CN107311991B - Puerarin derivative, its preparation method and application in preventing and treating cardiovascular and cerebrovascular diseases or diabetes and its complications - Google Patents
Puerarin derivative, its preparation method and application in preventing and treating cardiovascular and cerebrovascular diseases or diabetes and its complications Download PDFInfo
- Publication number
- CN107311991B CN107311991B CN201710464386.5A CN201710464386A CN107311991B CN 107311991 B CN107311991 B CN 107311991B CN 201710464386 A CN201710464386 A CN 201710464386A CN 107311991 B CN107311991 B CN 107311991B
- Authority
- CN
- China
- Prior art keywords
- compound
- puerarin
- pharmaceutical composition
- cerebrovascular diseases
- injection
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 208000024172 Cardiovascular disease Diseases 0.000 title claims abstract description 15
- 208000026106 cerebrovascular disease Diseases 0.000 title claims abstract description 15
- 230000002526 effect on cardiovascular system Effects 0.000 title claims abstract description 14
- 206010012601 diabetes mellitus Diseases 0.000 title claims abstract description 10
- HKEAFJYKMMKDOR-VPRICQMDSA-N puerarin Chemical class O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=C(O)C=CC(C2=O)=C1OC=C2C1=CC=C(O)C=C1 HKEAFJYKMMKDOR-VPRICQMDSA-N 0.000 title abstract description 64
- 150000001875 compounds Chemical class 0.000 claims abstract description 72
- 239000000203 mixture Substances 0.000 claims abstract description 25
- 239000007924 injection Substances 0.000 claims abstract description 11
- 238000002347 injection Methods 0.000 claims abstract description 11
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 30
- 229940125773 compound 10 Drugs 0.000 claims description 16
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 4
- 239000003978 infusion fluid Substances 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 206010002383 Angina Pectoris Diseases 0.000 claims description 3
- 206010020772 Hypertension Diseases 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 206010008111 Cerebral haemorrhage Diseases 0.000 claims description 2
- 206010019280 Heart failures Diseases 0.000 claims description 2
- 208000006011 Stroke Diseases 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 239000000178 monomer Substances 0.000 claims description 2
- 208000010125 myocardial infarction Diseases 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims 2
- 201000001320 Atherosclerosis Diseases 0.000 claims 1
- 239000007910 chewable tablet Substances 0.000 claims 1
- 229940068682 chewable tablet Drugs 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000007919 dispersible tablet Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000002662 enteric coated tablet Substances 0.000 claims 1
- 229940100688 oral solution Drugs 0.000 claims 1
- 239000006191 orally-disintegrating tablet Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 208000037803 restenosis Diseases 0.000 claims 1
- 150000003839 salts Chemical class 0.000 abstract description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 6
- 125000005843 halogen group Chemical group 0.000 abstract description 5
- 125000004430 oxygen atom Chemical group O* 0.000 abstract description 4
- 125000003545 alkoxy group Chemical group 0.000 abstract description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 238000002648 combination therapy Methods 0.000 abstract 1
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 abstract 1
- RXUWDKBZZLIASQ-UHFFFAOYSA-N Puerarin Natural products OCC1OC(Oc2c(O)cc(O)c3C(=O)C(=COc23)c4ccc(O)cc4)C(O)C(O)C1O RXUWDKBZZLIASQ-UHFFFAOYSA-N 0.000 description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 229940125898 compound 5 Drugs 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 10
- 206010008118 cerebral infarction Diseases 0.000 description 9
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 8
- 238000001704 evaporation Methods 0.000 description 8
- 201000006474 Brain Ischemia Diseases 0.000 description 7
- 206010008120 Cerebral ischaemia Diseases 0.000 description 7
- 206010063837 Reperfusion injury Diseases 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 238000012986 modification Methods 0.000 description 7
- 230000004048 modification Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000008602 contraction Effects 0.000 description 6
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 6
- 229960002748 norepinephrine Drugs 0.000 description 6
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 6
- 241000700198 Cavia Species 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 210000000709 aorta Anatomy 0.000 description 4
- 230000017531 blood circulation Effects 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000002441 reversible effect Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000004475 Arginine Substances 0.000 description 3
- 241000700199 Cavia porcellus Species 0.000 description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 3
- 239000004472 Lysine Substances 0.000 description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 239000003146 anticoagulant agent Substances 0.000 description 3
- 239000003472 antidiabetic agent Substances 0.000 description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 3
- 229940126904 hypoglycaemic agent Drugs 0.000 description 3
- 239000007928 intraperitoneal injection Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 2
- 239000001639 calcium acetate Substances 0.000 description 2
- 229960005147 calcium acetate Drugs 0.000 description 2
- 235000011092 calcium acetate Nutrition 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 229910001424 calcium ion Inorganic materials 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 210000000038 chest Anatomy 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 210000004351 coronary vessel Anatomy 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 238000005520 cutting process Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 208000028867 ischemia Diseases 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000000926 neurological effect Effects 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000002040 relaxant effect Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 229960000281 trometamol Drugs 0.000 description 2
- 230000003639 vasoconstrictive effect Effects 0.000 description 2
- WSNKEJIFARPOSQ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-(1-benzothiophen-2-ylmethyl)benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCC2=CC3=C(S2)C=CC=C3)C=CC=1 WSNKEJIFARPOSQ-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-UHFFFAOYSA-N Hydrogen atom Chemical compound [H] YZCKVEUIGOORGS-UHFFFAOYSA-N 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical class O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- 206010061481 Renal injury Diseases 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 206010047141 Vasodilatation Diseases 0.000 description 1
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 1
- SAHIZENKTPRYSN-UHFFFAOYSA-N [2-[3-(phenoxymethyl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound O(C1=CC=CC=C1)CC=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 SAHIZENKTPRYSN-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000879 anti-atherosclerotic effect Effects 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 230000002769 anti-restenotic effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 210000002376 aorta thoracic Anatomy 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 238000002306 biochemical method Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000005242 cardiac chamber Anatomy 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 208000037806 kidney injury Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 210000003516 pericardium Anatomy 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- ALDITMKAAPLVJK-UHFFFAOYSA-N prop-1-ene;hydrate Chemical group O.CC=C ALDITMKAAPLVJK-UHFFFAOYSA-N 0.000 description 1
- 210000001147 pulmonary artery Anatomy 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 210000001562 sternum Anatomy 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 210000001631 vena cava inferior Anatomy 0.000 description 1
- 210000002620 vena cava superior Anatomy 0.000 description 1
- 210000002417 xiphoid bone Anatomy 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/14—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a puerarin derivative, a preparation method thereof and application thereof in preventing and treating cardiovascular and cerebrovascular diseases or diabetes and complications thereof. The invention relates to a puerarin derivative shown in a formula (I) or a formula (II) or pharmaceutically acceptable salt thereof,
wherein the content of the first and second substances,
may represent a single bond or a double bond; r1Represents: oxygen atom, hydrogen atom, hydroxyl group, alkoxy group, and halogen atom; r2And R3Respectively represent: hydrogen atom, hydroxy group, hydroxymethyl group, halogen atom, -O (O) CR4、‑OSOR4、‑OSO2R4、‑O(O)PO2R4R5(ii) a The invention also relates to the therapeutically acceptable salts of the compounds; the invention also relates to a medical composition of the compound and the salt thereof, which can be used for preventing and treating cardiovascular and cerebrovascular diseases, diabetes and complications and is used as a main componentPreparing corresponding oral preparation, injection and the like; the present invention encompasses combination therapies with other cardiovascular and cerebrovascular disease treatment agents.
Description
Technical Field
The invention relates to the field of treatment of cardiovascular and cerebrovascular diseases and diabetes and the field of preparation of compounds, in particular to a structure of a novel puerarin derivative, a preparation method thereof and application of the derivative in treatment and prevention of cardiovascular and cerebrovascular diseases or diabetes and complications thereof.
Background
Research shows that puerarin is β receptor blocker and calcium ion antagonist, has pharmacological effects of dilating coronary artery, lowering blood pressure, resisting arrhythmia, lowering blood sugar, lowering blood fat, relaxing smooth muscle, inhibiting platelet aggregation, resisting oxidation, etc. it is mainly used in treating cardiac and cerebral vascular diseases, such as hypertension, coronary heart disease, angina pectoris, acute cerebral infarction, high blood viscosity, etc.
At present, puerarin has the defects of poor water solubility, low oral bioavailability and the like in the clinical use process, and the clinical use range of the puerarin is limited. Especially, the puerarin has low water solubility, which is only 4.5g/L, and in clinical use, the puerarin injection mostly needs to be added with high-concentration propylene glycol, lysine, arginine, histidine, nicotinamide and the like as cosolvent, and the cosolvent has limited effect, and may cause anaphylactic reaction of human body and toxic and side effects such as liver and kidney injury. Therefore, puerarin is subjected to structural modification and modification to develop a novel cardiovascular and cerebrovascular protection medicament and a hypoglycemic medicament so as to enhance the water solubility of the puerarin and improve the bioavailability and the biological activity, and the puerarin has great application value and market potential. The prior art also discloses various derivatives for enhancing the water solubility of puerarin by carrying out structural modification or modification on the puerarin and corresponding preparation methods, for example, CN101712676A discloses that the water solubility of drugs is enhanced by designing and synthesizing a high water-soluble novel puerarin derivative prodrug such as puerarin phosphate, sulfonate and the like; CN103382203A discloses that puerarin water solubility and fat solubility are improved by enhancing drug target modification; CN103694229A prepares puerarin derivatives with good water solubility and lipid solubility. The 8-position of puerarin is connected with glucopyranose-carbon glycoside, and the 7-position and the 4-position of puerarin are respectively provided with a phenolic hydroxyl group which is an active group of puerarin and is a concentrated site for modifying the structure of puerarin at present.
Disclosure of Invention
Aiming at the problems in the prior art, in order to overcome the defects and shortcomings of poor water solubility of puerarin, puerarin is used as a raw material, firstly, a skeleton of the puerarin is modified to reduce unsaturated double bonds of C ring α, a molecule rigid structure is damaged, and the solubility of the puerarin is improved, secondly, the polarity and the water solubility of molecules are improved by further reducing ketone carbonyl into hydroxyl, and finally, a plurality of puerarin derivatives with good water solubility are obtained.
Specifically, the invention relates to the following technical scheme:
first, an object of the present invention is to provide a compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof,
wherein the content of the first and second substances,
may represent a single bond or a double bond; r1Represents: oxygen atom, hydrogen atom, hydroxyl group, alkoxy group, and halogen atom; r2And R3Respectively represent: hydrogen atom, hydroxyl group, hydroxymethyl group, halogen atom, -O (O) CR4、-OSO3R4、-O(O)PO2R4R5；R4And R5Can be independently selected from hydrogenAtom, (C)1-C4) Alkyl, amino, metal ions, such as sodium ion, potassium ion, magnesium ion, calcium ion, zinc ion, or the like.
In a preferred embodiment of the present invention,
only represents a single bond.
The puerarin derivative is obtained by modifying a puerarin framework, reducing C-ring α unsaturated double bonds, destroying a molecular rigid structure and improving the solubility of the puerarin, and further reducing ketone carbonyl into hydroxyl to improve the molecular polarity and water solubility, wherein the water solubility of the puerarin derivative (compound 1-10) is obviously improved (4.5g/L) compared with puerarin, wherein the water solubility of the compound 5-10 is the best, 20-25g/L, and the water solubility of the compound 1-4 is slightly lower, about 10g/L, but is obviously improved compared with the solubility of the puerarin.
In a preferred embodiment of the present invention, the compound may be a compound selected from the following structures:
in a more preferred embodiment, the compounds according to the invention are selected from compounds 5, 6, 10.
In a preferred embodiment, a pharmaceutically acceptable salt of the compound of the present invention, which is a salt of the compound with an inorganic base, such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, calcium chloride, calcium acetate or magnesium chloride, or an organic base, such as tromethamine, aminoethanol, lysine or arginine, and the like, is also within the scope of the present invention.
Secondly, it is a second object of the present invention to provide a process for preparing the above compound or a pharmaceutically acceptable salt thereof, which comprises the following reaction,
obtaining the compound shown in the formula (IV) or the formula (VI) by carrying out catalytic hydrogenation reaction on the compound shown in the formula (III) or (V), wherein
May represent a single bond or a double bond; r1Represents: oxygen atom, hydrogen atom, hydroxyl group, alkoxy group, and halogen atom.
In a preferred embodiment, the compound of formula (IV) or formula (VI) is prepared from puerarin (III) or formula 7, 2' -anhydropuerarin (V), respectively, by the following method: puerarin or dehydrated puerarin is catalyzed by palladium carbon, and is reacted in methanol or ethyl acetate solution for controlling reaction time to obtain compounds with different reduction degrees as shown in formula (IV) or formula (VI), wherein
May represent a single bond or a double bond; r1Represents: oxygen atom, hydrogen atom and hydroxyl group.
It is still another object of the present invention to provide a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt thereof. The compounds may be used as monomers or as mixtures of isomers. The adjuvant used in the pharmaceutical composition can be solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, pills and suppositories. Powders and tablets may contain from about 5% to about 95% of the active ingredient. Suitable solid excipients may be magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, pills and capsules are solid dosage forms suitable for oral administration. Liquid form preparations include solutions, suspensions and emulsions, examples of which are aqueous parenteral solutions or water-propylene glycol solutions, or oral solutions with the addition of sweeteners and contrast agents. In addition, it can be made into small water injection for injection, lyophilized powder for injection, infusion solution or infusion solution.
Another object of the present invention is to provide the use of the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention and/or treatment of cardiovascular and cerebrovascular diseases or a hypoglycemic agent. These cardiovascular and cerebrovascular diseases include hypertension, angina pectoris, heart failure, myocardial infarction, stroke, cerebral hemorrhage, etc., and diabetes and its complications.
Still another object of the present invention is to provide a pharmaceutical composition comprising a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof as described above in combination with at least one other cardiovascular disease agent or hypoglycemic agent. Other cardiovascular disease agents or hypoglycemic agents are contemplated which differ in atomic composition or structure from the compounds of formula (I) or formula (II). Other cardiovascular disease agents which may be used in combination with the novel compounds of the present invention include agents having antithrombotic, antiplatelet aggregation, antiatherosclerotic, antirestenotic and/or anticoagulant, vasodilatory activity, as well as diabetes and its complications.
The invention achieves the following beneficial effects:
(1) the puerarin is used as a raw material, the unsaturated double bond of C ring α is reduced by modifying the skeleton of the puerarin, the rigid structure of the molecule is destroyed, the solubility of the puerarin is improved, and the polarity and the water solubility of the molecule are improved by further reducing ketocarbonyl into hydroxyl, so that a plurality of puerarin derivatives with good water solubility are finally obtained.
(2) Animal experiments prove that the composition can increase the coronary blood flow of guinea pigs, has a relaxation effect on arterial contraction caused by norepinephrine, has a protection effect on rat focal cerebral ischemia reperfusion injury, and effectively maintains or improves the physiological activity of puerarin while improving the bioavailability of the puerarin.
(3) The compound of the invention has the characteristics of simple and easy preparation, high compound activity, low preparation cost and the like, and can be used as a promising medicament for preventing and treating cardiovascular and cerebrovascular diseases.
Drawings
FIG. 1: effect of norepinephrine on arterial constriction-blank control
FIG. 2: relaxation of arterial contraction induced by norepinephrine with puerarin
FIG. 3: relaxation of norepinephrine-induced arterial contraction by Compound 10
FIG. 4: relaxation of arterial contraction induced by norepinephrine by mixture of compounds 5 and 6
Detailed Description
The present invention will be described in further detail below with reference to examples, but the embodiments of the present invention are not limited thereto. Various modifications and changes may be made by those skilled in the art, and any modification, equivalent replacement or improvement made without departing from the spirit and principle of the present invention should be covered within the protection scope of the present invention.
The first embodiment is as follows: the structure of the compound of the invention is as follows:
the pharmaceutically acceptable salts of the above compounds are salts of the compounds with inorganic bases such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, calcium chloride, calcium acetate or magnesium chloride, or salts with organic bases such as trometamol, aminoethanol, lysine or arginine.
Example two: preparation of Compounds 1 and 2
Weighing the compound puerarin (III) and placing in a dry round-bottom flask, adding ethyl acetate to dissolve the compound puerarin (III), then adding 10% palladium carbon, stirring at room temperature for reaction for 6 hours, monitoring the reaction progress by TLC, filtering off the palladium carbon after the reaction is finished, evaporating the solvent, passing the obtained product through a Flash reverse phase column, eluting with a methanol/water gradient as a mobile phase, and finally evaporating the solvent under reduced pressure to obtain white solid compounds 1 and 2.
Compound 1: MS M/z 419(M + 1);1H NMR(400MHz,MeOD)δ7.75(d,J＝8.8Hz,1H),7.08(d,J＝8.6Hz,2H),6.75(d,J＝8.5Hz,2H),6.54(d,J＝8.8Hz,1H),4.93–4.88(m,2H),4.63–4.52(m,2H),4.04(s,1H),3.87(dd,J＝11.9,1.9Hz,1H),3.73(dd,J＝11.9,4.9Hz,1H),3.50–3.36(m,3H).
compound 2: MS M/z 419(M + 1);1H NMR(400MHz,MeOD)δ7.75(d,J＝8.8Hz,1H),7.12(d,J＝8.5Hz,2H),6.74(d,J＝8.5Hz,2H),6.55(d,J＝8.8Hz,1H),4.95–4.89(m,2H),4.64–4.54(m,2H),4.01(s,1H),3.87(dd,J＝12.0,2.0Hz,1H),3.77–3.70(m,1H),3.50–3.37(m,3H).
example three: preparation of Compounds 3 and 4
Weighing the compound of dehydrated puerarin (V) and placing the compound of dehydrated puerarin (V) in a dry round-bottom flask, adding ethyl acetate to dissolve the compound of dehydrated puerarin (V), then adding 10% palladium carbon, stirring and reacting for 6 hours at room temperature, monitoring the reaction progress by TLC, filtering off the palladium carbon after the reaction is finished, evaporating the solvent, passing the obtained product through a Flash reverse phase column, performing gradient elution by using methanol/water as a mobile phase, and finally evaporating the solvent under reduced pressure to obtain white solid compounds 3 and 4.
Compound 3: MS M/z 401(M + 1);1H NMR(600MHz,CD3OD)δ7.92(d,J＝8.6Hz,1H),7.08(d,J＝8.6Hz,2H),6.77(d,J＝8.6Hz,2H),6.68(d,J＝8.6Hz,1H),5.18(d,J＝3.3Hz,1H),4.70–4.55(m,3H),4.00-3.97(m,2H),3.84(dd,J＝12.1,2.5Hz,1H),3.64(dd,J＝12.1,5.7Hz,1H),3.60(t,J＝9.4Hz,1H),3.35(ddd,J＝9.3,5.7,2.3Hz,1H).
compound 4: MS M/z 401(M + 1);1H NMR(600MHz,CD3OD)δ7.92(d,J＝8.6Hz,1H),7.09(d,J＝8.6Hz,2H),6.74(d,J＝8.6Hz,2H),6.68(d,J＝8.5Hz,1H),5.18(d,J＝3.3Hz,1H),4.71–4.63(m,3H),3.98(dd,J＝9.5,4.8Hz,1H),3.88(dd,J＝7.4,5.3Hz,1H),3.84(dd,J＝12.0,2.4Hz,1H),3.64(dd,J＝12.1,5.8Hz,1H),3.59(t,J＝9.4Hz,1H),3.35(ddd,J＝8.0,5.8,2.4Hz,1H).
example four: preparation of Compounds 5-8
Weighing the compound puerarin (III) and placing in a dry round-bottom flask, adding ethyl acetate to dissolve the compound, then adding 10% palladium carbon, stirring at room temperature for reaction for 48 hours, monitoring the progress of the reaction by TLC, filtering off the palladium carbon after the reaction is finished, evaporating the solvent, passing the obtained product through a silica gel reverse phase column, eluting with a methanol/dichloromethane gradient as a mobile phase, and evaporating the solvent under reduced pressure to obtain a mixture of compounds 5, 6, 7 and 8. Finally, the mixture is processed by an HPLC reversed phase column, and acetonitrile/water is taken as a mobile phase, so that pure compounds 5, 6, 7 and 8 are respectively obtained.
Compound 5: MS M/z 421(M + 1);1H NMR(400MHz,MeOD)δ7.24(d,J＝8.6Hz,1H),7.07(d,J＝8.5Hz,2H),6.73(d,J＝8.5Hz,2H),6.46(d,J＝8.5Hz,1H),4.77(d,J＝7.2Hz,1H),4.29(dd,J＝11.1,3.6Hz,1H),4.17(dd,J＝11.0,8.6Hz,1H),4.01–3.91(m,1H),3.84(dd,J＝11.8,1.8Hz,1H),3.74(dd,J＝12.1,5.0Hz,1H),3.46(t,J＝7.3Hz,2H),3.40-3.36(m,1H),3.01(td,J＝8.1,3.5Hz,1H).
compound 6: MS M/z 421(M + 1);1H NMR(400MHz,MeOD)δ7.12(d,J＝8.6Hz,2H),7.08(d,J＝8.5Hz,1H),6.76(d,J＝8.6Hz,2H),6.44(d,J＝8.4Hz,1H),4.60(d,J＝2.2Hz,1H),4.47(dd,J＝11.9,10.7Hz,1H),4.22(dd,J＝10.3,2.6,1H),3.99(t,J＝8.9Hz,1H),3.85(dd,J＝12.1,2.2Hz,1H),3.75(dd,J＝12.1,4.9Hz,1H),3.49(t,J＝7.3Hz,2H),3.40-3.36(m,1H),3.11(dt,J＝12.0,3.2Hz,1H).
compound 7: MS M/z 421(M + 1);1H NMR(400MHz,MeOD)δ7.12(d,J＝8.5Hz,2H),7.09(d,J＝8.4Hz,1H),6.76(d,J＝8.5Hz,2H),6.44(d,J＝8.4Hz,1H),4.61(d,J＝2.1Hz,1H),4.45(dd,J＝12.0,10.5Hz,1H),4.25(dd,J＝10.3,2.4Hz,1H),3.99(t,J＝8.7Hz,1H),3.85(dd,J＝12.0,2.1Hz,1H),3.76(dd,J＝12.0,4.8Hz,1H),3.48(t,J＝8.3Hz,2H),3.43–3.37(m,1H),3.15(dt,J＝12.1,3.2Hz,1H).
compound 8: MS M/z 421(M + 1);1H NMR(400MHz,MeOD)δ7.21(d,J＝8.6Hz,1H),7.11(d,J＝8.3,2H),6.73(d,J＝8.3Hz,2H),6.45(dd,J＝8.4,3.1Hz,1H),4.71(d,J＝6.8Hz,1H),4.30(dd,J＝11.1,3.7Hz,1H),4.22(dd,J＝11.1,7.8Hz,1H),3.96(t,J＝8.9Hz,1H),3.85(dd,J＝12.0,2.2Hz,1H),3.76(dd,J＝12.1,4.7Hz,1H),3.48(t,J＝8.1Hz,2H),3.43–3.37(m,1H),2.99(td,J＝7.4,3.7Hz,1H).
example five: preparation of Compounds 9 and 10
Weighing the compound 3, placing the compound in a dry round-bottom flask, adding ethyl acetate to dissolve the compound, adding 10% palladium carbon, stirring the palladium carbon at room temperature for reacting for 36 hours, monitoring the reaction progress by TLC, filtering the palladium carbon after the reaction is finished, evaporating the solvent, passing the obtained product through a silica gel reverse phase column, eluting by using a methanol/dichloromethane gradient as a mobile phase, and evaporating the solvent under reduced pressure to obtain a mixture of the compounds 9 and 10. Finally, the mixture is processed by an HPLC reversed phase column, and the mobile phase is acetonitrile/water, so that the pure compounds 9 and 10 are respectively obtained.
Compound 9: MS M/z:403(M + 1);1H NMR(600MHz,CD3OD)δ7.36(d,J＝8.3Hz,1H),7.08(d,J＝8.5Hz,2H),6.73(d,J＝8.6Hz,2H),6.53(d,J＝8.3Hz,1H),5.07(d,J＝3.3Hz,1H),4.80(d,J＝7.3Hz,1H),4.52(dd,J＝4.7,3.4Hz,1H),4.35(dd,J＝11.1,3.7Hz,1H),4.27(dd,J＝11.1,8.4Hz,1H),3.93(dd,J＝9.5,4.8Hz,1H),3.84(dd,J＝12.0,2.3Hz,1H),3.60(dd,J＝12.1,6.1Hz,1H),3.55(t,J＝9.4Hz,1H),3.34–3.32(m,1H),3.03(td,J＝7.9,3.6Hz,1H).
compound 10: MS M/z:403(M + 1);1H NMR(400MHz,CD3OD)δ7.09(d,J＝8.3Hz,2H),7.08(d,J＝8.4Hz,1H),6.68(d,J＝8.5Hz,2H),6.43(d,J＝8.1Hz,1H),4.92(d,J＝3.1Hz,1H),4.52–4.40(m,3H),4.35(dd,J＝4.8,3.1Hz,1H),4.21–4.10(m,1H),3.76(dd,J＝9.4,4.7Hz,1H),3.68–3.55(m,1H),3.42-3.38(m,1H),3.13(ddd,J＝8.9,5.3,1.9Hz,1H),3.05(dt,J＝12.3,2.9Hz,1H).
the water solubility test of the compounds 1-10 at room temperature (25 ℃) is carried out, the water solubility of puerarin derivatives (compounds 1-10) is obviously improved (4.5g/L) compared with puerarin, wherein the water solubility of the compounds 5-10 is the best, namely 20-25g/L, the water solubility of the compounds 1-4 is slightly lower, namely about 10g/L, and the subsequent test is carried out on the compounds 10, 5 and 6 with better water solubility.
Example six: effect of Compounds of formula (I) or formula (II) on isolated Guinea pig coronary flow
1. Materials:
animals: guinea pig
The instrument comprises the following steps: constant temperature device, oxygen supply system, constant pressure device, aorta sleeve and surgical instrument
Medicine preparation: the puerarin injection, the compound 10, the compound 5 and the compound 6 are respectively dissolved into 10mg/mL and 5mg/mL by sterile normal saline, and the volume of intraperitoneal injection and intragastric administration is 0.5mL/100 g.
2. The method comprises the following steps:
(1) each of guinea pigs, weighing 250-350g, were randomly divided into a normal group, a puerarin group (50mg/kg), a compound 10 low dose group (25mg/kg), a compound 10 high dose group (50mg/kg), a compound 5 and 6 mixture low dose group (25mg/kg), and a compound 5 and 6 mixture high dose group (50mg/kg), and each group contained 4-5 animals, which were intraperitoneally injected once a day for 10 days.
In addition, the normal group, the compound 10 high dose group (50mg/kg), and the compound 5 and 6 mixture high dose group (50mg/kg) were administered by gavage for 7 days.
(2) The Langendorff method is adopted to observe the influence of the compound on the coronary flow, and a constant-temperature and constant-pressure perfusion instrument is adjusted: the temperature is 37 plus or minus 0.5 ℃, the oxygen is 2 to 3 per second, and the pressure is 40 to 60cm of water column.
(3) 30min after the last administration, 20% urethane (0.5ml/100g) was anesthetized, the chest skin was cut, the sternum was cut from the xiphoid process, the chest was opened rapidly, the heart was exposed, the heart was held gently with the left hand, the tissues of the superior and inferior vena cava, pulmonary artery, aorta and around the heart were cut, and the heart was removed. Placing in an oxygenated culture dish of 4 deg.C NITRO' S solution, gently squeezing heart with fingers to discharge residual blood in heart chamber, removing pericardium, and finding out aorta. The excrescences such as lung lobes and trachea which are connected to the heart are trimmed, and the aorta is hung on the aortic cannula and supplied to the isolated condition. After stabilizing for 10min, the flow rate of each minute of coronary artery is continuously measured for 20 min.
3. As a result:
the puerarin group (50mg/kg), the compound 10 low dose group (25mg/kg), the compound 10 high dose group (50mg/kg), the compound 5 and 6 mixture low dose group (25mg/kg), and the compound 5 and 6 mixture high dose group (50mg/kg) all increased coronary blood flow in guinea pigs as compared with the normal group. The compound 5 and 6 mixture high dose group (50mg/kg) was statistically significant compared to the normal group (i.p. 0.05 i.p.; gavage. P0.01). The increase in coronary blood flow in guinea pigs was more pronounced in the high dose group (50mg/kg) of the compound 5 and 6 mixture compared to the puerarin group, with specific results shown in table 1.
Table 1: effect of Puerarin derivatives on isolated guinea pig coronary flow
Compared to the normal group of the same route of administration:*P0.05，**P0.01。
4. and (4) conclusion: the increase in coronary blood flow in guinea pigs was more pronounced with the mixture of puerarin derivatives 5 and 6.
Example seven: effect of Compounds of formula (I) or formula (II) on Rabbit aortic Ring
1. The method comprises the following steps:
the rabbit is taken, stunned by hitting with a rod, the carotid artery is killed by bloodletting, the thoracic aorta is taken out quickly by thoracotomy, the rabbit is placed in the Kong Heng's fluid for cooling, the surrounding tissues are separated and cut into rings with the size of 0.5mm for standby, the artery rings are placed in a constant temperature bath (10 ml of Kong's fluid is filled in the constant temperature bath), and are connected with a pressure transducer, (the front load is set to be 2g), and the electric signals are transmitted into a computer. Constant temperature of 37 ℃ and O connection2After 2 hours of stabilization, 10 hours of administration-6After the peak of the arterial contraction, adding the puerarin, the compound 10, the compound 5 and the 6 mixture with the accumulative concentration of 0.1mg/ml, 0.5mg/ml, 1mg/ml and 2mg/ml respectively (adding physiological saline with the same volume into the physiological saline group), and observing the vasodilatation condition of the blood vessels.
2. Results
The results are shown in fig. 1 to 4, wherein the ordinate represents the arterial vasoconstrictive tension, and the higher the value, the greater the vasoconstrictive tension. The abscissa represents time. From the results, it was found that compound 10 and the mixture of compounds 5 and 6 had a relaxing effect on the arterial contraction caused by norepinephrine.
Example eight: pharmacodynamic observation of protective effect of compound of formula (I) or formula (II) on rat focal cerebral ischemia reperfusion injury
1. The method comprises the following steps:
90 SD male rats with weight of 280-320g are randomly divided into 5 groups, and water is not forbidden in fasting state 12 hours before the experiment. The 2% pentobarbital sodium solution is 0.2ml/100g for intraperitoneal injection anesthesia, the lower position is fixed, a focal cerebral ischemia reperfusion injury model is manufactured by a embolus method (ischemia is performed for 2 hours and reperfusion is performed for 24 hours), the intravenous injection is performed immediately after the ischemia (the mixture of puerarin, compound 10, compound 5 and compound 6 is 100mg/kg, NS with the same volume is applied to the sham group and the model group; 402 is intraperitoneal injection), and the neurological score is observed after 24 hours; taking blood from heart (centrifuging at 4000 rpm for 10min, collecting serum for use), cutting head, collecting brain, freezing in refrigerator for 30min, transversely cutting rat brain into 6 pieces, placing in TTC dye solution, water bath at 37 deg.C for 30min, taking out, taking picture, and calculating percentage of infarct face machine with Jetta 801 morphological analysis software. The contents of SOD and MDA are detected by a biochemical method.
2. Results
The specific experimental results are shown in tables 2 and 3:
table 2: protective effect of compound 10, compound 5 and compound 6 mixture on cerebral ischemia-reperfusion injury
Note:###p<0.001, vs sham group;*p<0.05,**p<0.01,***p<0.001, vs model set.
Table 3: effect of compound 10, compound 5 and 6 mixture on serum SOD and MDA of cerebral ischemia-reperfusion injury
Note:###p<0.001, vs sham group;***p<0.001, vs model set.
3. Conclusion
(1) The compound 10, the compound 5 and the compound 6 can reduce the area of cerebral infarction caused by the focal cerebral ischemia-reperfusion injury of rats and reduce the neurological score.
(2) The compound 10, compound 5 and compound 6 can increase serum SOD content caused by focal cerebral ischemia reperfusion injury and reduce MDA content.
Claims (8)
1. A compound having the structure shown in formulas 5, 6 and 10:
2. a pharmaceutical composition comprising a compound of claim 1, compound 10 used as a monomer, and compounds 5 and 6 used as an isomeric mixture.
3. The pharmaceutical composition of claim 2, further comprising one or more pharmaceutically acceptable carriers, excipients, co-solvents, and/or diluents.
4. The pharmaceutical composition according to claim 2 or 3, wherein the pharmaceutical composition is a solid oral formulation, a liquid oral formulation or an injection.
5. The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition is a dispersible tablet, an enteric coated tablet, a chewable tablet, an orally disintegrating tablet, a capsule, a sugar coated agent, a granule, an oral solution, a small water injection for injection, a freeze-dried powder injection for injection, a large infusion solution or a small infusion solution.
6. Use of a compound according to claim 1 or a pharmaceutical composition according to any one of claims 2 to 5 in the preparation of a medicament for the prevention and/or treatment of cardiovascular and cerebrovascular diseases and/or diabetes and complications thereof.
7. Use according to claim 6, characterized in that the cardiovascular and cerebrovascular diseases are selected from atherosclerosis, restenosis, hypertension, angina pectoris, heart failure, myocardial infarction, stroke and cerebral hemorrhage.
8. Use according to claim 6, characterized in that the compound according to claim 1 or the pharmaceutical composition according to any one of claims 2 to 5 is used in clinical combination with other drugs for treating cardiovascular and cerebrovascular diseases or other drugs for treating diabetes.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710464386.5A CN107311991B (en) | 2017-06-19 | 2017-06-19 | Puerarin derivative, its preparation method and application in preventing and treating cardiovascular and cerebrovascular diseases or diabetes and its complications |
| PCT/CN2017/093148 WO2018232805A1 (en) | 2017-06-19 | 2017-07-17 | Puerarin derivative, preparation method therefor, and use thereof for prevention and treatment of cardiovascular and cerebrovascular diseases or diabetes and complications thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710464386.5A CN107311991B (en) | 2017-06-19 | 2017-06-19 | Puerarin derivative, its preparation method and application in preventing and treating cardiovascular and cerebrovascular diseases or diabetes and its complications |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107311991A CN107311991A (en) | 2017-11-03 |
| CN107311991B true CN107311991B (en) | 2020-02-28 |
Family
ID=60184077
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710464386.5A Expired - Fee Related CN107311991B (en) | 2017-06-19 | 2017-06-19 | Puerarin derivative, its preparation method and application in preventing and treating cardiovascular and cerebrovascular diseases or diabetes and its complications |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN107311991B (en) |
| WO (1) | WO2018232805A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101353346A (en) * | 2007-07-23 | 2009-01-28 | 北京美倍他药物研究有限公司 | Puerarin amino acid ester derivative and medicine use thereof |
| CN101921282A (en) * | 2010-04-29 | 2010-12-22 | 山东大学 | 7,2'-dehydration puerarin, salt derivatives as well as preparation method and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107098893A (en) * | 2017-05-31 | 2017-08-29 | 陕西中医药大学 | A kind of puerarin derivate and its preparation method and application |
-
2017
- 2017-06-19 CN CN201710464386.5A patent/CN107311991B/en not_active Expired - Fee Related
- 2017-07-17 WO PCT/CN2017/093148 patent/WO2018232805A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101353346A (en) * | 2007-07-23 | 2009-01-28 | 北京美倍他药物研究有限公司 | Puerarin amino acid ester derivative and medicine use thereof |
| CN101921282A (en) * | 2010-04-29 | 2010-12-22 | 山东大学 | 7,2'-dehydration puerarin, salt derivatives as well as preparation method and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| A genomic approach to isoflavone biosynthesis in kudzu (Pueraria lobata).;XianZhi He, et al.,;《Planta》;20110111;第233卷;第843-855页. * |
| Glucose uptake enhancing activity of puerarin and the role of C-glucoside suggested from activity of related compounds.;Eisuke Kato, et al.,;《Bioorganic & Medicinal Chemistry Letters》;20100617;第20卷;第4333-4336页. * |
| Isoflavanone glycoside from the leaf of Mangifera indica L.;Norizan Ahmat, et al.,;《Journal of Chemical and Pharmaceutical Research》;20151231;第7卷(第3期);第246-249页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107311991A (en) | 2017-11-03 |
| WO2018232805A1 (en) | 2018-12-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5294509B2 (en) | Cycloastragenol monoglucoside, process for its production and use as a pharmaceutical composition | |
| CN100384830C (en) | Derivative of cyclo membranousol kind and application thereof | |
| CN106916177B (en) | A kind of deuterated dipeptide boronic acid or its ester type compound and its synthetic method and purposes | |
| CN105120866A (en) | Toxic aldehyde related diseases and treatment | |
| EP2292242B1 (en) | A scutellarin derivative, the preparing process, the pharmaceutical composition and the use thereof | |
| TW201536306A (en) | Traditional chinese medicine composition, and preparation and application thereof | |
| CN106883279B (en) | A kind of prodrug, preparation method, medical composition and its use | |
| CN107530352A (en) | Use the method for indane acetic acid derivatives treatment hepatopathy | |
| CN103191174B (en) | Chemical component of eucommia bark used is as the new application of blood vessel protective agent | |
| EP2361907A1 (en) | The five crystal forms of the nicousamide, the preparation methods, the pharmaceutical compositions and the uses thereof | |
| EP2902399B1 (en) | Water-soluble derivatives and prodrugs of acacetin and methods of making and using thereof | |
| CN104341481B (en) | The synthesis and application of a kind of sulfonamide compounds | |
| CN101926788B (en) | Cardiovascular/cerebral and ophthalmological medicines, and preparation and use thereof | |
| CN111471080B (en) | ocotillol type ginsengenin A-ring amino thiazole ring derivative and preparation method thereof | |
| CN107311991B (en) | Puerarin derivative, its preparation method and application in preventing and treating cardiovascular and cerebrovascular diseases or diabetes and its complications | |
| CN114699401A (en) | Application of isorhamnetin in preparation of thoracic aorta vasodilation drugs | |
| EP2292241A1 (en) | A scutellarin derivative, the preparing process, the pharmaceutical composition and the use thereof | |
| CN107753469B (en) | Application of NDGA analogue in preparing antioxidant drugs | |
| CN106478764B (en) | Tanshinone IIA phosphoric acid derivatives and its synthesis and the application as medicine | |
| WO2005003146A1 (en) | The c-glycosylisoflavones having alkylaminoalkoxyl substituent, the preparation and the use of the same | |
| CN106699828A (en) | Deuterated HCV NS5b inhibitor nucleotide derivative and application thereof | |
| CN113105391B (en) | Lappaconitine derivative with analgesic activity and preparation method and application thereof | |
| WO2013083014A1 (en) | Daidzein derivative, pharmaceutically acceptable salt and preparation method thereof, and pharmaceutical composition containing same | |
| CN107652265A (en) | 1 (base of piperidines 4) 2 benzimidazole ketone compounds and its application | |
| JPH04159225A (en) | Acetylcholine esterase inhibitor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20200228 |