NO761525L - - Google Patents
Info
- Publication number
- NO761525L NO761525L NO761525A NO761525A NO761525L NO 761525 L NO761525 L NO 761525L NO 761525 A NO761525 A NO 761525A NO 761525 A NO761525 A NO 761525A NO 761525 L NO761525 L NO 761525L
- Authority
- NO
- Norway
- Prior art keywords
- tetrahydro
- naphthyloxy
- formula
- compound
- propanol
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims description 122
- 239000001257 hydrogen Substances 0.000 claims description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 5
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 239000007818 Grignard reagent Substances 0.000 claims description 3
- 150000004795 grignard reagents Chemical class 0.000 claims description 3
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 3
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 239000012458 free base Substances 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 164
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 65
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 29
- BTANRVKWQNVYAZ-UHFFFAOYSA-N 2-butanol Substances CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- -1 1,2,3,4-tetrahydro-naphthyloxy aliphatic alcohols Chemical class 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 238000001035 drying Methods 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 235000019441 ethanol Nutrition 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000002883 imidazolyl group Chemical group 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 230000003288 anthiarrhythmic effect Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 150000003840 hydrochlorides Chemical class 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 125000002636 imidazolinyl group Chemical group 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- MOIPGXQKZSZOQX-UHFFFAOYSA-N carbonyl bromide Chemical compound BrC(Br)=O MOIPGXQKZSZOQX-UHFFFAOYSA-N 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 150000008050 dialkyl sulfates Chemical class 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 229910052987 metal hydride Inorganic materials 0.000 description 2
- 150000004681 metal hydrides Chemical class 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 description 1
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical class C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- YXGBQJQAKULVEL-UHFFFAOYSA-N 2-(1-bromoethyl)oxirane Chemical compound CC(Br)C1CO1 YXGBQJQAKULVEL-UHFFFAOYSA-N 0.000 description 1
- RILZRCJGXSFXNE-UHFFFAOYSA-N 2-[4-(trifluoromethoxy)phenyl]ethanol Chemical compound OCCC1=CC=C(OC(F)(F)F)C=C1 RILZRCJGXSFXNE-UHFFFAOYSA-N 0.000 description 1
- SCWNNOCLLOHZIG-UHFFFAOYSA-N 5,6,7,8-tetrahydro-1-naphthol Chemical compound C1CCCC2=C1C=CC=C2O SCWNNOCLLOHZIG-UHFFFAOYSA-N 0.000 description 1
- 206010001497 Agitation Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010003830 Automatism Diseases 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 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 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 241000134884 Ericales Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 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 1
- 229930195725 Mannitol Natural products 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 238000005874 Vilsmeier-Haack formylation reaction Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000004061 bleaching Methods 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005661 deetherification reaction Methods 0.000 description 1
- XXTZHYXQVWRADW-UHFFFAOYSA-N diazomethanone Chemical compound [N]N=C=O XXTZHYXQVWRADW-UHFFFAOYSA-N 0.000 description 1
- 125000000950 dibromo group Chemical group Br* 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical class CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- ROFVJSWBDQUQGW-UHFFFAOYSA-N piperidin-1-ium;bromide Chemical compound Br.C1CCNCC1 ROFVJSWBDQUQGW-UHFFFAOYSA-N 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000000197 pyrolysis Methods 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- QJDUDPQVDAASMV-UHFFFAOYSA-M sodium;ethanethiolate Chemical compound [Na+].CC[S-] QJDUDPQVDAASMV-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
- C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
- C07C217/38—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system containing rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/06—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/108—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
- C07C2603/72—Ethanonaphthalenes; Hydrogenated ethanonaphthalenes
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- Chemical & Material Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
FREMGANGSMÅTE VED FREMSTILLING AV ALIFATISKE ALKOHOLDERIVATER. PROCEDURE FOR THE MANUFACTURE OF ALIPHATIC ALCOHOL DERIVATIVES.
Foreliggende oppfinnelse védrorer en fremgangsmåte for fremstilling av N-heterocykliske derivater av 1,4-metan og 1,4 etan-^4- The present invention provides a method for the production of N-heterocyclic derivatives of 1,4-methane and 1,4 ethane-^4-
dihydro og 1,2, 3,4-tetrahydro-naftyloksy alifatiske alkoholer. dihydro and 1,2,3,4-tetrahydro-naphthyloxy aliphatic alcohols.
Forbindelsene ifolge oppfinnelsen har den folgende formel (I)The compounds according to the invention have the following formula (I)
hvori in which
symbolet - z^ jz. utgjor en enkel eller en dobbelt binding; the symbol - z^ jz. form a single or a double bond;
n er 1 eller 2; n is 1 or 2;
hver av og R2er uavhengig valgt fra gruppen bestående av hydrogen, halogen, hydroksy, C -C alkyl, C-C, alkoksy>trihalogen-16 l b each of and R 2 is independently selected from the group consisting of hydrogen, halogen, hydroxy, C -C alkyl, C -C, alkoxy>trihalogen-16 l b
metyl, nitro, formyl, hydroksymetyl, amino, usubstituert eller substituert ved en eller to C^- C^ alkyl grupper, C^-C^alkyltio, C1~C6alkylsulfinyl, C^-Cg alkylsulfonyl,C^-Og alkansulfonamido, methyl, nitro, formyl, hydroxymethyl, amino, unsubstituted or substituted by one or two C^-C^ alkyl groups, C^-C^alkylthio, C1~C6alkylsulfinyl, C^-Cg alkylsulfonyl, C^-Og alkanesulfonamido,
en rest -NHCOR7, hvori R^er C-^-Cg alkyl, en rest ■ hvpri hver av Rg og Rg uavhengig er valgt fra gruppen bestående av hydrogen og C-^-Cg alkyl; a residue -NHCOR7, wherein R^ is C-^-C8 alkyl, a residue ■ hvpri each of Rg and Rg is independently selected from the group consisting of hydrogen and C-^-C8 alkyl;
er en mettet eller umettet heterocyklisk ring som inne- is a saturated or unsaturated heterocyclic ring containing
holder minst et nitrogen-atom og eventuelt ett eller flere andre heteroatomer valgt fra gruppen bestående av N, S, og 0, hvor nevnte ring er substituert eller usubstituert ved en eller flere substituenter valgt fra gruppen bestående av ci~ cq alkyl,. ci~ c^ alkoksy, nitro, halogen, -C00R, hvori R er hydrogen eller C^-Cg alkyl; holds at least one nitrogen atom and optionally one or more other heteroatoms selected from the group consisting of N, S, and 0, where said ring is substituted or unsubstituted by one or more substituents selected from the group consisting of ci~cq alkyl,. C 1 - C 6 alkoxy, nitro, halogen, -C00R, wherein R is hydrogen or C 1 -C 8 alkyl;
hver av R^, R^, og R^er uavhengig valgt fra gruppen bestående av hydrogen og C^-Cg alkyl. each of R 1 , R 1 , and R 1 is independently selected from the group consisting of hydrogen and C 1 -C 8 alkyl.
Gjenstand for foreliggende oppfinnelse er likeledes salter av forbindelsene med formel (I) med farmasoytisk fordragelige syrer såvel som de kvaternære ammonium salter. The object of the present invention is likewise salts of the compounds of formula (I) with pharmaceutically acceptable acids as well as the quaternary ammonium salts.
Det skal også bemerkes at den overnevnte definisjon av forbindelsen ifolge oppfinnelsen omfatter alle mulige diastereoisbmere og stereoisomere, såvel som deres blandinger. It should also be noted that the above definition of the compound according to the invention includes all possible diastereoisomers and stereoisomers, as well as their mixtures.
Alkyl, alkoksy og alkansulfonamido gruppene kan være forgrenede eller rette kjeder. The alkyl, alkoxy and alkanesulfonamido groups can be branched or straight chains.
Fortrinnsvis utgjor symbolet - - - - en enkeltbinding. Preferably, the symbol - - - - constitutes a single bond.
Fortrinnsvis er den eterkjeden som baerér en heterocyklisk ringPreferably, the ether chain bearing is a heterocyclic ring
i fremstillingen.in the manufacture.
Fortrinnsvis er R5og R^ hydrogen og R4er hydrogen eller c1-c3alkyl. Når R^og/eller R2 er trihalogenmetyl, er trihalogenmetyl-gruppen fortrinnsvis trifluormetyl. Preferably, R 5 and R 1 are hydrogen and R 4 is hydrogen or C 1 -C 3 alkyl. When R 1 and/or R 2 is trihalomethyl, the trihalomethyl group is preferably trifluoromethyl.
Fortrinnsvis er hver av R^og R2 uavhengig valgt fra gruppen bestående av hydrogen, halogen, hydroksy, C^-C^ alkyl, C]_~C5alkoksy, trifluormetyl, formyl, hydroksymetyl, C^-Cg alkyltio, cl"c6alkYlsulfinyl, C-^-Cg alkylsulfonyl og resten -NHCOR7, hvori R- er om ovenfor angitt. Preferably, each of R₁ and R₂ is independently selected from the group consisting of hydrogen, halogen, hydroxy, C₁-C₁ alkyl, C₁-C₆ alkoxy, trifluoromethyl, formyl, hydroxymethyl, C₁-C₆ alkylthio, C₁-C₆ alkylsulfinyl, C -^-C 8 alkylsulfonyl and the residue -NHCOR 7 , in which R- is as indicated above.
Når R^og/eller R_ er halogen er halogenet fortrinnsvis klor eller brom. When R^ and/or R^ is halogen, the halogen is preferably chlorine or bromine.
Den heterocykliske ringen The heterocyclic ring
er enten en mpnocyklisk eller bicyklisk eller tricyklisk ring. representerer en heteromonocyklisk ring, er den fortrinnsvis pyrrolidinyl, pyrazolidmyl, lmidazolidinyl, pyrrolinyl, pyrazolinyl, imidazolinyl, piperidyl, piperazinyl, morfolinyl, tiomorfolinyl, pyrrolyl, pyrazolyl, triazolyl eller imidazolyl, usubstituert eller substituert som ovenfor angitt. er en bicyklisk ring er den fortrinnsvis indolyl, isoindolyl, indazolyl eller benzimidazolyl, usubstituert eller substituert som ovenfor angitt. er en tricyklisk ring er den fortrinnsvis karbazolyl, fenotiazinyl eller fenoksazinyl, usubstituert eller substituert som ovenfor angitt. Fortrinnsvis er is either an mpnocyclic or bicyclic or tricyclic ring. represents a heteromonocyclic ring, it is preferably pyrrolidinyl, pyrazolidmyl, imidazolidinyl, pyrrolinyl, pyrazolinyl, imidazolinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, pyrazolyl, triazolyl or imidazolyl, unsubstituted or substituted as indicated above. is a bicyclic ring, it is preferably indolyl, isoindolyl, indazolyl or benzimidazolyl, unsubstituted or substituted as indicated above. is a tricyclic ring, it is preferably carbazolyl, phenothiazinyl or phenoxazinyl, unsubstituted or substituted as indicated above. Preferably is
en heteromonocyklisk ring, særlig a heteromonocyclic ring, esp
imidazolyl eller imidazolinyl, spesielt imidazolyl.imidazolyl or imidazolinyl, especially imidazolyl.
Særlig foretrukne forbindelser ifolge oppfinnelsen er de hvori symbolet - - - - representerer en enkelbinding, R^ er halogen, spesielt klor i 8-stillingen, R2 er hydrogen eller halogen, Particularly preferred compounds according to the invention are those in which the symbol - - - - represents a single bond, R^ is halogen, especially chlorine in the 8-position, R2 is hydrogen or halogen,
spesielt klor i 6-stillingen, R^og Rg er hydrogen, R^er especially chlorine in the 6-position, R^ and Rg are hydrogen, R^ are
hydrogen eller metyl og hydrogen or methyl and
er imidazolyl eller imidazolinyl, eventuelt substituert ved en eller to substituenter valgt fra gruppen bestående av C^-C4alkyl og halogen. Fortrinnsvis i disse særlige foretrukne forbindelser er R^ hydrogen og imidazolyl. is imidazolyl or imidazolinyl, optionally substituted by one or two substituents selected from the group consisting of C 1 -C 4 alkyl and halogen. Preferably in these particular preferred compounds R 1 is hydrogen and imidazolyl.
Eksempler på farmasoytisk fordragelige salter er enten dem med uorganiske syrer, f.eks. saltsyre>bromhydrogensyre og svovelsyre eller med organiske syrer, f. eks. sitron-, vin-r> maléinT, f urna r-og metansulfonsyre. Examples of pharmaceutically acceptable salts are either those with inorganic acids, e.g. hydrochloric acid>hydrobromic acid and sulfuric acid or with organic acids, e.g. citric-, wine-r> maleicT, f urna r-and methanesulfonic acid.
Forbindelsene ifolge oppfinnelsen fremstilles ved en fremgangsmåte bestående av: The compounds according to the invention are produced by a method consisting of:
(a) omsetning av en forbindelse med formel (II)(a) reaction of a compound of formula (II)
hvori symbolet - £,n, R,, og R„ er som ovenfor angitt og Z er en av restene og in which the symbol - £,n, R,, and R„ are as above indicated and Z is one of the residues and
hvori R., R_ og R^er som ovenfor definert og X er halogen, in which R., R. and R. are as defined above and X is halogen,
4 D D4D D
med en forbindelse med formel (III)with a compound of formula (III)
eller et salt derav hvori er som ovenfor definert; (b) omsetning av en forbindelse med formel (IV) or a salt thereof wherein is as defined above; (b) reaction of a compound of formula (IV)
hvori in which
symbolet - - - -, n, R^og R2 er som ovenfor definert, eller et salt derav med en forbindelse med formel (V) the symbol - - - -, n, R^ and R2 are as defined above, or a salt thereof with a compound of formula (V)
er som ovenfor definert og Y er en av de folgende rester: is as defined above and Y is one of the following residues:
hvori in which
X, R^, R^og Rg er som ovenfor definert; X, R^, R^ and Rg are defined as above;
(c) reduksjon av en forbindelse med formel (VI) (c) reduction of a compound of formula (VI)
hvori in which
symbolet - - - -, n, R^, R^, R^, R^ og the symbol - - - -, n, R^, R^, R^, R^ and
er som ovenfor definert, hvorved oppnås en forbindelse med formelen (I) hvori R er hydrogen; 6 (d) omsetning av. en forbindelse med formel (VI) med én Grignard reagens med formel R^MgX, hvori X er som ovenfor angitt og R6 . er C 1 -C,6,, alkyl, hvorved erholdes en forbindelse med formel (I), hvori Rcer C.-C, alkyl; is as defined above, whereby a compound of the formula (I) is obtained in which R is hydrogen; 6 (d) turnover of. a compound of formula (VI) with one Grignard reagent of formula R^MgX, wherein X is as indicated above and R 6 . is C 1 -C 6 , alkyl, whereby a compound of formula (I) is obtained, in which Rcer is C 1 -C 6 alkyl;
D lb D lb
og om onsket, overforing av en forbindelse med formel (I) i en annen forbindelse med formel (I), og/eller om onsket omsetning av en forbindelse med formel (I) med en farmasoytisk fordragelig syre for å gi et salt derav og/eller om onsket overfore et salt i en fri base og/eller om onsket overfore en forbindelse med formel (I) i et kvaternært ammonium salt derav og/eller om and if desired, converting a compound of formula (I) into another compound of formula (I), and/or if desired reacting a compound of formula (I) with a pharmaceutically acceptable acid to give a salt thereof and/ or if desired convert a salt into a free base and/or if desired convert a compound of formula (I) into a quaternary ammonium salt thereof and/or if desired
onsket opplose en blanding av isomere i de enkelte isomere.wanted to dissolve a mixture of isomers into the individual isomers.
Når forbindelsene med formelene (III) og (IV) omsettes i form avWhen the compounds with the formulas (III) and (IV) are reacted in the form of
et salt, er dette saltet fortrinnsvis med et alkalimetallatom eller med et solvatom. a salt, this salt is preferably with an alkali metal atom or with a solvate atom.
X er fortrinnsvis klor eller bromX is preferably chlorine or bromine
Omsetningen av forbindelsen med formel (II) med forbindelsen med formel (III), eller et salt derav utfores fortrinnsvis ved en. temperatur som ligger mellom rundt 50°c og rundt 250°C, enten i nærvær eller i fravær av løsningsmidler. Når løsningsmidler benyttes er de f.eks. toluen, xylen og etanol. Når i forbindelsen med formél (III) -N R 3 representerer en aromatisk heterocyklisk ring, f.eks. pyrrolyl, pyrazolyl og imidazolyl utfores reaksjonen av forbindelsen med formel (II) med en forbindelse med formel (III) eller et salt derav, fortrinnsvis i et organisk lbsningsmiddel valgt av gruppen bestående dimetylformamid, dimetylacetamid, heksametylfosforsyretriamid og dimetylsulfoksyd i nærvær av en base som f.eks. natrium hydrid, natrium hydroksyd, natrium etoksyd. The reaction of the compound of formula (II) with the compound of formula (III), or a salt thereof, is preferably carried out by a temperature between about 50°C and about 250°C, either in the presence or in the absence of solvents. When solvents are used, they are e.g. toluene, xylene and ethanol. When in the compound of formula (III) -NR R 3 represents an aromatic heterocyclic ring, e.g. pyrrolyl, pyrazolyl and imidazolyl, the reaction of the compound of formula (II) with a compound of formula (III) or a salt thereof is carried out, preferably in an organic solvent selected from the group consisting of dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide and dimethylsulfoxide in the presence of a base such as .ex. sodium hydride, sodium hydroxide, sodium ethoxide.
Likeledes utfores reaksjonen av forbindelsen med formelen (IV) med en forbindelse med formel (V) under de samme betingelser som reaksjonen (a) og fortrinnsvis i nærvær av en base som natriumhydroksyd, kaliumhydroksyd og natriummetoksyd. Likewise, the reaction of the compound of formula (IV) with a compound of formula (V) is carried out under the same conditions as reaction (a) and preferably in the presence of a base such as sodium hydroxide, potassium hydroxide and sodium methoxide.
Når i forbindelsen med formelen (VI) symbolet er en dobbeltbinding og det er onsket å erholde en forbindelse med formel (I) hvori dette symbolet er en erikeltbinding utfores reduksjonen av forbindelsen med formelen (VI) ved katalytisk hydrogenering ved å f.eks. å bruke Pd/C eller PtC^ som katalysator. When in the compound of formula (VI) the symbol is a double bond and it is desired to obtain a compound of formula (I) in which this symbol is an erical bond, the reduction of the compound of formula (VI) is carried out by catalytic hydrogenation by e.g. to use Pd/C or PtC^ as catalyst.
Når det derimot er onsket å redusere bare ketogruppen i forbindelsen med formel (VI), gjennomføres reduksjonen fortrinnsvis ved å bruke blandede metallhydrider som natrium borhydrid eller litium aluminiumhydrid i organiske løsningsmidler som etyleter og tetrahydrofuran og ved en temperatur som ligger mellom 0°C og rundt 60°C. When, on the other hand, it is desired to reduce only the keto group in the compound of formula (VI), the reduction is preferably carried out using mixed metal hydrides such as sodium borohydride or lithium aluminum hydride in organic solvents such as ethyl ether and tetrahydrofuran and at a temperature between 0°C and around 60°C.
Grignard reaksjonen med forbindelsen med formel (VI) utforesThe Grignard reaction with the compound of formula (VI) is carried out
under de betingelser som vanligvis brukes for denne type reaksjoner, f.eks. ved tilbakelopstemperatur i dietyleter. under the conditions that are usually used for this type of reaction, e.g. at reflux temperature in diethyl ether.
Enten kan overforingen av en forbindelse med formel (I) i annen forbindelse med formel (I)( eller saltdannelsen (eller overforingen av en forbindelse med formel (I)iet kvaternært ammoniumsalt eller opplosningen av en blanding av isomere i de enkelte isomere utfores ved konvensjonelle metoder. Either the conversion of a compound of formula (I) into another compound of formula (I) or the salt formation (or the conversion of a compound of formula (I) into the quaternary ammonium salt or the dissolution of a mixture of isomers into the individual isomers can be carried out by conventional methods.
Således kan f.eks. en forbindelse med formel (I) hvori og/eller R2er C^-Cg alkoksy selektiv deeterifiseres, f.eks. ved å arbeide ved en temperatur lavere enn 160°C til å gi en forbindelse med formel (I), hvori R^og/eller R^er hydroksy ved omsetning med et pyridin salt, f.eks. pyridih hydroklorid. Thus, e.g. a compound of formula (I) in which and/or R 2 is C 1 -C 8 alkoxy is selectively deetherified, e.g. by working at a temperature lower than 160°C to give a compound of formula (I) wherein R^ and/or R^ is hydroxy by reaction with a pyridine salt, e.g. pyridinium hydrochloride.
En forbindelse med formel (I) hvori R^og/eller R2er hydroksyA compound of formula (I) wherein R 1 and/or R 2 is hydroxy
kan overfores i en forbindelse med formel (I) hvori R^og/eller R2er C^-Cg alkoksy ved saltdannelse av hydroksygruppene,f.eks. can be transferred in a compound of formula (I) in which R₁ and/or R₂ are C₁-C₆ alkoxy by salt formation of the hydroxy groups, e.g.
med et alkalihydroksyd og så behandle den resulterende forbindelse med Ci-Cg alkylreaktive estere av sterke sider, f.eks. ci_cg alkyl halider eller c-^-cg dialkyl sufater. with an alkali hydroxide and then treat the resulting compound with C 1 -C 8 alkyl reactive esters of strong sides, e.g. ci_cg alkyl halides or c-^-cg dialkyl sulfates.
En forbindelse med formel med (I) hvor R^og/ellef R2er nitroA compound of formula (I) wherein R 1 and/or R 2 is nitro
kan reduseres til å gi en forbindelse med formel (I) hvori R^og/eller R2er amino, f.eks. ved hydrogenering med Pd/C; i dette tilfellet når i utgangsmaterialet symbolet - - - - representerer en dobbeltbinding, reduseres også denne dobbeltbindingen til en enkeltbinding. can be reduced to give a compound of formula (I) in which R 1 and/or R 2 is amino, e.g. by hydrogenation with Pd/C; in this case, when in the starting material the symbol - - - - represents a double bond, this double bond is also reduced to a single bond.
Når reaksjonen istedet utfores f.eks. med tinnklorid og saltsyre i edikksyre, reduseres bare nitrogruppen uten reduksjon av den eventuelt tilstedeværende dobbeltbinding. En forbindelse med formel (I) hvori R-^ og/eller R2er usubstituert amino, kan overfores i en forbindelse med formel (I) hvori R^og/eller R2er en mono- eller di-alkyl substituert amino ved kjente metoder, f.eks. ved omsetning ved reaktive estere av alkoholer. Forbindelsene som brukes som utgangsmaterialer er allerede kjent eller hvis de er nye, fremstilles de på allerede kjent måte. Forbindelsen med formel (II) hvori Z er When the reaction is instead carried out e.g. with stannous chloride and hydrochloric acid in acetic acid, only the nitro group is reduced without reduction of any double bond present. A compound of formula (I) in which R 1 and/or R 2 is unsubstituted amino can be converted into a compound of formula (I) in which R 2 and/or R 2 is a mono- or di-alkyl substituted amino by known methods, e.g. e.g. by reaction with reactive esters of alcohols. The compounds used as starting materials are already known or, if they are new, they are prepared in an already known manner. The compound of formula (II) wherein Z is
, hvori R4, R5og R^er som ovenfor definert, kan fremstilles ved omsetning av en forbindelse med formel (IV) med en forbindelse med formel (VII) , in which R 4 , R 5 and R 5 are as defined above, can be prepared by reacting a compound of formula (IV) with a compound of formula (VII)
hvori in which
X, R^, Rj. og Rg er som ovenfor definert.X, R^, Rj. and Rg is defined as above.
Reaksjonene av forbindelsen med formel (IV) med forbindelsen med formel (VII) utfores fortrinnsvis ved en temperatur som ligger mellom rundt 0°C og rundt 150°C i et løsningsmiddel f.eks. valgt fra gruppen bestående av vann, dioksan, tetrahydrofuran, dietyleter, dimetylformamid og dimetylsulfoksyd i nærvær av minst en ekvivalent av en base valgt f.eks. fra gruppen bestående av The reactions of the compound of formula (IV) with the compound of formula (VII) are preferably carried out at a temperature between about 0°C and about 150°C in a solvent, e.g. selected from the group consisting of water, dioxane, tetrahydrofuran, diethyl ether, dimethylformamide and dimethylsulfoxide in the presence of at least one equivalent of a base selected e.g. from the group consisting of
natriumhydroksyd, kaliumhydroksyd, natrium amid og natrium metoksyd. sodium hydroxide, potassium hydroxide, sodium amide and sodium methoxide.
Forbindelsen med formel (II) hvori Z er The compound of formula (II) wherein Z is
hvori R4, wherein R4,
Rc, Rcog X er som ovenfor definert, kan fremstilles ved å under Rc, Rcog X are as above defined, can be produced by under
bo stay
analoge betingelser omsette forbindelsen med formelen (IV) med forbindelsen med formel (VII), imidlertid i nærvær av en katalytisk mengde av en base fortrinnsvis valgt blant piperidin og pyridin, eller behandling av forbindelsen med formel (II) hvori Z er analogous conditions reacting the compound of formula (IV) with the compound of formula (VII), however, in the presence of a catalytic amount of a base preferably selected from piperidine and pyridine, or treating the compound of formula (II) wherein Z is
hydrogen halogen syre. Alternativt kan forbindelsen med formel (II) hvori Z er ■ hydrogen halogen acid. Alternatively, the compound of formula (II) wherein Z is ■
, hvori R4 og R5er som ovenfor definert, og R&er hydrogen, fremstilles ved å omsette en for bindelse med formel (VIII) , wherein R4 and R5 are as above defined, and R& is hydrogen, is produced by reacting a for bond of formula (VIII)
hvori in which
symbolet - - - -, ni R^, R2 og X er som ovenfor definert, med et diazoalkan med formel (IX) the symbol - - - -, nine R^, R2 and X are as defined above, with a diazoalkane of formula (IX)
hvori in which
R^og Rg er som ovenfor definert i et organisk løsningsmiddel som dietyleter, tetrahydrofuran og dioksan og så behandle det resulterende diazoketon i det samme løsningsmiddel med en hydro-genhalogen syre, f.eks. gassformig saltsyre eller bromhydrogensyre, til å gi en forbindelse med formel (X) R^ and Rg are defined as above in an organic solvent such as diethyl ether, tetrahydrofuran and dioxane and then treat the resulting diazoketone in the same solvent with a hydrohalic acid, e.g. gaseous hydrochloric or hydrobromic acid, to give a compound of formula (X)
hvori in which
symbolet - - - -, n, R^, R2, R^, R^, og X er som ovenfor definert, som deretter reduseres, f.eks. med natriumborhydrid i nærvær av en base som natrium-eller kalium-hydroksyd i et løs-ningsmiddel som alkohol( eller tetrahydrofuran. the symbol - - - -, n, R^, R2, R^, R^, and X are as above defined, which are then reduced, e.g. with sodium borohydride in the presence of a base such as sodium or potassium hydroxide in a solvent such as alcohol (or tetrahydrofuran.
Forbindelsen med formel (VI) kan fremstilles f.eks. ved å omsette en forbindelse med formel (X) med en forbindelse med formel (III). Reaksjonen kan utfores hovedsakelig som ovenfor beskrevet for reaksjonen (a). I forbindelsen med formelen (X) kan ketogruppen eventuelt beskyttes ved kjente metoder, f.eks. ved dannelsen The compound of formula (VI) can be prepared, e.g. by reacting a compound of formula (X) with a compound of formula (III). The reaction can be carried out essentially as described above for reaction (a). In the connection with the formula (X), the keto group can optionally be protected by known methods, e.g. at the formation
av et ketal.of a ketal.
Forbindelsen med formel (VI) hvori symbolet - - - representerer en enkeltbinding kan fremstilles ved konvensjonelle metoder, f.eks. ifolge Europ. J. Med. Chem. 9, 501 (1974). The compound of formula (VI) in which the symbol - - - represents a single bond can be prepared by conventional methods, e.g. according to Europ. J. Med. Chem. 9, 501 (1974).
Således kan f.eks. forbindelsen med formel (IV) hvori R.^og/ eller R^er klor og symbolet - -■■- er en enkeltbinding fremstilles ved å omsette forbindelsen med formel (IV) hvori R^og R2er hydrogen, symbolet - - - - er en enkeltbinding og hydroksygruppen er beskyttet ved dannelsen av en metyleter, med sulfurylklorid med formelen S02C12 i et klorert lbsningsmiddel som metylenklorid og klorbform, ved en temperatur som ligger mellom rundt -10°C og rundt +10°C, fortrinnsvis ved 0°C, og ved påfolgende deeterifisering av metoksygruppen til å gi den fri hydroksygruppen, f.eks. ved omsetning med pyriding hydroklorid. Thus, e.g. the compound of formula (IV) in which R^ and/or R^ is chlorine and the symbol - -■■- is a single bond is prepared by reacting the compound of formula (IV) in which R^ and R2 is hydrogen, the symbol - - - - is a single bond and the hydroxy group is protected by the formation of a methyl ether, with sulfuryl chloride of the formula SO2C12 in a chlorinated solvent such as methylene chloride and chloroform, at a temperature between about -10°C and about +10°C, preferably at 0°C, and by subsequent deetherification of the methoxy group to give the free hydroxy group, e.g. by reaction with pyriding hydrochloride.
Avhengig av de molare forhold av de brukte reagenser er det mulig å oppnå enten monoklor-derivatet eller diklor-derivatet. Forbindelsene med formel (IV) hvori R^ og/eller R 2 er "brom og symbolet - - - er en enkeltbinding kan oppnås f.eks. ved bromering av forbindelsen med formel (IV), hvori R^dg R^er hydrogen og symbolet - - - er en enkeltbinding med brom i klorerte løsnings-midler som metylenklorid og kloroform ved en temperatur som ligger mellom rundt -40°C og rundt -10°C. Depending on the molar ratios of the reagents used, it is possible to obtain either the monochloro derivative or the dichloro derivative. The compounds of formula (IV) in which R^ and/or R 2 are "bromine and the symbol - - - is a single bond can be obtained, for example, by bromination of the compound of formula (IV), in which R^dg R^ is hydrogen and the symbol - - - is a single bond with bromine in chlorinated solvents such as methylene chloride and chloroform at a temperature between about -40°C and about -10°C.
Også i dette tilfellet erholdes enten monobrom-derivatet eller dibrom-derivatet avhengig av de molare forhold av reagensene. Forbindelsen med formel (IV), hvori R^og/eller R2er fluor og symbolet - - - er en enkeltbinding, kan oppnås ved diazotering av forbindelsen med formel (IV) , hvori R-^ og/eller R2er amino, In this case too, either the monobromo derivative or the dibromo derivative is obtained depending on the molar ratios of the reagents. The compound of formula (IV), in which R^ and/or R 2 is fluorine and the symbol - - - is a single bond, can be obtained by diazotizing the compound of formula (IV), in which R-^ and/or R 2 is amino,
og symbolet - - - er en enkeltbinding, med HCl og NaN02ved påfolgende reaksjon av den dannede forbindelse med fluorborsyre og til s-lutt termisk spaltning av det dannede diazbnium fluor-borat. and the symbol - - - is a single bond, with HCl and NaN02 by subsequent reaction of the compound formed with fluoroboric acid and finally thermal cleavage of the diazbnium fluoroborate formed.
Forbindelsen med formel (IV) hvori R^ og/eller R2 er formyl og The compound of formula (IV) in which R 1 and/or R 2 are formyl and
symbolet - - "- er en enkeltbinding, kan erholdes ved åthe symbol - - "- is a single bond, can be obtained by
starte med forbindelsen med formel (IV), hvori R, og/eller R2er hydrogen og symbolet - - - - er en enkeltbinding, ved start with the compound of formula (IV), in which R, and/or R2 is hydrogen and the symbol - - - - is a single bond, by
en Vilsmeier-Haack reaksjon.a Vilsmeier-Haack reaction.
Forbindelsen med formel (IV) , hvori R^ og/eller R2er hydroksymetyl og symbolet - - - er en enkeltbinding kan fremstilles ved reduksjon av forbindelsen med formel(IV), hvori R^ og/eller R2The compound of formula (IV), in which R^ and/or R2 are hydroxymethyl and the symbol - - - is a single bond can be prepared by reduction of the compound of formula (IV), in which R^ and/or R2
er formyl og symbolet - - - - er en enkeltbinding, f.eks. med blandede metallhydrider som NaBH^. Også kan forbindelsen med formel (IV), hvori symbolet - - - - er en dobbeltbinding fremstilt ved kjente metoder. is formyl and the symbol - - - - is a single bond, e.g. with mixed metal hydrides such as NaBH^. The compound of formula (IV), in which the symbol - - - - is a double bond, can also be prepared by known methods.
Således kan f.eks. forbindelsen med formel (IV), hvori en avThus, e.g. the compound of formula (IV), wherein one of
R^og R2 er hydroksy og den andre er hydrogen, og symboletR 1 and R 2 are hydroxy and the other is hydrogen, and the symbol
-i - - - representerer en dobbeltbinding fremstilles ved å behandle et kinon med formelen (XI) -i - - - represents a double bond is prepared by treating a quinone with the formula (XI)
med saltsyre<p>g diklormetan. Kinonet kan i sin tur fremstilles ved å omsette jd-benzo-kinon med cykloheksadien eller cyklo-pentadien. with hydrochloric acid<p>g dichloromethane. The quinone can in turn be prepared by reacting jd-benzo-quinone with cyclohexadiene or cyclopentadiene.
Forbindelsen med formel (IV), hvori R^.og R2 er hydrogen og symbolet - - - er en dobbeltbinding kan erholdes f.eks. ved å behandle 5,8-diokso-l,4-metan -1,4-dihydronaftalen eller 5,8-diokso-1,4-etan -1,4-dihydronaftalen,• som allerede er kjent (Diels et al., Ber., 62, 2337-2372 (1929)), medet trialkoksy fosfin med en temperatur som ligger mellom rundt 15 C og rundt 30°C i et inert organisk løsningsmiddel som f.eks. benzen, toluen , i et tidsrom som ligger mellom rundt 45 minutter og rundt 4 timer, og så omsette det resulterende 5-alkosky-8-(di-O-alkylfosfono)-1,4-dihydro-l,4-etan eller 1,4-metan - naftalen i et organisk løsningsmiddel som dietyleter med flytende ammoniakk og litium, hvorved erholdes det tilsvarende 5-alkoksy-l,4-dihydro-l,4-etan - eller 1,4-metan - naftalen. The compound of formula (IV), in which R 1 and R 2 are hydrogen and the symbol - - - is a double bond can be obtained e.g. by treating 5,8-dioxo-1,4-methane-1,4-dihydronaphthalene or 5,8-dioxo-1,4-ethane-1,4-dihydronaphthalene,• which is already known (Diels et al., Ber., 62, 2337-2372 (1929)), with trialkoxy phosphine at a temperature of between about 15°C and about 30°C in an inert organic solvent such as e.g. benzene, toluene, for a period of time ranging from about 45 minutes to about 4 hours, and then reacting the resulting 5-alkosky-8-(di-O-alkylphosphono)-1,4-dihydro-1,4-ethane or 1 ,4-methane - naphthalene in an organic solvent such as diethyl ether with liquid ammonia and lithium, whereby the corresponding 5-alkyl-1,4-dihydro-1,4-ethane - or 1,4-methane - naphthalene is obtained.
Den sistnevnte reaksjonen utfores ved å forst under rbring til-sette ved en temperatur som ligger mellom rundt -80°C og rundt -35°c ammoniakk til en loaning av 5-alkoksy-8-(di-O-alkylfosfono)-1,4-dihydro-l,4-etan - eller 1,4-metan -naftalen i dietyleter, også til. reaksjonsblandingen å sette rundt 2 mol litium pr. The latter reaction is carried out by first adding, under stirring, at a temperature between around -80°C and around -35°C ammonia to a loan of 5-Alkoxy-8-(di-O-alkylphosphono)-1, 4-dihydro-1,4-ethane - or 1,4-methane -naphthalene in diethyl ether, also to. the reaction mixture to put around 2 moles of lithium per
mol av 1,4-etan eller 1,4-metan' -naftalen derivat. Det således erholdte 5-alkoksy-l,4-dihydro-l>4-etan - eller 1,4-metan - naftalen overfores endelig i 5-hydroksy-l,4-dihydro-l,4-etan >-eller 1,4-metan -naftalen ved reaksjon f.eks. med rundt 10 mol natrium etantiolat pr. mol 5-alkoksy-l,4-dihydro-l,4-etan eller 1,4-metan -naftalen i et organisk løsningsmiddel som dimetylformamid ved en tempera ur på rundt 100°c. moles of 1,4-ethane or 1,4-methane'-naphthalene derivative. The thus obtained 5-hydroxy-1,4-dihydro-1>4-ethane - or 1,4-methane - naphthalene is finally transferred into 5-hydroxy-1,4-dihydro-1,4-ethane>-or 1, 4-methane-naphthalene by reaction e.g. with around 10 mol sodium ethanethiolate per mol of 5-Alkoxy-1,4-dihydro-1,4-ethane or 1,4-methane-naphthalene in an organic solvent such as dimethylformamide at a temperature of around 100°c.
Forbindelsen med formel (IV), hvori en av R, og Rn er C.-C,The compound of formula (IV), wherein one of R, and Rn is C.-C,
12. i b alkoksy , og den andre er hydrogen og symbolet - - - er en dobbeltbinding kan erholdes f.eks. ved selektiv alkylering av forbindelsen med formel (IV), hvori en av R^og R^er hydroksy og den andre er hydrogen, og symbolet - - - er en dobbeltbinding, f.eks. med et dialkylsulfat. 12. i b alkoxy , and the other is hydrogen and the symbol - - - is a double bond can be obtained e.g. by selective alkylation of the compound of formula (IV), in which one of R^ and R^ is hydroxy and the other is hydrogen, and the symbol - - - is a double bond, e.g. with a dialkyl sulfate.
Forbindelsen med formel (IV), hvori en av R. og R. er C.-C, The compound of formula (IV), wherein one of R. and R. is C.-C,
12 1b alkyltio og den andre er hydrogen, og symbolet - - - er en dobbeltbinding, kan fremstilles ved å omsette forbindelsen med formel-(IV), hvori R^og R er hydrogen og symbolet - - - - 12 1b alkylthio and the other is hydrogen, and the symbol - - - is a double bond, can be prepared by reacting the compound of formula (IV), in which R^ and R are hydrogen and the symbol - - - -
er en dobbeltbinding med et C±- C£ dialkylsulfoksyd i nærvær av saltsyre og påfolgende pyrolyse. De tilsvarende sulfoksyder og sulfiner kan fremstilles ved å oksydere f.eks. med natrium periodat eller respektive med pereddiksyre, forbindelsen med formel (IV), hvori en av ^ og R2er C1-C&alkyltio og den andre er hydrogen og symbolet - - - er en dobbeltbinding og hvori hydroksygruppen er beskyttet på konvensjonell måte f.eks. ved forestring. Forbindelsen med formel (IV) , hvori en av R-^og R2er nitro og den andre er hydrogen og symbolet - - - er en dobbeltbinding, kan erholdes ved nitrering, f.eks. med en blanding av konsentrert svovelsyre og natriumnitrat i vann, is a double bond with a C±-C£ dialkyl sulfoxide in the presence of hydrochloric acid and subsequent pyrolysis. The corresponding sulfoxides and sulfines can be prepared by oxidizing e.g. with sodium periodate or respectively with peracetic acid, the compound of formula (IV), in which one of ^ and R 2 is C 1 -C 3 alkylthio and the other is hydrogen and the symbol - - - is a double bond and in which the hydroxy group is protected in a conventional manner e.g. by esterification. The compound of formula (IV), in which one of R 1 and R 2 is nitro and the other is hydrogen and the symbol - - - is a double bond, can be obtained by nitration, e.g. with a mixture of concentrated sulfuric acid and sodium nitrate in water,
eller med en blanding av salpetersyre og eddiksyre anhydrid av forbindelsen med formel (IV), hvori både R1ogR2er hydrogen or with a mixture of nitric acid and acetic anhydride of the compound of formula (IV), in which both R1 and R2 are hydrogen
og symbolet - - - er en dobbeltbinding og ved påfolgende adskillelse, f.eks. ved fraksjonert krystallisasjon av blandingen av de således erholdte 8-nitro og 6- nitro derivater. and the symbol - - - is a double bond and upon subsequent separation, e.g. by fractional crystallization of the mixture of the thus obtained 8-nitro and 6-nitro derivatives.
Forbindelsen med formel (IV), hvori en av R., og R2 er amino og den andre er hydrogen og symbolet - er en dobbeltbinding, kan erholdes ved hydrogenering av det tilsvarende nitroderivat f.eks. med NaBfr^S-j, som i sin tur kan fremstilles som beskrevet i Canad. J. Chem., 49, 2990 (1971). The compound of formula (IV), in which one of R. and R2 is amino and the other is hydrogen and the symbol - is a double bond, can be obtained by hydrogenation of the corresponding nitro derivative, e.g. with NaBfr^S-j, which in turn can be prepared as described in Canad. J. Chem., 49, 2990 (1971).
Om onsket kan en forbindelse hvori en av R^ og R2er usubstituert amino og den andre er hydrogen, alkyleres på en konvensjonell måte for å gi en forbindelse hvori amino-gruppen er substituert ved en eller to C^-Cg alkylgrupper; om onsket kan den samme forbindelsen alkyleres på konvensjonell måte for å gi en forbindelse hvori aminogruppen er substituert ved en -COR^ rest. If desired, a compound in which one of R 1 and R 2 is unsubstituted amino and the other is hydrogen can be alkylated in a conventional manner to give a compound in which the amino group is substituted by one or two C 1 -C 8 alkyl groups; if desired, the same compound may be alkylated in a conventional manner to give a compound in which the amino group is substituted by a -COR^ residue.
Forbindelsen med formel (IV), hvori en av R. og R„ er C,-C, alkansulfonamido og den andre er hydrogen og symbolet - - - - er en dobbeltbinding, kan f.eks. erholdes ved å omsette forbindelsen med formel (IV), hvori en av R±og R2er usubstituert amino og den andre er hydrogen og symbolet - - - er en dobbeltbinding med anhydridet av alkansulfonsyren. The compound with formula (IV), in which one of R. and R. is obtained by reacting the compound of formula (IV), in which one of R ± and R 2 is unsubstituted amino and the other is hydrogen and the symbol - - - is a double bond with the anhydride of the alkanesulfonic acid.
Også de gjenstående forbindelser med formel (IV), hvori symboletAlso the remaining compounds of formula (IV), in which the symbol
- - - er en dobbeltbinding og R^og/eller R2har de ovenfor angitte betydninger kan fremstilles på konvensjonell måte, dvs. ved vanlige metoder i organisk kjemi, f.eks. ved å folge de ovenfor indikerte metoder for fremstillingen av forbindelsene med formel (IV), hvori symbolet - - - er en enkeltbinding og R^og/ eller R2har de tilsvarende betydninger. - - - is a double bond and R^ and/or R 2 have the meanings stated above can be prepared in a conventional way, i.e. by usual methods in organic chemistry, e.g. by following the methods indicated above for the preparation of the compounds of formula (IV), in which the symbol - - - is a single bond and R1 and/or R2 have the corresponding meanings.
Forbindelsen ifblge oppfinnelsen besitter sterk anti-arytmisk aktivitet og har ingen virkning på cardial og bronchial (3-adrenergiske reseptorer; Disse forbindelsenes spesifikke virk-ningsmåte gir grunnlaget for effektiv bruk i behandlingen av f.eks. uregelmessigheter i kardial rytme fremkalt ved oket myocardial eksitabilitet og automatisme dg eller ved patologiske forand-ringer i impulsledningen. The compound according to the invention possesses strong anti-arrhythmic activity and has no effect on cardiac and bronchial (3-adrenergic receptors; The specific mode of action of these compounds provides the basis for effective use in the treatment of, for example, irregularities in cardiac rhythm caused by increased myocardial excitability and automatism dg or with pathological changes in the impulse line.
Den antiarytmiske aktiviteten av forbindelsene ifolge oppfinnelsen ble målt på isolerte guinea-gris aurikler ifolge The antiarrhythmic activity of the compounds according to the invention was measured on isolated guinea pig auricles as follows
metoden beskrevet av Dawes (G.S. Dawes, Brit. J. Pharm. Chemoter. 1946, 1, 90). the method described by Dawes (G.S. Dawes, Brit. J. Pharm. Chemoter. 1946, 1, 90).
Deres antiarytmiske potensial og ED 40% ble sammenlignet med kinidin, hvis antiarytmiske aktivitet ble gitt grunnverdien 1.. Resultatene av denne undersokelsen er angitt i den folgende tabell: Their antiarrhythmic potential and ED 40% were compared with quinidine, whose antiarrhythmic activity was given the basic value 1. The results of this investigation are indicated in the following table:
Forbindelsen ifolge oppfinnelsen administreres fortrinnsvis oralt og de farmasoytiske komposisjonene som inneholder dem er fortrinnsvis tabletter, piller eller gelatin kapsler som inneholder den aktive substans sammen med fortynningsmidler som lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, smoremidler, f.eks. silica, talkum, stearinsyre, magnesium eller kalsium stearat, og/eller polyetylenglykoller; eller de kan også inneholde bindemidler som stivelser, gummiarabicum, polyvinylpyrrolidon, disintergreringsmidler som algininsyre og alginater, bruse-blandinger; fargestoffer; sotningsmidler; fuktemidler som lecithin, polysorbater, laurylsulfater. De farmasøytiske komposisjonene for oral administrering av forbindelsen ifolge oppfinnelsen kan også være i flytende form som dråper eller sirup. The compound according to the invention is preferably administered orally and the pharmaceutical compositions containing them are preferably tablets, pills or gelatin capsules containing the active substance together with diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; or they may also contain binders such as starches, gum arabic, polyvinylpyrrolidone, disintegrants such as alginic acid and alginates, fizzy mixtures; dyes; sooting agents; humectants such as lecithin, polysorbates, lauryl sulphates. The pharmaceutical compositions for oral administration of the compound according to the invention can also be in liquid form such as drops or syrup.
Den passende dosering for oral administrasjon til voksene mennesker er fortrinnsvis rundt 30-100 mg pr. dose, f.eks. 2-3 ganger om dagen. The appropriate dosage for oral administration to adults is preferably around 30-100 mg per dose, e.g. 2-3 times a day.
De farmasoytiske komposisjoner som inneholder forbindelsene ifolge oppfinnelsen kan også være egnet for andre administreringsmåter, f.eks. kan de være suppositorer for rektal administrering eller injiserbare losninger. Både suppositorer og injiserbare losninger fremstilles på en konvensjonell måte og inneholder vanlige bæremidler og respektive losningsmidler. F.eks. er egnede losningsmidler for injeksjoner sterilt vann, fysiologisk saltlbsning, vandig dextrose losninger. The pharmaceutical compositions containing the compounds according to the invention may also be suitable for other administration methods, e.g. they may be suppositories for rectal administration or injectable solutions. Both suppositories and injectable solutions are manufactured in a conventional manner and contain usual carriers and respective solvents. E.g. suitable solvents for injections are sterile water, physiological saline solution, aqueous dextrose solutions.
De folgende eksempler illustrerer, men . begrenser ikke den foreliggende oppfinnelse. The following examples illustrate, but . does not limit the present invention.
Eksempel 1Example 1
5- hydroksy-l,2,3,4-tetrahydronaftalen (44 g) , 1,2-epoksy-3-klor-propan (180 ml) og piperidin (0,5 ml) ble kokt ved tilbakelop 12 timer. Etter torking ble resten behandlet med en blanding av 10% natriumhydroksyd (300 ml) og dioksan (400 ml). Etter roring i to timer ved romtemperatur ble dioksanet avdampet under vakuum. Det basiske vann ble ekstrahert med etyleter, eteren ble kraftig vasket med vann og etter torking erholdtes en olje som ble krystallisert fra etanol og gav 5-(2,3-epoksy-propoksy)-1,2,3,4-tetrahydro-l,4-etan-naftalen (35 g) (KpQ2132-133°C). 5-hydroxy-1,2,3,4-tetrahydronaphthalene (44 g), 1,2-epoxy-3-chloro-propane (180 ml) and piperidine (0.5 ml) were refluxed for 12 hours. After drying, the residue was treated with a mixture of 10% sodium hydroxide (300 ml) and dioxane (400 ml). After stirring for two hours at room temperature, the dioxane was evaporated under vacuum. The basic water was extracted with ethyl ether, the ether was washed vigorously with water and after drying an oil was obtained which was crystallized from ethanol to give 5-(2,3-epoxy-propoxy)-1,2,3,4-tetrahydro-1 ,4-ethane-naphthalene (35 g) (KpQ2132-133°C).
Ved å gå frem analogt ble folgende forbindelser erholdt:: 6- (2,3-epoksy-propoksy)-1,2,3,4-tetrahydro-l,4-etan-naftalen, KpQ 2 130-132°C; By proceeding analogously, the following compounds were obtained: 6-(2,3-epoxy-propoxy)-1,2,3,4-tetrahydro-1,4-ethane-naphthalene, KpQ 2 130-132°C;
5-(2,3-epoksy-propoksy)-7-metyl-l,2,3,4-tetrahydro-l,4-etan-naf talen, 5-(2,3-epoxy-propoxy)-7-methyl-1,2,3,4-tetrahydro-1,4-ethane-naphthalene,
Kp0/15138°C{ Kp0/15138°C{
,5-(2,3-epoksy-propoksy)-8-metyl-l,2,3,4-tetrahydro-l,4-etan-naftalen, Kp04145-150°C; ,5-(2,3-epoxy-propoxy)-8-methyl-1,2,3,4-tetrahydro-1,4-ethane-naphthalene, Kp04145-150°C;
5- (2, 3-epoksy-propoksy) -8-klor-l, 2,3, 4-tetrahydro-l, 4-etannaftalen, 5-(2,3-epoxy-propoxy)-8-chloro-1,2,3,4-tetrahydro-1,4-ethanenaphthalene,
smp. 74-75°C; m.p. 74-75°C;
5-(2,3-epoksy-propoksy)-6,8-diklor-l, 2,3,4-tetrahydro-l,4-etannaftalen, 5-(2,3-epoxy-propoxy)-6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethanenaphthalene,
smp. 85-88°C; m.p. 85-88°C;
5- (2, 3-epoksy-propoksy) -6-klor-l, 2, 3, 4-tetrahydro-l, 4-etanJ-naftalen; 5-(2,3-epoxy-propoxy)-6-chloro-1,2,3,4-tetrahydro-1,4-ethane N-naphthalene;
5-(2,3-epoksy-propoksy)-8-fluor-1,2,3,4-tetrahydro-l,4-etannaftalen; 5-(2,3-epoxy-propoxy)-8-fluoro-1,2,3,4-tetrahydro-1,4-ethanenaphthalene;
5-(2,3-epoksy-propoksy)-8-metyltio-l,2,3,4-tetrahydro-l,4-etannaftalen (olje); 5-(2,3-epoxy-propoxy)-8-methylthio-1,2,3,4-tetrahydro-1,4-ethanenaphthalene (oil);
5-(2,3-epoksy-propoksy)-8-metoksy-l,2,3,4-tetrahydro-l,4-etan-naf talen, 5-(2,3-epoxy-propoxy)-8-methoxy-1,2,3,4-tetrahydro-1,4-ethane-naphthalene,
smp. 52-55°C; m.p. 52-55°C;
5- ( 2, 3-epoksy-propoksy) -8-hydroksy-l, 2,3, 4-tetrahydro-l, 4-etan-naf talen; 5-(2,3-epoxy-propoxy)-8-hydroxy-1,2,3,4-tetrahydro-1,4-ethane-naphthalene;
5-(2,3-epoksy-propoksy)-8-metylsulfonamido-1,2,3,4-tetrahydro-1,4-etan-naftalen; 5-(2,3-epoxy-propoxy)-8-methylsulfonamido-1,2,3,4-tetrahydro-1,4-ethane-naphthalene;
5-(2,3-epoksy-propoksy)-8-nitro-l,2,3,4-tetrahydro-l,4-etan-naf talen, 5-(2,3-epoxy-propoxy)-8-nitro-1,2,3,4-tetrahydro-1,4-ethane-naphthalene,
smp. 106-108°C; m.p. 106-108°C;
5-(2,3-epoksy-propoksy)-6-klor-8-hydroksy-l,2,3,4-tetrahydro-1,4-etan-naftalen; 5-(2,3-epoxy-propoxy)-6-chloro-8-hydroxy-1,2,3,4-tetrahydro-1,4-ethane-naphthalene;
5- (2,3-epoksy-propoksy)-1,2,3,4-tetrahydro-l,4-metan-naftalen, Kp02 122°C; 5-(2,3-epoxy-propoxy)-1,2,3,4-tetrahydro-1,4-methane-naphthalene, KpO 2 122°C;
6- (2,3-epoksy-propoksy)-1,2,3,4-tetrahydro-l,4-metan-naftalen, KpQ 2 120-123°C; 6-(2,3-epoxy-propoxy)-1,2,3,4-tetrahydro-1,4-methane-naphthalene, KpQ 2 120-123°C;
5-(2,3-epoksy-propoksy)-1,2,3,4-tetrahydro-l,4-metan-naftalen, K<p>0 05114-116°C; 5-(2,3-epoxy-propoxy)-1,2,3,4-tetrahydro-1,4-methane-naphthalene, K<p>0 05114-116°C;
5-(2,3-epoksy-propoksy)-8-mety1-1,2,3,4-tetrahydro-l,4-metan-naf talen; 5-(2,3-epoxy-propoxy)-8-methyl-1,2,3,4-tetrahydro-1,4-methane-naphthalene;
5-(2,3-epoksy-propoksy)-8-klor-l,2,3,4-tetrahydro-l, 4-metan-naf talen; 5-(2,3-epoxy-propoxy)-8-chloro-1,2,3,4-tetrahydro-1,4-methane-naphthalene;
5- (2, 3-epoksy-propoksy)-6,8-diklor-1, 2,3, 4-tetrahydro-l, 4-metan-naftalen; 5-(2,3-epoxy-propoxy)-6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-naphthalene;
5- (2, 3-epoksy-propoksy)-6-klor-l, 2, 3, 4-tetrahydro-l, 4-metan-naf talen; 5-(2,3-epoxy-propoxy)-6-chloro-1,2,3,4-tetrahydro-1,4-methane-naphthalene;
5-(2,3-epoksy-propoksy)-8-fluor-1,2,3,4-tetrahydro-l,4-metan-naftalen; 5-(2,3-epoxy-propoxy)-8-fluoro-1,2,3,4-tetrahydro-1,4-methane-naphthalene;
5-(2,3-epoksy-propoksy)-8-metyltio-l,2,3,4-tetrahydro-l,4-metan-naftalen; 5-(2,3-epoxy-propoxy)-8-methylthio-1,2,3,4-tetrahydro-1,4-methane-naphthalene;
5-(2,3-epoksy-propoksy)-8-metoksy-l,2,3,4-tetrahydro-l,4-metan-naftalen; 5-(2,3-epoxy-propoxy)-8-methoxy-1,2,3,4-tetrahydro-1,4-methane-naphthalene;
5-(2,3-epoksy-propoksy)-8-hydroksy-l,2,3,4-tetrahydro-l,4-metan-naftalen; 5-(2,3-epoxy-propoxy)-8-hydroxy-1,2,3,4-tetrahydro-1,4-methane-naphthalene;
5-(2,3-epoksy-propoksy)-8-metylsulfonamido-1,2,3,4-tetrahydro-1,4-metan-naftalen; 5-(2,3-epoxy-propoxy)-8-methylsulfonamido-1,2,3,4-tetrahydro-1,4-methane-naphthalene;
5-(2,3-epoksy-propoksy)-8-nitro-l,2,3,4-tetrahydro-l,4-metan-naftalen; 5-(2,3-epoxy-propoxy)-8-nitro-1,2,3,4-tetrahydro-1,4-methane-naphthalene;
5-(2,3-epoksy-propoksy)-6-klor-8-hydroksy-l,2,3,4-tetrahydro^l,4-metan-naftalen; 5-(2,3-epoxy-propoxy)-6-chloro-8-hydroxy-1,2,3,4-tetrahydro-1,4-methane-naphthalene;
og dé analoge 1,4-dihydro derivater.and the analogous 1,4-dihydro derivatives.
Eksempel 2Example 2
5-hydroksy-l,2,3,4-tetrahydro-l,4-etan-naftalen (5 g) og 1,2-epoksy-3-brombutan (5,3 g) i dimetylsulfoksyd (20 ml) ble behandlet med natriumhydroksyd (1,4 g) lost i vann (10 ml). Reaksjonsblandingen ble varmet ved 60°C i 1 time, så helt i vann og ekstrahert med etyleter. Det organiske ekstraktet ble avdestil-lert og 5-(2,3-epoksy-butoksy)-1,2,3,4-tetrahydro-l,4-etannaftalen (4,9 g) ble oppsamlet ved 146°C/0,5 mm. 5-hydroxy-1,2,3,4-tetrahydro-1,4-ethane-naphthalene (5 g) and 1,2-epoxy-3-bromobutane (5.3 g) in dimethylsulfoxide (20 ml) were treated with sodium hydroxide (1.4 g) dissolved in water (10 ml). The reaction mixture was heated at 60°C for 1 hour, then poured into water and extracted with ethyl ether. The organic extract was distilled off and 5-(2,3-epoxy-butoxy)-1,2,3,4-tetrahydro-1,4-ethanenaphthalene (4.9 g) was collected at 146°C/0, 5 mm.
Ved å gå frem analogt ble folgende forbindelser fremstilt: 5-(2,3-eposky-butoksy)-1,2,3,4-tetrahydro-l,4-metan-naftalen; By proceeding analogously, the following compounds were prepared: 5-(2,3-epoxy-butoxy)-1,2,3,4-tetrahydro-1,4-methane-naphthalene;
5-(2,3-epoksy-butoksy)-8-klor-l, 2,3, 4-tetrahydro-l,4-metan-naftalen; 5-(2,3-epoxy-butoxy)-8-chloro-1,2,3,4-tetrahydro-1,4-methane-naphthalene;
5-(2,3-epoksy-butoksy)-6,8-diklor-l,2,3,4-tetrahydro-l,4-metan-naftalen; 5-(2,3-epoxy-butoxy)-6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-naphthalene;
5-(2,3-epoksy-butoksy)-8-klor-l,2,3,4-tetrahydro-l,4-etannaftalen, 5-(2,3-epoxy-butoxy)-8-chloro-1,2,3,4-tetrahydro-1,4-ethanenaphthalene,
Kp0^3145-148°C; Kp0^3145-148°C;
5-(2,3-epoksy-butoksy)-6,8-diklor-1,2,3,4-tetrahydro-l,4-etan-naf talen; 5-(2,3-epoxy-butoxy)-6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethane-naphthalene;
så vel som de andre (2,3-epoksy-butoksy) derivater, enten av 1,2,3,4-tetrahydro-1,4-etan-naftalen eller av 1,2,3,4-tetrahydro-l,4-metan-naftalen eller av 1,4-dihydro-l,4-etan-naftalen eller av, 1, 4-dihydro-l, 4-metan-naf talen, hvori R-^ og/eller R2har de samme betydninger som nevnt i eksempel 1. as well as the other (2,3-epoxy-butoxy) derivatives, either of 1,2,3,4-tetrahydro-1,4-ethane-naphthalene or of 1,2,3,4-tetrahydro-1,4 -methane-naphthalene or of 1,4-dihydro-1,4-ethane-naphthalene or of, 1,4-dihydro-1,4-methane-naphthalene, in which R-1 and/or R2 have the same meanings as mentioned in example 1.
Eksempel 3 Example 3
5-(2,3-epoksy-propoksy)-1,2,3,4-tetrahydro-l,4-etan-naftalen (23 g; 5-(2,3-epoxy-propoxy)-1,2,3,4-tetrahydro-1,4-ethane-naphthalene (23 g;
0,1 mol) ble lost i dioksan (600 ml), så ble 48% bromhydrogensyre (100 ml) fortynnet med vann (100 ml) tilsatt. Etter rbring i 2 timer ved romtemperatur ble vann (1000 ml) ti lsatt. EkStraksjon med etyleter, vasking av eteren med vann, torking, bleking og torking gav en kromatografisk ren olje, som etter henstand storknet og gav 5-(3-brom-2-hydroksy)-propoksy-1,2,3,4-tetrahydro-l,4-etan-naf talen i et praktisk kvantitativt utbytte (smp. 65-68°C). 0.1 mol) was dissolved in dioxane (600 ml), then 48% hydrobromic acid (100 ml) diluted with water (100 ml) was added. After stirring for 2 hours at room temperature, water (1000 ml) was added. Extraction with ethyl ether, washing the ether with water, drying, bleaching and drying gave a chromatographically pure oil, which on standing solidified to give 5-(3-bromo-2-hydroxy)-propoxy-1,2,3,4-tetrahydro -1,4-ethane-naphthalene in a practical quantitative yield (m.p. 65-68°C).
Ved å gå frem analogt ble de folgende forbindelser fremstilt: 5-(3-brom-2-hydroksy)-propoksy-1,2,3,4-tetrahydro-l,4-metan-naftalen; Proceeding analogously, the following compounds were prepared: 5-(3-bromo-2-hydroxy)-propoxy-1,2,3,4-tetrahydro-1,4-methane-naphthalene;
5-(3-brom-2-hydroksy)-propoksy-8-klor-l,2,3,4-tetrahydro-l,4-metan-naf talen; 5-(3-bromo-2-hydroxy)-propoxy-8-chloro-1,2,3,4-tetrahydro-1,4-methane-naphthalene;
5-(3-brom-2-hydroksy)-propoksy-6,8-diklor-l,2,3,4-tetrahydro-l,4-metan-naftalen; 5-(3-bromo-2-hydroxy)-propoxy-6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-naphthalene;
5-(3-brom-2-hydroksy)propoksy-8-klor-l,2,3,4-tetrahydro-l,4-etannaftalen; 5-(3-bromo-2-hydroxy)propoxy-8-chloro-1,2,3,4-tetrahydro-1,4-ethanenaphthalene;
5-(3-brom-2-hydroksy)-propoksy-6,8-diklor-l,2,3,4-tetrahydro-l,4-etan-naftalen; 5-(3-bromo-2-hydroxy)-propoxy-6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethane-naphthalene;
så vel som de andre (3-brom-2-hydroksy)-propoksy derivater, enten av 1,2,3,4-tetrahydro-l,4-etan-naftalen eller av 1,2,3,4-tetrahydro-l, 4-metan-naf talen eller av 1,4-dihydro-l,4-etan-naftalen eller av 1,4-dihydro-l,4-metan-naftalen,hvori R^ og/eller R2as well as the other (3-bromo-2-hydroxy)-propoxy derivatives, either of 1,2,3,4-tetrahydro-1,4-ethane-naphthalene or of 1,2,3,4-tetrahydro-1 , 4-methane-naphthalene or of 1,4-dihydro-1,4-ethane-naphthalene or of 1,4-dihydro-1,4-methane-naphthalene, in which R 1 and/or R 2
har de samme betydninger som i eksempel 1.have the same meanings as in example 1.
Eksempel 4 Example 4
5-(2,3-epoksy-butoksy)-1,2,3,4-tetrahydro-l,4-etan-naftalen (5 g) og morfolin (30 ml) ble kokt ved tilbakelop i 72 timer. Etter konsentrering i vakuum, opplbsning i etyleter ekstraksjon med 8% saltsyre, filtrering og alkalisering med 5% NH^OH utskiltes en olje som ble ekstrahert med etyleter, så ble eteren vasket med vann. Torkning og metning med gassformig HCl gav f eining av et produkt som etter krystallisasjon fra isopropylalkohol, gav 3-N-morfolinyl-1-(1,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-butanol HCl, smp. 213-216°C. 5-(2,3-epoxy-butoxy)-1,2,3,4-tetrahydro-1,4-ethane-naphthalene (5 g) and morpholine (30 ml) were refluxed for 72 hours. After concentration in vacuo, dissolution in ethyl ether, extraction with 8% hydrochloric acid, filtration and alkalization with 5% NH^OH, an oil separated which was extracted with ethyl ether, then the ether was washed with water. Drying and saturation with gaseous HCl yielded a product which, after crystallization from isopropyl alcohol, gave 3-N-morpholinyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2 -butanol HCl, m.p. 213-216°C.
Ved å gå frem analogt ble folgende forbindelse fremstilt: 3-N-pyrrolidinyl-l-(1,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2- butanol; By proceeding analogously, the following compound was prepared: 3-N-pyrrolidinyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-butanol;
3- N-pyrazolidinyl-l- (1, 2, 3, 4-tetrahydro-l,4-etan-5-naftyloksy)-2- butanol; 3- N -pyrazolidinyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-butanol;
3- N-imidazolidinyl-l-(1,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2- butanol; 3- N -imidazolidinyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-butanol;
3- N-piperidyl-l-(1,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-butanol; 3- N -piperidyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-butanol;
3-N-piperazinyl-l- (1, 2, 3, 4-tetrahydro-l, 4-etan-5-naf tyloksy)-2-butanol; 3-N-piperazinyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-butanol;
3-N-tiomorfolinyl-l- (1, 2, 3, 4-tetrahydro-l, 4-etan-5-naf tyloksy) -2-butanol; 3-N-thiomorpholinyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-butanol;
3-N-morfolinyl-l-(1,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2- butanol; 3-N-morpholinyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-butanol;
3- N-pyrrolidinyl-l-(1,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2- butanol; 3- N -pyrrolidinyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-butanol;
3- N-pyrazolidinyl-l- (1, 2, 3, 4-tetrahydro-l, 4^-metan-5-naf tyloksy) - 2- butanol;. 3-N-pyrazolidinyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-butanol;.
3- N-imidazolidinyl-l-(1,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2- butanol; 3- N -imidazolidinyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-butanol;
3- N-piperidyl-l-(1,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-butanol; 3- N -piperidyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-butanol;
3-N-piperazinyl-l-(1,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2- butanol; 3-N-piperazinyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-butanol;
3- N-tiomorfolinyl-l-(1,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2- butanol; 3-N-thiomorpholinyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-butanol;
så vel som 3-N morfolinyl, 3-N-pyrrolidinyl, 3-N-pyrazolidinyl, 3- N-imidazolidinyl, 3-N-piperidyl, 3-N-piperazinyl, 3-N-tiomorfolinyl derivater enten av 1-(1,2,3,4-tetrahydro-l,4-etan-naf tyloksy) -2-butanol eller av 1-(1,2,3,4-tetrahydro-l,4-metan-naf tyloksy) -2-butanol eller av 1-(1,4-dihydro-l,4-etan-naftyloksy)-2-butanol eller av 1-(1,4-dihydro-l,4-metan-naftyloksy)-2-butanol, hvori R., og/eller R^ har de andre betydninger nevnt i eksempel 1. as well as 3-N-morpholinyl, 3-N-pyrrolidinyl, 3-N-pyrazolidinyl, 3-N-imidazolidinyl, 3-N-piperidyl, 3-N-piperazinyl, 3-N-thiomorpholinyl derivatives either of 1-(1 ,2,3,4-tetrahydro-1,4-ethane-naphthyloxy)-2-butanol or of 1-(1,2,3,4-tetrahydro-1,4-methane-naphthyloxy)-2-butanol or of 1-(1,4-dihydro-1,4-ethane-naphthyloxy)-2-butanol or of 1-(1,4-dihydro-1,4-methane-naphthyloxy)-2-butanol, wherein R , and/or R^ have the other meanings mentioned in example 1.
Eksempel 5Example 5
Til en suspensjon av natriumhydrid (0,75 g) i torr dimetylformamid (300 ml), ble imidazol (2 g) tilsatt porsjonsvis, så etter ca. en halv time, 5-(3-brom-2-hydroksy)-propoksy-1,2,3,4-tetrahydro-1,4-etan-naftalen (10 g) . Etter å ha fått stå ved 60 C i 8 timer ble løsningsmiddelt avdampet, resten opplost i benzen og benzenlosningen ble kraftig vasket med vann. Etter torking ble resten krystallisert fra toluen og gav 3-N-imidazolyl-1-(1,2,3,4-tetrahydro-lT4-etan-5-naftyloksy)2-propanol (7,5 g; To a suspension of sodium hydride (0.75 g) in dry dimethylformamide (300 ml), imidazole (2 g) was added portionwise, then after approx. half an hour, 5-(3-bromo-2-hydroxy)-propoxy-1,2,3,4-tetrahydro-1,4-ethane-naphthalene (10 g). After being allowed to stand at 60° C. for 8 hours, the solvent was evaporated, the residue dissolved in benzene and the benzene solution was vigorously washed with water. After drying, the residue was crystallized from toluene to give 3-N-imidazolyl-1-(1,2,3,4-tetrahydro-1T4-ethane-5-naphthyloxy)2-propanol (7.5 g;
smp. 139-141°C). m.p. 139-141°C).
Ved å gå frem analogt ble de folgende forbindelser fremstilt: 3-N-imidazolyl-l-(1,2,3,4-tetrahydro-l,4-etan-6-naftyloksy)-2- propanol; By proceeding analogously, the following compounds were prepared: 3-N-imidazolyl-1-(1,2,3,4-tetrahydro-1,4-ethane-6-naphthyloxy)-2-propanol;
3- N-imidazolyl-l-(6-klor-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2- propanol; 3- N -imidazolyl-1-(6-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3- N-imidazolyl-l-(7-metyl-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2- propanol; 3- N -imidazolyl-1-(7-methyl-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3- N-imidazolyl-l-(8-klor-l,2,3,4-tetrahydro-l,4-etan-5-riaftyl-oksy) -2-propanol, 3- N-imidazolyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-riaphthyl-oxy)-2-propanol,
smp. 125-129°C; m.p. 125-129°C;
3-N-imidazolyl-l-(8-fluor-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy ) -2-propanol, 3-N-imidazolyl-1-(8-fluoro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol,
smp. 146-148°C; m.p. 146-148°C;
3-N-imidazolyl-l-(8-hydroksy-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy) -2-^propanol, 3-N-imidazolyl-1-(8-hydroxy-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol,
smp. 153-156°C; m.p. 153-156°C;
3-N-imidazolyl-l-(8-metyl-l,2,3,4-tetrahydro-l,4-etan-5-naf-tyloksyW-r propanol, 3-N-imidazolyl-1-(8-methyl-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-r propanol,
smp. 112-114°C; m.p. 112-114°C;
3-N-imidazolyl-l-(8-metylsulfonamido-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol, 3-N-imidazolyl-1-(8-methylsulfonamido-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol,
smp. 131-135°C; m.p. 131-135°C;
3-N-imidazolyl-l-(8-nitro-l,2,3,4-tetrahydro-l, 4-etan-5-naftyloksy)-2-propanol, 3-N-imidazolyl-1-(8-nitro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol,
smp. 116-119°C; m.p. 116-119°C;
3-N-imidazolyl-l-(6-klor-8-hydroksy-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3-N-imidazolyl-1-(6-chloro-8-hydroxy-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-imidazolyl-l-(6,8-diklor-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3-N-imidazolyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
smp. 139-141°C; m.p. 139-141°C;
3-N-imidazolyl-l-(1,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)- 2-propanol; 3-N-imidazolyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-imidazolyl-l-(6-klor-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-imidazolyl-1-(6-chloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-imidazolyl-l-(7-metyl-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanolJ 3-N-imidazolyl-1-(7-methyl-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanolJ
3-N-imidazolyl-l-(8-klor-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy) 2-propanol; 3-N-imidazolyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy) 2-propanol;
3-N-imidazolyl-l-(8-fluor-1,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-imidazolyl-1-(8-fluoro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-imidazolyl-l-(8-hydroksy-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-imidazolyl-1-(8-hydroxy-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-imidazolyl-l-(8-metyl-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-imidazolyl-1-(8-methyl-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-imidazolyl-l-(8-metylsulfonamidé-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-imidazolyl-1-(8-methylsulfonamide-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-imidazolyl-l-(8-nitro-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy )- 2-propanol ; 3-N-imidazolyl-1-(8-nitro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-imidazolyl-l-(6-klor-8-hydroksy-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-imidazolyl-1-(6-chloro-8-hydroxy-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-imidazolyl-l-(6, 8-diklor-l, 2, 3, 4-tetrahydro-l, 4-metan-5-naftyloksy)-2-propanol; 3-N-imidazolyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-imidazolinyl-l-(1,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3-N-imidazolinyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-imidazolinyl-1-(6-klor-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3-N-imidazolinyl-1-(6-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-imidazolinyl-1-(7-metyl-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2^-propanol; 3-N-imidazolinyl-1-(7-methyl-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2H-propanol;
3rN-imidazolinyl-l-(8-klor-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3n-imidazolinyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-imidazolinyl-l-(8-fluor-1,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3-N-imidazolinyl-1-(8-fluoro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-imidazolinyl-l- (8-hydroksy-l, 2, 3, 4-tetrahydro-l, 4-etan-5-naftyloksy)-2-propanol; 3-N-imidazolinyl-1-(8-hydroxy-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-imidazolinyl-l-(8-metyl-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3-N-imidazolinyl-1-(8-methyl-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-imidazolinyl-l-(8-metylsulfonamido-l,2,3,4-tétrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3-N-imidazolinyl-1-(8-methylsulfonamido-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-imidazolinyl-l-(8-nitro-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3-N-imidazolinyl-1-(8-nitro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-imidazolinyl-l-(6-klor-8-hydroksy-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3-N-imidazolinyl-1-(6-chloro-8-hydroxy-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-imidazolinyl-l-(6,8-diklor-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3-N-imidazolinyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-imiazolinyl-l-(1,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol, 3-N-imiazolinyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol,
smp. 106-109°C; m.p. 106-109°C;
3-N-imidazolinyl-l-(6-klor-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-imidazolinyl-1-(6-chloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-imidazolinyl-l-(7-metyl-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-imidazolinyl-1-(7-methyl-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-imidazolinyl-l-(8-klor-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-imidazolinyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-imidazolinyl-l-(8-fluor-1,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-imidazolinyl-1-(8-fluoro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-imidazolinyl-l-(8-hydroksy-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-imidazolinyl-1-(8-hydroxy-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-imidazolinyl-l-(8-metyl-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-prppanol; 3-N-imidazolinyl-1-(8-methyl-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-imidazolinyl-l-(8-metylsulfonamido-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-imidazolinyl-1-(8-methylsulfonamido-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-imidazolinyl-l-(8-nitro-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-imidazolinyl-1-(8-nitro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-imidazolinyl-l-(6-klor-8-hydroksy-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-imidazolinyl-1-(6-chloro-8-hydroxy-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-imidazolinyl-l-(6,8-diklor-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-imidazolinyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-pyrazolyl-l-(1,2,3,4-tétrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3-N-pyrazolyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-pyrazolyl-l-(6-klor-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2- propanol; 3-N-pyrazolyl-1-(6-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3- N-pyrazolyl-l- (7-metyl-l, 2,3, 4-tetrahydroi*l, 4-etan-5-naf ty loksy)_ 2- propanol; ;3- N-pyrazolyl-l-(8-klor-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; ;3-N-pyrazolyl-l-(8-fluor-1,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2- propanol; ;3- N-pyrazolyl-l-(8-hydroksy-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; ;3-N-pyrazolyl-l-(8-metyl-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2- propanol; ;3- N-pyrazolyl-l-(8-metylsulfonamido-1,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; ;3-N-pyrazolyl-l-(8-nitro-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2- propanol; ;3- N-pyrazolyl-l-(6-klor-8-hydroksy-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; ;3-N-pyrazolyl-l-(6,8-diklor-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy ) -2-propanol ; ;3-N-pyrazolyl-l-(1,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; ;3-N-pyrazolyl-l- (6-klor-l, 2, 3, 4*-tetrahydro-l, 4-metan-5-naf tyloksy)-2-propanol; 3-N-pyrazolyl-1-(7-methyl-1,2,3,4-tetrahydroyl,4-ethane-5-naphthyloxy)-2-propanol; ;3- N -pyrazolyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol; ;3-N-pyrazolyl-1-(8-fluoro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol; ;3- N -pyrazolyl-1-(8-hydroxy-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol; ;3-N-pyrazolyl-1-(8-methyl-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol; ;3- N -pyrazolyl-1-(8-methylsulfonamido-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol; ;3-N-pyrazolyl-1-(8-nitro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol; ;3- N -pyrazolyl-1-(6-chloro-8-hydroxy-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol; ; 3-N-pyrazolyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol; ;3-N-pyrazolyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol; ;3-N-pyrazolyl-1-(6-chloro-1,2,3,4*-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-pyrazolyl-l- (7-metyl-l, 2, 3, 4-tetrahydro-l, 4-metan-5-naftyloksy)-2-propanol; 3-N-pyrazolyl-1-(7-methyl-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-pyrazolyl-l-(8-klor-l,2,3,4-tetrahydro-l,4-metair-5-naftyloksy)-2- propanol; 3-N-pyrazolyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-methyl-5-naphthyloxy)-2-propanol;
3- N-pyrazolyl-l-(8-fluor-1,2,3,4-tetrahydro-l,4-metan-5-naftyloksy) -2-propanol; 3- N -pyrazolyl-1-(8-fluoro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
34tpyrazolyl-l-(8-hydroksy-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy) -2-propanol; 34tpyrazolyl-1-(8-hydroxy-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-pyrazolyl-l- (8-metyl-l, 2, 3, 4-tetrahydrb-l, 4-metan-5-naf-tylosky-2-propanol; 3-N-pyrazolyl-1-(8-methyl-1,2,3,4-tetrahydrb-1,4-methane-5-naphthyloxy-2-propanol;
3-N-pyrazolyl-l-(8-metylsulfonamido-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-pyrazolyl-1-(8-methylsulfonamido-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-pyrazolyl-l-(8-nitro-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-pyrazolyl-1-(8-nitro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-pyrazolyl-l-(6-klor-8-hydroksy-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-pyrazolyl-1-(6-chloro-8-hydroxy-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-pyrazolyl-l-(6,8-diklor-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-pyrazolyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-pyrazolinyl-l-(1,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2- propanblf, 3-N-pyrazolinyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propaneblf,
3- N-pyrazolinyl-l-(6-klor-l, 2,3,4-tetrahydro-l,4-étan-5-naftyloksy)-2-propanol; - 3- N -pyrazolinyl-1-(6-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol; -
3-N-pyrazolinyl-l-(7-metyl-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy) -2-propanol; 3-N-pyrazolinyl-1-(7-methyl-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-pyrazolinyl-l-(8-klor-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3-N-pyrazolinyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-pyrazolinyl-l-(8-fluor-1,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3-N-pyrazolinyl-1-(8-fluoro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-pyrazolinyl-l-(8-hydroksy-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3-N-pyrazolinyl-1-(8-hydroxy-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-pyrazolinyl-l-(8-metyl-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3-N-pyrazolinyl-1-(8-methyl-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-pyrazolinyl-l-(8^metylsulfonamido-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3-N-pyrazolinyl-1-(8-methylsulfonamido-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-pyrazolinyl-l-(8-nitro-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3-N-pyrazolinyl-1-(8-nitro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-pyrazolinyl-l-(6-klor-8-hydroksy-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3-N-pyrazolinyl-1-(6-chloro-8-hydroxy-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-pyrazolinyl-l- (6, 8-dii;lor-l, 2, 3, 4-tetrahydro-l, 4-etan-5-naftyloksy)-2-propanol; 3-N-pyrazolinyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-pyrazolinyl-l- (1, 2, 3, 4-terahydro-l, 4-metan-5-naftyloksy,J-2-propanol; 3-N-pyrazolinyl-1-(1,2,3,4-terahydro-1,4-methane-5-naphthyloxy,N-2-propanol;
3-N-pyrazolinyl-l- (6-klor-l, 2, 3, 4-tetrahydro-l, 4-metano-5-naftyloksy)-2-propanol; 3-N-pyrazolinyl-1-(6-chloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-pyrazolinyl-l-(7-metyl-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-pyrazolinyl-1-(7-methyl-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-pyrazolinyl-l(8-klor-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-pyrazolinyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-pyrazolinyl-l-(8-fluor-1,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-pyrazolinyl-1-(8-fluoro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-pyrazolinyl-l-(8-hydroksy-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-pyrazolinyl-1-(8-hydroxy-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-pyrazolinyl-l-(8-metyl-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-pyrazolinyl-1-(8-methyl-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-pyrazolinyl-l- (8-metylsulfonamido-l, 2, 3, 4-tetrahydro-l,4 -metan-5-naftyloksy)-2-propanol; 3-N-pyrazolinyl-1-(8-methylsulfonamido-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-pyrazolinyl-l-(8-nitro-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-pyrazolinyl-1-(8-nitro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-pyrazolinyl-l-(6-klor-8-hydroksy-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-pyrazolinyl-1-(6-chloro-8-hydroxy-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-pyrazolinyl-l-(6,8-diklor-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-pyrazolinyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-triazolyl-l-(1,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3-N-triazolyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-triazolyl-l-(6-klor-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2- propanol; 3-N-triazolyl-1-(6-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3- N-triazolyl-l-(7-metyl-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy ) -2-propanol ; 3-N-triazolyl-1-(7-methyl-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-triazolyl-l-(8-klor-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2- propanol; 3-N-triazolyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3- N-triazolyl-l-(8-fluor-1,2,3,4-tetrahydro-l,4-etan^5-naftyloksy) -2-propanol; 3- N -triazolyl-1-(8-fluoro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-triazolyl-l-(8-hydroksy-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy- 2-propanol; 3-N-triazolyl-1-(8-hydroxy-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy-2-propanol;
3-N-triazolyl-l-(8-metyl-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy) -2-propanol; 3-N-triazolyl-1-(8-methyl-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-triazolyl-l-(8-metylsulfonamido-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3-N-triazolyl-1-(8-methylsulfonamido-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-triazolyl-l-(8-nitro-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2- propanol; 3-N-triazolyl-1-(8-nitro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3- N-triazolyl-l-(6-klor-8-hydroksy-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3- N -triazolyl-1-(6-chloro-8-hydroxy-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-triazolyl-H6, 8-diklor-l, 2, 3, 4-tetrahydro-l, 4-etan-5-naf tyloksy) 2-propanol; 3-N-triazolyl-H6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)2-propanol;
3-N-triazolyl-l-(1,2,3,4-tetrahydro-l,4-metan-5-nåftyloksy)-2-propanoi; 3-N-triazolyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-aminoethyloxy)-2-propanoyl;
3-N-triazolyl-l- (6-klor-l, 2, 3, 4-tetrahydro-l, 4-metan-5-naftyloksy) -2-propanol; 3-N-triazolyl-1-(6-chloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-triazolyl-l- (7-metyl-l, 2,3, 4-tetrahydro-l, 4-metan-5-naf tyloksy) -2-propanol; 3-N-triazolyl-1-(7-methyl-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-triazolyl-l-(8-klor-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy )- 2-propanol ; 3-N-triazolyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-triazolyl-l-(8-fluor-1,2,3,4-tetrahydro-l,4-metan-5-naftyloksy) -2-propanol; 3-N-triazolyl-1-(8-fluoro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-triazolyl-l-(8-hydroksy-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol;, 3-N-triazolyl-1-(8-hydroxy-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;,
3-N-triazolyl-l- (8-metyl-l, 2, 3, 4-tetrahydro-l., 4-metan-5-naf tyloksy )-2-propanol; 3-N-triazolyl-1-(8-methyl-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-triazolyl-l-(8-metylsulfonamido-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-triazolyl-1-(8-methylsulfonamido-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-triazolyl-l-(8-nitro-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)- 2-, propanol; 3-N-triazolyl-1-(8-nitro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-triazolyl-l-(6-klor-8-hydroksy-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-triazolyl-1-(6-chloro-8-hydroxy-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-triazolyl-l-(6,8-diklor-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy) -2-propanol, 3-N-triazolyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol,
samt de andre 3-N-imidazolyl, 3-N-imidazolinyl, 3-N-pyrazolyl, 3-N-pyrazolinyl og 3-N-triazolyl derivater enten av 1-(1,4-dihydro-1,4-etan-naftyloksy)-2-propanol eller av 1-(1,4-dihydro-l,4-metan-naf tyloksy)-2-propanol, hvori R, og/eller R2har de overnevnte betydninger. as well as the other 3-N-imidazolyl, 3-N-imidazolinyl, 3-N-pyrazolyl, 3-N-pyrazolinyl and 3-N-triazolyl derivatives either of 1-(1,4-dihydro-1,4-ethane- naphthyloxy)-2-propanol or of 1-(1,4-dihydro-1,4-methane-naphthyloxy)-2-propanol, in which R, and/or R2 have the above meanings.
Eksempel 6Example 6
Til en suspensjon av natriumhydrid (0,31 g) i vannfri dimetyl formamid, ble imidazol tilsatt (0,88 g). Blandingen ble rort i 30 minutter, så tilsatt 5-(3-brom-2-hydrdksy)-propoksy-8-klor-1, 2, 3, 4-tetia hydro-1, 4-etan-naf talen (4,5 g). Etter roring i 24 timer ved romtemperatur, filtrering, torking under vakuum, To a suspension of sodium hydride (0.31 g) in anhydrous dimethyl formamide, imidazole (0.88 g) was added. The mixture was stirred for 30 minutes, then 5-(3-bromo-2-hydroxy)-propoxy-8-chloro-1,2,3,4-tetrahydro-1,4-ethane-naphthalene (4.5 g). After stirring for 24 hours at room temperature, filtering, drying under vacuum,
ble resten opplost i kloroform, så etter vasking med vann og torking Igjen erholdtes 3-N-imidazolyl-l-(8-klor-l,2,3,4-tetrahydro-l, 4-etan-5-naf tyloksy) -2-propanol (3,9 g; smp. 125-129°) the residue was dissolved in chloroform, then after washing with water and drying 3-N-imidazolyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy) was again obtained - 2-propanol (3.9 g; m.p. 125-129°)
(krystallisasjon fra toluen).(crystallization from toluene).
3-N-imidazolyl-l-(8-klor-l,2,3,4- tetrahydro-1,4 etan-5-naftyloksy)-2-propanpl (3,9 g) ble kraftig rort i 23% HCl (150 ml) under kjoling. Etter få minutter feltes hydrokloridet av 3-N-imidazolyl-1-(8-klor-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol (3,8 g); smp. 223-227°c).3-N-imidazolyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4 ethane-5-naphthyloxy)-2-propanepl (3.9 g) was vigorously stirred in 23% HCl ( 150 ml) during dressing. After a few minutes, the hydrochloride of 3-N-imidazolyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol precipitates (3.8 g); m.p. 223-227°c).
Ved analog fremgangsmåte ble hydrokloridene av forbindelsene nevntBy an analogous procedure, the hydrochlorides of the compounds mentioned were obtained
i eksemplene 4 og 5 fremstilt.in examples 4 and 5 prepared.
Eksempel 7Example 7
Til en losning av 1,2,3,4-tetrahydro-l,4-etan-5-naftyloksy-acetylklorid (10 g) i etyleter (250 ml) inneholdende trietylamin (5,7 ml) kjolt til -5°C ble diazométan (2,6 g) opplost i etyleter (400 ml) tilsatt. Etter roring i 15 timer ved 0°C ble hydrokloridet av trietylamin frafiltrert og den organiske fasen, ble etter vask med vann torket over MgSO^. Den torre losningen ble deretter kjolt til -15°C, så langsomt mettet med gassformig. HBr. Etter henstand natten over ved romtemperatur ble eterlosningen vasket med vann til noylralitet så torket og konsentrert for å gi den rå bromketonet (9 g) i form av en rodlig rest. Til nevnte rå bromketon lost i tetrahydrofuran (100 ml), kjolt til 5°C, ble NaBH4 (2 g) opplost i vann (10 ml) tilsatt i porsjoner. Etter 3 timers henstand ved romtemperatur ble NaOH 2N (10 ml) tilsatt. Blandingen ble så oppvarmet véd 35°C i en halv time, konsentrert under vakuum og resten ble fordelt mellom vann og etyleter. Fra den organiske fasen erholdtes en rest etter vanlig behandling som ble destillert i vakuum og gav 5-(.2, 3-epoksy-propoksy)-1, 2, 3, 4-tetrahydro-1,4-etan-naftalen (5 g; kokepunkt: 117°C/0, 2 mm). To a solution of 1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy-acetyl chloride (10 g) in ethyl ether (250 ml) containing triethylamine (5.7 ml) cooled to -5°C diazométane (2.6 g) dissolved in ethyl ether (400 ml) added. After stirring for 15 hours at 0°C, the hydrochloride of triethylamine was filtered off and the organic phase, after washing with water, was dried over MgSO 4 . The dry solution was then cooled to -15°C, then slowly saturated with gaseous. HBr. After standing overnight at room temperature, the ether solution was washed with water until neutral then dried and concentrated to give the crude bromoketone (9 g) as a reddish residue. To said crude bromoketone dissolved in tetrahydrofuran (100 ml), cooled to 5°C, NaBH 4 (2 g) dissolved in water (10 ml) was added in portions. After standing for 3 hours at room temperature, NaOH 2N (10 ml) was added. The mixture was then heated at 35°C for half an hour, concentrated under vacuum and the residue partitioned between water and ethyl ether. From the organic phase, a residue was obtained after usual treatment which was distilled in vacuum and gave 5-(.2, 3-epoxy-propoxy)-1, 2, 3, 4-tetrahydro-1,4-ethane-naphthalene (5 g ; boiling point: 117°C/0.2 mm).
Ved analog fremgangsmåte ble det i folgende forbindelse fremstilt: 5-(2,3-epoksy-propoksy)-1,2,3,4-tetrahydro-l,4-metannaftalen, Kp0/2122°C; By an analogous method, the following compound was prepared: 5-(2,3-epoxy-propoxy)-1,2,3,4-tetrahydro-1,4-methanenaphthalene, Kp0/2122°C;
5-(2,3-epoksy-propoksy)-8~klor-l,2,3,4-tetrahydro-l,4- .etannaftalen, smp. 74-75°C. 5-(2,3-epoxy-propoxy)-8-chloro-1,2,3,4-tetrahydro-1,4-ethanenaphthalene, m.p. 74-75°C.
5-(2,3-epoksy-propoksy)-8-klor-l,2,3,4-tetrahydro-l,4-metannaftalen; 5-(2,3-epoxy-propoxy)-8-chloro-1,2,3,4-tetrahydro-1,4-methanenaphthalene;
5-(2,3-epoksy-propoksy)-6,8-diklor-l,2,3,4-tetrahydro-l,4-etannaftalen, 5-(2,3-epoxy-propoxy)-6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethanenaphthalene,
smp. 85-88°C; m.p. 85-88°C;
5- (2, 3-epoksy-propoksy)-6, 8-diklor-l, 2, 3, 4-tetrahydro-l, 4-metan-naftalen; 5-(2,3-epoxy-propoxy)-6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-naphthalene;
5-(2,3-epoksy-butoksy)-1,2,3,4-tetrahydro-l,4-etannaftalen; 5-(2,3-epoxy-butoxy)-1,2,3,4-tetrahydro-1,4-ethanenaphthalene;
5-(2,3-epoksy-butoksy)-1,2,3,4-tetrahydro-l,4-metannaftalen; 5-(2,3-epoxy-butoxy)-1,2,3,4-tetrahydro-1,4-methanenaphthalene;
5-(2,3-epoksy-butoksy)-8-klor-l,2,3,4-tetrahydro-l,4-etannaftalen; 5-(2,3-epoxy-butoxy)-8-chloro-1,2,3,4-tetrahydro-1,4-ethanenaphthalene;
5-(2,3-epoksy-butoksy)-8-klor-l,2,3,4-tetrahydro-l,4-metan-naftalen; 5-(2,3-epoxy-butoxy)-8-chloro-1,2,3,4-tetrahydro-1,4-methane-naphthalene;
5-(2,3-epoksy-butoksy)-6,8-diklor-l,2,3,4-tetrahydro-l,4-etannaftalen, 5-(2,3-epoxy-butoxy)-6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethanenaphthalene,
5-(2,3-epoksy-butoksy)-6,8-diklor-l,2,3,4-tetrahydro-l,4-metan-naftalen, 5-(2,3-epoxy-butoxy)-6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-naphthalene,
så vel som de andre epoksy derivater allerede beskrevet i eksemplene 1 og 2. as well as the other epoxy derivatives already described in examples 1 and 2.
Eksempel 8Example 8
En losning av 5-hydroksy-l>2,3,4-tetrahydro-l,4-etannaftalen (3,5 g) i etyl alkohol (20 ml) inneholdende hydrobromidet (6,3 g) av 1- brom-3-N-morfolino-2-butanol og NaOH 2N (10 ml) ble kokt ved tilbakelop 2 timer. Etter torking ble resten fordelt mellom vann og etyleter. Eterekstraket ble mettet med.gassformig saltsyre og den faste fellingen ble frafiltrert og krystallisert fra aceton/etyleter og gav 3-N-raorfolinyl-1-(1,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-butanol, hydroklorid (1,5 g; smp. 213-216°C). A solution of 5-hydroxy-1>2,3,4-tetrahydro-1,4-ethanenaphthalene (3.5 g) in ethyl alcohol (20 ml) containing the hydrobromide (6.3 g) of 1-bromo-3- N-morpholino-2-butanol and NaOH 2N (10 mL) were refluxed for 2 hours. After drying, the residue was partitioned between water and ethyl ether. The ether extract was saturated with hydrochloric acid gas and the solid precipitate was filtered off and crystallized from acetone/ethyl ether to give 3-N-aminopholinyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy) -2-butanol, hydrochloride (1.5 g; mp 213-216°C).
Ved analog fremgangsmåte ble hydrokloridet av den folgende forbindelse fremstilt; By analogous procedure, the hydrochloride of the following compound was prepared;
3-N-morfolinyl-1-(1,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2- butanol; 3-N-morpholinyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-butanol;
samt hydrokloridene av de andre ovennexmte forbindelser i eksempel.'. 4. as well as the hydrochlorides of the other above mentioned compounds in example.'. 4.
Eksempel 9Example 9
En losning av 1-(1,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-3-brom-2-butanon (6,5 g) i tetrahydrofuran (50 ml) som inneholder piperidin (4,3 ml) ble latt stå ved romtemperatur i 5 dager. A solution of 1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-3-bromo-2-butanone (6.5 g) in tetrahydrofuran (50 mL) containing piperidine ( 4.3 ml) was left at room temperature for 5 days.
Det utfelte piperidin hydrobromid ble frafiltrert og løsnings-middelet avdampet under vakuum. Den dljeaktige rest ble behandlet med 23% HCl (50 ml) og etyleter (50 ml) og rort i 30 minutter. Det således erholdte faste stoff ble oppsamlet på et filter, så vasket med 10% HCl og etyleter. Den resulterende hvite faste stoff ble deretter krystallisert fra isopropanol/etyleter og gav 1-(1,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-3-N-piperidyl-2-butanon hydroklorid (4,9 g) som så ble opplost i metanol (100 ml) og behandlet med NaOH IN (15,5 ml) og NaBH^(lg). Etter koking ved tilbakelop i 2 timer og konsentrering til torrhet, ble produktet isolert ved ekstraksjon med etyleter. Ved metning av eter ekstraket med gassformig HCl og krystallisasjon fra aceton erholdtes hydrokloridet (4 g) av 3-N-piperidy1-1-(1,2,3,4-tetrahydro-l, 4-etan-5-naf tyloksy) -2-buranol (smp. 195-196°C). The precipitated piperidine hydrobromide was filtered off and the solvent evaporated under vacuum. The cake-like residue was treated with 23% HCl (50 mL) and ethyl ether (50 mL) and stirred for 30 minutes. The solid thus obtained was collected on a filter, then washed with 10% HCl and ethyl ether. The resulting white solid was then crystallized from isopropanol/ethyl ether to give 1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-3-N-piperidyl-2-butanone hydrochloride (4 .9 g) which was then dissolved in methanol (100 ml) and treated with NaOH IN (15.5 ml) and NaBH 2 (lg). After refluxing for 2 hours and concentrating to dryness, the product was isolated by extraction with ethyl ether. By saturating the ether extract with gaseous HCl and crystallization from acetone, the hydrochloride (4 g) of 3-N-piperidyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy) was obtained - 2-buranol (m.p. 195-196°C).
Ved analog fremgangsmåte ble hydrokloridet av den folgende forbindelse fremstilt: 3-N-piperidyl-l-(1,2,3, 4-tetrahydro-l,4-metan-5-naftyloksy)-2-butanol; By an analogous procedure, the hydrochloride of the following compound was prepared: 3-N-piperidyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-butanol;
så vel som hydrokloridene av de andre forbindelsene nevnte i eksempel 4. as well as the hydrochlorides of the other compounds mentioned in Example 4.
Eksempel 10Example 10
Til en losning holdt ved 5°C av imidazol (34 g) i dimetylformamid (60 ml), ble en losning av 1-(1,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-3-brom-2-propanon (25 g) i acetonitril (60 ml) satt dråpevis. Etter henstand natten over ved romtemperatur ble blandingen helt i overskudd av vann, så ekstrahert med 1000 ml etyleter. Eteret ble vasket med vann, og inndamping til torrhet, ble resten opplost i etanol redusert ved tilsetning av NaBH^(3 g) porsjonsvis til losningen ved tilbakelopstemperatur. Blandingen ble så kokt ved tilbakelop i 10 minutter, derpå torket og tatt opp i HCl (200 ml). Etter nøytralisering med 8% NaOH, ekstcak-sjon med etyleter, kraftig vasking med vann og torking, ble To a solution kept at 5°C of imidazole (34 g) in dimethylformamide (60 ml), a solution of 1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-3 -bromo-2-propanone (25 g) in acetonitrile (60 ml) was added dropwise. After standing overnight at room temperature, the mixture was poured into an excess of water, then extracted with 1000 ml of ethyl ether. The ether was washed with water, and evaporated to dryness, the residue was dissolved in ethanol reduced by adding NaBH^ (3 g) portionwise to the solution at reflux temperature. The mixture was then refluxed for 10 minutes, then dried and taken up in HCl (200 mL). After neutralization with 8% NaOH, extraction with ethyl ether, vigorous washing with water and drying,
resten krystallisert fra petroleter/toluen og gav 3-N-imidazolyl-1- 1(1,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol (16,2 gi smp. 139-141°C). the residue crystallized from petroleum ether/toluene to give 3-N-imidazolyl-1-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol (16.2 g m.p. 139 -141°C).
Ved analog fremgangsmåte fremstilles de folgende forbindelser: 3-N-imidazolyl-l-(1,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol, By an analogous method, the following compounds are prepared: 3-N-imidazolyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol,
smp. 106-109°C; m.p. 106-109°C;
3-N-imidazolyl-l-(8-klor-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2- propanol, 3-N-imidazolyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol,
smp. 125-129°C; m.p. 125-129°C;
3- N-imidazolyl-l-(8-klor-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2- propanol; 3- N -imidazolyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3- N-imidazolyl-l-(6,8-diklor-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol, 3- N -imidazolyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol,
smp. 139-141°C; m.p. 139-141°C;
3-N-imidazolyl-l-(6,8-diklor-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol, 3-N-imidazolyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol,
så vel som de andre forbindelser nevnt i eksempel 5.as well as the other compounds mentioned in Example 5.
Eskempel 11Example 11
Til en losning av en Grignard reagens fremstilt av metyljodid (3,4 g) og magnesium i etyleter, tilsattes porsjonsvis 3-N-imidazolyl-l- (1,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanon (6 g) . Blandingen ble kokt ved tilbakelop i 3 timer, To a solution of a Grignard reagent prepared from methyl iodide (3.4 g) and magnesium in ethyl ether, 3-N-imidazolyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5- naphthyloxy)-2-propanone (6 g). The mixture was refluxed for 3 hours,
så ekstrahert med fortynnet HCl. Noytralisasjon, ekstraksjon med etyleter, vasking med vann, torking og metning med gassformig HCl, gav 3-N-imidazolyl-2-mety1-1-(1,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol. HCl (3,l,g; smp. 243-245°C). then extracted with dilute HCl. Neutralization, extraction with ethyl ether, washing with water, drying and saturation with gaseous HCl gave 3-N-imidazolyl-2-methyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy )-2-propanol. HCl (3.1.g; mp 243-245°C).
Ved analog fremgangsmåte fremstiltes hydrokloridene av de folgende forbindelser: 3-N-imidazolyl-2-metyl-l-(1,2,3,4-tetrahydro-l,4-metan-5-naftyloksy) -2-propanol; By an analogous method, the hydrochlorides of the following compounds were prepared: 3-N-imidazolyl-2-methyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-imidazolyl-2-metyl-l-(8-klor-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3-N-imidazolyl-2-methyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-imiazolyl-2-metyl-l- (8i-klor-l, 2, 3, 4-tetrahydro-l, 4-metan-5-naftyloksy)-2-propanol; 3-N-imiazolyl-2-methyl-1-(8i-chloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-imidazolyl-2-metyl-l-(6,8-diklor-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3-N-imidazolyl-2-methyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-imidazolyl-2-metyl-l-(6,8-diklor-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-imidazolyl-2-methyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-pyrazolyl-2-metyl-l-(1,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2- propanol; 3-N-pyrazolyl-2-methyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3- N-parazolyl-2-mety1-1-(1,2,3,4-tetrahydro-1,4-metan-5-naftyloksy)-; 2-propanol; 3- N -parazolyl-2-methyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-; 2-propanol;
3-N-pyrazolyl-2-metyl-l-(8-klor-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3-N-pyrazolyl-2-methyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-pyrazolyl-2-metyl-l-(8-klor-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-pyrazolyl-2-methyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-pyrazolyl-2-metyl-l-(6,8-diklor-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3-N-pyrazolyl-2-methyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-pyrazolyl-2-mety1-1-(6,8-diklor-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol;, 3-N-pyrazolyl-2-methyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;,
3-N-pyrazolinyl-2-metyl-l-(1,2,3,4-tetrahydro-l,4-etan-5-naftyloksy) -2-propanol; 3-N-pyrazolinyl-2-methyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-Nrpyrazolinyl-2-metyl-l-(1,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-pyrazolinyl-2-methyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-pyrazolinyl-2-metyl-l-(8-klor-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3-N-pyrazolinyl-2-methyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-pyrazolinyl-2-metyl-l-(8-klor-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-pyrazolinyl-2-methyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-pyrazolinyl-2-metyl-l- (6, 8-diklor-],2, 3, 4, -tetrahydro-1, 4-etan-5-naftyloksy)-2-propanol; 3-N-pyrazolinyl-2-methyl-1-(6,8-dichloro-],2,3,4,-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-pyrazolinyl-2-metyl-l-(6,8-diklor-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-pyrazolinyl-2-methyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-imidazolinyl-2-metyl-l-(1,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3-N-imidazolinyl-2-methyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-imidazolinyl-2-metyl-l-(1,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-imidazolinyl-2-methyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-imidazolinyl-2-metyl-l-(8-klor-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3-N-imidazolinyl-2-methyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-imidazolinyl-2-metyl-l- (8-klor-l, 2, 3, 4-tetrahydro-l, 4-metan-5-naftyloksy)-2-propanol; 3-N-imidazolinyl-2-methyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-imidazolinyl-2-metyl-l-(6,8-diklor-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3-N-imidazolinyl-2-methyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-imidazolinyl-2-metyl-l-(6,8-diklor-l,2,3,4-tetrahydro-l, 4-metan-5-naftyloksy)-2-propanol; 3-N-imidazolinyl-2-methyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-triazoly1-2-metyl-l-(1,2,3,4-tetrahydro-l,4-etan-5-naftyloksy) -2-propanol; 3-N-triazolyl-2-methyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-triazolyl-2-metyl-l-(1,2,3,4-tetrahydro-l,4-metan-5-naftyloksy) -2-propanol; 3-N-triazolyl-2-methyl-1-(1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-triazolyl-2-metyl-l-(8-klor-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol; 3-N-triazolyl-2-methyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;
3-N-triazolyl-2-metyl-l-(8-klor-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol; 3-N-triazolyl-2-methyl-1-(8-chloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol;
3-N-triazolyl-2-mety1-1-(6,8-diklor-l,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)-2-propanol;, 3-N-triazolyl-2-methyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-2-propanol;,
3-N-triazolyl-2-metyl-l-(6,8-diklor-l,2,3,4-tetrahydro-l,4-metan-5-naftyloksy)-2-propanol, 3-N-triazolyl-2-methyl-1-(6,8-dichloro-1,2,3,4-tetrahydro-1,4-methane-5-naphthyloxy)-2-propanol,
så vel som de andre 3-N-imidazolyl-2-mety1, 3-N-imidazolinyl-2-metyl, 3-N-pyrazolyl-2-metyl, 3-N-pyra£olinyl-2-metyl, og 3-N-triazolyl-2-metyl derivater enten av 1-(1,2,3,4-tetrahydro-1,4-etan-naftyloksy)-2-propanol eller av 1-(1,2,3,4-tetrahydro-1,4-metan-naftyloksy)-2-propanol eller av 1-(1,4-dihydro -1, 4-etan -naftyloksy)-2-propanol eller av 1-(1,4-dihydro-l,4-metan-naf tyloksy) -2-propanol hvori R. og/eller R2har de andre betydninger nevnt i eksempel 5. as well as the other 3-N-imidazolyl-2-methyl, 3-N-imidazolinyl-2-methyl, 3-N-pyrazolyl-2-methyl, 3-N-pyra£olinyl-2-methyl, and 3- N-triazolyl-2-methyl derivatives either of 1-(1,2,3,4-tetrahydro-1,4-ethane-naphthyloxy)-2-propanol or of 1-(1,2,3,4-tetrahydro- 1,4-methane-naphthyloxy)-2-propanol or of 1-(1,4-dihydro-1,4-ethane-naphthyloxy)-2-propanol or of 1-(1,4-dihydro-1,4- methane-naphthyloxy)-2-propanol in which R. and/or R2 have the other meanings mentioned in example 5.
Eksempel 12 Example 12
3-N-morfolinyl-1-(1,2,3,4-tetrahydro-l,4-etan-5-naftyloksy)- 3-N-morpholinyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy)-
2-butanol (2 g) ble lost i toluen, og losningen ble tilsatt metyliodid (2 ml). Etter koking i 3 timer og påfolgende kjolirig ble det krystallinske faste stoff som således erholdtes filtrert og gav 3-N-metyl-morfolinyl-1-(1,2,3,4-tetrahydro-l, 4-etan- 5-naftyloksy)-2-butanol, hydrojodid. 2-Butanol (2 g) was dissolved in toluene, and methyl iodide (2 ml) was added to the solution. After boiling for 3 hours and subsequent cooling, the crystalline solid thus obtained was filtered and gave 3-N-methyl-morpholinyl-1-(1,2,3,4-tetrahydro-1,4-ethane-5-naphthyloxy) -2-butanol, hydroiodide.
Claims (1)
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IT2297675 | 1975-05-05 |
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NO761525L true NO761525L (en) | 1976-11-08 |
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NO761525A NO761525L (en) | 1975-05-05 | 1976-05-04 |
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JP (1) | JPS51136665A (en) |
AU (1) | AU1346776A (en) |
BE (1) | BE841478A (en) |
DE (1) | DE2618979A1 (en) |
DK (1) | DK199276A (en) |
FI (1) | FI761174A (en) |
FR (1) | FR2310129A1 (en) |
IL (1) | IL49505A0 (en) |
NL (1) | NL7604812A (en) |
NO (1) | NO761525L (en) |
SE (1) | SE7605071L (en) |
ZA (1) | ZA762697B (en) |
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AU542623B2 (en) * | 1980-05-16 | 1985-02-28 | Bayer Aktiengesellschaft | 1-hydroxyethyl-azole derivatives |
DE10305089A1 (en) * | 2003-02-07 | 2004-08-26 | Merckle Gmbh | New heteroaryl-substituted acetone derivatives as inhibitors of phospholiphase A2 |
-
1976
- 1976-04-28 FI FI761174A patent/FI761174A/fi not_active Application Discontinuation
- 1976-04-29 AU AU13467/76A patent/AU1346776A/en not_active Expired
- 1976-04-29 DE DE19762618979 patent/DE2618979A1/en active Pending
- 1976-04-30 IL IL7649505A patent/IL49505A0/en unknown
- 1976-05-04 JP JP51051260A patent/JPS51136665A/en active Pending
- 1976-05-04 DK DK199276A patent/DK199276A/en unknown
- 1976-05-04 NO NO761525A patent/NO761525L/no unknown
- 1976-05-04 SE SE7605071A patent/SE7605071L/en unknown
- 1976-05-05 NL NL7604812A patent/NL7604812A/en unknown
- 1976-05-05 ZA ZA762697A patent/ZA762697B/en unknown
- 1976-05-05 BE BE166748A patent/BE841478A/en unknown
- 1976-05-05 FR FR7613428A patent/FR2310129A1/en not_active Withdrawn
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DK199276A (en) | 1976-11-06 |
SE7605071L (en) | 1976-11-06 |
IL49505A0 (en) | 1976-06-30 |
AU1346776A (en) | 1977-11-03 |
FI761174A (en) | 1976-11-06 |
JPS51136665A (en) | 1976-11-26 |
ZA762697B (en) | 1977-04-27 |
BE841478A (en) | 1976-09-01 |
NL7604812A (en) | 1976-11-09 |
DE2618979A1 (en) | 1976-11-25 |
FR2310129A1 (en) | 1976-12-03 |
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