NO144069B - Difluorbutyrofenonderivater som er anvendelige for fremstilling av terapeutisk aktive butyrofenonderivater - Google Patents
Difluorbutyrofenonderivater som er anvendelige for fremstilling av terapeutisk aktive butyrofenonderivater Download PDFInfo
- Publication number
- NO144069B NO144069B NO324273A NO324273A NO144069B NO 144069 B NO144069 B NO 144069B NO 324273 A NO324273 A NO 324273A NO 324273 A NO324273 A NO 324273A NO 144069 B NO144069 B NO 144069B
- Authority
- NO
- Norway
- Prior art keywords
- alkyl
- hydrogen
- formula
- alkoxy
- derivatives
- Prior art date
Links
- FFSAXUULYPJSKH-UHFFFAOYSA-N butyrophenone Chemical class CCCC(=O)C1=CC=CC=C1 FFSAXUULYPJSKH-UHFFFAOYSA-N 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title claims description 6
- 230000001225 therapeutic effect Effects 0.000 title 1
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- NVPFWBRYRHCQHD-UHFFFAOYSA-N 2,2-difluoro-1-phenylbutan-1-one Chemical class CCC(F)(F)C(=O)C1=CC=CC=C1 NVPFWBRYRHCQHD-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 239000007858 starting material Substances 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 229940054053 antipsychotics butyrophenone derivative Drugs 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 3
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- -1 methoxy, ethoxy, n-propoxy, isopropoxy Chemical group 0.000 description 32
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- VPLMFLLATQHABK-UHFFFAOYSA-N 2,4-difluoro-1-phenylbutan-1-one Chemical class FCCC(F)C(=O)C1=CC=CC=C1 VPLMFLLATQHABK-UHFFFAOYSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 150000003335 secondary amines Chemical class 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 3
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 238000005907 ketalization reaction Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-UHFFFAOYSA-N 0.000 description 2
- INKXUVDVFWOIBB-UHFFFAOYSA-N 2-(3-chloropropyl)-2-(2,4-difluorophenyl)-1,3-dioxolane Chemical compound FC1=CC(F)=CC=C1C1(CCCCl)OCCO1 INKXUVDVFWOIBB-UHFFFAOYSA-N 0.000 description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 2
- XAVTZZKOKMHGAA-UHFFFAOYSA-N 8-[3-[2-(2,4-difluorophenyl)-1,3-dioxolan-2-yl]propyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one Chemical compound FC1=CC(F)=CC=C1C1(CCCN2CCC3(CC2)C(NCN3C=2C=CC=CC=2)=O)OCCO1 XAVTZZKOKMHGAA-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- VYMPLPIFKRHAAC-UHFFFAOYSA-N 1,2-ethanedithiol Chemical compound SCCS VYMPLPIFKRHAAC-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- HTQWGIHCFPWKAS-UHFFFAOYSA-N 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one Chemical compound C1CNCCC11C(=O)NCN1C1=CC=CC=C1 HTQWGIHCFPWKAS-UHFFFAOYSA-N 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- LZAYOZUFUAMFLD-UHFFFAOYSA-N 4-(4-chlorophenyl)-4-hydroxypiperidine Chemical compound C=1C=C(Cl)C=CC=1C1(O)CCNCC1 LZAYOZUFUAMFLD-UHFFFAOYSA-N 0.000 description 1
- LZEZXTQEZRUGDD-UHFFFAOYSA-N 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-2,4-difluoro-1-phenylbutan-1-one;hydrochloride Chemical compound Cl.C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1C(F)CC(F)C(=O)C1=CC=CC=C1 LZEZXTQEZRUGDD-UHFFFAOYSA-N 0.000 description 1
- VVFUIVWYNQSYSD-UHFFFAOYSA-N 4-chloro-2,4-difluoro-1-phenylbutan-1-one Chemical compound FC(Cl)CC(F)C(=O)C1=CC=CC=C1 VVFUIVWYNQSYSD-UHFFFAOYSA-N 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- GJFNEDLTTVTJQE-UHFFFAOYSA-N 8-(1,3-difluoro-4-oxo-4-phenylbutyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one Chemical compound C1CC2(C(NCN2C=2C=CC=CC=2)=O)CCN1C(F)CC(F)C(=O)C1=CC=CC=C1 GJFNEDLTTVTJQE-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002921 anti-spasmodic effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000000506 psychotropic effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000001665 trituration Methods 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
- C07D295/10—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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/16—Radicals substituted by halogen atoms or nitro radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Foreliggende oppfinnelse angår nye difluorbutyrofenonderivater som er anvendelige som utgangsmaterialer ved fremstilling av terapeutisk aktive butyrofenonderivater.
De nye difluorbutyrofenonderivater er forbindelser med den generelle formel:
hvor Z er en sekundær aminogruppe med formelen: 1 2 3 hvor R er hydrogen eller hydroxyl, og R og R er hver hydrogen, halogen, c1_c4 alkyl, C^-C^ alkoxy eller trifluormethyl, eller med formelen:
13 14
hvor R og R er hydrogen, C-^-C^ alkyl, C1~C4 alkoxy eller trifluormethyl, med det forbehold at når den ene av
Il 14
substituentene R og R er hydrogen, er den andre hydrogen, C"L~C4 alkyl eller C^-C^ alkoxy, eller med formelen
a 5 6 hvor R er hydrogen eller C1~C4 alkyl, R og R er hver hydrogen, halogen eller C^-C^ alkyl, og den prikkede linje er en eventuell binding mellom carbonatomene i 3- og 4-stillingen av piperidinringen, eller med formelen 7 8 hvor R er hydrogen eller C^-C^ alkyl, og R er hydrogen, halogen, C^-C^ alkyl eller C1~C4 alkoxy, eller med formelen hvor R 9 er hydrogen, halogen, C^-C^ alkyl, C^ C^ alkoxy eller trifluormethyl, og m er 0, 1 eller 2, eller med formelen
hvor R<10> er hydrogen, halogen, hydroxy, C1-C4 alkyl eller C1~C4 alkoxy,
eller de er syreaddisjonssalter av forbindelsene av formel (IIA).
I de betydninger som er definert ovenfor, innbefatter alkyl methyl, ethyl, n-propyl, isopropyl, n-butyl og sek.-butyl, mens C1_C4 alkoxy innbefatter methoxy, ethoxy, n-propoxy, isopropoxy og t-butoxy; ^^- C^ cycloalkyl innbefatter cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl og cycloheptyl; hydroxy-substituert C^-Cg alkyl innbefatter 2-hydroxyethyl, 3-hydroxy-n-propyl, 2-hydroxy-n-propyl, 2-hydroxy-l-methylethyl-l-hydroxymethyl-n-propyl, 2-hydroxy-1,1-dimethylethyl og 5-hydroxy-n-pentyl; C^~C4 alkoxy-substituert C1-Cg alkyl innbefatter 2-methoxyethyl, 2-ethoxyethyl, 2-methoxy-l-methylethyl og 3-methoxy-n-propyl; dialkylamino-substituert C-^Cg alkyl innbefatter 2-methylaminoethyl, 3-dimethyl-amino-n-propyl, 2-diethylaminoethyl og 4-diethylamino-o-methyl-n-butyl; halogen innbefatter fluor, klor, brom og jod; og aralkyl innbefatter eventuelt substituert benzyl, fenethyl, benzhydryl og nafthylmethyl (f.eks. benzyl, p-methoxybenzyl, p-methylbenzyl, o,p-dimethylbenzyl, p-f luorbenzyl, p-klorbenzyl, ct-ethylbenzyl, fenethyl, 3,4-dihydroxyfenethyl, benzhydryl, 1-nafthalenmethyl.
De nye difluorbutyrofenonforbindelser (IIA) er nyttige som utgangsmaterialer ved fremstilling av terapeutisk aktive butyro-fenonforbindelser med formelen:
i hvilken Z er som ovenfor angitt og W er en sekundær aminogruppe som Z eller morfolino, pyrrolidino, piperidino eller en gruppe med
formelen:
11 12
hvor R og R hver er hydrogen, C^-Cg alkyl, hydroxy-substituert C1~Cg alkyl, C^-C^ alkoxy-substituert C^-Cgalkyl, di-(C1~C4 alkyl)-amino-substituert C^-Cg alkyl, C3~C7 cycloalkyl eller eventuelt substituert benzyl.
Butyrofenonforbindelsene av formel (I) har et vidt spektrum av farmakologisk aktivitet og er nyttige som psykotropiske, be-roligende, analgetiske, antispasmodiske, autonomotropiske, anti-inflammatoriske og/eller antifungale midler.
De terapeutisk aktive butyrofenonderivater med formelen (I) lar seg fremstille ved at en difluorbutyrofenonforbindelse ifølge oppfinnelsen,med formelen:
hvor Z er som ovenfor angitt, eller et syreaddisjonssalt av denne forbindelse, omsettes med et amin av formelen H-W, hvor W er som ovenfor angitt, i nærvær av et lite polart oppløsningsmiddel,
og, når W er en gruppe med formelen:
11 12
hvor R og R er som ovenfor angitt, men minst én av dem er en eventuelt substituert benzyljruppe , hydrogeneres eventuelt den erholdte forbindelse på kjent måte for å få den tilsvarende forbindelse hvor den eventuelt substituerte benzylgruppe er eliminert.
Når difluorbutyrofenonforbindelsen (IIA) eller et syreaddisjonssalt av denne omsettes med aminet H-W som ovenfor angitt, skulle man, ut fra det som tidligere er kjent fra f.eks. P. Tarrant: "Fluorine Chemistry Review", Vol. 7, Marcel Dekker, Inc., New York, 1974, sider 1 - 114, vente at reaksjonen med aminet H-W like gjerne ville skje ved fluoratomet i fenylkjernens para-stilling som ved fluoratomet i ortho-stillingen. Det har imidlertid vist seg at når reaksjonen foretas i nærvær av et lite polart oppløsningsmiddel, såsom benzen, toluen, xylen, n-hexan, dioxan eller carbon-tetraklorid, skjer reaksjonen selektivt ved fluoratomet i fenylkjernens ortho-stilling.
For en mer detaljert beskrivelse av fremstillingen av de terapeutisk aktive butyrofenonderivater av formel (I) vises det til patentsøknad nr. 1072/73.
De nye 2,4-difluorbutyrofenonforbindelser (IIA) ifølge oppfinnelsen fremstilles ut fra forbindelser med formelen: hvor X er halogen og R er oxygen, ethylendioxy eller ethylendithio, ved omsetning med et sekundært amin med formelen: hvor Z er som ovenfor angitt. Når R er ethylendioxy eller ethylendithio, hydrolyseres den erholdte forbindelse.
y-Halogen-butyrofenonforbindelsen (III) som anvendes som utgangsmateriale ved fremstilling av de nye difluorbutyrofenonderivater, kan bekvemt fremstilles ved en Friedel-Crafts-reaksjon mellom m-difluorbenzen og et y-halogen-butyrylhalogenid med
formelen:
hvor X<1> er halogen, og X er som ovenfor angitt, med påfølgende ketalisering av den dannede forbindelse (HIA) dersom ketalforbindelsen (UIB) ønskes.
Fremstillingen av de nye difluorbutyrofenonderivater ifølge oppfinnelsen belyses ved følgende reaksjonsskjerna:
I reaksjonsskjemaet er Z, R, X og X<1> som ovenfor angitt. Y er ethylendioxy eller ethylendithio.
Difluorbutyrofenonforbindelsen (IIA) kan fremstilles ved å omsette forbindelsen (HIA) med det sekundære amin med formelen H-Z, hvor Z er som ovenfor angitt, i et inert oppløsningsmiddel.
Reaksjonen utføres fortrinnsvis i nærvær av et syrebindings-middel som en uorganisk base (f.eks. kaliumcarbonat, natriumcarbonat, natriumbicarbonat) eller et tertiært amin (f.eks. pyridin, triethylamin, dimethylanilin). Eksempler på inerte opp-løsningsmidler er amider som dimethylformamid, dimethylacetamid og formamid, aromatiske hydrocarboner som benzen, toluen og xylen, alkanoler som ethanol, propanol og butanol, og alkanoner som aceton, 2-butanon og 4-methyl-2-pentanon. Reaksjonen påskyndes vanligvis ved å forhøye temperaturen. En liten mengde av et katalytisk stoff som kaliumjodid er også nyttig for å påskynde reaksjonen. Reaksjonen er vanligvis fullstendig i løpet av 1 - 48 timer, og en foretrukken reaksjonstid er 5 - 20 timer.
Difluorbutyrofenonforbindelsen (IIA) kan også fremstilles ved å ketalisere forbindelsen (HIA) , omsette den erholdte ketal-forbindelse (UIB) med det sekundære amin som ovenfor, og derpå hydrolysere den dannede alkylerte forbindelse (IIB).
Skjønt reaksjonen mellom ketalforbindelsen (UIB) og det sekundære amin kan utføres under samme betingelser som ved reaksjonen mellom forbindelsen (HIA) og det sekundære amin, kan først-nevnte vanligvis utføres under mildere betingelser enn sistnevnte. Eksempelvis kan reaksjonen utføres ved en temperatur fra 25 til 100°C i løpet av 3 timer. Ved den nevnte metode fremstilles ketal-forbindelsene (IIB) lett.
Ketaliseringen og den påfølgende hydrolyse kan utføres etter i og for seg kjente konvensjonelle metoder. Eksempelvis utføres ketaliseringen ved å behandle forbindelsen (HIA) med et ketali-seringsmiddel som ethylenglycol eller ethylendithioglycol,. i nærvær av en dehydratiserende katalysator som p-toluensulfonsyre eller konsentrert svovelsyre, vanligvis i et inert oppløsningsmiddel (f.eks. benzen, toluen, xylen) ved forhøyet temperatur. Videre
kan f.eks. hydrolysen utføres ved å behandle den alkylerte forbindelse (IIB) med en sur forbindelse som en mineralsyre (f.eks. saltsyre, svovelsyre, fosforsyre), en organisk syre (f.eks. oxalsyre, vinsyre) eller en sur ionebytteharpiks i vann eller en alkanol (f.eks. methanol, ethanol, propanol), vanligvis under
milde betingelser, f.eks. ved værelsetemperatur.
Den således fremstilte 2,4-difluorbutyrofenonforbindelse (IIA) kan lett overføres til sine organiske eller uorganiske syreaddisjonssalter på i og for seg kjent vis.
De nedenstående eksempler illustrerer fremstillingen av de nye difluorbutyrofenonforbindelser.
Fremstilling av utgangsmaterialer
(A) Til en blanding av 340 g aluminiumklorid og 1 liter carbondisulfid ble tilsatt 114 g m-difluorbenzen under avkjøling.
En oppløsning av 14 2,5 g Y-klorbutyrylklorid i 200 ml carbondisulfid ble så tilsatt dråpevis til reaksjonsblandingen ved en temperatur under 15°C. Den dannede blanding ble gradvis oppvarmet under kontinuerlig tilbakeløp i 2 timer. Etter avkjøling ble reaksjonsblandingen hellet over i 3 liter vann og ekstrahert med diklormethan. Ekstraktet ble vasket med vann, en fortynnet vandig oppløsning av natriumhydroxyd og en mettet vandig oppløsning av natriumklorid, i denne rekkefølge, og deretter tørret over vannfritt natriumsulfat og inndampet, hvorved man fikk en oljerest. Vakuumdestillasjon av oljen ga rent Y-klor-2,4-difluorbutyrofenon. Kokepunkt 97 - 111°C (1,0 - 1,5 mmHg). n^<6>= 1,507.
(B) Mens en blanding av 102,3 g Y~klor-2,4-difluorbutyro-fenon, 58,1 g ethylenglycol, 3,2 g p-toluensulfonsyre-hydrat og
500 g benzen ble oppvarmet under tilbakeløp i 30 timer, ble det dannede vann fjernet som en azeotrop blanding. Etter avkjøling ble reaksjonsblandingen vasket med vann og tørret over vannfritt natriumsulfat. Benzenskiktet ble inndampet, hvorved man fikk en oljerest. Vakuumdestillasjon av oljen ga rent 4-klor-l-(2,4-difluorfenyl)-1,1-ethylendioxybutan. Kokepunkt 109 - 120°C
(1,3 - 1,5 mmHg). n^<7->l,495.
Eksempel 1
En blanding av 14,2 g y-klor-2,4-difluorbutyrofenon, 13,8 g 4-(4-klorfenyl)-4-hydroxypiperidin, 9,0 g vannfritt kaliumcarbonat, 0,5 g kaliumjodid og 170 ml dimethylformamid ble oppvarmet i 20 timer ved 90 - 110°C. Etter avkjøling ble reaksjonsblandingen fortynnet med vann og ekstrahert med ether. Etherekstraktet ble vasket tilstrekkelig med vann, tørret over vannfritt natriumsulfat, behandlet med hydrogenklorid og derpå inndampet. Triturering og omkrystallisasjon av residuet fra methanol ga y-[4-(4-klorfenyl)-4-hydroxypiperidin-l-yl]-2,4-difluorbutyrofenon-hydroklorid. Smeltepunkt 245°C (spaltn.).
Eksempel 2
En blanding av 5,3 g 4-klor-l-(2,4-difluorfenyl)-1,1-ethylen-dioxybutan, 4,6 g 4-oxo-l-fenyl-1,3,8-triazaspiro-[4,5]-decan,
0,1 g vannfritt kaliumcarbonat og 58 ml dimethylformamid ble oppvarmet under tilbakeløp i 2,5 timer. Efter avkjøling ble reaksjonsblandingen hellet i 400 ml kaldt vann under kraftig omrøring, og bunnfallet ble oppsamlet og vasket med vann, hvorved man fikk 4-(4-oxo-l-fenyl-1,3,8-triazaspiro-[4,5]-decan-8-yl)-1-(2,4-di-fluorfenyl)-1,1-ethylendioxybutan. Smeltepunkt 58 - 62°C.
Eksempel 3
En blanding av 2,0 g 4-(4-oxo-l-fenyl-1,3,8-triazaspiro-[4,5]-decan-8-yl)-1-(2,4-difluorfenyl)-1,1-ethylendioxybutan, 29 ml methanol, 4,7 ml 35%-ig saltsyre og 10 ml vann ble oppvarmet under tilbakeløp i 30 minutter. Etter avkjøling ble reaksjonsblandingen fortynnet med vann, gjort alkalisk med en mettet vandig op<p>løsning av natriumcarbonat og ekstrahert med kloroform.
Ekstraktet ble vasket med vann, tørret over vannfritt natriumsulfat og inndampet i vakuum. Residuet ble omkrystallisert fra ethanol, hvorved man fikk y-(4-oxo-l-fenyl-1,3,8-triazaspiro-[4,5]-decan-8-yl)-2,4-difluorbutyrofenon. Smeltepunkt 190 - 204°C.
Eksempel 4
På samme måte som i eksempler 1-3 fikk man følgende forbindelser: Y-[4-(2-oxo-l-benzimidazolinyl)-piperidin-l-yl]-2,4-difluor-butyrof enon-hydroklorid , smp. 160-165°C;
y-(4-fenylpiperazin-l-yl)-2,4-difluorbutyrofenon-hydroklorid, smp. 219-225°C (spaltn.);
Y-[4-(2-methoxyfenyl)-piperazin-l-yl]-2,4-difluorbutyrofenon-dihydroklorid, smp. 206-208°C.
Y - (1,2,3,4-tetrahydroisokinolin-2-yl)-2,4-difluorbutyrifenon-hydroklorid, smp. 205-208°C.
Y-[4-(4-klor-3-trifluormethylfenyl)-4-hydroxypiperidin-l-yl]-2,4-difluorbutyrofenon-hydroklorid, smp. 226°C (spaltn.);
Y-[4-(4-klorbenzyl)-4-hydroxypiperidin-l-yl]-2,4-difluor-butyrof enon-hydroklorid, smp. 183-184°C;
Y-(4-benzyl-4-hydroxypiperidin-l-yl)-2,4-difluorbutyro-fenon-hydroklorid, smp. 164,5-166,5°C.
Claims (2)
1. Difluorbutyrofenonderivater som er anvendelige som utgangsmaterialer ved fremstilling av terapeutisk aktive butyrofenonderivater med formelen:
i hvilken Z er en sekundær aminogruppe med formelen:
hvor R<1> er hydrogen eller hydroxyl, R 2 og R 3 er hver hydrogen, halogen, C^-C^ alkyl, C^-C^ alkoxy eller trifluormethyl, eller med formelen: 13 14
hvor R og R er hydrogen, C^-C^ alkyl, C^-C^ alkoxy eller trifluormethyl, med det forbehold at når den ene av substituentene R 13 og R 14 er hydrogen, er den andre hydrogen, C1~C4 alk^1 eller ci"C4 alkoxy, eller med formelen
hvor R4 er hydrogen eller C^-C^ alkyl, R5 og R6 er hver hydrogen, halogen eller C1~C4 alkyl, og den prikkede linje er en eventuell binding mellom carbonatomene i 3- og 4-stillingen av piperidinringen, eller med formelen
hvor R 7 er hydrogen eller C^-C4 alkyl, og R 8er hydrogen, halogen, C -C4 alkyl eller C^-C4 alkoxy, eller med formelen
hvor R 9 er hydrogen, halogen, C - C^ alkyl, C^ C^ alkoxy eller trifluormethyl, og m er 0,1 eller 2, eller med formelen hvor R er hydrogen, halogen, hydroxy, C^-C^ alkyl eller C^-C^ alkoxy,
og i hvilken W er en sekundær aminogruppe som Z eller morfolino, pyrrolidino^ piperidino eller en gruppe med formelen: 11 12 hvor R og R hver er hydrogen, C,-CQ alkyl, hydroxy-substituert C^^-Cg alkyl, C1~C4 alkoxy-substituert C^-Cg alkyl, di-(C1~C4 alkylj-amino-substituert c-^~Cg alkyl, C3~C7 cycloalkyl eller eventuelt substituert aralkyl, og deres syreaddisjonssalter, karakterisert ved at de har den generelle formel:
hvor Z er som ovenfor angitt, eller er syreaddisjonssalter av disse forbindelser av formel (IIA).
2. Difluorbutyrofenonderivater ifølge krav 1, karakterisert ved at Z er én av gruppene:
hvor R1, R2, R3, R13 og R14 er som ovenfor angitt, eller
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP47027610A JPS5755714B2 (no) | 1972-03-18 | 1972-03-18 | |
JP47057249A JPS4914476A (no) | 1972-06-07 | 1972-06-07 |
Publications (2)
Publication Number | Publication Date |
---|---|
NO144069B true NO144069B (no) | 1981-03-09 |
NO144069C NO144069C (no) | 1981-06-17 |
Family
ID=26365557
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO107273A NO144068C (no) | 1972-03-18 | 1973-03-16 | Fremgangsmaate ved fremstilling av butyrofenonderivater |
NO324273A NO144069C (no) | 1972-03-18 | 1973-08-15 | Difluorbutyrofenonderivater som er anvendelige for fremstilling av terapeutisk aktive butyrofenonderivater |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO107273A NO144068C (no) | 1972-03-18 | 1973-03-16 | Fremgangsmaate ved fremstilling av butyrofenonderivater |
Country Status (10)
Country | Link |
---|---|
AU (1) | AU470114B2 (no) |
CA (1) | CA1024984A (no) |
CH (2) | CH589626A5 (no) |
FI (1) | FI58636C (no) |
FR (1) | FR2183683B1 (no) |
GB (1) | GB1423576A (no) |
HU (1) | HU167671B (no) |
NL (1) | NL7303854A (no) |
NO (2) | NO144068C (no) |
SE (1) | SE419441B (no) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS595587B2 (ja) * | 1974-04-18 | 1984-02-06 | 住友化学工業株式会社 | シンキナブチロフエノンユウドウタイ オヨビ ソノエン ノ セイホウ |
JPS5116677A (ja) * | 1974-07-29 | 1976-02-10 | Sumitomo Chemical Co | Shinkinabuchirofuenonjudotai oyobi sonosanfukaennoseiho |
FR2530632A1 (fr) * | 1982-07-26 | 1984-01-27 | Bouchara Emile | Nouveaux derives substitues du 2,5-diamino 1,4-diazole, leurs procedes de preparation et les compositions pharmaceutiques en renfermant |
US4569933A (en) * | 1984-04-13 | 1986-02-11 | Cornu Pierre Jean | Antihypertensive substituted derivatives of 2,5-diamino 1,4-diazole |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FI52216C (fi) * | 1969-07-16 | 1977-07-11 | Sumitomo Chemical Co | Menetelmä gamma-piperidinobutyrofenonijohdannaisten valmistamiseksi. |
CA928710A (en) * | 1970-02-06 | 1973-06-19 | Sumitomo Chemical Company | 1,2,3,4-tetrahydroisoquinoline derivatives |
NL7103002A (no) * | 1970-03-06 | 1971-09-08 | ||
US3799932A (en) * | 1970-03-20 | 1974-03-26 | Sumitomo Chemical Co | Gamma-piperidinobutyrophenones |
-
1973
- 1973-03-16 GB GB1280473A patent/GB1423576A/en not_active Expired
- 1973-03-16 HU HUSU000807 patent/HU167671B/hu unknown
- 1973-03-16 CA CA166,245A patent/CA1024984A/en not_active Expired
- 1973-03-16 CH CH389373A patent/CH589626A5/xx not_active IP Right Cessation
- 1973-03-16 NO NO107273A patent/NO144068C/no unknown
- 1973-03-16 FI FI82473A patent/FI58636C/fi active
- 1973-03-16 CH CH514476A patent/CH599939A5/xx not_active IP Right Cessation
- 1973-03-16 SE SE7303729A patent/SE419441B/xx unknown
- 1973-03-16 FR FR7309598A patent/FR2183683B1/fr not_active Expired
- 1973-03-19 AU AU53468/73A patent/AU470114B2/en not_active Expired
- 1973-03-19 NL NL7303854A patent/NL7303854A/xx not_active Application Discontinuation
- 1973-08-15 NO NO324273A patent/NO144069C/no unknown
Also Published As
Publication number | Publication date |
---|---|
GB1423576A (en) | 1976-02-04 |
FR2183683A1 (no) | 1973-12-21 |
AU5346873A (en) | 1974-09-19 |
NO144069C (no) | 1981-06-17 |
CH589626A5 (no) | 1977-07-15 |
HU167671B (no) | 1975-11-28 |
NO144068B (no) | 1981-03-09 |
FI58636B (fi) | 1980-11-28 |
CA1024984A (en) | 1978-01-24 |
FI58636C (fi) | 1981-03-10 |
NO144068C (no) | 1981-06-17 |
AU470114B2 (en) | 1976-03-04 |
SE419441B (sv) | 1981-08-03 |
NL7303854A (no) | 1973-09-20 |
FR2183683B1 (no) | 1976-12-31 |
CH599939A5 (no) | 1978-06-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
NO151240B (no) | Analogifremgangsmaate til fremstilling av terapeutisk aktive nitroimidazoler | |
US3293263A (en) | Diphenylbenzocycloalkenes | |
US3853915A (en) | 9-or 10-halo-4h-benzo{8 4,5{9 cyclo-hepta{8 1,2-b{9 thiophen-4-ones | |
EP0109562B1 (en) | Succinimide derivatives and their production | |
US3600394A (en) | 2-aminoalkyl-3-arylisocarbostyrils | |
US5852019A (en) | Pyrimidinylpyrazole derivatives | |
US3674799A (en) | (4'-(phenyl-3 6-dihydro-1-(2h)-pyridyl)-2-hydroxy propoxy-anilides and derivatives thereof | |
US3721668A (en) | Novel 5-nitro-imidazole antimicrobially effective compounds | |
BIEL et al. | Central Stimulants. II. Cholinergic Blocking Agents1 | |
US3678111A (en) | Dialkylaminomethylphenyl benzyl alcohols | |
NO144069B (no) | Difluorbutyrofenonderivater som er anvendelige for fremstilling av terapeutisk aktive butyrofenonderivater | |
US3979390A (en) | Butyrophenone derivatives and production thereof | |
SU592350A3 (ru) | Способ получени производных бутирофенона или их солей | |
US3751417A (en) | 1-acyl-3-(2-(4-phenyl-1-piperazinyl)ethyl)indolines | |
US4216326A (en) | Intermediates for preparing anti-inflammatory phenyl-lower-alkylamines | |
US3311636A (en) | Organic chemical compounds and process | |
US2979502A (en) | Phenthiazine derivatives | |
SU512704A3 (ru) | Способ получени замещенных в 5-ом положении 5,10-дигидро-11 н-дибензо (в,е) (1,4)диазепин-11-онов | |
US4772705A (en) | Processes for the preparation of trans 1,3,4,6,7,11b-hexahydro-7-aryl-2H-pyrazinol[2,1-a]isoquinolines | |
US2771469A (en) | Quaternary ammonium salts of deltahydrocarbyoxyphenyl gamma-hydroxy amines | |
US3839341A (en) | Substituted 1,3,8-triazaspiro(4.5)decanes | |
NO121212B (no) | ||
US3317527A (en) | 3a and 5a tertiaryamino cycloalkylene of 5 to 7[alpha]benzofuranols | |
US4061774A (en) | Halogenated amino methyl adamantane derivatives | |
US4308382A (en) | 4-[[3-[α-Aminobenzyl]phenyl]methyl]morpholine and 4-[-[3-benzoylphenyl]ethyl]morpholine |