EP0000035A1 - Alpha-amino-acides, compositions et procédé pour la préparation de ces composés - Google Patents
Alpha-amino-acides, compositions et procédé pour la préparation de ces composés Download PDFInfo
- Publication number
- EP0000035A1 EP0000035A1 EP78100058A EP78100058A EP0000035A1 EP 0000035 A1 EP0000035 A1 EP 0000035A1 EP 78100058 A EP78100058 A EP 78100058A EP 78100058 A EP78100058 A EP 78100058A EP 0000035 A1 EP0000035 A1 EP 0000035A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compounds
- alpha
- diphenylmethylenedioxybenzyl
- aminoprop
- benzylidene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 50
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 4
- 239000000203 mixture Substances 0.000 title abstract description 12
- 150000001371 alpha-amino acids Chemical class 0.000 title abstract 2
- 235000008206 alpha-amino acids Nutrition 0.000 title abstract 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 5
- 125000006702 (C1-C18) alkyl group Chemical group 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 125000001589 carboacyl group Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 claims 1
- CUFLZUDASVUNOE-UHFFFAOYSA-N methyl 3,4-dihydroxybenzoate Chemical compound COC(=O)C1=CC=C(O)C(O)=C1 CUFLZUDASVUNOE-UHFFFAOYSA-N 0.000 abstract description 4
- APLIVPRJXXETFC-UHFFFAOYSA-N 4-chloro-7,8-diphenyl-4h-1,3-benzodioxine Chemical class ClC1OCOC(C=2C=3C=CC=CC=3)=C1C=CC=2C1=CC=CC=C1 APLIVPRJXXETFC-UHFFFAOYSA-N 0.000 abstract description 3
- KRYBNWHUYUMPQM-UHFFFAOYSA-N 7,8-diphenyl-4h-1,3-benzodioxin-4-ol Chemical compound OC1OCOC(C=2C=3C=CC=CC=3)=C1C=CC=2C1=CC=CC=C1 KRYBNWHUYUMPQM-UHFFFAOYSA-N 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- WQTKNGJGJOYBFS-UHFFFAOYSA-N 1-phenyl-n-(3-trimethylsilylprop-2-ynyl)methanimine Chemical compound C[Si](C)(C)C#CCN=CC1=CC=CC=C1 WQTKNGJGJOYBFS-UHFFFAOYSA-N 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 2
- OPTDDWCXQQYKGU-UHFFFAOYSA-N diphenyldichloromethane Chemical compound C=1C=CC=CC=1C(Cl)(Cl)C1=CC=CC=C1 OPTDDWCXQQYKGU-UHFFFAOYSA-N 0.000 abstract description 2
- 150000002148 esters Chemical class 0.000 abstract description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 abstract description 2
- IEJDRGFSWQHPAR-NSHDSACASA-N (2r)-2-amino-2-[(3,4-dihydroxyphenyl)methyl]but-3-ynoic acid Chemical compound C#C[C@](C(O)=O)(N)CC1=CC=C(O)C(O)=C1 IEJDRGFSWQHPAR-NSHDSACASA-N 0.000 abstract 1
- FEPOHBCBQQCLOF-UHFFFAOYSA-N 1-phenyl-n-prop-2-ynylmethanimine Chemical compound C#CCN=CC1=CC=CC=C1 FEPOHBCBQQCLOF-UHFFFAOYSA-N 0.000 abstract 1
- XHXWSXRYHAEBMV-UHFFFAOYSA-N N-[1-(2,2-diphenyl-1,3-benzodioxol-5-yl)-4-trimethylsilylbut-3-yn-2-yl]-1-phenylmethanimine Chemical compound C1(=CC=CC=C1)C1(OC2=CC=C(CC(C#C[Si](C)(C)C)N=CC3=CC=CC=C3)C=C2O1)C1=CC=CC=C1 XHXWSXRYHAEBMV-UHFFFAOYSA-N 0.000 abstract 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 abstract 1
- 229940073608 benzyl chloride Drugs 0.000 abstract 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 abstract 1
- 238000005984 hydrogenation reaction Methods 0.000 abstract 1
- 230000001131 transforming effect Effects 0.000 abstract 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 238000006460 hydrolysis reaction Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 5
- -1 2-ethylhexyl Chemical group 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 206010020772 Hypertension Diseases 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 239000007832 Na2SO4 Substances 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 238000004949 mass spectrometry Methods 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 150000003840 hydrochlorides Chemical class 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- MCSXGCZMEPXKIW-UHFFFAOYSA-N 3-hydroxy-4-[(4-methyl-2-nitrophenyl)diazenyl]-N-(3-nitrophenyl)naphthalene-2-carboxamide Chemical compound Cc1ccc(N=Nc2c(O)c(cc3ccccc23)C(=O)Nc2cccc(c2)[N+]([O-])=O)c(c1)[N+]([O-])=O MCSXGCZMEPXKIW-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 2
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-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
- 150000007513 acids Chemical class 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 229940030600 antihypertensive agent Drugs 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 230000001631 hypertensive effect Effects 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- HRYJKXADUURXNB-UHFFFAOYSA-N methyl 2-amino-2-(7,8-diphenyl-4h-1,3-benzodioxin-4-yl)but-3-enoate Chemical compound COC(=O)C(N)(C=C)C1OCOC(C=2C=3C=CC=CC=3)=C1C=CC=2C1=CC=CC=C1 HRYJKXADUURXNB-UHFFFAOYSA-N 0.000 description 2
- XXUBBODTEQKFAU-UHFFFAOYSA-N methyl 2-amino-2-(7,8-diphenyl-4h-1,3-benzodioxin-4-yl)but-3-ynoate Chemical compound COC(=O)C(N)(C#C)C1OCOC(C=2C=3C=CC=CC=3)=C1C=CC=2C1=CC=CC=C1 XXUBBODTEQKFAU-UHFFFAOYSA-N 0.000 description 2
- NODUQGHLIDCPIL-UHFFFAOYSA-N methyl 6,7-diphenyl-2,4-dioxabicyclo[3.2.2]nona-1(7),5,8-triene-9-carboxylate Chemical compound COC(=O)C1=CC(=C2C=3C=CC=CC=3)OCOC1=C2C1=CC=CC=C1 NODUQGHLIDCPIL-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 150000002994 phenylalanines Chemical class 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000002516 radical scavenger Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 0 CC(*)(Cc(cc1)cc2c1OC(c1ccccc1)(c1ccccc1)O2)N Chemical compound CC(*)(Cc(cc1)cc2c1OC(c1ccccc1)(c1ccccc1)O2)N 0.000 description 1
- CJCSPKMFHVPWAR-UHFFFAOYSA-N CC(Cc(cc1)cc(O)c1O)(C(O)=O)N Chemical compound CC(Cc(cc1)cc(O)c1O)(C(O)=O)N CJCSPKMFHVPWAR-UHFFFAOYSA-N 0.000 description 1
- 241000790917 Dioxys <bee> Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 150000004753 Schiff bases Chemical group 0.000 description 1
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 150000001295 alanines Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- WPUJEWVVTKLMQI-UHFFFAOYSA-N benzene;ethoxyethane Chemical compound CCOCC.C1=CC=CC=C1 WPUJEWVVTKLMQI-UHFFFAOYSA-N 0.000 description 1
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Substances [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 125000003438 dodecyl 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([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 125000000268 heptanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- GNKNVDAYKUWZSL-UHFFFAOYSA-N methyl 2-(benzylideneamino)-2-(7,8-diphenyl-4h-1,3-benzodioxin-4-yl)-4-trimethylsilylbut-3-ynoate Chemical compound O1COC(C(=C(C=2C=CC=CC=2)C=C2)C=3C=CC=CC=3)=C2C1C(C(=O)OC)(C#C[Si](C)(C)C)N=CC1=CC=CC=C1 GNKNVDAYKUWZSL-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- HPFRRIJVIFKIDA-UHFFFAOYSA-N n-[1-(7,8-diphenyl-4h-1,3-benzodioxin-4-yl)-3-trimethylsilylprop-2-ynyl]-1-phenylmethanimine Chemical compound O1COC(C(=C(C=2C=CC=CC=2)C=C2)C=3C=CC=CC=3)=C2C1C(C#C[Si](C)(C)C)N=CC1=CC=CC=C1 HPFRRIJVIFKIDA-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([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([H])([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])[H] 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([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([H])([H])C([H])([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- 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
- C07D317/44—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 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—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 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
Definitions
- the present invention is concerned with a-ethynyl-and a-vinyl-3,4-disubstituted phenylalanines and especially the 3,4-dihydroxyphenyla- lanine species.
- a-Methyl-3,4-dihydroxyphenylalanine, particularly its L-isomer, is a known antihypertensive agent. (U.S. 2,868,818; U. S . 3,344,023).
- Novel a-ethynyl-and a-vinyl-3,4-disubstituted phenylalanines have been discovered. These novel alanines have pharmaceutical activity including antihypertensive action.
- the present invention is embodied in a-ethynyl or a-vinyl phenylalanine compounds having the formula wherein
- the pharmaceutically acceptable salts of the formula I compounds are also included. These salts generally are acid addition salts of suitable organic or inorganic acids. Preferred salts are the hydrohalides such as the hydrobromides, the hydrochlorides, the hydrogen iodides. Most preferred salts are the hydrochlorides.
- the compounds of formula I have a chiral center and may occur in optically active forms, i.e., as optical isomers. These isomers are conventionally designated as D and L, d and 1, + and -, (S) and (R) or by a combination of these symbols. Where the compound name or formula does not specify the isomer form, all forms are included, i.e., the individual isomers, mixtures thereof and racemates.
- R may be H or an alkyl group, preferably a C 1 -C 18 alkyl group.
- suitable alkyl groups are octadecyl, 2-ethylhexyl, lauryl, undecyl, methyl, isopropyl, hexyl and the like.
- Preferred R groups are H and C l -C 6 alkyl. Most preferred R groups are H and ethyl.
- R 1 and R 2 include H and C2-C6 alkanoyl groups.
- suitable alkanoyl groups are acetyl, octanoyl, pivaloyl, 2-methylpropanoyl, heptanoyl, butanoyl and the like.
- the most preferred R l/ R 2 substituent is hydrogen.
- a preferred class of compounds of the present invention is that having the formula
- R is hydrogen or C 1 -C 6 alkyl, preferably ethyl.
- the L-isomer form of the formula II compound is also more preferred.
- Another preferred class of compounds of the present invention is that having the formula
- R is hydrogen or C 3 -C 6 alkyl, preferably ethyl.
- the L-isomer form of the formula III compounds are also more preferred.
- the compounds of the present invention have pharmaceutical activity especially as antihypertensive agents.
- the present compounds are useful for treating hypertension in humans.
- the present compounds may be administered to the hypertensive patient orally, parenterally or via any other suitable administration route.
- Conventional dosage forms are used such as tablets, troches, capsules, liquid formulations, e.g., solutions, dispersions, emulsiions, elixirs and the like.
- Conventional compounding ingredients i.e., diluents, carriers, etc. and conventional preparation procedures are utilized.
- the daily dosage of the present compounds may be varied as required.
- a daily dosage range for the hypertensive patient is about 50 mg. to about 5000 mg.
- a preferred daily dosage range is about 100 mg. to about 3500 mg.
- a more preferred daily dosage range is about 250 to about 1500 mg.
- Compounds of the present invention may be prepared by any convenient process.
- the hydrolysis is carried out using conventional reagents and conditions, for example using an acid such as HCl, HBr, H 3 PO 4 , in a suitable solvent such as water, aqueous alkanols and the like.
- the hydrolysis may be carried out at room temperature or at elevated temperatures up to about 140°C.
- the reaction time will vary depending on other parameters such as temperature, etc.
- R in formula I is an alkyl group
- the compound is prepared by conventional esterification of the corresponding compound where R is H as illustrated by the following equation
- the pharmaceutically acceptable salts of the present compounds may be obtained directly from the hydrolysis reaction described above. Such salts may also be obtained by treatment of the formula I free base with an appropriate acid under suitable conditions.
- the compounds of the present invention may be separated into the individual enantiomers by conventional resolution techniques. Such techniques commonly involve the formation of salts of the present racemeic acids with optically active bases.
- the resolution is preferably carried out on the O,O,N-triacyl derivatives of the racemic acid mixture. These acyl derivatives are prepared by treatment of the free acid mixture with a suitable acylating agent as illustrated by the following equation:
- the reaction may be carried out in an acid medium, e.g., glacial acetic acid.
- an acid medium e.g., glacial acetic acid.
- An example illustrating such an acylation system is in U.S. 3,983,138.
- the mass spectrum showed a large molecular ion peak at 501.
- the HCl salt obtained in Example 1 H.) may be conventionally neutralized or treated with an HC1 scavenger such as propylene oxide to obtain the corresponding free amino acid.
- the HC1 salt obtained in Example 2 B may be conventionally neutralized or treated with an HC1 scavenger such as propylene oxide to obtain the corresponding free amino acid.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US802390 | 1977-06-01 | ||
| US05/802,390 US4401676A (en) | 1977-06-01 | 1977-06-01 | Novel α-amino acids |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0000035A1 true EP0000035A1 (fr) | 1978-12-20 |
| EP0000035B1 EP0000035B1 (fr) | 1982-01-06 |
Family
ID=25183567
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP78100058A Expired EP0000035B1 (fr) | 1977-06-01 | 1978-06-01 | Alpha-amino-acides, compositions et procédé pour la préparation de ces composés |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US4401676A (fr) |
| EP (1) | EP0000035B1 (fr) |
| JP (1) | JPS543036A (fr) |
| DE (1) | DE2861499D1 (fr) |
| DK (1) | DK240778A (fr) |
| IE (1) | IE47073B1 (fr) |
| IT (1) | IT7849636A0 (fr) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2827805A1 (de) * | 1977-07-01 | 1979-01-18 | Merrell Toraude & Co | Alpha-vinyl-aminosaeuren und verfahren zu ihrer herstellung |
| DE2827824A1 (de) * | 1977-07-01 | 1979-01-18 | Merrell Toraude & Co | Alpha-acetylenische aminosaeuren |
| DE2827866A1 (de) * | 1977-07-01 | 1979-01-18 | Merrell Toraude & Co | Alpha-acetylenische derivate von alpha-aminosaeuren sowie verfahren zu deren herstellung |
| EP0007615A2 (fr) * | 1978-07-24 | 1980-02-06 | Merck & Co. Inc. | Procédé pour la préparation d'amino-acides et d'esters |
| EP0008658A1 (fr) * | 1978-07-24 | 1980-03-19 | Merck & Co. Inc. | Alpha-éthinyle-alpha-amino-acides et leurs esters et compositions pharmaceutiques les contenant |
| EP0008657A1 (fr) * | 1978-07-24 | 1980-03-19 | Merck & Co. Inc. | Alpha-vinyl-alpha-aminoacides et leurs esters et compositions pharmaceutiques les contenant |
| EP0309827A1 (fr) * | 1987-09-18 | 1989-04-05 | Banyu Pharmaceutical Co., Ltd. | Dérivés de L-dopa ou leurs sels d'addition, procédé pour les produire et leur utilisation |
| WO1996008483A1 (fr) * | 1994-09-16 | 1996-03-21 | Roussel Uclaf | Derives de l'acide gallique, leur procede de preparation et leur application a titre de medicaments |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH09501178A (ja) * | 1993-08-06 | 1997-02-04 | スミスクライン・ビーチャム・コーポレイション | エンドセリン受容体アンタゴニスト |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1850M (fr) * | 1961-02-24 | 1963-06-10 | Merck & Co Inc | Dérivés de la phénylalanine. |
| US3132176A (en) * | 1960-08-19 | 1964-05-05 | Merck & Co Inc | Preparation of o, o-dialkanoyl derivatives of d, l-alpha-alkyl-beta-3, 4-dihydroxyphenylalanine by preferential acylation |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2868818A (en) * | 1953-12-15 | 1959-01-13 | Merck & Co Inc | Alpha methyl phenylalanines |
| NL263355A (fr) * | 1960-04-08 | |||
| CH441362A (de) * | 1963-12-24 | 1967-08-15 | Hoffmann La Roche | Verfahren zur Herstellung von Phenylalaninderivaten |
| US3395176A (en) * | 1964-03-06 | 1968-07-30 | Merck & Co Inc | Alpha-hydroxymethylphenylalanine compounds |
| US3488363A (en) * | 1965-10-22 | 1970-01-06 | Merck & Co Inc | Preparation of alpha-methylphenyl alanines |
| CH475193A (de) * | 1966-06-07 | 1969-07-15 | Hoffmann La Roche | Verfahren zur Herstellung von Phenylalaninderivaten |
| US3714241A (en) * | 1969-10-29 | 1973-01-30 | Merck & Co Inc | PREPARATION OF alpha -METHYL-3,4-DISUBSTITUTED PHENYLALANINES |
| JPS5025465B1 (fr) * | 1970-12-29 | 1975-08-23 | ||
| US4022910A (en) * | 1972-12-22 | 1977-05-10 | Richardson-Merrell Inc. | L-3-hydroxymethyltyrosine and salts thereof for lowering blood pressure |
| US3983138A (en) * | 1973-09-25 | 1976-09-28 | Merck & Co., Inc. | Amino acid esters |
| US4051251A (en) * | 1976-02-13 | 1977-09-27 | Merck & Co., Inc. | Novel anti-hypertensive compositions |
-
1977
- 1977-06-01 US US05/802,390 patent/US4401676A/en not_active Expired - Lifetime
-
1978
- 1978-05-30 IE IE1079/78A patent/IE47073B1/en unknown
- 1978-05-31 IT IT7849636A patent/IT7849636A0/it unknown
- 1978-05-31 DK DK240778A patent/DK240778A/da not_active Application Discontinuation
- 1978-06-01 JP JP6501778A patent/JPS543036A/ja active Pending
- 1978-06-01 EP EP78100058A patent/EP0000035B1/fr not_active Expired
- 1978-06-01 DE DE7878100058T patent/DE2861499D1/de not_active Expired
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3132176A (en) * | 1960-08-19 | 1964-05-05 | Merck & Co Inc | Preparation of o, o-dialkanoyl derivatives of d, l-alpha-alkyl-beta-3, 4-dihydroxyphenylalanine by preferential acylation |
| FR1850M (fr) * | 1961-02-24 | 1963-06-10 | Merck & Co Inc | Dérivés de la phénylalanine. |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2827805A1 (de) * | 1977-07-01 | 1979-01-18 | Merrell Toraude & Co | Alpha-vinyl-aminosaeuren und verfahren zu ihrer herstellung |
| DE2827824A1 (de) * | 1977-07-01 | 1979-01-18 | Merrell Toraude & Co | Alpha-acetylenische aminosaeuren |
| DE2827866A1 (de) * | 1977-07-01 | 1979-01-18 | Merrell Toraude & Co | Alpha-acetylenische derivate von alpha-aminosaeuren sowie verfahren zu deren herstellung |
| FR2401133A1 (fr) * | 1977-07-01 | 1979-03-23 | Merrell Toraude & Co | Nouveaux derives d'aminoacides a-acetyleniques, leur preparation et leur utilisation comme inhibiteurs de la decarboxylase des aminoacides aromatiques |
| EP0007615A2 (fr) * | 1978-07-24 | 1980-02-06 | Merck & Co. Inc. | Procédé pour la préparation d'amino-acides et d'esters |
| EP0008658A1 (fr) * | 1978-07-24 | 1980-03-19 | Merck & Co. Inc. | Alpha-éthinyle-alpha-amino-acides et leurs esters et compositions pharmaceutiques les contenant |
| EP0008657A1 (fr) * | 1978-07-24 | 1980-03-19 | Merck & Co. Inc. | Alpha-vinyl-alpha-aminoacides et leurs esters et compositions pharmaceutiques les contenant |
| EP0007615A3 (en) * | 1978-07-24 | 1980-05-28 | Merck & Co. Inc. | Process for preparing amino acids and esters, and intermediates therefor |
| EP0309827A1 (fr) * | 1987-09-18 | 1989-04-05 | Banyu Pharmaceutical Co., Ltd. | Dérivés de L-dopa ou leurs sels d'addition, procédé pour les produire et leur utilisation |
| WO1996008483A1 (fr) * | 1994-09-16 | 1996-03-21 | Roussel Uclaf | Derives de l'acide gallique, leur procede de preparation et leur application a titre de medicaments |
| FR2724654A1 (fr) * | 1994-09-16 | 1996-03-22 | Roussel Uclaf | Nouveaux derives de l'acide gallique, leur procede de preparation, les nouveaux intermediaires obtenus, leur application a titre de medicaments et les compositions pharmaceutiques les renfermant |
Also Published As
| Publication number | Publication date |
|---|---|
| IT7849636A0 (it) | 1978-05-31 |
| DE2861499D1 (en) | 1982-02-25 |
| US4401676A (en) | 1983-08-30 |
| DK240778A (da) | 1979-01-12 |
| EP0000035B1 (fr) | 1982-01-06 |
| JPS543036A (en) | 1979-01-11 |
| IE47073B1 (en) | 1983-12-14 |
| IE781079L (en) | 1978-12-01 |
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