CA2719457C - Arylsulfonamide-based matrix metalloprotease inhibitors - Google Patents
Arylsulfonamide-based matrix metalloprotease inhibitors Download PDFInfo
- Publication number
- CA2719457C CA2719457C CA2719457A CA2719457A CA2719457C CA 2719457 C CA2719457 C CA 2719457C CA 2719457 A CA2719457 A CA 2719457A CA 2719457 A CA2719457 A CA 2719457A CA 2719457 C CA2719457 C CA 2719457C
- Authority
- CA
- Canada
- Prior art keywords
- chloro
- benzenesulfonamide
- alkyl
- aryl
- mmol
- 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.)
- Expired - Fee Related
Links
- 239000011159 matrix material Substances 0.000 title description 3
- 125000004421 aryl sulphonamide group Chemical group 0.000 title description 2
- 239000003475 metalloproteinase inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 147
- 102100027995 Collagenase 3 Human genes 0.000 claims abstract description 14
- 102100026802 72 kDa type IV collagenase Human genes 0.000 claims abstract 4
- 101710151806 72 kDa type IV collagenase Proteins 0.000 claims abstract 4
- 108050005238 Collagenase 3 Proteins 0.000 claims abstract 2
- 125000003118 aryl group Chemical group 0.000 claims description 74
- 239000000203 mixture Substances 0.000 claims description 60
- 150000003839 salts Chemical class 0.000 claims description 47
- 125000001072 heteroaryl group Chemical group 0.000 claims description 42
- 125000000217 alkyl group Chemical group 0.000 claims description 40
- 230000003287 optical effect Effects 0.000 claims description 36
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 32
- 239000001257 hydrogen Substances 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 229920006395 saturated elastomer Polymers 0.000 claims description 28
- 125000001424 substituent group Chemical group 0.000 claims description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 27
- 125000003545 alkoxy group Chemical group 0.000 claims description 27
- 125000005843 halogen group Chemical group 0.000 claims description 26
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 21
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 20
- 125000005842 heteroatom Chemical group 0.000 claims description 20
- 150000002431 hydrogen Chemical class 0.000 claims description 20
- 125000000623 heterocyclic group Chemical group 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical group 0.000 claims description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 125000002619 bicyclic group Chemical group 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 125000002950 monocyclic group Chemical group 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 9
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- 125000004122 cyclic group Chemical group 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 5
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 125000003003 spiro group Chemical group 0.000 claims description 5
- 125000004434 sulfur atom Chemical group 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- CHGNAKGPILPPCD-UHFFFAOYSA-N 2-chloro-5-(3-ethyl-2h-indazole-6-carbonyl)benzenesulfonamide Chemical compound C=1C=C2C(CC)=NNC2=CC=1C(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 CHGNAKGPILPPCD-UHFFFAOYSA-N 0.000 claims description 2
- DTRZUFASQTXIBR-UHFFFAOYSA-N 2-chloro-5-(3-methyl-2h-indazole-6-carbonyl)benzenesulfonamide Chemical compound C=1C=C2C(C)=NNC2=CC=1C(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 DTRZUFASQTXIBR-UHFFFAOYSA-N 0.000 claims description 2
- LATDUVZCOVBCGO-UHFFFAOYSA-N 2-chloro-5-(3-propan-2-yl-2h-indazole-6-carbonyl)benzenesulfonamide Chemical compound C=1C=C2C(C(C)C)=NNC2=CC=1C(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 LATDUVZCOVBCGO-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims 4
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- KGKRQBPPXHTAKU-UHFFFAOYSA-N 2-chloro-5-(4-pyridin-3-ylbenzoyl)benzenesulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(=O)C=2C=CC(=CC=2)C=2C=NC=CC=2)=C1 KGKRQBPPXHTAKU-UHFFFAOYSA-N 0.000 claims 1
- IGKNUXGYZWAESX-UHFFFAOYSA-N 2-chloro-5-(4-pyridin-4-ylbenzoyl)benzenesulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(=O)C=2C=CC(=CC=2)C=2C=CN=CC=2)=C1 IGKNUXGYZWAESX-UHFFFAOYSA-N 0.000 claims 1
- PAIXOWFRQLYALT-UHFFFAOYSA-N 2-chloro-5-(4-pyrrol-1-ylbenzoyl)benzenesulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(=O)C=2C=CC(=CC=2)N2C=CC=C2)=C1 PAIXOWFRQLYALT-UHFFFAOYSA-N 0.000 claims 1
- WNGVSONMLMDXPQ-UHFFFAOYSA-N 2-chloro-5-(4-thiophen-2-ylbenzoyl)benzenesulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(=O)C=2C=CC(=CC=2)C=2SC=CC=2)=C1 WNGVSONMLMDXPQ-UHFFFAOYSA-N 0.000 claims 1
- FWVXOZDBSYDDMD-UHFFFAOYSA-N 2-chloro-5-(4-thiophen-3-ylbenzoyl)benzenesulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(=O)C=2C=CC(=CC=2)C2=CSC=C2)=C1 FWVXOZDBSYDDMD-UHFFFAOYSA-N 0.000 claims 1
- ZUHSQVCBPVSKDN-UHFFFAOYSA-N 2-chloro-5-[3-(2-cyclopentylethyl)-2h-indazole-6-carbonyl]benzenesulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(=O)C=2C=C3NN=C(CCC4CCCC4)C3=CC=2)=C1 ZUHSQVCBPVSKDN-UHFFFAOYSA-N 0.000 claims 1
- YWOMUTWIHUMKPN-UHFFFAOYSA-N 2-chloro-5-[4-(2-chloropyridin-4-yl)benzoyl]benzenesulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(=O)C=2C=CC(=CC=2)C=2C=C(Cl)N=CC=2)=C1 YWOMUTWIHUMKPN-UHFFFAOYSA-N 0.000 claims 1
- WAAWXHSMICFDTO-UHFFFAOYSA-N 5-(1-benzyl-3-ethylindazole-6-carbonyl)-2-chlorobenzenesulfonamide Chemical compound C12=CC(C(=O)C=3C=C(C(Cl)=CC=3)S(N)(=O)=O)=CC=C2C(CC)=NN1CC1=CC=CC=C1 WAAWXHSMICFDTO-UHFFFAOYSA-N 0.000 claims 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 abstract description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 8
- 102100027998 Macrophage metalloelastase Human genes 0.000 abstract description 6
- 201000010099 disease Diseases 0.000 abstract description 6
- 102100030411 Neutrophil collagenase Human genes 0.000 abstract description 5
- 101710118230 Neutrophil collagenase Proteins 0.000 abstract description 5
- 101710187853 Macrophage metalloelastase Proteins 0.000 abstract description 4
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 abstract description 4
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 abstract description 4
- 230000001404 mediated effect Effects 0.000 abstract description 2
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
- 208000035475 disorder Diseases 0.000 abstract 2
- 230000002159 abnormal effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 406
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 254
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 160
- 239000000243 solution Substances 0.000 description 156
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 131
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 129
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 105
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 103
- 238000006243 chemical reaction Methods 0.000 description 98
- -1 alkoxy-alkyl-- Chemical group 0.000 description 88
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 86
- 239000011541 reaction mixture Substances 0.000 description 75
- 238000000034 method Methods 0.000 description 70
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 69
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 62
- 238000005160 1H NMR spectroscopy Methods 0.000 description 52
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 48
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 43
- 235000019341 magnesium sulphate Nutrition 0.000 description 43
- NNJMFJSKMRYHSR-UHFFFAOYSA-N 4-phenylbenzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CC=CC=C1 NNJMFJSKMRYHSR-UHFFFAOYSA-N 0.000 description 42
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
- 238000010898 silica gel chromatography Methods 0.000 description 39
- 238000000746 purification Methods 0.000 description 38
- 239000007787 solid Substances 0.000 description 38
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 35
- 239000002253 acid Substances 0.000 description 35
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 31
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 31
- 238000010992 reflux Methods 0.000 description 30
- 239000000284 extract Substances 0.000 description 29
- 238000003756 stirring Methods 0.000 description 29
- 238000007792 addition Methods 0.000 description 27
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 27
- 239000012074 organic phase Substances 0.000 description 22
- 239000000725 suspension Substances 0.000 description 21
- 229940002612 prodrug Drugs 0.000 description 20
- 239000000651 prodrug Substances 0.000 description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 18
- 229910052938 sodium sulfate Inorganic materials 0.000 description 18
- 235000011152 sodium sulphate Nutrition 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 16
- 239000003921 oil Substances 0.000 description 16
- 235000019198 oils Nutrition 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 239000000460 chlorine Substances 0.000 description 15
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- 235000019270 ammonium chloride Nutrition 0.000 description 14
- 238000003818 flash chromatography Methods 0.000 description 14
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 14
- 238000001953 recrystallisation Methods 0.000 description 14
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 13
- 239000000843 powder Substances 0.000 description 13
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 12
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 12
- 235000011114 ammonium hydroxide Nutrition 0.000 description 12
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 11
- 239000000908 ammonium hydroxide Substances 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 11
- 150000002576 ketones Chemical class 0.000 description 11
- 108010076503 Matrix Metalloproteinase 13 Proteins 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
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- 239000000758 substrate Substances 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- SCYSJFKWFQZRJW-UHFFFAOYSA-N 4-chloro-3-sulfamoylbenzoyl chloride Chemical compound NS(=O)(=O)C1=CC(C(Cl)=O)=CC=C1Cl SCYSJFKWFQZRJW-UHFFFAOYSA-N 0.000 description 7
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 229940124761 MMP inhibitor Drugs 0.000 description 7
- 108010016165 Matrix Metalloproteinase 2 Proteins 0.000 description 7
- 102000000424 Matrix Metalloproteinase 2 Human genes 0.000 description 7
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 7
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 125000002252 acyl group Chemical group 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
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- 230000003647 oxidation Effects 0.000 description 7
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- 125000006239 protecting group Chemical group 0.000 description 7
- 239000012047 saturated solution Substances 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- ABTIADUZLHZTGU-UHFFFAOYSA-N 2-chloro-5-formylbenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC(C=O)=CC=C1Cl ABTIADUZLHZTGU-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- 239000005711 Benzoic acid Substances 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- 239000003810 Jones reagent Substances 0.000 description 6
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- 150000007513 acids Chemical class 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 5
- MPZMVUQGXAOJIK-UHFFFAOYSA-N 4-bromopyridine;hydron;chloride Chemical compound Cl.BrC1=CC=NC=C1 MPZMVUQGXAOJIK-UHFFFAOYSA-N 0.000 description 5
- YMLYFZDEUUBSTB-UHFFFAOYSA-N 4-chloro-n-methoxy-n-methyl-3-sulfamoylbenzamide Chemical compound CON(C)C(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 YMLYFZDEUUBSTB-UHFFFAOYSA-N 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 5
- 150000001412 amines Chemical group 0.000 description 5
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
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- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/402—1-aryl substituted, e.g. piretanide
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
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- A—HUMAN NECESSITIES
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
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| CN102186820B (zh) | 2008-08-15 | 2013-08-28 | 乔治城大学 | Rassf1a表达和人癌细胞增殖的荧光调节剂 |
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| HUE044867T2 (hu) | 2011-05-12 | 2019-11-28 | Proteostasis Therapeutics Inc | Proteosztázis szabályzók |
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| LT6064B (lt) | 2012-10-15 | 2014-08-25 | Vilniaus Universitetas | Fluorinti benzensulfonamidai kaip karboanhidrazės inhibitoriai |
| KR101970505B1 (ko) * | 2012-12-26 | 2019-04-19 | (주)아모레퍼시픽 | 멜라닌 형성 억제제를 함유하는 미백용 피부 외용제 조성물 |
| US9849135B2 (en) | 2013-01-25 | 2017-12-26 | President And Fellows Of Harvard College | USP14 inhibitors for treating or preventing viral infections |
| 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 |
| CN108989649B (zh) | 2013-08-01 | 2021-03-19 | 核心光电有限公司 | 具有自动聚焦的纤薄多孔径成像系统及其使用方法 |
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| US9751888B2 (en) | 2013-10-04 | 2017-09-05 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| WO2015073528A1 (en) | 2013-11-12 | 2015-05-21 | Proteostasis Therapeutics, Inc. | Proteasome activity enhancing compounds |
| WO2015074123A1 (en) * | 2013-11-25 | 2015-05-28 | Novogen ltd | Functionalised and substituted indoles as anti-cancer agents |
| MX382033B (es) | 2014-03-19 | 2025-03-13 | Infinity Pharmaceuticals Inc | Compuestos heterocíclicos para utilizarlos en el tratamiento de trastornos mediados por pi3k-gamma. |
| EA201650031A1 (ru) | 2014-05-15 | 2017-06-30 | Итеос Терапьютик | Производные пирролидин-2,5-диона, фармацевтические композиции и способы применения в качестве ингибиторов ido1 |
| JOP20150177B1 (ar) | 2014-08-01 | 2021-08-17 | Janssen Pharmaceutica Nv | مركبات 6 ، 7 ثاني هيدرو بيرازولو [ 1، 5 الفا ] بيرازين – 4 (5 يد) – اون واستخدامها كمنظمات الوسترية سلبية لمستقبلات ملجور 2 |
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| WO2016054491A1 (en) | 2014-10-03 | 2016-04-07 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| RU2711382C2 (ru) | 2014-12-03 | 2020-01-16 | Янссен Фармацевтика Нв | 6,7-ДИГИДРОПИРАЗОЛО[1,5-a]ПИРАЗИН-4(5H)-ОНОВЫЕ СОЕДИНЕНИЯ И ИХ ПРИМЕНЕНИЕ В КАЧЕСТВЕ ОТРИЦАТЕЛЬНЫХ АЛЛОСТЕРИЧЕСКИХ МОДУЛЯТОРОВ РЕЦЕПТОРОВ MGLUR2 |
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| US11053255B2 (en) | 2015-06-22 | 2021-07-06 | Georgetown University | Synthesis of mahanine and related compounds |
| EP3334733A1 (en) * | 2015-08-10 | 2018-06-20 | Pfizer Inc | 3-indol substituted derivatives, pharmaceutical compositions and methods for use |
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- 2009-03-23 KR KR1020107023599A patent/KR101673621B1/ko not_active Expired - Fee Related
- 2009-03-23 CA CA2719457A patent/CA2719457C/en not_active Expired - Fee Related
- 2009-03-23 EA EA201001523A patent/EA020114B1/ru not_active IP Right Cessation
- 2009-03-23 PT PT97244834T patent/PT2268612E/pt unknown
- 2009-03-23 BR BRPI0908603-0A patent/BRPI0908603A2/pt not_active Application Discontinuation
- 2009-03-23 PL PL09724483T patent/PL2268612T3/pl unknown
- 2009-03-23 WO PCT/EP2009/053390 patent/WO2009118292A1/en not_active Ceased
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| Publication number | Publication date |
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| JP2011517446A (ja) | 2011-06-09 |
| CA2719457A1 (en) | 2009-10-01 |
| PL2268612T3 (pl) | 2015-02-27 |
| AU2009228765B2 (en) | 2012-05-31 |
| AU2009228765A1 (en) | 2009-10-01 |
| CN102036953A (zh) | 2011-04-27 |
| US20150045398A1 (en) | 2015-02-12 |
| KR101673621B1 (ko) | 2016-11-07 |
| JP5490092B2 (ja) | 2014-05-14 |
| EP2268612A1 (en) | 2011-01-05 |
| PT2268612E (pt) | 2014-11-13 |
| ES2524259T3 (es) | 2014-12-04 |
| US9822092B2 (en) | 2017-11-21 |
| US20130096105A1 (en) | 2013-04-18 |
| EA020114B1 (ru) | 2014-08-29 |
| US8222424B2 (en) | 2012-07-17 |
| KR20100127291A (ko) | 2010-12-03 |
| MX2010010525A (es) | 2010-10-25 |
| US8362063B2 (en) | 2013-01-29 |
| BRPI0908603A2 (pt) | 2020-08-18 |
| US20110014186A1 (en) | 2011-01-20 |
| US8975439B2 (en) | 2015-03-10 |
| EA201001523A1 (ru) | 2011-06-30 |
| CN102036953B (zh) | 2015-05-06 |
| US20120258954A1 (en) | 2012-10-11 |
| EP2268612B1 (en) | 2014-08-20 |
| WO2009118292A1 (en) | 2009-10-01 |
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