CN1293665A - New compounds and their use as positive AMPA receptor modulators - Google Patents
New compounds and their use as positive AMPA receptor modulators Download PDFInfo
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- CN1293665A CN1293665A CN99804196A CN99804196A CN1293665A CN 1293665 A CN1293665 A CN 1293665A CN 99804196 A CN99804196 A CN 99804196A CN 99804196 A CN99804196 A CN 99804196A CN 1293665 A CN1293665 A CN 1293665A
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- alkyl
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 319
- 102000003678 AMPA Receptors Human genes 0.000 title claims abstract description 26
- 108090000078 AMPA Receptors Proteins 0.000 title claims abstract description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 239
- 239000001257 hydrogen Substances 0.000 claims abstract description 238
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 105
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 372
- 238000000034 method Methods 0.000 claims description 273
- 125000003545 alkoxy group Chemical group 0.000 claims description 232
- -1 amino, sulfenyl Chemical group 0.000 claims description 231
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 209
- 125000003118 aryl group Chemical group 0.000 claims description 207
- 229910052736 halogen Inorganic materials 0.000 claims description 190
- 150000002367 halogens Chemical class 0.000 claims description 190
- 125000000623 heterocyclic group Chemical group 0.000 claims description 185
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 162
- 150000002431 hydrogen Chemical class 0.000 claims description 133
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 119
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 101
- 125000000304 alkynyl group Chemical group 0.000 claims description 99
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 99
- 125000001188 haloalkyl group Chemical group 0.000 claims description 91
- 239000000460 chlorine Substances 0.000 claims description 87
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 claims description 82
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 68
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 62
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 56
- 150000001412 amines Chemical class 0.000 claims description 55
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 45
- 201000010099 disease Diseases 0.000 claims description 40
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 40
- 229910052801 chlorine Inorganic materials 0.000 claims description 39
- 229910052794 bromium Inorganic materials 0.000 claims description 38
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 38
- 230000015572 biosynthetic process Effects 0.000 claims description 33
- 125000004429 atom Chemical group 0.000 claims description 32
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 30
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 30
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 29
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 29
- 125000005842 heteroatom Chemical group 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 28
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 27
- 239000002253 acid Substances 0.000 claims description 22
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 22
- 150000003053 piperidines Chemical group 0.000 claims description 22
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 21
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 20
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 18
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 claims description 17
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 16
- 238000006467 substitution reaction Methods 0.000 claims description 16
- 125000002837 carbocyclic group Chemical group 0.000 claims description 15
- 229910052731 fluorine Inorganic materials 0.000 claims description 15
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 13
- 208000024827 Alzheimer disease Diseases 0.000 claims description 13
- 125000003282 alkyl amino group Chemical group 0.000 claims description 13
- 125000004414 alkyl thio group Chemical group 0.000 claims description 13
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 229940124530 sulfonamide Drugs 0.000 claims description 12
- 125000002252 acyl group Chemical group 0.000 claims description 11
- 229910052740 iodine Inorganic materials 0.000 claims description 11
- 125000005574 norbornylene group Chemical group 0.000 claims description 10
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 9
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 claims description 8
- 241001465754 Metazoa Species 0.000 claims description 8
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 7
- 230000035945 sensitivity Effects 0.000 claims description 7
- 210000003169 central nervous system Anatomy 0.000 claims description 6
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 230000002950 deficient Effects 0.000 claims description 6
- 150000002829 nitrogen Chemical class 0.000 claims description 6
- 208000012201 sexual and gender identity disease Diseases 0.000 claims description 6
- 208000015891 sexual disease Diseases 0.000 claims description 6
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 5
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 5
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 5
- 206010039966 Senile dementia Diseases 0.000 claims description 5
- 208000006011 Stroke Diseases 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 208000035475 disorder Diseases 0.000 claims description 5
- 208000024732 dysthymic disease Diseases 0.000 claims description 5
- 201000000980 schizophrenia Diseases 0.000 claims description 5
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 4
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims description 4
- FTAHXMZRJCZXDL-UHFFFAOYSA-N 3-piperideine Chemical compound C1CC=CCN1 FTAHXMZRJCZXDL-UHFFFAOYSA-N 0.000 claims description 4
- PMZBHPUNQNKBOA-UHFFFAOYSA-N 5-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=CC(C(O)=O)=CC(C(O)=O)=C1 PMZBHPUNQNKBOA-UHFFFAOYSA-N 0.000 claims description 4
- 208000007848 Alcoholism Diseases 0.000 claims description 4
- 208000000044 Amnesia Diseases 0.000 claims description 4
- 206010003805 Autism Diseases 0.000 claims description 4
- 208000020706 Autistic disease Diseases 0.000 claims description 4
- 201000006474 Brain Ischemia Diseases 0.000 claims description 4
- 206010008120 Cerebral ischaemia Diseases 0.000 claims description 4
- 206010013654 Drug abuse Diseases 0.000 claims description 4
- 208000026139 Memory disease Diseases 0.000 claims description 4
- 208000028017 Psychotic disease Diseases 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 201000007930 alcohol dependence Diseases 0.000 claims description 4
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 4
- 206010008118 cerebral infarction Diseases 0.000 claims description 4
- 230000006735 deficit Effects 0.000 claims description 4
- ZICQBHNGXDOVJF-UHFFFAOYSA-N diamantane Chemical compound C1C2C3CC(C4)CC2C2C4C3CC1C2 ZICQBHNGXDOVJF-UHFFFAOYSA-N 0.000 claims description 4
- 206010015037 epilepsy Diseases 0.000 claims description 4
- 230000006984 memory degeneration Effects 0.000 claims description 4
- 208000023060 memory loss Diseases 0.000 claims description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 4
- XIUYBDCCFRIFSK-UHFFFAOYSA-N n,n,3-trimethyl-1,1-dioxo-4h-1$l^{6},2,4-benzothiadiazine-7-sulfonamide Chemical compound N1=C(C)NS(=O)(=O)C2=CC(S(=O)(=O)N(C)C)=CC=C21 XIUYBDCCFRIFSK-UHFFFAOYSA-N 0.000 claims description 4
- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 claims description 4
- 208000011117 substance-related disease Diseases 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- PDXCOWCINSIDPO-UHFFFAOYSA-N 2h-thiadiazine 1,1-dioxide Chemical compound O=S1(=O)NN=CC=C1 PDXCOWCINSIDPO-UHFFFAOYSA-N 0.000 claims description 3
- 206010052428 Wound Diseases 0.000 claims description 3
- 208000027418 Wounds and injury Diseases 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 230000001537 neural effect Effects 0.000 claims description 3
- JFNLZVQOOSMTJK-KNVOCYPGSA-N norbornene Chemical compound C1[C@@H]2CC[C@H]1C=C2 JFNLZVQOOSMTJK-KNVOCYPGSA-N 0.000 claims description 3
- QDOQLKXQYLZYEA-UHFFFAOYSA-N (3-cyclohexyl-1,1-dioxo-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazin-8-yl)methanol Chemical compound N1S(=O)(=O)C=2C(CO)=CC=CC=2NC1C1CCCCC1 QDOQLKXQYLZYEA-UHFFFAOYSA-N 0.000 claims description 2
- LCDBKCCPUXCASM-UHFFFAOYSA-N 1,1-dioxo-3-phenyl-4h-1$l^{6},2,4-benzothiadiazine-7-sulfonamide Chemical compound N1S(=O)(=O)C2=CC(S(=O)(=O)N)=CC=C2N=C1C1=CC=CC=C1 LCDBKCCPUXCASM-UHFFFAOYSA-N 0.000 claims description 2
- ZPASABDAIAXPEY-UHFFFAOYSA-N 1-sulfonyl-2,3-dihydropyrrolo[2,1-c][1,2,4]benzothiadiazine 5,5-dioxide Chemical compound S(=O)(=O)=C1CCC2=NS(C3=C(N21)C=CC=C3)(=O)=O ZPASABDAIAXPEY-UHFFFAOYSA-N 0.000 claims description 2
- RWUDZOCZVQBJNI-UHFFFAOYSA-N 2,3,10,10a-tetrahydro-1h-pyrrolo[1,2-b][1,2,4]benzothiadiazine 5,5-dioxide Chemical compound N1C2=CC=CC=C2S(=O)(=O)N2C1CCC2 RWUDZOCZVQBJNI-UHFFFAOYSA-N 0.000 claims description 2
- BQFHXNJPWFQYES-UHFFFAOYSA-N 2-(3-cyclohexyl-1,1-dioxo-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazin-7-yl)-n,n-dimethylbenzenesulfonamide Chemical compound CN(C)S(=O)(=O)C1=CC=CC=C1C1=CC=C(NC(NS2(=O)=O)C3CCCCC3)C2=C1 BQFHXNJPWFQYES-UHFFFAOYSA-N 0.000 claims description 2
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims description 2
- JURGPCFAAKMAIA-UHFFFAOYSA-N 2-cyclohexyl-1,2,3,4-tetrahydroquinazoline-6-sulfonamide Chemical compound N1CC2=CC(S(=O)(=O)N)=CC=C2NC1C1CCCCC1 JURGPCFAAKMAIA-UHFFFAOYSA-N 0.000 claims description 2
- CCCLGUCOGQADHQ-UHFFFAOYSA-N 2-ethyl-2-methyl-3h-1,3-benzoxazin-4-one Chemical compound C1=CC=C2OC(CC)(C)NC(=O)C2=C1 CCCLGUCOGQADHQ-UHFFFAOYSA-N 0.000 claims description 2
- MOFJSTXFUSYCDO-UHFFFAOYSA-N 2-methyl-2,3-dihydro-1,3-benzoxazin-4-one Chemical compound C1=CC=C2OC(C)NC(=O)C2=C1 MOFJSTXFUSYCDO-UHFFFAOYSA-N 0.000 claims description 2
- AMZRLVJMBHMIPA-UHFFFAOYSA-N 2-phenyl-2,3-dihydro-1,3-benzoxazin-4-one Chemical compound O1C2=CC=CC=C2C(=O)NC1C1=CC=CC=C1 AMZRLVJMBHMIPA-UHFFFAOYSA-N 0.000 claims description 2
- ZXTHWIZHGLNEPG-UHFFFAOYSA-N 2-phenyl-4,5-dihydro-1,3-oxazole Chemical compound O1CCN=C1C1=CC=CC=C1 ZXTHWIZHGLNEPG-UHFFFAOYSA-N 0.000 claims description 2
- UOCUSOBVEHOMMB-UHFFFAOYSA-N 2h-1$l^{6},2,3-benzothiadiazine 1,1-dioxide Chemical compound C1=CC=C2S(=O)(=O)NN=CC2=C1 UOCUSOBVEHOMMB-UHFFFAOYSA-N 0.000 claims description 2
- XSVCDKNLLZPUHQ-UHFFFAOYSA-N 3-(1-adamantyl)-5,7-dibromo-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine 1,1-dioxide Chemical compound C1C(C2)CC(C3)CC2CC13C1NC2=C(Br)C=C(Br)C=C2S(=O)(=O)N1 XSVCDKNLLZPUHQ-UHFFFAOYSA-N 0.000 claims description 2
- IXKMHMLMLKFTME-UHFFFAOYSA-N 3-cyclohexyl-1,1-dioxo-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazin-7-amine Chemical compound N1S(=O)(=O)C2=CC(N)=CC=C2NC1C1CCCCC1 IXKMHMLMLKFTME-UHFFFAOYSA-N 0.000 claims description 2
- XUQWBBUOVQYUAZ-UHFFFAOYSA-N 3-cyclohexyl-1,1-dioxo-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine-7-carbonitrile Chemical compound N1C2=CC=C(C#N)C=C2S(=O)(=O)NC1C1CCCCC1 XUQWBBUOVQYUAZ-UHFFFAOYSA-N 0.000 claims description 2
- IWCUSNNKTQYZRR-UHFFFAOYSA-N 3-cyclohexyl-1,1-dioxo-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine-7-carboxamide Chemical compound N1S(=O)(=O)C2=CC(C(=O)N)=CC=C2NC1C1CCCCC1 IWCUSNNKTQYZRR-UHFFFAOYSA-N 0.000 claims description 2
- RGDFUTUYFYKNHL-UHFFFAOYSA-N 3-cyclohexyl-1,1-dioxo-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine-7-sulfonamide Chemical compound N1S(=O)(=O)C2=CC(S(=O)(=O)N)=CC=C2NC1C1CCCCC1 RGDFUTUYFYKNHL-UHFFFAOYSA-N 0.000 claims description 2
- RKQNBZGBUDFCGQ-UHFFFAOYSA-N 3-cyclohexyl-6-(2-methoxyphenyl)-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine 1,1-dioxide Chemical compound COC1=CC=CC=C1C1=CC=C2S(=O)(=O)NC(C3CCCCC3)NC2=C1 RKQNBZGBUDFCGQ-UHFFFAOYSA-N 0.000 claims description 2
- ISRRWUNTXIBXAA-UHFFFAOYSA-N 3-cyclohexyl-6-(2-methoxyphenyl)-7-methyl-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine 1,1-dioxide Chemical compound COC1=CC=CC=C1C(C(=C1)C)=CC2=C1S(=O)(=O)NC(C1CCCCC1)N2 ISRRWUNTXIBXAA-UHFFFAOYSA-N 0.000 claims description 2
- YHCXRGBPUHDXAT-UHFFFAOYSA-N 3-cyclohexyl-6-methyl-1,1-dioxo-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine-7-sulfonamide Chemical compound N1S(=O)(=O)C=2C=C(S(N)(=O)=O)C(C)=CC=2NC1C1CCCCC1 YHCXRGBPUHDXAT-UHFFFAOYSA-N 0.000 claims description 2
- LTTNPGLVTMWWQN-UHFFFAOYSA-N 3-cyclohexyl-7-(1-methylimidazol-2-yl)-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine 1,1-dioxide Chemical compound CN1C=CN=C1C1=CC=C(NC(NS2(=O)=O)C3CCCCC3)C2=C1 LTTNPGLVTMWWQN-UHFFFAOYSA-N 0.000 claims description 2
- WZECQUDNNKHKQK-UHFFFAOYSA-N 3-cyclohexyl-7-(2,4-dimethoxyphenyl)-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine 1,1-dioxide Chemical compound COC1=CC(OC)=CC=C1C1=CC=C(NC(NS2(=O)=O)C3CCCCC3)C2=C1 WZECQUDNNKHKQK-UHFFFAOYSA-N 0.000 claims description 2
- ZJYBPAKREINUPO-UHFFFAOYSA-N 3-cyclohexyl-7-(2-methoxyphenyl)-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine 1,1-dioxide Chemical compound COC1=CC=CC=C1C1=CC=C(NC(NS2(=O)=O)C3CCCCC3)C2=C1 ZJYBPAKREINUPO-UHFFFAOYSA-N 0.000 claims description 2
- JOOYBBYBBFKNIT-UHFFFAOYSA-N 3-cyclohexyl-7-(4-methylpiperidin-1-yl)sulfonyl-3,4-dihydro-2H-1lambda6,2,4-benzothiadiazine 1,1-dioxide Chemical compound CC1CCN(CC1)S(=O)(=O)C2=CC3=C(C=C2)NC(NS3(=O)=O)C4CCCCC4 JOOYBBYBBFKNIT-UHFFFAOYSA-N 0.000 claims description 2
- PERVUQCEACNMMX-UHFFFAOYSA-N 3-cyclohexyl-7-pyrrolidin-1-ylsulfonyl-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine 1,1-dioxide Chemical compound C=1C=C2NC(C3CCCCC3)NS(=O)(=O)C2=CC=1S(=O)(=O)N1CCCC1 PERVUQCEACNMMX-UHFFFAOYSA-N 0.000 claims description 2
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- SJXMJUXZVDLBTM-UHFFFAOYSA-N 3-cyclohexyl-8-methyl-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine 1,1-dioxide Chemical compound N1S(=O)(=O)C=2C(C)=CC=CC=2NC1C1CCCCC1 SJXMJUXZVDLBTM-UHFFFAOYSA-N 0.000 claims description 2
- OFRSZWPEVPVADE-UHFFFAOYSA-N 3-cyclohexyl-n,n-diethyl-1,1-dioxo-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine-7-sulfonamide Chemical compound N1S(=O)(=O)C2=CC(S(=O)(=O)N(CC)CC)=CC=C2NC1C1CCCCC1 OFRSZWPEVPVADE-UHFFFAOYSA-N 0.000 claims description 2
- PMMNAVXGIVYGHU-UHFFFAOYSA-N 3-phenyl-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine 1,1-dioxide Chemical compound N1C2=CC=CC=C2S(=O)(=O)NC1C1=CC=CC=C1 PMMNAVXGIVYGHU-UHFFFAOYSA-N 0.000 claims description 2
- YYPWDMFWDGAUPK-UHFFFAOYSA-N 4-oxo-2-(trifluoromethyl)-1h-quinazoline-6-sulfonamide Chemical compound N1=C(C(F)(F)F)NC(=O)C2=CC(S(=O)(=O)N)=CC=C21 YYPWDMFWDGAUPK-UHFFFAOYSA-N 0.000 claims description 2
- CFCVLMZNGXXJGA-UHFFFAOYSA-N 5,7-dibromo-3-methyl-4h-1$l^{6},2,4-benzothiadiazine 1,1-dioxide Chemical class C1=C(Br)C=C2S(=O)(=O)NC(C)=NC2=C1Br CFCVLMZNGXXJGA-UHFFFAOYSA-N 0.000 claims description 2
- XGOZNHPMPZJDPE-UHFFFAOYSA-N 5,7-dibromo-3-phenyl-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine 1,1-dioxide Chemical compound N1S(=O)(=O)C2=CC(Br)=CC(Br)=C2NC1C1=CC=CC=C1 XGOZNHPMPZJDPE-UHFFFAOYSA-N 0.000 claims description 2
- PBSYDJWXTZFDNB-UHFFFAOYSA-N 5,7-dibromo-4h-1$l^{6},2,4-benzothiadiazine 1,1-dioxide Chemical compound N1=CNS(=O)(=O)C2=CC(Br)=CC(Br)=C21 PBSYDJWXTZFDNB-UHFFFAOYSA-N 0.000 claims description 2
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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Abstract
The invention provides novel compounds represented by general formula (I) wherein the bond represented by the broken line may be a single, double bond or absent; and if the bond is absent, then the nitrogen is substituted with a hydrogen and R<2>; X represents SO2 or C=O of CH2; Y represents -CH(R<4>)-, -N(R<4>)- or -N(R<4>)-CH2-, O; and the meaning of R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, and R<8> are as defined in the application. The compounds are useful as positive modulators of the AMPA-receptor.
Description
The present invention relates to new compound, contain the pharmaceutical composition of this compound and their therepic use as the responsive glutamate receptor modulators of AMPA.
L-L-glutamic acid is that the main excitor nerve in the mammalian central nervous system transmits matter, and it activates the hypotype of several ionotropies and metabotropic acceptor.According to structure and pharmacology difference, the ionotropy acceptor can be divided into three kinds of hypotype: NMDA again, AMPA and kainic acid ester acceptor.
In many neurological diseases such as presenile dementia, senile dementia is observed in the apoplexy, and the damage of L-glutamic acid energy neurotransmission relates to loss (McEntee and the Crook of learning and memory, " neuropharmacology " (Psycopharmacology), 111:391-401 (1993)).Extensive received theory is that learning and memory relates to long-term reinforcement (LTP) and induces, and after high frequency stimulated repeatedly, the cynapse intensity stabilization of this long-term reinforcement increased.Experimental study shows, increases induce (Arai and Lynch, " brain research " (Brain Research), the 598:173-184 (1992)) that can be improved LTP by the cynapse response of ampa receptor mediation.For the foregoing reasons, the compound that ampa receptor responds in the stimulation brain can be induced the improvement of intelligence behavior and performance.
To cause quick receptor desensitization with L-L-glutamic acid or selective excitement agent AMPA activation ampa receptor, although promptly exist stimulant, receptor channel still can not be opened.Therefore, can desensitize and obtain the increase of cynapse intensity by reducing the normal ampa receptor of discharging of endogenous neurotransmitter L-L-glutamic acid.
People such as Ito once reported in nineteen ninety (" physiology magazine " (J.Physiol.), 424:533-543), ionotropy medicine aniracetam (N-methoxybenzoyl-2-Pyrrolidone) can increase with the AMPA inductive electric current in the ovocyte of mouse brain mRNA injection.Another research has disclosed the compound 1-(1 that a kind of raising is transmitted by the cynapse of ampa receptor inductive to people, 3-benzo dioxole-5-base carbonyl)-1,2,3, the 6-tetrahydropyridine, when giving the laboratory animal administration with unusual high dosage (120mg/kg) to improve memory be effectively (people such as Staubli, " NAS's journal " (Pro.Natl.Acad.Sci.USA), 91:11158-11162 (1994)).
Benzothiadiazine cyclothiazide (benzothiadiazide cyclothiazide) is the conditioning agent (people such as Johanson of stronger than aniracetam in effective external ampa receptor electric current, " molecular pharmacology " (Mol.Pharmacal.), 48:946-955 (1995)).Cyclothiazide to the mechanism of action of ampa receptor electric current exercise performance obviously with aniracetam different (people such as Partin, " neuroscience magazine " (J.Neuroscience), 16:6634-6647 (1996)).But, because cyclothiazide can not pass the blood cerebral disorders after peripheral administration, so it regulates readily good therapeutic effect to ampa receptor.The low usefulness of known compound also meets the high requirement to high resolution, because will use the higher dosage administration.
US 5,488, and 049 has discussed the method with benzothiadiazine derivatives treatment memory and study relative disease.Wherein said compound is structurally very close with The compounds of this invention.But The compounds of this invention still demonstrates stronger effectiveness when low concentration.(US 5,488,049 Fig. 3)
US 4,184, and 039 discloses the purposes of benzothiadiazine aspect the promotion hair growth.
DE 1470316 has described the preparation method of some benzothiadiazines that are used as zinc-plated bath additive.
In " synthesizing " (Synthesis) (10), 183, p.851 in relevant for benzothiadiazine-1,1-dioxide preparation method's description.Compound wherein is used as antihypertensive drug and antiseptic-germicide.
(J.Med.Chem.) (15, No.4), p.400-403 people are to benzothiadiazine-1 in (1972), and it is the research of antihypertensive active aspect that the π substituent constant of 1-dioxide has carried out structure-activity at " pharmaceutical chemistry magazine ".
WO 9812185 discloses the benzothiadiazine different with the The compounds of this invention structure.
Purpose of the present invention provides the AMPA conditioning agent of enthusiasm, treats illness or the disease that Mammals comprises the people with them, particularly treats ampa receptor in the brain is regulated responsive disease and illness.
Another object of the present invention provides the treatment Mammals and comprises illness or the disease of people to ampa receptor conditioning agent sensitivity, comprises the administration The compounds of this invention to this treatment of needs.
The 3rd purpose of the present invention provides the treatment Mammals and comprises that the people is to the illness of ampa receptor conditioning agent sensitivity or the pharmaceutical composition of disease.
Other purposes of the present invention it will be apparent to those skilled in the art that.
The present invention especially comprises the following compounds of one or combining form:
The compound of formula I representative,
Wherein the key represented of dotted line can be a singly-bound, two keys or do not have key; If there is not key, then this nitrogen is by hydrogen and R
2Replace;
X represents SO
2Or C=O or CH
2
Y representative-CH (R
4)-,-N (R
4)-or-N (R
4)-CH
2-, O;
R
2Represent hydrogen, alkyl, cycloalkyl, aryl, benzyl; CO-R
9, R wherein
9Represent alkyl, cycloalkyl, benzyl, aryl; Or
R
2With R
3And their continuous atom formation 4-7 person rings, this ring is replaced by one or more following substituting groups arbitrarily: halogen, and alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, and contain one or more heteroatomss arbitrarily, reach and contain carbonyl arbitrarily;
R
3Represent hydrogen, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyano group alkyl, alkoxyalkyl, alkoxyl group, halogenated alkoxy, acyl group, alkyl-NR
13R
14, alkyl-S-R
13, R wherein
13And R
14Represent hydrogen respectively, alkyl, cycloalkyl; Or R
13And R
14The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle; Arbitrarily by halogen, alkyl, 7-12 person's carbocyclic ring that hydroxyl or alkoxyl group replace; Arbitrarily by halogen, alkyl, the 3-8 element heterocycle that hydroxyl or alkoxyl group replace; This heterocycle is arbitrarily with aryl-condensed; Arbitrarily by the benzyl of one or more following substituting groups replacements: halogen, cycloalkyl, alkyl, hydroxyl, alkoxyl group, amino or sulfenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino; Arbitrarily by the aryl of one or more following substituting groups replacements: halogen, cycloalkyl, alkyl, hydroxyl, alkoxyl group, amino or sulfenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino; Or
R
3With R
2Or R
4And the atom that links to each other with them formation 4-7 person ring, this ring is replaced by one or more following substituting groups arbitrarily: halogen, and alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, and contain one or more heteroatomss arbitrarily, and contain carbonyl arbitrarily;
R
4Represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl ,-CO-R
10Or CO
2R
10, R wherein
10Represent hydrogen, cycloalkyl, alkyl, aryl or benzyl; Or
R
4With R
3And the atom that links to each other with them formation 4-7 person ring, this ring is replaced by one or more following substituting groups arbitrarily: halogen, and alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, and contain one or more heteroatomss arbitrarily, and contain carbonyl arbitrarily;
R
5Represent hydrogen, halogen, alkyl, thiazolinyl, alkynyl, aryl ,-SO
2-NR
11R
12, R wherein
11And R
12Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
11And R
12The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed;
R
6Represent hydrogen, halogen, alkyl, cyano group, cyano group alkyl, nitro, alkoxyl group, halogenated alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, ring haloalkyl ,-NR
15R
16,-NHSO
2-R
15,-NHSO
2-aryl, wherein aryl is replaced by one or more following substituting groups arbitrarily: halogen, alkyl, cycloalkyl, hydroxyl, alkoxyl group, amino, sulfenyl, CF
3, OCF
3, NO
2Or aryl; Arbitrarily by the aryl of one or more following substituting groups replacements: alkyl, cycloalkyl, alkoxyl group, haloalkyl, halogenated alkoxy, hydroxyalkyl, alkoxyalkyl or amino; Arbitrarily by the HET of one or more following substituting groups replacements: alkyl, cycloalkyl, alkoxyl group, halogen, haloalkyl or halogenated alkoxy;-(alkyl)
m-S-R
15,-(alkyl)
m-SO-R
15,-(alkyl)
m-SO
2-R
15,-(alkyl)
m-SO
2O-R
15,-(alkyl)
m-SO
2-NR
15R
16,-(alkyl)
m-NHCOR
15,-(alkyl)
m-CONR
15R
16,-(alkyl)
m-CR '=NOR " ,-(alkyl)
m-CO-R
15,-(alkyl)
m-CO
2-R
15, wherein m is 0 or 1; And R ' and R " represent hydrogen, alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, benzyl respectively; And R
15And R
16Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
15And R
16The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed;
R
7Represent hydrogen, halogen, alkyl, cyano group, cyano group alkyl, nitro, 4-nitro alkyl, alkoxyl group, halogenated alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, ring haloalkyl;-NR
17R
18,-NHSO
2-R
17,-NHSO
2-aryl, wherein aryl is replaced by one or more following substituting groups arbitrarily: halogen, alkyl, cycloalkyl, hydroxyl, alkoxyl group, amino, sulfenyl, CF
3, OCF
3, NO
2Or aryl;-(alkyl)
m-S-R
17,-(alkyl)
m-SO-R
17,-(alkyl)
m-SO
2-R
17,-(alkyl)
m-SO
2O-R
17,-(alkyl)
m-SO
2-NR
17R
18,-(alkyl)
m-NHCOR
17,-(alkyl)
m-CONR
17R
18,-(alkyl)
m-CR '=NOR " ,-(alkyl)
m-CO-R
17,-(alkyl)
m-CO
2-R
17, wherein m is 0 or 1; And R ' and R " represent hydrogen, alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, benzyl respectively; And R
17And R
18Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
17And R
18The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed; Arbitrarily by the HET of one or more following substituting groups replacements: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, alkoxyl group, amino, sulfenyl, aryl ,-S-alkyl ,-S-aryl, SO-alkyl, SO-aryl, SO
2-alkyl, SO
2-aryl, SO
2NR
17R
18Arbitrarily by the aryl of one or more following substituting groups replacements: alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, hydroxyalkyl, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF
3,-SO
2NR
17R
18, R wherein
17And R
18Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
17And R
18The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed; Or
R
7With R
6Or R
8Be formed with 5-7 person's ring of one of array structure down together :-O-(CH
2)
n-O-, wherein n is 1,2 or 3;-SO
2-NR-(CH
2)
n-, wherein n is 1 or 2;-SO-NR-(CH
2)
n-, wherein n is 1 or 2;-SO
2-(CH
2)
n-, wherein n is 2 or 3;-SO-(CH
2)
n-, wherein n is 2 or 3;-CO-CH=CH-NH-;-CO-CH=CH-O-;-CO-(CH
2)
n-NH-, wherein n is 1 or 2;-CO-NH-(CH
2)
n-, wherein n is 1 or 2;-CO-(CH
2)
2-O-;-O-(CH
2)
n-O-, wherein n is, 2 or 3;
R
8Represent hydrogen, alkyl, alkoxyl group, hydroxyalkyl, halogen, haloalkyl, CN, cyano group alkyl, nitro, 4-nitro alkyl; Arbitrarily by the aryl of one or more following substituting groups replacements: halogen, CF
3, OCF
3, NO
2, alkyl, cycloalkyl, alkoxyl group; Arbitrarily by the HET of one or more following substituting groups replacements: halogen, CF
3, OCF
3, NO
2, alkyl, cycloalkyl, alkoxyl group;-(alkyl)
m-S-R
19,-(alkyl)
m-SO-R
19,-(alkyl)
m-SO
2-R
19,-(alkyl)
m-SO
2O-R
19,-(alkyl)
m-SO
2-NR
19R
20,-(alkyl)
m-NHCOR
19,-(alkyl)
m-CONR
19R
20,-(alkyl)
m-CR '=NOR " ,-(alkyl)
m-CO-R
19,-(alkyl)
m-CO
2-R
19, wherein m is 0 or 1; And R ' and R " represent hydrogen, alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, benzyl respectively; And R
19And R
20Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
19And R
20The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed; Condition is: if the two keys of the representative of the dotted line in the formula I, X represents SO
2, Y represents NH, and compound is mono-substituted, and then it can not be R
3Single substitution compound for following groups: OCH
3, methyl, amyl group, the tertiary butyl, aminophenyl, 2-vinylbenzene, styroyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, norbornylene, benzyl, thienyl, furyl, aryl, by the 4-methyl, 4-methoxyl group, 4-chlorine, the aryl that 4-nitro or 3-nitro replace; And, if compound is R wherein
3Be two substitution compounds of methyl, then R
5Not Cl, CH
3Or R
7Not F, Cl, Br, I, CH
3, CF
3, nitro, SO
2N (CH
3)
2Or R
6Not Cl, Br, CH
3, CF
3, ethyl, methoxyl group; Perhaps, if R
7Be chlorine, R then
3Not ethyl, butyl, sec-butyl, the tertiary butyl, cyclobutyl, 2,2-dimethyl propyl, phenyl; And if compound is two substitution compounds, then it can not be two substitution compounds that following situation is arranged: R
6=OMe, R
3=ethyl; R
6=methyl, R
3=propyl group; R
7=SO
2NH
2, R
6=Cl; R
7=SO
2NH
2, R
3=phenyl; R
7=Br, R
3=phenyl; And condition is: if compound is trisubstituted, then it can not be three substitution compounds that following situation is arranged: R
3=CH
3, R
5=NO
2, R
7=Cl; R
3=CH
3, R
6=NO
2, R
7=Cl; R
3=CH
3, R
5=NH
2, R
7=Cl; And condition is: if the dotted line in the formula I is represented singly-bound, X represents SO
2And Y represents NH, and then compound is not R wherein
7Or R
6Be chlorine and R
3Be two substitution compounds of following groups: alkyl, cyclobutyl, cyclopropyl, cyclohexyl, tetrahydrobenzene, norbornene, the norborneol alkyl, ethylmercapto group methyl, ethoxyl methyl, ethoxyethyl group, methoxymethyl, methylamino, the 2-chloroethyl, chloromethyl, dichloromethyl, trifluoromethyl, amino; And compound can not be R
3Be CH
3And three substitution compounds with following situation: R
5=sec.-propyl, R
7=F; R
5=ethyl, R
7=Cl; R
5=propyl group, R
7=Cl; R
5=propyl group, R
7=F; R
5=methyl, R
7=Cl; R
5=ethyl, R
7=methyl; R
5=Cl, R
7=methyl; R
5=methyl, R
7=Cl; R
4=methyl, R
5=ethyl; Or R
4=methyl, R
5=methyl, R
7=F.
Contain the above-claimed cpd for the treatment of significant quantity and the pharmaceutical composition of pharmaceutically acceptable carrier or vehicle.
The compound of formula I representative is used to prepare the purposes that treatment is regulated the medicine of responsive illness or disease to the ampa receptor mixture,
Wherein the key represented of dotted line can be a singly-bound, two keys or do not have key; If there is not key, then this nitrogen is by hydrogen and R
2Replace;
X represents SO
2Or C=O or CH
2
Y representative-CH (R
4)-,-N (R
4)-or-N (R
4)-CH
2-, O;
R
2Represent hydrogen, alkyl, cycloalkyl, aryl, benzyl; CO-R
9, R wherein
9Represent alkyl, cycloalkyl, benzyl, aryl; Or
R
2With R
3And their continuous atom formation 4-7 person rings, this ring is replaced by one or more following substituting groups arbitrarily: halogen, and alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, and contain one or more heteroatomss arbitrarily, reach and contain carbonyl arbitrarily;
R
3Represent hydrogen, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyano group alkyl, alkoxyalkyl, alkoxyl group, halogenated alkoxy, acyl group, alkyl-NR
13R
14, alkyl-S-R
13, R wherein
13And R
14Represent hydrogen respectively, alkyl, cycloalkyl; Or R
13And R
14The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle; Arbitrarily by halogen, alkyl, 7-12 person's carbocyclic ring that hydroxyl or alkoxyl group replace; Arbitrarily by halogen, alkyl, the 3-8 element heterocycle that hydroxyl or alkoxyl group replace; This heterocycle is arbitrarily with aryl-condensed; Arbitrarily by the benzyl of one or more following substituting groups replacements: halogen, cycloalkyl, alkyl, hydroxyl, alkoxyl group, amino or sulfenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino; Arbitrarily by the aryl of one or more following substituting groups replacements: halogen, cycloalkyl, alkyl, hydroxyl, alkoxyl group, amino or sulfenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino; Or
R
3With R
2Or R
4And their continuous atom formation 4-7 person rings, this ring is replaced by one or more following substituting groups arbitrarily: halogen, and alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, and contain one or more heteroatomss arbitrarily, reach and contain carbonyl arbitrarily;
R
4Represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl ,-CO-R
10Or CO
2R
10, R wherein
10Represent hydrogen, cycloalkyl, alkyl, aryl or benzyl; Or
R
4With R
3And their continuous atom formation 4-7 person rings, this ring is replaced by one or more following substituting groups arbitrarily: halogen, and alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, and contain one or more heteroatomss arbitrarily, reach and contain carbonyl arbitrarily;
R
5Represent hydrogen, halogen, alkyl, thiazolinyl, alkynyl, aryl ,-SO
2-NR
11R
12, R wherein
11And R
12Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
11And R
12The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is condensed into aryl arbitrarily;
R
6Represent hydrogen, halogen, alkyl, cyano group, cyano group alkyl, nitro, alkoxyl group, halogenated alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, ring haloalkyl;-NR
15R
16,-NHSO
2-R
15,-NHSO
2-aryl, wherein aryl is replaced by one or more following substituting groups arbitrarily: halogen, alkyl, cycloalkyl, hydroxyl, alkoxyl group, amino, sulfenyl, CF
3, OCF
3, NO
2Or aryl; Arbitrarily by the aryl of one or more following substituting groups replacements: alkyl, cycloalkyl, alkoxyl group, haloalkyl, halogenated alkoxy, hydroxyalkyl, alkoxyalkyl or amino; Arbitrarily by the HET of one or more following substituting groups replacements: alkyl, cycloalkyl, alkoxyl group, halogen, haloalkyl or halogenated alkoxy;-(alkyl)
m-S-R
15,-(alkyl)
m-SO-R
15,-(alkyl)
m-SO
2-R
15,-(alkyl)
m-SO
2O-R
15,-(alkyl)
m-SO
2-NR
15R
16,-(alkyl)
m-NHCOR
15,-(alkyl)
m-CONR
15R
16,-(alkyl)
m-CR '=NOR " ,-(alkyl)
m-CO-R
15,-(alkyl)
m-CO
2-
R
15, wherein m is 0 or 1; And R ' and R " represent hydrogen, alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, benzyl respectively; And R
15And R
16Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
15And R
16The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed;
R
7Represent hydrogen, halogen, alkyl, cyano group, cyano group alkyl, nitro, 4-nitro alkyl, alkoxyl group, halogenated alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, ring haloalkyl;-NR
17R
18,-NHSO
2-R
17,-NHSO
2-aryl, wherein aryl is replaced by one or more following substituting groups arbitrarily: halogen, alkyl, cycloalkyl, hydroxyl, alkoxyl group, amino, sulfenyl, CF
3, OCF
3, NO
2Or aryl;-(alkyl)
m-S-R
17,-(alkyl)
m-SO-R
17,-(alkyl)
m-SO
2-R
17,-(alkyl)
m-SO
2O-R
17,-(alkyl)
m-SO
2-NR
17R
18,-(alkyl)
m-NHCOR
17,-(alkyl)
m-CONR
17R
18,-(alkyl)
m-CR '=NOR " ,-(alkyl)
m-CO-R
17,-(alkyl)
m-CO
2-R
17, wherein m is 0 or 1; And R ' and R " represent hydrogen, alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, benzyl respectively; And R
17And R
18Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
17And R
18The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed; Arbitrarily by the HET of one or more following substituting groups replacements: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, alkoxyl group, amino, sulfenyl, aryl ,-S-alkyl ,-S-aryl, SO-alkyl, SO-aryl, SO
2-alkyl, SO
2-aryl, SO
2NR
17R
18Arbitrarily by the aryl of one or more following substituting groups replacements: alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, hydroxyalkyl, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF
3,-SO
2NR
17R
18, R wherein
17And R
18Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
17And R
18The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed; Or
R
7With R
6Or R
8Form 5-7 person's ring that one of following array structure is arranged together :-O-(CH
2)
n-O-, wherein n is 1,2 or 3;-SO
2-NR-(CH
2)
n-, wherein n is 1 or 2;-SO-NR-(CH
2)
n-, wherein n is 1 or 2;-SO
2-(CH
2)
n-, wherein n is 2 or 3;-SO-(CH
2)
n-, wherein n is 2 or 3;-CO-CH=CH-NH-;-CO-CH=CH-O-;-CO-(CH
2)
n-NH-, wherein n is 1 or 2;-CO-NH-(CH
2)
n-, wherein n is 1 or 2;-CO-(CH
2)
2-O-;-O-(CH
2)
n-O-, wherein n is 1,2 or 3;
R
8Represent hydrogen, alkyl, alkoxyl group, hydroxyalkyl, halogen, haloalkyl, CN, cyano group alkyl, nitro, 4-nitro alkyl; Arbitrarily by the aryl of one or more following substituting groups replacements: halogen, CF
3, OCF
3, NO
2, alkyl, cycloalkyl, alkoxyl group; Arbitrarily by the HET of one or more following substituting groups replacements: halogen, CF
3, OCF
3, NO
2, alkyl, cycloalkyl, alkoxyl group;-(alkyl)
m-S-R
19,-(alkyl)
m-SO-R
19,-(alkyl)
m-SO
2-R
19,-(alkyl)
m-SO
2O-R
19,-(alkyl)
m-SO
2-NR
19R
20,-(alkyl)
m-NHCOR
19,-(alkyl)
m-CONR
19R
20,-(alkyl)
m-CR '=NOR " ,-(alkyl)
m-CO-R
19,-(alkyl)
m-CO
2-R
19, wherein m is 0 or 1; And R ' and R " represent hydrogen, alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, benzyl respectively; And R
19And R
20Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
19And R
20The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed.
Treatment is regulated the responsive illness or the method for disease to the ampa receptor complex compound, comprises that the compound that the formula I of treatment significant quantity is represented carries out administration,
Wherein the key represented of dotted line can be a singly-bound, two keys or do not have key; If there is not key, then this nitrogen is by hydrogen and R
2Replace;
X represents SO
2Or C=O or CH
2
Y representative-CH (R
4)-,-N (R
4)-or-N (R
4)-CH
2-, O;
R
2Represent hydrogen, alkyl, cycloalkyl, aryl, benzyl; CO-R
9, R wherein
9Represent alkyl, cycloalkyl, benzyl, aryl; Or
R
2With R
3And their continuous atom formation 4-7 person rings, this ring is replaced by one or more following substituting groups arbitrarily: halogen, and alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, and contain one or more heteroatomss arbitrarily, reach and contain carbonyl arbitrarily;
R
3Represent hydrogen, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyano group alkyl, alkoxyalkyl, alkoxyl group, halogenated alkoxy, acyl group, alkyl-NR
13R
14, alkyl-S-R
13, R wherein
13And R
14Represent hydrogen respectively, alkyl, cycloalkyl; Or R
13And R
14The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle; Arbitrarily by halogen, alkyl, 7-12 person's carbocyclic ring that hydroxyl or alkoxyl group replace; Arbitrarily by halogen, alkyl, the 3-8 element heterocycle that hydroxyl or alkoxyl group replace; This heterocycle is condensed into aryl arbitrarily; Arbitrarily by the benzyl of one or more following substituting groups replacements: halogen, cycloalkyl, alkyl, hydroxyl, alkoxyl group, amino or sulfenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino; Arbitrarily by the aryl of one or more following substituting groups replacements: halogen, cycloalkyl, alkyl, hydroxyl, alkoxyl group, amino or sulfenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino; Or
R
3With R
2Or R
4And their continuous atom formation 4-7 person rings, this ring is replaced by one or more following substituting groups arbitrarily: halogen, and alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, and contain one or more heteroatomss arbitrarily, reach and contain carbonyl arbitrarily;
R
4Represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl ,-CO-R
10Or CO
2R
10, R wherein
10Represent hydrogen, cycloalkyl, alkyl, aryl or benzyl; Or
R
4With R
3And their continuous atom formation 4-7 person rings, this ring is replaced by one or more following substituting groups arbitrarily: halogen, and alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, and contain one or more heteroatomss arbitrarily, reach and contain carbonyl arbitrarily;
R
5Represent hydrogen, halogen, alkyl, thiazolinyl, alkynyl, aryl ,-SO
2-NR
11R
12, R wherein
11And R
12Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
11And R
12The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed;
R
6Represent hydrogen, halogen, alkyl, cyano group, cyano group alkyl, nitro, alkoxyl group, halogenated alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, ring haloalkyl;-NR
15R
16,-NHSO
2-R
15,-NHSO
2-aryl, wherein aryl is replaced by one or more following substituting groups arbitrarily: halogen, alkyl, cycloalkyl, hydroxyl, alkoxyl group, amino, sulfenyl, CF
3, OCF
3, NO
2Or aryl; Arbitrarily by the aryl of one or more following substituting groups replacements: alkyl, cycloalkyl, alkoxyl group, haloalkyl, halogenated alkoxy, hydroxyalkyl, alkoxyalkyl or amino; Arbitrarily by the HET of one or more following substituting groups replacements: alkyl, cycloalkyl, alkoxyl group, halogen, haloalkyl or halogenated alkoxy;-(alkyl)
m-S-R
15,-(alkyl)
m-SO-R
15,-(alkyl)
m-SO
2-R
15,-(alkyl)
m-SO
2O-R
15,-(alkyl)
m-SO
2-NR
15R
16,-(alkyl)
m-NHCOR
15,-(alkyl)
m-CONR
15R
16,-(alkyl)
m-CR '=NOR " ,-(alkyl)
m-CO-R
15,-(alkyl)
m-CO
2-R
15, wherein m is 0 or 1; And R ' and R " represent hydrogen, alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, benzyl respectively; And R
15And R
16Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
15And R
16The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed;
R
7Represent hydrogen, halogen, alkyl, cyano group, cyano group alkyl, nitro, 4-nitro alkyl, alkoxyl group, halogenated alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, ring haloalkyl;-NR
17R
18,-NHSO
2-R
17,-NHSO
2-aryl, wherein aryl is replaced by one or more following substituting groups arbitrarily: halogen, alkyl, cycloalkyl, hydroxyl, alkoxyl group, amino, sulfenyl, CF
3, OCF
3, NO
2Or aryl;-(alkyl)
m-S-R
17,-(alkyl)
m-SO-R
17,-(alkyl)
m-SO
2-R
17,-(alkyl)
m-SO
2O-R
17,-(alkyl)
m-SO
2-NR
17R
18,-(alkyl)
m-NHCOR
17,-(alkyl)
m-CONR
17R
18,-(alkyl) m-CR '=NOR " ,-(alkyl) m-CO-R
17,-(alkyl)
m-CO
2-R
17, wherein m is 0 or 1; And R ' and R " represent hydrogen, alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, benzyl respectively; And R
17And R
18Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
17And R
18The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed; Arbitrarily by the HET of one or more following substituting groups replacements: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, alkoxyl group, amino, sulfenyl, aryl ,-S-alkyl ,-S-aryl, SO-alkyl, SO-aryl, SO
2-alkyl, SO
2-aryl, SO
2NR
17R
18Arbitrarily by the aryl of one or more following substituting groups replacements: alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, hydroxyalkyl, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF
3,-SO
2NR
17R
18, R wherein
17And R
18Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
17And R
18The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed; Or
R
7With R
6Or R
8Form 5-7 person's ring that one of following array structure is arranged together :-O-(CH
2)
n-O-, wherein n is 1,2 or 3;-SO
2-NR-(CH
2)
n-, wherein n is 1 or 2;-SO-NR-(CH
2)
n-, wherein n is 1 or 2;-SO
2-(CH
2)
n-, wherein n is 2 or 3;-SO-(CH
2)
n-, wherein n is 2 or 3;-CO-CH=CH-NH-;-CO-CH=CH-O-;-CO-(CH
2)
n-NH-, wherein n is 1 or 2;-CO-NH-(CH
2)
n-, wherein n is 1 or 2;-CO-(CH
2)
2-O-;-O-(CH
2)
n-O-, wherein n is 1,2 or 3;
R
8Represent hydrogen, alkyl, alkoxyl group, hydroxyalkyl, halogen, haloalkyl, CN, cyano group alkyl, nitro, 4-nitro alkyl; Arbitrarily by the aryl of one or more following substituting groups replacements: halogen, CF
3, OCF
3, NO
2, alkyl, cycloalkyl, alkoxyl group; Arbitrarily by the HET of one or more following substituting groups replacements: halogen, CF
3, OCF
3, NO
2, alkyl, cycloalkyl, alkoxyl group;-(alkyl)
m-S-R
19,-(alkyl)
m-SO-R
19,-(alkyl)
m-SO
2-R
19,-(alkyl)
m-SO
2O-R
19,-(alkyl)
m-SO
2-NR
19R
20,-(alkyl)
m-NHCOR
19,-(alkyl)
m-CONR
19R
20,-(alkyl)
m-CR '=NOR " ,-(alkyl)
m-CO-R
19,-(alkyl)
m-CO
2-R
19, wherein m is 0 or 1; And R ' and R " represent hydrogen, alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, benzyl respectively; And R
19And R
20Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
19And R
20The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed.
The invention provides above-mentioned new formula I compound.The preferred embodiment of the invention is each group above-mentioned formula I compound as follows wherein:
R
2Represent hydrogen, alkyl, cycloalkyl, aryl, benzyl; Or
R
2With R
3And their continuous atom formation 5-6 person rings, this ring is replaced by one or more following substituting groups arbitrarily: halogen, and alkyl, hydroxyl, alkoxyl group, amino or sulfenyl, and contain one or more heteroatomss arbitrarily, reach and contain carbonyl arbitrarily;
R
3Represent hydrogen, cycloalkyl, cycloalkylalkyl, alkyl, haloalkyl, alkoxyl group, 7-10 person's carbocyclic ring; The 5-6 element heterocycle; Benzyl; Aryl; Or
R
3With R
2Or R
4Form 5-6 person's ring together;
R
4Represent hydrogen, alkyl; Or
R
4With R
3And their continuous atom formation 5-6 person rings, this ring is replaced by one or more following substituting groups arbitrarily: halogen, and alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, and contain one or more heteroatomss arbitrarily, reach and contain carbonyl arbitrarily;
R
5Represent hydrogen, halogen, alkyl, thiazolinyl, alkynyl, phenyl ,-SO
2-NR
11R
12, R wherein
11And R
12Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
11And R
12The nitrogen-atoms that links to each other with them forms the 5-6 element heterocycle;
R
6Represent hydrogen, Br, F, I, cycloalkyl, alkyl, alkoxyl group, alkoxyalkyl; Arbitrarily by the phenyl of one or more following substituting groups replacements: alkyl, alkoxyl group; HET;-S-R
15,-SO-R
15,-SO
2-R
15,-SO
2O-R
15,-SO
2-NR
15R
16,-NHCOR
15,-CONR
15R
16,-CR '=NOR " ,-CO-R
15,-CO
2-R
15, wherein R ' and R " and represent hydrogen, alkyl, cycloalkyl, phenyl, benzyl respectively; And R
15And R
16Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
15And R
16The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, phenyl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed;
R
7Represent hydrogen, Br, F, I, alkyl, cyano group, cyano group alkyl, nitro, 4-nitro alkyl, alkoxyl group, halogenated alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, ring haloalkyl ,-(alkyl)
m-NR
17R
18,-NHSO
2-R
17,-S-R
17,-SO-R
17,-SO
2-R
17,-SO
2O-R
17,-SO
2-NR
17R
18,-NHCOR
17,-CONR
17R
18,-CR '=NOR " ,-CO-R
17,-CO
2-R
17, wherein R ' and R " and represent hydrogen, alkyl, cycloalkyl, phenyl, benzyl respectively; And R
17And R
18Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
17And R
18The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: alkyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed; Arbitrarily by the HET of one or more following substituting groups replacements: halogen, alkyl, phenyl, SO
2NR
17R
18Arbitrarily by the phenyl of one or more following substituting groups replacements: alkyl, hydroxyl, alkoxyl group, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF
3,-SO
2NR
17R
18, R wherein
17And R
18Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
17And R
18The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed; Or
R
7With R
6Or R
8Form 5-7 person's ring that one of following array structure is arranged together :-O-(CH
2)
n-O-, wherein n is 1,2 or 3;-SO
2-NR-(CH
2)
n-, wherein n is 1 or 2;-SO-NR-(CH
2)
n-, wherein n is 1 or 2;-SO
2-(CH
2)
n-, wherein n is 2 or 3;-SO-(CH
2)
n-, wherein n is 2 or 3;-CO-CH=CH-NH-;-CO-CH=CH-O-;-CO-(CH
2)
n-NH-, wherein n is 1 or 2;-CO-NH-(CH
2)
n-, wherein n is 1 or 2;-CO-(CH
2)
2-O-;-O-(CH
2)
n-O-, wherein n is 1,2 or 3;
R
8Represent hydrogen, alkyl, alkoxyl group, hydroxyalkyl, halogen, haloalkyl, CN, cyano group alkyl, nitro, 4-nitro alkyl; Arbitrarily by the phenyl of one or more following substituting groups replacements: alkyl, cycloalkyl, alkoxyl group; HET;-S-R
19,-SO-R
19,-SO
2-R
19,-SO
2O-R
19,-SO
2-NR
19R
20,-NHCOR
19,-CONR
19R
20,-CR '=NOR " ,-CO-R
19,-CO
2-R
19, wherein R ' and R " and represent hydrogen, alkyl, cycloalkyl, phenyl, benzyl respectively; And R
19And R
20Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
19And R
20The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, phenyl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed.
Condition is: if X represents SO
2, Y represents N, and dotted line represents singly-bound, then R
7Or R
6
Be not chlorine, if R
2, R
4, R
5, R
8With a remaining R
6Or R
7All be hydrogen; Or
Condition is: have only the R of working as
5Be hydrogen or R
7R when being not sulfamyl
3Just can represent CH
3Condition is: if X represents SO
2, Y represents N, and dotted line representative two key, then R
7Or R
6Not all be chlorine, if R
2, R
4, R
5, R
8With a remaining R
6Or R
7All be hydrogen; Or condition is: R
2, R
4, R
5, R
6, R
7And R
8Not hydrogen; Or condition is: work as R
7Be fluorine, bromine, iodine, CF
3, CH
3, NO
2, SO
2N (CH
3)
2, or R
6Be bromine, CF
3, CH
3, ethyl, methoxyl group, or R
5When being chlorine, or R
8When being chlorine, this compound is not R
3Be CH
3Two substitution compounds; Or condition is: this compound is not a following compounds: 3-ethyl-6-methoxyl group-1,2,4-benzothiadiazine-1,1-dioxide; 3-propyl group-6-methoxyl group-1,2,4-benzothiadiazine-1,1-dioxide; 3-ethyl-6-methoxyl group-1,2,4-benzothiadiazine-1,1-dioxide; 3-phenyl-7-bromo-1,2,4-benzothiadiazine-1,1-dioxide; 3-phenyl-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide; 5-bromo-7-chloro-3-methyl isophthalic acid, 2,4-benzothiadiazine-1,1-dioxide; 5-iodo-7-chloro-3-methyl isophthalic acid, 2,4-benzothiadiazine-1,1-dioxide; 5-nitro-7-chloro-3-methyl isophthalic acid, 2,4-benzothiadiazine-1,1-dioxide; 6-nitro-7-chloro-3-methyl isophthalic acid, 2,4-benzothiadiazine-1,1-dioxide; Or 6-amino-7-chloro-3-methyl isophthalic acid, 2,4-benzothiadiazine-1,1-dioxide.
The preferred embodiment of the present invention is each group above-mentioned formula I compound as follows: R wherein
2Represent hydrogen, alkyl, cycloalkyl; Or R
2With R
3And their continuous atom formation 5-6 person rings, this ring is replaced by one or more following substituting groups arbitrarily: halogen, and alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, and contain one or more heteroatomss arbitrarily, reach and contain carbonyl arbitrarily;
R
3Represent hydrogen, cycloalkyl, alkyl, haloalkyl, alkoxyl group, 7-10 person's carbocyclic ring; The 5-6 element heterocycle; Benzyl; Aryl; Or
R
3With R
2Or R
4Form 5-6 person's ring together, this ring is replaced by one or more following substituting groups arbitrarily: halogen, and alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, and contain one or more heteroatomss arbitrarily, and contain carbonyl arbitrarily;
Another preferred embodiment is wherein
R
4Represent hydrogen, alkyl; Or
R
4With R
3And their continuous atom formation 5-6 person rings, this ring is replaced by one or more following substituting groups arbitrarily: halogen, and alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, and contain one or more heteroatomss arbitrarily, reach and contain carbonyl arbitrarily;
Another preferred embodiment is wherein
R
5Represent hydrogen, halogen, alkyl, thiazolinyl, alkynyl, phenyl ,-SO
2-NR
11R
12, R wherein
11And R
12Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
11And R
12The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle;
Another preferred embodiment is wherein
R
6Represent hydrogen, halogen, cycloalkyl, alkyl, alkoxyl group, alkoxyalkyl; Arbitrarily by the aryl of one or more following substituting groups replacements: alkyl, alkoxyl group; HET;-S-R
15,-SO-R
15,-SO
2-R
15,-SO
2O-R
15,-SO
2-NR
15R
16,-NHCOR
15,-CONR
15R
16,-CR '=NOR " ,-CO-R
15,-CO
2-R
15, wherein R ' and R " and represent hydrogen, alkyl, cycloalkyl, phenyl, benzyl respectively; And R
15And R
16Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
15And R
16The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, phenyl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed;
Another preferred embodiment is wherein
R
7Represent hydrogen, halogen, alkyl, cyano group, cyano group alkyl, nitro, alkoxyl group, halogenated alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, ring haloalkyl ,-(alkyl)
m-NR
17R
18,-NHSO
2-R
17,-S-R
17,-SO-R
17,-SO
2-R
17,-SO
2O-R
17,-SO
2-NR
17R
18,-NHCOR
17,-CONR
17R
18,-CR '=NOR " ,-CO-R
17,-CO
2-R
17, wherein R ' and R " and represent hydrogen, alkyl, cycloalkyl, phenyl, benzyl respectively; And R
17With
18Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
17And R
18The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: alkyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed; Arbitrarily by the HET of one or more following substituting groups replacements: halogen, alkyl, phenyl, SO
2NR
17R
18Arbitrarily by the phenyl of one or more following substituting groups replacements: alkyl, hydroxyl, alkoxyl group, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF
3,-SO
2NR
17R
18, R wherein
17And R
18Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
17And R
18The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed; Or
R
7With R
6Or R
8Form 5-7 person's ring that one of following array structure is arranged together :-O-(CH
2)
n-O-, wherein n is 1,2 or 3;-SO
2-NR-(CH
2)
n-, wherein n is 1 or 2;-SO-NR-(CH
2)
n-, wherein n is 1 or 2;-SO
2-(CH
2)
n-, wherein n is 2 or 3;-SO-(CH
2)
n-, wherein n is 2 or 3;-CO-CH=CH-NH-;-CO-CH=CH-O-;-CO-(CH
2)
n-NH-, wherein n is 1 or 2;-CO-NH-(CH
2)
n-, wherein n is 1 or 2;-CO-(CH
2)
2-O-;-O-(CH
2)
n-O-, wherein n is 1,2 or 3;
Another preferred embodiment is wherein
R
8Represent hydrogen, alkyl, alkoxyl group, hydroxyalkyl, halogen, haloalkyl, CN, cyano group alkyl, nitro, 4-nitro alkyl; Arbitrarily by the phenyl of one or more following substituting groups replacements: alkyl, cycloalkyl, alkoxyl group; HET;-S-R
19,-SO-R
19,-SO
2-R
19,-SO
2O-R
19,-SO
2-NR
19R
20,-NHCOR
19,-CONR
19R
20,-CR '=NOR " ,-CO-R
19,-CO
2-R
19, wherein R ' and R " and represent hydrogen, alkyl, cycloalkyl, phenyl, benzyl respectively; And R
19And R
20Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
19And R
20The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, phenyl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed.Particularly preferred embodiment is each group above-mentioned formula I compound as follows wherein:
X represents SO
2
Y represents N;
Dotted line is represented singly-bound;
R
2Represent hydrogen;
R
3Representation ring alkyl, 7-10 person's carbocyclic ring; The 5-6 element heterocycle;
R
4Represent H;
R
5Represent H;
R
6Represent hydrogen, alkyl or halogen;
R
7Represent the cyano group alkyl, 4-nitro alkyl, haloalkyl ,-(alkyl)
m-SO-R
17,-(alkyl)
m-SO
2-R
17,-(alkyl)
m-SO
2-NR
17R
18,-(alkyl)
m-CONR
17R
18,-(alkyl)
m-CR '=NOR " ,-(alkyl)
m-CO-R
17,-(alkyl)
m-CO
2-R
17, wherein m is 0 or 1; R ' and R " represent hydrogen, alkyl, cycloalkyl, phenyl, benzyl respectively; And R
17And R
18Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
17And R
18The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: alkyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed; HET; Or
R
7With R
6Or R
8Form 5-7 person's ring that one of following array structure is arranged together :-O-(CH
2)
n-O-, wherein n is 1,2 or 3;-SO
2-NR-(CH
2)
n-, wherein n is 1 or 2;-SO-NR-(CH
2)
n-, wherein n is 1 or 2;-SO
2-(CH
2)
n-, wherein n is 2 or 3;-SO-(CH
2)
n-, wherein n is 2 or 3;-CO-CH=CH-NH-;-CO-CH=CH-O-;-CO-(CH
2)
n-NH-, wherein n is 1 or 2;-CO-NH-(CH
2)
n-, wherein n is 1 or 2;-CO-(CH
2)
2-O-;-O-(CH
2)
n-O-, wherein n is 1,2 or 3;
R
8Represent alkyl, halogen, cyano group alkyl, 4-nitro alkyl, haloalkyl ,-(alkyl)
m-SO-R
17,-(alkyl)
m-SO
2-R
17,-(alkyl)
m-SO
2-NR
17R
18,-(alkyl)
m-CONR
17R
18,-(alkyl)
m-CR '=NOR " ,-(alkyl)
m-CO-R
17,-(alkyl)
m-CO
2-R
17, wherein m is 0 or 1; R ' and R " represent hydrogen, alkyl, cycloalkyl, phenyl, benzyl respectively; And R
17And R
18Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
17And R
18The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: alkyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed; HET; Specific embodiment of the present invention relates to above-mentioned formula I compound entirely.One embodiment of the invention is wherein
R
3Represent hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl group, sec.-propyl, CF
3, oxyethyl group, norbornylene, norbornane, diamantane, benzyl; Phenyl; Or
R
3With R
2Or R
4The atom that links to each other with them forms 5 Yuans rings together;
Another embodiment of the invention is wherein
R
4Represent hydrogen, methyl, ethyl; Or
R
4With R
3The atom that links to each other with them forms 5 Yuans rings together;
Another embodiment of the invention is wherein
R
5Represent hydrogen, chlorine, bromine, methyl, phenyl ,-SO
2NH
2
Another embodiment of the invention is wherein
R
6Represent hydrogen, 2-p-methoxy-phenyl, 2-pyridyl, 3-pyridyl, methyl, methoxyl group, chlorine or bromine;
Another embodiment of the invention is wherein
R
7Represent hydrogen, chlorine, bromine, methyl, 1-hydroxyethyl, ethanoyl ,-(CH
3) C=N-OH, CONH
2, CO
2-ethyl, cyano group, phenyl, 2-N-acetylamino phenyl, 2-nitrophenyl; the 2-p-methoxy-phenyl, 4-trifluoromethyl-2-p-methoxy-phenyl, 2,4-Dimethoxyphenyl, 2-N; N-dimethylamino alkylsulfonyl phenyl, 2-chloro-phenyl-, 2-fluorophenyl, 3-hydroxy phenyl, 2-pyridyl; the 3-pyridyl, 2-pyrimidyl, 2-furyl, 3-furyl; the 2-thienyl, 2-(N-methyl)-imidazolyl, 5-triazolyl, 4-phenyl-triazolyl-5-base; the 5-methyl isophthalic acid, 2,4-oxadiazole-3-base, CH
3CONH-, CH
3SO
2NH-, NO
2, SO
2OH, phenyl-SO
2-, sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl, N-phenyl-N-methyl-sulfamyl, N-cyclohexyl-sulfamyl ,-SO
2-heterocycle, this heterocycle is selected from piperidines, tetramethyleneimine, 1,2,5,6-tetrahydropyridine, tetrahydroquinoline, N methyl piperazine, N-alkylsulfonyl methyl-piperazine, morpholine;
Another embodiment is wherein
R
8Represent hydrogen, methyl, methylol, 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 2-pyridyl, methoxyl group; Particularly preferred embodiment is the formula I compound of above-mentioned representative, wherein
X represents SO
2
Y represents N;
Dotted line is represented singly-bound;
R
2Represent hydrogen or CH
3
R
3Represent cyclohexyl, cyclopentyl, norbornylene, norbornane, diamantane, phenyl, oxyethyl group;
R
4Represent hydrogen or CH
3
R
5Represent hydrogen, CH
3, phenyl, sulfamyl, chlorine, bromine;
R
6Represent hydrogen, CH
3, 2-p-methoxy-phenyl, methoxyl group, chlorine, bromine, 2-pyridyl, 3-pyridyl;
R
7Represent hydrogen, chlorine, bromine, methyl, 1-hydroxyethyl, ethanoyl ,-(CH
3) C=N-OH, CONH
2, CO
2-ethyl, cyano group, phenyl, 2-N-acetylamino phenyl, 2-nitrophenyl; the 2-p-methoxy-phenyl, 4-trifluoromethyl-2-p-methoxy-phenyl, 2,4-Dimethoxyphenyl, 2-N; N-dimethylamino alkylsulfonyl phenyl, 2-chloro-phenyl-, 2-fluorophenyl, 3-hydroxy phenyl, 2-pyridyl; the 3-pyridyl, 2-pyrimidyl, 2-furyl, 3-furyl; the 2-thienyl, 2-(N-methyl)-imidazolyl, 5-triazolyl, 4-phenyl-triazolyl-5-base; the 5-methyl isophthalic acid, 2,4-oxadiazole-3-base, CH
3CONH-, CH
3SO
2NH-, NO
2, SO
2OH, phenyl-SO
2-, sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl, N-phenyl-N-methyl-sulfamyl, N-cyclohexyl-sulfamyl ,-SO
2-heterocycle, this heterocycle is selected from piperidines, tetramethyleneimine, 1,2,5,6-tetrahydropyridine, tetrahydroquinoline, N methyl piperazine, N-alkylsulfonyl methyl-piperazine, morpholine;
R
8Represent methylidene, methylol, 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 2-pyridyl, methoxyl group.
Another particularly preferred embodiment of the present invention is above-mentioned formula I compound, wherein
X is SO
2
Y is N;
The two keys of dotted line representative;
R
3Be CH
3Or CF
3, or
R
3With R
4And the atom that they link to each other together;
R
4, R
6And R
8Be hydrogen;
R
5Represent hydrogen or halogen;
R
7Be N-methyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N-cyclohexyl-sulfamyl, tetrahydropyridine-alkylsulfonyl;-SO
2OH, sulfamyl; Another particularly preferred embodiment of the present invention is above-mentioned formula I compound, wherein
X is C=O;
Y is N, O or CH;
R
2Represent hydrogen;
R
3Represent hydrogen, CH
3, CF
3, cyclohexyl, norbornylene, phenyl, ethyl;
R
7Represent hydrogen, N, N-dimethylamino alkylsulfonyl, N-cyclohexyl sulfamyl, tetrahydro pyridyl alkylsulfonyl, morpholino Herbicidal sulphonylamino alkylsulfonyl, bromine;
R
5Represent hydrogen or bromine;
R
4, R
6And R
8All represent hydrogen;
Another particularly preferred embodiment of the present invention is above-mentioned formula I compound, and wherein X is CH
2Y is N; R
3Represent cyclohexyl or norbornylene; R
5Represent hydrogen or bromine; R
7Represent bromine or sulfamyl; R
2, R
4, R
6And R
8All represent hydrogen;
Another particularly preferred embodiment of the present invention is above-mentioned formula I compound, and wherein X is SO
2Y is NH; Dotted line represents not have key; R
2, R
4, R
5And R
8All represent hydrogen; R
3Represent cyclohexyl, methyl or hydrogen; R
7Represent N, N-dimethylamino alkylsulfonyl, tetrahydro pyridyl alkylsulfonyl, bromine; R
6Represent bromine or hydrogen;
Another particularly preferred embodiment of the present invention is above-mentioned formula I compound, and wherein X is SO
2Y is-NHCH
2-; R
3Represent 3-methyl fourth-2-base, phenyl or cyclohexyl; R
7Represent 1-piperidino-(1-position only)-alkylsulfonyl.
The most preferred embodiment of the present invention is a compound of the formula Ⅰ, wherein the compound is as follows:
2 - cyclohexyl-4 - O 2,3,4 - tetrahydro-quinazoline;
2 - phenyl-4 - O 2,3,4 - tetrahydro-quinazoline;
2 - methyl-3 ,4 - dihydro-1,3 - benzoxazin-4 - one;
2 - phenyl-3 ,4 - dihydro-1,3 - benzoxazin-4 - one;
3 - bicyclo [2.2.1] hept-5'-en-2'-yl-1, 2,3,4 - tetrahydro-1 ,2,4 - benzo
Thiadiazine 1,1 - dioxide;
3 - phenyl-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine-1, 1 - dioxide;
1,2,3,5,10,10 a-hexahydro-benzo [e] pyrrolo [1,2-b] -1,2,4 - thiadiazine -
5,5 - dioxide;
2 - ethyl-2 - methyl-3 ,4 - dihydro-1,3 - benzoxazin-4 - one;
3 - cyclohexyl-6 - (2 - methoxyphenyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzo
Thiadiazine 1,1 - dioxide;
3 - cyclohexyl-6 - (2 - pyridyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclohexyl-6 - (3 - pyridyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclohexyl-7 - (2 - hydroxyethyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclohexyl-7 - acetyl-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine-1 ,1
- Two oxides;
3 - cyclohexyl-7 - (1 - hydroxy-imino-ethyl) -1,2,3,4 - tetrahydro-1 ,2,4 -
Benzothiadiazin 1,1 - dioxide;
3 - cyclohexyl-7 - carbamoyl-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
1,1 - dioxide;
3 - cyclohexyl-7 - ethoxycarbonyl-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine -
1,1 - dioxide;
3 - cyclohexyl-7 - cyano-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine-1 ,1 -
Dioxide;
3 - bicyclo [2.2.1] hept-5'-en-2'--7 - phenyl-1, 2,3,4 - tetrahydro -
1,2,4 - benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl-7 - (2'-acetylamino-phenyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzene
And thiadiazine 1,1 - dioxide;
3 - cyclohexyl-7 - (2-nitrophenyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzothiazol
Diazine 1,1 - dioxide;
3 - cyclohexyl-7 - (2'-methoxyphenyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzo
Thiadiazine 1,1 - dioxide;
3 - cyclohexyl-7 - (2'-methoxy-4'-trifluoromethyl-phenyl) -1,2,3,4 - tetrahydro-
2,4 - benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl-7 - (2 ', 4'-dimethoxyphenyl) -1,2,3,4 - tetrahydro-1 ,2,4
- Benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl -7 - (2'-(N, N-dimethylsulfamoyl) phenyl) -1,2,3,4 -
Tetrahydro-1 ,2,4 - benzothiadiazine-1, 1 - dioxide;
3 - cyclohexyl-7 - (2'-chlorophenyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclohexyl-7 - (2'-fluorophenyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclohexyl-7 - (2'-hydroxyphenyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzothiazol
Diazine 1,1 - dioxide;
3 - cyclohexyl-7 - (2'-pyridyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclohexyl-7 - (3'-pyridyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclohexyl-7 - (2'-pyrimidinyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclohexyl-7 - (2'-furyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclohexyl-7 - (3'-furyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclohexyl-7 - (2'-thienyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclohexyl-7 - (1 - methyl-1H-2-imidazolyl) -1,2,3,4 - tetrahydro -
1,2,4 - benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl-7 - (1 ', 2', 3'-triazol-4'-yl) -1,2,3,4 - tetrahydro-1 ,2,4
- Benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl-7 - (5'-phenyl-1 ', 2', 3'-triazol-4'-yl) -1,2,3,4 -
Tetrahydro-1 ,2,4 - benzothiadiazine-1, 1 - dioxide;
3 - cyclohexyl-7 - (5'-methyl-1 ', 2', 3'-oxadiazol-3 - yl) -1,2,3,4
- Tetrahydro-1 ,2,4 - benzothiadiazine-1, 1 - dioxide;
3 - cyclohexyl-7 - acetamido-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine -
1,1 - dioxide;
3 - cyclohexyl-7 - methylsulfonyl-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzothiazol
Diazine 1,1 - dioxide;
3 - cyclohexyl-7 - amino-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine-1 ,1 -
Dioxide;
3 - cyclohexyl-7 - phenyl-sulfonyl-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
1,1 - dioxide;
2 - cyclohexyl-1, 2,3,4 - tetrahydro-6 - quinazoline sulfonamide;
3 - cyclohexyl-7 - sulfamoyl-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine -
1,1 - dioxide;
3 - methyl-7 - dimethylsulfamoyl-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
2 - cyclohexyl-1, 2,3,4 - tetrahydro-6 - quinazoline N, N-dimethyl-sulfonamide;
3 - cyclohexyl-7 - dimethylamino-sulfonyl-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiazol
Diazine 1,1 - dioxide;
3 - cyclohexyl -7 - (N, N-diethylamino) sulfonyl-1, 2,3,4 - tetrahydro-1 ,2,4
- Benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl-7 - pyrrolidino-sulfonyl-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzo
Thiadiazine 1,1 - dioxide;
3 - methyl-7 - piperidino-sulfonyl-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclopropyl-7 - piperidino-sulfonyl-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzothiazol
Diazine 1,1 - dioxide;
3 - isopropyl-7 - piperidino-sulfonyl-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzothiazol
Diazine 1,1 - dioxide;
3 - propyl -7 - piperidino-sulfonyl-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - benzyl-7 - piperidino-sulfonyl-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclopentyl-7 - piperidino-sulfonyl-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzothiazol
Diazine 1,1 - dioxide;
3 - cyclohexyl-7 - piperidino-sulfonyl-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzothiazol
Diazine 1,1 - dioxide;
3 - bicyclo [2.2.1] hept-5'-en-2'--7 - piperidino-sulfonyl-1 ,2,3,4
- Tetrahydro-1 ,2,4 - benzothiadiazine-1, 1 - dioxide;
3 - cyclohexyl-7 - (1 ', 2', 3 ', 6'-tetrahydro-piperidino) sulfonyl-1 ,2,3,4 - Four
,2,4 - Benzothiadiazin-1, 1 - dioxide;
3 - cyclohexyl -7 - (N-methyl-N-phenyl-amino) sulfonyl-1, 2,3,4 - tetrahydro-
2,4 - benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl-7 - (1'-(1 ', 2', 3 ', 4'-tetrahydroquinolinyl)) sulfonyl-1 ,2,3,4
- Tetrahydro-1 ,2,4 - benzothiadiazine-1, 1 - dioxide;
3 - cyclohexyl-7 - (4'-methyl-piperidino) sulfonyl-1, 2,3,4 - tetrahydro-1 ,2,4
- Benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl-7 - (4'-methyl-sulfonyl-piperidino) sulfonyl-1, 2,3,4 - tetrahydro-
2,4 - benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl-7 - morpholino-sulfonyl-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - bicyclo [2.2.1] hept-5'-en-2'--7 - bromo-1, 2,3,4 - tetrahydro -
1,2,4 - benzothiadiazine 1,1 - dioxide;
2 - methyl -4 - oxo-3 ,4 - dihydro-6 - quinazoline-N, N-dimethyl-sulfonamide;
2 - trifluoromethyl-4 - oxo-3 ,4 - dihydro-6 - quinazoline sulfonamide;
2 - trifluoromethyl-4 - oxo-3 ,4 - dihydro-6 - quinazoline-N, N-dimethylsulfamoyl
Amines;
2 - trifluoromethyl-4 - oxo-3 ,4 - dihydro-6 - quinazolin-1 ', 2', 3 ', 6'-tetrahydro-piperazine
Piperidino sulfonamide;
2 - trifluoromethyl-4 - oxo-3 ,4 - dihydro-6 - quinazoline N-cyclohexyl-sulfonamide;
2 - trifluoromethyl-4 - oxo-3 ,4 - dihydro-6 - morpholino quinazoline sulfonamide;
2 - cyclohexyl-4 - oxo-3 ,4 - dihydro-6 - quinazoline-N, N-dimethyl-sulfonamide;
3 - methyl-7 - sulfamoyl -1,2 - dihydro-1 ,2,4 - benzothiadiazine-1 ,1 - two
Oxide;
3 - methyl-7 - dimethylsulfamoyl-1 ,2 - dihydro-1 ,2,4 - benzothiadiazine -
1,1 - dioxide;
3 - methyl-7 - (1 ', 2', 3 ', 6'-tetrahydro-piperidino) sulfonyl-1 ,2 - dihydro -
1,2,4 - benzothiadiazine 1,1 - dioxide;
3 - methyl-7 - cyclohexyl-sulfamoyl-1 ,2 - dihydro-1 ,2,4 - benzothiadiazine -
1,1 - dioxide;
3 - methyl-7 - dimethylsulfamoyl-1 ,2 - dihydro-1 ,2,4 - benzothiadiazine -
1,1 - dioxide;
2 - trifluoromethyl-4 - oxo-3 ,4 - dihydro-6 - quinazoline acid;
3 - cyclohexyl-8 - methyl-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine-1 ,1 -
Dioxide;
3 - cyclohexyl-8 - hydroxymethyl-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine -
1,1 - dioxide;
3 - cyclohexyl-8 - (2 - methoxyphenyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzo
Thiadiazine 1,1 - dioxide;
3 - cyclohexyl-8 - (3 - methoxyphenyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzo
Thiadiazine 1,1 - dioxide;
3 - cyclohexyl-8 - (2 - pyridyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclohexyl-8 - methoxy-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine-1 ,1
- Two oxides;
5,7 - dibromo - 1,2 - dihydro-1 ,2,4 - benzothiadiazine-1, 1 - dioxide;
3 - cyclohexyl-2 - methyl-7 - morpholino-sulfonyl-1, 2,3,4 - tetrahydro-1 ,2,4 -
Benzothiadiazin 1,1 - dioxide;
3 - cyclohexyl-4 - methyl-7 - morpholino-sulfonyl-1, 2,3,4 - tetrahydro-1 ,2,4 -
Benzothiadiazin 1,1 - dioxide;
7 - methylsulfonyl group -1,2,3,3 a, 4,5 - hexahydro-benzo [e] pyrrolo [2,1-c] -
1,2,4 - thiadiazine 5,5 - dioxide;
7 - sulfamoyl -1,2,3,3 a, 4,5 - hexahydro-benzo [e] pyrrolo [2,1-c] -1,2,4
- Thiadiazine 5,5 - dioxide;
7 - sulfamoyl -1,2,3,3 a, 4,5 - hexahydro-benzo [e] pyrrolo [2,1-c] -
1,2,4 - thiadiazine 5,5 - dioxide;
7 - cyclohexyl-sulfamoyl -1,2,3,3 a, 4,5 - hexahydro-benzo [e] pyrrolo [2,1-c] -
1,2,4 - thiadiazine 5,5 - dioxide;
7 - dimethylsulfamoyl group -1,2,3,3 a, 4,5 - hexahydro-benzo [e] pyrrolo [2,1-c] -
1,2,4 - thiadiazine 5,5 - dioxide;
7 - methyl-sulfamoyl-1 ,2,3,5 - tetrahydro-benzo [e] pyrrolo [2,1-c] -1,2,4 -
Thiadiazine 5,5 - dioxide;
7 - dimethylsulfamoyl-1 ,2,3,5 - tetrahydro-benzo [e] pyrrolo [2,1-c] -1,2,4
- Thiadiazine 5,5 - dioxide;
7 - cyclohexyl-sulfamoyl-1 ,2,3,5 - tetrahydro-benzo [e] pyrrolo [2,1-c] -1,2,4
- Thiadiazine 5,5 - dioxide;
7 - (1 ', 2', 3 ', 6'-tetrahydro-piperidino) sulfonyl-1 ,2,3,5 - tetrahydro-benzo [e]
Pyrrolo [2,1-c] -1,2,4 - thiadiazine 5,5 - dioxide;
3 - bicyclo [2.2.1] hept-5'-en-2'-yl-5 ,7 - dimethyl-1 ,2,3,4 - tetrahydro-
2,4 - benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl -7 - (N, N-diethyl-sulfamoyl) -5 - methyl-1 ,2,3,4 - Four
,2,4 - Benzothiadiazine 5,5 - dioxide;
3 - bicyclo [2.2.1] hept-5'-en-2'-yl -5,7 - diphenyl-1, 2,3,4 - tetrahydro-
2,4 - benzothiadiazine 1,1 - dioxide;
3 - bicyclo [2.2.1] hept-5'-en-2'-yl -5,7 - diamino-sulfonyl-1 ,2,3,4 -
Tetrahydro-1 ,2,4 - benzothiadiazine-1, 1 - dioxide;
3 - bicyclo [2.2.1] hept-5'-en-2'-yl 5,7 - dichloro-1, 2,3,4 - tetrahydro -
1,2,4 - benzothiadiazine 1,1 - dioxide;
5 - bromo-3 - cyclohexyl-7-sulfamoyl-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
2 - bicyclo [2.2.1] hept-5'-en-2'-yl 6,8 - dibromo-1, 2,3,4 - tetrahydro-quinoline
Oxazoline;
2 - bicyclo [2.2.1] hept-5'-en-2'-yl 6,8 - dibromo - 4 - O-1 ,2,3,4
- Tetrahydro-quinazoline;
3 - bicyclo [2.2.1] hept-5'-en-2'-yl-5 ,7 - dibromo-1, 2,3,4 - tetrahydro -
1,2,4 - benzothiadiazine 1,1 - dioxide;
5,7 - dibromo-3 - bicyclo [2.2.1] hept-2'-yl-1, 2,3,4 - tetrahydro-1 ,2,4 -
Benzothiadiazin 1,1 - dioxide;
3 - cyclohexyl-5 ,7 - dibromo-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine-1 ,1
- Two oxides;
3 - adamantyl 5,7 - dibromo-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine -
1,1 - dioxide;
3 - phenyl-5,7 - dibromo-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine-1 ,1 -
Dioxide;
3 - ethoxy-5 ,7 - dibromo-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine-1 ,1
- Two oxides;
3 - methyl-5,7 - dibromo - 1,2 - dihydro-1 ,2,4 - benzothiadiazine-1, 1 - dioxide
Compounds;
3 - cyclohexyl-6 - methyl-7 - (2'-pyridyl) -1,2,3,4 - tetrahydro-1 ,2,4
- Benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl-6 - methyl-7 - (4'-triazolyl) -1,2,3,4 - tetrahydro-1 ,2,4
- Benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl-6 - methyl-7 - sulfamoyl-1, 2,3,4 - tetrahydro-1 ,2,4 - benzo
Thiadiazine 1,1 - dioxide;
3 - cyclohexyl-6 - methyl-7 - piperidino-sulfonyl-1 ,2,3,4 - tetrahydro-1 ,2,4
- Benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl-6 - methyl -7 - morpholino-sulfonyl-1, 2,3,4 - tetrahydro-1 ,2,4 -
Benzothiadiazin 1,1 - dioxide;
3 - cyclohexyl-6 - (2 - methoxy-phenyl) -7 - methyl-1, 2,3,4 - tetrahydro -
1,2,4 - benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl-6 - methoxy-7 - piperidino-sulfonyl-1 ,2,3,4 - tetrahydro -
1,2,4 - benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl-7 ,8 - ethylenedioxy-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzothiazol
Diazine 1,1 - dioxide;
3 - cyclohexyl-6, 7 - ethylenedioxy-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiazol
Diazine 1,1 - dioxide;
3 - cyclohexyl-6 - chloro-7 - sulfamoyl-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiazol
Diazine 1,1 - dioxide;
3 - phenyl-6 - chloro-7 - sulfamoyl-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclohexyl-6 - bromo-7 - piperidino-sulfonyl-1 ,2,3,4 - tetrahydro-1 ,2,4 -
Benzothiadiazin 1,1 - dioxide;
2 - cyclohexyl-methylamino-5-N, N-dimethylsulfamoyl-benzenesulfonamide;
2 - ethyl-7 - (1 ', 2', 3 ', 6'-tetrahydro-piperidino) sulfonyl benzene sulfonamide;
3 - iso-butyl-8 - (piperidino-sulfonyl) -2,3,4,5 - tetrahydro-1 ,2,5 - benzo
Thiadiazine 1,1 - dioxide;
3 - cyclohexyl-7 - cyclopentyl-sulfinyl-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzothiazol
Diazine 1,1 - dioxide; or
3 - cyclohexyl-7 - cyclopentyl-sulfinyl-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzothiazol
Diazine 1,1 - dioxide;
Or a pharmaceutically acceptable salt thereof.
...
The compounds of this invention can provide the compound of any suitable form of medication.The prodrug forms of suitable form comprises pharmaceutically acceptable (promptly physiologically acceptable) salt or The compounds of this invention.
The example of pharmaceutically acceptable additive salt comprises, but be not limited to, nontoxic mineral acid and organic acid addition salt, as from acetate deutero-acetate, from equisetic acid deutero-aconitate, from xitix deutero-ascorbate salt, from Phenylsulfonic acid deutero-benzene sulfonate, from phenylformic acid deutero-benzoate, from styracin deutero-cinnamate, from citric acid deutero-Citrate trianion, from pamoic acid deutero-embonate, from enanthic acid deutero-enanthate, from formic acid deutero-formate, fumarate from fumarate derivative, from the glutaminate of glutamic acid derivative, from oxyacetic acid deutero-glycollate, from hydrochloric acid deutero-hydrochloride, from Hydrogen bromide deutero-hydrobromate, from lactic acid deutero-lactic acid salt, from toxilic acid deutero-maleate, from propanedioic acid deutero-malonate, from amygdalic acid deutero-mandelate, from methylsulfonic acid deutero-mesylate, from naphthalene-2-sulfonic acid deutero-naphthalene-2-sulfonic acid salt, from nitric acid deutero-nitrate, from perchloric acid deutero-perchlorate, from phosphoric acid deutero-phosphoric acid salt, from phthalic acid deutero-phthalate, from salicylic acid deutero-salicylate, from Sorbic Acid deutero-sorbate, the stearate of deriving from stearic acid is from succsinic acid deutero-succinate, from sulfuric acid deutero-vitriol, the tartrate of deriving from tartrate is from tosic acid deutero-tosilate etc.These salt can be made with currently known methods and the described method of document.
Other acid, as be considered to pharmaceutically unacceptable oxalic acid, also can be used as the intermediate that obtains The compounds of this invention and pharmaceutically acceptable acid additive salt thereof and the preparation that is used for salt.
The metal-salt of The compounds of this invention comprises an alkali metal salt, as contains the sodium salt of the The compounds of this invention of hydroxyl.
The compounds of this invention can also solubilized form or not solubilized form provide with acceptable solvent, said solvent comprises water, ethanol etc.Solubilized form can comprise hydrate forms, as monohydrate, and dihydrate, semihydrate, trihydrate, tetrahydrate etc.In a word, for the present invention, solubilized form is of equal value with solubilized form not.The substituting group definition
Halogen refers to fluorine, chlorine, bromine or iodine.
The cycloalkyl that alkyl refers to that the straight or branched alkyl of 1-6 carbon atom is arranged or 3-7 carbon atom arranged includes, but not limited to methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, hexyl, preferred methyl, ethyl, propyl group and sec.-propyl wherein.
Haloalkyl refers to by the abovementioned alkyl of one or more halogens replacements defined above.Preferred embodiment is CF
3, C
2F
5, CH
2Cl, CHCl
2,-CHFCH
2F ,-CHClCH
2Cl.
Cycloalkyl refers to have the annular alkyl of 3-7 carbon atom, as cyclopropyl, and cyclobutyl, cyclopentyl, cyclohexyl, suberyl.
Cycloalkylalkyl refers to above-mentioned cycloalkyl and abovementioned alkyl, on the contrary alkyl wherein can be considered to cycloalkyl substituting group or.Preferred cycloalkylalkyl is C
3-6Cycloalkyl and C
1-4Alkyl, as-(CH
2)-cyclopropyl ,-cyclopropyl-(C
1-4Alkyl) ,-(CH
2)
n-cyclohexyl ,-cyclohexyl-(C
1-4Alkyl), (C
1-4Alkyl)-and cyclobutyl ,-cyclobutyl (C
1-4Alkyl), (C
1-4Alkyl) cyclopentyl ,-cyclopentyl (C
1-4Alkyl), (C
1-4Alkyl) cyclohexyl ,-cyclohexyl (C
1-4Alkyl).
Halogenated cycloalkyl refers to be included, but are not limited to by the above-mentioned annular alkyl of one or more above-mentioned halogens replacements, the chlorine cyclopropyl, fluorine cyclopropyl, iodine cyclopropyl, the dichloro cyclopropyl, difluoro cyclopropyl, chlorine cyclobutyl, the fluorine cyclobutyl, chlorine cyclopentyl, fluorine cyclopentyl, the iodine cyclopentyl, chlorine cyclohexyl, fluorine cyclohexyl, the dichloro cyclohexyl, difluoro cyclohexyl, iodine cyclohexyl.Preferred embodiment is one or two substituted cycloalkyls that 3-6 carbon atom arranged, as the dichloro cyclopropyl, and difluoro cyclopropyl, chlorine cyclohexyl, fluorine cyclohexyl, iodine cyclohexyl, chlorine cyclopentyl, fluorine cyclopentyl.
Thiazolinyl refers to that 2-6 carbon atom arranged and contains the straight or branched group of two keys, includes, but not limited to vinyl, 1-propenyl, 2-propenyl, 1-butylene base, crotyl and 3-butenyl.
Alkynyl refers to have 2-6 carbon atom and contains a triple-linked straight or branched group, includes, but not limited to ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base and 3-butynyl.
Alkoxyl group refers to the O-alkyl, and alkyl definition wherein as above.
Alkoxyalkyl refers to alkyl-O-alkyl, and alkyl definition wherein as above.
Hydroxyalkyl refers to the abovementioned alkyl that replaced by OH.
Amino is NH
2Or NH-alkyl or N-(alkyl)
2, wherein the alkyl definition as above.
Alkylamino refers to by the above-mentioned amino alkyl as defined above that replaces.Preferred embodiment is-CH
2-N (alkyl)
2,-CH-N (alkyl)
2CH
3,-CH
2CH
2-N (alkyl)
2,-CH
2-NH
2-,-CH-(NH
2)-CH
3,-CH
2CH
2-NH
2
Cyano group is CN.
The cyano group alkyl refers to the alkyl defined above that replaced by CN.
Nitro is-NO
2
4-nitro alkyl refers to the alkyl defined above that replaced by nitro defined above.
Sulfenyl is SH or S-alkyl, and wherein the alkyl definition as above.
Alkylthio refers to the abovementioned alkyl that replaced by sulfenyl defined above.
Acyl group is (C=O)-R
0Or (C=S)-R
0, R wherein
0It is alkyl; The phenyl that is replaced by one or more following substituting groups: halogen, CF
3, NO
2, amino, alkyl, alkoxyl group, phenyl and SO
2NR ' R ", wherein R ' and R " be respectively hydrogen or alkyl, perhaps R ' and R " be (CH together
2)
m, wherein m is 2,3,4,5 or 6; Perhaps, R
0Be benzyl or NR
IIIR
IV, R wherein
IIIAnd R
IVBe respectively hydrogen or alkyl, perhaps R
IIIAnd R
IVBe (CH together
2)
p, wherein p is 2,3,4,5 or 6.
Acyl amino is acyl group-NH-, and wherein the acyl group definition as above.
Aryl is an aromatic carbocyclic, as phenyl or xenyl, and the condensed carbocyclic ring, as naphthyl.
HET is a 5-6 person annular heteroaryl, Bao Kuo oxazole-2-Ji ， oxazole-4-Ji ， oxazole-5-base ， isoxazole-3-base isoxazole-4-base ， isoxazole-5-base for example, thiazol-2-yl, thiazole-4-base, thiazole-5-base, isothiazole-3-base, isothiazole-4-base, isothiazole-5-base, 1,2,4-oxadiazole-3-base, 1,2,4-oxadiazole-5-base, 1,2,4-thiadiazoles-3-base, 1,2,4-thiadiazoles-5-base, 1,2,5-oxadiazole-3-base, 1,2,5-oxadiazole-4-base, 1,2,5-thiadiazoles-3-base, 1,2,5-thiadiazoles-4-base, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, the 1-pyrryl, 2-pyrryl, 3-pyrryl, 2-furyl, 3-furyl, the 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, the 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 4-pyridazinyl, the 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl and 4-pyrazolyl, furyl, tetrahydrofuran base, pyrryl, pyrrolidyl, imidazolyl ， oxadiazole base, pyridyl, thienyl ， isoxazolyl, pyrimidyl, pyrazolyl, triazolyl.The particularly preferred heterocycle of the present invention is a pyridyl, pyrimidyl, triazolyl, thienyl ， oxadiazole base, imidazolyl.
7-12 person's carbocyclic ring structure comprises one, two and tricyclic structure.Preferred embodiment is 7-10 person's ring structure, as
3-8 element heterocycle structure comprises partly or entirely saturated heterocycle structure, as aziridine, and tetramethyleneimine, piperidines, piperazine, high piperidines, high piperazine, Azacyclooctane, 1,3-diazacyclo octane, 1,4-diazacyclo octane, tetrahydrofuran (THF), tetramethylene sulfide, morpholine, tetrahydropyridine, and following compounds, as
Preferred embodiment is the 5-6 person's ring that contains a nitrogen-atoms at least, as tetramethyleneimine, and piperidines, piperazine, morpholine, tetrahydropyridine.
The 4-7 person's annular that is fused to formula I ring structure is formed in substituent R
2And R
3Between, or R
3And R
4Between, or R
5And R
6Between, or R
6And R
7Between, or R
7And R
8Between, this ring contains heteroatoms arbitrarily, and contains carbonyl arbitrarily.Preferred ring is 5 Yuans and 6 Yuans carbocyclic rings.
Be formed at substituent R
7And R
6Or R
8Between between ring be to contain O, C=O, S=O or SO
2Group also contains 5 Yuans or 6 Yuans rings of nitrogen-atoms arbitrarily.Preferred ring is-O-(CH
2)
n-O-, wherein n is 1,2 or 3;-SO
2-NR-(CH
2)
n-, wherein n is 1 or 2;-SO-NR-(CH
2)
n-, wherein n is 1 or 2;-SO
2-(CH
2)
n-, wherein n is 2 or 3;-SO-(CH
2)
n-, wherein n is 2 or 3;-CO-CH=CH-NH-;-CO-CH=CH-O-;-CO-(CH
2)
n-NH-, wherein n is 1 or 2;-CO-NH-(CH
2)
n-, wherein n is 1 or 2;-CO-(CH
2)
2-O-.
The compounds of this invention can the non-solvent compound form, also can the solvate forms in acceptable solvent exist, and acceptable solvent comprises water, ethanol etc.In a word, for the present invention, solvate forms and non-solvent compound form are of equal value.Steric isomer
The compounds of this invention can also (+) and (-) form and racemic form existence.The racemic modification of these isomer and these isomer itself all belong to the scope of the invention.
Racemic form can be divided into optical antipode with currently known methods and technology folding.A kind of mode of separating diastereoisomeric salt is to use optically active acid, and by discharging optically active amines with alkaline purification.The another kind of method that racemic modification is resolved into optical antipode is on the chromatography basis that is based upon the optical activity matrix.Therefore, racemic compound of the present invention can be broken down into their optical antipode, for example, adopts Steppecd crystallization to separate to d-or the l-salt of enumerating (tartrate, mandelate or camsilate).
Can also pass through The compounds of this invention and optical activity activatory carboxylic acid, as from (+) or (-) phenylalanine, (+) or (-) phenylglycocoll, (+) or (-) dextrocamphoric acid deutero-acid-respons forms the diastereomer acid amides, perhaps splits The compounds of this invention by reactions such as The compounds of this invention and optical activity chloro-formic ester are formed the diastereomer carbamate.
The method that other splits optical isomer is known in the art.These methods comprise Jaques J., and Collet A. and Wilen S. are at " enantiomorph, racemic modification and fractionation " (Enantiomers, Racemates, and Resolutions), John Wiley andSons, those methods described in the New York (1981).
And oxime compounds of the present invention also can two kinds of forms exist, genial anti-form (Z and E form), and this depends on-the substituent arrangement on every side of the two keys of C=N-.Therefore, The compounds of this invention can be suitable or anti-form (Z or E form), and perhaps the form of mixtures with them exists.
If possible, The compounds of this invention also comprises introversive and export-oriented isomeric forms and tautomeric forms.Pharmaceutical composition
One aspect of the present invention provides the new pharmaceutical compositions that contains the The compounds of this invention for the treatment of significant quantity, and the purposes of The compounds of this invention aspect the medicine of preparation treatment disease specific or illness.
Though the The compounds of this invention that is used for the treatment of can the original chemical form administration, but preferably with activeconstituents, can select the form of physiologically acceptable salt, with one or more assistant agents, vehicle, carrier, buffer reagent, thinner and/or other common drug auxiliarys constitute pharmaceutical composition together.
In preferred version, the invention provides and contain The compounds of this invention or its pharmacologically acceptable salt or derivative, together with one or more pharmaceutically acceptable carrier, the optional pharmaceutical composition that contains other treatment and/or prevention composition.Said carrier must be " acceptable " with the consistency of other compositions in preparation, must be harmless to its recipient.
Pharmaceutical composition of the present invention can be suitable oral, rectum, segmental bronchus, nose, local (comprising oral cavity and hypogloeeis), transdermal, vagina or parenteral (comprise skin, subcutaneous, intramuscular and intravenous injection) form of administration, or be suitable for sucking or being blown into the form of administration.
Therefore, The compounds of this invention can with assistant agent commonly used, carrier or thinner are made pharmaceutical compositions and single agent form thereof together.These forms comprise solid form, tablet particularly, filled capsules, pulvis and pill; Liquid form, the particularly aqueous solution or non-aqueous solution, suspension, emulsion, the capsule form of elixir and filling liquid all is used for oral administration, is used for the suppository of rectal administration and is used for the aseptic parenteral solution of parenteral admin.These pharmaceutical compositions and single agent form thereof can contain the conventional ingredient of conventional ratio, contain or do not contain other active compounds or material, and so single agent form can contain any suitable effective amount and activeconstituents that every day, used dosage range matched.
The compounds of this invention can multiple oral and parenteral dosage form administration.To those skilled in the art, the pharmacologically acceptable salt that contains The compounds of this invention or The compounds of this invention is conspicuous as the following formulation of activeconstituents.For by the The compounds of this invention pharmaceutical compositions, can use solid or liquid pharmaceutically acceptable carrier.The preparation of solid form comprises pulvis, tablet, pill, capsule, cachet, but suppository and discrete particles.Solid carrier can be one or more materials, and effect can be a thinner, correctives, solvating agent, lubricant, suspension agent, tackiness agent, sanitas, the disintegrating agent of tablet or the packaged material of wafer.
In the pulvis, carrier is and the well-mixed fine solid of meticulous activeconstituents.
In the tablet, activeconstituents and carrier that required adhesive capacity is arranged are pressed into desired shape and size then with the suitable proportion thorough mixing.
In pulvis and tablet, preferably contain 5 or 10% to about 70% active compound.Suitable carriers has magnesiumcarbonate, Magnesium Stearate, talcum, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose gum, sodium carboxy methyl cellulose, low melt wax, coconut wet goods.Terms " formulation " is to want to comprise that active compound and packaged material as carrier are to obtain the prescription that capsule carries out, and wherein, no matter have other carriers or not, activeconstituents all is that suppressed by vector surrounds, and therefore, carrier is all relevant with activeconstituents.Similarly, this situation also comprises cachet and lozenge.Tablet, pulvis, capsule, pill, cachet and lozenge can be as the solid dosages that is suitable for oral administration.
For preparation suppository, at first stir, the mixture of low melt wax such as fatty acid glycerine or Oleum Cocois melts earlier, makes activeconstituents disperse out equably.Then, pour the uniform mixture that melts the mould of common size into, can cool off, make its curing.
The composition that is suitable for intravaginal administration can be made hysterophore, stopper, and emulsifiable paste, gel, paste, foam or spray form wherein except that containing activeconstituents, also contain suitable carrier well known by persons skilled in the art.
Liquid preparation comprises solution, suspension and emulsion, for example, the aqueous solution or water-propylene glycol solution.For example, parenteral injectable liquid body preparation can be mixed with solution in aqueous solution of propylene glycol.
Therefore, The compounds of this invention can be used for parenteral admin (for example, by injection as injector to inject or continuous drip administration) through preparation, and can add sanitas and make ampoule, prefilled syringe, this unit dosage of small volume instillation container or multi-dose container form.These compositions can be the suspension that forms in oiliness or aqueous carrier, and solution or emulsion also can contain ingredients such as suspension agent, stablizer and/or dispersion agent again.Perhaps,, or, obtain pulverous activeconstituents, rebuild (injection liquid) with suitable carrier such as aseptic no heat source water before use by from the freeze-drying of solution form by the aseptic separation of sterilization solid.
The aqueous solution that is suitable for orally using can be by being dissolved in water with activeconstituents, and add suitable toning agent as required, correctives, and stablizer and thickening material are made.
The aqeous suspension that is suitable for orally using can be dispersed in by the fine powder with activeconstituents in the water that has viscous substance, said viscous substance comprise natural or synthetic gummy, resin, methylcellulose gum, Xylo-Mucine, or make in other known suspension agents.
Also being included in soon, use is transformed into the preparation that liquid form preparation is used for oral administration with the preparation of solid form before.These liquid forms comprise solution, suspension and emulsion.Except containing activeconstituents, these liquid forms can also contain toning agent, correctives, stablizer, buffer reagent, artificial and natural sweeteners, dispersion agent, thickening material, solvating agent etc.
For being carried out topical, epidermis The compounds of this invention can be mixed with ointment, emulsifiable paste or washing lotion, or make transdermal patch.Ointment and emulsifiable paste, for example, can use or oleaginous base and add suitable thickening and/or jelling agent is formulated.Washing lotion also can use or oleaginous base formulated, and also contain one or more emulsifying agent, stablizer, dispersion agent, suspension agent, thickening material or toning agent usually.
The composition that is suitable for oral cavity local medication comprises that activeconstituents is inclusive in flavoured base, normally the lozenge in sucrose and gum arabic or the tragacanth gum; Activeconstituents is contained in the pastille in inert base such as gelatin and glycerine or sucrose and the gum arabic; And activeconstituents is included in the collutory in the suitable liquid vehicle.
Available common tool, dropper for example, volumetric pipette or atomizer directly are applied to nasal cavity with solution or suspension.Composition therefor can be single agent or multiple doses form.Situation for using dropper or volumetric pipette can realize by solution or the suspension of using suitable pre-determined volume to the patient.For using atomizer, for example, can adopt metering atomisation pump.
Respiratory tract administration can realize that wherein said preparation is with suitable propelling agent such as Chlorofluorocarbons (CFC), for example Refrigerant 12 with aerosol preparations, trichlorofluoromethane or dichloro tetrafluoro ethane, carbonic acid gas, or other suitable gas are made the activeconstituents pressurized package.Aerosol generally can contain tensio-active agent such as Yelkin TTS.The dosage of medicine can be controlled with the supply of the valve that measured.
Perhaps, activeconstituents can be made into dry powder form, for example, the pulverulent mixture that compound forms in suitable powdery matrix, these matrix comprise lactose, starch, starch derivative such as Vltra tears and Polyvinylpyrolidone (PVP) (PVP).Usually powder carrier can be in nasal cavity.Powder composition can be made unit dosage form, for example, make capsule or cartridge case,, can carry out the administration of pulvis with sucker by it as with gelatin or cartridge bag.
Comprise intranasal compositions in the composition that carries out respiratory tract administration, active compound is made particle diameter usually at 5 μ m or littler granule.Size particles can be made with means known in the art such as micronization method like this.
If desired, can use employing to delay the composition of release of active ingredients.
The preferably single agent form of pharmaceutical preparation.Preparation is subdivided into the unit dosage that contains an amount of activeconstituents in this form.Unit dosage can be packaged into preparation, and bag contains the preparation of discrete magnitude, as coated tablet, and capsule.With lozenge or ampoule powder.Also have, unit dosage can be a capsule, tablet, cachet or lozenge, or any in the dressing form of these medicaments.
The liquid of the tablet of oral administration or capsule and intravenous administration and continuous drip is preferred composition.
Dosage certainly must be according to the age of the individuality that will treat, body weight and physical qualification, and route of administration, and formulation and scheme, and the effect that will reach is carefully regulated.
Activeconstituents can be once a day or administration several times.In some cases, low 0.1 μ g/kg i.v. and the 1 μ g/kg p.o. of reaching of dosage just can obtain the result that is satisfied with.At present, we think that the upper limit of dosage range is about 10mg/kg i.v. and 100mg/kg p.o..The preferred dosage scope is about 0.1 μ g/kg-10mg/kg/ days i.v. and 1 μ g/kg-100mg/kg/ days p.o..Methods of treatment
The compounds of this invention is the ampa receptor stimulator, therefore, can be used for illness or treatment of diseases to ampa receptor conditioning agent sensitivity.As scheme of the present invention, disease is responsive to the positive adjusting of ampa receptor.This compound can be used for central nervous system disease, the treatment of the illness or the state of an illness, prevent, prevention and relax, said disease comprises neuronic disease, cognition or be losing one's memory, the disease of memory and study aspect, the attention disease is because the age, wound, the disease of the learning and memory aspect that apoplexy and epilepsy reason cause, alzheimer's disease, dysthymia disorders, schizophrenia, memory loss, AIDS-dementia, senile dementia, the learning capacity defective, cognition defective, sexual disorder, psychosis, sexual disorder, knowledge weakens disease, schizophrenia, dysthymia disorders or autism, attention deficit, or by neuropoison, alcoholism, drug abuse, illness or disease that heart bypass operation or cerebral ischemia cause.Proper dosage is 0.1-500mg/ days, particularly 10-70mg/ days.Be administered once every day or twice, this depends on the concrete mode of administration usually, form of administration, administration at symptom, related (treatment) object and relate to the body weight of object, and be responsible for the doctor of treatment or animal doctor's hobby and experience.
I.p. referring to the intraperitoneal administration, is well-known route of administration.
P.o. referring to oral administration, is well-known route of administration.
Therefore, the present invention comprises the combination of following every or each clause separately:
The purposes of above-claimed cpd, wherein the disease that will treat is that ampa receptor is regulated responsive disease.
The purposes of above-claimed cpd is used to prepare responsive disease is regulated in treatment to ampa receptor medicine.
Such use, wherein said disease are the diseases of memory and study aspect, psychosis, sexual disorder, knowledge weakens disease, schizophrenia, dysthymia disorders or autism, alzheimer's disease, the learning capacity defective, cognition defective, sexual disorder, attention deficit, memory loss or senile dementia, or by wound, apoplexy, epilepsy, alzheimer's disease, neuropoison, at the age, neural distortion is sick, alcoholism, drug abuse, illness or disease that heart bypass operation or cerebral ischemia cause.Biology
3H-AMPA bonded vitro inhibition
L-L-glutamic acid (salt) is that excitatory neuron main in the mammalian central nervous system transmits matter (GLU).According to electronics Physiologic Studies and associativity result of study, have at least three kinds of GLU receptor subtypes to exist, temporary transient called after N-methyl-D-aspartate (salt) is acceptor, Quisqualic Acid (salt) acceptor and kainic acid (salt) acceptor (NMDA).Quisqualic Acid (salt) and responsive this group GLU receptor subtype of kainic acid (salt) usually are known as non-NMDA receptor.Agonist with mark
3H-AMPA (alpha-amino group-3-hydroxy-5-methyl base-4-isoxazole propionic acid) (at Quisqualic Acid (salt) acceptor) has shown different antagonism selectivity and areal distribution with the receptors bind Journal of Sex Research that 3H-kainic acid (salt) (at kainic acid (salt) acceptor) carries out.People just know that AMPA will become the strong selective agonist that is called Quisqualic Acid (salt) acceptor traditionally several years ago.AMPA is to the activation and the Na that causes the umpolarization effect of Quisqualic Acid (salt) acceptor
+Flow into and K
+Flow out relevant.
Non-NMDA receptor has been reclassified the Quisqualic Acid ester that connects inositol three phosphides and DG acid esters metabolite in metabotropic (metabotropic) acceptor type activated recently.AMPA does not interact with metabotropic Quisqualic Acid (ester) acceptor, and only with the ionotropy acceptor interaction.The selectivity activation of metabotropic type stated at instead-ACPD.The someone described and had the ability and competitive non-NMDA receptor antagonist CNQX and NBQX recently, and existingly reported that CNQX does not hinder Quisqualic Acid (ester) to the effect of metabotropic receptor subtype.
3H-AMPA is the selective emission part of mark ion-transfer type Quisqualic Acid ester (AMPA) acceptor.The preparation of tissue
Preparation work is carried out at 0-4 ℃, except as otherwise noted.To in 20ml Tris-HCl (30mM, pH 7.4), use Ultra-Turrax homogenizer homogenize 5-10 second from the brains that male Wistar rats (150-200g) obtains.With gained suspension centrifugal 15 minutes, then with damping fluid flushing particle three times (with centrifugal 10 minutes of 27,000 * g speed) with 27,000 * g speed.With particle homogenize in the 20ml damping fluid of washing, and in water-bath (37 ℃), cultivate 30 minutes, centrifugal 10 minutes then with 27,000 * g speed with life glutamate removing in.Then with particle homogenize in damping fluid, and at 27,000 * g speed centrifugal 10 minutes.The particle suspension that obtains at last in the 30ml damping fluid, and, is stored in-20 ℃ with the goods freeze-drying then.Measure
Membrane product is melted, then 2 ℃ with 27,000 * g speed centrifugal 10 minutes.With containing 2.5mM CaCl
220ml 30mM Tris-HCl (pH 7.4) washed twice in the Ultra-Turrax homogenizer, centrifugal 10 minutes then with 27,000 * g speed.With the particle suspension that obtains at last in containing 2.5mM CaCl
2With the 30mM Tris-HCl (pH7.4,100ml/g fundamental weave) of 100mM KSCN, carry out associativity with it and measure.Several parts of above-mentioned suspension of 0.5 (0.2) ml are added to 25 (20) μ l testing liquids and 25 (20) μ l respectively
3H-AMPA (5nM, ultimate density) mixes the back and cultivated 30 minutes at 2 ℃.Measure non-single-minded associativity with L-glutamate (0.6mM, ultimate density).After the cultivation 550 μ l samples are added in the 5ml ice-cold buffer, and under puffing regimens, it directly are poured on the Whatman GF/C glass fiber filter paper, then immediately with the ice-cold damping fluid washing of 5ml.Collect through the filtering 240 μ l samples of glass fiber filter paper with the Skatron cell harvestor.With the ice-cold damping fluid washing filter paper of 3ml.Radioactive activity on the filter paper is measured with conventional liquid scintillation counting method.Concrete associativity equals total binding and deducts non-single-minded associativity.The result
Trial value IC
50(suppress
3H-AMPA is specifically in conjunction with 50% substances concentration (μ M)) expression.It is as shown in the table that test-results is tried compound:
AMPA induce [
3H] strengthening effect that discharges from the cortical neuron of cultivating of GABA
| Compound | IC 50(μM) |
| ????13 | ????22．0 |
| ????14 | ????45．0 |
| ????15 | ????39．0 |
| ????44 | ????3．5 |
| ????47 | ????5．3 |
| ????48 | ????4．4 |
| ????49 | ????17．0 |
| ????57 | ????26．0 |
| ????58 | ????3．4 |
| ????61 | ????8．5 |
| ????62 | ????6．0 |
| ????63 | ????6．0 |
| ????113 | ????13．0 |
| ????114 | ????33．0 |
| ????115 | ????7．0 |
The neurone of expressing excitatory amino acid receptor can be with this compound umpolarization, and this umpolarization effect will finally cause transmitting matter and discharge from neurone.The neurone that obtains from 16 age in days mice embryonic cortexes mainly is the GABA energy through cultivating, and expresses all types of excitatory amino acid receptors.This means and can use high (concentration) potassium (55mM) or excitatory amino acid NMDA (20 μ M), AMPA (5 μ M) and kainic acid ester (5 μ M) stimulate them to make them discharge neurotransmitter GABA.
3The GABA that H-GABA can be used in the labeled neurons transmits the matter pond,
3The release of H-GABA from neurone also can be as research excitatory amino acid receptor agonist, the simple functions model of the action effect of antagonist and additive.The method cell cultures
The brain skin of 15-16 age in days mice embryonic is cut into the square fritter of 0.4 * 0.4mm, and this tissue decomposes through flexible trypsin acting (0.1% (wt/vol) trypsinase, 37 ℃, 10 minutes) then.Then, (300 ten thousand/ml) are inoculated in the 30mm Petri dish (3ml/ dish) of poly-L-Lysine parcel with cell suspending liquid, wherein fill and replenished para-amino benzoic acid ester (7 μ M), the altered a little DMEM (24.5mM KCl) of Regular Insulin (100mU/L) and 10% (vol/vol) horse serum.Cell was cultivated in substratum 5-7 days, and external interpolation antimitotic agent cytosine arabinoside was to prevent gliosis from the 2nd day.Details sees also people's such as Drejer article (" brain research experiment " (Exp.Brain Res.), 47,259 (1982)).Release experiment
The described models of people (" life science " (Life Sci.), 38,2077 (1986)) such as release experiment employing Drejer carry out.Testing the brain cutaneous nerve unit that will cultivate in Petri dish (30mm) in preceding 1 hour is added among 100mM γ-vinyl-GABA to suppress GABA and degrades in neurone.Test preceding 30 minutes with 5 μ Ci
3H-GABA is added in each substratum.The monolayer cell of dish bottom hides with the protection cell not by physical damage with a slice nylon wire after the prepackage, and is convenient to substratum and disperses on cellular layer.Remove the substratum of prepackage, the Petri dish is put into one cross cooling system, this system is by the cold substratum of a mistake (HEPES buffer saline (HBS): 10mM HEPES, 135mM NaCl, 5mM KCl, 0.6mM MgSO that will be tending towards 37 ℃ from storage tank continuously
4, 1.0mM CaCl
2With 6mM D-glucose; PH 7.4) peristaltic pump delivered to a little above the Petri dish that tilts forms.Collect substratum continuously in the lower floor that talks endlessly, deliver to run tank then.At first, make cell overflow 30 minutes (flow velocity 2ml/min), then by changing overflowing 30 seconds of per 4 minutes irritation cells of substratum the substratum from HBS to the correspondence that contains 5 μ M AMPA (conditioning agent is not essential) with HBS.
Substances is dissolved in and contains in 50%DMSO and the 48% alcoholic acid medium.DMSO and alcoholic acid ultimate density must not surpass 0.1% when recording.The result
It is right to discharge (cpm) according to average background respectively before and after stimulating
3The release (cpm) of inducing of H-GABA is revised, and this value is used to calculate trial value.
Substances shows relevant with the strengthening effect of cyclothiazide (30 μ M) inductive AMPA response to the strengthening effect of AMPA response.The result
Test-results is shown in Fig. 1 and 2.This result shows, 115 couples of AMPA of compound that Fig. 1 shows induce [
3H] GABA significantly increases from the strengthening effect that the cutaneous nerve unit of cultivating discharges.It is relevant with 30 μ M cyclothiazide inductive strengthening effects that this strengthening effect shows.
Fig. 2 show 114 couples of AMPA of compound induce [
3H] strengthening effect that discharges from the cutaneous nerve unit of cultivating of GABA.It is relevant with 30 μ M cyclothiazide inductive strengthening effects that this strengthening effect shows.The voltage clamping method
Experiment is carried out in the voltage folder with the conventional full cell patch pincers method of people such as (, 1998) Mathiesen basically as previously mentioned people such as (, 1981) Hamill, wherein uses following salts solution (mM): NaCl (140), KCl (4), CaCl
2(2), MgCl
2(1), sucrose (30), tetraodotoxin (0.0003), methiodideization ratio button button clever alkali (0.005) and HEPES (10, pH7.4); Solution (mM): CsCl (120) in the cell, CsF (20), MgCl
2(2), EGTA (10) and HEPES (10, pH 7.2).Cell cultures
Basically cultivate the neocortex of mouse with the described method of people such as Drejer (1987).In simple terms, be under aseptic condition, forebrain to be taken out from NMRI mouse embryo, then this tissue is cut into the square fritter of 0.4mm, and with trypsin 12.5 μ g/ml) and DNAse (2.5 μ g/ml) 37 ℃ of grindings 15 minutes.With cell with 1 * 10
6Cell/ml concentration is suspended among the DMEM that changes a little, wherein contains horse serum (10% (v/v)), penicillin (333U/ml), para-amino benzoic acid (1mg/ml), L-glutamine (0.5mM), Regular Insulin (0.08U/ml) and KCl (23.8mM).Then, cell suspending liquid is inoculated in the 35mmPetri dish (2ml/ dish) of poly-L-Lysine parcel, but before parcel, glass cover-plate (3.5mm) will be put into dish.Cultivate the alternative above-mentioned substratum of substratum that replenishes liquid after 24 hours with the 1%N2 that contains substitute blood serum that has just made.
The experiment carry out before with cell at 37 ℃ of (5%CO
2/ 95%O
2) cultivated 7-14 days.Electronics, program is obtained with data: used amplifier is the EPC-9 (HEKA-electronics, Lambract, Germany) that links to each other with PowerMacintosh G3 computer by the ITC-16 interface.Experiment condition is by the Pulse software setting that is used with amplifier.Data through low-pass filtering with the speed Direct Sampling of 3 times of limiting frequency to hard disk.Volumetric pipette and electrode: from borosilicate glass, extract with horizontal electrode puller (Modulohm, Copenhagen, Denmark).The impedance of volumetric pipette is 1.7-2.4MW in experiment used salt solution.The volumetric pipette electrode is a silver chloride lead, and standard electrode is the silver chloride volumetric pipette electrode (In Vivo Metric, Haier's Regensburg, the U.S.) that is fixed on the experimental box.Volumetric pipette counter electrode in bath with opening before sealing returns to zero.Experimental procedure: cover plate is put in the 15ml experimental box that is installed on anticaustic microscope (IMT-2, the Olympus) platform that the Nomarski optical lens is housed.With the flow velocity of 2.5ml/min neurone is overflowed with extracellular salt solution.G sealing (giga-seal) forms back (1-5GW, success ratio about 90%) and obtains whole cell configuration by suction strainer.
Cell is remained on-60mV controls voltage, and at least 30 seconds of continuously measured electric current are to guarantee stable peak point current when each experiment beginning.
The solution that will contain AMPA is delivered in the experimental box by the stream pipe of a special segregation drive, and stream tip head is apart from the about 50 μ m of cell.When making the pipeline compression that connects the stream pipe, the valve of Pulse software control starts application program.Gather 1 second AMPA (30 μ M) per 45 seconds.After obtaining the response that can repeat to amplify, testing compound is put into the bath of experimental box and contains in the AMPA solution.But up to obtaining compound occurring after the new duplicate responses.
Sampling interval in all experiments is 310 μ s.
All experiments are carried out under room temperature (20-25 ℃).Material
Obtain the NMRI mouse of pregnancy (9 days) from Bomholtgaard breeding research center (Ry, Denmark).
Horse serum, N2 replenishes liquid and substratum is buied from Life Technologies, Inc. (GIBCO, Rosklide, Denmark).
AMPA (alpha-amino group-3-hydroxy-5-methyl base-4-isoxazole propionic acid) is synthetic at NeuroSearch A/S.Tetraodotoxin from the Alomone laboratory (Jerusalem, Israel) buy, (MA USA) buys methiodideization, and sucrose is buied from FlukaChemie (Buchs, Switzerland), and other raw materials are buied from SIGMA (U.S.) from RBI than the clever alkali of button button.The result
Result such as Fig. 3 are to shown in Figure 7.
Compound 56 (Fig. 3), 63 (Fig. 4), 111 (Fig. 6), 114 (Fig. 7) and 115 (Fig. 5) are all strengthened the electric current that causes behind the application 30 μ M AMPA.Each examples for compounds is as follows.As can be seen, strengthening effect is a reversible under every kind of situation, even also will adhere to several minutes in the effect that washes out compound 56 after the compound and 63.What APMA stimulated was 45 seconds at interval.Scale: compound 63:200pA/2sec; 56:500pA/5sec; 115:50pA/2sec; 111:400pA/3sec; 114:40pA/3sec.Shown in the experiment in compound concentrations be 3 μ M (compound 56,63 and 114) and 10 μ M (compound 111 and 115).With compound 114 is example (scale: 200pA/5sec; Fig. 8), the effect of compound depends on concentration.Reference Drejer J., Honore T. and Schousboe A., " excitability amino acid is induced
3H-GABA discharges from the mouse brain intracutaneous neurone of cultivating " (Excitatory amino acid-inducedrelease of
3H-GABA from cultured mouse cerebral cortexinterneurons), " neuroscience magazine " (J.Neurosci.), 7:2910-16 (1987).Hamill O.P., Marty A., Neher E., Sakmann B. and Sigworth F.J., " be used to write down the improved patch clamping technique of cell and acellular film spot high resolution electric current " (Improved patch-clamp techniques for high-resolution currentrecording from cells and cell-free membrane patches), Pflugers Arch, 7:85-100 (1981).Mathiesen C., Varming T. and Jensen L.H., " in the body of ampa receptor antagonist in the mouse cortical neuron of mouse hippocampal neuron and cultivation and external assessment " (In vivoand in vitro evaluation of AMPA receptor antagonists in rathippocampal neurones and cultured mouse cortical neurones), " European pharmacology magazine " (Eur.J.Pharmacol.), 353:159-167 (1998).The application purpose of iontherapy
The peak shape activity enthusiasm effect in vivo that assessment AMPA conditioning agent (PAMs) excites AMPA in the mouse hippocampus.Principle
The strong influence of the mononeural peak shape active receiving of hippocampus excitability input, and the application of AMPA iontherapy is introduced peak shape activity people such as (, 1998) Mathiesen in vivo in the mode of dependent dose.The peak shape activity that AMPA excites can be suppressed (people such as Mathiesen, 1998) by the intravenously of ampa receptor antagonist (i.v.) administration on a large scale, and this shows that excitation mainly mediates by ampa receptor.PAMs has strengthened ampa receptor in external activation, if this mechanism also is so in vivo, then intravenous injection PAM should be able to improve the peak shape activity that AMPA excites.Therefore, the purpose of this research is the effect in vivo of the outer active PAMs group of test body.Peak shape active ability by their raising AMPA stimulations after the research i.v. administration just can realize this purpose.Preparation
Experiment is at the male Wistar rats (M﹠amp of body weight 280-380g; B, Denmark) carry out on one's body, closing in every cage has two, and they can freely obtain food and water.With Sodital (50mg/kg, i.p.) mouse is anaesthetized, for monitoring blood pressure inserts conduit at femoral artery, and also insert conduit, and inject 0.9%NaCl (0.5-1.0ml/h) and Sodital (5-10mg/h) continuously at intravenously in order to carry out intravenous drug injection.If mouse is pinched pinching of metapedes and responds, some narcotic of i.v. more also then.In tracheae, insert sleeve pipe, then mouse is put into a gunning stick, ventilate with grinding tooth ventilator (Ugo Basile, Comerio-Varese, Italy).With the DC heating cushion temperature in the body is remained on 37.5 ℃.Take off the left side and the back portion of parietal bone by operation of opening cranium, extract endocranium out, the brain of pia mater and lower floor is come out, cover with 0.9%NaCl.Compound/reagent
(Sigma USA) is dissolved in 0.2M NaCl, and concentration is 10mM with AMPA.(Sigma USA) is dissolved in 100mM NaCl, and concentration is 100mM with NMDA.With NaOH two kinds of solution are adjusted to pH 7.5-8.0.Compound 61 is dissolved in 200mM CH
3SO
3 -Na
+, concentration is 10mM (pH 7.4), is used for iontherapy and uses, and be dissolved in etc. and ooze glucose (278mM), is used for the i.v. administration.Same method, with cyclothiazide, compound 63,56,115 and 114 all are dissolved in 5% chromophore's solution, and concentration is 5mg/ml.Parameter
With the neurone peak shape activity that the computer on-line analysis excites, preserve the time that single spike and incident take place.With the activity of neurone peak shape (quantity of action potential, s
-1) the supervision result with the expression AMPA, compound 61 and carrier applicable cases indicator value be presented on the pulsing rate histogram.Step
With a tip diameter be 10-12 μ m five glass microelectrodes (5B120F-6, World Precision Instrument Inc., Sarasota, Florida USA) does the extracellular recording of single hippocampal neuron spike.Each is equipped with 5M NaCl (being used for record) respectively, 400mM NaCl (being used for current balance type), and 10mM compound 61 is in 200mM CH
3SO
3 -Na
+(pH 7.4), 200mM CH
3SO
3 -Na
+(pH 7.4, carrier), last wound packages be AMPA.
(H=2.0-3.0mm is according to Paxinos﹠amp for A=5.5-6.5mm, L=1.5-2.0mm hippocampal neuron in experiment; Watson, 1986) carry out on.Adopt the iontherapy of AMPA, stimulated 10-15 second, the neurone peak shape activity that excites every 1.5 minutes.(California USA) amplifies 5000 times with single neurone peak shape activity to the amplifier of dedicated bandwidth 0.3 and 3kHz for the CyberAmp 320 that has AI 402 * 50 mini probes, Axon Instruments.Cooperate 1401plus interface (Cambridge ElectronicDesign Limited, England) to carry out online and off-line analysis with the Spike2 program.Computer has also write down mean arterial blood pressure, and the monitoring ion electroosmotic drainage is used.
Regular periods with 100-105 second is injected hippocampus with AMPA.Neurone response stable (variation that AMPA that the time surveys responds through 10 seconds is no more than 10%) at least after half an hour with cyclothiazide, compound 63,56,115,61 and 114 single agent (10mg/kg) are expelled in the thigh vein.Intravenous injection is the activity of continuous recording neurone peak shape after at least 45 minutes.Microiontophoresis application testing PAM response capacity by compound 61 (20nA, figure).The result
Fig. 8 shows the applicable cases of the iontherapy of the peak shape active compound 61 that raising AMPA excites, the peak shape activity that carrier does not wherein have influence to excite.Cyclothiazide intravenous administration (10mg/kg) does not improve the peak shape activity (Figure 10) that AMPA excites.
Fig. 9, the applicable cases of the iontherapy of the single neurone peak shape active compound 61 that raising AMPA excites.Carrier is used iontherapy does not influence the peak shape activity that AMPA excites.
Figure 10, (10mg/kg i.v.) does not influence the peak shape activity that the AMPA in the hippocampus excites to cyclothiazide.The shaded block of AMPAl track top is represented administration time (registration beginning 1500 seconds afterwards).
Effect depends on control group peak shape activity level in the active body of peak shape that PAMs excites AMPA.Stimulate by low strength AMPA, compound 63 has improved the response of a small amount of AMPA, also is that a large amount of AMPA responses are just had effect (Figure 11) but stimulate by high strength AMPA.I.v. be to suppress the AMPA response at first after the administration, begin after 15-30 minute to improve (Figure 11).Figure 12 has shown the example that improves the AMPA response with compound 56 (10mg/kg).Began in about 10 minutes after the administration to take place (Figure 12).
Figure 11, (10mg/kg i.v.) has improved low strength AMPA response (12nA) to compound 63, but high strength AMPA response (17nA) is only just had effect.Obtained 10mg/kg compound 63 behind the start-of-record in 1500 seconds.Represent with the shaded block of AMPA2 track top inject time.
Figure 12, (10mg/kg i.v.) has improved the peak shape activity that AMPA excites to compound 56.Compound 56 injections were carried out in the registration beginning in back 1250 seconds.Represent with the shaded block of AMPA track top inject time.
Figure 13 has shown the example that the activity of AMPA peak shape improves after compound 115 (10mg/kg) the i.v. administration.I.v. came into effect and continued more than 2 hours in 2 minutes after the administration.Compound 61 (10mg/kg) has also improved AMPA in the intravital response of hippocampus.The peak shape activity that compound 61 began AMPA is excited after administration in 20 minutes increases by 3 times, and continues (Figure 14) more than 2 hours.If lower (the 21-209 spike/response of control group level of AMPA response, average response, Figure 15), compound 114 (10mg/kg) makes the AMPA response increase by 10 times, and big control group response only observe less raising (124-204 spike/response, Figure 16).
Figure 13, (10mg/kg i.v.) has improved the peak shape activity that AMPA excites in the hippocampus to compound 115.Shaded block is represented the time of i.v. injection, back 1900 seconds of registration beginning.The effect of compound 115 continued more than 2 hours.
Figure 14, (10mg/kg i.v.) has improved the response of AMPA in the hippocampus to compound 61, and administration (shaded block by the track top is represented) the last 1000 seconds is carried out in the registration beginning.The effect of compound 61 continued more than 2.5 hours.
Figure 15, (10mg/kg i.v.) has improved the peak shape activity that AMPA excites to compound 114.Administration was carried out in the registration beginning in back 1730 seconds, was represented by the shaded block of track top.
Figure 16, (10mg/kg, i.v.) response with AMPA has increased by one times to compound 114.In the time of the 3900th second, carry out the i.v. administration, represent by the shaded block of track top.
The result shows, do not shown any effect in vivo after the cyclothiazide i.v. administration, and compound 63,56,115,61 and 114 has all improved the peak shape activity that AMPA excites to rely on active mode.Reference Mathiesen C., Varming T. and Jensen L.H., " in the body of ampa receptor antagonist in the mouse cortical neuron of mouse hippocampal neuron and cultivation and external assessment " (In vivoand in vitro evaluation of AMPA receptor antagonists in rathippocampal neurones and cultured mouse cortical neurones), " European pharmacology magazine " (Eur.J.Pharmacol.), 353:159-167 (1998).Paxinos G. and Watson C., " the mouse brain in the directed coordination/coordinate " (The rat brainin stereotaxic coordinates), the 2nd edition, 1986.Test objective avoids negative: for the pharmacological action of test compounds to associative memory.Principle: with a mouse be placed on one with bright compartment that dark compartment communicates in.If it enters dark compartment, foot can be subjected to electric shock (0.4mA).Test is emitted and is subjected to the cognation that the unhappy risk that shocks by electricity enters dark compartment again after 24 hours.Animal: the female NMRI mouse (Bomholdtgaard, Denmark) of using body weight 22-25g.Mouse is closed in the Macrolon plastics cage, freely pickuping food (Altromin, Denmark) and tap water.Be familiar with custom laboratory (7:00am turns on light/7:00 pm light-off) will for before the test at least 3 days time of mouse.Equipment: (ENV-307, MED-Associates USA) constitute the device that avoids negative by the modularization proofing box.Bright chamber and darkroom are by equidimension (15 * 17 * 13cm that is adorning the metal grid floor; Wide * length * height) the synthetic glass box constitute.The lock formula that falls door is contained in the hole of two compartments of perforation (on 4 * 4cm).(ENV-412, MED-Associates USA) provide 0.4mA foot electric shock with manual grid scrambler.Parameter: the waiting time (second) of measuring the reentry darkroom.Step: before with the test compound training, mouse is carried out pre-treatment (being generally 30 minutes).Training a: mouse is placed in the bright chamber, and opens the gate that leads to the darkroom.After 4 claws of mouse all stride into the darkroom, give its foot electric shock (0.4mA), then it is put back in the original cage.Test: mouse will reenter bright chamber after 24 hours, and measure the waiting time that enters the darkroom, exceed with 2 minutes.If mouse does not also enter the darkroom within maximum test period (2 minutes), then will be designated as 2 minutes the waiting time.Carrier: 10%Tween80.Potion dose: 10ml/kgn=10.The result: with every treated animal on average enter the waiting time (± SEM) expression.
The result as shown in figure 17, demonstration be the action effect of compound 61 memory of different concns.
The accompanying drawing summary
Fig. 1 and Fig. 2 show be The compounds of this invention to AMPA induce [
3H] strengthening effect that discharges from the cutaneous nerve unit of cultivating of GABA.
Fig. 3 to Fig. 8 shows the voltage folder experimental result of The compounds of this invention.Compound 56 (Fig. 3), 63 (Fig. 4), 111 (Fig. 6), 114 (Fig. 7) and 115 (Fig. 5) are all to using the electric current of introducing behind the 30 μ M AMPA that strengthening effect is arranged.
Fig. 8 shows that The compounds of this invention (114) relies on the action effect of concentration.
Fig. 9 to Figure 16 is the iontherapy experimental result.
Fig. 9, the iontophoresis of compound 61 is used and carrier ion electroosmotic drainage applicable cases.
Figure 10, cyclothiazide application in hippocampus.
Figure 11, the application of compound 63.
Figure 12, the application of compound 56.
Figure 13, the application of compound 115.
Figure 13, compound 115 is used to hippocampus.
Figure 14, compound 61 is used to hippocampus.
Figure 15, compound 114.
Figure 16, compound 114.
Figure 17, the test that avoids negative of compound 61.
The general sulphonamide glycosylation reaction of method for transformation method A that embodiment is general
The compound of wanting chlorsulfonic acidization (32.5mmol) is dissolved in chlorsulfonic acid (75ml), and in 110 ℃ of oil baths, heats, show to react up to TLC and finished *.Reaction mixture is poured on ice, forms precipitation, then filtering separation.Isolated solid is also dry with the less water washing on filter paper.The gained solid is dissolved in anhydrous THF (200ml), and adds excessive amine (230ml), at room temperature stirred reaction mixture spends the night then.Reaction mixture is evaporated to dried, adds water then and stir, filtering separation also on filter paper with the EtOAc washing, obtain solid.Can be further purified with column chromatography or from EtOAc/ hexane recrystallization, productive rate is generally 60-90%.*: take out on a small quantity, be added in the test tube that fills ice, use Na
2CO
3Neutralization extracts with EtOAc then.Remove water, organic phase is added in the piperidines, place for some time then.Carry out TLC with a small amount of reaction mixture that so obtains.The adjacent sulfamylization of method B aniline
Be to add ClSO in the stirred solution of-50 ℃ the nitroethane of aminophenyl derivative (250ml) or Nitromethane 99Min. (100ml)
2The nitroethane of NCO (275mmol) or Nitromethane 99Min. (75ml) solution, and make temperature of reaction be no more than-30 ℃.Remove cooling bath, allow this thick reaction mixture to be warming up to 0 ℃.Add a collection of solid AlCl
3(300mmol).Limpid brown reaction mixture was heated 20 minutes in 120 ℃ of oil baths, and cool to room temperature is poured a large beaker that the frozen water (1L) that is stirring is housed into then.Isolate the precipitation * of formation after filtration.Intermediate urea (98mmol) is suspended in diox (250ml) and 6M H
2SO
4Mixture (or having only dense HCl), reflux is spent the night then.With the reaction mixture cool to room temperature, filter and from filtrate, remove diox by evaporation.With 4M NaOH with the water-based residuum pH 7-8 that neutralizes.Leach the precipitation of formation, water and EtOAc washing *.Overall yield is 10-75%.
See also Girard Y., Atkinson J.G. and Rokach J., " Chemical Society's magazine " (J.Chem.Soc.), Perkin I, 1043 (1979).*: the aniline of a replacement causes two kinds of possible mixture of isomers, it can the urea intermediate stage by separating from the MeOH crystallization, also can produce the stage by separating at end product from the crystallization of EtOAc/ hexane or by chromatography.The protection of method C trifluoroacetyl group
In the anhydrous THF (75ml) of the 2-aminobenzene sulfonamide derivative (27mmol) that is stirring in 0 ℃ solution, add trifluoroacetic anhydride, and reaction mixture temperature be no more than+10 ℃.With reaction mixture in stirring at room up to consuming whole starting raw materials.Reaction mixture is evaporated to dried, adds water and stir, filter and use hexane wash.Isolated solid is added among the PPA (250g), and in 140 ℃ of oil baths, heated 2.5 hours.Reaction mixture is cooled to 60-70 ℃, is poured in the churned mechanically frozen water solution.Leach the precipitation of formation, air-dry.Overall yield is generally 85-90%.The deprotection of method D trifluoroacetyl group
To be dissolved in 1M KOH (30ml) trifluoroacetyl group protection compound (3.6mmol) solution stirring and 80 ℃ of heating 1 hour.With the reaction mixture cool to room temperature, use dense HCl (aq.) that pH is transferred to 7 then.Reaction mixture is cooled to 0 ℃ and filtration.Isolated solid washes with water, and is air-dry.Productive rate is generally 85-95%.Method E prepares dihydrobenzo thiadiazine-1 by 2-amino-benzene-sulphonamide, the 1-dioxide
To the 2-aminobenzene sulfonamide derivative (148mmol) that is stirring in 5 ℃, triethylamine (150mmol) adds carboxylic acid chlorine in the 600ml THF solution of 4-(N, N-dimethylamino) pyridine (7.5mmol).Reaction mixture is continued stirring spend the night, be evaporated to dried then.Crude product is stirred with water, filter then.Isolated solid is dissolved in 1M NaOH (250ml), and 80 ℃ of heating 3 hours.With the reaction mixture cool to room temperature, pH is transferred to 7 with dense HCl.Reaction mixture is cooled to 0 ℃ and filtration.Separate the precipitation that forms, from the i-PrOH recrystallization.Overall yield is 80-90%.Method F dihydrobenzo thiadiazine-1,1-dioxide be to tetrahydro benzo thiadiazine-1, the reduction of 1-dioxide
To the dihydrobenzo thiadiazine-1 that is stirring in-70 ℃, add the toluene (33ml of 1.5M DIBALH in anhydrous THF (200ml) solution of 1-dioxide (19.4mmol); 50mmol) solution.Reaction mixture is continued stirring spend the night, allow temperature slowly be increased to-15 ℃ simultaneously from-70 ℃.In reaction mixture, add water (10ml), add 1M NaOH (5ml) then.Reaction mixture is risen to room temperature, extract with EtOAc.The organic phase MgSO that merges
4Drying, and be evaporated to dried.Can be further purified product with column chromatography in some cases.Productive rate is 45-85%.Method G prepares tetrahydro benzo thiadiazine-1 by 2-amino-benzene-sulphonamide, the 1-dioxide
With the 2-aminobenzene sulfonamide derivative (7mmol) that is stirring, aldehyde (10mmol) and MgSO
4Anhydrous THF (20mmol) or no Shui diox (40ml) solution are at N
2Following backflow shows that up to TLC 2-aminobenzene sulfonamide derivative all runs out of (generally wanting 12-36 hour).Filter reaction mixture thoroughly washs the precipitation that leaches with THF Huo diox.Filtrate is evaporated to dried, adds water and extract with EtOAc.The organic phase MgSO that merges
4Drying is evaporated to dried then.Obtain pure products through column chromatography purifying (EtOAc/ hexane).Productive rate is generally 25-75%.Method H uses the catalytic cross-coupling reaction of Pd to prepare the compound of aryl or heteroaryl replacement
Suzuki coupling: with the aryl halide (2mmol) that stirs, aryl or heteroaryl boric acid, boric acid ester or Dialkylborane (6mmol), K
2CO
3(10mmol), Pd (PPh
3)
4(30mg), 1, ammediol (10mmol), glycol dimethyl ether (50ml) and H
2The mixture of O (25ml) is at N
2Down 70 ℃ of heating 3 hours.With the reaction mixture cool to room temperature.Add water and extract with EtOAc.The organic phase MgSO that merges
4Drying is evaporated to dried then.Obtain pure products through the column chromatography purifying.Productive rate is 40-100%.The method I contains the preparation of triazolyl substituting group compound
Sonogashira coupling: with aryl iodide or aromatic bromide (2mmol), acetylene (10mmol), Pd (PPh
3)
2Cl
2(140mg; 0.2mmol), CuI (40mg; 0.1mmol) and the mixture of triethylamine (10ml) at room temperature stir (if adopt aromatic bromide, be necessary temperature is brought up to 60 ℃) and spend the night.Add THF and use the diatomite filtration reaction mixture, then filtrate is evaporated to dried.Obtain the aromatic hydrocarbons of ethinylation through the column chromatography purifying.For aromatic bromide, productive rate is 40-53%; To aryl iodide, productive rate is 40-97%.R '=TMS takes off the trimethyl silyl reaction: the MeOH (2ml that MeOH (8ml) solution of the aromatic hydrocarbons (1.7mmol) of ethinylation is added to 1M KOH; 2mmol) in the solution, and stirring at room 2 hours.Use the THF diluted reaction mixture, absorb with silicon-dioxide, chromatographic separation obtains desilylation acetylene aromatic hydrocarbons.Productive rate 61-73%.The preparation of triazole: with acetylene aromatic hydrocarbons (0.7mmol) and TMS-N
3(2ml; 15mmol) in an ampoule, heated 50 hours in 70 ℃.With the reaction mixture cool to room temperature, and be evaporated near absolutely dry (attention: because some HN
3Existence, be evaporated to do and can cause blast! ).Add MeOH, reaction mixture is stirred 1 hour (to remove the TMS group in the TMS-triazole).Absorb on the silicon-dioxide, use chromatography purification.Productive rate 20-72%.The synthetic compound 12-cyclohexyl-4-oxygen-1,2,3 of each compound, the 4-tetrahydro quinazoline
Employing method G (using hexanaphthene formaldehyde) is transformed by anthranilamide.m．p．172-174℃。Compound 22-phenyl-4-oxygen-1,2,3, the 4-tetrahydro quinazoline
Employing method G (using phenyl aldehyde) is transformed by anthranilamide.m．p．221-222℃。Compound 32-methyl-3,4-dihydro-1,3-benzoxazine-4-ketone
Employing method G (using Metaldehyde) is transformed by the 2-hydroxybenzamide.m．p．124-126℃。Compound 42-phenyl-3,4-dihydro-1,3-benzoxazine-4-ketone
Employing method G (using phenyl aldehyde) is transformed by the 2-hydroxybenzamide.m．p．157-160℃。Compound 53-dicyclo [2.2.1]-5 '-alkene-2 ' in heptan-Ji-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Employing method G (with the racemize inside/outside mixture of isomers of 2-norbornylene formaldehyde) is transformed by the 2-aminobenzene sulfonamide.m．p．206-209℃。Compound 63-phenyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Employing method G (using phenyl aldehyde) is transformed by the 2-aminobenzene sulfonamide.m．p．125．5-128．5℃。Compound 71,2,3,5,10,10a-hexahydrobenzene be [e] pyrrolo-[1,2-b]-1,2 also, 4-thiadiazine-5,5-dioxide
Make starting raw material with the 2-aminobenzene sulfonamide, carry out following conversion successively: employing method E (uses the 4-chlorobutanoylchloride.Reaction mixture does not carry out the catalytic ring ring-closure reaction of NaOH, but it will be dissolved in H
2SO
4, and 100 ℃ of heating 72 hours, be placed on then and make its precipitation on ice).m．p．149-154℃。Compound 82-ethyl-3,4-dihydro-1,3-benzoxazine-4-ketone
Employing method G (using butanone) is transformed by the 2-hydroxybenzamide.m．p．76-78℃。Compound 93-cyclohexyl-6-(2-p-methoxy-phenyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Employing method B (seeing compound 121) changes into 4-bromo-2-aminobenzene sulfonamide by 3-bromo-aniline.
With 4-bromo-2-aminobenzene sulfonamide (140mg, 0.56mmol), 2-anisole ylboronic acid (106mg, 0.70mmol), Pd (PPh
3)
2Cl
2(20mg, 5mol%) 1,2-glycol dimethyl ether (30ml) and Na
2CO
3(6mmol) mixture is at N for 3M, 3ml
2Under refluxed 4 hours.The saturated NaHCO of removal of solvent under reduced pressure, residuum
3(20ml) handle, with EtOAc extraction (2 * 40ml).Organic phase is washed with salt solution (20ml), dry (Na
2SO
4), solvent removed by evaporation at reduced pressure.Product is at SiO
2The last purified by flash chromatography of using, and usefulness EtOAc/ normal hexane (1: 1, v/v) wash-out, obtaining 155mg (100%) 2-amino-4-(2-p-methoxy-phenyl)-benzsulfamide is colourless powder.With the further converted product of method G (using hexanaphthene formaldehyde).m．p．219-221℃。Compound 103-cyclohexyl-6-(2-pyridyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
N
2Down with 3-aminophenyl boric acid Hemisulphate (5.58g, 30mmol), the 2-bromopyridine (2.7ml, 28mmol), Pd (PPh
3)
2Cl
2(100mg, 5mol%), 2M K
2CO
3(50ml) 1, refluxed 24 hours in the 2-glycol dimethyl ether (50ml).Mixture CH
2Cl
2(100ml) dilution, saturated NaHCO
3(50ml) washing.Dry (Na
2SO
4) organic phase, solvent removed by evaporation at reduced pressure.Through purification by flash chromatography, use CH
2Cl
2Wash-out, obtaining 3-(2-pyridyl) aniline is yellow oil.With method B and method G (using hexanaphthene formaldehyde) 3-(2-pyridyl) aniline is changed into title compound.m．p．213-216℃。Compound 113-cyclohexyl-6-(3-pyridyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Employing method B (seeing compound 121) changes into 4-bromo-2-aminobenzene sulfonamide by 3-bromo-aniline.
With 4-bromo-2-aminobenzene sulfonamide (250mg, 1.0mmol), diethyl-3-pyridyl borine (225mg, 1.5mmol), Pd (PPh
3)
2Cl
2(35mg, 5mol%) 1,2-glycol dimethyl ether (30ml) and Na
2CO
3(6mmol) mixture is at N for 2M, 3ml
2Under refluxed 4 hours.The saturated NaHCO of removal of solvent under reduced pressure, residuum
3(20ml) handle, with EtOAc extraction (2 * 40ml).Organic phase is washed with salt solution (20ml), dry (Na
2SO
4), solvent removed by evaporation at reduced pressure.Product is at SiO
2The last purified by flash chromatography of using, and usefulness EtOAc/ normal hexane (1: 1, v/v) wash-out, obtaining 240mg (96%) 2-amino-4-(3-pyridyl)-benzsulfamide is colourless powder.With the further converted product of method G (using hexanaphthene formaldehyde).m．p．240-243℃。Compound 123-cyclohexyl-7-(1-hydroxyethyl)-1; 2; 3; 4-tetrahydrochysene-1; 2,4-benzothiadiazine-1,1-dioxide 2-amino-5-(1-hydroxyethyl) benzsulfamide: with 5-ethanoyl-2-aminobenzene sulfonamide (seeing compound 13) (0.95g; 4.4mmol) be suspended in 96%EtOH (50ml), and disposable adding NaBH
4(0.46g, 12mmol).Mixture was stirred 4 hours at 25 ℃, use diatomite filtration then, and removal of solvent under reduced pressure.The saturated NaHCO of residuum
3(50ml) handle, with the EtOAc extraction (2 * 50ml), dry (Na
2SO
4), and be evaporated to dried.Through purification by flash chromatography, with EtOAc/ normal hexane/Et
3N (200: 100: 4, v/v/v) wash-out, obtaining 0.35g (37%) 2-amino-5-(1-hydroxyethyl)-benzsulfamide is light brown powder.m．p．160-162℃。Compound 133-cyclohexyl-7-ethanoyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
(5.8ml, (1.7M is in pentane, and 25ml 40mmol), and stirs mixture 1 hour at-78 ℃ to add t-BuLi among the anhydrous THF (50ml) 60mmol) to ethyl vinyl ether in-78 ℃.Remove cooling bath, allow mixture slowly be warming up to 0 ℃, stirred then 30 minutes.Mixture is cooled to-78 ℃ again, slowly adds ZnCl
2(2M is in THF, 20ml, 40mmol).Remove cooling bath again, and be warming up to 20 ℃.Add 5-iodo-2-aminobenzene sulfonamide (seeing compound 37) (1.8g, 6mmol) and Pd (PPh
3)
4(0.2g 3mol%), refluxes mixture 6 hours.THF is removed in evaporation, and residuum seethed with excitement 30 minutes in 1M hydrochloric acid (30ml) and MeOH (30ml).Add EDTA (14.6g 50mmol), adds 1M NaOH and makes it be alkalescence (pH is about 8-9) a little, then with the EtOAc extraction (3 * 150ml), dry (Na
2SO
4), and evaporation obtains brown solid except that desolvating.It is ground with normal hexane, obtain that 0.95g (74%) 5-ethanoyl-the 2-aminobenzene sulfonamide is a cream-coloured powder.With the further converted product of method G (using hexanaphthene formaldehyde).M.p.224-226 ℃ (decomposition).Compound 143-cyclohexyl-7-(1-oxyimino ethyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
(0.45g adds H in 96%EtOH 2.1mmol) (40ml) suspension to 5-ethanoyl-2-aminobenzene sulfonamide (seeing compound 13)
2NOHHCl (0.28g, 4mmol) and 2MNaOH (2ml).With mixture boiling 2 hours, evaporation removed and desolvates.Residuum water (20ml) grinds..Leach product and dry, obtain 0.39g (81%) 2-amino-5-(1-oxyimino ethyl) benzsulfamide, be yellow powder.Product further uses method G (using hexanaphthene formaldehyde) to transform.m．p．230-233℃。Compound 153-cyclohexyl-7-formamyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
With 5-cyano group-2-aminobenzene sulfonamide (seeing compound 37) (2g, 10mmol), dense H
2SO
4(4ml) mixture with anhydrous EtOH (4ml) heated 5 hours at 80 ℃, and 50 ℃ of heated overnight.Mixture is poured on ice, uses EtOAc (1 *) extraction * then.Outwell organic phase, water Na
2CO
3Neutralization, and with EtOAc extracts (3 *).The evaporate to dryness organic phase is carried out column chromatography (EtOAc/ hexane=2/1) and is separated, and obtains this methane amide of 200mg (9%).Further transform methane amide with method G (using hexanaphthene formaldehyde).m．p．235-237℃。*: contain nitrile (starting raw material) and another kind of by product in the extract for the first time.Compound 163-cyclohexyl-7-ethoxycarbonyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
With 5-cyano group-2-aminobenzene sulfonamide (seeing compound 37) (3g, 15mmol), dense H
2SO
4(5ml) and the mixture of anhydrous EtOH (15ml) 80 ℃ of heated overnight.Mixture is poured on ice.Leach the gained precipitation,, obtain the pure ethyl ester of 2.01g (55%) with the EtOAc washing.Further transform this ester with method G (using hexanaphthene formaldehyde).m．p．234-236℃。Compound 173-cyclohexyl-7-cyano group-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
With method G (using hexanaphthene formaldehyde), be transformed by 5-cyano group-2-aminobenzene sulfonamide (seeing compound 37).m．p．234-237℃。Compound 183-dicyclo [2.2.1]-5 '-alkene-2 ' in heptan-Ji-7-phenyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide 5-bromo-2-aminobenzene sulfonamide: the 2-aminobenzene sulfonamide (1.72g that will stir; AcOH 10mmol) (15ml) solution is added to Br
2(0.55ml; 10.5mmol) AcOH (5ml) solution in.Pour reaction mixture into H
2O (100ml) also filters.Isolated solid is absorbed on the silicon-dioxide, and carries out purification by flash chromatography, obtain 1.428g (57%) product and (650mg (20%) 3,5-two br-derivatives).3-dicyclo [2.2.1]-5 '-alkene-2 ' in heptan base-7-phenyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide (18): employing method H (using phenyl-boron dihydroxide) and method G (with dicyclo [2.2.1] heptan-5-alkene-2-formaldehyde), be transformed by 5-bromo-2-aminobenzene sulfonamide.m．p．190．5-195．0℃。Compound 193-cyclohexyl-7-(2 '-acetylamino phenyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide N-nitrophenyl boric acid: with-15 ℃ phenyl-boron dihydroxide (10g; Diacetyl oxide 82mmol) (100ml) is with being added to the HNO of being fuming in 30 minutes
3(5ml; Mixture is remained on below-10 ℃.Allow reaction mixture to rise to room temperature, stir simultaneously and spend the night.Reaction mixture is poured on ice, is concentrated into 50ml then.In residuum, add water (100ml) repeatedly and evaporate 5 times, obtain the 7.1g crude product after the filtration, be mixture of isomers.Through column chromatography purifying (CH
2Cl
2/ EtOH=10/0.5), obtain 4.8g (35%) pure products and be oil.2-acetyl amino phenyl ylboronic acid: with 2-nitrophenyl boric acid (2g; 12mmol) and EtOH (100ml) mixture hydrogenation under 1bar pressure of 5%Pd/C (100mg), show that up to TLC starting raw material all transforms.Use the diatomite filtration reaction mixture, filtrate is evaporated to dried.The residuum hexane wash obtains 900mg (55%) 2-aminophenyl boric acid after the filtration.
With 2-aminophenyl boric acid (900mg; 6.6mmol), triethylamine (0.57ml; 7mmol) and Acetyl Chloride 98Min. (0.5ml; Mixture 7mmol) stirred 1 hour at room temperature.Reaction mixture is evaporated to dried, adds water and stir, filter and obtain 750mg (63%) product.3-cyclohexyl-7-(2 '-acetylamino phenyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide (19): usefulness method H (with 2-acetyl amino phenyl ylboronic acid) and method G (using hexanaphthene formaldehyde) are transformed by 5-iodo-2-aminobenzene sulfonamide (seeing compound 37).m．p．245-249℃。Compound 203-cyclohexyl-7-(2 '-nitrophenyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
With method H (with 2-nitrophenyl boric acid (seeing compound 19)) and method G (using hexanaphthene formaldehyde), be transformed by 5-iodo-2-aminobenzene sulfonamide (seeing compound 37).m．p．204-207℃。Compound 213-cyclohexyl-7-(2 '-p-methoxy-phenyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
With method H (with 2-anisole ylboronic acid) and method G (using hexanaphthene formaldehyde), be transformed by 5-iodo-2-aminobenzene sulfonamide (seeing compound 37).m．p．219-222℃。Compound 223-cyclohexyl-7-(2 '-methoxyl group-4 '-trifluoromethyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide 4-trifluoromethyl phenylmethylether: with sodium (12.78g; 555mmol) be added among the anhydrous MeOH (100ml).Treat after venting stops reaction mixture being evaporated to dried.Successively add NMP (250ml), Cu (s) (35.3; 555mmol) with 4-bromo-trifluoromethylbenzene (25g; 111mmol).Reaction mixture 130 ℃ of heating 4 hours, is cooled to room temperature then, and filters.In filtrate, add water (500ml), use Et then
2O extraction (2 * 200ml).Merge organic phase, wash with water (2 * 100ml), dry (MgSO
4), and be evaporated to dried.Obtain 8.05g (41%) product through the column chromatography purifying.2-methoxyl group-5-trifluoromethyl phenyl boronic acid: with 4-trifluoromethyl phenylmethylether (8g; Anhydrous THF (80ml) solution 45mmol) in-30 ℃ at N
2Be added to the hexane (20ml of 2.5M n-BuLi down; 50mmol) in the solution.Reaction mixture was stirred 1 hour at-30 ℃, be cooled to-70 ℃ and add B (Oi-Pr) then
3(14.1ml; 64mmol).Allow reaction mixture through slowly rising to room temperature a night.Add 2M HCl (40ml) in reaction mixture, THF is removed in evaporation then.Water-based residuum Et
2(4 * 20ml), the organic phase of merging extracts (5 * 17ml) with 1M NaOH in the O extraction.The water that merges neutralizes with 10M HCl.Leach the gained precipitation,, obtain 8.1g (81%) product with 1M HCl washing.3-cyclohexyl-7-(2 '-methoxyl group-4 '-trifluoromethyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide (22): usefulness method H (with 2-methoxyl group-5-trifluoromethyl phenyl boronic acid) and method G (using hexanaphthene formaldehyde) are transformed by 5-iodo-2-aminobenzene sulfonamide (seeing compound 37).m．p．255-257℃。Compound 233-cyclohexyl-7-(2 ', 4 '-Dimethoxyphenyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
With method H (with 2,4-dimethoxy benzene ylboronic acid) and method G (using hexanaphthene formaldehyde), be transformed by 5-iodo-2-aminobenzene sulfonamide (seeing compound 37).m．p．208-213℃。Compound 243-cyclohexyl-7-(2 '-(N, N-dimethylamino alkylsulfonyl) phenyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide 2-(N, N-dimethylamino alkylsulfonyl) phenyl-boron dihydroxide: with benzene sulfonyl chloride (10ml; THF 78mmol) (100ml) solution is added to the H of 40% dimethylamine
2O (20ml; 160mmol) in the solution, make temperature of reaction remain on 50 ℃.With reaction mixture at room temperature.In reaction mixture, add H
2O, THF is removed in evaporation.Leach precipitation, air-dry, obtain 14g (97%) N, the N-dimethyl benzene sulfonamide.
With N, N-dimethyl benzene sulfonamide (9.25g; Anhydrous Et 50mmol)
2O (150ml) solution is at N
2Under be cooled to-70 ℃, add the hexane (24ml of 2.5M n-BuLi; 60mmol) solution remains on below-60 ℃ temperature of reaction.Remove cooling bath, allow reaction mixture slowly be warming up to+20 ℃.Reaction mixture is cooled to again-70 ℃ and add B (Oi-Pr)
3(16.1ml; 70mmol).Reaction mixture taken after cooling environment makes it to spend the night, rise to room temperature.Add 2M HCl (40ml) in reaction mixture, THF is removed in evaporation then.In reaction mixture, add 2M HCl (40ml).Add 1M HCl (100ml), and continue stirring at room 1 hour.Reaction mixture Et
2(2 * 50ml), the organic phase of merging extracts (4 * 50ml) with 1M NaOH in the O extraction.The water that merges is used Et with 10M HCl neutralization
2O extraction (4 * 100ml).Dry (Na
2SO
4) organic phase that merges, be evaporated to dried then.Use Et
2The O/ hexane wash obtains 3.4g (30%) product.3-cyclohexyl-7-(2 '-(N; N-dimethylamino alkylsulfonyl) phenyl)-1; 2; 3,4-tetrahydrochysene-1,2; 4-benzothiadiazine-1; 1-dioxide (24): usefulness method H (with 2-(N, N-dimethylamino alkylsulfonyl) phenyl-boron dihydroxide) and method G (using hexanaphthene formaldehyde) are transformed by 5-iodo-2-aminobenzene sulfonamide (seeing compound 37).m．p．290-300℃。Compound 253-cyclohexyl-7-(2 '-chloro-phenyl-)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
With method H (using the 2-chlorophenylboronic acid) and method G (using hexanaphthene formaldehyde), be transformed by 5-iodo-2-aminobenzene sulfonamide (seeing compound 37).m．p．233-236℃。Compound 263-cyclohexyl-7-(2 '-fluorophenyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
With method H (with 2-fluorophenyl boric acid) and method G (using hexanaphthene formaldehyde), be transformed by 5-iodo-2-aminobenzene sulfonamide (seeing compound 37).m．p．249-250℃。Compound 273-cyclohexyl-7-(3 '-hydroxy phenyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide 3-hydroxy phenyl boric acid: will be at the 3-aminophenyl boric acid Hemisulphate (6.2g of-2 ℃ stirring with 1 hour; 33.3mmol) and 50%H
2SO
4(3.7ml; 33.3mmol) H
2O (100ml) solution is added to NaNO
2(2.5g; 36.3mmol) H
2In O (20ml) solution.Reaction mixture slowly is added to the dense H that stirs and reflux
2SO
4H (25ml)
2In O (20ml) solution.With reaction mixture refluxed 30 minutes, cooling then added gac, is heated to backflow, uses diatomite filtration after adding.Filtrate is saturated with NaCl (s), filters, and uses Et
2O extraction (5 * 100ml).Dry (Na
2SO
4) organic phase that merges and be evaporated to driedly, obtain 4.3g (94%) product.3-cyclohexyl-7-(3 '-hydroxy phenyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide (27): usefulness method H and method G (using hexanaphthene formaldehyde) are transformed by 3-hydroxy phenyl boric acid.m．p．238-246℃。Compound 283-cyclohexyl-7-(2 '-pyridyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide 4-(2 '-pyridyl)-2-aminobenzene sulfonamide: N
2Down with the 5-iodo-2-aminobenzene sulfonamide (1g that stirs; 3.3mmol), 2-tributyl stannyl pyridine (5.5g; 15mmol), Pd (PPh
3)
4(240mg; 0.34mmol) and Ag
2O (780mg; 3.36mmol) DMF (50ml) mixture 100 ℃ the heating 6 hours, then in stirred overnight at room temperature.Reaction mixture is evaporated to dried, is suspended in H
2Also stir among the O/EtOAc, filter at last.Separate organic phase, water extracts (2 * water volume) with EtOAc.Dry (Na
2SO
4) organic phase that merges, evaporation separates as for laggard capable column chromatography, obtains 200mg (24%) product.3-cyclohexyl-7-(2 '-pyridyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide (28): usefulness method G (using hexanaphthene formaldehyde) is transformed by 4-(2 '-pyridyl)-2-aminobenzene sulfonamide.m．p．222-224℃。Compound 293-cyclohexyl-7-(3 '-pyridyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
With method H (with diethyl-3-pyridyl borine) and method G (using hexanaphthene formaldehyde), be transformed by 5-iodo-2-aminobenzene sulfonamide (seeing compound 37).m．p．240-242℃。Compound 303-cyclohexyl-7-(2 '-pyrimidyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide 4-((2,2-dimethyl propylene acyl group) amino) phenyl-boron dihydroxide: at-78 ℃ 4-bromo-N-pivalyl aniline (1.56g; Add among the anhydrous THF (50ml) 6mmol) t-BuLi (1.5M is in pentane, 13.3ml, 20mmol), then with yellow mixture at N
2The middle stirring 1 hour.With B (OCH
3)
3(1.7ml; 15mmol) cancellation reaction, restir is 1 hour in-78 ℃.Reaction mixture is risen to room temperature, with 0.5M hydrochloric acid (50ml) hydrolysis.With EtOAc extraction (3 * 80ml), dry (Na
2SO
4), be concentrated into about 40ml then.Slowly add normal hexane (120ml), leach gained clear crystal and dry, obtain 1.26g (95%) product.N-(4-(2-pyrimidyl) phenyl)-2,2-dimethyl propylene acid amides: with 4-((2,2-dimethyl propylene acyl group) amino) phenyl-boron dihydroxide (2.0g; 9mmol), 2-chloropyrimide (0.8g; 7mmol), Pd (PPh
3)
2Cl
2(100mg; 2mol%), 1,2-glycol dimethyl ether (40ml) and Na
2CO
3(mixture 14mmol) is at N for 2M, 7ml
2The middle backflow 5 hours.Use 10%Na
2CO
3(20ml) diluted mixture thing is then with EtOAc extraction (3 * 50ml).Dry (Na
2SO
4) organic phase, solvent removed in vacuo.Crude product obtains 0.52g (85%) N-(4-(2-pyrimidyl) phenyl)-2 from MeOH/ water (1: 1) recrystallization, and 2-dimethyl propylene acid amides is a clear crystal.4-(2-pyrimidyl) aniline: with N-(4-(2-pyrimidyl) phenyl)-2,2-dimethyl propylene acid amides (1.41g; 5.48mmol) 6M hydrochloric acid (40ml) boiling 2 hours.Cooling mixture also uses NaOH (s) with its highly basicization, uses CH
2Cl
2Extraction (2 * 50ml), dry (Na
2SO
4), solvent removed in vacuo.Grind with normal hexane, obtaining 0.83g (88%) 4-(2-pyrimidyl) aniline is buff powder.With method B and the further converted product of method G (using hexanaphthene formaldehyde).m．p．236-238℃。Compound 313-cyclohexyl-7-(2 '-furyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
With method H (with furyl-2-boric acid) and method G (using hexanaphthene formaldehyde), be transformed by 5-iodo-2-aminobenzene sulfonamide (seeing compound 37).m．p．226-228℃。Compound 323-cyclohexyl-7-(3 '-furyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
With method H (with furyl-3-boric acid) and method G (using hexanaphthene formaldehyde), be transformed by 5-iodo-2-aminobenzene sulfonamide (seeing compound 37).m．p．204-205℃。Compound 333-cyclohexyl-7-(2 '-thienyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
With method H (with thienyl-2-boric acid) and method G (using hexanaphthene formaldehyde), be transformed by 5-iodo-2-aminobenzene sulfonamide (seeing compound 37).m．p．234-236℃。Compound 343-cyclohexyl-7-(1-methyl isophthalic acid H-2-imidazolyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
In-78 ℃ at 1-Methylimidazole (4.8ml; (2.5M is in hexane, and 26ml 65mmol), and stirs yellow mixture 45 minutes at-78 ℃ to add n-BuLi in anhydrous THF (120ml) solution 60mmol).Slowly add ZnCl
2(2M is in THF, and 75ml 150mmol), removes cooling bath, and the gained colourless solution was stirred 10 minutes at 0 ℃.Add 5-iodo-2-aminobenzene sulfonamide (seeing compound 37) (2.1g, 7mmol) and Pd (PPh
3)
4(0.5g 5mol%), refluxes mixture 6 hours then.Steam and remove THF, (53g 0.18mol) handles residuum with EDTA.Handle to make it to be a little alkalescence (pH ≈ 8-9) with 1M NaOH, then with the EtOAc extraction (3 * 150ml), dry (Na
2SO
4), steaming desolventizes, and obtains dark oil, through purification by flash chromatography, and the CH of 5%MeOH
2Cl
2Wash-out, (1-methyl isophthalic acid H-2-imidazolyl)-the 1-benzsulfamide is a crystal to obtain 1.33g (75%) 2-amino-5-.With the further converted product of method G (using hexanaphthene formaldehyde).M.p.＞250 ℃ (decomposition).Compound 353-cyclohexyl-7-(1 ', 2 ', 3 '-triazole-4 '-yl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
With method I (using trimethyl silyl acetylene) and method G (using hexanaphthene formaldehyde), be transformed by 5-iodo-2-aminobenzene sulfonamide (seeing compound 37).M.p.230-234 ℃ (decomposition).Compound 363-cyclohexyl-7-(5 '-phenyl-1 ', 2 ', 3 '-triazole-4 '-yl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
With method I (using phenylacetylene) and method G (using hexanaphthene formaldehyde), be transformed by 5-iodo-2-aminobenzene sulfonamide (seeing compound 37).M.p.231-232 ℃ (decomposition).Compound 373-cyclohexyl-7-(5 '-methyl isophthalic acid ', 2 ', 4 '-oxadiazoles-3-yl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide 5-iodo-2-aminobenzene sulfonamide: with 1 hour cold (0 ℃) 2-aminobenzene sulfonamide (17.2g in stirring; CHCl 100mmol)
3(200ml) add iodine monochloride (17.1g in the solution; CHCl 105mmol)
3(50ml) solution.Allow reaction mixture slowly to rise to room temperature, stir subsequently and spend the night.Filter reaction mixture, the solid that leaches are successively used CHCl on filter paper
3(3 * 20ml), NaHCO
3(saturated aqueous solution, 1 * 20ml) and H
2O (4 * 50ml) washings, air-dry then, obtain 27.3g (92%) product.5-cyano group-2-aminobenzene sulfonamide: N
2In with 5-iodo-2-aminobenzene sulfonamide (17.9g; 60mmol), Zn (CN)
2(4.9g; 41.9mmol) and Pd (PPh
3)
4(2.5g; 2.2mmol) DMF (150ml) mixture 80 ℃ the heating 2 hours.Pour reaction mixture into NaHCO
3(saturated aqueous solution, 600ml), with EtOAc extraction (9 * 200ml).Merge organic phase, use NaHCO
3(saturated aqueous solution) and NaCl (saturated aqueous solution) washing, dry (Na
2SO
4), filter, be evaporated to dried.Residuum water and hexane wash are filtered and are obtained 10.9g (92%) product.5-(N-hydroxyl amidino groups)-2-aminobenzene sulfonamide: with hydroxylamine hydrochloride (764mg; 11mmol) and NaOMe (616mg; 11.4mmol) MeOH (10ml) mixture stirring at room 1 hour, add 5-cyano group-2-aminobenzene sulfonamide (1g then; 5mmol).Reaction mixture is continued to stir 48 hours, pour into then in the water, with EtOAc extraction (2 * 50ml).Merge organic phase, dry (Na
2SO
4), be evaporated to dried.Obtain 200mg (17%) product through the column chromatography purifying.3-cyclohexyl-7-(5 '-methyl isophthalic acid ', 2 ', 4 '-oxadiazoles-3-yl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide (37); With 5-(N-hydroxyl amidino groups)-2-aminobenzene sulfonamide (200mg; 0.9mmol), NaOMe (50mg; 1mmol), the mixture of the anhydrous EtOH (20ml) of EtOAc (5ml) and broken MS3A (2g) is 70 ℃ of heated overnight.Reaction mixture is evaporated to dried, adds water and stir, extract with EtOAc.Merge organic phase, dry (Na
2SO
4), be evaporated to driedly, obtain brown oil.Its usefulness method G (using hexanaphthene formaldehyde) is further transformed 8mg product after the chromatographic separation.m．p．249-251℃。Compound 383-cyclohexyl-7-acetylaminohydroxyphenylarsonic acid 1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide 7-amino-3-cyclohexyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide: N
2Following to the 7-of-70 ℃ of stirrings amino-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (0.5g; Toluene (the 2.7ml that adds 1.5M DIBALH in anhydrous THF (10ml) solution 2mmol); 4mmol) solution.Reaction mixture was stirred 2 hours at-70 ℃, stirred 2 hours, rise to 0 ℃ then at-40 ℃.Use H
2O cancellation reaction was stirred 30 minutes at 0 ℃, spent the night+5 ℃ of placements then.Mixture is evaporated to dried, is suspended in MeOH then, filter.Isolated solid thoroughly washs with MeOH, filters then.With the filtrate of silica gel merger, (EtOAc) obtains the 200mg product through the column chromatography purifying.7-acetylaminohydroxyphenylarsonic acid 3-cyclohexyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide (38): with 7-amino-3-cyclohexyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide (100mg; 0.26mmol), Acetyl Chloride 98Min. (20 μ l; 0.29mmol) and triethylamine (42 μ l; 0.3mmol) mixture stirring at room 2 hours.Reaction mixture is suspended in H
2O filters.Isolated solid obtains 22mg compound 27a through column chromatography purifying (EtOAc).m．p．202-206℃。Compound 393-cyclohexyl-7-methyl sulphonyl amino-1,2,3,4-tetrahydrochysene-1; 2,4-benzothiadiazine-1,1-dioxide 3-cyclohexyl-1,2-dihydro-1; 2,4-benzothiadiazine-1, the 1-dioxide: usefulness method E (using hexanaphthene formaldehyde) is transformed by the 2-aminobenzene sulfonamide.3-cyclohexyl-7-nitro-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: in 5 ℃ of KNO that stirring
3(1.2g; 11.5mmol) and dense H
2SO
4(8ml) add 3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1, the dense H of 1-dioxide in the solution
2SO
4(8ml) solution.Reaction mixture is risen to room temperature, continue to stir and spend the night.Slowly add ice and make the product precipitation, leach precipitation then.Crude product (4.3g) need not to be further purified.7-amino-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: the 3-cyclohexyl-7-nitro-1 that will stir, 2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (4.2g; 14mmol) and anhydrous EtOH (100ml) suspension hydrogenation under 1bar pressure of 10%Pd/C (400mg).The H of calculated amount
2Exhaust back diatomite filtration reaction mixture.With DMF (75ml) washing diatomite twice, be evaporated to the organic phase that merges dried then.Residuum is suspended in EtOAc/i-PrOH again, forms precipitation and separate after filtration.Isolated solid is dissolved in 0.5M NaOH (aqueous solution), uses 4M HCl (aqueous solution) to precipitate again.Filtration obtains the 1.6g product.7-methyl sulphonyl amino-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: the 7-amino-3-cyclohexyl-1 that will stir, 2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (1 g; 3.6mmol) and triethylamine (1.2ml; Anhydrous THF (25ml) solution 8mmol) is added in the methylsulfonyl chloride, and stirring at room 2 hours.Reaction mixture is evaporated to dried, residuum is suspended in H again
2O/EtOAc filters then.Filtrate is absorbed on the silica gel, through column chromatography purifying (CH
2Cl
2: acetone=9: 1) obtain the 210mg product.3-cyclohexyl-7-methyl sulphonyl amino-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide (39): usefulness method F transforms 7-methyl sulphonyl amino-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide.m．p．255-258℃。Compound 403-cyclohexyl-7-nitro-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide 3-Trifluoromethyl-1,2,4-benzothiadiazine-1,1-dioxide: the 2-aminobenzene sulfonamide is carried out the trifluoroacetyl group protection with method C.At 0 ℃ with products therefrom (1g; H 4mmol)
2SO
4(16ml) solution is added to KNO
3(4.4mmol).Allow reaction mixture to rise to room temperature, and stir and spend the night.Pour reaction mixture into frozen water (150ml), filtration is also air-dry, and obtaining 1.11g (94%) pure products is yellow solid.3-cyclohexyl-7-nitro-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide (40): use method D and method F (using hexanaphthene formaldehyde) to transform 3-Trifluoromethyl-1,2,4-benzothiadiazine-1,1-dioxide successively.m．p．209-211℃。Compound 413-cyclohexyl-7-phenyl sulfonyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Make starting raw material with 4-phenyl sulfonyl aniline, use method B and method G (using hexanaphthene formaldehyde) to transform successively.m．p．243-245℃。Compound 422-cyclohexyl-1,2,3,4-tetrahydrochysene-6-quinazoline sulphonamide
With 2-amino-benzylamine (3g; THF 25mmol) (50ml) solution is added to trifluoroacetic anhydride (3.8ml; 27mmol), and stirring at room 2 hours.Reaction mixture is evaporated to dried, adds water and stir, filter then.Crude product (is used 25%NH with method A
3(aq.) as amine) and method G (using hexanaphthene formaldehyde) transform.m．p．178-180℃。Compound 433-cyclohexyl-7-sulfamyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide 4-sulfamyl benzamide: with the ClSO that stirs
3H (20ml) solution branch is added to aminobenzamide (7.5g in small batches; 55mmol).Reaction mixture 100 ℃ of heating 1 hour, is poured in the frozen water (300ml) then.Leach the precipitation of generation, dry on filter paper.The gained solid is dissolved in 25%NH
3(aq.), and in stirred overnight at room temperature.Water washs with EtOAc, is concentrated into 20ml then.Water is saturated with NaCl (s), with THF extraction (3 * 50ml).The organic phase that merges is evaporated to dried, obtains the 13mg product through the column chromatography purifying.3-cyclohexyl-7-sulfamyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide (43): usefulness method G (using hexanaphthene formaldehyde) is transformed by 4-sulfamyl benzamide.Fab+310.
1H-NMR (DMSO-d
6): 8.1 (1H; Br.), 8.0 (1H; D), 7.58 (1H; Dd), 7.3 (1H; Br.), 7.05 (2H; Br.), 6.79 (1H; D), 4.5 (1H; M), 1.8-1.5 (6H; M), 1.2-1.0 (5H; M). compound 443-cyclohexyl-7-sulfamyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
With method G (using hexanaphthene formaldehyde), be transformed by 2-amino-5-sulfamyl benzsulfamide.m．p．252-254℃。Compound 453-methyl-7-dimethylamino alkylsulfonyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Use method F, by 3-methyl-7-dimethylamino alkylsulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1, the reduction of 1-dioxide forms.m．p．210-212℃。Compound 462-cyclohexyl-1,2,3,4-tetrahydrochysene-6-quinazoline N, N-dimethyl methyl acid amides
With 2-amino-benzylamine (3g; THF 25mmol) (50ml) solution is added to trifluoroacetic anhydride (3.8ml; 27mmol), and stirring at room 2 hours.Reaction mixture is evaporated to dried, adds water and stir, filter then.Crude product is used method A (using dimethylamine as amine) successively, and method D and method G (using hexanaphthene formaldehyde) transform.m．p．＞300℃。MS (EFI) M
+323.
1H-NMR (DMSO-d
6): 7.2 (1H; Dd); 7.1 (1H; D); 6.68 (1H; Br); 6.62 (1H; D); 3.85 (1H; S); 3.8 (2H; S); 2.2 (1H; Br); 1.8-1.0 (11H; M). compound 473-cyclohexyl-7-3,5-dimethylphenyl alkylsulfonyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Make starting raw material with the 2-aminobenzene sulfonamide, use method E (using the hexanaphthene carbonyl chloride) successively, method A (with dimethylamine as amine) and method F transform.m．p．243-245℃。Compound 483-cyclohexyl-7-(N, N-diethylin) alkylsulfonyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Make starting raw material with the 2-aminobenzene sulfonamide, use method E (using the hexanaphthene carbonyl chloride) successively, method A (with diethylamine as amine) and method F transform.m．p．207-209℃。Compound 493-cyclohexyl-7-pyrrolidyl alkylsulfonyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Make starting raw material with the 2-aminobenzene sulfonamide, use method E (using the hexanaphthene carbonyl chloride) successively, method A (with tetramethyleneimine as amine) and method F transform.m．p．244-246℃。Compound 503-methyl-7-piperidino-(1-position only) alkylsulfonyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Make starting raw material with the 2-aminobenzene sulfonamide, use method C successively, method A (using piperidines) as amine, method D and method G (with the TsOH of Metaldehyde and catalytic amount) transform.m．p．255-256℃。Compound 513-cyclopropyl-7-piperidino-(1-position only) alkylsulfonyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Make starting raw material with the 2-aminobenzene sulfonamide, use method C successively, method A (using piperidines) as amine, method D and method G (using cyclopanecarboxaldehyde) transform.m．p．228-231℃。Compound 523-sec.-propyl-7-piperidino-(1-position only) alkylsulfonyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Make starting raw material with the 2-aminobenzene sulfonamide, use method C successively, method A (using piperidines) as amine, method D and method G (using isobutyric aldehyde) transform.m．p．237-239℃。Compound 533-propyl group-7-piperidino-(1-position only) alkylsulfonyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Make starting raw material with the 2-aminobenzene sulfonamide, use method C successively, method A (using piperidines) as amine, method D and method G (using butyraldehyde) transform.m．p．147．4-151．2℃。Compound 543-benzyl-7-piperidino-(1-position only) alkylsulfonyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Make starting raw material with the 2-aminobenzene sulfonamide, use method C successively, method A (using piperidines) as amine, method D and method G (using phenyl acetaldehyde) transform.m．p．242-244℃。Compound 553-cyclopentyl-7-piperidino-(1-position only) alkylsulfonyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide pentamethylene formaldehyde: N
2Down with the Cyclopentane carboxylic acid (2.16ml that stirs under the room temperature; Anhydrous THF (50ml) solution 20mmol) is added to NaBH
4(2.28g; 60mmol), and continue to stir 20 minutes.Reaction mixture is cooled to 0 ℃, with 1 hour adding BF
3OEt
2(10ml; 80mmol), simultaneously temperature of reaction is remained on+below 3 ℃.Allow reaction mixture to rise to room temperature, stir simultaneously and spend the night.Reaction mixture is added to NaHCO
3(saturated aqueous solution) and H
2Among the O, extract with EtOAc.The organic phase that merges is washed with NaCl (saturated aqueous solution), dry (Na
2SO
4), and be evaporated to driedly, and obtain 1.4g oil, need not to be further purified and can use.
Should be dissolved in CH by oil (1.4g)
2Cl
2(75ml), be added in Al
2O
3On PPC (30g; 30mmol) * stirred 1 hour then at room temperature.Filter reaction mixture, filtrate is evaporated on silicon-dioxide, obtains pure aldehyde through the column chromatography purifying, with CH
2Cl
2The solution form use.*: see Cheng Y.-S., Liu W.-L. and Chen S.-H., " synthesizing " (Synthesis), (1980) 223.3-cyclopentyl-7-piperidino-(1-position only) alkylsulfonyl-1,2,3,4-tetrahydrochysene-1; 2,4-benzothiadiazine-1,1-dioxide (55): make starting raw material with the 2-aminobenzene sulfonamide; use method C successively, method A (using piperidines) as amine, method D and method G (using pentamethylene formaldehyde) transform.m．p．258-260℃。Compound 563-cyclohexyl-7-piperidino-(1-position only) alkylsulfonyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Make starting raw material with the 2-aminobenzene sulfonamide, use method E (using the hexanaphthene carbonyl chloride) successively, method A (with piperidines as amine) and method F transform.m．p．262-264℃。Compound 573-dicyclo [2.2.1]-5 '-alkene-2 ' in heptan-Ji-7-piperidino-(1-position only) alkylsulfonyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Make starting raw material with the 2-aminobenzene sulfonamide, use method C successively, method A (using piperidines) as amine, method D and method G (with the racemize inside/outside mixture of 2-norbornylene) transform.Separate obtaining two kinds of non-enantiomer mixtures that separate, A:m.p.240-242 ℃ and B:m.p.234-238 ℃.Compound 583-cyclohexyl-7-(1 ', 2 ', 3 ', 6 '-tetrahydrochysene piperidino-(1-position only)) alkylsulfonyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Make starting raw material with the 2-aminobenzene sulfonamide, use method E (using the hexanaphthene carbonyl chloride) successively, method A (with 1,2,3, the 6-tetrahydropyridine is as amine) and method F transform.m．p．237-239℃。Compound 593-cyclohexyl-7-(N-methyl-N-phenyl amino) alkylsulfonyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Make starting raw material with the 2-aminobenzene sulfonamide, use method E (using the hexanaphthene carbonyl chloride) successively, method A (with methylphenylamine as amine) and method F transform.m．p．210-212℃。Compound 603-cyclohexyl-7-(1 '-(1 ', 2 ', 3 ', 4 '-tetrahydric quinoline group)) alkylsulfonyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Make starting raw material with the 2-aminobenzene sulfonamide, use method E (using the hexanaphthene carbonyl chloride) successively, method A (with 1,2,3, the 4-tetrahydroquinoline is as amine) and method F transform.m．p．218-220℃。Compound 613-cyclohexyl-7-(4 '-methylpiperazine subbase) alkylsulfonyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Make starting raw material with the 2-aminobenzene sulfonamide, use method C successively, method A (using N methyl piperazine) as amine, method D and method G (using hexanaphthene formaldehyde) transform.m．p．227-229℃。The mesylate of compound 61: with compound 61 (0.6g; 1.4mmol) be dissolved in 99%EtOH (30ml), and add 1M CH
3SO
3The 99%EtOH solution of H.With mixture precipitation 2 hours, leach the salt of formation.Check the composition of this salt with HPLC, so that itself and free alkali are carried out the comparison of stability.Finding that relatively salt shows more stablely for hydrolysis with this understanding, is 10mg/ml to the solvability of water.Compound 623-cyclohexyl-7-(4 '-methyl sulphonyl Piperazino) alkylsulfonyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide N-methylsulfonyl piperazine (pierazinium) chlorine: at+5 ℃ of piperazine (4.3g to stirring; CH 50mmol)
2Cl
2(50ml) add CH in the solution
3SO
2Cl (4.25ml; CH 55mmol)
2Cl
2(15ml) solution.The heavy-gravity reaction mixture stirring at room 12 hours, is added CH again
2Cl
2(100ml), use 1M HCl (300ml) extraction then.Leach the precipitation that aqueous phase forms, obtain 2.66g N-methylsulfonyl piperazine chlorine (32%).3-cyclohexyl-7-(4 '-methyl sulphonyl Piperazino) alkylsulfonyl-1; 2; 3; 4-tetrahydrochysene-1,2,4-benzothiadiazine-1; 1-dioxide (62): make starting raw material with the 2-aminobenzene sulfonamide; use method E (using the hexanaphthene carbonyl chloride) successively, method A (as amine (1.5eq.), uses 3eq.K with N-methylsulfonyl piperazine chlorine
2CO
3Carry out neutralization reaction) and method F transform.m．p．272-274℃。Compound 633-cyclohexyl-7-morpholino alkylsulfonyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Make starting raw material with the 2-aminobenzene sulfonamide, use method E (using the hexanaphthene carbonyl chloride) successively, method A (with morpholine as amine) and method F transform.m．p．262-264℃。Compound 643-dicyclo [2.2.1]-5 '-alkene-2 ' in heptan-Ji-7-bromo-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Method G (with dicyclo [2.2.1] heptan-racemize inside/outside mixture of 5-alkene-2-formaldehyde) is transformed by 5-bromo-2-aminobenzene sulfonamide (seeing compound 18).m．p．200-204℃。Compound 652-methyl-4-oxygen-3,4-dihydro-6-quinazoline N, N-dimethyl methyl acid amides 2-methyl-4-oxygen-3,4-dihydroquinazoline: with anthranilamide (13.6g; Acetate 100mmol) (100ml) solution refluxed 60 hours.Reaction mixture is evaporated to dried, is suspended in H then
2O filters and uses NaHCO
3Thoroughly washing is 8-8.5 up to pH.2-methyl-4-oxygen-3,4-dihydro-6-quinazoline N, N-dimethyl methyl acid amides: usefulness method A (using dimethylamine as amine), by 2-methyl-4-oxygen-3, the 4-dihydroquinazoline is transformed.m．p．264-266℃。Compound 662-trifluoromethyl-4-oxygen-3,4-dihydro-6-quinazoline sulphonamide
(use 0.5M NH with method A
3THF as amine), be transformed by 2-trifluoroacetamido benzamide (seeing compound 68).m．p．311-314℃。Compound 672-trifluoromethyl-4-oxygen-3,4-dihydro-6-quinazoline N, N-dimethyl methyl acid amides
With method A (using dimethylamine), be transformed by 2-trifluoroacetamido benzamide (seeing compound 68) as amine.m．p．257-258℃。Compound 682-trifluoromethyl-4-oxygen-3,4-dihydro-6-quinazoline 1 ', 2 ', 3 ', 6 '-tetrahydrochysene piperidino-(1-position only) sulphonamide
At 0 ℃ of anthranilamide (13.6g that will stir; THF 100mmol) (100ml) mixture is added to trifluoroacetic anhydride (15.2ml; 110mmol).Allow to rise to room temperature, and continue to stir and spend the night.Isolated solid is air-dry, obtain 21.6g (93%) 2-trifluoroacetamido benzamide.With method A (with 1,2,3, the 6-tetrahydropyridine is as amine) 2-trifluoroacetamido benzamide is transformed.m．p．227-230℃。Compound 692-trifluoromethyl-4-oxygen-3,4-dihydro-6-quinazoline N-cyclohexyl sulfonamide
With method A (using cyclo-hexylamine), be transformed by 2-trifluoroacetamido benzamide (seeing compound 68) as amine.m．p．261-263℃。Compound 702-trifluoromethyl-4-oxygen-3,4-dihydro-6-quinazoline morpholino sulphonamide
With method A (using morpholine), be transformed by 2-trifluoroacetamido benzamide (seeing compound 68) as amine.m．p．282-285℃。Compound 712-cyclohexyl-4-oxygen-3,4-dihydro-6-quinazoline-N, N-dimethyl methyl acid amides
Make starting raw material with anthranilamide, use method A (to use 25%NH successively
3(aq.) as amine.It is single and 5 to contain 5-in the reaction mixture, and the 7-disulfonic acid amide can separate with chromatography) and method G (use hexanaphthene formaldehyde.The aminal autoxidation becomes aromatic hydroxyl quinazoline) transform.m．p．306-310℃。Compound 723-methyl-7-sulfamyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide
(use 0.5M NH with method A
3THF as amine), by the 3-methyl isophthalic acid, 2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (seeing compound 73) is transformed.m．p．295-297℃。Compound 733-methyl-7-dimethylamino alkylsulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide
With 2-aminobenzene sulfonamide (17.2g; 100mmol) in AcOH, refluxed 5 days.Leach the precipitation of generation, wash with water, obtain 17.8g (91%) 3-methyl isophthalic acid, 2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide.Transform 3-methyl isophthalic acid, 2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide with method A (using dimethylamine) as amine.m．p．260-261℃。Compound 743-methyl-7-(1 ', 2 ', 3 ', 6 '-tetrahydrochysene piperidino-(1-position only)) alkylsulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide
With method A (with 1,2,3,6-tetrahydrochysene piperidines is as amine), by the 3-methyl isophthalic acid, 2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (seeing compound 73) is transformed.m．p．265-268℃。Compound 753-methyl-7-cyclohexyl sulfamyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide
With method A (using hexahydroaniline) as amine, by the 3-methyl isophthalic acid, 2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (seeing compound 73) is transformed.m．p．239-242℃。Compound 763-trifluoromethyl-7-dimethylamino alkylsulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide
Make starting raw material with the 2-aminobenzene sulfonamide, use method C and method A (with dimethylamine as amine) to transform successively.m．p．240-242℃。Compound 772-trifluoromethyl-4-oxygen-3,4-dihydro-6-quinazoline sulfonic acid
Make starting raw material with the 2-aminobenzene sulfonamide, use method C and method A (replacing amine) to transform successively with NaOH.m．p．＞330℃。Compound 783-cyclohexyl-8-methyl isophthalic acid, 2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Make starting raw material with meta-aminotoluene, use method B (, from 2-amino-4-methyl benzenesulfonamide, isolating 2-amino-6-methyl benzenesulfonamide) successively by from EtOAc/ hexane recrystallization.With column chromatography 2-amino-6-methyl benzenesulfonamide is further purified, method G (using hexanaphthene formaldehyde) transforms then.m．p．228-230℃。Compound 793-cyclohexyl-8-methylol-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide 5-chloro-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide-8-formic acid: N
2Descend 5-chloro-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (seeing compound 80) (0.30g at-78 ℃; 1.0mmol) anhydrous THF (15ml) solution in add s-BuLi hexanaphthene (1.3M, 1.6ml, 2.1mmol).Yellow mixture was stirred 15 minutes at-78 ℃, and in solution, blast anhydrous CO
2Gas 30 minutes.Remove cooling bath, allow mixture to rise to 0 ℃.Removal of solvent under reduced pressure, (0.2M 12ml) develops residuum with hydrochloric acid.Crude product obtains 300mg (82%) 5-chloro-3-cyclohexyl-1 from the 50%MeOH recrystallization, 2-dihydro-1,2, and 4-benzothiadiazine-1,1-dioxide-8-formic acid is clear crystal.3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide-8-carboxylic acid: with 5-chloro-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide-8-formic acid (160mg; 0.47mmol) be dissolved in 99%EtOH (50ml), and with Pd/C (10%, 10mg) hydrogenation 24 hours under 1bar pressure.(1M 12ml), uses Celite to add NaOH
TMThe cake filtration mixture, and mixture is concentrated into 10ml.Slowly add concentrated hydrochloric acid and make the product precipitation, obtain 110mg (76%) 3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1 dioxide-8-formic acid is colourless powder.3-cyclohexyl-8-methylol-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide (79): with NaBH
4Triglyme (2M, 0.75ml 1.5mmol) are dissolved in anhydrous THF (20ml), at N
2In be cooled to-50 ℃.Add BF
3(0.25ml 2.0mmol), stirs mixture 10 minutes at-50 ℃-ether compound.Disposable adding solid 3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide-8-formic acid (170mg; 0.55mmol), gained suspension was stirred 6 hours at-50 ℃, spend the night 20 ℃ of stirrings then.With hydrochloric acid (1M, 2ml) hydrolysed mix, removal of solvent under reduced pressure.Residuum uses salt solution (10ml) to wash with EtOAc (50ml) extraction, organic phase, dry (Na
2SO
4), and be evaporated to dried.Product is at SiO
2On carry out purification by flash chromatography, with the EtOAc/ normal hexane (2: 1, v/v) wash-out obtains 100mg (62%) 3-cyclohexyl-8-methylol-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide are colourless spicule.With the further converted product of method F.m．p．220-223℃。Compound 803-cyclohexyl-8-(2-p-methoxy-phenyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide 5-chloro-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: make starting raw material with the 3-chloroaniline, use method B and method E (using the cyclohexyl carbonyl chloride) to transform successively.5-chloro-3-cyclohexyl-8-iodo-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: N
2Descend 5-chloro-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (596mg at-78 ℃; The hexanaphthene of adding s-BuLi in anhydrous THF (20ml) solution 2mmol) (1.3M, 3.8ml, 5mmol).Yellow mixture was stirred 15 minutes at-78 ℃, add I then
2(1.27g; Anhydrous THF (5ml) solution 5mmol).Remove cooling bath, allow mixture to rise to 0 ℃.Add NaHSO
3(5%; 20ml), with EtOAc extraction (2 * 30ml), dry (Na
2SO
4), and be evaporated to driedly, obtain 0.76g (90%) 5-chloro-3-cyclohexyl-8-iodo-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide.5-chloro-3-cyclohexyl-8-(2-p-methoxy-phenyl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: with 5-chloro-3-cyclohexyl-8-iodo-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (290mg; 0.68mmol), 2-anisole ylboronic acid (122mg; 0.80mmol), Pd (PPh
3)
2Cl
2(10mg; 2mol%) 1,2-dimethoxy hexane (50ml) and Na
2CO
3(mixture 4mmol) is at N for 2M, 2ml
2Under refluxed 2 hours.Removal of solvent under reduced pressure, residuum with EtOAc extraction (2 * 40ml), the saturated NaHCO of organic phase
3(20ml) washing, dry (Na
2SO
4), and removal of solvent under reduced pressure.Product is at SiO
2On carry out purification by flash chromatography, with the EtOAc/ normal hexane (1: 2, v/v) wash-out obtains 200mg (73%) 5-chloro-3-cyclohexyl-8-(2-p-methoxy-phenyl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide are clear crystal.3-cyclohexyl-8-(2-p-methoxy-phenyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide (80): with 5-chloro-3-cyclohexyl-8-(2-p-methoxy-phenyl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (190mg; 0.47mmol) be dissolved in 99%EtOH (30ml), and with Pd/C (10%, 10mg) hydrogenation under 1bar pressure.Use Celite
TMThe cake filtration mixture, removal of solvent under reduced pressure obtains 174mg (100%) 5-chloro-3-cyclohexyl-8-(2-p-methoxy-phenyl)-1 then, 2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide are clear crystal.With the further converted product of method F.m．p．100-105℃。Compound 813-cyclohexyl-8-(3-p-methoxy-phenyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Method with synthetic compound 80 is synthesized (carrying out the catalytic cross-coupling reaction of Pd with 3-anisole ylboronic acid).m．p．108-115℃。Compound 823-cyclohexyl-8-(2-pyridyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide 5-chloro-3-cyclohexyl-8-(dihydroxyl boryl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: N
2Descend 5-chloro-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (seeing compound 80) (0.60g at-78 ℃; 2.0mmol) anhydrous THF (15ml) solution in add s-BuLi hexanaphthene (1.3M, 3.8ml, 5mmol).Yellow mixture was stirred 15 minutes at-78 ℃, add B (OCH then
3)
3(0.57ml; 5mmol).Remove cooling bath, allow mixture to rise to 0 ℃, and continue to stir 1 hour.Mixture hydrochloric acid (0.5M; 12ml) be hydrolyzed, with EtOAc extraction (2 * 50ml), dry (Na
2SO
4), and be evaporated to driedly, obtain 0.65g (95%) 5-chloro-3-cyclohexyl-8-(dihydroxyl boryl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide.5-chloro-3-cyclohexyl-8-(2-pyridyl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: with 5-chloro-3-cyclohexyl-8-(dihydroxyl boryl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (440mg; 1.28mmol), 2-bromopyridine (0.14ml; 1.50mmol), Pd (PPh
3)
2Cl
2(10mg; 2mol%) 1,2-glycol dimethyl ether (30ml) and Na
2CO
3(mixture 6mmol) is at N for 2M, 3ml
2Under refluxed 24 hours.The saturated NH of removal of solvent under reduced pressure, residuum
4Cl (10ml) handles, with EtOAc extraction (2 * 40ml).Organic phase water (20ml) washing, dry (Na
2SO
4), and removal of solvent under reduced pressure.Product is at SiO
2On carry out purification by flash chromatography, with the EtOAc/ normal hexane (2: 1, v/v) wash-out obtains 280mg (58%) 5-chloro-3-cyclohexyl-8-(2-pyridyl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide are clear crystal.3-cyclohexyl-8-(2-pyridyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide (82): with 5-chloro-3-cyclohexyl-8-(2-pyridyl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (0.268g; 0.713mmol) be dissolved in 99%EtOH (50ml), and with Pd/C (10%, 10mg) hydrogenation 24 hours under 4bar pressure.Use Celite
TMCake filtration mixture, removal of solvent under reduced pressure then.Residuum is dissolved in EtOAc (50ml), with phosphate buffered saline buffer (pH=7,10ml) washing, dry (Na
2SO
4), and removal of solvent under reduced pressure, obtain 200mg (82%) 3-cyclohexyl-8-(2-pyridyl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide are clear crystal.With the further converted product of method F.m．p．200-203℃。Compound 833-cyclohexyl-8-methoxyl group-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Make starting raw material with m-anisidine, use method B (separate (EtOAc/ hexane) through flash chromatography, from 2-amino-4-methoxybenzenesulphoismide, isolate 2-amino-6-methoxybenzenesulphoismide) and method G (using hexanaphthene formaldehyde) to transform successively.m．p．221-223℃。Compound 845,7-two bromo-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide
With method G (with the triethylamine of ethyl formate and catalytic amount), by 2-amino-3,5-dibromobenzene sulphonamide (seeing compound 125) is transformed.m．p．289-292℃。Compound 85 and 863-cyclohexyl-2-methyl-7-morpholino alkylsulfonyl-1,2,3; 4-tetrahydrochysene-1,2,4-benzothiadiazine-1; 1-dioxide (85) and 3-cyclohexyl-4-methyl-7-morpholino alkylsulfonyl-1,2,3; 4-tetrahydrochysene-1; 2,4-benzothiadiazine-1,1-dioxide (86) 3-cyclohexyl-7-morpholino alkylsulfonyl-1; 2-dihydro-1; 2,4-benzothiadiazine-1,1-dioxide: make starting raw material with the 2-aminobenzene sulfonamide; use method E (using the hexanaphthene carbonyl chloride) and method A (with morpholine as amine) to transform successively; obtain 3-cyclohexyl-7-morpholino alkylsulfonyl-1,2-dihydro-1,2; 4-benzothiadiazine-1, the 1-dioxide.3-cyclohexyl-2-methyl-7-morpholino alkylsulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide and 3-cyclohexyl-4-methyl-7-morpholino alkylsulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: with 3-cyclohexyl-7-morpholino alkylsulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (2g; 5mmol), DEAD (2.35ml; 15mmol), PPh
3(4g; Anhydrous THF (30ml) mixture 15mmol) is cooled to 0 ℃, adds MeOH (1.25ml then; 30mmol).In stirred overnight at room temperature, be evaporated to dried then reaction mixture.Add EtOAc and stir, filter then.With isolated precipitation and CH
2Cl
2Stir together, filter back 2-methyl isomer and stay in the filtrate, 4-methyl isomer becomes throw out.4-methyl isomer is through the DMSO/H that associates
2The O recrystallization is able to purifying; 2-methyl isomer is through column chromatography purifying (EtOAc).3-cyclohexyl-2-methyl-7-morpholino alkylsulfonyl-1,2,3,4-tetrahydrochysene-1; 2,4-benzothiadiazine-1,1-dioxide (85): usefulness method F reduction 3-cyclohexyl-2-methyl-7-morpholino alkylsulfonyl-1,2-dihydro-1; 2,4-benzothiadiazine-1,1-dioxide.m．p．243-245℃。3-cyclohexyl-4-methyl-7-morpholino alkylsulfonyl-1,2,3,4-tetrahydrochysene-1; 2,4-benzothiadiazine-1,1-dioxide (86): usefulness method F reduction 3-cyclohexyl-4-methyl-7-morpholino alkylsulfonyl-1,2-dihydro-1; 2,4-benzothiadiazine-1,1-dioxide.m．p．207-210℃。Compound 877-methyl sulphonyl amino-1,2,3; 3a, 4, the 5-hexahydrobenzene is [e] pyrrolo-[2 also; 1-c]-1,2,4-benzothiadiazine-5; 5-dioxide 1,2,3; 5-tetrahydro benzo [e] pyrrolo-[2,1-c]-1,2; 4-benzothiadiazine-5,5-dioxide: usefulness method E (using the 4-chlorobutanoylchloride) transforms the 2-aminobenzene sulfonamide and gets.7-nitro-1,2,3,5-tetrahydro benzo [e] pyrrolo-[2,1-c]-1,2,4-benzothiadiazine-5, the 5-dioxide: will be in 1,2,3 of 5 ℃ of stirrings, 5-tetrahydro benzo [e] pyrrolo-[2,1-c]-1,2,4-benzothiadiazine-5,5-dioxide (222mg; H 1mmol)
2SO
4(2ml) solution is added to KNO
3(122mg; 1.2mmol) H
2SO
4(2ml) in the solution.Allow reaction mixture to rise to room temperature, and stirred 2 hours.Reaction mixture is poured in the frozen water, and filtration is also air-dry, obtains 190mg (71%) product.7-amino-1,2,3,5-tetrahydro benzo [e] pyrrolo-[2,1-c]-1,2,4-benzothiadiazine-5,5-dioxide: will be in the 7-of-50 ℃ of stirrings nitro-1,2,3,3a, 4, the 5-hexahydrobenzene is [e] pyrrolo-[2,1-c]-1,2 also, 4-benzothiadiazine-5,5-dioxide (167mg; 0.6mmol) a collection of LiAlH that is added to of anhydrous THF (2ml) solution
4(115mg; 3mmol).Allow reaction mixture to rise to room temperature, and stir and spend the night.Add H
2O and 10MNaOH cancellation reaction mixture stir, and use diatomite filtration, are evaporated to driedly, obtain the 150mg product.7-methyl sulphonyl amino-1,2,3,3a, 4, the 5-hexahydrobenzene is [e] pyrrolo-[2,1-c]-1 also, 2,4-benzothiadiazine-5,5-dioxide (87): with the 7-amino-1 that stirs, 2,3,3a, 4, the 5-hexahydrobenzene is [e] pyrrolo-[2,1-c]-1 also, 2,4-benzothiadiazine-5,5-dioxide (150mg; 0.5mmol) and triethylamine (70 μ l; 0.5mmol) THF (1ml) solution be added to CH
3SO
2Cl (40 μ l; 0.5mmol) in the solution, and in stirred overnight at room temperature.Reaction mixture is evaporated to dried, is suspended in H then
2O extracts with EtOAc again.Organic phase is evaporated to dried, obtains the 40mg product through the column chromatography purifying.m．p．177-180℃。Compound 887-sulfamyl-1,2,3,3a, 4, the 5-hexahydrobenzene is [e] pyrrolo-[2,1-c]-1,2 also, 4-benzothiadiazine-5,5-dioxide
Make starting raw material with the 2-aminobenzene sulfonamide, use method E (using the 4-chlorobutanoylchloride) successively, method A (uses 0.5M NH
3THF as amine) and method F (use LiAlH
4, room temperature) transform.m．p．260-262℃。Compound 897-methyl sulfamyl-1,2,3,3a, 4, the 5-hexahydrobenzene is [e] pyrrolo-[2,1-c]-1,2 also, 4-benzothiadiazine-5,5-dioxide
Make starting raw material with the 2-aminobenzene sulfonamide, use method E (using the 4-chlorobutanoylchloride) successively, method A (with methylamine as amine) and method F (use LiAlH
4, room temperature) transform.m．p．244-245℃。Compound 907-cyclohexyl sulfamyl-1,2,3,3a, 4, the 5-hexahydrobenzene is [e] pyrrolo-[2,1-c]-1,2 also, 4-benzothiadiazine-5,5-dioxide
Make starting raw material with the 2-aminobenzene sulfonamide, use method E (using the 4-chlorobutanoylchloride) successively, method A (with hexahydroaniline as amine) and method F (use LiAlH
4, room temperature) transform.m．p．195-197℃。Compound 917-dimethylamino alkylsulfonyl-1,2,3,3a, 4, the 5-hexahydrobenzene is [e] pyrrolo-[2,1-c]-1,2 also, 4-benzothiadiazine-5,5-dioxide
Make starting raw material with the 2-aminobenzene sulfonamide, use method E (using the 4-chlorobutanoylchloride) successively, method A (with dimethylamine as amine) and method F (use LiAlH
4, room temperature) transform.m．p．240-243℃。Compound 927-methyl sulfamyl-1,2,3,5-tetrahydro benzo [e] pyrrolo-[2,1-c]-1,2,4-benzothiadiazine-5,5-dioxide
Use method E (using the 4-chlorobutanoylchloride) and method A (using methylamine) to transform the 2-aminobenzene sulfonamide successively as amine.m．p．244-247℃。Compound 937-dimethylamino alkylsulfonyl-1,2,3,5-tetrahydro benzo [e] pyrrolo-[2,1-c]-1,2,4-benzothiadiazine-5,5-dioxide
Use method E (using the 4-chlorobutanoylchloride) and method A (using dimethylamine) to transform the 2-aminobenzene sulfonamide successively as amine.m．p．251-253℃。Compound 947-cyclohexyl sulfamyl-1,2,3,5-tetrahydro benzo [e] pyrrolo-[2,1-c]-1,2,4-benzothiadiazine-5,5-dioxide
Use method E (using the 4-chlorobutanoylchloride) and method A (using hexahydroaniline) to transform the 2-aminobenzene sulfonamide successively as amine.m．p．151-153℃。Compound 957-(1 ', 2 ', 3 ', 6 '-tetrahydrochysene piperidino-(1-position only)) alkylsulfonyl-1,2,3,5-tetrahydro benzo [e] pyrrolo-[2,1-c]-1,2,4-benzothiadiazine-5,5-dioxide
Make starting raw material with the 2-aminobenzene sulfonamide, use method E (using the 4-chlorobutanoylchloride) and method A (with 1,2,3, the 6-tetrahydropyridine is as amine) to transform successively.m．p．204-206℃。Compound 963-dicyclo [2.2.1]-5 '-alkene-2 ' in heptan-Ji-5,7-dimethyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
With 2, the 4-xylidine is made starting raw material, uses method B and method G (with dicyclo [2.2.1] heptan-racemize inside/outside mixture of 5-alkene-2-formaldehyde successively.The column chromatography separation obtains two kinds of diastereomers, respectively is the mixture of two diastereomers) transform.Isomer mixture A, m.p.160-165 ℃; Isomer mixture B, m.p.182-187 ℃.Compound 973-cyclohexyl-7-(N, N-diethyl amino alkylsulfonyl)-5-methyl isophthalic acid, 2; 3,4-tetrahydrochysene-1,2; 4-benzothiadiazine-1; 1-dioxide 3-cyclohexyl-7-(N, N-diethyl amino alkylsulfonyl)-5-formyl radical-1,2-dihydro-1; 2; 4-benzothiadiazine-1,1-dioxide: make starting raw material with the 2-aminobenzene sulfonamide, use method E (using the hexanaphthene carbonyl chloride) and method A (with diethylamine as amine) to transform successively.N
2Down at-78 ℃ of conversion products therefrom (0.60g that will be dissolved in anhydrous THF (15ml); 1.5mmol) be added to s-BuLi hexanaphthene (1.3M, 2.5ml, 3.2mmol) in.Yellow mixture was stirred 25 minutes at-78 ℃.With dry DMF (0.3ml; 4mmol) cancellation reaction is stirred mixture 20 minutes at-78 ℃ then.Remove cooling bath, allow mixture to rise to 0 ℃.Add hydrochloric acid (0.5M; 10ml), mixture extracts (40ml) with EtOAc.Organic phase is washed with salt solution (10ml), dry (Na
2SO
4), and be evaporated to dried.Residuum is dissolved in acetone (8ml).In several minutes, add Et
2O (30ml) makes the product crystallization, obtains 0.41g (64%) 3-cyclohexyl-7-(N, N-diethyl amino alkylsulfonyl)-5-formyl radical-1,2-dihydro-1,2, and 4-benzothiadiazine-1,1-dioxide are clear crystal.3-cyclohexyl-7-(N, N-diethyl amino alkylsulfonyl)-5-methyl isophthalic acid, 2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide (97): with 3-cyclohexyl-7-(N, N-diethyl amino alkylsulfonyl)-and 5-formyl radical-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (0.20g; 0.46mmol) be dissolved in 99%EtOH (60ml).Splash into a droplet concentrated hydrochloric acid to guarantee complete hydrogenation.With mixture with Pd/C (10%, 10mg) hydrogenation 24 hours under 4bar pressure.Use Celite
TMThe cake filtration mixture is evaporated to dried then.Residuum is dissolved in EtOAc (50ml), washes with water, dry (Na
2SO
4), and be evaporated to driedly, and obtain 0.18g (95%) 3-cyclohexyl-7-(N, N-diethyl amino alkylsulfonyl)-5-methyl isophthalic acid, 2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide are colourless powder.With the further converted product of method F.m．p．206-208℃。Compound 983-dicyclo [2.2.1]-5 '-alkene-2 ' in heptan-Ji-5,7-phenylbenzene-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
A (uses 25%NH with method
3(aq.) as amine) and method G (with dicyclo [2.2.1] heptan-racemize inside/outside mixture of 5-alkene-2-formaldehyde) transform the 2-aminobenzene sulfonamide.m．p．172-180℃。Compound 1003-dicyclo [2.2.1]-5 '-alkene-2 ' in heptan-Ji-5,7-two chloro-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Transform 2,4 dichloro aniline with method B and method G (with the racemize inside/outside mixture of dicyclo [2.2.1] heptan-5-alkene-2-formaldehyde, product is separated as non-enantiomer mixture).m．p．149-151℃。Compound 1015-bromo-3-cyclohexyl-7-sulfamyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide 2-amino-5-sulfamyl benzsulfamide: with the 2-amino-4-chloro-5-sulfamyl benzsulfamide (11.4g that stirs; 40mmol) and EtOH (300ml) suspension hydrogenation under 1bar pressure of Pd/C (750mg), stop (24 hours) up to hydrogen consumption.Reaction mixture is evaporated to dried, is suspended in THF more again, use diatomite filtration.Filtrate is evaporated to dried, isolated solid with ebullient EtOAc washing (2 * 150ml), obtain 9.58g (95%) product.2-amino-3-bromo-5-sulfamyl benzsulfamide: with the 2-amino-5-sulfamyl benzsulfamide (3.77g that stirs; AcOH 15mmol) (50ml) solution is added to Br
2(0.78ml; In AcOH 15mmol) (10ml) solution.70 ℃ of heating 6 days, be evaporated to dried then reaction mixture.Again be suspended in MeOH (85ml), add solid KOH (3.8g; 68mmol).With reaction mixture 60 ℃ of heating 2.5 hours (make the 3-methyl of formation-, the 3-brooethyl-, 3-two brooethyls-and 3-trisbromomethyl-1,2-dihydro-1,2, the hydrolysis then and there of 4-benzothiadiazine), filter, neutralize and be evaporated to dried.Separate through column chromatography, obtain 3.1g (63%) product.5-bromo-3-cyclohexyl-7-sulfamyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide (101): usefulness method G (using hexanaphthene formaldehyde) transforms 2-amino-3-bromo-5-sulfamyl benzsulfamide.m．p．254-258℃。Compound 1022-dicyclo [2.2.1]-5 '-alkene-2 ' in heptan-Ji-6,8-two bromo-1,2,3,4-tetrahydro quinazoline 2-amino-3,5-dibromo benzylamine: with 0 ℃ 2-amino-benzylamine (6.1g; CHCl 50mmol)
3(100ml) mixture is added to Br
2(5.1ml; CHCl 100mmol)
3(45ml) in the solution and make temperature of reaction remain on+below 2 ℃.Remove cooling bath, with reaction mixture in stirred overnight at room temperature.Filter reaction mixture is used the EtOAc washing precipitate, carries out purifying with column chromatography.2-dicyclo [2.2.1]-5 '-alkene-2 ' in heptan-Ji-6,8-two bromo-1,2,3,4-tetrahydro quinazoline (102): usefulness method G (with the racemize inside/outside mixture of 2-norbornylene formaldehyde) transforms 2-amino-3,5-dibromo benzylamine.m．p．240℃。Compound 1032-dicyclo [2.2.1]-5 '-alkene-2 ' in heptan-Ji-6,8-two bromo-4-oxygen-1,2,3,4-tetrahydro quinazoline 3,5-dibromo anthranilamide: with the anthranilamide (13.6g that stirs; 0.1mol) AcOH (350ml) suspension be added to Br
2(10.3ml; 0.2mol) in the solution.Reaction mixture was stirred 120 minutes at 45 ℃, pour H then into
2Among the O (1.5L), filter.From 96%EtOH (about 1L) recrystallization (comprising the insulation filtration), obtain 23.6g (80%) product.2-dicyclo [2.2.1]-5 '-alkene-2 ' in heptan-Ji-6,8-two bromo-4-oxygen-1,2,3,4-tetrahydro quinazoline (103): usefulness method G (with dicyclo [2.2.1] heptan-racemize inside/outside mixture of 5-alkene-2-formaldehyde) transforms 3,5-dibromo anthranilamide.Product is separated into separately non-enantiomer mixture.A：m．p．213-215℃；B：m．p．209-210℃。Compound 1043-dicyclo [2.2.1]-5 '-alkene-2 ' in heptan-Ji-5,7-two bromo-4-oxygen-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Transform 2-amino-3,5-dibromobenzene sulphonamide (seeing compound 125) with method G (with dicyclo [2.2.1] heptan-racemize inside/outside mixture of 5-alkene-2-formaldehyde).The gained non-enantiomer mixture is carried out the column chromatography purifying, obtain three kinds in four kinds of possible in theory diastereomers.A：m．p．202-206℃；B：m．p．196-199℃；C：m．p．180-184℃。Compound 1055,7-two bromo-3-dicyclo [2.2.1] heptane-2 '-Ji-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide dicyclo [2.2.1] heptane-2-formaldehyde: with the 2-norcamphyl methyl alcohol (0.5ml that stirs; 5.8mol) and at Al
2O
3On the CH of PCC*
2Cl
2(25ml) suspension stirred 1 hour at 2-3 ℃, allowed slowly to rise to room temperature then.Filter reaction mixture, solid matter CH
2Cl
2Washing (2 * 25ml).The organic phase that merges is absorbed on the silicon-dioxide, obtains 300mg (42%) product after the chromatographic separation and be oil.*: see Cheng Y.-S., Liu W.-L. and Chen S.-H., " synthesizing ", (1980) 223.5,7-two bromo-3-norcamphyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide (105): usefulness method G (with the racemize inside/outside mixture of dicyclo [2.2.1] heptane-2-formaldehyde) transforms 2-amino-3,5-dibromobenzene sulphonamide (seeing compound 125).m．p．182-183℃。Compound 1063-cyclohexyl-5,7-two bromo-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Transform 2-amino-3,5-dibromobenzene sulphonamide (seeing compound 125) with method G (using hexanaphthene formaldehyde).m．p．166-167℃。Compound 1073-adamantyl-5,7-two bromo-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide 1-diamantane formaldehyde: the method that will be used for 2-norcamphyl methyl alcohol (seeing compound 105) is used for oxidation 1-adamantyl methyl alcohol *.*: see Cheng Y.-S., Liu W.-L. and Chen S.-H., " synthesizing ", (1980) 223.3-adamantyl-5,7-two bromo-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide (107): usefulness method G (with 1-adamantyl formaldehyde) transforms 2-amino-3,5-dibromobenzene sulphonamide (seeing compound 125).m．p．270-273℃。Compound 1083-phenyl-5,7-two bromo-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Transform 2-amino-3,5-dibromobenzene sulphonamide (seeing compound 125) with method G (using phenyl aldehyde).m．p．186-189℃。Compound 1093-oxyethyl group-5,7-two bromo-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
With the 2-amino-3 that stirs, 5-dibromobenzene sulphonamide (seeing compound 125) (666mg; 2mmol), ethyl orthoformate (15ml; 90mmol) and H
2SO
4(0.05ml) mixture refluxes and spends the night.Reaction mixture is evaporated to dried, carries out the column chromatography purifying.m．p．96-98℃。Compound 1103-methyl-5,7-two bromo-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide
With the 2-amino-3 that stirs, 5-dibromobenzene sulphonamide (seeing compound 125) (660mg; 2mmol) solution is at Ac
2O (25ml; Reflux 265mmol) and spend the night.Pour in the ice reaction mixture and filtration.Isolated solid Et
2The O washing.m．p．287-289℃。Compound 1113-cyclohexyl-6-methyl-7-(2 '-pyridyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
(1.7M is in pentane, and 25ml adds 2-bromopyridine (1.9ml in anhydrous THF (50ml) solution 42mmol) to t-BuLi to keep temperature to be no more than-70 ℃ speed at-78 ℃; 20mmol).Mixture is continued to stir 30 minutes at-78 ℃.Slowly add ZnCl
2(2M is in THF, 30ml, 60mmol) solution.Remove cooling bath, be warming up to 20 ℃.Add 5-iodo-2-aminobenzene sulfonamide (seeing compound 37) (1.0g, 3.2mmol) and Pd (PPh
3)
4(0.3g 8mol%), refluxes mixture 6 hours.THF is removed in evaporation, residuum with EDTA (53g 0.18mol) handles, and makes it be alkalescence (pH ≈ 8-9) a little with 1M NaOH, then with the EtOAc extraction (3 * 100ml), drying (Na
2SO
4).Organic phase is concentrated into about 40ml, slowly adds normal hexane.Leach product, obtaining 0.72g (87%) 2-amino-4-methyl-5-(2-pyridyl)-1-benzsulfamide is pale yellow crystals.With the further converted product of method G (using hexanaphthene formaldehyde).m．p．229-231℃。Compound 1123-cyclohexyl-6-methyl-7-(4 '-triazolyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide 5-iodo-4-methyl-2-aminobenzene sulfonamide: usefulness method B transforms meta-aminotoluene, separate two isomer with column chromatography then, obtain 4-methyl-2-aminobenzene sulfonamide.
Will be at the 4-of 0 ℃ of stirring methyl-2-aminobenzene sulfonamide (620mg; 3.3mmol) CHCl
3(7ml) suspension is added to iodine monochloride (1.6g; 9.9mmol) CHCl
3(7ml) in the solution.Reaction mixture 0 ℃ of stirring, is shown that up to H-NMR starting raw material all changes.Filter reaction mixture, isolated solid is used a small amount of CHCl successively
3, NaHCO
3(saturated aqueous solution) and H
2O washing obtains 640mg (62%) product after air-dry.3-cyclohexyl-6-methyl-7-(4 '-triazolyl)-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide (112): usefulness method I (using trimethyl silyl acetylene) and method G (using hexanaphthene formaldehyde) transform 5-iodo-4-methyl-2-aminobenzene sulfonamide.FAB+348.
1H-NMR (DMSO-d
6): 8.0 (1H; Br); 7.65 (1H; Br); 7.25 (1H; S); 7.22 (1H; S); 6.95 (1H; Br); 6.8 (1H; S); 4.45 (1H; Dd); 2.35 (3H; S); 1.95-1.8 (2H; M); 1.8-1.6 (3H; M); 1.3-1.0 (6H; M). compound 1133-cyclohexyl-6-methyl-7-sulfamyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide N-ethanoyl-3-monomethylaniline: with meta-aminotoluene (10ml; 93mmol) be added in diacetyl oxide (30ml) solution that is stirring.Stirring at room 1.5 hours, be evaporated to driedly then reaction mixture, add H
2O stirs, and obtains 13g (94%) product after the filtration.3-cyclohexyl-6-methyl-7-sulfamyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1, the 1-dioxide: A (uses 25%NH with method
3(aq.) as amine.Deacetylated reaction is finished) and method G (using hexanaphthene formaldehyde) conversion N-ethanoyl-3-monomethylaniline.m．p．231-233℃。Compound 1143-cyclopentyl-6-methyl-7-piperidino-(1-position only) alkylsulfonyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide pentamethylene carbonyl chloride: with Cyclopentane carboxylic acid (0.55ml; 5mmol) in thionyl chloride (1ml), refluxed 3 hours.With the reaction mixture cool to room temperature, be evaporated to driedly then, need not purifying can directly use.3-cyclopentyl-6-methyl-7-piperidino-(1-position only) alkylsulfonyl-1; 2; 3; 4-tetrahydrochysene-1,2,4-benzothiadiazine-1; 1-dioxide (114): make starting raw material with meta-aminotoluene; use method B (separating 2-amino-6-methyl benzenesulfonamide from 2-amino-4-methyl benzenesulfonamide) successively by recrystallization (EtOAc/ hexane), method E (using the pentamethylene carbonyl chloride), method A (with piperidines as amine) and method F transform.m．p．229-230℃。Compound 1153-cyclohexyl-6-methyl-7-morpholino alkylsulfonyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Make starting raw material with meta-aminotoluene, use method B (separating 2-amino-6-methyl benzenesulfonamide from 2-amino-4-methyl benzenesulfonamide) successively by recrystallization (EtOAc/ hexane), method E (using the pentamethylene carbonyl chloride), method A (with morpholine as amine) and method F transform.m．p．268-271℃。Compound 1163-cyclohexyl-6-(2-p-methoxy-phenyl)-7-methyl isophthalic acid, 2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Transform 3-bromo-4-monomethylaniline with method B (by from this isomer of MeOH Crystallization Separation), obtain 2-amino-4-bromo-5-methyl benzenesulfonamide.
With 2-amino-4-bromo-5-methyl benzenesulfonamide (100mg, 0.38mmol), 2-anisole ylboronic acid (76mg, 0.50mmol), Pd (PPh
3)
2Cl
2(13mg, 5mol%) 1,2-glycol dimethyl ether (20ml) and Na
2CO
3(2mmol) mixture is at N for 2M, 1ml
2Under refluxed 4 hours.The saturated NaRCO of removal of solvent under reduced pressure, residuum
3(10ml) handle, with EtOAc extraction (2 * 25ml).Organic phase is washed with salt solution (20ml), dry (Na
2SO
4), removal of solvent under reduced pressure.Product is at SiO
2The last purified by flash chromatography of using, and usefulness EtOAc/ normal hexane (1: 1, v/v) wash-out, obtaining 100mg (90%) 2-amino-4-(2-p-methoxy-phenyl)-5-methyl benzenesulfonamide is colourless powder.With the further converted product of method G (using hexanaphthene formaldehyde).m．p．172-175℃。Compound 1173-cyclohexyl-6-methoxyl group-7-piperidino-(1-position only) alkylsulfonyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Make starting raw material with meta-aminotoluene, use method B (separating 2-amino-6-methoxybenzenesulphoismide from 2-amino-4-methoxybenzenesulphoismide) successively by flash chromatography technology (EtOAc/ hexane), method C, method A (using piperidines as amine), method D and method G (using hexanaphthene formaldehyde) transform.m．p．237-240℃。Compound 118 and 1223-cyclohexyl-7,8-ethylenedioxy-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide (122) and 3-cyclohexyl-6,7-ethylenedioxy-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide (118)
With 6-amino-1, the 4-benzodioxan is made starting raw material, converts it into ethylenedioxy-2-aminobenzene sulfonamide mixture of isomers with method B again.Separate this two isomer with column chromatography.3-cyclohexyl-6,7-ethylenedioxy-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide (118): usefulness method G (using hexanaphthene formaldehyde) transforms 2-amino-5,6-ethylenedioxy benzsulfamide.m．p．196-200℃。3-cyclohexyl-7,8-ethylenedioxy-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide (122): usefulness method G (using hexanaphthene formaldehyde) transforms 2-amino-7,8-ethylenedioxy benzsulfamide.m．p．268-270℃。Compound 1193-cyclohexyl-6-chloro-7-sulfamyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Transform 2-amino-4-chloro-5-sulfamyl benzsulfamide with method G (using hexanaphthene formaldehyde).m．p．274-276℃。Compound 1203-phenyl-6-chloro-7-sulfamyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Transform 2-amino-4-chloro-5-sulfamyl benzsulfamide with method G (using phenyl aldehyde).m．p．235-238℃。Compound 1213-cyclohexyl-6-bromo-7-piperidino-(1-position only) alkylsulfonyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide
Make starting raw material with m-bromoaniline, use method B (separating 2-amino-6-bromobenzene sulphonamide from 2-amino-4-bromobenzene sulphonamide) successively by recrystallization (EtOAc/ hexane), method C, method A (using piperidines) as amine, method D and method G (using hexanaphthene formaldehyde) transform.m．p．238-241℃。Compound 122
See compound 118.Compound 1232-cyclohexyl methyl amino-5-N, N-dimethylamino alkylsulfonyl benzsulfamide
Make starting raw material with the 2-aminobenzene sulfonamide, use method E (using the hexanaphthene carbonyl chloride) successively, method A (using dimethylamine) as amine, method F (the reaction mixture placement is spent the night, at room temperature stir with DIBALH simultaneously) transforms.m．p．123-125℃。Compound 1242-ethylamino-7-(1 ', 2 ', 3 ', 6 '-tetrahydrochysene piperidino-(1-position only)) alkylsulfonyl benzsulfamide
Use method A (with 1,2,3,6-tetrahydrochysene piperidines is as amine) and method F (to use LiAlH successively
4Room temperature) transforms 3-methyl isophthalic acid, 2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (seeing compound 73).m．p．175-177℃。Compound 1252-amino-3,5-dibromobenzene sulphonamide
With the 2-aminobenzene sulfonamide (8.6g that stirs; AcOH 50mmol) (100ml) solution slowly is added to Br
2(5.13ml; In AcOH 100mmol) (20ml) solution.Reaction mixture 55 ℃ of heating 60 hours, is poured in the frozen water (800ml) then, filtered, be absorbed on the silicon-dioxide, and use the column chromatography purifying, obtain 11.1g (67%) product.m．p．165-169℃。Compound 1262-P-acetamido benzene sulfonyl amine
Will be at the 2-of 0 ℃ of stirring aminobenzene sulfonamide (1.72g; 10mmol) and triethylamine (1.53ml; THF 11mmol) (25ml) solution is added to AcCl (0.85ml; 12mmol), and continue stirring in room temperature and spend the night.Reaction mixture is filtered post-absorption on silicon-dioxide, use the column chromatography purifying, obtain 1.7g (79%) product.m．p．153．5-155．5℃。Compound 1273-isobutyl--8-(piperidino-(1-position only) alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1,2,5-benzothiadiazine-1,1-dioxide N-(3 '-methyl isophthalic acid '-carboxybutyl)-the 2-nitrobenzene sulfonamide: with 2-nitrobenzene sulfonyl chloride (11g; 50mmol) and NaOH (2.1g; H 53mmol)
2O (100ml) solution is added to DL-leucine (6.55g; 50mmol), and in stirred overnight at room temperature.In reaction mixture, add 4M NaOH (12.5ml), filter then.Filtrate extracts with EtOAc with 1M HCl (50ml) acidifying.Dry (Na
2SO
4) organic phase that merges, be evaporated to driedly then, obtain 6.7g (42%) product.3-isobutyl--4-oxygen-2,3,4,5-tetrahydrochysene-1,2,5-benzothiadiazine-1,1-dioxide: with the N-that stirs (3 '-methyl isophthalic acid '-carboxybutyl)-2-nitrobenzene sulfonamide (6.7g; 21.2mmol) and anhydrous EtOH suspension hydrogenation under 1bar pressure of 10%Pd/C (200mg).Use the diatomite filtration reaction mixture, be evaporated to dried then.In anhydrous THF (50ml) solution, add N-hydroxy-succinamide (2.53g at 0 ℃ crude product; 22mmol) and DCC (4.54g; 22mmol).Reaction mixture is slowly risen to room temperature, and stir and spend the night.Filter reaction mixture is with THF washing gained solid.The organic phase that merges is evaporated to dried, in residuum, adds H
2O extracts with EtOAc.Dry (Na
2SO
4) organic phase that merges, be evaporated to driedly then, obtain 3g (53%) product.3-isobutyl--8-piperidino-(1-position only) alkylsulfonyl-2,3,4,5-tetrahydrochysene-1,2,5-benzothiadiazine-1,1-dioxide: N
2Down in 0 ℃ with 3-isobutyl--4-oxygen-2,3,4,5-tetrahydrochysene-1,2,5-benzothiadiazine-1,1-dioxide (500mg; 1.8mmol) anhydrous THF (20ml) solution be added to 2M BH
3SMe
2(9.2ml; 18mmol) in the solution.After having added reaction mixture is risen to room temperature, refluxed then 2 hours.With the reaction mixture cool to room temperature, carefully add 6M HCl (15ml).Add 7.5M NaOH (aq.) and make reaction mixture be strong basicity, and extract with EtOAc.Dry (Na
2SO
4) organic phase that merges, be evaporated to driedly then, obtain 320mg (70%) product.With method A (using piperidines) converted product as amine.m．p．209-211℃。Compound 1283-cyclohexyl-8-(piperidino-(1-position only) alkylsulfonyl)-2,3,4,5-tetrahydrochysene-1,2,5-benzothiadiazine-1,1-dioxide DL-Cyclohexylglycine: with NH
4Cl (17g; 0.32mol) be added to NaCN (15.9g; 0.32mol) H
2In O (60ml) solution, add hexanaphthene formaldehyde (37ml then; 0.32mol) MeOH (60ml) solution.With reaction mixture room temperature vigorous stirring 2 hours.Reaction mixture H
2O (100ml) dilution is with toluene extraction (2 * 70ml).The organic phase H that merges
2The O washing (2 * 50ml), with 6M HCl extraction (2 * 90ml).The precipitation that forms in acid water and the acidization is merged, refluxed then 24 hours.With the reaction mixture cool to room temperature, use 25%NH
3(aq.) make it to be a little alkalescence.Leach the precipitation of formation, use cold H
2O washing obtains 13g (26%) total free aminoacids after air-dry.
Method synthetic compound 128 (using the DL-Cyclohexylglycine) with synthetic compound 127 as amino acid.Compound 1293-cyclohexyl-7-cyclopentyl sulfinyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide 2-amino-5-encircles penta sulfenyl benzsulfamide: N
2Down with 5-iodo-2-aminobenzene sulfonamide (1.192g; 4mmol), triethylamine (750 μ l; 10mmol), CuI (76mg; 0.4mmol); Cyclopentyl mercaptan (590 μ l; 6mmol) and Pd (PPh
3)
4(462mg; 0.4mmol) no Shui diox (10ml) mixture one the band blind nut ampoule in spend the night in 130 ℃ of stirrings.With the reaction mixture cool to room temperature, use H
2The O dilution makes it to be alkalescence with 4M NaOH again, uses diatomite filtration.Filtrate is neutralized to pH8.5, is evaporated to dried then.Obtain 327mg (30%) product through the column chromatography purifying.3-cyclohexyl-7-cyclopentyl sulfinyl-1,2,3,4-tetrahydrochysene-1,2,4-benzothiadiazine-1,1-dioxide (129): under Ali and the described condition of Bohnert (" synthesizing ", (1998) 1238), with 2 equivalent Br
22-amino-5-is encircled penta sulfenyl benzsulfamide to carry out bromine in ring and turns usefulness (3) and S oxygenizement into.With product 96%EtOH reduction with 5%Pd/C under 1bar pressure, use method G (using hexanaphthene formaldehyde) to transform then.
Following table has gathered above-claimed cpd.
Claims (30)
1. the compound of formula I representative,
Wherein the key represented of dotted line can be a singly-bound, two keys or do not have key; If there is not key, then this nitrogen is by hydrogen and R
2Replace;
X represents SO
2Or C=O or CH
2
Y representative-CH (R
4)-,-N (R
4)-or-N (R
4)-CH
2-, O;
R
2Represent hydrogen, alkyl, cycloalkyl, aryl, benzyl; CO-R
9, R wherein
9Represent alkyl, cycloalkyl, benzyl, aryl; Or
R
2With R
3And their continuous atom formation 4-7 person rings, this ring is replaced by one or more following substituting groups arbitrarily: halogen, and alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, and contain one or more heteroatomss arbitrarily, reach and contain carbonyl arbitrarily;
R
3Represent hydrogen, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyano group alkyl, alkoxyalkyl, alkoxyl group, halogenated alkoxy, acyl group, alkyl-NR
13R
14, alkyl-S-R
13, R wherein
13And R
14Represent hydrogen respectively, alkyl, cycloalkyl; Or R
13And R
14The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle; Arbitrarily by halogen, alkyl, 7-12 person's carbocyclic ring that hydroxyl or alkoxyl group replace; Arbitrarily by halogen, alkyl, the 3-8 element heterocycle that hydroxyl or alkoxyl group replace; This heterocycle is arbitrarily with aryl-condensed; Arbitrarily by the benzyl of one or more following substituting groups replacements: halogen, cycloalkyl, alkyl, hydroxyl, alkoxyl group, amino or sulfenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino; Arbitrarily by the aryl of one or more following substituting groups replacements: halogen, cycloalkyl, alkyl, hydroxyl, alkoxyl group, amino or sulfenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino; Or
R
3With R
2Or R
4And their continuous atom formation 4-7 person rings, this ring is replaced by one or more following substituting groups arbitrarily: halogen, and alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, and contain one or more heteroatomss arbitrarily, reach and contain carbonyl arbitrarily;
R
4Represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl ,-CO-R
10Or CO
2R
10, R wherein
10Represent hydrogen, cycloalkyl, alkyl, aryl or benzyl; Or
R
4With R
3And their continuous atom formation 4-7 person rings, this ring is replaced by one or more following substituting groups arbitrarily: halogen, and alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, and contain one or more heteroatomss arbitrarily, reach and contain carbonyl arbitrarily;
R
5Represent hydrogen, halogen, alkyl, thiazolinyl, alkynyl, aryl ,-SO
2-NR
11R
12, R wherein
11And R
12Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
11And R
12The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed;
R
6Represent hydrogen, halogen, alkyl, cyano group, cyano group alkyl, nitro, alkoxyl group, halogenated alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, ring haloalkyl ,-NR
15R
16,-NHSO
2-R
15,-NHSO
2-aryl, wherein aryl is replaced by one or more following substituting groups arbitrarily: halogen, alkyl, cycloalkyl, hydroxyl, alkoxyl group, amino, sulfenyl, CF
3, OCF
3, NO
2Or aryl; Arbitrarily by the aryl of one or more following substituting groups replacements: alkyl, cycloalkyl, alkoxyl group, haloalkyl, halogenated alkoxy, hydroxyalkyl, alkoxyalkyl or amino; Arbitrarily by the HET of one or more following substituting groups replacements: alkyl, cycloalkyl, alkoxyl group, halogen, haloalkyl or halogenated alkoxy;-(alkyl)
m-S-R
15,-(alkyl)
m-SO-R
15,-(alkyl)
m-SO
2-R
15,-(alkyl)
m-SO
2O-R
15,-(alkyl)
m-SO
2-NR
15R
16,-(alkyl)
m-NHCOR
15,-(alkyl)
m-CONR
15R
16,-(alkyl)
m-CR '=NOR " ,-(alkyl) m-CO-R
15,-(alkyl)
m-CO
2-
R
15, wherein m is 0 or 1; And R ' and R " represent hydrogen, alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, benzyl respectively; And R
15And R
16Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
15And R
16The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed;
R
7Represent hydrogen, halogen, alkyl, cyano group, cyano group alkyl, nitro, 4-nitro alkyl, alkoxyl group, halogenated alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, ring haloalkyl;-NR
17R
18,-NHSO
2-R
17,-NHSO
2-aryl, wherein aryl is replaced by one or more following substituting groups arbitrarily: halogen, alkyl, cycloalkyl, hydroxyl, alkoxyl group, amino, sulfenyl, CF
3, OCF
3, NO
2Or aryl;-(alkyl)
m-S-R
17,-(alkyl)
m-SO-R
17,-(alkyl)
m-SO
2-R
17,-(alkyl)
m-SO
2O-R
17,-(alkyl)
m-SO
2-NR
17R
18,-(alkyl)
m-NHCOR
17,-(alkyl)
m-CONR
17R
18,-(alkyl)
m-CR '=NOR " ,-(alkyl)
m-CO-R
17,-(alkyl)
m-CO
2-R
17, wherein m is 0 or 1; And R ' and R " represent hydrogen, alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, benzyl respectively; And R
17And R
18Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
17And R
18The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed; Arbitrarily by the HET of one or more following substituting groups replacements: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, alkoxyl group, amino, sulfenyl, aryl ,-S-alkyl ,-S-aryl, SO-alkyl, SO-aryl, SO
2-alkyl, SO
2-aryl, SO
2NR
17R
18Arbitrarily by the aryl of one or more following substituting groups replacements: alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, hydroxyalkyl, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF
3,-SO
2NR
17R
18, R wherein
17And R
18Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
17And R
18The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed; Or
R
7With R
6Or R
8Form 5-7 person's ring that one of following array structure is arranged together :-O-(CH
2)
n-O-, wherein n is 1,2 or 3;-SO
2-NR-(CH
2)
n-, wherein n is 1 or 2;-SO-NR-(CH
2)
n-, wherein n is 1 or 2;-SO
2-(CH
2)
n-, wherein n is 2 or 3;-SO-(CH
2)
n-, wherein n is 2 or 3;-CO-CH=CH-NH-;-CO-CH=CH-O-;-CO-(CH
2)
n-NH-, wherein n is 1 or 2;-CO-NH-(CH
2)
n-, wherein n is 1 or 2;-CO-(CH
2)
2-O-;-O-(CH
2)
n-O-, wherein n is 1,2 or 3;
R
8Represent hydrogen, alkyl, alkoxyl group, hydroxyalkyl, halogen, haloalkyl, CN, cyano group alkyl, nitro, 4-nitro alkyl; Arbitrarily by the aryl of one or more following substituting groups replacements: halogen, CF
3, OCF
3, NO
2, alkyl, cycloalkyl, alkoxyl group; Arbitrarily by the HET of one or more following substituting groups replacements: halogen, CF
3, OCF
3, NO
2, alkyl, cycloalkyl, alkoxyl group;-(alkyl)
m-S-R
19,-(alkyl)
m-SO-R
19,-(alkyl)
m-SO
2-R
19,-(alkyl)
m-SO
2O-R
19,-(alkyl)
m-SO
2-NR
19R
20,-(alkyl)
m-NHCOR
19,-(alkyl)
m-CONR
19R
20,-(alkyl)
m-CR '=NOR " ,-(alkyl) m-CO-R
19,-(alkyl)
m-CO
2-R
19, wherein m is 0 or 1; And R ' and R " represent hydrogen, alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, benzyl respectively; And R
19And R
20Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
19And R
20The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed; Condition is: if the two keys of the representative of the dotted line in the formula I, X represents SO
2, Y represents NH, and compound is mono-substituted, and then it can not be R wherein
3Single substitution compound for following groups: OCH
3, methyl, amyl group, the tertiary butyl, aminophenyl, 2-vinylbenzene, styroyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, norbornylene, benzyl, thienyl, furyl, aryl, by the 4-methyl, 4-methoxyl group, 4-chlorine, the aryl that 4-nitro or 3-nitro replace; And, if compound is R wherein
3Be two substitution compounds of methyl, then R
5Not Cl, CH
3Or R
7Not F, Cl, Br, I, CH
3, CF
3, nitro, SO
2N (CH
3)
2Or R
6Not Cl, Br, CH
3, CF
3, ethyl, methoxyl group; Perhaps, if R
7Be chlorine, R then
3Not ethyl, butyl, sec-butyl, the tertiary butyl, cyclobutyl, 2,2-dimethyl propyl, phenyl; And if compound is two substitution compounds, then it can not be two substitution compounds that following situation is arranged: R
6=OMe, R
3=ethyl; R
6=methyl, R
3=propyl group; R
7=SO
2NH
2, R
6=Cl; R
7=SO
2NH
2, R
3=phenyl; R
7=Br, R
3=phenyl; And condition is: if compound is trisubstituted, then it can not be three substitution compounds that following situation is arranged: R
3=CH
3, R
5=NO
2, R
7=Cl; R
3=CH
3, R
6=NO
2, R
7=Cl; R
3=CH
3, R
5=NH
2, R
7=Cl; And condition is: if the dotted line in the formula I is represented singly-bound, X represents SO
2And Y represents NH, and then compound is not R wherein
7Or R
6Be chlorine and R
3Be two substitution compounds of following groups: alkyl, cyclobutyl, cyclopropyl, cyclohexyl, tetrahydrobenzene, norbornene, the norborneol alkyl, ethylmercapto group methyl, ethoxyl methyl, ethoxyethyl group, methoxymethyl, methylamino, the 2-chloroethyl, chloromethyl, dichloromethyl, trifluoromethyl, amino; And compound can not be R
3Be CH
3And three substitution compounds with following situation: R
5=sec.-propyl, R
7=F; R
5=ethyl, R
7=Cl; R
5=propyl group, R
7=Cl; R
5=propyl group, R
7=F; R
5=methyl, R
7=Cl; R
5=ethyl, R
7=methyl; R
5=Cl, R
7=methyl; R
5=methyl, R
7=Cl; R
4=methyl, R
5=ethyl; Or R
4=methyl, R
5=methyl, R
7=F.
2. according to the formula I compound of claim 1, wherein
R
2Represent hydrogen, alkyl, cycloalkyl, aryl, benzyl; Or
R
2With R
3And their continuous atom formation 5-6 person rings, this ring is replaced by one or more following substituting groups arbitrarily: halogen, and alkyl, hydroxyl, alkoxyl group, amino or sulfenyl, and contain one or more heteroatomss arbitrarily, reach and contain carbonyl arbitrarily;
R
3Represent hydrogen, cycloalkyl, cycloalkylalkyl, alkyl, haloalkyl, alkoxyl group, 7-10 person's carbocyclic ring; The 5-6 element heterocycle; Benzyl; Aryl; Or
R
3With R
2Or R
4Form 5-6 person's ring together;
R
4Represent hydrogen, alkyl; Or
R
4With R
3And their continuous atom formation 5-6 person rings, this ring is replaced by one or more following substituting groups arbitrarily: halogen, and alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, and contain one or more heteroatomss arbitrarily, reach and contain carbonyl arbitrarily;
R
5Represent hydrogen, halogen, alkyl, thiazolinyl, alkynyl, phenyl ,-SO
2-NR
11R
12, R wherein
11And R
12Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
11And R
12The nitrogen-atoms that links to each other with them forms the 5-6 element heterocycle;
R
6Represent hydrogen, Br, F, I, cycloalkyl, alkyl, alkoxyl group, alkoxyalkyl; Arbitrarily by the phenyl of one or more following substituting groups replacements: alkyl, alkoxyl group; HET;-S-R
15,-SO-R
15,-SO
2-R
15,-SO
2O-R
15,-SO
2-NR
15R
16,-NHCOR
15,-CONR
15R
16,-CR '=NOR " ,-CO-R
15,-CO
2-R
15, wherein R ' and R " and represent hydrogen, alkyl, cycloalkyl, phenyl, benzyl respectively; And R
15And R
16Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
15And R
16The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, phenyl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed;
R
7Represent hydrogen, Br, F, I, alkyl, cyano group, cyano group alkyl, nitro, 4-nitro alkyl, alkoxyl group, halogenated alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, ring haloalkyl ,-(alkyl)
m-NR
17R
18,-NHSO
2-R
17,-S-R
17,-SO-R
17,-SO
2-R
17,-SO
2O-R
17,-SO
2-NR
17R
18,-NHCOR
17,-CONR
17R
18,-CR '=NOR " ,-CO-R
17,-CO
2-R
17, wherein R ' and R " and represent hydrogen, alkyl, cycloalkyl, phenyl, benzyl respectively; And R
17And R
18Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
17And R
18The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: alkyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed; Arbitrarily by the HET of one or more following substituting groups replacements: halogen, alkyl, phenyl, SO
2NR
17R
18Arbitrarily by the phenyl of one or more following substituting groups replacements: alkyl, hydroxyl, alkoxyl group, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF
3,-SO
2NR
17R
18, R wherein
17And R
18Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
17And R
18The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed; Or
R
7With R
6Or R
8Form 5-7 person's ring that one of following array structure is arranged together :-O-(CH
2)
n-O-, wherein n is 1,2 or 3;-SO
2-NR-(CH
2)
n-, wherein n is 1 or 2;-SO-NR-(CH
2)
n-, wherein n is 1 or 2;-SO
2-(CH
2)
n-, wherein n is 2 or 3;-SO-(CH
2)
n-, wherein n is 2 or 3;-CO-CH=CH-NH-;-CO-CH=CH-O-;-CO-(CH
2)
n-NH-, wherein n is 1 or 2;-CO-NH-(CH
2)
n-, wherein n is 1 or 2;-CO-(CH
2)
2-O-;-O-(CH
2)
n-O-, wherein n is 1,2 or 3;
R
8Represent hydrogen, alkyl, alkoxyl group, hydroxyalkyl, halogen, haloalkyl, CN, cyano group alkyl, nitro, 4-nitro alkyl; Arbitrarily by the phenyl of one or more following substituting groups replacements: alkyl, cycloalkyl, alkoxyl group; HET;-S-R
19,-SO-R
19,-SO
2-R
19,-SO
2O-R
19,-SO
2-NR
19R
20,-NHCOR
19,-CONR
19R
20,-CR '=NOR " ,-CO-R
19,-CO
2-R
19, wherein R ' and R " and represent hydrogen, alkyl, cycloalkyl, phenyl, benzyl respectively; And R
19And R
20Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
19And R
20The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, phenyl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And with aryl-condensed, condition is this heterocycle: if X represents SO arbitrarily
2, Y represents N, and dotted line represents singly-bound, then R
7Or R
6Be not chlorine, if R
2, R
4, R
5, R
8With a remaining R
6Or R
7All be hydrogen; Or condition is: have only the R of working as
5Be hydrogen or R
7R when being not sulfamyl
3Just can represent CH
3And
Condition is: if X represents SO
2, Y represents N, and dotted line representative two key, then R
7Or R
6Can not be chlorine, if R
2, R
4, R
5, R
8With a remaining R
6Or R
7All be hydrogen; Or condition is: R
2, R
4, R
5, R
6, R
7And R
8Not hydrogen; Or condition is: work as R
7Be fluorine, bromine, iodine, CF
3, CH
3, NO
2, SO
2N (CH
3)
2, or R
6Be bromine, CF
3, CH
3, ethyl, methoxyl group, or R
5When being chlorine, or R
8When being chlorine, this compound is not R
3Be CH
3Two substitution compounds; Or condition is: this compound is not a following compounds: 3-ethyl-6-methoxyl group-1,2,4-benzothiadiazine-1,1-dioxide; 3-propyl group-6-methyl isophthalic acid, 2,4-benzothiadiazine-1,1-dioxide; 3-ethyl-6-methoxyl group-1,2,4-benzothiadiazine-1,1-dioxide; 3-phenyl-7-bromo-1,2,4-benzothiadiazine-1,1-dioxide; 3-phenyl-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide; 5-bromo-7-chloro-3-methyl isophthalic acid, 2,4-benzothiadiazine-1,1-dioxide; 5-iodo-7-chloro-3-methyl isophthalic acid, 2,4-benzothiadiazine-1,1-dioxide; 5-nitro-7-chloro-3-methyl isophthalic acid, 2,4-benzothiadiazine-1,1-dioxide; 6-nitro-7-chloro-3-methyl isophthalic acid, 2,4-benzothiadiazine-1,1-dioxide; Or 6-amino-7-chloro-3-methyl isophthalic acid, 2,4-benzothiadiazine-1,1-dioxide.
3. the formula I compound that one of requires according to aforesaid right, wherein
R
2Represent hydrogen, alkyl, cycloalkyl, phenyl, benzyl; Or
R
2With R
3And their continuous atom formation 5-6 person rings, this ring is replaced by one or more following substituting groups arbitrarily: halogen, and alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, and contain one or more heteroatomss arbitrarily, reach and contain carbonyl arbitrarily.
4. the formula I compound that one of requires according to aforesaid right, wherein
R
3Represent hydrogen, cycloalkyl, alkyl, haloalkyl, alkoxyl group, 7-10 person's carbocyclic ring; The 5-6 element heterocycle; Benzyl; Aryl; Or
R
3With R
2Or R
4Form 5-6 person's ring together, this ring is replaced by one or more following substituting groups arbitrarily: halogen, and alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, and contain one or more heteroatomss arbitrarily, and contain carbonyl arbitrarily.
5. the formula I compound that one of requires according to aforesaid right, wherein
R
4Represent hydrogen, alkyl; Or
R
4With R
3And their continuous atom formation 5-6 person rings, this ring is replaced by one or more following substituting groups arbitrarily: halogen, and alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, and contain one or more heteroatomss arbitrarily, reach and contain carbonyl arbitrarily.
6. the formula I compound that one of requires according to aforesaid right, wherein
R
5Represent hydrogen, halogen, alkyl, thiazolinyl, alkynyl, phenyl ,-SO
2-NR
11R
12, R wherein
11And R
12Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
11And R
12The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle.
7. the formula I compound that one of requires according to aforesaid right, wherein
R
6Represent hydrogen, halogen, cycloalkyl, alkyl, alkoxyl group, alkoxyalkyl; Arbitrarily by the aryl of one or more following substituting groups replacements: alkyl, alkoxyl group; HET;-S-R
15,-SO-R
15,-SO
2-R
15,-SO
2O-R
15,-SO
2-NR
15R
16,-NHCOR
15,-CONR
15R
16,-CR '=NOR " ,-CO-R
15,-CO
2-R
15, wherein R ' and R " and represent hydrogen, alkyl, cycloalkyl, phenyl, benzyl respectively; And R
15And R
16Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
15And R
16The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, phenyl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed.
8. the formula I compound that one of requires according to aforesaid right, wherein
R
7Represent hydrogen, halogen, alkyl, cyano group, cyano group alkyl, nitro, alkoxyl group, halogenated alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, ring haloalkyl ,-(alkyl)
m-NR
17R
18,-NHSO
2-R
17,-S-R
17,-SO-R
17,-SO
2-R
17,-SO
2O-R
17,-SO
2-NR
17R
18,-NHCOR
17,-CONR
17R
18,-CR '=NOR " ,-CO-R
17,-CO
2-R
17, wherein R ' and R " and represent hydrogen, alkyl, cycloalkyl, phenyl, benzyl respectively; And R
17And R
18Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
17And R
18The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: alkyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed; Arbitrarily by the HET of one or more following substituting groups replacements: halogen, alkyl, phenyl, SO
2NR
17R
18Arbitrarily by the phenyl of one or more following substituting groups replacements: alkyl, hydroxyl, alkoxyl group, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF
3,-SO
2NR
17R
18, R wherein
17And R
18Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
17And R
18The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed; Or
R
7With R
6Or R
8Form 5-7 person's ring that one of following array structure is arranged together :-O-(CH
2)
n-O-, wherein n is 1,2 or 3;-SO
2-NR-(CH
2)
n-, wherein n is 1 or 2;-SO-NR-(CH
2)
n-, wherein n is 1 or 2;-SO
2-(CH
2)
n-, wherein n is 2 or 3;-SO-(CH
2)
n-, wherein n is 2 or 3;-CO-CH=CH-NH-;-CO-CH=CH-O-;-CO-(CH
2)
n-NH-, wherein n is 1 or 2;-CO-NH-(CH
2)
n-, wherein n is 1 or 2;-CO-(CH
2)
2-O-;-O-(CH
2)
n-O-, wherein n is 1,2 or 3.
9. the formula I compound that one of requires according to aforesaid right, wherein
R
8Represent hydrogen, alkyl, alkoxyl group, hydroxyalkyl, halogen, haloalkyl, CN, cyano group alkyl, nitro, 4-nitro alkyl; Arbitrarily by the phenyl of one or more following substituting groups replacements: alkyl, cycloalkyl, alkoxyl group; HET;-S-R
19,-SO-R
19,-SO
2-R
19,-SO
2O-R
19,-SO
2-NR
19R
20,-NHCOR
19,-CONR
19R
20,-CR '=NOR " ,-CO-R
19,-CO
2-R
19, wherein R ' and R " and represent hydrogen, alkyl, cycloalkyl, phenyl, benzyl respectively; And R
19And R
20Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
19And R
20The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, phenyl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed.
10. the formula I compound that one of requires according to aforesaid right, wherein
X represents SO
2
Y represents N;
Dotted line is represented singly-bound;
R
2Represent hydrogen;
R
3Representation ring alkyl, 7-10 person's carbocyclic ring; The 5-6 element heterocycle;
R
4Represent H;
R
5Represent H;
R
6Represent hydrogen, alkyl or halogen;
R
7Represent the cyano group alkyl, 4-nitro alkyl, haloalkyl ,-(alkyl)
m-SO-R
17,-(alkyl)
m-SO
2-R
17,-(alkyl)
m-SO
2-NR
17R
18,-(alkyl)
m-CONR
17R
18,--(alkyl)
m-CR '=NOR " ,-(alkyl)
m-CO-R
17,-(alkyl)
m-CO
2-R
17, wherein m is 0 or 1; R ' and R " represent hydrogen, alkyl, cycloalkyl, phenyl, benzyl respectively; And R
17And R
18Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
17And R
18The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: alkyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed; HET; Or
R
7With R
6Or R
8Form 5-7 person's ring that one of following array structure is arranged together :-O-(CH
2)
n-O-, wherein n is 1,2 or 3;-SO
2-NR-(CH
2)
n-, wherein n is 1 or 2;-SO-NR-(CH
2)
n-, wherein n is 1 or 2;-SO
2-(CH
2)
n-, wherein n is 2 or 3;-SO-(CH
2)
n-, wherein n is 2 or 3;-CO-CH=CH-NH-;-CO-CH=CH-O-;-CO-(CH
2)
n-NH-, wherein n is 1 or 2;-CO-NH-(CH
2)
n-, wherein n is 1 or 2;-CO-(CH
2)
2-O-;-O-(CH
2)
n-O-, wherein n is 1,2 or 3;
R
8Represent alkyl, halogen, cyano group alkyl, 4-nitro alkyl, haloalkyl ,-(alkyl)
m-SO-R
17,-(alkyl)
m-SO
2-R
17,-(alkyl)
m-SO
2-NR
17R
18,-(alkyl)
m-CONR
17R
18,--(alkyl)
m-CR '=NOR " ,-(alkyl)
m-CO-R
17,-(alkyl)
m-CO
2-R
17, wherein m is 0 or 1; R ' and R " represent hydrogen, alkyl, cycloalkyl, phenyl, benzyl respectively; And R
17And R
18Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
17And R
18The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: alkyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed; HET.
11. according to the formula I compound of one of aforesaid right requirement, wherein
R
3Represent hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl group, sec.-propyl, CF
3, oxyethyl group, norbornylene, norbornane, diamantane, benzyl; Phenyl; Or
R
3With R
2Or R
4The atom that links to each other with them forms 5 Yuans rings together.
12. according to the formula I compound of one of aforesaid right requirement, wherein
R
4Represent hydrogen, methyl, ethyl; Or
R
4With R
3The atom that links to each other with them forms 5 Yuans rings together.
13. according to the formula I compound of one of aforesaid right requirement, wherein
R
5Represent hydrogen, chlorine, bromine, methyl, phenyl ,-SO
2NH
2
14. according to the formula I compound of one of aforesaid right requirement, wherein
R
6Represent hydrogen, 2-p-methoxy-phenyl, 2-pyridyl, 3-pyridyl, methyl, methoxyl group, chlorine or bromine.
15. according to the formula I compound of one of aforesaid right requirement, wherein
R
7Represent hydrogen, chlorine, bromine, methyl, 1-hydroxyethyl, ethanoyl ,-(CH
3) C=N-OH, CONH
2, CO
2-ethyl, cyano group, phenyl, 2-N-acetylamino phenyl, 2-nitrophenyl; the 2-p-methoxy-phenyl, 4-trifluoromethyl-2-p-methoxy-phenyl, 2,4-Dimethoxyphenyl, 2-N; N-dimethylamino alkylsulfonyl phenyl, 2-chloro-phenyl-, 2-fluorophenyl, 3-hydroxy phenyl, 2-pyridyl; the 3-pyridyl, 2-pyrimidyl, 2-furyl, 3-furyl; the 2-thienyl, 2-(N-methyl)-imidazolyl, 5-triazolyl, 4-phenyl-triazolyl-5-base; the 5-methyl isophthalic acid, 2,4-oxadiazole-3-base, CH
3CONH-, CH
3SO
2NH-, NO
2, SO
2OH, phenyl-SO
2-, sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl, N-phenyl-N-methyl-sulfamyl, N-cyclohexyl-sulfamyl ,-SO
2-heterocycle, this heterocycle is selected from piperidines, tetramethyleneimine, 1,2,5,6-tetrahydropyridine, tetrahydroquinoline, N methyl piperazine, N-alkylsulfonyl methyl-piperazine, morpholine.
16. according to the formula I compound of one of aforesaid right requirement, wherein
R
8Represent hydrogen, methyl, methylol, 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 2-pyridyl, methoxyl group.
17. according to the formula I compound of one of aforesaid right requirement, wherein
X represents SO
2
Y represents N;
Dotted line is represented singly-bound;
R
2Represent hydrogen or CH
3
R
3Represent cyclohexyl, cyclopentyl, norbornylene, norbornane, diamantane, phenyl, oxyethyl group;
R
4Represent hydrogen or CH
3
R
5Represent hydrogen, CH
3, phenyl, sulfamyl, chlorine, bromine;
R
6Represent hydrogen, CH
3, 2-p-methoxy-phenyl, methoxyl group, chlorine, bromine, 2-pyridyl, 3-pyridyl;
R
7Represent hydrogen, chlorine, bromine, methyl, 1-hydroxyethyl, ethanoyl ,-(CH
3) C=N-OH, CONH
2, CO
2-ethyl, cyano group, phenyl, 2-N-acetylamino phenyl, 2-nitrophenyl; the 2-p-methoxy-phenyl, 4-trifluoromethyl-2-p-methoxy-phenyl, 2,4-Dimethoxyphenyl, 2-N; N-dimethylamino alkylsulfonyl phenyl, 2-chloro-phenyl-, 2-fluorophenyl, 3-hydroxy phenyl, 2-pyridyl; the 3-pyridyl, 2-pyrimidyl, 2-furyl, 3-furyl; the 2-thienyl, 2-(N-methyl)-imidazolyl, 5-triazolyl, 4-phenyl-triazolyl-5-base; the 5-methyl isophthalic acid, 2,4-oxadiazole-3-base, CH
3CONH-, CH
3SO
2NH-, NO
2, SO
2OH, phenyl-SO
2-, sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl, N-phenyl-N-methyl-sulfamyl, N-cyclohexyl-sulfamyl ,-SO
2-heterocycle, this heterocycle is selected from piperidines, tetramethyleneimine, 1,2,5,6-tetrahydropyridine, tetrahydroquinoline, N methyl piperazine, N-alkylsulfonyl methyl-piperazine, morpholine;
R
8Represent methylidene, methylol, 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 2-pyridyl, methoxyl group.
18. according to the formula I compound of one of aforesaid right requirement, wherein
X is SO
2
Y is N;
The two keys of dotted line representative;
R
3Be CH
3Or CF
3, or
R
3With R
4And the atom that they link to each other together;
R
4, R
6And R
8Be hydrogen;
R
5Represent hydrogen or halogen;
R
7Be N-methyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N-cyclohexyl-sulfamyl, tetrahydropyridine-alkylsulfonyl;-SO
2OH, sulfamyl.
19. according to the formula I compound of one of aforesaid right requirement, wherein
X is C=O;
Y is N, O or CH;
R
2Represent hydrogen;
R
3Represent hydrogen, CH
3, CF
3, cyclohexyl, norbornylene, phenyl, ethyl;
R
7Represent hydrogen, N, N-dimethylamino alkylsulfonyl, N-cyclohexyl sulfamyl, tetrahydro pyridyl alkylsulfonyl, morpholino Herbicidal sulphonylamino alkylsulfonyl, bromine;
R
5Represent hydrogen or bromine;
R
4, R
6And R
8All represent hydrogen.
20. according to the formula I compound of one of aforesaid right requirement, wherein
X is CH
2
Y is N;
R
3Represent cyclohexyl or norbornylene;
R
5Represent hydrogen or bromine;
R
7Represent bromine or sulfamyl;
R
2, R
4, R
6And R
8All represent hydrogen.
21. according to the formula I compound of one of aforesaid right requirement, wherein
X is SO
2
Y is NH;
Dotted line represents not have key;
R
2, R
4, R
5And R
8All represent hydrogen;
R
3Represent cyclohexyl, methyl or hydrogen;
R
7Represent N, N-dimethylamino alkylsulfonyl, tetrahydro pyridyl alkylsulfonyl, bromine;
R
6Represent bromine or hydrogen.
22. according to the formula I compound of one of aforesaid right requirement, wherein
X is SO
2
Y is-NHCH
2-;
R
3Represent 3-methyl fourth-2-base, phenyl or cyclohexyl;
R
7Represent 1-piperidino-(1-position only)-alkylsulfonyl.
23. According to claim 1, a compound of formula Ⅰ, said compound comprising:
2 - cyclohexyl-4 - O 2,3,4 - tetrahydro-quinazoline;
2 - phenyl-4 - O 2,3,4 - tetrahydro-quinazoline;
2 - methyl-3 ,4 - dihydro-1,3 - benzoxazin-4 - one;
2 - phenyl-3 ,4 - dihydro-1,3 - benzoxazin-4 - one;
3 - bicyclo [2.2.1] hept-5'-en-2'-yl-1, 2,3,4 - tetrahydro-1 ,2,4 - benzo
Thiadiazine 1,1 - dioxide;
3 - phenyl-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine-1, 1 - dioxide;
1,2,3,5,10,10 a-hexahydro-benzo [e] pyrrolo [1,2-b] -1,2,4 - thiadiazine -
5,5 - dioxide;
2 - ethyl-2 - methyl-3 ,4 - dihydro-1,3 - benzoxazin-4 - one;
3 - cyclohexyl-6 - (2 - methoxyphenyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzo
Thiadiazine 1,1 - dioxide;
3 - cyclohexyl-6 - (2 - pyridyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclohexyl-6 - (3 - pyridyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclohexyl-7 - (2 - hydroxyethyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclohexyl-7 - acetyl-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine-1 ,1
- Two oxides;
3 - cyclohexyl-7 - (1 - hydroxy-imino-ethyl) -1,2,3,4 - tetrahydro-1 ,2,4 -
Benzothiadiazin 1,1 - dioxide;
3 - cyclohexyl-7 - carbamoyl-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
1,1 - dioxide;
3 - cyclohexyl-7 - ethoxycarbonyl-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine -
1,1 - dioxide;
3 - cyclohexyl-7 - cyano-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine-1 ,1 -
Dioxide;
3 - bicyclo [2.2.1] hept-5'-en-2'--7 - phenyl-1, 2,3,4 - tetrahydro -
1,2,4 - benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl-7 - (2'-acetylamino-phenyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzene
And thiadiazine 1,1 - dioxide;
3 - cyclohexyl-7 - (2-nitrophenyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzothiazol
Diazine 1,1 - dioxide;
3 - cyclohexyl-7 - (2'-methoxyphenyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzo
Thiadiazine 1,1 - dioxide;
3 - cyclohexyl-7 - (2'-methoxy-4'-trifluoromethyl-phenyl) -1,2,3,4 - tetrahydro-
2,4 - benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl-7 - (2 ', 4'-dimethoxyphenyl) -1,2,3,4 - tetrahydro-1 ,2,4
- Benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl -7 - (2'-(N, N-dimethylsulfamoyl) phenyl) -1,2,3,4 -
Tetrahydro-1 ,2,4 - benzothiadiazine-1, 1 - dioxide;
3 - cyclohexyl-7 - (2'-chlorophenyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclohexyl-7 - (2'-fluorophenyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclohexyl-7 - (2'-hydroxyphenyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzothiazol
Diazine 1,1 - dioxide;
3 - cyclohexyl-7 - (2'-pyridyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclohexyl-7 - (3'-pyridyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclohexyl-7 - (2'-pyrimidinyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclohexyl-7 - (2'-furyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclohexyl-7 - (3'-furyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclohexyl-7 - (2'-thienyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclohexyl-7 - (1 - methyl-1H-2-imidazolyl) -1,2,3,4 - tetrahydro -
1,2,4 - benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl-7 - (1 ', 2', 3'-triazol-4'-yl) -1,2,3,4 - tetrahydro-1 ,2,4
- Benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl-7 - (5'-phenyl-1 ', 2', 3'-triazol-4'-yl) -1,2,3,4 -
Tetrahydro-1 ,2,4 - benzothiadiazine-1, 1 - dioxide;
3 - cyclohexyl-7 - (5'-methyl-1 ', 2', 3'-oxadiazol-3 - yl) -1,2,3,4
- Tetrahydro-1 ,2,4 - benzothiadiazine-1, 1 - dioxide;
3 - cyclohexyl-7 - acetamido-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine -
1,1 - dioxide;
3 - cyclohexyl-7 - methylsulfonyl-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzothiazol
Diazine 1,1 - dioxide;
3 - cyclohexyl-7 - amino-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine-1 ,1 -
Dioxide;
3 - cyclohexyl-7 - phenyl-sulfonyl-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
1,1 - dioxide;
2 - cyclohexyl-1, 2,3,4 - tetrahydro-6 - quinazoline sulfonamide;
3 - cyclohexyl-7 - sulfamoyl-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine -
1,1 - dioxide;
3 - methyl-7 - dimethylsulfamoyl-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
2 - cyclohexyl-1, 2,3,4 - tetrahydro-6 - quinazoline N, N-dimethyl-sulfonamide;
3 - cyclohexyl-7 - dimethylamino-sulfonyl-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiazol
Diazine 1,1 - dioxide;
3 - cyclohexyl -7 - (N, N-diethylamino) sulfonyl-1, 2,3,4 - tetrahydro-1 ,2,4
- Benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl-7 - pyrrolidino-sulfonyl-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzo
Thiadiazine 1,1 - dioxide;
3 - methyl-7 - piperidino-sulfonyl-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclopropyl-7 - piperidino-sulfonyl-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzothiazol
Diazine 1,1 - dioxide;
3 - isopropyl-7 - piperidino-sulfonyl-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzothiazol
Diazine 1,1 - dioxide;
3 - propyl -7 - piperidino-sulfonyl-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - benzyl-7 - piperidino-sulfonyl-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclopentyl-7 - piperidino-sulfonyl-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzothiazol
Diazine 1,1 - dioxide;
3 - cyclohexyl-7 - piperidino-sulfonyl-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzothiazol
Diazine 1,1 - dioxide;
3 - bicyclo [2.2.1] hept-5'-en-2'--7 - piperidino-sulfonyl-1 ,2,3,4
- Tetrahydro-1 ,2,4 - benzothiadiazine-1, 1 - dioxide;
3 - cyclohexyl-7 - (1 ', 2', 3 ', 6'-tetrahydro-piperidino) sulfonyl-1 ,2,3,4 - Four
,2,4 - Benzothiadiazin-1, 1 - dioxide;
3 - cyclohexyl -7 - (N-methyl-N-phenyl-amino) sulfonyl-1, 2,3,4 - tetrahydro-
2,4 - benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl-7 - (1'-(1 ', 2', 3 ', 4'-tetrahydroquinolinyl)) sulfonyl-1 ,2,3,4
- Tetrahydro-1 ,2,4 - benzothiadiazine-1, 1 - dioxide;
3 - cyclohexyl-7 - (4'-methyl-piperidino) sulfonyl-1, 2,3,4 - tetrahydro-1 ,2,4
- Benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl-7 - (4'-methyl-sulfonyl-piperidino) sulfonyl-1, 2,3,4 - tetrahydro-
2,4 - benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl-7 - morpholino-sulfonyl-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - bicyclo [2.2.1] hept-5'-en-2'--7 - bromo-1, 2,3,4 - tetrahydro -
1,2,4 - benzothiadiazine 1,1 - dioxide;
2 - methyl -4 - oxo-3 ,4 - dihydro-6 - quinazoline-N, N-dimethyl-sulfonamide;
2 - trifluoromethyl-4 - oxo-3 ,4 - dihydro-6 - quinazoline sulfonamide;
2 - trifluoromethyl-4 - oxo-3 ,4 - dihydro-6 - quinazoline-N, N-dimethylsulfamoyl
Amines;
2 - trifluoromethyl-4 - oxo-3 ,4 - dihydro-6 - quinazolin-1 ', 2', 3 ', 6'-tetrahydro-piperazine
Piperidino sulfonamide;
2 - trifluoromethyl-4 - oxo-3 ,4 - dihydro-6 - quinazoline N-cyclohexyl-sulfonamide;
2 - trifluoromethyl-4 - oxo-3 ,4 - dihydro-6 - morpholino quinazoline sulfonamide;
2 - cyclohexyl-4 - oxo-3 ,4 - dihydro-6 - quinazoline-N, N-dimethyl-sulfonamide;
3 - methyl-7 - sulfamoyl -1,2 - dihydro-1 ,2,4 - benzothiadiazine-1 ,1 - two
Oxide;
3 - methyl-7 - dimethylsulfamoyl-1 ,2 - dihydro-1 ,2,4 - benzothiadiazine -
1,1 - dioxide;
3 - methyl-7 - (1 ', 2', 3 ', 6'-tetrahydro-piperidino) sulfonyl-1 ,2 - dihydro -
1,2,4 - benzothiadiazine 1,1 - dioxide;
3 - methyl-7 - cyclohexyl-sulfamoyl-1 ,2 - dihydro-1 ,2,4 - benzothiadiazine -
1,1 - dioxide;
3 - methyl-7 - dimethylsulfamoyl-1 ,2 - dihydro-1 ,2,4 - benzothiadiazine -
1,1 - dioxide;
2 - trifluoromethyl-4 - oxo-3 ,4 - dihydro-6 - quinazoline acid;
3 - cyclohexyl-8 - methyl-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine-1 ,1 -
Dioxide;
3 - cyclohexyl-8 - hydroxymethyl-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine -
1,1 - dioxide;
3 - cyclohexyl-8 - (2 - methoxyphenyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzo
Thiadiazine 1,1 - dioxide;
3 - cyclohexyl-8 - (3 - methoxyphenyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzo
Thiadiazine 1,1 - dioxide;
3 - cyclohexyl-8 - (2 - pyridyl) -1,2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclohexyl-8 - methoxy-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine-1 ,1
- Two oxides;
5,7 - dibromo - 1,2 - dihydro-1 ,2,4 - benzothiadiazine-1, 1 - dioxide;
3 - cyclohexyl-2 - methyl-7 - morpholino-sulfonyl-1, 2,3,4 - tetrahydro-1 ,2,4 -
Benzothiadiazin 1,1 - dioxide;
3 - cyclohexyl-4 - methyl-7 - morpholino-sulfonyl-1, 2,3,4 - tetrahydro-1 ,2,4 -
Benzothiadiazin 1,1 - dioxide;
7 - methylsulfonyl group -1,2,3,3 a, 4,5 - hexahydro-benzo [e] pyrrolo [2,1-c] -
1,2,4 - thiadiazine 5,5 - dioxide;
7 - sulfamoyl -1,2,3,3 a, 4,5 - hexahydro-benzo [e] pyrrolo [2,1-c] -1,2,4
- Thiadiazine 5,5 - dioxide;
7 - sulfamoyl -1,2,3,3 a, 4,5 - hexahydro-benzo [e] pyrrolo [2,1-c] -
1,2,4 - thiadiazine 5,5 - dioxide;
7 - cyclohexyl-sulfamoyl -1,2,3,3 a, 4,5 - hexahydro-benzo [e] pyrrolo [2,1-c] -
1,2,4 - thiadiazine 5,5 - dioxide;
7 - dimethylsulfamoyl group -1,2,3,3 a, 4,5 - hexahydro-benzo [e] pyrrolo [2,1-c] -
1,2,4 - thiadiazine 5,5 - dioxide;
7 - methyl-sulfamoyl-1 ,2,3,5 - tetrahydro-benzo [e] pyrrolo [2,1-c] -1,2,4 -
Thiadiazine 5,5 - dioxide;
7 - dimethylsulfamoyl-1 ,2,3,5 - tetrahydro-benzo [e] pyrrolo [2,1-c] -1,2,4
- Thiadiazine 5,5 - dioxide;
7 - cyclohexyl-sulfamoyl-1 ,2,3,5 - tetrahydro-benzo [e] pyrrolo [2,1-c] -1,2,4
- Thiadiazine 5,5 - dioxide;
7 - (1 ', 2', 3 ', 6'-tetrahydro-piperidino) sulfonyl-1 ,2,3,5 - tetrahydro-benzo [e]
Pyrrolo [2,1-c] -1,2,4 - thiadiazine 5,5 - dioxide;
3 - bicyclo [2.2.1] hept-5'-en-2'-yl-5 ,7 - dimethyl-1 ,2,3,4 - tetrahydro-
2,4 - benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl -7 - (N, N-diethyl-sulfamoyl) -5 - methyl-1 ,2,3,4 - Four
,2,4 - Benzothiadiazine 5,5 - dioxide;
3 - bicyclo [2.2.1] hept-5'-en-2'-yl -5,7 - diphenyl-1, 2,3,4 - tetrahydro-
2,4 - benzothiadiazine 1,1 - dioxide;
3 - bicyclo [2.2.1] hept-5'-en-2'-yl -5,7 - diamino-sulfonyl-1 ,2,3,4 -
Tetrahydro-1 ,2,4 - benzothiadiazine-1, 1 - dioxide;
3 - bicyclo [2.2.1] hept-5'-en-2'-yl 5,7 - dichloro-1, 2,3,4 - tetrahydro -
1,2,4 - benzothiadiazine 1,1 - dioxide;
5 - bromo-3 - cyclohexyl-7-sulfamoyl-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
2 - bicyclo [2.2.1] hept-5'-en-2'-yl 6,8 - dibromo-1, 2,3,4 - tetrahydro-quinoline
Oxazoline;
2 - bicyclo [2.2.1] hept-5'-en-2'-yl 6,8 - dibromo - 4 - O-1 ,2,3,4
- Tetrahydro-quinazoline;
3 - bicyclo [2.2.1] hept-5'-en-2'-yl-5 ,7 - dibromo-1, 2,3,4 - tetrahydro -
1,2,4 - benzothiadiazine 1,1 - dioxide;
5,7 - dibromo-3 - bicyclo [2.2.1] hept-2'-yl-1, 2,3,4 - tetrahydro-1 ,2,4 -
Benzothiadiazin 1,1 - dioxide;
3 - cyclohexyl-5 ,7 - dibromo-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine-1 ,1
- Two oxides;
3 - adamantyl 5,7 - dibromo-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine -
1,1 - dioxide;
3 - phenyl-5,7 - dibromo-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine-1 ,1 -
Dioxide;
3 - ethoxy-5 ,7 - dibromo-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine-1 ,1
- Two oxides;
3 - methyl-5,7 - dibromo - 1,2 - dihydro-1 ,2,4 - benzothiadiazine-1, 1 - dioxide
Compounds;
3 - cyclohexyl-6 - methyl-7 - (2'-pyridyl) -1,2,3,4 - tetrahydro-1 ,2,4
- Benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl-6 - methyl-7 - (4'-triazolyl) -1,2,3,4 - tetrahydro-1 ,2,4
- Benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl-6 - methyl-7 - sulfamoyl-1, 2,3,4 - tetrahydro-1 ,2,4 - benzo
Thiadiazine 1,1 - dioxide;
3 - cyclohexyl-6 - methyl-7 - piperidino-sulfonyl-1 ,2,3,4 - tetrahydro-1 ,2,4
- Benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl-6 - methyl -7 - morpholino-sulfonyl-1, 2,3,4 - tetrahydro-1 ,2,4 -
Benzothiadiazin 1,1 - dioxide;
3 - cyclohexyl-6 - (2 - methoxy-phenyl) -7 - methyl-1, 2,3,4 - tetrahydro -
1,2,4 - benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl-6 - methoxy-7 - piperidino-sulfonyl-1 ,2,3,4 - tetrahydro -
1,2,4 - benzothiadiazine 1,1 - dioxide;
3 - cyclohexyl-7 ,8 - ethylenedioxy-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzothiazol
Diazine 1,1 - dioxide;
3 - cyclohexyl-6, 7 - ethylenedioxy-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiazol
Diazine 1,1 - dioxide;
3 - cyclohexyl-6 - chloro-7 - sulfamoyl-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiazol
Diazine 1,1 - dioxide;
3 - phenyl-6 - chloro-7 - sulfamoyl-1, 2,3,4 - tetrahydro-1 ,2,4 - benzothiadiazine
Triazine 1,1 - dioxide;
3 - cyclohexyl-6 - bromo-7 - piperidino-sulfonyl-1 ,2,3,4 - tetrahydro-1 ,2,4 -
Benzothiadiazin 1,1 - dioxide;
2 - cyclohexyl-methylamino-5-N, N-dimethylsulfamoyl-benzenesulfonamide;
2 - ethyl-7 - (1 ', 2', 3 ', 6'-tetrahydro-piperidino) sulfonyl benzene sulfonamide;
3 - iso-butyl-8 - (piperidino-sulfonyl) -2,3,4,5 - tetrahydro-1 ,2,5 - benzo
Thiadiazine 1,1 - dioxide;
3 - cyclohexyl-7 - cyclopentyl-sulfinyl-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzothiazol
Diazine 1,1 - dioxide; or
3 - cyclohexyl-7 - cyclopentyl-sulfinyl-1 ,2,3,4 - tetrahydro-1 ,2,4 - benzothiazol
Diazine 1,1 - dioxide;
Or a pharmaceutically acceptable salt thereof.
...
24. pharmaceutical composition contains the compound or pharmaceutically acceptable salt thereof of one of the claim 1-23 of significant quantity and pharmaceutically acceptable vehicle, carrier or thinner.
25. the compound of formula I representative is used to prepare the purposes of the medicine of disease that the life animal is arranged that treatment comprises the people or symptom,
Wherein the key represented of dotted line can be a singly-bound, two keys or do not have key; If there is not key, then this nitrogen is by hydrogen and R
2Replace;
X represents SO
2Or C=O or CH
2
Y representative-CH (R
4)-,-N (R
4)-or-N (R
4)-CH
2-, O;
R
2Represent hydrogen, alkyl, cycloalkyl, aryl, benzyl; CO-R
9, R wherein
9Represent alkyl, cycloalkyl, benzyl, aryl; Or
R
2With R
3And their continuous atom formation 4-7 person rings, this ring is replaced by one or more following substituting groups arbitrarily: halogen, and alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, and contain one or more heteroatomss arbitrarily, reach and contain carbonyl arbitrarily;
R
3Represent hydrogen, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyano group alkyl, alkoxyalkyl, alkoxyl group, halogenated alkoxy, acyl group, alkyl-NR
13R
14, alkyl-S-R
13, R wherein
13And R
14Represent hydrogen respectively, alkyl, cycloalkyl; Or R
13And R
14The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle; Arbitrarily by halogen, alkyl, 7-12 person's carbocyclic ring that hydroxyl or alkoxyl group replace; Arbitrarily by halogen, alkyl, the 3-8 element heterocycle that hydroxyl or alkoxyl group replace; This heterocycle is arbitrarily with aryl-condensed; Arbitrarily by the benzyl of one or more following substituting groups replacements: halogen, cycloalkyl, alkyl, hydroxyl, alkoxyl group, amino or sulfenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino; Arbitrarily by the aryl of one or more following substituting groups replacements: halogen, cycloalkyl, alkyl, hydroxyl, alkoxyl group, amino or sulfenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino; Or
R
3With R
2Or R
4And their continuous atom formation 4-7 person rings, this ring is replaced by one or more following substituting groups arbitrarily: halogen, and alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, and contain one or more heteroatomss arbitrarily, reach and contain carbonyl arbitrarily;
R
4Represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl ,-CO-R
10Or CO
2R
10, R wherein
10Represent hydrogen, cycloalkyl, alkyl, aryl or benzyl; Or
R
4With R
3And their continuous atom formation 4-7 person rings, this ring is replaced by one or more following substituting groups arbitrarily: halogen, and alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, and contain one or more heteroatomss arbitrarily, reach and contain carbonyl arbitrarily;
R
5Represent hydrogen, halogen, alkyl, thiazolinyl, alkynyl, aryl ,-SO
2-NR
11R
12, R wherein
11And R
12Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
11And R
12The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed;
R
6Represent hydrogen, halogen, alkyl, cyano group, cyano group alkyl, nitro, alkoxyl group, halogenated alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, ring haloalkyl;-NR
15R
16,-NHSO
2-R
15,-NHSO
2-aryl, wherein aryl is replaced by one or more following substituting groups arbitrarily: halogen, alkyl, cycloalkyl, hydroxyl, alkoxyl group, amino, sulfenyl, CF
3, OCF
3, NO
2Or aryl; Arbitrarily by the aryl of one or more following substituting groups replacements: alkyl, cycloalkyl, alkoxyl group, haloalkyl, halogenated alkoxy, hydroxyalkyl, alkoxyalkyl or amino; Arbitrarily by the HET of one or more following substituting groups replacements: alkyl, cycloalkyl, alkoxyl group, halogen, haloalkyl or halogenated alkoxy;-(alkyl)
m-S-R
15,-(alkyl)
m-SO-R
15,-(alkyl)
m-SO
2-R
15,-(alkyl)
m-SO
2O-R
15,-(alkyl)
m-SO
2-NR
15R
16,-(alkyl)
m-NHCOR
15,-(alkyl)
m-CONR
15R
16,-(alkyl)
m-CR '=NOR " ,-(alkyl)
m-CO-R
15,-(alkyl)
m-CO
2-R
15, wherein m is 0 or 1; And R ' and R " represent hydrogen, alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, benzyl respectively; And R
15And R
16Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
15And R
16The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed;
R
7Represent hydrogen, halogen, alkyl, cyano group, cyano group alkyl, nitro, 4-nitro alkyl, alkoxyl group, halogenated alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, ring haloalkyl;-NR
17R
18,-NHSO
2-R
17,-NHSO
2-aryl, wherein aryl is replaced by one or more following substituting groups arbitrarily: halogen, alkyl, cycloalkyl, hydroxyl, alkoxyl group, amino, sulfenyl, CF
3, OCF
3, NO
2Or aryl;-(alkyl)
m-S-R
17,-(alkyl)
m-SO-R
17,-(alkyl)
m-SO
2-R
17,-(alkyl)
m-SO
2O-R
17,-(alkyl)
m-SO
2-NR
17R
18,-(alkyl)
m-NHCOR
17,-(alkyl)
m-CONR
17R
18,-(alkyl)
m-CR '=NOR " ,-(alkyl)
m-CO-R
17,-(alkyl)
m-CO
2-
R
17, wherein m is 0 or 1; And R ' and R " represent hydrogen, alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, benzyl respectively; And R
17And R
18Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
17And R
18The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed; Arbitrarily by the HET of one or more following substituting groups replacements: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, alkoxyl group, amino, sulfenyl, aryl ,-S-alkyl ,-S-aryl, SO-alkyl, SO-aryl, SO
2-alkyl, SO
2-aryl, SO
2NR
17R
18Arbitrarily by the aryl of one or more following substituting groups replacements: alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, hydroxyalkyl, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF
3,-SO
2NR
17R
18, R wherein
17And R
18Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
17And R
18The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed; Or
R
7With R
6Or R
8Form 5-7 person's ring that one of following array structure is arranged together :-O-(CH
2)
n-O-, wherein n is 1,2 or 3;-SO
2-NR-(CH
2)
n-, wherein n is 1 or 2;-SO-NR-(CH
2)
n-, wherein n is 1 or 2;-SO
2-(CH
2)
n-, wherein n is 2 or 3;-SO-(CH
2)
n-, wherein n is 2 or 3;-CO-CH=CH-NH-;-CO-CH=CH-O-;-CO-(CH
2)
n-NH-, wherein n is 1 or 2;-CO-NH-(CH
2)
n-, wherein n is 1 or 2;-CO-(CH
2)
2-O-;-O-(CH
2)
n-O-, wherein n is 1,2 or 3;
R
8Represent hydrogen, alkyl, alkoxyl group, hydroxyalkyl, halogen, haloalkyl, CN, cyano group alkyl, nitro, 4-nitro alkyl; Arbitrarily by the aryl of one or more following substituting groups replacements: halogen, CF
3, OCF
3, NO
2, alkyl, cycloalkyl, alkoxyl group; Arbitrarily by the HET of one or more following substituting groups replacements: halogen, CF
3, OCF
3, NO
2, alkyl, cycloalkyl, alkoxyl group;-(alkyl)
m-S-R
19,-(alkyl)
m-SO-R
19,-(alkyl)
m-SO
2-R
19,-(alkyl)
m-SO
2O-R
19,-(alkyl)
m-SO
2-NR
19R
20,-(alkyl)
m-NHCOR
19,-(alkyl)
m-CONR
19R
20,-(alkyl)
m-CR '=NOR " ,-(alkyl)
m-CO-R
19,-(alkyl)
m-CO
2-
R
19, wherein m is 0 or 1; And R ' and R " represent hydrogen, alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, benzyl respectively; And R
19And R
20Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
19And R
20The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is any and aryl-condensed,
Said illness or disease are to the adjusting sensitivity of ampa receptor complex compound in the central nervous system.
26. according to the purposes of claim 25, comprise using comprising the illness on the person or the medicine of disease that said illness or disease are to the adjusting sensitivity of ampa receptor complex compound in the central nervous system according to the compound of claim 1-23 treatment Live Animals.
27. purposes according to one of claim 25-26, wherein said illness or disease are selected from the disease of memory and study aspect, psychosis, sexual disorder, knowledge weakens disease, schizophrenia, dysthymia disorders or autism, alzheimer's disease, the learning capacity defective, attention deficit, memory loss or senile dementia, or by wound, apoplexy, epilepsy, alzheimer's disease, neuropoison, age, neural distortion is sick, alcoholism, drug abuse, illness or disease that heart bypass operation or cerebral ischemia cause.
28. the treatment Live Animals comprises the illness on the person or the method for disease, said illness or disease be to the adjusting sensitivity of ampa receptor complex compound in the central nervous system, and this method comprises that the compound of formula I representative that will the treatment significant quantity carries out administration,
Wherein the key represented of dotted line can be a singly-bound, two keys or do not have key; If there is not key, then this nitrogen is by hydrogen and R
2Replace;
X represents SO
2Or C=O or CH
2
Y representative-CH (R
4)-,-N (R
4)-or-N (R
4)-CH
2-, O;
R
2Represent hydrogen, alkyl, cycloalkyl, aryl, benzyl; CO-R
9, R wherein
9Represent alkyl, cycloalkyl, benzyl, aryl; Or
R
2With R
3And their continuous atom formation 4-7 person rings, this ring is replaced by one or more following substituting groups arbitrarily: halogen, and alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, and contain one or more heteroatomss arbitrarily, reach and contain carbonyl arbitrarily;
R
3Represent hydrogen, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyano group alkyl, alkoxyalkyl, alkoxyl group, halogenated alkoxy, acyl group, alkyl-NR
13R
14, alkyl-S-R
13, R wherein
13And R
14Represent hydrogen respectively, alkyl, cycloalkyl; Or R
13And R
14The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle; Arbitrarily by halogen, alkyl, 7-12 person's carbocyclic ring that hydroxyl or alkoxyl group replace; Arbitrarily by halogen, alkyl, the 3-8 element heterocycle that hydroxyl or alkoxyl group replace; This heterocycle is arbitrarily with aryl-condensed; Arbitrarily by the benzyl of one or more following substituting groups replacements: halogen, cycloalkyl, alkyl, hydroxyl, alkoxyl group, amino or sulfenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino; Arbitrarily by the aryl of one or more following substituting groups replacements: halogen, cycloalkyl, alkyl, hydroxyl, alkoxyl group, amino or sulfenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino; Or
R
3With R
2Or R
4And their continuous atom formation 4-7 person rings, this ring is replaced by one or more following substituting groups arbitrarily: halogen, and alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, and contain one or more heteroatomss arbitrarily, reach and contain carbonyl arbitrarily;
R
4Represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl ,-CO-R
10Or CO
2R
10, R wherein
10Represent hydrogen, cycloalkyl, alkyl, aryl or benzyl; Or
R
4With R
3And their continuous atom formation 4-7 person rings, this ring is replaced by one or more following substituting groups arbitrarily: halogen, and alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, and contain one or more heteroatomss arbitrarily, reach and contain carbonyl arbitrarily;
R
5Represent hydrogen, halogen, alkyl, thiazolinyl, alkynyl, aryl ,-SO
2-NR
11R
12, R wherein
11And R
12Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
11And R
12The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed;
R
6Represent hydrogen, halogen, alkyl, cyano group, cyano group alkyl, nitro, alkoxyl group, halogenated alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, ring haloalkyl;-NR
15R
16,-NHSO
2-R
15,-NHSO
2-aryl, wherein aryl is replaced by one or more following substituting groups arbitrarily: halogen, alkyl, cycloalkyl, hydroxyl, alkoxyl group, amino, sulfenyl, CF
3, OCF
3, NO
2Or aryl; Arbitrarily by the aryl of one or more following substituting groups replacements: alkyl, cycloalkyl, alkoxyl group, haloalkyl, halogenated alkoxy, hydroxyalkyl, alkoxyalkyl or amino; Arbitrarily by the HET of one or more following substituting groups replacements: alkyl, cycloalkyl, alkoxyl group, halogen, haloalkyl or halogenated alkoxy;-(alkyl)
m-S-R
15,-(alkyl)
m-SO-R
15,-(alkyl)
m-SO
2-R
15,-(alkyl)
m-SO
2O-R
15,-(alkyl)
m-SO
2-NR
15R
16,-(alkyl)
m-NHCOR
15,-(alkyl)
m-CONR
15R
16,-(alkyl)
m-CR '=NOR " ,-(alkyl)
m-CO-R
15,-(alkyl)
m-CO
2-
R
15, wherein m is 0 or 1; And R ' and R " represent hydrogen, alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, benzyl respectively; And R
15And R
16Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
15And R
16The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed;
R
7Represent hydrogen, halogen, alkyl, cyano group, cyano group alkyl, nitro, 4-nitro alkyl, alkoxyl group, halogenated alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, ring haloalkyl;-NR
17R
18,-NHSO
2-R
17,-NHSO
2-aryl, wherein aryl is replaced by one or more following substituting groups arbitrarily: halogen, alkyl, cycloalkyl, hydroxyl, alkoxyl group, amino, sulfenyl, CF
3, OCF
3, NO
2Or aryl;-(alkyl)
m-S-R
17,-(alkyl)
m-SO-R
17,-(alkyl)
m-SO
2-R
17,-(alkyl)
m-SO
2O-R
17,-(alkyl)
m-SO
2-NR
17R
18,-(alkyl)
m-NHCOR
17,-(alkyl)
m-CONR
17R
18,-(alkyl)
m-CR '=NOR " ,-(alkyl)
m-CO-R
17,-(alkyl)
m-CO
2-
R
17, wherein m is 0 or 1; And R ' and R " represent hydrogen, alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, benzyl respectively; And R
17And R
18Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
17And R
18The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed; Arbitrarily by the HET of one or more following substituting groups replacements: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, alkoxyl group, amino, sulfenyl, aryl ,-S-alkyl ,-S-aryl, SO-alkyl, SO-aryl, SO
2-alkyl, SO
2-aryl, SO
2NR
17R
18Arbitrarily by the aryl of one or more following substituting groups replacements: alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, hydroxyalkyl, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF
3,-SO
2NR
17R
18, R wherein
17And R
18Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
17And R
18The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed; Or
R
7With R
6Or R
8Form 5-7 person's ring that one of following array structure is arranged together :-O-(CH
2)
n-O-, wherein n is 1,2 or 3;-SO
2-NR-(CH
2)
n-, wherein n is 1 or 2;-SO-NR-(CH
2)
n-, wherein n is 1 or 2;-SO
2-(CH
2)
n-, wherein n is 2 or 3;-SO-(CH
2)
n-, wherein n is 2 or 3;-CO-CH=CH-NH-;-CO-CH=CH-O-;-CO-(CH
2)
n-NH-, wherein n is 1 or 2;-CO-NH-(CH
2)
n-, wherein n is 1 or 2;-CO-(CH
2)
2-O-;-O-(CH
2)
n-O-, wherein n is 1,2 or 3;
R
8Represent hydrogen, alkyl, alkoxyl group, hydroxyalkyl, halogen, haloalkyl, CN, cyano group alkyl, nitro, 4-nitro alkyl; Arbitrarily by the aryl of one or more following substituting groups replacements: halogen, CF
3, OCF
3, NO
2, alkyl, cycloalkyl, alkoxyl group; Arbitrarily by the HET of one or more following substituting groups replacements: halogen, CF
3, OCF
3, NO
2, alkyl, cycloalkyl, alkoxyl group;-(alkyl)
m-S-R
19,-(alkyl)
m-SO-R
19,-(alkyl)
m-SO
2-R
19,-(alkyl)
m-SO
2O-R
19,-(alkyl)
m-SO
2-NR
19R
20,-(alkyl)
m-NHCOR
19,-(alkyl)
m-CONR
19R
20,-(alkyl)
m-CR '=NOR " ,-(alkyl)
m-CO-R
19,-(alkyl)
m-CO
2-
R
19, wherein m is 0 or 1; And R ' and R " represent hydrogen, alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, benzyl respectively; And R
19And R
20Represent hydrogen respectively, alkyl, cycloalkyl, benzyl, aryl; Or R
19And R
20The nitrogen-atoms that links to each other with them forms the 3-8 element heterocycle, and this heterocycle is replaced by following substituting group arbitrarily: halogen, alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl group, amino or sulfenyl, aryl, benzyl, SO
2-alkyl, SO
2-aryl, SO
2-benzyl; And this heterocycle is arbitrarily with aryl-condensed.
29. comprise the illness on the person or the method for disease according to the treatment Live Animals of claim 28, said illness or disease are to the adjusting sensitivity of ampa receptor complex compound in the central nervous system, and this method comprises that the compound according to one of claim 1-23 with the treatment significant quantity carries out administration.
30. method according to one of claim 28-29, wherein said illness or disease are selected from the disease of memory and study aspect, psychosis, sexual disorder, knowledge weakens disease, schizophrenia, dysthymia disorders or autism, alzheimer's disease, the learning capacity defective, attention deficit, memory loss or senile dementia, or by wound, apoplexy, epilepsy, alzheimer's disease, neuropoison, age, neural distortion is sick, alcoholism, drug abuse, illness or disease that heart bypass operation or cerebral ischemia cause.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK22698 | 1998-02-18 | ||
| DK0226/98 | 1998-02-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1293665A true CN1293665A (en) | 2001-05-02 |
Family
ID=8091151
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99804196A Pending CN1293665A (en) | 1998-02-18 | 1999-02-18 | New compounds and their use as positive AMPA receptor modulators |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP1071426A2 (en) |
| JP (1) | JP2002504481A (en) |
| CN (1) | CN1293665A (en) |
| AU (1) | AU751384B2 (en) |
| CA (1) | CA2320354A1 (en) |
| EE (1) | EE200000468A (en) |
| HU (1) | HUP0101280A3 (en) |
| IL (1) | IL137720A0 (en) |
| IS (1) | IS5581A (en) |
| NO (1) | NO20004121L (en) |
| NZ (1) | NZ506251A (en) |
| PL (1) | PL342843A1 (en) |
| RU (1) | RU2214405C2 (en) |
| SK (1) | SK11892000A3 (en) |
| TR (1) | TR200002427T2 (en) |
| WO (1) | WO1999042456A2 (en) |
| ZA (1) | ZA991301B (en) |
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1999
- 1999-02-18 ZA ZA9901301A patent/ZA991301B/en unknown
- 1999-02-18 SK SK1189-2000A patent/SK11892000A3/en unknown
- 1999-02-18 IL IL13772099A patent/IL137720A0/en unknown
- 1999-02-18 HU HU0101280A patent/HUP0101280A3/en unknown
- 1999-02-18 EE EEP200000468A patent/EE200000468A/en unknown
- 1999-02-18 RU RU2000121882/04A patent/RU2214405C2/en not_active IP Right Cessation
- 1999-02-18 EP EP99904730A patent/EP1071426A2/en not_active Withdrawn
- 1999-02-18 WO PCT/DK1999/000070 patent/WO1999042456A2/en not_active Application Discontinuation
- 1999-02-18 AU AU25123/99A patent/AU751384B2/en not_active Ceased
- 1999-02-18 NZ NZ506251A patent/NZ506251A/en unknown
- 1999-02-18 JP JP2000532408A patent/JP2002504481A/en not_active Withdrawn
- 1999-02-18 CN CN99804196A patent/CN1293665A/en active Pending
- 1999-02-18 PL PL99342843A patent/PL342843A1/en unknown
- 1999-02-18 CA CA002320354A patent/CA2320354A1/en not_active Abandoned
- 1999-02-18 TR TR2000/02427T patent/TR200002427T2/en unknown
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| CN102361860A (en) * | 2009-03-20 | 2012-02-22 | 瑟维尔实验室 | Benzothiadiazepine derivatives used as AMPA and NMDA receptor modulators |
| CN102361860B (en) * | 2009-03-20 | 2014-09-10 | 瑟维尔实验室 | Benzothiadiazepine derivatives used as AMPA and NMDA receptor modulators |
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| CN103153973A (en) * | 2010-09-16 | 2013-06-12 | 瑟维尔实验室 | Dihydrobenzoxathiazepine derivatives, preparation thereof, pharmaceutical compositions and use as AMPA receptor modulators |
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Also Published As
| Publication number | Publication date |
|---|---|
| CA2320354A1 (en) | 1999-08-26 |
| HUP0101280A3 (en) | 2003-02-28 |
| TR200002427T2 (en) | 2001-01-22 |
| EE200000468A (en) | 2002-04-15 |
| NO20004121D0 (en) | 2000-08-17 |
| IL137720A0 (en) | 2001-10-31 |
| RU2214405C2 (en) | 2003-10-20 |
| AU2512399A (en) | 1999-09-06 |
| IS5581A (en) | 2000-08-04 |
| SK11892000A3 (en) | 2001-02-12 |
| EP1071426A2 (en) | 2001-01-31 |
| HUP0101280A2 (en) | 2001-10-28 |
| PL342843A1 (en) | 2001-07-16 |
| NO20004121L (en) | 2000-10-17 |
| NZ506251A (en) | 2003-01-31 |
| ZA991301B (en) | 1999-09-13 |
| JP2002504481A (en) | 2002-02-12 |
| WO1999042456A3 (en) | 1999-10-07 |
| AU751384B2 (en) | 2002-08-15 |
| WO1999042456A2 (en) | 1999-08-26 |
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