NO864818L - Fremgangsmaate for fremstilling av nye terapeutisk virksomme tetrahydroisokinolinderivater. - Google Patents
Fremgangsmaate for fremstilling av nye terapeutisk virksomme tetrahydroisokinolinderivater.Info
- Publication number
- NO864818L NO864818L NO864818A NO864818A NO864818L NO 864818 L NO864818 L NO 864818L NO 864818 A NO864818 A NO 864818A NO 864818 A NO864818 A NO 864818A NO 864818 L NO864818 L NO 864818L
- Authority
- NO
- Norway
- Prior art keywords
- dimethoxyphenyl
- formula
- cyano
- compound
- dimethoxy
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims description 50
- 238000000034 method Methods 0.000 title claims description 34
- 150000001875 compounds Chemical class 0.000 claims description 237
- 239000000203 mixture Substances 0.000 claims description 90
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- 150000003839 salts Chemical class 0.000 claims description 39
- -1 sulfonyloxy Chemical group 0.000 claims description 34
- 125000000217 alkyl group Chemical group 0.000 claims description 32
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 32
- 239000002253 acid Substances 0.000 claims description 31
- 238000004519 manufacturing process Methods 0.000 claims description 26
- AABJQPAMCMMSDZ-UHFFFAOYSA-N 5-(6,7-dimethoxy-2-methyl-3,4-dihydro-1h-isoquinolin-3-yl)-2-(3,4-dimethoxyphenyl)-2-propan-2-ylpentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1C(C(C)C)(C#N)CCCC1N(C)CC2=CC(OC)=C(OC)C=C2C1 AABJQPAMCMMSDZ-UHFFFAOYSA-N 0.000 claims description 25
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- 239000002585 base Substances 0.000 claims description 22
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 16
- 235000019253 formic acid Nutrition 0.000 claims description 16
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 14
- 230000003197 catalytic effect Effects 0.000 claims description 13
- 239000003054 catalyst Substances 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 10
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- 206010002383 Angina Pectoris Diseases 0.000 claims description 8
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- 229910052796 boron Inorganic materials 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 5
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- 239000012458 free base Substances 0.000 claims description 5
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 claims description 5
- 238000012546 transfer Methods 0.000 claims description 5
- 229910000510 noble metal Inorganic materials 0.000 claims description 4
- 239000002168 alkylating agent Substances 0.000 claims description 3
- 229940100198 alkylating agent Drugs 0.000 claims description 3
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 150000004673 fluoride salts Chemical class 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 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
- 238000002156 mixing Methods 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 230000002526 effect on cardiovascular system Effects 0.000 claims 2
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims 1
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- 238000006243 chemical reaction Methods 0.000 description 52
- 239000000243 solution Substances 0.000 description 51
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 37
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 35
- 239000000543 intermediate Substances 0.000 description 33
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- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 25
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
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- 239000012044 organic layer Substances 0.000 description 15
- 241000700159 Rattus Species 0.000 description 13
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 239000012267 brine Substances 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 238000002844 melting Methods 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
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- 238000002474 experimental method Methods 0.000 description 9
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- 229920006395 saturated elastomer Polymers 0.000 description 9
- 239000012279 sodium borohydride Substances 0.000 description 9
- 229910000033 sodium borohydride Inorganic materials 0.000 description 9
- GPBCUPBBPPJTHE-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5,5-diethoxy-2-propan-2-ylpentanenitrile Chemical compound CCOC(OCC)CCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 GPBCUPBBPPJTHE-UHFFFAOYSA-N 0.000 description 8
- MONXZHWLGFSZPQ-UHFFFAOYSA-N 6-amino-2,7-bis(3,4-dimethoxyphenyl)-2-propan-2-ylheptanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CC(N)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 MONXZHWLGFSZPQ-UHFFFAOYSA-N 0.000 description 8
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- QHDRKFYEGYYIIK-UHFFFAOYSA-N isovaleronitrile Chemical compound CC(C)CC#N QHDRKFYEGYYIIK-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000004571 lime Substances 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- APARFNQLJKEQHH-UHFFFAOYSA-N methyl 5-(6,7-dimethoxy-2-methyl-3,4-dihydro-1h-isoquinolin-3-yl)-2-(3,4-dimethoxyphenyl)-2-propan-2-ylpentanoate Chemical compound C1C2=CC(OC)=C(OC)C=C2CN(C)C1CCCC(C(=O)OC)(C(C)C)C1=CC=C(OC)C(OC)=C1 APARFNQLJKEQHH-UHFFFAOYSA-N 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 230000010016 myocardial function Effects 0.000 description 1
- RELJLSDJHOEOOH-UHFFFAOYSA-N n-[6-(1,3-benzodioxol-2-yl)-6-cyano-1-(3,4-dimethoxyphenyl)-7-ethylnonan-2-yl]formamide Chemical compound O1C2=CC=CC=C2OC1C(C(CC)CC)(C#N)CCCC(NC=O)CC1=CC=C(OC)C(OC)=C1 RELJLSDJHOEOOH-UHFFFAOYSA-N 0.000 description 1
- XHEGAGXUSSYWLY-UHFFFAOYSA-N n-[6-(1,3-benzodioxol-2-yl)-6-cyano-1-(3,4-dimethoxyphenyl)-7-methylnonan-2-yl]formamide Chemical compound O1C2=CC=CC=C2OC1C(C(C)CC)(C#N)CCCC(NC=O)CC1=CC=C(OC)C(OC)=C1 XHEGAGXUSSYWLY-UHFFFAOYSA-N 0.000 description 1
- NAVJQLOPQSMZHF-UHFFFAOYSA-N n-[6-(1,3-benzodioxol-2-yl)-6-cyano-1-(3,4-dimethoxyphenyl)-7-methyloctan-2-yl]formamide Chemical compound C1=C(OC)C(OC)=CC=C1CC(NC=O)CCCC(C#N)(C(C)C)C1OC2=CC=CC=C2O1 NAVJQLOPQSMZHF-UHFFFAOYSA-N 0.000 description 1
- ICBZXJQBTMCEAM-UHFFFAOYSA-N n-[6-(1,3-benzodioxol-2-yl)-6-cyano-1-(3,4-dimethoxyphenyl)heptan-2-yl]formamide Chemical compound C1=C(OC)C(OC)=CC=C1CC(NC=O)CCCC(C)(C#N)C1OC2=CC=CC=C2O1 ICBZXJQBTMCEAM-UHFFFAOYSA-N 0.000 description 1
- DSBFIXPYAIMCDY-UHFFFAOYSA-N n-[6-(1,3-benzodioxol-2-yl)-6-cyano-1-(3,4-dimethoxyphenyl)octan-2-yl]formamide Chemical compound O1C2=CC=CC=C2OC1C(CC)(C#N)CCCC(NC=O)CC1=CC=C(OC)C(OC)=C1 DSBFIXPYAIMCDY-UHFFFAOYSA-N 0.000 description 1
- ZBYYVDZPLICTES-UHFFFAOYSA-N n-[6-cyano-1,6-bis(3,4-dimethoxyphenyl)-7-ethylnonan-2-yl]formamide Chemical compound C=1C=C(OC)C(OC)=CC=1C(C(CC)CC)(C#N)CCCC(NC=O)CC1=CC=C(OC)C(OC)=C1 ZBYYVDZPLICTES-UHFFFAOYSA-N 0.000 description 1
- WOBMDQTXJBXQPS-UHFFFAOYSA-N n-[6-cyano-1,6-bis(3,4-dimethoxyphenyl)-7-methylnonan-2-yl]formamide Chemical compound C=1C=C(OC)C(OC)=CC=1C(C(C)CC)(C#N)CCCC(NC=O)CC1=CC=C(OC)C(OC)=C1 WOBMDQTXJBXQPS-UHFFFAOYSA-N 0.000 description 1
- BJVIWTAUGOQFNS-UHFFFAOYSA-N n-[6-cyano-1,6-bis(3,4-dimethoxyphenyl)octan-2-yl]formamide Chemical compound C=1C=C(OC)C(OC)=CC=1C(CC)(C#N)CCCC(NC=O)CC1=CC=C(OC)C(OC)=C1 BJVIWTAUGOQFNS-UHFFFAOYSA-N 0.000 description 1
- YXQUPYDORDPNQF-UHFFFAOYSA-N n-[6-cyano-6-(2,3-dihydro-1,4-benzodioxin-3-yl)-1-(3,4-dimethoxyphenyl)-7-ethylnonan-2-yl]formamide Chemical compound C1OC2=CC=CC=C2OC1C(C(CC)CC)(C#N)CCCC(NC=O)CC1=CC=C(OC)C(OC)=C1 YXQUPYDORDPNQF-UHFFFAOYSA-N 0.000 description 1
- XYUOWUPXVMAZSD-UHFFFAOYSA-N n-[6-cyano-6-(2,3-dihydro-1,4-benzodioxin-3-yl)-1-(3,4-dimethoxyphenyl)-7-methylnonan-2-yl]formamide Chemical compound C1OC2=CC=CC=C2OC1C(C(C)CC)(C#N)CCCC(NC=O)CC1=CC=C(OC)C(OC)=C1 XYUOWUPXVMAZSD-UHFFFAOYSA-N 0.000 description 1
- ADTSUJBKHPSTNM-UHFFFAOYSA-N n-[6-cyano-6-(2,3-dihydro-1,4-benzodioxin-3-yl)-1-(3,4-dimethoxyphenyl)-7-methyloctan-2-yl]formamide Chemical compound C1=C(OC)C(OC)=CC=C1CC(NC=O)CCCC(C#N)(C(C)C)C1OC2=CC=CC=C2OC1 ADTSUJBKHPSTNM-UHFFFAOYSA-N 0.000 description 1
- PUIRMILENSQHPS-UHFFFAOYSA-N n-[6-cyano-6-(2,3-dihydro-1,4-benzodioxin-3-yl)-1-(3,4-dimethoxyphenyl)heptan-2-yl]formamide Chemical compound C1=C(OC)C(OC)=CC=C1CC(NC=O)CCCC(C)(C#N)C1OC2=CC=CC=C2OC1 PUIRMILENSQHPS-UHFFFAOYSA-N 0.000 description 1
- NZMNMDDNZLCSMK-UHFFFAOYSA-N n-[6-cyano-6-(2,3-dihydro-1,4-benzodioxin-3-yl)-1-(3,4-dimethoxyphenyl)octan-2-yl]formamide Chemical compound C1OC2=CC=CC=C2OC1C(CC)(C#N)CCCC(NC=O)CC1=CC=C(OC)C(OC)=C1 NZMNMDDNZLCSMK-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 238000011587 new zealand white rabbit Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- SUSQOBVLVYHIEX-UHFFFAOYSA-N o-phenylene-diaceto-nitrile Natural products N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229910052762 osmium Inorganic materials 0.000 description 1
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- HQSHAZLGVDYADJ-UHFFFAOYSA-N pentan-2-yl 4-methylbenzenesulfonate Chemical compound CCCC(C)OS(=O)(=O)C1=CC=C(C)C=C1 HQSHAZLGVDYADJ-UHFFFAOYSA-N 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- DUCKXCGALKOSJF-UHFFFAOYSA-N pentanoyl pentanoate Chemical compound CCCCC(=O)OC(=O)CCCC DUCKXCGALKOSJF-UHFFFAOYSA-N 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- 230000036581 peripheral resistance Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- SDQCGKJCBWXRMK-UHFFFAOYSA-N propan-2-yl 4-methylbenzenesulfonate Chemical compound CC(C)OS(=O)(=O)C1=CC=C(C)C=C1 SDQCGKJCBWXRMK-UHFFFAOYSA-N 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- ABNDTCRZJDZKFZ-CQSZACIVSA-N tert-butyl N-[(2R)-1-(2,5-diethoxy-3,4-dimethoxyphenyl)-3-hydroxypropan-2-yl]carbamate Chemical compound CCOC1=CC(C[C@H](CO)NC(=O)OC(C)(C)C)=C(OCC)C(OC)=C1OC ABNDTCRZJDZKFZ-CQSZACIVSA-N 0.000 description 1
- DPKLODYLUUZKKH-HXUWFJFHSA-N tert-butyl N-[(2R)-1-(3,4-dimethoxy-2,5-dipentoxyphenyl)-3-hydroxypropan-2-yl]carbamate Chemical compound CCCCCOC1=CC(C[C@H](CO)NC(=O)OC(C)(C)C)=C(OCCCCC)C(OC)=C1OC DPKLODYLUUZKKH-HXUWFJFHSA-N 0.000 description 1
- JOVFDXRTAQUDLS-GFCCVEGCSA-N tert-butyl N-[(2R)-1-(3,4-dimethoxyphenyl)-3-hydroxypropan-2-yl]carbamate Chemical compound COC1=CC=C(C[C@H](CO)NC(=O)OC(C)(C)C)C=C1OC JOVFDXRTAQUDLS-GFCCVEGCSA-N 0.000 description 1
- PRVXBMLGGMYJMQ-GFCCVEGCSA-N tert-butyl N-[(2R)-1-hydroxy-3-(3,4,5-trimethoxyphenyl)propan-2-yl]carbamate Chemical compound COC1=CC(C[C@H](CO)NC(=O)OC(C)(C)C)=CC(OC)=C1OC PRVXBMLGGMYJMQ-GFCCVEGCSA-N 0.000 description 1
- HQPOLOZUQWNNSB-IFIVVKAWSA-N tert-butyl N-[(2R)-6-cyano-6-(3,4-dimethoxyphenyl)-1-(3,4,5-trimethoxyphenyl)nonan-2-yl]carbamate Chemical compound COC=1C=C(C=C(C1OC)OC)C[C@@H](CCCC(C1=CC(=C(C=C1)OC)OC)(CCC)C#N)NC(=O)OC(C)(C)C HQPOLOZUQWNNSB-IFIVVKAWSA-N 0.000 description 1
- DPKLODYLUUZKKH-FQEVSTJZSA-N tert-butyl N-[(2S)-1-(3,4-dimethoxy-2,5-dipentoxyphenyl)-3-hydroxypropan-2-yl]carbamate Chemical compound CCCCCOC1=CC(C[C@@H](CO)NC(=O)OC(C)(C)C)=C(OCCCCC)C(OC)=C1OC DPKLODYLUUZKKH-FQEVSTJZSA-N 0.000 description 1
- PRVXBMLGGMYJMQ-LBPRGKRZSA-N tert-butyl N-[(2S)-1-hydroxy-3-(3,4,5-trimethoxyphenyl)propan-2-yl]carbamate Chemical compound COC1=CC(C[C@@H](CO)NC(=O)OC(C)(C)C)=CC(OC)=C1OC PRVXBMLGGMYJMQ-LBPRGKRZSA-N 0.000 description 1
- KEPDMECFXHXYBN-ACXKHFGCSA-N tert-butyl N-[(2S)-6-cyano-1,6-bis(3,4-dimethoxyphenyl)nonan-2-yl]carbamate Chemical compound C([C@H](CCCC(CCC)(C#N)C=1C=C(OC)C(OC)=CC=1)NC(=O)OC(C)(C)C)C1=CC=C(OC)C(OC)=C1 KEPDMECFXHXYBN-ACXKHFGCSA-N 0.000 description 1
- HQPOLOZUQWNNSB-RUBXLXHKSA-N tert-butyl N-[(2S)-6-cyano-6-(3,4-dimethoxyphenyl)-1-(3,4,5-trimethoxyphenyl)nonan-2-yl]carbamate Chemical compound COC=1C=C(C=C(C1OC)OC)C[C@H](CCCC(C1=CC(=C(C=C1)OC)OC)(CCC)C#N)NC(=O)OC(C)(C)C HQPOLOZUQWNNSB-RUBXLXHKSA-N 0.000 description 1
- XKXIQBVKMABYQJ-UHFFFAOYSA-N tert-butyl hydrogen carbonate Chemical class CC(C)(C)OC(O)=O XKXIQBVKMABYQJ-UHFFFAOYSA-N 0.000 description 1
- 150000003526 tetrahydroisoquinolines Chemical class 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000011995 wilkinson's catalyst Substances 0.000 description 1
- UTODFRQBVUVYOB-UHFFFAOYSA-P wilkinson's catalyst Chemical compound [Cl-].C1=CC=CC=C1P(C=1C=CC=CC=1)(C=1C=CC=CC=1)[Rh+](P(C=1C=CC=CC=1)(C=1C=CC=CC=1)C=1C=CC=CC=1)P(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 UTODFRQBVUVYOB-UHFFFAOYSA-P 0.000 description 1
Classifications
-
- 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
- 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
- C07D405/06—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 carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
-
- 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
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
- C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Denne oppfinnelse angår nye 3-(4-cyano-4-fenylalkyl)-tetrahydroisokinolinderivater og de i farmasøytisk henseende aksepterbare salter derav, farmasøytiske preparater inneholdende disse derivater eller salter og bruk av disse for behandling av cardiovasculær forstyrrelse, deriblant angina, hypertensio og hjertesykdom som følge av stor blodtilstrøm-ning samt nye fremgangsmåter for fremstilling av forbindelsene ifølge oppfinnelsen og nye mellomprodukter for anvendelse ved fremgangsmåtene.
Visse andre kalsiumkanal-blokkeringsmidler er kjent, såsom verapamil, N-[4-(3-dimethoxyfenyl)-4-cyano-4-(prop-2-yl)-butyl]-N-(3,4-dimethoxyfenethyl)-N-methylamin, (US patentskrift nr. 3 261 859). Skjønt verapamil har hatt en betydelig kommersiell suksess, er virkningen kortvarig, og det er nødvendig med administrering tre eller fire ganger pr. dag. Dessuten virker dette middel cardiodepressivt, og det reduserer hjerteledningen. Det har nu vist seg at de nye forbindelser er mindre cardiodepressive og virker i lengre tid enn verapamil. De nye forbindelser er oralt aktive og reduserer hjertetrykket før og etter, samtidig som de øker blodstrømningen i hjertet. De nye forbindelser øker dessuten produktet av hjerteslagtakt og trykk, uten å øke hjerteslaget. De nye forbindelser forårsaker ingen patologisk forlengelse
av A-V-ledningen i effektive konsentrasjoner, og de forårsaker ingen orthostatisk hypotensio. De nye forbindelser reduserer EGG-ST-segment-forhøyelsen ved hjertetakt-frembragt angina.
Slik de benyttes i beskrivelsen og i de etterfølgende krav, har de følgende uttrykk og betegnelser de følgende betydninger, med mindre annet er uttrykkelig angitt: Uttrykket "lavere alkyl" refererer seg til en rettkjedet eller forgrenet, énverdig substituent som består utelukkende av carbon og hydrogen, som ikke inneholder noen umettethet og som har fra 1 til5 carbonatomer. Eksempler på lavere alkyl-grupper er methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl og 3-pentyl.
Uttrykket "lavere alkoxy" refererer seg til radikaler av formelen RO-, hvor R er lavere alkyl som ovenfor angitt.
Uttrykket "alkanol" refererer seg til lavere alkylal-koholer, såsom methanol, ethanol, propanol, isopropanol, butanol og lignende.
Uttrykket "halogen" refererer seg til klor, brom og jod.
Uttrykket "aryl" refererer seg til aromatiske radikaler bestående utelukkende av carbon og hydrogen og inneholdende fra 6 til 12 carbonatomer. Eksempler på arylgrupper er fenyl, nafthyl og lignende.
Uttrykket "acyleringsmiddel" refererer seg til forbindelser som er anvendelige for å addere et radikal av formen RC(0)- (hvor R er lavere alkyl) til en hydroxygruppe, f.eks. for å overføre HO- til CH^COO-. Acyleringsmidler innbefatter acetyleringsmidler såsom eddiksyreanhydrid og acetylklorid. 1 Andre acyleringsmidler som faller innenfor rammen av denne definisjon, er acylanhydrider og acylhalogenider, såsom pro-panoylklorid, butanoylbromid, 3-methylbutanoylklorid og lignende .
Uttrykket "syreanhydrid" refererer seg til forbindelser med formelen RgC(0)-0-C(0)R^, hvor R^og R^uavhengig av hverandre betegner lavere alkyl, som vanligvis dannes ved kondensering av to lavere-alkylcarboxylsyrer. Eksempler på syreanhydrider er maursyreanhydrid, eddiksyreanhydrid, maursyre-eddiksyreanhydrid, maursyre-pentansyreanhydrid og pentan-syre-pentansyreanhydrid.
Uttrykket "edelmetallkatalysator" refererer seg til katalysatorer i hvilke den aktive bestanddel først og fremst er et edelmetall, såsom platina, palladium, osmium og lignende. Slike katalysatorer blir vanligvis benyttet ved katalytisk hydrogenering, hydrogenolyse og lignende reaksjoner.
Uttrykket "katalytisk mengde" refererer seg til den mengde katalysator som må tilsettes for å oppnå effektiv katalyse, dvs. for å øke reaksjonsutbyttet eller reaksjons-hastigheten i en vesentlig grad. På grunn av naturen av katalyse vil den "katalytiske mengde" variere meget med reaksjonen og den benyttede katalystor. Med en gitt katalysator og en gitt reaksjon vil imidlertid en fagmann på området kunne bestemme den katalytiske mengde gjennom rutineforsøk.
Uttrykket "formaldehydkilde" refererer seg til formaldehyd og forbindelser som kan benyttes for å tilføre formaldehyd til en reaksjonsblanding. Eksempelvis spaltes paraformaldehyd i oppløsning under dannelse av formaldehyd, og dette er således en formaldehydkilde som omfattes av definisjonen. Også formalin faller innenfor rammen av denne definisjon.
Uttrykket "paraformaldehyd" refererer seg til polymeri-sert formaldehyd, (CH20)n. Paraformaldehyd er å få i handelen, og den benyttes som en kilde for formaldehyd i kjemiske reaksjoner.
Uttrykket "reduksjonsmiddel på borbasis" refererer
seg til natriumborhydrid, diboran og lignende alkylbor-reduk-sjonsmidler. ,
Uttrykket "metallisk base" refererer seg til baser
på metallbasis, såsom natrium, NaH, Raney-nickel, kalium-tert-butoxyd, lithiumaluminiumhydrid, NaNH^og lignende.
Uttrykket "beskyttende gruppe" refererer seg til en gruppe som benyttes for å hindre hydroxy- eller carbonyl-grupper i å reagere på uønsket måte under fremstillingen av de nye forbindelser. Eksempler på beskyttende grupper er benzylethere, ketaler (f.eks. acetonider) og estere. Det ideelle er at beskyttende grupper lett lar seg innføre og fjerne under betingelser som er forskjellige fra de reaksjons-betingelser som benyttes under fremstilingen. Eksempelvis er tert-butyl-carbonatestere stabile under de SN^-reaksjons-betingelser som benyttes ved fremstillingen av forbindelser med formel 1, mens de lett fortrenges ved bruk av maursyre og maursyre-eddiksyreanhydrid.
Uttrykket "i farmasøytisk henseende aksepterbare salter" refererer seg til salter av de angjeldende forbindelser som oppviser den ønskede farmakologiske aktivitet, og som hverken er ugunstige i biologisk henseende eller i annen henseende. Disse salter er syreaddisjonssalter dannet med uorganiske syrer, såsom saltsyre, bromhydrogensyre, svovel syre, saltpetersyre eller fosforsyre, eller med organiske syrer, såsom eddiksyre, propionsyre, glycolsyre, pyrodruesyre, malonsyre, ravsyre, maleinsyre, fumarsyre, vinsyre, sitronsy-re, benzoesyre, kanelsyre, mandelsyre, methansulfonsyre, ethansulfonsyre, p-toluensulfonsyre og lignende.
Uttrykket "behandling" som her benyttes, dekker enhver behandling av en sykdom hos mennesker og pattedyr og innbefatter: (i) å hindre sykdommen i å slå ut hos en pasient som kan være predisponert for sykdommen, men som ennu ikke er blitt vist å ha den, (ii) å hemme sykdommen, dvs. å hemme dens utvikling, eller (iii) å lindre sykdommen, dvs. å bevirke at sykdommen går tilbake.
Forbindelsene med formel 1 benevnes og besifres som isokinolinderivater under anvendelse av en modifisert form av IUPAC-nomenklaturen. Eksempelvis benevnes den nedenstående forbindelse 3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyano butyl]-6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydrisokinolin:
Forbindelsene med formel 1 har to asymmetriske seter, C-. og C. (ovenfor merket henholdsvis<*>og<**>), og de kan
således foreligge som diastereomerer. Individuelle isomerer av forbindelsene med formel 1 benevnes her under anvendelse av IUPAC-R-S-konvensjonen, som av og til betegnes "sekvens-
regelen". En beskrivelse av R-S-konvensjonen vil finnes f.eks. i "Introduction to Organic Chemistry" av A. Streitwieser, Jr. og C. Heathcock, (Macmillan Pub. Co., New York, 1976), sider 110-114. Diastereomerer vil bli angitt som (3R, 4'S), (3R, 4'R), (3S, 4'S) eller (3S, 4'R), avhengig av hva som passer. Eksempelvis er den ovenfor angitte forbindelse en (3R, 4'S)-forbindelse. Der hvor det passer, kan den optiske aktivitet av en forbindelse angis ved (-), hvilke tegn viser til retningen i hvilken en oppløsning av oppløsningen dreier et plan av polarisert lys.
I henhold til et aspekt av oppfinnelsen tilveiebringes en forbindelse med formelen
eller et i farmasøytisk henseende aksepterbart syreaddisjonssalt derav, i hvilken forbindelse R^ og R ? uavhengig av hverandre betegner -H eller lavere alkoxy, R^ og R. uavhengig av hverandre betegner lavere alkyl, og R^og R^hver betegner -OCH^eller sammen danner en gruppe - OCH^ O- eller -OCh^CP^O-.
I henhold til et annet aspekt av oppfinnelsen tilveiebringes én blanding av forbindelser med formel 1 .
I henhold til annet aspekt av oppfinnelsen tilveiebringes et farmasøytisk preparat som inneholder en forbindelse med formel 1 og en i farmasøytisk henseende aksepterbar eksipient.
I henhold til et annet aspekt av oppfinnelsen tilveiebringes en metode for å behandle cardiovasculære sykdommer som lar seg behandle ved kalsiumkanalblokkade, hvilke sykdommer innbefatter angina, hypertensio, hjertesvikt som følge
av øket blodtilførsel.
I henhold til ytterligere et aspekt av oppfinnelsen tilveiebringes en ny fremgangsmåte for fremstilling av forbindelser med formel 1.
I henhold til et annet aspekt av oppfinnelsen tilveiebringes et mellomprodukt med formel 11, som er anvendelig for fremstilling av forbindelser med formel 1:
og i farmasøytisk henseende aksepterbare salter derav, i hvilken formel R^ , R2 , R^, R^og R^er som ovenfor angitt.
I henhold til et annet aspekt av oppfinnelsen tilveiebringes et mellomprodukt med formel 8, som er anvendelig for fremstilling av mellomprodukter med formel 11:
og i farmasøytisk henseende aksepterbare salter derav, i hvilken formel R^, R2 , R^ , R^og R^er som ovenfor angitt.
I henhold til ytterligere et aspekt av oppfinnelsen tilveiebringes en forbindelse med formel 29, som er anvendelig for fremstilling av forbindelser med formel 1:
og syreaddisjonssalter derav, hvor R^ , R^, R^, R^, R^og Rg er som ovenfor angitt.
I henhold til ytterligere et aspekt av oppfinnelsen tilveiebringes en forbindelse med formel 34, som er anvendelig for fremstilling av forbindelser med formel 1:
og syreaddisjonssalter derav, hvor R^, R^, R^, R^, R^og R^ er som ovenfor angitt.
I henhold til enda et aspekt av oppfinnelsen tilveiebringes en forbindelse med formel 39, som er anvendelig for fremstilling av forbindelser med formel 1:
og syreaddisjonssalter derav, i hvilken formel , R^, R^ > R^, R^og Rg er som ovenfor angitt. I henhold til enda et aspekt av oppfinnelsen tilveiebringes en forbindelse med formel 37 eller med formel 38, som er anvendelig for fremstilling av forbindelser med formel 1:
og syreaddisjonssaltene derav, i hvilke formler R^ og R^uavhengig av hverandre betegner H eller lavere alkoxy, R^ og R^uavhengig av hverandre betegner lavere alkyl, R,- og R, hver betegner -OCH_, eller sammen danner -OCH-0 eller
-OCr^Cr^O, og Z er hydroxy eller oxo.
I henhold til et aspekt av oppfinnelsen tilveiebringes en forbindelse med formelen
eller et i farmasøytisk henseende aksepterbart syreaddisjonssalt derav, i hvilken formel R^og R^uavhengig av hverandre betegner -H eller lavere alkoxy, R^og R^uavhengig av hverandre betegner lavere alkyl, og R<- og R^hver betegner -OCH^
eller sammen danner en gruppe -OCH^O- eller -OCr^Cr^O-. En foretrukken undergruppe av forbindelser som tilveiebringes ved hjelp av oppfinnelsen, er forbindelser hvor er isopropyl. En foretrukken klasse utgjøres av forbindelser hvor R^er methyl. En foretrukken underklasse av forbindelser
er forbindelser hvor R^og R^ begge er H, spesielt når R,-
og Rg begge er -OCH^, spesielt i fenylgruppens 3- og 4-stillinger. En for tiden foretrukken forbindelse er forbindelsen (3S, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobu-tyl]-6,7-dimethoxy-N-methyl-1,2,3,4 -tetrahydroisokinolin.
En annen forbindelse som for tiden foretrekkes, er (3S, 4'S)-3- [4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-l ,2,3,4-tetrahydroisokinolin•HC1.
I henhold til et annet aspekt av oppfinnelsen tilveiebringes en blanding av forbindelser med formel 1. En foretrukken klasse utgjøres av en omtrent racemisk blanding av diastereomerer. En for tiden foretrukken blanding er blandingen av (3S, 4'S)-, (3S, 4'R)-, (3R, 4'S)- og (3R, 4'R)-isomerer av 3[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydroisokinolin. En annen blanding som for tiden foretrekkes, er blandingen av (3S, 4'S)-, (3S, 4'R)-, (3R, 4'S)- og (3R, 4'R)-isomerer av 3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1 ,2,3,4-tetrahydroisokinolin.HC1. En annen foretrukken blanding er en omtrent ekvimolar blanding av (3S, 4'S)- og (3S, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4- cyanobutyl]-6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydroisokinolin .
I henhold til et enda et aspekt av oppfinnelsen tilveiebringes et farmasøytisk preparat som inneholder en forbindelse med formel 1 og en i farmasøytisk henseende aksepterbar eksipient.
I henhold til ytterligere et aspekt av oppfinnelsen tilveiebringes en metode til å behandle cardiovasculære sykdommer som lar seg behandle med kalsiumkanalblokkeringsmidler, hvilke sykdommer innbefatter angina, hypertensio og hjertesvikt som følge av øket blodtilstrømning. Denne metode går ut på administrere en effektiv mengde av en forbindelse med formel 1 til mennesker og pattedyr som har behov for
behandlingen.
I henhold til ytterligere et aspekt av oppfinnelsen tilveiebringes en fremgangsmåte for fremstilling av forbindelser med formel 1, ved hvilken man i 1-24 timer oppvarmer ved 70-110°C en blanding av maursyre, en kilde for formaldehyd og en forbindelse med formel 11:
hvor R., og R^uavhengig av hverandre betegner -H eller lavere alkoxy, R^er lavere alkyl, og R^og R^begge er -OCH^, eller sammen danner -OCr^O- eller -OCI-^Cr^O-. En foretrukken utfø-relsesform av oppfinnelsen er en fremgangsmåte hvor R^og R^begge er -H, R^er prop-2-yl og R,- og R^begge er -OCH^.
I henhold til en annen foretrukken utførelsesform oppvarmes blandingen ved ca. 80°C i 2-8 timer. I henhold til en annen foretrukken utførelsesform av fremgangsmåten fremstilles forbindelsen med formel 11 ved at man i et inert oppløsnings-middel blander et acyleringsmiddel (fortrinnsvis eddiksyreanhydrid), en katalytisk mengde base (fortrinnsvis 4-dimethylaminopyridin) og en forbindelse med formel 8
hvor R 1 og R_ uavhengig av hverandre betegner -H eller lavere alkoxy, R^er lavere alkyl, og R^ og R^begge er -OCH3eller sammen danner -OCH20- eller -OCH2CH20-, for dannelse av et første produkt, hvoretter en blanding av dette første produkt, en første alkanol (fortrinnsvis 2-propanol), et inert oppløsningsmiddel (fortrinnsvis CH2C12) og et reduksjonsmiddel på borbasis (fortrinnsvisNaBH^) oppvarmes ved 2 5-45°C for dannelse av et andre produkt, og en blanding av dette andre produkt, ammoniumformiat, en edelmetallkatalysator (fortrinnsvis 5% Pd/C) og en andre alkanol (fortrinnsvis methanol) oppvarmes ved 30-60°C. I henhold til en foretrukken utførel-sesform av fremgangsmåten blir forbindelsen med formel 8 fremstilt ved oppvarmning (ved 40-65°C) av en blanding av en tredje lavere alkanol (fortrinnsvis 2-propanol), en katalytisk mengde av et fluoridsalt (fortrinnsvis KF), en forbindelse med formel 4 og en forbindelse med formel 7:
hvor R^og R2uavhengig av hverandre betegner -H eller lavere alkoxy, R^er lavere alkyl og R^og R^ begge er -OCH3eller sammen danner -OCH20- eller -OCH2CH20-.
I henhold til et annet aspekt av oppfinnelsen tilveiebringes en forbindelse med formel 29:
og syreaddisjonssalter derav, i hvilken formel R., og R ? uavhengig av hverandre betegner H eller lavere alkoxy, R^ og R^uavhengig av hverandre betegner lavere alkyl, og R^ og Rg begge er -OCH^ eller sammen danner - OCH^ O- eller -OCr^CP^O-. En foretrukken klasse av slike forbindelser er de forbindelser hvor R^ og R^begge er H, R^ er methyl og R^er isopropyl.
I henhold til et annet aspekt av oppfinnelsen tilveiebringes en forbindelse med formel 34:
og syreaddisjonssalter derav, i hvilken formel R^ og R^uavhengig av hverandre betegner H eller lavere alkoxy, R^ og R^uavhengig av hverandre betegner lavere alkyl, og R,- og
R6begge er -OCH3eller sammen danner -OC^O- eller -OCr^Cr^O-. En foretrukken klasse av disse forbindelser er de forbindelser hvor R^og R2hver er H, R^ er methyl og R^er isopropyl.
I henhold til ytterligere et aspekt av oppfinnelsen tilveiebringes en forbindelse med formelen 39:
I henhold til enda et aspekt av oppfinnelsen tilveiebringes en oppfinnelse med formel 37 eller formel 38:
og syreaddisjonssaltene derav, i hvilke formler R., og R2uavhengig av hverandre betegner H eller lavere alkoxy, R^ og R^uavhengig av hverandre betegner lavere alkyl, R^og R, begge er -OCH_. eller sammen danner -OCH_0- eller -0CH_CHo0-, 6 3 2 2 2 og Z er hydroxy eller oxo. En foretrukken klasse av disse forbindelser er de forbindelser hvor R^og R^begge er H,
R^er methyl og R^er isopropyl.
Et annet aspekt av den foreliggende oppfinnelse angår farmasøytiske preparater som er anvendelige for behandling av cardiovasculære sykdommer, såsom hypertensio, hjertesvikt som følge av stor blodtilstrømning, angina, migrene og vasospastiske forstyrrelser, spesielt for behandling av hypertensio hos mennesker og pattedyr. Preparatene omfatter en terapeutisk effektiv mengde av en forbindelse med formel 1, eller et i farmasøytisk henseende aksepterbart syreaddisjonssalt derav, i blanding med en i farmasøytisk henseende aksepterbar ikke-toksisk bærer. En terapeutisk effektiv mengde er den mengde som, når den administreres til et menneske eller et pattedyr som har behov for behandlingen, er tilstrekkelig til å gi en behandling som ovenfor definert. Således kan mengden av drogen i preparatet variere fra 5 vekt% til 95 vekt%, beregnet på preparatets totalvekt, mens mengden av eksipient er fra 5 vekt% til 95 vekt%. Fortrinnsvis er drogen tilstede i en mengde av fra 10 til 70 vekt%.
Anvendelige farmasøytiske bærere for fremstilling
av de her beskrevne farmasøytiske preparater kan være faste eller væskeformige. Således kan preparatene ha form av tabletter, piller, kapsler, pulvere, preparater for frigjøring av den aktive bestanddel over tid, oppløsninger, suspensjoner, eliksirer, aerosoler og lignende. Bærerne kan velges blant de forskjellige oljer, deriblant de av petroleumopprinnelse, eller av animalsk, vegetabilsk eller syntetisk opprinnelse, såsom f.eks. peanøttolje, søyabønneolje, mineralolje, sesam-olje og lignende. Vann, saltoppløsning, vandig dextrose og glycoler er foretrukne væskeformige bærere, spesielt for injiserbare oppløsninger. Egnede farmasøytiske eksipienter innbefatter stivelse, cellulose, talkum, glucose, lactose, sucrose, gelatin, malt, ris, mel, kalk, silicagel, magnesium-stearat, natriumstearat, glycerolmonostearat, natriumklorid, tørret, skummet melk, glycerol, propylenglycol, vann, ethanol og lignende. Andre egnede farmasøytiske bærere og deres sam-mensetning er beskrevet i " Remington' s Pharmaceutical Scien-ces " av E.W. Martin.
I henhold til et annet aspekt av oppfinnelsen tilveiebringes en metode for behandling av cardiovasculære sykdommer, såsom hypertensio, hjertesvikt som følge av stor blod-tilstrømning, angina og vasospastiske forstyrrelser hos mennesker og pattedyr, i henhold til hvilken det administreres en terapeutisk effektiv mengde av en forbindelse med formel 1, eller et i farmasøytisk henseende aksepterbart syreaddisjonssalt derav, til et menneske eller et pattedyr som har behov for behandlingen, spesielt til et menneske.
Ved utøvelsen av den ovenfor beskrevne metode ifølge oppfinnelsen blir en terapeutisk effektiv mengde av forbindelsen med formel 1 eller et farmasøytisk preparat inneholdende samme administrert ved hjelp av en hvilken som helst av de vanlige og aksepterte metoder som er kjent i faget, enten alene eller i kombinasjon med én eller flere andre av de nye forbindelser eller i kombinasjon med andre farma-søytiske midler. Disse forbindelser eller preparater kan således administreres oralt, systemisk (f.eks. gjennom huden, gjennom nesen eller ved hjelp av stikkpiller) eller paren-teralt (f.eks. intramuskulært, subcutant eller intravenøst), og de kan administreres enten i form av faste eller væskeformige doseformer, f.eks. som tabletter, oppløsninger, suspensjoner, aerosoler og lignende slik det er nærmere angitt ovenfor. Det foretrekkes å administrere forbindelser med formel 1 oralt.
Preparatet kan adminstreres i enhetsdoseform for kon-tinuerlig behandling eller i enhetsdoseform ad libitum, når det ønskes å lindre symptomene.
Forsøket med spontant hypertensive rotter (SHR = Spon-taneously Hypertensive Rat) er en akseptert test for bestem-melse av antihypertensiv aktivitet, se f.eks. J. Roba, et al., Arch. Int. Pharmacodyn., 2 00, 182 (1972). De nye forbindelser oppviser antihypertensiv aktivitet ved SHR-testen.
Adnre aksepterte tester for cardiovasculær aktivitet innbefatter forsøk med aortastrimler fra rotter, ultrasonisk todimensjonal echocardiografi og forsøk med anestetiserte hunder, se f.eks. P. Gueret, M.D., et al., Circulation, 62(6), 1308 (1980), og M. Tripp, American J. of Physiology, 2 32(2 ) , H173 (1977). De nye forbindelser oppviser positiv aktivitet også ved disse tester.
Den effektive dose av forbindelsene kan variere innenfor vide grenser, i avhengighet av hva som er sagt ovenfor, og i avhengighet av graden av den tilstand som behandles, pasientens alder osv. Alle disse faktorer vil kunne bestemmes rutinemessig av en fagmann på området. Vanligvis vil en tera peutisk effektiv mengde ligge i området fra 1 til 10 mg/kg,. spesielt fra 0,7 til 7 mg/kg, kroppsvekt pr. dag og ligger fortrinnsvis, f.eks. for antihypertensiv bruk, i området fra 0,8 til 1,5 mg/kg kroppsvekt pr. dag. Uttrykt på en alter-nativ måte vil dette si at den terapeutisk effektive mengde for et voksent menneske på 70 kg fortrinnsvis vil være fra 50 mg til 500 mg pr. dag pr. pasient, fortrinnsvis fra 60
mg til 100 mg pr. dag pr. pasient.
De nye forbindelser som fremstilles ved hjelp av de fremgangsmåter som er illustrert i reaksjonsskjemaer I-X. Reaksjonsskjema I illustrerer den for tiden foretrukne fremgangsmåte for fremstilling av forbindelser med formel 1. Reaksjonsskjema II illustrerer en fremgangsmåte for fremstilling av optisk rene diastereomerer ut fra kommersielt tilgjengelige utgangsmaterialer. Reaksjonsskjemaer III-X illustrerer alternative fremgangsmåter for fremstilling av de nye forbindelser.
I de ovenstående reaksjonsskjemaer betegner Ac acetyl (CH^CO-), mens LDA betegner lithiumdiisopropylamid, DMAPbetegner 4-dimethylaminopyridin, X betegner halogen, Y betegner -CN eller -COOR, Ts betegner (p-toluensulfonyl), DAB betegner disianylboran, Ms betegner mesyl (methylsulfonyl),
Me betegner methyl (CH^-), Et betegner ethyl, i-Pr betegner isopropyl, t-Bu betegner tert-butyl og (jp betegner fenyl.
Hver R er, uavhengig av de øvrige, lavere alkyl, og R2 , R2, R^, R^, Rj. og R^ har de betydninger som er angitt under den mest vidtfavnende beskrivelse av oppfinnelsen.
I henhold til Reaksjonsskjema I blir et eventuelt substituert dimethoxybenzaldehyd med formel 2, nitromethan og en katalytisk mengde ammoniumacetat (ca. 10 moll av di-methoxybenzaldehydet) oppvarmet til 70-100°C i 2-6 timer.
Det resulterende produkt utfelles fra en blanding av vann
og isopropanol (ca. 7:1), hvorved det fåes et nitrostyren-derivat med formel 3 (trinn 1). Eksempelvis behandles 3,4-dimethoxybenzaldehyd med Nh^OAc og nitromethan under dannelse av 3 ,4-dimethoixy-|3-nitrostyren (3). Alternativt kan 3,4-dimethoxy-|3-nitrostyren kjøpes.
Nitrostyrenderivatet (3) blir så avkjølt til en temperatur i området fra -10° til +10°C, behandlet med silicagel og redusert under anvendelse av 1,5-4 ekvivalenter av et reduksjonsmiddel på borbasis, f.eks. natriumborhydrid,
i 2-propanol og et inert oppløsningsmiddel, f.eks. CH2C12, ved en temperatur fra -10° til +10°C i 20-60 minutter, hvorved det dannes et nitrofenylethanderivat med formel 4 (trinn 2). Eksempelvis behandles 3,4-dimethoxy~3-nitrostyren (3)
med 2-propanol og SiC>2 i CH2C12ved 0-10°C i 20 minutter, hvoretter det foretaes reduksjon med 1,5 ekvivalenter NaBH^ved 5 C i 30 minutter. Derved fåes 2-(3,4-dimethoxyfenyl)-nit-roethan (4).
Et eventuelt substituert fenylacetonitril eller en eventuelt substituert lavere-alkyl-fenyleddiksyreester blir så alkylert med et tø-halogenpropionaldehyd-acetal under anvendelse av en sterk metallbase i et polart, aprotisk opp- løsningsmiddel. Det ønskede fenylacetonitrilderivat eller lavere-alkyl-fenyleddiksyreesterderivat blir ført deprotonert ved tilsetning av ca. 1 ekvivalent av en sterk metallbase, f.eks. NaH, i et polart aprotisk oppløsningsmiddel ved 15-21°C i 25-50 minutter. Den resulterende blanding blir så omrørt i 1-3 timer, og ca. 1 ekvivalent 3-klorpropional-dehyd-diethylacetal tilsettes, hvorved det fåes et derivat med formel 5 (trinn 3). Eksempelvis blir 2-(3,4-dimethoxyfe-nyl)-acetonitril i dimethylformamid (DMF) satt til NaH ved 18-20°C i løpet av 30 minutter, hvoretter blandingen omrøres i 1 time og så behandles med 3-klorpropionaldehyd-diethylace-tal i DMF, hvorved som produkt fåes 2-(3,3-diethoxypropyl)-2 -
(3,4-dimethoxyfenyl)-acetonitril (5).
Det resulterende acetalderivat med formel 5 alkyleres så med ca. 1 ekvivalent av et alkylhalogenid under anvendelse av en sterk metallbase og en katalytisk mengde av en jodkilde, f.eks. 2-jodpropan eller NaJ, i et polart, aprotisk oppløsningsmiddel ved i10-40°C i 2-18 timer, hvoretter det foretaes behandling med en tilstrekkelig mengde isvann til å spalte overskudd av base. Derved fåes et dialkylert derivat med formel 6. Eksempelvis blir 2-(3,3-diethoxypropyl)-2 -
(3,4-dimethoxyfenyl)-acetonitril (5) i DMF behandlet med et svakt molart overskudd av 2-klorpropan (og 0,1-5 mol% 2-jodpropan) ved 20°C, hvoretter blandingen omrøres i 10 minutter og så behandles med 1 ekvivalent NaH i mineralolje og langsomt oppvarmes til 40°C. Etter tilsetning av 200 ml isvann og rensning av produktet fåes 2-(3,3-diethoxypropyl)-2-(prop-2-yl)-2-(3,4-dimethoxyfenyl)-acetonitril (6).
Det resulterende acetal-mellomprodukt med formel 6 blir så hydrolysert under anvendelse av en konsentrert pro-tisk syre og et polart oppløsningsmiddel ved 30-60°C i 5-60 minutter (trinn 5). Eksempelvis oppvarmes 2-(3,3-diethoxy-propyl )-2 -(prop-2-yl)-2 -(3,4-dimethoxyfenyl)-acetonitril (6) ved 55°C i THF/vann (3:1) med konsentrert HC1 i 15 minutter, 'hvorved det fåes 1-(i-propyl)-1-(3,4-dimethoxyfenyl)-1-cyanobutanal (7).
Forbindelser med formel 6 hvor Y er -COOR, kan forsåpes
under reaksjonsbetingelsene ved denne prosedyre, men de kan lett forestres på ny under anvendelse av den passende lavere alkanol. Eksempelvis behandles 1 -(i-propyl)-1 -(3,4-dimethoxy-fenyl)-1 -(carboxymethyl)-butanal med methanol under sur katalyse under dannelse av 1-(i-propyl)-1-(3,4-dimethoxyfenyl)-1 -(carbomethoxymethyl)-butanal (7).
Det resulterende mellomprodukt med formel 7 konden-seres så med mellomproduktet med formel 4 i nærvær av en katalytisk mengte (0,1-5 mol%) av et fluoridsalt, f.eks. KF,
og en base i et alkoholoppløsningsmiddel ved 40-65°C i 12-60 timer for dannelse av en diarylnitrohexanol med formel 8 (trinn 6). Eksempelvis omsettes 1-(prop-2-yl)-1-(3,4-dimethoxyf enyl ) -1 -cyanobutanal (7) med 2-(3,4-dimethoxyfenyl)-nitroethan (4) i 2-propanol under anvendelse av en katalytisk mengde KF for dannelse av 1-(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxyfenyl)-hexan-3-ol (8).
Det resulterende nitrohexanolmellomprodukt med formel 8 acyleres så med et acyleringsmiddel (f.eks. eddiksyreanhydrid og en katalytisk mengde dimethylaminopyridin (DMAP) eller acetylklorid) i et inert, aprotisk, polart oppløsningsmiddel i 20-120 minutter for dannelse av et nitro-hexanolacylat med formel 9 (trinn 7). Eksempelvis blandes 1-(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(prop-2-yl)-6 - ( 3 , 4-dimethoxyfenyl)-hexan-3-ol (8) med AC2O og DMAP i CH2CI2i 40 minutter for dannelse av 0-acetyl-1-(3,4-dimethoxyfenyl)-2- nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxyfenyl)-hexan-3- ol (9).
Det resulterende nitrohexanolacetat med formel 9 reduseres så under anvendelse av et reduksjonsmiddel på borbasis, f.eks. natriumborhydrid, i en 2° eller 3° alkanol ved 25-80°C i 3-15 timer for dannelse av et nitrohexanderivat med formel 10 (trinn 8). Eksempelvis oppvarmes 0-acetyl-1-(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(i-propyl)-6-( (3,4-dimethoxyfenyl)-hexan-3-ol (9) med NaBH4i 2-propanol under tilbakeløpsbetingelser i 3-15 timer, hvorved det fåes 1-(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(prop-2-yl) -6-(3,4-dimethoxyfenyl)-hexan (10).
Mellomproduktet med formel 10 reduseres så til et amin med formel 11, f.eks. ved behandling med ammoniumformiat i alkohol under anvendelse av en Pd/C-katalysator ved 30-60°C i en tid fra 30 minutter til 48 timer (trinn 9). Eksempelvis oppvarmes 1-(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxyfenyl)-hexan (10) under tilbake-løpsbetingelser med HCO2NH4i methanol over 5% Pd/C i ca. 24 timer, hvorved det fåes 1-(3,4-dimethoxyfenyl)-2-amino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyfenyl)-hexan (11).
Mellomproduktet med formel 11 ringsluttes deretter, og aminet methyleres ved omsetning med en formaldehydkilde (f.eks. formaldehyd, formalin, paraformaldehyd e.l.) og maursyre ved 70-110°C i 1-24 timer, hvorved det fåes et tetrahydroisokinolin med formel 1 (trinn 10). Eksempelvis oppvarmes 1 -(3,4-dimethoxyfenyl)-2-amino-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxyfenyl)-hexan (11) ved 80-100°C med paraformaldehyd og maursyre i 2-8 timer, hvorved det fåes 3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-l , 2 , 3 , 4 -tetrahydroisokinolin (1) som en racemisk blanding.
Forbindelser med formel 11 hvor Y er -COOR, overføres til forbindelser med formel 1 i henhold til den ovenfor beskrevne ringslutning/methylering med de følgende ytterligere trinn. Esteren ("formel 11.1") kan forsåpes under vanlige betingelser, f.eks. ved behandling med en fortynnet vandig mineralsyre, såsom HC1 og den resulterende carboxylsyre ("formel 11.2") overføres til det tilsvarende amid ("formel 11.3") ved behandling av syren eller syrehalogenidet med ammoniakk. Alternativt kan esteren overføres direkte til amidet, se J. March, "Advanced Organic Chemistry", tredje utgave, (Wiley-Interscience, New York, 1985), side 375 og de publikasjoner som det der er henvist til. Det resulterende amid med formel 11.3 overføres deretter til nitrilet med formel 1 ved dehydratisering, under anvendelse av f.eks.
P2O5, POCI3, PCI5, CCl4-Pf3, hexamethylfosfortriamid (HMPT), trifluoreddiksyreanhydrid-pyridin, trimethylsilylpolyfosfat, SOCI2e.l. Eksempelvis oppvarmes 3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-(formamido)-butyl]-6,7-dimethoxy-N-methyl-
I, 2,3,4-tetrahydroisokinolin med P2O5i ether for dannelse
av 3-t 4-(3,4-dimethoxyfenyl)-4-isopropy1-4-cyanobutyl1-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin (1). Alternativt kan syren med formel 11.2 overføres direkte til forbindelsen med formel 1 ved oppvarmning av dens ammoniumsalt med et av de ovennevnte dehydratiseringsmidler, se J. March, "Advanced Organic Chemistry", tredje utgave, (Wiley-Interscience, New York, 1985), sider 932-933 og de publikasjoner som det der er henvist til. Om ønsket kan man skille fra hverandre de optiske isomerer av mellomproduktet med formel II. 2, før dette overføres til forbindelsen med formel 1, f.eks. ved fraksjonert krystallisasjon med en optisk aktiv base. Egnede optisk aktive baser innbefatter optisk aktive aminer, såsom cinchonidin, kinidin, strychnin, brucin, morfin, d-a-fenethylamin, 1-arginin, dehydrobiethylamin, cinchonicin, 1-2-amino-1-propanol, d-amfetamin, glucosamin, conessin, anabasin, N-alkyl-D-glucamin o.l.
Alternativt kan man overføre estergruppen i forbindelse 11.1 direkte til cyanogruppen ved behandling med 2 ekvivalenter dimethylaluminiumamid (S. Winreb, et al., Tetra-hedron Lett., 4907 (1979). Denne reaksjon utføres i et egnet aprotisk hydrocarbonoppløsningsmiddel, fortrinnsvis et høyt-kokende oppløsningsmiddel, såsom xylen. 2 ekvivalenter Me2AlNH2i CH2CI2settes til en oppløsning av esteren med formel 11.1
i det egnede oppløsningsmiddel og oppvarmes ved 80-170°C, fortrinnsvis i xylen som kokes med tilbakeløpskjøling i et tidsrom av fra 30 minutter til 20 timer. Reaksjonen følges ved tynnskiktkromatografering (TLC). Eksempelvis oppvarmes 3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-(carbomethoxy)-butyl]-6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydroisokinolin (11.1) i tilbakeløpskokende xylen med Me2AlNH2i ca. 15 timer, hvorved det fåes 3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydroisokinolin (1).
Den frie base med formel 1 kan overføres til et i farmasøytisk henseende aksepterbart salt, om så ønskes, ved at basen oppløses i et egnet oppløsningsmiddel, såsom en alkohol, og behandles med den passende syre. Eksempelvis oppløses 3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]- 6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydroisokinolin (1) i isopropanol, hvoretter HCl-gass bobles igjennom oppløsningen. Oppløsningen mettes så med ether for å felle ut 3-[4-(3,4-dimethoxyf enyl) -4-isopropy.l-4-cyanobutyl ] -6 , 7-dimethoxy-N-methyl-l ,2,3,4-tetrahydroisokinolin•HC1.
Sammenfatningsvis kan forbindelser med formel 1 fremstilles etter Reaksjonsskjerna I ved oppvarmning ved 70-110°C i 1-24 timer av en blanding av en forbindelse med formel 11 hvor Y er -CN, en formaldehydkilde og maursyre. Forbindelser med formel 1 kan også fremstilles ved dehydratisering av et eventuelt optisk spaltet amid med formel 11.3 eller et eventuelt optisk spaltet ammoniumsalt av en syre med formel 11.2 med et egnet dehydratiseringsmiddel, f.eks. P2O5, POCI3, PCI5CCI4-PP3, HMPT, trifluoreddiksyreanhydrid-pyridin, trimethylsilylpolyfosfat eller SOCI2. Forbindelser med formel 1 kan også fremstilles ved behandling av en ester med formel 11.1 med Me2AlNH2-
Spesifikke optiske isomerer kan fremstilles etter den metode som er vist i Reaksjonssjerna II. L-3,4-demethoxy-fenylalaninol (12) eller et annet egnet fenylaminopropanol-derivat fremstilles som beskrevet av A.W. Schrecker og J.L. Hartwell, J. Am. Chem. Soc., 79, 3827 (1957). Aminogruppen beskyttes da gjennom omsetning med di-t-butyldicarbonat, hvorved det fåes et carbamatderivat med formel 13 (trinn 1). Eksempelvis kokes L-3,4-dimethoxyfenylalaninol (12) med til-bakeløpskjøling i tetrahydrofuran (THF) i 1 time med di-t-butyldicarbonat, hvorved det fåes 3-(3,4-dimethoxyfenyl)-L-2-(t-butoxycarbonylamino)-propan-1-ol (13).
Hydroxygruppen overføres så til en egnet uttredende gruppe, f.eks. ved overføring til et tosylat (trinn 2). Eksempelvis omrøres 3-(3,4-dimethoxyfenyl)-L-2-t-butoxy-carbonylamino)-propan-1-ol (13) ved romtemperatur i 2 dager med p-toluensulfonylklorid og en katalytisk mengde DMAP i pyridin, hvorved det fåes 3-(3,4-dimethoxyfenyl)-L-2-(t-butoxycarbonylamino)-1-tosyloxypropan (14).
Tosylatet med formel 14 behandles så med vinylmag-nesiumbromid og CuJ i et inert oppløsningsmiddel for dannelse av det tilsvarende pent-1-en-derivat med formel 15 (trinn 3). Eksempelvis behandles 3-(3,4-dimethoxyfenyl)-L-2-(t-butoxycarbonylamino)-1-tosyloxypropan (14) med vinylmagnesium-bromid og CuJ i THF ved -70°C i 30 minutter, hvoretter blandingen tillates å oppvarmes til 0°C. Derved fåes 5-(3,4-dimethoxyf enyl )-L-4-(t-butoxycarbonylamino)-pent-1-en (15).
Det resulterende pentenderivat overføres så til et pentanolderivat, f.eks. ved omsetning med DAB i et egnet inert oppløsningsmiddel (trinn 4). Eksempelvis settes 5-(3,4-dimethoxyfenyl)-L-4-(t-butoxycarbonylamino)-pent-1-en (15) til DAB i THF ved 0°C, hvoretter det omrøres i 30 minutter ved 20°C og det foretas behandling med NaOH og N2O2ved romtemperatur i 30 minutter. Derved fåes 5-(3,4-dimethoxy-fenyl)-L-4-(t-butoxycarbonylamino)-pentan-1-ol (16).
Pentanolderivatet overføres så til et pentyljodid-derivat med formel 17, f.eks. ved overføring av pentanolderivatet til et mesylat og påfølgende behandling av mesylatet med natriumjodid (trinn 5). Eksempelvis behandles 5-(3,4-dimethoxyf enyl )-L-4-(t-butoxycarbonylamino)-pentan-1-ol (16)
med NEt3og methansulfonylklorid i CH2CI2ved 0°C i 10 minutter. Produktet fraskilles, oppløses i aceton og kokes med tilbakeløpskjøling i 30 minutter med NaJ, hvorved det fåes 5-(3,4-dimethoxyfenyl)-L-4-(t-butoxycarbonylamino)-1 -jodpentan (17) .
Et egnet 2-(substituert fenyl)-2-alkylacetonitril (formel 6a) behandles med en sterk base, f.eks. LDA, i et inert oppløsningsmiddel og omsettes deretter med jodpentan-derivatet med formel 17 for dannelse av aminohexanderivatet med formel 18 (trinn 6). Eksempelvis blir (±)-2-(i-propyl)-2-(3,4-dimethoxyfenyl)-acetonitril (6a) deprotonert med LDA
i THF ved -70°C og deretter omsatt med 5-(3,4-dimethoxy-fenyl)-L-4-(t-butoxycarbonylamino)-1-jodpentan (17), hvorved det fåes 1-(3,4-dimethoxyfenyl)-L-(2-t-butoxycarbonylamino)-(±)-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyfenyl)-hexan (18).
Det resulterende beskyttede aminohexanderivat overføres så til et formylaminohexanderivat med formel 19 (trinn 7). Eksempelvis behandles 1-(3,4-dimethoxyfenyl)-L-(2-t-butoxycarbonylamino)-(±)-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyfenyl)-hexan (18) først med maursyre og deretter med maursyre-eddiksyreanhydrid for dannelse av 1-(3,4-dimethoxyf en<y>l )-L-2-(form<y>lamino)-(±)-6-c<y>ano-6-(i-<p>rop<y>l)-6-(3,4-dimethoxyfenyl)-hexan (19). (+)- og (-)-isomerene kan så skilles fra hverandre ved kromatografering under middels høyt trykk under anvendelse av ethylacetat som oppløsnings-middel. (-)- isomeren, nemlig 1-(3 4-dimethoxyfenyl)-L-2-(formylamino)-(-)-6-cyano-6-(i-propyl)-6-((3,4-dimethoxy-fenyl)-hexan (19A), elueres først, og deretter 1-(3,4-dimethoxyf enyl)-L-2-(formylamino)-(+)-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyfenyl)-hexan (19B).
Formylaminohexanderivatet ringsluttes så til et tetrahydroisokinolin med formel 20, f.eks. ved behandling med POCI3og deretter med NaBH4(trinn 8). Eksempelvis behandles 1 - ( 3,4-dimethoxyfenyl)-L-2-(formylamino)- (-)-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyfenyl)-hexan (19A) med POCI3i CH3CN, hvoretter det foretas omsetning med NaBH4i ethanol. Derved våes L-(-)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl] - 6 ,7-dimethoxy-1,2,3,4-tetrahydroisokinolin (20A).
Det resulterende isokinolinderivat med formel 20 blir så N-alkylert, f.eks. under anvendelse av paraformaldehyd i maursyre, for dannelse av en forbindelse med formel 1. Eksempelvis omsettes L-(-)-3-[ 4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisokinolin (20A). Alternativt kan et mellomprodukt med formel 19 alkyleres under anvendelse av en sterk base og et alkyle-ringsmiddel av formen R3-L, hvor L er en egnet uttredende gruppe, såsom tosyl. Eksempelvis omsettes L-(-)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisokinolin (20A) med LDA og propyltosylat for dannelse av L-(-)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-propyl-1,2,3,4-tetrahydroisokinolin (1 ) .
Alternativt kan man fremstille forbindelser ifølge oppfinnelsen ved hjelp av prosedyrene vist i Reaksjonsskjerna III. I det første trinn alkyleres et derivat med formel 6a
(se Reaksjonsskjerna II) med et 1,3-dihalogenpropan under anvendelse av en sterk base i et egnet aprotisk oppløsnings-middel for dannelse av et derivat med formel 21 (trinn 1).
Eksempelvis behandles 2-(3,4-dimethoxyfenyl)-2-isopropylaceto-nitril med natriumamid i toluen og 1-brom-3-klorpropan for dannelse av 2-(3,4-dimethoxyfenyl)-2-isopropyl-2-(3-klorpro-pyl)-acetonitril (21).
Klorderivatet med formel 21 overføres så til et jodderivat med formel 22 ved behandling med et egnet salt (trinn 2). Eksempelvis behandles 2-(3,4-dimethoxyfenyl)-2-isopropyl-2-(3-klorpropyl)-acetonitril (21) med NaJ i aceton under kokning med tilbakeløpskjøling for dannelse av 2-(3,4-dimethoxyfenyl)-2-isopropyl-2-(3-jodpropyl)-acetonitril (22).
Jodderivatet med formel 22 omsettes så med et 3-(3,4-dimethoxyfenyl)-propionsyrederivat (eventuelt substituert i fenylgruppens stillinger 2 og/eller 5) i nærvær av en sterk base for dannelse av et derivat med formel 23 (trinn 3). Eksempelvis omsettes 2-(3,4-dimethoxyfenyl)-2-isopropyl-2-( 3-j odpropyl)-acetonitril (22) med lithiumdiisopropylamid.. hexamethylfosforamid og 3-(3,4-dimethoxyfenyl)-propionsyre i THF for dannelse av 1-(3,4-dimethoxyfenyl)-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyfenyl)-hexan-2-syre (23).
Derivatet med formel 23 overføres så til et forma-midderivat med formel 19, f.eks. ved behandling med difenylfosforylazid og base og påfølgende behandling med natriumborhydrid. Eksempelvis behandles 1-(3,4-dimethoxyfenyl)-6-cyano-6-(i-propyl)-(3,4-dimethoxyfenyl)-hexan-2-syre (23) med triethylamin og difenylfosforylazid i THF, hvoretter det foretas omsetning med NaBH4i dimethoxyethan. Derved fåes 1-(3,4-dimethoxyfenyl)-2-{formylamino)-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyfenyl)-hexan (19). Mellomproduktene med formel 19 kan separeres i diastereomere par ved kromatografering på silicagel under anvendelse av ethylacetat-hexan (4:1) som elueringsmiddel. Mellomproduktene med formel 19 kan overføres til forbindelser med formel 1 etter prosedyrene ifølge Reaksjonsskjerna II, trinn 8-9.
Den frie base med formel 1 kan overføres til et i farmasøytisk henseende aksepterbart salt, om så ønskes, ved at basen oppløses i et egnet oppløsningsmiddel, såsom en alkohol, og behandles med den passende syre. Eksempelvis oppløses L-(-)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyano- butyl1-6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydroisokinolin (1) i isopropanol, hvoretter HCl-gass bobles gjennom oppløs-ningen. Oppløsningen mettes så med ether for å felle ut L-(-)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin•HC1.
Alternativt kan man fremstille forbindelser ifølge oppfinnelsen etter prosedyrene vist på Reaksjonsskjerna IV. I det første trinn behandles et benzaldehydderivat med ethyl-glycinat-hydroklorid i CH2CI2, Et3N og MgS04ved romtemperatur for dannelse av en iminester med formel 24 (trinn 1). Eksempelvis oppslemmes 3-4-dimethoxybenzaldehyd i en CH2CI2-OPP-løsning av I-^NCF^COOEt • HCl, Et3N og MgS04under omrøring ved 20°C, hvorved det fåes 1-(carboethoxy)-methyliminomethyl-3,4-dimethoxybenzen (24).
Det resulterende imin med formel 24 blir så deprotonert under anvendelse av en egnet sterk base og omsatt med en forbindelse med formel 22 for å danne en forbindelse med formel 25 (trinn 2). Eksempelvis blir 1-(carboethoxy)-methyl-iminomethyl-3,4-dimethoxybenzen (24) oppslemmet i en oppløsning av LiNiPr2i THF/HMPA ved -78°C og deretter omsatt med 2-(3,4-dimethoxyfenyl)-2-isopropyl-2-(3-j odpropyl)-acetonitril (22) for å danne N-[1-carboethoxy-5-(3,4-dimethoxyfenyl)-5-cyano-5-(isopropyl)-pentyl1-iminomethyl-3,4-dimethoxybenzen (25) .
Det resulterende imin med formel 25 N-alkyleres deretter med en forbindelse med formelen R3-L, hvor L er en egnet uttredende gruppe, såsom f.eks. jod eller alkylsulfonat, i et egnet oppløsningsmiddel, såsom f.eks. acetonitril eller aceton, ved en temperatur mellom 15°C og tilbakeløpstempera-turen, hvorved det fåes en iminiumforbindelse med formel 26 (trinn 3). Eksempelvis oppløses N-[carboethoxy-5-(3,4-dimethoxyf enyl )-5-cyano-5-(isopropyl)-pentyl]-iminomethyl-3,4-dimethoxybenzen (25) i aceton med methyljodid og dimethylsul-fat, idet blandingen kokes med tilbakeløpskjøling, hvorved det fåes N-methyl-N-[1-carboethoxy-5-((3,4-dimethoxyfenyl)-5-cyano-5-(isopropyl)-pentyl1-N-(3,4-dimethoxybenzyl)-iminium-jodid eller methylsulfat (26).
Det resulterende iminiumsalt med formel 26 hydro generes deretter for dannelse av et amin med formel 27 (trinn 4). Eksempelvis behandles N-methyl-N-[1-carboethoxy-5-(( 3 , 4-dimethoxyfenyl)-5-cyano-5-(isopropyl)-pentyl]-N-(3,4-dimethoxy-benzyl)-iminiumjodid (26) med NaBH4i MeOH ved en temperatur på 0-25°C for dannelse av N-[1-carboethoxy-5-((3,4-dimethoxy-fenyl)-5-cyano-5-(prop-2-yl)-pentyl]-N-(3,4-dimethoxybenzyl)-N-methylamin (27).
Det resulterende ester-amin med formel 27 reduseres deretter til en alkohol med formel 28 (trinn 5). Eksempelvis oppslemmes N-[1-carboethoxy-5-(3,4-dimethoxyfenyl)-5-cyano-5- ( prop-2-yl)-pentyl]-N-(3,4-dimethoxybenzyl)-N-methylamin (27) i en oppløsning av NaBH4i t-BuOH ved tilbakeløpstempe-ratur. Deretter tilsettes MeOH langsomt, hvorved det fåes N-[1-hydroxy-6-(3,4-dimethoxyfenyl)-6-cyano-6-(prop-2-yl)-hex-2-yl]-N-(3,4-dimethoxybenzyl)-N-methylamin (28).
Alkoholen med formel 28 overføres deretter til et klorid med formel 29 (trinn 6). Eksempelvis oppslemmes N-[1-hydroxy-6-(3,4-dimethoxyfenyl)-6-cyano-6-(prop-2-yl)-hex-2-yl]-N-(3,4-dimethoxybenzyl)-N-methylamin (28) i ether ved 0-25°C, hvoretter tørr HCl-gass bobles gjennom suspensjonen. Deretter tilsettes en oppløsning av SOCI2i CH2CI2for dannelse av N-[1-klor-6-(3,4-dimethoxyfenyl)-6-cyano-6-(prop-2-yl)-hex-2-ylJ-N-(3,4-dimethoxybenzyl)-N-methylammoniumklorid (29).
Ammoniumforbindelsen med formel 29 ringsluttes så for dannelse av en forbindelse med formel 1 (trinn 7). Denne reaksjon utføres under anvendelse av 1-1,5 mol av en Lewis-syre, såsom AICI3, FeCl3, BF3o.l., i et egnet aprotisk opp-løsningsmiddel, fortrinnsvis et halogenert hydrocarbonopp-løsningsmiddel, nitromethan eller nitrobenzen, spesielt CH2CI2, ved en temperatur på fra -10°C til 80°C, i et tidsrom av fra 10 minutter til 5 timer, fortrinnsvis i ca. 2 timer. Eksempelvis blir N-[1-klor-6-(3,4-dimethoxyfenyl)-6-cyano-6-(prop-2-yl)-hex-2-yl]-N-(3,4-dimethoxybenzyl)-N-methylammonium-klorid (29) oppslemmet i CH2CL2ved 0°C og omrørt med 1,5
mol AICI3i to timer, hvorved det fåes 3-[4-(3,4-dimethoxy-fenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1 ,2,3,4-tetrahydroisokinolin (1 ).
Alternativt kan det fremstilles forbindelser ifølge oppfinnelsen ved hjelp av prosedyren ifølge Reaksjonsskjerna V. Det velges først et egnet dopa-derivat, f.eks. 3-(3,4-dimethoxyf enyl)-2-aminopropionsyre. Dette derivat blir så ringsluttet og N-methylert ved behandling med en formaldehydkilde (f.eks. formaldehyd, formalin, paraformaldehyd e.l.)
og maursyre ved 70-110°C i 1-24 timer for dannelse av et tetrahydroisokinolin med formel 30 som vist i Reaksjonsskjema I, trinn 10 (trinn 1). Eksempelvis oppvarmes 3-(3,4-dimethoxy-fenyl)-2-aminopropionsyre med paraformaldehyd og maursyre i 2- 8 timer ved 80-100°C, hvorved det fåes 3-carboxy-6,7-dimethoxy-N-methyl-l ,2,3,4-tetrahydroisokinolin (30).
Det resulterende tetrahydroisokinolinderivat med formel 30 blir så forestret med en egnet lavere alkanol etter standard metoder, hvorved det fåes en tetrahydroisokinolinester med formel 31 (trinn 2). Eksempelvis behandles 3- carboxy-6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydroisokinolin (30) med HC1 i EtOH, hvorved det fåes 3-carboethoxy-6,7-dimethoxy-N-methyl-1 ,2,3,4-tetrahydroisokinolin (31 ).
Den resulterende ester med formel 31 behandles så med et jodalkan med formel 22 (se Reaksjonsskjema III, trinn 2) i nærvær av en sterk base, hvorved det fåes en alkylert tetrahydroisokinolinester med formel 32. Eksempelvis blir 3-carboethoxy-6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydroisokinolin (31) satt til en oppløsning av LDA i THF ved -70°C og blandingen tillatt å stå i 5-60 minutter, fortrinnsvis i ca. 10 minutter. Til denne reaksjonsblanding settes det så 2-(3,4-dimethoxyfenyl)-2-isopropyl-2-(3-jodpropyl)-acetonitril ( 22)
i THF, og den resulterende blanding tillates å oppvarmes til ca. 0°C. Blandingen blir så surgjort, f.eks. med fortynnet HC1, og produktet ekstraheres og renses, hvorved det fåes 3-carboethoxy-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyano-butyl ]-6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydroisokinolin (32) .
Den resulterende alkylerte ester med formel 32 hydrolyseres så ved at den oppvarmes i 6N HC1, hvorved man får et carboxylsyre-ammoniumsalt med formel 33 (trinn 4). Eksempelvis oppvarmes 3-carboethoxy-3-[4-(3,4-dimethoxyfenyl)-4- isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-l ,2,3,4- tetrahydroisokinolin (32) ved 35°C i 6N HC1 for dannelse av 3- carboethoxy-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyano-butyl1-6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydroisokinolinium-klorid (33).
Det resulterende salt med formel 33 decarboxyleres deretter for dannelse av et dihydroisokinoliniumsalt med formel 34 (trinn 5). Eksempelvis behandles 3-carboethoxy-3-[4 -(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisokinoliniumklorid (33) med Et3N og deretter med POCI3for dannelse av 3-t4-(3,4-dimethoxyf enyl )-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-l ,4-dihydroisokinoliniumklorid (34) .
Dihydroisokinoliniumsaltet med formel 34 hydrogeneres så for dannelse av en forbindelse med formel 1 (trinn 6). Denne reaksjon utføres under anvendelse av et egnet hydro-generingsmiddel, fortrinnsvis et borhydridderivat, spesielt NaBH4. Oppløsningsmidlet som benyttes, er fortrinnsvis en lavere alkanol, spesielt MeOH. Reaksjonen utføres ved en temperatur på fra -10°C til 50°C, fortrinnsvis ved ca. 0°C,
i løpet av fra 10 minutter til 3 timer, fortrinnsvis i 1
time. Eksempelvis blir 3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4- cyanobutyl]-6,7-dimethoxy-N-methyl-l,4-dihydroisokinoliniumklorid (34) oppslemmet i MeOH ved 0°C og deretter behandlet med NaBH4i ca. 1 time, hvorved det fåes 3-(4-(3,4-dimethoxy-fenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin (1).
Forbindelser ifølge oppfinnelsen kan også fremstilles ved at man følger prosedyren vist i Reaksjonsskjema VII. Først overføres en ester med formel 27 til et ammoniumsalt med formel 35 ved at den behandles med konsentrert HCl (trinn 1). Eksempelvis oppvarmes N-[1-carboethoxy-5-(3,4-dimethoxy-fenyl)-5-cyano-5-(prop-2-yl)-pentyl1-N-(3,4-dimethoxybenzyl)-N-methylamin (27) ved 35°C i 6N HCl for dannelse av N-[1-carboxy-5-(3,4-dimethoxyfenyl)-5-cyano-5-(prop-2-yl)-pentyl]-N-(3,4-dimethoxybenzyl)-N-methylammoniumklorid (35).
Det resulterende ammoniumsalt med formel 35 overføres så til et syreklorid med formel 36 (trinn 2). Eksempelvis behandles N-[1-carboxy-5-(3,4-dimethoxyfenyl)-5-cyano-5-
(prop-2-yl)-pentyl]-N-(3,4-dimethoxybenzyl)-N-methylammonium-klorid (35) med PCI5i ether for dannelse av N-[1-klorcarbonyl-5-(3,4-dimethoxyfenyl)-5-cyano-5-(prop-2-yl)-pentyl)-N-(3,4-dimethoxybenzyl)-N-methylammoniumklorid (36).
Acylkloridet med formel 36 ringsluttes så under Friedel-Crafts-acyleringsbetingelser for dannelse av et tetrahydroisokinolinonderivat med formel 37 (trinn 3) Eksempelvis omsettes N-[1-klorcarbonyl-5-(3,4-dimethoxyfenyl)-5-cyano-5-(prop-2-yl)-pentylj-N-(3,4-dimethoxybenzyl)-N-methyl-ammoniumklorid (36) med 1-1,5 ekvivalenter av en Lewis-syre, f.eks. AICI3i CH2CI2, ved en temperatur på fra -10°C til 50°C for dannelse av 3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-4-oxo-1,2,3,4-tetra-hydroisokinoliniumklorid (37).
Saltet med formel 37 reduseres så til en alkohol
med formel 38 under anvendelser av et egnet borhydrid-hydro-generingsmiddel i et oppløsningsmiddel bestående av en lavere alkanol (trinn 4). Eksempelvis behandles 3-[4-(3,4-dimethoxy-fenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-4-oxo-1,2,3,4-tetrahydroisokinoliniumklorid (37) med NaBH4i MeOH ved en temperatur på 0-25°C for dannelse av 4-hydroxy-3-[4 - ( 3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-l ,2,3,4-tetrahydroisokinolin (38).
Et molekyl H2O elimineres så fra alkoholen med formel 38 for å danne et 1,2-dihydroisokinolinderivat med formel 39 (trinn 5). Eksempelvis behandles 4-hydroxy-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7-dimethoxy-N-methyl-l , 2 , 3 , 4-tetrahydroisokinolin (38) med vandig HCl, hvoretter det foretas reaksjon med NaOH, for dannelse av 3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-l ,2-dihydroisokinolin (39).
Forbindelsen med formel 39 kan også fåes ved at en forbindelse med formel 34 behandles med en egnet base, såsom NaOH eller Na2C03. Eksempelvis behandles 3-[4-(3,4-dimethoxy-fenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-l,4-dihydroisokinoliniumklorid (34) med vandig NaOH, hvorved det fåes 3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-l,2-dihydroisokinolin (39).
Den resulterende forbindelse med formel 39 hydrogeneres så for dannelse av en forbindelse med formel 1 .
Denne hydrogenering kan utføres ved bruk av NaBH/j. Oppløsnings-midlet som benyttes, er fortrinnsvis en lavere alkanol, spesielt MeOH. Reaksjonen utføres ved en temperatur på fra
-10°C til 50°C, fortrinnsvis ved ca. 0°C, i et tidsrom av fra 10 minutter til 3 timer, fortrinnsvis i 1 time. Alternativt kan det benyttes H2med en heterogen katalysator, såsom Pd/C
i EtOH, eller en homogen katalysator, såsom Wilkinsons katalysator, RhCl(P^3)3. Reaksjonen kan utføres ved temperaturer mellom 0 og 200°C, fortrinnsvis ved 25-60°C, ved et trykk på fra 0,5 til 100 atmosfærer, fortrinnsvis ved ca. 3 atmosfærer, i et tidsrom av fra 20 minutter til 24 timer, fortrinnsvis i ca. 6 timer. Egnede oppløsningsmidler innbefatter polare organiske oppløsningsmidler, f.eks. lavere alkanoler, spesielt MeOH, EtOH eller isopropanol. Mengdeforholdet mellom katalysator og substrat er vanligvis ca. 1:1000. Eksempelvis settes 3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7-dimethoxy-N-methyl-1,2-dihydroisokinolin (39) til en oppløsning av RhCl(P(p3)3i isopropanol ved 3 atm, hvoretter blandingen oppvarmes ved 50°C i fire timer. Produktet renses, hvorved det fåes 3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl)-6,7-dimethoxy-N-methyl-l ,2,3,4-tetrahydroisokinolin (1 ). Alternativt kan man hydrogenere dobbeltbindingen stereoselek-tivt under anvendelse av en hydrogeneringskatalysator med en egnet chiral-ligand, f.eks. 1,2-bis-[P-(2-methoxyfenyl)-P-f enylf osf inyl ]-ethan , som vanligvis forkortes til "DiPAMP'<T>,
se Knowles, Acc. Chem. Res., 16, 106-112 (1983) og de publikasjoner som det der er henvist til. Eksempelvis kan 3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-l , 2-dihydroisokinolin (39) settes til en oppløsning av Rh(DiPAMP>2i isopropanol under H2av 3 atmosfærers trykk, og blandingen oppvarmes ved 50°C i fire timer. Produktet renses, hvorved det fåes optisk aktivt 3-[4-(3,4-dimethoxy-fenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1 ,2,3,4-tetrahydroisokinolin (1).
Alternativt kan det fremstilles en forbindelse med formel 1 direkte fra ammoniumsaltet med formel 37 ved reduksjon med NaCNBIl3 og ZnJ2som vist i Reaks j onsskj ema VII. Denne reaksjon utføres ved en temperatur på mellom 0 og 100°C, fortrinnsvis ved ca. 20°C, i et egnet halogenert hydrocarbon-oppløsningsmiddel, såsom 1,1-diklorethan, i 2-36 timer, fortrinnsvis i ca. 20 timer, se C.K. Lau, et al., J. Org. Chem., 51, 3038-3043 (1986). Eksempelvis settes 3-(4-(3,4-dimethoxy-fenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-4-oxo-1,2,3,4-tetrahydroisokinoliniumklorid (37) til en oppløs-ning av NaCNBH3og ZnJ2i 1 ,1-diklorethan, hvoretter blandingen omrøres ved omgivelsenes temperatur i 20 timer. Dermed fåes 3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin (1).
Alternativt kan det fremstilles en forbindelse med formel 1 direkte fra alkoholen med formel 38 ved reduksjon med NaCNBH3og ZnJ2, som vist i Reaksjonsskjema VIII. Denne reduksjon utføres under de samme betingelser som i Reaksjonsskjema VII. Således kan f.eks. 4-hydroxy-3-[4-(3,4-dimethoxy-fenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin (38) settes til en oppløsning av NaCNBH3og ZnJ2i 1,1-diklorethan og blandingen omrøres ved omgivelsenes temperatur i 20 timer, hvorved det fåes 3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-l ,2,3,4-tetrahydroisokinolin (1 ) .
Forbindelser med formel 1 kan også fremstilles i henhold til Reaksjonsskjema IX. En forbindelse med formel 19 ringsluttes til et 3,4-dihydroisokinolin med formel 40 under anvendelse av POCI3og deretter Na2C03(trinn 1). Eksempelvis behandles 1-(3,4-dimethoxyfenyl)-2-(formylamino)-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyfenyl)-hexan (19) med POCI3i Et20, hvoretter det foretas omrøring i vandig Na2C03«Derved fåes 3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-3,4-dihydroisokinolin (40).
Dihydroisokinolinderivatet med formel 40 blir så N-alkylert under anvendelse av en forbindelse med formel
R3-L for dannelse av et 3,4-dihydroisokinoliniumderivat med formel 41 (trinn 2). Eksempelvis blir 3-[4-(3,4-dimethoxy-fenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-3,4-dihydroisokinolin (40) oppløst i aceton med methyljodid og kokt med tilbakeløpskjøling for dannelse av 3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-3,4-di-hydroisokinoliniumjodid (41).
Den resulterende forbindelse med formel 41 hydrogeneres så for dannelse av en forbindelse med formel 1.
Denne hydrogenering utføres fortrinnsvis ved bruk av NaBIl4. Oppløsningsmidlet som benyttes, er fortrinnsvis en lavere alkanol, spesielt MeOH. Reaksjonen utføres ved en temperatur på fra -10°C til 50°C, fortrinnsvis ved ca. 0°C, i et tidsrom av fra 10 minutter til 3 timer, fortrinnsvis i 1 time. Eksempelvis blir 3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyano-butyl]-6,7-dimethoxy-N-methyl-3,4-dihydroisokinoliniumj odid (41) oppslemmet i MeOH ved 0°C og deretter behandlet med NaBH4i ca. 1 time, hvorved det fåes 3-[4-(3,4-dimethoxy-fenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin (1).
Alternativt kan man fremstille forbindelser med formel 1 ved å følge Reaksjonsskjema I, men utelate trinn 4 (Reaksjonsskjema X). Således utføres trinn 5-10 med forbindelser med formler 6-11 hvor R4er H. Forbindelsen med formel 11 hvor R4er H, er betegnet med "formel 42". Den avsluttende alkylering utføres under anvendelse av en sterk protonekstra-herende base, såsom LDA, Li-Bu eller NaH, i et aprotisk opp-løsningsmiddel, såsom CH2CI2. Eksempelvis blir 3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-l , 2 , 3 , 4-tetrahydroisokinolin (42) oppslemmet i en oppløsning av NaH i CH2CI2og deretter behandlet med 2-brom-propan for dannelse av 3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydroisokinolin (1 ) .
De følgende Fremstillinger og Eksempler tjener til
å illustrere oppfinnelsen.
Fremstilling 1
(Mellomprodukter med formel 3)
(A) En blanding av 100 g (0,60 mol) av 3,4-dimethoxybenzaldehyd (2), tilveiebragt fra Aldrich Chemical Co., 10 g
ammoniumacetat fra Aldrich og 800 ml nitromethan ble oppvarmet
over et dampbad i 2,5 timer. Blandingen ble så avkjølt til romtemperatur, blandet med 500 ml isopropanol og langsomt satt til 3,5 liter vann for utfelning av produktet. Det ble erholdt 114 g 3,4-dimethoxy-S-nitrostyren (3) med smeltepunkt 142-143<0>C. (B) På tilsvarende måte, idet man går frem som angitt under punkt (A) ovenfor, men benytter 3,4,5-trimethoxybenzaldehyd, 2,3,4-trimethoxybenzaldehyd, 2 , 3,4,5-tetramethoxy-benzaldehyd, 3,4-dimethoxy-2,5-diethoxybenzaldehyd, eller 3,4-dimethoxy-2,5-dipentoxybenzaldehyd i stedet for 3,4-dimethoxybenzaldehyd, fåes: 3,4,5-trimethoxyfenyl-B-nitrostyren,
2,3,4-trimethoxyfenyl-B-nitrostyren,
2,3,4,5-tetramethoxyfenyl-B-nitrostyren, 3,4-dimethoxy-2,5-diethoxyfenyl-B-nitrostyren, og 3,4-dimethoxy-2,5-dipentoxyfenyl-B-nitrostyren.
Fremstilling 2
(Mellomprodukter med formel 4)
(A) En blanding av 140 g (0,67 mol) 3,4-dimethoxy-S-nitrostyren (3) (av 3°C), 3,2 1 methylenklorid og 2,0 1
isopropanol ble kjølt til 5°C og behandlet med 1,32 kg silicagel (70-230 mesh, EM-reagenser). Etter omrøring ved 5°C i 20 minutter ble det tilsatt 88,6 g (2,34 mol) (Alfa Chemicals)
i løpet av 30 minutter, hvoretter blandingen ble omrørt i 30 minutter ved 5°C. Reaksjonen ble så stoppet ved tilsetning av 280 ml 10%-ig vandig HCl. Silicagelen ble frafiltrert og vasket med 2 x 150 ml CH2C12- De sammenslåtte filtrater ble vasket med 1,0 1 vann og deretter med 1,0 1 saltoppløsning. Det organiske skikt ble fjernet i vakuum, hvorved det ble erholdt 132 g 2-(3,4-dimethoxyfenyl)-1-nitroethan (4) med smeltepunkt 50-52°C i form av en blekgul olje som størknet ved henstand.
(B) På tilsvarende måte, idet man går frem som angitt under punkt (A) ovenfor, men benytter forbindelsene
fremstilt under Fremstilling 1(B) istedenfor 3,4-dimethoxy-B-nitrostyren, fåes: 2-(3,4,5-trimethoxyfenyl)-1-nitroethan,
2-(2,3,4-trimethoxyfenyl)-1-nitroethan, 2 -(2,3,4,5-tetramethoxyfenyl)-1-nitroethan,
2-(3,4-dimethoxy-2,5-diethoxyfenyl)-1-nitroethan,
og
2-(3,4-dimethoxy-2,5-dipentoxyfenyl)-1-nitroethan.
Fremstilling 3
(Mellomprodukter med formel 5)
(A) En blanding av 55 g (0,31 mol) 2-(3,4-dimethoxy-fenyl)-acetonitril (5) (fra Aldrich) i 200 ml dimethylformamid
(DMF) i en dråpetrakt ble tilsatt til en blanding av 15,84 g (0,33 mol) Na EI (50%-ig NaH i mineralolje) i 50 ml DMF i løpet av 30 minutter ved 18-20°C. Etter omrøring i 1 time ble det tilsatt en oppløsning av 53 ml (0,316 mol) 3-klor-propanaldiethylacetal (fra Aldrich) i 50 ml DMF, og blandingen ble omrørt i ca. 3 timer, hvorved man fikk 2-(3,4-dimethoxy-fenyl)-2-(3,3-diethoxypropyl)-acetonitril (5), som ble benyttet i det neste trinn uten ytterligere rensning.
(B) På tilsvarende måte, idet man går frem som angitt under punkt (A) ovenfor, men benytter 2-nitriloethyl-benzo-1,4-dioxan eller 2-nitrilo-ethylbenzo-1,3-dioxol istedenfor 2-(3,4-dimethoxyfenyl)-acetonitril, fåes de følgende forbindelser: 2-(1,3-benzodioxol-2-yl)-2-(3,3-diethoxypropyl)-acetonitril og
2-(1,4-benzodioxan-2-yl)-2-(3,3-diethoxypropyl)-acetonitril.
Fremstilling 4
(Mellomprodukter med formel 6)
(A) Til produktblandingen erholdt under Fremstilling 3(A) ovenfor ble det i én porsjon tilsatt en oppløsning av
39,5 ml (0,43 mol) 2-klorpropan og 0,04 ml 2-jodpropan i 50
ml DMF. Etter omrøring i 10 minutter ble det tilsatt 15,9 g (0,33 mol) NaH (50% i mineralolje), og den resulterende blanding ble oppvarmet til 40°C og omrørt i 18 timer. Blandingen ble så avkjølt til romtemperatur, og det ble tilsatt
200 ml isvann. Blandingen ble ekstrahert med 500 ml hexan for å fjerne mineraloljen, som så ble hevet. Det vandige DMF-skikt ble fortynnet med 800 ml vann og ekstrahert med 3
x 500 ml ethylacetat. Ethylacetatekstrakten ble inndampet, hvorved det ble erholdt 97,6 g 2-(3,4-dimethoxyfenyl)-2-(3,3-diethoxypropyl)-2-isopropylacetonitril i form av en olje. Kokepunkt 164-166°C/0,2 mmHg. MS m/e 349(M+)).
(B) På tilsvarende måte, idet man går frem som angitt under punkt (A) ovenfor, men benytter methylklorid, klorethan, 2-klorbutan eller 3-brompentan istedenfor klorpen-tan, fåes de følgende forbindelser: 2-(3,4-dimethoxyfenyl)-2-(3,3-diethoxypropyl)-2-methylacetonitril, 2-(3,4-dimethoxyfenyl)-2 -(3,3-diethoxypropyl)-2 - ethylacetonitril, 2-(3,4-dimethoxyfenyl)-2-(3,3-diethoxypropyl)-2-(but-2-yl)-acetonitril og 2-(3,4-dimethoxyfenyl)-2-(3,3-diethoxypropyl)-2-(pent-3-yl)-acetonitril. (C) På tilsvarende måte, idet man går frem som angitt under punkter (A-B) ovenfor, men benytter forbindelsene fremstilt under Fremstilling 3(B) istedenfor det angitte utgangsmateriale, fåes de følgende forbindelser: 2-( 1 ,3-benzodioxol-2-yl)-2-(3,3-diethoxypropyl)-2-methylacetonitril,
2-(1 ,3-benzodioxol-2-yl)-2-(3,3-diethoxypropyl)-2-ethylacetonitril,
2-(1 ,3-benzodioxol-2-yl)-2-(3,3-diethoxypropyl)-2-isopropylacetonitril,
2-(1 ,3-benzodioxol-2-yl)-2-(3,3-diethoxypropyl)-2-(but-2-yl)-acetonitril,
2-( 1 ,3-benzodioxol-2-yl)-2-(3,3-diethoxypropyl)-2-(pent-3-yl)-acetonitril,
2-(1,4-benzodioxan-2-yl)-2-(3,3-diethoxypropyl)-2-methylacetonitril,
2-(1,4-benzodioxan-2-yl)-2-(3,3-diethoxypropyl)-2-ethylacetonitril,
2-(1,4-benzodioxan-2-yl)-2-(3,3-diethoxypropyl)-2-
isopropylacetonitril,
2-(1,4-benzodioxan-2-yl)-2-(3,3-diethoxypropyl)-2-(but-2-yl)-acetonitril og
2-(1,4-benzodioxan-2-yl)-2-(3,3-diethoxypropyl)-2-(pent-3-yl)-acetonitri1.
Fremstilling 5
(Mellomprodukter med formel 7)
(A) 97,6 g (0,28 mol) 2-(3,4-dimethoxyfenyl)-2-(3,3-diethoxypropyl)-2-isopropylacetonitril i 1,4 1 THF og
550 ml vann ble tilberedt ved 55°C. Det ble så tilsatt 66 ml konsentrert HCl i løpet av 15 minutter, og blandingen ble omrørt i ytterligere 30 minutter. THF-oppløsningsmidlet ble så fjernet i vakuum, og den vandige rest ble ekstrahert med 1,3 1 CH2CI2og 500 ml vann. Det organiske skikt ble fraskilt, vasket med 500 ml mettet vandig NaHC03og inndampet, hvorved det ble erholdt 71,7 g 2-(3,4-dimethoxyfenyl)-2-(3-oxopropyl)-2-isopropylacetonitril (7) i form av en tykk olje. MS m/e 275 (M+).
(B) På tilsvarende måte, idet man går frem som angitt under punkt (A) ovenfor, men benytter forbindelsene
fremstilt under Fremstilling 4(B) istedenfor 2-(3,4-dimethoxy-fenyl)-2-(3,3-diethoxypropyl)-2-isopropylacetonitril, fåes de følgende forbindelser:
2-(3-oxopropyl)-2-(3,4-dimethoxyfenyl)-2-methyl-acetonitril, 2-(3-oxopropyl)-2-(3,4-dimethoxyfenyl)-2-(ethyl-acetonitril , 2-(3-oxopropyl)-2-(3,4-dimethoxyfenyl)-2-(but-2-yl)-acetonitril, 2-(3-oxopropyl)-2-(3,4-dimethoxyfenyl)-2-(pent-3-yl)-acetonitril, 2-(3-oxopropyl)-2-(1,3-benzodioxol-2-yl)-2-methyl-acetonitril, 2-(3-oxopropyl)-2-(1,3-benzodioxol-2-yl)-2-ethyl-acetonitril , 2-(3-oxopropyl)-2-(1,3-benzodioxol-2-yl)-2-isopropyl-acetonitril , 2 - (3-oxopropyl)-2-(1,3-benzodioxol-2-yl)-2-(but-2-yl)-acetonitril,
2-(3-oxopropyl)-2-(1,3-benzodioxol-2-yl)-2-(pent-3-yl)-acetonitril,
2-(3-oxopropyl)-2-(1,4-benzodioxan-2-yl)-2-methyl-acetonitril,
2-(3-oxopropyl)-2-(1,4-benzodioxan-2-yl)-2-ethyl-acetonitril ,
2-(3-oxopropyl)-2-(1,4-benzodioxan-2-yl)-2-isopropyl-acetonitril ,
2-(3-oxopropyl)-2-(1,4-benzodioxan-2-yl)-2-(but-2-yl)-acetonitril og
2-(3-oxopropyl)-2-(1,4-benzodioxan-2-yl)-2-(pent-3-yl)-acetonitril.
Fremstilling 6
(Mellomprodukter med formel 8)
(A) En blanding av 135 g (0,64 mol) 2-(3,4-dimethoxyf enyl ) -1 -nitroethan (4), 156 g (0,57 mol) 2-(3,4-dimethoxyf enyl)-2-(3-oxopropyl)-2-isopropylacetonitril (7) og 19,3 g vannfritt KF (fra Aldrich) i 2,0 1 2-propanol ble oppvarmet ved 50-55°C i ca. 40 timer. Blandingen ble så avkjølt til romtemperatur, og isopropanolen ble fjernet i vakuum. Residuet ble oppløst i 1,6 1 CH2CI2og filtrert gjennom 50 g Celite. Filtratet ble ekstrahert med 2 x 500 ml mettet, vandig NaHCC>3. Det organiske skikt ble inndampet, og produktet ble omkrystallisert fra ethylacetat-hexan (1:1), hvorved det ble erholdt 205 g 1-(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyfenyl)-hexan-3-ol (8) med smeltepunkt 171-173°C. MS m/e 486(M+). (B) På tilsvarende måte, idet man går frem som angitt under punkt (A) ovenfor, men benytter forbindelsene fremstilt under Fremstilling 5(B) istedenfor 2-(3,4-dimethoxy-fenyl)-2-(3-oxopropyl)-2-isopropylacetonitril (7), fåes de følgende forbindelser: 1-(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxyfenyl)-hexan-3-ol,
1-(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(ethyl)-
6-(3,4-dimethoxyfenyl)-hexan-3-ol, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(but-2-yl) -6-(3,4-dimethoxyfenyl)-hexan-3-ol, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxyfenyl)-hexan-3-ol,
1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxyfenyl)-hexan-3-ol, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxyfenyl)-hexan-3-ol, 1 - (1 ,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(prop-2- yl)-6-(3,4-dimethoxyfenyl)-hexan-3-ol, 1 - (1 ,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxyfenyl)-hexan-3-ol, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(pent-3- yl)-6-(3,4-dimethoxyfenyl)-hexan-3-ol, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxyfenyl)-hexan-3-ol, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxyfenyl)-hexan-3-ol, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(prop-2- yl)-6-(3,4-dimethoxyfenyl)-hexan-3-ol, 1 - (1 ,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxyfenyl)-hexan-3-ol og 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(pent-3- yl)-6-(3,4-dimethoxyfenyl)-hexan-3-ol. (C) På tilsvarende måte, idet man går frem som angitt under punktene (A-B) ovenfor, men benytter forbindelsene fremstilt under Fremstilling 2(B) istedenfor 2-(3,4-dimethoxyfenyl)-1-nitroethan (4), fåes de følgende forbindelser: 1-(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(methyl)-6-(3,4,5-trimethoxyfenyl)-hexan-3-ol, 1-(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4,5-trimethoxyfenyl)-hexan-3-ol, 1-(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4,5-trimethoxyfenyl)-hexan-3-ol, 1-(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(but-2-yl) -6-(3,4,5-trimethoxyfenyl)-hexan-3-ol, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(pent-3 - yl) - 6-(3,4,5-trimethoxyfenyl)-hexan-3-ol, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4,5-trimethoxyfenyl)-hexan-3-ol, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4,5-trimethoxyfenyl)-hexan-3-ol, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(prop-2- yl)-6-(3,4,5-trimethoxyfenyl)-hexan-3-ol, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4,5-trimethoxyfenyl)-hexan-3-ol, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(pent-3- yl)-6-(3,4,5-trimethoxyfenyl)-hexan-3-ol, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4,5-trimethoxyfenyl)-hexan-3-ol, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(ethyl)-6 - ( 3 , 4,5-trimethoxyfenyl)-hexan-3-ol, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(prop-2- yl)-6-(3,4,5-trimethoxyfenyl)-hexan-3-ol, 1 -(1 ,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(but-2-yl) - 6-(3,4,5-trimethoxyfenyl)-hexan-3-ol, 1 -(1 ,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(pent-3- yl)-6-(3,4,5-trimethoxyfenyl)-hexan-3-ol, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(methyl)-6 - ( 2 ,3 ,4-trimethoxyfenyl)-hexan-3-ol, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(ethyl)-6-(2,3,4-trimethoxyfenyl)-hexan-3-ol, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(2,3,4-trimethoxyfenyl)-hexan-3-ol, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(but-2-yl)-6-(2,3,4-trimethoxyfenyl)-hexan-3-ol, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(2,3,4-trimethoxyfenyl)-hexan-3-ol, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(2,3,4-trimethoxyfenyl)-hexan-3-ol, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(2,3,4-trimethoxyfenyl)-hexan-3-ol, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(2,3,4-trimethoxyfenyl)-hexan-3-ol, 1 -(1 , 3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(2,3,4-trimethoxyfenyl)-hexan-3-ol, 1 - (1 ,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(2,3,4-trimethoxyfenyl)-hexan-3-ol, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(2,3,4-trimethoxyfenyl)-hexan-3-ol, 1 -(1 ,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(2,3,4-trimethoxyfenyl)-hexan-3-ol, 1 -(1 ,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(prop-2- yl)-6-(2,3,4-trimethoxyfenyl)-hexan-3-ol, 1 -(1 ,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(2,3,4-trimethoxyfenyl)-hexan-3-ol, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(pent-3- yl)-6-(2,3,4-trimethoxyfenyl)-hexan-3-ol, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(methyl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan-3-ol, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(ethyl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan-3-ol, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(prop-2-yl)-6- ( 2,3,4,5-tetramethoxyfenyl)-hexan-3-ol, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(but-2-yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan-3-ol, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan-3-ol, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan-3-ol, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan-3-ol, 1 - (1 ,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(prop-2- yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan-3-ol, 1 - (1 ,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan-3-ol, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(pent-3- yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan-3-ol,
1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan-3-ol,
1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan-3-ol, 1 -(1 ,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(prop-2- yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan-3-ol, 1 - (1 ,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan-3-ol,
1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(pent-3- yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan-3-ol, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan-3-ol, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan-3-ol, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan-3-ol, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan-3-ol, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(pent-3 - yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan-3-ol, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan-3-ol, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan-3-ol, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(prop-2- yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan-3-ol, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan-3-ol, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(pent-3- yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan-3-ol, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan-3-ol, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan-3-ol, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(prop-2- yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan-3-ol, 1 - (1 ,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3 ,4-dimethoxy-2,5-diethoxyfenyl)-hexan-3-ol, 1 - (1 ,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(pent-3- yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan-3-ol, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan-3-ol, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan-3-ol, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan-3-ol, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan-3-ol, 1 -(3 , 4-dimethoxyfenyl)-2-nitro-6-cyano-6-(pent-3-yl)-6 -(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan-3-ol, 1 - (1 ,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan-3-ol, 1 -(1 ,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan-3-ol,
1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(prop-2- yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan-3-ol, 1 -(1 ,3-benzod ioxol-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan-3-ol, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(pent-3- yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan-3-ol, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan-3-ol, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(ethyl)-6 -(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan-3-ol, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(prop-2- yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan-3-ol, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(but-2-yl) - 6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan-3-ol og 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(pent-3- yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan-3-ol.
Fremstilling 7
(Mellomprodukter med formel 9)
(A) En blanding av 75 g (0,154 mol) 1-(3,4-dimethoxyf enyl )-2-nitro-6-cyano-6-(i-propyl)-6-((3,4-dimethoxy-fenyl)-hexan-3-ol (8), 1,5 g 4-dimethylaminopyridin ("DMAP") fra Aldrich) og 23 ml eddiksyreanhydrid i 700 ml CH2CI2ble kokt med tilbakeløpskjøling i 40 minutter, hvorved man fikk 1 -(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyfenyl)-hexan (9), som ble benyttet i det
neste trinn uten å isoleres.
(B) På tilsvarende måte, idet man går frem som angitt under del (A) ovenfor, men benytter forbindelsene
fremstilt under Fremstilling 6(B-C) istedenfor 1-(3,4-dimethoxyf enyl )-2-nitro-6-cyano-6-(i-propyl)-6-(3,4-dimethoxy-fenyl)-hexan-3-ol, fåes de følgende forbindelser:
1-(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-' 6 -(methyl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxyfenyl)-hexan, 1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1-(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6 -(prop-2-yl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6 -(3,4,5-trimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(1 ,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1-(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(1 ,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1-(1 ,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1-(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 - (1 ,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6 -(prop-2-yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1-(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6 -(ethyl)-6 -(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1-(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan,
1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan,
1-(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6 -(pent-3-yl)-6 -(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan,
1 -(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(1 ,3-benzodioxol-2-y1)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan og 1 -(1,4-benzodioxan-2-yl)-2-nitro-3-acetoxy-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan.
Fremstilling 8
(Mellomprodukter med formel 10)
(A) Reaksjonsblandingen inneholdende 1-(3,4-dimethoxyf enyl )-2-nitro-3-acetoxy-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyfenyl)-hexan (9) fremstilt under Fremstilling 7(A)
ble avkjølt til romtemperatur og fortynnet med 350 ml isopropanol. 15 g (0,4 mol) fast MaBH4ble tilsatt i løpet av 15 minutter ved 25°C. Blandingen ble så kokt med tilbake-løpskjøling (ca. 40°C) i 15 timer og deretter avkjølt til 5°C. 30 ml 10%-ig HCl ble langsomt tilsatt og deretter 100
ml vann. Det organiske skikt ble ekstrahert, vasket med 200
ml mettet, vandig NH4CI og 200 ml mettet, vandig NaHC03. Det organiske skikt ble inndampet, hvorved man fikk 58,7 g 1-(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-{i-propyl)-6-(3,4-dimethoxyf enyl)-hexan (10) som et blekgult fast stoff. Smeltepunkt 107-110°C. MS m/e 470(M+).
(B) På tilsvarende måte, idet man går frem som angitt under del (A) ovenfor, men benytter forbindelsene
fremstilt under Fremstilling 7(B) istedenfor 1 -(3,4-dimethoxy-fenyl)-2-nitro-3-acetoxy-6-cyano-6-(i-propyl)-6-(3,4-dimethoxy-fenyl)-hexan, fåes de følgende forbindelser:
1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(1 ,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(prop-2- yl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(1 ,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(1 ,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(pent-3- yl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(1 ,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(1 ,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(prop-2- yl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(pent-3- yl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(methyl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(prop-2-yl) - 6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(pent-3 - yl) - 6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(prop-2- yl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(pent-3- yl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4,5-trimethoxyfenyl)-hexan,
1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4,5-trimethoxyfenyl)-hexan,
1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(prop-2- yl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(pent-3- yl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(methyl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(ethyl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(but-2-yl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)- 2-nitro-6-cyano-6-(pent-3-yl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1-(1 ,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(2,3,4-trimethoxyfenyl)-hexan,
1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(1 ,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(prop-2- yl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(2,3,4-trimethoxyfenyl)-hexan,
1-(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(pent-3- yl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(1 ,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(prop-2- yl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(pent-3- yl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(methyl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(ethyl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(but-2-yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(methyl)-6 -(2,3,4,5-tetramethoxyfenyl)-hexan, 1 - (1 ,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(ethyl)-6 -(2,3,4,5 -tetramethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(prop-2- yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 - (1 ,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(pent-3- yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan , 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(2 , 3,4,5-tetramethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(prop-2- yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan,
1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(1 ,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(pent-3- yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan,
1-(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan,
1-(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 - (1 ,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan,
1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(prop-2- yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6 -(but-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(pent-3- yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(ethyl)-6 -(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(3 , 4-dimethoxyfenyl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(1 ,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(prop-2- yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(1 ,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-nitro-6-cyano-6-(pent-3- yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan,
1-(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1-(1 ,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(but-2 - yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan og 1 -(1,4-benzodioxan-2-yl)-2-nitro-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan.
Fremstilling 9
(Mellomprodukter med formel 11)
(A) En blanding av 58,7 g (0,125 mol) 1-(3,4-dimethoxyf enyl )-2-nitro-6-cyano-6-(i-propyl)-6-(3,4-dimethoxy-fenyl)-hexan (10) og 950 ml methanol ble satt til en kolbe,
og kolben ble evakuert for å fjerne oxygen. Katalysatoren, bestående av 5% Pd på carbon (50% vann, 19g, fra Engelhard Co.) ble tilsatt under KT2-atmosfære. Etter omrøring i 10 minutter ved romtemperatur ble det tilsatt 65g fast HCO2NH4(fra Aldrich), og den resulterende blanding ble omrørt i én time. Blandingen ble så langsomt oppvarmet til 50°C i løpet av 48 timer og deretter avkjølt til romtemperatur og filtrert gjennom 50 g Celite. Det faste stoff ble vasket med 50 ml methanol, og filtratene ble inndampet i vakuum. Det resulterende faste stoff ble oppløst i CH2CI2. Oppløsningen ble ekstrahert med 500 ml mettet, vandig NH4CL og 300 ml mettet, vandig NaHC03og det organiske skikt ble inndampet, hvorved man fikk 52,3 g 1-(3,4-dimethoxyfenyl)-2-amino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyfenyl)-hexan (11) i form av en blekgul olje. MS m/e 440(M+). (B) På tilsvarende måte, idet man går frem som angitt under punkt (A) ovenfor, men benytter forbindelsene fremstilt under Fremstilling 8(B) istedenfor 1 -(3,4-dimethoxy-fenyl)-2-nitro-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyfenyl)-hexan, fåes de følgende forbindelser: 1 -(3,4-dimethoxyfenyl)-2-amino-6-cyano-6-(methyl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-amino-6-cyano-6-(ethyl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-amino-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-amino-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxyfenyl)-hexan, 1 - (1 ,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(methyl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(ethyl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(prop-2- yl)-6-(3,4-dimethoxyfenyl)-hexan,
1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(T,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(pent-3- yl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(methyl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(ethyl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(prop-2- yl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(pent-3- yl)-6-(3,4-dimethoxyfenyl)-hexan,
1-(3,4-dimethoxyfenyl)-2-amino-6-cyano-6-(methyl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-amino-6-cyano-6-(ethyl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-amino-6-cyano-6-(prop-2-yl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 - ( 3 ,4-dimethoxyfenyl)-2-amino-6-cyano-6-(but-2-yl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-amino-6-cyano-6-(pent-3 - yl)-6-(3,4,5-trimethoxyfenyl)-hexan,
1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(methyl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(ethyl)-6-(3,4,5-trimethoxyfenyl)-hexan,
1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(prop-2-yl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(but-2-yl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(pent-3-yl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6 -(methyl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(1 ,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(ethyl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(prop-2- yl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(but-2-yl) -6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(pent-3- yl)-6-(3,4,5-trimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-amino-6-cyano-6-(methyl)-6-(2,3,4-trimethoxyfenyl)-hexan,
1-(3,4-dimethoxyfenyl)-2-amino-6-cyano-6-(ethyl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-amino-6-cyano-6-(prop-2-yl) - 6-(2,3,4-trimethoxyfenyl)-hexan,
1-(3,4-dimethoxyfenyl)-2-amino-6-cyano-6-(but-2-yl) - 6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(3 , 4-dimethoxyfenyl)-2-amino-6-cyano-6-(pent-3-yl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(methyl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(ethyl)-6 -(2,3,4-trimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(prop-2- yl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(but-2-yl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(pent-3- yl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(methyl)-6-(2,3,4-trimethoxyfenyl)-hexan,
1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(ethyl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(prop-2-yl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 - (1 ,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(but-2-yl)-6-(2,3,4-trimethoxyfenyl)-hexan,
1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6 -(pent-3-yl)-6-(2,3,4-trimethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-amino-6-cyano-6-(methyl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-amino-6-cyano-6-(ethyl)-6-(2,3,4 ,5-tetramethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-amino-6-cyano-6-(prop-2-yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-amino-6-cyano-6-(but-2-yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 - ( 3 ,4-dimethoxyfenyl)-2-amino-6-cyano-6-(pent-3-yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(methyl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(ethyl)-6 -(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(prop-2- yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan,
1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(but-2-yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(pent-3- yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(methyl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(ethyl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan,
1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(prop-2- yl) - 6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(1 ,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(but-2-yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(pent-3- yl)-6-(2,3,4,5-tetramethoxyfenyl)-hexan,
1-(3,4-dimethoxyfenyl)-2-amino-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-amino-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 - ( 3 , 4-dimethoxyf enyl) -2-amino-6-cyano-6-.( prop-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-amino-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-amino-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(ethyl)-6 -(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1-(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(prop-2- yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1-(1 ,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(1 ,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(pent-3- yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan,
1-(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(1 ,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(1 ,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(prop-2- yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(1 ,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(pent-3- yl)-6-(3,4-dimethoxy-2,5-diethoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-amino-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-amino-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-amino-6-cyano-6-(prop-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-amino-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(3,4-dimethoxyfenyl)-2-amino-6-cyano-6-(pent-3-yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(1 ,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(1 ,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(prop-2- yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(1,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(but-2-yl) - 6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(1 ,3-benzodioxol-2-yl)-2-amino-6-cyano-6-(pent-3- yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(1 ,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(methyl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(1 ,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(ethyl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(1 ,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(prop-2- yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan, 1 -(1,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(but-2-yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan og 1 -(1 ,4-benzodioxan-2-yl)-2-amino-6-cyano-6-(pent - 3- yl)-6-(3,4-dimethoxy-2,5-dipentoxyfenyl)-hexan.
Fremstilling 10
(Mellomprodukter med formel 13)
(A) L-3,4-dimethoxyfenylalaninol (12) ble fremstilt etter metoden beskrevet av A.W. Schrecker og J.L. Hartwell,
J. Amer. Chem. Soc, 79, 3827 (1957). En oppløsning av 23,3 g (110 mmol) L-3,4-dimethoxyfenylalaninol i 400 ml THF ble blandet med 24,0 g (110 mmol) di-t-butyldicarbonat, og den resulterende oppløsning ble kokt med tilbakeløpskjøling i én time. Blandingen ble så inndampet under forminsket trykk, og residuet ble filtrert gjennom silicagel under anvendelse av ethylacetat. Filtratet ble så inndampet, hvorved man fikk 32,4 g L-3-(3,4-dimethoxyfenyl)-2-(t-butoxycarbonylamino)-propan-1-ol (13) med smeltepunkt 92-93°C. ta]^<5>= -19,6°
(MeOH). Beregnet for C16H25N05: C=61,72, H=8,09, N=4,50. Funnet: C=61,62, H=8,13, N=4,47.
(B) På tilsvarende måte, idet man går frem som angitt under punkt (A) ovenfor, men benytter D-3,4-dimethdxy-fenylalaninol, L-3,4,5-trimethoxyfenylalaninol, D-3,4,5-trimethoxyfenylalaninol, L-3,4-dimethoxy-2,5-diethoxyfenyl-
alaninol, D-3,4-dimethoxy-2,5-diethoxyfenylalaninol, L-3,4-dimethoxy-2,5-dipentoxyfenylalaninol eller D-3,4-dimethoxy-2,5-dipentoxyfenylalaninol istedenfor L-3,4-dimethoxyfenyl-alaninol, fåes de følgende forbindelser: D-3-(3,4-dimethoxyfenyl)-2-(t-butoxycarbonylamino)-propan-1-ol, L-3-(3,4,5-trimethoxyfenyl)-2-(t-butoxycarbonyl-amino) -propan-1-ol, D-3-(3,4,5-trimethoxyfenyl)-2-(t-butoxycarbonyl-amino ) -propan-1-ol, L-3-(3,4-dimethoxyfenyl-2,5-diethoxyfenyl)-2-(t-butoxycarbonylamino)-propan-1 -ol, D-3-(3,4-dimethoxy-2,5-diethoxyfenyl)-2-(t-butoxy-carbonylamino )-propan-1-ol, L-3-(3,4-dimethoxy-2,5-dipentoxyfenyl)-2-(t-butoxy-carbonylamino ) -propan-1 -ol og D-3-(3,4-dimethoxy-2,5-dipentoxyfenyl)-2-(t-butoxy-carbonylamino )-propan-1-ol.
Fremstilling 11
(Mellomprodukter med formel 14)
(A) En oppløsning av 32,4 g (104 mmol) L-3-(3,4-dimethoxyfenyl)-2-(t-butoxycarbonylamino)-propan-1 -ol (13), 29,8 g (156 mmol) p-toluensulfonylklorid og 0,63 g DMAP i 100 ml pyridin ble omrørt ved romtemperatur i to dager. Den resulterende blanding ble så fortynnet med ether og vasket med vandig CUSO4og vann, hvoretter det organiske skikt ble tørret over MgSC>4 og inndampet. Residuet ble renset ved kromatografering ved middels trykk (30% ethylacetat-hexan), hvorved man fikk L-3-(3,4-dimethoxyfenyl)-2-(t-butoxycarbonyl-amino )-1 -tosyloxypropan (14) med smeltepunkt 1 46-1 48°C.
[dif)5 = -15,4° (CHCI3). Beregnet for C23<H>31NO7S: C=59,34, H=6,71, N=3,01. Funnet: C=59,37, H=6,73, N=2,98. (B) På tilsvarende måte, idet man går frem som angitt under punkt (A) ovenfor, men benytter forbindelsene fremstilt under Fremstilling 10(B) istedenfor L-3-(3,4-dimethoxyf enyl) -2- (t-butoxycarbonylamino) -propan-1 -ol fåes de følgende forbindelser: D-3-(3,4-dimethoxyfenyl)-2-(t-butoxycarbonylamino)-1- tosyloxypropan, L-3-(3,4,5-trimethoxyfenyl)-2-(t-butoxycarbonyl-amino)-1-tosyloxypropan, D-3-(3,4,5-trimethoxyfenyl)-2-(t-butoxycarbonyl-amino )-1-tosyloxypropan, L-3-(3,4-dimethoxyfenyl-2,5-diethoxyfenyl) -2 - (t-butoxycarbonylamino)-1-tosyloxypropan, D-3-(3,4-dimethoxy-2,5-diethoxyfenyl)-2-(t-butoxy-carbonylamino )-1-tosyloxypropan, L-3-(3,4-dimethoxy-2,5-dipentoxyfenyl)-2-(t-butoxy-carbonylamino) -1-tosyloxypropan og D-3-(3,4-dimethoxy-2,5-dipentoxyfenyl)-2-(t-butoxy-carbonylamino )-1-tosyloxypropan.
Fremstilling 12
(Mellomprodukter med formel 15)
(A) 37,3 ml av en 1,6 molar oppløsning av vinyl-magnesiumbromid i THF ble satt til en suspensjon av temperatur
-5°C .av 5,8 g (29,8 mmol) CuJ i 75 ml THF. Blandingen ble kjølt til -70°C, og 4,6 g (9,9 mmol) L-3-(3,4-dimethoxyfenyl)-2- (t-butoxycarbonylamino)-1-tosyloxypropan (14) i 80 ml THF ble tilsatt langsomt. Blandingen ble omrørt ved -70°C i 30 minutter og deretter tillatt å oppvarmes til 0°C. Den resulterende blanding ble hellet over i vandig NH4CI og ekstrahert med ether. Det organiske skikt ble tørret over MgSC>4 og inndampet, og residuet ble renset ved kromatografering ved middels trykk, hvorved det ble erholdt 2,0 g L-5-(3,4-dimethoxyf enyl )-4-(t-butoxycarbonylamino)-pent-1-en (15). Smeltepunkt 91-92°C. [alp<5>= -20,9° (MeOH). Beregnet for C18H27NO4: C=67,26, H=8,47, N=4,36. Funnet: C=67,33, H=8,49, N=4,32. (B) På tilsvarende måte, idet man går frem som angitt under punkt (A) ovenfor, men benytter forbindelsene fremstilt under Fremstilling 11(B) ovenfor istedenfor L-3-(3,4-dimethoxyfenyl)-4-(t-butoxycarbonylamino)-pent-1-en, fåes de følgende forbindelser: D-5-(3,4-dimethoxyfenyl)-4-(t-butoxycarbonylamino)-
pent-1-en,
L-5- (3,4,5-trimethoxyfenyl)-4-(t-butoxycarbonyl-amino) -pent-1-en, D-5-(3,4,5-trimethoxyfenyl)-4 -(t-butoxycarbonyl-amino )-pent-1-en, L-5-(3,4-dimethoxyfenyl-2,5-diethoxyfenyl)-4-(t-butoxycarbonylamino)-pent-1-en, D-5-(3,4-dimethoxy-2,5-diethoxyfenyl)-4-(t-butoxy-carbonylamino ) -pent-1 -en, L-5-(3,4-dimethoxy-2,5-dipentoxyfenyl)-4-(t-butoxy-carbonylamino) -pent-1 -en og D-5-(3,4-dimethoxy-2,5-dipentoxyfenyl)-4-(t-butoxy-carbonylamino )-pent-1-en.
Fremstilling 13
(Mellomprodukter med formel 16)
(A) En oppløsning av 1,6 g (5 mmol) L-5-(3,4-dimethoxyf enyl ) -4 -( t-butoxycarbonylamino ) -pent-1 -en (15) i 10
ml THF ble satt til en oppløsning av temperatur 0°C av 7,5 mmol disiamylboran i 25 ml THF. Blandingen ble omrørt ved romtemperatur i én time og deretter avkjølt til 0°C, hvoretter det ble tilsatt 1,7 ml 3N NaOH og deretter 1,7 ml 30% H202. Den resulterende oppløsning ble omrørt ved romtemperatur i
30 minutter, fortynnet med ether og vasket med vann og salt-oppløsning. Etheren ble avdampet, og residuet ble omkrystallisert fra ether/hexan, hvorved man fikk 1,2 g D-5-(3,4-dimethoxyf enyl ) -4- ( t-butoxycarbonylamino ) -pentan-1 -ol (16) med smeltepunkt 73-75°C. la]^<5>= +0,89° (MeOH). Beregnet for C18H29N05: C=63,69, H=8,61, N=4,13. Funnet: C=63,58, H=8,64, N=4,06. (B) Pa tilsvarende måte, idet man går frem som angitt under punkt (A) ovenfor, men benytter forbindelsene fremstilt under Fremstilling 12(B) istedenfor L-5-(3,4-dimethoxyf enyl )-4-(t-butoxycarbonylamino)-pent-1-en, fremstilles de følgende forbindelser: L-5-(3,4-dimethoxyfenyl)-4-(t-butoxycarbonylamino)-pentan-1-ol, L-5-(3 , 4,5-trimethoxyfenyl)-4-(t-butoxycarbonyl- amino)-pentan-1-ol, D-5-(3,4,5-trimethoxyfenyl)-4-(t-butoxycarbonyl-amino) -pentan-1-ol, L-5-(3,4-dimethoxyfenyl-2,5-diethoxyfenyl)-4-(t-butoxycarbonylamino)-pentan-1-ol, D-5-(3,4-dimethoxy-2,5-diethoxyfenyl)-4-(t-butoxy-carbonylamino )-pentan-1-ol, L-5-(3,4-dimethoxy-2,5-dipentoxyfenyl)-4-(t-butoxy-carbonylamino ) -pentan-1 -ol og D-5-(3,4-dimethoxy-2,5-dipentoxyfenyl)-4-(t-butoxy-carbonylamino )-pentan-1-ol.
Fremstilling 14
(Mellomprodukter med formel 17)
(A) En oppløsning av 1,0 g (2,98 mmol) D-5-(3,4-dimethoxyfenyl)-4-(t-butoxycarbonylamino)-pentan-1-ol (16)
og 1,3 ml triethylamin i 15 ml CH2CI2ble avkjølt, og 0,26
ml (3,3 mmol) methansulfonylklorid ble tilsatt. Etter 10 minutter ble blandingen tilsatt til vann og det organiske skikt fraskilt og tørret over MgS04. Diklormethanet ble avdampet, og det resulterende hvite, faste stoff ble oppløst i 10 ml aceton. 3 g NaJ ble tilsatt, og blandingen ble kokt med tilbakeløpskjøling i 30 minutter. Blandingen ble så hellet over i vann og ekstrahert med ether, og etheren ble vasket med vandig NaHS03, vann og saltoppløsning. Etherskiktet ble så tørret over MgSC>4 og inndampet, hvorved man fikk et urent D-5-(3,4-dimethoxyfenyl)-4-(t-butoxycarbonylamino)-1 - jodpentan (17), som straks ble benyttet.
(B) Pa tilsvarende måte, idet man går frem som angitt under punkt (A) ovenfor, men benytter forbindelsene
fremstilt under Fremstilling 13(B) istedenfor D-5-(3,4-dimethoxyf enyl )-4-(t-butoxycarbonylamino)-pentan-1-ol, fremstilles de følgende forbindelser:
L-5-(3,4-dimethoxyfenyl)-4-(t-butoxycarbonylamino)-1-j odpentan, L-5-(3,4,5-trimethoxyfenyl)-4-(t-butoxycarbonyl-amino ) -1 -j odpentan , D-5-(3,4,5-trimethoxyfenyl)-4-(t-butoxycarbonyl- amino)-1 -j odpentan, L-5-(3,4-dimethoxyfenyl-2,5-diethoxyfenyl)-4-(t-butoxycarbonylamino)-1 j odpentan, D-5-(3,4-dimethoxy-2,5-diethoxyfenyl)-4-(t-butoxy-carbonylamino)-1-j odpentan, L-5-(3,4-dimethoxy-2,5-dipentoxyfenyl)~4-(t-butoxy-carbonylamino)-1-jodpentan og D-5-(3 , 4-dimethoxy-2,5-dipentoxyfenyl)-4 -(t-butoxy-carbonylamino )-1-jodpentan.
Fremstilling 15
(Mellomprodukter med formel 18)
(A) En oppløsning av 1,3 g (6 mmol) 2-(3,4-dimethoxyf enyl)-2-isopropylacetonitri1 (6a) i 5 ml THF ble satt
til en oppløsning av temperatur -70°C av 6 mmol lithiumdiisopropylamid (LDA) i 20 ml THF. Etter 10 minutter ved -70°C
ble en oppløsning av ca. 3 mmol urent L-5-(3,4-dimethoxy-fenyl)-4-(t-butoxycarbonylamino)-1-jodpentan (17) i 5 ml THF tilsatt og den resulterende blanding tillatt å oppvarmes til 0°C. Vandig HCl ble tilsatt, og blandingen ble ekstrahert med ether. Det organiske skikt ble vasket med vann og salt-oppløsning, tørret over MgS04og inndampet, og residuet ble renset ved kromatografering ved middels trykk (30% ethylacetat-hexan), hvorved man fikk 400 mg (2R)-1-(3,4-dimethoxyfenyl)-2-t-butoxycarbonylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxy-fenyl)-hexan (18).
(B) På tilsvarende måte, idet man går frem som angitt under punkt (A) ovenfor, men benytter forbindelsene
fremstilt under Fremstilling 14(B) istedenfor D-5-(3,4-dimethoxyf enyl)-4-(t-butoxycarbonylamino)-1-jodpentan, fåes de følgende forbindelser: (2S)- 1 -(3,4-dimethoxyfenyl)-2-(t-butoxycarbonyl-amino )-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyfenyl)-hexan,
(2R ) -1 -(3,4,5-trimethoxyfenyl)-2-(t-butoxycarbonyl-amino) -6 -cyano-6 - (i-propyl)-6-(3,4-dimethoxyfenyl)-hexan,
(2S)-1-(3,4,5-trimethoxyfenyl)-2-(t-butoxycarbonyl-amino ) -6 -cyano-6 - ( i-propyl)-6-(3,4-dimethoxyfenyl)-hexan,
(2R)-1 -(3,4-dimethoxy-2,5-diethoxyfenyl)-2-(t-
butoxycarbonylamino)-6-cyano-6-(i-propyl)-6-(3,4-dimethoxy-fenyl)-hexan,
(2S)-1 -(3,4-dimethoxy-2,5-diethoxyfenyl)-2-(t-butoxycarbonylamino)-6-cyano-6-(i-propyl)-6-(3,4-dimethoxy-fenyl)-hexan,
(2R)-1 -(3,4-dimethoxy-2,5-dipentoxyfenyl)-2-(t-butoxycarbonylamino)-6-cyano-6-(i-propyl)-6-(3,4-dimethoxy-fenyl)-hexan og
(2S)-1 -(3,4-dimethoxy-2,5-dipentoxyfenyl)-2-(t-butoxycarbonylamino)-6-cyano-6-(i-propyl)-6-(3,4-dimethoxy-fenyl)-hexan.
Fremstilling 16
(Mellomprodukter med formel 19)
(A) En oppløsnings av 400 mg (2R)-1 -(3,4-dimethoxy-fenyl)-2-(t-butoxycarbonylamino)-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyfenyl)-hexan (18) i 5 ml maursyre ble kokt med tilbakeløpskjøling i 15 minutter. Blandingen ble inndampet,
og residuet ble behandlet med 2 ml maursyre-eddiksyreanhydrid. Det ble tilsatt ether, og blandingen ble vasket med vann, vandig NaHCC>3 og saltoppløsning, og oppløsningen ble tørret over Na2S04. Etheren ble avdampet, og residuet ble renset ved kromatografering ved middels trykk, under anvendelse av ethylacetat. Den første komponent som ble eluert, var (2R, 6S)-1 -(3,4-dimethoxyfenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyfenyl)-hexan (19A), som ble oppnådd i en mengde av 180 mg. [alp 25= -4,3° (MeOH). Den andre komponent som ble eluert, var (2R, 6R)-1-(3,4-dimethoxyfenyl)-2-formyl-amino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyfenyl)-hexan (19B), som ble oppnåo dd i en mengde av 40 mg. [a]^ 25 = +2,3°
(MeOH).
(B) På tilsvarende måte, idet man går frem som angitt under punkt (A) ovenfor, men benytter forbindelsene
fremstilt under Fremstilling 15(B) istedenfor (2R)-1-(3,4-dimethoxyfenyl)-2-t-butoxycarbonylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyfenyl)-hexan, fåes de følgende forbindelser: (2S, 6R)-1-(3,4-dimethoxyfenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyfenyl)-hexan,
( 2S , 6S)-1 -(3,4-dimethoxyfenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyfenyl)-hexan,
(2R, 6R ) -1 -(3,4,5-trimethoxyfenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyfenyl)-hexan,
(2R, 6S)-1 -(3,4,5-trimethoxyfenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyfenyl)-hexan,
(2S, 6R)-1-(3,4,5-trimethoxyfenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyfenyl)-hexan,
(2S, 6S)-1 -(3,4,5-trimethoxyfenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyfenyl)-hexan,
(2R, 6R)-1-(3,4-dimethoxy-2,5-diethoxyfenyl)-2-formylamino-6-cyano-6-(i-propyl)-6 -(3,4-dimethoxyfenyl)-hexan,
(2R, 6S)-1-(3,4-dimethoxy-2,5-diethoxyfenyl)-2-formylamino-6-cyano-6-(i-propyl)-6 -(3,4-dimethoxyfenyl)-hexan,
(2S, 6R)-1-(3,4-dimethoxy-2,5-diethoxyfenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyfenyl)-hexan,
(2S, 6S)-1-(3,4-dimethoxy-2,5-diethoxyfenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyfenyl)-hexan,
(2R, 6R)-1-(3,4-dimethoxy-2,5-dipentoxyfenyl)-2 - formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyfenyl)-hexan,
(2R , 6S)-1 -(3,4-dimethoxy-2,5-dipentoxyfenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyfenyl)-hexan,
(2S, 6R)-1-(3,4-dimethoxy-2,5-dipentoxyfenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyfenyl)-hexan og
(2S, 6S)-1-(3,4-dimethoxy-2,5-dipentoxyfenyl)-2-formylamino-6-cyano-6-(i-propyl)-6 -(3,4-dimethoxyfenyl)-hexan.
Fremstilling 17
(Mellomprodukter med formel 20)
(A) 2,3 ml fosforoxyklorid (POCI3) ble satt til en oppløsning av 5,1 g (11 mmol) (2R, 6S)-1-(3,4-dimethoxy-fenyl )-2-formylamino-6-cyano-6 -(i-propyl)-6 -(3,4-dimethoxy-fenyl)-hexan (19A) i 75 ml acetonitril, og blandingen ble omrørt ved romtemperatur i to timer. Den resulterende blanding ble inndampet, og residuet ble oppløst i ether og ekstrahert med kald, vandig NH4OH. Etheren ble avdampet, residuet ble oppløst i 100 ml ethanol, og 0,5 g natriumborhydrid ble
tilsatt. Blandingen ble omrørt i én time og deretter satt til vann, surgjort med HCl og ekstrahert med ether. Det organiske skikt ble vasket med saltoppløsning, tørret og inndampet til en farveløs olje bestående av (3R, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl~4-cyanobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisokinolin (20A).
(B) På tilsvarende måte, idet man går frem som angitt under punkt (A), men benytter forbindelsene fremstilt
under Fremstilling 16(B) istedenfor (2R, 6S)-1-(3,4-dimethoxy-fenyl )-2 -formylamino-6-cyano-6-(i-propyl)-6 -(3,4-dimethoxy-fenyl)-hexan, fåes de følgende forbindelser: (3S, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxyfenyl-1,2,3,4-tetrahydroisokinolin,
(3R, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyfenyl-1,2,3,4-tetrahydroisokinolin,
(3S, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7,8-trimethoxyfenyl-1,2,3,4-tetrahydroisokinolin,
(3S, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7,8-trimethoxyfenyl-1,2,3,4-tetrahydroisokinolin,
(3S, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7,8-trimethoxyfenyl-1,2,3,4-tetrahydroisokinolin,
(3R, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7-dimethoxy-5,8-diethoxyfenyl-1,2,3,4-tetrahydroisokinolin ,
(3R, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7-dimethoxy-5,8-diethoxyfenyl-1,2,3,4-tetrahydroisokinolin ,
(3S, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7-dimethoxy-5,8-diethoxyfenyl-1,2,3,4-tetrahydroisokinolin ,
(3S, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7-dimethoxy-5,8-diethoxyfenyl-1,2,3,4-tetrahydroisokinolin ,
(3R, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7-dimethoxy-5,8-dipentoxyfenyl-1,2,3,4-tetrahydroisokinolin,
(3R, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7-dimethoxy-5,8-dipentoxyfenyl-1,2,3,4-tetra-
hydroisokinolin,
(3S, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyfenyl-1,2,3,4-tetrahydroisokinolin og
(3S, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyfenyl-1,2,3,4-tetrahydroisokinolin .
Fremstilling 18
(Mellomprodukter med formel 21)
(A) En oppløsning av 2-(3,4-dimethoxyfenyl)-2-isopropylacetonitril (6a)i toluen ble langsomt tilsatt til 1,5
ekvivalenter natriumamid i toluen, og den resulterende blanding ble oppvaret ved 80-90°C i én time. Blandingen ble så avkjølt til 15°C, og 2 ekvivalenter 1-brom-3-klorpropan ble tilsatt langsomt. Blandingen ble omrørt i to timer ved romtemperatur. Blandingen ble så forsiktig hellet over i isvann, ekstrahert med CH2CI2og vakuumdestillert, hvorved man fikk 2-(3,4-dimethoxyf enyl ) -2-isopropyl-2- ( 3-klorpropyl ) -acetonitril (21) med kokepunkt 160-165°C/0,05 mmHg.
(B) På tilsvarende måte, idet man går frem som angitt under punkt (A) ovenfor, men benytter forbindelsene
fremstilt under Fremstilling 3(B-C) istedenfor 2-(3,4-dimethoxyf enyl ) -2-isopropylacetonitril , fåes de følgende forbindelser : 2-(3,4-dimethoxyfenyl)-2-methyl-2-(3-klorpropyl)-acetonitril,
2-(3,4-dimethoxyfenyl)-2-ethyl-2-(3-klorpropyl)-acetonitril,
2-(3,4-dimethoxyfenyl)-2-(but-2-yl)-2-(3-klorpropyl)-acetonitril,
2-(3,4-dimethoxyfenyl)-2-(pent-3-yl)-2-(3-klor-propyl )-acetonitril,
2-(1,3-benzodioxol-2-yl)-2-methyl-2-(3-klorpropyl)-acetonitril,
2-(1,3-benzodioxol-2-yl)-2-ethyl-2-(3-klorpropyl)-acetonitril,
2-(1,3-benzodioxol-2-yl)-2-isopropyl-2-(3-klor-
propyl)-acetonitril,
2-(1,3-benzodioxol-2-yl)-2-(but-2-yl)-2-(3-klor-propyl )-acetonitril,
2-(1,3-benzodioxol-2-yl)-2 -(pent-3-yl)-2-(3-klor-propyl )-acetonitril,
2-(1,4-benzodioxan-2-yl)-2-methyl-2-(3-klorpropyl)-acetonitril,
2-(1,4-benzodioxan-2-yl)-2-ethyl-2-(3-klorpropyl)-acetonitril,
2-(1,4-benzodioxan-2-yl)-2-isopropyl-2-(3-klor-propyl )-acetonitril,
2-(1,4-benzodioxan-2-yl)-2-(but-2-yl)-2-(3-klor-propyl ) -acetonitril og
2-(1,4-benzodioxan-2-yl)-2-(pent-3-yl)-2-(3-klor-propyl )-acetonitril.
Fremstilling 19
(Mellomprodukter med formel 22)
(A) En oppløsning av 21,4 g (72 mmol) 2-(3,4-dimethoxyf enyl ) -2 -isopropyl -2 -( 3 -klorpropyl ) -acetonitril (2 ), 30 g natriumjodid og 250 ml aceton ble kokt med tilbakeløps-kjøling i 12 timer. Blandingen ble så filtrert og acetonet avdampet, og residuet ble fordelt mellom ether og vann. Det organiske skikt ble vasket med vandig NaSC>3 og saltoppløsning, tørret over Na2S04og inndampet, hvorved det ble erholdt 28 g 2-(3,4-dimethoxyfenyl)-2-isopropyl-2-(3-jodpropyl)-acetonitril (22) i form av en tykk olje. (B) På tilsvarende måte, idet man går frem som angitt under punkt (A) ovenfor, men benytter forbindelsene fremstilt under Fremstilling 18(B) istedenfor 2-(3,4-dimethoxyf enyl)-2-isopropyl-2-(3-klorpropyl)-acetonitril, fåes de følgende forbindelser: 2-(3,4-dimethoxyfenyl)-2-methyl-2-(3-jodpropyl)-acetonitril,
2-(3,4-dimethoxyfenyl)-2-ethyl-2-(3-j odpropyl)-acetonitril,
2-(3,4-dimethoxyfenyl)-2-(but-2-yl)-2-(3-jodpropyl)-acetonitril,
2-(3,4-dimethoxyfenyl)-2-(pent-3-yl)-2-(3-jod-propyl )-acetonitril,
2-(1 ,3-benzodioxol-2-yl)-2-methyl-2-(3-j odpropyl)-acetonitril,
2-(1 ,3-benzodioxol-2-yl)-2-ethyl-2-(3-jodpropyl)-acetonitril,
2-(1,3-benzodioxol-2-yl)-2-isopropyl-2-(3-j od-propyl)-acetoni tri 1,
2-(1 ,3-benzodioxol-2-yl)-2-(but-2-yl)-2-(3-jod-propyl)-acetonitril,
2-(1,3-benzodioxol-2-yl)-2-(pent-3-yl)-2-(3-jod-propyl )-acetonitril,
2-(1 ,4-benzodioxan-2-yl)-2-methyl-2-(3-jodpropyl)-acetonitril,
2-(1 ,4-benzodioxan-2-yl)-2-ethyl-2 -(3-j odpropyl)-acetonitril,
2-( 1 ,4-benzodioxan-2-yl)-2-isopropyl-2 -(3-jod-propyl )-acetonitril,
2-(1 ,4-benzodioxan-2-yl)-2-(but-2-yl)-2-(3-jod-propyl )-acetonitril og
2-(1,4-benzodioxan-2-yl)-2-(pent-3-yl)-2-(3-jod-propyl ) -acetonitril .
Fremstilling 20
(Mellomprodukter med formel 23)
(A) En 1,6M oppløsning av N-butyllithium i hexan (91,8 ml, 147 mmol) ble satt til en oppløsning av temperatur
-20°C av 21 ml (150 mmol) diisopropylamin i 480 ml THF. 56
ml hexamethylfosforamid ble tilsatt, og blandingen ble holdt ved -20°C mens en oppløsning av 15,1 g (72 mmol) 3-(3,4-dimethoxyf enyl ) -propionsyre i 75 ml THF ble tilsatt. Den resulterende oppløsning ble omrørt ved romtemperatur i én time og deretter kjølt til -50°C. En oppløsning av 27,9 g (72 mmol) 2-(3,4-dimethoxyfenyl)-2-isopropyl-2-(3-j odpropyl)-acetonitril (22), ble tilsatt, og blandingen ble tillatt å oppvarmes til romtemperatur i løpet av 12 timer, mens den ble omrørt. Den resulterende blanding ble tilsatt til vann, surgjort med HCl og ekstrahert tre ganger med ether. Det organiske skikt ble
vasket med vandig Na2S03og saltoppløsning, tørret over Na2SC>4og inndampet, hvorved man fikk 31 g 1 - ( 3 , 4-dimethoxy-fenyl)-2-carboxy-6-cyano-6-(i-propyl)-6 -(3,4-dimethoxyfenyl)-hexan (23) som en tykk olje.
(B) På tilsvarende måte, idet man går frem som angitt under punkt (A) ovenfor, men benytter forbindelsene
fremstilt under Fremstilling 19(B) istedenfor 2-(3,4-dimethoxyf enyl ) -2-isopropyl-2- ( 3-j odpropyl ) -acetonitril , fåes de følgende forbindelser:
1 -(3,4-dimethoxyfenyl)-2-carboxy-6-(3,4-dimethoxy-fenyl) -6-methyl-6-cyanohexan, 1 -(3,4-dimethoxyfenyl)-2-carboxy-6-(3,4-dimethoxy-fenyl) -6-ethyl-6-cyanohexan, 1 -(3,4-dimethoxyfenyl)-2-carboxy-6-(3,4-dimethoxy-fenyl)-6-(but-2-yl)-6-cyanohexan, 1 -(3,4-dimethoxyfenyl)-2-carboxy-6-(3,4-dimethoxy-fenyl )-6-(pent-3-yl)-6-cyanohexan, 1 -(3,4-dimethoxyfenyl)-2-carboxy-6-(1,3-benzodioxol-2-yl)-6-methyl-6-cyanohexan, 1 -(3,4-dimethoxyfenyl)-2-carboxy-6-(1,3-benzodioxol-2-yl)-6-ethyl-6-cyanohexan, 1 -(3,4-dimethoxyfenyl)-2-carboxy-6-(1,3-benzodioxol-2-yl)-6-isopropyl-6-cyanohexan, 1 -(3,4-dimethoxyfenyl)-2-carboxy-6-(1 ,3-benzodioxol-2-yl)-6-(but-2-yl)-6-cyanohexan, 1 -(3,4-dimethoxyfenyl)-2-carboxy-6-(1,3-benzodioxol-2-yl)-6-(pent-3-yl)-6-cyanohexan, 1 -(3,4-dimethoxyfenyl)-2-carboxy-6-(1,4-benzodioxan-2-yl)-6-methyl-6-cyanohexan, 1 -(3,4-dimethoxyfenyl)-2-carboxy-6-(1,4-benzodioxan-2-yl)-6-ethyl-6-cyanohexan, 1 -(3,4-dimethoxyfenyl)-2-carboxy-6-(1,4-benzodioxan-2-yl)-6-isopropyl-6-cyanohexan, 1 -(3,4-dimethoxyfenyl)-2-carboxy-6-(1,4-benzodioxan-2-yl)-6-(but-2-yl)-6-cyanohexan og 1 -(3,4-dimethoxyfenyl)-2-carboxy-6-(1,4-benzodioxan-2-yl)-6-(pent-3-yl)-6-cyanohexan.
Fremstilling 21
(Mellomprodukter med formel 19 via Reaksjonsskjema III)
(A) En blanding av 16,6 g (35 mmol) 1-(3,4-di-methoxyfenyl )-2-carboxy-6-cyano-6-(i-propyl)-6-(3,4-dimethoxy-fenyl ) -hexan (24), 5,9 ml triethylamin, 7,6 ml (35 mmol) difenylfosforylazid og 200 ml toluen ble oppvarmet til til-bakeløpstemperaturen og kokt med tilbakeløps i 15 minutter. Oppløsningsmidlene ble fjernet under redusert trykk, og residuet ble oppløst i 200 ml dimethoxyethan (DME). Oppløs-ningen ble kjølt i et isbad, og 1,6 g NaBH4ble langsomt tilsatt. Oppløsningen ble omrørt i én time, konsentrert i vakuum og fordelt mellom vandig 5%-ig HCl og ethylacetat. De organiske skikt ble vasket med vann og saltoppløsning, tørret over Na2S04og inndampet, hvorved man fikk 20,6 g 1-(3,4-di-methoxyfenyl)-2-formylamino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyf enyl)-hexan (19) som en diastereomer blanding av tykke oljer. (B) På tilsvarende måte, idet man går frem som angitt under punkt (A) ovenfor, men benytter forbindelsene fremstilt under Fremstilling 20(B) istedenfor 1-(3,4-dimethoxyf enyl )-2-carboxy-6-cyano-6-(i-propyl)-6-(3,4-dimethoxy-fenyl ) -hexan , fåes de følgende forbindelser: 1 -(3,4-dimethoxyfenyl)-2-formylamino-6-(3,4-dimethoxyf enyl )-6-methyl-6-cyanohexan, 1 -(3,4-dimethoxyfenyl)-2-formylamino-6-(3,4-dimethoxyf enyl )-6-ethyl-6-cyanohexan, 1 -(3,4-dimethoxyfenyl)-2-formylamino-6-(3,4-di-methoxyfenyl )-6-(but-2-yl)-6-cyanohexan, 1 -(3,4-dimethoxyfenyl)-2-formylamino-6-(3,4-dimethoxyf enyl )-6-(pent-3-yl)-6-cyanohexan, 1 -(3,4-dimethoxyfenyl)-2-formylamino-6-(1,3-benzo-dioxol-2-yl)-6-methyl-6-cyanohexan, 1 -(3,4-dimethoxyfenyl)-2-formylamino-6-(1,3-benzo-dioxol-2-yl)-6-ethyl-6-cyanohexan, 1 -(3,4-dimethoxyfenyl)-2-formylamino-6-(1,3-benzo-dioxol-2-yl)-6-isopropyl-6-cyanohexan,
1-(3,4-dimethoxyfenyl)-2-formylamino-6-(1,3-benzo-dioxol-2-yl)-6-(but-2-yl)-6-cyanohexan, 1 -(3,4-dimethoxyfenyl)-2-formylamino-6-(1,3-benzo-dioxol -2 -yl )-6-(pent-3-yl)-6-cyanohexan, 1 -(3,4-dimethoxyfenyl)-2-formylamino-6-(1,4-benzo-dioxan-2-yl )-6-methyl-6-cyanohexan, 1 -(3,4-dimethoxyfenyl)-2-formylamino-6-(1,4-benzo-dioxan-2-yl )-6-ethyl-6-cyanohexan, 1 -(3,4-dimethoxyfenyl)-2-formylamino-6-(1,4-benzo-dioxan-2-yl)-6-isopropyl-6-cyanohexan, 1 -(3,4-dimethoxyfenyl)-2-formylamino-6-(1,4-benzo-dioxan-2-yl )-6-(but-2-yl)-6-cyanohexan og 1 -(3,4-dimethoxyfenyl)-2-formylamino-6-(1 ,4-benzo-dioxan-2-yl)-6-(pent-3-yl)-6-cyanohexan.
Eksempel 1
(Forbindelser med formel 1 via Reaksjonsskjema I)
(A) En blanding av 52,3 g (0,12 mol) 1-(3,4-dimethoxyf enyl )-2-amino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxy-fenyl) -hexan (11), 27 g paraformaldehyd (fra Aldrich) og 380
ml 97%-ig maursyre ble oppvarmet ved 85-95°C i 4-5 timer.
Det meste av maursyren ble fjernet ved vakuumdestillasjon,
og residuet ble avkjølt til romtemperatur og fortynnet med 700 ml ethylacetat og 300 ml vann. 300 ml mettet saltoppløsning ble tilsatt forsiktig, og den resulterende blanding ble ekstrahert med 300 ml saltoppløsning. Det organiske skikt ble så fraskilt og konsentrert til ca. 100 ml. Den resulterende blanding ble tilsatt til en silicagelkolonne med 300 g silicagel og eluert med ethylacetat. Etter at 500 eluat var blitt oppsamlet ble resten eluert med aceton. Produktfraksjonene ble slått sammen og inndampet, hvorved det ble erholdt 53,7 g raceraisk 3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydroisokinolin (1) i form av en tykk olje. MS m/e 466(M+).
(B) På tilsvarende måte, idet man går frem som angitt under punkt (A) ovenfor, men benytter forbindelsene
fremstilt under Fremstilling 9(B) istedenfor 1-(3,4-dimethoxyf enyl )-2-amino-6-cyano-6-(i-propyl)-6-(3,4-dimethoxy-fenyl ) -hexan , fåes de følgende forbindelser: 3-[4-(3,4-dimethoxyfenyl)-4-methyl-4-cyanobutyl]-
6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydroisokinolin,
3-t 4-(3,4-dimethoxyfenyl)-4-ethyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-l ,2,3, 4-tetrahydroisokinolin,
3 -[4 -(3,4-dimethoxyfenyl)-4-(buty-2-yl)-4-cyano-butyl]-6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydroisokinolin,
3-[4-(3,4-dimethoxyfenyl)-4-(pent-3-yl)-4-cyano-butyl ]-6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydroisokinolin, 3-[4-(1 ,3-benzodioxol-2-yl)-4-methyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydroisokinolin, 3-[4-(1 ,3-benzodioxol-2-yl)-4-ethyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydroisokinolin,
3-[4-(1,3-benzodioxol-2-yl)-4-(prop-2-yl)-4-cyano-butyl ]-6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydroisokinolin, 3-[4-(1 ,3-benzodioxol-2-yl)-4-(but-2-yl)-4-cyano-butyl ]-6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydroisokinolin, 3-[4-(1 ,3-benzodioxol-2-yl)-4-(pent-3-yl)-4-cyano-butyl]-6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydroisokinolin, 3-[4 - (1 ,4-benzodioxan-2-yl)-4-methyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydroisokinolin, 3 —[4 — (1 ,4-benzodioxan-2-yl)-4-ethyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydroisokinolin,
3-[4-(1 ,4-benzodioxan-2-yl)-4-(prop-2-yl)-4-cyano-butyl 1-6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydroisokinolin,
3-[4 - (1 ,4-benzodioxan-2-yl)-4-(but-2-yl)-4-cyano-butyl ]-6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydroisokinolin,
3-[4-(1 , 4-benzodioxan-2-yl)-4-(pent-3-yl)-4-cyano-butyl]-6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydroisokinolin,
3-[4-(3,4-dimethoxyfenyl)-4-methyl-4-cyanobutyl]-6,7,8-trimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin,
3-[4-(3,4-dimethoxyfenyl)-4-ethyl-4-cyanobutyl]-6,7,8-trimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin,
3-[4-(3,4-dimethoxyfenyl)-4-(buty-2-yl)-4-cyano-butyl ]-6,7,8-trimethoxy-N-methy1-1,2,3,4-tetrahydroisokinolin,
3-[4-(3,4-dimethoxyfenyl)-4-(pent-3-yl)-4-cyano-butyl ]-6,7,8-trimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin,
3-[4-(1,3-benzodioxol-2-yl)-4-methyl-4-cyanobutyl]-6,7,8-trimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin,
3-[4-(1,3-benzodioxol-2-yl)-4-ethyl-4-cyanobutyl]-
6,7,8-trimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin,
3-[4-(1,3-benzodioxol-2-yl)-4-(prop-2-yl)-4-cyano-butyl]-6,7,8-trimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin,
3-[4-(1,3-benzodioxol-2-yl)-4-(but-2-yl)-4-cyano-butyl ]-6,7,8-trimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin,
3-[4-(1,3-benzodioxol-2-yl)-4-(pent-3-yl)-4-cyano-butyl ]-6,7,8-trimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin,
3-[4-(1 ,4-benzodioxan-2-yl)-4-methyl-4-cyanobutyl1 - 6,7,8-trimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin, 3 - f 4 -(1 ,4-benzodioxan-2-y1)-4-ethyl-4-cyanobutyl]-6,7,8-trimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin,
3-[4-(1,4-benzodioxan-2-yl)-4-(prop-2-yl)-4-cyano-butyl]-6,7,8-trimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin,
3-[4-(1,4-benzodioxan-2-yl)-4-(but-2-yl)-4-cyano-butyl ]-6,7,8-trimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin,
3-[4-(1 ,4-benzodioxan-2-yl)-4-(pent-3-yl)-4-cyano-butyl ]-6,7,8-trimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin,
3-[4-(3,4-dimethoxyfenyl)-4-methyl-4-cyanobutyl]-5,6,7-trimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin,
3-[4-(3,4-dimethoxyfenyl)-4-ethyl-4-cyanobutyl]-5,6,7-trimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin,
3-[4-(3,4-dimethoxyfenyl)-4-(buty-2-yl)-4-cyano-butyl ]-5,6,7-trimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin,
3-[4-(3,4-dimethoxyfenyl)-4-(pent-3-yl)-4-cyano-butyl ]-5,6,7-trimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin,
3-t 4-(1,3-benzodioxol-2-yl)-4-methyl-4-cyanobutyl]-5,6,7-trimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin,
3-[4-(1 ,3-benzodioxol-2-yl)-4-ethyl-4-cyanobutyl)-5,6,7-trimethoxy-N-methyl-1 ,2,3 , 4-tetrahydroisokinolin,
3-[4-(1,3-benzodioxol-2-yl)-4-(prop-2-yl)-4-cyano-butyl ]-5,6,7-trimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin,
3-[4-(1,3-benzodioxol-2-yl)-4-(but-2-yl)-4-cyano-butyl ]-5,6,7-trimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin,
3-[4-(1,3-benzodioxol-2-yl)-4-(pent-3-yl)-4-cyano-butyl ]-5,6,7-trimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin,
3-[4-(1,4-benzodioxan-2-yl)-4-methyl-4-cyanobutyl)-5,6,7-trimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin,
3-[4-(1,4-benzodioxan-2-yl)-4-ethyl-4-cyanobutyl]-
5,6,7-trimethoxy-N-methyl-1 ,2,3 , 4-tetrahydroisokinolin, 3 - [4-(1 ,4-benzodioxan-2-yl)-4-(prop-2-yl)-4-cyano-butyl ]-5,6,7-trimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin, 3 -[4-(1 ,4-benzodioxan-2-yl)-4 -(but-2-yl)-4-cyano-butyl ]-5,6,7-trimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin, 3-[4 -(1,4-benzodioxan-2-yl)-4-(pent-3-yl)-4-cyano-butyl ]-5,6,7-trimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin, 3 -[4-(3,4-dimethoxyfenyl)-4-methyl-4-cyanobutyl]-5,6,7 , 8-tetramethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin,
3-[4-(3,4-dimethoxyfenyl)-4-ethyl-4-cyanobutyl]-5,6,7,8-tetramethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin, 3 - [ 4 -(3,4-dimethoxyfenyl)-4-(buty-2-yl)-4-cyano-butyl ]-5,6,7,8-tetramethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin , 3-t 4-(3,4-dimethoxyfenyl)-4-(pent-3-yl)-4-cyano-butyll-5,6,7,8-tetramethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin ,
3-[4-(1,3-benzodioxol-2-yl)-4-methyl-4-cyanobutyl]-5,6,7,8-tetramethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin, 3 —[4 -(1 ,3-benzodioxol-2-yl)-4-ethyl-4-cyanobutyl1 - 5,6,7,8-tetramethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin,
3-[4-(1,3-benzodioxol-2-yl)-4-(prop-2-yl)-4-cyano-butyl ]-5,6,7,8-tetramethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin ,
3-[4-(1,3-benzodioxol-2-yl)-4-(but-2-yl)-4-cyano-butyl ]-5,6,7,8-tetramethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin , 3 - [4-(1,3-benzodioxol-2-yl)-4-(pent-3-yl)-4-cyano-butyl 1-5,6,7,8-tetramethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin ,
3-[4-(1,4-benzodioxan-2-yl)-4-methyl-4-cyanobutyl]-5,6,7,8-tetramethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin,
3-[4-(1,4-benzodioxan-2-yl)-4-ethyl-4-cyanobutyl]-5,6,7,8-tetramethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin,
3-[4-(1,4-benzodioxan-2-yl)-4-(prop-2-yl)-4-cyano-butyl 1-5,6,7,8-tetramethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin ,
3-[4-(1,4-benzodioxan-2-yl)-4-(but-2-yl)-4-cyano-
butyl]-5,6,7,8-tetramethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin,
3-[4-(1 ,4-benzodioxan-2-yl)-4-(pent-3-yl)-4-cyano-butyl]-5,6,7,8-tetramethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin, 3 -[4 -(3,4-dimethoxyfenyl)-4-methyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxy-N-methyl-1 ,2,3,4-tetrahydroisokinolin ,
3-[4-(3,4-dimethoxyfenyl)-4-ethyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin ,
3-[4-(3,4-dimethoxyfenyl)-4-(buty-2-yl)-4-cyano-butyl J-6,7-dimethoxy-5,8-diethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin ,
3-[4-(3,4-dimethoxyfenyl)-4-(pent-3-yl)-4-cyano-butyl J-6,7-dimethoxy-5,8-diethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin ,
3-[4-(1 ,3-benzodioxol-2-yl)-4-methyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin,
3-[4-(1,3-benzodioxol-2-yl)-4-ethyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin ,
3-[4-(1,3-benzodioxol-2-yl)-4-(prop-2-yl)-4-cyano-butyl ]-6,7-dimethoxy-5,8-diethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin ,
3-[4-(1,3-benzodioxol-2-yl)-4-(but-2-yl)-4-cyano-butyl ]-6,7-dimethoxy-5,8-diethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin ,
3-[4-(1,3-benzodioxol-2-yl)-4-(pent-3-yl)-4-cyano-butyl ]-6,7-dimethoxy-5,8-diethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin ,
3-[4-(1,4-benzodioxan-2-yl)-4-methyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin,
3-[4-(1,4-benzodioxan-2-yl)-4-ethyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin ,
3-[4-(1,4-benzodioxan-2-yl)-4-(prop-2-yl)-4-cyano-butyl ]-6,7-dimethoxy-5,8-diethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin , 3 -{4 -(1 ,4-benzodioxan-2-yl)-4-(but-2-yl)-4-cyano-butyl ]-6,7-dimethoxy-5,8-diethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin , 3-t 4-(1,4-benzodioxan-2-yl)-4-(pent-3-yl)-4-cyano-butyl]-6,7-dimethoxy-5,8-diethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin ,
3-[4-(3,4-dimethoxyfenyl)-4-methyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxy-N-methyl-1,2,3,4-tetrahydroisokinolin ,
3-[4-(3,4-dimethoxyfenyl)-4-ethyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxy-N-methyl-1,2,3,4-tetrahydroisokinolin, 3 -[4 -(3,4-dimethoxyfenyl)-4 -(buty-2-yl)-4-cyano-butyl ] -6,7-dimethoxy-5,8-dipentoxy-N-methyl-1,2,3,4-tetrahydroisokinolin ,
3-[4-(3,4-dimethoxyfenyl)-4-(pent-3-yl)-4-cyano-butyl ]-6,7-dimethoxy-5,8-dipentoxy-N-methyl-1,2,3,4-tetrahydroisokinolin, 3 — t 4 — (1,3-benzodioxol-2-yl)-4-methyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxy-N-methyl-1,2,3,4-tetrahydroisokinolin ,
3-[4-(1,3-benzodioxol-2-yl)-4-ethyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxy-N-methyl-1,2,3,4-tetrahydroisokinolin ,
3-[4-(1,3-benzodioxol-2-yl)-4-(prop-2-yl)-4-cyano-butyl ]-6,7-dimethoxy-5,8-dipentoxy-N-methyl-1,2,3,4-tetrahydroisokinolin ,
3-[4-(1 ,3-benzodioxol-2-yl)-4-(but-2-yl)-4-cyano-butyl ]-6,7-dimethoxy-5,8-dipentoxy-N-methyl-1,2,3,4-tetrahydroisokinolin ,
3-[4-(1,3-benzodioxol-2-yl)-4-(pent-3-yl)-4-cyano-butyl 1-6,7-dimethoxy-5,8-dipentoxy-N-methyl-1,2,3,4-tetrahydroisokinolin ,
3-E 4-(1,4-benzodioxan-2-yl)-4-methyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxy-N-methyl-1,2,3,4-tetrahydroiso-
kinolin,
3-[4-(1,4-benzodioxan-2-yl)-4-ethyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxy-N-methyl-1,2,3,4-tetrahydroisokinolin ,
3-[4-(1 ,4-benzodioxan-2-yl)-4-(prop-2-yl)-4-cyano-butyl ]-6,7-dimethoxy-5,8-dipentoxy-N-methyl-1 ,2,3,4-tetrahydroisokinolin ,
3-[4-(1,4-benzodioxan-2-yl)-4-(but-2-yl)-4-cyano-butyl 1 -6 , 7-dimethoxy-5,8-dipentoxy-N-methyl-1,2,3,4-tetra - hydroisokinolin og
3-[4-(1,4-benzodioxan-2-yl)-4-(pent-3-yl)-4-cyano-butyl J-6,7-dimethoxy-5,8-dipentoxy-N-methyl-1,2,3,4-tetrahydroisokinolin
Eksempel 2
(Forbindelser med formel 1 via Reaksjonsskjema 2)
(A) En blanding av ca. 5 g (3R, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisokinolin (20A), 20 ml formalin og 25 ml maursyre ble omrørt i én time ved 100°C, avkjølt til romtemperatur og tilsatt til vann. Den resulterende blanding ble gjort basisk med NH4OH og ekstrahert tre ganger med ether.
Den organiske ekstrakt ble vasket med saltoppløsning, tørret over MgSC>4og inndampet, hvorved man fikk (3R, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-l ,2,3,4-tetrahydroisokinolin ((-)-1 A).
Den urene frie base ble oppløst i ethanol og surgjort med HCl, og det ble tilsatt ether inntil det begynte å utkrys-talliseres (3R, 4<1>S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydroisokinolin-HCl ((-)-1A-HC1). Smeltepunkt 110-113°C. [alp<5>= -24,4°
(MeOH). Beregnet for C28H39CIN2O4•0,5 H20: C=65,74, H=7,78, N=5,48. Funnet: C=65,69, H=7,89, N=5,46.
(B) På tilsvarende måte, idet man går frem som angitt under punkt (A) ovenfor, men benytter forbindelsene
fremstilt under Fremstilling 17(B) istedenfor (3R, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-l , 2 , 3 , 4-tetrahydroisokinolin , fåes de følgende for-
bindelser:
(3S, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxyfenyl-N-methyl-1,2,3,4-tetrahydroisokinolin • HCl ,
(3R, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7,8-trimethoxyfenyl-N-methyl-1,2,3,4-tetrahydroisokinolin • HCl ,
(3R, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyfenyl-N-methyl-1,2,3,4-tetrahydroisokinolin* HCl,
(3S, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7,8-trimethoxyfenyl-N-methyl-1,2,3,4-tetrahydroisokinolin • HCl,
(3S, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7,8-trimethoxyfenyl-N-methyl-1,2,3,4-tetrahydroisokinolin -HCl,
(3R, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7-dimethoxy-5,8-diethoxyfenyl-N-methyl-1 ,2,3,4-tetrahydroisokinolin«HCl,
(3R, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyll-6,7-dimethoxy-5,8-diethoxyfenyl-N-methyl-1 ,2,3,4-tetrahydroisokinolin•HCl,
(3S, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7-dimethoxy-5,8-diethoxyfenyl-N-methyl-1,2,3,4-tetrahydroisokinolin-HCl,
(3S, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7-dimethoxy-5,8-diethoxyfenyl-N-methyl-1,2,3,4-tetrahydroisokinolin•HCl,
(3R, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7-dimethoxy-5,8-dipentoxyfenyl-N-methyl-1 ,2,3,4-tetrahydroisokinolin'HCl,
(3R, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7-dimethoxy-5,8-dipentoxyfenyl-N-methyl-1,2,3,4-tetrahydroisokinolin■HCl,
(3S, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7-dimethoxy-5,8-dipentoxyfenyl-N-methyl-1,2,3,4-tetrahydroisokinolin-HCl og
(3S, 4<1>S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-
cyanobutyl1-6,7-dimethoxy-5,8-dipentoxyfenyl-N-methyl-1 ,2,3,4-tetrahydroisokinolin•HCl.
Eksempel 3
(Forbindelser med formel 1 via Reaksjonsskjema 2)
(A) En blanding av ca. 5 g (3R, 4 *S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisokinolin (20A), 1 ekvivalent LDA og 1,5 ekvivalenter propyltosylat i 200 ml THF ble omrørt i én time ved 70°C, avkjølt til romtemperatur og tilsatt til vann. Den resulterende blanding ble surgjort med HCl og ekstrahert tre ganger med ether. Den organiske ekstrakt ble vasket med vandig NaHCC>3 og saltoppløsning, tørret over MgSC>4 og inndampet, hvorved man fikk et urent (3R, 41S )-3-[ 4-(3,4-dimethoxyf enyl )-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-propyl-1,2,3,4-tetrahydroisokinolin ((-)-1 A). (B) På tilsvarende måte, idet man går frem som angitt under punkt (A) ovenfor, men i stedet benytter ethyl-tosylat, isopropyltosylat, butyltosylat eller 2-pentyltosylat, fåes de følgende forbindelser: (3R, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-ethyl-1,2,3,4-tetrahydroisokinolin, (3R, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-(2-propyl-1,2,3,4-tetrahydroisokinolin , (3R, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-butyl-1,2,3,4-tetrahydroisokinolin og (3R, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-pent-2-yl-1,2,3,4-tetrahydroisokinolin. (C) På tilsvarende måte, idet man går frem som angitt under punkt (A-B) ovenfor, men benytter forbindelsene fremstilt i Fremstilling 17(B) istedenfor (3R, 4<*>S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisokinolin, fåes de følgende N-alkyl-forbindelser: (3S, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7-dimethoxyfenyl-N-ethyl-1,2,3,4-tetrahydroisokinolin ,
(3R, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyfenyl-N-ethyl-1 ,2,3,4-tetrahydroisokinolin ,
(3R, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7,8-trimethoxyfenyl-N-ethyl-1,2,3,4-tetrahydroisokinolin ,
(3S, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7,8-trimethoxyfenyl-N-ethyl-1,2,3,4-tetrahydroisokinolin ,
(3S, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7,8-trimethoxyfenyl-N-ethyl-1,2,3,4-tetrahydroisokinolin,
(3R, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7-dimethoxy-5,8-diethoxyfenyl-N-ethyl-1,2,3,4-tetrahydroisokinolin,
(3R, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7-dimethoxy-5,8-diethoxyfenyl-N-ethyl-1,2,3,4-tetrahydroisokinolin,
(3S, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7-dimethoxy-5,8-diethoxyfenyl-N-ethyl-1 ,2,3,4-tetrahydroisokinolin,
(3S, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7-dimethoxy-5,8-diethoxyfenyl-N-ethyl-1 ,2,3,4-tetrahydroisokinolin,
(3R, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7-dimethoxy-5,8-dipentoxyfenyl-N-ethyl-1 ,2,3,4-tetrahydroisokinolin,
(3R, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyfenyl-N-ethyl-1 ,2,3,4-tetrahydroisokinolin,
(3S, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7-dimethoxy-5,8-dipentoxyfenyl-N-ethyl-1 ,2,3,4-tetrahydroisokinolin,
(3S, 4'S)-3-t4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7-dimethoxy-5,8-dipentoxyfenyl-N-ethyl-1,2,3,4-
tetrahydroisokinolin,
(3S, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1 - 6,7-dimethoxyfenyl-(N-prop-2-yl)-1,2,3,4-tetrahydroisokinolin,
(3R, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4 - cyanobutyl]-6,7,8-trimethoxyfenyl-(N-prop-2-yl)-1 ,2,3,4-tetrahydroisokinolin,
(3R, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyfenyl-(N-prop-2-yl)-1 ,2,3,4-tetrahydroisokinolin,
(3S, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl ] -6 , 7 , 8-trimethoxyf enyl - (NT-prop-2 -yl) -1 ,2,3,4-tetrahydroisokinolin,
(3S, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyfenyl-(N-prop-2-yl)-1 ,2,3,4-tetrahydroisokinolin,
(3R, 4'R)-3-t4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyfenyl-(N-prop-2-yl)-1 , 2 , 3 , 4-tetrahydroisokinolin,
(3R, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyfenyl-(N-prop-2-yl)-1,2,3,4-tetrahydroisokinolin,
(3S, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7-dimethoxy-5,8-diethoxyfenyl-(N-prop-2-yl)-1 ,2 , 3 , 4-tetrahydroisokinolin,
(3S, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyfenyl-(N-prop-2-yl)-1 , 2 , 3,4-tetrahydroisokinolin,
(3R, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyfenyl-(N-prop-2-yl)-1 ,2,3,4-tetrahydroisokinolin,
(3R, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyfenyl-(N-prop-2-yl)-1 , 2,3,4-tetrahydroisokinolin,
(3S, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyfenyl-(N-prop-2-yl)-1 , 2,3,4-tetrahydroisokinolin,
(3S, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-
cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyfenyl-(N-prop-2-yl)-1,2,3,4-tetrahydroisokinolin,
(3S, 4'S)-3-t4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxyfenyl-N-butyl-1,2,3,4-tetrahydroisokinolin ,
(3R, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyfenyl-N-butyl-1,2,3,4-tetrahydroisokinolin ,
(3R, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7,8-trimethoxyfenyl-N-butyl-1 ,2,3,4-tetrahydroisokinolin,
(3S, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyfenyl-N-butyl-1,2,3,4-tetrahydroisokinolin ,
(3S, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyfenyl-N-butyl-1,2,3,4-tetrahydroisokinolin ,
(3R, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyfenyl-N-butyl-1 ,2,3,4-tetrahydroisokinolin,
(3R, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyfenyl-N-butyl-1 ,2,3,4-tetrahydroisokinolin,
(3S, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyfenyl-N-butyl-1,2,3,4-tetrahydroisokinolin,
(3S, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7-dimethoxy-5,8-diethoxyfenyl-N-butyl-1 ,2,3,4-tetrahydroisokinolin,
(3R, 4'R)-3-I4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyfenyl-N-butyl-1 ,2,3,4-tetrahydroisokinolin,
(3R, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyfenyl-N-butyl-1 ,2,3,4-tetrahydroisokinolin,
(3S, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyfenyl-N-butyl-1,2,3,4-tetrahydroisokinolin,
(3S, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4 - cyanobutyl1-6,7-dimethoxy-5,R-dipentoxyfenyl-N-butyl-1 ,2,3,4-tetrahydroisokinolin,
(3S, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxyfenyl-(N-pent-2-yl)-1,2,3,4-tetrahydroisokinolin ,
(3R, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyfenyl-(N-pent-2-yl)-1,2,3,4-tetrahydroisokinolin,
(3R, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7,8-trimethoxyfenyl-(N-pent-2-yl)-1 ,2,3,4-tetrahydroisokinolin,
(3S, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyfenyl-(N-pent-2-yl)-1,2,3,4-tetrahydroisokinolin,
(3S, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7,8-trimethoxyfenyl-(N-pent-2-yl)-1 ,2,3,4-tetrahydroisokinolin,
(3R, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyfenyl-(N-pent-2-yl)-1 , 2 , 3,4-tetrahydroisokinolin,
(3R, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyfenyl-(N-pent-2-yl)-1 , 2 , 3,4-tetrahydroisokinolin,
(3S, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-diethoxyfenyl-(N-pent-2-yl)-1 ,2 , 3 , 4-tetrahydroisokinolin,
(3S, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7-dimethoxy-5,8-diethoxyfenyl-(N-pent-2-yl)-1 , 2 , 3,4-tetrahydroisokinolin,
(3R, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyfenyl-(N-pent-2-yl)-1 ,2 , 3 , 4-tetrahydroisokinolin,
(3R, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyfenyl-(N-pent-2-yl)-1 ,2,3,4-tetrahydroisokinolin,
(3S, 4'R)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyfenyl-(N-pent-2-yl)-
1 ,2,3,4-tetrahydroisokinolin og
( 3S, 4'S)-3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4 - cyanobutyl]-6,7-dimethoxy-5,8-dipentoxyfenyl-(N-pent-2-yl)-1 , 2 , 3,4-tetrahydroisokinolin.
Eksempel 4
(Salter av forbindelser med formel 1 via Reaksjonsskjema I)
(A) 15 g (0,032 mol) av den frie base, 3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-l , 2 , 3 , 4-tetrahydroisokinolin (1) ble oppløst i 70 mg isopropanol ved 70°C, og 6 M HCl i 5,6 ml isopropanol ble tilsatt langsomt. Etter avkjøling til romtemperatur ble det tilsatt ether (40 ml) inntil oppløsningen ble uklar (mettet), og den resulterende blanding ble omrørt natten over. Det resulterende faste stoff ble oppsamlet, vasket grundig med 50 ml ether-isopropanol (1:1) og tørret i vakuum ved 50°C, hvorved man fikk 13,7 g 3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydroisokinolin-HCl (1-HC1) som et hvitt pulver. Smeltepunkt 115-120°C. (B) Pa tilsvarende måte, idet man går frem som angitt under punkt (A) ovenfor, men benytter forbindelsene fremstilt i Eksempel 1(B), fåes de tilsvarende hydroklorid-salter. (C) På tilsvarende måte, idet man går frem som angitt under punkt (A-B) ovenfor, men benytter hydrobromsyre,
svovelsyre, salpetersyre, fosforsyre, eddiksyre, propionsyre, glycolsyre, pyrodruesyre, malonsyre, ravsyre, maleinsyre, eplesyre, fumarsyre, vinsyre, citronsyre, benzoesyre, kanelsyre, mandelsyre, methansulfonsyre, ethansulfonsyre eller p-toluensulfonsyre istedenfor saltsyre, fåes de tilsvarende salter.
Eksempel 5
Preparater
Det følgende eksempel illustrerer fremstillingen av representative farmasøytiske preparater inneholdende en aktiv forbindelse med formel 1, f.eks. 3-[4-(3,4-dimethoxy- fenyl)-4-cyano-4-isopropylbutyl]-6,7-dimethoxy-N-methyl-1 , 2,3,4-tetrahydroisokinolin (1 ).
Preparat for intravenøs administrering
Den aktive forbindelse oppløses i propylenglycol, polyethylenglycol 400 og "Tween 80". En tilstrekkelig mengde 0,9% saltoppløsning tilsettes deretter under omrøring, inntil det er dannet 100 ml av I.V.-oppløsningen, som filtreres gjennom et 0,2 jim membranfilter og pakkes under sterile betingelser.
Tablettpreparat
De ovenfor angitte bestanddeler tørrblandes og fylles i kapsler som inneholder ca. 100 mg aktiv forbindelse pr. kapsel.
Eksempel 6
Forsøk med spontant hypertensive rotter
24 på forhånd trenede voksne, spontant hypertensive rotter ble inndelt i seks grupper (fire dyr pr. gruppe) med omtrent samme midlere systoliske blodtrykk. De seks grupper ble undersøkt samtidig i et forsøk for utvelgelse av forbindelser som strakte seg over to dager.
Testforbindelsene tildeles tilfeldig til hver sin gruppe. Fem grupper gis potensielle antihypertensive midler og én kontrollgruppe gis utelukkende bærer (vann og "Tween 80"-polysorbat 80).
Ca. 17 timer før den første doseringsdag fjernes eller tilbakeholdes maten fra rotteburene. Om morgenen Dag 1 gis en gruppe på fire rotter oralt ved gavage 25 mg/kg av en forbindelse med formel 1 oppløst/suspendert i vann (under anvendelse av 2-3 dråper "Tween 80" med en homogenisator i slike konsentrasjoner at det administreres 0,1 ml oppløsning pr. 10 g kroppsvekt. 4,5 timer etter at dosen er blitt gitt, bringes maten tilbake i burene, og rottene tillates å spise 1 2,5 timer, hvoretter maten på ny fjernes. Om morgenen Dag 2 gis rottene en oral dose som ovenfor beskrevet. Umiddelbart etter at dosen er gitt anbringes rottene i bevegelsesinn-skrenkende innretninger og anbringes i et oppvarmet kammer (30 t 1,0°C) hvor de holdes i fire timer. Normal foring gjenopptas etter avsluttet undersøkelse Dag 2.
Det systoliske blodtrykk (dvs. trykket ved fore-komsten av den første puls) registreres under anvendelse av fotoelektriske omformere. Halebenarteriene hos tre rotter (i en horisontal gruppe) avstenges samtidig ved hjelp av opp-pumpbare halemansjetter som automatisk pumpes opp til 300 mmHg og deretter tømmes. En trykk-kurve og halepulsene registreres samtidig ved hjelp av en MFE-skriver. Fire på hverandre følgende (med 30 sekunders intervaller) spor registreres for hver rotte i en gitt horisontal gruppe på tidspunkter én,
to, tre og fire timer etter administreringen av forbindelsen. Etterfølgende horisontale grupper testes automatisk på samme måte.
Det midlere systoliske blodtrykk (SBP) for hver rotte beregnes for hvert iakttagelsestidspunkt. Dyrenes SBP
i hver dosegruppe sammenlignes med SBP for dyrene i kontroll-gruppen (kun bærer) for hvert iakttagelsestidspunkt ved bruk av en énveis variansanalysetest. Data som gir p<0,05 på et gitt iakttagelsestidspunkt anses å indikere en forbindelse som oppviser signifikant antihypertensiv aktivitet. Forbindelser som signifikant senker blodtrykket 20 mmHg eller mer i forhold til kontrollverdiene på samtlige fire iakttagelses-tidspunkter, anses verdige til å undersøkes nærmere. I disse tilfeller ble hjerteratene beregnet og testet med hensyn til signifikante endringer i forhold til kontrollhjerterateverdier under anvendelse av Ounnet-testen. De ble ansett å være signifikant forskjellige fra hjerteratene for kontrolldyr som var behandlet med bærer, når p s 0,05. De nye forbindelser
oppviser positiv antihypertensiv aktivitet ved denne test. Eksempelvis ga forbindelsen ifølge eksempel 1(A) de følgende resultater.
Eksempel 7
Forsøk med aortastrimler fra rotter
Fire Sprague-Dawley-hanrotter (250-300 g pr. rotte, skaffet fra Bantin & Kingman) ble avlivet ved cervikal dis-lokasjon. Brystaortaene ble hurtig fjernet, og det ytre bindevev ble omhyggelig fjernet. Aortaene ble kuttet i spiral-formede strimler av bredde 2-3 mm og lengde 30 mm. Strimlene ble montert vertikalt i vevbad inneholdende 10 ml modifisert Krebs-oppløsning av 37°C og luftet med en gassblanding inneholdende 95% O2og 5% CO2.
Et begynnelsesstrekk på 1 g ble påført strimlene. Systemene ble tillatt å komme i likevekt i én time, hvorunder strimlene ble vasket seks ganger. Strimlene ble så bragt i kontakt med enten ~\ 0- 3m BaCl2eller 10~^M fenylefrin og ble tillatt å nå en stabil respons. Strimlene ble så underkastet trinnvis økende konsentrasjoner av de nye forbindelser, og responsene ble registrert under anvendelse av Grass FT 03 omformere koblet til en Beckman R611 Dynograph skriver. De nye forbindelser oppviste høy vasorelakserende aktivitet som kalsiumkanalblokkeringsmidler ved dette forsøk.
<p>EC5o~verdiene (-lo<g>5ø) for forbindelsen ifølge Eksempel 1(A) for bariumklorid- og fenylefrin-sammensnørede strimler (fenylefrin = PE) er: pEC5o(Ba<++>) = 6,52±0,11 og pEC5ø(PE) = 6,38±0,13. EC^n-verdien er den konsentrasjon av forbindelsen som gir 50% relaksasjon av barium- eller fenylefrin-sammensnørede aortastrimler fra rotter.
Eksempel 8
Vevselektivitet for kalsiumblokkering
Fire hvite New Zealand hankaniner (2,5-3,5 kg pr. kanin: Elkhorn) ble avlivet under anvendelse av pentobarbital-natrium (50 mg/kg intravenøst via ørevenen) og raskt kuttet hodet av. Hjernene ble raskt fjernet og anbragt i en skål med modifisert Krebs-buffer som var luftet med 95% 02/5%
CO2. Basilararteriene ble skåret ut og anbragt i en separat luftet skål med buffer. En seksjon av den sentrale ørearterie fra hver kanin ble fjernet fra midten av øret og anbragt i en luftet bufferskål. Basilararteriene og ørearteriene ble renset omhyggelig og skåret opp på tvers i ringer. Basilararterieringene var ca. 3 mm lange, mens ørearterieringene var ca. 2 mm lange. Ringene ble montert i holdere i vevbad inneholdende 10 ml modifisert Krebs-oppløsning av 37°C og ble luftet med en gassblanding inneholdende 95% O2og 5% CO2.
En begynnelsesspenning på 0,5 g ble påført både basilararterieringene og ørearterieringene. Systemene ble tillatt å komme i likevekt i én time, hvorunder ringene ble vasket seks ganger. Ringene ble deretter behandlet med KC1 for å avstedkomme omtrent 1 g kontraksjon og ble så tillatt å nå en stabil respons. Ringene ble så underkastet trinnvis økende konsentrasjoner av de nye forbindelser, og responsene ble registrert under anvendelse av Statham UC-2-omformere koblet til en Beckman R611 Dynograph skriver. De nye forbindelser oppviste høy karrelakserende aktivitet og god selek-tivitet overfor den cerebrale arterie ved dette forsøk. For forbindelsen ifølge Eksempel 1(A) fåes:
PEC50(basilararterie) = 6,97±0,01
PEC50(ørearterie) = 6,57±0,08
Denne forbindelse er således 2,8 ganger mer selektiv overfor basilararterien enn overfor ørearterien.
Forbindelsen ifølge Eksempel 1(A) oppviser en oral LD50for rotter som er høyere enn 1000 mg/kg.
Eksempel 9
Intravenøse undersøkelser utført på hunder
Bedøvede dyr med normal spenning
Hos pentobarbitalbedøvede hunder av blandingsrase med åpnet bryst forårsaket den racemiske forbindelse 3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl1-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin i doseområdet 0,1-0,5 mg/kg doseavhengige minskninger i aortablodtrykket, hjerteraten og produktet av hjerteråte og trykk. Hjerteblodstrømningen øket.
Todimensjonal echocardiografisk analyse av den myocardiale funksj on
Hos pentobarbitalbedøvede hunder av blandingsrase med lukket bryst forårsaket intravenøs administrering av forbindelsen ifølge Eksempel 1(A) doseavhengige minskninger i det slutt-systoliske volum og det slutt-diastoliske volum i venstre ventrikkel sammen med økninger i venstre ventrikkels utstøtningsfraksjon og slagvolum. Også minskninger i det systoliske, diastoliske og midlere blodtrykk var åpenbare, sammen med minskninger i den systemiske karresistens. Denne hemodynamiske profil hos forbindelsen gjør, sammen med dens hjertekarutvidende virkning og dens virkning med hensyn til å redusere produktet av hjerteråte og trykk, denne forbindelse til en potensielt god forbindelse for behandling av angina pectoris.
Eks empel 10
De følgende forbindelser ble fremstilt under anvendelse av de metoder som er angitt i tabellen nedenfor.
Formel (1 ) : R-| og R2= H
Claims (25)
1. Forbindelse av formelen
(1)
eller et i farmasøytisk henseende aksepterbart syreaddisjonssalt derav, i hvilken forbindelse R, og R2 uavhengig av hverandre betegner -H eller lavere alkoxy, og R4 uavhengig av hverandre betegner lavere alkyl, og R^ og R6 hver betegner
-OCH3 eller sammen danner en gruppe -OCH2 0- eller -OCH2 CH2 0-.
2. Forbindelse ifølge krav 1, hvor R^ er isopropyl.
3. Forbindelse iflge krav 2, hvor R^ er methyl.
4. Forbindelse ifølge krav 3, hvor R^ og R2 hver er -H.
5. Forbindelse ifølge krav 4, hvor R<_ og R^ hver er -OCH^ .
6. Forbindelse ifølge krav 5, som er 3-[4-(3,4-dimethyoxy-fenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisokinolin.
7. Forbindelse ifølge krav 5, hvor stereokjemien ved C3 er S.
8. Forbindelse ifølge krav 7, som er (3S, 4'S) 3-[4 - ( 3,4-dimethoxyfenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-l ,2,3,4-tetrahydroisokinolin.
9. Fremgangsmåte for fremstilling av forbindelser med formel 1
hvor og R_, uavhengig av hverandre er -H eller lavere alkoxy; R^ er lavere alkyl; og R^ og R^ begge er -OCH^ eller sammen danner -OCH2 0- eller -OCH2 CH2 0-, karakterisert ved at man i 1-24 timer oppvarmer ved 70-110°C en blanding av maursyre, en kilde for formaldehyd og en forbindelse med formel 11:
hvor R^ og R2 uavhengig av hverandre betegner -H eller lavere alkoxy; R^ er lavere alkyl; og R,- og R^ begge er-OCH^ eller sammen danner -OCH2 0- eller -OCH2 CH2 0-.
10. Fremgangsmåte ifølge krav 9, karakterisert ved at blandingen oppvarmes ved en temperatur på ca. 90°C.
11. Fremgangsmåte ifølge krav 9, karakterisert ved at det anvendes en forbindelse med formel 11 som er fremstilt ved at man i et inert oppløsningsmiddel blander et acyleringsmiddel, en katalytisk mengde base og en forbindelse med formel 8
hvor R"*" og R2 uavhengig av hverandre betegner -H eller lavere alkoxy, R^ er lavere alkyl, og R^ og R^ begge er~ OCH3 eller sammen danner -OCH2 0- eller -OCH2 CH2 0-, for dannelse av et første produkt, hvoretter en blanding av dette første produkt, en første alkanol, et inert oppløs-ningsmiddel og et reduksjonsmiddel på borbasis oppvarmes ved 25-45°C for dannelse av et andre produkt, og en blanding av dette andre produkt, ammoniumformiat, en edelmetallkatalysator og en andre alkanol oppvarmes ved 30-60°C.
12. Fremgangsmåte ifølge krav 11, karakterisert ved at forbindelsen med formel 8 er erholdt ved oppvarmning ved 40-65°C av en blanding av en tredje lavere alkanol, en katalytisk mengde av et fluoridsalt, en forbindelse med formel 4 og en forbindelse med formel 7 :
hvor og R2 uavhengig av hverandre betegner -H eller lavere alkoxy; R4 er lavere alkyl; og R5 og Rg begge er -OCH3 eller sammen danner -OCH2 0- eller -OCH2 CH2 0-.
13. Farmasøytisk preparat for behandling av angina, hypertensio eller hjertesvikt som følge av overbelastning, omfat-tende en i farmasøytisk henseende aksepterbar bærer og en effektiv mengde av en forbindelse med formel 1:
hvor R^ og R2 uavhengig av hverandre betegner -H eller lavere alkoxy; R^ og R^ uavhengig av hverandre betegner lavere alkyl; og R^- og R^ hver betegner -OCH^ eller sammen danner en gruppe
-OCH2 0 eller -OCH2 CH2 0-.
14. Preparat ifølge krav 13, hvor forbindelsen med formel 1 (racemisk) 3-[4 -(3,4-dimethoxyfenyl)-4-cyano-4-isopropyl-butyl]-6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydroisokinolin.
15. Forbindelse som er anvendelig for fremstilling av cardiovasculære farmasøytiske forbindelser, karakterisert ved at den har formelen:
hvor R 1 og R,> uavhengig av hverandre er -H eller lavere alkoxy;
R^ er lavere alkyl; og R,- og R^ hver er -OCH^ eller sammen danner -OCH2 0- eller -OCH2 CH2 0-.
16. Forbindelse som er anvendelig for fremstilling av cardiovasculære farmasøytiske forbindelser, karakterisert ved at den har formelen:
hvor R^ og R2 uavhengig av hverandre er -H eller lavere alkoxy; R4 er lavere alkyl; og R<- og R^ hver er -OCH^ eller sammen danner -OCH2 0 eller -OCH2 CH2 0-, eller er et i farmasøytisk henseende aksepterbart salt av en forbindelse med formel 8.
17. Forbindelse med formel 2 9
og syreaddisjonssalter derav, i hvilken formel R 1 og R_ uavhengig av hverandre betegner -H eller lavere alkoxy, R^ og R^ uavhengig av hverandre betegner lavere alkyl, og R^ og Rg hver betegner -OCH^ eller sammen danner en gruppe -OCI-^O-eller -OCH2 CH2 0-.
18. Forbindelse ifølge krav 17, hvor R^ og R2 begge er H, R^ er methyl og R^ er isopropyl.
19. Forbindelse med formel 34 eller 39:
hvor R., og R^ uavhengig av hverandre betegner -H eller lavere alkoxy; R^ og R^ uavhengig av hverandre betegner lavere alkyl; og R,, og R^ hver betegner -OCH^ eller sammen danner en gruppe
-OCH2 0- eller -OCH2 CH2 0-.
20. Forbindelse ifølge krav 19, hvor R^ og R2 begge er H, R^ er methyl og R^ er isopropyl.
21. Forbindelse med formel 37 eller 38:
og syreaddisjonssaltene derav, hvor R^ og R2 uavhengig av hverandre betegner -H eller lavere alkoxy; R^ og R^ uavhengig av hverandre betegner lavere alkyl; R^ og R^ hver betegner
-OCH^ eller sammen danner en gruppe -0CH2 0- eller -OCH2 CH2 0-;
og Z er HO- eller 0=.
22. Forbindelse ifølge krav 21, hvor R^ og R2 begge er H, R^ er methyl og R^ er isopropyl.
23. Fremgangsmåte for fremstilling av en forbindelse med formelen:
eller et i farmasøytisk henseende aksepterbart syreaddisjonssalt derav, i hvilken forbindelse R 1 og R^ uavhengig av hverandre betegner -H eller lavere alkoxy; R^ og R^ uavhengig av hverandre betegner lavere alkyl; og R,- og R^ hver betegner
-OCH^ eller sammen danner en gruppe -OCH^ O- eller -OC^Cr^O-, karakterisert ved at man(a) ringslutter en forbindelse med formel 11:
eller et syreaddisjonssalt derav, i hvilken forbindelse R^ , R^ , R^ , R^ og Rg er som ovenfor angitt, i nærvær av maursyre og en formaldehydkilde til en forbindelse med formel 1,(b) alkylerer en forbindelse med formel 20A:
hvor R,, R_, R., Rc og R, er som ovenfor angitt, med et lavere-alkyl-alkyleringsmiddel, såsom R-^ -L hvor R^ er som ovenfor angitt og L er en uttredende gruppe (halogen, sulfonyloxy, såsom lavere alkylsulfonyloxy, eller C^-C^_arYlsulfonyloxy) eller en formaldehydkilde og maursyre for dannelse av en forbindelse med formel 1,(c) ringslutter en forbindelse rriéd formel 29:
hvor R^ , , R^ , R^ , R^ og R^ er som ovenfor angitt, til en forbindelse med formel 1,(d) reduserer en forbindelse med formel 34:
hvor R^ , R^ , R^ , R^ , R^ og R^ er som ovenfor angitt, og hvor den stiplede linje betegner en dobbeltbinding mellom stillingene 1 og 2 eller mellom stillingene 2 og 3, til en forbindelse med formel 1, spesielt hvor R^ er methyl,
(e) reduserer en forbindelse med formel 39:
hvor R^ , R^ , R^ , R^ , R^ og R^ er som ovenfor angitt, til en forbindelse med formel 1,(f) reduserer en forbindelse med formel 37:
hvor R^ , R^ , R^ , R^ , R<- og R^ er som ovenfor angitt, og Hal betegner klor, brom eller jod, til en forbindelse med formel 1, (g) reduserer en forbindelse med formel 38:
hvor , R2 , R^ , R^ , R^_ og R er som ovenfor angitt, til en forbindelse med formel 1,(h) alkylerer en forbindelse med formel 42:
hvor R^ , R2 , R^ , R^ og R^ er som ovenfor angitt, med et lavere-alkyl-alkyleringsmiddel med formelen R^ -L hvor R^ er lavere alkyl og L er en uttredende gruppe,
(i) overfører en forbindelse med formel 1 til et syre-addis j ons salt derav,
(k) overfører et syreaddisjonssalt av en forbindelse med formel 1 til den frie base med formel 1,
(1) overfører et syreaddisjonssalt av en forbindelse med formel 1 til et annet syreaddisjonssalt av forbindelsen,
(m) dehydratiserer et amid med formelen
hvor R^ , R2 , R^ , R^ , R^ og R^ er som ovenfor angitt, til en forbindelse med formel 1, eller(n) overfører en ester med formelen
hvor R^ , R^ , R^ , R^ , R^ og R^ er som ovenfor angitt og Alkyl betegner lavere alkyl, til en forbindelse med formel 1.
24. Fremgangsmåte ifølge krav 23, for fremstilling av forbindelsen 3-[4-(3,4-dimethoxyfenyl)-4-isopropyl-4-cyano-butyl]-6,7-dimethoxy-N-methyl-l,2,3,4-tetrahydroisokinolin eller et i farmasøytisk henseende aksepterbart salt derav, karakterisert ved at det benyttes dertil egnede utgangsmaterialer.
25. Fremgangsmåte ifølge krav 23 eller 24, hvor det dessuten fremstilles et i farmasøytisk henseende aksepterbart preparat som inneholder en forbindelse med formel 1.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06/803,464 US4613606A (en) | 1985-12-02 | 1985-12-02 | Tetrahydroisoquinoline derivatives |
US06/909,659 US4667038A (en) | 1985-12-02 | 1986-09-22 | Tetrahydroisoquinoline derivatives |
Publications (2)
Publication Number | Publication Date |
---|---|
NO864818D0 NO864818D0 (no) | 1986-12-01 |
NO864818L true NO864818L (no) | 1987-06-03 |
Family
ID=27122597
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO864818A NO864818L (no) | 1985-12-02 | 1986-12-01 | Fremgangsmaate for fremstilling av nye terapeutisk virksomme tetrahydroisokinolinderivater. |
Country Status (11)
Country | Link |
---|---|
US (1) | US4667038A (no) |
EP (1) | EP0229944A3 (no) |
KR (1) | KR900000672B1 (no) |
CN (1) | CN86108089A (no) |
AU (2) | AU598772B2 (no) |
DK (1) | DK576986A (no) |
FI (1) | FI864893A (no) |
HU (1) | HU197312B (no) |
IL (1) | IL80824A0 (no) |
NO (1) | NO864818L (no) |
PL (1) | PL262734A1 (no) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
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US5948820A (en) | 1994-08-22 | 1999-09-07 | Yoshitomi Pharmaceutical Industries, Ltd. | Benzene compound and pharmaceutical use thereof |
EP0778263B1 (en) * | 1994-08-22 | 2002-01-09 | Welfide Corporation | Benzene compound and medicinal use thereof |
SI1471054T1 (sl) * | 2002-01-11 | 2009-12-31 | Daiichi Sankyo Co Ltd | Amino alkoholni derivati ali derivati fosfoniäśne kisline in medicinski sestavki, ki vsebujejo le-te |
BRPI0507944A (pt) | 2004-02-24 | 2007-07-24 | Sankyo Co | composição farmacêutica |
KR100870576B1 (ko) * | 2008-08-27 | 2008-11-27 | 울산대학교 산학협력단 | 퇴행성질환 및 염증질환에 대한 예방치료 효과를 갖는 7-하이드록시-6-메톡시-1,2,3,4-테트라하이드로이소퀴놀린 유도체 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1154810B (de) * | 1961-04-01 | 1963-09-26 | Knoll Ag | Verfahren zur Herstellung basisch substituierter Phenylacetonitrile |
DE1802804A1 (de) * | 1968-10-12 | 1970-06-11 | Knoll Ag | 1-[3'-Cyan-3'-(2'',3''-dimethoxyphenyl)-4'-methylpentyl]-2-methyl-6,7-dimethoxy-1,2,3,4-Tetrahydroisochinolin |
US4613606A (en) * | 1985-12-02 | 1986-09-23 | Syntex (U.S.A.) Inc. | Tetrahydroisoquinoline derivatives |
-
1986
- 1986-09-22 US US06/909,659 patent/US4667038A/en not_active Expired - Fee Related
- 1986-12-01 EP EP86116669A patent/EP0229944A3/en not_active Withdrawn
- 1986-12-01 NO NO864818A patent/NO864818L/no unknown
- 1986-12-01 AU AU65849/86A patent/AU598772B2/en not_active Ceased
- 1986-12-01 CN CN198686108089A patent/CN86108089A/zh active Pending
- 1986-12-01 DK DK576986A patent/DK576986A/da not_active Application Discontinuation
- 1986-12-01 HU HU864957A patent/HU197312B/hu unknown
- 1986-12-01 IL IL80824A patent/IL80824A0/xx unknown
- 1986-12-01 PL PL1986262734A patent/PL262734A1/xx unknown
- 1986-12-01 FI FI864893A patent/FI864893A/fi not_active Application Discontinuation
- 1986-12-02 KR KR1019860010263A patent/KR900000672B1/ko not_active IP Right Cessation
-
1990
- 1990-04-19 AU AU53630/90A patent/AU5363090A/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
HU197312B (en) | 1989-03-28 |
US4667038A (en) | 1987-05-19 |
KR900000672B1 (ko) | 1990-02-02 |
HUT43043A (en) | 1987-09-28 |
CN86108089A (zh) | 1987-09-16 |
DK576986D0 (da) | 1986-12-01 |
AU5363090A (en) | 1990-09-13 |
NO864818D0 (no) | 1986-12-01 |
DK576986A (da) | 1987-06-03 |
AU598772B2 (en) | 1990-07-05 |
EP0229944A3 (en) | 1987-10-21 |
IL80824A0 (en) | 1987-03-31 |
KR870006042A (ko) | 1987-07-08 |
PL262734A1 (en) | 1988-07-21 |
AU6584986A (en) | 1987-06-04 |
EP0229944A2 (en) | 1987-07-29 |
FI864893A0 (fi) | 1986-12-01 |
FI864893A (fi) | 1987-06-03 |
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