CN101235020B - Substituted cinnamamide derivatives and application of the same as nerve protecting agent - Google Patents
Substituted cinnamamide derivatives and application of the same as nerve protecting agent Download PDFInfo
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- CN101235020B CN101235020B CN200810020419A CN200810020419A CN101235020B CN 101235020 B CN101235020 B CN 101235020B CN 200810020419 A CN200810020419 A CN 200810020419A CN 200810020419 A CN200810020419 A CN 200810020419A CN 101235020 B CN101235020 B CN 101235020B
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- substituted
- phenyl
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- pyridine
- alkene
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- APEJMQOBVMLION-UHFFFAOYSA-N cinnamamide Chemical class NC(=O)C=CC1=CC=CC=C1 APEJMQOBVMLION-UHFFFAOYSA-N 0.000 title description 9
- 210000005036 nerve Anatomy 0.000 title 1
- 239000003223 protective agent Substances 0.000 title 1
- 239000003814 drug Substances 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 13
- 230000005779 cell damage Effects 0.000 claims description 7
- 208000037887 cell injury Diseases 0.000 claims description 7
- 229930195712 glutamate Natural products 0.000 claims description 5
- 230000006698 induction Effects 0.000 claims description 5
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000004090 neuroprotective agent Substances 0.000 abstract description 2
- 230000000320 anti-stroke effect Effects 0.000 abstract 1
- 210000002569 neuron Anatomy 0.000 abstract 1
- 230000001681 protective effect Effects 0.000 abstract 1
- APEJMQOBVMLION-VOTSOKGWSA-N trans-cinnamamide Chemical class NC(=O)\C=C\C1=CC=CC=C1 APEJMQOBVMLION-VOTSOKGWSA-N 0.000 abstract 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 60
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 239000007787 solid Substances 0.000 description 32
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 30
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 29
- -1 benzhydryl piperazidine compounds Chemical class 0.000 description 29
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 19
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 18
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 12
- 150000001851 cinnamic acid derivatives Chemical class 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000000217 alkyl group Chemical group 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 125000003118 aryl group Chemical group 0.000 description 7
- 238000010586 diagram Methods 0.000 description 7
- 125000000623 heterocyclic group Chemical group 0.000 description 7
- 230000000324 neuroprotective effect Effects 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 150000002367 halogens Chemical class 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 229940049906 glutamate Drugs 0.000 description 4
- 229960002989 glutamic acid Drugs 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 150000001263 acyl chlorides Chemical class 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- JRZJOMJEPLMPRA-UHFFFAOYSA-N 1-nonene Chemical compound CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
- QGZCUOLOTMJILH-UHFFFAOYSA-N 2h-tetrazol-2-ium;bromide Chemical compound [Br-].C1=N[NH+]=NN1 QGZCUOLOTMJILH-UHFFFAOYSA-N 0.000 description 2
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- ZDVDCDLBOLSVGM-UHFFFAOYSA-N [chloro(phenyl)methyl]benzene Chemical compound C=1C=CC=CC=1C(Cl)C1=CC=CC=C1 ZDVDCDLBOLSVGM-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229960003328 benzoyl peroxide Drugs 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 244000309466 calf Species 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- QILSFLSDHQAZET-UHFFFAOYSA-N diphenylmethanol Chemical compound C=1C=CC=CC=1C(O)C1=CC=CC=C1 QILSFLSDHQAZET-UHFFFAOYSA-N 0.000 description 2
- NWVNXDKZIQLBNM-UHFFFAOYSA-N diphenylmethylpiperazine Chemical compound C1CNCCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 NWVNXDKZIQLBNM-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- QELUYTUMUWHWMC-UHFFFAOYSA-N edaravone Chemical group O=C1CC(C)=NN1C1=CC=CC=C1 QELUYTUMUWHWMC-UHFFFAOYSA-N 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 210000004907 gland Anatomy 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000002769 thiazolinyl group Chemical group 0.000 description 2
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 1
- ZRYZBQLXDKPBDU-UHFFFAOYSA-N 4-bromobenzaldehyde Chemical compound BrC1=CC=C(C=O)C=C1 ZRYZBQLXDKPBDU-UHFFFAOYSA-N 0.000 description 1
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 1
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 125000005518 carboxamido group Chemical group 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 229950009041 edaravone Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- AFFLGGQVNFXPEV-UHFFFAOYSA-N n-decene Natural products CCCCCCCCC=C AFFLGGQVNFXPEV-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a substituted cinnamide derivate and an application as neuroprotective agent in pharmacy, wherein the derivate is represented as a formula (I), which has neuron protective activity and can be used to prepare anti-stroke drug.
Description
Technical field
The invention belongs to pharmacy field, relate to a kind of new substituted cinnamamide derivative, and this verivate is as the purposes of neuroprotective.
Background technology
The bibliographical information cinnamic acid derivative has certain neuro-protective effect.According to another bibliographical information, the benzhydryl piperazidine compounds has anti-oxidant activity preferably.But substituted cinnamic acid derivative was not disclosed and the benzhydryl piperazidine compounds is condensed into substituted cinnamamide derivative, the report that does not also have these substituted cinnamamide derivatives whether to have neuro-protective effect and Stroke therapeutic activity.
Summary of the invention
One of technical issues that need to address of the present invention are to disclose a kind of new substituted cinnamamide derivative with medical value.
Two of the technical issues that need to address of the present invention are to disclose above-mentioned substituted cinnamamide derivative as the application of neuroprotective in preparation Stroke medicine.
For addressing the above problem, following technical scheme is provided:
Formula (I) compound
Wherein, R
1, R
2, R
3, R
4And R
5Identical or different, represent H, halogen, nitro, amino, itrile group, hydroxyl, alkoxyl group, alkyl, aryl, heterocyclic radical, aryl, substituted hydrocarbon radical, substituted arene base, substituted heterocycle, substituted aryl independently of one another;
R
6And R
7Identical or different, represent H, halogen, alkyl, the substituted alkyl of halogen, nitro, amino, itrile group, hydroxyl, alkoxyl group, aralkoxy, heterocycle alkoxyl group independently of one another.
Said general formula (I) compound is characterized in that: R
1, R
2, R
3, R
4, R
5, R
6Or R
7Aryl in aryl, aryl or the aralkoxy of representative is benzene, biphenyl or naphthalene, perhaps is F, Cl, Br, I, C
1～10Alkyl, C
1～10Alkoxyl group, nitro or amino substituted benzene, biphenyl or naphthalene.
Said general formula (I) compound is characterized in that: R
1, R
2, R
3, R
4, R
5, R
6Or R
7The alkyl, the alkyl in the aryl of representative refer to have the alkyl of the straight or branched of 1-10 carbon atom, or the thiazolinyl of the straight or branched of 2-10 carbon atom, or the naphthenic base of the straight or branched of 3-10 carbon atom; Alkyl in alkoxyl group or aralkoxy or the heterocycle alkoxyl group refers to have the alkyl of the straight or branched of 1-10 carbon atom.Wherein alkyl is methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec.-butyl, amyl group, neo-pentyl, hexyl, heptyl, octyl group, nonyl, decyl; Thiazolinyl is vinyl, propenyl, allyl group, crotonyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonene base, decene base; Naphthenic base is cyclopropyl, cyclobutyl, cyclohexyl, suberyl, ring octyl group, ring nonyl, ring decyl.
Said general formula (I) compound is characterized in that: R
1, R
2, R
3, R
4, R
5, R
6Or R
7Heterocyclic radical in heterocyclic radical, substituted heterocycle or the heterocycle alkoxyl group of representative refers to contain one or more heteroatomic saturated heterocyclic or aromatic heterocycle optional from oxygen, nitrogen, sulphur atom.
Said general formula (I) compound is characterized in that: R
1, R
2, R
3, R
4, R
5, R
6Or R
7The halogen of representative is F, Cl, Br or I.
Said general formula (I) compound is characterized in that: R
1, R
2, R
3, R
4, R
5, R
6Or R
7In substituted alkyl, aryl, heterocyclic radical, aryl, its substituting group is halogen, nitro, amino, hydroxyl, ether, carboxyl, ester group and carboxamido-group.
Said general formula (I) compound is characterized in that: amino is NH
2, R
8NH, R
9R
10N; R wherein
8, R
9Or R
10Be the described alkyl of claim 3, perhaps R
9R
10N is the ternary～eight yuan heterocycle of nitrogen atom.
The application of above-claimed cpd in preparation Neuroprotective Agents and Stroke medicine.
The present invention uses various substituted phenyl aldehydes to be starting raw material, by ordinary method and the substituted cinnamic acid derivative of the corresponding phenyl ring of propanedioic acid condensation prepared; Substituted UVNUL MS-40 prepares corresponding substituted benzhydryl piperazidine by ordinary method reduction, halo, replacement; Substituted then cinnamic acid derivative and the corresponding acyl chlorides of sulfur oxychloride prepared in reaction; With substituted benzhydryl piperazidine reaction; Prepared a series of new substituted cinnamamide derivatives, these compounds have neuro-protective effect preferably and Stroke therapeutic activity.
The preparation method of general formula (I) compound may further comprise the steps:
A. substituted phenyl aldehyde (II) obtains substituted cinnamic acid derivative (IV) with propanedioic acid (III) condensation;
B. substituted UVNUL MS-40 (V) obtains substituted benzhydryl piperazidine (VI) through reduction, halo, replacement;
C. with substituted cinnamic acid derivative (IV) and the corresponding acyl chlorides of sulfur oxychloride prepared in reaction, with substituted benzhydryl piperazidine (VI) condensation; Get general formula (I) compound;
(annotate: the R among compound I I, III, IV, V, the VI
1, R
2, R
3, R
4, R
5, R
6With R
7The substituting group of representative is identical with above-mentioned qualification in compound I).
Wherein, the substituted general formula of acetoxyl group (IV) compound obtains corresponding oxy-compound acetylize.
The preparation method that substituted cinnamic acid derivative of the general formula that the present invention relates to (I) and benzhydryl piperazidine compounds are condensed into substituted cinnamamide derivative can be represented by synthetic synoptic diagram 1～3:
A. substituted phenyl aldehyde and propanedioic acid condensation obtain substituted cinnamic acid derivative (seeing synthetic synoptic diagram 1);
B. substituted UVNUL MS-40 obtains substituted benzhydryl piperazidine (seeing synthetic synoptic diagram 2) through reduction, halo, replacement;
C. with substituted cinnamic acid derivative and the corresponding acyl chlorides of sulfur oxychloride prepared in reaction, with substituted benzhydryl piperazidine condensation (seeing synthetic synoptic diagram 3);
D. the condensation products therefrom is used the absolute ethyl alcohol recrystallization, get target compound.
Synthetic synoptic diagram 1:
Synthetic synoptic diagram 2:
Synthetic synoptic diagram 3:
Beneficial effect of the present invention:
At present, the screening of neuroprotective activity is to embody with the provide protection of compound for glutamate induction PC12 cell injury by routine.
Experimental data (seeing embodiment 30 for details) shows: part verivate of the present invention has stronger provide protection to the PC12 cell injury of glutamate induction.
Embodiment
Following embodiment can make those skilled in the art more fully understand the present invention, but does not limit the present invention in any way.
Embodiment 1
(E)-3-(3,4-diacetoxy phenyl) vinylformic acid
In the round-bottomed flask of the 250ml that reflux condensing tube is housed, add 3, and the 4-Dihydroxy benzaldehyde (13.8g, 0.1mol), propanedioic acid (15.6g, 0.15mol), pyridine (68ml), hexahydropyridine (1.8ml) is heated to 95 ℃ of reactions 3 hours.Cooling removes solvent under reduced pressure, and resistates is poured in the mixed solution of concentrated hydrochloric acid (68ml) and ice (150ml), stirs, and separates out the off-white color solid.Filter, the absolute ethyl alcohol recrystallization gets off-white powder coffic acid 6.4g, yield 35.2%, mp205.9-209.5 ℃.
Coffic acid (5.2g, 0.029mol), diacetyl oxide (24ml), pyridine (20ml) is added in the reaction flask stirred overnight at room temperature.Remove solvent under reduced pressure, resistates is poured in the frozen water, gets faint yellow solid, and the absolute ethyl alcohol recrystallization gets white solid 6.5g, yield 85.9%, mp197.1-199.7 ℃.
Embodiment 2
(E)-3-(3-methoxyl group-4-acetoxyl group phenyl) vinylformic acid
The preparation method is with embodiment 1, vanillin food grade,1000.000000ine mesh (15.2g, 0.1mol), propanedioic acid (15.6g, 0.15mol), pyridine (68ml), hexahydropyridine (1.8ml) is heated to 95 ℃ of reactions, FLA 9.2g, yield 47.4%, mp170.7-172.4 ℃.
FLA (5.6g, 0.029mol), diacetyl oxide (12ml), pyridine (20ml) room temperature reaction gets white solid 6.1g, yield 89.1%, mp168.5-169.9 ℃.
Embodiment 3
(E)-3-(4-fluorophenyl) vinylformic acid
The preparation method is with embodiment 1, the 4-fluorobenzaldehyde (12.4g, 0.1mol), propanedioic acid (15.6g, 0.15mol), pyridine (68ml), hexahydropyridine (1.8ml) is heated to 95 ℃ of reactions, white solid 13g, yield 78.3%, mp209.1-210.8 ℃.
Embodiment 4
(E)-3-(4-aminomethyl phenyl) vinylformic acid
The preparation method is with embodiment 1, the 4-tolyl aldehyde (12.0g, 0.1mol), propanedioic acid (15.6g, 0.15mol), pyridine (68ml), hexahydropyridine (1.8ml) is heated to 95 ℃ of reactions, white solid 12.3g, yield 75.9%, mp195.1-196 ℃.
Embodiment 5
(E)-3-(4-acetoxyl group phenyl) vinylformic acid
The preparation method is with embodiment 1, and the 4-hydroxy benzaldehyde (12.2g, 0.1mol), propanedioic acid (15.6g; 0.15mol), pyridine (68ml), hexahydropyridine (1.8ml) is heated to 95 ℃ of reactions; Get (E)-3-(4-hydroxy phenyl) vinylformic acid 6.4g, yield 39%, mp210-213 ℃.
(E)-and 3-(4-hydroxy phenyl) vinylformic acid (4.74g, 0.029mol), diacetyl oxide (12ml), pyridine (20ml) room temperature reaction gets white solid 5.4g, yield 90.7%, mp157.3-158.5 ℃.
Embodiment 6
(E)-3-(4-p-methoxy-phenyl) vinylformic acid
The preparation method is with embodiment 1, the 4-methoxybenzaldehyde (13.6g, 0.1mol), propanedioic acid (15.6g, 0.15mol), pyridine (68ml), hexahydropyridine (1.8ml) is heated to 95 ℃ of reactions, white solid 12.6g, yield 70.8%, mp173.2-174.4 ℃.
Embodiment 7
(E)-3-(benzo [d] [1,3] dioxole-5-yl) vinylformic acid
The preparation method is with embodiment 1, piperonylaldehyde (15.0g, 0.1mol), propanedioic acid (15.6g, 0.15mol), pyridine (68ml), hexahydropyridine (1.8ml) is heated to 95 ℃ of reactions, white solid 13.1g, yield 68.2%, mp241.5-244.4 ℃.
Embodiment 8
(E)-3-(4-chloro-phenyl-) vinylformic acid
The preparation method is with embodiment 1, the 4-chlorobenzaldehyde (14.5g, 0.1mol), propanedioic acid (15.6g, 0.15mol), pyridine (68ml), hexahydropyridine (1.8ml) is heated to 95 ℃ of reactions, white solid 13.2g, yield 72.3%, mp238.3-240.5 ℃.
Embodiment 9
(E)-3-(4-bromophenyl) vinylformic acid
The preparation method is with embodiment 1, the 4-bromobenzaldehyde (18.4g, 0.1mol), propanedioic acid (15.6g, 0.15mol), pyridine (68ml), hexahydropyridine (1.8ml) is heated to 95 ℃ of reactions, white solid 15.9g, yield 70%, mp246.3-248.3 ℃.
Embodiment 10
1-(diphenyl-methyl) piperazine
In the round-bottomed flask of the 500ml that reflux condensing tube is housed, add sodium hydroxide (30g), and UVNUL MS-40 (30g, 0.164mol), zinc powder (30g, 0.462mol), 95% ethanol (300ml), stirring reaction 3 hours.Filter, filtrating is slowly poured in the mixed solution of concentrated hydrochloric acid (76ml) and ice (1500ml), stirs, and gets white solid.Use the absolute ethyl alcohol recrystallization, get white crystal benzhydrol 21.8g, yield 71.9%, mp67-68 ℃.
Benzhydrol (18.7g), hydrochloric acid (29ml) add in the reaction flask, stirring at room 4 hours.Add toluene (10ml), obtain toluene layer, saturated solution of sodium bicarbonate is given a baby a bath on the third day after its birth inferior, washes anhydrous Na three times
2SO
4Dry.Filter, filtrating is reclaimed toluene, gets faint yellow oily thing diphenyl-chloromethane.
Piperazine anhydrous (10.8g, 0.125mol), Pottasium Hydroxide (3.5g; 0.065mol), Tetrabutyl amonium bromide (1.25g), toluene (50ml); Water (13.5ml) adds in the reaction flask; (12.5g 0.05mol) with the mixed solution of toluene (50ml), continues stirring and refluxing 12h slowly to splash into diphenyl-chloromethane under the stirring and refluxing.Cooling adds water (30ml), obtains toluene layer, and the 3mol/L hydrochloric acid extraction is used in washing twice then, and the water layer of extraction merges the back and is neutralized to pH11 with the 3mol/L sodium hydroxide solution, and the oily matter of separating out is used ethyl acetate extraction.Calcium Chloride Powder Anhydrous is dry, boils off solvent, gets yellow solid, uses re-crystallizing in ethyl acetate, gets light yellow crystal 8.7g, yield 69%, mp61-62 ℃.
Embodiment 11
1-[two-(4-fluorophenyl) methyl] piperazine
Sodium hydroxide (30g), and two-(4-fluorophenyl) ketones (35.8g, 0.164mol), zinc powder (30g, 0.462mol), 95% ethanol (300ml), other are operated with embodiment 10, get white solid 10.7g, mp89-91 ℃.
Embodiment 12
(E)-[4-[two-(4-fluorophenyl) methyl] piperazine-1-yl]-3-(3 ,-diacetoxy phenyl)-third-2-alkene-1-ketone (WB-01)
Adding (E)-3-(3,4-diacetoxy phenyl) vinylformic acid in the 50ml round-bottomed flask that straight type drying tube is housed (1.056g, 4mmol), methylene dichloride (15ml), sulfur oxychloride (1.5ml), pyridine (1), stirring at room 3.5 hours.Remove solvent under reduced pressure, resistates adds anhydrous propanone (15ml) dissolving, with gained solution slowly splash into be equipped with 1-[two-(4-fluorophenyl) methyl] piperazine (1.31g, 6mmol), acetone (15ml), in the 50ml round-bottomed flask of triethylamine (5ml), stirred overnight.Filter, the gained filtrate decompression concentrates, and resistates is used the absolute ethyl alcohol recrystallization, gets faint yellow solid 1.1g, yield 51.5%, mp187.2-190.7 ℃.ESI-MS(m/z)：535.2(M+H)
+；
1HNMR(δ，ppm，CDCl
3)：2.39-2.40(m，4H，N(CH
2)
2)；2.81(s，6H，CH
3COO*2)；3.62-3.67(m，4H，CON(CH
2)
2)；4.27(s，1H，CH(Ph)
2)；6.62-6.67(d，1H，＝CHCO)；6.79-7.48(m，12H，Ph)；7.56-7.59(d，1H，Ph-CH＝)。
Embodiment 13
(E)-[4-[two-(4-fluorophenyl) methyl] piperazine-1-yl]-3-[(3-methoxyl group-4-acetoxyl group) phenyl]-third-2-alkene-1-ketone (WB-02)
(E)-and 3-(3-methoxyl group-4-acetoxyl group phenyl) vinylformic acid (0.944g, 4mmol), methylene dichloride (15ml), sulfur oxychloride (1.5ml), pyridine (1), other are operated with embodiment 12.Get faint yellow solid 1.3g, yield 64.2%, mp178.5-182.4 ℃.ESI-MS(m/z)：507.3(M+H)
+；
1HNMR(δ，ppm，CDCl
3)：2.31(s，3H，CH
3COO)；2.39-2.42(m，4H，N(CH
2)
2)；3.59-3.73(m，4H，CON(CH
2)
2)；3.84(s，3H，CH
3O)；4.26(s，1H，CH(Ph)
2)；6.69-6.73(d，1H，＝CHCO)；6.88-7.39(m，11H，Ph)；7.56-7.63(d，1H，Ph-CH＝)。
Embodiment 14
(E)-[4-[two-(4-fluorophenyl) methyl] piperazine-1-yl]-3-(4-fluorophenyl)-third-2-alkene-1-ketone (WB-03)
(E)-and 3-(4-fluorophenyl) vinylformic acid (0.664g, 4mmol), methylene dichloride (15ml), sulfur oxychloride (1.5ml), pyridine (1), other are operated with embodiment 12.Get faint yellow solid 1.2g, yield 68.8%, mp156.8-157.4 ℃.ESI-MS(m/z)：459.1(M+Na)
+；
1HNMR(δ，ppm，CDCl
3)：2.39-2.41(m，4H，N(CH
2)
2)；3.64-3.72(m，4H，CON(CH
2)
2)；4.26(s，1H，CH(Ph)
2)；6.73-6.76(d，1H，＝CHCO)；6.97-7.48(m，12H，Ph)；7.60-7.63(d，1H，Ph-CH＝)。
Embodiment 15
(E)-[4-[two-(4-fluorophenyl) methyl] piperazine-1-yl]-3-(4-aminomethyl phenyl)-third-2-alkene-1-ketone (WB-04)
(E)-and 3-(4-aminomethyl phenyl) vinylformic acid (0.648g, 4mmol), methylene dichloride (15ml), sulfur oxychloride (1.Sml), pyridine (1), other are operated with embodiment 12.Get faint yellow solid 1.1g, yield 63.7%, mp139.1-139.9 ℃.ESI-MS(m/z)：455.3(M+Na)
+；
1HNMR(δ，ppm，CDCl
3)：2.34(s，3H，CH
3)；2.38-2.40(m，4H，N(CH
2)
2)；3.65-3.72(m，4H，CON(CH
2)
2)；4.25(s，1H，CH(Ph)
2)；6.76-6.79(d，1H，＝CHCO)；6.96-7.39(m，12H，Ph)；7.61-7.64(d，1H，Ph-CH＝)。
Embodiment 16
(E)-[4-[two-(4-fluorophenyl) methyl] piperazine-1-yl]-3-(4-acetoxyl group phenyl)-third-2-alkene-1-ketone (WB-05)
(E)-and 3-(4-acetoxyl group phenyl) vinylformic acid (0.824g, 4mmol), methylene dichloride (15ml), sulfur oxychloride (1.5ml), pyridine (1), other are operated with embodiment 12.Get faint yellow solid 1.0g, yield 52.5%, mp191.2-193.1 ℃.ESI-MS(m/z)：477.1(M+H)
+；
1HNMR(δ，ppm，CDCl
3)：2.30(s，3H，CH
3COO)；2.40-2.42(m，4H，N(CH
2)
2)；3.64-3.74(m，4H，CON(CH
2)
2)；4.26(s，1H，CH(Ph)
2)；6.76-6.79(d，1H，＝CHCO)；6.98-7.51(m，12H，Ph)；7.61-7.64(d，1H，Ph-CH＝)。
Embodiment 17
(E)-[4-[two-(4-fluorophenyl) methyl] piperazine-1-yl]-3-(4-p-methoxy-phenyl)-third-2-alkene-1-ketone (WB-06)
(E)-and 3-(4-p-methoxy-phenyl) vinylformic acid (0.712g, 4mmol), methylene dichloride (15ml), sulfur oxychloride (1.5ml), pyridine (1), other are operated with embodiment 12.Get faint yellow solid 0.9g, yield 50.2%, mp179.7-180.6 ℃.ESI-MS(m/z)：449.2(M+H)
+；
1HNMR(δ，ppm，CDCl
3)：2.38-2.40(m，4H，N(CH
2)
2)；3.65-3.72(m，4H，CON(CH
2)
2)；3.82(s，3H，CH
3O)；4.25(s，1H，CH(Ph)
2)；6.68-6.71(d，1H，＝CHCO)；6.86-7.45(m，12H，Ph)；7.60-7.63(d，1H，Ph-CH＝)。
Embodiment 18
(E)-3-(benzo [d] [1,3] dioxole-5-yl)-1-[4-[two-(4-fluorophenyl) methyl] piperazine-1-yl]-third-2-alkene-1-ketone (WB-07)
(E)-and 3-(benzo [d] [1,3] dioxole-5-yl) vinylformic acid (0.768g, 4mmol), methylene dichloride (15ml), sulfur oxychloride (1.5ml), pyridine (1), other are operated with embodiment 12.Get faint yellow solid 0.6g, yield 32.5%, mp186.5-187.2 ℃.ESI-MS(m/z)：463.2(M+H)
+；
1HNMR(δ，ppm，CDCl
3)：2.38-2.40(m，4H，N(CH
2)
2)；3.64-3.72(m，4H，CON(CH
2)
2)；4.25(s，1H，CH(Ph)
2)；5.97(s，2H，OCH
2O)；6.64-6.67(d，1H，＝CHCO)；6.77-7.36(m，12H，Ph)；7.55-7.58(d，1H，Ph-CH＝)。
Embodiment 19
(E)-[4-[two-(4-fluorophenyl) methyl] piperazine-1-yl]-3-(4-chloro-phenyl-)-third-2-alkene-1-ketone (WB-08)
(E)-and 3-(4-chloro-phenyl-) vinylformic acid (0.73g, 4mmol), methylene dichloride (15ml), sulfur oxychloride (1.5ml), pyridine (1), other are operated with embodiment 12.Get faint yellow solid 1.2g, yield 66.3%, mp157.4-158.6 ℃.ESI-MS(m/z)：453.2(M+H)
+；
1HNMR(δ，ppm，CDCl
3)：2.39-2.41(m，4H，N(CH
2)
2)；3.64-3.72(m，4H，CON(CH
2)
2)；4.26(s，1H，CH(Ph)
2)；6.78-6.81(d，1H，＝CHCO)；6.96-7.41(m，12H，Ph)；7.58-7.61(d，1H，Ph-CH＝)。
Embodiment 20
(E)-[4-[two-(4-fluorophenyl) methyl] piperazine-1-yl]-3-(4-bromophenyl)-third-2-alkene-1-ketone (WB-09)
(E)-and 3-(4-bromophenyl) vinylformic acid (0.908g, 4mmol), methylene dichloride (15ml), sulfur oxychloride (1.5ml), pyridine (1), other are operated with embodiment 12.Get faint yellow solid 1.1g, yield 55.4%, mp160.4-161.0 ℃.ESI-MS(m/z)：497.1(M+H)
+；
1HNMR(δ，ppm，CDCl
3)：2.39-2.41(m，4H，N(CH
2)
2)；3.64-3.73(m，4H，CON(CH
2)
2)；4.26(s，1H，CH(Ph)
2)；6.79-6.82(d，1H，＝CHCO)；6.97-7.49(m，12H，Ph)；7.56-7.59(d，1H，Ph-CH＝)。
Embodiment 21
(E)-(4-benzhydryl piperazidine-1-yl)-3-(3,4-diacetoxy phenyl)-third-2-alkene-1-ketone (WB-10)
Adding (E)-3-(3,4-diacetoxy phenyl) vinylformic acid in the 50ml round-bottomed flask that straight type drying tube is housed (1.056g, 4mmol), methylene dichloride (15ml), sulfur oxychloride (1.5ml), pyridine (1), stirring at room 3.5 hours.Remove solvent under reduced pressure, resistates adds anhydrous propanone (15ml) dissolving, with gained solution slowly splash into be equipped with 1-(diphenyl-methyl) piperazine (1.09g, 6mmol), acetone (15ml), in the 50ml round-bottomed flask of triethylamine (5ml), stirred overnight.Filter, the gained filtrate decompression concentrates, and resistates is used the absolute ethyl alcohol recrystallization, gets faint yellow solid 0.5g, yield 25.1%, mp208.3-211.2 ℃.ESI-MS(m/z)：499.2(M+H)
+；
1HNMR(δ，ppm，CDCl
3)：2.40-2.43(m，4H，N(CH
2)
2)；2.70(s，6H，CH
3COO*2)；3.61-3.67(m，4H，CON(CH
2)
2)；4.26(s，1H，CH(Ph)
2)；6.62-6.67(d，1H，＝CHCO)；6.79-7.48(m，14H，Ph)；7.56-7.59(d，1H，Ph-CH＝)。
Embodiment 22
(E)-(4-benzhydryl piperazidine-1-yl)-3-[(3-methoxyl group-4-acetoxyl group) phenyl]-third-2-alkene-1-ketone (WB-11)
(E)-and 3-(3-methoxyl group-4-acetoxyl group phenyl) vinylformic acid (0.944g, 4mmol), methylene dichloride (15ml), sulfur oxychloride (1.5ml), pyridine (1), other are operated with embodiment 21.Get faint yellow solid 0.6g, yield 31.9%, mp153.7-158.8 ℃.ESI-MS(m/z)：471.3(M+H)
+；
1HNMR(δ，ppm，CDCl
3)：2.31(s，3H，CH
3COO)；2.44(s，4H，N(CH
2)
2)；3.66-3.73(m，4H，CON(CH
2)
2)；3.84(s，3H，CH
3O)；4.27(s，1H，CH(Ph)
2)；6.73-6.78(d，1H，＝CHCO)；7.00-7.43(m，13H，Ph)；7.57-7.62(d，1H，Ph-CH＝)。
Embodiment 23
(E)-(4-benzhydryl piperazidine-1-yl)-3-(4-fluorophenyl)-third-2-alkene-1-ketone (WB-12)
(E)-and 3-(4-fluorophenyl) vinylformic acid (0.664g, 4mmol), methylene dichloride (15ml), sulfur oxychloride (1.5ml), pyridine (1), other are operated with embodiment 21.Get faint yellow solid 0.3g, yield 18.8%, mp227.7-231.6 ℃.ESI-MS(m/z)：401.1(M+H)
+；
1HNMR(δ，ppm，CDCl
3)：2.42-2.47(m，4H，N(CH
2)
2)；3.65-3.73(m，4H，CON(CH
2)
2)；4.27(s，1H，CH(Ph)
2)；6.72-6.78(d，1H，＝CHCO)；7.01-7.49(m，14H，Ph)；7.58-7.63(d，1H，Ph-CH＝)。
Embodiment 24
(E)-(4-benzhydryl piperazidine-1-yl)-3-(4-aminomethyl phenyl)-third-2-alkene-1-ketone (WB-13)
(E)-and 3-(4-aminomethyl phenyl) vinylformic acid (0.648g, 4mmol), methylene dichloride (15ml), sulfur oxychloride (1.5ml), pyridine (1), other are operated with embodiment 21.Get faint yellow solid 1.1g, yield 69.4%, mp124.1-126.1 ℃.ESI-MS(m/z)：397.2(M+H)
+；
1HNMR(δ，ppm，CDCl
3)：2.35(s，3H，CH
3)；2.42-2.44(m，4H，N(CH
2)
2)；3.65-3.74(m，4H，CON(CH
2)
2)；4.27(s，1H，CH(Ph)
2)；6.76-6.79(d，1H，＝CHCO)；7.14-7.43(m，14H，Ph)；7.60-7.63(d，1H，Ph-CH＝)。
Embodiment 25
(E)-(4-benzhydryl piperazidine-1-yl)-3-(4-acetoxyl group phenyl)-third-2-alkene-1-ketone (WB-14)
(E)-and 3-(4-acetoxyl group phenyl) vinylformic acid (0.824g, 4mmol), methylene dichloride (15ml), sulfur oxychloride (1.5ml), pyridine (1), other are operated with embodiment 21.Get faint yellow solid 1.2g, yield 68.2%, mp175.9-177.2 ℃.ESI-MS(m/z)：441.2(M+H)
+；
1HNMR(δ，ppm，CDCl
3)：2.29(s，3H，CH
3COO)；2.42-2.44(m，4H，N(CH
2)
2)；3.64-3.74(m，4H，CON(CH
2)
2)；4.26(s，1H，CH(Ph)
2)；6.76-6.79(d，1H，＝CHCO)；7.07-7.49(m，14H，Ph)；7.60-7.63(d，1H，Ph-CH＝)。
Embodiment 26
(E)-(4-benzhydryl piperazidine-1-yl)-3-(4-p-methoxy-phenyl)-third-2-alkene-1-ketone (WB-15)
(E)-and 3-(4-p-methoxy-phenyl) vinylformic acid (0.712g, 4mmol), methylene dichloride (15ml), sulfur oxychloride (1.5ml), pyridine (1), other are operated with embodiment 21.Get faint yellow solid 0.9g, yield 54.6%, mp177.1-178.6 ℃.ESI-MS(m/z)：413.2(M+H)
+；
1HNMR(δ，ppm，CDCl
3)：2.42-2.44(m，4H，N(CH
2)
2)；3.64-3.73(m，4H，CON(CH
2)
2)；3.83(s，3H，CH
3O)；4.27(s，1H，CH(Ph)
2)；6.76-6.79(d，1H，＝CHCO)；7.08-7.50(m，14H，Ph)；7.60-7.63(d，1H，Ph-CH＝)。
Embodiment 27
(E)-1-(4-benzhydryl piperazidine-1-yl)-3-(benzo [d] [1,3] dioxole-5-yl)-third-2-alkene-1-ketone (WB-16)
(E)-and 3-(benzo [d] [1,3] dioxole-5-yl) vinylformic acid (0.768g, 4mmol), methylene dichloride (15ml), sulfur oxychloride (1.5ml), pyridine (1), other are operated with embodiment 21.Get faint yellow solid 0.4g, yield 23.5%, mp177.2-180.8 ℃.ESI-MS(m/z)：427.2(M+H)
+；
1HNMR(δ，ppm，CDCl
3)：2.41-2.44(m，4H，N(CH
2)
2)；3.64-3.73(m，4H，CON(CH
2)
2)；4.26(s，1H，CH(Ph)
2)；5.98(s，2H，OCH
2O)；6.63-6.68(d，1H，＝CHCO)；6.77-7.43(m，13H，Ph)；7.54-7.59(d，1H，Ph-CH＝)。
Embodiment 28
(E)-(4-benzhydryl piperazidine-1-yl)-3-(4-chloro-phenyl-)-third-2-alkene-1-ketone (WB-17)
(E)-and 3-(4-chloro-phenyl-) vinylformic acid (0.73g, 4mmol), methylene dichloride (15ml), sulfur oxychloride (1.5ml), pyridine (1), other are operated with embodiment 21.Get faint yellow solid 1.0g, yield 60.0%, mp137.2-139.6 ℃.ESI-MS(m/z)：417.2(M+H)
+；
1HNMR(δ，ppm，CDCl
3)：2.42-2.44(m，4H，N(CH
2)
2)；3.64-3.73(m，4H，CON(CH
2)
2)；4.27(s，1H，CH(Ph)
2)；6.78-6.81(d，1H，＝CHCO)；7.20-7.42(m，14H，Ph)；7.57-7.60(d，1H，Ph-CH＝)。
Embodiment 29
(E)-(4-benzhydryl piperazidine-1-yl)-3-(4-bromophenyl)-third-2-alkene-1-ketone (WB-18)
(E)-and 3-(4-bromophenyl) vinylformic acid (0.908g, 4mmol), methylene dichloride (15ml), sulfur oxychloride (1.5ml), pyridine (1), other are operated with embodiment 21.Get faint yellow solid 0.8g, yield 43.5%, mp145.8-148.4 ℃.ESI-MS(m/z)：461.1(M+H)
+；
1HNMR(δ，ppm，CDCl
3)：2.42-2.44(m，4H，N(CH
2)
2)；3.64-3.74(m，4H，CON(CH
2)
2)；4.27(s，1H，CH(Ph)
2)；6.80-6.83(d，1H，＝CHCO)；7.18-7.48(m，14H，Ph)；7.55-7.58(d，1H，Ph-CH＝)。
Embodiment 30
The target verivate is for the activity data of the provide protection of the PC12 cell injury of glutamate induction among the embodiment.
This mensuration adopts tetrazolium bromide (MTT) colorimetric test method by routine, promptly uses rat suprarenal gland pheochromocyte tumor cell strain (PC12 cell), to contain the DMEM substratum of 10% calf serum, at 37 ℃ of 5%CO
2Cultivate in the incubator.Passage cell is observed passage cell under inverted microscope every other day.When the even adherent growth of cell, grow at 80% to 90% o'clock, behind tryptic digestion 1～2min of 0.25%; The high sugared DMEM substratum adjustment cell density that use contains 10% calf serum is 1 * 105/mL; Be seeded in 96 (24) well culture plates, every hole 100 (400) μ L are in 37 ℃ of 5%CO
2Cultivate 24h under the condition.Change with the substratum that contains L-glutamic acid and different pharmaceutical concentration to cell again behind the 24h and continue to cultivate 24h.Cultivate each hole and be divided into 7 groups: comprise that normal group, L-glutamic acid damage model group, Edaravone group and L-glutamic acid add four different concns drug group, every group is repeated 6 holes.Add 5mg/mL MTT 10 μ L/ holes after 24 hours in administration, hatch 4h for 37 ℃, stop cultivating, the careful suction abandoned the liquid in the culture plate, and every hole adds 150 μ L DMSO, and 37 ℃ of vibration 10min fully dissolve hyacinthine formazan crystallization.On ELIASA, measure each hole OD value with the 490nm wavelength.The inhibiting rate of the PC12 cell injury that L-glutamic acid is caused according to the computes medicine:
Inhibiting rate=(OD administration group-OD model group)/(OD control group-OD model group) * 100%.
With the drug level logarithmic value inhibiting rate is done linear regression, get straight-line equation, therefrom obtain the half-inhibition concentration (IC of medicine the PC12 cell injury
50).
Reagent source:
MTT: tetrazolium bromide (Thiazolyl Blue Tetrazolun Bromide), the import of Sigma company;
The PC12 cell: rat suprarenal gland pheochromocyte oncocyte, Shanghai Inst. of Cytobiology, Chinese Academy of Sciences provides;
Above-mentioned experiment shows: part verivate of the present invention has protection active for the PC12 cell injury of glutamate induction, and wherein verivate WB-07, WB-08, WB-13, WB-17 and WB-18 are suitable with the positive control Edaravone.
Claims (2)
1. following compound: (E)-3-(benzo [d] [1,3] dioxole-5-yl)-1-[4-[two-(4-fluorophenyl) methyl] piperazine-1-yl]-third-2-alkene-1-ketone, (E)-[4-[two-(4-fluorophenyl) methyl] piperazine-1-yl]-3-(4-chloro-phenyl-)-third-2-alkene-1-ketone, (E)-(4-benzhydryl piperazidine-1-yl)-3-(4-aminomethyl phenyl)-third-2-alkene-1-ketone, (E)-(4-benzhydryl piperazidine-1-yl)-3-(4-chloro-phenyl-)-third-2-alkene-1-ketone, (E)-(4-benzhydryl piperazidine-1-yl)-3-(4-bromophenyl)-third-2-alkene-1-ketone.
2. the said compound of claim 1 is protected the application in the medicine in preparation to glutamate induction PC12 cell injury.
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| CN103724296B (en) * | 2013-12-12 | 2015-09-02 | 南京医科大学 | Piperazine carbonyl derivative that aryl replaces and its preparation method and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB809760A (en) * | 1956-04-20 | 1959-03-04 | Lab Pharmaceutica Dr C Janssen | Improvements in or relating to pharmacologically active piperazine derivatives and processes for preparing them |
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Non-Patent Citations (3)
| Title |
|---|
| 吴红 等.(E)-1-二苯甲基-4-[3-(3,4-二羟苯基)-2-丙烯基]哌嗪(I)的合成及其SOD样活性测定.《第四军医大学学报》.1998,第19卷(第1期),第101-102页. * |
| 吴红等.(E)-1-二苯甲基-4-[3-(3 4-二羟苯基)-2-丙烯基]哌嗪(I)的合成及其SOD样活性测定.《第四军医大学学报》.1998 |
| 廖新成 等.1-[二-(4-氟苯)甲基]-4-酰基取代哌嗪类衍生物的合成.《化学研究与应用》.2004,第16卷(第4期),第496-498页. * |
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