CN1572295A - 苯并异硒唑酮类化合物抗缺血性心肌损伤的用途 - Google Patents
苯并异硒唑酮类化合物抗缺血性心肌损伤的用途 Download PDFInfo
- Publication number
- CN1572295A CN1572295A CN 03142553 CN03142553A CN1572295A CN 1572295 A CN1572295 A CN 1572295A CN 03142553 CN03142553 CN 03142553 CN 03142553 A CN03142553 A CN 03142553A CN 1572295 A CN1572295 A CN 1572295A
- Authority
- CN
- China
- Prior art keywords
- benzisoselenazol
- pyridyl
- hydroxy
- chloro
- pyrimidinyl
- 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.)
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 97
- 230000000302 ischemic effect Effects 0.000 title claims abstract description 19
- 230000003680 myocardial damage Effects 0.000 title claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 43
- NMHUEKTZORYKHX-UHFFFAOYSA-N 1$l^{4},2-benzoselenazole 1-oxide Chemical class C1=CC=C2[Se](=O)N=CC2=C1 NMHUEKTZORYKHX-UHFFFAOYSA-N 0.000 claims abstract description 5
- -1 benzisoselenazolone compound Chemical class 0.000 claims description 55
- 208000037891 myocardial injury Diseases 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 229940079593 drug Drugs 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical group 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- BZYXYGLNJWVQPG-UHFFFAOYSA-N 1,2-benzoselenazole Chemical compound C1=CC=C2C=N[se]C2=C1 BZYXYGLNJWVQPG-UHFFFAOYSA-N 0.000 claims description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 150000002825 nitriles Chemical class 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- XRQQATCJJLZZMC-UHFFFAOYSA-N 2-(2-phenylpyrazol-3-yl)-1,2-benzoselenazol-3-one Chemical compound [se]1C2=CC=CC=C2C(=O)N1C1=CC=NN1C1=CC=CC=C1 XRQQATCJJLZZMC-UHFFFAOYSA-N 0.000 claims description 4
- UJQSYINAUHEJRE-UHFFFAOYSA-N 2-(6-chloro-2-methylsulfanylpyrimidin-4-yl)-1,2-benzoselenazol-3-one Chemical compound CSC1=NC(Cl)=CC(N2C(C3=CC=CC=C3[se]2)=O)=N1 UJQSYINAUHEJRE-UHFFFAOYSA-N 0.000 claims description 4
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 claims description 4
- UTEZWCFJSDWZKZ-UHFFFAOYSA-N 5-(3-oxo-1,2-benzoselenazol-2-yl)-1h-pyrazole-4-carbonitrile Chemical compound [se]1C2=CC=CC=C2C(=O)N1C1=NNC=C1C#N UTEZWCFJSDWZKZ-UHFFFAOYSA-N 0.000 claims description 4
- DYEFUKCXAQOFHX-UHFFFAOYSA-N Ebselen Chemical compound [se]1C2=CC=CC=C2C(=O)N1C1=CC=CC=C1 DYEFUKCXAQOFHX-UHFFFAOYSA-N 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 125000000468 ketone group Chemical group 0.000 claims description 3
- QCJYZCMYWNEYLT-UHFFFAOYSA-N 2-(1,2,3,4-tetrahydropyridin-2-yl)-1,2-benzoselenazol-3-one Chemical compound [se]1C2=CC=CC=C2C(=O)N1C1CCC=CN1 QCJYZCMYWNEYLT-UHFFFAOYSA-N 0.000 claims description 2
- QIFTXMOZURIDNK-UHFFFAOYSA-N 2-(1,2,3,4-tetrahydroquinolin-8-yl)-1,2-benzoselenazol-3-one Chemical compound C1CCNC2=C1C=CC=C2N1C(=O)C2=CC=CC=C2[se]1 QIFTXMOZURIDNK-UHFFFAOYSA-N 0.000 claims description 2
- UTZGDIZYQZIRLM-UHFFFAOYSA-N 2-(1,2,4-benzotriazin-3-yl)-1,2-benzoselenazol-3-one Chemical compound C1=CC=CC2=NC(N3C(C4=CC=CC=C4[se]3)=O)=NN=C21 UTZGDIZYQZIRLM-UHFFFAOYSA-N 0.000 claims description 2
- HKMSRROQFXQFNX-UHFFFAOYSA-N 2-(1,2,4-triazol-4-yl)-1,2-benzoselenazol-3-one Chemical compound [se]1C2=CC=CC=C2C(=O)N1N1C=NN=C1 HKMSRROQFXQFNX-UHFFFAOYSA-N 0.000 claims description 2
- MZVBGPUVDNCSMM-UHFFFAOYSA-N 2-(1,3,4-thiadiazol-2-yl)-1,2-benzoselenazol-3-one Chemical compound [se]1C2=CC=CC=C2C(=O)N1C1=NN=CS1 MZVBGPUVDNCSMM-UHFFFAOYSA-N 0.000 claims description 2
- TYOHVSZUUIWKBS-UHFFFAOYSA-N 2-(1,3-benzothiazol-2-yl)-1,2-benzoselenazol-3-one Chemical compound C1=CC=C2SC(N3C(C4=CC=CC=C4[se]3)=O)=NC2=C1 TYOHVSZUUIWKBS-UHFFFAOYSA-N 0.000 claims description 2
- UJOWPGFRUZFDTE-UHFFFAOYSA-N 2-(1,3-thiazol-2-yl)-1,2-benzoselenazol-3-one Chemical compound [se]1C2=CC=CC=C2C(=O)N1C1=NC=CS1 UJOWPGFRUZFDTE-UHFFFAOYSA-N 0.000 claims description 2
- JFXOTUMIXMCPRY-UHFFFAOYSA-N 2-(1,3-thiazol-2-yl)-[1,3]dioxolo[4,5-g][1,2]benzoselenazol-3-one Chemical compound [se]1C2=C3OCOC3=CC=C2C(=O)N1C1=NC=CS1 JFXOTUMIXMCPRY-UHFFFAOYSA-N 0.000 claims description 2
- NUHBYJFBYPAGPK-UHFFFAOYSA-N 2-(1-benzothiophen-2-yl)-1,2-benzoselenazol-3-one Chemical compound C1=CC=C2SC(N3C(C4=CC=CC=C4[se]3)=O)=CC2=C1 NUHBYJFBYPAGPK-UHFFFAOYSA-N 0.000 claims description 2
- DLFBTKPNNFJIQZ-UHFFFAOYSA-N 2-(1-benzothiophen-3-yl)-1,2-benzoselenazol-3-one Chemical compound C1=CC=C2C(N3C(C4=CC=CC=C4[se]3)=O)=CSC2=C1 DLFBTKPNNFJIQZ-UHFFFAOYSA-N 0.000 claims description 2
- HBBAHZKZPGHMRK-UHFFFAOYSA-N 2-(1h-benzimidazol-2-yl)-1,2-benzoselenazol-3-one Chemical compound C1=CC=C2NC(N3C(C4=CC=CC=C4[se]3)=O)=NC2=C1 HBBAHZKZPGHMRK-UHFFFAOYSA-N 0.000 claims description 2
- LEECHSSWKAAWPJ-UHFFFAOYSA-N 2-(1h-indazol-5-yl)-1,2-benzoselenazol-3-one Chemical compound C1=C2NN=CC2=CC(N2C(C3=CC=CC=C3[se]2)=O)=C1 LEECHSSWKAAWPJ-UHFFFAOYSA-N 0.000 claims description 2
- SIPJNVFKQZZHTJ-UHFFFAOYSA-N 2-(1h-indazol-7-yl)-1,2-benzoselenazol-3-one Chemical compound [se]1C2=CC=CC=C2C(=O)N1C1=CC=CC2=C1NN=C2 SIPJNVFKQZZHTJ-UHFFFAOYSA-N 0.000 claims description 2
- DUCHSBIVWZIDJP-UHFFFAOYSA-N 2-(1h-indol-5-yl)-1,2-benzoselenazol-3-one Chemical compound C1=C2NC=CC2=CC(N2C(C3=CC=CC=C3[se]2)=O)=C1 DUCHSBIVWZIDJP-UHFFFAOYSA-N 0.000 claims description 2
- WYUUMLWFZIGJGH-UHFFFAOYSA-N 2-(1h-pyrazol-5-yl)-1,2-benzoselenazol-3-one Chemical compound [se]1C2=CC=CC=C2C(=O)N1C=1C=CNN=1 WYUUMLWFZIGJGH-UHFFFAOYSA-N 0.000 claims description 2
- QFGSXCKTZQXDOG-UHFFFAOYSA-N 2-(1h-pyrazolo[3,4-d]pyrimidin-4-yl)-1,2-benzoselenazol-3-one Chemical compound [se]1C2=CC=CC=C2C(=O)N1C1=NC=NC2=C1C=NN2 QFGSXCKTZQXDOG-UHFFFAOYSA-N 0.000 claims description 2
- VUCJVFOABPOLID-UHFFFAOYSA-N 2-(1h-pyridazin-2-yl)-1,2-benzoselenazol-3-one Chemical compound [se]1C2=CC=CC=C2C(=O)N1N1NC=CC=C1 VUCJVFOABPOLID-UHFFFAOYSA-N 0.000 claims description 2
- VSMGVKUAVZWZMR-UHFFFAOYSA-N 2-(2,1,3-benzothiadiazol-4-yl)-1,2-benzoselenazol-3-one Chemical compound C1=CC2=NSN=C2C(N2C(C3=CC=CC=C3[se]2)=O)=C1 VSMGVKUAVZWZMR-UHFFFAOYSA-N 0.000 claims description 2
- OHPACFAVPNBEQW-UHFFFAOYSA-N 2-(2,6-dichloropyridin-3-yl)-1,2-benzoselenazol-3-one Chemical compound ClC1=NC(Cl)=CC=C1N1C(=O)C2=CC=CC=C2[se]1 OHPACFAVPNBEQW-UHFFFAOYSA-N 0.000 claims description 2
- CWOISSFVGQNHQC-UHFFFAOYSA-N 2-(2,6-dimethylpyrimidin-4-yl)-1,2-benzoselenazol-3-one Chemical compound CC1=NC(C)=CC(N2C(C3=CC=CC=C3[se]2)=O)=N1 CWOISSFVGQNHQC-UHFFFAOYSA-N 0.000 claims description 2
- MWUIAOYCSZDSFN-UHFFFAOYSA-N 2-(2-chloro-5-nitropyrimidin-4-yl)-1,2-benzoselenazol-3-one Chemical compound [O-][N+](=O)C1=CN=C(Cl)N=C1N1C(=O)C2=CC=CC=C2[se]1 MWUIAOYCSZDSFN-UHFFFAOYSA-N 0.000 claims description 2
- MJGIIUCYKZBPPH-UHFFFAOYSA-N 2-(2-chloropyridin-3-yl)-1,2-benzoselenazol-3-one Chemical compound ClC1=NC=CC=C1N1C(=O)C2=CC=CC=C2[se]1 MJGIIUCYKZBPPH-UHFFFAOYSA-N 0.000 claims description 2
- YQLGIECPHHHBNB-UHFFFAOYSA-N 2-(2-methyl-1,3-benzothiazol-5-yl)-1,2-benzoselenazol-3-one Chemical compound [se]1C2=CC=CC=C2C(=O)N1C1=CC=C(SC(C)=N2)C2=C1 YQLGIECPHHHBNB-UHFFFAOYSA-N 0.000 claims description 2
- LQSXPACHXDRTJT-UHFFFAOYSA-N 2-(2-methylquinolin-4-yl)-1,2-benzoselenazol-3-one Chemical compound C1=CC=CC2=NC(C)=CC(N3C(C4=CC=CC=C4[se]3)=O)=C21 LQSXPACHXDRTJT-UHFFFAOYSA-N 0.000 claims description 2
- PBUNZSGQIFHFHV-UHFFFAOYSA-N 2-(2-methylsulfanyl-4-oxo-1h-pyrimidin-6-yl)-1,2-benzoselenazol-3-one Chemical compound CSC1=NC(O)=CC(N2C(C3=CC=CC=C3[se]2)=O)=N1 PBUNZSGQIFHFHV-UHFFFAOYSA-N 0.000 claims description 2
- ZIZJMAIAHWCNKO-UHFFFAOYSA-N 2-(2-oxo-1h-pyrimidin-6-yl)-1,2-benzoselenazol-3-one Chemical compound OC1=NC=CC(N2C(C3=CC=CC=C3[se]2)=O)=N1 ZIZJMAIAHWCNKO-UHFFFAOYSA-N 0.000 claims description 2
- DWBCDZRVNDCPBC-UHFFFAOYSA-N 2-(2h-benzotriazol-5-yl)-1,2-benzoselenazol-3-one Chemical compound C1=C2NN=NC2=CC(N2C(C3=CC=CC=C3[se]2)=O)=C1 DWBCDZRVNDCPBC-UHFFFAOYSA-N 0.000 claims description 2
- BEDMCANHCVKVPW-UHFFFAOYSA-N 2-(2h-tetrazol-5-yl)-1,2-benzoselenazol-3-one Chemical compound [se]1C2=CC=CC=C2C(=O)N1C1=NN=NN1 BEDMCANHCVKVPW-UHFFFAOYSA-N 0.000 claims description 2
- HJMXFLRGZPHVNL-UHFFFAOYSA-N 2-(3,5-dichloropyridin-2-yl)-1,2-benzoselenazol-3-one Chemical compound ClC1=CC(Cl)=CN=C1N1C(=O)C2=CC=CC=C2[se]1 HJMXFLRGZPHVNL-UHFFFAOYSA-N 0.000 claims description 2
- BYDOTJMKOMWDQU-UHFFFAOYSA-N 2-(3-hydroxypyridin-2-yl)-1,2-benzoselenazol-3-one Chemical compound OC1=CC=CN=C1N1C(=O)C2=CC=CC=C2[se]1 BYDOTJMKOMWDQU-UHFFFAOYSA-N 0.000 claims description 2
- LNKVUIIPAQVZCI-UHFFFAOYSA-N 2-(3-methyl-1,2-thiazol-5-yl)-1,2-benzoselenazol-3-one Chemical compound S1N=C(C)C=C1N1C(=O)C2=CC=CC=C2[se]1 LNKVUIIPAQVZCI-UHFFFAOYSA-N 0.000 claims description 2
- VHWJXTKTNNNYOA-UHFFFAOYSA-N 2-(3-methylpyridin-2-yl)-1,2-benzoselenazol-3-one Chemical compound CC1=CC=CN=C1N1C(=O)C2=CC=CC=C2[se]1 VHWJXTKTNNNYOA-UHFFFAOYSA-N 0.000 claims description 2
- MUNYIJDUCLDBOG-UHFFFAOYSA-N 2-(3-nitropyridin-2-yl)-1,2-benzoselenazol-3-one Chemical compound [O-][N+](=O)C1=CC=CN=C1N1C(=O)C2=CC=CC=C2[se]1 MUNYIJDUCLDBOG-UHFFFAOYSA-N 0.000 claims description 2
- JJAXINQYYXPXPT-UHFFFAOYSA-N 2-(3-oxo-1,2-benzoselenazol-2-yl)pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1N1C(=O)C2=CC=CC=C2[se]1 JJAXINQYYXPXPT-UHFFFAOYSA-N 0.000 claims description 2
- PHGDUOPFDHTPGV-UHFFFAOYSA-N 2-(3-oxo-2-phenyl-1h-pyrazol-5-yl)-1,2-benzoselenazol-3-one Chemical compound O=C1C=C(N2C(C3=CC=CC=C3[se]2)=O)NN1C1=CC=CC=C1 PHGDUOPFDHTPGV-UHFFFAOYSA-N 0.000 claims description 2
- MJLUQIHSHZJNPE-UHFFFAOYSA-N 2-(3h-1,2,4-triazin-4-yl)-1,2-benzoselenazol-3-one Chemical compound [se]1C2=CC=CC=C2C(=O)N1N1CN=NC=C1 MJLUQIHSHZJNPE-UHFFFAOYSA-N 0.000 claims description 2
- YSTMXINQUMQDPG-UHFFFAOYSA-N 2-(4,5-dihydro-1,3-thiazol-2-yl)-1,2-benzoselenazol-3-one Chemical compound [se]1C2=CC=CC=C2C(=O)N1C1=NCCS1 YSTMXINQUMQDPG-UHFFFAOYSA-N 0.000 claims description 2
- QBEMFSLLRMAIHI-UHFFFAOYSA-N 2-(4,6-dichloropyrimidin-2-yl)-1,2-benzoselenazol-3-one Chemical compound ClC1=CC(Cl)=NC(N2C(C3=CC=CC=C3[se]2)=O)=N1 QBEMFSLLRMAIHI-UHFFFAOYSA-N 0.000 claims description 2
- URUATXXWNDXORB-UHFFFAOYSA-N 2-(4,6-dichloropyrimidin-5-yl)-1,2-benzoselenazol-3-one Chemical compound ClC1=NC=NC(Cl)=C1N1C(=O)C2=CC=CC=C2[se]1 URUATXXWNDXORB-UHFFFAOYSA-N 0.000 claims description 2
- BECRCMAPNKRPHJ-UHFFFAOYSA-N 2-(4,6-dimethylpyridin-2-yl)-1,2-benzoselenazol-3-one Chemical compound CC1=CC(C)=NC(N2C(C3=CC=CC=C3[se]2)=O)=C1 BECRCMAPNKRPHJ-UHFFFAOYSA-N 0.000 claims description 2
- QOCMIPPJICPKNJ-UHFFFAOYSA-N 2-(4,6-dimethylpyrimidin-2-yl)-1,2-benzoselenazol-3-one Chemical compound CC1=CC(C)=NC(N2C(C3=CC=CC=C3[se]2)=O)=N1 QOCMIPPJICPKNJ-UHFFFAOYSA-N 0.000 claims description 2
- HJKZJXRTSHZEEV-UHFFFAOYSA-N 2-(4-chloro-1,3-benzothiazol-2-yl)-1,2-benzoselenazol-3-one Chemical compound [se]1C2=CC=CC=C2C(=O)N1C(S1)=NC2=C1C=CC=C2Cl HJKZJXRTSHZEEV-UHFFFAOYSA-N 0.000 claims description 2
- YPDWLLRSJQQVGL-UHFFFAOYSA-N 2-(4-chloro-1-nitro-2h-pyrimidin-2-yl)-1,2-benzoselenazol-3-one Chemical compound [O-][N+](=O)N1C=CC(Cl)=NC1N1C(=O)C(C=CC=C2)=C2[se]1 YPDWLLRSJQQVGL-UHFFFAOYSA-N 0.000 claims description 2
- GACPDXPRNSORRE-UHFFFAOYSA-N 2-(4-chloro-6-methylpyrimidin-2-yl)-1,2-benzoselenazol-3-one Chemical compound CC1=CC(Cl)=NC(N2C(C3=CC=CC=C3[se]2)=O)=N1 GACPDXPRNSORRE-UHFFFAOYSA-N 0.000 claims description 2
- LGMWGRQOIDWURW-UHFFFAOYSA-N 2-(4-chloropyridin-2-yl)-1,2-benzoselenazol-3-one Chemical compound ClC1=CC=NC(N2C(C3=CC=CC=C3[se]2)=O)=C1 LGMWGRQOIDWURW-UHFFFAOYSA-N 0.000 claims description 2
- BNXZYDNOVBJOLP-UHFFFAOYSA-N 2-(4-hydroxy-6-oxo-1h-pyrimidin-2-yl)-1,2-benzoselenazol-3-one Chemical compound OC1=CC(O)=NC(N2C(C3=CC=CC=C3[se]2)=O)=N1 BNXZYDNOVBJOLP-UHFFFAOYSA-N 0.000 claims description 2
- PDGKAOVONCBKPY-UHFFFAOYSA-N 2-(4-methoxy-1,3-benzothiazol-2-yl)-1,2-benzoselenazol-3-one Chemical compound [se]1C2=CC=CC=C2C(=O)N1C(S1)=NC2=C1C=CC=C2OC PDGKAOVONCBKPY-UHFFFAOYSA-N 0.000 claims description 2
- MNCHMRKWKNMVJP-UHFFFAOYSA-N 2-(4-methyl-1,3-benzothiazol-2-yl)-1,2-benzoselenazol-3-one Chemical compound [se]1C2=CC=CC=C2C(=O)N1C(S1)=NC2=C1C=CC=C2C MNCHMRKWKNMVJP-UHFFFAOYSA-N 0.000 claims description 2
- YZWVMSNZGIIMLK-UHFFFAOYSA-N 2-(4-methyl-1,3-thiazol-2-yl)-1,2-benzoselenazol-3-one Chemical compound CC1=CSC(N2C(C3=CC=CC=C3[se]2)=O)=N1 YZWVMSNZGIIMLK-UHFFFAOYSA-N 0.000 claims description 2
- ZNEBRBIAAFIDME-UHFFFAOYSA-N 2-(4-methylpyridin-2-yl)-1,2-benzoselenazol-3-one Chemical compound CC1=CC=NC(N2C(C3=CC=CC=C3[se]2)=O)=C1 ZNEBRBIAAFIDME-UHFFFAOYSA-N 0.000 claims description 2
- JGRAFAQQZWZJPC-UHFFFAOYSA-N 2-(4-methylpyrimidin-2-yl)-1,2-benzoselenazol-3-one Chemical compound CC1=CC=NC(N2C(C3=CC=CC=C3[se]2)=O)=N1 JGRAFAQQZWZJPC-UHFFFAOYSA-N 0.000 claims description 2
- CJJBMUDMXYGOQN-UHFFFAOYSA-N 2-(5,6-dimethyl-1,2,4-triazin-3-yl)-1,2-benzoselenazol-3-one Chemical compound N1=C(C)C(C)=NN=C1N1C(=O)C2=CC=CC=C2[se]1 CJJBMUDMXYGOQN-UHFFFAOYSA-N 0.000 claims description 2
- HLSWCIANZVDBPW-UHFFFAOYSA-N 2-(5,6-dimethyl-1,3-benzothiazol-2-yl)-1,2-benzoselenazol-3-one Chemical compound [se]1C2=CC=CC=C2C(=O)N1C1=NC(C=C(C(=C2)C)C)=C2S1 HLSWCIANZVDBPW-UHFFFAOYSA-N 0.000 claims description 2
- QBOIPPVCPSDYHU-UHFFFAOYSA-N 2-(5,6-dimethyl-1h-benzimidazol-2-yl)-1,2-benzoselenazol-3-one Chemical compound [se]1C2=CC=CC=C2C(=O)N1C1=NC(C=C(C(=C2)C)C)=C2N1 QBOIPPVCPSDYHU-UHFFFAOYSA-N 0.000 claims description 2
- OYQWALYJAWAGRI-UHFFFAOYSA-N 2-(5,6-diphenyl-1,2,4-triazin-3-yl)-1,2-benzoselenazol-3-one Chemical compound [se]1C2=CC=CC=C2C(=O)N1C(N=C1C=2C=CC=CC=2)=NN=C1C1=CC=CC=C1 OYQWALYJAWAGRI-UHFFFAOYSA-N 0.000 claims description 2
- YCYVYYPVBVOATN-UHFFFAOYSA-N 2-(5-chloro-1,3-thiazol-2-yl)-1,2-benzoselenazol-3-one Chemical compound S1C(Cl)=CN=C1N1C(=O)C2=CC=CC=C2[se]1 YCYVYYPVBVOATN-UHFFFAOYSA-N 0.000 claims description 2
- RKBHGKBYLVOVTH-UHFFFAOYSA-N 2-(5-chloropyridin-2-yl)-1,2-benzoselenazol-3-one Chemical compound N1=CC(Cl)=CC=C1N1C(=O)C2=CC=CC=C2[se]1 RKBHGKBYLVOVTH-UHFFFAOYSA-N 0.000 claims description 2
- FBZFZGGZPFCBII-UHFFFAOYSA-N 2-(5-ethoxy-2-ethylsulfanylpyrimidin-4-yl)-1,2-benzoselenazol-3-one Chemical compound CCOC1=CN=C(SCC)N=C1N1C(=O)C2=CC=CC=C2[se]1 FBZFZGGZPFCBII-UHFFFAOYSA-N 0.000 claims description 2
- BCUSWJZUTWODGS-UHFFFAOYSA-N 2-(5-methyl-1,3,4-thiadiazol-2-yl)-1,2-benzoselenazol-3-one Chemical compound S1C(C)=NN=C1N1C(=O)C2=CC=CC=C2[se]1 BCUSWJZUTWODGS-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
本发明公开了苯并异硒唑酮类化合物,尤其是如通式(I)所示的化合物作为抗缺血性心肌损伤药物的用途。这类化合物的特点是选择性抑制心肌Na/Ca交换,扩张冠脉,减少心肌耗氧量,具有活性高,特异性强,毒性低的优点。
Description
技术领域
本发明涉及苯并异硒唑酮化合物药物,尤其是作为抗缺血性心肌损伤药物的用途。
背景技术
随着社会生活水平的提高和人口的老龄化,心血管疾病,特别是缺血性心肌损伤的发病日益增加,已成为影响中老年人生活质量和寿命的重要因素。现今临床应用的扩张血管的硝酸酯类药物,二氢吡啶类钙通道拮抗剂以及β-肾上腺能阻滞剂等均伴随有不良反应,临床应用的选择余地小。
钠—钙交换是可兴奋细胞膜上一类重要离子交换系统,其主要功能是越过Na+-Ca2+交换,将细胞内的钙排出,使胞内钙回复到静息状态水平。在排出一个Ca2+同时,转入细胞内三个Na,因此有一个净电荷的跨膜移动,产生跨膜电流。钠—钙交换是个双向过程,心肌细胞缺血再灌注初期,心肌细胞膜损伤导致膜电位异常,膜的通透性改变,使大量Na+进入细胞,此时Na+-Ca2+交换的反向转运被激活。在排出过多的Na+,引起细胞内Ca2+超载,从而加重了心肌细胞的损伤和死亡。上述的反向转运,在病理状态下,会引起严重的不良后果。因而Na+-Ca2+交换反向转运被认为是缺血/再灌引起严重不良后果的重要机制。国内外至今尚无特异性阻断Na+-Ca2+交换反向转运的药物。
美国专利4711961公开了苯并异硒唑酮类化合物的制备方法,和预测了这类化合物在预防和治疗各种感染疾病,刺激免疫系统,硒缺乏疾病,动脉硬化,类风湿性疾病,特别是关节炎的用途,但没有给出实验或运用方面的证据。苯并异硒唑酮是一组模拟谷胱甘肽过氧化物还原酶的合成化合物,有代表性的依布硒啉(Ebselen)具有抗炎作用,并于临床上用作治疗蛛网膜下出血药物,但未见关于阻止Na+-Ca2+交换系统的报道。也未见关于心肌缺血的保护作用。
发明内容
为了填补现有技术的空白,本发明的目的在于提供苯并异硒唑酮化合物或含有它的药物组合物在预防和/或治疗缺血性心肌损伤的用途。
本发明另一方面提供了一种药物组合物,其包括作为活性成份的苯并异硒唑酮化合物及制药领域中常用的载体。
本发明再一方面提供了一种苯并异硒唑酮化合物及其组合物作为抗缺血性心肌损伤药物的应用。
本发明再一方面提供了一种预防和/或治疗缺血性心肌损伤的方法,其包括将苯并异硒唑酮或含有它的药物组合物给药于需预防和/或治疗的宿主。
Na+-Ca2+交换蛋白是可兴奋细胞膜上一种重要的双向离子转运蛋白,它的主要功能是排出细胞兴奋过程中进入细胞内的Ca2+,使细胞内Ca2+恢复到静息状态水平。在每排出1个Ca2+的同时,转入细胞内3个Na+,因此有一个净电荷的跨膜移动,产生跨膜电流,是内向的电流。心肌缺血再灌的初期,细胞膜的损伤导致膜电位异常,膜通透性改变,使大量的Na+进入细胞。此时Na+-Ca2+交换反向转运被激活,在向外排出3个Na+的同时向细胞内转入1个Ca2+,引起细胞内Ca2+超载,从而加重细胞的损伤及死亡。因而Na+-Ca2+交换反向转运被认为是缺血/再灌引起严重不良后果的重要机制。
钠-钙交换系统作为跨膜蛋白,是药物作用的重要靶点,迄今尚未见到作用于该蛋白的心肌保护药物的报道。因此,创制对钠—钙交换系统具有特异性阻断作用的药物对治疗缺血性心肌损伤(冠心病),保护心脏具有重要的临床价值。
本发明研究发现苯并异硒唑酮类化合物对Na+-Ca2+交换具有明显的阻滞作用。本发明的化合物是作用于钠—钙交换系统的新型抗缺血性心肌损伤的化合物。
细胞水平的实验结果表明,本发明化合物和Amiloride、KB-R7943相比较,对Na/Ca交换的靶点更加专一,选择性高。通过实验比较了Amiloride、KB-R7943及本发明化合物对Na+-Ca2+交换电流的作用。研究发现Amiloride在低浓度时对内、外向电流几乎没有作用,高浓度是对外向INa-Ca的抑制作用更明显;KB-R7943在双向离子条件下对内、外向INa-Ca无选择性,在阻断外向电流的同时,对内向电流也有抑制,而影响正常的排Ca2+功能;而本发明化合物抑制作用最强,而且选择性作用于外向电流,对外向INa-Ca的抑制作用明显强于其对内向INa-Ca的抑制作用,有利于抑制缺血/再灌时的钙超载和由此造成的心肌损伤。本发明的化合物均有一定的抑制Na/Ca交换反向转运的作用,抑制率40%以上的为作用较强化合物,作用最强着接近60%。
本发明人不仅在细胞水平的病理模型上说明了本发明化合物的抑制Na/Ca交换反向转运的作用,还在相应的离体、整体实验上验证本发明的化合物的抗心肌缺血损伤作用。
本发明在前期电生理细胞模型筛选的基础上,经对Na/Ca交换反向转运产生的外向电流的抑制率的比较,进一步进行了离体实验,实验采用大鼠离体心脏缺血再灌注(I/R)损伤模型。以心律失常的持续时间,室早,室速和室颤的发生率作为心肌损伤的指标,观察化合物的心肌保护作用。发现本发明化合物有显著心肌保护作用。
大鼠静脉注射本发明化合物对心肌保护作用。发明本发明化合物可显著性延长缺血-再灌注心律失常的潜伏期,降低VT和VF的发生率,缩短VT和VF的持续时间。说明大鼠静脉注射上述化合物,对冠状动脉缺血再灌注损伤有明显的保护作用。以心脏损伤后出现心律失常的程度作为评价指标。同样,大鼠口服给药的对心肌缺血保护作用。灌胃本发明的化合物后60min时结扎冠状动脉左前降支造成心脏缺血,15min后实现再灌注。本发明化合物可显著性缩短缺血-再灌注心律失常(P<0.01)的持续时间,降低VT(P<0.01)和VF(P<0.05)的发生率,缩短VT(P<0.01)和VF(P<0.05)的持续时间。本发明化合物,对冠状动脉缺血再灌注损伤有明显的保护作用。
本发明化合物具有明显改善犬急性心肌缺血和心肌梗塞的作用,减轻由心外膜电图标测的心肌缺血程度(∑-ST),降低心肌缺血范围(N-ST),减小经N-BT染色所显示的梗塞区。本发明和化合物有明显减轻心肌缺血程度(∑-ST)的作用,∑-ST在给药后180min和给药前相比下降了53.90±20.60%,与药前及对照组比较均有显著性差异(P<0.01)。心外膜电图(EEG)标测的实验结果表明,本发明化合物对实验性急性犬心肌缺血有明显的改善作用,可显著减轻心肌缺血程度(∑-ST),减小心肌缺血范围(N-ST)。本发明化合物能减少犬急性心肌梗塞范围。以定量组织学N-BT染色法显示,给予本发明化合物后明显缩少动物心肌梗塞区面积,较空白对照组降低了69.18%和67.94%,与对照组比较均有显著性差异(P<0.001)。本发明化合物能明显抑制CK、AST活性升高的作用,而对LDH活性的影响与对照组无明显差异。
本发明化合物有扩张冠状动脉血管的作用,有显著增加缺血和心肌梗塞时心脏冠脉血流量的作用,可扩张冠脉血管,促进侧支循环的开放,改善缺血心肌的供血。本发明药后30min冠脉血流量增加明显,比药前增加了15.02±22.16%,与对照组组比较,有明显差异(P<0.05)。本发明化合物药后能增加静脉血氧含量明显增加,与药前比较差异明显(P<0.05)。实验结果表明,本发明化合物可明显改善犬急性心肌缺血和心肌梗塞的病理表现,减轻心肌缺血程度,减小心肌梗塞面积;同时可扩张冠脉血管,增加冠脉血流量;并可抑制CK活性升高及AST的释放。以上结果与该化合物的药理学作用机理相吻合,即选择性阻断Na/Ca交换的反向转运,及由此引起的心肌缺血损伤和扩张冠状动脉,改善心脏供血状况。
本发明化合物对正常大鼠心功能和血流动力学无影响。实验结果表明本发明化合物对正常麻醉大鼠左心室收缩压(LVSP)、左心室舒张末压(LVEDP)、左心室等容期压力最大变化速率(±dp/dtmax)、动脉收缩压(SP)、动脉舒张压(DP)、平均动脉压(MAP)、心率(HR)均无明显影响。本发明化合物的各项指标同溶剂对照组相比无明显差异,经检验无统计学差异。
本发明化合物有改善大鼠缺血心脏的心功能和血流动力学的作用。本发明化合物使心脏缺血/再灌大鼠的LVSP基本保持平稳;模型对照组则波动较大。模型对照组LVEDP在再灌10min后急速上升,表明左心室舒张不全,舒张功能严重受损,本发明化合物组的LVEDP则基本保持正常,提示本发明化合物对心肌舒张功能的保护作用较强。本发明化合物组对心脏+dp/dtmax降低不明显,模型对照组降低较多,比本发明化合物组低54%,说明给药组的心肌收缩性能受损较小。-dp/dtmax是心肌舒张参数,是评价心室舒张功能的重要指标之一。接扎后,给药组的每一个时相点与对照组比较都有显著性差异。本发明化合物使心肌收缩性能下降的同时,舒张功能保持较好。由于本发明化合物能保护心脏功能,所以能维持较稳定的血压,模型对照组心肌受损严重,血压降低较多,波动也较大。大鼠心肌缺血/再灌后心率下降,本发明化合物对大鼠心率无影响,两组没有显著性差异。大鼠心肌缺血/再灌时心功能受损,表现为心脏收缩功能舒张功能降低,血压降低或波动较大,本发明化合物对大鼠的心功能有保护作用,尤其以心脏舒张功能的改善为显著,基本维持在正常范围内,且大鼠血压维持也较稳定,而本发明对心肌受损后心率下降无影响。
毒理学实验说明本发明化合物没有致突变作用、安全性高、毒性低。在Ames(致突变)实验中,采用不同的菌株,在不同的浓度下,本发明化合物的实验结果均为阴性。在急性毒性实验中,本发明化合物的各剂量组均未见动物死亡,半数致死量LD50>5g/kg。
本发明的苯并异硒唑化合物,包括但不限定于,如通式(I)所示的化合物
其中,R1选自氢原子,卤素,C1-C4的直链或支链烷基,C1-C4的直链或支链烷氧基,羟基,三氟甲基,硝基,二-(C1-C4烷基)-胺基,R1可以是亚甲二氧基氢,R1的取代位置是在苯并异硒唑中苯环的3-、4-、5-或6-位的任意位置;
R2是C0-C4的饱和或不饱和的链烃(当C0是R2表示一个连接R3和N的键),优选是C0-C2的饱和或不饱和的链烃,更优选是C0-C1的饱和或不饱和的链烃,最优选是C0即R3和N直接相连。
R3表示取代或非取代、饱和或不饱和的苯环基、杂环基;杂环基优选含有1到4个杂原子,更优选含有1到2个杂原子,杂原子选自氧原子、氮原子、硫原子;更优选的R3选自苯基,硫苯基,噻唑基,异噻唑基,咪唑基,吡唑基,噻二唑基,吡啶基,嘧啶基,吡嗪基,哒嗪基,苯并噻唑基,苯并咪唑基,苯并三唑基,三嗪基,三唑基,四唑基,喹啉基,异喹啉基,吲哚基,吲唑基,卡巴唑基,呋喃基;最优选的R3选自苯基、吡啶基;
杂环基可以是单取代,或二取代的,取代基可以相同或不同的,取代基选自卤素,C1-C4的直链或支链烷基,C1-C4的直链或支链烷氧基,C1-C4的直链或支链烷硫基,C1-C4的直链或支链的酮基,C1-C4的直链或支链卤烷基,羟基,硫基,硝基,腈基,羧基,烷氧羰基;
杂环上优选的取代基选自卤素,C1-C4的直链或支链烷基,C1-C4的直链或支链烷氧基,C1-C4的直链或支链烷硫基,C1-C4的直链或支链卤烷基,C1-C4的直链或支链的酮基,羟基,硫基,硝基,腈基,羧基,烷氧羰基;
杂环上的更优选取代基选自,氟,氯,溴,甲基,乙基,丁基,甲氧基,乙氧基,甲基硫基,乙基硫基,三氟甲基,羟基,硫基,,硝基,,腈基,羧基,烷氧羰基;
杂环上的最优选取代基选自,氟,氯,溴,甲基,甲氧基,乙氧基,甲基硫基,羟基,硫基,硝基,羧基、甲氧基羰基、乙氧基羰基。最优选的化合物选自:
2-苯基-1,2-苯并异硒唑-3(2H)-酮,
4-氟-2-苯基-1,2-苯并异硒唑-3(2H)-酮,
5-氟-2-苯基-1,2-苯并异硒唑-3(2H)-酮,
6-氟-2-苯基-1,2-苯并异硒唑-3(2H)-酮,
7-氟-2-苯基-1,2-苯并异硒唑-3(2H)-酮,
4-氯-2-苯基-1,2-苯并异硒唑-3(2H)-酮,
5-氯-2-苯基-1,2-苯并异硒唑-3(2H)-酮,
6-氯-2-苯基-1,2-苯并异硒唑-3(2H)-酮,
7-氯-2-苯基-1,2-苯并异硒唑-3(2H)-酮,
4-羟基-2-苯基-1,2-苯并异硒唑-3(2H)-酮,
5-羟基-2-苯基-1,2-苯并异硒唑-3(2H)-酮,
6-羟基-2-苯基-1,2-苯并异硒唑-3(2H)-酮,
7-羟基-2-苯基-1,2-苯并异硒唑-3(2H)-酮,
2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
4-氯-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
4-氯-2-(3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
4-氯-2-(4-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
5-氯-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
5-氯-2-(3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
5-氯-2-(4-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
6-氯-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
6-氯-2-(3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
6-氯-2-(4-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
7-氯-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
7-氯-2-(3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
7-氯-2-(4-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
4-氟-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
4-氟-2-(3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
4-氟-2-(4-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
5-氟-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
5-氟-2-(3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
5-氟-2-(4-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
6-氟-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
6-氟-2-(3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮
6-氟-2-(4-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
7-氟-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
7-氟-2-(3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
7-氟-2-(4-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
4-羟基-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
4-羟基-2-(3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
4-羟基-2-(4-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
5-羟基-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
5-羟基-2-(3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
5-羟基-2-(4-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
6-羟基-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
6-羟基-2-(3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
6-羟基-2-(4-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
7-羟基-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
7-羟基-2-(3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
7-羟基-2-(4-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(3-羟基-2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-氯-3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-氯-2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-甲氧基-3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2,6-二氯-3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4,6-二甲基-2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-羟基-2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(3-硝基-2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-硝基-2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
6-甲基-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
6-甲氧基-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
5-硝基-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
7-甲氧基-2-(2-吡啶基)-1,2--苯并异硒唑-3(2H)-酮,
6,7-亚甲二氧基-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(3-甲基-2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-甲基-2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-甲基-2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-甲基-2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(3,5-二氯-2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-氯-2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-羧基-5-氯-2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(3-羧基-2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-四氢吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(苯并噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-甲基-2-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-硝基-2-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4,6-二甲基-2-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
(2,6-二甲基-4-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-乙氧基-2-乙基硫基-4-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-乙氧基羰基-2-羟基-4-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮
2-(5-羧基-4-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-氯-2-甲基硫基-4-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-氯-2-甲基硫基-6-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-氯-6-甲基-2-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-氯-3-硝基-2-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-氯-5-硝基-4-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4,6-二氯-2-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4,6-二氯-5-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4,6-二羟基-2-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2,6-二羟基-4-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2,4-二羟基-5-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4,6-二硫基-2-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-羟基-2-硫基-4-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-羟基-2-甲基硫基-4-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-羟基-6-甲基-2-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-羟基-5-甲基-4-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(1-苯并吡唑基并(3,4-d)嘧啶-4-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(吡唑并(3,4-d)嘧啶-4-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-羟基吡唑并(3,4-d)嘧啶-4-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-硫基吡唑并(3,4-d)嘧啶-4-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-羟基-4-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-氯-2-苯并噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-甲氧基-2-苯并噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-甲氧基-2-苯并噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-甲基-2-苯并噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-甲基-5-苯并噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-硝基-2-苯并噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-溴-2-苯并噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5,6-二甲基-2-苯并噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-乙氧基-2-苯并噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
6-甲基-2-(2-噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
6-氯-2-(2-噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
6-甲氧基-2-(2-噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
5-硝基-2-(2-噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
5-氯-2-(2-噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
7-甲氧基-2-(2-噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
6,7-亚甲二氧基-2-(2-噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-甲基-2-噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-硝基-2-噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-噻唑啉基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-氯-2-噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(3-甲基-5-异噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-咪唑基)-1,2-苯并异硒唑-3(2H)酮,
2-(5-乙氧基羰基-2-咪唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(3-吡唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-氰基-5-吡唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-乙氧基羰基-3-吡唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-乙氧基羰基-2-苯基-3-吡唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-氰基-3-吡唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-苯基-3-吡唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(1-苯基-5-吡唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(1-苯基-5-吡唑啉酮-3-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-羟基-3-吡唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(1,3,4-噻二唑-2-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-硫基-1,3,4-噻二唑-2-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-甲基-1,3,4-噻二唑-2-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-三氟甲基-1,3,4-噻二唑-2-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-叔丁基-1,3,4-噻二唑-2-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-吡嗪基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-羧基-3-吡嗪基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-哒嗪基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-苯并咪唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5,6-二甲基-2-苯并咪唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-苯并三唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(7-氯-1,2,4-苯并三嗪-3-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(1,2,4-苯并三嗪-3-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(7-溴-1,2,4-苯并三嗪-3-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(7-氟-1,2,4-苯并三嗪-3-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(7-硝基-1,2,4-苯并三嗪-3-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-苯并噻吩基)-1,2-苯并异硒唑-3(2H)-酮,
2-(3-苯并噻吩基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-噻吩基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2,1,3-苯并噻二唑-4-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(1,2,4-三嗪-4-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2,6-二硫基-1,3,5-三嗪-4-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5,6-二甲基-1,2,4-三嗪-3-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5,6-二苯基-1,2,4-三嗪-3-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(1,2,4-三唑-4-基)-1,2-苯并异硒唑-3(2H)-酮,
2(5-硫基-1,2,4-三唑-3-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-四唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-喹啉基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-甲基-4-喹啉基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-硝基-5-喹啉基)-1,2-苯并异硒唑-3(2H)-酮,
2-(1,2,3,4-四氢喹啉-8-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-喹啉基)-1,2-苯并异硒唑-3(2H)-酮,
2-(3-喹啉基)-1,2-苯并异硒唑-3(2H)-酮,
2-(8-喹啉基)-1,2-苯并异硒唑-3(2H)-酮,
2(6-甲氧基-8-喹啉基)-1,2-苯并异硒唑-3(2H)-酮,
2-(1-异喹啉基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-异喹啉基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-吲哚基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-异吲哚)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-吲唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-氯-3-吲唑基)-1,2-苯并异硒唑-3(2H)-酮
2-(6-吲唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(7-吲唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(9-乙基-3-卡巴唑)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-3,4-二氢咪唑基-2-乙烯基)-1,2-苯并异硒唑-3(2H)-酮
2-(2-吡啶基甲基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-呋喃基甲基)-1,2-苯并异硒唑-3(2H)-酮,
2-[4-(2-羟亚氨基乙基)]-1,2-苯并异硒唑-3(2H)-酮
2-[4-(7-正丁基苯并(1,2-c二氢呋喃-2-酮))]-1,2-苯并异硒唑-3(2H)-酮。
本发明因此还涉及含有作为活性成份的有效剂量的至少一种通式(I)化合物和/或其立体异构体以及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0.1-90重量%的通式(I)化合物和/或其生理上可接受的盐。
药物组合物可根据本领域已知的方法制备。用于此目的时,如果需要,可将通式(I)化合物和/或立体异构体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。
本发明的通式(I)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、静脉、肌肉、皮下、鼻腔、口腔粘膜、皮肤、腹膜或直肠等。给药剂型例如片剂、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,可以是普通制剂、缓释制剂、控释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。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。为了将给药单元制成栓剂,可以广泛使用本领域公知的各种载体。关于载体的例子是,例如聚乙二醇、卵磷脂、可可脂、高级醇、高级醇的酯、明胶、半合成甘油酯等。为了将给药单元制成胶囊,将有效成分通式(I)化合物或其立体异构体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。也可将有效成分通式(I)化合物或其立体异构体制成微囊剂,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。为了将给药单元制成注射用制剂,如溶液剂、乳剂、冻干粉针剂和混悬剂,可以使用本领域常用的所有稀释剂,例如,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。
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。
本发明通式(I)化合物或其立体异构体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、体重及个体反应,所用的具体化合物,给药途径及给药次数等。通常对体重约75公斤患者,所给通式(I)化合物的日剂量为0.001mg/kg体重-100mg/kg体重,优选0.01mg/kg体重-20mg/kg体重,更优选是0.1mg/kg体重-5mg/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。
附图说明
图1.Amiloride对豚鼠心室肌细胞正反向Na+-Ca2+交换电流的作用
图2.KB-R7943对豚鼠心室肌细胞正反向Na+-Ca2+交换电流的作用
图3.IMM-001对豚鼠心室肌细胞正反向Na+-Ca2+交换电流的作用
图4.各给药组犬急性心肌缺血程度(∑-ST)的比较,心外膜电图标测。
图5.各给药组对犬急性心肌梗塞范围的影响
图6.各给药组犬血清肌酸激酶(CK)的比较
图7.各给药组犬乳酸脱氢酶(LDH)的比较
图8.各给药组犬血清谷草转氨酶(AST)变化的比较
图9.各给药组犬冠脉血流量变化比较
图10.各给药组犬静脉血氧含量变化比较
图11.IMM-004对大鼠心肌缺血/再灌左心室收缩压(LVSP)的影响
图12.IMM-004对大鼠心肌缺血/再灌左心室舒张末压(LVEDP)的影响
图13.IMM-004对大鼠心肌缺血/再灌动脉收缩压(SBP)的影响
图14.IMM-004对大鼠心肌缺血/再灌左心室等容期压力最大变化速率(±dp/dtmax)的影响
图15.IMM-004对大鼠心肌缺血/再灌平均动脉压(MAP)的影响
具体实施方式
下面的实施例及制备例用来进一步说明本发明,但这并不意味着对本发明的任何限制。
实施例化合物编号
Na+-Ca2+交换蛋白是可兴奋细胞膜上一种重要的双向离子转运蛋白,它的主要功能是排出细胞兴奋过程中进入细胞内的Ca2+,使细胞内Ca2+恢复到静息状态水平。在每排出1个Ca2+的同时,转入细胞内3个Na+,因此有一个净电荷的跨膜移动,产生跨膜电流。心肌缺血再灌的初期,细胞膜的损伤导致膜电位异常,膜通透性改变,使大量的Na+进入细胞,此时Na+-Ca2+交换反向转运被激活,引起细胞内Ca2+超载,从而加重细胞的损伤及死亡。因而Na+-Ca2+交换反向转运被认为是缺血/再灌引起严重不良后果的重要机制。国内外至今尚无特异性阻断Na+-Ca2+交换反向转运的药物。我们采用细胞水平的病理模型所进行的新药筛选工作及相应的离体、整体实验研究,为确定先导化合物,研制开发作用于Na+-Ca2+交换这一潜在的、重要的药物作用靶点的细胞保护药物,提供了重要的理论和实际指导。
1.Na/Ca交换双向转运电流测定方法的建立
由于Na+-Ca2+交换反向转运是造成缺血再灌损伤的主要原因之一,因而建立Na+-Ca2+交换反向转运的细胞模型对研制缺血损伤保护药物有重要意义。我们借助微电极向细胞内透析Na+的方法,成功建立了Na+-Ca2+交换反向转运模型,并用膜片钳方法稳定记录了这一电流。
在电极内灌注一定浓度的NaCl,形成膜片钳全细胞记录后电极内液与细胞内液发生离子交换,电极内液中的Na+进入细胞内,使胞内形成高Na+状态。将细胞钳制在-40mV,先去极化至+60mV,再给以持续2s速度为80mV·s-1的斜坡刺激,复极化至-100mV,频率为0.05Hz。在该刺激条件下,用双向离子条件台氏液(即可同时记录内、外向电流的离子条件)灌流,同时为了减少其他电流成分的干扰,实验时,台式液中加入:BaCl2 1mmol·L-1和CsCl 2mmol·L-1阻断钾通道,verapamil 1μmol·L-1阻断L-型钙通道,ouabain 20μmol·L-1阻断Na+-K+ATP酶。并在电极内液中加20mmol·L-1的TEA阻断钾通道。记录到一个由外向到内向的电流,在其它时间依赖性的电流都被阻断的情况下,记录到的电流几乎呈线性。随着胞内Na+的进一步增加和时间的延长,可进一步激活Na+-Ca2+交换的反向转运,使该电流的外向成份显著增加。我们用不同浓度的Na+,即0,15,25和35mmol·L-1进行比较,最后选择了25mmol·L-1NaCl进行透析,作为该模型的固定方法。在该条件下,细胞破膜后约3min,可使反向转运电流达到最大,持续记录8min,未观察到明显的“衰减”(run-down)现象。此时运用5mmol·L-1 Ni2+可显著抑制该电流的外向成分和内向成分,用Ni2+前后记录到的两条电流-电压曲线相减,得到单纯的对Ni2+敏感的电流即生电性Na+-Ca2+交换电流(INa-Ca)。INa-Ca的反转电位在-20mV左右。
用上述电生理模型对我所合成化合物进行筛选。发现新化合物IMM-001可选择性阻断Na+超载引起的Na+-Ca2+交换反向转运。与常用的Na+-Ca2+交换阻断剂Amiloride比较,作用明显强于后者,Amiloride从10-5mol·L-1开始起效,10-4mol·L-1出现明显作用,而IMM-00110-7至10-5mol·L-1均有非常明显的作用。
1996年,有报道一种新合成的Isothiourea衍生物KB-R7943对Na+-Ca2+交换有选择性抑制作用,且抑制作用明显。自此,KB-R7943一直被认为是最新的高效特异的Na+-Ca2+交换反向转运抑制剂而广泛用于药理学研究。但在他们的实验中,均人为地控制离子条件,使仅能选择性地记录到内、外向电流中的一种成分,这种单向离子条件,不符合生理、病理条件下,同时出现内、外向INa-Ca,即所谓双向离子条件的实际情况。我们用前述模型观察比较了KB-R7943对INa-Ca的抑制作用,发现KB-R7943在抑制Na+-Ca2+交换反向转运的同时,还抑制Na+-Ca2+交换的正向转运,选择性差。
据此,确定以IMM-001为母核,开发研制特异性更强,选择性更高的Na+-Ca2+交换反向转运抑制剂。
2.具体步骤:
2.1单个豚鼠心室肌细胞的制备
雄性豚鼠,体重250~280g,由中国医学科学院动物中心提供,击昏、颈动脉放血后,迅速开胸,取出心脏,在4℃无钙液(Ca2+-freesolution)中去除脂肪组织和心包膜,进行Langendorff灌流。具体过程:首先用无钙液经主动脉逆行灌流6min,使心脏内的残血彻底排尽,心脏膨大,呈粉红色时再用含有链霉蛋白酶E(pronase E)0.1mg/ml,脱脂牛血清白蛋白(BSA)0.5mg/ml,Ca2+浓度为150μM的无钙液(酶液)灌流2~3min,至心脏完全膨大松软后停止灌流。去除心房,将心室肌剪碎,用酶液37℃温孵搅拌5~10min,倒出上清液,用无钙液稀释5倍,其中含有BSA 0.5mg/ml,Ca2+浓度为1.8mM,室温下(20~24℃)静置1h后开始实验。在整个灌流过程中,压力维持在70cm水柱,37℃恒温,持续通95%的O2和5%的CO2混合气。
2.2膜片钳全细胞记录
选取杆状、横纹清晰、膜良好的细胞进行实验。细胞池体积约1ml,平放在连有微操纵器(MO-303)的倒置显微镜(Olympus IMT-2)上,细胞充分贴壁后,用台氏液(Tyrode’s solution)灌流,速度约为1~2ml/min。电极用玻璃毛细管(中科院上海脑所)经微电极拉制仪(PP-83)分两步拉制,充灌电极液后电阻为2~4MΩ。膜片钳全细胞记录过程中,刺激脉冲的产生和信号采集均由pCLAMP5.5.1软件(Axon Instrument)完成,离子通道电流通过膜片钳放大器(L/MEPC-7)放大,经AD/DA转换板(Axon TL-1)输入计算机。
记录Na+-Ca2+交换电流(INa-Ca)时,细胞钳制在-40mV,给予从+60mV复极化至-100mV、速度为80mV/s持续2s的反向斜坡脉冲(declining ramp pulse),刺激频率为0.05Hz。由于刺激形式是缓慢复极化的斜坡脉冲,因此细胞膜电容和串联电阻无需补偿。同时,为了减少其它电流成分的干扰,实验时台氏液中加入:ouabain 20μM以阻断生电性Na+-K+·ATP酶;BaCl2 1mM和CsCl 2mM阻断钾离子通道电流;verapamil 1μM阻断L型钙电流;电极内液中20mM的TEA也可以阻断钾离子通道电流。电极内液中高浓度的EGTA(42mM)和CaCl2(29mM)根据Fabiato & Fabiato公式计算得胞内游离Ca2+浓度为153nM。生电性的双向Na+-Ca2+交换电流可被细胞外高浓度的Ni2+(2或5mM)特异性阻断,用Ni2+前后的电流相减所得的电流曲线即Na+-Ca2+交换电流(INa-Ca)。为了排除因细胞体积大小不同而对电流值造成的影响,我们用电流密度(pA/pF)来表示电流值的大小,所有实验均在31℃~32℃之间进行。
2.3药品配置
无钙液(Ca2+-free solution)成分(mM):NaCl 90,KCl 10,KH2PO4 1.2,MgSO4 5,NaHCO3 15,taurine 30,glucose 20,用1N的NaOH调pH值至7.4
正常台氏液(normal Tyrode’s solution)成分(mM):NaCl 150,KCl 5.4,MgCl2 2,CaCl2 1.8,HEPES 5,Glucose 10,用1N NaOH调pH值至7.35
记录Na+-Ca2+交换电流的台氏液成分(mM):NaCl 140,MgCl2 2,CaCl2 1.8,HEPES 5,Glucose 10,用1N CsOH调pH值至7.4
正常电极液(normal pipette solution)成分(mM):KCl 140,MgCl2 0.5,EGTA 10,HEPES 10,1N KOH调pH值至7.2
记录Na+-Ca2+交换电流的电极液成分(mM):EGTA 42,CaCl2 29,MgCl2 13,Aspartic acid 42,TEA 20,HEPES 5,Na2ATP 5,1N的CsOH调pH至7.4。实验时,根据电极内液中不同的Na+浓度,分别加入NaCl 5,15和25mM,使电极液中的Na+浓度达到所要求的15,25和35mM。
所有溶液均用双蒸水配制,无钙液和台氏液每次用时新鲜配制,电极内液配好后,用0.22μm的微孔滤膜过滤,分装于Eppendorf管,冻存备用。
2.4统计学分析
用pCLAMP 5.5.1和pCLAMP 6.0.1软件对原始电流图进行测量分析,所有数据均为Mean±SE表示,n表示细胞数;配对和组间t检验,P<0.05认为差异有显著性。
细胞水平筛选结果
1.正常Na+-Ca2+交换电流的记录
将细胞钳制在-40mV,先去极化至+60mV,再给以持续2s速度为80mV/s的反向斜坡刺激,复极化至-100mV,刺激频率为0.05Hz。在该刺激条件下,用台氏液灌流时,记录到一个由外向到内向的电流-电压关系曲线(I-V curve),由于其它时间依赖性的电流都被阻断,因此记录到的电流几乎呈线性。在细胞外应用5mM的Ni2+时,该电流的外向成分和内向成分显著减小,用Ni2+前后记录到的两条电流-电压曲线相减,得到对Ni2+敏感的电流即生电性Na+-Ca2+交换电流(Na+-Ca2+ exchange current,INa-Ca)
2.Amiloride、KB-R7943和IMM-001对Na+-Ca2+交换电流的抑制作用的比较
我们比较了Na+-H+交换抑制剂Amiloride和近年来常作为工具药使用的Na+-Ca2+交换反向转运抑制剂2-[2-[4-(4-nitrobenzyloxy)phenyl]]isothiourea(KB-R7943)及新化合物IMM-001,对Na+-Ca2+交换电流的作用。研究发现在+50mV时,Amiloride 10,30和100μM对INa-Ca的抑制率分别是15%,23%和41%,-80mV时的抑制率则分别是6%,15%和23%。说明Amiloride对外向INa-Ca的抑制作用更明显;在+50mV时,KB-R7943 1,和10μM对INa-Ca的抑制率分别是29%和61%,-80mV时的抑制率则分别是22%和57%。说明KB-R7943在双向离子条件下对内、外向INa-Ca无选择性;IMM-001 0.10,1和10μM,对外向INa-Ca的抑制率在+50mV时分别是28%,48%和66%,对内向INa-Ca的抑制率在-80mV时则分别是15%,24%和42%,IMM-001对外向INa-Ca的抑制作用明显强于其对内向INa-Ca的抑制作用。结果表明Amiloride在低浓度时对内、外向电流几乎没有作用,KB-R7943在阻断外向电流的同时,对内向电流也有抑制,而影响正常的排Ca2+功能,IMM-001不仅在三者中抑制作用最强,而且选择性作用于外向电流。相对于其它化合物,IMM-001的作用靶点比较专一,选择性高。有利于抑制缺血/再灌时的钙超载和由此造成的心肌损伤。见图1、图2和图3。
3.二十二种IMM-001结构优化剂候选药物对心肌Na+-Ca2+交换电流的作用比较及筛选
因为IMM-001比KB-R7943和Amiloride选择性更高,抑制外向Na+-Ca2+交换电流作用更强,我所药化室以IMM-001为母核,合成了22个化合物,用上述膜片钳方法,建立胞内Na+负荷模型、激活INa-Ca,以IMM-001为阳性对照药,比较这些化合物对Na+-Ca2+交换电流的抑制作用,以期找到比IMM-001更好的选择性作用于外向Na+-Ca2+交换电流的化合物。结果见下表
表.22个候选化合物对Na+-Ca2+交换电流的抑制作用
化合物归档号 n 外向INa-Ca抑制率(%) 内向INa-Ca抑制率(%)
IMM-002 5 32* 34
IMM-003 6 22 —
IMM-004* 3 52* 44
IMM-058 5 3 —
IMM-059 6 8 15
IMM-065* 6 55* 43
IMM-623 4 11 15
IMM-030 4 12 17
IMM-313* 3 50* 28
IMM-141 4 — 2
IMM-142 3 46 57
IMM-143 3 — —
IMM-161 3 — —
IMM-163 4 14 19
IMM-164 4 8 22
IMM-125 3 35 14
IMM-127* 5 43* 21
IMM-128* 3 44* 42
IMM-129* 3 59* 57*
IMM-130 3 30 43
IMM-131 3 22 15
IMM-132* 3 44* 14
*P<0.05
在围绕IMM-001合成的22个化合物中,经电生理(心肌细胞水平)筛选,找到7个活性更高的化合物,它们对外向Na-Ca交换的抑制作用强于内向抑制,具有特异。
实施例1:离体实验
(1)心肌细胞水平的Na/Ca交换抑制作用
用本所药理室的特异性方法直接研究细胞水平Na/Ca交换正向及反向转运作用,发现上述化合物均有一定的抑制Na/Ca交换反向转运的作用,抑制率40%以上的为作用较强化合物,作用最强着接近60%,见下表。
化合物代号 | 外向INa-Ca抑制率(%) | 内向INa-Ca抑制率(%) |
IMM-065 | 55 | 43 |
IMM-313 | 50 | 28 |
IMM-004 | 52 | 44 |
IMM-127 | 43 | 21 |
IMM-128 | 44 | 42 |
IMM-129 | 59 | 57 |
IMM-132 | 44 | 14 |
(2)离体心脏缺血/再灌损伤的保护作用
根据前期电生理细胞模型筛选的结果,从22个待选化合物中,经对Na/Ca交换反向转运产生的外向电流的抑制率的比较,挑选出7个相对好的化合物进行离体实验,即结构式中含CL元素的IMM-313,IMM-004,IMM-132;结构式中含F元素的IMM-127,IMM-128,IMM-129,以及含OH的IMM-065。实验采用大鼠离体心脏缺血再灌注(I/R)损伤模型。以心律失常的持续时间,室早,室速和室颤的发生率作为心肌损伤的指标,观察化合物的心肌保护作用。结果如表所示:
化合物(10-6M) | n | 时间(min) | 发生率(%) | ||
AAT | VPS | VT | VF | ||
Control | 13 | 28.23±1.70 | 62 | 69 | 77 |
IMM-313 | 10 | 1.67±0.70** | 20* | 30 | 30* |
IMM-004 | 8 | 0.70±0.33** | 37.5 | 37.5 | 0** |
IMM-127 | 8 | 19.72±4.42 | 50 | 62.5 | 38 |
IMM-128 | 8 | 22.10±3.49 | 25 | 50 | 50 |
IMM-129 | 8 | 23.67±3.87 | 37.5 | 75 | 63 |
IMM-132 | 7 | 29.13±0.69 | 28.6 | 85.7 | 85.7 |
IMM-065 | 10 | 13.09±3.76** | 30 | 70 | 50 |
AAT:出现时间 VPS:室性早博次数 VT:室速 VF:室颤
*p<0.05,**p<0.01与对照组比较
结论:IMM-313和IMM-004及IMM-065在浓度为10-6时,有显著心肌保护作用。
实施例2:在体实验
(1)大鼠静脉注射给药的心肌保护作用
1)Verapamil股静脉注射0.3mg/Kg,可显著性延长缺血-再灌注心律失常的潜伏期,缩短心律失常的持续时间,降低VT、VF和VE的发生率,缩短VF的持续时间。
2)IMM-001股静脉注射3mg/Kg,可显著性缩短心律失常的持续时间,降低VT、VF的发生率,缩短VT和VF的持续时间。
3)IMM-004股静脉注射3mg/Kg,可显著性延长缺血—再灌注心律失常的潜伏期,降低VT、VF和VE的发生率,缩短VT和VF的持续时间。
4)IMM-313股静脉注射3mg/Kg后5min内(冠脉左前降支结扎前),41.2%(7/17)的大鼠心律显著减慢,且不可恢复,最后死亡。其余有效数据经统计,未观察到明显作用。
5)IMM-065股静脉注射3mg/Kg未观察到明显作用。
6)IMM-127股静脉注射3mg/Kg,可显著性延长缺血-再灌注心律失常的潜伏期,降低VT和VF的发生率,缩短VT和VF的持续时间。
大鼠静脉注射3mg/kg上述化合物,对冠状动脉缺血再灌注损伤有明显的保护作用。以心脏损伤后出现心律失常的程度作为评价指标。
静脉注射本发明化合物对麻醉大鼠心脏缺血/再灌注心律失常的保护作用
组别 | n | 出现时间(s) | 持续时间(s) | VT | VF | VE | ||
发生率(%) | 持续时间(s) | 发生率(%) | 持续时间(s) | 发生率(%) | ||||
control | 14 | 4.0±4.1 | 23.0±10.7 | 100 | 8.2±6.1 | 35.7 | 3.3±5.7 | 100 |
Verapamil(0.3mg/Kg) | 11 | 29.1±29.7* | 11.8±12.1* | 54.5** | 5.4±7.0 | 0* | 0* | 63.6* |
IMM-001(3mg/Kg) | 9 | 13.2±18.2 | 11.8±9.1* | 66.7* | 3.8±3.6* | 0* | 0* | 88.9 |
IMM-004(3mg/Kg) | 12 | 20.8±24.2* | 16.1±12.1 | 66.7* | 3.8±4.0* | 0* | 0* | 75* |
IMM-313(3mg/Kg) | 8 | 7.0±8.2 | 24.0±16.5 | 87.5 | 5.9±7.5 | 25 | 2.2±4.4 | 100 |
IMM-065(3mg/Kg) | 7 | 10.9±22.0 | 25.5±17.8 | 85.7 | 10.9±11.2 | 14.3 | 0.1±0.2 | 85.7 |
IMM-127(3mg/Kg) | 11 | 12.4±10.0* | 18.5±8.9 | 72.7* | 3.8±2.9* | 0* | 0* | 100 |
VT:室速 VF:室颤 VE:室早 *P<0.05,**P<0.01与对照组比较
(2)大鼠口服给药的心肌缺血保护作用
化合物IMM-004,IMM-127溶于乙醇∶PEG(体积比)=1∶9的溶剂中,并以该溶剂为对照组,灌胃容积均为10ml/Kg,灌胃后60min时结扎冠状动脉左前降支造成心脏缺血,15min后实现再灌注。
1)IMM-004
口服10mg/Kg,未观察到明显的保护作用。
口服30mg/Kg,可显著性缩短缺血-再灌注心律失常(P<0.01)的持续时间,降低VT(P<0.01)和VF(P<0.05)的发生率,缩短VT(P<0.01)的持续时间。
口服100mg/Kg,可显著性缩短缺血-再灌注心律失常(P<0.05)的持续时间,降低VT(P<0.05)的发生率,缩短VT(P<0.01)的持续时间。
2)IMM-127
口服10mg/Kg,可显著性缩短VT(P<0.05)的持续时间。
口服30mg/Kg,可显著性缩短缺血-再灌注心律失常(P<0.01)的持续时间,降低VF(P<0.05)的发生率,缩短VT(P<0.01)和VF(P<0.05)的持续时间。
口服100mg/Kg,可显著性降低VT(P<0.05),缩短VT(P<0.01)的持续时间。
大鼠口服给药10、30、100mg/kg上述化合物,对冠状动脉缺血再灌注损伤有明显的保护作用。以心脏损伤后出现心律失常的程度作为评价指标,
结论:以上实验证明,该类化合物静脉注射和口服,对心脏缺血损伤均有保护作用。
口服IMM-004,IMM-127对麻醉大鼠心脏缺血-再灌心律失常的保护作用
组别 | n | 出现时间(s) | 持续时间(s) | VT | VF | VE | ||
发生率(%) | 持续时间(s) | 发生率(%) | 持续时间(s) | 发生率(%) | ||||
control | 17 | 5.0±6.7 | 41.6±15.2 | 94.1 | 15.4±11.9 | 52.9 | 3.9±7.0 | 94.1 |
IMM-004(10mg/Kg) | 9 | 9.3±10.0 | 30.2±17.6 | 88.9 | 8.8±7.4 | 22.2 | 4.7±12.9 | 100 |
IMM-004(30mg/Kg) | 9 | 19.6±24.1 | 17.0±12.6* * | 44.4** | 3.3±5.7** | 11.1* | 0.4±1.3 | 66.7 |
IMM-004(100mg/Kg) | 9 | 16.4±25.1 | 22.7±19.4* | 55.5* | 3.9±6.8** | 33.3 | 5.5±10.2 | 66.7 |
IMM-127(10mg/Kg) | 9 | 15.5±21.5 | 32.1±26.1 | 66.7 | 6.6±7.2* | 22.2 | 2.5±6.4 | 100 |
IMM-127(30mg/Kg) | 9 | 9.6±9.2 | 18.0±11.4* * | 66.7 | 3.2±5.5** | 11.1* | 0.2±0.5* | 100 |
IMM-127(100mg/Kg) | 9 | 9.0±19.7 | 31.1±21.3 | 44.4** | 5.1±7.8* | 22.2 | 2.2±63 | 88.9 |
实施例3:改善麻醉犬心肌缺血的作用
本实验采用心外膜电图标测心肌缺血范围及程度,定量组织学(N-BT染色法)测定心肌梗塞范围,同时测定冠脉血流量、心肌耗氧量及血清CK、LDH、AST和血浆ET、TXB2、6-Keto-PGF1。活性的变化,研究了IMM-004消化道(十二指肠)给药对实验性犬急性心肌缺血、心肌梗塞及相关指标的影响。
实验分①空白对照组,聚乙二醇1ml/kg,n=5;②合心爽组,5mg/kg,n=5;③IMM-004 30mg/kg剂量组,n=5。试验药物用蒸馏水配制成同体积(1ml/kg),经十二指肠给药。
(1)减少梗塞面积和心肌缺血损伤的作用
1)对心肌缺血程度(∑-ST)的影响
对照组聚乙二醇药后心肌缺血程度(∑-ST)无明显变化;钙拮抗剂合心爽药后90min可降低∑-ST,可持续至药后180min。经十二指肠给入IMM-004 30mg/kg剂量组有明显减轻心肌缺血程度(∑-ST)的作用,药后180min∑-ST由药前325.20±55.95mv降至146.80±60.25mv,下降了53.90±20.60%,与药前及对照组比较均有显著性差异(P<0.01)。见图4。
心外膜电图(EEG)标测的实验结果表明,IMM-004对实验性急性犬心肌缺血有明显的改善作用,可显著减轻心肌缺血程度(∑-ST),减小心肌缺血范围(N-ST)。
2)对犬急性心肌梗塞范围(N-BT染色法测定)的影响。
各给药组对犬急性心肌梗塞范围的影响(n=5,X±SD)
剂量 心室面积
组别 心脏面积mm2 梗塞区面积mm2 梗塞区/心脏 梗塞区/心室
/kg mm2
聚乙二醇 1ml 12476.8±64.3 5483.0±405.3 861.80±70.2 6.62±1.14 15.85±1.01
合心爽 5mg 15185.8±876.8 5309.6±427.4 186.50±21.2*** 1.54±0.40*** 3.54±3.74***
IMM-004 30mg 17098.9±3224.4 5274.3±832.6 255.70±58.2*** 2.04±0.93*** 5.08±2.00***
注:与对照组比较:*P<0.05,**:P<0.01,***:P<0.001。
以定量组织学N-BT染色法显示心肌梗塞范围,聚乙二醇对照组动物心肌梗塞区分别占心脏及心室的6.62±1.14%和15.85±1.01%;阳性对照药合心爽及IMM-004可明显缩少动物心肌梗塞区面积,30mg/kg组心肌梗塞区面积分别占心脏及心室的2.04±0.93%、5.08±2.00%,分别较聚乙二醇对照组降低了69.18%和67.94%,与对照组比较均有显著性差异(P<0.001)。见图5。
3)对实验性心肌缺血犬血液生化学指标的影响(血清肌酸激酶(CK)及乳酸脱氢酶(LDH)活性)
结扎冠脉形成急性心肌缺血后,血清中CK、LDH、AST含量明显升高,IMM-004能明显抑制CK、AST活性升高的作用,而对LDH活性的影响与对照组无明显差异。结果见图6,7,8。
实验结果证实,IMM-004具有明显改善犬急性心肌缺血和心肌梗塞的作用,减轻由心外膜电图标测的心肌缺血程度(∑-ST),降低心肌缺血范围(N-ST),减小经N-BT染色所显示的梗塞区。
肌酸激酶(CK)广泛存在于胞浆中,尤以心肌细胞为多。当心肌细胞损伤时CK溢出,使其在血清中活性提高,血清CK活性越高,反映心肌损伤越重。乳酸脱氢酶(LDH)在心肌梗塞时从组织细胞内大量释放于体液中,测定冠状静脉窦血中其活性,亦反映心肌损伤的程度。本实验观察到持续结扎犬冠状动脉CK和LDH活性持续增加。实验观察到IMM-004可明显抑制CK活性升高的作用。同时研究发现,心肌细胞损伤时,心肌细胞功能酶AST释放量明显增加,而IMM-004可明显抑制AST的释放。
(2)扩张冠状动脉血管的作用
1)对实验性心肌缺血犬冠脉血流量的影响
结扎犬冠状动脉形成心肌缺血后,冠脉血流量出现短时代偿性增加,增加幅度10%左右。合心爽和IMM-004药后均有显著增加缺血心脏冠脉血流量的作用,IMM-004药后30min冠脉血流量增加明显,比药前增加了15.02±22.16%,与对照组组比较,有明显差异(P<0.05)。结果见图9。
2)对实验性心肌缺血犬动、静脉血氧含量影响
对照组聚乙二醇给药前后动脉、冠状静脉窦血氧含量及心肌耗氧量均无明显改变;合心爽可明显增加静脉窦血氧含量的同时显著降低心肌耗氧量。IMM-004药后120min和180min静脉血氧含量明显增加,与药前比较差异明显(P<0.05)。结果见图10。
由不同病因造成局部冠状动脉狭窄或冠状动脉闭塞形成心肌缺血或心肌梗塞时,其它冠状动脉分支代偿性扩张和开放,可使心肌缺血或心肌梗塞得到缓解。实验观察到IMM-004可明显增加心肌缺血和心肌梗塞时的冠脉血流量,表明其可扩张冠脉血管,促进侧支循环的开放,改善缺血心肌的供血。
上述结果表明,IMM-004可明显改善犬急性心肌缺血和心肌梗塞的病理表现,减轻心肌缺血程度,减小心肌梗塞面积;同时可扩张冠脉血管,增加冠脉血流量;并可抑制CK活性升高及AST的释放。以上结果与该化合物的药理学作用机理相吻合,即选择性阻断Na/Ca交换的反向转运,及由此引起的心肌缺血损伤和扩张冠状动脉,改善心脏供血状况。
实施例4:改善大鼠心功能和血流动力学作用
(1)对正常大鼠心功能和血流动力学的影响
方法;取300-350g雄性SD大鼠,禁食12小时,用20%的乌拉坦0.5ml/100g即1g/kg ip麻醉。选用PE-50聚乙烯导管行左股动、静脉和右股动脉插管,左心室插管,左股动脉插管供放血、左股静脉插管供补液给药用,右股动脉插管供测动脉血压用,左心室插管供测左心室压力用,右股动脉和左心室插管通过三通管接压力换能器输入多道生理记录仪及示波器。给药组大鼠灌胃IMM-004 30mg/kg,对照组灌胃同体积的溶剂(PEG)。分别在给药前40min给药后2h同步记录左心室收缩压(LVSP)、左心室舒张末压(LVEDP)、(左心室等容期压力最大变化速率(±dp/dtmax)、动脉收缩压(SP)、动脉舒张压(DP)、平均动脉压(MAP)、心率(HR)各项指标,连续观察,每隔10min记录一次。
结果:IMM-004对正常麻醉大鼠左心室收缩压(LVSP)、左心室舒张末压(LVEDP)、(左心室等容期压力最大变化速率(±dp/dtmax)、动脉收缩压(SP)、动脉舒张压(DP)、平均动脉压(MAP)、心率(HR)均无明显影响,说明IMM-004对正常大鼠的心功能和血流动力学无影响。IMM-004组的各项指标同溶剂对照组相比无明显差异,经检验无统计学差异。
结论:IMM-004对正常大鼠心功能和血流动力学无影响。
(2).改善心肌缺血/再灌大鼠心功能和血流动力学的作用
方法:取300-350g雄性SD大鼠,禁食12小时,用20%的乌拉坦0.5ml/100g即1g/kg ip麻醉。选用PE-50聚乙烯导管行左股动、静脉和右股动脉插管,左心室插管,左股动脉插管供放血、左股静脉插管供补液给药用,右股动脉插管供测动脉血压用,左心室插管供测左心室压力用,右股动脉和左心室插管通过三通管接压力换能器输入多道生理记录仪及示波器。给药组大鼠灌胃IMM-004 30mg/kg,对照组灌胃同体积的溶剂(PEG)。切开气管接呼吸机供开胸后人工呼吸(呼吸量为2ml/100g)。胸骨左缘第4-5肋间剪开胸壁,沿胸骨左缘2mm处剪断第4和第5肋骨,剪开心包膜。轻压胸壁,挤出心脏,用细小弯针在冠状动脉左前降支下穿3/0缝线后,将心脏放回胸腔,稳定10min后,连同直径3*8mm聚乙烯管一起结扎冠脉,压迫造成心脏缺血。15min后剪断缝线,取出聚乙烯管,恢复冠脉灌注。分别在开胸前、开胸后、缺血15min和再灌1h同步记录左心室收缩压(LVSP)、左心室舒张末压(LVEDP)、(左心室等容期压力最大变化速率(±dp/dtmax)、动脉收缩压(SP)、动脉舒张压(DP)、平均动脉压(MAP)、心率(HR)各项指标,连续观察,每隔10min记录一次。
结果:IMM-004组的LVSP从大鼠正常时的120mmHg左右降低至100mmHg左右,基本保持平稳;对照组则降低至60.8mmHg,波动较大。对照组LVEDP在再灌10min后急速上升,表明左心室舒张不全,舒张功能严重受损(+15mmHg),IMM-004组的LVEDP基本保持正常(-6mmHg左右),提示IMM-004对心肌舒张功能的保护作用较强。+dp/dtmax是评价心肌收缩性能的常用指标,IMM-004组的+dp/dtmax(+110mmHg/s左右),降低不明显,对照组降低较多(50mmHg/s左右),比IMM-004组低54%,说明给药组的心肌收缩性能受损较小。-dp/dtmax是心肌舒张参数,是评价心室舒张功能的重要指标之一。接扎后,给药组的每一个时相点与对照组比较都有显著性差异。IMM-004组从100mmHg/s降低至70mmHg/s,对照组从100mmHg/s减低至30mmHg/s提示IMM-004组大鼠心肌收缩性能下降的同时,舒张功能保持较好。
由于IMM-004能保护心脏功能,所以能维持较稳定的血压(SBP100mmHg左右,MAP80mmHg左右),对照组心肌受损严重,血压降低较多(SBP80mmHg左右,MAP60mmHg左右),波动也较大。由图可知,大鼠心肌缺血/再灌后心率下降(从461次/分降至400次/分),IMM-004对大鼠心率无影响,两组没有显著性差异。见图11,12,13,14,15。
结论:大鼠心肌缺血/再灌时心功能受损,表现为心脏收缩功能舒张功能降低,血压降低或波动较大,IMM-004对大鼠的心功能有保护作用,尤其以心脏舒张功能的改善为显著,基本维持在正常范围内,且大鼠血压维持也较稳定,而IMM-004对心肌受损后心率下降无影响。
实施例5:毒理学实验
(1)Ames(致突变)实验
我们采用4种菌株(TA97;TA98;TA100;TA102),共研究了5个化合物(IMM-004;IMM-065;IMM-127;IMM-128;IMM-313),每组均为4个浓度,即0.5、5、50和500μg/皿,实验结果均为阴性,说明该类化合物没有致突变作用。结果见下表
IMM-004的Ames试验
IMM-128的Ames试验
IMM-065的Ames试验
IMM-313的Ames试验
IMM-127的Ames试验
(2)急性毒性实验
以IMM-004和IMM-127为例进行了急性毒性实验,IMM-004;IMM-127由本所合成室提供。制剂呈粉状。将制剂分别研磨后加0.5%羧甲基纤维素钠溶解。
选雄性昆明种小鼠,体重19±2g。于动物房适应环境,实验前14小时禁食后随机分成组,每组10只动物。口服给药30min后,大剂量组动物活动减少。24h后,各剂量组动物恢复正常。观察7天,结果如下表:
化合物浓度 | 动物死亡数 | |
IMM-004 | IMM-127 | |
200mg/kg | -- | -- |
350mg/kg | -- | -- |
500mg/kg | -- | -- |
700mg/kg | -- | -- |
1g/kg | -- | -- |
2g/kg | -- | -- |
3g/kg | -- | |
5g/kg | -- | 7 |
结论:IMM-004各剂量组未见动物死亡,半数致死量LD50>5g/kg,提示此类化合物毒性较低。
Claims (9)
1、苯并异硒唑酮类化合物在制备抗缺血性心肌损伤药物中的应用。
2、根据权利要求1所述的应用,其特征在于,所述药物的作用靶点是Na+-Ca2+交换系统。
3、根据权利要求1的制备抗缺血性心肌损伤药物中的应用,其特征在于,所述的苯并异硒唑酮类化合物如通式(I)所示
其中,
R1选自氢原子,卤素,C1-C4的直链或支链烷基,C1-C4的直链或支链烷氧基,羟基,三氟甲基,硝基,二-(C1-C4烷基)-胺基,R1可以是亚甲二氧基,R1的取代位置是在苯并异硒唑中苯环的3-、4-、5-或6-位的任意位置;
R2是C0-C4的饱和或不饱和的链烃,其中当C0是R2表示一个连接R3和N的键;
R3表示取代或非取代、饱和或不饱和的苯环基、杂环基并且杂环基含有1到4个选自氧原子、氮原子、硫原子的杂原子。
4、根据权利要求3的制备抗缺血性心肌损伤药物中的应用,其特征在于,所述的苯并异硒唑酮类化合物如通式(I)所示
其中,
R1选自氢原子,卤素,C1-C4的直链或支链烷基,C1-C4的直链或支链烷氧基,羟基,三氟甲基,硝基,二-(C1-C4烷基)-胺基,R1可以是亚甲二氧基,R1的取代位置是在苯并异硒唑中苯环的3-、4-、5-或6-位的任意位置;
R2是C0-C2的饱和或不饱和的链烃,其中当C0是R2表示一个连接R3和N的键;
R3表示取代或非取代、饱和或不饱和的苯环基、杂环基并且杂环基含有1到2个选自氧原子、氮原子、硫原子的杂原子,杂环基可以是单取代,或二取代的,取代基可以相同或不同的,取代基选自杂环基可以是单取代,或二取代的,取代基可以相同或不同的,取代基选自卤素,C1-C4的直链或支链烷基,C1-C4的直链或支链烷氧基,C1-C4的直链或支链烷硫基,C1-C4的直链或支链的酮基,C1-C4的直链或支链卤烷基,羟基,硫基,硝基,腈基,羧基,烷氧羰基。
5、根据权利要求4的制备抗缺血性心肌损伤药物中的应用,其特征在于,所述的苯并异硒唑酮类化合物如通式(I)所示
其中,
R1选自氢原子,卤素,C1-C4的直链或支链烷基,C1-C4的直链或支链烷氧基,羟基,三氟甲基,硝基,二-(C1-C4烷基)-胺基,R1可以是亚甲二氧基,R1的取代位置是在苯并异硒唑中苯环的3-、4-、5-或6-位的任意位置;
R2是表示一个连接R3和N的键;
R3表示取代或非取代、饱和或不饱和的苯环基、杂环基并且杂环基含有1到2个选自选自氧原子、氮原子、硫原子的杂原子,杂环基可以是单取代,或二取代的,取代基可以相同或不同的,取代基选自,卤素,C1-C4的直链或支链烷基,C1-C4的直链或支链烷氧基,C1-C4的直链或支链烷硫基,C1-C4的直链或支链卤烷基,C1-C4的直链或支链的酮基羟基,硫基,硝基,腈基,羧基,烷氧羰基。
6、根据权利要求5的制备抗缺血性心肌损伤药物中的应用,其特征在于,所述的苯并异硒唑酮类化合物如通式(I)所示
其中,
R1选自氢原子,卤素,C1-C4的直链或支链烷基,C1-C4的直链或支链烷氧基,羟基,三氟甲基,硝基,二-(C1-C4烷基)-胺基,R1可以是亚甲二氧基氢,R1的取代位置是在苯并异硒唑中苯环的3-、4-、5-或6-位的任意位置;
R2是表示一个连接R3和N的键;
R3表示取代或非取代的苯基,硫苯基,噻唑基,异噻唑基,咪唑基,吡唑基,噻二唑基,吡啶基,嘧啶基,吡嗪基,哒嗪基,苯并噻唑基,苯并咪唑基,苯并三唑基,三嗪基,三唑基,四唑基,喹啉基,异喹啉基,吲哚基,吲唑基,卡巴唑基,呋喃基,它们可以是单取代,或二取代的,取代基可以相同或不同的,取代基选自氟,氯,溴,甲基,乙基,丁基,甲氧基,乙氧基,甲基硫基,乙基硫基,三氟甲基,羟基,硫基,,硝基,,腈基,羧基,烷氧羰基。
8、根据权利要求1的制备抗缺血性心肌损伤药物中的应用,其特征在于,所述的苯并异硒唑酮类化合物选自
2-苯基-1,2-苯并异硒唑-3(2H)-酮,
4-氟-2-苯基-1,2-苯并异硒唑-3(2H)-酮,
5-氟-2-苯基-1,2-苯并异硒唑-3(2H)-酮,
6-氟-2-苯基-1,2-苯并异硒唑-3(2H)-酮,
7-氟-2-苯基-1,2-苯并异硒唑-3(2H)-酮,
4-氯-2-苯基-1,2-苯并异硒唑-3(2H)-酮,
5-氯-2-苯基-1,2-苯并异硒唑-3(2H)-酮,
6-氯-2-苯基-1,2-苯并异硒唑-3(2H)-酮,
7-氯-2-苯基-1,2-苯并异硒唑-3(2H)-酮,
4-羟基-2-苯基-1,2-苯并异硒唑-3(2H)-酮,
5-羟基-2-苯基-1,2-苯并异硒唑-3(2H)-酮,
6-羟基-2-苯基-1,2-苯并异硒唑-3(2H)-酮,
7-羟基-2-苯基-1,2-苯并异硒唑-3(2H)-酮,
2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
4-氯-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
4-氯-2-(3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
4-氯-2-(4-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
5-氯-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
5-氯-2-(3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
5-氯-2-(4-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
6-氯-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
6-氯-2-(3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
6-氯-2-(4-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
7-氯-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
7-氯-2-(3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
7-氯-2-(4-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
4-氟-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
4-氟-2-(3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
4-氟-2-(4-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
5-氟-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
5-氟-2-(3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
5-氟-2-(4-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
6-氟-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
6-氟-2-(3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮
6-氟-2-(4-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
7-氟-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
7-氟-2-(3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
7-氟-2-(4-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
4-羟基-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
4-羟基-2-(3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
4-羟基-2-(4-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
5-羟基-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
5-羟基-2-(3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
5-羟基-2-(4-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
6-羟基-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
6-羟基-2-(3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
6-羟基-2-(4-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
7-羟基-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
7-羟基-2-(3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
7-羟基-2-(4-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(3-羟基-2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-氯-3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-氯-2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-甲氧基-3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2,6-二氯-3-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4,6-二甲基-2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-羟基-2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(3-硝基-2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-硝基-2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
6-甲基-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
6-甲氧基-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
5-硝基-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
7-甲氧基-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
6,7-亚甲二氧基-2-(2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(3-甲基-2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-甲基-2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-甲基-2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-甲基-2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(3,5-二氯-2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-氯-2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-羧基-5-氯-2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(3-羧基-2-吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-四氢吡啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(苯并噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-甲基-2-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-硝基-2-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4,6-二甲基-2-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
(2,6-二甲基-4-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-乙氧基-2-乙基硫基-4-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-乙氧基羰基-2-羟基-4-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮
2-(5-羧基-4-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-氯-2-甲基硫基-4-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-氯-2-甲基硫基-6-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-氯-6-甲基-2-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-氯-3-硝基-2-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-氯-5-硝基-4-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4,6-二氯-2-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4,6-二氯-5-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4,6-二羟基-2-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2,6-二羟基-4-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2,4-二羟基-5-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4,6-二硫基-2-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-羟基-2-硫基-4-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-羟基-2-甲基硫基-4-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-羟基-6-甲基-2-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-羟基-5-甲基-4-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(1-苯并吡唑基并(3,4-d)嘧啶-4-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(吡唑并(3,4-d)嘧啶-4-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-羟基吡唑并(3,4-d)嘧啶-4-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-硫基吡唑并(3,4-d)嘧啶-4-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-羟基-4-嘧啶基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-氯-2-苯并噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-甲氧基-2-苯并噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-甲氧基-2-苯并噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-甲基-2-苯并噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-甲基-5-苯并噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-硝基-2-苯并噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-溴-2-苯并噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5,6-二甲基-2-苯并噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-乙氧基-2-苯并噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
6-甲基-2-(2-噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
6-氯-2-(2-噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
6-甲氧基-2-(2-噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
5-硝基-2-(2-噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
5-氯-2-(2-噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
7-甲氧基-2-(2-噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
6,7-亚甲二氧基-2-(2-噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-甲基-2-噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-硝基-2-噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-噻唑啉基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-氯-2-噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(3-甲基-5-异噻唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-咪唑基)-1,2-苯并异硒唑-3(2H)酮,
2-(5-乙氧基羰基-2-咪唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(3-吡唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-氰基-5-吡唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-乙氧基羰基-3-吡唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-乙氧基羰基-2-苯基-3-吡唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(4-氰基-3-吡唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-苯基-3-吡唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(1-苯基-5-吡唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(1-苯基-5-吡唑啉酮-3-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-羟基-3-吡唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(1,3,4-噻二唑-2-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-硫基-1,3,4-噻二唑-2-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-甲基-1,3,4-噻二唑-2-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-三氟甲基-1,3,4-噻二唑-2-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-叔丁基-1,3,4-噻二唑-2-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-吡嗪基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-羧基-3-吡嗪基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-哒嗪基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-苯并咪唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5,6-二甲基-2-苯并咪唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-苯并三唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(7-氯-1,2,4-苯并三嗪-3-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(1,2,4-苯并三嗪-3-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(7-溴-1,2,4-苯并三嗪-3-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(7-氟-1,2,4-苯并三嗪-3-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(7-硝基-1,2,4-苯并三嗪-3-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-苯并噻吩基)-1,2-苯并异硒唑-3(2H)-酮,
2-(3-苯并噻吩基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-噻吩基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2,1,3-苯并噻二唑-4-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(1,2,4-三嗪-4-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2,6-二硫基-1,3,5-三嗪-4-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5,6-二甲基-1,2,4-三嗪-3-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5,6-二苯基-1,2,4-三嗪-3-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(1,2,4-三唑-4-基)-1,2-苯并异硒唑-3(2H)-酮,
2(5-硫基-1,2,4-三唑-3-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-四唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-喹啉基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-甲基-4-喹啉基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-硝基-5-喹啉基)-1,2-苯并异硒唑-3(2H)-酮,
2-(1,2,3,4-四氢喹啉-8-基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-喹啉基)-1,2-苯并异硒唑-3(2H)-酮,
2-(3-喹啉基)-1,2-苯并异硒唑-3(2H)-酮,
2-(8-喹啉基)-1,2-苯并异硒唑-3(2H)-酮,
2(6-甲氧基-8-喹啉基)-1,2-苯并异硒唑-3(2H)-酮,
2-(1-异喹啉基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-异喹啉基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-吲哚基)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-异吲哚)-1,2-苯并异硒唑-3(2H)-酮,
2-(5-吲唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(6-氯-3-吲唑基)-1,2-苯并异硒唑-3(2H)-酮
2-(6-吲唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(7-吲唑基)-1,2-苯并异硒唑-3(2H)-酮,
2-(9-乙基-3-卡巴唑)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-3,4-二氢咪唑基-2-乙烯基)-1,2-苯并异硒唑-3(2H)-酮
2-(2-吡啶基甲基)-1,2-苯并异硒唑-3(2H)-酮,
2-(2-呋喃基甲基)-1,2-苯并异硒唑-3(2H)-酮,
2-[4-(2-羟亚氨基乙基)]-1,2-苯并异硒唑-3(2H)-酮
2-[4-(7-正丁基苯并(1,2-c二氢呋喃-2-酮))]-1,2-苯并异硒唑-3(2H)-酮。
9、一种含有苯并异硒唑酮类化合物的组合物在制备抗缺血性心肌损伤药物中的应用。
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CN 03142553 CN1572295A (zh) | 2002-06-19 | 2003-06-13 | 苯并异硒唑酮类化合物抗缺血性心肌损伤的用途 |
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Cited By (5)
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CN101891736A (zh) * | 2010-06-30 | 2010-11-24 | 天津理工大学 | 基于苯并异硒唑酮结构的1,3,4-噻二唑(噁二唑)衍生物及其制备方法和应用 |
CN1990475B (zh) * | 2005-12-29 | 2011-09-07 | 曾慧慧 | 取代苯并异硒唑酮类化合物及其用途 |
CN103601684A (zh) * | 2013-11-29 | 2014-02-26 | 沈阳药科大学 | 5-芳硒基苯并咪唑类化合物及其用途 |
WO2020020099A1 (zh) * | 2018-07-22 | 2020-01-30 | 上海星叶医药科技有限公司 | 含硒异唑胺类化合物及其制备方法和用途 |
CN113200978A (zh) * | 2020-12-30 | 2021-08-03 | 中国海洋大学 | 异噻(硒)唑酮类衍生物及其在抗冠状病毒药物中的应用 |
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CN1990475B (zh) * | 2005-12-29 | 2011-09-07 | 曾慧慧 | 取代苯并异硒唑酮类化合物及其用途 |
CN101891736A (zh) * | 2010-06-30 | 2010-11-24 | 天津理工大学 | 基于苯并异硒唑酮结构的1,3,4-噻二唑(噁二唑)衍生物及其制备方法和应用 |
CN101891736B (zh) * | 2010-06-30 | 2012-11-14 | 天津理工大学 | 基于苯并异硒唑酮结构的1,3,4-噻二唑(噁二唑)衍生物及其制备方法和应用 |
CN103601684A (zh) * | 2013-11-29 | 2014-02-26 | 沈阳药科大学 | 5-芳硒基苯并咪唑类化合物及其用途 |
CN103601684B (zh) * | 2013-11-29 | 2016-01-20 | 沈阳药科大学 | 5-芳硒基苯并咪唑类化合物及其用途 |
WO2020020099A1 (zh) * | 2018-07-22 | 2020-01-30 | 上海星叶医药科技有限公司 | 含硒异唑胺类化合物及其制备方法和用途 |
CN110746396A (zh) * | 2018-07-22 | 2020-02-04 | 上海星叶医药科技有限公司 | 含硒异唑胺类化合物及其制备方法和用途 |
US20210292315A1 (en) * | 2018-07-22 | 2021-09-23 | Shanghai Xingye Pharmaceutical Technology Co., Ltd | Selenium-containing isoxazolamine compound, preparation method therefor, and use thereof |
CN110746396B (zh) * | 2018-07-22 | 2022-07-15 | 上海星叶医药科技有限公司 | 含硒异唑胺类化合物及其制备方法和用途 |
CN113200978A (zh) * | 2020-12-30 | 2021-08-03 | 中国海洋大学 | 异噻(硒)唑酮类衍生物及其在抗冠状病毒药物中的应用 |
CN113200978B (zh) * | 2020-12-30 | 2022-09-16 | 中国海洋大学 | 异噻(硒)唑酮类衍生物及其在抗冠状病毒药物中的应用 |
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