Cyclic peptide tyrosine tyrosine compounds as modulators of neuropeptide y receptors

Abstract

The present invention comprises compounds of Formula I.wherein:Z4, Z7, Z9, Z11, Z22, Z23, Z26, Z30, Z34, Z35, p, m, n, q, and BRIDGE are defined in the specification. The invention also relates to pharmaceutical compositions and methods for use thereof. The novel compounds are useful for preventing, treating or ameliorating diseases and disorders, such as obesity, type 2 diabetes, the metabolic syndrome, insulin resistance, and dyslipidemia, among others.

We claim: 
     
         1 . A compound of Formula I, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         p is 0 or 1; 
         m is 0, 1, 2, 3, 4, or 5; 
         n is 1, 2, 3, or 4; 
         q is 0 or 1; provided that q is 1 only when Z 30  is absent; 
         BRIDGE is -Ph-CH 2 —S—, -triazolyl-, —NHC(O)CH 2 S—, —(OCH 2 CH 2 ) 2 NHC(O)CH 2 S, —NHC(O)—, or —CH 2 S—; 
         Z 4  is K, A, E, S, or R; 
         Z 7  is A or K, wherein the amino side chain of said K is optionally acylated with 
       
       
         
           
           
               
               
           
         
         Z 9  is G or K, wherein the amino side chain of said K is optionally acylated with 
       
       
         
           
           
               
               
           
         
         
           wherein t is 0, 1, or 2; 
           u is 0 or 1; and 
           v is 14, 16, or 18; 
         
       
       
         
           
           
               
               
           
         
         Z 11  is D or K, wherein the amino side chain of said K is optionally acylated with 
       
       
         
           
           
               
               
           
         
         
           wherein w is 0, 1, 2, or 4; 
           x is 0 or 1; and 
           y is 14, 16, or 18; 
         
       
       
         
           
           
               
               
           
         
         Z 22  is A or K, wherein the amino side chain of said K is optionally acylated with 
       
       
         
           
           
               
               
           
         
         Z 23  is S or K, wherein the amino side chain of said K is optionally acylated with 
       
       
         
           
           
               
               
           
         
         Z 26  is A or H; 
         Z 30  is L, W, absent, or K, provided that Z 30  is absent only when q is 1, wherein the amino side chain of said K is optionally acylated with 
       
       
         
           
           
               
               
           
         
         
           wherein r is 0, 1, or 2; 
           s is 0 or 1; and 
           z is 14, 16, or 18; or 
         
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         Z 34  is 
       
       
         
           
           
               
               
           
         
         Z 35  is 
       
       
         
           
           
               
               
           
         
         wherein, at least one of Z 7 , Z 9 , Z 11 , Z 22 , Z 23 , or Z 30  is K. 
       
     
     
         2 . A compound of  claim 1  wherein
 m is 0, 1, 2, or 3; 
 n is 1, 2, or 4; 
 Z 7  is A or K, wherein the amino side chain of said K is acylated with 
 
       
         
           
           
               
               
           
         
         Z 9  is G or K, wherein the amino side chain of said K is optionally acylated with 
       
       
         
           
           
               
               
           
         
         
           wherein t is 0; 
           u is 1; and 
           v is 14; 
         
         Z 11  is D or K, wherein the amino side chain of said K is optionally acylated with 
       
       
         
           
           
               
               
           
         
         
           wherein w is 0, or 4; 
           x is 1; and 
           y is 14; 
         
       
       
         
           
           
               
               
           
         
         Z 22  is A or K, wherein the amino side chain of said K is optionally acylated with 
       
       
         
           
           
               
               
           
         
         Z 23  is S or K, wherein the amino side chain of said K is optionally acylated with 
       
       
         
           
           
               
               
           
         
         Z 30  is L, W, absent, or K, provided that Z 30  is absent only when q is 1, wherein the amino side chain of said K is optionally acylated with 
       
       
         
           
           
               
               
           
         
         
           wherein r is 0, or 2; 
           s is 1; and 
           z is 14, 16, or 18; or 
         
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         3 . A compound of  claim 1  selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO:110, or a pharmaceutically acceptable salt thereof. 
     
     
         4 . The compound of  claim 1  selected from the group consisting of SEQ ID NO: 4-8, 10, 11, 13-68, and 72. 
     
     
         5 . The compound of  claim 4  selected from the group consisting of SEQ ID NO: 23, 24, 27, 42, 44, 47, 48, 50, 68, and 72. 
     
     
         6 . A pharmaceutical composition comprising the compound of  claim 1 . 
     
     
         7 . The pharmaceutical composition of  claim 6 , further comprise at least one antidiabetic agent. 
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein said antidiabetic agent is a glucagon-like-peptide-1 receptor modulator. 
     
     
         9 . A method for preventing, treating or ameliorating obesity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 6 . 
     
     
         10 . A method for preventing, treating or ameliorating a metabolic disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 6 . 
     
     
         11 . The method of  claim 10  wherein said metabolic disorder is selected from the group consisting of obesity, type 2 diabetes, metabolic syndrome, insulin resistance and dyslipidemia. 
     
     
         12 . The method of  claim 11 , wherein said metabolic disorder is type 2 diabetes. 
     
     
         13 . A method for reducing food intake in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 6 . 
     
     
         14 . A method for modulating Y2 receptor activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 6 .