NO142783B - ANALOGY PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTIC ACTIVE QUINOLIC ACID DERIVATIVES - Google Patents
ANALOGY PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTIC ACTIVE QUINOLIC ACID DERIVATIVES Download PDFInfo
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- NO142783B NO142783B NO752224A NO752224A NO142783B NO 142783 B NO142783 B NO 142783B NO 752224 A NO752224 A NO 752224A NO 752224 A NO752224 A NO 752224A NO 142783 B NO142783 B NO 142783B
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- 238000000034 method Methods 0.000 title claims description 5
- GJAWHXHKYYXBSV-UHFFFAOYSA-N pyridinedicarboxylic acid Natural products OC(=O)C1=CC=CN=C1C(O)=O GJAWHXHKYYXBSV-UHFFFAOYSA-N 0.000 title 1
- 230000001225 therapeutic effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 29
- -1 nitro- Chemical class 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims description 2
- 230000000802 nitrating effect Effects 0.000 claims description 2
- 150000002828 nitro derivatives Chemical class 0.000 claims description 2
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical group C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- KYGZCKSPAKDVKC-UHFFFAOYSA-N Oxolinic acid Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC2=C1OCO2 KYGZCKSPAKDVKC-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 238000002329 infrared spectrum Methods 0.000 description 8
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000000921 elemental analysis Methods 0.000 description 6
- 229960000321 oxolinic acid Drugs 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000004323 potassium nitrate Substances 0.000 description 4
- 235000010333 potassium nitrate Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000002211 ultraviolet spectrum Methods 0.000 description 4
- DZKGUVVWZUCSJU-UHFFFAOYSA-N 9-amino-5-ethyl-8-oxo-[1,3]dioxolo[4,5-g]quinoline-7-carboxylic acid Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=C(N)C2=C1OCO2 DZKGUVVWZUCSJU-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 241000588767 Proteus vulgaris Species 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 230000003385 bacteriostatic effect Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 229940007042 proteus vulgaris Drugs 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- DQWPFSLDHJDLRL-UHFFFAOYSA-N triethyl phosphate Chemical compound CCOP(=O)(OCC)OCC DQWPFSLDHJDLRL-UHFFFAOYSA-N 0.000 description 2
- KWKXRFWDBXQXGV-UHFFFAOYSA-N 5-ethyl-9-nitro-8-oxo-[1,3]dioxolo[4,5-g]quinoline-7-carboxylic acid Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=C([N+]([O-])=O)C2=C1OCO2 KWKXRFWDBXQXGV-UHFFFAOYSA-N 0.000 description 1
- SNHCYVGJJIKKNG-UHFFFAOYSA-N 8-oxo-5h-[1,3]dioxolo[4,5-g]quinoline-7-carboxylic acid Chemical compound C1=C2C(=O)C(C(=O)O)=CNC2=CC2=C1OCO2 SNHCYVGJJIKKNG-UHFFFAOYSA-N 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000193755 Bacillus cereus Species 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 238000005620 Bechamp reaction Methods 0.000 description 1
- 244000056139 Brassica cretica Species 0.000 description 1
- 235000003351 Brassica cretica Nutrition 0.000 description 1
- 235000003343 Brassica rupestris Nutrition 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000370 acceptor Substances 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940035674 anesthetics Drugs 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 108700039708 galantide Proteins 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 235000010460 mustard Nutrition 0.000 description 1
- MHWLWQUZZRMNGJ-UHFFFAOYSA-N nalidixic acid Chemical compound C1=C(C)N=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 MHWLWQUZZRMNGJ-UHFFFAOYSA-N 0.000 description 1
- 229960000210 nalidixic acid Drugs 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 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 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- KMIOJWCYOHBUJS-HAKPAVFJSA-N vorolanib Chemical compound C1N(C(=O)N(C)C)CC[C@@H]1NC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C KMIOJWCYOHBUJS-HAKPAVFJSA-N 0.000 description 1
- ZJVTYKZWDWVIFD-UHFFFAOYSA-N zinc;hydrochloride Chemical compound Cl.[Zn] ZJVTYKZWDWVIFD-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Foreliggende oppfinnelse vedrorer fremstilling av nye, i 5-stilling substituerte kinolinkarboksylsyre-derivater av den generelle formel (I) The present invention relates to the production of new quinoline carboxylic acid derivatives substituted in the 5-position of the general formula (I)
I den generelle formel (I) betyr In the general formula (I) means
X nitro-f amino-, C ^ alkanolylamino eller en C^_4 alkyl- X nitro-f amino-, C ^ alkanolylamino or a C^_4 alkyl-
anino = gruppe, N,N-ciLalkylgruppe og anino = group, N,N-CiLalkyl group and
R og R?~ uavhengig av hverandre hydrogen eller en C^_4 alkylgruppe. Forbindelsene av den generelle formel (I) samt deres salter, R and R?~ independently of each other are hydrogen or a C1-4 alkyl group. The compounds of the general formula (I) as well as their salts,
hvilke foreliggende oppfinnelse også vedrorer, oppviser en sterk bakteriostatisk virkning. to which the present invention also relates, exhibit a strong bacteriostatic effect.
Som utgangsstoffer i fremgangsmåten ifolge foreliggende oppfinnelse blir oksolinsyren (N-etyl-1, 4-dihydro-4-okso-$,7-metylendioksy-kinolin-3-karboksylsyre) hhv. den som mellomprodukt av okso-linsyresyntesen kjente forbindelsen (1,4-dihydro-4-okso-6,7-metylendioksykinolin-3-karboksylsyren og dens estere) anvendt. As starting materials in the method according to the present invention, oxolinic acid (N-ethyl-1, 4-dihydro-4-oxo-$,7-methylenedioxy-quinoline-3-carboxylic acid) or the compound known as an intermediate of the oxolinic acid synthesis (1,4-dihydro-4-oxo-6,7-methylenedioxyquinoline-3-carboxylic acid and its esters) was used.
For fremstilling av nye, farmasoytisk virksomme oksolinsyre- For the production of new, pharmaceutically active oxolinic acid
derivater består i hele verden en stor interesse. Av denne grunn er det i den siste tiden utkommet mange publikasjoner og patentskrifter som befatter seg med denne gjenstanden. Derivatives are of great interest throughout the world. For this reason, many publications and patent documents dealing with this subject have recently appeared.
Alle disse fremgangsmåtene har til felles at strukturen til N-alkyl-4-oksokinolin-3-karboksylsyren blir bibeholdt og at All these methods have in common that the structure of the N-alkyl-4-oxoquinoline-3-carboxylic acid is maintained and that
bare substituentene i 6- og 7-stilling som befinner seg på kinolinringen blir variert. only the 6- and 7-position substituents on the quinoline ring are varied.
Ifolge fransk patentskrift nr. 2.o54.5o3 blir det erholdt forbindelser ved hvilke 6- og 7-stillingen er substituert ved en ring inneholdende en eller to oksygenatomer med 6 According to French patent document no. 2.o54.5o3, compounds are obtained in which the 6- and 7-positions are substituted by a ring containing one or two oxygen atoms with 6
ledd. joint.
Ifolge fransk patentskrift nr. 2.ol3.519 blir substituentene According to French patent document No. 2.ol3.519, the substituents are
i 6-, 7- eller 8-stilling slik valgt at det danner seg en 7,8- eller 6,7-propylenring, dvs. det blir fremstilt 6,7- in the 6-, 7- or 8-position chosen so that a 7,8- or 6,7-propylene ring is formed, i.e. 6,7-
eller 7,8-cyklopentankinoliner. or 7,8-cyclopentanequinolines.
I den japanske patentansSkning.nr. 73.11.118 blir 5,6-thiazolokinoliner beskrevet. Den japanske patentansokning nr. 72.2o.627 vedrorer 6,7-etylendioksy-substituerte kinoliner. In the Japanese patent application no. 73.11.118 5,6-thiazoloquinolines are described. Japanese Patent Application No. 72.2o.627 relates to 6,7-ethylenedioxy-substituted quinolines.
Foruten i disse patentskriftene, som bare er oppfort som eksempler, blir det også berettet om syntesene av forbindelser av lignende typer i tallrike publikasjoner. Av det som er offentliggjort fremgår det at det til nå ikke har lykkes å fremstille et bakteriostatikum hvis virkning når opp mot oksolinsyrens, eller overgår denne. In addition to these patent documents, which are listed only as examples, the syntheses of compounds of similar types are also reported in numerous publications. From what has been published, it appears that until now it has not been possible to produce a bacteriostatic whose effect equals that of oxolinic acid, or surpasses it.
De fremstilte forbindelser utmerker seg fremfor kjente oksolinsyrer når man som utgangsmateriale anvender en forbindelse av formel II hvori R er hydrogen og R1 er etyl, hvilket fremgår av de følgende data: The compounds produced are superior to known oxolinic acids when a compound of formula II is used as starting material in which R is hydrogen and R1 is ethyl, which is evident from the following data:
Forbindelsen ifølge eksempel 7 er virksom mot proteus vulgaris The compound according to example 7 is effective against proteus vulgaris
i dose på 25 mikro gram pr. ml bacillus cereus var, mycoides i dose nå 25 mikro gram pr. ml bacillus subtilis,. 15 mikro gram pr. ml av forbindelsen ifølge eksempel 8 er aktiv mot proteus vulgaris 60 201 i dose på 1,1 mikro gram pr. ml, mot proteus vulgaris 60 001 i en konsentrasjon på 0,9 mikro gram pr. ml. Med aktivitet menes i dette tilfelle den minimale inhiberende konsentrasjon. Det er overraskende at foreliggende forbindelser er aktive mot gram-positive bacillus-stammer, samt også mot gram- in a dose of 25 micrograms per ml bacillus cereus var, mycoides in a dose now 25 micro grams per ml bacillus subtilis,. 15 micrograms per ml of the compound according to example 8 is active against proteus vulgaris 60 201 in a dose of 1.1 microgram per ml, against proteus vulgaris 60 001 in a concentration of 0.9 microgram per ml. In this case, activity means the minimum inhibitory concentration. It is surprising that the present compounds are active against gram-positive bacillus strains, as well as against gram-
negative proteus-stammer,. da oksolinsyre i det vesentlige kun er aktive mot gram-negativstammer. Forbindelsene har således et bredere virkespektrum enn kjente oksolinsyrer. negative proteus strains,. as oxolinic acid is essentially only active against gram-negative strains. The compounds thus have a wider spectrum of action than known oxolinic acids.
Videre er det funnet at forbindelsene av den generelle formel (I), hvori betydningen av X, R og R1 er den samme som ovenfor, Furthermore, it has been found that the compounds of the general formula (I), in which the meanings of X, R and R1 are the same as above,
kan fremstilles idet man nitrerer forbindelser av den generelle formel (II) can be prepared by nitrating compounds of the general formula (II)
hvori betydningen av R og R"*" er den samme som ovenfor, ;hvori R og b} har de ovenfor gitte betydninger, ;og om ønsket reduseres nitroforbindelsen til den tilsvarende aminoforbindelse som, når R"*" er en alkylgruppe med 1-4 C-atomer, videre om ønsket kan alkanolyleres, eller om-ønsket c^_4~ alky-leres, og om ønsket overføres en forbindelse med den generelle formel (I) hvor R er alkyl i en forbindelse med den generelle formel (I) hvor R er hydrogen', eller en slik forbindelse (I) in which the meanings of R and R"*" are the same as above, ;wherein R and b} have the meanings given above, ;and if desired, the nitro compound is reduced to the corresponding amino compound which, when R"*" is an alkyl group with 1- 4 C atoms, further if desired can be alkanolylated, or if desired C^_4~ alkylated, and if desired a compound of the general formula (I) is transferred where R is alkyl in a compound of the general formula (I) where R is hydrogen', or such a compound (I)
hvor R er hydrogen overføres i en forbindelse med den generelle formel (I) hvor R er alkyl, og om ønsket overføres en forbindelse med formel (I) i et salt derav, eller et salt av en forbindelse med formel (I) overføres i den tilsvarende fri forbindelse. where R is hydrogen is transferred in a compound of the general formula (I) where R is alkyl, and if desired a compound of formula (I) is transferred in a salt thereof, or a salt of a compound of formula (I) is transferred in the corresponding free connection.
Forbindelsene av den generelle formel (II) blir fortrinnsvis nitrert i et surt medium i nærvær av kaliumnitrat ved lave temperaturer. The compounds of the general formula (II) are preferably nitrated in an acidic medium in the presence of potassium nitrate at low temperatures.
Nitrogengruppen kan reduseres ved katalytisk hydrering, The nitrogen group can be reduced by catalytic hydrogenation,
hvorved man fortrinnsvis anvender en palladiumaktivkarbon-katalysator. Ytterligere kan det arbeides etter Bechamps- whereby a palladium activated carbon catalyst is preferably used. Furthermore, work can be done according to Bechamps
reduksjon eller reduseres med et sink-saltsyre-system. reduction or is reduced with a zinc-hydrochloric acid system.
Reduksjonen blir utfort i et surt medium, fortrinnsvis i The reduction is carried out in an acidic medium, preferably in
nærvær av eddiksyre og saltsyre ved atmosfærisk trykk eller under trykk. presence of acetic acid and hydrochloric acid at atmospheric pressure or under pressure.
Hvis aminogruppen blir acylert, så kommer for dette de If the amino group is acylated, then for this they come
vanlige acyleringsmidlene, fortrinnsvis syreanhydrider, the usual acylating agents, preferably acid anhydrides,
i nærvær av natriumacetat på tale. in the presence of sodium acetate in speech.
Alkyleringen blir utfort med vanlige alkyleringsmidler, The alkylation is carried out with common alkylating agents,
fortrinnsvis med dimetylsulfat eller trietylfosfat, i nærvær av syreakseptorer. Alkyleringsmiddelet kan samtidig også tjene som reaksjonsmedium. preferably with dimethyl sulfate or triethyl phosphate, in the presence of acid acceptors. The alkylating agent can also serve as a reaction medium at the same time.
Reaksjonen blir hensiktsmessig utfort ved forhoyet temperatur, The reaction is suitably carried out at an elevated temperature,
f.eks. ved reaksjonsblandingens kokepunkt. e.g. at the boiling point of the reaction mixture.
Forbindelsene som inneholder som substituenten R en alkylgruppe The compounds which contain as the substituent R an alkyl group
av den generelle formel (I) blir omsatt til karboksylsyrer inneholdende som substituenten R hydrogen fortrinnsvis ved forsåpning. of the general formula (I) is converted to carboxylic acids containing as the substituent R hydrogen preferably by saponification.
Karboksylsyrene av den generelle formel (I) som inneholder The carboxylic acids of the general formula (I) which contain
som substituenten R hydrogen kan omsettes på kjente måter for forestring til sine estere. as the substituent R hydrogen can be reacted in known ways for esterification to its esters.
Som salter av forbindelsene av den generelle formel (I) kommer alkalimetallsaltene ( f.eks. natrium- og kaliumsalter), jordalkalimetallsaltene eller salter dannet med organiske baser ( f.eks. med aminer) på tale. Fremstillingen av saltene hhv. frigjbringen av forbindelsene av den generelle formel (I) fra sine salter blir gjennomfort på kjent måte. Salts of the compounds of the general formula (I) include the alkali metal salts (e.g. sodium and potassium salts), the alkaline earth metal salts or salts formed with organic bases (e.g. with amines). The production of the salts or the release of the compounds of the general formula (I) from their salts is carried out in a known manner.
N-etyl-1,4-dihydro-4-okso-5-amino-6,7-metylendioksykinolin-3-karboksylsyre ("Aminooxolinsyre") har vist seg som den mest virksomme av forbindelsene fremstilt ifolge foreliggende oppfinnelse. Dens virkning er vesentlig sterkere enn nalidikssyrens og når tilnærmat opp til oksolinsyrens. Resultatene av de kvantitative sammenligningsforsokene fremstilles i" den folgende tabell. 1-etyl-l,4-dihydro-7-metyl-4-okso-l,8-nafthydrin-3 karboksylsyre N-ethyl-1,4-dihydro-4-oxo-5-amino-6,7-methylenedioxyquinoline-3-carboxylic acid ("Aminooxolinic acid") has proven to be the most effective of the compounds prepared according to the present invention. Its effect is significantly stronger than that of nalidic acid and reaches almost that of oxolinic acid. The results of the quantitative comparison experiments are presented in the following table. 1-Ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthydrine-3-carboxylic acid
"Amino-oksolinsyrene" er ikke-toksiske. Ved undercokelsen på deres toksisitet forårsaket en dosering på 3ooo mg/kg i lopet av 72 timer ingen mortalitet. The "amino-oxolinic acids" are non-toxic. When underestimating their toxicity, a dosage of 3ooo mg/kg over 72 hours caused no mortality.
Forbindelsene av den generelle formel (I) hhv. deres salter The compounds of the general formula (I) or their salts
kan på grund av deres bakteriostatiske virkning finne anvendelse som virksomt stoff i legemidler. Legemidlene blir fremstilt idet man blander det virksomme stoff med vanlige, fysiologisk for-dragelige faste eller flytende, organiske eller uorganiske bærer- eller droyemidler og hvis onsket blir ytterligere tilsetningsstoffer, ■ eventuelt andre farmakologisk virksomme substanser tilsatt. Legemidlene blir formulert i de vanlige anvendelsesformene, fortrinnsvis som tabletter, kapsler, tabletter overtrukket med en film, dragéer, enterosolvene dragéer, piller, opplosninger, suspensjoner, granulater eller premiksburer. can, due to their bacteriostatic effect, find use as an active substance in pharmaceuticals. The medicines are prepared by mixing the active substance with normal, physiologically tolerable solid or liquid, organic or inorganic carriers or anesthetics and, if desired, further additives, ■ possibly other pharmacologically active substances are added. The drugs are formulated in the usual application forms, preferably as tablets, capsules, tablets coated with a film, dragees, enterosolvent dragees, pills, solutions, suspensions, granules or premix cages.
Fremgangsmåten ifolge oppfinnelsen blir nærmere beskrevet ved hjelp av folgende eksempler. The method according to the invention is described in more detail by means of the following examples.
EKSEMPEL.1_ EXAMPLE.1_
7,83 g (o,o3 mol) etyl-1,4-dihydro-4-okso-67-metylendioksy-kinolin-3-karboksylat ble opplost i 34,5 g (o,33 mol) konsentrert svovelsyre. Opplosningen blir avkjolt til 0°C og så langsomt, 7.83 g (0.03 mol) of ethyl 1,4-dihydro-4-oxo-67-methylenedioxy-quinoline-3-carboxylate were dissolved in 34.5 g (0.33 mol) of concentrated sulfuric acid. The solution is cooled to 0°C and then slowly,
i små porsjoner tilsatt 3,7o g (o,o31 mol) kaliumnitrat, hvorved temperaturen til reaksjonsblandingen ikke må overstige lo°C.Den eksoterme reaksjonen blir styrt ved kjoling og ved regulering av tilsetningshastigheten. Tilsetningen varer ca. 3o minutter. Deretter blir reaksjonsblandingen rort i enda 1 time ved under lo°C, så oppvarmet til romtemperatur og rort i ytterligere lo timer. Deretter blir reaksjonsblandingen helt i 3oo ml isvann.Den forst rode oljen felles ifolge fortynningen som et gult pulver. Dette blir frafiltrert, vasket noytralt og behandlet med alkohol. Man erholder 8,35 g (91%) etyl-1,4-dihydro-4-okso-5-nitro-6,7-metylendioksykinolin-3-karboksylat som sennepsfarget substans, som enda ikke ved 36o°C smelter. Også de ved omkrystallisering fra dimetylformamid erholdte lysgule krystallene har et smeltepunkt på over 35o°C. in small portions added 3.7o g (o.o31 mol) of potassium nitrate, whereby the temperature of the reaction mixture must not exceed lo°C. The exothermic reaction is controlled by cooling and by regulating the rate of addition. The addition lasts approx. 3o minutes. The reaction mixture is then stirred for a further 1 hour at below 10°C, then warmed to room temperature and stirred for a further 10 hours. The reaction mixture is then poured into 300 ml of ice water. The first red oil precipitates as a yellow powder after dilution. This is filtered off, washed neutrally and treated with alcohol. 8.35 g (91%) of ethyl 1,4-dihydro-4-oxo-5-nitro-6,7-methylenedioxyquinoline-3-carboxylate is obtained as a mustard colored substance, which does not yet melt at 36o°C. The pale yellow crystals obtained by recrystallization from dimethylformamide also have a melting point of over 35o°C.
Infrarodtspektrum (i KBr): 3155 (NH), 17o2 (C=0 Ester), Infrared spectrum (in KBr): 3155 (NH), 17o2 (C=0 Ester),
1648 (C=0), 1558 (N02), 127o og lo32 (C-O-C) cm<-1>. 1648 (C=0), 1558 (N02), 127o and 1032 (C-O-C) cm<-1>.
EKSEMPEL 2 EXAMPLE 2
12,24 g (o,o4 mol) etyl-1,4-dihydro-4-okso-5-nitro-6,7-metylen-dioksykinolin-3-karboksylat blir hydrert i en blanding av 3oo ml eddiksyre og loo ml kons. saltsyre i nærvær av 2,4 g palladium-aktivkarbon. Etter opptak av den teoretiske mengde hydrogen blir katalysatoren fjernet og filtratet inndampet i vakuum. 12.24 g (o.o4 mol) of ethyl 1,4-dihydro-4-oxo-5-nitro-6,7-methylene-dioxyquinoline-3-carboxylate are hydrated in a mixture of 3oo ml of acetic acid and loo ml of conc. . hydrochloric acid in the presence of 2.4 g of palladium activated carbon. After absorption of the theoretical amount of hydrogen, the catalyst is removed and the filtrate is evaporated in a vacuum.
Den faste, gule resten blir tatt opp i loo ml vann og suspen-sjonenes pH-verdi blir stilt til noytral med fortynnet natronlut. Det uopploste blir avfiltrert og vasket med vann. Man erholder 9,6 g (85,5%) av et gronnlig gult produkt som heller ikke smelter ved 36o°C. Etter omkrystallisering fra dimetylformamid erholder man etyl-1,4-dihydro-4-okso-5-amino-6,7-metylendioksykinolin-3-karboksylat i form av sandfargede krystaller. The solid, yellow residue is taken up in 100 ml of water and the pH value of the suspension is adjusted to neutral with diluted caustic soda. The undissolved material is filtered off and washed with water. 9.6 g (85.5%) of a greenish yellow product is obtained which also does not melt at 36o°C. After recrystallization from dimethylformamide, ethyl 1,4-dihydro-4-oxo-5-amino-6,7-methylenedioxyquinoline-3-carboxylate is obtained in the form of sand-colored crystals.
Elementæranalyse for ci3<H>i2N2°5 ^M = 276,251): Elemental analysis for ci3<H>i2N2°5 ^M = 276.251):
Infrarodtspektrum ( i KBr): 347o og 33oo (NH2), 318o (NU), Infrared spectrum (in KBr): 347o and 33oo (NH2), 318o (NU),
17o5 (C = 0 Ester), 1665 (C=0), 13oo, 118o og lo72 (C-O-C) cm'"1. 17o5 (C = 0 Ester), 1665 (C=0), 13oo, 118o and 1072 (C-O-C) cm'"1.
EKSEMPEL 3 EXAMPLE 3
a) 11,62 g (o,o5 mol) 6,7-metylendioksy-4-kinolin-3-karboksylsyre blir opplost under roring i 57 g (o,55 mol) kons. svovelsyre. Opplosningen blir avkjolt til 0°C tilsatt i små a) 11.62 g (0.05 mol) of 6,7-methylenedioxy-4-quinoline-3-carboxylic acid are dissolved with stirring in 57 g (0.55 mol) conc. sulfuric acid. The solution is cooled to 0°C and added in small portions
porsjoner med 5,55 g (o,ol mol) kaliumnitrat. Mens tilsetningen gjennomfores holdes temperaturen under lo°C, etter tilsetningen blir reaksjonsblandingen rort i enda en time ved lav temperatur .Deretter varmer man reaksjonsblandingen til romtemperatur og rorer den i enda lo timer. Den erholdte tykke oljen blir helt i 5oo ml isvann, hvorved det nitrerteproduktet felles til et gult pulver og kan avfiltreres. Produktet blir vasket med vann og behandlet med alkohol. Man erholder 12,7 g (92,4%) gult 1,4-dihydro-4-okso-5-nitro-6,7-métylen-dioksykinolin-3-karboksylsyre som heller ikke smelter véd' 36o°C.. Etter omkrystallisering fra dimetylformamid kan likeledes intet smeltepunkt måles, da produktet opptar et mol dimetylformamid og addisjonsproduktet spaltes ved 31o°C. portions of 5.55 g (o.ol mol) of potassium nitrate. While the addition is carried out the temperature is kept below 10°C, after the addition the reaction mixture is stirred for another hour at a low temperature. The reaction mixture is then heated to room temperature and stirred for another 10 hours. The resulting thick oil is poured into 5oo ml of ice water, whereby the nitrated product falls to a yellow powder and can be filtered off. The product is washed with water and treated with alcohol. 12.7 g (92.4%) of yellow 1,4-dihydro-4-oxo-5-nitro-6,7-methylene-dioxyquinoline-3-carboxylic acid is obtained, which also does not melt at 36o°C. After recrystallization from dimethylformamide likewise no melting point can be measured, as the product takes up one mole of dimethylformamide and the addition product decomposes at 31o°C.
b) 1,4-dihydro-4-okso-5-nitro-6,7-metylendioksykinolin-3-karboksylsyre kan også fremstilles ved hydrolyse fra etyl-1,4-dihydro-4-okso-5-nitro-6,7-metylendioksykinolin-3-karboksylat: 4,6 g (o,ol5 mol) etyl-1,4-dihydro-4-okso-5-nitro-6,7-metylen-dioksykinolin-3-karboksylat blir oppvarmet på et kokende vannbad i en time i en blanding av loo ml 5%'ig kalilut og 15 ml 96%'ig alkohol. Deretter blir reaksjonsblandingen klaret med aktivkarbon og filtrert. Filtratet blir surgjort pH 2 med 5%'ig saltsyre. Det utfelte bunnfallet blir frafiltrert og vasket med vann. Man erholder 3,2 g (76,8%) 1,4-dihydro-4-okso-5-nitro-6,7-metylendioksykinolin-3-karboksylsyre som ikke smelter ved 38o°C. Produktet viser seg å være identisk med produktet fremstilt ifolge punkt a) ved tynnsjiktskromatografiske og spektroskopiske undersøkelser. b) 1,4-dihydro-4-oxo-5-nitro-6,7-methylenedioxyquinoline-3-carboxylic acid can also be prepared by hydrolysis from ethyl-1,4-dihydro-4-oxo-5-nitro-6,7 -methylenedioxyquinoline-3-carboxylate: 4.6 g (0.ol5 mol) of ethyl 1,4-dihydro-4-oxo-5-nitro-6,7-methylene-dioxyquinoline-3-carboxylate are heated on a boiling water bath for one hour in a mixture of 100 ml of 5% potassium hydroxide and 15 ml of 96% alcohol. The reaction mixture is then clarified with activated carbon and filtered. The filtrate is acidified to pH 2 with 5% hydrochloric acid. The precipitate is filtered off and washed with water. 3.2 g (76.8%) of 1,4-dihydro-4-oxo-5-nitro-6,7-methylenedioxyquinoline-3-carboxylic acid is obtained which does not melt at 38o°C. The product turns out to be identical to the product manufactured in accordance with point a) by thin-layer chromatographic and spectroscopic investigations.
Elementæranalyse for C11<H>6<N>2°7 ^ M <=> 278'18°) Elemental analysis for C11<H>6<N>2°7 ^ M <=> 278'18°)
Infrarodtspektrum ( i KBr): 1725 (C=0 syre), 1648 (C=0), Infrared spectrum (in KBr): 1725 (C=0 acid), 1648 (C=0),
155o (N02), 127o og lo62 (C-O-C) an"<1>. 155o (N02), 127o and lo62 (C-O-C) an"<1>.
NMR (n-NaOD): 8,57 (1, s, 2H), 7,o2 (1, s, 8H), 6,o4 NMR (n-NaOD): 8.57 (1, s, 2H), 7.02 (1, s, 8H), 6.04
(2, s, 0-CH2-0) ppm. (2, s, 0-CH2-0) ppm.
EKSEMPEL 4 EXAMPLE 4
2,76 g (o,ol mol) etyl-1,4-dihydro-4-okso-5-amino-6,7-metylen-dioksykinolin-3-karboksylat blir oppvarmet i en blanding av 8o ml 5%'ig kalilut og lo ml alkohol i time på kokende vannbad. Mot slutten av reaksjonen har hele substansen blitt opplost. Opplosningen blir varmt klaret med aktivkarbon, kraftig, filtrert og syrnet til pH 2 med 5%'ig saltsyre. Det utfelte bunnfallet blir avfiltrert og vasket noytralt med vann. Man erholder 2,3 g (92,8%) gul 1,4-dihydro-4-okso-5-amino-6,7-metylen-dioksykinolin-3-karboksylsyre, som ikke smelter ved 36o°C. 2.76 g (0.01 mol) of ethyl 1,4-dihydro-4-oxo-5-amino-6,7-methylene-dioxyquinoline-3-carboxylate are heated in a mixture of 80 ml of 5% potassium chloride and leave ml of alcohol per hour in a boiling water bath. Towards the end of the reaction, the entire substance has been dissolved. The solution is clarified hot with activated carbon, strong, filtered and acidified to pH 2 with 5% hydrochloric acid. The precipitate is filtered off and washed neutrally with water. 2.3 g (92.8%) of yellow 1,4-dihydro-4-oxo-5-amino-6,7-methylene-dioxyquinoline-3-carboxylic acid is obtained, which does not melt at 36o°C.
Elementæranalyse for C11<H>8<N>2°5 (M <=> 248,197) Elemental analysis for C11<H>8<N>2°5 (M <=> 248.197)
Infrarodtspektrum (i KBr)i 3455, 339o (NH ^ ), 335o (NH), 1968_1 Infrared spectrum (in KBr)i 3455, 339o (NH ^ ), 335o (NH), 1968_1
(C=0 syre), 1662 (C=0), 1292 og lo5o (C-O-C) cm . (C=0 acid), 1662 (C=0), 1292 and lo5o (C-O-C) cm .
NMR (n-NaOD): 8,42 (1, s, 2H), 6,58 (l,s,8H), 5,96 (2,s, NMR (n-NaOD): 8.42 (1,s, 2H), 6.58 (1,s,8H), 5.96 (2,s,
0-CH2-0) ppm. 0-CH2-O) ppm.
EKSE MPEL 5 EXE MPEL 5
52,24 g (o,2 mol) N-etyl-1,4-dihydro-4-okso-6,7-metylendidksy-kinolin-3-karboksylsyre blir opplost under roring i 23o g (2,2 mol) konsentrert svovelsyre. Opplosning blir derved svakt oppvarmet. Etter omtrent 5o minutter erholder man en mork farget, viskos, oljeartig opplosning. Denne blir avkjolt til 0°C og tilsatt med 3o,3 g (o,3 mol) kaliumnitrat i små porsjoner, hvorved 52.24 g (0.2 mol) of N-ethyl-1,4-dihydro-4-oxo-6,7-methylenedioxy-quinoline-3-carboxylic acid are dissolved with stirring in 23o g (2.2 mol) of concentrated sulfuric acid . The solution is thereby slightly heated. After approximately 50 minutes, a dark colored, viscous, oily solution is obtained. This is cooled to 0°C and added with 3o.3 g (o.3 mol) of potassium nitrate in small portions, whereby
tilsetningshastigheten blir slik regulert at temperaturen til reaksjonsblandingen ved jevn kjoling ikke overstiger lo°C. Deretter blir reaksjonsblandingen rort ved 5°C i enda en time, deretter ved romtemperatur i videre 15 timer. Den morkerode, oljeartige opplbsningen blir helt i 2ooo ml isvann. Etter energisk rbring felles substansen til et gult pulver, hvilke avnutsjes og vaskes med vann. Man erholder 54,5 g (89%) N-etyl-1,4-dihydro-4-okso-5-nitro-6,7-metylen-dioksykinolin-3-karboksylsyre som smelter ved 315°C under spaltning. Etter omkrystallisering fra dimetylformamid stiger spaltningspunktet til 325°C. the rate of addition is regulated so that the temperature of the reaction mixture does not exceed lo°C during uniform cooling. The reaction mixture is then stirred at 5°C for another hour, then at room temperature for a further 15 hours. The dark red, oily solution is poured into 200 ml of ice water. After vigorous stirring, the substance falls to a yellow powder, which is ground and washed with water. 54.5 g (89%) of N-ethyl-1,4-dihydro-4-oxo-5-nitro-6,7-methylene-dioxyquinoline-3-carboxylic acid is obtained which melts at 315°C during decomposition. After recrystallization from dimethylformamide, the cleavage point rises to 325°C.
Elementæranalyse for <c>i3aio<N>207 ^M ~ 3o6,233) Elementary analysis for <c>i3aio<N>207 ^M ~ 3o6.233)
UV-spektrum (etanol): maksima ved 317 og 271 nm. Infrarodtspektrum ( i KBr): 173o (C=0 syre), 1646 (C=0), UV spectrum (ethanol): maxima at 317 and 271 nm. Infrared spectrum (in KBr): 173o (C=0 acid), 1646 (C=0),
1558 (N02), 1278 og lo52 (C-O-C) cm-<1>. 1558 (N02), 1278 and 1052 (C-O-C) cm-<1>.
NMR ( n-NaOD): 8,12 (l,s,2H), 8,lo (1, s, 8H), 6,55 NMR ( n -NaOD): 8.12 (1,s,2H), 8,10 (1,s,8H), 6.55
(2,s,0-CH2-0), 4,16 (2, q, CH^), 1,41 (2,t,CH3) ppm. (2,s,O-CH2-O), 4.16 (2,q,CH^), 1.41 (2,t,CH3) ppm.
EKS EMPEL 6 EKS EMPEL 6
21,44 g (o,o7 mol) N-etyl-1,4-dihydro-4-okso-5-nitro-6,7-metylendioksykinolin-3-karboksylsyré blir suspendert i en blanding av 525 ml eddiksyre og 175 ml kons. saltsyre og så hydrert ved atmosfærisk trykk i nærvær av 4 g palladium-karbon. Etter avslutning av hydrogenopptaket ble opplbsningen filtrert i 3ooo ml vann. Produktet ble med en gang utfelt. 21.44 g (0.07 mol) of N-ethyl-1,4-dihydro-4-oxo-5-nitro-6,7-methylenedioxyquinoline-3-carboxylic acid are suspended in a mixture of 525 ml of acetic acid and 175 ml of concentrated . hydrochloric acid and then hydrated at atmospheric pressure in the presence of 4 g of palladium-carbon. After completion of the hydrogen uptake, the solution was filtered in 300 ml of water. The product was immediately precipitated.
Det ble avfiltrert og nbytralt vasket med vann. Man erholder 16,6 g (86%) gul N-etyl-1,4-dihydro-4-okso-5-amino-6,7-metylen-dioksykinolin-3-karboksylsyre, som spaltes ved 292°C. Produktet som dames ved omkrystallisasjon fra dimetylformamid danner glinsende gule krystaller og spaltes ved 292-294°C. It was filtered off and neutrally washed with water. 16.6 g (86%) of yellow N-ethyl-1,4-dihydro-4-oxo-5-amino-6,7-methylene-dioxyquinoline-3-carboxylic acid are obtained, which decomposes at 292°C. The product obtained by recrystallization from dimethylformamide forms shiny yellow crystals and decomposes at 292-294°C.
Elementæranalyse for ci3Hi2N<2>°5 ^M = 276,251):Elemental analysis for ci3Hi2N<2>°5 ^M = 276.251):
UV-spektrum (etanol): maksima ved 358, 277 og 264 nm. Infrarodtspektrum ( i KBr): 3475 og 334o (NH2), 1726 (C=0 UV spectrum (ethanol): maxima at 358, 277 and 264 nm. Infrared spectrum (in KBr): 3475 and 334o (NH2), 1726 (C=0
syre), 1664 (C=0), 131o og lo42 (C-O-C) cm"<1>. acid), 1664 (C=0), 131o and lo42 (C-O-C) cm"<1>.
Massespektrum: 276 (M, loo%), 258 (M-18, 5%), 232 (M-44, Mass spectrum: 276 (M, loo%), 258 (M-18, 5%), 232 (M-44,
22%), 231 (M-45, 12%), 218 )M-58, 1,5%), 22%), 231 (M-45, 12%), 218 )M-58, 1.5%),
2o4 (M-72, 13%), 2o3 (M73, 2o%). 2o4 (M-72, 13%), 2o3 (M73, 2o%).
EKSEMPEL 7 EXAMPLE 7
5,52 g (o,o2 mol) N-etyl-1,4-dihydro-4-okso-5-amino-6,7-metylendioksykinolin-3-karboksylsyre blir suspendert i 6o ml eddiksyreanhydrid og tilsatt 1,6 g (o,o2 mol) 5.52 g (o.o2 mol) of N-ethyl-1,4-dihydro-4-oxo-5-amino-6,7-methylenedioxyquinoline-3-carboxylic acid are suspended in 6o ml of acetic anhydride and added 1.6 g ( o,o2 mol)
vannfritt natriumacetat. Blandingen blir kokt på oljebadet i 9o minutter, hvorved substansen langsomt går i opplosning. Deretter blir opplosningsmiddelet avdampet i vakuum, resten opptatt i 6o ml vann og latt stå over natten i kjoleskap. anhydrous sodium acetate. The mixture is boiled in the oil bath for 90 minutes, whereby the substance slowly dissolves. The solvent is then evaporated in a vacuum, the residue taken up in 60 ml of water and left overnight in a refrigerator.
Den andre dagen blir produktet oppsuget og vasket med vann. On the second day, the product is absorbed and washed with water.
Man erholder 6,32 (99,4%) N-etyl-1,4-dihydro-4-okso-5-acetylamino-6,7-metylendioksykinolin-3-karboksylsyre i form av en sand-farget substans, som spaltes ved 239°. Etter omkrystallisasjon fra eddiksyre erholder man hvite krystaller, som spaltes ved 242°C. 6.32 (99.4%) of N-ethyl-1,4-dihydro-4-oxo-5-acetylamino-6,7-methylenedioxyquinoline-3-carboxylic acid is obtained in the form of a sand-colored substance, which is decomposed by 239°. After recrystallization from acetic acid, white crystals are obtained, which decompose at 242°C.
Elementæranalyse for C.-H, .N.O, (M = 318,287) Elemental analysis for C.-H, .N.O, (M = 318.287)
J 15 14 2 6 J 15 14 2 6
UV-spektrum (etanol): maksima ved 338, 324 og 272 nm. Infrarodtspektrum (i KBr): 1725 (C=0 acetyl), 1712 (C=0 syre), UV spectrum (ethanol): maxima at 338, 324 and 272 nm. Infrared spectrum (in KBr): 1725 (C=0 acetyl), 1712 (C=0 acid),
1648 (C=0), 127o, 124o og lo4o (C-O-C) cm"<1>. 1648 (C=0), 127o, 124o and 104o (C-O-C) cm"<1>.
NMR (n-NaOD): 8,38 (l,s,2H), 6,89 (l,s,8H), 6,15(2,s,O-CH -0), NMR (n-NaOD): 8.38 (1,s,2H), 6.89 (1,s,8H), 6.15 (2,s,O-CH -0),
4,12 (2,q,N-CH2-0) , 2, 25 (3, s,C0-CH3) , l,.4o (3, t, -CH3) ppm. 4.12 (2,q,N-CH2-O), 2.25 (3,s,CO-CH3), 1.40 (3,t,-CH3) ppm.
Massespektrum: 318 (M, loo%), 3o3 (M-15, 48%), 3ol (M-17, 29o%), Mass spectrum: 318 (M, loo%), 3o3 (M-15, 48%), 3ol (M-17, 29o%),
285 (M-33, 124%), 276 (M-42, 17o%), 259 (M-59, 3o%), 258 (M-6o, 25%), 257 (M-61, 39%). 285 (M-33, 124%), 276 (M-42, 17o%), 259 (M-59, 3o%), 258 (M-6o, 25%), 257 (M-61, 39%).
I IN
EKSEMPEL_8 EXAMPLE_8
5,52 g (o,o2 mol) N-etyl-1, 4-dihydro-4-okso-5-amino-6,7-metylen-dioksykinolin-3-karboksylsyre, 17,1 ml (o,1 mol) trietylfosfat og 2,76 g (o,o2 mol) kaliumkarbonat ble kokt i en time under roring. Deretter blir 2oo ml lo%'ig natronlut tilsatt og ved en times oppvarming på kokende vannbad hydrolyseres esteren oppstått ved reaksjonen. Blandingen blir varmt filtrert og syrnet til pH 3 med halvkonsentrert saltsyre. Det utskilte produktet blir avfiltrert, vasket med vann og behandlet med alkohol. Man erholder 5 g av en substansblanding som spaltes ved 26o°C. Denne blir suspendert i 15o ml kloroform, 5.52 g (o.o2 mol) N-ethyl-1, 4-dihydro-4-oxo-5-amino-6,7-methylene-dioxyquinoline-3-carboxylic acid, 17.1 ml (o.1 mol) triethyl phosphate and 2.76 g (0.02 mol) of potassium carbonate were boiled for one hour with stirring. Then 200 ml of 10% caustic soda is added and by heating for one hour in a boiling water bath, the ester produced by the reaction is hydrolysed. The mixture is hot filtered and acidified to pH 3 with semi-concentrated hydrochloric acid. The separated product is filtered off, washed with water and treated with alcohol. 5 g of a substance mixture is obtained which decomposes at 26o°C. This is suspended in 15o ml of chloroform,
hvorved det monoetylerte produktet går i opplosning. Det uopp-loselige, som består av ikke-omsatt utgangsstoff, blir fjernet. Filtratet blir inndampet til torrhet i vakuum» Man erholder whereby the monoethylated product goes into solution. The insoluble matter, which consists of unreacted starting material, is removed. The filtrate is evaporated to dryness in vacuo» One obtains
2,o5 g (33,7%) gul N-etyl-1,4-dihydro-4-okso-5-etylamino-6, 7-metylendioksykin6lin-3-karboksylsyre, som smelter ved 22o°C, hvis smeltepunkt ikke forandrer seg etter omkrystallisasjon fra absolutt alkohol. 2.05 g (33.7%) yellow N-ethyl-1,4-dihydro-4-oxo-5-ethylamino-6, 7-methylenedioxyquinone-3-carboxylic acid, which melts at 22o°C, whose melting point does not change after recrystallization from absolute alcohol.
Elementæranalyse for <C>15H16<N>205 (M = 3o4,3o5) Elemental analysis for <C>15H16<N>205 (M = 3o4,3o5)
UV-spektrum (etanol): maksima ved 365 og 282 (infl.) nm. UV spectrum (ethanol): maxima at 365 and 282 (infl.) nm.
Infrarodtspektrum (i KBr): 3275(NH), 1715 (C=0 syre), 1648 (C=0), Infrared spectrum (in KBr): 3275(NH), 1715 (C=0 acid), 1648 (C=0),
1295 og lo6o (C-O-C) cm"1. 1295 and lo6o (C-O-C) cm"1.
NMR (CDCl3): 15,2 (1,s,C00H), 9,4 (l,b,NH), 8,58(L,s,2H), 6,3o (1, s, SH), 6,o5 (2,s,0-CH2-0) 4,2 (2,q,-N_Cg2), NMR (CDCl3): 15.2 (1,s,COOH), 9.4 (1,b,NH), 8.58(L,s,2H), 6.3o (1,s,SH), 6 ,o5 (2,s,0-CH2-0) 4,2 (2,q,-N_Cg2),
3,7 (2,q,NH-CH2), 1,53 (3,t,NCH2-CH3), 1,28 (3,t,NHCH2-CH3) ppm. 3.7 (2,q,NH-CH 2 ), 1.53 (3,t,NCH 2 -CH 3 ), 1.28 (3,t,NHCH 2 -CH 3 ) ppm.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HUCI1485A HU170681B (en) | 1974-06-25 | 1974-06-25 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO752224L NO752224L (en) | 1975-12-30 |
| NO142783B true NO142783B (en) | 1980-07-07 |
| NO142783C NO142783C (en) | 1980-10-15 |
Family
ID=10994523
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO752224A NO142783C (en) | 1974-06-25 | 1975-06-23 | ANALOGY PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTIC ACTIVE QUINOLIC ACID DERIVATIVES |
Country Status (10)
| Country | Link |
|---|---|
| AT (1) | AT341526B (en) |
| CS (1) | CS188379B1 (en) |
| DD (1) | DD118431A1 (en) |
| DK (1) | DK137927B (en) |
| ES (1) | ES438816A1 (en) |
| FI (1) | FI751869A (en) |
| FR (1) | FR2276049A1 (en) |
| HU (1) | HU170681B (en) |
| NO (1) | NO142783C (en) |
| SU (1) | SU582766A3 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994002145A2 (en) * | 1992-07-22 | 1994-02-03 | Genelabs Technologies, Inc. | 2-aryl-4-quinolones as antitumor compounds |
| US5571822A (en) * | 1994-09-30 | 1996-11-05 | The University Of North Carolina At Chapel Hill | Antitumor compounds |
-
1974
- 1974-06-25 HU HUCI1485A patent/HU170681B/hu unknown
-
1975
- 1975-06-23 AT AT478375A patent/AT341526B/en not_active IP Right Cessation
- 1975-06-23 FR FR7519545A patent/FR2276049A1/en active Granted
- 1975-06-23 NO NO752224A patent/NO142783C/en unknown
- 1975-06-23 CS CS754437A patent/CS188379B1/cs unknown
- 1975-06-24 DD DD186854A patent/DD118431A1/xx unknown
- 1975-06-24 ES ES438816A patent/ES438816A1/en not_active Expired
- 1975-06-24 DK DK287075AA patent/DK137927B/en not_active IP Right Cessation
- 1975-06-24 SU SU7502147968A patent/SU582766A3/en active
- 1975-06-24 FI FI751869A patent/FI751869A/fi not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| DK137927C (en) | 1978-10-30 |
| FR2276049B1 (en) | 1979-08-17 |
| FR2276049A1 (en) | 1976-01-23 |
| CS188379B1 (en) | 1979-03-30 |
| HU170681B (en) | 1977-08-28 |
| DD118431A1 (en) | 1976-03-05 |
| ES438816A1 (en) | 1977-02-01 |
| ATA478375A (en) | 1977-06-15 |
| DK287075A (en) | 1975-12-26 |
| FI751869A (en) | 1975-12-26 |
| NO142783C (en) | 1980-10-15 |
| AT341526B (en) | 1978-02-10 |
| NO752224L (en) | 1975-12-30 |
| SU582766A3 (en) | 1977-11-30 |
| DK137927B (en) | 1978-06-05 |
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