JP4450988B2 - ジペプチドニトリル - Google Patents
ジペプチドニトリル Download PDFInfo
- Publication number
- JP4450988B2 JP4450988B2 JP2000520468A JP2000520468A JP4450988B2 JP 4450988 B2 JP4450988 B2 JP 4450988B2 JP 2000520468 A JP2000520468 A JP 2000520468A JP 2000520468 A JP2000520468 A JP 2000520468A JP 4450988 B2 JP4450988 B2 JP 4450988B2
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- JP
- Japan
- Prior art keywords
- methyl
- mmol
- solution
- acid
- amide
- 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.)
- Expired - Fee Related
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- 150000002825 nitriles Chemical class 0.000 title description 15
- 108010016626 Dipeptides Proteins 0.000 title description 14
- 150000001875 compounds Chemical class 0.000 claims description 114
- 230000005764 inhibitory process Effects 0.000 claims description 16
- 108090000613 Cathepsin S Proteins 0.000 claims description 14
- 230000000694 effects Effects 0.000 claims description 13
- 108090000625 Cathepsin K Proteins 0.000 claims description 12
- 102000004171 Cathepsin K Human genes 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- UOBYKYZJUGYBDK-UHFFFAOYSA-N 2-naphthoic acid Chemical compound C1=CC=CC2=CC(C(=O)O)=CC=C21 UOBYKYZJUGYBDK-UHFFFAOYSA-N 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 101000761509 Homo sapiens Cathepsin K Proteins 0.000 claims description 4
- 102000049698 human CTSK Human genes 0.000 claims description 4
- PHHUDJQYUVMKFT-UHFFFAOYSA-N n-[1-(2-cyanopropan-2-ylamino)-4-methyl-1-oxopentan-2-yl]naphthalene-2-carboxamide Chemical compound C1=CC=CC2=CC(C(=O)NC(CC(C)C)C(=O)NC(C)(C)C#N)=CC=C21 PHHUDJQYUVMKFT-UHFFFAOYSA-N 0.000 claims description 4
- 101000983583 Homo sapiens Procathepsin L Proteins 0.000 claims description 3
- 102000050937 human CTSL Human genes 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- SBZLZNWFSWCYLJ-UHFFFAOYSA-N n-[1-(cyanomethylamino)-4-methyl-1-oxopentan-2-yl]-4-(2-pyrrolidin-1-ylethylsulfanyl)benzamide Chemical compound C1=CC(C(=O)NC(CC(C)C)C(=O)NCC#N)=CC=C1SCCN1CCCC1 SBZLZNWFSWCYLJ-UHFFFAOYSA-N 0.000 claims description 3
- USQYDMLPDUTMBP-UHFFFAOYSA-N n-[1-(cyanomethylcarbamoyl)cyclohexyl]-4-(imidazol-1-ylmethyl)benzamide Chemical compound C=1C=C(CN2C=NC=C2)C=CC=1C(=O)NC1(C(=O)NCC#N)CCCCC1 USQYDMLPDUTMBP-UHFFFAOYSA-N 0.000 claims description 3
- MXXKZSGEJDBTQU-UHFFFAOYSA-N 2-[[2-(4-chloroanilino)acetyl]amino]-n-(cyanomethyl)-4-methylpentanamide Chemical compound N#CCNC(=O)C(CC(C)C)NC(=O)CNC1=CC=C(Cl)C=C1 MXXKZSGEJDBTQU-UHFFFAOYSA-N 0.000 claims description 2
- VVGSHJCERNMTNI-UHFFFAOYSA-N C1=CC=CC2=CC(C(=O)NC(C(C)CC)C(=O)NCC#N)=CC=C21 Chemical compound C1=CC=CC2=CC(C(=O)NC(C(C)CC)C(=O)NCC#N)=CC=C21 VVGSHJCERNMTNI-UHFFFAOYSA-N 0.000 claims description 2
- BMFYRFFIWZYPGT-UHFFFAOYSA-N benzyl n-[1-[(1-cyano-2-phenylmethoxyethyl)amino]-4-methyl-1-oxopentan-2-yl]carbamate Chemical compound C=1C=CC=CC=1COCC(C#N)NC(=O)C(CC(C)C)NC(=O)OCC1=CC=CC=C1 BMFYRFFIWZYPGT-UHFFFAOYSA-N 0.000 claims description 2
- 238000000099 in vitro assay Methods 0.000 claims description 2
- BOFKWLMYQAUHND-UHFFFAOYSA-N n-[1-(2-cyanopropan-2-ylamino)-4-methyl-1-oxopentan-2-yl]-4-(imidazol-1-ylmethyl)benzamide Chemical compound C1=CC(C(=O)NC(CC(C)C)C(=O)NC(C)(C)C#N)=CC=C1CN1C=NC=C1 BOFKWLMYQAUHND-UHFFFAOYSA-N 0.000 claims description 2
- DEWILIAMQYFWKE-UHFFFAOYSA-N n-[1-(2-cyanopropan-2-ylcarbamoyl)cyclohexyl]-1h-indole-2-carboxamide Chemical compound C=1C2=CC=CC=C2NC=1C(=O)NC1(C(=O)NC(C)(C)C#N)CCCCC1 DEWILIAMQYFWKE-UHFFFAOYSA-N 0.000 claims description 2
- NDYOHZLPSKKWAU-UHFFFAOYSA-N n-[1-[(1-cyano-3-methylbutyl)amino]-3-methyl-1-oxopentan-2-yl]naphthalene-2-carboxamide Chemical compound C1=CC=CC2=CC(C(=O)NC(C(C)CC)C(=O)NC(CC(C)C)C#N)=CC=C21 NDYOHZLPSKKWAU-UHFFFAOYSA-N 0.000 claims description 2
- BMOBLEZARNPCGX-UHFFFAOYSA-N n-[1-[(1-cyano-3-methylbutyl)amino]-4-methyl-1-oxopentan-2-yl]naphthalene-2-carboxamide Chemical compound C1=CC=CC2=CC(C(=O)NC(CC(C)C)C(=O)NC(CC(C)C)C#N)=CC=C21 BMOBLEZARNPCGX-UHFFFAOYSA-N 0.000 claims description 2
- GQDZIGLYDFSVFF-UHFFFAOYSA-N n-[1-[[1-cyano-2-(1h-indol-3-yl)ethyl]amino]-4-methyl-1-oxopentan-2-yl]naphthalene-2-carboxamide Chemical compound C1=CC=C2C(CC(NC(=O)C(NC(=O)C=3C=C4C=CC=CC4=CC=3)CC(C)C)C#N)=CNC2=C1 GQDZIGLYDFSVFF-UHFFFAOYSA-N 0.000 claims description 2
- RUWBBBUXZRUXBG-UHFFFAOYSA-N 1-amino-n-(cyanomethyl)cyclohexane-1-carboxamide Chemical compound N#CCNC(=O)C1(N)CCCCC1 RUWBBBUXZRUXBG-UHFFFAOYSA-N 0.000 claims 1
- SSQQEDTWFQTNIE-UHFFFAOYSA-N 5-amino-n-[1-(cyanomethylamino)-4-methyl-1-oxopentan-2-yl]quinoline-2-carboxamide Chemical compound NC1=CC=CC2=NC(C(=O)NC(CC(C)C)C(=O)NCC#N)=CC=C21 SSQQEDTWFQTNIE-UHFFFAOYSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 372
- -1 hydroxy, amino Chemical group 0.000 description 202
- 239000000243 solution Substances 0.000 description 197
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 164
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 147
- 235000019439 ethyl acetate Nutrition 0.000 description 139
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 107
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 95
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 93
- 125000000217 alkyl group Chemical group 0.000 description 80
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 71
- 239000000203 mixture Substances 0.000 description 65
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 62
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 62
- 239000012267 brine Substances 0.000 description 53
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 53
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 50
- 239000007787 solid Substances 0.000 description 50
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 47
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
- 239000000047 product Substances 0.000 description 44
- 239000011541 reaction mixture Substances 0.000 description 44
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 38
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 38
- 150000003839 salts Chemical class 0.000 description 37
- 238000001704 evaporation Methods 0.000 description 36
- 102000005600 Cathepsins Human genes 0.000 description 33
- 108010084457 Cathepsins Proteins 0.000 description 33
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 33
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 31
- 235000019341 magnesium sulphate Nutrition 0.000 description 31
- 229910052799 carbon Inorganic materials 0.000 description 30
- 239000000284 extract Substances 0.000 description 29
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 229920006395 saturated elastomer Polymers 0.000 description 27
- 239000012043 crude product Substances 0.000 description 26
- 238000010898 silica gel chromatography Methods 0.000 description 26
- 238000003756 stirring Methods 0.000 description 26
- 229910052717 sulfur Inorganic materials 0.000 description 26
- 125000000623 heterocyclic group Chemical group 0.000 description 24
- 229910052760 oxygen Inorganic materials 0.000 description 24
- 125000002947 alkylene group Chemical group 0.000 description 22
- 125000003118 aryl group Chemical group 0.000 description 22
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 22
- 239000003921 oil Substances 0.000 description 22
- 239000000377 silicon dioxide Substances 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 21
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 20
- 239000012044 organic layer Substances 0.000 description 20
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 19
- 239000003112 inhibitor Substances 0.000 description 19
- 125000002837 carbocyclic group Chemical group 0.000 description 18
- 230000008020 evaporation Effects 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
- 201000010099 disease Diseases 0.000 description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 17
- 238000000034 method Methods 0.000 description 17
- 229910052757 nitrogen Inorganic materials 0.000 description 17
- 125000004432 carbon atom Chemical group C* 0.000 description 16
- 229910052736 halogen Inorganic materials 0.000 description 16
- 150000002367 halogens Chemical class 0.000 description 16
- 238000000746 purification Methods 0.000 description 16
- 238000011282 treatment Methods 0.000 description 16
- 125000003545 alkoxy group Chemical group 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 239000002253 acid Substances 0.000 description 14
- 125000000753 cycloalkyl group Chemical group 0.000 description 14
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 14
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 14
- 125000001424 substituent group Chemical group 0.000 description 14
- 150000002148 esters Chemical class 0.000 description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 13
- 239000000843 powder Substances 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
- 102100035654 Cathepsin S Human genes 0.000 description 12
- 241000124008 Mammalia Species 0.000 description 12
- 125000002252 acyl group Chemical group 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 125000001589 carboacyl group Chemical group 0.000 description 12
- 239000010410 layer Substances 0.000 description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 108090000624 Cathepsin L Proteins 0.000 description 11
- 102000004172 Cathepsin L Human genes 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 239000007858 starting material Substances 0.000 description 11
- 102000004190 Enzymes Human genes 0.000 description 10
- 108090000790 Enzymes Proteins 0.000 description 10
- 150000001721 carbon Chemical group 0.000 description 10
- 229940088598 enzyme Drugs 0.000 description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 description 10
- 229960005190 phenylalanine Drugs 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 235000011152 sodium sulphate Nutrition 0.000 description 10
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 9
- 229940124639 Selective inhibitor Drugs 0.000 description 9
- 125000005842 heteroatom Chemical group 0.000 description 9
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical class [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- 108090000712 Cathepsin B Proteins 0.000 description 8
- 102000004225 Cathepsin B Human genes 0.000 description 8
- 125000003342 alkenyl group Chemical group 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 239000012131 assay buffer Substances 0.000 description 8
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 8
- 125000004093 cyano group Chemical group *C#N 0.000 description 8
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 8
- 208000001132 Osteoporosis Diseases 0.000 description 7
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 7
- 125000000304 alkynyl group Chemical group 0.000 description 7
- 150000001602 bicycloalkyls Chemical group 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 7
- 235000015165 citric acid Nutrition 0.000 description 7
- 235000018417 cysteine Nutrition 0.000 description 7
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 230000001404 mediated effect Effects 0.000 description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- 125000004423 acyloxy group Chemical group 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 201000008482 osteoarthritis Diseases 0.000 description 6
- 229910052700 potassium Inorganic materials 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- 125000004076 pyridyl group Chemical group 0.000 description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- LESXFEZIFXFIQR-LURJTMIESA-N Leu-Gly Chemical compound CC(C)C[C@H](N)C(=O)NCC(O)=O LESXFEZIFXFIQR-LURJTMIESA-N 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 125000003275 alpha amino acid group Chemical group 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 229940024606 amino acid Drugs 0.000 description 5
- 235000001014 amino acid Nutrition 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 5
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 125000003226 pyrazolyl group Chemical group 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 125000004434 sulfur atom Chemical group 0.000 description 5
- 125000001544 thienyl group Chemical group 0.000 description 5
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 125000003435 aroyl group Chemical group 0.000 description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 230000005587 bubbling Effects 0.000 description 4
- 150000001735 carboxylic acids Chemical class 0.000 description 4
- 230000006806 disease prevention Effects 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 230000005284 excitation Effects 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000002480 mineral oil Substances 0.000 description 4
- 235000010446 mineral oil Nutrition 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 4
- 125000000335 thiazolyl group Chemical group 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
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- XTNPLRBTDKKLED-UHFFFAOYSA-N tert-butyl N-[1-(2-cyanopropan-2-ylamino)-4-methyl-1-oxopentan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC(CC(C)C)C(=O)NC(C)(C)C#N XTNPLRBTDKKLED-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- 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
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- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D333/40—Thiophene-2-carboxylic acid
-
- 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
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
- C07K5/06043—Leu-amino acid
-
- 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
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Physical Education & Sports Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Immunology (AREA)
- Oncology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Pyrrole Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Hydrogenated Pyridines (AREA)
- Quinoline Compounds (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9723407.4A GB9723407D0 (en) | 1997-11-05 | 1997-11-05 | Organic compounds |
| US98597397A | 1997-12-05 | 1997-12-05 | |
| US08/985,973 | 1997-12-05 | ||
| US9723407.4 | 1997-12-05 | ||
| PCT/EP1998/006937 WO1999024460A2 (en) | 1997-11-05 | 1998-11-03 | Dipeptide nitriles |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2001522862A JP2001522862A (ja) | 2001-11-20 |
| JP2001522862A5 JP2001522862A5 (enExample) | 2006-01-05 |
| JP4450988B2 true JP4450988B2 (ja) | 2010-04-14 |
Family
ID=26312558
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2000520468A Expired - Fee Related JP4450988B2 (ja) | 1997-11-05 | 1998-11-03 | ジペプチドニトリル |
Country Status (22)
| Country | Link |
|---|---|
| EP (1) | EP1028942B1 (enExample) |
| JP (1) | JP4450988B2 (enExample) |
| KR (1) | KR100518690B1 (enExample) |
| CN (1) | CN1273444C (enExample) |
| AR (1) | AR016665A1 (enExample) |
| AT (1) | ATE479651T1 (enExample) |
| AU (1) | AU751669B2 (enExample) |
| BR (1) | BR9813197A (enExample) |
| CA (1) | CA2306313C (enExample) |
| CO (1) | CO4970837A1 (enExample) |
| DE (1) | DE69841871D1 (enExample) |
| HU (1) | HUP0004400A3 (enExample) |
| ID (1) | ID24931A (enExample) |
| IL (1) | IL135508A (enExample) |
| MY (1) | MY133174A (enExample) |
| NO (1) | NO20002320L (enExample) |
| NZ (1) | NZ503889A (enExample) |
| PE (1) | PE123699A1 (enExample) |
| PL (1) | PL202226B1 (enExample) |
| SK (1) | SK6572000A3 (enExample) |
| TR (1) | TR200001189T2 (enExample) |
| WO (1) | WO1999024460A2 (enExample) |
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| EP1452522A3 (en) * | 1999-03-15 | 2005-02-09 | Axys Pharmaceuticals, Inc. | Novel compounds and compositions as protease inhibitors |
| HRP20010738B1 (en) * | 1999-03-15 | 2005-02-28 | Axys Pharmaceuticals | N-cyanomethyl amides as protease inhibitors |
| DE60028045T2 (de) | 1999-07-30 | 2007-02-15 | Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield | Neue bernsteinsäure derivative als cysteine-protease-inhibitoren |
| US6420364B1 (en) | 1999-09-13 | 2002-07-16 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compound useful as reversible inhibitors of cysteine proteases |
| GB9925264D0 (en) * | 1999-10-26 | 1999-12-29 | Zeneca Ltd | Chemical compounds |
| KR100468254B1 (ko) | 1999-12-24 | 2005-01-27 | 에프. 호프만-라 로슈 아게 | 카텝신 k 억제제로서의 니트릴 유도체 |
| GB0003111D0 (en) * | 2000-02-10 | 2000-03-29 | Novartis Ag | Organic compounds |
| US6653304B2 (en) * | 2000-02-11 | 2003-11-25 | Bristol-Myers Squibb Co. | Cannabinoid receptor modulators, their processes of preparation, and use of cannabinoid receptor modulators for treating respiratory and non-respiratory diseases |
| AU2001245764A1 (en) * | 2000-03-15 | 2001-09-24 | Axys Pharmaceuticals, Inc. | Novel compounds and compositions as protease inhibitors |
| AU9521401A (en) * | 2000-05-15 | 2001-11-26 | Novartis Ag | N-substituted peptidyl nitriles as cysteine cathepsin inhibitors |
| US6812237B2 (en) | 2000-05-15 | 2004-11-02 | Novartis Ag | N-substituted peptidyl nitriles as cysteine cathepsin inhibitors |
| US6462076B2 (en) | 2000-06-14 | 2002-10-08 | Hoffmann-La Roche Inc. | Beta-amino acid nitrile derivatives as cathepsin K inhibitors |
| EP1309591B1 (en) | 2000-08-14 | 2007-01-24 | Ortho-McNeil Pharmaceutical, Inc. | Substituted pyrazoles |
| US7332494B2 (en) | 2000-08-14 | 2008-02-19 | Janssen Pharmaceutica, N.V. | Method for treating allergies using substituted pyrazoles |
| KR100837193B1 (ko) | 2000-08-14 | 2008-06-13 | 오르토-맥네일 파마슈티칼, 인코퍼레이티드 | 치환된 피라졸 |
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| US7199102B2 (en) | 2000-08-24 | 2007-04-03 | The Regents Of The University Of California | Orally administered peptides synergize statin activity |
| EP1315741A2 (en) * | 2000-09-06 | 2003-06-04 | Ortho-McNeil Pharmaceutical, Inc. | A method for treating allergies |
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| EP1372655B1 (en) | 2001-03-02 | 2008-10-01 | Merck Frosst Canada Ltd. | Cathepsin cysteine protease inhibitors |
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| AU2002340031A1 (en) | 2001-10-02 | 2003-04-14 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compounds useful as reversible inhibitors of cysteine proteases |
| US6841571B2 (en) | 2001-10-29 | 2005-01-11 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compounds useful as reversible inhibitors of cysteine proteases |
| US6784288B2 (en) | 2001-11-08 | 2004-08-31 | Ortho-Mcneil Pharmaceutical, Inc. | Polynucleotide and polypeptide sequences of monkey cathepsin S |
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| KR20050044497A (ko) | 2001-11-14 | 2005-05-12 | 아벤티스 파마슈티칼스 인크. | 올리고펩티드 및 카텝신 s 억제제로서 이를 포함하는조성물 |
| AU2002352126A1 (en) | 2001-12-04 | 2003-06-17 | F. Hoffmann-La Roche Ag | Substituted 2-amino-cycloalkanecarboxamides and their use as cysteine protease inhibitors |
| US6759428B2 (en) | 2001-12-04 | 2004-07-06 | Roche Palo Alto Llc | Indole nitriles |
| US7282512B2 (en) | 2002-01-17 | 2007-10-16 | Smithkline Beecham Corporation | Cycloalkyl ketoamides derivatives useful as cathepsin K inhibitors |
| WO2003075836A2 (en) * | 2002-03-05 | 2003-09-18 | Merck Frosst Canada & Co. | Cathepsin cysteine protease inhibitors |
| AU2003298740A1 (en) * | 2002-12-05 | 2004-06-30 | Axys Pharmaceuticals, Inc. | Cyanomethyl derivatives as cysteine protease inhibitors |
| US7465745B2 (en) | 2003-03-13 | 2008-12-16 | Boehringer Ingelheim Pharmaceuticals, Inc. | Cathepsin S inhibitors |
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| JP2006527704A (ja) * | 2003-06-18 | 2006-12-07 | プロザイメックス・アクティーゼルスカブ | プロテアーゼ阻害剤 |
| KR100738230B1 (ko) * | 2003-06-30 | 2007-07-12 | 주식회사 오스코텍 | 메톡시아크릴레이트계 화합물을 포함하는, 골다공증 예방 또는 치료용 조성물 |
| US7317019B2 (en) | 2003-08-21 | 2008-01-08 | Bristol Myers Squibb Co. | N-alkylated diaminopropane derivatives as modulators of chemokine receptor activity |
| BRPI0410979A (pt) | 2003-09-18 | 2006-07-04 | Axys Pharm Inc | composto, composição farmacêutica, e, métodos para tratar uma doença em um animal mediada pela catepsina s e para tratar um paciente submetido a uma terapia |
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| EP1716120A1 (de) * | 2003-12-19 | 2006-11-02 | Basf Aktiengesellschaft | Herbizide heteroaroyl-substituierte phenylalanin-amide |
| US7737300B2 (en) * | 2004-09-17 | 2010-06-15 | Virobay, Inc. | Processes and intermediates preparing cysteine protease inhibitors |
| AR055283A1 (es) * | 2004-11-23 | 2007-08-15 | Merck Frosst Canada Ltd | Inhibidores de cisteinproteasa de catepsina |
| EP1819667B1 (en) | 2004-12-02 | 2012-10-17 | ViroBay, Inc. | Sulfonamide compounds as cysteine protease inhibitors |
| RU2414236C2 (ru) | 2004-12-06 | 2011-03-20 | Зе Риджентс Оф Зи Юнивесити Оф Кэлифонье | Способ улучшения структуры и/или функций артериол |
| GB0427380D0 (en) * | 2004-12-14 | 2005-01-19 | Novartis Ag | Organic compounds |
| WO2006076797A1 (en) * | 2005-01-19 | 2006-07-27 | Merck Frosst Canada Ltd. | Cathepsin k inhibitors and atherosclerosis |
| WO2006076796A1 (en) * | 2005-01-19 | 2006-07-27 | Merck Frosst Canada Ltd. | Cathepsin k inhibitors and obesity |
| EP1865940B1 (en) | 2005-03-21 | 2013-02-13 | Virobay, Inc. | Alpha ketoamide compounds as cysteine protease inhibitors |
| JP5215167B2 (ja) | 2005-03-22 | 2013-06-19 | ビロベイ,インコーポレイティド | システインプロテアーゼ阻害剤としてのスルホニル基含有化合物 |
| JP5311822B2 (ja) * | 2005-07-19 | 2013-10-09 | 第一三共株式会社 | 置換プロパンアミド誘導体及びそれを含む医薬組成物 |
| WO2007081530A2 (en) * | 2006-01-03 | 2007-07-19 | Med Institute, Inc. | Endoluminal medical device for local delivery of cathepsin inhibitors |
| WO2007137738A1 (de) | 2006-06-01 | 2007-12-06 | Sanofi-Aventis | Spiro-cyclische nitrile als protease-inhibitoren |
| US7893112B2 (en) | 2006-10-04 | 2011-02-22 | Virobay, Inc. | Di-fluoro containing compounds as cysteine protease inhibitors |
| CA2664878A1 (en) | 2006-10-04 | 2008-04-10 | Virobay, Inc. | Di-fluoro containing compounds as cysteine protease inhibitors |
| EP2719700A1 (en) | 2008-01-09 | 2014-04-16 | Amura Therapeutics Limited | Tetrahydrofuro(3,2-b)pyrrol-3-one derivatives as inhibitors of cysteine proteinases |
| WO2009103432A2 (en) * | 2008-02-21 | 2009-08-27 | Sanofi-Aventis | Covalently binding imaging probes |
| EP2198879A1 (en) | 2008-12-11 | 2010-06-23 | Institut Curie | CD74 modulator agent for regulating dendritic cell migration and device for studying the motility capacity of a cell |
| US8324417B2 (en) | 2009-08-19 | 2012-12-04 | Virobay, Inc. | Process for the preparation of (S)-2-amino-5-cyclopropyl-4,4-difluoropentanoic acid and alkyl esters and acid salts thereof |
| US9365612B2 (en) * | 2010-01-29 | 2016-06-14 | United States Of America As Represented By The Secretary, Department Of Health And Human Services | Caspase inhibitors |
| US9330026B2 (en) * | 2013-03-05 | 2016-05-03 | Qualcomm Incorporated | Method and apparatus for preventing unauthorized access to contents of a register under certain conditions when performing a hardware table walk (HWTW) |
| EP3342765B1 (en) * | 2015-08-29 | 2021-09-15 | Sunshine Lake Pharma Co., Ltd. | Cathepsin k inhibitor and application thereof |
| CN106478564B (zh) * | 2015-08-29 | 2021-11-12 | 广东东阳光药业有限公司 | 组织蛋白酶k抑制剂及其用途 |
| CN108368056A (zh) * | 2015-11-26 | 2018-08-03 | 豪夫迈·罗氏有限公司 | 锥虫抑制剂 |
| WO2020095983A1 (ja) | 2018-11-07 | 2020-05-14 | 中外製薬株式会社 | O-置換セリン誘導体の製造方法 |
| US11124497B1 (en) | 2020-04-17 | 2021-09-21 | Pardes Biosciences, Inc. | Inhibitors of cysteine proteases and methods of use thereof |
| US11174231B1 (en) | 2020-06-09 | 2021-11-16 | Pardes Biosciences, Inc. | Inhibitors of cysteine proteases and methods of use thereof |
| JP2023530627A (ja) * | 2020-06-09 | 2023-07-19 | パルデス バイオサイエンシーズ, インコーポレイテッド | システインプロテアーゼの阻害剤及びその使用方法 |
| US20240083845A1 (en) * | 2020-12-18 | 2024-03-14 | Heptares Therapeutics Limited | Sars-cov-2 mpro inhibitor compounds |
| GB202107385D0 (en) * | 2021-05-24 | 2021-07-07 | Heptares Therapeutics Ltd | Sars-cov-2 mpro inhibitor compounds |
| KR20220115062A (ko) | 2021-02-09 | 2022-08-17 | (주)오스티오뉴로젠 | 크로몬 구조의 화합물을 포함하는 골다공증의 예방 및 치료용 약학적 조성물 |
| CN116589425A (zh) * | 2022-12-29 | 2023-08-15 | 百放英库医药科技(北京)有限公司 | 组织蛋白酶l抑制剂 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3467691A (en) * | 1964-04-22 | 1969-09-16 | Tsutomu Irikura | N-(n-acylaminoacyl)-aminoacetonitriles |
| 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 |
| WO1997027200A1 (en) * | 1996-01-26 | 1997-07-31 | Smithkline Beecham Plc | Thienoxazinone derivatives useful as antiviral agents |
| IL129504A0 (en) * | 1996-11-22 | 2000-02-29 | Elan Pharm Inc | N-(aryl/heteroaryl/alkylacetyl) amino acid amides pharmaceutical compositions comprising same and methods for inhibiting beta-amyloid peptide release and/or its synthesis by use of such compounds |
-
1998
- 1998-11-03 HU HU0004400A patent/HUP0004400A3/hu unknown
- 1998-11-03 TR TR2000/01189T patent/TR200001189T2/xx unknown
- 1998-11-03 BR BR9813197-4A patent/BR9813197A/pt not_active Application Discontinuation
- 1998-11-03 CN CNB988107686A patent/CN1273444C/zh not_active Expired - Fee Related
- 1998-11-03 DE DE69841871T patent/DE69841871D1/de not_active Expired - Lifetime
- 1998-11-03 ID IDW20000830A patent/ID24931A/id unknown
- 1998-11-03 JP JP2000520468A patent/JP4450988B2/ja not_active Expired - Fee Related
- 1998-11-03 AT AT98958887T patent/ATE479651T1/de not_active IP Right Cessation
- 1998-11-03 PL PL340819A patent/PL202226B1/pl not_active IP Right Cessation
- 1998-11-03 KR KR10-2000-7004868A patent/KR100518690B1/ko not_active Expired - Fee Related
- 1998-11-03 IL IL135508A patent/IL135508A/en not_active IP Right Cessation
- 1998-11-03 EP EP98958887A patent/EP1028942B1/en not_active Expired - Lifetime
- 1998-11-03 SK SK657-2000A patent/SK6572000A3/sk unknown
- 1998-11-03 NZ NZ503889A patent/NZ503889A/en unknown
- 1998-11-03 WO PCT/EP1998/006937 patent/WO1999024460A2/en not_active Ceased
- 1998-11-03 AU AU14873/99A patent/AU751669B2/en not_active Ceased
- 1998-11-03 CA CA002306313A patent/CA2306313C/en not_active Expired - Fee Related
- 1998-11-04 MY MYPI98005030A patent/MY133174A/en unknown
- 1998-11-04 AR ARP980105565A patent/AR016665A1/es not_active Application Discontinuation
- 1998-11-05 PE PE1998001066A patent/PE123699A1/es not_active Application Discontinuation
- 1998-11-05 CO CO98065245A patent/CO4970837A1/es unknown
-
2000
- 2000-05-02 NO NO20002320A patent/NO20002320L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AR016665A1 (es) | 2001-07-25 |
| WO1999024460A2 (en) | 1999-05-20 |
| PE123699A1 (es) | 1999-12-17 |
| CN1278244A (zh) | 2000-12-27 |
| IL135508A (en) | 2006-12-10 |
| CO4970837A1 (es) | 2000-11-07 |
| NO20002320D0 (no) | 2000-05-02 |
| KR20010031800A (ko) | 2001-04-16 |
| MY133174A (en) | 2007-10-31 |
| AU751669B2 (en) | 2002-08-22 |
| NO20002320L (no) | 2000-07-04 |
| PL202226B1 (pl) | 2009-06-30 |
| NZ503889A (en) | 2002-07-26 |
| KR100518690B1 (ko) | 2005-10-05 |
| EP1028942A2 (en) | 2000-08-23 |
| CA2306313A1 (en) | 1999-05-20 |
| WO1999024460A3 (en) | 1999-09-02 |
| ID24931A (id) | 2000-08-31 |
| CN1273444C (zh) | 2006-09-06 |
| CA2306313C (en) | 2010-03-09 |
| ATE479651T1 (de) | 2010-09-15 |
| IL135508A0 (en) | 2001-05-20 |
| DE69841871D1 (en) | 2010-10-14 |
| AU1487399A (en) | 1999-05-31 |
| EP1028942B1 (en) | 2010-09-01 |
| PL340819A1 (en) | 2001-02-26 |
| SK6572000A3 (en) | 2000-10-09 |
| HUP0004400A2 (hu) | 2002-04-29 |
| JP2001522862A (ja) | 2001-11-20 |
| WO1999024460B1 (en) | 1999-10-28 |
| HUP0004400A3 (en) | 2002-10-28 |
| BR9813197A (pt) | 2000-08-29 |
| TR200001189T2 (tr) | 2000-09-21 |
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