NO131908B - - Google Patents
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- Publication number
- NO131908B NO131908B NO3347/71A NO334771A NO131908B NO 131908 B NO131908 B NO 131908B NO 3347/71 A NO3347/71 A NO 3347/71A NO 334771 A NO334771 A NO 334771A NO 131908 B NO131908 B NO 131908B
- Authority
- NO
- Norway
- Prior art keywords
- piperazine
- benzene
- methoxyphenyl
- mixture
- analysis
- Prior art date
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- -1 alkoxyalkyl halide Chemical class 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000011230 binding agent Substances 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N p-toluenesulfonic acid Substances CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- 150000004982 aromatic amines Chemical class 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical group 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 96
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- 239000000203 mixture Substances 0.000 description 24
- 239000000047 product Substances 0.000 description 24
- 229910052739 hydrogen Inorganic materials 0.000 description 22
- 229910052799 carbon Inorganic materials 0.000 description 19
- 239000002585 base Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 238000010992 reflux Methods 0.000 description 13
- 238000009835 boiling Methods 0.000 description 11
- 239000000284 extract Substances 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000002844 melting Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 229910052760 oxygen Inorganic materials 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 229960005141 piperazine Drugs 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- ITNSQDCAZVVFMS-UHFFFAOYSA-N 1-(2-methoxyphenyl)-4-(3-methoxypropyl)piperazine Chemical compound C1CN(CCCOC)CCN1C1=CC=CC=C1OC ITNSQDCAZVVFMS-UHFFFAOYSA-N 0.000 description 5
- VNZLQLYBRIOLFZ-UHFFFAOYSA-N 1-(2-methoxyphenyl)piperazine Chemical compound COC1=CC=CC=C1N1CCNCC1 VNZLQLYBRIOLFZ-UHFFFAOYSA-N 0.000 description 5
- 206010020772 Hypertension Diseases 0.000 description 5
- 230000036772 blood pressure Effects 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 4
- FAXDZWQIWUSWJH-UHFFFAOYSA-N 3-methoxypropan-1-amine Chemical compound COCCCN FAXDZWQIWUSWJH-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000001631 hypertensive effect Effects 0.000 description 3
- JHEGFJPJFFDLIB-UHFFFAOYSA-N n,n-bis(2-chloroethyl)-2-methoxyaniline Chemical compound COC1=CC=CC=C1N(CCCl)CCCl JHEGFJPJFFDLIB-UHFFFAOYSA-N 0.000 description 3
- PEVHLEAAXLKMSZ-UHFFFAOYSA-N 7-methoxyheptan-1-amine Chemical compound COCCCCCCCN PEVHLEAAXLKMSZ-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 208000032140 Sleepiness Diseases 0.000 description 2
- 206010041349 Somnolence Diseases 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 229940125717 barbiturate Drugs 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 150000004885 piperazines Chemical class 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- NCOMQNWYMLGJPF-UHFFFAOYSA-N 1-(2-methoxyphenyl)-4-(3-methoxypropyl)piperazine;phosphoric acid Chemical compound OP(O)(O)=O.C1CN(CCCOC)CCN1C1=CC=CC=C1OC NCOMQNWYMLGJPF-UHFFFAOYSA-N 0.000 description 1
- ZYXMVSPWOATGIW-UHFFFAOYSA-N 1-(2-methoxyphenyl)-4-methylpiperazine Chemical compound COC1=CC=CC=C1N1CCN(C)CC1 ZYXMVSPWOATGIW-UHFFFAOYSA-N 0.000 description 1
- CEVMYGZHEJSOHZ-UHFFFAOYSA-N 1-bromo-3-methoxypropane Chemical compound COCCCBr CEVMYGZHEJSOHZ-UHFFFAOYSA-N 0.000 description 1
- LPFDVSDSQQLJMA-UHFFFAOYSA-N 1-bromo-8-methoxyoctane Chemical compound COCCCCCCCCBr LPFDVSDSQQLJMA-UHFFFAOYSA-N 0.000 description 1
- OGWXTWGOYZGJTH-UHFFFAOYSA-N 1-bromo-9-methoxynonane Chemical compound COCCCCCCCCCBr OGWXTWGOYZGJTH-UHFFFAOYSA-N 0.000 description 1
- ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 description 1
- ZRJOUVOXPWNFOF-UHFFFAOYSA-N 3-dodecoxypropan-1-amine Chemical compound CCCCCCCCCCCCOCCCN ZRJOUVOXPWNFOF-UHFFFAOYSA-N 0.000 description 1
- SOYBEXQHNURCGE-UHFFFAOYSA-N 3-ethoxypropan-1-amine Chemical compound CCOCCCN SOYBEXQHNURCGE-UHFFFAOYSA-N 0.000 description 1
- NWGJTXNNXLHFSE-UHFFFAOYSA-N 3-hexoxypropan-1-amine Chemical compound CCCCCCOCCCN NWGJTXNNXLHFSE-UHFFFAOYSA-N 0.000 description 1
- HWZUQAKHJDKBOE-UHFFFAOYSA-N 3-methoxypropyl 4-methylbenzenesulfonate Chemical compound COCCCOS(=O)(=O)C1=CC=C(C)C=C1 HWZUQAKHJDKBOE-UHFFFAOYSA-N 0.000 description 1
- VHYUNSUGCNKWSO-UHFFFAOYSA-N 3-propan-2-yloxypropan-1-amine Chemical compound CC(C)OCCCN VHYUNSUGCNKWSO-UHFFFAOYSA-N 0.000 description 1
- YUUFAJOXLZUDJG-UHFFFAOYSA-N 4-methoxybutan-1-amine Chemical compound COCCCCN YUUFAJOXLZUDJG-UHFFFAOYSA-N 0.000 description 1
- DMRHQYSRQGGRCK-UHFFFAOYSA-N 5-methoxypentan-1-amine Chemical compound COCCCCCN DMRHQYSRQGGRCK-UHFFFAOYSA-N 0.000 description 1
- UVOBODVSFRKUQX-UHFFFAOYSA-N 6-methoxyhexan-1-amine Chemical compound COCCCCCCN UVOBODVSFRKUQX-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 200000000007 Arterial disease Diseases 0.000 description 1
- 206010062542 Arterial insufficiency Diseases 0.000 description 1
- 206010052895 Coronary artery insufficiency Diseases 0.000 description 1
- 206010011703 Cyanosis Diseases 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000037007 arousal Effects 0.000 description 1
- 150000008107 benzenesulfonic acids Chemical class 0.000 description 1
- 230000001914 calming effect Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000003457 ganglion blocking agent Substances 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 201000009939 hypertensive encephalopathy Diseases 0.000 description 1
- 208000015210 hypertensive heart disease Diseases 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 239000005554 hypnotics and sedatives Substances 0.000 description 1
- 229940005535 hypnotics and sedatives Drugs 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- NQQWFVUVBGSGQN-UHFFFAOYSA-N phosphoric acid;piperazine Chemical compound OP(O)(O)=O.C1CNCCN1 NQQWFVUVBGSGQN-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229940080360 rauwolfia alkaloid Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
Classifications
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01H—ELECTRIC SWITCHES; RELAYS; SELECTORS; EMERGENCY PROTECTIVE DEVICES
- H01H33/00—High-tension or heavy-current switches with arc-extinguishing or arc-preventing means
- H01H33/70—Switches with separate means for directing, obtaining, or increasing flow of arc-extinguishing fluid
- H01H33/72—Switches with separate means for directing, obtaining, or increasing flow of arc-extinguishing fluid having stationary parts for directing the flow of arc-extinguishing fluid, e.g. arc-extinguishing chamber
- H01H33/75—Liquid-break switches, e.g. oil-break
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01H—ELECTRIC SWITCHES; RELAYS; SELECTORS; EMERGENCY PROTECTIVE DEVICES
- H01H3/00—Mechanisms for operating contacts
- H01H3/60—Mechanical arrangements for preventing or damping vibration or shock
Landscapes
- Driving Mechanisms And Operating Circuits Of Arc-Extinguishing High-Tension Switches (AREA)
- Circuit Breakers (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Fremgangsmåte for fremstilling av terapeutisk aktive N-(o-alkoksyfenyl)-N'-alkoksyalkylpiperaziner. Process for the preparation of therapeutically active N-(o- alkoxyphenyl)-N'- alkoxyalkyl piperazines.
Nærværende oppfinnelse vedrører en fremgangsmåte for fremstilling av en ny rekke N- (o-alkoksyf enyl) -N'-alkoksyalkyl-piperaziner. The present invention relates to a process for the production of a new series of N-(o-alkyloxyphenyl)-N'-alkylalkyl piperazines.
Ved behandlingen av hypertensive tilstander krever terapien vanligvis admini-strasjon av en droge over et lengere tids-rom, og det er vesentlig at drogen er i be-siddelse av gode terapeutiske egenskaper uten noen alvorlige uønskede effekter. Særlig er det ønskelig at drogen er i det vesent-lige ikke giftig, oralt effektiv og har evnen til å fremkalle en betydelig reduksjon i blodtrykket. Det er også sterkt ønsket at pasientens blodtrykk både i liggende og stående stilling senkes av drogen. In the treatment of hypertensive conditions, the therapy usually requires the administration of a drug over a longer period of time, and it is essential that the drug has good therapeutic properties without any serious unwanted effects. In particular, it is desirable that the drug is essentially non-toxic, orally effective and has the ability to induce a significant reduction in blood pressure. It is also strongly desired that the patient's blood pressure both in a lying and standing position is lowered by the drug.
Forbindelsene fremstilt etter nærværende oppfinnelse synes å ha en dobbelt virkning ved at de virker perifert for å sen-ke den vaskulare motstand og således det effektive vaskulare blodtrykk og er også funnet å ha en markert sentral virkning som reduserer de kausative faktorer, som virker sentralt til å øke blodtrykket hos pasienten, som lider av hypertensjon. Forbindelsene er derfor særlig egnede for å behandle pasienter med progressiv hypertensjon og også de, som lider av hyperten-siv encefalopatia. På grunn av forbindel-sens vaso-dilaterende effektivitet har de også ytterligere anvendelighet ved behandlingen av mange sykdommer forbundet med alder, som koronær svekkelse, serebral svekkelse og arterial svekkelse, og sykdommer ved hvilke acrocyanosis er en kompo-nent, som Reynaud's sykdom, skleroderma og liknende. The compounds produced according to the present invention appear to have a double effect in that they act peripherally to lower the vascular resistance and thus the effective vascular blood pressure and are also found to have a marked central effect which reduces the causative factors, which act centrally to to increase the blood pressure of the patient, who suffers from hypertension. The compounds are therefore particularly suitable for treating patients with progressive hypertension and also those suffering from hypertensive encephalopathy. Because of the compounds' vasodilating effectiveness, they also have further utility in the treatment of many diseases associated with age, such as coronary insufficiency, cerebral insufficiency and arterial insufficiency, and diseases in which acrocyanosis is a component, such as Reynaud's disease, scleroderma and similar.
Forbindelsene fremstilt ifølge oppfinnelsen gir også somnolens eller sedasjon avhengig av den administrerte dose og pasientens tilstand. Forbindelsene reduserer dessuten opphisselsestilstander hos pasienten, og har således en beroligende virkning, og har også tendens til å slappe av pasientens skeletale muskler. Når en 25 mg's dose N-(o-metoksyfenyl) -N'-(3-metoksypropyl)-piperazinfosfat administreres til en gjen-nomsnittspasient ved leggetid, opptrer i tillegg til et raskt fall i blodtrykket en sund fredelig søvn fra hvilken pasienten lett våkner og vender tilbake til normal tilstand. Den forannevnte piperazinfosfatsalt som har en hypnotisk effekt av kortere va-righet enn barbituratene, er derfor også egnet for hypertensive pasienter som ønsker å ta en blund midt på dagen eller på annen måte spenne av midt under de anstrengel-ser som man er utsatt for i løpet av dagen. The compounds produced according to the invention also produce somnolence or sedation depending on the administered dose and the patient's condition. The compounds also reduce arousal states in the patient, and thus have a calming effect, and also tend to relax the patient's skeletal muscles. When a 25 mg dose of N-(o-methoxyphenyl)-N'-(3-methoxypropyl)-piperazine phosphate is administered to an average patient at bedtime, in addition to a rapid drop in blood pressure, a sound peaceful sleep occurs from which the patient readily awakens and returns to normal state. The aforementioned piperazine phosphate salt, which has a hypnotic effect of shorter duration than the barbiturates, is therefore also suitable for hypertensive patients who want to take a nap in the middle of the day or in some other way relax in the middle of the efforts to which they are exposed in during the day.
Da piperazinforbindelsene fremstilt etter nærværende oppfinnelse kan forenes med andre droger som vanligvis brukes for å behandle hypertensive tilstander, kan de, hvis ønsket, kombineres med disse andre droger, som hypnotika og sedativer inklu-dert barbituratene, hvor en forlenget somnolens er ønsket, rauwolfia alkaloider og glukosidene, urindrivende midler, ganglion-blokerende midler og med kombinasjoner av drogene vanligvis anvendt ved behandlingen av hypertensive hjertesykdommer. Since the piperazine compounds produced according to the present invention can be combined with other drugs that are usually used to treat hypertensive conditions, they can, if desired, be combined with these other drugs, such as hypnotics and sedatives including the barbiturates, where a prolonged somnolence is desired, rauwolfia alkaloids and the glucosides, diuretics, ganglion blocking agents and with combinations of the drugs commonly used in the treatment of hypertensive heart diseases.
Forbindelsene som fremstilles etter nærværende oppfinnelse har følgende ge-I nerelle formel: The compounds produced according to the present invention have the following general formula:
i hvilken R er en lavere alkylgruppe med 1 til 6 carbonatomer, R' er en alkylgruppe med 1 til 12 carbonatomer, og n er et helt tall med verdiene 2 til 12. in which R is a lower alkyl group of 1 to 6 carbon atoms, R' is an alkyl group of 1 to 12 carbon atoms, and n is an integer having the values 2 to 12.
Forbindelsene etter foranstående generelle formel kan fremstilles på følgende måte: 1. Ved å reagere et N,N-bis-(p-halo-etyl)-arylamin med det egnede alkoksyal-kylamin, fortrinnsvis i et inert organisk oppløsningsmiddel, som 95 %'s etanol, i overensstemmelse med den følgende generelle ligning: hvor R, R' og n har foran angitte betydning, og X er Cl, Br eller J. To ytterligere mol av aminet eller annen ekvivalent base kan brukes ved reaksjonen for å binde de to mol av den dannede hydrohalogensyre. 2. Ved reaksjon av et N-(o-alkoksyf e-nyl)-piperazin med det egnede alkoksyal-kylhalogenid i overensstemmelse med den følgende ligning: hvor R, R', n og X har foran angitte betydning. 3. Ved reaksjon i et egnet oppløsnings- middel av et N-( o-alkoksyf enyl)-piperazin med p-toluensulfonsyreesteren av det egnede alkoksykarbinol i overensstemmelse med den følgende generelle ligning: The compounds according to the above general formula can be prepared in the following way: 1. By reacting an N,N-bis-(p-halo-ethyl)-arylamine with the suitable alkoxyal-cylamine, preferably in an inert organic solvent, such as 95% s ethanol, in accordance with the following general equation: where R, R' and n have the meanings given above, and X is Cl, Br or J. Two additional moles of the amine or other equivalent base can be used in the reaction to bind the two moles of the hydrohalic acid formed. 2. By reaction of an N-(o-Alkoxyphenyl)-piperazine with the appropriate Alkoxyal-Cylhalide in accordance with the following equation: where R, R', n and X have the above meanings. 3. When reacting in a suitable solvent agent of an N-(o-alkoxy enyl)-piperazine with the p-toluenesulfonic acid ester of the appropriate alkoxycarbinol in accordance with the following general equation:
hvor R, R' og n har foran angitte betydning. Andre arylsulfonsyreestre kan brukes i stedet for p-toluensulfonsyreesteren, som benzensulfonsyreestre. where R, R' and n have the meanings given above. Other arylsulfonic acid esters can be used in place of the p-toluenesulfonic acid ester, such as benzenesulfonic acid esters.
Om ønskes, kan de erholdte baser omdannes til syreaddisjonssalter på i for seg If desired, the bases obtained can be converted into acid addition salts per se
-kjent måte. -known way.
De følgende eksempler vil illustrere oppfinnelsen nærmere. The following examples will illustrate the invention in more detail.
Eksempel 1: Example 1:
N- ( o- metoksyfenyl) - N'-( 3- metoksypropyl) - piperazin N-(o-Methoxyphenyl)-N'-(3-Methoxypropyl)-piperazine
I en flaske innføres en blanding av 124 g (0,5 mol) N,N-bis-(|3-kloretyl)-o-anisidin, 134 g (1,5 mol) 3-metoksypropylamin og 550 ml 95 %'s etanol. Blandingen oppvarmes under tilbakeløp i ca. tre timer eller inntil reaksjonen er fullendt og konsentreres derpå på et dampbad for å fjerne mes-teparten av oppløsningsmidlet. Residuet behandles med 500 ml vann og 200 ml benzen og rystes godt. Det vandige lag skilles fra og rystes igjen med 200 ml benzen. De forenede benzenoppløsninger rystes en gang med 100 ml vann, separeres og konsentreres. Destillasjon av den gjenværende olje gir 116 g av produktet, N-(o-metoksyfenyl)-N'-(3-metoksypropyl) -piperazin, en farge-løs olje som koker ved ca. 138° C ved 0,1 mm A mixture of 124 g (0.5 mol) of N,N-bis-(|3-chloroethyl)-o-anisidine, 134 g (1.5 mol) of 3-methoxypropylamine and 550 ml of 95% ethanol. The mixture is heated under reflux for approx. three hours or until the reaction is complete and then concentrated on a steam bath to remove most of the solvent. The residue is treated with 500 ml of water and 200 ml of benzene and shaken well. The aqueous layer is separated and shaken again with 200 ml of benzene. The combined benzene solutions are shaken once with 100 ml of water, separated and concentrated. Distillation of the remaining oil gives 116 g of the product, N-(o-methoxyphenyl)-N'-(3-methoxypropyl)-piperazine, a colorless oil boiling at approx. 138° C at 0.1 mm
25 25
trykk og n D = 1.5369. Kjemisk analyse kalkulert for C,-H,,N202: Teoretisk 68,14 % C; 9,15 % H og 10,60 % N; sammenlignet med den fundne analyse på 68,35 % C; 9,43 % H og 10,63 % N. pressure and n D = 1.5369. Chemical analysis calculated for C,-H,,N 2 O 2 : Theoretical 68.14% C; 9.15% H and 10.60% N; compared to the found analysis of 68.35% C; 9.43% H and 10.63% N.
Ved å følge fremgangsmåten anvendt i eksempel 1 er det mulig å oppnå det nevnte produkt ved å bruke et mol til molfor-hold av N,N-bzs-(p-kloretyl)-o-anisidin og 3-metoksypropylamin sammen med et mol natriumkarbonat, som nøytraliserer hydro-genkloridet som dannes ved reaksjonen. På liknende måte kan to mol trietylamin brukes i stedet for natriumkarbonatet som syrebindemiddel. By following the procedure used in example 1, it is possible to obtain the aforementioned product by using a mole to mole ratio of N,N-bzs-(p-chloroethyl)-o-anisidine and 3-methoxypropylamine together with one mole of sodium carbonate , which neutralizes the hydrogen chloride formed by the reaction. Similarly, two moles of triethylamine can be used instead of the sodium carbonate as acid binder.
Tallrike salter av foran nevnte baseprodukt kan fremstilles ved å behandle en oppløsning av den nevnte base i etanol med en etanolsk oppløsning av den egnede syre i passende molare mengder, kjøle reak-sjonsoppløsningen, filtrere det bunnfelte salt og tørke det. Således ble det funnet at monohydrokloridet av basen smeltet ved 155—158° C og dihydrokloridsaltet har et smeltepunkt på 205—206° C. Fumaratet av basen ble funnet å ha smeltepunktet 143° C og fosfatet av basen hadde et smeltepunkt på 143—144° C. Numerous salts of the aforementioned base product can be prepared by treating a solution of the aforementioned base in ethanol with an ethanolic solution of the appropriate acid in suitable molar amounts, cooling the reaction solution, filtering the precipitated salt and drying it. Thus the monohydrochloride of the base was found to melt at 155-158° C and the dihydrochloride salt had a melting point of 205-206° C. The fumarate of the base was found to have a melting point of 143° C and the phosphate of the base had a melting point of 143-144° C.
Utgangsmaterialet N,N-bis-((3-kloretyl)-o-anisidin med formelen: The starting material N,N-bis-((3-chloroethyl)-o-anisidine with the formula:
kan fremstilles som følger: can be produced as follows:
Til 31 g fosforoksyklorid tilsettes i porsjoner under rystning 21 g N,N-bis-((3-hy-droksyetyl)-o-anisidin. Blandingen oppvarmes derpå på et dampbad i en time og fortynnes med 200 cm<3> vann og får henstå i tre timer for å fullende reaksjonen. Den resulterende oppløsning rystes med to porsjoner benzen, hver på 100 cm<3>. De forenede benzenekstrakter destilleres og gir 16 g av et produkt som koker ved 146—150° C To 31 g of phosphorus oxychloride, 21 g of N,N-bis-((3-hydroxyethyl)-o-anisidine is added in portions while shaking. The mixture is then heated on a steam bath for one hour and diluted with 200 cm<3> of water to obtain stand for three hours to complete the reaction. The resulting solution is shaken with two portions of benzene, each 100 cm<3>. The combined benzene extracts are distilled to give 16 g of a product boiling at 146-150°C
25 25
ved 1 mm's trykk og n D = 1,5477. Aana- at 1 mm's pressure and n D = 1.5477. Aana-
lyse kalkulert for CnH^CUSK): Teoretisk 53,24 % C og 6,09 % H; sammenlignet med den fundne analyse på 53,48 % C og 5,88 lyse calculated for CnH^CUSK): Theoretical 53.24% C and 6.09% H; compared to the found analysis of 53.48% C and 5.88
%H. %H.
Eksempel 2: Example 2:
N- ( o- metoksyfenyl) - N'-( 3- metoksypropyl) - piperazin N-(o-Methoxyphenyl)-N'-(3-Methoxypropyl)-piperazine
En blanding av 8,2 g (0,0425 mol) N-(o-metoksyfenyl)-piperazin, 6,5 g (0,0425 mol) 3-brompropylmetyleter og 4,3 g 0,04^5 mol) trietylamin innføres i en 100 ml's 3-halset flaske sammen med 50 ml xylen. Blandingen oppvarmes i seks timer under tilbakeløp, kjøles derpå og ekstraheres med tre porsjoner 3n HC1 hver på 30 ml. Den sure oppløsning ekstraheres med tre porsjoner på 50 ml benzen og mettes derpå med kaliumkarbonat og ekstraheres igjen med tre porsjoner benzen hver på 50 ml. Benzen-ekstraktene vaskes fri for base med vann, og destilleres for å fjerne oppløsningsmid-let. Residuet destilleres under vakuum for å gi et produkt som koker ved 135—137° C ved 0,15 mm trykk. A mixture of 8.2 g (0.0425 mol) N-(o-methoxyphenyl)-piperazine, 6.5 g (0.0425 mol) 3-bromopropyl methyl ether and 4.3 g (0.04^5 mol) triethylamine is introduced in a 100 ml 3-necked flask together with 50 ml xylene. The mixture is heated for six hours under reflux, then cooled and extracted with three portions of 3n HCl each of 30 ml. The acidic solution is extracted with three portions of 50 ml of benzene and then saturated with potassium carbonate and extracted again with three portions of benzene each of 50 ml. The benzene extracts are washed free of base with water and distilled to remove the solvent. The residue is distilled under vacuum to give a product boiling at 135-137° C at 0.15 mm pressure.
Utgangsmaterialet N- (o-metoksyfenyl) - N'-metylpiperazin med formelen: The starting material N-(o-methoxyphenyl)-N'-methylpiperazine with the formula:
kan fremstilles som følger: can be produced as follows:
En blanding av 17,3 vektsdeler N,N-bis- A mixture of 17.3 parts by weight of N,N-bis-
((3-kloretyl)-o-anisidin og 29 deler 30 %'s vandig metylamin i 50 deler etanol oppvarmes i et lukket kar ved 125° C i 8 timer. Alkoholen fjernes derpå ved destillasjon og 150 deler tilsettes til residuet, som gjøres sterkt alkalisk med 25 deler natriumhydr-oksyd. Blandingen rystes derpå med to porsjoner benzen hver på 100 m<3> og de forenede ekstrakter destilleres og gir 11 g av et produkt som koker ved 100—101° C ved ((3-chloroethyl)-o-anisidine and 29 parts of 30% aqueous methylamine in 50 parts of ethanol are heated in a closed vessel at 125° C. for 8 hours. The alcohol is then removed by distillation and 150 parts are added to the residue, which is made strongly alkaline with 25 parts of sodium hydroxide The mixture is then shaken with two portions of benzene each of 100 m<3> and the combined extracts are distilled to give 11 g of a product boiling at 100-101° C. at
27 27
0,3 mm trykk, nD = 1,5483. Analyse kalkulert for C12<H>18N20: Teoretisk 69,86 % C; 8,79 % H; sammenlignet med den fundne analyse på 70,07 % C og 8,80 % H. 0.3 mm pressure, nD = 1.5483. Analysis calculated for C12<H>18N20: Theoretical 69.86% C; 8.79% H; compared to the found analysis of 70.07% C and 8.80% H.
Mononydrokloridsaltet fremstilles ved å oppløse det frie baseprodukt i isopropanol og tilsette en ekvivalent hydrogenklorid pr. mol base. Ved tilsetning av to volum tørr eter, bunnfeller N-(o-metoksyfenyl)-N'-metylpiperazinmonohydroklorid som et hvitt krystallinsk fast stoff, som samles opp og tørkes. Det smelter ved 200—201° C. Analyse kalkulert for Cj2H19CIN20: Teoretisk 59,37 % C; 7,89 % H; sammenlignet med den fundne analyse på 59,29 % C og 7,63 % H. The monohydrochloride salt is prepared by dissolving the free base product in isopropanol and adding an equivalent of hydrogen chloride per moles of base. On addition of two volumes of dry ether, N-(o-methoxyphenyl)-N'-methylpiperazine monohydrochloride precipitates as a white crystalline solid, which is collected and dried. It melts at 200-201° C. Analysis calculated for Cj2H19CIN20: Theoretical 59.37% C; 7.89% H; compared to the found analysis of 59.29% C and 7.63% H.
Eksempel 3: N-( o- metoksyfenyl) - N'-( 3- metoksypropyl) - piperazin Example 3: N-(o-Methoxyphenyl)-N'-(3-Methoxypropyl)-piperazine
Til 39 g n-(o-metoksyfenyl)-piperazin tilsettes langsomt under omrøring 25 g 3-mietoksypropyl-p-toluensulfonat. Blandingen oppvarmes i to timer på dampbad, kjø-les derpå og behandles med 200 ml 10 %'s vandig natriumhydroksydoppløsning. Blandingen ekstraheres med 200 ml benzen, og det organiske ekstrakt separeres og destilleres fraksjonert og gir produktet, N-(o-metoksyfenyl) -N'-( 3-metoksypropyl) -piperazin. To 39 g of n-(o-methoxyphenyl)-piperazine, slowly add 25 g of 3-methoxypropyl-p-toluenesulfonate while stirring. The mixture is heated for two hours on a steam bath, then cooled and treated with 200 ml of 10% aqueous sodium hydroxide solution. The mixture is extracted with 200 ml of benzene, and the organic extract is separated and fractionally distilled to give the product, N-(o-methoxyphenyl)-N'-(3-methoxypropyl)-piperazine.
Eksempel 4: Example 4:
N-( Oretoksyfenyl) - N'-( 3- metoksypropyl) - piperazin N-(Orethoxyphenyl)-N'-(3-Methoxypropyl)-piperazine
En blanding av 13,1 g N,N-bzs-((3-klor-etyl)-o-etoksyanilin, 13,4 g 3-metoksypropylamin og 75 ml 95 %'s etanol oppvarmes under tilbakeløp i 12,timer. Etter fordampning av oppløsningsmidlet tilsettes 250 ml vann til residuet, som derpå rystes med 100 ml's og 50 ml's porsjoner benzen. De forenede organiske ekstrakter rystes med 100 ml vann, separeres og destilleres. Dette gir 11,6 g produkt, N-(o-etoksyfenyl)-N'-(3-metoksypropyl) -piperazin, en fargeløs olje som koker ved 131—135° C ved 0,1 mm A mixture of 13.1 g of N,N-bzs-((3-chloro-ethyl)-o-ethoxyaniline, 13.4 g of 3-methoxypropylamine and 75 ml of 95% ethanol is heated under reflux for 12 hours. After evaporation of the solvent, 250 ml water is added to the residue, which is then shaken with 100 ml and 50 ml portions of benzene. The combined organic extracts are shaken with 100 ml water, separated and distilled. This gives 11.6 g of product, N-(o-ethoxyphenyl )-N'-(3-methoxypropyl)-piperazine, a colorless oil boiling at 131-135°C at 0.1 mm
25 25
trykk, og N D = 1,5270. Analyse beregnet pressure, and N D = 1.5270. Analysis calculated
for Cj8H2eN202: Teoretisk 69,03 % C; 9,41 % H og 10,06 % Na sammenlignet med den fundne analyse på 69,04 % C; 9,50 % H og 10,14 % N. for Cj8H2eN2O2: Theoretical 69.03% C; 9.41% H and 10.06% Na compared to the found analysis of 69.04% C; 9.50% H and 10.14% N.
Ved å oppløse den foran angitte base i isopropylalkohol og tilsette to ekvivalenter By dissolving the above base in isopropyl alcohol and adding two equivalents
hydrogenklorid pr. mol base får man dihydrokloridsaltet av denne som hvite kry-staller som har et smeltepunkt på 170° C. hydrogen chloride per mol of base gives the dihydrochloride salt of this as white crystals which have a melting point of 170° C.
Analyse kalkulert for C10H18Cl2N2O2: Teoretisk 7,97 % N; sammenlignet med den fundne analyse på 7,87 % N. Analysis calculated for C10H18Cl2N2O2: Theoretical 7.97% N; compared to the found analysis of 7.87% N.
Eksempel 5: N-( o- metoksyfenyl) - N'-( 2- metoksyetyl) - piperazin Example 5: N-(o-Methoxyphenyl)-N'-(2-Methoxyethyl)-piperazine
En oppløsning av 25 g N,N-bts-((3-klor-etyl)-o-anisidin og 23 g 2-metoksyetylamin A solution of 25 g of N,N-bts-((3-chloro-ethyl)-o-anisidine and 23 g of 2-methoxyethylamine
i 100 ml 95 %'s etanol oppvarmes under til-bakeløp i seks timer. Oppløsningsmidlet fordampes på et dampbad og residuet behandles med 200 ml vann. Blandingen rystes med 150 ml benzen og benzenekstraktet destilleres til å gi produktet, N-o-metoksyfenyl-N'-(2-metoksyetyl)-piperazin som har et kokepunkt på 134° C ved 0,1 mm trykk 25 in 100 ml of 95% ethanol is heated under reflux for six hours. The solvent is evaporated on a steam bath and the residue is treated with 200 ml of water. The mixture is shaken with 150 ml of benzene and the benzene extract is distilled to give the product, N-o-methoxyphenyl-N'-(2-methoxyethyl)-piperazine which has a boiling point of 134°C at 0.1 mm pressure 25
og n D = 1,5423. Kjemisk analyse kalkulert for C^H^Np-: Teoretisk 67,16 % C; and n D = 1.5423. Chemical analysis calculated for C^H^Np-: Theoretical 67.16% C;
8,86 % H; 11,19 % N og 12,78 % O; sammenlignet med den fundne analyse på 67,08 % C; 8,86 % H; 11,13 % N og 13,01 % O. Fos-fatsaltet for den nevnte base har et smeltepunkt på 158—159° C. 8.86% H; 11.19% N and 12.78% O; compared to the found analysis of 67.08% C; 8.86% H; 11.13% N and 13.01% O. The phosphate salt of the mentioned base has a melting point of 158-159°C.
Eksempel 6: N-( o- metoksyfenyl) - N'-( 3- isopropoksypro-pyl) - piperazin Example 6: N-(o-methoxyphenyl)-N'-(3-isopropoxypropyl)-piperazine
En oppløsning av 25 g N,N-b£s-(|3-klor-etyl)-o-anisidin og 35 g 3-isopropoksypro-pylamin i 100 ml 95 %'s etanol oppvarmes under tilbakeløp i tre timer. Oppløsnings-midlet fjernes på et dampbad og residuet behandles med 250 ml vann. Blandingen rystes med 150 ml benzen og benzenekstraktet separeres og destilleres for å oppnå produktet, N- (o-metoksyfenyl) -N'- (3-isoprop-oksypropyl)-piperazin, som har et kokepunkt på 153—155° C ved 0,2 mm trykk og 25 n D = 1,5245. Kjemisk analyse kalkulert for C17H,8N202: Teoretisk 69,82 % C; 9,65 % H; 9,58 % N og 10,94 % O; sammenlignet med den fundne analyse på 69,93 % C; A solution of 25 g of N,N-bis-([3-chloro-ethyl)-o-anisidine and 35 g of 3-isopropoxypropylamine in 100 ml of 95% ethanol is heated under reflux for three hours. The solvent is removed on a steam bath and the residue is treated with 250 ml of water. The mixture is shaken with 150 ml of benzene and the benzene extract is separated and distilled to obtain the product, N-(o-methoxyphenyl)-N'-(3-isopropoxypropyl)-piperazine, which has a boiling point of 153-155°C at 0, 2 mm pressure and 25 n D = 1.5245. Chemical analysis calculated for C17H,8N2O2: Theoretical 69.82% C; 9.65% H; 9.58% N and 10.94% O; compared to the found analysis of 69.93% C;
9,80 % H; 9,63 % N og 11,25 % O. Basens dihydrokloridsalt har et smeltepunkt på 175—180° C. 9.80% H; 9.63% N and 11.25% O. The dihydrochloride salt of the base has a melting point of 175-180°C.
Eksempel 7: N- ( o- metoksyfenyl) - N'- ( 3- etoksypropyl) - piperazin Example 7: N-(o-methoxyphenyl)-N'-(3-ethoxypropyl)-piperazine
En oppløsning av 25 g N,N-bis-(|3-klor-etyl)-o-anisidin og 31 g 3-etoksypropylamin i 75 ml 95 %'s etanol oppvarmes under til-bakeløp i tre timer. Alkoholen fjernes ved fordampning på et dampbad og residuet behandles med 200 ml vann. Blandingen rystes med 150 ml benzen og benzenekstraktet separeres og destilleres for å gi produktet, N-(o-metoksyfenyl)-N'-(3-etoksypropyl)-piperazin, som har et kokepunkt på 139—141° C ved et trykk på 0,1 mm og A solution of 25 g of N,N-bis-(|3-chloro-ethyl)-o-anisidine and 31 g of 3-ethoxypropylamine in 75 ml of 95% ethanol is heated under reflux for three hours. The alcohol is removed by evaporation on a steam bath and the residue is treated with 200 ml of water. The mixture is shaken with 150 ml of benzene and the benzene extract is separated and distilled to give the product, N-(o-methoxyphenyl)-N'-(3-ethoxypropyl)-piperazine, which has a boiling point of 139-141°C at a pressure of 0 ,1 mm and
25 25
en refraktiv indeks på n D= 1,5294. Kjemisk analyse kalkulert for C1(iH2(iN202: Teoretisk 69,03 % C; 9,41 % H; 10,06 %~N; sammenlignet med den fundne analyse på 69,05 % C; 9,33 % H og 9,44 % N. Dihydrokloridsaltet for den foran angitte base har et smeltepunkt på 174—175° C. a refractive index of n D= 1.5294. Chemical analysis calculated for C1(iH2(iN202: Theoretical 69.03% C; 9.41% H; 10.06%~N; compared to the found analysis of 69.05% C; 9.33% H and 9, 44% N. The dihydrochloride salt of the above base has a melting point of 174-175° C.
Eksempel 8: Example 8:
N-( o- metoksyfenyl) - N'-( 4- metoksy- n- bu-tyl)- piperazin N-(o-Methoxyphenyl)-N'-(4-Methoxy-n-butyl)-piperazine
En oppløsning av 25 g (0,1 mol) N,N-bis-(2-kloretyl)-o-anisidin og 31 g (0,3 mol) 4-metoksybutylamin i 100 m<:t> 95 %'s etanol oppvarmes under tilbakeløp i tre timer og konsentreres derpå på dampbad under vakuum. Til residuet tilsettes 150 ml vann, og blandingen rystes med 150 ml's og 100 ml's porsjoner benzen. De forenede benzenekstrakter konsentreres og destilleres og gir 24 g produkt, en lett olje som ko-25 A solution of 25 g (0.1 mol) N,N-bis-(2-chloroethyl)-o-anisidine and 31 g (0.3 mol) 4-methoxybutylamine in 100 m<:t> 95% ethanol heated under reflux for three hours and then concentrated on a steam bath under vacuum. 150 ml of water is added to the residue, and the mixture is shaken with 150 ml and 100 ml portions of benzene. The combined benzene extracts are concentrated and distilled to give 24 g of product, a light oil which co-25
ker ved 136—140° C ved 0,1 mm, n D = ker at 136—140° C at 0.1 mm, n D =
1,5318. Analyse: Kalkulert for ClcH2(iN202: C, 69,0 %; H, 9,41 %; N, 10,1 %; O 11, 5 %; funnet: C, 69,0 %; H, 9,39 %; N, 10,2 %; O, 11,4 %. 1.5318. Analysis: Calcd for ClcH2(iN2O2: C, 69.0%; H, 9.41%; N, 10.1%; O 11.5%; found: C, 69.0%; H, 9.39% ; N, 10.2%; O, 11.4%.
Produktet reagerer med pikrimsyre i alkoholoppløsningsmiddel og danner et dipikratsalt, s. p. 158—159°. Analyse: Kalkulert for a,8H.i2<N>HOl(.; N, 15,2 %. Funnet N, 15,2%. The product reacts with picric acid in alcohol solvent and forms a dipicrate salt, mp 158-159°. Analysis: Calculated for a,8H.i2<N>HOl(.; N, 15.2%. Found N, 15.2%.
Eksempel 9: N-( o- metoksyfenyl)- N'-( 5- metoksypentyl) - piperazin En oppløsning av 6,4 g N,N-bis-(2-klor-etyl)-o-anisidin og 9 g 5-metoksypentyla-min i 75 ml 95 %'s etanol oppvarmes under tilbakeløp over natten. Den konsentreres derpå og residuet behandles med 100 ml vann. Blandingen rystes med 100 ml's og 50 ml's porsjoner benzen og det forenede benzenekstrakt konsentreres og destilleres. Der oppnåes 5 g produkt, en lett olje som 25 koker ved 146—149° C ved 0,1 mm, n D = 1,5287. Analyse: Kalkulert for C17H,8N202: C, 69,8 %; H, 9,65 %; N, 9,58 %. Funnet C, 69,5 %; H, 9,37 %; N, 9,58 %. Example 9: N-(o-methoxyphenyl)-N'-(5-methoxypentyl)-piperazine A solution of 6.4 g of N,N-bis-(2-chloro-ethyl)-o-anisidine and 9 g of 5- methoxypentylamine in 75 ml of 95% ethanol is heated under reflux overnight. It is then concentrated and the residue is treated with 100 ml of water. The mixture is shaken with 100 ml and 50 ml portions of benzene and the combined benzene extract is concentrated and distilled. 5 g of product is obtained, a light oil which boils at 146-149° C at 0.1 mm, n D = 1.5287. Analysis: Calcd for C17H.8N2O2: C, 69.8%; H, 9.65%; N, 9.58%. Found C, 69.5%; H, 9.37%; N, 9.58%.
Produktet reagerer med alkoholisk pi-krinsyre og gir et dipikratsalt, s. p. 149— 150°. Analyse: Kalkulert for C2()H:MN801C: N, 14,9 %. Funnet 14,8 %. The product reacts with alcoholic picric acid and gives a dipicrate salt, m.p. 149-150°. Analysis: Calculated for C2()H:MN801C: N, 14.9%. Found 14.8%.
Eksempel 10: Example 10:
N- ( o- metoksyfenyl) - N'-( 6- metoksyheksyl) - piperizin N-(o-Methoxyphenyl)-N'-(6-Methoxyhexyl)-piperizine
En oppløsning av 8,2 g N,N-bis-((3-klor-etyl)-o-anisidin og 13,1 g 6-metoksyheksyl-amin i 75 m'f 95 %'s etanol oppvarmes under tilbakeløp i fire timer og konsentreres derpå. Til det halvfaste residuum tilsettes 150 ml vann og 100 ml benzen og blandingen rystes godt. Det organiske lag separeres og destilleres. Man får 8 g produkt, en lett olje som koker ved 155—160° C ved 0,1 A solution of 8.2 g of N,N-bis-((3-chloro-ethyl)-o-anisidine and 13.1 g of 6-methoxyhexylamine in 75 ml of 95% ethanol is heated under reflux for four hours and then concentrated. 150 ml of water and 100 ml of benzene are added to the semi-solid residue and the mixture is shaken well. The organic layer is separated and distilled. 8 g of product is obtained, a light oil boiling at 155-160° C at 0.1
25 mm, n 1,5252. Analyse: Kalkulert for CI8<H>3u<N>202: C, 70,6 %; H, 9,87 %; N, 9,14 %; funnet: C, 70,3 %; H, 9,64 %; N, 9,10 %. 25 mm, n 1.5252. Analysis: Calcd for Cl8<H>3u<N>202: C, 70.6%; H, 9.87%; N, 9.14%; found: C, 70.3%; H, 9.64%; N, 9.10%.
Basen reagerer i isopropylalkohol med hydrogenklorid og gir et dihydrokloridsalt, s. p. 172—176° C. Analyse: kalkulert for C18H.t,Cl2N20:>: C, 57,0 %; H, 8,50 %; N, 7,38 %; funnet: C, 56,7 %; H, 8,06 %; N, 7,38 %. The base reacts in isopropyl alcohol with hydrogen chloride to give a dihydrochloride salt, mp 172-176° C. Analysis: calculated for C18H.t,Cl2N20:>: C, 57.0%; H, 8.50%; N, 7.38%; found: C, 56.7%; H, 8.06%; N, 7.38%.
Eksempel 11: Example 11:
N-( o- metoksyfenyl) - N'- ( 7- metoksyheptyl) - piperazin N-(o-Methoxyphenyl)-N'-(7-Methoxyheptyl)-piperazine
En oppløsning av 7,5 g N,N-bis-(2-klor-etyl)-o-anisidin og 13 g 7-metoksyheptylamin i 100 ml 95 %'s etanol oppvarmes under tilbakeløp i 17 timer og konsentreres derpå til en olje som behandles med 100 ml vann. Blandingen rystes med 100 ml benzen og benzenlaget konsentreres og destilleres og gir 6,6 g produkt, en olje som 25 A solution of 7.5 g of N,N-bis-(2-chloro-ethyl)-o-anisidine and 13 g of 7-methoxyheptylamine in 100 ml of 95% ethanol is heated under reflux for 17 hours and then concentrated to an oil which is treated with 100 ml of water. The mixture is shaken with 100 ml of benzene and the benzene layer is concentrated and distilled to give 6.6 g of product, an oil which 25
koker ved 157—168° ved 0,2 mm, n D = boils at 157—168° at 0.2 mm, n D =
1,5219. Analyse: Kalkulert for C19HS9N902: C, 71,2 %; H, 10,1 %; N, 8,74 %/Funnet: C, 71,4 %; H, 10,2 %; N, 8,76 %. 1.5219. Analysis: Calcd for C19HS9N902: C, 71.2%; H, 10.1%; N, 8.74%/Found: C, 71.4%; H, 10.2%; N, 8.76%.
Produktet reagerer i alkoholisk oppløs-ning med vannfritt hydrogenklorid og danner et dihydrokloridsalt, som smelter ved 178°. Analyse: Kalkulert for C,nHrt,013,0,: C, 58,0 %; H, 8,71 %; N, 7,12 %. Funnet: C, 58,2 %; H, 8,61 %; N, 7,12 %. The product reacts in alcoholic solution with anhydrous hydrogen chloride and forms a dihydrochloride salt, which melts at 178°. Analysis: Calculated for C,nHrt,013.0,: C, 58.0%; H, 8.71%; N, 7.12%. Found: C, 58.2%; H, 8.61%; N, 7.12%.
a. 7-metoksyheptylamin a. 7-Methoxyheptylamine
En blanding av 15 g 6-metoksyenan-tonitril, 15 ml flytende ammoniakk, 7 g Raney nikkelkatalysator og 500 cm<3> metanol rystes ved 100° ved et trykk av hydro-gen på 105,5 kg pr. cm- i 20 minutter da hy-dreringen er fullendt. Blandingen filtreres og destilleres for å få 13 g produkt, k. p. A mixture of 15 g of 6-methoxyenantonitrile, 15 ml of liquid ammonia, 7 g of Raney nickel catalyst and 500 cm<3> of methanol is shaken at 100° at a hydrogen pressure of 105.5 kg per cm- for 20 minutes when the hydration is complete. The mixture is filtered and distilled to obtain 13 g of product, b.p.
25 25
106°/25 mm, N D = 1,4338. Analyse: Kalkulert for C8H19NO: C, 66,2 %; H, 13,2 %; N, 9,64 %. Funnet: C, 66,1 %; H, 13,1 %; N, 9,79 %. 106°/25mm, N D = 1.4338. Analysis: Calcd for C8H19NO: C, 66.2%; H, 13.2%; N, 9.64%. Found: C, 66.1%; H, 13.1%; N, 9.79%.
Andre høyere alkoksyalkylderivater av o-alkoksyfenyl-piperaziner, som kommer innenfor nærværende oppfinenlses områ-de, kan fremstilles etter enhver av de fore-gående metoder. Således fremstilles f. eks. N- (o-metoksyfenyl) -N'- (11 -metoksyunde-cyl)-piperazin ved å tilbakeløpsbehandle i ca. 12 timer en blanding av 11-bromunde-cyleter (0,1 mol) og N-(o-metoksyfenyl)-piperazin (0,1 mol) med et inert oppløs-ningsmiddel, som xylen, som inneholder trietylamin som et syrebindemiddel i overensstemmelse med fremgangsmåten beskre-vet i eksempel II. På samme måte fremstilles N-(o-metoksyfenyl) -N'-(8-metoksyok-tyl) -piperazin ved å tilbakeløpsbehandle en blanding av 8-bromoktylmetyleter (0,1 mol) og N-(o-metoksyfenyl)-piperazin (0,1 mol) som i eksempel 2, og N-(o-metoksyfenyl) N'-(9-metoksynonyl) -piperazin fremstilles ved å tilbakeløpsbehandle en blanding av 9-bromnonyl-metyleter (0,1 mol) og N-(o-metoksyfenyl)-piperazin (0,1 mol) som i eksempel 2. Other higher alkoxyalkyl derivatives of o-alkoxyphenyl-piperazines, which come within the scope of the present invention, can be prepared by any of the preceding methods. Thus, e.g. N-(o-methoxyphenyl)-N'-(11-methoxyundecyl)-piperazine by refluxing for approx. 12 hours a mixture of 11-bromoundecyl ether (0.1 mol) and N-(o-methoxyphenyl)-piperazine (0.1 mol) with an inert solvent, such as xylene, containing triethylamine as an acid binder in accordance with the method described in example II. Similarly, N-(o-methoxyphenyl)-N'-(8-methoxyoxyethyl)-piperazine is prepared by refluxing a mixture of 8-bromooctylmethyl ether (0.1 mol) and N-(o-methoxyphenyl)-piperazine ( 0.1 mol) as in Example 2, and N-(o-methoxyphenyl) N'-(9-methoxynonyl)-piperazine is prepared by refluxing a mixture of 9-bromononyl methyl ether (0.1 mol) and N-( o-methoxyphenyl)-piperazine (0.1 mol) as in Example 2.
Eksempel 12: Example 12:
N-( o- metoksyfenyl)- N'-( 3- n- heksyloksy-propyl) - piperazin N-(o-Methoxyphenyl)-N'-(3-n-hexyloxy-propyl)-piperazine
En blanding av 12 g (0,05 mol) N,N-bis-(p-kloretyl)-o-anisidin, 25 g (0,15 mol) 3-n-heksyloksypropylamin og 50 ml 95 %'s etanol tilbakeløpsbehandles i ca. 12 timer på et dampbad. Reaksjonsblandingen kjø-les derpå, fortynnes med 75 ml vann, og ekstraheres først med 50 ml benzen og derpå med fire porsjoner benzen, hver på 25—30 ml. De forenede benzenf raks joner oppvarmes for å fjerne benzenen og residuet underkastes en vakuumdestillasjon. Et utbytte på 11,3 g av produktet N-(o-metoksyfenyl)-N'-(3-7i-heksylpropyl)-piperazin oppnåes, som har et kokepunkt på 185° C ved et trykk på 0,6 mm kvikksølv og A mixture of 12 g (0.05 mol) N,N-bis-(p-chloroethyl)-o-anisidine, 25 g (0.15 mol) 3-n-hexyloxypropylamine and 50 ml 95% ethanol is refluxed in about. 12 hours in a steam bath. The reaction mixture is then cooled, diluted with 75 ml of water, and extracted first with 50 ml of benzene and then with four portions of benzene, each of 25-30 ml. The combined benzene fractions are heated to remove the benzene and the residue is subjected to a vacuum distillation. A yield of 11.3 g of the product N-(o-methoxyphenyl)-N'-(3-7i-hexylpropyl)-piperazine is obtained, which has a boiling point of 185° C. at a pressure of 0.6 mm of mercury and
25 25
en refraktiv indeks på nn = 1,5153. Kjemisk analyse av det nevnte produkt viser 71,22 % C; 10,59 % H; 9,28 % O og 8,32 % N; sammenlignet med en teoretisk analyse på 71,81 % C; 10,25 % H; 9,57 % O og 8,38 a refractive index of nn = 1.5153. Chemical analysis of the said product shows 71.22% C; 10.59% H; 9.28% O and 8.32% N; compared to a theoretical analysis of 71.81% C; 10.25% H; 9.57% O and 8.38
%N. %N.
Eksempel 13: Example 13:
N-( O- metoksyfenyl) - N'-( 3- n- dodecyloksy-propyl) - piperazin N-(O-Methoxyphenyl)-N'-(3-n-dodecyloxy-propyl)-piperazine
En blanding av 7 g (0,028 mol) N,N-bis-(p-kloretyl)-o-anisidin, 21 g (0,068 mol) 3-dodecyloksypropylamin og 50 ml 95 %'s etanol tilbakeløpsbehandles i ca. 12 timer på et dampbad. Reaksjonsbilandingen kjø-les derpå, fortynnes med 75 ml vann, og ekstraheres først med 50 ml benzen og derpå med fire porsjoner benzen, hver på 25 ml. De forenede benzenfraksj oner oppvarmes for å fjerne benzenet og residuet underkastes en vakuumdestillasjon. Produktet, N-(o-metoksyfenyl)-N'-(3-n-dodecyl-oksypropyl)-piperazin har et kokepunkt på 232—234° C ved et trykk på 0,5 mm kvikk - A mixture of 7 g (0.028 mol) N,N-bis-(p-chloroethyl)-o-anisidine, 21 g (0.068 mol) 3-dodecyloxypropylamine and 50 ml 95% ethanol is refluxed for approx. 12 hours in a steam bath. The reaction mixture is then cooled, diluted with 75 ml of water, and extracted first with 50 ml of benzene and then with four portions of benzene, each of 25 ml. The combined benzene fractions are heated to remove the benzene and the residue is subjected to a vacuum distillation. The product, N-(o-methoxyphenyl)-N'-(3-n-dodecyl-oxypropyl)-piperazine has a boiling point of 232—234° C at a pressure of 0.5 mm quick -
25 25
sølv og en refraktiv indeks på n D = 1,5030. silver and a refractive index of n D = 1.5030.
Det rå pikratsalt av det nevnte produkt The crude picrate salt of the said product
har et smeltepunkt på 127—129° C, og etter has a melting point of 127-129° C, and after
omkrystallisasjon fra metanol har det et recrystallization from methanol it has a
smeltepunkt på 131—131,5° C. Kjemisk analyse for nevnte pikratsalt viser 52,22 % C; melting point of 131-131.5° C. Chemical analysis for said picrate salt shows 52.22% C;
6,15 % H; 29,33 % O og 12,66 % N; sammenlignet med en teoretisk analyse på 52,05 % 6.15% H; 29.33% O and 12.66% N; compared to a theoretical analysis of 52.05%
C; 5,98 % H; 29,20 % O og 12,78 % N. C; 5.98% H; 29.20% O and 12.78% N.
Claims (1)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH1347270A CH521011A (en) | 1970-09-10 | 1970-09-10 | Low-oil circuit breaker |
Publications (2)
Publication Number | Publication Date |
---|---|
NO131908B true NO131908B (en) | 1975-05-12 |
NO131908C NO131908C (en) | 1975-08-20 |
Family
ID=4392731
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO3347/71A NO131908C (en) | 1970-09-10 | 1971-09-08 |
Country Status (15)
Country | Link |
---|---|
US (1) | US3742168A (en) |
AT (1) | AT308230B (en) |
AU (1) | AU456609B2 (en) |
BE (1) | BE772332A (en) |
BR (1) | BR7105893D0 (en) |
CA (1) | CA936199A (en) |
CH (1) | CH521011A (en) |
DE (2) | DE7037094U (en) |
ES (1) | ES394893A1 (en) |
FR (1) | FR2107418A5 (en) |
GB (1) | GB1316380A (en) |
NL (1) | NL7112340A (en) |
NO (1) | NO131908C (en) |
PL (1) | PL77828B1 (en) |
SE (1) | SE380129B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2548280B1 (en) * | 1983-06-30 | 1987-08-07 | Paris & Du Rhone | IMPROVEMENTS ON ELECTRIC STARTER CONTACTORS WHOSE AXIS IS INDEPENDENT OF THE MOBILE CORE |
NO321080B1 (en) * | 2004-11-04 | 2006-03-13 | Bennex As | Switch for high voltage and / or current |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE472305C (en) * | 1927-10-30 | 1929-02-26 | Siemens Schuckertwerke Akt Ges | Fire chamber for switch |
DE1298176B (en) * | 1961-12-23 | 1969-06-26 | Calor Emag Elektrizitaets Ag | Electrical switch with arc extinguishing through a flow of extinguishing agent |
-
1970
- 1970-09-10 CH CH1347270A patent/CH521011A/en not_active IP Right Cessation
- 1970-10-07 DE DE7037094U patent/DE7037094U/en not_active Expired
- 1970-10-07 DE DE19702049265 patent/DE2049265A1/en active Pending
-
1971
- 1971-06-14 AT AT510771A patent/AT308230B/en not_active IP Right Cessation
- 1971-07-26 AU AU31626/71A patent/AU456609B2/en not_active Expired
- 1971-08-19 US US00172970A patent/US3742168A/en not_active Expired - Lifetime
- 1971-08-25 CA CA121498A patent/CA936199A/en not_active Expired
- 1971-09-08 BR BR5893/71A patent/BR7105893D0/en unknown
- 1971-09-08 SE SE7111399A patent/SE380129B/xx unknown
- 1971-09-08 NO NO3347/71A patent/NO131908C/no unknown
- 1971-09-08 GB GB4189971A patent/GB1316380A/en not_active Expired
- 1971-09-08 PL PL1971150401A patent/PL77828B1/pl unknown
- 1971-09-08 BE BE772332A patent/BE772332A/en unknown
- 1971-09-08 FR FR7132403A patent/FR2107418A5/fr not_active Expired
- 1971-09-08 ES ES394893A patent/ES394893A1/en not_active Expired
- 1971-09-08 NL NL7112340A patent/NL7112340A/xx unknown
Also Published As
Publication number | Publication date |
---|---|
CH521011A (en) | 1972-03-31 |
BE772332A (en) | 1972-01-17 |
AU3162671A (en) | 1973-02-01 |
AT308230B (en) | 1973-06-25 |
DE7037094U (en) | 1971-08-19 |
ES394893A1 (en) | 1974-05-16 |
PL77828B1 (en) | 1975-04-30 |
DE2049265A1 (en) | 1972-03-16 |
NO131908C (en) | 1975-08-20 |
GB1316380A (en) | 1973-05-09 |
BR7105893D0 (en) | 1973-03-29 |
US3742168A (en) | 1973-06-26 |
SE380129B (en) | 1975-10-27 |
AU456609B2 (en) | 1974-12-19 |
FR2107418A5 (en) | 1972-05-05 |
CA936199A (en) | 1973-10-30 |
NL7112340A (en) | 1972-03-14 |
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