CA2272548A1 - Serine protease inhibitors - Google Patents
Serine protease inhibitors Download PDFInfo
- Publication number
- CA2272548A1 CA2272548A1 CA002272548A CA2272548A CA2272548A1 CA 2272548 A1 CA2272548 A1 CA 2272548A1 CA 002272548 A CA002272548 A CA 002272548A CA 2272548 A CA2272548 A CA 2272548A CA 2272548 A1 CA2272548 A1 CA 2272548A1
- Authority
- CA
- Canada
- Prior art keywords
- compound
- alkyl
- aryl
- carbonyl
- oxadiazolyl
- 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.)
- Abandoned
Links
- 239000003001 serine protease inhibitor Substances 0.000 title description 3
- 102000012479 Serine Proteases Human genes 0.000 claims abstract description 8
- 108010022999 Serine Proteases Proteins 0.000 claims abstract description 8
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 641
- 150000001875 compounds Chemical class 0.000 claims description 460
- 125000000217 alkyl group Chemical group 0.000 claims description 318
- -1 carboalkoxy Chemical group 0.000 claims description 265
- 125000003118 aryl group Chemical group 0.000 claims description 202
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 163
- 125000003342 alkenyl group Chemical group 0.000 claims description 148
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 137
- 125000005843 halogen group Chemical group 0.000 claims description 134
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 132
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 115
- 125000004350 aryl cycloalkyl group Chemical group 0.000 claims description 106
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 105
- 125000004414 alkyl thio group Chemical group 0.000 claims description 102
- 125000003545 alkoxy group Chemical group 0.000 claims description 94
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 94
- 229910052760 oxygen Inorganic materials 0.000 claims description 92
- 229910052717 sulfur Inorganic materials 0.000 claims description 91
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 87
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 76
- 125000001188 haloalkyl group Chemical group 0.000 claims description 76
- 125000000304 alkynyl group Chemical group 0.000 claims description 75
- 125000005431 alkyl carboxamide group Chemical group 0.000 claims description 74
- 229910052757 nitrogen Inorganic materials 0.000 claims description 74
- 125000003282 alkyl amino group Chemical group 0.000 claims description 72
- 125000004995 haloalkylthio group Chemical group 0.000 claims description 68
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 66
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 65
- 125000005842 heteroatom Chemical group 0.000 claims description 60
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 54
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 53
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 49
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 46
- 229910052799 carbon Inorganic materials 0.000 claims description 34
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 34
- 125000005018 aryl alkenyl group Chemical group 0.000 claims description 33
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 33
- 150000001408 amides Chemical class 0.000 claims description 29
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 26
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 24
- 101000851058 Homo sapiens Neutrophil elastase Proteins 0.000 claims description 21
- 102000052502 human ELANE Human genes 0.000 claims description 21
- 125000006180 3-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])[H])C([H])([H])* 0.000 claims description 20
- 102000016387 Pancreatic elastase Human genes 0.000 claims description 19
- 108010067372 Pancreatic elastase Proteins 0.000 claims description 19
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 18
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 17
- 125000000468 ketone group Chemical group 0.000 claims description 17
- 150000001409 amidines Chemical group 0.000 claims description 15
- 229930194542 Keto Chemical group 0.000 claims description 14
- 150000001413 amino acids Chemical class 0.000 claims description 13
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 12
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 12
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Chemical group CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 12
- 125000006350 alkyl thio alkyl group Chemical group 0.000 claims description 12
- HAMNKKUPIHEESI-UHFFFAOYSA-N aminoguanidine Chemical compound NNC(N)=N HAMNKKUPIHEESI-UHFFFAOYSA-N 0.000 claims description 12
- 229940024606 amino acid Drugs 0.000 claims description 11
- 235000001014 amino acid Nutrition 0.000 claims description 11
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 11
- 239000004474 valine Chemical group 0.000 claims description 10
- BVAUMRCGVHUWOZ-ZETCQYMHSA-N (2s)-2-(cyclohexylazaniumyl)propanoate Chemical compound OC(=O)[C@H](C)NC1CCCCC1 BVAUMRCGVHUWOZ-ZETCQYMHSA-N 0.000 claims description 9
- SNDPXSYFESPGGJ-BYPYZUCNSA-N L-2-aminopentanoic acid Chemical group CCC[C@H](N)C(O)=O SNDPXSYFESPGGJ-BYPYZUCNSA-N 0.000 claims description 9
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 9
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims description 9
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical group NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 9
- SNDPXSYFESPGGJ-UHFFFAOYSA-N L-norVal-OH Chemical group CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 claims description 9
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical group CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 claims description 9
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical group OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 9
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 9
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical group CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 9
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Chemical group NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 9
- 239000004472 Lysine Chemical group 0.000 claims description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 9
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims description 9
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 9
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 9
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims description 9
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 9
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 9
- 235000018417 cysteine Nutrition 0.000 claims description 9
- QNRXNRGSOJZINA-UHFFFAOYSA-N indoline-2-carboxylic acid Chemical group C1=CC=C2NC(C(=O)O)CC2=C1 QNRXNRGSOJZINA-UHFFFAOYSA-N 0.000 claims description 9
- 229960000310 isoleucine Drugs 0.000 claims description 9
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims description 9
- 229960003646 lysine Drugs 0.000 claims description 9
- 229960003104 ornithine Drugs 0.000 claims description 9
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Chemical group OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 9
- 239000011593 sulfur Substances 0.000 claims description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical group OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 8
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Chemical group OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 claims description 8
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical group NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 8
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical group OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims description 8
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical group OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 8
- JTTHKOPSMAVJFE-VIFPVBQESA-N L-homophenylalanine Chemical group OC(=O)[C@@H](N)CCC1=CC=CC=C1 JTTHKOPSMAVJFE-VIFPVBQESA-N 0.000 claims description 8
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical group CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 8
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical group OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 8
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Chemical group NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims description 8
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Chemical group OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 claims description 8
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Chemical group OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 8
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Chemical group CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims description 8
- 239000004473 Threonine Chemical group 0.000 claims description 8
- 229960001230 asparagine Drugs 0.000 claims description 8
- 235000009582 asparagine Nutrition 0.000 claims description 8
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 8
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Chemical group OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 8
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 8
- 229930182817 methionine Chemical group 0.000 claims description 8
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- YWIQQKOKNPPGDO-VURMDHGXSA-N phenyldehydroalanine Chemical group OC(=O)C(/N)=C/C1=CC=CC=C1 YWIQQKOKNPPGDO-VURMDHGXSA-N 0.000 claims description 8
- 125000003107 substituted aryl group Chemical group 0.000 claims description 8
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 claims description 8
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 8
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical group OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims description 7
- 125000004122 cyclic group Chemical group 0.000 claims description 7
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 7
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 7
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Chemical group OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims description 7
- 229960002743 glutamine Drugs 0.000 claims description 7
- 150000002978 peroxides Chemical class 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000004429 atom Chemical group 0.000 claims description 5
- 230000005764 inhibitory process Effects 0.000 claims description 5
- 125000005533 aryl carboxamido group Chemical group 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Chemical group CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 3
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims description 3
- 229940049706 benzodiazepine Drugs 0.000 claims description 3
- 125000002619 bicyclic group Chemical group 0.000 claims description 3
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Chemical group CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 3
- 230000002401 inhibitory effect Effects 0.000 claims description 3
- 125000002950 monocyclic group Chemical group 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- UWYZHKAOTLEWKK-UHFFFAOYSA-N tetrahydro-isoquinoline Natural products C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims description 2
- 239000005977 Ethylene Substances 0.000 claims 4
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims 4
- CQYBNXGHMBNGCG-RNJXMRFFSA-N octahydroindole-2-carboxylic acid Chemical group C1CCC[C@H]2N[C@H](C(=O)O)C[C@@H]21 CQYBNXGHMBNGCG-RNJXMRFFSA-N 0.000 claims 4
- 125000000000 cycloalkoxy group Chemical group 0.000 claims 3
- 125000004104 aryloxy group Chemical group 0.000 claims 2
- 229910052736 halogen Inorganic materials 0.000 claims 2
- WGUXTQDCAZNJIF-UHFFFAOYSA-N 1-methyl-3,5-bis(trifluoromethyl)benzene Chemical group CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 WGUXTQDCAZNJIF-UHFFFAOYSA-N 0.000 claims 1
- 125000006186 3,5-dimethyl benzyl group Chemical group [H]C1=C(C([H])=C(C([H])=C1C([H])([H])[H])C([H])([H])*)C([H])([H])[H] 0.000 claims 1
- 125000006506 3-phenyl benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C([H])C([H])=C([H])C(=C1[H])C([H])([H])* 0.000 claims 1
- 125000006495 3-trifluoromethyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])*)C(F)(F)F 0.000 claims 1
- 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 1
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical group COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims 1
- KCNKJCHARANTIP-SNAWJCMRSA-N allyl-{4-[3-(4-bromo-phenyl)-benzofuran-6-yloxy]-but-2-enyl}-methyl-amine Chemical group C=1OC2=CC(OC/C=C/CN(CC=C)C)=CC=C2C=1C1=CC=C(Br)C=C1 KCNKJCHARANTIP-SNAWJCMRSA-N 0.000 claims 1
- 125000005356 cycloalkylalkenyl group Chemical group 0.000 claims 1
- 125000005265 dialkylamine group Chemical group 0.000 claims 1
- 125000000262 haloalkenyl group Chemical group 0.000 claims 1
- 150000002367 halogens Chemical group 0.000 claims 1
- 125000006431 methyl cyclopropyl group Chemical group 0.000 claims 1
- XQAMLJAXMAXEPL-UHFFFAOYSA-N piperazine-2,5-dione Chemical compound C1C(=O)NCC(=O)N1.C1C(=O)NCC(=O)N1 XQAMLJAXMAXEPL-UHFFFAOYSA-N 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 abstract description 15
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical class C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 abstract description 3
- 150000003852 triazoles Chemical class 0.000 abstract description 3
- 108010043958 Peptoids Proteins 0.000 abstract description 2
- 150000004866 oxadiazoles Chemical class 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 281
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 198
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 115
- 238000006243 chemical reaction Methods 0.000 description 111
- 239000000243 solution Substances 0.000 description 107
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 102
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 102
- 238000003756 stirring Methods 0.000 description 73
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 67
- 230000002829 reductive effect Effects 0.000 description 65
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 65
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 64
- 239000000203 mixture Substances 0.000 description 64
- 239000012074 organic phase Substances 0.000 description 59
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 58
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 57
- 235000019341 magnesium sulphate Nutrition 0.000 description 57
- 239000012299 nitrogen atmosphere Substances 0.000 description 56
- 239000000741 silica gel Substances 0.000 description 48
- 229910002027 silica gel Inorganic materials 0.000 description 48
- 239000002904 solvent Substances 0.000 description 47
- 238000004440 column chromatography Methods 0.000 description 46
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 45
- 239000007787 solid Substances 0.000 description 41
- 101000912181 Arabidopsis thaliana Cysteine synthase, mitochondrial Proteins 0.000 description 40
- CCPHAMSKHBDMDS-UHFFFAOYSA-N Chetoseminudin B Natural products C=1NC2=CC=CC=C2C=1CC1(SC)NC(=O)C(CO)(SC)N(C)C1=O CCPHAMSKHBDMDS-UHFFFAOYSA-N 0.000 description 37
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 34
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 32
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 31
- 239000011541 reaction mixture Substances 0.000 description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- 238000001914 filtration Methods 0.000 description 30
- 230000015572 biosynthetic process Effects 0.000 description 29
- 238000003786 synthesis reaction Methods 0.000 description 27
- 238000002953 preparative HPLC Methods 0.000 description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 22
- 230000000694 effects Effects 0.000 description 22
- 239000000543 intermediate Substances 0.000 description 22
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 16
- 235000011089 carbon dioxide Nutrition 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000004480 active ingredient Substances 0.000 description 15
- 239000000047 product Substances 0.000 description 14
- 102000004190 Enzymes Human genes 0.000 description 13
- 108090000790 Enzymes Proteins 0.000 description 13
- 229940088598 enzyme Drugs 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 102000035195 Peptidases Human genes 0.000 description 11
- 108091005804 Peptidases Proteins 0.000 description 11
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 10
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 10
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- ZNJHFNUEQDVFCJ-UHFFFAOYSA-M sodium;2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid;hydroxide Chemical compound [OH-].[Na+].OCCN1CCN(CCS(O)(=O)=O)CC1 ZNJHFNUEQDVFCJ-UHFFFAOYSA-M 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- XJJBXZIKXFOMLP-ZETCQYMHSA-N tert-butyl (2s)-pyrrolidine-2-carboxylate Chemical compound CC(C)(C)OC(=O)[C@@H]1CCCN1 XJJBXZIKXFOMLP-ZETCQYMHSA-N 0.000 description 1
- MVTYQPHJBBEORH-UHFFFAOYSA-N tert-butyl 2-[benzyl(1h-pyrrole-2-carbonyl)amino]acetate Chemical compound C=1C=CNC=1C(=O)N(CC(=O)OC(C)(C)C)CC1=CC=CC=C1 MVTYQPHJBBEORH-UHFFFAOYSA-N 0.000 description 1
- SJMDMGHPMLKLHQ-UHFFFAOYSA-N tert-butyl 2-aminoacetate Chemical compound CC(C)(C)OC(=O)CN SJMDMGHPMLKLHQ-UHFFFAOYSA-N 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
-
- 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
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
-
- 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
- C07K5/06017—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
- C07K5/06052—Val-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
-
- 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
- C07K5/06086—Dipeptides with the first amino acid being basic
-
- 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
- C07K5/06104—Dipeptides with the first amino acid being acidic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- C07K5/06156—Dipeptides with the first amino acid being heterocyclic and Trp-amino acid; Derivatives thereof
-
- 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
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
-
- 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
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
-
- 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
- C07K5/12—Cyclic peptides with only normal peptide bonds in the ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Crystallography & Structural Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Enzymes And Modification Thereof (AREA)
Applications Claiming Priority (21)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/761,190 US5807829A (en) | 1994-11-21 | 1996-12-06 | Serine protease inhibitor--tripeptoid analogs |
| US08/760,916 | 1996-12-06 | ||
| US08/762,381 | 1996-12-06 | ||
| US08/760,916 US5861380A (en) | 1994-11-21 | 1996-12-06 | Serine protease inhibitors-keto and di-keto containing ring systems |
| US08/771,317 | 1996-12-06 | ||
| US08/762,381 US5891852A (en) | 1994-11-21 | 1996-12-06 | Serine protease inhibitors-cycloheptane derivatives |
| US08/761,313 | 1996-12-06 | ||
| US08/761,190 | 1996-12-06 | ||
| US08/761,313 US5869455A (en) | 1994-11-21 | 1996-12-06 | Serine protease inhibitors-N-substituted derivatives |
| US08/771,317 US5801148A (en) | 1994-11-21 | 1996-12-06 | Serine protease inhibitors-proline analogs |
| US98529897A | 1997-12-04 | 1997-12-04 | |
| US08/984,884 US6001811A (en) | 1994-11-21 | 1997-12-04 | Serine protease inhibitors--N-substituted derivatives |
| US08/985,298 | 1997-12-04 | ||
| US08/984,884 | 1997-12-04 | ||
| US08/984,881 | 1997-12-04 | ||
| US08/985,056 | 1997-12-04 | ||
| US08/984,881 US6015791A (en) | 1994-11-21 | 1997-12-04 | Serine protease inhibitors-cycloheptane derivatives |
| US08/985,201 | 1997-12-04 | ||
| US08/985,201 US6150334A (en) | 1994-11-21 | 1997-12-04 | Serine protease inhibitors-tripeptoid analogs |
| US08/985,056 US5998379A (en) | 1994-11-21 | 1997-12-04 | Serine protease inhibitors-proline analogs |
| PCT/US1997/021636 WO1998024806A2 (en) | 1996-12-06 | 1997-12-05 | Substituted oxadiazole, thiadiazole and triazole serine protease inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2272548A1 true CA2272548A1 (en) | 1998-06-11 |
Family
ID=27581319
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002272548A Abandoned CA2272548A1 (en) | 1996-12-06 | 1997-12-05 | Serine protease inhibitors |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0954526A2 (ja) |
| JP (1) | JP3220169B2 (ja) |
| CN (1) | CN1247542A (ja) |
| AU (1) | AU734615B2 (ja) |
| CA (1) | CA2272548A1 (ja) |
| HU (1) | HUP0100669A3 (ja) |
| NO (1) | NO992734L (ja) |
| NZ (1) | NZ336046A (ja) |
| RU (1) | RU2217436C2 (ja) |
| TR (2) | TR199901681T2 (ja) |
| WO (1) | WO1998024806A2 (ja) |
Families Citing this family (34)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6004933A (en) * | 1997-04-25 | 1999-12-21 | Cortech Inc. | Cysteine protease inhibitors |
| US6656910B2 (en) * | 1997-12-04 | 2003-12-02 | Cortech, Inc. | Serine protease inhibitors |
| EP1089752A4 (en) * | 1998-06-03 | 2002-01-02 | Cortech Inc | ALPHA-KETO OXADIAZOLE AS A SERINE PROTEASE INHIBITOR |
| WO2000009542A1 (en) * | 1998-08-17 | 2000-02-24 | Cortech, Inc. | SERINE PROTEASE INHIBITORS COMPRISING α-KETO HETEROCYCLES |
| FR2782997A1 (fr) * | 1998-09-08 | 2000-03-10 | Hoechst Marion Roussel Inc | Nouveaux derives de la benzodiazepinone, procede de preparation et intermediaires de ce procede, application a titre de medicaments et compositions pharmaceutiques les renfermant |
| WO2000051623A2 (en) * | 1999-03-05 | 2000-09-08 | The Trustees Of University Technology Corporation | Inhibitors of serine protease activity, methods and compositions for treatment of nitric oxide-induced clinical conditions |
| AU3731400A (en) * | 1999-03-05 | 2000-09-21 | Trustees Of University Technology Corporation, The | Methods and compositions useful in inhibiting apoptosis |
| WO2000051625A1 (en) * | 1999-03-05 | 2000-09-08 | The Trustees Of University Technology Corporation | Inhibitors of serine protease activity, methods and compositions for treatment of herpes viruses |
| WO2000052034A2 (en) * | 1999-03-05 | 2000-09-08 | The Trustees Of University Technology Corporation | Inhibitors of serine protease activity, methods and compositions for treatment of viral infections |
| CA2367418A1 (en) * | 1999-03-12 | 2000-09-21 | Ono Pharmaceutical Co., Ltd. | 1,3,4-oxadiazole derivatives and process for producing the same |
| AU5625900A (en) | 1999-06-17 | 2001-01-09 | Cortech, Inc. | Method and compounds for inhibiting activity of serine elastases |
| WO2001007407A1 (en) * | 1999-07-26 | 2001-02-01 | Bristol-Myers Squibb Pharma Company | Lactam inhibitors of hepatitis c virus ns3 protease |
| US7122627B2 (en) | 1999-07-26 | 2006-10-17 | Bristol-Myers Squibb Company | Lactam inhibitors of Hepatitis C virus NS3 protease |
| CA2385292A1 (en) * | 1999-09-27 | 2001-04-05 | Tsutomu Kojima | Pyrimidine compounds, processes for the preparation thereof and pharmaceutical compositions comprising the compounds as active ingredient |
| EP1234834A4 (en) * | 1999-12-03 | 2003-01-29 | Ono Pharmaceutical Co | 1,3,4-OXADIAZOLINE-2-ONE DERIVATIVES AND MEDICINAL PRODUCTS CONTAINING SUCH DERIVATIVES USEFUL AS ACTIVE INGREDIENT |
| US6797720B2 (en) | 1999-12-03 | 2004-09-28 | Ono Pharmaceutical Co., Ltd. | 1,3,4-oxadiazoline derivative and an agent comprising its derivative as active ingredient |
| KR20020072303A (ko) * | 2000-02-03 | 2002-09-14 | 오노 야꾸힝 고교 가부시키가이샤 | 1,3,4-옥사디아졸 유도체 및 그 제조 방법 |
| EP1253143A4 (en) * | 2000-02-03 | 2003-03-26 | Ono Pharmaceutical Co | 1,3,4-OXADIAZOLE DERIVATIVES AND A METHOD FOR THE PRODUCTION THEREOF |
| AU2001277736A1 (en) * | 2000-08-10 | 2002-02-25 | Ono Pharmaceutical Co. Ltd. | 2-(5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidyl)-n-(1-(2-( -t-butyl-1,3,4-oxadiazolyl)carbonyl)-2-(r,s)-methylpropyl) acetamide hydrochloride |
| EP1318150A4 (en) * | 2000-09-08 | 2004-04-14 | Ono Pharmaceutical Co | NEW CRYSTALS OF 1,3,4-OXADIAZOLE DERIVATIVES, METHOD FOR THE PRODUCTION OF THE CRYSTALS AND THE MEDICINAL PRODUCTS CONTAINING THEM AS AN ACTIVE SUBSTANCE |
| CA2423945A1 (en) * | 2000-09-29 | 2003-03-27 | Atsushi Nagai | Restrainers of airway mucus secretion |
| WO2003006014A1 (en) * | 2001-07-10 | 2003-01-23 | Ono Pharmaceutical Co., Ltd. | Medicine comprising combination of five-membered heterocyclic compound and drug compensating for or enhancing its activity |
| KR100926244B1 (ko) * | 2001-07-11 | 2009-11-12 | 버텍스 파마슈티칼스 인코포레이티드 | 브릿지된 바이사이클릭 세린 프로테아제 억제제 |
| IL148924A (en) * | 2002-03-26 | 2015-06-30 | Mor Research Applic Ltd | Use of substances that inhibit intracellular elastase activity in the preparation of a drug for the treatment and / or prevention of necrosis of cells and related diseases |
| CA2536918A1 (en) | 2003-08-26 | 2005-03-03 | Leland Shapiro | Compositions of, and methods for, alpha-1 antitrypsin fc fusion molecules |
| EP1533306A1 (en) | 2003-11-04 | 2005-05-25 | Ajinomoto Co., Inc. | Azlactone compound and method for preparation thereof |
| RU2419626C2 (ru) | 2006-05-23 | 2011-05-27 | Айрм Ллк | Соединения и композиции в качестве ингибиторов протеазы, активирующей каналы |
| TWI389899B (zh) * | 2006-08-08 | 2013-03-21 | Msd Oss Bv | 具口服活性之凝血酶抑制劑 |
| EA016327B1 (ru) | 2007-02-09 | 2012-04-30 | Айрм Ллк | Соединения и композиции в качестве ингибиторов протеазы, активирующей каналы |
| US9150556B2 (en) | 2007-05-22 | 2015-10-06 | Boehringer Ingelheim International Gmbh | Benzimidazolone chymase inhibitors |
| AU2012272636A1 (en) | 2011-06-24 | 2013-05-02 | Advent Bio Holdings Llc | Compositions, methods and uses for alpha-1 antitrypsin fusion molecules |
| AU2013202648B2 (en) | 2012-01-10 | 2016-05-19 | Konkuk University | Compositions, methods and uses for alpha-1 antitrypsin fusion molecules |
| US9458092B2 (en) * | 2013-05-08 | 2016-10-04 | Kissei Pharmaceutical Co., Ltd. | α-Substituted glycinamide derivative |
| JP2017523213A (ja) * | 2014-08-06 | 2017-08-17 | ノバルティス アーゲー | 抗菌薬としてのキノロン誘導体 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9216272D0 (en) * | 1991-08-15 | 1992-09-09 | Ici Plc | Substituted heterocycles |
| GB9307555D0 (en) * | 1992-04-16 | 1993-06-02 | Zeneca Ltd | Heterocyclic compounds |
| FR2694295B1 (fr) * | 1992-07-28 | 1994-09-02 | Adir | Nouveaux peptides dérivés de trifluoromethylcetones, leur procéde de préparation et les compositions pharmaceutiques qui les contiennent. |
| CA2189526C (en) * | 1994-06-02 | 2001-02-27 | William A. Metz, Jr. | Perfluoroalkyl ketone inhibitors of elastase and processes for making the same |
| US5618792A (en) * | 1994-11-21 | 1997-04-08 | Cortech, Inc. | Substituted heterocyclic compounds useful as inhibitors of (serine proteases) human neutrophil elastase |
-
1997
- 1997-12-05 WO PCT/US1997/021636 patent/WO1998024806A2/en not_active Application Discontinuation
- 1997-12-05 CN CN97180392A patent/CN1247542A/zh active Pending
- 1997-12-05 NZ NZ336046A patent/NZ336046A/xx unknown
- 1997-12-05 JP JP52565698A patent/JP3220169B2/ja not_active Expired - Fee Related
- 1997-12-05 EP EP97952232A patent/EP0954526A2/en not_active Withdrawn
- 1997-12-05 CA CA002272548A patent/CA2272548A1/en not_active Abandoned
- 1997-12-05 HU HU0100669A patent/HUP0100669A3/hu unknown
- 1997-12-05 AU AU55894/98A patent/AU734615B2/en not_active Ceased
- 1997-12-05 TR TR1999/01681T patent/TR199901681T2/xx unknown
- 1997-12-05 RU RU99114606/04A patent/RU2217436C2/ru not_active IP Right Cessation
- 1997-12-05 TR TR2001/03270T patent/TR200103270T2/xx unknown
-
1999
- 1999-06-04 NO NO992734A patent/NO992734L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| NO992734D0 (no) | 1999-06-04 |
| RU2217436C2 (ru) | 2003-11-27 |
| JP3220169B2 (ja) | 2001-10-22 |
| EP0954526A2 (en) | 1999-11-10 |
| NO992734L (no) | 1999-08-02 |
| TR199901681T2 (xx) | 2000-03-21 |
| JP2001507679A (ja) | 2001-06-12 |
| NZ336046A (en) | 2000-10-27 |
| CN1247542A (zh) | 2000-03-15 |
| HUP0100669A3 (en) | 2001-12-28 |
| WO1998024806B1 (en) | 1999-05-20 |
| AU5589498A (en) | 1998-06-29 |
| WO1998024806A3 (en) | 1998-10-15 |
| WO1998024806A2 (en) | 1998-06-11 |
| AU734615B2 (en) | 2001-06-21 |
| HUP0100669A2 (hu) | 2001-08-28 |
| TR200103270T2 (tr) | 2003-03-21 |
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| EEER | Examination request | ||
| FZDE | Discontinued |