DK161460B - Analogifremgangsmaade til fremstilling af 7-amino-1-cyclopropyl-4-oxo-1,4-dihydro-naphthyridin-3-carboxylsyrer - Google Patents
Analogifremgangsmaade til fremstilling af 7-amino-1-cyclopropyl-4-oxo-1,4-dihydro-naphthyridin-3-carboxylsyrer Download PDFInfo
- Publication number
- DK161460B DK161460B DK387781A DK387781A DK161460B DK 161460 B DK161460 B DK 161460B DK 387781 A DK387781 A DK 387781A DK 387781 A DK387781 A DK 387781A DK 161460 B DK161460 B DK 161460B
- Authority
- DK
- Denmark
- Prior art keywords
- naphthyridine
- oxo
- dihydro
- cyclopropyl
- carboxylic acid
- Prior art date
Links
- 239000002253 acid Substances 0.000 title claims description 4
- 238000000034 method Methods 0.000 title description 10
- 238000002360 preparation method Methods 0.000 title description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- PJMAOVIRNDKEOW-UHFFFAOYSA-N 7-amino-1,8-naphthyridine-3-carboxylic acid Chemical compound NC1=CC=C2C=C(C=NC2=N1)C(=O)O PJMAOVIRNDKEOW-UHFFFAOYSA-N 0.000 claims description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 241000588769 Proteus <enterobacteria> Species 0.000 description 11
- 241000589516 Pseudomonas Species 0.000 description 10
- 241000588748 Klebsiella Species 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 241000588724 Escherichia coli Species 0.000 description 8
- 230000000844 anti-bacterial effect Effects 0.000 description 8
- 241000191940 Staphylococcus Species 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- KGDXPVCMVZRFJK-UHFFFAOYSA-N 7-chloro-1-cyclopropyl-4-oxo-1,6-naphthyridine-3-carboxylic acid Chemical compound C12=CC(Cl)=NC=C2C(=O)C(C(=O)O)=CN1C1CC1 KGDXPVCMVZRFJK-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 241000194017 Streptococcus Species 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 238000002814 agar dilution Methods 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- UZSCYVLTFUBAGG-UHFFFAOYSA-N 7-amino-1-cyclopropyl-4-oxo-1,8-naphthyridine-3-carboxylic acid Chemical class N=1C(N)=CC=C(C(C(C(O)=O)=C2)=O)C=1N2C1CC1 UZSCYVLTFUBAGG-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- IXRSFGOAMNXZBZ-UHFFFAOYSA-N methyl 3-(cyclopropylamino)propanoate Chemical compound COC(=O)CCNC1CC1 IXRSFGOAMNXZBZ-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- 241000295644 Staphylococcaceae Species 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000003899 bactericide agent Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 150000001733 carboxylic acid esters Chemical class 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- JEJMDUMJSZTJTI-UHFFFAOYSA-N methyl 4,6-dichloropyridine-3-carboxylate Chemical class COC(=O)C1=CN=C(Cl)C=C1Cl JEJMDUMJSZTJTI-UHFFFAOYSA-N 0.000 description 2
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 2
- JOHZPMXAZQZXHR-UHFFFAOYSA-N pipemidic acid Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CN=C1N1CCNCC1 JOHZPMXAZQZXHR-UHFFFAOYSA-N 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- WDIZNCAFMVUKQV-UHFFFAOYSA-N 1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylic acid Chemical compound C1=CC=C2CC(C(=O)O)CNC2=N1 WDIZNCAFMVUKQV-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- KAGNQZHEDUAMKC-UHFFFAOYSA-N 3-(cyclopropylamino)propanoic acid Chemical class OC(=O)CCNC1CC1 KAGNQZHEDUAMKC-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- FIPWRIJSWJWJAI-UHFFFAOYSA-N Butyl carbitol 6-propylpiperonyl ether Chemical compound C1=C(CCC)C(COCCOCCOCCCC)=CC2=C1OCO2 FIPWRIJSWJWJAI-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- 241000588722 Escherichia Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000588768 Providencia Species 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 125000005396 acrylic acid ester group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000003674 animal food additive Substances 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 235000015278 beef Nutrition 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- NGXWRFCFYQIRAP-UHFFFAOYSA-N methyl 1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate Chemical compound C1=CC=C2CC(C(=O)OC)CNC2=N1 NGXWRFCFYQIRAP-UHFFFAOYSA-N 0.000 description 1
- QMWFLISYRFLDMC-UHFFFAOYSA-N methyl 7-chloro-1-cyclopropyl-4-oxo-1,6-naphthyridine-3-carboxylate Chemical compound C12=CC(Cl)=NC=C2C(=O)C(C(=O)OC)=CN1C1CC1 QMWFLISYRFLDMC-UHFFFAOYSA-N 0.000 description 1
- JITCOCYPMBDNAH-UHFFFAOYSA-N methyl 7-chloro-1-cyclopropyl-4-oxo-1,8-naphthyridine-3-carboxylate Chemical compound C12=NC(Cl)=CC=C2C(=O)C(C(=O)OC)=CN1C1CC1 JITCOCYPMBDNAH-UHFFFAOYSA-N 0.000 description 1
- -1 methylpiperazinyl Chemical group 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 238000003541 multi-stage reaction Methods 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
- 125000002560 nitrile group Chemical group 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 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
- 229960001180 norfloxacin Drugs 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007530 organic bases Chemical group 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960001732 pipemidic acid Drugs 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Pharmacology & Pharmacy (AREA)
- Communicable Diseases (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Fodder In General (AREA)
- Quinoline Compounds (AREA)
- Food Preservation Except Freezing, Refrigeration, And Drying (AREA)
- Medicinal Preparation (AREA)
Description
DK 161460 B
i
Den foreliggende opfindelse angår en analogifrem-gangsmåde til fremstilling af hidtil ukendte 7-amino-l-cyclo-propyl-4-oxo-l,4-dihydro-naphthyridin-3-carboxylsyrer.
Det er allerede kendt, at 7-amino-l-ethyl-4-oxo-l,4-5 -dihydro-naphthyridin-3-carboxylsyrer besidder antibakteri-elle egenskaber [Eur. J. Med. Chem. 12, 541-547 (1977)). Endvidere er det kendt, at forbindelser med lignende struktur, især norfloxacin, l-ethyl-6-fluor-l,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolincarboxylsyre, besidder antibak-10 terielle egenskaber, jf. DE-A1-2.840.910, EP-A1-0.004.279 og EP-A-0.014.393.
Det har nu vist sig, at hidtil ukendte 7-amino-l-cyclopropyl-4-oxo-l,4-dihydro-naphthyridin-3-carboxylsyrer udviser en i forhold til de kendte forbindelser overlegen 15 antibakteriel virkning.
Opfindelsen angår således en analogifremgangsmåde til fremstilling af hidtil ukendte 7-amino-l-cyclopropyl-4-oxo-1,4-dihydro-naphthyridin-3-carboxylsyrer med formlen 20 0 •y0Cr“ 2X Λ * Δ 25 hvor A betyder nitrogen eller CR3, hvor R3 betyder halogen, især fluor eller chlor, eller en nitrilgruppe, B betyder nitrogen eller C-H, og A og B ikke samtidigt er nitrogen, og R1 og R2 sammen med nitrogenatomet, som de substituerer, 30 betyder en piperazinylgruppe, som eventuelt er substitueret en eller flere gange med alkyl med 1-6 carbonatomer, eller en pyrrolidinylgruppe, med undtagelse af de forbindelser, hvori A betyder N, B betyder CH, og NR^R2 betyder piperazinyl eller methylpiperazinyl, eller farmaceutisk anvendelige 35 salte deraf, hvilken fremgangsmåde er ejendommelig ved det i kravets kendetegnende del anførte.
DK 161460B
2
Ved fremgangsmådevariant a) fremstilles 7-amino-l-cyclopropyl-4-oxo-l,4-dihydro-naphthyridin-3-carboxylsyrer med formlen I ved, at man omsætter en naphthyridon-3-carboxylsyre med formlen II 5
A ^ COOR
λ! ji
X B N
10 Δ hvor A og B har den ovenfor anførte betydning, og X betyder et halogenatom eller en alkylsulfonylgruppe med 1-4 carbon-atomer, med en forbindelse med formlen 15 R\ y NH (III) r2/ hvor R1 og har den ovenfor anførte betydning. Ved frem-20 gangsmådevariant b) omsættes 7-halogen-naphthyridin-3-car-boxylsyreestere med formlen (II), hvor R betyder alkyl, med en forbindelse med formlen (III), eventuelt i nærværelse af et syrebindemiddel, såsom triethylamin eller pyridin, hvorefter den fremkomne 7-amino-naphthyridin-3-carboxylsyreester 25 forsæbes alkalisk.
Såfremt man ved omsætningen af forbindelsen med formlen (II) med forbindelsen med formlen (III) eksempelvis anvender 7-chlor-l-cyclopropyl-4-oxo-l,4-dihydro-l,6-naph-thyridin-3-carboxylsyre og pyrrolidin som reaktanter, kan 30 reaktionsforløbet gengives ved følgende reaktionsskema:
O
3
DK 161460 B
^ i C O OH
jOm > d — " Λ o ^^y^COOH p 10 Γ^Ν-'^νλ i + f~JIH X HC1 Λ 15
Udgangsforbindelserne med formlen (II) kan fremstilles på følgende måde:
Man går eksempelvis ud fra i 6-stilling med X substituerede 4-halogen-pyridin-3-carboxylsyreestere med formlen (IV), 20 som med β-cyclopropylamino-propionsyreesterne med formlen (V), fortrinsvis methyl- eller ethylester, som er let tilgængelige ved omsætning af tilsvarende acrylsyreestere med cyclopropyl-amin, i vid udstrækning selektivt under udskiftning af det i 4-stilling værende halogenatom med amingruppen omsæt-25 tes til monosubstitutionsprodukterne med formlen (VI). Sidstnævnte går i nærværelse af en stærk base, såsom kalium-tert.-butanolat eller natriumhydrid, ved Dieckmann-cyclisering, over i tetrahydro-naphthyridin-3-carboxylsyreesteren med formlen (VII). Med brom eller sulfurylchlorid og triethylamin eller 30 pyridin som dehydrohalogeneringsmiddel får man ud fra forbindelsen med formlen (VII) carboxylsyreesteren med formlen (VIII), som kan forsæbes med alkali til carboxylsyrer-ne med formlen (II) (R=H, A=N, B=CH). Fremgangsmåden fremgår af følgende reaktionsskema: 35 4
DK 161460 B
/C00R CH, CHo COOR
014 fY001
X Hal Δ +NEt3 x^v^N-(CH2 )2C00R
5 IV Y VI ^ 200(0¾ )3 y 0 n “" s- PO ^ xy Δ Δ
VIII VII
15
Som fortyndingsmidler til reaktionen (II)—^ (I) anvendes fortrinsvis ethanol, dioxan, toluen, DMF og dimethyl-sulfoxid. Som syrebindemiddel kan fortrinsvis anvendes alkalimetalcarbonater, alkalimetalhydroxider eller tertiære 20 organiske baser, såsom triethylamin, pyridin osv.
Reaktionstemperaturerne kan varieres inden for et større område. Almindeligvis arbejdes der ved temperaturer mellem ca. 20° og ca. 180°C, fortrinsvis mellem 60° og 140°C.
Omsætningen kan gennemføres ved normaltryk, men også 25 ved forhøjet tryk. Almindeligvis arbejdes der ved tryk mellem ca. 1 og ca. 100 bar, fortrinsvis mellem 1 og 10 bar.
Ved gennemførelsen af fremgngsmåden anvendes der til 1 mol carboxylsyre 1-5 mol, fortrinsvis 2-3 mol forbindelse (II).
30 5
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Eksempler
En suspension af 7-chlor-l-cyclopropyl-4-oxo-l,4-dihydro-1,6-naphthyridin-3-carboxylsyre og (alkyl)-piperazin eller pyrrolidin i ethanol opvarmes til kogning under til-5 bagesvaling. Fortyndingsmidlet bortdestilleres under formindsket tryk, hvorpå remanensen opløses i 1 N NaOH, filtreres og syrnes med 10%'s saltsyre. Bundfaldet skilles fra ved sugning og vaskes med vand og ethanol. Omkrystallisationen kan ske fra N-dimethylformamid/ethanol.
10 Ved fremgangsmåden beskrevet ovenfor fås carboxyl- syrerne ifølge eksemplerne. Disse er sammenfattet i tabel I. Nummereringen af grupperne R1 og R2 refererer til formlen (I) i beskrivelsen. 1 6
DK 161460B
Tabel I
Eksempel .. 0 Søndd.
nr. AB R1 ΈΓ (°C) 1 N CH -CHa 0¾ CHa 0¾ - 330
H
2 CF CH -(CH2)2N(CH2)2- 256 . 306 (Hydrochlorid) 3 CF CH -(CH2)2N(CH2)2- 249 ch3 4 CF CH -(CH2)4- 323
H
5 C-CN N -(CH2)2N(CH2)2- 335 (Hydrochlorid) 6 C-CN N -(CH2)2N(CH2)2- 295 (Hydrochlorid) ch3 7 C-CN N -(CH2)4- 290 8 CF CH -(CH2)2N(CH2)2- 306 (Hydroiodid) C2H5
O
7
DK 161460 B
Den som udgangsmateriale anvendte 7-chlor-l-cyclopropyl--4-oxo-l,4-dihydro-l,6-naphthyridin-3-carboxylsyre kan fremstilles ved en flertrinsreaktion, f.eks. idet der gås ud fra de kendte 4,6-dichlor-nikotinsyremethylestere (Recueil 5 Trav. chim. Pays-bas. 6j), 687 (1950)).
1) 6-Chlor-4-(N-2-methoxycarbonylethyl-N-cyclopropyl-amino-pyridin-3-carboxylsyremethylester (VI, R = methyl, X = chlor).
Til en opløsning af 41,2 g 4,6-dichlor-pyridin-3-carb-10 oxylsyremethylester i 150 ml toluen sættes der under isafkøling og omrøring ved hurtig tildrypning en blanding af 28,6 g β-cyclopropylamino-propionsyremethylester og 21 g triethyl-amin ved 10-20°C. Isbadet fjernes, og der omrøres i 1/2 time ved stuetemperatur og opvarmes i 6 timer under tilbagesva-15 ling til kogning. Den fremkomne suspension vaskes med vand, tørres med Na2SO^, og opløsningsmidlet bortdestilleres under formindsket tryk. Der fås 59 g af den ovenfor anførte forbindelse som en brun olie.
Den som reaktant anvendte β-cyclopropylamino-propion-20 syremethylester fremstilles på følgende måde:
Til en til -60°C til -70°C afkølet opløsning af 57 g cyclopropylamin i 150 ml ethanol tildryppes der i løbet af ca. 3 timer 86 g til -60°C afkølet, frisk destilleret acryl-syremethylester. Derpå lader man opløsningen langsomt opnå 25 stuetemperatur natten over, bortdestillerer opløsningsmidlet under formindsket tryk, hvorpå man fraktionerer. Ved 84-86°C/ 22 Torr tilvejebringes der 95 g β-cyclopropylamino-propion-syremethylester.
2) 7-Chlor-l-cyclopropyl-4-oxo-l,2,3,4-tetrahydro-l,6-30 -naphthyridin-3-carboxylsyremethylester (VII, R = methyl, X = chlor).
59 g rå 6-chlor-4-(N-2-methoxycarbonylethyl-N-cyclo-propyl)-amino-pyridin-3-carboxylsyremethylester opløses i 240 ml vandfri toluen, og under omrøring tilsættes der hurtigt 35 23 g kalium-tert.butanolat. Man lader opløsningen henstå natten over, hvorpå man tilsætter 20 g iseddike og 100 ml 8
O
DK 161460 B
vand, adskiller faserne, vasker toluenopløsningen endnu engang med vand, tørrer med Na2SO^ og fjerner toluenen under formindsket tryk. Efter omkrystallisation fra methanol dannes der 18 g carboxylsyreester med et smp. på 155-157°C.
\ 5 3) 7-Chlor-l-cyclopropyl-4-oxo-l,4-dihydro-l,6-naphthy- ridin-3-carboxylsyremethylester (VIII, R = methyl, X = chlor).
9,8 g af den ifølge 2) fremstillede tetrahydro-naphthy-ridin-3-carboxylsyremethylester opløses i 200 ml methylenchlo-rid og under isafkøling ved 10-15°C tildryppes der hurtigt 10 en opløsning af 5,9 g brom i 40 ml CE^C^. Derefter omrøres der i yderligere 10 minutter ved ca. 10°C, hvorpå der tilsættes 8 g triethylamin, og isbadet fjernes. Der efterrøres i 3 timer, vaskes 2 gange med vand, tørres med Na2S0^, hvorpå opløsningsmidlet bortdestilleres under formindsket tryk, og 15 remanensen omkrystalliseres fra DMF/ethanol. Der dannes 8,8 g 7-chlor-l-cyclopropyl-4-oxo-l,4-dihydro-naphthyridin--3-carboxylsyremethylester med et smp. på 272°-274°C (sønderdeling).
4) 7-Chlor-l-cyclopropyl-4-oxo-l,4-dihydro-l,6-naphthy-20 ridin-3-carboxylsyre (II, R = H, A = N, B=CH, X= chlor).
Til 27,85 g af den ifølge 3) fremstillede ester sættes der en opløsning af 5,7 g ætskali i 300 ml vand. Under omrøring opvarmes der i 30 minutter til 85 til 95°C, hvorpå den fremkomne opløsning filtreres ved stuetemperatur og syrnes 25 med iseddike. Bundfaldet skilles fra ved sugning, vaskes med vand og tørres i et vakuumtørreskab over calciumchlorid.
Der dannes 20 g ren 7-chlor-l-cyclopropyl-4-oxo-l,4-dihydro--l,6-naphthyridin-3-carboxylsyre med et smp. på 226-227°C.
Det har desuden vist sig, at de her omhandlede forbin-30 delser besidder fremragende antimikrobielle egenskaber.
Især er de bredt bakteriostatisk og baktericidt virksomme mod grampositive bakterier, såsom staphylococcer og streptococcer, og gramnegative bakterier, såsom Escherichia, Proteus, Providencia, Enterobacter, Klebsiella, Salmonella 35 og Pseudomonas. Opremsningen af følsomme bakterier er eksempelvis.
9
DK 161460 B
o
Den forbedrede antibakterielle virkning af de her omhandlede, hidtil ukendte forbindelser er i sammenligning med 2-pipera-zino-8-ethyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidin-6--carboxylsyre ("Pipemidinsyre") eller den kendte l-ethyl-7-5 -methyl-4-naphthyridon-(1,8)-3-carboxylsyre ["Nalidixinsyre", Ehrhart/Ruschig, Arzneimittel, bind 2: Chemotherapeutika,
Verlag Chemie 1968, side 1568] in vitro og in vivo ved Staphylo-coccer, Escherichia coli, Proteus, Klebsiella, Pseudomonas osv. langt overlegen.
10 Den forbedrede brede antibakterielle virkning af de her omhandlede forbindelser muliggør deres anvendelse som virksomme stoffer både inden for human- og inden for veterinærmedicinen, hvor de kan anvendes både til forebyggelse og til behandling af systemiske eller lokale bakterielle infek-15 tioner, især af urinveje. De her omhandlede forbindelser kan desuden anvendes som fodertilsætningsmidler til fremme af væksten og til forbedring af foderudnyttelsen hos dyrehold, især hos fedekvægshold. Indgivelsen af de virksomme stoffer sker da fortrinsvis via foderet og/eller drikkevandet.
20
De her omhandlede forbindelser med formlen I kan eksempelvis anvendes i foderstofkoncentrater til dyrehold, som på gængs måde foruden de virksomme stoffer også kan indeholde vitaminer og/eller mineralsalte eller farmaceutiske præparater.
Λβ
Farmaceutiske præparater indeholder foruden de her omhandlede forbindelser på gængs måde ikke-toksiske, indifferente farmaceutisk acceptable bærestoffer. Sådanne farmaceutisk acceptable bærestoffer er eksempelvis fyldstoffer og strækkemidler, bindemidler, fugtighedsbevarende midler, 30 opløsningsretarderende midler, resorptionsfremskyndende midler, fugtemidler, adsorptionsmidler eller giidemidler, som kan have en fast, halvfast eller flydende konsistens.
Sådanne farmaceutisk acceptable bærestoffer kendes af enhver fagmand.
35
Som foretrukne farmaceutiske præparater skal nævnes
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10
DK 161460 B
tabletter, drageer, kapsler, piller, granulater, suppositorier, opløsninger, suspensioner og emulsioner, pastaer, salver, geler, cremer, lotioner, puddere og sprays. Fremstillingen af disse præparater sker ifølge kendte metoder på gængs måde, 5 eksempelvis ved sammenblanding af de her omhandlede virksomme stoffer med de gængse bære- og tilsætningsstoffer. Det aktive stof skal i de anførte farmaceutiske præparater være til stede i en koncentration på ca. 0,1 til 99,5, fortrinsvis på ca. 0,5 til 95 vægtprocent af den samlede blanding.
10 Tilvejebringelsen af nye baktericider til bekæmpelse af bakterier, der er resistente over for kendte baktericider, er en berigelse af den kendte teknik.
15 20 25 30 35 11
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DK 161460 B
γυυΥ"°η „ KMs^ i MK[ug/ml]Agarfortyndingstest(Isosensitest-Medium)Denley-Multipoint Inokulator
Escherichia coli A261 <0.015 455/7 < 0.5
Neumann <0.015
Klebsiella 8085 <0.015 63 <0.015
Proteus vulg. 1017 <0.015
Pseudomonas Walter 0.125
Pseudomonas aerug. K. 0.25
Staphylococcus 133 0.5
Streptococcus faec. 27101 0.25 FXrV“°B o.
^ A
CH3 MHK [pg/ml] Agarf ortyndingsi~-p.s t (Isosensitest-Medium) Denley Multipoint Inokulator
Escherichia coli Neumann <0.015
Klebsiella 8085 <0.015 63 0.03
Proteus 1017 0.03
Pseudomonas Waller 1
Staphylococcus 133 0.25 14
DK 161460 B
Ρ-γΧω0Η r Av
° A
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Escherichia coli A261 < 0.25
Neumann < 0.25
Klebsiella 8085 <0.25 63 0.5-1
Proteus 1017 0.25
Pseudomonas Walter 8
Staphylococcus 133 <0.25 nvJLcooh «> hn^ ^ MHK[pg/ml]Agarfortyndingstest(Isosensitest-Medium)Denley Multipoint Inokulator
Escherichia coli A261 <0.06
Neumann < 0.06
Klebsiella 8085 0.125 63 1
Proteus 1017 0.5 - 0.25
Pseudomonas Walter 4
Staphylococcus 133 < 128 / > 8
Streptococcus Walter 8
DK 161460 B
15 ”cnVc""» ^νλνλν;
A
CH3 ΑΛ MHK[ug/ml]Agarfortyndingstest(Isosensitest-Medium)Denley Multipoint Inokulator
Escherichia coli A261 0.125
Neumann 0.06
Klebsiella 8085 0.125 63 0.5
Proteus 1017 0.06
Pseudomonas Walter 4
Staphylococcus 133 8
Streptococcus Walter 8 nvJLcooh
^ A
MHK[ug/ml]Agarfortyndingstest(Isosensitest-Medium)Denley Multipoint Inokulator
Escherichia coli A261 0.5
Neumann 0.25
Klebsiella 8085 0.25 63 2
Proteus 1017 0.5 - 0.25
Pseudomonas Walter < 128/>8
Staphylococcus 133 0.25
Streptococcus Walter 8 16
DK 161460 B
Vr”·»
^ A
C2H5 11 MHK[ug/ml]Agarfortyndingstest (Isosensitest-Medium)Denley Multipoint Inokulator Escherichia coli 455/7 4
Neumann < 0.015
Klebsiella 63 0.03
Proteus mir. 8223 4
Proteus vulg. 1017 0.06
Proteus morg. 432 < 0.015
Pseudomonas Walter 0.5
Staphylococcus aur. 133 0.25
Streptococcus faec. 9790 0.5
Claims (1)
- 5 R2 hvor R1 og R2 har den ovenfor anførte betydning, eller (b) en 7-halogen-naphthyridon-3-carboxylsyreester med den almene formel (II), hvor R betyder alkyl, omsættes med en forbindelse med den almene formel (III) eventuelt i nær-10 værelse af et syrebindemiddel, såsom triethylamin eller pyridin, hvorefter den fremkomne 7-amino-naphthyridin-3-carboxyl syreester forsæbes alkalisk.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19803033157 DE3033157A1 (de) | 1980-09-03 | 1980-09-03 | 7-amino-1-cyclopropyl-4-oxo-1,4-dihydro-naphthyridin-3-carbonsaeuren, verfahren zu ihrer herstellung sowie diese enthaltende antibakterielle mittel |
DE3033157 | 1980-09-03 |
Publications (3)
Publication Number | Publication Date |
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DK387781A DK387781A (da) | 1982-03-04 |
DK161460B true DK161460B (da) | 1991-07-08 |
DK161460C DK161460C (da) | 1991-12-16 |
Family
ID=6111041
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Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DK387781A DK161460C (da) | 1980-09-03 | 1981-09-02 | Analogifremgangsmaade til fremstilling af 7-amino-1-cyclopropyl-4-oxo-1,4-dihydro-naphthyridin-3-carboxylsyrer |
Country Status (17)
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EP (1) | EP0049355B1 (da) |
JP (3) | JPS5777683A (da) |
KR (1) | KR870000441B1 (da) |
AR (1) | AR227063A1 (da) |
AT (1) | ATE9803T1 (da) |
AU (1) | AU540242B2 (da) |
CY (1) | CY1301A (da) |
DE (2) | DE3033157A1 (da) |
DK (1) | DK161460C (da) |
ES (1) | ES8206523A1 (da) |
HK (1) | HK61485A (da) |
IE (1) | IE51541B1 (da) |
KE (1) | KE3545A (da) |
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NL (2) | NL930032I2 (da) |
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Families Citing this family (64)
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DE3142854A1 (de) * | 1981-10-29 | 1983-05-11 | Bayer Ag, 5090 Leverkusen | 1-cyclopropyl-6-fluor-1,4-dihydro-4-oxo-7-piperazino-chinolin-3-carbonsaeuren, verfahren zu ihrer herstellung sowie diese enthaltende antibakterielle mittel |
JPS5925391A (ja) * | 1982-07-30 | 1984-02-09 | Dainippon Pharmaceut Co Ltd | ピリジルナフチリジン誘導体およびその塩 |
US4665079A (en) * | 1984-02-17 | 1987-05-12 | Warner-Lambert Company | Antibacterial agents |
US5281612A (en) * | 1982-09-09 | 1994-01-25 | Warner-Lambert Company | Naphthyridine antibacterial agents |
DE3248507A1 (de) * | 1982-12-29 | 1984-07-05 | Bayer Ag, 5090 Leverkusen | Mikrobizide mittel auf chinoloncarbonsaeure basis |
DE3248505A1 (de) * | 1982-12-29 | 1984-07-05 | Bayer Ag, 5090 Leverkusen | 1-cyclopropyl-6-fluor-1,4-dihydro-4-oxo-7(4- (oxoalkyl)-1-piperazinyl/-3-chinolincarbonsaeuren und ihre derivate, verfahren zu ihrer herstellung sowie diese enthaltende antibakterielle mittel |
DE3248506A1 (de) * | 1982-12-29 | 1984-07-05 | Bayer Ag, 5090 Leverkusen | 1-cyclopropyl-6-fluor-1,4-dihydro-4-oxo-7(alkyl-1-piperazinyl)-3-chinolincarbonsaeuren, verfahren zu ihrer herstellung sowie diese enthaltende antibakterielle mittel |
DE3306771A1 (de) * | 1983-02-25 | 1984-08-30 | Bayer Ag, 5090 Leverkusen | Chinoloncarbonsaeuren, verfahren zu ihrer herstellung sowie diese enthaltende antibakterielle mittel |
DE3306772A1 (de) * | 1983-02-25 | 1984-08-30 | Bayer Ag, 5090 Leverkusen | Chinolonsaeuren, verfahren zu ihrer herstellung sowie diese enthaltende antibakterielle mittel |
DE3308909A1 (de) * | 1983-03-12 | 1984-09-13 | Bayer Ag, 5090 Leverkusen | Bakterizide mittel auf chinoloncarbonsaeure-basis |
DE3308908A1 (de) * | 1983-03-12 | 1984-09-13 | Bayer Ag, 5090 Leverkusen | Bakterizide mittel |
DE3318145A1 (de) * | 1983-05-18 | 1984-11-22 | Bayer Ag, 5090 Leverkusen | 7-amino-1-cyclopropyl-6,8-difluor-1,4-dihydro-4-oxo-3-chinolincarbonsaeuren, verfahren zu ihrer herstellung sowie diese enthaltende antibakterielle mittel |
JPS6056959A (ja) * | 1983-07-18 | 1985-04-02 | アボツト ラボラトリ−ズ | キノリン抗菌性化合物 |
DE3326190A1 (de) * | 1983-07-20 | 1985-01-31 | Bayer Ag, 5090 Leverkusen | 5-cyclopropyl-5,8-dihydro-8-oxo-1,3-dioxolo-(4,5-g) chinolin-7-carbonsaeure, verfahren zu ihrer herstellung sowie diese enthaltende antibakterielle mittel |
CS274601B2 (en) | 1983-07-27 | 1991-09-15 | Dainippon Pharmaceutical Co | Method of 1,8-naphthyridine derivative production |
JPS6028978A (ja) * | 1983-07-27 | 1985-02-14 | Dainippon Pharmaceut Co Ltd | 1,8−ナフチリジン誘導体 |
JPS60260577A (ja) * | 1984-06-06 | 1985-12-23 | Dainippon Pharmaceut Co Ltd | 1,8−ナフチリジン誘導体 |
JPS6032790A (ja) * | 1983-08-01 | 1985-02-19 | Dainippon Pharmaceut Co Ltd | 1,8−ナフチリジン類 |
AU553415B2 (en) * | 1983-09-19 | 1986-07-17 | Abbott Japan Co., Ltd. | 6-fluoro-1-4-dihydro-4-oxo-7-substituted piperazinyl- quinoline-3-carboxylic acids |
JPS6089480A (ja) * | 1983-10-21 | 1985-05-20 | Dainippon Pharmaceut Co Ltd | ピリドンカルボン酸誘導体 |
US4551456A (en) * | 1983-11-14 | 1985-11-05 | Merck & Co., Inc. | Ophthalmic use of norfloxacin and related antibiotics |
JPS60126284A (ja) * | 1983-12-09 | 1985-07-05 | Dainippon Pharmaceut Co Ltd | ピリドンカルボン酸誘導体およびその塩 |
DE3574380D1 (en) * | 1984-02-17 | 1989-12-28 | Daiichi Seiyaku Co | 1,8-naphthyridine derivatives |
CA1285279C (en) * | 1984-02-17 | 1991-06-25 | Joseph P. Sanchez | 7-amine derivatives of 1-cyclopropyl-6,8-difluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acids and 1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine- 3-carboxylic acidsas antibacterial agents |
JPS60228479A (ja) * | 1984-04-26 | 1985-11-13 | Toyama Chem Co Ltd | 1,4−ジヒドロ−4−オキソナフチリジン誘導体およびその塩 |
US4732311A (en) * | 1984-05-31 | 1988-03-22 | Nippondenso Co., Ltd. | Process of producing lightweight and corrosion-resistant heat exchanger |
DE3420743A1 (de) * | 1984-06-04 | 1985-12-05 | Bayer Ag, 5090 Leverkusen | 7-amino-1-cyclopropyl-6,8-dihalogen-1,4-dihydro-4-oxo-3-chinolincarbonsaeuren, verfahren zu ihrer herstellung sowie diese enthaltende antibakterielle mittel |
DE3420770A1 (de) * | 1984-06-04 | 1985-12-05 | Bayer Ag, 5090 Leverkusen | 1-cyclopropyl-6-fluor-1,4-dihydro-4-oxo-7-(3-oxo-1-piperazinyl)-3-chinoloncarbonsaeuren, verfahren zu ihrer herstellung sowie diese enthaltende antibakterielle mittel |
DE3420798A1 (de) * | 1984-06-04 | 1985-12-05 | Bayer Ag, 5090 Leverkusen | 7-(3-aryl-l-piperazinyl)- sowie 7-(3-cyclohexyl-l-piperazinyl)-3-chinoloncarbonsaeuren |
US5468861A (en) * | 1984-06-04 | 1995-11-21 | Bayer Aktiengesellschaft | 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and alkyl esters thereof |
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IT1200470B (it) * | 1985-05-10 | 1989-01-18 | Schering Spa | Composti ad attivita' antibatterica,loro preparazione e composizioni farmaceutiche relative |
GB8512143D0 (en) * | 1985-05-14 | 1985-06-19 | Beecham Group Plc | Method of treatment |
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DE3542002A1 (de) * | 1985-11-28 | 1987-06-04 | Bayer Ag | 1-cyclopropyl-6-fluor-1,4-dihydro-4-oxo-7- (1-piperazinyl)-3-chinolincarbonsaeuren, verfahren zu ihrer herstellung sowie diese enthaltende antibakterielle mittel |
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HU198709B (en) * | 1987-04-08 | 1989-11-28 | Chinoin Gyogyszer Es Vegyeszet | Process for producing quinoline-carboxylic acid derivatives |
DE3713672A1 (de) * | 1987-04-24 | 1988-11-17 | Bayer Ag | Verfahren zur herstellung von parenteral verabreichbaren chinoloncarbonsaeuren |
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PT726270E (pt) | 1995-02-09 | 2001-08-30 | Bayer Ag | Derivados do acido 1,6-naftiridonocarboxilico |
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IT1280428B1 (it) * | 1995-07-14 | 1998-01-20 | R R A S R L | Composizione farmaceutica per uso topico |
KR100768034B1 (ko) | 1999-03-17 | 2007-10-17 | 다이이찌 세이야꾸 가부시기가이샤 | 의약 조성물 |
SE9904108D0 (sv) | 1999-11-15 | 1999-11-15 | New Pharma Research Ab | Nya föreningar |
JP4290381B2 (ja) * | 2002-04-11 | 2009-07-01 | 学校法人 聖マリアンナ医科大学 | ピリドンカルボン酸化合物含有エマルション |
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Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
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JPS4843508A (da) * | 1971-10-05 | 1973-06-23 | ||
JPS5732059B2 (da) * | 1974-02-09 | 1982-07-08 | ||
JPS5635188B2 (da) * | 1974-02-12 | 1981-08-15 | ||
JPS587626B2 (ja) * | 1974-02-13 | 1983-02-10 | 大日本製薬株式会社 | ナフチリジン オヨビ キノリンユウドウタイノセイホウ |
JPS5437151A (en) * | 1977-08-29 | 1979-03-19 | Mizusawa Industrial Chem | Method of improving basic lead sulfate |
JPS5466686A (en) * | 1977-09-20 | 1979-05-29 | Dainippon Pharmaceut Co Ltd | Quinoline-3-carboxylic acid derivative, its preparation, and pharmaceutical composition containig the same |
SE444566B (sv) * | 1977-09-20 | 1986-04-21 | Bellon Labor Sa Roger | 7-dialkylamin-6-halogen-4-oxo-1,4-dihydrokinolin-3-karboxylsyra, forfarande for framstellning derav och farmaceutiskt preparat derav |
DE2808070A1 (de) * | 1978-02-24 | 1979-08-30 | Bayer Ag | Verfahren zur herstellung von 4-pyridon-3-carbonsaeuren und/oder deren derivaten |
JPS5845426B2 (ja) * | 1978-09-29 | 1983-10-08 | 杏林製薬株式会社 | 置換キノリンカルボン酸誘導体 |
DE2903850A1 (de) * | 1979-02-01 | 1980-08-07 | Bayer Ag | 2-amino-8-cyclopropyl-5-oxo-5,8- dihydro-pyrido eckige klammer auf 2,3-d eckige klammer zu -pyrimidin-6-carnonsaeuren, verfahren zu ihrer herstellung sowie ihrer verwendung als antibakterielle mittel |
-
1980
- 1980-09-03 DE DE19803033157 patent/DE3033157A1/de not_active Withdrawn
-
1981
- 1981-08-21 CY CY1301A patent/CY1301A/xx unknown
- 1981-08-21 AT AT81106511T patent/ATE9803T1/de active
- 1981-08-21 DE DE8181106511T patent/DE3166619D1/de not_active Expired
- 1981-08-21 EP EP81106511A patent/EP0049355B1/de not_active Expired
- 1981-08-27 AU AU74680/81A patent/AU540242B2/en not_active Expired
- 1981-09-01 JP JP56136224A patent/JPS5777683A/ja active Granted
- 1981-09-02 ES ES505138A patent/ES8206523A1/es not_active Expired
- 1981-09-02 DK DK387781A patent/DK161460C/da not_active IP Right Cessation
- 1981-09-02 IE IE2032/81A patent/IE51541B1/en not_active IP Right Cessation
- 1981-09-02 ZA ZA816080A patent/ZA816080B/xx unknown
- 1981-09-03 KR KR1019810003285A patent/KR870000441B1/ko active
-
1982
- 1982-01-01 AR AR227063D patent/AR227063A1/es active
-
1985
- 1985-06-11 SG SG44685A patent/SG44685G/en unknown
- 1985-06-19 KE KE3545A patent/KE3545A/xx unknown
- 1985-08-15 HK HK614/85A patent/HK61485A/xx not_active IP Right Cessation
-
1987
- 1987-01-16 JP JP62006272A patent/JPS62161728A/ja active Granted
- 1987-01-16 JP JP62006271A patent/JPS62161763A/ja active Granted
- 1987-12-30 MY MY363/87A patent/MY8700363A/xx unknown
-
1993
- 1993-05-24 NL NL930032C patent/NL930032I2/nl unknown
- 1993-05-24 NL NL930033C patent/NL930033I1/nl unknown
Also Published As
Publication number | Publication date |
---|---|
JPS5777683A (en) | 1982-05-15 |
JPS62161763A (ja) | 1987-07-17 |
CY1301A (en) | 1985-12-06 |
NL930032I1 (nl) | 1993-08-02 |
MY8700363A (en) | 1987-12-31 |
JPH0316344B2 (da) | 1991-03-05 |
AR227063A1 (es) | 1982-09-15 |
JPH0314811B2 (da) | 1991-02-27 |
KE3545A (en) | 1985-07-19 |
IE812032L (en) | 1982-03-03 |
ATE9803T1 (de) | 1984-10-15 |
EP0049355B1 (de) | 1984-10-10 |
KR830007642A (ko) | 1983-11-04 |
EP0049355A1 (de) | 1982-04-14 |
HK61485A (en) | 1985-08-23 |
DE3166619D1 (en) | 1984-11-15 |
ES505138A0 (es) | 1982-08-16 |
NL930032I2 (nl) | 1997-03-03 |
SG44685G (en) | 1986-01-17 |
KR870000441B1 (ko) | 1987-03-10 |
IE51541B1 (en) | 1987-01-07 |
DK387781A (da) | 1982-03-04 |
ZA816080B (en) | 1982-08-25 |
AU540242B2 (en) | 1984-11-08 |
DK161460C (da) | 1991-12-16 |
ES8206523A1 (es) | 1982-08-16 |
DE3033157A1 (de) | 1982-04-01 |
JPS6356224B2 (da) | 1988-11-07 |
AU7468081A (en) | 1982-03-11 |
NL930033I1 (nl) | 1993-08-02 |
JPS62161728A (ja) | 1987-07-17 |
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