DE2359926B2 - l-Phenoxy-2-propanolamines, processes for their preparation and pharmaceuticals containing them - Google Patents

l-Phenoxy-2-propanolamines, processes for their preparation and pharmaceuticals containing them

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Publication number
DE2359926B2
DE2359926B2 DE2359926A DE2359926A DE2359926B2 DE 2359926 B2 DE2359926 B2 DE 2359926B2 DE 2359926 A DE2359926 A DE 2359926A DE 2359926 A DE2359926 A DE 2359926A DE 2359926 B2 DE2359926 B2 DE 2359926B2
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Prior art keywords
phenoxy
propanol
methyl
isopropyl
propanolamines
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DE2359926A
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German (de)
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DE2359926C3 (en
DE2359926A1 (en
Inventor
Juan Bermejo
Juan Ramon Conde
Antonio Fernando Montoro
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Laboratorios Liade SA
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Laboratorios Liade SA
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Publication of DE2359926C3 publication Critical patent/DE2359926C3/en
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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

Description

2. Verfahren zur Herstellung der Verbindungen2. Process for making the compounds

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 Ί0 bis 20 Stunden in an sich bekannter Weise zur Reaktion bringt, das Reaktionsgemisch 24 Stunden 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 inaccording to claim 1, characterized in that a corresponding phenol with epichlorohydrin in Presence of a catalyst at a temperature between 70 and 100 ° C within a period of time from Ί0 to 20 hours in a known manner to react, the reaction mixture for 24 hours treated with a solution of sodium hydroxide, the mixture extracted with chloroform, which Chloroform removed under vacuum and the residue distilled under reduced pressure, and then a corresponding amine after dissolving in

Äthanol oder Tetrahydrofuran mit dem in der vorhergehenden Stufe erhaltenen Glycidyläther in an sich bekannter Weise umsetztEthanol or tetrahydrofuran with the glycidyl ether obtained in the previous stage in implemented in a known manner

3. Arzneimittel, gekennzeichnet dutch einen Gehalt an einer Verbindung gemäß Anspruch 1 und pharmazeutisch üblichen Träger- bzw. Hilfsstoffen.3. Medicament, characterized dutch 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-Chlor-*henoxy)-3-bisr>hydroxyäthyI)-amino-2-propanol, 1) 1 - (4-chloro- * henoxy) -3-bisr> hydroxyäthyI) -amino-2-propanol,

2) 1 -(2-Isop>ropyl-5-methyI-phenoxy)-S-bisi^-hydroxyäthyl^aniino-i-propanol, 2) 1 - (2-Isopyl-5-methyI-phenoxy) -S-bisi ^ -hydroxyethyl ^ aniino-i-propanol,

3) 1 -(2-Isopropyl-5-methyl-phenvixy)-3-morpholino-2-propanol, 3) 1 - (2-isopropyl-5-methyl-phenvixy) -3-morpholino-2-propanol,

4) 1 -(2-Isopropyl-5-methyl-phenoxy)-3-(4-methyl-1 -piperazinyl)-2-propanol,4) 1 - (2-isopropyl-5-methyl-phenoxy) -3- (4-methyl-1-piperazinyl) -2-propanol,

5) 1 -(2-Isopropyl-5-methyl-phenoxy)-5) 1 - (2-isopropyl-5-methyl-phenoxy) -

3-piperidino-2-propanol,3-piperidino-2-propanol,

6) l-{2-Isopropyl-5-methyI-phenoxy)-3-{l,5-dimethyl-5-hydroxyhexyI)-amiiio-2-propanol, 6) 1- {2-isopropyl-5-methyI-phenoxy) -3- {l, 5-dimethyl-5-hydroxyhexyl) -amiiio-2-propanol,

7) 1 -(4-AHyl-2-methoxy-phenoxy)-3-bis(/?-hydroxyäthyl)-armno-2-propanol, 7) 1 - (4-AHyl-2-methoxyphenoxy) -3-bis (/? - hydroxyethyl) -armno-2-propanol,

8) 1 -(2-Isopropyl-5-methyI-phenoxy)-8) 1 - (2-isopropyl-5-methyI-phenoxy) -

)5 3-benzylamino-2-propanol und deren Salze.) 5 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 ICompound I

Cl-<f V-O-CH2-CH-CH2-N^ OH CH2-CH2OHCl- <f VO-CH 2 -CH-CH 2 -N ^ OH CH 2 -CH 2 OH

HCIHCI

CH2CH3OHCH 2 CH 3 OH

Verbindung 2Connection 2

-O-CH2-CH-CH2-N-O-CH 2 -CH-CH 2 -N

f LJ /"' IJ C LJ f LJ / "'IJ C LJ

vfij V_.rl ν Γ13vfij V_.rl ν Γ13

\ OH \ OH

CH2-CH2OHCH 2 -CH 2 OH

CH2-CH2OHCH 2 -CH 2 OH

HCIHCI

Verbindung 3Connection 3

^i-O-CH2-CH-CH2-N O HCI OH^ iO-CH 2 -CH-CH 2 -NO HCI OH

CH, CH-CH,CH, CH-CH,

Verbindung 4
CH3 Connection 4
CH 3

J-O-CH2-CH-CH2-N Ν—CH3-2HCl OHJO-CH 2 -CH-CH 2 -N Ν -CH 3 -2HCl OH

CH3-CH-CH3
Verbindung 5CH 3 -CH-CH 3
Connection 5

CHjCHj

Ο—CH,-CH-CH,-NΟ-CH, -CH-CH, -N

HCIHCI

CHj—CH-CHjCHj-CH-CHj

Verbindung 6
CH3 Connection 6
CH 3

OHOH

CH, CH,CH, CH,

0-CH2-CH-CH2-Nh-CH-CH2-CH2-CH2-C-CH3 · HCI0-CH 2 -CH-CH 2 -Nh-CH-CH 2 -CH 2 -CH 2 -C-CH 3 • HCl

CH3-CH-CH3 CH 3 -CH-CH 3

Verbindung 7Connection 7

OCH,OCH,

CH2=CH-CH2-/~~\~ Ο—CH2-CH-CH2-NsCH 2 = CH-CH 2 - / ~~ \ ~ Ο — CH 2 -CH-CH 2 -Ns

ν=/ Iν = / I

OH OHOH OH

CH2-CH2OHCH 2 -CH 2 OH

CH,-CH,OHCH, -CH, OH

HClHCl

Verbindung 8
CH3 Connection 8
CH 3

J— O — CH2-CH-CH,- NH-CH2- -<fVJ-O-CH 2 -CH-CH, -NH-CH 2 - - <fV

y I \ — /y I \ - /

OHOH

HCIHCI

CH3-CH-CH,CH 3 -CH-CH,

Zur Herstellung der erfindungsgemäßen Verbindungen werden die entsprechenden Phenole eingesetzt, die mit l-Chlor-23-epoxypropan in Gegenwart von Katalysatoren (Piperidin, Pi^eridinacetat, -chlorhydrat oder Piperazin) das entsprechende l-Chlor-Z-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 Hydrochloride!! 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, the corresponding phenols are used with l-chloro-23-epoxypropane in the presence of catalysts (Piperidine, piperidine acetate, chlorohydrate or piperazine) the corresponding l-chloro-Z-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 hydrochloride !! these compounds can also contain other salts with inorganic or organic acids are obtained, which are used for the preparation of therapeutically acceptable salts are suitable.

Die erfindungsgemi 3en Verbindungen besitzen die Wirkung, daß sie 0-adrenergische Rezeptoren blockieren. Sie zeigt sich im kardiovaskulären System durch die Hemmung der durch Isoprenalin bedingten Tensionsempfindlichkeit Die Verbindungen rufen eine begrenzte The compounds according to the invention have the Effect that they block O-adrenergic receptors. It manifests itself in the cardiovascular system by inhibiting the isoprenaline-induced tension sensitivity. The compounds call a limited one

W periphere Hypotonie zusammen mit einer Verminderung der chronotropen und inotropen Wirkungen hervor. Auch eine deutliche antiarrhythmische Wirkung in Hfzug auf den experimentellen arrhythmischen Zustand beim Hunde und Meerschweinchen wurdeW peripheral hypotension along with a decrease the chronotropic and inotropic effects. Also a clear anti-arrhythmic effect in reference to the experimental arrhythmic state in dogs and guinea pigs

r> festgestellt In der folgenden Tabelle ist die antiarrhythmiscke sowie die card'odepressive Wirksamkeit der Verbindung 2 den entsprechenden Wirkungen von Propranolol gegenübergestelii. Wie aus der Tabelle ersichtlich ist, r> found in the following table antiarrhythmiscke and card'odepressive activity of the compound 2 is gegenübergestelii the corresponding effects of propranolol. As can be seen from the table,

bo 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 sichbo sets the undesirable reduction in propranolol the force of contraction of the myocardium already at dosages that are below the dosages that develop the desired antirrhythmic effectiveness. The compound according to the invention is notable

tn demgegenüber dadurch aus, daß die Dosierungen für die gewünschte antirrhythmische Wirkung weit unter denen der unerwünschten cardiodepressiven Wirkung liegen. In contrast, it is characterized by the fact that the doses for the desired antirrhythmic effect are far below those of the undesired cardiodepressive effect.

Cardiodepressive WirksamkeitCardiodepressant effectiveness

Erfindungsgem. Verbindung I mg/kg 2 mg 4 mgAccording to the invention. Compound I mg / kg 2 mg 4 mg

8 mg8 mg

PropranololPropranolol

0,1 mg/kg 0,2 mg0.1 mg / kg 0.2 mg

0,4 mg0.4 mg

dp/dt - 8,5%dp / dt - 8.5%

Arterieller Druck - 5,7%Arterial pressure - 5.7%

Druck, linkes Ventrikel - 4,7Pressure, left ventricle - 4.7

Herzfrequenz -10,5%Heart rate -10.5%

Antiarrhythmische WirksamkeitAntiarrhythmic effectiveness

16,5%16.5% -35,5%-35.5% -53%-53% -72%-72% -75%-75% -75%-75% 10%10% -18,2%-18.2% -31%-31% -37,5%-37.5% -35%-35% -33%-33% 11%11% -10,2%-10.2% -29,3%-29.3% -46,5%-46.5% -44,5%-44.5% -39%-39% 14,2%14.2% -20%-20% -24%-24% -41,5%-41.5% -49,5%-49.5% -49.5%-49.5%

Erfindungsgem. Verbindung 0,625 mg/kg 1,5 mg 2,5 mgAccording to the invention. Compound 0.625 mg / kg 1.5 mg 2.5 mg

5 mg5 mg

PropranololPropranolol

I mg/kg 1,5 mg 2,5 mg 5 mgI mg / kg 1.5 mg 2.5 mg 5 mg

Harris-Arrhythmie +Harris arrhythmia +

Aconitin-Arrhythmie + + +Aconitine arrhythmia + + +

Digitalis-Arrhythmie
acetylcholin-ArrhythmieDigitalis arrhythmia
acetylcholine arrhythmia

Adrenalin-Arrhythmie
(L) = alle Tiere starben.Adrenaline arrhythmia
(L) = all animals died.

In Antagonismus zur Isoprenalinwirkung ist weiterhin besonders die j3-blockierende Wirkung der Verbindungen 3,5 und 8 überragend.The j3-blocking effect of the compounds is still particularly antagonistic to the effect of isoprenaline 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 ^-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 are known in many fields ^ -receptors are superior to blocking agents.

Die erfindungsgemäßen Verbindungen weisen auch günstige Toxizitätswerte auf. Die DLw der Verbindung 2 wurde oral zu 1750 mg/kg gemessen. Intravenös weisenThe compounds according to the invention also have favorable toxicity values. The DLw of connection 2 was measured orally at 1750 mg / kg. Assign intravenously

[4mg+++|
'8 mg+++'[4mg +++ |
'8 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, dafl 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, whereas the toxicity of propranolol is 45 mg / kg. Generally it can thus be established 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.

Erfindungsgemäße
verbindung 2According to the invention
connection 2 PropuinololPropuinolol ChinidinQuinidine anliarrhylhm. Aktivitätanliarrhylhm. activity 2.5-5 mg/kg2.5-5 mg / kg 1.5-2.5 mg/kg1.5-2.5 mg / kg 20-25 mg/kg20-25 mg / kg völlige
Reversiontotal
reversion unvollständige
Reversionincomplete
reversion keine vergleichbare
Reversionno comparable
reversion Toxizität (Ratte)Toxicity (rat) LD<„ mg/kgLD <"mg / kg !. V.! V. 113113 4545 23,123.1 p. o.p. O. 17501750 524524 590590

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.

Beispiel 1example 1 Herstellung von 1 -(2-Isopropyl-5-methyl-phenoxy)-Production of 1 - (2-isopropyl-5-methyl-phenoxy) -

3-bis(/J-hydroxyäthyr)-amino-2-propanol3-bis (/ J-hydroxyethyr) -amino-2-propanol

(Verbindung 2)(Connection 2)

Stufe 1step 1

Man gibt 150 g Thymol (1 Mol), 277,5 g l-Chlor-23-epoxypropan und 2 ml Piperidin in einen Dreihalskolben, der mit mechanischen Rührer, Tropftrichter und Kühler ausgerüstet ist Man erhitzt 16 Stunden unter Rühren. Den Überschuß 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.150 g of thymol (1 mol) and 277.5 g of 1-chloro-23-epoxypropane are added and 2 ml of piperidine in a three-necked flask equipped with mechanical stirrer, dropping funnel and It is equipped with a cooler. The mixture is heated for 16 hours with stirring. 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 dried 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:(C,3HlgO2)
Gefunden: C 75,89, H 8,80%;
berechnet: C 75,72, H 8,73%.Analysis: (C, 3H lg O 2 )
Found: C 75.89, H 8.80%;
Calculated: C 75.72, H 8.73%.

Gasphasen-Chromatographie
AusrüstungGas phase chromatography
equipment

Doppelkolonne; Flammen-Ionisations-DetektonTrägergas: Stickstoff-Strömungsgeschwindigkeit 30 ml/Minute; Aolonnentemperatur 1700C. Retentionszeit 256 Sekunden.Double column; Flame ionization detection carrier gas: nitrogen flow rate 30 ml / minute; Aolonnentemperatur 170 0 C. retention time 256 seconds.

Stufe 2Level 2

Man erhitzt 206 g (IMoI) des oben erhaltenen Produkts 4 bis 5 Stunden auf 70 bis 80°C mit 82,5 g (1,2MoI) Diäthanolamin. Man kühlt mit Eiswasser. Danach extrahiert man 5ma! 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 dsnn ein Strom von trockenem Ch!orw?.ss?rstnff in Hip Lösung zwecks Kristallisation geleitet. Den Niederschlag kristallisiert man aus absolutem Äthanol um. Man erhält insgesamt 200 g der Titelverbindung.206 g (1 mol) of the product obtained above are heated to 70 to 80 ° C. for 4 to 5 hours with 82.5 g (1.2 mol) of diethanolamine. It is cooled with ice water. Then extract 5ma! with 500 ml of ether and dries the ether extract z. B. with anhydrous magnesium sulfate. The ether is removed under vacuum, the residue is dissolved in absolute alcohol and dsnn a stream of dry Chloro w? .Ss? Rstnff in hip solution for crystallization passed. The precipitate is recrystallized from absolute ethanol. A total of 200 g of the title compound is obtained.

Ausbeute 75%. Schmelzpunkt 147°C.
Analyse: (C17H29NO4- HCl)Yield 75%. Melting point 147 ° C.
Analysis: (C 17 H 29 NO 4 - HCl)

Gefunden: C 58,75, H 8,71, N 4,18, Cl 10,29%;Found: C 58.75, H 8.71, N 4.18, Cl 10.29%;

berechnet: C 58,70, H 8,63, N 4,02, Cl 10,21%.Calculated: C 58.70, H 8.63, N 4.02, Cl 10.21%.

Beispiel 2Example 2

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 1-Chlor-23-epoxypropan wird mit 0,6 g KatalysatorA mixture of 03 mol of phenol and 0.9 mol of 1-chloro-23-epoxypropane is combined with 0.6 g of catalyst

Tabelle ITable I. Glycidyläther-Z wischenprodukteGlycidyl ether intermediates

(Piperidin, Piperidin-Acetat — Chlorhydrat oder Piperazin) 15 bis 17 Stunden auf eine Temperatur von 50 bis 100° C 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 destilliert.(Piperidine, piperidine acetate - chlorohydrate or piperazine) Heated for 15 to 17 hours to a temperature of 50 to 100 ° C. The excess epichlorohydrin is evaporated under vacuum and the residue with 150 ml of a 16 percent solution of caustic soda treated, the suspension being shaken vigorously at room temperature for 24 hours. The mixture is extracted several times with chloroform. The chloroform extract is made with sodium sulfate or a other drying agent dried. The chloroform is stripped off under vacuum and the residue at distilled at low pressure.

Zweite Stufe
Herstellung von 1 -Phenoxy-2-propanol-aminenSecond step
Production of 1-phenoxy-2-propanol amines

1,2 Mol des in Frage kommenden Amins werden zu t 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 t moles of that obtained in the previous phase Glycidyl ether given, dissolved in 1000 ml of ethanol and then heated under reflux for 4 to 5 hours. The mixture is then cooled with ice water extracted with ether and the extract is z. B. dried with anhydrous magnesium sulfate The ether is stripped off under vacuum and the residue is rectified under vacuum. The distillate is in dissolved in absolute alcohol; the desired compound becomes dry after cooling in a stream Brought hydrogen chloride to crystallize. It is crystallized from absolute ethanol or ethanol-ether mixtures around.

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.

Zwischenprodukt Siedepunkt BerechnetIntermediate boiling point calculated

für Verbindung Nr. Schmelzpunkt % c for compound no. melting point% c

% H% H

GerundenRounded

% C % H% C% H

Empirische
FormelEmpirical
formula

11 32° Fp.32 ° Fp. mbarmbar 58,5358.53 4,874.87 19,30C!19.30C! 58,6058.60 4,904.90 2-6 und 82-6 and 8 120°/2,67120 ° / 2.67 mbarmbar 75,7275.72 8,738.73 75,8975.89 8,808.80 77th !44°/1,33! 44 ° / 1.33 70,9070.90 7.277.27 70,8170.81 7,327.32 Tabelle IITable II EndprodukteEnd products

19,2719.27

C1 .,I I1,0,C 1. , II 1 , 0,

Verbin- Fp.Connect- Fp.

Nr. (QNo. (Q

BerechnetCalculated

%C% C

•AH•AH

% N % Cl% N% Cl

GefundenFound

% C % H % N% C% H% N

VoClVoCl

Empirische
FormelEmpirical
formula

11 115115 47,8547.85 6,446.44 4,294.29 21,7721.77 47,9047.90 6^06 ^ 0 4,314.31 21,8221.82 22 147147 58,7058.70 8,638.63 4,024.02 10,2110.21 58,7558.75 8,718.71 4,184.18 10,2910.29 33 131131 61,9161.91 8,498.49 4,244.24 10,7710.77 62,0062.00 841841 4,284.28 10,7510.75 44th 165165 56,9956.99 8,448.44 8,448.44 18,7318.73 57,0257.02 841841 8,498.49 18,8018.80 55 144144 65,9565.95 9,169.16 4,274.27 18,8318.83 66,0166.01 9,129.12 4,314.31 19,0019.00 66th 177177 65,0365.03 9,809.80 3,613.61 9,619.61 65,1065.10 9,859.85 3,703.70 9,189.18 77th 112112 56,4356.43 7,747.74 3,873.87 y,82y, 82 56405640 7,807.80 3,853.85 9,909.90

Hierzu 2 Blatt ZeichnungenFor this purpose 2 sheets of drawings

C3H20QNo4 · HCl
C17H29NO4 KCl
C17H27NO3 HCl
C18H30N2O2 · 2HCI
C18H29NO2 ■ HCl
C21H37NO3 · HCl
C17H25NO5 ■ HC!C 3 H 20 QNo 4 • HCl
C 17 H 29 NO 4 KCl
C 17 H 27 NO 3 HCl
C 18 H 30 N 2 O 2 • 2HCI
C 18 H 29 NO 2 ■ HCl
C 21 H 37 NO 3 • HCl
C 17 H 25 NO 5 ■ HC!

Claims (1)

Patentansprüche:Patent claims: 1. S -(^ChlorphenoxyJ-S-bisfJJ-hydroxyäthyl)-1. S - (^ chlorophenoxyJ-S-bisfJJ-hydroxyethyl) - amino-2-propanol,
-^-Isopropyl-S-methyl-phenoxy)-3-bis(/J-hydroxyäthyl)-amino-2-propanol, -^-Isopropyl-S-methyl-phenoxy)-amino-2-propanol,
- ^ - Isopropyl-S-methyl-phenoxy) -3-bis (/ J-hydroxyethyl) -amino-2-propanol, - ^ - Isopropyl-S-methyl-phenoxy) - 3-morpholino-2-propanoI, l-(2-Isopropyl-5-methyl-phenoxy)-3-morpholino-2-propanoI, 1- (2-isopropyl-5-methyl-phenoxy) - 3-(4-methyl-1 -piperazinyl)-2-propanol, l'(2-Isopropyl-5-methyl-phenoxy)-3- (4-methyl-1-piperazinyl) -2-propanol, l '(2-isopropyl-5-methyl-phenoxy) - 3-piperidino-2-propanol, l-(2-Isopropyl-5-methyl-phenoxy)-3-(l,5-dimethyl-5-hydroxyhexyl)-amino-2-propasiol, -(4-Allyl-2-methoxy-phenoxy)-3-bis-(j9-hydroxyäthyl)-amino-2-propanol, -(2-IsopropyI-5-methyI-phenoxy)-3-benzylamino-2-propanol und deren Salze.3-piperidino-2-propanol, 1- (2-isopropyl-5-methyl-phenoxy) -3- (l, 5-dimethyl-5-hydroxyhexyl) -amino-2-propasiol, - (4-Allyl-2-methoxyphenoxy) -3-bis- (j9-hydroxyethyl) -amino-2-propanol, - (2-IsopropyI-5-methyI-phenoxy) -3-benzylamino-2-propanol and salts thereof.
DE2359926A 1973-02-20 1973-12-01 1-Phenoxy-2-propanolamines, processes for their preparation and pharmaceuticals containing them Expired DE2359926C3 (en)

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)

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DE2359926A1 DE2359926A1 (en) 1974-08-29
DE2359926B2 true DE2359926B2 (en) 1979-08-23
DE2359926C3 DE2359926C3 (en) 1980-05-22

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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)

* Cited by examiner, † Cited by third party
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
CA2992219A1 (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

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* Cited by examiner, † Cited by third party
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

Also Published As

Publication number Publication date
GB1441976A (en) 1976-07-07
FR2218094B1 (en) 1977-07-01
BE808066A (en) 1974-03-15
ES411826A1 (en) 1976-01-01
FR2218094A1 (en) 1974-09-13
DE2359926C3 (en) 1980-05-22
NL7317220A (en) 1974-08-22
DE2359926A1 (en) 1974-08-29

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