CH530960A - Prepn of 3-n-(2-hydroxy-3-phenoxypropyl)-amino-1- - phenyl-propane - Google Patents
Prepn of 3-n-(2-hydroxy-3-phenoxypropyl)-amino-1- - phenyl-propaneInfo
- Publication number
- CH530960A CH530960A CH443172A CH443172A CH530960A CH 530960 A CH530960 A CH 530960A CH 443172 A CH443172 A CH 443172A CH 443172 A CH443172 A CH 443172A CH 530960 A CH530960 A CH 530960A
- Authority
- CH
- Switzerland
- Prior art keywords
- hydroxy
- phenyl
- dependent
- amino
- acid addition
- Prior art date
Links
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- JZEHWMUIAKALDN-UHFFFAOYSA-N 1-amino-3-phenoxypropan-2-ol Chemical compound NCC(O)COC1=CC=CC=C1 JZEHWMUIAKALDN-UHFFFAOYSA-N 0.000 claims abstract description 3
- KUIZKZHDMPERHR-UHFFFAOYSA-N 1-phenylprop-2-en-1-one Chemical compound C=CC(=O)C1=CC=CC=C1 KUIZKZHDMPERHR-UHFFFAOYSA-N 0.000 claims abstract description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims abstract 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- -1 2-Hydroxy-3 phenoxy-propyl Chemical group 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 3
- 235000011056 potassium acetate Nutrition 0.000 claims description 3
- KTJRGPZVSKWRTJ-UHFFFAOYSA-N 3-chloro-1-phenylpropan-1-one Chemical compound ClCCC(=O)C1=CC=CC=C1 KTJRGPZVSKWRTJ-UHFFFAOYSA-N 0.000 claims description 2
- 230000001419 dependent effect Effects 0.000 claims 7
- 239000007795 chemical reaction product Substances 0.000 claims 1
- 239000012458 free base Substances 0.000 claims 1
- 239000000376 reactant Substances 0.000 claims 1
- 239000002220 antihypertensive agent Substances 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 abstract 2
- DRMYIECWZSACES-UHFFFAOYSA-N 3-[(2-hydroxy-3-phenoxypropyl)amino]-1-phenylpropan-1-one Chemical compound OC(CNCCC(=O)C1=CC=CC=C1)COC1=CC=CC=C1 DRMYIECWZSACES-UHFFFAOYSA-N 0.000 abstract 1
- 241000282472 Canis lupus familiaris Species 0.000 abstract 1
- 241000282326 Felis catus Species 0.000 abstract 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 abstract 1
- 241000699670 Mus sp. Species 0.000 abstract 1
- 230000036772 blood pressure Effects 0.000 abstract 1
- 239000000932 sedative agent Substances 0.000 abstract 1
- 230000001624 sedative effect Effects 0.000 abstract 1
- 239000000126 substance Substances 0.000 description 4
- 230000037396 body weight Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 230000004531 blood pressure lowering effect Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000013016 damping Methods 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 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
- 230000001631 hypertensive effect Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 238000013421 nuclear magnetic resonance imaging Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000002226 simultaneous effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
3 ((2-hydroxy-3-phenoxypropyl)-amino) -1- phenyl- propan-1-one and its salts, e.g. the hydrochloride and maleate, are CNS sedative, hypotensive agents with low toxicity, and are well absorbed in the gut. Oral LD5o in mice 308 mg/Kg. 2.2 mg/Kg orally in dogs and 3.2 mg/Kg orally in cats lowers the blood pressure. Preparation is by reaction of 2-hydroxy-3-phenoxy-propylamine with (a) phenylvinyl ketone or (b) acetophenone, HCHO and HCl.
Description
Verfahren zur Herstellung von 3 -[N-(2-Hydroxy-3 -phenoxypropyl) arnino] -1-phenyl- propanon-(1) und dessen Säureadditionssalzen
Gegenstand der vorliegenden Erfindung ist ein Verfahren zur Herstellung von 3-[N-(2-Hydroxy-3-phenoxypropyl)amino]-1-phenyl-propanon-(1) von der Formel I
EMI1.1
und dessen Säureadditionssalze.
Das Verfahren zur Herstellung des neuen Keto-phenoxyamino-alkohols ist dadurch gekennzeichnet, dass man 2-Hy droxy-3 -phenoxy-propylamin (II)
EMI1.2
mit Phenylvinylketon, intermediär hergestellt aus ss-Chlorpropiophenon und Kaliumacetat, vorzugsweise bei höherer Temperatur, in einem geeigneten Lösungsmittel umsetzt und das auf diese Weise erhaltene 3-[N-(2-Hydroxy-3-phenoxy propyl)-amino]-1-phenyl-propanon(1) (I) zweckmässig aus dem Reaktionsgemisch als Säureadditionsverbindung isoliert und durch Behandeln mit geeigneten Lösungsmitteln, wie beispielsweise Methanol oder Aceton, und Umkristallisation aus Äthanol reinigt.
Dieses Ergebnis war nicht vorauszusehen und ist deshalb auch besonders überraschend, weil vergleichsweise die nach der Literatur bekannten Mannich-Kondensationen mit primären Aminen oft zu einem schwer entwirrbaren Gemisch der verschiedensten Verbindungen führen [Houben, Band XI/1, Seite 734 (1957)].
Der neue Keto-phenoxy-aminoalkohol zeichnet sich bei geringer Toxizität und guter enteraler Resorption durch eine gute zentraldämpfende Wirkung bei gleichzeitiger Wirkung auf den Kreislauf und das vegative Nervensystem aus. Es stellt ein blutdrucksenkendes Mittel mit dämpfender Wirkung auf das Zentralnervensystem dar. Die LDso an der Albino Maus (Stamm NMRI, männliche Tiere im Gewicht von 18 bis 20 g) betrug nach der Gabe per os 308 (237 bis 400) mg/ kg Körpergewicht. Am wachen Hund (Beagle) wurde eine blutdrucksenkende Wirkung mit 2,2 mg/kg Körpergewicht per os nachgewiesen. Eine mehrstündige Wirkung wurde mit 3,2 mg/kg Körpergewicht per os am wachen Hund (Beagle) beobachtet. Aus den tierexperimentellen Ergebnissen geht die gute therapeutische Breite der Substanz hervor.
Die Substanz wirkt bei Hochdruckpatienten nach der peroralen Gabe blutdrucksenkend. Die therapeutische Anwendung der Substanz beim Menschen kann in Form von Tabletten, die mit den üblichen Begleitsubstanzen hergestellt worden sind, erfolgen.
Im folgenden werden einige Ausführungsbeispiele des Verfahrens der Erfindung mitgeteilt.
Beispiel
6,74 gss-Chlorpropiophenon wurden mit 5 g wasserfreiem Kaliumacetat 5 Minuten unter Rückfluss erhitzt und die erhaltene Lösung zu 6,72 g 2-Hydroxy-3-phenoxy-propylamin (II) vom Schmelzpunkt 89 bis 93" C, 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. Der Niederschlag wurde abgesaugt und mit Isopropanol nachgewaschen. Anschliessend wurde der Niederschlag mit Methanol aufgekocht, das Gelöste vom Ungelösten abfiltriert und das Filtrat eingedampft. Der Trockenrückstand wurde mit Aceton aufgekocht. Nach dem Abkühlen wurde das Nichtgelöste abgesaugt und aus Äthanol umkristallisiert.
Es zeigte nach dem Kristallisieren einen Schmelzpunkt von 134 bis 138 C und gab keine Schmelzpunktdepression mit einem auf andere Weise erhaltenen 3 [N-(2-Hydroxy-3-phenoxypropyl)-amino]- 1 -phenyl-pro panon-(l)-hydrochlorld (1).
Process for the preparation of 3 - [N- (2-hydroxy-3-phenoxypropyl) arnino] -1-phenyl-propanone- (1) and its acid addition salts
The present invention relates to a process for the preparation of 3- [N- (2-hydroxy-3-phenoxypropyl) amino] -1-phenyl-propanone- (1) of the formula I
EMI1.1
and its acid addition salts.
The process for the preparation of the new keto-phenoxyamino-alcohol is characterized in that 2-Hy droxy-3-phenoxy-propylamine (II)
EMI1.2
with phenyl vinyl ketone, prepared as an intermediate from ß-chloropropiophenone and potassium acetate, preferably at a higher temperature, in a suitable solvent and the 3- [N- (2-hydroxy-3-phenoxy propyl) amino] -1-phenyl obtained in this way Propanone (1) (I) conveniently isolated from the reaction mixture as an acid addition compound and purified by treatment with suitable solvents, such as methanol or acetone, and recrystallization from ethanol.
This result could not be foreseen and is therefore particularly surprising because, in comparison, the Mannich condensations with primary amines known from the literature often lead to a mixture of the most varied of compounds that is difficult to disentangle [Houben, Volume XI / 1, page 734 (1957)].
The new keto-phenoxy-amino alcohol is characterized by low toxicity and good enteral absorption by a good central damping effect with a simultaneous effect on the circulatory and vegative nervous system. It is an antihypertensive agent with a depressant effect on the central nervous system. The LD 50 in the albino mouse (strain NMRI, male animals weighing 18 to 20 g) was 308 (237 to 400) mg / kg body weight after oral administration. A blood pressure lowering effect with 2.2 mg / kg body weight per os was demonstrated in the conscious dog (beagle). An effect lasting several hours was observed with 3.2 mg / kg body weight per os on the conscious dog (beagle). The results of animal experiments show that the substance has a good therapeutic range.
The substance has a blood pressure lowering effect in hypertensive patients after oral administration. The therapeutic use of the substance in humans can take place in the form of tablets that have been produced with the usual accompanying substances.
Some embodiments of the method of the invention are given below.
example
6.74 gss-chloropropiophenone were refluxed with 5 g of anhydrous potassium acetate for 5 minutes and the resulting solution was added to 6.72 g of 2-hydroxy-3-phenoxy-propylamine (II) with a melting point of 89 to 93 "C, dissolved in methanol, 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. The precipitate 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.
After crystallization it showed a melting point of 134 to 138 C and gave no melting point depression with a 3 [N- (2-hydroxy-3-phenoxypropyl) -amino] -1-phenyl-propanon- (l) - obtained in another way hydrochlorld (1).
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19681813061 DE1813061B1 (en) | 1968-12-06 | 1968-12-06 | 3-N- (2-Hydroxy-3-phenoxypropyl) -amino-1-phenyl-propanone- (1) and its acid addition salts |
| CH1677469A CH530959A (en) | 1968-12-06 | 1969-11-11 | Process for the preparation of 3- (N- (2-Hydroxy-3-phenoxypropyl) -amino) -1-phenyl-propanone- (1) and its acid addition salts |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH530960A true CH530960A (en) | 1972-11-30 |
Family
ID=25718456
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH443172A CH530960A (en) | 1968-12-06 | 1969-11-11 | Prepn of 3-n-(2-hydroxy-3-phenoxypropyl)-amino-1- - phenyl-propane |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH530960A (en) |
-
1969
- 1969-11-11 CH CH443172A patent/CH530960A/en not_active IP Right Cessation
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased |