DK156056B - Analogifremgangsmaade til fremstilling af 4-amino-3-quinolin-carboxylsyrederivater - Google Patents
Analogifremgangsmaade til fremstilling af 4-amino-3-quinolin-carboxylsyrederivater Download PDFInfo
- Publication number
- DK156056B DK156056B DK128380AA DK128380A DK156056B DK 156056 B DK156056 B DK 156056B DK 128380A A DK128380A A DK 128380AA DK 128380 A DK128380 A DK 128380A DK 156056 B DK156056 B DK 156056B
- Authority
- DK
- Denmark
- Prior art keywords
- ethyl
- amino
- alkyl
- methoxy
- quinoline
- Prior art date
Links
- 238000000034 method Methods 0.000 title description 11
- UEFKMJWKPVAVND-UHFFFAOYSA-N 4-aminoquinoline-3-carboxylic acid Chemical class C1=CC=C2C(N)=C(C(O)=O)C=NC2=C1 UEFKMJWKPVAVND-UHFFFAOYSA-N 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims description 38
- -1 cyano, carbamoyl Chemical group 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 3
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- 238000005809 transesterification reaction Methods 0.000 claims 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 30
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 30
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 18
- 150000002148 esters Chemical class 0.000 description 16
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 241000700159 Rattus Species 0.000 description 13
- 239000002253 acid Substances 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 230000002496 gastric effect Effects 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
- 241000282472 Canis lupus familiaris Species 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 229960001340 histamine Drugs 0.000 description 6
- 230000028327 secretion Effects 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000012458 free base Substances 0.000 description 5
- VMPITZXILSNTON-UHFFFAOYSA-N o-anisidine Chemical compound COC1=CC=CC=C1N VMPITZXILSNTON-UHFFFAOYSA-N 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- WBRPQQSADOCKCH-UHFFFAOYSA-N 2-methylsulfanylaniline Chemical compound CSC1=CC=CC=C1N WBRPQQSADOCKCH-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 208000025865 Ulcer Diseases 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 108010012944 Tetragastrin Proteins 0.000 description 3
- 230000001476 alcoholic effect Effects 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- BBOZDELEERNECG-UHFFFAOYSA-N ethyl 4-chloro-8-methoxyquinoline-3-carboxylate Chemical compound COC1=CC=CC2=C(Cl)C(C(=O)OCC)=CN=C21 BBOZDELEERNECG-UHFFFAOYSA-N 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 229910000372 mercury(II) sulfate Inorganic materials 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 235000011007 phosphoric acid Nutrition 0.000 description 3
- 210000001187 pylorus Anatomy 0.000 description 3
- RGYLYUZOGHTBRF-BIHRQFPBSA-N tetragastrin Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)CCSC)C(N)=O)C1=CC=CC=C1 RGYLYUZOGHTBRF-BIHRQFPBSA-N 0.000 description 3
- 230000036269 ulceration Effects 0.000 description 3
- ULHFFAFDSSHFDA-UHFFFAOYSA-N 1-amino-2-ethoxybenzene Chemical compound CCOC1=CC=CC=C1N ULHFFAFDSSHFDA-UHFFFAOYSA-N 0.000 description 2
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 2
- UFFBMTHBGFGIHF-UHFFFAOYSA-N 2,6-dimethylaniline Chemical compound CC1=CC=CC(C)=C1N UFFBMTHBGFGIHF-UHFFFAOYSA-N 0.000 description 2
- VBLXCTYLWZJBKA-UHFFFAOYSA-N 2-(trifluoromethyl)aniline Chemical compound NC1=CC=CC=C1C(F)(F)F VBLXCTYLWZJBKA-UHFFFAOYSA-N 0.000 description 2
- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical compound NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 description 2
- AKCRQHGQIJBRMN-UHFFFAOYSA-N 2-chloroaniline Chemical compound NC1=CC=CC=C1Cl AKCRQHGQIJBRMN-UHFFFAOYSA-N 0.000 description 2
- MLPVBIWIRCKMJV-UHFFFAOYSA-N 2-ethylaniline Chemical compound CCC1=CC=CC=C1N MLPVBIWIRCKMJV-UHFFFAOYSA-N 0.000 description 2
- JJYPMNFTHPTTDI-UHFFFAOYSA-N 3-methylaniline Chemical compound CC1=CC=CC(N)=C1 JJYPMNFTHPTTDI-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001448 anilines Chemical class 0.000 description 2
- 230000001262 anti-secretory effect Effects 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- HINLPSGAVZPTIW-UHFFFAOYSA-N ethyl 4,8-dichloroquinoline-3-carboxylate Chemical compound ClC1=CC=CC2=C(Cl)C(C(=O)OCC)=CN=C21 HINLPSGAVZPTIW-UHFFFAOYSA-N 0.000 description 2
- PGGVUZUNDXCMSS-UHFFFAOYSA-N ethyl 4-chloro-8-methylquinoline-3-carboxylate Chemical compound CC1=CC=CC2=C(Cl)C(C(=O)OCC)=CN=C21 PGGVUZUNDXCMSS-UHFFFAOYSA-N 0.000 description 2
- PTGKZGLBFDWBKY-UHFFFAOYSA-N ethyl 4-chloro-8-methylsulfanylquinoline-3-carboxylate Chemical compound CSC1=CC=CC2=C(Cl)C(C(=O)OCC)=CN=C21 PTGKZGLBFDWBKY-UHFFFAOYSA-N 0.000 description 2
- DWXQUAHMZWZXHP-UHFFFAOYSA-N ethyl 4-chloroquinoline-3-carboxylate Chemical class C1=CC=CC2=C(Cl)C(C(=O)OCC)=CN=C21 DWXQUAHMZWZXHP-UHFFFAOYSA-N 0.000 description 2
- YBEOYBKKSWUSBR-UHFFFAOYSA-N ethyl 4-oxo-1h-quinoline-3-carboxylate Chemical class C1=CC=C2C(=O)C(C(=O)OCC)=CNC2=C1 YBEOYBKKSWUSBR-UHFFFAOYSA-N 0.000 description 2
- CRJUJZNGVQRIJL-UHFFFAOYSA-N ethyl 8-methoxy-4-(2-methylanilino)quinoline-3-carboxylate Chemical compound CCOC(=O)C1=CN=C2C(OC)=CC=CC2=C1NC1=CC=CC=C1C CRJUJZNGVQRIJL-UHFFFAOYSA-N 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 210000004211 gastric acid Anatomy 0.000 description 2
- 150000002431 hydrogen Chemical group 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 229960004592 isopropanol Drugs 0.000 description 2
- NZWOPGCLSHLLPA-UHFFFAOYSA-N methacholine Chemical compound C[N+](C)(C)CC(C)OC(C)=O NZWOPGCLSHLLPA-UHFFFAOYSA-N 0.000 description 2
- 229960002329 methacholine Drugs 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- GTDQGKWDWVUKTI-UHFFFAOYSA-N o-aminoacetophenone Chemical compound CC(=O)C1=CC=CC=C1N GTDQGKWDWVUKTI-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 210000002784 stomach Anatomy 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
- PXJACNDVRNAFHD-UHFFFAOYSA-N (2-methoxyphenyl)methanamine Chemical compound COC1=CC=CC=C1CN PXJACNDVRNAFHD-UHFFFAOYSA-N 0.000 description 1
- CJAAPVQEZPAQNI-UHFFFAOYSA-N (2-methylphenyl)methanamine Chemical compound CC1=CC=CC=C1CN CJAAPVQEZPAQNI-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- AQFLVLHRZFLDDV-UHFFFAOYSA-N 1-phenylpropan-1-amine Chemical compound CCC(N)C1=CC=CC=C1 AQFLVLHRZFLDDV-UHFFFAOYSA-N 0.000 description 1
- VVAKEQGKZNKUSU-UHFFFAOYSA-N 2,3-dimethylaniline Chemical compound CC1=CC=CC(N)=C1C VVAKEQGKZNKUSU-UHFFFAOYSA-N 0.000 description 1
- GEQNZVKIDIPGCO-UHFFFAOYSA-N 2,4-dimethoxyaniline Chemical compound COC1=CC=C(N)C(OC)=C1 GEQNZVKIDIPGCO-UHFFFAOYSA-N 0.000 description 1
- JDMFXJULNGEPOI-UHFFFAOYSA-N 2,6-dichloroaniline Chemical compound NC1=C(Cl)C=CC=C1Cl JDMFXJULNGEPOI-UHFFFAOYSA-N 0.000 description 1
- YKOLZVXSPGIIBJ-UHFFFAOYSA-N 2-Isopropylaniline Chemical compound CC(C)C1=CC=CC=C1N YKOLZVXSPGIIBJ-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- HEQOJEGTZCTHCF-UHFFFAOYSA-N 2-amino-1-phenylethanone Chemical compound NCC(=O)C1=CC=CC=C1 HEQOJEGTZCTHCF-UHFFFAOYSA-N 0.000 description 1
- HLCPWBZNUKCSBN-UHFFFAOYSA-N 2-aminobenzonitrile Chemical compound NC1=CC=CC=C1C#N HLCPWBZNUKCSBN-UHFFFAOYSA-N 0.000 description 1
- PUBYDOJONNWFJJ-UHFFFAOYSA-N 2-aminoquinoline-3-carboxylic acid Chemical compound C1=CC=C2C=C(C(O)=O)C(N)=NC2=C1 PUBYDOJONNWFJJ-UHFFFAOYSA-N 0.000 description 1
- PHJFVCMMPGGIDV-UHFFFAOYSA-N 2-anilinoprop-2-enoic acid Chemical compound OC(=O)C(=C)NC1=CC=CC=C1 PHJFVCMMPGGIDV-UHFFFAOYSA-N 0.000 description 1
- GBOUQGUQUUPGLO-UHFFFAOYSA-N 2-chloro-5-methoxyaniline Chemical compound COC1=CC=C(Cl)C(N)=C1 GBOUQGUQUUPGLO-UHFFFAOYSA-N 0.000 description 1
- WFNLHDJJZSJARK-UHFFFAOYSA-N 2-chloro-6-methylaniline Chemical compound CC1=CC=CC(Cl)=C1N WFNLHDJJZSJARK-UHFFFAOYSA-N 0.000 description 1
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- HJXIRCMNJLIHQR-UHFFFAOYSA-N 2-n,2-n-dimethylbenzene-1,2-diamine Chemical compound CN(C)C1=CC=CC=C1N HJXIRCMNJLIHQR-UHFFFAOYSA-N 0.000 description 1
- DPJCXCZTLWNFOH-UHFFFAOYSA-N 2-nitroaniline Chemical compound NC1=CC=CC=C1[N+]([O-])=O DPJCXCZTLWNFOH-UHFFFAOYSA-N 0.000 description 1
- LBVJYRBNPYGXPJ-UHFFFAOYSA-N 3-(3-ethoxypentan-3-ylperoxy)-3-oxopropanoic acid Chemical compound CCC(CC)(OCC)OOC(=O)CC(=O)O LBVJYRBNPYGXPJ-UHFFFAOYSA-N 0.000 description 1
- PYSGFFTXMUWEOT-UHFFFAOYSA-N 3-(dimethylamino)propan-1-ol Chemical compound CN(C)CCCO PYSGFFTXMUWEOT-UHFFFAOYSA-N 0.000 description 1
- KCHLDNLIJVSRPK-UHFFFAOYSA-N 3-methylsulfanylaniline Chemical compound CSC1=CC=CC(N)=C1 KCHLDNLIJVSRPK-UHFFFAOYSA-N 0.000 description 1
- HJSCQRDGGJZGJH-UHFFFAOYSA-N 4-chloroquinoline-3-carboxylic acid Chemical compound C1=CC=CC2=C(Cl)C(C(=O)O)=CN=C21 HJSCQRDGGJZGJH-UHFFFAOYSA-N 0.000 description 1
- ILNJBIQQAIIMEY-UHFFFAOYSA-N 4-oxo-1h-quinoline-3-carboxylic acid Chemical class C1=CC=CC2=C(O)C(C(=O)O)=CN=C21 ILNJBIQQAIIMEY-UHFFFAOYSA-N 0.000 description 1
- DSBIJCMXAIKKKI-UHFFFAOYSA-N 5-nitro-o-toluidine Chemical compound CC1=CC=C([N+]([O-])=O)C=C1N DSBIJCMXAIKKKI-UHFFFAOYSA-N 0.000 description 1
- BASNAOYNNASHFC-UHFFFAOYSA-N 8-methoxy-4-(2-methylanilino)quinoline-3-carboxylic acid Chemical compound OC(=O)C1=CN=C2C(OC)=CC=CC2=C1NC1=CC=CC=C1C BASNAOYNNASHFC-UHFFFAOYSA-N 0.000 description 1
- CSFTWNYYKHEIRE-UHFFFAOYSA-N 8-methoxy-4-(2-methylanilino)quinoline-3-carboxylic acid;hydrochloride Chemical compound Cl.OC(=O)C1=CN=C2C(OC)=CC=CC2=C1NC1=CC=CC=C1C CSFTWNYYKHEIRE-UHFFFAOYSA-N 0.000 description 1
- 101100231508 Caenorhabditis elegans ceh-5 gene Proteins 0.000 description 1
- QVSGXIKORIKQFE-UHFFFAOYSA-N Cl.NC1=NC2=CC=CC=C2C=C1C(=O)O Chemical compound Cl.NC1=NC2=CC=CC=C2C=C1C(=O)O QVSGXIKORIKQFE-UHFFFAOYSA-N 0.000 description 1
- KIWBPDUYBMNFTB-UHFFFAOYSA-N Ethyl hydrogen sulfate Chemical compound CCOS(O)(=O)=O KIWBPDUYBMNFTB-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 238000009835 boiling Methods 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
- 150000007942 carboxylates Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- LTMHNWPUDSTBKD-UHFFFAOYSA-N diethyl 2-(ethoxymethylidene)propanedioate Chemical class CCOC=C(C(=O)OCC)C(=O)OCC LTMHNWPUDSTBKD-UHFFFAOYSA-N 0.000 description 1
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 1
- YJXIUXZCLMQKHA-UHFFFAOYSA-N dimethylamino 8-methoxy-4-(2-methylanilino)-2-propylquinoline-3-carboxylate Chemical compound C(CC)C1=NC2=C(C=CC=C2C(=C1C(=O)ON(C)C)NC1=C(C=CC=C1)C)OC YJXIUXZCLMQKHA-UHFFFAOYSA-N 0.000 description 1
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- WABGGQNMHPDKMX-UHFFFAOYSA-N ethanol;ethyl 4-(2-carbamoylanilino)-8-methoxyquinoline-3-carboxylate;hydrochloride Chemical compound Cl.CCO.CCOC(=O)C1=CN=C2C(OC)=CC=CC2=C1NC1=CC=CC=C1C(N)=O WABGGQNMHPDKMX-UHFFFAOYSA-N 0.000 description 1
- OFADIQXKAGJEBQ-UHFFFAOYSA-N ethanol;ethyl 8-methoxy-4-[(2-methylphenyl)methylamino]quinoline-3-carboxylate;hydrochloride Chemical compound Cl.CCO.CCOC(=O)C1=CN=C2C(OC)=CC=CC2=C1NCC1=CC=CC=C1C OFADIQXKAGJEBQ-UHFFFAOYSA-N 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- WZSFHLLAUDLBGE-UHFFFAOYSA-N ethyl 4-(2,3-dimethylanilino)-8-methoxyquinoline-3-carboxylate sulfuric acid Chemical compound S(=O)(=O)(O)O.COC=1C=CC=C2C(=C(C=NC12)C(=O)OCC)NC1=C(C(=CC=C1)C)C WZSFHLLAUDLBGE-UHFFFAOYSA-N 0.000 description 1
- BPRQLHKEHADPED-UHFFFAOYSA-N ethyl 4-(2,4-dimethoxyanilino)-8-methoxyquinoline-3-carboxylate Chemical compound CCOC(=O)C1=CN=C2C(OC)=CC=CC2=C1NC1=CC=C(OC)C=C1OC BPRQLHKEHADPED-UHFFFAOYSA-N 0.000 description 1
- IJJNSCKCJMFURY-UHFFFAOYSA-N ethyl 4-(2,6-dichloroanilino)-8-methoxyquinoline-3-carboxylate Chemical compound CCOC(=O)C1=CN=C2C(OC)=CC=CC2=C1NC1=C(Cl)C=CC=C1Cl IJJNSCKCJMFURY-UHFFFAOYSA-N 0.000 description 1
- JVSKAUIBUCQZAR-UHFFFAOYSA-N ethyl 4-(2,6-dimethylanilino)-8-methoxyquinoline-3-carboxylate;hydrobromide Chemical compound Br.CCOC(=O)C1=CN=C2C(OC)=CC=CC2=C1NC1=C(C)C=CC=C1C JVSKAUIBUCQZAR-UHFFFAOYSA-N 0.000 description 1
- GMKXWJUQDZTZQH-UHFFFAOYSA-N ethyl 4-(2-acetylanilino)-8-methoxyquinoline-3-carboxylate;hydrochloride Chemical compound Cl.CCOC(=O)C1=CN=C2C(OC)=CC=CC2=C1NC1=CC=CC=C1C(C)=O GMKXWJUQDZTZQH-UHFFFAOYSA-N 0.000 description 1
- RRZNSQNUZMCXSU-UHFFFAOYSA-N ethyl 4-(2-chloro-5-methoxyanilino)-8-methoxyquinoline-3-carboxylate;hydrobromide Chemical compound Br.CCOC(=O)C1=CN=C2C(OC)=CC=CC2=C1NC1=CC(OC)=CC=C1Cl RRZNSQNUZMCXSU-UHFFFAOYSA-N 0.000 description 1
- WDLHYKPECRHGNX-UHFFFAOYSA-N ethyl 4-(2-chloroanilino)-8-methoxyquinoline-3-carboxylate;hydrochloride Chemical compound Cl.CCOC(=O)C1=CN=C2C(OC)=CC=CC2=C1NC1=CC=CC=C1Cl WDLHYKPECRHGNX-UHFFFAOYSA-N 0.000 description 1
- SQJKQVCDNMSUBK-UHFFFAOYSA-N ethyl 4-(2-cyanoanilino)-8-methoxyquinoline-3-carboxylate;hydrochloride Chemical compound Cl.CCOC(=O)C1=CN=C2C(OC)=CC=CC2=C1NC1=CC=CC=C1C#N SQJKQVCDNMSUBK-UHFFFAOYSA-N 0.000 description 1
- AMZDIHIVIBCHRX-UHFFFAOYSA-N ethyl 4-(2-ethoxyanilino)-8-methoxyquinoline-3-carboxylate;hydrochloride Chemical compound Cl.CCOC(=O)C1=CN=C2C(OC)=CC=CC2=C1NC1=CC=CC=C1OCC AMZDIHIVIBCHRX-UHFFFAOYSA-N 0.000 description 1
- RPVDYDOFURVOTB-UHFFFAOYSA-N ethyl 4-(2-ethylanilino)-8-methoxyquinoline-3-carboxylate Chemical compound CCOC(=O)C1=CN=C2C(OC)=CC=CC2=C1NC1=CC=CC=C1CC RPVDYDOFURVOTB-UHFFFAOYSA-N 0.000 description 1
- QZPNMHNGXWHCAY-UHFFFAOYSA-N ethyl 4-(2-ethylanilino)-8-methoxyquinoline-3-carboxylate;phosphoric acid Chemical compound OP(O)(O)=O.CCOC(=O)C1=CN=C2C(OC)=CC=CC2=C1NC1=CC=CC=C1CC QZPNMHNGXWHCAY-UHFFFAOYSA-N 0.000 description 1
- HLIPVESJSJDQQI-UHFFFAOYSA-N ethyl 4-(2-ethylanilino)-8-methoxyquinoline-3-carboxylate;sulfuric acid Chemical compound OS(O)(=O)=O.CCOC(=O)C1=CN=C2C(OC)=CC=CC2=C1NC1=CC=CC=C1CC HLIPVESJSJDQQI-UHFFFAOYSA-N 0.000 description 1
- ZGIIOSQVHPDWCS-UHFFFAOYSA-N ethyl 4-(2-fluoroanilino)-8-methoxyquinoline-3-carboxylate;hydrochloride Chemical compound Cl.CCOC(=O)C1=CN=C2C(OC)=CC=CC2=C1NC1=CC=CC=C1F ZGIIOSQVHPDWCS-UHFFFAOYSA-N 0.000 description 1
- ZAKLWUUCPUBFER-UHFFFAOYSA-N ethyl 4-(2-methoxyanilino)-8-methylquinoline-3-carboxylate;hydrochloride Chemical compound Cl.CCOC(=O)C1=CN=C2C(C)=CC=CC2=C1NC1=CC=CC=C1OC ZAKLWUUCPUBFER-UHFFFAOYSA-N 0.000 description 1
- BCZGGRHBMFVMAL-UHFFFAOYSA-N ethyl 4-(2-methoxyanilino)-8-methylsulfanylquinoline-3-carboxylate;hydrochloride Chemical compound Cl.CCOC(=O)C1=CN=C2C(SC)=CC=CC2=C1NC1=CC=CC=C1OC BCZGGRHBMFVMAL-UHFFFAOYSA-N 0.000 description 1
- SUDISUGACXXEQH-UHFFFAOYSA-N ethyl 4-(2-methylanilino)-8-methylsulfanylquinoline-3-carboxylate Chemical compound CCOC(=O)C1=CN=C2C(SC)=CC=CC2=C1NC1=CC=CC=C1C SUDISUGACXXEQH-UHFFFAOYSA-N 0.000 description 1
- RAHPQXXWHQEGKO-UHFFFAOYSA-N ethyl 4-(benzylamino)-8-methoxyquinoline-3-carboxylate;phosphoric acid Chemical compound OP(O)(O)=O.CCOC(=O)C1=CN=C2C(OC)=CC=CC2=C1NCC1=CC=CC=C1 RAHPQXXWHQEGKO-UHFFFAOYSA-N 0.000 description 1
- SSGZZDSQOCMZNK-UHFFFAOYSA-N ethyl 4-anilino-8-(dimethylamino)quinoline-3-carboxylate;hydrochloride Chemical compound Cl.CCOC(=O)C1=CN=C2C(N(C)C)=CC=CC2=C1NC1=CC=CC=C1 SSGZZDSQOCMZNK-UHFFFAOYSA-N 0.000 description 1
- YMSKONPFQZCVPL-UHFFFAOYSA-N ethyl 4-anilino-8-methoxyquinoline-3-carboxylate Chemical compound CCOC(=O)C1=CN=C2C(OC)=CC=CC2=C1NC1=CC=CC=C1 YMSKONPFQZCVPL-UHFFFAOYSA-N 0.000 description 1
- DGFFVGQOZXGJAE-UHFFFAOYSA-N ethyl 4-anilino-8-methoxyquinoline-3-carboxylate;hydrochloride Chemical compound Cl.CCOC(=O)C1=CN=C2C(OC)=CC=CC2=C1NC1=CC=CC=C1 DGFFVGQOZXGJAE-UHFFFAOYSA-N 0.000 description 1
- JLVNAMDYLDOJGR-UHFFFAOYSA-N ethyl 4-chloro-8-(dimethylamino)quinoline-3-carboxylate Chemical compound CN(C)C1=CC=CC2=C(Cl)C(C(=O)OCC)=CN=C21 JLVNAMDYLDOJGR-UHFFFAOYSA-N 0.000 description 1
- UNMTVPUUJFYTOJ-UHFFFAOYSA-N ethyl 4-chloro-8-ethoxyquinoline-3-carboxylate Chemical compound CCOC1=CC=CC2=C(Cl)C(C(=O)OCC)=CN=C21 UNMTVPUUJFYTOJ-UHFFFAOYSA-N 0.000 description 1
- ULHHZGBLUSMTHM-UHFFFAOYSA-N ethyl 8-(dimethylamino)-4-(2-methylanilino)quinoline-3-carboxylate Chemical compound CCOC(=O)C1=CN=C2C(N(C)C)=CC=CC2=C1NC1=CC=CC=C1C ULHHZGBLUSMTHM-UHFFFAOYSA-N 0.000 description 1
- YJTVQXSFSKEYMR-UHFFFAOYSA-N ethyl 8-(dimethylamino)-4-oxo-1h-quinoline-3-carboxylate Chemical compound CN(C)C1=CC=CC2=C(O)C(C(=O)OCC)=CN=C21 YJTVQXSFSKEYMR-UHFFFAOYSA-N 0.000 description 1
- BIVZERGXYOKECF-UHFFFAOYSA-N ethyl 8-chloro-4-(2-methoxyanilino)quinoline-3-carboxylate;hydrochloride Chemical compound Cl.CCOC(=O)C1=CN=C2C(Cl)=CC=CC2=C1NC1=CC=CC=C1OC BIVZERGXYOKECF-UHFFFAOYSA-N 0.000 description 1
- OFPIUBQWPDRNCD-UHFFFAOYSA-N ethyl 8-chloro-4-(2-methylanilino)quinoline-3-carboxylate Chemical compound CCOC(=O)C1=CN=C2C(Cl)=CC=CC2=C1NC1=CC=CC=C1C OFPIUBQWPDRNCD-UHFFFAOYSA-N 0.000 description 1
- CVTZGJPEFPRNNB-UHFFFAOYSA-N ethyl 8-chloro-4-oxo-1h-quinoline-3-carboxylate Chemical compound C1=CC=C2C(=O)C(C(=O)OCC)=CNC2=C1Cl CVTZGJPEFPRNNB-UHFFFAOYSA-N 0.000 description 1
- LTPVJDPFDLGLRT-UHFFFAOYSA-N ethyl 8-ethoxy-4-(2-methoxyanilino)quinoline-3-carboxylate;hydrochloride Chemical compound Cl.CCOC(=O)C1=CN=C2C(OCC)=CC=CC2=C1NC1=CC=CC=C1OC LTPVJDPFDLGLRT-UHFFFAOYSA-N 0.000 description 1
- PIZUEXPYKUOJJJ-UHFFFAOYSA-N ethyl 8-ethoxy-4-(2-methylanilino)quinoline-3-carboxylate;hydrochloride Chemical compound Cl.CCOC(=O)C1=CN=C2C(OCC)=CC=CC2=C1NC1=CC=CC=C1C PIZUEXPYKUOJJJ-UHFFFAOYSA-N 0.000 description 1
- TWGHZFJRCAQPRL-UHFFFAOYSA-N ethyl 8-ethoxy-4-oxo-1h-quinoline-3-carboxylate Chemical compound C1=CC=C2C(=O)C(C(=O)OCC)=CNC2=C1OCC TWGHZFJRCAQPRL-UHFFFAOYSA-N 0.000 description 1
- MJNAFZWEKGYYQT-UHFFFAOYSA-N ethyl 8-methoxy-4-(1-phenylethylamino)quinoline-3-carboxylate;hydrate Chemical compound O.CCOC(=O)C1=CN=C2C(OC)=CC=CC2=C1NC(C)C1=CC=CC=C1 MJNAFZWEKGYYQT-UHFFFAOYSA-N 0.000 description 1
- GWABEZHJVSPHNE-UHFFFAOYSA-N ethyl 8-methoxy-4-(2-methoxyanilino)quinoline-3-carboxylate;hydrochloride Chemical compound Cl.CCOC(=O)C1=CN=C2C(OC)=CC=CC2=C1NC1=CC=CC=C1OC GWABEZHJVSPHNE-UHFFFAOYSA-N 0.000 description 1
- MGXKVCVQJWYAOB-UHFFFAOYSA-N ethyl 8-methoxy-4-(2-methylanilino)quinoline-3-carboxylate;phosphoric acid Chemical compound OP(O)(O)=O.CCOC(=O)C1=CN=C2C(OC)=CC=CC2=C1NC1=CC=CC=C1C MGXKVCVQJWYAOB-UHFFFAOYSA-N 0.000 description 1
- GWRHIGMXHHRFEC-UHFFFAOYSA-N ethyl 8-methoxy-4-(2-methylanilino)quinoline-3-carboxylate;sulfuric acid Chemical compound OS(O)(=O)=O.CCOC(=O)C1=CN=C2C(OC)=CC=CC2=C1NC1=CC=CC=C1C GWRHIGMXHHRFEC-UHFFFAOYSA-N 0.000 description 1
- LOPISVUVHAYYRS-UHFFFAOYSA-N ethyl 8-methoxy-4-(2-methylsulfanylanilino)quinoline-3-carboxylate;hydrochloride Chemical compound Cl.CCOC(=O)C1=CN=C2C(OC)=CC=CC2=C1NC1=CC=CC=C1SC LOPISVUVHAYYRS-UHFFFAOYSA-N 0.000 description 1
- ZLEIPGHLPPITMX-UHFFFAOYSA-N ethyl 8-methoxy-4-(2-nitroanilino)quinoline-3-carboxylate Chemical compound CCOC(=O)C1=CN=C2C(OC)=CC=CC2=C1NC1=CC=CC=C1[N+]([O-])=O ZLEIPGHLPPITMX-UHFFFAOYSA-N 0.000 description 1
- OPLNDEGFDPLWPZ-UHFFFAOYSA-N ethyl 8-methoxy-4-(2-propan-2-ylanilino)quinoline-3-carboxylate Chemical compound CCOC(=O)C1=CN=C2C(OC)=CC=CC2=C1NC1=CC=CC=C1C(C)C OPLNDEGFDPLWPZ-UHFFFAOYSA-N 0.000 description 1
- GQUGXNGXNZMBKS-UHFFFAOYSA-N ethyl 8-methoxy-4-(3-methylanilino)quinoline-3-carboxylate;hydrate;hydrochloride Chemical compound O.Cl.CCOC(=O)C1=CN=C2C(OC)=CC=CC2=C1NC1=CC=CC(C)=C1 GQUGXNGXNZMBKS-UHFFFAOYSA-N 0.000 description 1
- JUOFWQZLZCOSPM-UHFFFAOYSA-N ethyl 8-methoxy-4-(4-methylanilino)quinoline-3-carboxylate;hydrate;hydrochloride Chemical compound O.Cl.CCOC(=O)C1=CN=C2C(OC)=CC=CC2=C1NC1=CC=C(C)C=C1 JUOFWQZLZCOSPM-UHFFFAOYSA-N 0.000 description 1
- WTSHTUPDVKVIMP-UHFFFAOYSA-N ethyl 8-methoxy-4-[2-(trifluoromethyl)anilino]quinoline-3-carboxylate;hydrochloride Chemical compound Cl.CCOC(=O)C1=CN=C2C(OC)=CC=CC2=C1NC1=CC=CC=C1C(F)(F)F WTSHTUPDVKVIMP-UHFFFAOYSA-N 0.000 description 1
- HCYNWEIHLHVPEW-UHFFFAOYSA-N ethyl 8-methoxy-4-oxo-1h-quinoline-3-carboxylate Chemical compound C1=CC=C2C(=O)C(C(=O)OCC)=CNC2=C1OC HCYNWEIHLHVPEW-UHFFFAOYSA-N 0.000 description 1
- HYUYDOCMASKUMM-UHFFFAOYSA-N ethyl 8-methyl-4-oxo-1h-quinoline-3-carboxylate Chemical compound C1=CC=C2C(=O)C(C(=O)OCC)=CNC2=C1C HYUYDOCMASKUMM-UHFFFAOYSA-N 0.000 description 1
- MOYXAWSNAWARCE-UHFFFAOYSA-N ethyl 8-methylsulfanyl-4-(2-methylsulfanylanilino)quinoline-3-carboxylate Chemical compound CCOC(=O)C1=CN=C2C(SC)=CC=CC2=C1NC1=CC=CC=C1SC MOYXAWSNAWARCE-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000002198 insoluble material Substances 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
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- CDGNLUSBENXDGG-UHFFFAOYSA-N meta-Cresidine Chemical compound COC1=CC=C(N)C(C)=C1 CDGNLUSBENXDGG-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 1
- QJEXJBMBKNYZJY-UHFFFAOYSA-N methoxy(phenyl)methanamine Chemical compound COC(N)C1=CC=CC=C1 QJEXJBMBKNYZJY-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- KEBXGLIHHLGNJH-UHFFFAOYSA-N n-methylsulfanylaniline Chemical compound CSNC1=CC=CC=C1 KEBXGLIHHLGNJH-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000024717 negative regulation of secretion Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000286 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
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical compound C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 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
- 238000012360 testing method Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
DK 156056 B
o
Den foreliggende opfindelse angår en analogifrem-gangsmåde til fremstilling af hidtil ukendte 4-amino-3--quinolincarboxylsyrederivater med den i krav 11 s indledning anførte almene formel I, hvilke formindsker gastrisk 5 sekretion stimuleret af sekretionsfremmende midler, såsom histamin, tetragastrin og føde. De omhandlede derivater er nyttige til forebyggelse eller behandling af peptiske sårdannelser hos pattedyr.
Diuretisk og antidepressiv virkning af visse 4-ani-10 lino-3-quinolinearboxylsyreestere og 6-chlorderivater der af er beskrevet af Hanifin, J.W. i US patent nr. 3.470.186 og J. Med. Chem. 1969, 12(6), 1096-7.
Kermack et al., J. Chem. Soc., 1951, 1389-92 beskriver fremstillingen af 6-substituerede 4-anilino-3-qui-15 nolincarboxylsyrer og estere deraf. Sen. et al., J. Indian Chem. Soc., 34, 906-8 (1957) beskriver fremstillingen af 7-substituerede 4-amino-3-quinolincarboxylsyreamider.
Elslager et al., J. Med. Pharm. Chem. 5, 546-58 (1962) beskriver fremstillingen af 4-anilino-7-chlor-3-quinolin-20 carboxylsyre pg dens ethylester.
Antisekretorisk virkning og virkning mod sårdannelse af 4-amino-3-quinolincarboxylsyrer og estere deraf er hidtil ukendt.
De ved fremgangsmåden ifølge opfindelsen fremstil-25 lede forbindelser er 4-amino-3-quinolincarboxylsyrer og estere deraf med den almene formel NHRe —CO2R3 (I)
Ri hvori R1 betyder alkyl, O-alkyl, S-alkyl, halogen eller dialkylami-35 no, 2
O
2
DK 156056B
R betyder phenyl, phenyl-alkyl eller phenyl substitueret med 1-3 grupper valgt blandt alkyl, O-alkyl, S-alkyl, halogen, cyano, carbamoyl, carboxy, acetyl, trifluormethyl og nitro, og 3 5 R betyder hydrogen, alkyl, dimethylamino-alkyl eller alkoxy-alkyl, idet de nævnte alkyl- og alkoxygrupper er ligekædede eller forgrenede og indeholder 1-8 carbonatomer, således som det · også er tilfældet med de i øvrigt i den foreliggende be-10 skrivelse nævnte alkyIgrupper, eller farmaceutisk acceptable syreadditionssalte deraf.
Den antisekretoriske virkning på produktionen af mavesaft og saltsyre hos pylorus-underbundne rotter er på-vist ved indgivelse af estere af 4-amino-3-quinolincarboxyl:i; 15 syrerne fremstillet ifølge opfindelsen oralt, subcutant, intraperitonealt, intraduodenalt og intravenøst. Der påvises også en effektiv reduktion af sårdannelse hos pylorus -underbundne rotter. Det er også påvist, at forbindelserne med den ovenfor anførte formel I reducerer gastrisk 20 sekretion induceret af f.eks. histamin, tetragastrin og methacholin. Mavesyreproduktionen hos hunde med Heiden-hainpose stimuleret med føde reduceres også.
Opfindelsens formål er at tilvejebringe hidtil u-kendte 4-amino-3-quinolincarboxylsyrer og estere deraf, 25 der er særlig effektive til behandling af gastriske sårdannelser. .
Som ligekædede og forgrenede alkylgrupper med op til 8 carbonatomer kan der f.eks. nævnes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, amyl, iso-30 amyl, hexyl, heptyl og octyl.
Repræsentative eksempler på phenyl-alkyIgrupper er benzyl (phenylmethyl), α-methylbenzyl, phenylethyl, phénylpropyl og phenylbutyl.
Fremgangsmåden ifølge opfindelsen er ejendommelig 35 ved, at en forbindelse med den almene formel II
DK 156056B
O
3
Cl [^YYC°2R,3 (II) 6 hvori R^ har den ovenfor angivne betydning, og R' 3 betyder alkyl med 1-8 carbonatomer, omsættes med en amin med den almene formel R2NH2, hvori R2 har den ovenfor angivne 10 betydning, hvorefter den fremstillede forbindelse eventuelt hydrolyseres til erstatning af gruppen R'^ med hydrogen, eller R'2 i den fremstillede forbindelse eventuelt underkastes en omforestringsreaktion, hvorefter den fremstillede forbindelse eventuelt omdannes til et farmaceutisk accep-15 tabelt salt deraf.
Forbindelserne med formlen II fremstilles ved chlorering af 4-hydroxy-3-quinolincarboxylsyreestere med phosphoroxychlorid, generelt ved metoden, der beskrives af Kermack og Storey, J. Chem. Soc. 1951, s. 1389-92. Omsæt-20 ningen er følgende: OH C1 C02R'3 . P0.cl3...»
25 I T
R1 Rx (III) (II) hvori R^ har den ovenfor angivne betydning, og R'3 betyder 30 alkyl med 1-8 carbonatomer.
Forbindelserne med formlen III, hvori R'3 betyder ethyl, fremstilles ved opvarmning af en blanding af passende substituerede aniliner og diethyl-ethoxymethylenma-lonat til dannelse af et intermediært anilinoacrylat med 35 påfølgende ringslutning i et højtkogende opløsningsmiddel, såsom diphenyloxid, som beskrevet af Price og Roberts i
O
4
DK 156056B
J. Amer. Chem. Soc. 68_, 1204-8. Omsætningen er vist i følgende reaktionsligning:
5 Γ CalfeOgC C02 C2 HS
/ M + C2Hs0CH=C(C02C2H5)2 * Y\\ . ^AnA . .
R1 _R1 H
(V) 21^-250^./ 10 /^° (IV)
OH
/Sn/^v_C02C2H5 . R! (III') 15
Syrerne (R^hydrogen) ifølge den foreliggende opfindelse kan fremstilles ud fra estrene (R^alkyl) ved sædvanlige metoder til hydrolyse, og andre estere ifølge den foreliggende opfindelse kan fremstilles ved sædvanlige me-20 toder til omforestring.
Ved anvendelse af den ovennævnte metode ifølge Price og Roberts fremstilles følgende ethyl-4-hydroxy-3-quino-lincarboxylater med formlen III ud fra diethylethoxymethoxy-malonat og anilin eller kendte anilinderivater som følger: 25 Ethyl-4-hydroxy-8-methoxy-3-quinolincarboxylat ud fra 2-methoxyanilin; smp. 243-246°C.
Ethyl-4-hydroxy-8-ethoxy-3-quino1incarboxylat ud fra 2-ethoxyanilin; smp. 198-200°C.
30 Ethyl-4-hydroxy-8-methyl-3-quinolincarboxylat ud fra 2-methylanilin; smp. 271-274°C.
35 / *
O
5
DK 156056B
Ethyl-4-hydroxy-.8-methylthio-3-quinolincarboxylat ud fra 2-methylthioanilin; smp. 201-204°C.
Ethyl-4-hydroxy-8-chlor-3-quinolincarboxylat ud fra 2-chloranilin; smp. 255-259°C.
5 Ethyl-4-hydroxy-8-dimethylamino-3-quinolincarbo- xylat ud fra 2-dimethylaminoanilin; smp. 176-180°C.
Fremstillingseksempel a illustrerer synteseproceduren, der anvendes til fremstilling af 4-chlorforbindel-serne med formlen II, der er udgangsforbindelser til frem-10 stilling af forbindelserne med formlen I.
Eksempel a
Ethyl-4-chlor-8-methoxy-3-quinolincarboxylat.
En omrørt blanding af 66,63 g (0,269 mol) ethyl-15 -4-hydroxy-8-methoxyquinolin-3-carboxylat og 350 ml phos-phoroxychlorid opvarmes, indtil alt fast stof er opløst, og opvarmes derpå til tilbagesvaling i 2 timer. Efter afkøling til under 100°C koncentreres blandingen i en rotationsfordamper. Den tilbageværende olie opløses i 100 ml 20 acetone, og opløsningen udhældes på en blanding af is og vand (800 ml). Blandingen neutraliseres med 6N natriumhydroxidopløsning, og det faste produkt ekstraheres successivt med 450 ml, 250 ml og 100 ml's portioner af methylen- chlorid. Ekstrakterne forenes, vaskes med vand, tørres over 25 vandfrit magnesiumsulfat og koncentreres, hvorved der fas 68,16 g råprodukt. Dette råprodukt opløses i 500 ml varmt toluen, og der filtreres til fjernelse af en lille mængde uopløseligt materiale. Toluenopløsningen filtreres gennem et lag af 250 g fluorisil efterfulgt af 2 liter toluen og 30 4 liter chloroform. Den rensede opløsning koncentreres til dannelse af 64,17 g olie (89%), der krystalliserer til et næsten hvidt fast stof ved afkøling. Det faste stof smelter ved 75-77°C.
35 6
DK 156056B
o
Analyse: beregnet for C-j^Hj^NO^Cl: C,58.77; H,4.55 N,5.27 fundet : C,58.58; H,4.61 N,5.33 5
Eksempel b-f
Ved anvendelse af metoderi ifølge eksempel a og erstatningen med de pågældende ethyl-4~hydroxy-3-quinolincar-10 boxylater med formlen III, der er anført ovenfor, fremstil les følgende ethyl-4-chlor-quinolin-3-carboxylater og anvendes direkte: (b) Ethyl-4-chlor-8-ethoxy-3-quinolincarboxylat (c) Ethyl-4-chlor-8-methyl-3-quinolincarboxylat 15 (d) Ethyl-4-chlor-8-methylthio-3-quinolincarboxylat (e) Ethyi-4,8-dichlor-3-quinolincarboxylat ( f) Ethyl-4-chlor-8-(dimethylamino)-3-quinolin-carboxylat.
En generel metode til fremstilling af estere med 20 formlen I (R^alkyl) ifølge den foreliggende opfindelse er at omsætte en passende 4-chlor-3-quinolincarboxylsyrees-ter med en passende amin i et polært aprotisk opløsningsmiddel, såsom tetrahydrofuran eller dioxan, idet reaktionen følges ved tyndtlagskromatografi, og der anvendes 25 en sådan temperatur og tid, at omsætningen bliver fuldstændig. I nogle tilfælde kan den reagerende amin også anvendes som opløsningsmiddel. Der anvendes forskellige opløsningsmidler til omkrystallisation. Til fremstilling af den frie base ud fra et salt opløses saltet, der tilsættes 30 en base, såsom natriumhydroxid, og den frie base ekstrahe-res med et egnet organisk opløsningsmiddel. Til fremstilling af additionssalte blandes den frie base med en alkoholisk opløsning af en syre, f.eks. phosphorsyre eller svovlsyre.
35 7
DK 156056 B
O
Det foregående er en generel beskrivelse af, hvorledes estrene med formlen I fremstilles.De følgende eksempler 1 og 2 illustrerer fremstillingen af esterforbindelserne generelt. Estrene ifølge eksempel 3-45 og 48-54 frem-5 stilles også ved omsætning af en passende amin med et passende ethyl-4-chlor-3-quinolincarboxylat fra eksempel a til f. Eksempel 55-58 illustrerer fremstillingen af estere, hvori betyder alkyl, dimethylamino-alkyl eller alkoxy--alkyl ved omforestring af estere, hvori R^ betyder alkyl.
10 Fremstillingen af syrerne og syresaltene deraf med formlen I (R3=hydrogen) illustreres i eksempel 46 og 47, hvori esteren hydrolyseres til syren. Metalsalte af syrerne, såsom alkalimetalsalte, kan også fremstilles på sædvanlig måde ved omsætning med en alkalimetalbase og isolering af 15 saltene. Eksempel 59-62 illustrerer yderligere omdannelsen af frie baser af estere af forbindelser fremstillet ifølge opfindelsen til deres syreadditionssalte. De fysiske data og analyser er anført i tabel I og II.
Fremgangsmåden ifølge opfindelsen illustreres nn nærmere ved hjælp af de følgende eksempler.
Eksempel 1
Ethyl-8-methoxy-4-[(2-methylphenyl)-amino]-3-qui-nolin-carboxylat-hydrochlorid.
Til en opløsning af 5,31 g (19,98 mmol) ethyl-4--chlor-8-methoxy-3-quinolincarboxylat opløst i 40 ml te-trahydrofuran sættes 2,15 g (20,06 mmol) o-toluidin opløst i 40 ml tetrahydrofuran. Opløsningen omrøres under udelukkel-30 se af fugtighed ved 60°C i 18 timer. Det gule faste bundfald frafiltreres og vaskes med isopropylether, hvorved der fås et udbytte på 7*13 g (95,7%). Produktet omkrystalliseres 3 gange fra methylenchlorid: ethylacetat, smp.: 191-193,5°C. Analyse: beregnet for C2oH21C1N2°3: C,64.43; H,5.68; 35 N,7.51 fundet : C,64.36; H,5.65; N,7.62
DK 156056 B
8 o
Eksempel 2
Ethyl-4-(phenylamino)-8-methoxy-3-guinolincarboxylat.
Til en opløsning af 6,0 g (22,5 mmol) ethyl-4-chlor-8--methoxy-3-quinolincarboxylat i 80 ml tetrahydrofuran sættes 5 2,3 g (24,8 mmol) anilin i 60 ml tetrahydrofuran. Opløsningen opvarmes i kort tid, og efter henstand i 10 minutter begynder et gult fast stof at udfælde. Blandingen holdes ved stuetemperatur i 18 timer. Opløsningsmidlet afdampes i en rotationsfordamper. Remanensen opløses i 200 ml methanol, og der 10 indstilles til en let basisk pH-værdi (8) med natriumhydro-gencarbonat. Der tilsættes 700 ml vand, og der dannes en olie, der størkner og efter henstand udkrystalliserer en yderligere mængde fast stof. Det faste stof frafiltreres og tørres i luften, hvorved der fås 6,9 g (95%) af et rå-15 produkt. Det faste stof opløses i 300 ml varm isooctan, og opløsningen behandles med kul og filtreres. Filtratets volumen reduceres til 150 ml. Ved afkøling udfældes der bleggule nåle i en mængde på 6,5 g (89%) med et smp. på 120-121°C.
20 Analyse beregnet for ci9Hi8N2°3: C,70.79; H,5.63; N,8.69 fundet : C,70.91; H,5.65; N,8.77
Eksempel 3-45 I de følgende eksempler betegnes forbindelserne 25 fremstillet ifølge hvert enkelt eksempel blot ved eksemplets nummer eller bogstav.
3. Ethy1-8-methoxy-4-[(2-methylphenyl)amino]-3-qui-nolincarboxylat ved neutralisering af 1.
4. Ethyl-8-methoxy-4-[(2-methylphenyl)amino]-3-qui-30 nolincarboxylat-sulfat (1:1) ud fra 3 og svovlsyre.
5. Ethyl-8-methoxy-4-[(2-methylphenyl) amino]-3— -quinolincarboxylat-phosphat (1:1) ud fra 3 og phosphor-syre.
6. Ethyl-8-methoxy-4-(phenylamino)-3-quinolincar-35 boxylat-hydrochlorid ud fra a og anilin.
O
9
DK 156056B
7. Ethyl-8-methoxy-4-[(2-methoxyphenyl)amino]-3--quinolincarboxylat-hydrochlorid ud fra a og o-anisidin.
8. Ethyl-8-methoxy-4-[(2-methylthiophenyl)amino]--3-quinolincarboxylat-hydrochlorid ud fra a og 2-methylthio- 5 anilin.
9. Ethyl-4-[(2-chlorphenyl)amino]-8-methoxy-3-qui-nolincarboxylat-hydrochlorid ud fra a og 2-chloranilin.
10. Ethyl-4-[(2-cyanophenyl)amino]-8-methoxy-3-qui-nolincarboxylat-hydrochlorid ud fra a og 2-aminobenzonitril.
10 li. Ethyl-4-[(2-trifluormethylphenyl)amino]-8-metho- xy-3-quinolincarboxylat-hydrochlorid ud fra a og 2-trifluor-methylanilin.
12. Ethyl-4- {[2-(aminocarbonyl)phenyl]amino}-8-me-thoxy-3-quinolincarboxylat-monohydrochlorid-ethanol (5:2) 15 ud fra a og anthranilamid.
13. Ethyl-4-[(2-fluorophenyl)amino]-8-methoxy-3-qui-nolin-carboxylat-hydrochlorid ud fra a og 2-fluor-anilin.
14. Ethyl-4-[(2-acetylphenyl)amino]-8-methoxy-3-qui-nolincarboxylat-hydrochlorid ud fra a og 2'-aminoacetophenon.
20 15. Ethyl-8-methoxy-4-[(3-methylphenyl)amino]-3-qui- nolincarboxylat-hydrochlorid-monohydrat ud fra a og m-to~ luidin.
16. Ethyl-8-methoxy-4-[(4-methylphenyl)amino]-3-qui-nolincarboxylat-hydro'chlorid-monohydrat ud fra a og p-to- 25 luidin.
17. Ethyl-8-methoxy-4- £[ (2-methoxyphenyl)methyl]a-mino}-3-quinolincarboxylat ud fra a og 2-methoxybenzylamin.
18. Ethyl-8-methoxy-4-[(2-6-dimethylphenyl)amino]--3-quinolincarboxylat ud fra a og 2,6-dimethylanilin.
30 19. Ethyl-8-methoxy-4-[(2,6-dimethylphenyl)amino]- -3-quinolincarboxylat-hydrobromid ud fra 17 og HBr.
20. Ethyl-8-methoxy-4-[(1-phenylethyl)amino]-3-qui-nolincarboxylat-monohydrat ud fra a og a-methylbenzylamin.
35 10
DK 156056 B
O
21. Ethyl-4-[(2-chlor-5-methoxyphenyl)amino]-8-me-thoxy-3-quinolincarboxylat-hydrobromid ud fra a og 2-chlor--5-methoxyanilin.
22. Ethyl-8-methoxy-4-[(3-methylthio)phenyl)amino-5 -3-quinolincarboxylat ud fra a og 3-methylmercaptoanilin.
23. Ethyl-4-benzylamino-8-methoxy-3-quinolincarboxy-lat-phosphat (1:1)-methanolat (1:1) ud fra a og benzylamin.
24. Ethyl-8-methoxy-4-[(2,4-dimethoxyphenyl)amino]--3-quinolincarboxylat ud fra a og 2,4-dimethoxyanilin.
10 25. Ethyl-4-[(2-ethoxyphenyl)amino]-8-methoxy-3-qui- nolincarboxylat-hydrochlorid ud fra a og 2-ethoxyanilin.
26. Ethyl-8-methoxy-4-[4-methoxy-2-methylphenyl)a-mino]-3-quinolincarboxylat ud fra a og 2-methyl-4-methoxy-anilin.
15 27. Ethyl-4-[(2-ethylphenyl)amino]-8-methoxy-3-qui- nolincarboxylat ud fra a og 2-ethylanilin.
28. Ethyl-4-[(2-ethylphenyl)amino]-8-methoxy-3-qui-nolincarboxylat-phosphat (1:2) ud fra 27 og vandfri H^PO^.
29· Ethyl-4-[(2-ethylphenyl)amino]-8-methoxy-3-qui- 20 nolincarboxylat-sulfat (1:1) ud fra 27 og alkoholisk H2S04.
30. Ethyl-4-[(2,6-dichlorphenyl)amino]-8-methoxy--3-quinolincarboxylat ud fra a og 2,6-dichloranilin.
31. Ethyl-8-methoxy-4-[(2-methyl-5-nitrophenyl)ami-no-3-quinolincarboxylat ud fra a og 2-methyl-5-nitroanilin.
25 32. Ethyl-8-methoxy-4- {[ (2-methylphenyl)methyl]ami no} -3-quinolincarboxylat-hydrochlorid-ethanol (2:1) ud fra a og o-methylbenzylaminf ethanol og HC1.
33. Ethyl-8-ethoxy-4-[(2-methylphenyl)amino]-3-qui-nolincarboxylat-hydrochlorid ud fra b og o-toluidin.
30 34. Ethyl-8-ethoxy-4-[2-(trifluoromethylphenyl)ami no] -3-quinolincarboxylat-hydrobromid ud fra b og o-trifluor-methylanilin.
35. Ethyl-8-ethoxy-4-[(2-methoxyphenyl)amino]-3-qui-nolincarboxylat-hydrochlorid ud fra b og o-anisidin.
35 36. Ethyl-8-ethoxy-4-[2-(methylthiophenyl)amino]-3- -quinolincarboxylat-phosphat (1:1) ud fra b og methylthio-anilin og alkoholisk H^PO^.
11
DK 156056B
o 37. Ethyl-4-[(2-methylphenyl)amino]-8-methylthio--3-quinolincarboxylat ud fra d og o-toluidin.
38. Ethyl-4-[(2-methoxyphenyl) amino]-8-methylthio--3-quinolincarboxylat-hydrochlorid ud fra d og o-toluidin.
5 39. Ethyl-8-methylthio-4-[(2-methylthiophenyl)amino]- -3-quinolincarboxylat ud fra d og 2-methylthioanilin.
40. Ethyl-8-methyl-4-[2-(methylthiophenyl) amino]-3--quinolincarboxylat-hydrochlorid ud fra c og 2-methylthioanilin.
10 41. Ethyl-4-[(2-methoxyphenyl)amino]-8-methyl-3-qui- nolincarboxylat-hydrochlorid ud fra c og o-anisidin.
42. Ethyl-8-methyl-4-[(2-methylphenyl)methyl]amino--3-quinolincarboxylat-hydrobromid ud fra c og 2-methylben-zylamin.
15 43. Ethyl-8-chlor-4-[(2-methoxyphenyl)amino]-3-qui- nolincarboxylat-hydrochlorid ud fra c og o-anisidin, 44. Ethyl-8-(dimethylamino)-4-(phenylamino)-3-qui-nolincarboxylat-hydrochlorid ud fra f og anilin.
45. Ethyl-8-(dimethylamino)-4-[(2-methylphenyl)ami- 20 no]-3-quinolincarboxylat ud fra f og o-toluidin.
25 30 35
DK 156056B
O
12
Eksempel 46 8-Methoxy-4- [ (2-methylphenyl) -amino] -3-quinolincar-boxylsyre.
En blanding af 15,00 g (0,0445 mol) ethyl-8-methoxy-5 -4-[(2-methylphenyl)-amino]-3-quinolincarboxylat, 100 ml 3N natriumhydroxidopløsning og 100 ml ethanol omrøres ved stuetemperatur i 16 timer. Blandingen fortyndes med 300 ml vand og gøres sur til en pH-værdi på 6,8 med 6N saltsyre. Bundfaldet fraskilles ved filtrering, vaskes successivt med 10 vand og acetone og tørres i luften i ca. 1,5 time. Vægten af det faste stof er 13,41 g (98%) med et smp. på 272°C under sønderdeling.
Analyse: beregnet for ci8H16N2^3: C,70.12; H,5.23; N,9.09 fundet : C,70.10; H,5.27; N,9.09 15
Eksempel 47 8-Methoxy-4-[(2-methylphenyl)-amino]-3-quinolincar-boxylsyre-hydrochlorid.
En portion på 4,35 g 8-methoxy-4-[(2-methylphenyl)-20 -amino]-3-quinolincarboxylsyre fra eksempel 46 tritureres med 100 ml varm absolut ethanol. Efter afkøling fraskilles det faste stof ved filtrering og tørres i luften, hvorved det fås 3,87 g. Det faste stof suspenderes i 25 ml absolut ethanol, og der tilsættes et overskud af etherisk hydrogen-25 chloridopløsning. Der fås en klar opløsning. Ved tilsætning af isopropylether fås der et gult bundfald, der fraskilles og omkrystalliseres fra absolut ethanol/isopropylether, hvorved der fås 3,14 g fast stof med et smp. på 257°C under sønderdeling.
30 Analyse: beregnet for C^gH^^O^Cl: C,62.70; H,4.97; N,8.12 fundet : C,62.53;-H,4.93; N,8.18
Eksempel 48-54 35 48. Ethy1-8-methyl-4-[(2-methylphenyl)amino-3-qui- nolincarboxylat-monohydrochlorid ud fra c og o-toluidin.
O
13
DK 156Q56B
49. Ethyl-8-methoxy-4-[[2-(1-methylethyl)phenyl]amino] -3-quinolincarboxylat ud fra a og o-isopropylanilin.
50. Ethyl-8-chloro-4-[(2-methylphenyl)amino]-3--quinolincarboxylat ud fra e og o-toluidin.
5 51. Ethyl-[(2-chlor-6-methylphenyl)amino]-8-metho- xy-3-quinolinearboxylat-monohydrochlorid ud fra a og 2-chlor--6-methylanilin.
52. Ethyl-8-methoxy-4-[(2,3-dimethylphenyl)amino]--3-quinolincarboxylat-monosulfat ud fra a og 2,3-dimethyl- 10 anilin.
53. Ethyl-8-methoxy-4-[(2-nitrophenyl)amino]-3--quinolincarboxylat ud fra a og 2-nitroanilin.
54. Ethyl-8-methoxy-4-[(2-nitrophenyl)amino]-3- • i t -quinolincarboxylat, ethylsulfat (1:1), ethanol (1:1) ud 15 fra 53. og koncentreret svovlsyre i absolut ethanol.
Eksempel 55 l-Methylethyl-8-methoxy-4-[(2-methylphenyl)amino]--3-quinolincarboxylat-monohydrochlorid-monohydrat.
20 Til 150 ml tør 2-propanol sættes 2 natriumpellets og derefter 5,38 g (15,99 mmol) ethyl-8-methoxy-4-[(2-methylphenyl) -amino]-3-quinolincarboxylat opløst i 50 ml tør 2-propanol. Opløsningen omrøres og opvarmes til tilbagesvaling under udelukkelse af fugtighed i 6 timer, hvorunder der 25 opsamles 120 ml destillat i et Dean-Starke-apparat og bortkastes. Opløsningsmidlet afdampes, og remanensen opløses i 50 ml 2,9 M saltsyre, og der tilsættes 100 ml vand. Opløsningen indstilles til en pH-værdi på 8 med 1 M vandig na-triumhydrogencarbonatopløsning, og den udskilte olie eks-30 traheres 3 gange med 100 ml methylenchlorid. De forenede ekstrakter tørres over magnesiumsulfat. Opløsningsmidlet afdampes, hvorved der fås 4,60 g (82%) af den frie base af ovennævnte forbindelse med et smp. på 120-122°C efter omkrystallisation fra acetone/hexan.
35 Den frie base opløses i isopropylether, og der til sættes etherisk hydrogenchlorid. Opløsningsmidlet afdampes.
DK 156056B
O
14 og remanensen omkrystalliseres fra methylenchlorid/acetone, hvorved der fås ovennævnte forbindelse som et gult krystallinsk fast stof med et smp. på 140-143°C.
5 Eksempel 56 (2-Methoxyethyl)-8-methoxy-4-[(2-methylphenyl)-amino] -3-guinolincarboxylat.
Idet der gås frem som beskrevet i eksempel 55, om-forestres forbindelsen fra eksempel 3 med 2-methoxyethanol til dannelse af ovennævnte forbindelse.
10
Eksempel 57 3-(Dimethylamino)ethyl-8-methoxy-4-[(2-methylphenyl)- -amino]-3-quinolincarboxylat.
Idet der gås frem på lignende måde som i eksempel 55, 15 omforestres forbindelsen fra eksempel 3 med 2-dimethylamino-ethanol, idet der anvendes natriumethoxidkatalysator og toluen som opløsningsmiddel, hvorved der fås ovennævnte forbindelse.
20
Eksempel 58 3-(Dimethylamino)propyl-8-methoxy-4-[(2-methylphe- nyl)-amino]-3-quinolincarboxylat.
Idet der gås frem på lignende måde som i eksempel __ 55, omforestres forbindelsen fra eksempel 3 med 3-dimethyl- 25 amino-l-propanol, idet der anvendes toluen som opløsningsmiddel, hvorved der fås ovennævnte forbindelse.
Eksempel 59 30 2-(Dimethylamino)-ethyl-8-methoxy-4-[(2-methylphe nyl) -amino] -3-quinolincarboxylat-fumarat (1;1,5).
Ovennævnte forbindelse fremstilles ud fra forbindelsen fra eksempel 57 og fumarsyre.
35
O
DK 156056 B
15
Eksempel 60 3-(Dimethylamino)-propyl-8-methoxy-4-[(2-methylphe-nyl)-amino]-3-quinolincarboxylat-dihydrochlorid-monohydrat.
Ovennævnte forbindelse fremstilles ud fra forbin-5 delsen fra eksempel 58 og etherisk hydrogenchlorid.
Eksempel 61
Ethyl-8-Methoxy-4-[(2-methylphenyl)-amino]-3-qui-nolincarboxylat-ethansulfonat (1:1)(salt).
10 Ovennævnte forbindelse fremstilles ud fra forbin delsen fra eksempel 3 og ethansulfonsyre i absolut ethanol.
Eksempel 62
Ethyl-8-Methoxy-4-[(2-methylphenyl)-amino]-3-qui-15 nolincarboxylat-2-hydroxyethansulfonat (1:1)(salt).
Ovennævnte forbindelse fremstilles ud fra forbindelsen fra eksempel 3 og 2-hydroxyethylsulfonsyre i absolut ethanol.
20 25 30 35
DK 156056 B
16
Tabel I
(Eksempel 1-62) 4 NHIV: — COg R3 R1
Eksempel R2 R^ Salt Smp./°C.
1 8-CH3O- 2-CH3-CeH4- C2H5- HCl I9I-I93.5 2 8-CH30- CeH5- CgHg- - 120-121 3 8-CH30- 2-CH3-CeH4- CgHg- - 138.5-1^0 4 8-CH3O- 2-CH3-CeH4- C2H5- HgS04 192-194 5 8-CH3O- 2-CH3-CeH4- CgH5- h3po4 99-102 6 8-CH3O- CeHs- CgHg- HCl 165.5-168 7 8-CH30- 2-CH30-CeH4- CgH5- HCl 204-207 8 8-CHsO- 2-CH3S-CeH4- C2H5- HCl 275-278' 9 8-CH30- 2-Cl-CeH4- C2H5- HCl 193-194.5 10 8-CH30- 2-CN-CeH4- .C2H5- HCl 204-205-5 11 8-CH30- 2-CF3-CeH4- C2Hs- HCl 199-201(3 12 8-CH30- 2-NHgOC-CeH4- CgH5- 1 HCl* 251-154
0*4CgH50H
13 8-CH30- 2-F-CeH4- C2H5- HCl 204-205 14 8-CH30- 2-CH3C0-CeH4- C8H5- HCl 203-204d 15 8-CH3O- 3-CHsCeH4 C2H5- HCl · Hg O 156-158(3 16 8-CH30- 4-CH3CeH4- C2H5- HCl*H20 155-156(3 17 8-CH30- 2-CH30-CeH4CHg- C2H5- - 132-137 18 8-CH30- 2,6(CH3)2CeH3- C2H5- - 160-163 19 8-CH30- 2,6(CH3)2CeHs- C2H5- HBr 182-184 20 8-CH30- CeH5(CH3)CH- CgHg- Hg O 97-99 21 8-CH30- 2-Cl-5-CH30-CeH3- C8H5- HBr 160-162 22 8-ch3o- 3-ch3s-c6h4- c8h5- - 123-124.5 23 8-CH30- CeHgCHg- - C8 Hg- H3P04· 221-223
CH3OH
24 8-CH30- 2,4(CH30)2-CeH3- CgHs- - 128-131 25 8-CH30- 2-CgHs0-CeH4- C2H5- HCl 208(3 26 8-CH30- 2-CH3-4-CH30-CeHs- C2H5- - 175-176 27 8-CH30- 2-CgHg-CeH4- C2Hg- - 152-153 28 8-CH30- 2-C2H5-CeH4- C2H5- 2HsP04 140-142 29 8-CH30- 2-C2Hg-CeH4- CgHg- HgS04 177-178-5
30 8-CH30- 2,6-Cl-CeH3- C2H5- - I78-I8O
31 8-CH30- 2-CH3-5-N02-CeH3- C2H5- - 851*5-253
DK 156056 B
17
Ek sempel R2 Salt Smp.,°C.
32 8-CH30- 2-CH3-CeH4CH2- C2H5- HCl· 197-5-198
l/2C2HgOH
33 8-C2H50- 2-CH3-CeH4- C2H5 HCl 208-209 34 8-C2H50- 2~€F3-CeH4- C2Hs- HBr l85-191d 35 8-C2H50- 2-CH30-CeH4- C2Hs- HCl 205-20β-5 36 8-C2HsO- 2-CH3S-CeH4- C2Hs- H3P04 185-190 37 8-CH3S- 2-CH3-CeH7- C2H5- - 168-170 38 8-CH3S- 2-CH30-CeH4- C2Hs- HCl 169-172 39 8-CH3S- 2-CH3S-CeH4- C2H5- - ΐ4θ-$-1^2 40 8—CH3— 2-CH3S-CeH4- C2H5— HCl 172—17^d 41 8-CH3- 2-CH30-CeH4- C2H5- HCl 185-188 42 8-CH3- 2 -CHji-CeaiCHi»- C2Hs- HBr 182-185 43 8-Cl- 2-CH30-C 3H4- CaHg- HCl 205-205d 44 8-[CH3)2N- CeH5- CgHg- HCl 179-181 45 8-(cH3)2N- 2-CH3-CeH4- C2H5- - 110-114 46 8-CH3O- 2-CH3-C6H4- H - 272(d) 47 8-CH30- 2-CH3-C6H4 H HCl 257 48 8-CH3- 2-CH3-C6H4- C2H5- HCl 162-164 49 8-CH30- 2-(CH3)2CH- c6h4- c2H5- - 156-158 50 8-Cl 2-CH3-CeH4- C2H5- - 189-191 51 8-CH3O- 2-CH3-CeH4- C2H5- HCl 207-209 52 8-CH3O- 2,5-(CH3)2- C6H3- C2Hs- HgS04 177-181
DK 156056 B
18
Eksempel R2 R3 Salt Smp.,°C.
53 8-CH3O- 2-N02-CeH4- C2H5- - l80-l82 54 8-CH3O- 2-N02-CeH4- C2H5- C2H50H 85-90 .
55 8-CH3O- 2-CH3-CeH4- (CH3)2 HCl-IfeO 140-1^3 HC- 56 8-CH3O- 2-CH3-CeH4- CH30 HCl 18^1-187 (Ofe)2- 57 8-CH3O- 2-CH3-CeH4- (CH3)2 - 100-103 N(CIfe)2- 58 8-CH3O- 2-CH3-CeH4- (CH3)2 n(ch2)3- - 95-97.5 59 8-CH3O- 2-CH3-CeH4- (CH3)2 n(cH2/2 fumarat 180-189 60 8-CH3O- 2-CH3-CeH4- (CH3)2 .Ha O 177-Ιβθ N(CHfe)3- «HCl 61 8-CH3O- ' 2-CH3-C6H4- C2Hs- CH3CHa- 113-116
S020H
62 8-CH3O 2-CH3-CeH4- C2H5 HO-CIfe 1^2-14^
ClfeSOaOH
(a) svarer til smp. 99-100°C. givet i J. Pharm. Chem.
Soc. 1389 (1951).
d = sønderdeling
Tabel II
DK 156056 B
19
Analytiske data for forbindelserne fremstillet ifølge eksempel 1-62
Empirisk _Beregnet -Fufl_4gt-
Eks. formel C Η N C Η N
1 c20H2 iC1n2o3 64.63 5*68 7*51 64.36 5-65 7.62 2 CiBHibN203 70.79 5-63 8.69 70.91 5-65 6.77 3 CgoHaoNsOa 71-41 5-99 8.33 71-52 5-94 S.35 4 CgoHsaNsOrS 55-29 5-10 6*45 55-68 5-02 6.42 5 c2oh23n207p 55-30 5-54 6.45 54-92 5-37 6.53 6 ClsHieClN2o3 63-60 5-34 7.81 63.25 5-33 7.69 7 CsoHsiClN^ 61.78 5-44 7-20 61-55 5-57 7.07 8 CaoHsxClNaOsS , .59*33 5-23 6.92 59-04 5.38 6.87 9 CxbHibC12N203 58.03 4.61 7.12 57.89 4.69 7.13 10 C20H1BCIN3O3 62.59 4.7310.95 62.23 4.95 10.73- 11 C20HibN2 03F3C1 · 56.28 4.25 6.56 56.33 4.34 6.60 12 Cio4Hii2C15N15022 59-44 5.37 10.00 59-25 5-21 10.03 13 CieHieN203FCl 60.56 4.81 7.43 60.28 4.87 7.32 14 C2iH2iN£04cl 62.92 5.28 6.99 62.56 5.48 6.76 15 C2OH23N204Cl 61.46 5.93 7.17 61.40 5.92 7.21 16 C2oH2sN2o4cl 61.46 5-93 7-17 61.73 5-76 7-33 17 02ιΗ22Νε04 68.84 6.05 7.65 68.61 6.04 7.51 18 C2iH22N203 71.98 6.33 7.99 72.16 6.33 6.01 19 C2iH23BrN203 58.48 5-37 6.49 58.48 5.41 6.52 20 C2iH24N204 68.46 6.57 7.60 68.47 6.51 7.59 21 C2o«2oN204ClBr 5I.35 4.51 5.99 51.27 4.30 6.04 22 C2oH2ON203s 65.20 5-47 7.60 65.18 5-48 7.66 23 C2iH£7N20eP 54.08 5-84 6.01 54-32 5-56 6.23 24 C2iH22N205 65.96 5-80 7-33 66.Oo 5-75 7-28 25 C2iH23N204cl 62.61 5.75 6.95 62.61 5.84 6.94 26 c2iH22n204 68.84 6.05 7.65 68.94 6.06 7.68 27 C2iH22N203 71.98 6.33 7.99 72.02 6.29 8.03 28 C21¾ eN2 011P2 46.16 5.17 5-13 46.07 5-22 5*12- 29 C21¾ 4N207S .56.24 5.39 6.25 56.09 5-43 6-24 30 Cx8h16n2o3c12 58.33 4.12 7.16 58.52 4.13 7.21 31 C20HigN3o5 62.99 5.02 11.02 63-02 5.08 11.03 32 C44H52N407C12 64.46 6-39 6.83 64.09 6.22 6.96 33 02ιΗ£!3Ν20301 65.20 5-99 7-24 65.25 6.01 7.26 34 C2iH20N203F3Br 51.97 4.15 5-77 52.22 4.14 5.89 35 c2iH23n2o4c1 62.61 5-75 6.95 62.67 5-76 7.05 36 CeiHgsNsO-rSP 52-50 5-75 5-83 . 52.08 5-35 5-77 37 C2oH2On202S 68.16 5.72 7.95 68.19 5.76 8.14 38 CsoHsiClNsOgS 59.33 5.23 6-92 59.55 5.32 6.86 39 C2 0¾ oN2 02 S2 62.47 5-24 7.29 62.16 5.I6 7.12
DK 156056B
20
Tabel II (fortsat)
Analytiske data for forbindelserne fremstillet ifølge eksempel 1-62
Empirisk Beregnet _Fundet_
Eks. formel C Η N C Η N
40 C2oHeiN202SCl 61.77 5*44 7*20 61.84 5.41 7.31 41 C2 0¾ iC1n2o3 64.73 5.68 7*51 64.47 5.61 7.50 42 CaiHasBrNsOs 60.73 5-58 6.93 60.76 5.60 6.82 43 Ci9HiBN203Cl2 58.03 4.61 7-12 57-97 4.65 7.11 44 C20Hs2N302cl 64.60 5-96 11-30 64.60 5.96 11.39 45 C2 iHg 3N3O2 72.18 6.63 12.03 72.24 6.57 12.09 46 CieHleN203 70.12 5.23 9.Ο9 70.10 5.27 9-09 47 C18H17N2O3CI 62.70 4.97 8.12 62.53 4.93 8.18 48 C2oH2iClN202 67.32 5‘93 7.85 67.22 5.92 7.83 49 c22h24n2o3 72.51 6.64 7.69 72.56 6.55 7.67 50 Ci9H17N202C1 66.90 5.03 8.22 66.60 5.14 8.20 51 C2OH2ON203C12 58.98 4.95 6.88 58.90 4.94 6.90 52 C2iH24N207S 56.24 5.39 6.25 56.37 5.42 6.28 53 Ci9HxTn305 62.12 4.66 11.44 62.05 4.66 11.54 54 CsaHesNsOioS 51.20 5-^2 7-79 51-20 5.36 8.01 55 CsiHasClNsO.* 62-30 6.22 6-92 62.49 6.23 6-94 56 c2 iH23c1n204 62.61 5-75 6.95 62.72 5.76 7-04 57 c22h25n3o3 69.64 6.64 11.07 69-73 6.64 11.07 58 ο23η27ν3ο3 70.21 6.92 10.68 70.42 6.95 10.67 59 02θΗ3αΝ309 60-75 5-64 7.59 60.89 5-69 7-53 60 c23h31ci2n3o4 57.03 6.45 8.67 57.05 6.31 8.79 61 C22%>eN206s 59.18 5.87 6.27 59.16 5.93 6.25 62 c22Ha6N2o7s 57-13 5-67 6.06 57·θ8 5.71 6.10
DK 156056 B
O
21
Farmakologiske resultater
Virkningen af 4-amino-3-quinolincarboxylsyrer og 5 estere deraf ifølge opfindelsen på gastrisk sekretion undersøges hos rotter og hunde. Inhiberingen af sekretion måles og angives som procent produceret mavesyre. Der gennemføres også undersøgelser af virkningen mod sårdannelse hos rotter. Resultaterne af undersøgelserne med for-10 bindeiser ifølge opfindelsen er anført nedenfor. Andre forbindelser ifølge opfindelsen viser kvalitativt lignende virkninger ved ét eller flere af disse forsøg.
15 20 25 ............
30 35
Tabel III
DK 156056 B
22
Virkning af forbindelser ifølge opfindelsen på stimuleret gastrisk sekretion.
Forbindelse Dosis Indgivel- Stimulerende Inhibering^
Dyreart (eks. nr.) (pmol/kg) sesvej middel_ (%)_ 2 rotte 1 0,3 i.v. histamin 43 0,9 52 2.7 60 8.1 96 2 rotte 1 0,3 i.d. histamin 40 0,9 43 2.7 67 8.1 58 10,7 70 2 rotte 47 23,2 i.d. histamin 57 2 rotte 1 0,3 i.v. tetragastrin 27 0,9 52 2.7 61 8.1 85 2 rotte 1 0,9 i.v. methacholin 25 2.7 60 8.1 76 3 hund 1 2,7 i.v. føde 50 8.1 83 3 hund 1 32,4 p.o. føde 56
Tabel III (fortsat)
DK 156056 B
23
Forbindelse Dosis Indgivel- Stimulerende Inhibering^
Dyreart (eks. nr.) (mg/kg) sesvej middel_ (%)_ 2 rotte 1 2 i.v. histamin 86 14 98 7 4 86 8 4 99 9 4 58 11 2 73 11 4 81 17 4 71 19 4 97 21 4 56 24 4 80 25 4 90 26 4 74 27 4 94 28 4 95 29 4 88 30 4 93 33 4 94 34 4 77 35 4 95 36 4 83 37 4 67 40 4 86 41 4 94 43 4 86
O
DK 156056 B
24 1) Inhiberingen måles som produktion af mavesyre.
2) Undersøgelsen med rotter gennemføres ifølge en modifikation af metoden ifølge Ghosh og Shield, 1958, Brit.
J. Pharmacol. 13:54-61.
5 3) Hundene er hunde med Heidenhain-pose.
Forbindelsen ifølge eksempel 1 indgives til pylorus--underbundne rotter, der ikke modtager nogen kunstig stimulering af gastrisk sekretion. De anvendte doser er 33, 10 67 og 134 yjmol/kg. Syreproduktionen inhiberes med 38, 40 og 55%.
Virkningen mod gastriske sårdannelser af forbindelsen ifølge eksempel 1 undersøges hos rotter ved metoden ifølge Shay et al., 1945, Gastroenterology 5^:43-61.
15 Med doser på 12, 25, 50, 99 og 198 yjmol/kg opnås en beskyttelse mod sårdannelser på 4, 43, 58, 55 og 90%.
20 25 30 35
Claims (2)
- 5 NHPe XXrXr— C02 r3 kX X m Ri 10 hvori R, betyder alkyl, O-alkyl, S-alkyl, halogen eller 1 2 dialkylamino, R betyder phenyl, phenyl-alkyl eller phenyl substitueret med 1-3 grupper valgt blandt alkyl,
- 15 O-alkyl, S-alkyl, halogen, cyano, carbamoyl, carboxy, acetyl, trifluormethyl og nitro, og R^ betyder hydrogen, alkyl, dimethylamino-alkyl eller alkoxy-alkyl, idet de nævnte alkyl- og alkoxygrupper er ligekædede eller forgrenede og indeholder 1-8 carbonatomer, 20 eller farmaceutisk acceptable additionssalte deraf, kendetegnet ved, at en forbindelse med den almene formel: Cl lev JL J (H) *1 hvori R^ har den ovenfor angivne betydning, ogR'^ betyder 30 alkyl med 1-8 carbonatomer, omsættes med en amin med den almene formel R2NH2, hvori R2 har den ovenfor angivne betydning, hvorefter den fremstillede forbindelse eventuelt hydrolyseres til erstatning af gruppen R'^ med hydrogen, eller R'^ i den fremstillede forbindelse eventuelt underkas-35 tes en omforestringsreaktion, hvorefter den fremstillede forbindelse eventuelt omdannes til et farmaceutisk acceptabelt salt deraf.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US2398179A | 1979-03-26 | 1979-03-26 | |
| US2398179 | 1979-03-26 | ||
| US12715380 | 1980-03-04 | ||
| US06/127,153 US4343804A (en) | 1979-03-26 | 1980-03-04 | 4-Amino-3-quinolinecarboxylic acids and esters-antisecretory anti-ulcer compounds |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK128380A DK128380A (da) | 1980-09-27 |
| DK156056B true DK156056B (da) | 1989-06-19 |
| DK156056C DK156056C (da) | 1989-11-06 |
Family
ID=26697875
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK128380A DK156056C (da) | 1979-03-26 | 1980-03-25 | Analogifremgangsmaade til fremstilling af 4-amino-3-quinolin-carboxylsyrederivater |
Country Status (31)
| Country | Link |
|---|---|
| US (1) | US4343804A (da) |
| JP (1) | JPH02117663A (da) |
| AR (1) | AR230268A1 (da) |
| AT (1) | AT372373B (da) |
| AU (1) | AU528388B2 (da) |
| BR (1) | BR8001779A (da) |
| CA (1) | CA1147338A (da) |
| CH (1) | CH644105A5 (da) |
| DE (1) | DE3011490A1 (da) |
| DK (1) | DK156056C (da) |
| EG (1) | EG15009A (da) |
| ES (1) | ES8103048A1 (da) |
| FI (1) | FI77452C (da) |
| FR (1) | FR2452485B1 (da) |
| GB (1) | GB2047244B (da) |
| GR (1) | GR68006B (da) |
| HK (1) | HK67983A (da) |
| IE (1) | IE49577B1 (da) |
| IL (1) | IL59628A (da) |
| IN (1) | IN151446B (da) |
| IT (1) | IT1133079B (da) |
| MX (1) | MX6264E (da) |
| NL (1) | NL8001752A (da) |
| NO (1) | NO153927C (da) |
| NZ (1) | NZ193252A (da) |
| PH (1) | PH16416A (da) |
| PL (1) | PL125030B1 (da) |
| PT (1) | PT71008B (da) |
| SE (1) | SE435837B (da) |
| SG (1) | SG33683G (da) |
| YU (1) | YU41702B (da) |
Families Citing this family (44)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8610981D0 (en) * | 1986-05-06 | 1986-06-11 | Ici America Inc | Quinoline amides |
| GB8621425D0 (en) * | 1986-09-05 | 1986-10-15 | Smith Kline French Lab | Compounds |
| GB8804447D0 (en) * | 1988-02-25 | 1988-03-23 | Smithkline Beckman Intercredit | Compounds |
| GB8804444D0 (en) * | 1988-02-25 | 1988-03-23 | Smithkline Beckman Intercredit | Compounds |
| GB8804445D0 (en) * | 1988-02-25 | 1988-03-23 | Smithkline Beckman Intercredit | Compounds |
| GB8804446D0 (en) * | 1988-02-25 | 1988-03-23 | Smithkline Beckman Intercredit | Compounds |
| GB8804443D0 (en) * | 1988-02-25 | 1988-03-23 | Smithkline Beckman Intercredit | Compounds |
| GB8804448D0 (en) * | 1988-02-25 | 1988-03-23 | Smithkline Beckman Intercredit | Compounds |
| US5432182A (en) * | 1989-02-23 | 1995-07-11 | Smithkline Beecham Intercredit B.V. | Compounds substituted quinoline derivatives |
| CA2011086A1 (en) * | 1989-03-17 | 1990-09-17 | Karl-Heinz Geiss | 2-alkyl-4-arylmethylaminoquinolines, the use thereof and drugs prepared therefrom |
| DE3917233A1 (de) * | 1989-05-26 | 1990-11-29 | Basf Ag | 8-substituierte 4-(heterocyclylmethylamino)-chinoline, ihre verwendung und daraus hergestellte arzneimittel |
| GB8918265D0 (en) * | 1989-08-10 | 1989-09-20 | Smithkline Beckman Intercredit | Compounds |
| US5362743A (en) * | 1993-03-09 | 1994-11-08 | Pfizer Inc. | Aminoquinoline derivatives |
| IS4164A (is) * | 1993-06-11 | 1994-12-12 | Ab Astra | Efnasambönd sem hindra flæði magasýru |
| US5556863A (en) * | 1993-06-11 | 1996-09-17 | Astra Aktiebolag | Compound for gastric acid secretion inhibition |
| EP0720601B1 (en) * | 1993-08-10 | 2000-10-25 | James Black Foundation Limited | Gastrin and cck receptor ligands |
| US5650415A (en) * | 1995-06-07 | 1997-07-22 | Sugen, Inc. | Quinoline compounds |
| KR0169813B1 (ko) * | 1995-07-12 | 1999-01-15 | 김종인 | 4-아미노-3-아실나프티리딘 유도체 |
| US5760041A (en) * | 1996-02-05 | 1998-06-02 | American Cyanamid Company | 4-aminoquinazoline EGFR Inhibitors |
| US6875769B2 (en) * | 1996-05-23 | 2005-04-05 | Pfizer Inc. | Substituted6,6-hetero-bicyclicderivatives |
| US5929080A (en) * | 1997-05-06 | 1999-07-27 | American Cyanamid Company | Method of treating polycystic kidney disease |
| US6251912B1 (en) | 1997-08-01 | 2001-06-26 | American Cyanamid Company | Substituted quinazoline derivatives |
| US6323209B1 (en) | 1997-11-06 | 2001-11-27 | American Cyanamid Company | Method of treating or inhibiting colonic polyps |
| HU230728B1 (hu) | 1998-09-29 | 2017-12-28 | Wyeth Holdings Llc | Szubsztituált 3-cianokinolinok mint protein tirozin kinázok inhibitorai |
| WO2001047891A1 (en) * | 1999-12-28 | 2001-07-05 | Eisai Co., Ltd. | Heterocyclic compounds having sulfonamide groups |
| US6521618B2 (en) | 2000-03-28 | 2003-02-18 | Wyeth | 3-cyanoquinolines, 3-cyano-1,6-naphthyridines, and 3-cyano-1,7-naphthyridines as protein kinase inhibitors |
| US6576644B2 (en) * | 2000-09-06 | 2003-06-10 | Bristol-Myers Squibb Co. | Quinoline inhibitors of cGMP phosphodiesterase |
| UA80393C2 (uk) | 2000-12-07 | 2007-09-25 | Алтана Фарма Аг | Фармацевтична композиція, яка містить інгібітор фде 4, диспергований в матриці |
| MY140561A (en) | 2002-02-20 | 2009-12-31 | Nycomed Gmbh | Dosage form containing pde 4 inhibitor as active ingredient |
| ES2295816T3 (es) | 2003-01-14 | 2008-04-16 | Arena Pharmaceuticals, Inc. | Derivados arilo y heteroarilo 1,2,3-trisustituidos como moduladores del metabolismo, y profilaxis y tratamiento de transtornos relacionados con los mismos, tales como la diabetes y la hiperglucemia. |
| HRP20050399B1 (hr) | 2003-03-10 | 2013-09-30 | Takeda Gmbh | Novi postupci za dobivanje roflumilasta |
| US7132426B2 (en) * | 2003-07-14 | 2006-11-07 | Arena Pharmaceuticals, Inc. | Fused-aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto |
| US8663694B2 (en) * | 2005-03-16 | 2014-03-04 | Takeda Gmbh | Taste masked dosage form containing roflumilast |
| WO2011022216A1 (en) * | 2009-08-17 | 2011-02-24 | High Point Pharmaceuticals, Llc | Substituted pyridine derivatives, pharmaceutical compositions, and methods of use to treat oxidative stress |
| SG10201500639TA (en) | 2010-01-27 | 2015-03-30 | Arena Pharm Inc | Processes for the preparation of (r)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and salts thereof |
| EP2619198A1 (en) | 2010-09-22 | 2013-07-31 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
| PL3242666T3 (pl) | 2015-01-06 | 2025-02-17 | Arena Pharmaceuticals, Inc. | Związek do zastosowania w leczeniu dolegliwości związanych z receptorem s1p1 |
| JP6838744B2 (ja) | 2015-06-22 | 2021-03-03 | アリーナ ファーマシューティカルズ， インコーポレイテッド | Ｓ１Ｐ１レセプター関連障害における使用のための（Ｒ）−２−（７−（４−シクロペンチル−３−（トリフルオロメチル）ベンジルオキシ）−１，２，３，４−テトラヒドロシクロペンタ［ｂ］インドール−３−イル）酢酸（化合物１）の結晶性Ｌ−アルギニン塩 |
| ES2884073T3 (es) * | 2016-11-11 | 2021-12-10 | Bayer Animal Health Gmbh | Nuevos derivados antihelmínticos de quinolina-3-carboxamida |
| AU2018220521A1 (en) | 2017-02-16 | 2019-09-05 | Arena Pharmaceuticals, Inc. | Compounds and methods for treatment of primary biliary cholangitis |
| EP3700527A4 (en) * | 2017-10-25 | 2021-03-10 | Children's Medical Center Corporation | PAPD5 INHIBITORS AND METHOD OF USING THEM |
| EP3790874B1 (en) | 2018-05-09 | 2023-03-15 | Bayer Animal Health GmbH | Anthelmintic quinoline derivatives |
| KR102859841B1 (ko) | 2018-06-06 | 2025-09-12 | 아레나 파마슈티칼스, 인크. | S1p1 수용체와 관련된 병태의 치료 방법 |
| CN119798159A (zh) | 2019-04-24 | 2025-04-11 | 儿童医学中心公司 | Papd5抑制剂及其使用方法 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3470186A (en) * | 1967-06-02 | 1969-09-30 | American Cyanamid Co | Substituted 4-anilino-3-quinolinecarboxylic acids and esters |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4838712A (da) * | 1971-09-18 | 1973-06-07 |
-
1980
- 1980-03-04 US US06/127,153 patent/US4343804A/en not_active Expired - Lifetime
- 1980-03-14 IL IL59628A patent/IL59628A/xx unknown
- 1980-03-22 GR GR61513A patent/GR68006B/el unknown
- 1980-03-24 AT AT0156480A patent/AT372373B/de not_active IP Right Cessation
- 1980-03-24 FI FI800910A patent/FI77452C/fi not_active IP Right Cessation
- 1980-03-24 FR FR8006516A patent/FR2452485B1/fr not_active Expired
- 1980-03-24 IE IE605/80A patent/IE49577B1/en unknown
- 1980-03-24 MX MX808722U patent/MX6264E/es unknown
- 1980-03-25 DK DK128380A patent/DK156056C/da not_active IP Right Cessation
- 1980-03-25 DE DE19803011490 patent/DE3011490A1/de active Granted
- 1980-03-25 ES ES489887A patent/ES8103048A1/es not_active Expired
- 1980-03-25 IN IN345/CAL/80A patent/IN151446B/en unknown
- 1980-03-25 PH PH23804A patent/PH16416A/en unknown
- 1980-03-25 EG EG80174A patent/EG15009A/xx active
- 1980-03-25 PL PL1980222993A patent/PL125030B1/pl unknown
- 1980-03-25 NL NL8001752A patent/NL8001752A/nl not_active Application Discontinuation
- 1980-03-25 CH CH234080A patent/CH644105A5/fr not_active IP Right Cessation
- 1980-03-25 SE SE8002292A patent/SE435837B/sv not_active IP Right Cessation
- 1980-03-25 BR BR8001779A patent/BR8001779A/pt unknown
- 1980-03-25 NZ NZ193252A patent/NZ193252A/en unknown
- 1980-03-25 GB GB8009991A patent/GB2047244B/en not_active Expired
- 1980-03-25 NO NO800858A patent/NO153927C/no unknown
- 1980-03-25 PT PT71008A patent/PT71008B/pt unknown
- 1980-03-26 IT IT67465/80A patent/IT1133079B/it active
- 1980-03-26 AU AU56848/80A patent/AU528388B2/en not_active Ceased
- 1980-03-26 AR AR280455A patent/AR230268A1/es active
- 1980-03-26 YU YU844/80A patent/YU41702B/xx unknown
- 1980-03-26 CA CA000348417A patent/CA1147338A/en not_active Expired
-
1983
- 1983-06-13 SG SG336/83A patent/SG33683G/en unknown
- 1983-12-15 HK HK679/83A patent/HK67983A/xx unknown
-
1989
- 1989-09-26 JP JP1250369A patent/JPH02117663A/ja active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3470186A (en) * | 1967-06-02 | 1969-09-30 | American Cyanamid Co | Substituted 4-anilino-3-quinolinecarboxylic acids and esters |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DK156056B (da) | Analogifremgangsmaade til fremstilling af 4-amino-3-quinolin-carboxylsyrederivater | |
| FI64159C (fi) | Foerfarande foer framstaellning av oralt effektiva antiallergiska 11-oxo-11-h-pyrido(2,1-b)-kinazoliner | |
| FI103889B (fi) | Menetelmä terapeuttisesti käyttökelpoisten pyrrolo£3,2-c|-kinoliini-karboksyylihappojohdannaisten valmistamiseksi | |
| DK165921B (da) | 1h-imidazooe4,5-caaquinolin-5-oxyforbindelser | |
| KR20080016671A (ko) | 치환된 3-시아노퀴놀린 및 그것의 중간체를 합성하는 방법 | |
| NO164476B (no) | Analogifremgangsmaate ved fremstilling av terapeutisk virksomme 1,2,3,5-tetrahydroimidazo-(2,1-b)-kinazoliner. | |
| US5686458A (en) | Quinazoline deriviates for treating peptic ulcer | |
| CA2302453A1 (en) | Nitrogenous fused-ring compounds, process for the preparation of the same, and drugs | |
| US6028081A (en) | Substituted quinolone derivatives and pharmaceuticals containing the same | |
| SU548207A3 (ru) | Способ получени производных 2-ариламино-2-имидазолина или их солей | |
| US4578465A (en) | Phenyliperazine derivatives | |
| NO146058B (no) | Analogifremgangsmaate for fremstilling av substituerte benzamider. | |
| DK156066B (da) | Analogifremgangsmaade til fremstilling af oxaloamino- eller hydroxyacetylaminobenzopyranderivater eller salte deraf med baser | |
| IE41673B1 (en) | Fused pyrimidines and preparation thereof | |
| US3970661A (en) | 2-Amino, 5-carbamoyl pyridine compounds | |
| US2474820A (en) | Quinoline compounds and process of making same | |
| KR840000768B1 (ko) | 4-아미노-3-퀴놀린카복실산 및 에스테르의 제조방법 | |
| US5179089A (en) | Isoquinoline compounds, compositions and use | |
| US5464838A (en) | Aminocarboxylic acid derivatives having antiallergic/antiasthmatic effect and a process for their preparation | |
| FI70574B (fi) | Foerfarande foer framstaellning av nya farmaceutiskt anvaendbara derivat av 2-((4-kinolinyl)-amino)-5-fluor- bensoesyra | |
| US3970663A (en) | Certain amino-nicotinamide derivatives | |
| CA2125681A1 (en) | 4-amino-3-acyl quinoline derivatives and their use as inhibitors of gastric acid secretion | |
| CS216527B2 (cs) | Způsob výroby 4-amino-3-chinolinkarboxylových kyselin a jejich esterů | |
| CA1161757A (en) | 4-amino-3-quinolinecarboxylic acids and esters- antisecretory, anti-ulcer compounds | |
| JPS62123185A (ja) | ２−（２−イミダゾリン−２−イル）−ピリジン−３−カルボン酸誘導体、その製法及びこれを含有する除草剤 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |