FI94627B - Nya isoindolonderivat, deras framställning och användning - Google Patents
Nya isoindolonderivat, deras framställning och användning Download PDFInfo
- Publication number
- FI94627B FI94627B FI905770A FI905770A FI94627B FI 94627 B FI94627 B FI 94627B FI 905770 A FI905770 A FI 905770A FI 905770 A FI905770 A FI 905770A FI 94627 B FI94627 B FI 94627B
- Authority
- FI
- Finland
- Prior art keywords
- radicals
- solution
- 7ars
- 3ars
- perhydroisoindolone
- Prior art date
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- XTBAPWCYTNCZTO-UHFFFAOYSA-N isoindol-1-one Chemical class C1=CC=C2C(=O)N=CC2=C1 XTBAPWCYTNCZTO-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 239000000203 mixture Substances 0.000 claims abstract description 102
- -1 phenyl radicals Chemical class 0.000 claims abstract description 65
- 150000003254 radicals Chemical class 0.000 claims abstract description 35
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 29
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 125000005843 halogen group Chemical group 0.000 claims abstract description 10
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims abstract description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 64
- 229910052757 nitrogen Inorganic materials 0.000 claims description 47
- 239000002253 acid Substances 0.000 claims description 25
- 150000001875 compounds Chemical class 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 229920006395 saturated elastomer Polymers 0.000 claims description 11
- FWFSEYBSWVRWGL-UHFFFAOYSA-N cyclohex-2-enone Chemical class O=C1CCCC=C1 FWFSEYBSWVRWGL-UHFFFAOYSA-N 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 7
- 229910052717 sulfur Chemical group 0.000 claims description 7
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 239000007858 starting material Substances 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 239000011593 sulfur Chemical group 0.000 claims description 5
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims description 4
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 claims description 4
- WYBVWRBMKAWGRK-UHFFFAOYSA-N 7,7-diphenyl-2,3,3a,5,6,7a-hexahydro-1h-isoindol-4-one Chemical group C12CNCC2C(=O)CCC1(C=1C=CC=CC=1)C1=CC=CC=C1 WYBVWRBMKAWGRK-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 125000004442 acylamino group Chemical group 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 125000002950 monocyclic group Chemical group 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- BNJMRELGMDUDDB-UHFFFAOYSA-N $l^{1}-sulfanylbenzene Chemical compound [S]C1=CC=CC=C1 BNJMRELGMDUDDB-UHFFFAOYSA-N 0.000 claims description 2
- BSZYCEVZKJVXAF-UHFFFAOYSA-N 2-(nitromethyl)-6-oxocyclohexane-1-carbaldehyde Chemical compound [O-][N+](=O)CC1CCCC(=O)C1C=O BSZYCEVZKJVXAF-UHFFFAOYSA-N 0.000 claims description 2
- 238000006683 Mannich reaction Methods 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims description 2
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 2
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 claims description 2
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 2
- 125000005117 dialkylcarbamoyl group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- XRKSOEJBGBJURI-UHFFFAOYSA-N 7,7-bis(2-fluorophenyl)-2,3,3a,5,6,7a-hexahydro-1h-isoindol-4-one Chemical group FC1=CC=CC=C1C1(C=2C(=CC=CC=2)F)C2CNCC2C(=O)CC1 XRKSOEJBGBJURI-UHFFFAOYSA-N 0.000 claims 1
- STHKKMSLUUUGFI-UHFFFAOYSA-N 7,7-bis(3-chlorophenyl)-2,3,3a,5,6,7a-hexahydro-1h-isoindol-4-one Chemical group ClC1=CC=CC(C2(C3CNCC3C(=O)CC2)C=2C=C(Cl)C=CC=2)=C1 STHKKMSLUUUGFI-UHFFFAOYSA-N 0.000 claims 1
- IFYBQSQIVJDXQE-UHFFFAOYSA-N 7,7-bis(3-fluorophenyl)-2,3,3a,5,6,7a-hexahydro-1h-isoindol-4-one Chemical group FC1=CC=CC(C2(C3CNCC3C(=O)CC2)C=2C=C(F)C=CC=2)=C1 IFYBQSQIVJDXQE-UHFFFAOYSA-N 0.000 claims 1
- LEGIOUITPMGALL-UHFFFAOYSA-N 7,7-bis(3-methylphenyl)-2,3,3a,5,6,7a-hexahydro-1h-isoindol-4-one Chemical group CC1=CC=CC(C2(C3CNCC3C(=O)CC2)C=2C=C(C)C=CC=2)=C1 LEGIOUITPMGALL-UHFFFAOYSA-N 0.000 claims 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 192
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 177
- 239000000243 solution Substances 0.000 description 156
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 84
- 239000011541 reaction mixture Substances 0.000 description 81
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 72
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 60
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 58
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 58
- 239000013078 crystal Substances 0.000 description 49
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 47
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 47
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 42
- 235000019341 magnesium sulphate Nutrition 0.000 description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 41
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 35
- 239000000741 silica gel Substances 0.000 description 31
- 229910002027 silica gel Inorganic materials 0.000 description 31
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 239000012074 organic phase Substances 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 238000002844 melting Methods 0.000 description 24
- 230000008018 melting Effects 0.000 description 24
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 23
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 23
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 21
- 238000010992 reflux Methods 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- 239000012153 distilled water Substances 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000003921 oil Substances 0.000 description 15
- 235000019198 oils Nutrition 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 13
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 12
- KZMSVLOJRPGWDY-UHFFFAOYSA-N n-(butoxymethyl)-1-phenyl-n-(trimethylsilylmethyl)methanamine Chemical compound CCCCOCN(C[Si](C)(C)C)CC1=CC=CC=C1 KZMSVLOJRPGWDY-UHFFFAOYSA-N 0.000 description 11
- 239000002244 precipitate Substances 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- 239000002002 slurry Substances 0.000 description 10
- 150000001408 amides Chemical class 0.000 description 9
- 238000002329 infrared spectrum Methods 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- CIJLMNDNUOEELM-UHFFFAOYSA-N 7,7-diphenyl-2,3,3a,5,6,7a-hexahydro-1h-isoindol-4-one;hydrochloride Chemical compound Cl.C12CNCC2C(=O)CCC1(C=1C=CC=CC=1)C1=CC=CC=C1 CIJLMNDNUOEELM-UHFFFAOYSA-N 0.000 description 8
- FUSUHKVFWTUUBE-UHFFFAOYSA-N buten-2-one Chemical compound CC(=O)C=C FUSUHKVFWTUUBE-UHFFFAOYSA-N 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- 239000003960 organic solvent Substances 0.000 description 7
- CIJLMNDNUOEELM-CJRXIRLBSA-N (3ar,7ar)-7,7-diphenyl-2,3,3a,5,6,7a-hexahydro-1h-isoindol-4-one;hydrochloride Chemical compound Cl.O=C([C@H]1CNC[C@H]11)CCC1(C=1C=CC=CC=1)C1=CC=CC=C1 CIJLMNDNUOEELM-CJRXIRLBSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical group COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 229960001701 chloroform Drugs 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 229920002554 vinyl polymer Polymers 0.000 description 6
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 5
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 5
- 244000309464 bull Species 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 description 5
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 5
- DQSBXVQJLSMPKA-UHFFFAOYSA-N 2-[2-(dimethylamino)phenyl]acetic acid Chemical compound CN(C)C1=CC=CC=C1CC(O)=O DQSBXVQJLSMPKA-UHFFFAOYSA-N 0.000 description 4
- YDTCAOIRGWQXAI-UHFFFAOYSA-N 2-benzyl-7,7-diphenyl-1,3,3a,5,6,7a-hexahydroisoindol-4-one Chemical compound C1C2C(=O)CCC(C=3C=CC=CC=3)(C=3C=CC=CC=3)C2CN1CC1=CC=CC=C1 YDTCAOIRGWQXAI-UHFFFAOYSA-N 0.000 description 4
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 4
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 4
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical class C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 150000001409 amidines Chemical class 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 4
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 150000002825 nitriles Chemical class 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 3
- USRCWTXXFCGGNR-UHFFFAOYSA-N (7,7-diphenyl-1,4-dioxaspiro[4.5]decan-6-yl)methanamine Chemical compound C1CCC(C=2C=CC=CC=2)(C=2C=CC=CC=2)C(CN)C21OCCO2 USRCWTXXFCGGNR-UHFFFAOYSA-N 0.000 description 3
- QQPIWTIJSNRRQR-UHFFFAOYSA-N 2,2-bis(2-fluorophenyl)acetaldehyde Chemical compound FC1=CC=CC=C1C(C=O)C1=CC=CC=C1F QQPIWTIJSNRRQR-UHFFFAOYSA-N 0.000 description 3
- IVEWTCACRDEAOB-UHFFFAOYSA-N 2-(2-methoxyphenyl)acetic acid Chemical compound COC1=CC=CC=C1CC(O)=O IVEWTCACRDEAOB-UHFFFAOYSA-N 0.000 description 3
- MOMAXGLAOWQIBH-UHFFFAOYSA-N 2-(nitromethyl)-6-oxo-3,3-diphenylcyclohexane-1-carbaldehyde Chemical compound [O-][N+](=O)CC1C(C=O)C(=O)CCC1(C=1C=CC=CC=1)C1=CC=CC=C1 MOMAXGLAOWQIBH-UHFFFAOYSA-N 0.000 description 3
- NFIIDFQRGXRFOI-UHFFFAOYSA-N 2-[2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]phenyl]acetic acid Chemical compound CC(C)(C)OC(=O)N(C)C1=CC=CC=C1CC(O)=O NFIIDFQRGXRFOI-UHFFFAOYSA-N 0.000 description 3
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- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
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- UJLKIWCIXDWLIA-UHFFFAOYSA-N ethenyl 7-oxo-4,4-diphenyl-1,3,3a,5,6,7a-hexahydroisoindole-2-carboxylate Chemical compound C1N(C(=O)OC=C)CC(C(CC2)=O)C1C2(C=1C=CC=CC=1)C1=CC=CC=C1 UJLKIWCIXDWLIA-UHFFFAOYSA-N 0.000 description 1
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- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
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- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
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- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical group [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
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- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical class OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
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- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
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- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
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- 239000012071 phase Substances 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
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- 235000021317 phosphate Nutrition 0.000 description 1
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- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
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- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CHYQAQFTUPDJDO-UHFFFAOYSA-N tert-butyl n-methyl-n-[2-[2-oxo-2-(7-oxo-4,4-diphenyl-1,3,3a,5,6,7a-hexahydroisoindol-2-yl)ethyl]phenyl]carbamate Chemical compound CC(C)(C)OC(=O)N(C)C1=CC=CC=C1CC(=O)N1CC(C(CCC2=O)(C=3C=CC=CC=3)C=3C=CC=CC=3)C2C1 CHYQAQFTUPDJDO-UHFFFAOYSA-N 0.000 description 1
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- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- DWCSXQCXXITVKE-UHFFFAOYSA-N triethyloxidanium Chemical compound CC[O+](CC)CC DWCSXQCXXITVKE-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- 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
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
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- Medicinal Chemistry (AREA)
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- Pharmacology & Pharmacy (AREA)
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Claims (18)
1. Nytt isoindolonderivat, kännetecknat därav, att det har den allmänna formeln: 5 v •Φ- io 0 där R-radikalerna är väteatomer eller bildar till-sanunans en bindning, symbol R' är en väteatom eller bensyl och symbolerna R" är identiska och betecknar var och en en fenylradlkal, som kan vara substituerad med en halogenatom 15 eller en metylradikal i orto- eller meta-ställning, i (3aR,7aR)-form eller som blandning av (3aRS, 7aRS)-former, inklusive syraadditionssalter därav.
2. Nytt Isoindolonderivat enligt patentkrav 1, kännetecknat därav, att R-radikalerna är väte- 20 atomer eller bildar tillsammans en bindning, symbol R' är en väteatom eller en bensylradikal och symbolerna R" är fenylradikaler, som eventuellt i orto- eller meta-ställning är substituerade med fluor- eller kloratomer eller en metylradikal. 25 3. Förening, kännetecknad därav, att • · den är 7,7-difenyl-4-perhydroisoindolon i (3aR,7aR)- eller (3aRS,7aRS)-form, inklusive syraadditionssalter därav.
4. Förening, kännetecknad därav, att den är 7,7-bis-(3-fluorfenyl)-4-perhydroisoindolon i 30 (3aR,7aR)- eller (3aRS,7aRS)-form, Inklusive syraaddi- : tionssalter därav.
5. Förening, kännetecknad därav, att den är 7,7-bis-(2-fluorfenyl)-4-perhydroisoindolon i (3aR,7aR)- eller (3aRS,7aRS)-form, inklusive syraaddi- 35 tionssalter därav. • · « 66 94627
6. Förening, kännetecknad därav, att den är 7,7-bis-(3-klorfenyl)-4-perhydroisoindolon i (3aR, 7aR)- eller (3aRS,7aRS)-form, inklusive syraadditionssal-ter därav. 5 7. Förening, kännetecknad därav, att den är 7,7-bis-(3-tolyl)-4-perhydroisoindolon i (3aR, 7aR)- eller (3aRS,7aRS)-form, inklusive syraadditionssal-ter därav.
8. Förfarande för framställning av ett isoindolon-10 derivat enligt patentkrav 1 eller 2, känneteck- n a t därav, att ett silylderivat med den allmänna for-meln: ^^CH2Si(R° )3
15 R' - N<^ ^x:h2rc 0 där R* är bensyl, (R°)3 stär för alkylradikaler eller alkyl- och fenylradikaler, och Reo är en alkyloxi-, 20 cyan- eller fenyltioradikal, omsätts med ett cyklohexenon-derivat, som har den allmänna formeln: $ o där R definieras som i patentkrav 1, varefter R’ eventuellt avlägsnas, ifall man vill erhälla en isoindo-30 lon, där R' är en väteatom, isomererna eventuellt separe-ras och den erhälinä produkten eventuellt omvandlas tili ett sait.
9. Förfarande för framställning av ett isoindolon-derivat enligt patentkrav 1 eller 2, känneteck- 35. a t därav, att en oxazolidinon med den allmänna formeln: 67 94627 -0 V R' 5 där R' är bensyl, omsätts med ett cyklohexenonderi-vat, som har den allmänna formeln: R· » 0 15 där R definieras som i patentkrav 1, varefter, Ifall man önskar erhälla ett oxazolidinonderivat, där R' är en väteatom, avlägsnas bensylgruppen, Isomererna even-tuellt separeras och den erhällna produkten eventuellt omvandlas tili ett sait. 20 10. Förfarande för framställning av ett isoindolon- derivat enligt patentkrav 1 eller 2, där R är en väteatom, kännetecknat därav, att man använder Mannich-reaktion och en utgängsförening, som har den allmänna formeln: 25 .. R„ R" 30 t^ : där R' definieras som ovan, varefter isomererna eventuellt separeras och den erhällna produkten eventuellt omvandlas tili ett sait.
11. Förfarande för framställning av ett isoindolon- 35 derivat enligt patentkrav 1, där R och R' är väteatomer, I l 68 94627 kännetecknat därav, att man hydrerar kataly-tiskt en 2-formyl-3-nitrometylcyklohexanon/ som har den allmänna formeln:
5 R" R* 0 10 varefter isomererna eventuellt separeras och den erhällna produkten eventuellt omvandlas tili ett sait.
12. Användning av en förening enligt patentkrav 1, kännetecknad därav, att man framställer ett 15 isoindolonderivat, som har den allmänna formeln: R" R" ,X| K | H —C — CH-R.
20 I n r2 0 där R-radikalerna är identiska och betecknar väteatomer 25 eller tillsammans bildar en bindning; R"-radikalerna betecknar samma som ovan; symbol X är en syre- eller svavelatom eller en ra-dikal N-R3, där R3 är en väteatom, en alkylradikal som in-nehäller 1-12 kolatomer och är eventuellt substituerad 30 [med en eller flera av följande radikaler: karboxyl, dial-\m kylamino, acylamino, karbamoyl, alkylkarbamoyl, dialkyl- karbamoyl, alkyloxikarbonyl (alkyldelarna i dessa radikaler kan omfatta en dialkylamino- eller fenylsubstituent), eller med följande radikaler: fenyl, fenyl som är substi-35 tuerad (med halogen, alkyl, alkyloxi eller dialkylamino), 94627 naftyl, tienyl, furyl, pyridyl eller imidazolyl], eller en dialkylaminoradikal; symbol Rx är en fenylradikal, som eventuellt är substltuerad med en eller flera halogenatomer eller med 5 följande radikal: hydroxyl eller alkyl, som eventuellt kan vara substituerade (med halogenatomer eller amino-, alkyl-amino- eller dialkylaminoradikaler), alkyloxi eller alkyl-tio, som eventuellt kan vara substituerade (med hydroxyl-radikaler eller dialkylaminoradikaler, där alkyldelarna 10 kan bilda en heterocyklisk grupp innehällande 5-6 ring-medlemmar med kväveatomen till vilken de är bundna, vilken heterocyklisk grupp kan innehälla en annan heteroatom, som är syre, svavel eller kväve, och som eventuellt är substi-tuerad med en alkylradikal), eller substltuerad med ami-15 no-, alkylamino- eller dialkylaminoradikaler, där alkyldelarna kan bilda en ovan definierad heterocyklisk grupp med kväveatomen, till vilken de är bundna, eller den är en cyklohexadienyl- eller naftylradikal eller en mono- eller polycyklisk heterocyklisk radikal, som är mättad eller 20 omättad och innehäller 5-9 kolatomer och en eller flera heteroatomer, som var och en är syre, kväve eller svavel; och symbol R2 är en väte- eller halogenatom, eller en hydroxyl-, alkyl-, aminoalkyl-, alkylaminoalkyl-, dialkyl-25 aminoalkyl-, alkyloxi-, alkyltio-, acyloxi-, karboxyl-, ·· alkyloxikarbonyl-, dialkylaminoalkyloxikarbonyl-, bensyl-oxikarbonyl-, amino-, acylamino- eller alkyloxikarbonyl-aminoradikal. ·· ··<
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8915407A FR2654726B1 (fr) | 1989-11-23 | 1989-11-23 | Nouveaux derives de l'isoindolone et leur preparation. |
| FR8915407 | 1989-11-23 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| FI905770A0 FI905770A0 (sv) | 1990-11-22 |
| FI905770L FI905770L (sv) | 1991-05-24 |
| FI94627B true FI94627B (sv) | 1995-06-30 |
| FI94627C FI94627C (sv) | 1995-10-10 |
Family
ID=9387708
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI905770A FI94627C (sv) | 1989-11-23 | 1990-11-22 | Nya isoindolonderivat, deras framställning och användning |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US5112988A (sv) |
| EP (1) | EP0430771B1 (sv) |
| JP (1) | JPH03176468A (sv) |
| KR (1) | KR910009660A (sv) |
| AT (1) | ATE108774T1 (sv) |
| AU (1) | AU635984B2 (sv) |
| CA (1) | CA2030570A1 (sv) |
| DE (1) | DE69010851T2 (sv) |
| DK (1) | DK0430771T3 (sv) |
| ES (1) | ES2057488T3 (sv) |
| FI (1) | FI94627C (sv) |
| FR (1) | FR2654726B1 (sv) |
| HU (1) | HU214574B (sv) |
| IE (1) | IE64737B1 (sv) |
| IL (1) | IL96447A (sv) |
| NO (1) | NO174148C (sv) |
| NZ (1) | NZ236175A (sv) |
| PL (2) | PL164973B1 (sv) |
| PT (1) | PT95983B (sv) |
| RU (1) | RU2104269C1 (sv) |
| SK (1) | SK580690A3 (sv) |
| YU (1) | YU47437B (sv) |
| ZA (1) | ZA909370B (sv) |
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| FR2688219B1 (fr) | 1992-03-03 | 1994-07-08 | Sanofi Elf | Sels d'ammonium quaternaires de composes aromatiques amines, leur preparation et compositions pharmaceutiques les contenant. |
| FR2689889B1 (fr) * | 1992-04-10 | 1994-06-10 | Rhone Poulenc Rorer Sa | Nouveaux derives de perhydroisoindole, et leur preparation. |
| US5830854A (en) * | 1992-12-14 | 1998-11-03 | Merck Sharp & Dohme, Limited | Method of treating cystic fibrosis using a tachykinin receptor antagonist |
| FR2703679B1 (fr) * | 1993-04-05 | 1995-06-23 | Rhone Poulenc Rorer Sa | Nouveaux derives de perhydroisoindole, leur preparation et les compositions pharmaceutiques qui les contiennent. |
| FR2709752B1 (fr) * | 1993-07-30 | 1995-10-06 | Rhone Poulenc Rorer Sa | Nouveaux dérivés de perhydroisoindole, leur préparation et les compositions pharmaceutiques qui les contiennent. |
| FR2710913B1 (fr) * | 1993-10-07 | 1995-11-24 | Rhone Poulenc Rorer Sa | Nouveaux dérivés de perhydroisoindole, leur préparation et les compositions pharmaceutiques qui les contiennent. |
| TW365603B (en) * | 1993-07-30 | 1999-08-01 | Rhone Poulenc Rorer Sa | Novel perhydroisoindole derivatives, their preparation and pharmaceutical compositions which contain them |
| US5543530A (en) * | 1993-12-23 | 1996-08-06 | Ortho Pharmaceutical Corporation | 4-arylisoindole analgesics |
| FR2728165A1 (fr) | 1994-12-19 | 1996-06-21 | Oreal | Utilisation d'un antagoniste de substance p pour le traitement des rougeurs cutanees d'origine neurogene |
| FR2728166A1 (fr) | 1994-12-19 | 1996-06-21 | Oreal | Composition topique contenant un antagoniste de substance p |
| FR2728169A1 (fr) | 1994-12-19 | 1996-06-21 | Oreal | Utilisation d'un antagoniste de substance p pour le traitement des prurits et des dysesthesies oculaires ou palpebrales |
| FR2729954B1 (fr) | 1995-01-30 | 1997-08-01 | Sanofi Sa | Composes heterocycliques substitues, procede pour leur preparation et compositions pharmaceutiques les contenant |
| FR2741262B1 (fr) | 1995-11-20 | 1999-03-05 | Oreal | Utilisation d'un antagoniste de tnf-alpha pour le traitement des rougeurs cutanees d'origine neurogene |
| FR2755013B1 (fr) * | 1996-10-29 | 1998-11-27 | Rhone Poulenc Rorer Sa | Nouvelle application therapeutique des antagonistes de la substance p |
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-
1989
- 1989-11-23 FR FR8915407A patent/FR2654726B1/fr not_active Expired - Lifetime
-
1990
- 1990-11-20 US US07/616,044 patent/US5112988A/en not_active Expired - Fee Related
- 1990-11-21 NZ NZ236175A patent/NZ236175A/xx unknown
- 1990-11-22 DK DK90403300.8T patent/DK0430771T3/da active
- 1990-11-22 EP EP90403300A patent/EP0430771B1/fr not_active Expired - Lifetime
- 1990-11-22 ZA ZA909370A patent/ZA909370B/xx unknown
- 1990-11-22 SK SK5806-90A patent/SK580690A3/sk unknown
- 1990-11-22 CA CA002030570A patent/CA2030570A1/fr not_active Abandoned
- 1990-11-22 AU AU66828/90A patent/AU635984B2/en not_active Ceased
- 1990-11-22 HU HU907249A patent/HU214574B/hu not_active IP Right Cessation
- 1990-11-22 DE DE69010851T patent/DE69010851T2/de not_active Expired - Fee Related
- 1990-11-22 NO NO905067A patent/NO174148C/no unknown
- 1990-11-22 ES ES90403300T patent/ES2057488T3/es not_active Expired - Lifetime
- 1990-11-22 AT AT90403300T patent/ATE108774T1/de not_active IP Right Cessation
- 1990-11-22 JP JP2320570A patent/JPH03176468A/ja active Pending
- 1990-11-22 IL IL9644790A patent/IL96447A/en not_active IP Right Cessation
- 1990-11-22 KR KR1019900019099A patent/KR910009660A/ko not_active Abandoned
- 1990-11-22 IE IE423490A patent/IE64737B1/en not_active IP Right Cessation
- 1990-11-22 FI FI905770A patent/FI94627C/sv not_active IP Right Cessation
- 1990-11-23 PL PL90287908A patent/PL164973B1/pl unknown
- 1990-11-23 PT PT95983A patent/PT95983B/pt not_active IP Right Cessation
- 1990-11-23 PL PL90301462A patent/PL164955B1/pl unknown
- 1990-11-23 YU YU223590A patent/YU47437B/sh unknown
-
1992
- 1992-12-01 RU RU92004482A patent/RU2104269C1/ru active
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