CN1261276A - 蛋白酶抑制剂 - Google Patents
蛋白酶抑制剂 Download PDFInfo
- Publication number
- CN1261276A CN1261276A CN98806641A CN98806641A CN1261276A CN 1261276 A CN1261276 A CN 1261276A CN 98806641 A CN98806641 A CN 98806641A CN 98806641 A CN98806641 A CN 98806641A CN 1261276 A CN1261276 A CN 1261276A
- Authority
- CN
- China
- Prior art keywords
- thiazol
- hydrazide
- carbonyl
- leucyl
- methyl
- 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.)
- Pending
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- 239000000137 peptide hydrolase inhibitor Substances 0.000 title description 7
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 420
- 238000000034 method Methods 0.000 claims abstract description 77
- 201000010099 disease Diseases 0.000 claims abstract description 48
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 48
- 102000035195 Peptidases Human genes 0.000 claims abstract description 15
- 108091005804 Peptidases Proteins 0.000 claims abstract description 15
- 239000004365 Protease Substances 0.000 claims abstract description 15
- 108090000625 Cathepsin K Proteins 0.000 claims abstract description 14
- 208000001132 Osteoporosis Diseases 0.000 claims abstract description 12
- 210000000845 cartilage Anatomy 0.000 claims abstract description 11
- 206010065687 Bone loss Diseases 0.000 claims abstract description 9
- 201000008482 osteoarthritis Diseases 0.000 claims abstract description 9
- 230000015556 catabolic process Effects 0.000 claims abstract description 8
- 238000006731 degradation reaction Methods 0.000 claims abstract description 8
- 201000001245 periodontitis Diseases 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 8
- 208000007565 gingivitis Diseases 0.000 claims abstract description 7
- 102000004171 Cathepsin K Human genes 0.000 claims abstract 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 385
- -1 C 1-6Alkyl Chemical group 0.000 claims description 250
- 238000002360 preparation method Methods 0.000 claims description 225
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 171
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 145
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 90
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 70
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 58
- 229910052757 nitrogen Inorganic materials 0.000 claims description 58
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 57
- 239000002253 acid Substances 0.000 claims description 37
- 102000005927 Cysteine Proteases Human genes 0.000 claims description 35
- 108010005843 Cysteine Proteases Proteins 0.000 claims description 35
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 23
- 229910052799 carbon Inorganic materials 0.000 claims description 20
- 102000004190 Enzymes Human genes 0.000 claims description 19
- 108090000790 Enzymes Proteins 0.000 claims description 19
- 125000002252 acyl group Chemical group 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 19
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 18
- 239000000758 substrate Substances 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims description 15
- 230000005764 inhibitory process Effects 0.000 claims description 15
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 15
- 230000015572 biosynthetic process Effects 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 229920006395 saturated elastomer Polymers 0.000 claims description 14
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 12
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical group Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 10
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 10
- 235000019419 proteases Nutrition 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 239000007822 coupling agent Substances 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 238000005897 peptide coupling reaction Methods 0.000 claims description 6
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 claims description 6
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 6
- 102000012479 Serine Proteases Human genes 0.000 claims description 5
- 108010022999 Serine Proteases Proteins 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000002757 morpholinyl group Chemical group 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 125000005936 piperidyl group Chemical group 0.000 claims description 5
- 125000000335 thiazolyl group Chemical group 0.000 claims description 5
- MNCMBBIFTVWHIP-UHFFFAOYSA-N 1-anthracen-9-yl-2,2,2-trifluoroethanone Chemical group C1=CC=C2C(C(=O)C(F)(F)F)=C(C=CC=C3)C3=CC2=C1 MNCMBBIFTVWHIP-UHFFFAOYSA-N 0.000 claims description 4
- BUKITYALZCIHTM-UHFFFAOYSA-N 1-benzyl-5-methylimidazole Chemical compound CC1=CN=CN1CC1=CC=CC=C1 BUKITYALZCIHTM-UHFFFAOYSA-N 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 3
- 125000004638 2-oxopiperazinyl group Chemical group O=C1N(CCNC1)* 0.000 claims description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 3
- CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical compound NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 claims description 3
- 229910052786 argon Inorganic materials 0.000 claims description 3
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000002527 bicyclic carbocyclic group Chemical group 0.000 claims description 3
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 3
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 3
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
- 150000003214 pyranose derivatives Chemical class 0.000 claims description 3
- 125000003072 pyrazolidinyl group Chemical group 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000005493 quinolyl group Chemical group 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 125000001984 thiazolidinyl group Chemical group 0.000 claims description 3
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 3
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- UZOFELREXGAFOI-UHFFFAOYSA-N 4-methylpiperidine Chemical compound CC1CCNCC1 UZOFELREXGAFOI-UHFFFAOYSA-N 0.000 claims description 2
- 241000243328 Hydridae Species 0.000 claims description 2
- 102000011195 Profilin Human genes 0.000 claims description 2
- 108050001408 Profilin Proteins 0.000 claims description 2
- DPOPAJRDYZGTIR-UHFFFAOYSA-N Tetrazine Chemical compound C1=CN=NN=N1 DPOPAJRDYZGTIR-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 2
- WCNFFKHKJLERFM-UHFFFAOYSA-N thiomorpholinyl sulfone group Chemical group N1(CCSCC1)S(=O)(=O)N1CCSCC1 WCNFFKHKJLERFM-UHFFFAOYSA-N 0.000 claims description 2
- ZCAGUOCUDGWENZ-UHFFFAOYSA-N thiomorpholinyl sulfoxide group Chemical group N1(CCSCC1)S(=O)N1CCSCC1 ZCAGUOCUDGWENZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001425 triazolyl group Chemical group 0.000 claims description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N iso-quinoline Natural products C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims 22
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims 20
- 229950003188 isovaleryl diethylamide Drugs 0.000 claims 18
- IWNWRLUUSPDATD-UHFFFAOYSA-N 2-naphthalen-1-ylthiophene Chemical compound C1=CSC(C=2C3=CC=CC=C3C=CC=2)=C1 IWNWRLUUSPDATD-UHFFFAOYSA-N 0.000 claims 8
- 125000003277 amino group Chemical group 0.000 claims 6
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 claims 6
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 claims 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 4
- HZONRRHNQILCNO-UHFFFAOYSA-N 1-methyl-2h-pyridine Chemical compound CN1CC=CC=C1 HZONRRHNQILCNO-UHFFFAOYSA-N 0.000 claims 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims 2
- BFAKENXZKHGIGE-UHFFFAOYSA-N bis(2,3,5,6-tetrafluoro-4-iodophenyl)diazene Chemical compound FC1=C(C(=C(C(=C1F)I)F)F)N=NC1=C(C(=C(C(=C1F)F)I)F)F BFAKENXZKHGIGE-UHFFFAOYSA-N 0.000 claims 2
- ANCBHJKEYPZCTE-UHFFFAOYSA-N ethyl 5-carbamoyl-4-methyl-2-[(2,3,4,5,6-pentafluorobenzoyl)amino]thiophene-3-carboxylate Chemical compound CC1=C(C(N)=O)SC(NC(=O)C=2C(=C(F)C(F)=C(F)C=2F)F)=C1C(=O)OCC ANCBHJKEYPZCTE-UHFFFAOYSA-N 0.000 claims 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims 2
- GSYSFVSGPABNNL-UHFFFAOYSA-N methyl 2-dimethoxyphosphoryl-2-(phenylmethoxycarbonylamino)acetate Chemical group COC(=O)C(P(=O)(OC)OC)NC(=O)OCC1=CC=CC=C1 GSYSFVSGPABNNL-UHFFFAOYSA-N 0.000 claims 2
- 229960000210 nalidixic acid Drugs 0.000 claims 2
- 125000002114 valyl group Chemical group 0.000 claims 2
- 208000037147 Hypercalcaemia Diseases 0.000 abstract description 4
- 206010028980 Neoplasm Diseases 0.000 abstract description 4
- 201000011510 cancer Diseases 0.000 abstract description 4
- 208000024693 gingival disease Diseases 0.000 abstract description 4
- 230000000148 hypercalcaemia Effects 0.000 abstract description 4
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- 208000030136 Marchiafava-Bignami Disease Diseases 0.000 abstract description 3
- 208000029725 Metabolic bone disease Diseases 0.000 abstract description 3
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- 208000010191 Osteitis Deformans Diseases 0.000 abstract 1
- 208000027868 Paget disease Diseases 0.000 abstract 1
- 230000036210 malignancy Effects 0.000 abstract 1
- 208000027202 mammary Paget disease Diseases 0.000 abstract 1
- 239000011159 matrix material Substances 0.000 abstract 1
- 239000002585 base Substances 0.000 description 396
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 368
- 239000007787 solid Substances 0.000 description 266
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 234
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 125
- 229960003136 leucine Drugs 0.000 description 78
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 78
- 239000004395 L-leucine Substances 0.000 description 77
- 239000000243 solution Substances 0.000 description 75
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 73
- 150000003254 radicals Chemical class 0.000 description 72
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 68
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 68
- ODKSFYDXXFIFQN-UHFFFAOYSA-N Arginine Chemical compound OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 55
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 54
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 53
- QRDZFPUVLYEQTA-UHFFFAOYSA-N quinoline-8-carboxylic acid Chemical compound C1=CN=C2C(C(=O)O)=CC=CC2=C1 QRDZFPUVLYEQTA-UHFFFAOYSA-N 0.000 description 53
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 42
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 42
- 239000000203 mixture Substances 0.000 description 41
- MDXGYYOJGPFFJL-QMMMGPOBSA-N N(alpha)-t-butoxycarbonyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)OC(C)(C)C MDXGYYOJGPFFJL-QMMMGPOBSA-N 0.000 description 40
- 239000012141 concentrate Substances 0.000 description 39
- 235000008504 concentrate Nutrition 0.000 description 39
- 238000003756 stirring Methods 0.000 description 39
- 125000001980 alanyl group Chemical group 0.000 description 38
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 34
- 235000019341 magnesium sulphate Nutrition 0.000 description 34
- 238000005406 washing Methods 0.000 description 34
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 30
- 239000004475 Arginine Substances 0.000 description 28
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 28
- 230000008569 process Effects 0.000 description 28
- 238000001914 filtration Methods 0.000 description 25
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 25
- 239000000741 silica gel Substances 0.000 description 23
- 229910002027 silica gel Inorganic materials 0.000 description 23
- 229960001866 silicon dioxide Drugs 0.000 description 23
- 238000005481 NMR spectroscopy Methods 0.000 description 22
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 21
- 239000007864 aqueous solution Substances 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 229940088598 enzyme Drugs 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 18
- 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 17
- 210000000988 bone and bone Anatomy 0.000 description 17
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 16
- ULHLTDXPKWELHQ-UHFFFAOYSA-N 5-methyl-imidazole-4-carboxylic acid Chemical compound CC=1NC=NC=1C(O)=O ULHLTDXPKWELHQ-UHFFFAOYSA-N 0.000 description 15
- JKXKKNSEXGPUEU-UHFFFAOYSA-N B(O)O.C1=CC=CC2=CC=CC=C12.CC1=C(C=C(C(=O)O)C=C1)C(=O)O Chemical class B(O)O.C1=CC=CC2=CC=CC=C12.CC1=C(C=C(C(=O)O)C=C1)C(=O)O JKXKKNSEXGPUEU-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 15
- 238000000746 purification Methods 0.000 description 15
- 238000010992 reflux Methods 0.000 description 15
- RZOKQIPOABEQAM-UHFFFAOYSA-N 6-methylpyridine-3-carboxylic acid Chemical compound CC1=CC=C(C(O)=O)C=N1 RZOKQIPOABEQAM-UHFFFAOYSA-N 0.000 description 14
- 239000007788 liquid Substances 0.000 description 14
- TXNBSTNWVSFRLH-UHFFFAOYSA-N n-cyclopropyl-n-methylcyclopropanamine Chemical compound C1CC1N(C)C1CC1 TXNBSTNWVSFRLH-UHFFFAOYSA-N 0.000 description 14
- XDOKFEJMEJKVGX-UHFFFAOYSA-N ethyl 1,3-thiazole-4-carboxylate Chemical compound CCOC(=O)C1=CSC=N1 XDOKFEJMEJKVGX-UHFFFAOYSA-N 0.000 description 13
- 102100024940 Cathepsin K Human genes 0.000 description 12
- 108010033040 Histones Proteins 0.000 description 12
- 239000000460 chlorine Substances 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- LZTBZQSQFMLGQH-UHFFFAOYSA-N naphthalen-1-yloxyboronic acid Chemical compound C1=CC=C2C(OB(O)O)=CC=CC2=C1 LZTBZQSQFMLGQH-UHFFFAOYSA-N 0.000 description 12
- 210000002997 osteoclast Anatomy 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical class CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 11
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N Glutamine Chemical compound OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 11
- 239000003112 inhibitor Substances 0.000 description 11
- QKYWADPCTHTJHQ-UHFFFAOYSA-N n,2-dimethylpropan-1-amine Chemical compound CNCC(C)C QKYWADPCTHTJHQ-UHFFFAOYSA-N 0.000 description 11
- 239000010410 layer Substances 0.000 description 10
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- IHQKEDIOMGYHEB-UHFFFAOYSA-M sodium dimethylarsinate Chemical compound [Na+].C[As](C)([O-])=O IHQKEDIOMGYHEB-UHFFFAOYSA-M 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- PVGBHEUCHKGFQP-UHFFFAOYSA-N sodium;n-[5-amino-2-(4-aminophenyl)sulfonylphenyl]sulfonylacetamide Chemical compound [Na+].CC(=O)NS(=O)(=O)C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=C1 PVGBHEUCHKGFQP-UHFFFAOYSA-N 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
- 229910000080 stannane Inorganic materials 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 210000001258 synovial membrane Anatomy 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- HBEJJYHFTZDAHZ-QMMMGPOBSA-N tert-butyl (2s)-2-amino-4-methylpentanoate Chemical compound CC(C)C[C@H](N)C(=O)OC(C)(C)C HBEJJYHFTZDAHZ-QMMMGPOBSA-N 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000003556 thioamides Chemical class 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- XPEMYYBBHOILIJ-UHFFFAOYSA-N trimethyl(trimethylsilylperoxy)silane Chemical compound C[Si](C)(C)OO[Si](C)(C)C XPEMYYBBHOILIJ-UHFFFAOYSA-N 0.000 description 1
- 229960004799 tryptophan Drugs 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 229960004441 tyrosine Drugs 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Biochemistry (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Immunology (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US4506797P | 1997-04-29 | 1997-04-29 | |
US60/045,067 | 1997-04-29 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1261276A true CN1261276A (zh) | 2000-07-26 |
Family
ID=21935831
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN98806641A Pending CN1261276A (zh) | 1997-04-29 | 1998-04-29 | 蛋白酶抑制剂 |
Country Status (18)
Country | Link |
---|---|
EP (1) | EP1019046A4 (xx) |
JP (1) | JP2002504097A (xx) |
KR (1) | KR20010020391A (xx) |
CN (1) | CN1261276A (xx) |
AR (1) | AR012622A1 (xx) |
AU (1) | AU7365198A (xx) |
BR (1) | BR9809333A (xx) |
CA (1) | CA2287989A1 (xx) |
CO (1) | CO4940477A1 (xx) |
HU (1) | HUP0001294A3 (xx) |
IL (1) | IL132629A0 (xx) |
MA (1) | MA26487A1 (xx) |
NO (1) | NO995268L (xx) |
PE (1) | PE69099A1 (xx) |
PL (1) | PL337725A1 (xx) |
TR (1) | TR199902703T2 (xx) |
WO (1) | WO1998048799A1 (xx) |
ZA (1) | ZA983522B (xx) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104736530A (zh) * | 2012-08-23 | 2015-06-24 | 艾丽奥斯生物制药有限公司 | 治疗副粘病毒病毒性感染的化合物 |
US10358453B2 (en) | 2015-02-25 | 2019-07-23 | Alios Biopharma, Inc. | Antiviral compounds |
US11021444B2 (en) | 2013-08-21 | 2021-06-01 | Janssen Biopharma, Inc. | Antiviral compounds |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1037639A4 (en) | 1997-12-19 | 2002-04-17 | Smithkline Beecham Corp | HETEROARYL-SUBSTITUTED IMIDAZOLE COMPOUNDS, THEIR PHARMACEUTICAL COMPOSITIONS AND USES |
US6100282A (en) * | 1998-01-02 | 2000-08-08 | Hoffman-La Roche Inc. | Thiazole derivatives |
MA26618A1 (fr) * | 1998-04-09 | 2004-12-20 | Smithkline Beecham Corp | Composes et compositions pharmaceutiques pour le traitement du paludisme |
US6858617B2 (en) | 1998-05-26 | 2005-02-22 | Smithkline Beecham Corporation | Substituted imidazole compounds |
JP2002528506A (ja) | 1998-11-04 | 2002-09-03 | スミスクライン・ビーチャム・コーポレイション | ピリジン−4−イルまたはピリミジン−4−イル置換ピラジン |
CO5150165A1 (es) * | 1998-11-13 | 2002-04-29 | Smithkline Beecham Plc | Inhibidores de proteasa: tipo catepsina k |
US20030144175A1 (en) | 1998-12-23 | 2003-07-31 | Smithkline Beecham Corporation | Protease inhibitors |
EP1232155A4 (en) | 1999-11-10 | 2002-11-20 | Smithkline Beecham Corp | PROTEASE INHIBITORS |
US6534498B1 (en) | 1999-11-10 | 2003-03-18 | Smithkline Beecham Corporation | Protease inhibitors |
EP1232154A4 (en) | 1999-11-10 | 2004-06-23 | Smithkline Beecham Corp | PROTEASE INHIBITORS |
US6797720B2 (en) | 1999-12-03 | 2004-09-28 | Ono Pharmaceutical Co., Ltd. | 1,3,4-oxadiazoline derivative and an agent comprising its derivative as active ingredient |
AU1650501A (en) * | 1999-12-03 | 2001-06-12 | Ono Pharmaceutical Co. Ltd. | 1,3,4-oxadiazoline derivatives and drugs containing these derivatives as the active ingredient |
JP2003527429A (ja) | 2000-03-21 | 2003-09-16 | スミスクライン・ビーチャム・コーポレイション | プロテアーゼ阻害物質 |
WO2003062192A1 (en) | 2002-01-17 | 2003-07-31 | Smithkline Beecham Corporation | Cycloalkyl ketoamides derivatives useful as cathepsin k inhibitors |
WO2004007477A1 (fr) * | 2002-07-04 | 2004-01-22 | Aventis Pharma S.A. | Nouveaux derives acyl hydrazino du thiophene, leur procede de preparation, leur application a titre de medicaments, compositions pharmaceutiques et nouvelle utilisation |
KR100962972B1 (ko) | 2002-07-26 | 2010-06-09 | 주식회사유한양행 | 1-페닐피페리딘-3-온 유도체 및 그의 제조방법 |
WO2011015524A2 (en) * | 2009-08-03 | 2011-02-10 | Bayer Cropscience Ag | Fungicide heterocycles derivatives |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR19990067184A (ko) * | 1995-10-30 | 1999-08-16 | 스튜어트 알. 수터, 스티븐 베네티아너, 피터 존 기딩스 | 프로테아제 억제제 |
-
1998
- 1998-04-24 MA MA25047A patent/MA26487A1/fr unknown
- 1998-04-27 PE PE1998000320A patent/PE69099A1/es not_active Application Discontinuation
- 1998-04-28 ZA ZA983522A patent/ZA983522B/xx unknown
- 1998-04-29 TR TR1999/02703T patent/TR199902703T2/xx unknown
- 1998-04-29 CO CO98023491A patent/CO4940477A1/es unknown
- 1998-04-29 KR KR1019997010013A patent/KR20010020391A/ko not_active Application Discontinuation
- 1998-04-29 JP JP54738998A patent/JP2002504097A/ja active Pending
- 1998-04-29 HU HU0001294A patent/HUP0001294A3/hu unknown
- 1998-04-29 IL IL13262998A patent/IL132629A0/xx unknown
- 1998-04-29 WO PCT/US1998/008740 patent/WO1998048799A1/en not_active Application Discontinuation
- 1998-04-29 PL PL98337725A patent/PL337725A1/xx unknown
- 1998-04-29 CN CN98806641A patent/CN1261276A/zh active Pending
- 1998-04-29 BR BR9809333-9A patent/BR9809333A/pt not_active IP Right Cessation
- 1998-04-29 AU AU73651/98A patent/AU7365198A/en not_active Abandoned
- 1998-04-29 CA CA002287989A patent/CA2287989A1/en not_active Abandoned
- 1998-04-29 AR ARP980101999A patent/AR012622A1/es unknown
- 1998-04-29 EP EP98920926A patent/EP1019046A4/en not_active Withdrawn
-
1999
- 1999-10-28 NO NO995268A patent/NO995268L/no not_active Application Discontinuation
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104736530A (zh) * | 2012-08-23 | 2015-06-24 | 艾丽奥斯生物制药有限公司 | 治疗副粘病毒病毒性感染的化合物 |
US9724351B2 (en) | 2012-08-23 | 2017-08-08 | Alios Biopharma, Inc. | Compounds for the treatment of paramoxyvirus viral infections |
US11014935B2 (en) | 2012-08-23 | 2021-05-25 | Janssen Biopharma, Inc. | Compounds for the treatment of paramyxovirus viral infections |
US11021444B2 (en) | 2013-08-21 | 2021-06-01 | Janssen Biopharma, Inc. | Antiviral compounds |
US10358453B2 (en) | 2015-02-25 | 2019-07-23 | Alios Biopharma, Inc. | Antiviral compounds |
Also Published As
Publication number | Publication date |
---|---|
JP2002504097A (ja) | 2002-02-05 |
CA2287989A1 (en) | 1998-11-05 |
AU7365198A (en) | 1998-11-24 |
CO4940477A1 (es) | 2000-07-24 |
KR20010020391A (ko) | 2001-03-15 |
EP1019046A4 (en) | 2002-11-27 |
HUP0001294A3 (en) | 2001-06-28 |
MA26487A1 (fr) | 2004-12-20 |
ZA983522B (en) | 1998-10-29 |
NO995268D0 (no) | 1999-10-28 |
HUP0001294A2 (hu) | 2001-04-28 |
IL132629A0 (en) | 2001-03-19 |
AR012622A1 (es) | 2000-11-08 |
WO1998048799A1 (en) | 1998-11-05 |
NO995268L (no) | 1999-11-15 |
TR199902703T2 (xx) | 2000-02-21 |
PL337725A1 (en) | 2000-08-28 |
EP1019046A1 (en) | 2000-07-19 |
BR9809333A (pt) | 2000-07-04 |
PE69099A1 (es) | 1999-09-26 |
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