AT343642B - Verfahren zur herstellung von neuen naphthalinderivaten - Google Patents

Verfahren zur herstellung von neuen naphthalinderivaten

Info

Publication number
AT343642B
AT343642B AT501276A AT501276A AT343642B AT 343642 B AT343642 B AT 343642B AT 501276 A AT501276 A AT 501276A AT 501276 A AT501276 A AT 501276A AT 343642 B AT343642 B AT 343642B
Authority
AT
Austria
Prior art keywords
sep
formula
methoxy
oral
compounds
Prior art date
Application number
AT501276A
Other languages
English (en)
Other versions
ATA501276A (de
Original Assignee
Beecham Group Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Beecham Group Ltd filed Critical Beecham Group Ltd
Priority to AT501276A priority Critical patent/AT343642B/de
Publication of ATA501276A publication Critical patent/ATA501276A/de
Application granted granted Critical
Publication of AT343642B publication Critical patent/AT343642B/de

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/32—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions without formation of -OH groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
    • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
    • C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
    • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
    • C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
    • C07C29/145—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones with hydrogen or hydrogen-containing gases
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/17—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrogenation of carbon-to-carbon double or triple bonds
    • C07C29/175—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrogenation of carbon-to-carbon double or triple bonds with simultaneous reduction of an oxo group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/60—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by elimination of -OH groups, e.g. by dehydration
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/18—Monohydroxylic alcohols containing only six-membered aromatic rings as cyclic part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/28—Alcohols containing only six-membered aromatic rings as cyclic part with unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/40—Halogenated unsaturated alcohols
    • C07C33/46—Halogenated unsaturated alcohols containing only six-membered aromatic rings as cyclic parts
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/40—Halogenated unsaturated alcohols
    • C07C33/46—Halogenated unsaturated alcohols containing only six-membered aromatic rings as cyclic parts
    • C07C33/48—Halogenated unsaturated alcohols containing only six-membered aromatic rings as cyclic parts with unsaturation outside the aromatic rings
    • C07C33/486—Polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
    • C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
    • C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
    • C07C45/292—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups with chromium derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/62—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by hydrogenation of carbon-to-carbon double or triple bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
    • C07C45/66—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups by dehydration
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
    • C07C45/676—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton by elimination of carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C07C45/74—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/213—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing six-membered aromatic rings
    • C07C49/215—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing six-membered aromatic rings polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/213—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing six-membered aromatic rings
    • C07C49/217—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing six-membered aromatic rings having unsaturation outside the aromatic rings
    • C07C49/223—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing six-membered aromatic rings having unsaturation outside the aromatic rings polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/227—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing halogen
    • C07C49/233—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
    • C07C49/235—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings having unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/255—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups

Landscapes

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

Description


   <Desc/Clms Page number 1> 
 



   Die Erfindung bezieht sich auf ein Verfahren zur Herstellung von neuen, pharmazeutisch wirksamen Naphthalinderivaten. 



   Es ist bekannt, dass bestimmte Naphthalinderivate wertvolle entzündungshemmende Wirksamkeitbesitzen und daher zur Behandlung von verschiedenen rheumatischen und arthritischen Zuständen verwendet werden   können.   Ein besonders wirksames Naphthalinderivat, das klinische Anwendung gefunden hat, ist Naxopren der Formel 
 EMI1.1 
 
 EMI1.2 
 Wirksamkeiten derartiger Verbindungen sind auch in J. Med. Chem., 13,203 [1970] und J. Pham. Exp. 



  Thera., 179,114   [1971] beschrieben.   



   Leider wurde festgestellt, dass die Verbindung der Formel   (1)   bei manchen Personen in einer Dosis, die nicht wesentlich höher ist als die therapeutische Dosis, eine schwere Reizung des Magen-Darm-Traktesverursacht. 



   Es wurde nun gefunden, dass andere Naphthalinderivate gute entzündungshemmende Wirksamkeit aufweisen, während sie in bezug auf die Magen-Darm-Reizung ein verbessertes therapeutisches Verhältnis besitzen. Derartige Verbindungen be sitzen die allgemeine Formel 
 EMI1.3 
 worin X Chlor, Brom, Methoxy, Methylthio oder Alkyl mit 1 bis 4 C-Atomen bedeutet,    R Wasserstoff   oder 
 EMI1.4 
 
In derartigen Verbindungen ist X am zweckmässigsten eine Methoxy- oder Methylthiogruppe, vorzugsweise eine Methoxygruppe. 



   Besonders geeignete Verbindungen der Formel (11) sind solche der allgemeinen Formel 
 EMI1.5 
 
 EMI1.6 
 

 <Desc/Clms Page number 2> 

 
 EMI2.1 
 sind, worin    R   die obige Bedeutung hat. 



   Verbindungen der allgemeinen Formel   (in),   worin    R   Methyl ist, zeigen in hoher Dosis östrogene Wirkungen, wogegen solche, worin R Wasserstoff ist, derartige Wirkungen mit geringerer Wahrscheinlichkeit zeigen. Demgemäss sind bevorzugte Verbindungen   4- (6-Methoxy-2-naphthyl)-butan-2-on   und 4- (6-Methoxy-   - 2-naphthyl)-but-3-en-2-on.    



   Diese beiden Verbindungen und ihre Analoga, worin das a-Kohlenstoffatom einen Methylsubstituenten trägt, zeigten   eine verlängerte entzündungshemmende Wirksamkeit,   als sie in einer Dosis von 100 mg/kg/Tag gemäss dem   Ratten-Carrageen-Entzündungshemmungstestgeprüft wurden,   jedoch den Magen in einer dreimal so hohen Dosis nicht reizten. 



   Die Verbindungen der allgemeinen Formel   (11)   können entzündungshemmenden und/oder analgetischen Zusammensetzungen, die zur oralen Verabreichung an Menschen gedacht sind, einverleibt werden. Derartige Zusammensetzungen können jede übliche Form aufweisen, wie Tabletten, Kapseln, Täschchen, od. dgl. 



  Einheitsdosisformen enthalten im allgemeinen 20 bis 100 mg, vorzugsweise 100 bis 600 mg des aktiven Bestandteiles der Formel (II). Derartige Dosierungsformen können ein-oder mehrmals täglich (vorzugsweise zwei-bis viermal täglich) eingenommen werden, so dass die tägliche Dosis für einen 70 kg schweren Menschen gewöhnlich 300 bis 3000 mg, Insbesondere 500 bis 2000 mg, beispielsweise 600 bis 1600 mg, beträgt. 



   Das erfindungsgemässe Verfahren zur Herstellung der neuen Verbindungen der allgemeinen Formel (II) besteht darin, dass man eine   ss-Ketosäure   der allgemeinen Formel 
 EMI2.2 
 worin R,   Xund   die strichlierte Linie die oben angegebene Bedeutung haben, oder ein Salz hievon decarboxyliert, worauf gewünschtenfalls die CO-Gruppe der erhaltenen Verbindung der Formel (11) zu einer CHOHGruppe reduziert wird. 



   Die Decarboxylierung kann in der für   $-Ketosäuren   üblichen Weise bewirkt werden, beispielsweise durch Erhitzen gegebenenfalls in einem sauren Medium. 



   Die Säuren der Formel (III) können durch Hydrolyse von Äthylestern hievon hergestellt werden, die ihrerseits durch Umsetzen einer Verbindung der Formel    CH . CO. CHNa. CO Ät,   (IV) mit einer Verbindung der allgemeinen Formel 

 <Desc/Clms Page number 3> 

 
 EMI3.1 
 worin R1 und X die oben angegebene Bedeutung haben und    B   Chlor, Brom, Jod oder eine ähnliche ersetzbare Gruppe bedeutet, oder mit einer Verbindung der allgemeinen Formel 
 EMI3.2 
   worin R und X die oben angegebene Bedeutung haben, und nachfolgende Dehydratisierung hergestellt werden können. Derartige Reaktionen verlaufen unter üblichen Bedingungen.   



   Pharmakologische Daten
Unter Anwendung eines herkömmlichen Allen-Doisy-Tests wurde die östrogene Wirksamkeit bestimmter erfindungsgemäss erhältlicher Verbindungen festgestellt. Die Ergebnisse sind in Tabelle 1 gezeigt. Die entzündungshemmende Wirksamkeit bestimmter   erfindungsgemäss   erhältlicher Verbindungen wurde unter Anwendung eines Standard-Rattenpfoten-Carrageen-Tests festgestellt, Diese Ergebnisse sind ebenfalls in Tabelle 1 gezeigt. 



   Diese Ergebnisse zeigen, dass die erfindungsgemäss erhältlichen Verbindungen in einer Dosierung ein gutes Ausmass an Aktivität aufweisen, wo eine übermässige Östrogenität nicht zu erwarten war. Weiterhin wird angenommen, dass das Fehlen einer Verzweigung am a-Kohlenstoffatom jede Östrogenität stark reduziert, die vorhanden sein könnte, während es die entzündungshemmende Wirksamkeit der Verbindungen nicht stark berührt. 



   Weiterhin wurde beobachtet, dass Verbindungen der Formel 
 EMI3.3 
   worin R und die strichlierte Linie die obige Bedeutung haben, den Rattenmagen in einer Dosis von 300 mg/kg/Tag bei oraler Verabreichung nach 3 Tagen nicht übermässig reizen, während am Ende einer   1 1/2 Tage dauernden oralen Behandlung mit der Verbindung der Formel (I) in der gleichen Dosis eine sehr schwere Magenreizung festgestellt wurde. 

 <Desc/Clms Page number 4> 

 



  Tabelle 1 
 EMI4.1 
 
<tb> 
<tb> Verbindung <SEP> Östrogenität <SEP> Entzündungshemmung
<tb> Allen-Doisy-Test <SEP> Ratten-Carrageen-Test <SEP> 
<tb> 3- <SEP> (6'-Methoxy-2'-naphthyl)- <SEP> 50 <SEP> mg/kg <SEP> subkutan, <SEP> inaktiv <SEP> 100 <SEP> mg/kg <SEP> oral,
<tb> - <SEP> butan-2-on <SEP> (Maus) <SEP> aktiv
<tb> 600 <SEP> mg/kg <SEP> oral, <SEP> inaktiv
<tb> (Ratte)
<tb> 3-Hydroxy-3-methyl-4- <SEP> (6'- <SEP> 100 <SEP> mg/kg <SEP> subkutan, <SEP> aktiv <SEP> 50 <SEP> und <SEP> 100 <SEP> mg/kg <SEP> oral,
<tb> -methoxy-2'-naphthyl)-pentan- <SEP> (Maus) <SEP> aktiv
<tb> - <SEP> 2-on <SEP> 
<tb> 4- <SEP> (6'-Methoxy-2'-naphthyl)- <SEP> 100 <SEP> mg/kg <SEP> subkutan, <SEP> inaktiv <SEP> 100 <SEP> mg/kg <SEP> oral,
<tb> - <SEP> pent-3-en-2-on <SEP> (Maus) <SEP> aktiv
<tb> 4- <SEP> (6'-Methoxy-2'-naphthyl)-300 <SEP> mg/kg <SEP> oral, <SEP> aktiv <SEP> 300 <SEP> mg/kg,

   <SEP> oral
<tb> - <SEP> pentan-2 <SEP> -on <SEP> (Ratte) <SEP> aktiv
<tb> 4-(6'-Methoxy-2'-naphthyl)- <SEP> 200 <SEP> mg/kg <SEP> oral, <SEP> inaktiv <SEP> 50 <SEP> mg/kg <SEP> oral,
<tb> - <SEP> pentan-2 <SEP> -on <SEP> (Ratte) <SEP> schwach <SEP> aktiv,
<tb> 100 <SEP> mg/kg <SEP> oral,
<tb> Aktivität <SEP> 1 <SEP> h <SEP> nach <SEP> Verabreichung
<tb> 4-(6'-Methoxy-2'-naphthyl)- <SEP> 300 <SEP> mg/kg <SEP> oral, <SEP> inaktiv <SEP> 300 <SEP> mg/kg <SEP> oral,
<tb> -3-huten-2-on <SEP> (Ratte) <SEP> aktiv
<tb> 
 *) Aspirin (300 mg/kg) ergibt eine äquivalente Aktivität 2 h nach Verabreichung 

 <Desc/Clms Page number 5> 

 
Das folgende Beispiel soll die Erfindung näher erläutern, ohne dass diese jedoch hierauf beschränkt sein soll. 



   Beispiel :4-(6'-Methoxy-2'-naphthyl)-butan-2-on 
 EMI5.1 
 
0, 45 Mol   3-Äthoxycarbonyl-4- (61 -methoxy-21-naphthyl) -butan-2-on   in insgesamt 1200 ml Äthanol und 470 ml 5N   HCI   wurden 7 h unter Rückfluss gehalten, nach welcher Zeit Dünnschichtchromatographie beendete Reaktion anzeigte. Das Äthanol wurde unter vermindertem Druck entfernt, worauf sich ein brauner Feststoff 
 EMI5.2 
 gen Feststoffes erhalten, der bei Gasschichtchromatographie 70% der im Titel genannten Verbindung enthielt. 



   Durch Kristallisieren aus 80% ÄtOH/H 0 (588 ml) mit Tiefkühlung wurden 56,0 g (54,6%) cremefarbene Mikrokristalle der im Titel genannten Verbindung erhalten, Fp. 78,5 bis 79,   50C,   bei Gassehichtchromatographie zu 96% rein. 



   Bei Abdampfen des Lösungsmittels und Kristallisation von 46,6 g des dunklen Rückstandes aus 70 ml Äthanol mit Tiefkühlung wurden weitere 9,2 g (9,0%) Kristalle der im Titel genannten Verbindung erhalten, Fp. 78 bis 79,   5 C,   bei   Gasschichtehromatographie   zu 94% rein. 



   Das Material wurde wieder aus 275 ml Äthanol unter Tiefkühlung kristallisiert, wobei 55,9 g (54,5%) der im Titel genannten Verbindung in Form   blasscremefarbener   Mikronadeln erhalten wurden, Fp. 80,5 bis   81 C,   bei Gasschichtchromatographie zu   97,   7% rein. Das NMR-Spektrum stimmte mit der Struktur überein.

Claims (1)

  1. PATENTANSPRUCH : Verfahren zur Herstellung von neuen Naphthalinderivaten der allgemeinen Formel EMI5.3 worin X Chlor, Brom, Methoxy, Methylthio oder Alkyl mit 1 bis 4 C-Atomen bedeutet, R Wasserstoff oder EMI5.4 Formel EMI5.5 worin rut, X und die strichlierte Linie die oben angegebene Bedeutung haben, oder ein Salz hievon decarboxy- <Desc/Clms Page number 6> liert, worauf gewünschtenfalls die CO-Gruppe der erhaltenen Verbindung der Formel (11) zu einer CHOHGruppe reduziert wird.
AT501276A 1975-01-08 1975-01-08 Verfahren zur herstellung von neuen naphthalinderivaten AT343642B (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT501276A AT343642B (de) 1975-01-08 1975-01-08 Verfahren zur herstellung von neuen naphthalinderivaten

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AT501276A AT343642B (de) 1975-01-08 1975-01-08 Verfahren zur herstellung von neuen naphthalinderivaten
AT9375A AT338257B (de) 1975-01-08 1975-01-08 Verfahren zur herstellung von neuen naphthalinderivaten

Publications (2)

Publication Number Publication Date
ATA501276A ATA501276A (de) 1977-10-15
AT343642B true AT343642B (de) 1978-06-12

Family

ID=3481320

Family Applications (8)

Application Number Title Priority Date Filing Date
AT501876A AT343104B (de) 1975-01-08 1975-01-08 Verfahren zur herstellung von neuen naphthalinderivaten
AT501576A AT343102B (de) 1975-01-08 1975-01-08 Verfahren zur herstellung von neuen naphthalinderivaten
AT501276A AT343642B (de) 1975-01-08 1975-01-08 Verfahren zur herstellung von neuen naphthalinderivaten
AT501676A AT344152B (de) 1975-01-08 1975-01-08 Verfahren zur herstellung von neuen naphthalinderivaten
AT9375A AT338257B (de) 1975-01-08 1975-01-08 Verfahren zur herstellung von neuen naphthalinderivaten
AT501476A AT343643B (de) 1975-01-08 1975-01-08 Verfahren zur herstellung von neuen naphthylsubstituierten ketonen
AT501776A AT343103B (de) 1975-01-08 1975-01-08 Verfahren zur herstellung von neuen naphthalinderivaten
AT501176A AT344151B (de) 1975-01-08 1976-07-08 Verfahren zur herstellung von neuen naphthalinderivaten

Family Applications Before (2)

Application Number Title Priority Date Filing Date
AT501876A AT343104B (de) 1975-01-08 1975-01-08 Verfahren zur herstellung von neuen naphthalinderivaten
AT501576A AT343102B (de) 1975-01-08 1975-01-08 Verfahren zur herstellung von neuen naphthalinderivaten

Family Applications After (5)

Application Number Title Priority Date Filing Date
AT501676A AT344152B (de) 1975-01-08 1975-01-08 Verfahren zur herstellung von neuen naphthalinderivaten
AT9375A AT338257B (de) 1975-01-08 1975-01-08 Verfahren zur herstellung von neuen naphthalinderivaten
AT501476A AT343643B (de) 1975-01-08 1975-01-08 Verfahren zur herstellung von neuen naphthylsubstituierten ketonen
AT501776A AT343103B (de) 1975-01-08 1975-01-08 Verfahren zur herstellung von neuen naphthalinderivaten
AT501176A AT344151B (de) 1975-01-08 1976-07-08 Verfahren zur herstellung von neuen naphthalinderivaten

Country Status (1)

Country Link
AT (8) AT343104B (de)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2407907A1 (fr) * 1977-11-03 1979-06-01 Beecham Group Ltd Derives du naphtalene utilisables comme medicament
NL8700356A (nl) * 1986-02-15 1987-09-01 Beecham Group Plc Nieuwe werkwijze.

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8603777D0 (en) * 1986-02-15 1986-03-19 Beecham Group Plc Chemical process
GB8603768D0 (en) * 1986-02-15 1986-03-19 Beecham Group Plc Process
GB8707200D0 (en) * 1987-03-26 1987-04-29 Beecham Group Plc Chemical process
AU5656698A (en) * 1996-12-03 1998-06-29 Recordati S.A. Chemical And Pharmaceutical Company A process for the preparation of nabumetone
DE202009002071U1 (de) 2009-04-17 2010-09-02 Paul Hettich Gmbh & Co. Kg Dämpfer für Möbel

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2407907A1 (fr) * 1977-11-03 1979-06-01 Beecham Group Ltd Derives du naphtalene utilisables comme medicament
NL8700356A (nl) * 1986-02-15 1987-09-01 Beecham Group Plc Nieuwe werkwijze.

Also Published As

Publication number Publication date
AT343103B (de) 1978-05-10
AT338257B (de) 1977-08-10
AT343102B (de) 1978-05-10
ATA501676A (de) 1977-11-15
ATA501576A (de) 1977-09-15
AT344152B (de) 1978-07-10
ATA501776A (de) 1977-09-15
ATA501876A (de) 1977-09-15
AT343643B (de) 1978-06-12
AT343104B (de) 1978-05-10
ATA501276A (de) 1977-10-15
ATA9375A (de) 1976-12-15
ATA501476A (de) 1977-10-15
ATA501176A (de) 1977-11-15
AT344151B (de) 1978-07-10

Similar Documents

Publication Publication Date Title
DE1643224B2 (de) 1 -Phenyl-2-aminoäthanolderivate und deren Säureadditionssalze, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel
DE2557497A1 (de) Neue tryptophanderivate mit erhoehter wirkung auf das zentralnervensystem
DE2163911B2 (de) 2-Aminomethyl-phenole, Verfahren zur Herstellung derselben und diese enthaltende Arzneimittel
AT343642B (de) Verfahren zur herstellung von neuen naphthalinderivaten
DE1940566C3 (de) 1- (2-Nitrilophenoxy)-2-hydroxy-3äthylaminopropan, Verfahren zu dessen Herstellung und dieses enthaltende Arzneimittel
DE2723051B2 (de) N^AcyO-p-amino-N&#39;-Oi-decyl- und n-tridecyO-benzamide sowie diese enthaltende Arzneimittel
DE2221758A1 (de) Yohimbinderivate,Verfahren zu ihrer Herstellung und ihre Verwendung
DE1915230C3 (de) Hydroxyphenylalkylaminderivate, Verfahren zu deren Herstellung und Arzneimittel auf deren Basis
DE2428200A1 (de) Essigsaeurederivate, verfahren zu deren herstellung und diese derivate enthaltende arzneimittel
DE3121175A1 (de) Erythro-1,2,3-triphenyl-1-pentanon-derivate sowie verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
DE2336671A1 (de) Oxyessigsaeureaether von o-thymotinsaeureestern
DE2800015A1 (de) Neue chromderivate, verfahren zu deren herstellung und diese enthaltende arzneimittel
DE2640884A1 (de) Neue entzuendungshemmende l-oxo-isoindolin-derivate und verfahren zu ihrer herstellung
DE2004301A1 (de) Phenylserinderivate
DE1931927A1 (de) Neue Cyclohexylaminderivate
DD142875A5 (de) Verfahren zur herstellung von 2-aminoaethanolderivaten
DE1793828C3 (de) 2-(6&#39;-Fluor-2&#39;-naphthyl)-propionsäureamid und dessen Herstellung und Verwendung
AT212322B (de) Verfahren zur Herstellung von neuen Pyridazinon-Derivaten
AT360990B (de) Verfahren zur herstellung des neuen 1-methyl-4- (3-carboxy-10,11-dihydro-5h-dibenzo-(a,d)- -cyclohepten-5-yliden)-piperidin (10,11-dihydro -3-carboxy-cyproheptadin), seines n-oxids und seiner salze
AT343645B (de) Verfahren zur herstellung von neuen indanylcarbonsauren und deren salzen
AT366047B (de) Verfahren zur herstellung von neuen chinazolinderivaten und deren salzen
AT360016B (de) Verfahren zur herstellung des neuen 1-methyl-4- (3-carboxy-10,11-dihydro-5h-dibenzo-(a,d)- cyclohepten-5-yliden)-piperidin (10,11-dihydro- -3-carboxy-cyproheptadin), seines n-oxids und seiner salze
DE3008852A1 (de) Benzodiazepinderivate, verfahren zu ihrer herstellung und sie enthaltende arzneimittel
DE1420955C (de) alpha (o Benzylphenoxy)-beta piperidino propan, dessen Saureadditionssalze sowie Verfahren zur Herstellung dieser Verbm düngen
AT329021B (de) Verfahren zur herstellung von neuen sulfamylbenzoesauren sowie deren pharmazeutisch annehmbaren salzen und estern

Legal Events

Date Code Title Description
ELA Expired due to lapse of time
ELJ Ceased due to non-payment of the annual fee