Synthesis of Beta-Arrestin Effectors

Abstract

Embodiments disclosed herein provide compounds and methods for preparing Beta-Arrestin Effectors.

1 . A method of preparing a compound of Formula 1A 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, solvate, or hydrate thereof, the method comprising deprotecting a compound of Formula M 
       
         
           
           
               
               
           
         
         wherein 
         P 1  is a nitrogen protecting group, Cbz, Fmoc, Boc, Alloc, or TFA; 
         P 2  is H or a guanidine protecting group; 
         P 3  is H or a guanidine protecting group; 
         P 5  is H, tBu, Bom, TBS, allyl, or Bn; 
         P 8  is H, trityl, tBu, Born, or TBS; 
         R 9  is H or methyl; 
         R 10  is H, Me, Et, tBu, Bn, or TMS; 
         A 1  is H, OH, F, NO 2 , Cl, CH 3 , or Br; 
         A 2  is H, OH, F, NO 2 , Cl, CH 3 , or Br; 
         A 3  is H, OH, F, NO 2 , Cl, CH 3 , or Br; and 
         A 4  is H, OH, F, NO 2 , Cl, CH 3 , or Br. 
       
     
     
         2 . The method of  claim 1 , wherein the deprotecting comprises hydrogenation in a solution of acetic acid. 
     
     
         3 . The method of  claim 1 , wherein A 1 , A 2 , A 3 , A 4 , are H and R 9  is methyl. 
     
     
         4 . The method of  claim 1 , further comprising:
 preparing a compound of Formula M, the method comprising contacting a compound of Formula K with a compound of Formula C under conditions sufficient to produce a compound of Formula M;   preparing a compound of Formula K comprising contacting a compound of Formula A with a compound of Formula B under conditions sufficient to produce a compound of Formula K; or   preparing a compound of Formula M, the method comprising contacting a compound of Formula A with a compound of Formula F under conditions sufficient to produce a compound of Formula M.   
     
     
         5 - 6 . (canceled) 
     
     
         7 . The method of  claim 1 , further comprising preparing a compound of formula F comprising contacting a compound of Formula B and a compound of Formula C under conditions sufficient to produce a compound of Formula F. 
     
     
         8 . A method of preparing a compound of Formula (1): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, solvate, or hydrate thereof, the method comprising
 contacting H-His(HCl)-Pro-(D)-Ala-OR 4  with R 1 -Val-Tyr-Ile-OH under conditions sufficient to produce R 1 Val-Tyr-Ile-His-Pro-(D)-Ala-OR 4 ; 
 deprotecting R 1 -Val-Tyr-Ile-His-Pro-(D)-Ala-OR 4  to produce H-Val(acid)-Tyr-Ile-His-Pro-(D)-Ala-OR 4 ; 
 contacting H-Val(acid)-Tyr-Ile-His-Pro-(D)-Ala-OR 4  with Z-Sar-Arg-OH under conditions sufficient to produce Z-Sar-Arg-Val-Tyr-Ile-His-Pro-(D)-Ala-OR 4 ; and 
 deprotecting Z-Sar-Arg-Val-Tyr-Ile-His-Pro-(D)-Ala-OR 4  to produce 
 
       
         
           
           
               
               
           
         
         wherein 
         Z is carboxybenzyl; 
         R 1  is a nitrogen protecting group; and 
         R 4  is H, Me, Et, tert-Bu, Bn, TMS or other carboxylic acid protecting group, 
       
     
     
         9 . The method of  claim 8  further comprising preparing H-His(HCl)-Pro-(D)-Ala-OR 4 , the method comprising:
 contacting H-Pro(acid)-(D)-Ala-OR 4  with activated Boc-Histidine to form Boc-His-Pro-D-Ala-OBn, followed by deprotection in the presence of HCl or suitable acid to produce H-His(HCl)-Pro-(D)-Ala-OR 4 , 
 wherein: 
 R 1  is a nitrogen protecting group; and 
 R 4  is H, Me, Et, tert-Bu, Bn, TMS or other carboxylic acid protecting group. 
 
     
     
         10 - 11 . (canceled) 
     
     
         12 . The method of  claim 8 , wherein R 4  is Bn. 
     
     
         13 . The method of  claim 8 , wherein R 1  is carboxybenzyl, Fmoc, Boc, allyloxycarbonyl or trifluoroacetyl. 
     
     
         14 - 15 . (canceled) 
     
     
         16 . A method of preparing 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, solvate, or hydrate thereof, the method comprising,
 a) contacting H-His(HCl)-Pro-(D)-Ala-OR 4  with Z-Sar-Arg(NO 2 )-Val-Tyr-Ile-OH under conditions sufficient to produce Z-Sar-Arg(NO 2 )-Val-Tyr-Ile-His-Pro-(D)-Ala-OR 4 ; and 
 b) hydrogenating Z-Sar-Arg(NO 2 )-Val-Tyr-Ile-His-Pro-(D)-Ala-OR 4  to produce 
 
       
         
           
           
               
               
           
         
       
       wherein 
       Z is carboxybenzyl; and 
       R 4  is H, Me, Et, tert-Bu, Bn, TMS or other carboxylic acid protecting group. 
     
     
         17 - 22 . (canceled) 
     
     
         23 . A method of preparing Sar-Arg-Val-Ww-Zz-His-Pro-(D)-Ala
 a) contacting H-His(HCl)-Pro-(D)-Ala-OR 4  with R 1 -Val-Ww-Zz-OH under conditions sufficient to produce R 1 -Val-Ww-Zz-His-Pro-(D)-Ala-OR 4 ;   b) treating R 1 -Val-Ww-Zz-His-Pro-(D)-Ala-OR 4  with an acid to produce H-Val(HCl)-WW-Zz-His-Pro-(D)-Ala-OR 4 ;   c) contacting H-Val(HCl)-WW-Zz-His-Pro-(D)-Ala-OR 4  with   
       
         
           
             
               
                 Z 
                  
                 
                   - 
                 
                  
                 Sar 
                  
                 
                   - 
                 
                  
                 Arg 
                  
                 
                   - 
                 
                  
                 OH 
               
               4 
             
           
         
       
       under conditions sufficient to produce Z-Sar-Arg-Val-Ww-Zz-His-Pro-(D)-Ala-OR 4 ; and
 d) hydrogenating Z-Sar-Arg-Val-Ww-Zz-His-Pro-(D)-Ala-OR 4  to produce Sar-Arg-Val-Ww-Zz-His-Pro-(D)-Ala, wherein: 
 Z is carboxybenzyl; 
 
       R 1  is a nitrogen protecting group;
 R 4  is H, Me, Et, tert-Bu, Bn, TMS or other carboxylic acid protecting group 
 Ww is L-Tyr, 3-hydroxy-L-Tyr, 3-fluoro-L-Tyr, 2,6-difluoro-L-Tyr, 3-nitro-L-Tyr, 3,5-dinitro-L-tyrosine, 3-chloro-L-tyrosine, 2,6-dimethyl-L-tyrosine, 4-fluorophenyl-L-alanine, 3,5-dibromo-L-tyrosine, or O-allyl-L-tyrosine; and 
 Zz is L-Val or L-Ile. 
 
     
     
         24 - 26 . (canceled) 
     
     
         27 . The method of  claim 23 , wherein R 4  is Bn. 
     
     
         28 - 31 . (canceled) 
     
     
         32 . A method for preparing a compound of Formula 1, or a pharmaceutically acceptable salt thereof, solvate, or hydrate thereof, the method comprising deprotecting a compound of formula H: 
       
         
           
           
               
               
           
         
         wherein
 P 1  is a nitrogen protecting group; 
 P 2  is H or a guanidine protecting group; 
 P 3  is H or a guanidine protecting group; 
 P 5  is H, tBu, Bom, TBS, allyl, or Bn; 
 P 8  is H, trityl, tBu, Bom, or TBS; and 
 R 10  is H, Me, Et, tBu, Bn, or TMS. 
 
       
     
     
         33 . The method of  claim 32 , wherein P 1  is Cbz, P 2  is H, P 3  is H, P 5  is H, P 8  is H and R 10  is Bn. 
     
     
         34 - 35 . (canceled) 
     
     
         36 . The method of  claim 32 , further comprising preparing a compound of Formula H, the method comprising contacting a compound of Formula A, 
       
         
           
           
               
               
           
         
         wherein 
         P 1  is a nitrogen protecting group; 
         P 2  is H or a guanidine protecting group; 
         P 3  is H or a guanidine protecting group; and 
         R 5  is H, Me, Et, tert-Bu, Bn, or TMS, 
         with a compound of Formula E, 
       
       
         
           
           
               
               
           
         
       
       wherein
 P 4  is H, Cbz, Fmoc, Boc, Alloc, or TFA; 
 P 5  is H, tBu, Bom, TBS, allyl, or Bn; 
 P 8  is H, trityl, tBu, Bom, or TBS; 
 R 10  is H, Me, Et, tBu, Bn, or TMS, 
 under conditions sufficient to produce a compound of Formula H. 
 
     
     
         37 . A method of  claim 36 , wherein P 1  is Cbz, P 2  is H, P 3  is H, P 4  is H, P 5  is H, P 8  is H and R 10  is Bn. 
     
     
         38 . The method of  claim 32 , further comprising preparing a compound of Formula E, the method comprising contacting a compound of Formula B, 
       
         
           
           
               
               
           
         
         wherein
 P 4  is H, Cbz, Fmoc, Boc, Alloc, or TFA, 
 P 5  is tBu, Bom, TBS, allyl, or Bn; 
 R 8  is H, Me, Et, tBu, Bn, or TMS, 
 
         with a compound of Formula C 
       
       
         
           
           
               
               
           
         
         wherein
 P 6  is Cbz, Fmoc, Boc, Alloc, or TFA; 
 P 8  is trityl, tBu, Born, or TBS; and 
 R 10  is H, Me, Et, tBu, Bn, or TMS, to form a compound of formula E. 
 
       
     
     
         39 . The method of  claim 38 , wherein P 4  is Boc, P 5  is H, P 6  is H, P 8  is H, R 8  is H and R 10  is Bn. 
     
     
         40 . The method of  claim 32 , further comprising preparing a compound of Formula H, the method comprising contacting a compound of Formula J 
       
         
           
           
               
               
           
         
         wherein
 P 1  is a nitrogen protecting group; 
 P 2  is H or a guanidine protecting group; 
 P 3  is H or a guanidine protecting group; 
 P 5  is H, tBu, Bom, TBS, allyl, or Bn; and 
 R 8  is H, Me, Et, tBu, Bn, or TMS, with a compound of Formula C, to give a compound of Formula H. 
 
       
     
     
         41 . The method of  claim 40 , wherein P 1  is Cbz, P 2  is H, P 3  is NO 2 , P 5  is H, R 8  is H, P 6  is H, P 8  is H, and R 10  is Bn. 
     
     
         42 - 73 . (canceled)