DK159269B - Analogifremgangsmaade til fremstilling af svovlholdige indanylderivater - Google Patents
Analogifremgangsmaade til fremstilling af svovlholdige indanylderivater Download PDFInfo
- Publication number
- DK159269B DK159269B DK315979A DK315979A DK159269B DK 159269 B DK159269 B DK 159269B DK 315979 A DK315979 A DK 315979A DK 315979 A DK315979 A DK 315979A DK 159269 B DK159269 B DK 159269B
- Authority
- DK
- Denmark
- Prior art keywords
- general formula
- meaning
- nitroindane
- phenoxy
- groups
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 13
- 238000002360 preparation method Methods 0.000 title claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 17
- 230000008569 process Effects 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 150000007513 acids Chemical class 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 150000003457 sulfones Chemical class 0.000 claims description 4
- 150000003462 sulfoxides Chemical class 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 claims description 3
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 150000003458 sulfonic acid derivatives Chemical class 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- QYIQXNQEKPXETC-UHFFFAOYSA-N n-(6-phenoxy-1h-inden-5-yl)methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=2C=CCC=2C=C1OC1=CC=CC=C1 QYIQXNQEKPXETC-UHFFFAOYSA-N 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 36
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 20
- OJNRHKOJADOVAE-UHFFFAOYSA-N 5-bromo-6-nitro-2,3-dihydro-1h-indene Chemical compound C1=C(Br)C([N+](=O)[O-])=CC2=C1CCC2 OJNRHKOJADOVAE-UHFFFAOYSA-N 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- -1 diphenyl pure blue Chemical compound 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000009835 boiling Methods 0.000 description 9
- 238000001704 evaporation Methods 0.000 description 9
- 230000008020 evaporation Effects 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 150000002468 indanes Chemical class 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 235000011121 sodium hydroxide Nutrition 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- PYPIEUKDKXCSSI-UHFFFAOYSA-N 6-phenoxy-2,3-dihydro-1h-inden-5-amine Chemical compound NC1=CC=2CCCC=2C=C1OC1=CC=CC=C1 PYPIEUKDKXCSSI-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 239000007868 Raney catalyst Substances 0.000 description 4
- 229910000564 Raney nickel Inorganic materials 0.000 description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 4
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 4
- BVWQEBWCUCGHHZ-UHFFFAOYSA-N n-(1-oxo-6-phenoxy-2,3-dihydroinden-5-yl)methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=2CCC(=O)C=2C=C1OC1=CC=CC=C1 BVWQEBWCUCGHHZ-UHFFFAOYSA-N 0.000 description 4
- WDYGVVWWRZFQEO-UHFFFAOYSA-N n-(1-oxo-6-phenoxy-2-phenylsulfanyl-2,3-dihydroinden-5-yl)methanesulfonamide Chemical compound O=C1C=2C=C(OC=3C=CC=CC=3)C(NS(=O)(=O)C)=CC=2CC1SC1=CC=CC=C1 WDYGVVWWRZFQEO-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- QDKWLJJOYIFEBS-UHFFFAOYSA-N 1-fluoro-4-$l^{1}-oxidanylbenzene Chemical group [O]C1=CC=C(F)C=C1 QDKWLJJOYIFEBS-UHFFFAOYSA-N 0.000 description 3
- DUROKJUTAMUPAH-UHFFFAOYSA-N 1-nitro-2,3-dihydro-1h-indene Chemical compound C1=CC=C2C([N+](=O)[O-])CCC2=C1 DUROKJUTAMUPAH-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- OQRGTWJAXDMYQY-UHFFFAOYSA-N 5-nitro-6-phenoxy-2,3-dihydro-1h-indene Chemical compound [O-][N+](=O)C1=CC=2CCCC=2C=C1OC1=CC=CC=C1 OQRGTWJAXDMYQY-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 229950005499 carbon tetrachloride Drugs 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- HNQIVZYLYMDVSB-NJFSPNSNSA-N methanesulfonamide Chemical compound [14CH3]S(N)(=O)=O HNQIVZYLYMDVSB-NJFSPNSNSA-N 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 2
- GRFNBEZIAWKNCO-UHFFFAOYSA-N 3-pyridinol Chemical compound OC1=CC=CN=C1 GRFNBEZIAWKNCO-UHFFFAOYSA-N 0.000 description 2
- KCPQQVCJZPFLDU-UHFFFAOYSA-N 5-(2-fluorophenoxy)-6-nitro-2,3-dihydro-1h-indene Chemical compound [O-][N+](=O)C1=CC=2CCCC=2C=C1OC1=CC=CC=C1F KCPQQVCJZPFLDU-UHFFFAOYSA-N 0.000 description 2
- IRYAOHYKEVMSBJ-UHFFFAOYSA-N 5-(3-chlorophenoxy)-6-nitro-2,3-dihydro-1h-indene Chemical compound [O-][N+](=O)C1=CC=2CCCC=2C=C1OC1=CC=CC(Cl)=C1 IRYAOHYKEVMSBJ-UHFFFAOYSA-N 0.000 description 2
- GOYSYSPDXHHGKV-UHFFFAOYSA-N 5-(4-chlorophenoxy)-6-nitro-2,3-dihydro-1h-indene Chemical compound [O-][N+](=O)C1=CC=2CCCC=2C=C1OC1=CC=C(Cl)C=C1 GOYSYSPDXHHGKV-UHFFFAOYSA-N 0.000 description 2
- BKDBQNGKAXPOQZ-UHFFFAOYSA-N 5-(4-fluorophenoxy)-6-nitro-2,3-dihydro-1h-indene Chemical compound [O-][N+](=O)C1=CC=2CCCC=2C=C1OC1=CC=C(F)C=C1 BKDBQNGKAXPOQZ-UHFFFAOYSA-N 0.000 description 2
- YYGNFQHQWUTJNJ-UHFFFAOYSA-N 5-fluoro-6-nitro-2,3-dihydroinden-1-one Chemical compound C1=C(F)C([N+](=O)[O-])=CC2=C1CCC2=O YYGNFQHQWUTJNJ-UHFFFAOYSA-N 0.000 description 2
- BDQHCRZTZUVRMT-UHFFFAOYSA-N 6-phenylsulfanyl-2,3-dihydro-1h-inden-5-amine Chemical compound NC1=CC=2CCCC=2C=C1SC1=CC=CC=C1 BDQHCRZTZUVRMT-UHFFFAOYSA-N 0.000 description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- GUUVPOWQJOLRAS-UHFFFAOYSA-N Diphenyl disulfide Chemical compound C=1C=CC=CC=1SSC1=CC=CC=C1 GUUVPOWQJOLRAS-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000001741 anti-phlogistic effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- YADSGOSSYOOKMP-UHFFFAOYSA-N dioxolead Chemical compound O=[Pb]=O YADSGOSSYOOKMP-UHFFFAOYSA-N 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 210000000548 hind-foot Anatomy 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 229910044991 metal oxide Inorganic materials 0.000 description 2
- 150000004706 metal oxides Chemical class 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- SEOYFJMPFVYJAQ-UHFFFAOYSA-N n-(3-oxo-6-phenoxy-1,2-dihydroinden-5-yl)methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=2C(=O)CCC=2C=C1OC1=CC=CC=C1 SEOYFJMPFVYJAQ-UHFFFAOYSA-N 0.000 description 2
- HCBMEMPZHUPGHY-UHFFFAOYSA-N n-(6-phenoxy-2,3-dihydro-1h-inden-5-yl)methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=2CCCC=2C=C1OC1=CC=CC=C1 HCBMEMPZHUPGHY-UHFFFAOYSA-N 0.000 description 2
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 2
- IWDCLRJOBJJRNH-UHFFFAOYSA-N p-cresol Chemical compound CC1=CC=C(O)C=C1 IWDCLRJOBJJRNH-UHFFFAOYSA-N 0.000 description 2
- KMUONIBRACKNSN-UHFFFAOYSA-N potassium dichromate Chemical compound [K+].[K+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O KMUONIBRACKNSN-UHFFFAOYSA-N 0.000 description 2
- 239000012286 potassium permanganate Substances 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- 231100000397 ulcer Toxicity 0.000 description 2
- 239000000052 vinegar Substances 0.000 description 2
- 235000021419 vinegar Nutrition 0.000 description 2
- PWNBOTMWJZFKHV-UHFFFAOYSA-N 1,1,1-trifluoro-n-(6-phenoxy-2,3-dihydro-1h-inden-5-yl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)NC1=CC=2CCCC=2C=C1OC1=CC=CC=C1 PWNBOTMWJZFKHV-UHFFFAOYSA-N 0.000 description 1
- FQQLETXDJGPJPY-UHFFFAOYSA-N 1,1,1-trifluoro-n-(6-phenylsulfanyl-2,3-dihydro-1h-inden-5-yl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)NC1=CC=2CCCC=2C=C1SC1=CC=CC=C1 FQQLETXDJGPJPY-UHFFFAOYSA-N 0.000 description 1
- QLOKJRIVRGCVIM-UHFFFAOYSA-N 1-[(4-methylsulfanylphenyl)methyl]piperazine Chemical compound C1=CC(SC)=CC=C1CN1CCNCC1 QLOKJRIVRGCVIM-UHFFFAOYSA-N 0.000 description 1
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- VZDYWEUILIUIDF-UHFFFAOYSA-J cerium(4+);disulfate Chemical compound [Ce+4].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O VZDYWEUILIUIDF-UHFFFAOYSA-J 0.000 description 1
- 229910000355 cerium(IV) sulfate Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- AJYXQZZAMKCOJH-UHFFFAOYSA-N chloromethylsulfonyl chloromethanesulfonate Chemical compound ClCS(=O)(=O)OS(=O)(=O)CCl AJYXQZZAMKCOJH-UHFFFAOYSA-N 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- LXMQZGGLHVSEBA-UHFFFAOYSA-N chromium;trihydrate Chemical compound O.O.O.[Cr] LXMQZGGLHVSEBA-UHFFFAOYSA-N 0.000 description 1
- 239000003245 coal Substances 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- QDYBCIWLGJMJGO-UHFFFAOYSA-N dinitromethanone Chemical class [O-][N+](=O)C(=O)[N+]([O-])=O QDYBCIWLGJMJGO-UHFFFAOYSA-N 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 230000009841 epithelial lesion Effects 0.000 description 1
- CCJXQRNXZKSOGJ-UHFFFAOYSA-N ethylsulfonyl ethanesulfonate Chemical compound CCS(=O)(=O)OS(=O)(=O)CC CCJXQRNXZKSOGJ-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000002366 halogen compounds Chemical class 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- HMCHPJARCSHOPH-UHFFFAOYSA-N n,n-dimethyl-1-(5-nitro-6-phenoxy-2,3-dihydroinden-1-ylidene)methanamine Chemical compound C1=C2C(=CN(C)C)CCC2=CC([N+]([O-])=O)=C1OC1=CC=CC=C1 HMCHPJARCSHOPH-UHFFFAOYSA-N 0.000 description 1
- QFYRJDXCFZQEDI-UHFFFAOYSA-N n-(1-hydroxy-6-phenoxy-2,3-dihydro-1h-inden-5-yl)methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=2CCC(O)C=2C=C1OC1=CC=CC=C1 QFYRJDXCFZQEDI-UHFFFAOYSA-N 0.000 description 1
- PVASFPOPJZUISB-UHFFFAOYSA-N n-(3-hydroxy-6-phenoxy-2,3-dihydro-1h-inden-5-yl)methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=2C(O)CCC=2C=C1OC1=CC=CC=C1 PVASFPOPJZUISB-UHFFFAOYSA-N 0.000 description 1
- ZPTHYFLPJBOJCH-UHFFFAOYSA-N n-(3-oxo-6-phenylsulfanyl-1,2-dihydroinden-5-yl)methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=2C(=O)CCC=2C=C1SC1=CC=CC=C1 ZPTHYFLPJBOJCH-UHFFFAOYSA-N 0.000 description 1
- YTNLNHLOXYAXOG-UHFFFAOYSA-N n-(4-chlorophenoxy)-2,3-dihydro-1h-inden-5-amine Chemical compound C1=CC(Cl)=CC=C1ONC1=CC=C(CCC2)C2=C1 YTNLNHLOXYAXOG-UHFFFAOYSA-N 0.000 description 1
- AVEVSZXVFYABDM-UHFFFAOYSA-N n-(6-phenoxy-2,3-dihydro-1h-inden-5-yl)ethanesulfonamide Chemical compound CCS(=O)(=O)NC1=CC=2CCCC=2C=C1OC1=CC=CC=C1 AVEVSZXVFYABDM-UHFFFAOYSA-N 0.000 description 1
- LMQOHUWEDJFZLA-UHFFFAOYSA-N n-(6-phenylsulfanyl-2,3-dihydro-1h-inden-5-yl)methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=2CCCC=2C=C1SC1=CC=CC=C1 LMQOHUWEDJFZLA-UHFFFAOYSA-N 0.000 description 1
- NTPSXRBNACRUGB-UHFFFAOYSA-N n-(6-pyridin-2-ylsulfanyl-2,3-dihydro-1h-inden-5-yl)methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=2CCCC=2C=C1SC1=CC=CC=N1 NTPSXRBNACRUGB-UHFFFAOYSA-N 0.000 description 1
- RPFRQDPIUQYOLY-UHFFFAOYSA-N n-(6-pyridin-4-ylsulfanyl-2,3-dihydro-1h-inden-5-yl)methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=2CCCC=2C=C1SC1=CC=NC=C1 RPFRQDPIUQYOLY-UHFFFAOYSA-N 0.000 description 1
- RXJFAMXYFXHQFG-UHFFFAOYSA-N n-[1-oxo-6-phenoxy-2,2-bis(phenylsulfanyl)-3h-inden-5-yl]methanesulfonamide Chemical compound O=C1C=2C=C(OC=3C=CC=CC=3)C(NS(=O)(=O)C)=CC=2CC1(SC=1C=CC=CC=1)SC1=CC=CC=C1 RXJFAMXYFXHQFG-UHFFFAOYSA-N 0.000 description 1
- GCQBPXGXNPMPNK-UHFFFAOYSA-N n-[2-(benzenesulfinyl)-1-oxo-6-phenoxy-2,3-dihydroinden-5-yl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=2CC(S(=O)C=3C=CC=CC=3)C(=O)C=2C=C1OC1=CC=CC=C1 GCQBPXGXNPMPNK-UHFFFAOYSA-N 0.000 description 1
- YPCUTSFYKLJGAQ-UHFFFAOYSA-N n-[2-(benzenesulfonyl)-1-oxo-6-phenoxy-2,3-dihydroinden-5-yl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=2CC(S(=O)(=O)C=3C=CC=CC=3)C(=O)C=2C=C1OC1=CC=CC=C1 YPCUTSFYKLJGAQ-UHFFFAOYSA-N 0.000 description 1
- DQIZANOEMRQGLW-UHFFFAOYSA-N n-[6-(2-fluorophenoxy)-1-oxo-2,3-dihydroinden-5-yl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=2CCC(=O)C=2C=C1OC1=CC=CC=C1F DQIZANOEMRQGLW-UHFFFAOYSA-N 0.000 description 1
- DZGRQGKYBYNIOQ-UHFFFAOYSA-N n-[6-(2-methylphenoxy)-2,3-dihydro-1h-inden-5-yl]methanesulfonamide Chemical compound CC1=CC=CC=C1OC(C(=C1)NS(C)(=O)=O)=CC2=C1CCC2 DZGRQGKYBYNIOQ-UHFFFAOYSA-N 0.000 description 1
- YSGKHKGURPPFLM-UHFFFAOYSA-N n-[6-(3,4-dichlorophenoxy)-2,3-dihydro-1h-inden-5-yl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=2CCCC=2C=C1OC1=CC=C(Cl)C(Cl)=C1 YSGKHKGURPPFLM-UHFFFAOYSA-N 0.000 description 1
- PWLYYCXYMUAPOV-UHFFFAOYSA-N n-[6-(3-chlorophenoxy)-1-oxo-2,3-dihydroinden-5-yl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=2CCC(=O)C=2C=C1OC1=CC=CC(Cl)=C1 PWLYYCXYMUAPOV-UHFFFAOYSA-N 0.000 description 1
- PHPFQTCEMXGZFJ-UHFFFAOYSA-N n-[6-(3-fluorophenoxy)-2,3-dihydro-1h-inden-5-yl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=2CCCC=2C=C1OC1=CC=CC(F)=C1 PHPFQTCEMXGZFJ-UHFFFAOYSA-N 0.000 description 1
- ZHGLBGUIVDTMSA-UHFFFAOYSA-N n-[6-(4-chloro-2-methylphenoxy)-2,3-dihydro-1h-inden-5-yl]methanesulfonamide Chemical compound CC1=CC(Cl)=CC=C1OC(C(=C1)NS(C)(=O)=O)=CC2=C1CCC2 ZHGLBGUIVDTMSA-UHFFFAOYSA-N 0.000 description 1
- LIOFQCWKFQYUNI-UHFFFAOYSA-N n-[6-(4-chlorophenoxy)-1-oxo-2,3-dihydroinden-5-yl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=2CCC(=O)C=2C=C1OC1=CC=C(Cl)C=C1 LIOFQCWKFQYUNI-UHFFFAOYSA-N 0.000 description 1
- XTDBSSICEFGNDC-UHFFFAOYSA-N n-[6-(4-fluorophenoxy)-1-oxo-2,3-dihydroinden-5-yl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=2CCC(=O)C=2C=C1OC1=CC=C(F)C=C1 XTDBSSICEFGNDC-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000004540 pour-on Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- WHMDPDGBKYUEMW-UHFFFAOYSA-N pyridine-2-thiol Chemical compound SC1=CC=CC=N1 WHMDPDGBKYUEMW-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 150000004053 quinones Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001562 ulcerogenic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
- C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C205/36—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
- C07C205/38—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the oxygen atom of at least one of the etherified hydroxy groups being further bound to a carbon atom of a six-membered aromatic ring, e.g. nitrodiphenyl ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Description
DK 159269B
l
Den foreliggende opfindelse angår en analog i fremgangsmåde til fremstilling af hidtil ukendte svovlholdige indanylderivater med den almene formel I
5 AR-X
I A (I) r1so2nh 10 hvor AR er en phenylrest eller pyridylrest, der eventuelt er substitueret med 1-3 halogenatomer, alkylgrupper med 1-4 car-bonatomer eller trifluormethylgrupper, X er et oxygenatom eller et svovlatom, Rj er en alkylgruppe med 1-4 carbonatomer, 15 der eventuelt er substitueret med 1-3 fluoratomer eller chlor-atomer, og A er grupperne -ch2-ch2-ch2-, -CH=CH-CH2-, -co-ch2-ch2-, -CH0H-CH2-CH2-, -C0CH(S0nR2)CH2- eller 20 -CH(OH)CH-(SOnR2)CH2- hvor n er et tal 0, 1 eller 2, og R2 er en alkylgruppe med 1-4 carbonatomer eller en phenylgruppe, der eventuelt er substitueret med 1-3 halogenatomer, alkylgrupper med 1-4 carbonatomer, 25 nitrogrupper eller carboxyIgrupper, og deres salte med fysiologisk anvendelige baser eller syrer.
Indanylderivaterne med den almene formel I ifølge kravet er pharmakologisk virksomme stoffer, der f.eks. udmærker sig ved 30 en analgetisk, anti pyret i sk, trombocytaggregationshæmmende, diuretisk og især en antiphlogistisk virkning. En særlig fordel ved disse forbindelser ligger i, at de udmærker sig ved en stor dissociation mellem terapeutisk virkning og uønsket bivirkning (især ulcerogen virkning).
Den antiphlogistiske virkning af indanylderivaterne kan ifølge opfindelsen konstateres ved hjælp af den kendte adjuvans-arthritistest, der udføres som følger: 35
2 DK 159269 B
Der anvendes hunrotter og hanrotter af stammen Lewis (LEW) i vægtintervallet mellem 110-190 g. Dyrene får drikkevand og altrominpressefoder ad libitum.
For hver dosisgruppe anvendes 10 rotter.
5
Mycobacteriumbutyricum fra firmaet Difko, Detroit, anvendes som irritationsmiddel. En suspension af 0,5 mg mycobacterium-butyricum i 0,1 ml tyndtflydende paraffin (Deutsches Arznei-mittel Buch, 7. udgave) injiceres subplantart i højre bagpote.
10
Porsøgsstofferne gives oralt fra den 11. forsøgsdag dagligt i 4 dage. Stofferne gives som klare vandige opløsninger eller som krystalsuspensioner under tilsætning af MYRJ® 53 (85 mg %) i isotonisk natriumchloridopløsning.
15
Forsøgsopstilling:
Rotterne inddeles i forskellige grupper, mest muligt ensartet med hensyn til legemsvægt. Efter plethysmographisk rumfangsmåling af højre bagpote injiceres subplantart 0,1 ml adjuvans i denne. De højre bagpoter måles fra den 14. forsøgsdag til forsøgets afslutning. Forsøgets varighed er 3 uger.
Man bestemmer den kurering af bagpoterne, som opnås med de 2 5 givne doser.
En hyppig komplikation ved terapi med ikke-steroide betænde lseshæramende stoffer er optræden af mavesår. Denne bivirkning kan påvises ved dyreforsøg, idet antallet af iagttagne
w O
læsioner og deres samlede flade konstateres ved den givne dosis. Ulkusprøven udføres som følger:
Der anvendes han-Wistar-rotter (SPF). Dyrene ligger i vægtintervallet fra 130 + 10 g. 16 timer før forsøgets begyndel- 3 5 se tages foderet fra dyrene. De får vand ad libitum.
Pr. dosis anvendes 5 dyr. Stofferne indgives en gang oralt, opløst i natriumchlorid eller som krystalsuspension under tilsætning af 85 ml % MYRJ® 53.
3
DK 159269 B
3 timer efter stoffets applikation injicerer man 1 ml af en 3% opløsning af farvestoffet diphenylrenblåt intravenøst og dræber dyret. Maven undersøges mikroskopisk for antal og samlet størrelse af epithellæsioner og sår, som fremtræ-5 der på grund af farvestofberigelse.
Følgende tabel viser de ved disse prøver fremkomne resultater med forbindelserne ifølge opfindelsen, sammenlignet med det tidligere kendte indomethazin (stof 1). Af disse resultater fremgår overlegenheden af forbindelserne ifølge 10 opfindelsen især med hensyn til deres overlegne dissociation mellem antiinflammatorisk og ulcerogen virkning.
DK 159269 B
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6 DK 159269 B
De hidtil ukendte forbindelser egner sig i kombination med de i den galeniske farmaci sædvanlige bærestoffer til behandling af f.eks. akut og kronisk polyarthritis, neuro-dermatitis, astmabronchiale, høfeber og andet.
5 ^Fremstillingen af lægemiddelspecialiteterne sker på sædvanlig måde, idet man med egnede tilsætninger, bærestoffer og smagskorrigenser omdanner de virksomme stoffer til de ønskede applikationsformer såsom tabletter, drageer, kapsler, opløsninger , inhallationsmidler o.s.v.
10
Til oral anvendelse egner sig især tabletter, drageer og kapsler, der f.eks. indeholder 1-250 mg virksomt stof og 50 mg til 2 g pharmakologisk uvirksom bærer, f.eks. laktose,
amylose, talkum, gelatine, magniumstearat og lignende samt IS
de sædvanlige tilsætninger.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved, at man
a. kondenserer en forbindelse med den almene formel II
AR-X
20 I A (II) NH2
25 hvor AR, X og A har den ovennævnte betydning, med et sulfonsy-rederivat med den almene formel III
R1S02W (III) hvor Ri har den ovennævnte betydning, og W er et halogenatom 30 eller resten RjS020-, eller b. til fremstilling af indanderivater med den almene formel I, hvor A har betydningen -CO-CH2-CH2-» oxiderer et indanderivat med den almene formel I, hvor A har betydningen -CH2CH2CH2 35 *,,er c. til fremstilling af indanderivater med den almene formel I, 7
DK 159269 B
hvor A har betydningen -COCH(SOnR2)CH2-, omsætter et indande-rivat med den almene formel I, hvor A har betydningen -COCH2CH2-, i nærværelse af stærke baser med et disulfid med den almene formel IV
5 R2-S-S-R2 (IV) hvor R2 har den ovennævnte betydning, og eventuelt oxiderer de fremkomne thioforbindelser med den almene formel I til de tilsvarende sulfoxider eller sulfoner, eller 10 d. til fremstilling af indanderivater med den almene formel I, hvor A har betydningen -CHOH-CH2-CH2- eller -CHOH-CH-(S0nR2)CH2-, reducerer et indanderivat med den almene formel I, hvor A betyder -C0-CH2-CH2- eller -COCH(SOnR2)CH2-, eller e. til fremstilling af i ndander i vater med den almene formel I, 15 hvor A betyder -CH=CH-CH2-, dehydratiserer et indanderivat med den almene formel I, hvor A har betydningen -CHOH-CH2-CH2“· 20
Kondensationen af forbindelserne med den almene formel II med sulfonsyrechloriderne eller anhydriderne med den almene formel III ifølge fremgangsmådevariant a sker under de kend-2g te betingelser, f.eks. ved at man omsætter sulfonsyrechlori derne i nærværelse af basiske katalysatorer såsom natrium-carbonat, natriumhydroxid, kaliumbicarbonat, kaliumcarbonat, pyridin, lutidin eller collidin med forbindelserne af den almene formel II.
30
Oxydationen af methylengrupperne til de tilsvarende carbo-nylgrupper ifølge fremgangsmådevariant b kan f.eks. udføres med kaliumpermanganat i alkalisk,neutral eller svagt sur vandig opløsning eller ved hjælp af en opløsning af chrom (VI)-oxid i iseddike ved en temperatur på -10° C til 110° c.
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Fremgangsmådevariant c kan f.eks. udføres på den måde, at man omsætter udgangsforbindelserne i et aprot opløsningsmiddel (pyridin, dimethylformamid, hexamethylphosphorsyre-triamid, dioxan, tetrahydrofuran o.s.v.) med et alkalimetal-5 hydrid eller alkalimetalamid (f.eks. natriumhydrid eller lithiumdiisopropylamid) og lader det ønskede disulfid indvirke på den fremkomne reaktionsblanding. Denne reaktion udføres fortrinsvis ved en reaktionstemperatur på -60° C til + 20° C.
10 Den eventuelt påfølgende oxidation af thioforbindelserne til sulfoxiderne eller sulfonerne med den almene formel I sker på i og for sig kendte måder.
Til denne reaktion kan man som oxidationsmiddel f.eks. anvende persyrer såsom peredikkesyre, perbenzoesyre eller 15 m-chlorperbenzoesyre, hydrogenperoxyd, chinoner, såsom 2,3-dichlor-5,6-dicynobenzochinon, IV til VII-valente metaloxider eller -salte, såsom bly(IV)-oxid, mangan(IV)-oxid, chrom(VI)-oxid, cerium(IV)-sulfat, kaliumchromat, kaliumdichromat, kaliumpermanganat eller oxiderende halo-20 genforbindelser, såsom jod, natriumperjodat, N-bromrav-syreimid, N-chlorravsyreimid eller natriumchlorid.
Hvis man til denne oxidation anvender hydrogenperoxid eller metalloxider eller-salte, er det hensigtsmæssigt at udføre oxidationen i nærværelse af syrer. Egnede syrer er 25 mineralsyrer såsom saltsyre eller svovlsyre eller lavere carbonsyrer såsom edikkesyre eller propionsyre.
Som opløsningsmiddel kan man til denne reaktion anvende både protiske og aprote indifferente opløsningsmidler. Egnede opløsningsmidler er f.eks. lavere carbonsyrer såsom 30 edikkesyre eller propionsyre, tertiære alkoholer såsom tertiær butanol, ketoner såsom acetone, methylethylketon eller cyclohexanon, ethere såsom diethylether, diisopropylether, 9
DK 159269 B
tetrahydrofuran, dioxan eller glykoldimethylether, kulbrinter såsom benzol eller toluol eller chlorerede kulbrinter såsom methylenchlorid, chloroform, tetrachlorkul-stof, tetrachlorethan eller chlorbenzol. Til fremstilling 5 af sulfoner med den almene formel I anvender man som opløsningsmiddel fortrinsvis edikkesyre. Fremstillingen af sulfoxider sker fortrinsvis i acetone som opløsningsmiddel.
10
Fremgangsmådevariant d kan udføres på den måde, at man reducerer udgangsforbindelserne med komplekse metalhydrider 15 såsom natriumborhydrid (i en lavere alkohol såsom methanol, ethanol eller isopropanol som opløsningsmiddel) eventuelt under tilsætning af bortrifluorid eller trifluoredikkesy-re eller lithiumaluminiumhydrid (i en poleær ether såsom tetrahydrofuran eller dioxan som opløsningsmiddel).
20 På den anden side kan man også udføre denne variant på den måde, at man hydrogenerer udgangsforbindelserne i nærværelse af hydrogeneringskatalysatorer (Raney-nikkel, platinoxid, palladium på dyriske kul o.s.v.) med hydrogen ved 1-150 atm tryk.
25 Fremgangsmådevariant e udføres under de betingelser, som man sædvanligvis anvender til dehydratisering. Egnede metoder er f.eks. omsætning af forbindelserne med syrer (p-toluol-sulfonsyre, svovlsyre, polyphosphorsyre o.s.v.) eller vand-udtrækkende midler (kieselgel, phosphorpentoxid o.s.v.) 30 i indifferente opløsningsmidler (lavere ketoner såsom acetone, ethere såsom tetrahydrofuran eller dioxan eller aromatiske kulbrinter såsom benzol, toluol eller xylol).
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DK 159269 B
Udgangsforbindelserne til fremgangsmåden ifølge opfindelsen er kendt eller kan fremstilles på kend te måder.
Således kan man f.eks. fremstille forbindelserne af den 5 almene formel II ved kondensation af forbindelser af den
almene formel IV med forbindelser af den almene formel III og påfølgende reduktion af de fremkomne nitroforbindelser af den almene formel V
10
W
ARX H + | A -^ (III)
O0N
(IV) 15
ARX ARX
I -» ^A
(V) (II) 20 hvor ARX og A har den i kravet nævnte betydning/ og W betyder et chlor-, brom- eller jodatom.
25 Betingelserne, hvorunder disse udgangsforbindelser kan syn-teticeres, er beskrevet i de følgende eksempler med udvalgte repræsentanter. De følgende eksempler tjener til at belyse fremgangsmåden ifølge opfindelsen.
Eksempel 1.
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a. 12,1 g 5-brom-6-nitroindan, 0,75 g kobber(I)-chlorid, 17,3 g kaliumcarbonat og 18,4 g phenol i 200 ml absolut pyridin koges i 3 timer under tilbagesvaling.
5 Man inddamper i vacuum, sætter chloroform til rema nensen og frasuger uopløseligt stof. Moderluden ud-rystes hver 3 gange med 1 n-natronlud og 1 n-saltsyre og inddampes i vacuum. Efter destillation i vacuum fås 11,5 g 5-nitro-6-phenoxyindan med kogepunkt Q Q3 10 163-165° C. Smeltepunkt 41° C (hexan).
b. En opløsning af 17,7 g 5-nitro-6-phenoxyindan i 500 ml methanol hydrogeneres i nærværelse af 15 g Raney-nik-kel i 4 timer ved 70 ato. Man filtrerer fra katalysatoren, inddamper i vacuum og omkrystalliserer af van- 15 dig ethanol. Der fås 12,9 g 6-phenoxy-5-indanylamin med smeltepunkt 62° C.
c. I en opløsning af 7,8 g 6-phenoxy-5-indanylamin i 50 ml absolut pyridin inddryppes ved 0° C på 10 min.
4 ml methansulfonchlorid. Man omrører i 3 timer ved 20 0° C og 16 timer ved stuetemperatur og inddamper i vacuum. Remanensen optages i chloroform, udrystes 3 gange med 1 n-saltsyre og inddampes i vacuum. Derefter omkrystalliserer man af vandigt ethanol og får 9,5 g N-(6-phenoxy-5-indanyl)-methansulfonamid, smelte- 25 punkt 130° c.
Eksempel 2.
Analogt med eksempel 1 fås, når der gås ud fra 5-brom-6-ni- troindan og 4-chlorphenol: a. 5-(4-chlorphenoxy)-6-nitroindan, kogepunkt ved q q3 30 165-68° C, smeltepunkt 67° C (hexan).
DK 159269 12 b. 6-(4-chlorphenoxy)-5-indanylamin, smeltepunkt 66° C.
c. N-/6-(4-chlorphenoxy)-5-indanyl_7-methansulfonamid, smeltepunkt 57° C.
Eksempel 3.
5 Analogt med eksempel 1 fås ved at gå ud fra 5-brom-6-nitroin-dan og p-kresol: a. 5-nitro-6-(4-tolyloxy)-indan, kogepunktg g^ 168-73° C og smeltepunkt 58° C (hexan).
b. 6-(4-tolyloxy)-5-indanylamin som en olie.
10 c. N-/6-(4-tolyloxy)-5-indanyl_7-methansulfonamid, smelte punkt 139° C.
Eksempel 4,
Analogt med eksempel 1 fås, når der gås ud fra 5-brom-6-nitroindan og 4-fluorphenol: 15 a. 5-(4-fluorphenoxy)-6-nitroindan, kogepunktg g^ og smeltepunkt 63° C (hexan).
b. 6-(4-fluorphenoxy)-5-indanylamin, smeltepunkt 72° C.
c. N-/6-(4-fluorphenoxy)-5-indanyl_7-methansulfonamid, smeltepunkt 100° C.
20 Eksempel 5.
Analogt med eksempel 1 fås, når der gås ud fra 5-brom-6-nitroindan og 3-trifluormethylphenol: 13
DK 159269 B
a. 5-nitro-5-(3-trifluormethyl-phenoxy)-indan, kogepunkt ved 0 03 155 - 63° C og smeltepunkt 69° C (hexan).
b. 6-(3-trifluormethyl-phenoxy)-5-indanylamin som en olie.
5 c. N-/6-(3-trifluormethylphenoxy)-5-indanyl_/-methansul- fonamid, smeltepunkt 81° C.
Eksempel 6.
Analogt med eksempel 1 fås, når der gås ud fra 5-brom-6-ni- troindan og 4-chlor-2-methylphenols 10 a. 5-(4-chlor-2-methylphenoxy)-6-nitroindan, kogepunkt q Q2 187-90° C og smeltepunkt 61° C (hexan).
b. 6-(4-chlor-2-methylphenoxy)-5-indanylamin som en olie.
c. N-/6-(4-chlor-2-methyl-phenoxy)-5-indanyl_/-methansul-fonamid, smeltepunkt 116° C.
15 Eksempel 7.
Analogt med eksempel 1 fås, når der gås ud fra 5-brom-6-ni- troindan og 2-chlorphenol: a. 5-(2-chlorphenoxy)-6-nitroindan, kogepunkt q 175-78° C.
20 b. 6-(2-chlorphenoxy)-5-indanylamin som en olie.
c. N-/6-(2-chlorphenoxy)-5-indanyl_7“methansulfonamid, smeltepunkt 120° C.
Eksempel 8.
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Analogt med eksempel 1 fås, når der gås ud fra 5-brom-6- i nitroindan og 3-chlorphenol: a. 5-(3-chlorphenoxy)-6-nitroindan, kogepunkt ^ 5 176-82° C.
b. 6-(3-chlorphenoxy)-5-indanylamin som en olie. | c. N-/6-(3-chlorphenoxy)-5-indanyl_7-methansulfonamid, smeltepunkt 109-111° C.
Eksempel 9.
10 Analogt med eksempel 1 fås, når der gås ud fra 5-brom-6-nitroindan og 2-fluorphenol: a. 5-(2-fluorphenoxy)-6-nitroindan, kogepunkt n 155- 0 o u,uo 65 C og smeltepunkt 47 C.
b. 6-(2-fluorphenoxy)-5-indanylamin som en olie.
15 c. N-/6-(2-fluorphenoxy)-5-indanyl_7-methansulfonamid, smeltepunkt 78° C.
Eksempel 10.
Analogt med eksempel 1 fås, når der gås ud fra 5-brom-6-nitroindan og 2-chlor-4-fluorphenol: 20 a. 5-(2-chlor-4-fluorphenoxy)-6-nitroindan som en olie.
b. 6-(2-chlor-4-fluorphenoxy)-5-indanylamin, smeltepunkt 63° C.
15
DK 159269 B
c. N-/6-(2-chlor-4-fluorphenoxy)-5-indanyl_y-niethansulfon-amid, smeltepunkt 90° C.
Eksempel 11.
Analogt med eksempel 1 fås, når der gås ud fra 5-brom-6-5 nitroindan og 3,4-dichlorphenol: a. 5-(3,4-dichlorphenoxy)-6-nitroindan efter søjlerensning på kieselgel (system: tetrachlormethan/edikkesyreethyl- ester 30/1) som en olie.
b. 6-(3,4-dichlorphenoxy)-5-indanylamin, smeltepunkt 84° 10 C.
c. N-/6-(3,4-dichlorphenoxy)-5-indanyl_/-methansulfonamid, smeltepunkt 135° C.
Eksempel 12.
Analogt med eksempel 1 fås, når der gås ud fra 5-brom-6-15 nitroindan og 4-bromphenol: a. 5-(4-bromphenoxy)-6-nitroindan, kogepunkt Q 183-85° C.
b. 6-(4-bromphenoxy)-5-indanylamin, smeltepunkt 66° C.
c. N-/6-(4-bromphenoxy)-5-indanyl_7“methansulfonamid, 20 smeltepunkt 118° C.
Eksempel 13.
Analogt med eksempel 1 fås, når der gås ud fra 5-brom-6-nitroindan og 2,4-dichlorphenol: 16
DK 159269 B
a. 5-(2,4-dichlorphenoxy)-6-nitroindan, rensning over en kieselgelsøjle (system: tetrachlormethan/edikke- syreethylester, 30/1) som en olie.
b. 6-(2,4-dichlorphenoxy)-5-indanylamin som en olie.
5 c. N-/6-(2,4-dichlorphenoxy)-5-indanyl_7"methansulfon- amid, smeltepunkt 90° C.
Eksempel 14.
Analogt med eksempel 1 fås, når der gås ud fra 5-brom-6- nitroindan og o-kresol: 10 a. 5-nitro-6-(2-tolyloxy)indan, kogepunkt q 163-166° C.
b. 6-(2-tolyloxy)-5-indanylamin som en olie.
c. N-/6-(2-tolylosy)-5-indanyl_/-methansulfonamid, smeltepunkt 92° C.
15 Eksempel 15.
Analogt med eksempel 1 fås, når der gås ud fra 5-brom-6- nitroindan og 3-fluorphenol: a. 5-(3-fluorphenoxy)-6-nitroindan, kogepunkt q 155-63° C.
20 b. 6-(3-fluorphenoxy)-5-indanylamin, smeltepunkt 49° C.
c. N-/6-(3-fluorphenoxy)-5-indanyl_/-methansulfonamid, smeltepunkt 102° C.
Eksempel 16.
17
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a. 14,6 g 5-brom-6-nitroindan, 1,2 g kobber(I)-chlorid, 12,4 ml thiophenol og 8,4 g kaliumcarbonat i 150 ml absolut pyridin koges i 3 timer under tilbagesvaling 5 under nitrogen. Man inddamper i vacuum og oparbejder materialet som beskrevet i 11, a. Der omkrystalliseres af edikkesyreethylester, og man får 8,1 g 5-phenyl-thio-6-nitroindan, smeltepunkt 112° C.
b. I en opløsning af 9 g 5-phenylthio-6-nitroindan i 160 10 ml ethanol og 6,6 ml hydrazinhydrat indføres i koge varme 5 g Raney-nikkel, og der koges 1 1/4 time i tilbagesvaling. Man filtrerer fra katalysatoren, inddamper til krystallisation og får 7,1 g 6-phenylthio- 5-indanylamin, smeltepunkt 80° C.
15 c. Det fremkomne produkt omsættes som beskrevet i eksempel 11c til N-(6-phenylthio-5-indanyl)-methansulfonamid, smeltepunkt 115,5° C.
Eksempel 17,
Analogt med eksempel 16 fås, når der gås ud fra 5-brom-6-20 nitroindan og 4-tert-butylbenzolthiol: a. 5-(4-tert-butylphenylthio)-6-nitroindan, smeltepunkt 94° C.
b. 6-(4-tert-butylphenylthio)-5-indanylamin, smeltepunkt 92° C.
25 c. N-/6-(4-tert-butylphenylthio)-5-indanyl_/-methansulfon- amid, smeltepunkt 116° C.
Eksempel 18.
Analogt med eksempel 16 fås, når der gås ud fra 5-brom-6- nitroindan og 4-fluor-benzolthio : 18
DK 159269 B
a. 5-(4-fluorphenylthio)-6-nitroindan, smeltepunkt 106° 5 C.
b. 6-(4-fluorphenylthio)-5-indanylamin, smeltepunkt 60° C.
c. N-/6-(4-fluorphenylthio)-5-indanyl_7-methansulfonamid, smeltepunkt 139° C.
10 Eksempel 19.
a. 2,4 g 5-brom-6-nitroindan, 2,25 g kalium-tert-butylat og 2,9 g 4-chlorbenzolthio opvarmes i 30 ml absolut dimethylformamid under nitrogen i 3 timer til 60° C.
Der inddampes i vacuum, tilsættes edikkesyreethylester 15 og udrystes 3 gange med 2 n natronlud. Man inddamper igen og renser remanensen på en søjle af kieselgel (system: tetrachlormethan/edikkesyreethylester 25/1) og omkrystalliserer af ethanol. Der fremkom 1,2 g 5- (4-chlorphenylthio)-6-nitroindan, smeltepunkt 118° 20 C.
b. Analogt med eksempel 16, b, fås deraf: 6- (4-chlorphenylthio)-5-indanylamin, smeltepunkt 63° C.
c. Analogt med eksempel 1, c, fås deraf: 25 N-/6-(4-chlorphenylthio)-5-indanyl_7-methansulfonamid, smeltepunkt 109° C.
DK 159269B
Eksempel 20.
19 a. 4,8 .g 5-brom-6-nitroindan, 4,5 g kalium-tert-butylat, 4,4 g 2-pyridinthiol i 50 ml absolut dimethylformamid opvarmes i 3 timer under nitrogen til 80° C. Man ind- 5 damper i vacuum, sætter edikkesyreethylester til rema nensen og udryster 4 gange med vand. Edikkesyreethyl-esterfasen inddampes, og remanensen renses på en søjle af kieselgel (system; cyclohexan/edikkesyreethylester 4/1). Efter krystallisation af ethanol fås 3,3 g 10 5-nitro-6-(2-pyridylthio)-indan, smeltepunkt 74° C.
b. Analogt med eksempel 16, b, fås deraf; 6-(2-pyridylthio)-5-indanylamin, smeltepunkt 126° C.
c. Analogt med eksempel 1, c, fås deraf; N-/6-(2-pyridylthio)-5-indanyl_/-methansulfonamid, 15 smeltepunkt 141° C.
Eksempel 21.
a. 7,2 g 5-brom-6-nitroindan og 3,9 g 4-pyridinthiol opvarmes i 120 ml dimethylsulfoxid med 3,6 g natrium-hydrogencarbonat i 7 timer under nitrogen til 50° C.
20 Der inddampes, remanensen opløses i chloroform/vand og udrystes 3 gange med vand. Man inddamper og renser over en kieselgelsøjle (system; cyclohexan/edikke-ester 1/1). Efter krystallisation af ethanol fås 2 g 5- (4-pyridylthio)-6-nitroindan, smeltepunkt 113° C.
25 b. Analogt med eksempel 16, b, fås deraf; 6- (4-pyridylthio)-5-indanylamin, smeltepunkt 140° C.
c. Analogt med eksempel 1, c, fås deraf; N-/6-(4-pyridylthio)-5-indanyl_/-methansulfonamid, 30 smeltepunkt 156° C.
Analogt med eksempel 1 fås, idet der gås ud fra 5-brom-6- nitroindan og 3-hydroxypyridin:
Eksempel 22.
20
DK 159269 B
a. 6-(3-pyridyloxy)-5-nitroindan som en olie.
5 b. 6-(3-pyridiyloxy)-5-indanylamin, smeltepunkt 118° C.
c. N-/6- (3-pyridyloxy) - 5 - i ndany l__7_me thy lsulfonamid, smeltepunkt 126° C.
Eksempel 23.
lfl g 6-phenoxy-5-indanylamin opløses i 15 ml absolut pyri-10 din, og ved 0° C tilsættes i løbet af 10 min. 1,6 ml tri-fluormethansulfonsyreanhydrid i 5 ml absolut benzol. Man omrører i 3 timer ved 0° C og 16 timer ved stuetemperatur, inddamper i vacuum, optager remanensen i chloroform og udryster 3 gange med 1 n saltsyre. Derefter inddamper man 15 chloroformfasen i vacuum, renser remanensen på en kiesel- gelsøjle (system: chloroform) og omkrystalliserer af hexan.
Der fås 0,74 g N-(6-phenoxy-5-indanyl)-trifluormethansulfonamid, smeltepunkt 90° C.
Eksempel 24.
20 Analogt med eksempel 23 fås af 6-phenylthio-5-indanylamin: N-(6-phenylthio-5-indanyl)-trifluormethansulfonamid, smeltepunkt 67° C.
Eksempel 25.
Analogt med eksempel 23 fås af 6-(4-fluorphenoxy)-5-indanyl-25 amin: N-/6-(4-fluorphenoxy)-5-indanyl_7-trifluormethansulfonamid, smeltepunkt 123° C.
Eksempel 26.
21
DK 159269 B
Analogt med eksempel 23 fås af 4-chlorphenoxy-5-indanyl- amin: N-/6-(4-chlorphenoxy)-5-indanyl_7-trifluormethansulfon-5 amid, smeltepunkt 139° C.
Eksempel 27.
Analogt med eksempel 23 fås af 6-phenoxy-5-indanylamin med chlormethansulfonsyreanhydrid: N-(6-phenoxy-5-indany1)-chlormethansulfonamid, smelte-10 punkt 73° C.
Eksempel 28.
Analogt med eksempel 23 fås af 6-phenoxy-5-indanylamin med ethansulfonsyreanhydrid: N-(6-phenoxy-5-indanyl)-ethansulfonamid, smeltepunkt 89° 15 C.
Eksempel 29.
a. 11 g 5-nitro-6-phenoxyindan og 17,3 g bis-dimethylami-no-tert-butoxymethan opvarmes i 60 min. til 155° C og holdes i 60 min. ved denne temperatur, hvorved tert- 20 butanol aidestillerer. Derefter inddampes i vacuum, tilsættes 50 ml ethanol og frasuges. Der fås 9,2 g l-dimethylaminomethylen-5-nitro-6-phenoxyindan, smeltepunkt 97° C.
b. 6,2 g af denne enamin opløses i 100 ml chloroform og 25 ozoniseres ved -35° C. Efter filtrering over 30 g kieselgel med chloroform, inddampning og krystallisation af 30 ml ethanol fås 3,8 g 5-nitro-6-phenoxy-1-indanon, smeltepunkt 105° C.
22
DK 159269 B
c. 1,58 g af denne nitroketon opløses i 20 ml ethanol og 10 ml dioxan. Til opløsningen sættes 0,74 g hydrazinhydrat, og ved 35° C indføres portionsvis ca. 1,5 g Raney-nikkel (opslemmet i ethanol).
5 Efter 60 min. under tilbagesvaling afkøles, filtre res og inddampes. Omkrystallisation af ethanol giver 1,22 g 5-amino-6-phenoxy-l-indanon, smeltepunkt 170° C.
d. Til 1,2 g af denne aminoketon i 12 ml pyridin ved 0eC, sattes 0,5 ml methansulf.onylchlorid, og den henstilles i 3 10 timer ved stuetemperatur. Derefter inddampes i vacuum, og til remanensen sættes isvand, og der frasuges. Bundfaldet opløses i fortyndet natronlud, og den filtrerede opløsning syrnes med saltsyre. Frasugning og omkrystallisation af ethanol giver 1,35 g 5-methylsulfonylamino-6-phenoxy-l-indanon, smeltepunkt 15 175°C.
Eksempel 30.
Analogt med eksempel 29 fås, idet der gås ud fra 6-(4-chlorphenoxy)-5-nitroindan: a. 6-(4-chlorphenoxy)-l-dimethylaminomethylen-5-nitroin- 20 dan, smeltepunkt 117° C.
b. 6-(4-chlorphenoxy)-5-nitro-l-indanon, smeltepunkt 131 ° C.
c. 5-amino-6-(4-chlorphenoxy)-1-indanon, smeltepunkt 169° C.
25 d. 6-(4-chlorphenoxy)-5-methylsulfonylamino-l-indanon, smeltepunkt 185° C.
Eksempel 31.
23
DK 159269 B
Analogt med eksempel 29 fås, idet der gås ud fra 6-(4-fluorphenoxy) -5-nitroindan: a. l-dimethylaminomethylen-6-(4-fluorphenoxy)-5-nitroin- 5 dan, smeltepunkt 128° C.
b. 6-(4-fluorphenoxy)-5-nitro-l-indanon, smeltepunkt 150° C.
c. 5-amino-6-(4-fluorphenoxy)-1-indanon, smeltepunkt 167° C.
10 d. 6-(4-fluorphenoxy)-5-methylsulfonylamino-l-indanon, smeltepunkt 144° C.
Eksempel 32.
Analogt med eksempel 29 fås, idet der gås ud fra 6-(3- chlorphenoxy)-5-nitroindan: 15 a. 6-(3-chlorphenoxy)-l-dimethylaminomethylen-5-nitroin- dan, smeltepunkt 78° C.
b. 6-(3-chlorphenoxy)-5-nitro-l-indanon, smeltepunkt 92° C.
c. 5-amino-6-(3-chlorphenoxy)-1-indanon, smeltepunkt 20 162° C.
d. 6-(3-chlorphenoxy)-5-methylsulfonylamino-l-indanon, smeltepunkt 129° C.
Analogt med eksempel 29 fås, idet der gås ud fra 6-(2- fluorphenoxy)-5-nitroindan:
Eksempel 33.
24
DK 159269 B
a. l-dimethylaminomethylen-6-(2-fluorphenoxy)-5-nitroindan, 5 smeltepunkt 122° C.
b. 6-(2-fluorphenoxy)-5-nitro-l-indanon, smeltepunkt 104° C.
c. 5-amino-6-(2-fluorphenoxy)-1-indanon, smeltepunkt 164° C.
10 d. 6-(2-fluorphenoxy)-5-methylsulfonylamino-l-indanon, smeltepunkt 119° C.
Eksempel 34.
3,17 g 5-methylsulfonylamino-6-phenoxy-l-indanon i pyridin ved -40° C sættes 27 ml af en 10% opløsning af lithium-diiso-15 propylamid i hexan. Efter 20 min. ved -35° C tildryppes 4,4 g diphenyldisulfid i 10 ml pyridin. Efter 1 time ved -10° C og 2 timer ved 20° C tildryppes 10 ml 2-propanol.
Efter inddampning i vacuum optages i vand, filtreres, syr-nes og ekstraheres med chloroform. Inddampning og kroma-20 tografi af remanensen over 240 g kieselgel med chloroform som elusionsmiddel giver først 400 mg 5-methylsulfonylamino- 6-phenoxy-2,2-bis-(phenylthio)-1-indanon, smeltepunkt 162° C, og derefter 2 g 5-methylsulfonylamino-6-phenoxy-2-phenylthio-l-indanon, smeltepunkt 86° C.
25 Eksempel 35.
1,7 g 5-methylsulfonylamino-6-phenoxy-2-phenylthio-l-inda-non opløses i 20 ml methanol, og ved 20° C tilsættes 4 ml 25
DK 159269 B
af 1 n opløsning af perselensyre (litteratur: J. Drabo- wicz, M. Mikolajczyk, Synthesis 1978, 758) i methanol.
Efter 30 min. tilsættes 30 ml vand, methanol fjernes i vacuum og krystallisatet frasuges. Der fås 1,7 g 5-me-5 thylsulfonylamino-6-phenoxy-2-phenylsulfinyl-l-indanon, smeltepunkt 120° C.
Eksempel 36.
600 mg 5-methylsulfonylamino-6-phenoxy-2-phenylthio-l-indanon holdes i 30 min. ved 90° C i 5 ml edikkesyre med 10 2 ml 30%dig hydrogenperoxid. Derefter afkøles til 20° C, tilsættes 15 mm isvand og krystallisatet frasuges. Omkrystallisation af ethanol giver 400 mg 5-methylsulfo-nylamino-6-phenoxy-2-phenylsulfonyl-l-indanon, smeltepunkt 180° C.
15 Eksempel 37.
4,12 g 5-methylsulfonylamino-6-phenoxy-l-indanon opløses i 45 ml methanol og 13 ml 1 n natronlud. Ved 5° C tilsættes 0,98 g natriumborhydrid. Efter 16 timer ved 20° C inddampes, tilsættes isvand, neutraliseres med saltsyre og eks-20 traheres med chloroform. Vask af chloroformopløsningen med vand, inddampning og omkrystallisation af remanensen af tuluol giver 3,3 g 5-methylsulfonylamino-6-phenoxy-l-inda-nol, smeltepunkt 96° C.
Eksempel 38_ 25 3,58 g 5-methylsulfonylamino-6-phenoxy-2-phenylthio-l-inda- non opløses i 35 ml methanol og 9 ml 1 n natronlud. Ved 5° C tilsættes portionsvis 680 mg natriumborhydrid. Efter 16 timer ved 20° C indstilles til pH 8,2 med 22 ml 1 n saltsyre, og det udfældede krystallisat (3,50 g) frasuges. Kromatografi over 120 g kieselgel med chloroform giver først 2,5 g cis-5-methylsulfonylamino-6-phenoxy-2-phenyl-thio-l-indanol, smeltepunkt 135° C.
Eksempel 3.9
, DK 159269 B
26 a. 47,3 g 5-fluor-l-indanon behandles ved O til -5° C med 220 ml rygende salpetersyre (3 timer). Der hældes på isvand, ekstraheres med chloroform, og chloro- 5 formfasen vaskes neutral og inddampes. Omkrystallisa tion af remanensen af ethanol giver 20,4 g 5-fluor-6-nitro-l-indanon, smeltepunkt 89° C.
b. 20,3 g af denne forbindelse behandles i 130 ml dimethyl-sulfoxid i 3 timer ved 50° C med 9,8 g phenol og na- 10 triumhydrogencarbonat. Inddampning i vacuum, optagel se af remanensen i chloroform, vask med saltsyre og natronlud, tørring, inddampning og omkrystallisation af remanensen af ethanol giver 8,2 g 6-nitro-5-phenoxy-l-indanon, smeltepunkt 103° C.
15 c. 10,2 g af denne forbindelse reduceres som i eksempel 29, c. Der fås 5,7 g 6-amino-5-pheno.xy-l-indanon, smeltepunkt 133° C.
d. 4,57 g af denne forbindelse omsættes med methansulfonyl-chlorid som beskrevet i eksempel 29t d. Der fås 5,9 g 20 6-methylsulfony1amino-5-phenoxy-1-indanon, smeltepunkt 156° C.
Eksempel 40
Analogt med eksempel 37 fås af 6-methylsulfonylamino-5- phenoxy-1-indanon: 6-methylsulfonylamino-5-phenoxy-l-indanol, smeltepunkt 156° C.
25
Eksempel '41.
27
DK 159269 B
a. 1,56 g 5-fluor-6-nitro-l-indanon bliver i 28 ml dime-thylsulfoxid behandlet i 30 min. ved 20° C med 0,8 g natriumhydrogencarbonat og 0,88 g thiophenol. Inddamp-ning i vacuum, optagelse af remanensen i chloroform, vask med saltsyre og natronlud, tørring, inddampning og omkrystallisation af remanensen af ethanol giver 1,27 g 6-nitro-5-phenylthio-l-indanon, smeltepunkt 146° C.
b. 0,52 g af denne forbindelse reduceres som beskrevet i eksempel 29, c. Der fås 153 mg 6-amino-5-phenylthio-1-indanon, smeltepunkt 142° C.
15 c. 250 mg af denne forbindelse omsættes med methansulfonyl-chlorid som beskrevet i eksempel 29, d. Der fås 270 mg 6-methylsulfonylamino-5-phenylthio-l-indanon, smeltepunkt 166° C.
20
Eksempel 42 0,91 g N-(6-phenoxy-5-indanyl)-methansulfonamid opløses i 3 ml edikkesyre og 0,72 edikkesyreanhydrid, og ved 5-10° C tilsættes en opløsning af 0,39 chrom-VI-oxid i 0,3 ml 2 5 λ ^ og 2 ml edikkesyre. Efter 60 timer ved 20 C hældes på vand, og stoffet ekstraheres med edikkeester. Vask neutral og inddampning af opløsningen giver en stofblanding.
Ved kromatografi over kieselgel fås 0,47 g 5-methylsulfo- 30 nylamino-6-phenoxy-l-indanon, smeltepunkt 175° C.
35
Claims (1)
15 N-(6-phenoxy-5-indenyl)-methansulfonamid, smeltepunkt 126°C. Patentkrav. 20 Analogifremgangsmåde til fremstilling af svovlholdige indanyl-derivater med den almene formel I AR-X XX) R1S02NH 30 hvor AR er en phenylrest eller pyridylrest, der eventuelt er substitueret med 1-3 halogenatomer, alkylgrupper med 1-4 car-bonatomer eller trif1uormethylgrupper, X er et oxygenatom eller et svovlatom, Ri er en alkylgruppe med 1-4 carbonatomer, der eventuelt er substitueret med 1-3 fluoratomer eller chlor-35 atomer og A er grupperne -ch2-ch2-ch2-, -ch=ch-ch2-, -co-ch2-ch2-, -CH0H-CH2-CH2-, -C0CH(S0nR2)CH2- eller DK 159269 B -CH(0H)CH-(S0nR2)CH2- hvor n er et tal 0, 1 eller 2, og R2 er en alkylgruppe med 1-4 carbonatomer eller en phenylgruppe, der eventuelt er substitu-5 eret med 1-3 halogenatomer, alkylgrupper med 1-4 carbonatomer, nitrogrupper eller carboxylgrupper, og deres salte med fysiologisk anvendelige baser eller syrer, kendetegnet ved, at man 10 a. kondenserer en forbindelse med den almene formel II AR-X I (II) is NH2 hvor AR, X og A har den ovennævnte betydning, med et sulfonsy-rederivat med den almene formel III 20 RlS02W (III) hvor Ri har den ovennævnte betydning, og W er et halogenatom eller resten RiS020-, eller 25 b. til fremstilling af indånderivater med den almene formel I, hvor A har betydningen -CO-CH2-CH2-, oxiderer et indanderivat med den almene formel I, hvor A har betydningen -CH2CH2CH2-, eller 30 c. til fremstilling af i ndanderivater med den almene formel I, hvor A har betydningen -COCH(SOnR2)CH2-, omsætter et indanderivat med den almene formel I, hvor A har betydningen -C0CH2CH2-, i nærværelse af stærke baser med et disulfid med 35 den almene formel IV R2-S-S-R2 (IV) DK 159269 B hvor R2 har den ovennævnte betydning, og eventuelt oxiderer de fremkomne thioforbindelser med den almene formel I til de tilsvarende sulfoxider eller sulfoner, eller d. til fremstilling af indanderivater med den almene formel I, 5 hvor A har betydningen -CHOH-CH2-CH2- eller -CHOH-CH(SOnR2)CH2-, reducerer et indanderivat med den almene formel I, hvor A betyder -C0-CH2-CH2- eller -C0CH(S0nR2)CH2-, eller e. til fremstilling af indanderivater med den almene formel I, 10 hvor A betyder -CH=CH-CH2“, dehydratiserer et indanderivat med den almene formel I, hvor A har betydningen -CH0H-CH2-CH2-. 15 20 25 35
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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DE19782833202 DE2833202A1 (de) | 1978-07-27 | 1978-07-27 | Neue indanyl- und tetralinylamide, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische praeparate |
DE2833202 | 1978-07-27 | ||
DE19792923937 DE2923937A1 (de) | 1979-06-11 | 1979-06-11 | Neue indanyl-derivate, ihre herstellung und verwendung |
DE2923937 | 1979-06-11 |
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DK315979A DK315979A (da) | 1980-01-28 |
DK159269B true DK159269B (da) | 1990-09-24 |
DK159269C DK159269C (da) | 1991-02-18 |
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DK315979A DK159269C (da) | 1978-07-27 | 1979-07-26 | Analogifremgangsmaade til fremstilling af svovlholdige indanylderivater |
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US (1) | US4244960A (da) |
EP (1) | EP0009554B1 (da) |
AU (1) | AU532405B2 (da) |
BG (1) | BG36197A3 (da) |
CA (1) | CA1124724A (da) |
DD (1) | DD145101A5 (da) |
DE (1) | DE2965279D1 (da) |
DK (1) | DK159269C (da) |
DZ (1) | DZ206A1 (da) |
EG (1) | EG14394A (da) |
ES (1) | ES482918A1 (da) |
FI (1) | FI71306C (da) |
FR (1) | FR2433512A1 (da) |
GB (1) | GB2025973A (da) |
GR (1) | GR73006B (da) |
IE (1) | IE48783B1 (da) |
IL (1) | IL57901A (da) |
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Families Citing this family (20)
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DE3103372A1 (de) * | 1981-01-27 | 1982-09-02 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | Neue indanyl-derivate, ihre herstellung und verwendung |
DE3208079A1 (de) * | 1982-03-04 | 1983-09-08 | Schering AG, 1000 Berlin und 4709 Bergkamen | Neue indanyl-derivate, ihre herstellung und verwendung |
US4555406A (en) * | 1983-09-06 | 1985-11-26 | Schering Aktiengesellschaft | Indanyl derivatives, their preparation and use |
DE3343331A1 (de) * | 1983-11-28 | 1985-06-05 | Schering AG, 1000 Berlin und 4709 Bergkamen | Verfahren zur herstellung von indanyl-derivaten und deren verwendung |
US5035739A (en) * | 1987-02-10 | 1991-07-30 | Idemitsu Kosan Company Limited | Trifluoromethanesulfonamide derivative and a herbicide containing the same |
WO1988006155A1 (en) * | 1987-02-10 | 1988-08-25 | Idemitsu Kosan Company Limited | Trifluoromethanesulfonamide derivatives, process for their preparation, and herbicides containing same |
JPH0753725B2 (ja) * | 1987-10-08 | 1995-06-07 | 富山化学工業株式会社 | 4h―1―ベンゾピラン―4―オン誘導体およびその塩、それらの製造法並びにそれらを含有する抗炎症剤 |
GB9003551D0 (en) * | 1990-02-16 | 1990-04-11 | Ici Plc | Heterocyclic compounds |
US5604260A (en) * | 1992-12-11 | 1997-02-18 | Merck Frosst Canada Inc. | 5-methanesulfonamido-1-indanones as an inhibitor of cyclooxygenase-2 |
US5409944A (en) * | 1993-03-12 | 1995-04-25 | Merck Frosst Canada, Inc. | Alkanesulfonamido-1-indanone derivatives as inhibitors of cyclooxygenase |
WO1996023786A1 (en) * | 1995-01-31 | 1996-08-08 | Merck Frosst Canada Inc. | 5-methanesulfonamido-3h-isobenzofuran-1-ones as inhibitors of cyclooxygenase-2 |
ES2138902B1 (es) * | 1997-05-19 | 2000-09-16 | Salvat Lab Sa | "5-ariltio-6-sulfonamido-3(2h)-benzofuranonas como inhibidores de la cox-2". |
DE10142660A1 (de) * | 2001-08-31 | 2003-03-20 | Aventis Pharma Gmbh | Verwendung von Derivaten von C2-substituierten Indan-1-ol-Systemen zur Herstellung von Medikamenten zur Prophylaxe oder Behandlung von Obesitas |
DE10142659A1 (de) * | 2001-08-31 | 2003-03-20 | Aventis Pharma Gmbh | Verwendung von mehrfach substituierten Indan-1-ol. Systemen zur Herstellung von Medikamenten zur Prophylaxe oder Behandlung von Obesitas |
DE10142667B4 (de) | 2001-08-31 | 2004-06-09 | Aventis Pharma Deutschland Gmbh | C2-substituierte Indan-1-ole und ihre Derivate und ihre Verwendung als Arzneimittel |
DE10142661B4 (de) * | 2001-08-31 | 2004-06-09 | Aventis Pharma Deutschland Gmbh | Mehrfach substituierte Indan-1-ol-Systeme und ihre Verwendung als Arzneimittel |
DE10142662B4 (de) | 2001-08-31 | 2004-07-08 | Aventis Pharma Deutschland Gmbh | Derivate von C2-substituierten Indan-1-ol-Systemen und ihre Verwendung als Arzneimittel |
DE10142668A1 (de) * | 2001-08-31 | 2003-03-20 | Aventis Pharma Gmbh | Verwendung von C2-substituierten Indan-1-on-Systemen zur Herstellung von Medikamenten zur Prophylaxe oder Behandlung von Obesitas |
DE10142666A1 (de) * | 2001-08-31 | 2003-03-20 | Aventis Pharma Gmbh | Verwendung von C2-substituierten Indan-1-ol-Systemen zur Herstellung von Medikamenten zur Prophylaxe oder Behandlung von Obesitas |
DE10142722A1 (de) * | 2001-08-31 | 2003-03-27 | Aventis Pharma Deutschland GmbH, 65929 Frankfurt | C2-substituierte Indan-1-one und ihre Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
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US2921958A (en) * | 1954-09-03 | 1960-01-19 | Ruhrchemie Ag | 4.5.6.7.10.10-hexachloro-4.7-methylene-4.7.8.9-tetrahydroindane-sulfonic acid, saltsand acid amides thereof |
US3288852A (en) * | 1964-05-08 | 1966-11-29 | Dow Chemical Co | Anthracene dialkanesulfonamides |
AR206496A1 (es) * | 1972-07-03 | 1976-07-30 | Riker Laboratories Inc | Procedimiento para la preparacion de 2-fenoxi-4-nitro-alquil o haloalquilsulfonanilidas |
US4087549A (en) * | 1972-12-06 | 1978-05-02 | Merck & Co., Inc. | Sulphonic acid containing indenyl derivatives |
US4086255A (en) * | 1974-04-15 | 1978-04-25 | Minnesota Mining And Manufacturing Company | Perfluoroalkylsulfonamidoaryl compounds |
GB1472843A (en) * | 1976-02-12 | 1977-05-11 | Pfizer Ltd | Benzene sulphonamides |
GB2009146B (en) * | 1977-11-29 | 1982-03-24 | Ishihara Sangyo Kaisha | Sulphonanilide copmouds and herbicidal compositions therof |
-
1979
- 1979-07-20 DE DE7979102566T patent/DE2965279D1/de not_active Expired
- 1979-07-20 EP EP79102566A patent/EP0009554B1/de not_active Expired
- 1979-07-24 BG BG044445A patent/BG36197A3/xx unknown
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- 1979-07-24 NZ NZ191100A patent/NZ191100A/xx unknown
- 1979-07-25 PL PL1979217384A patent/PL126816B1/pl unknown
- 1979-07-25 DZ DZ795518A patent/DZ206A1/fr active
- 1979-07-25 GR GR59694A patent/GR73006B/el unknown
- 1979-07-25 EG EG448/79A patent/EG14394A/xx active
- 1979-07-26 FR FR7919301A patent/FR2433512A1/fr active Pending
- 1979-07-26 DK DK315979A patent/DK159269C/da not_active IP Right Cessation
- 1979-07-26 GB GB7926016A patent/GB2025973A/en not_active Withdrawn
- 1979-07-26 PT PT69986A patent/PT69986A/pt unknown
- 1979-07-26 NO NO792474A patent/NO147560C/no unknown
- 1979-07-26 PH PH22819A patent/PH20604A/en unknown
- 1979-07-26 IL IL57901A patent/IL57901A/xx unknown
- 1979-07-26 FI FI792347A patent/FI71306C/fi not_active IP Right Cessation
- 1979-07-27 ES ES482918A patent/ES482918A1/es not_active Expired
- 1979-07-27 CA CA332,665A patent/CA1124724A/en not_active Expired
- 1979-07-27 AU AU49325/79A patent/AU532405B2/en not_active Ceased
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US4244960A (en) | 1981-01-13 |
FI792347A (fi) | 1980-01-28 |
DD145101A5 (de) | 1980-11-19 |
AU4932579A (en) | 1980-02-07 |
BG36197A3 (en) | 1984-09-14 |
GB2025973A (en) | 1980-01-30 |
AU532405B2 (en) | 1983-09-29 |
ES482918A1 (es) | 1980-05-16 |
DE2965279D1 (en) | 1983-06-01 |
IE48783B1 (en) | 1985-05-15 |
NO147560C (no) | 1983-05-04 |
EG14394A (en) | 1983-12-31 |
PH20604A (en) | 1987-02-24 |
PT69986A (de) | 1979-08-01 |
EP0009554A1 (de) | 1980-04-16 |
PL126816B1 (en) | 1983-09-30 |
CA1124724A (en) | 1982-06-01 |
DK159269C (da) | 1991-02-18 |
DZ206A1 (fr) | 2004-09-13 |
NO147560B (no) | 1983-01-24 |
IL57901A (en) | 1983-11-30 |
FI71306B (fi) | 1986-09-09 |
NO792474L (no) | 1980-01-29 |
IE791422L (en) | 1980-01-27 |
GR73006B (da) | 1984-01-24 |
DK315979A (da) | 1980-01-28 |
PL217384A1 (da) | 1981-11-13 |
FI71306C (fi) | 1986-12-19 |
EP0009554B1 (de) | 1983-04-27 |
RO78632A (ro) | 1982-04-12 |
IL57901A0 (en) | 1979-11-30 |
FR2433512A1 (fr) | 1980-03-14 |
NZ191100A (en) | 1982-03-30 |
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