CN1255161A - 蛋白酶抑制剂 - Google Patents
蛋白酶抑制剂 Download PDFInfo
- Publication number
- CN1255161A CN1255161A CN98804791A CN98804791A CN1255161A CN 1255161 A CN1255161 A CN 1255161A CN 98804791 A CN98804791 A CN 98804791A CN 98804791 A CN98804791 A CN 98804791A CN 1255161 A CN1255161 A CN 1255161A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- amino
- leucine
- tetrahydrofuran
- het
- 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.)
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- 239000000137 peptide hydrolase inhibitor Substances 0.000 title description 4
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 title 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 86
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 51
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 32
- 201000010099 disease Diseases 0.000 claims abstract description 30
- 108090000625 Cathepsin K Proteins 0.000 claims abstract description 15
- 206010065687 Bone loss Diseases 0.000 claims abstract description 7
- 102000004171 Cathepsin K Human genes 0.000 claims abstract 3
- 229960003136 leucine Drugs 0.000 claims description 253
- 150000001875 compounds Chemical class 0.000 claims description 184
- 238000000034 method Methods 0.000 claims description 116
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 95
- -1 isobutyl- Chemical group 0.000 claims description 82
- 229910052799 carbon Inorganic materials 0.000 claims description 71
- 229910052739 hydrogen Inorganic materials 0.000 claims description 71
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 63
- 125000005605 benzo group Chemical group 0.000 claims description 35
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 33
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 32
- XDPCNPCKDGQBAN-SCSAIBSYSA-N (3r)-oxolan-3-ol Chemical compound O[C@@H]1CCOC1 XDPCNPCKDGQBAN-SCSAIBSYSA-N 0.000 claims description 28
- 239000000203 mixture Substances 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 27
- XDPCNPCKDGQBAN-UHFFFAOYSA-N 3-hydroxytetrahydrofuran Chemical compound OC1CCOC1 XDPCNPCKDGQBAN-UHFFFAOYSA-N 0.000 claims description 21
- IFQSXNOEEPCSLW-DKWTVANSSA-N L-cysteine hydrochloride Chemical compound Cl.SC[C@H](N)C(O)=O IFQSXNOEEPCSLW-DKWTVANSSA-N 0.000 claims description 20
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 16
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 12
- 239000000758 substrate Substances 0.000 claims description 12
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 10
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 210000000845 cartilage Anatomy 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 125000001216 2-naphthoyl group Chemical group C1=C(C=CC2=CC=CC=C12)C(=O)* 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 201000008482 osteoarthritis Diseases 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 125000000524 functional group Chemical group 0.000 claims description 6
- 208000024693 gingival disease Diseases 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 6
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 230000015556 catabolic process Effects 0.000 claims description 5
- 238000006731 degradation reaction Methods 0.000 claims description 5
- 150000001555 benzenes Chemical class 0.000 claims description 4
- AWXKVKOGYYLMEL-UHFFFAOYSA-N benzyl n-(4-oxooxolan-3-yl)carbamate Chemical compound C=1C=CC=CC=1COC(=O)NC1COCC1=O AWXKVKOGYYLMEL-UHFFFAOYSA-N 0.000 claims description 4
- 230000000903 blocking effect Effects 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- HQVKXDYSIGDGSY-QWWZWVQMSA-N (3s,4r)-4-aminooxolan-3-ol Chemical compound N[C@@H]1COC[C@H]1O HQVKXDYSIGDGSY-QWWZWVQMSA-N 0.000 claims description 3
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims description 2
- 238000006114 decarboxylation reaction Methods 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 230000001009 osteoporotic effect Effects 0.000 claims 2
- 230000005764 inhibitory process Effects 0.000 abstract description 11
- 239000003112 inhibitor Substances 0.000 abstract description 7
- 102000005927 Cysteine Proteases Human genes 0.000 abstract 1
- 108010005843 Cysteine Proteases Proteins 0.000 abstract 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical group C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 abstract 1
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical group C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 abstract 1
- 125000001909 leucine group Chemical class [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 abstract 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical group C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 abstract 1
- 239000002585 base Substances 0.000 description 108
- 238000002360 preparation method Methods 0.000 description 56
- 239000000243 solution Substances 0.000 description 44
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 38
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 32
- 238000005160 1H NMR spectroscopy Methods 0.000 description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
- 230000009467 reduction Effects 0.000 description 21
- JLPJFSCQKHRSQR-UHFFFAOYSA-N oxolan-3-one Chemical compound O=C1CCOC1 JLPJFSCQKHRSQR-UHFFFAOYSA-N 0.000 description 20
- 210000000988 bone and bone Anatomy 0.000 description 19
- 239000007787 solid Substances 0.000 description 19
- 238000009834 vaporization Methods 0.000 description 19
- 230000008016 vaporization Effects 0.000 description 19
- 238000005406 washing Methods 0.000 description 18
- 239000007795 chemical reaction product Substances 0.000 description 17
- 102000004190 Enzymes Human genes 0.000 description 16
- 108090000790 Enzymes Proteins 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 229940024606 amino acid Drugs 0.000 description 14
- 230000008569 process Effects 0.000 description 14
- ZRSGZIMDIHBXIN-UHFFFAOYSA-N 1,3-benzodioxole-5-carbonyl chloride Chemical compound ClC(=O)C1=CC=C2OCOC2=C1 ZRSGZIMDIHBXIN-UHFFFAOYSA-N 0.000 description 13
- 102100024940 Cathepsin K Human genes 0.000 description 13
- 235000001014 amino acid Nutrition 0.000 description 13
- 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 13
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 210000002997 osteoclast Anatomy 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 150000001263 acyl chlorides Chemical class 0.000 description 10
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 10
- 239000006260 foam Substances 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- MUCRYNWJQNHDJH-OADIDDRXSA-N Ursonic acid Chemical compound C1CC(=O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C MUCRYNWJQNHDJH-OADIDDRXSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 9
- 239000011259 mixed solution Substances 0.000 description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 208000001132 Osteoporosis Diseases 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 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 8
- FAHKAHMLFQVMPR-UHFFFAOYSA-N 4-azidooxolan-3-ol Chemical compound OC1COCC1N=[N+]=[N-] FAHKAHMLFQVMPR-UHFFFAOYSA-N 0.000 description 7
- 108010033040 Histones Proteins 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 7
- 239000012445 acidic reagent Substances 0.000 description 7
- 150000001413 amino acids Chemical class 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- DOLJOERLFKHNEY-UHFFFAOYSA-N 3,3-dimethoxyoxolane Chemical compound COC1(OC)CCOC1 DOLJOERLFKHNEY-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-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 6
- 102000035195 Peptidases Human genes 0.000 description 6
- 108091005804 Peptidases Proteins 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 239000011324 bead Substances 0.000 description 6
- 150000002576 ketones Chemical group 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 6
- 229940002612 prodrug Drugs 0.000 description 6
- 239000000651 prodrug Substances 0.000 description 6
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 6
- 239000000376 reactant Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 201000001245 periodontitis Diseases 0.000 description 5
- 238000012545 processing Methods 0.000 description 5
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 208000010191 Osteitis Deformans Diseases 0.000 description 4
- 208000027868 Paget disease Diseases 0.000 description 4
- 239000004365 Protease Substances 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 208000027202 mammary Paget disease Diseases 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 125000001624 naphthyl group Chemical group 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 235000019419 proteases Nutrition 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- NXFFJDQHYLNEJK-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)methyl]-7-fluoro-5-methylsulfonyl-2,3-dihydro-1h-cyclopenta[b]indol-3-yl]acetic acid Chemical compound C1=2C(S(=O)(=O)C)=CC(F)=CC=2C=2CCC(CC(O)=O)C=2N1CC1=CC=C(Cl)C=C1 NXFFJDQHYLNEJK-UHFFFAOYSA-N 0.000 description 3
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N Arginine Chemical compound OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 3
- 241000222716 Crithidia Species 0.000 description 3
- 239000004395 L-leucine Substances 0.000 description 3
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 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 3
- USPFMEKVPDBMCG-LBPRGKRZSA-N N-benzyloxycarbonyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 USPFMEKVPDBMCG-LBPRGKRZSA-N 0.000 description 3
- 241000233872 Pneumocystis carinii Species 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 238000013016 damping Methods 0.000 description 3
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
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- 150000002240 furans Chemical class 0.000 description 3
- 230000000148 hypercalcaemia Effects 0.000 description 3
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- 230000003211 malignant effect Effects 0.000 description 3
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- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
- XFDDJSOAVIFVIH-VKKIDBQXSA-N (3s,4r)-4-aminooxolan-3-ol;hydrochloride Chemical compound Cl.N[C@@H]1COC[C@H]1O XFDDJSOAVIFVIH-VKKIDBQXSA-N 0.000 description 2
- FAHKAHMLFQVMPR-QWWZWVQMSA-N (3s,4r)-4-azidooxolan-3-ol Chemical compound O[C@@H]1COC[C@H]1N=[N+]=[N-] FAHKAHMLFQVMPR-QWWZWVQMSA-N 0.000 description 2
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 2
- LAOOXBLMIJHMFO-UHFFFAOYSA-N 1-[2-(diethylamino)ethylamino]-4-methylthioxanthen-9-one;hydron;chloride Chemical compound Cl.S1C2=CC=CC=C2C(=O)C2=C1C(C)=CC=C2NCCN(CC)CC LAOOXBLMIJHMFO-UHFFFAOYSA-N 0.000 description 2
- DNGLRCHMGDDHNC-UHFFFAOYSA-N 1-benzothiophene-2-carbonyl chloride Chemical compound C1=CC=C2SC(C(=O)Cl)=CC2=C1 DNGLRCHMGDDHNC-UHFFFAOYSA-N 0.000 description 2
- IBXNCJKFFQIKKY-UHFFFAOYSA-N 1-pentyne Chemical compound CCCC#C IBXNCJKFFQIKKY-UHFFFAOYSA-N 0.000 description 2
- XNMQEEKYCVKGBD-UHFFFAOYSA-N 2-butyne Chemical compound CC#CC XNMQEEKYCVKGBD-UHFFFAOYSA-N 0.000 description 2
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 2
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- 229940122156 Cathepsin K inhibitor Drugs 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
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- WFVMVMAUXYOQSW-UHFFFAOYSA-N quinoline-2-carbonyl chloride Chemical compound C1=CC=CC2=NC(C(=O)Cl)=CC=C21 WFVMVMAUXYOQSW-UHFFFAOYSA-N 0.000 description 1
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- 238000012216 screening Methods 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- IHQKEDIOMGYHEB-UHFFFAOYSA-M sodium dimethylarsinate Chemical compound [Na+].C[As](C)([O-])=O IHQKEDIOMGYHEB-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D307/32—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/99—Enzyme inactivation by chemical treatment
-
- 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
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- 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
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/06—Anabolic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-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
- C07D307/18—Heterocyclic compounds containing five-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
- C07D307/22—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
- C07D307/83—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/86—Benzo [b] furans; Hydrogenated benzo [b] furans with an oxygen atom directly attached in position 7
-
- 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
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D309/30—Oxygen atoms, e.g. delta-lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Physical Education & Sports Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Genetics & Genomics (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Microbiology (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- Immunology (AREA)
- Neurology (AREA)
- Endocrinology (AREA)
- Biomedical Technology (AREA)
- General Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Pyrane Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US4575897P | 1997-05-06 | 1997-05-06 | |
| US60/045,758 | 1997-05-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1255161A true CN1255161A (zh) | 2000-05-31 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98804791A Pending CN1255161A (zh) | 1997-05-06 | 1998-05-06 | 蛋白酶抑制剂 |
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| Country | Link |
|---|---|
| EP (1) | EP1003846A4 (tr) |
| JP (1) | JP2001525804A (tr) |
| KR (1) | KR20010012256A (tr) |
| CN (1) | CN1255161A (tr) |
| AR (1) | AR013079A1 (tr) |
| AU (1) | AU7562598A (tr) |
| BR (1) | BR9809306A (tr) |
| CA (1) | CA2288868A1 (tr) |
| CO (1) | CO4950618A1 (tr) |
| HU (1) | HUP0002247A3 (tr) |
| IL (1) | IL132088A0 (tr) |
| NO (1) | NO995434D0 (tr) |
| NZ (1) | NZ337889A (tr) |
| PE (1) | PE71599A1 (tr) |
| PL (1) | PL336856A1 (tr) |
| TR (1) | TR199902766T2 (tr) |
| UY (1) | UY25143A1 (tr) |
| WO (1) | WO1998050533A1 (tr) |
| ZA (1) | ZA983762B (tr) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100354276C (zh) * | 2002-07-16 | 2007-12-12 | 阿姆拉医疗有限公司 | 生物活性化合物 |
| CN102224156A (zh) * | 2008-09-24 | 2011-10-19 | 美迪维尔公司 | 蛋白酶抑制剂 |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CO5150165A1 (es) * | 1998-11-13 | 2002-04-29 | Smithkline Beecham Plc | Inhibidores de proteasa: tipo catepsina k |
| DZ3083A1 (fr) * | 1999-02-19 | 2004-06-02 | Smithkline Beecham Corp | Composés nouveaux inhibiteurs de protéases, procédé pour leur préparation et compositions pharmaceutiques les conentant. |
| GB9911417D0 (en) * | 1999-05-18 | 1999-07-14 | Peptide Therapeutics Ltd | Furanone derivatives as inhibitors of cathepsin s |
| WO2001034599A1 (en) * | 1999-11-10 | 2001-05-17 | Smithkline Beecham Corporation | Protease inhibitors |
| US20040024000A1 (en) * | 2000-10-19 | 2004-02-05 | Rajeshwar Singh | Dihydropyrimidine derivatives as cysteine protease inhibitors |
| JP2004513942A (ja) * | 2000-11-17 | 2004-05-13 | メディヴァー ユーケイ リミテッド | システインプロテアーゼインヒビター |
| JP2004520439A (ja) * | 2000-11-17 | 2004-07-08 | メディヴィル・アクチボラグ | システインプロテアーゼインヒビター |
| JP2004522738A (ja) * | 2001-01-17 | 2004-07-29 | アミュラ テラピューティクス リミテッド | クルジパインおよび他のシステインプロテアーゼの阻害剤としての環状２−カルボニルアミノケトン |
| US7132449B2 (en) | 2001-01-17 | 2006-11-07 | Amura Therapeutics Limited | Inhibitors of cruzipain and other cysteine proteases |
| AU2002219397B2 (en) * | 2001-01-17 | 2008-02-14 | Grünenthal GmbH | Inhibitors of cruzipain and other cysteine proteases |
| NZ526912A (en) * | 2001-01-17 | 2005-02-25 | Amura Therapeutics Ltd | Inhibitors of cruzipain and other cysteine proteases |
| WO2003037892A1 (en) * | 2001-10-29 | 2003-05-08 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compounds useful as reversible inhibitors of cysteine proteases |
| KR100962972B1 (ko) | 2002-07-26 | 2010-06-09 | 주식회사유한양행 | 1-페닐피페리딘-3-온 유도체 및 그의 제조방법 |
| BRPI0413324A (pt) | 2003-08-06 | 2006-10-10 | Senomyx Inc | receptores de paladar hetero-oligoméricos t1r, linhas de células que expressam os ditos receptores, e compostos de paladar |
| AU2016206281B2 (en) * | 2003-08-06 | 2017-11-30 | Senomyx, Inc. | Novel flavors, flavor modifiers, tastants, taste enhancers, umami or sweet tastants, and/or enhancers and use thereof |
| DE602005019971D1 (de) * | 2004-01-08 | 2010-04-29 | Medivir Ab | Inhibitoren von cysteinprotease |
| CA2619706A1 (en) * | 2005-08-17 | 2007-02-22 | Schering Corporation | Novel high affinity quinoline-based kinase ligands |
| GB0614042D0 (en) | 2006-07-14 | 2006-08-23 | Amura Therapeutics Ltd | Compounds |
| MX2009012847A (es) * | 2007-06-13 | 2009-12-08 | Bristol Myers Squibb Co | Analogos dipeptidicos como inhibidores de factores de coagulacion. |
| US7893067B2 (en) | 2007-06-27 | 2011-02-22 | Medivir Ab | Cysteine protease inhibitors |
| EP2240491B1 (en) | 2008-01-09 | 2015-07-15 | Amura Therapeutics Limited | TETRAHYDROFURO(2,3-b)PYRROL-3-ONE DERIVATIVES AS INHIBITORS OF CYSTEINE PROTEINASES |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3190431B2 (ja) * | 1991-07-01 | 2001-07-23 | 三菱化学株式会社 | ケトン誘導体 |
| JPH05140063A (ja) * | 1991-11-19 | 1993-06-08 | Suntory Ltd | ジペプチド誘導体及びそれを有効成分とする骨疾患の予防及び治療剤 |
| CA2111930A1 (en) * | 1992-12-25 | 1994-06-26 | Ryoichi Ando | Aminoketone derivatives |
| JP2848232B2 (ja) * | 1993-02-19 | 1999-01-20 | 武田薬品工業株式会社 | アルデヒド誘導体 |
| JP3599287B2 (ja) * | 1993-04-28 | 2004-12-08 | 三菱化学株式会社 | スルホンアミド誘導体 |
| US5403952A (en) * | 1993-10-08 | 1995-04-04 | Merck & Co., Inc. | Substituted cyclic derivatives as novel antidegenerative agents |
| SK88997A3 (en) * | 1995-10-30 | 1998-05-06 | Smithkline Beecham Corp | Method of inhibiting cathepsin k |
| TW448172B (en) * | 1996-03-08 | 2001-08-01 | Pharmacia & Upjohn Co Llc | Novel hydroxamic acid derivatives useful for the treatment of diseases related to connective tissue degradation |
| WO1998004539A1 (fr) * | 1996-07-29 | 1998-02-05 | Mitsubishi Chemical Corporation | Derives heterocycliques oxygenes |
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1998
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- 1998-05-05 ZA ZA983762A patent/ZA983762B/xx unknown
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- 1998-05-06 WO PCT/US1998/003200 patent/WO1998050533A1/en not_active Application Discontinuation
- 1998-05-06 KR KR1019997010207A patent/KR20010012256A/ko not_active Application Discontinuation
- 1998-05-06 JP JP54804998A patent/JP2001525804A/ja active Pending
- 1998-05-06 BR BR9809306-1A patent/BR9809306A/pt not_active Application Discontinuation
- 1998-05-06 PL PL98336856A patent/PL336856A1/xx unknown
- 1998-05-06 HU HU0002247A patent/HUP0002247A3/hu unknown
- 1998-05-06 TR TR1999/02766T patent/TR199902766T2/tr unknown
- 1998-05-06 IL IL13208898A patent/IL132088A0/xx unknown
- 1998-05-06 NZ NZ337889A patent/NZ337889A/en unknown
- 1998-05-06 CA CA002288868A patent/CA2288868A1/en not_active Abandoned
- 1998-05-06 AU AU75625/98A patent/AU7562598A/en not_active Abandoned
- 1998-08-17 UY UY25143A patent/UY25143A1/es unknown
-
1999
- 1999-11-05 NO NO995434A patent/NO995434D0/no not_active Application Discontinuation
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100354276C (zh) * | 2002-07-16 | 2007-12-12 | 阿姆拉医疗有限公司 | 生物活性化合物 |
| CN102224156A (zh) * | 2008-09-24 | 2011-10-19 | 美迪维尔公司 | 蛋白酶抑制剂 |
| CN102224156B (zh) * | 2008-09-24 | 2014-06-25 | 美迪维尔公司 | 蛋白酶抑制剂 |
Also Published As
| Publication number | Publication date |
|---|---|
| NO995434L (no) | 1999-11-05 |
| KR20010012256A (ko) | 2001-02-15 |
| TR199902766T2 (tr) | 2000-02-21 |
| CA2288868A1 (en) | 1998-11-12 |
| EP1003846A1 (en) | 2000-05-31 |
| WO1998050533A1 (en) | 1998-11-12 |
| NO995434D0 (no) | 1999-11-05 |
| PL336856A1 (en) | 2000-07-17 |
| UY25143A1 (es) | 1998-11-27 |
| CO4950618A1 (es) | 2000-09-01 |
| JP2001525804A (ja) | 2001-12-11 |
| IL132088A0 (en) | 2001-03-19 |
| AR013079A1 (es) | 2000-12-13 |
| AU7562598A (en) | 1998-11-27 |
| HUP0002247A3 (en) | 2003-01-28 |
| PE71599A1 (es) | 1999-09-15 |
| HUP0002247A2 (hu) | 2001-05-28 |
| BR9809306A (pt) | 2000-07-04 |
| EP1003846A4 (en) | 2002-11-13 |
| NZ337889A (en) | 2001-09-28 |
| ZA983762B (en) | 1998-11-06 |
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