NO774456L - Fremgangsmaate til fremstilling av nye basisk substituerte o-propyloksimer og deres anvendelse som legemiddel - Google Patents
Fremgangsmaate til fremstilling av nye basisk substituerte o-propyloksimer og deres anvendelse som legemiddelInfo
- Publication number
- NO774456L NO774456L NO774456A NO774456A NO774456L NO 774456 L NO774456 L NO 774456L NO 774456 A NO774456 A NO 774456A NO 774456 A NO774456 A NO 774456A NO 774456 L NO774456 L NO 774456L
- Authority
- NO
- Norway
- Prior art keywords
- formula
- group
- carbon atoms
- atoms
- compounds
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 24
- 238000002360 preparation method Methods 0.000 title claims description 10
- 239000003814 drug Substances 0.000 title description 4
- -1 oxime compound Chemical class 0.000 claims description 31
- 150000001875 compounds Chemical class 0.000 claims description 30
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 150000002923 oximes Chemical class 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 5
- 125000001436 propyl group Chemical class [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 150000001728 carbonyl compounds Chemical class 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 150000002443 hydroxylamines Chemical class 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000000466 oxiranyl group Chemical group 0.000 claims description 3
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 230000010933 acylation Effects 0.000 claims description 2
- 238000005917 acylation reaction Methods 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 238000003780 insertion Methods 0.000 claims description 2
- 230000037431 insertion Effects 0.000 claims description 2
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 2
- 125000002950 monocyclic group Chemical group 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims 2
- 125000002947 alkylene group Chemical group 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- 229960003512 nicotinic acid Drugs 0.000 claims 1
- 235000001968 nicotinic acid Nutrition 0.000 claims 1
- 239000011664 nicotinic acid Substances 0.000 claims 1
- 125000002130 sulfonic acid ester group Chemical group 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 241000282472 Canis lupus familiaris Species 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 206010020772 Hypertension Diseases 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000009835 boiling Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 238000009530 blood pressure measurement Methods 0.000 description 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical class CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 229920000915 polyvinyl chloride Polymers 0.000 description 3
- 239000004800 polyvinyl chloride Substances 0.000 description 3
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 3
- 229960001289 prazosin Drugs 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- VTWKXBJHBHYJBI-SOFGYWHQSA-N (ne)-n-benzylidenehydroxylamine Chemical compound O\N=C\C1=CC=CC=C1 VTWKXBJHBHYJBI-SOFGYWHQSA-N 0.000 description 2
- WMPDAIZRQDCGFH-UHFFFAOYSA-N 3-methoxybenzaldehyde Chemical compound COC1=CC=CC(C=O)=C1 WMPDAIZRQDCGFH-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000000219 Sympatholytic Substances 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 230000001631 hypertensive effect Effects 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- JIQNWFBLYKVZFY-UHFFFAOYSA-N methoxycyclohexatriene Chemical compound COC1=C[C]=CC=C1 JIQNWFBLYKVZFY-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 150000002924 oxiranes Chemical class 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- KJPRLNWUNMBNBZ-QPJJXVBHSA-N (E)-cinnamaldehyde Chemical compound O=C\C=C\C1=CC=CC=C1 KJPRLNWUNMBNBZ-QPJJXVBHSA-N 0.000 description 1
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 1
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 description 1
- IHGHFMVCCDYILJ-UHFFFAOYSA-N 1,1-dibromopropan-2-ol Chemical compound CC(O)C(Br)Br IHGHFMVCCDYILJ-UHFFFAOYSA-N 0.000 description 1
- CVAVNAPWHIXWFP-UHFFFAOYSA-N 1,3,7-trimethyl-2,6-dioxopurine-8-carbaldehyde Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=C(C=O)N2C CVAVNAPWHIXWFP-UHFFFAOYSA-N 0.000 description 1
- MNUFRDKMBPRYTM-UHFFFAOYSA-N 1-(1-phenylethyl)imidazole-2-carbaldehyde Chemical compound C1=CN=C(C=O)N1C(C)C1=CC=CC=C1 MNUFRDKMBPRYTM-UHFFFAOYSA-N 0.000 description 1
- VNZLQLYBRIOLFZ-UHFFFAOYSA-N 1-(2-methoxyphenyl)piperazine Chemical compound COC1=CC=CC=C1N1CCNCC1 VNZLQLYBRIOLFZ-UHFFFAOYSA-N 0.000 description 1
- BUZYGTVTZYSBCU-UHFFFAOYSA-N 1-(4-chlorophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Cl)C=C1 BUZYGTVTZYSBCU-UHFFFAOYSA-N 0.000 description 1
- IKFGSOJYHVTNDV-UHFFFAOYSA-N 1-(4-phenylmethoxyphenyl)propan-1-one Chemical compound C1=CC(C(=O)CC)=CC=C1OCC1=CC=CC=C1 IKFGSOJYHVTNDV-UHFFFAOYSA-N 0.000 description 1
- NDJYVTLJWDGQGL-UHFFFAOYSA-N 1-aminooxypropan-2-ol Chemical class CC(O)CON NDJYVTLJWDGQGL-UHFFFAOYSA-N 0.000 description 1
- TVDCSPSRGSLXOV-UHFFFAOYSA-N 1-bromo-3-chloropropan-2-ol Chemical compound ClCC(O)CBr TVDCSPSRGSLXOV-UHFFFAOYSA-N 0.000 description 1
- YYTSGNJTASLUOY-UHFFFAOYSA-N 1-chloropropan-2-ol Chemical compound CC(O)CCl YYTSGNJTASLUOY-UHFFFAOYSA-N 0.000 description 1
- UEBFLTZXUXZPJO-UHFFFAOYSA-N 1-methylimidazole-2-carbaldehyde Chemical group CN1C=CN=C1C=O UEBFLTZXUXZPJO-UHFFFAOYSA-N 0.000 description 1
- SQAINHDHICKHLX-UHFFFAOYSA-N 1-naphthaldehyde Chemical compound C1=CC=C2C(C=O)=CC=CC2=C1 SQAINHDHICKHLX-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- PJKVFARRVXDXAD-UHFFFAOYSA-N 2-naphthaldehyde Chemical compound C1=CC=CC2=CC(C=O)=CC=C21 PJKVFARRVXDXAD-UHFFFAOYSA-N 0.000 description 1
- AKFKGPKEVRALPL-UHFFFAOYSA-N 4-(2-ethoxyphenyl)piperidine Chemical compound CCOC1=CC=CC=C1C1CCNCC1 AKFKGPKEVRALPL-UHFFFAOYSA-N 0.000 description 1
- SRAVSVBVHDLLPO-UHFFFAOYSA-N 4-(2-methoxyphenyl)piperidine Chemical compound COC1=CC=CC=C1C1CCNCC1 SRAVSVBVHDLLPO-UHFFFAOYSA-N 0.000 description 1
- YWIYMDPWBAXEKQ-UHFFFAOYSA-N 4-(2-phenoxyphenyl)piperidine Chemical compound C1CNCCC1C1=CC=CC=C1OC1=CC=CC=C1 YWIYMDPWBAXEKQ-UHFFFAOYSA-N 0.000 description 1
- JUOYRSLIORMKNB-UHFFFAOYSA-N 4-(4-chloro-2-methoxyphenyl)piperidine Chemical compound COC1=CC(Cl)=CC=C1C1CCNCC1 JUOYRSLIORMKNB-UHFFFAOYSA-N 0.000 description 1
- FSMYWBQIMDSGQP-UHFFFAOYSA-N 4-oxochromene-3-carbaldehyde Chemical compound C1=CC=C2C(=O)C(C=O)=COC2=C1 FSMYWBQIMDSGQP-UHFFFAOYSA-N 0.000 description 1
- UTBULQCHEUWJNV-UHFFFAOYSA-N 4-phenylpiperidine Chemical group C1CNCCC1C1=CC=CC=C1 UTBULQCHEUWJNV-UHFFFAOYSA-N 0.000 description 1
- UTCFOFWMEPQCSR-UHFFFAOYSA-N 5-formylsalicylic acid Chemical compound OC(=O)C1=CC(C=O)=CC=C1O UTCFOFWMEPQCSR-UHFFFAOYSA-N 0.000 description 1
- CSQUXTSIDQURDV-UHFFFAOYSA-N 6-bromo-1,3-benzodioxole-5-carbaldehyde Chemical compound C1=C(C=O)C(Br)=CC2=C1OCO2 CSQUXTSIDQURDV-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- KJPJBSQPYWKEJR-UHFFFAOYSA-N CCCOS(=O)(=O)C1=C2OC2=CC=C1 Chemical compound CCCOS(=O)(=O)C1=C2OC2=CC=C1 KJPJBSQPYWKEJR-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 241000723346 Cinnamomum camphora Species 0.000 description 1
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- 108010010803 Gelatin Proteins 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 description 1
- AMIMRNSIRUDHCM-UHFFFAOYSA-N Isopropylaldehyde Chemical compound CC(C)C=O AMIMRNSIRUDHCM-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Natural products OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/53—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- 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
- C07D211/18—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—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 substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—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 substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with 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
- C07D231/16—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with 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
- C07D231/38—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
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Description
Fremgangsmåte til fremstilling av nye basisksubstituerte O~propyloksimer og deres anvendelsessom legemiddel.
Det er allerede forsøkt med omsetning av salicylsyre-aldehyder med 0-/2- (4f-ihorf olinyl)-etylj-hydroksylamin av oksimer med dietylamino-, morfolino-, pyrrolidino- og 4-metylpipera-zino-alkylhalogenider og av 0-(2,3-epoksypropyl)-oksimer med ammoniakk, dimetyl-, dietyl- og n-propylamin resp. med isopropyl-og tert.butylamin og komme til farmakologisk aktive forbindelser med terapeutiske fordeler.
Overraskende er det nu funnet at man ved innføring av 4-fenylpiperazin- eller 4-fenylpiperidin-gruppen med minst en oksygenholdig substituent i fenylresten i sidekjeden av 0-pro-pylerte oksimer får farmakologisk høyaktive forbindelser, idet den terapeutiske virkning på det kardiovaskulære system står i foa<y>grunn.
Oppfinnelsens gjenstand er en fremgangsmåte til fremstilling av basisksubstituerte O-propyloksimer med den generelle formel (i)
hvori
R"'" betyr
a) hydrogen eller en karboksylgruppe,
b) en alkyl- eller alkenylgruppe med hver gang inntil 6 c-atomer som i tillegg kan hanen fenylgruppe,
c) en en- eller tokjernet arylgruppe som er substituert inntil tre ganger med alkyl eller alkoksy med hver
gang inntil 6 c-atomer, bensyloksy, halogenalkyl med inntil 2^c-atomer, halogen, cyano-, nitro-, eventuelt med metyl og/eller etyl substituert amino-,
karboksyl- eller hydroksylgrupper, metylendioksy-resten eller 0-/3-(4- ^2-metoksyf enyl^ -1-pipera-zinyl)-2-b.ydroksypropyl7-hyd.r,oksyiminometyl-resten hver gang alene eller- i kombinasjon eller d) en mono- eller bicyklisk heteroaromatisk gruppe med 1 til 4 nitrogenatomer eller et svovel- eller oksygenatom i ringsystemet som eventuelt er substituert inntil tre ganger med alkyl eller alkoksy med hver gang inntil 2 c-atomer, fenylalkyl med inntil 3 c-atomer i alkyldelen, halogen, metyl- eller dimetylaminogruppen hver gang alene eller i kombinasjon,
og
R betyr
hydrogen, en alkylgruppe med inntil 3 c-atomer, en cyklo-alkyirest med inntil 6 c-atomer eller en fenylrest eller 1 2
R og R betyr
sammen med c-atomet hvortil de er bundet, en eventuelt også ved. hjelp av hydrokarbonrester overbroet cykloalifatisk rest med inntil 10 c-atomer eller fluoren-9-yliden-resten,
3
R-^ betyr
hydrogen eller en hydroksylgruppe som eventuelt er acylert,
4
R betyr
hydrogen, en alkylgruppe med inntil 3 c-atomer eller en fenylrest,
5
R betyr
hydrogen, halogen, en alkoksygruppe med inntil 2 c-atomer eller hydroksyl og
X betyr
nitrogen eller en metingruppe,
idet fremgangsmåten erkarakterisert vedat forbindelser med strukturelementet
og forbindelser med grupperingen (ill) forbindes med hverandre ved innskyvning av broleddet idet A) karbonylforbindelser med formel eller deres < reaksjonsdyktige derivat omsettes med f" ved fenylresten substituerte hydroksylaminderivater med formel (Vi) eller deres salter eller B) oksimforbindelse med formel
Bl) omsettes med basisksubstituerte propylforbindelser med
formel (Vill)
eller deres salter eller B2) omdannes med propylderivater med formel i 6-oksylerte oksimer med formel og disse omsettes deretter med aminer med formel (Xl)
eller
C) forbindelser med formel (i) hvori R betyr hydroksyl acyleres
1 5
idet de ovennevnte formler har R til R og X ovennevnte betydning,
Y og Z betyr
hver halogen, fortrinnsvis klor eller brom eller en reaktiv sulfonsyreestergruppering eller Y danner sammen med R 3 og de to c-atomer hvortil de er bundet, en oksiranring og
M betyr
hydrogen, alkali eller jordalkali.
De basiske reaksjonsprodukter kan enten isoleres som sådanne eller fortrinnsvis med egnede syrer overføres i deres fysiologisk tålbare syreaddisjonssalter.
Egnede syrer er slike av organiske og uorganiske syrer
som muliggjør fremstillingen av ikke toksiske salter.
For det tilfelle at ifølge oppfinnelsen fremstilte forbindelser R 3 betyr en acyloksygruppe, avleder deres acylrest seg fortrinnsvis fra en rettkjedet eller forgrenet alkankarboksylsyre med inntil 6 c-atomer eller spesielt fra nikotin-en er eventuelt inntil tre ganger med alkoksy med hver gang 1 til h c-atomer substituerte banzosyre.
De nye forbindelser med formel (i) har verdifulle farmakologiske, spesielt blodtrykksenkende egenskaper i forbindelse med god tålbarhet og egner seg derfor i spesiell grad til be-handling av hypertonie.
Foretrukket er derved slike forbindelser ifølge formel (i), hvori
2
R betyr hydrogen. Blandt disse er igjen ofte slike forbindelser foretrukket hvori
R"*" c) og d) betyr en eventuelt substituert fenyl-, pyridyl- eller
imidazolylrest,
R 3 betyr hydrogen eller hydroksyl,
OR betyr en til fenylringen 2- eller 4-plassert hydroksyl-,
metoksy- eller etoksygruppe,
5
R betyr hydrogen og
X betyr nitrogen.
Acyleringen av forbindelsen ifølge oppfinnelsen med formel (i), hvori R betyr en hydroksylgruppe med de ved R nevnte karboksylsyrer kan f.eks. foregå i nærvær av kondensasjonsmidler som karbodiimider, spesielt imidlertid i form av deres reaksjonsdyktige funksjonelle derivater som syrehalogenidene, -anhydridehe eller reaktive estere.
Som karbonylforbindelse med formel (v) kommer det eksempelvis på tale aldehyder som acet-, isobutyr-, kroton- og kanelaldehyd, glyoksylsyre, benzaldehyd og dets forskjellig
substituerte derivater som 4-metyl-, 2,4,6-trimetyl-, 4-tert. butyl-, 2-, 3- eller 4-metoksy-, 3»4- eller 2,5-dimetoksy-,
3i4,5-trimetoksy-, 4-propoksy-, 4-butoksy-, 3-trifluormetyl-, 4-fluor-, 4-klor-, 4-brom-, 4-cyano-, 2- eller 3-nitro-, 4-dimetylamino-, 2-, 3- eller 4-hydroksy-, 4-hydroksy-3-metoksy-, 3,4-metylendioksy-, 2-brom-4,5-metylendioksy-benzaldehyd, tereftalaldehyd, 5-formylsalicylsyre og a- eller |3-naftaldehyd, ketoner so.m acetofenon, 4-kloracetofenon, benzofenon, cyklo-heksylfenylketon og 4-benzyloksy-propiofenon.
Egnede heteroaromatiske karbonylforbindelser ifølge formel (v) er bl.a. de tre stillingsisomere formyl- samt benzoyl-pyridiner, 3-indolaldehyd og dessuten 5-metoksy-derivat, 5~klor- eller 5-d.imetylamino-l, 3-»dimetyl-4-benzoyl-pyrazol, 1, 3-d-inietyl-4-metylamino-5-benzoylpyrazol, 1-metyl- eller l-(l-fenyletyl)-imidazol-2-karbaldehyd, 8-formylkoffein, tiofen-2-
og kromon-3-karbaldehyd.
Som cykliske ketonder med formel (v) skal det f.eks. nevnes cykloheksanon, kamfer, adamantan-2-on og fluorénon.
Alle disse karbonylforbindelser kan ikke bare anvendes per se, men også i form av deres reaksjonsdyktige derivater som halv- eller helacetaler, -merkaptaler, -aminaler eller acylaler . til reaksjon. Også aldimider, 'oksimer med formel VII_,_ok andre \ I hydrazoner, semikarbazoner, tiosemikarbazoner, cyanhydriner eller hydrogensulfitt-addisjonsforbindelsene er under tiden egnet som utgangsstoffer.
Foretrukkede forbindelser med formel (Vi) er de tilsvarende basisksubstituerte, litteraturkjente eller etter litt©-raturkjente fremgangsmåter lett fremstillbare O-propyl-hydroksyl-aminer og de i patentsøknad tilsvarende P 26 51 O83.8 omtalte 0-(2-hydroksypropyl)-hydroksylaminer som i 3-stilling av pro-pylgruppen eksempelvis har 4-(2- eller 4-hydroksyfenyl)-, 4-(2,4-dihydroksyfenyl)-, 4-(2-, 3- eller 4-metoksyfenyl)-, 4-(2,4-eller 3, 5-d.imetoksyf enyl) - , 4-(2-etoksyf enyl)-, 4-(2-f enoksy-fenyl)- eller 4-(4-klor-2-metoksyfenyl)-1-piperazinyl- eller
-1-piperidyl-rest.
De for fremgangsmåte B nødvendige oksimforbindelser med formel (vil) er for det meste kjent og lar seg fremstille etter litteraturkjente metoder ved omsetning av,aldehydene eller ketoner med formel (v) med hydroksylamin og eventuelt etterføl-gende saltdannelse uten vanskelighet.
Som utgangsstoffer med formel (Vill) kommer det fortrinnsvis i betraktning de i 4-stilling analogt forbindelsene (Vi) arylerte 1-(3-halogenpropyl)-, 1-(3-halogen-2-hydroksy-propyl)- og 1-(2, 3**epoksypropyl)-piperaziner resp. -piperidiner.
For omdannelsen av oksimforbindelsene (Vil) i slike mellomprodukter med formel (x)
hvori R 3 og Y sammen med de to c-atomer hvortil de er bundet, danner oksiranringen er eksempelvis epoksyder if&lge formel (ix) som epibromhydrin, 2,3-epoksypropyl-benzensulfonat, -p-toluensulfonat, -metansulfonat og spesielt epiklorhydrin, videre imidlertid også 1, 3-d.ihalogen-2-propanoler som 1,3-diklor-, 1, 3-d.ibrom- og l-brom-3-klor-2-propanol.
Mellomforbindelsene (x) hvori R betyr hydrogen, lar seg fremstille under foretrukket anvendelse av 3-halogenpropyl-sulfonater eller 1,3-dihalogenpropaner tilsvarende formel (ix), spesielt av l-brom-3-klorpropan.
Som aminer med formel (Xl)
kan bl. a. anvendes 4- (.2- eller 4-hydroksy f enyl) - , 4-(2,4-di-hydroksyfenyl)-, 4-(2-, 3- eller 4-metoksyfenyl)-, 4-(2,4- eller 3,5-dimetoksyfenyl)-, 4-(2-etoksyfenyl)-, 4-(2-fenoksyfenyl)-og 4-(4-klor-2-metoksyfenyl)-piperidin resp. -piperazin.
Omsetningene gjennomføres hensiktsmessig i et oppløs-nings- eller fordelingsmiddel.
Ved fremgangsmåte A arbeider man fortrinnsvis med ekvimolare mengder av reaksjonsdeltagerne i vandig-alkoholisk opp-løsning, men også andre overfor reaksjonskomponentene inerte oppløsningsmidler som pyridin, dimetylformamid og alkoholer (f.eks. metanol, etanol, de forskjellige propanoler eller buta noler) eller blandinger av disse oppløsningsmidler lar seg an-vende som reaksjonsmedium. Hydroksylaminderivatene med formel (Vi) anvendes derved fortrinnsvis i form av deres syreaddisjonssalter som hydrokloridene, hydrobromidene eller sulfatene. I dette tilfelle lønner det seg til reaksjonsblandingen å sette et syrebinendende middel, Sksempelvis alkali- eller jordalkali-hydroksyder eller -karbonater eller også en organisk base som trietylamin i minst støkiometrisk mengde. Kondensasjonsreak-sjonen gjennomføres ved temperaturer mellom 0°C og oppløsnings-midlets kokepunkt, fortrinnsvis mellom 50 og 100°C og spesielt mellom 50 og 80°C, idet reaksjonstiden kan vare fra få minutter til noen timer.
Alkyleringen av oksimforbindelsene (vil) med forbindelsen med formel (vill) eller (ix) i henhold til fremgangsmåte B, kan eksempelvis foregå i vannfri alkoholer, hydrokarboner, aprotiske oppløsningsmidler eller også i et overskudd av det eventuelt anvendte alkyleringsmiddel idet man ved omsetning av 6k-simene selv arbeider i nærvær av et basisk middel, som et alkali- eller jordalkali-hydroksyd, -karbonat, -hydrid eller alkoholat eller en organisk base (f.eks. trietylamin, pyridin, pikolin eller kinolin) eller anvender de adskilt fremstilte alkali- eller jordalkali-oksimater. Som alkoholer kommer det derved bl.a. på tale metanol, etanol, propanol, isopscopanol, eller forskjellige butanoler f.eks. også isobutanol, og som hydrokarboner heksan, cykloheksan, benzen, toluen eller xylen. Egnede aprotiske oppløsningsmidler er eksempelvis dimetylformamid, dimetylacetamid, N-metyl-pyrrolidon, tetrametylurinstoff, heksametylfosforsyretrisamid og dimetylsulfoksyd. Reaksjons-temperaturene ligger vanligvis alt etter fremgangsmåte mellom 0 oG og det anvendte oppløsningsmiddels kokepunktj hensiktsmessig ligger den imidlertid over 20°C. Fortrinnsvis arbeides i al-koholiske medier mellom 50 og 100°C og i aprotiske oppløsnings-midler fra 80 til 120°C, f.eks. rundt 100°C. Reaksjonstidene ligger derved vanligvis mellom 1 og 10 timer.
Omsetningen av mellomforbindelsene (x), hvor Y betyr halogen eller et reaktivt sulfonsyreestergruppering med aminene med formel (Xl) gjennomføres hensiktsmessig under samme betingel-ser som i første trinn. Aminolysen av 0-(2,3-epoksypropyl)-oksimr(formel X) hvori R og Y sammen betyr oksygen med aminene
(Xl) foregår derimot fortrinnsvis ved 1 til 5 timers oppvarming i høyerekokende alkoholer som n-propanol, isopropanol, n-
butanol eller isobutanol uten tilsetning av andre baser, idet reaksjonsdeltagerne fortrinnsvis anvendes i ekvimolare mengder.
For overføring av de som baser dannede forbindelser ifølge oppfinnelsen med formel (i) til fysiologisk tålbare syreaddisjonssalter egner det seg eksempelvis halogenhydrogen-syrer spesielt saltsyre, svovel-, fosfor-, eddik-, melke-, malein-, fumar-, oksal-, vin-, sitron-, glukon-, p-toluensulfon-, metansulfon- og cykloheksylamidosulfonsyre.
Forbindelsene ifølge oppfinnelsen med formel (i) kan
på grunn av den kjente oksim-isomeri opptre i den stereoisomere E- og/eller Z-form. Dessuten har de når R betyr en fri eller acylert hydroksylgruppe i tillegg et chiralitetssentrum og kan således foreligge i den optisk aktive D- og/eller L-form.
Oppfinnelsen vedrører derfor såvel de rene stereoisomere og enantiomere forbindelser som også deres blandinger. Til fremstilling av de rene antipoder kan man enten ved omsetningen i henhold til fremgangsmåte A og B gå ut fra det enantiomere utgangsforbindelser med formel (Vi) resp. (vill), og (ix) eller også oppspalte den enantiomere i etter en av de to metoder dannede racemater ved hjelp av i og for seg kjente fremgangsmåter, f.eks. ved fraksjonert krystallisasjon av de med en optisk aktiv syre dannede diastereomere syreaddisjonssalter.
De nye oksimer med formel (i) og deres fysiologisk tålbare salter kan på grunn av deres farmakologiske egenskaper finne anvendelse som legemidler, spesielt som slike til behand-ling av hypertone tilstander, idet man enten administrerer dem alene eller blandet med egnede bærestoffer. Oppfinnelsens gjenstand er således også legemidler som minst inneholder en forbindelse med formel (i) eventuelt i form av et av dens fysilo-gisk tålbare syreaddisjonssalter som virksomt stoff. Preparatene kan appliseres oralt og parenteralt. Dosis for pral administrering utgjør f.eks. vanligvis 1 til 10, fortrinnsvis 3 til 5 mg pr. menneske/dag. Ved dyr utgjør en engangsdose f.eks. 0,1 til 10, fortrinnsvis 0,3 til 3 mg/kg i.v. Hensiktsmessig ut-styres herved de virksomme stoffer med en tilsetning av vanlig fortynnings- og/eller drøyemidler. Men også administrering av mikrokapsler uten en slik tilsetning er mulig. Egnede faste eller flytende galeniske tilberedninger er eksempelvis granu-later, pulvere, tabletter, kapsler, siruper, emulsjoner, sus-pensjoner, dråper eller injiserbare oppløsninger samt preparater med protrahert virksomtstoff-frigjøring. Som ofte anvendte bærestoffer skal det f.eks. nevnes magnesiumkarbonat, forskjellige sukkere, stivelse, cellulosederivater, gelatiner, dyriske og planteoljer, polyetylenglykoler og oppløsningsmidler.
En spesiell anvendelse av forbindelsen ifølge oppfinnelsen tilsvarende formel (i) samt deres salter ligger i kombinasjon med andre egnede virksomme stoffer, eksempelvis diure-tika, saluretika, a- og spesielt |3~sympatholytika, tranquil-lanter, karutvidende midler og andre antihypertensiva. Farmakologiske undersøkelser og resultater.
Forbindelsene ifølge oppfinnelsen med formel (i) er såvel virksomt på narkotisert, normotone hunder hypotensivt som også på de med høyt blodtrykk (hund og rotte) antihypertensivt.
1. Hvpotensiv virkning.
Som forsøksdyr tjente bastard-hunder av begge kjønn
i nåtrium-pentobarbital-narkose (35 ** 40 mg/kg i.p.) som under forsøket lå på et til 37°C oppvarmet operasjonsbord, og pustet spontant gjennom en trachealtubus. Til opphevelse av blodkoa-gulering fikk de 2 mg/kg heparin i.v..
Applikasjon med prøvestoffene foregikk
a) intravenøst (i.v.) i vandig oppløsning over et polyvinyl-kloridkateter i vena femoralis. Applikasjonstiden utgjorde.
alltid 30 sekunder,
b) intraduodenalt (i.d.) i form av karboksymetylcellulose-sus-pensjoner over et polyvinylklorid-kateter i duodenum. Det ble målt følgende kardiovaskulære størrelser: 1. p = midlere arterielt blodtrykk i mm Hg over et polyvinylklorid-kateter og en elektronisk trykkopptager fra firma Statham, 2. Hjertefrekvens /min" 7 ved hjelp av et EKG (il. ekstremitets-avledning) ved uttelling av R-tagger,
3. dp/d.tmax/mm Hg . sek "*"7 ved hjelp av en differensierer.
De viktigste forsøksresultater er sammenfattet i tabell
1. Heri betyr n antall forsøksdyr.
2. Antihypertensiv virkning
a) Genetisk høytrykksrotte (rotter med høyt blodtrykk)
Som forsøksdyr ble det anvendt våkne genetiske høy-trykksrotter (Wistar SH) av f or søksdyrb.ehandling Buckshire Corp./Perkasie, Pennsylvania, USA. Grupper fra hver gang 5 til 6 dyr fikk på tre påhverandre følgende dager om morgen prøve-stoffet per os. Blodtrykkmålingene foregikk hver gang 2, k, og 24 timer etter preparatinngivning ved hjelp av piezoelek-triske pulsmikrofoner på dyrenes hale, idet impulsene ble over-ført over et forsterkersystem til en 6-kanalskriver fra firma Hellige.
Herved viste det seg at forbindelsene ifølge oppfinnelsen fra doser på 7>5mg/kg per os har en sterk blodtrykksenkende effekt som vedvarer lenger enn 6 timer. Over den maksimale senkning av blodtrykket i forhold til utgangsverdien på første forsøksdag, gir tabell 2 opplysninger. Heri betyr n antall forsøksdyr* b) Renal høytrykkshund (hund med høyt blodtrykk) Stoffundersøkelsen foregikk védrÆlere dagers forsøk
på en gruppe våkne"trenerte renrasede Beagle-hunder (n 5)
med stabilt renalt blodhøytrykk (aseptisk perinephritis ved omhylling av begge nyrer med en celleglassfolie). Blodtrykkmålingene ble foretatt på halarterien etter den vanlige Riva-Rocchi-metode. Dyrene fikk hver morgen etter første blodtrykks-måling (utgangsverdi) det eventuelle prøvestoff i gelatinkap-sler per os i den angitte dose (virkningsdose w). Ytterligere blodtrykksmålinger foregikk hver gang.1 l/2, 3>5 og 7 timer etter preparatinngivning. Deretter administrerte man til dyrene annen gang prøvestoffet (i beholdsdoser E) . Det fast-slåtte blodtrykkverdi av alle dyr for samme forsøkstider ble undersøkt ved hjelp av t-prøvér ifølge student i forhold til utgangsverdien til signifikant p (= feilsannsynlighet). Resul-tatene er oppstilt i tabell 3»
I forhold til det på markedet befinnende antihyperten-sive prazosin /" 1-(4-amino-6,7-dimetoksy-2-kinazolinyl)-4-(2-furoyl)-piperazin-hydroklorid 7 kvis blodtrykksenkning er fulgt av en uønsket tachykardi viser forebindelsene ifølge oppfinnelsen generelt en bradykardi og avlaster dermed hjertet. Den pressoriske reaksjon på eksogen tilført katecholaminer hemmes bare måtelig av dem mens sammenligningspreparatet frembringer en fullstendig blokkade av OC-reseptorene som uttrykker seg i en omvending av adrenalin-reaksjonen.
Overensstemmende hermed viser forbindelsene med formel (i) på den isolerte sædblære hos marsvin bare liten, prazosin derimot en til phentolamin sammenlignbar sterk a-sympatikoly-tisk virkning.
En ytterligere fordel overfor sammenligningspreparatet prazosin består i at det ved forbindelsene ifølge oppfinnelsen dreier seg om antihypertensiva med fortrinnsvis sentral virknings-mekanisme.
Eksempler
Strukturen av de nedenfor omtalte forbindelser ble vist ved elementæranalyse samt ved hjelp av IR- og "*"H-NMR-spektre.
1. 0-/3-(4- ^2-metoksyfenyl^ -1-piperazinyl)-2-hydroksypropyl7-3- metoksv- benzaldoksim- dihydroklorid(strukturformelsetabell4)
I henhold til fremgangsmåte A oppløses 20,4 g (0,15 mol) 3-metoksybenzaldehyd i 400 ml etanol. Etter tilsetning av 6lf3g (0,15 mol) 0-/3- (4-(2-metoksyfenyl)-1-piperazinyl^ -2-hydroksypropyl7-hydroksylamin-trihydroklorid-monohydrat i 150 ml vann, tildryppes under stadig omrøring ved værelsetemperatur en oppløsning av 23»9g (0»225 mol) natriumkarbonat i 125 ml vann. Deretter omrøres i 30 måmåtter ved værelsetemperatur og 1 time ved 60 til 70°C, avdestillerer deretter etanol under nedsatt trykk, blander residuet med eddiksyreetylester og fjerner natriumklorid ved flere gangers vasking med vann. Den organiske fase etterlater etter tørkning over natriumsulfat og inndampning under nedsatt trykk 100 $ råbase, som for omdannelse i dihydro-klorid og oppløses i tørr eddiksyreetylester og under omrøring og avkjøling blandes dråpevis med 0,3 mol etanolisk saltsyre. Man frasuger det utfelte produkt, vasker med dietyleter og om» krystalliserer eventuelt fra etanol under tilsetning av dietyleter i kokevarme til uklarhet.
Utbytte: 6l,5 g (86,8 <fo av det teoretiske), sm.p. 171-173°C,
2. 0-/3- (4-(2-metoksyf enylJ-l-piperazinyl^^-hydroksypropylZ-benz-^ ldoksim- hvdroklorid (strukturformel se tabell 4)
I henhold til fremgangsmåte B2 har man til en oppløsning av 5»75 g (0»25 gramatom) natrium i 250 ml vannfri etanol 30,3 g (0,25 mol) benzaldoksim, omrører 30 minutter ved værelsetemperatur og fjerner alkoholen under nedsatt trykk.
Det tørkede natrium-oksimat innføres i løpet av 30 minutter under omrøring ved 80°C porsjonsvis i 156 ml (2 mol) epiklorhydrin og holdes ytterligere i 5 timer ved denne temperatur. Etter avkjøling frafiltreres utfelt natriumklorid og overskytende epiklorhydrin avdestilleres under nedsatt trykk. Fraksjonert vakuumdestillasjon av det oljeaktige residu gir 29,2 g (65,9 $ av det teoretiske) 0-(2,3-epoksypropyl)-benzaldoksim av kokepunkt (0,3 torr) 121-124°G. 26,6 g (0,15 mol) av dette epoksyd oppløses sammen med 28,8 g (0,15 mol) 1-(2-metoksyfenyl)-piperazin i 100 ml isopropanol og oppvarmes 4 timer under tilbake-løp. Ved tilsetning av en støkiometrisk mengde etanolisk saltsyre til den dannede reaksjonsblanding danner det seg monohydro-klorid som krystalliseres fra etanol under tilsetning av dietyl-et.er i kokevarme inntil uklarhet.
Utbytte: 45,1 g (74 <?o av det teoretiske), sm.p. l63-l64°C,
Den til ovennevnte hydroklorid til grunn liggende base danner også et krystallinsk oksalat og cyklamat med smeltepunkter på 143-144°G resp. 90-91°C.
3, 0-/3- ^4-(2-metoksyfenyl)-1-piperidyl^ -2-hydroksypropyl7-benzaXdoksim- hydroklorid (strukturformel se tabell 4)
Tilsvarende fremgangsmåte B2 oppløses 5,3 g (0,03 mol) av det i første trinn som etter eksempel 2 fremstilte 0-(2,3-epoksypropyl)-benzaldoksim og 5,7 g (0,03 mol) 4-(2-metoksyfenyl)-piperidin i 50 ml isopropanol og kokes 4 timer under til-bakeløp. Man lar det avkjøle, blander med etanolisk saltsyre, adskiller den krystallinske utfelling og omkrystallisereE fra etanol.
Utbytte: 8,2 g (67,2 <fo av det teoretiske), sm.p. 155-157°C,
4. 0-/3- (4- (2-metoksyf enyl)-1-piperazinyl) -propyl7-t>enzal-doksim- dihydroklorid(strukturformel setabell ) I henhold til fremgangsmåte Bl har man til en oppløs-ning av 1,84 g (0,08 ,'ga?åmatom) natrium i 150 ml vannfri etanol, 9,7 g (0,08 mol) benzaldoksim og etteromrører 30 minutter ved værelsetemperatur, blander deretter med 21,5 g (0,08 mol) 3-^/<5>-(2-metoksyfenyl)-l-piperazinyl7-propylklorid og oppvarmer 8 timer under tilbakeløp. Deretter inndampes reaksjonsblandingen under nedsatt trykk, residuet blandes med vann og reaksjonspro-duktet ekstraheres med kloroform. Etter tørkning over natriumsulfat avdestillerer man oppløsningsmidlet igjen under redusert trykk, tar det oljeaktige residu i tørr eddiksyreetylester og surgjør med etanolisk saltsyre, idet produkter faller ut i form av dihydrokloridet som voluminøst fast stoff. Utbytte utgjør etter to gangers omkrystallisering fra isopropanol 22,4 g (65,3$ av det teoretiske). Sm.p. 188-189°C, C2.jHgpClgN^Og (MG = 426,4)
5. 0~^3-(4-(2-metoksyfenyl)-1-piperazinyl) -2-nikotinoyloksy-propyl7-benzaldoksim-dihydroklorid(strukturformelsetabell 4)
18, 5 g (9,05 mol) 0-/3-^4-(2-metoksyfenyl)-1-pipera-zinyi) -2-hydroksypropyl7-t>enzaldoksim fra eksempel 2 oppløses i-følge fremgangsmåte C i 200 ml kloroform og oppvarmes etter tilsetning av 8,5 g (0,06 mol) nikotinsyreklorid i 12 timer under tilbakeløp. Deretter lar man det avkjøle, vasker kloroformopp-løsning i rekkefølge med 2 n natronlut og vann, tørker over
natriumsulfat og inndamper under nedsatt trykk. Residuet opp-løses i varm isopropanol og blandes med etanolisk saltsyre, idet.ovennevnte forbindelse utkrystalliserer krystallinsk.
Flere gangers gjenoppløsning fra isopropanol gir 24,5 g (89,6 $ av det teoretiske) analyserent produkt av sm.p, 188-189°C,
Analogt lar det seg også fremstille øvrige i tabell h oppførte forbindelser etter fremgangsmåtevariant A, B eller C.
Claims (3)
1. Fremgangsmåte til fremstilling av basisksubstituerte O-propyloksimer med formel (i)
karakterisert ved at forbindelser med strukturelementet R" <*> "-C= (il) og forbindelser med gruppering med formel
R 2(III)
under innskyvning av broleddet
sammen-
i knyttes med hverandre idetA) karbonylforbindelser med formel
eller deres reak
sjonsdyktige derivater omsettes med eventuelt ved fenylresten substituerte hydroksylaminderivater (Vi)
eller deres salter eller B) oksimforbindelse med formel
Bl) omsettes med basisksubstituert propylforbindelser med formel
fVIII)
eller deres salter eller B2) omdannes med propylderivater med formel
i O-alkylerte oksimer med formel og disse omsettes deretter med aminer med formel (Xl)
idet i ovennevnte formeJter
R1 betyr
a) hydrogen eller en karboksylgruppe,
b) en alkyl- eller alkylengruppe med hver gang inntil 6 c-atomer som i tillegg kan ha en fenylgruppe,
c) en en- eller tokjernet arylgruppe som kan være substituert inntil tre ganger med alkyl eller alkoksy med hver gang inn-til 6 c-atomer, benzyloksy, halogenalkyl med inntil 2 c-atomer, halogen, cyano-, nitro-, eventuelt med metyl og/eller etyl substituert amino-, karboksyl- eller hydroksylgruppe, metylendioksy-resten eller 0-/3-(4-(2-metoksyfenyl^-1-pipe-razinyl)-2-hydroksypropyl7-hydroksiminometyl-resten hver gang alene eller i kombinasjon,
d) en mono- eller bicyklisk heteroaromatisk gruppe med ftitil 4 nitrogenatomer eller et svovel- eller oksygenatom i ring-systernet, som eventuelt er substituert inntil tre ganger med alkyl eller alkoksy med hver gang inntil 2 c-atomer, fenylalkyl med inntil 3 c-atomer i alkyldelen, halogen av metyl-eller dimetylaminogruppen, hver gang alene eller i kombinasjon,
R <2> betyr
hydrogen, en alkylgruppe med inntil 3 c-atomer, en cykloalkyl-rest med inntil 6 c-atomer eller en fenylrest eller R 1 og R 2danner sammen med c-atomet hvortil de er bundet en even
tuelt også med hydrokarbonrester overbroet cykloalifatisk rest med inntil 10 c-atomer eller f luoren-9-ylid.en-resten,
3
R-^ betyr
hydrogen eller en hydroksylgruppe som eventuelt er acylert,' R betyr
hydrogen, en alkylgruppe med inn-til 3 c-atomer eller en fenylrest,
5
R betyr
hydrogen, halogen, en alkoksygruppe med inntil 2 c-atomer eller hydroksyl og
X betyr
et nitrogenatom eller en metingruppe,
Y og Z betyr
hver et halogenatom, fortrinnsvis klor eller brom, eller en reaktiv.sulfonsyreestergruppering eller Y danner sammen med R 3 og de to c-atomer, hvortil de er bundet, en oksiranring, og M betyr
hydrogen, alkali eller jordalkali eller
C) forbindelser med formel (i), hvori R betyr hydroksyl acyler»r og de etter A) til C) dannede produkter med formel (i) isoleres enten i form av de fri baser eller overføres med egnede syrer i deres fysiologisk tålbare syreaddisjonssalter.
2. Fremgangsmåte ifølge krav 1, karakterisert ved acyleringen etter fremgangsmåte c) gjennomfares med en alkankarboksylsyre med inntil 6 c-atomer, nikotin- eller en eventuelt inntil tre ganger med alkoksy med hver gang 1 til 4 c-atomer substituerte benzosyre.
3. » Fremgangsmåte ifølge krav 1 eller 2, karakterisert ved at det fremstilles 0-/3-(4-(2-metoksyfenyl)-1-piperazinyl)-2-hydroksyp;ropyl7-benzaldoksium, - 3-me toksybenz-aldoksim eller 0-/3-(4-(2-metoksyfenyl)-1-piperazinyl)-2-hydrok-sypropyl/-3-pyridylaldoksim og deres syreaddisjonssalter.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19762658938 DE2658938A1 (de) | 1976-12-24 | 1976-12-24 | Neue basisch substituierte 0-propyloxime, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
Publications (1)
Publication Number | Publication Date |
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NO774456L true NO774456L (no) | 1978-06-27 |
Family
ID=5996701
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO774456A NO774456L (no) | 1976-12-24 | 1977-12-23 | Fremgangsmaate til fremstilling av nye basisk substituerte o-propyloksimer og deres anvendelse som legemiddel |
Country Status (24)
Country | Link |
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US (1) | US4328227A (no) |
JP (4) | JPS5379875A (no) |
AT (1) | AT360544B (no) |
AU (1) | AU512353B2 (no) |
BE (1) | BE862303A (no) |
CA (1) | CA1105933A (no) |
DE (1) | DE2658938A1 (no) |
DK (1) | DK575277A (no) |
ES (3) | ES465204A1 (no) |
FI (1) | FI773903A (no) |
FR (1) | FR2375225A1 (no) |
GB (1) | GB1543517A (no) |
GR (1) | GR70042B (no) |
HU (1) | HU177453B (no) |
IE (1) | IE46226B1 (no) |
IL (1) | IL53674A (no) |
IT (1) | IT1089233B (no) |
LU (1) | LU78770A1 (no) |
NL (1) | NL7714054A (no) |
NO (1) | NO774456L (no) |
PL (3) | PL111792B1 (no) |
PT (1) | PT67444B (no) |
SE (1) | SE7714685L (no) |
ZA (1) | ZA777586B (no) |
Families Citing this family (5)
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DE3704604A1 (de) * | 1987-02-13 | 1988-08-25 | Mack Chem Pharm | Oximether von 2,6-dioxabicyclo(3.3.0)octanonen, herstellungsverfahren und anwendung als arzneimittel |
HU212415B (en) * | 1989-08-25 | 1996-06-28 | Egyt Gyogyszervegyeszeti Gyar | Process for producing new cyclic oxym derivatives and pharmaceutical compositions containing them as active components |
DE4306392A1 (de) * | 1993-03-02 | 1994-09-08 | Basf Ag | ß-Hydroxyoximether und bei Raumtemperatur mit ß-Hydroxyoximethern vernetzbare Dispersionen oder Lösungen |
US5665756A (en) * | 1994-08-03 | 1997-09-09 | Hoechst Marion Roussel, Inc. | Aminoalkyloximes useful in the treatment of depression and obsessive compulsive disorders |
ATE294778T1 (de) * | 1995-01-23 | 2005-05-15 | Daiichi Suntory Pharma Co Ltd | Verbesserung oder heilung von durch ischämischen krankheiten hervorgerufenen symtomen und dafür verwendbare phenylpiperidinverbingungen |
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US2832804A (en) * | 1958-04-29 | Production of i-aminoindan derivatives | ||
US2712031A (en) * | 1953-10-27 | 1955-06-28 | Lasdon Foundation Inc | Monosubstituted salicylaldehyde alkoximes |
US3060177A (en) * | 1957-11-11 | 1962-10-23 | Ciba Geigy Corp | O-(aminoalkyl)oxime derivatives of heterocyclic aldehydes and ketones |
US3692835A (en) * | 1967-04-05 | 1972-09-19 | Jan Van Dijk | Pharmacologically active amino-ethyl oximes |
US3951983A (en) * | 1970-11-10 | 1976-04-20 | Pfizer Inc. | Phenoxypropanolpiperazines |
SE371193B (no) * | 1972-03-24 | 1974-11-11 | Kabi Ab | |
US3954763A (en) * | 1972-04-10 | 1976-05-04 | Synthelabo | N-Metatrifluoromethylthiophenyl-piperazine |
GB1415505A (en) * | 1972-06-01 | 1975-11-26 | Ici Ltd | Alkanolamine derivatives |
SE397088B (sv) * | 1972-06-17 | 1977-10-17 | Sumitomo Chemical Co | Forfarande for framstellning av nya 2-propanolderivat |
US4100282A (en) * | 1972-12-23 | 1978-07-11 | Boehringer Ingelheim Gmbh | N-Aryl-N'-(phenyl- or phenoxy-alkyl)-piperazines and salts thereof |
GB1437868A (en) * | 1973-05-09 | 1976-06-03 | Synthelabo | Arylpiperazinoalkyl esters |
US4207319A (en) * | 1973-10-19 | 1980-06-10 | Albert Rolland S.A. | Thienyl or furyl phenyl O-hetero amino alkyl oximes and use thereof |
US3960956A (en) * | 1974-11-21 | 1976-06-01 | E. I. Du Pont De Nemours & Company | Antidepressant 1,1a,6,10b-tetrahydrodibenzo(a,e)-cyclo-propa(c) cyclohepten-6-substituted oximes |
GB1474316A (en) * | 1975-02-12 | 1977-05-25 | Seperic | O-aminoalkyl oximes |
GB1493222A (en) * | 1976-01-27 | 1977-11-30 | Egyt Gyogyszervegyeszeti Gyar | Cycloalkanone oxime ethers and process for the preparation thereof |
US4187220A (en) * | 1977-08-30 | 1980-02-05 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara R.T. | New O-(3-amino-2-hydroxy-propyl)-amidoxime derivatives, process for the preparation thereof and pharmaceutical compositions containing same |
-
1976
- 1976-12-24 DE DE19762658938 patent/DE2658938A1/de not_active Withdrawn
-
1977
- 1977-12-19 NL NL7714054A patent/NL7714054A/xx not_active Application Discontinuation
- 1977-12-19 ES ES465204A patent/ES465204A1/es not_active Expired
- 1977-12-21 GB GB53220/77A patent/GB1543517A/en not_active Expired
- 1977-12-21 ZA ZA00777586A patent/ZA777586B/xx unknown
- 1977-12-21 AU AU31811/77A patent/AU512353B2/en not_active Expired
- 1977-12-22 IL IL53674A patent/IL53674A/xx unknown
- 1977-12-22 SE SE7714685A patent/SE7714685L/xx not_active Application Discontinuation
- 1977-12-22 GR GR55042A patent/GR70042B/el unknown
- 1977-12-22 IE IE2605/77A patent/IE46226B1/en unknown
- 1977-12-22 AT AT924777A patent/AT360544B/de not_active IP Right Cessation
- 1977-12-22 PT PT67444A patent/PT67444B/pt unknown
- 1977-12-22 FI FI773903A patent/FI773903A/fi not_active Application Discontinuation
- 1977-12-22 DK DK575277A patent/DK575277A/da not_active Application Discontinuation
- 1977-12-23 LU LU78770A patent/LU78770A1/xx unknown
- 1977-12-23 JP JP15547977A patent/JPS5379875A/ja active Pending
- 1977-12-23 HU HU77HO2037A patent/HU177453B/hu unknown
- 1977-12-23 BE BE183831A patent/BE862303A/xx unknown
- 1977-12-23 FR FR7739023A patent/FR2375225A1/fr active Granted
- 1977-12-23 NO NO774456A patent/NO774456L/no unknown
- 1977-12-23 IT IT31206/77A patent/IT1089233B/it active
- 1977-12-23 CA CA293,826A patent/CA1105933A/en not_active Expired
- 1977-12-24 PL PL1977214671A patent/PL111792B1/pl unknown
- 1977-12-24 PL PL1977214670A patent/PL112153B1/pl unknown
- 1977-12-24 PL PL1977203359A patent/PL110753B1/pl unknown
-
1978
- 1978-05-04 ES ES469456A patent/ES469456A1/es not_active Expired
- 1978-05-04 ES ES469455A patent/ES469455A1/es not_active Expired
-
1979
- 1979-02-28 JP JP2205679A patent/JPS54141784A/ja active Pending
-
1980
- 1980-05-19 US US06/150,705 patent/US4328227A/en not_active Expired - Lifetime
- 1980-06-12 JP JP7845480A patent/JPS5695166A/ja active Pending
- 1980-06-12 JP JP7845580A patent/JPS5677275A/ja active Pending
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