SK56798A3 - Protease inhibitors, pharmaceutical composition containing them and their use - Google Patents
Protease inhibitors, pharmaceutical composition containing them and their use Download PDFInfo
- Publication number
- SK56798A3 SK56798A3 SK567-98A SK56798A SK56798A3 SK 56798 A3 SK56798 A3 SK 56798A3 SK 56798 A SK56798 A SK 56798A SK 56798 A3 SK56798 A3 SK 56798A3
- Authority
- SK
- Slovakia
- Prior art keywords
- alkyl
- leucinyl
- benzyloxycarbonyl
- amino
- compound
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 10
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 title description 8
- 239000000137 peptide hydrolase inhibitor Substances 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 597
- 238000000034 method Methods 0.000 claims abstract description 63
- 201000010099 disease Diseases 0.000 claims abstract description 30
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 30
- 108090000625 Cathepsin K Proteins 0.000 claims abstract description 27
- 206010065687 Bone loss Diseases 0.000 claims abstract description 10
- 208000001132 Osteoporosis Diseases 0.000 claims abstract description 9
- 210000000845 cartilage Anatomy 0.000 claims abstract description 9
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 9
- 230000015556 catabolic process Effects 0.000 claims abstract description 7
- 238000006731 degradation reaction Methods 0.000 claims abstract description 7
- 208000007565 gingivitis Diseases 0.000 claims abstract description 7
- 201000008482 osteoarthritis Diseases 0.000 claims abstract description 7
- 201000001245 periodontitis Diseases 0.000 claims abstract description 7
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 6
- 102000004171 Cathepsin K Human genes 0.000 claims abstract 2
- -1 4-phenoxybenzoyl- Chemical group 0.000 claims description 379
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 279
- 125000000217 alkyl group Chemical group 0.000 claims description 223
- XEVRDFDBXJMZFG-UHFFFAOYSA-N carbonyl dihydrazine Chemical compound NNC(=O)NN XEVRDFDBXJMZFG-UHFFFAOYSA-N 0.000 claims description 129
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 68
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 59
- 125000003118 aryl group Chemical group 0.000 claims description 53
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 48
- 125000001072 heteroaryl group Chemical group 0.000 claims description 48
- 229910052739 hydrogen Inorganic materials 0.000 claims description 44
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 41
- 229910052799 carbon Inorganic materials 0.000 claims description 38
- 229910052757 nitrogen Inorganic materials 0.000 claims description 38
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 37
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 33
- 102000005927 Cysteine Proteases Human genes 0.000 claims description 29
- 108010005843 Cysteine Proteases Proteins 0.000 claims description 29
- 125000003545 alkoxy group Chemical group 0.000 claims description 29
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 24
- 229910052717 sulfur Inorganic materials 0.000 claims description 22
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 20
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- ZNEHOZABQGNGSG-NSHDSACASA-N (2s)-4-methyl-2-(pyridin-2-ylmethoxycarbonylamino)pentanoic acid Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=N1 ZNEHOZABQGNGSG-NSHDSACASA-N 0.000 claims description 9
- 229910052786 argon Inorganic materials 0.000 claims description 9
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 claims description 8
- 125000006189 4-phenyl benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 7
- 229940024606 amino acid Drugs 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- XKBQRCUXXCGCMC-UHFFFAOYSA-N 1,4-diphenylbutane-2,3-dione Chemical group C=1C=CC=CC=1CC(=O)C(=O)CC1=CC=CC=C1 XKBQRCUXXCGCMC-UHFFFAOYSA-N 0.000 claims description 6
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- SYWULVOOUWEIMG-WPNGARGVSA-N benzyl n-[(4s,6s)-6-amino-8-(dibenzofuran-2-ylsulfonylamino)-2-methyl-5,7-dioxononan-4-yl]carbamate Chemical compound N([C@@H](CC(C)C)C(=O)[C@H](N)C(=O)C(C)NS(=O)(=O)C=1C=C2C3=CC=CC=C3OC2=CC=1)C(=O)OCC1=CC=CC=C1 SYWULVOOUWEIMG-WPNGARGVSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 125000005518 carboxamido group Chemical group 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 125000004512 1,2,3-thiadiazol-4-yl group Chemical group S1N=NC(=C1)* 0.000 claims description 5
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 5
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 5
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 claims description 5
- MCNNGLLIMGMEMJ-DCCUJTHKSA-N benzyl n-[(4s)-6-amino-8-(dibenzofuran-2-ylsulfonylamino)-2-methyl-5,7-dioxooctan-4-yl]carbamate Chemical compound N([C@@H](CC(C)C)C(=O)C(N)C(=O)CNS(=O)(=O)C=1C=C2C3=CC=CC=C3OC2=CC=1)C(=O)OCC1=CC=CC=C1 MCNNGLLIMGMEMJ-DCCUJTHKSA-N 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000003047 N-acetyl group Chemical group 0.000 claims description 4
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 4
- ZWDDBYFYFAGWGC-PVCWFJFTSA-N benzyl n-[(4s)-6-amino-2-methyl-5,7-dioxo-8-[(4-phenoxyphenyl)sulfonylamino]octan-4-yl]carbamate Chemical compound N([C@@H](CC(C)C)C(=O)C(N)C(=O)CNS(=O)(=O)C=1C=CC(OC=2C=CC=CC=2)=CC=1)C(=O)OCC1=CC=CC=C1 ZWDDBYFYFAGWGC-PVCWFJFTSA-N 0.000 claims description 4
- 210000002805 bone matrix Anatomy 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 3
- GURAQQHHYRTKBI-ZCCOPBOASA-N C(=O)(OCC1=CC=CC=C1)N[C@@H](CC(C)C)C(=O)C(C(C(N)C([C@@H](NC(=O)OCC1=CC=CC=C1)CC(C)C)=O)=O)N Chemical compound C(=O)(OCC1=CC=CC=C1)N[C@@H](CC(C)C)C(=O)C(C(C(N)C([C@@H](NC(=O)OCC1=CC=CC=C1)CC(C)C)=O)=O)N GURAQQHHYRTKBI-ZCCOPBOASA-N 0.000 claims description 3
- FSOXYYNRYZULOL-UHFFFAOYSA-N NC(C(=O)NC(CC(C)C)C=1N=C(SC=1)C(=O)OCC)CC(C)C Chemical compound NC(C(=O)NC(CC(C)C)C=1N=C(SC=1)C(=O)OCC)CC(C)C FSOXYYNRYZULOL-UHFFFAOYSA-N 0.000 claims description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- BJVFZLZZXSLPJX-NSOVKSMOSA-N benzyl n-[(2s,8s)-6,6-diamino-10-methyl-3,5,7-trioxo-1-phenyl-8-(phenylmethoxycarbonylamino)undecan-2-yl]carbamate Chemical compound N([C@@H](CC(C)C)C(=O)C(N)(N)C(=O)CC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)C(=O)OCC1=CC=CC=C1 BJVFZLZZXSLPJX-NSOVKSMOSA-N 0.000 claims description 3
- RYFPPMDSGCIQDZ-AIBWNMTMSA-N benzyl n-[(4s)-6-amino-2-methyl-8-[(4-methylphenyl)sulfonylamino]-5,7-dioxooctan-4-yl]carbamate Chemical compound N([C@@H](CC(C)C)C(=O)C(N)C(=O)CNS(=O)(=O)C=1C=CC(C)=CC=1)C(=O)OCC1=CC=CC=C1 RYFPPMDSGCIQDZ-AIBWNMTMSA-N 0.000 claims description 3
- MVBBYHQLYRCGBR-ALLRNTDFSA-N benzyl n-[(4s)-6-amino-8-[[4-(3-chloro-2-cyanophenoxy)phenyl]sulfonylamino]-2-methyl-5,7-dioxooctan-4-yl]carbamate Chemical compound N([C@@H](CC(C)C)C(=O)C(N)C(=O)CNS(=O)(=O)C=1C=CC(OC=2C(=C(Cl)C=CC=2)C#N)=CC=1)C(=O)OCC1=CC=CC=C1 MVBBYHQLYRCGBR-ALLRNTDFSA-N 0.000 claims description 3
- FAHHIIAHWJYILR-DQEYMECFSA-N benzyl n-[(4s,10s)-6,6-diamino-2-methyl-5,7,9-trioxo-10-(phenylmethoxycarbonylamino)tetradecan-4-yl]carbamate Chemical compound N([C@@H](CCCC)C(=O)CC(=O)C(N)(N)C(=O)[C@H](CC(C)C)NC(=O)OCC=1C=CC=CC=1)C(=O)OCC1=CC=CC=C1 FAHHIIAHWJYILR-DQEYMECFSA-N 0.000 claims description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 3
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000002950 monocyclic group Chemical group 0.000 claims description 3
- JXPNAKDLVGIPPN-FQEVSTJZSA-N n-[(4s)-6,6-diamino-2-methyl-5,7,9-trioxo-9-(4-phenoxyphenyl)nonan-4-yl]acetamide Chemical compound C1=CC(C(=O)CC(=O)C(N)(N)C(=O)[C@@H](NC(C)=O)CC(C)C)=CC=C1OC1=CC=CC=C1 JXPNAKDLVGIPPN-FQEVSTJZSA-N 0.000 claims description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
- SFHFKCJQMMQUHT-GOTSBHOMSA-N N([C@@H](CC(C)C)C(=O)C(N)(N)C(=O)CC(=O)[C@H](CCC(O)=O)NC(=O)OCC=1C=CC=CC=1)C(=O)OCC1=CC=CC=C1 Chemical compound N([C@@H](CC(C)C)C(=O)C(N)(N)C(=O)CC(=O)[C@H](CCC(O)=O)NC(=O)OCC=1C=CC=CC=1)C(=O)OCC1=CC=CC=C1 SFHFKCJQMMQUHT-GOTSBHOMSA-N 0.000 claims description 2
- PYAGJADZMKVQBR-PMACEKPBSA-N benzyl n-[(4s,10s)-10-acetamido-6,6-diamino-2,12-dimethyl-5,7,9-trioxotridecan-4-yl]carbamate Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)CC(=O)C(N)(N)C(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 PYAGJADZMKVQBR-PMACEKPBSA-N 0.000 claims description 2
- 125000002527 bicyclic carbocyclic group Chemical group 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
- PKOPLDUHARSIKV-UHFFFAOYSA-N n-butylpentanamide Chemical compound CCCCNC(=O)CCCC PKOPLDUHARSIKV-UHFFFAOYSA-N 0.000 claims 1
- 239000004365 Protease Substances 0.000 abstract description 15
- 102000035195 Peptidases Human genes 0.000 abstract description 13
- 108091005804 Peptidases Proteins 0.000 abstract description 13
- 239000011159 matrix material Substances 0.000 abstract description 8
- 208000010191 Osteitis Deformans Diseases 0.000 abstract description 5
- 208000027868 Paget disease Diseases 0.000 abstract description 5
- 208000027202 mammary Paget disease Diseases 0.000 abstract description 5
- 208000029725 Metabolic bone disease Diseases 0.000 abstract description 4
- 206010003246 arthritis Diseases 0.000 abstract description 4
- 208000024693 gingival disease Diseases 0.000 abstract description 3
- 208000030136 Marchiafava-Bignami Disease Diseases 0.000 abstract description 2
- 206010020584 Hypercalcaemia of malignancy Diseases 0.000 abstract 1
- 208000008750 humoral hypercalcemia of malignancy Diseases 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 292
- 239000000243 solution Substances 0.000 description 270
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 202
- 239000007787 solid Substances 0.000 description 202
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 167
- 238000002360 preparation method Methods 0.000 description 152
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 139
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 120
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 116
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 112
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 102
- 235000019439 ethyl acetate Nutrition 0.000 description 97
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 97
- 238000003756 stirring Methods 0.000 description 91
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 87
- 239000000203 mixture Substances 0.000 description 86
- 238000005481 NMR spectroscopy Methods 0.000 description 85
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 75
- 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 69
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 64
- 238000006243 chemical reaction Methods 0.000 description 64
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 62
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 60
- 239000000741 silica gel Substances 0.000 description 59
- 229910002027 silica gel Inorganic materials 0.000 description 59
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 57
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical class CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 56
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 51
- 235000019341 magnesium sulphate Nutrition 0.000 description 51
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 48
- 239000012044 organic layer Substances 0.000 description 47
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- 239000011541 reaction mixture Substances 0.000 description 38
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 38
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 35
- 229960003136 leucine Drugs 0.000 description 35
- 229920006395 saturated elastomer Polymers 0.000 description 30
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 28
- 239000012267 brine Substances 0.000 description 28
- 239000000460 chlorine Substances 0.000 description 27
- 238000010992 reflux Methods 0.000 description 27
- 102100024940 Cathepsin K Human genes 0.000 description 26
- WXNXCEHXYPACJF-ZETCQYMHSA-N N-acetyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(C)=O WXNXCEHXYPACJF-ZETCQYMHSA-N 0.000 description 26
- 239000000010 aprotic solvent Substances 0.000 description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 25
- 239000003810 Jones reagent Substances 0.000 description 25
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 24
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 23
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 23
- 239000011734 sodium Substances 0.000 description 23
- 238000006467 substitution reaction Methods 0.000 description 23
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 22
- 108090000765 processed proteins & peptides Proteins 0.000 description 20
- 235000017557 sodium bicarbonate Nutrition 0.000 description 20
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 20
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 20
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 19
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 19
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 19
- 239000004395 L-leucine Substances 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 18
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 17
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 17
- BIXZZSTYTJMJKS-NSHDSACASA-N (2s)-4-methyl-2-(pyridin-4-ylmethoxycarbonylamino)pentanoic acid Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)OCC1=CC=NC=C1 BIXZZSTYTJMJKS-NSHDSACASA-N 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 15
- 238000004440 column chromatography Methods 0.000 description 15
- 238000003818 flash chromatography Methods 0.000 description 15
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- FTZNYGSHSMZEIA-UHFFFAOYSA-M sodium;hydrogen carbonate;sulfuric acid Chemical compound [Na+].OC([O-])=O.OS(O)(=O)=O FTZNYGSHSMZEIA-UHFFFAOYSA-M 0.000 description 1
- 239000008259 solid foam Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000012289 standard assay Methods 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
- 239000011550 stock solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 150000003900 succinic acid esters Chemical class 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 229940042055 systemic antimycotics triazole derivative Drugs 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- SGELYKFHPZWNDV-QMMMGPOBSA-N tert-butyl n-[(2s)-2-amino-4-methylpentanethioyl]carbamate Chemical compound CC(C)C[C@H](N)C(=S)NC(=O)OC(C)(C)C SGELYKFHPZWNDV-QMMMGPOBSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 150000004905 tetrazines Chemical class 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 150000004867 thiadiazoles Chemical class 0.000 description 1
- 150000007979 thiazole derivatives Chemical class 0.000 description 1
- 150000003557 thiazoles Chemical class 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 238000007070 tosylation reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- 150000003918 triazines Chemical class 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- LYRCQNDYYRPFMF-UHFFFAOYSA-N trimethyltin Chemical compound C[Sn](C)C LYRCQNDYYRPFMF-UHFFFAOYSA-N 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 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
- 238000003828 vacuum filtration Methods 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003738 xylenes Chemical class 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
- C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
- C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C243/34—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a carbon skeleton further substituted by nitrogen atoms
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
- C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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, directly attached to ring carbon atoms
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
- C07D211/96—Sulfur atom
-
- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/36—Sulfur atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having 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
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- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
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- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
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- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
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-
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
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- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
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- C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
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- C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
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- 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
- C07D307/91—Dibenzofurans; Hydrogenated dibenzofurans
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- 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
-
- 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
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6472—Cysteine endopeptidases (3.4.22)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
- C12Q1/37—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase involving peptidase or proteinase
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/573—Immunoassay; Biospecific binding assay; Materials therefor for enzymes or isoenzymes
Landscapes
- Chemical & Material Sciences (AREA)
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Biomedical Technology (AREA)
- Genetics & Genomics (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Physical Education & Sports Medicine (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Hematology (AREA)
- Analytical Chemistry (AREA)
- General Engineering & Computer Science (AREA)
- Physics & Mathematics (AREA)
- Urology & Nephrology (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Cell Biology (AREA)
- Biophysics (AREA)
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Applications Claiming Priority (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US810895P | 1995-10-30 | 1995-10-30 | |
US747395P | 1995-11-22 | 1995-11-22 | |
US899295P | 1995-12-21 | 1995-12-21 | |
US1376496P | 1996-03-20 | 1996-03-20 | |
US1374896P | 1996-03-20 | 1996-03-20 | |
US1374796P | 1996-03-20 | 1996-03-20 | |
US1745596P | 1996-05-17 | 1996-05-17 | |
US1789296P | 1996-05-17 | 1996-05-17 | |
US2204796P | 1996-07-22 | 1996-07-22 | |
US2349496P | 1996-08-07 | 1996-08-07 | |
PCT/US1996/018000 WO1997016433A1 (en) | 1995-10-30 | 1996-10-30 | Protease inhibitors |
Publications (1)
Publication Number | Publication Date |
---|---|
SK56798A3 true SK56798A3 (en) | 1998-12-02 |
Family
ID=27580625
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
SK567-98A SK56798A3 (en) | 1995-10-30 | 1996-10-30 | Protease inhibitors, pharmaceutical composition containing them and their use |
Country Status (17)
Country | Link |
---|---|
US (5) | US5998470A (ko) |
EP (1) | EP0934291A1 (ko) |
JP (1) | JP2000500742A (ko) |
KR (1) | KR19990067184A (ko) |
CN (3) | CN1341593A (ko) |
AP (1) | AP9801222A0 (ko) |
AU (1) | AU1118097A (ko) |
BG (1) | BG102475A (ko) |
CZ (1) | CZ132798A3 (ko) |
EA (1) | EA199800353A1 (ko) |
HU (1) | HUP9900964A3 (ko) |
NO (4) | NO981938L (ko) |
OA (1) | OA10764A (ko) |
PL (1) | PL326508A1 (ko) |
SK (1) | SK56798A3 (ko) |
TR (1) | TR199800767T2 (ko) |
WO (1) | WO1997016433A1 (ko) |
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WO1998050342A1 (en) * | 1997-05-08 | 1998-11-12 | Smithkline Beecham Corporation | Protease inhibitors |
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MA26631A1 (fr) * | 1998-05-21 | 2004-12-20 | Smithkline Beecham Corp | Composes a fonction bis-aminomethyl-carbonyle nouveaux, procede pour leur preparation et compositions pharmaceutiques les contenant |
EP1079821A4 (en) * | 1998-05-21 | 2001-08-29 | Smithkline Beecham Corp | PROTEASE INHIBITORS |
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-
1996
- 1996-10-30 TR TR1998/00767T patent/TR199800767T2/xx unknown
- 1996-10-30 EP EP96941981A patent/EP0934291A1/en not_active Withdrawn
- 1996-10-30 AP APAP/P/1998/001222A patent/AP9801222A0/en unknown
- 1996-10-30 CZ CZ981327A patent/CZ132798A3/cs unknown
- 1996-10-30 HU HU9900964A patent/HUP9900964A3/hu not_active Application Discontinuation
- 1996-10-30 SK SK567-98A patent/SK56798A3/sk unknown
- 1996-10-30 WO PCT/US1996/018000 patent/WO1997016433A1/en not_active Application Discontinuation
- 1996-10-30 AU AU11180/97A patent/AU1118097A/en not_active Abandoned
- 1996-10-30 PL PL96326508A patent/PL326508A1/xx unknown
- 1996-10-30 EA EA199800353A patent/EA199800353A1/ru unknown
- 1996-10-30 JP JP9517638A patent/JP2000500742A/ja not_active Ceased
- 1996-10-30 KR KR1019980703135A patent/KR19990067184A/ko not_active Application Discontinuation
-
1998
- 1998-04-29 NO NO981938A patent/NO981938L/no unknown
- 1998-04-30 OA OA9800049A patent/OA10764A/en unknown
- 1998-05-21 BG BG102475A patent/BG102475A/xx unknown
-
1999
- 1999-04-13 US US09/290,958 patent/US5998470A/en not_active Expired - Fee Related
- 1999-06-11 US US09/330,451 patent/US6232342B1/en not_active Expired - Fee Related
- 1999-06-11 US US09/330,287 patent/US6057362A/en not_active Expired - Fee Related
-
2000
- 2000-04-19 US US09/552,616 patent/US6284777B1/en not_active Expired - Fee Related
- 2000-04-19 US US09/551,968 patent/US6331542B1/en not_active Expired - Fee Related
- 2000-12-29 NO NO20006716A patent/NO20006716D0/no not_active Application Discontinuation
- 2000-12-29 NO NO20006717A patent/NO20006717D0/no not_active Application Discontinuation
- 2000-12-29 NO NO20006718A patent/NO20006718D0/no not_active Application Discontinuation
-
2001
- 2001-02-20 CN CN01104789A patent/CN1341593A/zh active Pending
- 2001-02-20 CN CN01104788A patent/CN1341592A/zh active Pending
- 2001-02-20 CN CN01104787A patent/CN1341590A/zh active Pending
Also Published As
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KR19990067184A (ko) | 1999-08-16 |
NO20006718L (no) | 1998-06-29 |
US6232342B1 (en) | 2001-05-15 |
AU1118097A (en) | 1997-05-22 |
EP0934291A4 (ko) | 1999-08-11 |
OA10764A (en) | 2002-12-11 |
WO1997016433A1 (en) | 1997-05-09 |
NO20006716D0 (no) | 2000-12-29 |
PL326508A1 (en) | 1998-09-28 |
NO20006716L (no) | 1998-06-29 |
AP9801222A0 (en) | 1998-06-30 |
NO20006717L (no) | 1998-06-29 |
EP0934291A1 (en) | 1999-08-11 |
EA199800353A1 (ru) | 1998-12-24 |
NO981938D0 (no) | 1998-04-29 |
CN1341593A (zh) | 2002-03-27 |
CZ132798A3 (cs) | 1999-02-17 |
NO20006718D0 (no) | 2000-12-29 |
HUP9900964A2 (hu) | 1999-07-28 |
HUP9900964A3 (en) | 2001-02-28 |
US6284777B1 (en) | 2001-09-04 |
BG102475A (en) | 1999-04-30 |
US5998470A (en) | 1999-12-07 |
MX9803548A (es) | 1998-09-30 |
NO981938L (no) | 1998-06-29 |
US6331542B1 (en) | 2001-12-18 |
JP2000500742A (ja) | 2000-01-25 |
NO20006717D0 (no) | 2000-12-29 |
TR199800767T2 (xx) | 1998-07-21 |
CN1341592A (zh) | 2002-03-27 |
CN1341590A (zh) | 2002-03-27 |
US6057362A (en) | 2000-05-02 |
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