AT344152B - Verfahren zur herstellung von neuen naphthalinderivaten - Google Patents

Verfahren zur herstellung von neuen naphthalinderivaten

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AT344152B
AT344152B AT501676A AT501676A AT344152B AT 344152 B AT344152 B AT 344152B AT 501676 A AT501676 A AT 501676A AT 501676 A AT501676 A AT 501676A AT 344152 B AT344152 B AT 344152B
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sep
methyl
compounds
oral
derivatives
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AT501676A
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ATA501676A (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 Wirkung besitzen und daher zur Behandlung von verschiedenen rheumatischen und arthritischen Zuständen verwendet werden können. Ein besonders wirksames Naphthalinderivat, das klinische Anwendung gefunden hat, ist Naxoprender Formel 
 EMI1.1 
 
Diese Verbindung und bestimmte verwandte Verbindungen sind in den GB-PS Nr.   1, 271, 132,   Nr. 1,274, 271, Nr. 1,274, 272, Nr. 1,274, 273, Nr. 1,291, 386, Nr. 1,211, 134, Nr.   1, 297, 306,   Nr.   1, 276, 261,   Nr.   1, 216, 882, Nr. 1, 289, 041, Nr. 1, 321, 347   und Nr.   1, 296, 493 beschrieben.   Die pharmakologischen Wirksamkeiten derartiger Verbindungen sind auch in J. Med. Chem. 13, 203   [1970]   und J. 



  Pharm. Exp. Thera., 179,114 [1971] beschrieben. 



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



   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 
 EMI1.2 
   worin R Wasserstoff oder Methyl ist, A eine Gruppe CO oder CHOH darstellt und die strichlierte Linie zwei Wasserstoffatome bedeutet oder eine zweite Bindung ist.   



   Verbindungen der Formel   (II),   worin    A   eine Gruppe CO bedeutet, können aktiver sein als die entsprechenden Verbindungen, worin    A   eine Gruppe CHOH ist. 



   Eine bevorzugte Gruppe von Verbindungen der Formel (II) ist jene der Formeln 
 EMI1.3 
 und 
 EMI1.4 
 

 <Desc/Clms Page number 2> 

 worin R1 die obige Bedeutung hat,
Verbindungen der allgemeinen Formel (II), worin Ri Methyl ist, zeigen in hoher Dosis östrogene Wirkungen, wogegen solche, worin Ri 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-Entzündungshemmungstest geprüft wurden, jedoch den Magen in einer dreimal so hohen Dosis nicht reizten. 



   Die Verbindungen der allgemeinen Formel (II) 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 o, 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   (fl)   besteht darin, dass man ein Naphtholderivat der allgemeinen Formel 
 EMI2.1 
 worin Ri, Ai und die strichlierte Linie die oben angegebene Bedeutung haben, mit Methylbromid, Methyljodid, Dimethylsulfat, Methylmethansulfonat, Methyl-p-toluolsulfonat oder Diazomethan methyliert. 



   Die Reaktion der Verbindungen der Formel (III) mit dem Methylierungsmittel geht unter konventionellen Bedingungen vor sich. 



   Ausser bei   der Reaktion mitDiazomethan   ist die Verbindung der Formel   (III)   vorzugsweise in Form ihres Anions oder es ist zumindest ein Äquivalent einer nichtnukleophilen Base vorhanden. Eine derartige Reaktion kann im allgemeinen unter Bedingungen stattfinden, bei welchen Phenol in Anisol übergeführt wird. 



   Pharmakologische Daten :
Unter Anwendung eines herkömmlichenAllen-Doisy-Tests wurde die östrogene Wirksamkeit bestimmter   erfindungsgemäss erhältlicher   Verbindungen festgestellt. Die Ergebnisse sind in Tabelle I gezeigt. Die entzündungshemmende Wirksamkeit bestimmter erfindungsgemäss erhältlicher Verbindungen wurde unter Anwendung eines Standard-Rattenpfoten-Carrageen-Tests festgestellt. Diese Ergebnisse sind ebenfalls in Tabelle I 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 bertihrt. 



   Weiterhin wurde beobachtet, dass Verbindungen der Formel 
 EMI2.2 
 worin Ri 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 

 <Desc/Clms Page number 3> 

   l   1/2 Tage dauernden oralen Behandlung mit der Verbindung der Formel (1) in der gleichen Dosis eine sehr schwere Magenreizung festgestellt wurde. 



   Tabelle I 
 EMI3.1 
 
<tb> 
<tb> Entzündungs <SEP> hemmung <SEP> 
<tb> Verbindung <SEP> Östrogenität <SEP> Ratten-CarraAllen-Doisy <SEP> -Test <SEP> geen-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'-100 <SEP> mg/kg <SEP> subkutan, <SEP> aktiv <SEP> 50 <SEP> und <SEP> 100 <SEP> mg/kg
<tb> - <SEP> methoxy-2'-naphthyl)-pentan- <SEP> (Maus) <SEP> oral, <SEP> aktiv
<tb> - <SEP> 2-on <SEP> 
<tb> 4- <SEP> (6'-Methoxy-2'-naphthyl)-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-on <SEP> (Ratte) <SEP> aktiv
<tb> 4- <SEP> (6'-Methoxy-2'-naphthyl)- <SEP> 200 <SEP> mg/kg <SEP> oral, <SEP> inaktiv <SEP> 50 <SEP> mg/kg <SEP> oral,
<tb> -pentan-2-on <SEP> (Ratte) <SEP> schwach <SEP> aktiv
<tb> 100 <SEP> mg/kg <SEP> oral,
<tb> Aktivität <SEP> 1 <SEP> h <SEP> nach
<tb> Verabreichung <SEP> *) <SEP> 
<tb> 4-(6'-Methoxy-2'-naphthyl)- <SEP> 300 <SEP> mg/kg <SEP> oral, <SEP> inaktiv <SEP> 300 <SEP> mg/kg <SEP> oral,
<tb> - <SEP> 3-buten-2-on <SEP> (Ratte) <SEP> aktiv
<tb> 
 *) Aspirin (300 mg/kg) ergibt eine äquivalente Aktivität 2 h nach Verabreichung 
Das folgende Beispiel soll die Erfindung näher erläutern, ohne dass diese hierauf beschränkt sein soll. 



   Beispiel :4-(6-Methoxy-2-naphthyl)-butan-2-on
4,35 g 4- (6-Hydroxy-2-naphthyl)-butan-2-on wurden in 100 ml Methanol und 30 ml konz. Schwefelsäure 3 h am   Rückfluss   gehalten. Die Mischung wurde in 500 ml Wasser gegossen und filtriert, wobei 3, 7 g eines braunen Feststoffes erhalten wurden, Fp. 65 C. Dieser wurde aus Äthanol/Wasser umkristallisiert, wobei   2,   15g der Im Titel genannten Verbind mg erhalten wurden, Fp. 78, 5 C.

Claims (1)

  1. PATENTANSPRUCH : Verfahren zur Herstellung von neuen Naphthalinderivaten der allgemeinen Formel EMI3.2 worin Ri Wasserstoff oder Methyl ist, Al eine Gruppe CO oder CHOH darstellt und die strichlierte Linie zwei Wasserstoffatome bedeutet oder eine zweite Bindung ist, dadurch gekennzeichnet, dass man ein Naphtholderivat der allgemeinen Formel <Desc/Clms Page number 4> EMI4.1 worin R1, A1 und die strichlierte Linie die oben angegebene Bedeutung haben, mit Methylbromid, Methyljodid, Dimethylsulfat, Methylmethansulfonat, Methyl-p-toluolsulfonat oder Diazomethan methyliert.
AT501676A 1975-01-08 1975-01-08 Verfahren zur herstellung von neuen naphthalinderivaten AT344152B (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT501676A AT344152B (de) 1975-01-08 1975-01-08 Verfahren zur herstellung von neuen naphthalinderivaten

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
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

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Publication Number Publication Date
ATA501676A ATA501676A (de) 1977-11-15
AT344152B true AT344152B (de) 1978-07-10

Family

ID=3481320

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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
AT501776A AT343103B (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
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
AT501476A AT343643B (de) 1975-01-08 1975-01-08 Verfahren zur herstellung von neuen naphthylsubstituierten ketonen
AT501176A AT344151B (de) 1975-01-08 1976-07-08 Verfahren zur herstellung von neuen naphthalinderivaten

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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
AT501776A AT343103B (de) 1975-01-08 1975-01-08 Verfahren zur herstellung von neuen naphthalinderivaten

Family Applications After (4)

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

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Country Link
AT (8) AT343104B (de)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2014993B (en) * 1977-11-03 1982-05-12 Beecham Group Ltd Chemical compounds
GB8603772D0 (en) * 1986-02-15 1986-03-19 Beecham Group Plc Process
GB8603768D0 (en) * 1986-02-15 1986-03-19 Beecham Group Plc Process
GB8603777D0 (en) * 1986-02-15 1986-03-19 Beecham Group Plc Chemical 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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Publication number Publication date
AT343103B (de) 1978-05-10
ATA501876A (de) 1977-09-15
ATA501476A (de) 1977-10-15
AT343643B (de) 1978-06-12
AT343642B (de) 1978-06-12
ATA501176A (de) 1977-11-15
ATA501676A (de) 1977-11-15
AT343102B (de) 1978-05-10
AT343104B (de) 1978-05-10
ATA9375A (de) 1976-12-15
AT344151B (de) 1978-07-10
ATA501576A (de) 1977-09-15
AT338257B (de) 1977-08-10
ATA501776A (de) 1977-09-15
ATA501276A (de) 1977-10-15

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