DK165292B - 3-piperidincarboxylsyrer og 3-tetrahydropyridincarboxylsyrer, n-substituerede med alkylethere af oximer, samt farmaceutiske praeparater indeholdende forbindelserne - Google Patents
3-piperidincarboxylsyrer og 3-tetrahydropyridincarboxylsyrer, n-substituerede med alkylethere af oximer, samt farmaceutiske praeparater indeholdende forbindelserne Download PDFInfo
- Publication number
- DK165292B DK165292B DK231489A DK231489A DK165292B DK 165292 B DK165292 B DK 165292B DK 231489 A DK231489 A DK 231489A DK 231489 A DK231489 A DK 231489A DK 165292 B DK165292 B DK 165292B
- Authority
- DK
- Denmark
- Prior art keywords
- ethyl
- methanone
- oxime
- oxime hydrochloride
- thienyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 48
- 150000002923 oximes Chemical class 0.000 title description 33
- QMDFHZOGAYONLN-UHFFFAOYSA-N 1,2,3,4-tetrahydropyridine-3-carboxylic acid Chemical class OC(=O)C1CNC=CC1 QMDFHZOGAYONLN-UHFFFAOYSA-N 0.000 title description 2
- XJLSEXAGTJCILF-UHFFFAOYSA-N nipecotic acid Chemical class OC(=O)C1CCCNC1 XJLSEXAGTJCILF-UHFFFAOYSA-N 0.000 title description 2
- 125000005011 alkyl ether group Chemical group 0.000 title 1
- 239000000825 pharmaceutical preparation Substances 0.000 title 1
- -1 azido, cyano, fluoro, chloro, bromo, iodo, hydroxy Chemical group 0.000 claims description 71
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 27
- 229960003692 gamma aminobutyric acid Drugs 0.000 claims description 16
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 4
- 206010015037 epilepsy Diseases 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 210000003169 central nervous system Anatomy 0.000 claims description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 208000024891 symptom Diseases 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 123
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 99
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- 229910004298 SiO 2 Inorganic materials 0.000 description 29
- 238000000034 method Methods 0.000 description 17
- 239000002253 acid Substances 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 238000010992 reflux Methods 0.000 description 13
- 239000000203 mixture Substances 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 10
- 239000002904 solvent Substances 0.000 description 9
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 229910052681 coesite Inorganic materials 0.000 description 8
- 229910052906 cristobalite Inorganic materials 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 229910052682 stishovite Inorganic materials 0.000 description 8
- 229910052905 tridymite Inorganic materials 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 7
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- 239000007787 solid Substances 0.000 description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 125000004494 ethyl ester group Chemical group 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- DCGOJWYRBNDGMQ-GMUIIQOCSA-N (3r)-1-[2-[[(2-ethylphenyl)-(3-methylthiophen-2-yl)methylidene]amino]oxyethyl]piperidine-3-carboxylic acid;hydrochloride Chemical compound Cl.CCC1=CC=CC=C1C(C1=C(C=CS1)C)=NOCCN1C[C@H](C(O)=O)CCC1 DCGOJWYRBNDGMQ-GMUIIQOCSA-N 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 150000002367 halogens Chemical class 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 230000000144 pharmacologic effect Effects 0.000 description 5
- 230000009103 reabsorption Effects 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 230000002441 reversible effect Effects 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- VLELULRXBDLFPJ-XFULWGLBSA-N (3r)-1-[2-[bis(3-methylthiophen-2-yl)methylideneamino]oxyethyl]piperidine-3-carboxylic acid;hydrochloride Chemical compound Cl.C1=CSC(C(=NOCCN2C[C@@H](CCC2)C(O)=O)C2=C(C=CS2)C)=C1C VLELULRXBDLFPJ-XFULWGLBSA-N 0.000 description 4
- MKDJEJQEZYSAIN-UNTBIKODSA-N (3r)-1-[2-[bis(4-fluoro-2-methylphenyl)methylideneamino]oxyethyl]piperidine-3-carboxylic acid;hydrochloride Chemical compound Cl.CC1=CC(F)=CC=C1C(C=1C(=CC(F)=CC=1)C)=NOCCN1C[C@H](C(O)=O)CCC1 MKDJEJQEZYSAIN-UNTBIKODSA-N 0.000 description 4
- RPWCLFUNNRFLDQ-UHFFFAOYSA-N 1-[2-(benzhydrylideneamino)oxyethyl]piperidin-1-ium-3-carboxylic acid;chloride Chemical compound Cl.C1C(C(=O)O)CCCN1CCON=C(C=1C=CC=CC=1)C1=CC=CC=C1 RPWCLFUNNRFLDQ-UHFFFAOYSA-N 0.000 description 4
- OKWIEDLUSNRHRY-UHFFFAOYSA-N 1-[2-[bis(2-methylphenyl)methylideneamino]oxyethyl]-3,6-dihydro-2h-pyridine-5-carboxylic acid;hydrochloride Chemical compound Cl.CC1=CC=CC=C1C(C=1C(=CC=CC=1)C)=NOCCN1CC(C(O)=O)=CCC1 OKWIEDLUSNRHRY-UHFFFAOYSA-N 0.000 description 4
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- CZIAWXYEFQFNKZ-UNTBIKODSA-N Cl.C1=CSC(C(=NOCCN2C[C@@H](CCC2)C(O)=O)C=2C(=CC=CC=2)C)=C1C Chemical compound Cl.C1=CSC(C(=NOCCN2C[C@@H](CCC2)C(O)=O)C=2C(=CC=CC=2)C)=C1C CZIAWXYEFQFNKZ-UNTBIKODSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- XJLSEXAGTJCILF-RXMQYKEDSA-N (R)-nipecotic acid zwitterion Chemical compound OC(=O)[C@@H]1CCCNC1 XJLSEXAGTJCILF-RXMQYKEDSA-N 0.000 description 3
- JKJIXCWIPRTBLJ-UHFFFAOYSA-N 1-[2-[[(3-fluorophenyl)-(2-methylphenyl)methylidene]amino]oxyethyl]-3,6-dihydro-2h-pyridine-5-carboxylic acid;hydrochloride Chemical compound Cl.CC1=CC=CC=C1C(C=1C=C(F)C=CC=1)=NOCCN1CC(C(O)=O)=CCC1 JKJIXCWIPRTBLJ-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000009102 absorption Effects 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 229920001971 elastomer Polymers 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- VMHYWKBKHMYRNF-UHFFFAOYSA-N (2-chlorophenyl)-phenylmethanone Chemical compound ClC1=CC=CC=C1C(=O)C1=CC=CC=C1 VMHYWKBKHMYRNF-UHFFFAOYSA-N 0.000 description 2
- MHZJWHBLWIWKAW-UHFFFAOYSA-N (2-methylphenyl)-(3-methylthiophen-2-yl)methanone Chemical compound C1=CSC(C(=O)C=2C(=CC=CC=2)C)=C1C MHZJWHBLWIWKAW-UHFFFAOYSA-N 0.000 description 2
- TXQKSMSLZVKQBI-UHFFFAOYSA-N 1-(4,4-diphenylbut-3-enyl)-3-piperidinecarboxylic acid Chemical compound C1C(C(=O)O)CCCN1CCC=C(C=1C=CC=CC=1)C1=CC=CC=C1 TXQKSMSLZVKQBI-UHFFFAOYSA-N 0.000 description 2
- IBYHHJPAARCAIE-UHFFFAOYSA-N 1-bromo-2-chloroethane Chemical compound ClCCBr IBYHHJPAARCAIE-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 2
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 2
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- 208000002193 Pain Diseases 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
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- 238000005804 alkylation reaction Methods 0.000 description 2
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 2
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- 238000001816 cooling Methods 0.000 description 2
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- 125000004093 cyano group Chemical group *C#N 0.000 description 2
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- 230000003111 delayed effect Effects 0.000 description 2
- QTDZOWFRBNTPQR-UHFFFAOYSA-N guvacine Chemical compound OC(=O)C1=CCCNC1 QTDZOWFRBNTPQR-UHFFFAOYSA-N 0.000 description 2
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- DNYZBFWKVMKMRM-UHFFFAOYSA-N n-benzhydrylidenehydroxylamine Chemical compound C=1C=CC=CC=1C(=NO)C1=CC=CC=C1 DNYZBFWKVMKMRM-UHFFFAOYSA-N 0.000 description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 2
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- NCLNHRBANMOMAJ-UHFFFAOYSA-N (3-azidophenyl)-phenylmethanone Chemical compound [N-]=[N+]=NC1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 NCLNHRBANMOMAJ-UHFFFAOYSA-N 0.000 description 1
- SHULEACXTONYPS-UHFFFAOYSA-N (3-hydroxyphenyl)-phenylmethanone Chemical compound OC1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 SHULEACXTONYPS-UHFFFAOYSA-N 0.000 description 1
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- NRIBYFYMKIFKPV-UNTBIKODSA-N (3r)-1-[2-[[(3-methoxyphenyl)-(4-methylthiophen-2-yl)methylidene]amino]oxyethyl]piperidine-3-carboxylic acid;hydrochloride Chemical compound Cl.COC1=CC=CC(C(=NOCCN2C[C@@H](CCC2)C(O)=O)C=2SC=C(C)C=2)=C1 NRIBYFYMKIFKPV-UNTBIKODSA-N 0.000 description 1
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- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- MNGHDLMVLNQNAB-OAQYLSRUSA-N ethyl (3r)-1-[2-(benzhydrylideneamino)oxyethyl]piperidine-3-carboxylate Chemical compound C1[C@H](C(=O)OCC)CCCN1CCON=C(C=1C=CC=CC=1)C1=CC=CC=C1 MNGHDLMVLNQNAB-OAQYLSRUSA-N 0.000 description 1
- CYMHSSPOIQTRGM-FSRHSHDFSA-N ethyl (3r)-1-[2-[bis(4-fluoro-2-methylphenyl)methylideneamino]oxyethyl]piperidine-3-carboxylate;hydrochloride Chemical compound Cl.C1[C@H](C(=O)OCC)CCCN1CCON=C(C=1C(=CC(F)=CC=1)C)C1=CC=C(F)C=C1C CYMHSSPOIQTRGM-FSRHSHDFSA-N 0.000 description 1
- PJDLDZFCAORHJK-FYZYNONXSA-N ethyl (3s)-1-[2-[[(2-methylphenyl)-(3-methylthiophen-2-yl)methylidene]amino]oxyethyl]piperidine-3-carboxylate;hydrochloride Chemical compound Cl.C1[C@@H](C(=O)OCC)CCCN1CCON=C(C=1C(=CC=CC=1)C)C1=C(C)C=CS1 PJDLDZFCAORHJK-FYZYNONXSA-N 0.000 description 1
- FACCHUVAUXAMKI-UHFFFAOYSA-N ethyl 1-[2-[[(2-chlorophenyl)-phenylmethylidene]amino]oxyethyl]-3,6-dihydro-2h-pyridine-5-carboxylate;hydrochloride Chemical compound Cl.C1C(C(=O)OCC)=CCCN1CCON=C(C=1C(=CC=CC=1)Cl)C1=CC=CC=C1 FACCHUVAUXAMKI-UHFFFAOYSA-N 0.000 description 1
- DQYOSZBIJVNWER-UHFFFAOYSA-N ethyl 1-[2-[[(2-methylphenyl)-(3-methylthiophen-2-yl)methylidene]amino]oxyethyl]-3,6-dihydro-2h-pyridine-5-carboxylate;hydrochloride Chemical compound Cl.C1C(C(=O)OCC)=CCCN1CCON=C(C=1C(=CC=CC=1)C)C1=C(C)C=CS1 DQYOSZBIJVNWER-UHFFFAOYSA-N 0.000 description 1
- OARBKQWSPSIBSH-UHFFFAOYSA-N ethyl 1-[2-[bis(2-methylphenyl)methylideneamino]oxyethyl]-3,6-dihydro-2h-pyridine-5-carboxylate;hydrochloride Chemical compound Cl.C1C(C(=O)OCC)=CCCN1CCON=C(C=1C(=CC=CC=1)C)C1=CC=CC=C1C OARBKQWSPSIBSH-UHFFFAOYSA-N 0.000 description 1
- HLSHZLJNHGUNKK-UHFFFAOYSA-N ethyl 1-[2-[bis(4-fluoro-2-methylphenyl)methylideneamino]oxyethyl]-3,6-dihydro-2h-pyridine-5-carboxylate;hydrochloride Chemical compound Cl.C1C(C(=O)OCC)=CCCN1CCON=C(C=1C(=CC(F)=CC=1)C)C1=CC=C(F)C=C1C HLSHZLJNHGUNKK-UHFFFAOYSA-N 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000003958 fumigation Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- DLQPOZVMYHDIBA-UHFFFAOYSA-N n-(2-chloroethoxy)-1,1-diphenylmethanimine Chemical compound C=1C=CC=CC=1C(=NOCCCl)C1=CC=CC=C1 DLQPOZVMYHDIBA-UHFFFAOYSA-N 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- LEVJVKGPFAQPOI-UHFFFAOYSA-N phenylmethanone Chemical compound O=[C]C1=CC=CC=C1 LEVJVKGPFAQPOI-UHFFFAOYSA-N 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 210000000063 presynaptic terminal Anatomy 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000725 suspension 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
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Description
i
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5 Nærværende opfindelse angår nye 3-piperidincarboxylsyrer eller 3-tetrahydropyridincarboxy1syrer, N-substituerede med alkylethere af oximer, og salte deraf, hvilke forbindelser har den i krav 1 angivne almene formel I. Opfindelsen angår endvidere farmaceutiske præparater indehol-10 dende forbindelserne- I de seneste år er der blevet udført megen farmakologisk forskning angående 6-aminosmørsyre (herefter kaldt GABA), som er en neurotransmissionsinhibitor i det manunale cen-15 tralnervesystem.
Inhibering af tilbageabsorptionen af GABA resulterer i øget tilgængelighed af denne neurotransmissionsinhibitor i den synaptiske kløft, hvilket medfører forøget GABA aktivitet.
20 Øget GABA aktivitet, kan være nyttig ved behandling af for eksempel iltmangel, smerte og epilepsi såvel som ved muskel- og bevægelsesforstyrrelser (se for eksempel Progress in Medicinal Chemistry - 22 (1985) 68^-112 (udgivet af G.P. Ellis og G:B. West, Elsevier Science Publishers, B«V~.).
25
En velkendt og stærk inhibitor af tilbageabsorption af , GABA fra den synaptiske kløft i præsynaptiske nerveender og glialceller er, for eksempel, piperidin-3-carboxylsyre (nipecotinsyre). Dog er det en relativ polær forbindelse 30 og derfor ude af stand til at passere blod-hjernebarrier- en, og piperiden-3-carboxylsyre har derfor ikke nogen praktiske anvendelighed som lægemiddel. 1 US patentbeskrivelserne nr. 4,383,999 og nr. 4,514,414 35 (SmithKline Beckman Corporation) og i de danske patentansøgninger nr. 1008/87 (som har ført til DK 156.398B) og 38/87 (Novo Industri A/S) omfatter kravene aryl og 2
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heteroarylderivater af N- (4,4-disubstituterede-3-buten-l-yl )azaheterocycliske carboxylsyrer som inhibitorer af tilbageabsorptionen af GABA. Endvidere, hævdes det i dansk patentansøgning nr. 5280/86 (Warner-Lambert Company) 5 at l-aryloxyalkylpyridin-3-carboxylsyrer også er inhibitorer af tilbageabsorptionen af GABA.
Ifølge J.Pharm.Exp. Therap. 228 (1984) 109 er, N-(4,4-diphenyl - 3 -buten-1 -yl) nipecotinsyre (betegnet SK&F 10 89976A), N-(4,4-diphenyl-3-buten-l-yl)guvacin (betegnet SK&F 100330A), N-(4,4-diphenyl-3-buten-l-yljhomo- 6-prolin (betegnet SK&F 100561) og N-(4-phenyl-4-(2-thienyl)-3-buten-l-yl)nipecotinsyre (betegnet SK&F 100604J) orale inhibitorer af GABA tilbageabsorption.
15 Disse data er opsummeret i Epilepsy Res. 1 (1987) 77-93.
Guvacin er 1,2,5,6-tetrahydro-pyridin-3-carboxylsyre og homo-B-prolin er pyrrolidin-3-eddikesyre.
20 Nærværende opfindelse angår nye O-substituerede oximer hvor 0-substituenten - indeholder ét derivat af piperidin- 3-carboxylsyre (nipecotinsyre) med den generelle formel
II. Forbindelserne ifølge opfindelsen, der således adskiller sig fra de ovennævnte kendte forbindelser: ved at 25 piperidin-3-carboxylsyren er substitueret med en O-substitueret oxim, har den generelle formel I
/0-(CH2)nCH(R3)<CH2)mR4
30 A=N
(I) hvor A er R1^
35 .C eller ' CH-CH
ΈΓ IT
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3 1 2 hvor R og R er identiske eller forskellige og hver betegner furanyl, imidazolyl, phenyl, pyrazolyl, pyridinyl, pyrrolyl, thienyl eller 1,2,4-triazolyl. Hver af disse kan valgfrit være substitueret med en, to, eller tre sub-5 stituenter udvalgt fra gruppen bestående af lavere alkoxy, azido, cyano, halogen, hydroxy, lavere alkyl, nitro og 3 trifluormethyl. R betegner hydrogen eller lavere alkyl 4
og n og m er uafhængigt af hinanden 0, 1 eller 2. R betegner en cyklisk aminosyredel med den generelle formel 10 II
r6 λΤχ5 —N V-R (II) 15 '-' 5 6 hvor R betegner hydrogen eller hydroxy, R betegner hy- 5 6 drogen eller R sammen med R betegner en yderligere 9 9 20 binding, X betegner--NH^ eller R , hvor R betegner hydroxy eller alkoxy, eller er farmaceutisk-acceptable syre- 9 additionssalte eller, hvis R er hydroxy, også farmaceutisk-acceptable metalsalte deraf. Forbindelserne med formel I har en større lipophilicitet - og dermed en bed-25 re adgang til hjernen - såvel som en betydeligt højere affinitet til GABA tilbageabsorptionsstederne sammenlignet med de aminosyrer som dé er afledt af (nipecotinsyre og guvacin), og de har derfor interessante og nyttige farmakologiske egenskaber.
30
Det er blevet påvist, at de nye forbindelser med den generelle formel I udviser inhiberende egenskaber på tilbage-absorptionen af GABÅ og har nyttige farmakologiske egenskaber i forbindelse med centralnervesystemet, f.eks. at 35 de forårsager en selektiv forøgelse af GABA aktivitet. Forbindelser med formel' I kan bruges til behandling af f.eks. smerte, angst, epilepsi og visse muskel- og bevæg- 4
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elsesforstyrrelser. De kan også bruges som sedativer og sovemidler.
1 2 I formel I vælges mindst en af grupperne R og R som er 5 identiske eller forskellige, og som eventuelt kan være substitueret, fortrinsvis fra gruppen bestående af furanyl, phenyl, pyrazolyl, pyrrolyl, thienyl og 1,2,4-triazolyl, mere foretrukket fra gruppen bestående af phenyl, pyrrolyl og thienyl.
10 1 2 I definitionen af R og R er furanyl 2-furanyl eller 3-furanyl; imidazolyl er 2-imidazolyl, 4-imidazolyl eller 5-imidazolyl; pyrazolyl er 3-pyrazolyl, 4-pyrazolyl eller 5-pyrazolyl; pyridyl er 2-pyridyl, 3-pyridyl eller 4-15 pyridyl; pyrrolyl er 2-pyrrolyl; thienyl er 2-thienyl eller 3-^thienyl og 1,2,4-triazolyl er l,2,4-triazol-3-yl eller l,2,4-triazol-5-yl.
i
Substituenterne, der. eventuelt vælges til øgrupperne. R og/ 2 20 eller R er fortrinsvis lavere., alkoxy, azido, cyano,: halogen, hydroxy, lavere alkyl eller trifluoromethyl, helst lavere alkoxy, halogen eller lavere alkyl. Benævnelsen halogen betegner i denne forbindelse fluor, chlor, brom og iod, fortrinsvis fluor, chlor og brom, og helst 25 fluor og chlor.
3 R er fortrinsvis hydrogen, methyl eller ethyl,, helst 3 er R hydrogen.
30 Fortrinsvis er n + m = 0, 1 eller 2, helst er n + m = 1.
5 R er fortrinsvis hydrogen eller repræsenterer sammen med g R° yderligere en binding.
6 5 35 R- er hydrogen eller repræsenterer sammen med R.....
yderligere en binding.
9 5
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X er fortrinsvis R .
9 9 R er hydroxy eller alkoxy, fortrinsvis er R hydroxy, g methoxy eller ethoxy; helst er R hydroxy.
5
Ved definitionen af forbindelserne ifølge formel I betegner udtrykket lavere alkyl når det bruges alene - medmindre andet er indikeret - en alkylgruppe med højst 4 carbon atomer, for eksempel methyl, ethyl, propyl, isopropyl, 10 cyclopropyl eller tert-butyl, hvor de foretrukne grupper er methyl, ethyl og cyclopropyl. Brugt ved kombinationer som alkoxy, alkylthio og alkylamino betegner udtrykket "lavere alkyl" ligeledes en alkylgruppe med ikke mere end 4 carbonatomer, fortrinsvis methyl og ethyl, således at 15 de foretrukne kombinationer er henholdsvis methoxy, ethoxy, methylthio, ethylthio, methylamino og ethylamino.
Eksempler på specifikke og foretrukne forbindelser med formel I er som følger; • 20 (R)-Diphenylmethanon 0[2-(3-carboxypiperidin-l-yl)- ethyl]-oxim (1) (R)-(2-Methylphenyl)-(3-methyl-2-thienyl)methanon 0[2-(3-25 carboxypiperidin-l-yl)ethyl]oxim hydrochlorid (2) (R)-Bis(3-methyl-2-thienyl)methanon O-[2-(3-carboxypiperi-din-l-yl)ethyl]oxim hydrochlorid (3) 30 (R)-(2-Ethylphenyl)-(3-methyl-2-thienyl)methanon 0-[2-(3- carboxypiperidin-1-yl)ethyl]oxim hydrochlorid (4) <R)-(3-Methyl-2^thienyl)- (2-thiényl)methanon 0-[2-(3'-car-boxypiperidin-1-yl)éthyl]oxim (5) (R)-(2-Méthylphényl)-{3-methyl-2-thienyl)methanon O-[2-(3-carboxypiperidin-1-y1)ethyl]oxim hydrochlorid (10) 35 6
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Diphenylmethanon 0-[2-(3-carboxypiperidin-l-yl)ethyl]-oxim hydrochlorid (25) (2-Methylphenyl)-(3-methyl-2-thienyl )methanon O- [2-(3-car-5 boxypiperidin-l-yl)ethyl] oxim hydrochlorid (26)
Diphenylmethanon 0- [ 2- (3 -carboxy-1,2,5,6 -tetrahydropyri-din-l-yl)ethyl]oxim (45) 10 (2-Methylphenyl)phenylmethanon 0-[2-(3-carboxy-l,2,5,6-tetrahydropyridin-l-yl)ethyl]oxim hydrochlorid (50) (3-Fluorphenyl)-(2-methylphenyl Jmethanon O- [2-(3-carboxy- 1.2.5.6- tetrahydropyridin-1 -yl) ethyl ] oxim hydrochlorid 15 (51) (R)-Bis( 4-fluor-2-methylphenyl )methanon O-[2-(3-carboxy-piperidin-l-yl)ethyl]oxim hydrochlorid (53) 20 (2;4rDichlorphenyl)-(3-methyl-2-thienyl.)methanon 0- [2- (3 -carboxy-1,2,5,6 -tetrahydropyridin-1 -yl) ethyl ] oxim hydrochlorid (58):
Bis(2-methylphenyl)methanon 0-[2-(3-carboxy-l,2,5,6-tetra-25 hydropyridin-l-yl)ethyl]oxim hydrochlorid (64) (2-Chlorphenyl) phenyl-methanon 0- [ 2- (3-ethoxycarbonyl- 1.2.5.6- tetrahydropyTidin-l-yl)ethyl]oxim hydrochlorid (76) 30 og farmaceutisk-acceptable syreadditionssalte eller metalsalte deraf.
Forbindelserne med formlen I kan forekomme som geometris-35 ke bg optiske isomere-og alle isomere og· blandinger heraf er inkluderet heri. Isomere former kan separeres ved brug af standardmetoder såsom kromatografiske metoder eller
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7 fraktioneret krystallisation af salte med optisk aktive syrer eller baser.
Farmaceutisk-acceptable syreadditionssalte af forbindelser 5 med formlen I inkluderer dem, der er afledt fra uorganiske eller organiske syrer såsom saltsyre, brombrintesyre, svolvsyre, fosforsyre, eddikesyre, mælkesyre, maleinsyre, ftalsyre, og fumarsyre.
10 Forbindelserne med den generelle formel I kan fremstilles ved følgende konventionelle metoder:
Metode A: 15' /0H 0-(CH2)nCH(R3)(CH ) R4
A—N + Y(CH2)nCH(RJ)(CH2)BR4 -> A«»K
20 · (V) (VI) (I) 25 Én oxim med formlen V, hvor A er som ovenfor defineret, bringes til at reagere med en forbindelse med formlen VI, 3 4 hvor R , R , n og m er som ovenfor defineret, og Y er en egnet fraspaltelig gruppe såsom halogen eller p-toluen-sulphonat. Denne reaktion kan udføres i et polært, inært 30 opløsningsmiddel, f.eks. acetone, ethanol eller N,N-dime-thylformamid i nærvær af en base, f.eks. kaliumcarbonat eller natriumhydrid ved en temperatur op til refluxtempe-ratur i løbet af 1 til 72 timer.
35
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8
Metode B:
5 ym 3 0,CH2)nCH(R1)(CH2)mZ
A=~N + Y(CH_) CH(R ; (CH_) z -*> A*/
Z Π Z O
(V) (VII) (Vin) 10 S2H .0-(CH2)nCH(R1)(CH2)iR2 —» A=N (I) 15
En oxlm med formlen V, hvor A er som ovenfor defineret, alkyleres med en forbindelse med formlen VII hvor Y er en egnet reaktiv fraspaltelig gruppe, såsom brom eller £ toluensulfonat, og Z er en mindre labil gruppe, f.eks.
20 chlor (eller alternativt en gruppe såsom hydroxy, der kan ' ’ 3 konverteres til en reaktiv fraspaltelig gruppe), og R , n og m er som ovenfor defineret. Denne reaktion kan gennemføres i et egnet opløsningsmiddel, f.eks. acetone, ethanol, eller N,N- dimethylformamid i nærvær af en base, 25 f.eks. kaliumcarbonat eller natriumhydrid ved en temperatur op til refluxtemperatur i løbet af 1 til 72 timer.
Produktet VIII fra denne reaktion hvor A, R , n, m og Z
2 er som ovenfor defineret, bringes til at reagere med R H, 4 30 hvor R er en aminosyre eller et aminosyrederivat som ovenfor specificeret. Denne alkyleringsreaktion kan gennemføres i et inert opløsningsmiddel, såsom acetone, i nærvær af en base f.eks. kaliumcarbonat og en katalysator, f.eks. et alkalimetaliodid ved en temperatur op til refluxtempe-35 ratur i løbet af 1 til 95 timer.
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9
Metode C: .0-(CH,) CH(R3)(CH,) R4 / z n z m
At—O + H2N
(IX) (x)
O-(CH2)nCH(R3)(CH2)mR4 A
10 (I)
En keton med formlen IX, hvor A defineres som ovenfor, bringes til at reagere med en alkyl hydroxylamin af for-3 4 15 mel X, hvor R , R , n og m defineres som ovenfor i et inert opløsningsmiddel f.eks. ethanol eller pyridin eller en kombination af opløsningsmidler ved en temperatur op til refluxtemperatur i 1/2 - 12 timer.
20 Under visse omstændigheder kan det være nødvendigt at beskytte de i de ovenfor nævnte metoder anvendte mellempro- 4 dukter (f.eks. R Η, V eller VI) med egnede beskyttelsesgrupper. I tilfælde, hvor A indeholder, en aminogruppe, kan denne beskyttes ved acylering, og i tilfælde hvor A og/- 4 25 eller R indeholder en hydroxygruppe, kan denne beskyttes for eksempel ved acylering eller ved æterdannelse. Carbo- 4 xylsyregrupperne i R kan for eksempel esterificeres. Introduktion og fjernelse af sådanne gruppe er beskrevet i "Protective Groups in Organic Chemistry" J.F.W. McOrnie 30 ed. (New York, 1973).
Hvis der er fremstillet estere efter metoderne A-C, kan forbindelser med formlen I hvor X er OH fremstilles ved hydrolyse af estergruppen, fortrinsvis ved stuetemperatur 35 i en blanding af en vandig alkalimetalhydroxidopløsning og en alkohol såsom methanol eller ethanol, i omkring 1/2 til 6 timer.
10
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♦
Forbindelser med formlen V kan fremstilles ved at omsætte den tilsvarende keton eller aldehyd med hydroxylamin (eller hydrochloridet) i et solvent såsom ethanol eller pyri-din (se f.eks. W.E. Bachmann, Orq.Syn., (1967) 70; W.G.
5 Honey et al., J.Pharm.Sci., 66 (1977) 1602-1606; S. Rossi et al., Farm. Ed♦Sci., 24 (1969) 685-703 eller P.L. Huerta et al., J.Pharm. Sci. 66 (1977) 1120-4.
Forbindelser med formlen VI kan fremstilles ved reaktion 4 10 af den tilsvarende aminosyre (R H) beskyttet for eksempel som ethylesteren med en 2-haloethanol f.eks. 2-brometha-nol i nærvær af en base, f.eks. triethylamin eller et alkalimetalcarbonat. Et passende opløsningsmiddel kan være ethanol, acetone, methyl ethyl keton eller Ν,Ν-dime- 15 thylformamid. Dette efterfølges af halogenering med et egnet halogeneringsmiddel i en inert solvent ved reflux-temperatur i løbet af 1/2 til 24 timer. Et passende-opløsningsmiddel kan være toluen og halogeneringsmidlet kan for eksempel være thionylchlorid.
20 .
Forbindelser med formlen X kan fremstilles ved at 0-alky-lere f.eks. acetoneoxim med forbindelsen VI i et egnet opløsningsmiddel såsom benzen, pyridin eller ethanol i nærværelse af en base, f.eks. et alkalimetalkarbonat, 25 f:eks. ved refluxtemperatur i løbet af 1/2 - 24 timer.
Dette efterfølges af hydrolyse af produktet under sure forhold for eksempel ved brug af 10% saltsyre som opløsningsmiddel ved refluxtemperatur i 1/2 - 24 timer (se F. J. Villiani et al., J.Pharm.Sci., 58 (1969) 138-141; G.
30 Aichinger et al., Arznem.Forsch., 19 (1969) 838-845).
35 3
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11
Farmakologiske metoder
In vitro inhiberingen af [ H]-GABA absorption blev bedømt hovedsageligt ved Fjailands metode (Acta Pharmacol. Toxi-5 col» 42 (1978) 73-76). Hjernebarkvæv fra Wistar hanrotte blev let homogeniseret manuelt ved brug af en glas teflon homogenisator i 10 rumfang 0,32 M sucrose. Inkubering udførtes i en 40 mM tris HC1 buffer (pH 7,5 ved 30°C) indeholdende 120 nM NaCl, 9,2 nM KC1, 4 mM MgSO^, 2,3 mM CaC^ 10 og 10 mM glucose, i 60 minutter ved 30°C. Ligandkoncentra-tionen var 0,2 nM.
Værdier for inhibering af GABA absorption for nogle repræsentative forbindelser ifølge opfindelsen såvel som 15 for forbindelser fra den nærmest liggende kendte teknik er vist i nedenstående tabel 1 og la.
20 25 30 35 12
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13
Noter til Tabel 1 (1) A er R1^
5 R2/C
(2) A er rI
^CH-CH
R2^ 10 5 6 (3) R og R danner en binding Tabel la 3 15 Inhibering af [ H]-GABA optagelse for nogle kendte nipecotinsyre-derivater:
Reference IC50 in vitro '20 - USP 4,383,999, Eksempel 18 (A) 465 USP 4,383,999, Eksempel 1 (B) 353 DK-ans. 5280/86, Eksempel VII (C) 1439 25 DK-ans. 5280/86, Eksempel VIII (D) 312 (A) er l-[(E/Z)-4-phenyl-4-(2-thienyl)-3-butenyl]-3-piperidincarboxylsyre, HC1 30 (B) er l-(4,4-diphenyl-3-butenyl)-3-piperidincarboxyl- syre, HC1 (C) ér; 1-[3-(diphenylmethoxy)propyl]-3-piperidincarboxyl-syre, HC1 35 (D) er l-[2-[bis(4-chlorphenyl)methoxy]ethyl]-3-piperidin-carbbxylsyre, HC1
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14
Forbindelser med formlen I er nyttige, fordi de har farmakologiske aktivitet i mennesker som inhibitorer af GABA absorption.
5 For ovennævnte indikationer vil dosis variere afhængigt af den anvendte forbindelse med formel I, af indgiftsmetoden og af den ønskede behandling. Der opnås imidlertid almindeligvis tilfredsstillende resultater med en dosis på fra ca. 0,5 mg til ca. 1000 mg, fortrinsvis fra ca. 1 10 mg til ca. 500 mg af forbindelser med formel I, bekvemt givet fra 1 til 5 gange dagligt, eventuelt med forsinket frigivelse. Sædvanligvis omfatter doser egnede til oral indgivelse fra ca. 0,5 mg til ca. 1000 mg, fortrinsvis fra ca. 1 mg til ca. 500 mg af forbindelserne med formel 15 I, blandet med et farmaceutisk bærestof eller fortyndingsmiddel. Der er ikke konstateret nogen toksiske virkninger.
Forbindelserne med formel I kan indgives i form af farma-r ceutisk-acceptabelt syreadditionssalt, eller hvor det er 20 muligt, som et metal- eller et lavere alkylammoniumsalt. Sådanne salte udviser- nogenlunde samme grad af aktivitet som de frie baser.
Opfindelsen angår også farmaceutiske præparater omfatten-25 de en forbindelse med formlen I, eller et farmaceutiskacceptabelt salt deraf. Disse præparater indeholder også et farmaceutisk bærestof eller et fortyndingsmiddel. Præparaterne kan fremstilles ved konventionel teknik, eller foreligge i konventionelle former for eksempel kapsler 30 eller tabletter.
Det farmaceutiske bærestof, der anvendes, kan være et konventionelt1, fåst eller flydende bærestof. Eksempler på faste bærestoffer er lactose, terra alba, sucrose, talkum 35 , gelatine, agar, pektin, acacia,· magnesium stearat og stearinsyre. Eksempler på flydende bærestoffer er sirup, jordnøddeolié, olivenolie og vand.
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15
Ligeledes kan bærestoffet eller fortyndingsmidlet omfatte et hvilket som helst kendt materiale med forsinket frigivelse, såsom glyceryl monostearat eller glyceryl distearat, alene eller blandet med en voks.
5
Hvis der anvendes et fast bærestof til oral indgivelse, kan præparatet tabletteres, anbringes i en hård gelatinekapsel i pulver- eller pelletform eller i form af en tro-kisk eller pastil. Mængden af fast bærestof kan variere 10 en del, men vil fortrinsvis være fra ca. 25 mg til ca. 1 g. Hvis et flydende bærestof anvendes, kan præparatet foreligge i form af en mikstur, emulsion, blød gelatinekapsel eller steril injicerbar væske, såsom en vandig eller ikke-vandig flydende suspension.
15
De farmaceutiske præparater kan fremstilles efter de konventionelle teknikker inden for den farmaceutiske industri, der indebærer at blande, granulere og sammenpresse, eller på forskellig måde atblandeog opløse ingredienserne med 20 henblik på at give det ønskede slutprodukt.
Indgiftvejen kan være enhver, som effektivt transporterer den aktive-forbindelse til det rette eller ønskede sted, såsom- oral eller parenteral ,· idet den orale foretrækkes.
25
De i den foreliggende beskrivelse med eksempler og krav beskrevne egenskaber kan, både separat og i enhver kombination deraf, være væsentlige for udøvelsen af den foreliggende opfindelse i dens forskellige udførelsesformer.
30
Fremgangsmåden til fremstilling af forbindelserne med formlen I'og præparater indeholdende disse er yderligere beskrevet i de følgende eksempler; Eksemplerne illustrerer nogle foretrukne udførélsesformer. 1 35 det følgende betegner tic tyndtlagskromatografi, THF tetrahydrofuran, DMF er Ν,Ν-dimethylformamid, og smp. er
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16 smeltepunkt. Forbindelsernes struktur verificeres ved NMR og elementar analyse. Hvor smeltepunkter opgives, er disse ukorrigerede. Alle temperaturer er angivet i °C. De som startmaterialer anvendte forbindelser er enten kendte for-5 bindeiser, eller forbindelser som umiddelbart kan fremstilles ved i og for sig kendte fremgangsmåder. Søjlekromatografi blev udført under anvendelse af den af W.C. Still et al. i J.Org.Chem., 43 (1978) 2923-2925 beskrevne teknik på Merck kieselgel 60 (Art. 9385) silica gel.
10 ......
15 20 25 30 35
Eksempel 1 (metode A):
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17 (H)-Diphenylmethanon 0- [2-(3-carboxypiperidin-l-yl)-ethyl]oxim 5 - (R)-enantiomeren af ethylnipecotat (100 g , 0,64 mol) (A.M. Akkerman et al., Rec. Trav. Chim., 70 (1951), 899; G. Bettoni et al., Gazz. Chim. I tal., 102 (1972) 189) blev 10 blandet i tør acetone (300 ml) med 2-bromethanol (84.98 0, 0,68 mol), tørret, pulveriseret kaliumcarbonat (176.91 g, 1,28 mol) og kaliumiodid (21,58 g, 0,13 mol). Reaktionsblandingen blev omrørt ved stuetemperatur i 18 timer og ved refluxtemperatur i 24 timer. Filtrering og inddampning 15 af filtratet gav en olie, som blev oprenset ved destillation in vacuo (110-115°C, 0,1 mmHg), udbytte 72,17 g (56%). Tic rf 0,20 (Si02; dichloromethan/methanol 19/1).
Ovennævnte alkohol (19,86 g, 0,099 mol) blev opløst i 20 toluen (125 ml). En opløsning af thionylchlorid (14,16 g, 0,119 mol) i toluen (50 ml) blev tilsat dråbevis og reaktionsblandingen omrørtes véd stuetemperatur i 2 timer. Afkøling i et isbad efterfulgt af filtrering frembragte (R)-N-(2-chlorethyl)nipecotinsyreethylesterén som et fast 25 stof. En prøve blev omkrystalliseret af 2-propanol, smp.
187,5-194,5°C.
Til hydrocloridet af ovennævnte ester (2,56 g, 10 mmol), tilsattes tørret, pulveriseret kaliumcarbonat (5,53 g, 40 30 mmol), acetone (200 ml) og benzophenonoxim (3,94 g, 20 mmol). Suspensionen blev opvarmet ved reflux i 96 timer, afkølet og filtreret. Opløsningsmiddlet blev fjernet fra filtratet in vacuo og efterlod en remanens. Vand (100 ml) og ethylacetat (100 ml) tilsattes. Det vandige lag blev 35 separeret og yderligere ekstraheret med ethylacetat (2 x 100 ml). De samlede organiske ekstrakt blev tørret (MgSO^) og inddampet hvilket gav en brim olie (6;2 g). Denne olie
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18 blev oprenset med "flash"-kromatografi ved eluering med cyclohexan/ethylacetat (5/1) hvilket gav (R)-diphenylme-thanon 0- [ 2 - (3-ethoxycarbonylpiperidin-1-yl) ethyl ] oxim (2,66 g, 70%) som en gummi, tic rf 0,067 (Si02, cyclohex-5 an/ethylacetat 5/1).
Den ovennævnte ester (2,66 g, 6,99 mmol) blev opløst i ethanol (100 ml) og 10 N natriumhydroxidopløsning (6,99 ml) blev tilsat. Efter 2 timer ved stuetemperatur blev opløs-10 ningen afkølet i et isbad og pH blev indstillet til 3 med 4 N saltsyre. Ekstraktion med dichlormethan (3 x 50 ml), tørring (MgSO^) af de samlede fraktioner og inddampning gav titel forbindelsen som hydrochlorid hydrat (1,3 g, 53%) smp. 241-242°C.
15
Ifølge ovennævnte generelle procedure blev følgende oxim-derivater fremstillet:
Eksempel 2 20 (R)-( 2-Methylphenyl )-(3-methyl-2-thienyl )methanon 0- [ 2- (3 -carboxypiperidin-1 -y 1) ethyl ] oxim hydrochlorid 25 Tic rf 0>30 (Si02, dichloromethan/methanol 1/1).
Eksempel 3 (R)-Bis(3-methyl-2-thienyl)methanon O-[2— (3-carboxy-30 piperidin-l-yl)ethyl]oxim hydrochlorid
Smp. 45°C.
35 (R) - (2-Ethylphenyl) - (3-methyl-2-thienyl )methanon O- [2- (3-carboxypiperidin-1 -yl)ethyl ] oxim hydrochlorid 5 -
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Eksempel 4 19 \
Smp. 202-203°C (acetone).
Eksempel 5 10 (R)-(3-Methyl-2-thienyl)-(2-thienyl)methanon 0-[2-(3-carboxypiperidin-l-yl) ethyl] oxim 15 Smp. 210-216°C.
Eksempel 6 (R) - (3-Methoxyphenyl) - (3-me thyl-2-thienyl) met hanem 20 O- [ 2- (3-carboxypiperidin-1 -yl) ethyl ] oxim· hydrochlorid
Tic rf 0,3 (Si02, dichloromethan/methanol 1/1) 25 Eksempel 7 (R) - (2-Methylphenyl) - (l-methyl-2-pyrrolyl )methanon 0- [ 2- (3-carboxypiperidin-1 -yl) ethyl ] oxim 30
Tic rf 0,29 (Si02, dichloromethan/methanol 1/1).
35 (R) - (l-Methyl-2-pyrrolyl )phenylmethanon 0-[2-( 3-carboxypiperidin-1 -y 1)ethyl ] oxim hydrochlorid 5 -
Eksempel 8 20
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Smp. 221,5-225°C.
Eksempel 9 10 (R) - (3-Methoxyphenyl) - (4-methyl-2-thienyl )methanon O- [ 2 - (3 -carboxypiperidin-1 -yl) ethyl ] oxim hydrochlorid 15 Tic, rf 0,31 (Si02, dichloromethan/methanol 1/1).
Eksempel 10 (R) - (2-Methy!p|ienyi) - (3 -^methyl - 2 ^thienyl )methanori 20 O- [-2-(-3-carboxypiperidin-1 -y 1) ethyl] oxim- hydrochlorid
Tic, rf 0,32 (Si02, dichloromethan/methanol 1/1).
25 Eksempel 11 (R) - (2-methyl-1,2,4-triazol-3-yl) - (2-thienyl )methanon O-[2-(3-carboxypiperidin-1-yl)ethyl]oxim hydrochlorid 30
Tic, rf 0,90 (omvendt fase, Whatman KC1 8F, methanol/ vand 4/1).
35 (R) - (3-Azidophenyl)-(3-methyl-2-thienyl)methanon O-[2-(3-carboxypiperidin-l-yl)ethyl]oxim hydrochlorid 5 -
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Eksempel 12 21
Tic, rf 0,20 (Si02, methanol).
Eksempel 13 10 (R) - (2 -Me t hy lpheny 1) - (3-methyl-2-thienyl )methanon 0-[2-(3-ethoxycarbonylpiperidin-l-yl)ethyl]oxim 15 Tic, rf 0,35 (Si02, cyclohexan/ethylacetat 1/1).
Eksempel 14 (R) -(2-Azidophenyl)phenylmethanon 0- [2-(3-carboxypiperi- 20 din-1-yl)ethyl]oxim hydrochlorid
Tic, rf 0,14 (Si02, dichlormethan/methanol 1/1).
Eksempel 15 25 (S) -Diphenylmethanon 0-[2-(3-carboxypiperidin-l-yl)ethyl]-oxim hydrochlorid 30 Tic, rf 0,38 (Si02, dichlormethan/methanol 1/1).
35 (R)-Bis(3-ethyl-2-thienyl)methanon 0-[2-(3-carboxypiperidin- 1 -yl) ethyl ] oxim hydrochloric! 5 ---
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Eksempel 16 22
Tic, rf 0,30 (S1O2, dichlormethan/methanol 1/1).
Eksempel 17 10 (R) - (2,4-Dichlorophenyl) - (3-methyl-2-thienyl )methanon 0- [2-(3-carboxypiperidin-l-yl )ethyl] oxim hydrochlorid 15 Tic, rf 0,52 (S1O2, dichlormethan/methanol 1/1).
Eksempel 18 (R) -t (3-Methoxyphenyl)phenylmethanon O- [2- (3-carboxypipe-20 ridin-l-yl)ethyl]oxim hydrochlorid
Snip. 180-185°C.
Eksempel 19 25 (R) - (3-Methoxyphenyl) - (2-methoxyphenyl )methanon O- [2- (3-car-boxypiperidin-1 -yl) ethyl ] oxim hydrochlorid 30 Smp. 185-190°C.
35 (R)-Bis(4-chlor-2-methylphenylJmethanon 0-[2-(3-carboxy- piperidin-l-yl)ethyl]oxim hydrochlorid 5 -
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Eksempel 20 23
Smp. 230-232°C.
Eksempel 21 10 (R) - (2-Methylphenyl)-(3-methyl-2-thienyl)methanon O-[2-(3-ethoxycarbonylpiperidin-l-yl)ethyl]oxim hydrochlorid 15
Smp. 124-125.5°C.
Eksempel 22 20 (R) - (4-Chlor-2-methylphenyl) - (3-methyl-2-thienyl )methanon 0-[2-(3-carboxypiperidin-l-yl)ethyl]oxim hydrochlorid
Smp. 170-175°C.
25 Eksempel 23 (R)-Bis(2-methylphenyl)methanon 0-[2-(3-carboxypiperidin-1 -yl)ethyl]oxim hydrochlorid 30
Tlc> rf. 0,49 (Si02, dichlormethan/methanol 1/1).
Ved anvendelse af (R,S)-N-(2-chlorethyl)nipecotinsyreethyl-ester som udgangsmateriale fremstilledes følgende (R,S)-35 enantiomere blandinger (ifølge metode A,- Eksempel 1):
Eksempel 24 24
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Diphenylmethanon O-[2-(3-carboxypiperidin-l-yl)ethyl]-oxim hydrochlorid 5 -=-
Smp. 234-235°C.
Eksempel 25 10 (2-Methylphenyl) - (3-methyl-2-thienyl )methanon O-[2-(3-carboxypiperidin-1-yl)ethyl]oxim hydrochlorid 15 Tic rf. 0,30 (Si02, dichlormethan/methanol 1/1).
Eksempel 26 (l-Methyl-2-imidazolyl)phenylmethanon O-[2-(3-carboxy-20 piperidin-l-yl)ethyl]oxim
Tic rf 0,07 (Si02; methanol/dichloromethan 1/1).
25 Eksempel 27
Phenyl- (2-pyridyl )methanon 0- [2- (3-carboxypiperidin-l-yl) ethyl] oxim hydrochlorid 30
Smp. 61-63°C.
35
Phenyl-(2-pyrrolyl )methanon O- [2-(3-carboxypiperidin-l- yl)ethyl]oxim hydrochlorid 5 -.
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Eksempel 28 25
Smp. 172,5-176°C.
Eksempel 29 10
Bis (4-chlorophenyl )methanon O- [ 2- (3-carboxypiperidin-l-yl)ethyl]oxim hydrochlorid 15 Tic rf 0,25 (Si02, dichlormethan/methanol 1/1).
Eksempel 30 (3 - Az idopheny 1) phenylmethanon 0- [ 2 - (3 -carboxypiperidin-20 1-yl)ethyl]oxim hydrochlorid
Tic, rf. 0,30 (Si02, methanol).
Eksempel 31 25 (4-Fluorphenyl) phenylmethanon 0- [ 2- (3-carboxypiperi-din-1-y1)ethyl]oxim hydrochlorid 30 Tic, rf. 0,35 (Si02, dichlormethan/methanol 1/1).
35 (2-Chlorphenyl) phenylmethanon O- [ 2- (3 -carboxypiperi - din-1-yl)ethyl]oxim hydrochlorid 5 -:-
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Eksempel 32 26 - Tic, rf. 0,35 (Si02, dichlormethan/methanol 1/1).
Eksempel 33 10 (4-Chlor-2-methylphenyl) - (2-methylphenyl )methanon O-[2-(3-carboxypiperidin-1-yl)ethyl]oxim hydrochlorid 15 Tic, rf. 0,33 (Si02, dichlormethan/methanol 1/1).
Eksempel 34 (3-Azidophenyl)phenylmethanon Or [2-( 3-carboxypiperidin-20 1-yl) ethyl] oxim hydrochlorid
Tic, rf. 0,30 (Si02, methanol).
Eksempel 35 25 (3-Nitrophenyl)phenylmethanon 0-[2-(3-carboxypiperi-din-l-yl)ethyl]oxim hydrochlorid 30 Tic, rf. 0,30 (SXO2, methanol).
35
Bis(2-hydroxyphenyl )methanon 0- [2- (3-carboxypiperidin- 1 -yl)ethyl]oxim hydrochlorid 5 -
Eksempel 36 27
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"\
Smp. 215-220°C (ikke omkrystalliseret).
Eksempel 37 10
Bis(3-methoxyphenyl )methanon 0-[2-(3-carboxypiperidin-1 -yl)ethyl]oxim hydrochlorid 4 15 Tic, rf. 0,31 (Si02, dichlormethan/methanol 1/1).
Eksempel 38 (2,4-Dichlorophenyl) τ (3-methyl-2-thienyl )methanon 20 0-[2-(3-carboxypiperidin-l-yl)ethyl]oxim hydrochlorid
Tic, rf. 0,30 (Si02, dichlormethan/methanol 1/1).
Eksempel 39 25 (2-Chlorophenyl)- (2-methylphenyl Jmethanon 0- [2-(3-carboxypiperidin-1-yl )ethyl]oxim hydrochlorid 30 Tic, rf. 0,57 (Si02, dichlormethan/methanol 1/1).
35 (2-Methylphenyl) - (3-methylphenyl )methanon 0-[2-( 3-carboxy- piperidin-1 -yl) ethyl ] oxim hydrochlorid 5 ----
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Eksempel 40 28
Smp. 174-176°C.
Eksempel 41 10 (2-Methylphenyl) -(3-methyl-2-thienyl )methanon 0- [2- (3-car-boxypiperidin-l-yl )ethyljoxim hydrochlorid 15 Smp. 209-211°C.
Eksempel 42 (3 -Hydroxyphenyl) phenylmethanon O- [ 2 - ( 3 -carboxypiper i -20 din-1-yl)ethyl] oxim hydrochlorid
Tic, rf. 0,40 (Si02, methanol).
Eksempel 43 25
Bis(2-methylphenyl )methanon 0- [2- (3-carboxypiperidin-l-yl)- 1-methylethyl] oxim hemihydrochlorid 30 Tic, rf. 0,52 (omvendt fase, Whatman KC1 8F, methanol/vand 4/1).
35
Eksempel 44 (Metode B): 29
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Diphenylmethanon O-[2-(3-carboxy-l,2,5,6-tetråhydropyri-din-1-yl)ethyl]oxlm 5 -i-
Benzophenon oxim (3,94 g, 20 mmol), l-brom-2-chlorethan (28,7 g, 200 mmol) og tørret, pulveriseret kaliumcarbonat (5,53 g, 80 mmol) i acetone (60 ml) opvarmedes under re-10 flux i 72 timer. Reaktionsblandingen blev afkølet og filtreret og filtratet blev inddampet til en olieagtig rest som blev oprenset ved "flash"-kromatografi (elueret med heptan/ethyl acetat 19/1) som gav diphenylmethanon O-(2-chloroethyl)oxim (3,82 g, 73%) som en olie, tic rf 0,36 15 (Si02, heptan/ethyl acetat 9/1).
Ovennævnte chlorethyloxim (1,309 g, 5 mmol) opløstes i acetone (25 ml) og guvacin methylester hydrochlorid (1,776 g, 10 mmol) pulveriseret, tørret kaliumcarbonat 20 (2,073 g, 15 mmol) og kaliumiodid (0,75 g, 5 mmol) blev tilsat. Reaktionsblandingen blev opvarmet under reflux i 18 timer og afkølet. Filtrering og inddampning af filtratet gav en olie som blev oprenset ved "flash"-kromatografi på kieselgel,feluering med cyclohexan/ethyl acetat (2/1) 25 gav diphenylmethanon 0-[2-(3-methoxycarbonyl-l,2,5,6-tetra-hydropyridin-l-yl)- ethyl]oxim (0,87 g, 48%) som en gummi, tic rf 0,30 (Si02/ heptan/ethylacetat 1/1). Der blev også isoleret noget af den som udgangsstof benyttede diphenylmethanon 0-(2-haloethyl)oxim (0,66 g, 50%).
30
Ovennævnte methylester (0,81 g, 2,39 mmol) blev opløst i ethanol (25 ml) og 10 N natriumhydroxidopløsning (2,39 ml) blev tilsat. Opløsningen omrøftes ved stuetemperatur i 4 timer og gjort sur til pH 2 med 2 N saltsyre. Væsken 35 ekstraheredes med dichlormethan (3 x 50 ml) og de samlede organiske ekstrakter blev tørret (MgSO^). Afdampning af opløsningsmidlet gaven gummi, som blev frysetørret, 30
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hvilket gav titelforbindelsen (0,825 g, 89%) som et hemi-hydrochlorid. Tic rf 0,40 (SiO^, dichlormethan/methanol 1/1). Fundet: C, 65,6; H, 6,3; N, 7,05; Cl, 4,9.
C21H22N2°3* ^21101^¾0 kræver cr 65,2; H, 6,4; N, 7,2; Cl, 5 4,6%.
Ved den ovennævnte generelle procedure (Eksempel 45,
Metode B) blev følgende oximderivater fremstillet: 10
Eksempel 45
Bis (3-methyl-2-thienyl)methanon 0-[2-(3-carboxy-1,2,5,6-tetrahydropyridin-1 -yl) ethyl ] oxim hydrochlorid 15 -
Smp. 79-80°C.
Eksempel 46 20 (S)-Bis(3-methyl-2-thienyl)methanon 0-[2-(3-carboxy-piperidin-l-yl) ethyl] oxim hydrochlorid 25 Smp. 168-169°C.
Eksempel 47 (S) - (2-Methylphenyl) - (3-methyl-2-thienyl )methanon .
0-[2-(3-carboxypiperidin-l-yl)ethyl]oxim hydrochlorid 30 -
Tic-rf 0,30 (Si02, dichlormethan/methanol 1/1).
35 -
DK 165292 B
Eksempel 48 31 (3-Methyl-2-thienyl)-(2-thienyl)methanon O-[2-(3-carboxy- 1.2.5.6- tetrahydropyridin-l-yl)ethyl]oxim hydrochlorid 5 -
Tic rf 0,8 (omvendt fase, Whatman KC18F, methanol/vand (4/1).
10 Eksempel 49 (2-Methylphenyl)phenylmethanon 0-[2-(3-carboxy-l,2,5,6-tetrahydropyridin-1-yl)ethyl]oxim hydrochlorid 15
Tic, rf. 0,49 (Si02, dichlormethan/methanol 1/1).
Eksempel 50 20 (3-Fluorphenyl) - (2-methylphenyl )methanon- O- [ 2- (3-carboxy- 1.2.5.6- tetrahydropyridin-l-yl )ethyl]oxim hydrochlorid
Smp. 219-223°C.
25 Eksempel 51 (R)-Bis(4-fluor-2-methylphenyl)methanon 0-[2-(3-ethoxycar-bonylpiperidin-1-yl)ethyl]oxim hydrochlorid 30
Smp. 102-103°C.
35 (R)-Bis(4-fluor-2-methylphenyl)methanon O-[2-(3-carboxy- piperidin-1-yl)ethyl]oxim hydrochlorid 5 -=-
Eksempel 52 32
DK 165292B
Smp. 181-182°C.
Eksempel 53 10 (2-Methylphenyl)-(3-methyl-2-thienylJmethanon 0-[2-(3-ethoxycarbonyl-1,2,5,6-tetrahydropyridin-l-yl)ethyl]oxim hydrochlorid 15
Srnpi 116-117°C.
Eksempel.54 20 (2-Methylphenyl )-(-3-methyl-2-thienyl )methanon O- [2-( 3-car- boxy-1,2,5,6-tetrahydropyridin-l-yl)ethyl]oxim hydrochlo-rid 25 Smp. 204-207°C.
Eksempel 55
Bis(4-fluor-2-methylphenyl)methanon O-[2-(3-ethoxycar-bonyl-1,2,5,6-tetrahydropyridin-l-yl)ethyl]oxim hydro-30 chlorid
Smp. 157-159°C.
35
Bis(4-fluor-2-methylphenyl )methanon 0-[2-( 3-carboxy- 1,2,5,6 —tet rahydropyr idin-1 -yl) ethyl ] oxim hydrochlorid 5--—— -—-
Eksempel 56 33
DK 165292B
Smp. 241-244°C.
Eksempel 57 10 (2,4-Dichlorphenyl)-(3-methyl-2-thienyl )methanon 0- [2-(3-carboxy-l, 2,5,6-tetrahydropyridin-l-yl )ethyl]oxim hydrochlorid 15
Tic, rf. 0,76 (omvendt fase, Whatman KC1 8F, methanol/ vand 4/1).
Eksempel 58 20 (2-Chlorphenyl)- (2-methylpheny 1 )methanon 0- [2- (3-carboxy- 1,2,5,6-tetrahydropyridin-l-yl)ethyl]oxim hydrochlorid 25 Smp. 152-155°C.
Eksempel 59 (2 -Methylphenyl) - (3 - tri f luorme thylphenyl) methanon 0- [ 2 -(3-carboxy-l ,2,5,6-tetrahydropyridin-l-yl )ethyl] oxim 30 hydrochlorid
Smp. 205-207°C.
35 (R) - (2-Methylphenyl) - (3-trif luormethylphenyl )methanon 0-[2-(3-carboxypiperidin-1 -yl)ethyl] oxim hydrochlorid 5 ---
Eksempel 60 34
DK 165292B
Smp. 156-158°C.
Eksempel 61 10 E/Z-2- (2-Methylphenyl) -2- (2-methyl-4-trif luormethylphenyl )acetaldehyd O-[2-(3-carboxy-1,2,5,5-tetrahydro-pyridin-1-yl)ethyl]oxim hydrochlorid 15
Smp. 195-200°C.
Eksempel 62 20 (S)— ( 2 -Methylphenyl) —(3-methyl-2-thienyl) methanon O- [2-(3-ethoxycarbonylpiperidin-l-yl )ethyl]oxim hydrochlorid 25 Tic, rf. 0,35 (SK^, cyclohexan/ethylacetat 1/1).
Eksempel 63
Bis( 2-methylphenyl)methanon O- [2-(3-carboxy-1,2,5,6-tetra-hydropyridin-l-yl )ethyl]oxim hydrochlorid 30 —---
Smp. 214-218.5°C.
35 (S) -Bis(2-methylphenyl )methanon O- [2- (3-carboxypiperidin- 1 -yl) ethyl ] oxim hydrochlorid 5 -
Eksempel 64 35
DK 165292B
-s
Tic, rf. 0,39 (S1O2, dichlormethan/methanol 1/1).
Eksempel 65 10
Diphenylmethanon 0- [2-(3-aminocarbonylpiperidin-l-yl)-ethyl]oxim 15 Tic, rf. 0,41 (S1O2, dichlormethan/methanol 9/1).
Eksempel 66 (4-Chlor-2 -methyl phenyl)- (2-methylphenyl )methanon 20 0-(2-( 3-carboxy-l, 2,5,6-tetrahydropyridin-l-yl) ethyl] oxim hydrochlorid
Tic, rf. 0,45 (S1O2, dichlormethan/methanol 1/1).
25 Eksempel 67 (2-Chlorphenyl )phenylmethanon 0-(2-(3-carboxy-l, 2,5,6-tetrahydropyridin-1 -y 1) ethyl ] oxim hydrochlorid 30
Smp. 198,5-200°C.
35 (2-Thienyl)phenylmethanon O-[2(3-carboxy-l,2,5,6-tetra- hydropyridin-1-yl)ethyl]oxim hydrochlorid 5 -:-:-
Eksempel 68 36
DK 165292B
Tic, rf. 0,63 (Si02, dichloromethan/methanol 1/1).
Eksempel 69 10 (3-Chlorphenyl)-(2-methylpheny1)methanon O-[2-(3-carboxy- 1,2,5,6-tetrahydropyridin-l-yl)ethyl]oxim hydrochlorid 15 Smp. 223°C (dekomp.).
Eksempel 70 (3 ^Methoxypheny 1) phenylmethanon 0- [ 2- (3 4carboxy-20 1,2> 5,6-tetrahydropyridin-l-yl )ethyl]oxim hydrochlorid
Smp. 140-145°C.
Eksempel 71 25 (3-Methoxyphenyl) - (2-methylphenyl)methanon 0-[2-(3-car-boxy-1,2,5,6-tetrahydropyridin-1 -yl) ethyl ] oxim hydrochlorid 30
Smp. 190-195°C.
35
Eksempel 72
DK 165292 B
37 (4-Fluor-2-methylphenyl) - (2-methylphenyl )methanon O- [ 2 - (3-carboxy-1,2,5,6 - tetrahydropyr idin-1 -yl) ethyl ] oxlm 5 hydrochlorid
Smp. 205-2l3°C.
10 Eksempel 73
Diphenylmethanon 0— C2—(3-ethoxycarbonyl-l ,2,5,6-tetra-hydropyridin-1-yl)ethyl]oxim hydrochlorid 15
Smp. 110-116°C (toluen/cyclohexan).
Eksempel 74 20 (2-Fluorphenyl)-(2-methylphenyl)methanon 0-[2-(3-carboxy- 1.2.5.6- tetrahydropyridin-l-yl )ethyl]oxim hydrochlorid
Smp. 195-196°C (dekomp.).
25 Eksempel 75 (2-Chlorphenyl)phenylmethanon 0-[2-(3-ethoxycarbony1- 1.2.5.6- tetrahydropyridin-l-yl)ethyl]oxim hydrochlorid 30
Tic; rf. 0>25 (SXO2/ cyclohexan/ethylacetat 1/1).
35
Eksempel 76 38
DK 165292B
Bis(2-methylpheny1)methanon 0-[2-(3-ethoxycarbonyl-l,2,5,6-tetrahydropyridin-l-yl )ethyl]oxim hydrochlorid 5 -
Smp. 163-164,5°C (toluen/cyclohexan).
Eksempel 77 10 (4-Chlor-2-methylphenyl) - (3-methyl-2-thienyl )methanon 0- [ 2- (3-carboxy-l ,2,5,6 -1 etr ahydropyr idin-1 -y 1 )ethyl] oxim hydrochlorid 15
Smp. 213-216°C.
Eksempel-78 20 (4-Fluor-2-methylphenyl)-(3-methyl-2-thienyl)methanon O- [ 2- (3-carboxy-l ,2,5,6-tetrahydropyridin-l-yl )ethyl] oxim hydrochlorid 25 Smp. 165-169°C.
Eksempel 79 (3,4-Dichlorphenyl) - (2-methylphenyl Jmethanon O- [2- (3-car-30 boxy-l,2,5,6-tetrahydropyridin-l-yl)ethyl]oxim hydrochlorid
Smp. 258-260°C.
35
Bis(2-ethylphenyl)methanon 0-[2-(3-carboxy-l,2,5,6-tetra- hydropyridin-l-yl) ethyl ] oxim hydrochlorld 5 -;-——
Eksempel 80
DK 165292 B
39
Smp. 130-135°C.
Eksempel 81 (Metode A) 10 (R,S)-Diphenylmethanon 0-[3-(3-carboxypiperldin-l-yl)-propyl]oxim hydrochlorid 15 (R,S)-ethylnipecotat (15,72 g, 100 mmol) blev blandet i tør acetone (120 ml) med 3-brom-1-propanol (20,85 g, 150 mmol) og tørret, pulveriseret kaliumcarbonat (20,73 g, 150 mmol). Reaktionsblandingen blev opvarmet under reflux i 3 timer, afkølet og filtreret* Filtratet blev inddampet til 20 en olie (32,8 g) som opløstes i dichlormethan. Til denne opløsning sattes phosphortribromid (30,45 g, 112,5 mmol) dråbevis under opretholdelse af reflux under tilsætningen, og da denne var afsluttet, fortsattes reflux i 2 1/2 time. Efter afkøling blev der tilsat tør methanol (30 ml) og 25 blandingen blev hældt i en blanding af mættet natriumbi- carbonatopløsning (250 ml) og vand (250 ml). Dichlormethan-laget blev skilt fra, og det vandige lag blev ekstraheret med ethylacetat (2 xl50 ml). De samlede organiske ekstrakter blev tørret (MgSO^) og inddampet til en olie som blev 30 oprenset ved "flash"-kromatografi. Eluering med cyclohexan/-tetrahydrofuran 3/1 gav N-(3-brompropyl)nipecotinsyre-ethylester (7,85 g, 28%) som et voksagtigt, fast stof.
Fundet C'f 47,3; 7,9; N, 4,7. C^^^BrtK^O,^ H^0 krævet C; -46,9; H, 7,2; N, 4,95%.· 35 ............
Denne forbindelse blev anvendt til alkylering af benzophe-nonoxim, som angivet i Eksempel 1, og den resulterende 40
DK 165292B
ester blev hydrolyseret til at give titelforbindelsen som et gummiagtigt, fast stof (0,5 g, 52% fra N-(3-brompropyl)-nipecotinsyreethylester). Tic rf 0,70 (omvendt fase, Whatman KC 18F, methanol/vand 8/2).
5
Ved anvendelse af (R)-N- (2-bromethyl Jnipecotinsyreethyl-ester hydrobromid og en 2,2-diarylacetaldehyd oxim som udgangsstof blev følgende forbindelser fremstillet (ifølge metode A, Eksempel 1).
10
Eksempel 82 E/z-(R)-2,2-Diphenylacetaldehyd 0-[2-(3-carboxy-piperi-din-1- yl)ethyl]oxim hydrochlorid 15 - rf. 0;34 (SiO^, dichlormethan/methanol 1/1) • - . . · *
Eksempel 83 20 E/Z-(R)-2-< 2fMethylpheriyl )-2-phenyl’acetaldehyd' 0- [ 2- (3-carboxypiperidin-l-yl)ethyl] oxim hydrochlorid' 25 rf. 0,40 (Si02, dichlormethan/methanol 1/1).
Eksempel 84 E/Z-(R)-2-(2-Methylphenyl)-2-(2-methyl-4-trifluormethyl-30 phenylJacetaldehyd 0-[2-(3-carboxy-piperidin-l-yl)ethyl]-oxim hydrochlorid
Smp. 190-200°C.
35
Eksempel 85
DK 165292 B
41
Fremstilling af kapsler 5
Ingredienser mg per kapsler (R)-diphenylmethanon 0- [2-(3-carboxypiperidin-l-yl)ethyl]oxim 10 10 Magnesium stearat 0.15
Lactose 15
Ovennævnte ingredienser blandes grundigt og anbringes i 15 hårde gelatinekapsler. Sådanne kapsler indgives oralt 1- 5 gange dagligt, til patienter der kræver behandling. Eksempel 86
Fremstilling af tabletter 20
Ingredienser mg per tablet (R)-diphenylmethanon 25 O-[2-(3-carboxypiperidin-l-yl)ethyl]oxim 200
Majsstivelse 50
Polyvinyl pyrrolidon 15
Magnesium stearat 1 30
Oximen blandes grundigt med 2/3 af majsstivelsen og granuleres. Det fremkomne granulat tørres, blandes med de resterende ingredienser og slås til tabletter.
35 De således fremstillede kapsler eller tabletter indgives oralt. På lignende måde kan andre oximer med formlen I anvendes. ......
Claims (9)
- 2. Forbindelser ifølge krav 1, hvor R og R uafhængigt af hinanden er furanyl, phenyl, pyrazolyl, pyrrolyl, thienyl eller 1,2,4-triazolyl, fortrinsvis phenyl, pyrrolyl eller thienyl, idet hver ring eventuelt er substitueret med en, to eller tre substituenter udvalgt fra gruppen 10 bestående af lavere alkoxy, azido, cyano, fluor, chlor, brom, iod, hydroxy og lavere alkyl, fortrinsvis lavere alkoxy, fluor, chlor og lavere alkyl. 4 3
- 3. Forbindelser ifølge krav 1 eller krav 2, hvor R beteg-15 ner hydrogen, methyl eller ethyl, fortrinsvis hydrogen eller methyl.
- 4. Forbindelser ifølge et hvilket som helst af de foregående krav, hvor n er 0 eller 1. 20
- 5. Forbindelser ifølge et hvilket som helst af de foregående krav, hvor m er 0 eller 1.
- 6. Forbindelser ifølge et hvilket som helst af de fore- Q 25 gående krav, hvor R er hydroxy, methoxy eller ethoxy.
- 7. Farmaceutisk præparat, KENDETEGNET VED, at det som aktiv komponent indeholder en forbindelse ifølge et vilkår- 30 ligt af kravene 1-6.
- 8. Farmaceutisk præparat ifølge krav 7, KENDETEGNET VED, at det indeholdér mellem 0,5 mg· og 1000 mg, fortrinsvis mellem 1 mg og 500 mg af forbindelsen med den generelle 35 formel I per enhedsdosis. DK 165292B
- 9. Farmaceutisk præparat til behandling af et symptom relateret til GABA aktivitet i centralnervesystemet, KENDETEGNET VED, at det som én aktiv bestanddel indeholder en forbindelse ifølge kravene 1-6. 5
- 10. Farmaceutisk præparat til behandling af epilepsi, KENDETEGNET VED, at det som en aktiv bestanddel indeholder en forbindelse ifølge kravene 1-6. 10 15 20 25 30 35
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK231489A DK165292C (da) | 1988-05-18 | 1989-05-12 | 3-piperidincarboxylsyrer og 3-tetrahydropyridincarboxylsyrer, n-substituerede med alkylethere af oximer, samt farmaceutiske praeparater indeholdende forbindelserne |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK270488 | 1988-05-18 | ||
| DK270488A DK270488D0 (da) | 1988-05-18 | 1988-05-18 | Hidtil ukendte o-substituerede ketoximer |
| DK231489 | 1989-05-12 | ||
| DK231489A DK165292C (da) | 1988-05-18 | 1989-05-12 | 3-piperidincarboxylsyrer og 3-tetrahydropyridincarboxylsyrer, n-substituerede med alkylethere af oximer, samt farmaceutiske praeparater indeholdende forbindelserne |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK231489D0 DK231489D0 (da) | 1989-05-12 |
| DK231489A DK231489A (da) | 1989-11-19 |
| DK165292B true DK165292B (da) | 1992-11-02 |
| DK165292C DK165292C (da) | 1993-03-22 |
Family
ID=26066488
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK231489A DK165292C (da) | 1988-05-18 | 1989-05-12 | 3-piperidincarboxylsyrer og 3-tetrahydropyridincarboxylsyrer, n-substituerede med alkylethere af oximer, samt farmaceutiske praeparater indeholdende forbindelserne |
Country Status (1)
| Country | Link |
|---|---|
| DK (1) | DK165292C (da) |
-
1989
- 1989-05-12 DK DK231489A patent/DK165292C/da not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DK231489A (da) | 1989-11-19 |
| DK231489D0 (da) | 1989-05-12 |
| DK165292C (da) | 1993-03-22 |
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