EP1200410A1 - Isoquinoline derivatives, pharmaceutical compositions containing the same, and a process for the preparation of the active substance - Google Patents
Isoquinoline derivatives, pharmaceutical compositions containing the same, and a process for the preparation of the active substanceInfo
- Publication number
- EP1200410A1 EP1200410A1 EP00949830A EP00949830A EP1200410A1 EP 1200410 A1 EP1200410 A1 EP 1200410A1 EP 00949830 A EP00949830 A EP 00949830A EP 00949830 A EP00949830 A EP 00949830A EP 1200410 A1 EP1200410 A1 EP 1200410A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- group
- hydrogen atom
- derivative
- independently
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 105
- 238000002360 preparation method Methods 0.000 title claims abstract description 46
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 25
- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 title abstract 2
- 239000013543 active substance Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 192
- 230000000949 anxiolytic effect Effects 0.000 claims abstract description 11
- 239000004480 active ingredient Substances 0.000 claims abstract description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 135
- -1 methylenedioxy group Chemical group 0.000 claims description 55
- 239000002253 acid Substances 0.000 claims description 51
- 150000003839 salts Chemical class 0.000 claims description 49
- 125000000217 alkyl group Chemical group 0.000 claims description 42
- 239000002585 base Substances 0.000 claims description 33
- 125000005843 halogen group Chemical group 0.000 claims description 31
- 125000003545 alkoxy group Chemical group 0.000 claims description 25
- 150000001408 amides Chemical class 0.000 claims description 25
- 150000007522 mineralic acids Chemical class 0.000 claims description 22
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 150000007524 organic acids Chemical class 0.000 claims description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 8
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 7
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 150000002500 ions Chemical class 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- JZZLDIIDMFCOGF-UHFFFAOYSA-N 1-methyl-3,4-dihydroisoquinoline Chemical compound C1=CC=C2C(C)=NCCC2=C1 JZZLDIIDMFCOGF-UHFFFAOYSA-N 0.000 claims description 2
- 229940006460 bromide ion Drugs 0.000 claims description 2
- 208000015114 central nervous system disease Diseases 0.000 claims description 2
- 238000006356 dehydrogenation reaction Methods 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 claims description 2
- 229940006461 iodide ion Drugs 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 2
- 210000003169 central nervous system Anatomy 0.000 abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 544
- 229910052757 nitrogen Inorganic materials 0.000 description 189
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 154
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 138
- 238000005160 1H NMR spectroscopy Methods 0.000 description 120
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 118
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 113
- 239000000243 solution Substances 0.000 description 108
- 238000004458 analytical method Methods 0.000 description 98
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 96
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 87
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 84
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 72
- 239000000203 mixture Substances 0.000 description 60
- 239000011541 reaction mixture Substances 0.000 description 54
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 41
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 36
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 34
- 239000012043 crude product Substances 0.000 description 33
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 30
- 239000013078 crystal Substances 0.000 description 30
- 229960004592 isopropanol Drugs 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- 239000007787 solid Substances 0.000 description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 22
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 21
- 239000000047 product Substances 0.000 description 21
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 18
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 18
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 17
- 239000007858 starting material Substances 0.000 description 16
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 238000000354 decomposition reaction Methods 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 12
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 12
- 239000012279 sodium borohydride Substances 0.000 description 11
- 229910000033 sodium borohydride Inorganic materials 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 9
- 235000011114 ammonium hydroxide Nutrition 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 9
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical class C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 5
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- APEJMQOBVMLION-UHFFFAOYSA-N cinnamic acid amide Natural products NC(=O)C=CC1=CC=CC=C1 APEJMQOBVMLION-UHFFFAOYSA-N 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000010908 decantation Methods 0.000 description 4
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 4
- 229960003529 diazepam Drugs 0.000 description 4
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000011976 maleic acid Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 4
- 230000007704 transition Effects 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 3
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical class C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 3
- PBYMYAJONQZORL-UHFFFAOYSA-N 1-methylisoquinoline Chemical compound C1=CC=C2C(C)=NC=CC2=C1 PBYMYAJONQZORL-UHFFFAOYSA-N 0.000 description 3
- NKSZCPBUWGZONP-UHFFFAOYSA-N 3,4-dihydroisoquinoline Chemical class C1=CC=C2C=NCCC2=C1 NKSZCPBUWGZONP-UHFFFAOYSA-N 0.000 description 3
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000002249 anxiolytic agent Substances 0.000 description 3
- OUGIDAPQYNCXRA-UHFFFAOYSA-N beta-naphthoflavone Chemical compound O1C2=CC=C3C=CC=CC3=C2C(=O)C=C1C1=CC=CC=C1 OUGIDAPQYNCXRA-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940126543 compound 14 Drugs 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 150000002391 heterocyclic compounds Chemical class 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 230000037023 motor activity Effects 0.000 description 3
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 230000002269 spontaneous effect Effects 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- WOGITNXCNOTRLK-VOTSOKGWSA-N (e)-3-phenylprop-2-enoyl chloride Chemical compound ClC(=O)\C=C\C1=CC=CC=C1 WOGITNXCNOTRLK-VOTSOKGWSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229910014263 BrF3 Inorganic materials 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- 239000001828 Gelatine Substances 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000006742 locomotor activity Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 2
- 230000001624 sedative effect Effects 0.000 description 2
- 125000005504 styryl group Chemical group 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- PLDWAJLZAAHOGG-UHFFFAOYSA-N 1-bromo-3-methoxybenzene Chemical compound COC1=CC=CC(Br)=C1 PLDWAJLZAAHOGG-UHFFFAOYSA-N 0.000 description 1
- NPZQXJLNCPZSIP-UHFFFAOYSA-N 10,12-dioxa-13-azatricyclo[7.3.1.02,7]trideca-1(13),2,4,6,8-pentaene Chemical compound C1=CC=C2C(OCO3)=NC3=CC2=C1 NPZQXJLNCPZSIP-UHFFFAOYSA-N 0.000 description 1
- MUBURCRSQQCPFF-UHFFFAOYSA-N 2-(1,3-benzodioxol-5-yl)ethanamine;hypochlorous acid Chemical compound ClO.NCCC1=CC=C2OCOC2=C1 MUBURCRSQQCPFF-UHFFFAOYSA-N 0.000 description 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- IOHOTIGNNIPUCP-UHFFFAOYSA-N 3-phenyl-n-[3,3,3-trifluoro-2-methoxy-2-(3-methoxyphenyl)propyl]prop-2-enamide Chemical compound COC1=CC=CC(C(CNC(=O)C=CC=2C=CC=CC=2)(OC)C(F)(F)F)=C1 IOHOTIGNNIPUCP-UHFFFAOYSA-N 0.000 description 1
- SUVHQJYRSITWJY-UHFFFAOYSA-N 4,6-dimethoxy-1-(2-phenylethenyl)-4-(trifluoromethyl)-3h-isoquinolin-2-ium;chloride Chemical compound [Cl-].[NH+]=1CC(OC)(C(F)(F)F)C2=CC(OC)=CC=C2C=1C=CC1=CC=CC=C1 SUVHQJYRSITWJY-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- LDRDWUHXWFCYOX-UHFFFAOYSA-N 5-[2-(4-fluorophenyl)ethenyl]-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline Chemical compound C1=CC(F)=CC=C1C=CC1C2=CC(OCO3)=C3C=C2CCN1 LDRDWUHXWFCYOX-UHFFFAOYSA-N 0.000 description 1
- YKZORQSBLUADRX-UHFFFAOYSA-N 5-[2-(4-fluorophenyl)ethenyl]-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline Chemical compound C1=CC(F)=CC=C1C=CC(C1=C2)=NCCC1=CC1=C2OCO1 YKZORQSBLUADRX-UHFFFAOYSA-N 0.000 description 1
- KZCWEOPDFRCBPU-UHFFFAOYSA-N 6-[2-[4-(trifluoromethyl)phenyl]ethenyl]-2,3-dihydro-[1,4]dioxino[2,3-g]isoquinoline Chemical compound C1=CC(C(F)(F)F)=CC=C1C=CC(C1=C2)=NC=CC1=CC1=C2OCCO1 KZCWEOPDFRCBPU-UHFFFAOYSA-N 0.000 description 1
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- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- QFFVPLLCYGOFPU-UHFFFAOYSA-N barium chromate Chemical compound [Ba+2].[O-][Cr]([O-])(=O)=O QFFVPLLCYGOFPU-UHFFFAOYSA-N 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 229940068911 chloride hexahydrate Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- GSOLWAFGMNOBSY-UHFFFAOYSA-N cobalt Chemical compound [Co][Co][Co][Co][Co][Co][Co][Co] GSOLWAFGMNOBSY-UHFFFAOYSA-N 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- LKFMVKAPKUEVGW-UHFFFAOYSA-N dihydrate;hydroiodide Chemical compound [H+].O.O.[I-] LKFMVKAPKUEVGW-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- OYJXTOVLKZDGFK-UHFFFAOYSA-N ethanol;2-propan-2-yloxypropane Chemical compound CCO.CC(C)OC(C)C OYJXTOVLKZDGFK-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 230000010240 hepatic drug metabolism Effects 0.000 description 1
- 230000010224 hepatic metabolism Effects 0.000 description 1
- VOAPTKOANCCNFV-UHFFFAOYSA-N hexahydrate;hydrochloride Chemical compound O.O.O.O.O.O.Cl VOAPTKOANCCNFV-UHFFFAOYSA-N 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- FKUUDDGRDRPAQQ-UHFFFAOYSA-M magnesium;methoxybenzene;bromide Chemical compound [Mg+2].[Br-].COC1=CC=C[C-]=C1 FKUUDDGRDRPAQQ-UHFFFAOYSA-M 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N mono-n-propyl amine Natural products CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 125000006606 n-butoxy group Chemical group 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
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 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
- 230000007935 neutral effect Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000007925 phenylethylamine derivatives Chemical class 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229920006395 saturated elastomer Polymers 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
- 239000000932 sedative agent Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- 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
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
-
- 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
-
- 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
Definitions
- the invention refers to novel isoquinohne derivatives, pharmaceutical compositions containing the same, and a process for the preparation of the active ingredient
- novel compounds have an influence on the central nervous system, and possess especially anxiolytic effect
- the invention refers to a novel isoquinohne derivative of the formula wherein
- R 1 ⁇ R 2 and R 3 represent, independently, a hydrogen atom, a halo atom, a hydroxy group or a C ⁇ -4 alkoxy group, or Ri forms with R 2 a methylenedioxy group or an ethylenedioxy group, R 4 stands for a hydrogen atom, a C 1-4 alkoxy group or a t ⁇ fluoromethyl group R 7 means a hydrogen atom or a C ⁇ -4 alkyl group,
- R 8 is a hydrogen atom or a C ⁇ - 4 alkyl group
- R5, Re, R9 represent, independently, a hydrogen atom, or
- R 5 forms with R 6 a valence bond, and simultaneously
- R 8 forms with R 9 a valence bond
- R 10 and Rn represent, independently, a hydrogen atom, a halo atom, a nitro group, a C 1-4 alkoxy group, a trifluoromethyl group or a cyano group
- X T and X 2 mean, independently, a hydrogen atom, or X T forms with X 2 a valence bond, furthermore pharmaceutically suitable acid addition salts thereof and a quaternary derivative of the formula
- Ri, R 2 , R3, R , R5, Re, R7, Re, R9, R10, R11, X1 s ⁇ d X 2 are as defined above,
- R' ⁇ stands for a C ⁇ - 4 alkyl group
- A represents a residue of an inorganic or organic acid of the formula HA, or, in formula I,
- R 3 , R 6 and R 7 represent, independently, a hydrogen atom
- R 8 forms with R 9 a valence bond
- R 4 stands for a hydrogen atom, a C ⁇ -4 alkoxy group or a C ⁇ -6 alkyl group
- R 5 means a hidrogen atom or a t ⁇ fluoromethyl group
- R 10 and Rn represent, independently, a hydrogen atom, a halo atom, a nitro group, a C 1- alkoxy group or a tnfluoro- methyl group
- Xi and X 2 mean, independently, a hydrogen atom, or Xi forms with X 2 a valence bond, furthermore pharmaceutically suitable acid addition salts thereof,
- R 3 , R 5 , Re and R 7 represent, independently, a hydrogen atom
- R 8 forms with R 9 a valence bond
- R 4 stands for a hydrogen atom or a C ⁇ -6 alkyl group
- R 10 and Rn represent, independently, a hydrogen atom, a halo atom, a C ⁇ . 4 alkoxy group or a t ⁇ fluoromethyl group
- Xi and X 2 mean, independently, a hydrogen atom, or Xi forms with X 2 a valence bond
- R's represents a C ⁇ -4 alkyl group
- A represents a residue of an inorganic or organic acid of the formula HA
- the aim of the invention is to prepare novel isoquinohne derivatives having more favourable activity than that of the known compounds
- a Ci -4 alkyl group is a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec -butyl, tert -butyl or isobutyl group, preferably a methyl group
- a C1-6 alkyl group can represent, for example, also an n-pentyl or an n-hexyl group in addition to the ones listed above under the definition of the C ⁇ - 4 alkyl group
- a C ⁇ - alkoxy group is primarily a methoxy, ethoxy, n-propoxy or n-butoxy group, preferably a methoxy group
- a pharmaceutically suitable acid addition salt is an acid addition salt formed with a pharmaceutically suitable inorganic acid such as hydrochloric acid, hydrogen bromide, sulfu ⁇ c acid, phosphoric acid etc , or with a pharmaceutically suitable organic acid such as formic acid, acetic acid, fuma ⁇ c acid, maleic acid, lactic acid, malic acid, tartaric acid, succinic acid, citric acid, methanesulfonic acid etc
- the acid of the formula HA is, preferably, a ann iinnoorrggaanniicc aacciidd ssuucchh aass hhyyddrogen chloride, hydrogen bromide, hydrogen iodide etc
- a subgroup of the compounds of the invention consists of 1 ,2,3,4-tetrahydro ⁇ soqu ⁇ nol ⁇ ne derivatives of the formula wherein
- Ri, R 2 and R 3 represent, independently, a hydrogen atom, a halo atom, a hydroxy group or a C ⁇ -4 alkoxy group, or Ri forms with R 2 a methylenedioxy group or an ethylenedioxy group
- R 4 stands for a hydrogen atom or a C 1- alkoxy group
- R 7 means a hydrogen atom or a C ⁇ - alkyl group
- R 8 is a hydrogen atom or a C 1-4 alkyl group
- R 10 and Rn represent, independently, a hydrogen atom, a halo atom, a Ci 4 alkoxy group or a t ⁇ fluoromethyl group
- Xi and X 2 mean, independently, a hydrogen atom, or Xi forms with X 2 a valence bond, furthermore pharmaceutically suitable acid addition salts thereof and a quaternary derivative of the formula wherein
- Ri, R 2 , 3, R4, R5, R ⁇ , R7, e, R9, R10, R11, Xi and X 2 are as defined above,
- R'a stands for a C ⁇ - alkyl group
- A represents a residue of an inorganic or organic acid of the formula HA
- Preferred 1 ,2,3,4-tetrahydro ⁇ soqu ⁇ nol ⁇ ne derivatives of the formula la are those, wherein
- Ri and R 2 represent, independently, a methoxy group, or Ri forms with R 2 a methylenedioxy group or an ethylenedioxy group
- R 3 stands for a hydrogen atom
- R 4 means a hydrogen atom
- R 7 is a hydrogen atom
- R 8 represents a hydrogen atom or a methyl group
- R 10 stands for a halo atom, a tnfluoromethyl group or a methoxy group
- Rn means a hydrogen atom or a methoxy group
- Xi and X 2 mean, independently, a hydrogen atom or Xi forms with X 2 a valence bond, furthermore pharmaceutically suitable acid addition salts thereof and quaternary derivatives of the formula I'a, wherein R-i, R 2 , R3, R 4 , R5, e, R7, R 8 , R9, R10, R11, Xi and X 2 are as defined above,
- R's stands for a methyl group, and A represents a hahde ion
- a further subgroup of the compounds of the invention consists of the isoquinohne derivatives of the formula
- Ri, R 2 and R 3 represent, independently, a hydrogen atom, a halo atom, a hydroxy group or a C ⁇ -4 alkoxy group, or Ri forms with R 2 a methylenedioxy group or an ethylenedioxy group
- R 4 stands for a hydrogen atom, a C 1- alkoxy group or a tnfluoromethyl group
- R 7 means a hydrogen atom or a C ⁇ - alkyl group
- R1 0 and Rn represent, independently, a hydrogen atom, a halo atom, a nitro group, a C ⁇ - alkoxy group, a tnfluoromethyl group or a cyano group
- Xi and X 2 mean, independently, a hydrogen atom, or Xi forms with X 2 a valence bond, furthermore pharmaceutically suitable acid addition salts thereof and a quaternary derivative of the formula
- R-i, R 2 , R 3 , R 4 , R 7 , R10, Rn, Xi and X 2 are as defined above,
- R' 8 stands for a C ⁇ - alkyl group
- A represents a residue of an inorganic or organic acid of the formula HA
- Preferred isoquinohne derivatives of the formula lb are those, wherein
- Ri, R 2 and R 3 represent, independently, a hydrogen atom or a methoxy group, or Ri forms with R 2 a methylenedioxy group or an ethylenedioxy group
- R 4 stands for a hydrogen atom, a C ⁇ _ 4 alkoxy group or a tnfluoromethyl group
- R 7 means a hydrogen atom or a methyl group
- R 10 represent a hydrogen atom, a halo atom, a nitro group, a methoxy group, a tnfluoromethyl group or a cyano group
- Rn is a hydrogen atom or a methoxy group
- Xi and X 2 mean, independently, a hydrogen atom, or Xi forms with X 2 a valence bond, furthermore pharmaceutically suitable acid addition salts thereof and a quaternary derivative of the formula I'b, wherein
- Ri, 2, R3, R , R7, R10, R11, Xi and X 2 are as defined above,
- R'a stands for a methyl group
- A represents a ha de ion
- Another subgroup of the compounds of the invention consists of the 3,4-d ⁇ hydro ⁇ soqu ⁇ nohne derivatives of the formula
- Ri and R 2 represent, independently, a hydrogen atom, a halo atom, a hydroxy group or a C1-4 alkoxy group, or Ri forms with R 2 a methylenedioxy group or an ethylenedioxy group
- R 4 stands for a hydrogen atom, a C ⁇ - alkoxy group or a C ⁇ -6 alkyl group
- R 5 means a hydrogen atom or a t ⁇ fluoromethyl group
- R1 0 and Rn represent, independently, a hydrogen atom, a halo atom, a nitro group, a C ⁇ - alkoxy group or a t ⁇ fluoro- methyl group
- Xi and X 2 mean, independently, a hydrogen atom, or Xi forms with X 2 a valence bond, furthermore pharmaceutically suitable acid addition salts thereof
- Preferred 3,4-d ⁇ hydro ⁇ soqu ⁇ nohne derivatives of the formula XIV are those, wherein
- Ri and R 2 represent, independently, a hydrogen atom, a chloro atom, a hydroxy group or a methoxy group, or Ri forms with R 2 a methylenedioxy group or an ethylenedioxy group
- R 4 stands for a hydrogen atom or a C ⁇ - 6 alkyl group
- R 5 means a hydrogen atom
- R 10 and R represent, independently, a hydrogen ator , a fluoro atom, a methoxy group or a tnfluoromethyl group
- Xi and X 2 mean, independently, a hydrogen atom, or X T forms with X 2 a valence bond, furthermore pharmaceutically suitable acid addition salts thereof
- Especially preferred 3,4-d ⁇ hydro ⁇ soqu ⁇ noh ⁇ e derivatives of the formula XIV are those, wherein Ri forms with R 2 a methylenedioxy group, R 4 stands for a C ⁇ . 6 alkyl group, R 5 means a hydrogen atom or a tnfluoromethyl group, R 10 and Rn represent, independently, a hydrogen atom, a methoxy group or a tnfluoromethyl group, Xi forms with X 2 a valence bond, furthermore pharmaceutically suitable acid addition salts thereof
- a still further subgroup of the compounds of the invention consists of the 3,4-d ⁇ hydro ⁇ soqu ⁇ ol ⁇ n ⁇ um derivatives of the formula
- Ri and R 2 represent, independently, a hydrogen atom, a halo atom, a hydroxy group or a C ⁇ -4 alkoxy group, or Ri forms with R 2 a methylenedioxy group or an ethylenedioxy group
- R 4 stands for a hydrogen atom or a d- 6 alkyl group
- R's means a C ⁇ - alkyl group
- R-io and Rn represent, independently, a hydrogen atom, a halo atom, a Ci alkoxy group or a tnfluoromethyl group
- Xi and X 2 mean, independently, a hydrogen atom, or X T forms with X 2 a valence bond
- A represents a residue of an inorganic or organic acid of the formula HA
- Ri and R 2 represent, independently, a hydroxy group, a chloro atom or a methoxy group, or Ri forms with R 2 a methylenedioxy group or an ethylenedioxy group
- R 4 stands for a hydrogen atom or a C ⁇ -3 alkyl group
- R's means a methyl group
- R 10 and Rn represent, independently, a hydrogen atom, a halo atom or a tnfluoromethyl group
- Xi and X 2 mean, independently, a hydrogen atom, or Xi forms with X 2 a valence bond
- A represents a residue of an inorganic acid of the formula HA
- Especially preferred 3,4-d ⁇ hydro ⁇ soqu ⁇ nol ⁇ n ⁇ um derivatives of the formula XI are those, wherein
- R 4 stands for a hydrogen atom or a C ⁇ . 3 alkyl group
- R's means a methyl group
- R 10 and Rn represent, independently, a hydrogen atom, a fluoro atom or a tnfluoromethyl group
- Xi and X 2 mean, independently, a hydrogen atom, or Xi forms with X 2 a valence bond
- A represents a bromide ion or a iodide ion
- the compounds of the invention are prepared as follows:
- R ⁇ 3 stands for a hydrogen atom, to catalytical dehydrogenation
- R ⁇ 2 stands for a C 1 4 alkyl group
- A is as defined in connection with formula I', with a reducing agent, or
- R 4 stands for a tnfluoromethyl group, reacting a 3,4-d ⁇ hydro ⁇ soqu ⁇ nohne derivative of the formula IV, wherein R 1 ( R 2 , R 3 , R 4 , R 7 , R10 Rn, Xi and X 2 are as stated above, R 13 represents a C ⁇ -4 alkoxy group, with an alkali metal hydroxide, or
- R 1 R 2 , R 3 , R and R 7 are as stated above
- R ⁇ 3 stands for a C ⁇ -4 alkyl group, with an aldehyde of the formula III, wherein R 10 and Rn are as stated above, in the presence of a condensing agent, or
- R 3 stands for a hydrogen atom, and R 3 represents a hydrogen atom or a tnfluoromethyl group, or
- R 1 ? R 2 , R 3 , R 4 , R 7 , R10, Rn, X T and X 2 are as defined in connection with formula I,
- R 8 stands for a hydrogen atom, to a compound of the formula la, wherein R 8 represents a C 1- alkyl group, by reaction with a C ⁇ - alkyl hahde, or
- R 1 R 2 , R 3 , R 4 , R5, Re, R7, Re, R9, R10, R11, Xi and X 2 are as defined in connection with formula I
- R' 8 represents a C ⁇ -4 alkyl group
- A stands for a residue of an inorganic or organic acid of the formula HA, by reaction with a compound of the formula R' 8 -A, wherein R' 8 and A are as stated above, or
- R-, R 2 , R 3 , R 4 , R 7 , R ⁇ 0 , Rn, Xi and X 2 are as defined in connection with formula I
- R' 8 stands for a C ⁇ - alkyl group
- A represents a residue of an inorganic or organic acid of the formula HA, to a compound of the formula la, wherein Ri, R 2 , R 3 , R 4 , R 7 , R ⁇ 0 , Rn, Xi and X 2 are as stated above, R 8 stands for a C ⁇ . alkyl group, by reaction with a reducing agent
- the 3,4-d ⁇ hydro ⁇ soqu ⁇ nol ⁇ ne derivative is hydrogenized using known literature processes [Houben-Weyl Meth Org Chem , 4/1 c, 121 , 271 -281 , 365, 401 , Georg Thieme Verlag, Stuttgart, (1981 )]
- the alkoxy group in position 4 is eliminated with an alkali metal hydroxide, preferably potassium hydroxide
- Process f) of the invention can be performed in a similar way as process a)
- condensing agent preferably a carboxylic anhydride, suitably acetic anhydride is used
- the acid amide of the formula VIII is cyc zed in a manner known from the literature [Heterocyclic compounds, Ed J Wiley and Sons, Inc , 38/3. 85-89 (1994), 38/1 , 173-175 (1994)]
- a C ⁇ -4 alkyl hahde suitably methyl iodide or methyl bromide is used as the reagent of the formula R' 8 -A, and the reaction is carried out in the presence of an indifferent organic solvent at 10 to 160 °C, in general
- the organic solvent can be apolar such as benzene, toluene, xylene, dichloromethane, etc , or polar protic such as methanol, ethanol etc
- Process i) of the invention is performed in an analogous manner as the processes known from the literature [Houben- Weyl, Meth Org Chem , Georg Thieme Verlag, Stuttgart, 4/1 c. 517-518 (1981)] An obtained isoquinohne derivative can be converted to another compound of the formula I in a manner known perse
- a styryl derivative wherein X forms with X 2 a valence bond
- a compound of the formula I wherein Xi and X 2 stand for a hydrogen atom by catalytical hydrogenation [Houben-Weyl Meth Org Chem , 4/1 d, 580-581 , Georg Thieme Verlag, Stuttgart, (1981 )]
- the nitrogen atom of a 1 ,2,3,4-tetrahydro ⁇ soqu ⁇ nohne derivative of the formula la, wherein R 8 represents a hydrogen atom, can be alkylated in a manner known per se, for example using an alkyl hahde
- the compound of the formula I can be reacted with a compound of the formula R' 8 -A, preferably a C 1 - 4 alkyl ha de to obtain a quaternary compound of the formula I'
- the reaction is carried out in an apolar solvent such as benzene, toluene, xylene, dichloromethane, dichloroethane, etc , or a polar protic solvent such as an alkanol at a temperature from 10 to 160 °C
- a quaternary isoquinohne derivative of the formula I'b can be reduced to obtain the corresponding 1 ,2,3,4-tetrahydro ⁇ so- quinohne of the formula la
- the reduction is performed using the methods described in the literature cited in connection with process c)
- the 1 -methyhsoqu ⁇ nohne derivatives of the formula II are partly known compounds
- the compounds of the formula II, wherein R 4 stands for a tnfluoromethyl group, can be prepared by the reaction of a 1 -methyl-1 ,2-d ⁇ hydro ⁇ soqu ⁇ nohne and potassium hydroxide
- the 1 -methyl-1 ,2-d ⁇ hydro ⁇ soqu ⁇ nohne of the formula VI is prepared by cychzing an acid amide of the formula wherein Ri, R 2 and R 3 are as defined in connection with formula I, R 4 stands for a tnfluoromethyl group, R ⁇ 3 represents a C 1 - 4 alkoxy group
- the cychzation reaction is carried out in a manner known from the literature [Heterocyclic Compounds, Ed J Wiley and Sons, Inc , 38/3, 65-89 (1994), 38/1 , 173-175 (1994)]
- the aldehydes of the formula III are known compounds that are commercially available
- the 1 ,2-d ⁇ hydro ⁇ soqu ⁇ nohne derivatives of the formula IV are novel compounds that are prepared by cychzing an acid amide of the formula VIII, wherein Ri, R 2 , R 3 , R 4 , R 10 , Rn, Xi and X 2 are as defined in connection with formula I, R 3 represents a Ci -4 alkoxy group
- the cychzation reaction is performed an an analogous manner as the cychzation of the acid amide of the formula VII
- the acid amide of the formula VIII can be prepared by reacting an acid derivative of the formula
- R 10 , Rn, Xi and X 2 are as defined in connection with formula I, with a phenylethylamine of the formula wherein Ri, R 2 , R 3 and R 4 are as defined in connection with formula I, R 13 stands for a C 1 - 4 alkoxy group, in an analogous manner as described in the literature [Houben-Weyl Meth Org Chem , E5/2, 993-1 100, Georg Thieme Verlag, Stuttgart, (1981 )]
- the acid derivatives of the formula IX and the phenylethylamines of the formula X are commercially available
- the tnfluoromethyl derivatives of the formula X can be prepared from the corresponding cyanohyd ⁇ ne of the formula
- the 1 ,2-d ⁇ hydro ⁇ soqu ⁇ nol ⁇ n ⁇ um derivative of the formula V can be prepared from the corresponding 1 ,2-d ⁇ hydro ⁇ soqu ⁇ nol ⁇ ne by reaction with an alkylating agent of the formula R1 2 -A, wherein R ⁇ 2 represents a C, 4 alkyl group, A is a residue of an inorganic or organic acid of the formula HA
- the 3,4-d ⁇ hydro ⁇ soqu ⁇ nol ⁇ ne derivative of the formula XII is prepared by cychzing an acid amide of the formula VIII
- the cychzation reaction is carried out in a manner described under the cychzation of the acid amide of the formula VII
- the pharmacological effect of the compounds of the invention have been proved by the following experiments
- Wistar rats weighing 140 to 160 g were used for the experiments The compounds to be tested were suspended in 0 4 % methylcellulose solution and administered in 100 mg/kg daily per os dose for 3 consecutive days ⁇ -Naphthoflavone treatment was used as positive control in 25 mg/kg per os dose.
- the typical reaction for CYP1 A isoenzyme has been monitored by the measurement of ethoxyresoruphine deethylase (EROD) activity according to the method of Pohl, R.J. and Fouts, J.R., Anal. Biochem., 107, 150-155 (1980). Control values from untreated animals have been considered as 100 %, and EROD activities have been expressed as percent of untreated control.
- Table III 1 -(4-Trifluoromethylstyryl)-6,7- methylenedioxyisoquinohne has been used as the reference compound.
- the compounds of the invention display marked CNS, especially anxiolytic effects
- the anxiolytic activity is significant in the "light-dark transition” test, while the known 1 -styryhsoquinohne derivatives were found to be practically ineffective in this test Moreover, the novel compounds did not influence spontaneous motor activity in a dose more than five times higher than that of the ID 50 value of the reference compound diazepam
- the compounds of the invention did not influence the key enzymes of hepatic drug metabolism
- the low and insignificant enzyme induction potency of the novel compounds is of great importance from drug safety approaches
- novel isoquinohne derivatives of the formula I can be any novel isoquinohne derivatives of the formula I.
- compositions / used as active ingredients in pharmaceutical compositions
- compositions of the invention contain a therapeutically active amount of the compound of the formula I or a pharmaceutically suitable acid addition salt thereof or a quaternary derivative of the formula I' and one or more conventional car ⁇ er(s)
- compositions of the invention are suitable for peroral, parenteral or rectal administration or for local treatment, and can be solid or liquid
- the solid pharmaceutical compositions suitable for peroral administration may be powders, capsules, tablets, film-coated tablets, microcapsules etc , and can comprise binding agents such as gelatine, sorbitol, poly(v ⁇ nylpyrrol ⁇ done) etc , filling agents such as lactose, glucose, starch, calcium phosphate etc , auxiliary substances for tabletting such as magnesium stearate, talc, poly(ethylene glycol), silica etc , wetting agents such as sodium laurylsulfate etc as the carrier
- the liquid pharmaceutical compositions suitable for peroral administration may be solutions, suspensions or emulsions and can comprise e g suspending agents such as gelatine, carboxymethylcellulose etc , emulsifiers such as sorbitane monooleate etc , solvents such as water, oils, glycerol, propylene glycol, ethanol etc , preservatives such as methyl p- hydroxybenzoate etc as the carrier
- compositions suitable for parenteral administration consist of sterile solutions of the active ingredient, in general
- compositions of the invention contain, in general, 0 1 to 95 0 per cent by mass of a compound of the formula I or a pharmaceutically suitable acid addition salt thereof or a quaternary derivative of the formula I'
- a typical dose for adult patients amounts to 0 1 to 1000 mg of the compound of the formula I, daily
- the above dose can be administered in one or more portions
- the actual dosage depends on many factors and is determined by the doctor
- compositions of the invention are prepared by admixing a compound of the formula I or a pharmaceutically suitable acid addition salt thereof or a quaternary derivative of the formula I' to one or more carr ⁇ er(s), and converting the mixture obtained to a pharmaceutical composition in a manner known per se Useful methods are known from the literature, e g Remington's Pharmaceutical Sciences mentioned above
- compositions of the invention contains a 1 ,2,3,4-tetrahydro ⁇ soqu ⁇ nohne of the formula la or a pharmaceutically suitable acid addition salt thereof or a quaternary derivative of the formula I'a
- a further subgroup of the pharmaceutical compositions of the invention contains an isoquinohne derivative of the formula lb or a pharmaceutically suitable acid addition salt thereof or a quaternary derivative of the formula I'b
- compositions of the invention contains a 3,4-d ⁇ hydro ⁇ soqu ⁇ nol ⁇ ne derivative of the formula XIV or a pharmaceutically suitable acid addition salt thereof
- a still further subgroup of the pharmaceutical compositions of the invention contains a 3,4-d ⁇ hydro ⁇ soqu ⁇ nohn ⁇ um derivative of the formula XI
- the invention includes also a method of treatment in which a patient suffering from especially a disease of the central nervous system is treated with a non-toxic dose of a 3,4- dihydroisoquino ne derivative of the formula I or a pharmaceutically suitable acid addition salt thereof or a quaternary derivative of the formula I'
- the invention includes the use of an isoquinohne derivative of the formula I or a pharmaceutically suitable acid addition salt thereof or a quaternary derivative of the formula I' for the preparation of a pharmaceutical composition having anxiolytic effect
- the title compound is prepared in a similar manner as the starting compound under 28)
- the crude product is fractionated under reduced pressure At a pressure of 373 Pa, the fraction from 84 to 85 °C is separated Yield 63 % Analysis for C 9 H 5 F 3 0 3 (218 134) calculated C 49 56 %, H 2 31 %, found C 49 43 %, H 2 20 %
- the title compound is prepared in a similar manner as the starting compound under 32)
- the crude product is fractionated under reduced pressure At a pressure of 147 Pa, the fraction from 1 14 to 1 16 °C is collected Yield 68 %
- the title compound is a colourless oil
- Example 14 The procedure described in Example 14 is followed to bta ⁇ n the title compound Yield 59 % M p 256-258 °C Analysis for C 2 ⁇ H 2 ⁇ FIN0 2 (503 30) calculated C 50 31 %, H 4 21 %, N 2 78 %, found C 49 88 %, H 4 25 %, N 2 87 %
- Example 28 1-/2-(3,4-D ⁇ methoxyphenyl)ethyl/-6,7-d ⁇ methoxy ⁇ soqu ⁇ nohne 3
- 51 g (0 01 moles) of 1 -(3,4-d ⁇ methoxystyryl)-6,7-d ⁇ methoxy- isoquinohne are dissolved in 100 cm 3 of acetic acid
- 0 5 g of Pd/C catalyst are added, and the mixture is hydrogenized at room temperature and 10 bar pressure until the end of hydrogen gas consumption
- the catalyst is removed by filtration, the filtrate is evaporated under reduced pressure
- the residue is dissolved in 50 cm 3 of methanol, and, by the addition of about 50 g of crushed ice and 10 cm 3 of 25 % aqueous ammonia, the base is prepared
- the precipitated crystalline product is filtered, and washed with cold water
- 1 5 g (43 %) of the title compound are obtained M p 146-147 °C
- the solution is extracted three times using 30 cm 3 of ethyl acetate each time, the combined organic phases are dried over anhydrous magnesium sulfate, and evaporated.
- the crude base is dissolved in 10 cm 3 of methanol, and, to the solution formed, a solution of 1.16 g (10 mmoles) of maleic acid in 10 cm 3 of methanol, then 40 cm 3 of diisopropyl ether are added, drop by drop.
- the precipitated crystals are filtered, washed with 10 cm 3 of diisopropyl ether.
- 2.54 g (53 %) of the title compound are obtained.
- Example 41 The procedure described in Example 41 is followed to obtain the title compound Yield 81 % M p 183-185 °C
- Example 62 1 -(4-Tr ⁇ fluoromethylstyryl)-6,7-methylened ⁇ oxy-3,4-d ⁇ hydro- isoquinohne hydrochlonde
- the crude product obtained is dissolved in dichloromethane and the pH is adjusted to 11 by the addition of 20 % aqueous sodium hydroxide solution under stirring
- the separated aqueous phase is extracted with dichloromethane twice using 50 cm 3 of dichloromethane each time
- the combined organic phases are dried over anhydrous sodium sulfate, evaporated to obtain 2.9 g (45 %) of oily product
- the crude product is dissolved in absolute ether, and, to the solution, an equimolar amount of anhydrous oxalic acid is added
- the crystalline salt is filtered. Thus, 3 22 g (41 %) of the title compound are obtained.
- Example 66 1 -(2-Phenylethyl)-6,7-methylened ⁇ oxy-3,4-d ⁇ hydro ⁇ soqu ⁇ nohne
- Example 67, section A The procedure described in Example 67, section A) is followed starting from 1 12 g (2 5 mmoles) of N-/3-(4-tr ⁇ fluoromethyl- phenyl)propanoyl/-3,3,3-t ⁇ fluoro-2-methoxy-2-(3-metho ⁇ y- phenyl)propylam ⁇ ne and 2 0 cm 3 (3 36 g, 22 mmoles) of phosphor(V) trichloride oxide The crude base is dissolved in
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Abstract
The invention refers to novel isoquinoline derivatives of formula (I), pharmaceutical compositions containing the same, and a process for the preparation of the active ingredient. The novel compounds have an influence on the central nervous system, and possess especially anxiolytic effect.
Description
ISOQUINOLINE DERIVATIVES , PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME , AND A PROCESS FOR THE PREPARATION OF THE ACTIVE SUBSTANCE
The invention refers to novel isoquinohne derivatives, pharmaceutical compositions containing the same, and a process for the preparation of the active ingredient The novel compounds have an influence on the central nervous system, and possess especially anxiolytic effect
More specifically, the invention refers to a novel isoquinohne derivative of the formula
wherein
R1 } R2 and R3 represent, independently, a hydrogen atom, a halo atom, a hydroxy group or a Cι-4 alkoxy group, or Ri forms with R2 a methylenedioxy group or an ethylenedioxy group, R4 stands for a hydrogen atom, a C1-4 alkoxy group or a tπfluoromethyl group
R7 means a hydrogen atom or a Cι-4 alkyl group,
R8 is a hydrogen atom or a Cι-4 alkyl group,
R5, Re, R9 represent, independently, a hydrogen atom, or
R5 forms with R6 a valence bond, and simultaneously
R8 forms with R9 a valence bond,
R10 and Rn represent, independently, a hydrogen atom, a halo atom, a nitro group, a C1-4 alkoxy group, a trifluoromethyl group or a cyano group, XT and X2 mean, independently, a hydrogen atom, or XT forms with X2 a valence bond, furthermore pharmaceutically suitable acid addition salts thereof and a quaternary derivative of the formula
wherein
Ri, R2, R3, R , R5, Re, R7, Re, R9, R10, R11, X1 sπd X2 are as defined above,
R'β stands for a Cι-4 alkyl group, and
A represents a residue of an inorganic or organic acid of the formula HA,
or, in formula I,
Ri and R2 are as stated above,
R3, R6 and R7 represent, independently, a hydrogen atom,
R8 forms with R9 a valence bond,
R4 stands for a hydrogen atom, a Cι-4 alkoxy group or a Cι-6 alkyl group, R5 means a hidrogen atom or a tπfluoromethyl group, R10 and Rn represent, independently, a hydrogen atom, a halo atom, a nitro group, a C1- alkoxy group or a tnfluoro- methyl group, Xi and X2 mean, independently, a hydrogen atom, or Xi forms with X2 a valence bond, furthermore pharmaceutically suitable acid addition salts thereof,
or, in formula I',
Ri and R2 are as stated above,
R3, R5, Re and R7 represent, independently, a hydrogen atom,
R8 forms with R9 a valence bond,
R4 stands for a hydrogen atom or a Cι-6 alkyl group,
R10 and Rn represent, independently, a hydrogen atom, a halo atom, a Cι.4 alkoxy group or a tπfluoromethyl group, Xi and X2 mean, independently, a hydrogen atom, or Xi forms with X2 a valence bond, R's represents a Cι-4 alkyl group, and A represents a residue of an inorganic or organic acid of the
formula HA
1-Styrylιsoquιnolιne derivatives having anxiolytic effect are known from the French Patent Applocation of publication No 2 719 586
The aim of the invention is to prepare novel isoquinohne derivatives having more favourable activity than that of the known compounds
It was found that the above aim is achieved by the compounds of the formula I and I' having remarkable anxiolytic effect in the so called "light-dark transition" test, while in case of the known 1 -styrylιsoquιnolιne derivatives such an activity is not experienced In addition, the novel compounds do not pr hardly induce the key enzymes of the liver metabolism which take part in the drug metabolism
In the description and Claims, in the definition of the substituents, under a halo atom primarily a fluoro, chloro, bromo or lodo atom, preferably a fluoro or chloro atom is meant
A Ci-4 alkyl group is a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec -butyl, tert -butyl or isobutyl group, preferably a methyl group
A C1-6 alkyl group can represent, for example, also an n-pentyl or an n-hexyl group in addition to the ones listed above under
the definition of the Cι-4 alkyl group
A Cι- alkoxy group is primarily a methoxy, ethoxy, n-propoxy or n-butoxy group, preferably a methoxy group
A pharmaceutically suitable acid addition salt is an acid addition salt formed with a pharmaceutically suitable inorganic acid such as hydrochloric acid, hydrogen bromide, sulfuπc acid, phosphoric acid etc , or with a pharmaceutically suitable organic acid such as formic acid, acetic acid, fumaπc acid, maleic acid, lactic acid, malic acid, tartaric acid, succinic acid, citric acid, methanesulfonic acid etc
n the definition of A, the acid of the formula HA is, preferably, a ann iinnoorrggaanniicc aacciidd ssuucchh aass hhyyddrogen chloride, hydrogen bromide, hydrogen iodide etc
A subgroup of the compounds of the invention consists of 1 ,2,3,4-tetrahydroιsoquιnolιne derivatives of the formula
wherein
Ri, R2 and R3 represent, independently, a hydrogen atom, a halo atom, a hydroxy group or a Cι-4 alkoxy group, or Ri forms with R2 a methylenedioxy group or an ethylenedioxy group, R4 stands for a hydrogen atom or a C1- alkoxy group, R7 means a hydrogen atom or a Cι- alkyl group, R8 is a hydrogen atom or a C1-4 alkyl group, R10 and Rn represent, independently, a hydrogen atom, a halo atom, a Ci 4 alkoxy group or a tπfluoromethyl group, Xi and X2 mean, independently, a hydrogen atom, or Xi forms with X2 a valence bond, furthermore pharmaceutically suitable acid addition salts thereof and a quaternary derivative of the formula
wherein
Ri, R2, 3, R4, R5, Rε, R7, e, R9, R10, R11, Xi and X2 are as defined above,
R'a stands for a Cι- alkyl group, and
A represents a residue of an inorganic or organic acid of the
formula HA
Preferred 1 ,2,3,4-tetrahydroιsoquιnolιne derivatives of the formula la are those, wherein
Ri and R2 represent, independently, a methoxy group, or Ri forms with R2 a methylenedioxy group or an ethylenedioxy group, R3 stands for a hydrogen atom, R4 means a hydrogen atom, R7 is a hydrogen atom,
R8 represents a hydrogen atom or a methyl group, R10 stands for a halo atom, a tnfluoromethyl group or a methoxy group, Rn means a hydrogen atom or a methoxy group, Xi and X2 mean, independently, a hydrogen atom or Xi forms with X2 a valence bond, furthermore pharmaceutically suitable acid addition salts thereof and quaternary derivatives of the formula I'a, wherein R-i, R2, R3, R4, R5, e, R7, R8, R9, R10, R11, Xi and X2 are as defined above,
R's stands for a methyl group, and A represents a hahde ion
A further subgroup of the compounds of the invention consists of the isoquinohne derivatives of the formula
wherein
Ri, R2 and R3 represent, independently, a hydrogen atom, a halo atom, a hydroxy group or a Cι-4 alkoxy group, or Ri forms with R2 a methylenedioxy group or an ethylenedioxy group, R4 stands for a hydrogen atom, a C1- alkoxy group or a tnfluoromethyl group, R7 means a hydrogen atom or a Cι- alkyl group, R10 and Rn represent, independently, a hydrogen atom, a halo atom, a nitro group, a Cι- alkoxy group, a tnfluoromethyl group or a cyano group, Xi and X2 mean, independently, a hydrogen atom, or Xi forms with X2 a valence bond, furthermore pharmaceutically suitable acid addition salts thereof and a quaternary derivative of the formula
wherein
R-i, R2, R3, R4, R7, R10, Rn, Xi and X2 are as defined above,
R'8 stands for a Cι- alkyl group, and
A represents a residue of an inorganic or organic acid of the formula HA
Preferred isoquinohne derivatives of the formula lb are those, wherein
Ri, R2 and R3 represent, independently, a hydrogen atom or a methoxy group, or Ri forms with R2 a methylenedioxy group or an ethylenedioxy group, R4 stands for a hydrogen atom, a Cι_4 alkoxy group or a tnfluoromethyl group, R7 means a hydrogen atom or a methyl group, R10 represent a hydrogen atom, a halo atom, a nitro group, a methoxy group, a tnfluoromethyl group or a cyano group, Rn is a hydrogen atom or a methoxy group, Xi and X2 mean, independently, a hydrogen atom, or
Xi forms with X2 a valence bond, furthermore pharmaceutically suitable acid addition salts thereof and a quaternary derivative of the formula I'b, wherein
Ri, 2, R3, R , R7, R10, R11, Xi and X2 are as defined above,
R'a stands for a methyl group, and
A represents a ha de ion
Another subgroup of the compounds of the invention consists of the 3,4-dιhydroιsoquιnohne derivatives of the formula
wherein
Ri and R2 represent, independently, a hydrogen atom, a halo atom, a hydroxy group or a C1-4 alkoxy group, or Ri forms with R2 a methylenedioxy group or an ethylenedioxy group, R4 stands for a hydrogen atom, a Cι- alkoxy group or a Cι-6 alkyl group R5 means a hydrogen atom or a tπfluoromethyl group, R10 and Rn represent, independently, a hydrogen atom, a halo atom, a nitro group, a Cι- alkoxy group or a tπfluoro-
methyl group, Xi and X2 mean, independently, a hydrogen atom, or Xi forms with X2 a valence bond, furthermore pharmaceutically suitable acid addition salts thereof
Preferred 3,4-dιhydroιsoquιnohne derivatives of the formula XIV are those, wherein
Ri and R2 represent, independently, a hydrogen atom, a chloro atom, a hydroxy group or a methoxy group, or Ri forms with R2 a methylenedioxy group or an ethylenedioxy group, R4 stands for a hydrogen atom or a Cι-6 alkyl group, R5 means a hydrogen atom, R10 and R represent, independently, a hydrogen ator , a fluoro atom, a methoxy group or a tnfluoromethyl group, Xi and X2 mean, independently, a hydrogen atom, or XT forms with X2 a valence bond, furthermore pharmaceutically suitable acid addition salts thereof
Especially preferred 3,4-dιhydroιsoquιnohπe derivatives of the formula XIV are those, wherein Ri forms with R2 a methylenedioxy group, R4 stands for a Cι.6 alkyl group, R5 means a hydrogen atom or a tnfluoromethyl group, R10 and Rn represent, independently, a hydrogen atom, a methoxy group or a tnfluoromethyl group,
Xi forms with X2 a valence bond, furthermore pharmaceutically suitable acid addition salts thereof
A still further subgroup of the compounds of the invention consists of the 3,4-dιhydroιsoquιπolιnιum derivatives of the formula
wherein
Ri and R2 represent, independently, a hydrogen atom, a halo atom, a hydroxy group or a Cι-4 alkoxy group, or Ri forms with R2 a methylenedioxy group or an ethylenedioxy group, R4 stands for a hydrogen atom or a d-6 alkyl group R's means a Cι- alkyl group, R-io and Rn represent, independently, a hydrogen atom, a halo atom, a Ci alkoxy group or a tnfluoromethyl group, Xi and X2 mean, independently, a hydrogen atom, or XT forms with X2 a valence bond, A represents a residue of an inorganic or organic acid of the
formula HA
Preferred 3,4-dιhydroιsoquιnohnιum derivatives of the formula
XI are those, wherein
Ri and R2 represent, independently, a hydroxy group, a chloro atom or a methoxy group, or Ri forms with R2 a methylenedioxy group or an ethylenedioxy group, R4 stands for a hydrogen atom or a Cι-3 alkyl group, R's means a methyl group, R10 and Rn represent, independently, a hydrogen atom, a halo atom or a tnfluoromethyl group, Xi and X2 mean, independently, a hydrogen atom, or Xi forms with X2 a valence bond, A represents a residue of an inorganic acid of the formula HA
Especially preferred 3,4-dιhydroιsoquιnolιnιum derivatives of the formula XI are those, wherein
Ri forms with R2 a methylenedioxy group or an ethylenedioxy group, R4 stands for a hydrogen atom or a Cι.3 alkyl group, R's means a methyl group, R10 and Rn represent, independently, a hydrogen atom, a fluoro atom or a tnfluoromethyl group, Xi and X2 mean, independently, a hydrogen atom, or Xi forms with X2 a valence bond, A represents a bromide ion or a iodide ion
The compounds of the invention are prepared as follows:
a) for the preparation of an isoquinohne derivative of the formula lb, wherein R1 t R2, R3, R4, R7, Rι0 and Rn are as defined in connection with formula I, Xi forms with X2 a valence bond, condensing a 1 -methylisoquinoline of the formula
wherein Ri, R2, R3, R4 and R7 are as stated above, with an aldehyde of the formula
wherein Rι0 and Rn are as defined in connection with formula I; or
b) for the preparation of an isoquinohne derivative of the formula lb, wherein R1 ( R2, R3, R , R7, Rio, Rn, Xi and X2 are as defined in connection with formula I, subjecting a 3,4- dihydroisoquinoline derivative of the formula
wherein Ri, R2, R3, R , R7, R10, Rn, Xi and X2 are as stated above, Rι3 stands for a hydrogen atom, to catalytical dehydrogenation; or
c) for the preparation of a 1 ,2,3,4-tetrahydroisoquinoline derivative of the formula la, wherein Ri, R2, R3, R4, R7, ,Rιo, Rn, Xi and X2 are as defined in connection with formula I, R8 represents a hydrogen atom, hydrogenizing a 3,4- dihydroisoquinoline derivative of the formula IV, wherein Ri, R2, R3, R4, R7, R10, R11, Xi and X2 are as stated above, R13 stands for a hydrogen atom; or
d) for the preparation of a 1 ,2,3,4-tetrahydroisoquinoline derivative of the formula la, wherein Ri, R2, R3, R4, R7, R10, Rn, . X-, and X2 are as defined in connection with formula I, R8 represents a Cι_4 alkyl group, reacting a 3,4-dihydro- isoquinolinium derivative of the formula
wherein Ri, R2, R3, R4, R7, R10 Rn, Xi and X2 are as stated above, Rι2 stands for a C1 4 alkyl group, A is as defined in connection with formula I', with a reducing agent, or
e) for the preparation of an isoquinohne derivative of the formula lb, wherein Ri, R2, R3, R7, R10 Rn, Xi and X2 a e as defined in connection with formula I, R4 stands for a tnfluoromethyl group, reacting a 3,4-dιhydroιsoquιnohne derivative of the formula IV, wherein R1 ( R2, R3, R4, R7, R10 Rn, Xi and X2 are as stated above, R13 represents a Cι-4 alkoxy group, with an alkali metal hydroxide, or
f) for the preparation of an isoquinohne derivative of the formula lb, wherein Ri, R2, R3, R7, Rio and Rn are as defined in connection with formula I, R4 stands for a tnfluoromethyl group, Xi forms with X2 a valence bond, reacting a 1 -methyl-3,4- dihydroisoquinohne of the formula
wherein R1 ( R2, R3, R and R7 are as stated above, Rι3 stands for a Cι-4 alkyl group, with an aldehyde of the formula III, wherein R10 and Rn are as stated above, in the presence of a condensing agent, or
g) for the preparation of a 3,4-dιhydroιsoquιπolιne derivative of the formula XIV, wherein Ri, R2, R4, R5, R10, Rn, Xi and X2 are as defined in connection with formula I, cychzing an acid amide of the formula
wherein Ri, R2, R4, R10, Rn, Xi and X2 are as stated above, R3 stands for a hydrogen atom, and R 3 represents a hydrogen atom or a tnfluoromethyl group, or
h) for the preparation of a 3,4-dιhydroιsoquιnohnιum derivative of the formula XI, wherein Ri, R2, R4, R'8, R10, Rn, Xi and X2 are as defined in connection with formula I, A represents a residue
of an inorganic acid of the formula HA, reacting a 3,4- dihydroisoquinohne derivative of the formula
wherein Ri, R2, R4, Rio, Rn, Xi and X2 are as defined above, with a reagent of the formula R'8-A, wherein R'8 and A are as stated above, or
/ i) for the preparation of a 3,4-dιhydroιsoquιnohnιum derivative of the formula XI, wherein Ri, R2, R4, R's, Rio, Rn, Xi and X2 are as defined in connection with formula I, A represents a residue of an inorganic acid of the formula HA, reacting a 1 ,2,3,4- tetrahydroisoquinohnium derivative of the formula
wherein Ri, R2, R4, R'8, R10, Rn, Xi and X2 are as stated above, with an oxidizing agent,
and, if desired,
converting an obtained compound of the formula I, wherein Ri, R2, R3, R4, R5, Re, R7, Ra, R9, R10 and R , are as defined in connection with formula I, Xi forms with X2 a valence bond, to a corresponding compound of the formula I, wherein Xi and X2 represent a hydrogen atom, by catalytical hydrogenation, or
converting an obtained 1 ,2,3,4-tetrahydroιsoquιnohne derivative of the formula la, wherein R1 ? R2, R3, R4, R7, R10, Rn, XT and X2 are as defined in connection with formula I, R8 stands for a hydrogen atom, to a compound of the formula la, wherein R8 represents a C1- alkyl group, by reaction with a Cι- alkyl hahde, or
converting an obtained compound of the formula I to a pharmaceutically suitable acid addition salt or liberating the base from the salt, or
converting an obtained compound of the formula I to a quaternary derivative of the formula I', wherein R1 ( R2, R3, R4, R5, Re, R7, Re, R9, R10, R11, Xi and X2 are as defined in connection with formula I, R'8 represents a Cι-4 alkyl group, A stands for a residue of an inorganic or organic acid of the formula HA, by reaction with a compound of the formula R'8-A,
wherein R'8 and A are as stated above, or
converting an obtained quaternary isoquinohne derivative of the formula I'b, wherein R-,, R2, R3, R4, R7, Rι0, Rn, Xi and X2 are as defined in connection with formula I, R'8 stands for a Cι- alkyl group, A represents a residue of an inorganic or organic acid of the formula HA, to a compound of the formula la, wherein Ri, R2, R3, R4, R7, Rι0, Rn, Xi and X2 are as stated above, R8 stands for a Cι. alkyl group, by reaction with a reducing agent
In process a) of the invention, 1 -methyhsoquιnohne of the formula II is condensed with the aldehyde of the formula I II using the process known from French Patent Application published under No 2 719 586
In process b) of the invention, the 3,4-dιhydroιsoquιnohne derivative of the formula IV is dehydrogenized in an analogous manner known from the literature [Heterocyclic Compounds, 38, 386-387, Ed John Wiley and Sons, Inc , New York, (1994)]
In process c) of the invention, the 3,4-dιhydroιsoquιnolιne derivative is hydrogenized using known literature processes [Houben-Weyl Meth Org Chem , 4/1 c, 121 , 271 -281 , 365, 401 , Georg Thieme Verlag, Stuttgart, (1981 )]
In process d) of the invention, the reduction of the 3,4- dihydroisoquinohnium derivative of the formula V is carried out
using methods described in the literature cited in connection with process c)
In process e) of the invention, the alkoxy group in position 4 is eliminated with an alkali metal hydroxide, preferably potassium hydroxide
Process f) of the invention can be performed in a similar way as process a) As condensing agent preferably a carboxylic anhydride, suitably acetic anhydride is used
In process g) of the invention, the acid amide of the formula VIII is cyc zed in a manner known from the literature [Heterocyclic compounds, Ed J Wiley and Sons, Inc , 38/3. 85-89 (1994), 38/1 , 173-175 (1994)]
In process h) of the invention, preferably a Cι-4 alkyl hahde, suitably methyl iodide or methyl bromide is used as the reagent of the formula R'8-A, and the reaction is carried out in the presence of an indifferent organic solvent at 10 to 160 °C, in general The organic solvent can be apolar such as benzene, toluene, xylene, dichloromethane, etc , or polar protic such as methanol, ethanol etc
Process i) of the invention is performed in an analogous manner as the processes known from the literature [Houben- Weyl, Meth Org Chem , Georg Thieme Verlag, Stuttgart, 4/1 c. 517-518 (1981)]
An obtained isoquinohne derivative can be converted to another compound of the formula I in a manner known perse
For example, a styryl derivative, wherein X forms with X2 a valence bond, can be transformed into a compound of the formula I, wherein Xi and X2 stand for a hydrogen atom by catalytical hydrogenation [Houben-Weyl Meth Org Chem , 4/1 d, 580-581 , Georg Thieme Verlag, Stuttgart, (1981 )]
The nitrogen atom of a 1 ,2,3,4-tetrahydroιsoquιnohne derivative of the formula la, wherein R8 represents a hydrogen atom, can be alkylated in a manner known per se, for example using an alkyl hahde
The compound of the formula I can be reacted with a compound of the formula R'8-A, preferably a C1-4 alkyl ha de to obtain a quaternary compound of the formula I' The reaction is carried out in an apolar solvent such as benzene, toluene, xylene, dichloromethane, dichloroethane, etc , or a polar protic solvent such as an alkanol at a temperature from 10 to 160 °C
A quaternary isoquinohne derivative of the formula I'b can be reduced to obtain the corresponding 1 ,2,3,4-tetrahydroιso- quinohne of the formula la The reduction is performed using the methods described in the literature cited in connection with process c)
The 1 -methyhsoquιnohne derivatives of the formula II are partly known compounds The compounds of the formula II, wherein R4 stands for a tnfluoromethyl group, can be prepared by the reaction of a 1 -methyl-1 ,2-dιhydroιsoquιnohne and potassium hydroxide
The 1 -methyl-1 ,2-dιhydroιsoquιnohne of the formula VI is prepared by cychzing an acid amide of the formula
wherein Ri, R2 and R3 are as defined in connection with formula I, R4 stands for a tnfluoromethyl group, Rι3 represents a C1-4 alkoxy group The cychzation reaction is carried out in a manner known from the literature [Heterocyclic Compounds, Ed J Wiley and Sons, Inc , 38/3, 65-89 (1994), 38/1 , 173-175 (1994)]
The aldehydes of the formula III are known compounds that are commercially available
The 1 ,2-dιhydroιsoquιnohne derivatives of the formula IV are novel compounds that are prepared by cychzing an acid amide of the formula VIII, wherein Ri, R2, R3, R4, R10, Rn, Xi and X2 are as defined in connection with formula I, R 3 represents a
Ci-4 alkoxy group The cychzation reaction is performed an an analogous manner as the cychzation of the acid amide of the formula VII
The acid amide of the formula VIII can be prepared by reacting an acid derivative of the formula
wherein R10, Rn, Xi and X2 are as defined in connection with formula I, with a phenylethylamine of the formula
wherein Ri, R2, R3 and R4 are as defined in connection with formula I, R13 stands for a C1-4 alkoxy group, in an analogous manner as described in the literature [Houben-Weyl Meth Org Chem , E5/2, 993-1 100, Georg Thieme Verlag, Stuttgart, (1981 )]
The acid derivatives of the formula IX and the phenylethylamines of the formula X are commercially available
The tnfluoromethyl derivatives of the formula X can be prepared from the corresponding cyanohydπne of the formula
wherein Ri, R2, R and R5 are as defined above, by reduction The cyanohydnne of the formula XV can be obtained by reacting the corresponding acetophenone of the formula
/ wherein Ri and R2 are as defined above, with an alkali metal cyanide
The 1 ,2-dιhydroιsoquιnolιnιum derivative of the formula V can be prepared from the corresponding 1 ,2-dιhydroιsoquιnolιne by reaction with an alkylating agent of the formula R12-A, wherein Rι2 represents a C, 4 alkyl group, A is a residue of an inorganic or organic acid of the formula HA
The 3,4-dιhydroιsoquιnolιne derivative of the formula XII is prepared by cychzing an acid amide of the formula VIII The cychzation reaction is carried out in a manner described under the cychzation of the acid amide of the formula VII
The pharmacological effect of the compounds of the invention have been proved by the following experiments
1. Light-dark transitions
18-38 g male NMRI mice were used for the experiments The animals were kept in reverse light-dark cycle for two weeks before the experiment in polycarbonate cages Behavioral testing was conducted in two-compartment (lit and dark) automated test chambers, horizontal and vertical activities were recorded as interruptions of infrared beams Test compounds were suspended in 0 4 % methylcellulose solution and were administered intrapentoneally 30 mm before testing Under the test conditions, the animals tend to explore the new environment, however, they are anxious of aversive stimuli (light) in the lit area Therefore, exploration of the new environment is limited Anxiolytic compounds reduce the time spent with exploration in the dark area and/or increase the exploration activity in the lit compartment The compound tested has been considered effective when the time spent with exploration has been statistically significantly changed compared to untreated controls in either one or both compartments
Minimal effective doses (i e the lowest dose producing statistically significant effects) were determined for each compounds investigated [Costall, B et al , Pharm Biochem Behav , 32, 777-785 (1989), Young, R and Johnson, D N ,
Pharm Biochem Behav , 40, 739-743 (1991 )]
1 -(4-Tπfluoromethylstyryl)-6,7-methylenedιoxyιsoquιnohne described in French Patent Application published under No 2 719 586 has been used as the reference compound The results obtained are summarized in Table I
Table I
Compound (Example No.) Minimum effective dose
(mg/kg ip.)
21 10
47 10
51 30 /
53 10
55 3
82 10
83 30
84 1
1 -(4-tπfluoromethylstyryl)- -6,7- above 30 methylenedioxyisoquinoline
Data in Table I clearly show that the examined compounds of the invention display significant effect in the "light-dark transition" test, while the known reference compound is
ineffective
2. Measurement of spontaneous motor activity
Every group consisted of 30 animals (15 males, 15 females) weighing 20 to 25 g The animals were treated with the test compound or the vehicle (control group) The compounds to be tested were suspended in 0 4 % methylcellulose solution and were administered per os in 20 ml/kg treatment volume to the animals 60 minutes before test session The method provides general information on the influence of the investigated compound on the natural locomotor activity of experimental animals, particularly on sedative effects For anxiolytic compounds, the presence or absence of sedative potential is crucial for further development (the latter is desirable) Measurement was conducted in a 10 channel "Digital moti ty meter" Locomotor activity of three mice per channel was determined by recording the number of interruptions of three infrared beams for 30 minutes ID50 (50 % inhibition dose) values were calculated for each investigated compounds [Borsy, I et al , Arch Int Pharmacodyn , 124, 180-190 (1960), Stille, G et al , II Farmaco Ed Pr , 26, 603-625 (1971 )]
The results obtained are summarized in Table II Diazepam [i e 7-chloro-1 ,3-dιhydro-1 -methyl-5-phenyl-2H-1 ,4-benzo- dιazepιne-2-one] was used as reference compound
Table II
Compound (Example No.) IDso (mg/kg p.o.)
10 higher than 100
21 higher than 100
45 higher than 100
47 higher than 100
53 higher than 100
55 higher than 100
82 higher than 100
83 higher than 100
84 higher than 100 diazepam 18 4
Data in Table II clearly show that the compounds of the invention did not influence the spontaneous motor activity of the animals even in a dose more than five times higher than that of the ID50 value of diazepam
3. Measurement of enzyme induction
Wistar rats weighing 140 to 160 g were used for the experiments The compounds to be tested were suspended in 0 4 % methylcellulose solution and administered in 100 mg/kg daily per os dose for 3 consecutive days β-Naphthoflavone
treatment was used as positive control in 25 mg/kg per os dose. The typical reaction for CYP1 A isoenzyme has been monitored by the measurement of ethoxyresoruphine deethylase (EROD) activity according to the method of Pohl, R.J. and Fouts, J.R., Anal. Biochem., 107, 150-155 (1980). Control values from untreated animals have been considered as 100 %, and EROD activities have been expressed as percent of untreated control. The results obtained are summarized in Table III 1 -(4-Trifluoromethylstyryl)-6,7- methylenedioxyisoquinohne has been used as the reference compound.
Table III
Compound (Example No.) Relative EROD activity (percentage of control)
10 99
21 87
45 103
47 102
51 133
53 74
55 1 1 1
82 1 14
83 97
84 75
1 -(4-tπfluoromethylstyryl)-6,7- 570 methylenedioxyisoquinohne β-naphthoflavone 550
Data in Table III clearly show that treatment with the reference isoquinohne derivative resulted in more than five times elevation in enzyme activity (similarly to the β-naphthoflavone used as positive control) while results obtained with the compounds of the invention are about the values of untreated control
According to the above summarized experimental results, the
compounds of the invention display marked CNS, especially anxiolytic effects The anxiolytic activity is significant in the "light-dark transition" test, while the known 1 -styryhsoquinohne derivatives were found to be practically ineffective in this test Moreover, the novel compounds did not influence spontaneous motor activity in a dose more than five times higher than that of the ID50 value of the reference compound diazepam
Unlike the known anxiolytic 1 -styrylιsoquιnohne derivatives, the compounds of the invention did not influence the key enzymes of hepatic drug metabolism The low and insignificant enzyme induction potency of the novel compounds is of great importance from drug safety approaches
Thus, the novel isoquinohne derivatives of the formula I can be
/ used as active ingredients in pharmaceutical compositions
The pharmaceutical compositions of the invention contain a therapeutically active amount of the compound of the formula I or a pharmaceutically suitable acid addition salt thereof or a quaternary derivative of the formula I' and one or more conventional carπer(s)
The pharmaceutical compositions of the invention are suitable for peroral, parenteral or rectal administration or for local treatment, and can be solid or liquid
The solid pharmaceutical compositions suitable for peroral
administration may be powders, capsules, tablets, film-coated tablets, microcapsules etc , and can comprise binding agents such as gelatine, sorbitol, poly(vιnylpyrrolιdone) etc , filling agents such as lactose, glucose, starch, calcium phosphate etc , auxiliary substances for tabletting such as magnesium stearate, talc, poly(ethylene glycol), silica etc , wetting agents such as sodium laurylsulfate etc as the carrier
The liquid pharmaceutical compositions suitable for peroral administration may be solutions, suspensions or emulsions and can comprise e g suspending agents such as gelatine, carboxymethylcellulose etc , emulsifiers such as sorbitane monooleate etc , solvents such as water, oils, glycerol, propylene glycol, ethanol etc , preservatives such as methyl p- hydroxybenzoate etc as the carrier
Pharmaceutical compositions suitable for parenteral administration consist of sterile solutions of the active ingredient, in general
Dosage forms listed above as well as other dosage forms are known per se, see e g Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co , Easton, USA (1990)
The pharmaceutical compositions of the invention contain, in general, 0 1 to 95 0 per cent by mass of a compound of the formula I or a pharmaceutically suitable acid addition salt thereof or a quaternary derivative of the formula I' A typical
dose for adult patients amounts to 0 1 to 1000 mg of the compound of the formula I, daily The above dose can be administered in one or more portions The actual dosage depends on many factors and is determined by the doctor
The pharmaceutical compositions of the invention are prepared by admixing a compound of the formula I or a pharmaceutically suitable acid addition salt thereof or a quaternary derivative of the formula I' to one or more carrιer(s), and converting the mixture obtained to a pharmaceutical composition in a manner known per se Useful methods are known from the literature, e g Remington's Pharmaceutical Sciences mentioned above
One subgroup of the pharmaceutical compositions of the invention contains a 1 ,2,3,4-tetrahydroιsoquιnohne of the formula la or a pharmaceutically suitable acid addition salt thereof or a quaternary derivative of the formula I'a
A further subgroup of the pharmaceutical compositions of the invention contains an isoquinohne derivative of the formula lb or a pharmaceutically suitable acid addition salt thereof or a quaternary derivative of the formula I'b
Another subgroup of the pharmaceutical compositions of the invention contains a 3,4-dιhydroιsoquιnolιne derivative of the formula XIV or a pharmaceutically suitable acid addition salt thereof
A still further subgroup of the pharmaceutical compositions of the invention contains a 3,4-dιhydroιsoquιnohnιum derivative of the formula XI
The invention includes also a method of treatment in which a patient suffering from especially a disease of the central nervous system is treated with a non-toxic dose of a 3,4- dihydroisoquino ne derivative of the formula I or a pharmaceutically suitable acid addition salt thereof or a quaternary derivative of the formula I'
In addition, the invention includes the use of an isoquinohne derivative of the formula I or a pharmaceutically suitable acid addition salt thereof or a quaternary derivative of the formula I' for the preparation of a pharmaceutical composition having anxiolytic effect
The invention is further elucidated by means of the following Examples
Preparation of the acid amides of the formula VII
1 ) N-Acetyl-3 3,3-trιfluoro-2-methoxy-2-(3-methoxyphenyl)- propylamine
To a solution of 12 46 g (50 mmoles) of 3,3,3-trιfluoro-2- methoxy-2-(3-methoxyphenyl)propylamιne in 90 cm3 of ethyl acetate, 4 91 cm3 (5 31 g, 52 mmoles) of acetic anhydride are
added, drop by drop, at 0 °C. The reaction mixture is stirred at room temperature for 2 hours, then poured onto 90 cm3 of water. The two phases are separated. The aqueous phase is extracted twice using 60 cm3 of ethyl acetate each time. The combined organic phases are dried over anhydrous magnesium sulfate, and the solvent is evaporated. Thus, 14.50 g (98 %) of the colourless title compound are obtained.
M.p.: 74-75 °C (2-propanol-water).
Analysis: for Cι3Hι6F3N03 (291.27) calculated: C 53.61 %, H 5.54 %, N 4.81 %; found: C 53.48 %, H 5.50 %, N 4.75 %.
IR (Kbr, cm"1): 3330, 1613, 1119.
1H-NMR (CDCI3 250 MHz) δ: 7.34 (1 H, t, J=8.3 Hz), 7.03 (2H, m), 6.93 (1 H, s), 5.79 (1 H, s), 4.13 (1 H, dd, H=14.8 Hz, J=5.4
Hz), 3.90 (1 H, ddd, J=I4.8 Hz, J=5.4 Hz, J=1.4 Hz), 3.83 (3H, s), 3,35 (3H, q, J=0.9 Hz), 1.99 (3H, s).
13C-NMR (CDCI3 62.9 MHz) δ: 170.1 , 159.9, 135.0, 129.8,
124.9 (q, 1JcF=288.8 Hz), 119.6, 114.5, 113.9, 80.7 (q,
2JCF=26.3 Hz), 55.4, 52.7, 41.0, 23.2.
2) N-Acetyl-3,3,3-trifluoro-2-methoxy-2-(3,4-methylenedioxy- phenyOpropylamine
The procedure described in the preparation of the starting compound 1) is followed to obtain the title compound. Yield: 98 %. M.p.: 119-120 °C (2-propanol-water). Analysis: for C13Hι4F3N04 (305.25)
calculated C 51 15 %, H 4 62 %, N 4 59 %, found C 51 38 %, H 4 67 %, N 4 69 %
IR (KBR cm"1) 3340, 1679, 1171 , 1111
1H-NMR (CDCI3 200 MHz) δ 6 97 (1 H, s), 6 93 (1 H, d, J=8 2
Hz), 6 83 (1 H, d, J=8 2 Hz), 6 00 (1 H, d, J=1 4 Hz), 5 99 (1 H, d,
J=1 4 Hz), 5 86 (1 H, bs), 4 09 (1 H, dd, J=14 8 Hz, J=5 3 Hz),
3 89 (1 H, ddq, J=14 8 Hz, J=5 3 Hz, J=1 2 Hz), 3 33 (3H, s),
1 99 (3H, s)
13C-NMR (CDCI3, 100 6 MHz) δ 170 0, 148 2, 126 8, 124 7 (q,
1 JCF=288 0 Hz), 121 1 , 108 2, 107 8, 101 4, 80 3 (q, 2JCF=26 6 Hz), 52 2, 40 7, 23 1
Preparation of 1-methyl-3,4-dihydroisoquinolines of the formula VI
3) 1 -Methyl-4,6-dιmethoxy-4-tπfluoromethyl-3,4-dιhydro- isoquinohne
2 91 g (10 mmoles) of N-acetyl-3,3,3-trιfluoro-2-methoxy-2-(3- methoxyphenyl)propylamιne are stirred in 4 46 cm3 (7 67 g, 50 mmoles) of phosphor(V) trichloride oxide at 85 °C for 16 hours The reaction mixture cooled to room temperature is poured onto 40 cm3 of ice water The pH is adjusted to 11 with concentrated aqueous ammonia, and the solution is extracted three times using 30 cm3 of ethyl acetate each time The combined organic phases are dried over anhydrous magnesium sulfate, and evaporated The crude base is
recrystalhzed from acetonitnle Thus, 2 22 g (81 %) of the colourless title compound are obtained
M p 203-204 °C (acetonitnle)
Analysis for Cι3Hι4F3N02 (273 25) calculated C 57 14 %, H 5 16 %, N 5 13 %, found C 57 27 %, H 5 26 %, N 5 11 %
IR(Kbr, cm1) 1609, 1247, 1178
1H-NMR (CDCI3 250 MHz) δ 7 56 (1 H, d, J=8 7 Hz), 7 19 (1 H, dd, J=2 6 Hz, J=0 8 Hz), 7 00 (1 H, dd, J=8 7 Hz, J=2 6 Hz),
4 12 (1 H, dq, J=17 5 Hz, J=1 5 Hz), 4 02 (1 H, dq, J=17 5 Hz,
J=1 5 Hz), 3 88 (3H, s), 3 27 (3H, s), 2 39 (3H, t, J=1 7 Hz)
13C-NMR (CDCI3 62 9 MHz) δ 162 7, 161 5, 131 2, 127 8,
125 1 (q, 1JCF=287 2 Hz), 123 2, 114 7, 112 4, 74 9 (q, JCF=27 9 Hz), 55 3, 52 1 , 48 9, 23 0
4) 1 -Methyl-6,7-methylenedιoxy-4-methoxy-4-trιfluoromethyl- 3,4-dιhydroιsoquιnohne
The procedure described in the preparation of starting compound 3) is followed to obtain the title compound recrystalhzed from acetonitnle Yield 75 % M p 203-204 °C (acetonitnle) Analysis for C13Hι2F3N03 (287 23) calculated C 54 36 %, H 4 21 %, N 4 88 %, found C 54 19 %, H 4 27 %, N 4 79 %
IR (KBr, cm 1) 1606, 1286, 1173 1H-NMR (CDCI3 400 MHz) δ 7 13 (1 H, q, J=0 9 Hz), 7 07 (1 H,
s), 6 06 (1 H, d, J=0 9 Hz), 6 06 (1 H, d, J=1 3 Hz), 4 01 (1 H, ddd, J=16 8 Hz, J=3 0 Hz, J=1 5 Hz), 4 00 (1 H, dd, J=16 8 Hz, J=1 5 Hz), 3 24 (3H, s), 2 37 (3H, t, J=1 7 Hz) 13C-NMR (CDCI3 100 6 MHz) δ 162 4, 149 8, 148 9, 125 2 (q, 1 JCF=287 3 Hz), 125 1 , 107 3 (q, 3JCF=1 9 Hz), 106 4, 102 0, 75 2 (q, 2JCF= 27 6 Hz), 52 1 , 49 1 , 23 6
Preparation of 1-methylisoquinolines of the formula II:
5) 1 -Methyl-6-methoxy-4-trιfluoromethyhsoquιnohne
To a solution of 2 73 g (10 mmoles) of 1 -methyl-4,6-dιmethoxy- 4-trιfluoromethyl-3,4-dιhydroιsoquιnohne in 20 cm3 of 2- propanol, 0 84 g (15 mmoles) of powdered potassium hydroxide are added The reaction mixture is stirred at 50 °C for 2- hours, then evaporated The residue is rubbed with 10 cm3 of water, and filtered The crystals are washed with 5 cm3 of water The crude product is recrystalhzed from petroleum ether (b.p 80- 100 °C) Thus, 2 05 g (85 %) of the colourless title compound are obtained M p 95-96 °C (petroleum ether) Analysis for Cι2Hι0F3NO (241 21 ) calculated C 59 75 %, H 4 18 %, N 5 81 %, found C 59 57 %, H 4 13 %, N 5 76 %
IR (Kbr crrϊ1) 1624, 1256, 1165, 1126
1H-NMR (CDCI3 250 MHz) δ 8 64 (1 H, d, 0 7 Hz), 8 10 (11-1, d, J=9 0 Hz), 7 35-7 20 (2H, m), 3 98 (3H, s), 2 96 (3H, s) 13C-NMR (CDCI3 62 9 MHz) δ 162 7, 161 5, 140 8 (q, 3JCF=6 7
Hz), 133 7, 128 0, 124 7 (q, 1JCF=272 4 Hz), 122 6, 120 2, 1 18 0 (q, 2JCF=28 9 Hz), 102 1 , 55 4, 22 8
6) 1 -Methyl-6,7-methylenedιoxy-4-trιfluoromethyhsoquιnohne
The procedure described in the preparation of the starting compound 5) is followed to obtain the title compound as colourless solids Yield 90 % M p 139-141 °C (petroleum ether, b p 80-100 °C)
Analysis for d2H8F3N02 (255 196) calculated C 56 48 %, H 3 16 %, N 5 49 %, found C 56 33 %, H 3 14 %, N 5 45 %
IR (Kbr, cm"1) 1477, 1 167, 1 1 12
1H-NMR (CDCI3 200 MHz) δ 8 58 (1 H, s), 7 44 (1 H, s), 7 40
(1 H, q, J=1 8 Hz), 6 17 (2H, s), 2 91 (3H, s)
13C-NMR (CDCI3 100 6 MHz) δ 161 1 , 151 8, 148 6, 139 3 (q,
3JCF=6 5 HZ), 130 1 , 124 7 (q, 1JCF=273 1 Hz), 124 6, 1 18 6 (q,
2JCF=30 5 HZ), 102 2, 100 6, 23 3
Preparation of acid amides of the formula VIII:
7) N-Cιnnamoyl-3,3,3-trιfluoro-2-methoxy-2-(3-methoxy- phenyl)propylamιne
To a suspension of 12 46 g (50 mmoles) of 3,3,3-trιfluoro-2- methoxy-2-(3-methoxyphenyl)propιonιtrιle, 30 cm3 of diethyl ether, 5 30 g (50 mmoles) of sodium carbonate and 50 cm3 of water, a solution of 8 33 g (50 mmoles) of cinnamoyl chloride in
50 ml of diethyl ether are added at 0 °C, drop by drop, and the reaction mixture is stirred for 2 hours The precipitated crystals are filtered, washed with 20 cm3 of diethyl ether Thus, 16 39 g
(90 %) of the title compound are obtained
M p 72-73 °C (2-propanol, water)
Analysis for C2oH20F3N03 (379 38) calculated C 63 32 %, H 5 31 %, N 3 69 %, found C 63 12 %, H 5 27 %, N 3 76 %
IR (Kbr, cm"1) 1662, 1630, 1179
1H-NMR (CDCI3 250 MHz) δ 7 63 (1 H, d, J=15 6 Hz), 7 55-7 45
(2H, ), 7 40-7 30 (4H, m), 7 10-7 05 (2H, m), 6 99-6 90 (1 H, m), 6 39 (1 H, d, J=15 6 Hz), 5 89 (1 H, bs), 4 27 (1 H, dd, J=15 0
Hz, J=5 4 Hz), 4 08 (1 H, dd, J=15 0 Hz, J=5 4 Hz), 3 83 (3H, s),
3 39 (3H, q, J=0 8 Hz)
13C-NMR (CDCI3 50 3 MHz) δ 165 7, 159 8, 141 7, 135. 0,
134 6, 129 8, 129 7, 128 8, 127 8, 124 9 (q, 1JCF=288 4 Hz),
120 1 , 1 19 5, 1 14 5, 1 13 6, 80 6 (q, 2JC =26 3 Hz), 55 3, 52 6,
40 9
8) N-(4-Fluorocιnnamoyl)-3,3,3-trιfluoro-2-methoxy-2-(3- methoxyphenyl)propylamιne
The procedure described in the preparation of the starting compound 7) is followed to obtain the title compound as colourless solids Yield 75 %
M p 100-101 °C (2-propanol, water)
Analysis for C20Hι9F4NO3 (397 37)
calculated C 60 45 %, H 4 82 %, N 3 52 %, found C 60 31 %, H 4 80 %, N 3 55 %
IR (Kbr, cm"1) 3293, 1661, 1628, 1227, 1149
1H-NMR (CDCI3 250 MHz) δ 7 59 (1 H, d, J=15 6 Hz), 7 51-7 44
(2H, m), 7 40-7 30 (1 H, m), 7 10-7 00 (4H, m), 7 00-6 91 (1 H, m), 6 31 (1 H, d, J=15 6 Hz), 5 88 (11-1, bs), 4 27 (11-1, dd, J=14 9
Hz, J=5 4 Hz), 4 06 (1 H, ddd, J=14 9 Hz, J=5 4 Hz, J=1 3 Hz),
3 83 (3H, s), 3 39 (3H, s)
13C-NMR (CDCI3 62 9 MHz) δ 163 5 (d, 1JCF=249 2 Hz), 159 7,
140 4, 134 8, 130 7, 119 6 (d, 2JCF=8 8 Hz), 129 3 (q,
1 JCF=289 1 Hz), 122 4, 119 6, 119 4, 117 8, 115 8 (d, 2JCF=22,6
Hz), 1 14 3, 1 13 5, 80 5 (q, 2JCF= 27 2 Hz), 55 2, 52 5, 40 9
9) N-(4-Trιfluoromethylcιnnamoyl)-3,3,3-trιfluoro-2-methoxy-2- (3-methoxyphenyl)propylamιne
The procedure described in the preparation of the starting compound 7) is followed to obtain the title compound as colourless solids Yield 72 %
M p 85-86 °C (2-propanol, water)
Analysis for C2ιHι9F6N03 (447 38) calculated C 56 38 %, H 4 28 %, N 3 13 %, found C 56 45 %, H 4 32 %, N 3 18 %
IR (Kbr, cm"1) 3436, 1672, 1324, 1133
1H-NMR (CDCI3 400 MHz) δ 7 64 (1 H, d, J=15 6 Hz), 7 64-7 60
(4H, m), 7 35 (1 H, t, J=8 2 Hz), 7 10-7 06 (2H, m), 6 97-6 92
(1 H, m), 6 46 (1 H, d, J=15 6 Hz), 5 92 (1 H, bs), 4 27 (1 H, dd,
J=14 9 Hz, J=5 4 Hz), 4 05 (1 H, ddq, J=14 9 Hz, J=5 4 Hz, J=1 1 Hz), 3 83 (3H, s), 3 40 (3H, s)
13C-NMR (CDCI3 100 6 MHz) δ 165 0, 159 9, 140 1 , 138 1 , 134 9, 131 4 (q, 2JCF=32 8 Hz), 129 8, 128 0, 126 5 (q, 1JCF=278 9 Hz), 125 8 (q, 3JCF=3 8 Hz), 124 8 (q, 1JCF=288 0 Hz), 122 5, 1 19 5, 1 14 5, 1 13 6, 80 7 (q, 2JCF=26 7 Hz), 55 4, 52 7, 41 2
10) N-(4-Nιtrocιnnamoyl)-3,3,3-trιfluoro-2-methoxy-2-(3- methoxyphenyl)propylamιne
The procedure described in the preparation of the starting compound 7) is followed to obtain the title compound as pale yellow solids Yield 64 %
M p 80-81 °C (2-propanol, water)
Analysis for C20Hι9F3N2O5 (424 38) calculated C 56 61 %, H 4 51 %, N 6 60 %, found C 56 36 %, N 4 52 %, N 6 60 %
IR (KBr, cm"1) 1659, 1515, 1345, 1 168, 1120
1H-NMR (CDCI3 200 MHz) δ 8 23 (2H, d, J=8 8 Hz), 7 67 (1 H, d, J=15 6 Hz), 7 65 (2H, d, J=8 8 Hz), 7 37 (1 H, t, J=8 2 Hz),
7 15-7 03 (2H, m), 7 00-6 90 (1 H, m), 6 55 (1 H, d, J=15 6 Hz),
6 02 (1 H, t, J=5 2 Hz), 4 30 (1 H, dd, J=15 0 Hz, J=5 5 Hz), 4 04
(1 H, ddq, J=15 0 Hz, J=5 5 Hz, J=1 6 HZ), 3 84 (3H, s), 3 40
(3H, s)
13C-NMR (CDCI3 50 3 MHz) δ 164 7, 159 9, 148 3, 140 9,
139 2, 134 8, 129 9, 128 5, 124 9 (q, 1JCF=288 8 Hz), 124 3,
124.2, 1 19.5, 1 14.5, 1 13.6, 80.7 (q, 2JCF=26.3 Hz), 55.3, 52.7, 41 .3.
1 1 ) The procedure described in the preparation of the starting compound 7) is followed to obtain the title compound as colourless solids. Yield: 85 %.
M.p.: 104-106 °C (2-propanol, water).
Analysis: for C2ιHi7F6N04 (461.36) calculated: C 54.67 %, H 3.71 %, N 3.04 %; found: C 54.46 %, H 3.70 %, N 3.05 %.
IR (Kbr, cm"1): 3310, 1665, 1630, 1326, 1 170, 1 125.
1H-NMR (CDCI3 200 MHz) δ: 7.66 (1 H, d, J=15.4 Hz), 7.61 (4H, m), 7.05-6.95 (2H, m), 6.85 (1 H, d, J=7.7 Hz), 6.48 (1 H, d,
J=15.4 Hz), 6.01 (2H, s), 5.96 (1 H, bs), 4.24 (1 H, dd, J=14.9
Hz, J=5.1 Hz), 4.04 (1 H, dd, J=14.9 Hz, J=5.1 Hz), 3.36 (3H, s).
13C-NMR (CDCI3 100.6 MHz) δ: 165.1 , 148.4, 148.2, 140.1 ,
138.0 (q, 4JCF=1 .5 Hz), 131 .3 (q, 2JCF=32.4 Hz), 128.0, 126.8,
125.7 (q, 3JCF=3.8 Hz), 124.8 (q, 1JCF=288.0 Hz), 123.8 (q,
1JCF=274.3 Hz), 122.5, 121 .2, 108.3, 107.9, 101 .48, 80.4 (q,
2JCF=26.7 Hz), 52.4, 41 .0.
12) N-/2-(3,4-Methylenedioxyphenyl)ethyl/-4-trifluoromethyl- cinnamamide
A solution of 4.6 g (0.023 moles) of (3,4-methylenedioxy- phenyl)ethylamine chlorohydrate in 50 cm3 of ether is added to a solution of 4.1 g (0.2 moles) of sodium hydroxide in 30 cm3 of
water, drop by drop, at 5 to 10 °C under stirring Then, a solution of 4 2 g (0 02 moles) of 4-trιfluoromethylcιnnamoyl chloride in 20 cm3 of ether is added to the mixture, drop by drop, in 35 minutes, and the reaction mixture is stirred for half an hour at 5 °C The precipitated carboxylic amide is filtered and dried Thus, 4 3 g (63 %) of the title product are obtained M p 206-208 °C
13) N-/2-(3,4-Methylenedιoxyphenyl)ethyl/-4-fluoro- cinnamamide
A mixture of 4 84 g (0 029 moles) of (3,4-methylenedιoxy- phenyl)ethylamιne 4 98 g (0 03 moles) of 4-fluorocιnnamιc acid and 10 cm3 of decahn is stirred at 180 °C for 1 hour To the cooled mixture, chloroform is added, and the mixture is stirred at 5 to 10 °C until the crystallization of the carboxylic amide The precipitated crystals are filtered, and recrystalhzed from ethanol Thus, 4 9 g (53 %) of the title product are obtained M p 160-162 °C
14) N-/3-(4-Trιfluoromethylphenyl)propanoyl/-3,3,3-trιfluoro- 2-methoxy-2-(3-methoxyphenyl)propylamιne
A suspension of 1 25 g (5 mmoles) of 3,3,3-tπfluoro-2-methoxy- 2-(3-methoxyphenyl)propylamιne and 1 09 g (5 mmoles) of 3- (4-trιfluoromethylphenyl)propιonιc acid is reacted at 150 °C for 4 hours The crude product is recrystalhzed from aqueous ethanol Thus, 1 55 g (69 %) of colourless title compound are
obtained M p 58-59 °C (ethanol-water)
Analysis for C2ιH2ιF6N03 (449 40) calculated C 56 13 %, H 4 71 %, N 3 12 %, found C 56 16 %, H 4 74 %, N 3 09 %
IR (KBr, cm'1) 3309, 1650, 1338, 1279
1H-NMR (CDCI3 200 MHz) δ 7 52 (2H, d, J=8 1 Hz), 7 35-7 25
(3H, m), 7 04-6 88 (3H, m), 5 62 (1 H, bs), 4 10 (1 H, dd, J=14 9
Hz, J=5 3 Hz), 3 85 (1 H, dd, J=4 4 Hz), 3 82 (3H, s), 3 24 (3H, s), 3 00 (2H, t, J=7 3 Hz), 2 50 (2H, t, J=7 3 Hz)
13C-NMR (CDCI3 100 6 MHz) δ 171 7, 159 8, 144 7, 134 7,
129 7, 128 7, 128 6 (q, 2JCF=32 3 Hz), 125 4 (q, 3JCF=3 7 Hz),
124 7 (q, 1 JCF= 288 6 Hz), 124 2 (q, 1 JCF=271 9 Hz), 119 4,
114 3, 113 5, 80 5 (q, 2JCF=26 4 Hz), 55 3, 52 5, 41 0, 37 6,
31 0
15) N-/3-(4-Fluorophenylpropanoyl)-3,3,3-trιfluoro-2-methoxy- 2-(3-methoxyphenyl)propylamιne
The procedure described in the preparation of the starting compound 14) is followed to obtain the title compound as colourless solids Yield 79 %
M p 59-61 °C (ethanol-water)
Analysis for C20H21F4NO3 (399 39) calculated C 60 15 %, H 5 30 %, N 3 51 %, found C 59 93 %, H 5 28 %, N 3 52 %
IR (KBr, cm"1) 3305, 1649, 151 1 , 1280
1H-NMR (CDCI3 200 MHz) δ 7 38-7 25 (1 H, m), 7 18-7 06 (2H,
m), 7 05-6 87 (5H, m), 5 60 (1 H, bs), 4 09 (1 H, dd, J=14 8 Hz, J=5 1 Hz), 3 86 (1 H, dd, J=14 8 Hz, J=4 0 Hz), 3 82 (3H, s), 3 26 (3H, s), 2 90 (2H, t, J=7 5 Hz), 2 46 (2H, t, J=7 5 Hz) 13C-NMR (CDCI3 100 6 MHz) δ 171 7, 161 5 (d, 1JCF=244 2 Hz), 159 8, 136 2 (d, 4JC =3 4 Hz), 134 8, 129 7 (d, 3JCF= 8 0 Hz), 129 7, 124 8 (q, 1 JCF=288 6 Hz), 1 19 4, 1 15 2 (d, 2JCF=21 0 Hz), 1 14 4, 1 13 5 (q, 4JCF=1 1 Hz), 80 5 (q, 2JCF=26 3 Hz), 55 3, 52 5, 40 8, 38 2, 30 5
16) N-/3-(4-Trιfluoromethylphenyl)propanoyl/-3,3,3-trιfluoro- 2-methoxy-2-(3,4-methylenedιoxyphenyl)propylamιne
The procedure described in the preparation of the starting compound 14) is followed to obtain the title compound as colourless solids Yield 84 %
M p 75-76 °C (ethanol-water)
Analysis for C2ιHι9F6N04 (463 38) calculated C 54 43 %, H 4 13 %, N 3 02 %, found C 54 52 %, H 4 19 %, N 3 05 %
IR (KBr, cm'1) 3317, 1620, 1334, 1247
1H-NMR (CDCI3 200 MHz) δ 7 53 (2H, d, J=7 7 Hz), 7 30 (2H, d, J=7 7 Hz), 7 00-6 80 (3H, m), 6 00 (2H, s), 4 06 (1 H, dd,
J=14 9 Hz, J=5 1 Hz), 3 84 (1 H, dd, J=14 9 Hz, J=5 1 Hz), 3 21
(3H, s), 3 01 (2H, t, J=7 5 Hz), 2 51 (2H, t, J=7 5 Hz)
13C-NMR (CDCI3 100 6 MHz) δ 171 4, 148 3, 148 1 , 144 7,
128 7 (q, 2JCF=32 4 Hz), 128 7, 126 8, 125 4 (q, 3JCF=3 7 Hz),
124 7 (q, 1 JCF=288 4 Hz), 124 2 (q, 1 JCF=271 7 Hz), 121 1 ,
108 2, 107 8, 101 5, 80 3 (q, 2JCF=26 4 Hz), 52 2, 40 7, 37 7, 31 1
17) N-/3-(4-Fluorophenyl)propanoyl/-3,3,3-trιfluoro-2-methoxy- 2-(3,4-methylenedιoxyphenyl)propylamιne
The procedure described in the preparation of the starting compound 14) is followed to obtain the title compound as colourless solids Yield 83 %
M p 92-94 °C (ethanol-water)
Analysis for C20Hι9F4NO4 (413 37) calculated C 58 1 1 %, H 4 63 %, N 3 39 %, found C 58 29 %, H 4 67 %, N 3 41 %,
IR (KBr, cm 1) 3325, 1658, 1510, 1217 H-NMR (CDCI3 200 MHz) δ 7 18-7 10 (2H, m), 7 02-6 75 (5H, m), 6 00 (2H, s), 5 61 (1 H, bs), 4 06 (1 H, dd, J=14 7 Hz, J=5 9
Hz), 3 85 (1 H, dd, J=14 7 Hz, J=4 2 Hz), 3 23 (3H, q, J=0 7 Hz),
2 92 (2H, t, J=7 5 Hz), 2 51 (2H, t, J=7 5 Hz)
13C-NMR (CDCI3 50 3 MHz) δ 171 7, 161 6 (d, 2JCF=244 1 Hz),
148 3, 148 1 , 136 2 (d, 4JCF=3 4 Hz), 129 7 (d, 4JCF=3 4 Hz),
129 7 (d, 3JCF=7 6 Hz), 126 8, 124 7 (q, 1JCF=288 4 Hz), 121 2,
1 15 2 (d, 2JCF=21 4 Hz), 108 2, 107 8, 101 5, 80 3 (q, 2JCF=26 5
Hz), 52 2, 40 6, 38 2, 30 5
18) N-/2-(3,4-Methylenedιoxyphenyl)ethyl/- 4-tπfluoromethyl- cinnamamide
A solution of 4 6 g (0 023 moles) of (3,4-methylenedιoxy- phenyl)ethylamιne chlorohydrate in 50 cm3 of ether is added to a solution of 4 1 g (0 2 moles) of sodium hydroxide in 30 cm3 of water, drop by drop, at 5 to 10 °C under stirring Then, a solution of 4 2 g (0 02 moles) of 4-trιfluoromethylcιnnamoyl chloride in 20 cm3 of ether is added to the mixture, drop by drop, in 35 minutes, and the reaction mixture is stirred for half an hour at 5 °C The precipitated carboxylic amide is filtered and dried Thus 4 3 g (63 %) of the title product are obtained M p 206-208 °C
19) N-/2-(3,4-Methylenedιoxyphenyl)ethyl/cιnnamamιde
To a solution of 8 5 g (0 037 moles) of (3,4-methylenedιoxy- phenyl)ethylamιne in 50 cm3 of dichloromethane, 5 g of sodium hydrogen carbonate are added, then a solution of 6 2 g (0 037 moles) of cinnamoyl chloride in 20 cm3 of dichloromethane is added in half an hour The reaction mixture is stirred at 40 °C for 2 hours, then filtered, and the dichloromethane is evaporated Thus, 10 6 g (96 %) of the title compound are obtained in the form of an oil
20) N-/2-(3,4-Ethylenedιoxyphenyl)ethyl/-3-(4-trιfluoromethyl- phenyl)propιonyl amide
14 3 g (0 08 moles) of (3,4-ethylenedιoxy-phenyl)ethylamιne and 18 4 g (0 08 moles) of 3-(4-trιfluoromethylphenyl)propιonιc acid are heated in 20 cm3 of decahn to 160-170 °C, and the
reaction mixture is stirred at this temperature for 4 hours The water formed is distilled off The mixture is cooled to 60 °C, and 50 cm3 of ethanol is added under intensive stirring The suspension cooled to 10 °C is filtered, washed with some cold ethanol Thus, 17 2 g (56 %) of the title compound are obtained as crude product M p 161 -163 °C
21 ) N-/2-(3,4-Methylenedιoxyphenyl)ethyl/-4-fluoro- cinnamamide
A mixture of 4 84 g (0 029 moles) of (3,4-methylenedιoxy- phenyl)ethylamιne, 4 98 g (0 03 moles) of 4-fluorocιnnamιc acid and 10 cm3 of decahn is stirred at 180 °C for 1 hour To the cooled mixture, chloroform is added, and the mixture is stirred at 5 to 10 °C until the crystallization of the carboxylic amide The precipitated crystals are filtered, and recrystalhzed from ethanol Thus, 4 9 g (53 %) of the title product are obtained M p 160-162 °C
22) N-/2-(4-Chlorophenylethyl)-3-(4-trιfluoromethylphenyl)- propionyl amide
7 8 g (0 05 moles) of (4-chlorophenyl)ethylamιne and 10 5 g (0 05 moles) of 4-tπfluoromethylcιnnamιc acid are heated in 25 cm3 of decahn to 180 °C and stirred at this temperature for 14 hours To the mixture cooled to room temperature, 50 cm3 of diethyl ether are added in portions The crystalline carboxylic amide obtained is filtered and washed with ether Thus, 14 g
(79 %) of the title compound are obtained as crude product M p 167-168 °C
23) N-/2-(3,4-Ethylenedιoxyphenyl)-2-propylethyl/-3-(4-trι- fluoromethylphenyl)propιonyl amide
11 0 g (0 05 moles) of 2-(3,4-ethylenedιoxyphenyl)-2- propylethylamine and 10 9 g (0 05 moles) of 3-(4-tπfluoro- methylphenyl)propιonιc acid are heated to 160 °C, and the melt obtained is stirred at this temperature for 4 hours The water that forms is distilled off The mixture is cooled to 0-5 °C, and the precipitated crystalline product is filtered The crude product is purified by column chromatography Thus, 10 g (47 %) of the title compound are obtained in the form of yellow resin
24) N-/2-(3,4-Methylenedιoxyphenyl)ethyl/-3-(4-trιfluoro- methylphenyl)propιonyl amide
A solution of 3 63 g of N-/2-(3,4-methylenedιoxyphenyl)ethyl/-4- tnfluoromethylcinnamamide in 100 cm3 of acetic acid is hydrogenized in the presence of 1 g of palladium/carbon catalyst at atmospheric pressure until the end of the hydrogen consumption The catalyst is filtered, and the solution is evaporated to dryness The crude product is recrystalhzed from acetone
25) N-/2-(3,4-Ethylenedιoxyphenyl)-2-propylethyl/-4-(tπfluoro- methyl)cιnnamamιde
12 3 g (55 mmoles) of 2-(3,4-ethylenedιoxyphenyl)-2-propyl- ethylamine and 12 0 g (55 mmoles) of 4-trιfluoromethylcιnnamιc acid are heated in 100 cm3 of deca n to 160-165 °C The mixture is stirred at the above temperature for 2 hours, then cooled to room temperature The solvent is removed by decantation, from the residue 50 cm3 of toluene are distilled off, and the brownish crude product is purified by column chromatography Thus, 12 1 g (52 %) of the title compound are obtained in the form of thick oil that solidifies
Preparation of the starting compounds of the formula XII:
26) 6,7-Ethylenedιoxy-1 -/2-(4-trιfluoromethylphenyl)ethyl/- 3,4-dιhydroιsoquιnohne
14 2 g (0 037 moles) of 2-(3,4-ethylenedιoxyphenyl)ethyl-N-/3- (4-trιfluoromethylphenyl)/propιonyl amide are dissolved in 80 cm3 of toluene To the solution obtained, 12 cm3 of phosphor(V) trichloride oxide are added, drop by drop, the reaction mixture is heated to 80 °C and stirred at this temperature for 2 5 hours The precipitated crystalline dihydroisoquinohπe is filtered and recrystalhzed from ethanol The product obtained (12 g) is dissolved in 90 cm3 of methanol, made alkaline to pH 9 by the addition of 20 % aqueous sodium hydroxide solution, the precipitated matter is filtered, washed
with aqueous methanol (5 1 ), and recrystalhzed from a mixture of ethanol and water Thus, 1 44 g (41 %) of the title compound are obtained
M p 85 °C
Analysis for C20Hι8NO2 (361 37) calculated C 66 48 %, H 5 02 %, N 3 88 %, found C 66 34 %, H 5 04 %, N 3 90 %
1H-NMR (CDCI3 400 MHz) δ 7 61 (2H, d, J=8 0 Hz), 7 47 (2H, d, J=8 0 Hz), 7 10 (1 H s), 6 74 (1 H, s), 4 24 (4H, m), 3 48 (2H, t, J=7 4 Hz), 2 96 (4H, m), 2 47 (2H, t, J=7 1 Hz)
27) 1 -(2-Phenylethyl)-6,7-methylenedιoxy-3,4-dιhydro- isoquinohne
A solution of 10 g (0 033 moles) of N-/2-(3,4-methylenedιoxy- phenyl)ethyl/-3-phenylpropιonyl amide and 30 cm3 of phosphor(V) trichloride oxide in 70 cm3 of absolute benzene is boiled for 1 5 hours, then cooled to 50 °C, and the precipitated crystals are filtered The crude hydrochloπde is dissolved in a mixture of 200 cm3 of water and 200 cm3 of methanol, the pH value of the solution is adjusted to 13 by the addition of 20 % aqueous sodium hydroxide solution The precipitated white crystalline base is filtered, washed with cold water, dried, and recrystalhzed from a mixture of ethanol and water Thus, 5 3 g (58 %) of the title compound are obtained M p 112-115 °C
Preparation of the starting compounds of the formula XVI:
28) α,α,α-Trιfluoro-3-methoxyacetophenone
To a solution of 35 52 g (0,25 mmoles) of ethyl tnfluoroacetate in 100 cm3 of tetrahydrofuran, a solution of 3-methoxyphenyl magnesium bromide /prepared from 46 76 g (0 25 moles) of 3- bromoanisole, 6 32 g (0 26 moles) of magnesium and 200 cm3 of tetrahydrofuran in the usual manner/ is added slowly at -70 °C, drop by drop The reaction mixture is stirred at -70 °C for an hour, than allowed to warm to 0 °C Then, 100 cm3 of 2N hydrochloric acid are added slowly to the reaction mixture, drop by drop The mixture is stirred for half an hour, the two phases are separated The tetrahydrofuran phase is dried over anhydrous magnesium sulfate, the solvent is evaporated The crude product is fractionated under reduced pressure At a pressure of 1600 Pa, the fraction from 83 to 85 °C is collected Thus, 39 81 g (78 %) of the title compound are obtained 1H-NMR (CDCI3, 250 MHz) δ 7 70-7 20 (4H, m), 3 88 (3H, s) literature value 1H-NMR δ 7 72-7 16 (4H, m), 3 81 (3H, s)
29) α,α,α-Tπfluoro-3,4-methylenedιoxyacetophenone
The title compound is prepared in a similar manner as the starting compound under 28) The crude product is fractionated under reduced pressure At a pressure of 373 Pa, the fraction from 84 to 85 °C is separated Yield 63 % Analysis for C9H5F303 (218 134)
calculated C 49 56 %, H 2 31 %, found C 49 43 %, H 2 20 %
IR (KBr, cm 1) 1702, 1614, 1364 H-NMR (CDCI3, 250 MHz) δ 7 68 (1 H, dd, J=8 3 Hz, J=1 2
Hz), 7 45 (1 H, d, J=1 2 Hz), 6 90 (1 H, d, J=8 3 Hz), 6 10 (2H, s)
Preparation of starting compounds of the formula XV:
30) 3,3,3-Trιfluoro-2-methoxy-2-(3-methoxyphenyl)propιonιtrιle
A suspension of 61 25 g (0 3 moles) of α,α,α-trιfluoro-3- methoxyacetophenone, 150 cm3 of 1 ,2-dιmethoxyethane and 32 56 g (0 50 moles) of potassium cyanide is stirred at room temperature for 15 minutes To the reaction mixture, 50 45 g (38 0 cm3, 0 40 moles) of dimethyl sulfate are added, drop by drop, the mixture is stirred at 60 °C for 5 minutes, then allowed to stand for a night The mixture is filtered, from the mother liquor, the solvent is distilled off The crude product is fractionated under reduced pressure At a pressure of 933 Pa, the fraction from 80 to 82 °C is separated Thus, 60 0 g (82 %) of the title compound are obtained Analysis for CnH10F3NO2 (245 20) calculated C 53 88 %, H 4 11 %, N 5 71 %, found C 53 50 %, H 4 10 %, N 5 51 %
IR (film, cm"1) 2850, 2250, 1190
1H-NMR (CDCI3, 250 MHz) δ 7 41 , (1 H, t, J=8 0 Hz), 7 30-7 00 (3H, m), 3 83 (3H, s), 3 49 (3H, s)
31 ) 3,3,3-Trιfluoro-2-methoxy-2-(3,4-methyleπedιoxyphenyl)- propionitnle
32 72 g (0 15 moles) of α, ,α-trιfluoro-3,4-methylenedιoxy- acetophenone are dissolved in 330 cm3 of 1 ,2-dιmethoxy- ethane, and the solution is stirred with 14 70 g (0 30 moles) of sodium cyanide for 15 minutes To the suspension formed, 20 73 g (0 15 moles) of potassium carbonate are added, and to the reaction mixture 42 7 cm3 (56 76 g, 0 45 moles) of dimethyl sulfate are added, drop by drop, and the mixture is stirred at room temperature for 3 hours Then, to the mixture cooled to 0 °C, 42 cm3 of 25 % aqueous ammonia solution are added, drop by drop The mixture is diluted with 330 cm3 of water and extracted twice with 160 cm3 of ethyl acetate each time The combined organic phases are washed twice using 160 cm3 of saturated aqueous sodium chloride solution each time and dried over anhydrous magnesium sulfate The solvent is distilled off Since the residue contains about 20 % of the starting cetone, the above steps are repeated using identical amounts of substances to obtain a more complete conversion The crude product is purified by fractionation under reduced pressure using a Vigreux column At a pressure of 40 Pa, the fraction from 78 to 88 °C is collected Thus, 27 60 g (71 %) of the title compound are obtained Analysis for CnH8F3N03 (259 19) calculated C 50 98 %, H 3 11 %, N 5 40 %, found C 50 75 %, H 3 17 %, N 5 45 %
IR (film, cm'1) 2909, 2248, 1492, 1254, 1189 1H-NMR (CDCI3, 200 MHz) δ 7 17 (1 H, dd, J=8 1 Hz, J=1 8 Hz), 7 05 (1 H, d, J=1 8 Hz), 6 89 (1 H, d, J=8 1 Hz), 6 05 (2H, s), 3 48 (3H, s)
Preparation of starting compounds of the formula X:
32) 3,3,3-Trιfluoro-2-methoxy-2-(3-methoxyphenyl)propyl- amine
To a suspension of 24 52 g (0 10 moles) of 3,3,3-trιfluoro-2- methoxy-2-(3-methoxyphenyl)propιonιtrιle, 23 78 g (0 10 moles) of cobalt(ll) chloride hexahydrate and 250 cm3 of methanol, 3 78 g (0 10 moles) of sodium tetrahydroborate(lll) are added in several portions at 0 °C The reaction mixture is stirred at room temperature and allowed to stand for a night The solvent is distilled off, and the residue is suspended in 500 cm3 of water The unreacted sodium tetrahydroborate(lll) is hydrohzed with 2N hydrochloric acid solution Then the pH is adjusted to 13 with 20 % aqueous sodium hydroxide solution The mixture is extracted three times using 300 cm3 of dichloromethane each time The combined organic phases are dried over anhydrous magnesium sulfate The solvent is evaporated The residue is fractionated under reduced pressure At a pressure of 533 Pa, the fraction from 103 to 104 °C is collected Thus, 15 20 g (61 %) of the title compound are obtained Analysis for CnH14F3N02 (249 23) calculated C 53 01 %, H 5 66 %, N 5 62 %,
found C 52 65 %, H 5 53 %, N 5 78 %
IR (film, cm'1) 2800, 1 174, 1119
1H-NMR (CDCI3, 250 MHz) δ 7 33 (1 H, t, J=8 2 Hz), 7 05 (2H, m), 6 90 (1 H, ddd, J=8 2 Hz, J=2 5 Hz, J=0 8 Hz), 3 82 (3H, s),
3 42 (3H, s), 3 36 (1 H, d, J=14 6 Hz), 3 13 (1 H, d, J=14 6 Hz),
1 20 (2H, s)
13C-NMR (CDCI3, 62 9 Mhz) δ 159 7, 135 8, 129 4, 125 4 (q,
1 JC =289 6 Hz), 1 19 2, 113 5, 82 2 (q, 2JCF=24 8 Hz), 54 9, 52 5,
45 7
Preparation of the hydrochloπde
12 46 g (50 mmoles) of the base 3,3,3-trιfluoro-2-(3-methoxy- phenyl)propylamιne are dissolved in 125 cm3 of diethyl ether, and, to the solution obtained, 8 6 cm3 of 2-propanol containing
(60 mmoles, 25 3 g/100 cm3) of hydrogen chloride are added, drop by drop The precipitated crystals are filtered, washed with
30 cm3 of diethyl ether Thus, the hydrochlonde of the title compound (12 28 g, 86 %) are obtained M p 219-220 °C (2- propanol, diethyl ether)
Analysis for CnHi5CIF3N02 (285 69) calculated C 46 25 %, H 5 29 %, Cl 12 41 %, N 4 90 %, found C 45 92 %, H 5 15 %, Cl 12 72 %, N 4 98 %
IR (film, cm"1) 2945, 1502, 1130
1H-NMR (DMSO-d6, 250 MHz) δ 8 47 (3H, s), 7 44 (1 H, t, J=7 9
Hz), 7 10 (3H, m), 3 96 (1 H, t, J=14 8 Hz), 3 80 (3H, s), 3 61
(1 H, t, J=14 8 Hz), 3 30 (3H, s)
33) 3,3,3-Tπfluoro-2-methoxy-2-(3,4-methylenedιoxyphenyl)- propylamine
The title compound is prepared in a similar manner as the starting compound under 32) The crude product is fractionated under reduced pressure At a pressure of 147 Pa, the fraction from 1 14 to 1 16 °C is collected Yield 68 % The title compound is a colourless oil
Analysis for CnHι2F3N03 (263 22) calculated C 50 19 %, H 4 60 %, N 5 32 % found C 49 96 %, H 458 %, N 5 34 %
IR (film, cm 1) 2951 , 1492, 1167
1H-NMR (CDCI3, 200 MHz) δ 6 97 (1 H, m), 6 93 (1 H, ddd, J=8 2 Hz, J=1 8 Hz, J=0 4 Hz), 6 83 (1 H, dd, J=8 2 Hz J=0 4 Hz), 5 97 (2H, s), 3 39 (3H, q, J=1 2 Hz), 3 36 (1 H, d, J=14 6 Hz), 3 12 (1 H, dq, J=14 6 Hz, J=1 6 Hz), 1 28 (2H, bs) 13C-NMR (CDCI3, 100 6 MHz) δ 147 9, 147 7, 127 8, 125 3 (q, 1JCF=289 5 Hz), 120 8 (q, J=1 5 Hz), 108 0, 107 7 (q, J=1 5 Hz), 101 2, 82 0 (q, 2JCF=24 8 Hz), 52 3 (q, J=289 6 Hz), 45 3 (q, 3JCF= 1 1 Hz)
Preparation of the hydrochloπde
A similar procedure is followed as in the preparation of the hydrochloπde under 32) Yield 81 % M p 248-249 °C Analysis for CnH13CIF3N03 (299 68)
calculated C 44 09 %, H 4 37 %, Cl 11 83 %, N 4 67 %, found C 44 31 %, H 4 40 %, Cl 11 81 %, N 4 65 %
IR (film, cm"1) 2925, 1449, 1 112, 1076 1H-NMR (DMSO-d6, 400 MHz) δ 8 55 (3H, bs), 7 1 (1 H„ s), 7 05-7 02 (2H m), 6 10 (2H, s), 3 90 (11-1, d, J=14 9 Hz), 3 57 (1 H, d, J=14 9 Hz), 3 29 (3H, s)
Example 1 6-Methoxy-1 -styryl-4-trιfluoromethyhsoquιnohne
Method A)
To a solution of 1 19 g (3 mmoles) of 4,6-dιmethoxy-1 -styryl-4- trιfluoromethyl-3,4-dιhydroιsoquιnohnιum chloride in 10 cm3 of methanol, 0 42 g (7 5 mmoles) of powdered potassium hydroxide are added at 0 °C, and the reaction mixture, is stirred at room temperature for 2 hours The mixture is evaporated, the residue is rubbed with 10 cm3 of water,, then filtered The crystals are washed with 5 cm3 of water, then twice with 3 cm3 of ethanol each time at 0 °C Thus, 0 94 g (95 %) of the title compound are obtained in the form of pale yellow matter M p 202-203 °C (chloroform)
Method B)
A suspension of 2 73 g (10 mmoles) of 1 -methyl-4,6-dιmethoxy- 4-trιfluoromethyl-3,4-dιhydroιsoquιnohne, 1 17 g (11 mmoles) of benzaldehyde and 1 33 g (13 mmoles) of acetic anhydride is reacted at 100 °C for 16 hours The precipitated crystals are filtered, washed twice with 5 cm3 of ethanol each time at 0 °C
Thus, 2 14 g (65 %) of the title compound are obtained M p 202-203 °C (chloroform)
Method C)
A suspension of 2 41 g (10 mmoles) of 1 -methyl-6-methoxy-4- tπfluoromethylisoquinoline, 1 17 g (11 mmoles) of benzaldehyde and 1 33 g (13 mmoles) of acetic anhydride is reacted at 100 °C for 16 hours The precipitated crystals are filtered, washed twice with 5 cm3 of ethanol at 0 °C each time
Thus, 1 98 g (60 %) of the title compound are obtained M p
202-203 °C (chloroform)
Analysis for Cι9Hι4F3NO (329 32) calculated C 69 20 %, H 4 28 %, N 4 25 %, found C 69 02 %, H 4 25 %, N 4 20 %
IR (KBr, cm 1) 1619, 141 1 , 1318, 1221 , 1 100
1H-NMR (CDCI3, 200 MHz) δ 8 79 (1 H, s), 8 36 (1 H, d, J=9 5
Hz), 8 07 (1 H, d, J=15 8 Hz), 7 92 (1 H, d, J=15 8 Hz), 7 75-7 65
(2H, m), 7 45-7 30 (5H, m), 3 99 (3H, s)
13C-NMR (CDCI3, 50 3 MHz) δ 161 7 157 8, 141 1 (q, 3JCF=6 5
Hz), 138 7, 136 3, 135 0, 129 3, 128 9, 127 7, 127 1 , 124 8 (q,
1JCF=273 1 Hz), 121 8, 120 5, 1 17 8 (q, 2JCF=30 1 Hz), 102 1 ,
55 6
MS (m/z, %) 329 (37), 328 (100), 314 (7), 310 (3), 298 (8), 286
(10), 285(37), 252(7)
6-Methoxy-1 -styryl-4-trιfluoromethyhsoquιnolιnιum chloride
0 99 g (3 mmoles) of the above base are reacted with 0 5 cm3 of 2-propanol containing 3 6 mmoles (25 3 g/100 cm3) of hydrogen chloride Thus, 0 74 g (67 %) of the title hydrochlonde are obtained in the form of pale yellow matter M p 189-190 °C (ethanol, dnsopropyl ether, decomposition) Analysis for d9Hι5CIF3NO (365 78) calculated C 62 39 %, H 4 13 %, Cl 9 69 %, N 3 83 %, found C 62 21 %, H 4 17 %, Cl 9 60 %, N 3 86 %
IR (film, cm"1) 1618, 1240
1H-NMR (DMSO-d6, 250 MHz) δ 8 92 (1 H, d, J=9 4 Hz), 8 76
(1 H, s), 8 28 (11-1, d, J=I5 7 Hz), 8 15 (1 H, d, J=15 7 Hz), 7 93-
7 89 (2H, m), 7 58 (1 H, d, J=9 4 Hz), 7 50-7 40 (3H, m), 7 32
(1 H, s), 4 00 (3H, s)
Example 2 1 -(4-Fluorostyryl)-6-methoxy-4-tπfluoromethyhsoquιnohne
Method A)
1 14 g (3 mmoles) of 1 -(4-fluorostyryl)-4,6-dιmethoxy-4-tπfluoro- methyl-3,4-dιhydroιsoquιnohne are dissolved in a mixture of 20 cm3 of toluene and 10 cm3 of methanol To the solution formed, 0 25 g (4 5 mmoles) of powdered potassium hydroxide are added at 0 °C, the reaction mixture is stirred at room temperature for 2 hours, then evaporated The residue is rubbed with 10 cm3 of water, and filtered The crystals are washed with 5 cm3 of water, then twice with 3 cm3 of ethanol at 0 °C each time Thus, 0 92 g (93 %) of the title compound are obtained in the form of pale yellow matter
M p 187-188 °C (chloroform)
Method B)
The procedure described in Example 1 , method B) is followed
Yield 64 % M p 188-189 °C (chloroform)
Method C)
The procedure described in Example 1 , method C) is followed
Yield 63 % M p 188-189 °C (chloroform)
Analysis for Cι9Hι3F4NO (347 32) calculated C 65 71 %, H 3 77 %, N 4 03 %, found C 65 84 %, H 3 79 %, N 4 08 %
IR (KBr, cm"1) 1618 1510, 1321 , 1275 1130
1H-NMR (CDCI3, 250 MHz) δ 8 77 (1 H, s), 8 31 (1 H, d, J=9 1
Hz), 8 01 (1 H, d, J=15 5 Hz), 7 81 (1 H, d, J=15 5 Hz), 7 70-7 63
(2H, m), 7 35-7 29 (2H, m), 7 1 1 (2H, t, J=8 7 Hz), 3 98 (3H, s)
13C-NMR (CDCI3 62 9 MHz) δ 165 2, 161 5, 159 5 (d,
1JCF=221 5 Hz), 141 3 (q, 3JCF=6 6 Hz), 136 9, 134 8, 132 6,
129 3, 129 2, 126 8, 124 8 (q, 1JCF=273 6 Hz), 121 8, 120 3,
117 7 (q, 2JCF=29 3 Hz), 1 15 8 (d, 2JCF=21 0 Hz), 102 1 , 55 4
MS (m/z, %) 347 (34), 346 (100), 332 (10), 328 (4), 316 (9),
304 (10), 303 (34), 252 (8)
1 -(4-Fluorostyryl)-6-methoxy-4-trιfluoromethyhsoquιnohnιum chloride
1 04 g (3 mmoles) of the above base are reacted with 0 5 cm3
of 2-propanol containing 3 6 mmoles (25 3 g/100 cm3) of hydrogen chloride Thus, 0 63 g (72 %) of the title hydrochloπde are obtained
M p 189-190 °C (ethanol, decomposition)
Analysis for Cι9Hι4CIF4NO (383 77) calculated C 59 46 %, H 3 68 %, Cl 9 24 %, N 3 65 %, found C 59 19 %, H 3 72 %, Cl 9 10 %, N 3 58 %
IR (film, cm 1) 3437, 1615, 1228, 1 162
1H-NMR (DMSO-d6, 250 MHz) δ 8 95 (1 H, d, J=9 5 Hz), 8 77
(1 H, s), 8 29 (1 H, d, J=15 6 Hz), 8 18 (1 H, d, J=15 6 Hz), 8 04
(1 H, d, J=5 6 Hz), 8 00 (1 H, d, J=5 6 Hz), 7 56 (1 H, dd, J=9 4
Hz, J=2 4 Hz), 7 33 (2H, t, J=8 8 Hz), 7 29 (1 H, s), 4 02 (3H, s)
Example 3
6-Methoxy-4-trιfluoromethyl-1 -(4-trιfluoromethylstyryl)- isoquinolme
Method A)
The procedure described in Example 1 , method A) is followed to obtain the title compound as pale yellow solids Yield 90 % M p 160-161 °C (chloroform)
Method B)
The procedure described in Example 1 , method B) is followed to obtain the title compound Yield 62 %
M p 160-161 °C (chloroform)
Method C)
The procedure described in Example 1 , method C) is followed to obtain the title compound Yield 70 %
M p 160-161 °C (chloroform)
Analysis for C20Hι3F6NO (397 32) calculated C 60 46 %, H 3 30 %, N 3 53 %, found C 60 70 %, H 3 27 %, N 3 63 %
IR (KBr, cm"1) 1620, 1409, 1324, 1121
1H-NMR (CDCI3, 250 MHz) δ 8 80 (1 H, s), 8 34 (1 H, d, J=9 7
Hz), 8 08 (1 H, d, J=15 6 Hz), 7 98 (1 H, d, J=15 6 Hz), 7 78 (2H, d, J=8 3 Hz), 7 68 (2H, d, J=8 3 Hz), 7 37 (1 H, s), 7 35 (1 H, dd,
J=9 7 Hz, J=2 5 Hz), 4 00 (3H, s)
13C-NMR (CDCI3 62 9 MHz) δ 161 7, 157 2, 141 4 (q, 3JCF=6 5
Hz), 139 8, 136 5, 135 0, 130 1 (q, 2JCF=32 5 Hz), 127 8, 126 8,
125 8 (q, 3JCF=4 6 Hz), 124 8 (q, 1JCF=271 8 Hz), 124 5, 124 2
(q, 1 JCF=271 0 Hz), 122 6, 120 8, 1 18 5 (q, 2JCF=27 8 Hz), 102 1 ,
55 6
MS (m/z, %) 397 (57), 396 (100), 382 (11), 378 (9), 366 (12),
354 (10), 353 (36), 328 (6), 285 (11), 252 (16), 69 (8)
6-Methoxy-4-trιfluoromethyl-1 -(4-trιfluoromethylstyryl)- isoquino nium chloride
1 19 g (3 mmoles) of the above base are reacted with 0 5 cm3 of 2-propanol containing 3 6 mmoles (25 3 g/100 cm3) of hydrogen chloride Thus, 0 72 g (66 %) of the yellow title hydrochlonde are obtained M p 189-190 °C (ethanol, decomposition)
Analysis for C20Hι4CIF6NO (433 78) calculated C 55 38 %, H 3 25 %, Cl 8 17 %, N 3 23 %, found C 55 62 %, H 3 37 %, Cl 8 29 %, N 3 19 %
IR (film, cm 1) 3433, 1613, 1319, 1 132
1H-NMR (DMSO-d6, 250 MHz) δ 8 92 (1 H, d, J=9 5 Hz), 8 83
(1 H, s), 8 47 (1 H, d, J=15 5 Hz), 8 20-8 13 (3H, s), 7 81 (2H, d,
J=8 2 Hz), 7 54 (1 H, dd, J=9 5 Hz, J=2 4 Hz), 7 29 (1 H, s), 4 00
(3H, s)
2-Methyl-6-methoxy-4-trιfluoromethyl-1 -(4-tπfluoromethylstyryl)- isoquinohnium iodide
A mixture of 1 00 g (2 5 mmoles) of the above base and 10 cm3 of methyl iodide are boiled for 40 hours The precipitated crystals are filtered, the crude product is recrystal zed^from ethanol Thus, 0 78 g (58 %) of the title quaternary salt are obtained in the form of orange yellow solids M p 213-215 °C (ethanol) Analysis for C2ιHι6F6INO (539 26) calculated C 46 77 %, H 2 99 %, N 2 60 %, found C 46 55 %, H 2 97 %, N 2 64 %
IR (KBr, cm 1) 3035, 1616 1324, 1249, 1 170 1130 1H-NMR (DMSO-d6, 400 MHz) δ 9 29 (1 H, s), 8 69 (1 H, d, J=9 5 Hz), 8 12 (2H, d, J=8 2 Hz), 7 94 (1 H, d, J=16 4 Hz), 7 92 (2H, d, J=8 2 Hz), 7 78 (1 H, dd, J=9 5 Hz, J=2 9 Hz), 7 47 (1 H, d, J=16 4 Hz), 7 46 (1 H, s), 4 36 (3H, s), 4 14 (3H, s) 13C-NMR (DMSO-d6 100 6 MHz) δ 166 5, 160 0, 144 7, 138 5
(q), 137 5 (q, 3JCF=6 9 Hz), 135 3, 134 5, 130 4 (q, 2JCF=31 9 Hz), 129 3, 126 0 (q, 3JCF=3 8 Hz), 124 1 (q, 1JCF=272 1 Hz), 123 5, 122 9 (q, 1JCF=273 7 Hz), 122 7, 1 19 8, 1 19 4 (q,
MS (m/z, %) 397 (48), 396 (74), 382 (18), 378 (10), 366 (18), 354 (12), 353 (33), 328 (4), 285 (10), 252 (15), 142 (100), 127 (39), 69 (5)
Example 4 6-Methoxy-1 -(4-πιtrostyryl)-4-tπfluoromethyhsoquιnolιne
Method A)
The procedure described in Example 1 , method A) is followed to obtain the title compound as lemon-yellow solids Yield 92 %) M p 223-224 °C (chloroform)
Method B)
The procedure described in Example 1 , method B) is followed to obtain the title compound Yield 74 %
M p 222-223 °C (chloroform)
Method C)
The procedure described in Example 1 method C) is followed to obtain the title compound Yield 73 %
M p 222-223 °C (chloroform)
Analysis for Cι9Hι3F3N203 (374 32) calculated C 60 97 %, H 3 50 %, N 7 48 %, found C 60 78 %, H 3 46 %, N 7 46 %
IR (KBr, cm"1) 1619, 1327, 1106
1H-NMR (DMSO-d6, 400 MHz) δ 8 92 (1 H, d, J=9 3 Hz), 8 87
(1 H, s), 8 56 (1 H, d, J=15 3 Hz), 8 29 (2H, d, J=8 7 Hz), 8 21
(2H, d, J=8 7 Hz), 8 18 (1 H, d, J=15 3 Hz), 7 55 (1 H, d, J=9 3
Hz), 7 30 (11-1, s), 4 00 (3H, s)
13C-NMR (CDCI3 50 3 MHz) δ 161 9, 157 4, 147 5, 142 8,
135 7, 134 2, 129 3, 128 7, 127 0, 126 2 (q, 1JCF=274 3 Hz),
124 1 , 121 8, 120 7, 1 16 4 (q, 2JCF=32 7 Hz), 101 7, 55 9
MS (m/z, %) 374 (100), 373 (99), 359 (12), 355 (7), 344 (12),
343 (28) 328 (27), 327 (68), 326 (15), 313 (15), 285 (29), 284
(23), 283 (16), 252 (26), 216 (12), 215 (19)
6-Methoxy-1 -(4-nιtrostyryl)-4-trιfluoromethylιsoquιnolιnιum chloride
1 12 g (3 mmoles) of the above base are reacted with 0 5 cm3 of 2-propanol containing 3 6 moles (25 3 g/100 cm3) of hydrogen chloride Thus, 0 86 g (70 %) of the title hydrochloπde are obtained in the form of light yellow solids
M p above 250 °C (ethanol)
Analysis for C19Hι4CIF3N203 (410 78) calculated C 55 56 % H 3 44 %, Cl 8 63 %, N 6 82 %, found C 55 87 %, H 3 29 % Cl 8 56 %, N 6 84 %
IR (film, cm 1) 2440, 1646, 1345, 1262
1H-NMR (DMSO-de, 200 MHz) δ 8 96 (1 H, d, J=9 5 Hz), 8 86
(1 H, s), 8 57 (1 H, d, J=I5 4 Hz), 8 36-8 14 (5H, m), 7 57 (1 H, dd,
J=9 5 Hz, J=2 2 Hz), 7 30 (1 H, s), 3 85 (3H, s)
Example 5
6,7-Methylenedιoxy-4-tπfluoromethyl-1 -(4-trιfluoromethylstyryl)- isoquinoline
Method A)
The procedure described in Example 1 , method A) is followed to obtain the title compound as pale yellow solids Yield 92 % M p 180-182 °C (chloroform)
Method B)
The procedure described in Example 1 , method B) is followed to obtain the title compound Yield 64 %
M p 180-182 °C (chloroform)
Method C)
The procedure described in Example 1 , method C) is followed to obtain the title compound Yield 68 %
M p 180-182 °C (chloroform)
Analysis for C20HnF6NO2 (41 1 30) calculated C 58 40 % H 2 70 %, N 3 41 %, found C 58 22 %, H 2 73 %, N 3 35 %
IR (KBr, cm"1) 1615, 1478, 1324, 1 104
1H-NMR (CDCI3, 200 MHz) δ 8 72 (1 H, s), 8 04 (1 H, d, J=15 4
Hz), 7 84 (1 H, d, J=15 4 Hz), 7 76 (2H, s), 7 69 (2H, s), 7 66
(1 H, s), 7 43 (1 H, q, J=1 8 Hz), 6 20 (2H, s)
13C-NMR (CDCI3 100 6 MHz) δ 155 8, 152 0, 149 0, 139 8 (q,
4JCF= 1 5 Hz), 136 7, 1 36 2, 131 5, 130 6 (q, 2JCF=32 8 Hz), 127 7, 125 8 (q, 3JCF=3 8 Hz), 124 6, 124 6 (q, 1JCF=273 1 Hz), 124 0 (q, 1 JCF=272 0 Hz), 124 0 102 4, 101 1 , 100 5 (q, 3JCF=2 7 Hz)
MS (m/z, %) 41 1 (37), 410 (100), 392 (10), 382 (13), 382 (2), 380 (2), 353 (1 1 ), 352 (7), 284 (7), 283 (7), 266 (28), 240 (3), 171 (16)
6,7-Methylenedιoxy-4-tπfluoromethyl-1 -(4-tπfluoromethylstyryl)- isoquino nium chloride
1 23 g (3 mmoles) of the above base are reacted with 0 5 cm3 of 2-propanol containing 3 6 mmoles (25 3 g/100 cm3) of hydrogen chloride Thus 1 03 g (77 %) of hydrochlonde are obtained in the form of light yellow solids
M p 259-260 °C (methanol dnsopropyl ether, decomposition)
Analysis for C20H12CIF6NO2 (447 77) calculated C 53 65 %, H 2 70 % Cl 7 92 %, N 3 13 %, found C 53 82 % H 2 63 % Cl 7 87 % N 3 16 %
IR (film, cm'1) 1630 1482, 1320 1 180, 1 134
1H-NMR (DMSO-d6, 400 MHz) δ 8 73 (1 H, s), 8 41 (1 H, s), 8 38
(1 H, d, J=15 4 Hz) 8 16 (2H d J=8 2 Hz) 8 1 1 (1 H, d, J=15 4
Hz), 7 80 (2H, d J=8 2 Hz), 7 34 (1 H, q, J=1 4 Hz), 6 36 (2H, s)
Example 6
1 -/2-(4-Trιfluoromethylpheπyl)ethyl/-6,7-ethylenedιoxy- isoquinohne
5.5 g (0.015 moles) of 1 -(4-trifluoromethylstyryl)-6,7- ethylenedioxyisoquinoline are dissolved in 100 cm3 of methanol. The solution obtained is hydrogenized in the presence of 1 g of palladium/carbon catalyst at a pressure of 15 bar. The catalyst is filtered, and, to the residue, concentrated aqueous ammonia solution is added until a pH value of 9. The precipitated crystalline matter is filtered, and crystallized from ethanol. Thus, 2.4 g (44 %) of the title product are obtained. M.p.: 110-1 1 1 °C. Analysis: for C20Hι6F3NO2 (359.35) calculated: C 66.85 %, H 4.49 %, N 3.90 %; found: C 66.34 %, H 4.42 %, N 4.03 %.
IR (KBr, cm"1): 1509, 1292, 1168, 1096, 1065. 1H-NMR (CDCI3, 400 MHz) δ: 8.27 (1 H, d, J=5.8 Hz), 7.53 (2H, d, J=8.1 Hz), 7.47 (1 H, s), 7.36 (3H, m), 7.21 (1 H, s), 4^37 ,(4H, m), 3.46 (2H, dd, ^=7.6 Hz, J2=8.6 Hz), 3.25 (2H, dd, J=7.6 Hz, J=8.6 Hz).
Example 7
1 -/2-(4-Trifluoromethylphenyl)ethyl/-2-methyl-6,7-ethylene- dioxy-1 ,2,3,4-tetrahydroisoquinoline fumarate
2.2 g (0.004 moles) of 1 -/2-(4-trifluoromethylphenyl)ethyl/-2- methyl-6,7-ethylenedioxy-3,4-dihydroisoquinolinium iodide are dissolved in 150 cm3 of methanol, and, to the solution formed, 1 g of sodium tetrahydroborate are added under stirring. The reaction mixture is stirred at room temperature for 2 hours, then evaporated. To the residue, 100 cm3 of water are added, the
aqueous phase is extracted with dichloromethane, dried over anhydrous sodium sulfate, and evaporated. The residual oily matter is dissolved in ethanol, and an equimolar quantity of fumaric acid dissolved in ethanol are poured to the latter solution. The precipitated crystals are filtered, and recrystalhzed from aqueous acetone. Thus, 1.33 g (67 %) of the title compound are obtained. M.p.: 192-194 °C. Analysis: for C25H26F3N02 (493.48) calculated: C 60.85 %, H 5.31 %, N 2.84 %; found: C 60.12 %, H 5.28 %, N 2.82 %.
1H-NMR (DMSO-d6, 400 MHz) δ: 7.60 (2H, d, J=8.1 Hz), 7.39 (2H, d, J=8.1 Hz), 6.64 (1 H, s), 6.61 (2H, s), 6.56 (1 H, s), 4.18 (4H, bs), 3.40 (1 H, t, J=5.2 Hz), 3.06 (1 H, m), 2.80-2.50 (5H, m), 2.39 (3H, s), 2.00 (2H, m).
Example 8
1 -/2-(4-Fluorophenyl)ethyl/-2-methyl-6,7-ethylenedioxy-1 ,2,3,4- tetrahydroisoquinoline hydrochlohde
5.0 g (12 mmoles) of 1 -/2-(4-fluorophenyl)ethyl/-2-methyl-6,7- ethylenedioxy-3,4-dihydroisoquinolinium iodide are dissolved in 370 cm3 of methanol. To the solution formed, 1 g (24 mmoles) of sodium tetrahydridoborate are added under ice cooling, then the reaction mixture is stirred at room temperature for 3 hours, evaporated to the half of the original volume, and 200 cm3 of water are added. The residual methanol is distilled off, and the aqueous phase is extracted with dichloromethane. The organic solution is dried, and evaporated under reduced pressure. The
residue is dissolved in diethyl ether, the pH is adjusted to 1 by the addition of 2-propanol containing hydrogen chloride The precipitated hydrochloπde is filtered, and recrystalhzed from 2- propanol Thus, 3 6 g (82 %) of the title compound are obtained M p 175-177 °C Analysis for C20H23CIFNO2 (363 86) calculated C 66 02 %, H 6 37 %, N 3 85 %, found C 65 45 %, H 6 35 %, N 3 95 %
1H-NMR (DMSO-d6, 400 MHz) δ 11 36 (1 H, bs), 7 29 (2H, dd, Jι=5 9 Hz, J2=8 2 Hz), 7 10 (2H, t, J=8 8 Hz), 6 76 (1 H, s), 6 74 (1 H, s), 4 30 (1 H, m), 4 23 (4H, m), 3 65-3 15 (2H, m), 2 98 (2H, m), 2 79 (5H, m), 2 44 (1 H, m), 2 05 (1 H, m)
Example 9
1-/2-(4-Fluorophenyl)ethyl/-2-methyl-6,7-methylenedιovy- 1 ,2,3,4-tetrahydroιsoquιnohne hydrochlonde
5 94 g (0 02 moles) of 1 -/2-(4-fluorophenyl)ethyl/-6,7- methylenedιoxy-3,4-dιhydroιsoquιnohne are dissolved in 50 cm3 of acetone To the solution formed, 14 1 g of methyl iodide are added, and the reaction mixture is allowed to stand at room temperature for 24 hours The precipitated quaternary isoquinolinium salt is filtered, then dissolved in 150 cm3 of methanol, and 3 5 g of sodium tetrahydridoborate are added in portions at 25-30 °C The reaction mixture is stirred for 2 hours, then evaporated to dryness To the residue, 200 cm3 of water are added, and the solution is extracted with dichloromethane The organic solution is dried over anhydrous sodium sulfate,
and evaporated to dryness The residue is recrystalhzed from ethanol Thus, 3 7 g (52 %) of the title compound are obtained
M p 208-211 °C
Analysis for Cι9H2ιCIFN02 (349 83) calculated C 65 23 %, H 6 05 %, N 4 00 %, found C 64 80 %, H 6 00 %, N 4 07 %
1H-NMR (DMSO-d6, 400 MHz) δ 11 53 (1 H, bs), 7 31 (2H, dd,
Jι=6 0 Hz, J2=8 1 Hz), 7 1 (2H, t, J=8 8 Hz), 6 83 (2H, s), 6 2
(2H, s), 4 43 (2H, t, J=5 6 Hz), 3 49 (1 H, m), 3 24 (1 H, m), 2 7-
3 1 (3H, m), 2 78 (3H, s), 2 45 (1 H, m), 2 8 (1 H, m)
Example 10
1-/2-(4-Trιfluoromethylphenyl)ethyl/-2-methyl-4-propyl-6,7- ethylenedioxyisoquinohnium iodide
4 0 g (0 01 moles) of 1 -/2-(4-tπfluoromethylphenyl)ethyl/-2- methyl-4-propyl-6,7-ethylenedιoxyιsoquιnohne are dissolved in 100 cm3 of nitromethane To the solution formed, 14 1 g of methyl iodide are added, and the reaction mixture is boiled for 3 hours The mixture is cooled to room temperature, and the crystalline isoquinohnium salt is filtered The crude product is recrystalhzed from a mixture of acetonitnle and ether Thus, 2 7 g (49 %) of the title compound are obtained
M p 214-216 °C
Analysis for C24H25F3IN02 (543 37) calculated C 53 05 %, H 4 64 %, N 2 58 %, found C 52 83 %, H 4 69 %, N 2 60 %
1H-NMR (DMSO-d6, 400 MHz) δ 8 29 (1 H, s), 7 78 (1 H, s), 7 62 (1 H, s), 7 53 (2H, m), 7 42 (2H, m), 4 5 (4H, m), 4 38 (3H, s),
3 87 (2H, t, J=7 8 Hz), 3 26 (2H, t, J=7 8 Hz), 3 4 (2H, t, J=7 8 Hz), 1 8 (2H, m), 1 7 (3H, t, J=7 4 Hz)
Example 11
1 -(4-Tπfluoromethylstyryl)-4-propyl-6,7-ethylenedιoxy- isoquinohnium chloride
6 2 g (0 015 moles) of N-/2-(3 4-ethylenedιoxyphenyl)ethyl/-4- tπfluoromethylcinnamamide are dissolved in 90 cm3 of absolute benzene To the solution formed, 25 cm3 of phosphor(V) trichloride oxide are added, and the reaction mixture is boiled for 4 hours To the still hot solution, 100 cm3 of methanol are poured, then evaporated to dryness The addition of methanol and the evaporation are repeated three times using 50 cm3 of methanol each time Then the methanohc solution of the isoquinohne hydrochlonde is transferred through the acidic ion exchanger Amberlist 46, and the product is precipitated with dnsopropyl ether Thus, 1 3 g (31 %) of the title compound are obtained M p 188-190 °C Analysis for C23H2ιCIF3N02 (435 87) calculated C 63 38 %, H 4 86 %, N 3 21 %, found C 63 39 %, H 4 85 %, N 3 19 %
1H-NMR (DMSO-d6, 400 MHz) δ 8 48 (1 H, s), 8 22 (1 H, d, J=16 2 Hz), 8 16 (4H, m), 7 86 (2H, d, J=8 3 Hz), 7 71 (1 H, s),
4 56 (2H, m), 4 52 (2H, m), 3 05 (2H, d, t, J=7 6 Hz), 1 7 (2H,
hx, J=7.4 Hz), 0.99 (3H, t, J=7.3 Hz).
Example 12
1 -/2-(4-Trifluoromethylphenyl)ethyl/-2-methyl-6,7-methylene- dioxy-1 ,2,3,4-tetrahydroisoquinoline
4.89 g (0.01 moles) of 1 -/2-(4-thfluoromethylphenyl)ethyl/-2- methyl-6,7-methylenedioxy-3,4-dihydroisoquιnolinium iodide are dissolved in 80 cm3 of methanol, and, to the solution formed, 2.1 g of sodium tetrahydridoborate are added in portions. The solution is stirred at room temperature for 3 hours, then evaporated to dryness. To the residue, 150 cm3 of water are added, and extracted with dichloromethane. The organic phase is dried over anhydrous sodium sulfate, evaporated under reduced pressure, and the residual white solids are recrystalhzed from ethanol. Thus, 2.8 g (77 %) of the title compound are obtained. M.p.: 51 -52 °C. Analysis: for C20H20F3NO2 (363.3) calculated: C 66.11 %, H 5.55 %, N 3.85 %; found: C 66.08 %, H 5.53 %, N 3.86 %.
1H-NMR (CDCI3, 400 MHz) δ: 7.5 (2H, d, J=8.2 Hz), 7.27 (2H, d, J=8.2 Hz), 6.54 (1 H, s), 6.53 (1 H, s), 5.88 (2H, s), 3.38 (1 H, t, J=5.4 Hz), 3.1 (1 H, m), 2.55-2.84 (5H, m), 2.45 (3H, s), 2.3 (2H, m).
Example 13
1 -(4-Thfluoromethylstyryl)-6,7-methylenedioxy-1 ,2,3,4- tetrahydroisoquinoline
3 4 g (0 01 moles) of 1 -(4-tπfluoromethylstyryl)-3,4-dιhydro- isoquinoline are dissolved in 150 cm3 of methanol To the solution formed, 1 4 g of sodium tetrahydridoborate are added in portions under stirring, and the solution is stirred at room temperature for 3 hours The mixture is evaporated to one fourth of the original volume, and, to the residue, 200 cm3 of water are added, any methanol present is distilled off, the solid matter is filtered, and washed with water until neutral The product is recrystalhzed from ethanol Thus, 2 6 g (74 %) of the title compound are obtained M p 124-125 °C Analysis for Cι9Hι6F3N02 (347 34) calculated C 65 70 %, H 4 64 %, N 4 03 %, found C 65 90 %, H 4 67 %, N 4 06 %
1H-NMR (CDCI3, 200 MHz) δ 7 56 (2H, d, J=8 5 Hz), 7/8 (2H, d, J=8 5 Hz), 6 61 (1 H, d, J=15 8 Hz), 6 6 (1 H, s), 6 58 (1 H, s), 6 4 (1 H, d, J=15 8 Hz), 5 89 (2H, s), 4 58 (1 H, d, J=7 7 Hz), 3 3- 3 0 (2H, m), 2 9-2 6 (2H, m)
Example 14
1 -/2-(4-Trιfluoromethylphenyl)ethyl/-2,2-dιmethyl-6,7- methylenedιoxy-1 ,2,3,4-tetrahydroιsoquιnolιnιum iodide
5 1 g (0 01 moles) of 1-/2-(4-tπfluoromethylphenyl)ethyl/-2- methyl-6,7-methylenedιoxy-1 ,2,3,4-tetrahydroιsoquιnolιne are dissolved in 60 cm3 of acetone To the solution formed, 8 cm3 of methyl iodide are added, and the reaction mixture is stirred at room temperature for 24 hours The precipitated matter is
filtered, and recrystalhzed from ethanol Thus, 4 2 g (83 %) of the title product are obtained M p 229-231 °C
Analysis for C2ιH23F3IN02 (505 32) calculated C 49 92 %, H 4 59 %, N 2 77 %, found C 49 01 %, H 4 61 %, N 2 73 %
1H-NMR (DMSO-de, 400 MHz) δ 7 66 (2H, d, J=8 8 Hz), 7 44
(2H, d, J=8 8 Hz), 6 89 (1 H, s), 6 82 (1 H, s), 6 06 (2H, s), 4 55
(1 H, m), 3 77 (2H, m), 3 62 (2H, m), 3 33 (2H, s), 3 29 (3H, s),
3 09-3 05 (2H, m), 2 88-2 86 (1 H, m), 2 69-2 68 (1 H, m)
Example 15
1-(4-Trιfluoromethylstyryl)-2,2-dιmethyl-6,7-methylenedιoxy- 1 ,2,3,4-tetrahydroιsoquιnohnιum iodide
The procedure described in Example 14 is followed to btaιn the title compound Yield 59 % M p 256-258 °C Analysis for C2ιH2ιFIN02 (503 30) calculated C 50 31 %, H 4 21 %, N 2 78 %, found C 49 88 %, H 4 25 %, N 2 87 %
Example 16
1 -/2-(4-Fluorophenyl)ethyl/-2,2-dιmethyl-6,7-methylenedιoxy- 1 ,2,3,4-tetrahydroιsoquιnohnιum iodide
2 93 g (6 5 mmoles) of 1 -/2-(4-fluorophenyl)ethyl/-2,2-dιmethyl- 6,7-methylenedιoxy-1 ,2,3,4-tetrahydroιsoquιnohne and 2 8 cm3 of methyl iodide are boiled in 40 cm3 of nitromethane under stirring for 3 hours The mixture is cooled to room temperature,
then allowed to stand in a refrigerator. The crystalline matter is filtered, washed with cold acetone, and recrystalhzed from ethanol. Thus, 1.3 g (43 %) of the title compound are obtained.
M.p.: 213-215 °C.
Analysis: for C20H23FINO2 (455.31) calculated: C 52.76 %, H 5.09 %, N 3.08 %; found: C 53.1 1 %, H 5.21 %, N 3.15 %.
1H-NMR (CDCI3, 400 MHz) δ: 7.28 (2H, m), 6.99 (2H, m), 6.78
(1 H, s), 6.7 (1 H, s), 6.02 (2H, s), 4.85 (1 H, m), 3.83 (2H, m),
3.45 (3H, s), 3.21 (3H, s), 3.15-3.1 (2H, m), 2.86-2.61 (2H, m),
2.52-2.0 (2H, m).
Example 17
1 -/2-(4-Fluorophenyl)ethyl/-2-methyl-6,7-methylenedioxy- isoquinolinium iodide
A solution of 5.9 g (0.02 moles) of 1 -/2-(4-fluorophenyl)ethyl/-2- methyl-6,7-methylenedioxy-isoquinoline and 6.1 cm3 of methyl iodide in 250 cm3 of acetone is allowed to stand at room temperature for 20 hours. The suspension obtained is cooled to 0 °C, filtered, washed with cold acetone, and the product is recrystalhzed from methanol. Thus, 4.7 g (54 %) of the title compound are obtained. M.p.: 224-227 °C. Analysis: for Cι9Hι7FIN02 (437.25) calculated: C 52.19 %, H 3.92 %, N 3.20 %; found: C 52.24 %, H 3.99 %, N 3.29 %.
IR (KBr, cm"1): 1031 , 932.
1H-NMR (DMSO-d6, 400 MHz) δ 8 58 (1 H, d, J=6 8 Hz), 8 19 (1 H, d, J=6 8 Hz), 8 05 (1 H, s), 7 71 (1 H, s), 7 41 (2H, dd, Jι=8 5 Hz, J2=5 7 Hz), 7 14 (2H, t, J=8 5 Hz), 6 46 (2H, s), 4 38 (3H, s), 3 78 (2H, t, J=8 1 Hz), 3 04 (2H, t, J=8 1 Hz)
Example 18
1 -/2-(4-Fluorophenyl)ethyl/-2,3-dιmethyl-6,7-methylenedιoxy- isoquinohnium iodide
3 0 g (0 0097 moles) of 1 -/2-(4-fluorophenyl)ethyl/-2,3-dιmethyl- 6,7-methylenedιoxyιsoquιnohne and 3 2 cm3 of methyl iodide are dissolved in 25 cm3 of nitromethane The reaction mixture is boiled for 1 5 hours, then 1 6 cm3 of methyl iodide are added, and the reaction mixture is boiled for further 1 hour The mixture is cooled to room temperature, 50 cm3 of diethyl ether are poured to it, stirred for 2 hours, then filtered The product is recrystalhzed from dimethylformamide Thus, 2 19 g (50 %) of the title compound are obtained M p 271 -273 °C Analysis for C20Hι9FINO2 (451 28) calculated C 53 23 %, H 4 24 %, N 3 10 %, found C 53 28 %, H 4 12 %, N 3 14 %
1H-NMR (DMSO-d6, 400 MHz) δ 8 09 (1 H, s), 7 92 (1 H, s), 7 53 (1 H, s), 7 40 (2H, m), 7 13 (2H, m), 6 40 (2H, s), 4 22 (3H, s), 3 83 (2H, t, J=8 0 Hz), 3 00 (2H, t, J=8 0 Hz), 2 80 (3H, s)
Example 19
1 -(4-Fluorostyryl)-6,7-methylenedioxy-1 ,2,3,4-tetrahydroisoquinoline
To a solution of 4.4 g (0.015 moles) of 1-(4-fluorostyryl)-6,7- methylenedioxy-3,4-dihydroisoquinoline in 200 cm3 of methanol, 1.6 g of sodium tetrahydridoborate are added in three portions under stirring. The reaction mixture is stirred at 25 to 30 °C for 2 hours (TLC benzene: methanol 8:2, Rf=0.46 UV), then evaporated to dryness under reduced pressure. To the residue, 150 cm3 of water are added, and the mixture is extracted three times with dichloromethane. The combined organic phases are dried over anhydrous sodium sulfate, evaporated, the residue is crystallized from diethyl ether. The product is filtered, and recrystalhzed from ethanol. Thus, 2.7 g (82 %) of the title compound are obtained. M.p.: 112-113 °C. Analysis: for Cι8H16FN02 (217.33) calculated: C 72.71 %, H 5.42 %, N 4.71 %; found: C 72.37 %, H 5.41 %, N 4.51 %.
1H-NMR (CDCIs, 200 MHz) δ: 7.32 (2H, m), 6.96 (2H, m), 6.93 (1 H, s), 6.55 (1 H, s), 6.53 (1 H, s), 6.47 (1 H, d, J=15.8 Hz), 6.18 (1 H, dd, Jι = 15.8 Hz, J2=8.0 Hz), 5.8 (2H, s), 4.51 -4.48 (1 H, m), 3.24-3.17 (1 H, m), 3 02-2.99 (1 H, m), 2.99-2.68 (2H, m).
Example 20
1 -/2-(4-Trifluoromethylphenyl)ethyl/-2-methyl-6,7-methylene- dioxyisoquinolinium iodide
5 1 g (0 015 moles) of 1-/2-(4-tπfluoromethylphenyl)ethyl/-2- methyl-6,7-methylenedιoxyιsoquιnohne and 5 cm3 of methyl iodide are boiled in 25 cm3 of nitromethane for 30 minutes, the mixture is cooled to room temperature, poured into 250 cm3 of acetone, and stirred The precipitated crystalline solids are filtered, washed with cold acetone, and the crude isoquinohnium salt is recrystalhzed from a mixture of hexane and ethanol in a ratio of 4 1 Thus, 5 4 g (75 %) of the title compound are obtained M p 258-260 °C
Analysis for C20Hι7F3INO2 (487 26) calculated C 49 30 %, H 3 52 %, N 2 87 %, found C 48 62 %, H 3 44 %, N 2 93 %
1H-NMR (DMSO-d6, 200 MHz) δ 8 61 (2H, d, J=6 8 Hz), 8 20
(2H, d, J=6 8 Hz), 8 05 (2H, s), 7 71 -7 61 (2H, m), 6 44 (2H, s),
4 43 (3H, s), 3 83 (2H, t, J=8 0 Hz), 3 14 (2H, t, J=8 0 Hz)
Example 21
1-(4-Trιfluoromethylstyryl)-2-methyl-6,7-methylenedιoxy- isoquinolinium iodide
6 8 g (0 02 moles) of 1-(4-trιfluoromethylstyryl)-2-methyl-6,7- methylenedioxyisoquinohπe are dissolved in 40 cm3 of dichloromethane, and, to the solution formed, 9 95 g (0 065 moles) of methyl iodide are added The reaction mixture is boiled for 1 5 hours, then evaporated to dryness, the residue is stirred with diethyl ether, cooled to 5 °C, filtered, washed with cold ether, and recrystalhzed from methanol Thus, 5 9 g (61 %) of the title compound are obtained M p 233-235 °C
Analysis for C20Hι5F3INO2 (485 25) calculated C 49 51 %, H 3 12 %, N 2 89 %, found C 49 05 %, H 3 18 %, N 2 82 %
1H-NMR (CDCI3, 400 MHz) δ 8 77 (1 H, d, J=11 Hz), 8 12 (1 H, d, J=11 0 Hz), 7 80 (3H, m), 7 63 (2H, d, J=13 2 Hz), 7 58 (1 H, s), 7 44 (1 H, s), 7 31 (1 H, m), 6 29 (2H, s), 4 62 (3H, s)
Example 22
1 -(4-Trιfluoromethylstyryl)-2-methyl-6,7-methylenedιoxy- 1 ,2,3,4-tetrahydroisoquinoline
5 6 g (0 012 moles) of 1 -(4-trιfluoromethylstyryl)-2-methyl-6,7- methylenedioxyisoquinohnium iodide are dissolved in 110 cm3 of methanol, and, to the solution formed, 0 8 g of sodium tetrahydridoborate are added in two portions The solu^'on is stirred for 1 hour, then evaporated under reduced pressure To the residue, 100 cm3 of water are added, and the mixture is extracted three times using 50 cm3 of dichloromethane each time The organic phase is dried over anhydrous sodium sulfate, and evaporated to dryness The residue is recrystalhzed from ethanol Thus, 2 5 g (57 %) of the title compound are obtained M p 85-88 °C Analysis for C20Hι8F3NO2 (361 37) calculated C 66 48 %, H 5 02 %, N 3 88 %, found C 66 60 %, H 5 13 %, N 3 91 %
IR (KBr, cm 1) 2844, 1166, 1 121 , 957 1H-NMR (DMSO-d6, 400 MHz) δ 7 69 (4H, m), 6 78 (1 H, d,
J=8 7 Hz), 6 69 (1 H, s), 6 56 (1 H, s), 6 34 (1 H, d, J=8 7 Hz), 5 93 (2H, m), 3 86 (1 H, m), 3 29 (3H, s), 3 1 -2 9 (4H, m)
Example 23
1-(4-Fluorostyryl)-2-methyl-6,7-methylenedιoxyιsoquιnolιnιum iodide
38 1 g (0 13 moles) of 1 -(4-fluorostyryl)-2-methyl-6,7- methylenedioxyisoquinohne are dissolved in 200 cm3 of nitromethane To the solution formed, 98 4 g of methyl iodide are added The reaction mixture is stirred at 120 °C for 1 5 hours The precipitated crystalline solids are filtered to obtain 50 9 g of crude product 12 g of the crude product are recrystalhzed from 70 ml of methanol Thus, 7 4 g (62 of the title compound are obtained M p 228-230 °C Analysis for d9Hι5FIN02 (435 25) calculated C 52 43 %, H 3 47 %, N 3 22 %, found C 52 05 %, H 3 38 %, N 3 25 %
1H-NMR (DMSO-d6, 200 MHz) δ 8 62 (1 H, d, J=6 0 Hz), 8 21 (1 H, d, J=6 0 Hz), 7 93 (2H, m), 7 80 (1 H, s), 7 75 (1 H, m), 7 62 (1 H, d, J=12 4 Hz), 7 38-7 32 (3H, m), 6 44 (2H, s), 4 34 (3H, s)
Example 24
1 -(4-Fluorostyryl)-2-methyl-6,7-methylenedιoxy-1 ,2,3,4-tetra- hydroisoquinolinium chloride
30 g (0 07 moles) of 1 -(4-fluorostyryl)-2-methyl-6,7- methylenedιoxy-1 ,2,3,4-tetrahydroιsoquιnolιnιum iodide are
dissolved in 1200 cm3 of methanol, and, to the solution formed, 4.7 g of sodium tetrahydridoborate are added in portions at 20 °C. The solution is stirred at room temperature for 1 hour, then evaporated under reduced pressure. To the residue, 500 cm3 of water are added. The aqueous solution is extracted with altogether 440 cm3 of dichloromethane. The organic phase is dried over anhydrous sodium sulfate. After the addition of 20 cm3 of ethanol containing hydrogen chloride, the solution is evaporated to dryness, the residue is crystallized from benzene to obtain 18.7 g of crude product which is recrystalhzed from 110 cm3 of 2-propanol. Thus, 16.3 g (76 %) of the title compound are obtained. M.p.: 210-213 °C. Analysis: for Cι9Hι9CIFN02 (347.33) calculated: C 65.61 %, H 5.51 %, N 4.03 %, found: C 65.68 %, H 5.59 %, N 3.98 %.
1H-NMR (CDCI3, 200 MHz) δ: 12.1 (1 H, bs), 7.36 (2H, m), 6.98 (2H, m), 6.59-6.52 (3H, m), 6.02 (1 H, m), 5.85 (2x1 H, 2xs), 3.78-3.75 (1 H, m), 3.01 -2.4 (4H, m), 3.45 (3H, s).
Example 25
1 -(4-Thfluoromethylstyryl)-2-ethyl-6,7-methylenedioxy- isoquinolinium iodide
2.0 g (5.8 mmoles) of 1 -(4-trifluoromethylstyryl)-2-ethyl-6,7- methylenedioxyisoquinoline are dissolved in 15 cm3 of nitromethane, and, to the solution formed, 4.7 cm3 of ethyl iodide are added. The solution is stirred at 120 °C for 4 hours, then evaporated under reduced pressure. The residue is
crystallized from diethyl ether, the crude product is recrystalhzed from acetone Thus, 1 9 g (65 %) of the title compound are obtained M p 234-236 °C Analysis for C2ιHι7F3IN02 (499 27) calculated C 50 52 %, H 3 43 %, N 2 81 %, found C 50 34 %, H 3 40 %, N 2 81 %
IR (KBr, cm 1) 1439, 1462, 1328 H-NMR (DMSO-d6, 400 MHz) δ 8 68 (1 H, d, J=6 9 Hz), 8 28 (1 H, d, J=6 9 Hz), 8 06 (2H, d, J=8 2 Hz), 7 89 (2H, d, J=8 2 Hz), 7 86 (1 H, d, J=16 7 Hz), 7 8 (1 H, s), 7 76 (11-1, s), 7 40 (11-1, d, J=16 7 Hz), 6 44 (2H, s), 4 70 (2H, q, J=7 2 Hz), 1 49 (3H, t, J=7 2 Hz)
Example 26
1 -(4-Cyaπostyryl-2-methyl-6,7,8-trιmethoxyιsoquιnohn" 'm iodide
1 8 g (55 mmoles) of 1-(4-cyanostyryl-2-methyl-6,7,8- tnmethoxyisoquinohne are dissolved in 15 cm3 of nitromethane To the solution obtained, 3 7 g of methyl iodide are added, and the reaction mixture is stirred at 120 °C for 4 hours The mixture is evaporated, the residue is crystallized from diethyl ether The crystals are dissolved in 40 cm3 of dichloromethane, and the product is precipitated by the addition of 10 ml of cyclohexane Thus, 1 g (40 %) of the title compound are obtained M p 130-133 °C Analysis for C23H23IN203 (502 35)
calculated N 5 58 %, found N 5 38 %
IR (KBr, cm 1) 3438, 2225, 1406
1H-NMR (DMSO-d6, 200 MHz) δ 8 15 (1 H, s), 8 02 (1 H, d,
J=16 9 Hz), 7 91 (4H, m), 7 45 (1 H, s), 6 95 (1 H, d, J=16 8 Hz),
4 14 (3H, s), 4 06 (3H, s), 3 85 (3H, s), 3 68 (3H, s), 2 80 (3H, s)
Example 27
1-/2-(3,4-Dιmethoxyphenyl)ethyl/-2-methyl-6,7-dιmethoxy- isoquinohnium iodide
7 2 g (0 02 moles) 1 -(2-(3,4-dιmethoxyphenyl)ethyl/-6,7- dimethoxyisoquiπoline are dissolved in 60 cm3 of nitromethane To the solution formed, 14 2 g of methyl iodide are added, and the reaction mixture is stirred at 120 °C for 4 hours Then the mixture is cooled, and 100 cm3 of diethyl ether are added to precipitate the product in crystalline form The crystals are filtered to obtain 8 7 g of crude product 5 7 g of the crude product are recrystalhzed from a mixture of water and ethanol Thus, 4 8 g (71 %) of the title compound are obtained M p 188-190 °C Analysis for C22H28IN05 (513 37) calculated N 2 73 %, found N 2 63 %
Example 28 1-/2-(3,4-Dιmethoxyphenyl)ethyl/-6,7-dιmethoxyιsoquιnohne
3 51 g (0 01 moles) of 1 -(3,4-dιmethoxystyryl)-6,7-dιmethoxy- isoquinohne are dissolved in 100 cm3 of acetic acid To the solution formed, 0 5 g of Pd/C catalyst are added, and the mixture is hydrogenized at room temperature and 10 bar pressure until the end of hydrogen gas consumption The catalyst is removed by filtration, the filtrate is evaporated under reduced pressure The residue is dissolved in 50 cm3 of methanol, and, by the addition of about 50 g of crushed ice and 10 cm3 of 25 % aqueous ammonia, the base is prepared The precipitated crystalline product is filtered, and washed with cold water Thus, 1 5 g (43 %) of the title compound are obtained M p 146-147 °C
Analysis for C2ιH23N04 (353 422) calculated C 71 37 %, H 6 56 %, N 3 96 %, found C 71 04 %, H 6 54 %, N 3 89 %
IR (KBr, cm"1) 1516, 1234, 1158
1H-NMR (CDCIs, 400 MHz) δ 8 35 (1 H, d, J=5 5 Hz), 7 39 (1 H, d, J=5 5 Hz), 7 22 (1 H, s), 7 05 (1 H, s), 6 81 (2H, s), 6 74 (1 H, s), 4 01 (3H, s), 3 96 (3H, s), 3 85 (3H, s), 3 80 (3H, s), 3 48 (2H, t, J=7 8 Hz), 3 15 (2H, t, J=7 8 Hz)
Example 29
1 -/2-(3,4-Dιmethoxyphenyl)ethyl/-2-methyl-6,7-dιmethoxy- 1 ,2,3,4-tetrahydroιsoquιnolιne fumarate
To a solution of 3 0 g (0 006 moles) of 1 -/2-(3,4-dιmethoxy- phenyl)ethyl/-2-methyl-6,7-dιmethoxy-1 ,2,3,4-tetrahydro-
isoquinohnium iodide in 200 cm3 of methanol, 0 45 g of sodium tetrahydridoborate are added at room temperature under stirring The reaction mixture is stirred for 2 hours, then evaporated under reduced pressure To the residue, 200 cm3 of water are added, the aqueous solution is extracted three times using 60 cm3 of dichloromethane each time The combined organic phases are dried over anhydrous sodium sulfate, and evaporated under reduced pressure to yield 2 g of crude product which are dissolved in 20 cm3 of ethanol To the solution formed, a solution of 0 62 g of fumanc acid in 40 cm3 of ethanol is poured The precipitated crystalline fumarate salt is filtered, washed with some cold ethanol Thus, 1 1 g (34 %) of the title compound are obtained M p 84-85 °C IR (KBr, cm"1) 3430, 2540, 1713, 1518, 1257 1H-NMR (DMSO-d6, 400 MHz) δ 6 83 (1 H, d, J=8 2 Hz), 6.76 (1 H, d, J=1 5 Hz), 6 69 (1 H, dd, J, = 1 6 Hz, J2=8 1 Hz), 6 67 (1 H, s), 6 65 (1 H, s), 6,60 (2H, s), 3 72 (3H, s), 3 70 (3H, s),
3 70 (3H, s), 3 49 (1 H, m), 3 15 (1 H, m), 2 70 (2H, m), 2 60 (2H, m), 2 45 (3H, s), 2 44 (1 H, m), 2 00 (2H, m)
Example 30
1-/2-(4-Trιfluoromethylphenyl)ethyl/-4-propyl-6,7-ethylenedιoxy- isoquinohne
4 8 g (0-012 moles) 1 -(4-trιfluoromethylstyryl)-4-propyl-6,7- ethylenedioxyisoquinohne are dissolved in 200 cm3 of acetic acid, and the solution is hydrogenized in the presence of 1 g of Pd/C catalyst at room temperature and 10 bar pressure until
the end of the hydrogen gas consumption. The catalyst is filtered, the filtrate is evaporated to dryness, the residue is dissolved in aqueous methanol, and concentrated aqueous ammonia is added to prepare the free base. Thus, 3.9 g (81 %) of the title compound are obtained. M.p.: 89-90 °C. Analysis: for C23H22F3N02 (401.432) calculated: C 68.82 %, H 5.52 %, N 3.49 %; found: C 68.19 %, H 5.51 %, N 3.46 %.
IR (KBr, cm"1): 1512, 1331 , 1109, 1069. 1H-NMR (CDCIs, 200 MHz) δ: 8.1 1 (1 H, s), 7.54 (2H, d, J=8.4 Hz), 7.50 (1 H, s), 7.41 (1 H, s), 7.39 (2H, d, J=6.0 Hz), 4.40 (4H, m), 3.50 (2H, m), 3.25 (2H, m), 2.88 (2H, t, J=7.7 Hz), 1.75 (2H, hx, J=7.6 Hz), 1.02 (3H, t, J=7.3 Hz).
Example 31
1-(4-Trifluoromethylstyryl)-4-propyl-6,7-ethylenedioxy- isoquinolinium chloride
0.9 g (3.7 mmoles) of 1 -methyl-6,7-ethylenedioxyisoquinoline, 0.7 g (4.1 mmoles) of 4-thfluoromethylbenzaldehyde and 3 cm3 of acetic anhydride are stirred at 150 to 160 °C for 3 hours, then the mixture is evaporated under reduced pressure. The 1.3 g of crude product obtained are dissolved in 25 cm3 of acetone. To the solution formed, 2-propanol containing hydrogen chloride is added, the precipitated hydrochlonde salt is filtered, washed with some cold acetone. Thus, 0.6 g (37 %) of the title compound are obtained. M.p.: 203-210 °C. Analysis: for C23H2ιCIF3N02 (435.87)
calculated C 63 38 %, H 4 86 %, N 3 21 %, found C 63 39 %, H 4 85 %, N 3 19 %
IR (KBr, cm"1) 3420, 2526, 1326, 1067
1H-NMR (DMSO-d6, 400 MHz) δ 8 48 (1 H, s), 8 32 (1 H, d,
J=16 2 Hz), 8 16 (4H, m), 7 86 (2H, d, J=8 3 Hz), 7 71 (1 H, s),
4 56 (2H, m), 4 52 (2H, m), 3 05 (2H, d, t, J=7 6 Hz), 1 70 (2H, hx, J=7 4 Hz), 0 99 (3H, t, J=7 3 Hz)
Example 32 1 -(3,4-Dιmethoxystyryl)-6,7-ethylenedιoxyιsoquιnohne
5 9 g (29 mmoles) of 1 -methyl-6,7-ethylenedιoxyιsoquιnohne and 5 2 g (31 mmoles) of 3,4-dιmethoxybenzaldehyde are stirred in 4 cm3 of acetic anhydride at 160 °C for 3 hours The reaction mixture is evaporated under reduced pressure,, and the residual oil is purified by column chromatography The crude product obtained is recrystalhzed twice from 2-propanol Thus, 5 1 g (50 %) of the title compound are obtained
M p 141 -143 °C
Analysis for C21H19N04 (349 39) calculated C 72 19 %, H 5 48 %, N 4 01 %, found C 71 56 %, H 5 60 %, N 3 98 %
IR (KBr, cm 1) 3420, 1505, 1271 , 1 137
1H-NMR (CDCI3, 200 MHz) δ 8 35 (1 H, d, J=5 39 Hz), 7 94 (1 H, d, J=15 8 Hz), 7 79 (1 H, s), 7 67 (1 H, d, J=15 8 Hz), 7 37 (1 H, d, J=5 5 Hz), 7 28 (1 H, m), 7 23 (2H, m), 6 91 (1 H, d, J=8 1 Hz),
4 40 (4H, s), 3 98 (3H, s), 3 93 (3H, s)
Example 33
1 -(4-Trιfluoromethylstyryl)-4-propyl-6,7-methylenedιoxy- isoquinohne
3 5 g (15 mmoles) of 1 -methyl-4-propyl-6,7-methylenedιoxy- isoquinohne and 4 0 g (22 6 mmoles) of 4-trιfluoromethyl- benzaldehyde are stirred in 35 cm3 of acetic anhydride at 160
°C for 4 hours The reaction mixture is evaporated under reduced pressure, and the residue is crystallized from diethyl ether The 2 17 g of crude product obtained are recrystalhzed from 40 cm3 of absolute ethanol Thus, 1 6 g (28 %) of the title compound are obtained
M p 156-158 °C
Analysis for C22Hι8F3N02 (385 389) calculated C 68 57 %, H 4 71 %, N 3 63 %, found C 68 43 % H 4 76 %, N 3 55 %
IR (KBr, cm 1) 1470, 1328, 1234, 1 120
1H-NMR (CDCI3, 400 MHz) δ 8 28 (1 H, s), 7 93 (1 H, d, J=15 6
Hz), 7 83 (1 H, d, J=15 6 Hz), 7 74 (2H, d, J=8 2 Hz), 7 63 (2H, d, J=8 1 Hz), 7 60 (1 H, s), 7 26 (1 H, s), 6 13 (2H, s), 2 90 (2H, t,
J=7 6 Hz), 1 75 (2H, hx, J=7 5 Hz), 1 03 (3H, t, J=7 4 Hz)
Example 34
1 -(4-Fluorostyryl)-6,7-methylenedιoxy-3,4-dιhydro- isoquinohnium chloride
12 5 g (0 04 moles) of N-/2-(3,4-methylenedιoxyphenyl)-ethyl/-
4-fluorocinnamamide are dissolved in 100 cm3 of benzene, and, to the solution formed, 25 ml of phosphor(V) trichloride oxide are poured. The mixture is boiled for 1.5 hours, then cooled to 10 °C, and stirred at the latter temperature for 1 hour. The crystalline crude product is filtered, washed with a low amount of benzene at 10 °C, and recrystalhzed from 400 cm3 of 2- propanol. Thus, 7.1 g (53.7 %) of the title compound are obtained. M.p.: 219-221 °C.
Example 35
1 -(4-Thfluoromethylstyryl)-6,7-methylenedioxy-3,4-dihydro- isoquinolinium chloride
20 g (0.055 moles) of 2-(3,4-methylenedioxyphenyl)ethyl-N-4- thfluoromethylcinnamamide are boiled in 70 cm3 of benzene in the presence of 20 cm3 of phosphor(V) trichloride oxide for 3.5 hours. The reaction mixture is cooled to 20 °C, the precipitated salt is washed with some hexane, and recrystalhzed from 110 cm3 of ethanol. Thus, 7.2 g (72 %) of the title compound are obtained. M.p.: 208-212 °C. Analysis: for Cι9Hι5CIF3N02 (381.70) calculated: C 59.78 %, H 3.96 %, Cl 9.29 %, N 3.67 %; found: C 59.78 %, H 3.94 %, Cl 9.32 %, N 3.61 %.
Example 36
A) 4,6-Dimethoxy-1 -styryl-4-trifluoromethyl-3,4-dihydro- isoquinolinium maleate
3.79 g (10 mmoles) of N-cinnamoyl-3,3,3-trifluoro-2-methoxy-2- (3-methoxyphenyl)propylamine are stirred in 4.46 cm3 (7.67 g, 50 mmoles) of phosphor(V) trichloride oxide at 85 °C for 16 hours. The reaction mixture cooled to room temperature is poured onto 40 cm3 of ice water. The pH is adjusted to 11 by the addition of concentrated aqueous ammonia. The solution is extracted three times using 30 cm3 of ethyl acetate each time, the combined organic phases are dried over anhydrous magnesium sulfate, and evaporated. The crude base is dissolved in 10 cm3 of methanol, and, to the solution formed, a solution of 1.16 g (10 mmoles) of maleic acid in 10 cm3 of methanol, then 40 cm3 of diisopropyl ether are added, drop by drop. The precipitated crystals are filtered, washed with 10 cm3 of diisopropyl ether. Thus, 2.54 g (53 %) of the title compound are obtained. M.p.: 149-151 °C (ethanol-diisopropyl ether). Analysis: for C24Hι2F3N06 (477.44) calculated: C 60.38 %, H 4.64 %, N 2.93 %; found: C 60.50 %, H 4.56 %, N 3.03 %. IR (film, cm"1): 1600, 1493, 1252, 1177. 1H-NMR (DMSO-d6, 400 MHz) δ: 8.14 (1 H, d, J=8.8 Hz), 7.86 (2H, dd, J=8.7 Hz, J=5.7 Hz), 7.57 (1 H, d, J=15.8 Hz), 7.50- 7.40 (3H, m), 7.13 (1 H, d, J=3.0 Hz), 6.21 (2H, s), 4.24 (2H, s), 3.92 (3H, s), 3.30 (3H, s).
B) 4,6-Dimethoxy-1 -styryl-4-trifluoromethyl-3,4-dihydro- isoquinolinium chloride
3.61 g (10 mmoles) of the crude base are dissolved in 40 cm3
of diisopropyl ether, and, to the solution formed, 1 73 cm3 of 2- propanol containing 12 moles (25 3 g/100 cm3) of hydrogen chloride are added, drop by drop The precipitated crystals are filtered, washed with 10 cm3 of diisopropyl ether Thus, 2 11 g
(53 %) of the title compound are obtained
M p 188 °C (ethanol)
Analysis for C20Hι9CIF3NO2 (397 82) calculated C 60 38 %, H 4 81 %, Cl 8 91 %, N 3 54 %, found C 60 24 %, H 4 84 %, Cl 8 92 %, N 3 49 %
IR (film, cm 1) 3435, 1508, 1477
1H-NMR (DMSO-d6 + CDCI3, 400 MHz) δ 8 49 (1 H, d, J=8 9
Hz), 8 22 (1 H, m), 7 88 (2H, dd, J=7 6 Hz, J=1 8 Hz), 7 73 (1 H, d, J=16 1 Hz), 7 53 (3H, m), 7 35 (1 H, dd, J=8 9 Hz, J=2 6 Hz),
7 29 (1 H, d, J=2 6 Hz), 6 60 (1 H, bs), 4 42 (1 H, d, J=16 0 Hz),
4 26 (1 H, d, J=16 0 Hz), 4 04 (3H, s), 3 42 (3H, s)
13C-NMR (DMSO-d6 + CDCI3, 100 6 Mhz) 166 9, 166 6, 149 6,
135 7, 134 2, 133 7, 132 3, 129 8, 129 3, 124 4 (q, 1JCF=287 5
Hz), 119 0, 115 9, 115 8, 114 7, 75 0 (2JCF=28 5 Hz), 55 8, 53 3,
42 2
Example 37
1 -/2-(4-Fluorophenyl)ethyl/-2-methyl-6,7-ethylenedιoxy-3,4- dihydroisoquinohnium bromide
2 33 g (0 0075 moles) of 1 -/2-(4-fluoropheπyl)ethyl/-2-methyl- 6,7-ethylenedιoxy-1 ,2,3,4-tetrahydroιsoquιnolιne are dissolved in 100 cm3 of dichloromethane The solution is cooled to 0-5 °C, and 1 6 g (0 009 moles) of N-bromosuccinimide are added in
several portions during 15 minutes. The mixture is stirred at the latter temperature for 1 hour, then at room temperature for 2 hours. The precipitated crystals are filtered, the filtrate is evaporated, and the residual solids are recrystalhzed from acetone. Thus, 1.76 g (58 %) of the title compound are obtained. M.p.: 177-180 °C. Analysis: for C20H2ιBrFNO2 (406.30) calculated: H 5.21 %, N 3.45 %; found: H 5.43 %, N 3.29 %.
IR (KBr, cm"1): 1735, 1301 , 1219.
1H-NMR (DMSO-d6, 200 MHz) δ: 7.61 (s, 1 H), 7.31 (m, 2H), 7.11 (m, 2H), 6.99 (s, 1 H), 4.35 (m, 4H), 3.95 (m, 2H), 3.66 (s, 3H), 3.47 (m, 2H), 2.94 (m, 4H).
Example 38
1-/2-(4-Trifluoromethylphenyl)ethyl/-2-methyl-6,7-ethylene- dioxy-3,4-dihydroisoquinolinium iodide
2.8 g (0.0075 moles) of 1 -/2-(4-thfluoromethylphenyl)ethyl/-2- methyl-6,7-ethylene-dioxy-3,4-dihydroisoquinoline are dissolved in 120 cm3 of acetone. To the solution formed, 5 cm3 of methyl iodide are added. The mixture is boiled for 1 hour, then cooled to 0-5 °C with ice water, and stirred at this temperature for 2-3 hours. After crystallization, the crystals are filtered, washed with cold acetone, and recrystallized from acetone. Thus, 2.2 g (58 %) of the title compound are obtained. M.p.: 205-207 °C. Analysis: for C2ιH2ιF3IN02 (503.30)
calculated C 50 12 %, H 4 21 %, N 2 78 %, found C 49 10 %, H 4 11 %, N 2 71 %
1H-NMR (CDCI3, 400 MHz) δ 7 56 (2H, d, J=8 2 Hz), 7 37 (2H, d, J=8 2 Hz), 7 18 (1 H, s), 6 78 (1 H, s), 4 36 (2H, m), 4 27 (2H, m), 4 12 (2H, t, J=7 6 Hz), 3 90 (3H, s), 3 53 (2H, t, J=7 6 Hz),
3 18 (4H, m)
Example 39
6,7-Ethylenedιoxy-1 -/2-(4-trιfluoromethylphenyl)ethyl/-3,4- dihydroisoquino ne
14 2 g (0 037 moles) of 2-(3,4-ethylenedιoxyphenyl)-ethyl-N-3- (4-trιfluoromethylphenyl)propιonyl amide are dissolved in 80 cm3 of toluene To the solution obtained, 12 cm3 of phosphor(V) trichloride oxide are added, drop by drop, the reaction mixture is heated to 80 °C and stirred at this temperature for 2 5 hours The precipitated crystalline dihydroisoquinohne is filtered and recrystalhzed from ethanol The product obtained (12 g) is dissolved in 90 cm3 of methanol, made alkaline to pH 9 by the addition of 20 % aqueous sodium hydroxide solution, the precipitated matter is filtered, washed with aqueous methanol (5 1), and recrystalhzed from a mixture of ethanol and water Thus, 1 44 g (41 %) of the title compound are obtained M p 85 °C
Analysis for C20Hι8NO2 (361 37) calculated C 66 48 %, H 5 02 %, N 3 88 %, found C 66 34 %, H 5 04 %, N 3 90 %
1H-NMR (DMSO-de, 400 MHz) δ 7 61 (2H, d, J=8 0 Hz), 7 47 (2H, d, J=8 0 Hz), 7 10 (1 H, s), 6 74 (1 H, s), 4 24 (4H, m), 3 48 (2H, t, J=7 4 Hz), 2 96 (4H, m), 2 47 (2H, t, J=7 1 Hz)
Example 40
7-Chloro-1-/2-(4-trιfluoromethylphenyl)ethyl/-3,4-dιhydro- isoquinohne hydrochlonde
10 0 g (0 028 moles) of N-/2-(4-chlorophenyl)ethyl/-3-(4- trιfluoromethylphenyl)propιonyl amide are dissolved in 80 cm3 of xylene To the stirred mixture, 12 g of phosphor(V) oxide are added, and the reaction mixture is stirred at 110 to 120 °C for 5 hours The mixture is cooled to room temperature, and, from the precipitated solids, the xylene is removed by decantation 100 cm3 of methanol are added, the crystals are filtered, the pH is adjusted to 8 by the addition of concentrated ammonium hydroxide, then 150 cm3 of water are added, and the methanol is distilled off The aqueous phase is extracted with dichloromethane (3x50 cm3) The combined organic phases are dried over anhydrous sodium sulfate, and evaporated to dryness 10 6 g of oily base are obtained which is purified by column chromatography using a mixture of toluene and methanol in a ratio of 8 2 An 1 4 g portion of the base obtained is converted to acid addition salt in a mixture of 10 cm3 of ethyl acetate and 5 cm3 of ether using isopropanol containing hydrogen chloride The salt is filtered and washed with a low amount of cold ether Thus, 1 35 g (87 %) of the title compound are obtained M p 173-175 °C
Analysis for Cι8H16CI2F3N (374 23) calculated C 57 77 %, H 4 31 %, N 3 74 %, Cl 18 95 %, found C 57 30 %, H 4 30 %, N 3 69 %, Cl 18 80 %
1H-NMR (CDCI3, 400 MHz) δ 15 81 (1 H, bs), 7 67 (1 H, d, J=7 6 Hz), 7 65 (1 H, s), 7 53 (2H, d, J=8 1 Hz), 7 43 (2H, d, J=8 1 Hz), 7 37 (1 H, d, J=8 3 Hz), 3 94 (2H, t, J=7 6 Hz), 3 68 (2H, t, J=7 6 Hz), 3 26 (2H, t, J=8 0 Hz), 3 01 (2H, t, J=8 0 Hz)
Example 41
1-(4-Fluorostyryl)-4-methyl-6,7-methylenedιoxy-3,4-dιhydro- isoquinoline hydrochlonde
To a solution of 3 27 g (0 01 moles) of N-/2-methyl-2-(3,4- methylenedιoxyphenyl)ethyl/-4-fluorocιnnamamιde in 50 cm3 of absolute toluene, 4 66 g (0 05 moles) of phosphor(V) tpchloπde oxide are added under stirring, and the reaction mixture is stirred at 120 °C under an argon atmosphere till the end of the reaction Then, to the warm solution, 50 cm3 of methanol are added, drop by drop, and the mixture is evaporated The residue is dissolved in methanol, then evaporated again This procedure is repeated 5 to 6 times, then the methanohc solution of the product is poured onto the ion exchanger Amberhst 46 resin The solution is evaporated, and diethyl ether is added The precipitated crystals are filtered Thus, 2 38 g (69 %) of the title compound are obtained M p decomposition above 200 °C 1H-NMR (DMSO-d6 + CDCI3, 400 MHz) δ 14 02 (11-1, bs), 8 44
(1H, d, J=161 Hz), 785 (2H, m), 751 (1H, s), 743 (1H, d, J=161 Hz), 715 (2H, m), 697(1H, s), 620 (2H, s), 389(1H, ddd, Jι=145 Hz, J2=55 Hz, J3=350 Hz), 371 (1H, ddd, J,=145 Hz, J2=72 Hz, J3=41 Hz), 319 (1H, hx, J=89 Hz), 132 (3H, d, J=71 Hz)
Example 42
1-(4-Fluorostyryl)-6,7-methylenedιoxy-4-propyl-3,4-dιhydro- isoquinohne hydrochlonde
The procedure described in Example 41 is followed to obtain the title compound Yield 74 % M p 184-185 °C 1H-NMR (CDCI3, 400 MHz) δ 1424 (1 H, bs), 842 (1 H, d, J=160 Hz), 779 (2H, m), 735 (1H, d, J=160 Hz), 732 (1H, s), 714 (2H, m), 687(1H, s), 617(2H, s), 404(1H, ddd.^148 Hz, J2=55 Hz, J3=1 Hz), 378 (1H, ddd, J,=148 Hz, J2=36 Hz, J3=26 Hz), 294 (1H, m), 125-160 (4H, m), 093 (3H, t, J=76 Hz)
Example 43
4-Butyl-1-(4-fluorostyryl)-6,7-methylenedιoxy-3,4-dιhydro- isoquino ne hydrochlonde
The procedure described in Example 41 is followed to obtain the title compound Yield 67% Mp 163-166 °C 1H-NMR (DMSO-d6+ CDCI3, 400 MHz) δ 1398 (1H, bs), 750 (1 H, s), 845 (1 H, d, J=158 Hz), 785 (2H, m), 742 (1 H, d,
J=158 Hz), 715 (2H, m), 691 (1 H, s), 620 (2H, s), 400 (1 H, dd, Jι=148 Hz, J2=53 Hz), 379 (1H, dd, J,=148 Hz, J2=33 Hz), 295 (1H, m), 125-160 (6H, m), 090 (3H, t, J=76 Hz)
Example 44
4-Ethyl-6,7-methylenedιoxy-1 -(4-trιfluoromethylstyryl)-3,4- dihydroisoquino ne hydrochlonde
The procedure described in Example 41 is followed to obtain the title compound Yield 60 % M p 162-165 °C 1H-NMR (DMSO-d6 + CDCI3, 400 MHz) δ 14 10 (1 H, bs), 8 47 (1 H, d, J=16 1 Hz), 7 98 (2H, d, J=14 7 Hz), 7 70 (2H, d, J=14 7 Hz), 7 62 (1 H, d, J=16 1 Hz), 7 58 (1 H, s), 6 94 (1 H, s), 6 20 (2H, s), 4 05 (1 H, brdd, Jι=14 9 Hz, J2=5 5 Hz), 3 83 (1 H, d, Jι=14 9 Hz, J2=3 50 Hz), 2 93 (1 H, m), 1 63 (2H, m), 1 j01 (3H, t, J=7 6 Hz)
Example 45
4-Butyl-6,7-methylenedιoxy-1 -(4-tπfluoromethylstyryl)-3,4- dihydroisoquinohne hydrochlonde
The procedure described in Example 41 is followed to obtain the title compound Yield 71 % M p 191 -193 °C 1H-NMR (DMSO-d6 + CDCI3, 400 MHz) δ 14 10 (1 H, bs), 8 50 (1 H, d, J=16 2 Hz), 7 95 (2H, d, J=8 1 Hz), 7 70 (2H, d, J=8 1 Hz), 7 59 (1 H, d, J=16 2 Hz), 7 50 (1 H, s), 6 91 (1 H, s), 6 20 (2H, s), 4 04 (1 H, ddd, J1 =15 0 Hz, J2=5 5 Hz, J3= above 1 Hz),
382 (1H, ddd, J,=150 Hz, J2=35 Hz, J3=34 Hz), 297 (1H, m), 12 + 160 (6H, m), 09 (3H, J=76 Hz)
Example 46
6,7-Methylenedιoxy-1-(4-methoxystyryl)-4-propyl-3,4-dιhydro- isoquinohne hydrochlonde
The procedure described in Example 41 is followed to obtain the title compound Yield 63 % M p 200-202 °C 1H-NMR (CDCIs, 400 MHz) δ 1402 (1H, bs), 847 (1H, d, J=160Hz), 774(2H, m), 732 (1H, s), 725 (1H, d, J=160 Hz), 695 (2H, m), 684 (1H, s), 616 (2H, s), 401 (1H, ddd, J,=148 Hz, J2=53 Hz, J3=26 Hz), 387 (3H, s), 375 (1H, ddd, J,=148 Hz, J2=36 Hz, J3=49 Hz), 291 (1H, m), 125 + 160 (4H, m), 092 (3H, t, 76 Hz)
Example 47
6,7-Methylenedιoxy-4-propyl-1-(4-trιfluoromethylstyryl)-3,4- dihydroisoquino ne hydrochlonde
The procedure described in Example 41 is followed to obtain the title compound Yield 70% Mp 201-204 °C 1H-NMR (CDCI3, 400 MHz) δ 1453 (1H, bs), 845 (1H, d, J=161 Hz), 788 (2H, d, J=80 Hz), 769 (2H, d, J=80 Hz), 750 (1H, d, J=161 Hz), 732(1H, s), 688(11-1, s), 618 (2H, s), 405 (1H, dd, J1=150 Hz, J2=36 Hz), 381 (1H, dd, J=150 Hz, J34=56 Hz), 296 (1 H, m), 125 + 160 (4H, m), 093 (3H, t,
J=76 Hz)
Example 48
4-Methyl-6,7-methylenedιoxy-1-(4-methoxystyryl)-3,4-dιhydro- isoquinohπe hydrochlonde
The procedure described in Example 41 is followed to obtain the title compound Yield 66 % M p 227-230 °C 1H-NMR (CDCIs, 400 MHz) δ 1408 (1H, bs), 847 (1H, d, J=160Hz), 774(2H, m), 733(11-1, s), 725 (1H, d, J=160 Hz),
695 (2H, m), 690 (1H, s), 616 (2H, s), 388 (1H, dd, J,=146 Hz, J2=76 Hz, J3=40 Hz), 387 (3H, s), 368 (1H, dd, Jι=146 Hz, J2=55 Hz, J3=36 Hz), 312 (1H, m), 130 (3H, d, J=70 Hz)
Example 49
4-Butyl-1-(3,4-dιmethoxystyryl)-6,7-methylenedιoxy-3,4- dihydroisoquinohne hydrochlonde
The procedure described in Example 41 is followed to obtain the title compound Yield 58 % M p 206-208 °C 1H-NMR (CDCI3, 400 MHz) δ 1398 (1H, bs), 840 (1H, d, J=160 Hz), 739 (1H, dd, Jι=83 Hz, J2=20 Hz), 736 (1H, s),
733 (1H, d, J=160 Hz), 730 (1H, d, J=20 Hz), 691 (1H, d, J=83 Hz), 685 (1H, s), 617 (2H, s), 399 (1H, dd, ^=150 Hz, J2=54 Hz, J3=24 Hz), 398 (3H, s), 395 (3H, s), 375 (1H, Jι=150 Hz, J2=39 Hz, J3=46 Hz), 288 (1H, m), 120 + 160 (6H, m), 089 (3H, t, J=76 Hz)
Example 50
4-Ethyl-1 -(4-fluorostyryl-6,7-methylenedιoxy-3,4-dιhydro- isoquinohne hydrochlonde
The procedure described in Example 41 is followed to obtain the title compound Yield 79 % M p 186-188 °C 1H-NMR (CDCI3, 400 MHz) δ 13 72 (1 H, bs), 8 40 (1 H, d, J=16 0 Hz), 7 88 (2H, m), 7 60 (1 H, s), 7 46 (1 H, d, J=16 0 Hz), 7 17 (2H, m), 6 95 (11-1, s), 6 21 (2H, s), 4 01 (1 H, dd, Jι=14 8 Hz, J2=5 54 Hz), 3 80 (1 H, dd, J,=14 8 Hz, J2=3 3 Hz), 2 92 (1 H, m), 1 62 (2H, m), 1 00 (3H, t, J=7 6 Hz)
Example 51
4-Ethyl-6,7-methylenedιoxy-1 -(4-methoxystyryl)-3,4-dιrydro- isoquinoline hydrochlonde
The procedure described in Example 41 is followed to obtain the title compound Yield 61 % M p 182-185 °C 1H-NMR (CDCI3, 400 MHz) δ 13 89 (1 H, bs), 7 33 (1 H, s), 8 44 (1 H, d, J=15 8 Hz), 7 75 (2H, m), 7 25 (1 H, d, J=15 8 Hz), 6 95 (2H, m), 6 87 (1 H, s), 6 16 (2H, s), 4 03 (1 H, m), 3 87 (3H, s), 3 76 (1 H, m), 2 82 (1 H, m), 1 63 (2H), 1 00 (3H, t, J=7 6 Hz)
Example 52
1 -(4-Fluorostyryl)-4-hexyl-6,7-methylenedιoxy-3,4-dιhydro- isoquino ne hydrochlonde
The procedure described in Example 41 is followed to obtain the title compound Yield 71 % Mp 158-160 °C 1H-NMR(DMSO-d6+CDCI3, 400 MHz) δ 1418(11-1, bs), 843 (1H, d, J=162 Hz), 782 (2H, m), 740 (1H, s), 738 (1H, d, J=162 Hz), 714 (2H, m), 688(11-1, s), 619(2H, s), 400(1H, brdd, Jι=18 Hz, J2=55 Hz), 379 (1H, brdd, ^=148 Hz, J2=35 Hz), 294 (1H, m), 120 + 160 (10H, m), 087 (3H, t, J=76 Hz)
Example 53
4-Hexyl-6,7-methylenedιoxy-1-(4-trιfluoromethylstyryl)-3,4- dihydroisoquinoline hydrochlonde
The procedure described in Example 41 is followed to obtain the title compound Yield 80% Mp 171-173 °C 1H-NMR (DMSO-d6 + CDCI3, 400 MHz) δ 1446 (1 H, bs), 848 (1 H, d, J=162 Hz), 792 (2H, d, J=80 Hz), 770 (2H, d, J=80 Hz), 755(1H, d, J=162 Hz), 740 (1H, s), 689(11-1, s), 620 (2H, s), 404 (1H, brdd, J1=149 Hz, J2=38 Hz), 382 (1H, brdd, Jι=149 Hz, J2=55 Hz), 295 (1H, m), 120 + 166 (10H, m), 088 (3H, t, J=76 Hz)
Example 54
4-Hexyl-6,7-methylenedιoxy-1-(4-methoxystyryl)-3,4-dιhydro- isoquinohne hydrochlonde
The procedure described in Example 41 is followed to obtain
the title compound Yield 74 % M p 129-131 °C 1H-NMR (CDCI3, 400 MHz) δ 14 02 (1 H, bs), 8 47 (1 H, d, J=15 7 Hz), 7 32 (1 H, s), 7 75 (2H, d, J=8 0 Hz), 7 25 (1 H, d, J=15 7 Hz), 6 95 (2H, d, J=8 0 Hz), 6 84 (1 H, s), 6 16 (2H, s), 3 87 (3H, s), 3 99 (1 H, m), 3 75 (1 H, m), 2 88 (1 H, m), 1 20 + 1.60 (10H, m), 0 88 (3H, t, J=7 6 Hz)
Example 55
4-Butyl-6,7-methylenedιoxy-1 -(4-methoxystyryl)-3,4-dιhydro- isoquinohne hydrochlonde
The procedure described in Example 41 is followed to obtain the title compound Yield 67 % M p 140-142 °C H-NMR (CDCI3, 400 MHz) δ 13 95 (1 H, bs), 8 45 (1 H, d, J=15 8 Hz), 7 74 (2H, d, J=8 0 Hz), 7 32 (1 H, s), 7.25 H, d, J=15 8 Hz), 6 95 (2H, d, J=8 0 Hz), 6 85 (1 H, s), 6 16 (2H, s), 3.87 (3H, s), 4 00 (1 H, brdd, J,=14 8 Hz, J2=3 8 Hz), 3 76 (1 H, brdd, Jι=14 8 Hz, J2= 5 2 Hz), 2 89 (1 H, m), 1 20 + 1 60 (6H, m), 0 89 (3H, t, J=7 6 Hz)
Example 56
1 -(3,4-Dιmethoxystyryl)-4-hexyl-6,7-methylenedιoxy-3,4- dihydroisoquino ne hydrochlonde
The procedure described in Example 41 is followed to obtain the title compound Yield 81 % M p 183-185 °C
1H-NMR (DMSO-d6 + CDCI3, 400 MHz) δ 13 25 (1 H, bs), 8 37
(1 H, d, J=158 Hz), 771 (1 H, s), 745 (1 H, d, J=20 Hz), 743 (1H, d, J=158 Hz), 741 (1H, dd, ^=82 Hz, J2=20 Hz), 696 (1 H, d, J=82 Hz), 693 (1 H, s), 622 (1 H, d, J=10 Hz), 621 (1H, d, J=10 Hz), 396 (3H, s), 394 (3H, s), 394 (1H, dd, Jι=149 Hz, J2=33 Hz), 376 (1H, dd, J,=149 Hz, J2=33 Hz), 376 (1H, dd, J,=149 Hz, J2=55 Hz), 298 (1H, m), 120-160 (10H, m), 087(3H, t J=76 Hz)
Example 57
1 -(3,4-Dιmethoxystyryl)- 6,7-methylenedιoxy-4-propyl-3,4- dihydroisoquino ne hydrochlonde
The procedure described in Example 41 is followed to obtain the title compound Yield 70% Mp 212-215 °C 1H-NMR (CDCI3, 400 MHz) δ 1286(1H, s), 825(1H, d, J=158 Hz), 789 (1H, s), 756 (1H, d, J=20 Hz), 752 (1H, d, J=158 Hz), 738 (1H, dd, Jι = 16 Hz, J2=60 Hz), 708 (1H, s), 704 (1H, d, J=82 Hz), 625 (1 H, s), 624 (1 H, s), 392 (3H, s), 389 (3H, s), 386 (1H, brdd, J,=148 Hz, J2=53 Hz), 377 (1H, brdd, Jι=148 Hz, J2=28 Hz), 306 (1 H, m), 125 + 155 (4H, m), 09 (3H, t, J=76 Hz)
Example 58
1 -(3,4-Dιmethoxystyryl)- 4-ethyl-6,7-methylenedιoxy-3,4- dihydroisoquino ne hydrochlonde
The procedure described in Example 41 is followed to obtain the title compound Yield 77% Mp 209-211 °C
1H-NMR (CDCI3, 400 MHz) δ 13 87 (1 H, bs), 8 37 (1 H, d, J=15 9 Hz), 7 39 (1 H, dd, Jι=8 3 Hz, J2=2 0 Hz), 7 38 (1 H, s), 7 33 (1 H, d, J=15 9 Hz), 7 30 (1 H, d, J=2 0 Hz), 6 91 (1 H, d, J=8 3 Hz), 6 86 (1 H, s), 6 17 (2H, s), 4 02 (1 H, ddd, J,=15 0 Hz, J2=5 4 Hz), J3=2 3 Hz), 3 98 (3H, s), 3 95 (3H, s), 3 75 (1 H, ddd, Jι=15 0 Hz, J2=4 2 Hz, J3=4 2 Hz), 2 82 (1 H, m), 1 61 (2H, m), 1 00 (3H, t, J=7 6 Hz)
Example 59
1 -(3,4-Dιmethoxystyryl)- 4-methyl-6,7-methylenedιoxy-3,4- dihydroisoquinohne hydrochlonde
The procedure described in Example 41 is followed to obtain the title compound Yield 63 % M p 201-203 °C 1H-NMR (CDCIs, 400 MHz) δ 13 91 (1 H, bs), 8 37 (1 H^d, J=15 8 Hz), 7 39 (1 H, dd, J=8 4 Hz, J=2 0 Hz), 7 38 (1 H, s), 7 32 (1 H, d, J=15 8 Hz), 7 30 (1 H, d, J=2 0 Hz), 6 91 (1 H, d, J=8 4 Hz), 6 91 (1 H, s), 6 16 (2H, s), 3 98 (3H, s), 3 95 (3H, s), 3 87 (1 H, ddd, J,=14 8 Hz, J2=7 5 Hz, J3=2 5 Hz), 3 67 (1 H, ddd, Jι=14 8 Hz, J2=5 2 Hz, J3=1 8 Hz), 3 12 (1 H, m), 1 30 (3H, d, J=7 0 Hz)
Example 60
4-Methyl-6,7-methylenedιoxy-1 -(4-trιfluoromethylstyryl)-3,4- dihydroisoquinohne hydrochlonde
The procedure described in Example 41 is followed to obtain
the title compound Yield 61 % M p 216-218 °C 1H-NMR (DMSO-d6 + CDCI3, 400 MHz) δ 14 18 (1 H, bs), 8 48 (1 H, d, J=16 0 Hz), 7 98 (2H, s), 7 70 (2H, s), 7 63 (1 H, d, J=16 0 Hz), 7 59 (1 H, s), 6 99 (1 H, s), 6 21 (2H, s), 3 93 (1 H, dd, Jι=14 6 Hz, J2=5 7 Hz), 3 74 (1 H, dd, J,=14 6 Hz, J2=5 2 Hz), 3 22 (1 H, m), 1 34 (3H, d, J=7 0 Hz)
Example 61
1 -(4-Fluorostyryl)-6,7-methylenedιoxy-3,4-dιhydroιsoquιnohne hydrochlonde
12 5 g of N-/2-(3,4-methylenedιoxyphenyl)ethyl/-4-fluoro- αnnamamide are dissolved in 100 cm3 of benzene, and, to the solution obtained, 25 cm3 of phosphor(V) trichloride oxide are poured The reaction mixture is boiled for 1 5 hours, then cooled to 10 °C and stirred at this temperature for 1 hour The crystalline crude product is filtered, washed with a small amount of benzene cooled to 10 °C, and recrystalhzed from 400 cm3 of 2-propanol Thus, 7 1 g (53 7 %) of the title compound are obtained M p 219-221 °C H-NMR (DMSO-d6, 200 MHz) δ 12 55 (1 H, bs), 8 3 (1 H, d, J=16 1 Hz), 7 96 (2H, m), 7 87 (1 H, s), 7 60 (1 H, d, J=16 1 Hz), 7 37 (2H, t, J=9 Hz), 7 17 (1 H, s), 6 25 (2H, s), 3 79 (2H, t, J=8 0 Hz), 3 04 (2H, t, J=8 0 Hz)
Example 62 1 -(4-Trιfluoromethylstyryl)-6,7-methylenedιoxy-3,4-dιhydro-
isoquinohne hydrochlonde
20 g (0 055 moles) of 2-(3,4-methylenedιoxyphenyl)ethyl-N-(4- trιfluoromethyl)cιnnamamιde are boiled in 70 cm3 of benzene in the presence of 20 cm3 of phosphor(V) trichloride oxide for 3 5 hours The reaction mixture is cooled to 20 °C, the precipitated salt is washed with some hexane, and recrystalhzed from 110 cm3 of ethanol Thus, 7 2 g (72 %) of the title compound are obtained M p 208-212 °C Analysis for Cι9Hι5CIF3N02 (381 70) calculated C 59 78 %, H 3 96 %, Cl 9 29 %, N 3 67 %, found C 59 74 %, H 3 94 %, Cl 9 22 %, N 3 61 %
1H-NMR (DMSO-d6, 200 MHz) δ 12 56 (11-1, bs), 8 23 (1 H, d, J=16 1 Hz), 8 09 (2H, d, J=8 1 Hz), 7 89 (1 H, s), 7 88 (2H, d, J=8 1 Hz), 7 78 (1 H, d, J=16 1 Hz), 7 2 (1 H, s), 6 26 (2H, s), 3 82 (2H, t, J=8 1 Hz), 3 09 (2H, d, J=8 1 Hz)
Example 63
6,7-Ethylenedιoxy-1 -/2-(4-trιfluoromethylpheπyl)ethyl/-4-propyl- 3,4-dιhydroιsoquιnohne oxalate
To a solution of 7 5 g (0 017 moles) of N-/2-(3,4-ethylenedιoxy- phenyl)ethyl/-3-(4-trιfluoromethylphenyl)propιonyl amide in 100 cm3 of absolute benzene, 6 cm3 of phosphor(V) trichloride oxide are added The reaction mixture is boiled for 3 hours, then evaporated under reduced pressure From the residue, 3x75 cm3 of methanol and 75 cm3 of benzene are distilled off The crude product is dissolved in 200 cm3 of dichloromethane, to
the solution obtained, crushed ice and 20 % aqueous sodium hydroxide solution are added under intensive stirring until the pH value of the aqueous phase remains 10 to 11 After half an hour's stirring, the phases are separated The aqueous phase is extracted twice using 80 cm3 of dichloromethane each time The combined organic phases are dried over anhydrous sodium sulfate and evaporated to dryness The residual crude product is purified by column chromatography to obtain 4 8*g of base that is converted to the oxalate salt in absolute diethyl ether Thus, 5 7 g (69 %) of the title compound are obtained M p 122-125 °C
1H-NMR (DMSO-d6 + CDCI3, 400 MHz) δ 7 63 (2H, d, J=8 1 Hz), 7 54 (1 H, s), 7 45 (2H, d, J=8 1 Hz), 6 88 (1 H, s), 4 37 (2H, m), 4 30 (2H, m), 3 69 (1 H, dd, J,=3 1 Hz, J2=15 4 Hz), 3 58 (1 H, dd, Jι=5 3 Hz, J2=14 9 Hz), 3 43 (1 H, m), 3 14 (2H, m), 3 01 (1 H, m), 2 75 (1 H, m), 1 23 (1 H, m), 1 11 (3H, m), 0 79 (3H, t, J=6 6 Hz) IR (KBr, cm 1) 3420, 2700, 1750, 1648, 1328
Example 64
6,7-Ethylenedιoxy-1 -/(4-trιfluoromethyl)styryl/-4-propyl-3,4- dihydroisoquinohne oxalate
To a solution of 6 8 g (0 016 moles) of N-/2-propyl-2-(3,4- ethylenedιoxyphenyl)ethyl/-4-trιfluoromethylcιnnamamιde in 70 cm3 of absolute benzene, 6 cm3 of phosphor(V) trichloride oxide are added The reaction mixture is boiled for 2 hours, then evaporated From the residue, 3x60 cm3 of methanol are
distilled off, 100 cm3 of ether are added, the mixture is stirred and boiled for 15 minutes, then the ether is removed by decantation, and this procedure is repeated twice. The crude product obtained is dissolved in dichloromethane and the pH is adjusted to 11 by the addition of 20 % aqueous sodium hydroxide solution under stirring The separated aqueous phase is extracted with dichloromethane twice using 50 cm3 of dichloromethane each time The combined organic phases are dried over anhydrous sodium sulfate, evaporated to obtain 2.9 g (45 %) of oily product The crude product is dissolved in absolute ether, and, to the solution, an equimolar amount of anhydrous oxalic acid is added The crystalline salt is filtered. Thus, 3 22 g (41 %) of the title compound are obtained. M.p/ 140-143 °C
Example 65
7-Hydroxy-1 -/2-(4-tπfluoromethylphenyl)ethyl/-6-methoxy-3,4- dihydroisoquinohne
A solution of 30 g (0 082 moles) of 1 -/2-(4-trιfluoromethyl- phenyl)ethyl/-6,7-dιmethoxy-3,4-dιhydroιsoquinohne in 250 cm3 of concentrated hydrochloric acid is stirred under nitrogen stream over an oil bath of 120 °C for 50 hours The solution is cooled in ice water, the crystalline matter is filtered, then dissolved in 300 cm3 of methanol By the addition of 100 cm3 of concentrated aqueous ammonia, the base is liberated. From the precipitated gummy matter the solvent is removed by decantation The residue is recrystalhzed from acetonitnle.
Thus, 11 7 g (33 %) of the title compound are obtained M p 129-132 °C
Example 66 1 -(2-Phenylethyl)-6,7-methylenedιoxy-3,4-dιhydroιsoquιnohne
A solution of 10 g (0 033 moles) of N-/2-(3,4-methylenedιoxy- phenyl)ethyl/-3-phenylpropιonyl amide and 30 cm3 of phosphor(V) trichloride oxide in 70 cm3 of absolute benzene is boiled for 1 5 hours, then cooled to 50 °C, and the precipitated crystals are filtered The crude hydrochlonde is dissolved in a mixture of 200 cm3 of water and 200 cm3 of methanol, the pH value of the solution is adjusted to 13 by the addition of 20 % aqueous sodium hydroxide solution The precipitated white crystalline base is filtered, washed with cold water, dried, and recrystalhzed from a mixture of ethanol and water Thus, 5 3 g (58 %) of the title compound are obtained M p 112-115 °C
Example 67
A) 4,6-Dιmethoxy-1 -styryl-4-tπfluoromethyl-3,4-dιhydro isoquinohnium maleate
A mixture of 3 79 (10 mmoles) of N-cιnnamoyl-3,3,3-trιfluoro-2- methoxy-2-(3-methoxyphenyl)propylamιne and 4 46 cm3 (7 67 g, 50 mmoles) of phosphor(V) trichloride oxide is stirred at 85 °C for 16 hours The reaction mixture cooled to room temperature is poured onto 40 cm3 of ice water The pH is adjusted to 11 by the addition of concentrated aqueous
ammonia The mixture is extracted three times using 30 cm3 of ethyl acetate each time The combined organic phases are dried over anhydrous magnesium sulfate, and evaporated The crude base is dissolved in 10 cm3 of methanol, and, to the solution obtained, a solution of 1 16 g (10 moles) of maleic acid in 10 cm3 of methanol, then 40 cm3 of diisopropyl ether are added, drop by drop The precipitated crystals are filtered, washed with 10 cm3 of diisopropyl ether Thus, 2 54 g (53 %) of the title compound are obtained
M p 149-151 °C (ethanol-dnsopropyl ether)
Analysis for C24Hι2F3N06 (477 4) calculated C 60 38 %, H 4 64 %, N 2 93 %, found C 60 50 %, H 4 56 %, N 3 03 %
IR (film, cm 1) 1600, 1493, 1252, 1177
1H-NMR (DMSO-d6, 400 MHz) δ 8 14 (1 H, d, J=8 8 Hz), 7 86
(2H, dd, J=8 7 Hz, J=5 7 Hz), 7 57 (1 H, d, J=15 8 Hz), 7 50-
7 40 (3H, m), 7 13 (1 H, d, J=3 0 Hz), 6 21 (2H, s), 4 24 (2H, s),
3 92 (3H, s), 3 30 (3H, s)
B) 4,6-Dιmethoxy-1 -styryl-4-tπfluoromethyl-3,4-dιhydro- isoquinohnium chloride
3 61 g of the crude base are dissolved in 40 cm3 of diisopropyl ether, then 1 73 cm3 of isopropanol containing 25 3 g/100 cm3 of hydrogen chloride (12 moles) are added, drop by drop The precipitated crystals are filtered, washed with 10 cm3 of diisopropyl ether Thus, 2 1 1 g (53 %) of the title compound are obtained M p 188 °C (ethanol)
Analysis for C2oHι9CIF3N02 (397 82) calculated C 60 38 %, H 4 81 %, Cl 8 91 %, N 3 54 %, found C 60 24 %, H 4 84 %, Cl 8 92 %, N 3 49 %
IR (film, cm'1) 3435, 1508, 1477
1H-NMR (DMSO-d6 + CDCI3, 400 MHz) δ 8 49 (1 H, d, J=8 9
Hz), 8 22 (1 H, m), 7 88 (2H, dd, J=7 6 Hz, J=1 8 Hz), 7 73 (1 H, d, J=16 1 Hz), 7 53 (3H, m), 7 35 (1 H, dd, J=8 9 Hz, J=2 6 Hz),
7 29 (1 H, d, J=2 6 Hz), 6 60 (1 H, bs), 4 42 (1 H, d, J=16 0 Hz),
4 26 (1 H, d, J=16 0 Hz), 4 04 (3H, s), 3 42 (3H, s) 3C-NMR (DMSO-d6 + CDCI3, 100 6 MHz) δ 166 9, 166 6,
149 6, 135 7, 134 2, 133 7, 132 3, 129 8, 129 3, 124 4 (q,
1JCF=287 5 Hz), 1 19 0, 1 15 9, 1 15 8, 1 14 7 75 0 (q, 2JCF=28 5
Hz), 55 8, 53 3, 42 2
Example 68
A) 1 -(4-Fluorostyryl)-4,6-dιmethoxy-4-trιfluoromethyl-3,4- dihydroisoquinohnium maleate
3 97 g (10 mmoles) of N-(4-fluorocιnnamoyl)-3,3,3-trιfluoro-2- methoxy-2-(3-methoxyphenyl)propylamιne are reacted with
4 46 cm3 (7 67 g, 50 mmoles) of phosphor(V) trichloride oxide in the manner described in Example 67, section A) The crude base obtained is recrystalhzed from hexane Thus, 2 54 g (67 %) of drab coloured 1 -(4-fluorostyryl)-4,6-dιmethoxy-4-tπfluoro- methyl-3,4-dιhydroιsoquιnohne are obtained
M p 92-93 °C (hexane)
Analysis for C20Hι7F4NO2 (379 35)
calculated C 63 32 %, H 4 52 %, N 3 69 %, found C 63 05 %, H 4 48 %, N 3 61 %
IR (KBr, cm ) 2959, 1646, 1510, 1180 1H-NMR (DMSO-d6, 400 MHz) δ 7 70 (1 H, d, J=8 6 Hz), 7 53 (2H, m), 7 42 (1 H, d, J=15 9 Hz), 7 24 (1 H, d, J=2 6 Hz), 7 14 (1 H, d, J=15 9 Hz), 7 10-7 02 (3H, m), 4 26 (1 H, d, J=17 2 Hz), 4 17 (1 H, d, J=17 2 Hz), 3 90 (3H, s), 3 32 (3H, s) 13C-NMR (CDCI3, 100 6 MHz) δ 163 1 (d, 1JCF=249 1 Hz), 161 8, 161 6, 135 5, 132 6, 132 4, 129 0 (d, 3JCF=8 4 Hz), 128 1 , 125 2 (q, 1JCF=286 1 Hz), 123 6 (d, 4JCF=2,3 Hz), 123 0, 115 8 (d, 2JCF=22 1 Hz), 114 8, 112 8, 75 1 (q, 2JCF=27 5 Hz), 55 6, 52 6, 49 4
1 90 g (5 mmoles) of the base obtained are dissolved in 7 cm3 of methanol To the solution obtained, a solution of 0 58 g (5 mmoles) of maleic acid in 7 cm3 of methanol, then 20 cm3 of diisopropyl ether are added, drop by drop The precipitated crystals are filtered, and washed with 7 cm3 of diisopropyl ether Thus, 1 66 g (67 %) of the title compound are obtained in the form of yellow solids
M p 139-140 °C (ethanol-dnsopropyl ether)
Analysis for C24H21F4N06 (495 43) calculated C 58 19 % H 4 27 %, N 2 83 %, found C 57 91 %, H 4 28 %, N 2 87 %
IR (KBr, cm 1) 1600, 1350, 1253, 1179
1H-NMR (DMSO-d6, 400 MHz) δ 8 16 (1 H, d, J=8 8 Hz), 7 90-
7 80 (2H m), 7 58 (2H, s), 7 40-7 20 (3H, m), 7 20-7 10 (1 H, m),
6 21 (2H, s), 4 25 (2H, s), 3 93 (3H, s), 3 31 (3H, s)
B) 1 -(4-Fluorostyryl)-4,6-dιmethoxy-4-trιfluoromethyl-3,4- dihydroisoquinohnium chloride
1 14 g (3 mmoles) of 1 -(4-fluorostyryl)-4,6-dιmethoxy-4- trιfluoromethyl-3,4-dιhydroιsoquιnohπe are reacted with 0 5 cm3 of 2-propanol containing 3 6 mmoles (25 3 g/100 cm3) of hydrogen chloride in the manner described in Example 67, section B) Thus, 0 94 g (75 %) of the title compound are obtained in the form of pale yellow solids
M p 213-214 °C (ethanol, decomposition)
Analysis for C20Hι8CIF4NO2 (415 81 ) calculated C 57 77 %, H 4 36 %, Cl 8 53 %, N 3 37 %, found C 57 54 %, H 4 31 %, Cl 8 57 %, N 3 40 %
IR (film, cm ) 2541 , 1599, 1241
1H-NMR (DMSO-d6, 400 MHz) δ 8 51 (1 H, d, J=8 8 Hz), 8 16
(1 H, d, J=15 8 Hz), 8 05-7 96 (2H, m), 7 77 (1 H, d, J=15 8 Hz),
7 50-7 30 (3H, m), 7 25 (1 H, s), 4 49 (11-1, d, J=16 1 Hz), 4 25 (1 H, d, J=16 1 Hz), 4 02 (3H, s), 3 39 (3H, s)
Example 69
A) 4,6-Dιmethoxy-4-(trιfluoromethyl)-1 -(4-trιfluoromethyl- styryl)-3,4-dιhydroιsoquιnolιnιum maleate
The procedure described in Example 67, section A) is followed starting from 4 47 g (10 mmoles) of N-(4-trιfluoromethyl- cιnnamoyl)-3,3,3-tπfluoro-2-methoxy-2-(3-methoxyphenyl)-
propylamine The crude base is recrystalhzed from hexane
Thus, 3 09 g (72 %) of drab coloured 4,6-dιmethoxy-4-
(trιfluoromethyl)-1 -(4-trιfluoromethylstyryl)-3,4-dιhydro- isoquinohne are obtained M p 87-88 °C (hexane)
Analysis for C2ιHι7F6N02 (429 36) calculated C 58 75 %, H 3 99 %, N 3 26 %, found C 58 58 %, H 3 95 %, N 3 30 %
IR (KBr, cm'1) 1608, 1325, 1166
1H-NMR (CDCI3, 400 MHz) δ 7 69 (1 H, d, J=8 7 Hz), 7 67-7 61
(4H, m), 7 48 (1 H, d, J=15 9 Hz), 7 30 (1 H, d, J=15 9 Hz), 7 25
(1 H, d, J=2 4 Hz), 7 04 (1 H, dd, J=8 7 Hz, J=2 4 Hz), 4 28 (1 H, d, J=17 5 Hz), 4 18 (1 H, d, J=17 5 Hz), 3 91 (3H, s), 3 33 (3H, s)
13C-NMR (CDCI3, 100 6 MHz) δ 161 9, 161 4, 139 7, 135 1 ,
132 8, 130 5 (q, 2JCF=32 4 Hz), 128 0, 127 5, 126 3, 125 4 (q,
1JCF=293 8 Hz), 125 8 (q, 3JCF=3 8 Hz), 124 0 (q, 1JCF=272 0
Hz), 122 8, 1 14 9, 1 12 9, 75 1 (q, 2JCF=27 8 Hz), 55 6, 52 6,
49 6
2 15 g (5 mmoles) of the base obtained is converted to the maleate in the manner described in Example 68 Thus, 1 96 g (72 %) of the yellow title compound are obtained M p 139-140 °C (ethanol-dnsopropyl ether) Analysis for C25H2ιF6N06 (545 44) calculated C 55 05 %, H 3 88 %, N 2 57 %, found C 55 18 %, H 3 80 %, N 2 69 %
IR (KBr, cm 1) 1605, 1335, 1252, 1168
1H-NMR (CDCI3, 400 MHz) δ 8 14 (1 H, d, J=8 8 Hz), 8 04 (1 H, s), 8 00 (1 H, s), 7 81 (1 H, s), 7 74 (2H, d, J=8 4 Hz), 7 60 (1 H, d, J=16 1 Hz), 7 35-7 20 (1 H, m), 7 14 (1 H, s), 6 25 (2H, s), 4 26 (2H, s), 3 92 (3H, s), 3 30 (3H, s)
B) 4,6-Dιmethoxy-4-(trιfluoromethyl)-1 -(4-tπfluoromethyl- styryl)-3,4-dιhydroιsoquιnohnιum chloride
1 29 g (3 mmoles) of the base obtained as described in section
A) are reacted with 0 5 cm3 of 2-propanol containing 25 3 g/100 cm3 (3 6 mmoles) of hydrogen chloride in the manner described in Example 67, section B) Thus, 0 86 g (72 %) of the pale yellow title compound are obtained
M p 234-235 °C (ethanol decomposition)
Analysis for C ιHι8CIF6N02 calculated C 54 15 %, H 3 89 %, Cl 7 61 %, N 3 01 %, found C 53 94 %, H 3 86 %, Cl 7 57 %, N 2 99 %
IR (film, cm 1) 1599, 1423, 1252
1H-NMR (DMSO-d6, 200 MHz) δ 8 56 (1 H, d, J=8 9 Hz), 8 31
(1 H, d, J=16 1 Hz), 8 13 (2H, d, J=8 2 Hz), 7 94 (1 H, d, J=16 1
Hz), 7 90 (2H, d, J=8 2 Hz), 7 43 (1 H, dd, J=8 9 Hz, J=2 4 Hz),
7 26 (1 H, bs), 4 54 (1 H, d, J=16 5 Hz), 4 27 (1 H, d, J=16 5 Hz),
4 03 (3H, s), 3 4 (3H, s)
Example 70
A) 4,6-Dιmethoxy-1 -(4-nιtrostyryl)-4-trιfluoromethyl-3,4- dihydroisoquinolinium maleate
The procedure described in Example 67, section A) is followed starting from 4 24 g (10 mmoles) of N-4-nιtrocιnnamoyl-3,3,3- trιfluoro-2-methoxy-2-(3-methoxyphenyl)propylamιne The crude base is recrystalhzed from hexane Thus, 2 58 g (63 %) of drab coloured 4,6-dιmethoxy-1 -(4-nιtrostyryl)-4-tπfluoro- methyl-3,4-dιhydroιsoquιnohne are obtained M p 146-147 °C (hexane) Analysis for C2oHι2F3N204 (406 36) calculated C 59 11 %, H 4 22 %, N 6 89 %, found C 58 87 %, H 4 24 %, N 6 83 %
IR (KBr, cm 1) 1612, 1514, 1313, 1178 1H-NMR (CDCI3, 200 MHz) δ 8 24 (2H, dd, J=8 8 Hz, J=1 9 Hz), 7 75-7 65 (3H, m), 7 53 (1 H, d, J=15 9 Hz), 7 37 (1 H, d, J=15 9 Hz), 7 25 (1 H, d, J=2 6 Hz), 7 06 (1 H, dd, J=8 3 Hz, J=2 6 Hz), 4 32 (1 H, d, J=17 6 Hz), 4 18 (1 H, d, J=17 7 Hz), 3 92 (3H, s), 3 34 (3H, s)
2 03 g (5 mmoles) of the base obtained are converted to the maleate salt in the manner described in Example 68 Thus,
1 65 g (63 %) of the yellow title compound are obtained
M p 168-170 °C (ethanol-dnsopropyl ether)
Analysis for C24H21F3N208 (522 44) calculated C 55 18 %, H 4 05 %, N 5 36 %, found C 55 32 %, H 4 07 %, N 5 26 %
IR (KBr, cm'1) 1599, 1251 , 1 176
1H-NMR (CDCI3, 200 MHz) δ 8 32 (2H, d, J=8 8 Hz), 7 97 (1 H,
d, J=8 8 Hz), 7 86 (1 H, s), 7 82 (1 H, s), 7 58 (1 H, d, J=16 0 Hz), 7 40-7 37 (1 H, m), 7 27 (1 H, m), 7 25-7 15 (1 H, m), 6 37 (2H, s), 4 33 (2H, d, J=7 4 Hz), 4 03 (3H, s), 3 45 (3H, s)
B) 4,6-Dιmethoxy-1 -(4-nιtrostyryl)-4-trιfluoromethyl-3,4- dihydroisoquinohnium chloride
1 22 g (3 mmoles) of the base obtained as described under section A) are reacted with 0 5 cm3 of 2-propanol containing
25 3 g/100 cm3 (3 6 mmoles) of hydrogen chloride in the manner described in Example 67 section B) Thus, 0 90 g (68
%) of the pale yellow title compound are obtained
M p 245-246 °C (ethanol, decomposition)
Analysis for C20Hι8CIF3N2O4 (442 82) calculated C 54 25 %, H 4 10 %, Cl 8 01 %, N 6 33 % found C 54 14 %, H 4 08 %, Cl 8 07 %, N 6 23 %
IR (film, cm 1) 1 599, 1345, 1250, 1 181
1H-NMR (DMSO-d6, 200 MHz) δ 8 48 (1 H, d, J=8 8 Hz), 8 36
(1 H, d, J=8 8 Hz), 8 24-8 06 (4H, m), 7 97 (1 H, d, J=16 1 Hz),
7 40 (1 H, dd, J=8 8 Hz, J=2 2 Hz), 7 25 (1 H, s), 4 51 (1 H, d,
J=16 5 Hz), 4 02 (1 H, d, J=16 5 Hz), 4 02 (3H, s), 3 38 (3H, s)
Example 71
6,7-Methylenedιoxy-4-methoxy-4-trιfluoromethyl-1-(4-tπfluoro- methylstyryl)-3,4-dιhydroιsoquιnohnιum chloride
The procedure described in Example 67, section A) is followed starting from 4 61 g (10 mmoles) of N-(4-trιfluoromethyl-
cιnnamoyl)-3,3,3-trιfluoro-2-methoxy-2-(3,4-methylenedιoxy- phenyl)propylamιne The crude base is recrystalhzed from hexane Thus, 2 44 g (55 %) of drab coloured 6,7- methylenedιoxy-4-methoxy-4-tπfluoromethyl-1 -(4- trιfluoromethylstyryl)-3,4-dιhydroιsoquιnohne are obtained
M p 87-88 °C (hexane)
Analysis for C2ιH15F6N03 (443 35) calculated C 56 89 %, H 3 41 %, N 3 16 %, found C 56 71 %, H 3 39 %, N 3 22 %
IR (KBr, cm 1) 1579, 1389, 1 167
1H-NMR (CDCI3, 400 MHz) δ 7 70-7 60 (4H, m), 7 46 (1 H, d,
J=15 9 Hz), 7 24 (1 H, d, J=15 9 Hz), 7 19 (1 H, s), 7 18 (1 H, s),
6 15 (11-1, d, J=1 3 Hz), 6 09 (1 H, d, J=1 3 Hz), 4 26 (1 H, d,
J=17 7 Hz), 4 16 (1 H, d J=17 7 Hz), 3 30 (3H, s)
13C-NMR (CDCI3, 100 6 MHz) δ 161 0, 150 1 , 148 9, 139 5,
135 4, 130 6 (q, 2JCF=32 4 Hz), 127 5, 126 1 , 125 7 (q, 3JCF=5 4
Hz), 125 6, 125 3 (q, 1JCF=287 3 Hz), 124 5, 124 0 (q,
1JCF=272 0 Hz), 107 6, 106 4, 102 1 , 75 2 (q, 2JCF=27 5 Hz),
52 4, 49 6
1 33 g (3 mmoles) of the base obtained above are reacted with 0 5 cm3 of 2-propanol containing 25 3 g/100 cm3 (3 6 mmoles) of hydrogen chloride Thus, 1 05 g (73 %) of the pale yellow title compound are obtained M p 248-250 °C (acetone, diisopropyl ether, decomposition) Analysis for C2ιHι6CIF8N03 (479 81)
calculated C 52 57 %, H 3 36 %, Cl 7 39 %, N 2 92 %, found C 52 61 %, H 3 38 %, Cl 7 38 %, N 2 94 %
IR (film, cm"1) 1623, 1514, 1394, 1325, 1 171 , 1 126
1H-NMR (DMSO-d6, 400 MHz) δ 8 15-8 05 (4H, m), 7 90-7 80
(3H, m), 7 32 (1 H, m), 6 37 (1 H, d, J=0 9 Hz), 6 34 (1 H, d, J=0 9
Hz), 4 45 (1 H, d, J=17 0 Hz), 4 24 (1 H, d, J=17 0 Hz), 3 60 (1 H, bs), 3 35 (3H, s)
Example 72
4,6-Dιmethoxy-4-trιfluoromethyl-1 -(2-(4-trιfluoromethylphenyl)- ethyl/-3,4-dιhydroιsoquιnohnιum chloride
The procedure described in Example 67, section A) is followed starting from 1 12 g (2 5 mmoles) of N-/3-(4-trιfluoromethyl- phenyl)propanoyl/-3,3,3-tπfluoro-2-methoxy-2-(3-methoχy- phenyl)propylamιne and 2 0 cm3 (3 36 g, 22 mmoles) of phosphor(V) trichloride oxide The crude base is dissolved in
10 cm3 of diisopropyl ether, and, to the solution formed, 0 4 cm3 of 2-propanol containing 25 3 g/100 cm3 (3 mmoles) of hydrogen chloride are added, drop by drop Thus, 0 96 g (82
%) of the colourless title compound are obtained
M p 185-187 °C (decomposition, ethanol)
Analysis for C21H20CIF6NO2 (467 84) calculated C 53 91 %, H 4 31 %, Cl 7 58 %, N 2 99 %, found C 53 72 %, H 4 30 %, Cl 7 56 %, N 2 97 %
IR (film, cm ') 2494, 1666, 1328, 1252
1H-NMR (DMSO-d6, 400 MHz) δ 8 38 (1 H, d, J=8 8 Hz), 7 66
(2H, d, J=8 5 Hz), 7 59 (2H, d, J=8 5 Hz), 7 36 (1 H, dd, J=8 8 Hz, J=2 4 Hz), 7 20 (11-1, s), 4 42 (1 H, d, J=16 3 Hz), 4 19 (1 H, d, J=16 3 Hz), 3 99 (3H, s), 3 75-3 40 (2H, m), 3 31 (3H, s), 3 20-3 00 (2H, m)
13C-NMR (DMSO-d6, 50 3 MHz) δ 175 0, 166 0, 144 1 , 134 8, 132 8, 129 6, 127 5 (q, 2JCF=31 7 Hz), 125 3 (q, 3JCF=3 8 Hz), 124 5 (q, 1JCF=270 2 HZ), 124 3 (q, 1JCF=287 4 Hz), 118 6, 116 0, 114 2, 74 8 (q, 2JCF=28 2 Hz), 56 7, 52 9, 42 4, 33 4, 33 0
Example 73
1 -/2-(4-Fluorophenyl)ethyl/-4,6-dιmethoxy-4-trιfluoromethyl-3,4- dihydroisoquinolinium chloride
The procedure described in Example 67, section A) is followed starting from 1 00 g (2 5 mmoles) of N-/3-(4-fluorophenyl)- propanoyl/-3,3 3-tπfluoro-2-methoxy-2-(3-methoxyphenyl)- propylamine and 2 0 cm3 of phosphor(V) trichloride oxide The crude base is dissolved in 10 cm3 of diisopropyl ether, and, to the solution formed, 0 4 cm3 of 2-propanol containing 25 3 g/100 cm3 (3 mmoles) of hydrogen chloride are added, drop by drop Thus, 0 86 g (82 %) of the colourless title compound are obtained M p 190-191 °C (ethanol, decomposition) Analysis for C2oH20CIF4N02 (417 84) calculated C 57 49 % H 4 82 %, Cl 8 48 %, N 3 35 %, found C 57 44 %, H 4 83 %, Cl 8 58 %, N 3 42 %
IR (film, cm"1) 1602, 1512 1254 1 177
1H-NMR (DMSO-d6, 400 MHz) δ 8 37 (1 H, d, J=8 6 Hz), 7 40- 7 35 (3H, m), 7 20 (1 H, d, J=2 3 Hz), 7 14 (2H, t, J=8 8 Hz), 4 41 (1 H, d, J=16 7 Hz), 4 20 (1 H, d, J=16 7 Hz), 4 00 (3H, s), 3 70-3 30 (2H, m), 3 31 (3H, s), 3 00-2 85 (2H, m) 13C-NMR (DMSO-d6, 50 3 MHz) δ 175 6, 166 2, 161 2 (d, 1JCF=241 9 Hz), 135 3, 135 0, 132 8, 130 6 (d, 3JCF=8 0 Hz), 124 3 (q, 1 JCF=287 6 Hz), 118 5, 116 1 , 115 3 (d, 2JCF= 21 4 Hz), 114 3, 74 8 (q, 2JCF=28 0 Hz), 56 8, 53 0, 42 1 , 33 5, 33 2
Example 74
6,7-Methylenedιoxy-4-methoxy-4-trιfluoromethyl-1 -/2-(4- trιfluoromethylphenyl)ethyl/-3,4-dιhydroιsoquιπohnιum chloride
The procedure described in Example 67, section A) is followed to obtain the title compound as colourless solids Yield 75 %
M p 196-197 °C (ethanol, decomposition)
Analysis for C2ιHι8CIF6N03 (481 83) calculated C 52 35 %, H 3 77 %, Cl 7 36 %, N 2 91 %, found C 52 16 %, H 3 79 %, Cl 7 33 %, N 2 90 %
IR (film, cm ) 2494, 1666, 1328, 1252
1H-NMR (DMSO-de 400 MHz) δ 7 95 (1 H, s), 7 67 (2H, d,
J=8 2 Hz), 7 58 (2H, d, J=8 2 Hz), 7 28 (1 H, s), 6 34 (2H, d,
J=14 9 Hz), 4 36 (1 H, d J=16 8 Hz), 4 16 (1 H, d, J=16 8 Hz),
3 80-3 35 (2H, m), 3 27 (3H, s), 3 15-2 90 (2H, m)
Example 75
1-/2-(4-Fluorophenyl)ethyl/-6,7-methylenedιoxy-4-methoxy-4- trιfluoromethyl-3,4-dιhydroιsoquιnohnιum chloride
The procedure described in Example 67, section A) is followed to obtain the title compound as colourless solids Yield 80 %
M p 195-196 °C (ethanol, decomposition)
Analysis for C20Hι8CIF4NO3 (431 82) calculated C 55 63 %, H 4 20 %, Cl 8 21 %, N 3 24 %, found C 55 36 %, H 4 24 %, Cl 8 20 %, N 3 27 %
IR (film, cm 1) 1671 , 1608 1512, 1300, 1179
1H-NMR (DMSO-d6, 400 MHz) δ 8 07 (1 H, s), 7 45-7 35 (2H, m), 7 32 (1 H, s), 7 14 (2H, t, J=8 8 Hz), 6 37 (2H, d, J=3 7 Hz),
4 44 (1 H, d, J=17 1 Hz), 4 15 (1 H, d, J=17 1 Hz), 3 70-3 30 (2H, m), 3 30 (3H, s), 3 05-2 95 (2H, m)
13C-NMR (DMSO-d6, 100 6 MHz) δ 175 8, 161 2 (d, 1JCF=242 2
Hz), 155 0, 150 1 , 135 2 (d, 4JCF=3 1 Hz), 130 7 (d, 3JCF=8 0
Hz), 130 6, 127 6, 124 2 (q, 1 JCF=287 6 Hz), 115 2 (d, 2JC =21 0
Hz), 110 8, 104 2, 75 1 (q, 'JCF=28 6 Hz), 52 8, 41 8, 33 8, 33 0
Example 76
1 -/2-(4-Tπfluoromethylphenyl)ethyl/-2-methyl-6,7-methylene- dιoxy-3,4-dιhydroιsoquιnohnιum bromide
6 g (0 0125 moles) of 1-/2-(4-trιfluoromethylphenyl)ethyl/-2- methyl-6,7-methylene-dιoxy-3,4-dιhydroιsoquιnohne are reacted with N-bromosuccinimide in dichloromethane at 0 °C
The reaction mixture is stirred for one hour at room temperature, then allowed to stand for 24 hours, and evaporated To the residue, diethyl ether is added, the precipitated crystals are filtered, recrystalhzed from a mixture of hexane and acetonitnle Thus, 1 5 g (30 %) of the title compound are obtained M p 244-245 °C Analysis for C20Hι9BrF3NO2 (392 27) calculated C 54 31 %, H 4 33 %, Br 18 70 %, N 3 17 %, found C 53 65 %, H 4 35 %, Br 18 21 %, N 3 28 %
1H-NMR (DMSO-d6, 200 MHz) δ 7 67 (1 H, s), 7 64 (2H, d, J=8 Hz), 7 54 (2H, d, J=8 Hz), 7 1 1 (11 H, s), 6 21 (2H, s), 3 95 (2H, t, J=8 Hz), 3 69 (3H, s), 3 49 (2H, t, J=8 Hz), 2 96 (4H, m)
Example 77
1-(2-Phenylethyl)-2-methyl-6,7-methylenedιoxy-3,4-dιl)ydro- isoquinohnium iodide
3 2 g (0 011 moles) of 1 -(2-phenylethyl)-6,7-methylenedιoxy- 3,4-dιhydroιsoquιnolιne are dissolved in 30 cm3 of acetone To the solution formed, 4 cm3 of methyl iodide are added, and the reaction mixture is allowed to stand at room temperature during a night The precipitated yellow crystalline matter is filtered, washed with some cold acetone, then recrystalhzed from acetone Thus, 3 5 g (76 %) of the title compound are obtained M p 180 °C
Analysis for C19H20INO2 (431 28) calculated N 3 32 % found N 3 25 %
1H-NMR (DMSO-d6, 200 MHz) δ. 7.69 (1 H, s), 7 28 (5H, m), 7.11 (1 H, s), 6 23 (2H, s), 3 92 (2H, t, J=7 6 Hz), 3 61 (3H, s), 3.47 (2H, t, J=7 6 Hz), 2 94 (4H, m).
Example 78
1-(4-Trιfluoromethylstyryl)-2-methyl-4-propyl-6,7-methylene- dioxy-3,4-dιhydroιsoquιnolιnιum iodide dihydrate
7.2 g (0 019 moles) of 1 -(4-tπfluoromethylstyryl)-4-propyl-6,7- methylene-dιoxy-3,4-dιhydroιsoquιnolιne are dissolved in 150 cm3 of acetone To the solution formed, 10 cm3 of methyl iodide are poured, and the reaction mixture is allowed to stand at room temperature for a night Then the mixture is evaporated to dryness, and the oily product is crystallized from a mixture of diisopropyl ether and diethyl ether The crystalline crude product is dissolved in 90 cm3 of acetone, precipitated by the addition of 300 cm3 of diisopropyl ether, and filtered. Thus, 1.7 g (16 %) of the title compound are obtained. M.p.- 203-205 °C. Analysis for C23H23F3IN02 (565 38) calculated- C 48 86 %, H 4 81 %, N 2.48 %, found. C 49 08 %, H 4 73 %, N 2 63 %
1H-NMR (DMSO-de, 200 MHz) δ 7 94 (2H, d, J=8 1 Hz), 7.84 (1 H, d, J=16 5 Hz), 7 72 (2H, d, J=8 1 Hz), 7 25 (1 H, d, J=16.5 , Hz), 7.18 (1 H, s), 6 85 (1 H, s), 6 15 (2H, s), 4.40 (1 H, dd, Jι=4.8 Hz, J2=14 7 Hz), 4 02 (3H, s), 3 90 (1 H, dd, ^=4.0 Hz, J2=14.7 Hz), 3.10 (1 H, m), 1 58 (2H, m), 1 44 (2H, m), 0.98 (3H, t, J=7.0 Hz).
Example 79
1 -/2-(4-Tπfluoromethylphenyl)ethyl-2-methyl-7-chloro-3,4- dihydroisoquinohnium iodide
1 7 g (0 005 moles) of 1 -/2-(4-tπfluoromethylρhenyl)ethyl-7- chloro-3,4-dιhydroιsoquιnohne are dissolved in 30 cm3 of acetone To the solution formed, 3 cm3 of methyl iodide are added, and the reaction mixture is allowed to stand at room temperature for 24 hours The mixture is cooled to 0 °C, filtered, and washed with cold acetone Thus, 1 5 g (62 %) of the title compound are obtained M p 224-227 °C Analysis for C19Hι8CIF3IN (479 71 ) calculated C 47 57 %, H 3 78 %, Cl 7 93 %, N 2 92 %, found C 47 26 %, H 3 75 %, Cl 7 11 %, N 2 93 %
1H-NMR (DMSO-d6, 400 MHz) δ 8 02 (1 H, d, J=2 2 Hz), 7 75 (1 H, dd, Jι=2 2 Hz, J2=8 1 Hz), 7 60 (2H, d, J=8 2 Hz), 7 52 (2H, d, J=8 2 Hz), 7 48 (1 H, d, J=8 1 Hz), 4 06 (2H, t, J=7 6 Hz), 3 81 (3H, s), 3 65 (2H, t, J=7 8 Hz), 3 1 1 (2H, t, J=7 6 Hz), 3 06 (2H, t, J=7 8 Hz)
Example 80
1 -/2-(4-Fluorophenyl)ethyl/-2-methyl-6,7-ethylenedιoxy-3,4- dihydroisoquinohnium bromide
8 85 g (27 mmoles) of 1 -/2-(4-fluorophenyl)ethyl/-2-methyl-6,7- ethylenedιoxy-3,4-dιhydroιsoquιnohne are dissolved in 200 cm3 of dichloromethane To the solution formed, 5 34 g (30 mmoles)
of N-bromosuccinimide are added at 0 °C The reaction mixture is stirred at room temperature for 3 hours, then concentrated to the half of the original volume under reduced pressure From the residue, the crude product is precipitated by the addition of cyclohexane, and recrystalhzed from 20 cm3 of isopropanol
Thus, 4 23 g (38 %) of the title compound are obtained
M p 177-180 °C
Analysis for C20H2ιBrFNO2 (406 30) calculated N 3 45 %, found N 3 29 %
1H-NMR (DMSO-de 200 MHz) δ 7 61 (1 H, s), 7 31 (2H, m),
7 11 (2H, m), 6 99 (1 H s), 4 35 (4H, m), 3 95 (2H, t, J=7 4 Hz),
3 66 (3H, s), 3 47 (2H, t, J=7 6 Hz), 2 94 (4H, m)
Example 81
1 -/2-(4-Trιfluoromethylphenyl)ethyl/-2-methyl-6-methoxy-7- hydroxy-3,4-dιhydroιsoquιnolιnιum iodide
2 0 g (6 mmoles) of 1 -/2-(4-trιfluoromethylphenyl)ethyl/-6- methoxy-7-hydroxy-3,4-dιhydroιsoquιnohne are dissolved in 30 cm3 of acetone, and to the solution formed, 5 cm3 of methyl iodide are added The precipitated crystals are filtered, washed with cold ether, dissolved in 350 cm3 of acetone, and precipitated by the addition of ether Thus, 1 87 g (63 ) of the title compound are obtained M p 210-213 °C Analysis for C20H2ιF3INO2 (491 29) calculated C 48 90 %, H 4 31 %, N 2 85 %, found C 48 56 %, H 4 42 %, N 2 96 %
1H-NMR (DMSO-d6, 400 MHz) δ 9 55 (1 H, bs), 7 67 (2H, d, J=8 0 Hz), 7 56 (2H, d, J=8 0 Hz), 7 40 (1 H, s), 7 09 (1 H, s),
3 97 (2H, t, J=7 6 Hz), 3 92 (3H, s), 3 69 (3H, s), 3 41 (2H, t, J=8 0 Hz), 3 02 (4H, t J=8 0 Hz)
Example 82
1 -/2-(4-Trιfluoromethylphenyl)ethyl/-2-methyl-4-propyl-6,7- ethylenedιoxy-3,4-dιhydroιsoquιnohnιum iodide
4 0 g (0 01 moles) of 1 -/2-(4-tπfluoromethylpheπyl)ethyl/-4- propyl-6,7-ethylenedιoxy-3 4-dιhydroιsoquιnohne are dissolved in 80 cm3 of acetone After the addition of 9 g of methyl iodide, the reaction mixture is allowed to stand at room temperature for 24 hours The precipitated quaternary salt is filtered and recrystalhzed from acetone Thus, 3 1 g (56 %) of the title compound are obtained M p 177-180 °C
Analysis for C24H27F3IN02 (545 38) calculated C 52 86 %, H 4 99 %, N 2 57 %, found C 52 73 %, H 5 04 %, N 2 62 %
1H-NMR (CDCI3, 400 MHz) δ 7 55 (2H, d, J=8 1 Hz), 7 34 (2H, d, J=8 1 Hz), 7 29 (1 H s), 6 77 (1 H, s), 4 38 (2H, m), 4 34 (1 H, dd, Jι=5 4 Hz, J2=14 1 Hz), 4 29 (2H, m), 3 83 (3H, s), 3 74 (1 H, dd, Jι=4 8 Hz, J2=14 4 Hz), 3 64 (2H, m), 3 22 (1 H, m), 3 13 (1 H, m), 3 01 (1 H, m), 1 5-1 2 (4H, m), 0 95 (3H, t, J=7 1 Hz)
Example 83
1 -/2-(4-Trιfluoromethylphenyl)ethyl/-2-methyl-6,7- ethylenedιoxy-3,4-dιhydroιsoquιnolinιum iodide
2.8 g (0 0075 moles) of 1 -/2-(4-trιfluoromethylphenyl)ethyl/-6,7- ethylenedιoxy-3,4-dιhydroιsoquιnohne are dissolved in 120 cm3 of acetone To the solution formed, 5 cm3 of methyl iodide are added The reaction mixture is heated under reflux for 1 hour, then cooled with ice water to 0-5 °C and stirred at this temperature for 2 to 3 hours After crystallization, the crystals are filtered, washed with cold acetone, and recrystalhzed from acetone Thus, 2 2 g (58 %) of the title compound are obtained M p 205-207 °C
Analysis for C2ιH2ιF3IN02 (503 30) calculated C 50 12 %, H 4 21 %, N 2 78 %, found C 49 61 %, H 4 25 %, N 2 82 % H-NMR (DMSO-de, 200 MHz) δ 7 64 (2H, d, J=8 3 Hz), 7 58
(1 H, s), 7 52 (2H, d, J=8 3 Hz), 6 96 (1 H, s), 4 33 (2H, m), 3.95
(2H, t, J=7 5 Hz), 3 69 (3H, s), 3 49 (2H, t, J=7 7 Hz), 2.99 (4H, m)
Example 84
1 -/2-(4-Fluorophenyl)ethyl/-2-methyl-6,7-methylenedioxy-3,4- dihydroisoquinohnium bromide
2.9 g (9 mmoles) of 1 -/2-(4-fluoroρhenyl)ethyl/-2-methyl-6,7- methylenedιoxy-3,4-dιhydroιsoquιnohne are dissolved in 70 cm3 of dichloroethane, and to the solution formed, 1 7 g (0.01
moles) of N-bromosuccinimide are added under stirring The reaction mixture is stirred at 0 °C for 3 hours, then evaporated under reduced pressure To the oily residue, ether is added, the mixture is stirred at 0 °C, and the precipitated crystals are filtered Thus, 1 9 g (53 %) of the title compound are obtained M p 191 -193 °C
Analysis for Cι9Hι9BrFN02 (392 27) calculated C 58 18 %, H 4 88 %, Br 20 37 %, N 3 57 %, found C 57 94 %, H 5 13 %, Br 20 59 %, N 3 69 %
1H-NMR (DMSO-d6, 400 MHz) δ 7 68 (1 H, s), 7 31 (2H, m), 7 11 (2H, m), 7 11 (1 H, s), 6 22 (2H, s), 3 93 (2H, t, J=7 7 Hz), 3 64 (3H, s), 3 46 (2H t, J=7 7 Hz), 2 98 (2H, t, J=7 7 Hz), 2 91 (2H, t, J=7 7 Hz)
Example 85
1-(4-Fluorostyryl)-2-methyl-6,7-methylenedιoxy-3,4-dιhydro- isoquinohnium bromide
To a solution of 4 39 g (0 0125 moles) of 1 -(4-fluorostyryl)-2- methyl-6,7-methylenedιoxy-1 ,2,3,4-tetrahydroιsoquιnolιne in 100 cm3 of dichloromethane, 4 6 g (0 025 moles) of N- bromosuccinimide are added at O CC, and the reaction mixture is stirred at room temperature for 3 hours Then the mixture is evaporated to dryness under reduced pressure, and, to the residue, acetonitnle is added The crystalline matter is filtered and recrystalhzed from acetonitnle Thus, 3 1 g (63 %) of the title compound are obtained M p 215-218 °C Analysis for Cι9Hι7BrFN02 (390 27)
calculated C 58 48 %, H 4 39 %, Br 20 48 %, N 4 39 %, found C 57 70 %, H 4 36 %, Br 20 12 %, N 4 60 %
1H-NMR (CDCI3, 250 MHz) δ 7 8-7 9 (2H, m), 7 65 (1 H, d, J=16 3 Hz), 7 18 (1 H, d, J=16 3 Hz), 7 08-7 15 (3H, m), 6 88 (1 H, s), 6 13 (21-1, s), 4 14 (2H, t, J=7 5 Hz), 4 07 (3H, s), 3 25 (2H, t, J=7 5 Hz)
Example 86
1-(4-Trιfluoromethylstyryl)-2-methyl-6,7-methylenedιoxy-3,4- dihydroisoquinohnium bromide
4 8 g (0 0135 moles) of 1 -(4-trιfluoromethylstyryl)-2-methyl-6,7- methylenedιoxy-3,4-dιhydroιsoquιnohne are dissolved in 100 cm3 of dichloromethane To the solution cooled to 0 °C, 2 5 g (0 0141 moles) of N-bromosuccinimide are added under stirring The reaction mixture is stirred at 0 °C for 1 hour, and at room temperature for further 2 hours The precipitated crystals are filtered and washed with some dichloromethane The crude product is recrystalhzed from a mixture (1 1 ) of ether and ethanol Thus, 2 4 g (41 %) of the title compound are obtained M p 213 °C
Analysis for C20Hι7BrF3NO3 (440 26) calculated C 54 56 % H 3 39 %, Br 17 76 %, N 3 18 %, found C 54 20 %, H 4 00 %, Br 17 70 %, N 3 11 % H-NMR (CDCI3, 250 MHz) δ 7 95 (2H, d, J=8 2 Hz), 7 83 (1 H, d, J=16 4 Hz), 7 69 (2H, d, J=8 2 Hz), 7 23 (1 H, d, J=16 4 Hz), 7 11 (1 H, s), 6 87 (1 H s), 6 13 (2H, s), 4 22 (2H, t, J=7 5 Hz),
4 08 (3H, s), 3 27 (2H, t, J=7 5 Hz)
Example 87
1 -/2-(4-Fluorophenyl)ethyl/-2-methyl-6,7-methylenedιoxy-3,4- dihydroisoquinohnium iodide
3 12 g (0 01 moles) of 1 -/2-(4-fluorophenyl)ethyl/-6,7- methylenedιoxy-3,4-dιhydroιsoquιnohne are dissolved in 30 cm3 of nitromethane To the solution formed, 7 76 g of methyl iodide are added, and the reaction mixture is stirred at 120 °C for 4 hours, then cooled to room temperature, and 50 cm3 of ether are added to precipitate the product The crystals are filtered, washed with ether, and recrystalhzed from acetone Thus, 3 6 g (82 %) of the title compound are obtained M p 197-198 °C
Analysis for Cι9Hι9FIN02 (439 272) calculated C 51 95 % H 4 36 %, N 3 19 %, found C 51 66 %, H 4 32 %, N 3 09 %
1H-NMR (DMSO-d6, 400 MHz) δ 7 68 (1 H, s), 7 32 (2H, m), 7 12 (2H, m), 7 1 1 (1 H, s), 6 23 (2H, s), 3 94 (2H, t, J=7 7 Hz), 3 64 (3H, s) 3 46 (2H, t, J=7 8 Hz), 3 00 (2H, t, J=7 8 Hz), 2 91 (2H, t, J=7 8 Hz)
Claims
Claims
1 An isoquinohne derivative of the formula
wherein
Ri, R2 and R3 represent, independently, a hydrogen atom, a halo atom, a hydroxy group or a Cι-4 alkoxy group, or Ri forms with R2 a methylenedioxy group or an ethylenedioxy group, R4 stands for a hydrogen atom, a Cι-4 alkoxy group or a tnfluoromethyl group R7 means a hydrogen atom or a Cι-4 alkyl group, R8 is a hydrogen atom or a Cι-4 alkyl group, Rs, Re, R9 represent, independently, a hydrogen atom, or R5 forms with R6 a valence bond, and simultaneously R8 forms with R9 a valence bond, R10 and Rn represent, independently, a hydrogen atom, a halo atom, a πitro group, a Cι_ alkoxy group, a tnfluoromethyl group or a cyano group, Xi and X2 mean, independently, a hydrogen atom, or
XT forms with X2 a valence bond, furthermore a pharmaceutically suitable acid addition salt thereof and a quaternary derivative of the formula
wherein
Ri, 2, R3, R4, R5, Rε, R7, Re, 9, R10, R11, Xi and X2 are as defined above,
R's stands for a Cι-4 alkyl group, and
A represents a residue of an inorganic or organic acid of the formula HA,
or, in formula I,
Ri and R2 are as stated above,
R3, R6 and R7 represent, independently, a hydrogen atom,
R8 forms with R9 a valence bond,
R4 stands for a hydrogen atom, a C1-4 alkoxy group or a d-β alkyl group, R5 means a hidrogen atom or a tnfluoromethyl group, R10 and Rn represent, independently, a hydrogen atom, a halo
atom, a nitro group, a Cι- alkoxy group or a tnfluoromethyl group,
Xi and X2 mean, independently, a hydrogen atom, or
Xi forms with X2 a valence bond, furthermore a pharmaceutically suitable acid addition salt thereof,
or, in formula I",
Ri and R2 are as stated above
R3, R5, Re and R7 represent, independently, a hydrogen atom,
R8 forms with R9 a valence bond,
R stands for a hydrogen atom or a Cι-6 alkyl group,
R10 and Rn represent, independently, a hydrogen atom, a halo atom, a Cι-4 alkoxy group or a tnfluoromethyl gro,up, Xi and X2 mean, independently, a hydrogen atom, or Xi forms with X2 a valence bond R's represents a Cι-4 alkyl group, and
A represents a residue of an inorganic or organic acid of the formula HA
2 A 1 ,2,3,4-tetrahydroιsoquιnohne derivative of the formula la as claimed in Claim 1 ,
wherein
Ri, R2 and R3 represent, independently, a hydrogen atom, a halo atom, a hydroxy group or a Cι.4 alkoxy group, or Ri forms with R2 a methylenedioxy group or an ethylenedioxy group, R4 stands for a hydrogen atom or a Cι-4 alkoxy group, R7 means a hydrogen atom or a Cι-4 alkyl group, R8 is a hydrogen atom or a C1-4 alkyl group, R10 and Rn represent, independently, a hydrogen atom, a halo atom, a Cι-4 alkoxy group or a tnfluoromethyl group, Xi and X2 mean, independently, a hydrogen atom, or Xi forms with X2 a valence bond, furthermore a pharmaceutically suitable acid addition salt thereof and a quaternary derivative of the formula
wherein
Ri, R2, R3, R4, R5, e, R7, Re, Θ, R10, R11, Xi and X2 are as defined above,
R's stands for a C1- alkyl group, and
A represents a residue of an inorganic or organic acid of the formula HA
3 A 1 ,2,3,4-tetrahydroιsoquιnohne derivative of the formula la as claimed in Claim 2, wherein
Ri and R2 represent, independently, a methoxy group, or Ri forms with R2 a methylenedioxy group or an ethylenedioxy group, R3 stands for a hydrogen atom, R4 means a hydrogen atom, R7 is a hydrogen atom,
R8 represents a hydrogen atom or a methyl group, R10 stands for a halo atom, a tnfluoromethyl group or a methoxy group, Rn means a hydrogen atom or a methoxy group,
Xi and X2 mean, independently, a hydrogen atom or
Xi forms with X2 a valence bond, furthermore a pharmaceutically suitable acid addition salt thereof and a quaternary derivative of the formula I'a, wherein
Ri, R2, 3, R4, R5, e, R7, e, R9, R10, 111 Xi and X2 are as defined above,
R's stands for a methyl group, and
A represents a hahde ion
4 An isoquinohne derivative of the formula
as claimed in Claim 1 , wherein
Ri, R2 and R3 represent, independently, a hydrogen atom, a halo atom, a hydroxy group or a Cι- alkoxy group, or Ri forms with R2 a methylenedioxy group or an ethylenedioxy group, R4 stands for a hydrogen atom a Cι- alkoxy group or a tnfluoromethyl group, R7 means a hydrogen atom or a Cι-4 alkyl group, R10 and Rn represent, independently, a hydrogen atom, a halo
atom, a nitro group, a Ci 4 alkoxy group, a tnfluoromethyl group or a cyano group, Xi and X2 mean, independently, a hydrogen atom, or Xi forms with X2 a valence bond, furthermore a pharmaceutically suitable acid addition salt thereof and a quaternary derivative of the formula
wherein
Ri, R2, R3, R , R7, R10, R11, Xi and X2 are as defined above,
R's stands for a Cι-4 alkyl group, and
A represents a residue of an inorganic or organic acid of the formula HA
5 An isoquinohne derivative of the formula lb as claimed in
Claim 4, wherein
Ri, R2 and R3 represent, independently, a hydrogen atom or a methoxy group, or Ri forms with R2 a methylenedioxy group or an ethylenedioxy group, R4 stands for a hydrogen atom, a Cι-4 alkoxy group or a
tnfluoromethyl group, R7 means a hydrogen atom or a methyl group, R10 represent a hydrogen atom, a halo atom, a nitro group, a methoxy group, a tnfluoromethyl group or a cyano group, Rn is a hydrogen atom or a methoxy group, Xi and X2 mean, independently, a hydrogen atom, or Xi forms with X2 a valence bond, furthermore a pharmaceutically suitable acid addition salt thereof and a quaternary derivative of the formula I'b, wherein Ri, R2, R3, R4, R7, R10, R11, Xi and X2 are as defined above, R's stands for a methyl group, and A represents a hahde ion
6 A 3,4-dιhydroιsoquιnohne derivative of the formula
as claimed in Claim 1 , wherein
Ri and R2 represent, independently, a hydrogen atom, a halo atom, a hydroxy group or a Cι-4 alkoxy group, or Ri forms with R2 a methylenedioxy group or an ethylenedioxy group,
R4 stands for a hydrogen atom, a C1-4 alkoxy group or a Cι-6 alkyl group
R5 means a hydrogen atom or a tnfluoromethyl group,
R10 and Rn represent, independently, a hydrogen atom, a halo atom, a nitro group, a Cι.4 alkoxy group or a tnfluoromethyl group,
Xi and X2 mean, independently, a hydrogen atom, or
Xi forms with X2 a valence bond, furthermore a pharmaceutically suitable acid addition salt thereof
7 A 3,4-dιhydroιsoquιnolιne derivative of the formula XIV as claimed in Claim 6, wherein
Ri and R represent, independently, a hydrogen atom, a chloro atom, a hydroxy group or a methoxy group, or ,
Ri forms with R2 a methylenedioxy group or an ethylenedioxy group,
R stands for a hydrogen atom or a Cι-6 alkyl group,
R5 means a hydrogen atom,
Rio and Rn represent, independently, a hydrogen atom, a fluoro atom, a methoxy group or a tnfluoromethyl group,
Xi and X2 mean, independently, a hydrogen atom, or
Xi forms with X2 a valence bond, furthermore a pharmaceutically suitable acid addition salt thereof
8 A 3,4-dιhydroιsoquιnohne derivative of the formula XIV as claimed in Claim 7, wherein
RT forms with R2 a methylenedioxy group,
R4 stands for a Cι-6 alkyl group,
R5 means a hydrogen atom or a tnfluoromethyl group,
R10 and Rn represent, independently, a hydrogen atom, a methoxy group or a tnfluoromethyl group, Xi forms with X2 a valence bond, furthermore a pharmaceutically suitable acid addition salt thereof
9 A 3,4-dιhydroιsoquιnolιnιum derivative of the formula
as claimed in Claim 1 , wherein
Ri and R2 represent, independently, a hydrogen atom, a halo atom, a hydroxy group or a Cι-4 alkoxy group, or Ri forms with R2 a methylenedioxy group or an ethylenedioxy group, R4 stands for a hydrogen atom or a Cι-6 alkyl group R's means a Cι-4 alkyl group, R-io and Rn represent, independently, a hydrogen atom, a halo atom, a Cι- alkoxy group or a tnfluoromethyl group,
X1 and X2 mean, independently, a hydrogen atom, or
X1 forms with X2 a valence bond,
A represents a residue of an inorganic or organic acid of the formula HA
10 A 3,4-dιhydroιsoquιnohnιum derivative of the formula XI as claimed in Claim 9, wherein
R1 and R2 represent, independently, a hydroxy group, a chloro atom or a methoxy group, or R! forms with R2 a methylenedioxy group or an ethylenedioxy group, R4 stands for a hydrogen atom or a Cι-3 alkyl group, R's means a methyl group, Rio and Rn represent, independently, a hydrogen atom, a halo atom or a tnfluoromethyl group, Xi and X2 mean, independently, a hydrogen atom, or Xi forms with X2 a valence bond, A represents a residue of an inorganic acid of the formula HA
11 A 3,4-dιhydroιsoquιnohnιum derivative of the formula XI as claimed in Claim 10, wherein
Ri forms with R2 a methylenedioxy group or an ethylenedioxy group, R4 stands for a hydrogen atom or a Cι-3 alkyl group, R's means a methyl group R10 and R represent, independently, a hydrogen atom, a fluoro atom or a tnfluoromethyl group, and X2 mean, independently, a hydrogen atom, or
Xi forms with X2 a valence bond,
A represents a bromide ion or a iodide ion.
12 A process for the preparation of an isoquinohne derivative of the formula I, wherein Ri, R2, R3, R4, R5, R6, R7, R8, R9, Rι0, Rn, Xi and X2 are as defined in Claim 1 , or a pharmaceutically suitable acid addition salt thereof or a quaternary derivative of the formula I', wherein R1 t R2, R3, R4, R5, R6, R7, Rs, R9, R10, Rn, Xi and X2 are as stated above, R'8 and A are as defined in Claim 1 , characterized by a) for the preparation of an isoquinohne derivative of the formula lb, wherein Ri R2, R3, R4, R7, R10 and Rn are as defined in connection with formula I, X forms with X2 a valence bond, condensing a 1 -methyhsoquιnolιne of the formula
wherein R1 ( R2, R3, R and R7 are as stated above, with an aldehyde of the formula
wherein R10 and Rn are as defined in connection with formula I;
or
b) for the preparation of an isoquinohne derivative of the formula lb, wherein Ri, R2, R3, R4, R7, R10 Rn, Xi and X2 are as defined in connection with formula I, subjecting a 3,4- dihydroisoquinohne derivative of the formula
wherein Ri, R2, R3, R4, R7, R10 Rn, Xi and X2 are as stated above, R 3 stands for a hydrogen atom, to catalytical dehydrogenation, or
c) for the preparation of a 1 ,2,3,4-tetrahydroιsoquιnohne derivative of the formula la, wherein Ri, R2, R3, R4, R7, R10 Rn, X1 and X2 are as defined in connection with formula I, R8 represents a hydrogen atom, hydrogenizing a 3,4- dihydroisoquinolme derivative of the formula IV, wherein Ri, R2, R3, R4, R7, R10 R11, Xi and X2 are as stated above, R13 stands for a hydrogen atom or
d) for the preparation of a 1 ,2,3,4-tetrahydroιsoquιnohne derivative of the formula la, wherein Ri, R2, R3, R , R7, Rio Rn, Xi and X2 are as defined in connection with formula I, R8 represents a Cι- alkyl group, reacting a 3,4-dιhydro- isoquinohmum derivative of the formula
wherein R1 ( R2, R3, R4, R7, R10 Rn, Xi and X2 are as stated above, R12 stands for a Ci 4 alkyl group, A is as defined in connection with formula I', with a reducing agent, or
e) for the preparation of an isoquinohne derivative of the formula lb, wherein Ri, R2, R3, R7, Rio Rn, Xi and X2 are as defined in connection with formula I, R4 stands for a tnfluoromethyl group, reacting a 3,4-dιhydroιsoquιnolιne derivative of the formula IV, wherein R-j, R2, R3, R4, R7, Rio, Rn, Xi and X2 are as stated above, R13 represents a Cι-4 alkoxy group, with an alkali metal hydroxide, or
f) for the preparation of an isoquinohne derivative of the formula lb, wherein Ri, R2, R3, R7, Rι0 and R are as defined in connection with formula I, R4 stands for a tnfluoromethyl group, X! forms with X2 a valence bond, reacting a 1 -methyl-3,4- dihydroisoquinoline of the formula
wherein Ri, R2, R3, R4 and R7 are as stated above, R13 stands for a Cι-4 alkyl group, with an aldehyde of the formula III, wherein Rι0 and Rn are as stated above, in the presence of a condensing agent, or
g) for the preparation of a 3,4-dιhydroιsoquιnohne derivative of the formula XIV, wherein Ri, R2, R4, R5, Rι0, Rn, Xi and X2 are as defined in connection with formula I, cychzing an acid amide of the formula
wherein Ri, R2, R4, Rι0, Rn, Xi and X2 are as stated above, R3 stands for a hydrogen atom, and R 3 represents a hydrogen atom or a tnfluoromethyl group; or
h) for the preparation of a 3,4-dιhydroιsoquinolinium derivative of the formula XI, wherein Ri, R2, R4, R'8, R10, Rn, Xi and X2 are as defined in connection with formula I, A represents a residue of an inorganic acid of the formula HA, reacting a 3,4- dihydroisoquinohne derivative of the formula
wherein Ri, R2, R4, Rι0, Rn, Xi and X2 are as defined above, with a reagent of the formula R'8-A, wherein R'8 and A are as stated above, or
i) for the preparation of a 3,4-dιhydroιsoquinolinium derivative of the formula XI, wherein R R2, R4, R'8, Rio, Rn, Xi and X2 are as defined in connection with formula I, A represents a residue of an inorganic acid of the formula HA, reacting a 1 ,2,3,4- tetrahydroisoquinohnium derivative of the formula
wherein Ri, R2, R4, R's, R10, Rn, Xi and X2 are as stated above, with an oxidizing agent,
and, if desired,
converting an obtained compound of the formula I, wherein Ri, R2, Rs, R4, R5, Re, R7, s 9, R10 and Rn, are as defined in connection with formula I, Xi forms with X2 a valence bond, to a corresponding compound of the formula I, wherein Xi and X2 represent a hydrogen atom, by catalytical hydrogenation, or
converting an obtained 1 ,2,3,4-tetrahydroιsoquιnohne derivative of the formula la wherein Ri, R2, R3, R4, R7, R10, Rn, X1 and X2 are as defined in connection with formula I, R8 stands for a hydrogen atom, to a compound of the formula la, wherein _ R8 represents a Cι-4 alkyl group, by reaction with a Cι-4 alkyl hahde, or
converting an obtained compound of the formula I to a pharmaceutically suitable acid addition salt or liberating the
base from the salt, or
converting an obtained compound of the formula I to a quaternary derivative of the formula I', wherein R^ R2, R3, R4, Rs, Re, R7, Rs, R9, R10, R11, Xi and X2 are as defined in connection with formula I, R'8 represents a C1-4 alkyl group, A stands for a residue of an inorganic or organic acid of the formula HA, by reaction with a compound of the formula R's-A, wherein R'8 and A are as stated above, or
converting an obtained quaternary isoquinohne derivative of the formula I'b, wherein Ri, R2, R3, R4, R7, R10, Rn, Xi and X2 are as defined in connection with formula I, R'8 stands for a Cι- alkyl group, A represents a residue of an inorganic or organic acid of the formula HA, to a compound of the formula la, wherein Ri, R2, R3, R4, R , R10, Rn, Xi and X2 are as stated above, R8 stands for a Cι.4 alkyl group, by reaction with a reducing agent
13 A pharmaceutical composition comprising an isoquinohne derivative of the formula I, wherein Ri, R2, R3, R4, R5, Re, R7, Rs, R9, R10, R11, Xi and X2 are as defined in Claim 1 , or a pharmaceutically suitable acid addition salt thereof or a quaternary derivative of the formula I', wherein Ri, R2, R3, R , R5, Re, R7, Rs, R9, R10, R11, Xi and X2 are as stated above, R'8 and A are as defined in Claim 1 , as the active ingredient and one or more conventional carner(s)
14 A pharmaceutical composition as claimed in Claim 13 comprising a 1 ,2,3,4-tetrahydroιsoquιnohne derivative of the formula la, wherein R R2, R3, R4, R7, R8, Rio, Rn, Xi and X2 are as defined in Claim 2, or a pharmaceutically suitable acid addition salt thereof or a quaternary derivative of the formula I', wherein Ri, R2, R3, R4, R7, Rs, R10, Rn, Xi and X2 are as stated above, R'8 and A are as defined in Claim 2, as the active ingredient
15 A pharmaceutical composition as claimed in Claim 13 comprising an isoquinohne derivative of the formula lb, wherein Ri, R2, R3, R4, R7, R10, R11, Xi and X2 are as defined in Claim 4, or a pharmaceutically suitable acid addition salt thereof or a quaternary derivative of the formula I'b, wherein R^ R2, R3, R4, R7, R10, R11, Xi and X2 are as stated above, R'8 and A are as defined in Claim 4 as the active ingredient
16 A pharmaceutical composition as claimed in Claim 13 comprising a 3 4-dιhydroιsoquιnohne derivative of the formula XIV, wherein Ri, R2l R4, R5, R10l Rn, Xi and X2 are as defined in Claim 6 or a pharmaceutically suitable acid addition salt thereof as the active ingredient
17 A pharmaceutical composition as claimed in Claim 13 comprising a 3,4-dιhydroιsoquιnohnιum compound of the formula XI, wherein R1 τ R2, R4, R'8, R10, Rn, Xi, X2 and A are as defined in Claim 9, as the active ingredient
18 A method of treatment in which a patient suffering from especially a disease of the central nervous system is treated with a non-toxic dose of an isoquinohne derivative of the formula I, wherein Ri, R2, R3, R4, R5, Re, R7, Rs, R9, R10, Rn, Xi and X2 are as defined in Claim 1 , or a pharmaceutically suitable acid addition salt thereof or a quaternary derivative of the formula I', wherein R-,, R2, R3, R4, R5, R6, R7, Rs, R9, R10, Rn, Xi and X2 are as stated above, R'8 and A are as defined in Claim
1
19 A process for the preparation of a pharmaceutical composition having especially anxiolytic effect, in which an isoquinohne derivative of the formula I, wherein Ri. R2, R3l R4, R5, Re, R7, Rs, R9, R10, R11, Xi and X2 are as defined in Claim 1 , or a pharmaceutically suitable acid addition salt thereof or a quaternary derivative of the formula I', wherein R^ R2, R3, R4, R5, Re, R7, Rs, Rg, R10, R11, Xi and X2 are as stated above, R'8 and A are as defined in Claim 1 , is converted to a pharmaceutical composition using one or more conventional carner(s)
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU9902590 | 1999-07-29 | ||
| HU9902592A HUP9902592A3 (en) | 1999-07-29 | 1999-07-29 | Isoquinoline derivatives, pharmaceutical compositions containing such active ingredients and process for producing them |
| HU9902590A HUP9902590A3 (en) | 1999-07-29 | 1999-07-29 | 3,4-dihydro isoquinolinium derivatives, pharmaceutical compositions containing them and process for producing them |
| HU9902591A HUP9902591A3 (en) | 1999-07-29 | 1999-07-29 | 3,4-dihydro isoquinolinium derivatives, pharmaceutical compositions containing such active ingredients and process for producing them |
| HU9902591 | 1999-07-29 | ||
| HU9902592 | 1999-07-29 | ||
| PCT/HU2000/000087 WO2001009101A1 (en) | 1999-07-29 | 2000-07-28 | Isoquinoline derivatives, pharmaceutical compositions containing the same, and a process for the preparation of the active substance |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1200410A1 true EP1200410A1 (en) | 2002-05-02 |
Family
ID=89998920
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP00949830A Withdrawn EP1200410A1 (en) | 1999-07-29 | 2000-07-28 | Isoquinoline derivatives, pharmaceutical compositions containing the same, and a process for the preparation of the active substance |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP1200410A1 (en) |
| JP (1) | JP2003506358A (en) |
| AU (1) | AU6308900A (en) |
| CZ (1) | CZ2002342A3 (en) |
| PL (1) | PL352041A1 (en) |
| SK (1) | SK1212002A3 (en) |
| WO (1) | WO2001009101A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MXPA03000966A (en) * | 2002-02-28 | 2003-09-04 | Pfizer Prod Inc | Antidiabetic agents. |
| PE20121403A1 (en) | 2009-06-26 | 2012-11-02 | Sanofi Sa | NEW SMOKING SALTS FROM A HISTAMINE H3 RECEPTOR ANTAGONIST |
| AU2019309942A1 (en) * | 2018-07-23 | 2021-02-18 | Ohio State Innovation Foundation | Derivatives of papaverine that are effective hypoxic tumor radiosensitizers |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH410007A (en) * | 1961-04-21 | 1966-03-31 | Hoffmann La Roche | Process for the preparation of tertiary amines |
| DE1902402A1 (en) * | 1968-05-21 | 1969-11-27 | Dresden Arzneimittel | 1-subst 6 7-dimethoxy-isoquinolines inhibitors of |
| DE1902559A1 (en) * | 1968-07-05 | 1970-03-26 | Dresden Arzneimittel | 1-substd-3 4-dihydro-6 7-dimethoxy-isoquinolines |
| GB1181959A (en) * | 1969-01-30 | 1970-02-18 | Dresden Arzneimittel | 6,7-Dimethoxy-3,4-Dihydroisoquinoline Derivatives |
| GB8419658D0 (en) * | 1984-08-01 | 1984-09-05 | Wellcome Found | Nitrogen containing heterocyclic compounds |
| HUT71407A (en) * | 1994-05-03 | 1995-11-28 | Egyt Gyogyszervegyeszeti Gyar | Heterocyclic compounds, pharmaceutical compositions containing them, and process for producing the active components |
| EP0787493A1 (en) * | 1996-02-03 | 1997-08-06 | F. Hoffmann-La Roche Ag | Tetrahydroisoquinoline derivatives |
-
2000
- 2000-07-28 AU AU63089/00A patent/AU6308900A/en not_active Abandoned
- 2000-07-28 WO PCT/HU2000/000087 patent/WO2001009101A1/en not_active Application Discontinuation
- 2000-07-28 EP EP00949830A patent/EP1200410A1/en not_active Withdrawn
- 2000-07-28 CZ CZ2002342A patent/CZ2002342A3/en unknown
- 2000-07-28 SK SK121-2002A patent/SK1212002A3/en unknown
- 2000-07-28 JP JP2001514304A patent/JP2003506358A/en active Pending
- 2000-07-28 PL PL00352041A patent/PL352041A1/en unknown
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| Title |
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| See references of WO0109101A1 * |
Also Published As
| Publication number | Publication date |
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| JP2003506358A (en) | 2003-02-18 |
| CZ2002342A3 (en) | 2002-06-12 |
| WO2001009101A1 (en) | 2001-02-08 |
| PL352041A1 (en) | 2003-07-28 |
| AU6308900A (en) | 2001-02-19 |
| SK1212002A3 (en) | 2002-11-06 |
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