AT344151B - Verfahren zur herstellung von neuen naphthalinderivaten - Google Patents

Verfahren zur herstellung von neuen naphthalinderivaten

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Publication number
AT344151B
AT344151B AT501176A AT501176A AT344151B AT 344151 B AT344151 B AT 344151B AT 501176 A AT501176 A AT 501176A AT 501176 A AT501176 A AT 501176A AT 344151 B AT344151 B AT 344151B
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Austria
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sep
derivatives
compounds
naphthalin
methoxy
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AT501176A
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ATA501176A (de
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Beecham Group Ltd
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    • 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
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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 Wirksamkeit besitzen 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 
 Diese Verbindung und bestimmte verwandte   Verbindungen sind in den GB-PSNr. l, 271, 132, Nr. 1, 274, 271,   
 EMI1.2 
 Nr.   1, 289, 041,   Nr.   l, 321, 347 und   Nr. 1, 296, 493 beschrieben. Die pharmakologischen Wirksamkeiten derartiger Verbindungen sind auch in   J. Med. Chem., 13,   203   [1970]   und J. Pham. Exp. Thera., 179, 114   h971]   beschrieben. 



   Leider wurde festgestellt, dass die Verbindung der Formel   (l)   bei manchen Personen in einer Dosis, die 
 EMI1.3 
 therapeutischeursacht. 



   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 besitzen die allgemeine Formel 
 EMI1.4 
 worin X Chlor, Brom, Methoxy, Methylthlo oder Alkyl mit 1 bis 4 C-Atomen bedeutet und   R1   Wasserstoff oder Methyl ist. 



   In derartigen Verbindungen ist X am zweckmässigsten eine Methoxy- oder Methylthiogruppe, vorzugsweise eine Methoxygruppe. 



   Besonders geeignete Verbindungen der Formel   (D)   sind solche der allgemeinen Formel 
 EMI1.5 
 worin R1 die oben angegebene Bedeutung hat. 



   Verbindungen der allgemeinen Formel   (li),   worin   R1   Methyl ist, zeigen in hoher Dosis östrogene Wirkungen, wogegen solche, worin   R1   Wasserstoff ist, derartige Wirkungen mit geringerer Wahrscheinlichkeit zeigen. Demgemäss ist eine bevorzugte Verbindung   4- (6-Methoxy2-naphthyl)-butan-2-on.   



     DieseVerbindung   und ihr Analogon, worin das s-Kohlenstoffatom einen Methylsubstituenten trägt, zeigten eine verlängerte entzündungshemmende Wirksamkeit, als sie in einer Dosis von 100   mg/kg/Tag   gemäss   demRatten-Carrageen-Entzündungshemmungstest   geprüft wurden, jedoch den Magen in einer dreimal so hohen Dosis nicht reizten. 



   Die Verbindungen der allgemeinen Formel (D) können entzündungshemmenden und/oder analgetischen Zu- 

 <Desc/Clms Page number 2> 

 sammensetzungen, die zur oralen Verabreichung an Menschen gedacht sind, einverleibt werden. Derartige Zusammensetzungen können jede übliche Form aufweisen, wie Tabletten, Kapseln, Täschchen   od. dgl. Ein-   heitsdosisformen enthalten im allgemeinen 20 bis 100 mg, vorzugsweise 100 bis 600 mg des aktiven Bestand- 
 EMI2.1 
 oderi bis viermal täglich) eingenommen werden, so dass die tägliche Dosis für einen 70 kg schweren Menschen ge- wöhnlich 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   (H)   besteht darin, dass man ein Naphthylalkenderivat der allgemeinen Formel 
 EMI2.2 
 
 EMI2.3 
 undR1wirkt. Die Reaktion kann bei jeder üblichen, nicht extremen Temperatur durchgeführt werden, jedoch ist
Umgebungstemperatur bevorzugt. Gewöhnlich wird die Reaktion in einem inerten organischen Lösungsmittel, wie Äthylacetat oder Äthanol, unter Anwendung von atmosphärischem oder schwach überatmosphärischem Wasserstoffdruck durchgeführt. 



   Die Reduktion mit einem komplexen Metallhydrid, wie   LiAIH4'unter   üblichen Reaktionsbedingungen für olefinische Reduktion eines   a, ss-ungesättigten Ketons   kann ebenfalls angewendet werden, wird   jedoch manch-   mal infolge der Reduktion der Carbonylgruppe weniger vorgezogen, da sie zu unerwünschten Produkten fährt. 



   Pharmakologische Daten
Unter Anwendung eines herkömmlichen Allen-Doisy- Tests wurde die östrogene Wirksamkeit bestimm- ter erfindungsgemäss erhältlicher Verbindungen festgestellt. Die Ergebnisse sind in der Tabelle gezeigt Die   entzündungshemmende Wirksamkeit   bestimmter erfindungsgemäss erhältlicher Verbindungen wurde unter An- wendung eines Standard-Rattenpfoten-Carrageen-Tests festgestellt. Diese Ergebnisse sind ebenfalls in der
Tabelle gezeigt Diese Ergebnisse zeigen, dass die erfindungsgemäss erhältlichen Verbindungen in einer Dosierung ein gu- tes Ausmass an Aktivität aufweisen, wo eine übermässige Östrogenität nicht zu erwarten war.

   Weiterhin wird angenommen, dass das Fehlen einer Verzweigung am   o'-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   (rib),   worin   R1   die obige Bedeutung hat, den
Rattenmagen in einer Dosis von300 mg/kg/Tag bei oraler Verabreichung nach 3 Tagen nicht übermässig rei- zen, 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 3> 

 



  Tabelle 
 EMI3.1 
 
<tb> 
<tb> Verbindung <SEP> Östrogenität <SEP> Entzündungshemmung
<tb> Allen-Doisy-Test <SEP> Ratten-Carrageen-Test <SEP> 
<tb> 3- <SEP> (6'- <SEP> Methoxy- <SEP> 2'-naphthyl) <SEP> - <SEP> 50 <SEP> mg/kg <SEP> subkutan, <SEP> 100 <SEP> mg/kg, <SEP> oral, <SEP> aktiv
<tb> butan-2-on <SEP> inaktiv <SEP> (Maus)
<tb> 600 <SEP> mg/kg <SEP> oral,
<tb> inaktiv <SEP> (Ratte)
<tb> 3-Hydroxy-3-methyl-4- <SEP> (6'- <SEP> 100 <SEP> mg/kg <SEP> subkutan, <SEP> 50 <SEP> und <SEP> 100 <SEP> mg/kg <SEP> oral,
<tb> methoxy-2@aphthyl)-pentan- <SEP> aktiv <SEP> (Maus) <SEP> aktiv
<tb> - <SEP> 2-on <SEP> 
<tb> 4- <SEP> (6'-Methoxy-2'-naphthyl)-300 <SEP> mg/kg <SEP> oral, <SEP> 300 <SEP> mg/kg <SEP> oral,
<tb> pentan-2-on <SEP> aktiv <SEP> (Ratte) <SEP> aktiv
<tb> 4- <SEP> (6'-Methoxy-2'-naphthyl)- <SEP> 200 <SEP> mg/kg <SEP> oral, <SEP> 50 <SEP> mg/kg <SEP> oral,

  
<tb> pentan- <SEP> 2-on <SEP> inaktiv <SEP> (Ratte) <SEP> schwach <SEP> aktiv
<tb> 100 <SEP> mg/kg <SEP> oral,
<tb> Aktivität <SEP> 1 <SEP> h
<tb> nach <SEP> Verabreichung+)
<tb> 
 +) Aspirin (300 mg/kg) ergibt eine äquivalente Aktivität 2 h nach Verabreichung 
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     32g 4- (6-Methoxy-2-naphthyl)-3-buten-2-on in   500 ml Äthylacetat wurden bei Raumtemperatur unter atmosphärischem Wasserstoffdruck über 3 g 10% Pd/C geschüttelt, bis keine Wasserstoffaufnahme mehr auftrat Dabei wurden 22, 5 g 4- (6-Methoxy-2-naphthyl)-butan-2-on erhalten, Fp.   78, 5 C.

Claims (1)

  1. PATENTANSPRUCH : Verfahren zur Herstellung von neuen Naphthalinderivaten der allgemeinen Formel EMI3.2 EMI3.3 <Desc/Clms Page number 4> EMI4.1 worin X und R1 die obige Bedeutung haben, hydriert
AT501176A 1975-01-08 1976-07-08 Verfahren zur herstellung von neuen naphthalinderivaten AT344151B (de)

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AT9375A AT338257B (de) 1975-01-08 1975-01-08 Verfahren zur herstellung von neuen naphthalinderivaten
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AT501676A AT344152B (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
AT501476A AT343643B (de) 1975-01-08 1975-01-08 Verfahren zur herstellung von neuen naphthylsubstituierten ketonen
AT9375A AT338257B (de) 1975-01-08 1975-01-08 Verfahren zur herstellung von neuen naphthalinderivaten
AT501876A AT343104B (de) 1975-01-08 1975-01-08 Verfahren zur herstellung von neuen naphthalinderivaten
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

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AT501676A AT344152B (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
AT501476A AT343643B (de) 1975-01-08 1975-01-08 Verfahren zur herstellung von neuen naphthylsubstituierten ketonen
AT9375A AT338257B (de) 1975-01-08 1975-01-08 Verfahren zur herstellung von neuen naphthalinderivaten
AT501876A AT343104B (de) 1975-01-08 1975-01-08 Verfahren zur herstellung von neuen naphthalinderivaten
AT501776A AT343103B (de) 1975-01-08 1975-01-08 Verfahren zur herstellung von neuen naphthalinderivaten

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GB2014993B (en) * 1977-11-03 1982-05-12 Beecham Group Ltd Chemical compounds
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
GB8603772D0 (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

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ATA501876A (de) 1977-09-15
ATA9375A (de) 1976-12-15
AT344152B (de) 1978-07-10
ATA501776A (de) 1977-09-15
ATA501676A (de) 1977-11-15
ATA501476A (de) 1977-10-15
AT343102B (de) 1978-05-10
AT338257B (de) 1977-08-10
AT343104B (de) 1978-05-10
AT343642B (de) 1978-06-12
AT343103B (de) 1978-05-10
AT343643B (de) 1978-06-12
ATA501276A (de) 1977-10-15
ATA501176A (de) 1977-11-15

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