JPH02273662A - Quinolinesulfonic acid derivative - Google Patents
Quinolinesulfonic acid derivativeInfo
- Publication number
- JPH02273662A JPH02273662A JP9437789A JP9437789A JPH02273662A JP H02273662 A JPH02273662 A JP H02273662A JP 9437789 A JP9437789 A JP 9437789A JP 9437789 A JP9437789 A JP 9437789A JP H02273662 A JPH02273662 A JP H02273662A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- group
- expressed
- acid
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- ZKIHLVYBGPFUAD-UHFFFAOYSA-N quinoline-2-sulfonic acid Chemical class C1=CC=CC2=NC(S(=O)(=O)O)=CC=C21 ZKIHLVYBGPFUAD-UHFFFAOYSA-N 0.000 title claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 4
- 125000004442 acylamino group Chemical group 0.000 claims abstract description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 125000003277 amino group Chemical group 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 21
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 abstract description 10
- 230000003834 intracellular effect Effects 0.000 abstract description 7
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 abstract description 6
- 239000002253 acid Substances 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 5
- 206010019280 Heart failures Diseases 0.000 abstract description 4
- 238000009825 accumulation Methods 0.000 abstract description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 abstract description 4
- KJPRLNWUNMBNBZ-QPJJXVBHSA-N (E)-cinnamaldehyde Chemical compound O=C\C=C\C1=CC=CC=C1 KJPRLNWUNMBNBZ-QPJJXVBHSA-N 0.000 abstract description 3
- 206010020772 Hypertension Diseases 0.000 abstract description 3
- 206010003119 arrhythmia Diseases 0.000 abstract description 3
- 230000006793 arrhythmia Effects 0.000 abstract description 3
- 229940117916 cinnamic aldehyde Drugs 0.000 abstract description 3
- KJPRLNWUNMBNBZ-UHFFFAOYSA-N cinnamic aldehyde Natural products O=CC=CC1=CC=CC=C1 KJPRLNWUNMBNBZ-UHFFFAOYSA-N 0.000 abstract description 3
- 210000004165 myocardium Anatomy 0.000 abstract description 3
- VBEGHXKAFSLLGE-UHFFFAOYSA-N n-phenylnitramide Chemical compound [O-][N+](=O)NC1=CC=CC=C1 VBEGHXKAFSLLGE-UHFFFAOYSA-N 0.000 abstract description 3
- 206010002383 Angina Pectoris Diseases 0.000 abstract description 2
- 201000010099 disease Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 210000002464 muscle smooth vascular Anatomy 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 235000010288 sodium nitrite Nutrition 0.000 abstract description 2
- 125000000217 alkyl group Chemical group 0.000 abstract 1
- 230000000747 cardiac effect Effects 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 29
- 239000000243 solution Substances 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 235000002639 sodium chloride Nutrition 0.000 description 12
- 239000011575 calcium Substances 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000001816 cooling Methods 0.000 description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- -1 alkali metal salts Chemical class 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- COHDHYZHOPQOFD-UHFFFAOYSA-N arsenic pentoxide Chemical compound O=[As](=O)O[As](=O)=O COHDHYZHOPQOFD-UHFFFAOYSA-N 0.000 description 4
- 229910001424 calcium ion Inorganic materials 0.000 description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 4
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 208000024172 Cardiovascular disease Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000008602 contraction Effects 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 150000001989 diazonium salts Chemical class 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 229940039009 isoproterenol Drugs 0.000 description 3
- 230000002107 myocardial effect Effects 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 210000003540 papillary muscle Anatomy 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 239000002876 beta blocker Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000012954 diazonium Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- CDZOGLJOFWFVOZ-UHFFFAOYSA-N n-propylaniline Chemical compound CCCNC1=CC=CC=C1 CDZOGLJOFWFVOZ-UHFFFAOYSA-N 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- MLFIYYDKLNZLAO-UHFFFAOYSA-N 2-aminoethane-1,1-diol Chemical compound NCC(O)O MLFIYYDKLNZLAO-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229910021592 Copper(II) chloride Inorganic materials 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical class C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- AXMVYSVVTMKQSL-UHFFFAOYSA-N UNPD142122 Natural products OC1=CC=C(C=CC=O)C=C1O AXMVYSVVTMKQSL-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 150000005010 aminoquinolines Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 230000011128 cardiac conduction Effects 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- OQNGCCWBHLEQFN-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC OQNGCCWBHLEQFN-UHFFFAOYSA-N 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 229960003280 cupric chloride Drugs 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 238000011597 hartley guinea pig Methods 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000000297 inotrophic effect Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000003680 myocardial damage Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical class C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 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
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Landscapes
- Quinoline Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野〕
本発明は、細胞内Ｃａ”の過蓄積を抑制する作用を有す
る新規なキノリンスルホン酸誘導体に関する。DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a novel quinoline sulfonic acid derivative that has the effect of suppressing hyperaccumulation of intracellular Ca.
（従来の技術および発明が解決しようとする課題）
心筋あるいは、血管平滑筋細胞内へのカルシウムイオン
（Ｃａ”）の過蓄積は、心筋障害、心臓伝導障害異常あ
るいは血管異常収縮等を招き、循環器系疾患の原因とな
る（ Ｊｏｈｎ Ａ、Ｗａｔｔｓ。(Prior Art and Problems to be Solved by the Invention) Excessive accumulation of calcium ions (Ca'') in myocardium or vascular smooth muscle cells leads to myocardial damage, abnormal cardiac conduction, or abnormal contraction of blood vessels, which impairs circulation. Causes organ disease (John A, Watts.
アメリカン ジャーナル オブ フィジオロジ−（Ａｍ
ｅｒｉｃａｎ Ｊｏｕｒｎａｌ ｏｆ Ｐｈｙｓｉｏｌ
ｏｇｙ ）第２３ｇ巻、ｑｏｑ〜９／６ページ、／りｇ
θ年あるいは、Ｇｏｒｄｏｎ Ｌ、 Ｔｏｄｄ ？カル
ディオバスキュラー リサーチ（Ｃａｒｄｉｏｖａｓｃ
ｕｌａｒ Ｒｅ５ｅａｒｃｈ ）第２０巻、＆４１！−
１．！／ページ、７９３６年）。American Journal of Physiology (Am
erican Journal of Physiol
ogy) Volume 23g, qoq~9/6 pages, /rig
θ year or Gordon L, Todd? Cardiovascular research
ular Research) Volume 20, &41! −
1. ! /page, 7936).
従って、これらの細胞内へのＣａ２＋の過蓄積を抑制す
る薬剤は、循環器系疾患、例えば、虚血性心疾患、心不
全、高血圧あるいは不整脈等に対して有用な予防および
治療薬となる。Therefore, drugs that suppress Ca2+ overaccumulation in these cells are useful preventive and therapeutic agents for cardiovascular diseases, such as ischemic heart disease, heart failure, hypertension, arrhythmia, and the like.
従来、心筋あるいは血管平滑細胞内Ｃａ２＋の過蓄積を
抑制する薬剤として、例えばＣａ拮抗薬あるいはβ−受
容体遮断薬が知られている。Conventionally, Ca antagonists and β-receptor blockers, for example, have been known as drugs that suppress hyperaccumulation of Ca2+ in myocardial or vascular smooth cells.
しかしこれらの薬剤はその使用量によっては、Ｃａ拮抗
剤の場合、細胞内Ｃａ”＋濃度の低下により、又β−遮
断薬の場合カテコールアミン作用の遮断により、心臓の
機能が抑制され、心不全状態をひきおこすことが知られ
ており（上田慶二、綜合臨床、３６巻、１１／〜ｔｚｑ
ページ、７９ｇ７年）、循環器疾患への適用範囲が限ら
れてきた。However, depending on the amount used, these drugs may suppress cardiac function by decreasing intracellular Ca''+ concentration in the case of Ca antagonists, or by blocking catecholamine action in the case of β-blockers, leading to heart failure. (Keiji Ueda, Sogo Clinical, Vol. 36, 11/~tzq)
Page 79g7), its applicability to cardiovascular diseases has been limited.
（課題を解決するための手段）
本発明者らは、細胞内Ｃａ”＋の過蓄積を抑制する化合
物の探索を行い鋭意検討した結果、循環器系への副作用
がな（、細胞内Ｃａ”＋の過蓄積を抑制する新規な化合
物を見出すことにより、本発明に到達した。(Means for Solving the Problems) The present inventors have searched for and intensively studied compounds that suppress the excessive accumulation of intracellular Ca" The present invention was achieved by discovering a new compound that suppresses the overaccumulation of +.
即ち、本発明の要旨は、
下記一般式（Ｉ）
（上記式中、Ｒ１およびＲ２はそれぞれ独立して水）基
、ＣＩ””Ｃ６のアルコキシ基、シアノ基、ニトロ基ま
たはトリフルオロメチル基を表す。）で示されるキノリ
ンスルホン酸誘導体またはその薬学的に許容し得る塩に
存する。That is, the gist of the present invention is that a group of the following general formula (I) (in the above formula, R1 and R2 are each independently water), an alkoxy group, a cyano group, a nitro group, or a trifluoromethyl group of CI""C6 represent. ) or a pharmaceutically acceptable salt thereof.
以下、本発明の詳細な説明する。The present invention will be explained in detail below.
本発明の化合物は上記一般式（Ｉ）で表される。The compound of the present invention is represented by the above general formula (I).
上記式中のＲ１およびＲ２としては水素原子；メチル基
、エチル基、ｎ−プロピル基、１ｓｏ−プロピル基、ｎ
−ブチル基、ｔ−ブチル基等Ｃ１〜Ｃ６基；メトキシ基
、エトキシ基、プロポキシ基等０１〜Ｃ６の直鎖または
分岐鎖アルコキシ基ニアセチルアミノ基、グロピオニル
アミノ基等０１〜ｃ６のアシルアミノ基；シアノ基：ニ
トロ基またはトリフルオロメチル基が挙げられる。In the above formula, R1 and R2 are hydrogen atoms; methyl group, ethyl group, n-propyl group, 1so-propyl group, n
- C1 to C6 groups such as butyl group, t-butyl group; 01 to C6 straight or branched alkoxy group such as methoxy group, ethoxy group, propoxy group Niacetylamino group, glopionylamino group etc. 01 to C6 acylamino group Group; Cyano group: A nitro group or a trifluoromethyl group can be mentioned.
上記一般式（Ｉ）で表される化合物としては例えば下記
表／記載のものが挙げられる。Examples of the compound represented by the above general formula (I) include those listed in the table/description below.
表 ｌ
また上記化合物の薬学的に許容されうる塩類も本発明の
範囲に包含される。Table 1 Also included within the scope of the present invention are pharmaceutically acceptable salts of the above compounds.
上記塩類は、アルカリ金属塩あるいはアルカリ土類金属
塩のような無毒性の塩であり、例えば、ナトリウム塩、
カリウム塩、マグネシウム塩、カルシウム塩、アルミニ
ウム塩等が挙げられる。アンモニウム塩、低級アルキル
アミン〔例、えば、トリエチルアミン〕塩、ヒドロキシ
低級アルキルアミン〔例えば、ニーヒドロキシエチルア
ミン、ビス−（２−ヒドロキシエチル）アミン、トリス
（ヒドロキシメチル）アミノメタンまたはＮ−メチル−
〇−グルカミン〕塩、シクロアルキルアミン〔例えば、
ジシクロヘキシルアミン〕塩、ベンジルアミン〔例えば
、Ｎ、Ｎ−ジベンジルエチレンジアミン〕塩およびジベ
ンジルアミン塩のような適切な無毒性のアミン塩も、同
様忙好ましいものである。The above salts are non-toxic salts such as alkali metal salts or alkaline earth metal salts, such as sodium salts,
Examples include potassium salts, magnesium salts, calcium salts, aluminum salts, and the like. Ammonium salts, lower alkyl amines [e.g. triethylamine] salts, hydroxy lower alkyl amines [e.g. dihydroxyethylamine, bis-(2-hydroxyethyl)amine, tris(hydroxymethyl)aminomethane or N-methyl-
〇-glucamine] salt, cycloalkylamine [e.g.
Suitable non-toxic amine salts, such as dicyclohexylamine] salt, benzylamine [eg, N,N-dibenzylethylenediamine] salt, and dibenzylamine salt, are also preferred.
本発明の化合物忙含まれる窒素を含んだ複素環に着目し
た場合、好ましい塩としては、塩酸塩、臭化水素酸塩、
硫酸塩、リン酸塩、フマル酸塩、コハク酸塩、シュウ酸
塩、乳酸塩等の無毒性の塩が挙げられる。When focusing on the nitrogen-containing heterocycle contained in the compound of the present invention, preferred salts include hydrochloride, hydrobromide,
Examples include non-toxic salts such as sulfates, phosphates, fumarates, succinates, oxalates, lactates and the like.
本発明に係わる化合物を心臓血管系用薬剤として用いる
場合、常法によりヒトに経口または非経口で適応される
。経口投与のための剤形としては、顆粒剤、細粒剤、散
剤、錠剤、硬カプセル剤、軟カプセル剤、シロップ剤、
乳剤、懸濁剤または液剤等が挙げられる。また、非経口
投与のための剤形としては、注射剤、座剤、経皮剤等が
挙げられる。When the compound according to the present invention is used as a drug for the cardiovascular system, it is administered orally or parenterally to humans in a conventional manner. Dosage forms for oral administration include granules, fine granules, powders, tablets, hard capsules, soft capsules, syrups,
Examples include emulsions, suspensions, and solutions. In addition, dosage forms for parenteral administration include injections, suppositories, transdermal preparations, and the like.
上記一般式（Ｉ）で示される化合物またはその薬学的に
許容されうる塩は、上記剤形中忙おいて、固体もしくは
液体の医薬用担体または賦形剤、安定剤、潤滑剤、甘味
剤、保存剤、懸濁化剤等の通常用いられる医薬用添加剤
とともに含まれており、治療上の有効成分の担体成分に
対する含有割合は１重量％〜ｑｏ重量％の範囲が好まし
い。The compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof may be used in the above dosage form as a solid or liquid pharmaceutical carrier or excipient, a stabilizer, a lubricant, a sweetener, It is included together with commonly used pharmaceutical additives such as preservatives and suspending agents, and the content ratio of the therapeutically active ingredient to the carrier component is preferably in the range of 1% by weight to qo% by weight.
用いられる固体担体の例としては、乳糖、白陶土、ショ
糖、結晶セルロース、コーンスタ−チ、タルク、寒天、
ペクチン、アカシア、ステアリン酸、ステアリン酸マグ
ネシウム、レシチン、塩化ナトリウムなどが挙げられる
。液状担体の例としては、シロップ、グリセリン、落花
生油、ポリビニルピロリドン、オリーブ油、エタノール
、ベンジルアルコール、プロピレングリコール、水など
が挙げられる。Examples of solid carriers that can be used include lactose, china clay, sucrose, crystalline cellulose, cornstarch, talc, agar,
Examples include pectin, acacia, stearic acid, magnesium stearate, lecithin, and sodium chloride. Examples of liquid carriers include syrup, glycerin, peanut oil, polyvinylpyrrolidone, olive oil, ethanol, benzyl alcohol, propylene glycol, water, and the like.
本発明の化合物を経口的に用いる場合は、その使用量は
成人に対して、１日０．０ ／ ７１１９〜１００θ〜
の範囲（好ましくは０．／〜〜１００〜）にあるが、年
令、性別、病態、症状、同時処理の有無等により、適宜
増減することが更に好ましい。また、投与回数は、７日
／回または適当な間隔をおいて、１日数回に分けて投与
してもよい。When the compound of the present invention is used orally, the dosage for adults is 0.0/7119-100θ/day.
(preferably 0./~100~), but it is more preferable to increase or decrease as appropriate depending on age, sex, pathological condition, symptoms, presence or absence of simultaneous treatment, etc. Further, the administration frequency may be 7 days/time or divided into several times a day at appropriate intervals.
本発明の化合物を注射剤として用いる場合には、成人に
対して／目量０．０ ／ Ｉｎ９〜ｉｏｏダを連続投与
または間欠投与することが好ましい。When the compound of the present invention is used as an injection, it is preferable to administer it continuously or intermittently to adults at a dosage of 0.0/In9 to ioo da.
次に本発明の化合物の製造方法について説明する。Next, a method for producing the compound of the present invention will be explained.
本発明の化合物は、例えば次のような経路（１）で製造
することができる。The compound of the present invention can be produced, for example, by the following route (1).
く経路（１）〉
（ＩＩ）
（ＩＩＩ）
（ＩＶ）
（Ｖ）
（Ｖａ）
（Ｖｂ ）
（Ｉン
（式中、Ｒ”およびＲ２は既に定義した通りであり、Ｈ
Ｘは各種の酸例えば塩酸、硫酸等を表す。）上記反応経
路（１）において、原料となる上記式（ｎ）で示される
ニトロアニリンは次の経路（２）で合成される。Route (1)〉 (II) (III) (IV) (V) (Va) (Vb) (In the formula, R'' and R2 are as defined above,
X represents various acids such as hydrochloric acid and sulfuric acid. ) In the above reaction route (1), the nitroaniline represented by the above formula (n) as a raw material is synthesized by the following route (2).
く経路（２）〉
Ｒ凰
（ＶＩ）
αわ
（Ｊｆｌ） （ｎ）（式中、
Ｒ’は既に定義した通りである）上記経路（２）で得ら
れるニトロアニリン（ｎ）と上記式＠）で示されるシン
ナムアルデヒドを適当な酸（例えば塩酸、硫酸等）と場
合によっては適当な酸化剤（例えばニトロベンゼン、五
酸化ヒ素等）の存在下、θ〜７ｋＯ℃で数分間〜２０時
間反応させることにより、上記式（ＩＶ）で示されるｇ
ニーニトロキノリンが得られる。Route (2)> R 凰 (VI) α わ (Jfl) (n) (in the formula,
R' is as defined above) Nitroaniline (n) obtained by the above route (2) and cinnamaldehyde represented by the above formula @) are mixed with a suitable acid (e.g. hydrochloric acid, sulfuric acid, etc.) By reacting for several minutes to 20 hours at θ to 7kO°C in the presence of an oxidizing agent (e.g. nitrobenzene, arsenic pentoxide, etc.), g represented by the above formula (IV) can be obtained.
Ninitroquinoline is obtained.
上記反応で得られたＣ−ニトロキノリン（ＩＶ）を適当
な還元法（例えば酸化白金、パラジウム、ラネー＝ｙケ
ル等の触媒の存在下、適当な溶媒、例えばメタノール、
エタノール、酢酸等に溶解または懸濁し、水素添加する
方法、亜鉛もしくは鉄と共に塩酸中で加熱する方法また
は塩化スズと塩酸中で加熱する方法等）により、上記式
（Ｖ）で示されるｇ−アミノキノリンが得られる。The C-nitroquinoline (IV) obtained in the above reaction is subjected to an appropriate reduction method (e.g., platinum oxide, palladium, in the presence of a catalyst such as Raney Kel, etc.), an appropriate solvent such as methanol,
The g-amino compound represented by the above formula (V) can be prepared by dissolving or suspending it in ethanol, acetic acid, etc. and hydrogenating it, heating it with zinc or iron in hydrochloric acid, or heating it in tin chloride and hydrochloric acid, etc. Quinoline is obtained.
上記反応で得られたｔ−アミノキノリン（Ｖ）を亜硝酸
す） ＩＪウムと適当な酸（例えば塩酸、硫酸等）に、
−コＯ−コＯ℃で反応させて上記式（Ｖａ）で示される
ジアゾニウム化合物を合成し、これを適当な溶媒（例え
ば酢酸等）に溶解した二酸化イオウと適当な触媒（例え
ば銅、塩化第一銅、塩化第二銅等）存在下で反応させて
上記式（ｖｂ ）で示されるキノリン−ｇ−スルホニル
クロリドを合成する。The t-aminoquinoline (V) obtained in the above reaction is mixed with nitrous acid and an appropriate acid (e.g. hydrochloric acid, sulfuric acid, etc.).
A diazonium compound represented by the above formula (Va) is synthesized by reacting the compound with the above formula (Va) at -CO-C0°C, which is then mixed with sulfur dioxide dissolved in an appropriate solvent (e.g. acetic acid, etc.) and an appropriate catalyst (e.g. copper, dichloride, etc.). (copper, cupric chloride, etc.) to synthesize quinoline-g-sulfonyl chloride represented by the above formula (vb).
上記反応で得られたキノリン−ざ−スルホニルクロリド
（ｖｂ ）を酸（例えば塩酸、硫酸等）もしくはアルカ
リ（例えば水酸化ナトリウム、水酸化カリウム等）水溶
液中あるいはそれらとメタノール、エタノール、ジオキ
サン等の極性溶媒との混合溶液中または水中で室温〜１
５θ℃で数分間から数時間加熱することにより上記式（
Ｉ）で示される本発明の化合物であるキノリンスルホン
酸が得られる。The quinoline-za-sulfonyl chloride (vb) obtained in the above reaction is dissolved in an acid (e.g., hydrochloric acid, sulfuric acid, etc.) or alkali (e.g., sodium hydroxide, potassium hydroxide, etc.) aqueous solution, or in a polar solution such as methanol, ethanol, dioxane, etc. In a mixed solution with a solvent or in water at room temperature ~ 1
By heating at 5θ℃ for several minutes to several hours, the above formula (
A quinoline sulfonic acid compound of the invention represented by I) is obtained.
（実施例）
次に本発明を実施例により更に詳細に説明するが、本発
明はその要旨を越えない限り実施例たより限定されるも
のではない。(Examples) Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to the Examples unless the gist thereof is exceeded.
参考例１
コーニトローＩＩ −ｎ−７’ロビルアニリンの合成
バラ−ｎ−プロピルアニリン２０９（／！ｒＯｍｍｏｌ
）を酢酸ｔｔｏｒｔｔｔに加え、無水酢酸／ ４Ｚ、
２＠ｌ （／ ！； Ｏｍｍｏｌ ）を加えた後、室
温で／、３時間攪拌させた。この反応液を氷水ｇｏｏｙ
ｘｔにあけ析出固体を濾取し、水で洗浄後、減圧乾燥さ
せることＫより、Ｎ−アセチル−バラ−ｎ−プロピルア
ニリンλｓ、 ／、 、！？ （収率９７．６％）を得
た。Reference Example 1 Synthesis of Konitro II-n-7'robylaniline Rose-n-propylaniline 209 (/!rOmmol
) to acetic acid ttorttt, acetic anhydride/4Z,
After adding 2@l (/!; Ommol), the mixture was stirred at room temperature for 3 hours. Add this reaction solution to ice water.
xt, the precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure. ? (yield 97.6%).
上記反応で得られたＮ−アセチル−バラーｎ−プロビル
アニリ７２０ｇ（／ ／ Ｊｍｍｏｌ ）を酢酸と無水
酢酸の／対ｌ混合溶液／！；ＯＲＩに溶解させ、７０〜
／ｊ−℃に冷却した後、９１Ｉ％発煙硝酸７．．７ｍＪ
（／ Ａ ＩＩ ｍｍｏｌ ）を内温が７３℃以上に
上昇しないように、３０分間かげて滴下した。さらにこ
の溶液を１５℃でコ時間撹拌した後、氷水／ｌにあけ析
出固体を濾取し、水で洗浄後、減圧乾燥させることによ
り、Ｎ−アセチルーコーニトローバラーｎ−プロピルア
ニリンココ、４’、９（収率ｆ ９．／％）を得た。720 g (/ / Jmmol) of N-acetyl-valer n-probylanili obtained in the above reaction was added to a //l mixed solution of acetic acid and acetic anhydride/! ;Dissolved in ORI, 70~
After cooling to /j-°C, 91I% fuming nitric acid7. ．． 7mJ
(/A II mmol) was added dropwise for 30 minutes so that the internal temperature did not rise above 73°C. This solution was further stirred at 15°C for an hour, poured into ice water/l, and the precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to obtain N-acetyl-conitrovalar n-propylaniline coco, 4 ', 9 (yield f 9./%) was obtained.
上記反応で得られたＮ−アセチル−ノーニトロ−バラ−
ｎ−プロピルアニリン２０９（９０ｒｎｍｏｌ ）を濃
塩酸とエタノールの／対／混合溶液２００−に溶解させ
た後、３時間加熱、還流させた。この反応液から、エタ
ノールを留去させた後、水を加え、アンモニア水で中和
（ｐＨＬｏ）し、塩化メチレンで抽出した。塩化メチレ
ン層を無水硫酸ナトリウムにより乾燥し、活性炭で処理
した後、塩化メチレンを留去することＫより２−二トロ
ーＩＩ −ｎ−プロピルアニリン１ｓｆｉ（収率９コ、
５％）を得た。N-acetyl-nonitro-bara obtained in the above reaction
After n-propylaniline 209 (90 rnmol) was dissolved in a mixed solution of concentrated hydrochloric acid and ethanol 200, the solution was heated and refluxed for 3 hours. After ethanol was distilled off from this reaction solution, water was added, neutralized with aqueous ammonia (pHLo), and extracted with methylene chloride. After drying the methylene chloride layer with anhydrous sodium sulfate and treating it with activated carbon, the methylene chloride was distilled off to give 2-nitro II-n-propylaniline 1sfi (yield 9 copies,
5%).
実施例／
ツーフェニル−６−ｎ−フ’ロピルーキノリンーｇ−ス
ルホン酸の合成
（１） 、２−フェニル−Ａ−ｎ−プロピル−ざ−二
トロキノリンの合成
濃塩酸／ＪＯ１ｄＫコーニトローダーｎ−プロビルアニ
リ７／ ２ｉ （６＆６ｍｍｏｌ ）、五酸化砒素り、
ｂ ｆｉ （，７ｊ、／ ｍｍｏｌ ）および塩化亜
鉛！、Ｊｇ（Ｊ ｇ、９ｍｍｏ１ ）を加え、加熱還流
下、ケイ皮アルデヒドＪＡ、ｌＩ、１ｉｌ（／ｑデ１ｇ
ｍｍｏｌ ）を３０分間かけて添加した。さらに６時間
還流した後、この反応液をクロロホルムで抽出し、分液
したクロロホルム層を濃塩酸で抽出した。残った反応液
と抽出した濃塩酸層を合わせて、水冷下、濃アンモニア
水でアルカリ性とした後、塩化メチレンで抽出した。塩
化メチレン層を無水硫酸ナトリウムにより乾燥した後、
濃縮し、得られた粗生成物をシリカゲルカラムクロマト
グラフィ（溶離液：クロロホルム−ｎ−ヘキサン）で精
製し、上記目的物ｐ、 ｒ ｇ （収率コＩ１．ｑ％）
を得た。Example/Synthesis of two-phenyl-6-n-propyl-quinoline-g-sulfonic acid (1), Synthesis of 2-phenyl-A-n-propyl-z-nitroquinoline Concentrated hydrochloric acid/JO1dK Konitroder n -Probil Anili 7/2i (6 & 6 mmol), arsenic pentoxide,
b fi (,7j,/mmol) and zinc chloride! , Jg (J g, 9 mmol) was added, and under heating reflux, cinnamic aldehyde JA, 1I, 1 il (/q de 1 g
mmol) was added over 30 minutes. After further refluxing for 6 hours, the reaction solution was extracted with chloroform, and the separated chloroform layer was extracted with concentrated hydrochloric acid. The remaining reaction solution and the extracted concentrated hydrochloric acid layer were combined, made alkaline with concentrated aqueous ammonia under water cooling, and then extracted with methylene chloride. After drying the methylene chloride layer with anhydrous sodium sulfate,
The obtained crude product was purified by silica gel column chromatography (eluent: chloroform-n-hexane) to obtain the above target products p, rg (yield: 1.q%).
I got it.
（２） コーフェニルー＆−ｎ−プロピル−ざ−アミ
ノキノリンの合成
濃塩酸３０ゴに塩化スズ（ｎ） ９． Ａ 、！ｉｒ
（グー、６ｍｍｏｌ ） ヲ加え、水冷下、コーフェニ
ルー６−ｎ−’；ｆロピルーざ一ニトロキノリン３ｇ（
／ ｐ、 、ｙ ｍｍｏｌ ）と濃塩酸／／、！；ｒａ
ｔの混合溶液を滴下した。滴下終了後、この反応液を３
０分間水冷下で攪拌した後、室温でさらに７時間攪拌し
た。反応混合物を水冷下、濃アンモニア水でアルカリ性
とした後、エーテルで抽出した。エーテル層を無水硫酸
ナトリウムにより乾燥した後、濃縮し、得られた粗生成
物をシリカゲルカラムクロマトグラフィ１１１１１ｉｉ
：’コロホルム−ｎ−へキサン）テ精製し、上記目的物
コ、Ａ！Ｉ（収率テロ、−％）を得た。(2) Synthesis of cophenylene and -n-propyl-za-aminoquinoline 30 g of concentrated hydrochloric acid and tin chloride (n) 9. A,! ir
(gu, 6 mmol) was added, and under water cooling, cophenylated 6-n-';
/ p, , y mmol ) and concentrated hydrochloric acid //,! ;ra
A mixed solution of t was added dropwise. After completing the dropwise addition, the reaction solution was diluted with 3
After stirring for 0 minutes under water cooling, the mixture was further stirred at room temperature for 7 hours. The reaction mixture was made alkaline with concentrated aqueous ammonia under water cooling, and then extracted with ether. The ether layer was dried over anhydrous sodium sulfate, concentrated, and the resulting crude product was subjected to silica gel column chromatography 11111ii.
A! I (yield rate, -%) was obtained.
（３） −一フェニル−Ａ−ｎ−７”ロビルキノリン
ーｇ−スルホン酸の合成
コーフェニルーＡ−ｎ−プロピル−ｇ−アミノキノリン
２ｇ（７，６ｍｍｏｌ ） Ｋ濃塩酸２０ｍ１を加え、
水冷下（０〜５℃）で、亜硝酸ナトリウム０． ｊ Ａ
９の水溶液ｇ ｍｅを滴下する。ことによりジアゾニ
ウム塩溶液を得た。−方亜硫酸ガスを飽和させた酢酸７
ゴに塩化銅（ＩＩ） ０．２ Ｋ ｇの水溶液０．６１
を加えた溶液を調製しておき、そこへ水冷下、ジアゾニ
ウム塩溶液を添加し、３．３時間攪拌した。この反応混
合物を氷水にあけ、クロロホルムにより抽出した。クロ
ロホルム層を炭酸水素ナトリウム水溶液および食塩水洗
より洗浄した後、無水硫酸ナトリウムにより乾燥した後
、濃縮し、得られた粗生成物をシリカゲルカラムクロマ
トグラフィ（溶離液：クロロホルム）でスルホニルクロ
リドを含むフラクションを集めることにより、２．６ｇ
の上記目的物と原料との混合物を得た。この混合物は、
それ以上精製することなく、メタノール１００−とコ規
定の水酸化ナトリウム水溶液３０プを加え、さらにｎ−
ブタノールを加えること釦より溶解させ、還流下７１７
時間加熱した。この反応液を水冷下、濃塩酸で弱酸性と
し、ｎ−ブタノールで抽出し、ｎ−ブタノールを濃縮、
乾固することにより上記目的物／、ｑ ｇ（収率３３．
３％）を得た。(3) Synthesis of -1-phenyl-A-n-7” lobilquinoline-g-sulfonic acid 2 g (7.6 mmol) of copheny-A-n-propyl-g-aminoquinoline 20 ml of concentrated K hydrochloric acid was added,
Under water cooling (0 to 5°C), sodium nitrite 0. j A
9 g me of the aqueous solution was added dropwise. A diazonium salt solution was thus obtained. - Acetic acid 7 saturated with sulfur dioxide gas
Copper(II) chloride 0.2 K g aqueous solution 0.61
A solution was prepared in advance, and a diazonium salt solution was added thereto under water cooling, and the mixture was stirred for 3.3 hours. This reaction mixture was poured into ice water and extracted with chloroform. The chloroform layer is washed with an aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product is subjected to silica gel column chromatography (eluent: chloroform) to collect fractions containing sulfonyl chloride. By this, 2.6g
A mixture of the above-mentioned target product and raw material was obtained. This mixture is
Without further purification, add 100 g of methanol and 30 g of aqueous normal sodium hydroxide solution, and then add n-
Add butanol and dissolve under reflux.
heated for an hour. The reaction solution was made weakly acidic with concentrated hydrochloric acid under water cooling, extracted with n-butanol, and concentrated with n-butanol.
By drying, the above target product /, q g (yield 33.
3%).
融点： ／ｇ９〜／ｑｆ℃（分解）
実施例コ
ツーフェニル−６−メチルキノリン−ざ−スルホン酸の
合成
実施例／の（１）および（２）と同様にして合成したコ
ーフェニルー６−メチルーｇ−アミノキノリンを出発原
料として、実施例１の（３）と同様にして、コーフェニ
ル−６−メチルキノリンーｇ −スルホン酸を合成した
。Melting point: /g9~/qf°C (decomposed) Example: Synthesis of co-phenyl-6-methylquinoline-sulfonic acid Co-phenylated-6-methyl-6-methyl-g- synthesized in the same manner as in (1) and (2) of Example Cophenyl-6-methylquinoline-g-sulfonic acid was synthesized in the same manner as in Example 1 (3) using aminoquinoline as a starting material.
融点： ３００℃以上
試験例／
本発明の化合物の薬理活性である細胞内Ｃａ”の過蓄積
の抑制の程度を評価するために、本発明の化合物を用い
てインプレテレノールの強心作用の抑制を測定した。Melting point: 300°C or higher Test Example: In order to evaluate the degree of suppression of hyperaccumulation of intracellular Ca, which is the pharmacological activity of the compound of the present invention, the compound of the present invention was used to suppress the inotropic effect of impreterenol. It was measured.
すなわち、イソプロテレノールは心筋細胞内へＣａ２＋
を過剰忙流入させることによりＣａ”の過蓄積を起すこ
とが知られているので（Ｆｌｅｃｋｅｎｓｔｅｉｎ Ａ
、 Ｊａｎｋｅ Ｊ、 Ｄｏｒｉｎｇ Ｈ。In other words, isoproterenol releases Ca2+ into myocardial cells.
It is known that excessive inflow of Ca causes overaccumulation of Ca (Fleckenstein A).
, Janke J, Doring H.
Ｌｅｄｅｒ Ｏ：Ｒｅｃｅｎｔ ａｄｖａｎｃｅｓ ｉ
ｎ ５ｔｕｄｉｅｓ ｏｎｃａｒｄｔａｃ ５ｔｒｕｃ
ｔｕｒｅ ａｎｄ ｍｅｔａｂｏｌｉｓｍ。Leder O:Recent advances i
n 5tudies oncardtac 5truc
ture and metabolism.
ｍｙｏｃａｒｄｉａｌ ｂｉｏｌｏｇｙ、 Ｖｏｌ、
ａ、 ｒ ｂ ３− ｒ ｇ ｏ。myocardial biology, Vol.
a, r b 3- r go.
ｉｑ’ｔｌＩ）、イソプロテレノールの作用を抑制する
化合物は細胞内Ｃａ”＋過蓄積を抑制するといえる。It can be said that a compound that suppresses the action of isoproterenol (iq'tlI) suppresses intracellular Ca''+ hyperaccumulation.
く方 法〉
雄性ハートレイ系モルモット（体重２りｏ〜３！；Ｏｆ
ｌ ）より摘出した右心室乳頭筋を栄養液（フレブルー
へンゼライト液）を満した臓器浴中に懸垂した。栄養液
の温度は３２’Ｃに保ち、９３％酸素と５％二酸化炭素
の混合ガスを通気した。乳頭筋には、約０．５１の静止
張力をかけ白金電極を介して持続／ ミＩ７秒、頻度ｌ
ヘルツ、閾値より７３％高い電圧の矩形波により電気刺
激した。乳頭筋の収縮力は、張カドランスジューサーを
介して測定し、ポリグラフにて記録した。約９０分間標
本を安定させた後、収縮が１００％以上増加する様に臓
器浴中忙インプロテレノール（１０−８〜１０−’Ｍ）
を加え最大反応が得られた時点に本発明の化合物を同様
に臓器浴中に加え、イソプロテレノールによる収縮増加
が何％抑制されるかを測定することにより、その抑制率
を求めた。Method: Male Hartley guinea pigs (weight 2.0~3.00;
The right ventricular papillary muscle extracted from 1) was suspended in an organ bath filled with a nutrient solution (Freblu-Henseleit solution). The temperature of the nutrient solution was maintained at 32'C, and a mixed gas of 93% oxygen and 5% carbon dioxide was bubbled through it. A resting tension of approximately 0.51 was applied to the papillary muscles via a platinum electrode for a duration of 7 seconds at a frequency of 1.
Electrical stimulation was performed using a square wave with a voltage 73% higher than the threshold in Hertz. The contractile force of the papillary muscles was measured via a tonic cadence juicer and recorded using a polygraph. After stabilizing the specimen for approximately 90 min, inproterenol (10-8 to 10-'M) was added to the organ bath so that contractions increased by more than 100%.
When the maximum reaction was obtained, the compound of the present invention was similarly added to the organ bath, and the inhibition rate was determined by measuring the percentage of increase in contraction caused by isoproterenol.
く結 果〉 各化合物の抑制率を下記表−コに示す。Results The inhibition rate of each compound is shown in the table below.
表λ
（発明の効果）
本発明の化合物は、心筋または血管平滑筋の細胞内Ｃａ
”＋の過蓄積を抑制する作用を有するので、本発明によ
れば各種の循環器系疾患、例えば狭心症、心筋梗塞、高
血圧、心不全あるいは不整脈等の予防および治療に有用
な新規なキノリンスルホン酸誘導体が提供される。Table λ (Effects of the Invention) The compound of the present invention has an effect on intracellular Ca of myocardium or vascular smooth muscle.
According to the present invention, a novel quinoline sulfone is useful for the prevention and treatment of various cardiovascular diseases, such as angina pectoris, myocardial infarction, hypertension, heart failure, and arrhythmia, because it has the effect of suppressing excessive accumulation of ``+''. Acid derivatives are provided.
Claims (1)
素原子、Ｃ＿１〜Ｃ＿６のアルキル基、ハロゲン原子、
カルボキシル基、アミノ基、Ｃ＿１〜Ｃ＿６のアシルア
ミノ基、Ｃ＿１〜Ｃ＿６のアルコキシ基、シアノ基、ニ
トロ基またはトリフルオロメチル基を表す。） で示されるキノリンスルホン酸誘導体またはその薬学的
に許容し得る塩。(1) The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼……(I) (In the above formula, R^1 and R^2 are each independently a hydrogen atom, C_1 to C_6 alkyl group, halogen atom,
It represents a carboxyl group, an amino group, an acylamino group of C_1 to C_6, an alkoxy group of C_1 to C_6, a cyano group, a nitro group, or a trifluoromethyl group. ) A quinoline sulfonic acid derivative or a pharmaceutically acceptable salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9437789A JPH02273662A (en) | 1989-04-14 | 1989-04-14 | Quinolinesulfonic acid derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9437789A JPH02273662A (en) | 1989-04-14 | 1989-04-14 | Quinolinesulfonic acid derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH02273662A true JPH02273662A (en) | 1990-11-08 |
Family
ID=14108629
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP9437789A Pending JPH02273662A (en) | 1989-04-14 | 1989-04-14 | Quinolinesulfonic acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH02273662A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006522073A (en) * | 2003-03-07 | 2006-09-28 | イタルファルマコ，ソシエダ アノニマ | Pharmaceutical composition comprising a sulfonic acid derivative |
| CN104710357A (en) * | 2015-03-13 | 2015-06-17 | 武汉瑞凯兴科技有限公司 | Synthetic method for 8-hydroxyquinoline |
-
1989
- 1989-04-14 JP JP9437789A patent/JPH02273662A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006522073A (en) * | 2003-03-07 | 2006-09-28 | イタルファルマコ，ソシエダ アノニマ | Pharmaceutical composition comprising a sulfonic acid derivative |
| CN104710357A (en) * | 2015-03-13 | 2015-06-17 | 武汉瑞凯兴科技有限公司 | Synthetic method for 8-hydroxyquinoline |
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