DK156474B - S-(carbamoylphenylselenyl)-derivater af mercaptaner, fremgangsmaade til fremstilling deraf samt farmaceutiske praeparater indeholdende samme - Google Patents
S-(carbamoylphenylselenyl)-derivater af mercaptaner, fremgangsmaade til fremstilling deraf samt farmaceutiske praeparater indeholdende samme Download PDFInfo
- Publication number
- DK156474B DK156474B DK552985A DK552985A DK156474B DK 156474 B DK156474 B DK 156474B DK 552985 A DK552985 A DK 552985A DK 552985 A DK552985 A DK 552985A DK 156474 B DK156474 B DK 156474B
- Authority
- DK
- Denmark
- Prior art keywords
- phenylselenyl
- carboxy
- hydroxy
- methoxy
- formula
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 9
- 239000000825 pharmaceutical preparation Substances 0.000 title description 2
- 238000004519 manufacturing process Methods 0.000 title 1
- 230000008569 process Effects 0.000 claims abstract description 3
- -1 carbamoyl-phenylselenyl Chemical group 0.000 claims description 68
- 150000001875 compounds Chemical class 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 9
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical class S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 230000032050 esterification Effects 0.000 claims description 4
- 238000005886 esterification reaction Methods 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 229910017604 nitric acid Inorganic materials 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 150000002926 oxygen Chemical class 0.000 abstract description 6
- 201000010099 disease Diseases 0.000 abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 4
- 230000005779 cell damage Effects 0.000 abstract description 3
- 208000037887 cell injury Diseases 0.000 abstract description 3
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 24
- 239000002253 acid Substances 0.000 description 18
- 239000000047 product Substances 0.000 description 14
- 229960003180 glutathione Drugs 0.000 description 12
- DYEFUKCXAQOFHX-UHFFFAOYSA-N Ebselen Chemical compound [se]1C2=CC=CC=C2C(=O)N1C1=CC=CC=C1 DYEFUKCXAQOFHX-UHFFFAOYSA-N 0.000 description 8
- 108010024636 Glutathione Proteins 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 7
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 7
- 102000006587 Glutathione peroxidase Human genes 0.000 description 6
- 108700016172 Glutathione peroxidases Proteins 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- NMHUEKTZORYKHX-UHFFFAOYSA-N 1$l^{4},2-benzoselenazole 1-oxide Chemical compound C1=CC=C2[Se](=O)N=CC2=C1 NMHUEKTZORYKHX-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 208000010125 myocardial infarction Diseases 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 229960004402 tiopronin Drugs 0.000 description 3
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 2
- NAOYSRBUEYWQNL-UHFFFAOYSA-N 2-benzyl-1,2-benzoselenazol-3-one Chemical compound [se]1C2=CC=CC=C2C(=O)N1CC1=CC=CC=C1 NAOYSRBUEYWQNL-UHFFFAOYSA-N 0.000 description 2
- PMNLUUOXGOOLSP-UHFFFAOYSA-N 2-mercaptopropanoic acid Chemical compound CC(S)C(O)=O PMNLUUOXGOOLSP-UHFFFAOYSA-N 0.000 description 2
- DKIDEFUBRARXTE-UHFFFAOYSA-N 3-mercaptopropanoic acid Chemical compound OC(=O)CCS DKIDEFUBRARXTE-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 108010053070 Glutathione Disulfide Proteins 0.000 description 2
- 206010067125 Liver injury Diseases 0.000 description 2
- 102000003992 Peroxidases Human genes 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 2
- 241000270295 Serpentes Species 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- PVBRSNZAOAJRKO-UHFFFAOYSA-N ethyl 2-sulfanylacetate Chemical compound CCOC(=O)CS PVBRSNZAOAJRKO-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- YPZRWBKMTBYPTK-BJDJZHNGSA-N glutathione disulfide Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@H](C(=O)NCC(O)=O)CSSC[C@@H](C(=O)NCC(O)=O)NC(=O)CC[C@H](N)C(O)=O YPZRWBKMTBYPTK-BJDJZHNGSA-N 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N methyl acetate Chemical compound COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- OQHJUHPKQKAVRN-UHFFFAOYSA-N n-(4-nitrophenyl)-2-phenylsulfanylselanylbenzamide Chemical compound C1=CC([N+](=O)[O-])=CC=C1NC(=O)C1=CC=CC=C1[Se]SC1=CC=CC=C1 OQHJUHPKQKAVRN-UHFFFAOYSA-N 0.000 description 2
- 230000036542 oxidative stress Effects 0.000 description 2
- 108040007629 peroxidase activity proteins Proteins 0.000 description 2
- 150000002978 peroxides Chemical class 0.000 description 2
- WHMDPDGBKYUEMW-UHFFFAOYSA-N pyridine-2-thiol Chemical compound SC1=CC=CC=N1 WHMDPDGBKYUEMW-UHFFFAOYSA-N 0.000 description 2
- 229910052711 selenium Inorganic materials 0.000 description 2
- 239000011669 selenium Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- GLGIHGJHHSONCV-UHFFFAOYSA-N 1-sulfanylpropane-1,2-diol Chemical compound CC(O)C(O)S GLGIHGJHHSONCV-UHFFFAOYSA-N 0.000 description 1
- JTJRNFGGGCLXSL-UHFFFAOYSA-N 2-(3-fluorophenyl)-1,2-benzoselenazol-3-one Chemical compound FC1=CC=CC(N2C(C3=CC=CC=C3[se]2)=O)=C1 JTJRNFGGGCLXSL-UHFFFAOYSA-N 0.000 description 1
- FSCGLKWYHHSLST-UHFFFAOYSA-N 2-(3-sulfanylpropanoylamino)acetic acid Chemical compound OC(=O)CNC(=O)CCS FSCGLKWYHHSLST-UHFFFAOYSA-N 0.000 description 1
- JWLXOHUMYJGZPC-UHFFFAOYSA-N 2-(4-nitrophenyl)-1,2-benzoselenazol-3-one Chemical compound C1=CC([N+](=O)[O-])=CC=C1N1C(=O)C2=CC=CC=C2[se]1 JWLXOHUMYJGZPC-UHFFFAOYSA-N 0.000 description 1
- PZLYGWBNSSZPDC-UHFFFAOYSA-N 2-[2-(phenylcarbamoyl)phenyl]selanylsulfanyloxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1OS[Se]C1=CC=CC=C1C(=O)NC1=CC=CC=C1 PZLYGWBNSSZPDC-UHFFFAOYSA-N 0.000 description 1
- CLKJBNAGQKQOAV-UHFFFAOYSA-N 2-hydroxy-1,2-benzoselenazol-3-one Chemical compound C1=CC=CC2=C1[se]N(O)C2=O CLKJBNAGQKQOAV-UHFFFAOYSA-N 0.000 description 1
- YOJJTXUAVALXQC-UHFFFAOYSA-N 2-sulfanyloxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1OS YOJJTXUAVALXQC-UHFFFAOYSA-N 0.000 description 1
- KIUMMUBSPKGMOY-UHFFFAOYSA-N 3,3'-Dithiobis(6-nitrobenzoic acid) Chemical compound C1=C([N+]([O-])=O)C(C(=O)O)=CC(SSC=2C=C(C(=CC=2)[N+]([O-])=O)C(O)=O)=C1 KIUMMUBSPKGMOY-UHFFFAOYSA-N 0.000 description 1
- MBXKCLHOVPXMCJ-UHFFFAOYSA-N 3-(mercaptomethylene)pyridine Chemical compound SCC1=CC=CN=C1 MBXKCLHOVPXMCJ-UHFFFAOYSA-N 0.000 description 1
- IOIYSDYSHYMTEP-UHFFFAOYSA-N 3-[2-methoxy-6-(phenylcarbamoyl)phenyl]selanylsulfanylpropanoic acid Chemical compound COC1=CC=CC(C(=O)NC=2C=CC=CC=2)=C1[Se]SCCC(O)=O IOIYSDYSHYMTEP-UHFFFAOYSA-N 0.000 description 1
- DFJATHACFJXJCK-UHFFFAOYSA-N 5-chloro-2-phenyl-1,2-benzoselenazol-3-one Chemical compound O=C1C2=CC(Cl)=CC=C2[se]N1C1=CC=CC=C1 DFJATHACFJXJCK-UHFFFAOYSA-N 0.000 description 1
- VYFOBZAIPIKAPR-UHFFFAOYSA-N 7-methoxy-2-phenyl-1,2-benzoselenazol-3-one Chemical compound COC1=CC=CC(C2=O)=C1[se]N2C1=CC=CC=C1 VYFOBZAIPIKAPR-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 102000016938 Catalase Human genes 0.000 description 1
- 108010053835 Catalase Proteins 0.000 description 1
- 108010001103 Glutathione oxidase Proteins 0.000 description 1
- VHJLVAABSRFDPM-IMJSIDKUSA-N L-1,4-dithiothreitol Chemical compound SC[C@H](O)[C@@H](O)CS VHJLVAABSRFDPM-IMJSIDKUSA-N 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 102000019197 Superoxide Dismutase Human genes 0.000 description 1
- 108010012715 Superoxide dismutase Proteins 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- OWBTYPJTUOEWEK-UHFFFAOYSA-N butane-2,3-diol Chemical compound CC(O)C(C)O OWBTYPJTUOEWEK-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- RFYISOIABSSLPE-UHFFFAOYSA-N ethyl 2-[2-(phenylcarbamoyl)phenyl]selanylsulfanylacetate Chemical compound CCOC(=O)CS[Se]C1=CC=CC=C1C(=O)NC1=CC=CC=C1 RFYISOIABSSLPE-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- ZONYXWQDUYMKFB-UHFFFAOYSA-N flavanone Chemical compound O1C2=CC=CC=C2C(=O)CC1C1=CC=CC=C1 ZONYXWQDUYMKFB-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- 150000002432 hydroperoxides Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000005865 ionizing radiation Effects 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- MKIJJIMOAABWGF-UHFFFAOYSA-N methyl 2-sulfanylacetate Chemical compound COC(=O)CS MKIJJIMOAABWGF-UHFFFAOYSA-N 0.000 description 1
- BAQGCWNPCFABAY-UHFFFAOYSA-N methyl 2-sulfanylbenzoate Chemical compound COC(=O)C1=CC=CC=C1S BAQGCWNPCFABAY-UHFFFAOYSA-N 0.000 description 1
- FJCNFYHJTAITQQ-UHFFFAOYSA-N methyl 2-sulfanyloxybenzoate Chemical compound COC(=O)C1=CC=CC=C1OS FJCNFYHJTAITQQ-UHFFFAOYSA-N 0.000 description 1
- SNWKNPMDQONHKK-UHFFFAOYSA-N methyl 2-sulfanylpropanoate Chemical compound COC(=O)C(C)S SNWKNPMDQONHKK-UHFFFAOYSA-N 0.000 description 1
- LDTLDBDUBGAEDT-UHFFFAOYSA-N methyl 3-sulfanylpropanoate Chemical compound COC(=O)CCS LDTLDBDUBGAEDT-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- PXIGQUDUOVAAHM-UHFFFAOYSA-N n-phenyl-2-phenylsulfanylselanylbenzamide Chemical compound C=1C=CC=C([Se]SC=2C=CC=CC=2)C=1C(=O)NC1=CC=CC=C1 PXIGQUDUOVAAHM-UHFFFAOYSA-N 0.000 description 1
- ZCLMZKJELLTLFH-UHFFFAOYSA-N n-phenyl-2-pyridin-2-ylsulfanylselanylbenzamide Chemical compound C=1C=CC=C([Se]SC=2N=CC=CC=2)C=1C(=O)NC1=CC=CC=C1 ZCLMZKJELLTLFH-UHFFFAOYSA-N 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 238000005502 peroxidation Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- NBOMNTLFRHMDEZ-UHFFFAOYSA-N thiosalicylic acid Chemical compound OC(=O)C1=CC=CC=C1S NBOMNTLFRHMDEZ-UHFFFAOYSA-N 0.000 description 1
- 229940103494 thiosalicylic acid Drugs 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- FXSGDOZPBLGOIN-UHFFFAOYSA-N trihydroxy(methoxy)silane Chemical compound CO[Si](O)(O)O FXSGDOZPBLGOIN-UHFFFAOYSA-N 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C391/00—Compounds containing selenium
- C07C391/02—Compounds containing selenium having selenium atoms bound to carbon atoms of six-membered aromatic rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Heart & Thoracic Surgery (AREA)
- Gastroenterology & Hepatology (AREA)
- Cardiology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Saccharide Compounds (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
DK 156474 B
Den foreliggende opfindelse angâr hidtil ukendte S-(carbamoyl-phenylselenyl)-derivater af alifatiske og aromatiske mercaptaner, der udmærker sig ved værdifulde farmakologiske egenskaber, en fremgangsmâde tî1 fremstilling deraf og anvendelsen af derivaterne $om aktive i 5 lægemidler. De kan specielt anvendes til behandling af sygdomme, der er fremkaldt af en cellebeskadigelse pâ grund af forpget dannelse af aktive oxygenmetabolitter, som f.eks. leverskader, hjerteinfarkt, betændelser, strâleskader.
Forbindelserne ifplge opfindelsen har den almene formel (I) 10 R1 0 .—^ R4 15 hvor R1,R2, R3 og R4 er ens eller forskellige og uafhængigt af hinanden betegner hydrogen, halogen, Cj^-alkyl, Cj^-alkoxy, trifluormethyl, nitro, cyano, hydroxy, carboxy, C^-alkoxycarbonyl, carboxy-Cj_^-al kyl, Cj_2~a^oxycarbonyl-C1 ^alkyl, og 20 A betegner en uforgrenet eller forgrenet C^alkylgruppe, som kan indeholde 1-3 substituenter udvalgt blandt carboxy, hydroxy, mercapto, carboxyalkylcarbamoyl, hvorhos forestring af den funktionelt modificer-bare carboxylgruppe med en Cj^-alkohol er mulig, eller betegner en phenyl-, carboxyphenyl-, alkoxycarbonylphenyl-, pyridyl- eller pyridyl-25 alkylgruppe og n er nul eller 1.
Halogen omfatter fluor, chlor og brom. Som alkylgrupper med 1-4 carbonatomer kan nævnes methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec.butyl og tert, butyl, og som alkoxygrupper med 1-3 carbon-30 atomer kommer methoxy, ethoxy og propoxy i betragtning.
Foretrukne forbindelser er sâdanne, hvor R1, R2, R3 og R4 er ens eller forskellige og uafhængigt af hinanden betegner hydrogen, fluor, chlor, methyl, methoxy, hydroxy, trifluormethyl, cyano, carboxy, Cj^-alkoxycarbonyl, carboxy-Cj ^-alkyl, Cj ^-alkoxycarbonyl-Cj ^-alkyl 35 eller nitro. Specielt foretrukne er forbindelser, hvor R1 og R2 er ens eller forskellige og uafhængigt af hinanden betegner hydrogen, fluor, chlor, methyl, methoxy, hydroxy, trifluormethyl eller nitro, mens R3 og R4 star for hydrogen, methoxy eller hydroxy.
2
DK 156474 B
A svarer til resten af mercaptoforbindelsen, sotn anvendes ved frem-stillingen af forbindelsen ifplge opfindelsen, f.rks. ethylmercaptan, mercaptoeddi kesyre, 2-mercaptopropi onsyre, 3-mercaptopropionsyre, mercaptoeddikesyremethylester, mercaptoeddikesyreethylester, 2-mercapto-5 propionsyremethylester, 3-mercaptopropionsyremethylester, 2-mercaptopropi onylglycin, 2-mercaptopropi onylglycinethylester, mercaptoravsyre, 3-mercapto-l,2-propandiol, threo-l,4-dimercapto-2,3-butandiol, thio-phenol, thiosalicylsyre, thiosaiicylsyremethylester, 2-mercaptopyridin, 3-mercaptomethylpyridi n.
10 Forbindelser med formlen (I), der besidder et kiralitetscentrum, kan ait efter arten af de anvendte udgangsforbindelser foreligge som racemater eller i form af D- eller L-enantiomerer. Hvis en adskillelse af racemater i optisk aktive isomerer pnskes, kan denne hensigtsmæssigt udfpres pâ i og for sig kendt mâde med egnede optisk aktive baser ved 15 dannelse af diastereomere salte eller gennem chromatografi pâ optisk aktivt sojlemateriale.
Forbindelser ifplge opfindelsen er f.eks.: S-(2-phenylcarbamoyl-phenylselenyl)-ethylmercaptan S-[2-(2-fluorphenylcarbamoyl)-phenylselenyl]-ethylmercaptan 20 S-(2-phenylcarbamoyl-phenylselenyl)-mercaptoeddikesyreethylester S-(2-phenylcarbamoyl-phenylselenyl)-3-mercaptopropionsyre S-(2-phenylcarbamoyl-6-methoxy-phenylselenyl)-3-mercaptopropi onsyre S-(2-phenylcarbamoyl-phenylselenyl)-DL-2-mercaptopropi onylglyci n S-(2-phenylcarbamoyl-phenylselenyl)-DL-2-mercaptopropi onylglyci nethyl-25 ester S-[2-(3-fluorphenylcarbamoyl)-phenylselenyl]-DL-2-mercaptopropi onyl-glycin S-[2-(4-methoxyphenylcarbamoyl)-phenylselenyl]-DL-2-mercaptopropi onyl-glycin 30 S-(2-phenylcarbamoyl)-5-chlor-phenylselenyl)-DL-2-mercaptopropionyl-glycin S-(2-phenylcarbamoyl-6-methoxy-phenylselenyl)-DL-2-mercaptopropionyl-glycin S-[2-(4-ni trophenylcarbamoyl)-phenylselenyl]-DL-2-mercaptopropi onyl-35 glycin S-[2-(4-chlorphenylcarbamoyl)-phenylselenyl]-DL-2-mercaptopropionyl-glycin S-(2-phenylcarbamoyl-phenylselenyl)-3-mercaptopropionylglycin 3
DK 156474 B
S-(2-phenylcarbamoyl-phenylselenyl)-3-mercaptopropi onylglycinethylester S-(2-phenylcarbamoyl-6-methoxy-phenylselenyl)-3-mercaptopropionylglycin S-[2-(4-ni trophenylcarbamoyl)-phenylselenyl]-3-mercaptopropi onylglyci n S-(2-phenylcarbamoyl-phenylselenyl)-DL-mercaptoravsyre 5 S-[2-(3-fluorphenylcarbamoyl)-phenylselenyl]-DL-mercaptoravsyre S-[2-(4-methoxyphenylcarbamoyl)-phenylselenyl]-DL-mercaptoravsyre S-(2-phenylcarbamoyl-5-chlor-phenylselenyl]-DL-mercaptoravsyre S-(2-phenylcarbamoyl-6-methoxy-phenylselenyl)-DL-mercaptoravsyre S-[2-(4-ni trophenylcarbamoyl)-phenylselenyl]-DL-mercaptoravsyre 10 S-[2-(4-chlorphenylcarbamoyl)-phenylselenyl]-DL-mercaptoravsyre S-[2-(4-chlorphenylcarbamoyl)-6-methoxy-phenylselenyl]-DL-mercaptoravsyre S-[2-(4-ni trophenylcarbamoyl)-6-methoxy-phenylselenyl]-DL-mercaptoravsyre 15 S-[2-(3,4-dichlorphenylcarbamoyl)-6-methoxy-phenylselenyl]-DL-mercaptoravsyre S-[2-(3,4-di fluorphenylcarbamoyl}-6-methoxy-phenylselenyl]-DL-mercaptoravsyre S-[2-(3-chlor-4-methoxy-phenylcarbamoyl)-6-methoxy-phenylselenyl]-DL-20 mercaptoravsyre S-[2-(3,4-di methoxyphenylcarbamoyl)-6-methoxy-phenylselenyl]-DL-mercaptoravsyre S-[2-(4-chlor-3-fluor-phenylcarbamoyl)-6-methoxy-phenylselenyl]-DL-mercaptoravsyre 25 S-[2-(4-methoxy-3-methyl-phenylcarbamoyl)-6-methoxy-phenylselenyl]-DL-mercaptoravsyre S-[2-(4-methoxy-2-nitro-phenylcarbamoyl)-6-methoxy-phenylselenyl]-DL-mercaptoravsyre S-(2-phenylcarbamoyl-phenylselenyl)-DL-threo-1,4-dimercapto-2,3-butan-30 diol S-(2-benzylcarbamoyl-phenylselenyl)-mercaptoeddi kesyre S-(2-benzylcarbamoyl-6-methoxy-phenylselenyl)-mercaptoeddi kesyre S-(2-benzylcarbamoyl-6-methoxy-phenylselenyl)-DL-2-mercaptopropionsyre S-(2-benzylcarbamoyl-phenylselenyl)-DL-2-mercaptopropionylglycin 35 S-(2-benzylcarbamoyl-6-methoxy-phenylselenyl)-DL-2-mercaptopropionyl-glycin S-(2-benzylcarbamoyl-phenylselenyl)-3-mercaptopropionylglycin S-(2-benzylcarbamoyl-6-methoxy-phenylselenyl)-3-mercaptopropionyl-glycin 4
DK 156474 B
S-(2-phenylcarbamoyl-phenylselenyl)-thi ophenol S-[2-(4-nitrophenylcarbamoyl)-phenylselenyl]-thiophenol S-(2-phenylcarbamoyl-phenylselenyl)-mercaptosali cyl syre S-(2-phenylcarbamoyl-phenylselenyl)-mercaptosali cylsyremethylester 5 S-(2-phenylcarbamoyl-phenylselenyl)-mercaptopyridin
Forbindelserne ifplge opfindelsen udviser glutathionperoxidase-agtige egenskaber og er fplgelig i stand til at erstatte dette enzym og sâledes i samvirke med mercaptaner (f.eks. glutathion) at forhin-dre den skadelige virkning af aktive oxygenmetabolitter.
10 Den selenafhængige glutathion(GSH)-peroxidase(Px) katalyserer reduktionen af H202 og af organîske hydroperoxider.
2 GSH + H202 GSH-PX; GSSG + 2H20 2 GSH + R00H GSH-Px^ GSSG + ROH + H20 15
Det selenholdige enzym beskytter cellerne mod peroxidation ogspiller en vigtig rolle ved modulering af arachidonsyre-stofskiftet (C.C. Reddy, E.J. Massaro, Fundam. and Appl. Toxicology (3), 9-10 (1983), s. 431-436 og L. Flohé i Free Radicals in Biology, bind V, udg.
20 af. W.A. Pryor 1982 Academie Press, s. 223-254).
Glutathion-peroxidase spiller en rolle ved aile sygdomstilfælde, hvor der er taie om en cellebeskadigelse af det pâgældende væv og til sidst om nekrose pâ grund af en forpget dannelse af aktive oxygenmetabolitter i form af peroxider (f.eks. lipidperoxid og hydrogen-25 peroxid). Dette sâkaldte "oxidative stress" kan iagttages f.eks. ved 1eversygdomme - induceret ved betændelsesagtige eller autoimmunologiske reaktioner, pâ grund af al kohol eller medikamenter - men ogsâ ved andre sygdomme, f.eks. hjerteinfarkt. Det er bekendt, at leucocytter efter et hjerteinfarkt trænger ind i det beskadigede omrâde, og at celle-30 destruktionen ledsages af en forpget frigprelse af disse aktive oxygenmetabolitter. Dette fprer til sidst til en fremadskridende vævsned-brydning.
I sâdanne tilfælde stilles der for store krav til det pâgældende vigtige og naturligt forekommende beskyttelsessystem, der bestâr af 35 forskellige peroxid-og aktiv-oxygennedbrydende enzymer. Hertil horer superoxiddismutase, katalase og især glutathion-redox-systemet med den dertil hprende glutathion-peroxidase enzymkomponent. Netop dette sidste princip tilskrives stor betydning, da det kan afgifte organiske per- 5
DK 156474 B
oxider sàvel som hydrogenperoxid. Det er bevist, at dette System spiller en stor rolle for den intakte leverfunktion (Wendel et al.: Biochemical Pharmacology, bind 31, s. 3601 (1982)) og at f.eks. omfanget af en eksperimentel leverskade netop afhænger af dette System, dvs. pâ den ene 5 side af leverens indhold af gluthathion og pâ den anden side af glutathion-peroxidase-enzymets aktivitet. Under forlobet af en almin-delig betændelse reduceres denne leverbeskyttelsesmekanisme stærkt (Bragt et al., Agents and Actions, suppl. 17, s. 214 (1980)), hvorved leveren kommer ud for et stærkt fordget "oxidativt stress".
10 De reaktive oxygenmetabolitter spiller en meget betydelig rolle som mediatorer af betændelser. De ser ud til at medvirke bâde ved leucotaxis, kargennemtrængelighed, bindevævsskader, psoriasis og immun-kompleks/komplement-inducerede virkninger og ogsâ ved skader, sâledes som de, der opstâr pâ grund af genindstrpmning i iskæmiske omrâder 15 (L. Fl ohé et al., i The Pharmacology of Inflammation, udg. II. Bonta et al., Handbook of Inflammation, bind V, Elsevier, Amsterdam, s. 255-270).
Ogsâ skader efter ioniserende bestrâling kan fpres tilbage til dannelsen af radikale og aktive oxygenmetabolitter. En vej til kemisk cytoprotektion bestâr derfor i at styrke glutathion/glutathionperoxi-20 dase-systemet.
Mâling af glutathion-peroxidase-aktiviteten udfdrtes ved frem-gangsmâden ifdlge A. Wendel (A. Wendel, Methods in Enzymology bind 77, 325-333 (1981)). Mercaptankoncentrationenen mâles ved dette forsdg under ( anvendelse af Ellmans reagens.
25 I dette tilfælde tjente glutathion ikke som reduktionsmiddel, men derimod den mercaptanholdige forbindelse, som anvendtes til syntese af den aktuelle forbindelse. Det har nu overraskende vist sig, at forbin-delserne ifplge opfindelsen med formel (I) besidder en glutathionper-oxidaseagtig virkning. Omsætning af benzisoselenazolon med mercaptaner 30 sker for eksempel med 2-phenyl-l,2-benzisoselenazol-3(2H)-on efter fdlgende ligning . ioC® A » mercaptanrest
DK 156474 B
6
Glutathionperoxidaseaqtig virknina
Katalyse af peroxidasenedbrydningen afprpvedes ved in-vitro-under-spgelser. Det blev herved fastslâet, at forbindelserne ifplge opfindel-sen kan erstatte glutathion-peroxidase.
5
ROOH Forbindelser ifdlqe opfindelsen^ ROH
h2o2 h2o
10 RSH R-S-S-R
Reaktionshastighederne underspgtes ved A. Wendels metode (A.
Wendel, Methods in Enzymology bind 77, s. 325-333 (1981)). Soin referenceforbindelse anvendtes S-(2-phenylcarbamoyl-phenylselenyl)-15 glutathion. I nærværelse af en 1 mmolær koncentration af glutathion iagttages med tert.-butylhydroperoxid en reaktionshastighed pà 1,17 x 106 enheder pr. mol. Denne aktivitet ansættes til 100% for at lette sammenligningen.
20 Katalytisk aktivitet % S-(2-phenylcarbamoyl-phenylselenyl)-DL-threo- 1.4- dimercapto-2,3-butandi ol 390 25 S-(2-phenylcarbamoyl-phenylselenyl)-thiophenol 28 S-(2-phenylcarbamoyl-phenylselenyl)-3-mercaptopropi onsyre 47 S-(2-phenylcarbamoyl-phenylselenyl)-mercaptoeddi kesyre-ethylester 330 S-[2-(4-ni trophenylcarbamoyl)-phenylselenyl]-thiophenol 67 30 S-(6-methoxy-2-phenylcarbamoyl)-phenylselenyl-DL-threo- 1.4- dimercapto-2,3-butandiol 580
Forbindelserne ifdlge opfindelsen hæmmer ogsâ det ved cobra venum faktor inducerede rottepotepdem.
35 Til dokumentation benyttedes fremgangsmàderne ifplge S. Leyck, E. Etschenberg, V. Hadding og J. Winkelmann, Agents and Actions, bind 13, 5/6 (1983).
Til ddemprovokation injiceres cobra venum faktor i et volumen pâ 7
DK 156474 B
0,1 ml vand subplantart i venstre bagpote hos Han-Wistar-rotter af begge kpn med en legemsvægt pâ 150 - 200 g.
Bestemmelsen af bdemet udfprtes plethysmografisk direkte fpr og 3 timer efter 0demprovokationen. De hos de enkelte grupper opnâede 5 differenceværdier registreredes og den procentuelle ændring i forhold til ubehandlede kontroller fastsloges. Resultaterne er sammenfattet i fplgende tabel.
Betændelseshæm-mende virkning i % 10 Forbindelse_Dosis 100 mg/kg i.ro.
S-(2-phenylcarbamoyl-phenylselenyl)- ethylmercaptan - 32 S-(2-phenylcarbamoyl-phenylselenyl)-DL-2-15 mercaptopropîonylglycin - 71 S-(2-phenylcarbamoyl-phenylselenyl)-DL-mercapto-ravsyre - 84 S-[2-(4-ni trophenylcarbamoyl)-phenylselenyl]-thiophen - 20 20 S-(2-phenylcarbamoyl-phenylselenyl)-3- mercaptopropionsyre - 52 S-(2-phenylcarbamoyl-phenylselenyl)-thiophenol - 25
Fremstilling af forbindelserne ifplge opfindelsen finder sted ved 25 at omsætte 1,2-benzisoselenazoloner med formlen (II) opnâet i henholds-vis DE-OS 30 27 073, DE-OS 30 27 074 og DE-OS 30 27 075 med mercaptaner.
30 +AStM NH ie ~^R3 - ^'Se-S-A
II . I
35
Omsætning med den respektive mercaptan finder sted enten i suspen-sioner af 1,2-benzisoselenazoloner.i chlorerede carbonhydrider sâsom rhlnrnfnrm. Hi rhl nv'mo+han Hîrhlnrpthnn ollor i tri fl imrpHHî kocvrp-
DK 156474 B
8 oplpsning under omrpring ved stuetemperatur i 12-24 timer. De til om-sætningen anvendte mercaptaner er kendte forbindelser.
Den foreliggende opfindelse angâr ligeledes farmaceutiske præpa-rater, der indeholder forbindelserne med formel (I). Da farmaceutiske 5 præparater ifplge opfindelsen er præparater til enterai sâsom oral eller rektal administrering samt parentéral administrering, hvilke præparater indeholder de farmaceutisk aktive stoffer alene eller sammen med et sædvanliat, farmaceutisk anvendeligt bærermateriale. Den farmaceutiske tilberedning af aktivstoffet foreligger fortrinsvis i form af enkelt-10 doser, der er afstemt efter den pnskede indgivelse, f. eks. tabletter, kapsler, dragéer, suppositorier, granulater, oplpsninger, emulsioner eller suspensioner. Dosering af forbindelserne ligger normalt mellem 10 og 1000 mg pr. dag, fortrinsvis mellem 30 og 300 mg pr. dag, og kan indgives i én portion eller flere delportioner, fortrinsvis i 2 eller 3 15 delportioner pr. dag.
Fremstilling af forbindelserne ifplge opfindelsen belyses naermere i de fdlgende eksempler.
De angivne smeltepunkter er malt med et "Büchi 510"-smeltepunkt-bestemmelsesapparat, angivet i °C og er ikke korrigeret.
20
Eksempel 1 $-(2-phenvlcarbamovl-phenvlsel envi)-ethvlmercaotan 5 g (18,2 mmol) 2-phenyl-l,2-benzisoselenazol-3(2H)-on suspenderes i 150 ml chloroform (kun delvis oplpseligt). Til denne suspension til-25 dryppes 2 g (32,2 mmol) ethylmercaptan. Der opnâs en klar oplpsning, som omrpres yderligere natten over. Oplpsningsmidlet inddampes, og rema-nensen behandles med 100 ml hexan. De sâledes opnâede krystaller fra-suges og vaskes med 50 ml hexan.
Udbytte: 5,2 g (85% af det teoretiske) 30 Smp.: 127 - 129°C.
Eksempel 2 S-(2-phenvlcarbamovl-phenvlsel envi 1-mercaotosali cvlsvre
Produktet fremstilles analogt med eksempel 1 ud fra 5 g (18,2 mmol) 35 2-phenyl-l,2-benzisoselenazol-3(2H)-on og 2,8 g (18,2 mmol) mercapto-salicylsyre.
Udbytte: 5 g (64,3% af det teoretiske)
Smp.: 239 - 241eC.
DK 156474 B
9
Eksempel 3 S-12-phenvlcarbamovl-phenvlselenvi)-mercaotosali cvlsvremethvlester
Produktet fremstilles analogt med eksempel 1 ud fra 5 g (18,2 mmol) 2-phenyl-l,2-benzisoselenazol-3(2H)-on og 3,1 g (18,4 mmol) mercapto-5 salicylsyremethylester.
lldbytte: 7,25 g (90% af det teoretiske)
Smp.: 138 - 140°C.
Eksempel 4 10 S-(2-ohenvlcarbamovl-phenvlselenvi 1-3-mercaptoprooionsyre
Produktet fremstilles analogt med eksempel 1 ud fra 5 g (18,2 mmol) 2-phenyl-l,2-benzisoselenazol-3(2H)-on og 2 g (18,9 mmol)-3-mercapto-propionsyre.
Udbytte: 5,85 g (85% af det teoretiske) 15 Smp.: 203 - 204°C.
Eksempel 5 S-{2-phenvlcarbamovl-phenvlsel envi)-mercaotoeddi kesvreethvlester
Produktet fremstilles analogt med eksempel 1 ud fra 2 g (7,3 mmol) 20 2-phenyl-l,2-benzisoselenazol-3(2H)-on og 1 g (8,3 mmol) mercapto-eddikesyreethylester.
Udbytte: 2,4 g (84% af det teoretiske)
Smp.: 92 - 94eC.
25 Eksempel 6 S-(2-ohenvlcarbamovl-phenvlsel envil-DL-mercaptopropionvlal vcin 1 g (3,65 mmol) 2-phenyl-l,2-benzisoselenazol-3(2H)-on og 0,6 g (3,68 mmol) DL-2-mercaptopropionylglycin opleses i 15 ml trifluoreddike-syre og omrpres videre i 18 timer ved stuetemperatur. Til denne oplds-30 ning saettes sa 100 ml af en is-vandblanding. Udfældningen ekstraheres med dichlormethan. Efter at oplpsningsmidlet er tprret og afdampet i vakuum omkrystalliseres faststoffet derefter fra éthanol/vand 7:3 Udbytte: 1,5 g (94% af det teoretiske)
Smp.: 199°C.
35
DK 156474 B
10
Eksempel 7 S-(2-phenvlcarbamovl-phenvlsel envi)-2-mercaptopvridin
Produktet fremstilles analogt med eksempel 1 ud fra 2,5 g (9,1 mmol) 2-phenyl-l,2-benzisoselenazol-3(2H)-on og 1,2 g (10,8 mmol) 5 2-mercaptopyridin.
Udbytte: 3,2 g (91,1% af det teoretiske)
Smp.: 67°C (dekomp.).
Eksempel 8 10 S-Γ2-(4-nitrophenvlcarbamovl)-phenvlsel envi 1-thiophenol
Produktet fremstilles analogt med eksempel 1 ud fra 5 g (15,7 mmol) 2-(4-nitrophenyl)-l,2-benzisoselenazol-3(2H)-on og 1,75 g (15,9 mmol) thiophenol.
Udbytte: 5,7 g (84,8% af det teoretiske) 15 Smp.: 60°C (dekomp.).
Eksempel 9 S-Γ2-(2-f1 uorphenvlcarbamovl1-phenvlsel envi 1-ethvlmercaptan
Produktet fremstilles analogt med eksempel 1 ud fra 5 g (17,1 mmol) 20 2-(3-fluorphenyl)-l,2-benzisoselenazol-3(2H)-on og 2,2 g (35,5 mmol) ethylmercaptan.
Udbytte; 3,9 g (64,3% af det teoretiske)
Smp.: 93-95°C.
25 Eksempel 10 S-(2-phenvlcarbamovl-phenvlsel envi 1-DL-mercaptoravsvre
Produktet fremstilles analogt med eksempel 1 ud fra 1 g (3,65 mmol) 2-phenyl-l,2-benzisoselenazol-3(2H)-on og 0,55 g (3,66 mmol) DL-mercaptoravsyre.
30 Udbytte: 1,3 g (84% af det teoretiske)
Smp.: 200eC (dekomp.).
Eksempel 11 S-(2-phenvlcarbamovl-phenvlsel envi)-2-mercaptoDropi onvlalvci n 35 Produktet fremstilles analogt med eksempel 1 ud fra 2 g (7,3 mmol) 2-phenyl-l,2-benzisoselenazol-3(2H)-on og 1,2 g (7,35 mmol) 3-mercapto-propionylglycin.
Udbytte: 3,0 g (94% af det teoretiske) 11
DK 156474 B
Smp.: 199°C.
Eksempel 12 S-12-benzvlcarbamovl-phenvlsel envi)-mercaptoeddi kesvre 5 Prpduktet fremstilles analogt med eksempel 1 ud fra 2,88 g (10,0 mrnol) 2-benzyl-l,2-benzisoselenazol-3(2H)-on og 0,95 g (10,3 mmol) mercaptoeddi kesyre.
Udbytte: 0,95 g (25% af det teoretiske)
Smp.: 145-147°C.
10
Eksempel 13 S-(2-benzvlcarbamovl-phenvlsel envi 1-3-mercapto-1,2-propandi ol
Produktet fremstilles analogt med eksempel 1 ud fra 2,88 g (10,0 mmol) 2-benzyl-l,2-benzisoselenazol-3(2H)-on og 1,1 g (10,2 mmol) 3-15 mercapto-1,2-propandiol.
Udbytte: 2,1 g (53% af det teoretiske)
Smp.: 187°C.
Eksempel 14 20 S-(2-phenvlcarbamovl-phenvlsel envi)-DL-threo-1.4-dimercapto-2.3-butan-di ol
Produktet fremstilles analogt med eksempel 6 af 2,74 g (10 mmol) 2-phenyl-l,2-benzisoselenazol-3(2H)-on og 1,55 g (10 mmol) DL-threo- l,4-dimercapto-2,3-butandiol.
25 Forbindelsen renses ved spjlechromatografi.
Udbytte: 0,5 g (11,6% af det teoretiske)
Smp.: 78 - 82°C.
Eksempel 15 30 S-(2-phenvlcarbamovl-6-methoxv-phenvlsel envi)-DL-2-mercaptopropi onvl-alvcin
Produktet fremstilles analogt med eksempel 1 ud fra 3,0 g (9,87 mmol) 7-methoxy-2-phenyl-l,2-benzisoselenazol-3(2H)-on og 1,63 g (10 mmol) DL-2-mercaptopropionylglycin.
35 Udbytte: 4,5 g (97,6% af det teoretiske)
Smp.: 242 - 245°C.
DK 156474 B
12
Eksempel 16 S-(2-phenvlcarbamovl-4-chlor-phenvlsel envi1-ethvlmercaptan
Produktet fremstilles analogt med eksempel 1 ud fra 3,0 g (9,72 mmol) 5-chlor-2-phenyl-l,2-benzisoselenazol-3(2H)-on og 1 g 5 (15,9 mmol) ethylmarcaptan.
Udbytte: 3,1 g (86% af det teoretiske)
Smp.: 163 - 166°C.
Claims (6)
1. S-(carbamoyl-phenylselenyl)-derivater af mercaptaner med den almene formel (I)
2. S-(carbamoyl-phenylselenyl)-derivater ifolge krav 1 KENDETEGNET ved, at
25 R1,R2,R3 og R4 er ens eller forskellige og uafhængigt af hin- anden betegner hydrogen, fluor, chlor, methyl, methoxy, hydroxy, tri-fiuormethyl, nitro, cyano, carboxy, Cj 2“alkoxycarbonyl, carboxy-Cj_^-alkyl, Cj 2-alkoxycarbonyl-Cj_4alkyl, og A betegner en uforgrenet eller forgrenet Cj_4-alkylgruppe, som kan inde-30 holde 1-3 substituenter udvalgt blandt carboxy, hydroxy, mercapto, carboxyalkylcarbamoyl, hvorhos forestring af den funktîonelt modificer-bare carboxylgruppe er mulig, eller betegner en phenyl-, carboxyphenyl-, alkoxycarbonylphenyl-, pyridyl- eller en pyridylilkylgruppe, og n er nul eller 1. 35
3. S-(carbamoyl-phenylselenyl)-derivater med formlen (I) ifplge krav 1, KENDETEGNET ved, at R1 ogR2 er ens eller forskellige og uafhængigt af hinanden betegner h vHrnnpn. fli/nr. rhlnr mpthvl. mpthnyv. hvrlYnYv. tri fl imv'mpthul p11 or DK 156474 B nitro og R3 og R4 er ens eller forskellige og uafhænigt af hinanden betegner hydrogen, fluor, chlor, methoxy, hydroxy, cyano, carboxy, Cj_2-alkoxy-carbonyl, carboxy-Cj_4-alkyl, Cj_2-a^oxycarbonyl-C1 _^alkyl og 5 A betegner en uforgrenet eller forgrenet C^-alkylgruppe, som kan inde-holde 1-3 substituenter udvalgt blandt carboxy, hydroxy, mercapto, carboxyalkylcarbamoyl, hvorhos forestring af den funktionelt modificer-bare carboxyIgruppe er mulig, og n er nul eller 1. 10
4. S-(carbamoyl-phenylselenyl)-derivater if0lge krav 1, KENDETEGNET ved, at Ri og R2 er ens eller forskellige og uafhængigt af hinanden betegner hydrogen, fluor, chlor, methyl, methoxy, hydroxy, trif1uormethyl, nitro og
15 R3 og R4 er ens eller forskellige og uafhængigt af hinanden betegner hydrogen, fluor, chlor, methoxy, hydroxy, cyano, carboxy, Cj_2-alkoxy-carbonyl, carboxy-Cj ^-alkyl, koxyeairboiiyl kyl og A betegner en phenyl-, carboxyphenyl-, methoxycarbonylphenyl-, pyridyl-eller pyridylmethylgruppe og 20 n er nul eller 1.
5. Fremgangsmâde til fremstilling af forbindelsen med den almene formel (I) ifplge krav 1-4, KENDETEGNET ved, at en 1,2-benzisoselen-azolon med formlen (II)
25. O ^ 30 hvori R1, R2, R3 og R4 har de i forbindelse med formel (I) angivne betydninger, suspenderet i et chloreret carbonhydrid eller oplpst i trifluoreddikesyre, omsættes med en mercaptan med formlen (III) 35 A - SH (III) hvor A har den i forbindelse med formel (I) angivne betydning, DK 156474 B under omr0ring i 12-24 timer ved stuetemperatur.
5 R1 0 j—V-R4 Se-S-A 10 hvori R1,R2,R3 og R4 er ens eller forskellige og uafhængigt af hin-anden betegner hydrogen, halogen, Cj^-alkyl, Cj^-alkoxy, trifluor-methyl, nitro, cyano, hydroxy, carboxy, C12-alkoxycarbonyl, carboxy-15 Cj_4-alkyl, Cjg-alkoxycarbonyl-Cj^alkyl og A betegner en uforgrenet eller forgrenet Cj ^-alkylgruppe, som kan indeholde 1 - 3 substituenter udvalgt blandt carboxy, hydroxy, mercapto, carboxyalkylcarbamoyl, hvorhos forestring af den funktîonelt modificer-bare carboxy!gruppe med en Cj_3-alkohol er mulig, eller betegner en 20 phenyl-, carboxyphenyl-, alkoxycarbonylphenyl-, pyridyl- eller en pyridylalkylgruppe, og n er nul eller 1.
6. Farmaceutiske præparater, KENDETGENET ved, at de indeholder en forbindelse med formel (I) ifplge krav 1-4 som aktivt stof i blanding med sædvanlige farmaceutiske hjælpe- og bærerstoffer. 5 10 20
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3443467 | 1984-11-29 | ||
| DE19843443467 DE3443467A1 (de) | 1984-11-29 | 1984-11-29 | Mercaptanderivate, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische praeparate |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK552985D0 DK552985D0 (da) | 1985-11-28 |
| DK552985A DK552985A (da) | 1986-05-30 |
| DK156474B true DK156474B (da) | 1989-08-28 |
| DK156474C DK156474C (da) | 1990-01-22 |
Family
ID=6251424
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK552985A DK156474C (da) | 1984-11-29 | 1985-11-28 | S-(carbamoylphenylselenyl)-derivater af mercaptaner, fremgangsmaade til fremstilling deraf samt farmaceutiske praeparater indeholdende samme |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US4730053A (da) |
| EP (1) | EP0187233B1 (da) |
| JP (1) | JPH0649678B2 (da) |
| AT (1) | ATE33022T1 (da) |
| DE (2) | DE3443467A1 (da) |
| DK (1) | DK156474C (da) |
| ES (1) | ES8701189A1 (da) |
| GR (1) | GR852867B (da) |
| IE (1) | IE58366B1 (da) |
| PT (1) | PT81576B (da) |
| ZA (1) | ZA859126B (da) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3626554A1 (de) * | 1986-08-06 | 1988-02-18 | Nattermann A & Cie | Diselenobis-benzoesaeureamide primaerer heterocyclischer amine, verfahren zur ihrer herstellung und diese enthaltende pharmazeutische praeparate |
| US5017753A (en) * | 1986-10-17 | 1991-05-21 | Board Of Regents, The University Of Texas System | Method and apparatus for producing parts by selective sintering |
| US5128365A (en) * | 1989-07-19 | 1992-07-07 | The Trustees Of Columbia University In The City Of New York | Compounds having glutathione peroxidase activity and use thereof |
| DE3937169A1 (de) * | 1989-11-08 | 1991-05-16 | Nattermann A & Cie | Benzylselenobenzamide von anilinen und benzylaminen |
| DE3937170A1 (de) * | 1989-11-08 | 1991-05-16 | Nattermann A & Cie | Benzylselenobenzamide von aminopyridinen und picolylaminen |
| DE3937171A1 (de) * | 1989-11-08 | 1991-05-16 | Nattermann A & Cie | Picolylselenobenzamide von aminopyridinen, anilinen und picolylaminen |
| EP0622076B1 (en) * | 1992-01-17 | 1997-04-02 | Daiichi Pharmaceutical Co., Ltd. | Inhibitor for restenosis after percutaneous coronary arterioplasty |
| WO2000058281A1 (en) * | 1999-03-31 | 2000-10-05 | Daiichi Pharmaceutical Co., Ltd. | Substrates for thioredoxin reductase |
| CA2354645A1 (en) * | 2000-08-04 | 2002-02-04 | Jack Spargur | Three dimensional insulation panel having unique surface for improved performance |
| WO2011069002A1 (en) * | 2009-12-02 | 2011-06-09 | Alquest Therapeutics, Inc. | Organoselenium compounds and uses thereof |
| US10058542B1 (en) | 2014-09-12 | 2018-08-28 | Thioredoxin Systems Ab | Composition comprising selenazol or thiazolone derivatives and silver and method of treatment therewith |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3027073C2 (de) * | 1980-07-17 | 1985-03-07 | A. Nattermann & Cie GmbH, 5000 Köln | Pharmazeutische Präparate, enthaltend 2-Phenyl-1,2-benzisoselenazol-3(2H)-on |
| DE3027075A1 (de) * | 1980-07-17 | 1982-02-18 | A. Nattermann & Cie GmbH, 5000 Köln | Benzisoselenazolone, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische praeparate |
| DE3568775D1 (en) * | 1984-06-22 | 1989-04-20 | Nattermann A & Cie | S-(carbamoyl-phenylselenyl) derivatives of glutathion and of amino mercaptocarboxylic acids, process for their preparation and pharmaceutical preparations containing them |
-
1984
- 1984-11-29 DE DE19843443467 patent/DE3443467A1/de not_active Withdrawn
-
1985
- 1985-11-16 EP EP85114610A patent/EP0187233B1/de not_active Expired
- 1985-11-16 DE DE8585114610T patent/DE3561884D1/de not_active Expired
- 1985-11-16 AT AT85114610T patent/ATE33022T1/de not_active IP Right Cessation
- 1985-11-25 US US06/801,561 patent/US4730053A/en not_active Expired - Fee Related
- 1985-11-27 GR GR852867A patent/GR852867B/el unknown
- 1985-11-28 ZA ZA859126A patent/ZA859126B/xx unknown
- 1985-11-28 DK DK552985A patent/DK156474C/da not_active IP Right Cessation
- 1985-11-28 PT PT81576A patent/PT81576B/pt not_active IP Right Cessation
- 1985-11-28 ES ES549367A patent/ES8701189A1/es not_active Expired
- 1985-11-28 IE IE299885A patent/IE58366B1/en not_active IP Right Cessation
- 1985-11-29 JP JP60267590A patent/JPH0649678B2/ja not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| IE58366B1 (en) | 1993-09-08 |
| ES8701189A1 (es) | 1986-11-16 |
| ZA859126B (en) | 1986-08-27 |
| GR852867B (da) | 1986-03-28 |
| DK552985A (da) | 1986-05-30 |
| JPS61137856A (ja) | 1986-06-25 |
| JPH0649678B2 (ja) | 1994-06-29 |
| DK156474C (da) | 1990-01-22 |
| DK552985D0 (da) | 1985-11-28 |
| ES549367A0 (es) | 1986-11-16 |
| ATE33022T1 (de) | 1988-04-15 |
| DE3561884D1 (en) | 1988-04-21 |
| US4730053A (en) | 1988-03-08 |
| PT81576A (en) | 1985-12-01 |
| DE3443467A1 (de) | 1986-05-28 |
| PT81576B (pt) | 1987-11-11 |
| EP0187233A1 (de) | 1986-07-16 |
| EP0187233B1 (de) | 1988-03-16 |
| IE852998L (en) | 1986-05-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4618669A (en) | S-(carbamoyl-phenylselenyl) derivatives of glutathione and of aminomercaptocarboxylic acids | |
| US6372733B1 (en) | Hexahydro-5-imino-1,4-1,4-thiazepine derivatives as inhibitors of nitric oxide synthases | |
| AU593606B2 (en) | Novel phenolic thioethers and sulphoxides as inhibitors of 5-lipoxygenase | |
| CA2224411A1 (fr) | Nouveaux inhibiteurs de farnesyl transferase, leur preparation et les compositions pharmaceutiques qui les contiennent | |
| DK156474B (da) | S-(carbamoylphenylselenyl)-derivater af mercaptaner, fremgangsmaade til fremstilling deraf samt farmaceutiske praeparater indeholdende samme | |
| SI9111318A (en) | Acetamide derivatives | |
| CA2580642A1 (en) | Novel tellurium compounds and their use as immunomodulators | |
| EP0190685A2 (en) | Heterocyclic amides | |
| US20040143016A1 (en) | Catalytic antioxidants and methods of use | |
| EP0479631B1 (fr) | Dérivés du spiro [4.5]décane leur procédé de préparation et les compositions pharmaceutiques les renfermant | |
| EP0198277B1 (de) | Diselenobis-benzoesäureamide primärer und sekundärer Amine, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Präparate | |
| EP0006789A1 (fr) | Composés bis (aryloxyalcanecarboxyliques), leur préparation et leur utilisation en thérapeutique | |
| MC1332A1 (fr) | Nouveaux derives de quinazoline et preparations pharmaceutiques | |
| NO171215B (no) | Analogifremgangsmaate for fremstilling av terapeutisk virksomme diselenobis-benzosyreamider | |
| EP0143016B1 (fr) | Dérivés de 4-(3-alkynyloxy-2-hydroxy-propyl)-piperazin-1-yl-N-phényl acétamide, leur préparation et leur application en thérapeutique | |
| EP0008269B1 (fr) | Nouveaux médicaments contenant, à titre de substance active, des composés de type benzènesulfone, nouveaux composés de ce type et procédé pour leur préparation | |
| US4166866A (en) | Immunosuppressive method with dithiocarbamates | |
| CN116162046B (zh) | 一种炔基砜衍生物及其制备方法与其应用 | |
| US4254142A (en) | Dithiocarbanilic acids and use thereof as immunosuppressive agent | |
| US4130578A (en) | Immunosuppressive dithiocarbanilates | |
| JPS625982A (ja) | チアゾリジン誘導体 | |
| EP0145304B1 (en) | Tetrahydro-beta-carboline derivatives and process for the preparation thereof | |
| DE3513070A1 (de) | Diselenobis-benzoesaeureamide primaerer amine, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische praeparate | |
| JPH0429985A (ja) | アスコルビン酸誘導体、その製法およびその用途 | |
| GB1570328A (en) | Thienopyridines |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |