JP5718647B2 - カテプシンｂの阻害剤 - Google Patents
カテプシンｂの阻害剤 Download PDFInfo
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- JP5718647B2 JP5718647B2 JP2010545997A JP2010545997A JP5718647B2 JP 5718647 B2 JP5718647 B2 JP 5718647B2 JP 2010545997 A JP2010545997 A JP 2010545997A JP 2010545997 A JP2010545997 A JP 2010545997A JP 5718647 B2 JP5718647 B2 JP 5718647B2
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- 229940123329 Cathepsin B inhibitor Drugs 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 177
- 108090000712 Cathepsin B Proteins 0.000 claims description 47
- 102000004225 Cathepsin B Human genes 0.000 claims description 47
- 230000000694 effects Effects 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 22
- 201000010099 disease Diseases 0.000 claims description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
- 241000124008 Mammalia Species 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 230000001684 chronic effect Effects 0.000 claims description 8
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 7
- 239000003112 inhibitor Substances 0.000 claims description 5
- 208000000668 Chronic Pancreatitis Diseases 0.000 claims description 4
- 206010033645 Pancreatitis Diseases 0.000 claims description 4
- 206010033647 Pancreatitis acute Diseases 0.000 claims description 4
- 206010033649 Pancreatitis chronic Diseases 0.000 claims description 4
- 206010039710 Scleroderma Diseases 0.000 claims description 4
- 201000009594 Systemic Scleroderma Diseases 0.000 claims description 4
- 206010042953 Systemic sclerosis Diseases 0.000 claims description 4
- 201000003229 acute pancreatitis Diseases 0.000 claims description 4
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 4
- 230000007863 steatosis Effects 0.000 claims description 4
- 231100000240 steatosis hepatitis Toxicity 0.000 claims description 4
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 208000006454 hepatitis Diseases 0.000 claims 1
- 231100000283 hepatitis Toxicity 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 249
- -1 amino, monosubstituted amino Chemical group 0.000 description 173
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 168
- 238000000034 method Methods 0.000 description 82
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 78
- 239000011541 reaction mixture Substances 0.000 description 68
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 63
- 125000000217 alkyl group Chemical group 0.000 description 58
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 56
- 230000002829 reductive effect Effects 0.000 description 56
- 239000012267 brine Substances 0.000 description 51
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 51
- 239000000243 solution Substances 0.000 description 49
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 46
- 238000006243 chemical reaction Methods 0.000 description 45
- 125000003118 aryl group Chemical group 0.000 description 40
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 39
- 235000019341 magnesium sulphate Nutrition 0.000 description 39
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 39
- 239000012071 phase Substances 0.000 description 39
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 38
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 38
- 239000000203 mixture Substances 0.000 description 37
- 230000008569 process Effects 0.000 description 34
- 125000001072 heteroaryl group Chemical group 0.000 description 32
- 239000007787 solid Substances 0.000 description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 28
- 238000001704 evaporation Methods 0.000 description 27
- 230000008020 evaporation Effects 0.000 description 27
- 208000019425 cirrhosis of liver Diseases 0.000 description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- 125000000753 cycloalkyl group Chemical group 0.000 description 24
- 125000000623 heterocyclic group Chemical group 0.000 description 24
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 23
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 21
- 239000002253 acid Substances 0.000 description 19
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 18
- 125000003710 aryl alkyl group Chemical group 0.000 description 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 18
- 238000003786 synthesis reaction Methods 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 206010016654 Fibrosis Diseases 0.000 description 17
- 125000004432 carbon atom Chemical group C* 0.000 description 17
- 229910052739 hydrogen Inorganic materials 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 16
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 16
- 125000004475 heteroaralkyl group Chemical group 0.000 description 16
- 150000003840 hydrochlorides Chemical class 0.000 description 16
- 239000001257 hydrogen Substances 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 16
- 125000003545 alkoxy group Chemical group 0.000 description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 15
- 239000012043 crude product Substances 0.000 description 15
- 125000005843 halogen group Chemical group 0.000 description 15
- VLJNHYLEOZPXFW-UHFFFAOYSA-N pyrrolidine-2-carboxamide Chemical compound NC(=O)C1CCCN1 VLJNHYLEOZPXFW-UHFFFAOYSA-N 0.000 description 15
- 230000004761 fibrosis Effects 0.000 description 14
- 125000001188 haloalkyl group Chemical group 0.000 description 14
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 14
- 125000006239 protecting group Chemical group 0.000 description 14
- 235000017557 sodium bicarbonate Nutrition 0.000 description 14
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 12
- 125000006317 cyclopropyl amino group Chemical group 0.000 description 11
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 11
- 239000000523 sample Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 125000004438 haloalkoxy group Chemical group 0.000 description 10
- 150000002430 hydrocarbons Chemical group 0.000 description 10
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 10
- OAWXZFGKDDFTGS-UHFFFAOYSA-N pyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)C1CCCN1C(O)=O OAWXZFGKDDFTGS-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 9
- 125000002723 alicyclic group Chemical group 0.000 description 9
- 125000003342 alkenyl group Chemical group 0.000 description 9
- 238000006460 hydrolysis reaction Methods 0.000 description 9
- 239000003960 organic solvent Substances 0.000 description 9
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 9
- 235000019345 sodium thiosulphate Nutrition 0.000 description 9
- 0 C*(C)*c1c[s]cc1 Chemical compound C*(C)*c1c[s]cc1 0.000 description 8
- 206010067125 Liver injury Diseases 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- 150000001204 N-oxides Chemical class 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 235000011054 acetic acid Nutrition 0.000 description 8
- 125000000304 alkynyl group Chemical group 0.000 description 8
- 125000004429 atom Chemical group 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 230000037396 body weight Effects 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 230000007062 hydrolysis Effects 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 239000000546 pharmaceutical excipient Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 7
- 108010082126 Alanine transaminase Proteins 0.000 description 7
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 7
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 7
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 7
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 7
- 230000007170 pathology Effects 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 102000005927 Cysteine Proteases Human genes 0.000 description 6
- 108010005843 Cysteine Proteases Proteins 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 6
- 125000004442 acylamino group Chemical group 0.000 description 6
- 125000001931 aliphatic group Chemical group 0.000 description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 6
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 229960004106 citric acid Drugs 0.000 description 6
- 235000015165 citric acid Nutrition 0.000 description 6
- 238000005859 coupling reaction Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 125000004185 ester group Chemical group 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 210000004185 liver Anatomy 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 6
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 5
- 229910004298 SiO 2 Inorganic materials 0.000 description 5
- 125000004414 alkyl thio group Chemical group 0.000 description 5
- 125000004103 aminoalkyl group Chemical group 0.000 description 5
- 125000004104 aryloxy group Chemical group 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 125000004181 carboxyalkyl group Chemical group 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 125000004093 cyano group Chemical group *C#N 0.000 description 5
- 125000005553 heteroaryloxy group Chemical group 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000012280 lithium aluminium hydride Substances 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 238000002953 preparative HPLC Methods 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
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- 239000000758 substrate Substances 0.000 description 5
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- 208000024891 symptom Diseases 0.000 description 5
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- RAAPXVRHYBAJQU-SSDOTTSWSA-N (2s)-2-(tert-butylcarbamoylamino)-3,3-dimethylbutanoic acid Chemical compound CC(C)(C)NC(=O)N[C@H](C(O)=O)C(C)(C)C RAAPXVRHYBAJQU-SSDOTTSWSA-N 0.000 description 4
- ZFQCBGWOHWQKDC-AYOQOUSVSA-N (2s,4r)-1-[(2s)-2-(tert-butylcarbamoylamino)-3,3-dimethylbutanoyl]-4-(2-pyridin-2-ylthieno[2,3-d]pyrimidin-4-yl)oxypyrrolidine-2-carboxylic acid Chemical compound C1[C@@H](C(O)=O)N(C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)C[C@@H]1OC1=NC(C=2N=CC=CC=2)=NC2=C1C=CS2 ZFQCBGWOHWQKDC-AYOQOUSVSA-N 0.000 description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 4
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-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
- WXIONIWNXBAHRU-UHFFFAOYSA-N [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium Chemical compound C1=CN=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 WXIONIWNXBAHRU-UHFFFAOYSA-N 0.000 description 4
- 229940024606 amino acid Drugs 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 206010003246 arthritis Diseases 0.000 description 4
- 125000005110 aryl thio group Chemical group 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 231100000234 hepatic damage Toxicity 0.000 description 4
- 125000005368 heteroarylthio group Chemical group 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 230000003834 intracellular effect Effects 0.000 description 4
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 4
- 239000012948 isocyanate Substances 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
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- 230000008818 liver damage Effects 0.000 description 4
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- BXGTVNLGPMZLAZ-UHFFFAOYSA-N n'-ethylmethanediimine;hydrochloride Chemical compound Cl.CCN=C=N BXGTVNLGPMZLAZ-UHFFFAOYSA-N 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
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- 150000007530 organic bases Chemical class 0.000 description 4
- 239000001301 oxygen Chemical group 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical group OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 4
- 239000011593 sulfur Chemical group 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- 238000010626 work up procedure Methods 0.000 description 4
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 3
- BENKAPCDIOILGV-MLWJPKLSSA-N (2s)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CC(O)C[C@H]1C(O)=O BENKAPCDIOILGV-MLWJPKLSSA-N 0.000 description 3
- GSXTZLOOZXSBLP-WBVHZDCISA-N (2s,4r)-4-(6-ethoxyisoquinolin-1-yl)oxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound N=1C=CC2=CC(OCC)=CC=C2C=1O[C@@H]1C[C@@H](C(O)=O)N(C(=O)OC(C)(C)C)C1 GSXTZLOOZXSBLP-WBVHZDCISA-N 0.000 description 3
- DNDTWMBDNYTXQG-UHFFFAOYSA-N 1-chloro-6-methoxy-3-methylisoquinoline Chemical compound ClC1=NC(C)=CC2=CC(OC)=CC=C21 DNDTWMBDNYTXQG-UHFFFAOYSA-N 0.000 description 3
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| CN103946213A (zh) * | 2011-11-25 | 2014-07-23 | 霍夫曼-拉罗奇有限公司 | 作为组织蛋白酶抑制剂的新吡咯烷衍生物 |
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| JP7164521B2 (ja) | 2016-06-21 | 2022-11-01 | オリオン・オフサルモロジー・エルエルシー | 炭素環式プロリンアミド誘導体 |
| MX392422B (es) | 2016-06-21 | 2025-03-24 | Orion Ophthalmology LLC | Derivados de prolinamida heterociclica |
| CN109661389A (zh) * | 2016-08-23 | 2019-04-19 | 豪夫迈·罗氏有限公司 | 作为htra1抑制剂的新型二氟酮酰胺衍生物 |
| US10834908B2 (en) * | 2017-04-26 | 2020-11-17 | InfiCure Bio AB | Model animal for fibrosis |
| MA49458A (fr) | 2017-06-21 | 2020-04-29 | SHY Therapeutics LLC | Composés interagissant avec la superfamille ras destinés à être utilisés dans le traitement de cancers, de maladies inflammatoires, de rasopathies et de maladies fibrotiques |
| WO2019018451A2 (en) * | 2017-07-17 | 2019-01-24 | The Regents Of The University Of Colorado | COMPOSITIONS AND METHODS FOR PREVENTING AND TREATING RADIATION-INDUCED PROXIMITY EFFECTS CAUSED BY RADIATION OR RADIATION THERAPY |
| EP3898609A1 (en) | 2018-12-19 | 2021-10-27 | Shy Therapeutics LLC | Compounds that interact with the ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease |
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|---|---|---|---|---|
| HUP0100287A3 (en) | 1997-11-11 | 2003-04-28 | Pfizer Prod Inc | Thienopyrimidine and thienopyridine derivatives useful as anticancer agents |
| US6404397B1 (en) | 1998-08-10 | 2002-06-11 | Raytheon Company | Compact all-weather electromagnetic imaging system |
| US6323180B1 (en) * | 1998-08-10 | 2001-11-27 | Boehringer Ingelheim (Canada) Ltd | Hepatitis C inhibitor tri-peptides |
| US6608027B1 (en) | 1999-04-06 | 2003-08-19 | Boehringer Ingelheim (Canada) Ltd | Macrocyclic peptides active against the hepatitis C virus |
| WO2001055123A1 (en) | 2000-01-26 | 2001-08-02 | Ono Pharmaceutical Co., Ltd. | Nitrogen-containing 5-membered cyclic compounds and drugs containing these compounds as the active ingredient |
| CA2369970A1 (en) * | 2002-02-01 | 2003-08-01 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis c inhibitor tri-peptides |
| AU2004274051A1 (en) | 2003-09-22 | 2005-03-31 | Boehringer Ingelheim International Gmbh | Macrocyclic peptides active against the hepatitis C virus |
| WO2006113942A2 (en) | 2005-04-20 | 2006-10-26 | Schering Corporation | Method of inhibiting cathepsin activity |
| US20060276406A1 (en) | 2005-06-02 | 2006-12-07 | Schering Corporation | Methods of treating hepatitis C virus |
| WO2006130554A2 (en) | 2005-06-02 | 2006-12-07 | Schering Corporation | Methods of treating hepatitis c virus |
| WO2006130688A2 (en) | 2005-06-02 | 2006-12-07 | Schering Corporation | Compounds for inhibiting cathepsin activity |
| US7608592B2 (en) * | 2005-06-30 | 2009-10-27 | Virobay, Inc. | HCV inhibitors |
| KR20090024834A (ko) * | 2006-07-05 | 2009-03-09 | 인터뮨, 인크. | Ｃ형 간염 바이러스 복제의 신규 억제제 |
| US20080161254A1 (en) | 2007-01-03 | 2008-07-03 | Virobay, Inc. | Hcv inhibitors |
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2009
- 2009-02-05 EA EA201001262A patent/EA201001262A1/ru unknown
- 2009-02-05 CA CA2713108A patent/CA2713108A1/en not_active Abandoned
- 2009-02-05 WO PCT/US2009/033229 patent/WO2009100225A1/en not_active Ceased
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- 2009-02-05 EP EP09709414.8A patent/EP2237793A4/en not_active Withdrawn
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| EA201001262A1 (ru) | 2011-04-29 |
| MX2010008371A (es) | 2010-10-04 |
| JP2011511089A (ja) | 2011-04-07 |
| BRPI0907729A2 (pt) | 2015-07-14 |
| CN101969973B (zh) | 2015-07-22 |
| EP2237793A4 (en) | 2013-07-31 |
| CA2713108A1 (en) | 2009-08-13 |
| JP2015051985A (ja) | 2015-03-19 |
| WO2009100225A1 (en) | 2009-08-13 |
| US20090203629A1 (en) | 2009-08-13 |
| EP2237793A1 (en) | 2010-10-13 |
| CN101969973A (zh) | 2011-02-09 |
| US8211897B2 (en) | 2012-07-03 |
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