CH634298A5 - Process for preparing phenylazacycloalkanes - Google Patents
Process for preparing phenylazacycloalkanes Download PDFInfo
- Publication number
- CH634298A5 CH634298A5 CH1529077A CH1529077A CH634298A5 CH 634298 A5 CH634298 A5 CH 634298A5 CH 1529077 A CH1529077 A CH 1529077A CH 1529077 A CH1529077 A CH 1529077A CH 634298 A5 CH634298 A5 CH 634298A5
- Authority
- CH
- Switzerland
- Prior art keywords
- lower alkyl
- carbon atoms
- compounds
- salt
- piperidine
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 57
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 41
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 28
- 239000001257 hydrogen Substances 0.000 claims abstract description 28
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 26
- 150000002367 halogens Chemical class 0.000 claims abstract description 23
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 15
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000000935 antidepressant agent Substances 0.000 claims abstract description 4
- 229940005513 antidepressants Drugs 0.000 claims abstract description 4
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 4
- 150000003839 salts Chemical group 0.000 claims description 53
- 238000000034 method Methods 0.000 claims description 27
- -1 p-phenylene radical Chemical class 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 150000003254 radicals Chemical group 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- MKJIEFSOBYUXJB-HOCLYGCPSA-N (3S,11bS)-9,10-dimethoxy-3-isobutyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one Chemical compound C1CN2C[C@H](CC(C)C)C(=O)C[C@H]2C2=C1C=C(OC)C(OC)=C2 MKJIEFSOBYUXJB-HOCLYGCPSA-N 0.000 claims description 4
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 claims description 4
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 claims description 4
- 229960003147 reserpine Drugs 0.000 claims description 4
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 claims description 4
- 229960005333 tetrabenazine Drugs 0.000 claims description 4
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 230000000144 pharmacologic effect Effects 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 claims description 2
- RFEKFSDDJLBQHM-UHFFFAOYSA-N 4-(2-chloro-4-ethylphenyl)piperidine Chemical compound ClC1=CC(CC)=CC=C1C1CCNCC1 RFEKFSDDJLBQHM-UHFFFAOYSA-N 0.000 claims description 2
- XQMLSRCSXJFFBV-UHFFFAOYSA-N 4-(4-butylphenyl)piperidine Chemical compound C1=CC(CCCC)=CC=C1C1CCNCC1 XQMLSRCSXJFFBV-UHFFFAOYSA-N 0.000 claims description 2
- GYUZJVKBNKDMHM-UHFFFAOYSA-N 4-(4-ethyl-2-methoxyphenyl)piperidine Chemical compound COC1=CC(CC)=CC=C1C1CCNCC1 GYUZJVKBNKDMHM-UHFFFAOYSA-N 0.000 claims description 2
- UWILYNPREMNRTF-UHFFFAOYSA-N 4-(4-methylphenyl)piperidine Chemical compound C1=CC(C)=CC=C1C1CCNCC1 UWILYNPREMNRTF-UHFFFAOYSA-N 0.000 claims description 2
- MFGWCAIQKXQIKK-UHFFFAOYSA-N 4-(4-propylphenyl)piperidine Chemical compound C1=CC(CCC)=CC=C1C1CCNCC1 MFGWCAIQKXQIKK-UHFFFAOYSA-N 0.000 claims description 2
- XOLKOAIOIAPUEE-UHFFFAOYSA-N 4-[4-(2-methylpropyl)phenyl]piperidine Chemical compound C1=CC(CC(C)C)=CC=C1C1CCNCC1 XOLKOAIOIAPUEE-UHFFFAOYSA-N 0.000 claims description 2
- 208000009132 Catalepsy Diseases 0.000 claims description 2
- 206010012374 Depressed mood Diseases 0.000 claims description 2
- 206010015995 Eyelid ptosis Diseases 0.000 claims description 2
- 206010047853 Waxy flexibility Diseases 0.000 claims description 2
- 230000003042 antagnostic effect Effects 0.000 claims description 2
- 230000003288 anthiarrhythmic effect Effects 0.000 claims description 2
- 210000004556 brain Anatomy 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- 210000000744 eyelid Anatomy 0.000 claims description 2
- 230000002631 hypothermal effect Effects 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 239000002899 monoamine oxidase inhibitor Substances 0.000 claims description 2
- 229960002748 norepinephrine Drugs 0.000 claims description 2
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 claims description 2
- 150000002894 organic compounds Chemical class 0.000 claims description 2
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 2
- 229940117803 phenethylamine Drugs 0.000 claims description 2
- 201000003004 ptosis Diseases 0.000 claims description 2
- 229940076279 serotonin Drugs 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 abstract description 10
- 230000001430 anti-depressive effect Effects 0.000 abstract 2
- UTBULQCHEUWJNV-UHFFFAOYSA-N 4-phenylpiperidine Chemical class C1CNCCC1C1=CC=CC=C1 UTBULQCHEUWJNV-UHFFFAOYSA-N 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 229920002472 Starch Polymers 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- NDPOGPAZKKPOPV-UHFFFAOYSA-N 4-(4-ethylphenyl)piperidine Chemical compound C1=CC(CC)=CC=C1C1CCNCC1 NDPOGPAZKKPOPV-UHFFFAOYSA-N 0.000 description 5
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- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000012442 inert solvent Substances 0.000 description 5
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
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- 229940100445 wheat starch Drugs 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
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- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
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- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Substances CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 229910017604 nitric acid Inorganic materials 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
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- 239000013543 active substance Substances 0.000 description 2
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- 229910052757 nitrogen Inorganic materials 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
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- AAWZDTNXLSGCEK-LNVDRNJUSA-N (3r,5r)-1,3,4,5-tetrahydroxycyclohexane-1-carboxylic acid Chemical compound O[C@@H]1CC(O)(C(O)=O)C[C@@H](O)C1O AAWZDTNXLSGCEK-LNVDRNJUSA-N 0.000 description 1
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- RUIMBVCRNZHCRQ-UHFFFAOYSA-N 1-(2,4-dimethylphenyl)piperazine Chemical compound CC1=CC(C)=CC=C1N1CCNCC1 RUIMBVCRNZHCRQ-UHFFFAOYSA-N 0.000 description 1
- ILPFACZLTZPIET-UHFFFAOYSA-N 1-(3,5-dinitrophenyl)piperazine Chemical compound [O-][N+](=O)C1=CC([N+](=O)[O-])=CC(N2CCNCC2)=C1 ILPFACZLTZPIET-UHFFFAOYSA-N 0.000 description 1
- WFCVCAFQEAUHQE-UHFFFAOYSA-N 1-(4-butylphenyl)piperazine Chemical compound C1=CC(CCCC)=CC=C1N1CCNCC1 WFCVCAFQEAUHQE-UHFFFAOYSA-N 0.000 description 1
- ZNACQQDARBIOQD-UHFFFAOYSA-N 1-(4-ethyl-2-methoxyphenyl)piperazine Chemical compound C1(=CC=C(CC)C=C1OC)N1CCNCC1 ZNACQQDARBIOQD-UHFFFAOYSA-N 0.000 description 1
- RGTQRTJBPMZYTC-UHFFFAOYSA-N 1-(4-ethylphenyl)piperidine Chemical compound C1=CC(CC)=CC=C1N1CCCCC1 RGTQRTJBPMZYTC-UHFFFAOYSA-N 0.000 description 1
- IFSPIWXCVCISKM-UHFFFAOYSA-N 1-(4-propylphenyl)piperazine Chemical compound C1=CC(CCC)=CC=C1N1CCNCC1 IFSPIWXCVCISKM-UHFFFAOYSA-N 0.000 description 1
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- PYYVGPHJPVYHHX-UHFFFAOYSA-N COCC[AlH]CCOC.[Na] Chemical compound COCC[AlH]CCOC.[Na] PYYVGPHJPVYHHX-UHFFFAOYSA-N 0.000 description 1
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- 229910017489 Cu I Inorganic materials 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
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- 239000005977 Ethylene Substances 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 244000151018 Maranta arundinacea Species 0.000 description 1
- 235000010804 Maranta arundinacea Nutrition 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- AAWZDTNXLSGCEK-ZHQZDSKASA-N Quinic acid Natural products O[C@H]1CC(O)(C(O)=O)C[C@H](O)C1O AAWZDTNXLSGCEK-ZHQZDSKASA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
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- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
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- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
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- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
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- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- CODNYICXDISAEA-UHFFFAOYSA-N bromine monochloride Chemical compound BrCl CODNYICXDISAEA-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- YUDHVHGOGZNPIV-UHFFFAOYSA-N ethyl 4-(4-ethylphenyl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCC1C1=CC=C(CC)C=C1 YUDHVHGOGZNPIV-UHFFFAOYSA-N 0.000 description 1
- HONIILCVDAWNPU-UHFFFAOYSA-N ethyl 4-(4-ethylphenyl)piperidine-4-carboxylate Chemical compound C=1C=C(CC)C=CC=1C1(C(=O)OCC)CCNCC1 HONIILCVDAWNPU-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
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- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229910052919 magnesium silicate Inorganic materials 0.000 description 1
- 235000019792 magnesium silicate Nutrition 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 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
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- JZWFDVDETGFGFC-UHFFFAOYSA-N salacetamide Chemical group CC(=O)NC(=O)C1=CC=CC=C1O JZWFDVDETGFGFC-UHFFFAOYSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/023—Preparation; Separation; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
- C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
4-(Phenyl)piperidine compounds of the general formula I <IMAGE> in which R1 represents a radical of the formula <IMAGE> in which R3 denotes hydrogen or lower alkyl, Ph denotes a p-phenylene radical which is optionally substituted by lower alkyl, lower alkoxy, nitro and/or halogen, and R2 represents lower alkyl and R3 denotes hydrogen, with the proviso that R2 has at least two carbon atoms if Ph is unsubstituted and R3 denotes hydrogen, have antidepressant properties and can be used as antidepressant active compounds for drugs. The compounds of the formula I are prepared by subjecting a compound of the general formula <IMAGE> in which R1' denotes a radical <IMAGE> to, e.g. thermal, decarboxylation.
Description
**WARNUNG** Anfang DESC Feld konnte Ende CLMS uberlappen **.
PATENTANSPRÜCHE
1. Verfahren zur Herstellung von-alkylsubstituierten 4-(Phenyl) I-azacycloalkanen der allgemeinen Formel I R1 - Ph - R2 (I) worin R1 einen Rest der Formel
EMI1.1
darstellt, in welchem R3 Wasserstoff oder Niederalkyl bedeutet, Ph einen gegebenenfalls durch Niederalkyl, Niederalkoxy, Nitro und/ oder Halogen substituierten p-Phenylenrest bedeutet, und R2 Niederalkyl darstellt, mit der Massgabe, dass R2 mindestens 2 Kohlenstoffatome aufweist, wenn Ph unsubstituiert ist und R3 Wasserstoff bedeutet, in freier Form oder in Salzform, dadurch gekennzeichnet, dass man eine Verbindung der allgemeinen Formel R'1 PhRz (II), worin R'1 einen Rest der Formel
EMI1.2
bedeutet,
der Decarboxylierung unterwirft und gewünschtenfalls eine erfindungsgemäss erhaltene freie Verbindung in ein Salz oder ein erfindungsgemäss erhaltenes Salz in die freie Verbindung überführt.
2. Verfahren gemäss Anspruch 1 zur Herstellung von Verbindungen der Formel I, worin Rl die in Anspruch 1 angegebene Bedeutung hat, Ph gegebebenfalls durch Niederalkyl, Niederalkoxy oder Halogen monosubstituiertes p-Phenylen bedeutet, R2 geradkettiges Niederalkyl mit bis zu 7 Kohlenstoffatomen bedeutet, und R3 Wasserstoff oder Niederalkyl mit bis zu 4 Kohlenstoffatomen bedeutet, mit der Massgabe, dass R2 mindestens 2 Kohlenstoffatome aufweist, wenn Ph unsubstituiert ist und R3 Wasserstoff bedeutet, in freier Form oder in Salzform.
3. Verfahren gemäss Anspruch 1 zur Herstellung von Verbindungen der Formel I, worin Rl die in Anspruch 1 angegebene Bedeutung hat, Ph unsubstituiertes oder durch Niederalkyl mit bis zu 4 Kohlenstoffatomen, Niederalkoxy mit bis zu 4 Kohlenstoffatomen oder Halogen bis Atomnummer 17 monosubstituiertes p-Phenylen bedeutet, R2 Niederalkyl mit bis zu 4 Kohlenstoffatomen bedeutet, und R3 Wasserstoff oder Niederalkyl mit bis zu 4 Kohlenstoffatomen bedeutet, mit der Massgabe, dass R2 mindestens 2 Kohlenstoffatome aufweist, wenn Ph unsubstituiert ist und R3 Wasserstoff bedeutet, in freier Form oder in Salzform.
4. Verfahren gemäss Anspruch 1, dadurch gekennzeichnet, dass man das 4-(PÄthylphenyl)piperidin oder ein Salz davon herstellt.
5. Verfahren gemäss Anspruch 1, dadurch gekennzeichnet, dass man das 4-(4-n-Butylphenyl)piperidin oder ein Salz davon herstellt.
6. Verfahren gemäss Anspruch 1, dadurch gekennzeichnet, dass man das l-Methyl-4-(4-äthylphenyl)piperidin oder ein Salz davon herstellt.
7. Verfahren gemäss Anspruch 1, dadurch gekennzeichnet, dass man das 4-(4-Äthyl-2-methoxyphenyl)piperidin oder ein Salz davon herstellt.
8. Verfahren gemäss Anspruch 1, dadurch gekennzeichnet, dass man das 4-(4-n-Propylphenyl)piperidin oder ein Salz davon herstellt.
9. Verfahren gemäss Anspruch 1, dadurch gekennzeichnet, dass man das 4-(4-Isobutylphenyl)piperidin oder ein Salz davon herstellt.
10. Verfahren gemäss Anspruch 1, dadurch gekennzeichnet, dass man das 4-(4-Äthyl-2-chlorphenyl)piperidin oder ein Salz davon herstellt.
11. Verwendung von gemäss Anspruch 1 erhältlichen Verbindungen der Formel I, worin R2 Niederalkyl ist, zur Herstellung entsprechender Verbindungen der Formel I, worin Rs Wasserstoff ist, gekennzeichnet, durch Umsetzung mit einem Halogenameisensäureester und nachfolgende Hydrolyse.
Gegenstand der Erfindung ist ein Verfahren zur Herstellung von alkylsubstituierten 4-(Phenyl)-l-azacycloalkanen der allgemeinen Formeln
R1 - Ph - R2 (1) worin Rl einen Rest der Formel
EMI1.3
darstellt, in welchem R3 Wasserstoff oder Niederalkyl bedeutet, Ph einen gegebenenfalls durch Niederalkyl, Niederalkoxy, Nitro und/ oder Halogen substituierten p-Phenylenrest bedeutet, und R2 Niederalkyl darstellt, mit der Massgabe, dass R2 mindestens 2 Kohlenstoffatome aufweist, wenn Ph unsubstituiert ist und R3 Wasserstoff bedeutet, in freier Form oder in Salzform.
Vor- und nachstehend werden unter niederen organischen Verbindungen und von diesen abgeleiteten Resten insbesondere solche Verbindungen und Reste verstanden, die bis zu 7, vor allem bis zu 4 Kohlenstoffatome aufweisen.
Niederalkyl enthält beispielsweise bis zu 7, vor allem bis zu 4 Kohlenstoffatome und kann verzweigt sowie in beliebiger Stellung gebunden sein, ist aber vorzugweise geradkettig. Als Beispiele seien vor allem Butyl, Propyl, Isopropyl und speziell Äthyl und Methyl genannt.
Niederalkoxy enthält beispielsweise bis zu 7, vor allem bis zu 4 Kohlenstoffatome und kann verzweigt sein, wobei die Oxygruppe in beliebiger Stellung gebunden sein kann, ist aber vorzugsweise geradkettig. Als Beispiele seien Butoxy, Propoxy, Isopropoxy, Äthoxy und insbesondere Methoxy genannt.
Halogen ist beispielsweise Halogen bis und mit Atomnummer 35, insbesondere Chlor.
Die Verbindungen der allgemeinen Formel I und ihre pharmazeutisch verwendbaren Salze besitzen wertvolle pharmakologische Eigenschaften. So zeigen sie eine ausgeprägte Reserpin-antagonistische Wirkung, die beispielsweise an der Maus anhand der Umkehr der durch Reserpin bewirkten Hypothermie nach Verabreichung in Dosen von etwa 3 bis etwa 100 mg/kg p.o. und an der Ratte im Lidspaltentest anhand der durch Reserpin hervorgerufenen Ptosis in Dosen von etwa 10 bis etwa 100 z.B. von etwa 3 bis etwa 30 mg/kg p.o.
nachgewiesen werden kann. Sie zeigen vor allem Tetrabenazinantagonistische Wirkung, die beispielsweise an der Ratte im Tetrabenazin-Katalepsietest in Dosen von etwa 3 bis etwa 30 mg/kg i.p.
nachgewiesen werden kann.
Weiterhin bewirken sie eine Hemmwirkung auf die Noradrenalinnahme, wie sich anhand der Noradrenalinaufnahme am Rattenhim in Dosen von etwa 10 bis 100 mg/kg p.o. zeigen lässt. Ferner bewirken sie in Dosen von etwa 30 bis etwa 300 mg/kg p.o. eine Monoaminoxidasehemmung im Rattenhirn, die mittels Serotonin oder Phenethylamine als Substrat nachgewiesen werden kann, und eine 5-Hydroxytryptamin-Potenzierung, die sich an der Maus in Dosen von etwa 10 bis 100 mg/kg p.o. zeigen lässt. Die neuen Verbindungen sind ferner besser verträglich als vorbekannte Verbindungen gleicher Wirkungsrichtung und ähnlicher Struktur.
Die neuen Verbindungen können daher als Psychopharmaka, insbesondere als Antidepressiva, beispielsweise zur Behandlung von Gemütsdepressionen, Anwendung finden.
Das 4-(p-Methylphenyl)piperidin ist bereits aus Coll. Czech.
Chem. Corumun. 40, 3905 - 3923 (1975) bekannt, ebenso gewisse antiarrhythmische Eigenschaften derselben. Ferner sei auf die vorpublizierten US-Patentschriften Nrn. 3458521 und 3334104 verwiesen.
Die Erfindung betrifft in erster Linie Verbindungen der allgemeinen Formel, worin Rl, R3 und Ph die angegebenen Bedeutungen haben, und R2 geradkettiges Niederalkyl bedeutet, in freier Form oder in Salzform.
Die Erfindung betrifft insbesondere Verbindungen der allgemeinen Formel I, worin Rl die angegebene Bedeutung hat, Ph gege
benenfalls durch Niederalkyl, vor allem mit bis zu 4 Kohlenstoffatomen, wie Methyl, Niederalkoxy, vor allem mit bis zu 4 Kohlenstoffatomen, wie Methoxy, oder Halogen, vor allem Halogen bis Atomnummer 35, wie Chlor, monosubstituiertes p-Phenylen bedeutet, R2 geradkettiges Niederalkyl mit jeweils bis zu 7, z.B. bis zu 4, Kohlenstoffatomen bedeutet, und R3 Wasserstoff oder Niederalkyl mit bis zu 4 Kohlenstoffatomen, wie Methyl, bedeutet, in freier Form oder in Salzform.
Die Erfindung betrifft vor allem Verbindungen der allgemeinen Formel I, worin Rl die angegebene Bedeutung hat, Ph durch Niederalkyl mit bis zu 4 Kohlenstoffatomen, wie Methyl, Niederalkoxy mit bis zu 4 Kohlenstoffatomen, wie Methoxy, oder Halogen bis Atomnummer 17, wie Chlor, monosubstituiertes oder vor allem unsubstituiertes p-Phenylen bedeutet, R2 Niederalkyl mit bis zu 4 Kohlenstoffatomen, nämlich Butyl, Propyl oder vor allem Äthyl oder Methyl, bedeutet, und R3 Wasserstoff oder Niederalkyl mit bis zu 4, z.B.
bis zu 2, Kohlenstoffatomen, wie Methyl, bedeutet, in freier Form oder in Salzform.
Die Erfindung betrifft namentlich die Herstellung der in den Beispielen genannten Verbindungen der allgemeinen Formel I in freier Form oder in Salzform.
Das erfindungsgemässe Verfahren zur Herstellung der neuen Verbindungen ist dadurch gekennzeichnet, dass man eine Verbindung der allgemeinen Formel R'1 - Ph - R2 (11) worin R'l einen Rest
EMI2.1
bedeutet, der, z.B. thermischen, Decarboxylierung unterwirft und gewünschtenfalls die erhältliche Verbindung in eine andere Verbindung der allgemeinen Formel I umwandelt, ein erhältliches Isomerengemisch (Racematgemisch) in die reinen Isomeren (Racemate) auftrennt, ein erhältliches Racemat in die optischen Antipoden aufspaltet und/oder eine erfindungsgemäss erhältliche freie Verbindung in ein Salz oder ein erfindundsgemäss erhältliches Salz in die freie Verbindung oder in ein anderes Salz überführt.
Verbindungen der Formel II können z.B. erhalten werden durch Umsetzung eines entsprechenden Phenylessigsäureesters mit einem N,N-Bis-(2-halogenäthyl)niederalkylamin in üblicher Weise und gegebenenfalls Hydrolyse des erhaltenen Esters.
Zweckmässig verwendet man für die Durchführung der erfindungsgemässen Reaktionen solche Ausgangsstoffe, die zu den eingangs besonders erwähnten Gruppen von Endstoffen und besonders zu den speziell beschriebenen oder hervorgehobenen Endstoffen führen.
In, beispielsweise wie angegeben erhältlichen, Verbindungen der allgemeinen Formel I kann man im Rahmen der Definition der Endstoffe Substituenten einführen, umwandeln oder abspalten.
So kann man in Verbindungen der Formel 1, worin R3 Wasserstoff ist, in üblicher Weise, beispielsweise durch übliche Umsetzung mit einem Alkylierungsmittel, wie einem reaktionsfähigen Ester, vorzugsweise einem Halogen- oder Sulfonsäureester, z.B. dem Chlor-, Brom- oder Jodwasserstoffsäureester oder Benzol-, p-Toluol-, p Brombenzol- oder Methansulfonsäureester, eines Niederalkanols, oder unter reduzierenden Bedingungen mit einem Niederalkanal oder Diniederalkylketon, beispielsweise in Gegenwart von, z.B.
durch Palladium, Platin oder Verbindungen davon, wie von Palladium auf Kohle oder von Raney-Nickel, katalytisch erregtem Wasserstoff, Niederalkyl R3 einführen, erforderlichenfalls in einem inerten Lösungsmittel und/oder bei erhöhtem Druck und/oder erhöhter Temperatur.
Ferner kann man in Verbindungen der Formel 1, in denen der Rest Ph mindestens ein substituierbares Wasserstoffatom aufweist, einen oder mehrere der genannten Substituenten, insbesondere Halogen oder Nitro, einführen. Die Phenylsubstitution kann in üblicher Weise erfolgen, zur Einführung von Halogen beispielsweise durch Umsetzung mit einem üblichen Kernhalogenierungsmittel, z.B. mit Brom in Gegenwart von Eisen oder mit N-Chlorsuccinimid bzw. seinen Komplex mit Dimethylformamid, erforderlichenfalls in einem inerten Lösungsmittel, und zur Einführung von Nitro durch übliche Nitrierung, z. B. mittels rauchender Salpetersäure.
Die Einführung von Niederalkoxy oder Halogen kann aber auch erfolgen, indem man die zu substituierende Verbindung zunächst in üblicher Weise, z.B. mittels eines Salpetersäure/Schwefelsäure-Gemisches, nitriert, in der erhaltenen Nitroverbindung in üblicher Weise, z.B. mit katalytisch erregtem Wasserstoff, die Nitrogruppe zur Aminogruppe reduziert, diese in üblicher Weise, z.B. mit salpetriger Säure, diazotiert und das erhaltene Diazoniumsalz in üblicher Weise mit einem Cu-I-halogenid, z.B. nach Sandmeyer, umsetzt oder mit einem Niederalkanol verkocht, wobei die entsprechende durch Halogen bzw. Niederalkoxy substituierte Verbindung der Formel I erhalten wird.
Ferner kann man in Verbindungen der Formal I Substituenten von Ph, insbesondere Halogen, abspalten. Die Abspaltung von Substituenten kann in üblicher Weise erfolgen. Halogen kann beispielsweise reduktiv abgespalten werden, z.B. durch Umsetzung mit Wasserstoffin Gegenwart eines Hydrierungskatalysators, wie eines der genannten, z.B. von Palladium auf Kohle oder von Raney-Nickel, erforderlichenfalls in einem inerten Lösungsmittel und/oder bei erhöhtem Druck und/oder bei erhöhter Temperatur, oder mit einem geeigneten Dileichtmetallhydrid, z.B. mit Natrium-bis-(2-methoxyäthyl)aluminiumhydrid in einem inerten Lösungsmittel, z.B. in Benzol oder Toluol, erforderlichenfalls in der Wärme.
Ferner kann man aus Verbindungen der Formel I worin R3 Niederalkyl, vor allem Methyl, ist, diese Gruppe in üblicher Weise, beispielsweise durch Umsetzung mit einem Halogenameisensäureester, z.B. mit Äthylchlorformiat, vorteilhaft im Überschuss und erforderlichenfalls in einem inerten Lösungsmittel, z.B. in Chloroform oder Benzol, und/oder bei erhöhter Temperatur, z.B. bei Siedetemperatur, und anschliessende üblicher Hydrolyse des erhaltenen Carbamates, beispielsweise in Gegenwart einer Säure, z.B. einer Halogenwasserstoffsäure, wie Salzsäure oder einer Base, z.B. eines Alkalimetallhydroxydes, gegen Wasserstoff austauschen.
Die genannten Reaktionen werden in üblicher Weise in An- oder Abwesenheit von Verdünnungs-, Kondensations- und/oder katalytischen Mitteln, bei erniedrigter, gewöhnlicher oder erhöhter Temperatur, gegebenenfalls im geschlossenen Gefäss durchgeführt.
Je nach den Verfahrensbedingungen und Ausgangsstoffen erhält man die Verbindungen der allgemeinen Formel I in freier Form oder in der ebenfalls in der Erfindung inbegriffenen Form ihrer Salze, vorzugsweise ihrer Säureadditionssalze. So können beispielsweise basische, neutrale oder gemischte Salze, gegebenenfalls auch Hemi-, Mono-, Sesqui- oder Polyhydrate davon erhalten werden. Die Säureadditionssalze der neuen Verbindungen können in an sich bekannter Weise in die freie Verbindung übergeführt werden, z.B. mit basischen Mitteln, wie Alkalien oder lonenaustauschern. Anderseits können die erhaltenen freien Basen mit organischen oder anorganischen Säuren Salze bilden. Zur Herstellung von Säureadditionssalzen werden insbesondere solche Säuren verwendet, die zur Bildung von therapeutisch verwendbaren Salzen geeignet sind.
Als solche Säuren seien beispielsweise genannt: Halogenwasserstoffsäuren, Schwefelsäuren, Phosphorsäuren, Salpetersäure, Perchlorsäure, aliphatische, alicyclische, aromatische oder heterocyclische Carbon- oder Sulfonsäuren, wie Ameisen-, Essig-, Propion-, Bernstein-, Glykol-, Milch-, Äpfel-, Wein-, Zitronen-, Ascorbin-, Malein-, Hydroxymalein-, Brenztrauben-, Phenylessig-, Benzoe-, p-Aminobenzoe-, Anthranil-, p-Hydroxybenzoe-, Salicyl-, p-Aminosalicycl-, Embon-, Methansulfon-, Äthansulfon-, Hydroxyäthansulfon-, Äthylensulfon-, Halogenbenzolsulfon-, Toluolsulfon-, Naphtalinsulfon- oder Sulfanilsäure.
Diese oder andere Salze der neuen Verbindungen, wie z.B. die Pikrate, können auch zur Reinigung der erhaltenen freien Basen dienen, indem man die freien Basen in Salze überführt, diese abtrennt und aus den Salzen wiederum die Basen freimacht. Infolge der engen Beziehungen zwischen den neuen Verbindungen in freier Form und in Form ihrer Salze sind im Vorausgegangenen und nachfolgend unter den freien Verbindungen sinn- und zweckmässig gegebenenfalls auch die entsprechenden Salze zu verstehen.
Die neuen Verbindungen können, je nach Wahl der Ausgangsstoffe und Arbeitsweisen, in Form eines der verschiedenen Stereoisomeren oder als Stereoisomerengemisch, z.B.je nach der Anzahl der asymmetrischen Kohlenstoffatome, als reine optische Isomere, z.B.
in Form eines reinen Antipoden, oder als Isomerengemische, wie Racemate, Diastereoisomerengemische oder Racematgemische, vorliegen.
Erhaltene Diastereomerengemische und Racematgemische können auf Grund der physikalisch-chemischen Unterschiede der Bestandteile in bekannter Weise in die reinen Diastereomeren oder Racemate aufgetrennt werden, beispielsweise durch Chromatographie und/oder fraktionierte Kristallisation.
Erhaltene Racemate lassen sich nach bekannten Methoden in die optischen Antipoden zerlegen, beispielsweise durch Umkristallisation aus einem optisch aktiven Lösungsmittel, mit Hilfe von Mikroorganismen, oder durch Umsetzen eines basischen Endstoffes mit einer mit der racemischen Base Salze bildenden optisch aktiven Säure und Trennung der auf diese Weise erhaltenen Salze, z.B. auf Grund ihrer verschiedenen Löslichkeiten, in die Diastereomeren, aus denen die Antipoden durch Einwirkung geeigneter Mittel freigesetzt werden können, zerlegen. Besonders gebräuchliche optisch aktive Säuren sind z.B. die d- und 1-Formen von Weinsäure, Di-o-toluylweinsäure, Äpfelsäure, Mandelsäure, Camphersulfonsäure oder Chinasäure.
Vorteilhaft isoliert man den wirksameren der beiden Antipoden.
Die pharmakologisch verwendbaren Zielverbindungen der vorliegenden Erfindung können z.B. Herstellung von pharmazeutischen Präparaten verwendet werden, welche eine wirksame Menge der Aktivsubstanz zusammen oder im Gemisch mit anorganischen oder organischen, festen oder flüssigen, pharmazeutisch verwendbaren Trägerstoffen enthalten, die sich zur enteralen Verabreichung eignen.
Vorzugsweise verwendet man Tabletten oder Gelatinekapseln, welche den Wirkstoff zusammen mit Verdünnungsmitteln, z.B. Laktose, Dextrose, Sukrose, Mannitol, SorbitoI, Cellulose und/oder Glycin und Schmiermitteln, z.B. Kieselerde, Talk, Stearinsäure oder Salze davon, wie Magnesium- oder Calciumstearat, und/oder Polyäthylenglycol, aufweisen; Tabletten enthalten ebenfalls Bindemittel, z.B. Magnesiumsilikat, Stärken, wie Mais-, Weizen-, Reis-, oder Pfeilwurzstärke, Gelatine, Traganth, Methylcellulose, Natriumcarboxymethylcellulose und/oder Polyvinylpyrrolidon, und, wenn erwünscht, Sprengmittel, z.B. Stärken, Agar, Alginsäure oder ein Salz davon, wie Natriumalginat, Enzyme der Bindemittel und/oder Brausemischungen, oder Adsorptionsmittel, Farbstoffe, Geschmackstoffe und Süssmittel.
Injizierbare Präparate sind vorzugsweise isotonische wässerige Lösungen oder Suspensionen, Suppositorien oder Salben in erster Linie Fettemulsionen oder -suspensionen. Die pharmakologischen Präparate können sterilisiert sein und/oder Hilfsstoffe, z.B. Konservier-, Stabilisier-, Netz- und/oder Emulgiermittel, Löslichkeitsvermittler, Salze zur Regulierung des osmotischen Drucks und/oder Puffer enthalten. Die vorliegenden pharmazeutischen Präparate, die, wenn erwünscht, weitere pharmakologisch wertvolle Stoffe enthalten können, werden in an sich bekannter Weise, z.B. mittels konventioneller Misch-, Granulier- oder Dragierverfahren, hergestellt und enthalten von etwa 0,1% bis etwa 75%, insbesondere von etwa 1% bis etwa 50% des Aktivstoffes.
Die erfindungsgemäss erhältlichen Verbindungen werden einem etwa 75 kg schweren Warmblüter vorteilhaft in Tagesdosen von etwa 5 bis etwa 150 mg, z.B. von etwa 10 bis etwa 75 mg, vorzugsweise in Form mehrerer gleicher Dosen über den Tag verteilt, verabreicht.
Die Erfindung wird in den folgenden Beispielen näher beschrieben. Die Temperaturen sind in Celsiusgraden angegeben.
Beispiel 1:
5,0 g rohes 4-Carboxy-4-(4-äthylphenyl)-1-methylpiperidin wird in einem Stickstoffstrom 30 min auf etwa 2503 erhitzt. Dann wird auf etwa 100" abgekühlt und im Hochvakuum destilliert. Die bei 90 bis 100" siedende Fraktion wird durch Chromatographie an 50 g Silicagel mit Äthylacetat und wenig Methanol als Elutionsmittel weiter gereinigt. Man erhält das 4-(4-Äthylphenyl)-l-methylpiperidin, das auf üblicher Weise in das Hydrochlorid (F. 209-210 ) überführt wird.
Das Ausgangsmaterial kann wie folgt erhalten werden:
Ausgehend von 4-Äthylphenylacetonnitril erhält man mit Bis-(2 Chloräthyl)methylamin analog zu dem im US-Patent Nr. 2167351 beschriebenen Verfahren das 4-Carboäthoxy-4-(4-äthylphenyl)piperidin. Ausgehend von 7 g dieses rohen Esters erhält man durch Behandlung mit 50 ml 2N-Natronlauge in 100 ml siedendem Äthanol das rohe 4-Carboxy-4-(4-äthylphenyl)-N-methylpiperidon, das ohne weitere Reinigung weiter verarbeitet werden kann.
Beispiel 2:
5 g 4-(4-Äthylphenyl)piperidin in möglichst wenig Äthanol wird mit der erforderlichen Menge einer warmen, 10%gen Lösung von 1 Weinsäure in Äthanol versetzt. Nach dem Abkühlen, erforderlichenfalls nach Zugabe von Äther, kristallisiert das 4-(4-Äthylphenyl)piperidin-l-tartrat vom Smp. 166-167 (aus Äthanol) aus.
In analoger Weise kann man auch das Fumarat vom Smp. 196 197 (aus Äthanol) sowie das Methansulfonat vom Smp. 147-148 (aus Äthanol/Äther) herstellen.
Beispiel 3:
Zu einer Lösung von 12 g 4-(4-Äthylphenyl)piperidin in 8,4 g Tri äthylamin und 400 ml Äther fügt man unter Rühren unter einer inerten Atmosphäre bei 15-20 tropfenweise eine Lösung von 8,95 g Chlorameisensäureäthylester in 80 ml Äther hinzu. Nach beendeter Zugabe wird 2 h bei Raumtemperatur nachgerührt. Dann extrahiert man mit 500 ml Wasser. Die organische Phase wird neutral gewaschen, über Natriumsulfat getrocknet und im Vakuum eingedampft.
Aus dem Eindampfrückstand erhält man nach Ausziehen mit Petroläther in der Kälte das N-Carboäthoxy-4-(4-äthylphenyl)piperidin vom Smp. 71".
Unter einer Stickstoffatmosphäre tropft man zu einer gerührten Suspension von 4 g Lithiumaluminiumhydrid in 300 ml absolutem Dioxan bei 80-95 langsam eine Lösung von 14 g N-Carboäthoxy-C (4-äthylphenyl)piperidin in 100 ml absolutem Dioxan hinzu. Nach beendeter Zugabe wird 3 h zum Rückfluss erhitzt. Dann lässt man auf 10 abkühlen und versetzt tropfenweise mit 120 ml Wasser. Der ausgefallene Niederschlag wird mit Hilfe von Kieselgur abfiltriert und im Vakuum eingedampft. Der Eindampfrückstand wird mit 100 ml Äther versetzt und mit Hilfe von Kieselgur filtriert. Das Filtrat wird zur Trockne eingedampft und der Eindampfrückstand mit äthanolischer Salzsäure behandelt, wobei man das l-Methyl-4-(4 äthylphenyl)piperidinhydrochlorid vom Smp. 209-210 erhält.
Beispiel 4:
In analoger Weise wie in den Beispielen 1 bis 3 beschrieben kann man ferner herstellen:
4-(4-Äthylphenyl)piperidin, Smp. des Hydrochlorides 198-220 , 4-(4-Äthyl-2-chlorphenyl)piperazin,Kp.0Os= 1300,
4-(4-Isobutylphenyl)piperazin, Smp. des Hydrochlorides 258 262", 4-(2,4-Dimethylphenyl)piperazin, Smp. des Hydrochlorides 283 285 ,
4-(4-Äthyl-2-methoxyphenyl)piperazin, Kp.oool = 1300, Smp.
des Hydrochlorides 238-239 , l-Äthyl-4-(4-äthylphenyl)piperazin, Kp.o 01 = 100 , Smp. des Hydrochlorides 119-120", 4-(4-n-Propylphenyl)piperazin. Kp.005 = 130-140 , Smp. des Hy drochlondes228-230",
4-(4-n-Butylphenyl)piperazin, Kr.004 = 1200, Smp. des Hydrochlorides 225-230 ,
4-(3,5-Dinitrophenyl)piperazin, Smp. 85-86
Tabletten enthaltend 100 mg Wirkstoff, z.B. 4-(4-Äthylphenyl)piperidin, oder dessen Hydrochlorid, Tartrat, Fumarat oder Me thansulfonat können beispielsweise in folgender Zusammensetzung hergestellt werden:
: Zusammensetzung Pro Tablette Wirkstoffz.B. 4-(4-Äthylphenyl)piperidin 100 mg Milchzucker 50 mg Weizenstärke 73 mg Kolloidale Kieselsäure 13mg Talk 12 mg Magnesiumstearat 2mg
250 mg Herstellung
Der Wirkstoffwird mit dem Milchzucker, einem Teil der Weizenstärke und mit kolloidaler Kieselsäure gemischt und die Mischung durch ein Sieb getrieben. Ein weiterer Teil der Weizenstärke wird mit der Sfachen Menge Wasser auf dem Wasserbad verkleistert und die Pulvermischung mit diesem Kleister angeknetet, bis eine schwach plastische Masse entstanden ist. Die Masse wird durch ein Sieb von ca. 3 mm Maschenweite getrieben, getrocknet, und das trockene Granulat nochmals durch ein Sieb getrieben. Darauf werden die restliche Weizenstärke, Talk und Magnesiumstearat zugemischt. Die erhaltene Mischung wird zu Tabletten von 250 ml mit Bruchkerbe(n) verpresst.
** WARNING ** beginning of DESC field could overlap end of CLMS **.
PATENT CLAIMS
1. A process for the preparation of alkyl-substituted 4- (phenyl) I-azacycloalkanes of the general formula I R1 - Ph - R2 (I) wherein R1 is a radical of the formula
EMI1.1
represents in which R3 represents hydrogen or lower alkyl, Ph represents a p-phenylene radical optionally substituted by lower alkyl, lower alkoxy, nitro and / or halogen, and R2 represents lower alkyl, with the proviso that R2 has at least 2 carbon atoms if Ph is unsubstituted and R3 is hydrogen, in free form or in salt form, characterized in that a compound of the general formula R'1 PhRz (II), in which R'1 is a radical of the formula
EMI1.2
means
subject to decarboxylation and, if desired, converting a free compound obtained according to the invention into a salt or a salt obtained according to the invention into the free compound.
2. The method according to claim 1 for the preparation of compounds of formula I, wherein Rl has the meaning given in claim 1, Ph is optionally monosubstituted by lower alkyl, lower alkoxy or halogen, p-phenylene, R2 is straight-chain lower alkyl having up to 7 carbon atoms, and R3 Hydrogen or lower alkyl having up to 4 carbon atoms means that R2 has at least 2 carbon atoms if Ph is unsubstituted and R3 means hydrogen, in free form or in salt form.
3. The method according to claim 1 for the preparation of compounds of formula I, wherein Rl has the meaning given in claim 1, Ph unsubstituted or monosubstituted by lower alkyl having up to 4 carbon atoms, lower alkoxy having up to 4 carbon atoms or halogen to atom number 17 means R2 means lower alkyl of up to 4 carbon atoms and R3 means hydrogen or lower alkyl of up to 4 carbon atoms, with the proviso that R2 has at least 2 carbon atoms when Ph is unsubstituted and R3 means hydrogen, in free form or in salt form.
4. The method according to claim 1, characterized in that the 4- (PÄthylphenyl) piperidine or a salt thereof is prepared.
5. The method according to claim 1, characterized in that the 4- (4-n-butylphenyl) piperidine or a salt thereof is prepared.
6. The method according to claim 1, characterized in that the l-methyl-4- (4-ethylphenyl) piperidine or a salt thereof is prepared.
7. The method according to claim 1, characterized in that the 4- (4-ethyl-2-methoxyphenyl) piperidine or a salt thereof is prepared.
8. The method according to claim 1, characterized in that the 4- (4-n-propylphenyl) piperidine or a salt thereof is prepared.
9. The method according to claim 1, characterized in that the 4- (4-isobutylphenyl) piperidine or a salt thereof is prepared.
10. The method according to claim 1, characterized in that the 4- (4-ethyl-2-chlorophenyl) piperidine or a salt thereof is prepared.
11. Use of compounds of the formula I obtainable according to claim 1, in which R 2 is lower alkyl, for the preparation of corresponding compounds of the formula I in which Rs is hydrogen, characterized by reaction with a halogen formate and subsequent hydrolysis.
The invention relates to a process for the preparation of alkyl-substituted 4- (phenyl) -l-azacycloalkanes of the general formulas
R1 - Ph - R2 (1) wherein Rl is a radical of the formula
EMI1.3
represents in which R3 represents hydrogen or lower alkyl, Ph represents a p-phenylene radical optionally substituted by lower alkyl, lower alkoxy, nitro and / or halogen, and R2 represents lower alkyl, with the proviso that R2 has at least 2 carbon atoms if Ph is unsubstituted and R3 means hydrogen, in free form or in salt form.
Above and below, lower organic compounds and radicals derived therefrom are understood in particular to mean those compounds and radicals which have up to 7, especially up to 4, carbon atoms.
Lower alkyl contains, for example, up to 7, especially up to 4, carbon atoms and can be branched or bound in any position, but is preferably straight-chain. Examples include butyl, propyl, isopropyl and especially ethyl and methyl.
Lower alkoxy contains, for example, up to 7, especially up to 4, carbon atoms and can be branched, the oxy group being bound in any position, but is preferably straight-chain. Examples include butoxy, propoxy, isopropoxy, ethoxy and especially methoxy.
Halogen is, for example, halogen up to and including atomic number 35, in particular chlorine.
The compounds of general formula I and their pharmaceutically usable salts have valuable pharmacological properties. For example, they show a pronounced reserpine-antagonistic effect, which can be seen in the mouse, for example, by reversing the hypothermia caused by reserpine after administration in doses of about 3 to about 100 mg / kg po.o. and on the rat in the eyelid cleft test based on the ptosis caused by reserpine in doses of about 10 to about 100 e.g. from about 3 to about 30 mg / kg p.o.
can be demonstrated. They show above all tetrabenazine antagonistic activity, which, for example, in the rat in the tetrabenazine catalepsy test in doses of about 3 to about 30 mg / kg i.p.
can be demonstrated.
They also have an inhibitory effect on noradrenaline intake, as can be seen in the dose of about 10 to 100 mg / kg p.o. shows. Furthermore, in doses of about 30 to about 300 mg / kg po.o. a monoamine oxidase inhibition in the rat brain, which can be detected by means of serotonin or phenethylamine as a substrate, and a 5-hydroxytryptamine potentiation, which can be administered to the mouse in doses of about 10 to 100 mg / kg p.o. shows. The new compounds are also better tolerated than previously known compounds with the same direction of action and a similar structure.
The new compounds can therefore be used as psychopharmaceuticals, in particular as antidepressants, for example for the treatment of mood depression.
The 4- (p-methylphenyl) piperidine is already from Coll. Czech.
Chem. Corumun. 40, 3905-3923 (1975), as well as certain antiarrhythmic properties thereof. Reference is also made to the previously published US Pat. Nos. 3458521 and 3334104.
The invention relates primarily to compounds of the general formula in which Rl, R3 and Ph have the meanings indicated, and R2 denotes straight-chain lower alkyl, in free form or in salt form.
The invention relates in particular to compounds of the general formula I in which R 1 has the meaning given, Ph versus
by lower alkyl, especially with up to 4 carbon atoms, such as methyl, lower alkoxy, especially with up to 4 carbon atoms, such as methoxy, or halogen, especially halogen up to atomic number 35, such as chlorine, means monosubstituted p-phenylene, R2 is straight-chain lower alkyl with up to 7 each, e.g. means up to 4, carbon atoms, and R3 means hydrogen or lower alkyl with up to 4 carbon atoms, such as methyl, in free form or in salt form.
The invention relates in particular to compounds of the general formula I in which R 1 has the meaning given, Ph is monosubstituted by lower alkyl having up to 4 carbon atoms, such as methyl, lower alkoxy having up to 4 carbon atoms, such as methoxy, or halogen to atom number 17, such as chlorine or especially unsubstituted p-phenylene, R2 means lower alkyl having up to 4 carbon atoms, namely butyl, propyl or especially ethyl or methyl, and R3 is hydrogen or lower alkyl having up to 4, for example
up to 2 carbon atoms, such as methyl, means in free form or in salt form.
The invention relates in particular to the preparation of the compounds of the general formula I mentioned in the examples in free form or in salt form.
The process according to the invention for the preparation of the new compounds is characterized in that a compound of the general formula R'1 - Ph - R2 (11) in which R'l is a radical
EMI2.1
means, e.g. subject to thermal decarboxylation and, if desired, converting the available compound into another compound of the general formula I, separating an available isomer mixture (racemate mixture) into the pure isomers (racemates), splitting an available racemate into the optical antipodes and / or a free compound obtainable according to the invention converted into a salt or a salt obtainable according to the invention into the free compound or into another salt.
Compounds of formula II can e.g. are obtained by reacting a corresponding phenylacetic acid ester with an N, N-bis (2-halogenoethyl) lower alkylamine in a conventional manner and optionally hydrolysing the ester obtained.
For the implementation of the reactions according to the invention, those starting materials are expediently used which lead to the groups of end products which were particularly mentioned at the outset and in particular to the end products which have been specifically described or highlighted.
In compounds of the general formula I obtainable, for example, as indicated, substituents can be introduced, converted or split off within the scope of the definition of the end substances.
Thus, in compounds of formula 1 in which R3 is hydrogen, it can be used in a conventional manner, for example by conventional reaction with an alkylating agent, such as a reactive ester, preferably a halogen or sulfonic acid ester, e.g. the chloro, bromine or hydroiodic acid ester or benzene, p-toluene, p bromobenzene or methanesulfonic acid ester, a lower alkanol, or under reducing conditions with a lower alkanal or di-lower alkyl ketone, for example in the presence of, e.g.
by palladium, platinum or compounds thereof, such as from palladium on carbon or from Raney nickel, catalytically excited hydrogen, lower alkyl R3, if necessary in an inert solvent and / or at elevated pressure and / or elevated temperature.
Furthermore, one or more of the substituents mentioned, in particular halogen or nitro, can be introduced into compounds of the formula 1 in which the radical Ph has at least one substitutable hydrogen atom. The phenyl substitution can be carried out in the usual way, for introducing halogen, for example by reaction with a conventional nuclear halogenating agent, e.g. with bromine in the presence of iron or with N-chlorosuccinimide or its complex with dimethylformamide, if necessary in an inert solvent, and to introduce nitro by conventional nitration, e.g. B. by smoking nitric acid.
Lower alkoxy or halogen can also be introduced, however, by first of all replacing the compound to be substituted, e.g. by means of a nitric acid / sulfuric acid mixture, nitrated, in the nitro compound obtained in a conventional manner, e.g. with catalytically excited hydrogen, which reduces the nitro group to the amino group, these in the usual way, e.g. with nitrous acid, diazotized and the diazonium salt obtained in the usual way with a Cu-I halide, e.g. according to Sandmeyer, reacted or boiled with a lower alkanol, the corresponding compound of the formula I substituted by halogen or lower alkoxy being obtained.
Furthermore, in compounds of the formal I substituents of Ph, in particular halogen, can be eliminated. The substituents can be split off in a conventional manner. Halogen can, for example, be eliminated reductively, e.g. by reaction with hydrogen in the presence of a hydrogenation catalyst such as one of those e.g. of palladium on carbon or of Raney nickel, if necessary in an inert solvent and / or at elevated pressure and / or at elevated temperature, or with a suitable light metal hydride, e.g. with sodium bis (2-methoxyethyl) aluminum hydride in an inert solvent, e.g. in benzene or toluene, if necessary under heat.
Furthermore, from compounds of the formula I in which R3 is lower alkyl, especially methyl, this group can be obtained in a customary manner, for example by reaction with a halogen formate, e.g. with ethyl chloroformate, advantageously in excess and, if necessary, in an inert solvent, e.g. in chloroform or benzene, and / or at elevated temperature, e.g. at boiling temperature, and subsequent customary hydrolysis of the carbamate obtained, for example in the presence of an acid, e.g. a hydrohalic acid such as hydrochloric acid or a base e.g. an alkali metal hydroxide, replace with hydrogen.
The reactions mentioned are carried out in the customary manner in the presence or absence of diluents, condensation agents and / or catalytic agents, at a reduced, usual or elevated temperature, if appropriate in a closed vessel.
Depending on the process conditions and starting materials, the compounds of the general formula I are obtained in free form or in the form of their salts, preferably their acid addition salts, which is also included in the invention. For example, basic, neutral or mixed salts, optionally also hemi-, mono-, sesqui or polyhydrates thereof, can be obtained. The acid addition salts of the new compounds can be converted into the free compound in a manner known per se, e.g. with basic agents, such as alkalis or ion exchangers. On the other hand, the free bases obtained can form salts with organic or inorganic acids. For the preparation of acid addition salts, in particular those acids are used which are suitable for the formation of therapeutically usable salts.
Examples of such acids are: hydrohalic acids, sulfuric acids, phosphoric acids, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, acetic, propionic, amber, glycolic, lactic, apple , Wine, lemon, ascorbic, maleic, hydroxymalein, pyruvate, phenylacetic, benzoic, p-aminobenzoic, anthranil, p-hydroxybenzoic, salicyl, p-aminosalicyclic, embon, methane sulfonic -, Ethanesulfonic, hydroxyethanesulfonic, ethylene sulfonic, halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic or sulfanilic acid.
These or other salts of the new compounds, e.g. the picrates can also be used to purify the free bases obtained by converting the free bases into salts, separating them and again freeing the bases from the salts. As a result of the close relationships between the new compounds in free form and in the form of their salts, in the preceding and below, the free compounds are also to be understood as meaningful and expedient, if appropriate, the corresponding salts.
Depending on the choice of starting materials and procedures, the new compounds can be in the form of one of the various stereoisomers or as a mixture of stereoisomers, e.g. depending on the number of asymmetric carbon atoms, as pure optical isomers, e.g.
in the form of a pure antipode, or as isomer mixtures, such as racemates, diastereoisomer mixtures or racemate mixtures.
Diastereomer mixtures and racemate mixtures obtained can be separated into the pure diastereomers or racemates in a known manner on account of the physico-chemical differences in the constituents, for example by chromatography and / or fractional crystallization.
Racemates obtained can be broken down into the optical antipodes by known methods, for example by recrystallization from an optically active solvent, with the aid of microorganisms, or by reacting a basic end product with an optically active acid which forms salts with the racemic base and separating the in this way obtained salts, e.g. due to their different solubilities, break down into the diastereomers from which the antipodes can be released by the action of suitable agents. Particularly common optically active acids are e.g. the d- and 1-forms of tartaric acid, di-o-toluyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid or quinic acid.
The more effective of the two antipodes is advantageously isolated.
The pharmacologically useful target compounds of the present invention can e.g. Production of pharmaceutical preparations can be used which contain an effective amount of the active substance together or in a mixture with inorganic or organic, solid or liquid, pharmaceutically usable excipients which are suitable for enteral administration.
Preferably tablets or gelatin capsules are used which contain the active ingredient together with diluents, e.g. Lactose, dextrose, sucrose, mannitol, sorbitoI, cellulose and / or glycine and lubricants, e.g. Have silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol; Tablets also contain binders, e.g. Magnesium silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and / or polyvinyl pyrrolidone, and, if desired, disintegrants, e.g. Starches, agar, alginic acid or a salt thereof, such as sodium alginate, enzymes of the binders and / or effervescent mixtures, or adsorbents, colors, flavors and sweeteners.
Injectable preparations are preferably isotonic aqueous solutions or suspensions, suppositories or ointments, primarily fat emulsions or suspensions. The pharmacological preparations can be sterilized and / or adjuvants, e.g. Preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. The present pharmaceutical preparations, which, if desired, may contain other pharmacologically valuable substances, are used in a manner known per se, e.g. by means of conventional mixing, granulating or coating processes, and contain from about 0.1% to about 75%, in particular from about 1% to about 50% of the active substance.
The compounds obtainable according to the invention are advantageously administered to a warm-blooded animal weighing approximately 75 kg in daily doses of approximately 5 to approximately 150 mg, e.g. from about 10 to about 75 mg, preferably in the form of several equal doses distributed over the day.
The invention is described in more detail in the following examples. The temperatures are given in degrees Celsius.
Example 1:
5.0 g of crude 4-carboxy-4- (4-ethylphenyl) -1-methylpiperidine is heated to about 2503 in a stream of nitrogen for 30 minutes. The mixture is then cooled to about 100 "and distilled under high vacuum. The fraction boiling at 90 to 100" is further purified by chromatography on 50 g of silica gel with ethyl acetate and a little methanol as the eluent. The 4- (4-ethylphenyl) -l-methylpiperidine is obtained, which is converted into the hydrochloride (mp 209-210) in a conventional manner.
The starting material can be obtained as follows:
Starting from 4-ethylphenylacetonitrile, 4-carboethoxy-4- (4-ethylphenyl) piperidine is obtained with bis- (2-chloroethyl) methylamine analogously to the process described in US Pat. No. 2,167,351. Starting from 7 g of this crude ester, the crude 4-carboxy-4- (4-ethylphenyl) -N-methylpiperidone is obtained by treatment with 50 ml of 2N sodium hydroxide solution in 100 ml of boiling ethanol and can be processed further without further purification.
Example 2:
5 g of 4- (4-ethylphenyl) piperidine in as little ethanol as possible is mixed with the required amount of a warm, 10% solution of 1 tartaric acid in ethanol. After cooling, if necessary after adding ether, the 4- (4-ethylphenyl) piperidine-1-tartrate of mp. 166-167 (from ethanol) crystallizes out.
The fumarate of mp. 196 197 (from ethanol) and the methanesulfonate of mp. 147-148 (from ethanol / ether) can also be prepared in an analogous manner.
Example 3:
A solution of 8.95 g of ethyl chloroformate in 80 ml of ether is added dropwise to a solution of 12 g of 4- (4-ethylphenyl) piperidine in 8.4 g of triethylamine and 400 ml of ether with stirring under an inert atmosphere at 15-20 added. When the addition is complete, the mixture is stirred at room temperature for 2 h. Then extracted with 500 ml of water. The organic phase is washed neutral, dried over sodium sulfate and evaporated in vacuo.
After removal with petroleum ether in the cold, the N-carboethoxy-4- (4-ethylphenyl) piperidine of melting point 71 "is obtained from the evaporation residue.
A solution of 14 g of N-carboethoxy-C (4-ethylphenyl) piperidine in 100 ml of absolute dioxane is slowly added dropwise to a stirred suspension of 4 g of lithium aluminum hydride in 300 ml of absolute dioxane at 80-95 under a nitrogen atmosphere. After the addition has ended, the mixture is heated under reflux for 3 h. Then allowed to cool to 10 and 120 ml of water are added dropwise. The precipitate is filtered off using kieselguhr and evaporated in vacuo. The evaporation residue is mixed with 100 ml of ether and filtered using diatomaceous earth. The filtrate is evaporated to dryness and the evaporation residue is treated with ethanolic hydrochloric acid, giving the l-methyl-4- (4 ethylphenyl) piperidine hydrochloride of mp. 209-210.
Example 4:
The following can also be prepared in an analogous manner to that described in Examples 1 to 3:
4- (4-ethylphenyl) piperidine, mp of the hydrochloride 198-220, 4- (4-ethyl-2-chlorophenyl) piperazine, bp.0Os = 1300,
4- (4-isobutylphenyl) piperazine, mp. Of the hydrochloride 258 262 ", 4- (2,4-dimethylphenyl) piperazine, mp. Of the hydrochloride 283 285,
4- (4-ethyl-2-methoxyphenyl) piperazine, bp. Oool = 1300, m.p.
of the hydrochloride 238-239, l-ethyl-4- (4-ethylphenyl) piperazine, b.p. 01 = 100, mp. of the hydrochloride 119-120 ", 4- (4-n-propylphenyl) piperazine 130-140, mp of the Hy drochlondes228-230 ",
4- (4-n-butylphenyl) piperazine, Kr.004 = 1200, mp of the hydrochloride 225-230,
4- (3,5-dinitrophenyl) piperazine, m.p. 85-86
Tablets containing 100 mg of active ingredient, e.g. 4- (4-ethylphenyl) piperidine, or its hydrochloride, tartrate, fumarate or methanesulfonate can be prepared, for example, in the following composition:
: Composition Per tablet of active ingredient e.g. 4- (4-ethylphenyl) piperidine 100 mg milk sugar 50 mg wheat starch 73 mg colloidal silica 13 mg talc 12 mg magnesium stearate 2 mg
250 mg manufacturing
The active ingredient is mixed with the milk sugar, part of the wheat starch and with colloidal silica and the mixture is passed through a sieve. Another part of the wheat starch is gelatinized with a multiple of the amount of water on the water bath and the powder mixture is kneaded with this paste until a weak plastic mass has formed. The mass is passed through a sieve of approximately 3 mm mesh size, dried, and the dry granules are again passed through a sieve. The remaining wheat starch, talc and magnesium stearate are then mixed in. The mixture obtained is pressed into tablets of 250 ml with notch (s).
Claims (11)
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH1529077A CH634298A5 (en) | 1977-12-13 | 1977-12-13 | Process for preparing phenylazacycloalkanes |
CH533781A CH634299A5 (en) | 1977-12-13 | 1977-12-13 | Process for preparing novel phenylazacycloalkanes |
IT4762578A IT1103120B (en) | 1977-01-17 | 1978-01-13 | Antidepressant 4-alkyl-phenyl-piperidine cpds. prepn. - by decarboxylation of corresp. 4-carboxylic acid derivs. |
IT7850329A IT7850329A0 (en) | 1977-12-13 | 1978-07-17 | NEW PHENYL-AZACYCLO-ALKANES AND PROCEDURE FOR PRODUCING THEM |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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CH1529077A CH634298A5 (en) | 1977-12-13 | 1977-12-13 | Process for preparing phenylazacycloalkanes |
Publications (1)
Publication Number | Publication Date |
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CH634298A5 true CH634298A5 (en) | 1983-01-31 |
Family
ID=4407900
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CH1529077A CH634298A5 (en) | 1977-01-17 | 1977-12-13 | Process for preparing phenylazacycloalkanes |
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CH (1) | CH634298A5 (en) |
IT (1) | IT7850329A0 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0548798A1 (en) * | 1991-12-18 | 1993-06-30 | Sanwa Kagaku Kenkyusho Co., Ltd. | Antiviral agent |
-
1977
- 1977-12-13 CH CH1529077A patent/CH634298A5/en not_active IP Right Cessation
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1978
- 1978-07-17 IT IT7850329A patent/IT7850329A0/en unknown
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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EP0548798A1 (en) * | 1991-12-18 | 1993-06-30 | Sanwa Kagaku Kenkyusho Co., Ltd. | Antiviral agent |
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IT7850329A0 (en) | 1978-07-17 |
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