JPS59204131A - 血栓症治療剤 - Google Patents
血栓症治療剤Info
- Publication number
- JPS59204131A JPS59204131A JP58075198A JP7519883A JPS59204131A JP S59204131 A JPS59204131 A JP S59204131A JP 58075198 A JP58075198 A JP 58075198A JP 7519883 A JP7519883 A JP 7519883A JP S59204131 A JPS59204131 A JP S59204131A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- reaction
- general formula
- compound
- 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.)
- Granted
Links
- 229960005356 urokinase Drugs 0.000 title abstract description 6
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- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 title abstract description 5
- 238000002360 preparation method Methods 0.000 title description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 37
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 24
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 19
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims abstract description 4
- 238000004519 manufacturing process Methods 0.000 claims description 21
- 238000009739 binding Methods 0.000 claims description 16
- 241000511343 Chondrostoma nasus Species 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 239000003463 adsorbent Substances 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 51
- 230000000694 effects Effects 0.000 abstract description 22
- 239000003527 fibrinolytic agent Substances 0.000 abstract description 12
- 239000007853 buffer solution Substances 0.000 abstract description 10
- 238000001179 sorption measurement Methods 0.000 abstract description 10
- 229940012957 plasmin Drugs 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 238000010521 absorption reaction Methods 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 102000009123 Fibrin Human genes 0.000 abstract 4
- 108010073385 Fibrin Proteins 0.000 abstract 4
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 abstract 4
- 229950003499 fibrin Drugs 0.000 abstract 4
- 125000004414 alkyl thio group Chemical group 0.000 abstract 2
- 125000002947 alkylene group Chemical group 0.000 abstract 2
- 125000002993 cycloalkylene group Chemical group 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 86
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- -1 methylene, ethylene, trimethylene, tetramethylene, pentamethylene Chemical group 0.000 description 54
- 238000000034 method Methods 0.000 description 50
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Natural products CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 41
- 239000002904 solvent Substances 0.000 description 41
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 37
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 34
- 238000003756 stirring Methods 0.000 description 34
- 239000000243 solution Substances 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 31
- 239000000872 buffer Substances 0.000 description 31
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 19
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 18
- 238000002835 absorbance Methods 0.000 description 18
- 239000003795 chemical substances by application Substances 0.000 description 17
- 235000018102 proteins Nutrition 0.000 description 17
- 229910052757 nitrogen Inorganic materials 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000007864 aqueous solution Substances 0.000 description 15
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 13
- 208000007536 Thrombosis Diseases 0.000 description 13
- 150000008065 acid anhydrides Chemical class 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000001816 cooling Methods 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 229960002317 succinimide Drugs 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 238000010898 silica gel chromatography Methods 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 229960000103 thrombolytic agent Drugs 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- 238000006297 dehydration reaction Methods 0.000 description 9
- 229920005654 Sephadex Polymers 0.000 description 8
- 239000012507 Sephadex™ Substances 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 239000002131 composite material Substances 0.000 description 8
- NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 8
- 150000007514 bases Chemical class 0.000 description 7
- 150000002170 ethers Chemical class 0.000 description 7
- 230000002101 lytic effect Effects 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 7
- 239000005711 Benzoic acid Substances 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 239000003513 alkali Substances 0.000 description 6
- 235000010233 benzoic acid Nutrition 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 238000009833 condensation Methods 0.000 description 6
- 230000005494 condensation Effects 0.000 description 6
- 230000018044 dehydration Effects 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000002798 polar solvent Substances 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 235000011118 potassium hydroxide Nutrition 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000011084 recovery Methods 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Inorganic materials [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- 230000002537 thrombolytic effect Effects 0.000 description 6
- 150000003923 2,5-pyrrolediones Chemical class 0.000 description 5
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 5
- 229920002684 Sepharose Polymers 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 5
- 235000011181 potassium carbonates Nutrition 0.000 description 5
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 206010062713 Haemorrhagic diathesis Diseases 0.000 description 4
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- 208000031169 hemorrhagic disease Diseases 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 150000002430 hydrocarbons Chemical class 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 4
- 239000011574 phosphorus Substances 0.000 description 4
- 229910052698 phosphorus Inorganic materials 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- 239000011736 potassium bicarbonate Substances 0.000 description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 235000017550 sodium carbonate Nutrition 0.000 description 4
- 239000012064 sodium phosphate buffer Substances 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 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 3
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- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- FRDYCXQDNBSHAL-UHFFFAOYSA-N acetic acid;chloroform;ethyl acetate Chemical compound CC(O)=O.ClC(Cl)Cl.CCOC(C)=O FRDYCXQDNBSHAL-UHFFFAOYSA-N 0.000 description 3
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- 125000004429 atom Chemical group 0.000 description 3
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- 210000004072 lung Anatomy 0.000 description 3
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- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
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- 239000011780 sodium chloride Substances 0.000 description 3
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- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 2
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- 241000283690 Bos taurus Species 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
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- OATSQCXMYKYFQO-UHFFFAOYSA-N S-methyl thioacetate Chemical compound CSC(C)=O OATSQCXMYKYFQO-UHFFFAOYSA-N 0.000 description 2
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
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- 239000003638 chemical reducing agent Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
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- SKCNIGRBPJIUBQ-UHFFFAOYSA-N chloroform;ethyl acetate Chemical compound ClC(Cl)Cl.CCOC(C)=O SKCNIGRBPJIUBQ-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
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- 238000006356 dehydrogenation reaction Methods 0.000 description 2
- 238000011033 desalting Methods 0.000 description 2
- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
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- 230000002140 halogenating effect Effects 0.000 description 2
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- 239000003112 inhibitor Substances 0.000 description 2
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-M lysinate Chemical compound NCCCCC(N)C([O-])=O KDXKERNSBIXSRK-UHFFFAOYSA-M 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
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- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
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Landscapes
- Enzymes And Modification Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58075198A JPS59204131A (ja) | 1983-04-28 | 1983-04-28 | 血栓症治療剤 |
| EP83111446A EP0109653A3 (en) | 1982-11-17 | 1983-11-15 | Process for preparing urokinase complex |
| US06/551,841 US4536391A (en) | 1982-11-17 | 1983-11-15 | Process for preparing urokinase complex |
| CA000441285A CA1212917A (en) | 1982-11-17 | 1983-11-16 | Process for preparing urokinase complex |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58075198A JPS59204131A (ja) | 1983-04-28 | 1983-04-28 | 血栓症治療剤 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS59204131A true JPS59204131A (ja) | 1984-11-19 |
| JPH0454648B2 JPH0454648B2 (enrdf_load_html_response) | 1992-08-31 |
Family
ID=13569255
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP58075198A Granted JPS59204131A (ja) | 1982-11-17 | 1983-04-28 | 血栓症治療剤 |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS59204131A (enrdf_load_html_response) |
-
1983
- 1983-04-28 JP JP58075198A patent/JPS59204131A/ja active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0454648B2 (enrdf_load_html_response) | 1992-08-31 |
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