US2002007071A1PendingUtilityA1

Benzimidzolyl neuropeptide Y receptor antagonists

51
Priority: Jan 9, 1996Filed: Nov 30, 2000Published: Jan 17, 2002
Est. expiryJan 9, 2016(expired)· nominal 20-yr term from priority
Inventors:Thomas C. BrittonRobert F. Bruns, Jr.Buddy Eugene CantrellPhilip Arthur HipskindKaren L. LobbJames A. NixonPaul Leslie OrnsteinEdward C. R. SmithHamideh ZarrinmayehDennis M. ZimmermanAnne Marie NunesJames Jeffry Howbert
A61K 31/454C07D 235/12C07D 401/06C07D 401/12C07D 401/14C07D 403/12C07D 417/14
51
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Claims

Abstract

This invention provides a series of substituted benzimidazoles which are useful in treating or preventing a condition associated with an excess of neuropeptide Y. This invention also provides methods employing these substituted benzimidazoles as well as pharmaceutical formulations with comprise as an active ingredient one or more of these compounds.

Claims

exact text as granted — not AI-modified
We claim:  
     
         1 . A method of treating or preventing a physiological disorder associated with an excess of neuropeptide Y, which method comprises administering to a mammal in need of said treatment an effective amount of a compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is phenyl, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, phenyl(C 1 -C 6  alkylenyl)-, phenyl(C 1 -C 6  alkoxy), phenoxy(C 1 -C 6  alkylenyl)-, phenyl(C 1 -C 6  alkoxy)-(C 1 -C 6  alkylenyl)-, naphthyl, naphthyl(C 1 -C 6  alkylenyl)-, naphthyl(C 1 -C 6  alkoxy), naphthyloxy(C 1 -C 6  alkylenyl)-, or naphthyl(Cl -C 6  alkoxy)-(C 1 -C 6  alkylenyl)-, 
 any one of which phenyl, C 3 -C 8  cycloalkyl, phenoxy, naphthyl, or naphthyloxy moieties may be substituted with one or groups selected from the group consisting of halo, trifluoromethyl, C 1 -C 6  alkyl, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C 1 -C 6  alkoxy, C 1 -C 6  alkylthio, C 1 -C 6  alkylamino, heterocyclic, unsaturated heterocyclic, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, phenyl, phenoxy, phenyl(C 1 -C 6  alkylenyl)-, phenyl(C 1 -C 6  alkoxy)-, benzoyl, phenyl(C 2 -C 7  alkanoyl)-, and phenyl(C 2 -C 7  alkanoyloxy)-;  
 
 R 2  is C 1 -C 12  alkyl, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C 2 -C 7  alkanoyl, C 1 -C 6  alkoxy, heterocyclic(C 1 -C 6  alkylenyl)-, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, unsaturated heterocyclic(C 1 -C 6  alkylenyl)-, heterocyclic(C 1 -C 6  alkoxy)-, unsaturated heterocyclic(C 1 -C 6  alkoxy)-, phenyl, phenyl(C 1 -C 6  alkylenyl)-, naphthyl, naphthyl(C 1 -C 6  alkylenyl)-, phenoxy(C 1 -C 6  alkylenyl)-, naphthyloxy(C 1 -C 6  alkylenyl)-, benzoyl(C 1 -C 6  alkylenyl)-, C 2 -C 7  alkenyl, C 2 -C 7  carbamoyl, C 2 -C 7  amido, C 1 -C 6  alkoxycarbonyl-, or C 1 -C 6  haloalkyl, 
 any one of which C 1 -C 12  alkyl, phenyl, naphthyl, phenoxy, naphthyloxy, benzoyl, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, heterocyclic(C 1 -C 6  alkoxy)-, unsaturated heterocyclic(C 1 -C 6  alkoxy)-, heterocyclic, or unsaturated heterocyclic moieties may be substituted with one or more groups selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkoxy, phenyl, naphthyl, phenyl(C 1 -C 6  alkylenyl)-, naphthyl(C 1 -C 6  alkylenyl)-, halo, trifluoromethyl, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C 1 -C 6  alkoxy, heterocyclic, unsaturated heterocyclic, heterocyclic(C 1 -C 6  alkylenyl)-, unsaturated heterocyclic( C 1 -C 6  alkylenyl)-, heterocyclic(C 1 -C 6  alkoxy)-, unsaturated heterocyclic(C 1 -C 6  alkoxy)-, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, C 2 -C 7  alkanoyl, C 2 -C 7  alkanoyloxy, C 1 -C 6  alkylamino, C 1 -C 6  alkylthio, C 1 -C 6  haloalkyl, amino, nitro, and hydroxy,  
 or R 2  may also be —(CH 2 ) n —NR 7 R 8 , where,  
 
 n is 0 to 10, and  
 R 7  and R 8  are independently hydrogen, C 1 -C 6  alkyl, C 2 -C 7  alkanoyl, C 1 -C 6  alkoxy, heterocyclic(C 1 -C 6  alkylenyl)-, unsaturated heterocyclic(C 1 -C 6  alkylenyl)-, phenyl, phenyl(C 1 -C 6  alkylenyl)-, naphthyl, naphthyl(C 1 -C 6  alkylenyl)-, phenoxy(C 1 -C 6  alkylenyl)-, naphthyloxy(C 1 -C 6  alkylenyl)-, benzoyl(C 1 -C 6  alkylenyl)-, heterocyclic(C 1 -C 6  alkoxy)-, unsaturated heterocyclic(C 1 -C 6  alkoxy)-, C 1 -C 6  haloalkyl, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C 3 -C 8  cycloalkenyl, or C 3 -C 8  cycloalkyl, 
 any one of which phenyl, naphthyl, phenoxy, naphthyloxy, C 3 -C 8  cycloalkyl, benzoyl, heterocyclic, unsaturated heterocyclic, heterocyclic(C 1 -C 6  alkoxy)-, or unsaturated heterocyclic(C 1 -C 6  alkoxy)- moieties may be substituted with one or more groups selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo, trifluoromethyl, alkoxy, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, heterocyclic, unsaturated heterocyclic, heterocyclic(C 1 -C 6  alkylenyl)-, unsaturated heterocyclic(C 1 -C 6  alkylenyl)-, heterocyclic(C 1 -C 6  alkoxy)-, unsaturated heterocyclic(C 1 -C 6  alkoxy)-, C 2 -C 7  alkanoyl, C 2 -C 7  alkanoyloxy, C 1 -C 6  alkylamino, C 1 -C 6  alkylthio, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C 1 -C 6  haloalkyl, amino, nitro, and hydroxy;  
 and  
 
 R 3 , R 4 , R 5 , and R 6  are independently hydrogen, halo, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C 2 -C 7  alkanoyl, C 2 -C 7  alkanoyloxy, C 1 -C 6  alkylamino, C 1 -C 6  alkylthio, benzoyl, phenoxy, phenyl(C 1 -C 6  alkylenyl)-, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, phenyl(C 1 -C 6  alkoxy)-, phenyl(C 1 -C 6  alkyleneamino)-, phenyl(C 1 -C 6  alkyleneamino)-, phenyl(C 2 -C 7  alkanoyl)-, phenyl(C 2 -C 7  alkanoyloxy)-, heterocyclic, unsaturated heterocyclic, heterocyclic(C 1 -C 6  alkylenyl)-, heterocyclic(C 1 -C 6  alkoxy)-, unsaturated heterocyclic(C 1 -C 6  alkylenyl)-, unsaturated heterocyclic(C 1 -C 6  alkoxy)-, amino, nitro, hydroxy, trifluoromethyl, or —(CH 2 ) n —NR 7 R 8 ;  
 or a pharmaceutically acceptable salt or solvate thereof.  
 
     
     
         2 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is phenyl, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, phenyl(C 1 -C 6  alkylenyl)-, phenyl(C 1 -C 6  alkoxy), phenoxy(C 1 -C 6  alkylenyl)-, phenyl(C 1 -C 6  alkoxy)-(C 1 -C 6  alkylenyl)-, naphthyl, naphthyl(C 1 -C 6  alkylenyl)-, naphthyl(C 1 -C 6  alkoxy), naphthyloxy(C 1 -C 6  alkylenyl)-, or naphthyl(C 1 -C 6  alkoxy)-(C 1 -C 6  alkylenyl)-, 
 any one of which phenyl, C 3 -C 8  cycloalkyl, phenoxy, naphthyl, or naphthyloxy moieties may be substituted with one or groups selected from the group consisting of halo, trifluoromethyl, C 1 -C 6  alkyl, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C 1 -C 6  alkoxy, C 1 -C 6  alkylthio, C 1 -C 6  alkylamino, heterocyclic, unsaturated heterocyclic, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, phenyl, phenoxy, phenyl(C 1 -C 6  alkylenyl)-, phenyl(C 1 -C 6  alkoxy)-, benzoyl, phenyl(C 2 -C 7  alkanoyl)-, and phenyl(C 2 -C 7  alkanoyloxy)-;  
 
 R 2  is C 1 -C 12  alkyl, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C 2 -C 7  alkanoyl, C 1 -C 6  alkoxy, heterocyclic(C 1 -C 6  alkylenyl)-, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, unsaturated heterocyclic(C 1 -C 6  alkylenyl)-, heterocyclic(C 1 -C 6  alkoxy)-, unsaturated heterocyclic(C 1 -C 6  alkoxy)-, phenyl, phenyl(C 1 -C 6  alkylenyl)-, naphthyl, naphthyl(C 1 -C 6  alkylenyl)-, phenoxy(C 1 -C 6  alkylenyl)-, naphthyloxy(C 1 -C 6  alkylenyl)-, benzoyl(C 1 -C 6  alkylenyl)-, C 2 -C 7  alkenyl, C 2 -C 7  carbamoyl, C 2 -C 7  amido, C 1 -C 6  alkoxycarbonyl-, or C 1 -C 6  haloalkyl, 
 any one of which C 1 -C 12  alkyl, phenyl, naphthyl, phenoxy, naphthyloxy, benzoyl, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, heterocyclic(C 1 -C 6  alkoxy)-, unsaturated heterocyclic(C 1 -C 6  alkoxy)-, heterocyclic, or unsaturated heterocyclic moieties may be substituted with one or more groups selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkoxy, phenyl, naphthyl, phenyl(C 1 -C 6  alkylenyl)-, naphthyl(C 1 -C 6  alkylenyl)-, halo, trifluoromethyl, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C 1 -C 6  alkoxy, heterocyclic, unsaturated heterocyclic, heterocyclic(C 1 -C 6  alkylenyl)-, unsaturated heterocyclic(C 1 -C 6  alkylenyl)-, heterocyclic(C 1 -C 6  alkoxy)-, unsaturated heterocyclic(C 1 -C 6  alkoxy)-, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, C 2 -C 7  alkanoyl, C 2 -C 7  alkanoyloxy, C 1 -C 6  alkylamino, C 1 -C 6  alkylthio, C 1 -C 6  haloalkyl, amino, nitro, and hydroxy,  
 or R 2  may also be —(CH 2 ) n —NR 7 R 8 , where,  
 
 n is 0 to 10, and  
 R 7  and R 8  are independently hydrogen, C 1 -C 6  alkyl, C 2 -C 7  alkanoyl, C 1 -C 6  alkoxy, heterocyclic(C 1 -C 6  alkylenyl)-, unsaturated heterocyclic(C 1 -C 6  alkylenyl)-, phenyl, phenyl(C 1 -C 6  alkylenyl)-, naphthyl, naphthyl(C 1 -C 6  alkylenyl)-, phenoxy(C 1 -C 6  alkylenyl)-, naphthyloxy(C 1 -C 6  alkylenyl)-, benzoyl(C 1 -C 6  alkylenyl)-, heterocyclic(C 1 -C 6  alkoxy)-, unsaturated heterocyclic(C 1 -C 6  alkoxy)-, C 1 -C 6  haloalkyl, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C 3 -C 8  cycloalkenyl, or C 3 -C 8  cycloalkyl, 
 any one of which phenyl, naphthyl, phenoxy, naphthyloxy, C 3 -C 8  cycloalkyl, benzoyl, heterocyclic, unsaturated heterocyclic, heterocyclic(C 1 -C 6  alkoxy)-, or unsaturated heterocyclic(C 1 -C 6  alkoxy)- moieties may be substituted with one or more groups selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo, trifluoromethyl, alkoxy, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, heterocyclic, unsaturated heterocyclic, heterocyclic(C 1 -C 6  alkylenyl)-, unsaturated heterocyclic(C 1 -C 6  alkylenyl)-, heterocyclic(C 1 -C 6  alkoxy)-, unsaturated heterocyclic(C 1 -C 6  alkoxy)-, C 2 -C 7  alkanoyl, C 2 -C 7  alkanoyloxy, C 1 -C 6  alkylamino, C 1 -C 6  alkylthio, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C 1 -C 6  haloalkyl, amino, nitro, and hydroxy;  
 and  
 
 R 3 , R 4 , R 5 , and R 6  are independently hydrogen, halo, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C 2 -C 7  alkanoyl, C 2 -C 7  alkanoyloxy, C 1 -C 6  alkylamino, C 1 -C 6  alkylthio, benzoyl, phenoxy, phenyl(C 1 -C 6  alkylenyl)-, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, phenyl(C 1 -C 6  alkoxy)-, phenyl(C 1 -C 6  alkyleneamino)-, phenyl(C 1 -C 6  alkyleneamino)-, phenyl(C 2 -C 7  alkanoyl)-, phenyl(C 2 -C 7  alkanoyloxy)-, heterocyclic, unsaturated heterocyclic, heterocyclic(C 1 -C 6  alkylenyl)-, heterocyclic(C 1 -C 6  alkoxy)-, unsaturated heterocyclic(C 1 -C 6  alkylenyl)-, unsaturated heterocyclic(C 1 -C 6  alkoxy)-, amino, nitro, hydroxy, trifluoromethyl, or —(CH 2 ) n —NR 7 R 8 ; or a salt or solvate thereof  
 
     
     
         3 . A pharmaceutical formulation comprising a compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is phenyl, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, phenyl(C 1 -C 6  alkylenyl)-, phenyl(C 1 -C 6  alkoxy), phenoxy(C 1 -C 6  alkylenyl)-, phenyl(C 1 -C 6  alkoxy)-(C 1 -C 6  alkylenyl)-, naphthyl, naphthyl(C 1 -C 6  alkylenyl)-, naphthyl(C 1 -C 6  alkoxy), naphthyloxy(C 1 -C 6  alkylenyl)-, or naphthyl(C 1 -C 6  alkoxy)-(C 1 -C 6  alkylenyl)-, 
 any one of which phenyl, C 3 -C 8  cycloalkyl, phenoxy, naphthyl, or naphthyloxy moieties may be substituted with one or groups selected from the group consisting of halo, trifluoromethyl, C 1 -C 6  alkyl, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C 1 -C 6  alkoxy, C 1 -C 6  alkylthio, C 1 -C 6  alkylamino, heterocyclic, unsaturated heterocyclic, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, phenyl, phenoxy, phenyl(C 1 -C 6  alkylenyl)-, phenyl(C 1 -C 6  alkoxy)-, benzoyl, phenyl(C 2 -C 7  alkanoyl)-, and phenyl(C 2 -C 7  alkanoyloxy)-;  
 
 R 2  is C 1 -C 12  alkyl, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C 2 -C 7  alkanoyl, C 1 -C 6  alkoxy, heterocyclic(C 1 -C 6  alkylenyl)-, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, unsaturated heterocyclic(C 1 -C 6  alkylenyl)-, heterocyclic(C 1 -C 6  alkoxy)-, unsaturated heterocyclic(C 1 -C 6  alkoxy)-, phenyl, phenyl(C 1 -C 6  alkylenyl)-, naphthyl, naphthyl(C 1 -C 6  alkylenyl)-, phenoxy(C 1 -C 6  alkylenyl)-, naphthyloxy(C 1 -C 6  alkylenyl)-, benzoyl(C 1 -C 6  alkylenyl)-, C 2 -C 7  alkenyl, C 2 -C 7  carbamoyl, C 2 -C 7  amido, C 1 -C 6  alkoxycarbonyl-, or C 1 -C 6  haloalkyl, 
 any one of which C 1 -C 12  alkyl, phenyl, naphthyl, phenoxy, naphthyloxy, benzoyl, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, heterocyclic(C 1 -C 6  alkoxy)-, unsaturated heterocyclic(C 1 -C 6  alkoxy)-, heterocyclic, or unsaturated heterocyclic moieties may be substituted with one or more groups selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkoxy, phenyl, naphthyl, phenyl(C 1 -C 6  alkylenyl)-, naphthyl(C 1 -C 6  alkylenyl)-, halo, trifluoromethyl, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C 1 -C 6  alkoxy, heterocyclic, unsaturated heterocyclic, heterocyclic(C 1 -C 6  alkylenyl)-, unsaturated heterocyclic(C 1 -C 6  alkylenyl)-, heterocyclic(C 1 -C 6  alkoxy)-, unsaturated heterocyclic(C 1 -C 6  alkoxy)-, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, C 2 -C 7  alkanoyl, C 2 -C 7  alkanoyloxy, C 1 -C 6  alkylamino, C 1 -C 6  alkylthio, C 1 -C 6  haloalkyl, amino, nitro, and hydroxy,  
 or R 2  may also be —(CH 2 ) n —NR 7 R 8 , where,  
 
 n is 0 to 10, and  
 R 7  and R 8  are independently hydrogen, C 1 -C 6  alkyl, C 2 -C 7  alkanoyl, C 1 -C 6  alkoxy, heterocyclic(C 1 -C 6  alkylenyl)-, unsaturated heterocyclic(C 1 -C 6  alkylenyl)-, phenyl, phenyl(C 1 -C 6  alkylenyl)-, naphthyl, naphthyl(C 1 -C 6  alkylenyl)-, phenoxy(C 1 -C 6  alkylenyl)-, naphthyloxy(C 1 -C 6  alkylenyl)-, benzoyl(C 1 -C 6  alkylenyl)-, heterocyclic(C 1 -C 6  alkoxy)-, unsaturated heterocyclic(C 1 -C 6  alkoxy)-, C 1 -C 6  haloalkyl, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C 3 -C 8  cycloalkenyl, or C 3 -C 8  cycloalkyl, 
 any one of which phenyl, naphthyl, phenoxy, naphthyloxy, C 3 -C 8  cycloalkyl, benzoyl, heterocyclic, unsaturated heterocyclic, heterocyclic(C 1 -C 6  alkoxy)-, or unsaturated heterocyclic(C 1 -C 6  alkoxy)- moieties may be substituted with one or more groups selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo, trifluoromethyl, alkoxy, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, heterocyclic, unsaturated heterocyclic, heterocyclic(C 1 -C 6  alkylenyl)-, unsaturated heterocyclic(C 1 -C 6  alkylenyl)-, heterocyclic(C 1 -C 6  alkoxy)-, unsaturated heterocyclic(C 1 -C 6  alkoxy)-, C 2 -C 7  alkanoyl, C 2 -C 7  alkanoyloxy, C 1 -C 6  alkylamino, C 1 -C 6  alkylthio, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C 1 -C 6  haloalkyl, amino, nitro, and hydroxy;  
 and  
 
 R 3 , R 4 , R 5 , and R 6  are independently hydrogen, halo, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C 2 -C 7  alkanoyl, C 2 -C 7  alkanoyloxy, C 1 -C 6  alkylamino, C 1 -C 6  alkylthio, benzoyl, phenoxy, phenyl(C 1 -C 6  alkylenyl)-, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkenyl, phenyl(C 1 -C 6  alkoxy)-, phenyl(C 1 -C 6  alkyleneamino)-, phenyl(C 1 -C 6  alkyleneamino)-, phenyl(C 2 -C 7  alkanoyl)-, phenyl(C 2 -C 7  alkanoyloxy)-, heterocyclic, unsaturated heterocyclic, heterocyclic(C 1 -C 6  alkylenyl)-, heterocyclic(C 1 -C 6  alkoxy)-, unsaturated heterocyclic(C 1 -C 6  alkylenyl)-, unsaturated heterocyclic(C 1 -C 6  alkoxy)-, amino, nitro, hydroxy, trifluoromethyl, or —(CH 2 ) n —NR 7 R 8 ;  
 or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more pharmaceutically acceptable carriers, excipients, or diluents therefore.

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