TW214542B - - Google Patents
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- TW214542B TW214542B TW081102613A TW81102613A TW214542B TW 214542 B TW214542 B TW 214542B TW 081102613 A TW081102613 A TW 081102613A TW 81102613 A TW81102613 A TW 81102613A TW 214542 B TW214542 B TW 214542B
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- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 239000000203 mixture Substances 0.000 claims description 23
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- XFZYPCNLVHSQTG-UHFFFAOYSA-N 2,2,5,7,8-pentamethyl-3,4-dihydrochromene Chemical compound C1CC(C)(C)OC2=C(C)C(C)=CC(C)=C21 XFZYPCNLVHSQTG-UHFFFAOYSA-N 0.000 claims 1
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical group C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 claims 1
- BEZDDPMMPIDMGJ-UHFFFAOYSA-N pentamethylbenzene Chemical group CC1=CC(C)=C(C)C(C)=C1C BEZDDPMMPIDMGJ-UHFFFAOYSA-N 0.000 claims 1
- 125000003386 piperidinyl group Chemical group 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 9
- 238000002360 preparation method Methods 0.000 abstract description 3
- MVTHUEOHHHQQKY-QMMMGPOBSA-N (2s)-2-(diaminomethylideneamino)-3-phenylpropanoic acid Chemical class NC(N)=N[C@H](C(O)=O)CC1=CC=CC=C1 MVTHUEOHHHQQKY-QMMMGPOBSA-N 0.000 abstract description 2
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 23
- 239000002253 acid Substances 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000002904 solvent Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- -1 amidine phenylalanine derivative Chemical class 0.000 description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 108090000790 Enzymes Proteins 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 8
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 8
- 229940088598 enzyme Drugs 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 229910052704 radon Inorganic materials 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 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 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- LYUQWQRTDLVQGA-UHFFFAOYSA-N 3-phenylpropylamine Chemical compound NCCCC1=CC=CC=C1 LYUQWQRTDLVQGA-UHFFFAOYSA-N 0.000 description 5
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 108010080798 N(alpha)-(2-naphthylsulfonylglycyl)-4-amidinophenylalanine piperidide Proteins 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 230000015271 coagulation Effects 0.000 description 5
- 238000005345 coagulation Methods 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- 239000004471 Glycine Substances 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 235000014676 Phragmites communis Nutrition 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 229940024606 amino acid Drugs 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 125000006239 protecting group Chemical class 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- JZRWCGZRTZMZEH-UHFFFAOYSA-N Thiamine Natural products CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 description 3
- 208000007536 Thrombosis Diseases 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 239000003146 anticoagulant agent Substances 0.000 description 3
- 229940127219 anticoagulant drug Drugs 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 150000002429 hydrazines Chemical class 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 230000014508 negative regulation of coagulation Effects 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 3
- 235000019157 thiamine Nutrition 0.000 description 3
- 229960003495 thiamine Drugs 0.000 description 3
- 239000011721 thiamine Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-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
- 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 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 244000062793 Sorghum vulgare Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 description 2
- 108090000190 Thrombin Proteins 0.000 description 2
- 229940122388 Thrombin inhibitor Drugs 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 150000001409 amidines Chemical class 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000023555 blood coagulation Effects 0.000 description 2
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 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
- 238000005336 cracking Methods 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- RWRIWBAIICGTTQ-UHFFFAOYSA-N difluoromethane Chemical compound FCF RWRIWBAIICGTTQ-UHFFFAOYSA-N 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000009434 installation Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000012022 methylating agents Substances 0.000 description 2
- 235000019713 millet Nutrition 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- ZNSWGHZWUUFFKV-UHFFFAOYSA-N piperidine;pyridine Chemical compound C1CCNCC1.C1=CC=NC=C1 ZNSWGHZWUUFFKV-UHFFFAOYSA-N 0.000 description 2
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 229960002429 proline Drugs 0.000 description 2
- ODLMAHJVESYWTB-UHFFFAOYSA-N propylbenzene Chemical compound CCCC1=CC=CC=C1 ODLMAHJVESYWTB-UHFFFAOYSA-N 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 150000003385 sodium Chemical class 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 229960004072 thrombin Drugs 0.000 description 2
- 239000003868 thrombin inhibitor Substances 0.000 description 2
- 239000000052 vinegar Substances 0.000 description 2
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- YESKNMSFHFWRFK-VIFPVBQESA-N (2s)-2-(cyanoamino)-3-phenylpropanoic acid Chemical class N#CN[C@H](C(=O)O)CC1=CC=CC=C1 YESKNMSFHFWRFK-VIFPVBQESA-N 0.000 description 1
- DWAOJPAYQGHHCY-LBPRGKRZSA-N (2s)-2-[cyano-[(2-methylpropan-2-yl)oxycarbonyl]amino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N(C#N)[C@H](C(O)=O)CC1=CC=CC=C1 DWAOJPAYQGHHCY-LBPRGKRZSA-N 0.000 description 1
- VJZRBVVLWLEXBB-VROPFNGYSA-N (2s)-n-[(2s)-5-(diaminomethylideneamino)-1-(4-nitroanilino)-1-oxopentan-2-yl]-1-[2-[(4-methylphenyl)sulfonylamino]acetyl]pyrrolidine-2-carboxamide;hydrochloride Chemical compound Cl.C1=CC(C)=CC=C1S(=O)(=O)NCC(=O)N1[C@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)NC=2C=CC(=CC=2)[N+]([O-])=O)CCC1 VJZRBVVLWLEXBB-VROPFNGYSA-N 0.000 description 1
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 1
- ZXNLLCMBYJJEQH-UHFFFAOYSA-N (4-nitrophenyl) n-[(2-methylpropan-2-yl)oxycarbonylamino]carbamate Chemical compound CC(C)(C)OC(=O)NNC(=O)OC1=CC=C([N+]([O-])=O)C=C1 ZXNLLCMBYJJEQH-UHFFFAOYSA-N 0.000 description 1
- WEEGYLXZBRQIMU-UHFFFAOYSA-N 1,8-cineole Natural products C1CC2CCC1(C)OC2(C)C WEEGYLXZBRQIMU-UHFFFAOYSA-N 0.000 description 1
- ICPVFOAWQNIBBW-UHFFFAOYSA-N 1-(bromomethyl)-4-propylbenzene Chemical compound CCCC1=CC=C(CBr)C=C1 ICPVFOAWQNIBBW-UHFFFAOYSA-N 0.000 description 1
- QSQAJROSUUVDOG-UHFFFAOYSA-N 1H-pyrimidine-2,4-dione urea Chemical compound NC(N)=O.O=C1C=CNC(=O)N1 QSQAJROSUUVDOG-UHFFFAOYSA-N 0.000 description 1
- HFFXLYHRNRKAPM-UHFFFAOYSA-N 2,4,5-trichloro-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C(=CC(Cl)=C(Cl)C=2)Cl)=N1 HFFXLYHRNRKAPM-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- JTNCEQNHURODLX-UHFFFAOYSA-N 2-phenylethanimidamide Chemical compound NC(=N)CC1=CC=CC=C1 JTNCEQNHURODLX-UHFFFAOYSA-N 0.000 description 1
- ZSLUVFAKFWKJRC-IGMARMGPSA-N 232Th Chemical compound [232Th] ZSLUVFAKFWKJRC-IGMARMGPSA-N 0.000 description 1
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- WFFZGYRTVIPBFN-UHFFFAOYSA-N 3h-indene-1,2-dione Chemical class C1=CC=C2C(=O)C(=O)CC2=C1 WFFZGYRTVIPBFN-UHFFFAOYSA-N 0.000 description 1
- PQFLLHLQSUSCJW-UHFFFAOYSA-N 4-(3-aminopropyl)benzenecarboximidamide Chemical compound NCCCC1=CC=C(C(N)=N)C=C1 PQFLLHLQSUSCJW-UHFFFAOYSA-N 0.000 description 1
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
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- 229930182832 D-phenylalanine Natural products 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
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- 229910052693 Europium Inorganic materials 0.000 description 1
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Classifications
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/62—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by hydrogenation of carbon-to-carbon double or triple bonds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Chemical Kinetics & Catalysis (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)
- Pharmacology & Pharmacy (AREA)
- Diabetes (AREA)
- Hematology (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)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Peptides Or Proteins (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
- Pyrrole Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Medicines Containing Plant Substances (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
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- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
Λ 6 Η6 五、發明説明（1 ) 請先閱誚背而之注意事項再填寫本頁) 本發明僳鼷於脒基苯基丙胺酸衍生物，其製法，用 途及含有此等化合物之轚藥組成物。 如已知，數種病理情況會引起抗凝血素III (AT工工工， 係I臟中賴要濟！J)之減少會弓馳程形成之樹楚性增娜爲已^ *如 具有AT III之先天缺陷之情況，當其降低到正常值之 75X則會有血栓併發症之後果。此種併發症經常在手術 後出現散佈性血管内凝血之情形，及呈現休克之狀態。 在許多情況下，會發生有生命威脅性之血凝塊，至於血 栓形成疾病之治療舆預防，直到目前像於醫第中使用具 有不同作用方式之抗凝血劑，至於血栓危險之急性控制 ，已使用如AT III,肝素及最近之水姪素等物質，長期 性預防亦已使用香豆素及茚滿二酮衍生物進行，.然而， — .- 在某些情況下，該抗凝血_會受到影留，因而有相當多 缺黏。 例如，肝素由於其多醣結構，僅能以爾腸外投藥， 經濟部十央標準局A工消"合作社印製 且其作用亦随著功能性抗凝血素III之量而異；香豆素 則直接妨礙蛋白質之生物合成，而使得與維他命K-相藺 之凝血因子II, VII, IX及X不再合宜可用，因而降低凝 血能力，由此，使凝血作用産生暫時延遲，已知之副作 用有出血性皮虜顔死^反胃及掉髮。 相對照下，低分子量凝血酶抑制爾之優點為其可採 輔助因子無關的方式，藉著直接與活性中心结合而直接 - 3 - 81. 4. 10,000張（H) 本紙張尺度逍用中國《家標毕(CNS) 1M規怙(2丨0x297公龙) 濟 -:!μ 屮 央 1% ζ Λ 6 Β6 五、發明説明（2 ) 作用在凝血酶上，因而可遮斷酵素；由於其化學结構， 此等物質可採口服投藥而立邸發揮其作用。 以精胺酸或脒苯基丙胺酸為主之胺基酸衍生物已逹 到特殊效用，第一組包含化合物，如D-苯基丙胺醒基--L-脯胺醒基精胺酸醛及（2R, 4R)-4-甲基-：l-[H2-(3-甲 基-1,2,3,4-四氫-8-喹琳磺醯基"L-精胺醯基]-4-晡啶羧 酸單水合物）”MD 805”）。MD 805亦為治療性使用之競争 性特異凝血酶抑制剤；另外，已知之脒苯基丙胺酸衍生 物為冷-萘基磺匿基甘胺醯基-R,S-4-脒苯基丙胺醯基瞞 啶（NAPAP),歐洲專利第0236163號及歐洲專利第 0236164號曾敘述NAPA8之衍生物，在此等衍生物中，甘 桉酸被NH2 -CHIU -C00H結構之胺基酸所取代，其中IU為 低级烷基，低级羥烷基，苯基或4-羥苯基。4-脒苯基丙 按酸（Aph)可被N-甲基化，得到N-甲基-Aph。此外，對 於NAPAP在芳磺匿基，”橋聯”甘胺酸，及眤啶琛上之多 種衍生作用也有敍述；最適k者傈在端之α-或/3-萘 磺醯基上之衍生作用，但雜芳磺醯基，如8-喹啉磺醛基 則不佳。在疏水性萘基與ΑρΗ間有橋胼構件之天然胺基 酸之缺點為：盤胺鍵對Aph之酵素性裂解，缺點在以口服 投藥之情況下恃別具有彩鬱性。然而，以其他橘聯構件 如冷-丙胺酸代替甘胺酸之置換，會引起凝血酶抑制作 用之活性明顯喪失，甚至，以亞胺酸如脯胺酸之置換亦 -4 - (請先閲讀背而之注意事項#填寫本頁) 裝· 4張尺度边用中8國家楳準（(：旧）'?4規格（2丨0父297公;《:) 81. 4. 10,000¾ (II) A 6 Η 6 五、發明説明（）3 會引起作用之喪失。 因此本發明之目的傜提供以脒苯基丙胺酸為主之新 穎化合物，其抗凝血活性比己知化合物優異，且在改良 耐久性之同時具有高的酵素抗性。 、 因此本發明傜關於式I之化合物。 H-f
R3 (i) (請先閲-ift背而之注龙事項#塡寫木頁) 裝· 訂- 經濟部屮央楛準局β工消#合作社印製 式中R1為一種萘基或苯基，可被含有速3值磺原子 之1到3値烷氧基，或被含有1或2倨硪原子，逹5個 烷基所衍生，或是為一種色谋基，其可被逹5值甲基所 衍生； R1為氫，具有逹4餹硪原子之低级烷基，羥烷基， 具有連7傾硪原子之芳烷基，或具有逹4傾磺原子之羧 烷基； H2及R3為相同或相異，且分別代表具有逹4儲磺原 子之烷基，其中ft2及R3可與氮原子合而形成一環，此琛 可被羧基.羥基或逹3艏硪原子之羥烷基所衍生； -5 - 本紙張尺度边用中a Η家標準(CNS)T4規格（210><297公；!1:) 81· 4. ]0,000張（1|) 五、發明説明（4) *表示存在在R或S結構，但以R結構較佔優勢。 與已知結構基本上不同處為R1所鍵結之原子傜以氮 原子取代碩原子。 NAPAP具有下列結構： 、
令人驚奇的是：在NAPAP中以氰雜胺基酸殘基置換 甘胺酸可能會增加抗凝血活；氮雜胺基酸殘基為可以下 式表示之已知化合物： 0 (請先閱讀背而之注意事項抖项筠本頁) 經濟部中央標準局A工消费合作社印製
氮雜胺基酸之结構性要素造成上述I中所示之結構。 其特殊處為：/9-萘磺酵基氮雜甘胺匿基-D-脒苯基 丙胺酵基脈啶之活性較甘胺酸化合物超過5倍，m雜胺 基酸與式I中疏水性殘基R1之組合可生成|^及c50值在 本紙5JL尺度逍用中a S家楳毕（CNS) T4規怙（210X297公*) 81. 4. 10,000¾ (II) 經濟部中央#準局貝工消1\-'合作社印製 A 6 B 6 五、發明説明（5 ) 撤微莫耳範圍内之化合物，含有氰雜胺基酸之化合物對 酵素降解具有抗性，因此本發明化合物之特徵除了增強 作用外，並且會增加安定性。 本發明之化合物可藉本身己為習知的方法製備，例 如，Houben-wey1之"Methoden der organischen chemie”（有機化學方法），第15卷（1+2), Georg Thieme Verlag Stuttgart, 1974,或 Erich Wunsch 於 PharBazie 39, 228 (1984)中所述之方法製備。 較佳為使Boc-氰苯基丙胺酸先與”胺成份”偶合，所 使用之胺成份為環狀胺，例如，哌啶，甲基脈啶或羥甲 基脈啶較佳，胜肽鍵傜以一般榡準方法産生，較佳為與 硝二醯亞胺，在羥苯并三唑存在下，於二甲基甲匿胺或 與其相當之溶剤中進行反應。將Η- α -保護之化合物單 離後，在本例中之B0C基，此保護基藉酸解法除去，為 了進行此步聚，若在溶剤如二氯甲烷中之時，俱使用三 氣醑酸進行裂解較佳，若在黯酸中則使用氯化氫較佳。 氰雜胺基酸之偶合亦可以本身爲已知之方法進行， 例如活化酯法，其中經保護之肼衍生物與氣甲酸酯反應 ，得到活化酶，尤其是使用對-硝基苯基酯，至於另外之可 能路徑為使氰苯基之胺基以肼衍生物活化，得到異臍酸 ，以便能進行随後之可能反慝。反應期間，胼之Ηβ官能 性以已知之保護基保護，為連此目的，使用苄氣羰基， 私紙張尺度边用中國《家標毕（CNS)T4規格（210x297公;jt) 81. 4. 10,000¾ (II) (請先閲讀背而之注意事項#堝窩木頁) 裝· 經濟部屮央橾準而β工消#合作社印51 6 五、發明説明（） 尤其是特是特丁氣羰基。保護基以酸解裂解後，於溶劑（ 如四氫呋喃，二鸣烷，二氣甲烷或DMF)中之芳香族或雜 環磺醯氯，會與添加之齡（如N -甲基嗎啉，三乙胺或二異 丙基乙胺）偶合，然而.，先使磺醯氣衍生物與胼衍生物 \ 偶合較有利，如此，可避免導入保護基。氰基轉化成脒 基官能基可藉已知之反應步驟進行，較佳於三乙胺/吡 啶中，使對應氰苯基丙胺酸之衍生物以硫化氫處理數天 ，將以此方法所形成之硫醒胺單離，並以甲基化劑（ 如甲基碘）將其轉化成硫醯亞胺甲酯化合物；以銨化合 物（如醋酸銨）處理，較佳為在作為溶劑之甲醇中進行 ，可«得目標之醯胺基苯基丙胺酸化合物。 此等化合物可藉習用的方法純化，較佳為使用於如 RSephadex LH_2〇之物質上之凝擊滲析色層分析法，或 於如CM繼維素等物質上之其他離子交換色層分析法，並 以使用醮酸邇缓衝液尤佳。本發明之化合物可藉薄層色 層分析法及HPLC純化而確定，確定方法係以元素分析及 NMR檢測。 本發明之抑制劑偽依據評估其活性之各種榡準而檢 測，較佳係以活體外或活體內之κί鐵1C 50值或部份凝血酶原 激酶時間（ΡΤΤ)而決定。因此所申_之化合物為具有特 異性且具有高度活性之凝血抑制劑，其抗凝血酶能力明 顯地比目前已知之低分子量抑制劑還要高。 A 6 It 6 (請先閲誚背而之注意事項#填¾本頁) 裝. 訂- 線. 本紙張尺度边用中® Η家標毕（CNS)IM規格（210x297公仗） 81. 4. 10,000張（II) 五、發明説明（7) Λ 6 η 6 上合 有化 含些 且這 並 ， , 且 用並 作’ 血物 凝成 抗組 有療 具治 8或 一 物 關成 有组 為斷 亦診 明之 發劑 本制 抑 述. 的 面 方 、 躲 藥 0 之 性 活 血 凝 抗 備 製 為 作 或 劑 斷 診 為 作 〇 是途 物用 明 發 本 述 敘 地 細 詳 更 將 例 施 實 列 下 (請先閲誚背而之注意事項#填筠木頁) 經濟部屮央標準局只工消赀合作杜印製 9 本紙張尺度边用中as家徉毕（CNS)^N規格（210x297公*) 81. 4. 10,000¾ (II) Λ 6 Π 6 經濟部中央楳準局β工消伢合作社印奴 五、發明説明（8 ) 實施例1 /3-萘磺睡基氰雜甘胺睡基-D-對-脒基苯基丙胺醯基眤 啶 l.Boc-Ό-對氡基苯基丙胺酵基脲啶。 、 50克（255毫某耳）對-気基苯甲基溴，55克（255毫其 耳）乙醯胺基丙二酸二乙酯及2克碘化鉀，在250毫升無 水二啤烷中加熱至沸騰，以3小時時間，將新裂備之含 6克（260毫莫耳）納之乙'醇溶液逐滴加到混合物中，迴 流下使其沸腾超過3小時後，使混合物冷卻到80¾，並 以3小時時間，加入170毫升之氫《化納溶液，-合物 加熱至95T4小時，冷卻後，以6NHC1調整至pH值為1 , 並蒸除二噚烷，濾除任何沈積之沈澱物，将混合物以氫氣 化納溶液諝整至pH值為9 ,並且以B酸乙酯萃取2次， 水相再以鹽酸調整至pH值為1,此時结晶析出N-乙酵基 氣苯基丙胺酸，收集此晶體，以水清洗數次，並於高真 空中進行乾燥，産率：47克（理論值79.2X)。 純度拥試：TLC Rf =0.5(氛仿50/甲酵10/冰醋酸2.5份體 積）〇 添加3N氫氣化納溶液使24克此産物溶於3升水中， 並且將pH值諝整到6-6.5,添加500萆克醯基酶到混合物 中，並於37¾中培餐4天，之後，以超過濾法将溶液中 之睡基酶除去，體積瀑縮成1升，pH值諝整到1之後， -10 - (請先閲讀背而之注意事項#填寫本頁) 裝- 訂_ 線· 本紙張尺度边用中a Β家楳毕（CNS) Ή規格（210X297公放） 81. 4. 10,000張（II) 修正補充 曰 A 6 B6 五、發明説明（9) 專利申請案第81 102613號 ROC Patent Appln Ho. 81 102613 _正及補充之中文說明書第a至i7.; —附件二 ^Aaended/Supplemented pages of the Chines^ Specification - End. II T民國S2年6 S丨（曰送S) (Subaitted on June (^. 1993) 混合物以醋酸乙酯萃取敦次，有榇祎以少量砻氛化筘溶 液洗综，並且以碇薛鈉乾燥之，蒸除溶割，得到8.2芫N- 乙窖基-D-氡苯基丙胺酸〔理論值之8 2¾ )。 - ‘將含冇22毫升冰醋酸及4.3毫升滢登酸之40毫升水 加到8克之此化合物中，使混合物加熱沸賸24小時，蒸 除裂解溶液後，隨後以甲醇吸附少量之酸蓀，此D-氰苯基 丙胺酸鹽酸鹽產物被溶解並且由甲醇/乙醚中再沈裔出來 產率：6.6克（理論值的85%)。 5克D-気苯基丙胺酸發酸發溶於14毫升水中，竝添 加7.5¾升二異·丙基乙胺，於混合物中添加含6芫第三丁 氣羰基羥亞胺基-2-苯基乙腈之17毫升二哼烷溶液，並 搔拌隔夜'添加40毫升水及50毫升醋酸乙酷，分ϋ出水 相，且有機相再以1Η硪酸氫羿萃取，合拼之水相再以 1〇毫升乙醚清洗，接著以鹽酸謓整MpH 3 ,使甭醛酸 乙醱進行萃取3次，有機相以氣化筘溶液清洗，以硫酸 •I舅乾燥，蒸除溶劑後，得5.6克（785：)Boc-D-氰苯基丙按 酸。 3.26克（10毫克耳）.日〇(：-刀-氡苯基丙按恝，1.49芫 (1:毫荚互）刊3了及2.42克（12毫荚耳）〇(：[：1浩於50毫升 -11 - (請先Μ讀背面之注意事項再塡寫本頁)
J .裝. -1Τ. ά· 本紙張又度適用中國因家標準（CNS)甲4規格（2W X 2m ) 82.3. 40,000 Λ 6 Β6 82.U 5 五、發明説明（ DMF ,溶液搜拌1小時，添加1毫升六氢吡啶，且混合 锪溲拌隔夜，濾除沈餒之二環己基脬，殘留物溶於醋酸 乙酯中，溶液以碩諉氫鉀清洗3次，以1M硫酸氢羿清淀 S次途以飽合氛化鈉溶掖清洗3次/便后硫裔筘乾燥有 接相後，以蒸揺移除溶劑，得3.16克（30WB〇c-D-氰苯 基丙胺藍基哌啶。 純度檢査：TLC Rf =0· 27 (氣仿） 、 2. D-氡苯基丙胺S基六氫吡啶留酸鹽 3克Boc-保護之化合容於50毫升之1. 2 HHC1之冰 醋裔中，混合物在室溫搜拌30分鐘，於真空中蒸除裂解 試劑，隨後以甲苯帶走溶劑，殘留物以少量乙醚分散， 收集结晶並於真空中乾燥，産率：2.2克。 3. Boc-氮雜甘胺酋基-D-氰苯基丙胺苣基六氫吡啶
Boc-気雜甘胺酸-對-硝基苯酯冬製備： 1.32克的胼基甲酸第三-丁酯和2.02克的氯甲酸對-硝基苯酯一起溶解在25毫升的四氫呋喃，並加入1.1毫升 的H-甲基嗎福啉。 將該混合物攙拌1小時並過濾，於真空中蒸除溶劑， 所得油性殘餘物則收集於乙酸乙酯並用5% ^JKHS(U溶液 萃取3次後M Ha2S〇4乾燥之。在除去溶劑後，得到2.4 克的Boc-氮雜甘胺酸-4-硝基苯酯。 -12 - 82.3. 40,000 (請先閱讀背面之注意事項再塡寫本頁) 丨裝· .ΤΓ. 經濟部中央標準局KK工消费/6'17杜印製 214542 82. 6. A 6 B6 經濟部中央標準局員工消f<6'作钍印髮 五、發明説明（，） 1 1 2.0 8克〔7毫克耳）8〇£：-氮雜甘技酸-對-碴基安篚及 2.06克（7¾莫耳）像宏基丙胺藍基六氫吡啶溶於50¾升 DMF,添加2.4毫升（14毫莫耳）二異丙基乙胺後，混合物 在室S暗處摄拌1天，真空中蒸除溶劑，殘留物吸酧於 葭荽乙醏中，溶疲以1M硫酸氢鉀清洗3次，以碩登氫鈣 Ϊ5寂清浣3次，且思邊氯化鈉溶液清洗2次，有樘稆以碇 薛銪乾燥，Μ蒸除溶劑，殘音物二異丙醚中摄拌，牧集 结晶竝乾烽，得2.29克8〇(：-気雜甘胺§基-0-氡苯基丙 菝莛基六氫ffli啶。 4.;3 -萘礒g基氮雜甘胺藍基-D-氣苯基丙胺莛基六氫吡 啶 2 . 0 8克（5毫莫耳）B 〇 c -氮雜甘胺薛基-D-氡苯基丙K 莛基六氫吡啶溶於50毫开之1.2N HC1之冰舘酸中，混合 窃在室S摄拌30分鐘，蒸除分裂試劑且隨後於真空中以 曱苯帶定後，殘萤物分散於匿中，並收集结晶，结晶藉 著添笳1.7毫升U0毫莫耳）二異丙基乙胺而溶於50毫弁、 二氯曱烷中，添加1.134克/3-萘道藍氯於混合窃，竝在 室适庚拌隔夜，以蒸围蒸除溶劑，殘留物吸.附於諳葭乙 趋=,溶寂以1 MS酸氫鋅溶液清洗3次，以碩荽g鈣溶 菝清浣3次，以蒺氯化佾溶液清洗2.次，有捷相在茳爵 -13 - (請先閲讀背面之注意事項再塡寫本頁) .裝- -π. ·ν. 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297 乂贷） 82.3. 40,000 Λ6 B6 經濟部中央標準局MK工消费合作社印紫 五、發明説明（ 鈷上乾燥，益蒸除溶劑，得1.75克/5萘磺藍基気雜甘按 莒基-D-m苯基丙胺匿基六氫吡啶。 5./3 -萘袭室基氮雜甘胺莛基-D-脖基苯基丙胺藍基六氫 …吡啶 - 1芫上違4中所得化合物溶於30毫升無水吡啶中，添 加1毫幵三乙按後，通入碇化氫氣韹3小時，在室溫靜 置3天後，溶疲铛入100芫冰及50毫升濃窆薛之混合物 ，以拮氣邊3沈葜锪，益以水洗狺，乾烽後，硫趦胺吸 衔於50毫幵丙弱中，旦溶液以1.5毫升甲基磅處理，在 迺流下煮荐30分窆，冷卽後，使周乙醚進行沈澱，沈葑 物溶於二氮曱烷Μ以水清洗2次，有榇相以硫酸鈉乾燥 ,竝移除溶筘後，殘昔岔吸附於30毫升無水曱薛中，並 添加200毫芫醋薛兹，茬合物在60它加熱3小時，宾空 中蒸除¥萄，産岔於^Sephadex !>ϋ-2〇上於曱醇中進行 層析连化： 産率：590¾克 - 铊度撿査：熔點1§2艺 TCL:Rf=c.4S(氛彷50 /曱P10 /沐薛酸2.5份證積） 、 驗證：分子量澍定（快速原子撞鼕）MH+ 523 由氰基官能基反瞜生成脒基官能基之解說： (請先閱讀背面之注意事項再埃窝本頁) i 丨裝. 訂. .%. 本紙張尺度適用中國國家標準（CNS)甲4規格X 297 U釐） 82.3. 40,000 經濟却中央揉準局8工消費4--作社印f 3l^42 一 . __:… '_Β6 五、發明説明（13_) 令氟基基團在鹼性溶液中（即砒啶加上三乙胺）*舆碇 化氫反睫生成一硫代亞胺部分，亦邸將碇化氫加成至該三 鍵。當甲基化試劑（例如甲基碘）加入時，該硫原子®被甲 基化。該甲基化碇可被一胺基基圍取代，在實例中其係藉 醋酸较之添加而完成，如此即形成一脒基部分。 萁施钶2 Pac-氮雜苜菝莛基->對脒基苯基丙胺蓖基晡啶 步毖1-3與前逾貢例相同 4. Pnc -氣雜Η按藍基-D -氡苯基P3胺酸Π浪症 1.67克（4毫其耳）Boc-氮雜甘胺薛基.-D-m苯基丙胺 莛基睬啶溶於50毫升之1.2N HCr冰醋酸中，混合物在室 溫摄捽30分羞，蒸除裂解試劑，·且隨後於真空中將其 — · 以曱苯帶定後，使殘留物分散於驗中，並牧集结晶，结 晶S添加1.36毫牙（8毫莫耳）二異P3基乙按ΓΤΠ溶於50毫 升二氣曱烷中，添加1.35克Pec氣化物於混合物中，並 在室适赍拌隔夜，殘昔物吸陪於醋酸乙酯中，旦溶液以 1-M硫笤氫弄溶寂清洗3次，以碩酸氫鉀溶液清浣3次， 以邊氯化鈷溶液清洗2次，有様相於硫酸鈉上乾燥並蒸 除溶劑，得1.95克P me-氮雜甘胺薛基-D-氡.苯基丙胺薛 基六氳社啶。 5. P:=c-m荽芑技卺基-.D-牌苯基丙胺藍基六氫也啶 1 . 5更二S 4宁f3/! ?寻化三培於J 〇笔ΤΓ焦广、二κ —-L5.- <請先閱讀背面之注意事項再填寫本頁) -裝. 訂. ',丨.% 本纸張尺度適用中國國家標準（CNS)甲4規格ί210 X 297公坌） 82.3. 40,000 214542 . H6 級濟部中央標準局Rx;r.f-6'作社印製 五、發明說明（1¾. ，添Sin毫开三乙胺後，通入硫化氫氣饈3小時，在室 溫靜置3天後，溶液街入100克冰與50毫升濃登酸之混 合物中，以拮氣過涟沈裔物，並以水清洗，乾燥後，硫 匿胺吸闲··於50毫升丙围中，並以1.5毫升甲基碘處理， 混合物於迺流下煮滂30分羞，冷卻後，使用乙链進行沈 箬，沈笤物溶於二氛曱烷中，並以水清洗2次，有捺雇 以碇登筘乾燥並移除溶劑後，殘留物吸附於30萆升無水 甲醇中，並添加300毫克篚酸玆，混合物在60 Ό加熱3 小時，真空中蒸除溶劑，産物於RSephadex LH-20上於 甲醇中進行層析純化，産率：990毫克，纯度檢査：熔點 149-1551 (镜结程，薛酸留） 1：(^:砑=0..52(氣仿50/曱酵10/冰酯蝥2.5份證積） 凝血薛抑刳作用之ICs〇值測定： 諸化合物以渐增之邊度，與人頚凝血酶於0.1M tris-HCl 缓衝掖/0.15M HaCl pH 8.2 中培 W, 1 小時後 ,S 添加基苣 ChromozyaRTli (Tos-Gly-Pr〇-A「s-pHA, 5 x 1〇15 H/I)閤始進行酵索反塵，1小時後於光度計 中在405 ΠΒ渐增東密度下測量pHA之釋出，於酵素活性 中引起50¾抑制作后之抑制劑盎度定為IC5〇 (.100S相對於 未捽制之酵索反匯）。 芾砑究之化合物Ki值傜使罔上逑凝血薛溶液測定， 為了道行澍定，屘S薛以约相葑於上述渕試所決定4之 〜16.— (請先«讀背面之注意事項再填寫本頁) 裝. 訂. 線， 未纸張尺度適用中园國家標準（CNS)甲4規格（21U X 297 H ) 82.3. 40,000 214542 。...... Β6 五、發明説明（15) IC 5Q值之抑詞劑邊度培冒，以各種邊度之基質 Chromozym TH (0.7-45 X 1〇15 m〇l/l)開始進行反惠， 以LineweaYer及Burk(美囯化學培會期刊，56，β58_ 666，1934)所述方法測定抑制型態及Ki值。 、 表1 (請先閱讀背面之注意事項再填寫本頁) 化 合 物.
Pmc-Gly-Aph-Pz.p Nas-AGly-Aph-?zp Pmc-AGly-Aph-rip NAPAP 凝血薛抑制作Μ IC«0 (mol/1) Kx (rnol/1) 1.4 x l〇'9 1-3 x 10*9 1.3 x l〇"3 2.6 x 10'9 1.6 x 10'12 9.2 x 10"11 2.8 x l〇'9 1.4 x 10"9 經濟部中央標準局員工消費合作社印紫 绖寫：
Boc:第三丁氣蒙基 ' TLC :苒層色層分析
Rf :蒱留傜敦 HOBt:翔苯并三睦 DCC Γ:二環己基頊二适亞胺 DHF :二甲基曱藍按
Pmc : 2,2,5,7,δ-五曱基色滿-6-磺藍基 17. 本紙張尺度適用中國國家標準（CN’S)甲4規格ί2】0 X 297 ί.·：坌） 82.3. 40,000
Claims (1)
- A7 B7 C7 D7 t)曰送呈） 30 , 1993) 六、申請專利範圍 專利申請茱第81 102613號 ROC Patent Appln No. 81 102613 修正之申請專利範圍中文本-附件（一） AmendedriTl a ins—ΠΓ Th Tnlbse : _ Enel. I (民團82¾年平7玥3 補无 (SubW-i 11θd -·»»J-ui» - 1. 一種如下列結構式（I )所示之化合物 (請先閲讀背面之注意事項再填寫本頁)ί£濟部中央標準局8工消費合作社印κ 式中R’為一種荼基或苯基，或是為一種色滿基，其可被 至多逹5個甲基所取代； R2與R3與氮原子一起形成一六氫吡啶環； *表示以R或S結構存在，MR结構較優。 2.如申請專利範圍第1項之化合物，其中R’為/3-蔡基· 且R2與R3共同生成六氫毗啶。 -18- 93-9behr i n.740-L 本紙張尺度適用中國國家標準（CNS)甲4规格（210 X 297公釐） A7 B7 C7 D7 六、申請專利範圍 3. 如申請專利範圍第1項之化合物，其中R’為2,2,5,7,8-五甲基色滿，且R2與R3共同生成六氫毗啶。 4. 如申請專利範圍第i項之化合物，其中R’為五甲基苯基 •及R2與R3共同生成毗啶。 · 5. —種具有抗擬血活性的轚藥組成物，其係包含如申請專 利範圍第1項的化合物。 丨裝------訂— l·---Z (請先閲讀背面之注意事項再塡寫本頁) 經濟部中央標準局員工消費合作社印製 -19 - 本纸張尺度適用中國國家標準（CNS)甲4规格（210 X 297公釐）
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4111394A DE4111394A1 (de) | 1991-04-09 | 1991-04-09 | Amidinophenylalaninderivate, verfahren zu deren herstellung, deren verwendung und diese enthaltende mittel |
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| Publication Number | Publication Date |
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| TW214542B true TW214542B (zh) | 1993-10-11 |
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| TW081102613A TW214542B (zh) | 1991-04-09 | 1992-04-07 |
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| US (1) | US5274098A (zh) |
| EP (1) | EP0508220B1 (zh) |
| JP (1) | JPH0597793A (zh) |
| KR (1) | KR920019738A (zh) |
| CN (1) | CN1067431A (zh) |
| AT (1) | ATE125549T1 (zh) |
| AU (1) | AU650526B2 (zh) |
| BG (1) | BG60683B1 (zh) |
| BR (1) | BR9201253A (zh) |
| CA (1) | CA2065585A1 (zh) |
| CS (1) | CS106492A3 (zh) |
| DE (2) | DE4111394A1 (zh) |
| DK (1) | DK0508220T3 (zh) |
| ES (1) | ES2076595T3 (zh) |
| FI (1) | FI921525A (zh) |
| GR (1) | GR3017107T3 (zh) |
| HU (1) | HUT65359A (zh) |
| IE (1) | IE67347B1 (zh) |
| IL (1) | IL101529A (zh) |
| MA (1) | MA22495A1 (zh) |
| MX (1) | MX9201642A (zh) |
| NO (1) | NO921382L (zh) |
| NZ (1) | NZ242246A (zh) |
| PL (1) | PL294148A1 (zh) |
| RO (1) | RO109197B1 (zh) |
| TW (1) | TW214542B (zh) |
| UY (1) | UY23395A1 (zh) |
| ZA (1) | ZA922535B (zh) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
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| DE4115468A1 (de) * | 1991-05-11 | 1992-11-12 | Behringwerke Ag | Amidinophenylalaninderivate, verfahren zu deren herstellung, deren verwendung und diese enthaltende mittel als antikoagulantien |
| DE4242655A1 (de) * | 1992-12-17 | 1994-06-23 | Behringwerke Ag | Verwendung von Thrombin-Inhibitoren zur Inhibition okularer Fibrinbildung |
| DE4342154A1 (de) * | 1993-12-10 | 1995-06-14 | Behringwerke Ag | Amidinophenylalaninderivate, Verfahren zu deren Herstellung, deren Verwendung und diese enthaltende Mittel als Antikoagulantien |
| AU3107795A (en) * | 1994-08-09 | 1996-03-07 | Pentapharm Ag | Inhibitors of the benzamidine type |
| US5525617A (en) * | 1994-08-24 | 1996-06-11 | Merck & Co., Inc. | Fibrinogen receptor antagonists |
| DE19517198C1 (de) * | 1995-05-11 | 1996-10-10 | Samson Ag | Verfahren zur Führung der Hubstellung eines Stellgliedes |
| US5766932A (en) * | 1995-12-20 | 1998-06-16 | Hoechst Marion Roussel, Inc. | Process for preparing N-acetyl(L)-4-cyanophenylalanine from a mixture of the corresponding D,L ethyl esters using subtilisin |
| US5840733A (en) * | 1996-07-01 | 1998-11-24 | Redcell, Canada, Inc. | Methods and compositions for producing novel conjugates of thrombin inhibitors and endogenous carriers resulting in anti-thrombins with extended lifetimes |
| KR19990074598A (ko) * | 1998-03-12 | 1999-10-05 | 성재갑 | 고체상 반응을 이용한 벤즈아미딘 유도체의 신규한 제조방법 |
| ATE497385T1 (de) | 2000-08-18 | 2011-02-15 | Ajinomoto Kk | Neue phenylalanin-derivate |
| SI21137A (sl) * | 2002-01-24 | 2003-08-31 | LEK, tovarna farmacevtskih in kemičnih izdelkov, d.d. | Derivati azafenilalanina |
| DE10330900B4 (de) * | 2003-07-01 | 2006-09-14 | Leibniz-Institut Für Polymerforschung Dresden E.V. | Biomaterial mit einem modularen Beschichtungssystem zur Anwendung in Medizinprodukten mit direktem Blutkontakt |
| AU2004303696B2 (en) * | 2003-12-22 | 2011-03-31 | Ea Pharma Co., Ltd. | Novel phenylalanine derivative |
| EP1827446A4 (en) | 2004-12-06 | 2011-01-12 | Siga Technologies Inc | SULFONYL SEMICARBAZIDES, SEMICARBAZIDES AND URETINS, PHARMACEUTICAL COMPOSITIONS THEREOF AND METHOD FOR TREATING HEMORRHAGIC FEVER VIRUSES, INCLUDING INFECTIONS WITH ARENA VIRUSES |
| US8410149B2 (en) | 2004-12-06 | 2013-04-02 | Siga Technologies Inc. | Sulfonyl semicarbazides, semicarbazides and ureas, pharmaceutical compositions thereof, and methods for treating hemorrhagic fever viruses, including infections associated with arenaviruses |
| US7994221B2 (en) | 2004-12-06 | 2011-08-09 | Siga Technologies, Inc. | Sulfonyl semicarbazides, carbonyl semicarbazides, semicarbazides and ureas, pharmaceutical compositions thereof, and methods for treating hemorrhagic fever viruses, including infections associated with arenaviruses |
| CN101034257B (zh) * | 2007-04-06 | 2010-09-08 | 上海复旦天臣新技术有限公司 | 用于全息记录的感光薄膜及其制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4028380A (en) * | 1974-06-01 | 1977-06-07 | Akzona Incorporated | Hydrazino-imidazole derivatives |
| DD155954B1 (de) * | 1981-02-03 | 1988-11-09 | Wagner Guenter | Verfahren zur herstellung von n tief alpha arly-bzw. n tief alpha heteroarylsulfonylaminoacylierten amidinophenylalaninamiden |
| DD235866B1 (de) * | 1985-03-29 | 1988-12-28 | Univ Leipzig | Verfahren zur herstellung von n alpha (2-naphthyl)-sulfonylaminoacylierten amidinophenylalanisamiden |
| PT84170B (pt) * | 1986-01-24 | 1989-03-30 | Sanofi Sa | Processo para a preparacao de derivados n alfa-substituidos das n alfa-aril-sulfonilaminoacil d-amidinofenil-alaninamidas |
| PT84171B (pt) * | 1986-01-24 | 1989-03-30 | Sanofi Sa | Processo para a preparacao de derivados das n alfa-aril-sulfonilamiminoacil-p- -amidinofenil-alaninamidas, bem como dos seus derivados de sintese e das composicoes farmaceuticas que os contem |
-
1991
- 1991-04-09 DE DE4111394A patent/DE4111394A1/de not_active Withdrawn
-
1992
- 1992-03-25 DE DE59203006T patent/DE59203006D1/de not_active Expired - Fee Related
- 1992-03-25 EP EP92105138A patent/EP0508220B1/de not_active Expired - Lifetime
- 1992-03-25 DK DK92105138.9T patent/DK0508220T3/da active
- 1992-03-25 ES ES92105138T patent/ES2076595T3/es not_active Expired - Lifetime
- 1992-03-25 AT AT92105138T patent/ATE125549T1/de not_active IP Right Cessation
- 1992-04-02 BG BG96171A patent/BG60683B1/bg unknown
- 1992-04-06 UY UY23395A patent/UY23395A1/es unknown
- 1992-04-06 NZ NZ242246A patent/NZ242246A/en unknown
- 1992-04-07 CN CN92102446A patent/CN1067431A/zh active Pending
- 1992-04-07 TW TW081102613A patent/TW214542B/zh active
- 1992-04-07 RO RO92-200477A patent/RO109197B1/ro unknown
- 1992-04-07 US US07/864,547 patent/US5274098A/en not_active Expired - Fee Related
- 1992-04-07 MA MA22776A patent/MA22495A1/fr unknown
- 1992-04-07 FI FI921525A patent/FI921525A/fi not_active Application Discontinuation
- 1992-04-08 JP JP4085807A patent/JPH0597793A/ja active Pending
- 1992-04-08 AU AU14703/92A patent/AU650526B2/en not_active Ceased
- 1992-04-08 NO NO92921382A patent/NO921382L/no unknown
- 1992-04-08 PL PL29414892A patent/PL294148A1/xx unknown
- 1992-04-08 ZA ZA922535A patent/ZA922535B/xx unknown
- 1992-04-08 CS CS921064A patent/CS106492A3/cs unknown
- 1992-04-08 HU HU9201189A patent/HUT65359A/hu unknown
- 1992-04-08 KR KR1019920005804A patent/KR920019738A/ko not_active Application Discontinuation
- 1992-04-08 IE IE921123A patent/IE67347B1/en not_active IP Right Cessation
- 1992-04-08 IL IL10152992A patent/IL101529A/en not_active IP Right Cessation
- 1992-04-08 BR BR929201253A patent/BR9201253A/pt not_active Application Discontinuation
- 1992-04-08 CA CA002065585A patent/CA2065585A1/en not_active Abandoned
- 1992-04-09 MX MX9201642A patent/MX9201642A/es not_active IP Right Cessation
-
1995
- 1995-08-11 GR GR950402218T patent/GR3017107T3/el unknown
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