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 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.  
       
     
     
         2 . The compound of  claim 1  wherein each of R 1  to R 6  is independently H or a noninterfering substituent which is alkyl (C 1-10 ), alkenyl (C 2-10 ), alkynyl (C 2-10 ), aryl (“C” 5-12 ), arylalkyl, arylalkenyl, or arylalkynyl, each of which may optionally contain one or more heteroatoms selected from O, S, and N and each of which may further be substituted; or optionally substituted forms of acyl, arylacyl, alkyl- alkenyl-, alkynyl- or arylsulfonyl and forms thereof which contain heteroatoms in the alkyl, alkenyl, alkynyl or aryl moieties; or which is OR, SR, NR 2 , COOR, CONR 2 , where R is H or optionally substituted alkyl, alkenyl, alkynyl or aryl as defined above; and wherein, when the substituted atom is C, the noninterfering substituent may be halo, OOCR, NROCR, where an R is H or a substituent set forth above, or may be ═O.  
     
     
         3 . The compound of  claim 1  wherein said compound is of the formula  
       
         
           
           
               
               
           
         
       
       or the salts or pro-drug forms thereof, and including any stereoisomeric forms thereof; 
 wherein R 1 -R 6  and n1-n3 are as defined for Formula I.  
 
     
     
         4 . The compound of  claim 3  wherein each of R 1  to R 6  is independently H or a noninterfering substituent which is alkyl (C 1-10 ), alkenyl (C 2-10 ), alkynyl (C 2-10 ), aryl (“C” 5-12 ), arylalkyl, arylalkenyl, or arylalkynyl, each of which may optionally contain one or more heteroatoms selected from O, S, and N and each of which may further be substituted; or optionally substituted forms of acyl, arylacyl, alkyl- alkenyl-, alkynyl- or arylsulfonyl and forms thereof which contain heteroatoms in the alkyl, alkenyl, alkynyl or aryl moieties; or which is OR, SR, NR 2 , COOR, CONR 2 , where R is H or optionally substituted alkyl, alkenyl, alkynyl or aryl as defined above; and wherein, when the substituted atom is C, the noninterfering substituent may be halo, OOCR, NROCR, where an R is H or a substituent set forth above, or may be ═O.  
     
     
         5 . The compound of  claim 1  wherein said compound is of the formula  
       
         
           
           
               
               
           
         
         or the salts or pro-drug forms thereof; and including any stereoisomeric forms thereof;  
         wherein d is 0-3, the dotted line represents an optional π bond and R 1 -R 6  are defined as in  claim 1 .  
       
     
     
         6 . The compound of  claim 5  wherein each of R 1  to R 6  is independently H or a noninterfering substituent which is alkyl (C 1-10 ), alkenyl (C 2-10 ), alkynyl (C 2-10 ), aryl (“C” 5-12 ), arylalkyl, arylalkenyl, or arylalkynyl, each of which may optionally contain one or more heteroatoms selected from O, S, and N and each of which may further be substituted; or optionally substituted forms of acyl, arylacyl, alkyl- alkenyl-, alkynyl- or arylsulfonyl and forms thereof which contain heteroatoms in the alkyl, alkenyl, alkynyl or aryl moieties; or which is OR, SR, NR 2 , COOR, CONR 2 , where R is H or optionally substituted alkyl, alkenyl, alkynyl or aryl as defined above; and wherein, when the substituted atom is C, the noninterfering substituent may be halo, OOCR, NROCR, where an R is H or a substituent set forth above, or may be ═O.  
     
     
         7 . The compound of  claim 1  wherein said compound is of the formula  
       
         
           
           
               
               
           
         
         or the salts or pro-drug forms thereof; and including any stereoisomeric forms thereof;  
         wherein d is 0-3, the dotted line is an optional π bond, and R 1 -R 6  are defined as in  claim 1 .  
       
     
     
         8 . The compound of  claim 7  wherein each of R 1  to R 6  is independently H or a noninterfering substituent which is alkyl (C 1-10 ), alkenyl (C 2-10 ), alkynyl (C 2-10 ), aryl (“C” 5-12 ), arylalkyl, arylalkenyl, or arylalkynyl, each of which may optionally contain one or more heteroatoms selected from O, S, and N and each of which may further be substituted; or optionally substituted forms of acyl, arylacyl, alkyl- alkenyl-, alkynyl- or arylsulfonyl and forms thereof which contain heteroatoms in the alkyl, alkenyl, alkynyl or aryl moieties; or which is OR, SR, NR 2 , COOR, CONR 2 , where R is H or optionally substituted alkyl, alkenyl, alkynyl or aryl as defined above; and wherein, when the substituted atom is C, the noninterfering substituent may be halo, OOCR, NROCR, where an R is H or a substituent set forth above, or may be ═O.  
     
     
         9 . The compound of  claim 1  wherein said compound is of the formula  
       
         
           
           
               
               
           
         
         or the salts or pro-drug forms thereof; and including any stereoisomeric forms thereof;  
         wherein R 1 -R 6  are defined as in  claim 1 , and n4 is 2-6.  
       
     
     
         10 . The compound of  claim 9  wherein each of R 1  to R 6  is independently H or a noninterfering substituent which is alkyl (C 1-10 ), alkenyl (C 2-10 ), alkynyl (C 2-10 ), aryl (“C” 5-12 ), arylalkyl, arylalkenyl, or arylalkynyl, each of which may optionally contain one or more heteroatoms selected from O, S, and N and each of which may further be substituted; or optionally substituted forms of acyl, arylacyl, alkyl- alkenyl-, alkynyl- or arylsulfonyl and forms thereof which contain heteroatoms in the alkyl, alkenyl, alkynyl or aryl moieties; or which is OR, SR, NR 2 , COOR, CONR 2 , where R is H or optionally substituted alkyl, alkenyl, alkynyl or aryl as defined above; and wherein, when the substituted atom is C, the noninterfering substituent may be halo, OOCR, NROCR, where an R is H or a substituent set forth above, or may be ═O.  
     
     
         11 . The compound of  claim 1  wherein each R 1  is independently H, halo, alkyl, alkoxy, or CF 3 .  
     
     
         12 . The compound of  claim 1  wherein each R 2  is independently H or alkyl.  
     
     
         13 . The compound of  claim 1  wherein R 3  is H, alkyl, alkenyl, arylalkyl, or aryl.  
     
     
         14 . The compound of  claim 1  wherein each R 4  is H or alkyl or wherein two R 4  together form an aromatic ring.  
     
     
         15 . The compound of  claim 1  wherein each R 5  is independently H, alkyl, or alkenyl, wherein said alkyl or alkenyl may optionally be substituted.  
     
     
         16 . The compound of  claim 15  wherein said alkyl or alkenyl substituents on a single carbon or on nonadjacent or adjacent carbons form a saturated or unsaturated ring, wherein said ring cannot be aromatic.  
     
     
         17 . The compound of  claim 1  wherein one R 5  is an oxime, an alkylated oxime, alkylated hydroxylamine, hydroxylamine or halo.  
     
     
         18 . The compound of  claim 1  wherein each R 6  is independently H, or optionally heteroatom-containing arylalkyl, arylsulfonyl, or comprises a guanidyl, carbonyl, or carbamino group.  
     
     
         19 . The compound of  claim 1  wherein two R 6  form a saturated, unsaturated or aromatic ring, wherein said ring may optionally contain one or more heteroatoms (N, S or O).  
     
     
         20 . The compound of  claim 1  wherein one R 5  and one R 6  form a saturated or unsaturated or aromatic ring, which ring may optionally contain an additional heteroatom.  
     
     
         21 . A pharmaceutical composition which comprises at least one compound of  claim 1 , in admixture with a pharmaceutically acceptable excipient.  
     
     
         22 . The composition of  claim 21  which comprises at least one additional biologically active agent.  
     
     
         23 . A method to modulate the CXCR4 and/or CCR5 receptor, which method comprises contacting cells displaying said receptor(s) with an amount of the compound of  claim 1  effective to modulate said receptor(s).  
     
     
         24 . A method to treat conditions characterized by inappropriate activity of the CXCR4 and/or CCR5 receptor, which method comprises administering to a subject in need of such treatment an effective amount of the compound of  claim 1  or a pharmaceutical composition thereof.  
     
     
         25 . A method to treat an undesired condition in a human or animal subject which method comprises administering to a subject in need of such treatment an effective amount of the compound of  claim 1  or a pharmaceutical composition thereof by a clinically acceptable route of administration according to a clinically effective regime.  
     
     
         26 . The method of  claim 25 , wherein said condition is modulated by a chemokine receptor.  
     
     
         27 . The method of  claim 26 , wherein the chemokine receptor is the CXCR4 or the CCR5 receptor.  
     
     
         28 . The method of  claim 25 , wherein said condition is characterized by angiogenesis.  
     
     
         29 . The method of  claim 26 , wherein said condition comprises tumors.  
     
     
         30 . The method of  claim 29 , wherein said tumors are of brain, breast, prostate, lung or haematopoetic tissues.  
     
     
         31 . The method of  claim 26 , wherein said condition is HIV infection.  
     
     
         32 . The method of  claim 26 , wherein said condition is rheumatoid arthritis.  
     
     
         33 . The method of  claim 26 , wherein said condition is an inflammatory or allergic disease.  
     
     
         34 . The method of  claim 33 , wherein said condition is asthma.  
     
     
         35 . The method of  claim 26 , wherein said condition is 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; autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, myastenia gravis, juvenile onset diabetes; glomerulonephritis, autoimmune throiditis, graft rejection, including allograft rejection or graft-versus-host disease; inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis; spondyloarthropathies; scleroderma; psoriasis; dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis; eosinphilic myotis, eosiniphilic fasciitis; or cancers.  
     
     
         36 . The method of  claim 26 , wherein the condition is associated with immunosuppression.  
     
     
         37 . The method of  claim 36 , wherein said subject is undergoing chemotherapy, radiation therapy, wound healing, burn treatment, or therapy for autoimmune disease.  
     
     
         38 . The use of the compound of  claim 1  for preparation of a medicament for the treatment of HIV.  
     
     
         39 . The use of the compound of  claim 1  for the preparation of a medicament for treating conditions mediated by chemokine receptors.