DE2359926C3 - 1-Phenoxy-2-propanolamines, processes for their preparation and pharmaceuticals containing them - Google Patents
1-Phenoxy-2-propanolamines, processes for their preparation and pharmaceuticals containing themInfo
- Publication number
- DE2359926C3 DE2359926C3 DE2359926A DE2359926A DE2359926C3 DE 2359926 C3 DE2359926 C3 DE 2359926C3 DE 2359926 A DE2359926 A DE 2359926A DE 2359926 A DE2359926 A DE 2359926A DE 2359926 C3 DE2359926 C3 DE 2359926C3
- Authority
- DE
- Germany
- Prior art keywords
- phenoxy
- methyl
- propanol
- connection
- isopropyl
- 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
Classifications
-
- 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
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- 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
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
-
- 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
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/24—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Hydrogenated Pyridines (AREA)
Description
3-morpholino-2-propanol, l-(2-Isopropyl-5-methyl-phenoxy)-3-morpholino-2-propanol, l- (2-isopropyl-5-methyl-phenoxy) -
3-(4-methyl-1 -pipera2inyl)-2-propanol, l-(2-Isopropyl-5-methyl-phenoxy}3- (4-methyl-1-pipera2inyl) -2-propanol, 1- (2-isopropyl-5-methyl-phenoxy)
3-piperidino-2-propanol, l-(2-Isopropyl-5-methyl-phenoxy)-3-(l,5-di-3-piperidino-2-propanol, l- (2-isopropyl-5-methyl-phenoxy) -3- (l, 5-di-
methyl-5-hydroxyhexyl)-amino-2-propanol, -(4-Allyl-2-methoxy-phenoxy)-methyl-5-hydroxyhexyl) -amino-2-propanol, - (4-Allyl-2-methoxyphenoxy) -
3-bis-(/?-hydroxyäthyl)-amino-2-propanol, l-(2-Isopropyl-5-methyl-phenoxy)-3-bis - (/? - hydroxyethyl) -amino-2-propanol, l- (2-isopropyl-5-methyl-phenoxy) -
3-benzylamino-2-propanol und deren Salze.3-benzylamino-2-propanol and its salts.
2. Verfahren zur Herstellung der Verbindungen nach Anspruch 1, dadurch gekennzeichnet, daß man ein entsprechendes Phenol mit Epichlorhydrin in Gegenwart eines Katalysators bei einer Temperatur zwischen 70 und 100° C innerhalb einer Zeitspanne von 10 bis 20 Stunden in an sich bekannter Weise zur Reaktion bringt, das Reaktionsgemisch 24 Stunden2. Process for the preparation of the compounds according to claim 1, characterized in that one a corresponding phenol with epichlorohydrin in the presence of a catalyst at a temperature between 70 and 100 ° C within a period of 10 to 20 hours in a known manner for Reaction brings the reaction mixture 24 hours
ίο mit einer Lösung von Natriumhydroxid behandelt, das Gemisch mit Chloroform extrahiert, das Chloroform unter Vakuum entfernt und den Rückstand bei erniedrigtem Druck destilliert, und dann ein entsprechendes Amin nach Lösen in Äthanol oder Tetrahydrofuran mit dem in der vorhergehenden Stufe erhaltenen Glycidyläther in an sich bekannter Weise umsetzt.ίο treated with a solution of sodium hydroxide, the mixture extracted with chloroform, the chloroform removed under vacuum and the Distilled residue at reduced pressure, and then a corresponding amine after dissolving in Ethanol or tetrahydrofuran with the glycidyl ether obtained in the previous stage in implemented in a known manner.
3. Arzneimittel, gekennzeichnet durch einen Gehalt an einer Verbindung gemäß Anspruch 1 und pharmazeutisch üblichen Träger- bzw. Hilfsstoffen.3. Medicament, characterized by a content of a compound according to claim 1 and pharmaceutically customary carriers or excipients.
Die Erfindung betrifft folgende l-Phenoxy-2-propanolamine: The invention relates to the following l-phenoxy-2-propanolamines:
1) 1 -(4-Chlorphenoxy)-3-bis(0-hydroxyäthyl)-amino-2-propanol, 1) 1 - (4-chlorophenoxy) -3-bis (0-hydroxyethyl) -amino-2-propanol,
2) 1 -(2-Isopropyl-5-methyl-phenoxy)-3-bis(jS-hydroxyäthyl)-amino-2-propanoI, 2) 1 - (2-isopropyl-5-methyl-phenoxy) -3-bis (jS-hydroxyethyl) -amino-2-propanoI,
3) 1 -(2-lsopropyl-5-methyl-phenoxy)-3-morpholino-2-propanol, 3) 1 - (2-isopropyl-5-methyl-phenoxy) -3-morpholino-2-propanol,
4) 1 -^-Isopropyl-S-methyl-phenoxy)-3-(4-methyl-1 -piperazinyl)-2-propanol,4) 1- ^ - Isopropyl-S-methyl-phenoxy) -3- (4-methyl-1 -piperazinyl) -2-propanol,
5) l-(2-lsopropyl-5-methyl-phenoxy)-5) l- (2-isopropyl-5-methyl-phenoxy) -
3-piperidino-2-propanol,3-piperidino-2-propanol,
6) l-(2-Isopropyl-5-methyl-phenoxy)-3-(l,5-dimethyl-5-hydroxyhexy])-amino-2-propanol, 6) 1- (2-isopropyl-5-methyl-phenoxy) -3- (l, 5-dimethyl-5-hydroxyhexy]) - amino-2-propanol,
7) 1 -(4-AIlyl-2-methoxy-phenoxy)-3-bis(/?-hydroxyäthyl)-amino-2-propanol, 7) 1 - (4-Allyl-2-methoxy-phenoxy) -3-bis (/? - hydroxyethyl) -amino-2-propanol,
8) 1 -^-Isopropyl-S-methyl-phenoxy)-8) 1 - ^ - Isopropyl-S-methyl-phenoxy) -
3-benzylamino-2-propanol und deren Salze.3-benzylamino-2-propanol and its salts.
Den erfindungsgemäßen Verbindungen kommen folgende Formeln zu:The compounds according to the invention have the following formulas:
Verbindung 1Connection 1
CH2-CH2OHCH 2 -CH 2 OH
—/~~S—O —CH,-CH—CH-,-N -HCl- / ~~ S-O-CH, -CH-CH -, - N -HCl
ClCl
OHOH
CH2-CH2OHCH 2 -CH 2 OH
Verbindung 2
CH3 Connection 2
CH 3
O -CH, CH-CH2-NO -CH, CH-CH 2 -N
CH3-CHCH.,CH 3 -CHCH.,
OHOH
CH-,- CH2OHCH -, - CH 2 OH
HClHCl
"CH2-CH2OH"CH 2 -CH 2 OH
Verbindung 3Connection 3
" X-Q-CH, CH-CH, -r/ O- HCI" XQ- CH, CH-CH, -r / O-HCI
"I N"IN
CH3-CH-CH3 CH 3 -CH-CH 3
OHOH
Verbindung 4
CH3 Connection 4
CH 3
//—0—CH1-CH-CH1- N Ν —CH3-IHCl // - 0- CH 1 -CH-CH 1 - N Ν -CH 3 -IHCl
CH3-CH-CH3 CH 3 -CH-CH 3
Verbindung 5
CH,Connection 5
CH,
OHOH
-0-CH1-CH-CH1-I
OH-0-CH 1 -CH-CH 1 -I
OH
HCIHCI
CH3 CH3 CH 3 CH 3
CH3-CH-CH3
Verbindung 6CH 3 -CH-CH 3
Connection 6
Jl J-0 — CH, —CH — CH, —NH — CH —CH2-CH2-CH2-C-CH, ■ HClJl J-0-CH, -CH-CH, -NH-CH -CH 2 -CH 2 -CH 2 -C-CH, ■ HCl
CH3-CH-CH3 0Η 0Η CH 3 -CH-CH 3 0Η 0Η
Verbindung 7Connection 7
OCH3 OCH 3
CH, = Cl·CH, = Cl
Verbindung 8Connection 8
CH1-CH1OHCH 1 -CH 1 OH
-CH2-CH-CH1-N OH-CH 2 -CH-CH 1 -N OH
HClHCl
CIU-CH7OHCIU-CH 7 OH
J-O-CH1-CH-CH1-NH-CH-,--^JO-CH 1 -CH-CH 1 -NH-CH -, - ^
kV ι kV ι
HClHCl
CH3-CH-CH3 CH 3 -CH-CH 3
OHOH
Zur Herstellung der erfindungsgemäßen Verbindungen werden dift entsprechenden Phenole eingesetzt, die mit l-Chlor-2,3-epoxypropan in Gegenwart von Katalysatoren (Piperidin, Piperidinacetat, -chlorhydrat oder Piperazin) das entsprechende l-Chlor^-hydroxy-S-phenoxypropan ergeben. Durch Behandlung mit kaustischer Soda oder Pottasche in verschiedenen Konzentrationen oder in Äther-Suspension gibt dieses Chlorwasserstoff ab und bildet die entsprechenden Epoxy-Derivate. In einer zweiten Stufe reagieren diese Glycidyläther mit den entsprechenden Aminen zu den Phenoxy-propanolaminen in Form einer freien Base. Nach einer Destillation werden die Aminoalkohole in absolutem Alkohol gelöst und die Hydrochloride in einem Strom trockenen Chlorwasserstoffs zum Kristallisieren gebracht. Neben den Hydrochloriden dieser Verbindungen können auch andere Salze mit anorganischen oder organischen Säuren erhalten werden, die für die Herstellung therapeutisch verträglicher Salze geeignet sind.To prepare the compounds according to the invention, phenols corresponding to dift are used which with l-chloro-2,3-epoxypropane in the presence of catalysts (piperidine, piperidine acetate, chlorohydrate or Piperazine) the corresponding l-chloro ^ -hydroxy-S-phenoxypropane result. By treatment with caustic soda or potash in various concentrations or in ether suspension, this releases hydrogen chloride and forms the corresponding epoxy derivatives. In a second stage, these glycidyl ethers react with the corresponding amines to form the Phenoxy-propanolamines in the form of a free base. After a distillation, the amino alcohols are in dissolved in absolute alcohol and the hydrochloride in a stream of dry hydrogen chloride to crystallize brought. In addition to the hydrochlorides of these compounds, other salts with inorganic or organic acids are obtained, which are used for the preparation of therapeutically acceptable salts are suitable.
Die erfindungsgemäßen Verbindungen besitzen die Wirkung, daß sie ß-adrenergische Rezeptoren blockieren. Sie zeigt sich im kardiovaskulären System durch die Hemmung der durch Isoprenalin bedingten Tensionsempfindlichkeit. Die Verbindungen rufen eine begrenzte periphere Hypotonie zusammen mit einer Verminderung der chronotropen und inotropen Wirkungen hervor. Auch eine deutliche antiarrhythmische Wirkung in bezug auf den experimentellen urrhythmischen Zustand beim Hunde und Meerschweinchen wurdeThe compounds according to the invention have the effect of blocking β-adrenergic receptors. It manifests itself in the cardiovascular system by inhibiting the sensitivity to tension caused by isoprenaline. The connections call a limited one peripheral hypotension along with a decrease in chronotropic and inotropic effects emerged. Also a clear anti-arrhythmic effect in relation to the experimental rhythmic one Condition in dogs and guinea pigs
55 festgestellt.55 found.
In der folgenden Tabelle ist die antiarrhythmische sowie die cardiodepressive Wirksamkeit der Verbindung 2 den entsprechenden Wirkungen von Propranolol gegenübergestellt. Wie aus der Tabelle ersichtlich ist, setzt beim Propranolol die unerwünschte Herabsetzung der Kontraktionskraft des Myocards bereits bei Dosierungen ein, die unter den Dosierungen liegen, die die gewünschte antirrhythmische Wirksamkeit entfalten. Die erfindungsgemäße Verbindung zeichnet sich demgegenüber dadurch aus, daß die Dosierungen für die gewünschte antirrhythmische Wirkung weit unter denen der unerwünschten cardiodepressiven Wirkung liegen.The following table shows the antiarrhythmic as well as the cardiodepressant efficacy of the compound 2 compared to the corresponding effects of propranolol. As can be seen from the table, With propranolol, the undesired decrease in the contraction force of the myocardium is already added Dosages that are below the dosages that develop the desired antirrhythmic effectiveness. The compound according to the invention is characterized in that the dosages for Desired antirrhythmic effect far below those of the undesirable cardiodepressive effect lie.
Harris-Arrhythmie
Aconitin-Arrhythmie
Digitalis-Arrhythmie
acetyl cholin-ArrhythmieHarris arrhythmia
Aconitine arrhythmia
Digitalis arrhythmia
acetyl choline arrhythmia
Adrenalin-Arrhythmie
(L) = alle Tiere starben.Adrenaline arrhythmia
(L) = all animals died.
In Antagonismus zur Isoprenalinwirkung ist weiterhin besonders die ^-blockierende Wirkung der Verbindungen 3,5 und 8 überragend.In antagonism to the isoprenaline effect, the ^ -blocking effect of the compounds is still particularly evident 3.5 and 8 outstanding.
Die vorstehenden Ausführungen zeigen, daß die erfindungsgemäßen Verbindungen als ^-Rezeptoren blockierende Mittel ein breites Wirkungsspektrum besitzen und auf vielen Gebieten bekannten j3-Rezeptoren blockierenden Mitteln überlegen sind.The preceding statements show that the compounds according to the invention as ^ receptors blocking agents have a broad spectrum of activity and j3 receptors known in many fields are superior to blocking agents.
Die erfindungsgemäßen Verbindungen weisen auch günstige Toxizitätswerte auf. Die DL50 der Verbindung 2 wurde oral zu 1750 mg/kg gemessen. Intravenös weisenThe compounds according to the invention also have favorable toxicity values. The DL50 of connection 2 was measured orally at 1750 mg / kg. Assign intravenously
/4 mg+++]
18 mg+++// 4 mg +++]
18 mg +++ /
0,625 mg++0.625 mg ++
die Verbindungen 2,3,5 und 7 Toxizitäten von 113, etwa 85, etwa 50 bzw. etwa 80 mg/kg auf, wohingegen die Toxizität von Propranolol 45 mg/kg beträgt. Allgemein läßt sich also feststellen, daß die akute und die chronische Toxizität der erfindungsgemäßen Verbindungen geringer ist, als die von Propranolol und Practolol.compounds 2,3,5 and 7 toxicities of 113, approximately 85, about 50 and about 80 mg / kg, respectively, whereas the toxicity of propranolol is 45 mg / kg. Generally it can thus be determined that the acute and chronic toxicity of the compounds according to the invention is lower than that of Propranolol and Practolol.
Der folgende Vergleich der antiarrhythmischen Aktivität (äquiaktive Dosen) sowie der Toxizitäten zeigt die Überlegenheit der erfindungsgemäßen Verbindungen im Vergleich mit Propranolol und Chinidin.The following comparison shows the antiarrhythmic activity (equivalent doses) and the toxicities the superiority of the compounds according to the invention in comparison with propranolol and quinidine.
Die erfindungsgemäßen Verbindungen sind also bei großer therapeutischer Breite im Vergleich mit bekannten Verbindungen durch ihre selektive antiarrhythmische Wirksamkeit überlegen.The compounds according to the invention are therefore with a large therapeutic range in comparison with superior to known compounds due to their selective antiarrhythmic effectiveness.
Die folgenden Beispiele dienen zur Erläuterung der Erfindung.The following examples serve to illustrate the invention.
Herstellung von 1 -(2-Isopropyl-5-methyl-phenoxy)-Production of 1 - (2-isopropyl-5-methyl-phenoxy) -
3-bis(ß-hydroxyäthyl)-amino-2-propanol3-bis (ß-hydroxyethyl) -amino-2-propanol
(Verbindung 2)(Connection 2)
Stufe 1step 1
Man gibt 150 g Thymol (1 Mol), 277,5 g l-C'nlor-2,3-epoxypropan und 2 ml Piperidin in einen Dreihalskol-150 g of thymol (1 mol) and 277.5 g of 1-chloro-2,3-epoxypropane are added and 2 ml of piperidine in a three-necked
ben, der mit mechanischen Rührer, Tropftrichter und Kühler ausgerüstet ist Man erhitzt 16 Stunden unter Rühren. Den Oberschuß an Epichlorhydrin entfernt man unter Vakuum, behandelt den Rückstand mit 500 ml einer 16prozentigen kaustischen Soda-Lösung und setzt das Rühren über 24 Stunden bei Raumtemperatur fort Das Gemisch extrahiert man mehrere Male mit Chloroform und trocknet mit wasserfreiem Natriumsulfat Man entfernt das Chloroform am Vakuum-Rotationsverdampfer und destilliert den Rückstand unter erniedrigtem Druck. Siedepunkt 120°C/2,67 mbar.ben, which is equipped with a mechanical stirrer, dropping funnel and condenser. It is heated under for 16 hours Stir. The excess epichlorohydrin is removed under vacuum, treats the residue with 500 ml of a 16 percent caustic soda solution and sets stirring continued for 24 hours at room temperature. The mixture is extracted several times with Chloroform and dry with anhydrous sodium sulfate. The chloroform is removed on a vacuum rotary evaporator and the residue is distilled under reduced pressure. Boiling point 120 ° C / 2.67 mbar.
Analyse: (Ci3H18O2)
Gefunden: C 75,89, H 8,80%;
berechnet: C 75,72, H 8,73%.Analysis: (Ci 3 H 18 O 2 )
Found: C 75.89, H 8.80%;
Calculated: C 75.72, H 8.73%.
& i
&
51f *
51
ii
Gasphasen-Chromatographie AusrüstungGas phase chromatography equipment
Doppelkolonne; Flammen-Ionisations-DetektonTrägergas: Stickstoff-Strömungsgeschwindigkeit 30 ml/Minute; Kolonnentemperatur 170°G Retentionszeit 256 Sekunden.Double column; Flame ionization detector carrier gas: Nitrogen flow rate 30 ml / minute; Column temperature 170 ° G retention time 256 Seconds.
Stufe 2Level 2
1010
Man erhitzt 206 g (1 MoI) des oben erhaltenen Produkts 4 bis 5 Stunden auf 70 bis 8O0C mit 82^ g (1,2 Mol) Diethanolamin. Man kühlt mit Eiswasser. Danach extrahiert man 5mal mit 500 ml Äther und trocknet den Ätherextrakt z.B. mit wasserfreiem Magnesiumsulfat Der Äther wird unter Vakuum entfernt, der Rückstand in absolutem Alkohol gelöst und dann ein Strom von trockenem Chlorwasserstoff in die Lösung zwecks Kristallisation geleitet Den Niederschlag kristallisiert man aus absolutem Äthanol um. Man erhält insgesamt 200 g der Titelverbindung.The mixture is heated 206 g (1 mol) of the product obtained above 4 to 5 hours at 70 to 8O 0 C with 82 ^ g (1.2 mol) of diethanolamine. It is cooled with ice water. Then it is extracted 5 times with 500 ml of ether and the ether extract is dried, for example with anhydrous magnesium sulfate. The ether is removed under vacuum, the residue is dissolved in absolute alcohol and a stream of dry hydrogen chloride is then passed into the solution for crystallization.The precipitate is recrystallized from absolute ethanol . A total of 200 g of the title compound is obtained.
Ausbeute 75%. Schmelzpunkt 147° C.Yield 75%. Melting point 147 ° C.
Analyse: (C17H29NO4- HCl)Analysis: (C 17 H 29 NO 4 - HCl)
Gefunden: C 58,75, H 8,71, N 4,18, Cl 103%; berechnet: C 58,70, H 8,63, N 4,02, Cl 10,21%.Found: C 58.75, H 8.71, N 4.18, Cl 103%; Calculated: C 58.70, H 8.63, N 4.02, Cl 10.21%.
Die Herstellung der übrigen erfindungsgemäßen Verbindungen erfolgt nach folgender Arbeitsweise:The other compounds according to the invention are prepared using the following procedure:
Erste Stufe
Herstellung der GlycidylätherFirst stage
Manufacture of glycidyl ethers
Ein Gemisch aus 03 Mol Phenol und 0,9 Mol l-Chlor-2,3-epoxypropan wird mit 0,6 g Katalysator (Piperidin, Piperidin-Acetat — Chlorhydrat oder Piperazin) !5 bis 17 Stunden auf eine Temperatur von 50 bis 1000C erhitzt Der Überschuß an Epichlorhydrin wird unter Vakuum abgedampft und der Rückstand mit 150 ml einer 16prozentigen Lösung kaustischer Soda behandelt, wobei die Suspension 24 Stunden bei Raumtemperatur heftig geschüttelt wird. Das Gemisch wird mehrere Male mit Chloroform extrahiert. Der Chloroform-Extrakt wird mit Natriumsulfat oder einem anderen Trocknungsmittel getrocknet Das Chloroform wird unter Vakuum abgetrieben und der Rückstand bei niedrigem Druck destilliertA mixture of 03 mol of phenol and 0.9 mol of 1-chloro-2,3-epoxypropane is mixed with 0.6 g of catalyst (piperidine, piperidine acetate - chlorohydrate or piperazine) for 5 to 17 hours at a temperature of 50 to 100 0 C. The excess epichlorohydrin is evaporated off in vacuo and the residue is treated with 150 ml of a 16 percent strength solution of caustic soda, the suspension being shaken vigorously at room temperature for 24 hours. The mixture is extracted several times with chloroform. The chloroform extract is dried with sodium sulfate or another drying agent. The chloroform is stripped off under vacuum and the residue is distilled at low pressure
Zweite Stufe
Herstellung von l-Phenoxy-2-propanoI-aminenSecond step
Production of l-phenoxy-2-propanoI-amines
1,2 Mol des in Frage kommenden Amins werden zu 1 Mol des in der vorangegangenen Phase erhaltenen Glycidyläthers gegeben, in 1000 ml Äthanol gelöst und danach 4 bis 5 Stunden unter Rückfluß erhitzt Das Gemisch wird mit Eiswasser abgekühlt Danach wird mit Äther extrahiert und der Extrakt wird z.B. mit wasserfreiem Magnesiumsulfat getrocknet Der Äther wird unter Vakuum abgetrieben und der Rückstand unter Vakuum rektifiziert Das Destillat wird in absolutem Alkohol gelöst; die gewünschte Verbindung wird nach Kühlung in einem Strom trockenen Chlorwasserstoffs zum Kristallisieren gebracht Man kristallisiert aus absolutem Äthanol oder Äthanol-Äther-Gemischen um.1.2 moles of the amine in question become 1 mole of that obtained in the previous phase Given glycidyl ether, dissolved in 1000 ml of ethanol and then refluxed for 4 to 5 hours The mixture is cooled with ice water. Then it is extracted with ether and the extract is e.g. dried anhydrous magnesium sulfate. The ether is stripped off under vacuum and the residue rectified under vacuum The distillate is dissolved in absolute alcohol; the desired connection is caused to crystallize after cooling in a stream of dry hydrogen chloride. Man recrystallizes from absolute ethanol or ethanol-ether mixtures.
Die Schmelzpunkte der erfindungsgemäßen Verbindungen und ihre Analysenwerte sind in Tabelle II, die der Glycidyläther-Zwischenprodukte in Tabelle I aufgeführtThe melting points of the compounds according to the invention and their analytical values are given in Table II, the the glycidyl ether intermediates are listed in Table I.
In den F i g. 1 bis 8 sind die Infrarot-Spektren der Verbindungen Nr. 1 bis 8 wiedergegeben.In the F i g. 1 to 8 are the infrared spectra of the compounds No. 1 to 8 shown.
Schmelzpunkt Mr
Melting point
Claims (1)
l-(2-lsopropyl-5-methyl-phenoxy)-amino-2-propanol,
l- (2-isopropyl-5-methyl-phenoxy) -
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES411826A ES411826A1 (en) | 1973-02-20 | 1973-02-20 | Process for preparing pharmacologically active 1-aryloxy-2- propanolamines |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DE2359926A1 DE2359926A1 (en) | 1974-08-29 |
| DE2359926B2 DE2359926B2 (en) | 1979-08-23 |
| DE2359926C3 true DE2359926C3 (en) | 1980-05-22 |
Family
ID=8463472
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE2359926A Expired DE2359926C3 (en) | 1973-02-20 | 1973-12-01 | 1-Phenoxy-2-propanolamines, processes for their preparation and pharmaceuticals containing them |
Country Status (6)
| Country | Link |
|---|---|
| BE (1) | BE808066A (en) |
| DE (1) | DE2359926C3 (en) |
| ES (1) | ES411826A1 (en) |
| FR (1) | FR2218094B1 (en) |
| GB (1) | GB1441976A (en) |
| NL (1) | NL7317220A (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2623314C2 (en) * | 1976-05-25 | 1984-08-02 | Hoechst Ag, 6230 Frankfurt | 1-aryloxy-2-hydroxy-3-aminopropanes, processes for their preparation and pharmaceuticals containing them |
| DE2824764A1 (en) * | 1978-06-06 | 1979-12-20 | Hoechst Ag | NEW PYRIDYL PIPERAZINE DERIVATIVES AND PROCESS FOR THEIR PRODUCTION |
| EP0252007A3 (en) * | 1986-06-28 | 1989-07-05 | Ciba-Geigy Ag | 2-propanol derivatives as corrosion inhibitors |
| CA3215310A1 (en) * | 2010-04-12 | 2011-10-20 | Supernus Pharmaceuticals Inc. | Methods for producing viloxazine salts and novel polymorphs thereof |
| FR3030514A1 (en) * | 2014-12-18 | 2016-06-24 | Centre De Coop Int En Rech Agronomique Pour Le Dev (Cirad) | POLYAROMATIC DIMERS |
| CZ309081B6 (en) * | 2019-11-21 | 2022-01-19 | Fakultní nemocnice Hradec Králové | 1-Aryloxy-3- (4- (2-hydroxyethyl) piperazin-1-yl) propan-2-oly, preparation process and use |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3524851A (en) * | 1966-10-21 | 1970-08-18 | Merck & Co Inc | 1-phenoxy-3-morpholino alkylamino-2-propanols |
-
1973
- 1973-02-20 ES ES411826A patent/ES411826A1/en not_active Expired
- 1973-10-31 GB GB5057373A patent/GB1441976A/en not_active Expired
- 1973-11-27 FR FR7342192A patent/FR2218094B1/fr not_active Expired
- 1973-11-30 BE BE138389A patent/BE808066A/en unknown
- 1973-12-01 DE DE2359926A patent/DE2359926C3/en not_active Expired
- 1973-12-14 NL NL7317220A patent/NL7317220A/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DE2359926A1 (en) | 1974-08-29 |
| GB1441976A (en) | 1976-07-07 |
| BE808066A (en) | 1974-03-15 |
| FR2218094B1 (en) | 1977-07-01 |
| DE2359926B2 (en) | 1979-08-23 |
| ES411826A1 (en) | 1976-01-01 |
| FR2218094A1 (en) | 1974-09-13 |
| NL7317220A (en) | 1974-08-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE2434911C2 (en) | Phenylethylamine derivatives and pharmaceutical compositions | |
| DE2500110A1 (en) | 3-ARYLOXY-3-PHENYLPROPYLAMINE AND THE PROCESS FOR THEIR MANUFACTURING | |
| DE2130393B2 (en) | 6,7-Dihrdroxy -5,6,7,8-tetrahydronaphthyloxyaminopropanols and their salts with acids and their use in combating heart disease | |
| DE2007751C2 (en) | Alkanolamine derivatives and pharmaceutical compositions containing them | |
| DE2223184C3 (en) | Benzofuran derivatives and their pharmaceutically acceptable acid addition salts as well as a process for their preparation and pharmaceuticals containing these compounds | |
| DE2615406A1 (en) | BETA ADRENERGIC RECEPTOR BLOCKER | |
| EP0074014B1 (en) | 2-(2'-hydroxy-3'-(1,1,-dimethyl propylamino)-propoxy)-beta propiophenone, its addition salts, process for its preparation and medicaments | |
| DE2359926C3 (en) | 1-Phenoxy-2-propanolamines, processes for their preparation and pharmaceuticals containing them | |
| DE1815808C3 (en) | 1 - (Alkanoylaminophenoxy) -3-alkylamino-2-propanols, their manufacturing processes and pharmaceutical compositions based on them | |
| DE2607305A1 (en) | 6-OXO-7-SUBSTITUTED- AND -7,7-DISUBSTITUTED-6H-INDENO SQUARE BRACKET ON 5.4 SQUARE BRACKET FOR FURANIC (AND THIOPHEN) CARBONIC ACIDS | |
| DE2504045A1 (en) | 16.17 DIHYDRO-APOVINCAMIC ACID ESTERS, THE PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS | |
| DE2360318C3 (en) | 1-Phenyl-2-propanone derivatives and their preparation | |
| CH637108A5 (en) | Process for preparing novel 1-aryloxy-2-hydroxy-3-aminopropanes | |
| CH643250A5 (en) | (3-ALKYLAMINO-2-HYDROXYPROPOXY) -FURAN-2-CARBONIC ACID ANILIDE. | |
| DE69001461T2 (en) | STEREOISOMERE. | |
| DE2126169C3 (en) | Alkanolamine derivatives and pharmaceutical compositions containing them | |
| DE2736106A1 (en) | NEW ARYLOXY-1-AMINO-3-PROPANOLE-2, METHOD FOR MANUFACTURING AND THERAPEUTIC APPLICATION OF THE SAME | |
| DD142875A5 (en) | PROCESS FOR THE PREPARATION OF 2-AMINOAETHANOL DERIVATIVES | |
| DE2822473A1 (en) | ALKANOLAMINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME | |
| DE2651750A1 (en) | AMINOAETHANOL DERIVATIVES, PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS | |
| DE2519163C2 (en) | 2-Formyl-1,2,3,4-tetrahydro-5- (2-hydroxy-3-tert-butyl-aminopropoxy) -isoquinoline, its salts, process for their preparation and their use | |
| AT297681B (en) | Process for the preparation of new äthinyl-substituted 1-phenoxy-2-hydroxy-3-butylaminopropanes, their optically active isomers and acid addition salts | |
| DE2163000A1 (en) | (Piperidin-4-spiro) -5-oxazolidinones, processes for their preparation and pharmaceutical preparations containing these compounds | |
| DE2205170A1 (en) | Alkanolamine derivatives | |
| DE1593901C3 (en) | Basically substituted benzofurans or indoles and processes for their preparation and pharmaceuticals containing these compounds |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C3 | Grant after two publication steps (3rd publication) | ||
| EHJ | Ceased/non-payment of the annual fee |