USRE32975E - 4-Pyridone-3-carboxylic acids and/or derivatives thereof - Google Patents
4-Pyridone-3-carboxylic acids and/or derivatives thereof Download PDFInfo
- Publication number
- USRE32975E USRE32975E US06/733,996 US73399685A USRE32975E US RE32975 E USRE32975 E US RE32975E US 73399685 A US73399685 A US 73399685A US RE32975 E USRE32975 E US RE32975E
- Authority
- US
- United States
- Prior art keywords
- carbon atoms
- group
- alkyl
- iaddend
- iadd
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 238000000034 method Methods 0.000 claims abstract description 55
- 150000001875 compounds Chemical class 0.000 claims abstract description 53
- 239000000203 mixture Substances 0.000 claims abstract description 27
- 241001465754 Metazoa Species 0.000 claims abstract description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 57
- 238000006243 chemical reaction Methods 0.000 claims description 51
- -1 cyano, carboxyl Chemical group 0.000 claims description 50
- 125000000217 alkyl group Chemical group 0.000 claims description 41
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical group C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- 239000003085 diluting agent Substances 0.000 claims description 23
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 23
- 239000003814 drug Substances 0.000 claims description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 20
- 125000003118 aryl group Chemical group 0.000 claims description 18
- 125000003277 amino group Chemical group 0.000 claims description 15
- 150000002081 enamines Chemical class 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 13
- 239000004480 active ingredient Substances 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 11
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 239000000010 aprotic solvent Substances 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 8
- 125000001931 aliphatic group Chemical group 0.000 claims description 8
- 239000002775 capsule Substances 0.000 claims description 7
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 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 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 239000003826 tablet Substances 0.000 claims description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 7
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical group C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000004414 alkyl thio group Chemical group 0.000 claims description 6
- 239000008298 dragée Substances 0.000 claims description 6
- 239000006187 pill Substances 0.000 claims description 6
- 239000004094 surface-active agent Substances 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical class CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 5
- 239000000829 suppository Substances 0.000 claims description 5
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 208000035143 Bacterial infection Diseases 0.000 claims description 3
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical group C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 235000008935 nutritious Nutrition 0.000 claims description 3
- 230000001737 promoting effect Effects 0.000 claims description 3
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical group C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims 5
- 125000000532 dioxanyl group Chemical group 0.000 claims 4
- 239000003937 drug carrier Substances 0.000 claims 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims 2
- 150000004767 nitrides Chemical class 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 8
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 7
- 239000003242 anti bacterial agent Substances 0.000 abstract description 2
- 229940121375 antifungal agent Drugs 0.000 abstract 1
- 239000003429 antifungal agent Substances 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 39
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 239000002585 base Substances 0.000 description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 235000019441 ethanol Nutrition 0.000 description 17
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 16
- 238000002844 melting Methods 0.000 description 16
- 230000008018 melting Effects 0.000 description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 11
- 238000001816 cooling Methods 0.000 description 11
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 10
- 238000010992 reflux Methods 0.000 description 9
- 150000003254 radicals Chemical class 0.000 description 8
- 238000009835 boiling Methods 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000000354 decomposition reaction Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000007792 addition Methods 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 238000007127 saponification reaction Methods 0.000 description 5
- ZDWXDEDBIUIQMY-UHFFFAOYSA-N 2-chloro-6-methylpyridine-3-carbonyl chloride Chemical compound CC1=CC=C(C(Cl)=O)C(Cl)=N1 ZDWXDEDBIUIQMY-UHFFFAOYSA-N 0.000 description 4
- 150000001735 carboxylic acids Chemical class 0.000 description 4
- 230000001427 coherent effect Effects 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 239000013067 intermediate product Substances 0.000 description 4
- 238000005580 one pot reaction Methods 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 4
- OGLKKYALUKXVPQ-UHFFFAOYSA-N 2-chloro-5-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(Cl)=O)=C1 OGLKKYALUKXVPQ-UHFFFAOYSA-N 0.000 description 3
- LKPFDPSGMYVOLT-UHFFFAOYSA-N 4-chloro-2-ethylsulfanylpyrimidine-5-carbonyl chloride Chemical compound CCSC1=NC=C(C(Cl)=O)C(Cl)=N1 LKPFDPSGMYVOLT-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000004982 aromatic amines Chemical class 0.000 description 3
- 235000012216 bentonite Nutrition 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- QIMCIIVGSIZXFU-UHFFFAOYSA-N 3-chloroquinoxaline-2-carbonyl chloride Chemical compound C1=CC=C2N=C(Cl)C(C(=O)Cl)=NC2=C1 QIMCIIVGSIZXFU-UHFFFAOYSA-N 0.000 description 2
- CSQKICWPCREIJP-UHFFFAOYSA-N 4-chloropyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CN=CC=C1Cl CSQKICWPCREIJP-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 241000206672 Gelidium Species 0.000 description 2
- 241000588748 Klebsiella Species 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- OJGMBLNIHDZDGS-UHFFFAOYSA-N N-Ethylaniline Chemical compound CCNC1=CC=CC=C1 OJGMBLNIHDZDGS-UHFFFAOYSA-N 0.000 description 2
- 241000588769 Proteus <enterobacteria> Species 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000003674 animal food additive Substances 0.000 description 2
- 150000005840 aryl radicals Chemical class 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000003899 bactericide agent Substances 0.000 description 2
- 239000000440 bentonite Substances 0.000 description 2
- 229910000278 bentonite Inorganic materials 0.000 description 2
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 239000001913 cellulose Chemical class 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Chemical class 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- FARYTWBWLZAXNK-WAYWQWQTSA-N ethyl (z)-3-(methylamino)but-2-enoate Chemical compound CCOC(=O)\C=C(\C)NC FARYTWBWLZAXNK-WAYWQWQTSA-N 0.000 description 2
- AOMLYOQNVYJEPU-UHFFFAOYSA-N ethyl 2-methyl-1-(morpholin-4-ylamino)-6-nitro-4-oxoquinoline-3-carboxylate Chemical compound C12=CC=C([N+]([O-])=O)C=C2C(=O)C(C(=O)OCC)=C(C)N1NN1CCOCC1 AOMLYOQNVYJEPU-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- MEFCRZOOCKJWMB-WAYWQWQTSA-N methyl (z)-3-(2,2-dimethylhydrazinyl)but-2-enoate Chemical compound COC(=O)\C=C(\C)NN(C)C MEFCRZOOCKJWMB-WAYWQWQTSA-N 0.000 description 2
- ZNWOGGJMSYSKHX-UHFFFAOYSA-N methyl 3-(cyclopropylamino)prop-2-enoate Chemical compound COC(=O)C=CNC1CC1 ZNWOGGJMSYSKHX-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000006072 paste Substances 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 229940116362 tragacanth Drugs 0.000 description 2
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- 150000002170 ethers Chemical class 0.000 description 1
- CERJZDBFSRPBMI-PTNGSMBKSA-N ethyl (z)-2-(2-chloro-5-nitrobenzoyl)-3-(morpholin-4-ylamino)but-2-enoate Chemical compound C=1C([N+]([O-])=O)=CC=C(Cl)C=1C(=O)/C(C(=O)OCC)=C(\C)NN1CCOCC1 CERJZDBFSRPBMI-PTNGSMBKSA-N 0.000 description 1
- DMRHWSLUTHXPPA-SREVYHEPSA-N ethyl (z)-3-(2,2-dimethylhydrazinyl)but-2-enoate Chemical compound CCOC(=O)\C=C(\C)NN(C)C DMRHWSLUTHXPPA-SREVYHEPSA-N 0.000 description 1
- VCDKJCZDQCVIMW-KTKRTIGZSA-N ethyl (z)-3-(4-methoxyanilino)but-2-enoate Chemical compound CCOC(=O)\C=C(\C)NC1=CC=C(OC)C=C1 VCDKJCZDQCVIMW-KTKRTIGZSA-N 0.000 description 1
- PFMZXZYYDKQAOO-KTKRTIGZSA-N ethyl (z)-3-(cyclohexylamino)but-2-enoate Chemical compound CCOC(=O)\C=C(\C)NC1CCCCC1 PFMZXZYYDKQAOO-KTKRTIGZSA-N 0.000 description 1
- MRDCWMLXFWVCIR-SREVYHEPSA-N ethyl (z)-3-(ethylamino)but-2-enoate Chemical compound CCN\C(C)=C/C(=O)OCC MRDCWMLXFWVCIR-SREVYHEPSA-N 0.000 description 1
- NFKZYOBSOYUQNU-HJWRWDBZSA-N ethyl (z)-3-(morpholin-4-ylamino)but-2-enoate Chemical compound CCOC(=O)\C=C(\C)NN1CCOCC1 NFKZYOBSOYUQNU-HJWRWDBZSA-N 0.000 description 1
- ORLKHIMJYKHIFP-KTKRTIGZSA-N ethyl (z)-3-(piperidin-1-ylamino)but-2-enoate Chemical compound CCOC(=O)\C=C(\C)NN1CCCCC1 ORLKHIMJYKHIFP-KTKRTIGZSA-N 0.000 description 1
- WASODUMMSSUHNJ-UHFFFAOYSA-N ethyl 1,2,7-trimethyl-4-oxo-1,8-naphthyridine-3-carboxylate Chemical compound CC1=CC=C2C(=O)C(C(=O)OCC)=C(C)N(C)C2=N1 WASODUMMSSUHNJ-UHFFFAOYSA-N 0.000 description 1
- OUIIOINZTCLLEE-UHFFFAOYSA-N ethyl 1-ethyl-4-oxoquinoline-3-carboxylate Chemical compound C1=CC=C2C(=O)C(C(=O)OCC)=CN(CC)C2=C1 OUIIOINZTCLLEE-UHFFFAOYSA-N 0.000 description 1
- UVMPQGCIJHOPCP-UHFFFAOYSA-N ethyl 3-(cyclohexylamino)prop-2-enoate Chemical compound CCOC(=O)C=CNC1CCCCC1 UVMPQGCIJHOPCP-UHFFFAOYSA-N 0.000 description 1
- BHSGAIADOGMHRR-UHFFFAOYSA-N ethyl 3-(morpholin-4-ylamino)prop-2-enoate Chemical compound CCOC(=O)C=CNN1CCOCC1 BHSGAIADOGMHRR-UHFFFAOYSA-N 0.000 description 1
- IFEQICYBUQFYKP-UHFFFAOYSA-N ethyl 3-anilinoprop-2-enoate Chemical compound CCOC(=O)C=CNC1=CC=CC=C1 IFEQICYBUQFYKP-UHFFFAOYSA-N 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 239000010642 eucalyptus oil Substances 0.000 description 1
- 229940044949 eucalyptus oil Drugs 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
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- 235000003599 food sweetener Nutrition 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000003630 growth substance Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N hydroxymaleic acid group Chemical group O/C(/C(=O)O)=C/C(=O)O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- WTAKNNAKLBSKHA-WQLSENKSSA-N methyl (z)-2-(2-chloro-5-nitrobenzoyl)-3-(2,2-dimethylhydrazinyl)but-2-enoate Chemical compound CN(C)NC(\C)=C(C(=O)OC)\C(=O)C1=CC([N+]([O-])=O)=CC=C1Cl WTAKNNAKLBSKHA-WQLSENKSSA-N 0.000 description 1
- AXORQBCXTPWEFF-FPLPWBNLSA-N methyl (z)-3-(cyclopentylamino)but-2-enoate Chemical compound COC(=O)\C=C(\C)NC1CCCC1 AXORQBCXTPWEFF-FPLPWBNLSA-N 0.000 description 1
- CCLSSOPVHNHJHQ-WAYWQWQTSA-N methyl (z)-3-(ethylamino)but-2-enoate Chemical compound CCN\C(C)=C/C(=O)OC CCLSSOPVHNHJHQ-WAYWQWQTSA-N 0.000 description 1
- QAKYFFYZPIPLDN-PLNGDYQASA-N methyl (z)-3-(methylamino)but-2-enoate Chemical compound CN\C(C)=C/C(=O)OC QAKYFFYZPIPLDN-PLNGDYQASA-N 0.000 description 1
- SNULKSHOMYJVKT-SREVYHEPSA-N methyl (z)-3-(propylamino)but-2-enoate Chemical compound CCCN\C(C)=C/C(=O)OC SNULKSHOMYJVKT-SREVYHEPSA-N 0.000 description 1
- LAPKGJRJPQKJKI-HJWRWDBZSA-N methyl (z)-3-anilinobut-2-enoate Chemical compound COC(=O)\C=C(\C)NC1=CC=CC=C1 LAPKGJRJPQKJKI-HJWRWDBZSA-N 0.000 description 1
- WLMHEIGKYWRAJM-UHFFFAOYSA-N methyl 1-(dimethylamino)-2-methyl-6-nitro-4-oxoquinoline-3-carboxylate Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)C(C(=O)OC)=C(C)N(N(C)C)C2=C1 WLMHEIGKYWRAJM-UHFFFAOYSA-N 0.000 description 1
- YTSPXCZEHWCGIT-UHFFFAOYSA-N methyl 1-cyclopropyl-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate Chemical compound C12=NC(C)=CC=C2C(=O)C(C(=O)OC)=CN1C1CC1 YTSPXCZEHWCGIT-UHFFFAOYSA-N 0.000 description 1
- PMZZKLUKCIYOJP-UHFFFAOYSA-N methyl 3-(ethylamino)prop-2-enoate Chemical compound CCNC=CC(=O)OC PMZZKLUKCIYOJP-UHFFFAOYSA-N 0.000 description 1
- DYFZSBKQRHAKHZ-UHFFFAOYSA-N methyl 3-(propylamino)prop-2-enoate Chemical compound CCCNC=CC(=O)OC DYFZSBKQRHAKHZ-UHFFFAOYSA-N 0.000 description 1
- ATNATTSORLUZLI-UHFFFAOYSA-N methyl 3-(tert-butylamino)prop-2-enoate Chemical compound COC(=O)C=CNC(C)(C)C ATNATTSORLUZLI-UHFFFAOYSA-N 0.000 description 1
- DLMNOVFTAIOSQN-UHFFFAOYSA-N methyl 3-anilinoprop-2-enoate Chemical compound COC(=O)C=CNC1=CC=CC=C1 DLMNOVFTAIOSQN-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- IMAKHNTVDGLIRY-UHFFFAOYSA-N methyl prop-2-ynoate Chemical compound COC(=O)C#C IMAKHNTVDGLIRY-UHFFFAOYSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000003020 moisturizing effect Effects 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- MHWLWQUZZRMNGJ-UHFFFAOYSA-N nalidixic acid Chemical compound C1=C(C)N=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 MHWLWQUZZRMNGJ-UHFFFAOYSA-N 0.000 description 1
- 229960000210 nalidixic acid Drugs 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000003605 opacifier Substances 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- QOQVKGBSDFIDCT-FPLPWBNLSA-N propyl (z)-3-(ethylamino)but-2-enoate Chemical compound CCCOC(=O)\C=C(\C)NCC QOQVKGBSDFIDCT-FPLPWBNLSA-N 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical group OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 230000000979 retarding effect Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 101150035983 str1 gene Proteins 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000003799 water insoluble solvent Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/58—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems with hetero atoms directly attached to the ring nitrogen atom
Definitions
- the invention relates to a process for the preparation of 4-pyridone-3-carboxylic acids and/or derivatives thereof, to certain new 4-pyridone-3-carboxylic acids and/or derivatives thereof, and to their use as antibacterial agents and as feed additives.
- R 4 and R 5 can be identical or different, and denote a straight-chain or branched C 1 to C 4 alkyl group or, together with the nitrogen atom which they substitute, and optionally a further hetero-atom, form a 5-membered to 7-membered ring,
- R 2 denotes a hydrogen atom, or an alkyl, aralkyl or aryl group and
- R 3 denotes a derivative (as hereinafter defined) of a carboxyl group
- the advantage of the process according to the invention is that only single compounds are formed in a so-called one-pot reaction which is simple to carry out.
- the free carboxylic acids and subsequently the salts of carboxylic acids, preferably the pharmaceutically usable salts, for example the alkali metal salts or alkaline earth metal salts, from the 4-pyridone-3-carboxylic acid derivatives of the invention, by suitable acid or alkaline saponification methods.
- the term "derivative" in respect of a carboxylic acid means a derivative thereof which may be converted by the acid by an acid or alkaline saponification method.
- Preferred alkyl radicals R 1 and R 2 are saturated or unsaturated, straight-chain or branched alkyl radicals with 1 to 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, hexyl, propenyl, butenyl, pentenyl or hexenyl.
- Preferred aliphatic radicals R 1 and R 2 are those with 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert.-butyl.
- Particularly preferred aliphatic radicals R 1 are ethyl or tert.-butyl.
- Preferred cycloalkyl radical R 1 are saturated or unsaturated carbocyclic ring systems with 3 to 7 carbon atoms which are optionally substituted by methyl or ethyl groups, for example cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl or cycloheptenyl.
- the cyclopropyl radical and the cyclohexyl radical may be mentioned as preferred cycloaliphatic radicals R 1 .
- Aralkyl radicals R 1 and R 2 which may be mentioned as preferred radicals are radicals with 1 to 4 carbon atoms in the aliphatic part and 6 to 10 carbon atoms in the aromatic part, for example benzyl, ⁇ -phenylethyl, naphthylmethyl or ⁇ -naphthylethyl.
- the benzyl radical is particularly preferred.
- Aryl radicals R 1 and R 2 which may be mentioned as preferred radicals are aromatic, carbocyclic ring systems with 6 to 10 carbon atoms, for example phenyl, naphthyl, o-biphenyl, m-biphenyl or p-biphenyl.
- the phenyl radical is particularly preferred.
- R 1 is the --NR 4 R 5 grouping, in which R 4 and R 5 denote identical or different, straightchain or brnached C 1 to C 4 alkyl radicals which are for example methyl, ethyl, propyl, isopropyl, butyl or isobutyl, preferably methyl and ethyl and particularly preferably methyl.
- the alkyl radicals R 4 and R 5 together with the nitrogen atom, of the amino group, which they substitute, and optionally a further hetero-atom, can also form a 5-membered to 7-membered heterocyclic ring.
- Possible optional further hetero-atoms are oxygen, sulphur or nitrogen, preferably oxygen or sulphur. Examples of such heterocyclic ring systems which may be mentioned are: pyrrolidine, piperidine, hexamethyleneimine, morpholine or thiomorpholine, preferably morpholine.
- Preferred derivatives of the carboxyl group R 3 are the nitrile group, an ester group --COOR 6 or an acid amide group --CO--NR 7 R 8 , R 6 , R 7 and R 8 denotes a C 1 to C 4 alkyl, preferably methyl or ethyl.
- radicals R 7 and R 8 also denote hydrogen.
- the radical R 8 can furthermore denote optionally substituted phenyl.
- the symbols A, B, D and E together form a carbocyclic or heterocyclic aromatic ring fused onto the 5-position or 6-position of the pyridone ring.
- the heteroatoms can be up to 3 nitrogen atoms.
- the symbols A to E mentioned can have, for example, the following meanings: all the symbols A to E are optionally substituted carbon atoms; A is a nitrogen atom and B, D and E are optionally substituted carbon atoms; D is a nitrogen atom and A, B and E are optionally substituted carbon atoms; A and B are nitrogen atoms and D and E are optionally substituted carbon atoms; A and D are nitrogen atoms and B and E are optionally substituted carbon atoms; A and E are nitrogen atoms and B and D are optionally substituted carbonatoms; A, B and E are nitrogen atoms and D is an optionally substituted carbon atom; and A, D and E are nitrogen atoms and B is an optionally substituted carbon atom.
- substituted carbon atoms can be the grouping --C--R 9 , wherein R 9 can be identical or different in the case of individual carbon atoms and can have, for example, the following meaning: hydrogen, C 1 to C 6 alkyl, C 1 to C 4 alkoxy, C 1 to C 6 alkylmercapto, trifluoromethyl, halogen, cyano, carboxyl which is esterified by C 1 to C 4 alkyl, benzyl or phenyl which can each be substituted by C 1 to C 3 alkyl, nitro or halogen, or amino substituted by carbalkoxy.
- halogen which may be mentioned are: fluorine, chlorine, bromine and iodine, preferably chlorine or bromine.
- Two of the radicals R 9 which are on two adjacent carbon atoms, for example on A and B or on B and D or on D and E, can represent, together with the two adjacent carbon atoms, a further fused-on benzene nucleus.
- Halogen radicals X 1 and X 2 are, for example, fluorine, chlorine, bromine or iodine, preferably chlorine or bromine and particularly preferably chlorine.
- the process according to the invention is preferably carried out using an enamine of the general formula ##STR3## in which R 1' denotes a tert.-alkyl, a C 3 to C 7 cycloalkyl, or a dialkylamino group --NR 4' R 5' , in which
- R 4' and R 5' denote a C 1 to C 2 alkyl group, or together complete a morpholinyl radical
- R 2' denotes a hydrogen atom, a C 1 to C 4 alkyl group or an optionally substituted benzyl or phenyl radical and
- R 3 has the above-mentioned meaning.
- the process according to the invention is particularly preferably carried out using an enamine of the general formula ##STR4## in which R 1" denotes a tert.-butyl, cyclopropyl, cyclohexyl or dimethylamino group or a N-morpholinyl radical.
- R 2" denotes a hydrogen atom or a C 1 to C 4 alkyl group
- R 3 has the above-mentioned meaning.
- Enamines which can be employed in the process according to the invention can be prepared, for example, by reacting propiolic acid methyl ester with primary amines according to Chem. Ber. 99, 2526 (1966), or from N,N-di-substituted hydrazines with acetoacetic acid derivatives according to Chem. Ber. 108, 1659 (1975).
- ⁇ -enamino-carboxylic acid derivatives and ⁇ -enhydroazino-carboxylic acid derivatives may be mentioned as examples: ⁇ -methylaminocrotonic acid methyl ester, ⁇ -ethylaminocrotonic acid methyl ester, ⁇ -ethylaminocrotonic acid ethyl ester, ⁇ -ethylaminocrotonic acid n-propyl ester, ⁇ -n-propylaminocrotonic acid methyl ester, ⁇ -cyclopentylaminocrotonic acid methyl ester, ⁇ -cyclohexylaminocrotonic acid ethyl ester, 3-(2,2-dimethylhydrazino)crotonic acid methyl ester, 3-(2,2-dimethylhydrazino)crotonic acid ethyl ester, ⁇ -morpholinyl-aminocrotonic acid methyl ester, ⁇ -piperidinylamino-crotonic acid ethyl este
- the process according to the invention is preferably carried out using those o-chloro-(hetero-)arylcarboxylic acid chlorides of the formula ##STR5## in which the symbols A, B, D and E have the above-mentioned meaning, but the heterocyclic radical optionally present contains at most two nitrogen atoms.
- Optionally substituted carbon atoms can in each case be the --CR 9 group described.
- o-Halogeno-(hetero-)aryl-carboxylic acid halides which can be employed in the process according to the invention, and processes for their preparation, are known.
- J. Am. Chem. Soc. 40,233 (1908) describes the preparation of 2-ethylmercapto-6-chloropyrimidine-5-carboxylic acid chloride by reacting 2-ethylmercapto-4-oxo-3,4-dihydropyrimidine-5-carboxylic acid with phosphorus oxychloride.
- Examples which may be mentioned of o-halogeno(hetero-)aryl-carboxylic acid halides which can be employed in the process according to the invention are: 2-chloro-5-nitro-benzoyl chloride, 2-chloro-5-nitro-benzoyl bromide, 2-chloro-3-nitro-benzoyl chloride, 2-chloro-3-nitro-5-trifluoromethyl-benzoyl chloride, 2,4-dichloro-3-nitro-benzoyl chloride, 2,4-dichloro-5-nitro-benzoyl chloride, 2,4-dichloro-3,5-dinitro-benzoyl chloride, 2,6-dichloro-3,5-dinitro-benzoyl chloride, 2-chloro-3,5-dinitro-benzoyl chloride, 2-chloro-3,5-dinitro-benzoyl bromide, 2,4,5-trichloro-3-nitro-benzoyl chloride, 2,4,6-trichlor
- the first reaction stage of the process according to the invention is carried out in the temperature range from 0° to 80° C. and the second reaction stage is carried out in the temperature range from 80° to 250° C.
- the first reaction stage is carried out from 10° to 60° C. and the second reaction stage from 100° to 150° C.
- the process according to the invention is carried out in an anhydrous, aprotic solvent or in a mixture of such solvents.
- Such a solvent can belong, for example, to the group comprising hydrocarbons, such as, for example, ligroin, cyclohexane, benzene or toluene, the group comprising chlorinated hydrocarbons, such as, for example, methylene chloride, chloroform, carbon tetrachloride, chlorobenzene or o-dichlorobenzene, the group comprising nitriles, such as, for example, acetonitrile, or the group comprising ethers, such as, for example, diethyl ether, tetrahydrofurane or dioxane.
- Dioxane is preferably employed as the solvent.
- the solvents from the list of examples, which have boiling points above about 80° C. can also be further used directly for the second reaction stage. Both reaction stages can be carried out in a so-called one-pot reaction in the case of this process variant.
- the low-boiling solvent is distilled off and replaced by a higher-boiling solvent.
- a higher-boiling solvent in addition to the examples of higher-boiling solvents listed, other solvents can also be used, for example dimethylformamide, dimethylsulphoxide, N-methylpyrrolidone, sulpholane or hexamethylphosphoric acid triamide.
- the further reaction can be carried out with the low-boiling solvent from the first reaction stage if the second reaction stage is carried out under pressure.
- the process according to the invention is usually carried out under normal pressure.
- Both reaction stages of the process according to the invention are carried out in the presence of bases.
- Bases which may be mentioned for the first reaction stage of the process according to the invention are tertiary organic amines, for example pyridine, triethylamine, N-methylmorpholine, N-methylpiperidine, quinoline or triethylenediamine.
- the first reaction stage is preferably carried out in the presence of pyridine or especially triethylamine.
- the second reaction stage of the process according to the invention is carried out in the presence of a base, such as an amine, quaternary ammonium hydroxide, an alkali or alkaline earth hydroxide, bicarbonate, carbonate, etc. which is additionally added.
- a base such as an amine, quaternary ammonium hydroxide, an alkali or alkaline earth hydroxide, bicarbonate, carbonate, etc.
- bases such as an amine, quaternary ammonium hydroxide, an alkali or alkaline earth hydroxide, bicarbonate, carbonate, etc.
- bases such as an amine, quaternary ammonium hydroxide, an alkali or alkaline earth hydroxide, bicarbonate, carbonate, etc.
- bases such as an amine, quaternary ammonium hydroxide, an alkali or alkaline earth hydroxide, bicarbonate, carbonate, etc.
- bases such as an amine, quaternary ammonium hydrox
- the starting compounds of the formula (I) and (II) for the process according to the invention and the base in the first reaction step are generally employed in equimolar amounts relative to one another.
- a further equimolar amount of base is added in the second reaction stage. It can be advantageous to employ an excess of base of 10 mol %.
- reaction product of the formula (VI) from the first reaction stage is then further reacted, in an anhydrous, aprotic solvent with a boiling point above 80° C., with an equimolar amount of a base from the group for the second reaction stage.
- Working up is carried out analogously to that after the first reaction stage.
- the product can be recrystallised from ethanol, acetonitrile or ethyl acetate.
- sequence of the addition of the starting materials for the first reaction stage can be changed.
- the sequence can be, for example: 1. enamine, 2- o-halogeno-(hetero-)aroyl halide, and 3. the base.
- sequence of addition can be, for example: 1. enamine and base together, and 2. the o-halogeno-(hetero-)aroyl halide.
- both reaction stages of the process according to the invention can be carried out successively in one apparatus in a so-called one-pot reaction without separate isolation of the intermediate product of the formula (VI).
- a base from the group of those suitable for the second reaction stage is merely added. Since the bases mentioned above for the second reaction stage, for example DBU, are frequently stronger than the bases which have been mentioned above for the first reaction stage, it is often necessary, when carrying out the one-pot process, to employ twice the molar amount of base for the second reaction stage, since half of this amount is necessaryy to liberate the weaker base of the first reaction stage.
- the invention furthermore relates to new compounds which are 4-pyridone-3-carboxylic acids, and/or derivatives thereof, of the formula (VII) ##STR8## or a salt thereof in which R 1a denotes tert.-alkyl, cycloalkyl or an amino group --NR 4 R 5 ,
- R 3a denotes the carboxyl group or a derivative thereof (as hereinbefore defined)
- R 2 , R 4 , R 5 , A, B, D and E have the meanings indicated above.
- the invention particularly relates to new 4-pyridone-3-carboxylic acids, and/or derivatives thereof, of the formula (VIII) ##STR9## in which R 3a , R 1a , R 2 , A, B, D and E have the abovementioned meaning, but the heterocyclic radical optionally present contains at most two nitrogen atoms, and pharmaceutically usable salts thereof.
- the invention very particularly relates to new 4-pyridone-3-carboxylic acids of the formula (IX) ##STR10## in which A, B, D and E have the abovementioned meaning, and pharmaceutically usable salts thereof.
- new compounds according to the invention have outstanding antibacterial and fungicidal properties and moreover are active as growth regulators.
- the improved antibacterial activity of the compounds according to the invention permits them to be used as active compounds in medicine, and they can be employed both for the prevention and for the treatment of systemic or local bacterial infections.
- the compounds according to the invention can also be used as feed additives for promoting growth and for improving feed utilisation in keeping animals, especially in keeping fatstock.
- the active compounds are preferably administered via the feed and/or drinking water.
- the present invention furthermore relates to agents which contain the new compounds according to the invention.
- agents which contain the new compounds according to the invention include, for example, feedstuff concentrates, for keeping animals, which, in the customary manner, can also contain vitamins and/or mineral salts in addition to the active compounds, or pharmaceutical formulations.
- the invention preferably relates to antibacterially active agents which contain compounds of the formula (VIII).
- the invention particularly preferably relates to those anti-bacterially active agents which contain the compounds of the formula (IX) or alkali metal salts or alkaline earth metal salts thereof.
- the present invention provides a pharmaceutical composition containing as active ingredient a compound of the invention in admixture with a solid or liquefied gaseous diluent, or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 (preferably less than 350) except in the presence of a surface active agent.
- the invention further provides a pharmaceutical composition containing as active ingedient a compound of the invention in the form of a sterile and/or physiologically isotonic aqueous solution.
- the invention also provides a medicament in dosage unit form comprising a compound of the invention.
- the invention also provides a medicament in the form of tablets (including lozenges and granules), dragees, capsules, pills, ampoules or suppositories comprising a compound of the invention.
- “Medicament” as used in this Specification means physically discrete coherent portion suitable for medical administration.
- “Medicament in dosage unit form” as used in this Specification means physically discrete coherent units suitable for medical administration each containing a daily dose or a multiple (up to four times) or submultiple (down to a fortieth) of a daily dose of the compound of the invention in association with a carrier and/or enclosed within an envelope. Whether the medicament contains a daily dose or, for example, a half, a third or a quarter of a daily dose will depend on whether the medicament is to be administered once or, for example, twice, three times or four times a day respectively.
- compositions according to the invention may, for example, take the form of ointments, gels, pastes, creams, sprays (including aerosols), lotions, suspensions, solution and emulsions of the active ingredient in aqueous or non-aqueous diluents, syrups, granulates or powders.
- the diluents to be used in pharmaceutical compositions include the following: (a) fillers and extenders, e.g. starch, sugars, mannitol, and silicic acid; (b) binding agents, e.g. carboxymethyl cellulose and other cellulose derivatives, alginates, gelatine and polyvinyl pyrrolidone; (c) moisturizing agents, e.g. glycerol; (d) disintegrating agents, e.g. agar-agar, calcium carbonate and sodium bicarbonate; (e) agents for retarding dissolution e.g.
- fillers and extenders e.g. starch, sugars, mannitol, and silicic acid
- binding agents e.g. carboxymethyl cellulose and other cellulose derivatives, alginates, gelatine and polyvinyl pyrrolidone
- moisturizing agents e.g. glycerol
- disintegrating agents e.g. agar-agar,
- paraffin paraffin
- resorption accelerators e.g. quaternary ammonium compounds
- surface active agents e.g. cetyl alcohol, glycerol monostearate
- adsorptive carriers e.g. kaolin and bentonite
- lubricants e.g. talc, calcium and magnesium stearate and solid polyethyl glycols.
- the tablets, dragees, capsules and pills formed from the pharmaceutical compositions of the invention can have the customary coatings, envelopes and protective matrices, which may contain opacifiers. They can be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period of time.
- the coatings, envelopes and protective matrices may be made, for example, of polymeric substances or waxes.
- the ingredient can also be made up in microencapsulated form together with one or several of the above-mentioned diluents.
- the diulents to be used in pharmaceutical compositions adapted to be formed into suppositories can, for example, be the usual water-soluble diluents, such as polyethylene glycols and fats (e.g. cocoa oil and high esters [e.g. C 14 -alcohol with C 16 -fatty acid]) or mixtures of these diluents.
- water-soluble diluents such as polyethylene glycols and fats (e.g. cocoa oil and high esters [e.g. C 14 -alcohol with C 16 -fatty acid]) or mixtures of these diluents.
- the pharmaceutical composition which are ointments, pastes, creams and gels can, for example, contain the usual diluents, e.g. animal and vegetable fats, eaxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixture of these substances.
- diluents e.g. animal and vegetable fats, eaxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixture of these substances.
- compositions which are powders and sprays can, for example, contain the usual diluents, e.g. lactose, talc, silicic acid, aluminium hydroxide, calcium silicate, and polyamide powder or mixtures of these substances.
- Aerosol sprays can, for example, contain the usual propellants, e.g. chlorofluorohydrocarbons.
- compositions which are solutions and emulsions can, for example, contain the customary diluents (with, of course, the above-mentioned exclusion of solvent having a molecular weight below 200 except in the presence of a surface-active agent), such as solvents, dissolving agents and emulsifiers; specific examples of such diluents are water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils [for example ground nut oil], glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitol or mixtures thereof.
- a surface-active agent such as solvents, dissolving agents and emulsifiers
- specific examples of such diluents are water, ethyl alcohol,
- solution and emulsions should be sterile, and, if appropriate, blood-isotonic.
- compositions which are suspensions can contain the usual diluents, such as liquid diluents, e.g. water, ethyl alcohol, propylene glycol, surface-active agents (e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbite and sorbitane esters), microcrystalline cellulose, aluminium methahydroxide, bentonite, agar-agar and tragacanth or mixtures thereof.
- liquid diluents e.g. water, ethyl alcohol, propylene glycol
- surface-active agents e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbite and sorbitane esters
- microcrystalline cellulose aluminium methahydroxide
- bentonite agar-agar and tragacanth or mixtures thereof.
- compositions according to the invention can also contain colouring agents and preservatives as well as perfumes and flavouring additions (e.g. peppermint oil and eucalyptus oil) and sweetening agents (e.g. saccharin).
- perfumes and flavouring additions e.g. peppermint oil and eucalyptus oil
- sweetening agents e.g. saccharin
- compositions according to the invention generalll contain from 0.1 to 99.5%, usually from 0.5 to 95% of the active ingredient by weight of the total composition.
- compositions and medicaments according to the invention can also contain other pharmaceutically active compounds. They may also contain a plurality of compounds of the invention.
- Any diluent in the medicaments of the present invention may be any of those mentioned above in relation to the pharmaceutical compositions of the present invention.
- Such medicaments may include solvents of molecular weight less than 200 as sole diluent.
- the discrete coherent portions constituting the medicament according to the invention will generally be adapted by virtue of their shape or packaging for medical administration and may be, for example, any of the following: tablets (including lozenges and granulates), pills, dragees, capsules, suppositories and ampoules. Some of these forms may be made up for delayed release of the active ingredient. Some, such as capsules, include a protective envelope which renders the portions of the medicament physically discrete and coherent.
- compositions and medicaments are carried out by any method known in the art, for example, by mixing the active ingredient(s) with the diluent(s) to form a pharmaceutical composition (e.g. a granulate) and then forming the composition into the medicament (e.g. tablets).
- a pharmaceutical composition e.g. a granulate
- the medicament e.g. tablets
- This invention further provides a method of combating (including prevention, relief and cure of) the abovementioned diseases in warm-blooded animals, which comprises administering to the animals a compound of the invention alone or in admixture with a diluent or in the form of a medicament according to the invention.
- the invention further relates to a medicated fodder comprising a compound of the present invention and a nutritious material.
- esters and carboxylic acids of Examples 2 to 18 were obtained by a procedure analogous to that in Example 1. They are summarised in Table 1.
- the labelling of the radicals A, B, D, E, R 1 , R 2 and R 3 relates to formulae (I) and (II) in the description.
- the chloroform phase is dried with sodium sulphate and the chloroform is distilled off. After crystallising the residue from acetonitrile, 8.5 g of 1-cyclopropyl-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid methyl ester of melting point 204° to 205° C. are obtained.
- the corresponding carboxylic acid obtained by saponification analogously to Example 1, melts at 229° to 230° C. (with decomposition).
- the dioxane is then distilled off in vacuo, the residue is taken up in chloroform and the chloroform phase is washed with water.
- the crude ester is heated under reflux directly with 80 ml of ethyl alcohol and a solution of 17 g of pottassium hydroxide in 80 ml of water for 4 hours.
- the ethyl alcohol is distilled off in vacuo, the potassium salt of the carboxylic acid formed is dissolved in water, the solution is filtered and the carboxylic acid is precipitated from the filtrate with 10% strength hydrochloric acid, whilst cooling with ice.
- the precipitate which has been filtered off and dried, is recrystallised from ethyl alcohol. 38.5 g of 1-cyclopentyl-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid of melting point 236° to 237° C. (with decomposition) are obtained.
- a resulting basic compound can be converted into a corresponding acid addition salt, for example by reacting it with an inorganic or organic acid, such as therapeutically useful acid, or with a corresponding anion exchange preparation, and isolating the desired salt.
- An acid addition salt may be converted into the free compound by treatment with a base, e.g., a metal hydroxide, ammonina or a hydroxyl ion exchange preparation.
- Therapeutically useful acids are, for example, inorganic acids, e.g.
- Salts of the above-mentioned acids or other salts can also be used for purification of the base obtained; the bases are converted into salts, the salts are separated and the base are liberated from the salts.
- a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.
- the new free 4-pyridone-3-carboxylic acids of the general formula (VII) and their salts can be interconverted in any suitable manner; methods for such interconversion are known in the art.
- the present invention also comprises pharmaceutically acceptable bioprecursors of the active compounds of the present invention.
- the term "pharmaceutically acceptable bioprecursor" of an active compound of the invention means a compound having a structural formula different from the active compound but which nonetheless, upon administration to a warm-blooded animal is converted in the animal's body to the active compound.
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Abstract
The invention provides 4-pyridone-3-carboxylic acids and derivatives thereof together with a method for their preparation. Also included in the invention are compositions containing said 4-pyridone-3-carboxylic acids and derivatives and the use of said compounds and compositions as antibacterial and/or antifungal agents or for animal growth promotion or improved feed utilization.
Description
The invention relates to a process for the preparation of 4-pyridone-3-carboxylic acids and/or derivatives thereof, to certain new 4-pyridone-3-carboxylic acids and/or derivatives thereof, and to their use as antibacterial agents and as feed additives.
The preparation of 1-ethyl-4-quinolone-3-carboxylic acid ethyl ester by reacting N-ethyl-aniline with ethoxymethylene-malonic acid diethyl ester and subsequent cyclisation of the product in the presence of a polyphosphoric acid ester at elevated temperature is described in J. Het. Chem. 12, 557 (1975).
According to the present invention we provide a process for the production of 4-pyridone-3-carboxylic acids and/or derivatives thereof, in which an enamine of the general formula ##STR1## in which R1 denotes alkyl, cycloalkyl, aralkyl, aryl or an amino group --NR4 R5,
in which
R4 and R5 can be identical or different, and denote a straight-chain or branched C1 to C4 alkyl group or, together with the nitrogen atom which they substitute, and optionally a further hetero-atom, form a 5-membered to 7-membered ring,
R2 denotes a hydrogen atom, or an alkyl, aralkyl or aryl group and
R3 denotes a derivative (as hereinafter defined) of a carboxyl group,
is reacted with an o-halogeno-(hetero-)aryl-carboxylic acid halide of the general formula ##STR2## in which up to 3 of the symbols A, B, D and E denote a nitrogen atom and the symbols A, B, D and E remaining in each case denote an optionally substituted carbon atom, and X1 and X2 denote identical or different halogen atoms, in a first reaction stage at 0° to 80° C. in an anhydrous, aprotic solvent and in the presence of a base, and in a second reaction stage at 80° to 250° C. in the presence of a base, if appropriate the group R3 is converted into the carboxyl group, and if appropriate this carboxyl group is converted into a salt thereof.
It is to be described as decidingly surprising that the enamines of the formula (I) are acylated on the carbon in the β-position relative to the nitrogen by the o-halogeno-(hetero-)aroyl halides of the formula (II) in the first reaction stage of the process according to the invention, whilst it is known from Chem. Ber. 50, 65 (1917) that benzoyl chlorides which are substituted in the ortho-position by bromine, nitro or acetoxy only react with acylation of the nitrogen. Furthermore, it is surprising that the intermediate products, of the formula (VI), from the first reaction stage of the process according to the invention react further in an unambiguous manner to give the end product of the formula (VII) according to the invention, in spite of the cis/trans isomerism made possible by the double bond.
The advantage of the process according to the invention is that only single compounds are formed in a so-called one-pot reaction which is simple to carry out.
It is, of course, possible to prepare the free carboxylic acids, and subsequently the salts of carboxylic acids, preferably the pharmaceutically usable salts, for example the alkali metal salts or alkaline earth metal salts, from the 4-pyridone-3-carboxylic acid derivatives of the invention, by suitable acid or alkaline saponification methods. Thus in the present application the term "derivative" in respect of a carboxylic acid means a derivative thereof which may be converted by the acid by an acid or alkaline saponification method. Preferred alkyl radicals R1 and R2 are saturated or unsaturated, straight-chain or branched alkyl radicals with 1 to 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, hexyl, propenyl, butenyl, pentenyl or hexenyl. Preferred aliphatic radicals R1 and R2 are those with 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert.-butyl.
Particularly preferred aliphatic radicals R1 are ethyl or tert.-butyl.
Preferred cycloalkyl radical R1 are saturated or unsaturated carbocyclic ring systems with 3 to 7 carbon atoms which are optionally substituted by methyl or ethyl groups, for example cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl or cycloheptenyl. The cyclopropyl radical and the cyclohexyl radical may be mentioned as preferred cycloaliphatic radicals R1.
Aralkyl radicals R1 and R2 which may be mentioned as preferred radicals are radicals with 1 to 4 carbon atoms in the aliphatic part and 6 to 10 carbon atoms in the aromatic part, for example benzyl, β-phenylethyl, naphthylmethyl or β-naphthylethyl. The benzyl radical is particularly preferred.
Aryl radicals R1 and R2 which may be mentioned as preferred radicals are aromatic, carbocyclic ring systems with 6 to 10 carbon atoms, for example phenyl, naphthyl, o-biphenyl, m-biphenyl or p-biphenyl. The phenyl radical is particularly preferred.
Preferred amino groups R1 is the --NR4 R5 grouping, in which R4 and R5 denote identical or different, straightchain or brnached C1 to C4 alkyl radicals which are for example methyl, ethyl, propyl, isopropyl, butyl or isobutyl, preferably methyl and ethyl and particularly preferably methyl.
The alkyl radicals R4 and R5, together with the nitrogen atom, of the amino group, which they substitute, and optionally a further hetero-atom, can also form a 5-membered to 7-membered heterocyclic ring. Possible optional further hetero-atoms are oxygen, sulphur or nitrogen, preferably oxygen or sulphur. Examples of such heterocyclic ring systems which may be mentioned are: pyrrolidine, piperidine, hexamethyleneimine, morpholine or thiomorpholine, preferably morpholine.
Preferred derivatives of the carboxyl group R3 are the nitrile group, an ester group --COOR6 or an acid amide group --CO--NR7 R8, R6, R7 and R8 denotes a C1 to C4 alkyl, preferably methyl or ethyl.
The radicals R7 and R8 also denote hydrogen. The radical R8 can furthermore denote optionally substituted phenyl.
The symbols A, B, D and E together form a carbocyclic or heterocyclic aromatic ring fused onto the 5-position or 6-position of the pyridone ring. The heteroatoms can be up to 3 nitrogen atoms.
The symbols A to E mentioned can have, for example, the following meanings: all the symbols A to E are optionally substituted carbon atoms; A is a nitrogen atom and B, D and E are optionally substituted carbon atoms; D is a nitrogen atom and A, B and E are optionally substituted carbon atoms; A and B are nitrogen atoms and D and E are optionally substituted carbon atoms; A and D are nitrogen atoms and B and E are optionally substituted carbon atoms; A and E are nitrogen atoms and B and D are optionally substituted carbonatoms; A, B and E are nitrogen atoms and D is an optionally substituted carbon atom; and A, D and E are nitrogen atoms and B is an optionally substituted carbon atom.
Optionally, substituted carbon atoms can be the grouping --C--R9, wherein R9 can be identical or different in the case of individual carbon atoms and can have, for example, the following meaning: hydrogen, C1 to C6 alkyl, C1 to C4 alkoxy, C1 to C6 alkylmercapto, trifluoromethyl, halogen, cyano, carboxyl which is esterified by C1 to C4 alkyl, benzyl or phenyl which can each be substituted by C1 to C3 alkyl, nitro or halogen, or amino substituted by carbalkoxy. Examples of halogen which may be mentioned are: fluorine, chlorine, bromine and iodine, preferably chlorine or bromine.
Two of the radicals R9 which are on two adjacent carbon atoms, for example on A and B or on B and D or on D and E, can represent, together with the two adjacent carbon atoms, a further fused-on benzene nucleus.
It is, of course, also possible for all the alkyl, cycloalkyl, aralkyl or aryl radicals R1 to R8 listed to be substituted by substituents which are inert under the reaction conditions of the process according to the invention. Examples of possible substituents are those mentioned in the definition of R9.
Halogen radicals X1 and X2 are, for example, fluorine, chlorine, bromine or iodine, preferably chlorine or bromine and particularly preferably chlorine.
The process according to the invention is preferably carried out using an enamine of the general formula ##STR3## in which R1' denotes a tert.-alkyl, a C3 to C7 cycloalkyl, or a dialkylamino group --NR4' R5', in which
R4' and R5' denote a C1 to C2 alkyl group, or together complete a morpholinyl radical,
R2' denotes a hydrogen atom, a C1 to C4 alkyl group or an optionally substituted benzyl or phenyl radical and
R3 has the above-mentioned meaning.
The process according to the invention is particularly preferably carried out using an enamine of the general formula ##STR4## in which R1" denotes a tert.-butyl, cyclopropyl, cyclohexyl or dimethylamino group or a N-morpholinyl radical.
R2" denotes a hydrogen atom or a C1 to C4 alkyl group and
R3 has the above-mentioned meaning.
Enamines which can be employed in the process according to the invention can be prepared, for example, by reacting propiolic acid methyl ester with primary amines according to Chem. Ber. 99, 2526 (1966), or from N,N-di-substituted hydrazines with acetoacetic acid derivatives according to Chem. Ber. 108, 1659 (1975).
The following β-enamino-carboxylic acid derivatives and β-enhydroazino-carboxylic acid derivatives may be mentioned as examples: β-methylaminocrotonic acid methyl ester, β-ethylaminocrotonic acid methyl ester, β-ethylaminocrotonic acid ethyl ester, β-ethylaminocrotonic acid n-propyl ester, β-n-propylaminocrotonic acid methyl ester, β-cyclopentylaminocrotonic acid methyl ester, β-cyclohexylaminocrotonic acid ethyl ester, 3-(2,2-dimethylhydrazino)crotonic acid methyl ester, 3-(2,2-dimethylhydrazino)crotonic acid ethyl ester, β-morpholinyl-aminocrotonic acid methyl ester, β-piperidinylamino-crotonic acid ethyl ester, β-ethylamino-acrylic acid methyl ester, β-i-propylaminoacrylic acid methyl ester, β-cyclopropylamino-acrylic acid methyl ester, β-cyclohexylamino-acrylic acid ethyl ester, β-t-butylamino-acrylic acid methyl ester, β-morpholinylamino-acrylic acid ethyl ester, β-methylaminocrotonic acid anilide, β-morpholinyl-amino-crotonic acid 4-chloroaniline, β-methylaminocrotonic acid nitrile, β-anilino-crotonic acid methyl ester, β-anilino-acrylic acid methyl ester, β-anilinoacrylic acid ethyl ester and β-(4-methoxyphenylamino)crotonic acid ethyl ester.
The process according to the invention is preferably carried out using those o-chloro-(hetero-)arylcarboxylic acid chlorides of the formula ##STR5## in which the symbols A, B, D and E have the above-mentioned meaning, but the heterocyclic radical optionally present contains at most two nitrogen atoms.
Optionally substituted carbon atoms can in each case be the --CR9 group described.
o-Halogeno-(hetero-)aryl-carboxylic acid halides which can be employed in the process according to the invention, and processes for their preparation, are known. Thus, for example, J. Am. Chem. Soc. 40,233 (1908) describes the preparation of 2-ethylmercapto-6-chloropyrimidine-5-carboxylic acid chloride by reacting 2-ethylmercapto-4-oxo-3,4-dihydropyrimidine-5-carboxylic acid with phosphorus oxychloride. The reaction of 2-hydroxy-quinoxaline-3-carboxylic acid with thionyl chloride in the presence of a catalytic amount of dimethylformamide to give 2-chloroquinoxaline-3-carboxylic acid chloride is described in Arch. Pharm. 306, 401 (1973). The reaction 4-chloronicotinic acid with thionyl chloride under reflex to give 4-chloronicotinic acid chloride is described in J. Chem. Soc. (C), 1966, 1816.
Examples which may be mentioned of o-halogeno(hetero-)aryl-carboxylic acid halides which can be employed in the process according to the invention are: 2-chloro-5-nitro-benzoyl chloride, 2-chloro-5-nitro-benzoyl bromide, 2-chloro-3-nitro-benzoyl chloride, 2-chloro-3-nitro-5-trifluoromethyl-benzoyl chloride, 2,4-dichloro-3-nitro-benzoyl chloride, 2,4-dichloro-5-nitro-benzoyl chloride, 2,4-dichloro-3,5-dinitro-benzoyl chloride, 2,6-dichloro-3,5-dinitro-benzoyl chloride, 2-chloro-3,5-dinitro-benzoyl chloride, 2-chloro-3,5-dinitro-benzoyl bromide, 2,4,5-trichloro-3-nitro-benzoyl chloride, 2,4,6-trichloro-3,5-dinitro-benzoyl chloride, 2-fluoro-5-nitro-benzoyl chloride, 2-chloro-nicotinic acid chloride, 2-chloro-4-methyl-nicotinic acid chloride, 2-chloro-6-methyl-nicotinic acid chloride, 4-chloro-nicotinic acid chloride, 2,6-dichloro-nicotinic acid chloride, 2,5,6-trichloro-nicotinic acid chloride, 2-bromonicotinic acid chloride, 2,5-dichloro-nicotinic acid choride, 2-chloro-5-nitro-nicotinic acid chloride, 2-chloro-4,6-dimethyl-5-nitro-nicotinic acid chloride, 2-methylmercapto-4-chloro-pyrimidine-5-carboxylic acid chloride, 2-ethylmercapto-4-chloro-pyrimidine-5-carboxylic acid chloride, 4-chloro-6-methoxy-pyrimidine-5-carboxylic acid chloride, 4-chloro-6-phenyl-pyrimidine-5-carboxylic acid chloride, 2,4-dichloro-pyrimidine-5-carboxylic acid chloride, 3-chloro-pyridazine-4-carboxylic acid chloride, 2,6-dichloro-pyridazine-4-carboxylic acid chloride, 2-chloro-pyrazine-3-carboxylic acid chloride and 2-chloro-quinoxaline-3-carboxylic acid chloride.
The first reaction stage of the process according to the invention is carried out in the temperature range from 0° to 80° C. and the second reaction stage is carried out in the temperature range from 80° to 250° C. Preferably, the first reaction stage is carried out from 10° to 60° C. and the second reaction stage from 100° to 150° C. The process according to the invention is carried out in an anhydrous, aprotic solvent or in a mixture of such solvents. Such a solvent can belong, for example, to the group comprising hydrocarbons, such as, for example, ligroin, cyclohexane, benzene or toluene, the group comprising chlorinated hydrocarbons, such as, for example, methylene chloride, chloroform, carbon tetrachloride, chlorobenzene or o-dichlorobenzene, the group comprising nitriles, such as, for example, acetonitrile, or the group comprising ethers, such as, for example, diethyl ether, tetrahydrofurane or dioxane. Dioxane is preferably employed as the solvent.
The solvents, from the list of examples, which have boiling points above about 80° C. can also be further used directly for the second reaction stage. Both reaction stages can be carried out in a so-called one-pot reaction in the case of this process variant.
In another process variant, after carrying out the first reaction stage, the low-boiling solvent is distilled off and replaced by a higher-boiling solvent. In this case, in addition to the examples of higher-boiling solvents listed, other solvents can also be used, for example dimethylformamide, dimethylsulphoxide, N-methylpyrrolidone, sulpholane or hexamethylphosphoric acid triamide.
In another process variant, the further reaction can be carried out with the low-boiling solvent from the first reaction stage if the second reaction stage is carried out under pressure. However, the process according to the invention is usually carried out under normal pressure.
Both reaction stages of the process according to the invention are carried out in the presence of bases. Bases which may be mentioned for the first reaction stage of the process according to the invention are tertiary organic amines, for example pyridine, triethylamine, N-methylmorpholine, N-methylpiperidine, quinoline or triethylenediamine. The first reaction stage is preferably carried out in the presence of pyridine or especially triethylamine.
The second reaction stage of the process according to the invention is carried out in the presence of a base, such as an amine, quaternary ammonium hydroxide, an alkali or alkaline earth hydroxide, bicarbonate, carbonate, etc. which is additionally added. Examples of possible bases for this purposes are: 1,5-diazabicyclo-[4.3.0]-non-5-ene (DBN), 1,8-diazabicyclo-[5.4.0]-undec-7-ene (DBU), triethylenediamine, triethylamine, potassium hydroxide, sodium hydroxide, sodium methylate, sodium ethylate, sodium hydride, butyl-lithium, lithium-phenyl or phenyl-magnesium bromide. 1,8-Diazabicyclo-[5.4.0]-undec-7-ene (DBU) is preferably employed for the second reaction stage.
The starting compounds of the formula (I) and (II) for the process according to the invention and the base in the first reaction step are generally employed in equimolar amounts relative to one another. In the second reaction stage, a further equimolar amount of base is added. It can be advantageous to employ an excess of base of 10 mol %.
The process according to the invention can be represented by the equations which follow, using the reaction of 2-ethylmercapto-4-chloro-pyrimidine-5-carboxylic acid chloride with β-methylamino-crotonic acid ethyl ester as an example: ##STR6##
The process according to the invention can be carried out, for example, as follows:
(a) The enamine of the formula (I) and the tertiary amine from the group of bases for the first reaction stage are added successively to a solution of the o-halogeno-(hetero-)aroyl halide of the formula (II) in an anhydrous, aprotic solvent. After the reaction has ended, the solvent is distilled off. For working up, the reaction mixture of a water-insoluble solvent, such as, for example, methylene chloride or chloroform, and water and washed. The intermediate product of the formula (VI) ##STR7## which can be purified by recrystallisation, is obtained from the organic phase by distilling off the solvent. The reaction product of the formula (VI) from the first reaction stage is then further reacted, in an anhydrous, aprotic solvent with a boiling point above 80° C., with an equimolar amount of a base from the group for the second reaction stage. Working up is carried out analogously to that after the first reaction stage. For purification, for example, the product can be recrystallised from ethanol, acetonitrile or ethyl acetate.
(b) The sequence of the addition of the starting materials for the first reaction stage can be changed. Thus, the sequence can be, for example: 1. enamine, 2- o-halogeno-(hetero-)aroyl halide, and 3. the base.
Furthermore, the sequence of addition can be, for example: 1. enamine and base together, and 2. the o-halogeno-(hetero-)aroyl halide.
(c) It is, of course, possible to employ directly in the second reaction stage of the process according to the invention intermediate products of the formula (VI) which have been obtained, for example, by another route.
(d) If an anhydrous, aprotic solvent with a boiling point above 80° C. is used for the first reaction stage, both reaction stages of the process according to the invention can be carried out successively in one apparatus in a so-called one-pot reaction without separate isolation of the intermediate product of the formula (VI). Before increasing the reaction temperature for the second reaction stage, a base from the group of those suitable for the second reaction stage is merely added. Since the bases mentioned above for the second reaction stage, for example DBU, are frequently stronger than the bases which have been mentioned above for the first reaction stage, it is often necessary, when carrying out the one-pot process, to employ twice the molar amount of base for the second reaction stage, since half of this amount is necesary to liberate the weaker base of the first reaction stage.
The invention furthermore relates to new compounds which are 4-pyridone-3-carboxylic acids, and/or derivatives thereof, of the formula (VII) ##STR8## or a salt thereof in which R1a denotes tert.-alkyl, cycloalkyl or an amino group --NR4 R5,
R3a denotes the carboxyl group or a derivative thereof (as hereinbefore defined) and
R2, R4, R5, A, B, D and E have the meanings indicated above.
The invention particularly relates to new 4-pyridone-3-carboxylic acids, and/or derivatives thereof, of the formula (VIII) ##STR9## in which R3a, R1a, R2, A, B, D and E have the abovementioned meaning, but the heterocyclic radical optionally present contains at most two nitrogen atoms, and pharmaceutically usable salts thereof.
The invention very particularly relates to new 4-pyridone-3-carboxylic acids of the formula (IX) ##STR10## in which A, B, D and E have the abovementioned meaning, and pharmaceutically usable salts thereof.
It has furthermore been found that new compounds according to the invention have outstanding antibacterial and fungicidal properties and moreover are active as growth regulators.
In particular, they have a bacteriostatic and bactericidal action, for example against Gram-negative bacteria, such as Escherichia, Proteus and Klebsiella. The improved antibacterial action of the new compounds according to the invention becomes particularly clear in the case of 1-cyclopropyl-7-methyl-1,8-naphthyrid-4-one-3-carboxylic acid (compound from Example 19), which, in comparison with 1-ethyl-7-methyl-1,8-naphthyrid-4-one-3-carboxylic acid, which is known ("nalidixic acid"; Ehrhart/ruschig, Arzneimittel (Medicaments) Volume 2: Chemotherapeutika (Chemotherapeutic Agents), Verlag Chemie 1968, page 1,568) proved far superior in vitro and in vivo against Staphylococci, Escherichia coli, Proteus, Klebsiella, Pseudomonas and the like.
The improved antibacterial activity of the compounds according to the invention permits them to be used as active compounds in medicine, and they can be employed both for the prevention and for the treatment of systemic or local bacterial infections. Furthermore, the compounds according to the invention can also be used as feed additives for promoting growth and for improving feed utilisation in keeping animals, especially in keeping fatstock. In this case, the active compounds are preferably administered via the feed and/or drinking water.
The present invention furthermore relates to agents which contain the new compounds according to the invention. These include, for example, feedstuff concentrates, for keeping animals, which, in the customary manner, can also contain vitamins and/or mineral salts in addition to the active compounds, or pharmaceutical formulations.
The invention preferably relates to antibacterially active agents which contain compounds of the formula (VIII). The invention particularly preferably relates to those anti-bacterially active agents which contain the compounds of the formula (IX) or alkali metal salts or alkaline earth metal salts thereof.
The present invention provides a pharmaceutical composition containing as active ingredient a compound of the invention in admixture with a solid or liquefied gaseous diluent, or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 (preferably less than 350) except in the presence of a surface active agent.
The invention further provides a pharmaceutical composition containing as active ingedient a compound of the invention in the form of a sterile and/or physiologically isotonic aqueous solution.
The invention also provides a medicament in dosage unit form comprising a compound of the invention.
The invention also provides a medicament in the form of tablets (including lozenges and granules), dragees, capsules, pills, ampoules or suppositories comprising a compound of the invention.
"Medicament" as used in this Specification means physically discrete coherent portion suitable for medical administration. "Medicament in dosage unit form" as used in this Specification means physically discrete coherent units suitable for medical administration each containing a daily dose or a multiple (up to four times) or submultiple (down to a fortieth) of a daily dose of the compound of the invention in association with a carrier and/or enclosed within an envelope. Whether the medicament contains a daily dose or, for example, a half, a third or a quarter of a daily dose will depend on whether the medicament is to be administered once or, for example, twice, three times or four times a day respectively.
The pharmaceutical compositions according to the invention may, for example, take the form of ointments, gels, pastes, creams, sprays (including aerosols), lotions, suspensions, solution and emulsions of the active ingredient in aqueous or non-aqueous diluents, syrups, granulates or powders.
The diluents to be used in pharmaceutical compositions (e.g. granulates) adapted to be formed into tablets, dragees, capsules and pills include the following: (a) fillers and extenders, e.g. starch, sugars, mannitol, and silicic acid; (b) binding agents, e.g. carboxymethyl cellulose and other cellulose derivatives, alginates, gelatine and polyvinyl pyrrolidone; (c) moisturizing agents, e.g. glycerol; (d) disintegrating agents, e.g. agar-agar, calcium carbonate and sodium bicarbonate; (e) agents for retarding dissolution e.g. paraffin; (f) resorption accelerators, e.g. quaternary ammonium compounds; (g) surface active agents, e.g. cetyl alcohol, glycerol monostearate; (h) adsorptive carriers, e.g. kaolin and bentonite; (i) lubricants, e.g. talc, calcium and magnesium stearate and solid polyethyl glycols.
The tablets, dragees, capsules and pills formed from the pharmaceutical compositions of the invention can have the customary coatings, envelopes and protective matrices, which may contain opacifiers. They can be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period of time. the coatings, envelopes and protective matrices may be made, for example, of polymeric substances or waxes.
The ingredient can also be made up in microencapsulated form together with one or several of the above-mentioned diluents.
The diulents to be used in pharmaceutical compositions adapted to be formed into suppositories can, for example, be the usual water-soluble diluents, such as polyethylene glycols and fats (e.g. cocoa oil and high esters [e.g. C14 -alcohol with C16 -fatty acid]) or mixtures of these diluents.
The pharmaceutical composition which are ointments, pastes, creams and gels can, for example, contain the usual diluents, e.g. animal and vegetable fats, eaxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixture of these substances.
The pharmaceutical compositions which are powders and sprays can, for example, contain the usual diluents, e.g. lactose, talc, silicic acid, aluminium hydroxide, calcium silicate, and polyamide powder or mixtures of these substances. Aerosol sprays can, for example, contain the usual propellants, e.g. chlorofluorohydrocarbons.
The pharmaceutical compositions which are solutions and emulsions can, for example, contain the customary diluents (with, of course, the above-mentioned exclusion of solvent having a molecular weight below 200 except in the presence of a surface-active agent), such as solvents, dissolving agents and emulsifiers; specific examples of such diluents are water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils [for example ground nut oil], glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitol or mixtures thereof.
For parenteral administration, solution and emulsions should be sterile, and, if appropriate, blood-isotonic.
The pharmaceutical compositions which are suspensions can contain the usual diluents, such as liquid diluents, e.g. water, ethyl alcohol, propylene glycol, surface-active agents (e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbite and sorbitane esters), microcrystalline cellulose, aluminium methahydroxide, bentonite, agar-agar and tragacanth or mixtures thereof.
All the pharmaceutical compositions according to the invention can also contain colouring agents and preservatives as well as perfumes and flavouring additions (e.g. peppermint oil and eucalyptus oil) and sweetening agents (e.g. saccharin).
The pharmaceutical compositions according to the invention generalll contain from 0.1 to 99.5%, usually from 0.5 to 95% of the active ingredient by weight of the total composition.
In addition to a compound of the invention, the pharmaceutical compositions and medicaments according to the invention can also contain other pharmaceutically active compounds. They may also contain a plurality of compounds of the invention.
Any diluent in the medicaments of the present invention may be any of those mentioned above in relation to the pharmaceutical compositions of the present invention. Such medicaments may include solvents of molecular weight less than 200 as sole diluent.
The discrete coherent portions constituting the medicament according to the invention will generally be adapted by virtue of their shape or packaging for medical administration and may be, for example, any of the following: tablets (including lozenges and granulates), pills, dragees, capsules, suppositories and ampoules. Some of these forms may be made up for delayed release of the active ingredient. Some, such as capsules, include a protective envelope which renders the portions of the medicament physically discrete and coherent.
The product of the above-mentioned pharmaceutical compositions and medicaments is carried out by any method known in the art, for example, by mixing the active ingredient(s) with the diluent(s) to form a pharmaceutical composition (e.g. a granulate) and then forming the composition into the medicament (e.g. tablets).
This invention further provides a method of combating (including prevention, relief and cure of) the abovementioned diseases in warm-blooded animals, which comprises administering to the animals a compound of the invention alone or in admixture with a diluent or in the form of a medicament according to the invention.
The invention further relates to a medicated fodder comprising a compound of the present invention and a nutritious material.
The process, which belongs to the state of the art, for the preparation of 4-quinolone-3-carboxylic acid derivatives by reacting aromatic amines with alkoxymethylenemalonic acid diethyl ester gives reaction products which are single compounds only in the case of unsubstituted aromatic amines. Isomer mixtures are frequently obtained in the case of substituted aromatic amines (J. Het. Chem. 12, 557 (1975)).
The provision of new bactericides for combating bacteria which have become resistant towards known bactericides is an advance in the art.
The following Examples illustrate reactions of the present invention, some of which produce the novel compounds of the present invention.
33 g of β-methylaminocrotonic acid ethyl ester and 23.5 g of triethylamine are successively added dropwise to a solution of 43.9 g of 2-chloro-6-methyl-nicotinic acid chloride in 120 ml of absolute dioxane, whilst cooling with ice. The mixture is stirred at 25° C. for 2 hours, 72 g of 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) are added dropwise and the mixture is heated under reflux for 5 hours. The solvent is then distilled off in vacuo and the residue is taken up in a chloroform/water mixture. The chloroform phase is dried over sodium sulphate and the chloroform is distilled off in vacuo. By recrystallisation of the residue from toluene/cyclohexane, 32.6 g (54% of the theoretical yield) of 1,27-trimethyl-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester of melting point 122° to 123° C. are obtained.
Saponification of the ester:
26 of 1,2,7-trimethyl-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester are heated to the boil under reflux with a solution of 6.2 g of potassium hydroxide in 100 ml of water and 100 ml of ethanol for about 4 hours. The ethyl alcohol is distilled off in vacuo, the aqueous solution is filtered, further water being added if appropriate, and the filtrate is acidified down to a pH value of 1 to 2 with 10% strength hydrochloric acid, whilst cooling with ice. The precipitate which forms is filtered off, washed with water and dried in vacuo at about 60° to 80° C. The resulting free carboxylic acid can be recrystallised from ethyl alcohol.
Yield: 9 g; melting point: 224° C.
The esters and carboxylic acids of Examples 2 to 18 were obtained by a procedure analogous to that in Example 1. They are summarised in Table 1. The labelling of the radicals A, B, D, E, R1, R2 and R3 relates to formulae (I) and (II) in the description.
TABLE 1 __________________________________________________________________________ Melting Melting point point Example (°C.) (°C.) No. A B D E R.sup.1 R.sup.2 R.sup.3 (Ester) (Acid) __________________________________________________________________________ 2 CH CH CNO.sub.2 CH ##STR11## CH.sub.3 COOC.sub.2 H.sub.5 211 210 (D).sup.+ 3 CH CH CNO.sub.2 CH CH.sub.3 CH.sub.3 COOC.sub.2 H.sub.5 228 290 (D) 4 CH CH CNO.sub.2 CH (CH.sub.3).sub.2 N CH.sub.3 COOCH.sub.3 203 277 (D) 5 CH CCl CNO.sub.2 CH (CH.sub.3).sub.2 N CH.sub.3 COOCH.sub.3 193 -- 6 CNO.sub.2 CH CH CH CH.sub.3 CH.sub.3 COOCH.sub.3 238 285 (D) 7 CH CH CNO.sub.2 CH CH.sub.3 CH.sub.3 CN 216 -- 8 N CSC.sub.2 H.sub.5 N CH ##STR12## H COOCH.sub.3 147 229 (D) 9 CH CH CNO.sub.2 CH C.sub.2 H.sub.5 CH.sub.3 COOCH.sub.3 205 242 (D) 10 CH CH CNO.sub.2 CH ##STR13## CH.sub.3 COOC.sub.2 H.sub.5 212 317 (D) 11 CH CH CNO.sub.2 CH ##STR14## CH.sub.3 COOCH.sub.3 211 -- 12 N CCH.sub.3 CH CH ##STR15## CH.sub.3 COOCH.sub.3 204 285 (D) 13 N CCH.sub.3 CH CH CH.sub.3 CH.sub.3 COOCH.sub.3 162 230 (D) 14 CH CH CNO.sub.2 CH ##STR16## CH.sub.3 COOC.sub.2 H.sub.5 210 204 15 N CCH.sub.3 CH CH C.sub.2 H.sub.5 CH.sub.3 COOCH.sub.3 160 226 (D) 16 N CSC.sub.2 H.sub.5 N CH CH.sub.3 CH.sub.3 COOCH.sub.3 184 252 (D) 17 CH CSC.sub.4 H.sub.9n CNO.sub.2 CH (CH.sub.3).sub.2N CH.sub.3 COOCH.sub.3 204 184 18 CH CH CNO.sub.2 CH C.sub.6 H.sub.5 CH.sub.3 COOC.sub.2 H.sub.5 220 -- 19 N CH CH CH ##STR17## H COOCH.sub.3 190-192 20 N CCH(CH.sub.3).sub.2 CH CH ##STR18## H COOCH.sub.3 181-186 __________________________________________________________________________ .sup.+ (D) means melting point with (partial) decomposition
First 14.1 g of β-cyclopropylaminoacrylic acid methyl ester and then 10.4 g of triethylamine are added dropwise to a solution of 19 g of 2-chloro-6-methylnicotinic acid chloride in 70 ml of absolute dioxane, whilst cooling with ice and stirring. The mixture is stirred at room temperature for 4 hours and at 40° C. for 0.5 hour, 31 g of 1,8-diazabicyclo-[5.4.0]-undec-7-ene (DBU) are added, whilst cooling with ice, and the mixture is heated under reflux for 6 hours. The solvent is then distilled off in vacuo and the residue is taken up in a chloroform/water mixture. The chloroform phase is dried with sodium sulphate and the chloroform is distilled off. After crystallising the residue from acetonitrile, 8.5 g of 1-cyclopropyl-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid methyl ester of melting point 204° to 205° C. are obtained. The corresponding carboxylic acid, obtained by saponification analogously to Example 1, melts at 229° to 230° C. (with decomposition).
33.8 g of β-cyclopenylaminoacrylic acid methyl ester in 20 ml of dioxane are added dropwise to a solution of 38 g of 2-chloro-6-methyl-nicotinic acid chloride in 120 ml of absolute dioxane, whilst cooling with ice and stirring, and 20.4 g of triethylamine are then added dropwise, a temperature of 10° to 15° C. being maintained. The mixture is then stirred at room temperature for 4 hours and at about 40° C. for 0.5 hour and, after cooling to 20° C., 63 g of DBU are added and the mixture is heated under reflux for 7 hours. The dioxane is then distilled off in vacuo, the residue is taken up in chloroform and the chloroform phase is washed with water. After the chloroform has been distilled off, the crude ester is heated under reflux directly with 80 ml of ethyl alcohol and a solution of 17 g of pottassium hydroxide in 80 ml of water for 4 hours. The ethyl alcohol is distilled off in vacuo, the potassium salt of the carboxylic acid formed is dissolved in water, the solution is filtered and the carboxylic acid is precipitated from the filtrate with 10% strength hydrochloric acid, whilst cooling with ice. The precipitate, which has been filtered off and dried, is recrystallised from ethyl alcohol. 38.5 g of 1-cyclopentyl-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid of melting point 236° to 237° C. (with decomposition) are obtained.
The procedure followed in Examples 23 to 31 is analogous to that indicated in Example 22. The results are summarised in Table 2. As in the case of Table 1, the symbols A to R3 relate to the formulae (I) and (II).
TABLE 2 __________________________________________________________________________ R.sup.1 Melting Example saponified point No. A B D E R.sup.1 R.sup.2 to (°C.) __________________________________________________________________________ 23 N CCH.sub.3 CH CH ##STR19## CH.sub.3 COOH 295 (D).sup.+ 24 N CCH.sub.3 CH CH ##STR20## H COOH 272 (D) 25 N CCH.sub.3 CH CH (CH.sub.3).sub.3 C H COOH 291 (D) 26 N CCH.sub.3 CH CH ##STR21## H COOH 199 (D) 27 N CCH.sub.3 CH CH ##STR22## CH.sub.3 COOH 213 (D) 28 N CCH.sub.3 CH CH n-C.sub.3 H.sub.5 H COOH 208 (D) 29 N CCH.sub.3 CH CH C.sub.2 H.sub.5 H COOH 227 (D) 30 N CCH.sub.3 CH CH CH.sub.3 CH.sub.3 COOH 230 (D) 31 N CSC.sub.2 H.sub.5 N CH ##STR23## H COOH 215 (D) 32 N CSCH.sub.3 N CH ##STR24## H COOH 250 (D) __________________________________________________________________________ .sup.+ (D) means melting point with (partial) decomposition
77.5 g of β-morpholinylamino-crotonic acid anilide are added in portions to 65.4 g of 2-chloro-5-nitro-benzoyl chloride in 250 ml of absolute dioxane, whilst cooling with ice and stirring, and 24 g of pyridine are then added dropwise. The mixture is stirred at room temperature for 4 hours and at 50° to 60° C. for 2 hours, the dioxane is distilled off in vacuo and the reaction mixture is taken up in water. The precipitate which has formed is filtered off and, after drying, is recrystallised from ethyl acetate/acetonitrile. The yellow crystals of α-(2-chloro-5-nitro-benzoyl)-β-morpholinyl-amino-crotonic acid anilide melt at 190° to 191° C. Yield: 48 g.
19.3 g of the anilide are heated under reflux in 100 ml of dioxane with 7 g of DBU for 6 hours. The dioxane is then distilled off in vacuo and the residue is taken up in water. The precipitate is filtered off and washed with water. After drying, it is recrystallised from dimethylformamide/ethanol and 14 g of 2-methyl-1-morpholinyl-6-nitro-4-quinolone-3-carboxylic acid anilide of melting point 276° C. (with decomposition) are obtained.
138 g of β-(2,2-dimethylhydrazino)-crotonic acid methyl ester are added dropwise to a solution of 191.1 g of 2-chloro-5-nitro-benzyol chloride in 500 ml of anhydrous dioxane, whilst cooling with ice and stirring. 88.2 g of triethylamine are then added dropwise at about 10° to 15° C. and the mixture is stirred at room temperature for one hour and at 50° to 60° C. for 2.5 hours. The solvent is distilled off in vacuo and the residue is taken up in a chloroform/water mixture. The chloroform phase is dried over sodium sulphate. The chloroform is then distilled off in vacuo. After recrystallising the residue from ethyl acetate, 215.5 g of α-(2-chloro-5-nitro-benzoyl)-β-(2,2-dimethylhydrazino)-crotonic acid methyl ester are obtained. Melting point: 142° to 143° C.
A solution of 5.7 g of potassium hydroxide in 150 ml of ethyl alcohol is added to 34 g of the ester described. The mixture is then heated to 40° C. for 0.5 hour and under reflux for 4 hours. After working up as in the first reaction stage, 19.8 g of light yellow crystals of 1-dimethylamino-2-methyl-6-nitro-4-quinolone-3-carboxylic acid methyl ester are obtained. Melting point: 201° to 202° C.
A solution of 66 g of 2-chloro-5-nitro-benzoyl chloride in 30 ml of dioxane is added dropwise to a solution of 64.2 g of β-morpholinylamino-crotonic acid ethyl ester and 24 g of pyridine in 120 ml of absolute dioxane, whilst cooling with ice and stirring. The mixture is stirred at room temperature for one hour and at about 40° C. for one hour. It is worked up as in Example 33. After recrystallising the product from methanol, 82.3 g of α-(2-chloro-5-nitro-benzoyl)-β-morpholinylaminocrotonic acid ethyl ester are obtained. Melting point: 137° to 138° C.
39.7 g of the acyclic ester described are heated under reflux in 100 ml of absolute dioxane with 16 g of DBU for 6 hours. The dioxane is distilled off in vacuo, the residue is worked up as in Example 33 and the product is recrystallised from ethanol, 16.5 g of 1-morpholinylamino-2-methyl-6-nitro-4-quinolone-3-carboxylic acid ethyl ester of melting point 210° to 211° C. are obtained.
26.5 g of the acyclic ester described above are added in portions to a solution of 1.54 g of metallic sodium in 150 ml of absolute ethanol, whilst cooling with ice and stirring, and the mixture is then heated under reflux for 4 hours. It is worked up as in Example 33 and the product is recrystallised from ethanol/acetonitrile, 18.6 g of 1-morpholinylamino-2-methyl-6-nitro-4-quinolone-3-carboxylic acid ethyl ester of melting point 209° to 210° C. are obtained.
26.5 g of the acyclic ester described above are rapidly added to 3.8 g of potassium hydroxide in 150 ml of ethanol. The mixture is heated under flux for 4 hours and worked up as described above. After recystallising the product from ethyl alcohol/acetonitrile, 22 g of the 4-quinolone ester already described under (a) and (b), of melting point 209° to 211° C., are obtained. The 1-morpholinylamino-2-methyl-6-nitro-4-quinolone-3-carboxylic acid obtainable by saponification melts at 265° C. (with decomposition).
Among the new 4-pyridone-3-carboxylic acid salts of the invention, those salts that are pharmaceutically acceptable are particularly important and are preferred. A resulting basic compound can be converted into a corresponding acid addition salt, for example by reacting it with an inorganic or organic acid, such as therapeutically useful acid, or with a corresponding anion exchange preparation, and isolating the desired salt. An acid addition salt may be converted into the free compound by treatment with a base, e.g., a metal hydroxide, ammonina or a hydroxyl ion exchange preparation. Therapeutically useful acids are, for example, inorganic acids, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric, nitric or perchloric acid, or organic acids, e.g. carboxylic or sulfonic acids, such as formic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, pyroracemic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicyclic, aminosalicyclic, embonic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, benzenesulfonic, halogenbenzenesulfonic, toluensulfonic, naphthalenesulfonic and sulfanilic acid; methionine, tryptophan, lysine and arginine.
Salts of the above-mentioned acids or other salts, for example, the picrates, can also be used for purification of the base obtained; the bases are converted into salts, the salts are separated and the base are liberated from the salts. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.
The new free 4-pyridone-3-carboxylic acids of the general formula (VII) and their salts can be interconverted in any suitable manner; methods for such interconversion are known in the art.
The present invention also comprises pharmaceutically acceptable bioprecursors of the active compounds of the present invention.
For the purposes of this Sepcification the term "pharmaceutically acceptable bioprecursor" of an active compound of the invention means a compound having a structural formula different from the active compound but which nonetheless, upon administration to a warm-blooded animal is converted in the animal's body to the active compound.
It will be understood that the specification examples are illustrative but not limitative of the present invention and that other embodiments within the spirit and scope of the invention will suggest themselves to those skilled in the art.
Claims (26)
1. A compound of the formula ##STR25## or a .Iadd.pharmaceutically usable .Iaddend.salt thereof in which R1a denotes a cycloalkyl group having 3 to 7 carbon atoms or an amino group --NR4 R5, in which
R4 and R5 are identical or different, and denote a straight-chain or branched C1 to C4 alkyl group or, together with the nitrogen atom which they substitute, form a 5-membered to 7-membered ring, .Iadd.said ring selected from the group consisting of pyrrolidine, piperidine, hexamethyleneimine, morpholine and thiomorpholine, .Iaddend.
R2 denotes a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, an aralkyl group having 1 to 4 carbon atoms in the aliphatic part and 6 to 10 carbon atoms in the aromatic part or an aryl group having 6 to 10 carbon atoms and
R3a denotes a carboxyl group or a derivative which is a nitrile, an ester.Iadd.--COOR6 .Iaddend.or an acid amide .Iadd.--CO--NR7 R8, wherein R6, R7 and R8 denote a C1 -C4 alkyl, .Iaddend.
the symbols A and D are nitrogen atoms and the symbols B and E remaining in each represent a carbon atom which is unsubstituted or substituted by C1 to C6 alkyl, C1 to C4 alkoxy, C1 to C6 alkylmercapto, trifluoromethyl, halogen, cyano, carboxyl which is esterified by C1 to C4 alkyl, benzyl or phenyl each of which is unsubstituted or substituted by C1 to C3 alkyl, nitro or halogen, or amino substituted by carbalkoxy.
2. A process for the production of a 4-pyridone-3-carboxylic acid or a derivative thereof which comprises reacting .Iadd.an .Iaddend.enamine of the formula ##STR26## in which R1 denotes an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an aralkyl group having 1 to 4 carbon atoms in the aliphatic part and 6 to 10 carbon atoms in the aromatic part or an aryl group having 6 to 10 carbon atoms or an amino group --NR4 R5,
in which
R4 and R5 are identical or different, and denote a straight-chain or branched C1 to C4 alkyl group or, together with the nitrogen atom which they substitute, form a 5-membered to 7-membered ring, R2 denotes a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, an aralkyl group having 1 to 4 carbon atoms in the aliphatic part and 6 to 10 carbon atoms in the aromatic part or an aryl group having 6 to 10 carbon atoms and
R3 denotes an ester or acid amide derivative of the carboxyl group, with .[.an o-halogeno-(hetero)-aryl-.]. .Iadd.a .Iaddend.carboxylic acid halide of the formula ##STR27## in which the symbols A and D are nitrogen atoms and the symbols B and E remaining in each case denote a carbon atom, and which is unsubstituted or substituted by C1 to C6 alkyl, C1 to C4 alkoxy, C1 to C6 alkylmercapto, trifluoromethyl, halogen, cyano, carboxyl which is esterified by C1 to C4 alkyl, benzyl or phenyl each of which is unsubstituted or substituted by C1 to C3 alkyl, nitro or halogen, or amino substituted by carbalkoxy .Iadd.and wherein X1 and X2 denote identical or different halogen atoms.Iaddend..
3. A medicated fodder comprising an amount of a compound as claimed in claim 1 effective for promoting growth and improving feed utilization and a nutritious material.
4. A process according to claim 2 in which the aprotic solvent is dioxane.
5. A process according to claim 2 in which the first reaction stage is carried out from 10° to 60° C. and the second reaction stage is carried out from 100° to 150° C. and the aprotic solvent is dioxane.
6. A process according to claim 2 in which R' is cyclopropyl or cyclohexyl.
7. A process according to claim 2 in which the base in the first reaction stage is triethylamine and the base in the second reaction stage is 1,8-diazabicyclo-[5.4.0]-undec-7-ene.
8. A process according to claim 2 in which the enamine is of the formula ##STR28## in which R1' denotes a tert.alkyl, a C3, to C7 cycloalkyl, or a dialkyl amino group --NR4' --R5',
in which
R4' and R5' denote a C1 or C2 alkyl group or together complete a morpholinyl radical,
R2' denotes a hydrogen atom or a C1 to C4 alkyl group or an optionally substituted benzyl or phenyl radical and
R3 has the same meaning as in claim 2.
9. A process according to claim 2 in which the enamine is of the formula ##STR29## in which R1" denotes a tert.-butyl, cyclopropyl, cyclohexyl or dimethylamino group or a N-morpholinyl radical,
R2" denotes a hydrogen atom or a C1 to C4 alkyl group and
R3 has the same meaning as in claim 2.
10. A process according to claim 2 in which the .[.o-halogeno-(hetero-)aryl-.].carboxylic acid halide is a compound of the formula ##STR30## in which the symbols A, B, D and E have the same meaning as in claim 2, but the heterocyclic radical .[.optionally present.]. contains at most two nitrogen atoms.
11. A compound according to claim 1 in which R1a denotes a tert.-butyl, cyclopropyl, cyclohexyl, dimethylamino or N-morpholinyl radical.
12. A compound according to claim 1 of the formula ##STR31## in which A, B D and E have the same meanings as in claim 1.
13. A pharmaceutical composition containing as an active ingredient an antibacterially or antifungally effective amount of a compound according to claim 1 in admixture with a solid or liquefied gaseous diluent or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 except in the presence of a surface-active agent.
14. A pharmaceutical composition containing as an active ingredient as antibacterially or antifungally effective amount of a compound according to claim 1 in the form of a sterile or physiologically isotonic aqueous solution.
15. A comparison according to claim 13 containing from 0.5 to 95% by weight of the said active ingredient.
16. A medicament in dosage unit form comprising an antibacterially or antifungally effective amount of a compound according to claim 1 together with an inert pharmaceutical carrier.
17. A medicament of claim 16 in the form of tablets, pills, dragees, capsules, ampoules, or suppositories.
18. A method of combating bacterial diseases in warm-blooded animals which comprises administering to the said animals an effective amount of an active compound according to claim 1 either alone or in admixture with a diluent or in the form of a medicament. .Iadd.
19. A compound of the formula ##STR32## or a pharmaceutically useable salt thereof in which R1a denotes a cycloalkyl group having 3 to 7 carbon atoms or an amino group --NR4 R5, in which
R4 and R5 are identical or different, and denote a straight-chain or branched C1 to C4 alkyl group or, together with the nitrogen atom which they substitute, form a 5-membered to 7-membered ring, said ring selected from the group consisting of pyrrolidine, piperidine, hexamethyleneimine, morpholine and thiomorpholine,
R2 denotes a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, an aralkyl group having 1 to 4 carbon atoms in the aliphatic part and 6 to 10 carbon atoms in the aromatic part or an aryl group having 6 to 10 carbon atoms and
R3a denotes a carboxyl group or a derivative which is a nitride, an ester--COOR6 or an acid amide --CO--NR7 R8, wherein R6, R7 and R8 denote a C1 -C4 alkyl, the symbols A, B, D and E at most represent two nitrogen atoms and the remaining symbols in each case represent a carbon atom which is unsubstituted or substituted by C1 to C6 alkyl, C1 to C4 alkoxy, C1 to C6 alkylmercapto, trifluoromethyl, halogen, cyano, carboxyl which is esterified by C1 to C4 alkyl, benzyl or phenyl said benzyl or phenyl being unsubstituted or substituted by C1 to C3 alkyl, nitro or halogen, or amino substituted by carbalkoxy. .Iaddend. .Iadd.
20. A compound according to claim 19, wherein each of A, B, D and E is a carbon atom. .Iaddend. .Iadd.21. A compound according to claim 20 of the formula ##STR33## in which A, B, D and E have the same meanings as in claim 20. .Iaddend.
.Iadd.22. A pharmaceutical composition containing as an active ingredient an antibacterially or antifungally effective amount of a compound according to claim 20 in admixture with a solid or liquefied gaseous diluent or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 except in the presence of a surface-active agent. .Iaddend. .Iadd.23. A pharmaceutical composition containing as an active ingredient an antibacterially or antifungally effective amount of a compound according to claim 20 in the form of a sterile or physiologically isotonic aqueous solution. .Iaddend. .Iadd.24. A composition according to claim 21 containing from 0.5 to 95% by weight of the said active ingredient. .Iaddend. .Iadd.25. A medicament in dosage unit form comprising an antibacterially or antifungally effective amount of a compound according to claim 20 together with an inert pharmaceutical carrier. .Iaddend. .Iadd.26. A medicament of claim 25 in the form of tablets, pills, dragees, capsules, ampoules, or suppositories. .Iaddend. .Iadd.27. A method of combating bacterial diseases in warm-blooded animal which comprises administering to the said animals an effective amount of an active compound according to claim 20 either alone or in admixture with
a diluent or in the form of a medicament. .Iaddend. .Iadd.28. A medicated fodder comprising an amount of a compound as claimed in claim 20 effective for promoting growth and improving feed utilization and a nutritious material. .Iaddend. .Iadd.29. A process for the production of a 4-pyridone-3-carboxylic acid or a derivative thereof which comprises reacting an enamine of the formula ##STR34## in which R1 denotes an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an aralkyl group having 1 to 4 carbon atoms in the aliphatic part and 6 to 10 carbon atoms in the aromatic part or an aryl group having 6 to 10 carbon atoms or an amino group --NR4 R5,
in which
R4 and R5 can be identical or different, and denote a straight-chain or branched C1 to C4 alkyl group or, together with the nitrogen atom which they substitute, form a 5-membered to 7-membered ring, R2 denotes a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, an aralkyl group having 1 to 4 carbon atoms in the aliphatic part and 6 to 10 carbon atoms in the aromatic part or an aryl group having 6 to 10 carbon atoms and
R3 denotes an ether or acid amide derivative of the carboxyl group, with an o-halogeno-(hetero)-aryl-carboxylic acid halide of the formula ##STR35## in which at most two of the symbols A, B, D and E are nitrogen atoms and the symbols remaining in each case denote a carbon atom, and which is unsubstituted or substituted by C1 to C6 alkyl, C1 to C4 alkoxy, C1 to C6 alkylmercapto, trifluoromethyl, halogen, cyano, carboxyl which is esterified by C1 to C4 alkyl, benzyl or phenyl each of which is unsubstituted or substituted by C1 to C3 alkyl, nitro or halogen, or amino substituted by carbalkoxy.
.Iaddend. .Iadd.30. A process according to claim 29, wherein A, B, D and E each is a carbon atom. .Iaddend. .Iadd.31. A process according to claim 30 in which the aprotic solvent is dioxane. .Iaddend. .Iadd.32. A process according to claim 30 in which the first reaction stage is carried out from 10° to 60° C. and the second reaction stage is carried out from 100° to 150° C. and the aprotic solvent is dioxane.
.Iaddend. .Iadd.33. A process according to claim 30 in which R' is cyclopropyl or cyclohexyl. .Iaddend. .Iadd.34. A process according to claim 30 in which the base in the first reaction stage is triethylamine and the base in the second reaction stage is 1,8-diazabicyclo-[5.4.0]-undec-7-ene. .Iaddend. .Iadd.35. A process according to claim 30 in which the enamine is of the formula ##STR36## in which R1 denotes a tert.alkyl, a C3 to C7 cycloalkyl, or a dialkyl amino group --NR4 --R5,
in which
R4 and R5 denote a C1 or C2 alkyl group or together complete a morpholinyl radical,
R2 denotes a hydrogen atom or a C1 to C4 alkyl group or an optionally substituted benzyl or phenyl radical and
R3 denotes an ester or acid amide derivative of the carboxyl group, with a carboxylic acid halide of the formula ##STR37## in which at most two of the symbols A, B, D and E are nitrogen atoms and the symbols remaining in each case denote a carbon atom, and which is unsubstituted or substituted by C1 to C6 alkyl, C1 to C4 alkoxy, C1 to C6 alkylmercapto, trifluoromethyl, halogen, cyano, carboxyl which is esterified by C1 to C4 alkyl, benzyl or phenyl each of which is unsubstituted or substituted by C1 to C3 alkyl, nitro or halogen, or amino substituted by carbalkoxy.
.Iaddend. .Iadd.36. A process according to claim 30 in which the enamine is of the formula ##STR38## in which R1 denotes a tert.-butyl, cyclopropyl, cyclohexyl or dimethylamino group or a N-morpholinyl radical,
R2 denotes a hydrogen atom or a C1 to C4 alkyl group and
R1 denotes an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an aralkyl group having 1 to 4 carbon atoms in the aliphatic part and 6 to 10 carbon atoms in the aromatic part or an aryl group having 6 to 10 carbon atoms or an amino group --NR4
R5. .Iaddend. .Iadd.37. A process according to claim 30 in which the o-halogeno-aryl-carboxylic acid halide is a compound of the formula ##STR39## in which the symbols A, B, D and E have the same meaning as in claim 30. .Iaddend.
Priority Applications (1)
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US06/733,996 USRE32975E (en) | 1978-02-24 | 1985-05-14 | 4-Pyridone-3-carboxylic acids and/or derivatives thereof |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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DE2808070 | 1978-02-24 | ||
DE19782808070 DE2808070A1 (en) | 1978-02-24 | 1978-02-24 | PROCESS FOR THE PRODUCTION OF 4-PYRIDONE-3-CARBONIC ACIDS AND / OR DERIVATIVES |
US06/733,996 USRE32975E (en) | 1978-02-24 | 1985-05-14 | 4-Pyridone-3-carboxylic acids and/or derivatives thereof |
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US06/008,634 Reissue US4284629A (en) | 1978-02-24 | 1979-02-01 | Process for the preparation of 4-pyridone-3-carboxylic acids and/or derivatives thereof |
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US06/733,996 Expired - Lifetime USRE32975E (en) | 1978-02-24 | 1985-05-14 | 4-Pyridone-3-carboxylic acids and/or derivatives thereof |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4959363A (en) * | 1989-06-23 | 1990-09-25 | Sterling Drug Inc. | Quinolonecarboxamide compounds, their preparation and use as antivirals. |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3472859A (en) * | 1966-11-01 | 1969-10-14 | Sterling Drug Inc | 1-alkyl-1,4-dihydro-4-oxo-3 quinoline-carboxylic acids and esters |
US3673184A (en) * | 1970-09-02 | 1972-06-27 | Dainippon Pharmaceutical Co | Certain 2-substituted-5,8-dihydro-5-oxopyrido{8 2,3-d{9 pyrimidine-6-carboxylic acid derivatives |
EP0004279A1 (en) * | 1978-02-24 | 1979-10-03 | Bayer Ag | Process for the preparation of 4-pyridone-3-carboxylic acids, 1-cyclopropyl-4-pyridone-3-carboxylic acid derivatives and medicines containing them |
-
1985
- 1985-05-14 US US06/733,996 patent/USRE32975E/en not_active Expired - Lifetime
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US3472859A (en) * | 1966-11-01 | 1969-10-14 | Sterling Drug Inc | 1-alkyl-1,4-dihydro-4-oxo-3 quinoline-carboxylic acids and esters |
US3673184A (en) * | 1970-09-02 | 1972-06-27 | Dainippon Pharmaceutical Co | Certain 2-substituted-5,8-dihydro-5-oxopyrido{8 2,3-d{9 pyrimidine-6-carboxylic acid derivatives |
EP0004279A1 (en) * | 1978-02-24 | 1979-10-03 | Bayer Ag | Process for the preparation of 4-pyridone-3-carboxylic acids, 1-cyclopropyl-4-pyridone-3-carboxylic acid derivatives and medicines containing them |
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US4959363A (en) * | 1989-06-23 | 1990-09-25 | Sterling Drug Inc. | Quinolonecarboxamide compounds, their preparation and use as antivirals. |
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