RU2114111C1 - 4-пиримидин- или пиридинильные производные индол-3-ил-алкилпиперазинов, фармацевтическая композиция - Google Patents
4-пиримидин- или пиридинильные производные индол-3-ил-алкилпиперазинов, фармацевтическая композиция Download PDFInfo
- Publication number
- RU2114111C1 RU2114111C1 RU92016241A RU92016241A RU2114111C1 RU 2114111 C1 RU2114111 C1 RU 2114111C1 RU 92016241 A RU92016241 A RU 92016241A RU 92016241 A RU92016241 A RU 92016241A RU 2114111 C1 RU2114111 C1 RU 2114111C1
- Authority
- RU
- Russia
- Prior art keywords
- indol
- methoxy
- propyl
- mmol
- pyrimidinyl
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 9
- 125000004076 pyridyl group Chemical group 0.000 title claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 100
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims abstract description 30
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 28
- 239000001257 hydrogen Substances 0.000 claims abstract description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 22
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 13
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 150000002367 halogens Chemical class 0.000 claims abstract description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 5
- 125000003277 amino group Chemical group 0.000 claims abstract description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 4
- 150000002431 hydrogen Chemical class 0.000 claims abstract 8
- -1 5-methoxy-4-pyrimidinyl Chemical group 0.000 claims description 219
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 136
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 81
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 73
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 29
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 229940076279 serotonin Drugs 0.000 claims description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 3
- 230000001270 agonistic effect Effects 0.000 claims description 2
- 150000003230 pyrimidines Chemical class 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims 2
- JMNJPZYYLUALFK-UHFFFAOYSA-N 1-[3-[3-[4-(5-methoxypyrimidin-4-yl)piperazin-1-yl]propyl]-1h-indol-5-yl]ethanone Chemical compound COC1=CN=CN=C1N1CCN(CCCC=2C3=CC(=CC=C3NC=2)C(C)=O)CC1 JMNJPZYYLUALFK-UHFFFAOYSA-N 0.000 claims 1
- HYHYARGSQDRKBV-UHFFFAOYSA-N 2-[3-[3-[4-(5-methoxypyrimidin-4-yl)piperazin-1-yl]propyl]-1h-indol-5-yl]acetamide Chemical compound COC1=CN=CN=C1N1CCN(CCCC=2C3=CC(CC(N)=O)=CC=C3NC=2)CC1 HYHYARGSQDRKBV-UHFFFAOYSA-N 0.000 claims 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims 1
- RZQIGQUOKAWBDA-UHFFFAOYSA-N 3-[3-[4-(3-methoxypyridin-4-yl)-2-methylpiperazin-1-yl]propyl]-1h-indole Chemical compound COC1=CN=CC=C1N1CC(C)N(CCCC=2C3=CC=CC=C3NC=2)CC1 RZQIGQUOKAWBDA-UHFFFAOYSA-N 0.000 claims 1
- IZKSPDDPCCFXFI-UHFFFAOYSA-N 3-[3-[4-(3-methoxypyridin-4-yl)piperazin-1-yl]propyl]-1h-indole Chemical compound COC1=CN=CC=C1N1CCN(CCCC=2C3=CC=CC=C3NC=2)CC1 IZKSPDDPCCFXFI-UHFFFAOYSA-N 0.000 claims 1
- IBTDQBCNOPVYCJ-UHFFFAOYSA-N 3-[3-[4-(5-methoxypyrimidin-4-yl)piperazin-1-yl]propyl]-1h-indol-5-amine Chemical compound COC1=CN=CN=C1N1CCN(CCCC=2C3=CC(N)=CC=C3NC=2)CC1 IBTDQBCNOPVYCJ-UHFFFAOYSA-N 0.000 claims 1
- RTPGEMPUQWTOTJ-UHFFFAOYSA-N 3-[3-[4-(5-methoxypyrimidin-4-yl)piperazin-1-yl]propyl]-1h-indole-5-carbonitrile Chemical compound COC1=CN=CN=C1N1CCN(CCCC=2C3=CC(=CC=C3NC=2)C#N)CC1 RTPGEMPUQWTOTJ-UHFFFAOYSA-N 0.000 claims 1
- SYVBXSCDUSJDPO-UHFFFAOYSA-N 3-[3-[4-(5-methoxypyrimidin-4-yl)piperazin-1-yl]propyl]-5-nitro-1h-indole Chemical compound COC1=CN=CN=C1N1CCN(CCCC=2C3=CC(=CC=C3NC=2)[N+]([O-])=O)CC1 SYVBXSCDUSJDPO-UHFFFAOYSA-N 0.000 claims 1
- GAFUZWCJMTXSDI-UHFFFAOYSA-N 3-[3-[4-(5-methoxypyrimidin-4-yl)piperazin-1-yl]propyl]-n-methyl-1h-indole-5-carboxamide Chemical compound C12=CC(C(=O)NC)=CC=C2NC=C1CCCN(CC1)CCN1C1=NC=NC=C1OC GAFUZWCJMTXSDI-UHFFFAOYSA-N 0.000 claims 1
- 239000000654 additive Substances 0.000 claims 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims 1
- WRZVGHXUPBWIOO-UHFFFAOYSA-N avitriptan Chemical compound C12=CC(CS(=O)(=O)NC)=CC=C2NC=C1CCCN(CC1)CCN1C1=NC=NC=C1OC WRZVGHXUPBWIOO-UHFFFAOYSA-N 0.000 claims 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims 1
- DHFOXXSSNOLXLQ-UHFFFAOYSA-N n-butyl-3-[3-[4-(5-methoxypyrimidin-4-yl)piperazin-1-yl]propyl]-1h-indole-5-carboxamide Chemical compound C12=CC(C(=O)NCCCC)=CC=C2NC=C1CCCN(CC1)CCN1C1=NC=NC=C1OC DHFOXXSSNOLXLQ-UHFFFAOYSA-N 0.000 claims 1
- DVRMBCHHTORHDP-UHFFFAOYSA-N n-ethyl-3-[3-[4-(5-methoxypyrimidin-4-yl)piperazin-1-yl]propyl]-1h-indole-5-carboxamide Chemical compound C12=CC(C(=O)NCC)=CC=C2NC=C1CCCN(CC1)CCN1C1=NC=NC=C1OC DVRMBCHHTORHDP-UHFFFAOYSA-N 0.000 claims 1
- 150000003222 pyridines Chemical class 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 68
- 230000015572 biosynthetic process Effects 0.000 abstract description 28
- 239000000126 substance Substances 0.000 abstract description 19
- 238000003786 synthesis reaction Methods 0.000 abstract description 17
- 230000000694 effects Effects 0.000 abstract description 8
- 230000003042 antagnostic effect Effects 0.000 abstract 1
- 150000002391 heterocyclic compounds Chemical class 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 246
- 239000000243 solution Substances 0.000 description 217
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 189
- 239000000203 mixture Substances 0.000 description 168
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 155
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 134
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 105
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 103
- 239000011541 reaction mixture Substances 0.000 description 80
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 66
- 239000000460 chlorine Substances 0.000 description 61
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 61
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
- 238000002844 melting Methods 0.000 description 55
- 230000008018 melting Effects 0.000 description 55
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 48
- 238000000921 elemental analysis Methods 0.000 description 47
- 239000007864 aqueous solution Substances 0.000 description 45
- 239000012044 organic layer Substances 0.000 description 44
- 239000007787 solid Substances 0.000 description 43
- 239000000741 silica gel Substances 0.000 description 42
- 229910002027 silica gel Inorganic materials 0.000 description 42
- 239000000047 product Substances 0.000 description 38
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- 238000010992 reflux Methods 0.000 description 36
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 33
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 31
- 208000019695 Migraine disease Diseases 0.000 description 29
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 28
- 239000000725 suspension Substances 0.000 description 27
- 238000004587 chromatography analysis Methods 0.000 description 26
- 239000012141 concentrate Substances 0.000 description 26
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 24
- 206010027599 migraine Diseases 0.000 description 24
- 206010019233 Headaches Diseases 0.000 description 22
- 231100000869 headache Toxicity 0.000 description 22
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 20
- 229920006395 saturated elastomer Polymers 0.000 description 20
- 238000010898 silica gel chromatography Methods 0.000 description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 19
- 239000011734 sodium Substances 0.000 description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- 229910052757 nitrogen Inorganic materials 0.000 description 18
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 18
- 239000012267 brine Substances 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 17
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
- 238000011282 treatment Methods 0.000 description 17
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 16
- 239000000284 extract Substances 0.000 description 16
- 239000000543 intermediate Substances 0.000 description 16
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 150000001412 amines Chemical class 0.000 description 15
- 238000000354 decomposition reaction Methods 0.000 description 15
- 238000002329 infrared spectrum Methods 0.000 description 15
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 14
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 14
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 13
- 239000000908 ammonium hydroxide Substances 0.000 description 13
- 235000008504 concentrate Nutrition 0.000 description 13
- 238000001914 filtration Methods 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 12
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 12
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 11
- 239000002244 precipitate Substances 0.000 description 11
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 238000001228 spectrum Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- 208000001407 Vascular Headaches Diseases 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- JOMNTHCQHJPVAZ-UHFFFAOYSA-N 2-methylpiperazine Chemical compound CC1CNCCN1 JOMNTHCQHJPVAZ-UHFFFAOYSA-N 0.000 description 8
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 8
- 229910052786 argon Inorganic materials 0.000 description 8
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 8
- 239000006260 foam Substances 0.000 description 8
- 125000006261 methyl amino sulfonyl group Chemical group [H]N(C([H])([H])[H])S(*)(=O)=O 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- 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 8
- IJQIGKLDBGKSNT-UHFFFAOYSA-N 4,6-dichloro-5-methoxypyrimidine Chemical compound COC1=C(Cl)N=CN=C1Cl IJQIGKLDBGKSNT-UHFFFAOYSA-N 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 6
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- CVVIJWRCGSYCMB-UHFFFAOYSA-N hydron;piperazine;dichloride Chemical compound Cl.Cl.C1CNCCN1 CVVIJWRCGSYCMB-UHFFFAOYSA-N 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 5
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 230000029936 alkylation Effects 0.000 description 5
- 238000005804 alkylation reaction Methods 0.000 description 5
- 239000012300 argon atmosphere Substances 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- FRYHCSODNHYDPU-UHFFFAOYSA-N ethanesulfonyl chloride Chemical compound CCS(Cl)(=O)=O FRYHCSODNHYDPU-UHFFFAOYSA-N 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 239000012458 free base Substances 0.000 description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 5
- 238000001819 mass spectrum Methods 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- DKORSYDQYFVQNS-UHFFFAOYSA-N propyl methanesulfonate Chemical compound CCCOS(C)(=O)=O DKORSYDQYFVQNS-UHFFFAOYSA-N 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 230000006103 sulfonylation Effects 0.000 description 5
- 238000005694 sulfonylation reaction Methods 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- CTMIYYREUVYVEL-UHFFFAOYSA-N 4-chloro-5-methoxypyrimidine Chemical compound COC1=CN=CN=C1Cl CTMIYYREUVYVEL-UHFFFAOYSA-N 0.000 description 4
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- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P25/06—Antimigraine agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pain & Pain Management (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US81066191A | 1991-12-19 | 1991-12-19 | |
| US07/810661 | 1991-12-19 | ||
| US95959292A | 1992-10-13 | 1992-10-13 | |
| US07/959592 | 1992-10-13 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| RU92016241A RU92016241A (ru) | 1995-08-20 |
| RU2114111C1 true RU2114111C1 (ru) | 1998-06-27 |
Family
ID=27123378
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| RU92016241A RU2114111C1 (ru) | 1991-12-19 | 1992-12-17 | 4-пиримидин- или пиридинильные производные индол-3-ил-алкилпиперазинов, фармацевтическая композиция |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US5434154A (cg-RX-API-DMAC7.html) |
| EP (1) | EP0548813A1 (cg-RX-API-DMAC7.html) |
| JP (1) | JPH05262762A (cg-RX-API-DMAC7.html) |
| CN (1) | CN1085556A (cg-RX-API-DMAC7.html) |
| AU (1) | AU661527B2 (cg-RX-API-DMAC7.html) |
| CA (1) | CA2084531A1 (cg-RX-API-DMAC7.html) |
| CZ (1) | CZ359292A3 (cg-RX-API-DMAC7.html) |
| FI (1) | FI925737L (cg-RX-API-DMAC7.html) |
| IL (1) | IL104024A (cg-RX-API-DMAC7.html) |
| MX (1) | MX9207114A (cg-RX-API-DMAC7.html) |
| NO (1) | NO302522B1 (cg-RX-API-DMAC7.html) |
| NZ (1) | NZ245439A (cg-RX-API-DMAC7.html) |
| PH (1) | PH30988A (cg-RX-API-DMAC7.html) |
| RU (1) | RU2114111C1 (cg-RX-API-DMAC7.html) |
| TW (1) | TW221420B (cg-RX-API-DMAC7.html) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2295519C2 (ru) * | 2001-01-23 | 2007-03-20 | Мерк Патент Гмбх | Способ получения (3-циано-1h-индол-7-ил)[4-(4-фторфенетил)пиперазин-1-ил] метанона и его солей |
| RU2383532C2 (ru) * | 2004-09-28 | 2010-03-10 | Мерк Патент Гмбх | Новая кристаллическая форма (3-циано-1н-индол-7-ил)-[4-(4-фторфенэтил)пиперазин-1-ил]метанона гидрохлорида |
| RU2461556C2 (ru) * | 2006-12-30 | 2012-09-20 | Эбботт Гмбх Унд Ко. Кг | Замещенные производные оксидола и их применение в качестве лигандов рецептора вазопрессина |
Families Citing this family (43)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5521188A (en) * | 1993-09-16 | 1996-05-28 | Bristol-Myers Squibb Company | Antimigraine cyclobutenedione derivatives of indolylalkyl-pyridinyl and pyrimidinylpiperazines |
| CA2130078A1 (en) * | 1993-09-16 | 1995-03-17 | Jonas A. Gylys | Antimigraine cyclobutenedione derivatives of indolylalkyl-pyridinyl and pyrimidinylpiperazines |
| US5468768A (en) * | 1994-01-06 | 1995-11-21 | Bristol-Myers Squibb Company | Antimigraine derivatives of indolylcycloalkanylamines |
| JPH10501212A (ja) * | 1994-05-19 | 1998-02-03 | メルク シヤープ エンド ドーム リミテツド | ５−ｈｔ▲下１ｄ▼−アルファ作働薬としてのインドール−３−イルアルキルのピペラジン、ピペリジンおよびテトラヒドロピリジン誘導体 |
| GB9410031D0 (en) * | 1994-05-19 | 1994-07-06 | Merck Sharp & Dohme | Therapeutic agents |
| US5552402A (en) * | 1994-05-19 | 1996-09-03 | Merck, Sharp & Dohme Ltd. | Five-membered heteroaromatic compounds as 5-HT receptor agonists |
| US5567824A (en) * | 1994-05-24 | 1996-10-22 | Merck & Co., Inc. | Palladium catalyzed ring closure of triazolyltryptamine |
| ES2079323B1 (es) * | 1994-06-21 | 1996-10-16 | Vita Invest Sa | Derivados de indol utiles para el tratamiento de la migraña, composicion y uso correspondientes. |
| GB9415575D0 (en) * | 1994-08-02 | 1994-09-21 | Merck Sharp & Dohme | Therapeutic agents |
| US5550239A (en) * | 1994-11-08 | 1996-08-27 | Bristol-Myers Squibb Company | Process for large-scale production of indolyl alkyl pyrimidinyl piperazine compounds |
| GB9423682D0 (en) * | 1994-11-23 | 1995-01-11 | Merck Sharp & Dohme | Therapeutic agents |
| GB9501865D0 (en) * | 1995-01-31 | 1995-03-22 | Merck Sharp & Dohme | Therapeutic agents |
| US5618816A (en) * | 1995-03-02 | 1997-04-08 | Bristol-Myers Squibb Company | Antimigraine 1,2,5-thiadiazole derivatives of indolylalkyl-pyridnyl and pyrimidinylpiperazines |
| US5889010A (en) * | 1995-05-18 | 1999-03-30 | Pfizer Inc. | Benzimidazole derivatives having dopaminergic activity |
| CA2228286A1 (en) * | 1995-08-07 | 1997-02-20 | Merck Sharp & Dohme Limited | Substituted 1-indolylpropyl-4-phenethylpiperazine derivatives |
| JPH09124643A (ja) * | 1995-08-14 | 1997-05-13 | Bristol Myers Squibb Co | 抗うつ作用を有する１−アリールアルキル−４−（アルコキシピリジニル）−又は４−（アルコキシピリミジニル）ピペラジン誘導体 |
| GB9519563D0 (en) * | 1995-09-26 | 1995-11-29 | Merck Sharp & Dohme | Therapeutic agents |
| EP0854714A1 (en) * | 1995-09-28 | 1998-07-29 | MERCK SHARP & DOHME LTD. | Substituted indolylpropyl-piperazine derivatives as 5-ht 1dalpha? agonists |
| US5998415A (en) * | 1995-11-02 | 1999-12-07 | Merck Sharp & Dohme Ltd. | Bicyclic heteroaryl-alkylene-(homo)piperazinones and thione analogues thereof, their preparation, and their use of as selective agonists of 5-HT1 -like receptors |
| GB9523250D0 (en) * | 1995-11-14 | 1996-01-17 | Merck Sharp & Dohme | Therapeutic agents |
| GB9609374D0 (en) * | 1996-05-03 | 1996-07-10 | Merck Sharp & Dohme | Therapeutic agents |
| US5808064A (en) * | 1996-08-13 | 1998-09-15 | Merck & Co., Inc. | Palladium catalyzed indolization |
| US5877329A (en) * | 1996-08-13 | 1999-03-02 | Merck & Co., Inc. | Palladium catalyzed indolization |
| US5811551A (en) * | 1996-08-13 | 1998-09-22 | Merck & Co., Inc. | Palladium catalyzed indolization |
| US5891885A (en) * | 1996-10-09 | 1999-04-06 | Algos Pharmaceutical Corporation | Method for treating migraine |
| GB9714383D0 (en) * | 1997-07-08 | 1997-09-10 | Pfizer Ltd | Improved process |
| DE19756036A1 (de) | 1997-12-17 | 1999-06-24 | Merck Patent Gmbh | Amid- und Harnstoffderivate |
| JP2004517081A (ja) * | 2000-11-29 | 2004-06-10 | イーライ・リリー・アンド・カンパニー | １−（２−ｍ−メタンスルホンアミドフェニルエチル）−４−（ｍ−トリフルオロメチルフェニル）ピペラジンならびにその医薬的に許容しうる塩および溶媒和物 |
| US6685951B2 (en) | 2001-07-05 | 2004-02-03 | R. T. Alamo Ventures I, Inc. | Administration of dihydroergotamine as a sublingual spray or aerosol for the treatment of migraine |
| US20030198669A1 (en) * | 2001-07-05 | 2003-10-23 | R.T. Alamo Ventures I, Llc | Compositions and methods for rapid dissolving formulations of dihydroergotamine and caffeine for the treatment of migraine |
| US20030017175A1 (en) * | 2001-07-05 | 2003-01-23 | R.T. Alamo Ventures I, Inc. | Sublingual administration of dihydroergotamine for the treatment of migraine |
| DE60233076D1 (de) | 2002-02-13 | 2009-09-03 | Meiji Dairies Corp | Indolderivate substituiert mit langkettigen alcoholen und sie enthaltende arzneimittel |
| WO2006129190A1 (en) * | 2005-06-03 | 2006-12-07 | Glenmark Pharmaceuticals Limited | Process for the preparation of almotriptan |
| ES2538082T3 (es) | 2007-02-11 | 2015-06-17 | Map Pharmaceuticals Inc | Método de administración terapéutica de DHE para permitir el rápido alivio de migraña mientras que se minimiza el perfil de efectos secundarios |
| EP2036888A1 (en) * | 2007-09-17 | 2009-03-18 | Laboratorios del Dr. Esteve S.A. | Naphthyl-substituted sulfonamides |
| ES2751388T3 (es) | 2011-07-22 | 2020-03-31 | Univ Chicago | IGF-1 para su uso en el tratamiento de la jaqueca |
| AU2013361337A1 (en) | 2012-12-21 | 2015-07-09 | Map Pharmaceuticals, Inc. | 8'-Hydroxy-Dihydroergotamine compounds and compositions |
| CN104163813B (zh) * | 2013-05-16 | 2017-02-01 | 广东东阳光药业有限公司 | 取代的吲哚化合物及其使用方法和用途 |
| CN104337812B (zh) | 2013-07-29 | 2018-09-14 | 广东东阳光药业有限公司 | 取代的杂芳基化合物及其使用方法和用途 |
| CN104725363B (zh) * | 2013-12-20 | 2019-03-01 | 广东东阳光药业有限公司 | 取代的哌嗪化合物及其使用方法和用途 |
| US9714232B2 (en) * | 2013-12-20 | 2017-07-25 | Sunshine Lake Pharma Co., Ltd. | Substituted piperazine compounds and methods of use thereof |
| CN106243088B (zh) * | 2015-06-03 | 2019-01-04 | 广东东阳光药业有限公司 | 取代的哌嗪化合物及其使用方法和用途 |
| WO2019082143A1 (en) * | 2017-10-27 | 2019-05-02 | Fresenius Kabi Oncology Ltd. | IMPROVED PROCESS FOR THE PREPARATION OF RIBOCICLIB AND ITS SALTS |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0354094B1 (fr) * | 1988-08-03 | 1991-12-27 | Synthelabo | Dérivés d'indolone, leur préparation et leur application en thérapeutique |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB944443A (cg-RX-API-DMAC7.html) * | 1959-09-25 | 1900-01-01 | ||
| GB1189064A (en) | 1967-05-01 | 1970-04-22 | Sterling Drug Inc | Indole Derivatives |
| GR79215B (cg-RX-API-DMAC7.html) | 1982-06-07 | 1984-10-22 | Glaxo Group Ltd | |
| GB2162522B (en) | 1984-08-01 | 1988-02-24 | Glaxo Group Ltd | An indole derivative |
| US4954502A (en) * | 1988-06-10 | 1990-09-04 | Bristol-Myers Squibb Company | 1-indolyalkyl-4-(substituted-pyridinyl)piperazines |
| GB8830312D0 (en) | 1988-12-28 | 1989-02-22 | Lundbeck & Co As H | Heterocyclic compounds |
| JP2871811B2 (ja) | 1990-02-28 | 1999-03-17 | サントリー株式会社 | 縮合７員環系化合物 |
| US5077293A (en) | 1990-06-29 | 1991-12-31 | Bristol-Myers Squibb Co. | 1-indolyalkyl-4-(alkoxypyrimidinyl)piperazines |
| CA2043709C (en) * | 1990-06-29 | 2002-01-22 | David W. Smith | Antimigraine alkoxypyrimidine derivatives |
-
1992
- 1992-12-04 CA CA002084531A patent/CA2084531A1/en not_active Abandoned
- 1992-12-07 CZ CS923592A patent/CZ359292A3/cs unknown
- 1992-12-08 IL IL104024A patent/IL104024A/xx not_active IP Right Cessation
- 1992-12-09 MX MX9207114A patent/MX9207114A/es unknown
- 1992-12-10 NO NO924764A patent/NO302522B1/no unknown
- 1992-12-10 AU AU30034/92A patent/AU661527B2/en not_active Ceased
- 1992-12-11 NZ NZ245439A patent/NZ245439A/xx unknown
- 1992-12-14 TW TW081110009A patent/TW221420B/zh active
- 1992-12-15 PH PH45427A patent/PH30988A/en unknown
- 1992-12-17 EP EP92121519A patent/EP0548813A1/en not_active Ceased
- 1992-12-17 RU RU92016241A patent/RU2114111C1/ru active
- 1992-12-17 FI FI925737A patent/FI925737L/fi not_active Application Discontinuation
- 1992-12-18 JP JP4361763A patent/JPH05262762A/ja active Pending
-
1993
- 1993-01-02 CN CN93101186A patent/CN1085556A/zh active Pending
-
1994
- 1994-04-26 US US08/233,545 patent/US5434154A/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0354094B1 (fr) * | 1988-08-03 | 1991-12-27 | Synthelabo | Dérivés d'indolone, leur préparation et leur application en thérapeutique |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2295519C2 (ru) * | 2001-01-23 | 2007-03-20 | Мерк Патент Гмбх | Способ получения (3-циано-1h-индол-7-ил)[4-(4-фторфенетил)пиперазин-1-ил] метанона и его солей |
| RU2383532C2 (ru) * | 2004-09-28 | 2010-03-10 | Мерк Патент Гмбх | Новая кристаллическая форма (3-циано-1н-индол-7-ил)-[4-(4-фторфенэтил)пиперазин-1-ил]метанона гидрохлорида |
| RU2461556C2 (ru) * | 2006-12-30 | 2012-09-20 | Эбботт Гмбх Унд Ко. Кг | Замещенные производные оксидола и их применение в качестве лигандов рецептора вазопрессина |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1085556A (zh) | 1994-04-20 |
| JPH05262762A (ja) | 1993-10-12 |
| AU3003492A (en) | 1994-03-24 |
| NZ245439A (en) | 1995-07-26 |
| FI925737A0 (fi) | 1992-12-17 |
| CZ359292A3 (en) | 1994-01-19 |
| FI925737A7 (fi) | 1993-06-20 |
| FI925737L (fi) | 1993-06-20 |
| US5434154A (en) | 1995-07-18 |
| MX9207114A (es) | 1993-07-01 |
| IL104024A (en) | 1997-04-15 |
| CA2084531A1 (en) | 1993-06-20 |
| TW221420B (cg-RX-API-DMAC7.html) | 1994-03-01 |
| PH30988A (en) | 1997-12-23 |
| AU661527B2 (en) | 1995-07-27 |
| EP0548813A1 (en) | 1993-06-30 |
| NO924764L (no) | 1993-06-21 |
| NO302522B1 (no) | 1998-03-16 |
| NO924764D0 (no) | 1992-12-10 |
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