DK162281B - Cyclopent-1-enalkansyreestere og fremgangsmaade til deres fremstilling - Google Patents
Cyclopent-1-enalkansyreestere og fremgangsmaade til deres fremstilling Download PDFInfo
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- DK162281B DK162281B DK613487A DK613487A DK162281B DK 162281 B DK162281 B DK 162281B DK 613487 A DK613487 A DK 613487A DK 613487 A DK613487 A DK 613487A DK 162281 B DK162281 B DK 162281B
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- 239000002253 acid Substances 0.000 title claims description 15
- 238000000034 method Methods 0.000 title claims description 4
- 238000002360 preparation method Methods 0.000 title claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- -1 2-methoxyethoxy Chemical group 0.000 claims description 5
- 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 claims description 4
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 4
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- USLNCUQJFUQEQD-UHFFFAOYSA-N 10-hydroxydec-6-yn-2-one Chemical compound CC(=O)CCCC#CCCCO USLNCUQJFUQEQD-UHFFFAOYSA-N 0.000 claims description 3
- OSQGZMMXEOHSCF-UHFFFAOYSA-N 2-[1-[2-(oxan-2-yl)pent-4-ynoxy]pent-4-yn-2-yl]oxane Chemical compound C1CCCOC1C(CC#C)COCC(CC#C)C1CCCCO1 OSQGZMMXEOHSCF-UHFFFAOYSA-N 0.000 claims description 3
- 150000004645 aluminates Chemical class 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 claims description 2
- OFERIRWCHSOJJT-UHFFFAOYSA-N 2-(3-chloropropyl)-2-methyl-1,3-dioxolane Chemical compound ClCCCC1(C)OCCO1 OFERIRWCHSOJJT-UHFFFAOYSA-N 0.000 claims description 2
- 239000003810 Jones reagent Substances 0.000 claims description 2
- LOMVENUNSWAXEN-UHFFFAOYSA-N Methyl oxalate Chemical compound COC(=O)C(=O)OC LOMVENUNSWAXEN-UHFFFAOYSA-N 0.000 claims description 2
- 125000005070 decynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 230000007062 hydrolysis Effects 0.000 claims 1
- 238000006460 hydrolysis reaction Methods 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 239000000203 mixture Substances 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 235000011152 sodium sulphate Nutrition 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 150000002085 enols Chemical group 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- DHNDDRBMUVFQIZ-UHFFFAOYSA-N 4-hydroxycyclopent-2-en-1-one Chemical compound OC1CC(=O)C=C1 DHNDDRBMUVFQIZ-UHFFFAOYSA-N 0.000 description 2
- JJWGWDOXXKOHRY-UHFFFAOYSA-N 4-hydroxycyclopentane-1,3-dione Chemical compound OC1CC(=O)CC1=O JJWGWDOXXKOHRY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 2
- PLIKDTHMOISVIW-UHFFFAOYSA-N cyclopentane-1,2,4-trione Chemical compound O=C1CC(=O)C(=O)C1 PLIKDTHMOISVIW-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- IETMOWNAWUCICT-UHFFFAOYSA-N methyl 2-oxo-2-(2,3,5-trioxocyclopentyl)acetate Chemical compound O=C1CC(C(C1=O)C(=O)C(=O)OC)=O IETMOWNAWUCICT-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VMAKIQSICJHVNP-UHFFFAOYSA-N 2-(3-bromopropyl)-2-methyl-1,3-dioxolane Chemical compound BrCCCC1(C)OCCO1 VMAKIQSICJHVNP-UHFFFAOYSA-N 0.000 description 1
- RGXGGXHUHMONMJ-UHFFFAOYSA-N 3,4-dimethylfuran-2-carboxylic acid Chemical compound CC1=COC(C(O)=O)=C1C RGXGGXHUHMONMJ-UHFFFAOYSA-N 0.000 description 1
- FDOHCJHRMXFWKP-UHFFFAOYSA-N 4-triethylsilyloxycyclopent-2-en-1-one Chemical compound CC[Si](CC)(CC)OC1CC(=O)C=C1 FDOHCJHRMXFWKP-UHFFFAOYSA-N 0.000 description 1
- ADPFLRFLSQTOCK-UHFFFAOYSA-N 5-hydroxy-3-methoxycyclopent-2-en-1-one Chemical compound COC1=CC(=O)C(O)C1 ADPFLRFLSQTOCK-UHFFFAOYSA-N 0.000 description 1
- CDURMMHZRYRSPG-PAMZHZACSA-N 7-[(1s,2r)-2-(4-hydroxyoctyl)cyclopentyl]heptanoic acid Chemical class CCCCC(O)CCC[C@H]1CCC[C@@H]1CCCCCCC(O)=O CDURMMHZRYRSPG-PAMZHZACSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 108010079943 Pentagastrin Proteins 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
- 150000001844 chromium Chemical class 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000005825 oxyethoxy group Chemical group [H]C([H])(O[*:1])C([H])([H])O[*:2] 0.000 description 1
- CRWVOXFUXPYTRK-UHFFFAOYSA-N pent-4-yn-1-ol Chemical compound OCCCC#C CRWVOXFUXPYTRK-UHFFFAOYSA-N 0.000 description 1
- ANRIQLNBZQLTFV-DZUOILHNSA-N pentagastrin Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1[C]2C=CC=CC2=NC=1)NC(=O)CCNC(=O)OC(C)(C)C)CCSC)C(N)=O)C1=CC=CC=C1 ANRIQLNBZQLTFV-DZUOILHNSA-N 0.000 description 1
- 229960000444 pentagastrin Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/90—Unsaturated compounds containing keto groups containing singly bound oxygen-containing groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/80—Unsaturated compounds containing keto groups containing rings other than six-membered aromatic rings
- C07C59/82—Unsaturated compounds containing keto groups containing rings other than six-membered aromatic rings the keto group being part of a ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/16—Radicals substituted by halogen atoms or nitro radicals
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- 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)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cosmetics (AREA)
- Steroid Compounds (AREA)
Description
DK 162281 B
Den foreliggende opfindelse angår hidtil ukendte cyclopent-l-enalkansyreestere, som er ejendommelige ved, at de har den almene formel (I) 0 5 Π rrr cooro f- (i) / 10 0R2 hvor R3 betyder alkyl med 1-6 carbonatomer, og R2 betyder hydrogen, tri- (lavere alkyl)-silyl, tetrahydrofuranyl eller tetrahydropyranyl.
15 De alkylgrupper, som indgår i ovenstående struktur formel (I) , er methyl, ethyl, propyl, butyl, pentyl, hexyl og de tilsvarende grupper med forgrenet kæde.
De her omhandlede estere med formel (I) er værdifulde udgangsmaterialer til fremstilling af hidtil ukendte, tera- 20 peutisk aktive 4,5-umættede 16-hydroxyprostansyrederivater med den almene formel O- 5 «7 2 9|| 6 3
25 10ί^^νΝι''· R
n|_L ti “ (IV) / (CH2)n -CH3 HO ‘ H° R1 30 hvor R betyder -COOR·, hvor R' betyder hydrogen eller alkyl med 1-6 carbonatomer, Rx betyder alkyl med 1-6 carbonatomer, n er 2, 3 eller 4, og (±) refererer til den viste forbindelse, dens spejlbillede og blandingen af racemater.
35 Fremstillingen af forbindelserne med formel (IV) ud fra forbindelser med formel (I) samt den terapeutiske ak- 2
DK 162281 B
tivitet af forbindelserne med formel (IV) er beskrevet i DK--patentansøgning nr. 5046/80.
Af DK-patentansøgning nr. 5046/80 fremgår således, at forbindelserne med formel (IV) er i stand til at hæmme den 5 mavesekretion, som stimuleres af secretogoger, såsom histamin og pentagastrin, medens de ydermere har den overraskende fordel, at de mangler de kraftige uønskede bivirkninger, som beslægtede forbindelser udviser.
Sådanne forbindelser er f.eks. de fra US-patentskrift 10 nr. 4.028.419 kendte prostaglandinanaloge, som imidlertid er 15-hydroxyforbindelser, medens forbindelserne med formel (IV) er 16-hydroxyforbindelser. I prostaglandinkemien er det imidlertid velkendt, at denne tilsyneladende ringe strukturforskel resulterer i en væsentlig forskel i egenskaber.
15 Lige så overraskende er det, at forbindelserne med formel (IV) er væsentligt mere aktive end de tilsvarende 4,5-mættede forbindelser, som er kendte, jfr. E.Z. Dajani et al., Am. J. Dig. Dis. 21, 1049 (1976), P.W. Collins et al., J. Med. Chem. 20, 1152 (1977). Dette gælder specielt 20 ved oral (intragastrisk) indgivelse.
Den foreliggende opfindelse angår endvidere en fremgangsmåde til fremstilling af de her omhandlede cyclopent--1-enalkansyreestere med formel (I). Den her omhandlede fremgangsmåde er ejendommelig ved det i den kendetegnende 25 del af krav 2 angivne, og den kan skematisk illustreres som følger:
O
3
DK 162281 B
O „ O
CH3CCH2CH2CH2C1 -5^-?· CH3CCH2CH2CB2Br + 5 ? \ hc=cch2ch2ch2o-^ /-X ^ 0 S'0
C^‘CCH2CH2CH2C=CCH2CH2CH2OTHP
10 i h3°+ o o
CH3C(CH2)3C=C(CH2)3OH -°n-e-—> CH3C(CH2)3C=C(CH2)2COOH
15 h2 Pd 0 0 ^ " " o o
CH o-c-o J H
\^\^n^='v^svC00H CH3C (CH2) 3CH=CH (CH2) 2C00H
___ dimethyloxalat 2° ^ % HC1 o ^ o
NaBH4 ji
r^Y^S^=^^COOH
25 J_I J_I
0^ \ ΙΚΓ Sd HC1
MeOH
OCH3 \ / 2,2-dimethoxypropan cooch3
natriumdihydrobis-(2-meth- I I
30 oxyethoxy) -aluminat (+) E(/— % 0 ψ ho' 35 4
DK 162281 B
O
Fremgangsmåden ifølge opfindelsen er nærmere illustreret i de efterfølgende eksempler, hvor mængderne af materialer er angivet i vægtdele, medmindre andet er angivet .
5
Eksempel 1 4,0 dele 5-chlor-2-pentanonethylenketal blandes 10 med 9,0 dele lithiumbromid og 2,0 dele diisopropylethyl- amin i 30 volumendele tetrahydrofuran, som er destilleret . fra 1ithiumaluminiumhydrid. Blandingen tilbagesvales under nitrogen i 48 timer, afkøles og hældes ud i en blanding af ether og vand til ekstraktion. Etherlaget vaskes to gange 15 med vand, derefter med 1 N saltsyre og derpå igen to gange med vand. Etherlaget tørres dernæst over natriumsulfat og inddampes ved formindsket tryk til opnåelse af 5-brom-2--pentanonethylenketal med formlen 20 /~λ CH3CCH2CH2CH2Br
Eksempel 2 25 0,1 del p-toluensulfonsyre sættes til en omrørt blanding -af 4,2 dele 4-pentyn-l-ol og 5,0 dele dihydro-pyran. Efter ca. 30 minutters forløb behandles blandingen med 0,5 dele triethylamin og vakuumdestilleres til op-30 nåelse af 2-tetrahydropyranyl-4-pentynylether med formlen .
\ r~\ hc=cch2ch2ch2o V / 35
Eksempel 3
O
5
DK 162281 B
En opløsning indeholdende 18,5 dele 2-tetrahydro-pyranyl-4-pentynylether fra eksempel 2 i 125 volumendele 5 tetrahydrofuran, som er frisk destilleret fra lithiumalu- miniumhydrid, afkøles til ca. -30°C og behandles med 46 volumendele af en 2,4 M n-butyllithiumopløsning i hexan. Opløsningen får lov at komme op på stuetemperatur. Efter ca.
30 minutter ved stuetemperatur tilsættes 21 dele 5-brom- 10 -2-pentanonethylenketal fra eksempel 1, hvorefter der under omrøring tilsættes 3Q volumendele hexamethylphosphortri-amid. Efter 1 time hældes reaktionsblandingen ud i en blanding af ether dg 1 N saltsyre. Etherlaget vaskes med vand, tørres over natriumsulfat og befries for opløsningsmiddel 15 i vakuum til opnåelse af et produkt, som er en farveløs, viskos væske, og som har formlen /“λ 20 V S f~\
Eksempel 4 25 30 dele af decynylketalen fra eksempel 3 opløses i en blanding af 15Q volumendele 1 N saltsyre, 200 volumendele tetrahydrofuran og 50 volumendele methanol. Opløsningen holdes ved stuetemperatur i 48 timer og tilbagesvales der-30 efter i 5-6 timer. Derpå afkøles opløsningen til stuetemperatur, og der tilsættes fast kaliumcarbonat, indtil pH-vær-dien når op på 7. Dernæst inddampes opløsningen til det halve af dens volumen, fortyndes med vand og ekstraheres to gange med ether. Etherekstrakterne forenes, vaskes med vand, tør- res over natriumsulfat og befries for opløsningsmiddel til opnåelse af 9-oxodec-4-yn-l-ol, som anvendes uden rensning i eksempel 5.
35
DK 162281 B
O
Eksempel 5 - 6 2Q dele 9-oxodec-4-yn-l-ol fra eksempel 4 opløses 5 i 20Q volumendele acetone og afkøles til Q°C. Den kolde op løsning omrøres og behandles dråbevis med 90 volumendele 2,67 M Jones-reagens (chromsyre i svovlsyre og vand). Acetoneopløsningen dekanteres fra de faste chromsalte, som derefter skylles med frisk acetone. Acetoneopløsningerne for-10 enes og hældes ud i en blanding af ether og vand. Etherlaget skilles fra vandet, vaskes en gang med vand og ekstraheres derefter tre gange méd 5%'s kaliumcarbonatopløsnirig. De alkaliske ekstrakter forenes, syrnes med koncentreret saltsyre og ekstraheres to gange med ether og 1 gang med ethyl-15 acetat. Ekstrakterne forenes, tørres over natriumsulfat og befries for opløsningsmiddel til opnåelse af det rene produkt, 9-oxodec-4-ynsyre.
Eksempel 6 20 LO, dele 9-oxodec-4-ynsyre fra eksempel 5 hydrogeneres ved stuetemperatur i toluen indeholdende ca. 0,5% quinolin med 5%'s palladium-på-bariumsulfat som katalysator. Toluenopløsningen vaskes med 1 N saltsyre og derefter 25 med vand. Opløsningen tørres over natriumsulfat og befries for opløsningsmiddel til opnåelse af produktet cis-9-oxodec--4-ensyre som en gul olie.
Eksempel 7 30 3,2 dele metallisk kalium sættes til 50 volumendele t-butylalkohol, og blandingen tilbagesvales under argon. Efter at alt kalium er opløst, tilsættes en opløsning af 2,52 dele cis-9-oxodec-4-ensyre fra eksempel 6 og 4,85 dele di-35 methyloxolat, som er omkrystalliseret fra hexan, i 25 volu mendele t-butylalkohol dråbevis til den tilbagesvalende op-
DK 162281 B
O
7 løsning i løbet af 1 time. Reaktionsblandingen tilbagesvales i yderligere 2 timer, afkøles til stuetemperatur og filtreres under argon. Den orange filterkage sættes til en blanding af chloroform og 1 N saltsyre. Chloroformlaget va-5 skes med en mættet natriumchloridopløsning, tørres over na triumsulfat og befries for opløsningsmiddel til opnåelse af produktet 7-(2,3,5-trioxo-4-methoxalylcyclopentan)-hept--4-cis-ensyre med formlen 0 0 o „ INI II _ .
10 H-CO-C-Gv \ -3 y cooh J-1 o o 15 og dens forskellige tautomere enolformer.
- Eksempel 8 2Q 4,0. dele 7-(2,3,5-trioxo-4-methoxalylcyclopentan)- -hept-4-cis-ensyre fra eksempel 7 sættes til 100 volumendele 1 N saltsyre og tilbagesvales under argon i 3 timer. Opløsningen afkøles til stuetemperatur, filtreres og ekstra-heres to gange med ethylacetat. Ekstrakterne forenes og vaskes to gange med mættet natriumchloridopløsning, tørres og be-25 fries for opløsningsmiddel til opnåelse af en rød olie. Den røde olie chromatograferes på silicagel (60% ethylacetat, 39% hexan og 1% eddikesyre som elueringsmiddel) til opnåelse af 7-(2,3,5-trioxocyclopentan)-hept-4-cis-ensyre som et gult Λ fast stof, som smelter ved 78-80°C, og som har formlen 30 0
I COOH
35 J ^ 0' o og dens forskellige tautomere enolformer.
Eksempel 9 8
DK 162281 B
O
1,15 dele 7-(2,3,5-trioxocyclopentan)-hept-4-cis-en-syre fra eksempel 8 opløses i 35 volumendele ethanol og 30 5 ø volumendele vand og afkøles til 0 C, 0,55 dele natriumborhy-drid opløses i 5,0 volumendele vand og sættes dråbevis til ethanolopløsningen. Efter at tilsætningen er afsluttet, omrøres opløsningen ved 0°C i 30 minutter. Opløsningen hældes ud i ethylacetat og 1' N saltsyre. Det vandige lag ekstraheres tre gange med yderligere ethylacetat. Ethylacetatekstrakterne forenes, vaskes en gang med mættet natriumchloridopløsning, tørres over natriumsulfat og befries for opløsningsmiddel til opnåelse af (-)-7-(2,5-dioxo-3-hydroxycyclopentan)-hept-4— -cis-ensyre, som er en viskos gul olie, og som har formlen
COOH
20 ^ ^
HO O
og dens forskellige tautomere enolformer.
Eksempel 10 25 ----
Til en opløsning af 2,0 dele (-)-7-(2,5-dioxo-3--hydroxycyclopentan)-hept-4-cis-ensyre fra eksempel 9 i 30 volumendele tørt methanol sættes 10 volumendele 2,2-dimeth-30 oxypropan og 4 volumendele 1%'s methanolisk saltsyre. Blan dingen får lov at henstå ved stuetemperatur i 48 timer og inddampes derpå til tørhed ved stuetemperatur ved formindsket tryk. Ca. 4 volumendele ether tilsættes, og blandingen får lov at henstå ved stuetemperatur i yderligere 48 ti-35 mer. Den størknede blanding optages i toluen indeholdende 1% triethylamin, og opløsningen vaskes successivt med fortyndet kaliumcarbonat og vand, tørres over natriumsulfat og befries for opløsningsmiddel. Remanensen omkrystalliseres
O
9
DK 162281 B
fra ether til opnåelse af produktet (-)-methyl-7-(4-hy-droxy-2-methoxy-5-oxocyclopent-l-en)-hept-4-cis-enoat som et hvidt fast stof, som smelter ved 82-84°C, og som har formlen 5 OCH3 COOCH-j
Eksempel 11 15 100 volumendele tørt toluen anbringes i en tre hal set kolbe og afkøles til -70°C i et bad af isopropyl-alkohol og tøris. I separate tildrypningstragte fyldes 15,5 volumendele 1,83 M natrium-dihydrobis-(2-methoxy-ethoxy)-aluminat fortyndet med 100 volumendele toluen og 20 en opløsning af 6,92 dele (i)-methyl-7-(4-hydroxy-2-
-methoxy-5-oxocyclopent-l-en)-hept-4-cis-enoat fra eksempel 10 i 200 volumendele toluen. De to opløsninger sættes dråbevis og samtidig til kolben. Kolbens temperatur bør ikke få lov at overstige -60°C under tilsætningen. Blan-25 dingen omrøres ved -70°C i 3,5 timer og derefter ved 0°C
i 15 minutter, reaktionen afbrydes med en opløsning af 5,0 volumendele methanol i 10 volumendele toluen, og blandingen syrnes med 150 volumendele 1 N saltsyre. Det organiske lag skilles fra, vaskes med vand, tørres over 30 natriumsulfat og befries for opløsningsmiddel. Remanensen chromatograferes på silicagel (70% ethylacetat, 30% hexan som elueringsmiddel) til opnåelse af (-)-methyl-7-(3-hy-droxy-5-oxocyclopent-l-en)-hept-4-cis-enoat, som er en viskos olie, og som har formlen 35 0
DK 162281 B
ίο
O
M _ |T cooch3 s f
HO
Eksempel 12 10 2,6 dele (-)-methyl-7-(3-hydroxy-5-oxocyclopent--1-en)-hept-4-cis-enoat fra eksempel 11 opløses i 20 volumendele dimethy1formamid og behandles successivt med 1,0 del imidazol og 1,9 dele triethylsilylchlorid. Opløs-15 ningen omrøres i 1 time ved stuetemperatur, fortyndes med ether, vaskes med vand 3-4 gange, tørres over natriumsulfat og befries for opløsningsmiddel. Produktet er (-)--methyl-7-(3-triethylsilyloxy-5-oxocyclopent-l-en)-hept--4-cis-enoat med formlen 20 j || cooch3 f OSiEt, 25 3 30 35
Claims (4)
1. Cyclopent-l-enalkansyreestere, kendetegnet ved, at de har formlen 5 0 J II COOR- I 3 ^ (I) 10 hvor R3 betyder alkyl med 1-6 carbonatomer, og R2 betyder hydrogen, tri-(lavere alkyl)-silyl, tetrahydrofuranyl eller tetrahydropyranyl.
2. Fremgangsmåde til fremstilling af cyclopent-1- -enalkansyreestere med formel (I) ifølge krav 1, kendetegnet ved, at en 5-chlor-2-pentanonethylenketal med formlen 20 CH2H2-CH2CH2CH2C1 (II) omsættes med LiBr og derefter med 2-tetrahydropyranyl-4— pentynylether til opnåelse af en decynylketal med formlen 25 f h^V^ch2) 3c-c (ch2) 3a-<^° ^ 30 som hydrolyseres til 9-oxodec-4-yn-l-ol, som oxideres med Jones-reagens til den tilsvarende syre, som hydrogeneres katalytisk til cis-9-oxodec-4-ensyre med formlen
35 CH3 CO(CH2)3 CH=CH(CH2)2 cOOH DK 162281 B som omsættes med dimethyloxalat til et produkt med formlen
00 O II II w H-.CO-C-C --- . O ^0 ' 10 som hydrolyseres, hvorefter den ved hydrolyse fremkomne forbindelse reduceres med natriumborhydrid, den herved fremkomne forbindelse omsættes med 2,2-dimethoxypropan og derefter med natrium-dihydrobis-(2-methoxyethoxy)-aluminat, eventuelt efterfulgt af hydroxybeskyttelse til dannelse af en 15 cyclopent-l-enalkansyreester med den almene formel (I).
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US9829079 | 1979-11-28 | ||
US06/098,290 US4271314A (en) | 1979-11-28 | 1979-11-28 | 4,5-Unsaturated prostanoic acid derivatives |
Publications (4)
Publication Number | Publication Date |
---|---|
DK613487D0 DK613487D0 (da) | 1987-11-23 |
DK613487A DK613487A (da) | 1987-11-23 |
DK162281B true DK162281B (da) | 1991-10-07 |
DK162281C DK162281C (da) | 1992-03-16 |
Family
ID=22268646
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DK504680A DK504680A (da) | 1979-11-28 | 1980-11-27 | 4,5-umaettede 16-hydroxyprostansyrederivater og deres fremstilling samt mellemprodukter hertil og disses fremstilling |
DK613487A DK162281C (da) | 1979-11-28 | 1987-11-23 | Cyclopent-1-enalkansyreestere og fremgangsmaade til deres fremstilling |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
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DK504680A DK504680A (da) | 1979-11-28 | 1980-11-27 | 4,5-umaettede 16-hydroxyprostansyrederivater og deres fremstilling samt mellemprodukter hertil og disses fremstilling |
Country Status (23)
Country | Link |
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US (1) | US4271314A (da) |
JP (1) | JPS5699457A (da) |
AT (1) | AT379144B (da) |
AU (1) | AU539192B2 (da) |
BE (1) | BE886370A (da) |
CA (1) | CA1192903A (da) |
CH (1) | CH646147A5 (da) |
DE (1) | DE3044794A1 (da) |
DK (2) | DK504680A (da) |
ES (2) | ES8204418A1 (da) |
FI (1) | FI71552C (da) |
FR (1) | FR2473516A1 (da) |
GB (1) | GB2065117B (da) |
GR (1) | GR72283B (da) |
IE (1) | IE50574B1 (da) |
IL (1) | IL61575A (da) |
IT (1) | IT1207155B (da) |
NL (1) | NL191386C (da) |
NO (1) | NO155289C (da) |
NZ (1) | NZ195666A (da) |
PT (1) | PT72129B (da) |
SE (1) | SE436873B (da) |
ZA (1) | ZA807415B (da) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
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US4529811A (en) * | 1981-03-02 | 1985-07-16 | G. D. Searle & Co. | Process for isolating organic compounds and lithium salt complexes useful in said process |
US4312994A (en) * | 1981-03-25 | 1982-01-26 | G. D. Searle & Co. | α Chain dienic prostanoic acid derivatives |
US4499296A (en) * | 1983-11-14 | 1985-02-12 | G. D. Searle & Co. | Omega cycloalkyl prostaglandins |
US4754059A (en) * | 1984-11-07 | 1988-06-28 | G. D. Searle & Co. | Omega cycloalkyl prostaglandins |
GB8410396D0 (en) * | 1984-04-24 | 1984-05-31 | Glaxo Group Ltd | Carbocyclic compounds |
US4785124A (en) * | 1987-06-08 | 1988-11-15 | G. D. Searle & Co. | Process for preparing higher order cuprate complexes |
US5011958A (en) * | 1987-06-08 | 1991-04-30 | G. D. Searle & Co. | Process for preparing higher order cuprate complexes |
US4777275A (en) * | 1987-06-09 | 1988-10-11 | G. D. Searle & Co. | Process of preparing higher order cuprate complexes |
US5191109A (en) * | 1990-02-02 | 1993-03-02 | Sumitomo Chemical Company, Limited | Process for preparing optically active cyclopentenones |
AU742787B2 (en) | 1997-07-09 | 2002-01-10 | Androsolutions, Inc. | Improved methods and compositions for treating male erectile dysfunction |
US6103765A (en) | 1997-07-09 | 2000-08-15 | Androsolutions, Inc. | Methods for treating male erectile dysfunction |
EP1245562A4 (en) * | 2000-01-05 | 2004-12-15 | Ono Pharmaceutical Co | ALCOHOLS 5-THIA- "OMEGA" - (PHENYL SUBSTITUTED) - PROSTAGLANDIN E, PROCESS FOR THE PREPARATION OF SUCH ALCOHOLS AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE ALCOHOLS AS ACTIVE INGREDIENT. |
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US3965143A (en) * | 1974-03-26 | 1976-06-22 | G. D. Searle & Co. | 16-Oxygenated prostanoic acid derivatives |
US4028419A (en) * | 1976-01-08 | 1977-06-07 | The Upjoin Company | 2-Decarboxy-2-hydroxymethyl-cis-4,5-didehydro-PGE, compounds |
GB1595118A (en) * | 1977-05-31 | 1981-08-05 | Sumitomo Chemical Co | Prostadienoic acids processes for producing them and compositions containing them |
-
1979
- 1979-11-28 US US06/098,290 patent/US4271314A/en not_active Expired - Lifetime
-
1980
- 1980-11-27 DK DK504680A patent/DK504680A/da not_active Application Discontinuation
- 1980-11-27 IE IE2471/80A patent/IE50574B1/en not_active IP Right Cessation
- 1980-11-27 NL NL8006473A patent/NL191386C/xx not_active IP Right Cessation
- 1980-11-27 NO NO803592A patent/NO155289C/no unknown
- 1980-11-27 CH CH879980A patent/CH646147A5/de not_active IP Right Cessation
- 1980-11-27 SE SE8008300A patent/SE436873B/sv not_active IP Right Cessation
- 1980-11-27 IT IT8050259A patent/IT1207155B/it active
- 1980-11-27 AU AU64766/80A patent/AU539192B2/en not_active Ceased
- 1980-11-27 NZ NZ195666A patent/NZ195666A/xx unknown
- 1980-11-27 CA CA000365636A patent/CA1192903A/en not_active Expired
- 1980-11-27 ZA ZA00807415A patent/ZA807415B/xx unknown
- 1980-11-27 BE BE0/202950A patent/BE886370A/fr not_active IP Right Cessation
- 1980-11-27 IL IL61575A patent/IL61575A/xx unknown
- 1980-11-27 AT AT0579280A patent/AT379144B/de not_active IP Right Cessation
- 1980-11-27 FI FI803685A patent/FI71552C/fi not_active IP Right Cessation
- 1980-11-28 PT PT72129A patent/PT72129B/pt unknown
- 1980-11-28 JP JP16791280A patent/JPS5699457A/ja active Granted
- 1980-11-28 GR GR63485A patent/GR72283B/el unknown
- 1980-11-28 ES ES497260A patent/ES8204418A1/es not_active Expired
- 1980-11-28 FR FR8025347A patent/FR2473516A1/fr active Granted
- 1980-11-28 DE DE19803044794 patent/DE3044794A1/de active Granted
- 1980-11-28 GB GB8038362A patent/GB2065117B/en not_active Expired
-
1981
- 1981-11-30 ES ES507577A patent/ES8300089A1/es not_active Expired
-
1987
- 1987-11-23 DK DK613487A patent/DK162281C/da active
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