Methods to mobilize progenitor/stem cells

Abstract

Methods to elevate progenitor and stem cell counts in animal subjects using compounds which bind to the chemokine receptor CXCR4 are disclosed. Preferred embodiments of such compounds are of the formula Z-linker-Z′  (1) or pharmaceutically acceptable salt thereof wherein Z is a cyclic polyamine containing 9-32 ring members of which 3-8 are nitrogen atoms, said nitrogen atoms separated from each other by at least 2 carbon atoms, and wherein said heterocycle may optionally contain additional heteroatoms besides nitrogen and/or may be fused to an additional ring system; or Z is of the formula wherein A comprises a monocyclic or bicyclic fused ring system containing at least one N and B is H or an organic moiety of 1-20 atoms, Z′ may be embodied in a form as defined by Z above, or alternatively may be of the formula —N(R)—(CR 2 ) n —X wherein each R is independently H or straight, branched or cyclic alkyl (1-6C), n is 1 or 2, and X is an aromatic ring, including heteroaromatic rings, or is a mercaptan; “linker” represents a bond, alkylene (1-6C) or may comprise aryl, fused aryl, oxygen atoms contained in an alkylene chain, or may contain keto groups or nitrogen or sulfur atoms.

1 . A method for treating a population of stem cells ex vivo for a subject in need of a stem cell transplant which method comprises:
 (a) harvesting stem cells from a donor; followed by   (b) administering to the stem cells a compound of the formula
   Z-linker-Z′  (1)
 
   or a pharmaceutically acceptable salt or metal complex thereof   wherein Z is a cyclic polyamine containing 9-32 ring members of which 2-8 are nitrogen atoms, said nitrogen atoms separated from each other by at least 2 carbon atoms, and wherein said heterocycle may optionally contain additional heteroatoms besides nitrogen and/or may be fused to an additional ring system;   or Z is of the formula   
       
         
           
           
               
               
           
         
         wherein A comprises a monocyclic or bicyclic fused ring system containing at least one N and B is H or an organic moiety of 1-20 atoms, 
         Z′ is either embodied in a form as defined by Z above, or is of the formula
   —N(R)—(CR 2 ) n —X
 
 
         wherein each R is independently H or straight, branched or cyclic alkyl (1-6C), n is 1 or 2, and X is an aromatic ring, including heteroaromatic rings, or is a mercaptan; 
         “linker” represents a bond, alkylene (1-6C) or may comprise aryl, fused aryl, and/or oxygen atoms contained in an alkylene chain, and/or may contain keto groups and/or nitrogen or sulfur atoms; 
         in an amount effective to form an enhanced stem cell population; followed by 
         (c) administering the enhanced stem cell population to the subject. 
       
     
     
         2 . The method of  claim 1  wherein Z and Z′ are both cyclic polyamines. 
     
     
         3 . The method of  claim 1  wherein Z and Z′ are identical. 
     
     
         4 . The method of  claim 1  wherein Z is a cyclic polyamine that contains 10-24 members and contains 4 nitrogen atoms. 
     
     
         5 . The method of  claim 3  wherein Z and Z′ are both 1,4,8,11-tetraazacyclotetradecane. 
     
     
         6 . The method of  claim 1  wherein the linker comprises an aromatic ring bracketed by two methylene moieties. 
     
     
         7 . The method of  claim 6  wherein the linker is 1,4-phenylene-bis-methylene. 
     
     
         8 . The method of  claim 1  wherein the compound of formula (1) is 1,1′-[1,4-phenylene-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane or a pharmaceutically acceptable salt or metal complex thereof. 
     
     
         9 . The method of  claim 1  wherein the compound of formula (1) is a pharmaceutically acceptable salt of 1,1′-[1,4-phenylene-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane. 
     
     
         10 . The method of  claim 1  wherein the compound of formula (1) is a metal complex of 1,1′-[1,4-phenylene-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane. 
     
     
         11 . The method of  claim 1  wherein the compound of formula (1) is 1,1′-[1,4-phenylene-bis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane. 
     
     
         12 . The method of  claim 1  wherein
 Z is of the formula 
 
       
         
           
           
               
               
           
         
         wherein A comprises a monocyclic or bicyclic fused ring system containing at least one N and B is H or an organic moiety of 1-20 atoms. 
       
     
     
         13 . The method of  claim 1  wherein Z′ is
   —N(R)—(CR 2 ) n —X
 
 wherein each R, N and X are as therein defined. 
 
     
     
         14 . The method of  claim 10  wherein the linker is 1,4-phenylene-bis-(methylene). 
     
     
         15 . The method of  claim 1  wherein Z′ is 2-aminomethyl-pyridine. 
     
     
         16 . The method of  claim 1  wherein the compound of formula (1) is N-[1,4,8,11-tetraazacyclotetradecanyl-1,4-phenylene-bis-(methylene)]-2-aminomethylpyridine, or a pharmaceutically acceptable salt or metal complex thereof. 
     
     
         17 . The method of  claim 1  wherein formula (1) is in the form of an acid addition salt thereof. 
     
     
         18 . The method of  claim 17  wherein the acid addition salt is hydrochloride. 
     
     
         19 . The method of  claim 1  wherein the transplant is autologous. 
     
     
         20 . The method of  claim 1  wherein the transplant is allogeneic. 
     
     
         21 . The method of  claim 1  which further comprises administering to the stem cells a mobilizing factor prior to performing step (c). 
     
     
         22 . The method of  claim 21  wherein the mobilizing factor is G-CSF. 
     
     
         23 . The method of  claim 21  wherein the mobilizing factor is GM-CSF. 
     
     
         24 . The method of  claim 1  wherein the stem cells are harvested by apheresis. 
     
     
         25 . The method of  claim 1  wherein the stem cells are CD34 +  cells.