JP2008513472A - システインプロテアーゼインヒビターの調製のための方法及び中間体 - Google Patents
システインプロテアーゼインヒビターの調製のための方法及び中間体 Download PDFInfo
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- JP2008513472A JP2008513472A JP2007532479A JP2007532479A JP2008513472A JP 2008513472 A JP2008513472 A JP 2008513472A JP 2007532479 A JP2007532479 A JP 2007532479A JP 2007532479 A JP2007532479 A JP 2007532479A JP 2008513472 A JP2008513472 A JP 2008513472A
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- 238000000034 method Methods 0.000 title claims abstract description 63
- 238000002360 preparation method Methods 0.000 title abstract description 6
- 239000002852 cysteine proteinase inhibitor Substances 0.000 title abstract description 4
- 239000000543 intermediate Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 516
- -1 amino Monosubstituted amino Chemical group 0.000 claims description 353
- 125000000217 alkyl group Chemical group 0.000 claims description 144
- 239000001257 hydrogen Substances 0.000 claims description 139
- 229910052739 hydrogen Inorganic materials 0.000 claims description 139
- 125000003118 aryl group Chemical group 0.000 claims description 138
- 239000002253 acid Substances 0.000 claims description 100
- 125000001188 haloalkyl group Chemical group 0.000 claims description 99
- 229940080818 propionamide Drugs 0.000 claims description 94
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 90
- 125000005843 halogen group Chemical group 0.000 claims description 74
- 150000003839 salts Chemical class 0.000 claims description 72
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 68
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 68
- 238000006243 chemical reaction Methods 0.000 claims description 65
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 65
- 125000001072 heteroaryl group Chemical group 0.000 claims description 64
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 63
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 62
- 125000003545 alkoxy group Chemical group 0.000 claims description 57
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 57
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 48
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 45
- 125000000623 heterocyclic group Chemical group 0.000 claims description 45
- 150000002431 hydrogen Chemical class 0.000 claims description 44
- 125000006239 protecting group Chemical group 0.000 claims description 43
- 125000002723 alicyclic group Chemical group 0.000 claims description 38
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 38
- 125000002252 acyl group Chemical group 0.000 claims description 36
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 36
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 30
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 28
- 229910052799 carbon Inorganic materials 0.000 claims description 28
- 239000012458 free base Substances 0.000 claims description 24
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 24
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 24
- 125000004432 carbon atom Chemical group C* 0.000 claims description 21
- 239000003960 organic solvent Substances 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 125000002947 alkylene group Chemical group 0.000 claims description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 15
- 125000004414 alkyl thio group Chemical group 0.000 claims description 15
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 13
- 150000007530 organic bases Chemical class 0.000 claims description 13
- 125000004043 oxo group Chemical group O=* 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 150000007529 inorganic bases Chemical class 0.000 claims description 11
- 230000001590 oxidative effect Effects 0.000 claims description 11
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 11
- 125000004980 cyclopropylene group Chemical group 0.000 claims description 10
- 239000007800 oxidant agent Substances 0.000 claims description 10
- 150000003457 sulfones Chemical class 0.000 claims description 10
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 9
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- 150000001408 amides Chemical class 0.000 claims description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 7
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 239000002274 desiccant Substances 0.000 claims description 5
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 5
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 5
- 238000011065 in-situ storage Methods 0.000 claims description 5
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- SPXOTSHWBDUUMT-UHFFFAOYSA-N 138-42-1 Chemical compound OS(=O)(=O)C1=CC=C([N+]([O-])=O)C=C1 SPXOTSHWBDUUMT-UHFFFAOYSA-N 0.000 claims description 4
- OVOJUAKDTOOXRF-UHFFFAOYSA-N 2,4-dinitrobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O OVOJUAKDTOOXRF-UHFFFAOYSA-N 0.000 claims description 4
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 230000008878 coupling Effects 0.000 claims description 4
- 238000010168 coupling process Methods 0.000 claims description 4
- 238000005859 coupling reaction Methods 0.000 claims description 4
- 239000012024 dehydrating agents Substances 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 3
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 3
- 125000005160 aryl oxy alkyl group Chemical group 0.000 claims description 3
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 3
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 3
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 3
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000005326 heteroaryloxy alkyl group Chemical group 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 3
- 239000011593 sulfur Substances 0.000 claims description 3
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000005418 aryl aryl group Chemical group 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
- MGWVXCJVOQWUQG-UHFFFAOYSA-N bromomethanesulfonic acid Chemical compound OS(=O)(=O)CBr MGWVXCJVOQWUQG-UHFFFAOYSA-N 0.000 claims description 2
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 claims description 2
- 125000003395 phenylethylamino group Chemical group [H]N(*)C([H])([H])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000006514 pyridin-2-ylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 2
- 230000001131 transforming effect Effects 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 60
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 58
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 50
- 239000000243 solution Substances 0.000 description 49
- 239000011541 reaction mixture Substances 0.000 description 45
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- 239000002904 solvent Substances 0.000 description 33
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 238000003786 synthesis reaction Methods 0.000 description 27
- 235000019439 ethyl acetate Nutrition 0.000 description 25
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 25
- 235000019341 magnesium sulphate Nutrition 0.000 description 25
- 239000000203 mixture Substances 0.000 description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 21
- 230000015572 biosynthetic process Effects 0.000 description 20
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 229910001868 water Inorganic materials 0.000 description 18
- 239000012267 brine Substances 0.000 description 17
- 150000001721 carbon Chemical group 0.000 description 17
- 238000003756 stirring Methods 0.000 description 14
- 150000003573 thiols Chemical group 0.000 description 13
- 239000007787 solid Substances 0.000 description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 11
- 125000004429 atom Chemical group 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- 0 CCC(*)C1C=CC*1 Chemical compound CCC(*)C1C=CC*1 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 9
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 8
- 239000007821 HATU Substances 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- PCEIEQLJYDMRFZ-UHFFFAOYSA-N (1-cyanocyclopropyl)azanium;chloride Chemical compound Cl.N#CC1(N)CC1 PCEIEQLJYDMRFZ-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 7
- 239000002808 molecular sieve Substances 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 6
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 5
- 150000001413 amino acids Chemical group 0.000 description 5
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 5
- 239000003638 chemical reducing agent Substances 0.000 description 5
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 125000002541 furyl group Chemical group 0.000 description 5
- 125000002883 imidazolyl group Chemical group 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 125000004076 pyridyl group Chemical group 0.000 description 5
- 125000000168 pyrrolyl group Chemical group 0.000 description 5
- 238000002390 rotary evaporation Methods 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 5
- GQHFCGULTKNUQX-UHFFFAOYSA-N (2,2,2-trifluoro-1-phenylethyl) trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)OC(C(F)(F)F)C1=CC=CC=C1 GQHFCGULTKNUQX-UHFFFAOYSA-N 0.000 description 4
- BDQHSIMDNYIOMB-UHFFFAOYSA-N 2,2,2-trifluoro-1-(4-fluorophenyl)ethanol Chemical compound FC(F)(F)C(O)C1=CC=C(F)C=C1 BDQHSIMDNYIOMB-UHFFFAOYSA-N 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- GUMFXMMDJLWNTM-UHFFFAOYSA-N [2,2,2-trifluoro-1-(4-fluorophenyl)ethyl] trifluoromethanesulfonate Chemical compound FC1=CC=C(C(OS(=O)(=O)C(F)(F)F)C(F)(F)F)C=C1 GUMFXMMDJLWNTM-UHFFFAOYSA-N 0.000 description 4
- 230000001476 alcoholic effect Effects 0.000 description 4
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000007822 coupling agent Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 235000019260 propionic acid Nutrition 0.000 description 4
- 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 4
- 238000010992 reflux Methods 0.000 description 4
- 125000004434 sulfur atom Chemical group 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 4
- SQRINZHKHZUCJL-VJSCVCEBSA-N (2R)-2-[[2,2,2-trifluoro-1-(4-fluorophenyl)ethyl]amino]propanoic acid Chemical compound FC(C(C1=CC=C(C=C1)F)N[C@@H](C(=O)O)C)(F)F SQRINZHKHZUCJL-VJSCVCEBSA-N 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 3
- OSKHEBDRYLYZPN-UHFFFAOYSA-N 4-amino-1-ethylpiperidine-4-carbonitrile Chemical compound CCN1CCC(N)(C#N)CC1 OSKHEBDRYLYZPN-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
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- HYWCXWRMUZYRPH-UHFFFAOYSA-N trimethyl(prop-2-enyl)silane Chemical compound C[Si](C)(C)CC=C HYWCXWRMUZYRPH-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/02—Preparation of sulfones; Preparation of sulfoxides by formation of sulfone or sulfoxide groups by oxidation of sulfides, or by formation of sulfone groups by oxidation of sulfoxides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/28—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
- C07C317/48—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C321/00—Thiols, sulfides, hydropolysulfides or polysulfides
- C07C321/12—Sulfides, hydropolysulfides, or polysulfides having thio groups bound to acyclic carbon atoms
- C07C321/16—Sulfides, hydropolysulfides, or polysulfides having thio groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
-
- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/32—Sulfur atoms
-
- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/32—Sulfur atoms
- C07D213/34—Sulfur atoms to which a second hetero atom is attached
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
- C07D309/14—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Peptides Or Proteins (AREA)
- Enzymes And Modification Thereof (AREA)
- Pyrane Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Pyridine Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US61080604P | 2004-09-17 | 2004-09-17 | |
| PCT/US2005/033051 WO2006034004A2 (en) | 2004-09-17 | 2005-09-16 | Processes and intermediates for preparing cysteine protease inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2008513472A true JP2008513472A (ja) | 2008-05-01 |
| JP2008513472A5 JP2008513472A5 (enExample) | 2008-07-03 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| JP2007532479A Pending JP2008513472A (ja) | 2004-09-17 | 2005-09-16 | システインプロテアーゼインヒビターの調製のための方法及び中間体 |
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| US (1) | US7737300B2 (enExample) |
| EP (1) | EP1799645A2 (enExample) |
| JP (1) | JP2008513472A (enExample) |
| KR (1) | KR20070061877A (enExample) |
| CN (1) | CN101068783A (enExample) |
| AU (1) | AU2005287046A1 (enExample) |
| BR (1) | BRPI0515470A (enExample) |
| CA (1) | CA2580065A1 (enExample) |
| CR (1) | CR8993A (enExample) |
| EC (1) | ECSP077321A (enExample) |
| IL (1) | IL181792A0 (enExample) |
| MX (1) | MX2007003118A (enExample) |
| NO (1) | NO20071937L (enExample) |
| WO (1) | WO2006034004A2 (enExample) |
| ZA (1) | ZA200703102B (enExample) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008534510A (ja) * | 2005-03-22 | 2008-08-28 | セレーラ ジェノミックス | システインプロテアーゼ阻害剤としてのスルホニル基含有化合物 |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2521811A1 (en) | 2003-09-18 | 2005-03-31 | Axys Pharmaceuticals, Inc. | Haloalkyl containing compounds as cysteine protease inhibitors |
| WO2006060810A1 (en) | 2004-12-02 | 2006-06-08 | Schering Aktiengesellschaft | Sulfonamide compounds as cysteine protease inhibitors |
| PL1865940T3 (pl) | 2005-03-21 | 2013-06-28 | Virobay Inc | Alfa-ketoamidowe związki jako inhibitory proteaz cysteinowych |
| US20090270511A1 (en) * | 2006-09-08 | 2009-10-29 | Merck Frosst Canada Ltd. | Prodrugs of inhibitors of cathepsin s |
| WO2008037072A1 (en) | 2006-09-25 | 2008-04-03 | Merck Frosst Canada Ltd. | Cathepsin b inhibitors |
| DK2079683T3 (en) | 2006-10-04 | 2015-04-27 | Virobay Inc | Difluoro-containing compounds as cysteine protease inhibitors |
| US7893112B2 (en) | 2006-10-04 | 2011-02-22 | Virobay, Inc. | Di-fluoro containing compounds as cysteine protease inhibitors |
| US8450336B2 (en) | 2006-12-14 | 2013-05-28 | Nps Pharmaceuticals, Inc | Use of D-serine derivatives for the treatment of anxiety disorders |
| AU2008234380B2 (en) * | 2007-04-02 | 2013-01-24 | Merck Canada Inc. | Amidation process for the preparation of cathepsin K inhibitors |
| HRP20150882T1 (hr) | 2008-10-17 | 2015-09-25 | Xenon Pharmaceuticals Inc. | Spirooksindolski spojevi i njihova upotreba kao terapijska sredstva |
| US20120101053A1 (en) * | 2009-06-22 | 2012-04-26 | Cameron Black | Cathepsin cysteine protease inhibitors for the treatment of various diseases |
| US8324417B2 (en) | 2009-08-19 | 2012-12-04 | Virobay, Inc. | Process for the preparation of (S)-2-amino-5-cyclopropyl-4,4-difluoropentanoic acid and alkyl esters and acid salts thereof |
| WO2012119941A1 (en) | 2011-03-04 | 2012-09-13 | Prozymex A/S | Peptidyl nitrilcompounds as peptidase inhibitors |
| JP2014518218A (ja) * | 2011-06-17 | 2014-07-28 | ビロベイ，インコーポレイティド | 中枢神経系におけるミクログリア媒介ニューロン消失を処置するためのカテプシン阻害剤 |
| CN106478564B (zh) * | 2015-08-29 | 2021-11-12 | 广东东阳光药业有限公司 | 组织蛋白酶k抑制剂及其用途 |
| CN107922315B (zh) * | 2015-08-29 | 2021-03-26 | 广东东阳光药业有限公司 | 组织蛋白酶k抑制剂及其用途 |
| AU2020250933A1 (en) | 2019-04-05 | 2021-10-28 | Centre Hospitalier Régional Et Universitaire De Brest | Protease-activated receptor-2 inhibitors for the treatment of sensory neuropathy induced by a marine neurotoxic poisoning |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001522862A (ja) * | 1997-11-05 | 2001-11-20 | ノバルティス アクチエンゲゼルシャフト | ジペプチドニトリル |
| JP2002537293A (ja) * | 1999-02-20 | 2002-11-05 | アストラゼネカ アクチボラグ | カテプシンｌおよび／またはカテプシンｓの阻害剤としてのアセタミドアセトニトリル誘導体 |
| JP2005526753A (ja) * | 2002-03-05 | 2005-09-08 | メルク フロスト カナダ アンド カンパニー | カテプシンシステインプロテアーゼ阻害剤 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9723407D0 (en) * | 1997-11-05 | 1998-01-07 | Ciba Geigy Ag | Organic compounds |
| EP1434769A2 (en) * | 2001-10-02 | 2004-07-07 | Boehringer Ingelheim Pharmaceuticals Inc. | Compounds useful as reversible inhibitors of cysteine proteases |
| DE60232547D1 (de) * | 2002-03-11 | 2009-07-16 | Kao Corp | Kosmetika |
-
2005
- 2005-09-16 AU AU2005287046A patent/AU2005287046A1/en not_active Abandoned
- 2005-09-16 KR KR1020077008584A patent/KR20070061877A/ko not_active Withdrawn
- 2005-09-16 CN CNA2005800389964A patent/CN101068783A/zh active Pending
- 2005-09-16 MX MX2007003118A patent/MX2007003118A/es not_active Application Discontinuation
- 2005-09-16 JP JP2007532479A patent/JP2008513472A/ja active Pending
- 2005-09-16 BR BRPI0515470-7A patent/BRPI0515470A/pt not_active Application Discontinuation
- 2005-09-16 EP EP05796693A patent/EP1799645A2/en not_active Withdrawn
- 2005-09-16 US US11/662,933 patent/US7737300B2/en active Active
- 2005-09-16 CA CA002580065A patent/CA2580065A1/en not_active Abandoned
- 2005-09-16 WO PCT/US2005/033051 patent/WO2006034004A2/en not_active Ceased
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2007
- 2007-03-08 IL IL181792A patent/IL181792A0/en unknown
- 2007-03-15 EC EC2007007321A patent/ECSP077321A/es unknown
- 2007-03-15 CR CR8993A patent/CR8993A/es unknown
- 2007-04-16 NO NO20071937A patent/NO20071937L/no not_active Application Discontinuation
- 2007-04-16 ZA ZA200703102A patent/ZA200703102B/xx unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001522862A (ja) * | 1997-11-05 | 2001-11-20 | ノバルティス アクチエンゲゼルシャフト | ジペプチドニトリル |
| JP2002537293A (ja) * | 1999-02-20 | 2002-11-05 | アストラゼネカ アクチボラグ | カテプシンｌおよび／またはカテプシンｓの阻害剤としてのアセタミドアセトニトリル誘導体 |
| JP2005526753A (ja) * | 2002-03-05 | 2005-09-08 | メルク フロスト カナダ アンド カンパニー | カテプシンシステインプロテアーゼ阻害剤 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008534510A (ja) * | 2005-03-22 | 2008-08-28 | セレーラ ジェノミックス | システインプロテアーゼ阻害剤としてのスルホニル基含有化合物 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1799645A2 (en) | 2007-06-27 |
| MX2007003118A (es) | 2007-05-24 |
| CN101068783A (zh) | 2007-11-07 |
| NO20071937L (no) | 2007-06-15 |
| KR20070061877A (ko) | 2007-06-14 |
| US7737300B2 (en) | 2010-06-15 |
| WO2006034004A2 (en) | 2006-03-30 |
| US20080114175A1 (en) | 2008-05-15 |
| AU2005287046A1 (en) | 2006-03-30 |
| WO2006034004A3 (en) | 2006-11-23 |
| ECSP077321A (es) | 2007-04-26 |
| ZA200703102B (en) | 2009-09-30 |
| BRPI0515470A (pt) | 2008-07-22 |
| IL181792A0 (en) | 2007-07-04 |
| CR8993A (es) | 2007-10-04 |
| CA2580065A1 (en) | 2006-03-30 |
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