Chemokine receptor binding heterocyclic compounds with enhanced efficacy

Abstract

The invention relates to heterocyclic compounds consisting of a core nitrogen atom surrounded by three pendant groups, wherein two of the three pendant groups are preferably benzimidazolyl methyl and tetrahydroquinolyl, and the third pendant group contains N and optionally contains additional rings. The compounds bind to chemokine receptors, including CXCR4 and CCR5, and demonstrate protective effects against infection of target cells by a human immunodeficiency virus (HIV).

1 . A method to enhance the population of progenitor and/or stem cells in a subject, the method comprises:
 administering to said subject a compound of the formula   
       
         
           
           
               
               
           
         
       
       or the salts or pro-drug forms thereof; and including any stereoisomeric forms thereof:
 X and Y are independently N or CR 1 ; 
 Z is S, O, NR 1 , or CR 1   2 ; 
 each R 1 -R 6  is independently H or a noninterfering substituent; 
 n1 is 0-4; 
 n2 is 0-1, wherein the * signifies C≡C may be substituted for CR 5 ═CR 5 ; 
 n3 is 0-4; 
 wherein n1+n2+n3 is greater than or equal to 2; 
 b is 0-2; 
 wherein the following combinations of R groups may be coupled to generate a ring, which ring may be saturated or unsaturated: 
 R 2 +R 2    
 one R 2 +R 3    
 R 3 +one R 4 , 
 R 4 +R 4 , 
 one R 5 +another R 5 , 
 one R 5 +one R 6 , and 
 R 6 +R 6 ; 
 wherein the ring may not be aromatic when the participants in ring formation are two R 5 ; and 
 wherein when n2 is 1, neither n1 nor n3 can be 0; 
 in an amount effective to elevate said progenitor and/or stem cell population in said subject. 
 
     
     
         2 . A method of treating a condition modulated by the CXCR4 receptor, CCR5 receptor, or both, in a subject, the method comprising administering to the subject in need thereof an effective amount of a compound of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, and including any stereoisomeric forms thereof, wherein:
 each R 1  is independently H; 
 each R 2  is independently H or alkyl; 
 R 3  is H, alkyl, alkenyl, arylalkyl, or aryl; 
 each R 4  is independently H or alkyl; or the two R 4  groups may be taken together with the ring to which they are attached to form an optionally substituted 6-membered aromatic ring; 
 each R 6  is independently H, arylalkyl, arylacyl, or arylsulfonyl; and 
 n4 is 2-4; 
 
       to thereby treat the subject. 
     
     
         3 . A method of treating a cancer or a condition characterized by angiogenesis, the method comprising administering to a subject in need thereof an effective amount of a compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, and including any stereoisomeric forms thereof, wherein:
 each R 1  is independently H; 
 each R 2  is independently H or alkyl; 
 R 3  is H, alkyl, alkenyl, arylalkyl, or aryl; 
 each R 4  is independently H or alkyl; or the two R 4  groups may be taken together with the ring to which they are attached to form an optionally substituted 6-membered aromatic ring; 
 each R 6  is independently H, arylalkyl, arylacyl, or arylsulfonyl; and 
 n4 is 2-4; 
 
       to thereby treat the subject. 
     
     
         4 . The method of  claim 3 , wherein the cancer comprises a tumor. 
     
     
         5 . The method of  claim 4 , wherein the tumor is a tumor of the breast or brain. 
     
     
         6 . The method of  claim 3 , wherein the subject exhibits a hematopoietic deficiency from chemotherapy or radiation therapy. 
     
     
         7 . The method of  claim 3 , further comprising administration of one or more active agents. 
     
     
         8 . The method of  claim 3 , wherein each R 2  is independently H, R 3  is H, two R 4  groups are taken together with the ring to which they are attached to form an unsubstituted phenyl ring, and each R 6  is H. 
     
     
         9 . A method of treating asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias, delayed-type hypersensitivity, interstitial lung disease, systemic anaphylaxis or hypersensitivity responses, drug allergies, insect sting allergies, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, myasthenia gravis, juvenile onset diabetes, glomerulonephritis, autoimmune thyroiditis, graft rejection, allograft rejection, graft-versus-host disease, inflammatory bowel diseases, Crohn's disease, ulcerative colitis; spondyloarthropathies, scleroderma, psoriasis, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticarial, vasculitis, eosinphilic myotis, or eosiniphilic fasciitis, the method comprising:
 administering to the subject in need thereof an effective amount of a compound of the formula   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, and including any stereoisomeric forms thereof, wherein:
 each R 1  is independently H; 
 each R 2  is independently H or alkyl; 
 R 3  is H, alkyl, alkenyl, arylalkyl, or aryl; 
 each R 4  is independently H or alkyl; or the two R 4  groups may be taken together with the ring to which they are attached to form an optionally substituted 6-membered aromatic ring; 
 each R 6  is independently H, arylalkyl, arylacyl, or arylsulfonyl; and 
 n4 is 2-4; 
 
       to thereby treat the subject. 
     
     
         10 . A method to effect regeneration of cardiac tissue in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, and including any stereoisomeric forms thereof, wherein:
 each R 1  is independently H; 
 each R 2  is independently H or alkyl; 
 R 3  is H, alkyl, alkenyl, arylalkyl, or aryl; 
 each R 4  is independently H or alkyl; or the two R 4  groups may be taken together with the ring to which they are attached to form an optionally substituted 6-membered aromatic ring; 
 each R 6  is independently H, arylalkyl, arylacyl, or arylsulfonyl; and 
 n4 is 2-4; 
 
       to thereby treat the subject. 
     
     
         11 . A method to elevate the white blood cell count in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, and including any stereoisomeric forms thereof, wherein:
 each R 1  is independently H; 
 each R 2  is independently H or alkyl; 
 R 3  is H, alkyl, alkenyl, arylalkyl, or aryl; 
 each R 4  is independently H or alkyl; or the two R 4  groups may be taken together with the ring to which they are attached to form an optionally substituted 6-membered aromatic ring; 
 each R 6  is independently H, arylalkyl, arylacyl, or arylsulfonyl; and 
 n4 is 2-4; 
 
       to thereby treat the subject. 
     
     
         12 . A pharmaceutical composition comprising a compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, and including any stereoisomeric forms thereof, wherein:
 each R 1  is independently H; 
 each R 2  is independently H or alkyl; 
 R 3  is H, alkyl, alkenyl, arylalkyl, or aryl; 
 each R 4  is independently H or alkyl; or the two R 4  groups may be taken together with the ring to which they are attached to form an optionally substituted 6-membered aromatic ring; 
 each R 6  is independently H, arylalkyl, arylacyl, or arylsulfonyl; and 
 N4 is 2-4; 
 
       and a pharmaceutically acceptable excipient. 
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein each R 2  is independently H. 
     
     
         14 . The pharmaceutical composition of  claim 12 , wherein R 3  is H. 
     
     
         15 . The pharmaceutical composition of  claim 12 , wherein two R 4  groups are taken together with the ring to which they are attached to form an unsubstituted phenyl ring. 
     
     
         16 . The pharmaceutical composition of  claim 12 , wherein each R 6  is H. 
     
     
         17 . The pharmaceutical composition of  claim 12 , wherein each R 2  is independently H, R 3  is H, two R 4  groups are taken together with the ring to which they are attached to form an unsubstituted phenyl ring, and each R 6  is H. 
     
     
         18 . The pharmaceutical composition of  claim 12 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         19 . The pharmaceutical composition of  claim 12 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         20 . The pharmaceutical composition of  claim 12 , wherein the compound is a hydrochloride salt.