CA2161216A1 - Inhibiteurs d'enzymes de type tryspine, a base de derives de substitution amidino et guanidino d'acide borique - Google Patents
Inhibiteurs d'enzymes de type tryspine, a base de derives de substitution amidino et guanidino d'acide boriqueInfo
- Publication number
- CA2161216A1 CA2161216A1 CA002161216A CA2161216A CA2161216A1 CA 2161216 A1 CA2161216 A1 CA 2161216A1 CA 002161216 A CA002161216 A CA 002161216A CA 2161216 A CA2161216 A CA 2161216A CA 2161216 A1 CA2161216 A1 CA 2161216A1
- Authority
- CA
- Canada
- Prior art keywords
- pro
- phe
- borophe
- alkyl
- nhc
- 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
- 239000003112 inhibitor Substances 0.000 title description 24
- 102000004190 Enzymes Human genes 0.000 title description 10
- 108090000790 Enzymes Proteins 0.000 title description 10
- 150000001642 boronic acid derivatives Chemical class 0.000 title description 7
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 title description 7
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 title description 4
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 19
- -1 C1-C7-alkoxy Chemical group 0.000 claims description 41
- 150000001875 compounds Chemical class 0.000 claims description 34
- 125000003118 aryl group Chemical group 0.000 claims description 23
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 21
- WEQJQNWXCSUVMA-RYUDHWBXSA-N Phe-Pro Chemical compound C([C@H]([NH3+])C(=O)N1[C@@H](CCC1)C([O-])=O)C1=CC=CC=C1 WEQJQNWXCSUVMA-RYUDHWBXSA-N 0.000 claims description 18
- 101100516563 Caenorhabditis elegans nhr-6 gene Proteins 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 125000000539 amino acid group Chemical group 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 125000001931 aliphatic group Chemical group 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 229910052796 boron Inorganic materials 0.000 claims description 4
- ZHXTWWCDMUWMDI-UHFFFAOYSA-N dihydroxyboron Chemical compound O[B]O ZHXTWWCDMUWMDI-UHFFFAOYSA-N 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 2
- 101100294102 Caenorhabditis elegans nhr-2 gene Proteins 0.000 claims description 2
- COQOYMRZIFLJII-UHFFFAOYSA-N boron;2,3-dimethylbutane-2,3-diol Chemical compound [B].CC(C)(O)C(C)(C)O COQOYMRZIFLJII-UHFFFAOYSA-N 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 7
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 120
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 50
- 239000000047 product Substances 0.000 description 34
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- 238000000034 method Methods 0.000 description 28
- 238000003786 synthesis reaction Methods 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- 230000015572 biosynthetic process Effects 0.000 description 25
- 239000000243 solution Substances 0.000 description 23
- 239000000203 mixture Substances 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 108090000190 Thrombin Proteins 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 229960004072 thrombin Drugs 0.000 description 15
- 229940024606 amino acid Drugs 0.000 description 14
- 235000001014 amino acid Nutrition 0.000 description 14
- 238000003756 stirring Methods 0.000 description 13
- 150000001413 amino acids Chemical class 0.000 description 12
- 229940092714 benzenesulfonic acid Drugs 0.000 description 12
- IVDFJHOHABJVEH-UHFFFAOYSA-N HOCMe2CMe2OH Natural products CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 11
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 10
- KZZCOWMDDXDKSS-CIUDSAMLSA-N Leu-Ser-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O KZZCOWMDDXDKSS-CIUDSAMLSA-N 0.000 description 10
- 150000002148 esters Chemical group 0.000 description 10
- MOILFCKRQFQVFS-BDNRQGISSA-N (1r,3s,4r,5r)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol Chemical compound C1[C@@H]2C(C)(C)[C@H]1C[C@H](O)[C@@]2(O)C MOILFCKRQFQVFS-BDNRQGISSA-N 0.000 description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 229940088598 enzyme Drugs 0.000 description 9
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical class NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 9
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- 239000003146 anticoagulant agent Substances 0.000 description 7
- 229940127219 anticoagulant drug Drugs 0.000 description 7
- 230000023555 blood coagulation Effects 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 206010053567 Coagulopathies Diseases 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 6
- 125000005620 boronic acid group Chemical class 0.000 description 6
- 238000004949 mass spectrometry Methods 0.000 description 6
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 6
- 102000004196 processed proteins & peptides Human genes 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 5
- 230000035602 clotting Effects 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000012545 processing Methods 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 4
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 4
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 229940122388 Thrombin inhibitor Drugs 0.000 description 4
- 150000001450 anions Chemical class 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 229940093476 ethylene glycol Drugs 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 4
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000017854 proteolysis Effects 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 239000003868 thrombin inhibitor Substances 0.000 description 4
- 230000001810 trypsinlike Effects 0.000 description 4
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 3
- PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-N 0.000 description 3
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 3
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 3
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 108010000499 Thromboplastin Proteins 0.000 description 3
- 102000002262 Thromboplastin Human genes 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 229910021529 ammonia Inorganic materials 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
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 3
- DKRMKJKQCXCUGJ-UHFFFAOYSA-N dichloromethylboronic acid Chemical compound OB(O)C(Cl)Cl DKRMKJKQCXCUGJ-UHFFFAOYSA-N 0.000 description 3
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- JPUTTYRVDANTBN-UHFFFAOYSA-N ethyl methanimidate;hydrochloride Chemical compound Cl.CCOC=N JPUTTYRVDANTBN-UHFFFAOYSA-N 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000002198 insoluble material Substances 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 125000002524 organometallic group Chemical group 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 2
- CVKOOKPNCVYHNY-UHFFFAOYSA-N 3-(bromomethyl)benzonitrile Chemical compound BrCC1=CC=CC(C#N)=C1 CVKOOKPNCVYHNY-UHFFFAOYSA-N 0.000 description 2
- 206010003178 Arterial thrombosis Diseases 0.000 description 2
- 108090000317 Chymotrypsin Proteins 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-Glutamic acid Natural products OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-Tyrosine Natural products OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- 125000000393 L-methionino group Chemical group [H]OC(=O)[C@@]([H])(N([H])[*])C([H])([H])C(SC([H])([H])[H])([H])[H] 0.000 description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Natural products C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 2
- 125000002707 L-tryptophyl group Chemical group [H]C1=C([H])C([H])=C2C(C([C@](N([H])[H])(C(=O)[*])[H])([H])[H])=C([H])N([H])C2=C1[H] 0.000 description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- ODCJPWIWKMHQAJ-UHFFFAOYSA-N OBOC(Cl)Cl Chemical compound OBOC(Cl)Cl ODCJPWIWKMHQAJ-UHFFFAOYSA-N 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 102000035195 Peptidases Human genes 0.000 description 2
- 108010001014 Plasminogen Activators Proteins 0.000 description 2
- 102000001938 Plasminogen Activators Human genes 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 229910006069 SO3H Inorganic materials 0.000 description 2
- 229920005654 Sephadex Polymers 0.000 description 2
- 239000012507 Sephadex™ Substances 0.000 description 2
- 108010022999 Serine Proteases Proteins 0.000 description 2
- 102000012479 Serine Proteases Human genes 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Chemical compound CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 2
- 230000001594 aberrant effect Effects 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- AOPRFYAPABFRPU-UHFFFAOYSA-N amino(imino)methanesulfonic acid Chemical compound NC(=N)S(O)(=O)=O AOPRFYAPABFRPU-UHFFFAOYSA-N 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000008366 buffered solution Substances 0.000 description 2
- 229960002376 chymotrypsin Drugs 0.000 description 2
- 238000001816 cooling Methods 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
- 239000012043 crude product Substances 0.000 description 2
- 150000002009 diols Chemical class 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000010265 fast atom bombardment Methods 0.000 description 2
- 239000003527 fibrinolytic agent Substances 0.000 description 2
- 230000003480 fibrinolytic effect Effects 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229940127126 plasminogen activator Drugs 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- KRRBFUJMQBDDPR-UHFFFAOYSA-N tetrabutylazanium;cyanide Chemical compound N#[C-].CCCC[N+](CCCC)(CCCC)CCCC KRRBFUJMQBDDPR-UHFFFAOYSA-N 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 1
- YDMBNDUHUNWWRP-VJBWXMMDSA-N (2s)-1-[(2r)-2-amino-3-phenylpropanoyl]-n-[(2s)-5-(diaminomethylideneamino)-1-(4-nitroanilino)-1-oxopentan-2-yl]piperidine-2-carboxamide Chemical compound C([C@@H](N)C(=O)N1[C@@H](CCCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NC=1C=CC(=CC=1)[N+]([O-])=O)C1=CC=CC=C1 YDMBNDUHUNWWRP-VJBWXMMDSA-N 0.000 description 1
- NMDDZEVVQDPECF-LURJTMIESA-N (2s)-2,7-diaminoheptanoic acid Chemical compound NCCCCC[C@H](N)C(O)=O NMDDZEVVQDPECF-LURJTMIESA-N 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- PHKBWGVAGDUJIS-UHFFFAOYSA-N (diaminomethylideneamino)thiourea Chemical group NC(=N)NNC(N)=S PHKBWGVAGDUJIS-UHFFFAOYSA-N 0.000 description 1
- YBPBQQSHRUTWFG-UHFFFAOYSA-N (methylhydrazinylidene)methanesulfonic acid Chemical compound CNN=CS(O)(=O)=O YBPBQQSHRUTWFG-UHFFFAOYSA-N 0.000 description 1
- JHDMMNYIVVWNOF-UHFFFAOYSA-N 1,2-dicyclohexylethane-1,1-diol Chemical compound C1CCCCC1C(O)(O)CC1CCCCC1 JHDMMNYIVVWNOF-UHFFFAOYSA-N 0.000 description 1
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- OBGFNGZXMSFPAR-UHFFFAOYSA-N 2,5-dimethylhexane-3,3-diol Chemical compound CC(C)CC(O)(O)C(C)C OBGFNGZXMSFPAR-UHFFFAOYSA-N 0.000 description 1
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 1
- UMLFTCYAQPPZER-UHFFFAOYSA-N 4-(bromomethyl)benzonitrile Chemical compound BrCC1=CC=C(C#N)C=C1 UMLFTCYAQPPZER-UHFFFAOYSA-N 0.000 description 1
- LOQLDQJTSMKBJU-UHFFFAOYSA-N 4-(chloromethyl)benzonitrile Chemical compound ClCC1=CC=C(C#N)C=C1 LOQLDQJTSMKBJU-UHFFFAOYSA-N 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- JEDOBLVMBKRNHF-UHFFFAOYSA-N 5-amino-1H-imidazole-2-carboximidamide Chemical compound NC(=N)C1=NC(N)=CN1 JEDOBLVMBKRNHF-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 108090000107 Acrosin Proteins 0.000 description 1
- 102100026041 Acrosin Human genes 0.000 description 1
- 102000004400 Aminopeptidases Human genes 0.000 description 1
- 108090000915 Aminopeptidases Proteins 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000028185 Angioedema Diseases 0.000 description 1
- 102000004411 Antithrombin III Human genes 0.000 description 1
- 108090000935 Antithrombin III Proteins 0.000 description 1
- 101100111947 Arabidopsis thaliana CYP72C1 gene Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 101100439244 Glycine max CHI2-A gene Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- QNAYBMKLOCPYGJ-UWTATZPHSA-N L-Alanine Natural products C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-Leucine Natural products CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- 235000019766 L-Lysine Nutrition 0.000 description 1
- FFEARJCKVFRZRR-UHFFFAOYSA-N L-Methionine Natural products CSCCC(N)C(O)=O FFEARJCKVFRZRR-UHFFFAOYSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-Phenylalanine Natural products OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-Tryptophan Natural products C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 229930064664 L-arginine Natural products 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- 235000013878 L-cysteine Nutrition 0.000 description 1
- 239000004201 L-cysteine Substances 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- 125000003338 L-glutaminyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C([H])([H])C(=O)N([H])[H] 0.000 description 1
- 229930182844 L-isoleucine Natural products 0.000 description 1
- 125000002061 L-isoleucyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])[C@](C([H])([H])[H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000004395 L-leucine Substances 0.000 description 1
- 235000019454 L-leucine Nutrition 0.000 description 1
- 125000003440 L-leucyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C(C([H])([H])[H])([H])C([H])([H])[H] 0.000 description 1
- 229930195722 L-methionine Natural products 0.000 description 1
- HXEACLLIILLPRG-YFKPBYRVSA-N L-pipecolic acid Chemical compound [O-]C(=O)[C@@H]1CCCC[NH2+]1 HXEACLLIILLPRG-YFKPBYRVSA-N 0.000 description 1
- 229930182821 L-proline Natural products 0.000 description 1
- 125000002842 L-seryl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])O[H] 0.000 description 1
- 125000003798 L-tyrosyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C([H])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- KQJQICVXLJTWQD-UHFFFAOYSA-N N-Methylthiourea Chemical compound CNC(N)=S KQJQICVXLJTWQD-UHFFFAOYSA-N 0.000 description 1
- 125000000729 N-terminal amino-acid group Chemical group 0.000 description 1
- 229910017912 NH2OH Inorganic materials 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229920002594 Polyethylene Glycol 8000 Polymers 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 108010039286 S 2238 Proteins 0.000 description 1
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 1
- FIDMVVBUOCMMJG-CIUDSAMLSA-N Ser-Asn-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO FIDMVVBUOCMMJG-CIUDSAMLSA-N 0.000 description 1
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 102000057032 Tissue Kallikreins Human genes 0.000 description 1
- 108700022175 Tissue Kallikreins Proteins 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000005076 adamantyloxycarbonyl group Chemical group C12(CC3CC(CC(C1)C3)C2)OC(=O)* 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- RMRFFCXPLWYOOY-UHFFFAOYSA-N allyl radical Chemical compound [CH2]C=C RMRFFCXPLWYOOY-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 125000006242 amine protecting group Chemical group 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 229960005348 antithrombin iii Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001743 benzylic group Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- IULFXBLVJIPESI-UHFFFAOYSA-N bis(methylsulfanyl)methylidenecyanamide Chemical compound CSC(SC)=NC#N IULFXBLVJIPESI-UHFFFAOYSA-N 0.000 description 1
- 239000010836 blood and blood product Substances 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 229940125691 blood product Drugs 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- AOJDZKCUAATBGE-UHFFFAOYSA-N bromomethane Chemical compound Br[CH2] AOJDZKCUAATBGE-UHFFFAOYSA-N 0.000 description 1
- OWBTYPJTUOEWEK-UHFFFAOYSA-N butane-2,3-diol Chemical compound CC(O)C(C)O OWBTYPJTUOEWEK-UHFFFAOYSA-N 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- UEIHHVGIYYSXAY-UHFFFAOYSA-N carbon dioxide;tetrachloromethane Chemical compound O=C=O.ClC(Cl)(Cl)Cl UEIHHVGIYYSXAY-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 101150071577 chi2 gene Proteins 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 230000004154 complement system Effects 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- QPJDMGCKMHUXFD-UHFFFAOYSA-N cyanogen chloride Chemical compound ClC#N QPJDMGCKMHUXFD-UHFFFAOYSA-N 0.000 description 1
- 125000004802 cyanophenyl group Chemical group 0.000 description 1
- FUGIIBWTNARRSF-UHFFFAOYSA-N decane-5,6-diol Chemical compound CCCCC(O)C(O)CCCC FUGIIBWTNARRSF-UHFFFAOYSA-N 0.000 description 1
- 238000011026 diafiltration Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- OKGXJRGLYVRVNE-UHFFFAOYSA-N diaminomethylidenethiourea Chemical compound NC(N)=NC(N)=S OKGXJRGLYVRVNE-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- SLIKWVTWIGHFJE-UHFFFAOYSA-N diphenoxymethylidenecyanamide Chemical compound C=1C=CC=CC=1OC(=NC#N)OC1=CC=CC=C1 SLIKWVTWIGHFJE-UHFFFAOYSA-N 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 208000009190 disseminated intravascular coagulation Diseases 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- HEZYPWDHDAPLSB-UHFFFAOYSA-N ethyl methanimidate Chemical compound CCOC=N HEZYPWDHDAPLSB-UHFFFAOYSA-N 0.000 description 1
- 230000004720 fertilization Effects 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 229960002885 histidine Drugs 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940124280 l-arginine Drugs 0.000 description 1
- HXEACLLIILLPRG-RXMQYKEDSA-N l-pipecolic acid Natural products OC(=O)[C@H]1CCCCN1 HXEACLLIILLPRG-RXMQYKEDSA-N 0.000 description 1
- 229960003136 leucine Drugs 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- GQNMAZUQZDEAFI-UHFFFAOYSA-N lithium;1h-naphthalen-1-ide Chemical compound [Li+].[C-]1=CC=CC2=CC=CC=C21 GQNMAZUQZDEAFI-UHFFFAOYSA-N 0.000 description 1
- 125000001288 lysyl group Chemical group 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229960004452 methionine Drugs 0.000 description 1
- 238000004452 microanalysis Methods 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- LSCYTCMNCWMCQE-UHFFFAOYSA-N n-methylpyridin-4-amine Chemical compound CNC1=CC=NC=C1 LSCYTCMNCWMCQE-UHFFFAOYSA-N 0.000 description 1
- 125000006124 n-propyl sulfonyl group Chemical group 0.000 description 1
- 230000017570 negative regulation of blood coagulation Effects 0.000 description 1
- 230000014508 negative regulation of coagulation Effects 0.000 description 1
- 101150009274 nhr-1 gene Proteins 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- BDSVELRAKXNYGM-UHFFFAOYSA-N phenyl carbamimidate Chemical compound NC(=N)OC1=CC=CC=C1 BDSVELRAKXNYGM-UHFFFAOYSA-N 0.000 description 1
- 229960005190 phenylalanine Drugs 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- VPRUMANMDWQMNF-UHFFFAOYSA-N phenylethane boronic acid Chemical compound OB(O)CCC1=CC=CC=C1 VPRUMANMDWQMNF-UHFFFAOYSA-N 0.000 description 1
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229940012957 plasmin Drugs 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 229940121649 protein inhibitor Drugs 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical group C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 1
- 229960001153 serine Drugs 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
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000012622 synthetic inhibitor Substances 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003441 thioacyl group Chemical group 0.000 description 1
- 150000003585 thioureas Chemical class 0.000 description 1
- 229960002898 threonine Drugs 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 229960004799 tryptophan Drugs 0.000 description 1
- 229960004441 tyrosine Drugs 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- 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
- C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-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
- C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/02—Linear peptides containing at least one abnormal peptide link
-
- 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)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Diabetes (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US5283593A | 1993-04-27 | 1993-04-27 | |
| US08/052,835 | 1993-04-27 | ||
| US20405594A | 1994-03-02 | 1994-03-02 | |
| US08/204,055 | 1994-03-02 | ||
| PCT/US1994/004058 WO1994025049A1 (fr) | 1993-04-27 | 1994-04-21 | Acide boronique a substitution amidino et guanidino en tant qu'inhibiteur d'enzymes de type trypsine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2161216A1 true CA2161216A1 (fr) | 1994-11-10 |
Family
ID=26731141
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002161216A Abandoned CA2161216A1 (fr) | 1993-04-27 | 1994-04-21 | Inhibiteurs d'enzymes de type tryspine, a base de derives de substitution amidino et guanidino d'acide borique |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0696199A4 (fr) |
| JP (1) | JPH08509723A (fr) |
| AU (1) | AU6703894A (fr) |
| CA (1) | CA2161216A1 (fr) |
| IL (1) | IL109319A0 (fr) |
| TW (1) | TW286318B (fr) |
| WO (1) | WO1994025049A1 (fr) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL111175A0 (en) * | 1993-10-07 | 1994-12-29 | Du Pont Merck Pharma | Electrophilic peptide analogs as inhibitors of trypsin-like serine proteases and pharmaceutical compositions containing them |
| US5561146A (en) * | 1994-06-10 | 1996-10-01 | Bristol-Myers Squibb Company | Modified guanidino and amidino thrombin inhibitors |
| FR2721611B1 (fr) * | 1994-06-22 | 1996-09-27 | Adir | Nouveaux dérivés peptidiques de l'acide boronique, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent . |
| WO1997005108A1 (fr) | 1995-07-26 | 1997-02-13 | Mitsubishi Chemical Corporation | Derives de penicillinamine amide |
| FR2739858B1 (fr) * | 1995-10-11 | 1997-11-14 | Synthelabo | Derives de n-sulfonyl- et n-sulfamoylpeptidylprolinamide, leur preparation et leur application en therapeutique |
| US6649593B1 (en) * | 1999-10-13 | 2003-11-18 | Tularik Inc. | Modulators of SREBP processing |
| PT1399468E (pt) | 2001-05-30 | 2006-05-31 | Novartis Ag | Derivados do acido 2-{[n-(2-amino-3-(heteroaril ou aril)propionil)-aminoacil]-amino}-alquilboronico |
| US7371729B2 (en) | 2002-09-09 | 2008-05-13 | Trigen Limited | Boronic acid salts useful in parenteral formulations |
| MXPA05002662A (es) | 2002-09-09 | 2005-09-20 | Trigen Ltd | Sales de metal multivalente de acidos boronicos para el tratamiento de trombosis. |
| US7576206B2 (en) | 2003-08-14 | 2009-08-18 | Cephalon, Inc. | Proteasome inhibitors and methods of using the same |
| US7223745B2 (en) | 2003-08-14 | 2007-05-29 | Cephalon, Inc. | Proteasome inhibitors and methods of using the same |
| US7468383B2 (en) | 2005-02-11 | 2008-12-23 | Cephalon, Inc. | Proteasome inhibitors and methods of using the same |
| RU2354647C2 (ru) * | 2007-06-28 | 2009-05-10 | Общество С Ограниченной Ответственностью "Бионика" | Новые соединения, обладающие функцией ингибиторов тромбина, и фармацевтические композиции на их основе |
| RU2353619C2 (ru) * | 2007-06-28 | 2009-04-27 | Общество С Ограниченной Ответственностью "Бионика" | Новые соединения, обладающие функцией антикоагулянтов, фармацевтические композиции на их основе для лечения тромботических состояний и плазмозамещающий раствор для коррекции гиперкоагуляционных нарушений при гемодилюции |
| WO2011087822A1 (fr) | 2009-12-22 | 2011-07-21 | Cephalon, Inc. | Inhibiteurs du protéasome et leurs procédés de préparation, d'épuration et d'utilisation |
| UA124672C2 (uk) | 2016-06-21 | 2021-10-27 | Оріон Офтальмолоджі Ллс | Гетероциклічні похідні пролінаміду |
| JP7164521B2 (ja) | 2016-06-21 | 2022-11-01 | オリオン・オフサルモロジー・エルエルシー | 炭素環式プロリンアミド誘導体 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4537773A (en) * | 1983-12-05 | 1985-08-27 | E. I. Du Pont De Nemours And Company | α-Aminoboronic acid derivatives |
| US4499082A (en) * | 1983-12-05 | 1985-02-12 | E. I. Du Pont De Nemours And Company | α-Aminoboronic acid peptides |
| GB9024129D0 (en) * | 1990-11-06 | 1990-12-19 | Thrombosis Research Trust | Inhibitors and substrates of thrombin |
| IL111175A0 (en) * | 1993-10-07 | 1994-12-29 | Du Pont Merck Pharma | Electrophilic peptide analogs as inhibitors of trypsin-like serine proteases and pharmaceutical compositions containing them |
-
1994
- 1994-04-13 IL IL10931994A patent/IL109319A0/xx unknown
- 1994-04-21 JP JP6524316A patent/JPH08509723A/ja active Pending
- 1994-04-21 CA CA002161216A patent/CA2161216A1/fr not_active Abandoned
- 1994-04-21 AU AU67038/94A patent/AU6703894A/en not_active Abandoned
- 1994-04-21 EP EP94914776A patent/EP0696199A4/fr not_active Withdrawn
- 1994-04-21 WO PCT/US1994/004058 patent/WO1994025049A1/fr not_active Application Discontinuation
- 1994-05-07 TW TW083104198A patent/TW286318B/zh active
Also Published As
| Publication number | Publication date |
|---|---|
| EP0696199A1 (fr) | 1996-02-14 |
| WO1994025049A1 (fr) | 1994-11-10 |
| JPH08509723A (ja) | 1996-10-15 |
| IL109319A0 (en) | 1994-07-31 |
| TW286318B (fr) | 1996-09-21 |
| EP0696199A4 (fr) | 1997-06-25 |
| AU6703894A (en) | 1994-11-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0293881B1 (fr) | Inhibiteurs peptides de l'acide boronique de proteases de type trypsine | |
| CA2200192C (fr) | Inhibiteurs amidino et guanidino substitues d'enzymes semblables a la trypsine | |
| US5242904A (en) | Peptide boronic acid inhibitors of trypsin-like proteases | |
| US5250720A (en) | Intermediates for preparing peptide boronic acid inhibitors of trypsin-like proteases | |
| CA2161216A1 (fr) | Inhibiteurs d'enzymes de type tryspine, a base de derives de substitution amidino et guanidino d'acide borique | |
| US5462928A (en) | Inhibitors of dipeptidyl-aminopeptidase type IV | |
| US7230074B2 (en) | Inhibitors of dipeptidyl-aminopeptidase type IV | |
| EP1050540B1 (fr) | Inhibiteurs de dipeptidyl-aminopeptidase de type IV | |
| US4499082A (en) | α-Aminoboronic acid peptides | |
| CA2080474A1 (fr) | Inhibiteurs de la dipeptidyl-aminopeptidase de type iv | |
| WO1995009634A1 (fr) | Analogues peptidiques electrophiles servant d'inhibiteurs a des enzymes apparentees a la trypsine | |
| US5639739A (en) | Imidazole containing aminoboronic acids | |
| WO1995009859A1 (fr) | Inhibiteurs boropeptidiques de la thrombine contenant un noyau de pyrrolidine substitue | |
| US5462964A (en) | Dipeptide boronic acid inhibitors of trypsin-like enzymes | |
| US6127340A (en) | Serine protease inhibitors | |
| US5731439A (en) | Piperidine containing aminobornic acids | |
| CA1333208C (fr) | Peptides contenant de l'acide boronique inhibant les proteases apparentees a la trypsine | |
| JP2002519430A (ja) | ヒトアンギオテンシン変換酵素のｎ−末端部位選択的阻害薬 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |