NO309924B1 - Anvendelse av fenalkylaminer og nye fenylalkylaminer - Google Patents
Anvendelse av fenalkylaminer og nye fenylalkylaminer Download PDFInfo
- Publication number
- NO309924B1 NO309924B1 NO942606A NO942606A NO309924B1 NO 309924 B1 NO309924 B1 NO 309924B1 NO 942606 A NO942606 A NO 942606A NO 942606 A NO942606 A NO 942606A NO 309924 B1 NO309924 B1 NO 309924B1
- Authority
- NO
- Norway
- Prior art keywords
- phenyl
- methyl
- allyl
- amino
- bromo
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 13
- 150000002367 halogens Chemical class 0.000 claims abstract description 13
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 claims abstract description 9
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims abstract description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims abstract description 4
- 239000002253 acid Substances 0.000 claims abstract description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- 229910052801 chlorine Inorganic materials 0.000 claims description 14
- 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 description 13
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- -1 2,6-dimethyl-5-heptyl Chemical group 0.000 claims description 11
- 229910052794 bromium Inorganic materials 0.000 claims description 10
- 239000012965 benzophenone Substances 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 7
- 125000003119 4-methyl-3-pentenyl group Chemical group [H]\C(=C(/C([H])([H])[H])C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 6
- RNTIMLQORXMWOI-UHFFFAOYSA-N (4-bromophenyl)-[4-[6-[methyl(prop-2-enyl)amino]hexoxy]phenyl]methanone Chemical compound C1=CC(OCCCCCCN(C)CC=C)=CC=C1C(=O)C1=CC=C(Br)C=C1 RNTIMLQORXMWOI-UHFFFAOYSA-N 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
- CMYCCJYVZIMDFU-UHFFFAOYSA-N Ro 48-8071 Chemical compound FC1=CC(OCCCCCCN(C)CC=C)=CC=C1C(=O)C1=CC=C(Br)C=C1 CMYCCJYVZIMDFU-UHFFFAOYSA-N 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- OHZDMBQUJHJOTJ-SNAWJCMRSA-N (4-bromophenyl)-[4-[(e)-4-[ethyl(methyl)amino]but-2-enoxy]phenyl]methanone Chemical compound C1=CC(OC/C=C/CN(C)CC)=CC=C1C(=O)C1=CC=C(Br)C=C1 OHZDMBQUJHJOTJ-SNAWJCMRSA-N 0.000 claims description 2
- PHWCMMNCJNFLCS-UHFFFAOYSA-N 1,7-bis[4-[4-[(dimethylamino)methyl]phenyl]phenyl]heptan-4-one Chemical compound C1=CC(CN(C)C)=CC=C1C(C=C1)=CC=C1CCCC(=O)CCCC1=CC=C(C=2C=CC(CN(C)C)=CC=2)C=C1 PHWCMMNCJNFLCS-UHFFFAOYSA-N 0.000 claims description 2
- YXJBCOJMFLUVLM-UHFFFAOYSA-N [3-chloro-4-[4-(dimethylamino)but-2-enoxy]phenyl]-phenylmethanone Chemical compound C1=C(Cl)C(OCC=CCN(C)C)=CC=C1C(=O)C1=CC=CC=C1 YXJBCOJMFLUVLM-UHFFFAOYSA-N 0.000 claims description 2
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 claims description 2
- NVYFMEJWCVZVKH-UHFFFAOYSA-N bis[3-(3,4-dichlorophenyl)-4-[4-[(dimethylamino)methyl]phenyl]phenyl]methanone Chemical compound ClC=1C=C(C=CC=1Cl)C1=C(C=CC(=C1)C(=O)C1=CC(=C(C=C1)C1=CC=C(C=C1)CN(C)C)C1=CC(=C(C=C1)Cl)Cl)C1=CC=C(C=C1)CN(C)C NVYFMEJWCVZVKH-UHFFFAOYSA-N 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 claims description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 60
- 239000000243 solution Substances 0.000 description 38
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 21
- IOXXVNYDGIXMIP-UHFFFAOYSA-N n-methylprop-2-en-1-amine Chemical compound CNCC=C IOXXVNYDGIXMIP-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 17
- LJVHJHLTRBXGMH-HNQUOIGGSA-N (e)-1,4-dibromobut-1-ene Chemical compound BrCC\C=C\Br LJVHJHLTRBXGMH-HNQUOIGGSA-N 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000000284 extract Substances 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- SGRHVVLXEBNBDV-UHFFFAOYSA-N 1,6-dibromohexane Chemical compound BrCCCCCCBr SGRHVVLXEBNBDV-UHFFFAOYSA-N 0.000 description 6
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229940024874 benzophenone Drugs 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 6
- 238000009835 boiling Methods 0.000 description 5
- 239000007903 gelatin capsule Substances 0.000 description 5
- 239000011541 reaction mixture Substances 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
- 239000013543 active substance Substances 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- BNOUBIJDOMWKPY-UHFFFAOYSA-N (4-bromophenyl)-(2-fluoro-4-hydroxyphenyl)methanone Chemical compound FC1=CC(O)=CC=C1C(=O)C1=CC=C(Br)C=C1 BNOUBIJDOMWKPY-UHFFFAOYSA-N 0.000 description 3
- HRQGKJVRJYEBPA-UHFFFAOYSA-N (4-bromophenyl)-(3-fluoro-4-hydroxyphenyl)methanone Chemical compound C1=C(F)C(O)=CC=C1C(=O)C1=CC=C(Br)C=C1 HRQGKJVRJYEBPA-UHFFFAOYSA-N 0.000 description 3
- GCSYLFJQFPSOBR-UHFFFAOYSA-N (4-bromophenyl)-(4-hydroxyphenyl)methanone Chemical compound C1=CC(O)=CC=C1C(=O)C1=CC=C(Br)C=C1 GCSYLFJQFPSOBR-UHFFFAOYSA-N 0.000 description 3
- SWJPEBQEEAHIGZ-UHFFFAOYSA-N 1,4-dibromobenzene Chemical compound BrC1=CC=C(Br)C=C1 SWJPEBQEEAHIGZ-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000007818 Grignard reagent Substances 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- IYPKEFFZXIOKJL-UHFFFAOYSA-N [3-bromo-4-(4-bromobut-2-enoxy)phenyl]-(4-bromophenyl)methanone Chemical compound C1=C(Br)C(OCC=CCBr)=CC=C1C(=O)C1=CC=C(Br)C=C1 IYPKEFFZXIOKJL-UHFFFAOYSA-N 0.000 description 3
- SYFFUZGMEFPESB-UHFFFAOYSA-N [4-(6-bromohexoxy)-3-chlorophenyl]-(4-bromophenyl)methanone Chemical compound C1=C(OCCCCCCBr)C(Cl)=CC(C(=O)C=2C=CC(Br)=CC=2)=C1 SYFFUZGMEFPESB-UHFFFAOYSA-N 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000001530 fumaric acid Substances 0.000 description 3
- 150000004795 grignard reagents Chemical class 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000000052 vinegar Substances 0.000 description 3
- 235000021419 vinegar Nutrition 0.000 description 3
- UMMBAAGFWRINMM-UHFFFAOYSA-N (2,6-difluorophenyl)-(3-fluoro-4-hydroxyphenyl)methanone Chemical compound C1=C(F)C(O)=CC=C1C(=O)C1=C(F)C=CC=C1F UMMBAAGFWRINMM-UHFFFAOYSA-N 0.000 description 2
- AQUALGKCHBFFCK-UHFFFAOYSA-N (3,4-dichlorophenyl)-[4-(4-methylphenyl)phenyl]methanone Chemical compound C1=CC(C)=CC=C1C1=CC=C(C(=O)C=2C=C(Cl)C(Cl)=CC=2)C=C1 AQUALGKCHBFFCK-UHFFFAOYSA-N 0.000 description 2
- ZKIHKABXBPHQCE-UHFFFAOYSA-N (3-bromo-4-hydroxyphenyl)-(4-bromophenyl)methanone Chemical compound C1=C(Br)C(O)=CC=C1C(=O)C1=CC=C(Br)C=C1 ZKIHKABXBPHQCE-UHFFFAOYSA-N 0.000 description 2
- FUUHDAKJQKNBEF-UHFFFAOYSA-N (3-chloro-4-hydroxyphenyl)-phenylmethanone Chemical compound C1=C(Cl)C(O)=CC=C1C(=O)C1=CC=CC=C1 FUUHDAKJQKNBEF-UHFFFAOYSA-N 0.000 description 2
- VFLIJYQKWRGEKI-UHFFFAOYSA-N (4-bromophenyl)-[3-chloro-4-[6-(dimethylamino)hexoxy]phenyl]methanone Chemical compound C1=C(Cl)C(OCCCCCCN(C)C)=CC=C1C(=O)C1=CC=C(Br)C=C1 VFLIJYQKWRGEKI-UHFFFAOYSA-N 0.000 description 2
- IEXMDLWVLFRZDB-UHFFFAOYSA-N 1-(3-fluoro-4-hydroxyphenyl)-6-methylhept-5-en-2-one Chemical compound CC(C)=CCCC(=O)CC1=CC=C(O)C(F)=C1 IEXMDLWVLFRZDB-UHFFFAOYSA-N 0.000 description 2
- ZRCSJVMJTNVKKZ-UHFFFAOYSA-N 1-(3-fluoro-4-methoxyphenyl)-5-methylhexan-1-one Chemical compound COC1=CC=C(C(=O)CCCC(C)C)C=C1F ZRCSJVMJTNVKKZ-UHFFFAOYSA-N 0.000 description 2
- KJDIRVZPWWVSDH-UHFFFAOYSA-N 1-(4-bromophenyl)-2-(3-fluoro-4-hydroxyphenyl)ethanone Chemical compound C1=C(F)C(O)=CC=C1CC(=O)C1=CC=C(Br)C=C1 KJDIRVZPWWVSDH-UHFFFAOYSA-N 0.000 description 2
- ZVDWVVMNDONXPR-UHFFFAOYSA-N 1-(4-bromophenyl)-2-(4-hydroxyphenyl)ethanone Chemical compound C1=CC(O)=CC=C1CC(=O)C1=CC=C(Br)C=C1 ZVDWVVMNDONXPR-UHFFFAOYSA-N 0.000 description 2
- KJZTZIQNEYTQSN-UHFFFAOYSA-N 1-(4-hydroxyphenyl)-5-methylhex-4-en-1-one Chemical compound CC(C)=CCCC(=O)C1=CC=C(O)C=C1 KJZTZIQNEYTQSN-UHFFFAOYSA-N 0.000 description 2
- RWBMJSWTNLBNLN-UHFFFAOYSA-N 1-(4-hydroxyphenyl)-5-methylhexan-1-one Chemical compound CC(C)CCCC(=O)C1=CC=C(O)C=C1 RWBMJSWTNLBNLN-UHFFFAOYSA-N 0.000 description 2
- XLZVHOFYSQGUQA-UHFFFAOYSA-N 1-[2-(4-bromophenyl)phenyl]-n,n-dimethylmethanamine Chemical compound CN(C)CC1=CC=CC=C1C1=CC=C(Br)C=C1 XLZVHOFYSQGUQA-UHFFFAOYSA-N 0.000 description 2
- WAEKCHUPDOGQJY-UHFFFAOYSA-N 1-chloro-3-(4-methylphenyl)benzene Chemical group C1=CC(C)=CC=C1C1=CC=CC(Cl)=C1 WAEKCHUPDOGQJY-UHFFFAOYSA-N 0.000 description 2
- YDKOXGXRYCTKLM-UHFFFAOYSA-N 2-(3-fluoro-4-trimethylsilyloxyphenyl)-n-methoxy-n-methylacetamide Chemical compound CON(C)C(=O)CC1=CC=C(O[Si](C)(C)C)C(F)=C1 YDKOXGXRYCTKLM-UHFFFAOYSA-N 0.000 description 2
- ZTWGIBUESKWKHQ-UHFFFAOYSA-N 2-chloro-4-(4-methylphenyl)benzaldehyde Chemical compound C1=CC(C)=CC=C1C1=CC=C(C=O)C(Cl)=C1 ZTWGIBUESKWKHQ-UHFFFAOYSA-N 0.000 description 2
- PCQMBPJCAHOPOF-UHFFFAOYSA-N 4-(3-fluoro-4-hydroxybenzoyl)benzonitrile Chemical compound C1=C(F)C(O)=CC=C1C(=O)C1=CC=C(C#N)C=C1 PCQMBPJCAHOPOF-UHFFFAOYSA-N 0.000 description 2
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- DENKGPBHLYFNGK-UHFFFAOYSA-N 4-bromobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Br)C=C1 DENKGPBHLYFNGK-UHFFFAOYSA-N 0.000 description 2
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- 206010003210 Arteriosclerosis Diseases 0.000 description 2
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- 208000035150 Hypercholesterolemia Diseases 0.000 description 2
- 102000000853 LDL receptors Human genes 0.000 description 2
- 108010001831 LDL receptors Proteins 0.000 description 2
- 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 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- FLAJEHZOIBLCHA-UHFFFAOYSA-N [4-[4-(bromomethyl)phenyl]phenyl]-(3,4-dichlorophenyl)methanone Chemical compound C1=C(Cl)C(Cl)=CC=C1C(=O)C1=CC=C(C=2C=CC(CBr)=CC=2)C=C1 FLAJEHZOIBLCHA-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- NEHNMFOYXAPHSD-UHFFFAOYSA-N citronellal Chemical compound O=CCC(C)CCC=C(C)C NEHNMFOYXAPHSD-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 2
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
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- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 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
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000012178 vegetable wax Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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- C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
- C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
- C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
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- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- 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
- C07C217/06—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 only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/14—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 only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
- C07C217/18—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 only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
- C07C217/22—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 only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by carbon atoms having at least two bonds to oxygen atoms
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Description
Foreliggende oppfinnelse vedrører anvendelsen av forbindelser med formel
hvor
en av R<1> og R2 er <C>1.7-alkyl og den andre er C1_7-alkyl eller C2_6-alkenyl-metyl,
L er C^-j^-alkylen eller C2_11-alkenylen eventuelt bundet til fenylgruppen via et O-atom, eller L er 1,4-fenylen,
n =0 eller, i tilfellet L inneholder et O-atom, betyr n 0 eller 1,
Q er C1_7-alkyl, C2_10-alkenyl eller en gruppe med formel
Q' :
R er H, halogen, CF3, CN eller N02,
R<3> og R<4> er H, <C>1_4-alkyl eller halogen og
R<5> er H eller, i tilfellet R er H, H eller halogen,
og deres farmasøytisk akseptable syreaddisjonssalter ved fremstilling av kolesterolsenkende legemidler.
Dessuten vedrører oppfinnelsen nye forbindelser med formel I, såsom
4-t[6-(allylmetylamino)heksyl]oksy] -3-klorbenzofenon
4-[[6-(allylmetylamino)heksyl]oksy]-3,4'-dibrombenzofenon,
4-[[4-(allylmetylamino)-2-butenyl]oksy]-3,4'-dibrombenzofenon,
3- klor-4'-jod-4-[[6-(allylmetylamino)heksyl]oksy]-benzofenon,
4' -brom-3-klor-4-[[6-(allylmetylamino)heksyl]oksy]-benzofenon,
2,4-[[(4-dimetylamino)-2-butenyl]oksy]-3,4'-dibrombenzofenon,
4- t[4-(dimetylamino)-2-butenyl]oksy]-3-klorbenzofenon,
4' -brom-3-klor-4-[[6-(dimetylamino)heksyl]oksy]benzof enon,
3 , 4-diklorfenyl-4'-[(dimetylamino)metyl]-4-bifenyl-ylketon, 4' -[(allylmetylamino)metyl]-4-bifenylyl-3,4-diklor-fenylketon,
(RS)-4'-(dimetylaminometyl)-4-bifenyl-2,6-dimetyl-5-heptenylketon,
p-bromfenyl-2-klor-4'-[(dimetylamino)metyl]-4-bife-nylylketon, 4' -[(dimetylamino)metyl]-4-bifenylyl-propylketon, [4-[6-(allyl-metyl-amino)-heksyloksy]-fenyl]-(4-brom-fenyl)-metanon,
[4-[4-(allyl-metyl-amino)-butoksy]-fenyl]-(4-brom-fenyl)-metanon,
[4-[6-(allyl-metyl-amino)-heksyloksy]-3-fluor-fenyl]-(4-brom-fenyl)-metanon,
[4-[6-(allyl-metyl-amino)-heksyloksy]-2-fluor-fenyl]-(4-brom-fenyl)-metanon, (E)-[4- [4-(allyl-metyl-amino)-but-2-enyloksy]-fenyl]-(4-trifluormetyl-fenyl)-metanon,
(E)-[4-[4-(allyl-metyl-amino)-but-2-enyloksy]-3-fluor-fenyl]-(4-brom-fenyl)-metanon,
(E)-1-[4-[4-(allyl-metyl-amino)-but-2-enyloksy]-fenyl]-5-metyl-heksan-l-on,
(E)-[4-[4-(allyl-metyl-amino)-but-2-enyloksy]fenyl]-(4-jod-fenyl)-metanon,
(E)-1-[4-(allyl-metyl-amino)-but-2-enyloksy]-3-fluor-fenyl]-5-metylheksan-l-on,
(E)-[4-[4-(allyl-metyl-amino)-but-2-enyloksy]-3-fluor-benzoyl]-benzonitril, (E)-4- [4-[4-(allyl-metyl-amino)-but-2-enyloksy]-ben-zoyl]-benzonitril, (E)- [4- [4-(allyl-metyl-amino)-but-2-enyloksy]-3-fluor-fenyl]-(2,6-difluor-fenyl)-metanon, (E)-1- [4-[4-(allyl-metyl-amino)-but-2-enyloksy]-fenyl]-5-metyl-heks-4-en-l-on, (E)- [4- [4- (allyl-metyl-amino)-but-2-enyloksy]-2-fluor-fenyl]-(4-brom-fenyl)-metanon,
(E)-[4-[4-(allyl-metyl-amino)-but-2-enyloksy]-fenyl]-(4-fluor-fenyl)-metanon, (E)-1- [4-[4-(allyl-metyl-amino)-but-2-enyloksy]-3-fluor-fenyl]-6-metyl-hept-5-en-2-on, (E)-2- [4-[4-(allyl-metyl-amino)-but-2-enyloksy]-3-fluor-fenyl]-1-(4-brom-fenyl)-etanon, (E)-2- [4-[4-(allyl-metyl-amino)-but-2-enyloksy)-fenyl]-1-(4-brom-fenyl)-etanon,
(E)-(4-brom-fenyl)-[4-[4-(etyl-metyl-amino)-but-2-enyloksy]-fenyl]-metanon.
Uttrykkene "alkyl" og "alkylen" betegner rettkjedede eller forgrenede, mettede hydrokarbonrester med én hhv. to frie valenser, såsom metyl, etyl, propyl, isobutyl og t-butyl, hhv. metylen, pentametylen og heksametylen. Uttrykkene "alkenyl" og "alkenylen" betegner rettkjedede eller forgrenede hydrokarbonrester som inneholder en dobbeltbinding, med én hhv. to frie valenser, såsom vinyl og propenyl, hhv. propenylen.
Som farmasøytisk akseptable syreaddisjonssalter kommer salter av forbindelsene I med uorganiske og organiske syrer, såsom HC1, HBr, H2S04, HN03, sitronsyre, eddiksyre, ravsyre, fumarsyre, vinsyre, metansulfonsyre og p-toluen-sulfonsyre i betraktning.
Foretrukne forbindelser med formel I er de forbindelser hvor n = 0 og R<5> er H.
Foretrukne forbindelser med formel I er dessuten forbindelser hvor a) R<1> er metyl og R<2> er metyl, etyl, propyl eller allyl og/eller b) L er gruppen -CH=CHCH20-, spesielt i trans-form,
-(C<H>2)5-,-(CH2)6-,-(CH2)30-,-(CH2)50,-(C<H>2)60- eller 1,4-fenylen og/eller
c) R<3> er H, Br, Cl, F eller CH3 og/eller
d) Q er propyl, pentyl, isoheksyl, 4-metyl-3-pentenyl eller 2, 6-dimetyl-5-heptyl eller
e) Q er en gruppe Q', hvor R er H, Br, Cl, F, I, CF3, CN eller N02 og/eller R<4> er H, Br, Cl, F, eller CH3 og/eller R<5> er H eller F.
Spesielt foretrukket er forbindelsene med formel I, hvor
a) L er C5_1:L-alkylen eller C5_11-<a>lkylenoksy, spesielt - (C<H>2)6- eller - (CH2) 50- ; C3.1:L-alkenylenoksy, spesielt -CH=CHCH20-, eller 1,4-fenylen og/eller
b) R<3> er H eller halogen og/eller
c) Q er C2_10-alkenyl, spesielt 4-metyl-3-pentenyl; eller en gruppe Q' , hvor R er CN, N02 eller halogen, spesielt Br, Cl eller F, og R<4> er H eller Cl,
spesielt de forbindelser, hvor
a) R<1> er metyl og R<2> er metyl eller allyl og/eller
b) L er -(CH2)50-, -CH=CHCH20- eller 1,4-fenylen og/eller
c) R<3> er H eller F og/eller
d) Q er 4-metyl-3-pentenyl eller en gruppe Q', hvor R er Br, Cl, CN eller N02, R<4> er H eller Cl og R<5> er H.
Eksempler på foretrukne forbindelser er
trans-4-[[4-(allylmetylamino)-2-butenyl]oksy]-4'-brom-benzofenon,
trans-4-[[4-(allylmetylamino)-2-butenyl]oksy]-4'-nit robenz o f enon,
p-t[4'-[(allylmetylamino)metyl]-4-bifenylyl]karbo-nyl] benzonitril,
2-klor-4-nitrofenyl-4'-[(dimetylamino)metyl]-4-bife-nylyl-keton,
trans-4-[[4-(allylmetylamino)-2-butenyl]oksy]-2',4'-diklorbenzofenon,
[4-[6-(allyl-metyl-amino)-heksyloksy]-fenyl]-(4-brom-fenyl)-metanon,
[4-[6-(allyl-metyl-amino)-heksyloksy]-3-fluor-fenyl]-(4-brom-fenyl)-metanon,
[4-[6-(allyl-metyl-amino)-heksyloksy]-2-fluor-fenyl]-(4-brom-fenyl)-metanon,
(E)-[4-[4-(allyl-metyl-amino)-but-2-enyloksy]-3-fluor-fenyl]-(4-brom-fenyl)-metanon, (E)-1-[4-[4-(allyl-metyl-amino)-but-2-enyloksy]-fenyl]-5-metyl-heks-4-en-l-on, (E)-[4-[4-(allyl-metyl-amino)-but-2-enyloksy] -2-fluor-fenyl]-(4-brom-fenyl)-metanon.
Forbindelsene med formel I og deres salter kan fremstilles slik som beskrevet i US-patent nr. 5106878, 5137920 og 5177067. De forbindelser som ikke spesifikt er nevnt i disse patentskrifter, er gjenstand for foreliggende oppfinnelse. Fremstillingen av slike nye forbindelser er beskrevet i de etterfølgende eksempler.
Forbindelsene I og deres salter har en kolesterolsenkende virkning og kan således anvendes spesielt ved bekjempelsen hhv. forebyggelsen av hyperkolesterolemi og arteriosklerose som er ansvarlig for de fleste kardiovaskulære sykdommer.
For å bevise den kolesterolsenkende virkning av forbindelsene I og deres salter, ble det av D.L. Brasaemle og Attie A.D. (Biotechniques 6, 1988, 418-419) gjennomført en modifikasjon av eksperimentet av M.Krieger (Anal. Biochem. 135, 1983, 383-391). I dette eksperiment anvendes koleste-rolsyntesehemmernes egenskap å beskytte cellene CHO-K1 (ovarceller fra kinesisk hamster) mot de cytotoksiske effekter av polyenantibiotikumet Amphotericin B. Koleste-rolsyntesens hemning angis som beskyttelse av levende celler og denne beskyttelse angis igjen som antall av de overlevende celler sammenlignet med ubehandlede celler. EC50-verdiene i nM/1 i den efterfølgende tabell A tilsvarer konsentrasjonen hvor 50 % av cellene overlever: I ovennevnte eksperiment ble det for 2,4-difluorfenyl-4'-[ (allyl-metylamino)metyl]-4-bifenylylketon-hydrokloridet bestemt en EC50-verdi på 4,00 nM/1.
Til ytterligere bevis for den kolesterolsenkende virkning av forbindelsene med formel I og deres salter ble det gjennomført et eksperiment som er analogt med det som er beskrevet i J. Biol. Chem. 256 (1981), 11923-11931. Herved ble hemningen av kolesterolsyntesen i humane hepatomaceller (Hep G2) bestemt ved hjelp av den parallelt induserte oppregulering av LDL-reseptoren. Cellene ble sådd i mikro-titerplater og behandlet med kolesterolsyntesehemmerne.
LDL-reseptorens konsentrasjon ble målt ved hjelp av en ELISA-metode, idet C7-LDL-antistoffer ble brukt som primære antistoffer. EC50-verdiene i nM/1 i den etterfølgende tabell B tilsvarer kolesterolsyntesehemmerens konsentrasjon, hvor reseptorens aktivitet i forhold til kontrollen (dvs. ikke behandlede celler) ble øket med 50 %.
2- hhv. 3-stillingen av en substituent R<3> i de foregående tabeller A og B tilsvarer orto- hhv. meta-stillingen i gruppen -(<CH>2)nC(0)Q i formel I.
Toksisiteten av disse forbindelser er liten, men forbin-delsen nr. 20 har en LD50 på 1250-2500 mg/kg pr. os hos mus.
Forbindelsene I og deres salter kan anvendes som virkestoffer i farmasøytiske preparater. De farmasøytiske
preparater administreres oralt, f.eks. i form av tabletter, lakktabletter, drageer, hård- og mykgelatinkapsler, oppløs-ninger, emulsjoner eller suspensjoner. For fremstilling av slike preparater kan virkestoffet blandes med farmasøytisk inerte, uorganiske eller organiske bærere. Som bærer kan man for tabletter, lakktabletter, drageer og hårdgelatin-kapsler anvende f.eks. laktose, maisstivelse, talkum, stearinsyre eller deres salter. For mykgelatinkapsler egner seg som bærer f.eks. planteoljer, voks eller fett; alt efter virkestoffets beskaffenhet, er det imidlertid hos mykgelatinkapsler overhode ikke nødvendig med noen bærere. For fremstilling av oppløsninger og sirupper egner seg som bærere f.eks. vann, sakkarose, invertsukker og glukose. De farmasøytiske preparater kan dessuten inneholde konserve-ringsmidler, oppløsningsfremmende midler, stabiliserings-midler, fuktemidler, emulgeringsmidler, søtningsstoffer, farvestoffer, aromatiseringsmidler, salter til forandring av det osmotiske trykk, buffer, overtrekksmidler eller antioksydanter. De kan også inneholde andre terapeutisk verdifulle stoffer.
Som innledningsvis nevnt, er kolesterolsenkende legemidler som inneholder en forbindelse med formel I eller et far-masøytisk aksepterbart salt, også gjenstand for foreliggende oppfinnelse, som er karakterisert ved at man bringer ett eller flere av de nevnte virkestoffer og eventuelt ett eller flere andre terapeutisk verdifulle stoffer i en galenisk administrasjonsform. Som innledningsvis nevnt, kan disse virkestoffer anvendes ved bekjempelsen hhv. forebyggelsen av sykdommer såsom hyperkolesterolemi og arteriosklerose. Doseringen kan variere innen vide grenser og skal tilpasses naturlig i hvert enkelt tilfelle til de individuelle forhold. Generelt turde ved oral administra-sjon en daglig dose på ca. 2 mg til ca. 2 g, fortrinnsvis ca. 10 til ca. 100 mg være egnet. Den daglige dose inntas i én, to eller tre enkeltdoser, f.eks. til ett eller flere måltider.
I de etterfølgende eksempler skal det beskrives fremstillingen av hittil ukjente forbindelser med formel I.
Eksempel 1
Til en oppløsning av 34,5 g 1,6-dibromheksan, 9,9 g 3-klor-4-hydroksybenzofenon og 1,6 g tetrabutylammoniumbromid i 100 ml metylenklorid tilsettes 100 ml av en 10% vandig natronlut. Den heterogene blanding røres natten over ved romtemperatur. Den organiske fase skilles, tørkes over natriumsulfat og dampes inn. Ved kromatografering av resten på kiselgel med heksan/eddiksyreetylester 7:3 oppnås 4-[(6-bromheksyl)oksy]-3-klorbenzofenon, smp. 58°C.
En oppløsning av 3,0 g av det erholdte benzofenon i 30 ml etanol oppvarmes til 90°C med 16 ml av en 33% oppløsning av N-allyl-metylamin i etanol i 1,5 timer i et trykkrør. Efter avkjøling helles blandingen på vann og ekstraheres tre ganger med eddikester. De over natriumsulfat tørkede organiske faser inndampes og resten kromatograferes nøy-tralt med heksan/eddikester (7:3) på aluminiumoksyd. Man oppnår 4-[[6-(allylmetylamino)heksyl]oksy]-3-klorbenzo-fenon, hydrokloridets smp. 133°C.
Eksempel 2
Analogt med eksempel 1 oppnår man
a) fra 3 , 4'-dibrom-4-hydroksybenzofenon, via 4-[(6-bromheksyl)oksy]-3,4'-dibrombenzofenon, smp. 97°C, 4-[ [6-(allylmetylamino) heksyl] oksy] -3,4' -dibrombenzofenonet, hydrokloridets smp. 126-127°C, b) fra 3,4'-dibrom-4-hydroksybenzofenon og trans 1,4-dibrombuten, via 4-[ (4-brom-2-butenyl) oksy]-3,4' -dibrom-benzof enon, 4- [ [4- (allylmetylamino) -2-butenyl] oksy] 3,4' - dibrombenzofenonet, hydrokloridets smp. 115-116°C, c) fra 3-klor-4' -jod-4-hydroksybenzofenon og 1,6-dibromheksan, via 3-klor-4' - jod-4-[ (6-bromheksyl) oksy] benzof enon, 3-klor-4' - jod-4- [ [6- (allylmetylamino) heksyl] oksy] benzo-fenonet som overføres til hydrokloridet, MS:m/e 511 (M<+>,2,4%), 484 (2%), 482 (4%), 231 (2,5%), 154 (3,3%), 84 (100%), d) via 4' -brom-3-klor-4-[ (6-bromheksyl) oksy]benzofenon (eksempel 3c) 4'-brom-3-klor-4-[[6-(allylmetylamino)heksyl] oksy] benzof enonet som overføres til hydrokloridet, MS: m/e 465 (M<+>,2%), 463 (1,5%), 436 (4%), 434 (3%), 155 (3%), 154 (4%), 84 (100%).
Eksempel 3
Analogt med eksempel 1 oppnår man
a) via 4-[ (4-brom-2-butenyl)oksy]-3,4' -dibrombenzofenon (eksempel 2b) med dimetylamin i stedet for N-allyl-metyl-amin, 2, 4 - [ [ (4-dimetylamino) -2-butenyl] oksy] -3,4' dibrom-benzof enonet som overføres til hydrokloridet, smp. 166-167°C,
b) fra 3-klor-4-hydroksybenzofenon og 1,4-dibrombuten, via 4-[4-brom-2-butenyl)oksy]-3-klorbenzofenon, smp. 96-97°C, 4-[[4-(dimetylamino)-2-butenyl]oksy]3-klorbenzofenonet som overføres til hydrokloridet, smp. 195°C,
c) fra 4'-brom-3-klor-4-hydroksybenzofenon og 1,6-dibromheksan, via 4'-brom-3-klor-4-[(6-bromheksyl)oksy] benzofenon, 4'-brom-3-klor-4-[[6-(dimetylamino)heksyl] oksy]-benzofenonet som overføres til hydrokloridet, MS:m/e 402 (M<+>"C1, 0,2%), 185 (1,3%), 183 (1,6%), 155 2%), 128 (4%), 58 (100%) .
Eksempel 4
a) 35 ml nitrobenzen avkjøles i et isbad og behandles efter hverandre med 5,2 g aluminiumklorid og 5,0 g 4-metylbifenyl. Blandingen bringes til romtemperatur og blandes derefter med 7,7 g 3,4-diklorbenzoylklorid. Blandingen røres ved romtemperatur, helles på vann og ekstraheres med metylenklorid. Ekstraktene vaskes med 2N saltsyre og vann, tørkes over magnesiumsulfat og inndampes. Resten kromatograferes på kiselgel med toluen/eddikester 9:1. Man oppnår 3,4-diklorfenyl-4'-metyl-4-bifenylylketon. b) En blanding av 5,0 g 3,4-diklorfenyl-4'-metyl-4-bife-nylylketon, 2,7 g N-bromsuccinimid og 20 mg azaisobutyro-nitril i 70 ml tetraklorkarbon oppvarmes ved tilbakeløp til kokepunktet. Det utfelte materiale avfiltreres og filtra-tet inndampes. Resten omkrystalliseres fra toluen/cyklo-heksan. Man oppnår 3,4-diklorfenyl-4'-brommetyl-4-bi-fenylylketon. c) 1,0 g 3,4-diklorfenyl-4'-brommetyl-4-bifenylylketon og 20 ml av en 30% oppløsning av dimetylamin i etanol oppvarmes i 4 timer til kokepunktet, hvorefter blandingen inndampes. Resten opptas i eter og behandles med en ete-risk oppløsning av hydrogenklorid. Det utfelte hydroklorid avfiltreres og tørkes. Man oppnår 3,4-diklorfenyl-4'-[(dimetylamino)metyl]-4-bifenylylketon-hydroklorid, smp. 223°C.
Eksempel 5
1,0 g 3,4-diklorfenyl-4'-brommetyl-4-bifenylylketon, 1,5 ml N-allylmetylamin og 0,84 g kaliumkarbonat i 25 ml etanol oppvarmes i 4 timer til kokepunktet ved tilbakeløp. Blandingen inndampes og resten ekstraheres med eter. Ekstraktene tørkes over magnesiumsulfat og behandles med en ete-risk oppløsning av hydrogenklorid. Det utfelte hydroklorid avfiltreres og tørkes. Man oppnår 4'-[(allylmetylamino)-metyl]-4-bifenylyl-3,4-diklorfenylketon-hydroklorid, smp. 160°C.
Eksempel 6
a) En oppløsning av Grignard-reagensen som er fremstilt av 344 mg magnesium og 2,27 g 1,4-dibrombenzen i 15 ml THF, tilsettes dråpevis til en suspensjon av 2 g 4-brom-N,N-dimetylbenzylamin og 158 mg tetrakistrifenyl-fosfinpalla-dium i 10 ml THF. Tilsetningen skjer ved romtemperatur og under argonatmosfære. Efter avslutning av tilsetningen oppvarmes blandingen i enda 5 timer til kokepunktet og inndampes derefter under forminsket trykk. Man blander derefter med eter og mettet ammoniumkloridoppløsning og separerer den vandige fase. Denne ekstraheres med eter. De organiske uttrekk vaskes med mettet natriumkloridoppløs-ning, tørkes over magnesiumsulfat og inndampes. Resten renses ved kromatografi på kiselgel under eluering med metylenklorid/metanol 9:1. Man oppnår 4'-brom-N,N-dimetyl-bif enylmetanamin, smp. 60-62°C.
b) En oppløsning av Gr ignard-reagensen som er fremstilt av 0,94 g 4'-brom-N,N-dimetylbifenylmetanamin og 146 mg magnesium i 5 ml THF, tilsettes dråpevis en oppløsning av 1.07 g
Citronellal i 10 ml THF. Tilsetningen skjer ved romtemperatur og under argonatmosfære. Blandingen røres derefter i 6 timer ved romtemperatur og hydrolyseres derefter med 50 ml mettet ammoniumkloridoppløsning. Man ekstraherer med eter, tørker ekstraktene over magnesiumsulfat og inndamper disse. Efter kromatografi på kiselgel med metylenklorid/- metanol 9:1 som elueringsmiddel, oppnår man (RS)-4'-[(di-metylaminmetyl) -4-bifenyl] -a- (2, 6-dimetyl-5-heptenyl) - metanol, MS m/e: M<+> 365 (21%), 321 (19%, 280 (36%), 58 (100%).
c) En oppløsning av 406 mg DMSO i 2 ml metylenklorid tilsettes til en oppløsning av 327 mg oksalylklorid i 10 ml
metylenklorid ved -70°C. Reaksjonsblandingen røres i 2 minutter, hvorefter en oppløsning av 810 mg av produktet fra b) i 5 ml metylenklorid tilsettes. Man rører i ytterligere 15 minutter og blander reaksjonsblandingen derefter ved -70°C med 1,18 g trietylamin. Reaksjonsblandingen oppvarmes til romtemperatur og blandes med en vandig opp-løsning av natriumkarbonat. Den vandige fase ekstraheres med metylenklorid. De organiske faser samles, vaskes med mettet natriumkloridoppløsning og tørkes over magnesium-sulf at. Materialet som oppnås efter filtrering og inndampning tilsettes til en varm oppløsning av 263 mg fumarsyre i 5 ml etanol. Det utfelte fumarat omkrystalliseres fra etanol. Man oppnår (RS)-4'-(dimetylaminmetyl)-4-bifenyl-2,6-dimetyl-5-heptenylketonfumarat, smp. 116-123°C.
Eksempel 7
a) Anlaogt med eksempel 6 a) oppnår man fra 4-bromtoluen og 3-klorbrombenzen 3-klor-4'-metylbifenyl, kp. 110-115°-C/20Pa. b) En blanding av 4,76 g 3-klor-4'-metylbifenyl, 2,94 g heksametylentetramin og 3 0 ml trifluoreddiksyre oppvarmes
til kokepunktet i 5 dager ved tilbakeløp. Reaksjonsblandingen konsentreres og blandes med isvann, røres i 15 minutter, gjøres basisk med natriumkarbonat og ekstraheres med eter. Efter inndampning av de eteriske ekstrakter og kromatografi av resten på kiselgel med metylenklorid/metanol 9:1 som elueringsmiddel, oppnår man 2-klor-4-(4'-metyl-fenyl)benzaldehyd, kp. 210-215°C/25Pa. c) Analogt med eksempel 6b) og 6 c) oppnår man fra 2-klor-4-(4'-metylfenyl)benzaldehyd og 1,4-dibrombenzen p-bromfenyl-2-klor-4' -metyl-4-bifenylketon som farveløs olje, MS m/e: 386 (M<+>, 46%), 306 (9%), 229 (100%). d) Analogt med eksempel 4 b) oppnår man fra p-bromfenyl-2-klor-4'-metyl-4-bifenylketon 4'-brommetyl-2-klor-p-brom-fenyl-4-bifenylketon. e) Analogt med eksempel 4 c) oppnår man ved behandling av 4'-brommetyl-2-klor-p-bromfenyl-4-bifenylketon med dimetylamin og derefter med hydrogenklorid p-bromfenyl-2-klor-4'-[ (dimetylamino)metyl] -4-bifenylylketon-hydroklorid, smp. 189-191°C.
Eksempel 8
En oppløsning av Grignard-reagensen som er fremstilt av 228 mg magnesium og 1,42 g n-propylbromid i 10 ml THF, tilsettes dråpevis til en oppløsning av 1,16 g 4'-[(dimetylamino) metyl]-N-metoksy-N-metyl-4-bifenylkarboksamid i 10 ml THF ved 0°C under argon. Efter avslutning av tilsetningen røres blandingen i enda 5 timer ved romtemperatur og inndampes derpå under forminsket trykk. Man blander med metylenklorid og mettet ammoniumkloridoppløsning og separerer den vandige fase. Denne ekstraheres med metylenklorid. De organiske uttrekk vaskes med mettet natriumkloridoppløs-ning, tørkes over mangesiumsulfat og inndampes. Resten
renses ved kromatografi på kiselgel under eluering med metylenklorid-metanol 95:5. Efter omsetning med fumarsyre
i etanol oppnår man 4'-[ (dimetylamino) metyl]-4-bif enylyl-propylketonfumarat, smp. 155-156°C.
Eksempel 9
Utganqsmaterialer
A) En blanding av 41 g 4-hydroksybenzosyre og 400 ml heksametyldisilazan oppvarmes i 2 timer ved tilbakeløp, avkjøles, inndampes og oppløses i 400 ml metylenklorid. Efter tilsetning av 3 dråper DMF tilsettes dråpevis 2 8 ml oksalylklorid. Dette røres, inndampes og tørkes. Det oppnådde syreklorid suspenderes med 31 g N,O-dimetylhy-droksylamin-hydroklorid i 52 0 ml metylenklorid og blandes ved 0°C i 2 timer med 73 ml N-metylmorfolin. Det oppvarmes natten over, tas opp i eddikester og vaskes med vann, 10% vandig KHS04- og mettet vandig NaHC03-oppløsning. Den organiske fase tørkes, avfiltreres og inndampes. Man oppnår 76 g N-metoksy-N-metyl-trimetylsilanyloksy-benzamid, MS: m/e 238 (M<+->CH3).
B) Analogt med avsnitt A oppnår man
Ba) fra 4-hydroksyfenyleddiksyre N-metoksy-N-metyl-2-(4-trimetylsilanyloksy-fenyl)acetamid, MS: m/e 267 (M+) , 252 (M+-CH3) ,
Bb) fra 3-fluor-4-hydroksy-fenyleddiksyre N-metoksy-N-metyl-2- (3-fluor-4-trimetylsilanyloksy-fenyl)-acetamid, MS: m/e 285 (M+) .
C) Til en Grignard-reagens som er fremstilt av 1 g magnesium og 5,7 g 1-brom-4-metyl-3-penten, tilsettes dråpevis ved 0°C en oppløsning av 6,3 g N-metoksy-N-metyl-trimetylsilanyloksy-benzamid. Reaksjonen får henstå natten over ved romtemperatur under omrøring. Den blandes med 10% vandig KHSO-oppløsning og ekstraheres med eddikester. Den
organiske fase vaskes nøytralt med 10% vandig NaCl-oppløs-ning, tørkes og inndampes. Silylgruppen spaltes i 10% vandig THF med IN saltsyre. Derefter opptas den i metylenklorid, tørkes og inndampes. Efter kromatografi over silikagel under eluering med metylenklorid/O,5% metanol oppnås 2,1 g 1-(4-hydroksy-fenyl)-5-metyl-heks-4-en-l-on. MS: m/e 2 04 (M+) . D) Analogt med avsnitt C) oppnås fra N-metoksy-N-metyl-2-(3-fluor-4-trimetylsilanyloksy-fenyl)-acetamid (avsnitt Bb) 1-(3-fluor-4-hydroksyfenyl)-6-metyl-hept-5-en-2-on, MS: m/e 236 (M+) . E) En oppløsning av 45 ml n-butyllitium (1,6M i heksan) tilsettes dråpevis til en til -78°C nedkjølt suspensjon av 18,2 g 1,4-dibrombenzen i 140 ml THF. Derefter tilsettes dråpevis ved -78°C 10g N-metoksy-N-metyl-2-(3-fluor-4-trimetylsilanyloksy-fenyl)-acetamid (avsnitt Bb)) i 35 ml THF. Reaksjonsblandingen røres i 2 timer ved -78°C og skal derefter henstå i 1 time ved romtemperatur under omrøring. Efter fortynning med eddikester, vaskes med 10% vandig KHS4-, mettet NaHC03- og 10% vandig NaCl-oppløsning. Efter ekstraksjon med eddikester, tørkes og inndampes de organiske faser. Derefter avspaltes silylgruppen med 105ml THF, 11 ml H20 og 5 dråper IN HC1. Inndampning, oppløsning i metylenklorid, tørkning og søylekromatografi over kiselgel med metylenklorid/O,5% metanol som eluat gir 9,2g l-(4-brom-fenyl)-2-(3-fluor-4-hydroksy-fenyl)-etanon. MS: m/e 308 M<+>, 1 Br). F) Analogt med avsnitt E) oppnår man fra N-metoksy-N-metyl-2- (4-trimetyl-silanyloksy-fenyl)-acetamid (avsnitt Ba)) 1-(4-brom-fenyl)-2-(4-hydroksy-fenyl)-etanon, MS: m/e 290 (M<+>, 1 Br). G) 14 ml nitrobenzen kjøles i isbad og blandes efter hverandre med 3,8 g A1C13 og 3,7 g 5-metyl-heksansyreklorid i 5 ml nitrobenzen. Blandingen røres og blandes med 2,7 ml 2-fluor-anisol. Oppløsningen røres natten over, heles på isvann og ekstraheres med metylenklorid. Ekstraktene vaskes med vann og 10 % vandig NaCl-oppløsning, tørkes og inndampes og utkrystalliseres med pentan. Det oppnås 5,3 g 1-(3-fluor-4-metoksyfenyl)-5-metyl-heksan-l-on, MS: m/e 238 (M+) .
H) Analogt med avsnitt G) oppnår man;:
Ha) fra 4-brom-benzoylklorid og 2-fluor-anisol (4-brom-fenyl)- (3-fluor-4-metoksy-fenyl)-metanon, smp. 142-143°C,
Hb) fra 4-cyano-benzoylklorid og 2-fluor-anisol 4-(3-fluor-4-metoksy-benzoyl)-benzonitril, smp. 132,5-133°C,
Hc) fra 4-brom-benzoylklorid og 3-fluor-anisol (4-brom-fenyl)- (2-fluor-4-metoksy-fenyl) -metanon, MS: m/e 308 (M<+>, 1 Br) ,
Hd) fra 2,6-difluor-benzoylklorid og 2-fluor-anisol (2,6-difluorfenyl)-(3-fluor-4-metoksy-fenyl) -metanon, smp. 79-83°C.
I) En oppløsning av 3,9 g (2,6-difluor-fenyl)-(3-fluor-4-metoksy-fenyl)-metanon (avsnitt Hd) ) i 30 ml eddiksyre røres med 20 ml vandig 62% HBr-oppløsning ved 125°C, inndampes, efterdampes med toluen og tas opp i eddikester. Den organiske fase vaskes med mettet vandig NaHC03-oppløs-ning og 10% NaCl-oppløsning og tørkes. Det oppnås 3,6 g (2, 6-dif luor-fenyl) - (3-f luor-4-hydroksy-f enyl) -metanon, MS: m/e 252 (M<+>).
J) Analogt oppnår man:
Ja) fra (4-brom-fenyl)-(3-fluor-4-metoksy-fenyl)-metanon (avsnitt Ha))
(4-brom-fenyl)-(3-fluor-4-hydroksy-fenyl)-metanon, smp. 183-184°C,
Jb) fra (4-brom-fenyl)-(2-fluor-4-metoksy-fenyl)-metanon (avsnitt Hc)
(4-brom-fenyl)- (2-fluor-4-hydroksy-fenyl)-metanon, MS: m/e 294 (M<+>, 1 Br),
Jc) fra anisol og 5-metyl-heksansyreklorid via 1-(4-metoksy-fenyl)-5-metyl-heksan-l-on
direkte 1-(4-hydroksy-fenyl)-5-metyl-heksan-l-on, MS: m/e 206 (M+) .
K) En oppløsning av 50 g 4-(3-fluor-4-metoksy-benzoyl)-benzonitril i 550 ml metylenklorid blandes ved 5°C med 70 ml BBr3 og røres ved romtemperatur. Under iskjøling tilsettes dråpevis 1 1 IM NaOH. Derefter ekstraheres med mettet vandig NH4C1-oppløsning og metylenklorid. Den organiske fase vaskes med vann og tørkes. Efter omkry-stallisasjon fra eter oppnås 34 g 4-(3-fluor-4-hydroksy-benzoyl)-benzonitril, smp. 168,5-169,5°C.
Produkter
Analogt med eksempel 1 oppnår man
a) fra 4'-brom-4-hydroksybenzofenon og 1,6-dibromheksan, via 4'-brom-4-[(6-bromheksyl)oksy]benzofenon og reaksjon med N-allyl-metylamin
[4-[6-(allyl-metyl-amino)-heksyloksy]-fenyl]-(4-brom-fenyl)-metanon-hydrobromid, smp. 117-119°C,
b) fra 4'-brom-4-hydroksybenzofenon og 1,4-dibrombutan, via 4'-brom-4-[(6-brombutyl)oksy]benzofenon og reaksjon med N-allyl-metylamin
[4- [4-(allyl-metyl-amino)-butoksy]-fenyl]-(4-brom-fenyl)-metanon-hydrobromid, smp. 149-151°C,
c) fra (4-brom-fenyl) -(3-fluor-4-hydroksy-fenyl)-metanon (avsnitt Ja) og 1,6-dibromheksan, via [4-(6-brom-heksyl)-3-fluor-fenyl]-(4-brom-fenyl)-metanon og reaksjon med N-allyl-metylamin
[4- [6-(allyl-metyl-amino) -heksyloksy]-3-fluor-fenyl]-(4-brom-fenyl)-metanon som overføres til hydrokloridet, MS: m/e 447 (M<+>, 1 Br) ,
d) fra (4-brom-fenyl) -(2-fluor-4-hydroksy-fenyl)-metanon (avsnitt Jb) og 1,6-dibromheksan, via [4-(6-brom-heksyl)-2-fluor-fenyl]-(4-brom-fenyl)metanon og reaksjon med N-allyl-metylamin
[4- [6-(allyl-metyl-amino)-heksyloksy]-2-fluor-fenyl]-(4-brom-fenyl)-metanon som overføres til hydrokloridet, smp. 106-109°C,
e) fra 4'-trifluormetyl-4-hydroksybenzofenon og (E)-l,4-dibrombuten, via (E)-[4-[4-brom-but-2-enyloksy]-fenyl]-(4-trifluormetyl-fenyl)-metanon og reaksjon med N-allyl-metyl-amin
(E) - [4- [4-(allyl-metyl-amino)-but-2-enyloksy]-fenyl]-(4-trifluormetyl-fenyl)-metanon som overføres til hydrokloridet, MS: m/e M 390 (M+H+) . f) fra (4-brom-fenyl)-(3-fluor-4-hydroksy-fenyl)-metanon (avsnitt Ja) og (E)-1,4-dibrombuten, via (E)-[4-(4-brom-but-2-enyloksy)-3-fluor-fenyl] -(4-brom-fenyl)-metanon og reaksjon med N-allyl-metylamin (E)-[4-[4-(allyl-metyl-amino)-but-2-enyloksy]-3-fluor-fenyl]-(4-brom-fenyl)-metanon som overføres til hydrokloridet, MS: m/e 418 (M+H<+>, 1 Br), g) fra 1-(4-hydroksy-fenyl)-5-metyl-heksan-l-on (avsnitt Jc) og (E)-1,4-dibrombuten, via (E)-1-[4-[4-brombut-2-enyloksy]-fenyl]-5-metyl-heksan-l-on og reaksjon med N-allyl-metylamin (E)-1-[4-[4-(allyl-metyl-amino)-but-2-enyloksy]-fenyl]-5-metyl-heksan-l-on som overføres til hydrokloridet, smp. 105-106°C, h) fra (4-hydroksy-fenyl)-(4-jod-fenyl)-metanon og (E)-1,4-dibrom-buten, via (E)-[4-[4-brom-but-2-enyloksy] - fenyl]-(4-jod-fenyl)-metanon og reaksjon med N-allyl-metyl-amin (E)-[4-[4-(allyl-metyl-amino)-but-2-enyloksy]-fenyl]-(4-jod-fenyl)-metanon som overføres til hydrokloridet, smp. 152-153°C, i) fra 1-(3-fluor-4-metoksy-fenyl)-5-metyl-heksan-l-on (avsnitt G), via 1-(3-fluor-4-hydroksy-fenyl)-5-metyl-heksan-l-on og (E)-1-[4-brom-but-2-enyloksy]-3-fluor-fenyl] -5-metyl-heksan-l-on og reaksjon med N-allyl-metyl-amin
(E)-1-[4-(allyl-metyl-amino)-but-2-enyloksy]-3-fluor-fenyl]-5-metyl-heksan-l-on som isoleres som hydrobromid, smp. 106-107°C, j) fra 4-(3-fluor-4-hydroksy-benzoyl)-benzonitril (avsnitt K) med (E)-1,4-dibrombuten, via (E)-4-[4-(4-brom-but-2-enyloksy)-3-fluor-benzoyl]-benzonitril og reaksjon med N-allyl-metylamin (E)-[4-[4-(allyl-metyl-amino)-but-2-enyloksy]-3-fluor-benzoyl]-benzonitril, MS: m/e 364 (M+) , k) fra 4-(4-hydroksy-benzoyl)-benzonitril med (E)-l,4-dibrombuten, via (E)-4-[4-(4-brom-but-2-enyloksy)-benzoyl]-benzonitril og reaksjon med N-allyl-metylamin (E)-4-[4-[4-(allyl-metyl-amino)-but-2-enyloksy]-benzoyl]-benzonitril, MS: m/e 346 (M+) , 1) fra (2, 6-dif luor-fenyl) - (3-f luor-4-hydroksy-f enyl) - metanon (avsnitt I) og (E)-1,4-dibrombuten, via (E)-[4-[4-brom-but-2-enyloksy] -3-f luor-fenyl] - (2, 6-dif luor-f enyl) - metanon og reaksjon med N-allyl-metylamin (E) - [4- [4- (allyl-metyl-amino) -but-2-enyloksy] -3-fluor-fenyl]-(2,6-difluor-fenyl)-metanon som isoleres som hydrobromid, smp. 162°C,
m) fra 1-(4-hydroksy-fenyl)-5-metyl-heks-4-en-1 -on (avsnitt C) og (E) -1,4-dibrombuten, via (E)-1-[4-[4-brom-but-2-enyloksy]-fenyl]-5-metyl-heks-4-en-l-on og reaksjon med N-ally1-metylamin
(E) -1- [4- [4- (allyl-metyl-amino) -but-2-enyloksy] -fenyl] -5-metyl-heks-4-en-l-on som isoleres som fumarat, MS: m/e 327
(M+) ,
n) fra (4-brom-fenyl) - (2-fluor-4-hydroksy-fenyl) -metanon (avsnitt Jb) og (E)-1,4-dibrombuten, via (E) -[4-[4-brom-but-2-enyloksy] -2-fluor-fenyl] - (4-brom-fenyl) -metanon og reaksjon med N-allyl-metyl-amin (E)-[4-[4-(allyl-metyl-amino)-but-2-enyloksy]-2-fluor-fenyl] - (4-brom-f enyl) -metanon som isoleres som hydroklorid, smp. 88-92°C,
o) fra 4-fluor-4'-hydroksy-benzofenon og (E)-1,4-dibrombuten, via (E) - [4-[4-brom-but-2-enyloksy]-fenyl] - (4-fluor-fenyl) -metanon og reaksjon med N-allyl-metylamin
(E)-[4-[4-(allyl-metyl-amino)-but-2-enyloksy]-fenyl]- (4-fluor-fenyl)-metanon som isoleres som hydroklorid, MS: m/e
338 (M-H+) ,
p) fra 1- (3-fluor-4-hydroksy-fenyl)-6-metyl-hept-5-en-2-on (avsnitt D) og (E)-1,4-dibrombuten, via (E)-1-[4-[4-brom-but-2-enyloksy] -3-fluor-fenyl]6-metyl-nept-5-en-2-on og reaksjon med N-allyl-metylamin (E)-1- [4- [4-(allyl-metyl-amino)-but-2-enyloksy]-3-fluor-fenyl]-6-metyl-hept-5-en-2-on som isoleres som fumarat, MS: m/e 359 (M+) ,
q) fra 1-(4-brom-fenyl)-2-(3-fluor-4-hydroksy-fenyl)-etanon (avsnitt E) og (E)-1,4-dibrombuten, via (E)-2-[4-[4-brom-but-2-enyloksy]-3-fluor-fenyl] -(4-brom-fenyl)-etanon og reaksjon med N-allyl-metylamin
(E)-2-[4-[4-(allyl-metyl-amino) -but-2-enyloksy]-3-fluor-fenyl]-(4-brom-fenyl)-etanon som isoleres som hydroklorid, smp. 114-116°C, r) fra 1-(4-brom-fenyl)-2-(4-hydroksy-fenyl)-etanon (avsnitt Fa) og (E)-1,4-dibrombuten, via (E)-2-[4-(4-brom-but-2-enyloksy)-fenyl]-1-(4-brom-fenyl)-etanon og reaksjon med N-allyl-metylamin (E)-2-[4- [4-(allyl-metyl-amino) -but-2-enyloksy)-fenyl]-1-(4-brom-fenyl)-etanon som isoleres som hydroklorid, smp. 150-153°C, s) fra 4'-brom-4-hydroksybenzofenon og (E)-1,4-dibrombuten, via (E)- [4- (4-brom-but-2-enyloksy)-fenyl]-(4-brom-fenyl)-metanon og reaksjon med N-etyl-metylamin (E) - (4-brom-fenyl) - [4- [4- (etyl-metyl-amino) -but-2-enylok-sy]-f enyl]-metanon-hydrobromid, smp. 171,5°C (spaltning).
Eksempel 10
Analogt med eksempel 4c) oppnår man ved behandling av 4'-brom-metyl-2-klor-p-bromfenyl-4-bifenylketonet med N-allyl-metylamin
4'-[(allylmetylamino)metyl]-2-klor-4-bifenylyl-p-bromfe-nylketon, MS: m/e 453 (M<+>, 1 Br) .
Eksempel 11
Analogt med eksempel 8 oppnår man fra 5-brom-2-metyl-penten og 4'-[(N-allylmetylamino)metyl]-N-metyl-4-bifenylkarboks-amid
4'- [ (allylmetylamino)metyl]-4-bifenyl-4-metyl-3-pentenyl-keton, MS: m/e 347 (M+) .
Galenisk eksempel
En hårdgelatinkapsel inneholder f.eks. 3,125, 6.25, 12,5, 25 eller 50 mg av en forbindelse med formel I eller et salt derav og finkrystallinsk laktose inntil en total fyllvekt på 580-590 mg.
Claims (9)
1. Anvendelse av forbindelser med formel
hvor
en av R<1> og R<2> er <C>1_7-alkyl og den andre er C1_7-alkyl eller <C>2_6-alkenyl-metyl,
L er C-L.-^-alkylen eller C2_11-alkenylen eventuelt bundet
til fenylgruppen via et O-atom, eller L er 1,4-
fenylen,
n =0 eller, i tilfellet L inneholder et O-atom, betyr n 0 eller 1,
Q er C1_7-alkyl, C2_10-alkenyl eller en gruppe med formel Q' :
R er H, halogen, CF3, CN eller N02,
R<3> og R4 er H, <C>1_4-alkyl eller halogen og
R<5> er H eller, i tilfellet R er H, H eller halogen,
og deres farmasøytisk akseptable syreaddisjonssalter ved fremstilling av kolesterolsenkende legemidler.
2. Anvendelse av forbindelsene ifølge krav 1,
hvor n = 0 og R<5> er H.
3. Anvendelse av forbindelser ifølge krav 1 eller 2, hvor a) R<1> er metyl og R<2> er metyl, etyl, propyl eller allyl og/eller b) L er gruppen -CH=CHCH20-, spesielt i trans-form, - (CH2)5-, - (CH2)6-, - (CH2) 30-, - (CH2)50, - (CH2)60- eller 1,4-fenylen og/eller c) R<3> er H, Br, Cl, F eller CH3 og/eller d) Q er propyl, pentyl, isoheksyl, 4-metyl-3-pentenyl eller 2,6-dimetyl-5-heptyl eller e) Q er en gruppe Q', hvor R er H, Br, Cl, F, I, CF3, CN eller N02 og/eller R<4> er H, Br, Cl, F, eller CH3 og/eller R<5> er H eller F.
4. Anvendelse av forbindelser ifølge krav 1 eller 2, hvor a) L er C5_1:L-alkylen eller C5.11-alkylenoksy, spesielt -(C<H>2)6- eller - (CH2) 50- ; C3_11-alkenylenoksy, spesielt -CH=CHCH20-, eller 1,4-fenylen og/eller b) R<3> er H eller halogen og/eller c) Q er C2.10-alkenyl, spesielt 4-metyl-3-pentenyl; eller en gruppe Q' , hvor R er CN, N02 eller halogen, spesielt Br, Cl eller F, og R<4> er H eller Cl.
5. Anvendelse av forbindelser ifølge krav 4,
hvor a) R<1> er metyl og R<2> er metyl eller allyl og/eller b) L er -(CH2)50-, -CH=CHCH20- eller 1,4-fenylen og/eller c) R<3> er H eller F og/eller d) Q er 4-metyl-3-pentenyl eller en gruppe Q' , hvor R er Br, Cl, CN eller N02, R<4> er H eller Cl og R<5> er H.
6. Anvendelse av følgende forbindelser med formel I ifølge krav 1 eller 2: trans-4-[[4-(allylmetylamino) -2-butenyl] oksy]-4'-brom-benzofenon, trans-4- [ [4- (allylmetylamino) -2-butenyl] oksy] -4' - nitrobenzofenon, p- [ [4' - [ (allylmetylamino)metyl] -4-bifenylyl] karbo-nyl] benzonitril, 2-klor-4-nitrofenyl-4'-[(dimetylamino)metyl]-4-bife-nylyl-keton, trans-4-[[4-(allylmetylamino)-2-butenyl]oksy] -2',4' - diklorbenzofenon.
7. Anvendelse av følgende forbindelser med formel I ifølge krav 1: [4- [6- (allyl-metyl-amino) -heksyloksy] -fenyl] - (4-brom-fenyl)-metanon, [4-[6-(allyl-metyl-amino)-heksyloksy] -3-fluor-fenyl]-(4-brom-fenyl)-metanon, [4- [6- (allyl-metyl-amino) -heksyloksy] -2-f luor-f enyl] - (4-brom-fenyl)-metanon, (E) - [4- [4- (allyl-metyl-amino) -but-2-enyloksy] -3-fluor-fenyl] -(4-brom-fenyl)-metanon, (E)-1-[4- [4-(allyl-metyl-amino)-but-2-enyloksy]-fenyl]-5-metyl-heks-4-en-l-on, (E)-[4-[4-(allyl-metyl-amino)-but-2-enyloksy]-2-fluor-fenyl] -(4-brom-fenyl)-metanon.
8. Forbindelsene med formel I ifølge krav 1 eller 2 fra gruppen av følgende: 4- [ [6- (allylmetylamino) heksyl] oksy] -3-klorbenzof enon 4- [ [6- (allylmetylamino) heksyl] oksy] -3,4' -dibromben-zof enon, 4- [ [4- (allylmetylamino) -2-butenyl] oksy] -3,4' -dibrom-benzof enon, 3- klor-4' - jod-4- [ [6- (allylmetylamino) heksyl] oksy] - benzofenon, 4' -brom-3-klor-4- [ [6- (allylmetylamino) heksyl] oksy] - benzofenon, 2, 4- [ [ (4-dimetylamino) -2-butenyl] oksy] - 3,4' -dibrom-benzof enon, 4- [ [4- (dimetylamino) -2-butenyl] oksy] -3-klorbenzof enon, 4' -brom-3-klor-4- [ [6- (dimetylamino) heksyl] oksy] benzof enon, 3, 4-diklorf enyl-4' - [ (dimetylamino) metyl] -4-bif enyl-ylketon, 4' - [ (allylmetylamino) metyl] -4-bif enylyl-3, 4-diklor-fenylketon, (RS) -4' - (dimetylaminometyl) -4-bif enyl-2, 6-dimetyl-5-heptenylketon, p-bromf enyl-2-klor-4' - [ (dimetylamino) metyl] -4-bif e-nylylketon, 4' - [ (dimetylamino)metyl] -4-bifenylyl-propylketon.
9. Forbindelsene med formel I ifølge krav 1 fra gruppen av følgende: [4- [6- (allyl-metyl-amino) -heksyloksy] -fenyl] - (4-brom-fenyl)-metanon, [4- [4- (allyl-metyl-amino) -butoksy] -fenyl] - (4-brom-fenyl)-metanon, [4- [6- (allyl-metyl-amino) -heksyloksy] -3-f luor-f enyl] - (4-brom-fenyl)-metanon, [4- [6-(allyl-metyl-amino)-heksyloksy]-2-fluor-fenyl]-(4-brom-fenyl)-metanon, (E)- [4-[4-(allyl-metyl-amino)-but-2-enyloksy]-fenyl]-(4-trifluormetyl-fenyl)-metanon, (E)- [4-[4-(allyl-metyl-amino)-but-2-enylbksy]-3-fluor-fenyl]-(4-brom-fenyl)-metanon, (E) -1- [4- [4-(allyl-metyl-amino)-but-2-enyloksy]-fenyl]-5-metyl-heksan-l-on, (E)- [4-[4-(allyl-metyl-amino)-but-2-enyloksy]fenyl]-(4-jod-fenyl)-metanon, (E) -1- [4- (allyl-metyl-amino)-but-2-enyloksy]-3-fluor-fenyl]-5-metylheksan-l-on, (E)- [4-[4-(allyl-metyl-amino)-but-2-enyloksy]-3-fluor-benzoyl]-benzonitril, (E)-4- [4-[4-(allyl-metyl-amino)-but-2-enyloksy]-ben-zoyl] -benzonitril, (E) - [4- [4- (allyl-metyl-amino) -but-2-enyloksy] -3-fluor-fenyl]- (2,6-difluor-fenyl)-metanon, (E)-1-[4-[4-(allyl-metyl-amino)-but-2-enyloksy]-fenyl]-5-metyl-heks-4-en-l-on, (E) - [4- [4- (allyl-metyl-amino) -but-2-enyloksy] -2-fluor-fenyl]-(4-brom-fenyl)-metanon, (E)-[4-[4-(allyl-metyl-amino)-but-2-enyloksy]-fenyl]-(4-fluor-fenyl)-metanon, (E)-1-[4-[4-(allyl-metyl-amino)-but-2-enyloksy]-3-fluor-fenyl]-6-metyl-hept-5-en-2-on, (E) -2- [4- [4-(allyl-metyl-amino)-but-2-enyloksy]-3-fluor-fenyl]-1-(4-brom-fenyl)-etanon, (E)-2-[4-[4-(allyl-metyl-amino)-but-2-enyloksy)-fenyl]-1-(4-brom-fenyl)-etanon, (E)-(4-brom-fenyl)-[4-[4-(etyl-metyl-amino)-but-2-enyloksy]-fenyl]-metanon,
4'- [ (allylmetylamino)metyl] -2-klor-4-bifenylyl-p-bromfenylketon.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH210793 | 1993-07-14 | ||
| CH132094 | 1994-04-28 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO942606D0 NO942606D0 (no) | 1994-07-12 |
| NO942606L NO942606L (no) | 1995-01-16 |
| NO309924B1 true NO309924B1 (no) | 2001-04-23 |
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ID=25687322
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| NO942606A NO309924B1 (no) | 1993-07-14 | 1994-07-12 | Anvendelse av fenalkylaminer og nye fenylalkylaminer |
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| US (3) | US5495048A (no) |
| EP (1) | EP0636367B1 (no) |
| JP (1) | JP2519022B2 (no) |
| KR (1) | KR100312441B1 (no) |
| CN (1) | CN1087934C (no) |
| AT (1) | ATE191142T1 (no) |
| AU (1) | AU684507B2 (no) |
| CA (1) | CA2126518C (no) |
| CZ (1) | CZ288518B6 (no) |
| DE (1) | DE59409248D1 (no) |
| DK (1) | DK0636367T3 (no) |
| ES (1) | ES2144471T3 (no) |
| GR (1) | GR3033645T3 (no) |
| HU (1) | HUT70835A (no) |
| IL (1) | IL110254A (no) |
| NO (1) | NO309924B1 (no) |
| NZ (1) | NZ260968A (no) |
| PH (1) | PH31092A (no) |
| PT (1) | PT636367E (no) |
| RU (1) | RU2141942C1 (no) |
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| UA (1) | UA37199C2 (no) |
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| CA2190699A1 (en) * | 1995-12-08 | 1997-06-09 | Johannes Aebi | Tertiary amines |
| CA2190708A1 (en) * | 1995-12-08 | 1997-06-09 | Johannes Aebi | Aminoalkyl substituted benzo-heterocyclic compounds |
| WO2002006189A2 (en) * | 2000-07-18 | 2002-01-24 | F. Hoffmann-La Roche Ag | Aniline derivatives |
| PL361783A1 (en) | 2000-08-16 | 2004-10-04 | F.Hoffmann-La Roche Ag | Novel aminocyclohexane derivatives |
| US6964974B2 (en) | 2000-09-08 | 2005-11-15 | Hoffmann-La Roche Inc. | 2,3-oxidosqualene-lanosterol cyclase inhibitors |
| US6503907B2 (en) * | 2000-11-28 | 2003-01-07 | Hoffmann-La Roche Inc. | Indole and dihydroindole derivatives |
| US6706751B2 (en) | 2000-12-21 | 2004-03-16 | Hoffman-La Roche Inc. | Dihydroindole and tetrahydroquinoline derivatives |
| IL162104A0 (en) * | 2001-12-12 | 2005-11-20 | Hoffmann La Roche | Substituted cyclohexane derivatives |
| US7012077B2 (en) | 2001-12-20 | 2006-03-14 | Hoffmann-La Roche Inc. | Substituted cyclohexane derivatives |
| US6727277B1 (en) | 2002-11-12 | 2004-04-27 | Kansas State University Research Foundation | Compounds affecting cholesterol absorption |
| TW200524849A (en) * | 2003-07-02 | 2005-08-01 | Hoffmann La Roche | Hydroxyalkylamide derivatives |
| RU2006113550A (ru) * | 2003-09-22 | 2007-11-10 | Ф.Хоффманн-Ля Рош Аг (Ch) | Циклогексильные производные, замещенные аминоалкиламидами |
| JP2010509392A (ja) * | 2006-11-13 | 2010-03-25 | ファイザー・プロダクツ・インク | ジアリール、ジピリジニルおよびアリール−ピリジニル誘導体ならびにその使用 |
| CN108530390B (zh) * | 2017-03-06 | 2020-04-21 | 西南化工研究设计院有限公司 | 一种4-羟基二苯甲酮的烷基化方法 |
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| US3647863A (en) * | 1968-11-25 | 1972-03-07 | Richardson Merrell Inc | Aminoalkoxy-triphenyl ethylenes and the salts thereof |
| US3928449A (en) * | 1969-04-03 | 1975-12-23 | Sandoz Ag | Aminoalkoxy-terphenyls and the salts thereof |
| CA2016738A1 (en) * | 1989-06-08 | 1990-12-08 | Philippe Guerry | Substituted aminoalkylbenzene derivatives |
| CA2020888A1 (en) * | 1989-07-27 | 1991-01-28 | Philippe Guerry | Substituted aminoalkoxybenzene derivatives |
| US5214046A (en) * | 1989-07-27 | 1993-05-25 | Hoffmann-La Roche Inc. | Substituted aminoalkoxybenzene anti-fungicidal compositions and use |
| CA2044533A1 (en) * | 1990-06-29 | 1991-12-30 | Philippe Guerry | Substituted aminoalkylbiphenyl derivatives |
| US5239084A (en) * | 1990-06-29 | 1993-08-24 | Hoffmann-La Roche Inc. | Substituted aminoalkyl biphenyl compounds |
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Also Published As
| Publication number | Publication date |
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| HU9402085D0 (en) | 1994-09-28 |
| TW438774B (en) | 2001-06-07 |
| NO942606L (no) | 1995-01-16 |
| ES2144471T3 (es) | 2000-06-16 |
| US5574071A (en) | 1996-11-12 |
| UA37199C2 (uk) | 2001-05-15 |
| US5637771A (en) | 1997-06-10 |
| NZ260968A (en) | 1996-06-25 |
| CN1087934C (zh) | 2002-07-24 |
| CA2126518A1 (en) | 1995-01-15 |
| JP2519022B2 (ja) | 1996-07-31 |
| ATE191142T1 (de) | 2000-04-15 |
| CZ288518B6 (cs) | 2001-07-11 |
| EP0636367A1 (de) | 1995-02-01 |
| GR3033645T3 (en) | 2000-10-31 |
| HUT70835A (en) | 1995-11-28 |
| PT636367E (pt) | 2000-07-31 |
| AU6735894A (en) | 1995-01-27 |
| IL110254A0 (en) | 1994-10-21 |
| KR100312441B1 (ko) | 2002-10-31 |
| NO942606D0 (no) | 1994-07-12 |
| DK0636367T3 (da) | 2000-07-31 |
| US5495048A (en) | 1996-02-27 |
| KR960014096A (ko) | 1996-05-22 |
| CZ167694A3 (en) | 1995-01-18 |
| RU94026094A (ru) | 1996-05-20 |
| EP0636367B1 (de) | 2000-03-29 |
| AU684507B2 (en) | 1997-12-18 |
| DE59409248D1 (de) | 2000-05-04 |
| IL110254A (en) | 1998-04-05 |
| JPH0753479A (ja) | 1995-02-28 |
| RU2141942C1 (ru) | 1999-11-27 |
| PH31092A (en) | 1998-02-05 |
| CN1103781A (zh) | 1995-06-21 |
| CA2126518C (en) | 2006-11-21 |
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