FI86638B - Foerfarande foer framstaellning av terapeutiskt effektiva omaettade fosfonsyror. - Google Patents
Foerfarande foer framstaellning av terapeutiskt effektiva omaettade fosfonsyror. Download PDFInfo
- Publication number
- FI86638B FI86638B FI875097A FI875097A FI86638B FI 86638 B FI86638 B FI 86638B FI 875097 A FI875097 A FI 875097A FI 875097 A FI875097 A FI 875097A FI 86638 B FI86638 B FI 86638B
- Authority
- FI
- Finland
- Prior art keywords
- formula
- carboxy
- lower alkyl
- carboxylic acid
- compound
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims abstract description 113
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 60
- 150000003839 salts Chemical class 0.000 claims abstract description 41
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 16
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 15
- ABLZXFCXXLZCGV-UHFFFAOYSA-N phosphonic acid group Chemical group P(O)(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims abstract description 14
- 125000004450 alkenylene group Chemical group 0.000 claims abstract description 10
- 230000002378 acidificating effect Effects 0.000 claims abstract description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 9
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 5
- 125000002837 carbocyclic group Chemical group 0.000 claims abstract description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims abstract description 3
- -1 carboxy, carboxy Chemical group 0.000 claims description 104
- 125000000217 alkyl group Chemical group 0.000 claims description 70
- 239000000203 mixture Substances 0.000 claims description 50
- 238000000034 method Methods 0.000 claims description 33
- 239000001257 hydrogen Substances 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 29
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 24
- 238000002360 preparation method Methods 0.000 claims description 21
- 125000005042 acyloxymethyl group Chemical group 0.000 claims description 18
- 230000008569 process Effects 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 150000002431 hydrogen Chemical group 0.000 claims description 16
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 7
- 230000003287 optical effect Effects 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 150000002576 ketones Chemical class 0.000 claims description 6
- 150000007522 mineralic acids Chemical class 0.000 claims description 5
- 150000003007 phosphonic acid derivatives Chemical class 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- MBKDYNNUVRNNRF-UHFFFAOYSA-N medronic acid Chemical class OP(O)(=O)CP(O)(O)=O MBKDYNNUVRNNRF-UHFFFAOYSA-N 0.000 claims description 4
- 150000003009 phosphonic acids Chemical class 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims description 2
- 230000002452 interceptive effect Effects 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims 4
- HXEACLLIILLPRG-RXMQYKEDSA-N l-pipecolic acid Natural products OC(=O)[C@H]1CCCCN1 HXEACLLIILLPRG-RXMQYKEDSA-N 0.000 claims 3
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- HXEACLLIILLPRG-UHFFFAOYSA-N pipecolic acid Chemical compound OC(=O)C1CCCCN1 HXEACLLIILLPRG-UHFFFAOYSA-N 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 claims 1
- 150000001413 amino acids Chemical class 0.000 abstract description 12
- 241000124008 Mammalia Species 0.000 abstract description 11
- 239000005557 antagonist Substances 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 118
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 105
- 239000000243 solution Substances 0.000 description 100
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 81
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 58
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 36
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- 238000003818 flash chromatography Methods 0.000 description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 238000010992 reflux Methods 0.000 description 23
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000002253 acid Substances 0.000 description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- 229910052938 sodium sulfate Inorganic materials 0.000 description 17
- 235000011152 sodium sulphate Nutrition 0.000 description 17
- 239000007858 starting material Substances 0.000 description 17
- 125000002252 acyl group Chemical group 0.000 description 16
- 239000000284 extract Substances 0.000 description 16
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 15
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 13
- 229960000583 acetic acid Drugs 0.000 description 12
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 150000001299 aldehydes Chemical class 0.000 description 11
- 229940024606 amino acid Drugs 0.000 description 11
- 235000001014 amino acid Nutrition 0.000 description 11
- 238000009833 condensation Methods 0.000 description 11
- 230000005494 condensation Effects 0.000 description 11
- 239000012299 nitrogen atmosphere Substances 0.000 description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 229960004373 acetylcholine Drugs 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 7
- 125000005115 alkyl carbamoyl group Chemical group 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 206010010904 Convulsion Diseases 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- 239000013543 active substance Substances 0.000 description 6
- 229910021529 ammonia Inorganic materials 0.000 description 6
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000008107 starch Substances 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- 230000001960 triggered effect Effects 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- 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 5
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- UIKAPMLQQHMWEB-UHFFFAOYSA-N ethyl 4-(2-hydroxyethyl)piperidine-2-carboxylate Chemical compound CCOC(=O)C1CC(CCO)CCN1 UIKAPMLQQHMWEB-UHFFFAOYSA-N 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 208000028867 ischemia Diseases 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 201000006474 Brain Ischemia Diseases 0.000 description 4
- 206010008120 Cerebral ischaemia Diseases 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 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 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 125000005907 alkyl ester group Chemical group 0.000 description 4
- 150000001735 carboxylic acids Chemical class 0.000 description 4
- 206010008118 cerebral infarction Diseases 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 235000015424 sodium Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 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 4
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 4
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 4
- STJWVOQLJPNAQL-UHFFFAOYSA-N 1-[diethoxyphosphorylmethyl(ethoxy)phosphoryl]oxyethane Chemical compound CCOP(=O)(OCC)CP(=O)(OCC)OCC STJWVOQLJPNAQL-UHFFFAOYSA-N 0.000 description 3
- CQCAYWAIRTVXIY-UHFFFAOYSA-N 2-(triphenyl-$l^{5}-phosphanylidene)acetaldehyde Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC=O)C1=CC=CC=C1 CQCAYWAIRTVXIY-UHFFFAOYSA-N 0.000 description 3
- XCXJLWLQQPJVDR-UHFFFAOYSA-N 3-(azepan-2-yl)quinoline Chemical compound C1CCCCNC1C1=CN=C(C=CC=C2)C2=C1 XCXJLWLQQPJVDR-UHFFFAOYSA-N 0.000 description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 239000008272 agar Substances 0.000 description 3
- 235000010419 agar Nutrition 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 3
- 150000001340 alkali metals Chemical class 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 150000003863 ammonium salts Chemical class 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- KVNCZZJKTVYNPJ-VHSXEESVSA-N diethyl (2r,3s)-3-(2-hydroxyethyl)pyrrolidine-1,2-dicarboxylate Chemical compound CCOC(=O)[C@H]1[C@H](CCO)CCN1C(=O)OCC KVNCZZJKTVYNPJ-VHSXEESVSA-N 0.000 description 3
- OGLLNWKZEDMTLS-VHSXEESVSA-N diethyl (2r,3s)-3-(2-oxoethyl)pyrrolidine-1,2-dicarboxylate Chemical compound CCOC(=O)[C@H]1[C@H](CC=O)CCN1C(=O)OCC OGLLNWKZEDMTLS-VHSXEESVSA-N 0.000 description 3
- 229940042400 direct acting antivirals phosphonic acid derivative Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 206010015037 epilepsy Diseases 0.000 description 3
- SGAPKKQPDRIYBH-UHFFFAOYSA-N ethyl 4-(2-hydroxyethyl)pyridine-2-carboxylate Chemical compound CCOC(=O)C1=CC(CCO)=CC=N1 SGAPKKQPDRIYBH-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001640 fractional crystallisation Methods 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 125000004970 halomethyl group Chemical group 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- SJFNDMHZXCUXSA-UHFFFAOYSA-M methoxymethyl(triphenyl)phosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(COC)C1=CC=CC=C1 SJFNDMHZXCUXSA-UHFFFAOYSA-M 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 229910003446 platinum oxide Inorganic materials 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 2
- POTIYWUALSJREP-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroquinoline Chemical class N1CCCC2CCCCC21 POTIYWUALSJREP-UHFFFAOYSA-N 0.000 description 2
- VYXQDROPKKIIOK-UHFFFAOYSA-N 1-o-tert-butyl 2-o-ethyl 4-(2-hydroxyethyl)piperidine-1,2-dicarboxylate Chemical compound CCOC(=O)C1CC(CCO)CCN1C(=O)OC(C)(C)C VYXQDROPKKIIOK-UHFFFAOYSA-N 0.000 description 2
- IEVVCMJCBOPHDZ-UHFFFAOYSA-N 1-o-tert-butyl 2-o-ethyl 4-(2-oxoethyl)piperidine-1,2-dicarboxylate Chemical compound CCOC(=O)C1CC(CC=O)CCN1C(=O)OC(C)(C)C IEVVCMJCBOPHDZ-UHFFFAOYSA-N 0.000 description 2
- KTBVDZLAJXBLNM-UHFFFAOYSA-N 1-o-tert-butyl 2-o-ethyl 4-(hydroxymethyl)piperidine-1,2-dicarboxylate Chemical compound CCOC(=O)C1CC(CO)CCN1C(=O)OC(C)(C)C KTBVDZLAJXBLNM-UHFFFAOYSA-N 0.000 description 2
- HVOAMIOKNARIMR-UHFFFAOYSA-N 1-pyridin-4-ylethanol Chemical compound CC(O)C1=CC=NC=C1 HVOAMIOKNARIMR-UHFFFAOYSA-N 0.000 description 2
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/12—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with only hydrogen atoms attached to the ring nitrogen atom
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/60—Quinoline or hydrogenated quinoline ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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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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- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
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- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/59—Hydrogenated pyridine rings
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- Health & Medical Sciences (AREA)
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Claims (9)
1. Förfarande för framställning av terapeutiskt effektiva omättade fosfonsyror med formeln I | HO_ V\ iH i T!)» <>) samt deras salter, i vilken formel den ena eller bäda av de, sura hydroxigrupperna av fosfonsyradelen kan vara företrade med lägalkyl, bensyl, i fenyldelen med halogen, lägalkyl eller lägalkoxi substituerad bensyl, lägalkano-yloximetyl eller i oximetyldelen med lägalkyl eller cyk-loalkylsubstituerad lägalkanoyloximetyl m är 1 eller 0, R1 betecknar karboxi, med lägalkyl eller lägalkanoyloximetyl förestrad karboxi eller osubstituerad eller N-lägalkyle-rad karbamoyl, den heterocykliska ringen med 5 eller 6 medlemmar kan ytterligare vara substituerad i en kolatom med lctgalkyl eller fenyllägalkyl och/eller i kväve med lägalkyl, fenyllägalkyl, lägalkanoyl eller lägalkoxikar-bonyl, den kan innehälla en kol-kol-dubbelbindning eller den kan vara kondenserad med en karbocyklisk ring med 6 medlemmar utgäende frän intilliggande kolatomer, och A betecknar lägalkenylen, kännetecknat därav, att a) en aldehyd eller keton med formeln VII X ("CHz) (VII) ! Y 6 -, B ό 6 5 8 i vilken formel symbolerna m och R1 och den heterocykliska ringen har de vid formeln I angivna beteckningarna, var-vid R1 och aminogrupperna dock förekommer i skyddad form och A’ betecknar lägalkyl, som är substituerad med oxo och som har en kolatom mindre än i alkenylengruppen A, kondenseras med ett tetraesterderivat av metylendifosfon-syra under basiska förhällanden och, vid behov, avspaltas skyddsgrupperna frän den erhällna produkten, sä att en förening med formeln I erhälls, i vilken dubbelbindningen av gruppen A är omedelbart intill fosfonogruppen, eller b) en förening med formeln VIII X“V\ i (VIII) Y~" i vilken symbolerna A, m och R1 och den heterocykliska ringen har de vid formeln I angivna betydelserna och X betecknar reaktionsduglig förestrad hydroxi, kondenseras med en förening, som förmär binda en fosfonsyrahälft och som har formeln IX eller X H—P—OR" (IX) P(R"')3 (X) OR" vilka R" betecknar lägalkyl och R"' betecknar halogen eller lägalkoxi, och vid behov omvandlas det bildade fos-fonsyraderivatet till en fosfonsyra eller ett annat es-terderivat därav, eller 62 86638 c) i motsvarande föreningar med formeln XI HOl V\ "A ; (xi) Y~ cyanogruppen eller eventuellt lägalkylerad amidinogrupp X! omvandlas hydrolytiskt, varvid i formeln den ena eller bäda av fosfonsyradelens sura hydroxigrupper kan vara förestrade pä angivet sätt och den heterocykliska ringen med 5 eller 6 medlemmar kan vara substituerad pä angivet sätt och A betecknar detsamma som ovan och Xj betecknar detsamma som R1 ovan, och, om s4 önskas, i den erhällna föreningen med formeln I, vari den ena eller bäda av fosfonsyradelens sura hydroxigrupper är företrad pä angivet sätt, frigörs fosfonsyradelen, i den erhällna föreningen med formeln I, vari R1 betecknar pä angivet sätt förestrad eller amiderad karboxi, frigörs karboxigruppen, eller i en erhällen förening med formeln I, vari R1 betecknar karboxi, förestras karboxigruppen pä angivet sätt, i en er-hällen förening med formeln I, vari R1 är fri eller pä angivet sätt förestrad karboxi, amideras denna tili eventuellt lägalkylerad karboxi, frän en erhällen förening med formeln I, vari kvävet är substituerat pä angivet sätt, avspaltas N-substituenten frän den heterocykliska ringen i en förening, som för övrigt är identisk med föreningen enligt uppfinningen; dessa förfaranden utförs ocksä vid behov genom att skydda tillfälligt alla störan-de reaktionsdugliga grupper och genom att frigöra den därefter bildade föreningen enligt uppfinningen, och/el-ler, om sä önskas, omvandlas en bildad fri förening tili ett sait eller ett bildat salt tili en fri förening och/eller en erhällen isomerblandning eller racematbald-ning separeras tili enskilda isomerer eller racemat och/- 63 86638 eller, om sä önskas, separeras ett racemat till optiska antipoder.
2. Förfarande enligt patentkravet 1, känneteck-n a t därav, att det heterocsykliska ringsystemet till-sammans med substituenten R1 betecknar eventuellt substi-tuerad 2-karboxipyrrolidinyl, 2-karboxi-2,5-dihydropyrro-lyl, 2-karboxi-l,2,3,6-tetrahydropyridinyl, 2-karboxi- 1,2,5,6-tetrahydropyridinyl, 2-karboxipiperidinyl, 2-kar-boxi-tetrahydrokinolinyl, 2-karboxi-perhydrokinolinyl, 2-karboxi-2,3-dihydroindolyl eller 2-karboxiperhydroindo-lyl, i vilka karboxi kan vara förestrad eller amiderad.
3- Förfarande enligt patentkravet 1 för framställning av föreningar med formeln II A - P OH' / . L r3—ί- i Yv och sädana föreningar med formeln II, vilka har en dub-belbindning mellan C-3- och C-4- eller C-4- och C-5-ato-merna av piperidinylringen, och salter av dessa föreningar, i vilken formel kedjan, som innehäller fosfono, är bunden tili piperidinyl- eller tetrahydropyridinylringens 3- , 4- eller 5-ställning, och i vilken R och R' betecknar oberoende av varandra väte eller lägalkyl, R1 betecknar karboxi, lägalkoxikarbonyl eller karbamoyl, R2 betecknar väte, lägalkyl, lägalkanoyl eller lägalkoxikarbonyl, R3 betecknar väte eller lägalkyl och A betecknar lägalkeny-len.
4. Förfarande enligt patentkravet 1 för framställning av 4- [1-(3-fosfonoprop-2-enyl)]-piperidin-2-karboxylsyra, 4- 64 86638 [1-(3-fosfonoprop-l-enyl)]-piperidin-2-karboxylsyra och deras farmaceutiskt godtagbara salter.
5. Förfarande enligt patentkravet 1 för framställning av föreningar enligt formeln IV A—P—OR' L R“-t II I (IVJ X"YV eller deras perhydroderivat samt deras salter, i vilken formel R och R' betecknar oberoende av varandra väte eller lägalkyl, R1 betecknar karboxi, lägalkoxikarbonyl eller karbamoyl, R2 betecknar väte, lägalkyl, lägalkanoyl eller lägalkoxikarbonyl, R4 betecknar väte eller lägalkyl och A betecknar lägalkenylen.
6. Förfarande enligt patentkravet 1 för framställning av föreningar med formeln VI R3-f 4—A—P—OR' (VI) T"L och sädana föreningar med formeln VI, vilka har en dub-belbindning mellan pyrrolidinylringens C-3- och C-4-ato-mer samt deras salter, i vilken formel R och R' betecknar oberoende av varandra väte eller lägalkyl, R1 betecknar karboxi, lägalkoxikarbonyl eller karbamoyl, Rz betecknar väte, lägalkanoyl eller lägalkoxikarbonyl, Rs betecknar väte eller lägalkyl och A betecknar lägalkenylen.
7. Förfarande enligt patentkravet 1 för framställning av trans-3-[1—(4-fosfonobut-3-enyl)]-pyrrolidin-2-karboxyl- ,,. 86638 bo syra, trans-3-[1-(4-fosfonobut-2-enyl)]-pyrrolidin-2-kar-boxylsyra samt deras farmaceutiskt godtagbara salter.
8. Förfarande enligt patentkravet 1 för framställning av följande föreningar: cis-4-[l-(3-fosfonoprop-2-enyl)]-piperidin-2-karboxylsyra, trans-4-[l-(3-fosfonoprop-2-enyl)]-piperidin-2-karboxylsyra, cis-4-[l-(3-fosfonop-rop-l-enyl)]-piperidin-2-karboxylsyra, trans-4-[1-(3-fos-fonoprop-l-enyl)]-piperidin-2-karboxylsyra och cis-3-[l- (4-fosfonobut-3-enyl)]-pyrrolidin-2-karboxylsyra samt deras farmaceutiskt godtagbara salter.
9. Förfarande enligt patentkravet 1, känneteck-n a t därav, att en förening med formeln II, IV eller VI, i vilken R och R' betecknar lägalkyl och R1 ja R2 be-tecknar lägalkoxikarbonyl, omvandlas genom att behandla med en oorganisk syra eller vattenhaltiga alkalier tili en förening med formeln II, IV eller VI, i vilka R och R' betecknar väte, R1 betecknar karboxi och R2 betecknar vä-te.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US93370286A | 1986-11-21 | 1986-11-21 | |
| US93370286 | 1986-11-21 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| FI875097A0 FI875097A0 (fi) | 1987-11-18 |
| FI875097A FI875097A (fi) | 1988-05-22 |
| FI86638B true FI86638B (fi) | 1992-06-15 |
| FI86638C FI86638C (sv) | 1992-09-25 |
Family
ID=25464377
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI875097A FI86638C (sv) | 1986-11-21 | 1987-11-18 | Förfarande för framställning av terapeutiskt effektiva omättade fosfon syror |
Country Status (21)
| Country | Link |
|---|---|
| EP (1) | EP0275820B1 (sv) |
| JP (1) | JPH0686470B2 (sv) |
| KR (1) | KR880006195A (sv) |
| AT (1) | ATE60776T1 (sv) |
| AU (1) | AU610841B2 (sv) |
| CA (1) | CA1312608C (sv) |
| DD (1) | DD273837A5 (sv) |
| DE (1) | DE3768000D1 (sv) |
| DK (1) | DK609487A (sv) |
| ES (1) | ES2031927T3 (sv) |
| FI (1) | FI86638C (sv) |
| GR (1) | GR3001443T3 (sv) |
| HU (1) | HU199857B (sv) |
| IE (1) | IE60534B1 (sv) |
| IL (1) | IL84492A0 (sv) |
| MX (1) | MX9437A (sv) |
| NO (1) | NO170853C (sv) |
| NZ (1) | NZ222607A (sv) |
| PH (1) | PH25465A (sv) |
| PT (1) | PT86168B (sv) |
| ZA (1) | ZA878699B (sv) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4968678A (en) * | 1988-02-19 | 1990-11-06 | Eli Lilly And Company | Tetrazole excitatory amino acid receptor antagonists |
| CA2000901A1 (en) * | 1988-10-21 | 1990-04-21 | Alexis A. Cordi | Phosphono-hydroisoquinoline compounds useful in reducing neurotoxic injury |
| US4902695A (en) * | 1989-02-13 | 1990-02-20 | Eli Lilly And Company | Excitatory amino acid receptor antagonists |
| EP0424179A3 (en) * | 1989-10-20 | 1991-12-27 | John William Olney | Use of combined excitatory amino acid and cholinergic antagonists to prevent neurological deterioration |
| US5238958A (en) * | 1990-02-26 | 1993-08-24 | Warner-Lambert Company | Substituted α-amino acids having selected acidic moieties for use as excitatory amino acid antagonists in pharmaceuticals |
| US5194430A (en) * | 1990-05-17 | 1993-03-16 | Merrell Dow Pharmaceuticals Inc. | Heterocyclic-nmda antagonists |
| SE9003652D0 (sv) * | 1990-11-15 | 1990-11-15 | Astra Ab | New heterocyclic compounds |
| US5260286A (en) * | 1992-10-16 | 1993-11-09 | Japan Tobacco, Inc. | 2-piperidinecarboxylic acid derivatives useful as NMDA receptor antagonists |
| JP4380803B2 (ja) | 1997-06-12 | 2009-12-09 | アベンテイス・フアルマ・リミテツド | イミダゾリル−環式アセタール |
| EP3427729A1 (en) | 2017-07-13 | 2019-01-16 | Paris Sciences et Lettres - Quartier Latin | Probenecid for use in treating epileptic diseases, disorders or conditions |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2104079B (en) * | 1981-08-14 | 1985-08-21 | London Polytech | New aminoacid isomers, their production and their medicinal use |
| PH23848A (en) * | 1985-05-24 | 1989-11-23 | Ciba Geigy Ag | Certain phosphonic acids and derivatives |
-
1987
- 1987-11-16 EP EP87810662A patent/EP0275820B1/de not_active Expired - Lifetime
- 1987-11-16 IL IL84492A patent/IL84492A0/xx unknown
- 1987-11-16 ES ES198787810662T patent/ES2031927T3/es not_active Expired - Lifetime
- 1987-11-16 DE DE8787810662T patent/DE3768000D1/de not_active Expired - Lifetime
- 1987-11-16 AT AT87810662T patent/ATE60776T1/de active
- 1987-11-18 PH PH36083A patent/PH25465A/en unknown
- 1987-11-18 FI FI875097A patent/FI86638C/sv not_active IP Right Cessation
- 1987-11-19 PT PT86168A patent/PT86168B/pt not_active IP Right Cessation
- 1987-11-19 DD DD87309215A patent/DD273837A5/de not_active IP Right Cessation
- 1987-11-19 NZ NZ222607A patent/NZ222607A/xx unknown
- 1987-11-19 CA CA000552204A patent/CA1312608C/en not_active Expired - Fee Related
- 1987-11-20 NO NO874854A patent/NO170853C/no unknown
- 1987-11-20 JP JP62292195A patent/JPH0686470B2/ja not_active Expired - Lifetime
- 1987-11-20 AU AU81455/87A patent/AU610841B2/en not_active Ceased
- 1987-11-20 DK DK609487A patent/DK609487A/da not_active Application Discontinuation
- 1987-11-20 KR KR870013064A patent/KR880006195A/ko not_active Application Discontinuation
- 1987-11-20 ZA ZA878699A patent/ZA878699B/xx unknown
- 1987-11-20 HU HU875161A patent/HU199857B/hu not_active IP Right Cessation
- 1987-11-20 IE IE314987A patent/IE60534B1/en not_active IP Right Cessation
- 1987-11-23 MX MX943787A patent/MX9437A/es unknown
-
1991
- 1991-02-07 GR GR90401113T patent/GR3001443T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0275820A3 (en) | 1988-08-03 |
| MX9437A (es) | 1994-01-31 |
| GR3001443T3 (en) | 1992-09-25 |
| NO874854D0 (no) | 1987-11-20 |
| NZ222607A (en) | 1990-10-26 |
| EP0275820A2 (de) | 1988-07-27 |
| HUT46331A (en) | 1988-10-28 |
| FI86638C (sv) | 1992-09-25 |
| JPH0686470B2 (ja) | 1994-11-02 |
| DK609487A (da) | 1988-05-22 |
| DE3768000D1 (de) | 1991-03-14 |
| PT86168A (en) | 1987-12-01 |
| KR880006195A (ko) | 1988-07-22 |
| FI875097A0 (fi) | 1987-11-18 |
| AU610841B2 (en) | 1991-05-30 |
| NO874854L (no) | 1988-05-24 |
| DD273837A5 (de) | 1989-11-29 |
| IL84492A0 (en) | 1988-04-29 |
| NO170853C (no) | 1992-12-16 |
| HU199857B (en) | 1990-03-28 |
| NO170853B (no) | 1992-09-07 |
| JPH01135791A (ja) | 1989-05-29 |
| ATE60776T1 (de) | 1991-02-15 |
| IE60534B1 (en) | 1994-07-27 |
| DK609487D0 (da) | 1987-11-20 |
| PT86168B (pt) | 1990-08-31 |
| EP0275820B1 (de) | 1991-02-06 |
| PH25465A (en) | 1991-07-01 |
| ES2031927T3 (es) | 1993-01-01 |
| IE873149L (en) | 1988-05-21 |
| FI875097A (fi) | 1988-05-22 |
| ZA878699B (en) | 1988-05-23 |
| AU8145587A (en) | 1988-05-26 |
| CA1312608C (en) | 1993-01-12 |
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| Date | Code | Title | Description |
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| BB | Publication of examined application | ||
| PC | Transfer of assignment of patent |
Owner name: NOVARTIS AG |
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| MM | Patent lapsed | ||
| MM | Patent lapsed |
Owner name: NOVARTIS AG |