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 increase white blood cell (WBC) count by enhancing the population of progenitor and/or stem cells in a subject, which method comprises
 administering to said subject a compound of the formula   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or pro-drug form thereof; and including any stereoisomeric forms thereof; 
         wherein n4 is 2-4; 
         each R 1  is independently H, halo, alkyl, alkoxy, or CF 3 ; 
         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 or heteroaromatic ring; and 
         each R 6  is independently H or alkyl, acyl, arylacyl, or arylsulfonyl, wherein the aryl moieties thereof optionally contain one or more heteroatoms selected from the group consisting of O, S, and N; 
         in an amount effective to increase said WBC count in said subject. 
       
     
     
         2 . The method of  claim 1  wherein each R 1  is H. 
     
     
         3 . The method of  claim 1  wherein each R 2  is H. 
     
     
         4 . The method of  claim 1  wherein R 3  is H. 
     
     
         5 . The method of  claim 1  wherein each R 6  is H. 
     
     
         6 . The method of  claim 1  wherein the subject exhibits a hematopoietic deficit from chemotherapy or radiation therapy. 
     
     
         7 . The method of  claim 1  wherein the subject has a condition selected from the group consisting of aplastic anemia, leukemia and drug-induced anemia. 
     
     
         8 . The method of  claim 1  wherein the subject is a transplantation recipient. 
     
     
         9 . The method of  claim 1  wherein said increase of WBC count enhances wound healing. 
     
     
         10 . The method of  claim 1  wherein said increase of WBC count ameliorates bacterial inflammation. 
     
     
         11 . The method of  claim 1  wherein the compound of formula IIIe is administered to said subject by an intravenous or subcutaneous route or oral route. 
     
     
         12 . The method of  claim 11  wherein the compound of formula IIIe is administered to said subject by an oral route. 
     
     
         13 . The method of  claim 1  wherein the compound of formula IIIe is administered to said subject in the dosage range of about 0.1 μg/kg-5 mg/kg of body weight. 
     
     
         14 . The method of  claim 1  wherein the subject is human. 
     
     
         15 . The method of  claim 1  wherein the compound of formula IIIe is N 1 -(1H-Benzimidazol-2-ylmethyl)-N 1 -(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine or a pharmaceutically acceptable salt thereof. 
     
     
         16 . The method of  claim 1  wherein the compound of formula IIIe is N 1 -(1H-Benzimidazol-2-ylmethyl)-N 1 -(R)-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine or a pharmaceutically acceptable salt thereof. 
     
     
         17 . The method of  claim 1  wherein the compound of formula IIIe is N 1 -(1H-Benzimidazol-2-ylmethyl)-N 1 -(S)-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine or a pharmaceutically acceptable salt thereof. 
     
     
         18 . A pharmaceutical composition in unit dosage form for increasing white blood cell (WBC) count in a subject comprising an effective amount of a compound of formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or pro-drug form thereof; and including any stereoisomeric forms thereof; 
         wherein n4 is 2-4; 
         each R 1  is independently H, halo, alkyl, alkoxy, or CF 3 ; 
         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 or heteroaromatic ring; and 
         each R 6  is independently H, arylalkyl, acyl, arylacyl, or arylsulfonyl, wherein the aryl moieties thereof optionally contain one or more heteroatoms selected from the group consisting of O, S, and N; and 
         a pharmaceutically acceptable excipient. 
       
     
     
         19 . The pharmaceutical composition of  claim 18  wherein the compound of formula IIIe is N′-(1H-Benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine or a pharmaceutically acceptable salt thereof. 
     
     
         20 . The pharmaceutical composition of  claim 18  wherein the compound of formula IIIe is N 1 -(1H-Benzimidazol-2-ylmethyl)-N′-(R)-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine or a pharmaceutically acceptable salt thereof. 
     
     
         21 . The pharmaceutical composition of  claim 18  wherein the compound of formula IIIe is N′-(1H-Benzimidazol-2-ylmethyl)-N′-(S)-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine or a pharmaceutically acceptable salt thereof.