JPS6237032B2 - - Google Patents
Info
- Publication number
- JPS6237032B2 JPS6237032B2 JP2257179A JP2257179A JPS6237032B2 JP S6237032 B2 JPS6237032 B2 JP S6237032B2 JP 2257179 A JP2257179 A JP 2257179A JP 2257179 A JP2257179 A JP 2257179A JP S6237032 B2 JPS6237032 B2 JP S6237032B2
- Authority
- JP
- Japan
- Prior art keywords
- guanidinobenzoyloxy
- acid
- addition salt
- acid addition
- guanidinobenzoic
- 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.)
- Expired
Links
- 239000002253 acid Substances 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 12
- FCEQRBOTYXIORK-UHFFFAOYSA-N 2-(diaminomethylideneamino)benzoic acid Chemical class NC(=N)NC1=CC=CC=C1C(O)=O FCEQRBOTYXIORK-UHFFFAOYSA-N 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- YFUQTMNUQVFBBS-UHFFFAOYSA-N (4-sulfamoylphenyl) 4-(diaminomethylideneamino)benzoate Chemical compound C1=CC(N=C(N)N)=CC=C1C(=O)OC1=CC=C(S(N)(=O)=O)C=C1 YFUQTMNUQVFBBS-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- YCMLQMDWSXFTIF-UHFFFAOYSA-N 2-methylbenzenesulfonimidic acid Chemical compound CC1=CC=CC=C1S(N)(=O)=O YCMLQMDWSXFTIF-UHFFFAOYSA-N 0.000 claims 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 239000013078 crystal Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- -1 That is Chemical group 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- CGQXODYXKCGVJV-UHFFFAOYSA-N 4-(diaminomethylideneamino)benzoyl chloride Chemical compound NC(N)=NC1=CC=C(C(Cl)=O)C=C1 CGQXODYXKCGVJV-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 102000004142 Trypsin Human genes 0.000 description 4
- 108090000631 Trypsin Proteins 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 229940012957 plasmin Drugs 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 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
- 229940079593 drug Drugs 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000012588 trypsin Substances 0.000 description 3
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- JBSRWFDTGDGNLG-UHFFFAOYSA-N 4-(diaminomethylideneamino)benzoyl chloride;hydrochloride Chemical compound Cl.NC(=N)NC1=CC=C(C(Cl)=O)C=C1 JBSRWFDTGDGNLG-UHFFFAOYSA-N 0.000 description 2
- SXTSBZBQQRIYCU-UHFFFAOYSA-N 4-guanidinobenzoic acid Chemical compound NC(=N)NC1=CC=C(C(O)=O)C=C1 SXTSBZBQQRIYCU-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- AGJQVFDKHHNRRR-UHFFFAOYSA-N 2-(diaminomethylideneamino)benzoyl chloride;hydrochloride Chemical compound Cl.NC(N)=NC1=CC=CC=C1C(Cl)=O AGJQVFDKHHNRRR-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- RHPDIBUPEZIAAU-UHFFFAOYSA-N 4-hydroxy-n-methylbenzenesulfonamide Chemical compound CNS(=O)(=O)C1=CC=C(O)C=C1 RHPDIBUPEZIAAU-UHFFFAOYSA-N 0.000 description 1
- DIRCLGLKRZLKHG-UHFFFAOYSA-N 4-hydroxybenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=C(O)C=C1 DIRCLGLKRZLKHG-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 206010033647 Pancreatitis acute Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- AAYFRLMXUYDMMG-UHFFFAOYSA-N [4-(butan-2-ylsulfamoyl)phenyl] 4-(diaminomethylideneamino)benzoate Chemical compound C1=CC(S(=O)(=O)NC(C)CC)=CC=C1OC(=O)C1=CC=C(NC(N)=N)C=C1 AAYFRLMXUYDMMG-UHFFFAOYSA-N 0.000 description 1
- JPGDBQMCMOHGJN-UHFFFAOYSA-N [4-(butylsulfamoyl)phenyl] 4-(diaminomethylideneamino)benzoate Chemical compound C1=CC(S(=O)(=O)NCCCC)=CC=C1OC(=O)C1=CC=C(NC(N)=N)C=C1 JPGDBQMCMOHGJN-UHFFFAOYSA-N 0.000 description 1
- BWRCEBPVDSZVAY-UHFFFAOYSA-N [4-(ethylsulfamoyl)phenyl] 4-(diaminomethylideneamino)benzoate Chemical compound C1=CC(S(=O)(=O)NCC)=CC=C1OC(=O)C1=CC=C(NC(N)=N)C=C1 BWRCEBPVDSZVAY-UHFFFAOYSA-N 0.000 description 1
- WCRUAZLSCNPINA-UHFFFAOYSA-N [4-(methylsulfamoyl)phenyl] 4-(diaminomethylideneamino)benzoate Chemical compound C1=CC(S(=O)(=O)NC)=CC=C1OC(=O)C1=CC=C(NC(N)=N)C=C1 WCRUAZLSCNPINA-UHFFFAOYSA-N 0.000 description 1
- RFJPPSBLGGVRSR-UHFFFAOYSA-N [4-(propan-2-ylsulfamoyl)phenyl] 4-(diaminomethylideneamino)benzoate Chemical compound C1=CC(S(=O)(=O)NC(C)C)=CC=C1OC(=O)C1=CC=C(NC(N)=N)C=C1 RFJPPSBLGGVRSR-UHFFFAOYSA-N 0.000 description 1
- LGAKPCIDNADZFK-UHFFFAOYSA-N [4-(propylsulfamoyl)phenyl] 4-(diaminomethylideneamino)benzoate Chemical compound C1=CC(S(=O)(=O)NCCC)=CC=C1OC(=O)C1=CC=C(NC(N)=N)C=C1 LGAKPCIDNADZFK-UHFFFAOYSA-N 0.000 description 1
- XDJGEDXMMDAWEY-UHFFFAOYSA-N [4-(tert-butylsulfamoyl)phenyl] 4-(diaminomethylideneamino)benzoate Chemical compound C1=CC(S(=O)(=O)NC(C)(C)C)=CC=C1OC(=O)C1=CC=C(NC(N)=N)C=C1 XDJGEDXMMDAWEY-UHFFFAOYSA-N 0.000 description 1
- BUNUZNQBNMBTOS-UHFFFAOYSA-N [4-[butyl(ethyl)sulfamoyl]phenyl] 4-(diaminomethylideneamino)benzoate Chemical compound C1=CC(S(=O)(=O)N(CC)CCCC)=CC=C1OC(=O)C1=CC=C(NC(N)=N)C=C1 BUNUZNQBNMBTOS-UHFFFAOYSA-N 0.000 description 1
- KFLPEURXZCBICA-UHFFFAOYSA-N [4-[butyl(methyl)sulfamoyl]phenyl] 4-(diaminomethylideneamino)benzoate Chemical compound C1=CC(S(=O)(=O)N(C)CCCC)=CC=C1OC(=O)C1=CC=C(NC(N)=N)C=C1 KFLPEURXZCBICA-UHFFFAOYSA-N 0.000 description 1
- FIUIYNYXJSAWSQ-UHFFFAOYSA-N [4-[butyl(propyl)sulfamoyl]phenyl] 4-(diaminomethylideneamino)benzoate Chemical compound C1=CC(S(=O)(=O)N(CCC)CCCC)=CC=C1OC(=O)C1=CC=C(NC(N)=N)C=C1 FIUIYNYXJSAWSQ-UHFFFAOYSA-N 0.000 description 1
- FPFWKTPKCHHPGK-UHFFFAOYSA-N [4-[ethyl(methyl)sulfamoyl]phenyl] 4-(diaminomethylideneamino)benzoate Chemical compound C1=CC(S(=O)(=O)N(C)CC)=CC=C1OC(=O)C1=CC=C(NC(N)=N)C=C1 FPFWKTPKCHHPGK-UHFFFAOYSA-N 0.000 description 1
- HETVLUQITRTHIO-UHFFFAOYSA-N [4-[ethyl(propan-2-yl)sulfamoyl]phenyl] 4-(diaminomethylideneamino)benzoate Chemical compound C1=CC(S(=O)(=O)N(C(C)C)CC)=CC=C1OC(=O)C1=CC=C(NC(N)=N)C=C1 HETVLUQITRTHIO-UHFFFAOYSA-N 0.000 description 1
- IILZPOAPVBXRBQ-UHFFFAOYSA-N [4-[ethyl(propyl)sulfamoyl]phenyl] 4-(diaminomethylideneamino)benzoate Chemical compound C1=CC(S(=O)(=O)N(CC)CCC)=CC=C1OC(=O)C1=CC=C(NC(N)=N)C=C1 IILZPOAPVBXRBQ-UHFFFAOYSA-N 0.000 description 1
- ZUMMMQAOCNLWOC-UHFFFAOYSA-N [4-[methyl(propan-2-yl)sulfamoyl]phenyl] 4-(diaminomethylideneamino)benzoate Chemical compound C1=CC(S(=O)(=O)N(C)C(C)C)=CC=C1OC(=O)C1=CC=C(NC(N)=N)C=C1 ZUMMMQAOCNLWOC-UHFFFAOYSA-N 0.000 description 1
- PBOIUCAZZXTWGD-UHFFFAOYSA-N [4-[methyl(propyl)sulfamoyl]phenyl] 4-(diaminomethylideneamino)benzoate Chemical compound C1=CC(S(=O)(=O)N(C)CCC)=CC=C1OC(=O)C1=CC=C(NC(N)=N)C=C1 PBOIUCAZZXTWGD-UHFFFAOYSA-N 0.000 description 1
- XPBLLVZUOYHPCC-UHFFFAOYSA-N [4-[propan-2-yl(propyl)sulfamoyl]phenyl] 4-(diaminomethylideneamino)benzoate Chemical compound C1=CC(S(=O)(=O)N(C(C)C)CCC)=CC=C1OC(=O)C1=CC=C(NC(N)=N)C=C1 XPBLLVZUOYHPCC-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 201000003229 acute pancreatitis Diseases 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000006704 dehydrohalogenation reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000031169 hemorrhagic disease Diseases 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 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
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明は医薬として有用な一般式〔〕
（式中、R1、R2は水素又は低級アルキル基を表わ
す。）
で示されるグアニジノ安息香酸誘導体の酸付加塩
に関する。
ここで一般式〔〕のＲが表わす低級アルキル
基の例としては、直鎖又は分枝鎖のアルキル基、
すなわちメチル基、エチル基、ｎ−プロピル基、
イソプロピル基、ｎ−ブチル基、sec−ブチル
基、tert−ブチル基などがあげられる。
本発明によれば前記一般式〔〕で示されるグ
アニジノ安息香酸誘導体の酸付加塩は一般式
〔〕
（式中、Ｘはハロゲン原子を表わす。）
で示される化合物の酸付加塩と一般式〔〕
（式中、R1、R2は前記と同じ意味を表わす。）
で示される化合物を不活性溶媒中、脱ハロゲン化
水素剤の存在下に−20℃ないし室温で１〜５時間
反応させることにより製造することができる。
上記の反応に用いることができる脱ハロゲン化
水素剤としては、例えばトリエチルアミン、トリ
−ｎ−ブチルアミン、Ｎ・Ｎ−ジメチルアニリ
ン、Ｎ−メチルピペリジン、ピリジン等の第三級
アミンがあげられる。溶媒としては、例えばベン
ゼン、トルエン、ジエチルエーテル、テトラヒド
ロフラン、ジオキサン、アセトン、アセトニトリ
ル、ピリジン等、あるいはこれらの二種以上の混
合溶媒があげられるが、なかでもピリジンは溶媒
としても又脱ハロゲン化水素剤としても作用する
点で好ましい。
反応生成物は酸付加塩の形で生成するので、そ
のまゝ単離してもよいし、あるいは、反応液、又
は反応溶媒を減圧留去した残留物、又は反応生成
物に不溶性な溶媒を反応液中に加えて大部分の溶
媒を除いた残留物に重炭酸ソーダの水溶液を加え
て析出する結晶を分取してもよい。
一般式〔〕で示される化合物の酸付加塩は必
要により薬理学的に許容され得る酸の酸付加塩に
たやすく変換することができる。このような酸と
しては、例えば塩酸、硫酸、リン酸、臭化水素
酸、硝酸などの無機酸、酢酸、乳酸、コハク酸、
酒石酸、リンゴ酸、クエン酸、ベンゼンスルホン
酸、トルエンスルホン酸、メタンスルホン酸など
の有機酸があげられる。
一般式〔〕で示される化合物の酸付加塩はｐ
−グアニジノ安息香酸から通常の方法で製造でき
る。例えば、チオニルクロライドと加温すること
によりｐ−グアニジノ安息香酸クロライドの塩酸
塩が得られ、これをこのまゝ次の反応に使用す
る。
本発明によつて得られる化合物はトリプシンや
プラスミンを阻害する作用を有しており、これら
の阻害作用は極めて低い濃度で強く現われた。
又本発明化合物は水に対する溶解性にもすぐれ
ており、薬物として、水溶液、生理食塩水、ブド
ウ糖液、その他の溶液で投与するのにも適してい
る。
インビトロ（in vitro）でのトリプシン及びプ
ラスミンの阻害作用を松村等の方法〔トリプシン
についてはザ・ジヤーナル・オブ・バイオケミス
トリー（The Journal of Biochemistry）、58、
214（1965）；プラスミンについては同誌、57、
402（1964）参照〕を用いて測定し、第一表に示
すような結果を得た。
The present invention has a general formula useful as a medicine. (In the formula, R 1 and R 2 represent hydrogen or a lower alkyl group.) The present invention relates to an acid addition salt of a guanidinobenzoic acid derivative represented by the following formula. Examples of the lower alkyl group represented by R in the general formula [] include linear or branched alkyl groups,
That is, methyl group, ethyl group, n-propyl group,
Examples include isopropyl group, n-butyl group, sec-butyl group, and tert-butyl group. According to the present invention, the acid addition salt of the guanidinobenzoic acid derivative represented by the general formula [] is the acid addition salt of the guanidinobenzoic acid derivative represented by the general formula [] (In the formula, X represents a halogen atom.) Acid addition salt of the compound represented by the general formula [] (In the formula, R 1 and R 2 have the same meanings as above.) Reacting the compound represented by the formula in an inert solvent in the presence of a dehydrohalogenating agent at -20°C to room temperature for 1 to 5 hours. It can be manufactured by Examples of the dehydrohalogenation agent that can be used in the above reaction include tertiary amines such as triethylamine, tri-n-butylamine, N.N-dimethylaniline, N-methylpiperidine, and pyridine. Examples of the solvent include benzene, toluene, diethyl ether, tetrahydrofuran, dioxane, acetone, acetonitrile, pyridine, etc., or a mixed solvent of two or more of these. Among them, pyridine is used both as a solvent and as a dehydrohalogenating agent. This is preferable in that it also acts as a catalyst. Since the reaction product is produced in the form of an acid addition salt, it may be isolated as is, or the reaction solution, the residue obtained by distilling off the reaction solvent under reduced pressure, or a solvent insoluble in the reaction product may be used for the reaction. The precipitated crystals may be collected by adding an aqueous solution of sodium bicarbonate to the residue obtained by removing most of the solvent from the solution. The acid addition salt of the compound represented by the general formula [] can be easily converted into an acid addition salt of a pharmacologically acceptable acid, if necessary. Examples of such acids include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, nitric acid, acetic acid, lactic acid, succinic acid,
Examples include organic acids such as tartaric acid, malic acid, citric acid, benzenesulfonic acid, toluenesulfonic acid, and methanesulfonic acid. The acid addition salt of the compound represented by the general formula [] is p
- Can be prepared from guanidinobenzoic acid by conventional methods. For example, by heating with thionyl chloride, the hydrochloride of p-guanidinobenzoic acid chloride is obtained, which is used as is in the next reaction. The compound obtained according to the present invention has the effect of inhibiting trypsin and plasmin, and these inhibitory effects were strongly manifested at extremely low concentrations. The compounds of the present invention also have excellent solubility in water, and are suitable for administration as drugs in aqueous solutions, physiological saline, glucose solutions, and other solutions. The inhibitory effects of trypsin and plasmin in vitro were determined by the method of Matsumura et al. [For trypsin, see The Journal of Biochemistry, 58 ;
214 (1965); about plasmin in the same magazine, 57 ;
402 (1964)], and the results shown in Table 1 were obtained.
【表】【table】
【表】
このように一般式〔〕で示されるグアニジノ
安息香酸誘導体の酸付加塩は蛋白分解酵素トリプ
シンやプラスミンを強力に阻害する作用を有して
おり急性膵炎等の治療用医薬としてあるいは抗プ
ラスミン剤として出血性疾患等の治療用医薬とし
て有用である。
本発明に含まれる一般式〔〕で示されるグア
ニジノ安息香酸誘導体の酸付加塩としては、
ｐ−（ｐ−グアニジノベンゾイルオキシ）−ベン
ゼンスルホンアミド、
ｐ−（ｐ−グアニジノベンゾイルオキシ）−Ｎ−
メチルベンゼンスルホンアミド、
ｐ−（ｐ−グアニジノベンゾイルオキシ）−Ｎ−
エチルベンゼンスルホンアミド、
ｐ−（ｐ−グアニジノベンゾイルオキシ）−Ｎ−
ｎ−プロピルベンゼンスルホンアミド、
ｐ−（ｐ−グアニジノベンゾイルオキシ）−Ｎ−
iso−プロピルベンゼンスルホンアミド、
ｐ−（ｐ−グアニジノベンゾイルオキシ）−Ｎ−
ｎ−ブチルベンゼンスルホンアミド、
ｐ−（ｐ−グアニジノベンゾイルオキシ）−Ｎ−
sec−ブチルベンゼンスルホンアミド、
ｐ−（ｐ−グアニジノベンゾイルオキシ）−Ｎ−
tert−ブチルベンゼンスルホンアミド、
ｐ−（ｐ−グアニジノベンゾイルオキシ）−Ｎ・
Ｎ−ジメチルベンゼンスルホンアミド、
ｐ−（ｐ−グアニジノベンゾイルオキシ）−Ｎ・
Ｎ−ジエチルベンゼンスルホンアミド、
ｐ−（ｐ−グアニジノベンゾイルオキシ）−Ｎ・
Ｎ−ジ−ｎ−プロピルベンゼンスルホンアミド、
ｐ−（ｐ−グアニジノベンゾイルオキシ）−Ｎ・
Ｎ−ジ−iso−プロピルベンゼンスルホンアミ
ド、
ｐ−（ｐ−グアニジノベンゾイルオキシ）−Ｎ・
Ｎ−ジ−ｎ−ブチルベンゼンスルホンアミド、
ｐ−（ｐ−グアニジノベンゾイルオキシ）−Ｎ−
メチル−Ｎ−エチルベンゼンスルホンアミド、
ｐ−（ｐ−グアニジノベンゾイルオキシ）−Ｎ−
メチル−Ｎ−ｎ−プロピルベンゼンスルホンアミ
ド、
ｐ−（ｐ−グアニジノベンゾイルオキシ）−Ｎ−
メチル−Ｎ−iso−プロピルベンゼンスルホンア
ミド、
ｐ−（ｐ−グアニジノベンゾイルオキシ）−Ｎ−
メチル−Ｎ−ｎ−ブチルベンゼンスルホンアミ
ド、
ｐ−（ｐ−グアニジノベンゾイルオキシ）−Ｎ−
エチル−Ｎ−ｎ−プロピルベンゼンスルホンアミ
ド、
ｐ−（ｐ−グアニジノベンゾイルオキシ）−Ｎ−
エチル−Ｎ−iso−プロピルベンゼンスルホンア
ミド、
ｐ−（ｐ−グアニジノベンゾイルオキシ）−Ｎ−
エチル−Ｎ−ｎ−ブチルベンゼンスルホンアミ
ド、
ｐ−（ｐ−グアニジノベンゾイルオキシ）−Ｎ−
ｎ−プロピル−Ｎ−iso−プロピルベンゼンスル
ホンアミド、
ｐ−（ｐ−グアニジノベンゾイルオキシ）−Ｎ−
ｎ−プロピル−Ｎ−ｎ−ブチルベンゼンスルホン
アミド、
ｐ−（ｐ−グアニジノベンゾイルオキシ）−Ｎ−
ｎ−ブチル−Ｎ−sec−ブチルベンゼンスルホン
アミド
などの酸付加塩が挙げられる。
次に実施例をあげて本発明を説明する。
実施例 １
ｐ−（ｐ−グアニジノベンゾイルオキシ）Ｎ・
Ｎ−ジメチルベンゼンスルホンアミド・メタン
スルホン酸塩の製造
ｐ−グアニジノ安息香酸2.7ｇにチオニルクロ
ライド25mlを加えて、70〜75℃で30分加熱撹拌
し、これに石油エーテルを加えて得られたｐ−グ
アニジノ安息香酸クロライド塩酸塩の結晶を取
し、石油エーテルで洗浄した。
Ｎ・Ｎ−ジメチル−ｐ−ビドロキシベンゼンス
ルホンアミド3.0ｇをピリジン20mlにとかし、先
に得たｐ−グアニジノ安息香酸クロライドの結晶
を０℃で加えて２時間撹拌した。反応液に飽和の
重炭酸ソーダ水溶液を加え、析出して来た結晶を
取し、水、アセトンで洗浄乾燥した。この結晶
をメタノールに懸濁させ、メタンスルホン酸を加
えて溶解させ、過後、液にエーテルを加え
た。析出した結晶を取し、乾燥させた後、ジメ
チルホルムアミドから再結晶して標題化合物2.75
ｇを得た。
融点：211〜213℃。
元素分析値：C16H18N4O4SCH3SO3Hとして
Ｃ Ｈ Ｎ Ｓ
計算値（％） 41.91 3.96 12.22 13.98
実測値（％） 42.22 3.74 12.47 14.19。
実施例 ２
ｐ−（ｐ−グアニジノベンゾイルオキシ）Ｎ−
メチルベンゼンスルホンアミド・メタンスルホ
ン酸塩の製造
実施例１と同様にして、ｐ−グアニジノ安息香
酸4.48ｇからｐ−グアニジノ安息香酸クロライド
塩酸塩を製造した。Ｎ−メチル−ｐ−ヒドロキシ
ベンゼンスルホンアミド4.68ｇをピリジン32mlに
とかし、先に得たｐ−グアニジノ安息香酸クロラ
イドの結晶を０℃で加えそのまゝ２時間撹拌し
た。この後は実施例１の如く後処理と再結晶を行
ない、標題化合物3.89ｇを得た。
融点：220〜223℃。
元素分析値：C15H16N4O4SCH3SO3Hとして
Ｃ Ｈ Ｎ Ｓ
計算値（％） 40.53 3.63 12.61 14.43
実測値（％） 40.71 3.90 12.44 14.65。
実施例 ３
ｐ−（ｐ−グアニジノベンゾイルオキシ）−ベン
ゼンスルホンアミドメタンスルホン酸塩の製造
実施例１と同様にしてｐ−グアニジノ安息香酸
3.58ｇからｐ−グアニジノ安息香酸クロライド塩
酸塩を製造した。
ｐ−ヒドロキシベンゼンスルホンアミド3.46ｇ
をピリジン26mlにとかし、先に得たｐ−グアニジ
ノ安息香酸クロライドの結晶を室温で加え、その
まゝ２時間撹拌した。この後は実施例１の如く後
処理と再結晶を行ない標題化合物3.87ｇを得た。
融点：225℃以上。
元素分析値：C14H14N4O4SCH3SO3Hとして
Ｃ Ｈ Ｎ Ｓ
計算値（％） 39.06 3.28 13.02 14.90
実測値（％） 39.23 3.06 13.15 14.81。[Table] The acid addition salt of the guanidinobenzoic acid derivative represented by the general formula [] has the effect of strongly inhibiting proteolytic enzymes trypsin and plasmin, and is used as a drug for the treatment of acute pancreatitis etc. It is useful as a drug for treating bleeding disorders and the like. Acid addition salts of guanidinobenzoic acid derivatives represented by the general formula [] included in the present invention include p-(p-guanidinobenzoyloxy)-benzenesulfonamide, p-(p-guanidinobenzoyloxy)-N-
Methylbenzenesulfonamide, p-(p-guanidinobenzoyloxy)-N-
Ethylbenzenesulfonamide, p-(p-guanidinobenzoyloxy)-N-
n-propylbenzenesulfonamide, p-(p-guanidinobenzoyloxy)-N-
iso-propylbenzenesulfonamide, p-(p-guanidinobenzoyloxy)-N-
n-Butylbenzenesulfonamide, p-(p-guanidinobenzoyloxy)-N-
sec-Butylbenzenesulfonamide, p-(p-guanidinobenzoyloxy)-N-
tert-Butylbenzenesulfonamide, p-(p-guanidinobenzoyloxy)-N.
N-dimethylbenzenesulfonamide, p-(p-guanidinobenzoyloxy)-N.
N-diethylbenzenesulfonamide, p-(p-guanidinobenzoyloxy)-N.
N-di-n-propylbenzenesulfonamide, p-(p-guanidinobenzoyloxy)-N.
N-di-iso-propylbenzenesulfonamide, p-(p-guanidinobenzoyloxy)-N.
N-di-n-butylbenzenesulfonamide, p-(p-guanidinobenzoyloxy)-N-
Methyl-N-ethylbenzenesulfonamide, p-(p-guanidinobenzoyloxy)-N-
Methyl-N-n-propylbenzenesulfonamide, p-(p-guanidinobenzoyloxy)-N-
Methyl-N-iso-propylbenzenesulfonamide, p-(p-guanidinobenzoyloxy)-N-
Methyl-N-n-butylbenzenesulfonamide, p-(p-guanidinobenzoyloxy)-N-
Ethyl-N-n-propylbenzenesulfonamide, p-(p-guanidinobenzoyloxy)-N-
Ethyl-N-iso-propylbenzenesulfonamide, p-(p-guanidinobenzoyloxy)-N-
Ethyl-N-n-butylbenzenesulfonamide, p-(p-guanidinobenzoyloxy)-N-
n-propyl-N-iso-propylbenzenesulfonamide, p-(p-guanidinobenzoyloxy)-N-
n-propyl-N-n-butylbenzenesulfonamide, p-(p-guanidinobenzoyloxy)-N-
Examples include acid addition salts such as n-butyl-N-sec-butylbenzenesulfonamide. Next, the present invention will be explained with reference to Examples. Example 1 p-(p-guanidinobenzoyloxy)N.
Production of N-dimethylbenzenesulfonamide methanesulfonate 25 ml of thionyl chloride was added to 2.7 g of p-guanidinobenzoic acid, heated and stirred at 70 to 75°C for 30 minutes, and petroleum ether was added to the resulting p. - Crystals of guanidinobenzoic acid chloride hydrochloride were collected and washed with petroleum ether. 3.0 g of N.N-dimethyl-p-hydroxybenzenesulfonamide was dissolved in 20 ml of pyridine, and the previously obtained crystals of p-guanidinobenzoic acid chloride were added at 0°C, followed by stirring for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the precipitated crystals were collected, washed with water and acetone, and dried. The crystals were suspended in methanol, methanesulfonic acid was added to dissolve them, and after filtration, ether was added to the solution. The precipitated crystals were collected, dried, and recrystallized from dimethylformamide to give the title compound 2.75.
I got g. Melting point: 211-213℃. Elemental analysis value: C 16 H 18 N 4 O 4 SCH 3 SO 3 H Calculated value (%) 41.91 3.96 12.22 13.98 Actual value (%) 42.22 3.74 12.47 14.19. Example 2 p-(p-guanidinobenzoyloxy)N-
Production of methylbenzenesulfonamide methanesulfonate In the same manner as in Example 1, p-guanidinobenzoic acid chloride hydrochloride was produced from 4.48 g of p-guanidinobenzoic acid. 4.68 g of N-methyl-p-hydroxybenzenesulfonamide was dissolved in 32 ml of pyridine, and the previously obtained crystals of p-guanidinobenzoic acid chloride were added at 0°C, followed by stirring for 2 hours. Thereafter, post-treatment and recrystallization were carried out as in Example 1 to obtain 3.89 g of the title compound. Melting point: 220-223℃. Elemental analysis value: C 15 H 16 N 4 O 4 SCH 3 SO 3 H Calculated value (%) 40.53 3.63 12.61 14.43 Actual value (%) 40.71 3.90 12.44 14.65. Example 3 Production of p-(p-guanidinobenzoyloxy)-benzenesulfonamide methanesulfonate p-guanidinobenzoic acid in the same manner as in Example 1
p-guanidinobenzoic acid chloride hydrochloride was produced from 3.58 g. p-hydroxybenzenesulfonamide 3.46g
was dissolved in 26 ml of pyridine, the crystals of p-guanidinobenzoic acid chloride obtained earlier were added at room temperature, and the mixture was stirred for 2 hours. Thereafter, post-treatment and recrystallization were carried out as in Example 1 to obtain 3.87 g of the title compound. Melting point: 225℃ or higher. Elemental analysis value: C 14 H 14 N 4 O 4 SCH 3 SO 3 H Calculated value (%) 39.06 3.28 13.02 14.90 Actual value (%) 39.23 3.06 13.15 14.81.
Claims (1)
す。） で示されるグアニジノ安息香酸誘導体の酸付加
塩。 ２ ｐ−（ｐ−グアニジノベンゾイルオキシ）−
Ｎ・Ｎ−ジメチルベンゼンスルホンアミドの酸付
加塩である特許請求の範囲第１項記載の化合物。 ３ ｐ−（ｐ−グアニジノベンゾイルオキシ）−Ｎ
−メチルベンゼンスルホンアミドの酸付加塩であ
る特許請求の範囲第１項記載の化合物。 ４ ｐ−（ｐ−グアニジノベンゾイルオキシ）−ベ
ンゼンスルホンアミドの酸付加塩である特許請求
の範囲第１項記載の化合物。[Claims] 1. General formula [] (In the formula, R 1 and R 2 represent hydrogen or a lower alkyl group.) An acid addition salt of a guanidinobenzoic acid derivative represented by the following formula. 2 p-(p-guanidinobenzoyloxy)-
The compound according to claim 1, which is an acid addition salt of N.N-dimethylbenzenesulfonamide. 3 p-(p-guanidinobenzoyloxy)-N
- The compound according to claim 1, which is an acid addition salt of methylbenzenesulfonamide. 4. The compound according to claim 1, which is an acid addition salt of p-(p-guanidinobenzoyloxy)-benzenesulfonamide.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2257179A JPS55115865A (en) | 1979-03-01 | 1979-03-01 | Guanidinobenzoic acid derivative and its preparation |
| GB8003854A GB2044760B (en) | 1979-03-01 | 1980-02-05 | Guanidinobenzoic acid derivatives |
| DE19803005580 DE3005580A1 (en) | 1979-03-01 | 1980-02-14 | GUANIDINOBENZOESAE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE DERIVATIVES |
| US06/123,609 US4283418A (en) | 1979-03-01 | 1980-02-22 | Guanidinobenzoic acid derivatives and process for their preparation |
| FR8004573A FR2450251A1 (en) | 1979-03-01 | 1980-02-29 | GUANIDINOBENZOIC ACID DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2257179A JPS55115865A (en) | 1979-03-01 | 1979-03-01 | Guanidinobenzoic acid derivative and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS55115865A JPS55115865A (en) | 1980-09-06 |
| JPS6237032B2 true JPS6237032B2 (en) | 1987-08-10 |
Family
ID=12086555
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2257179A Granted JPS55115865A (en) | 1979-03-01 | 1979-03-01 | Guanidinobenzoic acid derivative and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS55115865A (en) |
-
1979
- 1979-03-01 JP JP2257179A patent/JPS55115865A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS55115865A (en) | 1980-09-06 |
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