DK171935B1 - Quinolin-forbindelser - Google Patents
Quinolin-forbindelser Download PDFInfo
- Publication number
- DK171935B1 DK171935B1 DK028892A DK28892A DK171935B1 DK 171935 B1 DK171935 B1 DK 171935B1 DK 028892 A DK028892 A DK 028892A DK 28892 A DK28892 A DK 28892A DK 171935 B1 DK171935 B1 DK 171935B1
- Authority
- DK
- Denmark
- Prior art keywords
- dihydro
- trifluoro
- cyclopropyl
- mmol
- acid
- Prior art date
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- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 26
- -1 quinoline compound Chemical class 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- CQPUZLMNORVQPG-UHFFFAOYSA-N 5-amino-1-cyclopropyl-6,7,8-trifluoro-4-oxoquinoline-3-carboxylic acid Chemical group C1=C(C(O)=O)C(=O)C=2C(N)=C(F)C(F)=C(F)C=2N1C1CC1 CQPUZLMNORVQPG-UHFFFAOYSA-N 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 150000001768 cations Chemical group 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- FKRCODPIKNYEAC-UHFFFAOYSA-N propionic acid ethyl ester Natural products CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 5
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- RUGZVPRCKQMYAZ-UHFFFAOYSA-N 2,3,4,5-tetrafluoro-6-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=C(F)C(F)=C(F)C(F)=C1C(Cl)=O RUGZVPRCKQMYAZ-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 3
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000002585 base Chemical class 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- XMSGWEPSTPUTJE-UHFFFAOYSA-N ethyl 5-acetamido-1-cyclopropyl-6,7,8-trifluoro-4-oxoquinoline-3-carboxylate Chemical compound C12=C(F)C(F)=C(F)C(NC(C)=O)=C2C(=O)C(C(=O)OCC)=CN1C1CC1 XMSGWEPSTPUTJE-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 231100000760 phototoxic Toxicity 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 150000003248 quinolines Chemical class 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- JZSQIYJMXLNQEI-UHFFFAOYSA-N 2-acetamido-3,4,5,6-tetrafluorobenzoic acid Chemical compound CC(=O)NC1=C(F)C(F)=C(F)C(F)=C1C(O)=O JZSQIYJMXLNQEI-UHFFFAOYSA-N 0.000 description 1
- PBYXLJLQKIWYJJ-UHFFFAOYSA-N 2-acetamido-3,4,5,6-tetrafluorobenzoyl chloride Chemical compound CC(=O)NC1=C(F)C(F)=C(F)C(F)=C1C(Cl)=O PBYXLJLQKIWYJJ-UHFFFAOYSA-N 0.000 description 1
- CNSGPAMLXMBLNA-UHFFFAOYSA-N 2-amino-3,4,5,6-tetrafluorobenzoic acid Chemical compound NC1=C(F)C(F)=C(F)C(F)=C1C(O)=O CNSGPAMLXMBLNA-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical group 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- PRNXYRWUZSNSFK-UHFFFAOYSA-N ethyl 1-cyclopropyl-6,7,8-trifluoro-5-nitro-4-oxoquinoline-3-carboxylate Chemical compound C12=C(F)C(F)=C(F)C([N+]([O-])=O)=C2C(=O)C(C(=O)OCC)=CN1C1CC1 PRNXYRWUZSNSFK-UHFFFAOYSA-N 0.000 description 1
- BOFBKJLYZUFZMV-UHFFFAOYSA-N ethyl 5-amino-1-cyclopropyl-6,7,8-trifluoro-4-oxoquinoline-3-carboxylate Chemical compound C12=C(F)C(F)=C(F)C(N)=C2C(=O)C(C(=O)OCC)=CN1C1CC1 BOFBKJLYZUFZMV-UHFFFAOYSA-N 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000005497 microtitration Methods 0.000 description 1
- BUQMHUKZYMREQT-UHFFFAOYSA-N n-(pyrrolidin-3-ylmethyl)ethanamine Chemical compound CCNCC1CCNC1 BUQMHUKZYMREQT-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- XRXDAJYKGWNHTQ-UHFFFAOYSA-N quipazine Chemical class C1CNCCN1C1=CC=C(C=CC=C2)C2=N1 XRXDAJYKGWNHTQ-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Communicable Diseases (AREA)
- Animal Behavior & Ethology (AREA)
- Oncology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
- Quinoline Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
DK 171935 B1
Den foreliggende opfindelse angår quinolin-forbindelser som er anvendelige som mellemprodukter i fremstillingen af forbindelser med antibakteriel aktivitet.
5 Chemical Abstracts 100: 51467 y omhandler pipera- zinylquinoliner. De herfra kendte forbindelser adskiller sig fra slutprodutkerne opnåelige ud fra de af opfindelsen omhandlede mellemprodukter ved substituen-terne i 1- og 7-stillingen af quinolin-skelettet.
10 I EP patentansøgning nr. 106.489 omhandles for bindelser med den almene formel ; χκίτ1' k 20 hvor X kan være CH, CF eller N, og Z kan være forskellige former for N-holdige ringe. Disse kendte forbindelser adskiller sig fra slutproduktet opnåeligt ud fra mellemprodukterne ifølge opfindelsen ved ikke at 25 være substitueret i 5-stillingen med en Nl^-gruppe. De kendte forbindelser besidder en udtalt fototoksisk egenskab medens slutprodukterne for mellemprodukterne ifølge opfindelsen er langt mindre fototoksiske.
Quinolin-forbindelserne ifølge opfindelsen er 30 ejendommelige ved at de har den almene formel
NH2 M
'xxV”"1 35 k 2 DK 171935 B1 hvor X betegner CH, CF eller N og
Rj betegner hydrogen, C^-Cg alkyl eller en kation.
En foretrukken forbindelse er 5-amino-l-cyclo-5 propyl-6,7,8-trifluor-l,4-dihydro-4-oxoquinolin-3-carboxylsyre.
Forbindelserne ifølge opfindelsen kan fremstilles ved en række reaktioner, hvor der gås ud fra 3,4,5,6-tetrafluoranthranilsyre. Syren omsættes med eddikesyre-10 anhydrid og eddikesyre til dannelse af 2-acetylamino- 3.4.5.6- tetrafluorbenzosyre. Denne forbindelse omsættes med oxalylchlorid og dichlormethan i nærværelse af Ν,Ν-dimethylformamid som katalysator til opnåelse af 2-acetylamino-3,4,5,6-tetrafluorbenzoylchlorid. Dette 15 produkt behandles med n-butyllithium og malonsyre-halvester til dannelse af 2-acetylamino-3,4,5,6-tetra-fluor-8-oxobenzen-propionsyreethylester.
Dette produkt kan omdannes til 5-acetylamino-l-cyclopropyl-6,7,8-trifluor-l,4-dihydro-4-oxoquinolin-20 3-carboxylsyre-ethylester ved en tretrins-reaktion.
2-Acetylamino-3,4,5,6-tetrafluor-p-oxobenzen-propion-syreethylesteren behandles først med triethylorthofor-mat og eddikesyreanhydrid. Efter fjernelse af opløsningsmidlet behandles resten med en opløsning af cyclo-25 propylamin i t-butanol. Efter afsluttet reaktion tilsættes en opløsning af kalium-t-butoxid i t-butanol. Det resulterende produkt er 5-acetylamino-l-cyclopro-pyl-6,7,8-trifluor-l,4-dihydro-4-oxo-quinolin-3-carboxylsyre-ethylester. Esteren hydrolyseres til dannelse 30 af l-cyclopropyl-5-amino-6,7,8-trifluor-l,4-dihydro-4-oxo-3-quinolincarb-oxylsyre.
ved en alternativ vej til fremstilling af forbindelserne ifølge opfindelsen startes med 2-nitro- 3.4.5.6- tetrafluor-benzoylchlorid. Dette udgangsmate-35 riale behandles med n-butyl-lithium og malonsyre- DK 171935 B1 3 halvester til dannelse af 2-nitro-3,4,5,6-tetrafluor-8-oxo-benzenpropionsyre-ethylester. Dette produkt kan omdannes til 5-nitro-l-cyclopropyl-6,7,8-trifluor-l,4-dihydro-4-oxo-guinolin-3-carboxylsyre-ethylester ved 5 en tretrins-reaktion. Udgangsmaterialet behandles først med triethylorthoformat og derefter med cyclo-propylamin i t-butylalkohol. Produktet ringsluttes med kalium-t-butoxid til dannelse af 5-nitro-l-cyclopropyl-6,7,8-trifluor-l,4-dihydro-4-oxoquinolin-3-carboxyl- 10 syre-ethylester. Dette produkt hydrogeneres til dannelse af den tilsvarende 5-amino-forbindelse. Denne hydrolyseres derefter til dannelse af l-cyclopropyl-5-amino-6,7,8-trifluor-l,4-dihydro-4-oxo-3-guinolin-car-boxylsyre.
15 De således fremstillede forbindelser ifølge op findelsen kan omdannes til forbindelserne med antibak-teriel aktivitet omhandlet i stamansøgningen til nærværende ansøgning (dansk patentansøgning nr. 3028/85), ved behandling med en cyklisk amin med strukturformlen 20 H N ^"'wiCR.R.) "NR,R.
V—eller 25 Ila /^(CH2 > <CRSR6 > 3 0 H-N Y N —R3 V_^<ch2) n-,y V_<ch2) n-
Ilb 35 4 DK 171935 B1 hvor n er 1, 2, 3 eller 4; n' er 1, 2, 3 eller 4, idet n + n' tilsammen er 2, 3, 4 eller 5, og n" er 0, 1 eller 2; R3 betegner hydrogen, alkyl med fra et til fire car-5 bonatomer eller cycloalkyl med fra tre til seks car-bonatomer; R4 betegner hydrogen, alkyl med fra et til fire carbonatomer, hydroxyalkyl med fra to til fire carbonatomer, trifluorethyl eller R7CO-, hvori R7 betegner alkyl med fra et til fire carbonatomer, eller 10 alkoxy med fra et til fire carbonatomer; R5 betegner hydrogen eller alkyl med fra et til tre carbonatomer,
Rg betegner hydrogen eller alkyl med fra et til tre carbonatomer; og farmaceutisk acceptable syreadditionssalte eller basesalte deraf.
15 Det resulterende produkt, som er omhandlet af stamansøgningen har følgende strukturformel NH, 0 F'vJ^LAJ:02R1 ,ο iTT 111 *2 hvori 25 R2 betegner alkyl med fra et til fire carbonatomer, vinyl, halogenalkyl eller hydroxyalkyl med fra to til fire carbonatomer eller cycloalkyl med fra tre til seks carbonatomer, og Z betegner 30 35 5 DK 171935 B1 /^(CH2>ns^ —N ^>— (CRsR6)n”NR3R4 5 V_(CH2)n' eller — N A N—R,
10 ^---icH,)'S\^icn,) ' S J
« π x n —^ hvori Rlt X, R3, R4, R5 og R6 samt n, n' og n" har de tidligere definerede betydninger.
Disse forbindelser udviser antibakteriel aktivi-15 tet, når de afprøves ved mikrotitrerings-fortyndings-metoden som beskrevet i Heifetz et al., Antimicr. Agents & Chemoth., 6, 124 (1974).
Ved reaktionen kan alkylamin-substituenten i forbindelsen Ila eller Ilb, om ønsket, være beskyttet 20 med en gruppe, som gør den i det væsentlige indifferent under reaktionsbetingelserne. Således kan f.eks. anvendes følgende beskyttelsesgrupper: Carboxyliske acyl- grupper, såsom formyl, acetyl, trifluoracetyl; alkoxy-carbonylgrupper, såsom ethoxycarbonyl, t-butoxycarbo-25 nyl, β,β,β-trichlorethoxycarbonyl, β-iodethoxycarbonyl; aryloxycarbonylgrupper, såsom benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, phenoxycarbonyl; silylgrup-per, såsom trimethylsilyl; og grupper, såsom trityl, tetrahydropyranyl, vinyloxycarbonyl, o-nitrophenylsul-30 fenyl, diphenylphosphinyl, p-toluensulfonyl og benzyl. Beskyttelsesgruppen kan, om ønsket, fjernes efter reaktionen mellem forbindelse IV og V og forbindelse via eller vib ved for fagmanden kendte fremgangsmåder. For eksempel kan ethoxycarbonylgruppen fjernes ved syre-35 eller base-hydrolyse, og tritylgruppen kan fjernes ved hydrogenolyse.
6 DK 171935 B1
Reaktionen mellem forbindelsen ifølge opfindelsen og en passende beskyttet forbindelse med formlen Ila eller Ilb kan udføres med eller uden opløsningsmiddel, fortrinsvis ved forhøjet temperatur i en tid, der er 5 tilstrækkelig til, at reaktionen er i det væsentlige fuldendt. Reaktionen udføres fortrinsvis i nærværelse af en syreacceptor, såsom et alkalimetal- eller jordal-kalimetalcarbonat eller -bicarbonat, en tertiær amin, såsom triethylamin, pyridin eller picolin. Alternativt 20 kan anvendes et overskud af forbindelsen med formlen VI som syreacceptor.
Egnede opløsningsmidler ved reaktionen er ikke-reaktionsdygtige opløsningsmidler, såsom acetonitril, tetrahydrofuran, ethanol, chloroform, dimethylsulfoxid, 15 dimethylformamid, pyridin, picolin, vand og lignende. Opløsningsmiddelblandinger kan også anvendes.
Egnede reaktionstemperaturer er i området fra ca. 20 til ca. 150°C; ved højere temperuaturer kræves sædvanligvis kortere reaktionstider.
20 Fjernelsen af beskyttelsesgurppen R4 kan udføres enten før eller efter isolering af produktet III. Alternativt behøver beskyttelsesgruppen R4 ikke at fjernes .
25 Eksempler:
Eksempel 1
Fremstilling af 5-amino-l-cyclopropyl-6,7,8-trifluor- 1,4-dlhvdro-4-oxo-3-quinollncarboxylat_ 30 Ovennævnte forbindelse blev opnået ved en frem gangsmåde i 5 trin ud fra en kendt forbindelse:
Trin 1: 7 DK 171935 B1 2-Nitro-3,4,5,6-tetrafluorbenzoylchlorid_
En opløsning af 6,7 g (29 mmol) 2-nitro-3,4,5,-5 6-tetrafluorbenzoesyre (Tetrahedron, 23, 4719, 1967), 3,8 g (30 mmol) oxalylchlorid og 50 ml dichlormethan blev behandlet med fire dråber Ν,Ν-dimethylformamid og omrørt ved stuetemperatur natten over. Opløsningsmidlet blev fjernet, og resten blev anvendt som sådant 10 uden yderligere rensning.
Trin 2: 2-Nitro-3,4,5,6-tetrafluor-β-oxobenzenpropionsyre- 15 ethylester_
Til en opløsning af 7,5 g (56,8 mmol) malonsyre-halvester i 125 ml tør tetrahydrofuran blev sat 20 mg 2,2'bipyridyl. Reaktionsblandingen blev afkølet til -30°C og behandlet ved dråbevis tilsætning af 24 ml 20 (57.6 mmol) 2,4 N n-butyllithium. Reaktionsblandingen blev derefter henstillet til opvarmning til -5eC, hvorefter der blev tilsat et yderligere ækvivalent, 24 ml (57,6 mmol), 2,4 N n-butyllithium, indtil en lyserød farve holdt sig i 15 minutter. Reaktionsblandingen blev 25 derefter afkølet til -75°C og behandlet ved dråbevis tilsætning af en opløsning af 7,2 g (28 mmol) 2-nitro- 3,4,5,6-tetrafluorbenzoylchlorid i 15 ml tetrahydrofuran. Reaktionsblandingen blev omrørt ved -75°C i en time, opvarmet til -35°C og bratkølet ved udhældning på 30 en opløsning af 28 ml koncentreret saltsyre i 50 ml isvand. Reaktionsblandingen blev ekstraheret med 3 x 200 ml dichlormethan, og det organiske lag blev vasket med 2 x 100 ml 5% vandig natriumbicarbonat og med 1 x 100 ml 1,0 M saltsyre, tørret (MgS04) og inddampet i vakuum 35 til opnåelse af 7,3 g af titelforbindelsen, der blev anvendt i det efterfølgende trin uden yderligere rensning.
8 DK 171935 B1
Trin 3:
Ethyl-l-cyclopropyl-5-nitro—66,7,8-trifluor-l,4-dihy- 5 dro-4-oxo-3-quinolincarboxylat_
En opløsning af 6,8 g (22 mmol) 2-nitro-3,4,5,6 tetrafluor-8-oxobenzenpropionsyre-ethylester, 4,9 g (33 mmol) triethylorthoformat og 50 ml eddikesyreanhy-drid blev opvarmet til tilbagesvaling i to timer.
10 Opløsningsmidlet blev fjernet i vakuum og derefter i høj vakuum ved 80°C i 1,5 timer. Resten blev opløst i 25 ml t-butanol og behandlet med 1,4 3 g (25 mmol) cyclopropylamin. Blandingen blev opvarmet til 45°C i fire timer, afkølet til stuetemperatur og behandlet ved 15 dråbevis tilsætning af en opløsning af 2,47 g (25 mmol) kalium-t-butoxid i 25 ml t-butanol. Reaktionsblandingen blev opvarmet til 60°C i seks timer, og opløsningsmidlet blev fjernet i vakuum. Resten blev opløst i chloroform, vasket med vand, tørret (MgS04) og inddampet i 20 vakuum. Resten blev kromatograferet over silicagel, idet der blev elueret med chloroform/ethylacetat (80/20) til opnåelse af 1,9 g af titelforbindelsen i form af en olie, der blev anvendt uden yderligere rensning.
25
Trin 4:
Ethyl-5-amino-l-cyclopropyl-6,7,8-trifluor-l,4-dihydro- 4-oxo-3-quinolincarboxylat_ 30 En opløsning af 1,9 g (5,3 mmol) ethyl-l-cy- clopropyl-5-nitro-6,7,8-trifluor-l,4-dihydro-4-oxo-3-quinolincarboxylat, 0,5 g Raney-nikkel og 100 ml ethanol blev omrystet i hydrogenatmosfære ved et tryk på 42,5-50 psi og en temperatur på fra 24-26,5°C i ti ti-35 mer. Blandingen blev filtreret gennem celit, og uopløseligt produkt blev opløst i tetrahydrofuran efter- 9 DK 171935 B1 fulgt af filtrering. De kombinerede filtrater blev inddampet i vakuum, og resten blev kromatograferet på selicagel til opnåelse af 600 mg af titelforbindelsen med smp. 223-225°C.
5
Trin 5: 5-amino-l-cyclopropyl-6,7,8-trifluor-l, 4-dihydro-4-oxo- 3-eruinolincarboxylsvre____ 10 En opløsning af 0,5 g (1,5 mmol) ethyl-5-amino- l-cyclopropyl-6,7,8-trifluor-l,4-dihydro-4-oxo-3-quino-lincarboxylat, 5 ml 6,0 M saltsyre og 5 ml ethanol blev opvarmet til tilbagesvaling i to timer. Opløsningsmidlet blev fjernet i vakuum til opnåelse af 4 30 15 mg af ti-telforbindelsen med smp. 269-271°C.
Eksempel 2
Fremstilling af slutproduktet, 5-amino-l-cyclopropyl-20 6,8-difluor-7-[(3-ethylamino-methyl)-1-pyrrolidinyl]- 1,4-dihydro-4-oxo-3-quinolincarb-oxylsyre, ud fra et mellemprodukt ifølge opfindelsen_
En opløsning af 0,43 g (1,5 mmol) 5-amino-l-cyclopropyl-6,7,8-trifluor-l,4-dihydro-4-oxo-3-quino-25 lincarboxylsyre, 0,61 g (6,0 mmol) triethylamin, 0,77 g (6,0 mmol) 3-(ethylaminomethyl)pyrrolidin og 25 ml ace-tonitril blev opvarmet til tilbagesvaling i to timer. Opløsningsmidlet blev fjernet i vakuum, og resten blev opløst i vand og filtreret gennem en glasfiberpude til 30 fjernelse af spor af uopløseligt materiale. Filtratet blev indstillet til pH 7,0, og det resulterende bundfald blev fjernet ved filtrering, vasket med vand og tørret i vakuum til opnåelse af 200 mg af titelforbindelsen med smp. 250-252°C.
Claims (2)
1. Quinolin-forbindelse, kendetegnet 5 ved, at den har den almene formel NH2 U 'xxV‘v‘ ίο * ** I Δ hvor X betegner CH, CF eller N og R1 betegner hydrogen, C1-C6 alkyl eller en kation.
2. Forbindelse ifølge krav 1, kendeteg net ved, at den er 5-amino-l-cyclopropyl-6,7,8-tri-fluor-1,4-dihydro-4-oxoquinolin-3-carboxylsyre.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US63315384A | 1984-07-20 | 1984-07-20 | |
| US63315384 | 1984-07-20 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK28892A DK28892A (da) | 1992-03-04 |
| DK28892D0 DK28892D0 (da) | 1992-03-04 |
| DK171935B1 true DK171935B1 (da) | 1997-08-18 |
Family
ID=24538490
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK302885A DK302885A (da) | 1984-07-20 | 1985-07-03 | Anti-bakterielle forbindelser, fremgangsmaade til fremstilling deraf og farmaceutiske praeparater indeholdende disse |
| DK028892A DK171935B1 (da) | 1984-07-20 | 1992-03-04 | Quinolin-forbindelser |
| DK006193A DK6193A (da) | 1984-07-20 | 1993-01-19 | Quinoliner, naphthyridiner og benzoxaziner, en fremgangsmaade til fremstilling heraf og farmaceutiske praeparater indeholdende disse |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK302885A DK302885A (da) | 1984-07-20 | 1985-07-03 | Anti-bakterielle forbindelser, fremgangsmaade til fremstilling deraf og farmaceutiske praeparater indeholdende disse |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK006193A DK6193A (da) | 1984-07-20 | 1993-01-19 | Quinoliner, naphthyridiner og benzoxaziner, en fremgangsmaade til fremstilling heraf og farmaceutiske praeparater indeholdende disse |
Country Status (18)
| Country | Link |
|---|---|
| EP (1) | EP0172651B1 (da) |
| JP (2) | JPH0791288B2 (da) |
| KR (1) | KR900003495B1 (da) |
| AR (1) | AR241183A1 (da) |
| AT (1) | ATE50255T1 (da) |
| AU (3) | AU576252B2 (da) |
| CA (1) | CA1331381C (da) |
| DE (1) | DE3575924D1 (da) |
| DK (3) | DK302885A (da) |
| ES (3) | ES8704161A1 (da) |
| FI (1) | FI83648C (da) |
| GR (1) | GR851648B (da) |
| IE (1) | IE58742B1 (da) |
| NO (1) | NO171638C (da) |
| NZ (1) | NZ212805A (da) |
| PH (3) | PH22341A (da) |
| PT (1) | PT80836B (da) |
| ZA (1) | ZA855038B (da) |
Families Citing this family (31)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4822801A (en) * | 1984-07-20 | 1989-04-18 | Warner-Lambert Company | 4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivative as antibacterial agents |
| IE58742B1 (en) * | 1984-07-20 | 1993-11-05 | Warner Lambert Co | Substituted-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7h-pyrido[1,2,3-de] [1,4]benzoxauine-6-carboxylic acids; sibstituted-5-amino-6-6fluoro-4-oxo.1,4-dihydroquinoline-3 carboxylic acids; substituted-5-amino-6-fluoro-1,4-dihydro-4-oxo-1.8-naphthyridine-3-carboxylic acids; derivatives thereof; pharmaceutical compositions comprising the compounds; and processes for producing the compounds |
| US4657913A (en) * | 1985-04-18 | 1987-04-14 | Warner-Lambert Company | Trifluoro- quinoline -3- carboxylic acids and their use as anti-bacterial agents |
| IL79189A (en) * | 1985-06-26 | 1990-07-12 | Daiichi Seiyaku Co | Quinoline and/or naphthyridine-4-oxo-3-carboxylic acid derivatives,process for their preparation and pharmaceutical compositions comprising them |
| AU594983B2 (en) | 1985-10-29 | 1990-03-22 | Dainippon Pharmaceutical Co. Ltd. | Novel quinoline derivatives and processes for preparation thereof |
| DE3705621C2 (de) * | 1986-02-25 | 1997-01-09 | Otsuka Pharma Co Ltd | Heterocyclisch substituierte Chinoloncarbonsäurederivate |
| EP0242789A3 (en) * | 1986-04-25 | 1990-09-05 | Dainippon Pharmaceutical Co., Ltd. | Novel quinoline derivates and processes for preparation thereof |
| US4771055A (en) * | 1986-07-28 | 1988-09-13 | Warner-Lambert Company | 7-[[3-(aminomethyl)-3-alkyl]-1-pyrrolidinyl]-quinoline-carboxylic acids |
| DE3635846C2 (de) * | 1986-10-22 | 1995-08-03 | Teves Gmbh Alfred | Blockiergeschützte Bremsanlage mit Antriebsschlupfregelung |
| JPS63185607A (ja) * | 1987-01-27 | 1988-08-01 | Matsushita Electric Works Ltd | シ−ト状成形材料の製法 |
| DE3711193A1 (de) * | 1987-04-02 | 1988-10-13 | Bayer Ag | 5-substituierte chinolon- und naphthyridoncarbonsaeure-derivate |
| US4780468A (en) * | 1987-08-07 | 1988-10-25 | Warner-Lambert Company | 8-trifluoromethyl quinolones as antibacterial agents |
| US4839355A (en) * | 1987-09-09 | 1989-06-13 | Sterling Drug Inc. | Tricyclic-pyridinylquinoline compounds, their preparation and use |
| JP2844079B2 (ja) * | 1988-05-23 | 1999-01-06 | 塩野義製薬株式会社 | ピリドンカルボン酸系抗菌剤 |
| KR910003630B1 (ko) * | 1988-06-17 | 1991-06-07 | 한국과학기술원 | 벤조일 아세틱 에스테르 유도체 및 그 제조방법 |
| JPH0674261B2 (ja) * | 1988-06-21 | 1994-09-21 | 塩野義製薬株式会社 | キノロンカルボン酸誘導体 |
| WO1990002123A1 (en) * | 1988-08-23 | 1990-03-08 | Pfizer Inc. | Amino-substituted bridged azabicyclic quinolone carboxylic acids and esters |
| US5286723A (en) * | 1988-08-31 | 1994-02-15 | Daiichi Seiyaku Co., Ltd. | Spiro compound |
| CA1336090C (en) * | 1988-08-31 | 1995-06-27 | Isao Hayakawa | Spiro-substituted cyclic amines of quinolone derivatives |
| CA2001203C (en) * | 1988-10-24 | 2001-02-13 | Thomas P. Demuth, Jr. | Novel antimicrobial dithiocarbamoyl quinolones |
| SG47533A1 (en) | 1990-04-18 | 1998-04-17 | Procter & Gamble Pharma | Antimicrobial quinolonyl lactams |
| DE4032560A1 (de) * | 1990-10-13 | 1992-04-16 | Bayer Ag | 7-(2,7-diazabicyclo(3.3.0)octyl)-3-chinolon- und -naphtyridoncarbonsaeure-derivate |
| US5342846A (en) * | 1990-12-05 | 1994-08-30 | Synphar Laboratories, Inc. | 7-substituted-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid compounds and 7-(substituted triazolyl pyrrolidin-1-yl) 4-oxoquinoline-3-carboxylic acid derivatives useful as antibacterial agents |
| CA2099591C (en) * | 1990-12-05 | 2002-11-12 | Rajeshwar Singh | 7-substituted-6-fluoro-1,4-dihydro-4-oxo-quinoline-3- carboxylic acid compounds useful as antibacterial agents |
| US5646163A (en) * | 1992-10-30 | 1997-07-08 | The Procter & Gamble Company | Quinolone 5-(N-heterosubstituted amino) antimicrobials |
| TW252107B (da) * | 1993-08-27 | 1995-07-21 | Hokuriku Pharmacetical Co Ltd | |
| AU697025B2 (en) * | 1995-01-24 | 1998-09-24 | Hokuriku Seiyaku Co. Ltd | Quinoline carboxylic acid |
| CA2536429C (en) | 2003-09-10 | 2012-02-14 | Kyorin Pharmaceutical Co., Ltd. | 7-(4-substituted-3-cyclopropylaminomethyl-1-pyrrolidinyl) quinolonecarboxylic acid derivative |
| US7563805B2 (en) | 2005-05-19 | 2009-07-21 | Daiichi Pharmaceutical Co., Ltd. | Tri-, tetra-substituted-3-aminopyrrolidine derivative |
| US8222407B2 (en) | 2007-05-24 | 2012-07-17 | Kyorin Pharmaceutical Co., Ltd. | Mutilin derivative having heterocyclic aromatic ring carboxylic acid structure in substituent at 14-position |
| USD808799S1 (en) | 2015-11-17 | 2018-01-30 | Hunter Fan Company | Carton with color striping |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3033157A1 (de) * | 1980-09-03 | 1982-04-01 | Bayer Ag, 5090 Leverkusen | 7-amino-1-cyclopropyl-4-oxo-1,4-dihydro-naphthyridin-3-carbonsaeuren, verfahren zu ihrer herstellung sowie diese enthaltende antibakterielle mittel |
| 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 |
| JPS57149286A (en) * | 1981-03-13 | 1982-09-14 | Dai Ichi Seiyaku Co Ltd | 8-aminopyrido(1,2,3-de)(1,4)banzoxazine derivative |
| JPS58174367A (ja) * | 1982-04-07 | 1983-10-13 | Tanabe Seiyaku Co Ltd | キノリン誘導体及びその製法 |
| IE55898B1 (en) * | 1982-09-09 | 1991-02-14 | Warner Lambert Co | Antibacterial agents |
| US4665079A (en) * | 1984-02-17 | 1987-05-12 | Warner-Lambert Company | Antibacterial agents |
| US4571396A (en) * | 1984-04-16 | 1986-02-18 | Warner-Lambert Company | Antibacterial agents |
| IE58742B1 (en) * | 1984-07-20 | 1993-11-05 | Warner Lambert Co | Substituted-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7h-pyrido[1,2,3-de] [1,4]benzoxauine-6-carboxylic acids; sibstituted-5-amino-6-6fluoro-4-oxo.1,4-dihydroquinoline-3 carboxylic acids; substituted-5-amino-6-fluoro-1,4-dihydro-4-oxo-1.8-naphthyridine-3-carboxylic acids; derivatives thereof; pharmaceutical compositions comprising the compounds; and processes for producing the compounds |
| US4657913A (en) * | 1985-04-18 | 1987-04-14 | Warner-Lambert Company | Trifluoro- quinoline -3- carboxylic acids and their use as anti-bacterial agents |
| DE3525108A1 (de) * | 1985-06-07 | 1986-12-11 | Bayer Ag, 5090 Leverkusen | Antibakteriell wirksame chinoloncarbonsaeureester |
-
1985
- 1985-07-02 IE IE166685A patent/IE58742B1/en not_active IP Right Cessation
- 1985-07-03 ZA ZA855038A patent/ZA855038B/xx unknown
- 1985-07-03 FI FI852624A patent/FI83648C/fi not_active IP Right Cessation
- 1985-07-03 CA CA000486270A patent/CA1331381C/en not_active Expired - Fee Related
- 1985-07-03 DK DK302885A patent/DK302885A/da not_active Application Discontinuation
- 1985-07-04 GR GR851648A patent/GR851648B/el unknown
- 1985-07-04 AU AU44581/85A patent/AU576252B2/en not_active Ceased
- 1985-07-18 EP EP85305123A patent/EP0172651B1/en not_active Expired - Lifetime
- 1985-07-18 AT AT85305123T patent/ATE50255T1/de not_active IP Right Cessation
- 1985-07-18 DE DE8585305123T patent/DE3575924D1/de not_active Expired - Fee Related
- 1985-07-18 KR KR1019850005120A patent/KR900003495B1/ko not_active Expired
- 1985-07-18 PH PH32534A patent/PH22341A/en unknown
- 1985-07-19 NO NO852885A patent/NO171638C/no not_active IP Right Cessation
- 1985-07-19 JP JP60158483A patent/JPH0791288B2/ja not_active Expired - Fee Related
- 1985-07-19 ES ES545390A patent/ES8704161A1/es not_active Expired
- 1985-07-19 NZ NZ212805A patent/NZ212805A/xx unknown
- 1985-07-19 PT PT80836A patent/PT80836B/pt not_active IP Right Cessation
- 1985-07-22 AR AR85301059A patent/AR241183A1/es active
-
1986
- 1986-04-25 ES ES554376A patent/ES8800245A1/es not_active Expired
- 1986-04-25 ES ES554375A patent/ES8800244A1/es not_active Expired
-
1988
- 1988-01-25 PH PH36396A patent/PH24824A/en unknown
- 1988-01-25 PH PH36394A patent/PH23474A/en unknown
- 1988-06-02 AU AU17313/88A patent/AU613372B2/en not_active Ceased
- 1988-06-02 AU AU17312/88A patent/AU602585B2/en not_active Ceased
-
1992
- 1992-03-04 DK DK028892A patent/DK171935B1/da not_active IP Right Cessation
-
1993
- 1993-01-19 DK DK006193A patent/DK6193A/da not_active Application Discontinuation
-
1994
- 1994-07-25 JP JP6172420A patent/JPH0826003B2/ja not_active Expired - Fee Related
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