NO175365B - Analogous Process for Preparing Therapeutically Active 2- (Aminoalkylthio) Methyl-1,4-Dihydropyridine Derivatives - Google Patents
Analogous Process for Preparing Therapeutically Active 2- (Aminoalkylthio) Methyl-1,4-Dihydropyridine DerivativesInfo
- Publication number
- NO175365B NO175365B NO880865A NO880865A NO175365B NO 175365 B NO175365 B NO 175365B NO 880865 A NO880865 A NO 880865A NO 880865 A NO880865 A NO 880865A NO 175365 B NO175365 B NO 175365B
- Authority
- NO
- Norway
- Prior art keywords
- methyl
- formula
- group
- ethoxycarbonyl
- dihydropyridine
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title description 5
- ZKIJTTNWOULCBY-UHFFFAOYSA-N 1-methyl-4h-pyridine Chemical class CN1C=CCC=C1 ZKIJTTNWOULCBY-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 57
- 238000000034 method Methods 0.000 claims description 22
- -1 alkylidene compound Chemical class 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 229910052698 phosphorus Inorganic materials 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 5
- 230000003647 oxidation Effects 0.000 claims description 5
- 238000007254 oxidation reaction Methods 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000005228 aryl sulfonate group Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 2
- ZCCCZWLGENWLCF-UHFFFAOYSA-N 3-o-ethyl 5-o-methyl 2-(2-formamido-2-phenylethyl)sulfanyl-1,6-dimethyl-4-(3-nitrophenyl)-4h-pyridine-3,5-dicarboxylate Chemical compound CN1C(C)=C(C(=O)OC)C(C=2C=C(C=CC=2)[N+]([O-])=O)C(C(=O)OCC)=C1SCC(NC=O)C1=CC=CC=C1 ZCCCZWLGENWLCF-UHFFFAOYSA-N 0.000 claims description 2
- JOJQWMGDRIWKBU-UHFFFAOYSA-N 3-o-ethyl 5-o-methyl 2-[(1-formylpyrrolidin-2-yl)methylsulfanylmethyl]-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound N1C(C)=C(C(=O)OC)C(C=2C=C(C=CC=2)[N+]([O-])=O)C(C(=O)OCC)=C1CSCC1CCCN1C=O JOJQWMGDRIWKBU-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 230000032050 esterification Effects 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 150000003335 secondary amines Chemical group 0.000 claims description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 229910001868 water Inorganic materials 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 230000036772 blood pressure Effects 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 238000011282 treatment Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 241000282472 Canis lupus familiaris Species 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 230000003276 anti-hypertensive effect Effects 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 230000001631 hypertensive effect Effects 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 239000012047 saturated solution Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 231100000403 acute toxicity Toxicity 0.000 description 4
- 230000007059 acute toxicity Effects 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- DOQSTWXMDNAXBT-YVMONPNESA-N ethyl (z)-3-amino-4-(2-formamidoethylsulfanyl)but-2-enoate Chemical compound CCOC(=O)\C=C(/N)CSCCNC=O DOQSTWXMDNAXBT-YVMONPNESA-N 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 150000003573 thiols Chemical class 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-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
- 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 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 238000006000 Knoevenagel condensation reaction Methods 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002220 antihypertensive agent Substances 0.000 description 3
- 229910052681 coesite Inorganic materials 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 229910052906 cristobalite Inorganic materials 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 150000004965 peroxy acids Chemical class 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- 229910052682 stishovite Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229910052905 tridymite Inorganic materials 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- RPTUSVTUFVMDQK-UHFFFAOYSA-N Hidralazin Chemical compound C1=CC=C2C(NN)=NN=CC2=C1 RPTUSVTUFVMDQK-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229910004298 SiO 2 Inorganic materials 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 229940030600 antihypertensive agent Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- KDZWTEVTULYVHV-UHFFFAOYSA-N ethyl 4-(2-formamidoethylsulfanyl)-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)CSCCNC=O KDZWTEVTULYVHV-UHFFFAOYSA-N 0.000 description 2
- XBECWGJPSXHFCS-UHFFFAOYSA-N imidazole-1-carbaldehyde Chemical compound O=CN1C=CN=C1 XBECWGJPSXHFCS-UHFFFAOYSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 238000013160 medical therapy Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- XYPISWUKQGWYGX-UHFFFAOYSA-N 2,2,2-trifluoroethaneperoxoic acid Chemical compound OOC(=O)C(F)(F)F XYPISWUKQGWYGX-UHFFFAOYSA-N 0.000 description 1
- OGMADIBCHLQMIP-UHFFFAOYSA-N 2-aminoethanethiol;hydron;chloride Chemical compound Cl.NCCS OGMADIBCHLQMIP-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- GLVYLTSKTCWWJR-UHFFFAOYSA-N 2-carbonoperoxoylbenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1C(O)=O GLVYLTSKTCWWJR-UHFFFAOYSA-N 0.000 description 1
- AZTYHYHSDPMHRA-UHFFFAOYSA-N 2-formamido-2-phenylacetic acid Chemical compound O=CNC(C(=O)O)C1=CC=CC=C1 AZTYHYHSDPMHRA-UHFFFAOYSA-N 0.000 description 1
- ZOBLAHKFBSIYCK-UHFFFAOYSA-N 2-methoxyethyl 4-(2-formamidoethylsulfanyl)-3-oxobutanoate Chemical compound COCCOC(=O)CC(=O)CSCCNC=O ZOBLAHKFBSIYCK-UHFFFAOYSA-N 0.000 description 1
- UXHRTKANNFEQIU-UHFFFAOYSA-N 2-methoxyethyl 4-chloro-3-oxobutanoate Chemical compound COCCOC(=O)CC(=O)CCl UXHRTKANNFEQIU-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 description 1
- SRWILAKSARHZPR-UHFFFAOYSA-N 3-chlorobenzaldehyde Chemical compound ClC1=CC=CC(C=O)=C1 SRWILAKSARHZPR-UHFFFAOYSA-N 0.000 description 1
- ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-UHFFFAOYSA-N 0.000 description 1
- NCPRZAIJPGXTLB-UHFFFAOYSA-N 3-o-ethyl 5-o-methyl 2-(2-aminoethylsulfanylmethyl)-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(CSCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC([N+]([O-])=O)=C1 NCPRZAIJPGXTLB-UHFFFAOYSA-N 0.000 description 1
- DEPMHZHLRPAVBB-UHFFFAOYSA-N 3-o-ethyl 5-o-methyl 2-(2-formamidoethylsulfanyl)-1,6-dimethyl-4-(3-nitrophenyl)-4h-pyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(SCCNC=O)N(C)C(C)=C(C(=O)OC)C1C1=CC=CC([N+]([O-])=O)=C1 DEPMHZHLRPAVBB-UHFFFAOYSA-N 0.000 description 1
- CLMNTOZRDYXVRT-UHFFFAOYSA-N 3-o-ethyl 5-o-methyl 2-(2-formamidoethylsulfanylmethyl)-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(CSCCNC=O)NC(C)=C(C(=O)OC)C1C1=CC=CC([N+]([O-])=O)=C1 CLMNTOZRDYXVRT-UHFFFAOYSA-N 0.000 description 1
- LBXBXTWTGBCMHZ-UHFFFAOYSA-N 3-o-ethyl 5-o-methyl 2-(2-formamidoethylsulfanylmethyl)-6-methyl-4-(5-methylsulfanyl-2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(CSCCNC=O)NC(C)=C(C(=O)OC)C1C1=CC(SC)=CC=C1[N+]([O-])=O LBXBXTWTGBCMHZ-UHFFFAOYSA-N 0.000 description 1
- UPDNJGMYCCGIIH-UHFFFAOYSA-N 3-o-ethyl 5-o-methyl 2-(2-formamidoethylsulfinylmethyl)-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(CS(=O)CCNC=O)NC(C)=C(C(=O)OC)C1C1=CC=CC([N+]([O-])=O)=C1 UPDNJGMYCCGIIH-UHFFFAOYSA-N 0.000 description 1
- KILRPPWVHWSNIN-UHFFFAOYSA-N 3-o-ethyl 5-o-methyl 2-(chloromethyl)-6-methyl-4-(2-methylsulfanylphenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(CCl)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1SC KILRPPWVHWSNIN-UHFFFAOYSA-N 0.000 description 1
- ZJICKBYEOPLJPK-UHFFFAOYSA-N 3-o-ethyl 5-o-methyl 4-(2,3-dichlorophenyl)-2-(2-formamidoethylsulfanylmethyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(CSCCNC=O)NC(C)=C(C(=O)OC)C1C1=CC=CC(Cl)=C1Cl ZJICKBYEOPLJPK-UHFFFAOYSA-N 0.000 description 1
- AALHLYAZVGRDJY-UHFFFAOYSA-N 3-o-ethyl 5-o-methyl 4-(2-chlorophenyl)-2-(2-formamidoethylsulfanylmethyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(CSCCNC=O)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl AALHLYAZVGRDJY-UHFFFAOYSA-N 0.000 description 1
- SWWJXZCKWZJDGC-UHFFFAOYSA-N 3-o-ethyl 5-o-methyl 4-(3-chlorophenyl)-2-(2-formamidoethylsulfanylmethyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(CSCCNC=O)NC(C)=C(C(=O)OC)C1C1=CC=CC(Cl)=C1 SWWJXZCKWZJDGC-UHFFFAOYSA-N 0.000 description 1
- UCTNTYHJFWMUBD-UHFFFAOYSA-N 4-chloro-3-oxobutanoic acid Chemical compound OC(=O)CC(=O)CCl UCTNTYHJFWMUBD-UHFFFAOYSA-N 0.000 description 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 1
- HNBRQEOURHKDLP-UHFFFAOYSA-N 5-O-ethyl 3-O-methyl 1-(2-formamidoethylsulfanyl)-2-methyl-4-(3-nitrophenyl)-4H-pyridine-3,5-dicarboxylate Chemical compound C(=O)NCCSN1C=C(C(C(=C1C)C(=O)OC)C1=CC(=CC=C1)[N+](=O)[O-])C(=O)OCC HNBRQEOURHKDLP-UHFFFAOYSA-N 0.000 description 1
- WUGKQRBRHVFHEZ-UHFFFAOYSA-N 5-methyl-2-nitrothiobenzaldehyde Chemical compound CC1=CC=C([N+]([O-])=O)C(C=S)=C1 WUGKQRBRHVFHEZ-UHFFFAOYSA-N 0.000 description 1
- MCQWQOZNEMXYEM-UHFFFAOYSA-N 5-o-ethyl 3-o-methyl 2-methyl-4-(3-nitrophenyl)-6-(sulfanylmethyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(CS)NC(C)=C(C(=O)OC)C1C1=CC=CC([N+]([O-])=O)=C1 MCQWQOZNEMXYEM-UHFFFAOYSA-N 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- CJCVWADKXJQYHT-UHFFFAOYSA-N CCOC(=O)C1=C(N(C(=C(C1C2=CC(=CC=C2)[N+](=O)[O-])C(=O)OC)C)C)S(=O)(=O)CCN Chemical compound CCOC(=O)C1=C(N(C(=C(C1C2=CC(=CC=C2)[N+](=O)[O-])C(=O)OC)C)C)S(=O)(=O)CCN CJCVWADKXJQYHT-UHFFFAOYSA-N 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical class C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 238000003445 Hantzsch reaction Methods 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 125000003047 N-acetyl group Chemical group 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000004133 Sodium thiosulphate Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-M acetoacetate Chemical compound CC(=O)CC([O-])=O WDJHALXBUFZDSR-UHFFFAOYSA-M 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000008051 alkyl sulfates Chemical class 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical class C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 230000037020 contractile activity Effects 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 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 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229940097265 cysteamine hydrochloride Drugs 0.000 description 1
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- OHLRLMWUFVDREV-UHFFFAOYSA-N ethyl 4-chloro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)CCl OHLRLMWUFVDREV-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960002474 hydralazine Drugs 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 229960003151 mercaptamine Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- XKORCTIIRYKLLG-ARJAWSKDSA-N methyl (z)-3-aminobut-2-enoate Chemical compound COC(=O)\C=C(\C)N XKORCTIIRYKLLG-ARJAWSKDSA-N 0.000 description 1
- HFLMYYLFSNEOOT-UHFFFAOYSA-N methyl 4-chloro-3-oxobutanoate Chemical compound COC(=O)CC(=O)CCl HFLMYYLFSNEOOT-UHFFFAOYSA-N 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000011458 pharmacological treatment Methods 0.000 description 1
- 125000000006 phenylethylthio group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])S* 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- NGZDDEPMSYNJIJ-UHFFFAOYSA-N s-[2-[butyl(formyl)amino]ethyl] ethanethioate Chemical compound CCCCN(C=O)CCSC(C)=O NGZDDEPMSYNJIJ-UHFFFAOYSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-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
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000005732 thioetherification reaction Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D211/80—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 two double bonds between ring members or between ring members and non-ring members
- C07D211/84—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 two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 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)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Description
Foreliggende oppfinnelse analogifremgangsmåte ved fremstilling av terapeutisk aktive 2-(formylaminoalkyltio)-metyl-1,4-dihydropyridiner. Present invention analogue method for the production of therapeutically active 2-(formylaminoalkylthio)-methyl-1,4-dihydropyridines.
Forbindelsene i fremstilt i henhold til foreliggende oppfinnelse har følgende generelle formel I The compounds produced according to the present invention have the following general formula I
hvori in which
R, representerer en gruppe med formel C02R5; Rg er en C,-C6-alkylkjede usubstituert eller substituert med benzylalkylamino; R 1 represents a group of formula CO 2 R 5 ; R 8 is a C 1 -C 6 alkyl chain unsubstituted or substituted with benzylalkylamino;
R2 er en fenylring usubstituert eller substituert med en eller flere trifluormetyl, halogen, nitro, cyano eller C^-C^alkoxy; R 2 is a phenyl ring unsubstituted or substituted with one or more trifluoromethyl, halogen, nitro, cyano or C 1 -C 4 alkoxy;
R3 er en gruppe med formel C02R5; R 3 is a group of formula CO 2 R 5 ;
P er valgt fra gruppen bestående av hydrogen, -(CH2)<p>-<W>P is selected from the group consisting of hydrogen, -(CH2)<p>-<W>
og rettkjedet eller forgrenet C.,-C8 alkyl, and straight chain or branched C 1 -C 8 alkyl,
N-P,, er resten av en primær eller sekundær amingruppe, N-P,, is the residue of a primary or secondary amine group,
hvori P, er valgt fra gruppen bestående av hydrogen, lavere rettkjedet eller forgrenet 0,-C^-alkyl og wherein P 1 is selected from the group consisting of hydrogen, lower straight chain or branched 0, -C 1 -alkyl and
-(CH2)p-W, eller -(CH2)p-W, or
P danner sammen med P1 og nitrogenatomet til hvilket P1P forms together with P1 and the nitrogen atom of which P1
er forbundet en pyrrolidinring, is connected a pyrrolidine ring,
W er CN eller en fenylring eventuelt substituert med ett eller flere halogenatomer eller C.,-C3 alkoksy-grupper, W is CN or a phenyl ring optionally substituted with one or more halogen atoms or C1-C3 alkoxy groups,
m er et helt tall fra 1 til 3, m is an integer from 1 to 3,
n er 0 eller et helt tall fra 1 til 2, n is 0 or an integer from 1 to 2,
p er 0 eller et helt tall fra 1 til 3, p is 0 or an integer from 1 to 3,
deres salter, enantiomere, diastereoisomere eller blandinger derav. their salts, enantiomers, diastereoisomers or mixtures thereof.
Også de farmasøytisk akseptable salter samt de optiske antipoder, dvs. de enantiomere, de mulige geometriske isomere, diastereoisomere og blandinger derav omfattes av omfanget til foreliggende oppfinnelse. Also the pharmaceutically acceptable salts as well as the optical antipodes, i.e. the enantiomers, the possible geometric isomers, diastereoisomers and mixtures thereof are covered by the scope of the present invention.
Alkyl, alkenyl, alkoksy og alkanoyloksygruppene er rett-kjedede eller forgrenede i grupper. Alkyl, alkenyl, alkoxy and alkanoyloxy groups are straight-chained or branched in groups.
En halogen-C^-C^-alkylgruppe er fortrinnsvis trihalogen-C.,-C6-alkyl, særlig trifluormetyl. A halo-C 1 -C 6 -alkyl group is preferably trihalo-C 1 -C 6 -alkyl, especially trifluoromethyl.
En halogen-C^-C^-alkoksygruppe er fortrinnsvis -OCHF2. A halo-C 1 -C 4 -alkyloxy group is preferably -OCHF 2 .
En -C,,-C6-alkylgruppe er fortrinnsvis metyl, etyl, isopropyl eller t-butyl. A -C 1 -C 6 -alkyl group is preferably methyl, ethyl, isopropyl or t-butyl.
En arylgruppe er fortrinnsvis fenyl. An aryl group is preferably phenyl.
En C3-C5-alkenylgruppe er fortrinnsvis allyl. A C3-C5 alkenyl group is preferably allyl.
En C3-C5-alkynylgruppe er fortrinnsvis propargyl. A C3-C5 alkynyl group is preferably propargyl.
En C3-C7-cykloalifatisk gruppe er fortrinnsvis cyklo-pentyl, cykloheksyl eller cykloheptyl. A C3-C7 cycloaliphatic group is preferably cyclopentyl, cyclohexyl or cycloheptyl.
En monoalkylaminogruppe er fortrinnsvis en metyl-, etyl-, isopropyl- eller benzylamino-gruppe. A monoalkylamino group is preferably a methyl, ethyl, isopropyl or benzylamino group.
En C,-C3-alkoksygruppe er fortrinnsvis metoksy eller isopropoksy. A C 1 -C 3 alkoxy group is preferably methoxy or isopropoxy.
En C^-C^-alkyltiogruppe er fortrinnsvis metyltio eller isopropyltio. A C 1 -C 4 -alkylthio group is preferably methylthio or isopropylthio.
En C,-C4 alkoksykarbonyl er fortrinnsvis en metoksy-, etoksy-, eller ter-butoksy-karbonylgruppe. A C 1 -C 4 alkoxycarbonyl is preferably a methoxy, ethoxy or tert-butoxy carbonyl group.
Når R2 er en 5- eller 6-leddet heterocyklisk ring, er den fortrinnsvis pyridyl, furanyl eller tienyl. When R 2 is a 5- or 6-membered heterocyclic ring, it is preferably pyridyl, furanyl or thienyl.
De ikke-toksiske salter som er farmasøytisk akseptable, omfatter hydrokloridene, hydrobromidene, hydrojodidene, lavere alkylsulfater, (lavere) alkyl og arylsulfonater, fosfater, sulfater, maleater, fumarater, succinater, tartrater, citrater og andre vanlig brukte salter i faget. The non-toxic salts which are pharmaceutically acceptable include the hydrochlorides, hydrobromides, hydroiodides, lower alkyl sulfates, (lower) alkyl and aryl sulfonates, phosphates, sulfates, maleates, fumarates, succinates, tartrates, citrates and other commonly used salts in the art.
Saltene som erholdes ved variasjon av syren som anvendes, har i noen tilfeller spesielle fordeler grunnet øket stabilitet, øket solubilitet, nedsatt solubilitet, forbe-dret krystallisasjon, manglende ubehagelig smak osv., men alle disse er av underordnet betydning i forhold til den grunnleggende fysiologiske virkning av den frie base-, som er uavhengig av hvilken syre som anvendes ved fremstilling av saltet. The salts obtained by varying the acid used have in some cases special advantages due to increased stability, increased solubility, reduced solubility, improved crystallization, lack of unpleasant taste, etc., but all of these are of subordinate importance in relation to the basic physiological effect of the free base, which is independent of which acid is used in the preparation of the salt.
Spesielle eksempler på foretrukne forbindelser i henhold til oppfinnelsen er: 4-(3-nitrofenyl), (3-klorfenyl), (3-cyanofenyl), (3-met-oksyfenyl), (4-fluorfenyl)-2-(2-formylaminoetyltio))metyl-3-etoksykarbonyl-5-metoksykarbonyl-6-metyl-l,4-dihydropyridin; en diastereoisomer av 2-(2-formylamino-2-fenyletyltio)-metyl-3-etoksykarbonyl-5-metoksykarbonyl-4- (m-nitro-fenyl)-6-metyl-l,4-dihydropyridin; en diastereoisomer av 2-(N-formyl-pyrrolidin-2-yll-metyltio)metyl-3-etoksykarbonyl-5-metoksykarbonyl-4-(m-nitro-fenyl)-6-metyl-l,4-dihydropyridin; 2-[2-N-(2-cyanoetyl)-N-formylaminoetyltio]metyl-3-etoksy-karbonyl-5-metoksykarbonyl-4-(m-nitrofenyl)-6-metyl-l,4-dihydropyridin; og 2-(2-formylaminoetyltio)metyl-3-etoksykarbonyl-5-(2-N-metyl-N-benzylamino)etoksykarbonyl-4-(m-nitrofenyl)-6-mety1-1,4-dihydropyridin. Forbindelsene i henhold til oppfinnelsen erholdes ved en fremgangsmåte bestående av a) å danne en tioeterbinding ved omsetning av en forbindelse med generell formel II med en forbindelse med formel III Special examples of preferred compounds according to the invention are: 4-(3-nitrophenyl), (3-chlorophenyl), (3-cyanophenyl), (3-methoxyphenyl), (4-fluorophenyl)-2-(2- formylaminoethylthio)methyl-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine; a diastereoisomer of 2-(2-formylamino-2-phenylethylthio)-methyl-3-ethoxycarbonyl-5-methoxycarbonyl-4-(m-nitro-phenyl)-6-methyl-1,4-dihydropyridine; a diastereoisomer of 2-(N-formyl-pyrrolidin-2-yl-methylthio)methyl-3-ethoxycarbonyl-5-methoxycarbonyl-4-(m-nitro-phenyl)-6-methyl-1,4-dihydropyridine; 2-[2-N-(2-cyanoethyl)-N-formylaminoethylthio]methyl-3-ethoxy-carbonyl-5-methoxycarbonyl-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine; and 2-(2-formylaminoethylthio)methyl-3-ethoxycarbonyl-5-(2-N-methyl-N-benzylamino)ethoxycarbonyl-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine. The compounds according to the invention are obtained by a method consisting of a) forming a thioether bond by reacting a compound of general formula II with a compound of formula III
hvori in which
R,, R2, R3, m, P, N-P1 er som definert ovenfor, og R1, R2, R3, m, P, N-P1 are as defined above, and
enten Y eller Y1 representerer en tiol- eller maskert tiolgruppe såsom tio C2-C12-alkanoylester eller et tiouronium-salt -S-(C=NR6)NR7<R>8<e>Y2<6> og den andre er en kjent avgangsgruppe, såsom klor, brom, jod, trifluormetansulfonat, et alkyl- eller en arylsulfonat, either Y or Y1 represents a thiol or masked thiol group such as thio C2-C12 alkanoyl ester or a thiouronium salt -S-(C=NR6)NR7<R>8<e>Y2<6> and the other is a known leaving group , such as chlorine, bromine, iodine, trifluoromethanesulfonate, an alkyl or an aryl sulfonate,
R6, R7, R8, som er like eller forskjellige, er hydrogen R 6 , R 7 , R 8 , which are the same or different, are hydrogen
eller en C^-C^-alkylgruppe, og Y2e er et farmasøytisk akseptabelt anion, or a C 1 -C 4 alkyl group, and Y 2e is a pharmaceutically acceptable anion,
b) å cyklisere en forbindelse med formel IV b) cyclizing a compound of formula IV
med en alkylidenforbindelse med formel V with an alkylidene compound of formula V
hvori in which
R,, R2, R3, P, NP1 og m er som definert °venfor, R1, R2, R3, P, NP1 and m are as defined above,
c) å formylere en forbindelse med formel VIII c) formylating a compound of formula VIII
hvori in which
R.,, Rj, R3, P, P1 og n er som definert ovenfor, og produk-tene erholdt ved nevnte reaksjoner a) til c) eventuelt utsettes for oksydasjon, forestring og/eller separasjon av isomerer. R., R.sub.j, R.sub.3, P, P.sub.1 and n are as defined above, and the products obtained by said reactions a) to c) are optionally subjected to oxidation, esterification and/or separation of isomers.
Reaksjonene a) til c) som oppført ovenfor gir forbindelser med formel I som eventuelt kan utsettes for ytterligere reaksjonstrinn, såsom oksydering, saltdannelse, separasjon av isomere osv. The reactions a) to c) listed above give compounds of formula I which can optionally be subjected to further reaction steps, such as oxidation, salt formation, separation of isomers, etc.
Tioforetringsreaksjonen mellom en forbindelse med formel II og en forbindelse med formel III kan utføres i henhold til det som er kjent i faget under anvendelse av nesten ekvimolare mengder av reagenser i et inert løsningsmiddel ved en temperatur som varierer fra -20 °C til +60 °C, i nærvær av en base. The thioforetheration reaction between a compound of formula II and a compound of formula III can be carried out according to what is known in the art using nearly equimolar amounts of reagents in an inert solvent at a temperature ranging from -20°C to +60° C, in the presence of a base.
Egnede løsningsmidler kan velges fra gruppen bestående av alkoholer, amider, lineære eller cykliske etere, ketoner, estere, halogenerte hydrokarboner, mens basen kan være et alkali eller jordalkali metallhydroksyd, karbonater, bikarbonater, alkoholater, hydrider, amider eller organiske baser, såsom trietylamin, pyridin osv. Suitable solvents may be selected from the group consisting of alcohols, amides, linear or cyclic ethers, ketones, esters, halogenated hydrocarbons, while the base may be an alkali or alkaline earth metal hydroxide, carbonates, bicarbonates, alcoholates, hydrides, amides or organic bases, such as triethylamine, pyridine etc.
Den selektive oksydasjon av tioeterbindigen i forbindelse med formel I hvor n=0 for å danne forbindelser med formel I, hvori n=l eller 2, utføres i et inert løsningsmiddel, såsom etylacetonat, etylformiat, diklormetan, 1,2-dikloretan, kloroform eller blandinger derav. Ved omsetning med en eller flere molare ekvivalenter av en persyre såsom perbenzosyre, m-klor-perbenzosyre, perjodsyre, monoper-ftalsyre, pereddiksyre, permaursyre eller peroksytri-fluoreddiksyre, ved å arbeide i et temperaturområde som varierer fra -30 °C til romtemperatur. Fortrinnsvis utfø-res reaksjonen ved mere enn 0 °C. Forbindelser med formel I hvori n=l erholdes under anvendelse av en molekvivalent med persyrer, mens anvendelsen av 2 eller 3 molekvivalen-ter av persyrer gir forbindelser med n=2. The selective oxidation of the thioether bond in connection with formula I in which n=0 to form compounds of formula I in which n=1 or 2 is carried out in an inert solvent, such as ethyl acetonate, ethyl formate, dichloromethane, 1,2-dichloroethane, chloroform or mixtures thereof. By reaction with one or more molar equivalents of a peracid such as perbenzoic acid, m-chloro-perbenzoic acid, periodic acid, monoperphthalic acid, peracetic acid, permauric acid or peroxytrifluoroacetic acid, by working in a temperature range varying from -30 °C to room temperature. The reaction is preferably carried out at more than 0 °C. Compounds of formula I in which n=1 are obtained using one molar equivalent of peracids, while the use of 2 or 3 molar equivalents of peracids gives compounds with n=2.
Cyklisering av enaminoderivater med formel IV og VI med et etylenderivat med formel V og VII er den velkjente Hantzsch-reaksjonen, beskrevet i [F. Brody og P.R. Ruby i "Pyridines and its derivatives", del I, s. 355-533, A. Wiessberger - Interscience, New York 1960]. Cyclization of enamino derivatives of formula IV and VI with an ethylene derivative of formula V and VII is the well-known Hantzsch reaction, described in [F. Brody and P.R. Ruby in "Pyridines and its derivatives", Part I, pp. 355-533, A. Wiessberger - Interscience, New York 1960].
Formuleringsreaksjonen av en forbindelse med generell formel VIII utføres også under anvendelse av velkjente teknikker, f.eks. ved behandling i et inert løsningsmid-del såsom dimetylformamid eller dimetylacetamid, med et 5-10 molart overskudd av maursyre og under oppvarming av blandingen i 18 timer ved en temperatur som varierer fra 70 til 120 °C. The formulation reaction of a compound of general formula VIII is also carried out using well-known techniques, e.g. by treatment in an inert solvent such as dimethylformamide or dimethylacetamide, with a 5-10 molar excess of formic acid and while heating the mixture for 18 hours at a temperature varying from 70 to 120 °C.
Alternativt omsettes en aminoforbindelse med formel VIII i et tørt inert løsningsmiddel, såsom tetrahydrofuran, benzen, etylacetat, dimetylformamid eller deres blandinger med minst et 0,1 molart overskudd av N-formyl-imid-azol, foretrukne reaksjonsbetingelser er fra romtemperatur til 5 °C i et tidsrom på fra 10 minutter til 1-2 timer. Alternatively, an amino compound of formula VIII is reacted in a dry inert solvent, such as tetrahydrofuran, benzene, ethyl acetate, dimethylformamide or their mixtures with at least a 0.1 molar excess of N-formyl-imidazole, preferred reaction conditions are from room temperature to 5 °C in a period of from 10 minutes to 1-2 hours.
Alternativt omsettes et salt av en forbindelse med formel VIII (hydrobromid, nitrat, sulfat eller hemisulfat) med et overskudd av formamid ved en temperatur som varierer fra 60-90°C i et tidsrom på noen minutter til 3 timer. Alternatively, a salt of a compound of formula VIII (hydrobromide, nitrate, sulfate or hemisulfate) is reacted with an excess of formamide at a temperature varying from 60-90°C for a period of a few minutes to 3 hours.
De optiske oppløsningsprosesser utføres fortrinnsvis på forbindelser med formel I, hvori n=0 eller 2, mens chi-rale forbindelser hvori n=l erholdes fortrinnsvis ved oksydasjon av antipodene hvori n er 0. The optical resolution processes are preferably carried out on compounds of formula I, in which n=0 or 2, while chiral compounds in which n=1 are obtained preferably by oxidation of the antipodes in which n is 0.
Optiske oppløsningsprosesser utføres på diastereoisomere derivater av forbindelser med formel I. For eksempel kan diastere isomere salter av forbindelser I med optisk rene syrer eller baser fremstilles ved hjelp av kjente salt-dannelsesmetoder og utsettes eventuelt for optisk oppløs-ning. Optical resolution processes are carried out on diastereoisomeric derivatives of compounds of formula I. For example, diastereoisomeric salts of compounds I with optically pure acids or bases can be prepared using known salt formation methods and optionally subjected to optical resolution.
Når Ra inneholder en aminogruppe, anvendes det optisk rene syrer, men når Ra er hydrogen, anvendes det optisk aktive baser for etter oppløsningsprosessen å danne optisk rene syrer med formel I, som eventuelt kan forestres på kjent måte. På den andre side kan racemiske syrer med formel I forestres med optisk rene alkoholer, og de erholdte diastereoisomere alkoholer kan eventuelt utsettes for oppløsning ved krystallisering eller kromatografiske fremgangsmåter. De erholdte optisk rene estere kan omdan-nes ved hjelp av kjente metoder til syrer eller estere med formel I. When Ra contains an amino group, optically pure acids are used, but when Ra is hydrogen, optically active bases are used to form optically pure acids of formula I after the dissolution process, which can optionally be esterified in a known manner. On the other hand, racemic acids of formula I can be esterified with optically pure alcohols, and the obtained diastereoisomeric alcohols can optionally be subjected to dissolution by crystallization or chromatographic methods. The obtained optically pure esters can be converted using known methods into acids or esters of formula I.
Forbindelsene med formel II, hvori Y er halogen, er beskrevet i søknad nr. 21875 A/85 av 6. august 1985 og forbindelsene med generell formel IV, hvori Y er en tiol eller en maskert tiolfunksjon, er beskrevet i PCT/EP86/ 00445. The compounds of formula II, in which Y is halogen, are described in application No. 21875 A/85 of 6 August 1985 and the compounds of general formula IV, in which Y is a thiol or a masked thiol function, are described in PCT/EP86/00445 .
Forbindelsene med formel III kan, hvis de ikke allerede er kjent, men letthet fremstilles fra kommersielt tilgjengelige forbindelser under anvendelse av velkjente, sikre og billige fremgangsmåter. The compounds of formula III can, if not already known, be readily prepared from commercially available compounds using well-known, safe and inexpensive methods.
En generell kilde for forbindelsene med formel III er aminoalkoholer IX A general source for the compounds of formula III is amino alcohols IX
hvori m, P, Pl er som tidligere definert; nevnte alkoholer er kommersielt tilgjengelige eller fremstilles ved reduksjon av de tilsvarende aminokarboksyestere eller lactamer. wherein m, P, Pl are as previously defined; said alcohols are commercially available or are produced by reduction of the corresponding aminocarboxyesters or lactams.
Forbindelser med generell formel IX kan med letthet om-dannes til forbindelser med formel III ved hjelp av kjente omsetninger, såsom formulering eller omdannelse av den alkoholiske gruppe til en tiol. Compounds of general formula IX can easily be converted into compounds of formula III by means of known reactions, such as formulation or conversion of the alcoholic group into a thiol.
Forbindelser med generell formel V fremstilles fra forbindelser med generell formel X Compounds of general formula V are prepared from compounds of general formula X
(P, P,,, X, m og Ra er som definert ovenfor) ved Knoevenagel kondensasjon med et aldehyd med formel XI (P, P,,, X, m and Ra are as defined above) by Knoevenagel condensation with an aldehyde of formula XI
(R2 er som definert ovenfor) (R2 is as defined above)
mens forbindelser med formel VII fremstilles fra forbindelser med formel X ved omsetning med ammoniakk eller et ammoniumsalt. while compounds of formula VII are prepared from compounds of formula X by reaction with ammonia or an ammonium salt.
Forbindelser med formel X fremstilles f.eks. via tio-foretringsreaksjon av forbindelser med formel III med 4-klor-3-okso-butansyre. Compounds of formula X are prepared, e.g. via thio etherification reaction of compounds of formula III with 4-chloro-3-oxo-butanoic acid.
Forbindelser med generell formel IV og XI er kjente eller lett tilgjengelige. Compounds of general formulas IV and XI are known or readily available.
Noen formylaminoalkyltiometylderivater i henhold til oppfinnelsen, såsom 2-formylamino-etyltio-4-(m-nitro-fenyl) -3-karboetoksy-5-karbometoksy-6-metyl-l,4-dihydropyridin, viser spesielle egenskaper, som lav akutt toksisitet og høy tolererbarhet i noen mottakelige forsøksdyr, f.eks. hunder, kombinert med en utpreget og langvarig anti-hypertensiv aktivitet ved meget lave doser (f.eks. 0,2 mg/kg/os) når testet oralt i bevisste SH-rotter en gang daglig. Some formylaminoalkylthiomethyl derivatives according to the invention, such as 2-formylamino-ethylthio-4-(m-nitro-phenyl)-3-carboethoxy-5-carbomethoxy-6-methyl-1,4-dihydropyridine, show special properties, such as low acute toxicity and high tolerability in some susceptible laboratory animals, e.g. dogs, combined with a marked and long-lasting anti-hypertensive activity at very low doses (eg 0.2 mg/kg/os) when tested orally in conscious SH rats once daily.
Den antihypertensive effekt er doserelatert i det under-søkte doseområde, f.eks. fra 0,05 - 0,8 mg/kg. Den mak-simale hypertensive effekt, proporsjonal til den adminis-trerte dose, finner sted 5-7 timer etter administrering og blodtrykket holdes på et senket nivå i ytterligere 4-5 timer i det minste. The antihypertensive effect is dose-related in the examined dose range, e.g. from 0.05 - 0.8 mg/kg. The maximal hypertensive effect, proportional to the administered dose, takes place 5-7 hours after administration and the blood pressure is maintained at a lowered level for a further 4-5 hours at least.
Den gradvise start av den hypertensive effekt synes ikke å være koblet med reflex-tachicardia, hvilket ofte observeres etter behandling med andre antihypertensive midler, som f.eks. hydralasin og mange dihydropyridiner i de samme eksperimentelle modeller. The gradual onset of the hypertensive effect does not seem to be linked with reflex tachycardia, which is often observed after treatment with other antihypertensive agents, such as e.g. hydralazine and many dihydropyridines in the same experimental models.
I motsetning til dette observeres etter én dag oral administrering av de samme forbindelser til normotensive bevisste rotter i samme dosenivå ingen vesentlige modifi-kasjoner av gjennomsnittlig blodtrykk og hjertehastighet. In contrast, after one day of oral administration of the same compounds to normotensive conscious rats at the same dose level, no significant modifications of average blood pressure and heart rate are observed.
Etter en to ukers behandling bestående av en daglig oral administrering under anvendelse av et doseområde fra 0.1 til 0,8 mg/kg, observeres en gradvis senkning av gjennomsnittlig blodtrykk som også er doserelatert i de behand-lede bevisste SH-rotter. After a two-week treatment consisting of a daily oral administration using a dose range from 0.1 to 0.8 mg/kg, a gradual lowering of mean blood pressure is observed which is also dose-related in the treated conscious SH rats.
Doser på 0,2 - 0,4 mg/kg er tilstrekkelige for gradvis å stabilisere det gjenomsnittlige blodtrykk til et lavere nivå i en 24-timers periode. Utfallet ved den farmakolo-giske behandling kombineres ikke med en akutt hypertensiv effekt, men i de følgende 2-3 dager vil det gjennomsnittlige blodtrykk gradvis øke til de opprinnelige verdier. Doses of 0.2 - 0.4 mg/kg are sufficient to gradually stabilize the average blood pressure to a lower level over a 24-hour period. The outcome of the pharmacological treatment is not combined with an acute hypertensive effect, but in the following 2-3 days the average blood pressure will gradually increase to the original values.
En lignende farmakologisk profil deles av mange 2-amino-alkyltio-metyl-1,4-dihydropyridiner med formel III. Generelt vil de vise seg å være effektive antihypertensive midler når de testes oralt i bevisste SH-rotter og vel-tolererte i subkroniske toksikologiske studier utført på hann- og hunn-normotensive rotter, uavhengig av det fak-tum at mange av disse substanser viser lave LD50 verdier i mus når de administreres oralt eller intraperinonealt. A similar pharmacological profile is shared by many 2-amino-alkylthio-methyl-1,4-dihydropyridines of formula III. In general, they will prove to be effective antihypertensive agents when tested orally in conscious SH rats and well-tolerated in subchronic toxicological studies performed on male and female normotensive rats, regardless of the fact that many of these substances show low LD50 values in mice when administered orally or intraperinoneally.
Representative resultater av akutte toksisitetesstudier Representative results of acute toxicity studies
er oppført i tabell 1. De samme substanser testet oralt i bevisste SH-rotter (200-250 g/kroppsvekt) viser en maksi-mal senkning av det gjennomsnittlige blodtrykk på ca. 30-80 mm Hg ved 1,6 mg/kg, bortsett fra forbindelsene 1, 4, 21, 20, 31 (blodtrykket varierer fra 10 til 25 mm Hg); 2, 5, 6, 7, 10, 11, 12 (blodtrykket høyere enn 85 mm Hg), mens forbindelsen 16 d er praktisk talt inaktiv ved 3,2 mg/kg. are listed in table 1. The same substances tested orally in conscious SH rats (200-250 g/body weight) show a maximal lowering of the average blood pressure of approx. 30-80 mm Hg at 1.6 mg/kg, except for compounds 1, 4, 21, 20, 31 (blood pressure ranges from 10 to 25 mm Hg); 2, 5, 6, 7, 10, 11, 12 (blood pressure higher than 85 mm Hg), while compound 16 d is practically inactive at 3.2 mg/kg.
Imidlertid døde hunn- og hann-beaglehunder som ble testet oralt med 1,5 mg/kg/dag (bolus administrering) av forbin-deisene 11 og 15 etter tre dagers behandling. Acylering av aminogruppen i en forbindelse med formel VIII, (f.eks. 2-acetylamino eller 2-benzoylamino-deriva-tene til forbindelsene 11 og 15) reduserer den akutte toksisitet i mus, men generelt går den langvarige antihypertensive virkning tapt i SH-rotter og forbindelsene krever nesten to administreringer daglig for å stabilisere de gjennomsnittlige blodtrykksverdier til lavere nivå-er i 24 timers perioder. Overraskende viser 2-formylamino-alkyl-tio-metyl-1,4-dihydropyridin-derivatene i henhold til foreliggende oppfinnelse ikke bare langvarig hypertensiv effekt og lavere akutt toksisitet (f.eks. 2-formyl-amino-etyltio-metyl-4- (m-nitrofenyl) -3-karbo-etoksy-5-karboetoksy-4-m-niitrofenyl-6-metyl-l,4-dihydropyridin viser LD50 i mus på henholdsvis 200 og 150 mg/kg oralt og i.p.), men er veltolerert i hunder. Hann- og hunn-beaglehunder ble behandlet oralt med sistnevnte substans i henhold til oppfinnelsen i doser i en høyde på 5-12,5 mg/kg/dag (bolus administrering) og døde ikke etter to ukers behandling. However, female and male beagle dogs tested orally with 1.5 mg/kg/day (bolus administration) of compounds 11 and 15 died after three days of treatment. Acylation of the amino group in a compound of formula VIII, (e.g. 2-acetylamino or 2-benzoylamino derivatives of compounds 11 and 15) reduces the acute toxicity in mice, but in general the long-term antihypertensive effect is lost in SH- rats and the compounds require nearly two administrations daily to stabilize the mean blood pressure values to lower levels over 24 hour periods. Surprisingly, the 2-formylamino-alkyl-thio-methyl-1,4-dihydropyridine derivatives according to the present invention not only show a long-term hypertensive effect and lower acute toxicity (e.g. 2-formyl-amino-ethylthio-methyl-4- (m-nitrophenyl)-3-carbo-ethoxy-5-carboethoxy-4-m-nitrophenyl-6-methyl-1,4-dihydropyridine shows LD50 in mice of 200 and 150 mg/kg orally and i.p. respectively), but is well tolerated in dogs. Male and female beagle dogs were treated orally with the latter substance according to the invention in doses as high as 5-12.5 mg/kg/day (bolus administration) and did not die after two weeks of treatment.
Etter N-formulering av aminofunksjnen i sidekjeden på forbindelsen med formel VIII i tabell 1, observeres en 5 til 12 ganger lavere akutt toksisitet i mus. For eksempel øker N-formulering av forbindelse 8 LD50 i mus (oralt) fra 8 mg/kg - 90 mg/kg. After N-formulation of the amino function in the side chain of the compound of formula VIII in Table 1, a 5 to 12 times lower acute toxicity in mice is observed. For example, N formulation of compound 8 increases the LD50 in mice (oral) from 8 mg/kg - 90 mg/kg.
Videre var evnen til forbindelsene i henhold til oppfinnelsen å hemme in vitro kontraktilitetsaktiviteten indu-sert ved å øke konsentrasjonen av kalsiumioner i IC^-depol-ariserte rotteaortastrimler undersøkt i henhold til tek-nikkene fra [T. Godfraind et al. (Arch. Int. Pharmacodyn, 172. 235, 1968)]. Representative resultater av disse studier med forbindelse 11 og dens N-acetyl og N-formyl-derivater er oppført i tabell II. Furthermore, the ability of the compounds according to the invention to inhibit in vitro the contractile activity induced by increasing the concentration of calcium ions in IC₂-depolarized rat aortic strips was examined according to the techniques of [T. Godfraind et al. (Arch. Int. Pharmacodyn, 172. 235, 1968)]. Representative results of these studies with compound 11 and its N-acetyl and N-formyl derivatives are listed in Table II.
De oppførte resultater bekrefter videre at det kan observeres bedre hemmende aktiviteter (ID50 varierer fra IO"<7 >til IO'10) etter lengere inkubasjonstidsrom med de under-søkte vevpreparasjoner enn etter kortere tidsrom (ID50 varierer fra IO'<5> til IO"9) , mens aktiviteten til stan-dardforbindelsen nifedipin ikke er avhengig av inkuba- The listed results further confirm that better inhibitory activities can be observed (ID50 varies from 10'<7> to 10'10) after longer incubation periods with the examined tissue preparations than after shorter periods (ID50 varies from 10'<5> to 10 "9) , while the activity of the standard compound nifedipine does not depend on incubation
sjonstiden. tion time.
Den kortere varende antihypertensive effekt til N-acetyl-forbindelsen og den lengre varende effekt til forbindelsen 11 og til dens N-formylderivat synes ikke å stå i samsvar med in vitro eksperimentelle resultater vedrøren-de den antatte Ca-antagonistaktivitet og evne til å re-laksere glatte muskler, fenomener som ikke lett kan for-klares på basis av foreliggende kunnskaper. The shorter-lasting antihypertensive effect of the N-acetyl compound and the longer-lasting effect of compound 11 and of its N-formyl derivative do not seem to be consistent with in vitro experimental results regarding the supposed Ca-antagonist activity and ability to re- relax smooth muscles, phenomena that cannot be easily explained on the basis of current knowledge.
Uavhengig av dette aspekt gir den spesielle antihypertensive effekt, dens gradvise start, den langvarige virkning kombinert med lavere alkyltoksisitet og med øket tolererbarhet i hunder bevis for at forbindelsen i henhold til oppfinnelsen er nyttige i human- og veterinærmedisinsk terapi til behandling av hypertensive situasjoner av ulik opprinnelse og for behandling og forebyggelse av kardio-vaskulære og koronærsykdommer. Regardless of this aspect, the special antihypertensive effect, its gradual onset, the prolonged action combined with lower alkyl toxicity and with increased tolerability in dogs provide evidence that the compound according to the invention is useful in human and veterinary medical therapy for the treatment of hypertensive situations of various origin and for the treatment and prevention of cardio-vascular and coronary diseases.
For å oppnå de ønskede virkninger i human- og veterinærmedisinsk terapi kan forbindelsene i henhold til opppfin-nelsen administreres parenteralt, f.eks. ved intravenøs, hypodermisk, intramuskulær injeksjon, ved infusjon, rek-talt eller oralt. Forbindelsene kan også administreres i ren form eller i form av en farmasøytisk blanding. In order to achieve the desired effects in human and veterinary medical therapy, the compounds according to the invention can be administered parenterally, e.g. by intravenous, hypodermic, intramuscular injection, by infusion, rectally or orally. The compounds can also be administered in pure form or in the form of a pharmaceutical mixture.
Formulering av egnede farmasøytiske blandinger kan fremstilles i henhold til teknikker som er velkjente i faget, så som beskrevet i ["Remington<1>s Pharmaceutical Science Handbook", Hack Publishing Co., U.S.A.]. Formulation of suitable pharmaceutical compositions can be prepared according to techniques well known in the art, such as described in ["Remington<1>'s Pharmaceutical Science Handbook", Hack Publishing Co., U.S.A.].
Når forbindelsene i henhold til oppfinnelsen anvendes som antihypertensive medikamenter, vil doseringen variere i forhold til styrken av hypertensjonen og av administre-rings-måten. When the compounds according to the invention are used as antihypertensive drugs, the dosage will vary in relation to the strength of the hypertension and the method of administration.
Oppfinnelsen illustreres ved de følgende eksempler, hvori forkortelsene EtOH, DME, MeOH, THF, Et20, AcOEt, AcOH betyr etanol, dimetoksyetan, metanol, tetrahydrofuran, etyleter, etylacetat og eddiksyre. The invention is illustrated by the following examples, in which the abbreviations EtOH, DME, MeOH, THF, Et2O, AcOEt, AcOH mean ethanol, dimethoxyethane, methanol, tetrahydrofuran, ethyl ether, ethyl acetate and acetic acid.
Fremstilling 1 Production 1
En rørt oppløsning av cysteaminhydroklorid (20 g) i formamid (20 ml) oppvarmes til 75-80°C i 2 timer. Etter av-kjøling til romtemperatur filtreres NH4Cl-utfellingen og vaskes med litt formamid. Oppløsningen av N-formylcyste-amin (ca 18 g) i formamid fortynnes deretter med EtOH (160 ml), avkjøles til o°C og behandles i en nitrogen-atmosfære ved omrøring med 20% vandig NaOH (170 ml) og med en oppløsning av etyl-4-klor-3-okso-butanoat (28,4 g) 1 EtOH (20 ml). Etter 30 minutter helles blandingen på vann (2000 ml) og ekstraheres med AcOEt (3x200 ml). De samlede ekstrakter vaskes med en mettet oppløsning av Na<H>2P04 (3x50 ml) H20 (3x100 ml) , tørkes med Na2S04 og fordampes til tørrhet i vakuum for å gi 40,5 g etyl-4-(2-formylaminoetyoltio)-3-okso-butanoat som en olje. A stirred solution of cysteamine hydrochloride (20 g) in formamide (20 ml) is heated to 75-80°C for 2 hours. After cooling to room temperature, the NH4Cl precipitate is filtered and washed with a little formamide. The solution of N-formyl cysteamine (about 18 g) in formamide is then diluted with EtOH (160 ml), cooled to o°C and treated in a nitrogen atmosphere by stirring with 20% aqueous NaOH (170 ml) and with a solution of ethyl 4-chloro-3-oxo-butanoate (28.4 g) 1 EtOH (20 ml). After 30 minutes, the mixture is poured onto water (2000 ml) and extracted with AcOEt (3x200 ml). The combined extracts are washed with a sat. 3-oxo-butanoate as an oil.
1H-NMR (CDC13) , 6(TMS) : 1,10-1,30 (3H, t) ; 2,20-2,60 (4H, m) ; 3,40-4,10 (6H, m) ; 6,60 (iH, ut); 8,10 (1H, S) . 1 H-NMR (CDCl 3 ), δ(TMS): 1.10-1.30 (3H, t); 2.20-2.60 (4H, m); 3.40-4.10 (6H, m); 6.60 (inH, out); 8.10 (1H, S).
Under anvendelse av den samme fremgangsmåte og metyl-4-klor-3-oksobutanoat og metoksyetyl-4-klor-3-oksobutanoat ble det fremstilt metyl-4-(2-formylaminoetyltio)-3-okso-butanoat og metoksyetyl-4-(2-formylaminoetyltio)-3-okso-butanoat . Using the same procedure and methyl-4-chloro-3-oxobutanoate and methoxyethyl-4-chloro-3-oxobutanoate, methyl 4-(2-formylaminoethylthio)-3-oxo-butanoate and methoxyethyl-4-( 2-Formylaminoethylthio)-3-oxo-butanoate.
Fremstilling 2 Manufacturing 2
Eddiksyre tilsettes til en oppløsning av etyl-4-(2-formylamino-etyltio)-3-okso-butanoat (12,5 g) i MeOH (120 ml), forut mettet med ammoniakk ved 0°C og avkjølt til o°C, opp til pH 4-4,5. Blandingen kokes ved tilbakeløp i 2 timer og overskuddet av oppløsingsmidlet fordampes i vakuum for å gi en sirup fra hvilken et fast materale adskilles ved behandling med AcOEt. Etter filtrering vaskes den organiske fase med vann (8x10 ml) og med en mettet vandig oppløsning av NaHC03 (3x10 ml), tørkes (Na2S04) og fordampes i vakuum for å gi 11,5 g av etyl-3-amino-4-(2-formylammino-etyltio) krotonat som en gul olje. Acetic acid is added to a solution of ethyl 4-(2-formylamino-ethylthio)-3-oxo-butanoate (12.5 g) in MeOH (120 ml), previously saturated with ammonia at 0°C and cooled to o°C , up to pH 4-4.5. The mixture is refluxed for 2 hours and the excess solvent is evaporated in vacuo to give a syrup from which a solid material is separated by treatment with AcOEt. After filtration, the organic phase is washed with water (8 x 10 ml) and with a saturated aqueous solution of NaHCO 3 (3 x 10 ml), dried (Na 2 SO 4 ) and evaporated in vacuo to give 11.5 g of ethyl 3-amino-4-( 2-Formylamino-ethylthio) crotonate as a yellow oil.
1H-NMR: (CDC13) , 6(TMS): 1,10-1,20(3H,t); 1 H-NMR: (CDCl 3 ), δ(TMS): 1.10-1.20(3H,t);
2,20-2,60 (4H, m) ; 3,80-4,10 (4H, m) ; 5,20-5,40 (2H, m) ; 2.20-2.60 (4H, m); 3.80-4.10 (4H, m); 5.20-5.40 (2H, m);
5,70 (1H, m); 6,60 (1H, m); 8,10 (1H, s); Metyl-3-amino-4-(2-formylaminoetyltio)-krotonat og metoksyetyl-3-amino-4-(2-formylaminoetyltio)-krotonat fremstilles på lignende måte. 5.70 (1H, m); 6.60 (1H, m); 8.10 (1H, s); Methyl 3-amino-4-(2-formylaminoethylthio)crotonate and methoxyethyl 3-amino-4-(2-formylaminoethylthio)crotonate are prepared in a similar manner.
Fremstilling 3 Manufacturing 3
En oppløsning av 3-klorbenzaldehyd (10 g), etyl-4-(2-formylaminoetyltio)-3-okso-butanoat (16,7 g), AcOH ( ml) og piperidin (0,6 ml) i benzen (120 ml) kokes ved til-bakeløp i et Dean-Stark-apparat i 6 timer. Etter avkjø-ling ved romtemperatur vaskes blandingen med vann (3x20 ml) , med en mettet oppløsning av NaHC03 (3x10 ml) , med en oppløsning av H2S04 (2N, 3x10 ml) og igjen med vann (3x30 ml). Den organiske fase tørkes (Na2S04) og konsentreres i vakuum for å gi 16 g etyl 2-Z, E-(3-klorfenylmetylen)-4-(2-formylamino-etyltio)-3-okso-butanoat, som en olje. A solution of 3-chlorobenzaldehyde (10 g), ethyl 4-(2-formylaminoethylthio)-3-oxo-butanoate (16.7 g), AcOH (ml) and piperidine (0.6 ml) in benzene (120 ml ) is refluxed in a Dean-Stark apparatus for 6 hours. After cooling at room temperature, the mixture is washed with water (3x20 ml), with a saturated solution of NaHCO 3 (3x10 ml), with a solution of H 2 SO 4 (2N, 3x10 ml) and again with water (3x30 ml). The organic phase is dried (Na 2 SO 4 ) and concentrated in vacuo to give 16 g of ethyl 2-Z,E-(3-chlorophenylmethylene)-4-(2-formylamino-ethylthio)-3-oxo-butanoate as an oil.
1H-NMR(CDC13) , 5 (TMS), 1,1-1,2. (3H, t) ; 2,2-2,4 (2H,t); 2,7-3,0 (2H, m); 8,9-4,2 (4H, m); 6,8-7,9 (7H, m). 1 H-NMR (CDCl 3 ), δ (TMS), 1.1-1.2. (3H, t) ; 2.2-2.4 (2H,t); 2.7-3.0 (2H, m); 8.9-4.2 (4H, m); 6.8-7.9 (7H, m).
Eksempel 1 Example 1
En oppløsning av etyl-3-amino-4-(2-formylamino-etyltio) krotonat (5,3 g) og 3-Z, E-(m-nitrofenylmetylen-2,4-pentandio (4,9 g; fra Knoevenagel kondensasjon av 3-nitrobenzaldehyd med 2,4-pentandion) i EtOH (100 ml) kokes under tilbakeløp i 4 timer, avkjøles ved 0°C og gjøres surt (pH 1:2) med noen få dråper EtOH mettet med HC1 i gassform. Etter 15 minutter fordampes oppløsningen ved redusert trykk, resten oppløses i AcOEt (80 ml), vaskes med en mettet oppløsning av NaHC03 (3x15 ml), med vann (3x30 ml), tørkes (Na2S04) og konsentreres. Resten renses ved kromatografi på Si02 (300 g, eluent AcOEt/MeOH 80/20) for å gi 4,9 g av 2-(2-formylaminoetyltio)-metyl-1,4-dihydropyridin, smp. 140-142°C (EtOH). A solution of ethyl 3-amino-4-(2-formylamino-ethylthio)crotonate (5.3 g) and 3-Z,E-(m-nitrophenylmethylene-2,4-pentanedio) (4.9 g; from Knoevenagel condensation of 3-nitrobenzaldehyde with 2,4-pentanedione) in EtOH (100 mL) is refluxed for 4 h, cooled at 0°C and acidified (pH 1:2) with a few drops of EtOH saturated with gaseous HC1. After 15 minutes, the solution is evaporated under reduced pressure, the residue is dissolved in AcOEt (80 mL), washed with a saturated solution of NaHCO 3 (3x15 mL), with water (3x30 mL), dried (Na 2 SO 4 ) and concentrated.The residue is purified by chromatography on SiO 2 (300 g, eluent AcOEt/MeOH 80/20) to give 4.9 g of 2-(2-formylaminoethylthio)-methyl-1,4-dihydropyridine, mp 140-142°C (EtOH).
Eksempel 2 Example 2
En oppløsning av etyl 3-amino-4-(2-formylaminoetyltio)-krotonat (lg) og metyl-2-Z, E-(2-nitro-S-metyltiofenyl-metylen) -3-oksobutanoat (0,95 g, smp. 69-7, erholdt ved Knoevenagel condensasjon av metylacetoacetat og 2-nitro-5-metyltiobenzaldehyd), i EtOH (10 ml) kokes ved tilbake-løp i 24 timer og fordampes til tørrhet. Resten oppløses i Et20 (30 ml), vaskes med HC1 (2N, 3x5 ml), vann (3x10 ml), tørkes og konsentreres i vakuum. Etter kolonnekromatografi på Si02 (30 g) , eluent Et20/AcOEt (60/40) , erholdes 1,1 g av 2-(2-formylamino-etyltio)metyl-3-etoksykar-bonyl-5-metoksy-karbonyl-4-(2-nitro-5-metyltiofenyl)-6-metyl-1,4-dihydropyridin, smp. 148-150°C (Et20) . A solution of ethyl 3-amino-4-(2-formylaminoethylthio)-crotonate (1g) and methyl 2-Z,E-(2-nitro-S-methylthiophenyl-methylene)-3-oxobutanoate (0.95 g, mp 69-7, obtained by Knoevenagel condensation of methyl acetoacetate and 2-nitro-5-methylthiobenzaldehyde), in EtOH (10 ml) is refluxed for 24 hours and evaporated to dryness. The residue is dissolved in Et 2 O (30 ml), washed with HCl (2N, 3x5 ml), water (3x10 ml), dried and concentrated in vacuo. After column chromatography on SiO2 (30 g), eluent Et20/AcOEt (60/40), 1.1 g of 2-(2-formylamino-ethylthio)methyl-3-ethoxycarbonyl-5-methoxy-carbonyl-4- (2-nitro-5-methylthiophenyl)-6-methyl-1,4-dihydropyridine, m.p. 148-150°C (Et 2 O).
Ved samme fremgangsmåte som i eksempel 1 eller 2 fremstilles følgende forbindelse: 2-(2-formylaminoetyltio)metyl-3-etoksykarbonyl-5-metoksy-karbonyl-4-(2,3-diklorfenyl)-6-metyl-l,4-dihydropyridin, smp. 122-124°C, By the same procedure as in example 1 or 2, the following compound is prepared: 2-(2-formylaminoethylthio)methyl-3-ethoxycarbonyl-5-methoxycarbonyl-4-(2,3-dichlorophenyl)-6-methyl-1,4- dihydropyridine, m.p. 122-124°C,
Eksempel 3 Example 3
En oppløsning av etyl-3-amino-4-(2-formylamino-etyltio)-krotonat (7 g) og metyl-2-E,Z-(3-nitro-fenylmetylen)-3-oksobutanoat (6 g) i ETOH (70 ml) kokes under tilbakeløp i 18 timer, of konsentreres i vakuum. Resten oppløses i AcOEt (100 ml), vaskes med HCL (2N, 3x30 ml), H20 (3x50 ml), tørkes på Na2S04, konsentreres i vakuum og renses ved kolonnekromatografi over Si02 (3 00 g, eluent AcOEt-heksan 90/10). Det erholdes 8 g av 2-(2-formylaminoetyltio)-metyl-3-etoksykarbonyl-5-metooksykarbonyl-4-(m-nitro-fenyl) -6-metyl-l, 4-dihydropyridin, smp. 109-111°C. A solution of ethyl 3-amino-4-(2-formylamino-ethylthio)-crotonate (7 g) and methyl 2-E,Z-(3-nitro-phenylmethylene)-3-oxobutanoate (6 g) in ETOH (70 ml) is boiled under reflux for 18 hours, or concentrated in vacuo. The residue is dissolved in AcOEt (100 ml), washed with HCL (2N, 3 x 30 ml), H 2 O (3 x 50 ml), dried over Na 2 SO 4 , concentrated in vacuo and purified by column chromatography over SiO 2 (3 00 g, eluent AcOEt-hexane 90/10 ). 8 g of 2-(2-formylaminoethylthio)-methyl-3-ethoxycarbonyl-5-methoxycarbonyl-4-(m-nitro-phenyl)-6-methyl-1,4-dihydropyridine are obtained, m.p. 109-111°C.
Eksempel 4 Example 4
En oppløsning av etyl-2-Z,E-(3-klorfenylmetylen)-4-(2-formyllaminoetyltio)-3-okso-butanoat (4 g) og metyl 3-amino-krotonat (1,2 g) i EtOH (40ml) kokes under tilbake-løp i 3 timer, blandingen avkjøles ved romtemperatur, surgjøres til pH 1:2 med noen få dråper EtOH mettet med gassformig HC1, og etter 20 minutter fordampes den til tørrhet. En oppløsning av resten i AcOEt (60 ml) vaskes med en mettet NaHC03 oppløsning (3x10 ml) , med H20 (3x20 ml), tørkes (Na2S04) og konsentreres i vakuum. Etter kromatografi over silikagel (150 g, eluent AcOEt) erholdes 4,3 g 2-(2-formylaminoetyltio)metyl-3-etoksykarbonyl-4-(3-klorfenyl)5-metoksykarbonyl-6-metyl-l,4-dihydropyridin som et skum. A solution of ethyl 2-Z,E-(3-chlorophenylmethylene)-4-(2-formylaminoethylthio)-3-oxo-butanoate (4 g) and methyl 3-amino-crotonate (1.2 g) in EtOH ( 40ml) is refluxed for 3 hours, the mixture is cooled at room temperature, acidified to pH 1:2 with a few drops of EtOH saturated with gaseous HCl, and after 20 minutes it is evaporated to dryness. A solution of the residue in AcOEt (60 ml) is washed with a saturated NaHCO 3 solution (3x10 ml), with H 2 O (3x20 ml), dried (Na 2 SO 4 ) and concentrated in vacuo. After chromatography over silica gel (150 g, eluent AcOEt), 4.3 g of 2-(2-formylaminoethylthio)methyl-3-ethoxycarbonyl-4-(3-chlorophenyl)5-methoxycarbonyl-6-methyl-1,4-dihydropyridine are obtained as a foam.
1H-NMR (CDC13) : 6 (TMS) = 1,10-1,25 (3H, t) ; 1 H-NMR (CDCl 3 ): δ (TMS) = 1.10-1.25 (3H, t);
2,20-2,80 (5H, m); 3,20-3,70 (5H, m); 2.20-2.80 (5H, m); 3.20-3.70 (5H, m);
3,80-4,20 (4H, m); 5,00 (1H, s); 6,50 (1H, m); 7,00-7,20 (5H, m); 8,10 (1H, s). 3.80-4.20 (4H, m); 5.00 (1H, p); 6.50 (1H, m); 7.00-7.20 (5H, m); 8.10 (1H, p).
Ved å bruke den ovenfor beskrevne fremgangsmåte fremstilles følgende forbindelse: 2-(2-formyamnoetyltio)metyl-3-etoksykarbonyl-5-metoksy-karbonyl-4-(m-nitrofenyl)-6-metyl-l,4-dihydropyridin, smp. 109-111°C. By using the method described above, the following compound is prepared: 2-(2-formyamnoethylthio)methyl-3-ethoxycarbonyl-5-methoxycarbonyl-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine, m.p. 109-111°C.
Eksempel 5 Example 5
En rørt blanding av 2-merkaptometyl-3-etoksykarbonyl-5-metoksykarbonyl-4(m-nitrofenyl)-6-metyl-l,4-dihydropyridin (5 g), K2C03 (2 g) og (S)-2-formylamino-2-fenyl-etanolmetan-sulfonat (3 g fra S (+)-N-formylfenylglycin) A stirred mixture of 2-mercaptomethyl-3-ethoxycarbonyl-5-methoxycarbonyl-4(m-nitrophenyl)-6-methyl-1,4-dihydropyridine (5 g), K 2 CO 3 (2 g) and (S)-2-formylamino -2-Phenyl-ethanolmethane-sulfonate (3 g from S (+)-N-formylphenylglycine)
i DMAF (50 ml) oppvarmes ved 50°C i 12 timer. Den avkjøl-te blanding helles i isvann (500 ml) og ekstraheres med AcOEt (30 ml x 3). Etter vanlig fremgangsmåte blir de organiske ekstrakter fordampet til tørrhet, og det erholdes en diastereoisomer blanding av 4 (S)2'(S) og 4(R)2-<1>(S)-2-(2<1->formylamino-2<1->fenyletyltio)metyl-3-etoksykar-bonyl-5-metoksykarbonyl-4-(m-nitrofenyl)-6-metyl-l,4-dihydropyridin, som separeres ved HPL-kromatografi over Si02 (eluent AcOEt/heksan). De mer polære diastereoisomere (1,7 g) er skumformede, de mindre polære erholdes som en krystallinsk forbindelse (2,2 g, smp. 66-70°C, C7<H>29<N>3<0>7<S>.-2/3Et20) . in DMAF (50 ml) is heated at 50°C for 12 hours. The cooled mixture is poured into ice water (500 ml) and extracted with AcOEt (30 ml x 3). According to the usual method, the organic extracts are evaporated to dryness, and a diastereoisomeric mixture of 4 (S)2'(S) and 4(R)2-<1>(S)-2-(2<1->formylamino) is obtained -2<1->phenylethylthio)methyl-3-ethoxycarbonyl-5-methoxycarbonyl-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine, which is separated by HPL chromatography over SiO2 (eluent AcOEt/ hexane). The more polar diastereoisomers (1.7 g) are foamy, the less polar are obtained as a crystalline compound (2.2 g, m.p. 66-70°C, C7<H>29<N>3<0>7<S >.-2/3Et20) .
Ved å anvende den ovenfor beskrevne fremgangsmåte fremstilles de følgende forbindelse: 2-(2-formylaminoetyltio)metyl-3-etoksykarbonyl-5-metoksy-karbonyl-4-(m-nitrofenyl-6-metyl-l,4-dihydropyridin, By using the method described above, the following compound is prepared: 2-(2-formylaminoethylthio)methyl-3-ethoxycarbonyl-5-methoxycarbonyl-4-(m-nitrophenyl-6-methyl-1,4-dihydropyridine,
smp. 109-lll<o>C. m.p. 109-lll<o>C.
Eksempel 6 Example 6
En oppløsning av 2-klormetyl-3-etoksykarbonyl-4-(o-met-yltiofenyl)-5-metoksykarbonyl-6-metyl-l,4-dihydropyridin (2,1 g) i EtOH (10 ml) tilsettetes dråpevis ved 0°C til en oppløsning av N-n-butyl-N-(2-acetyltioetyl)formamid (1,2 g) og NaOH (20% vannoppløsning, 1,2 g). Etter 3 timer ved 0°C oppvarmes reaksjonsblandingen ved romtemperatur og røres i 30 minutter og konsentreres i vakuum. Etter tidligere nevnte fremgangsmåte og kolonnekromatografi over Si02 (80 g, eluent AcOEt/Et20 70/90) erholdes 1,8 g av 2/2-(N-formyl-N-butylamino)etyltio/metyl-3-et-oksykarbonyl-4-(o-metyltiofenyl)-5-metoksykarbonyl-6-metyl-1,4-dihydropyridin som et skum. A solution of 2-chloromethyl-3-ethoxycarbonyl-4-(o-methylthiophenyl)-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (2.1 g) in EtOH (10 mL) was added dropwise at 0 °C to a solution of N-n-butyl-N-(2-acetylthioethyl)formamide (1.2 g) and NaOH (20% aqueous solution, 1.2 g). After 3 hours at 0°C, the reaction mixture is heated at room temperature and stirred for 30 minutes and concentrated in vacuo. Following the previously mentioned procedure and column chromatography over SiO2 (80 g, eluent AcOEt/Et2O 70/90) 1.8 g of 2/2-(N-formyl-N-butylamino)ethylthio/methyl-3-ethoxycarbonyl-4 is obtained -(o-methylthiophenyl)-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine as a foam.
<1>H-NMR (CDC13) : (TMS) 0,1-1,3 (6H, m) ; 1,5-2,0 (4H, m) ; <1>H-NMR (CDCl 3 ) : (TMS) 0.1-1.3 (6H, m) ; 1.5-2.0 (4H, m);
2,1-3,0 (10H, m); 3,20-4,20 (8H, m) ; 5,10 (1H, s); 6,8 (1H, m);; 6,9-7,4 (6H, m) ; 8,1 (1H, s). 2.1-3.0 (10H, m); 3.20-4.20 (8H, m); 5.10 (1H, s); 6.8 (1H, m);; 6.9-7.4 (6H, m); 8.1 (1H, p).
Ved å anvende den ovenfor beskrevne fremgangsmåte fremstilles de følgende forbindelser: 2-(2-formylaminoetyltio)metyl-3-etoksykarbonyl-5-metoksy-karbonyl-4-(m-nitrofenyl)-6-metyl-l,4-dihydropyridin, smp. 109-111°C By applying the method described above, the following compounds are prepared: 2-(2-formylaminoethylthio)methyl-3-ethoxycarbonyl-5-methoxycarbonyl-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine, m.p. . 109-111°C
2-(2-formylaminoetyltio)metyl-3-etoksykarbonyl-4-[benzo-(2,3-b)-1,4-dioksan-a-yl]-5-metoksykarbonyll-6-metyl-l,4-dihydropyridin, 2-(2-Formylaminoethylthio)methyl-3-ethoxycarbonyl-4-[benzo-(2,3-b)-1,4-dioxan-a-yl]-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine ,
2-(2-formylaminoetyltio)metyl-3-etoksykarbonyl-5-(2-N-metyl-N-benzylamino)etoksykarbonyl-4-(m-nitrofenyl)-6-metyl-1,4-dihydropyridin. 2-(2-Formylaminoethylthio)methyl-3-ethoxycarbonyl-5-(2-N-methyl-N-benzylamino)ethoxycarbonyl-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine.
Eksempel 7 Example 7
En oppløsning av 2-(2-aminoetyltio)metyl-3-etoksykarbon-yl-5-metoksykarbonyl-4-(2-klorfenyl)-6-metyl-l,4-dihydropyridin (4,4 g) i THF (44 ml) tilsettes til en rørt opp-løsning av N-formylimidazol, fremstilt in situ fra maursyre (0,6 ml) og N,N-karbonyldiimidazol (2,5 g) i THF (25 ml) ved 0°C. A solution of 2-(2-aminoethylthio)methyl-3-ethoxycarbonyl-yl-5-methoxycarbonyl-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine (4.4 g) in THF (44 mL ) is added to a stirred solution of N-formylimidazole, prepared in situ from formic acid (0.6 ml) and N,N-carbonyldiimidazole (2.5 g) in THF (25 ml) at 0°C.
Etter 30 minutter helles reaksjonsblandingen i isvann (2/1, 500 ml), ekstraheres med AcOEt (3x50 ml). De samlede ekstrakter vaskes med en mettet oppløsning av NaH2P04 (3x10 ml), en mettet oppløsning av NaHC03 (3xl0ml) og så med H20 (3x50 ml) , tørkes (Na2S04) og konsentreres i vakuum. After 30 minutes, the reaction mixture is poured into ice water (2/1, 500 ml), extracted with AcOEt (3x50 ml). The combined extracts are washed with a saturated solution of NaH 2 PO 4 (3x10 ml), a saturated solution of NaHCO 3 (3x10 ml) and then with H 2 O (3x50 ml), dried (Na 2 SO 4 ) and concentrated in vacuo.
3,7 g av 2-(2-formylaminoetyltio)metyl-3-etoksykarbonyl-5-karbometoksy-4-(2-klorfenyl)-6-metyl-l,4-dihydropyridin erholdes fra Et20. 3.7 g of 2-(2-formylaminoethylthio)methyl-3-ethoxycarbonyl-5-carbomethoxy-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine are obtained from Et 2 O.
Eksempel 8 Example 8
En oppløsning av 2-/2-[N-(2-cyanoetyl)aminoetyl]-tio/- metyl-3-etoksykarbonyl-5-metoksykarbonyl-4-(m-nitro-fenyl) -6-metyl-l, 4-dihydropyridin (5,8 g) i N,N-dinetyl-formamid (100 ml) og maursyre (100 ml) varmes ved 100 °C i 6 timer, helles så i isvann (500 ml), ekstraheres med Et20 (3x50 ml). De samlede organiske ekstrakter vaskes med en mettet oppløsning av NaHC03 (3x 3 0 ml) , H20 (3 x 20 ml), tørkes (Na2S04) og fordampes til tørrhet. Resten krystalliseres fra EtOH for å gi 4,15 g av 2-[2-N-(2-cyanoetyl)-N-formylaminoetyltio]metyl-3-etoksykarbonyl-5-metoksykarbonyl-4-(m-nitrofenyl)-6-metyl-l,4-dihydropyridin, smp. 110-112"C. A solution of 2-/2-[N-(2-cyanoethyl)aminoethyl]-thio/- methyl-3-ethoxycarbonyl-5-methoxycarbonyl-4-(m-nitro-phenyl)-6-methyl-1,4- dihydropyridine (5.8 g) in N,N-dinethylformamide (100 ml) and formic acid (100 ml) is heated at 100 °C for 6 hours, then poured into ice water (500 ml), extracted with Et2O (3x50 ml) . The combined organic extracts are washed with a saturated solution of NaHCO 3 (3 x 30 ml), H 2 O (3 x 20 ml), dried (Na 2 SO 4 ) and evaporated to dryness. The residue is crystallized from EtOH to give 4.15 g of 2-[2-N-(2-cyanoethyl)-N-formylaminoethylthio]methyl-3-ethoxycarbonyl-5-methoxycarbonyl-4-(m-nitrophenyl)-6-methyl -1,4-dihydropyridine, m.p. 110-112"C.
Eksempel 9 Example 9
En oppløsning av m-klorperbenzosyre (1.3 g, 1 ekviv. mol) i 1,2-dikloretan (15 ml) tilsettes ved -10°C til en opp-løsning av 2-(2-formylaminoetyltio)metyl-3-etoksykar-bonyl-5-metoksykarbonyl-4-(m-nitro-fenyl)-6-metyl-l,4-dihydropyridin (3,5 g) i 1,2-dikloretan (30 ml). A solution of m-chloroperbenzoic acid (1.3 g, 1 equiv. mol) in 1,2-dichloroethane (15 ml) is added at -10°C to a solution of 2-(2-formylaminoethylthio)methyl-3-ethoxycar- bonyl-5-methoxycarbonyl-4-(m-nitro-phenyl)-6-methyl-1,4-dihydropyridine (3.5 g) in 1,2-dichloroethane (30 ml).
Etter 30 minutter filtreres oppløsningen, vaskes med Na2S203 (5% vannløsning), 3x5 ml), NaHC03 (mettet vannløs-ning, 3x10 ml) , H20 (3x10 ml) , tørkes (Na2S04) og fordampes i vakuum for å gi 3,4 g av 2-(2-formylaminoetylsul-finyl)metyl-3-etoksykarbonyl-5-metoksykarbonyl-4-(m-nit-rofenyl) -6-metyl-l, 4-dihhydropyridin som skum. After 30 minutes, the solution is filtered, washed with Na2S2O3 (5% aqueous solution, 3x5 ml), NaHCO3 (saturated aqueous solution, 3x10 ml), H2O (3x10 ml), dried (Na2SO4) and evaporated in vacuo to give 3.4 g of 2-(2-formylaminoethylsulfinyl)methyl-3-ethoxycarbonyl-5-methoxycarbonyl-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine as foam.
1H-NMR (CDC13 6 (TMS) : 1.00-1,2 (3H, t) ; 1H-NMR (CDCl 3 6 (TMS) : 1.00-1.2 (3H, t) );
2,1 (3H, t); 2,80-3,70 (4H, m); 3,90-4,30 (4H, m); 5,10 (1H, m); 6,50 (1H, m); 7,10-8,20 (6H, m). 2.1 (3H, t); 2.80-3.70 (4H, m); 3.90-4.30 (4H, m); 5.10 (1H, m); 6.50 (1H, m); 7.10-8.20 (6H, m).
Eksempel 10 Example 10
En oppløsning av m-klorperbenzosyre (3,8 g, ekviv. mol) i MeOH (30 ml) tilsettes ved 10°C til en oppløsning av 2-(2-aminoetyltio)metyl-3-etoksykarbonyl-5-metoksykar-bonyl-4-(m-nitrofenyl)-6-metyl-l,4-dihydropyridin (5 g) i MeOH (100 ml). Blandingen varmes ved 15-20°C og røres i 10 minutter. Oppløsningen fordampes så ved redusert trykk, og resten fordeles mellom CH2C12 (80 ml) og H20 (30 ml) , den organiske fase vaskes med natriumtiosulfat (5% vannløsning) og behandles så videre som beskrevet i eksempel 8 for å gi 4,8 g av 2-(2-aminoetyl-sulfonyl)-metyl-3-etoksykarbonyl-5-metoksykarbonyl-4-(m-nitro-fenyl) -6-metyl-l, 4-dihydropyridin som et amorft fast-stoff. A solution of m-chloroperbenzoic acid (3.8 g, equiv. mol) in MeOH (30 ml) is added at 10°C to a solution of 2-(2-aminoethylthio)methyl-3-ethoxycarbonyl-5-methoxycarbonyl- 4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine (5 g) in MeOH (100 mL). The mixture is heated at 15-20°C and stirred for 10 minutes. The solution is then evaporated under reduced pressure, and the residue is distributed between CH2C12 (80 ml) and H20 (30 ml), the organic phase is washed with sodium thiosulphate (5% aqueous solution) and further treated as described in Example 8 to give 4.8 g of 2-(2-aminoethyl-sulfonyl)-methyl-3-ethoxycarbonyl-5-methoxycarbonyl-4-(m-nitro-phenyl)-6-methyl-1,4-dihydropyridine as an amorphous solid.
1H-NMR (CDC13) 8 (TMS) 1,0-1,2 (3H, t) ; 1 H-NMR (CDCl 3 ) δ (TMS) 1.0-1.2 (3H, t);
2,1 (3H, t); 3,0-3,7 (4H, m), 4,10-4,30 (4H, m) ; 2.1 (3H, t); 3.0-3.7 (4H, m), 4.10-4.30 (4H, m);
5,1 (1H, m); 6,8 (1H, m) 7,10-8,20 (6H, m) . 5.1 (1H, m); 6.8 (1H, m) 7.10-8.20 (6H, m) .
Eksempel 11 Example 11
Fraksjonert krystallisering av (+)2-(2-ammonium-metyltio)metyl-3-etoksykarbonyl-5-metoksykarbonyl-4-(m-nitro-fenyl) -6-metyl-l, 4-dihydropyridin salt med (+) og (-)kam-fer-10-sulfonsyrer fra EtOH gir to optiske isomerer: (+)fri base [a]D = +1,8 (MeOH c = 10%) som (+) emif imarat-salt, smp. 105-107°C, [cc]D = 3,6 (MeOOH c = 9,7%) og (-) fri base, [cc]D = -1,7 (MeOH c = 19,8%), som emifumarat-salt, smp. 106-108-C, [a]D = 3,4 (MeOH c = 9,4%). Fractional crystallization of (+)2-(2-ammonium-methylthio)methyl-3-ethoxycarbonyl-5-methoxycarbonyl-4-(m-nitro-phenyl)-6-methyl-1,4-dihydropyridine salt with (+) and (-)camphor-10-sulfonic acids from EtOH give two optical isomers: (+)free base [a]D = +1.8 (MeOH c = 10%) as (+) emimimarate salt, m.p. 105-107°C, [cc]D = 3.6 (MeOOH c = 9.7%) and (-) free base, [cc]D = -1.7 (MeOH c = 19.8%), which emifumarate salt, m.p. 106-108-C, [α]D = 3.4 (MeOH c = 9.4%).
Ved å starte med de rene enantiomereer som frie baser, og ved å følge fremgangsmåtene beskrevet i eksemplene 7 og 8, erholdes de enantiomere 2-(2-formylaminometyltio)-metyl-3-etoksykarbony1-5-metoksykarbony1-4-(m-nitro-fenyl) -6-metyl-l, 4-dihydropyridiner som amorfe faststof-fer. By starting with the pure enantiomers as free bases, and by following the procedures described in examples 7 and 8, the enantiomers 2-(2-formylaminomethylthio)-methyl-3-ethoxycarbonyl1-5-methoxycarbonyl1-4-(m-nitro) are obtained -phenyl)-6-methyl-1,4-dihydropyridines as amorphous solids.
(+)N-formylamino-isomer: C21<H>35<N>307S. 1/2 H20 (+)N-formylamino isomer: C21<H>35<N>307S. 1/2 H2O
[a]D = +13,6, [a]546 = +22,2 (MeOH, c = 2,14) [a]D = +13.6, [a]546 = +22.2 (MeOH, c = 2.14)
(-)N-formylamino-isomer: C21<H>35<N>307S. 1/2 H20 (-)N-formylamino isomer: C21<H>35<N>307S. 1/2 H2O
[a]D = -13,7, [a]546 = -22 , 3 (MeOH, c = 2,07). [α]D = -13.7, [α]546 = -22.3 (MeOH, c = 2.07).
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT20965/86A IT1204421B (en) | 1986-06-27 | 1986-06-27 | 2- (AMINOALKYLTIO) METHYL-1,4-DIHYDROPYRIDINE, A METHOD FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| PCT/EP1987/000335 WO1988000187A1 (en) | 1986-06-27 | 1987-06-25 | 2-(aminoalkylthio)methyl-1,4-dihydropyridine, a method for the preparation thereof and pharmaceutical compositions containing them |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO880865D0 NO880865D0 (en) | 1988-02-26 |
| NO880865L NO880865L (en) | 1988-04-22 |
| NO175365B true NO175365B (en) | 1994-06-27 |
| NO175365C NO175365C (en) | 1994-10-05 |
Family
ID=26069506
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO880865A NO175365C (en) | 1986-06-27 | 1988-02-26 | Analogous Process for Preparing Therapeutically Active 2- (Aminoalkylthio) Methyl-1,4-Dihydropyridine Derivatives |
Country Status (2)
| Country | Link |
|---|---|
| DE (1) | DE3781411T2 (en) |
| NO (1) | NO175365C (en) |
-
1987
- 1987-06-25 DE DE8787904520T patent/DE3781411T2/en not_active Expired - Fee Related
-
1988
- 1988-02-26 NO NO880865A patent/NO175365C/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| NO880865L (en) | 1988-04-22 |
| DE3781411D1 (en) | 1992-10-01 |
| DE3781411T2 (en) | 1993-02-11 |
| NO175365C (en) | 1994-10-05 |
| NO880865D0 (en) | 1988-02-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0060674B1 (en) | Dihydropyridine anti-ischaemic and antihypertensive agents, processes for their production, and pharmaceutical compositions containing them | |
| DK170891B1 (en) | 1,4-dihydropyridine-3,5-dicarboxylic acid derivatives and process for their preparation as well as pharmaceutical agent containing them | |
| AU593278B2 (en) | Pharmaceutically active 2-thiomethyl-substituted-1,4- dihydropyridines | |
| FI79700B (en) | FRUIT PROCEDURE FOR FRAMSTAELLNING AV NYA, PHARMACEUTICAL FORM OF DIHYDROPYRIDINE DERIVATIVES. | |
| JPH05271078A (en) | Dihydropyridine compound | |
| JPS6131100B2 (en) | ||
| US4423052A (en) | 1,4-Dihydropyridine-3,5-dicarboxylic acid ester derivatives | |
| SU1395143A3 (en) | Method of producing derivatives of 1,6-naphthyredene in the form of racemates or enantiomers or acid-additive salts thereof | |
| NO175365B (en) | Analogous Process for Preparing Therapeutically Active 2- (Aminoalkylthio) Methyl-1,4-Dihydropyridine Derivatives | |
| SU1731049A3 (en) | Method for synthesis of symmetric ester of 4-substituted 1,4-dihydropyridine-3,5-dicarboxylic acid or its physiologically acceptable salt | |
| JPH0413679A (en) | Novel dihydropyridine derivative | |
| US5047414A (en) | 2-(aminoalkylthio)methyl-1,4-dihydropyridine, a method for the preparation thereof and pharmaceutical compositions containing them | |
| CA1267416A (en) | 1,4-dihydropyridine derivatives useful for the treatment of cardiovascular disorders | |
| AU2001247320B2 (en) | Thiepino (3,2-b) dihydropyridines and related compositions and methods | |
| HU201942B (en) | Process for producing thiqcycloalkeno(3,2-b)pyridine derivative intermediates | |
| US4782160A (en) | 1,4-dihydropyridine derivatives | |
| HU224442B1 (en) | Phenyl-substituted 1,4-dihydro-pyridine derivatives, process for producing thereof and pharmaceutical compositions comprising them | |
| JPH0253774A (en) | 1, 4-dihydropyridine-threonine derivative | |
| IE77041B1 (en) | Dihydropyridine derivatives their preparation and their use | |
| CA2398615A1 (en) | Benzoxathiepino[3,4-b]pyridine derivatives, process for their preparation and their use as medicaments | |
| CS213378B2 (en) | Method of making the derivatives of 6-acylaminotetrahydro-1,3,5-triazin-2,4-dion | |
| CS271498B2 (en) | Method of new dihydropyridinamides production |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM1K | Lapsed by not paying the annual fees |
Free format text: LAPSED IN DECEMBER 2001 |