CN1301249C - 黄皮酰胺c5羟基衍生物及n取代衍生物、其制法和其药物组合物与用途 - Google Patents
黄皮酰胺c5羟基衍生物及n取代衍生物、其制法和其药物组合物与用途 Download PDFInfo
- Publication number
- CN1301249C CN1301249C CNB2003101238748A CN200310123874A CN1301249C CN 1301249 C CN1301249 C CN 1301249C CN B2003101238748 A CNB2003101238748 A CN B2003101238748A CN 200310123874 A CN200310123874 A CN 200310123874A CN 1301249 C CN1301249 C CN 1301249C
- Authority
- CN
- China
- Prior art keywords
- clausenamide
- racemization
- preparation
- light
- 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.)
- Expired - Lifetime
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 125000002887 hydroxy group Chemical group [H]O* 0.000 title claims abstract description 13
- 239000000203 mixture Substances 0.000 title abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 17
- WGYGSZOQGYRGIP-UHFFFAOYSA-N neoclausenamide Natural products C=1C=CC=CC=1C1C(O)C(=O)N(C)C1C(O)C1=CC=CC=C1 WGYGSZOQGYRGIP-UHFFFAOYSA-N 0.000 claims description 91
- VRSSZILNAITUII-UHFFFAOYSA-N Clausenamide Natural products OC1C(=O)N(C)C=CC2=CC=CC=C2C1C1=CC=CC=C1 VRSSZILNAITUII-UHFFFAOYSA-N 0.000 claims description 80
- WGYGSZOQGYRGIP-MWDXBVQZSA-N (3r,4s,5s)-3-hydroxy-5-[(r)-hydroxy(phenyl)methyl]-1-methyl-4-phenylpyrrolidin-2-one Chemical compound C1([C@@H](O)[C@H]2N(C([C@H](O)[C@H]2C=2C=CC=CC=2)=O)C)=CC=CC=C1 WGYGSZOQGYRGIP-MWDXBVQZSA-N 0.000 claims description 53
- 150000001875 compounds Chemical class 0.000 claims description 31
- -1 Hydroxy Chemical class 0.000 claims description 23
- 230000006340 racemization Effects 0.000 claims description 21
- 239000003795 chemical substances by application Substances 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 230000003287 optical effect Effects 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical group ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 230000018044 dehydration Effects 0.000 claims description 2
- 238000006297 dehydration reaction Methods 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims description 2
- 230000002605 anti-dotal effect Effects 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 150000001408 amides Chemical class 0.000 abstract description 31
- 238000000034 method Methods 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 5
- 235000008738 Clausena lansium Nutrition 0.000 abstract description 3
- 239000013543 active substance Substances 0.000 abstract description 3
- 230000032683 aging Effects 0.000 abstract description 3
- 150000003953 γ-lactams Chemical class 0.000 abstract description 3
- 238000011161 development Methods 0.000 abstract description 2
- 230000018109 developmental process Effects 0.000 abstract description 2
- 230000001737 promoting effect Effects 0.000 abstract description 2
- 241000757020 Pontederia Species 0.000 abstract 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 21
- JCYPECIVGRXBMO-UHFFFAOYSA-N 4-(dimethylamino)azobenzene Chemical compound C1=CC(N(C)C)=CC=C1N=NC1=CC=CC=C1 JCYPECIVGRXBMO-UHFFFAOYSA-N 0.000 description 20
- 206010048245 Yellow skin Diseases 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 239000007864 aqueous solution Substances 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 210000001178 neural stem cell Anatomy 0.000 description 10
- 235000002639 sodium chloride Nutrition 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 229960002668 sodium chloride Drugs 0.000 description 9
- WGYGSZOQGYRGIP-VVLHAWIVSA-N (3r,4s,5r)-3-hydroxy-5-[(s)-hydroxy(phenyl)methyl]-1-methyl-4-phenylpyrrolidin-2-one Chemical compound C1([C@H](O)[C@@H]2N(C([C@H](O)[C@H]2C=2C=CC=CC=2)=O)C)=CC=CC=C1 WGYGSZOQGYRGIP-VVLHAWIVSA-N 0.000 description 8
- 210000004556 brain Anatomy 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- 208000024827 Alzheimer disease Diseases 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 230000001777 nootropic effect Effects 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 5
- 206010039966 Senile dementia Diseases 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 230000004663 cell proliferation Effects 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 238000010025 steaming Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- WGYGSZOQGYRGIP-NCOADZHNSA-N (3s,4r,5r)-3-hydroxy-5-[(s)-hydroxy(phenyl)methyl]-1-methyl-4-phenylpyrrolidin-2-one Chemical compound C1([C@H](O)[C@@H]2N(C([C@@H](O)[C@@H]2C=2C=CC=CC=2)=O)C)=CC=CC=C1 WGYGSZOQGYRGIP-NCOADZHNSA-N 0.000 description 4
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical compound CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- GMZVRMREEHBGGF-UHFFFAOYSA-N Piracetam Chemical compound NC(=O)CN1CCCC1=O GMZVRMREEHBGGF-UHFFFAOYSA-N 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 229960004526 piracetam Drugs 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 206010012289 Dementia Diseases 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 230000036749 excitatory postsynaptic potential Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000001727 glucose Nutrition 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 210000001320 hippocampus Anatomy 0.000 description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 3
- 239000002207 metabolite Substances 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 210000005036 nerve Anatomy 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 230000004936 stimulating effect Effects 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 239000005995 Aluminium silicate Substances 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000014644 Brain disease Diseases 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- 239000001828 Gelatine Substances 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 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 2
- 241001465754 Metazoa Species 0.000 description 2
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-methylmorpholine Substances CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- 229910052772 Samarium Inorganic materials 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 240000006474 Theobroma bicolor Species 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 235000012211 aluminium silicate Nutrition 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 230000003712 anti-aging effect Effects 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 210000001218 blood-brain barrier Anatomy 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 230000003727 cerebral blood flow Effects 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 230000003412 degenerative effect Effects 0.000 description 2
- 239000003405 delayed action preparation Substances 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 235000012907 honey Nutrition 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000012204 lemonade/lime carbonate Nutrition 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 210000001161 mammalian embryo Anatomy 0.000 description 2
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- KZUNJOHGWZRPMI-UHFFFAOYSA-N samarium atom Chemical compound [Sm] KZUNJOHGWZRPMI-UHFFFAOYSA-N 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- DAJSVUQLFFJUSX-UHFFFAOYSA-M sodium;dodecane-1-sulfonate Chemical compound [Na+].CCCCCCCCCCCCS([O-])(=O)=O DAJSVUQLFFJUSX-UHFFFAOYSA-M 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 150000003527 tetrahydropyrans Chemical class 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 229950004288 tosilate Drugs 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 229940124549 vasodilator Drugs 0.000 description 2
- 239000003071 vasodilator agent Substances 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- UXFQFBNBSPQBJW-UHFFFAOYSA-N 2-amino-2-methylpropane-1,3-diol Chemical compound OCC(N)(C)CO UXFQFBNBSPQBJW-UHFFFAOYSA-N 0.000 description 1
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 101100400452 Caenorhabditis elegans map-2 gene Proteins 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- 108010009685 Cholinergic Receptors Proteins 0.000 description 1
- 229940122041 Cholinesterase inhibitor Drugs 0.000 description 1
- FITPCXSHEGAMCJ-JJKGCWMISA-N ClC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.[Na] Chemical compound ClC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.[Na] FITPCXSHEGAMCJ-JJKGCWMISA-N 0.000 description 1
- 244000089795 Clausena lansium Species 0.000 description 1
- 206010010254 Concussion Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 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
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 1
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 229920001543 Laminarin Polymers 0.000 description 1
- 235000006662 Lansium Nutrition 0.000 description 1
- 241001156382 Lansium Species 0.000 description 1
- 101150064138 MAP1 gene Proteins 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 102000004129 N-Type Calcium Channels Human genes 0.000 description 1
- 108090000699 N-Type Calcium Channels Proteins 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 102000015336 Nerve Growth Factor Human genes 0.000 description 1
- 108090000189 Neuropeptides Proteins 0.000 description 1
- 102000003797 Neuropeptides Human genes 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 241001093501 Rutaceae Species 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 102000003691 T-Type Calcium Channels Human genes 0.000 description 1
- 108090000030 T-Type Calcium Channels Proteins 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- NOICVUZFTAVDNM-UHFFFAOYSA-N acetamide;pyrrolidin-2-one Chemical compound CC(N)=O.O=C1CCCN1 NOICVUZFTAVDNM-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 102000034337 acetylcholine receptors Human genes 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- PZZYQPZGQPZBDN-UHFFFAOYSA-N aluminium silicate Chemical compound O=[Al]O[Si](=O)O[Al]=O PZZYQPZGQPZBDN-UHFFFAOYSA-N 0.000 description 1
- 229910000323 aluminium silicate Inorganic materials 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- ZUVQXWUBMQNMGL-UHFFFAOYSA-N butan-2-ylboron Chemical compound [B]C(C)CC ZUVQXWUBMQNMGL-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 125000006355 carbonyl methylene group Chemical group [H]C([H])([*:2])C([*:1])=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000010370 cell cloning Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 230000009514 concussion Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000007831 electrophysiology Effects 0.000 description 1
- 238000002001 electrophysiology Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 210000001353 entorhinal cortex Anatomy 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 238000007046 ethoxylation reaction Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 229940126864 fibroblast growth factor Drugs 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000000971 hippocampal effect Effects 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- DBTMGCOVALSLOR-VPNXCSTESA-N laminarin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1O[C@@H]1[C@@H](O)C(O[C@H]2[C@@H]([C@@H](CO)OC(O)[C@@H]2O)O)O[C@H](CO)[C@H]1O DBTMGCOVALSLOR-VPNXCSTESA-N 0.000 description 1
- 210000000088 lip Anatomy 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000002398 materia medica Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229940053128 nerve growth factor Drugs 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 210000001020 neural plate Anatomy 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 229960000715 nimodipine Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002664 nootropic agent Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 210000000196 olfactory nerve Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 210000001871 perforant pathway Anatomy 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229940093916 potassium phosphate Drugs 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000012109 statistical procedure Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明涉及羟苄基、羟基、苯基取代γ-内酰胺(黄皮酰胺)的C5羟基取代黄皮酰胺的立体异构体,N取代衍生物及它们的制备方法,以它们作为活性物质的药物组合物,和它们在制备促智,抗衰老药物的应用。
Description
技术领域
本发明涉及黄皮酰胺C5羟基取代的立体异构体,N取代衍生物及它们的制备方法,以它们作为活性物质的药物组合物,和它们在制备促智,抗衰老药物的应用。
背景技术
目前我国人口的平均寿命已超过70岁,比解放时的人均寿命增加了一倍。国外一项科学研究预测:到2025年时,15岁以下儿童的比例将占总人口的18.6%,而65岁及65岁以上的老年人将超过童数,达到18.8%,这个数字表明,再过20余年,每5个人中就有1个老年人。早老性痴呆症(Alzheimer’s Disease)多发生在50余岁。因脑血管病变引发的多发性栓塞性痴呆或老年性痴呆多发生在60岁以后。可见,由于人口的老龄化,早老性痴呆症和老年性痴呆症的发病率也必将增加。老年人及其特有的神经退化性疾病——各种痴呆症要经历两种死亡,首先是精神上的死亡,后是肉体上的死亡,苦不堪言,更给社会和家庭带来沉重负担。人口老龄化被认为是仅次于战争,瘟疫,饥荒,资源能源短缺而影响社会发展和安定的不利因素。
防治衰老和治疗老年痴呆的药物种类繁多。脑血管扩张药,通过改善脑血流量有助于提供能量和改善智能,但真正有价值的脑血管扩张药必须具有高度选择性,不影响脑代谢,无“窃血”现象,有抗血小板聚集和抗血栓作用。钙拮抗剂尼莫地平虽符合上述某些条件,但它仅作用于电压依赖性钙通道中的L-通道,对N型和T型钙通道无影响。增强胆碱系统功能的药物中,Ach前体仅有微弱的治疗作用,Ach受体激动剂和胆碱脂酶抑制剂虽有一定效果,但作用较短暂,毒副作用较大。多种神经肽和神经生长因子曾被认为有治疗痴呆症的希望,但临床效果不佳,可能主要归因于这类物质难以通过血脑屏障进入脑内发挥作用,2-吡咯烷酮乙酰胺(piracetam国内已生产,商品名脑复康)问世后,在早期文献中属没有争论的一类新型促智药(nootropil,该词是从希腊词noo(脑)和tropein(向)衍化而来),近几年来国内外报道,该药对各类型的记忆障碍和老年痴呆作用轻微或尚无定论,一个主要原因是该药为水溶性化合物,通过血脑屏障率低,不易集中到靶点发挥作用。
本发明人从芸香科植物黄皮[Clausena Lansium(lour.)Skells]中第一次分离出含有脑复康药的γ-内酰胺骨架的化合物,称之为黄皮酰胺(Clausenamide)。黄皮酰胺是具有四个手性中心的γ-内酰胺,天然品为消旋体,消旋黄皮酰胺的合成方法曾申请欧洲专利,其申请号为 EP0414020,中国专利申请为86107090,90107145.5和90107144.7。左旋黄皮酰胺具有较好的促智作用,该化合物的纯物质、制备方法及其潜在的医药应用本发明人已申请专利,CN00124630.5。
黄皮酰胺分子中有4个手性中心,应有16个光活的立体异构体,组成互为非对映关系的8对对映异构体(其构型与命名如表1)
表18对光活立体异构体
黄皮酰胺(I1)(-)3S,4R,5R,6S(+)3R,4S,5S,6R | 新黄皮酰胺(I2)(-)3S,4R,5S,6R(+)3R,4S,5R,6S | |
C6异构体 | 表黄皮酰胺(I3)(+)3S,4R,5R,6R(-)3R,4S,5S,6S | 表新黄皮酰胺(I4)(-)3S,4R,5S,6S(+)3R,4S,5R,6R |
C3异构体(C3/C4顺式) | 顺黄皮酰胺(I5)(+)3S,4S,5S,6R(-)3R,4R,5R,6S | 顺新黄皮酰胺(I6)(-)3S,4S,5R,6S(+)3R,4R,5S,6R |
顺表黄皮酰胺(I7)(+)3S,4S,5S,6S(-)3R,4R,5R,6R | 顺表新黄皮酰胺(I8)(-)3S,4S,5R,6R(+)3R,4R,5S,6S |
其中黄皮酰胺的一对对映体(I1)本发明人已申请专利(专利申请号:CN00124630.5)。消旋的新黄皮酰胺(I2)和消旋的表新黄皮酰胺(I4)是公知的,但光活新黄皮酰胺(I2)和表新黄皮酰胺(I4)及其制备方法未见文献报道。(-)和(+)黄皮酰胺(I1)的体内、外代谢的研究结果表明:两者的代谢物的种类基本相同,而(-)黄皮酰胺的代谢物中(-)N-羟甲基去甲黄皮酰胺[(-)-CM1]和(-)-5-羟基黄皮酰胺[(-)-CM2]的含量明显高于(+)黄皮酰胺的代谢产物中相应的[(+)-CM1]和[(+)-CM2]的含量。其母体(-)黄皮酰胺的药理试验表明,具有明显的促智作用,而(+)黄皮酰胺无此作用,并有拮抗作用,据此合成了代谢物CM1和CM2的一对对映体及其衍生物,其中CM11的制备本发明人已发表,。
现有技术不能直接用于制备本发明所述的具有光学活性黄皮酰胺及其衍生物。
发明内容
本发明的目的是提供一类新的黄皮酰胺C5羟基衍生物及N取代衍生物。
本发明的另一目的在于提供制备黄皮酰胺C5羟基衍生物及N取代衍生物的方法;
本发明的另一目的在于提供黄皮酰胺C5羟基衍生物及N取代衍生物在制备促智,抗衰老作用药物的应用。
根据本发明,涉及如通式(II)所示的光活黄皮酰胺C5羟基的衍生物
结构特征在于:消旋II1构型为(3S*,4S*,5S*,6R*),
消旋II2构型为(3S*,4S*,5R*,6S*),
消旋II3构型为(3S*,4S*,5S*,6S*)。
光活II1构型为:(3S,4S,5S,6R)(+)II1或(3R,4R,5R,6S)(-)II1;
光活II2构型为:(3S,4S,5R,6S)(+)II2或(3R,4R,5S,6R)(-)II2;
光活II3构型为:(3R,4R,5R,6R)(+)II3或(3S,4S,5S,6S)(-)II3。
根据本发明,还涉及通式(II)所示的光活黄皮酰胺C5羟基的衍生物的制备方法如线路图1所示。
路线图1
(1)消旋3-O-乙酰黄皮酰胺(1)及其光活体的脱水,脱水剂可用POCl3/Py,或先制备黄皮酰胺的甲磺酸酯再以DBU脱除甲磺酸。其中优选POCl3/Py。
(2)消旋3-O-乙酰-Δ5,6-黄皮酰胺(2)及其光活体的水解可选用常规的酸或碱性条件。
(3)消旋Δ5,6-黄皮酰胺(3)及其光活体的双羟基化可用OsO4/NMO、KHSO5/CH3COCF3、WO3/H2O2等,其中优选OsO4/NMO。
(4)(3S*,4S*,5S*,6R*)-3-O-乙酰基-5-羟基黄皮酰胺(3-O-乙酰II1)及其光活体可用KMnO4/CuSO4,MnO2,DMSO/ClCOCOCl/TEA,DMSO/三氟乙酸酐(TFAA)/TEA等氧化剂。其中优选DMSO/ClCOCOCl/TEA。
(5)(3S*,4S*,5S*)-3-O-乙酰基-5-羟基黄皮酰胺酮(II1酮)及其光活体的还原可选用各种硼氢化试剂,优选硼氢化钠、三仲丁基硼锂。
(6)(3S*,4S*,5S*,6S*)-3-乙酰氧基-5-羟基黄皮酰胺(II3)及其光活体的水解选用各种酸、碱或Sm(钐)/I2/CH3OH,优选Sm/I2/CH3OH。
根据本发明,还涉及如通式(III)所示的黄皮酰胺的N取代衍生物
其特征在于相对构型为(3S*,4R*,5R*,6S*),
取代基R选自:CH2COR1、CH2OCOR2,CHR3
R2选自C1-8烷氧基
R3中选自
通式(III)所示的黄皮酰胺的N取代衍生物,当R选自CH2COR1、CH2OCOR2时的制备方法如线路图2所示
路线图2
由去甲黄皮酰胺(1)和二氢吡喃在吡啶对甲苯磺酸盐催化下制备3,6-二-O-四氢吡喃去甲黄皮酰胺(2)。将3,6-二-O-四氢吡喃去甲黄皮酰胺(2)溶于无水苯中,加入氢钠,油浴加热半小时,再在室温下搅10分钟,加入溴乙酸酯的无水苯溶液,油浴60℃下反应20分钟后,将反应液温度降至室温,加入水搅拌,用二氯甲烷稀释,盐酸调至中性,分出有机层,洗涤干燥,蒸发溶剂得到油状物。将此油状物用乙醇溶解,加入10mg对甲苯磺酸,油浴60℃下反应脱四氢吡喃保护,反应完全后直接柱层析纯化,得到N-(烷氧(氮)羰基亚甲基)去甲黄皮酰胺(III4)。
将N-(乙氧羰基亚甲基)去甲黄皮酰胺(III4)60mg,以大大过量的NH3/CH3OH溶液处理,放置过夜,柱层析纯化后得到N-(氨羰基亚甲基)去甲黄皮酰胺(III1)。
将去甲黄皮酰胺(1)溶于丙酮中,滴加一定量的水,然后加入多聚甲醛和碳酸钾,外温升至60℃,25分钟后停止加热,将反应混合物用冰水快速冷却,减压蒸发溶剂得粘稠的液体。柱层析得N-羟甲基去甲黄皮酰胺(3)。将N-羟甲基去甲黄皮酰胺(3)溶于无水四氢呋喃中,冰盐浴下搅拌20分钟,滴加相应的酸酐和吡啶的无水THF溶液,在此温度下搅拌3小时,加入少量水,二氯甲烷稀释,分出有机层,洗涤,蒸除溶剂后柱层析分离得到相应的N-(酰氧基亚甲基)-去甲黄皮酰胺(III3)。
通式(III)所示的黄皮酰胺的N取代衍生物,当R选自CH2R3时的制备方法:利用CM1的中间体N-苄基或对甲氧基苄基黄皮酰胺酮还原制得,如线路图3所示
线路图3
本发明因此还涉及含有作为活性成份的本发明化合物和常规药物赋形剂或辅剂的药物组合物。通常本发明药物组合物含有0.1-95重量%的本发明化合物。
本发明化合物的药物组合物可根据本领域公知的方法制备。用于此目的时,如果需要,可将本发明化合物与一种或多种固体或液体药物赋形剂和/或辅剂结合,制成可作为人药或兽药使用的适当的施用形式或剂量形式。
本发明化合物或含有它的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、肌肉、皮下、鼻腔、口腔粘膜、皮肤、腹膜或直肠等,优选口服。
本发明化合物或含有它的药物组合物的给药途径可为注射给药。注射包括静脉注射、肌肉注射、皮下注射和皮内注射等。
给药剂型可以是液体剂型、固体剂型。如液体剂型可以是真溶液类、胶体类、微粒剂型、乳剂剂型、混悬剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂等。
本发明化合物可以制成普通制剂、也可以是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将单位给药剂型制成片剂,可以广泛使用本领域公知的各种载体。关于载体的例子是,例如稀释剂与吸收剂,如淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化钠、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝等;湿润剂与粘合剂,如水、甘油、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等;崩解剂,例如干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢钠与枸橼酸、碳酸钙、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素等;崩解抑制剂,例如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等;吸收促进剂,例如季铵盐、十二烷基硫酸钠等;润滑剂,例如滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡、聚乙二醇等。还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。
例如为了将给药单元制成丸剂,可以广泛使用本领域公知的各种载体。关于载体的例子是,例如稀释剂与吸收剂,如葡萄糖、乳糖、淀粉、可可脂、氢化植物油、聚乙烯吡咯烷酮、Gelucire、高岭土、滑石粉等;粘合剂,如阿拉伯胶、黄蓍胶、明胶、乙醇、蜂蜜、液糖、米糊或面糊等;崩解剂,如琼脂粉、干燥淀粉、海藻酸盐、十二烷基磺酸钠、甲基纤维素、乙基纤维素等。
例如为了将给药单元制成胶囊,将有效成分本发明化合物与上述的各种载体混合,并将由此得到的混合物置于硬的明胶胶囊或软胶囊中。也可将有效成分本发明化合物制成微囊剂,混悬于水性介质中形成混悬剂,亦可装入硬胶囊中或制成注射剂应用。
例如,将本发明化合物制成注射用制剂,如溶液剂、混悬剂溶液剂、乳剂、冻干粉针剂,这种制剂可以是含水或非水的,可含一种和/或多种药效学上可接受的载体、稀释剂、粘合剂、润滑剂、防腐剂、表面活性剂或分散剂。如稀释剂可选自水、乙醇、聚乙二醇、1,3-丙二醇、乙氧基化的异硬脂醇、多氧化的异硬脂醇、聚氧乙烯山梨醇脂肪酸酯等。另外,为了制备等渗注射液,可以向注射用制剂中添加适量的氯化钠、葡萄糖或甘油,此外,还可以添加常规的助溶剂、缓冲剂、pH调节剂等。这些辅料是本领域常用的
此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂、甜味剂或其它材料。
为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物药物组合物的给药剂量取决于许多因素,例如所要预防或治疗疾病的性质和严重程度,患者或动物的性别、年龄、体重、性格及个体反应,给药途径、给药次数、治疗目的,因此本发明的治疗剂量可以有大范围的变化。一般来讲,本发明中药学成分的使用剂量是本领域技术人员公知的。可以根据本发明化合物组合物中最后的制剂中所含有的实际药物数量,加以适当的调整,以达到其治疗有效量的要求,完成本发明的预防或治疗目的。本发明化合物的每天的合适剂量范围本发明的化合物的用量为0.001-150mg/Kg体重,优选为0.01-100mg/Kg体重,更优选为0.01-60mg/Kg体重,最优选为0.1-10mg/Kg体重。上述剂量可以单一剂量形式或分成几个,例如二、三或四个剂量形式给药这受限于给药医生的临床经验以及包括运用其它治疗手段的给药方案。
每一种治疗所需总剂量可分成多次或按一次剂量给药。本发明的化合物或组合物可单独服用,或与其他治疗药物或对症药物合并使用并调整剂量。
在对人胚胎脑神经干细胞克隆形成率的试验中本发明的化合物具有明显促进人胚胎脑神经干细胞克隆形成的作用,说明本发明的化合物具有治疗老年性神经退行性疾病如老年性痴呆的作用。
在对大鼠海马长时程增强(LTP)的试验中本发明化合物对大鼠海马长时程增强(LTP)具有明显的增强作用。本发明化合物对神经细胞基础突触传递有增强作用,说明本发明的化合物有促智作用。
具体实施方式
实施例1 制备消旋(3S*,4S*,5R*,6S*)-5-羟基黄皮酰胺(II2)(路线1)。
消旋3-O-乙酰黄皮酰胺(1)1.00g在干燥条件下,用6mL无水吡啶溶解,冰水浴下搅拌20分钟,滴加1.0mL重蒸的三氯氧磷的4mL无水吡啶溶液,半小时滴完,继续冰水浴下搅拌24小时,将反应液冲入冰水中,待固体全部析出后过滤,滤饼用二氯甲烷重新溶解,依次用水和氯化钠水溶液洗,无水硫酸钠干燥,蒸除溶剂得固体,柱层析分离得到消旋3-O-乙酰基-Δ5,6-黄皮酰胺(2)746mg,,白色固体,收率71%,mp 148-150℃。
取消旋3-O-乙酰-Δ5,6-黄皮酰胺(2)400mg溶于15mL二氯甲烷中,加入3mL 10%氢氧化钠乙醇溶液,3分钟后用2mol/L盐酸将反应液调至中性,加20mL二氯甲烷稀释,1mol/L碳酸氢钠水溶液洗涤,氯化钠水溶液洗涤,无水硫酸钠干燥。蒸发溶剂得到Δ5,6-黄皮酰胺(3)330mg,白色固体,收率95%,mp 162-163℃。
取消旋Δ5,6黄皮酰胺(3)260mg溶于1mL丙酮和5mL四氢呋喃中,加入氧化N-氧-N-甲基吗啉545mg,再用注射器加入0.6mL四氧化锇的4%水溶液,室温下搅拌24小时之后,向反应液中加入650mg无水亚硫酸钠和3mL水,搅拌1小时,用二氯甲烷稀释反应液,分出有机相,水层二氯甲烷提取,合并有机相,氯化钠水溶液洗涤,无水硫酸钠干燥.蒸发溶剂得油状物280mg。柱层析得到。(±)-(3S*,4S*,5R*,6S*)-5-羟基黄皮酰胺(II2)150mg,白色固体,mp:134-136℃,收率50%。
同时得到副产物(±)-(3S*,4S*,5S*,6R*)-5-羟基黄皮酰胺(II1)70mg,白色固体,mp:127-129℃,收率24%。
实施例2 制备(±)-(3S*,4S*,5S*,6R*)-5-羟基黄皮酰胺(II1)(路线2)
将上述所得的消旋3-O-乙酰基-Δ5,6黄皮酰胺(2)240mg溶于4mL四氢呋喃/丙酮(5/1)中,加入N-氧-N-甲基吗啉581mg,再加入1.9mL四氧化锇的10mg/mL水溶液,室温下搅拌,48小时之后向反应液中加入500mg无水亚硫酸钠和10mL水,搅拌1小时,转移至分液漏斗中,用二氯甲烷洗涤,有机相用氯化钠水溶液洗涤,无水硫酸钠干燥,蒸发溶剂得油状物300mg,乙酸乙酯重结晶后制备薄层分离(乙酸乙酯)分离,共得(±)-(3S*,4S*,5S*,6R*)-3-O-乙酰-5-羟基黄皮酰胺(3-O-乙酰-II1)217mg,收率82%,mp163-165℃。
(±)-(3S*,4S*,5S*,6R*)-3-O-乙酰基-5-羟基黄皮酰胺(3-O-乙酰基-II1)以Sm/I2/CH3OH脱乙酰制备得到(±)-(3S*,4S*,5S*,6R*)-5-羟基黄皮酰胺(II1),mp:127-129℃,具体操作与实例7最后水解一步相同。
光活(3S,4S,5R,6S)-5-羟基黄皮酰胺(II2)、(3R,4R,5S,6R)-5-羟基黄皮酰胺(II2)和光活(3S,4S,5S,6R)-5-羟基黄皮酰胺(II1)、(3R,4R,5R,6S)-5-羟基黄皮酰胺(II1)的制备
同A中消旋体的制备方法,不同在于以光活3-O-乙酰基黄皮酰胺(1)为原料,所得的各步产率与消旋体相近,各步化合物的熔点和旋光值如下:
(-)-3-O-乙酰-Δ5,6-黄皮酰胺,mp:119-120℃,[α]D 18=-330(c,0.870,CHCl3)
(+)-3-O-乙酰-Δ5,6-黄皮酰胺,mp:119-120℃,[α]D 18=+326(c,0.870,CHCl3)
(-)-Δ5,6-黄皮酰胺,mp:125-127℃,[α]D 18=-17.1(c,0.700,CHCl3)
(+)-Δ5,6-黄皮酰胺,mp:125-127℃,[α]D 18=+16.7(c,0.738,CHCl3)
(+)-(3S,4S,5S,6R)-5-羟基黄皮酰胺,油状物,[α]D 25=+113(c,0.505,CH3OH)
(-)-(3R,4R,5R,6S)-5-羟基黄皮酰胺,油状物,[α]D 25=-117(c,0.200,CH3OH)
(+)-(3S,4S,5R,6S)-5-羟基黄皮酰胺,mp:147-149℃,[α]D 25=+202(c,0.510,CH3OH)
(-)-(3R,4R,5S,6)-5-羟基黄皮酰胺,mp:145-147℃,[α]D 25=-208(c,0.620,CH3OH)
(-)-(3S,4S,5S,6R)-3-O-乙酰基-5-羟基黄皮酰胺(3-O-乙酰II1),mp:125-128℃,[α]D 15=-323(c,0.870,CH3OH)
(+)-(3R,4R,5R,6S)-3-O-乙酰基-5-羟基黄皮酰胺(3-O-乙酰II1),mp:125-127℃,[α]D 16=+327(c,0.470,CH3OH)
实施例3
A:消旋(±)-(3S*,4S*,5S*,6S*)-5-羟基黄皮酰胺(II3)的制备(路线3)
向干燥三口瓶中加入5mL干燥四氢呋喃,冷却至-50~-60℃,在N2保护下加入草酰氯(重蒸)453ul,搅拌1分钟后,缓慢加入DMSO(分子筛干燥)767ul,保持温度在-50~-60℃之间,加完后搅拌5分钟,再缓慢加入150mg(±)-(3S*,4S*,5S*,6R*)-3-O-乙酰基-5-羟基黄皮酰胺(3-O-乙酰-II1)的10mL四氢呋喃溶液,加完后在上述温度下搅拌2小时,之后滴加1mL三乙胺,在此温度下保持半小时后缓慢的升至室温,加入10mL水,减压蒸去四氢呋喃,残余物用乙酸乙酯萃取至水层无产物,有机层用1mol/L盐酸,碳酸氢钠水溶液,饱和氯化钠水溶液洗涤,无水硫酸镁干燥。蒸发溶剂得250mg油状物,柱层析纯化得(±)-(3S*,4S*,5S*)-3-O-乙酰-5-羟基黄皮酰胺酮(3-O-乙酰-II1酮),95mg,收率:71%。
取(±)-(3S*,4S*,5S*)-3-O-乙酰-5-羟基黄皮酰胺酮(3-O-乙酰-II1酮)82mg用3mL甲醇溶解,冰水浴下搅拌20分钟后加入硼氢化钠30mg,继续在冰水浴下搅拌10分钟,用1mol/L盐酸将反应液小心调至中性,加入少量水后减压蒸去有机溶剂,残余物用乙醚溶解,分出醚层,水层用乙醚洗,合并醚层用氯化钠水溶液洗涤,无水硫酸钠干燥,蒸发溶剂得油状物,柱层析分离得到(3S*,4S*,5S*,6S*)-3-O-乙酰-5-羟基黄皮酰胺(3-O-乙酰-II3)60mg,mp:144-147℃,收率73%。
(3S*,4S*,5S*,6S*)-3-O-乙酰基-5-羟基黄皮酰胺50mg溶于5mL无水甲醇中,加入单质碘38mg和单质钐23mg,在空气下反应12小时,用乙酸乙酯稀释反应液并转移至分液漏斗中,硫代硫酸钠水溶液(25%)洗涤,分出有机层后用氯化钠水溶液洗涤,无水硫酸钠干燥,减压蒸去溶剂,柱层析纯化得(±)-(3S*,4S*,5S*,6S*)-5-羟基-黄皮酰胺(II3)25mg,乙酸乙酯/石油醚重结晶得到白色固体mp:114-116℃,收率56%。
B:(3S,4S,5S,6S)-5-羟基-黄皮酰胺(II3)和(3R,4R,5R,6R)-5-羟基-黄皮酰胺(II3)的制备。
同A中消旋体的制备方法,以(-)-(3S,4S,5S,6R)-3-O-乙酰基-5-羟基黄皮酰胺(3-O-乙酰II1)或(+)-(3R,4R,5R,6S)-3-O-乙酰基-5-羟基黄皮酰胺(3-O-乙酰II1)为原料,所得的各步产率与消旋体相同,各步化合物的熔点和旋光值如下:
(-)-(3S,4S,5S)-3-O-乙酰基-5-羟基黄皮酰胺酮(3-O-乙酰II1酮),mp:125-128℃,[α]D 15=-310(c,0.360,CHCl3)
(+)-(3R,4R,5R)-3-O-乙酰基-5-羟基黄皮酰胺酮(3-O-乙酰II1酮),mp:127-129℃,[α]D 18=+312(c,0.442,CHCl3)
(-)-(3S,4S,5S,6S)-3-O-乙酰基-5-羟基黄皮酰胺(3-O-乙酰II3),mp:153-157℃,[α]D 15=-31.9(c,0.455,CH3OH)
(+)-(3R,4R,5R,6R)-3-O-乙酰基-5-羟基黄皮酰胺(3-O-乙酰II3),mp:152-156℃,[α]D 18=+31.7(c,0.480,CH3OH)
(-)-(3S,4S,5S,6S)-5-羟基黄皮酰胺(II3),油状物,[α]D 18=-53.6(c,0.470,CH3OH)
(+)-(3R,4R,5R,6R)-5-羟基黄皮酰胺(II3),油状物,[α]D 18=+54.1(c,0.480,CH3OH)
线路图3
实施例4 N-(乙氧羰基亚甲基)去甲黄皮酰胺(III4)的制备(如线路图3)
(1)光活3,6-二-O-四氢吡喃基新黄皮酰胺酮的制备
(-)-(3R,4S,5R)-新黄皮酰胺酮443mg(1.5mmol),280mg 3,4-二氢吡喃(4.5mmol)38mg吡啶对甲苯磺酸盐(0.15mmol),搅拌过夜,反应完成后,用10ml二氯甲烷稀释,用NaCl水溶液洗滌,无水硫酸钠干燥,浓缩得(+)-3,6-二-O-四氢吡喃基新黄皮酰胺酮0.51g,收率89.6%,m.p.181-7℃,[α]D 15+13.46(c,0.42,CHCl3)。
(+)-(3S,4R,5S)-新黄皮酰胺酮0.35g参照上法得(-)-3,6-二-O-四氢吡喃基新黄皮酰胺酮416mg,收率91.4%,m.p.194-200℃,[α]D15-11.9(c,0.24,CHCl3)。
将3,6-二-O-四氢吡喃去甲黄皮酰胺(2)120mg溶于5mL无水苯中,加入氢钠21mg,油浴加热半小时,再在室温下搅10分钟,加入66mg溴乙酸乙酯的5mL无水苯溶液,油浴60℃下反应20分钟后,将反应液温度降至室温,加入3mL水搅拌,用二氯甲烷稀释,2N盐酸调至中性,分出有机层,用氯化钠水溶液洗涤,无水硫酸钠干燥,蒸发溶剂得到油状物,将此油状物用乙醇溶解,加入10mg对甲苯磺酸,油浴60℃下反应脱四氢吡喃保护,反应完全后直接柱层析纯化,得到标题化合物,79mg,油状物,收率82%。
实施例10 N-(氨羰基亚甲基)去甲黄皮酰胺(III1)的制备
将N-(乙氧羰基亚甲基)去甲黄皮酰胺(III4)60mg,以大大过量的NH3/CH3OH溶液处理,放置过夜,柱层析纯化后得到标题化合物40mg,为白色固体,mp:146-148℃,收率72%。
实施例5 N-(乙酰氧基亚甲基)-去甲黄皮酰胺(III3)的制备
将去甲黄皮酰胺(1)200mg溶于7.5mL丙酮中,滴加3滴水,然后加入33mg的多聚甲醛和碳酸钾9mg,外温升至60℃,25分钟后停止加热,将反应混合物用冰水快速冷却,减压蒸发溶剂得208mg粘液。柱层析得162mg N-羟甲基去甲黄皮酰胺(3)的白色固体,mp:199-201℃,收率73%。
将N-羟甲基去甲黄皮酰胺(3)155mg溶于10mL无水四氢呋喃中,冰盐浴下(-8℃)搅拌20分钟,滴加75mg醋酐和59mg的吡啶2mL无水THF溶液,在此温度下搅拌3小时,加入少量水,二氯甲烷稀释,分出有机层,用水和氯化钠水溶液各洗一次,无水硫酸钠干燥,蒸除溶剂后柱层析分离得到N-(乙酰氧基亚甲基)-去甲黄皮酰胺(III3),60mg,mp:137-139℃,,收率32%。
药理实验
实验例1 C5羟基取代黄皮酰胺的立体异构体及N-取代黄皮酰胺衍生物对小鼠脑神经干细胞的细胞增殖的影响
1、目的和意义:
神经干细胞数量的增加或寿命的延长对增加神经元和防止神经元丢失具有特别重要的意义。我们采用小鼠脑神经干细胞研究C5羟基取代黄皮酰胺的立体异构体及N-取代黄皮酰胺衍生物是否具有促进神经干细胞增殖的作用。
2.方法:
小鼠C17-2脑神经干细胞在1640培养基、10%马血清、10%胎牛血清、5%CO2和37℃培养箱的条件下连续培养。用0.1%胰蛋白酶溶液将小鼠神经干细胞消化成单细胞悬液,离心1000rpm×5min,再用培养基冲洗,细胞经接种于96孔培养板中,神经干细胞1×103细胞/孔,每组3孔,连续培养。24h后加药,C5羟基取代黄皮酰胺的立体异构体及N-取代黄皮酰胺衍生物(名称见表1)的给药剂量为0.1μM,1μM和10μM,每天一次在显微镜下观测细胞的生长状态,于第4天吸去培养液,加含有MTT的磷酸盐缓冲液,再培养4小时,吸尽液体,加DMSO溶液,37度震荡培养10分钟,在多功能工作站的490nm中测定每孔的OD值。对照组细胞生长率定为100%。各剂量组分别与对照组进行比较。并用t检验进行统计学处理。
3.结果
C5羟基取代黄皮酰胺的立体异构体及N-取代黄皮酰胺衍生物对小鼠神经干细胞的细胞增殖率的结果见表1。16种化合物中两种C5羟基取代黄皮酰胺立体异构体(5号(-)II1(C18H19NO4 313.36)和8号(+)II1(C18H19NO4,313.36))和一种N-取代黄皮酰胺衍生物(12号(±)III5(C27H28N2O4444.54))在0.1μM和1μM的剂量下具有明显促进小鼠神经干细胞的增殖作用。
表1.C5羟基取代黄皮酰胺的立体异构体及N-取代
黄皮酰胺衍生物对小鼠神经干细胞增殖的影响
代号 | 化合物名称 | 分子式 | 分子量 | 给药剂量 | 结果(OD) | 细胞增殖% |
对照 | DMSO | 0 | 0.137±0.021 | 100.00 | ||
阳性对照 | 成纤维细胞生长因子 | 5mg/L | 0.340±0.035** | 248.17 | ||
1 | (-)Δ5.6-I | C18H17NO2 | 279.34 | 10-5M | 0.076±0.016 | 55.47 |
10-6M | 0.165±0.011 | 120.44 | ||||
10-7M | 0.246±0.005 | 179.56 | ||||
2 | (-)II1 | C18H19N | 313.36 | 10-5M | 0.126±0.016 | 91.97 |
10-6M | 0.236±0.049* | 172.26 | ||||
10-7M | 0.256±0.020** | 186.86 | ||||
3 | (+)II1 | C18H19NO4 | 313.36 | 10-5M | 0.093±0.007 | 67.88 |
10-6M | 0.264±0.036* | 192.70 | ||||
10-7M | 0.250±0.016** | 182.48 | ||||
4 | (-)-3-0-AC-II1 | C20H21NO5 | 355.39 | 10-5M | 0.063±0.014 | 45.99 |
10-6M | 0.072±0.006 | 52.55 | ||||
10-7M | 0.179±0.004 | 130.66 | ||||
5 | (-)II2 | C18H19NO4 | 313.36 | 10-5M | 0.156±0.095 | 113.87 |
10-6M | 0.163±0.038 | 118.98 | ||||
10-7M | 0.233±0.033 | 170.07 | ||||
6 | (+)II2 | C18H19NO4 | 313.36 | 10-5M | 0.076±0.008 | 55.47 |
10-6M | 0.220±0.023 | 160.58 | ||||
10-7M | 0.175±0.059 | 127.74 | ||||
7 | (-)II3 | C18H19NO4 | 313.36 | 10-5M | 0.088±0.006 | 64.23 |
10-6M | 0.187±0.020 | 136.50 | ||||
10-7M | 0.168±0.076 | 122.63 | ||||
8 | (+)II3 | C18H19NO4 | 313.36 | 10-5M | 0.131±0.009 | 95.62 |
10-6M | 0.199±0.024 | 145.26 | ||||
10-7M | 0.253±0.020* | 184.67 | ||||
9 | (±)III1 | C19H20N2O4 | 340.38 | 10-5M | 0.104±0.009 | 75.91 |
10-6M | 0.205±0.006 | 149.64 | ||||
10-7M | 0.240±0.017* | 175.18 | ||||
10 | (±)III2 | C19H19NO5 | 341.37 | 10-5M | 0.100±0.018 | 72.99 |
10-6M | 0.175±0.006 | 127.74 | ||||
10-7M | 0.218±0.012 | 159.12 | ||||
11 | (-)III3 | C20H21NO5 | 355.39 | 10-5M | 0.061±0.007 | 44.53 |
10-6M | 0.147±0.021 | 107.30 | ||||
10-7M | 0.217±0.024 | 158.39 | ||||
12 | (±)III5 | C27H28N2O4 | 444.54 | 10-5M | 0.171±0.035 | 124.82 |
10-6M | 0.227±0.011* | 165.69 | ||||
10-7M | 0.304±0.051** | 221.90 | ||||
13 | (±)III6 | C25H24N2O4 | 416.48 | 10-5M | 0.147±0.051 | 107.30 |
10-6M | 0.163±0.003 | 118.98 | ||||
10-7M | 0.230±0.013 | 167.88 | ||||
14 | (±)III7 | C24H21NO3 | 371.44 | 10-5M | 0.146±0.011 | 106.57 |
10-6M | 0.196±0.007 | 143.07 | ||||
10-7M | 0.219±0.017 | 159.85 | ||||
15 | (-)III8 | C24H23NO3 | 373.46 | 10-5M | 0.096±0.022 | 70.07 |
10-6M | 0.144±0.038 | 105.11 | ||||
10-7M | 0.221±0.043 | 161.31 | ||||
16 | (±)III9 | C25H25NO4 | 403.48 | 10-5M | 0.120±0.027 | 87.59 |
10-6M | 0.138±0.012 | 100.73 | ||||
10-7M | 0.212±0.011 | 154.74 |
4.小结
本发明的C5羟基取代黄皮酰胺的立体异构体及N-取代黄皮酰胺衍生物对促进小鼠神经干细胞的增殖有一定的作用,其中有两种C5羟基取代黄皮酰胺立体异构体(5号(-)II1和8号(+)II1和一种N-取代黄皮酰胺衍生物(12号(±)III5)具有明显地促进小鼠神经干细胞的增殖作用。
实验例2.C5羟基取代黄皮酰胺的立体异构体及N-取代黄皮酰胺衍生物对大鼠海马长时程增强(LTP)的影响
1.目的和意义
黄皮酰胺在多种行为学实验中表现出明显的促智作用,但其对突触传递活动的影响目前还不清楚,而突触是神经系统中细胞间信息传递和加工的基础环节,其功能活动和形态结构上的改变是学习记忆活动的神经生物学基础,因此,本实验采用电生理学技术从突触水平对黄皮酰胺的促智作用进行研究。
2.方法
成年雄性SD大鼠(5只/组)以20%(w/v)乌拉坦(1.0g·kg-1,ip)麻醉并固定于立体定位仪上。参照Pellegrino大鼠脑立体定位图谱,在海马齿状回颗粒细胞层埋藏记录电极(外覆绝缘层,尖端裸露0.2mm,直径0.2mm的不锈钢针)。侧脑室给予表9所示的4对光学活性的黄皮酰胺。刺激电极(两枚间距0.5mm,外覆聚四氟乙烯绝缘层,尖端裸露0.2mm,直径0.15mm的不锈钢针构成)埋植于大鼠内嗅区穿通路(perforant path,PP)纤维间。电子刺激器产生持续的电流刺激后,经刺激隔离器和刺激电极输向PP。调整刺激电极的位置,直到观察到典型的兴奋性突触后电位(EPSP)。电流通过放大器放大后,经过计算机DataWave软件处理。刺激强度则采用引起最大群峰电位(Population spike,PS)所需刺激强度的1/2。在整个实验过程中,每30秒钟给予一次测试刺激频率,记录群峰电位幅度(Populationspike amplitude,PSA),根据公式(PSA/基础幅度值)计算出相对的PSA百分率。
3.结果
由实验结果(表2)可知,本发明的化合物基本对基础突触传递都有一定的增强作用;其中1号(-)Δ5,6-I,2号(+)II1,7号(+)II3和9号(±)III2对基础突触传递有明显的增强作用(P<0.05vscontrol,n=5)。
表2、C5羟基取代黄皮酰胺的立体异构体及N-取代黄皮酰胺衍生物LTP筛选结果
样品号 | 化合物 | 分子式 | 分子量 | 动物数(只) | 相对群峰电位(PSA%) | ||||
给药前 | 给药后15min | 给药后30min | 给药后45min | 给药后60min | |||||
对照1234567891011121314 | Control(-)Δ5,6-I(+)II1(-)II1-3-OAC(-)II2(+)II2(-)II3(+)II3(±)III1(±)III2(-)III3(±)III5(±)III7(±)III8(±)III9 | C18H17NO2C18H19NO4C20H21NO5C18H19NO4C18H19NO4C18H19NO4C18H19NO4C19H20N2O4C19H19NO5C20H21NO5C27H28N2O4C24H21NO3C24H23NO3C25H25NO4 | 279.34313.36355.39313.36313.36313.36313.36340.38341.37355.39444.54371.44373.46403.48 | 354333343455344 | 100100100100100100100100100100100100100100100 | 107.10±10.08123.37±14.80144.86±49.5378.91±13.90110.55±7.2781.48±6.1392.83±17.5491.74±17.2185.24±17.4199.41±9.2790.33±16.1187.51±19.5795.08±5.5267.75±26.84115.6±17.94 | 103.53±6.12138.79±10.94**168.02±49.1683.73±13.59103.09±10.1277.33±8.9387.11±30.54117.87±14.9379.82±22.33117.34±14.74100.15±7.4897.43±32.1598.53±11.8168.48±21.15107.18±20.09 | 97.86±3.18158.89±23.04*194.32±56.65*94.60±8.8794.49±10.5382.56±1.8797.34±25.71161.14±13.94**96.00±19.78140.2±10.96**118.33±25.07111.47±46.02109.13±14.8279.25±16.62103.77±15.36 | 95.99±11.08181.50±35.88*233.24±55.62*102.66±2.8888.40±14.4299.92±6.2698.30±28.59188.03±5.28***117.37±13.49153.36±13.23**141.37±30.83137.15±57.17107.55±21.2798.97±14.26112.72±8.95 |
Test*p<0.05,**p<0.01,***p<0.001vs Control.
Claims (4)
1、如通式(II)所示的光学活性黄皮酰胺C5羟基的衍生物:
其结构特征在于:消旋II1相对构型为(3S*,4S*,5S*,6R*),
消旋II2相对构型为(3S*,4S*,5R*,6S*);
光活II1构型为:(3S,4S,5S,6R)
(3R,4R,5R,6S);
光活II2构型为:(3S,4S,5R,6S)
(3R,4R,5S,6R)。
2、如权利要求1所述光学活性黄皮酰胺C5羟基的衍生物的制备方法,其包括如下步骤
(a)使式1消旋3-O-乙酰黄皮酰胺及其光活体脱水,脱水剂为POCl3/Py,或先制备黄皮酰胺的甲磺酸酯再以DBU脱除甲磺酸;
(b)采用常规的酸或碱性条件进行式2消旋3-O-乙酰-Δ5,6-黄皮酰胺及其光活体的水解;
(c)采用OsO4/NMO,KHSO5/CH3COCF3,WO3/H2O2进行式3消旋Δ5,6-黄皮酰胺及其光活体的双羟基化。
3、药物组合物,其含有有效剂量的如权利要求1所述的任一化合物,以及药学上可接受的载体。
4、如通式(II)所示的光学活性的黄皮酰胺C5羟基的衍生物用于制备促智、抗衰老的药物的用途:
结构特征在于:消旋II1相对构型为(3S*,4S*,5S*,6R*),
消旋II2相对构型为(3S*,4S*,5R*,6S*);
光活II1构型为:(3S,4S,5S,6R)
(3R,4R,5R,6S);
光活II2构型为:(3S,4S,5R,6S)
(3R,4R,5S,6R);。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CNB2003101238748A CN1301249C (zh) | 2002-12-31 | 2003-12-31 | 黄皮酰胺c5羟基衍生物及n取代衍生物、其制法和其药物组合物与用途 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN02159343.4 | 2002-12-31 | ||
CN02159343 | 2002-12-31 | ||
CNB2003101238748A CN1301249C (zh) | 2002-12-31 | 2003-12-31 | 黄皮酰胺c5羟基衍生物及n取代衍生物、其制法和其药物组合物与用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1513837A CN1513837A (zh) | 2004-07-21 |
CN1301249C true CN1301249C (zh) | 2007-02-21 |
Family
ID=34276124
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB2003101238748A Expired - Lifetime CN1301249C (zh) | 2002-12-31 | 2003-12-31 | 黄皮酰胺c5羟基衍生物及n取代衍生物、其制法和其药物组合物与用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN1301249C (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102249976B (zh) * | 2011-06-10 | 2012-11-14 | 中国科学院化学研究所 | 一种光学纯的(-)-黄皮酰胺类化合物的制备方法 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0414020A2 (de) * | 1989-08-19 | 1991-02-27 | Bayer Ag | Verfahren zur Herstellung von Clausenamid und Neoclausenamid und deren Derivate |
CN1345721A (zh) * | 2000-09-28 | 2002-04-24 | 中国医学科学院药物研究所 | 光活(一)黄皮酰胺制备方法 |
-
2003
- 2003-12-31 CN CNB2003101238748A patent/CN1301249C/zh not_active Expired - Lifetime
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0414020A2 (de) * | 1989-08-19 | 1991-02-27 | Bayer Ag | Verfahren zur Herstellung von Clausenamid und Neoclausenamid und deren Derivate |
CN1345721A (zh) * | 2000-09-28 | 2002-04-24 | 中国医学科学院药物研究所 | 光活(一)黄皮酰胺制备方法 |
Also Published As
Publication number | Publication date |
---|---|
CN1513837A (zh) | 2004-07-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN103209704B (zh) | 有机化合物 | |
CN101687886B (zh) | 七元环化合物及其在防治糖尿病及代谢综合征中的药学用途 | |
US11203597B2 (en) | Crystalline spirocyclic compound, a dosage form containing, a method for using in treatment of disease, and a method for recrystallizing | |
CN1128789C (zh) | 苯并环庚并噻吩化合物 | |
CN1513452A (zh) | Cgmp磷酸二酯酶抑制剂治疗阳痿的用途 | |
CN1309565A (zh) | 用于治疗或预防睡眠障碍的药物组合物 | |
CN104583201B (zh) | 作为用于在治疗ep4介导的疾病和病状中使用的ep4受体选择性激动剂的二氟内酰胺化合物 | |
JP5554496B2 (ja) | 神経発生を刺激するための、およびニューロン変性を阻害するための方法および組成物 | |
CN102838505A (zh) | 酰胺类化合物、其制备方法及应用 | |
CN100335480C (zh) | 咪唑并吡啶衍生物、它们的制备方法以及含有它们的药物组合物 | |
CN106431988A (zh) | 视蛋白结合配体、组合物及使用方法 | |
CN1047494A (zh) | 新的8-取代的2-氨基-1,2,3,4-四氢化萘类化合物 | |
EA033769B1 (ru) | ОТСЕЛЕКТИРОВАННЫЙ АМИД γ-ГИДРОКСИМАСЛЯНОЙ КИСЛОТЫ И ЕГО ПРИМЕНЕНИЯ ПРИ ЛЕЧЕНИИ ЗЛОУПОТРЕБЛЕНИЯ АЛКОГОЛЕМ | |
CN1301249C (zh) | 黄皮酰胺c5羟基衍生物及n取代衍生物、其制法和其药物组合物与用途 | |
CN1036714C (zh) | 晶状的碳代青霉烯衍生物 | |
CN1227538A (zh) | 含有4-氧代-丁酸的药物组合物 | |
CN1275961C (zh) | 光活双环醇及其制备方法和其药物组合物与用途 | |
CN1511520A (zh) | 丁二酸酯衍生物治疗痴呆症的用途 | |
CN102317261B (zh) | 三重再摄取抑制剂及其应用方法 | |
JP7508140B2 (ja) | 新規なラパコニチン酸化誘導体及びその用途 | |
CN1046511C (zh) | 苯甲酰基芽子碱,芽子碱和芽子定衍生物 | |
CN1295215C (zh) | 黄皮酰胺的光学活性衍生物、其制法和其药物组合物与用途 | |
CN110818720A (zh) | 褪黑激素(mt1/mt2)受体激动剂、其制备方法和用途 | |
CN104292126B (zh) | 萘衍生物及其在药物上的应用 | |
CN113527273B (zh) | 靶向泛素化降解hmgcr的化合物或其可药用的盐、制备方法及用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CX01 | Expiry of patent term | ||
CX01 | Expiry of patent term |
Granted publication date: 20070221 |