compound 7 to ishemic stroke rat
About 2cm long notch is opened vertically at the positive middle part of the neck of male SD rat (300 ± 20g of weight), along nutator
Inside fate separates out right common carotid artery, external carotid artery and internal carotid.It is pressed from both sides respectively with noninvasive artery clamp and closes internal carotid opening
With arteria carotis communis proximal part, the distal end of external carotid artery is ligatured, 1 osculum is cut in external carotid artery, unclamps arteria carotis communis proximal part
Artery clamp takes 10 μ L blood, closes the proximal part of arteria carotis communis with noninvasive artery clamp folder again later.10 μ L blood of acquirement are placed on
Make blood clotting within room temperature 30 minutes in 1mL EP pipe, is then transferred in -20 DEG C of refrigerators and places 1 hour, make blood clotting
It is solid.Rat 10% chloraldurate intraperitoneal injection of anesthesia, dosage 400mg/kg.Blood clotting is taken out, 1mL physiology salt is added
Blood clotting is pounded uniform tiny thrombi with steel shovel by water, is prepared the suspension of tiny thrombus and is transferred to 1mL injection
In device.The artery clamp for unclamping arteria carotis communis proximal part slowly passes through 1mL thrombus suspension from rat external carotid artery to proximal part
Then the brain of internal carotid injection rat ligatures external carotid artery proximal part, open and obtain artery at internal carotid and arteria carotis communis
Folder restores blood flow.Wait revival.Rat presses Zealonga method after reviving 24 hours and evaluates neurological functional deficit.0 point of table
Show without any neurological deficit sign, 1 point indicates not damaging side forelimb not tensible, and 2 points indicate to walk to not damaging skidding, 3
Expression is divided to turn-take into shape walking of knocking into the back to side is not damaged, for 4 points of expression disturbances of consciousness without autonomous, 5 points of expressions are dead.According to
Divide average packet.It is 100nmol/kg that each group rat injects 17 dosage of compound through tail vein daily.Continuous injection 6 days, often
Its scoring.As a result it is included in table 3.Table 3 statistics indicate that, continuously treatment can make 6 cerebral ischemias, 24 hours rats in 6 days to compound 7
Neurobiology scoring is 0 point, and can make the scoring of 7 cerebral ischemias, 24 hours rat nerve biology is that Neurobiology scoring is
1 point.Because rear 5 maintenance doses need 2 μm of ol/kg unlike the compound initial dose having disclosed needs 5 μm of ol/kg, change
6 dosage for closing object 7 are 100nmol/kg.So, initial dose and maintenance dose reduce 50 times and 20 times respectively.
The continuously influence to the scoring of 24 hours rat nerve biology of cerebral ischemia in treatment 6 days of 3 compound 7 of table
N=13, target compound dosage=100nmol/kg, tail vein injection administration.
Claims (5)
1. 1- hydroxyl -2- [3- (formyl-Gly) -4- (oxygen acetyl-Ala) phenyl] -4,4,5,5- tetramethyl imidazolines of following formula,
2. 1- hydroxyl -2- [3- (formyl-Gly) -4- (oxygen acetyl-Ala) phenyl] -4,4,5,5- tetramethyl miaow of claim 1
The preparation method of oxazoline, method includes the following steps:
(1) 2,3- dimethyl -2,3- dinitrobutane is prepared;
(2) 2,3- dimethyl -2,3- dihydroxy amido butane is prepared;
(3) 2- (3- carboxyl -4- hydroxy phenyl) -1,3- dihydroxy -4,4,5,5- tetramethyl imidazolidine is prepared;
(4) 2- (3- carboxyl -4- hydroxy phenyl) -1,3- dioxy -4,4,5,5- tetramethyl imidazoline is prepared;
(5) 2- [3- (formyl-Gly-OtBu) -4- hydroxy phenyl] -1,3- dioxy -4,4,5,5- tetramethyl imidazoline is prepared;
(6) 2- [3- (formyl-Gly-OtBu) -4- (ethoxycarbonylmethoxy) phenyl] -1,3- dioxy -4,4,5,5- tetramethyl is prepared
Base imidazoline;
(7) 2- [3- (formyl-Gly-OtBu) -4- (carboxymethoxyl) phenyl] -1,3- dioxy -4,4,5,5- tetramethyl imidazoles is prepared
Quinoline;
(8) 2- [3- (formyl-Gly-OtBu) -4- (oxygen acetyl-Ala-OtBu) phenyl] -4,4,5,5- tetramethyl -1,3- is prepared
Two Sinerols;
(9) 1- hydroxyl -2- [3- (formyl-Gly) -4- (oxygen acetyl-Ala) phenyl] -4,4,5,5- tetramethyl imidazoline is prepared.
3. 1- hydroxyl -2- [3- (formyl-Gly) -4- (oxygen acetyl-Ala) phenyl] -4,4,5,5- tetramethyl miaow of claim 1
Oxazoline is preparing the application in antithrombotic reagent.
4. 1- hydroxyl -2- [3- (formyl-Gly) -4- (oxygen acetyl-Ala) phenyl] -4,4,5,5- tetramethyl miaow of claim 1
Oxazoline is preparing the application in thrombolytic agent.
5. 1- hydroxyl -2- [3- (formyl-Gly) -4- (oxygen acetyl-Ala) phenyl] -4,4,5,5- tetramethyl miaow of claim 1
Application of the oxazoline in preparation treatment cerebral arterial thrombosis drug.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510689618.8A CN106608849B (en) | 2015-10-22 | 2015-10-22 | 2- (substituted-phenyl) -4,4,5,5- tetramethyl -1- hydroxyl-imidazoline, synthesis, activity and application |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510689618.8A CN106608849B (en) | 2015-10-22 | 2015-10-22 | 2- (substituted-phenyl) -4,4,5,5- tetramethyl -1- hydroxyl-imidazoline, synthesis, activity and application |
Publications (2)
Publication Number | Publication Date |
---|---|
CN106608849A CN106608849A (en) | 2017-05-03 |
CN106608849B true CN106608849B (en) | 2019-02-22 |
Family
ID=58611543
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201510689618.8A Active CN106608849B (en) | 2015-10-22 | 2015-10-22 | 2- (substituted-phenyl) -4,4,5,5- tetramethyl -1- hydroxyl-imidazoline, synthesis, activity and application |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN106608849B (en) |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102898507B (en) * | 2012-09-05 | 2015-05-27 | 上海晟顺生物科技有限公司 | Thrombolysis oligopeptide-imidazolidine binary conjugate, preparation method and uses thereof |
CN102898505A (en) * | 2012-09-05 | 2013-01-30 | 永光制药有限公司 | ARPAK/imidazolidine/RGD ternary conjugate, preparation method and uses thereof |
-
2015
- 2015-10-22 CN CN201510689618.8A patent/CN106608849B/en active Active
Also Published As
Publication number | Publication date |
---|---|
CN106608849A (en) | 2017-05-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102898505A (en) | ARPAK/imidazolidine/RGD ternary conjugate, preparation method and uses thereof | |
CN102887941A (en) | PAK (polyester alkyd)/ imidazoline/RGD (arginine-glycine-aspartic acid) ternary conjugate and preparation method and use thereof | |
CN102875644A (en) | GRPAK/tetrahydroglyoxaline/RGD ternary conjugate as well as preparation method and application thereof | |
CN102898507B (en) | Thrombolysis oligopeptide-imidazolidine binary conjugate, preparation method and uses thereof | |
CN106317181B (en) | Two Sinerol of G- tetramethyl -1,3-, synthesis, activity and application | |
CN106608849B (en) | 2- (substituted-phenyl) -4,4,5,5- tetramethyl -1- hydroxyl-imidazoline, synthesis, activity and application | |
CN106608850B (en) | 1- hydroxyl -2- (substituted-phenyl) -4,4,5,5- tetramethyl imidazoline, synthesis, activity and application | |
CN106317171B (en) | Ring histidyl--KK, synthesis, thrombus related activity and application | |
CN108948146A (en) | 1R- methyl-beta-tetrahydro carboline acyl-K (ARPAK)-RGDV, synthesis, activity and application | |
CN108929372A (en) | 1R- methyl-beta-tetrahydro carboline acyl-K (GRPAK)-RGDV, synthesis, activity and application | |
CN106432413B (en) | Five methoxytryptamine base carbonyl propionyl-K (PAK), preparation, activity and application | |
CN102898506A (en) | RPAK/imidazolidine/RGD ternary conjugate, preparation method and uses thereof | |
CN106317184B (en) | Two Sinerol of A- tetramethyl -1,3-, synthesis, activity and application | |
CN106317192B (en) | 3,4- dihydroxy-F (PAK)-RGD-AA, synthesis, activity and application | |
CN106317196A (en) | Imidazole-pyridine-formyl-K(K)-AA1-AA2-AA3-AK, synthesis, activity and application thereof | |
CN108948145A (en) | 1R- methyl-beta-tetrahydro carboline acyl-K (PAK)-RGDV, synthesis, activity and application | |
CN108948155A (en) | 1R- methyl-beta-tetrahydro carboline acyl-K (QRPAK)-RGDV, synthesis, activity and application | |
CN106317189B (en) | Five methoxytryptamine base carbonyl propionyl-RPAK peptides, preparation, activity and application | |
CN111848724B (en) | Preparation, activity and application of theanyl tetrahydroimidazopyridine-6-formyl acidic amino acid | |
CN106349333B (en) | 11 peptide of The-K (KAPRG) RGDV, preparation, activity and application | |
CN106317198B (en) | GRPAK-The-RGDV, preparation, activity and application | |
CN111848730B (en) | Preparation, activity and application of theanyl tetrahydroimidazopyridine-6-formyl polar amino acid | |
CN106608901A (en) | Dihydroxy dimethyl tetrahydroisoquinoline-3-formyl-Lys (Ala-Lys) and synthesis, activity and application thereof | |
CN106317199B (en) | The-GRPAKRGDV decapeptide, preparation, activity and application | |
CN110615828B (en) | 1S-methyl-beta-tetrahydrocarboline acyl-K and synthesis, activity and application thereof |
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 | ||
TR01 | Transfer of patent right | ||
TR01 | Transfer of patent right |
Effective date of registration: 20220330 Address after: Room 705, No.9, Shuangying Road, Fengtai District, Beijing 100075 Patentee after: Beijing Hengrun Taisheng Pharmaceutical Technology Co.,Ltd. Address before: The 100069 Beijing Fengtai District right outside the West No. 10 Patentee before: Peng Li |