AU668694B2 - Saccharin derivative proteolytic enzyme inhibitors - Google Patents
Saccharin derivative proteolytic enzyme inhibitors Download PDFInfo
- Publication number
- AU668694B2 AU668694B2 AU28292/92A AU2829292A AU668694B2 AU 668694 B2 AU668694 B2 AU 668694B2 AU 28292/92 A AU28292/92 A AU 28292/92A AU 2829292 A AU2829292 A AU 2829292A AU 668694 B2 AU668694 B2 AU 668694B2
- Authority
- AU
- Australia
- Prior art keywords
- alkyl
- alkoxy
- phenyl
- compound
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
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- 102000035195 Peptidases Human genes 0.000 title claims abstract description 14
- 108091005804 Peptidases Proteins 0.000 title claims abstract description 14
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical class C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 title description 6
- 239000002532 enzyme inhibitor Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- 238000000034 method Methods 0.000 claims abstract description 18
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 230000002255 enzymatic effect Effects 0.000 claims abstract description 5
- -1 cyano, amino Chemical group 0.000 claims description 60
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- 125000005843 halogen group Chemical group 0.000 claims description 15
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 8
- 229940081974 saccharin Drugs 0.000 claims description 8
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000005605 benzo group Chemical group 0.000 claims description 7
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 150000001447 alkali salts Chemical class 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 5
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 4
- 125000001246 bromo group Chemical group Br* 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
- 125000000524 functional group Chemical group 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 2
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims 2
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 125000001891 dimethoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 1
- 230000002797 proteolythic effect Effects 0.000 claims 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 abstract description 6
- 235000013350 formula milk Nutrition 0.000 description 52
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 239000000203 mixture Substances 0.000 description 29
- 239000000243 solution Substances 0.000 description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- 238000003756 stirring Methods 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000007787 solid Substances 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- IAVWIJNTOZKJNL-UHFFFAOYSA-N 2-(chloromethyl)-6-methoxy-1,1-dioxo-4-propan-2-yl-1,2-benzothiazol-3-one Chemical compound CC(C)C1=CC(OC)=CC2=C1C(=O)N(CCl)S2(=O)=O IAVWIJNTOZKJNL-UHFFFAOYSA-N 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- 238000001953 recrystallisation Methods 0.000 description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- 102000004190 Enzymes Human genes 0.000 description 10
- 108090000790 Enzymes Proteins 0.000 description 10
- 229940088598 enzyme Drugs 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000002844 melting Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 9
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 101000856199 Homo sapiens Chymotrypsin-like protease CTRL-1 Proteins 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- DTRAMHZJAGWMIU-UHFFFAOYSA-N 2-(chloromethyl)-1,1-dioxo-4-propan-2-yl-1,2-benzothiazol-3-one Chemical compound CC(C)C1=CC=CC2=C1C(=O)N(CCl)S2(=O)=O DTRAMHZJAGWMIU-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 101000851058 Homo sapiens Neutrophil elastase Proteins 0.000 description 4
- 102100033174 Neutrophil elastase Human genes 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
- 230000002901 elastaselike Effects 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 238000010183 spectrum analysis Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 239000003039 volatile agent Substances 0.000 description 4
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 102100025566 Chymotrypsin-like protease CTRL-1 Human genes 0.000 description 3
- 241000283891 Kobus Species 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001241 acetals Chemical class 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 150000001450 anions Chemical class 0.000 description 3
- 150000001768 cations Chemical class 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000006264 debenzylation reaction Methods 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 239000002480 mineral oil Substances 0.000 description 3
- 235000010446 mineral oil Nutrition 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- DDLHDRRADMRZTL-UHFFFAOYSA-N 1,1-dioxo-2-(phenylsulfanylmethyl)-4-propan-2-yl-1,2-benzothiazol-3-one Chemical compound CC(C)C1=CC=CC(S2(=O)=O)=C1C(=O)N2CSC1=CC=CC=C1 DDLHDRRADMRZTL-UHFFFAOYSA-N 0.000 description 2
- MRPAHFZTHXMLRO-UHFFFAOYSA-N 1,1-dioxo-4-propan-2-yl-1,2-benzothiazol-3-one Chemical compound CC(C)C1=CC=CC2=C1C(=O)NS2(=O)=O MRPAHFZTHXMLRO-UHFFFAOYSA-N 0.000 description 2
- GEUAWNMVARSYHO-UHFFFAOYSA-N 1-(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)ethanone Chemical compound COC1=C(O)C(C(C)=O)=C(OC)C2=C1OC=C2 GEUAWNMVARSYHO-UHFFFAOYSA-N 0.000 description 2
- OEBXWWBYZJNKRK-UHFFFAOYSA-N 1-methyl-2,3,4,6,7,8-hexahydropyrimido[1,2-a]pyrimidine Chemical compound C1CCN=C2N(C)CCCN21 OEBXWWBYZJNKRK-UHFFFAOYSA-N 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 2
- CHMOXOZMBYAKCO-UHFFFAOYSA-N 4-(cyclodecen-1-yl)-2-methyl-5,6,7,8,9,10-hexahydro-1h-triazecine Chemical compound CN1NCCCCCCC(C=2CCCCCCCCC=2)=N1 CHMOXOZMBYAKCO-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 206010014561 Emphysema Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 206010033645 Pancreatitis Diseases 0.000 description 2
- 102000012479 Serine Proteases Human genes 0.000 description 2
- 108010022999 Serine Proteases Proteins 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 125000005529 alkyleneoxy group Chemical group 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- WACQKHWOTAEEFS-UHFFFAOYSA-N cyclohexane;ethyl acetate Chemical compound CCOC(C)=O.C1CCCCC1 WACQKHWOTAEEFS-UHFFFAOYSA-N 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 2
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 2
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 2
- 230000002849 elastaseinhibitory effect Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 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
- WOKBBEMSLMPMML-UHFFFAOYSA-N n,n-diethyl-2-propan-2-yl-6-sulfamoylbenzamide Chemical compound CCN(CC)C(=O)C1=C(C(C)C)C=CC=C1S(N)(=O)=O WOKBBEMSLMPMML-UHFFFAOYSA-N 0.000 description 2
- WSEACOLMAYJBDZ-UHFFFAOYSA-N n,n-diethyl-2-propan-2-ylbenzamide Chemical compound CCN(CC)C(=O)C1=CC=CC=C1C(C)C WSEACOLMAYJBDZ-UHFFFAOYSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 150000004965 peroxy acids Chemical class 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000000527 sonication Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- KPZGRMZPZLOPBS-UHFFFAOYSA-N 1,3-dichloro-2,2-bis(chloromethyl)propane Chemical compound ClCC(CCl)(CCl)CCl KPZGRMZPZLOPBS-UHFFFAOYSA-N 0.000 description 1
- LECYCYNAEJDSIL-UHFFFAOYSA-N 1-bromo-2-propan-2-ylbenzene Chemical compound CC(C)C1=CC=CC=C1Br LECYCYNAEJDSIL-UHFFFAOYSA-N 0.000 description 1
- VIIZQSYUDKFSAG-UHFFFAOYSA-N 2-[(5-acetyl-4,7-dimethoxy-1-benzofuran-6-yl)oxymethyl]-6-methoxy-1,1-dioxo-4-propan-2-yl-1,2-benzothiazol-3-one Chemical compound CC(C)C1=CC(OC)=CC(S2(=O)=O)=C1C(=O)N2COC(C(=C1OC)C(C)=O)=C(OC)C2=C1C=CO2 VIIZQSYUDKFSAG-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
- C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Cosmetics (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyrrole Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Beans For Foods Or Fodder (AREA)
- Fertilizers (AREA)
- Bakery Products And Manufacturing Methods Therefor (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (2)
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|---|---|---|---|
| US81026591A | 1991-12-19 | 1991-12-19 | |
| US810265 | 1991-12-19 |
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| AU2829292A AU2829292A (en) | 1993-07-08 |
| AU668694B2 true AU668694B2 (en) | 1996-05-16 |
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| AU28292/92A Ceased AU668694B2 (en) | 1991-12-19 | 1992-11-12 | Saccharin derivative proteolytic enzyme inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008040057A1 (en) * | 2006-10-04 | 2008-04-10 | Bionomics Limited | Novel benzofuran potassium channel blockers and uses thereof |
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| US5378720A (en) * | 1991-12-19 | 1995-01-03 | Sterling Winthrop Inc. | Saccharin derivative proteolytic enzyme inhibitors |
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| US5541168A (en) * | 1994-12-02 | 1996-07-30 | Sterling Winthrop Inc. | Substituted 2-(phosphinyloxymethyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxides and compositions and method of use thereof |
| DE19533643A1 (de) * | 1995-09-12 | 1997-03-13 | Nycomed Arzneimittel Gmbh | Neue cyclische Derivate von Benzolsulfonamiden |
| US5750550A (en) * | 1995-09-15 | 1998-05-12 | Sanofi | 2-(pyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3 (2H)-One 1, 1-dioxides and compositions and method of use thereof |
| CA2469435A1 (en) | 2001-12-21 | 2003-07-24 | X-Ceptor Therapeutics, Inc. | Modulators of lxr |
| US7482366B2 (en) | 2001-12-21 | 2009-01-27 | X-Ceptor Therapeutics, Inc. | Modulators of LXR |
| AP1822A (en) | 2002-02-14 | 2008-01-30 | Pharmacia Corp | Substituted pyridinones as modulators of P38 MAP kinase. |
| AR059898A1 (es) | 2006-03-15 | 2008-05-07 | Janssen Pharmaceutica Nv | Derivados de 3-ciano-piridona 1,4-disustituida y su uso como moduladores alostericos de los receptores mglur2 |
| WO2008076427A2 (en) | 2006-12-18 | 2008-06-26 | Amgen Inc. | Naphthalenone compounds exhibiting prolyl hydroxylase inhibitory activity, compositions, and uses thereof |
| AU2007334321B2 (en) | 2006-12-18 | 2012-03-08 | Amgen Inc. | Azaquinolone based compounds exhibiting prolyl hydroxylase inhibitory activity, compositions, and uses thereof |
| TW200845978A (en) | 2007-03-07 | 2008-12-01 | Janssen Pharmaceutica Nv | 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives |
| TW200900065A (en) | 2007-03-07 | 2009-01-01 | Janssen Pharmaceutica Nv | 3-cyano-4-(4-pyridinyloxy-phenyl)-pyridin-2-one derivatives |
| JP2010524942A (ja) | 2007-04-18 | 2010-07-22 | アムジエン・インコーポレーテツド | プロリルヒドロキシラーゼを阻害するキノロン及びアザキノロン |
| EP2155680B1 (en) | 2007-04-18 | 2013-12-04 | Amgen, Inc | Indanone derivatives that inhibit prolyl hydroxylase |
| CA2685216C (en) | 2007-05-04 | 2014-07-08 | Amgen Inc. | Thienopyridine and thiazolopyridine derivatives that inhibit prolyl hydroxylase activity |
| WO2008137084A2 (en) | 2007-05-04 | 2008-11-13 | Amgen Inc. | Diazaquinolones that inhibit prolyl hydroxylase activity |
| RS51660B (sr) | 2007-09-14 | 2011-10-31 | Ortho-Mcneil-Janssen Pharmaceuticals Inc. | 1`,3`-disupstituisani-4-fenil-3,4,5,6-tetrahidro-2h, 1`h-[1,4`] bipiridinil-2`-oni |
| EP2344470B1 (en) | 2008-09-02 | 2013-11-06 | Janssen Pharmaceuticals, Inc. | 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors |
| JP5690277B2 (ja) | 2008-11-28 | 2015-03-25 | ジャンセン ファーマシューティカルズ， インコーポレイテッド． | 代謝型グルタミン酸受容体の調節因子としてのインドールおよびベンゾオキサジン誘導体 |
| MY153913A (en) | 2009-05-12 | 2015-04-15 | Janssen Pharmaceuticals Inc | 7-aryl-1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors |
| KR20120035158A (ko) | 2009-05-12 | 2012-04-13 | 얀센 파마슈티칼즈, 인코포레이티드 | 1,２,４?트리아졸로［４,３?ａ］피리딘 유도체 및 ｍＧｌｕＲ２ 수용체의 양성 알로스테릭 조절자로서의 그의 용도 |
| US8937060B2 (en) | 2009-05-12 | 2015-01-20 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders |
| CN103298809B (zh) | 2010-11-08 | 2016-08-31 | 杨森制药公司 | 1,2,4-三唑并[4,3-a]吡啶衍生物及其作为MGLUR2受体的正变构调节剂的用途 |
| CA2814996C (en) | 2010-11-08 | 2019-10-01 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors |
| EP2643320B1 (en) | 2010-11-08 | 2015-03-04 | Janssen Pharmaceuticals, Inc. | 1,2,4-TRIAZOLO[4,3-a]PYRIDINE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS |
| JO3368B1 (ar) | 2013-06-04 | 2019-03-13 | Janssen Pharmaceutica Nv | مركبات 6، 7- ثاني هيدرو بيرازولو [5،1-a] بيرازين- 4 (5 يد)- اون واستخدامها بصفة منظمات تفارغية سلبية لمستقبلات ميجلور 2 |
| JO3367B1 (ar) | 2013-09-06 | 2019-03-13 | Janssen Pharmaceutica Nv | مركبات 2،1، 4- ثلاثي زولو [3،4-a] بيريدين واستخدامها بصفة منظمات تفارغية موجبة لمستقبلات ميجلور 2 |
| CN109999033B (zh) | 2014-01-21 | 2022-12-23 | 詹森药业有限公司 | 包括代谢型谷氨酸能受体亚型2的正别构调节物或正位激动剂的组合及其用途 |
| HRP20191646T1 (hr) | 2014-01-21 | 2019-12-13 | Janssen Pharmaceutica Nv | Kombinacije koje sadržavaju pozitivne alosteričke modulatore ili ortosteričke agoniste metabotropnog glutamatergičnog receptora podtip 2 i njihova uporaba |
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| AU2605792A (en) * | 1991-11-15 | 1993-05-20 | Sanofi | Saccharin derivative proteolytic enzime inhibitors |
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| US4276298A (en) * | 1978-03-24 | 1981-06-30 | Merck & Co., Inc. | 2-Aryl-1,2-benzisothiazolinone-1,1-dioxides and their use as selective protease inhibitors |
| DE3617976A1 (de) * | 1986-05-28 | 1988-01-14 | Alter Sa | 1,4-dihydropyridin, verfahren zu dessen herstellung und dessen verwendung in antithrombotischen medikamenten |
| ES2110414T3 (es) * | 1989-05-04 | 1998-02-16 | Sanofi Sa | Derivados de sacarina utiles como inhibidores de enzimas proteoliticas y su preparacion. |
| AU642537B2 (en) * | 1990-11-01 | 1993-10-21 | Sanofi | 2-saccharinylmethyl aryl carboxylates useful as proteolytic enzyme inhibitors and compositions and method of use thereof |
-
1992
- 1992-11-12 AU AU28292/92A patent/AU668694B2/en not_active Ceased
- 1992-11-18 TW TW081109245A patent/TW225532B/zh active
- 1992-12-08 CA CA002084857A patent/CA2084857A1/en not_active Abandoned
- 1992-12-11 MY MYPI92002285A patent/MY110104A/en unknown
- 1992-12-15 AT AT92203917T patent/ATE233250T1/de not_active IP Right Cessation
- 1992-12-15 SG SG1996007465A patent/SG52659A1/en unknown
- 1992-12-15 EP EP92203917A patent/EP0547708B1/en not_active Expired - Lifetime
- 1992-12-15 DE DE69232929T patent/DE69232929D1/de not_active Expired - Lifetime
- 1992-12-17 JP JP33703492A patent/JP3179600B2/ja not_active Expired - Fee Related
- 1992-12-17 KR KR1019920024707A patent/KR100292995B1/ko not_active Expired - Fee Related
- 1992-12-18 RU RU92016244A patent/RU2107685C1/ru not_active IP Right Cessation
- 1992-12-18 NO NO924915A patent/NO300770B1/no unknown
- 1992-12-18 MX MX9207449A patent/MX9207449A/es not_active IP Right Cessation
- 1992-12-18 CZ CS923746A patent/CZ283257B6/cs not_active IP Right Cessation
- 1992-12-18 HU HU9204029A patent/HU219950B/hu not_active IP Right Cessation
- 1992-12-18 SK SK3746-92A patent/SK374692A3/sk unknown
- 1992-12-18 NZ NZ245518A patent/NZ245518A/en unknown
- 1992-12-18 FI FI925787A patent/FI925787L/fi unknown
- 1992-12-18 IL IL10415492A patent/IL104154A/en not_active IP Right Cessation
-
2000
- 2000-10-20 KR KR1020000061842A patent/KR100378968B1/ko not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2605792A (en) * | 1991-11-15 | 1993-05-20 | Sanofi | Saccharin derivative proteolytic enzime inhibitors |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008040057A1 (en) * | 2006-10-04 | 2008-04-10 | Bionomics Limited | Novel benzofuran potassium channel blockers and uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0547708B1 (en) | 2003-02-26 |
| NO300770B1 (no) | 1997-07-21 |
| NO924915D0 (no) | 1992-12-18 |
| JP3179600B2 (ja) | 2001-06-25 |
| MY110104A (en) | 1998-01-27 |
| CZ283257B6 (cs) | 1998-02-18 |
| CZ374692A3 (en) | 1993-08-11 |
| HU219950B (hu) | 2001-09-28 |
| RU2107685C1 (ru) | 1998-03-27 |
| HU9204029D0 (en) | 1993-04-28 |
| KR100378968B1 (ko) | 2003-04-08 |
| FI925787A0 (fi) | 1992-12-18 |
| IL104154A0 (en) | 1993-05-13 |
| JPH05345771A (ja) | 1993-12-27 |
| ATE233250T1 (de) | 2003-03-15 |
| IL104154A (en) | 1996-09-12 |
| NZ245518A (en) | 1995-06-27 |
| KR100292995B1 (ko) | 2001-09-17 |
| HUT67039A (en) | 1995-01-30 |
| TW225532B (cg-RX-API-DMAC7.html) | 1994-06-21 |
| DE69232929D1 (de) | 2003-04-03 |
| NO924915L (no) | 1993-06-21 |
| MX9207449A (es) | 1994-03-31 |
| FI925787A7 (fi) | 1993-06-20 |
| SG52659A1 (en) | 1998-09-28 |
| AU2829292A (en) | 1993-07-08 |
| SK278390B6 (en) | 1997-02-05 |
| SK374692A3 (en) | 1997-02-05 |
| FI925787L (fi) | 1993-06-20 |
| EP0547708A1 (en) | 1993-06-23 |
| CA2084857A1 (en) | 1993-06-20 |
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