IE48418B1 - Therapeutic composition containing thienopyridone or furopyridone derivatives - Google Patents
Therapeutic composition containing thienopyridone or furopyridone derivativesInfo
- Publication number
- IE48418B1 IE48418B1 IE1036/79A IE103679A IE48418B1 IE 48418 B1 IE48418 B1 IE 48418B1 IE 1036/79 A IE1036/79 A IE 1036/79A IE 103679 A IE103679 A IE 103679A IE 48418 B1 IE48418 B1 IE 48418B1
- Authority
- IE
- Ireland
- Prior art keywords
- group
- phenyl
- composition
- derivative
- active ingredient
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 14
- 230000001225 therapeutic effect Effects 0.000 title claims abstract description 9
- FNPYPLBPZILBRT-UHFFFAOYSA-N 3h-furo[3,2-b]pyridin-2-one Chemical class C1=CC=C2OC(=O)CC2=N1 FNPYPLBPZILBRT-UHFFFAOYSA-N 0.000 title claims description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- 239000004480 active ingredient Substances 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 125000003118 aryl group Chemical group 0.000 claims abstract description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 6
- 229910052717 sulfur Chemical group 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 125000005843 halogen group Chemical group 0.000 claims abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims abstract description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 3
- 239000001301 oxygen Substances 0.000 claims abstract description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 3
- 125000004434 sulfur atom Chemical group 0.000 claims abstract description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 27
- 238000002360 preparation method Methods 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000012442 inert solvent Substances 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims 2
- 125000006840 diphenylmethane group Chemical group 0.000 claims 1
- 239000002552 dosage form Substances 0.000 claims 1
- 210000001772 blood platelet Anatomy 0.000 abstract description 12
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 9
- 208000010110 spontaneous platelet aggregation Diseases 0.000 abstract description 9
- 230000002401 inhibitory effect Effects 0.000 abstract description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 abstract 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 abstract 2
- 229910052736 halogen Chemical group 0.000 abstract 1
- 150000002367 halogens Chemical group 0.000 abstract 1
- WLMSZVULHUTVRG-UHFFFAOYSA-N prop-2-enoyl azide Chemical class C=CC(=O)N=[N+]=[N-] WLMSZVULHUTVRG-UHFFFAOYSA-N 0.000 abstract 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical group OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 abstract 1
- 229930192474 thiophene Chemical group 0.000 abstract 1
- 239000013078 crystal Substances 0.000 description 17
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 13
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- MPOYBFYHRQBZPM-UHFFFAOYSA-N 3h-pyridin-4-one Chemical compound O=C1CC=NC=C1 MPOYBFYHRQBZPM-UHFFFAOYSA-N 0.000 description 8
- 150000001540 azides Chemical class 0.000 description 8
- WWECJGLXBSQKRF-UHFFFAOYSA-N n,n-dimethylformamide;methanol Chemical compound OC.CN(C)C=O WWECJGLXBSQKRF-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 238000011835 investigation Methods 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- -1 6-(3,4-Dimethoxy-phenyl) -thieno (3,2-c)pyrid-4-one Chemical compound 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 102000008186 Collagen Human genes 0.000 description 4
- 108010035532 Collagen Proteins 0.000 description 4
- 108010058846 Ovalbumin Proteins 0.000 description 4
- 229920001436 collagen Polymers 0.000 description 4
- 229940092253 ovalbumin Drugs 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 241000700159 Rattus Species 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 230000002776 aggregation Effects 0.000 description 3
- 238000004220 aggregation Methods 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 230000002110 toxicologic effect Effects 0.000 description 3
- 231100000027 toxicology Toxicity 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- KKMZQOIASVGJQE-UHFFFAOYSA-N 3-thiophen-2-ylprop-2-enoic acid Chemical compound OC(=O)C=CC1=CC=CS1 KKMZQOIASVGJQE-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 235000010418 carrageenan Nutrition 0.000 description 2
- 229920001525 carrageenan Polymers 0.000 description 2
- CZZYITDELCSZES-UHFFFAOYSA-N diphenylmethane Chemical compound C=1C=CC=CC=1CC1=CC=CC=C1 CZZYITDELCSZES-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 201000008482 osteoarthritis Diseases 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- APLNAFMUEHKRLM-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)N=CN2 APLNAFMUEHKRLM-UHFFFAOYSA-N 0.000 description 1
- AXLMAIGHIMDIKK-UHFFFAOYSA-N 2-chloro-6-phenyl-2H-thieno[3,2-c]pyridin-4-one Chemical compound ClC1C=C2C(N=C(C=C2S1)C1=CC=CC=C1)=O AXLMAIGHIMDIKK-UHFFFAOYSA-N 0.000 description 1
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 101100205030 Caenorhabditis elegans hars-1 gene Proteins 0.000 description 1
- 229920003137 Eudragit® S polymer Polymers 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 208000007353 Hip Osteoarthritis Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010048961 Localised oedema Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 230000004931 aggregating effect Effects 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 230000003501 anti-edematous effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 230000002497 edematous effect Effects 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000003137 locomotive effect Effects 0.000 description 1
- 210000001872 metatarsal bone Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 230000000793 phophlogistic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 229940045860 white wax Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Hematology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Therapeutic compositions having, in particular, blood-platelet aggregation inhibiting and anti- inflammatory activities comprising, have as active ingredient, an efficient amount of a thienopyridone derivative having the following general formulae: in which X is an oxygen or sulfur atom, R is hydrogen or halogen or a C1-4 alkyl radical and Ar represents an aryl or heteroaryl group optionally substituted with at least a halogen atom or a lower alkyl, lower alkoxy, hydroxy, trifluoromethyl or nitro group. The compounds are prepared by cyclisation of a furan or thiophene substituted acrylic acid azide to form the pyridone ring. The compounds other than where R is H, X is 5 and Ar is phenyl are claimed per se.
Description
This invention relates to a therapeutic composition comprising, as active ingredient, thieno-and furopyridone derivatives.
Thus, this invention relates to a therapeutic 5 composition having in particular blood-platelet aggregating inhibiting and anti-inflammatory activities, comprising, as active ingredient, an efficient amount of a thienopyridone or furopyridone derivative having the following general formulae :
in which X is an oxygen or sulfur atom; R represents a hydrogen or halogen atom or a alkyl group, and Ar represents an aryl or heteroaryl group optionally substituted with at least a halogen atom or lower alkyl, lower alkoxy, hydroxy, trifluoromethyl or nitro group.
Illustrative aryl groups are phenyl and naphthyl groups optionally substituted as indicated above, and an illustrative heteroaryl group is a pyridyl group optionally substituted with the above defined groups.
Of all the compounds represented by the general formula (I) or (II), only the compound of the formula (II) in which R = Η, X = S, and Ar = CgHg is a known compound.
It has already been mentioned in the literature (D.E. AMES & I. RIBEIRO, J.C.S. Perkin I, 1975, 1390), but it has never been studied from a therapeutic standpoint and the process for its preparation is relatively complex.
Thus, the invention relates to theino- or furopyridone derivatives of formula (I) or (II) as defined above, excluding compounds in which R is Η, X is S and Ar is phenyl.
This invention relates also to a process for the preparation of derivatives of the formula (I) or (II), comprising heating in an inert solvent and at a temperature of at least 150°C a compound having the following formula (III) or (IV):
(IV) in which X, R and Ar have the above-defined meanings.
The solvent inert with respect to the reagents and the reaction products is diphenylmethane or diphenyl 5 ether, for example. This reaction by heat treatment, involves the rearrangement of the aaides of the formula (III) or (IV) to the isocyanates of the formula (V) or (VI) which undergo thermal cyclization to the derivatives (I) and (II), according to the following reaction scheme :
The starting compounds of the formulae (III) and (IV) are prepared from the corresponding acids Of the formulae (VII) and (VIII) which are first converted to
8 418' or mixed anhydrides (XI) and (XII), the acid chlorides of the formulae (ιχ) arid (X),/ the latter being, in turn, conventionally converted to the azides, for example by reaction with sodium azide in aqueous solution, according to the following reaction scheme :
COCH /'/a.
Ar
LUX
NaN.
io
3_> (HI) (VII)
Y = Cl : (IX)
Y = OCOOC2H5 : (XI)
y = Cl : (X) y = 0C00C2Hs : (XII)
The following acids of the' formula (VII), in which : X = S, R = H, Ar = CgH-,· X = S, R = H,
Ar = 4-Cl-CgH^; X = S, R = H, Ar = -l-CH^CgHj J X = S,
R = H, Ar = 4-NO2-CgH4 and X = 0, R = H, Ar = CgHg, are 10 described in the literature = S. FISICHELLA, G. SCARLATA & D. SCHIOTTO, Ann. Chim. (Italia), 1973, 63, 55; S. FISICHELLA, G. MINESI, G. SCARLATA & D. SCIOTTO, ibid. 1973, 6_3, 779.
The other acids of the formulae (VII) and (VIII)
8 4 18 which are used in the method according to this invention are new and were prepared according to the process described in the above-mentioned references, according to the following reaction scheme :
Ac_O, Et-N —-2-> (VII)
Ac-0, Et N —-----> (VIII)
The following non-limiting Examples illustrate the process for the preparation of derivatives of this invention.
EXAMPLE 1
6-Phenyl-thleno(3,2-c)pyrid-4-one (Derivative No·. 1)
a) Preparation of azide (III)
To a solution of O< -phenyl-y#-(2-thienyl)acrylic acid (50 g; 0.217 mole) in triethylamine (31 ml; 0.22 mole) and chloroform (350 ml) cooled to -5°C are added dropwise 21 ml (ro 0.22 mole) ethyl chloroformate. After stirring the mixture for 1/2 hour at -5°C, a solution of sodium
8 418 azide (17 g; 0.26 mole) in 60 ml water is added dropwise thereto. On completion of the addition, the resulting material is stirred at 0°C for 1 hour, after which water is added thereto and it is then decanted. The organic phase is washed with water and then dried over sodium sulfate and filtered, b) 'Preparation of derivative (I)
The filtrate obtained in step a) is added dropwise to 200 ml diphenyl methane previously heated at
160eC, the chloroform distilling off gradually. When the addition is complete, the material is stirred for a further 15 minutes at the same temperature, after which it is cooled, di/ sopropyl ether is added thereto, and the material Is then filtered and washed with the same ether and dried in vacuo, to give 31.55 g (Yield : 63.5%) beige crystals (M.p. = 230°C) which may be recrystallized from methanol-dimethylformamide.
EXAMPLE 2
6-fc>~Fluorophenyl)-thieno (3,2-c)pyrid-4-one (Derivative No. 2)
This compound is prepared according to the procedure of Example 1, from -(4-fluoro-phenyl)-fi-(2thienyl)acrylic acid (M.p. = 191eC) : beige crystals,
M.p. = 262°C (methanol-dimethylformamide). Yield : 44.5%. EXAMPLE 3
6-fc>.ChlorophenyjF-thieno(3,2-c)pyrid-4-one (Derivative N°3)
This compound is prepared according to the procedure of Example 1, from ¢( -(2-chloro-phenyl)- fi-(2thienyl)acrylic acid (M.p. = 197eC): beige crystals,
8 118
M.p. = 232°C; yield : 27%.
EXAMPLE 4
6-fr>-Chlorophsnyl)-thieno (3,2-c)pv;ria-4-one (Derivative No. 4)
Prepared according to the procedure of Example 5 1, from o<-(4-chloro-phenyl)-/-(2-thienyl)acrylic acid (M.p. = 224°C): pale green crystals; M.p. ; 260°C;
Yield : 60%.
EXAMPLE 5
6-^~Toly3}-thier.o (3,2-c)pyrld-4-one (Derivative No. 5)
Prepared according to the procedure of Example
1, from Λ -{p„Tolyl)-/3-(2-thienyl)-acrylic acid (M.p. = 209°C): Yellow crystals, M.p. 260aC (methanoldimethylformamide), Yield : 51%.
EXAMPLE 6
6~(p-MethoxyphenyV-thieno (3,2-c)pyrld-4-one (Derivative Ho. 6
Prepared according to the procedure of Example 1, from Λ- (4-methoxy-phenyl)-{3- (2-thienyl) acrylic acid (M.p. = 203°C): greenish crystals, M.p. = 251eC (dimethylformamide) ; Yield : 64%.
EXAMPLE 7
6-(3,4-Dimethoxy-phenyl) -thieno (3,2-c)pyrid-4-one (Derivative No. 7)
Prepared according to the procedure of Example 1, from C<-(3,4-dimethoxy-phenyl)-/5-(2-thienyl)acrylic acid (M.p. = 220°C); yellow crystals, M.p. = 220eC (methanoldimethylformamide); Yield : 60.5%.
8418
EXAMPLE 8
6--(3,4,5--Trimethoxy-phenyl) -thleno (3,2-c)pyrid-4-one (Derivative No. 8)
Prepared according to the procedure of 5 Example 1, from o4-(3,4,5-trimethoxy-phenyl)-/ -(2thienyl)acrylic acid (M.p. = 217°C): yellow crystals,
M.p. = 240°C (methanol-dimethylformamide); Yield : 62%. EXAMPLE 9
6-(o,Nltrophenyl)-thieno (3,2-c)pyrid-4-one (Derivative No. 9)
Prepared according to the procedure of
Example 1, from £<-(2-nitro-phenyl)-fi-(2-thienyl)acrylic acid (M.p. = 211®C): yellow crystals, M.p. = 236°C (methanol-dimethylformamide); Yield : 20%.
EXAMPLE 10
6-(p_Nitrophenyl)-thieno (3,2-c)pyrid-4-one (Derivative No. 10)
Prepared according to the procedure of Example 1, from ©(-(4-nitro-phenyl)-fi-(2-thienyl)acrylic acid (M.p. = 236°C): yellow crystals, M.p.^260°C;
Yield : 51%.
EXAMPLE 11
6r^iu,Trifluoroaethylphenyl)-thieno (3,2-c)pyrid-4-one (Derivative No. 11)
Prepared according to the procedure of Example 1, from
M.p. - 245°C (methanol-dimethylformamide); Yield : 58%.
Ί8418
EXAMPLE 12
2-Chloro-6-phenyl-thieno (3,2-c)pyrid-4-one (Derivative No. JJ
Prepared according to the procedure of
Example 1, from Ox-phenyl-/?-(5-chloro-2-thienyl)acrylic 5 acid (M.p. 215°C) . Orange crystals, M.p.>>.260oC (dimethylformamide) , Yield : 64%.
EXAMPLE 13
2-Methyl-6-phenyl-thieno(3,2-c)pyrid-4-pne (Derivative No. 1;
Prepared according to the procedure cf
Example 1, from c(-phenyl-y$ -(5-methyl-2-thienyl)acrylic acid (M.p. = 207cC, : beige crystals; M.p.^-260°C (dimethylformamide); yield : 54%.
EXAMPLE 14
6- (3-Pyridyl)-thieno (3,2-c)pyrid-4-one (Derivative No. 14)
Prepared according to the procedure of
Example 1, from o(-(3-pyridyl)-( -(2-thienyl)acrylic acid (M.p. = 210°C) : Yellow crystals, M.p.J^. 260°C (dimethylformamide) ; Yield : 41%.
EXAMPLE 15
-Phenyl-thieno,(3,2-c)pyrid-7-one (Derivative No. 15)
Prepared according to the procedure of Example 1, from cX-phenyl-/?-(3-thienyl)acrylic acid (M.p. = l75eC) : pinkish crystals, M.p. = 203°C (methanoldimethylformamide); Yield : 50%.
EXAMPLE 16
-fc>_Chloropheny3)-thieno (3,2-c)pyrid-7-one (Derivative No.. 16)
Prepared according to the procedure of π
4611
Example 1, from o<-(2-chlorophenyl)-/5-(3-thienyl)acrylic acid (M.p. = 196°C): beige crystals, M.p. = 229eC;
Yield : 39%.
EXAMPLE 17 .
6-Phenyl-furo(3,2-c)pyrid4-one (Derivative No. 17)
Prepared according to the procedure of Example 1, from ίΧ-phenyl-^-(2-furyl)acrylic acid (M.p. = 346°C): Beige crystals, M.p. = 210°C; Yield : 65%. EXAMPLE 18
6-(c<-Maphthy2)-furo (3,2-c)pyrid-4-one (Derivative No. 18)
Prepared according to the procedure of Example 1 from θί-(1-naphthyl)-fi -(2-furyl)acrylic acid (M.p.= 219°C) Beige crystals, M.p. = 230°C; Yield : 39.5%.
The results of toxicological and pharmacological 15 investigations reported below demonstrate the useful activities of the derivatives of this invention, particularly their blood-platelet aggregation inhibiting and anti-inflammatory activities.
I. TOXICOLOGICAL INVESTIGATION 20 The compounds according to this invention benefit from an excellent tolerance and a low toxicity. Thus, the LDjq/24 hrs/kg body weight in animals, as determined in mice by the technique according to Miller & Tainter, by the oral route, is in excess of 400 mg for all derivatives.
In addition, the tests relating to acute, chronic, sub-chronic and delayed toxicity effected in various animal species failed to evidence any local or •18 4 18 systemic reaction, any perturbation in the regularly effected biological control tests, or any anomaly in the microscopic and macroscopic examinations in the animals sacrificed and autopsied at the end of the experiments.
II. PHARMACOLOGICAL INVESTIGATION.
1® Blood-platelet aggregation inhibiting activity
Blood is taken from the jugular vein of Wistar rats. From this citrated blood, and after centrifugation, is reconstituted a plasma containing 600.000 - 20.000 blood-platelets per mm , vzhich will be used in all aggregation determinations.
a) Determination of A.D.P.-induced blood-platelet aggregation
0.4 ral plasma are placed in a siliconized tube 15 provided vzith a bar magnet / which is also siliconized.
The tube is introduced into an aggregometer coupled with an apparatus designed to record the optical density variations. When light transmission has reached a stable value, 0.5 ml of a solution containing 10 /fM A D P (Adenosine-Di Phosphate) are introduced into the tube.
Blood-platelet aggregation then produces an increase of the light transmission, followed by a decrease subsequent to the deaggregation stage.
The maximal variation of the optical density thus determined characterizes the intensity of the aggregation.
8 418
b) Determination of collagen-induced blood-platelet aggregation
The ADP solution is substituted with a collagen (bovine tendon extract) solution.
c) Results
Different groups of 20 rats are used, each group being orally administered a test derivative at a dosage of 100 mg/kg body weight. The results obtained in both tests are given in following Table I which indicates the percent inhibition of blood-platelet aggregation obtained, with respect to the control group, 3 hours after treatment with the compounds of this invention, in the A.D.P. and collagen tests.
118
TABLE I
Treatment Percent inhibition A.D.P. Collagen Derivative No. 1 62.0 91.4 tl Ilo. 2 60.5 91.7 tt No. 3 58.8 92.0 tt No. 4. 61.2 90.5 Π No. 5 62.6 91.4 tl No. 6 62.2 91.7 II No. 7 61.7 90.6 n No. 8 60.4 92.2 tt No. 9 59.1 90.8 It NO. 10 60.4 90.2 It Ho. 11 60.1 90.7 tt No. 12 60.6 91.4 tt No. 13 61.5 90.5 tt No. 14 60.8 91.2 π No. 15 62.5 90.8 tt No. 16 60.1 90.2 n No. 17 59.8 90.4
2° Anti-inflammatory activity
a) Method of the carrageenin-induced localized edema
0.1 ml of a 1% carrageer.in solution is injected in the metatarsal flexor muscles of the right rear limb of 25 rats at time 0, The animals of the treated group are additionally orally administered 100 mg/kg of the test derivative, respectively one hour prior to, simultaneously with, and 1 and 2.5 hours after injection of the phlogogenic agent. The determinations effected with a ROCH micrometer at
8 418 times Ο, 1 hr,2 hrs,3 hrs and 5 hrs after carrageenin administration are a measure, as a function of time, of the percent anti-inflammatory activity by comparison with the reference group.
The results obtained are reported in following
Table XI :
8 4 18
b) Method of the ovalbumin-induced systemic edema ml ovalbumin and 0.5 ml of a 1% Evans Blue solution are simultaneously injected in rats by the intraperitoneal route. On the other hand, the animals of the treated group are orally administered 100 mg/kg of the test derivative 1 hour prior to and simultaneously with the ovalbumin. The intensity of the phenomenon thus induced is rated according to a scale from 1 to 5, as a function of the progress of the inflammatory syndrome. The mean edematous intensity and the percent decrease of the edema reaction with respect to the control group are thus determined as a function of time.
The percent anti-inflammatory activity obtained hrs and 3 hrs after ovalbumin injection are set forth 15 in following Table III.
8 4 18
TABLE III
Derivative No. percent anti-inflanmatory activity 2 hrs 3 hrs 1 45 52 2 48 54 3 48 55 4 47 53 5 50 55 6 52 58 7 48 55 3 46 53 9 46 52 10 49 55 11 51 57 12 45 52 13 46 53 14 48 54 15 47 53 16 46 54 17 45 51
The results of the above investigations demonstrate the good tolarance and the useful bloodplatelet aggregation inhibiting and anti-inflammatory
- 48448 properties of the derivatives of the formulae (I) and (II) which make them highly useful in human and veterinary medicine.
The therapeutic composition of this invention 5 may be formulated for oral administration as tablets, coated tablets, capsules, drops and syrups. It may also be formulated for rectal administration as suppositories and, for parenteral administration, as injectable solutions.
Each unit dose contains advantageously 0.040-0.750 g active ingredient. The daily dosage regimen may vary from 0.040 g to 1.50 g active ingredient, according to the age of the patient and the condition treated.
Non-limiting Examples of pharmaceutical formulations of the therapeutic composition of this invention are given below.
1. TABLETS
Derivative No. 1 0.125 g
Excipient : lactose, polyvinylpyrrolidone, alginic acid, potato starch, magnesium stearate.
2. COATED TABLETS
Derivative No. 4 0.100 g
Excipient : Eudragit S, talc, magnesium stearate, gum arabic, white sugar for pharmaceuticals, white wax, carnauba wax.
8 4 18
3.
CAPSULES
Derivative No. 6 0.150 g
Excipient : magnesium stearate, talc, lactose.
4.
INJECTABLE AMPOULES
Derivative No. 12 0.100 g
Excipient : isotonic solvent, sufficient to make 3 ml
.
SUPPOSITORIES
Derivative No. 15 0.150 g
Excipient ; Semi-synthetic triglycerides.
The toxicological and pharmacological investigations reported above demonstrate the low toxicity of the derivatives of this invention together with their outstanding blood-platelet aggregation inhibiting and anti-inflammatory activities.
Thus, the therapeutic composition of this invention may profitably be administered to humans, for preventive or curative purposes, in the treatment of diseases which induce a pathological modification of blood-platelet aggregation, such as the thrombo-embolic diseases.
It may also be administered for its antiinflammatory and anti-edematous properties in the treatment of all inflammatory reactions without thereby interfering with the evolution of the underlying pathological process.
It is applicable in such cases as rheumatic polyarthrosis, arthrosis, coxarthrosis, ankylosing spondylarthritis, gout, acute conditions of the locomotor system, in post-operative surgery and in odonto-stomatology.
Claims (11)
1. A therapeutic composition comprising, as active ingredient, an effective amount of a thienopyridone or furopyridone derivative having the following in which X is an oxygen or sulfur atom, R represents a hydrogen or halogen atom or a C^_ 4 alkyl group, and Ar represents an aryl or heteroaryl group optionally substit10 uted with at least a halogen atom or lower alkyl, lower alkoxy, hydroxy, trifluoromethyl or nitro group.
2. A composition as claimed in claim 1, wherein the aryl group is a phenyl or naphthyl group and the heteroaryl group is a pyridyl group. 15
3. A composition as claimed in claim 1 or 2 formulated in a form suitable for oral, parenteral or rectal administration, the active ingredient being combined with a therapeutically acceptable carrier.
4. A composition as claimed in any one of the 20 claims 1 to 3 in unit dosage form, each unit dose containing 0.040 - 0.750 g active ingredient.
5. Thieno- or furopyridones as defined in claim 1, excluding compounds in which R is Η, X is S and Ar is phenyl. 4 8 418 - 21
6. Compounds as claimed in claim 5, wherein the aryl group is a phenyl or naphthyl group and the heteroaryl group is the pyridyl group.
7. A process for the preparation of a compound as 5 claimed in claim 5 which comprises heating in an inert solvent at a temperature of at least 150°C a compound of formula (III) or (IV). (III) (IV) wherein X, R, and Ar are as defined in claim 5. 10
8. A process as claimed in claim 7, wherein the inert solvent is diphenylmethane or diphenyl ether.
9. A composition as claimed in claim 1 substantially as described herein in any one of the pharmaceutical examples.
10. A composition as claimed in claim 1 wherein the 15 active ingredient is any one of Derivatives 1-18 described herein.
11. A compound as claimed in claim 5, said compound being any one of Derivatives 2-14 and 16-18 described herein.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7818684A FR2429219A1 (en) | 1978-06-22 | 1978-06-22 | MEDICINE BASED ON THIENOPYRIDONE OR FUROPYRIDONE DERIVATIVES |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE791036L IE791036L (en) | 1979-12-22 |
| IE48418B1 true IE48418B1 (en) | 1985-01-09 |
Family
ID=9209842
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE1036/79A IE48418B1 (en) | 1978-06-22 | 1979-08-08 | Therapeutic composition containing thienopyridone or furopyridone derivatives |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0006772B1 (en) |
| JP (1) | JPS552698A (en) |
| BE (1) | BE877157A (en) |
| CH (1) | CH638214A5 (en) |
| DE (1) | DE2961213D1 (en) |
| DK (1) | DK259379A (en) |
| FR (1) | FR2429219A1 (en) |
| GB (1) | GB2023599B (en) |
| IE (1) | IE48418B1 (en) |
| IT (1) | IT1117227B (en) |
| LU (1) | LU81237A1 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57147852A (en) * | 1981-03-10 | 1982-09-11 | Toshiba Corp | Mask convergence-type color picture tube |
| JPS5818845A (en) * | 1981-07-24 | 1983-02-03 | Toshiba Corp | Color cathode-ray tube |
| KR930000551B1 (en) * | 1988-02-02 | 1993-01-25 | 다이니뽄 스크린 세이조 가부시끼 가이샤 | Slot type shadow mask |
| WO2002057219A1 (en) * | 2001-01-18 | 2002-07-25 | Welichem Biotech Inc. | Novel 1,2-diphenylethene derivatives for treatment of immune diseases |
| EP1594863A1 (en) * | 2003-02-11 | 2005-11-16 | Prosidion Limited | Tri(cyclo) substituted amide glucokinase activator compounds |
| WO2010080415A2 (en) * | 2008-12-19 | 2010-07-15 | The University Of North Carolina At Chapel Hill | Substituted afpo (6-aryl-4h-furo[3,2-c]pyran-4-one) derivatives as anti-cancer agents |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2115006A1 (en) * | 1970-11-20 | 1972-07-07 | Anvar | 2,7-dinitro and 2-nitro furo 3,2-c pyridine - useful as antibacterials |
| GB1576511A (en) * | 1977-03-29 | 1980-10-08 | Parcor | Thieno(2,3 - c) and (3,2 - c) pyridines process for their preparation and therapeutic applications thereof |
-
1978
- 1978-06-22 FR FR7818684A patent/FR2429219A1/en active Granted
-
1979
- 1979-04-30 CH CH402979A patent/CH638214A5/en not_active IP Right Cessation
- 1979-05-02 DE DE7979400282T patent/DE2961213D1/en not_active Expired
- 1979-05-02 EP EP79400282A patent/EP0006772B1/en not_active Expired
- 1979-05-09 LU LU81237A patent/LU81237A1/en unknown
- 1979-06-21 BE BE0/195879A patent/BE877157A/en not_active IP Right Cessation
- 1979-06-21 DK DK259379A patent/DK259379A/en not_active Application Discontinuation
- 1979-06-21 IT IT49482/79A patent/IT1117227B/en active
- 1979-06-22 GB GB7921911A patent/GB2023599B/en not_active Expired
- 1979-06-22 JP JP7897579A patent/JPS552698A/en active Granted
- 1979-08-08 IE IE1036/79A patent/IE48418B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| JPS552698A (en) | 1980-01-10 |
| GB2023599A (en) | 1980-01-03 |
| FR2429219A1 (en) | 1980-01-18 |
| DK259379A (en) | 1979-12-23 |
| FR2429219B1 (en) | 1980-10-24 |
| GB2023599B (en) | 1982-11-03 |
| IE791036L (en) | 1979-12-22 |
| LU81237A1 (en) | 1979-09-10 |
| IT1117227B (en) | 1986-02-17 |
| DE2961213D1 (en) | 1982-01-14 |
| CH638214A5 (en) | 1983-09-15 |
| JPS6345394B2 (en) | 1988-09-09 |
| BE877157A (en) | 1979-12-21 |
| EP0006772B1 (en) | 1981-11-04 |
| IT7949482A0 (en) | 1979-06-21 |
| EP0006772A1 (en) | 1980-01-09 |
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| MM4A | Patent lapsed |