CH639073A5 - 4-Pyridone-3-carboxylic acid derivatives and their preparation - Google Patents
4-Pyridone-3-carboxylic acid derivatives and their preparation Download PDFInfo
- Publication number
- CH639073A5 CH639073A5 CH51278A CH51278A CH639073A5 CH 639073 A5 CH639073 A5 CH 639073A5 CH 51278 A CH51278 A CH 51278A CH 51278 A CH51278 A CH 51278A CH 639073 A5 CH639073 A5 CH 639073A5
- Authority
- CH
- Switzerland
- Prior art keywords
- oxo
- ethyl
- acid
- methyl
- alkyl
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 14
- 239000001257 hydrogen Substances 0.000 claims abstract description 14
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 12
- 150000002367 halogens Chemical class 0.000 claims abstract description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 9
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 8
- 210000003169 central nervous system Anatomy 0.000 claims abstract description 7
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims abstract description 6
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims abstract description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 6
- SSHRVPMSFQLCAG-UHFFFAOYSA-N 1,2,3,4-tetrahydropyridine-5-carboxylic acid Chemical class OC(=O)C1=CNCCC1 SSHRVPMSFQLCAG-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 4
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 4
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims abstract description 4
- 230000004936 stimulating effect Effects 0.000 claims abstract description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000006356 dehydrogenation reaction Methods 0.000 claims abstract description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 24
- -1 4-methylthiophenyl Chemical group 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 239000011541 reaction mixture Substances 0.000 claims description 6
- 239000007858 starting material Substances 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- 150000004057 1,4-benzoquinones Chemical class 0.000 claims description 4
- YOEBQJYTBWGBTO-UHFFFAOYSA-N 6-(4-chlorophenyl)-1-ethyl-4-oxopyridine-3-carboxylic acid Chemical compound CCN1C=C(C(O)=O)C(=O)C=C1C1=CC=C(Cl)C=C1 YOEBQJYTBWGBTO-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- NXFQHRVNIOXGAQ-YCRREMRBSA-N nitrofurantoin Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)NC(=O)C1 NXFQHRVNIOXGAQ-YCRREMRBSA-N 0.000 claims description 4
- 229960000564 nitrofurantoin Drugs 0.000 claims description 4
- XXPANQJNYNUNES-UHFFFAOYSA-N nomifensine Chemical compound C12=CC=CC(N)=C2CN(C)CC1C1=CC=CC=C1 XXPANQJNYNUNES-UHFFFAOYSA-N 0.000 claims description 4
- 229960001073 nomifensine Drugs 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- PESNWCFMIWRFJR-UHFFFAOYSA-N 1-ethyl-4-oxo-6-(4-pyrrolidin-1-ylphenyl)pyridine-3-carboxylic acid Chemical compound CCN1C=C(C(O)=O)C(=O)C=C1C1=CC=C(N2CCCC2)C=C1 PESNWCFMIWRFJR-UHFFFAOYSA-N 0.000 claims description 3
- YCVRGAXZRFMTJK-UHFFFAOYSA-N 1-ethyl-6-(4-methoxyphenyl)-4-oxopyridine-3-carboxylic acid Chemical compound CCN1C=C(C(O)=O)C(=O)C=C1C1=CC=C(OC)C=C1 YCVRGAXZRFMTJK-UHFFFAOYSA-N 0.000 claims description 3
- NEUHGQSWPQSVGM-UHFFFAOYSA-N 1-ethyl-6-[3-methyl-4-(methylamino)phenyl]-4-oxopyridine-3-carboxylic acid Chemical compound CCN1C=C(C(O)=O)C(=O)C=C1C1=CC=C(NC)C(C)=C1 NEUHGQSWPQSVGM-UHFFFAOYSA-N 0.000 claims description 3
- HBXCFZJFGXBNPH-UHFFFAOYSA-N 6-(1,3-benzodioxol-5-yl)-1-ethyl-4-oxopyridine-3-carboxylic acid Chemical compound CCN1C=C(C(O)=O)C(=O)C=C1C1=CC=C(OCO2)C2=C1 HBXCFZJFGXBNPH-UHFFFAOYSA-N 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- OPSXYAFWJPPHQK-UHFFFAOYSA-N 1,2,3,6-tetrahydropyridine-3-carboxylic acid Chemical class OC(=O)C1CNCC=C1 OPSXYAFWJPPHQK-UHFFFAOYSA-N 0.000 claims description 2
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims description 2
- IKDHBJPCSGCSKG-UHFFFAOYSA-N 1-cyclopropyl-6-(4-methoxyphenyl)-4-oxopyridine-3-carboxylic acid Chemical compound C1=CC(OC)=CC=C1C1=CC(=O)C(C(O)=O)=CN1C1CC1 IKDHBJPCSGCSKG-UHFFFAOYSA-N 0.000 claims description 2
- JCVZOYIGRRGTAA-UHFFFAOYSA-N 1-ethyl-4-oxo-6-(3,4,5-trimethoxyphenyl)pyridine-3-carboxylic acid Chemical compound CCN1C=C(C(O)=O)C(=O)C=C1C1=CC(OC)=C(OC)C(OC)=C1 JCVZOYIGRRGTAA-UHFFFAOYSA-N 0.000 claims description 2
- HFLHLTVNZJBRRY-UHFFFAOYSA-N 1-ethyl-4-oxo-6-pyridin-3-ylpyridine-3-carboxylic acid Chemical compound CCN1C=C(C(O)=O)C(=O)C=C1C1=CC=CN=C1 HFLHLTVNZJBRRY-UHFFFAOYSA-N 0.000 claims description 2
- WZEVMSQCRFQUGF-UHFFFAOYSA-N 1-ethyl-6-(4-hydroxyphenyl)-4-oxopyridine-3-carboxylic acid Chemical compound CCN1C=C(C(O)=O)C(=O)C=C1C1=CC=C(O)C=C1 WZEVMSQCRFQUGF-UHFFFAOYSA-N 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 claims description 2
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical compound N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- FSQCLECWIGVZHF-UHFFFAOYSA-N 6-(3,4-dimethoxyphenyl)-1-ethyl-4-oxopyridine-3-carboxylic acid Chemical compound CCN1C=C(C(O)=O)C(=O)C=C1C1=CC=C(OC)C(OC)=C1 FSQCLECWIGVZHF-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 claims description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 150000003863 ammonium salts Chemical class 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 238000004587 chromatography analysis Methods 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000000524 functional group Chemical group 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- MLHIPDCLSKOPGD-UHFFFAOYSA-N methyl 6-(1,3-benzodioxol-5-yl)-1-ethyl-4-oxopyridine-3-carboxylate Chemical compound CCN1C=C(C(=O)OC)C(=O)C=C1C1=CC=C(OCO2)C2=C1 MLHIPDCLSKOPGD-UHFFFAOYSA-N 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 229960003512 nicotinic acid Drugs 0.000 claims description 2
- 239000011664 nicotinic acid Substances 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 235000005985 organic acids Nutrition 0.000 claims description 2
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 229930192474 thiophene Natural products 0.000 claims description 2
- 150000003852 triazoles Chemical class 0.000 claims description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 1
- MBELGTLJWJJGLF-UHFFFAOYSA-N 1,4-dihydropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CNC=CC1 MBELGTLJWJJGLF-UHFFFAOYSA-N 0.000 claims 1
- SSXUWHGRDQXTIW-UHFFFAOYSA-N 6-(3-chlorophenyl)-1-ethyl-4-oxopyridine-3-carboxylic acid Chemical compound CCN1C=C(C(O)=O)C(=O)C=C1C1=CC=CC(Cl)=C1 SSXUWHGRDQXTIW-UHFFFAOYSA-N 0.000 claims 1
- 125000003282 alkyl amino group Chemical group 0.000 claims 1
- 125000004414 alkyl thio group Chemical group 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- 239000000243 solution Substances 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound 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 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- DQIZKUMHBKFRKB-UHFFFAOYSA-N 1-ethyl-4-oxo-6-phenylpyridine-3-carboxylic acid Chemical compound CCN1C=C(C(O)=O)C(=O)C=C1C1=CC=CC=C1 DQIZKUMHBKFRKB-UHFFFAOYSA-N 0.000 description 3
- AKBXSBHUDQHSJE-UHFFFAOYSA-N 6-[4-(dimethylamino)phenyl]-1-ethyl-4-oxopyridine-3-carboxylic acid Chemical compound CCN1C=C(C(O)=O)C(=O)C=C1C1=CC=C(N(C)C)C=C1 AKBXSBHUDQHSJE-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- FUTACNYXCNCZTF-UHFFFAOYSA-N methyl 2-(4-chlorophenyl)-1-ethyl-4-oxo-2,3-dihydropyridine-5-carboxylate Chemical compound CCN1C=C(C(=O)OC)C(=O)CC1C1=CC=C(Cl)C=C1 FUTACNYXCNCZTF-UHFFFAOYSA-N 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 2
- CVXHXXJSTHFTCT-UHFFFAOYSA-N 1-ethyl-6-(4-methylsulfanylphenyl)-4-oxopyridine-3-carboxylic acid Chemical compound CCN1C=C(C(O)=O)C(=O)C=C1C1=CC=C(SC)C=C1 CVXHXXJSTHFTCT-UHFFFAOYSA-N 0.000 description 2
- OPHQOIGEOHXOGX-UHFFFAOYSA-N 3,4,5-trimethoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC(OC)=C1OC OPHQOIGEOHXOGX-UHFFFAOYSA-N 0.000 description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 2
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229960000632 dexamfetamine Drugs 0.000 description 2
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 2
- 229950007554 levmetamfetamine Drugs 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
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- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
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- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
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- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- CPYUVWPVQVORNT-UHFFFAOYSA-N methyl 1-ethyl-4-oxo-2-(3,4,5-trimethoxyphenyl)-2,3-dihydropyridine-5-carboxylate Chemical compound CCN1C=C(C(=O)OC)C(=O)CC1C1=CC(OC)=C(OC)C(OC)=C1 CPYUVWPVQVORNT-UHFFFAOYSA-N 0.000 description 1
- OZBCMVXVAVQXPC-UHFFFAOYSA-N methyl 2-(3,4-dimethoxyphenyl)-1-ethyl-4-oxo-2,3-dihydropyridine-5-carboxylate Chemical compound CCN1C=C(C(=O)OC)C(=O)CC1C1=CC=C(OC)C(OC)=C1 OZBCMVXVAVQXPC-UHFFFAOYSA-N 0.000 description 1
- XJKBJDDNXKBPRC-UHFFFAOYSA-N methyl 2-(ethylaminomethylidene)-3-oxo-5-(3,4,5-trimethoxyphenyl)pent-4-enoate Chemical compound CCNC=C(C(=O)OC)C(=O)C=CC1=CC(OC)=C(OC)C(OC)=C1 XJKBJDDNXKBPRC-UHFFFAOYSA-N 0.000 description 1
- QJLFXLFSPWDJKD-UHFFFAOYSA-N methyl 2-(ethylaminomethylidene)-3-oxo-5-(4-pyrrolidin-1-ylphenyl)pent-4-enoate Chemical compound C1=CC(C=CC(=O)C(C(=O)OC)=CNCC)=CC=C1N1CCCC1 QJLFXLFSPWDJKD-UHFFFAOYSA-N 0.000 description 1
- QVFOEHVPDHSCJZ-UHFFFAOYSA-N methyl 2-(ethylaminomethylidene)-3-oxo-5-phenylpent-4-enoate Chemical compound CCNC=C(C(=O)OC)C(=O)C=CC1=CC=CC=C1 QVFOEHVPDHSCJZ-UHFFFAOYSA-N 0.000 description 1
- XRERRIIXULJOAL-UHFFFAOYSA-N methyl 2-(ethylaminomethylidene)-3-oxo-5-pyridin-3-ylpent-4-enoate Chemical compound CCNC=C(C(=O)OC)C(=O)C=CC1=CC=CN=C1 XRERRIIXULJOAL-UHFFFAOYSA-N 0.000 description 1
- IVNOQZKUPJLRGU-UHFFFAOYSA-N methyl 2-(ethylaminomethylidene)-5-(4-methylsulfanylphenyl)-3-oxopent-4-enoate Chemical compound CCNC=C(C(=O)OC)C(=O)C=CC1=CC=C(SC)C=C1 IVNOQZKUPJLRGU-UHFFFAOYSA-N 0.000 description 1
- POYAJQWUGLSYFQ-UHFFFAOYSA-N methyl 2-(ethylaminomethylidene)-5-[3-methyl-4-(methylamino)phenyl]-3-oxopent-4-enoate Chemical compound CCNC=C(C(=O)OC)C(=O)C=CC1=CC=C(NC)C(C)=C1 POYAJQWUGLSYFQ-UHFFFAOYSA-N 0.000 description 1
- BKRLHJCQYAWQCT-UHFFFAOYSA-N methyl 2-[(cyclopropylamino)methylidene]-5-(4-methoxyphenyl)-3-oxopent-4-enoate Chemical compound C=1C=C(OC)C=CC=1C=CC(=O)C(C(=O)OC)=CNC1CC1 BKRLHJCQYAWQCT-UHFFFAOYSA-N 0.000 description 1
- LNDZIQFNSBRIST-UHFFFAOYSA-N methyl 5-(1,3-benzodioxol-5-yl)-2-(ethylaminomethylidene)-3-oxopent-4-enoate Chemical compound CCNC=C(C(=O)OC)C(=O)C=CC1=CC=C2OCOC2=C1 LNDZIQFNSBRIST-UHFFFAOYSA-N 0.000 description 1
- IYPDNXHYXYSYNV-UHFFFAOYSA-N methyl 5-(1,3-benzodioxol-5-yl)-2-[(cyclopropylamino)methylidene]-3-oxopent-4-enoate Chemical compound C=1C=C2OCOC2=CC=1C=CC(=O)C(C(=O)OC)=CNC1CC1 IYPDNXHYXYSYNV-UHFFFAOYSA-N 0.000 description 1
- JUEZXBOTTQNYPP-UHFFFAOYSA-N methyl 5-(2,6-dichlorophenyl)-2-(ethylaminomethylidene)-3-oxopent-4-enoate Chemical compound CCNC=C(C(=O)OC)C(=O)C=CC1=C(Cl)C=CC=C1Cl JUEZXBOTTQNYPP-UHFFFAOYSA-N 0.000 description 1
- IQTBPDHJGYTSDR-UHFFFAOYSA-N methyl 5-(3,4-dimethoxyphenyl)-2-(ethylaminomethylidene)-3-oxopent-4-enoate Chemical compound CCNC=C(C(=O)OC)C(=O)C=CC1=CC=C(OC)C(OC)=C1 IQTBPDHJGYTSDR-UHFFFAOYSA-N 0.000 description 1
- ONDLANNXONXESA-UHFFFAOYSA-N methyl 5-(4-chlorophenyl)-2-(dimethylaminomethylidene)-3-oxopent-4-enoate Chemical compound COC(=O)C(=CN(C)C)C(=O)C=CC1=CC=C(Cl)C=C1 ONDLANNXONXESA-UHFFFAOYSA-N 0.000 description 1
- BCWOZNWPPAFBEY-UHFFFAOYSA-N methyl 5-[4-(dimethylamino)-3-methylphenyl]-2-(ethylaminomethylidene)-3-oxopent-4-enoate Chemical compound CCNC=C(C(=O)OC)C(=O)C=CC1=CC=C(N(C)C)C(C)=C1 BCWOZNWPPAFBEY-UHFFFAOYSA-N 0.000 description 1
- MVZKJPNQMHVHEG-UHFFFAOYSA-N methyl 5-[4-(dimethylamino)phenyl]-2-(ethylaminomethylidene)-3-oxopent-4-enoate Chemical compound CCNC=C(C(=O)OC)C(=O)C=CC1=CC=C(N(C)C)C=C1 MVZKJPNQMHVHEG-UHFFFAOYSA-N 0.000 description 1
- UIRKEFHMCBPTFL-UHFFFAOYSA-N methyl 6-(4-chlorophenyl)-1-ethyl-4-oxopyridine-3-carboxylate Chemical compound CCN1C=C(C(=O)OC)C(=O)C=C1C1=CC=C(Cl)C=C1 UIRKEFHMCBPTFL-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Natural products OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
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- 235000019698 starch Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
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- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B28—WORKING CEMENT, CLAY, OR STONE
- B28B—SHAPING CLAY OR OTHER CERAMIC COMPOSITIONS; SHAPING SLAG; SHAPING MIXTURES CONTAINING CEMENTITIOUS MATERIAL, e.g. PLASTER
- B28B5/00—Producing shaped articles from the material in moulds or on moulding surfaces, carried or formed by, in or on conveyors irrespective of the manner of shaping
- B28B5/04—Producing shaped articles from the material in moulds or on moulding surfaces, carried or formed by, in or on conveyors irrespective of the manner of shaping in moulds moved in succession past one or more shaping stations
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Manufacturing & Machinery (AREA)
- Ceramic Engineering (AREA)
- Mechanical Engineering (AREA)
- Pyridine Compounds (AREA)
Abstract
4-Pyridone-3-carboxylic acid derivatives of the formula <IMAGE> in which R<1> denotes C1-6-alkyl or C3-6-cycloalkyl; R<2> denotes hydrogen or C1-6-alkyl; R<3> denotes a phenyl radical which is optionally substituted by R<4>, R<5> and/or R<6>, or an aromatic heterocyclic 6-membered ring containing one or more N atoms, which is optionally substituted by R<7> and which is bonded via a ring C atom; R<4> and R<5> denote halogen, hydroxyl, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkyl, amino, C1-6-alkylamino, di-C1-6-alkylamino, a 5- or 6-membered heterocycle bonded via a ring N or C atom, or both radicals R<4> and R<5> together denote C1-6-alkylenedioxy; R<6> denotes C1-6-alkoxy and R<7> denotes halogen, hydroxyl, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkyl, amino, C1-6-alkylamino or di-C1-6-alkylamino, and their salts, and a process for their preparation by dehydrogenation of corresponding 1,4,5,6-tetrahydronicotinic acid derivatives. The said compounds have antibacterial activity and/or a stimulant effect on the central nervous system.
Description
**WARNUNG** Anfang DESC Feld konnte Ende CLMS uberlappen **.
einen Gehalt an einEm 4-Pyridon-3-carbonsäurederivat der Formel I oder einem Salz davon.
Die vorliegende Erfindung betrifft neue 4-Pyridon-3-carbonsäurederivate und pharmazeutische Präparate mit einem Gehalt an diesen Verbindungen sowie deren Herstellung.
Die neuen Verbindungen sind antibakteriell aktiv und/ oder zeigen eine Wirkung auf das Zentralnervensystem, wobei sie gegenüber bekannten Verbindungen gleicher Wirkungsrichtung, z.B. gegenüber Nitrofurantoin oder Nomifensin, Vorteile aufweisen.
Die erfindungsgemässen 4-Pyridon-3-carbonsäurederivate sind solche der allgemeinen Formel
EMI2.1
worin
R1 Cl 6-Alkyl, C3 6-Cycloalkyl;
R2 Wasserstoff oder C1ff-Alkyl;
R3 einen gegebenenfalls durch R4, R5 und/oder R6 substituierten Phenylrest oder einen gegebenenfalls durch R7 substituierten, ein oder mehrere N-Atome enthaltenden aromatisch heterocyclischen 6-Ring, der über ein Ring-C-atom gebunden ist;
R4 und R5 Halogen, Hydroxy, C1*-Alkoxy, C1 6-Alkyl- thio, C1 6-Alkyl, Amino, C16-AWylamino, Di-C1ff-alkylamino, einen über ein Ring-N- oder -C-atom gebundenen 5- oder 6gliedrigen Heterocyclus oder beide Reste R4 und R5 gemeinsam C16-AWylendioxy;
;
R6 C1 6-Alkoxy und
R7 Halogen, Hydroxy, C1 6-Alkoxy, C1ff-Alkylthio, C16- Alkyl, Amino, C1 6-Alkylamino oder Di-C1 6-alkylamino bedeuten, - mit der Einschränkung, dass R2 nicht Wasserstoff ist, wenn R1 Methyl und gleichzeitig R3 Phenyl darstellen - und deren Salze.
Das erfindungsgemässe Verfahren ist dadurch gekennzeichnet, dass man ein 1, 4, 5, 6-Tetrahydronicotinsäurederivat der Formel
EMI2.2
worin
R1, R2 und R3 die oben angegebenen Bedeutungen besitzen, in 5,6-Stellung dehydriert und gewünschtenfalls die erhaltene Verbindung der Formel I in ein Salz überführt.
Beispiele von C1 6-Alkylgruppen, die gerad- oder verzweigtkettig sein können, sind Methyl, Äthyl, Propyl, Isopropyl, Butyl, sek.- oder tert.-Butyl, wobei Methyl und Äthyl bevorzugt sind; Beispiele von C1 6-Alkylendioxy sind Methylen- und Äthylendioxy. Als C3ff-Cycloalkylrest ist Cyclopropyl bevorzugt. Der Ausdruck Halogen umfasst Fluor, Chlor, Brom und Jod.
Beispiele für den Substituenten R8 in der Bedeutung eines ein oder mehrere N-Atome enthaltenden aromatischen heterocyclischen 6-Ringes sind 2-, 3- oder 4 Pyridyl, 3- oder 4Pyridazyl, 2-, 4- oder 5-Pyrimidyl und 2oder 3-Pyrazyl, während als Substituenten R4 und/oder R5 in der Bedeutung eines über ein Ring-N- oder -C-Atom gebundenen 5- oder 6gliedrigen Heterocyclus' beispielsweise Pyrrol, ein Pyrrolin, Pyrrolidin, Isoxazol, Oxazol, Thiophen, Thiazol, Pyrazol, Imidazol, ein Imidazolin, Imidazolidin, Triazol, Oxadiazol, Pyridin, Piperidin, Morpholin, Piperazin, Thiazin, Pyridazin, Pyrimidin oder ein Triazin genannt werden können.
Als Salze von Verbindungen der Formel I kommen Alkalimetall-, Erdalkalimetall- und (ggf. substituierte) Ammoniumsalze in Frage, wenn R2 Wasserstoff bedeutet und, sofern basische Substituenten im Molekül vorliegen, Additionssalze mit physiologisch verträglichen, starken anorganischen und organischen Säuren, wie z.B. Salzsäure, Schwefelsäure, Phosphorsäure, Methansulfonsäure oder p-Toluolsulfonsäure.
Bevorzugte Verbindungen der Formel I sind einerseits solche, in denen R1 Methyl oder Äthyl ist, andererseits solche, in denen R2 Wasserstoff oder Methyl darstellt und schliesslich solche, in denen R3 einen substituierten Phenylrest darstellt, wobei ein Substituent, insbesondere eine substituierte Aminogruppe oder ein stickstoffhaltiger Heterocyclus, in 4-Stellung besonders bevorzugt ist.
Die erfindungsgemässe Dehydrierung einer Verbindung II kann nach an sich bekannten Methoden, zweckmässigerweise mit einem substituierten Benzochinon, wie 2,3-Dichlor-5,6 -dicyan-1,4-benzochinon (DDQ) oder Tetrachlor-1,4-benzochinon (Chloranil), in einem inerten organischen Lösungsmittel, wie Methylenchlorid, Benzol oder Dioxan, und innerhalb eines Temperaturbereichs von Raumtemperatur bis zur Rückflusstemperatur des Reaktionsgemisches durchgeführt werden. Im allgemeinen geht man so vor, dass man zu der Lösung des Tetrahydronicotinsäurederivats eine Lösung des substituierten Benzochinons zutropft, wobei man darauf achtet, dass äquimolekulare Mengen umgesetzt werden. Bei ungefärbtem Ausgangsmaterial ist das Ende der Reaktion leicht durch die auftretende Färbung des Reaktionsgemisches zu erkennen.
Das Reaktionsprodukt kann in üblicher Weise aus dem Gemisch isoliert und z.B. durch Umkristallisation oder chromatographische Verfahren gereinigt werden.
Die Substituenten R2 und R8 können in an sich bekannter Weise innerhalb der angegebenen Definitionen modifiziert werden.
So kann beispielsweise die Carboxylgruppe verestert oder eine Estergruppe -COOR2 verseift werden. Eine im Substituenten R3 vorkommende Aminogruppe kann alkyliert, eine Hydroxygruppe veräthert, eine Alkoxygruppe gespalten, ein Halogenatom gegen ein anderes Halogenatom oder eine andere funktionelle Gruppe ausgetauscht werden. Ferner kann ein gesättigter heterocyclischer Substituent gewünschtenfalls dehydriert, ein teilweise oder völlig ungesättigter Heterocyclus hydriert werden, ohne dass dadurch die allen erfindungsgemässen Verbindungen gemeinsame Grundstruktur verändert wird.
Die Ausgangsverbindungen der Formel II können durch Erwärmen eines 2-(R1-Aminomethylen)-3-oxo-4-pentensäure- derivates der Formel
EMI3.1
worin R' und R3 die oben angegebenen Bedeutungen haben, zweckmässigerweise in einem inerten polaren aprotischen organischen Lösungsmittel, wie z.B. Dimethylformamid (DMF), Dimethylsulfoxid (DMSO) oder Hexamethylphosphorsäuretriamid, hergestellt werden. Die Lösung wird eine bis mehrere Stunden auf eine Temperatur von etwa 100"C bis zur Rückflusstemperatur erhitzt, wobei Ringschluss zum 1,4,5,6 Tetrahydropyridon erfolgt.
Die Herstellung der Verbindungen III wiederum kann in an sich bekannter Weise in einer mehrstufigen Synthese aus Aldehyden der Formel R3-CHO erfolgen.
Im folgenden Reaktionsschema (Seite 7) ist die Herstellung von 1-Äthyl-6-phenyl-4-oxo-1 ,4 < Iihydronicotinsäure aus Benzaldehyd generisch und in Beispiel 1 die Herstellung von 1 -Äthyl-6-(4-chlorphenyl)-4oxo- 1 ,4-dihydronicotinsäure bzw.
deren Methylester im Detail beschrieben.
Durch Variation des Ausgangsaldehyds VII-1, der Ester gruppe der Triphenylphosphoniumverbindung oder des Amins bei der Umsetzung einer Verbindung IV-1 zu einer Verbin dung III-1 können in analoger Weise prinzipiell alle erfindungsgemässen Verbindungen hergestellt werden.
Die Verbindungen der Formel I sind pharmakologisch aktiv. Sie weisen antibakterielle Aktivität und/oder eine stimulierende Wirkung auf das Zentralnervensystem auf, wobei sie durch geringe akute Toxizitäten gekennzeichnet sind. So ist beispielsweise 1-Athyl-4-oxo-6-phenyl-1 ,4-dihydronicotin- säure dem Nomifensin, bei etwa gleicher LD10, wirkungsmässig wesentlich überlegen, während es sich vom d-Amphetamin und d-Methamphetamin bei etwa gleich starker Wirkung durch die wesentlich niedrigere LD10 vorteilhaft abhebt (s. Tabelle 1).
EMI3.2
TABELLE 1
Verbindung LD5o Turning rat
Test' > min.
aktive Dosis (mg/kg) i.p.
1 -Äthyl-4-oxo-6-phenyl -1,4-dihydronicotinsäure 300-600 p.o. 1 Nomifensin 300-600 p.o. 3 d-Amphetamin.42 H2SO4 35 p.o., 1
14 i.v., 22 s.c.
d-Methamphetamin.HCl 9.5 i.v., 14 s.c. 1 ') Arch. int. Pharmacodyn. Ther. 217, 118-130 (1975)
Was die antibakterielle Aktivität der neuen Verbindungen angeht, so eignen sie sich besonders als Therapeutika bei Harnweginfektionen. Gegenüber bekannten Verbindungen mit dieser Indikation, z.B. gegenüber Nitrofurantoin, zeichnen sie sich durch erhöhte Aktivität gegenüber speziellen Erregern, beispielsweise Escherichia coli, aus (s. Tabelle 2).
TABELLE 2
Verbindung Escheria coli in vitro in vivo
MIC (Maus) ED5o ug/ml mg/kg p.o.
Nitrofurantoin 5 > 100 1 -Äthyl-6-(4-methyloxyphenyl)- -4-oxo-1,4-dihydronicotinsäure 2,5 > 100
1-Äthyl-6-(3,4-methylendioxyphe- nyl)-4-oxo- 1 ,4-dihydronicotin- säure 2,5 > 100
1 -Äthyl-6-(4-methylthiophenyl) -4-oxo-1,4-dihydronicotinsäure 2,5 82
1 -Äthyl-6-(4-pyrrolophenyl)-4 -oxo- 1 ,4-dihydronicotinsäure 1,2 34
1 -Äthyl-6-(4-pyrrolidinophenyl) -4-oxo-1,4-dihydronicotinsäure 1,2 19
1 -Athyl-6-(4-dimethylaminophe- nyl)-4-oxo- 1 ,4-dihydronicotin- säure 0,6 8,8 1 -Äthyl-6-(3-methyl-4-methylami- nophenyl)-4-oxo- 1,4-dihydroni cotinsäure 0,6 3,5
Die erfindungsgemässen 4-Pyridon-3-carbonsäurederivate der Formel I können daher bei der Therapie und Prophylaxe von Krankheiten,
insbesondere von bakteriellen Infektionen, sowie zur Stimulierung des Zentralnervensystems in Form pharmazeutischer Präparate mit direkter oder verzögerter Freigabe des Wirkstoffes in Mischung mit einem für die orale, rektale oder parenterale Applikation geeigneten organischen oder anorganischen inerten Trägermaterial, z.B. Wasser, Gelatine, Gummi arabicum, Milchzucker, Stärke, Magnesiumstearat, Talk, pflanzlichen Ölen, Polyalkylenglykolen, Vaseline, usw. verwendet werden. Die pharmazeutischen Präparate können in fester Form, z.B. als Tabletten, Dragees, Suppositorien, Kapseln; in halbfester Form, z.B. als Salben; oder in flüssiger Form, z.B. als Lösungen, Suspensionen oder Emulsionen, vorliegen.
Gegebenenfalls sind sie sterilisiert und bzw. oder enthalten weitere Hilfsstoffe, wie Konservierungs-, Stabilisierungs-, Netz- oder Emulgiermittel, Mittel zur geschrnacklichen Verbesserung, Salze zur Veränderung des osmotischen Druckes oder Puffersubstanzen.
Die Herstellung der pharmazeutischen Präparate kann in der jedem Fachmann geläufigen Weise, nämlich dadurch erfolgen, dass man die Wirksubstanz mit dem zur therapeutischen Verabreichung geeeigneten, nicht-toxischen, inerten Trägermaterial vermischt und das erhaltene Gemisch in die geeignete galenische Form bringt.
Als Dosierungsrichtlinie kann für die Verbindungen der Formel I als antibakterielle Mittel eine Menge von 10-100 mg/kg, vorzugsweise etwa 50 mg/kg Körpergewicht pro Tag gelten, als Mittel mit Wirkung auf das Zentralnervensystem eine Menge von 100 ,ug - 10 mg/kg.
Beispiel 1
3 g 1-Äthyl-6-(4-chlorphenyl)-4-oxo-1,4,5,6-tetrahydronicotinsäure-methylester wurden in 50 ml Benzol auf 80" erwärmt und tropfenweise mit einer benzolischen Lösung von 4 g Dichlordicyanbenzochinon (DDQ) versetzt, bis keine Entfärbung mehr sichtbar war. Es wurde gekühlt und das dabei ausfallende kristalline Material abgenutscht.
Das erhaltene Material, ein Gemisch von 1-Äthyl-6-(4 -chlorphenyl)-4-oxo- 1 ,4-dihydronicotinsäuremethylester mit DDQ, wurde mit 20 ml 1N Natronlauge bei Raumtemperatur während 30 Minuten gerührt, die klare Lösung mit 50 ml Eiswasser verdünnt und mit 0,5 N Salzsäure vorsichtig auf pH 6,5 angesäuert. Dabei fiel das Produkt in fast reiner Form an. Es wurde aus Essigester umkristallisiert. Ausbeute: 2,1 g 1-Äthyl-6-(4-chlorphenyl)-4-oxo-1,4-dihydronicotinsäure, Smp. 215-217 C.
Das Ausgangsmaterial wurde folgendermassen erhalten:
14 g 4-Chlorbenzaldehyd und 47 g [2-Methoxy-3-(meth oxycarbonyl)-allyl] -triphenylphosphoniumbromid wurden in 130 ml Methylenchlorid gelöst. Dazu liess man bei Raumtemperatur und unter gutem Rühren 100 ml 50% wässrige Natronlauge zufliessen, wobei ein Temperaturanstieg beobachtet wurde. Es wurde 20 Minuten weitergerührt, auf Eis gegossen und mit Methylenchlorid extrahiert. Der nach Trocknen mit Natriumsulfat und Absaugen des Lösungsmittels verbleibende Rückstand wurde aus Methanol kristallisiert, die Mutterlauge in Hexan/Äther (4:1 v/v), durch eine kurze Silicagelsäure filtriert und das aus dem Eluat auskristallisierte Produkt mit dem Hauptprodukt vereinigt.
Ausbeute insgesamt: 23,5 ,93,3 %) reiner 5-(4-Chlorphenyl)-3 -methoxy-2,4pentadien-carbonsäuremethylester, Smp. 69 bis 720C.
23,5 g 5-(p-Chlorphenyl)-3-methoxy-2,4-pentadiencarbonsäuremethylester, gelöst in 250 ml Dioxan, wurden mit 150 ml 0,1 N Schwefelsäure versetzt und während 3 Stunden auf 100"C gehalten. Man kühlte ab extrahierte mit Essigester und kristallisierte nach Trocknen der Lösung durch Zugabe von Hexan. Man erhielt 14,8 g (66,7%) 5-(4-Chlorphenyl)-3-oxo-4-pentensäuremethylester, Smp. 78-800C.
14,8 g 5-(4-Chlorphenyl)-3-oxo-4-pentensäuremethylester wurden in 100 ml Benzol gelöst und mit N,N-Dimethylformamid-dimethylacetal versetzt. Man rührte die rotbraun gefärbte Lösung während 30 Minuten bei 60"C, entfernte Lösungsmittel und überschüssiges Reagens und erhielt 5-(4-Chlorphenyl)-2-(dimethylaminomethylen)-3-oXo-4-pen- tensäuremethylester in Form eines rotbraunen Öles, das in dieser Form weiterverarbeitet wurde.
Das erhaltene Öl wurde in 50 ml Benzol gelöst und mit 100 ml einer gesättigten benzolischen Lösung von Äthylamin bei Raumtemperatur 30 Minuten gerührt. Danach wurde das Lösungsmittel entfernt und der Rückstand aus Äther-Hexan kristallisiert. Man erhielt 12,4 g (68% über 2 Stufen) 2 -(Äthylaminomethylen)-5-(4-chlorphenyl)- -oxo-4-penten- säuremethylester, Smp. 78-800C.
5,2 g 2-(Äthylaminomethylen)-5-(4-chlorphenyl)-3-oxo-4 -pentensäuremethylester in 50 ml Dimethylformamid wurden während 3 Stunden bei 140,1500C gehalten. Nach Entfernung des Lösungsmittels wurde 1-Äthyl-6-(4-chlorphenyl)-4 -oxo- 1 ,4,5,6-tetrahydronicotinsäuremethylester als einheitlicher, öliger Rückstand erhalten.
Beispiel 2 800 mg 1-Äthyl-6-(4-chlorphenyl)-4-oxo-1,4,5,6-tetrahy- dro-nicotinsäure in 20 ml Benzol wurde bei 80"C tropfenweise mit einer Lösung von 1,5 g DDQ in 30 ml Benzol versetzt, bis sich die Lösung nicht mehr entfärbte. Man kühlte ab, nutschte den Niederschlag ab, löste diesen in 20 ml 1N Natronlauge auf und säuerte die Lösung vorsichtig mit kalter 0,5 N Salzsäure auf pH 6,5 an. Das ausfallende, farblose Produkt wurde mit Wasser und dann mit Äther gewaschen.
Ausbeute 0,7 g (88%) 1-Äthyl-6-(4-chlorphenyl)-4-oxo-1,4 -dihydronicotinsäure, Smp. 214-215"C.
Das Ausgangsmaterial wurde dadurch erhalten, dass man 1,85 g gemäss Beispiel 1 erhaltenen 1-Äthyl-6-(4-chlorphe- nyl)-4-oxo-1 ,4,5,6-tetrahydronicotinsäuremethylester in 10 ml Dioxan und 10 ml Methanol löste und in Gegenwart von 20 ml 1N Natronlauge während 3 Stunden unter Rückfluss erhitzte. Man kühlte ab, säuerte mit 0,5 N Salzsäure an, nutschte die ausgefallenen Kristalle ab und kristallisierte sie aus Methanol/Äther um. Ausbeute 1,3 g (74%), Smp. 142 bis 144"C.
Beispiel 3
In Analogie zu den Beispielen 1 und 2 wurde aus Benzaldehyd 2-(Äthylaminomethylen)-3-oxo-5-phenyl-penten- säuremethylester, Smp. 92-940C, hergestellt, dieser zu 1 -Äthyl-4-oxo-6-phenyl- 1 ,4,5,6-tetrahydronicotinsäure, Smp.
148-1500C, cyclisiert und verseift und anschliessend zu 1-Äthyl-4-oxo-6-phenyl-1,4-dihydronicotinsäure, Smp. 166 bis 167"C, dehydriert.
Beispiel 4
In Analogie zu Beispiel 1 wurde aus 4-(Dimethylamino) -benzaldehyd 2-(Äthylaminomethylen)-5- [4-(dimethylamino)- -phenyl]-3-oxo-4-pentensäuremethylester, Smp. 129-1 300C, hergestellt, dieser zu 1-Äthyl-6- [4-(dimethylamino)-phenylj - -4-oxo- 1 ,4,5,6-tetrahydronicotinsäuremethylester, Smp. 85 bis 87"C. cyclisiert und zu 1-Äthyl-6-[4-(dimethylamino)-phe- nyl]-4-oxo-1,4-dihydronicotinsäure, Smp. 258-2590C, dehydriert und verseift.
Beispiel 5
In Analogie zu Beispiel 1 wurde aus 3-Methyl-4-(dimethylamino)-benzaldehyd 2-(Äthylaminomethylen)-5-[3-me- thyl-4-(dimethylamino)-phenyl] -3 -oxo-4-pentensäuremethylester, Smp. 98-1000C, hergestellt, dieser zu 1-Äthyl-6-[3-me- thyl-4-(dimethylamino)-phenyl] -4-oxo- 1 ,4,5,6-tetrahydronico- tinsäuremethylester cyclisiert, zu 1 -Äthyl-6- 13-methyl4-(di- methylamino)-phenyl] -4-oxo- 1 ,4-dihydronicotinsäuremethyl- ester, Smp. 132-1340C, dehydriert und zu 1-Äthyl-6-[3-me- thyl-4-(dimethylamino)-phenyl] -4-oxo-1,4-dihydronicotinsäure, Smp. 160-1620C, verseift.
Beispiel 6
In Analogie zu den Beispielen 1 und 2 wurde aus 4-Pyrrolobenzaldehyd 2-(Äthylaminomethylen)-3-oxo-5-(4-pyrrolo- phenyl)-4-pentensäuremethylester, Smp. 1 19-1210C, hergestellt, dieser zu 1 -Äthyl-6-(4-pyrrolophenyl)-Poxo- 1,4,5,6- -tetrahydronicotinsäure cyclisiert und verseift und anschliessend zu 1 -Äthyl-6-(4-pyrrolophenyl)-4-oxo- 1,4-dihydronico- tinsäure, Smp. > 300"C, dehydriert.
Beispiel 7
In Analogie zu den Beispielen 1 und 2 wurde aus 4 -Methoxybenzaldehyd 2-(Äthylaminomethylen)-3 -oxo-5-(4 -methoxyphenyl)-4-pentensäuremethylester hergestellt, dieser zu 1-Athyl-6-(4-methoxyphenyl)-4-oxo-1,4,5,6-tetrahydro- nicotinsäure, Smp. 173-174"C, cyclisiert und verseift und anschliessend zu l-Äthyl-6-(Pmethoxyphenyl)-4-oxo- 1,4-dihydronicotinsäure, Smp. 215-217"C, dehydriert.
Beispiel 8
In Analogie zu den Beispielen 1 und 2 wurde aus 4-Methoxybenzaldehyd 2-(Cyclopropylaminomethylen)-5-(4-methoxyphenyl)-3-oxo-4-pentensäuremethylester, Smp. 125- 127 C, hergestellt, dieser zu 1-Cyclopropyl-6-(4-methoxyphenyl)-4oxo-1,4,5,6-tetrahydronicotinsäure, Smp. 137-139"C, cyclisiert und verseift und anschliessend zu 1-Cyclopropyl-6-(4 -methoxyphenyl)-4-oxo-1,4-dihydronicotinsäure, Smp. 159 bis 161"C, dehydriert.
Beispiel 9
In Analogie zu den Beispielen 1 und 2 wurde aus 3,4-Dimethoxybenzaldehyd 2-(Äthylaminomethylen)-5-(3 ,4-dimeth oxyphenyl)-3-oxo-4-pentensäuremethylester hergestellt, dieser zu 1-Äthyl-6-(3,4-dimethoxyphenyl)-4-oxo 1,4,5,6-tetra- hydronicotinsäuremethylester, Smp. 134-1350C, cyclisiert, zu 1-Äthyl-6-(3,4-dimethoxyphenyl)-4-oxo-1,4,5,6-tetrahydro- nicotinsäure, Smp. 182-1830C, verseift und anschliessend zu 1-Äthyl-6-(3 ,4-dimethoxyphenyl)-4-oxo- 1 ,4-dihydronicotin- säure, Smp. 232-2340C, dehydriert.
Beispiel 10
In Analogie zu den Beispielen 1 und 2 wurde aus 3,4 Methylendioxybenzaldehyd 2-(Äthylaminomethylen)-5-(3 ,4 -methylendioxyphenyl)-3 -oxo-4-pentensäuremethylester, Smp.
124-1250C, hergestellt, dieser zu 1-Äthyl-6-(3,4-methylen dioxyphenyl)-4-oxo-1,4,5,6-tetrahydronicotinsäure, Smp.
173-175"C, cyclisiert und verseift und anschliessend zu 1-Äthyl-6-(3,4-methylendioxyphenyl)-4-oxo- 1,4-dihydronicotinsäure, Smp. 269-270"C, dehydriert.
Diese Verbindung wurde in an sich bekannter Weise in den 1-Äthyl-6-(3,4-methylendioxyphenyl)-4-oxo- 1,4-dihydro- nicotinsäuremethylester, Smp. 183-185"C, übergeführt.
Beispiel 11
In Analogie zu den Beispielen 1 und 2 wurde aus 3,4-Methylendioxybenzaldehyd 2-(Cyclopropylaminomethylen)-5 -(3 ,4-methylendioxyphenyl)-3 -oxo-4-pentensäuremethylester, Smp. 158-1600C, hergestellt, dieser zu 1-Cyclopropyl-6-(3,4 -methylendioxyphenyl)-4-oxo- 1,4,5,6-tetrahydronicotinsäure, Smp. 122-1240C, cyclisiert und verseift und anschliessend zu I-Cyclopropyl-a-O ,4-methylendioxyphenyl)-4-oxo- 1 ,4-dihy- dronicotinsäure, Smp. 211-2120C, dehydriert.
Beispiel 12
In Analogie zu den Beispielen 1 und 2 wurde aus 3,4,5 -Trimethoxybenzaldehyd 2-(Äthylaminomethylen)-3-oxo-5 -(3 ,4,5-trimethoxyphenyl)-4-pentensäuremethylester in Form eines Öls hergestellt, dieses zu 1-Äthyl-4-oxo-6-(3,4,5-tri- methoxyphenyl)-1 ,4,5,6-tetrahydronicotinsäuremethylester cyclisiert und anschliessend zu 1-Äthyl-4-oxo-6-(3,4,5-tri methoxyphenyl)- 1,4-dihydronicotinsäure, Smp. 200-201"C, dehydriert und verseift.
Beispiel 13
In Analogie zu den Beispielen 1 und 2 wurde aus 4-(Methylthio)-benzaldehyd 2-(Äthylaminomethylen)-5-(4-methylthiophenyl)-3-oxo-4-pentensäuremethylester hergestellt, dieser zu 1 -Äthyl-6-(4-methylthiophenyl)-4-oxo- 1 ,4,5,64etra- hydronicotinsäure, Smp. 173-1740C, cyclisiert und verseift und anschliessend zu 1-Äthyl-6-(4-methylthiophenyl)-4-oxo - 1 ,4-dihydronicotinsäure, Smp. 195-197 C, dehydriert.
Beispiel 14
In Analogie zu den Beispielen 1 und 2 wurde aus p-Hydroxybenzaldehyd 2-(Äthylaminomethylen)-5-(4-hydroxyphenyl)-3-oxo-4-pentensäuremethylester hergestellt, dieser zu l-Äthyl-6-(4-hydroxyphenyl)-4-oxo- l,4,5,6-tetrahydronicotin- säure cyclisiert und verseift und anschliessend zu 1-Äthyl-6 -(4-hydroxyphenyl)-4-oxo- 1,4-dihydronicotinsäure, Smp.
243-245"C, dehydriert.
Diese Verbindung kann auch folgendermassen erhalten werden:
3,7 g einer 50%igen Natriumhydriddispersion werden in 50 ml Dimethylformamid (DMF) bei Raumtemperatur unter Rühren mit 5 g Äthylmercaptan versetzt. Anschliessend wird dazu die Lösung von 4,3 g 1-Athyl-6-(4-methoxyphenyl)-4- -oxo-1,4-dihydronicotinsäure (Beispiel 7) in 50 ml DMF zugefügt und das Gemisch auf 100"C erhitzt, wobei zunächst eine klare Lösung entsteht. Nach ca. 30 Minuten entsteht wieder ein Niederschlag. Man lässt 16 Stunden bei 100"C rühren, kühlt dann ab und nimmt das Reaktionsgemisch in Essigester auf. Diese Lösung wird mit kalter 0,1 N Salzsäure neutralgewaschen, mit Natriumsulfat getrocknet und das Lösungsmittel entfernt. Der Rückstand wird aus Methanol / Äther kristallisiert.
Ausbeute 3,4 g (83 %), Smp. 245-2470C.
Beispiel 15
In Analogie zu den Beispielen 1 und 2 wurde aus m Chlorbenzaldehyd 2-(Äthylaminomethylen)-5-(3-chlorphenyl)-3-oxo-4-pentensäuremethylester hergestellt, dieser zu 1 -Äthyl-6-(3-chlorphenyl)-4-oxo- 1 ,4'5,6-tetrahydwm.cotin- säure, Smp. 143-1450C, cyclisiert und verseift und anschliessend zu 1-Athyl-6-(3-chlorphenyl)-4-oxo-1,4-dihydronicotin- säure, Smp. 212-2130C, dehydriert.
Beispiel 16
In Analogie zu den Beispielen 1 und 2 wurde aus 2,6 Dichlorbenzaldehyd 2-(Äthylaminomethylen)-5-(2,6-dichlorphenyl)-3-oxo-4-pentensäuremethylester hergestellt, dieser zu
1 -Athyl-6-(2,6-dichlorphenyl)-4-oxo- 1,4, 1 ,4,5,6-tetrahydronico- tinsäure cyclisiert und verseift und anschliessend zu 1-Äthyl -6-(2,6-dichlorphenyl)-4-oxo- 1 ,4-dihydronicotinsäure, Smp.
200-201"C, dehydriert.
Beispiel 17
In Analogie zu den Beispielen 1 und 2 wurde aus p-Chlorbenzaldehyd 5-(4-Chlorphenyl)-2-(methylaminomethylen)-3 -oxo-4-pentensäuremethylester, Smp. 114-1 160C, hergestellt, dieser zu 6-(4-Chlorphenyl)- 1 -methyl-4oxo- 1,4,5,6-tetrahydronicotinsäure, Smp. 205-206"C, cyclisiert und verseift und anschliessend zu 6-(4-Chlorphenyl)-1-methyl-4-oxo-1,4- -nicotinsäure, Smp. 275-280"C (Zers.), dehydriert.
Beispiel 18
In Analogie zu den Beispielen 1 und 2 wurde aus 3-Methyl-4-methylamino-benzaldehyd 2-(Äthylaminomethylen)-5 -(3-methyl-4-methylaminophenyl)-3-oxo-4-pentensäureme- thylester hergestellt, dieser zu 1-Äthyl-6-(3-methyl-4-me- thylaminophenyl)-4-oxo- 1 ,4,5,6-tetrahydronicotinsäure cyclisiert und verseift und anschliessend zu 1-Äthyl-6-(3-me thyl-4-methylaminophenyl)-4-oxo- 1 ,4-dihydronicotinsäure, Smp. 243-2440C, dehydriert.
Beispiel 19
In Analogie zu den Beispielen 1 und 2 wurde aus Nicotinaldehyd 2-(Äthylaminomethylen)-3-oxo-5-(3-pyridyl)-4- -pentensäuremethylester, Smp. 78-800C, hergestellt, dieser zu 1-Athyl-4-oxo-6-(3-pyridyl)- 1,4,5,6-tetrahydronicotinsäure, Smp. 197-1990C, cyclisiert und verseift und anschliessend zu 1-Äthyl-4-oxo-6-(3-pyridyl)-1 ,4-dihydronicotinsäure, Smp.
209-210"C, dehydriert.
Beispiel 20
In Analogie zu den Beispielen 1 und 2 wurde aus 4-Pyrrolidinobenzaldehyd 2-(Athylaminomethylen)-3-oxo-5-(4- -pyrrolidinophenyl)-4-pentensäuremethylester hergestellt, dieser zu l-Äthyl-4-oxo-6-(4-pyrrolidinophenyl)- 1,4,5.6-tetra- hydronicotinsäure cyclisiert und verseift und anschliessend zu 1-Äthyl-6-(4-pyrrolidinophenyl)-4-oxo- 1 ,4-dihydronicotin- säure, Smp. 276-2780C, dehydriert.
Diese Verbindung kann auch folgendermassen erhalten werden.
7,8 g 1-Athyl-4-oxo-6-(4-pyrrolophenyl)-1,4-dihydronico- tinsäuremethylester werden bei Raumtemperatur mit 8.5 g 5% Palladiumkohle in 800 ml Methanol hydriert. Nach Entfernung des Katalysators wird das Reaktionsgemisch zur Trockene eingedampft und der Rückstand mit Methylenchlorid aufgenommen. Die organische Lösung wird mit eiskalter
1N Salzsäure extrahiert, der wässrige Extrakt mit 1N Natronlauge neutralisiert und mit Methylenchlorid extrahiert.
Nach Trocknen der Lösung und Eindampfen erhält man 7,0 g 1-Äthyl-4-oxo-6-(4-Dyrrolidinophenyl)-l ,4-dihydro- nicotinsäuremethylester, Smp. 157-159 (aus Methanol).
In Analogie zu Beispiel 1 kann der Ester dann zur Säure verseift werden.
Beispiel 21
Es wurden Tabletten zu 120 mg bzw. 500 mg hergestellt, enthaltend l-Äthyl-4-oxo-6-phenyl-1,4-dihydro nicotinsäure 10,0 mg 1 -Äthyl-6- [4-(dimethylamino)-phe nyl] -4-oxo-1 ,4-dihydronicotinsäure - 150 mg
Maisstärke 50,0 mg 160 mg
Milchzucker 58,0 mg 180 mg
Talk 1,5 mg 7 mg
Magnesiumstearat 0,5 mg 3 mg
120,0 mg 500 mg
** WARNING ** beginning of DESC field could overlap end of CLMS **.
contains an Em 4-pyridone-3-carboxylic acid derivative of the formula I or a salt thereof.
The present invention relates to new 4-pyridone-3-carboxylic acid derivatives and pharmaceutical preparations containing these compounds and their preparation.
The new compounds are antibacterially active and / or have an effect on the central nervous system, compared to known compounds with the same direction of action, e.g. have advantages over nitrofurantoin or nomifensin.
The 4-pyridone-3-carboxylic acid derivatives according to the invention are those of the general formula
EMI2.1
wherein
R1 Cl 6 alkyl, C3 6 cycloalkyl;
R2 is hydrogen or C1ff-alkyl;
R3 is a phenyl radical which is optionally substituted by R4, R5 and / or R6 or an aromatically heterocyclic 6-ring which is optionally substituted by R7 and contains one or more N atoms and is bonded via a ring carbon atom;
R4 and R5 halogen, hydroxy, C1 * alkoxy, C1 6-alkylthio, C1 6-alkyl, amino, C16-AWylamino, di-C1ff-alkylamino, a bonded via a ring N or -C atom 5 - or 6-membered heterocycle or both radicals R4 and R5 together C16-AWylenedioxy;
;
R6 C1 6 alkoxy and
R7 is halogen, hydroxy, C1 6-alkoxy, C1ff-alkylthio, C16-alkyl, amino, C1 6-alkylamino or di-C1 6-alkylamino - with the restriction that R2 is not hydrogen if R1 is methyl and R3 at the same time Represent phenyl - and their salts.
The process according to the invention is characterized in that a 1, 4, 5, 6-tetrahydronicotinic acid derivative of the formula
EMI2.2
wherein
R1, R2 and R3 have the meanings given above, are dehydrated in the 5,6-position and, if desired, the compound of the formula I obtained is converted into a salt.
Examples of C1 6-alkyl groups which can be straight or branched chain are methyl, ethyl, propyl, isopropyl, butyl, sec- or tert-butyl, with methyl and ethyl being preferred; Examples of C1 6-alkylenedioxy are methylene and ethylenedioxy. Cyclopropyl is preferred as the C3ff cycloalkyl radical. The term halogen includes fluorine, chlorine, bromine and iodine.
Examples of the substituent R8 meaning an aromatic heterocyclic 6-ring containing one or more N atoms are 2-, 3- or 4 pyridyl, 3- or 4-pyridazyl, 2-, 4- or 5-pyrimidyl and 2 or 3-pyrazyl while as substituents R4 and / or R5 meaning a 5- or 6-membered heterocycle bonded via a ring N or -C atom, for example pyrrole, pyrroline, pyrrolidine, isoxazole, oxazole, thiophene, thiazole, pyrazole, imidazole , an imidazoline, imidazolidine, triazole, oxadiazole, pyridine, piperidine, morpholine, piperazine, thiazine, pyridazine, pyrimidine or a triazine.
Suitable salts of compounds of the formula I are alkali metal, alkaline earth metal and (optionally substituted) ammonium salts if R2 is hydrogen and, if basic substituents are present in the molecule, addition salts with physiologically tolerated, strong inorganic and organic acids, such as e.g. Hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid or p-toluenesulfonic acid.
Preferred compounds of the formula I are on the one hand those in which R 1 is methyl or ethyl, on the other hand those in which R 2 is hydrogen or methyl and finally those in which R 3 is a substituted phenyl radical, a substituent, in particular a substituted amino group or a nitrogen-containing one Heterocycle, in the 4-position is particularly preferred.
The dehydrogenation of a compound II according to the invention can be carried out according to methods known per se, expediently with a substituted benzoquinone, such as 2,3-dichloro-5,6-dicyan-1,4-benzoquinone (DDQ) or tetrachloro-1,4-benzoquinone (chloranil ), in an inert organic solvent, such as methylene chloride, benzene or dioxane, and within a temperature range from room temperature to the reflux temperature of the reaction mixture. The general procedure is to add a solution of the substituted benzoquinone to the solution of the tetrahydronicotinic acid derivative, taking care to ensure that equimolecular amounts are reacted. If the starting material is not colored, the end of the reaction can easily be recognized by the color of the reaction mixture that occurs.
The reaction product can be isolated from the mixture in a conventional manner and e.g. can be purified by recrystallization or chromatographic methods.
The substituents R2 and R8 can be modified in a manner known per se within the definitions given.
For example, the carboxyl group can be esterified or an ester group -COOR2 can be saponified. An amino group present in the substituent R3 can be alkylated, a hydroxy group etherified, an alkoxy group cleaved, a halogen atom can be exchanged for another halogen atom or another functional group. Furthermore, a saturated heterocyclic substituent can, if desired, be dehydrated and a partially or completely unsaturated heterocycle can be hydrogenated without changing the basic structure common to all compounds according to the invention.
The starting compounds of the formula II can be obtained by heating a 2- (R1-aminomethylene) -3-oxo-4-pentenoic acid derivative of the formula
EMI3.1
wherein R 'and R3 have the meanings given above, expediently in an inert polar aprotic organic solvent, such as e.g. Dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or hexamethylphosphoric acid triamide can be produced. The solution is heated to a temperature of about 100 ° C. to the reflux temperature for one to several hours, ring closure leading to 1,4,5,6 tetrahydropyridone.
The compounds III can in turn be prepared in a manner known per se in a multi-stage synthesis from aldehydes of the formula R3-CHO.
In the following reaction scheme (page 7), the preparation of 1-ethyl-6-phenyl-4-oxo-1,4, <ihydronicotinic acid from benzaldehyde is generic and in Example 1 the preparation of 1-ethyl-6- (4-chlorophenyl) - 4oxo-1,4-dihydronicotinic acid or
the methyl ester described in detail.
By varying the starting aldehyde VII-1, the ester group of the triphenylphosphonium compound or the amine in the reaction of a compound IV-1 to a compound III-1, in principle all compounds according to the invention can be prepared in an analogous manner.
The compounds of formula I are pharmacologically active. They have antibacterial activity and / or a stimulating effect on the central nervous system, whereby they are characterized by low acute toxicities. For example, 1-ethyl-4-oxo-6-phenyl-1, 4-dihydronicotinic acid is significantly superior to nomifensin, with approximately the same LD10, while it differs from d-amphetamine and d-methamphetamine with approximately the same strength stands out due to the much lower LD10 (see Table 1).
EMI3.2
TABLE 1
Connection LD5o Turning rat
Test '> min.
active dose (mg / kg) i.p.
1-ethyl-4-oxo-6-phenyl -1,4-dihydronicotinic acid 300-600 p.o. 1 nomifensin 300-600 p.o. 3 d-amphetamine. 42 H2SO4 35 po.o., 1
14 IV, 22 SC
d-methamphetamine.HCl 9.5 i.v., 14 s.c. 1 ') Arch. Int. Pharmacodyn. Ther. 217, 118-130 (1975)
As far as the antibacterial activity of the new compounds is concerned, they are particularly suitable as therapeutic agents for urinary tract infections. Compared to known compounds with this indication, e.g. compared to nitrofurantoin, they are characterized by increased activity against special pathogens, for example Escherichia coli (see Table 2).
TABLE 2
Escheria coli compound in vitro in vivo
MIC (mouse) ED5o ug / ml mg / kg p.o.
Nitrofurantoin 5> 100 1 -ethyl-6- (4-methyloxyphenyl) - -4-oxo-1,4-dihydronicotinic acid 2.5> 100
1-ethyl-6- (3,4-methylenedioxyphenyl) -4-oxo-1,4-dihydronicotinic acid 2.5> 100
1-ethyl-6- (4-methylthiophenyl) -4-oxo-1,4-dihydronicotinic acid 2.5 82
1-ethyl-6- (4-pyrrolophenyl) -4-oxo-1,4-dihydronicotinic acid 1,2 34
1-ethyl-6- (4-pyrrolidinophenyl) -4-oxo-1,4-dihydronicotinic acid 1.2 19
1-ethyl-6- (4-dimethylaminophenyl) -4-oxo-1,4-dihydronicotinic acid 0.6 8.8 1-ethyl-6- (3-methyl-4-methylaminophenyl) -4 -oxo- 1,4-dihydronicotinic acid 0.6 3.5
The 4-pyridone-3-carboxylic acid derivatives of the formula I according to the invention can therefore be used in the therapy and prophylaxis of diseases,
in particular bacterial infections, and for stimulating the central nervous system in the form of pharmaceutical preparations with direct or delayed release of the active ingredient in a mixture with an organic or inorganic inert carrier material suitable for oral, rectal or parenteral administration, e.g. Water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc. can be used. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragees, suppositories, capsules; in semi-solid form, e.g. as ointments; or in liquid form, e.g. as solutions, suspensions or emulsions.
If necessary, they are sterilized and / or contain further auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers, agents for rapid improvement, salts for changing the osmotic pressure or buffer substances.
The pharmaceutical preparations can be prepared in a manner familiar to any person skilled in the art, namely by mixing the active substance with the non-toxic, inert carrier material suitable for therapeutic administration and bringing the mixture obtained into the suitable galenic form.
An amount of 10-100 mg / kg, preferably about 50 mg / kg, of body weight per day can be used as the antibacterial agent for the compounds of the formula I, as an agent with an effect on the central nervous system, an amount of 100, ug - 10 mg / kg.
example 1
3 g of methyl 1-ethyl-6- (4-chlorophenyl) -4-oxo-1,4,5,6-tetrahydronicotinate were heated to 80 "in 50 ml of benzene and added dropwise with a benzene solution of 4 g of dichlorodicyanobenzoquinone (DDQ ) until no discoloration was visible, the mixture was cooled and the resulting crystalline material was filtered off with suction.
The material obtained, a mixture of 1-ethyl-6- (4-chlorophenyl) -4-oxo-1, 4-dihydronicotinic acid methyl ester with DDQ, was stirred with 20 ml of 1N sodium hydroxide solution at room temperature for 30 minutes, the clear solution with 50 ml Diluted ice water and carefully acidified to pH 6.5 with 0.5 N hydrochloric acid. The product was almost pure. It was recrystallized from ethyl acetate. Yield: 2.1 g of 1-ethyl-6- (4-chlorophenyl) -4-oxo-1,4-dihydronicotinic acid, mp. 215-217 C.
The starting material was obtained as follows:
14 g of 4-chlorobenzaldehyde and 47 g of [2-methoxy-3- (meth oxycarbonyl) allyl] triphenylphosphonium bromide were dissolved in 130 ml of methylene chloride. For this purpose, 100 ml of 50% aqueous sodium hydroxide solution were allowed to flow in at room temperature and with good stirring, a rise in temperature being observed. The stirring was continued for 20 minutes, poured onto ice and extracted with methylene chloride. The residue which remained after drying with sodium sulfate and suction filtration of the solvent was crystallized from methanol, the mother liquor in hexane / ether (4: 1 v / v), filtered through a short silica gel acid and the product which had crystallized out from the eluate was combined with the main product.
Total yield: 23.5, 93.3%) of pure 5- (4-chlorophenyl) -3-methoxy-2,4-pentadiene-carboxylic acid methyl ester, mp. 69 to 720C.
23.5 g of methyl 5- (p-chlorophenyl) -3-methoxy-2,4-pentadienecarboxylate, dissolved in 250 ml of dioxane, were mixed with 150 ml of 0.1 N sulfuric acid and kept at 100 ° C. for 3 hours. The mixture was cooled extracted with ethyl acetate and crystallized after drying the solution by adding hexane, giving 14.8 g (66.7%) of methyl 5- (4-chlorophenyl) -3-oxo-4-pentenoate, mp 78-800C.
14.8 g of methyl 5- (4-chlorophenyl) -3-oxo-4-pentenoate were dissolved in 100 ml of benzene and N, N-dimethylformamide-dimethyl acetal was added. The red-brown colored solution was stirred for 30 minutes at 60 ° C., removed solvent and excess reagent, and methyl 5- (4-chlorophenyl) -2- (dimethylaminomethylene) -3-oXo-4-pentenoate was obtained in the form of a red-brown oil, which was processed in this form.
The oil obtained was dissolved in 50 ml of benzene and stirred with 100 ml of a saturated benzene solution of ethylamine at room temperature for 30 minutes. The solvent was then removed and the residue was crystallized from ether-hexane. 12.4 g (68% over 2 steps) of 2 - (ethylaminomethylene) -5- (4-chlorophenyl) - -oxo-4-pentenoic acid methyl ester, mp. 78-800C.
5.2 g of methyl 2- (ethylaminomethylene) -5- (4-chlorophenyl) -3-oxo-4-pentenoate in 50 ml of dimethylformamide were kept at 140.1500C for 3 hours. After removal of the solvent, 1-ethyl-6- (4-chlorophenyl) -4-oxo-1, 4,5,6-tetrahydronicotinic acid methyl ester was obtained as a uniform, oily residue.
Example 2 800 mg of 1-ethyl-6- (4-chlorophenyl) -4-oxo-1,4,5,6-tetrahydro-nicotinic acid in 20 ml of benzene was added dropwise at 80 ° C. with a solution of 1.5 g of DDQ in 30 ml of benzene until the solution no longer decolorized, cooled, filtered off with suction, dissolved in 20 ml of 1N sodium hydroxide solution and carefully acidified the solution to pH 6.5 with cold 0.5N hydrochloric acid The precipitated, colorless product was washed with water and then with ether.
Yield 0.7 g (88%) of 1-ethyl-6- (4-chlorophenyl) -4-oxo-1,4-dihydronicotinic acid, mp. 214-215 "C.
The starting material was obtained by 1.85 g of 1-ethyl-6- (4-chlorophenyl) -4-oxo-1, 4,5,6-tetrahydronicotinic acid methyl ester obtained in Example 1 in 10 ml of dioxane and 10 ml Methanol dissolved and heated in the presence of 20 ml of 1N sodium hydroxide solution under reflux for 3 hours. The mixture was cooled, acidified with 0.5 N hydrochloric acid, the precipitated crystals were filtered off and recrystallized from methanol / ether. Yield 1.3 g (74%), mp. 142 to 144 "C.
Example 3
In analogy to Examples 1 and 2, 2- (ethylaminomethylene) -3-oxo-5-phenyl-pentenoic acid methyl ester, mp 92-940C, was prepared from benzaldehyde, this to 1-ethyl-4-oxo-6-phenyl - 1, 4,5,6-tetrahydronicotinic acid, mp.
148-1500C, cyclized and saponified and then dehydrated to 1-ethyl-4-oxo-6-phenyl-1,4-dihydronicotinic acid, mp. 166 to 167 "C.
Example 4
Analogously to Example 1, 4- (dimethylamino) benzaldehyde was used to prepare 2- (ethylaminomethylene) -5- [4- (dimethylamino) - phenyl] -3-oxo-4-pentenoic acid methyl ester, mp. 129-1 300C, this cyclized to 1-ethyl-6- [4- (dimethylamino) phenylj - -4-oxo-1, 4,5,6-tetrahydronicotinic acid methyl ester, mp. 85 to 87 "C. and to 1-ethyl-6- [ 4- (dimethylamino) phenyl] -4-oxo-1,4-dihydronicotinic acid, mp. 258-2590C, dehydrated and saponified.
Example 5
In analogy to Example 1, 3-methyl-4- (dimethylamino) benzaldehyde was converted to 2- (ethylaminomethylene) -5- [3-methyl-4- (dimethylamino) phenyl] -3-oxo-4-pentenoic acid methyl ester, 98-1000C, prepared, this cyclized to 1-ethyl-6- [3-methyl-4- (dimethylamino) phenyl] -4-oxo-1, 4,5,6-tetrahydronico-acidic acid methyl ester 1-ethyl-6- 13-methyl4- (dimethylamino) phenyl] -4-oxo-1,4-dihydronicotinic acid methyl ester, mp. 132-1340C, dehydrated and to 1-ethyl-6- [3-me - thyl-4- (dimethylamino) phenyl] -4-oxo-1,4-dihydronicotinic acid, mp 160-1620C, saponified.
Example 6
Analogously to Examples 1 and 2, 4-pyrrolobenzaldehyde was used to prepare 2- (ethylaminomethylene) -3-oxo-5- (4-pyrrolo-phenyl) -4-pentenoic acid methyl ester, mp 1 19-1210C, to give 1 - Ethyl-6- (4-pyrrolophenyl) -poxo-1,4,5,6- -tetrahydronicotinic acid cyclized and saponified and then to 1-ethyl-6- (4-pyrrolophenyl) -4-oxo-1,4-dihydronico- tic acid, mp> 300 "C, dehydrated.
Example 7
In analogy to Examples 1 and 2, methyl 4-methoxybenzaldehyde was used to produce 2- (ethylaminomethylene) -3-oxo-5- (4-methoxyphenyl) -4-pentenoate, this to give 1-ethyl-6- (4-methoxyphenyl) - 4-oxo-1,4,5,6-tetrahydro-nicotinic acid, mp. 173-174 "C, cyclized and saponified and then to l-ethyl-6- (pmethoxyphenyl) -4-oxo-1,4-dihydronicotinic acid, M.p. 215-217 "C, dehydrated.
Example 8
In analogy to Examples 1 and 2, 2- (cyclopropylaminomethylene) -5- (4-methoxyphenyl) -3-oxo-4-pentenoic acid methyl ester, mp 125-127 C, was prepared from 4-methoxybenzaldehyde, this to 1-cyclopropyl- 6- (4-methoxyphenyl) -4oxo-1,4,5,6-tetrahydronicotinic acid, mp. 137-139 "C, cyclized and saponified and then to 1-cyclopropyl-6- (4-methoxyphenyl) -4-oxo- 1,4-dihydronicotinic acid, mp. 159 to 161 "C, dehydrated.
Example 9
Analogously to Examples 1 and 2, 3,4-dimethoxybenzaldehyde was used to prepare 2- (ethylaminomethylene) -5- (3,4-dimethoxyphenyl) -3-oxo-4-pentenoic acid methyl ester, which was converted into 1-ethyl-6- ( 3,4-dimethoxyphenyl) -4-oxo 1,4,5,6-tetra-hydronicotinic acid methyl ester, mp. 134-1350C, cyclized, to 1-ethyl-6- (3,4-dimethoxyphenyl) -4-oxo-1 , 4,5,6-tetrahydro nicotinic acid, mp. 182-1830C, saponified and then to 1-ethyl-6- (3, 4-dimethoxyphenyl) -4-oxo-1, 4-dihydronicotinic acid, mp. 232 -2340C, dehydrated.
Example 10
In analogy to Examples 1 and 2, from 3,4 methylenedioxybenzaldehyde was methyl 2- (ethylaminomethylene) -5- (3,4-methylenedioxyphenyl) -3-oxo-4-pentenoate, mp.
124-1250C, prepared this to 1-ethyl-6- (3,4-methylene dioxyphenyl) -4-oxo-1,4,5,6-tetrahydronicotinic acid, mp.
173-175 "C, cyclized and saponified and then dehydrated to 1-ethyl-6- (3,4-methylenedioxyphenyl) -4-oxo-1,4-dihydronicotinic acid, mp. 269-270" C.
This compound was converted into the 1-ethyl-6- (3,4-methylenedioxyphenyl) -4-oxo-1,4-dihydro-nicotinic acid methyl ester, mp. 183-185 "C, in a manner known per se.
Example 11
Analogously to Examples 1 and 2, from 3,4-methylenedioxybenzaldehyde, 2- (cyclopropylaminomethylene) -5 - (3, 4-methylenedioxyphenyl) -3-oxo-4-pentenoic acid methyl ester, mp 158-1600C, was prepared to give 1 - Cyclopropyl-6- (3,4-methylenedioxyphenyl) -4-oxo-1,4,5,6-tetrahydronicotinic acid, mp 122-1240C, cyclized and saponified and then to I-cyclopropyl-aO, 4-methylenedioxyphenyl) - 4-oxo-1,4-dihydronicotinic acid, mp. 211-2120C, dehydrated.
Example 12
In analogy to Examples 1 and 2, 3,4,5-trimethoxybenzaldehyde was used to produce 2- (ethylaminomethylene) -3-oxo-5 - (3, 4,5-trimethoxyphenyl) -4-pentenoic acid methyl ester in the form of an oil 1-Ethyl-4-oxo-6- (3,4,5-trimethoxyphenyl) -1, 4,5,6-tetrahydronicotinic acid methyl ester cyclized and then to 1-ethyl-4-oxo-6- (3,4, 5-tri methoxyphenyl) - 1,4-dihydronicotinic acid, mp. 200-201 "C, dehydrated and saponified.
Example 13
In analogy to Examples 1 and 2, 4- (methylthio) benzaldehyde was used to prepare 2- (ethylaminomethylene) -5- (4-methylthiophenyl) -3-oxo-4-pentenoic acid methyl ester, which was converted into 1-ethyl-6- (4th -methylthiophenyl) -4-oxo- 1, 4,5,64etra-hydronicotinic acid, mp. 173-1740C, cyclized and saponified and then to 1-ethyl-6- (4-methylthiophenyl) -4-oxo - 1, 4- dihydronicotinic acid, mp 195-197 C, dehydrated.
Example 14
In analogy to Examples 1 and 2, methyl p-hydroxybenzaldehyde was used to prepare 2- (ethylaminomethylene) -5- (4-hydroxyphenyl) -3-oxo-4-pentenoate, this to give l-ethyl-6- (4-hydroxyphenyl) - 4-oxol, 4,5,6-tetrahydronicotinic acid cyclized and saponified and then to 1-ethyl-6 - (4-hydroxyphenyl) -4-oxo-1,4-dihydronicotinic acid, mp.
243-245 "C, dehydrated.
This connection can also be obtained as follows:
3.7 g of a 50% sodium hydride dispersion in 50 ml of dimethylformamide (DMF) are mixed with 5 g of ethyl mercaptan at room temperature with stirring. The solution of 4.3 g of 1-ethyl-6- (4-methoxyphenyl) -4- -oxo-1,4-dihydronicotinic acid (Example 7) in 50 ml of DMF is then added and the mixture is heated to 100 ° C. initially a clear solution is formed. After about 30 minutes, a precipitate forms again. The mixture is stirred at 100 ° C. for 16 hours, then cooled and the reaction mixture is taken up in ethyl acetate. This solution is washed neutral with cold 0.1 N hydrochloric acid, dried with sodium sulfate and the solvent is removed. The residue is crystallized from methanol / ether.
Yield 3.4 g (83%), mp 245-2470C.
Example 15
Analogously to Examples 1 and 2, methyl m-chlorobenzaldehyde was used to produce 2- (ethylaminomethylene) -5- (3-chlorophenyl) -3-oxo-4-pentenoate, this to give 1-ethyl-6- (3-chlorophenyl) -4 -oxo- 1, 4'5,6-tetrahydwm.cotinic acid, mp. 143-1450C, cyclized and saponified and then to 1-ethyl-6- (3-chlorophenyl) -4-oxo-1,4-dihydronicotin acid, mp 212-2130C, dehydrated.
Example 16
Analogously to Examples 1 and 2, 2- (ethylaminomethylene) -5- (2,6-dichlorophenyl) -3-oxo-4-pentenoic acid methyl ester was prepared from 2,6 dichlorobenzaldehyde, and this to
1 -Athyl-6- (2,6-dichlorophenyl) -4-oxo-1,4, 1, 4,5,6-tetrahydronicotinic acid cyclized and saponified and then to 1-ethyl -6- (2,6- dichlorophenyl) -4-oxo-1,4-dihydronicotinic acid, mp.
200-201 "C, dehydrated.
Example 17
Analogously to Examples 1 and 2, p-chlorobenzaldehyde was used to produce 5- (4-chlorophenyl) -2- (methylaminomethylene) -3-oxo-4-pentenoate, mp 114-1 160C, to give 6- (4 -Chlorphenyl) - 1 -methyl-4oxo- 1,4,5,6-tetrahydronicotinic acid, mp. 205-206 "C, cyclized and saponified and then to 6- (4-chlorophenyl) -1-methyl-4-oxo- 1,4- nicotinic acid, m.p. 275-280 "C (dec.), Dehydrated.
Example 18
Analogously to Examples 1 and 2, 2- (ethylaminomethylene) -5 - (3-methyl-4-methylaminophenyl) -3-oxo-4-pentenoic acid methyl ester was prepared from 3-methyl-4-methylamino-benzaldehyde to give it 1-ethyl-6- (3-methyl-4-methylaminophenyl) -4-oxo-1, 4,5,6-tetrahydronicotinic acid cyclized and saponified and then to 1-ethyl-6- (3-methyl-4 -methylaminophenyl) -4-oxo-1,4-dihydronicotinic acid, mp. 243-2440C, dehydrated.
Example 19
In analogy to Examples 1 and 2, 2- (ethylaminomethylene) -3-oxo-5- (3-pyridyl) -4- -pentenic acid methyl ester, mp 78-800C, was prepared from nicotinaldehyde, this to 1-ethyl-4- oxo-6- (3-pyridyl) - 1,4,5,6-tetrahydronicotinic acid, mp 197-1990C, cyclized and saponified and then to 1-ethyl-4-oxo-6- (3-pyridyl) -1, 4-dihydronicotinic acid, m.p.
209-210 "C, dehydrated.
Example 20
In analogy to Examples 1 and 2, 4-pyrrolidinobenzaldehyde was used to prepare 2- (ethylaminomethylene) -3-oxo-5- (4--pyrrolidinophenyl) -4-pentenoic acid methyl ester, which was converted to l-ethyl-4-oxo-6- ( 4-pyrrolidinophenyl) - 1,4,5,6-tetrahydronicotinic acid cyclized and saponified and then to 1-ethyl-6- (4-pyrrolidinophenyl) -4-oxo-1,4-dihydronicotinic acid, mp. 276-2780C, dehydrated.
This connection can also be obtained as follows.
7.8 g of 1-ethyl-4-oxo-6- (4-pyrrolophenyl) -1,4-dihydronicotate are hydrogenated at room temperature with 8.5 g of 5% palladium-carbon in 800 ml of methanol. After removal of the catalyst, the reaction mixture is evaporated to dryness and the residue is taken up in methylene chloride. The organic solution is ice cold
1N hydrochloric acid extracted, the aqueous extract neutralized with 1N sodium hydroxide solution and extracted with methylene chloride.
After drying the solution and evaporation, 7.0 g of 1-ethyl-4-oxo-6- (4-dyrrolidinophenyl) -1, 4-dihydro-nicotinic acid methyl ester, mp. 157-159 (from methanol).
In analogy to Example 1, the ester can then be saponified to form an acid.
Example 21
Tablets of 120 mg and 500 mg were prepared, respectively, containing l-ethyl-4-oxo-6-phenyl-1,4-dihydro nicotinic acid 10.0 mg 1-ethyl-6- [4- (dimethylamino) -phenyl ] -4-oxo-1,4-dihydronicotinic acid - 150 mg
Corn starch 50.0 mg 160 mg
Milk sugar 58.0 mg 180 mg
Talc 1.5 mg 7 mg
Magnesium stearate 0.5 mg 3 mg
120.0 mg 500 mg
Claims (7)
Priority Applications (30)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH51278A CH639073A5 (en) | 1978-01-18 | 1978-01-18 | 4-Pyridone-3-carboxylic acid derivatives and their preparation |
| CA318,702A CA1110234A (en) | 1978-01-18 | 1978-12-28 | 4-pyridone-3-carboxylic acids and process for the preparation thereof |
| AU43296/79A AU521148B2 (en) | 1978-01-18 | 1979-01-11 | 4-pyridone-3-carboxylic acids |
| ZA00790120A ZA79120B (en) | 1978-01-18 | 1979-01-11 | 4-pyridone-3-carboxylic acids and process for the preparation thereof |
| PH22054A PH15202A (en) | 1978-01-18 | 1979-01-12 | 4-pyridone-3-carboxylic acid and process for the preparation thereof |
| NL7900264A NL7900264A (en) | 1978-01-18 | 1979-01-12 | 4-PYRIDONE-3-CARBONIC ACID DERIVATIVES AND THEIR PREPARATION. |
| IL56421A IL56421A (en) | 1978-01-18 | 1979-01-12 | 4-pyridone-3-carboxylic acid derivatives,their preparation and pharmaceutical compositions containing them |
| FI790103A FI790103A (en) | 1978-01-18 | 1979-01-12 | 4-PYRIDON-3-CARBONSYRADERIVAT OCH DERAS FRAMSTAELLNING |
| NZ189379A NZ189379A (en) | 1978-01-18 | 1979-01-15 | 4-pyridone-3-carboxylic acid derivatives;intermediates;pharmaceutical compositions |
| HU79HO2130A HU179487B (en) | 1978-01-18 | 1979-01-15 | Process for producing new 4-pyridone-3-carboxylic acid derivatives |
| SE7900318A SE7900318L (en) | 1978-01-18 | 1979-01-15 | 4-PYRIDONE-3-CARBONIC ACID DERIVATIVES AND PREPARATION THEREOF |
| MC791356A MC1239A1 (en) | 1978-01-18 | 1979-01-15 | ACIDS AND DERIVATIVES OF 4-PYRIDONE-3-CARBOXYLIC ACIDS THEIR PREPARATION AND APPLICATION AS MEDICINAL PRODUCTS |
| GR58105A GR73088B (en) | 1978-01-18 | 1979-01-16 | |
| JP233079A JPS54100382A (en) | 1978-01-18 | 1979-01-16 | 44pyridonee33carboxylic acid derivative |
| LU80794A LU80794A1 (en) | 1978-01-18 | 1979-01-16 | 4-PYRIDON-3-CARBONIC ACID DERIVATIVES AND THEIR PRODUCTION |
| FR7900974A FR2415103A1 (en) | 1978-01-18 | 1979-01-16 | ACIDS AND DERIVATIVES OF 4-PYRIDONE-3-CARBOXYLIC ACIDS, THEIR PREPARATION AND THEIR APPLICATION AS MEDICINAL PRODUCTS |
| AR275201A AR223663A1 (en) | 1978-01-18 | 1979-01-17 | PROCEDURE FOR THE PREPARATION OF DERIVATIVES 1,6-DISSTITUTED ACID 4-PIRIDON-3-CARBOXILICO |
| AT0035079A AT369731B (en) | 1978-01-18 | 1979-01-17 | METHOD FOR PRODUCING NEW 4-PYRIDON-3-CARBONIC ACID DERIVATIVES AND THEIR SALTS |
| ES476917A ES476917A1 (en) | 1978-01-18 | 1979-01-17 | 4-Pyridone-3-carboxylic acid derivatives, pharmaceutical compositions containing them, processes for their preparation, their application. |
| BE0/192932A BE873527A (en) | 1978-01-18 | 1979-01-17 | 4-PYRIDONE-3-CARBOXYLIC ACIDS AND DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICINAL PRODUCTS |
| GB7901668A GB2013190B (en) | 1978-01-18 | 1979-01-17 | 4 pyridone 3 carboxylic acid derivatives |
| KR7900120A KR820002111B1 (en) | 1978-01-18 | 1979-01-17 | Process for preparing 4-pyridone-3-carboxylic acids |
| NO790165A NO152089C (en) | 1978-01-18 | 1979-01-17 | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 4-PYRIDON-3-CARBOXYLIC ACID DERIVATIVES |
| PT7969093A PT69093A (en) | 1978-01-18 | 1979-01-17 | Process for preparing 4-pyridone-3-carboxylic acid derivatives |
| DK20279A DK20279A (en) | 1978-01-18 | 1979-01-17 | PROCEDURE FOR THE PREPARATION OF 4-PYRIDONE-3-CARBOXYLIC ACID DERIVATIVES |
| DE19792901868 DE2901868A1 (en) | 1978-01-18 | 1979-01-18 | 4-PYRIDONE-3-CARBONIC ACID DERIVATIVES AND THEIR PRODUCTION |
| EP79100149A EP0003144B1 (en) | 1978-01-18 | 1979-01-18 | 4-pyridone-3-carboxylic acid derivatives, pharmaceutical compositions containing them, processes for their preparation, their application |
| IE113/79A IE47784B1 (en) | 1978-01-18 | 1979-01-30 | 4-pyridone-3-carboxylic acid derivatives |
| US06/369,778 US4521535A (en) | 1978-01-18 | 1982-04-19 | 4-Pyridone-3-carboxylic acid derivatives |
| US06/667,528 US4549022A (en) | 1978-01-18 | 1984-11-02 | 4-Pyridone-3-carboxylic acid derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH51278A CH639073A5 (en) | 1978-01-18 | 1978-01-18 | 4-Pyridone-3-carboxylic acid derivatives and their preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH639073A5 true CH639073A5 (en) | 1983-10-31 |
Family
ID=4188704
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH51278A CH639073A5 (en) | 1978-01-18 | 1978-01-18 | 4-Pyridone-3-carboxylic acid derivatives and their preparation |
Country Status (3)
| Country | Link |
|---|---|
| BE (1) | BE873527A (en) |
| CH (1) | CH639073A5 (en) |
| ZA (1) | ZA79120B (en) |
-
1978
- 1978-01-18 CH CH51278A patent/CH639073A5/en not_active IP Right Cessation
-
1979
- 1979-01-11 ZA ZA00790120A patent/ZA79120B/en unknown
- 1979-01-17 BE BE0/192932A patent/BE873527A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| BE873527A (en) | 1979-07-17 |
| ZA79120B (en) | 1979-12-27 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased |