AU597719B2 - Naphthalene and indan derivatives - Google Patents
Naphthalene and indan derivatives Download PDFInfo
- Publication number
- AU597719B2 AU597719B2 AU78297/87A AU7829787A AU597719B2 AU 597719 B2 AU597719 B2 AU 597719B2 AU 78297/87 A AU78297/87 A AU 78297/87A AU 7829787 A AU7829787 A AU 7829787A AU 597719 B2 AU597719 B2 AU 597719B2
- Authority
- AU
- Australia
- Prior art keywords
- group
- formula
- dimethoxy
- ethyl
- hydroxy
- 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.)
- Ceased
Links
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 title abstract description 18
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical class C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 70
- 239000002253 acid Substances 0.000 claims abstract description 32
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 8
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 7
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 7
- 150000007524 organic acids Chemical class 0.000 claims abstract description 7
- -1 nitro, amino Chemical group 0.000 claims description 128
- 239000000460 chlorine Chemical group 0.000 claims description 37
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims description 31
- 239000001257 hydrogen Substances 0.000 claims description 31
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 28
- 125000000217 alkyl group Chemical group 0.000 claims description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical group ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 14
- 229910052801 chlorine Inorganic materials 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 13
- 125000005843 halogen group Chemical group 0.000 claims description 12
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 7
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- 125000001589 carboacyl group Chemical group 0.000 claims description 6
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 6
- 125000002071 phenylalkoxy group Chemical group 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 4
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 4
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 4
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 4
- 238000006264 debenzylation reaction Methods 0.000 claims description 4
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 4
- 208000031225 myocardial ischemia Diseases 0.000 claims description 4
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 208000007888 Sinus Tachycardia Diseases 0.000 claims description 3
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 3
- 150000002440 hydroxy compounds Chemical class 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- 125000006557 (C2-C5) alkylene group Chemical group 0.000 claims description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 2
- 239000005977 Ethylene Substances 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000005085 alkoxycarbonylalkoxy group Chemical group 0.000 claims description 2
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000005159 cyanoalkoxy group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims 2
- 102100025027 E3 ubiquitin-protein ligase TRIM69 Human genes 0.000 claims 1
- 101000830203 Homo sapiens E3 ubiquitin-protein ligase TRIM69 Proteins 0.000 claims 1
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims 1
- YDHSVUHYSNSMFM-UHFFFAOYSA-N n-[2-(3,4-dimethoxyphenyl)ethyl]-3-(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-n-methylpropan-1-amine Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC1CC2=CC(OC)=C(OC)C=C2CC1 YDHSVUHYSNSMFM-UHFFFAOYSA-N 0.000 claims 1
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims 1
- 235000005985 organic acids Nutrition 0.000 abstract description 5
- 230000000144 pharmacologic effect Effects 0.000 abstract description 4
- 125000003392 indanyl group Chemical class C1(CCC2=CC=CC=C12)* 0.000 abstract 1
- 125000001424 substituent group Chemical group 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 88
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 76
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 70
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 57
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 40
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- 239000000203 mixture Substances 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- 239000000243 solution Substances 0.000 description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 23
- 239000002904 solvent Substances 0.000 description 23
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 230000000694 effects Effects 0.000 description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 17
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 14
- 239000003826 tablet Substances 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- 239000012965 benzophenone Substances 0.000 description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 12
- 239000012280 lithium aluminium hydride Substances 0.000 description 12
- 239000013543 active substance Substances 0.000 description 11
- 230000007935 neutral effect Effects 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
- 235000019341 magnesium sulphate Nutrition 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 6
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- 238000009835 boiling Methods 0.000 description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical class C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 150000007530 organic bases Chemical group 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 5
- HNJWKRMESUMDQE-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-n-methylethanamine Chemical compound CNCCC1=CC=C(OC)C(OC)=C1 HNJWKRMESUMDQE-UHFFFAOYSA-N 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 4
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 239000008120 corn starch Substances 0.000 description 4
- 229960004132 diethyl ether Drugs 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 229940093915 gynecological organic acid Drugs 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000000600 sorbitol Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- 239000011975 tartaric acid Substances 0.000 description 4
- 235000002906 tartaric acid Nutrition 0.000 description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- MMBOUFXPBUASEF-UHFFFAOYSA-N 2-[3-[2-(3,4-dimethoxyphenyl)ethyl-methylamino]propyl]-5,6-dimethoxy-2,3-dihydro-1h-inden-1-ol Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC1C(O)C2=CC(OC)=C(OC)C=C2C1 MMBOUFXPBUASEF-UHFFFAOYSA-N 0.000 description 3
- LIRAMCXRJJDURG-UHFFFAOYSA-N 3-(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-n-methylpropan-1-amine Chemical compound COC1=C(OC)C=C2CC(CCCNC)CCC2=C1 LIRAMCXRJJDURG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 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
- 238000001816 cooling Methods 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-M fumarate(1-) Chemical compound OC(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-M 0.000 description 3
- 229940116364 hard fat Drugs 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical group CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 description 2
- XSWLYTXTDXAZHF-UHFFFAOYSA-N 3-(5,6-dimethoxy-3-oxo-1,2-dihydroinden-2-yl)-n-[2-(3,4-dimethoxyphenyl)ethyl]-n-methylpropanamide Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)C(=O)CCC1C(=O)C2=CC(OC)=C(OC)C=C2C1 XSWLYTXTDXAZHF-UHFFFAOYSA-N 0.000 description 2
- CDVNLMGHEAPIPB-UHFFFAOYSA-N 5,6-dimethoxy-2-[3-[2-(4-methoxyphenyl)ethyl-methylamino]propyl]-2,3-dihydro-1h-inden-1-ol Chemical compound C1=CC(OC)=CC=C1CCN(C)CCCC1C(O)C2=CC(OC)=C(OC)C=C2C1 CDVNLMGHEAPIPB-UHFFFAOYSA-N 0.000 description 2
- 229910015900 BF3 Inorganic materials 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
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- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- BZLLBZROWJVDKB-UHFFFAOYSA-N [4-[2-[3-(1-hydroxy-6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propyl-methylamino]ethyl]phenyl] methanesulfonate Chemical compound OC1C=2C=C(OC)C(OC)=CC=2CCC1CCCN(C)CCC1=CC=C(OS(C)(=O)=O)C=C1 BZLLBZROWJVDKB-UHFFFAOYSA-N 0.000 description 1
- JFBZPFYRPYOZCQ-UHFFFAOYSA-N [Li].[Al] Chemical compound [Li].[Al] JFBZPFYRPYOZCQ-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- ZZCNKSMCIZCVDR-UHFFFAOYSA-N barium(2+);dioxido(dioxo)manganese Chemical compound [Ba+2].[O-][Mn]([O-])(=O)=O ZZCNKSMCIZCVDR-UHFFFAOYSA-N 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
- 230000004071 biological effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000002213 calciumantagonistic effect Effects 0.000 description 1
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- AWMRTXKVNPWQNB-UHFFFAOYSA-N ethyl 2-[4-[2-[3-(1-hydroxy-6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propyl-methylamino]ethyl]phenoxy]acetate Chemical compound C1=CC(OCC(=O)OCC)=CC=C1CCN(C)CCCC1C(O)C2=CC(OC)=C(OC)C=C2CC1 AWMRTXKVNPWQNB-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 150000002238 fumaric acids Chemical class 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 150000002689 maleic acids Chemical class 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- AVCDRJCQXMOBRW-UHFFFAOYSA-N methyl 3-(5,6-dimethoxy-3-oxo-1,2-dihydroinden-2-yl)propanoate Chemical compound COC1=C(OC)C=C2C(=O)C(CCC(=O)OC)CC2=C1 AVCDRJCQXMOBRW-UHFFFAOYSA-N 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- PPUVRPZLIMYXHV-UHFFFAOYSA-N n-[4-[2-[3-(6,7-dimethoxy-1-oxo-3,4-dihydro-2h-naphthalen-2-yl)propyl-methylamino]ethyl]phenyl]methanesulfonamide Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CCC1CCCN(C)CCC1=CC=C(NS(C)(=O)=O)C=C1 PPUVRPZLIMYXHV-UHFFFAOYSA-N 0.000 description 1
- CVEXPVRWWNQJNH-UHFFFAOYSA-N n-ethyl-n-methyl-4-phenylmethoxyaniline Chemical compound C1=CC(N(C)CC)=CC=C1OCC1=CC=CC=C1 CVEXPVRWWNQJNH-UHFFFAOYSA-N 0.000 description 1
- PTPPVTUXJDJAGY-UHFFFAOYSA-N n-methyl-2-(4-nitrophenyl)ethanamine Chemical compound CNCCC1=CC=C([N+]([O-])=O)C=C1 PTPPVTUXJDJAGY-UHFFFAOYSA-N 0.000 description 1
- QJQAMHYHNCADNR-UHFFFAOYSA-N n-methylpropanamide Chemical compound CCC(=O)NC QJQAMHYHNCADNR-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 150000002913 oxalic acids Chemical class 0.000 description 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 150000003444 succinic acids Chemical class 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/385—Saturated compounds containing a keto group being part of a ring
- C07C49/417—Saturated compounds containing a keto group being part of a ring polycyclic
- C07C49/423—Saturated compounds containing a keto group being part of a ring polycyclic a keto group being part of a condensed ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
- C07F9/5304—Acyclic saturated phosphine oxides or thioxides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Feedback Control In General (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
Abstract
Naphthalene and indane derivatives of the formula <IMAGE> in which the substituents have the meaning given in the description, their enantiomers, their diastereomers and their acid addition salts with inorganic or organic acids which have useful pharmacological properties, in particular a heart rate-reducing action. The novel compounds can be prepared by processes known per se.
Description
~4I Australia PATENTS ACT 1952 597719 Form COMPLETE SPECIFICATION
(ORIGINAL)
FOR OFFICE USE Short Title: Int. Cl: Application Number: Lodged: Complete Specification-Lodged: Accepted: Lapsed: Published: SPrfority: I ~mrnmrr:ihi Cl "~61 arnc~l2 .2i2 )vinfjpg rT~y Related Art: Name of Applicant: Address of Applicant: Actual Inventor: Address for Service: TO BE COMPLETED BY APPLICANT DR. KARL THOMAE G.m.b.H.
D-7950 Biberach an der Riss, Federal Republic of Germany.
MANFRED PSIORZ, JOACHIM HEIDER, ANDREAS BOMHARD, NORBERT HAUEL, KLAUS NOLL, BERTHOLD NARR, CHRISTIAN LILLIE, WALTER KOBINGER and JURGEN DAMMGEN.
CALLINAN AND ASSOCIATES, Patent Attorneys, of 48-50 Bridge Road, Richmond, State of Victoria, Australia.
"NAPHTHALENE AND INDAN DERIVATIVES" Complete Specification for the invention entitled: i i The following statement is a full description of this invention, including the best mtethod of performing it known to me:-' SNote: The description is to be typed in double spacing, pica type fIce, In an area not exceeding 250 mm in depth "iii 60 mm in width, on tough white paper of good quality and it is to be inserted inside this form.
y w -I i ;I m
A
r-7-44 lA- MJ 52-007 Naphthalene and indan derivatives 9 .4 4 4@ .4 .4 4 4 4.
9* 4 .4.
0 44.
.4 4 4 0.44.4 ~0 4.4 4 The present invention relates to certain new naphthalene and indan derivatives, their preparation and pharmaceutical compositions containing them.
Tetrahydronaphthalenes which are substituted in the 2-position by a hydroxy group optionally substituted by an acyl group have been described in EP-A-177960.
These compounds have a marked calcium-antagonistic activity and can therefore be used in pharmaceutical 10 compositions, particularly for the treatment and prevention of angina pectoris, ischaemia, arrhythmia and high blood pressure.
We have now surprisingly found that certain new naphthalene and indan derivatives possess other valuable pharmacological properties, particularly a heart rate lowering effect and an effect of reducing the 0 2 -requirements of the heart.
According to one aspect of the present invention therefore we provide a compound of formula I 0 ~CtL'4 0 4 44444.
4 A N R 7
R
C3 ,1 2 )n R
R
6 (wherein n represents the integer 1 or 2; A represents a carbonyl group and R 7 represents a hydrogen atom, or 2- 8 A represents a group of formula -CH- (wherein R 8 represents a hydrogen atom or a hydroxy, alkanoyloxy or alkoxycarbonyloxy group) and R 7 represents a hydrogen atom, or A and R 7 together form a group of formula -CH=; E represents a straight-chained C3- 4 alkylene group optionally substituted by an alkyl group; G represents a straight chained C 2 5 alkylene group optionally substituted by an alkyl group;
R
1 represents a hydrogen or halogen atom, or a trifluoromethyl, nitro, amino, alkylamino, dialkylamino, 15 alkyl, hydroxy, alkoxy or phenylalkoxy group, and
R
2 represents a hydrogen or halogen atom or a hydroxy, alkoxy, phenylalkoxy or alkyl group, or R, and R 2 together represent a C 1 2 alkylenedioxy group; e.
o R 3 represents a hydrogen, an alkyl group or a 9* alkenyl group; **ss R 4 represents a hydrogen or halogen atom, or an alkyl, amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulphonylamino, bis(alkylsulphonyl)-amino, N-alkyl-alkylsulphonylamino, cyano, alkylmercapto, alkylsulphinyl or alkylsulphonyl group, or a hydroxy group optionally substituted by an alkyl, phenylalkyl, 2-hydroxyethyl, 3-hydroxyn-propyl, 2-hydroxy-n-propyl, alkylsulphonyl, cyanoalkyl, alkoxycarbonyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, trifluoromethyl, difluoromethyl or trifluoromethyl-' sulphonyl group, and 0 ifl alkyl, hydroxy, alkoxy, nitro, cyano or trifluoromethyl group, or
R
4 and R 5 together represent a C1_ 2 alkylenedioxy group; and
R
6 represents a hydrogen or halogen atom or an alkyl or alkoxy group; wherein unless otherwise defined any alkyl or alkoxy moiety contains 1 to 3 carbon atoms and any alkanoyl moiety contains 2 or 3 carbon atoms) or San enantiomer, diastereomer or acid addition salt 15 thereof. Insofar as the salts of the compounds of formula I are concerned, for pharmaceutical use the physiologically acceptable acid addition salts, e.g. with inorganic or organic acids, are of course preferred; nonetheless other salts may 20 be useful in the preparation of the physiologically 900 acceptable salts or of the free bases or of such salts or bases in particular stereoisomeric forms and so are seemed to fall within the scope of the present invention.
ft. The following are examples of atoms..or groups which comply with the definitions of the groups given hereinbefore:
R
1 may represent a hydrogen, fluorine, chlorine or bromine atom or a methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, nitro, amino, methylamino, ethylamino, n-propylamino, isopropylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methylethylamino, methyl-n-propylamino, methyl-isopropylamino, ethyl-n-propylamino, benzyloxy, 1-phenylethoxy, -4- 1-phenyipropoxy, 2-phenylethoxy or 3-phenyipropoxy group, R 2 may represent a hydrogen, chlorine or bromine atom or a methyl, ethyl, n-propyl, isopropyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 2-phenylpropoxy or 3-phenylpropoxy group or together with R1it may represent a methylenedioxy or ethylenedioxy group, R 3 may represent a hydrogen atom or a methyl, ethyl, n-propyl, isopropyl, allyl, crotyl or n-pent-2group, R 4 may represent a hydrogen, fluorine, chlorine, bromine or iodine atom or a methyl, ethyl, n-propyl, isopropyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, amino, :nethylamino, ethylamino, n-Dropylamino, isopropylamino, dimethylamino, diethylamino, di,- *n-propylaminr), diisopropylamino, methyl-eth XIamino, methyl-n-propylamino, methyl-isopropylamino, ethyln-propylamino, acetylamino, propionylamino, methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, methylsuiphonylamino, ethylsulphonylamino, n-propylsulphonylamino, bis (methylsulphonyl) -aminio, bis (ethylsuiphonyl) -aminio, N-methyl-methylsulphonylamino, cyano, methylmercapto, ethylmercapto, n-propylmercapto, Joe**methylsulphinyl, ethylsulphinyl, isopropylsulphinyl, methylsuiphonyl, ethylsiudphonyl, n-propylsulphonyl, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 2-phenylpropoxy, 3-phenyipropoxy, 2-hydroxy-ethoxy, 2-hydroxyn-propoxy, 3-hydroxy-n-propoxy, methylsuiphonyloxy, C ethylsuiphonyloxy, isopropylsuiphonyloxy, methoxycarbonyloxy, ethoxycarbonyloxy, isopropoxycarbonyloxy, hydroxycarbonylmethoxy, 2- (hydroxycarbony1) -ethoxy, methoxycarbonylmethoxy, ethoxycarbonylmethoxy, -77 isopropoxycarbonylmethoxy, 2-(iethoxycarbonyl)ethoxy, 2-(n-propoxycarbonyl)-ethoxy, cyanomethoxy, 2-cyanoethoxy, 3-cyano-n-propoxy, trifluoromethoxy or difluoronethoxy group,
R
5 may represent a hydrogen, chlorine or bromine atom or a methyl, ethyl, n-propyl, isopropyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, nitro, cyano or trifluoromethyl group or R 4and R 5 together may represent a methylenedioxy or ethylenedioxy group
R
6 may represent a hydrogen, chlorine or bromine atom or a methyl, ethyl, n-propyl, isopropyl, hydroxy, 15 methoxy, ethoxy, n-propoxy or isopropoxy group, A may represent a methylene, hydroxymethylene, acetoxymethylene, propionyloxymethylene, methoxycarbonyloxymethylene, ethoxycarbonyloxymethylene, n-propoxycarbonyloxymethylene or carbonyl group, *R may represent a hydrogen atom or together with A it may represent a -CH= group, E may represent an n-propylene, 1-methyl-n-propylene, 2-methyl-n-propylene, 3-methyl-n-propylene, 1-ethyln-propylene, 2-n-propyl-n-propylene, 3-ethyl-npropylene, n-butylene, l-methyl-n-butylene or 1ethyl-n-butylene group, and G may represent an ethylene, 1-methyl-ethylene, i-ethyl-ethylene, 1-propyl-ethylene, 2-methyl-ethylene, 2-ethyl-ethylene, n-propylene, n-butylene, n-pentylene, 1-methyl-n-propylene, l-methyl-n-butylene, 1-methyln-pentylene, 1-ethyl-n-propylene, 2-ethyl-n-propylene or l-methyl-n-butylene group.
A -6 By way of example, the following are compounds which fall within the scope of the present invention: 6,7-dimethoxy-2-[3-( (2-(4-methylphenyl)-ethyl)methylamino) -propyl] 4-tetrahydronaphthalene; 6,7-dimethoxy--2-[3-( (2-(3-methylphenyl)-ethyl)methylamino) -propyl] 2,3, 4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3-( (2-(3-methoxyphenyl) -ethyl)methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3-( (4-difluoromethoxyphenyl)ethyl) -methylamino) -propylll-1,2,3, 4-tetrahydronaphthalene; 6,7-dimethoxy-2-13-((2-(4-(2-hydroxyethoxy)-phenyl)ethyl) -methylarnino) -propyl] 4-tetrahydronaphthalene; 00 6,7-dimethoxy-2-[3-( (3-(4-amino-3,5-dibromo-phenyl)propyl)-methylamino)-propy1]--1,2,3,4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3-( (3,4-methylenedioxyphenyl)ethyl)-methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3-( (2-(3,4-dichlorophenyl) -ethyl)methylamino)-propylll-1,2,3,4-tetrahydronaphthalene; 6,7-dimethoxy-2-13-( (3-(4-cyanophenyl)-propyl)methylamino) -propyl]-1-hydroxy-1, 2,3,4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3- (4-methylsulphonylphenyl) ethyl) -methylamino) -propylij-1-hydroxy-1,2,3,4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3-((2-(4-methoxyphenyl)-ethyl)methylamino) -propyl ]-l-hydroxy-l, 2,3, 4-tetrahydronaphthalene; -7- 6,7-dimethoxy-2-[3- ((2-phenyl-ethyl) -methylamino) propyl] -1-hydroxy-1,2,3, 4-tetrahydronaphthalene; 6,7-flimethoxy-2-[3-( (3-(4-bromophenyl)-propyl)methylamino) -propyl] -1-hydroxy-1,2, 3 ,4-tetrahydronaphthalene; 6,7-dimethoxy-2-13-( (2-(4-methylphenyl)-ethyl)methylamirio)-propyl]-l-hydroxy-1,2,3,4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3-( (2-(3-methylphenyl) -ethyl)niethylamino) -propyl] -l-hydroxy-1, 2,3, 4-tetrahydro- **.naphthalene; 6,7-dimethoxy-2-[3-((2-(3--methoxyphenyl)-ethyl)methylamino) -propyl] -1-hydroxy-l 4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3-( (4-trifluoromethylsulphonyloxyphenyl)-ethyl)-methylamino)-propyl]--1-hydroxy-1,2,3,4tetrahydronaphthalene; SOO:%6,7-dimethoxy-2-[3-((2-(4-cyanomethoxyphenyl)-ethyl)methylamino)-propyl]-1-hydroxy-1,2,3,4-tetrahydronaphthalene; 6,7,-dimethoxy-2-[3-( (2-(4-difluoromethoxypnenyl)ethyl)-methylamino)-propyl]-l-hydroxy-1,2,3,4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3- (4-trifluoromethoxyphenyl) ethyl) -methylamino) -propyl] -l-hydroxy-1, 2,3, 4-tetrahydronaphthalene; 6,7-dimetho' (2-(4-methanesulphonylaminophenyl)ethyl)-methylamino)-propyl]-l-hydroxy-l,2,3,4-tetrahydronaphthalene; 'r'r -8- 6,7-dimethoxy-2-[3- (4-methoxycarbonylaminophenyl)ethyl) -methylamino) -propyl] -l--hydroxyt-1, 2,3, 4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3-( (2-(4-ethoxycarbonylmethoxyphenyl)ethyl)methylamino)-propyl]-l-hydroxy-1,2,3,4-tetrahydronaphthalene; 6,7-dimethoxy-2-.3-( (2-(4-hydroxycarbonylrnethoxyphenyl)ethyl)-methylamino)-propyl]-l-hydroxy-1,2,3,4-tetrahydronaphthalene; 6,7-dimethoxy-2-13- ((3-(4-amino-3,5-dibromo-phenyl)propyl) -methyllamino) -propyl] -l-hydroxy-1, 2,3,4tetrahydronaphthalene; 0 006,7-dimethoxy-2-[3-( (2-(3,4-methylenedioxyphenyl)ethyl)-rnethylamino) -propyl] -1-hydroxy-1, 2,3, 4-tetrahydro- 6,7-dimethoxy-2-[3-( (2-(3,4-dichlorophenyl)-ethyl)- CR methylamino) -propyl] -1-hydroxy-1,2,3, 4-tetrahydro- C rnaphthalene; 6,7-dmethoxy-2-[3-( (3-(4-cyanophenyl)-propyl)-methylamiio)propyl] -1-oxo-1,2,3, 4-tetrahydronaphthalene; I C 6,7-dimethoxy-2-113-((2-(4-methylsulphonylphenyl)- C ethyl)-methylamino) -propyl]-1l-oxo-1,2,3,4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3- ((2-(4-methox3yphenyl) -ethyl) methylamino) -propyl]-l-oxo-1, 2,3, 4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3-( (2-phenyl-ethyl)-methylamino)propyl] -l-oxo-1, 2,3, 4-tetrahydronaphthalene; -9- 6,7-dimethoxy-2-[3-( (3-(4-bromophenyl)-propyl)methylamino) -propy -l-oxo-1, 2,3, 4-tetrahydroiaphthaleie; 6,7-dimethoxy-2-[3-( (2-(4-rnethylphenyl) -ethyl)methylamino)-propyl]-l-oxo-1,2,3,4-tetrahydroflaphthalele; 6,7-dimethoxy-2-[3-( (2-(3-methylphenyl)-ethyl)methylamino)-propyl]ll--oxo-1,2,3,4-tetrahydroflaphthalele; 6,7-dimethoxy-2-[3-( (2-(3-methoxyphenyl) -ethyl)inethylamino) -propyl]-l-oxo-1,2,3,4-tetrahydronaphthaleie; 6,7-dimethoxy-2-[3-( (4-trifluoromethylsulphonyloxys..,..phenyl) -ethyl) -methylanino) -propyl] -l-oxo-1, 2,3,4tetrahydronaphthalene; 6,7-dimethoxy-2-[3-( (2-(4-cyanornethoxyphenyl) -ethyl)methylamino)-propyl]-l-oxo-1,2,3,4-tetrahydroflaphthalele; 6,7-dimethoxy-2-[3-( (4-difluoromethoxyphenyl)ethyl)-methylamino)-propyl]-l-oxo-1,2,3,4-tetrahydroa naphthalene; '0400"6,7-dimethoxy-2-[3-( (2-(4-trifluoromethoxypheiyl)- 0 625 ethyl) -methylamino) -propyl] -l-oxo-1,2,3 ,4-tetrahydronaphthalene; I' 6,7-dimethoxy-2-[3-( (2-(4-methanesulphonylaminophenyl)ethyl) -methylamino) -propyl] -l-oxo-1,2,3 ,4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3- (4-methoxycarbonylaminophenyl) ethyl) -methylamino) -propyl] -1-oxo-l, 2,3, 4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3- ((2-(4-ethoxycarboriylmethoxyphenyl) ethyl) -methylamino) -propyl] -1-oxo-l, 2,3, 4-tetrahydronaphthalene; 10 6,7-dimethoxy-2-[3-((2-(4-hydroxycarbonylmethoxyphenyl)ethyl)-methylamino)-propyl]-1-oxo-1,2,3,4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3-((3-(4-amino-3,5-dibromo-phenyl)propyl)-methylamino)-propyl]-1-oxo-1,2,3,4-tetrahydronaphthalene; 6,7-dimethoxy-2-[3-((2-(3,4-methylenedioxyphenyl)ethyl)-methylamino)-propyl]-1-oxo-1,2,3,4tetrahydronaphthalene; 6,7-dimethoxy-2-[3-((2-(3,4-dichlorophenyl)-ethyl)methylamino)-propyl]-1-oxo-1,2,3,4-tetrahydronaphthalene; 15 and the enantiomers, diastereomers and acid addition 9 90 salts thereof.
.9 Preferred among the compounds of the invention are those of formula I wherein too n represents the integer 1 or 2, A represents a carbonyl group and R, represents a hydrogen atom, or
R
A represents a group of formula -CH- (wherein R 1represents a hydrogen atom or a hydroxy group) and R 7 represents a hydrogen atom, or A and R together represent a group of formula -CH=, E represents an n-propylene group, G represents an ethylene or n-propylene group,
R
1 represents a methyl or methoxy group, ct rrr~ lle& I Vi 11
R
2 represents a hydrogen atom or a methoxy group,
R
3 represents a methyl group,
R
4 represents a hydrogen, chlorine or bromine atom, a hydroxy, methoxy, cyanop cyanomethoxy, hydroxycarbonylmethoxy, methoxycarbonylmethoxy, ethoxycarbonylmethoxy, methyl, amino, acetylamino, methoxycarbonylamino, methylsulphonyloxy, trifluoromethylsulphonyloxy, benzyloxy, methylsulphonylamino or bis(methylsulphonyl)amino group,
R
5 represents a hydrogen, chlorine or bromine atom or a methoxy or nitro group, and R6 iepresents a hydrogen, chlorine or bromine atom, and the enantiomers, diastereomers and acid addition salts of such compounds.
Particularly preferred compounds according to the invention include those of formula I wherein
R
1 to R 3 A, E, G and n are as hereinbefore defined, t Sr a I J a.
1 I 1I *r a t, t ~ri
R
4 represents a methoxy group,
R
5 represents a methoxy group, and
R
6 represents a hydrogen atom, and the enantiomers, diastereomers and acid addition salts thereof.
In another aspect of the present invention we provide a process for preparing the compounds of the invention, i sulphonyl group, and /3
J
12 said process comprising at least one of the following steps: a) (to prepare compounds of formula I wherein R 7 and R 8 each represent a hydrogen atom or R7 and A together represent a -CH= group) reacting a compound of formula II
A
R 7 C E -X
(II)
S t f I 1 I 4 t
I
00 4 I 04 (wherein
R
1
R
2 n and E are as hereinbefore defined;
R
A1 represents a group of formula -CH-(wherein
R
8 represents a hydrogen atom) and R 7 represents a hydrogen atom, or A 1 and R 7 together represent a -CH= group; and X represents a nucleophilically exchangeable group, such as a halogen atom or a sulphonyloxy group, e.g. a chlorine, bromine or iodine atom, a methanesulphonyloxy, p-toluenesulphonyloxy or ethoxysulphonyloxy group) with an amine of formula III 0*0 0 01 *0 6 C C C P
C
I,
I' t~ t~ #4
B
R,3 H If G
(III)
(wherein 'If 13 R 3 to R6and G are as hereinbefore defined); b) reacting a compound of formula IV
A
R2 C
(C
2 )n
(IV)
Ra
R
E-N
H
C.
96 pq,.
9.
9. 9 *q 0 9 9.
*0 S S 99 .9 9 999 .9 .9 999 9.
9 9 9999 9 9 99 0 t 9#
S
9 (wherein n. A, E, to R 3 and R7are as hereinbefore defined) with a compound of formula V Y -G (wherein Rto R 6 and G are as hereinbefore defined, and Y represents a nucleophilically exchangeable group, such as a halogen atom or a sulphonyloxy group, e.g. a chlorine, bromine or iodine atom or a methanesuiphonyloxy, p-toluenesulphonyloxy.,or ethoxysulphonyloxy group); c) (to prepare compounds of formula I wherein ,8 A represents a group of formula -CH- (wherein R.
represents a hydrogen atom or a hydroxy group) reducing a compound of formula VI p.
14
A
2 7
R
R C -1a (CH N
G
I
(VI)
R
5
S
I 050 .4.5 t9 *5 5 4. 0 *4 5* 0 0 *0 0 0*.
S
*00 0S 0 0 50 9 9 *5 9
S
I 555 S S 4 551.40* 0 (wherein n and R 1 to R 6 are as hereinbefore defined;
A
2 represents a carbonyl group and R 7 represents a hydrogen atom, or R8
A
2 represents a group of formula -CH- (wherein
R
8 represents a hydrogen atom or a hydroxy group) 15 and R 7 represents a hydrogen atom; E' and G' have the meanings given hereinbefore for E and G but with the exception that in the groups E' or G' a carbonyl group takes 20 the place of a inmthylene group adjacent to the N-R moiety); 3 d) (to prepare compounds of formula represents as carbonyl group) oxidizing a compound of formula VII
OH
n t I wherein A SH
R
^E
G
(VII)
(wherein n, E, G and R to R 6 are as hereinbefore.defined); p e) (to prepare compounds of formula I wherein R represents an alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsuiphonylamino, bis (alkylsuiphonyl) amino, N-alkyl-alkylsulphonylamino, alkylmercapto, alkoxy, alkoxycarbonyloxy, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, phenylalkoxy, trifluoromnethoxy, difluoromethoxy, cyanoalkoxy, alkylsuiphonyloxy or trifluoromethylsuiphonyloxy group) reacting a compound of formula VIII RI AR9 R2 C R 3 R 5 5
(VIII)
'EN G
R
6 2) 06R (wherein
R
1 ,R 2 R 3 R 5 R 6 R 7 A, E, G and n are as hereinbefore defined, and R 9represents a hydroxy, amino or C13alkylamino 0'':':group) with a compound of formula IX Z R 0(IX) (wherein Z represents a nucleophilically exchangeable group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, and R 10represents an alkyl, alkanoyl, alkoxycarbonyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, alkylsulphonyl, phenylalkyl, trifluoromethyl, difluoromethyl or cyanoalkyl group, m m
*I
I 2 5 16 wherein any alkyl or alkoxy moieties each contain from 1 to 3 carbon atoms and any alkanoyl moiety contains 2 or 3 carbon atoms); f) (to prepare compounds of formula I wherein A and R 7 together represent a -CH= group) dehydrating a compound of formula X
R
1 R3 E-N
G
4 .4.
4 4 *4 4* 4 *4 4 o S6B *a t 4 0 (wherein n, E, G, RIR 2
,R
31
R
4
,R
5
,R
6 and R 7 are as hereinbefore defined); 20 g) if necessary, suheequently splitting off any protecting group used in the reaction steps a) to g) in order to protect reactive groups; h) converting a compound of formula I thus obtained wherein R 4 represents a benzyloxy group by debenzylation into the corresponding hydroxy compound; i) resolving a compound of formula I thus obtained, if it contains at least one chiral centre, into its diastereomers or its enantiomers; j) converting a compound of formula I thus obtained into an acid addition salt thereof, particularly its physiologically acceptable addition salt with 35 an inorganic or organic acid.
6" 1.
6 17 17 The reaction of step is conveniently carried out in a solvent or mixture of solvents such as acetone, diethylether, methylformamide, dimethylformamide, dimethylsulphoxide, benzene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran, dioxane or in an excess of the compounds of formulae II and/or III used and optionally in the presence of an acid binding agent, e.g. an alkoxide such as potassium tert.butoxide, an alkali metal hydroxide such as sodium or potassium hydroxide, an alkali metal carbonate such as potassium carbonate, an alkali metal amide such as sodium amide, an alkali metal hydride such as sodium hydride, a tertiary organic base such as triethylamine or Ow pyridine (the latter may simultaneously also serve as solvent), or a reaction accelerator such as potassium 15 iodide (depending on the reactivity of the nucleophilically S. exchangeable group), conveniently at temperatures of between 0 and 150 0 C, preferably at temperatures of between 50 and 120 0 C, e.g. at the boiling temperature of the solvent used. However the reaction may 20 also be carried out without a solvent. It is, however, particularly preferred to perform the reaction in the presence of a tertiary organic base or an excess of the amine of formula III used.
The reaction of step is conveniently carried C "AC| out in a solvent or mixture of solvents such as (i ttacetone, diethylether, methylformamide, dimethylformamide, dimethylsulphoxide, benzene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran, dioxane or in an excess of the compounds of formulae IV and/or V used and optionally in the presence of an acid binding agent, e.g. an alkoxide such as potassium tert.butoxide, i 'A metho~ycarbonylmethoxy, ethoxycarbonylmethoxy, 18 an alkali metal hydroxide such as sodium or potassium hydroxide, an alkali metal carbonate such as potassium carbonate, an alkali metal amide such as sodium amide, an alkali metal hydride such as sodium hydride, a tertiary organic base such as triethylamine or pyridine (the latter may simultaneously also serve as solvent), or a reaction accelerator such as potassium iodide (depending on the reactivity of the nuclepphilically exchangeable group), conveniently at temperatures of between 0 and 150 0 C, preferably at temperatures of between 50 and 120 0 C, e.g. at the boiling temperature of the solvent used. However the reaction may also be carried out without a solvent. It is, however, particularly preferred to perform the reaction in the presence of a tertiary S*I organic base or an excess of the amine of formula IV used.
The reduction of step is conveniently carried out in a solvent and is preferably carried out with a metal hydride such as lithium aluminium hydride or diborane or with a complex of borane and a thioether, e.g. with borane/dimethylsulphide complex, optionally in the presence of a Lewis acid such as boron trifluoride in a suitable solvent such as diethylether or tetrahydrofuran, at temperatures of between 0 and 80 0 C, but preferably at the boiling temperature of the solvent used, e.g. at temperatures of between 35 and 65 0
C.
If A2 in a compound of formula VI used represents a carbonyl group or R 8 represents a hydroxy group, in order to prepare compounds of formula I wherein
R
8 represents a hydrogen atom the reduction is preferably carried out in the presence of a Lewis acidi e.g. with borane-dimethylsulphide complex in the presence of boron trifluoride, or hydrxid, analkli mtalcarbnat suc aspotasiu 19 if A 2 in a compound of formula VI used represents the carbonyl group or R 8 represents a hydroxy group, in order to prepare compounds of formula I wherein
R
8 represents a hydroxy group the reduction is preferably carried out with lithium aluminium hydride.
Oxidation in step is preferably effected with an oxidising agent such as potassium permanganate, barium manganate, potassium dichromate or with a ketone in the presence of a base (Oppenauer method), e.g. with acetone/aluminium isopropoxide or benzophenone- /potassium tert.butoxide, in a suitable solvent such as water, water/dioxane, glacial acetic acid, S...water/acetic acid or toluene at temperatures of between 0 and 150 0 C. Oxidation with an inorganic 15 oxidising agent, however, is preferably carried S. out at temperatures of between 0 and 50 0 C and the Oppenauer oxidation, i.e. with an organic oxidising agent, is preferably carried out at the boiling temperature of the reaction mixture, e.g. at temperatures S 20 of between 50 and 115 0
C.
The reaction of step is conveniently carried out in a solvent or mixture of solvents such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, S" acetonitrile or dimethyl formamide, optionally r ct: in the presence of an acid-activating agent or a dehydrating agent, e.g. in the presence of ethyl chloroformate, thionyl chloride, phosphorus trichloride, F 30 phosphors pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-carbonyldiimidazole or N,N'-thionyl diimidazole, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethyl- 20 amine or pyridine, the latter two of which may simultaneously be used as solvent, at temperatures of between -25 0 C and 250 0 C, but preferably at temperatures of between -10 0 C and the boiling temperature of i, 5 the solvent us;-d.
The dehydration of step is conveniently carried out in a solvent such as acetone, methanol, ethanol, tetrahydrofuran or dioxane and preferably in the presence of an acid such as hydrochloric or sulphuric acid, preferably in the presence of an alcoholic acid such as methanolic hydrochloric acid, at temperatures of between 0 and 50 0 C, preferably at ambient temperature.
15 In the reactions described hereinbefore, any reactive groups present such as hydroxy, amino or imino groups may be protected during the reaction by conventional protecting groups which may then be split off again after the reaction.
Suitable protecting groups for a hydroxy group include, for example, trimethylsilyl, acetyl, benzoyl, benzyl and tetrahydropyranyl groups and suitable protecting groups for an imino or amino group include the acetyl, benzoyl, ethoxycarbonyl and benzyl groups.
The optional subsequent splitting off of a protecting group used is preferably carried out by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water tetrahydrofuran/water or dioxane/water, in the presence of an acid such as hydrochloric or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide, at temperatures of between 0 and 100 0 C, preferably at the boiling temperature of the reaction mixture.
However, a benzyl group is preferably split off 'r i l I 'i 1 21 21 by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid, at temperatures of between 0 and 50 0 C, but preferably at ambient temperature, under a hydrogen pressure of from 1 to 7 bar, preferably from 3 to 5 bar.
If a compound of formula I is obtained wherein R4 represents a benzyloxy group, this may be converted into the corresponding hydroxy compound by debenzylation.
The subsequent debenzylation of step is preferably S 15 carried out in a solvent such as water, water/ethanol, *methanol, glacial acetic acid, ethyl acetate or dimethyl formamide, conveniently with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium/charcoal, at temperatures of between 0 and 50 0 C, but preferably at ambient temperature.
If they have at least one chiral centre, the compounds of formula I obtained may be resolved by conventional methods into their diastereomers, for example by column chromatography, and into their enantiomers, S for example by column chromatography on a chiral phase or by crystallisation with optically active acids, e.g. with D- or L-monomethyl tartaric acid, 30 D- or L-diacetyl tartaric acid, D- or L-tartaric acid, D- or L-lactic acid, D- or L-camphoric acid, D- or L-dibenzoyl tartaric acid, D- or L-camphorsulphonic acid or D- or L-camphanoic acid.
The compounds of formula I obtained may also be converted into the acid addition salts thereof, particularly the physiologically acceptable acid 22 addition salts thereof with inorganic or organic acids for pharmaceutical use. Suitable acids include, for example, hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic, fumaric and oxalic acids.
The compounds of general formulae II to X used as starting materials are known from the literature in some cases or may be obtained using methods known per se.
For example, a starting compound of formula II may be obtained by reduction of a corresponding carboxylic acid of formula XI 0 20R2 CH E COOH
SH(XI)
(wherein
R
1
R
2 E and n are as hereinbefore defined) or t a corresponding ester to yield the corresponding alcohol and subsequent reaction with a halogenating agent such as phosphorus tribromide or hydrogen bromide. The carboxylic acid of formula XI required may be obtained by Michael Addition of a corresponding acrylic ester to a compound of formula XII RI 0 n
C
0 (cu R CH C R 1
(XII)
S(CH
2 23 (wherein R1, R 2 and n are as hereinbefore defined, and
R
11 represents a hydrogen atom or a lower (e.g.
C1-6) alkoxy group). The compound of formula XII required for this may, in turn, be obtained by reaction of a corresponding ketone with a formic acid ester or a dialkylcarbonate in the presence of a strong base such as an alkali metal alkoxide or an alkali me'al hydride.
A starting compound of formula IV may be obtained for example by reacting a carboxylic acid of formula XI with a corresponding amine in the presence of N,N'-carbonyldiimidazole and subsequent reduction 15 of the amide thus obtained.
.e A compound of formulae VI, VII, VIII or X used as starting material may be obtained by reacting a corresponding 4-halogen compound with a corresponding amine.
*0e already mentioned hereinbefore, the new compounds of formula I and the physiologically acceptable acid addition salts thereof with inorganic or organic acids have valuable pharmacological properties, particularly a heart rate lowering effect I and the effect of reducing the 0 -requirement of u the heart, with only minor side-effects on the central nervous system.
For example, the following compounds: A) 6,7-diethoxy-2-[3-((2-(3,4-dimethoxyphenyl)ethyl)-methylamino)-propyl]-l-oxo-l,2,3,4-tetrahydronaphthalene,
I~
i i i- BI;, -i a~ c_
I!
r *r 4 4, 4* 4 I 4 4i 24 B) 6,7-dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)ethyl)-methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene hydrochloride, and C) 5,6-dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)ethyl)-methylamino)-propyl]-l-hydroxy-indan were tested for their biological properties as follows: The effect on heart rate in rats The effect of the test substances on heart rate was investigated, for each dosage, on 2 rats with an average weight of 250-300 g. The rats were 15 first anaesthetised with pentobarbital (50 mg/kg i.p. and 10 mg/kg The test substances were injected in aqueous solution into the jugular vein (0.1 ml/100 g).
20 The blood pressure was measured by means of a cannula inserted in a carotid artery and the heart rate was recorded from an ECG derived by means of needle electrodes (2nd or 3rd derivation). The heart rate of the animals in the control period was between 350 and 400 beats per minute (b/min).
The following Table shows the results obtained: Substance Dosage Lowering of heart rate, measured [mg/kg] 5 minutes after administration of substance [b/min] A 5.0 157 B 5.0 150 C 5.0 152 0!.
~g~knrrrarrrrrsm~*r~,-~I~ 25 The compounds prepared according to the invention have no toxic side effects whatever when administered in therapeutic doses. Thus, for example, when substances A and C were administered intravenously to mice, even at a high dosage of 10 mg/kg, no toxic side effects could be detected other than a slight sedation.
In view of their pharmacological properties, the compounds prepared according to the invention are suitable for the treatment of sinus tachycardia of various origins and for the prophylaxis and t treatment of ischaemic heart disease.
15 The dosage required to achieve this effect is conveniently from 0.03 to 0.4 mg/kg of body weight, preferably from 0.07 to 0.25 mg/kg of body weight, once or twice a day.
Thus, according to a further aspect of the present invention we provide a method of treatment of the r. human or non-human animal body to combat sinus 0# tachycardia or ischaemic heart disease comprising the adminstration to said body of a compound of formula I (as hereinbefore defined) or a physiologically acceptable acid addition salt thereof.
Sc: According to a yet further aspect of the present invention we provide the use of a compound of formula I (as hereinbefore defined) or a physiologically acceptable acid addition salt thereof for the manufacture of a therapeutic agent for use in a method of treatment of the human or non-human animal body to combat sinus tachycardia or ischaemic heart disease.
Thus, accotding to another aspect of the present invention we provide a pharmaceutical composition 7 1W (wherein ?Ui ii? c :ii i i a~' LIIIIIL- I~I--CU- i~ _ili.i ii-_.IYillli ld- T9':4 1 i- i; illllil:- i~__li l Li-i i i .1 I i I Iii-i: Al
I
26 comprising a compound of formula I as hereinbefore described or a physiologically acceptable acid addition salt thereof together with at least one pharmaceutical carrier or excipient.
The compounds of formula I and the physiologically acceptable acid addition salts thereof with inorganic or organic acids produced according to the invention may be incorporated, optionally together with other active substances, with one or more inert conventional carriers and/or diluents, e.g. with corn starah, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sor- 15 bitol, water/polyethyleneglycol, propylene glycol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as tablets, coated tablets, capsules, powders, suspensions, drops, ampoules, syrups or suppositories.
The following Examples are provided to illustrate the invention in a non-limiting manner (percentages and ratios are by weight unless otherwise specified): t I #t Vi r.
i S 9* I ii *i *9 .9 9 4 I 59 9449 *i 4 Icel t
I
lf--;r-
L
o i i 27 Example A 6,7-Dimethoxy-l-oxo-l,2,3,4-tetrahydronaphthalen- 2-carbaldehyde 187.5 g (0.909 mol) of 6,7-dimethoxy-l-oxo-1,2,3,4tetrahydronaphthalene are suspended in 4.0 litres of diethylether and 123.4 g (1.1 mol) of potassium tert.butoxide are added with stirring. After minutes, 89 ml (1.1 mol) of ethyl formate are added dropwise to the precipitate formed. After 5 hours, the reddish-blue suspension is mixed with 1 litre of water. The aqueous phase is separated off and acidified with concentrated hydrochloric acid, 15 whereupon a yellow precipitate is formed. The hydrochloric acid phase is extracted three times Example B Methyl 3-(6,7-dimethoxy-l-oxo-1,2,3,4-tetrahydro- 25 naphthalen-2-yl)-propionate 8 A mixture of 128.8 g (0.55 mol) of 6,7-dimethoxyc; 1-oxo-1,2,3,4-tetrahydronaphthalen-2-carbaldehyde, 125 ml (1.38 mol) of methyl acrylate and 82.5 ml (0.6 mtol) of triethylamine is refluxed for 6 hours.
The mixture is then evaporated down in vacuo and the residue obtained is chromatographed over 1600 g of aluminium oxide (neutral, activity II-III) with methylene chloride and then with increasing amounts of ethanolt (up to Yield: 186.2 g (87.4% of theory) 153-154point: 04-06 1 Example B Methyl 3-(6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydronaphthalen-2-yl)-propionate jA mixture of 128.8 g (0.55 mol) of 6,7-dimethoxy- 1-oxo-l,2,3,4-tetrahydronaphthalen-2-carbaldehyde, 125 ml (1.38 mol) of methyl acrylate and 82.5 ml (0.6 mol) of triethylamine is refluxed for 6 hours.
The mixture is then evaporated down in vacuo and the residue obtained is chromatographed over 1600 g of aluminium oxide (neutral, activity II-III) with methylene chloride and then with increasing amounts of ethanol (up to Yield: 144.5 g (90% of theory), Melting point: 104-106 0
C.
1 o L" .t -28- Example C 3- 7-Dimethoxy-l-oxo-1, 2,3, 4-tetrahydronaphthalen- 2-yl)-propionic acid 169 g (0.578 mol) of methyl 3-(6,7-dimet1~oxy-1,2,3,4tetrahydronaphthalen-2-yl) -propionate are suspended in 15litres of 8% sodium hydroxide solution and refluxed for 90 minutes. The mixture is then poured onto ice and acidified with concentrated hydrochloric acid. The precipitate formed is suction filtered.
Yield: 152.1 g (94.5% of theory), 156-158-C.
Example D .4 3-(6,7-Dimethoxy-l-oxo-1,2,3,4-tetrahydronaphthalel- 2-yl) 4-dimethoxyphenyl) -ethyl) -N-methylpropionic acid amide 8.35 g (0.03 mol) of 3-(6,7-dimethoxy-l-oxo-l,2,3,4tetrahydronaphthalen-2-yl) -propionic acid amide are suspended in 120 ml of ethyl acetate, mixed with 4.86 g (0.03 mol) of N,N'-carbonyldiimidazole and the mixture is stirred for 60 minutes. 5.86 g (0.030 mol) of N-methyl-homoveratrylamine, dissolved 30 ml of ethyl acetate, are added to this suspailsiorl.
After 1 hour the mixture is extracted twice with 8% sodium hydroxide solution. The organic phase is dried over magnesium rulphate and concentrated by evaporation in vacuo.
Yield: 12.4 g (91% of theory) R Rf value: 0.8 (aluminium oxide, neutral; eluant: 3% ethanol in methylene chloride).
Example E -29 3- (6,7-Dimethoxy-l-oxo-1, 2,3,4-tetrahydronaphthalen- 2-vi) (4-benzyloxyphenyl) -ethyl) -N-methylpropionic acid amide Prepared analogously to Example D from 3-(6,7-dimethoxyl-oxo-1, 2,3, 4-tetrahydronaphthalen-2-yl) -propionic acid, N,N'-carbonyldiimidazole and N-methyl-(2- (4-benzoyloxyphenyl) -ethylamine.
Yield: 91% of theory, 126-128-C.
Example F 3-(6,7-Dimethoxy-l-oxo-1,2,3,4-tetrahydronaphthalen- S 15 2-yl)-N-(2-(4-nitrophenyl)-ethyl)-N-methyl-propionic .:acid amide Prepared analogously to Example D from 3-(6,7-dimethoxy- 1-oxo-l,2,3, 4-tetrahydronaphthalen-2-yl) -propionic acid, N,N'-carbonyldiimidazole and N-methyl-2-(4nitrophenyl) ethylamine.
Yield: 87.8% of theory, 'A 41 128-130 0
C.
saw.&% Example G 3- 7-Dimethoxy-l-oxo-1,2,3, 4-tetrahydronaphthalen- 2-.yl)-N-(2-(4-aminophenyl)-ethyl)-N-methyl-propionic acid amide 10.0 g (0.023 mol) of 3-(6,7-dimethoxy-1-oxc;-l,2,3,4tetrahydronaphthalen-2-yl) (4-nitropheryl) ethyl)-N-methyl)-propionic acid amide are hydrogenated in 120 ml of methanol in the presence of 1.0 g of 10% palladium/charcoal for 2 hours at ambient temperature and under 5 bars of hydrogen. The catalyst is then removed by suction filtering and the methanol is distilled off in vacuo.
Yield: 9.3 g (100% of theory), Rf value: 0.4 (aluminium oxide, neutral; eluant: 3% ethanol in methylene chloride).
Example H E-Dimethoxy-l1-oxo-indane-2-carbaldehyde Prepared analogously to Example A from 5,6-dimethoxy- 1-oxo-indan.
Yield: 81% of theory, 145-147-C.
Example I Methyl 3 6 -dimethoxy-l-oxo-indan-2-y~l)-propionate *~*Prepared from 5, 6 -dimethoxy-l-oxo-indan-2-carbaldehyde and methyl acrylate analogously to Example B.
Yield: 38% of theory, 59-62 0
C.
Example K 0 0 3 6 -Dimethoxy-l-oxo-indan-.2-yl)-propionic acid Prepared from methyl 3- (5,6-dimethoxy-l-oxo-indan- 2-yl)-propionate analogously to Example C.
a: 0Yield: 60% of theory, .146-148*C.
r 31 Example L 04 So *5 9 3-(5,6-Dimethoxy-l-oxo-indan-2-yl)-N-(2-(3,4-dimethoxyphenyl)-ethyl)-N-methyl propionic acid amide Prepared from 3-(5,6-dimethoxy-l-oxo-indan-2-yl)propionic acid and N-methylhomoveratrylamine analogously to Example D.
Yield: 83% of theory, Rf value: 0.48 (aluminium oxide, neutral; methylene chloride 2% ethanol) Example M 6,7-Dimethoxy-2-(3-methylaminopropyl)-1,2,3,4-tetrahydronaphthalene a) 3-(6,7-Dimethoxy-l-oxo-l,2,3,4-tetrahydronaphthalen- 2-yl)-N-methyl propionic acid amide 8.35 g (0.03 mol) of 3-(6,7-dimethoxy-l-oxo-l,2,3,4tetrahydronaphthalen-2-yl)-propionic acid are suspended in 120 ml of ethyl acetate, mixed with 4.86 g (0.03 mol) of N,N'-carbonyldiimidazole and stirred for minutes at 50 0 C. 4.65 g (0.15 mol) of methylamine are introduced into this suspension within 30 minutes.
The mixture is stirred for a further 30 minutes, the precipitate is suction filtered and washed with cold ethyl acetate.
Yield: 6.9 g (79% of theory), 160-161 0
C,
Calculated: C 65.96 H 7.27 N 4.81 Found: 66.15 7.29 4.96 6 56 9* a,,oo 4 i.
ii
.,I
I
i 32 b) 6,7-Dimethoxy-2-(3-methylaminopropyl)-1, 2 3 4 tetrahydronaphthalene 6.7 g (0.023 mol) of 3-(6,7-dimethoxy-1-oxo-1, 2 3 4 tetrahydronapthalen-2-yl)-N-methyl-propionic acid amide are suspended in 80 ml of tetrahydrofuran.
Under nitrogen, 3.26 g (0.023 mol) of boron trifluoride etherate are added thereto and the whole is heated to 60 0 C. At this temperature, 5.8 ml (0.058 mol) of borane dimethylsulphide complex (10 molar solution) are then added dropwise. The mixture is then refluxed for 5 hours. After the reaction mixture has been cooled, methanol is added dropwise thereto, then 10 ml of methanolic hydrochloric acid are added 15 and the resulting mixture is refluxed for a further r 2 hours. After evaporation of the solvent the f.2 .mixture is taken up in 2 molar sodium hydroxide 54 solution and extracted with ethyl acetate. The organic phases are dried over magnesium sulphate, evaporated down in vacuo and the residue is purified over aluminium oxide (neutral, activity II-III) 4with methylene chloride and increasing quantities *of methanolic ammonia.
Yield: 33% of theory, 25 R value: 0.15 (aluminium oxide neutral, eluant: 3% ethanol in methylene chloride) .Example N 6,7-Dimethoxy-2-(3-bromopro pyl-l)-1,2,3,4-tetrahydronaphthalene a) 3-(6,7-Dimethoxy-1,2,3,4-tetrahydronaphthalen- 2-yl)-propan-l-ol Prepared analogously to Example M(b) from 3-(6,7dimethoxy-l-oxo-1,2,3,4-tetrahydronaphthalen-2-
L
th I I ii_ i r i -i 33 yl)-propionic acid.
Yield: 84% of theory, Rf value: 0.4 (silica gel plates manufactured by Macherey-Nagel, Polygram, eluant: 3% ethanol in methylene chloride).
b) 6,7-Dimethoxy-2-(3-bromoprop-l-yl)-1,2,3,4-tetrahydronaphthalene 3.8 g (0.0152 mol) of 3-(6,7-dimethoxy-l,2,3,4tetrahydronaphthalen-2-yl)-propan-l-ol are dissolved in 40 ml of toluene. Then 1.57 ml (0.0167 mol) of phosphorus tribromide dissolved in 5 ml of toluene are added dropwise within 30 minutes. The mixture 15 is stirred for a further hour at ambient temperature.
Water is added, whilst cooling with ice, and the mixture is then extracted 3 times with ethyl acetate.
The combined organic phases are dried over magnesium sulphate, filtered and concentrated by evaporation 20 in vacuo.
Yield: 4.4 g (92% of theory), Rf value: 0.9 (silica gel plates made by Macherey-Nagel, eluant: methylene chloride) 9*
S.,
0#
S
e 5
S
S S -i -a Ij.; ii
S
S
*0 S *0 S *0 r S '55 5 5 .4 *i S i09r 34 Example 1 6,7-Dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)methylamino)-propyl]-1-hydroxy-1,2,3,4-tetrahydronaphthalene 9.6 g (0.021 mol) of 3-(6,7-dimethoxy-l-oxo-1,2,3,4tetrahydronaphthalen-2-yl)-N-(2-(3,4-dimethc.xy-phenyl)ethyl)-N-methyl-propionic acid amide, dissolved in 50 ml of dry tetrahydrofuran, are added d:opwise to 1.60 g (0.042 mol) of lithium aluminium hydride in 150 ml of dry tetrahydrofuran. The mixture is then refluxed for 1 hour, then 1.6 ml of water, 1.6 ml of 15% sodium hydroxide solution and 5 ml 15 of water are added, whilst cooling is carried out with ice water. The precipitate is suction filtered, washed with tetrahydrofuran and the filtrate is evaporated down in vacuo.
Yield: 5.0 g (50% of theory), 20 Oil, Rf value: 0.61 (aluminium oxide, eluant: 3% ethanol in methylene chloride) Calculated: C 70.40 H 8.41 N 3.16 Found: 70.26 8.33 3.05 Example 2 6,7-Dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene hydrochloride To a solution of 2.73 g (0.006 mol) of 3-(6,7-dimethoxy- 1-oxo-l,2,3,4-tetrahydro-naphthalen-2-yl)-N-(2-(3,4dimethoxy-phenyl)-ethyl)-N-methyl-propionic acid amide in 30 ml of absolute tetrahydrofuran, 0.74 ml (0.006 mol) of boron trifluoride etherate are added, under nitrogen, and then 1.5 ml (0.015 mol) of borane-dimethylsulphide complex (10 molar solution) gt -I ~5 ii r r r I f 35 o 0 *i are added dropwise. The mixture is then refluxed for 6 hours. After the reaction mixture has cooled, methanol is added dropwise thereto. Then 5 ml of methanolic hydrochloric acid are added and the resulting mixture is refluxed for a further 2 hours.
The methanol and tetrahydrofuran are distilled off and after the addition of water to the residue it is neutralised with 2 molar sodium hydroxide solution. The greasy precipitate is extracted with methylene chloride. The organic phase is dried over magnesium sulphate, evaporated down in vacuo and the residue obtained is purified over 120 g of aluminium oxide (neutral, activity II-III) with methylene chloride and then increasing amounts 15 of ethanol (up to The hydrochloride is precipitated from a solution in acetone using methanolic hydrochloric acid.
Yield: 1.24 g (44.6% of theory), 143-145°C, Calculated: C 67.29 H 8.25 N 3.02 Found: 67.16 8.18 3.07 Example 3 6,7-Dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)methylamino)-propyll]-1-oxo-1,2,3,4-tetrahydronaphthalene hydrochloride A mixture of 4.43 g (0.01 mol) of 6,7-dimethoxy- 2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)-methylamino)p lopyll]-l-hydroxy-1,2,3,4-tetrahydronaphthalene, 21 80 g (0.025 mol) of potassium tert.butoxide, 9.10 g (0.05 mol) of benzophenone and 100 ml of toluene is refluxed for 4 hours. After cooling, the reaction mixture is washed twice with water, then extracted three times with 1% hydrochloric acid. The hydrochloric acid phases are combined and neutralised with concentrated sodium hydroxide .e rr i.
r r r r Ci-(t~ L i rr i i
Q
IIUU4~- -36 solution. The greasy precipitate is extracted with methylene chloride. The organic phase is dried over magnesium sulphate, concentrated by evaporation in vacuo and purified over 300 g of aluminium oxide (neutral, activity II-III) with methylene chloride~ and then with increasing amounts of ethanol Cup to The hydrochloride is precipitated from a solution in acetone using methanolic hydrochloric acid.
Yield: 1.7 g (35.6% of theory), 160-162-C, Calculated: C 65.33 H 7.59 N 2.93 Found: 65.40 7.50 2.77 15 Example 4 0 6,7-Dimethoxy-2-[3-( (2-(4-benzyloxyphenyl)-ethyl)- *0 methylamino) -propyl]-1,2,3,_4-tetrahydronaphthalene hydrochloride Prepared analogously to Example 2 from 3-(6,7-dimethoxy- 000 l-oxo-l,2,3,4-tetrahydronaphthalen-2-yl) (2-(4-benzoyloxyphenyl) -ethyl) -N-methyl-propionic acid amide.
Yield: 21% of theory, "O.VO 25 171-173 0
C,
Calculated: C 72.99 H 7.90 N 2.75 Found: 73.10 8.07 2.71 Example 6,7-Dimethoxy-2-[3-( (4-aminophenyl) -ethyl) -methylamino) pro yl]l2,3,4-tetrahydronaphthalene dihydrochloride Prepared analogously to Example 2 from 3-(6,7-dimethoxy- 1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-N-(2-(4aminophenyl) ethyl) -N-methyl-propionic acid amide.
Yield: 320 mg (23% of theory), -37 220-C, Calculated: C 63.29 H 7.97 N 6.15 Found: 63.10 7.91 6.08 Example 6 6,7-Dimethoxy-2-[3-( (2-(4-nitrophenyl)-ethyl)_-methylamino) -propyll 4-tetrahydronaphthalene A mixture of 1.0 g (0.0038 mol) of 6,7-dimethoxy- 2- (3-methylaminopropyl) 4-tetrahydronaphthalene, 0.87 g (0.038 mol) of 2-(4-nitrophenyl)ethyl bromide and 1.1 ml (0.008 mol) of triethylamine is refluxed for 2 hours. After the reaction mixture has cooled it is dissolved in a mixture of 2 molar sodium hydroxide solution and methylene chloride. The organic phase is separated off, washed with water, dried over magnesium sulphate, evaporated down in vacuo and purified over 120 g of aluminium oxide (neutral, activity II-III) with methylene chloride and then with increasing amounts of ethanol (up to Yield: 210 mg (16% of theory), Oil, R f value: 0.69 (aluminium oxide, eluant: 2% ethanol in methylene chloride) Calculated: C 69.88 H 7.82 N 6.79 Found: 69.87 7.61 6.67 Example 7 6,7-Dimethoxy-_2-[3-( (2-(4-acetaminophenyl) -ethyl)methylamino) -propyl] 4-tetrahydronaphthalene hydrochloride 0.76 g (0.002 mol) of 6,7-dimethoxy-2-[3-((2-(4aminophenyl)-ethyl)-methylamino)-propyl]-l,2,3,4tetrahydronaphthalene and 0.3 ml (0.002 7 mol) 1 a
F
38 of triethylamine are dissolved in 10 ml of methylene chloride and 0.16 ml (0.0022 mol) of acetyl chloride are added dropwise with stirring. After 30 minutes, water is added. The aqueous phase is extracted three times with methylene chloride. The organic phase is dried over magnesium sulphate and evaporated down in vacuo. The hydrochloride is precipitated from a solution of the resulting residue in acetone, using ethereal hydrochloric acid.
Yield: 0.25 g (27% of theory), 129-131 0
C,
Calculated: C 67.73 H 8.09 N 6.08 Cl 7.69 Found: 67.60 8.45 5.89 7.73 t I#t t1 ~-4 I I 4* I *1 I I ~1
I.
I
I.
I.
III
I.
I I I 14* I 1.1 I
I.
1114 S I 9* I t I I S
S
*e~44JS S I 15 Example 8 6,7-Dimethoxy-2-[3-((2-(4-hydroxyphenyl)-ethyl)methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene 9.1 g (0.019 mol) of 6,7-dimethoxy-2-[3-((2-(4benzyloxyphenyl)-ethyl)-methylamino)-propyl]-1,2,3,4tetrahydronaphthalene are hydrogenated in 100 ml of glacial acetic acid in the presence of 1.2 g of 10% palladium/charcoal for 5 hours at ambient 25 temperature under 5 bars of hydrogen. Then the catalyst is removed by suction filtering and the glacial acetic acid is distilled off in vacuo.
The residue obtained is mixed with 10% sodium hydroxide solution and extracted three times with ethyl acetate.
The organic phase is dried over magnesium sulphate and evaporated down in vacuo.
Yield: 6.1 g (83% of theory), 90-91 0
C,
Calculated: C 75.16 H 8.67 N 3.65 Found: 75.00 8.79 3.73
I
in 39 Example 9 6,7-Dimethoxy-2-[3-( (4-methanesulphonyloxyphcnyl) ethyl) -methylamino) -propyl] 4-tetrahydronaphthal.ene hydrochloride 0.96 g (0.0025 mol) of 6,7-dimethoxy-2-[3-((2-(4hydroxyphenyl) -ethyl) -methylamino) -propyll-1, 2,3,4tetrahydronaphthalene are dissolved in 5 ml of pyridine and 0.27 ml (0.0035 mol) of methanesuiphonic acid chloride are added dropwise with stirring.
-After 1 hour, 10% sodium hydroxide solution is added. The aqueous phase is extracted three times with methylene chloride. The organic phase is 15 dried over magnesium sulphate and evaporated down in vacuo and purified over 80 g of aluminium oxide (neutral, activity II-III) with methyl chloride.
The residue obtained is taken up in ether and the hydrochloride is precipitated with ethereal hydrochloric 20 acid.
Yield: 0.38 g (31% of theory) 145-146 0
C,
Calculated: C 60.29 H 7.29 N 2.81 S 6.44 Cl 7.12 Found: 60.35 7.38 2.85 6.27 7.39 C C( r C C C C C 4 t I I 4 cct 4 44 Example
I
(~I
S
9
S
4~4 9 6,7-Dimethoxv-2-[3-( (2-(4-benzyloxyphenyl) -ethyl)methylamino) -propyl]j-1,2,3,4-tetrahydronaphthalene hydrochloride Prepared analogously to Example 6 from 6,7-dimethoxy- 2- (3-bromopropyl) 2,3, 4-tetrahydronaphthalene and N-methyl- (4-benzyloxyphenyl) -ethylamine.
Yield: 43% of theory 171-1-i31-C
N
-I)
AW'
40 Example 11 6,7-Dimethoxy-2-[3-((2- (4-trifluoromethanesulphonyloxyphenyl) -ethyl) -methylamino) -propyll 4-tetrahydronaphthalene hydrochloride Prepared from 6,7-dimethoxy-2-j3-( (2-(4-hydroxyphenyl)ethyl) -methylamino) -propyll 4-tetrahydronaphthalene and trifiuoromethanesulphonic acid chloride analogously to Example 9.
Yield: 69% of theory, 135-137-C, Calculated: C 54.39 H 6.03 N 2.54 Cl 6.42 S 5.81 Found: 54.34 6.28 2.74 6.69 6.05 #0 t Example 12 ~6,7-Dimethoxy-2-73-( (4-cyanomethoxpey)-ty) methylamino) -propyll-1,2,3, 4-tetrahydronaphthalene hydrogen tartrate Prepared from 6,7-dimethoxy-2-[3- (4-hydroxyphenyl)- 0 Oae -methylamino) -propyl] 4-tetrahydronaphthalene and chloroacetonitrile analogously 425 to Example 16.
Yield: 31% of theory, 63-68-C Calculated: C 62.92 H 7.04 N 4.89 Foundfl 62.64 7.01 4.80 Example 13 6,7-Dimethoxy-2-[3-((2-(4-trifluoromethoxyphenyl)ethyl) -methylamino) -propyl] 4-tetrahydronaphthalene-hydrochloride Prepared from 6,7-dimethoxy-2- (3-methylaminopropyl) 1,2,3,4-tetrahydronaphthalene and 2-(4-trifluoromethoxy- -41phenyl)-ethyl bromide analogously to Example 6.
Yield: 50% of theory, M.P. 124-125 0
C
Calculated: C 61.53 H 6.82 N 2.87 Cl 7.27 Found: 61.43 7.03 2.85 7.55 Example 14 6,7-Dimethoxy-2-[3-( (2-(4-methanesulphonylaminophenyl)ethyl)-methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene hydrochloride Prepared from 6,7-dimethoxy-2-[3-( (2-(4-aminophenyl)- -methylamino) -propyl] 4-tetrahydroaphthalene and methanesulphonic acid chloride analogously to Example 7.
Yield: 30% of theory, 177-179 0
C
Calculated: C 60.40 H 7.50 N 5.64 Found: 60.60 7.61 5.70 Example 6,7 Dimethoxcy-2-[3-( (2-(4-methoxycarbonylaminophenyl) 25 ethyl) -methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene hydrogen fumarate ~*Prepared 'from 6,7-dimethoxy-2-[3-((2-(4-aminophenyl)ethyl) -methylamino) -propyl]-l,2,3, 4-tetrahydronaphthalene and methyl chloroformate analogously to Example 7.
Yield: 23% of theory, 156-160 0 C (decomposition) Calculated: C 64.73 H 7.24 N 5.03 Found: 65.03 7.08 5.20 42 Example 16 6,7-Dimethoxy-[3-((2-(4-ethoxycarbonylmethoxyphenyl)ethyl)-methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene hydrochloride A mixture of 1.15 g (0.003 mol) of 6,7-dimethoxy- 2-[3-((2-(4-hydroxyphenyl)-ethyl)-nmethylamino)propyl]-1,2,3,4-tetrahydronaphthalene, 0.34 g (0.003 mol) of potassium tert.butoxide and 10 ml of dimethyl sulphoxide is heated to 50 0 C for 1 hour. Then g (0.003 mol) of bromoacetic acid ester are added and the mixture is heated to 50 0 C for a further hour. After the reaction mixture has cooled, water
I.
is added and it is extracted with ethyl acetate.
tes The organic phase is dried over magnesium sulphate, evaporated down in vacuo and purified over 60 g *0* of silica gel (32-63 microns, Messrs. Woelm) with methylene chloride and then with increasing amounts S" 20 of ethanol (up to The hydrochloride is precipitated from a solution in acetone using methanolic hydrochloric acid.
*4 Yield: 0.2 g (13% of theory), 134-136 0
C
's 25 Calculated: C 66.45 H 7.97 N 2.77 Cl 7.01 Found: 66.31 7.91 2.74 7.15 C"Eek Example 17 C a 6,7-Dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)methylamino)-propll-1,2-dihydronaphthalene hydrochloride g (0.011 mol) of 6,7-dimethoxy-2-[3-((2-(3,4dimethoxyphenyl)-ethyl)-methylamino)-propyl]-lhydroxy-1,2,3,4-tetrahydronaphthalene are dissolved in 40 mi of acetone and methanolic hydrochloric acid is added. The resulting mixture is.stirred 0I 4 J_ I 43 43 for 30 minutes at ambient temperature, then ether is added dropwise until slight turbidity occurs and the mixture is then stirred for a further minutes. The precipitate obtained is suction filtered and dried.
Yield: 4.8 g (92% of theory), 171-172 0
C
Calculated: C 67.59 H 7.85 N 3.03 Found: 67.51 8.06 3.27 Example 18 I 5,6-Dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)methylamino) -propyl]-l-hydroxy-indan ,i Is a, Prepared from 3-(5,6-dimethoxy-l-oxo-indan-2-yl)- N-(2-(3,4-dimethoxyphenyl)-ethyl)-N-methylpropionic acid amide analogously to Example 1.
Yield: 58% of theory, 20 83-85 0
C
Calculated: C 69.90 H 8.11 N 3.26 Found: 69.18 8.19 3.13 Example 19 5,6-Dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)- Sv methylamino)-propyl]-l-oxo-indan Prepared from 5,6-dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)ethyl)-methylamino)-propyl]-1-hydroxy-indan and benzophenone analogously to Example 3.
Yield: 16% of theory, 98-100oC Calculated: C 64.71 H 7.39 N 3.02 Found: 64.80 7.39 2.95 4 r" v4~.7 jT:l.~; I
I
~lrY~a~snrsl~nr~wars~~-i s"p"- I Qr,.
44 Example o 9 4 9 .o
S
4 9 6,7-Dimethoxy-2-[3-((2-(4-hydroxycarbonylmethoxyphenyl)ethyl)-methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene 4.1 ml of 0.1 N sodium hydroxide solution are added dropwise to a solution of 700 mg (0.014 mol) of 6,7-dimethoxy-2-[3-((2-(4-ethoxycarbonylmethoxyphenyl)ethyl)-methylamino)-propyl]-l,2,3,4-tetrahydronaphthalene in 10 ml of methanol, then the mixture 10 is stirred for 25 minutes at ambient temperature and finally 4.1 ml of 0.1 N hydrochloric acid are added. The solution is extracted several times with ethyl acetate and after the combined organic phases have been dried over magnesium sulphate 15 they are evaporated down in vacuo. The residue is taken up in a little methylene chloride, filtered and the filtrate is evaporated to dryness.
Yield: 240 mg (36% of theory), 71 0
C
Calculated: C 70.72 H 7.99 N 3.17 Found: 70.49 7.74 3.06 Example 21 44444'
S
544544 L 4 25 6,7-Dimethoxy-2-[3-((2-(4-(N,N-bis-methanesulphonylamino)-phenyl)-ethyl)-methylamino)-propyl]-1,2,3,4tetrahydronaphthalene hydrochloride Prepared from 6,7-dimethoxy-2-[3-((2-(4-aminophenyl)ethyl)-methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene and methanesulphonic a id chloride analogously to Example 14.
Yield: 15% of theory, 106-108 0 C (decomp.) Calculated: C 54.29 H 6.83 N 4.87 if ~s ~rl 7
I
45 Found:- 54.10 6.77 4.62
I:
I-
f. ttr It ft t I I ft I If I I I I I II
I.
4 I 4.
*4 *4 4 44* V V
V.
I
V
V# V 4k f I.ct ~.Ct t I Example 22 6,7-Dimethoxy-2-[3-( (3-(4-brornophenyl)-propyl) methylamino) -propyl 1-1,2,3, 4-tetrahydronaphthalerie hydrogen fumarate Prepared from 6,7-dimethoxy-2-(3-methylamino-propyl) 1,2,3,4-tetrahydronaphthalene and 3-(4-bromophenyl)- 1-bromopropane analogously to Example 6.
Yield: 35% of theory, 59-C Calculated: C 60.42 H 6.65 N 2.43 15 Found: 60.10 6.43 2.40 Example 23 6,7-Djmethoxy-2-13-( (3-(4-cyanophenyl)-propyl) 20 methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene hydrogen fumarate Prepared from 6, 7-dimethoxy-2- (3-methylamino-propyl) l,2,3,4-tetrahydronaphthalene and 3-(4-cyano-phenyl) 1-bromopropane analogously to Example 6.
Yield: 58% of theory, decomposition from 57 0
C
Calculated: C 68.94 H 7.33 N 5.36 Found: 68.71 7.15 5.20 Example 24 6,7-Dimethoxy-2-13-( (2-(4-methylsulphonylphenyl) ethyl) -methylamino) -propyl 1-1,2,3, 4-tetrahydronaphthalene Prepared from 6,7-dimethoxy-2-(3-methylamino-propyl) i,2,3,4-tetrahydronaphthalene and 2- (4-methylsulphonyljj m -fig' -46 phenyl)-l-bromoethane analogously to Example 6.
Yield: 10.4% of theory, Oil, R f value: 0.63 (aluminium oxide, eluant: 3% ethanol in methylene chloride) Calculated: C 67.32 H 7.85 N 3.14 Found: 67.14 7.98 3.25 Example 6,7-Dimethoxy-2-[3-( (4-methoxyphenyl) -propyl) methylamino) -propyl]-1,2,3,4-tetrahydronaphthalene Ge.. Prepared from 6,7-dimethoxy-2- (3-methylamino-propyl) C l,2,3,4-tetrahydronaphthalene and 3-(4-methoxyphenyl)- .:15 1-bromopropane analogously to Example 6.
Yield: 68.7% of theory, 39-C Calculated: C 75.87 H 8.82 N 3.40 Found: 75.69 8.94 3.59 .Example 26 C 6,7-Dimethoxy-2-[3-( (2-phenyl-ethyl) -methylamino)propyl] 4-tetrahydronaphthalene Prepared from 2-phenyl-1-chloroethane and 6,7-dimethoxy- 2- (3-methylamino-propyl) 4-tetrahydronaphthalene analogously to Example 6.
Yield: 42% of theory, Oil, R f-value: 0.42 (aluminium oxide, eluant: 2% ethanol in methylene chloride) Calculated: C 78.43 H 9.05 N 3.81 Found: 78.63 9.29 3.66
IV~
47 Example 27 5,6-Dimethoxy-2- ((4-benzyloxyphenyl) -ethyl) -methylamino) -propyl) -1-hydroxy-indan Prepared from 3- (5 ,6-dimethoxy-l-oxo-indan-2-Yl) N-(2-(4-benzyloxyphenyl) -ethyl) -N-methyl propionic acid amide and lithium aluminium hydride analogously to Example 1.
#3 999 3 9 39 9 99 9 .3 9 *3 .9 9 *3 .9 .9.
S 993 9 9 93 4 99 a .9.99.
a a 4e9993 3 Yield: 90% of theory, 80-83 0
C
Calculated: C 75.76 Found: 75.58 H 7.84 N 2.95 8.01 2.79 Example 28 6, 7-Dimethoxy-2- (2-hydroxyethoxy) -phenyl) ethyl) -methylamino) -propyl 1-1,2,3, 4-tetrahydronaphthalene 20 hydrochloride Prepared from 6,7-dimethoxy-2-[3- ((2-(4-ethoxycarbonylmethoxyphenyl) -ethyl) -methylamino) -propyl 1-1,2,3,4tetrahydronaphthalene and lithium aluminium hydride analngously to Example 1.
Yield: 43% of theory, 141-143-C Calculated: C 67.30 H 8.25 N 3.02 Cl 7.64 Found: 67.20 -8.28 3.04 7.65 Example 29 6,7-Dimethoxy-2-_[3-( (2-(4-(4-benzyloxyphenyl)-ethvl)methylamino) -propyl] -l-hydroxy-1, 2,3, 4-tetrahydronaphthalene Prepared from 3-(6,7-dimethoxy-l-oxo-1,2,3,4-tetrahydronaphthalen-2-yi) (4-benzyloxyphenyl) -ethyl) N-methylpropionic acid amide and lithium aluminium
H
48 hydride analogously to Example 1.
Yield: 53.6% of theory, 75 0
C
Calculated: C 70.77 H 7.66 N 2.66 Found: 71.00 7.52 2.56 Example 6,7-Dimethoxy-2-[3-((2-(4-hydroxypheuyl)-ethyl)methylamino) -propyl] -l-hydroxy-1, 2,3, 4-tetrahydronaphthalene Prepared from 6,7-dimethoxy-2-[3-((2-(4-benzyloxyphenyl) -ethyl) -methylamino) -propyll -l-hydroxy-1, 2,3,4- 15 tetrahydronaphthalene and hydrogen analogously to Example 8.
Yield: 47.5% of theory, 97 0
C
Calculated: C 72.15 H 8.33 N 3.51 Found: 72.14 8.43 3.53 Example 31 9*49 6,7-Dimethoxy-2-[3-((2-(4-methanesulphonyloxy--phenyl)ethyl)-methylamino)-propyl]-l-hydroxy-1,2,3,4-tetrahydro- ***etc naphthalene Prepared from 6,7-dimethoxy-2-[3-((2-(4-hydroxyphenyl)-ethyl)-methylamino)-propyl-l-hydroxy-i,2,3,4tetrahydro-naphthalene and methanesulphonic acid chloride analogously to Example 9.
Yield: 16.7% of theory, oil, Rf value: 0.4 (aluminium oxide, eluant: 5% ethanol in methylene chloride) Calculated: C 62.87 H 7.39 N 2.93 Cl 6.71 Found: 62.05 7.50 2.75 6.88 a i P1- 49 Example 32 6,7-Dimethoxy-2-[3-( (2-(4-trifluoromethanesulphoflyloxyphenyl) -ethyl) -methylamino)-ppyj]-l-ydroxy-1, 2 3 4 tetrahydronaphthalene Prepared from 6,7-dimethoxy-2-[3-( (2-(4-hydroxyphenyl) -ethyl) -methylamino) -propyll -l-hydroxy-1, 2,3,4tetrahydronaphthalene and trifluoromethanesuiphonic acid chloride analogously to Example 9.
Yield: 54.8% of theory, 119-C Calculated: C 56.49 H 6.07 N 2.63 Cl 6.03 Found: 56.36 6.01 2.49 6.86
'I
ti 4 4 U It I 41 t 4 4 4 w ii
SI
44 4 4 44 .4 4 440 4 4*4 4* ~4 4 4 4. 4 44494 9 4 Example 33 6, 7-Dimethoxy-2- (4-ethoxycarbonylmethoxyv~henvl) -ethyl) -methylamino) -propyll -l-hydroxy-1, 2,3,4- 20 tetrahydronaphthalene Prepared from 6,7-dimethoxy-2-[3-( (2-(4-hydroxyphenyl) -ethyl) -methylamino) -propyl]-1-hydroxy-l,2,3,4tetrahydronaphthalene and ethyl bromoacetate analogously to Example 9.
Yield: 29% of theory, Oil, R f value: 0.2 (aluminium oxide, eluant: 3% ethanol in methylene chloride) Calculated: C 69.25 H 8.09 N 2.88 Found: 69.00 7.93 2.63 Aft rn F 50 Example 34 6,7-Dimethoxy-2-[3-( (4-hydroxycarbonylmethoxyphenyl) -ethyl) -methylamino) -propyl] -l-hydroxy-l, 2,3,4.tetrahydronaphthalene Prepared from 6,7-dimethoxy-2-113-( (4-hydroxyphenyl) -ethyl) -methylamino) -propyl] -l-hydroxy-l,2,3, 4tetrahydronaphthalene and ethyl bromoacetate/sodium hydroxide solution analogously to Example Yield: 37% of theory, 92-C Calculated: C 68.25 H 7.71 N 3.06 Found: 68.58 7.63 2.92 r ff@ S S I 55 I 5* a is 5 5# 5 *5 a.
S
a *5* p p5 p p.
S S 4* S *54 lIt
I
S
I I' I I I I Example 6,7-Dimethoxy-2-[3-((2-(4-benzyloxyphenyl)-ethyl)methylamino) -propyl]-l-oxo-1, 2,3, 4-tetrahydronaphthalene 20 hydrochloride Prepared from 6,7-dimethoxy-2-[3-( (2-(4-benzyloxyphenyl) -ethyl) -methylamino) -propyl] -l-hydroxy-l, 2,3,4tetrahydronaphthalene and potassium tert. butoxide/benzophenone analogously to Example 3.
Yield: 26% of theory, 191-C Calculated: C 71.04 H 7.31 N 2.67 Cl 6.76 Found: 71.12 7.24 2.61 6.87 Example 36 6,7-Dimethoxy-2-[3-((2-(4-benzyloxyphenyl)-ethyl)methy, lamino)-propyl]-3,4-dihydronaphthalene hydrochloride Prepared from 6,7-dimethoxy-2-[3-( (2-(4-benzyloxyphenyl) thyl) -methylamino) -propyl] -1-hydroxy-1,2,3, 4- -51tetrahydronaphthalene and hydrochloric acid analogously to Example 17.
Yield: 18.6% of theory, 185-C Calculated: C 73.28 H 7.54 N 2.76 Cl 6.98 Found: 73.66 7.20 2.78 7.43 Example 37 6,7-Dimethoxy-2-[3( ((2-(4-hyd,.o.,phenyl)-ethyl)methylamino) -propyl]-3 ,4-dihydronaphthalene Prepared from 6,7-dirnethoxy-2-[3-( (2-(4-hydroxya 4 t f phenyl) -ethyl) -methylamino) -propyl]-1-hydroxy-1, 2,3,4tetrahydronaphthalene and hydrochloric acid analogously to Example 17.
Yield: 65% of theory, 0 air Oil, R f value: 0.83 (aluminium oxide, eluant: ethanol in methylene chloride) Calculated: C 75.56 H 8.19 N 3.67 Found: 75.29 8.10 3.62 Exarm~ple 38 6,7-Dimethoxy-2-[3- (4-methanesulphonyloxyphenyl) ethyl) -methylamino) -propyl]-3 ,4-dihydronaphthalene hydrochloride Prepared from 6,7-dimethoxy-2-[3-( (2-(4-methanesulphonyloxy-phenyl)-ethyl)-methylamino)-propyl]- 1-hydroxy-1,2,3,4-tetrahydronaphthalene and hydrochloric acid analogously to Example 17.
Yield: 42.8% of theory, 81 0 C (sinters from 59 0
C)
Calculated: C 58.41 H 7.06 N 2.72 Cl 6.89 S 6.24 Found: 58.60 7.07 2.54 7.00 6.37 I
I
ijr--i a i.e ci.
CO
0* a. a
C@
a.
.i.
a 0 a.
*0 a *4* a.
a 0~* 9* a a.
a a. e 52 Example 39 6,7-Dimethoxy-2-[3-( (4-trifluoromethanesulphonyloxyphenyl) -ethyl) -methylamino) -propyll-3 ,4-dihydronaphthalene Prepared from 6,7-dimethoxy-2-[3-( (2-(4-trifluoromethanesuiphonyloxyphenyl) -ethyl) -methylamino) -propyll-hydroxy-l,2,3,4-tetrahydronaphthalene and hydrochloric acid analogously to Example 17.
Yield: 77% of theory, Oil, R f value: 0.92 (aluminium oxide, eluant: 3% ethanol in methylene chloride) Calculated: C 58.47 H 5.89 N 2.73 Cl 6.24 Found: 58.61 5.88 2.54 6.75 Example 6-Dimethoxy-2-[ 3- (4-methoxyphenyl) -ethyl) methylamino) -propylj-l-hydroxy-indan oxalate Prepared from 3- 6-dimethoxy-1-oxo-indan-2-yl) N- (4-methoxyphenyl) -ethyl) -N-methylpropionic acid amide and lithium aluminium hydride analogously to Example 1.
Yield: 90% of theory, 80-83 0
C
Calculated: C 63.79 H 7.21 N 2.86 Found: 63.55 7.31 3.02 Example 41 5,6-Dimethoxy-2-13- (4-methoxyphenyl) -ethyl) methylamino) -propyl]-l-oxo-indan hydrochloride Prepared from 5,6-dimethoxy-2-[3-( (2-(4-methoxyphenyl)ethyl) -methylamino) -propyl]-1-hydroxy-indan and benzophenone analogously to Example 13.
I t I *4 eat C a C Cit a a 11 53 Yield: 21% of theory, 193-194 0
C
Calculated: C 66.42 Found: 66.30 H 7.43 N 3.23 7.58 3.39 Cl 8. 17 8.30 9* 9 *9* .9 .9 9 *9 .9 .4 9 9 .4
S.
9 9.
*99 p 94 9 9 99 9S 9. 5 tr 9 1 5 1 5
S
Example 42 5,6-Digaethoxy-2-[3- (4-benzyloxyphenyl) -ethyl) methylamino) -propyllj-l-hydroxy-indan Prepared from 3-(5,6-dimethoxy-1-oxo-indan-2--yl)- N- (4-benzyloxyphenyl) -ethyl) -N-methylpropionic acid amide and lithium aluminium hydride analogously to Example 1.
15 Yield: 90% of theory, 80-83-C Calculated: C 75.76 H 7.84 N 2.95 Found: 75.58 8.07 2.79 20 Example 43 5,6-Dimethoxy-2-13- ((2--(4-benzyloxyphenyl) -ethyl) methylamino) -propyl]-l-oxo-indan hdrochloride Prepared from 5,6-dimethoxy-2-[3-( (2-(4-benzyloxyphenyl)ethyl) -methylamino) -propyl]-l-hydroxy-indan and benzophenone analogously to Example 3.
Yield: 12% of theory, 189-191 0
C
Calculated: C 70.64 H 7.11 N 2.75 C1 6.95 Found: 70.50 7.22 2.83 7.20 -11 e:reparea rrom to,/-aimetnoxy-z-(i-metnyiaminopropyl)-I l,2,3,4-tetrahydronaphthalene and 2-(4-trifluoromethoxy- 54 Example 44 5,6-Dimethoxy-2-[3-( (4-methylphenyl) -ethyl) methylamino) -propyl]-1-hydroxy-indan Prepared from 3- (5,6-dimethoxy-l-oxo-indan-2-yl) N- (4-methyiphenyl) -ethyl) -N-methylpropionic acid amide and lithium aluminium hydride analogously to Example 1.
Yield: 83% of theory, 89-90-C Calculated: C 75.16 H 8.67 N 3.65 Found: 74.96 8.65 3.58 15 Example 5,6-Dimethoxy-2-[3- (4-methylphenyl) -ethyl) 4.
4 S *4 9
S
SO
S.
*t 9 9 *9 4.
9..
methylamino) -propyl]-l-oxo-indan hydrochloride 9.
9# o 94, *4 @4 4*4e @4 9* 9 4.
444 44.~ 4.
4 20 Prepared from 5,6-dimiethoxy-2-[3- (4-methiylphenyl) ethyl) -methylamino) -propyl]-l-hydroxy-indan and benzophenone analogously to Exam~ple 3.
Yield: 19% of theory, 193-194 0
C
Calculated: C 68.96 H 7.72 N 3.35 Cl 8.48 Found: 68.86 7.72 3.45 8.63 Example 46 4-Methyl-2-t 3-C methylamino) -propyl]-1-hydroxy-indan oxalate Prepared from 3-(4-methyl-l-oxo-indan-2-yl)-N- (2- 5-dimethoxy-phenyl) -ethyl) -N-methylpropionic acid amide and lithium aluminium hydride analogously to Example 1.
Yield: 90% of theory, 7 p..
he 55 M.p.:82-83 0
C
Calculated: Found: C 65.94 66.03 H 7.45 N 2.96 7.55 3.05 r
I
I t LI I It
II
4 6 *1 4, 4 .44 .4 4.
444 4.
.4 4 4.
.444 4.
44 4
I
I
I
Example 47 4-Methyl-2-[3-( (2-(3,5-dimethoxyphenyl)-ethyl)methylamino) -propyl]-l-oxo-indan Prepared from 4-methyl-2-[3-( (2-(3,5-dimethoxyphenyl)ethyl) -methylamino) -propyl]-l-hydroxy-indan and benzophenone analogously to Example 3.
Example 48 20 4-Methyl-2-13-( (2-phenylethyl) -methylamino) -propyll- 1-hydroxy-indan oxalate Prepared from 3- (4-methyl-l-oxo-indan-2-yl) (2phenylethyl) -N-methylpropionic acid and lithium aluminium hydride an -'logously to Example 1.
Yield: 90% of theory, 88-90*C Calculated: C 69.71 H 7.56 N 3.39 Found: 69.57 7.63 3.31 Tqq Example 49 4-Methiyi-2-[ 3- ((2-phenyl-ethyl)-methylamino) -propyll- 3-oxo-indan fumarate Prepared from 4-methyl-2-[3-( (2-phenyl-ethyl)-methylamino)propyll-1-hydroxy-indan and benzophenone analogously
I
56 to Example 3.
yield: 5% of theory, 118-121 0
C
Calculated: C 71.37 Found: 71.91 H 7.14 N 3. 7.33 3.31 4.
4 444 44*4 4.
#4 4 44 4 4 9 4 44 4 9 49 4.
4 9 444 44 4 4 .4, 44 94 4 4 #4 ExaMplte 4-Methyl-2-13-( (2-(3,4,5-trimethoxyphenyl)-ethYl)methylamino) -propyi'J-l-hydroxy-indan Prepared from 3-t4-methyl-1-oxo-indan-2-yl) (3,4,5-trimethoxyphenyl)-ethyl) -N-methylpropionic acid amide and lithium aluminium hydride analogously 15 to Example 1.
,Yield: 85% of theory, 75-77*C Calculated: C 64.40 H 7.41 N 2.78 Found: 64.49 7.38 3.09 Example 51 .444 4 49 44 4 4-Methyl-2-[3-( (2-(3,4,5-trimethox phenyl)-ethyl)methylamino) -propyll-1-oxo-indan Prepared from 4-.methyl-2-[3-( (2-(3,4,5-trimethoxyphe,'nyl) -ethyl) -methylamino) propyl]-l-hydroxy-indan and benzophenone analogously to Example 3.
4' ('f
C
I C 4 -57 Example 52 5,6-Dimethoxy-2-[j3-( (2-(4-benzyloxypheny l)-ethylmethylamino)-propyl]-indene hydrochloride Prepared from 5,6-dimethoxy-2-13-( (2-(4-benzyloxyphenyl)ethyl) -methylamino) -propyl]-1-hydroxy-indan and hydrochloric acid analogously to Example 17.
Yield: 88% of theory, 181-183-C Calculated: C 72.93 H 7.34 N 2.84 Cl 7.18 Found: 72.50 7.39 2.62 7.32 Example 53 5,6-Dimethoxy-2-[3- (4-methoxyphenyl) -ethyl)methylamino) -propyl]-indene hydrochloride Prepared from 5,6-dimethoxy-2-[3-( (2-(4-methoxyphenyl)ethyl)-methylamino)-propyl]-l-hydroxy-indan and hydrochloric acid analogously to Example 17.
Yield: 68% of theory, aM.p.: 188-190 0
C
Calculated: C 68.96 H 7,72 N 3.35 Cl 8.48 Found: 68.86 7.72 3.25 8.68 Example 54 5,6-Dimethoxy-2-[3- (4-methylphenyl)-ethyl)methylamino)-propyl]-indene hydrochloride Prepared from 5,6-dimethoxy-2-[3-( (2-(4-methylphenyl)ethyl) -methylamino) -propyl]-l-hydroxy-indan and hydrochloric acid analogously to Example 17.
Yield: 72% of theory, 205-207 0
C
Calculated: C 71.71 H 8.02 N 3.48 Cl 8.82 1 1 58 Found: 71.63 8.04 3.48 8.94 Example 7-Methyl-2-[3-( methylamino) -propyl]-indene oxalate Prepared from 4-methyl-2-13-( (2-(3,5-dimethoxyphenyl)ethyl) -methylamino) -propyl]-1-hydroxy-indan and hydrochloric acid analogously to Example 17.
Yield: 37% of theory, 133-134-C Calculated: C 68.55 H 7.30 N 3.07 Found: 68.43 7.45 3.17 44' t 44 004 .0 Example 569 7-Methyl-2-I 3- ((2-phenylethyl) -methylamino) -propyl]indene fumarate Prepared from 4-methyl-2-[3- ((2-phenylethyl) -methylamino) propyl]-l-hydroxy-indan and hydrochloric acid analogously to Example 17.
Yield: 33% of theory, 124-126 0
C
Calculated: C 74.08 H 7.41 N 3.32 Found: 73.83 7.38 3.52 Example 57 7-Methyl-2-[3-((2-(3,4,5-trimethoxyphenyl)-ethyl)methylamino) -propyl]-indene oxalate Prepared from 4-methyl-2-[3-( (2-(3,4,5-trimethoxyphenyl)ethyl)-methylamino)-propyl]-l-hydroxy-indan and hydrochloric acid analogously to Example 17.
Yield: 28% of theory, A W1
I
59 102-104*C (decomp) Calculated: C 66.78 H 7.27 N 2.88 Found: 66.59 7.48 2.62 4 IE'( I- t f'~ 4, t 4£
I.
44 I 1£
'I
V C .9.
Ce
'C
a. gee b 04 4 b 4.
Example 58 5,6-Dimethoxy-2-[3-( (2-(4-benzyloxy,?henyl)-ethyl)methyl-amino) -propyl I-1-oxo- mnda hydrochlor ide Prepared from 5,6-dirnethoxy-2-[3-( (2-(4-benzyloxyphenyl)ethyl) -methylamino) -propyl]-l-hydroxy-indan and benzophenone analogously to Example 3.
Yield: 12% of theory, 189-191 0
C
15 Calculated: C 70.64 H 7.11 N 2.75 Cl1 6.05 Found: 70.50 7.22 2.83 7.10 Example 59 20 6,7-Dimethoxy-3-[3-( (2-(3-benzyloxyphenyl)-ethyl)methyl-amino) -propyl]-1,2-dihydro-naphthalene hydrochloride Prepared from 6 ,7-dimethoxy-2-[3- (3-benzyloxyphenyl) -ethyl) -methylamino) -propyl] 4-tetrahydro- 25 l-hydroxynaphthalene and hydrochloric acid analogously to Example 17.
Yield: 23% of theory, Calculated: C 73.28 H 7.54 N 2.76 Cl 6.98 Found: 73.12 7.46 2.89 7.02
IL
te kt -59a- Example 6, 7-Dimethoxy-2-[13- (4-methanesulphonyloxyphenyl ethyl)-methylamino )-propyl 11-l-oxo-l, 2, 3,4-tetrahydronaphthalene hydrochloride Prepared from 6, 7-dimethoxy-2- (2-(4-methanesulphonyloxy-phenyl )-ethyl )-methylamino)-propyl -l-hydroxy-l,2,3, 4-tetrahydronaphthalene and benzophenone analogously to Example 3.
Yield :53% of theory, Melting Point :183 0
C
Calculated C 58.64 H 6.69 N. 2.73 Cl 6.92 S 6.26 Found 58.48 6.93 2.68 7.22 6.50 Example 61 6,7-Dimethoxy-2-[ 3-methanesulphonyloxyphenyl ethyl )-methylamino)-propyl ]-l-oxo-l 2,3 ,4-tetrahydronaphthalene hydrochloride Prepared from 6,7-dimethoxy-2- 3-((2-(3-methanesulphonyloxyphenyl )-ethyl )-methylamino)-propyl -l-hydroxy-l ,2,3,4tetrahydronaphthalene and benzophenone analogously to Example 3.
Yield 28% of theory, 0 0 melting Point 81 ~C (sintering from 66 C) Calculated ;C58.64 H 6.69 N 2.74 Found .58.56 6.83 2.69 Example 62 6,7-Dimethoxy-2-[3-( (2-(3-benzyloxyphenyl)-ethyl)methylamino)-propylI-l-oxo- 2,3,4-tetrahydronaphthalene hydrochloride TF Prepared from 6,7-dimethoxy-2- (2-(3-benzyloxyphenyl)ethyl) -methylamino )-propyl -l-hydroxy-l 4-tetrahydronaphthalene and benzophenone analogously to Example 3.
Yield :27% of theory, Melting Point t 70 0 Calculated: C 71.04 H 7.31 N 2.67 Cl 6.77 Found 70.20 7.31 2.64 6.68 -59b- Example 63 6,7-Dimethoxy-2-[3-( (2-(3-hydroxyphenyl)-ethyl)methylamiino )-propyl]I-l-hydroxy- 2 4-tetrahydronaphthalene oxalate Prepared from 6,7-dimethoxy-2- (2-C 3-benzyloxyphenyl ethyl )-methylamino)-propyl -1-hydroxy 1,2,3, 4-tetrahydronaphthalene and hydrogen in the presence of palladium! charcoal analogously to Example 8.
Yield: 84% of theory, Melting Point: 77 C Calculated: C 63.79 H 7.21 N 2.86 Found 63.57 7.40 2.68 Example 64 6,7-Dimethoxy-2-[3-( (2-(3-hydroxyphenyl)-ethyl)methylamino)-propyl 3,4-tetrahydro-naphthalene hydrochloride Prepared from 6,7-dimethoxy-3- 3-C (2-(3-benzyloxyphenyl)ethyl) -methylamino) -propyl 1, 2-dihydronaphthalene and hydrogen in the presence of palladium/charcoal and in ethanol as solvent analogously to Example 8.
Yield: 65% of theory, S.0 Melting Point: sintering from 72 C Calculated: C 68.64 H 8.16 N 3.34 Cl 8.44 Found :68.50 7.95 3.02 8.84 Example 6,7-Dimethoxy-2-[3-( (2-(3-benzyloxyphenyl)-ethyl)methylamino )-propyl ]-l-hydroxy-1,2,3, 4-tetrahydronaphthalene oxalate Prepared from 7-dimethoxy-l-oxo-l, 2, 3,4-tetrahydronaphtha:Lene-2-yl 3-benzyloxyphenyl )-ethyl N-methylpropionic acid amide and lithium aluminium hydride analogously to Example 1.
Yield: 51% of theory, Melting Point: decomposition by 108 0
C
Calculated: C 68.37 H 7.13 N 2.42 Found :68.09 7.08 2.38 r 11I ExampleI Tablets containing 10 mg of 6,7-dimethoxy-2-3- 2 3 4 -dirnethoxyphenyl)-ethyl)-methylamino)propyl..
l-oxo-l, 2,3 ,4-tetrahydronaphithalene Composition: 1 tablet contains: Active substance Corn starch Lactose Polyvinylpyrrolidone Magnesium stearate 10.0 mg 57.0 mg 48.0 mg 4.0 mg 1.0 mg 120.0 mg 4.
4 *44 4.
4. 4 4. 4 4.
*4 4 4.
4 4.4 *4 04 o 4 .4 4.4.
4 9 4. 444404 4 4 *44*44 4 15 Preparation The active substance, corn starch, lactose and polyvinylpyrrolidone are mixed together and moistened with water. The moist mixture is pushed 20 through a screen with a mesh size of 1.5 mm and dried at about 45 0 C. The dry granulate is passed through a 1.0 mm mesh screen and mixed with magnesium stearate. The final mixture is compressed in a tablet press with dies 7 mm in diameter provided 25 with a dividing notch to form tablets.
Weight of tablet: 120 mg.
Example II Coated tablets containing 5 mg- of 6,7-dimethoxy- 30 2-f73-( 2 3 ,4-dimethoxyphenyl)-ethvl)-methvlamino)propyl] -l-oxo-l, 2,3, 4-tetrahydronaphthalene 1 tablet core contains: Active substance Corn starch Lactose Polyvinylpyr rol idone 5. 0 mg 41.5 mg 30.0 mg 3. 0 mg i. 61 Magnesium stearate Preparation 0.5 mg 80.0 mg The active substance, corn starch, lactose and polyvinylpyrrolidone are thoroughly mixed and moistened with water. The moist mass is forced through a 1 mm screen, dried at about 45 0 C and then the granulate is passed through the same screen. After magnesium stearate has been added, convex tablet cores with a diameter of 6 mm are compressed in a tablet making machine. The tablet cores thus produced are coated in known manner with a coating consisting essentially 15 of sugar and talc. The finished coated tablets are polished with wax.
Weight of coated tablet: 130 mg.
Example III Ampoules containing 5 mg of 6,7-dimethoxy-2-[3- ((2-(3,4-dimethoxyphenyl)-ethyl)-methylamino)-propyl]- 1-oxo-l,2,3,4-tetrahydronaphthalene
S..
SS S S S 0
S
S*
5 9 9
S
*4 *i t I t Sr 9c~
(O
L:
1 ampoule contains: 25 Active substance Sorbitol Water for injections ad 5.0 mg 50.0 mg 2.0 ml Preparation In a suitable mixing vessel the active substance is dissolved in water for injections and the solution is made isotonic with sorbitol. After being filtered through a diaphragm filter the solution is transfered under a current of N 2 into purified and sterilized ampoules and autoclaved for 20 minutes in a jet of steam.
62 Example IV Suppositories containing 15 mg of 6,7-dimethoxy- 2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)-methylamino)propyl]-l-oxo-1,2,3,4-tetrahydronaphthalene 1 suppository contains: Active substance 0.015 g Hard fat Witepsol H 19 and W 45) 1.685 g 1.700 g Preparation ;r *4 4.
4.
.4 .4 .4 4 4 '.4.e
I
C
The hard fat is melted. At 38 0 C the ground active substance is homogeneously dispersed in the melt.
15 It is cooled to 35°C and poured into slightly chilled suppository moulds.
Example V Drops solution containing 10 mg of 6,7-dimethoxy- 20 2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)-rthylamino)propyl]-1-oxo-1,2,3,4-tetrahydronaphthalene 100 ml of solution contain: Active substance Hydroxyethylcellulose Tartaric acid Sorbitol solution with dry matter Glycerol 30 Benzoic acid Dist. water 0.2 g 0.15g 0.1 g
S
4 30.0 g 10.0 g 0.1F g ad 100 ml Preparation The distilled water is heated to 70 0 C. The hydroxyethylcellulose, benzoic acid and tartaric acid are dissolved therein with stirring. The mixture is cooled to ail o r I-y I-q, 6 *0 9 9* #6 9 9 9 .9 #6.
6 *9* *P 9 -63 ambient temperature and the glycerol and sorbitol solution are added with stirring. At ambient temperature the active substance is added and stirred until completely dissolved. The syrup is then evacuated of any air with stirring.
K.
Claims (3)
1. A compound of formula I A R C 13 E N G 'CH2 E R (I) R 6 (wherein n represents the integer 1 or 2; 9, .99 *999 9 9 99 49 9 9 9 99 9 9* 9 9 9
4. 999 909 99 9 9 99 401k A represents a carbonyl group and R 7 represents a hydrogen atom, or R A represents a group of formula -CH- (wherein R 8 represents a hydrogen atom or a hydroxy, alkanoyloxy or alkoxycarbonyloxy group) and R 7 represents a hydrogen atom, or A and R 7 together form a group of formula -CH=; E represents a straight-chained C3- 4 alkylene group optionally substituted by an alkyl group; 9 499999 9 9
99.9.9 4 9 it. G represents a straight chained C2- 5 alkylene group optionally substituted by an alkyl group; R 1 represents a hydrogen or halogen atom, or a trifluoromethyl, nitro, amino, alkylamino, dialkylamino, alkyl, hydroxy, alkoxy or phenylalkoxy group, and R 2 represents a hydrogen or halogen atom or a hydroxy, alkoxy, phenylalkoxy or alkyl group, or _I jv i 1 4* *q 9* *r 0 0 U a a 0* .4 0* 65 R1 and R 2 together represent a C 1 2 alkylenedioxy group; R 3 represents a hydrogen, an alkyl group or a C3_ alkenyl group; R 4 represents a hydrogen or halogen atom, or an alkyl, amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulphonylamino, bis(alkyl- sulphonyl)-amino, N-alkyl-alkylsulphonylamino, cyano, alkylmercapto, alkylsulphinyl or alkylsulphonyl group, or a hydroxy group optionally substituted by an alkyl, phenylalkyl, 2-hydroxyethyl, 3-hydroxy- n-propyl, 2-hydroxy-n-propyl, alkylsulphonyl, cyanoalkyl, 15 alkoxycarbonyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, trifluoromethyl, difluoromethyl or trifluoromethyl- sulphonyl group, and R 5 represents a hydrogen or halogen atom or an 20 alkyl, hydroxy, alkoxy, nitro, cyano or trifluoromethyl group, or R 4 and R 5 together represent a C1- 2 alkylenedioxy group; and R 6 represents a hydrogen or halogen atom or an alkyl or alkoxy group; wherein unless otherwise defined any alkyl or alkoxy 30 moiety contains 1 to 3 carbon atoms and any alkanoyl moiety contains 2 or 3 carbon atoms) or an enantiomer, diastereomer or acid addition salt thereof. a 'C. EL 9 ai s *.00 I-r; 66 2. A compound of formula I as claimed in claim 1, wherein n represents the integer 1 or 2, A represents a carbonyl group and R 7 represents a hydrogen atom or R A represents a group of formula -CH- (wherein R 8 represents a hydrogen atom or a hydroxy group) and R 7 represents a hydrogen atom, or A and R 7 together represent a group of formula -CH=, E represents an n-propylene group, o* G represents an ethylene or n-propylene group, 4 R 1 represents a methyl or methoxy group, 20 R 2 represents a hydrogen atom or a methoxy group, R 3 represents a methyl group, R represents a hydrogen, chlorine or bromine atom, or a hydroxy, methoxy, cyano, cyanomethoxy, hydroxycarb- onylmethoxy, methoxycarbonylmethoxy, ethoxycarbonyl- methoxy, methyl, amino, acetylamino, methoxycarbonyl- amino, methylsulphonyloxy, trifluoromethylsulphonyloxy, I benzyloxy, methylsulphonylamino or bis(methylsulphonyl)- 30 amino group, R 5 represents a hydrogen, chlorine or bromine atom or a methoxy or nitro group, and R 6 represents a hydrogen, chlorine or bromine atom; i. 7 I I r a, a a *c a c a. Sc a Sa 4. ai a a. a., *i a 67 or an enantiomer, diastereomer or acid addition salt thereof. 3. A compound of formula I as claimed in either one of claims 1 and 2, wherein R 1 to R3, A, E, G and n are as defined in claim 1 or claim 2, R 4 represents a methoxy group, R 5 represents a methoxy group, and R 6 represents a hydrogen atom, or an enantiomer, diastereomer or acid addition salt thereof. 4. A compound of formula I as claimed in claim 1 being: 6,7-dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)- ethyl)-methylamino)-propyll-l-oxo-l,2,3,4-tetrahydro- naphthalene; 25 6,7-dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)- ethyl)-methylamino)-propyl]-1,2,3,4-tetrahydro- naphthalene; or an acid addition salt thereof. A compound as claimed in any one of claims 1 to 4 being a physiologically acceptable acid addition salt of a compound of formula I. 6. A pharmaceutical composition comprising a compound of formula I as claimed in any one of "i i i Ii 1 1 68 claims 1 to 4 or a physiologically acceptable acid addition salt thereof together with at least one pharmaceutical carrier or excipient. 7. A process for preparing compounds as claimed in any one of claims 1 to 5, said process comprising at least one of the following steps: a) (to prepare compounds of formula I wherein R 7 and R 8 each represent a hydrogen atom or R7 and A together represent a -CH= group) reacting a compound of formula II .9 9 V W9 S PS S 9*r *i V P4 A,1 A (C 2n -X (cH 2 )i (II) i 9. .1 o V .4 C PVV* (wherein R 1 R 2 n and E are as defined in claims 1 to 3; R 8 A 1 represents a group of formUla -CH- (wherein 25 R 8 represents a hydrogen atbm) and R 7 represents a hydrogen atom, or A 1 and R 7 and R 8 together represent a and X represents a nucleophilically exchangeable group) is reacted with an amine of formula III H 3- H N G (III) 4. J r-s- 0. C C *5 Sr o* 5 4 S S 9 5 69 (wherein R 3 to R 6 and G are as defined in any one of claims 1 to 3); b) reacting a compound of formula IV R 1 A R y 7 R2 CN R3 (IV) -O P /E N (CH 2 n E H (wherein n, A, E, R 1 to R 3 and R 7 are as defined in any one of claims 1 to 3) with a compound of formula V R4 Y- G 5 V) R 6 (wherein R 4 to R 6 and G are as defined in any one of claims 25 1 to 3, and Y represents a nucleophilically exchangeable group); c) (to prepare compounds of formula I wherein R8 A represents a group of formula -CH- (wherein R 8 represents a hydrogen atom or a hydroxy group)) reducing a compound of formula VI (7' y v j__I2 70 R A 2 R 2CH E N (G,.j 2 )n N ,C R (VI) R 6 ee 9 1 *0@ 04* 9 9* 9 S. 9 I 9. 9i *r *9 0 (wherein n and R 1 to R 6 are as defined in any one of claims 1 to 3; A 2 represents a carbonyl group and R 7 represents a hydrogen atom, or R 15 ,8 A 2 represents a group of formula -CH- (wherein R8 represents a hydrogen atom or a hydroxy group) and R 7 represents a hydrogen atom; 20 E' and G' have the meanings given in any one of claims 1 to 3 for E and G but with the exception that in the groups E' or G' a carbonyl group takes the place of a methylene group adjacent to the >N-R 3 25 moiety); d) (to prepare compounds of formula I wherein A represents a carbonyl group) oxidizing a compound of formula VII OH o I n *1 4 4t 9 9 n R 3 G (VII) R2 1- i -71 (where in n, E, G and Rlto R 6 are as defined in any one of claims 1 to 3); e) (to prepare compounds of formula I wherein R represents an aikylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulphonylamino, bis (alkyl- suiphonyl) amino, N-alkyl-alkylsulphonylamino, alkyl- mercapto, alkoxy, alkoxycarbonyloxy, hydroxycarbonyl- alkoxy, alkoxycarbonylalkoxy, phenylalkoxy, trifluoro- methoxy, difluoromethoxy, cyanoalkoxy, alkylsulphonyloxy or trifluoromethylsulphonyloxy group) reacting a compound of formula VIII R R IA 9 R9 R 6 6*9(wherein Rl, R j R r R 5 R r R A, E, G and n are as defined in any one of claims 1 to 3, and Rrepresents a hydroxy, amino or C alkylamino 9 C 1 3 group) with a compound of formula IX aa:Z R (IX) (wherein Z represents a nucleophilically exchangeable group, and R 10 represents an alkyl, alkanoyl, alkoxycarbonyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, alkylsulphonyl, phenylalkyl, trif'luoromethyl, difluoromethyl or cyanoalkyl group, 72 wherein any alkyl or alkoxy moieties each contain from 1 to 3 carbon atoms and any alkanoyl moiety contains 2 or 3 carbon atoms); f) (to prepare compounds of formula I wherein A and R 7 together represent a -CH= group) dehydrating a compound of formula X OH R I 'R4 CH 7 R2 C 5 (X) (CHN- G 2R 6 a• 0 0% 0 ao i h e r e in 00 n, E, G, R 1 R 2 R 3 R 4 R 5 R 6 and R are as defined in claims 1 to 3); g) if necessary, subsequently splitting off any protecting group used in the reaction steps a) to g) in order to protect reactive groups; h) converting a compound of formula I thus obtained wherein R 4 represents a benzyloxy group by debenzylation 04 0000 into the corresponding hydroxy compound; i) resolving a compound of formula I thus obtained, if it contains at least one chiral centre, into its diastereomers or its enantiomers; j) converting a compound of formula I thus obtained into an acid addition salt thereof, particularly a physiologically acceptable addition salt with an inorganic or organic acid. li-; l 73 8. A method of treatment of the human or non- human animal body to combat sinus tachycardia or ischaemic heart disease comprising the administration to said body of a compound of formula I (as defined in any one of claims 1 to 3) or a physiologically acceptable acid addition salt thereof. 9. Compounds of formula I as defined in claim 1 and salts thereof, substantially as herein disclosed in any one of the Examples. D A T E D this 9th day of March, 1990. DR. KARL THOMAW GMBH By its Patent Attorneys: *4 9 4 4 .4 9 9. 4~ CALLINAN LAWRIE ~IJ 4 9 V I I' t 94 49 9 4 44 rAIL 9 i411
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3630903 | 1986-09-11 | ||
| DE19863630903 DE3630903A1 (en) | 1986-09-11 | 1986-09-11 | NEW TETRAHYDRONAPHTHALINE AND INDANDERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THE MEDICINAL PRODUCTS CONTAINING THEM |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU7829787A AU7829787A (en) | 1988-03-17 |
| AU597719B2 true AU597719B2 (en) | 1990-06-07 |
Family
ID=6309344
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU78297/87A Ceased AU597719B2 (en) | 1986-09-11 | 1987-09-11 | Naphthalene and indan derivatives |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP0259782B1 (en) |
| JP (1) | JPS6377842A (en) |
| KR (1) | KR880003889A (en) |
| AT (1) | ATE59378T1 (en) |
| AU (1) | AU597719B2 (en) |
| DD (1) | DD263525A5 (en) |
| DE (2) | DE3630903A1 (en) |
| DK (1) | DK472387A (en) |
| FI (1) | FI873917A (en) |
| HU (1) | HU206077B (en) |
| IL (1) | IL83850A (en) |
| NO (1) | NO166528C (en) |
| NZ (1) | NZ221766A (en) |
| PH (1) | PH25680A (en) |
| PT (1) | PT85689B (en) |
| ZA (1) | ZA876768B (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8809314D0 (en) * | 1988-04-20 | 1988-05-25 | Wellcome Found | Anti-hypertensive sulfonanilides |
| EP0361577B1 (en) * | 1988-09-19 | 1993-05-05 | Akzo N.V. | Tetrahydronaphthalene and indane derivatives |
| JP2931986B2 (en) * | 1989-02-17 | 1999-08-09 | 武田薬品工業株式会社 | Aralkylamine derivatives |
| US5166209A (en) * | 1989-04-21 | 1992-11-24 | Burroughs Wellcome Co. | Pharmacologically active compounds |
| US5643784A (en) * | 1990-12-04 | 1997-07-01 | H, Lundbeck A/S | Indan derivatives |
| NZ243065A (en) | 1991-06-13 | 1995-07-26 | Lundbeck & Co As H | Piperidine derivatives and pharmaceutical compositions |
| SE9103745D0 (en) * | 1991-12-18 | 1991-12-18 | Wikstroem Haakan | ARYL-TRIFLATES AND RELATED COMPOUNDS |
| DK78692D0 (en) * | 1992-06-12 | 1992-06-12 | Lundbeck & Co As H | DIMER PIPERIDINE AND PIPERAZINE DERIVATIVES |
| US5508306A (en) * | 1992-11-13 | 1996-04-16 | Synaptic Pharmaceutical Corporation | Aromatic amine derivatives |
| AU7692394A (en) * | 1993-09-09 | 1995-03-27 | Smithkline Beecham Plc | Phosphinic acid derivatives with anti-hyper glycemic and/or anti-obesity activity |
| US6048877A (en) * | 1997-02-21 | 2000-04-11 | Bristol-Myers Squibb Company | Tetralone derivatives as antiarrhythmic agents |
| ES2300119T3 (en) | 1997-02-27 | 2008-06-01 | Takeda Pharmaceutical Company Limited | AMINA COMPOUNDS, ITS PRODUCTION AND ITS USE AS INHIBITORS OF THE PRODUCTION OF BETA-AMILOID. |
| DE60136446D1 (en) | 2000-04-03 | 2008-12-18 | Takeda Pharmaceutical | PROCESS FOR THE PREPARATION OF AMINE DERIVATIVES |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2678088A (en) * | 1987-12-14 | 1989-06-22 | Beecham Group Plc | Novel indane derivatives possessing smooth muscle relaxant activity |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CS159795B2 (en) * | 1971-04-19 | 1975-01-31 | ||
| CH654294A5 (en) * | 1982-07-09 | 1986-02-14 | Yason Srl | CARDIAC AND CEREBRAL LEVEL CALCIUM BLOCKING COMPOUNDS, METHOD FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS. |
| NZ213651A (en) * | 1984-10-11 | 1989-07-27 | Hoffmann La Roche | Tetrahydronapthalene derivatives and medicaments |
-
1986
- 1986-09-11 DE DE19863630903 patent/DE3630903A1/en not_active Withdrawn
-
1987
- 1987-09-03 AT AT87112865T patent/ATE59378T1/en not_active IP Right Cessation
- 1987-09-03 EP EP87112865A patent/EP0259782B1/en not_active Expired - Lifetime
- 1987-09-03 DE DE8787112865T patent/DE3767094D1/en not_active Expired - Lifetime
- 1987-09-09 NZ NZ221766A patent/NZ221766A/en unknown
- 1987-09-09 DD DD87306821A patent/DD263525A5/en not_active IP Right Cessation
- 1987-09-10 JP JP62227532A patent/JPS6377842A/en active Pending
- 1987-09-10 NO NO873784A patent/NO166528C/en unknown
- 1987-09-10 PH PH35795A patent/PH25680A/en unknown
- 1987-09-10 FI FI873917A patent/FI873917A/en not_active IP Right Cessation
- 1987-09-10 IL IL83850A patent/IL83850A/en not_active IP Right Cessation
- 1987-09-10 KR KR870010008A patent/KR880003889A/en not_active Application Discontinuation
- 1987-09-10 ZA ZA876768A patent/ZA876768B/en unknown
- 1987-09-10 DK DK472387A patent/DK472387A/en not_active Application Discontinuation
- 1987-09-10 HU HU874035A patent/HU206077B/en unknown
- 1987-09-11 AU AU78297/87A patent/AU597719B2/en not_active Ceased
- 1987-09-11 PT PT85689A patent/PT85689B/en not_active IP Right Cessation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2678088A (en) * | 1987-12-14 | 1989-06-22 | Beecham Group Plc | Novel indane derivatives possessing smooth muscle relaxant activity |
Also Published As
| Publication number | Publication date |
|---|---|
| DK472387A (en) | 1988-03-12 |
| PH25680A (en) | 1991-09-04 |
| ATE59378T1 (en) | 1991-01-15 |
| DD263525A5 (en) | 1989-01-04 |
| FI873917A (en) | 1988-03-12 |
| AU7829787A (en) | 1988-03-17 |
| DK472387D0 (en) | 1987-09-10 |
| HUT46885A (en) | 1988-12-28 |
| DE3630903A1 (en) | 1988-03-24 |
| EP0259782A1 (en) | 1988-03-16 |
| IL83850A0 (en) | 1988-02-29 |
| NZ221766A (en) | 1989-05-29 |
| EP0259782B1 (en) | 1990-12-27 |
| NO873784L (en) | 1988-03-14 |
| HU206077B (en) | 1992-08-28 |
| PT85689B (en) | 1990-06-29 |
| PT85689A (en) | 1987-10-01 |
| KR880003889A (en) | 1988-05-30 |
| ZA876768B (en) | 1989-05-30 |
| FI873917A0 (en) | 1987-09-10 |
| IL83850A (en) | 1991-09-16 |
| NO873784D0 (en) | 1987-09-10 |
| NO166528C (en) | 1991-08-07 |
| JPS6377842A (en) | 1988-04-08 |
| DE3767094D1 (en) | 1991-02-07 |
| NO166528B (en) | 1991-04-29 |
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