DE1813061C - 3 N (2 hydroxy 3 phenoxypropyl) amino 1 phenyl propanone (1) and its acid addition salts - Google Patents
3 N (2 hydroxy 3 phenoxypropyl) amino 1 phenyl propanone (1) and its acid addition saltsInfo
- Publication number
- DE1813061C DE1813061C DE1813061C DE 1813061 C DE1813061 C DE 1813061C DE 1813061 C DE1813061 C DE 1813061C
- Authority
- DE
- Germany
- Prior art keywords
- hydroxy
- amino
- phenoxypropyl
- acid addition
- addition salts
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 239000002253 acid Substances 0.000 title claims description 4
- 150000003839 salts Chemical class 0.000 title claims description 3
- 239000011780 sodium chloride Substances 0.000 title claims description 3
- JHBIVOKWCGAEPT-UHFFFAOYSA-N OC(CC(C(C)=O)(C1=CC=CC=C1)N)COC1=CC=CC=C1 Chemical compound OC(CC(C(C)=O)(C1=CC=CC=C1)N)COC1=CC=CC=C1 JHBIVOKWCGAEPT-UHFFFAOYSA-N 0.000 title 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- -1 2-Hydroxy-3-phenoxypropyl Chemical group 0.000 claims description 5
- 101710014631 CHURC1 Proteins 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-L maleate(2-) Chemical compound [O-]C(=O)\C=C/C([O-])=O VZCYOOQTPOCHFL-UPHRSURJSA-L 0.000 claims description 2
- 238000002844 melting Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M Potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- KWOLFJPFCHCOCG-UHFFFAOYSA-N methylphenylketone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000003276 anti-hypertensive Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- FSTYOUCNSTZVDF-UHFFFAOYSA-N 1-amino-1-phenylpropan-2-one Chemical compound CC(=O)C(N)C1=CC=CC=C1 FSTYOUCNSTZVDF-UHFFFAOYSA-N 0.000 description 2
- JZEHWMUIAKALDN-UHFFFAOYSA-N 1-amino-3-phenoxypropan-2-ol Chemical compound NCC(O)COC1=CC=CC=C1 JZEHWMUIAKALDN-UHFFFAOYSA-N 0.000 description 2
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 2
- 102100000129 CHURC1 Human genes 0.000 description 2
- 210000003169 Central Nervous System Anatomy 0.000 description 2
- BJOIZNZVOZKDIG-MDEJGZGSSA-N Reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 2
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229960003147 reserpine Drugs 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- KUIZKZHDMPERHR-UHFFFAOYSA-N 1-phenylprop-2-en-1-one Chemical compound C=CC(=O)C1=CC=CC=C1 KUIZKZHDMPERHR-UHFFFAOYSA-N 0.000 description 1
- 210000003403 Autonomic Nervous System Anatomy 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000000994 depressed Effects 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000002045 lasting Effects 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 238000001050 pharmacotherapy Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001624 sedative Effects 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
Description
Gegenstand der Erfindung ist das 3-N-(2-Hydroxy-3'phenQxypropy|)-arnino4-phenyl"pröpttnon'<(l) der FormelThe subject of the invention is the 3-N- (2-Hydroxy-3'phenQxypropy |) -arnino4-phenyl "pröpttnon '<(l) the formula
OHOH
beschrieben: »Reserpin wurde in ausgedehntem Maße
zur Behandlung der arteriellen Hypertonie benutzt, aber sein blutdrucksenkender Effekt ist meist zu
sohwaoh oder fehlt oft ganz,« (Knud O. Meiler
S in »Pharmakologie als theoretische Grundlage einer rationellen Pharmakothcrapie«, Sohwabo&Co. Verlag,
Basel, 1966, auf S. 337, Absatz 4.)
Die Beispiele erläutern die Erfindung.described: "Reserpine has been used extensively for the treatment of arterial hypertension, but its antihypertensive effect is usually too sohwaoh or is often completely absent," (Knud O. Meiler S in "Pharmacology as the theoretical basis of a rational pharmacotherapy", Sohwabo & Co. Verlag, Basel, 1966, on p. 337, paragraph 4.)
The examples illustrate the invention.
sowie dessen Säureadditionssalze. toas well as its acid addition salts. to
Die Herstellung des neuen Keto-phenoxy-aminoalkohols erfolgt dadurch, daß man 2-Hydroxy-3-phenoxy-propylamin The production of the new keto-phenoxy-amino alcohol takes place by adding 2-hydroxy-3-phenoxypropylamine
~- OCH1CHCH11NH,
OH ~ - OCH 1 CHCH 11 NH,
OH
mit Salzsäure, Acetophenon und Formaldehyd oder ao mit Phenylvinylketon, intermediär hergestellt aus /9-Chlorpropiophenon und Kaliumacetat, vorzugsweise bei höherer Temperatur in einem Lösungsmittel umsetzt und das auf diese Weise erhaltene 3-N-(2-Hydroxy-3-phenoxypropyl)-amino-l-phenyl-propanon-(l) as zweckmäßig aus dem Reaktionsgemisch als Säureadditionsverbindung isoliert und durch Behandeln mit Lösungsmitteln, z. B. Methanol oder Aceton, und Umkristallisation aus Äthanol reinigt.with hydrochloric acid, acetophenone and formaldehyde or ao with phenyl vinyl ketone, made from intermediates / 9-chloropropiophenone and potassium acetate, preferably Reacts at a higher temperature in a solvent and the 3-N- (2-hydroxy-3-phenoxypropyl) -amino-1-phenyl-propanone- (l) obtained in this way as expediently from the reaction mixture as an acid addition compound isolated and treated with solvents, e.g. B. methanol or acetone, and Recrystallization from ethanol cleans.
Das Hydrochlorid des neuen Keto-phenoxy-aminoalkohols zeichnet sich bei geringer Toxizität und guter enteraler Resorption durch eine gute zentraldämpfende Wirkung bei gleichzeitiger Wirkung auf den Kreislauf und das vegetative Nervensystem aus. Es stellt ein blutdrucksenkendes Mittel mit dämpfender Wirkung auf das Zentralnervensystem dar. Die beanspruchte Substanz zeigt mit einer Dosis von 2,2 mg/kg Körpergewicht per os am wachen Hund eine blutdrucksenkende Wirkung mittlerer Stärke bis zu einer Gesamtdauer von weniger als einer Stunde und mehr als 40 Minuten. Mit der höheren Dosis von 3,2 mg/kg Körpergewicht per os am wachen Hund zeigt die Substanz eine starke blutdrucksenkende Wirkung von insgesamt mehr als 2 Stunden Dauer. Die mittlere letale Dosis (LDSO) beträgt nach der Gabe per os an Albino-Mäusen (Stamm NMRI) 308 (237 bis 400) mg/kg Körpergewicht. Aus den tierexperimentellen Ergebnissen geht die gute therapeutische Breite der Substanz hervor.The hydrochloride of the new keto-phenoxy-amino alcohol is characterized by low toxicity and good enteral absorption thanks to a good central damping system Effect with simultaneous effect on the circulatory system and the autonomic nervous system. It is an antihypertensive agent with a depressant effect on the central nervous system. The claimed The substance shows up with a dose of 2.2 mg / kg body weight per os on the conscious dog a moderate antihypertensive effect for a total duration of less than an hour and more than 40 minutes. With the higher dose of 3.2 mg / kg body weight per os on the conscious dog the substance shows a strong antihypertensive effect lasting more than 2 hours in total. The mean lethal dose (LDSO) after oral administration to albino mice (strain NMRI) is 308 (237 to 400) mg / kg body weight. The results of animal experiments give good therapeutic results Width of the substance.
Die Substanz wirkt, wie erste Versuche an Patienten so zeigten, in gleicher Weise wie an Tieren bevorzugt auf den arteriellen Blutdruck im Sinne einer von der Dosis abhängigen Senkung. Bei den Patienten kam die sedierende Wirkung auf das zentrale Nervensystem nur in abgeschwächter Form zum Ausdruck.The substance works like the first tests on patients showed, in the same way as on animals, preferably on arterial blood pressure in the sense of one of the Dose-dependent reduction. In the patients, the sedative effect came on the central nervous system only expressed in a weakened form.
138 g S-Hydroxy-S-phenoxypropylumin-hydrochlorid vom Schmelzpunkt 129 bis 1350C, 164 g Acetophenon und 40 g Paraformaldehyd wurden in 500 ml Isopropanol 4 Stunden unter Rückfluß erhitzt. Der beim Abkühlen ausgefallene Niederschlag wurde abgesaugt und mit Isopropanol nachgewaschen. Anschließend wurde der Niederschlag mit Methanol aufgekocht, das Gelöste vom Ungelösten abfiltriert und das Filtrat eingedampft. Der TrockenrUckstand wurde mit Aceton aufgekocht. Nach dem Abkühlen wurde das Nichtgelöste abgesaugt und aus Äthanol umkristallisiert. Das erhaltene 3-N-(2-Hydroxy-3-phenoxypropyl >amino-l-phenyl-propanon-(l)-hydrochlorid zeigte einen Schmelzpunkt von 134 bis 1380C, die Ausbeute betrug 50°/0. Die Base zeigte einen Schmelzpunkt von 104 bis 105° C und gab mit Maleinsäure ein Maleinat vom Schmelzpunkt 118 bis 1190C.138 g of S-hydroxy-S-phenoxypropylumin hydrochloride of melting point 129-135 0 C, 164 g of acetophenone and 40 g of paraformaldehyde were heated in 500 ml of isopropanol for 4 hours under reflux. The precipitate which separated out on cooling was filtered off with suction and washed with isopropanol. The precipitate was then boiled up with methanol, the dissolved matter was filtered off from the undissolved matter and the filtrate was evaporated. The dry residue was boiled with acetone. After cooling, the undissolved material was filtered off with suction and recrystallized from ethanol. The obtained 3-N- (2-hydroxy-3-phenoxypropyl> amino-l-phenyl-propanone (l) hydrochloride showed a melting point 134-138 0 C, the yield was 50 ° / 0th The base showed a Melting point of 104 to 105 ° C and gave a maleate with maleic acid with a melting point of 118 to 119 0 C.
6,74 g /9-Chlorpropiophenon wurden mit 5 g wasserfreiem Kaliumacetat 5 Minuten unter Rückfluß erhitzt und die erhaltene Lösung zu 6,72 g 2-Hydroxy-3-phenoxypropylamin vom Schmelzpunkt 89 bis 930C, gelöst in Methanol, getropft. Nach 12 Stunden wurde die Reaktionslösung filtriert und eingedampft. Der Rückstand wurde in Äther gelöst und durch Einleiten von Chlorwasserstoffgas ein Hydrochlorid ausgefällt, das analog Beispiel 1 aufgearbeitet und gereinigt wurde. Es zeigte nach dem Umlösen aus Äthanol einen Schmelzpunkt von 134 bis 138°C und gab keine Schmelzpunktdepression mit dem nach Beispiel 1 erhaltenen 3-N-(2-Hydroxy-3-phenoxypropyi·· irnin^" l-phenyl-propanon-(l)-hydrochlorid.6.74 g / 9-chloropropiophenone were heated with 5 g of anhydrous potassium acetate 5 minutes under reflux and the resulting solution to 6.72 g of 2-hydroxy-3-phenoxypropylamin of melting point 89 to 93 0 C, dissolved in methanol dropwise. After 12 hours the reaction solution was filtered and evaporated. The residue was dissolved in ether and a hydrochloride was precipitated by passing in hydrogen chloride gas, which was worked up and purified analogously to Example 1. After redissolving from ethanol it showed a melting point of 134 to 138 ° C and gave no melting point depression with the 3-N- (2-hydroxy-3-phenoxypropanone- (l-phenyl-propanone- (l-phenyl-propanone- (l ) hydrochloride.
Claims (1)
Family
ID=
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