Synthesis of Drug Conjugates Via Reaction With Epoxide-Containing Linkers

Abstract

The present invention relates to drug derivatives and linkers. The invention specifically relates to compounds and methods of phosphonates and linkers, that are useful as carriers for imaging agents and useful in the treatment of various bone diseases.

1 . A compound of the formula: CH 2 [O]CH(CH 2 ) n R 1 ,
 comprising a C3 or longer alkyl chain where one end is an oxirane that can be conjugated to a compound or drug, and the other, a group R 1  that can be conjugated to a second compound; and wherein the resulting compound may be used to link a compound or drug to another drug, modify a moiety, link a compound or drug to a bead, link a compound or drug to a support, or link a compound or drug to an imaging label.   
     
     
         2 . The compound of  claim 1  wherein the tertiary oxirane carbon is racemic. 
     
     
         3 . The compound of  claim 1  wherein the tertiary oxirane carbon is substantially pure as and R or S isomer. 
     
     
         4 . The compound of  claim 1  wherein n is 1-12 and R 1  is an amino, hydroxyl, halogen, or other reactive group. 
     
     
         5 . The compound of  claim 1  wherein n is 1 and R 1  is NH2. 
     
     
         6 . The compound of  claim 1  wherein n is 1 and R 1  is a protected amino group. 
     
     
         7 . The compound of  claim 1  wherein n is 1 and R 1  is NHtBOC. 
     
     
         8 . The compound of  claim 1  wherein n is 2 and R 1  is an oxirane group. 
     
     
         9 . A method of synthesizing a linkable compound comprising reacting the compound of  claim 1  with a second compound containing a group capable of reacting with an oxirane. 
     
     
         10 . The method of  claim 9  wherein n is 1 and R 1  is NHtBOC, and the tBOC protecting group is removed after formation of the conjugate by reaction with trifluoroacetic acid in water, aqueous DMF, or aqueous MeOH. 
     
     
         11 . A method of preparing the compound of  claim 1  comprising:
 (a) reacting an alkene comprising CH 2 ═CH—(CH2) n R 1  with a reagent to protect R 1  and; 
 (b) oxidizing the alkene group to an oxirane using meta-chloroperbenzoic acid. 
 
     
     
         12 . The method of  claim 11  wherein n is 1 and R 1  is NHtBOC. 
     
     
         13 . A method of preparing a linker conjugate compound comprising:
 (a) dissolving a first compound of formula: CH 2 [O]CH(CH 2 )nR 1  in a solvent; and   (b) reacting a second compound containing an amino group with said first compound;   wherein n is 1 and R 1  is NHtBOC of said first compound, and wherein said NHtBOC is dissolved in a solvent.   
     
     
         14 . The method of  claim 13  wherein said NHtBOC dissolved in a solvent comprising MeOH or DMF. 
     
     
         15 . The method of  claim 13  wherein said second compound comprises a pyridyl group or other nitrogen-containing heterocyclic group, or tertiary amino group. 
     
     
         16 . The method of  claim 15  wherein said second compound is a methylenebisphosphonate or phosphonocarboxylate. 
     
     
         17 - 31 . (canceled)