NO152788B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PIPERAZINYLBENZOHETEROCYCLIC COMPOUNDS - Google Patents
ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PIPERAZINYLBENZOHETEROCYCLIC COMPOUNDS Download PDFInfo
- Publication number
- NO152788B NO152788B NO791224A NO791224A NO152788B NO 152788 B NO152788 B NO 152788B NO 791224 A NO791224 A NO 791224A NO 791224 A NO791224 A NO 791224A NO 152788 B NO152788 B NO 152788B
- Authority
- NO
- Norway
- Prior art keywords
- group
- formula
- compound
- compounds
- mixture
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 126
- 238000002360 preparation method Methods 0.000 title claims description 21
- 238000000034 method Methods 0.000 title claims description 13
- 230000001225 therapeutic effect Effects 0.000 title description 2
- -1 p-toluenesulfonyl group Chemical group 0.000 claims description 49
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 32
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 230000007062 hydrolysis Effects 0.000 claims description 9
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 150000001450 anions Chemical class 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 77
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 72
- 239000000243 solution Substances 0.000 description 59
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 58
- 239000013078 crystal Substances 0.000 description 58
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 54
- 238000006243 chemical reaction Methods 0.000 description 52
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 37
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 35
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 33
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 28
- 239000002904 solvent Substances 0.000 description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 25
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
- 238000001914 filtration Methods 0.000 description 22
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 21
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 17
- 210000002966 serum Anatomy 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 230000000845 anti-microbial effect Effects 0.000 description 15
- 238000001953 recrystallisation Methods 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 10
- 238000000921 elemental analysis Methods 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- 239000002198 insoluble material Substances 0.000 description 8
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 7
- 238000004821 distillation Methods 0.000 description 7
- 239000012442 inert solvent Substances 0.000 description 7
- 229920000137 polyphosphoric acid Polymers 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 6
- 239000004599 antimicrobial Substances 0.000 description 6
- 150000002170 ethers Chemical class 0.000 description 6
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 5
- 150000007514 bases Chemical class 0.000 description 5
- LTMHNWPUDSTBKD-UHFFFAOYSA-N diethyl 2-(ethoxymethylidene)propanedioate Chemical compound CCOC=C(C(=O)OCC)C(=O)OCC LTMHNWPUDSTBKD-UHFFFAOYSA-N 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 238000007363 ring formation reaction Methods 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 229940124597 therapeutic agent Drugs 0.000 description 5
- 125000005270 trialkylamine group Chemical group 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 230000003301 hydrolyzing effect Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- RQCXFWRVUJHEFD-UHFFFAOYSA-N 8-(1-piperazinyl)-6,7-dihydro-1-oxo-1h,5h-benzo[ij]-quinolizine-2-carboxylic acid Chemical compound C1=CC(=C23)C(=O)C(C(=O)O)=CN2CCCC3=C1N1CCNCC1 RQCXFWRVUJHEFD-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 3
- 208000035473 Communicable disease Diseases 0.000 description 3
- 241000588914 Enterobacter Species 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 241000194017 Streptococcus Species 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000008272 agar Substances 0.000 description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical group OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 238000006798 ring closing metathesis reaction Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 235000017550 sodium carbonate Nutrition 0.000 description 3
- TXLWDZJPQCYYQY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinolin-5-yl methanesulfonate Chemical compound N1CCCC2=C1C=CC=C2OS(=O)(=O)C TXLWDZJPQCYYQY-UHFFFAOYSA-N 0.000 description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 2
- NJZVTNYJNDWQND-UHFFFAOYSA-N 5-chloro-3,4-dihydro-1h-quinolin-2-one Chemical compound N1C(=O)CCC2=C1C=CC=C2Cl NJZVTNYJNDWQND-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- XDNVXLVTNVTOHU-UHFFFAOYSA-N 8-chloro-6,7-dihydro-1-oxo-1h,5h-benzo-[ij]quinolizine-2-carboxylic acid Chemical compound C1CCC2=C(Cl)C=CC3=C2N1C=C(C(=O)O)C3=O XDNVXLVTNVTOHU-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 229930194542 Keto Natural products 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 241000589516 Pseudomonas Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 2
- 229960000723 ampicillin Drugs 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 2
- 239000000920 calcium hydroxide Substances 0.000 description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 229920001429 chelating resin Polymers 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 150000002085 enols Chemical class 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 238000005187 foaming Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000002054 inoculum Substances 0.000 description 2
- 229910052806 inorganic carbonate Inorganic materials 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- SMUQFGGVLNAIOZ-UHFFFAOYSA-N quinaldine Chemical compound C1=CC=CC2=NC(C)=CC=C21 SMUQFGGVLNAIOZ-UHFFFAOYSA-N 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 150000003248 quinolines Chemical class 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 125000004954 trialkylamino group Chemical group 0.000 description 2
- VWBKZKSFICZCGA-UHFFFAOYSA-N (2-oxo-3,4-dihydro-1h-quinolin-5-yl) 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OC1=CC=CC2=C1CCC(=O)N2 VWBKZKSFICZCGA-UHFFFAOYSA-N 0.000 description 1
- XHWOXLCXKDATQS-UHFFFAOYSA-N (2-oxo-3,4-dihydro-1h-quinolin-5-yl) methanesulfonate Chemical compound N1C(=O)CCC2=C1C=CC=C2OS(=O)(=O)C XHWOXLCXKDATQS-UHFFFAOYSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- QNRATNLHPGXHMA-XZHTYLCXSA-N (r)-(6-ethoxyquinolin-4-yl)-[(2s,4s,5r)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]methanol;hydrochloride Chemical compound Cl.C([C@H]([C@H](C1)CC)C2)CN1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OCC)C=C21 QNRATNLHPGXHMA-XZHTYLCXSA-N 0.000 description 1
- PCOCNNBMYRKIPJ-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinolin-5-yl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OC1=CC=CC2=C1CCCN2 PCOCNNBMYRKIPJ-UHFFFAOYSA-N 0.000 description 1
- RKCDIJOQOWHUFN-UHFFFAOYSA-N 1-azatricyclo[7.3.1.05,13]trideca-2,5,7,9(13)-tetraen-4-one Chemical class C1CCC2=CC=CC3=C2N1C=CC3=O RKCDIJOQOWHUFN-UHFFFAOYSA-N 0.000 description 1
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 1
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical class CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical class CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- XNSPDJAXCBZCRV-UHFFFAOYSA-N 4-chloro-1,3-dihydroindol-2-one Chemical compound ClC1=CC=CC2=C1CC(=O)N2 XNSPDJAXCBZCRV-UHFFFAOYSA-N 0.000 description 1
- BBHMZHDPVNXFMI-UHFFFAOYSA-N 4-chloro-2,3-dihydro-1h-indole Chemical compound ClC1=CC=CC2=C1CCN2 BBHMZHDPVNXFMI-UHFFFAOYSA-N 0.000 description 1
- PAFKJCJIJXBWED-UHFFFAOYSA-N 4-chloro-2-methyl-1h-indole Chemical compound C1=CC=C2NC(C)=CC2=C1Cl PAFKJCJIJXBWED-UHFFFAOYSA-N 0.000 description 1
- YOYCNNJAIOQWMD-UHFFFAOYSA-N 4-chloro-2-methyl-2,3-dihydro-1h-indole Chemical compound C1=CC=C(Cl)C2=C1NC(C)C2 YOYCNNJAIOQWMD-UHFFFAOYSA-N 0.000 description 1
- MUDSDYNRBDKLGK-UHFFFAOYSA-N 4-methylquinoline Chemical compound C1=CC=C2C(C)=CC=NC2=C1 MUDSDYNRBDKLGK-UHFFFAOYSA-N 0.000 description 1
- 125000002471 4H-quinolizinyl group Chemical class C=1(C=CCN2C=CC=CC12)* 0.000 description 1
- RQHMSLUJYYOUKP-UHFFFAOYSA-N 5-amino-3,4-dihydro-1h-quinolin-2-one Chemical compound N1C(=O)CCC2=C1C=CC=C2N RQHMSLUJYYOUKP-UHFFFAOYSA-N 0.000 description 1
- BKEUNVPURFJRTB-UHFFFAOYSA-N 5-chloro-1,2,3,4-tetrahydroquinoline Chemical compound N1CCCC2=C1C=CC=C2Cl BKEUNVPURFJRTB-UHFFFAOYSA-N 0.000 description 1
- YMSHIIDMJGHMIX-UHFFFAOYSA-N 5-chloro-2,3,4,9-tetrahydro-1h-carbazole Chemical compound C1CCCC2=C1NC1=C2C(Cl)=CC=C1 YMSHIIDMJGHMIX-UHFFFAOYSA-N 0.000 description 1
- GIVJUQCBPFAKJK-UHFFFAOYSA-N 5-chloro-2-methyl-1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2NC(C)CCC2=C1Cl GIVJUQCBPFAKJK-UHFFFAOYSA-N 0.000 description 1
- UTTJAIFHRUAFED-UHFFFAOYSA-N 5-hydroxy-3,4-dihydro-2(1h)-quinolinone Chemical compound N1C(=O)CCC2=C1C=CC=C2O UTTJAIFHRUAFED-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- JUNNGQWAVALNRH-UHFFFAOYSA-N 8,10-dichloro-6,7-dihydro-1-oxo-1h,5h-benzo[ij]quinolizine-2-carboxylic acid Chemical compound C1CCC2=C(Cl)C=C(Cl)C3=C2N1C=C(C(=O)O)C3=O JUNNGQWAVALNRH-UHFFFAOYSA-N 0.000 description 1
- ZWWBXDVZMPJJBE-UHFFFAOYSA-N 8-(1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-1h,5h-benzo[ij]quinolizine-2-carboxylic acid Chemical compound C1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)CCC3=C1N1CCNCC1 ZWWBXDVZMPJJBE-UHFFFAOYSA-N 0.000 description 1
- LOOFXSBPKWWZDK-UHFFFAOYSA-N 8-(p-toluenesulfonyloxy)-6,7-dihydro-1-oxo-1h,5h-benzo-[ij]quinolizine-2-carboxylic acid Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OC1=CC=C2C(=O)C(C(O)=O)=CN3CCCC1=C32 LOOFXSBPKWWZDK-UHFFFAOYSA-N 0.000 description 1
- XMLKZFJCWUKBGF-UHFFFAOYSA-N 8-chloro-5-methyl-6,7-dihydro-1-oxo-1h,5h-benzo-[ij]quinolizine-2-carboxylic acid Chemical compound C1CC(C)N2C=C(C(O)=O)C(=O)C3=C2C1=C(Cl)C=C3 XMLKZFJCWUKBGF-UHFFFAOYSA-N 0.000 description 1
- MBMRTJANBKFZPV-UHFFFAOYSA-N 9-chloro-6-oxo-1,2-dihydro-6h-pyrrolo-[3,2,1-ij]quinoline-5-carboxylic acid Chemical compound C1CC2=C(Cl)C=CC3=C2N1C=C(C(=O)O)C3=O MBMRTJANBKFZPV-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- FBEHFRAORPEGFH-UHFFFAOYSA-N Allyxycarb Chemical compound CNC(=O)OC1=CC(C)=C(N(CC=C)CC=C)C(C)=C1 FBEHFRAORPEGFH-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000304886 Bacilli Species 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- GIQAYMAXJDJUPO-UHFFFAOYSA-N ClC1=CC=C2C(C(=CN3C(CCC1=C23)C)C(C)=O)=O Chemical compound ClC1=CC=C2C(C(=CN3C(CCC1=C23)C)C(C)=O)=O GIQAYMAXJDJUPO-UHFFFAOYSA-N 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 231100000111 LD50 Toxicity 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- HKHDKJUAGXTOCG-UHFFFAOYSA-N N1(CCNCC1)C=1CCN2CC=C(C(C23C1C=CC=C3)=O)C(=O)O Chemical compound N1(CCNCC1)C=1CCN2CC=C(C(C23C1C=CC=C3)=O)C(=O)O HKHDKJUAGXTOCG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 206010058667 Oral toxicity Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 241000607720 Serratia Species 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000011162 ammonium carbonates Nutrition 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 1
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- SLJXUJZUTPFXRJ-UHFFFAOYSA-N buzepide Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)N)CCN1CCCCCC1 SLJXUJZUTPFXRJ-UHFFFAOYSA-N 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- DMSZORWOGDLWGN-UHFFFAOYSA-N ctk1a3526 Chemical compound NP(N)(N)=O DMSZORWOGDLWGN-UHFFFAOYSA-N 0.000 description 1
- 229940045803 cuprous chloride Drugs 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000005949 ethanesulfonyloxy group Chemical group 0.000 description 1
- XDHWYQRLMSOZOP-UHFFFAOYSA-N ethyl 5-ethoxy-3-oxopent-4-enoate Chemical compound CCOC=CC(=O)CC(=O)OCC XDHWYQRLMSOZOP-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 231100000418 oral toxicity Toxicity 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000002195 soluble material Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- RKBCYCFRFCNLTO-UHFFFAOYSA-N triisopropylamine Chemical compound CC(C)N(C(C)C)C(C)C RKBCYCFRFCNLTO-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
Foreliggende oppfinnelse vedrører en analogifremgangsmåte for fremstilling av terapeutisk aktive piperazinylbenzoheterocykliske forbindelser med formel (I) The present invention relates to an analogous method for the production of therapeutically active piperazinylbenzoheterocyclic compounds of formula (I)
hvori R står for et hydrogenatom eller en lavere alkyl-gruppe, R 2 stpr for et hydrogenatom, R 3 står for et hydrogenatom, en lavere alkyl-gruppe, en lavere alkanoyl-gruppe, en lavere alkansulfonyl-gruppe, en fenyl-lavere-alkyl-gruppe, en benzoyl-gruppe, en p-toluensulfonyl-gruppe eller en gruppe med formel in which R stands for a hydrogen atom or a lower alkyl group, R 2 stpr for a hydrogen atom, R 3 stands for a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a lower alkanesulfonyl group, a phenyl lower- alkyl group, a benzoyl group, a p-toluenesulfonyl group or a group of formula
R 4 står for et hydrogenatom eller en halogen-gruppe, n er R 4 stands for a hydrogen atom or a halogen group, n is
1 2 1 2
et helt tall 0 eller 1, eller R og R danner sammen med de karbonatomer som de er knyttet til en cykloheksanring når n er 0, eller farmasøytisk tålbare salter derav, og det karakteristiske ved oppfinnelsen er at enten an integer 0 or 1, or R and R together with the carbon atoms to which they are attached form a cyclohexane ring when n is 0, or pharmaceutically acceptable salts thereof, and the characteristic of the invention is that either
a) omsettes en benzoheterocyklisk forbindelse med formel a) a benzoheterocyclic compound with formula is reacted
(II) (II)
i 2 4 hvori R , R , R og n har den ovennevnte betydning, og R 5 star for et halogenatom, en lavere alkansulfonyl-gruppe, eller en arylsulfonyloksy -gruppe, med en piperazinforbindelse med formel (III) in 2 4 in which R , R , R and n have the above meaning, and R 5 stands for a halogen atom, a lower alkanesulfonyl group, or an arylsulfonyloxy group, with a piperazine compound of formula (III)
hvori R"^ har den ovennevnte betydning, eller wherein R"^ has the above meaning, or
b) en forbindelse med formel (I") b) a compound of formula (I")
hvori R og R' er hydrogen eller lavere alkyl, Y betyr en aromatisk ring som inneholder et tertiært nitrogenatom hvormed den er tilknyttet eller Y betyr en trialkylaminogruppe, og 1 betyr et anion, underkastes en hydrolyse og, om ønsket, for fremstilling av forbindelser med formel wherein R and R' are hydrogen or lower alkyl, Y means an aromatic ring containing a tertiary nitrogen atom to which it is attached or Y means a trialkylamino group, and 1 means an anion, is subjected to a hydrolysis and, if desired, for the preparation of compounds with formula
(Ib) (Ib)
12 4 9 hvori R , R , R og na har den ovennevnte betydning og R står for en lavere alkyl-gruppe, en lavere alkanoyl-gruppe, en benzoyl-gruppe, en lavere alkansylfonyl-gruppe, en p-toluensulfonyl-gruppe, en fenyl-lavere-alkyl-gruppe eller en gruppe representert ved formel omsettes en erholdt forbindelse med formel (Ia) 12 4 hvori R , R , R og n har den ovennevnte betydning, med en forbindelse med formel 12 4 9 in which R , R , R and na have the above meaning and R stands for a lower alkyl group, a lower alkanoyl group, a benzoyl group, a lower alkanesulfonyl group, a p-toluenesulfonyl group, a phenyl-lower-alkyl group or a group represented by formula, an obtained compound of formula (Ia) 12 4 in which R , R , R and n have the above meaning is reacted with a compound of formula
hvori R 9 har den ovennevnte betydning og X er et halogenatom og, om ønsket, omsettes en erholdt forbindelse I i et farmasøytisk tålbart salt. wherein R 9 has the above meaning and X is a halogen atom and, if desired, a compound I obtained is reacted in a pharmaceutically acceptable salt.
Disse trekk ved oppfinnelsen fremgår av patentkravet. These features of the invention appear in the patent claim.
De nye forbindelser er nyttige som antimikrobielle midler, The new compounds are useful as antimicrobial agents,
se mer detaljert redegjørelse i det følgende. see more detailed explanation below.
Det er kjent at visse typer av polyheterocykliske forbindelser fremviser antimikrobielle virkninger. F.eks. omhandler US patentskrift nr. 3.917.609 substituerte derivater av 1,2-dihydro-6-okso-6H-pyrrolo[3,2,1-ijJkinolin som er nyttige som antimikrobielle midler eller som utgangsmaterial for fremstilling av antimikrobielle midler.. It is known that certain types of polyheterocyclic compounds exhibit antimicrobial effects. E.g. US patent document no. 3,917,609 deals with substituted derivatives of 1,2-dihydro-6-oxo-6H-pyrrolo[3,2,1-ijJquinoline which are useful as antimicrobial agents or as starting material for the production of antimicrobial agents..
Også US patentskrifter nr. 3.896.131, 3.985.882, Also US Patent Nos. 3,896,131, 3,985,882,
3.969.463, 4.001.243, og 4.014.877 omhandler 6,7-dihydro-l-okso-lH,5H-benzo[ij]kinolizin-derivater med antimikrobielle virkninger. 3,969,463, 4,001,243, and 4,014,877 relate to 6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine derivatives with antimicrobial effects.
Betegnelsen "halogen" som anvendt heri omfatter et kloratom, et bromatom, et jodatom og et fluoratom. The term "halogen" as used herein includes a chlorine atom, a bromine atom, an iodine atom and a fluorine atom.
Betegnelsen "lavere alkyl" som anvendt heri refererer til en rettkjedet eller forgrenet alkyl-gruppe med 1 til 4 karbonatomer som f.eks. en metyl-gruppe, en etyl-gruppe, The term "lower alkyl" as used herein refers to a straight or branched chain alkyl group of 1 to 4 carbon atoms such as a methyl group, an ethyl group,
en propyl-gruppe, en isopropyl-gruppe, en butyl-gruppe, en tert.butyl-gruppe o.l. a propyl group, an isopropyl group, a butyl group, a tert.butyl group and the like.
Betegnelsen "lavere alkanoyl" som"anvendt heri refererer The term "lower alkanoyl" as used herein refers to
til en rettkjedet eller forgrenet alkanoyl-gruppe med 1 to a straight-chain or branched alkanoyl group with 1
til 4 karbonatomer som f.eks. en formyl-gruppe, en acetyl-gruppe, en propanoyl-gruppe, en butanoyl-gruppe, en iso- to 4 carbon atoms such as e.g. a formyl group, an acetyl group, a propanoyl group, a butanoyl group, an iso-
butanoyl-gruppe o.l. butanoyl group, etc.
Betegnelsen "lavere alkansulfonyl" som anvendt heri refererer til en rettkjedet eller forgrenet alkansulfonyl-gruppe med 1 til 4 karbonatomer som f.eks. en metansulfonylgruppe, en etansulfonyl-gruppe, en propansulfonyl,gruppe, en isopropansulfonyl-gruppe, en butansulfonyl-gruppe, en tert.butuansulfonyl-gruppe o.l. The term "lower alkanesulfonyl" as used herein refers to a straight chain or branched alkanesulfonyl group of 1 to 4 carbon atoms such as e.g. a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group, an isopropanesulfonyl group, a butanesulfonyl group, a tert.butanesulfonyl group, and the like.
Betegnelsen "fenyl-lavere-alkyl" som anvendt heri refererer til en fenylalkyl-gruppe bestående av en fenyl-gruppe og en rettkjedet eller forgrenet alkylen-gruppe med 1 til 4 karbonatomer som f.eks. en benzyl-gruppe, en 2-fenyletyl-gruppe, en 3-fenylpropyl-gruppe, en 4-fenylbutyl-gruppe, en 1-fenyletyl-gruppe, en 1,l-dimetyl-2-fenyletyl-gruppe o.l. The term "phenyl-lower-alkyl" as used herein refers to a phenylalkyl group consisting of a phenyl group and a straight-chain or branched alkylene group of 1 to 4 carbon atoms such as e.g. a benzyl group, a 2-phenylethyl group, a 3-phenylpropyl group, a 4-phenylbutyl group, a 1-phenylethyl group, a 1,1-dimethyl-2-phenylethyl group and the like.
I den ovennevnte formel (I) er gruppen med formel In the above formula (I) is the group of formula
som står for R 3 tilstede som en tautomer, dvs. som which stands for R 3 present as a tautomer, ie as
en gruppe av enoltypen (A), dvs. en 4-hydroksy-l,5-naftyridin-3-karbonyl-gruppe og en gruppe av ketotypen (B), dvs- en 4-okso-l,4-dihydro-l,5-naftyridin-3-karbonyl-gruppe. Oppfinnelsen omfatter fremstillingen av både tautomerene av enoltypen og ketotypen. a group of the enol type (A), i.e. a 4-hydroxy-1,5-naphthyridine-3-carbonyl group and a group of the keto type (B), i.e. a 4-oxo-1,4-dihydro-1, 5-naphthyridine-3-carbonyl group. The invention encompasses the preparation of both the tautomers of the enol type and the keto type.
Forbindelsene som kan fremstilles ved hjelp av fremgangsmåten i henhold til oppfinnelsen er spesielt effektive overfor bakterier som hører til slektene streptococcus, pseudomonas, enterobacter, etc. og fremviser kraftig antibakteriell virkning mot disse bakterier som er resistente overfor streptomycin, ampicillin og/eller tetracyklin. The compounds which can be produced using the method according to the invention are particularly effective against bacteria belonging to the genera streptococcus, pseudomonas, enterobacter, etc. and exhibit strong antibacterial action against these bacteria which are resistant to streptomycin, ampicillin and/or tetracycline.
Med betegnelsen "lavere alkansulfonyloksy" som anvendt heri menes en rett eller forgrenet alkansulfonyloksygruppe med 1 The term "lower alkanesulfonyloxy" as used herein means a straight or branched alkanesulfonyloxy group with 1
til 4 karbonatomer som f.eks. enmetansulfonyloksygruppe, en etansulfonyloksygruppe, en propansulfonyloksygruppe, en isopropansulfonyloksygruppe, en butansulfonyloksygruppe, en tert-butansulfonyloksygruppe o.l. to 4 carbon atoms such as e.g. a methanesulfonyloxy group, an ethanesulfonyloxy group, a propanesulfonyloxy group, an isopropanesulfonyloxy group, a butanesulfonyloxy group, a tert-butanesulfonyloxy group and the like.
Med betegnelsen "arylsulfonyloksy" som anvendt heri menes en benzensulfonyloksygruppe, en naftalensulfonyloksygruppe o.l. Arylringen inkludert i arylsulfonyloksygruppen kan være substituert med 1 eller flere halogenatomer, en lavere alkyl-gruppe, en hydroksygruppe, en nitrogruppe o.l. Mer spesielt kan reaksjonen mellom forbindelsen med formel (II) og forbindelsen med formel (III) gjennomfbres i et inert løsningsmiddel under trykkbetingelser, dvs. ved et trykk på fra 1 til 20 atm., foretrukket 1 til 10 atm. ved en temperatur på fra 100 til 250°C, foretrukket ved 140 til 200°C i lopet av fra 5 til 20 timer. The term "arylsulfonyloxy" as used herein means a benzenesulfonyloxy group, a naphthalenesulfonyloxy group and the like. The aryl ring included in the arylsulfonyloxy group may be substituted with 1 or more halogen atoms, a lower alkyl group, a hydroxy group, a nitro group, etc. More particularly, the reaction between the compound of formula (II) and the compound of formula (III) can be carried out in an inert solvent under pressure conditions, i.e. at a pressure of from 1 to 20 atm., preferably 1 to 10 atm. at a temperature of from 100 to 250°C, preferably at 140 to 200°C in the course of from 5 to 20 hours.
I den ovennevnte reaksjon er mengdeforhold mellom forbindelse med formel (III) og forbindelse med formel (II) ikke spesielt begrenset og kan varieres innen vide grenser. Vanligvis kan reaksjonen gjennomfbres ved å anvende i det minste en ekvimolar mengde, foretrukket 1 til 5 mol, av forbindelsen med formel (III) pr. mol av forbindelsen med formel (II). In the above-mentioned reaction, the quantity ratio between compound of formula (III) and compound of formula (II) is not particularly limited and can be varied within wide limits. Generally, the reaction can be carried out by using at least an equimolar amount, preferably 1 to 5 mol, of the compound of formula (III) per moles of the compound of formula (II).
Passende eksempler på det inerte lbsningsmiddel er vann, lavere alkoholer som metanol, etanol, isopropanol, etc, arom*i.ske hydrokarboner som f.eks. benzen, toluen, xylen, etc, etere som f.eks. tetrahydrofuran, dioksan, diglym (dietylenglykoldimetyl-eter), etc, dimetylsulfoksyd, dimetylformamid, heksametylfosforsyretriamid o.l., idet dimetylsulfoksyd, dimetylformamid og heksametylfosiorsyre-triamid foretrekkes. Suitable examples of the inert solvent are water, lower alcohols such as methanol, ethanol, isopropanol, etc., aromatic hydrocarbons such as e.g. benzene, toluene, xylene, etc., ethers such as tetrahydrofuran, dioxane, diglyme (diethylene glycol dimethyl ether), etc., dimethylsulfoxide, dimethylformamide, hexamethylphosphoric acid triamide and the like, with dimethylsulfoxide, dimethylformamide and hexamethylphosphoric acid triamide being preferred.
Den ovennevnte reaksjon kan gjennomfdres i nærvær av et deoksydasjonsmiddel i en mengde på minst 1 omtrent ekvimolar mengde, foretrukket 1 til 2 mol, av deoksyderende middel pr. mol av forbindelsen med formel (II). The above-mentioned reaction can be carried out in the presence of a deoxidizing agent in an amount of at least 1 approximately equimolar amount, preferably 1 to 2 moles, of deoxidizing agent per moles of the compound of formula (II).
Eksempler på passende deoksyderende midler omfatter alkalimetall hydroksyder som f.eks. natriumhydroksyd, kaliumhydroksyd, etc, uorganiske karbonater som f.eks. natriumkarbonat, kaliumkarbonat, kaliumhydrogenkarbonat, natriumhydrogenkarbonat, etc, tertiære aminer som f.eks. pyridin, kinolin, trietylamin, Examples of suitable deoxidising agents include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc., inorganic carbonates such as sodium carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc, tertiary amines such as pyridine, quinoline, triethylamine,
etc. etc.
Med hensyn til de benzoheterocykliske forbindelser med formel (II) som kan anvendes som utgangsmaterial for fremstilling av forbindelsene med formel (I), er enkelte av dem kjente forbindelser- som beskrevét i US patentskrift nr. 3.917.609, 3.896.131, 3.985.882, 3.969.463, 4u001.243;og 4.014.877 mens andre forbindelser er nye og kan fremstilles ved hjelp av det etterfølgende reaksjonsskjema 1. På den annen side er forbindelsene med formel (III), et annet utgangsmaterial for fremstilling av de n/e forbindelser med formel (I), kjente forbindelser og kan fås i handelen eller kan lett fremstilles ved hjelp av konvensjonelle prosesser fra kommersielt tilgjengelig piperazfn. With regard to the benzoheterocyclic compounds of formula (II) which can be used as starting material for the preparation of the compounds of formula (I), some of them are known compounds - as described in US patent documents no. 3,917,609, 3,896,131, 3,985. 882, 3,969,463, 4,001,243 and 4,014,877 while other compounds are new and can be prepared using the following reaction scheme 1. On the other hand, the compounds of formula (III) are another starting material for the preparation of the n /e compounds of formula (I), known compounds and are commercially available or can be easily prepared by conventional processes from commercially available piperazfn.
I de ovenstående formler (II), (IV), (V), (VI) og (VII), har R'1", R<2>, R<4>, R5 og n den tidligere angitte betydning og R^ og , som kan være like eller forskjellige, står hver for en lavere alkylgruppe. In the above formulas (II), (IV), (V), (VI) and (VII), R'1", R<2>, R<4>, R5 and n have the previously indicated meaning and R^ and , which may be the same or different, each represent a lower alkyl group.
I reaksjonsskjerna - 1 ovenfor er de forbindelser med formel (IV) og som anvendes som et utgangsmaterial, og hvori R står for et halogenatom, kjente forbindelser som beskrevet i de tidligere nevnte US patentskrifter, videre Bayer, Annalen 278, 105 In the reaction core - 1 above, the compounds of formula (IV) and which are used as a starting material, and in which R stands for a halogen atom, are known compounds as described in the previously mentioned US patents, further Bayer, Annalen 278, 105
(1894), Schmidt og Sitward, Berichte 45, 1979 (1912), etc. eller kan lett fremstilles ved hjelp av kjente prosesser beskrevet deri, mens de forbindelser hvori R<5> står for en lavere alkansulf onyloksygruppe eller en arylsulfonyloksygruppe er nye forbindelser og kan lett fremstilles i samsvar med den fremgangsmåte som er vist i reaksjonsskjerna - 2 vist i det folgende. (1894), Schmidt and Sitward, Berichte 45, 1979 (1912), etc. or can be readily prepared by known processes described therein, while those compounds in which R<5> represents a lower alkanesulfonyloxy group or an arylsulfonyloxy group are new compounds and can be easily prepared in accordance with the method shown in reaction core - 2 shown below.
På den annen side er forbindelsene med formel (V), et annet mulig utgangsmaterial, kjente forbindelser og kan fås i handelen. On the other hand, the compounds of formula (V), another possible starting material, are known compounds and are commercially available.
Videre kan også forbindelsene med formel (IV) hvori R<5> står for et halogenatom lett fremstilles i samsvar med fremgangsmåten vist i det etterfolgende reaksjonsskjerna - 2. Furthermore, the compounds of formula (IV) in which R<5> stands for a halogen atom can also be easily prepared in accordance with the method shown in the following reaction core - 2.
12 4 5 12 4 5
I de ovennevnte formler har R , R , R , R og n den samme betydning som nevnt ovenfor og R 8står for en lavere alkansulf onylgruppe eller en arylsulfonylgruppe og x står for et halogenatom. In the above formulas, R , R , R , R and n have the same meaning as mentioned above and R 8 represents a lower alkanesulfonyl group or an arylsulfonyl group and x represents a halogen atom.
Betegnelsen "lavere alkansulfonyl" som anvendt heri refererer til en rettkjedet eller forgrenet alkansulf onylgruppe med 1 til 4 karbonatomer som f.eks. en metansulfonylgruppe, en etan-sulfonylgruppe, en propansulfonylgruppe, en isopropansulfonyl-gruppe, en butansulfonylgruppe, en tert-butansulfonylgruppe o.l. The term "lower alkanesulfonyl" as used herein refers to a straight chain or branched alkanesulfonyl group of 1 to 4 carbon atoms such as a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group, an isopropanesulfonyl group, a butanesulfonyl group, a tert-butanesulfonyl group and the like.
Betegnelsen "arylsulfonyl" som anvendt heri refererer til en benzensulfonylgruppe, en naftalensulfonylgruppe o.l. Arylringen inkludert i arylsulfonylgruppen kan være substituert med et eller flere halogenatomer, en lavere alkylgruppe, en hydroksygruppe, en nitrogruppe o.l. Mer spesielt kan i henhold til reaksjonsskjema - 1 reaksjonen mellom forbindelsen med formel (IV) og forbindelsen med formel (V) gjennomføres i fravær av løsningsmidler eller i nærvær av løsningsmidler som f.eks. metanol, etanol, isopropanol, acetonitril, dimetylformamid, dimetylsulfoksyd, heksametylfosforsyre-triamid o.l., foretrukket i fravær av løsningsmidler. The term "arylsulfonyl" as used herein refers to a benzenesulfonyl group, a naphthalenesulfonyl group, and the like. The aryl ring included in the arylsulfonyl group can be substituted with one or more halogen atoms, a lower alkyl group, a hydroxy group, a nitro group, etc. More particularly, according to reaction scheme - 1, the reaction between the compound of formula (IV) and the compound of formula (V) can be carried out in the absence of solvents or in the presence of solvents such as e.g. methanol, ethanol, isopropanol, acetonitrile, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide and the like, preferably in the absence of solvents.
Forbindelsen med formel (V) kan anvendes i overskuddsmengder i forhold til en ekvimolar mengde av forbindelsen med formel (IV), foretrukket i en ekvimolar mengde i fravær av løsningsmiddel og i en mengde på fra 1,1 til 1,5 mol pr. mol av forbindelsen med formel (III) i nærvær av løsningsmidler. Reaksjonen kan generelt gjennomforgs ved en temperatur på fra romtemperatur The compound of formula (V) can be used in excess amounts in relation to an equimolar amount of the compound of formula (IV), preferably in an equimolar amount in the absence of solvent and in an amount of from 1.1 to 1.5 mol per moles of the compound of formula (III) in the presence of solvents. The reaction can generally be carried out at a temperature of from room temperature
(15 - 30°C) til 150 C, foretrukket 100 til 130°C, i lopet av (15 - 30°C) to 150°C, preferably 100 to 130°C, in the course of
et tidsrom fra 0,5 til 6 timer og gir derved lett forbindelsen representert ved formel (VI). a period of time from 0.5 to 6 hours, thereby readily yielding the compound represented by formula (VI).
Den etterfølgende ringslutningsreaksjon av den således oppnådde forbindelse med formel (VI) kan gjennomfores i samsvar med konvensjonelle ringslutningsreaksjoner, f.eks. ved oppvarming av forbindelsen med formel (VI) eller ved ringslutningsmetoder som anvender en sur substans som f.eks., fosforoksyklorid, fosfor-pentaklorid, fosfortriklorid, tionylklorid, konsentrert svovels/re, polyfosforsyre o.l. Når ringslutningen gjennomfbres ved oppvarming foretrekkes det å oppvarme forbindelsen med formel (VI) i et lbsningsmiddel som f.eks. hbytkokende hydrokarboner eller hbytkokende etere, f.eks. tetralin-difenyleter, diet/lenglykoldimetyleter, etc. ved en temperatur på 100 til 250°C, foretrukket 150 til 200°C i en periode på 0,5 til 6 timer. Når ringslutningen gjennomfores under anvendelse av en sur substans kan ringslutningen gjennomfores i nærvær av den sure substans i en mengde fra omtrent ekvimolar mengde til en stor overskuddsmengde, foretrukket 10 til 20 molart overskudd av syre i forhold til mengden av forbindelse med formel (VI) ved en temperatur på fra 100 til 150°C i et tidsrom av fra 0,5 til 6 timer, hvorved de bnskede forbindelser med formel (VII) fordelaktig kan fremstilles. The subsequent cyclization reaction of the thus obtained compound of formula (VI) can be carried out in accordance with conventional cyclization reactions, e.g. by heating the compound of formula (VI) or by cyclization methods that use an acidic substance such as, for example, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, concentrated sulphur, polyphosphoric acid, etc. When the ring closure is carried out by heating, it is preferred to heat the compound of formula (VI) in a solvent such as e.g. high-boiling hydrocarbons or high-boiling ethers, e.g. tetralin-diphenyl ether, diethylene glycol dimethyl ether, etc. at a temperature of 100 to 250°C, preferably 150 to 200°C for a period of 0.5 to 6 hours. When the ring closure is carried out using an acidic substance, the ring closure can be carried out in the presence of the acidic substance in an amount from about an equimolar amount to a large excess amount, preferably 10 to 20 molar excess of acid in relation to the amount of compound of formula (VI) by a temperature of from 100 to 150°C for a period of from 0.5 to 6 hours, whereby the desired compounds of formula (VII) can be advantageously prepared.
I det foregående reaksjonsskjerna - 1. kan hydrolysen av forbindelsen med formel (VII) til forbindelsen med formel (II) oppnås ved en konvensjonell hydrolysemetode i nærvær av en vanlig typisk hydrolysekatalysator, f.eks. en basisk forbindelse som f.eks. natriumhydroksyd, kaliumh/droksyd, bariumhydroksyd o.l., eller en uorganisk eller organisk syre som f.eks. svovelsyre, saltsyre, salpetersyre, eddiksyre, en aromatisk sulfon-s/re o.l. Hydrol/sen kan gjennomfbres i et lbsningsmiddel som f.eks. vann, metanol, etanol, isopropanol, aceton, metyletyl-keton, dioksan, etylenglykol, eddiks/re o.l. ved temperatur på fra romtemperatur til 200°C, foretrukket 50 til 150°C i et tidsrom på fra 0,5 til 6 timer, slik at man lett oppnår forbindelsen med formel (II). In the preceding reaction core - 1. the hydrolysis of the compound of formula (VII) to the compound of formula (II) can be achieved by a conventional hydrolysis method in the presence of a common typical hydrolysis catalyst, e.g. a basic compound such as sodium hydroxide, potassium hydroxide, barium hydroxide etc., or an inorganic or organic acid such as sulfuric acid, hydrochloric acid, nitric acid, acetic acid, an aromatic sulphonic acid, etc. Hydrol/sen can be carried out in a solvent such as e.g. water, methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, dioxane, ethylene glycol, vinegar, etc. at a temperature of from room temperature to 200°C, preferably 50 to 150°C for a period of from 0.5 to 6 hours, so that the compound of formula (II) is easily obtained.
I det foregående reaksjonsskjerna - 2 er en passende mengde av forbindelsen med formel (X) som skal omsettes med forbindelsen med formel (VIII) eller (IX) i det minste en omtrent ekvimolar mengde, idet foretrukket 1 til 2 mol av forbindelsen med formel (X) omsettes pr. mol av forbindelsen med formel (VIII) eller In the preceding reaction core - 2, a suitable amount of the compound of formula (X) to be reacted with the compound of formula (VIII) or (IX) is at least an approximately equimolar amount, preferably 1 to 2 mol of the compound of formula ( X) is traded per moles of the compound of formula (VIII) or
(IX). (IX).
Reaksjonen foregår vanligvis i et inert løsningsmiddel i nærvær The reaction usually takes place in the presence of an inert solvent
av et deoksydasjonsmiddel i en mengde på i det minste en omtrent ekvimolar mengde, foretrukket 1 til 2 mol, av det oksyderende middel pr. mol av forbindelsen med formel (VIII) eller (IX) ved en temperatur på fra 0 til 100°C, foretrukket ved romtemperatur i lopet av 0,5 til 6 timer og gir derved forbindelsen med formel (IV) eller (XII). of a deoxidizing agent in an amount of at least an approximately equimolar amount, preferably 1 to 2 mol, of the oxidizing agent per mol of the compound of formula (VIII) or (IX) at a temperature of from 0 to 100°C, preferably at room temperature over the course of 0.5 to 6 hours and thereby gives the compound of formula (IV) or (XII).
Eksempler på passende deoksydasjonsmidler omfatter alkalimetall-hydroksyder som f.eks. natriumhydroksyd, kaliumhydroksyd, etc, uorganiske karbonater som f.eks. natriumkarbonat, kalium- Examples of suitable deoxidising agents include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc., inorganic carbonates such as sodium carbonate, potassium
karbonat, kaliumhydrogenkarbonat, natriumhydrogenkarbonat, natriumhydrogenkarbonat, etc, tertiære aminer som f.eks. pyridin, kinolin, trietylamin, etc carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium hydrogen carbonate, etc, tertiary amines such as pyridine, quinoline, triethylamine, etc
Eksempler på passende inerte losningsmidler omfatter lavere alkoholer som f.eks. metanol, etanol, isopropanol, etc, etere Examples of suitable inert solvents include lower alcohols such as methanol, ethanol, isopropanol, etc, ethers
som f.eks. dioksan, tetrahydrofuran, diglym, etc, aromatiske hydrokarboner som f.eks. benzen, toluen etc., dimetylsulfoksyd, dimet/lformamid, heksametylfosforsyretriamid, pyridin, etc. like for example. dioxane, tetrahydrofuran, diglyme, etc., aromatic hydrocarbons such as benzene, toluene, etc., dimethylsulfoxide, dimethylformamide, hexamethylphosphoric acid triamide, pyridine, etc.
I reaksjonsskjerna - 2 ovenfor kan reduksjonen av forbindelsene med formel (XI) eller (XII) gjennomfores katalytisk eller ved å anvende et konvensjonelt hydrogenerende middel som f.eks. en kombinasjon av natriumborhydrid eller litiumaluminiumhydrid og en lavere fettsyre, f.eks. eddiksyre, trifluoreddiksyre, propionsyre, etc. In reaction core - 2 above, the reduction of the compounds of formula (XI) or (XII) can be carried out catalytically or by using a conventional hydrogenating agent such as e.g. a combination of sodium borohydride or lithium aluminum hydride and a lower fatty acid, e.g. acetic acid, trifluoroacetic acid, propionic acid, etc.
Passende mengder av natriumborhydrid eller litiumaluminiumhydrid Appropriate amounts of sodium borohydride or lithium aluminum hydride
og den lavere fetts yre er en mengde fra en omtrent ekvimolar mengde til en stor overskuddsmengde, foretrukket 3 til 5 mol pr. mol av forbindelsen med formel (XI) eller (XII). and the lower fatty acid is an amount from an approximately equimolar amount to a large excess amount, preferably 3 to 5 moles per mol. moles of the compound of formula (XI) or (XII).
Reduksjonsreaksjonen under anvendelse av et hydrogenerende middel kan foredelaktig foregå i et inert lbsningsmiddel som f.eks. The reduction reaction using a hydrogenating agent can advantageously take place in an inert solvent such as e.g.
etere som dioksan, tetrahydrofuran, diglym, etc, aromatiske hydrokarboner som f.eks. benzen, toluen, etc, lavere fetts/rer som f.eks. trifluoreddiksyre, propionsyre, etc. ved en ethers such as dioxane, tetrahydrofuran, diglyme, etc., aromatic hydrocarbons such as e.g. benzene, toluene, etc, lower fatty acids such as e.g. trifluoroacetic acid, propionic acid, etc. by a
temperatur på fra romtemperatur til 100°C, foretrukket 50 til 100°C i en ueriode på fra 1 til 6 timer. temperature of from room temperature to 100°C, preferably 50 to 100°C for a period of from 1 to 6 hours.
Forbindelsene med formel (I) kan også fremstilles ved hjelp av det etterfølgende reaksjonsskjerna - 2a The compounds of formula (I) can also be prepared using the following reaction nucleus - 2a
Reaksionsskjerna - 2a Reaction nucleus - 2a
hvori R og R' står for ot hydrogenatom eller en lavere alkyl-gruppe, f står for en aromatisk heterocyklisk ring inneholdende et tertiært nitrogenatom hvorigjennom den er forbundet eller • 12 står for en trialkylaminogruppe, Z står for et anion, og R , R , R^, R<*>, R^, R^, R^ og n har den ovennevnte betydning. in which R and R' represent a hydrogen atom or a lower alkyl group, f represents an aromatic heterocyclic ring containing a tertiary nitrogen atom through which it is connected or • 12 represents a trialkylamino group, Z represents an anion, and R , R , R^, R<*>, R^, R^, R^ and n have the above meaning.
I det ovennevnte reaksjonskjema - 2a kan reaksjonen mellom forbindelsen med (IV) og forbindelsen med formel (V) gjennomfores på samme måte som reaksjonen mellom forbindelsen med formel (IV) og forbindelsen med formel (V) beskrevet ovenfor. Ringslutningen av forbindelsen med formel (VI<1>) kan gjennomfores på samme måte som ringslutningen av forbindelsen med formel (VI) beskrevet ovenfor. Reaksjonen mellom forbindelsen med formel (VII<*>) og forbindelsen med formel (III) kan gjennomfores på samme måte som reaksjonen mellom forbindelsen med formel (II) og forbindelsen med formel (III). In the above reaction scheme - 2a, the reaction between the compound of (IV) and the compound of formula (V) can be carried out in the same way as the reaction between the compound of formula (IV) and the compound of formula (V) described above. The cyclization of the compound of formula (VI<1>) can be carried out in the same way as the cyclization of the compound of formula (VI) described above. The reaction between the compound of formula (VII<*>) and the compound of formula (III) can be carried out in the same way as the reaction between the compound of formula (II) and the compound of formula (III).
Fremstillingen av forbindelsene med formel (I) fra forbindelsen med formel (I<*>) kan gjennomfores ved oppvarming av forbindelsen med formel (I<1>) med en aromatisk heterocyklisk forbindelse som inneholder et tertiært nitrogenatom, eller et trialkylamin, og en anion-donorforbindelse i et passende inert lbsningsmiddel til å gi en forbindelse med formel (I") og hydrolysering av forbindelsen med formel (I") oppnådd derved etter isolering eller uten isolering derav. The preparation of the compounds of formula (I) from the compound of formula (I<*>) can be carried out by heating the compound of formula (I<1>) with an aromatic heterocyclic compound containing a tertiary nitrogen atom, or a trialkylamine, and an anion -donor compound in a suitable inert solvent to give a compound of formula (I") and hydrolyzing the compound of formula (I") obtained thereby after isolation or without isolation thereof.
I den ovennevnte reaksjon er eksempler på passende aromatiske heterocykliske forbindelser som inneholder et tertiært nitrogenatom usubstituert pyridin og alkylsubstituerte pyridin-forbindelser som f.eks. picoliner, lutidiner, etc, kinolin og alkylsubstituerte kinoliner som f.eks. kinaldin, lepidin, etc. In the above reaction, examples of suitable aromatic heterocyclic compounds containing a tertiary nitrogen atom are unsubstituted pyridine and alkyl-substituted pyridine compounds such as picolines, lutidines, etc, quinoline and alkyl-substituted quinolines such as e.g. quinaldine, lepidin, etc.
Eksempler på passende trialkylaminer omfatter trialkylaminer med 1 til 6 karbonatomer i hver alkyldel, som f.eks. trimetylamin, triet/lamin, tripropylamin, triisopropylamin, etc. Examples of suitable trialkylamines include trialkylamines with 1 to 6 carbon atoms in each alkyl moiety, such as e.g. trimethylamine, triet/lamine, tripropylamine, triisopropylamine, etc.
Eksempler på passende anion-donorforbindelser omfatter de forbindelser som kan donere et halogenion som f.eks. et jodion, et bromion, et klorion, etc. eller f.eks. jod, brom, klor eller de forbindelser som kan donere en sulfatrest, en fosfatrest, en perkloratrest, etc, f.eks. svovelsyre, fosforsyre, perklorsyre, etc. Examples of suitable anion-donor compounds include those compounds which can donate a halogen ion such as, for example an iodine ion, a bromine ion, a chlorine ion, etc. or e.g. iodine, bromine, chlorine or the compounds which can donate a sulfate residue, a phosphate residue, a perchlorate residue, etc., e.g. sulfuric acid, phosphoric acid, perchloric acid, etc.
Eksempler på passende inerte løsningsmidler som kan anvendes i den ovennevnte reaksjon omfatter lavere alkoholer som f.eks. metanol, etanol, isopropanol, etc, aromatiske hydrokarboner som f.eks. benzen, toluen, etc, etere som f.eks. tetrahydrofuran, dioksan, diglym, etc, dimetylsulf oksyd, dimetylf ormamid, heksametylfosforsyretriamid, pyridin, etc. Examples of suitable inert solvents which can be used in the above reaction include lower alcohols such as e.g. methanol, ethanol, isopropanol, etc., aromatic hydrocarbons such as benzene, toluene, etc., ethers such as tetrahydrofuran, dioxane, diglyme, etc., dimethylsulphoxide, dimethylformamide, hexamethylphosphoric acid triamide, pyridine, etc.
Den aromatiske heterocykliske forbindelse som inneholder det tertiære nitrogenatom og den anion-donerende forbindelse kan anvendes i overskuddsmengder utover den ekvimolare mengde i forhold til forbindelsene med formel (I<1>) foretrukket i en mengde på fra 1 til 2 mol pr. mol av forbindelsen med formel (I'). The aromatic heterocyclic compound containing the tertiary nitrogen atom and the anion-donating compound can be used in excess amounts beyond the equimolar amount in relation to the compounds of formula (I<1>), preferably in an amount of from 1 to 2 mol per moles of the compound of formula (I').
Reaksjonen kan vanligvis gjennomfores ved fra romtemperatur til omtrent 120°C, foretrukket 50 til 100°C i fra 30 min. til 6 timer. The reaction can usually be carried out at from room temperature to approximately 120°C, preferably 50 to 100°C for from 30 min. to 6 hours.
Hydrolysen av forbindelsen med formel (I") oppnådd på denne måte kan gjennomfores i et passende løsningsmiddel i fravær eller nærvær av et surt hydrolyserende middel eller et alkalisk hydrolyserende middel, foretrukket i nærvær av et slikt middel. The hydrolysis of the compound of formula (I") thus obtained can be carried out in a suitable solvent in the absence or presence of an acidic hydrolysing agent or an alkaline hydrolysing agent, preferably in the presence of such an agent.
Eksempler på passende alkaliske hydrolyserende midler som kan anvendes i den ovenstående hydrolysereaksjon omfatter alkali-metallhydroksyder som f.eks. natriumhydroksyd, kaliumhydroksyd, etc, jordalkalimetallhydroksyder, som f.eks. kalsiumhydroksyd, etc, ammon iumhydr oksyd og karbonater av disse metaller og ammonium. Examples of suitable alkaline hydrolyzing agents which can be used in the above hydrolysis reaction include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc., alkaline earth metal hydroxides, such as calcium hydroxide, etc., ammonium hydroxide and carbonates of these metals and ammonium.
Hydrolysen av forbindelsen med formel (I") kan også gjennomfores i et vandig medium i nærvær av et trialkylamin som f.eks. et lavere trialkylamin, f.eks. trimetylamin, trietylamin, etc. Eksempler på passende løsningsmidler som kan anvendes omfatter lavere alkoholer som f.eks. metanol, etanol, isopropanol, etc., aromatiske hydrokarboner som f.eks. benzen, toluen, etc, etere som f.eks. tetrahydrofuran, dioksan, diglym, etc, vann, pyridin, dimetylsulfoksyd, dimetylf ormamid, heksametylf osf orsyretriamid, etc. The hydrolysis of the compound of formula (I") can also be carried out in an aqueous medium in the presence of a trialkylamine such as a lower trialkylamine, e.g. trimethylamine, triethylamine, etc. Examples of suitable solvents which can be used include lower alcohols such as methanol, ethanol, isopropanol, etc., aromatic hydrocarbons such as benzene, toluene, etc., ethers such as tetrahydrofuran, dioxane, diglyme, etc., water, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric acid triamide, etc.
Hydrolysen kan vanligvis gjennomfores ved fra 20 til 150°C, foretrukket 80 til 120°C i lopet av fra 30 min. til 6 timer. The hydrolysis can usually be carried out at from 20 to 150°C, preferably 80 to 120°C in the course of from 30 min. to 6 hours.
Den ovennevnte hydrolyse kan påskyndes ved tilsetning av en lavere alkohol. The above hydrolysis can be accelerated by the addition of a lower alcohol.
Forbindelser med formel (I) hvori R 3 står for en lavere alkyl-gruppe, en lavere alkanoylgruppe, en benzoylgruppe, en lavere alkansulfonylgruppe, en p-toluensulfonylgruppe, en fenyl-lavere-alkyl-gruppe, eller en gruppe med den følgende formel Compounds of formula (I) in which R 3 represents a lower alkyl group, a lower alkanoyl group, a benzoyl group, a lower alkanesulfonyl group, a p-toluenesulfonyl group, a phenyl lower alkyl group, or a group of the following formula
(forbindelser med formel (lb) anfort i det folgende) kan også fremstilles ved å omsette forbindelser hvori R 3 står for et hydrogenatom (forbindelser med formel Ia i det etterfølgende) med en forbindelse med formel (XIII) i nærvær av et deoksydasjons-• middel. I de ovenstående formler har R 1, R 2 , R 4, n og X den samme betydning som definert ovenfor, og R Qstår for en lavere alkyl-gruppe, en lavere alkanoylgruppe, en benzoylgruppe, en Lavere alkansulfonylgruppe, en p-toluensulfonylgruppe, en fenyl-lavere-alkyl-gruppe eller en gruppe med den følgende formel (compounds of formula (lb) hereinafter) can also be prepared by reacting compounds in which R 3 stands for a hydrogen atom (compounds of formula Ia hereinafter) with a compound of formula (XIII) in the presence of a deoxidation medium. In the above formulas, R 1 , R 2 , R 4 , n and X have the same meaning as defined above, and R Q stands for a lower alkyl group, a lower alkanoyl group, a benzoyl group, a lower alkanesulfonyl group, a p-toluenesulfonyl group, a phenyl lower alkyl group or a group of the following formula
Forbindelsene med formel (I) fremstilt som beskrevet ovenfor The compounds of formula (I) prepared as described above
kan danne farmasoytisk tålbare salter med syrer når forbindelsen med formel (I) har en basisk gruppe, og de farmasoytisk tålbare syrer som kan anvendes for saltdannelsen kan være forskjellige organiske eller uorganiske syrer, f.eks. saltsyre, svovelsyre, salpetersyre, bromhydrogensyre, fosforsyre, eddiksyre, oksalsyre, malonsyre, ravsyre, maleinsyre, fumarsyre, eplesyre, mandelsyre, etansulfonsyre, p-toluensulfonsyre o.l. can form pharmaceutically acceptable salts with acids when the compound of formula (I) has a basic group, and the pharmaceutically acceptable acids which can be used for salt formation can be various organic or inorganic acids, e.g. hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, mandelic acid, ethanesulfonic acid, p-toluenesulfonic acid, etc.
De benzoheterocykliske forbindelser med formel (I) kan omdannes til et tilsvarende karboksylat ved å omsette karboksylsyren med en farmasoytisk tålbare basisk forbindelse. Eksempler på basiske forbindelser er uorganiske basiske forbindelser som natriumhydroksyd, kaliumhydroksyd, kalsiumhydroksyd, aluminium-hydroksyd, natriumbikarbonat o.l. og organiske basiske forbindelser som f.eks. morfolin, piperazin, pyridin, piperidin, etylamin, dimetylamin, trietylamin, anilin o.l. The benzoheterocyclic compounds of formula (I) can be converted into a corresponding carboxylate by reacting the carboxylic acid with a pharmaceutically acceptable basic compound. Examples of basic compounds are inorganic basic compounds such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, sodium bicarbonate etc. and organic basic compounds such as e.g. morpholine, piperazine, pyridine, piperidine, ethylamine, dimethylamine, triethylamine, aniline, etc.
Forbindelsene med formel (I) og salter derav oppnådd som beskrevet ovenfor kan isoleres fra de respektive reaksjons-blandinger etter fullfort reaksjon og kan renses ved hjelp av konvensjonelle metoder som f.eks. losningsmiddelekstråksjon, fortynning, utfelling, omkrystallisering, kolonnekromatografering o.l. The compounds of formula (I) and salts thereof obtained as described above can be isolated from the respective reaction mixtures after completion of the reaction and can be purified using conventional methods such as e.g. solvent extraction, dilution, precipitation, recrystallization, column chromatography, etc.
Forbindelsene med formel (I) og salter derav fremviser utmerket antimikrobiell aktivitet pa bred basis overfor grampositive og gramnegative bakterier ved lave konsentrasjoner. De er nyttige forbindelser som viser spesiell kraftig antibakteriell aktivitet mot Streptococcus, iøseudomonas, Enterobacter, etc. overfor hvilke konvensjonelle syntetiske antibakterielle midler ikke er effektive eller bare litt effektive. I tillegg viser de en hoy antibakteriell aktivitet mot koliforme basiller, stafylokokker, etc. som er vesentlige kilder til infeksjonssykdommer og forbindelsene er også effektive mot Serratia, Krebsiella etc. som også bevirker infeksjonssykdommer som nylig er blitt viet bred oppmerksomhet og forbindelsene er for meget klinisk nyttige. The compounds of formula (I) and salts thereof exhibit excellent broad-based antimicrobial activity against gram-positive and gram-negative bacteria at low concentrations. They are useful compounds that show particularly strong antibacterial activity against Streptococcus, icesudomonas, Enterobacter, etc. against which conventional synthetic antibacterial agents are not effective or only slightly effective. In addition, they show a high antibacterial activity against coliform bacilli, staphylococci, etc. which are significant sources of infectious diseases and the compounds are also effective against Serratia, Krebsiella etc. which also cause infectious diseases which have recently been given wide attention and the compounds are for very clinical useful.
Forbindelsene med formel (I) er fordelaktige ikke bare på grunn av at de karakteriseres ved en bredspektret antimikrobiell og kraftig aktivitet, men også på grunn av at de ikke viser noen nedsettelse av antimikrobiell aktivitet men heller viser en tendens til okning i antimikrobiell aktivitet endog i nærvær av et serttm. Dette forhold er overraskende for den fagkyndige da det hittil er iakttatt at konvensjonelle farmasoytiske produkter med antimikrobiell aktivitet viser nedsatt aktivitet i nærvær av et serum. Dette tyder sterkt på at forbindelsene med formel (I) kan fremvise kraftig antimikrobiell aktivitet i blodet. The compounds of formula (I) are advantageous not only because they are characterized by a broad-spectrum antimicrobial and powerful activity, but also because they show no reduction in antimicrobial activity but rather show a tendency to increase in antimicrobial activity even in presence of a serttm. This situation is surprising to the person skilled in the art as it has been observed so far that conventional pharmaceutical products with antimicrobial activity show reduced activity in the presence of a serum. This strongly suggests that the compounds of formula (I) can exhibit strong antimicrobial activity in the blood.
Den orale giftighet av forbindelsene med formel (I) er meget The oral toxicity of the compounds of formula (I) is very high
lav i sammenligning med effektiv oral dosering, og forbindelsene har utmerket antimikrobiell aktivitet mot bakterier som er resistente eller har oppnådd resistens overfor konvensjonelle antibiotika som f.eks. penicillin, cefalosporin, ampicillin, streptomycin, erytromycin, kanamycin, nalidiksins/re, etc. low in comparison with effective oral dosing, and the compounds have excellent antimicrobial activity against bacteria that are resistant or have acquired resistance to conventional antibiotics such as e.g. penicillin, cephalosporin, ampicillin, streptomycin, erythromycin, kanamycin, nalidixins/re, etc.
Det vil være klart for den fagkyndige at forbindelsene med It will be clear to the person skilled in the art that the connections with
formel (I) kan eksistere i optisk aktive former. formula (I) may exist in optically active forms.
Ved bruk av forbindelsene med formel (I) og saltene derav som terapeutiske midler, kan forbindelsene sammensettes til farmasoytiske preparater sammen med vanlige farmasoytisk tålbare bærere, som f.eks. fortynningsmidler eller tilsetningsmidler som fyllstoffer, strekkmidler, bindemidler, fuktemidler, desintegrasjonsmidler, overflateaktive midler og smoremidler som vanligvis anvendes for fremstilling av preparater avhengig av typen av tilforselsformer. When using the compounds of formula (I) and their salts as therapeutic agents, the compounds can be compounded into pharmaceutical preparations together with usual pharmaceutical-tolerable carriers, such as e.g. diluents or additives such as fillers, extenders, binders, wetting agents, disintegrants, surface-active agents and lubricants which are usually used for the production of preparations depending on the type of supply forms.
Forskjellige tilforselsformer for de terapeutiske midler som et antimikrobielt middel kan velges alt etter terapiformålet. Different delivery forms for the therapeutic agents such as an antimicrobial agent can be chosen depending on the therapeutic purpose.
Typiske tilforselsformer som kan anvendes er tabletter, piller, pulvere, flytende preparater, suspensjoner, emulsjoner, granuler, kapsler, suppositorier og injiserbare preparater som losninger, suspensjoner, etc. Typical administration forms that can be used are tablets, pills, powders, liquid preparations, suspensions, emulsions, granules, capsules, suppositories and injectable preparations such as solutions, suspensions, etc.
Mengden av forbindelse med formel (I) og de farmasoytisk tålbare salter derav som en aktiv bestanddel som skal inneholdes i et farmasoytisk preparat egnet som et antimikrobielt middel er ikke spesielt begrenset og kan variere innen vide grenser. En passende terapeutisk effektiv mengde av forbindelsen med den generelle formel (I) og de farmasoytisk tålbare salter derav er vanligvis fra 1 til 70 vekt*, fortrukket 5 til 50 vekt*, basert The amount of compound of formula (I) and the pharmaceutically acceptable salts thereof as an active ingredient to be contained in a pharmaceutical preparation suitable as an antimicrobial agent is not particularly limited and may vary within wide limits. A suitable therapeutically effective amount of the compound of general formula (I) and the pharmaceutically acceptable salts thereof is usually from 1 to 70 weight*, preferably 5 to 50 weight*, based
på det totale preparat. on the total preparation.
Der er ingen spesiell begrensning med hensyn til tilforselsmåten for det terapeutiske middel og dette kan tilfores på hvilken som helst måte egnet for de spesielle former av det terapeutiske middel, f.eks. tilfores tabletter, piller, flytBnde preparater, suspensjoner, emulsjoner, granuler og kapsler oralt og injiserbare preparater tilfores intravenost enten alene eller sammen med vanlige hjelpemidler som f.eks. glukose og aminosyrer. Om nbdvendig kan det terapeutiske middel tilfores i seg selv intra muskulært, intra-Jsutant, subkutant eller intra peritonealt. Suppositorier tilfores intra rectalt og salver påfores på huden. There is no particular limitation with respect to the method of administration of the therapeutic agent and this may be administered in any manner suitable for the particular forms of the therapeutic agent, e.g. Tablets, pills, liquid preparations, suspensions, emulsions, granules and capsules are administered orally and injectable preparations are administered intravenously either alone or together with common aids such as e.g. glucose and amino acids. If necessary, the therapeutic agent itself can be administered intramuscularly, intrajustantly, subcutaneously or intraperitoneally. Suppositories are administered intrarectally and ointments are applied to the skin.
Doseringen av det antimikrobielle middel velges alt etter formålet med hensyn til bruka symptomer, etc. og vanligvis foretrekkes tilforsel av forbindelser med formel (I) på fra 10 mg til 5 g/kg legemsvekt pr. dogn i form av 3 til 4 deldoser. The dosage of the antimicrobial agent is chosen according to the purpose with regard to the symptoms used, etc. and usually the preferred supply of compounds of formula (I) is from 10 mg to 5 g/kg body weight per dogn in the form of 3 to 4 partial doses.
I. Antimikrobiell aktivitet I. Antimicrobial activity
1. Test- metode 1. Test method
Den antimikrobielle aktivitet av f olgende test-forbindelser på forskjellige test-organismer gjengitt i det etterfolgende ble bestemt ved hjelp av serie-fortynningsmetode på agarplate The antimicrobial activity of the following test compounds on various test organisms listed below was determined using the serial dilution method on agar plates
(Heart Infusion Agar fremstilt av Difco Co.) (se CHEMOTH ER APY 22, side 1126 - 1128 (1974)) og de minste inhiberende konsentrasjoner (mcg/ml) oppnådd er vist i det etterfolgende tabell 1. (Heart Infusion Agar manufactured by Difco Co.) (see CHEMOTH ER APY 22, pages 1126 - 1128 (1974)) and the minimum inhibitory concentrations (mcg/ml) obtained are shown in the following Table 1.
En prove av hver test-organisme ble fremstilt slik at popula-sjonen av organismen var 1 x 10 Q celler/ml (O.D. 660 my = 0,07 til 0,16) og 1 x 10^ cller/ml (oppnådd ved fortynning av det ovennevnte 1 x 10 Q celler/ml preparat). A sample of each test organism was prepared so that the population of the organism was 1 x 10 Q cells/ml (O.D. 660 my = 0.07 to 0.16) and 1 x 10 3 cells/ml (obtained by dilution of the above 1 x 10 Q cells/ml preparation).
3. Test- forbindelse 3. Test connection
(II) Innvirkning av tilsetning av heste-serum på den minste (II) Effect of addition of horse serum on the smallest
inhiberende konsentrasjon av kinolin-derivater. inhibitory concentration of quinoline derivatives.
Den minste inhiberende konsentrasjon av test-forbindelsene A, The minimum inhibitory concentration of the test compounds A,
C og F på forskjellige test-organismer vist i tabell 3 ble bestemt. Bestemmelsen ble gjennomfbrt ved å bedomme den minste inhiberende konsentrasjon av hver test-forbindelse ved serie-messig platemetode under anvendelse av dyrkingsmedium av "Heart Infusion Agar" (et produkt fra Difco Co.) inneholdende heste-resum med en endelig konsentrasjon på 0, 10, 20 eller 40 volum% med inoculum-stbrrelsen av hver test-organisme på IO<8> celler/ml (CHEMOTHERAPY, 22, side 1126 - 1128 (1974)). C and F on various test organisms shown in Table 3 were determined. The determination was carried out by judging the minimum inhibitory concentration of each test compound by serial plate method using culture medium of "Heart Infusion Agar" (a product of Difco Co.) containing horse serum with a final concentration of 0.10 , 20 or 40% by volume with the inoculum size of each test organism of 10<8> cells/ml (CHEMOTHERAPY, 22, pages 1126-1128 (1974)).
De oppnådde resultater er vist i den etterfolgende tabell 3. The results obtained are shown in the following table 3.
På samme måte som ovenfor ble den antimikrobielle aktivitet In the same way as above, it was antimicrobial activity
for de fblgende forbindelser mot forskjellige test-organismer som bevirker infeksjonssykdommer i fisk bestemt. De oppnådde resultater er vist i den etterfølgende tabell 2. for the following compounds against various test organisms that cause infectious diseases in specific fish. The results obtained are shown in the following table 2.
(III) Inaktiverings-forhold på grunn av protein fra human-serum. (III) Inactivation ratio due to protein from human serum.
En i/15 mol/l fosfat-buffer ble tilsatt til pulveret av A 1/15 mol/l phosphate buffer was added to the powder of
•Moni-Trol" 1 (dehydratisert preparat av human-serum, et produkt av Midori Juji Co., Ltd.) for fremstilling av en blanding med samme serum-proteinkonsentrasjon som naturlig human-serum og dette preparat ble merket "100% human-serum", og en del av "100% human-serum"-preparatet ble blandet med samme volum av bufferen for å fremstille "50% human-serum" og en annen del ble blandet med det firedobbelte volum av buffer for fremstilling av "20% human-serum". •Moni-Trol" 1 (dehydrated preparation of human serum, a product of Midori Juji Co., Ltd.) for the preparation of a mixture with the same serum protein concentration as natural human serum and this preparation was labeled "100% human serum", and one part of the "100% human serum" preparation was mixed with the same volume of the buffer to make "50% human serum" and another part was mixed with the quadruple volume of buffer to make "20 % human serum".
Hver av test-forbindelsene A og E ble opplost i en passende Each of the test compounds A and E was dissolved in an appropriate
mengde av de ovennevnte serum-préparater siik at slutt-konsentrasjonene var 12,5 ug/ml og 3,1 ug/ml. Etter inkubasjon av de resulterende preparater ved 37°C i 2 timer, ble mengden av aktiv komponent bedomt ved å bestemme aktiviteten av test-forbindelsen i human-serumet mot Escherichia coli As-19 quantity of the above-mentioned serum preparations such that the final concentrations were 12.5 ug/ml and 3.1 ug/ml. After incubation of the resulting preparations at 37°C for 2 hours, the amount of active component was assessed by determining the activity of the test compound in the human serum against Escherichia coli As-19
(Inoculum storrelse: 10 celler/ml). (Inoculum size: 10 cells/ml).
Inaktiverings-forholdet for test-forbindelsene A og E i human-serum ble beregnet i samsvar med folgende ligning: The inactivation ratio for the test compounds A and E in human serum was calculated in accordance with the following equation:
"hvori Co angir konsentrasjonen av test-forbindelse i fravær av serum og C konsentrasjonen av aktiv komponent i serumet. "where Co denotes the concentration of test compound in the absence of serum and C the concentration of active component in the serum.
De oppnådd resultater er vist i den etterfolgende tabell 4. The results obtained are shown in the following table 4.
Akutt giftighet Acute toxicity
Den akutte giftighet av forbindelsene med formel (I) ble bestemt ved intravenøs tilførsel (i.v.) i mus som ikke hadde fått tilført føde i 12 timer før testen. LD^Q-verdien (50% letal dose) som ble oppnådd var som følger. The acute toxicity of the compounds of formula (I) was determined by intravenous administration (i.v.) in mice that had not been fed for 12 hours before the test. The LD^Q value (50% lethal dose) obtained was as follows.
På samme måte somovenfor ble LD^Q-verdier for andre testforbindelser oppnådd og disse utgjorde 500 mg/kg eller mer. In the same manner as above, LD^Q values for other test compounds were obtained and these amounted to 500 mg/kg or more.
Oppsummert fremviser forbindelsene fremstilt i samsvar med oppfinnelsen overlegen antimikrobiell aktivitet, spesielt mot Pseudomonas, Streptococcus bg Enterobacter, sammenlignet med sammenligningsforbindelsene F og G. Forbindelsene fremstilt i samsvar med oppfinnelsen har videre lavt bindingsforhold med serum og nedsettelse av deres antimikrobielle virkning in vivo i nærvær av serum er bemerkelsesverdig lav, i sammenligning med sammenligningsforbindelsene. In summary, the compounds produced in accordance with the invention exhibit superior antimicrobial activity, especially against Pseudomonas, Streptococcus bg Enterobacter, compared to the comparative compounds F and G. The compounds produced in accordance with the invention further have low binding ratio with serum and reduction of their antimicrobial action in vivo in the presence of serum is remarkably low, compared to the comparator compounds.
Oppfinnelsen skal videre illustreres ved hjelp av de folgende undereksempler og hovedeksempler, og den antimikrobielle aktivitet av typiske forbindelser med formel (I) er også vist i eksemplene. Med mindre annet er angitt er alle deler, %-andeler og forhold på vektbasis. The invention shall be further illustrated by means of the following sub-examples and main examples, and the antimicrobial activity of typical compounds of formula (I) is also shown in the examples. Unless otherwise stated, all parts, percentages and ratios are by weight.
Med mindre annet er angitt ble elementaeranalyser utfort ved Unless otherwise stated, elemental analyzes were carried out by
en temperatur på 70 til 80°C ved redusert trykk (1 til 2 mmHg) a temperature of 70 to 80°C at reduced pressure (1 to 2 mmHg)
i 6 timer ved å anvende P2°5 som tor^emi^del. for 6 hours using P2°5 as tor^emi^del.
Undereksempel 1 Subexample 1
10 g 5-hydroksy-3,4-dihydrokarbostyril ble tilsatt til 100 ml metanol hvori det var opplost .3,8 g kaliumhydroksyd og blandingen ble omrort ved romtemperatur i 30 min. etterfulgt av fjernelse av metanol under redusert trykk. Benzen ble tilsatt til resten for å danne krystaller og deretter ble benzen fjernet ved avdamping. Den således oppnådde rest ble suspendert i 50 ml dimetylformamid og 10,6 g metansulfonylklorid ble tilsatt dråpevis til suspensjonen under isavkjoling og omroring. Etter tilsetning av 3,5 g metansulfonylklorid ble den resulterende blanding omrort ved romtemperatur i 4 timer. Etter fullfort reaksjon ble losningsmidlet fjernet under redusert trykk og resten ble renset ved hjelp av silikagel-kolonnékromatografering (silikagel:"Wako C-200", en handelsbetegnelse for et produkt fra Wako Junyaku Co., Ltd.; elueringsmiddel: kloroform). Omkrystallisering av det eluerte produkt fra vannholdig etanol ga 5,7 g 5-metan-sulfonyloksy-3,4-dihydrokarbostyril som farvelose prismåtiske krystaller med smp. 227 til 231°C. 10 g of 5-hydroxy-3,4-dihydrocarbostyril was added to 100 ml of methanol in which 3.8 g of potassium hydroxide had been dissolved and the mixture was stirred at room temperature for 30 min. followed by removal of methanol under reduced pressure. Benzene was added to the residue to form crystals and then benzene was removed by evaporation. The residue thus obtained was suspended in 50 ml of dimethylformamide and 10.6 g of methanesulfonyl chloride was added dropwise to the suspension under ice-cooling and stirring. After addition of 3.5 g of methanesulfonyl chloride, the resulting mixture was stirred at room temperature for 4 hours. After completion of the reaction, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (silica gel: "Wako C-200", a trade name for a product of Wako Junyaku Co., Ltd.; eluent: chloroform). Recrystallization of the eluted product from aqueous ethanol gave 5.7 g of 5-methane-sulfonyloxy-3,4-dihydrocarbostyril as colorless prismatic crystals with m.p. 227 to 231°C.
Undereksempel 2 Subexample 2
På samme måte som i undereksempel 1 ble dét oppnådd 5-(p-toluensulfonyloksy)-3,4-dihydrokarbostyril med et smp. 215 - 216°C. In the same way as in sub-example 1, 5-(p-toluenesulfonyloxy)-3,4-dihydrocarbostyril was obtained with a m.p. 215 - 216°C.
Undereksempel 3 Subexample 3
45 g 5-amino-3,4-dihydrokarbostyril ble suspendert i 250 ml 15% saltsyre og 2 50 ml vann hvori det var opplost 20 g natrium-nitrit ble tilsatt dråpevis til blandingen etterfulgt av omroring ved romtempetatur i 1 time. Den resulterende opplosning ble tilsatt dråpevis til en opplosning fremstilt ved opplosning av 41,2 g cuproklorid i 120 ml konsentrert saltsyre ved romtemperatur under omroring. Etter fullfort tilsetning ble blandingen oppvarmet på et vannbad ved 50 til 60°C i 1 time under omroring. Etter at blandingen hadde fått avkjole seg for utfelling av krystaller ble disse samlet ved filtrering og vasket med vann. De fuktige krystaller ble opplost i kloroform og uopploselige materialer ble fjernet ved filtrering. Resten ble torket over vannfritt natriumsulfat. Etter fjernelse av losningsmidlet, ble resten opplost ved hjelp av oppvarming og opplosningen ble behandlet med aktivkull i varm tilstand. Etanolopplosningen behandlet på denne måte ble inndampet under redusert trykk. Omkrys tallisering av konsentratet fra etanol ga 31,5 g 5-klor-3,4-dihydrokarbostyril med smp. 1<Q>3 - 194°C. 45 g of 5-amino-3,4-dihydrocarbostyril was suspended in 250 ml of 15% hydrochloric acid and 250 ml of water in which 20 g of sodium nitrite had been dissolved was added dropwise to the mixture followed by stirring at room temperature for 1 hour. The resulting solution was added dropwise to a solution prepared by dissolving 41.2 g of cuprous chloride in 120 ml of concentrated hydrochloric acid at room temperature with stirring. After complete addition, the mixture was heated on a water bath at 50 to 60°C for 1 hour with stirring. After the mixture had been allowed to cool for precipitation of crystals, these were collected by filtration and washed with water. The moist crystals were dissolved in chloroform and insoluble materials were removed by filtration. The residue was dried over anhydrous sodium sulfate. After removal of the solvent, the residue was dissolved by heating and the solution was treated with activated carbon in a hot state. The ethanol solution treated in this way was evaporated under reduced pressure. Recrystallization of the concentrate from ethanol gave 31.5 g of 5-chloro-3,4-dihydrocarbostyril with m.p. 1<Q>3 - 194°C.
Undereksempel 4 Subexample 4
42,5 g 5-klor-3,4-dihydrokarbostyril ble suspendert i 250 ml dioksan og 44,3 g NaBH^ ble tilsatt til suspensjonen. Deretter ble 67 ml eddiksyre (d=l,05) tilsatt dråpevis til blandingen ved romtemperatur. Etter, koking under tilbakelop av den resulterende blanding i 2 timer ble losningsmidlet fjernet under redusert trykk. Vann ble tilsatt til resten og uopploselige materialer ble fjernet ved filtrering etterfulgt av vasking med diet/leter. Resten ble ekstrahert med dietyleter, torket over vannfritt natriumsulfat og destillert under redusert trykk til å gi 36,0 g 5-klor-l,2,3,4-tetrahydrokinolin med kokepunkt 116 til 120°C/0,2 mmHg. 42.5 g of 5-chloro-3,4-dihydrocarbostyril was suspended in 250 ml of dioxane and 44.3 g of NaBH 2 was added to the suspension. Then 67 ml of acetic acid (d=1.05) was added dropwise to the mixture at room temperature. After refluxing the resulting mixture for 2 hours, the solvent was removed under reduced pressure. Water was added to the residue and insoluble materials were removed by filtration followed by washing with diethyl ether. The residue was extracted with diethyl ether, dried over anhydrous sodium sulfate and distilled under reduced pressure to give 36.0 g of 5-chloro-1,2,3,4-tetrahydroquinoline bp 116 to 120°C/0.2 mmHg.
Undereksempel 5 Subexample 5
4,5 g 5-metansulfonyloksy-3,4-dihydrokarbostyril ble suspendert i 90 ml dioksan og 35 g NaBH^ ble tilsatt til suspensjonen og deretter ble 5,3 ml eddiks/re tilsatt dråpevis til blandingen. Etter koking under tilbakelop av den resulterende blanding i 1 time ble losningsmidlet fjernet under redusert trykk. En mettet vandig losning av natriumbikarbonat ble tilsatt til resten for å danne bunnfall som ble frafiltrert og vasket med kloroform. Filtratet ble ekstrahert med kloroform og kloroform-laget ble torket over Na2SO^ etterfulgt av fjernelse av losningsmidlet. Resten ble renset ved hjelp av silikagel-kolonnekromatografering (silikagel:"Wako C-200" som er en handelsbetegnelse på et produkt fra Wako Junyaku Co., Ltd.; elueringsmiddel:kloroform) og det således oppnådde eluerte produkt ble krystallisert fra petroleter. Omkrysta!lisering av krystallene oppnådd på denne måte fra metanol ga 1, g 5-metansulfonyloksy-1,2,3,4-tetrahydrokinolin som farvelose prismer med smp. 74 til 76°C. 4.5 g of 5-methanesulfonyloxy-3,4-dihydrocarbostyryl was suspended in 90 ml of dioxane and 35 g of NaBH 2 was added to the suspension and then 5.3 ml of acetic acid was added dropwise to the mixture. After refluxing the resulting mixture for 1 hour, the solvent was removed under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to the residue to form a precipitate which was filtered off and washed with chloroform. The filtrate was extracted with chloroform and the chloroform layer was dried over Na 2 SO 4 followed by removal of the solvent. The residue was purified by silica gel column chromatography (silica gel: "Wako C-200" which is a trade name of a product of Wako Junyaku Co., Ltd.; eluent: chloroform) and the eluted product thus obtained was crystallized from petroleum ether. Recrystallization of the crystals thus obtained from methanol gave 1.g of 5-methanesulfonyloxy-1,2,3,4-tetrahydroquinoline as colorless prisms with m.p. 74 to 76°C.
Undereksempel 6 Subexample 6
På samme måte som i undereksempel 5 ble det oppnådd 5-(p-toluen-sulfon/loksy)-1,2,3,4-tetrahydrokinolin med smp. 112 til U3°C. In the same way as in sub-example 5, 5-(p-toluene-sulfone/oxy)-1,2,3,4-tetrahydroquinoline was obtained with m.p. 112 to U3°C.
Undereksempel 7 Subexample 7
5,5 g 4-klor-oksindol ble opplost i 80 ml dioksan og 6,2 g natriumborhydrid ble suspendert i den resulterende losning og 12,7 ml trif luoreddiksyre (d=l, 48) ,-ble tilsatt dråpevis dertil ved romtemperatur under omroring. Etter koking av blandingen under tilbakelop i 4,5 timer ble losningsmidlet fjernet derfra under redusert tr/kk. Vann ble tilsatt til resten og vannuopploselige materialer ble fjernet ved filtrering og vasket med dietyleter. Filtratet ble ekstrahert med dietyleter og eter-laget ble torket over vannfritt natriumsulfat ettsfulgt av fjernelse av losningsmidlet. Resten ble destillert under 5.5 g of 4-chlorooxindole was dissolved in 80 ml of dioxane and 6.2 g of sodium borohydride was suspended in the resulting solution and 12.7 ml of trifluoroacetic acid (d=1, 48) was added dropwise thereto at room temperature under agitation. After refluxing the mixture for 4.5 hours, the solvent was removed therefrom under reduced pressure. Water was added to the residue and water insoluble materials were removed by filtration and washed with diethyl ether. The filtrate was extracted with diethyl ether and the ether layer was dried over anhydrous sodium sulfate followed by removal of the solvent. The remainder was distilled below
redusert trykk til å gi 3,9 g 4-klorir.dol som et farvelost oljeaktig produkt med kokepunkt 135°C ved 10 mmHg. reduced pressure to give 3.9 g of 4-chloroirdol as a colorless oily product bp 135°C at 10 mmHg.
Undereksempel 8 Subexample 8
5 g natriumborhydrid ble tilsatt til 66 ml pyridin hvori det var opplost 4,4 g 2-met/l-4-klorindol. Til blandingen ble gradvis tilsatt 10,6 g av et finpulverisert aluminiumklorid under isavkjoling under omroring. Etter fullfort tilsetning ble blandingen omrort og fikk reagere ved romtemperatur i 2 7 timer. Losningsmidlet ble fjernet derfra under redusert trykk. Vann ble tilsatt til resten og blandingen ble ekstrahert med 100 ml benzen. Benzenlaget ble vasket med en mettet vandig natriumkloridlosning etterfulgt av inndamping. Til resten ble tilsatt en 10% vandig saltsyre som bevirket skumming. Etter at skummingen opphorte ble blandingen innstilt til noytral reaksjon ved en vandig natrium-karbonatlbsning etterfulgt av ekstråksjon av blandingen med 100 ml benzen. Benzenlaget ble torket over vannfritt natriumsulfat. Etter fjernelse av losningsmidlet under redusert trykk ble ekstrakten renset ved silikagel-kolonnekromatografering (elueringsmiddel: kloroform) til å gi 3,4 g 2-metyl-4-klorindol bekreftet ved hjelp av NMR. 5 g of sodium borohydride was added to 66 ml of pyridine in which 4.4 g of 2-meth/1-4-chloroindole had been dissolved. 10.6 g of a finely powdered aluminum chloride was gradually added to the mixture under ice-cooling with stirring. After complete addition, the mixture was stirred and allowed to react at room temperature for 27 hours. The solvent was removed therefrom under reduced pressure. Water was added to the residue and the mixture was extracted with 100 ml of benzene. The benzene layer was washed with a saturated aqueous sodium chloride solution followed by evaporation. A 10% aqueous hydrochloric acid was added to the residue, which caused foaming. After foaming ceased, the mixture was neutralized with an aqueous sodium carbonate solution followed by extraction of the mixture with 100 ml of benzene. The benzene layer was dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the extract was purified by silica gel column chromatography (eluent: chloroform) to give 3.4 g of 2-methyl-4-chloroindole confirmed by NMR.
Undereksempel 9 Subexample 9
21,6 g etyl-etoksymetylenmalonat ble tilsatt til 22,4 g 5-metansulfonyloksy-l,2,3,4-tetrahydrokinolin og blandingen ble oppvarmet ved 110°C på et oljebad i 30 min. under omroring, hvorunder det ble iakttatt av-destillasjon av etanol. Etter oppvarming ble 240 g polyfosforsyre fremstilt fra 120 g fosforsyre og 120 g fosforpentoksyd tilsatt til blandingen og blandingen fikk reagere på et oljebad ved 140°C i 45 min. Etter fullfort reaksjon fikk blandingen avkjble seg til romtemperatur og ble helt ut i 400 ml vann, etterfulgt av at blandingen ble innstilt til noytral reaksjon med en 40% vandig natriumhydroksyd-lbsning for utfelling av krystaller. De således oppnådde krystaller ble blandet med 150 ml av en 10% vandig natrium-hydroksydlbsning og blandingen ble kokt under tilbakelop i 40 min. 21.6 g of ethyl ethoxymethylene malonate was added to 22.4 g of 5-methanesulfonyloxy-1,2,3,4-tetrahydroquinoline and the mixture was heated at 110°C on an oil bath for 30 min. with stirring, during which de-distillation of ethanol was observed. After heating, 240 g of polyphosphoric acid prepared from 120 g of phosphoric acid and 120 g of phosphorus pentoxide were added to the mixture and the mixture was allowed to react in an oil bath at 140°C for 45 min. After complete reaction, the mixture was allowed to cool to room temperature and was poured into 400 ml of water, followed by the mixture being set to neutral reaction with a 40% aqueous sodium hydroxide solution to precipitate crystals. The crystals thus obtained were mixed with 150 ml of a 10% aqueous sodium hydroxide solution and the mixture was refluxed for 40 min.
hvorunder krystallene opploste seg til å danne en ensartet opplosning. Opplosningen ble behandlet med aktivkull i varm tilstand og filtrert. Filtratet fikk avkjble seg og ble innstilt til pH 2 for utfelling av krystaller som ble fra- during which the crystals dissolved to form a uniform solution. The solution was treated with activated charcoal in a hot state and filtered. The filtrate was allowed to cool and was adjusted to pH 2 to precipitate crystals which were
filtrert. Omkrystallisering av de rå krystaller oppnådd på filtered. Recrystallization of the crude crystals obtained on
denne måte fra dimetylformamid ga 21,3 g 8-metansulfonyloksy-6, 7-dihydro-l-okso-lH, 5H-benzo/ijj/kinolizin-2-karboksylsyre som hvite nåler med et smp. på 270 til 275°C. this way from dimethylformamide gave 21.3 g of 8-methanesulfonyloxy-6,7-dihydro-1-oxo-1H,5H-benzo[ijj]quinolizine-2-carboxylic acid as white needles with a m.p. at 270 to 275°C.
Undereksempel 10 Subexample 10
21,6 g etyl-etoksymetylenmalonat ble tilsatt til 30,0 g 5-(p-toluensulfonyloksy)-1,2,3,4-tetrahydrokinolin og blandingen ble oppvarmet ved 110°C på et oljebad i 30 min. under omroring, hvorunder avdestillering av etanol ble iakttatt. Etter oppvarming ble 240 g polyfosforsyre fremstilt fra 120 g fosforsyre og 120 g fosforpentoksyd tilsatt til blandingen og blandingen fikkreagere på et oljebad ved 140°C i 40 min. Etter fullfort reaksjon fikk blandingen avkjble seg til romtemperatur og ble helt ut i 400 ml vann, etterfulgt av at blandingen ble innstilt til noytral reaksjon med en 40% vandig natriumhydroksyd-lbsning for utfelling av kr/staller. De således oppnådde krystaller ble blandet med 150 ml av en 10% vandig natrium-hydroksydlbsning og blandingen ble kokt under tilbakelop i 40 min. hvorunder krystallene ble opplost til en ensartet losning. Lbsningen ble filtrert og filtratet fikk avkjble seg og ble innstilt til pH 2 for utfelling av krystaller som ble samlet ved filtrering. OmkrjStallisering av de rå krystaller oppnådd på 21.6 g of ethyl ethoxymethylene malonate was added to 30.0 g of 5-(p-toluenesulfonyloxy)-1,2,3,4-tetrahydroquinoline and the mixture was heated at 110°C on an oil bath for 30 min. with stirring, during which distillation of ethanol was observed. After heating, 240 g of polyphosphoric acid prepared from 120 g of phosphoric acid and 120 g of phosphorus pentoxide were added to the mixture and the mixture was allowed to react in an oil bath at 140°C for 40 min. After the reaction was complete, the mixture was allowed to cool to room temperature and was poured into 400 ml of water, followed by the mixture being adjusted to a neutral reaction with a 40% aqueous sodium hydroxide solution to precipitate NOK/stable. The crystals thus obtained were mixed with 150 ml of a 10% aqueous sodium hydroxide solution and the mixture was refluxed for 40 min. during which the crystals were dissolved into a uniform solution. The solution was filtered and the filtrate was allowed to cool and was adjusted to pH 2 to precipitate crystals which were collected by filtration. Circastalization of the raw crystals obtained on
denne måte fra dimetylformamid ga 27,4 g av en 8-(p-toluen-sulf onyloks/)-6, 7-dihydro-l-okso-lH,5H-benzo/i j/kinolizin-2-karboksylsyre som hvite nåler med et smp. på over 300°C. this way from dimethylformamide gave 27.4 g of a 8-(p-toluenesulfonyloxy)-6,7-dihydro-1-oxo-1H,5H-benzo[i]quinolizine-2-carboxylic acid as white needles with a m.p. of over 300°C.
Undereksempel 11 Subexample 11
4,4 g dietyl-etoks/met/lenmalonat ble tilsatt 3 g 4-klorindolin og blandingen ble oppvarmet på et oljebad ved 110 til 120°C hvorunder det ble iakttatt frigivelse av etanol. 20 g polyfosforsyre fremstilt fra 10 g fosforsyre og 10 g fosforpentoksyd 4.4 g of diethyl ethoxy/meth/lenmalonate was added to 3 g of 4-chloroindoline and the mixture was heated on an oil bath at 110 to 120°C during which the release of ethanol was observed. 20 g of polyphosphoric acid prepared from 10 g of phosphoric acid and 10 g of phosphorus pentoxide
ble tilsatt og blandingen ble oppvarmet på et oljebad ved 130 til 140°C i 40 min. Etter fullfort reaksjon fikk blandingen avkjole seg til 60°C, helt ut i vann og innstilt til noytral reaksjon med en 10% vandig natriumhydroksydlosning. De utfelte krystaller ble samlet ved filtrering og vasket med vann. De således behandlede krystaller ble blandet med 50 ml av en was added and the mixture was heated on an oil bath at 130 to 140°C for 40 min. After the reaction was complete, the mixture was allowed to cool to 60°C, poured into water and set to neutral reaction with a 10% aqueous sodium hydroxide solution. The precipitated crystals were collected by filtration and washed with water. The crystals thus treated were mixed with 50 ml of a
10% vandig natriumhydroksydlosning og blandingen ble kokt under tilbakelop på et oljebad i 1 time. Ettersom reaksjonen foregikk gikk blandingen over til en ensartet losning. Losningen ble behandlet med aktivkull i varm tilstand etterfulgt av filtrering. Filtratet ble innstilt til sur reaksjon med konsentrert saltsyre for utfelling av krystaller. Omkrystallisering av krystallene fra dimetylformamid ga 3,5 g 9-klor-6-okso-l,2-dihydro-6H-pyrrolo/3,2,l-ij/kinolin-5-karboksylsyre som hvite nåler med et smp. på 307,5°C (spalting). 10% aqueous sodium hydroxide solution and the mixture was refluxed in an oil bath for 1 hour. As the reaction proceeded, the mixture turned into a uniform solution. The solution was treated with activated charcoal in a hot state followed by filtration. The filtrate was adjusted to an acidic reaction with concentrated hydrochloric acid to precipitate crystals. Recrystallization of the crystals from dimethylformamide gave 3.5 g of 9-chloro-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid as white needles with a m.p. at 307.5°C (decomposition).
Undereksempel 12 Subexample 12
4,4 g dietyl-etoksymetylenmalonat ble tilsatt til 3,4 g 2-metyl-4-klorindolin og blandingen ble oppvarmet på et oljebad ved 110 til 120°C i 40 min. 20 g polyfosforsyre fremstilt fra 10 g fosforsyre og 10 g fosforpentoksyd ble tilsatt dertil og blandingen ble oppvarmet på et oljebad ved 130 til 140°C i 1 time. Etter fullfort reaksjon fikk blandingen avkjole seg til 60°C, ble helt ut i isblandet vann og innstilt til noytral reaksjon med en 10% vandig natriumhydroksydlosning. De utfelte krystaller ble samlet ved filtrering og vasket med vann. De således behandlede krystaller ble blandet med 50 ml av en 10% vandig natriumhydroksydlosning og blandingen ble oppvarmet under tilbakelop på et oljebad i 1 time. Ettersom reaksjonen foregikk endret blandingen seg til en ensartet losning. Losningen ble behandlet med aktivkull i varm tilstand etterfulgt av filtrering. Filtratet ble innstilt til sur reaksjon med konsentrert saltsyre for utfelling av krystaller. Omkrystallisering av produktet fra dimetylformamid ga 3,8 g 9-klor-2-metyl-6-okso-l,2-dihydro-6H-pyrrolo/3, 2,1-ij7kinolin-5-karboksylsyre som hvite nåler med et smp. på 288 til 290°C. 4.4 g of diethyl ethoxymethylene malonate was added to 3.4 g of 2-methyl-4-chloroindoline and the mixture was heated in an oil bath at 110 to 120°C for 40 min. 20 g of polyphosphoric acid prepared from 10 g of phosphoric acid and 10 g of phosphorus pentoxide was added thereto and the mixture was heated in an oil bath at 130 to 140°C for 1 hour. After the reaction was complete, the mixture was allowed to cool to 60°C, poured into ice-mixed water and set to neutral reaction with a 10% aqueous sodium hydroxide solution. The precipitated crystals were collected by filtration and washed with water. The crystals thus treated were mixed with 50 ml of a 10% aqueous sodium hydroxide solution and the mixture was heated under reflux in an oil bath for 1 hour. As the reaction proceeded, the mixture changed to a uniform solution. The solution was treated with activated charcoal in a hot state followed by filtration. The filtrate was adjusted to an acidic reaction with concentrated hydrochloric acid to precipitate crystals. Recrystallization of the product from dimethylformamide gave 3.8 g of 9-chloro-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij7quinoline-5-carboxylic acid as white needles with a m.p. of 288 to 290°C.
Undereksempel 13 Subexample 13
25 g etyl-etoksymetylenmalonat ble tilsatt til 21 g 5-klor-2-metyl-1,2,3,4-tetrahydrokinolin og blandingen ble oppvarmet på 25 g of ethyl ethoxymethylene malonate was added to 21 g of 5-chloro-2-methyl-1,2,3,4-tetrahydroquinoline and the mixture was heated at
et oljebad ved 110 til 120°C hvorunder avdestillering av etanol ble iakttatt. Etter oppvarming av blandingen ved samme temperatur som ovenfor i 30 min. ble 160 g polyfosforsyre fremstilt fra 80 g fosforsyre og 80 g fosforpentoksyd tilsatt dertil etterfulgt av oppvarming på et oljebad ved 130 til 140 C an oil bath at 110 to 120°C during which distillation of ethanol was observed. After heating the mixture at the same temperature as above for 30 min. 160 g of polyphosphoric acid was prepared from 80 g of phosphoric acid and 80 g of phosphorus pentoxide was added thereto followed by heating in an oil bath at 130 to 140 C
i 1 time. Etter fullfort reaksjon ble reaksjonsblandingen helt ut i 600 ml vann og den resulterende blanding ble gjort noytral med en 10% vandig natriumhydroksydlosning for utfelling av krystaller som ble samlet ved filtrering og blandet med 20 ml av en 10% vandig natriumhydroksydlosning og blandingen ble kokt under tilbakelop i 1 time hvorunder krystallene ble opplost til å danne en ensartet losning. Losningen ble behandlet med aktivkull i varm tilstand og filtrert. Filtratet fikk avkjole seg og pH ble innstilt med konsentrert saltsyre til pH 2 for utfelling av krystaller. Omkrystallisering av de derved oppnådde rå krystaller fra dimetylformamid ga 22 g 8-klor-5-metyl-6, 7-dihydro-l-okso-lH, 5H-benzo/ij/kinolizin-2-karboksylsyre som farvelose rombiske krystaller méd smp. 290 til 291°C. for 1 hour. After completion of the reaction, the reaction mixture was poured into 600 ml of water and the resulting mixture was neutralized with a 10% aqueous sodium hydroxide solution to precipitate crystals which were collected by filtration and mixed with 20 ml of a 10% aqueous sodium hydroxide solution and the mixture was refluxed for 1 hour during which time the crystals dissolved to form a uniform solution. The solution was treated with activated charcoal in a hot state and filtered. The filtrate was allowed to cool and the pH was adjusted with concentrated hydrochloric acid to pH 2 to precipitate crystals. Recrystallization of the thus obtained crude crystals from dimethylformamide gave 22 g of 8-chloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as colorless rhombic crystals with m.p. 290 to 291°C.
Undereksempel 14 Subexample 14
På samme måte som i undereksempel 13 ble det oppnådd 8-klor-6,7-dihydro-l-okso-lH,5H-benzo/ij/kinolizin-2-karboksylsyre som farvelose nåler med et smp. på ikke under 300°C. In the same way as in subexample 13, 8-chloro-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid was obtained as colorless needles with a m.p. of not less than 300°C.
Undereksempel 15 Subexample 15
9 g dietyl-etoksymetylenmalonat ble tilsatt til 9g 5-klor-l,2, 3,4-tetrahydrokarbazol og blandingen ble oppvarmet uten losningsmiddel ved 110°C på et oljebad i 30 min. under omroring hvorunder avdestillasjon av etanol ble iakttatt. Etter oppvarming ble 100 g pol/fosforsyre fremstilt fra 50 g fosforsyre og 50 g fosforpentoksyd tilsatt til blandingen og blandingen fikk reagere på et oljebad ved 140°C i 40 min. Etter fullfort reaksjon fikk blandingen avkjole seg til 60DC oc helt ut i 500 ml isblandet vann for utfelling av lysegule krystaller. De således dannede krystaller ble frafiltrert og vasket med tilstrekkelig vann etterfulgt av koking under tilbakelop med 100 ml av en 10% vandig NaOH-losning i 1 time. Krystallene ble opplost til å gi en ensartet losning som så ble behandlet med aktivkull i varm tilstand og pH i losningen ble innstilt til pH 2 med konsentrert saltsyre til å gi 9,3 g l-klor-7a,8, 9,10, 11,lla-heksahydro-4H-pyrido/3,2,1-j k/karbazol-4-okso-5-karboksylsyre som lysegule krystaller med et smp. på 273 til 275°C. 9 g of diethyl ethoxymethylene malonate was added to 9 g of 5-chloro-1,2,3,4-tetrahydrocarbazole and the mixture was heated without solvent at 110°C in an oil bath for 30 min. with stirring during which distillation of ethanol was observed. After heating, 100 g of pol/phosphoric acid prepared from 50 g of phosphoric acid and 50 g of phosphorus pentoxide was added to the mixture and the mixture was allowed to react in an oil bath at 140°C for 40 min. After complete reaction, the mixture was allowed to cool to 60°C and poured into 500 ml of ice-mixed water to precipitate pale yellow crystals. The crystals thus formed were filtered off and washed with sufficient water followed by refluxing with 100 ml of a 10% aqueous NaOH solution for 1 hour. The crystals were dissolved to give a uniform solution which was then treated with hot activated charcoal and the pH of the solution was adjusted to pH 2 with concentrated hydrochloric acid to give 9.3 g of l-chloro-7a,8,9,10,11 ,11a-hexahydro-4H-pyrido[3,2,1-j k]carbazole-4-oxo-5-carboxylic acid as pale yellow crystals with a m.p. of 273 to 275°C.
Undereksempel 16, Subexample 16,
21,6 g etyl-etoksymetylenacetoacetat ble tilsatt til 18 g 5-klor-2-met/l-l,2,3,4-tetrahydrokinolin og blandingen ble oppvarmet på et oljebad ved 120°C i 40 min. hvorunder avdestillasjon av etanol ble iakttatt. Deretter ble 100 g polyfosforsyre fremstilt fra 50 g fosforsyre og 50 g fosforpentoksyd tilsatt dertil etterfulgt av oppvarming av blandingen på et oljebad ved 140°C i 30 min. for reaksjon. Etter fullfort reaksjon fikk feaksjonsblandingen avkjole seg til 60°C og ble helt ut i 200 ml vann etterfulgt av innstilling av blandingen til pH 7 med en 40% vandig natriumhydroksydlosning for utfelling av krystaller. Omkrystallisering av de således oppnådde krystaller fra etanol-vann ga 15 g 8-klor-5-metyl-2-acetyl-6, 7-dihydro-l-okso-lH,5H-benzo/ij/kinolizin med smp. °C. 21.6 g of ethyl ethoxymethylene acetoacetate was added to 18 g of 5-chloro-2-meth/1-1,2,3,4-tetrahydroquinoline and the mixture was heated on an oil bath at 120°C for 40 min. during which distillation of ethanol was observed. Then 100 g of polyphosphoric acid was prepared from 50 g of phosphoric acid and 50 g of phosphorus pentoxide was added thereto followed by heating the mixture in an oil bath at 140°C for 30 min. for reaction. After complete reaction, the reaction mixture was allowed to cool to 60°C and poured into 200 ml of water followed by adjusting the mixture to pH 7 with a 40% aqueous sodium hydroxide solution to precipitate crystals. Recrystallization of the crystals thus obtained from ethanol-water gave 15 g of 8-chloro-5-methyl-2-acetyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine with m.p. °C.
Undereksempel 17 Subexample 17
8 g vannfritt piperazin ble tilsatt til 5 g 8-klor-5-metyl-2-acetyl-6,7-dihydro-l-okso-lH,5H-benzo/ijyT^inolizin. 70 ml heksamet/lfosforsyre-triamid ble tilsatt dertil og blandingen fikk reagere ved 140°C på et oljebad i 6 timer. Etter fullfort reaksjon ble eventuelt overskudd av løsningsmiddel og piperazin fjernet ved destillasjon under redusert trykk og 100 ml etylacetat 8 g of anhydrous piperazine was added to 5 g of 8-chloro-5-methyl-2-acetyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]T-inolyzine. 70 ml of hexameth/phosphoric acid triamide was added thereto and the mixture was allowed to react at 140°C in an oil bath for 6 hours. After the reaction was complete, any excess of solvent and piperazine was removed by distillation under reduced pressure and 100 ml of ethyl acetate
ble tilsatt til resten for utfelling av lysegule krystaller. was added to the residue to precipitate pale yellow crystals.
De således oppnådde krystaller ble fjernet ved filtrering og 300 ml vann ble tilsatt dertil etterfulgt av at den resulterende losning ble innstilt til pH 2 med IN saltsyre. Opplosningen ble oppvarmet og filtrert. Filtratet ble inndampet til 50 ml og gjort alkalisk med en 10% vandig natriumhydroksydlosning til å gi 3,2 g 8-(1-piperazinyl)-5-metyl-2-acetyl-6,7-dihydro-l-okso-1H,5H-benzo/ij/kinolizin. The crystals thus obtained were removed by filtration and 300 ml of water was added thereto followed by the resulting solution being adjusted to pH 2 with 1N hydrochloric acid. The solution was heated and filtered. The filtrate was evaporated to 50 ml and made alkaline with a 10% aqueous sodium hydroxide solution to give 3.2 g of 8-(1-piperazinyl)-5-methyl-2-acetyl-6,7-dihydro-1-oxo-1H, 5H-benzo/ij/quinolizine.
Hovedeksempel 1 Main example 1
19,2 g 8-klor-6,7-dihydro-l-okso-lH,5H-benzo/ij/kinolizin-2-karboksylsyre og 35,5 g piperazin ble tilsatt til 350 ml vannfritt dimetylsulfoksyd og blandingen ble oppvarmet på et oljebad ved 170 til 180°C i 6 timer under omroring. Etter fullfort reaksjon ble losningsmidlet fjernet under redusert trykk. 500 ml vann ble tilsatt til resten og pH-verdien i blandingen ble innstilt til pH 2 etterfulgt av frafiltrering av vannuopploselige materialer. Filtratet ble konsentrert til 100 ml under redusert trykk og gjort alkalisk (pH=9) med en 10% vandig natriumhydroksydlosning. Etter ekstrahering av den vandige alkalildsning med kloroform for derved å fjerne kloroform-opploselige materialer fikk det vandige alkali-opplosnings-lag stå for utfelling av krystaller som ble frafiltrert. De 19.2 g of 8-chloro-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid and 35.5 g of piperazine were added to 350 ml of anhydrous dimethylsulfoxide and the mixture was heated on a oil bath at 170 to 180°C for 6 hours with stirring. After the reaction was complete, the solvent was removed under reduced pressure. 500 ml of water was added to the residue and the pH of the mixture was adjusted to pH 2 followed by filtration of water insoluble materials. The filtrate was concentrated to 100 ml under reduced pressure and made alkaline (pH=9) with a 10% aqueous sodium hydroxide solution. After extracting the aqueous alkali solution with chloroform to thereby remove chloroform-soluble materials, the aqueous alkali solution layer was left to precipitate crystals which were filtered off. The
således oppnådde krystaller ble opplost i 10 ml av en 10% vandig natriumhydroksydlosning og opplosningen ble behandlet med aktivkull og innstilt til pH 8 med en 10% vandig saltsyrelosning for utfelling av krystaller som ble frafiltrert og vasket med tilstrekkelig vann. Omkrystallisering av krystallene fra dimetylformamid ga 6,5 g 8-(1-piperazinyl)-6,7-dihydro-l-okso-1H,5H-benzo/ij/kinolizin-2-karboksylsyre som hvite nåler med et smp. på 267 til 268°C. crystals thus obtained were dissolved in 10 ml of a 10% aqueous sodium hydroxide solution and the solution was treated with activated carbon and adjusted to pH 8 with a 10% aqueous hydrochloric acid solution to precipitate crystals which were filtered off and washed with sufficient water. Recrystallization of the crystals from dimethylformamide gave 6.5 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as white needles with a m.p. at 267 to 268°C.
Elementæranalyse for g°3N3 • 4H2° Elementary analysis for g°3N3 • 4H2°
Den ovennevnte elementæranalyse ble gjennomfort ved romtemperatur under redusert trykk (1 til 2 mmHg) i 6 timer under anvendelse av ^^ 0^ som torremiddel. The above-mentioned elemental analysis was carried out at room temperature under reduced pressure (1 to 2 mmHg) for 6 hours using ^^ 0^ as the drying agent.
6,4 g 8- (1-piperazinyl )-6, 7-dihydro-l-okso-lH, 5H-benzo/i jy7-kinolizin-2-karboksylsyre oppnådd på denne måte ble suspendert i 50 ml vann og 15 ml av en 10% vandig saltsyrelosning ble tilsatt til den resulterende losning. Etter fjernelse av de uopploselige materialer ved filtrering ble vann avdestillert til å gi 5,7 g 8- (1-piperazinyl)-6, 7-dihydro-l-oks-lH, 5H-benzo/i j_7_ kinolizin-2-karboksylsyre-hydroklorid som hvite amorfe i krystaller med et smp. på 300°C eller mer. 6.4 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[i]-quinolizine-2-carboxylic acid obtained in this way was suspended in 50 ml of water and 15 ml of a 10% aqueous hydrochloric acid solution was added to the resulting solution. After removal of the insoluble materials by filtration, water was distilled off to give 5.7 g of 8-(1-piperazinyl)-6,7-dihydro-1-ox-1H,5H-benzo[i]j_7_quinolizine-2-carboxylic acid- hydrochloride as white amorphous crystals with a m.p. of 300°C or more.
Elementæranalyse for C ^ H^g°3N3.HC1.H20 Elemental analysis for C ^ H^g°3N3.HC1.H20
Hovedeksempel 2 Main example 2
19,5 g 8-klor-5-metyl-6,7-dihydro-l-okso-lH,5H-benzo/ij7-kinolizin-2-karboksylsyre og 35,5 g piperazin ble tilsatt til 3 50 ml vannfritt dimetyl-sulfoksyd og blandingen ble oppvarmet på et oljebad ved 170 til 180°C i 6 timer under omroring. Behandling av reaksjonsblandingen på samme måte som i hovedeksempel 1 ga 5,3 g 8-(1-piperazinyl)-5-metyl-6,7-dihydro-l-okso-1H,5H-benzo/ijykinolizin-2-karboksylsyre-hydroklorid som hvite amorfe krystaller med smp. på 300°C eller mer. 19.5 g of 8-chloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij7-quinolizine-2-carboxylic acid and 35.5 g of piperazine were added to 350 ml of anhydrous dimethyl- sulfoxide and the mixture was heated on an oil bath at 170 to 180°C for 6 hours with stirring. Treatment of the reaction mixture in the same manner as in main example 1 gave 5.3 g of 8-(1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ylquinolizine-2-carboxylic acid hydrochloride as white amorphous crystals with m.p. of 300°C or more.
Elementæranalyse for C-^<g>^i°3N3-HC1 .^0 Elemental analysis for C-^<g>^i°3N3-HC1 .^0
3,8 g 8-(1-piperazinyl)-5-metyl-6,7-dihydro-l-okso-lH,5H-benzo-/ij_7kinolizin-2-karboksylsyre-hydroklorid ble tilsatt til 100 ml vann og IN vandig natriumhydroksydlosning ble tilsatt dertil etterfulgt av oppvarming av blandingen for å danne en ensartet losning. Losningen ble gjort alkalisk (pH=8) med fortynnet saltsyre til å gi 3,1 g 8-(1-piperazinyl)-5-metyl-6,7-dihydro-l-okso-lH, 5H-benzo/T.jJ7kinolizin-2-karboksylsyre som farvelose nåler med et smp. på 264 til 265°C. 3.8 g of 8-(1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo-[ij_7quinolizine-2-carboxylic acid hydrochloride was added to 100 ml of water and 1N aqueous sodium hydroxide solution was added thereto followed by heating the mixture to form a uniform solution. The solution was made alkaline (pH=8) with dilute hydrochloric acid to give 3.1 g of 8-(1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo/T.jJ7quinolizine -2-carboxylic acid as colorless needles with a m.p. of 264 to 265°C.
Elementæranalyse for C^8H21°3N3Elemental analysis for C^8H21°3N3
Hovedeksempel 3 Main example 3
På samme måte som i hovedeksempel 2 ble 8-(1-piperazinyl)-9-f luor-5-metyl-6, 7-dihydro-l-okso-lH, 5H-benzo/JijJ7kinolizin-2-karboksyls/re fremstilt. In the same way as in main example 2, 8-(1-piperazinyl)-9-fluoro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[1]quinolizine-2-carboxyl was prepared.
Hovedeksempel 4 Main example 4
4,0 g 8-klor-6,7-dihydro-l-okso-lH,5H-benzo/ijL7kinolizin-2-karboksylsyre og 4,6 g N-metylpiperazin ble tilsatt til 10 ml vannfritt dimetylsulfoksyd og blandingen ble oppvarmet på et oljebad ved 150 til 160°C i 8 timer under omroring. Etter fullfort reaksjon ble losningsmidlet og overskudd av N-metylpiperazin fjernet under redusert trykk og en blanding av metanol og dietyleter ble tilsatt for å danne bunnfall som ble fra- 4.0 g of 8-chloro-6,7-dihydro-1-oxo-1H,5H-benzo[ijL7quinolizine-2-carboxylic acid and 4.6 g of N-methylpiperazine were added to 10 ml of anhydrous dimethylsulfoxide and the mixture was heated on a oil bath at 150 to 160°C for 8 hours with stirring. After completion of the reaction, the solvent and excess N-methylpiperazine were removed under reduced pressure and a mixture of methanol and diethyl ether was added to form a precipitate which was
separert ved filtrering og vasket med dietyleter. De således oppnådde kr/staller ble suspendert i 20 ml av en 10% vandig saltsyrelosning og uopploselige materialer ble fjernet ved filtrering. Filtratet ble renset ved hjelp av kolonnekromatografering under anvendelse av "Amberlite LH-20" (en handelsbetegnelse for et produkt fra Tokyo Organic Chemical Industries Ltd.) (elueringsmiddel: vann, etanol). Omkrystallisering av eluatet fra dimetylformamid ga 1,0 g 8-(4-metyl-l-piperazinyl)-6,7-dihydro-l-okso-lH,5H-benzo/ii7kinolizin-2-karboksylsyre som lysegule plater med et smp. på 278 til 280,5°C. separated by filtration and washed with diethyl ether. The NOK thus obtained were suspended in 20 ml of a 10% aqueous hydrochloric acid solution and insoluble materials were removed by filtration. The filtrate was purified by column chromatography using "Amberlite LH-20" (a trade name of a product of Tokyo Organic Chemical Industries Ltd.) (eluent: water, ethanol). Recrystallization of the eluate from dimethylformamide gave 1.0 g of 8-(4-methyl-1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ii7quinolizine-2-carboxylic acid as pale yellow plates with a m.p. of 278 to 280.5°C.
Elementæranalyse for c^gH2i°3<N>3 Elemental analysis for c^gH2i°3<N>3
Hovedeksempel 5 Main example 5
4,4 g 8,10-diklor-6,7-dihydro-l-okso-lH,5H-benzo/ij/kinolizin-2-karboksylsyre og 4,5 g piperazin ble tilsatt til 10 ml vannfritt dimetylsulfoksyd og blandingen ble oppvarmet på et oljebad ved 160 til 170°C i 7 timer under omroring. Behandling av reaksjonsblandingen på samme måte som i hovedeksempel 4 ga 0, 9 g 8-(1-piperazin/l)-10-klor-6,7-dihydro-l-okso-lH,5H-benzo-/ijJ7kinolizin-2-karboksylsyre-hydroklorid som hvite amorfe krystaller med et smp. på 300°C eller mer. 4.4 g of 8,10-dichloro-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid and 4.5 g of piperazine were added to 10 ml of anhydrous dimethylsulfoxide and the mixture was heated in an oil bath at 160 to 170°C for 7 hours with stirring. Treatment of the reaction mixture in the same manner as in main example 4 gave 0.9 g of 8-(1-piperazine/l)-10-chloro-6,7-dihydro-1-oxo-1H,5H-benzo-[ijJ7quinolizine-2- carboxylic acid hydrochloride as white amorphous crystals with a m.p. of 300°C or more.
Elementæranalyse for C17H1803<N>3<C>1.HC1.H20Elemental analysis for C17H1803<N>3<C>1.HC1.H20
Hovedeksempler 6- 14 Main examples 6-14
På samme måte som beskrevet i hovedeksempel 1 til 5 ble folgende forbindelser med forskjellige substituenter vist i den etterfolgende tabell 5 fremstilt. Smeltepunktet og krystallformen av de resulterende produkter er også vist i den etterfolgende tabell 5. Elementæranalyse av forbindelsene fremstilt i samsvar med hovedeksemplene 6-14 er vist i den etterfølgende tabell 6. In the same way as described in main examples 1 to 5, the following compounds with different substituents shown in the following table 5 were prepared. The melting point and crystal form of the resulting products are also shown in the following Table 5. Elemental analysis of the compounds prepared in accordance with main examples 6-14 is shown in the following Table 6.
Hovedeksempel 15 Main example 15
19,1 g 8-(p-toluensulfonyloksy)-6,7-dihydro-l-okso-lH,5H-benzo/ii/kinolizin-2-karboksylsyre og 12,9 g piperazin ble tilsatt til 200 ml vannfritt dimetylsulfoksyd og blandingen ble oppvarmet i en autoklav under nitrogenstrom ved 10 atm. ved en temperatur på 150 til 160°C i 18 timer under omroring. Etter fullfort reaksjon ble losningsmidlet og overskudd av piperazin fjernet under redusert trykk og en blanding av metanol og etanol ble tilsatt til resten. De dannede bunnfall ble fraseparert ved filtrering og vasket med dietyleter. De således oppnådde krystaller ble suspendert i en blanding av 200 ml vann og 40 ml av en 10% vandig saltsyrelosning og uopploselige materialer ble fjernet ved filtrering. Filtratet ble gjort noytralt med mettet vandig opplosning av natriumbikarbonat og renset gjennom kolonnekromatografering under anvendelse av "Amberlite LH-20" 19.1 g of 8-(p-toluenesulfonyloxy)-6,7-dihydro-1-oxo-1H,5H-benzo[ii]quinolizine-2-carboxylic acid and 12.9 g of piperazine were added to 200 ml of anhydrous dimethylsulfoxide and the mixture was heated in an autoclave under nitrogen flow at 10 atm. at a temperature of 150 to 160°C for 18 hours with stirring. After the reaction was complete, the solvent and excess piperazine were removed under reduced pressure and a mixture of methanol and ethanol was added to the residue. The formed precipitates were separated by filtration and washed with diethyl ether. The crystals thus obtained were suspended in a mixture of 200 ml of water and 40 ml of a 10% aqueous hydrochloric acid solution and insoluble materials were removed by filtration. The filtrate was neutralized with saturated aqueous sodium bicarbonate and purified by column chromatography using "Amberlite LH-20"
(en haridelsbetegnelse for et produkt fra Tokyo Organic Chemical Industries, Ltd.) (elueringsmiddel: vann, etanol). Omkrystallisering av eluatet fra dimetylformamid ga 2,7 g 8-(1-piperazinyl)-6, 7-dihydro-l-okso-lH, 5H-benzo//i j7kinolizin-2-karboksylsyre som hvite nåler med et smp. på 267 til 268°C. (a trade name for a product of Tokyo Organic Chemical Industries, Ltd.) (eluent: water, ethanol). Recrystallization of the eluate from dimethylformamide gave 2.7 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[/i]quinolizine-2-carboxylic acid as white needles with a m.p. at 267 to 268°C.
Hovedeksempel 16 Main example 16
20,0 g 8-(p-nitrobenzensulfonyloksy)-6,7-dihydro-l-okso-lH, 5H-benzo/ijykinolizin-2-karboksylsyre og 12,9 g piperazin ble tilsatt til 200 ml vannfritt dimetylsulfoksyd og blandingen ble oppvarmet i en autoklav under nitrogenstrom ved 10 atm. ved en temperatur på 150 til 160°C i 17 timer under omroring. Behandling på samme r.åte som i hovedeksempel 15 ga 2,1 g 8-(1-piperazinyl)-6,7-dihydro-l-okso-lH,5H-benzo/i jJ7kinolizin-2-karboksylsyre som hvite nåler med et smp. på 267 til 268°C. 20.0 g of 8-(p-nitrobenzenesulfonyloxy)-6,7-dihydro-1-oxo-1H,5H-benzo[ylquinolizine-2-carboxylic acid and 12.9 g of piperazine were added to 200 ml of anhydrous dimethylsulfoxide and the mixture was heated in an autoclave under nitrogen flow at 10 atm. at a temperature of 150 to 160°C for 17 hours with stirring. Treatment in the same manner as in Main Example 15 gave 2.1 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[i]j7quinolizine-2-carboxylic acid as white needles with a m.p. at 267 to 268°C.
Hovedeksempel 17 Main example 17
15,4 g 8-metansulfon/loksyd-5-metyl-6,7-dihydro-l-okso-lH,5H-benzo/1 jJ7kinolizin-2-karboksylsyre og piperazin 12,9 g ble tilsatt til 200 ml vannfritt dimetylsulfoksyd og blandingen ble 15.4 g of 8-methanesulfonyloxide-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[l]quinolizine-2-carboxylic acid and piperazine 12.9 g were added to 200 ml of anhydrous dimethylsulfoxide and the mixture became
oppvarmet i en autoklav under nitrogenstrom ved 8 atm. ved en temperatur på 170 til 180°C i 20 timer under omroring. Behandling på samme måte som i hovedeksempel 15 ga 1,7 g 8-(1-piperazinyl)-5-metyl-6,7-dihydro-l-okso-lH,5H-benzo/l j/kinolizin-2-karboksyls/re-hydroklorid som hvite amorfe krystaller med et smp. på ikke under 300°C. heated in an autoclave under a stream of nitrogen at 8 atm. at a temperature of 170 to 180°C for 20 hours with stirring. Treatment in the same manner as in main example 15 gave 1.7 g of 8-(1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[l]quinolizine-2-carboxyls -hydrochloride as white amorphous crystals with a m.p. of not less than 300°C.
Hovedeksempel 18 Main example 18
18,5 g 8-benzensulfonyloksy-6,7-dihydro-l-okso-lH,5H-benzo-/ij7kinolizin-2~karboksylsyre og 12,9 g piperazin ble tilsatt til 200 ml vannfritt dimetylsulfoksyd og blandingen ble oppvarmet i en autoklav under nitrogenstrom ved 18 atm. ved en temperatur på 160 til 170°C i 20 timer under omroring. Behandling på samme måte som i hovedeksempel 15 ga 1,5 g 8-(l-piperazinyl)-6,7-dihydro-l-okso-lH,5H-benzo/Ij/kinolizin-2-karboksylsyre som hvite nåler med smp. på 267 til 268°C. 18.5 g of 8-benzenesulfonyloxy-6,7-dihydro-1-oxo-1H,5H-benzo-[ij7quinolizine-2-carboxylic acid and 12.9 g of piperazine were added to 200 ml of anhydrous dimethyl sulfoxide and the mixture was heated in an autoclave under nitrogen stream at 18 atm. at a temperature of 160 to 170°C for 20 hours with stirring. Treatment in the same manner as in main example 15 gave 1.5 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[I]/quinolizine-2-carboxylic acid as white needles with m.p. at 267 to 268°C.
Hovedeksempel 19 Main example 19
20,7 g 8-(o-metoksybenzensulfonyloksy)-5-metyl-6,7-dihydro-l-okso-lH, 5H-benzo</>ijL7kinolizin-2-karboksylsyre og 12,9 g piperazin ble tilsatt til 200 ml vannfritt dimetylsulfoksyd og blandingen ble oppvarmet i en autoklav under en nitrogenstrom ved 10 atm. ved en temperatur på 150 til 160°C i 18 timer under omroring. Behandling på samme måte som i hovedeksempel 17 ga 2,5 g 8-(l-piperazinyl)-5-metyl-6,7-dihydro-l-okso-lH,5H-benzo-/ix7kinolizin-2-karboksylsyre som hvite amorfe kr/staller med et smp. på ikke under 300°C. 20.7 g of 8-(o-methoxybenzenesulfonyloxy)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo</>ijL7quinolizine-2-carboxylic acid and 12.9 g of piperazine were added to 200 ml anhydrous dimethylsulfoxide and the mixture was heated in an autoclave under a stream of nitrogen at 10 atm. at a temperature of 150 to 160°C for 18 hours with stirring. Treatment in the same manner as in main example 17 gave 2.5 g of 8-(1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo-[ix]quinolizine-2-carboxylic acid as white amorphous NOK/stables with a smp. of not less than 300°C.
Hovedeksempler 20 - 26 Main examples 20 - 26
På samme måte som beskrevet i hovedeksempel 15 til 19 ble folgende forbindelser med forskjellige substituenter vist i den etterfølgende tabell 7 fremstilt. Snp. og krystallform av de resulterende produkter er også vist i tabell 7. In the same way as described in main examples 15 to 19, the following compounds with different substituents shown in the subsequent table 7 were prepared. Snp. and crystal form of the resulting products are also shown in Table 7.
Hovedeksempel 2 7 Main example 2 7
2,0 g 8-(1-piperazinyl)-6,7-dihydro-l-okso-lH, 5H-benzo/ii/- kinolizin-2-karboksylsyre og 1,2 g natriumhydrogenkarbonat ble tilsatt til 30 ml vann og blandingen ble omrort ved romtemperatur i 30 min. 5 ml aceton hvori det var opplost 1,0 g benzoylklorid ble tilsatt dråpevis til blandingen under isavkjoling etterfulgt av omroring ved den samme temperatur som ovenfor i 30 min. og deretter ved romtemperatur i 1,5 time for utfelling av krystaller, som ble separert ved filtrering og vasket med vann. Omkr/stallisering av de således oppnådde krystaller fra dimetylformamid ga 2,4 g 8-(4-benzo/l-l-piperazinyl) -6,7-dihydro-l-okso-lH,5H-benzo/ij/kinolizin-2-karboksylsyre som hvite nåler med smp. ikke lavere enn 300°C. 2.0 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ii]-quinolizine-2-carboxylic acid and 1.2 g of sodium bicarbonate were added to 30 ml of water and the mixture was stirred at room temperature for 30 min. 5 ml of acetone in which 1.0 g of benzoyl chloride had been dissolved was added dropwise to the mixture under ice-cooling followed by stirring at the same temperature as above for 30 min. and then at room temperature for 1.5 hours to precipitate crystals, which were separated by filtration and washed with water. Recrystallisation of the thus obtained crystals from dimethylformamide gave 2.4 g of 8-(4-benzo[l-l-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[l]quinolizine-2-carboxylic acid as white needles with m.p. not lower than 300°C.
Hovedeksempel 28 Main example 28
2,0 g 8-(1-piperazinyl )-6, 7-dihydro-l-okso-lH, 5H-benzo/ij.7-kinolizin-2-karboks/lsyre ble opplost i 20 ml vann hvori det var opplost 0,8 g kaliumhydroksyd og 0,8 g metansulfonylklorid ble tilsatt dråpevis til opplosningen. Den resulterende blanding fikk stå over natten ved den samme temperatur som ovenfor under omroring. De utfelte krystaller ble fraseparert ved filtrering og vasket med vann. De således behandlede krystaller ble opplost i IN vandig natriumhydroksydlosning og losningen ble behandlet med aktivkull og gjort noytral med en 10% vandig saltsyrelosning for utfelling av krystaller, som ble fraseparert ved filtrering og vasket med vann. Omkrystallisering av de således oppnådde kr/staller fra dimetylformanid ga 1,0 g 8-(4-metan-sulf onyl-l-piperazinyl) -6, 7-dihydro-l-okso-lH, 5H-benzo//i\ J-kinolizin-2-karboksylsyre som hvite nåler med et smp. på ikke under 300°C. 2.0 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij,7-quinolizine-2-carboxylic acid] were dissolved in 20 ml of water in which was dissolved 0 .8 g of potassium hydroxide and 0.8 g of methanesulfonyl chloride were added dropwise to the solution. The resulting mixture was allowed to stand overnight at the same temperature as above with stirring. The precipitated crystals were separated by filtration and washed with water. The crystals thus treated were dissolved in 1N aqueous sodium hydroxide solution and the solution was treated with activated charcoal and neutralized with a 10% aqueous hydrochloric acid solution to precipitate crystals, which were separated by filtration and washed with water. Recrystallization of the crystals thus obtained from dimethylformamide gave 1.0 g of 8-(4-methane-sulfonyl-1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo//i\ J -quinolizine-2-carboxylic acid as white needles with a m.p. of not less than 300°C.
Hovedeksempel 2 9 Main example 2 9
2,0 g 8-(1-piperazinyl)-6,7-dihydro-l-okso-lH,5H-benzo/ij7-kinolizin-2-karboksylsyre ble tilsatt til 20 ml vann hvori det var opplost 2,0 g kaliumkarbonat og blandingen ble omrort ved 2.0 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij7-quinolizine-2-carboxylic acid was added to 20 ml of water in which 2.0 g of potassium carbonate had been dissolved and the mixture was stirred at
romtemperatur i 30 min. Etter fullstendig opplosning av uopploselige materialer med tilsetning av 3 ml IN vandig natriumhydroksydlosning, ble 10 ml metanol hvori det var opplost 0,9 g benzylklorid tilsatt dråpevis til blandingen under isavkjoling. Etter fullfort tilsetning ble den resulterende blanding kokt under tilbakelop i 3 timer for å danne en ensartet losning. Den oppnådde losning ble behandlet med aktivkull i varm tilstand og gjort noytral med en 10% vandig saltsyre for utfelling av krystaller som ble separert ved filtrering og vasket med vann. Omkrystallisering av de således behandlede krystaller fra dimetylformamid ga 0,25 g 8-(4-benzyl-l-piperazinyl)-6,7-dihydro-l-okso-lH,SH-benzo/i jy'kinolizin-2-karboksylsyre med et smp. på 274 til 278°C. room temperature for 30 min. After complete dissolution of insoluble materials with the addition of 3 mL of 1N aqueous sodium hydroxide solution, 10 mL of methanol in which 0.9 g of benzyl chloride was dissolved was added dropwise to the mixture under ice-cooling. After complete addition, the resulting mixture was refluxed for 3 hours to form a uniform solution. The solution obtained was treated with activated carbon in a hot state and neutralized with a 10% aqueous hydrochloric acid to precipitate crystals which were separated by filtration and washed with water. Recrystallization of the thus treated crystals from dimethylformamide gave 0.25 g of 8-(4-benzyl-1-piperazinyl)-6,7-dihydro-1-oxo-1H,SH-benzo[i]quinolizine-2-carboxylic acid with a m.p. of 274 to 278°C.
Hovedeksempel 30 Main example 30
20 ml dimetylsulfoksyd ble tilsatt til en blanding av 3 g 9-klor-6-okso-l,2-dihydro-6H-pyrrolo/3,2,1-i jJ7kinolin-5-karboksylsyre og 6 g vannfritt piperazin og blandingen ble oppvarmet på et oljebad ved 140 til 150°C. Etter fullstendig reaksjon ble losningsmidlet fjernet derfra under redusert trykk og 50 ml vann ble tilsatt til resten for opplosning av denne. Opplosningen ble rystet med 100 ml kloroform og vannlaget ble fraskilt og behandlet med aktivkull. Den vandige losning ble gjort sur med en 10% vandig salts/re og filtrert. Filtratet ble pånytt behandlet ed aktivkull etterfulgt av inndampning. Tilsetning av metanol til konsentratet forte til krystaller som ble omkrystallisert fra etanol-vann til å gi 1,5 g 9-(1-piperazinyl)-6-okso-l,2-dihydro-6H-pyrrolo/3,2 , l-ii7-kinolin-5-karboksylsyre-hydroklorid som lysegule nåler med et smp. på 300°C eller mer. 20 ml of dimethylsulfoxide was added to a mixture of 3 g of 9-chloro-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-1]j7quinoline-5-carboxylic acid and 6 g of anhydrous piperazine and the mixture was heated in an oil bath at 140 to 150°C. After complete reaction, the solvent was removed therefrom under reduced pressure and 50 ml of water was added to the residue to dissolve it. The solution was shaken with 100 ml of chloroform and the aqueous layer was separated and treated with activated carbon. The aqueous solution was acidified with a 10% aqueous solution and filtered. The filtrate was treated again with activated carbon followed by evaporation. Addition of methanol to the concentrate gave rise to crystals which were recrystallized from ethanol-water to give 1.5 g of 9-(1-piperazinyl)-6-oxo-1,2-dihydro-6H-pyrrolo/3,2,1- ii7-quinoline-5-carboxylic acid hydrochloride as pale yellow needles with a m.p. of 300°C or more.
Elementæranalyse for <C>16<H>17°3<N>3<-H>C1•4H2°Elemental analysis for <C>16<H>17°3<N>3<-H>C1•4H2°
Hovedeksempel 31 Main example 31
20 ml dimetyl-sulfoksyd ble tilsatt til en blanding av 1,6 g 9-klor-2-metyl-6-okso-l, 2-dihydro-6H-pyrrolo/3, 2, l-ii7kinolin-5-karboksyls/re og 3 g vannfritt piperazin og blandingen ble oppvarmet på et oljebad ved 140 til 150°C i 6 timer. Etter fullfort reaksjon ble losningsmidlet fjernet derfra under redusert trykk og 50 ml vann ble tilsatt til resten for opplosning av denne. Opplosningen ble rystet med 100 ml kloroform og vannlaget ble fraseparert og behandlet med aktivkull. Den vandige losning ble gjort sur ved en 10% vandig saltsyrelosning og filtrert. Filtratet ble pånytt behandlet med aktivkull etterfulgt av inndampning. Tilsetning av etanol til konsentratet ga krystaller som ble omkrystallisert fra etanol-vann til. å gi 0,9 g 9-(1-piperazinyl)-2metyl-6-okso-l,2-dihydro-6H-pyrrolo/3,2,1-ij_7kinolin-5-karboksylsyre-hydroklorid som lysegule nåler med et smp. på 269 - 273°C (spalting). Elementæranalyse for g°3N3-HC1 -H20 20 ml of dimethyl sulfoxide was added to a mixture of 1.6 g of 9-chloro-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ii7quinoline-5-carboxyl] and 3 g of anhydrous piperazine and the mixture was heated on an oil bath at 140 to 150°C for 6 hours. After the reaction was complete, the solvent was removed therefrom under reduced pressure and 50 ml of water was added to the residue to dissolve it. The solution was shaken with 100 ml of chloroform and the aqueous layer was separated and treated with activated carbon. The aqueous solution was acidified with a 10% aqueous hydrochloric acid solution and filtered. The filtrate was treated again with activated carbon followed by evaporation. Addition of ethanol to the concentrate gave crystals which were recrystallized from ethanol-water to. to give 0.9 g of 9-(1-piperazinyl)-2methyl-6-oxo-1,2-dihydro-6H-pyrrolo/3,2,1-ij_7quinoline-5-carboxylic acid hydrochloride as pale yellow needles with a m.p. at 269 - 273°C (decomposition). Elemental analysis for g°3N3-HC1 -H20
Hovedeksempel 32 Main example 32
3,1 g l-klor-7a, 8, 9,10,11, lla-heksahydro-4H-pyrido/3, 2,1-jkJ-karbazol-4-okso-5-karboksylsyre ble blandet med 5 g vannfritt piperazin og 50 ml dimetylsulfoksyd og blandingen ble oppvarmet ved 140 til 150°C på et oljebad i 4 timer under omroring. Etter fullfort reaksjon ble losningsmidlet fjernet under redusert trykk. 200 ml vann og 200 ml kloroform ble tilsatt til resten og etter omrysting ble vannlaget fraseparert. Etter innstilling av pH-verdien i laget til en pH på 3 ble vannlaget filtrert. Filtratet ble behandlet med aktivkull og inndampet til å gi lysegult bunnfall. Bunnfallene ble vasket med en liten r.engde vann og torket til å gi 1,3 g 1-(1-piperazinyl)-7a,8,9,1C, 11, 1la- 3.1 g of 1-chloro-7a,8,9,10,11,11a-hexahydro-4H-pyrido[3,2,1-jkJ-carbazole-4-oxo-5-carboxylic acid was mixed with 5 g of anhydrous piperazine and 50 ml of dimethylsulfoxide and the mixture was heated at 140 to 150°C on an oil bath for 4 hours with stirring. After the reaction was complete, the solvent was removed under reduced pressure. 200 ml of water and 200 ml of chloroform were added to the residue and, after shaking, the aqueous layer was separated. After setting the pH value in the layer to a pH of 3, the water layer was filtered. The filtrate was treated with activated carbon and evaporated to give a pale yellow precipitate. The precipitates were washed with a small amount of water and dried to give 1.3 g of 1-(1-piperazinyl)-7a,8,9,1C,11,1la-
heksahydro-4H-p/rido/3 , 2 , l-jk7karbazo.l-4-okso-5-karboksylsyre-hydroklorid med et smp. på 289 til 294°C (spalting). hexahydro-4H-p/rido/3 , 2 , 1-jk7carbazo.1-4-oxo-5-carboxylic acid hydrochloride with a m.p. of 289 to 294°C (decomposition).
Elementæranalyse for <c>2o<H>23<N>3°3•<H>C1•3H2°Elemental analysis for <c>2o<H>23<N>3°3•<H>C1•3H2°
Hovedeksempel 33, Main example 33,
a) 3 g jod og 20 ml pyridin ble tilsatt til 2,75 g 8-(1-piperazinyl)-5-metyl-2-acetyl-6,7-dihydro-l-okso-lH, 5H-benzo/ijJTkinolizin og blandingen ble oppvarmet ved 100°C i 1 time. Etter fullfort reaksjon ble de utfelte krystaller fraseparert ved filtrering og vasket med 10 ml kold pyridin og 10 ml metanol til å gi 8-(1-piperazinyl)-5-metyl-6,7-dihydro-l-okso-lH, 5H-benzo/i j/kinolizin-2-karbonylmetylpyridiniumjodid. a) 3 g of iodine and 20 ml of pyridine were added to 2.75 g of 8-(1-piperazinyl)-5-methyl-2-acetyl-6,7-dihydro-1-oxo-1H,5H-benzo[ijJTquinolizine and the mixture was heated at 100°C for 1 hour. After completion of the reaction, the precipitated crystals were separated by filtration and washed with 10 ml of cold pyridine and 10 ml of methanol to give 8-(1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-1H, 5H- benzo/i j/quinolizine-2-carbonylmethylpyridinium iodide.
b) Produktet oppnådd under a) ovenfor tilsatt til 50 ml metanol og 50 ml av en 10% vandig natriumhydroksydlosning ble b) The product obtained under a) above added to 50 ml of methanol and 50 ml of a 10% aqueous sodium hydroxide solution was
tilsatt dertil og blandingen ble kokt under tilbakelop i 1 time. Etter fullfort reaksjon ble metanol fjernet ved avdestillering under redusert trykk etterfulgt av innstilling av konsentratet til pH 7 med IN saltsyre til å gi 1,8 g 8-(1-piperazinyl)-5-met/1-6,7-dihydro-l-okso-lH,5H-benzo/i jv^kinolizin-2-karboks/ls/re som farvelose nåler med et smp. på 264 til 265°C. added thereto and the mixture was refluxed for 1 hour. After completion of the reaction, methanol was removed by distillation under reduced pressure followed by adjustment of the concentrate to pH 7 with 1N hydrochloric acid to give 1.8 g of 8-(1-piperazinyl)-5-meth/1-6,7-dihydro-1 -oxo-1H,5H-benzo/i jv^quinolizine-2-carbox/ls/re as colorless needles with a m.p. of 264 to 265°C.
Den således oppnådde forbindelse ble omdannet til korresponderende s/resalt med salts/re til å gi 8-(1-piperazinyl)-5-metyl-6, 7-dihydro-l-okso-lH,5H-benzo/ii/ki noii zin-2-karboksylsyre-hydroklorid som hvite amorfe krystaller med et smp. på 300°C. The compound thus obtained was converted to the corresponding s/resalt with salt/re to give 8-(1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ii]ki noii zin-2-carboxylic acid hydrochloride as white amorphous crystals with a m.p. at 300°C.
Hovedeksempel 34 Main example 34
På samme måte som i hovedeksempel 33 ble 8-(1-piperazinyl)-6,7-dihydro-l-okso-lH,5H-benzo/ij7kinolizin-2-karboksylsyre oppnådd som hvite nåler med et smp. på 267 til 268°C. In the same manner as in main example 33, 8-(1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid was obtained as white needles with a m.p. at 267 to 268°C.
Hovedeksempel 3 5 Main example 3 5
På samme måte som i hovedeksempel 33 ble 8-(4-metyl-l-piperazinyl)-6,7-dihydro-l-okso-lH,5H-benzo/i jJ7kinolizin-2-karboksylsyre oppnådd som lysegule plate med et smp. på 278 til 280,5°C. In the same way as in main example 33, 8-(4-methyl-1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[i]j7quinolizine-2-carboxylic acid was obtained as pale yellow plates with a m.p. of 278 to 280.5°C.
Hovedeksempel 36 Main example 36
På samme måte som i hovedeksempel 33 ble 8-(1-piperazinyl)-10-klor-6,7-dihydro-l-okso-lH,5H-benzo/i j/kinolizin-2-karboksylsyre-hydroklorid oppnådd som hvite amorfe krystaller med et smp. på ikke under 300°C. In the same manner as in main example 33, 8-(1-piperazinyl)-10-chloro-6,7-dihydro-1-oxo-1H,5H-benzo[i]quinolizine-2-carboxylic acid hydrochloride was obtained as white amorphous crystals with a m.p. of not less than 300°C.
Hovedeksem<p>el 3 7 Main example<p>el 3 7
På samme måte som i hovedeksempel 33 ble 8-(4-benzoyl-l-piperazinyl)-6,7-dih/dro-l-okso-lH,5H-benzo/T.i/kinolizin-2-karboksylsyre oppnådd som hvite nåler med et smp. på ikke under 300°C. In the same manner as in main example 33, 8-(4-benzoyl-1-piperazinyl)-6,7-dih[dro-1-oxo-1H,5H-benzo[T.i]quinolizine-2-carboxylic acid was obtained as white needles with a m.p. of not less than 300°C.
Hovedeksempel 38 Main example 38
På . samme måte som i hovedeksempel 33 ble 8-(4-benzyl-l-piperazinyl)-6,7-dihydro-l-okso-lH,5H-benzo/ii7kinolizin-2-karboksylsyre oppnådd som lysegule flak med et smp. på 274 til 278°C. On . same way as in main example 33, 8-(4-benzyl-1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ii7quinolizine-2-carboxylic acid was obtained as pale yellow flakes with a m.p. of 274 to 278°C.
Hovedeksempel 3 9 Main example 3 9
På samme måte som i hovedeksempel 33 ble 9-(1-piperazinyl)-2-metyl-6-okso-l, 2-dihydro-6H-pyrrolo/3, 2,1-ij[/kinolin-5- . karboksylsyre-hydroklorid oppnådd som lysegule nåler med et smp. på 269 til 273°C. (spalting). In the same manner as in main example 33, 9-(1-piperazinyl)-2-methyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij[/quinoline-5- . carboxylic acid hydrochloride obtained as pale yellow needles with a m.p. of 269 to 273°C. (cleavage).
Hovedeksempel 40 Main example 40
På samme måte som i hovedeksempel 33 ble 9-(1-piperazinyl)-6-okso-1, 2-dihydro-6H-pyrrolo/3, 2 , l-ij_7kinolin-5-karboksylsyre-hydroklorid oppnådd som lysegule nåler med et smp. på ikke under 300°C. In the same manner as in main example 33, 9-(1-piperazinyl)-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij_7quinoline-5-carboxylic acid hydrochloride was obtained as pale yellow needles with a m.p. . of not less than 300°C.
Hovedeksempel 41 Main example 41
På samme måte som i hovedeksempel 33 ble 1-(1-piperazinyl)-7a,8, 9,10, 11,lla-heksahydro-4H-pyrido/3,2,l-jk7karbazol-4-okso-5-karboksylsyre-hydroklorid oppnådd med et smp. på 289 til 294°C. In the same way as in main example 33, 1-(1-piperazinyl)-7a,8,9,10,11,11a-hexahydro-4H-pyrido/3,2,1-jk7carbazole-4-oxo-5-carboxylic acid- hydrochloride obtained with a m.p. of 289 to 294°C.
(spalting). (cleavage).
Claims (1)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP10738778A JPS5576875A (en) | 1978-08-31 | 1978-08-31 | Benzo ij quinolizine-2-carboxylic acid derivative and its preparation |
JP13715778A JPS5564588A (en) | 1978-11-06 | 1978-11-06 | Pyrrolo (3, 2, 1-ij) quinoline-5-carboxylic acid derivative and its preparation |
JP14273178A JPS5569583A (en) | 1978-11-17 | 1978-11-17 | Pyrido 3,2,1-jk carbazole derivative |
Publications (3)
Publication Number | Publication Date |
---|---|
NO791224L NO791224L (en) | 1980-03-03 |
NO152788B true NO152788B (en) | 1985-08-12 |
NO152788C NO152788C (en) | 1985-11-20 |
Family
ID=27310966
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO791224A NO152788C (en) | 1978-08-31 | 1979-04-10 | ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PIPERAZINYLBENZOHETEROCYCLIC COMPOUNDS. |
Country Status (8)
Country | Link |
---|---|
AT (1) | AT376673B (en) |
DK (1) | DK160306C (en) |
ES (1) | ES480274A1 (en) |
FI (1) | FI66612C (en) |
MX (1) | MX6158E (en) |
NO (1) | NO152788C (en) |
PT (1) | PT69474A (en) |
SU (1) | SU993818A3 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2634122C1 (en) * | 2016-12-14 | 2017-10-24 | федеральное государственное автономное образовательное учреждение высшего образования "Казанский (Приволжский) федеральный университет" (ФГАОУ ВО КФУ) | Fluoroquinolones based on 4-deoxypyridoxine |
-
1979
- 1979-04-10 DK DK149379A patent/DK160306C/en not_active IP Right Cessation
- 1979-04-10 NO NO791224A patent/NO152788C/en unknown
- 1979-04-11 MX MX786779U patent/MX6158E/en unknown
- 1979-04-11 PT PT6947479A patent/PT69474A/en unknown
- 1979-04-11 AT AT269179A patent/AT376673B/en not_active IP Right Cessation
- 1979-04-11 ES ES480274A patent/ES480274A1/en not_active Expired
- 1979-04-11 FI FI791191A patent/FI66612C/en not_active IP Right Cessation
- 1979-04-11 SU SU792751555A patent/SU993818A3/en active
Also Published As
Publication number | Publication date |
---|---|
ES480274A1 (en) | 1980-02-01 |
DK160306B (en) | 1991-02-25 |
NO152788C (en) | 1985-11-20 |
PT69474A (en) | 1979-05-01 |
FI66612C (en) | 1984-11-12 |
DK160306C (en) | 1991-07-29 |
FI791191A (en) | 1980-03-01 |
SU993818A3 (en) | 1983-01-30 |
DK149379A (en) | 1980-03-01 |
FI66612B (en) | 1984-07-31 |
ATA269179A (en) | 1984-05-15 |
NO791224L (en) | 1980-03-03 |
AT376673B (en) | 1984-12-27 |
MX6158E (en) | 1984-11-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
FI70216C (en) | PROCEDURE FOR THE FRAMEWORK OF NYA 1-ETHYL-6-FLUORO-7- (3-SUBSTITUERAD-1-PYRROLIDINYL) -1,8-NAPHTHYRIDINE-3-CARBOXYL SYRADERATED ANVAENDBARA SOM ANTIBACTERIELLA MEDEL | |
US4017622A (en) | Piperazine derivatives | |
KR880001625B1 (en) | Process for the preparation of benzoheterocyclic compounds | |
KR910006806B1 (en) | Process for preparing quinaline derivatives | |
US4499091A (en) | 1-Amino (or substituted amino)-1,4-dihydro-4-oxo-6-fluoro-7-heterylquinoline-3-carboxylic acids and their use as antibacterial agents | |
US4416884A (en) | Piperazinylbenzoheterocyclic compounds | |
NO312032B1 (en) | New quinolone or naphthylidone carboxylic acid derivatives or salts thereof and their use | |
US3962443A (en) | Antibacterial pharmaceutical compositions and processes for preparation thereof | |
EP0090424B1 (en) | New quinolone compounds and preparation thereof | |
NO860199L (en) | INTERMEDIATES FOR THE PREPARATION OF 6,7-DISUBSTITUTED 1-CYCLOPROPYL-1,4-DIHYDRO-4-OXO-1,8-NAFTYRIDINE-3-CARBOXYL ACID. | |
CA1153374A (en) | Piperazinylbenzoheterocyclic compounds | |
CA2011939A1 (en) | 5-substituted-1,4-dihydro-4-oxo-naphthyridine-3-carboxylate antibacterial agents | |
JPH0141127B2 (en) | ||
CA1156232A (en) | Benzo(ij)quinolizine-2-carboxylic acid compounds, therapeutic composition containing same and process for producing same | |
NO309936B1 (en) | 2,7-Substituted octahydro-pyrrol [1,2-a] pyrazine derivatives, their use, pharmaceutical preparations, and intermediates for the preparation of the derivatives | |
JP2000508299A (en) | Substituted quinoline derivatives having antiviral activity | |
NO152788B (en) | ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PIPERAZINYLBENZOHETEROCYCLIC COMPOUNDS | |
US5753658A (en) | Quinolonecarboxylic acid derivatives | |
CS270600B2 (en) | Method of new quinoline derivatives production | |
JPH02191257A (en) | Benzo-heterocyclic compound | |
CA1074798A (en) | Vinyl derivatives and process for preparing them | |
JPH03223289A (en) | Thienoquinoline derivative, thienonaphthyridine derivative and salt thereof | |
SU1029829A3 (en) | Process for preparing derivatives of 1,8-naphthiridine or their pharmaceutically acceptable salts | |
EP0216323A2 (en) | Quinolonecarboxylic acid derivatives and their preparation | |
JPS622598B2 (en) |