Orally Active Melanocortin Receptor-4 Compounds

Abstract

A compound of the formulawhere R1, R2, R3, R4, R5, R6a, and R6b are as defined in the specification and claims, or an enantiomer, stereoisomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the use thereof in the treatment of diseases, disorders, syndromes and conditions responsive to modulation of a melanocortin receptor.

What is claimed is: 
     
         1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         or an enantiomer, stereoisomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 1  is —R 7  or —NR 8 R 9 ; 
         R 2  and R 3  are each independently a C 1  to C 17  linear or branched alkyl, cycloalkyl, alkylcycloalkyl, aryl, and alkylaryl, optionally substituted with one or more substituents, and when one or more substituents are present, such substituents are the same or different and independently comprising oxo, carboxy, amino, monosubstituted amino, disubstituted amino, or nitro, and when R 2  and R 3  are different, including all sterioisomers thereof, provided that taken together R 2  and R 3  can form cycloalkyl, optionally substituted, or alternatively that taken together one of R 2  and R 3  and one of R 8  and R 9  comprising a part of R 4  can form heterocycloalkyl, optionally substituted; 
         R 4  is —OH, —OR 7 , or —NR 8 R 9 ; 
         R 5  is
 H, 
 a C 1  to C 17  linear or branched alkyl, cycloalkyl, or alkylcycloalkyl, 
 a C 1  to C 7  acyl group, 
 sulfonyl, 
 carbamoyl, or 
 urea, 
 in each instance optionally substituted with one or more substituents, and when one or more substituents are present, such substituents are the same or different and independently halo, amino, monosubstituted amino, disubstituted amino, hydroxy, or carboxy; 
 
         R 6a  and R 6b  are each independently H, alkyl, haloalkyl, cycloalkyl, alkoxy, alkythio, halo, nitro, acyl, cyano, aryl, alkylaryl, aryloxy, oxo, amino, monosubstituted amino, disubstituted amino, sulfonamide, hydroxy, carboxy, or alkoxy-carbonyl; 
         R 7  is a C 1  to C 17  linear or branched alkyl, cycloalkyl, or alkylcycloalkyl, optionally substituted with one or more substituents comprising oxo, terminal amide, amino, monosubstituted amino, disubstituted amino, or nitrile; and 
         R 8  and R 9  are each independently H or a C 1  to C 17  linear or branched alkyl, cycloalkyl, or alkylcycloalkyl, optionally substituted with one or more substituents comprising oxo, amino, monosubstituted amino, disubstituted amino, or nitrile, provided that R 8  and R 9  taken together can form heterocycloakyl, optionally substituted. 
       
     
     
         2 . The compound of  claim 1  in which R 1  is:
 —CH 3 , 
 —CH 2 —CH 3 , or 
 —CH—(CH 3 ) 2 . 
 
     
     
         3 . The compound of  claim 1  in which R 5  is:
 —H, 
 —CH 3 , 
 —CH 2 —CH 3 , 
 —CH—(CH 3 ) 2 , 
 —CH 2 —CH—(CH 3 ) 2 , 
 —C(═O)—CH 3 , 
 —C(═O)—O—CH 2 —CH 3 , 
 —C(═O)—NH—CH 2 —CH 3 , 
 —C(═O)—CH—(CH 3 ) 2 , or 
 —methyl-cyclopropane. 
 
     
     
         4 . The compound of  claim 1  in which at least one of R 6a  and R 6b  are halo. 
     
     
         5 . The compound of  claim 4  in which one of R 6a  and R 6b  are halo. 
     
     
         6 . The compound of  claim 1  wherein:
 R 1  is —R 7 ; 
 R 2  and R 3  are each independently a C 1  to C 17  linear alkyl; 
 R 4  is —NR 8 R 9 ; 
 R 5  is a C 1  to C 17  linear or branched alkyl; 
 R 6a  and R 6b  are each independently H or halo; 
 R 7  is a C 1  to C 17  linear or branched alkyl; and 
 R 8  and R 9  are each independently H or a C 1  to C 17  linear or branched alkyl. 
 
     
     
         7 . The compound of  claim 1  wherein:
 R 1  is —R 7 ; 
 R 2  and R 3  are each independently a C 1  to C 17  linear alkyl which taken together form cycloalkyl; 
 R 4  is —NR 8 R 9 ; 
 R 5  is a C 1  to C 17  linear or branched alkyl; 
 R 6a  and R 6b  are each independently H or halo; 
 R 7  is a C 1  to C 17  linear or branched alkyl; and 
 R 8  and R 9  are each independently H or a C 1  to C 17  linear or branched alkyl. 
 
     
     
         8 . The compound of  claim 1  which is a compound of formula II: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 8  in which R 1  is:
 —CH 3 , 
 —CH 2 —CH 3 , or 
 —CH—(CH 3 ) 2 . 
 
     
     
         10 . The compound of  claim 8  in which R 5  is:
 —H, 
 —H 3 , 
 —CH 2 —CH 3 , 
 —CH—(CH 3 ) 2 , 
 —CH 2 —CH—(CH 3 ) 2 , 
 —C(═O)—CH 3 , 
 —C(═O)—O—CH 2 —CH 3 , 
 —C(═O)—NH—CH 2 —CH 3 , 
 —C(═O)—CH—(CH 3 ) 2 , or 
 methyl-cyclopropane. 
 
     
     
         11 . The compound of  claim 8  in which at least one of R 6a  and R 6b  are halo. 
     
     
         12 . The compound of  claim 1  in which one of R 6a  and R 6b  are halo. 
     
     
         13 . The compound of  claim 8  wherein:
 R 1  is —R 7 ; 
 R 2  and R 3  are each independently a C 1  to C 17  linear alkyl; 
 R 4  is —NR 8 R 9 ; 
 R 5  is a C 1  to C 17  linear or branched alkyl; 
 R 6a  and R 6b  are each independently H or halo; 
 R 7  is a C 1  to C 17  linear or branched alkyl; and 
 R 8  and R 9  are each independently H or a C 1  to C 17  linear or branched alkyl. 
 
     
     
         14 . The compound of  claim 8  wherein:
 R 1  is —R 7 ; 
 R 2  and R 3  are each independently a C 1  to C 17  linear alkyl which taken together form cycloalkyl; 
 R 4  is —NR 8 R 9 ; 
 R 5  is a C 1  to C 17  linear or branched alkyl; 
 R 6a  and R 6b  are each independently H or halo; 
 R 7  is a C 1  to C 17  linear or branched alkyl; and 
 R 8  and R 9  are each independently H or a C 1  to C 17  linear or branched alkyl. 
 
     
     
         15 . The compound of  claim 1  which is a compound of formula III: 
       
         
           
           
               
               
           
         
         or an enantiomer, stereoisomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof. 
       
     
     
         16 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         17 . The pharmaceutical composition of  claim 16 , further comprising at least one additional active pharmaceutical agent. 
     
     
         18 . A method of treating a patient with a disease, disorder, condition or syndrome responsive to modulation of a melanocortin receptor, comprising administration to the patient of a pharmaceutically effective amount of a pharmaceutical composition of  claim 16 . 
     
     
         19 . The method of  claim 18 , wherein the disease, disorder, condition or syndrome responsive to modulation of a melanocortin receptor comprises obesity. 
     
     
         20 . The method of  claim 18 , wherein the disease, disorder, condition or syndrome responsive to modulation of a melanocortin receptor comprises metabolic syndrome. 
     
     
         21 . The method of  claim 18 , wherein the disease, disorder, condition or syndrome responsive to modulation of a melanocortin receptor comprises pro-opiomelanocortin deficiency due to mutations in the POMC gene (POMC heterozygous deficiency obesity), Prader-Willi syndrome, obesity due to MC4r deficiency, leptin deficiency obesity, leptin receptor deficiency obesity, Bardet Biedl syndrome or Alström syndrome.