JPH0522706B2 - - Google Patents
Info
- Publication number
- JPH0522706B2 JPH0522706B2 JP17392284A JP17392284A JPH0522706B2 JP H0522706 B2 JPH0522706 B2 JP H0522706B2 JP 17392284 A JP17392284 A JP 17392284A JP 17392284 A JP17392284 A JP 17392284A JP H0522706 B2 JPH0522706 B2 JP H0522706B2
- Authority
- JP
- Japan
- Prior art keywords
- reaction
- compound
- formula
- group
- benzothiazolyl
- 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 - Lifetime
Links
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 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
- 238000006243 chemical reaction Methods 0.000 description 33
- 150000001875 compounds Chemical class 0.000 description 26
- -1 methoxy, ethoxy, propoxy, isopropoxy, butoxy Chemical group 0.000 description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 238000000921 elemental analysis Methods 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 4
- 102000016349 Myosin Light Chains Human genes 0.000 description 4
- 108010067385 Myosin Light Chains Proteins 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000003793 antidiarrheal agent Substances 0.000 description 4
- 229940125714 antidiarrheal agent Drugs 0.000 description 4
- 210000004204 blood vessel Anatomy 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 3
- OPRJGGPLBMHEQK-UHFFFAOYSA-N 2-(1,3-benzothiazol-2-yl)benzenesulfonamide Chemical class S1C(=NC2=C1C=CC=C2)C2=C(C=CC=C2)S(=O)(=O)N OPRJGGPLBMHEQK-UHFFFAOYSA-N 0.000 description 3
- XBHOUXSGHYZCNH-UHFFFAOYSA-N 2-phenyl-1,3-benzothiazole Chemical class C1=CC=CC=C1C1=NC2=CC=CC=C2S1 XBHOUXSGHYZCNH-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 108091000080 Phosphotransferase Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 3
- 230000008602 contraction Effects 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 102000020233 phosphotransferase Human genes 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000002040 relaxant effect Effects 0.000 description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 2
- 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 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- 208000014644 Brain disease Diseases 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical group C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 210000003975 mesenteric artery Anatomy 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000003449 preventive effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000013049 sediment Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- RLFXFUXPVGYCSU-UHFFFAOYSA-N 2-(2,3-dimethoxyphenyl)-1,3-benzothiazole Chemical compound COC1=CC=CC(C=2SC3=CC=CC=C3N=2)=C1OC RLFXFUXPVGYCSU-UHFFFAOYSA-N 0.000 description 1
- UAKADWQYPAMUOJ-UHFFFAOYSA-N 2-(2-methoxyphenyl)-1,3-benzothiazole Chemical compound COC1=CC=CC=C1C1=NC2=CC=CC=C2S1 UAKADWQYPAMUOJ-UHFFFAOYSA-N 0.000 description 1
- MXZROAOUCUVNHX-UHFFFAOYSA-N 2-Aminopropanol Chemical compound CCC(N)O MXZROAOUCUVNHX-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005806 3,4,5-trimethoxybenzyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1C([H])([H])* 0.000 description 1
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- KNLCRNWJXCLJHQ-UHFFFAOYSA-N 3-(4-phenylpiperazin-1-yl)propan-1-amine Chemical compound C1CN(CCCN)CCN1C1=CC=CC=C1 KNLCRNWJXCLJHQ-UHFFFAOYSA-N 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- UTBULQCHEUWJNV-UHFFFAOYSA-N 4-phenylpiperidine Chemical compound C1CNCCC1C1=CC=CC=C1 UTBULQCHEUWJNV-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010004016 Bacterial diarrhoea Diseases 0.000 description 1
- 102000005701 Calcium-Binding Proteins Human genes 0.000 description 1
- 108010045403 Calcium-Binding Proteins Proteins 0.000 description 1
- 206010008132 Cerebral thrombosis Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 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
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 206010015719 Exsanguination Diseases 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 201000001429 Intracranial Thrombosis Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 102100035044 Myosin light chain kinase, smooth muscle Human genes 0.000 description 1
- 108010074596 Myosin-Light-Chain Kinase Proteins 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 241000283977 Oryctolagus Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- ZKHQWZAMYRWXGA-MVKANHKCSA-N [[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxy(32P)phosphoryl] phosphono hydrogen phosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO[32P](O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-MVKANHKCSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000001142 anti-diarrhea Effects 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- SKCNIGRBPJIUBQ-UHFFFAOYSA-N chloroform;ethyl acetate Chemical compound ClC(Cl)Cl.CCOC(C)=O SKCNIGRBPJIUBQ-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 229940079919 digestives enzyme preparation Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000004665 fatty acids Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000000415 inactivating effect 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
- 208000028774 intestinal disease Diseases 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002350 laparotomy Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 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
- 238000004519 manufacturing process Methods 0.000 description 1
- 210000001363 mesenteric artery superior Anatomy 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- RHMQNXNXUZLEIY-UHFFFAOYSA-N methanol;2-propan-2-yloxypropane Chemical compound OC.CC(C)OC(C)C RHMQNXNXUZLEIY-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- QAXZWHGWYSJAEI-UHFFFAOYSA-N n,n-dimethylformamide;ethanol Chemical compound CCO.CN(C)C=O QAXZWHGWYSJAEI-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 235000020030 perry Nutrition 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 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
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 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
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
産業上の利用分野
本発明は脳および心臓血管系疾患の予防・治療
剤、制癌剤、止瀉剤として有用な新規ベンゾチア
ゾリールベンゼンスルホン酸アミド誘導体に関す
る。
従来の技術
ベンゾチアゾリールベンゼン誘導体は特開昭50
−88226号公報やアンチバイオテイクス・アン
ド・ケモセラピー（Antibiotics and
Chemotherapy）第８巻、第33〜36頁（1958年）
に記載されている。
発明が解決しようとする問題点
特開昭50−88226号公報においては、防ダニ剤
として有用な２−フエニルベンゾチアゾール誘導
体が開示され、また、Antibiotics and
Chemotherapyには抗結核活性を有する２−フエ
ニルベンゾチアゾール誘導体が開示されている
が、いずれの文献とも、ベンゾチアゾールの２位
に結合するフエニル基にスルフアモイル基が導入
された化合物に対しての言及が全くなく、また循
環器系に対する作用、制癌作用および止瀉作用に
関する言及も全くない。
本発明者らは脳および心臓血管系疾患の予防・
治療剤、制癌剤、止瀉剤として有用な化合物を鋭
意研究した結果、優れた作用を有するベンゾチア
ゾリールベンゼンスルホン酸アミド誘導体の合成
に成効し、本発明を完成した。
問題点を解決するための手段
本発明は式
〔式中、R1およびR2はそれぞれ水素または低級
アルコキシを示し、R3およびR4はそれぞれ低級
アルキルまたは置換されていてもよいアラルキル
を示すか、または隣接する窒素原子とともに環を
形成し、Ａは低級アルキレンを示す〕で表わされ
る化合物およびその塩を提供するものである。
上記式（）に関しR1またはR2で示される低
級アルコキシ基としてはたとえばメトキシ、エト
キシ、プロポキシ、イソプロポキシ、ブトキシ、
イソブトキシ、sec−ブトキシ、tert−ブトキシ
などの炭素数１〜４程度のアルコキシ基があげら
れる。
R3またはR4で示される低級アルキルとしては
メチル、エチル、プロピル、イソプロピル、ブチ
ル、イソブチル、sec−ブチル、tert−ブチルな
どの炭素数１〜４程度のアルキル基があげられ
る。
R3またはR4で示されるアラルキル基としては
たとえばベンジル、フエネチル、３−フエニルプ
ロピル、α−メチルベンジル、α−エチルベンジ
ル、α−メチルフエネチル、β−メチルフエネチ
ル、β−エチルフエネチルなどのフエニル−低級
（C1-4）アルキル基があげられ、該フエニル−低
級アルキル基におけるフエニル基は１ないし３個
のたとえばハロゲン（例、フツ素、塩素、臭素、
ヨウ素など）、低級（C1-4）アルキル基（例、メ
チル、エチル、プロピル、ブチルなど）、低級
（C1-4）アルコキシ基（例、メトキシ、エトキシ、
プロポキシ、イソプロポキシ、ブトキシなど）、
メチレンジオキシ基、アミノ基、ニトロ基、ヒド
ロキシ基などによつて置換されていてもよい。か
かる置換フエニル−低級アルキル基の例としては
たとえば、２−（４−クロロフエニル）エチル、
２−（４−ヒドロキシフエニル）エチル、２−（４
−メトキシフエニル）エチル、２−（３，４−ジ
メトキシフエニル）エチル、２−（３，４，５−
トリメトキシフエニル）エチル、２−（３，４−
メチレンジオキシフエニル）エチル、２−（ｐ−
トリル）エチル、３，４−ジメトキシベンジル、
３，４−メチレンジオキシベンジル、３，４，５
−トリメトキシベンジル、４−エチルベンジル、
４−クロロベンジルなどがあげられる。
R3およびR4が隣接する窒素原子とともに形成
する環としては該窒素原子の他に窒素、酸素、硫
黄などのヘテロ原子を有していてもよい環状アミ
ノ基があげられ、たとえばピロリジニル、モリホ
リニル、ピペリジル、ピペラジニル、ホモピペラ
ジニルなどの５ないし７員環の飽和または一部飽
和した脂環式の環状アミノ基が含まれる。該環状
アミノ基は置換可能な位置に置換基を有していて
もよく、かかる置換基としてはたとえば低級
（C1-4）アルキル基（例、メチル、エチル、プロ
ピル、ブチル）アリール、アラルキル、アシルな
どがあげられる。
置換基としてのアリール基としてはたとえばフ
エニル基があげられ、該フエニル基は１ないし３
個のたとえばハロゲン（例、フツ素、塩素、臭
素、ヨウ素）、低級（C1-4）アルキル基（例、メ
チル、エチル、プロピル、ブチル）、低級（C1-4）
アルコキシ基（例、メトキシ、エトキシ、プロポ
キシ、イソプロポキシ、ブトキシ）、メチレンジ
オキシ基、アミノ基、ニトロ基、ヒドロキシ基な
どによつて置換されていてもよい。また、置換基
としてのアラルキルはたとえば、ベンジル、フエ
ネチルなどのフエニル−低級（C1-4）アルキル、
ベンヅヒドリルなどのジフエニル−低級（C1-4）
アルキルおよびトリフエニル−低級（C1-4）アル
キルなどがあげられる。置換基としてのアシルと
してはたとえば、アセチル、プロピオニル、ブチ
リルなどの低級（C1-4）脂肪酸残基ベンゾイル、
シンナモイルなどの芳香族有機残基などがあげら
れる。該アラルキル基および芳香族有機酸残基に
おけるフエニル基は１ないし３個のたとえばハロ
ゲン（例、フツ素、塩素、臭素、ヨウ素）、低級
（C1-4）アルキル基（例、メチル、エチル、プロ
ピル、ブチル）、低級（C1-4）アルコキシ基（例、
メトキシ、エトキシ、プロポキシ、イソプロポキ
シ、ブトキシ）、メチレンジオキシ基、アミノ基、
ニトロ基、ヒドロキシ基などによつて置換されて
いてもよい。
Ａで示される低級アルキレンとしてはたとえば
エチレン、トリメチレンなどがあげられる。
化合物（）の塩としてはたとえば、塩酸塩、
臭化水素酸塩、硫酸塩、硝酸塩、燐酸塩などの無
機酸塩、たとえば酢酸塩、酒石酸塩、クエン酸
塩、フマール酸塩、マレイン酸塩、トルエンスル
ホン酸塩、メタンスルホン酸塩などの有機酸との
塩などの薬理学的に許容されうる塩があげられ
る。
本発明化合物（）はたとえば式
〔式中、各記号は前記と同意義〕と式
〔式中、各記号は前記と同意義〕で表わされる化
合物とを縮合反応させることによつて製造するこ
とができる。該縮合反応は水または適当な有機溶
媒（例、ジオキサン、テトラヒドロフラン、メタ
ノール、塩化メチレン、クロロホルム、Ｎ，Ｎ−
ジメチルホルムアミド、ジメチルスルホキシドな
ど）およびこれらの任意の混合溶媒中で行なうこ
とができる。反応温度は通常−20℃〜＋100℃程
度が好ましく、反応速度を高めるためにたとえば
トリエチルアミン、ピリジン、Ｎ，Ｎ−ジメチル
アニリンなどの有機塩基、たとえば炭酸カリウ
ム、炭酸ナトリウム、炭酸水素ナトリウムなどの
無機塩基を、触媒として添加してもよい。
化合物（）はまた式
〔式中、R1，R2およびＡは前記と同意義、Ｘは
ハロゲンまたは式R′SO2−Ｏ−（式中R′は低級
（C1-4）アルキル、フエニルまたはｐ−トリルを
示す）で表わされる化合物に一般式
〔式中、R3およびR4は前記と同意義〕で示され
るアミン類を反応させても製造することができ
る。化合物（）とアミン類（）との反応は適
当な有機溶媒（例、メタノール、エタノール、ジ
オキサン、アセトニトリル、テトラヒドロフラ
ン、Ｎ，Ｎ−ジメチルホルムアミド、ジメチルス
ルホキシドおよびこれらの任意の混合溶媒）中で
行なうことができる。
反応温度は通常０℃〜＋150℃程度が好ましく、
反応速度を高めるためにたとえば、トリエチルア
ミン、ピリジン、Ｎ，Ｎ−ジメチルアニリンなど
の有機塩基、たとえば炭酸カリウム、炭酸ナトリ
ウム、炭酸水素ナトリウムなどの無機塩基を触媒
として添加してもよい。
かくして得られる本発明の目的化合物（）は
反応混合物から通常の分離精製手段、たとえば抽
出、濃縮、中和、過、再結晶、カラムクロマト
グラフイー、薄層クロマトグラフイーなどの手段
を用いることによつて単離することができる。
本発明の原料化合物（）はたとえば次の反応
式で示される方法によつて容易に製造することが
できる。
〔R1およびR2は前記と同意義〕
上記反応式に示される（）の製造法につい
て、さらに詳しく説明すると（）→（）の反
応はクロルスルホン酸と（）を適当な溶媒中あ
るいは無溶媒で反応させて製造することができ
る。溶媒としては、塩化メチレン、クロロホル
ム、ベンゼンなどの有機溶媒が用いられ、通常−
20℃〜＋100℃程度の温度範囲で反応が行われる。
また原料化合物（）はたとえば次の反応式で
示される方法によつて製造できる。
〔式中、R1，R2，ＸおよびＡは前記と同意義〕
前記反応式で得られた化合物（）にアミノア
ルコール（）を反応させて化合物（）を得
る。本反応は化合物（）→（）と同様の反応
条件で行なうことができる。ついで化合物（）
の水酸基をハロゲン化する方法は例えば化合物
（）に塩化チオニル、三臭化リンなどのハロゲ
ン化剤を反応させて製造することができる。本反
応は適当な有機溶媒（例、ベンゼン、ヘキサン、
塩化メチレン、クロロホルム、酢酸エチル、テト
ラヒドロフランおよびこれらの任意の混合溶媒）
中で行なうことができる。反応温度は通常−20℃
〜＋100℃程度が好ましい。また反応速度を高め
るために有機塩基（例、ピリジン、トリエチルア
ミン、４−ジメチルアミノピリジン、Ｎ，Ｎ−ジ
メチルアニリンなど）を反応系中に添加してもよ
い。
また化合物（）のスルホン酸エステル化は、
化合物（）にスルホン酸クロリド類（例、トル
エンスルホン酸クロリド、メタンスルホン酸クロ
リドなど）を反応させて製造することができる。
本反応は適当な有機溶媒（例、ベンゼン、塩化メ
チレン、クロロホルム、テトラヒドロフラン、ピ
リジン、Ｎ，Ｎ−ジメチルアニリンなどおよびこ
れらの適当な混合溶媒）中で行なうことができ
る。反応温度は通常−20℃〜＋100℃程度が好ま
しい。また有機塩基（例、ピリジン、トリエチル
アミン、４−ジメチルアミノピリジン、ジメチル
アニリンなど）を反応速度を促進させるために共
存させることが好ましい。
作 用
本発明の化合物すなわち式（）で示されるベ
ンゾチアゾリールベンゼンスルホン酸アミド誘導
体はカルシウム結合蛋白（カルモジユリン）を不
活性化させる作用が強力であり、またそれに続く
ミオシン軽鎖キナーゼの活性を抑制する作用を有
し、したがつて細胞内カルシウムによる生理作用
を抑制する作用が期待できることが明らかとな
り、また平滑筋弛緩作用、血管拡張作用、心筋保
護作用およびホスホジエステラーゼ阻害作用を有
する。かかる生物活性にもとづく血管拡張剤、狭
心症治療剤、脳循環改善剤、血圧降下剤として脳
および心臓血管系の疾患の予防および治療剤、さ
らに制癌剤および止瀉剤（下痢止め）として有用
である。本発明化合物は低毒性で経口投与でも吸
収がよく、安定性にもすぐれているので、上記の
医薬として用いる場合、それ自体あるいは適宜の
薬理学的に許容される担体、賦形剤、希釈剤と混
合し、粉末、顆粒、錠剤、カプセル剤、注射剤な
どの医薬組成物として経口的または非経口的に、
人または他の温血動物に安全に投与することがで
きる。投与量は対象疾患の状態、投与ルートによ
つても異なるが、たとえば高血圧症、脳血栓症、
細菌性下痢などの脱水を併なう腸疾患の治療の目
的で成人患者に投与する場合、経口投与では通常
１回量約0.01〜100mg／Kgとりわけ0.01〜10mg／
Kg程度が好ましく、これらの服用量を症状に応じ
て１日約１〜３回程度投与するのが望ましい。
実施例
参考例 １
クロルスルホン酸９mlの溶液に、−20〜−10℃
でかき混ぜながら、２−（２，３−ジメトキシフ
エニル）ベンゾチアゾール3.0ｇを少しずつ加え
る。２時間かき混ぜた後反応液を氷水中に投入す
る。生ずる淡黄色析出物をろ取し、水洗、乾燥し
３−（２−ベンゾチアゾリール）−４，５−ジメト
キシベンゼンスルホン酸クロリドの粗生成物3.6
ｇを得る。本品は精製することなくつぎの反応に
使用する。
参考例 ２
参考例１で得た３−（２−ベンゾチアゾリール）
−４，５−ジメトキシベンゼンスルホン酸クロリ
ド2.9ｇをジオキサン30mlに懸濁した溶液に、３
−アミノプロパノール1.5ｇをジオキサン10mlに
溶解した溶液を室温でかき混ぜながら滴下する。
１時間かき混ぜた後、反応液を減圧濃縮する。残
留物を酢酸エチルに溶解し、水洗乾燥後、減圧濃
縮する。残留物を含水エタノールから再結晶する
と、３−（２−ベンゾチアゾリール）−４，５−ジ
メトキシ−Ｎ−（３−ヒドロキシプロピル）ベン
ゼンスルホン酸アミドの白色結晶1.45ｇを得る。
融点 184−186℃
NMRスペクトル（d6−DMSO−D2O）δ
（ppm）：1.4〜1.8（2H，multiplet）、2.85（2H，
triplet，Ｊ＝５Hz）、3.38（2H，triplet，Ｊ＝５
Hz）、3.83（3H，singlet）、4.03（3H，singlet）、
7.3−7.7（3H，multiplet）、8.0〜8.2（2H）、8.40
（1H，doudlet，Ｊ＝２Hz）
元素分析値
C18H20N2O5S2として
計算値：Ｃ、52.93；Ｈ、4.93；Ｎ、6.86
実測値：Ｃ、53.15；Ｈ、4.86；Ｎ、6.83
参考例 ３
参考例２で得た３−（２−ベンゾチアゾリール）
−４，５−ジメトキシ−Ｎ−（３−ヒドロキシプ
ロピル）ベンゼンスルホン酸アミド3.5ｇを塩化
メチレン100mlに溶解し、塩化チオニル７mlを加
え、５時間加熱還流する。反応液を減圧濃縮し、
残留物を、クロロホルム−イソプロピルエーテル
から再結晶し、３−（２−ベンゾチアゾリール）−
４，５−ジメトキシ−Ｎ−（３−ヒドロキシプロ
ピル）ベンゼンスルホン酸アミドの白色結晶3.6
ｇを得る。
融点 189−196℃
NMRスペクトル（CDCl3−d6−DMSO）δ
（ppm）：1.7〜2.1（2H，multiplet）、3.00（2H，
quatet，Ｊ＝４Hz）、3.57（2H，triplet，Ｊ＝４
Hz）、3.98（3H，singlet）、4.08（3H，singlet）、
7.3−7.6（3H，multiplet）、7.8〜8.2（2H）、8.55
（1H，doublet，Ｊ＝２Hz）
元素分析値
C18H19ClN2O4S2として
計算値：Ｃ、50.64；Ｈ、4.49；Ｎ、6.56
実測値：Ｃ、50.76；Ｈ、4.62；Ｎ、6.39
参考例 ４
２−（２−メトキシフエニル）ベンゾチアゾー
ルを実施例１と同様にクロルスルホン酸を反応さ
せて、３−（２−ベンゾチアゾリール）−４−メト
キシベンゼンスルホン酸クロリドの淡黄色粉末を
得る。本品は精製することなくつぎの反応に使用
することができる。
実施例 １
３−（４−フエニルピペラジラル）プロピルア
ミン1.3ｇおよびトリエチルアミン1.6mlをクロロ
ホルム45mlに溶解した溶液に、参考例１で得た３
−（２−ベンゾチアゾリール）−４，５−ジメトキ
シベンゼンスルホン酸クロリド2.0を室温でかき
混ぜながら少しずつ加え、２時間室温でかき混ぜ
る。反応液を水洗、無水硫酸ナトリウムで乾燥
後、溶媒を減圧下に留去する。得られる残留物を
シリカゲルのカラムクロマトグラフイー（溶出
液：クロロホルム−酢酸エチル＝４：１）で精製
する。得られる粗生成物を塩酸塩とし、エタノー
ル−Ｎ，Ｎ−ジメチルホルムアミドから再結晶
し、３−（２−ベンゾチアゾリール）−４，５−ジ
メトキシ−Ｎ−〔３−（４−フエニルピペラジニ
ル）プロピル〕ベンゼンスルホン酸アミド・塩酸
塩を無色針状晶1.6ｇを得る。
融点 232−234℃
元素分析値
C28H32N4O4S2・HClとして
計算値：Ｃ、57.08；Ｈ、5.65；Ｎ、9.51
実測値：Ｃ、57.09；Ｈ、5.78；Ｎ、9.51
実施例 ２
実施例１と同様の方法によつて、３−ジメチル
アミノプロピルアミンと３−（２−ベンゾチアゾ
リール）−４，５−ジメトキシ−ベンゼンスルホ
ン酸クロリドの反応より得られる３−（２−ベン
ゾチアゾリール）−４，５−ジメトキシ−Ｎ−（３
−ジメチルアミノプロピル）ベンゼンスルホン酸
アミドをしゅう酸処理してしゅう酸塩として得
る。メタノール−イソプロピルエーテルから再結
晶し、白色結晶となる。
融点 208−211℃
元素分析値
C20H25N3O4S2・CO2H）2として
計算値：Ｃ、50.28；Ｈ、5.18；Ｎ、7.99
実測値：Ｃ、50.35；Ｈ、5.33；Ｎ、7.65
実施例 ３
参考例３で得た３−（２−ベンゾチアゾリール）
−Ｎ−（３−クロロプロピル）−４，５−ジメトキ
シベンズスルホン酸アミド2.2ｇ、４−フエニル
ピペリジン0.9ｇ、トリエチルアミン1.1ml、ヨウ
化カリウム1.1ｇおよびＮ，Ｎ−ジメチルホルム
アミド10mlの混合物を100℃で１時間かき混ぜる。
反応液に水を加え酢酸エチルで抽出する。有機層
を水洗、無水硫酸ナトリウムで乾燥後溶媒を減圧
下に留去する。
得られる残留物を塩酸塩とし、エタノールから
再結晶し、３−（２−ベンゾチアゾリール）−４，
５−ジメトキシ−Ｎ−〔３−（４−フエニルピペリ
ジニル）プロピル〕ベンゼンスルホン酸アミド塩
酸塩の淡黄色結晶1.1ｇを得る。
融点 225〜227℃
元素分析値
C29H32N3O4S2・HCl・1/2H2Oとして
計算値：Ｃ、58、33；Ｈ、5.91；Ｎ、7.04
実測値：Ｃ、58、51；Ｈ、5.80；Ｎ、7.10
実施例 ４〜11
実施例３と同様の方法で３−（２−ベンゾチア
ゾリール）−Ｎ−（３−クロロプロピル）−４，５
−ジメトキシベンゼンスルホン酸アミドとアミン
類との置換反応により実施例４〜11の３−（２−
ベンゾチアゾリール）−４，５−ジメトキシベン
ゼンスルホン酸アミド類を得る。
INDUSTRIAL APPLICATION FIELD The present invention relates to a novel benzothiazolylbenzenesulfonic acid amide derivative useful as a preventive/therapeutic agent for brain and cardiovascular diseases, an anticancer agent, and an antidiarrheal agent. Conventional technology Benzothiazolylbenzene derivatives were disclosed in Japanese Unexamined Patent Application Publication No. 1973
−88226 Publication and Antibiotics and Chemotherapy
Chemotherapy) Volume 8, pp. 33-36 (1958)
It is described in. Problems to be Solved by the Invention In JP-A-50-88226, 2-phenylbenzothiazole derivatives useful as anti-mite agents are disclosed.
Chemotherapy discloses 2-phenylbenzothiazole derivatives that have anti-tuberculosis activity, but all references refer to compounds in which a sulfamoyl group is introduced into the phenyl group bonded to the 2-position of benzothiazole. There is also no mention of effects on the circulatory system, anticancer effects, or antidiarrheal effects. The present inventors aim to prevent and prevent brain and cardiovascular diseases.
As a result of intensive research into compounds useful as therapeutic agents, anticancer agents, and antidiarrheal agents, the present invention was successfully completed by successfully synthesizing benzothiazolylbenzenesulfonic acid amide derivatives having excellent effects. Means for solving the problems The present invention is based on the formula [In the formula, R 1 and R 2 each represent hydrogen or lower alkoxy, R 3 and R 4 each represent lower alkyl or optionally substituted aralkyl, or form a ring together with the adjacent nitrogen atom, A represents lower alkylene] and salts thereof. Examples of the lower alkoxy group represented by R 1 or R 2 in the above formula () include methoxy, ethoxy, propoxy, isopropoxy, butoxy,
Examples include alkoxy groups having about 1 to 4 carbon atoms such as isobutoxy, sec-butoxy, and tert-butoxy. Examples of the lower alkyl represented by R 3 or R 4 include alkyl groups having about 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. Examples of the aralkyl group represented by R 3 or R 4 include phenyl-lower ( C 1-4 ) alkyl group, and the phenyl group in the phenyl-lower alkyl group contains 1 to 3 halogens (e.g., fluorine, chlorine, bromine,
iodine, etc.), lower (C 1-4 ) alkyl groups (e.g., methyl, ethyl, propyl, butyl, etc.), lower (C 1-4 ) alkoxy groups (e.g., methoxy, ethoxy,
propoxy, isopropoxy, butoxy),
It may be substituted with a methylenedioxy group, an amino group, a nitro group, a hydroxy group, etc. Examples of such substituted phenyl-lower alkyl groups include 2-(4-chlorophenyl)ethyl,
2-(4-hydroxyphenyl)ethyl, 2-(4
-methoxyphenyl)ethyl, 2-(3,4-dimethoxyphenyl)ethyl, 2-(3,4,5-
trimethoxyphenyl)ethyl, 2-(3,4-
methylenedioxyphenyl)ethyl, 2-(p-
tolyl)ethyl, 3,4-dimethoxybenzyl,
3,4-methylenedioxybenzyl, 3,4,5
-trimethoxybenzyl, 4-ethylbenzyl,
Examples include 4-chlorobenzyl. The ring formed by R 3 and R 4 together with the adjacent nitrogen atom includes a cyclic amino group which may have a heteroatom such as nitrogen, oxygen, or sulfur in addition to the nitrogen atom, such as pyrrolidinyl, morpholinyl, Included are 5- to 7-membered saturated or partially saturated alicyclic cyclic amino groups such as piperidyl, piperazinyl, and homopiperazinyl. The cyclic amino group may have a substituent at a substitutable position, and examples of such substituents include lower (C 1-4 ) alkyl groups (e.g., methyl, ethyl, propyl, butyl), aryl, aralkyl, Examples include acyl. Examples of the aryl group as a substituent include a phenyl group, and the phenyl group has 1 to 3
For example, halogen (e.g., fluorine, chlorine, bromine, iodine), lower (C 1-4 ) alkyl group (e.g., methyl, ethyl, propyl, butyl), lower (C 1-4 )
It may be substituted with an alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy), methylenedioxy group, amino group, nitro group, hydroxy group, etc. Aralkyl as a substituent includes, for example, phenyl-lower (C 1-4 ) alkyl such as benzyl and phenethyl,
Diphenyl-lower (C 1-4 ) such as benzhydryl
Examples include alkyl and triphenyl-lower (C 1-4 ) alkyl. Examples of acyl as a substituent include lower (C 1-4 ) fatty acid residues such as acetyl, propionyl, butyryl, benzoyl,
Examples include aromatic organic residues such as cinnamoyl. The phenyl group in the aralkyl group and aromatic organic acid residue has one to three halogens (e.g., fluorine, chlorine, bromine, iodine), lower (C 1-4 ) alkyl groups (e.g., methyl, ethyl, propyl, butyl), lower (C 1-4 ) alkoxy groups (e.g.
methoxy, ethoxy, propoxy, isopropoxy, butoxy), methylenedioxy group, amino group,
It may be substituted with a nitro group, a hydroxy group, etc. Examples of the lower alkylene represented by A include ethylene and trimethylene. Examples of salts of compound () include hydrochloride,
Inorganic acid salts such as hydrobromide, sulfate, nitrate, phosphate, organic salts such as acetate, tartrate, citrate, fumarate, maleate, toluenesulfonate, methanesulfonate Examples include pharmacologically acceptable salts such as salts with acids. The compound of the present invention () has the formula [In the formula, each symbol has the same meaning as above] and the formula It can be produced by carrying out a condensation reaction with a compound represented by [wherein each symbol has the same meaning as above]. The condensation reaction is carried out in water or a suitable organic solvent (e.g. dioxane, tetrahydrofuran, methanol, methylene chloride, chloroform, N,N-
(dimethylformamide, dimethyl sulfoxide, etc.) and any mixed solvent thereof. The reaction temperature is usually about -20°C to +100°C, and to increase the reaction rate, organic bases such as triethylamine, pyridine, N,N-dimethylaniline, and inorganic bases such as potassium carbonate, sodium carbonate, and sodium bicarbonate are used. may be added as a catalyst. Compound () is also the formula [In the formula, R 1 , R 2 and A have the same meanings as above, X is halogen or the formula R'SO 2 -O- (wherein R' is lower (C 1-4 ) alkyl, phenyl or p-tolyl) ) to the compound represented by the general formula It can also be produced by reacting amines represented by the formula [wherein R 3 and R 4 have the same meanings as above]. The reaction between compound () and amines () should be carried out in a suitable organic solvent (e.g., methanol, ethanol, dioxane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, and any mixed solvent thereof). I can do it. The reaction temperature is usually preferably about 0°C to +150°C,
To increase the reaction rate, for example, organic bases such as triethylamine, pyridine, N,N-dimethylaniline, etc., and inorganic bases such as potassium carbonate, sodium carbonate, sodium bicarbonate, etc. may be added as catalysts. The object compound () of the present invention thus obtained can be separated and purified from the reaction mixture using conventional separation and purification methods such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography, thin layer chromatography, etc. It can then be isolated. The starting compound () of the present invention can be easily produced, for example, by the method shown in the following reaction formula. [R 1 and R 2 have the same meanings as above] To explain in more detail the method for producing () shown in the above reaction formula, the reaction () → () involves the reaction of chlorosulfonic acid and () in a suitable solvent or without It can be produced by reacting with a solvent. Organic solvents such as methylene chloride, chloroform, and benzene are used as solvents, and usually -
The reaction takes place in a temperature range of about 20°C to +100°C. Further, the raw material compound () can be produced, for example, by the method shown by the following reaction formula. [In the formula, R 1 , R 2 , X and A have the same meanings as defined above] The compound () obtained in the above reaction formula is reacted with an amino alcohol () to obtain the compound (). This reaction can be carried out under the same reaction conditions as for compound ()→(). Then compound ()
The hydroxyl group of can be halogenated by, for example, reacting the compound () with a halogenating agent such as thionyl chloride or phosphorus tribromide. This reaction can be carried out using a suitable organic solvent (e.g. benzene, hexane,
(methylene chloride, chloroform, ethyl acetate, tetrahydrofuran and any mixed solvent thereof)
It can be done inside. Reaction temperature is usually -20℃
~+100°C is preferable. Further, an organic base (eg, pyridine, triethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, etc.) may be added to the reaction system to increase the reaction rate. In addition, the sulfonic acid esterification of compound () is
It can be produced by reacting the compound () with a sulfonic acid chloride (eg, toluenesulfonic acid chloride, methanesulfonic acid chloride, etc.).
This reaction can be carried out in a suitable organic solvent (eg, benzene, methylene chloride, chloroform, tetrahydrofuran, pyridine, N,N-dimethylaniline, etc., and a suitable mixed solvent thereof). The reaction temperature is usually preferably about -20°C to +100°C. Further, it is preferable to coexist an organic base (eg, pyridine, triethylamine, 4-dimethylaminopyridine, dimethylaniline, etc.) in order to accelerate the reaction rate. Effect The compound of the present invention, that is, the benzothiazolylbenzenesulfonic acid amide derivative represented by the formula (), has a strong effect of inactivating calcium-binding protein (calmodillin) and inhibits the subsequent activity of myosin light chain kinase. Therefore, it has been revealed that it can be expected to suppress the physiological effects of intracellular calcium, and also has smooth muscle relaxing, vasodilatory, myocardial protective, and phosphodiesterase inhibitory effects. Based on such biological activity, it is useful as a vasodilator, a therapeutic agent for angina pectoris, an agent for improving cerebral circulation, an antihypertensive agent, a preventive and therapeutic agent for diseases of the brain and cardiovascular system, and an anticancer agent and an antidiarrheal agent (antidiarrheal agent). . The compound of the present invention has low toxicity, good absorption even when administered orally, and excellent stability. Therefore, when used as the above-mentioned medicine, the compound of the present invention can be used by itself or in an appropriate pharmacologically acceptable carrier, excipient, or diluent. Orally or parenterally as a pharmaceutical composition such as powder, granules, tablets, capsules, and injections by mixing with
Can be safely administered to humans or other warm-blooded animals. The dosage varies depending on the condition of the target disease and administration route, but for example, for hypertension, cerebral thrombosis,
When administered to adult patients for the purpose of treating intestinal diseases accompanied by dehydration such as bacterial diarrhea, the oral dosage is usually about 0.01 to 100 mg/kg, especially 0.01 to 10 mg/kg.
Kg is preferable, and it is desirable to administer these doses about 1 to 3 times a day depending on the symptoms. Reference Example 1 Add a solution of 9 ml of chlorosulfonic acid to -20 to -10°C.
While stirring, add 3.0 g of 2-(2,3-dimethoxyphenyl)benzothiazole little by little. After stirring for 2 hours, the reaction solution was poured into ice water. The resulting pale yellow precipitate was collected by filtration, washed with water, and dried to obtain a crude product of 3-(2-benzothiazolyl)-4,5-dimethoxybenzenesulfonic acid chloride 3.6
get g. This product will be used in the next reaction without purification. Reference example 2 3-(2-benzothiazolyl) obtained in reference example 1
-To a solution of 2.9 g of -4,5-dimethoxybenzenesulfonic acid chloride suspended in 30 ml of dioxane, 3
- A solution of 1.5 g of aminopropanol dissolved in 10 ml of dioxane is added dropwise at room temperature while stirring.
After stirring for 1 hour, the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried, and concentrated under reduced pressure. The residue was recrystallized from aqueous ethanol to obtain 1.45 g of white crystals of 3-(2-benzothiazolyl)-4,5-dimethoxy-N-(3-hydroxypropyl)benzenesulfonic acid amide. Melting point 184−186℃ NMR spectrum (d 6 −DMSO−D 2 O) δ
(ppm): 1.4-1.8 (2H, multiplet), 2.85 (2H,
triplet, J=5Hz), 3.38(2H, triplet, J=5
Hz), 3.83 (3H, singlet), 4.03 (3H, singlet),
7.3-7.7 (3H, multiplet), 8.0-8.2 (2H), 8.40
(1H, doudlet, J=2Hz) Elemental analysis value C 18 H 20 N 2 O 5 S 2 Calculated value: C, 52.93; H, 4.93; N, 6.86 Actual value: C, 53.15; H, 4.86; N, 6.83 Reference Example 3 3-(2-Benzothiazolyl) obtained in Reference Example 2
3.5 g of -4,5-dimethoxy-N-(3-hydroxypropyl)benzenesulfonic acid amide is dissolved in 100 ml of methylene chloride, 7 ml of thionyl chloride is added, and the mixture is heated under reflux for 5 hours. Concentrate the reaction solution under reduced pressure,
The residue was recrystallized from chloroform-isopropyl ether to give 3-(2-benzothiazolyl)-
White crystals of 4,5-dimethoxy-N-(3-hydroxypropyl)benzenesulfonic acid amide 3.6
get g. Melting point 189−196℃ NMR spectrum (CDCl 3 −d 6 −DMSO) δ
(ppm): 1.7-2.1 (2H, multiplet), 3.00 (2H,
quatet, J=4Hz), 3.57(2H, triplet, J=4
Hz), 3.98 (3H, singlet), 4.08 (3H, singlet),
7.3-7.6 (3H, multiplet), 7.8-8.2 (2H), 8.55
(1H, doublet, J=2Hz) Elemental analysis value C 18 H 19 ClN 2 O 4 S 2 Calculated value: C, 50.64; H, 4.49; N, 6.56 Actual value: C, 50.76; H, 4.62; N, 6.39 Reference Example 4 2-(2-methoxyphenyl)benzothiazole was reacted with chlorosulfonic acid in the same manner as in Example 1 to obtain a diluted 3-(2-benzothiazolyl)-4-methoxybenzenesulfonic acid chloride. A yellow powder is obtained. This product can be used in the next reaction without purification. Example 1 3-(4-phenylpiperaziral)propylamine obtained in Reference Example 1 was added to a solution of 1.3 g of propylamine and 1.6 ml of triethylamine dissolved in 45 ml of chloroform.
-(2-Benzothiazolyl)-4,5-dimethoxybenzenesulfonic acid chloride 2.0 is added little by little while stirring at room temperature, and the mixture is stirred at room temperature for 2 hours. After washing the reaction solution with water and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: chloroform-ethyl acetate = 4:1). The obtained crude product was converted into a hydrochloride salt, recrystallized from ethanol-N,N-dimethylformamide, and 3-(2-benzothiazolyl)-4,5-dimethoxy-N-[3-(4-phenyl) Obtain 1.6 g of colorless needle-like crystals of (piperazinyl)propyl]benzenesulfonic acid amide hydrochloride. Melting point 232-234℃ Elemental analysis value C 28 H 32 N 4 O 4 S 2・HCl Calculated value: C, 57.08; H, 5.65; N, 9.51 Actual value: C, 57.09; H, 5.78; N, 9.51 Implemented Example 2 By the same method as in Example 1, 3-(2 -benzothiazolyl)-4,5-dimethoxy-N-(3
-dimethylaminopropyl)benzenesulfonic acid amide is treated with oxalic acid to obtain the oxalate salt. Recrystallize from methanol-isopropyl ether to give white crystals. Melting point 208-211℃ Elemental analysis value C 20 H 25 N 3 O 4 S 2・CO 2 H) 2 Calculated value: C, 50.28; H, 5.18; N, 7.99 Actual value: C, 50.35; H, 5.33; N, 7.65 Example 3 3-(2-benzothiazolyl) obtained in Reference Example 3
A mixture of 2.2 g of -N-(3-chloropropyl)-4,5-dimethoxybenzsulfonamide, 0.9 g of 4-phenylpiperidine, 1.1 ml of triethylamine, 1.1 g of potassium iodide and 10 ml of N,N-dimethylformamide was added. Stir at 100℃ for 1 hour.
Add water to the reaction solution and extract with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was made into a hydrochloride salt and recrystallized from ethanol to give 3-(2-benzothiazolyl)-4,
1.1 g of pale yellow crystals of 5-dimethoxy-N-[3-(4-phenylpiperidinyl)propyl]benzenesulfonic acid amide hydrochloride are obtained. Melting point 225-227℃ Elemental analysis value C 29 H 32 N 3 O 4 S 2・HCl・1/2H 2 O Calculated value: C, 58, 33; H, 5.91; N, 7.04 Actual value: C, 58, 51; H, 5.80; N, 7.10 Examples 4 to 11 3-(2-Benzothiazolyl)-N-(3-chloropropyl)-4,5 in the same manner as in Example 3
-3-(2-
Benzothiazolyl)-4,5-dimethoxybenzenesulfonic acid amide is obtained.
【表】【table】
【表】
実施例 12
参考例４で得た３−（２−ベンゾチアゾリール）
−４−メトキシベンゼンスルホン酸クロリドと３
−（４−フエニルピペラジニル）プロピルアミン
とを実施例１と同様に処理し、３−（２−ベンゾ
チアゾール）−４−メトキシ−Ｎ−〔３−（４−フ
エニルピペラジニル）プロピル〕ベンゼンスルホ
ン酸アミド塩酸塩を得る。エタノール−Ｎ，Ｎ−
ジメチルホルムアミドから再結晶し淡黄色結晶と
なる。
融点 241〜243℃（分解点）
元素分析値
C27H30N4O3S2・HClとして
計算値：Ｃ、58.00；Ｈ、5.59；Ｎ、10.02
実測値：Ｃ、57.98；Ｈ、5.63；Ｎ、9.98
発明の効果
試験例
腸間膜動脈に対する弛緩作用
家兎（日本在来種、体重約３Kg）を放血致死後
開腹し、上腸間膜動脈を摘出する。血管を常法に
したがい、２mm×25mmに螺旋状に切り、95％
O2：５％CO2の混合ガスを通したクレプス・ヘン
スライト栄養液を満たした20mmのオーガンパスに
吊す。血管の一方を等尺性トランスデユーサーに
接続し、1.5ｇの荷重をかけると、血管の収縮お
よび弛緩反応がトランスデユーサー（日本光電
FDピツクアツプTB−912T）にかゝる荷重とし
て記録される。15〜20mMKClでKClの最大収縮
のほゞ1/2収縮条件下に本発明化合物を加え、そ
の弛緩作用を観察した。その完全弛緩を100％と
し、50％弛緩させる濃度（ED50）を表−２に示
した。
表 ２
化合物No. 腸間膜動脈弛緩作用（実施例番号） ED50（μM）
１ 2.2
２ 5.3
３ 0.54
４ 0.6
５ 4.0
６ 21
７ 5.6
８ 6.1
９ 25
10 35
11 0.3312 0.61
試験例 ２
カルシウム、カルモジユリン依存性PDEに対
する影響
酵素標品は豚大脳皮質により、既報（Mo1.
Pharmacol.15巻、49頁、1979年およびBiochem.
Biophys.Res.Commun.84巻、277頁、1978年）に
準じて部分精製して用いた。実施条件は上記既報
にしたがつて、結果は表−３に示す如くである。
本発明化合物の酵素阻害活性の測定は、Ca
お
よびカルモジユリン依存性標品を用いて行なつ
た。非活性化反応は0.2mM−EGTA存在下で測
定し、一方、活性化反応は0.2mMCaCl28単位カ
ルモジユリン存在下で行なつた。その活性は50％
阻害に要する濃度（I50、μM）にて示した。[Table] Example 12 3-(2-benzothiazolyl) obtained in Reference Example 4
-4-methoxybenzenesulfonic acid chloride and 3
-(4-phenylpiperazinyl)propylamine was treated in the same manner as in Example 1, and 3-(2-benzothiazole)-4-methoxy-N-[3-(4-phenylpiperazinyl) Propyl]benzenesulfonic acid amide hydrochloride is obtained. Ethanol-N,N-
Recrystallize from dimethylformamide to give pale yellow crystals. Melting point 241-243℃ (decomposition point) Elemental analysis value C 27 H 30 N 4 O 3 S 2・HCl Calculated value: C, 58.00; H, 5.59; N, 10.02 Actual value: C, 57.98; H, 5.63; N, 9.98 Effect test example of the invention: Relaxation effect on mesenteric artery A domestic rabbit (Japanese native species, weight approximately 3 kg) was sacrificed by exsanguination and then laparotomy was performed to remove the superior mesenteric artery. Cut the blood vessel spirally into 2 mm x 25 mm according to the standard method, and cut the blood vessel into 95%
Suspended in a 20 mm organ path filled with Krebs-Hensleit nutrient solution passed through a gas mixture of O 2 :5% CO 2 . When one side of the blood vessel is connected to an isometric transducer and a load of 1.5 g is applied, the contraction and relaxation reactions of the blood vessel are caused by the transducer (Nihon Kohden).
It is recorded as the load corresponding to the FD pickup TB-912T). The compound of the present invention was added under conditions of contraction of approximately 1/2 of the maximum contraction of KCl at 15 to 20 mM KCl, and its relaxing effect was observed. The complete relaxation is taken as 100%, and the concentration (ED 50 ) that causes 50% relaxation is shown in Table 2. Table 2 Compound No. Mesenteric artery relaxing effect (Example number) ED 50 (μM) 1 2.2 2 5.3 3 0.54 4 0.6 5 4.0 6 21 7 5.6 8 6.1 9 25 10 35 11 0.33 12 0.61 Test example 2 Calcium, Effects on calmodilin-dependent PDE Enzyme preparations were obtained from pig cerebral cortex and were previously reported (Mo1.
Pharmacol. vol. 15, p. 49, 1979 and Biochem.
It was partially purified and used according to Biophys.Res.Commun. vol. 84, p. 277, 1978). The implementation conditions were as previously reported, and the results are as shown in Table 3.
The enzyme inhibitory activity of the compounds of the present invention was measured using Ca and calmodilin dependent preparations. Non-activation reactions were measured in the presence of 0.2mM-EGTA, while activation reactions were carried out in the presence of 0.2mM CaCl 2 8 units calmodilin. Its activity is 50%
The concentration required for inhibition (I 50 , μM) is shown.
【表】
試験例 ３
ミオキシ軽鎖キナーゼに対する作用
ミオキシ軽鎖キナーゼ（MLCK）の活性は、
ミオシン軽鎖（MLC）に取り込まれた32Pの量に
よ測定した。MLCKはAdelsteinとKlee(1)の方法
により、MLCはPerrieとPerryの方法(2)によりハ
イ鶏砂のうから調製した。反応溶液0.2ml中に
20mMTris・HCl0.05mM〔α32−Ｐ〕ATP
（1μCi／assay tube）、5mMMgCl、10μM MLC、
24nMcalmodulin 0.1mMCaCl2、0.1μｇ／ml
MLCKおよび適当量の化合物を含む。反応は30
℃で行い、４分后20％TCAを１ml添加すること
により停止させた。さらに0.1mlのBSA（mg／ml）
を加え混和后、2000ｇで15分間遠心し、その沈渣
を５％TCA3mlで懸濁遠心后沈渣を２ml1N
NaOHで溶かし、ラジオアクテイビテイをリキ
ツドシンチレーシヨンカウンターで測定した。化
合物のIC50は対数正規確立紙を用いて求めた。
(1) Adelstein、R.S.and Klee、C.B.；J.Biol.
Chem.256：7501−7509（1981）
(2) Perrie、W.T.and Perry、S.V.；Biochem.
J.，119：31−38（1970）
表 ４
化合物No. ミオキシ軽鎖キナーゼ阻害作用（実施例番号） IC50（μM）
１ ３
３ ５
４ 8.5
５ 7.511 ４ [Table] Test example 3 Effect on myoxy light chain kinase The activity of myoxy light chain kinase (MLCK) is
It was determined by the amount of 32 P incorporated into myosin light chain (MLC). MLCK was prepared from high chicken litter by the method of Adelstein and Klee (1) and MLC by the method of Perrie and Perry (2) . in 0.2ml of reaction solution
20mMTris・HCl0.05mM [α 32 -P]ATP
(1μCi/assay tube), 5mMgCl, 10μM MLC,
24nMcalmodulin 0.1mMCaCl2 , 0.1μg/ml
Contains MLCK and appropriate amount of compound. reaction is 30
℃ and stopped after 4 minutes by adding 1 ml of 20% TCA. Additionally 0.1ml BSA (mg/ml)
After mixing, centrifuge at 2000g for 15 minutes, suspend the sediment in 3ml of 5% TCA, and after centrifugation, add 2ml of the sediment to 1N.
It was dissolved in NaOH and radioactivity was measured using a liquid scintillation counter. The IC 50 of a compound was determined using lognormal establishment paper. (1) Adelstein, RSand Klee, CB; J.Biol.
Chem. 256 :7501-7509 (1981) (2) Perrie, WTand Perry, SV; Biochem.
J., 119 :31-38 (1970) Table 4 Compound No. Myoxy light chain kinase inhibitory effect (Example number) IC 50 (μM) 1 3 3 5 4 8.5 5 7.5 11 4
Claims (1)
アルコキシを示し、R3およびR4はそれぞれ低級
アルキルまたは置換されていてもよいアラルキル
を示すか、または隣接する窒素原子とともに環を
形成し、Ａは低級アルキレンを示す〕で表わされ
る化合物またはその塩。[Claims] 1 formula [In the formula, R 1 and R 2 each represent hydrogen or lower alkoxy, R 3 and R 4 each represent lower alkyl or optionally substituted aralkyl, or form a ring together with the adjacent nitrogen atom, A is lower alkylene] or a salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17392284A JPS6150975A (en) | 1984-08-20 | 1984-08-20 | Benzothiazolylbenzenesulfonamide derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17392284A JPS6150975A (en) | 1984-08-20 | 1984-08-20 | Benzothiazolylbenzenesulfonamide derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6150975A JPS6150975A (en) | 1986-03-13 |
| JPH0522706B2 true JPH0522706B2 (en) | 1993-03-30 |
Family
ID=15969559
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP17392284A Granted JPS6150975A (en) | 1984-08-20 | 1984-08-20 | Benzothiazolylbenzenesulfonamide derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6150975A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0696616B2 (en) * | 1987-03-19 | 1994-11-30 | チッソ株式会社 | Method for producing vinyl chloride polymer |
| JP2556722B2 (en) * | 1988-02-18 | 1996-11-20 | 興和株式会社 | Novel sulfonamide compound |
-
1984
- 1984-08-20 JP JP17392284A patent/JPS6150975A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6150975A (en) | 1986-03-13 |
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