CN1441784A - 含有氨基异喹啉基团的凝血酶抑制剂 - Google Patents
含有氨基异喹啉基团的凝血酶抑制剂 Download PDFInfo
- Publication number
- CN1441784A CN1441784A CN01812607A CN01812607A CN1441784A CN 1441784 A CN1441784 A CN 1441784A CN 01812607 A CN01812607 A CN 01812607A CN 01812607 A CN01812607 A CN 01812607A CN 1441784 A CN1441784 A CN 1441784A
- Authority
- CN
- China
- Prior art keywords
- compound
- cyclohexyl
- amino
- methyl
- group
- 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.)
- Pending
Links
- 239000003868 thrombin inhibitor Substances 0.000 title description 8
- 229940122388 Thrombin inhibitor Drugs 0.000 title description 7
- OSILBMSORKFRTB-UHFFFAOYSA-N isoquinolin-1-amine Chemical group C1=CC=C2C(N)=NC=CC2=C1 OSILBMSORKFRTB-UHFFFAOYSA-N 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 65
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims abstract description 13
- 108090000190 Thrombin Proteins 0.000 claims abstract description 11
- 229960004072 thrombin Drugs 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 201000010099 disease Diseases 0.000 claims abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 3
- 239000003814 drug Substances 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 230000001404 mediated effect Effects 0.000 abstract description 2
- 230000014508 negative regulation of coagulation Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 239000000243 solution Substances 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- 238000012360 testing method Methods 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 238000013016 damping Methods 0.000 description 10
- 239000012530 fluid Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 9
- 230000000903 blocking effect Effects 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- -1 benzyloxy carbonyl (Cbz) group Chemical group 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 229960001866 silicon dioxide Drugs 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- 239000004019 antithrombin Substances 0.000 description 5
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 210000002381 plasma Anatomy 0.000 description 5
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- AKGGYBADQZYZPD-UHFFFAOYSA-N benzylacetone Chemical compound CC(=O)CCC1=CC=CC=C1 AKGGYBADQZYZPD-UHFFFAOYSA-N 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 230000009466 transformation Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 230000002785 anti-thrombosis Effects 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 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
- 239000012141 concentrate Substances 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 238000005497 microtitration Methods 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- WXKPEOSDDROAEB-UHFFFAOYSA-N 6-(aminomethyl)-3-methylisoquinolin-1-amine Chemical compound NCC1=CC=C2C(N)=NC(C)=CC2=C1 WXKPEOSDDROAEB-UHFFFAOYSA-N 0.000 description 2
- LWDVTRXNUGVQES-UHFFFAOYSA-N 6-(aminomethyl)isoquinolin-1-amine Chemical compound NC1=NC=CC2=CC(CN)=CC=C21 LWDVTRXNUGVQES-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 208000005189 Embolism Diseases 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 206010047249 Venous thrombosis Diseases 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 229960004676 antithrombotic agent Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 150000004982 aromatic amines Chemical group 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 150000001733 carboxylic acid esters Chemical class 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000007822 coupling agent Substances 0.000 description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- BTZNPZMHENLISZ-UHFFFAOYSA-N fluoromethanesulfonic acid Chemical compound OS(=O)(=O)CF BTZNPZMHENLISZ-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 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
- WEQJQNWXCSUVMA-NEPJUHHUSA-N (2s)-1-[(2r)-2-azaniumyl-3-phenylpropanoyl]pyrrolidine-2-carboxylate Chemical compound C([C@@H](N)C(=O)N1[C@@H](CCC1)C(O)=O)C1=CC=CC=C1 WEQJQNWXCSUVMA-NEPJUHHUSA-N 0.000 description 1
- CSKSDAVTCKIENY-WCCKRBBISA-N (2s)-pyrrolidine-2-carboxamide;hydrochloride Chemical compound Cl.NC(=O)[C@@H]1CCCN1 CSKSDAVTCKIENY-WCCKRBBISA-N 0.000 description 1
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- WHWXEUUKHBARIS-UHFFFAOYSA-N 1-amino-3-methylisoquinolin-6-ol Chemical compound OC1=CC=C2C(N)=NC(C)=CC2=C1 WHWXEUUKHBARIS-UHFFFAOYSA-N 0.000 description 1
- 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 1
- AFXVXXUGDMGQAM-UHFFFAOYSA-N 7-(aminomethyl)isoquinolin-1-amine Chemical compound C1=CN=C(N)C2=CC(CN)=CC=C21 AFXVXXUGDMGQAM-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 208000031104 Arterial Occlusive disease Diseases 0.000 description 1
- 206010003162 Arterial injury Diseases 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 101000772006 Bombus ignitus Venom serine protease Bi-VSP Proteins 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 229940123900 Direct thrombin inhibitor Drugs 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 239000012901 Milli-Q water Substances 0.000 description 1
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 208000006193 Pulmonary infarction Diseases 0.000 description 1
- 108010039286 S 2238 Proteins 0.000 description 1
- 102000008847 Serpin Human genes 0.000 description 1
- 108050000761 Serpin Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- RMLHVYNAGVXKKC-UHFFFAOYSA-N [SH2]=N.C(F)(F)F Chemical compound [SH2]=N.C(F)(F)F RMLHVYNAGVXKKC-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 208000021328 arterial occlusion Diseases 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- PXXJHWLDUBFPOL-UHFFFAOYSA-N benzamidine Chemical compound NC(=N)C1=CC=CC=C1 PXXJHWLDUBFPOL-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- LDECUSDQMXVUMP-UHFFFAOYSA-N benzyl 3-[6-[[2-(butylamino)-1-[3-methoxycarbonyl-4-(2-methoxy-2-oxoethoxy)phenyl]-2-oxoethyl]-hexylamino]-6-oxohexyl]-4-methyl-2-oxo-6-(4-phenylphenyl)-1,6-dihydropyrimidine-5-carboxylate Chemical compound O=C1NC(C=2C=CC(=CC=2)C=2C=CC=CC=2)C(C(=O)OCC=2C=CC=CC=2)=C(C)N1CCCCCC(=O)N(CCCCCC)C(C(=O)NCCCC)C1=CC=C(OCC(=O)OC)C(C(=O)OC)=C1 LDECUSDQMXVUMP-UHFFFAOYSA-N 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
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 239000003085 diluting agent Substances 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
- 229940079593 drug Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000012821 model calculation Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000007575 pulmonary infarction Effects 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 230000000250 revascularization Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000003001 serine protease inhibitor Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960003766 thrombin (human) Drugs 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 201000005060 thrombophlebitis Diseases 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom 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
- C07K5/04—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
-
- 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
- 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)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及具有式(I)的化合物,其中R1是环戊基、环己基或支链(3-4C)烷基;R2是环己基或苯基;R3是H或甲基;A是未取代的饱和4、5或6-元环;或其可药用盐。本发明的化合物具有抗凝活性并且可用于治疗或预防凝血酶介导和凝血酶有关的疾病。
Description
本发明涉及一种含有氨基异喹啉基团的凝血酶抑制剂、含有这种抑制剂的药物组合物、以及所述抑制剂用于生产治疗和预防凝血酶有关的疾病的药物的用途。
文献中公开了大量肽样凝血酶抑制剂。这些凝血酶抑制剂中大多数在其所谓的P1-位含有碱基,例如碱性氨基酸精氨酸和赖氨酸,但是也有苄脒等。认为这种碱性部分对抗凝血酶活性是必不可少的。另一方面,这些化合物的碱度可以赋予化合物当通过口服途径释放时在小肠内的吸收。在WO 98/47876中公开了一类凝血酶抑制剂,它具有氨基异喹啉部分作为碱性基团,这样显示了提高的经皮转运性能。现已证实在后面一类化合物中一类新选择的化合物具有更高的药理性能。
其中R1是环戊基、环己基或支链(3-4C)烷基;
R2是环己基或苯基;
R3是H或甲基;和
A是未经取代的饱和的4、5或6-元环;
或其可药用盐,
是具有显著增加的血浆半衰期的有效凝血酶抑制剂。需要抗血栓形成性药物的大多数临床状况一般需要延长的半衰期(参见Sixma,J.J.等,Thromb.Res.67;305-311(特别是307),1992)。因此本发明的化合物在本领域是一个重要的改进。
本发明的化合物可用于治疗和预防凝血酶介导的和凝血酶有关的疾病。这包括大量血栓形成性和其中凝血级联被激活的前血栓形成状态,包括,但不限于,深静脉血栓形成、肺栓塞、血栓静脉炎、血栓形成或栓塞引起的动脉闭塞、血管形成术或血栓溶解期间或之后的动脉再闭塞,动脉损伤或侵入性心脏手术之后的再狭窄、手术后的静脉血栓形成或栓塞、急性或慢性动脉粥样硬化、中风、心肌梗塞、癌和转移、以及神经变性疾病。本发明的化合物还可用作体外血液循环中,必要的话在透析和手术中的抗凝剂。本发明的化合物还可用作体外抗凝剂。
本发明优选的凝血酶抑制剂是A为一5-元环的化合物。优选R2是环己基。其它优选的化合物是R3是H的那些。更优选R1是环己基的化合物。最优选的本发明凝血酶抑制剂是R1是环己基,R2是环己基,R3是H且A是5-元环的化合物。
术语支链(3-4C)烷基意思是具有3个或4个碳原子的支链烷基,例如异丙基。
本发明还包括所述凝血酶抑制剂的制备方法,包括将适当保护的氨基酸与氨基异喹啉衍生物偶联,然后除去这些保护基团。
式(I)的化合物可以常用于这些化合物的方式制备。它们可以通过连接有式(II)的化合物的肽与用作偶联剂的式(III)的化合物例如N,N-二环己基碳二亚胺(DCCI)和1-羟基苯并三唑(HOBT)或2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓四氟硼酸盐(TBTU)制备,其中R1、R2、R3和A具有前面定义的意义。式(II)的化合物的N-端可以任选载有一保护基团如叔丁氧基羰基(Boc)。式(III)的化合物的芳基胺基团可以任选载有一保护基团,例如可以在偶联反应之后除去的苯甲酰基。
式(II)的化合物可以由式(IV)的化合物,其中Pg1是羧酸酯保护基团如苯甲酯,用例如环己酮或丙酮的适宜酮和例如三乙酰氧基硼氢化钠的还原剂在酸性条件下处理式(IV)的化合物,然后除去所述羧酸酯保护基团制备。
R3=H的式(III)的化合物(1-氨基-6-(氨基甲基)异喹啉)描述在WO98/47876中。R3=Me的式(III)的化合物(1-氨基-6-(氨基甲基)-3-甲基异喹啉)可以由1-氨基-6-甲氧基-3-甲基异喹啉使用WO 98/47876中所述用于将1-氨基-6-甲氧基异喹啉转化成1-氨基-7-(氨基甲基)异喹啉的步骤制备。1-氨基-6-甲氧基-3-甲基异喹啉可以由3-甲氧基苯基丙酮使用W.Zielinski和M.Mazik在Heterocycles 38,375(1994)中所述的方法制备。
或者,式(I)的化合物可以由式(V)的化合物,通过例如环己酮或丙酮的适宜酮和例如三乙酰氧基硼氢化钠的还原剂在酸性条件下处理式(V)的化合物制备。在该反应中式(V)的化合物的芳基胺基团可以任选通过一基团如在该还原胺化之后可以除去的苯甲酰基加以保护。
式(V)的化合物可以通过连接有在N-端用一保护基团如Boc基团保护的二肽的肽和式(III)的化合物使用前面所述的偶联剂制备。
α-氨基官能团的保护通常通过尿烷官能团如酸-不稳定的叔丁氧基羰基(Boc)、苯甲氧基羰基(Cbz)基团和经取代的类似物、碱-不稳定的9-芴基甲氧基羰基(Fmoc)基团或邻苯二甲酰基(Phth)基团发生。其它适宜的氨基保护基团包括Nps、Bpoc、Msc等。可以不同方式进行保护基团的除去,这取决于这些保护基团的性质。通常在酸性条件下在有清除剂的情况下进行去保护。Cbz基团也可以通过催化氢化除去。对氨基保护基团及其除去方法的概述给在The Peptides,Analysis,Synthesis,Biology,第3卷,E.Gross和J.Meienhofer编辑(Academic Press,New York,1981)。
羧基的保护可以通过形成酯,例如碱-不稳定的酯如甲酯或乙酯、酸不稳定的酯如叔丁酯、或氢化-不稳定的酯如苯甲酯进行。
本发明的化合物,可以是自由碱形式,可以可药用盐的形式与反应混合物分离。这些可药用盐也可以通过用有机酸或无机酸如盐酸、溴化氢、碘化氢、硫酸、磷酸、乙酸、丙酸、乙醇酸、马来酸、丙二酸、甲磺酸、富马酸、琥珀酸、酒石酸、柠檬酸、苯甲酸和抗坏血酸处理式(I)的自由碱获得。
本发明的化合物具有一个或多个手性碳原子,并且因此可以纯对映异构体、纯非对映异构体、对映异构体的混合物、或者含有非对映异构体的混合物获得。所述纯对映异构体的获得方法在本领域为公知,例如将由光学活性酸及其外消旋混合物获得的盐结晶,或者使用手性柱色谱。对非对映异构体可以使用顺相柱或逆相柱。
本发明的化合物可以经肠或者非肠道给药,并且就人而言优选每日剂量是0.001-100mg/kg体重,优选0.01-10mg/kg体重。与药用适宜的辅料混合,例如标准参考,Gennaro等,Remington’sPharmaceutical Sciences,(第18版,Mack Publishing Company,1990,尤其参见第8部分:Pharmaceutical Preparations and TheirManufacture)中所述的,可以将这些化合物压制成固体剂量单元,例如丸剂、片剂,或者加工成胶囊或栓剂。借助药用适宜的液体,还可以将这些化合物以溶液、悬液、乳液形式施加,例如用作注射剂,或者用作喷剂,例如用作喷鼻剂使用。
为了制备剂量单元,例如片剂,包括使用传统添加剂如填料、着色剂、聚合粘合剂等。一般说来不与所述活性化合物的功能冲突的任何可药用添加剂都可以使用。可以组合物给药的适宜载体包括以适宜量使用的乳糖、淀粉、纤维素衍生物等,或其混合物。
本发明化合物的消除半衰期和百分比生物利用度可以按照以下试验在狗中适宜地测定。
在静脉给药或口服给药之后通过测定血浆中的抗-IIa活性可以测定直接凝血酶抑制剂在雌性Beagle狗中的停留时间和百分比生物利用度。鉴于本发明蛋白酶抑制剂的选择性,凝血酶的抑制与测定的蛋白酶抑制剂的浓度线性相关。静脉或口服给药丝氨酸蛋白酶抑制剂之后,在白天的不同时间点从颈静脉收集血液。将这些血液离心之后,在微量滴定平皿显色试验中使用待测化合物本身的校准曲线测定该血浆样品的血浆抗-IIa活性。获得的数据由血浆~时间曲线例如借助计算机化迭代程序,根据Simplex方法进行分析。随后,使用不依赖于浓度的相对误差模型计算消除半衰期,并用梯形规则测定曲线下的面积(AUC)。假定线性动力学,通过口服给药之后获得的AUC除以静脉注射给药该剂量之后的平均所需标准化AUC(X100%)计算百分比生物利用度。
通过以下实施例进一步描述本发明。
实施例
在BRUKER DRX 400分光光度计上以400MHz的1H频率进行1H NMR测定。用PE-sciex API-165记录质谱(MS)。
实施例1
N-环己基-3-环己基-D-丙氨酰基-N-[(1-氨基-6-异喹啉基)甲
基]-L-脯氨酰胺盐酸盐(N-环己基-D-Cha-Pro-6Aiq.HCl)
将0.91g的3-环己基-N-[(1,1-二甲基乙氧基)羰基]-D-丙氨酰基-L-脯氨酸苯基甲酯(Boc-D-Cha-Pro-OBz1)在2.5mL的二氯甲烷和2.5mL的三氟乙酸中的溶液于室温下搅拌2小时之后,将反应混合物于真空下浓缩获得0.94g油。将该油溶于10mL含1%(v/v)乙酸的N,N-二甲基甲酰胺中并加入0.26mL环己酮和0.64g三乙酰氧基硼氢化钠。室温下搅拌16小时之后向该反应混合物中加入5mL水并用二氯甲烷萃取。有机萃取物在硫酸镁上干燥并浓缩得到0.90g油(TLC;硅胶,二氯甲烷/甲醇=95/5(v/v)Rf=0.8)。将该油溶于50mL乙酸乙酯中,使用乙酸将溶液的pH调整至5,加入0.10g Pd/C(10%),并将该悬液于大气压、室温下氢化1小时。过滤除去该Pd催化剂并在减压下蒸发除去溶剂。将残余物溶于甲苯中并在减压下将甲苯蒸发得到0.56g的N-环己基-D-Cha-Pro-OH。将该酸(0.35g)溶于10mL的N,N-二甲基甲酰胺中并加入0.19mg的1-氨基-6-氨基甲基异喹啉(WO9847876)和0.4g的2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓四氟硼酸盐(TBTU)。使用N,N-二异丙基乙胺(DIPEA)将反应混合物的pH调整至8。室温下搅拌24小时之后加入另外的0.1g TBTU,并在室温下将反应混合物搅拌另外18小时。之后将反应混合物真空浓缩。残余物溶于50mL的二氯甲烷中并用含水碳酸氢钠洗涤两次,在硫酸镁上干燥并浓缩。将残余物溶于水中并使用20%A/80%B至20%A/30%B/50%C的梯度洗脱系统在60分钟内以40ml/min的流速直接装入在预备的HPLC DeltaPak RP-C18上(A:0.5M磷酸盐缓冲液pH2.1,B:水,C:乙腈/水=6/4(v/v))。产量:0.25g的标题化合物。
1H-NMR 400MHz(CD3OD)δ:0.84-2.41(27H,m),2.91-3.01(1H,m),3.57-3.65(1H,m),3.81-3.88(1H,m),4.30(1H,t,J=7Hz),4.49-4.77(3H,m),7.26(1H,d,J=7Hz),7.57(1H,d,J=7Hz),7.73(1H,dd,J=2Hz和J=9Hz),7.92(1H,d,J=2Hz),8.38(1H,d,J=9Hz)。
实施例2
N-环己基-3-环己基-D-丙氨酰基-N-[(1-氨基-3-甲基-6-异喹啉
基)甲基-L-脯氨酰胺盐酸盐(N-环己基-D-Cha-Pro-6(3Me)Aiq.HCl)
2a.
1-氨基-6-甲氧基-3-甲基-异喹啉
将2.12g 3-甲氧基苯基丙酮和1.26mL磷酰氯的45mL无水甲苯溶液在回流下加热。30分钟之后将该混合物冷却至0℃并滴加0.57g氰酰胺的23mL无水醚溶液。将反应混合物加热至室温并在该温度下搅拌1小时。然后将该搅拌混合物冷却至0℃并滴加1.5mL四氯化钛。将该反应混合物在回流下加热2.5小时,冷却,加入34mL水,将混合物过滤并用乙酸乙酯将残余物洗涤。使用2N氢氧化钠水溶液使滤液呈碱性并用乙酸乙酯萃取。将有机萃取物用生理盐水洗涤,在硫酸镁上干燥并浓缩。残余物通过二氧化硅色谱法(二氯甲烷/甲醇=95/5)提纯,得到0.42g标题化合物。1H-NMR 400MHz(CDCl3)δ:2.45(3H,s),3.91(3H,s),5.0(2H,br.s),6.81(1H,s),6.90(1H,d,J=3Hz),7.02(1H,dd,J=3Hz和J=9Hz),7.65(1H,d,J=9Hz)。2b.
1-氨基-6-羟基-3-甲基-异喹啉
0℃下将三溴化硼(4mL)的6mL二氯甲烷滴加到1-氨基-6-甲氧基-3-甲基异喹啉(2g)的10mL二氯甲烷的搅拌溶液中。室温下搅拌16小时之后将反应混合物倒在冰上,除去有机层并通过加入浓氨水将含水层的pH调整至pH9。过滤收集沉淀物并在真空下干燥得到1.6g标题化合物。ESI-MS:175(ME+)。2c.
三氟-甲磺酸1-氨基-3-甲基异喹啉-6-基酯
将1.4g1-氨基-6-羟基-3-甲基-异喹啉和4.3g N-苯基二(三氟甲磺酰亚胺)的19.5mL二氯甲烷和19.5mL二噁烷的混合物在冰浴中冷却并滴加2.8mL N,N-二异丙基乙基胺。将所得混合物于70℃下加热24小时,之后在真空下除去挥发物。将剩余残余物溶于乙酸乙酯中,用连续部分的2N氢氧化钠水溶液、水和生理盐水洗涤并干燥(硫酸钠)。过滤并浓缩获得一无色油,将其在甲苯中研磨得到1.3g固体。甲苯溶液通过二氧化硅色谱法(甲苯/乙醇=95/5)提纯得到另外0.6g标题化合物。总产量是1.9g。ESI-MS:307(MH+)。2d.
1-氨基-6-氰基-3-甲基异喹啉
在190℃下将乙酸钯(0.28g)加入到三氟-甲磺酸1-氨基-3-甲基异喹啉-6-基酯(1.9g)、氰化锌(0.74g)和三苯基膦(0.33g)的24mLN-甲基-吡咯烷酮的热混合物中(放热!)。在190℃下连续搅拌2小时。冷却至室温之后,加入乙酸乙酯并将该有机混合物用2N氨水、水和生理盐水洗涤并干燥(硫酸镁)。过滤和浓缩得到淡棕色油,通过二氧化硅色谱法将其提纯(二氯甲烷/甲醇=98/2),得到0.68g标题化合物。ESI-MS:184(MH+)。
2e.1-氨基-6-(氨基甲基)-3-甲基异喹啉
在室温、氮气环境下向1-氨基-6-氰基-3-甲基异喹啉(0.68g)的15mL四氢呋喃的搅拌溶液中加入8.4mL的2M硼烷-二甲硫络合物的四氢呋喃溶液,之后在60℃下加热50分钟。将该反应混合物在冰浴中冷却并慢慢加入7.5mL甲醇。15分钟之后加入18.8mL的1M氯化氢的醚溶液。将该反应混合物加热至室温并搅拌另外16小时。将固体分离得到0.34g的1-氨基-6-(氨基甲基)-3-甲基异喹啉盐酸盐。滤液用柱色谱法提纯(硅胶;甲醇/氨水=98/2),得到另外0.15g的1-氨基-6-(氨基甲基)-3-甲基异喹啉。ESI-MS:188(MH+)。
2f.
N-环己基-3-环己基-D-丙氨酰基-N-[(1-氨基-3-甲基-6-异 喹啉基)甲基]-L-脯氨酰胺盐酸盐(N-环己基-D-Cha-Pro-6(3Me) Aiq.HCl)
室温下在1小时内向0.17g1-氨基-6-(氨基甲基)-3-甲基异喹啉盐酸盐、0.30g N-环己基-D-Cha-Pro-OH、0.5mL乙腈和0.37mLN,N-二异丙基乙胺的3mL N,N-二甲基甲酰胺的搅拌混合物中加入0.35g六氟磷酸溴三吡咯烷酮鏻(PyBroP)的1.3mL N,N-二甲基甲酰胺溶液。室温下搅拌24小时之后将该反应混合物于真空下浓缩。将残余物溶于乙酸乙酯并用碳酸氢钠水溶液和盐水洗涤,在硫酸镁上干燥并浓缩。残余物通过硅色谱法提纯(二氯甲烷/甲醇=9/1)并从叔丁醇/盐酸冷冻干燥得到0.13g标题化合物。1H-NMR 400MHz(CD3OD)δ:0.85-2.40(27H,m),2.50(0.3H,s),2.51(2.7H,s),2.92-3.00(1H,m),3.54-3.68(1H,m),3.81-3.88(1H,m),4.30(1H,t,J=7Hz),4.46-4.74(3H,m),7.02(1H,s),7.64(1H,dd,J=2Hz和J=9Hz),7.80(1H,d,J=2Hz),8.32(1H,d,J=9Hz)。
实施例3.
N-环己基-D-苯基丙氨酰基-N-[(1-氨基-6-异喹啉基)甲基]-L-脯氨酰
胺盐酸盐(N-环己基-D-Phe-Pro-6Aiq.HCl)
用0.85g N-[(1,1-二甲基乙氧基)羰基]-D-苯基丙氨酰基-L-脯氨酸苯基甲基酯(Boc-D-Phe-Pro-OBzl)开始,使用实施例1中对N-环己基-D-Cha-Pro-OH所述的步骤得到0.82g N-环己基-D-苯基丙氨酰基-L-脯氨酸(N-环己基-D-Phe-Pro-OH)。将N-环己基-D-Phe-Pro-OH(0.82 g)溶于10 mL N,N-二甲基甲酰胺并加入0.33 mg1-氨基-6-氨基甲基异喹啉和1.1 g六氟磷酸O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓(HATU),并使用N,N-二异丙基乙胺(DIPEA)将其pH调整至8。室温下搅拌16小时之后将该反应混合物于真空下浓缩。将残余物溶于50 mL二氯甲烷并用水和盐水洗涤两次,在硫酸镁上干燥并浓缩。将残余物通过硅色谱法(二氯甲烷/甲醇(含2%氨水)=9/1)提纯并从叔丁醇/盐酸冷冻干燥,得到0.19 g标题化合物。1H-NMR 400MHz(CD3OD)δ:0.87-2.13(14H,m),2.38-2.45(1H,m),2.94-3.03(1H,m),3.06-3.13(1H,m),3.25-3.38(2H,m),4.33-4.73(4H,m),7.25-7.40(6H,m),7.58(1H,d,J=7Hz),7.71(1H,dd,J=2Hz和J=9Hz),7.92(1H,d,J=2Hz),8.35(1H,d,J=9Hz)。
实施例4.
N-环戊基-3-环己基-D-丙氨酰基-N-[(1-氨基-6-异喹啉基)甲基]-L-
脯氨酰胺盐酸盐(N-环戊基-D-Cha-Pro-6Aia.HCl)
使用实施例1中所述的步骤用0.30 g Boc-D-Cha-Pro-OBzl为原料使用环戊酮代替环己酮得到粗N-环戊基-D-Cha-Pro-6Aiq,使用柱色谱法(硅胶;二氯甲烷/甲醇=10/1至5/1梯度)提纯。从叔丁醇/盐酸冷冻干燥得到0.16g的标题化合物。1H-NMR 400MHz(CD3OD)δ:0.85-2.41(25H,m),3.43-3.52(1H,m),3.59-3.65(1H,m),3.80-3.86(1H,m),4.20(1H,t,J=7Hz),4.51-4.73(3H,m),7.25(1H,d,J=7Hz),7.57(1H,d,J=7Hz),7.73(1H,dd,J=2Hz和J=9Hz),7.90(1H,d,J=2Hz),8.38(1H,d,J=9Hz)。
实施例5.
N-(1-甲基乙基)-3-环己基-D-丙氨酰基-N-[(1-氨基-6-异喹啉基)甲
基]-L-脯氨酰胺盐酸盐(N-(1-甲基乙基)-D-Cha-Pro-6Aiq.HCl)
使用实施例1中所述的步骤用0.92g Boc-D-Cha-Pro-OBzl为原料使用丙酮代替环己酮得到0.04g N-(1-甲基乙基)-D-Cha-Pro-6Aiq.HCl。1H-NMR 400MHz(CD3OD)δ:0.85-2.41(23H,m),3.27-3.35(1H,m),3.59-3.65(1H,m),3.82-3.89(1H,m),4.27(1H,t,J=7Hz),4.51-4.74(3H,m),7.26(1H,d,J=7Hz),7.57(1H,d,J=7Hz),7.72(1H,dd,J=2Hz和J=9Hz),7.91(1H,d,J=2Hz),8.38(1H,d,J=9Hz)。
抗凝血酶试验
本发明化合物的抗凝血酶活性是通过分光光度测定由凝血酶产生的显色底物s-2238的水解速度来评价的。将缓冲体系中抗凝血酶活性的该试验用于评价试验化合物的IC50-值。
试验介质:氨丁三醇-NaCl-聚乙二醇6000(TNP)缓冲液
参照化合物:I2581(Kabi)
载体:TNP缓冲液。可以用二甲亚砜、甲醇、乙醇、乙腈或叔丁醇帮助增溶,它们在最终反应混合物中浓度高达2.5%时没有副作用。
方法
试剂*1.氨丁三醇-NaCl(TN)缓冲液[缓冲液的组成:氨丁三醇(Tris)6.057g(50mmol)、NaCl 5.844g(100mmol),水至1L。37℃下用HCl(10mmol.l-1)]将溶液的pH调整至7.4;2.TNP缓冲液(将聚乙二醇6000溶于TN缓冲液中得到3g.l-1的浓度);3.S-2238溶液[将一小瓶S-2238(25mg;Kabi Diagnostica,Sweden)溶于20ml TN缓冲液得到1.25mg.ml-1(2mmol.l-1的浓度)];4.凝血酶溶液[将人凝血酶(16 000nKat.小瓶-1;Centraal Laboratorium voorBloedtransfusie,Amsterdam,The Netherlands)溶于TNP缓冲液中得到835nKat.ml-1原液。就在使用前将该溶液用TNP缓冲液稀释得到3.34nKat.ml-1的浓度。]
*-所用的所有组分都是分析级
-就水溶液而言使用超纯水(Milli-Q质量)。
试验和参照化合物溶液的制备
将试验和参照化合物溶于Milli-Q水中得到10-2mol.l-1的原始浓度。每一浓度逐步用载体稀释得到10-3、10-4和10-5mol.l-1的浓度。将这些稀释液,包括原液,用于本试验(反应混合物的最终浓度分别为:3.10-3;10-3;3.10-4;10-4;3.10-5;10-5;3.10-6和10-6mol.l-1)。
步骤
室温下将0.075ml和0.025ml试验化合物或参照化合物溶液或载体交替地吸移到微量滴定平皿的孔中,并且这些溶液分别用0.115ml和0.0165ml TNP缓冲液稀释。将等量的0.030ml S-2238溶液加入每一孔中并将平皿预热,在恒温箱(Amersham)中于37℃下摇动预培养10分钟。在预培养之后向每一孔中加入0.030ml凝血酶溶液开始S-2238的水解。在37℃下将平皿培养(摇动,持续30秒)。开始培养1分钟之后,使用动力微量滴定平皿读数器(Twinreader plus,Flow Laboratories)每2分钟测定每一样品在405nm下的吸光度,持续90分钟。
使用LOTUS-MEASURE将所有数据收集在IBM个人计算机中。就每一化合物浓度(以mol.l-1反应混合物表示)和空白,将其吸光度相对反应时间(以分钟计)绘图。
反应的评价:对每一最终浓度由试验曲线计算其最大吸光度。使用如Hafner等的分对数转化分析(Arzneim.-Forsch./Drug Res.1977;27(II):1871-3)计算其IC50-值(最终浓度,以μmol.l-1表示,造成空白的最大吸光度的50%抑制)。
抗凝血酶活性:
实施例 | IC50(mol.l-1) |
1 | 0.03 |
2 | 0.14 |
3 | 0.13 |
4 | 0.12 |
5 | 0.29 |
Claims (9)
2、权利要求1的化合物,其中A是5-元环。
3、权利要求1的化合物,其中R2是环己基。
4、权利要求1的化合物,其中R3是H。
5、权利要求1的化合物,其中R1是环己基。
6、权利要求5的化合物,其中R1是环己基,R2是环己基,R3是H且A是5-元环。
7、一种药物组合物,含有权利要求1-6中任一的化合物和药用适宜的辅料。
8、权利要求1-6中任一的化合物,用于治疗。
9、权利要求1-6中任一的化合物用于生产用于治疗或预防凝血酶有关的疾病的药物的用途。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP00202491 | 2000-07-12 | ||
EP00202491.7 | 2000-07-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1441784A true CN1441784A (zh) | 2003-09-10 |
Family
ID=8171793
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN01812607A Pending CN1441784A (zh) | 2000-07-12 | 2001-07-09 | 含有氨基异喹啉基团的凝血酶抑制剂 |
Country Status (23)
Country | Link |
---|---|
US (1) | US6642253B2 (zh) |
EP (1) | EP1303491A1 (zh) |
JP (1) | JP2004502759A (zh) |
KR (1) | KR20030022270A (zh) |
CN (1) | CN1441784A (zh) |
AR (1) | AR029596A1 (zh) |
AU (1) | AU2001278476A1 (zh) |
BR (1) | BR0112338A (zh) |
CA (1) | CA2413035A1 (zh) |
CZ (1) | CZ200392A3 (zh) |
EC (1) | ECSP034422A (zh) |
HR (1) | HRP20030017A2 (zh) |
HU (1) | HUP0301258A2 (zh) |
IL (1) | IL153611A0 (zh) |
MX (1) | MXPA03000337A (zh) |
NO (1) | NO20030145D0 (zh) |
NZ (1) | NZ523553A (zh) |
PE (1) | PE20020209A1 (zh) |
PL (1) | PL359787A1 (zh) |
RU (1) | RU2003104017A (zh) |
SK (1) | SK322003A3 (zh) |
WO (1) | WO2002004423A1 (zh) |
ZA (1) | ZA200300080B (zh) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101511816B (zh) * | 2006-08-08 | 2013-01-02 | Msd欧斯股份有限公司 | 具有改善的生物利用度的氨基异喹啉凝血酶抑制剂 |
CN109810174A (zh) * | 2017-11-21 | 2019-05-28 | 首都医科大学 | 异喹啉-3-甲酰-TARGD(aa)aa, 其制备, 抗静脉血栓活性和应用 |
CN109810173A (zh) * | 2017-11-21 | 2019-05-28 | 首都医科大学 | 二氢异喹啉-3-甲酰-TARGD(aa)aa, 其制备, 抗静脉血栓活性和应用 |
CN109810172A (zh) * | 2017-11-21 | 2019-05-28 | 首都医科大学 | 异喹啉-3-甲酰-PARGD(aa)aa, 其制备, 抗静脉血栓活性和应用 |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HUP0400651A2 (hu) | 2000-11-07 | 2004-06-28 | Bristol-Myers Squibb Company | Szerin proteáz inhibitorokként alkalmazható savszármazékok és ezeket tartalmazó gyógyszerkészítmények |
US6906192B2 (en) | 2000-11-07 | 2005-06-14 | Bristol Myers Squibb Company | Processes for the preparation of acid derivatives useful as serine protease inhibitors |
PL2102164T3 (pl) * | 2006-12-27 | 2011-05-31 | Sanofi Aventis | Pochodne izochinoliny i izochinolinonu podstawione cykloalkiloaminami |
US7927378B2 (en) * | 2007-03-05 | 2011-04-19 | Scussel Sbj Systems, Llc | Vacuum assisted prosthetic sleeve and socket |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL123986A (en) * | 1997-04-24 | 2011-10-31 | Organon Nv | Medicinal compounds |
-
2001
- 2001-07-09 US US10/332,792 patent/US6642253B2/en not_active Expired - Fee Related
- 2001-07-09 HU HU0301258A patent/HUP0301258A2/hu unknown
- 2001-07-09 BR BR0112338-6A patent/BR0112338A/pt not_active IP Right Cessation
- 2001-07-09 SK SK32-2003A patent/SK322003A3/sk not_active Application Discontinuation
- 2001-07-09 NZ NZ523553A patent/NZ523553A/en unknown
- 2001-07-09 CN CN01812607A patent/CN1441784A/zh active Pending
- 2001-07-09 AU AU2001278476A patent/AU2001278476A1/en not_active Abandoned
- 2001-07-09 EP EP01956519A patent/EP1303491A1/en not_active Withdrawn
- 2001-07-09 RU RU2003104017/04A patent/RU2003104017A/ru not_active Application Discontinuation
- 2001-07-09 CZ CZ200392A patent/CZ200392A3/cs unknown
- 2001-07-09 WO PCT/EP2001/007887 patent/WO2002004423A1/en not_active Application Discontinuation
- 2001-07-09 KR KR10-2003-7000363A patent/KR20030022270A/ko not_active Application Discontinuation
- 2001-07-09 CA CA002413035A patent/CA2413035A1/en not_active Abandoned
- 2001-07-09 IL IL15361101A patent/IL153611A0/xx unknown
- 2001-07-09 MX MXPA03000337A patent/MXPA03000337A/es unknown
- 2001-07-09 JP JP2002509290A patent/JP2004502759A/ja not_active Withdrawn
- 2001-07-09 PL PL35978701A patent/PL359787A1/xx not_active Application Discontinuation
- 2001-07-10 PE PE2001000684A patent/PE20020209A1/es not_active Application Discontinuation
- 2001-07-11 AR ARP010103283A patent/AR029596A1/es not_active Application Discontinuation
-
2003
- 2003-01-03 ZA ZA200300080A patent/ZA200300080B/en unknown
- 2003-01-10 EC EC2003004422A patent/ECSP034422A/es unknown
- 2003-01-10 NO NO20030145A patent/NO20030145D0/no not_active Application Discontinuation
- 2003-01-10 HR HR20030017A patent/HRP20030017A2/hr not_active Application Discontinuation
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101511816B (zh) * | 2006-08-08 | 2013-01-02 | Msd欧斯股份有限公司 | 具有改善的生物利用度的氨基异喹啉凝血酶抑制剂 |
CN109810174A (zh) * | 2017-11-21 | 2019-05-28 | 首都医科大学 | 异喹啉-3-甲酰-TARGD(aa)aa, 其制备, 抗静脉血栓活性和应用 |
CN109810173A (zh) * | 2017-11-21 | 2019-05-28 | 首都医科大学 | 二氢异喹啉-3-甲酰-TARGD(aa)aa, 其制备, 抗静脉血栓活性和应用 |
CN109810172A (zh) * | 2017-11-21 | 2019-05-28 | 首都医科大学 | 异喹啉-3-甲酰-PARGD(aa)aa, 其制备, 抗静脉血栓活性和应用 |
CN109810173B (zh) * | 2017-11-21 | 2020-11-27 | 首都医科大学 | 二氢异喹啉-3-甲酰-TARGD(aa)aa,其制备,抗静脉血栓活性和应用 |
CN109810172B (zh) * | 2017-11-21 | 2021-01-01 | 首都医科大学 | 异喹啉-3-甲酰-PARGD(aa)aa,其制备,抗静脉血栓活性和应用 |
CN109810174B (zh) * | 2017-11-21 | 2021-01-01 | 首都医科大学 | 异喹啉-3-甲酰-TARGD(aa)aa,其制备,抗静脉血栓活性和应用 |
Also Published As
Publication number | Publication date |
---|---|
PL359787A1 (en) | 2004-09-06 |
ECSP034422A (es) | 2003-03-10 |
WO2002004423A9 (en) | 2003-05-15 |
ZA200300080B (en) | 2004-04-05 |
HUP0301258A2 (hu) | 2003-08-28 |
MXPA03000337A (es) | 2004-04-05 |
AR029596A1 (es) | 2003-07-02 |
IL153611A0 (en) | 2003-07-06 |
NO20030145L (no) | 2003-01-10 |
US6642253B2 (en) | 2003-11-04 |
NO20030145D0 (no) | 2003-01-10 |
BR0112338A (pt) | 2003-07-22 |
HRP20030017A2 (en) | 2003-04-30 |
SK322003A3 (en) | 2003-06-03 |
JP2004502759A (ja) | 2004-01-29 |
CA2413035A1 (en) | 2002-01-17 |
WO2002004423A8 (en) | 2003-03-06 |
RU2003104017A (ru) | 2004-08-20 |
PE20020209A1 (es) | 2002-03-19 |
EP1303491A1 (en) | 2003-04-23 |
AU2001278476A1 (en) | 2002-01-21 |
CZ200392A3 (cs) | 2003-05-14 |
WO2002004423A1 (en) | 2002-01-17 |
KR20030022270A (ko) | 2003-03-15 |
US20030166579A1 (en) | 2003-09-04 |
NZ523553A (en) | 2004-04-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0975353B1 (en) | Peptidyl-2-amino-1-hydroxyalkanesulfonic acid cysteine protease inhibitors | |
KR102558265B1 (ko) | 펩타이드 보레이트 에스테르류 화합물의 합성 및 용도 | |
JPH07509731A (ja) | トロンビン阻害剤としての置換されたフェニルアラニン誘導体のピペラジド | |
CN112592331B (zh) | 一种奥司他韦protac化合物及其制备方法与在抗流感病毒药物中的应用 | |
CN1072667C (zh) | 含咪唑取代基的巯基烷基肽基化合物及其用作基质金属蛋白酶(mmp)和/或肿瘤坏死因子(tnf)抑制剂 | |
EP1114024B1 (de) | Urokinase-inhibitoren | |
CN103387601B (zh) | 抗登革热病毒(denv)杂环肽类化合物及其制备方法和用途 | |
KR20240029066A (ko) | 케토아미드 유도체 및 이의 용도 | |
JPH05222005A (ja) | 3(s)−アミノ−4−シクロヘキシル−2(r)−ヒドロキシ酪酸若しくは4−シクロヘキシル−(2r,3s)−ジヒドロキシ酪酸又は関連類似体を含む環状レニン阻害剤 | |
CN109096219B (zh) | 一种新型抗pd-l1化合物、其应用及含其的组合物 | |
CN1441784A (zh) | 含有氨基异喹啉基团的凝血酶抑制剂 | |
CN1407989A (zh) | 抗血栓形成化合物 | |
CN101454309B (zh) | 焦谷氨酸衍生物的合成和用途 | |
TW515803B (en) | Thrombin inhibitors | |
CN101724016B (zh) | 一类肽化合物、其制备方法及用途 | |
KR100584032B1 (ko) | 항혈전제로서의 비스피페리딘 | |
CN103421083A (zh) | 具有1,2,3-三氮唑结构的抗登革热病毒杂环肽类化合物及其制备方法和用途 | |
CN102924567B (zh) | 一类肽化合物、其制备方法及用途 | |
CN101511816B (zh) | 具有改善的生物利用度的氨基异喹啉凝血酶抑制剂 | |
CN105524049A (zh) | 氘代的丙型肝炎病毒ns5a蛋白抑制剂 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |