AT344143B - METHOD FOR PRODUCING NEW SUBSTITUTED 1-ARYLOXY-4-AMINO-2-BUTANOLS AND THEIR ACID ADDITION SALTS - Google Patents

METHOD FOR PRODUCING NEW SUBSTITUTED 1-ARYLOXY-4-AMINO-2-BUTANOLS AND THEIR ACID ADDITION SALTS

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Publication number
AT344143B
AT344143B AT805575A AT805575A AT344143B AT 344143 B AT344143 B AT 344143B AT 805575 A AT805575 A AT 805575A AT 805575 A AT805575 A AT 805575A AT 344143 B AT344143 B AT 344143B
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acid addition
aryloxy
amino
addition salts
butanols
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AT805575A
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German (de)
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ATA805575A (en
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Robins Co Inc A H
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    • 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
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

  

   <Desc/Clms Page number 1> 
 



   Die Erfindung betrifft ein Verfahren zur Herstellung neuer 1-Aryloxy-4-amino-butan-2-ole der allgemeinen Formel 
 EMI1.1 
 worin Ar eine 1- oder 2-Naphthyl-, 4-oder 5-Idenyl, 3-oder 5-Chlor-2-pyridyl-oder eine gegebenenfalls 1- oder 2fach durch Alkyl, Alkoxy, Trifluormethyl, Acetyl, Acetylamino und/oder durch ein Halogen substituierte Phenylgruppe darstellt, Ri eine Alkylgruppe mit bis zu 8 C-Atomen, eine Phenyl- oder Phenalkyl- 
 EMI1.2 
 
 EMI1.3 
 
 EMI1.4 
 

 <Desc/Clms Page number 2> 

 stoffatomen, Phenylalkylamino-,   2-Hydroxymethyl-2-propylamino-oder   Phenylaminogruppe ist, sind ebenso von besonderem Interesse wegen ihrer antiarrhythmischen Wirksamkeit. 



   Die Symbole der vorausgehenden Formel (I) in der Beschreibung sowie in den Ansprüchen werden wie folgt definiert: Unter "Alkyl mit bis zu 8 C-Atomen"sindgerade oder verzweigtkettige Gruppen zu verstehen, beispielsweise Methyl-, Äthyl-, Propyl-, Isopropyl-, tert. Butyl-, Amyl-, Isoamyl, Hexyl-, Heptyl- oder   Octylgruppen.   



   Unter Halogenen werden hier Fluor, Chlor oder Brom verstanden. 



   In dem substituierten Phenylreste Ar können die Substituenten verschiedene verfügbare Stellungen am Phenylkern einnehmen und sofern mehr als ein Substituent vorhanden, können die Substituenten gleich und verschieden sein und sie können im Verhältnis zueinander in verschiedenen Kombinationen vorliegen. Die Niedrigalkyl- und Niedrigalkoxysubstituenten haben jeweils vorzugsweise 1 bis 4 Kohlenstoffatome, die in geraden oder verzweigten Ketten angeordnet sein können. Eine Gesamtzahl von 9 Kohlenstoffatomen in allen Ringsubstituenten unter Bildung einer Gesamtzahl von 15 Kohlenstoffatomen in dem Rest, ist das bevorzugte Maximum. 



   Das erfindungsgemässe Verfahren zur Herstellung der neuen Verbindungen (I) ist dadurch gekennzeichnet, dass man ein 4-Chlor-l-aryloxybutan-2-ol der allgemeinen Formel 
 EMI2.1 
 in der Ar obige Bedeutung hat, mit einem Amin der allgemeinen Formel 
 EMI2.2 
 worin Ri und   R2   obige Bedeutung haben, umsetzt und gewünschtenfalls eine erhaltene Base in ein Säureadditionssalz   überführt.   Die erfindungsgemäss erhältlichen Verbindungen werden am zweckmässigsten in Form von pharmazeutisch verträglichen Säureadditionssalzen verwendet. Derartige Salze haben verbesserte Wasserlöslichkeit gegenüber den freien Basen.

   Zu geeigneten Säureadditionssalzen gehören solche, die von Mineralsäuren wie Salzsäure, Bromwasserstoffsäure, Schwefel- und Phosphorsäure und organischen Säuren, wie Essig-, Zitronen-, Milch-, Malein-, Oxal-,   Fumar- und   Weinsäure abstammen. Das bevorzugte Säureadditionssalz ist das Hydrochlorid. Die Säureadditionssalze werden zweckmässigerweise dadurch hergestellt, dass man die Basenverbindungen mit der ausgewählten Säure umsetzt, wobei einer oder beide in Form von Äther-, Alkohol- oder Acetonlösungen eingesetzt werden können. 
 EMI2.3 
 chlor-butan-2-ol   (Cl-CH-CHOH-CHs-CH-Cl)   umsetzt. Die Zugabe erfolgt bei oder unter 7 0 C, vorzugsweise bei 30 bis   65 C   während etwa 3 bis 8 h.

   Nach der Zugabe erhitzt man das Reaktionsgemisch bei etwa 50 bis 750C, vorzugsweise 60 bis   700C   etwa 6 bis 48 h, gewöhnlich 12 bis 18 h. Das   1-Aryloxy-4-chlor-bu-     tan-2-ol   (II) isoliert man aus dem Reaktionsgemisch durch Extraktion unter Verwendung eines geeigneten organischen Lösungsmittels, wie beispielsweise Äther, Isopropyläther oder Chloroform, verdampft das Lösungsmittel nach dem Trocknen unter Bildung des 2-Butanols, das durch geeignete Mittel wie Destillation oder Kristallisation isoliert wird. 



   Man kann auch 1-Aryloxy-4-chlor-butan-2-ol dadurch herstellen, dass man eine wässerige basische Lösung zu einem Gemisch des Phenols oder der Verbindung, die eine saure Hydroxylgruppe aufweist und ein   1, 4-Dichlor-butan-2-01 in   einer solchen Geschwindigkeit zugibt, dass man ein Reaktionsgemisch mit einem PH-Wert von etwa 9,0 bis etwa 10,5 vorzugsweise 9,5 bis 10,0 erhält. Das Produkt isoliert man wie vorausgehend beschrieben. 



   Die neuen Verbindungen (I) eignen sich für pharmazeutische Zubereitungen, die als Wirkstoffe wenigstens eine der neuen Verbindungen zusammen mit einem pharmazeutischen Träger oder Exzipienten enthalten. Die Verbindungen werden dargeboten in einer Form, die zur oralen, rektalen parenteralen oder intracardialen Verabfolgung geeignet ist. So sind beispielsweise Zubereitungen zur oralen Verabfolgung vorzugsweise Feststoffe und sie können in Form von Kapseln, Tabletten   oder beschichteten Tabletten, die herkömm-   licherweise verwendete Träger enthalten, verabfolgt werden. Zu geeigneten Tablettenexzipienten gehören Lactose, Kartoffel- und Maisstärke, Talkum, Gelatine und Stearin- und Kieselsäuren, Magnesiumstearat 

 <Desc/Clms Page number 3> 

 und Polyvinylpyrrolidon. 



   Zur parenteralen Verabfolgung kann der Träger oder Exzipient eine sterile, parenteral verträgliche Flüssigkeit, z. B. Wasser oder ein parenteral verträgliches Öl, z. B. Erdnussöl, enthalten in Ampullen, sein. 



   Die Zubereitungen zur rektalen Verabfolgung können als Träger eine Suppositorienbasis, z. B. Kakaobutter oder Glycerid enthalten. 



   Zweckmässigerweise werden die Zubereitungen als Dosierungseinheiten formuliert, wobei jede Einheit vorgesehen ist, eine bestimmte Dosis Wirkstoff zuzuführen. Tabletten, beschichtete Tabletten, Kapseln, Ampullen und Suppositorien sind Beispiele für bevorzugte Dosierungseinheitsformen nach der Erfindung. Jede Dosierungseinheit zur oralen Verabfolgung geeignet, kann geeigneterweise 10 bis 40 mg Wirkstoff enthalten. Jede Dosierungseinheit, die zur intracardialen oder intravenösen Verabfolgung geeignet ist, kann zweckmässigerweise 1 bis 2 mg pro cm3 Wirkstoff enthalten, während jede Dosierungseinheit, die zur intramuskulären Verabfolgung geeignet ist, zweckmässigerweise 5 bis 10 mg pro cm'Wirkstoff enthalten kann. 



   Die erfindungsgemässe Reaktion zur Herstellung der Verbindungen der Formel (I) kann durchgeführt werden durch A) Erhitzen eines Gemisches der Chlorverbindung und des Amins mit einem Lösungsmittel in einer Stahlbombe, B) Erhitzen eines Gemisches der Chlorverbindung und des Amins ohne ein Lösungsmittel in einer Stahlbombe, C) am Rückflusshalten eines Gemisches der Chlorverbindung, des Amins und eines Lösungsmittels bei atmosphärischem Druck oder D) Erhitzen eines Gemisches der Chlorverbindung und des Amins ohne ein Lösungsmittel bei atmosphärischem Druck. Das ausgewählte Verfahren ist etwas abhängig von der Natur des   Aminreaktionspartners.   Wenn daher das Amin ein flüchtiges Amin mit niederem Molekulargewicht ist, bevorzugt man das Verfahren A oder B und erhitzt den Inhalt des Reaktors auf Temperaturen von etwa 100 bis 1500C etwa 12 bis 24 h.

   Wenn das Amin ein nicht flüchtiges Amin mit hohem Molekulargewicht oder ein Amin mit geringer Flüchtigkeit ist, bevorzugt man das Verfahren C oder D und hält das Reaktionsgemisch bei der Temperatur des verwendeten Lösungsmittels am Rückfluss oder erhitzt das Gemisch bei Temperaturen von etwa 100 bis 150 C. Die Reaktionszeit kann variiert werden ; wobei etwas kürzere Reaktionszeiten verwendet werden können, wenn die Chlorverbindung und das Amin zusammen ohne ein Lösungsmittel umgesetzt werden und höhere Reaktionstemperaturen verwendet werden.

   Das Reaktionsprodukt wird in jedem Falle mittels herkömmlicher Säure-Base-Extraktionsverfahren isoliert und die freie Base wandelt man, wenn gewünscht, m ein pharmazeutisch verträgliches Säureadditionssalz um, das weiter durch Auskristallisieren aus einem geeigneten Lösungsmittel oder Lösungsmittelsystem gereinigt werden kann. 



    I-Aryloxy-4-amino-butan-2-0Ie,   die keine genau definierten Salze liefern, können mittels Vakuumdestillation gereinigt werden. 



   Die nachfolgenden Beispiele erläutern die erfindungsgemässe Herstellung der neuen   1-Aryloxy-4-amino-     - butan-2-olverbindungen durch   eine der vier wahlweisen Arbeitsweisen. Die Tabelle I fasst die physikalisehen Werte weiterer Verbindungen im Bereich der Formel (I) zusammen und gibt gleichzeitig das zur Herstellung jeder Verbindung verwendete Verfahren an. 



    Bei s pi eIl : 4-Isopropylamino-I- (1'-naphthyloxy) -butan-2-01. Hydrochlorid :   
Ein Gemisch von 27, 1 g (0, 1 Mol) von   1- (1-Naphthyloxy)-2-hydroxybutylehlorid und   100 ml Isopropylamin erhitzt man in einer Stahlbombe bei   120 C   24 h. Man mischt das Reaktionsgemisch mit 300 ml 6N Salzsäure und extrahiert mit Äther bei Raumtemperatur. Die saure wässerige Lösung macht man basisch, extrahiert mit Isopropyläther, trocknet über Natriumsulfat und konzentriert zur Trockne. Den Rückstand löst maninisopropanolund mischt mit ätherischem Chlorwasserstoff. Den weissen kristallinen Niederschlag kristallisiert man aus Isopropanol und Isopropyläther um, unter Bildung des Hydrochloridsalzes ; Schmelzpunkt 126 bis   128 C.   



   Analyse : 
 EMI3.1 
 bei Raumtemperatur bildet sich ein kristalliner Niederschlag. Das Gemisch filtriert man, konzentriert das Filtrat zur Trockne unter reduziertem Druck und kristallisiert den halbfesten Rückstand aus Aceton um. Man erhält 12,2 g kristallines festes Material ; Schmelzpunkt 169 bis   171 C.   



   Analyse :   Errechnet für C HCINC : 71, 96   C,   6, 83   H,   3, 65   N gefunden : 71, 69 C,   6, 76   H,   3, 60   N 
 EMI3.2 
 

 <Desc/Clms Page number 4> 

 Phenäthylamin erhitzt   man bei 1200C   20min auf einer heissen Platte. Das erhaltene Gemisch mischt man mit 250 ml Aceton, erhitzt zum Siedepunkt und filtriert bei Raumtemperatur. Das Filtrat behandelt man mit 50ml ätherischem Chlorwasserstoff. Den erhaltenen weissen Niederschlag filtriert man. Den weissen kristallinen Feststoff kristallisiert man aus Aceton um und erhält 11, 8 g Hydrochloridsalz ; Schmelzpunkt 163 bis 1650C. 



   Analyse :
Errechnet für C22    H26     NO2 Cl: 71,05   C,   7, 05   H, 3,77 N gefunden : 70, 99 C,   6, 98   H, 3, 61 N 
 EMI4.1 
 hiert zweimal mit 100 ml Isopropyläther. Die wässerige saure Lösung macht man basisch, extrahiert mit Isopropylätherundbehandelt mit ätherischem Chlorwasserstoff. Nach Umkristallisieren mit Isopropanol erhält man 6 g Hydrochlorid-Hydrat des Produkts ; Schmelzpunkt 118 bis   120 C.   



   Analyse :
Errechnet für   CHClNOg ; 59, 07   C,   6, 52   H,   3, 63   N gefunden   : 59,   08 C,   6, 51   H,   3, 55   N 
 EMI4.2 
 misch filtriert man. Das Filtrat konzentriert man zur Trockne und mischt es mit 200 ml 3N Salzsäure, extrahiert mit Äther und macht die wässerige Schicht basisch. Das basische unlösliche Öl extrahiert man mit Isopropyläther, trocknet über Natriumsulfat und konzentriert zur Trockne. Den Rückstand löst man in Isopropanol und mischt mit 20 ml ätherischem Chlorwasserstoff. Den harzigen Niederschlag kristallisiert man unter Verwendung von Isopropyläther und Isopropanol um. Das Hydrochlorid (8, 3 g) hat einen Schmelzpunkt bei 83 bis 85 C. 



   Analyse : 
 EMI4.3 
 kristallisiert man mit Isopropanol um unter Bildung von 36 g freier Base des Produkts ; Schmelzpunkt 100 bis 101, 50C. 



   Analyse : 
 EMI4.4 
 oxy-4-chlor-2-butanolen und einem ausgewählten Amin nach den Verfahren A, B, C und D sind in der Tabelle I angegeben. 

 <Desc/Clms Page number 5> 

 
 EMI5.1 
 
 EMI5.2 
 
 EMI5.3 
 

 <Desc/Clms Page number 6> 

 
 EMI6.1 
 
 EMI6.2 
 

 <Desc/Clms Page number 7> 

 
 EMI7.1 
 
 EMI7.2 




   <Desc / Clms Page number 1>
 



   The invention relates to a process for the preparation of new 1-aryloxy-4-amino-butan-2-ols of the general formula
 EMI1.1
 wherein Ar is a 1- or 2-naphthyl-, 4- or 5-idenyl, 3- or 5-chloro-2-pyridyl- or optionally 1- or 2-fold by alkyl, alkoxy, trifluoromethyl, acetyl, acetylamino and / or by represents a halogen-substituted phenyl group, Ri is an alkyl group with up to 8 C atoms, a phenyl or phenalkyl
 EMI1.2
 
 EMI1.3
 
 EMI1.4
 

 <Desc / Clms Page number 2>

 Substance atoms, phenylalkylamino, 2-hydroxymethyl-2-propylamino or phenylamino group are also of particular interest because of their antiarrhythmic activity.



   The symbols of the preceding formula (I) in the description and in the claims are defined as follows: "Alkyl having up to 8 carbon atoms" is to be understood as meaning straight or branched-chain groups, for example methyl, ethyl, propyl, isopropyl, , tert. Butyl, amyl, isoamyl, hexyl, heptyl or octyl groups.



   Halogens are understood here as fluorine, chlorine or bromine.



   In the substituted phenyl radical Ar, the substituents can occupy different positions available on the phenyl nucleus and, if there is more than one substituent, the substituents can be the same and different and they can exist in different combinations in relation to one another. The lower alkyl and lower alkoxy substituents each preferably have 1 to 4 carbon atoms, which can be arranged in straight or branched chains. A total of 9 carbon atoms in all ring substituents to form a total of 15 carbon atoms in the remainder is the preferred maximum.



   The process according to the invention for the preparation of the new compounds (I) is characterized in that a 4-chloro-l-aryloxybutan-2-ol of the general formula
 EMI2.1
 in which Ar has the above meaning, with an amine of the general formula
 EMI2.2
 where R 1 and R 2 have the meaning given above, and, if desired, convert a base obtained into an acid addition salt. The compounds obtainable according to the invention are most suitably used in the form of pharmaceutically acceptable acid addition salts. Such salts have improved water solubility over the free bases.

   Suitable acid addition salts include those derived from mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric and phosphoric acids and organic acids such as acetic, citric, lactic, maleic, oxalic, fumaric and tartaric acids. The preferred acid addition salt is the hydrochloride. The acid addition salts are expediently prepared by reacting the base compounds with the selected acid, one or both of which can be used in the form of ether, alcohol or acetone solutions.
 EMI2.3
 chlor-butan-2-ol (Cl-CH-CHOH-CHs-CH-Cl). The addition takes place at or below 7 0 C, preferably at 30 to 65 C for about 3 to 8 h.

   After the addition, the reaction mixture is heated at about 50 to 750 ° C., preferably 60 to 700 ° C. for about 6 to 48 hours, usually 12 to 18 hours. The 1-aryloxy-4-chlorobutan-2-ol (II) is isolated from the reaction mixture by extraction using a suitable organic solvent, such as, for example, ether, isopropyl ether or chloroform, the solvent is evaporated after drying to form the 2-butanol, which is isolated by suitable means such as distillation or crystallization.



   1-Aryloxy-4-chloro-butan-2-ol can also be prepared by adding an aqueous basic solution to a mixture of the phenol or the compound which has an acidic hydroxyl group and a 1,4-dichlorobutane-2 -01 admits at such a rate that a reaction mixture with a pH of about 9.0 to about 10.5, preferably 9.5 to 10.0, is obtained. The product is isolated as previously described.



   The new compounds (I) are suitable for pharmaceutical preparations which contain at least one of the new compounds together with a pharmaceutical carrier or excipient as active ingredients. The compounds are presented in a form suitable for oral, rectal, parenteral, or intracardial administration. For example, preparations for oral administration are preferably solids and can be administered in the form of capsules, tablets or coated tablets which contain carriers which are conventionally used. Suitable tablet excipients include lactose, potato and corn starch, talc, gelatin and stearic and silica, magnesium stearate

 <Desc / Clms Page number 3>

 and polyvinyl pyrrolidone.



   For parenteral administration, the carrier or excipient can be a sterile, parenterally compatible liquid, e.g. B. water or a parenterally compatible oil, e.g. B. peanut oil contained in ampoules.



   The preparations for rectal administration can be a suppository base, e.g. B. cocoa butter or glyceride.



   The preparations are expediently formulated as dosage units, each unit being intended to supply a specific dose of active ingredient. Tablets, coated tablets, capsules, ampoules and suppositories are examples of preferred dosage unit forms according to the invention. Each unit dose suitable for oral administration may suitably contain 10 to 40 mg of active ingredient. Each dosage unit suitable for intracardial or intravenous administration can conveniently contain 1 to 2 mg per cm3 of active ingredient, while each dosage unit suitable for intramuscular administration can conveniently contain 5 to 10 mg per cm'active ingredient.



   The reaction according to the invention for the preparation of the compounds of the formula (I) can be carried out by A) heating a mixture of the chlorine compound and the amine with a solvent in a steel bomb, B) heating a mixture of the chlorine compound and the amine without a solvent in a steel bomb, C) refluxing a mixture of the chlorine compound, the amine and a solvent at atmospheric pressure, or D) heating a mixture of the chlorine compound and the amine without a solvent at atmospheric pressure. The method chosen is somewhat dependent on the nature of the amine reactant. Therefore, if the amine is a volatile, low molecular weight amine, method A or B is preferred and the contents of the reactor are heated to temperatures of about 100 to 1500 ° C for about 12 to 24 hours.

   If the amine is a non-volatile, high molecular weight amine or a low volatility amine, process C or D is preferred and the reaction mixture is refluxed at the temperature of the solvent used or the mixture is heated at temperatures of about 100 to 150 C. The response time can be varied; somewhat shorter reaction times can be used if the chlorine compound and the amine are reacted together without a solvent and higher reaction temperatures are used.

   The reaction product is in each case isolated using conventional acid-base extraction methods and, if desired, the free base is converted into a pharmaceutically acceptable acid addition salt which can be further purified by crystallization from a suitable solvent or solvent system.



    I-aryloxy-4-amino-butane-2-0Ie, which do not provide precisely defined salts, can be purified by vacuum distillation.



   The following examples illustrate the preparation of the new 1-aryloxy-4-amino-butan-2-ol compounds according to the invention by one of the four optional procedures. Table I summarizes the physical values of other compounds in the range of the formula (I) and at the same time gives the process used to prepare each compound.



    For s pi eIl: 4-isopropylamino-I- (1'-naphthyloxy) -butane-2-01. Hydrochloride:
A mixture of 27.1 g (0.1 mol) of 1- (1-naphthyloxy) -2-hydroxybutyl chloride and 100 ml of isopropylamine is heated in a steel bomb at 120 ° C. for 24 hours. The reaction mixture is mixed with 300 ml of 6N hydrochloric acid and extracted with ether at room temperature. The acidic aqueous solution is made basic, extracted with isopropyl ether, dried over sodium sulfate and concentrated to dryness. The residue is dissolved in isopropanol and mixed with ethereal hydrogen chloride. The white crystalline precipitate is recrystallized from isopropanol and isopropyl ether to form the hydrochloride salt; Melting point 126 to 128 C.



   Analysis:
 EMI3.1
 a crystalline precipitate forms at room temperature. The mixture is filtered, the filtrate is concentrated to dryness under reduced pressure and the semi-solid residue is recrystallized from acetone. 12.2 g of crystalline solid material are obtained; Melting point 169 to 171 C.



   Analysis: Calculated for C HCINC: 71, 96 C, 6, 83 H, 3, 65 N found: 71, 69 C, 6, 76 H, 3, 60 N
 EMI3.2
 

 <Desc / Clms Page number 4>

 Phenethylamine is heated at 1200C for 20min on a hot plate. The mixture obtained is mixed with 250 ml of acetone, heated to the boiling point and filtered at room temperature. The filtrate is treated with 50 ml of ethereal hydrogen chloride. The white precipitate obtained is filtered. The white crystalline solid is recrystallized from acetone and 11.8 g of hydrochloride salt are obtained; Melting point 163 to 1650C.



   Analysis:
Calculated for C22 H26 NO2 Cl: 71.05 C, 7.05 H, 3.77 N found: 70, 99 C, 6, 98 H, 3.61 N
 EMI4.1
 twice with 100 ml of isopropyl ether. The aqueous acidic solution is made basic, extracted with isopropyl ether and treated with ethereal hydrogen chloride. After recrystallization with isopropanol, 6 g of hydrochloride hydrate of the product are obtained; Melting point 118 to 120 C.



   Analysis:
Calculated for CHClNOg; 59, 07 C, 6, 52 H, 3, 63 N found: 59, 08 C, 6, 51 H, 3, 55 N
 EMI4.2
 mixed you filter. The filtrate is concentrated to dryness and mixed with 200 ml of 3N hydrochloric acid, extracted with ether and the aqueous layer is made basic. The basic insoluble oil is extracted with isopropyl ether, dried over sodium sulfate and concentrated to dryness. The residue is dissolved in isopropanol and mixed with 20 ml of ethereal hydrogen chloride. The resinous precipitate is recrystallized using isopropyl ether and isopropanol. The hydrochloride (8.3 g) has a melting point of 83 to 85 C.



   Analysis:
 EMI4.3
 is recrystallized with isopropanol to give 36 g of free base of the product; Melting point 100 to 101, 50C.



   Analysis:
 EMI4.4
 oxy-4-chloro-2-butanols and a selected amine according to processes A, B, C and D are given in Table I.

 <Desc / Clms Page number 5>

 
 EMI5.1
 
 EMI5.2
 
 EMI5.3
 

 <Desc / Clms Page number 6>

 
 EMI6.1
 
 EMI6.2
 

 <Desc / Clms Page number 7>

 
 EMI7.1
 
 EMI7.2

Claims (1)

EMI7.3 EMI7.4 EMI7.5 EMI7.6 EMI7.7 <Desc/Clms Page number 8> 1-Beispiele 7 bisbutan-2-ol der allgemeinen Formel EMI8.1 in der Ar obige Bedeutung hat, mit einem Amin der allgemeinen Formel EMI8.2 worin Ri und R2 obige Bedeutung haben, umsetzt und gewunschtenfalls eine erhaltene Base in ein Säuread- ditionssalz überführt. EMI7.3 EMI7.4 EMI7.5 EMI7.6 EMI7.7 <Desc / Clms Page number 8> 1-Examples 7 bisbutan-2-ol of the general formula EMI8.1 in which Ar has the above meaning, with an amine of the general formula EMI8.2 where R 1 and R 2 have the meaning given above, and, if desired, convert a base obtained into an acid addition salt.
AT805575A 1974-10-25 1975-10-22 METHOD FOR PRODUCING NEW SUBSTITUTED 1-ARYLOXY-4-AMINO-2-BUTANOLS AND THEIR ACID ADDITION SALTS AT344143B (en)

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AT344143B true AT344143B (en) 1978-07-10

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ZA756524B (en) 1976-09-29
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