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
- 239000003921 oil Substances 0.000 description 10
- 125000006239 protecting group Chemical group 0.000 description 10
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 10
- 239000000758 substrate Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 9
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 9
- 210000002744 extracellular matrix Anatomy 0.000 description 9
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 9
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 238000010828 elution Methods 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 7
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- CQYBNXGHMBNGCG-FXQIFTODSA-N (2s,3as,7as)-2,3,3a,4,5,6,7,7a-octahydro-1h-indol-1-ium-2-carboxylate Chemical compound C1CCC[C@@H]2[NH2+][C@H](C(=O)[O-])C[C@@H]21 CQYBNXGHMBNGCG-FXQIFTODSA-N 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- 239000004365 Protease Substances 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 210000000224 granular leucocyte Anatomy 0.000 description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
- 235000019833 protease Nutrition 0.000 description 5
- 229910001923 silver oxide Inorganic materials 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- YSIHYROEMJSOAS-QGZVFWFLSA-N 2-(5-amino-6-oxo-2-phenylpyrimidin-1-yl)-n-[(2r)-1-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-3-methyl-1-oxobutan-2-yl]acetamide Chemical compound N([C@H](C(C)C)C(=O)C=1OC(=NN=1)C(C)(C)C)C(=O)CN(C(C(N)=CN=1)=O)C=1C1=CC=CC=C1 YSIHYROEMJSOAS-QGZVFWFLSA-N 0.000 description 4
- YSIHYROEMJSOAS-KRWDZBQOSA-N 2-(5-amino-6-oxo-2-phenylpyrimidin-1-yl)-n-[(2s)-1-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-3-methyl-1-oxobutan-2-yl]acetamide Chemical compound N([C@@H](C(C)C)C(=O)C=1OC(=NN=1)C(C)(C)C)C(=O)CN(C(C(N)=CN=1)=O)C=1C1=CC=CC=C1 YSIHYROEMJSOAS-KRWDZBQOSA-N 0.000 description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 4
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 4
- 108090000317 Chymotrypsin Proteins 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 230000036765 blood level Effects 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000006260 foam Substances 0.000 description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 4
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 4
- GOFAZNNHAIDEBD-ROLXFIACSA-N (3s)-3-amino-2-hydroxy-4-methylpentanoic acid Chemical compound CC(C)[C@H](N)C(O)C(O)=O GOFAZNNHAIDEBD-ROLXFIACSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- QDHHCQZDFGDHMP-UHFFFAOYSA-N Chloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 3
- 108090000227 Chymases Proteins 0.000 description 3
- 102000003858 Chymases Human genes 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 108090000190 Thrombin Proteins 0.000 description 3
- 108090000631 Trypsin Proteins 0.000 description 3
- 102000004142 Trypsin Human genes 0.000 description 3
- 102000001400 Tryptase Human genes 0.000 description 3
- 108060005989 Tryptase Proteins 0.000 description 3
- 229920000392 Zymosan Polymers 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 125000000539 amino acid group Chemical group 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 150000001733 carboxylic acid esters Chemical class 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229960002376 chymotrypsin Drugs 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 230000003413 degradative effect Effects 0.000 description 3
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- LPAGFVYQRIESJQ-UHFFFAOYSA-N indoline Chemical compound C1=CC=C2NCCC2=C1 LPAGFVYQRIESJQ-UHFFFAOYSA-N 0.000 description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical group C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 3
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 3
- 229960004072 thrombin Drugs 0.000 description 3
- 239000012588 trypsin Substances 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 2
- IHCVLWZQQGFWNW-LSLKUGRBSA-N (3S)-2-acetyloxy-4-methyl-3-(phenylmethoxycarbonylamino)pentanoic acid Chemical compound C(C1=CC=CC=C1)OC(=O)N[C@H](C(C(=O)O)OC(C)=O)C(C)C IHCVLWZQQGFWNW-LSLKUGRBSA-N 0.000 description 2
- 150000005071 1,2,4-oxadiazoles Chemical class 0.000 description 2
- 150000005072 1,3,4-oxadiazoles Chemical class 0.000 description 2
- OUWDAXHGMLTVKF-UHFFFAOYSA-N 1-phenylpiperazine-2,5-dione Chemical compound O=C1CNC(=O)CN1C1=CC=CC=C1 OUWDAXHGMLTVKF-UHFFFAOYSA-N 0.000 description 2
- YSIHYROEMJSOAS-UHFFFAOYSA-N 2-(5-amino-6-oxo-2-phenylpyrimidin-1-yl)-n-[1-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-3-methyl-1-oxobutan-2-yl]acetamide Chemical compound N=1N=C(C(C)(C)C)OC=1C(=O)C(C(C)C)NC(=O)CN(C(C(N)=CN=1)=O)C=1C1=CC=CC=C1 YSIHYROEMJSOAS-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- IIAQEAGMUQVSNS-UHFFFAOYSA-N 2-[2-(4-fluorophenyl)-6-oxo-5-(phenylmethoxycarbonylamino)pyrimidin-1-yl]acetic acid Chemical compound O=C1N(CC(=O)O)C(C=2C=CC(F)=CC=2)=NC=C1NC(=O)OCC1=CC=CC=C1 IIAQEAGMUQVSNS-UHFFFAOYSA-N 0.000 description 2
- MAMSTWHAOJXMLW-UHFFFAOYSA-N 2-[benzyl(1h-pyrrole-2-carbonyl)amino]acetic acid Chemical compound C=1C=CNC=1C(=O)N(CC(=O)O)CC1=CC=CC=C1 MAMSTWHAOJXMLW-UHFFFAOYSA-N 0.000 description 2
- LKDMKWNDBAVNQZ-UHFFFAOYSA-N 4-[[1-[[1-[2-[[1-(4-nitroanilino)-1-oxo-3-phenylpropan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-oxobutanoic acid Chemical compound OC(=O)CCC(=O)NC(C)C(=O)NC(C)C(=O)N1CCCC1C(=O)NC(C(=O)NC=1C=CC(=CC=1)[N+]([O-])=O)CC1=CC=CC=C1 LKDMKWNDBAVNQZ-UHFFFAOYSA-N 0.000 description 2
- CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-UHFFFAOYSA-N 0.000 description 2
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 108090000617 Cathepsin G Proteins 0.000 description 2
- 102000004173 Cathepsin G Human genes 0.000 description 2
- 102000005593 Endopeptidases Human genes 0.000 description 2
- 108010059378 Endopeptidases Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- VLJNHYLEOZPXFW-BYPYZUCNSA-N L-prolinamide Chemical compound NC(=O)[C@@H]1CCCN1 VLJNHYLEOZPXFW-BYPYZUCNSA-N 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- 206010036790 Productive cough Diseases 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 206010063837 Reperfusion injury Diseases 0.000 description 2
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 2
- GIAZPLMMQOERPN-YUMQZZPRSA-N Val-Pro Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(O)=O GIAZPLMMQOERPN-YUMQZZPRSA-N 0.000 description 2
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 2
- 125000005596 alkyl carboxamido group Chemical group 0.000 description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 150000007942 carboxylates Chemical class 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 description 2
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 235000019419 proteases Nutrition 0.000 description 2
- WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical compound OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 208000024794 sputum Diseases 0.000 description 2
- 210000003802 sputum Anatomy 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 2
- VYWSMHZWCYFPKV-PXYINDEMSA-N (3S)-2-hydroxy-4-methyl-3-(phenylmethoxycarbonylamino)pentanoic acid Chemical compound C(C1=CC=CC=C1)OC(=O)N[C@H](C(C(=O)O)O)C(C)C VYWSMHZWCYFPKV-PXYINDEMSA-N 0.000 description 1
- CUSGSDUYPXBYHI-MRXNPFEDSA-N (3r)-1,3-dibenzylpiperazine-2,5-dione Chemical compound N([C@H](CC=1C=CC=CC=1)C1=O)C(=O)CN1CC1=CC=CC=C1 CUSGSDUYPXBYHI-MRXNPFEDSA-N 0.000 description 1
- MJCOATFQVUUHFN-XFFZJAGNSA-N (3z)-1-acetyl-3-benzylidenepiperazine-2,5-dione Chemical compound O=C1N(C(=O)C)CC(=O)N\C1=C/C1=CC=CC=C1 MJCOATFQVUUHFN-XFFZJAGNSA-N 0.000 description 1
- PGNYGDAFMUYUNJ-SNVBAGLBSA-N (6r)-6-benzylpiperazin-2-one Chemical compound N1C(=O)CNC[C@H]1CC1=CC=CC=C1 PGNYGDAFMUYUNJ-SNVBAGLBSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical compound C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 description 1
- YGTAZGSLCXNBQL-UHFFFAOYSA-N 1,2,4-thiadiazole Chemical class C=1N=CSN=1 YGTAZGSLCXNBQL-UHFFFAOYSA-N 0.000 description 1
- FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical group C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 description 1
- 150000004869 1,3,4-thiadiazoles Chemical class 0.000 description 1
- SNMBKCRPRYZTRZ-UHFFFAOYSA-N 1-benzoylpiperazine-2,5-dione Chemical compound C=1C=CC=CC=1C(=O)N1CC(=O)NCC1=O SNMBKCRPRYZTRZ-UHFFFAOYSA-N 0.000 description 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- XAMFYTPAVYBBBX-UHFFFAOYSA-N 2-(3-methylphenyl)acetohydrazide Chemical compound CC1=CC=CC(CC(=O)NN)=C1 XAMFYTPAVYBBBX-UHFFFAOYSA-N 0.000 description 1
- RACZCUSQYCSZAE-UHFFFAOYSA-N 2-(4-oxo-2-phenyl-1,3-thiazolidin-3-yl)acetic acid Chemical compound S1CC(=O)N(CC(=O)O)C1C1=CC=CC=C1 RACZCUSQYCSZAE-UHFFFAOYSA-N 0.000 description 1
- KGSVNOLLROCJQM-UHFFFAOYSA-N 2-(benzylamino)acetic acid Chemical compound OC(=O)CNCC1=CC=CC=C1 KGSVNOLLROCJQM-UHFFFAOYSA-N 0.000 description 1
- DWEGAKYZZLWLRF-RBUKOAKNSA-N 2-[(4r)-2,5-dioxo-4-propan-2-ylimidazolidin-1-yl]-n-[(2s)-3-methyl-1-[5-[(3-methylphenyl)methyl]-1,3,4-oxadiazol-2-yl]-1-oxobutan-2-yl]acetamide Chemical compound N([C@@H](C(C)C)C(=O)C=1OC(CC=2C=C(C)C=CC=2)=NN=1)C(=O)CN1C(=O)N[C@H](C(C)C)C1=O DWEGAKYZZLWLRF-RBUKOAKNSA-N 0.000 description 1
- OURIYGWWUSWKFS-QHCPKHFHSA-N 2-[5-amino-2-(4-fluorophenyl)-6-oxopyrimidin-1-yl]-n-[(2s)-3-methyl-1-[5-[(3-methylphenyl)methyl]-1,3,4-oxadiazol-2-yl]-1-oxobutan-2-yl]acetamide Chemical compound N([C@@H](C(C)C)C(=O)C=1OC(CC=2C=C(C)C=CC=2)=NN=1)C(=O)CN(C(C(N)=CN=1)=O)C=1C1=CC=C(F)C=C1 OURIYGWWUSWKFS-QHCPKHFHSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- MJLVLHNXEOQASX-UHFFFAOYSA-M 2-bromo-3,3-dimethylbutanoate Chemical compound CC(C)(C)C(Br)C([O-])=O MJLVLHNXEOQASX-UHFFFAOYSA-M 0.000 description 1
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 description 1
- LGCYVLDNGBSOOW-UHFFFAOYSA-N 2H-benzotriazol-4-ol 1-hydroxybenzotriazole Chemical compound OC1=CC=CC2=C1N=NN2.C1=CC=C2N(O)N=NC2=C1 LGCYVLDNGBSOOW-UHFFFAOYSA-N 0.000 description 1
- KWMUSDDZNYHIBR-UHFFFAOYSA-N 3-amino-1h-quinolin-2-one Chemical compound C1=CC=C2NC(=O)C(N)=CC2=C1 KWMUSDDZNYHIBR-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- LVUFMEUZYQQOQT-UHFFFAOYSA-N 3-chloro-1H-1,2-benzodiazepine Chemical compound ClC1=NNc2ccccc2C=C1 LVUFMEUZYQQOQT-UHFFFAOYSA-N 0.000 description 1
- HDLQOFWHVHAPGP-UHFFFAOYSA-N 4-oxoindole-2-carboxylic acid Chemical compound C1=CC(=O)C2=CC(C(=O)O)=NC2=C1 HDLQOFWHVHAPGP-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- HGIUIFMGXFFOEZ-UHFFFAOYSA-N 5-morpholin-4-yl-5-oxopentanoic acid Chemical compound OC(=O)CCCC(=O)N1CCOCC1 HGIUIFMGXFFOEZ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102100036599 Alanine and arginine-rich domain-containing protein Human genes 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 102000016942 Elastin Human genes 0.000 description 1
- 108010014258 Elastin Proteins 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 108010088842 Fibrinolysin Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- 101000929721 Homo sapiens Alanine and arginine-rich domain-containing protein Proteins 0.000 description 1
- 108010028275 Leukocyte Elastase Proteins 0.000 description 1
- 102000016799 Leukocyte elastase Human genes 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 208000034486 Multi-organ failure Diseases 0.000 description 1
- 208000010718 Multiple Organ Failure Diseases 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 1
- 229910017974 NH40H Inorganic materials 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 108090000113 Plasma Kallikrein Proteins 0.000 description 1
- 102100034869 Plasma kallikrein Human genes 0.000 description 1
- 108010001014 Plasminogen Activators Proteins 0.000 description 1
- 102000001938 Plasminogen Activators Human genes 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 102000056251 Prolyl Oligopeptidases Human genes 0.000 description 1
- 101710178372 Prolyl endopeptidase Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- QAOWNCQODCNURD-KHWXYDKHSA-N ac1l2g1h Chemical compound O[35S](O)(=O)=O QAOWNCQODCNURD-KHWXYDKHSA-N 0.000 description 1
- 206010069351 acute lung injury Diseases 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 108010027597 alpha-chymotrypsin Proteins 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 210000000702 aorta abdominal Anatomy 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- PMEVEYYKPSSKLE-UHFFFAOYSA-N benzyl n-(2-oxo-1h-quinolin-3-yl)carbamate Chemical compound C=1C2=CC=CC=C2NC(=O)C=1NC(=O)OCC1=CC=CC=C1 PMEVEYYKPSSKLE-UHFFFAOYSA-N 0.000 description 1
- LXHVEKHVIYKCLN-MYKRZTLLSA-N benzyl n-[(2s)-3-methyl-1-[(2s)-2-[[(2s)-3-methyl-1-[5-[(3-methylphenyl)methyl]-1,2,4-oxadiazol-3-yl]-1-oxobutan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxobutan-2-yl]carbamate Chemical compound N([C@@H](C(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)C=1N=C(CC=2C=C(C)C=CC=2)ON=1)C(=O)OCC1=CC=CC=C1 LXHVEKHVIYKCLN-MYKRZTLLSA-N 0.000 description 1
- FPGAGACTKJTPFT-MYKRZTLLSA-N benzyl n-[(2s)-3-methyl-1-[(2s)-2-[[(2s)-3-methyl-1-[5-[(3-methylphenyl)methyl]-1,3,4-oxadiazol-2-yl]-1-oxobutan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxobutan-2-yl]carbamate Chemical compound N([C@@H](C(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)C=1OC(CC=2C=C(C)C=CC=2)=NN=1)C(=O)OCC1=CC=CC=C1 FPGAGACTKJTPFT-MYKRZTLLSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 238000012754 cardiac puncture Methods 0.000 description 1
- GPRBEKHLDVQUJE-VINNURBNSA-N cefotaxime Chemical compound N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C(O)=O)=O)C(=O)/C(=N/OC)C1=CSC(N)=N1 GPRBEKHLDVQUJE-VINNURBNSA-N 0.000 description 1
- 229960004261 cefotaxime Drugs 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 201000007717 corneal ulcer Diseases 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical compound [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000011833 dog model Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 229920002549 elastin Polymers 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- DUVOZUPPHBRJJO-UHFFFAOYSA-N ethyl 2-isocyanatoacetate Chemical compound CCOC(=O)CN=C=O DUVOZUPPHBRJJO-UHFFFAOYSA-N 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000006984 memory degeneration Effects 0.000 description 1
- 208000023060 memory loss Diseases 0.000 description 1
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 1
- BHFLUDRTVIDDOR-MRVPVSSYSA-N methyl (2r)-2-amino-2-phenylacetate Chemical compound COC(=O)[C@H](N)C1=CC=CC=C1 BHFLUDRTVIDDOR-MRVPVSSYSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 244000309715 mini pig Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 208000029744 multiple organ dysfunction syndrome Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- ZOISRJXBLYEARJ-LJAQVGFWSA-N n-[(2s)-3-methyl-1-[5-[(3-methylphenyl)methyl]-1,3,4-oxadiazol-2-yl]-1-oxobutan-2-yl]-2-(2-oxo-5-phenyl-3h-1,4-benzodiazepin-1-yl)acetamide Chemical compound N([C@@H](C(C)C)C(=O)C=1OC(CC=2C=C(C)C=CC=2)=NN=1)C(=O)CN(C(CN=1)=O)C2=CC=CC=C2C=1C1=CC=CC=C1 ZOISRJXBLYEARJ-LJAQVGFWSA-N 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
- 150000002926 oxygen Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 208000028169 periodontal disease Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- BXRNXXXXHLBUKK-UHFFFAOYSA-N piperazine-2,5-dione Chemical compound O=C1CNC(=O)CN1 BXRNXXXXHLBUKK-UHFFFAOYSA-N 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 229940012957 plasmin Drugs 0.000 description 1
- 229940127126 plasminogen activator Drugs 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- DOYOPBSXEIZLRE-UHFFFAOYSA-N pyrrole-3-carboxylic acid Natural products OC(=O)C=1C=CNC=1 DOYOPBSXEIZLRE-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000003345 scintillation counting Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 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)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (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 |
| US08/761,313 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 |
| US08/762,381 US5891852A (en) | 1994-11-21 | 1996-12-06 | Serine protease inhibitors-cycloheptane derivatives |
| US08/760,916 US5861380A (en) | 1994-11-21 | 1996-12-06 | Serine protease inhibitors-keto and di-keto containing ring systems |
| US98529897A | 1997-12-04 | 1997-12-04 | |
| US08/771,317 | 1997-12-04 | ||
| US08/985,056 US5998379A (en) | 1994-11-21 | 1997-12-04 | Serine protease inhibitors-proline analogs |
| US08/985,201 | 1997-12-04 | ||
| US08/984,884 US6001811A (en) | 1994-11-21 | 1997-12-04 | Serine protease inhibitors--N-substituted derivatives |
| US08/760,916 | 1997-12-04 | ||
| US08/761,190 | 1997-12-04 | ||
| US08/985,056 | 1997-12-04 | ||
| US08/762,381 | 1997-12-04 | ||
| US08/984,884 | 1997-12-04 | ||
| US08/984,881 | 1997-12-04 | ||
| US08/984,881 US6015791A (en) | 1994-11-21 | 1997-12-04 | Serine protease inhibitors-cycloheptane derivatives |
| US08/761,313 | 1997-12-04 | ||
| US08/985,298 | 1997-12-04 | ||
| US08/985,201 US6150334A (en) | 1994-11-21 | 1997-12-04 | Serine protease inhibitors-tripeptoid 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 (zh) |
| JP (1) | JP3220169B2 (zh) |
| CN (1) | CN1247542A (zh) |
| AU (1) | AU734615B2 (zh) |
| CA (1) | CA2272548A1 (zh) |
| HU (1) | HUP0100669A3 (zh) |
| NO (1) | NO992734L (zh) |
| NZ (1) | NZ336046A (zh) |
| RU (1) | RU2217436C2 (zh) |
| TR (2) | TR200103270T2 (zh) |
| WO (1) | WO1998024806A2 (zh) |
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 |
| JP2003520185A (ja) * | 1998-06-03 | 2003-07-02 | コーテック インコーポレーテッド | セリンプロテアーゼ阻害剤としてのα−ケトオキサジアゾール類 |
| AU9031598A (en) * | 1998-08-17 | 2000-03-06 | Cortech, Inc. | Serine protease inhibitors comprising alpha-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 |
| 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 |
| WO2000051624A2 (en) | 1999-03-05 | 2000-09-08 | The Trustees Of University Technology Corporation | Methods and compositions useful in inhibiting apoptosis |
| 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 |
| AU3511500A (en) * | 1999-03-05 | 2000-09-21 | Trustees Of University Technology Corporation, The | Inhibitors of serine protease activity, methods and compositions for treatment of nitric oxide-induced clinical conditions |
| NZ513921A (en) * | 1999-03-12 | 2001-09-28 | Ono Pharmaceutical Co | 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 |
| EP1206449A1 (en) * | 1999-07-26 | 2002-05-22 | Bristol-Myers Squibb 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 |
| WO2001057005A1 (fr) * | 2000-02-03 | 2001-08-09 | Ono Pharmaceutical Co., Ltd. | Derives de 1,3,4-oxadiazole et leur procede de production |
| AU2001232226A1 (en) * | 2000-02-03 | 2001-08-14 | Ono Pharmaceutical Co., Ltd. | 1,3,4-oxadiazole derivatives and process for producing the same |
| WO2002014310A1 (fr) * | 2000-08-10 | 2002-02-21 | Ono Pharmaceutical Co., Ltd. | 2-[5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidyl]-n-[1-(2-[5-t-butyl-1,3,4-oxadiazolyl]carbonyl)-2-(r,s)-methylpropyl]acetamide chlorhydrate |
| WO2002020516A1 (fr) * | 2000-09-08 | 2002-03-14 | Ono Pharmaceutical Co., Ltd. | Nouveaux cristaux de dérivé 1,3,4-oxadiazole, procédé de production de ces cristaux, et médicament à base de tels principes actifs |
| 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 |
| WO2003006490A1 (en) * | 2001-07-11 | 2003-01-23 | Vertex Pharmaceuticals Incorporated | Bridged bicyclic serine protease inhibitors |
| 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 |
| US7850970B2 (en) | 2003-08-26 | 2010-12-14 | The Regents Of The University Of Colorado | Inhibitors of serine protease activity and their use in methods and compositions for treatment of bacterial infections |
| EP1533306A1 (en) | 2003-11-04 | 2005-05-25 | Ajinomoto Co., Inc. | Azlactone compound and method for preparation thereof |
| KR101069051B1 (ko) | 2006-05-23 | 2011-09-29 | 아이알엠 엘엘씨 | 채널 활성화 프로테아제 억제제로서의 화합물 및 조성물 |
| TWI389899B (zh) * | 2006-08-08 | 2013-03-21 | Msd Oss Bv | 具口服活性之凝血酶抑制劑 |
| BRPI0807483A2 (pt) | 2007-02-09 | 2014-05-13 | Irm Llc | Compostos e composições como inibidores de protease de ativação de canal |
| CA2687821C (en) | 2007-05-22 | 2015-04-14 | Boehringer Ingelheim International Gmbh | Benzimidazolone chymase inhibitors |
| EP2723370A4 (en) | 2011-06-24 | 2015-06-03 | Univ Colorado Regents | COMPOSITIONS, PROCESS AND USE OF ALPHA-1-ANTITRYPHIN FUSION MOLECULES |
| KR20140137347A (ko) | 2012-01-10 | 2014-12-02 | 더 리젠츠 오브 더 유니버시티 오브 콜로라도, 어 바디 코포레이트 | 알파-1 안티트립신 융합 분자용 조성물, 방법 및 용도 |
| ES2645847T3 (es) * | 2013-05-08 | 2017-12-11 | Kissei Pharmaceutical Co., Ltd. | Derivado de glicinamida alfa-sustituido |
| WO2016020836A1 (en) * | 2014-08-06 | 2016-02-11 | Novartis Ag | Quinolone derivatives as antibacterials |
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. |
| US6008196A (en) * | 1994-06-02 | 1999-12-28 | Hoechst Marion Roussel, Inc. | 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 HU HU0100669A patent/HUP0100669A3/hu unknown
- 1997-12-05 RU RU99114606/04A patent/RU2217436C2/ru not_active IP Right Cessation
- 1997-12-05 CA CA002272548A patent/CA2272548A1/en not_active Abandoned
- 1997-12-05 CN CN97180392A patent/CN1247542A/zh active Pending
- 1997-12-05 WO PCT/US1997/021636 patent/WO1998024806A2/en not_active Application Discontinuation
- 1997-12-05 NZ NZ336046A patent/NZ336046A/xx unknown
- 1997-12-05 TR TR2001/03270T patent/TR200103270T2/xx unknown
- 1997-12-05 EP EP97952232A patent/EP0954526A2/en not_active Withdrawn
- 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 JP JP52565698A patent/JP3220169B2/ja not_active Expired - Fee Related
-
1999
- 1999-06-04 NO NO992734A patent/NO992734L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| RU2217436C2 (ru) | 2003-11-27 |
| NO992734L (no) | 1999-08-02 |
| AU734615B2 (en) | 2001-06-21 |
| AU5589498A (en) | 1998-06-29 |
| CN1247542A (zh) | 2000-03-15 |
| WO1998024806A2 (en) | 1998-06-11 |
| HUP0100669A2 (hu) | 2001-08-28 |
| JP2001507679A (ja) | 2001-06-12 |
| NO992734D0 (no) | 1999-06-04 |
| EP0954526A2 (en) | 1999-11-10 |
| TR200103270T2 (tr) | 2003-03-21 |
| WO1998024806B1 (en) | 1999-05-20 |
| JP3220169B2 (ja) | 2001-10-22 |
| TR199901681T2 (xx) | 2000-03-21 |
| HUP0100669A3 (en) | 2001-12-28 |
| WO1998024806A3 (en) | 1998-10-15 |
| NZ336046A (en) | 2000-10-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2272548A1 (en) | Serine protease inhibitors | |
| US5869455A (en) | Serine protease inhibitors-N-substituted derivatives | |
| AU639212B2 (en) | Non-peptide renin inhibitors | |
| WO1999062538A1 (en) | Alpha-keto oxadiazoles as serine protease inhibitors | |
| US6015791A (en) | Serine protease inhibitors-cycloheptane derivatives | |
| CA2000929A1 (en) | Heterocyclic peptide renin inhibitors | |
| US6001811A (en) | Serine protease inhibitors--N-substituted derivatives | |
| US6150334A (en) | Serine protease inhibitors-tripeptoid analogs | |
| WO2002064559A2 (en) | Thrombin inhibitors | |
| US6656911B2 (en) | Serine protease inhibitors | |
| IE902446A1 (en) | Peptidyl aminodiol renin inhibitors | |
| US20040204368A1 (en) | Oxadiazole derivative compounds and drugs containing these compounds as the active ingredient | |
| US5998379A (en) | Serine protease inhibitors-proline analogs | |
| US6656910B2 (en) | Serine protease inhibitors | |
| KR100426545B1 (ko) | 세린 프로테아제 억제제 | |
| JP2001192398A (ja) | セリンプロテアーゼ阻害剤 | |
| MXPA99005240A (en) | Serine protease inhibitors | |
| JP2001509790A (ja) | 金属タンパク質分解酵素阻害剤 | |
| TW593340B (en) | Serine protease inhibitors | |
| AU2002240389A1 (en) | Thrombin inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |