US2007021478A1PendingUtilityA1

Benzothiazolyl derivatives

54
Individually held — no corporate assignee on recordPriority: Jun 20, 2003Filed: Sep 26, 2006Published: Jan 25, 2007
Est. expiryJun 20, 2023(expired)· nominal 20-yr term from priority
Inventors:Matthias NettekovenStephan Roever
A61P 3/04C07D 277/82
54
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Claims

Abstract

The present invention relates to compounds of formula (I) wherein R 1 , R 2 , R 3 R 3a and R 3b are as provided in the description, and pharmaceutically acceptable salts thereof, for use in the treatment and/or prophylaxis of diseases which are associated with the modulation of CB1 receptors such as obesity.

Claims

exact text as granted — not AI-modified
1 . A compound of formula (I)  
     
       
         
         
             
             
         
       
       wherein  
       R 1  is phenyl, or phenyl mono-, di- or tri-substituted, independently, by a group selected from the group consisting of lower alkyl, halogenated-lower alkoxy and di-lower alkylamino;  
       R 2  is phenyl, or phenyl mono-, di- or tri-substituted, independently, by a group selected from the group consisting of halogen, halogenated-lower alkyl, nitro and cyano;  
       R 3  is hydrogen, lower alkyl, benzyl, lower alkoxy, halogen, cyano, nitro, amino, —NHSO 2 —R 3a  or —NHCO—R 3b ;  
       R 3a  is lower alkyl, di-lower alkylamino, benzyl, phenyl or phenyl mono-, di- or tri-substituted, independently, by lower alkyl;  
       R 3b  is benzyl, phenyl or phenyl mono-, di- or tri-substituted, independently, by lower alkyl;  
       or a pharmaceutically acceptable salt thereof.  
     
   
   
       2 . The compound according to  claim 1 , wherein R 2  is phenyl mono-substituted with halogen.  
   
   
       3 . The compound according to  claim 1 , wherein R 3  is hydrogen, nitro, amino, —NHSO 2 —R 3a  or —NHCO—R 3b .  
   
   
       4 . The compound according to  claim 3 , wherein R 3  is hydrogen.  
   
   
       5 . The compound according to  claim 1 , wherein substituent R 3  is at the 6-position of the benzthiazole ring.  
   
   
       6 . The compound according to  claim 3  in which R 3  is —NHSO 2 —R 3a , wherein R 3a  is methyl, n-butyl, dimethylamino, benzyl, phenyl or phenyl mono-, di- or tri-substituted methyl.  
   
   
       7 . The compound according to  claim 3  in which R 3  is —NHCO—R 3b , wherein R 3b  is benzyl or phenyl mono-substituted by lower alkyl.  
   
   
       8 . A compound of formula (Ia)  
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, wherein  
       R 1  is phenyl, or phenyl mono-, di- or tri-substituted, independently, by a group selected from the group consisting of halogen, lower alkoxy, lower alkyl, halogenated-lower alkoxy and di-lower alkylamino;  
       R 2  is phenyl, or phenyl mono-, di- or tri-substituted, independently, by a group selected from the group consisting of halogen, halogenated-lower alkyl, nitro and cyano;  
       R 3  is hydrogen, lower alkyl, benzyl, lower alkoxy, cyano, nitro, amino, —NHSO 2 —R 3a  or —NHCO—R 3b ;  
       R 3a  is lower alkyl, di-lower alkylamino, benzyl, phenyl or phenyl mono-, di- or tri-substituted, independently, by lower alkyl;  
       R 3b  is benzyl, phenyl or phenyl mono-, di- or tri-substituted, independently, by lower alkyl;  
       provided that when R 3  is hydrogen, R 1  is selected from the group consisting of 2-halogen-phenyl, 4-lower alkoxy-phenyl, 3-lower alkyl-phenyl, 4-halogen-2-lower alkyl-phenyl, 3-halogen-2-lower alkyl-phenyl, 4-halogen-3-lower alkyl-phenyl, 2-halogen-4-lower alkyl-phenyl, 3-halogen-4-lower alkyl-phenyl, 2-lower alkoxy-4-lower alkyl-phenyl, 3-lower alkoxy-4-lower alkyl-phenyl, 4-lower alkoxy-2-lower alkyl-phenyl, 4-lower alkoxy-3-lower alkyl-phenyl, 3-lower alkoxy-2-lower alkyl-phenyl, phenyl substituted by halogenated-lower alkoxy or di-lower alkylamino, phenyl substituted by two or three groups independently selected from halogen, lower alkoxy, halogenated alkoxy and di-lower alkylamino, phenyl substituted by a lower alkyl group and one or two groups selected from halogenated alkoxy and di-lower alkylamino, and phenyl substituted by two lower alkyl groups and a group selected from halogen, lower alkoxy, halogenated alkoxy and di-lower alkylamino.  
     
   
   
       9 . The compound of formula (Ia) according to  claim 8  or pharmaceutically acceptable salt thereof, wherein 
 R 3  is lower alkyl, benzyl, lower alkoxy, cyano, nitro, amino, —NHSO 2 —R 3a  or —NHCO—R 3b .    
   
   
       10 . The compound of formula (Ia) according to  claim 8 , selected from the group consisting of: 
 2-chloro-N-(4-ethoxy-phenyl)-4-fluoro-N-(6-nitro-benzothiazol-2-yl)-benzamide;    2-chloro-N-(4-ethoxy-phenyl)-N-(6-nitro-benzothiazol-2-yl)-benzamide;    2,4-dichloro-N-(4-ethoxy-phenyl)-N-(6-nitro-benzothiazol-2-yl)-benzamide;    2,4-dichloro-N-(3,4-dimethoxy-phenyl)-N-(6-nitro-benzothiazol-2-yl)-benzamide;    N-(6-amino-benzothiazol-2-yl)-2,4-dichloro-N-(3,4-dimethoxy-phenyl)-benzamide;    2,4-dichloro-N-(3,4-dimethoxy-phenyl)-N-(6-methanesulfonylamino-benzothiazol-2-yl)-benzamide;    N-[6-(butane-1-sulfonylamino)-benzothiazol-2-yl]-2,4-dichloro-N-(3,4-dimethoxy-phenyl)-benzamide;    N-[6-(dimethylamino-1-sulfonylamino)-benzothiazol-2-yl]-2,4-dichloro-N-(3,4-dimethoxy-phenyl)-benzamide;    N-(6-benzenesulfonylamino-benzothiazol-2-yl)-2,4-dichloro-N-(3,4-dimethoxy-phenyl)-benzamide; and    2,4-dichloro-N-(3,4-dimethoxy-phenyl)-N-(6-phenylmethanesulfonylamino-benzothiazol-2-yl)-benzamide;    or a pharmaceutically acceptable salt thereof.    
   
   
       11 . The compound of formula (Ia) according to  claim 8 , selected from the group consisting of: 
 2,4-dichloro-N-(3,4-dimethoxy-phenyl)-N-[6-(toluene-2-sulfonylamino)-benzothiazol-2-yl]-benzamide;    2,4-dichloro-N-(3,4-dimethoxy-phenyl)-N-(6-phenylacetylamino-benzothiazol-2-yl)-benzamide;    2-chloro-N-(3,4-dimethoxy-phenyl)-N-(6-nitro-benzothiazol-2-yl)-benzamide;    N-(6-amino-benzothiazol-2-yl)-2-chloro-N-(3,4-dimethoxy-phenyl)-benzamide;    2-chloro-N-(3,4-dimethoxy-phenyl)-N-(6-methanesulfonylamino-benzothiazol-2-yl)-benzamide;    N-[6-(butane-1-sulfonylamino)-benzothiazol-2-yl]-2-chloro-N-(3,4-dimethoxy-phenyl)-benzamide;    N-[6-(dimethylamino-1-sulfonylamino)-benzothiazol-2-yl]-2-chloro-N-(3,4-dimethoxy-phenyl)-benzamide;    N-(6-benzenesulfonylamino-benzothiazol-2-yl)-2-chloro-N-(3,4-dimethoxy-phenyl)-benzamide;    2-chloro-N-(3,4-dimethoxy-phenyl)-N-(6-phenylmethanesulfonylamino-benzothiazol-2-yl)-benzamide;    2-chloro-N-(3,4-dimethoxy-phenyl)-N-[6-(toluene-2-sulfonylamino)-benzothiazol-2-yl]-benzamide; and    N-(6-(2-methylbenzoylamino)-benzothiazol-2-yl)-2-chloro-N-(3,4-dimethoxy-phenyl)-benzamide;    or a pharmaceutically acceptable salt thereof.    
   
   
       12 . The compound of formula (Ia) according to  claim 8 , wherein R 3  is hydrogen, and R 1  is selected from the group consisting of 3,5-dichlorophenyl, 3,4-dichlorophenyl, 4-chloro-2-methyl-phenyl and 4-chloro-3-methoxyphenyl.  
   
   
       13 . The compounds of formula (Ia) according to  claim 8 , wherein R 3  is hydrogen, and R 1  is selected from the group consisting of 4-lower alkoxy-phenyl, 3,4-di-lower alkoxy-phenyl, 3,4,5-tri-lower alkoxy-phenyl and 3-lower alkoxy-4-lower alkyl-phenyl.  
   
   
       14 . The compound of formula (Ia) according to  claim 1 , wherein R 3  is hydrogen, and R 1  is phenyl substituted by a group selected from the group consisting of halogenated-lower alkoxy and di-lower alkylamino.  
   
   
       15 . The compound of formula (Ia) according to  claim 8 , selected from the group consisting of: 
 N-benzothiazol-2-yl-2-chloro-N-(3,5-dichloro-phenyl)-benzamide;    N-benzothiazol-2-yl-2-chloro-N-(3,4-dichloro-phenyl)-benzamide;    N-benzothiazol-2-yl-2,4-dichloro-N-(3,4-dichloro-phenyl)-benzamide;    N-benzothiazol-2-yl-2-chloro-N-(4-methoxy-phenyl)-benzamide;    N-benzothiazol-2-yl-2,4-dichloro-N-(4-methoxy-phenyl)-benzamide;    N-benzothiazol-2-yl-2,4-dichloro-N-(4-chloro-2-methyl-phenyl)-benzamide;    N-benzothiazol-2-yl-2-fluoro-N-(4-methoxy-phenyl)-4-trifluoromethyl-benzamide;    N-benzothiazol-2-yl-N-(4-methoxy-phenyl)-2,4-bis-trifluoromethyl-benzamide;    N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(4-methoxy-phenyl)-benzamide; and    N-benzothiazol-2-yl-2-chloro-N-(4-methoxy-phenyl)-4-nitro-benzamide;    or a pharmaceutically acceptable salt thereof.    
   
   
       16 . The compound of formula (Ia) according to  claim 8 , selected from the group consisting of: 
 N-benzothiazol-2-yl-4-cyano-N-(4-methoxy-phenyl)-benzamide;    N-benzothiazol-2-yl-N-(4-ethoxy-phenyl)-2-fluoro-4-trifluoromethyl-benzamide;    N-benzothiazol-2-yl-2-chloro-N-(4-ethoxy-phenyl)-4-fluoro-benzamide;    N-benzothiazol-2-yl-2-chloro-N-(4-ethoxy-phenyl)-4-nitro-benzamide;    N-benzothiazol-2-yl-4-cyano-N-(4-ethoxy-phenyl)-benzamide;    N-benzothiazol-2-yl-2-chloro-N-(4-ethoxy-phenyl)-benzamide;    N-benzothiazol-2-yl-2,4-dichloro-N-(4-ethoxy-phenyl)-benzamide;    N-benzothiazol-2-yl-N-(3,4-dimethoxy-phenyl)-2-fluoro-4-trifluoromethyl-benzamide;    N-benzothiazol-2-yl-N-(3,4-dimethoxy-phenyl)-2,4-bis-trifluoromethyl-benzamide; and    N-benzothiazol-2-yl-2-chloro-N-(3,4-dimethoxy-phenyl)-4-fluoro-benzamide;    or a pharmaceutically acceptable salt thereof.    
   
   
       17 . The compound of formula (la) according to  claim 8 , selected from the group consisting of: 
 N-benzothiazol-2-yl-2-chloro-N-(4-dimethylamino-phenyl)-4-fluoro-benzamide;    N-benzothiazol-2-yl-2-chloro-N-(4-dimethylamino-phenyl)-benzamide;    N-benzothiazol-2-yl-2-chloro-N-(4-diethylamino-phenyl)-4-nitro-benzamide; and    N-benzothiazol-2-yl-2,4-dichloro-N-(4-diethylamino-phenyl)-benzamide;    or a pharmaceutically acceptable salt thereof.    
   
   
       18 . The compound of formula (Ia) according to  claim 8 , selected from the group consisting of: 
 N-benzothiazol-2-yl-2-chloro-N-(4-trifluoromethoxy-phenyl)-benzamide;    N-benzothiazol-2-yl-2,4-dichloro-N-(4-trifluoromethoxy-phenyl)-benzamide; and    N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(4-trifluoromethoxy-phenyl)-benzamide;    or a pharmaceutically acceptable salt thereof.    
   
   
       19 . The compound of formula (I) in accordance with  claim 1 , selected from the group consisting of: 
 N-benzothiazol-2-yl-2-chloro-N-(4-dimethylamino-phenyl)-4-fluoro-benzamide;    N-benzothiazol-2-yl-2-chloro-N-(4-dimethylamino-phenyl)-benzamide;    N-benzothiazol-2-yl-2-chloro-N-(4-diethylamino-phenyl)-4-nitro-benzamide; and    N-benzothiazol-2-yl-2,4-dichloro-N-(4-diethylamino-phenyl)-benzamide;    or a pharmaceutically acceptable salt thereof.    
   
   
       20 . The compound of formula (I) in accordance with  claim 1 , selected from the group consisting of: 
 N-benzothiazol-2-yl-2-chloro-N-(4-trifluoromethoxy-phenyl)-benzamide;    N-benzothiazol-2-yl-2,4-dichloro-N-(4-trifluoromethoxy-phenyl)-benzamide; and    N-benzothiazol-2-yl-2-chloro-4-fluoro-N-(4-trifluoromethoxy-phenyl)-benzamide;    or a pharmaceutically acceptable salt thereof.    
   
   
       21 . A pharmaceutical composition comprising a compound of formula (I)  
     
       
         
         
             
             
         
       
       wherein  
       R 1  is phenyl, or phenyl mono-, di- or tri-substituted, independently, by a group selected from the group consisting of halogen, lower alkoxy, lower alkyl, halogenated-lower alkoxy and di-lower alkylamino;  
       R 2  is phenyl, or phenyl mono-, di- or tri-substituted, independently, by a group selected from the group consisting of halogen, halogenated-lower alkyl, nitro and cyano;  
       R 3  is hydrogen, lower alkyl, benzyl, lower alkoxy, halogen, cyano, nitro, amino, —NHSO 2 —R 3a  or —NHCO—R 3b ;  
       R 3a  is lower alkyl, di-lower alkylamino, benzyl, phenyl or phenyl mono-, di- or tri-substituted, independently, by lower alkyl;  
       R 3b  is benzyl, phenyl or phenyl mono-, di- or tri-substituted, independently, by lower alkyl;  
       or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.  
     
   
   
       22 . A method for the treatment of obesity in a patient in need thereof, comprising administering to said patient a compound according to  claim 1  or a pharmaceutically acceptable salt thereof in an amount of from about 1 mg to 1000 mg.  
   
   
       23 . The method according to  claim 22 , wherein the amount is from about 1 mg to 100 mg.

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