Affinity medicant conjugate

Abstract

In an embodiment of the invention, a composition for treating a cell population comprises an Affinity Medicant Conjugate (AMC). The medicant moiety can be a toxin including an acylfulvene or a drug moiety. The affinity moiety can be an antibody, a binding protein, a steroid, a lipid, a growth factor, a protein, a peptide or non peptidic. The affinity moiety can be covalently bound to the medicant via a linker. Novel linkers that can be directed to cysteine, arginine or lysine residues based on solution pH allow greater flexibility in preserving and/or generating specific epitopes in the AMC.

What is claimed is: 
     
         1 . A compound of the formula I: 
       
         
           
           
               
               
           
         
         an optical isomer thereof, a pharmaceutically acceptable salt thereof, wherein R 7  is selected from the group consisting —NH—, —NR 8 —, —S—, —O—, —CH 2 —, —CHR 8 —, —CHR 8 R 9 —, —OC(═O)—, —N(R 3 )S(═O)—, and —N(═N)—; R 1  is selected from the group consisting of 4-sulfonyl benzoyl, 3-sulfonyl benzoyl and 2-sulfonyl benzoyl; R 2 , R 3 , R 5 , R 6  each independently represent —H, —OH, —OCH 3 , —OC(═O)CH 3 , —CH 3 , —CH 2 —CH 3 , —CH—(CH 3 ) 2 , —C(CH 3 ) 3 , —CH 2 —CH 2 —CH 3 , —CH 2 —CH—(CH 3 ) 2 , —CH—C—(CH 3 ) 3 , —C(═O)CH 3 , —CH 2 OH, and (C 1 -C 4 )alkyl; R 4  represents —H, —CH 3 , —CH 2 —CH 3 , —CH—(CH 3 ) 2 , —C(CH 3 ) 3 , —CH 2 —CH 2 —CH 3 , —CH 2 —CH—(CH 3 ) 2 , —CH—C—(CH 3 ) 3 , —C(═O)CH 3 , —CH 2 OH, and (C 1 -C 4 )alkyl; and R 8  represents —F. 
       
     
     
         2 . A composition comprising one or more racemic mixtures of the compound of  claim 1 . 
     
     
         3 . A composition comprising one or more enantiomers of the compound of  claim 1 . 
     
     
         4 . The compound of  claim 1 , further comprising an Affinity Moiety selected from the group consisting of an antibody, an antibody fragment, a receptor protein, a peptidic growth factor, an anti-angiogenic protein, a specific binding peptide, a protease cleavable peptide, a glycopeptide, a peptide, a natural peptidic toxin, a protein toxin and an oligonucleotide, where the Affinity Moiety is covalently bound by displacement of R 8 . 
     
     
         5 . A composition comprising the compound of  claim 4  and a physiologically compatible excipient. 
     
     
         6 . The composition of  claim 5  forming a medicant. 
     
     
         7 . The compound of  claim 1 , where R 2  represents OH; R 4 , represents H; R 3 , R 5 , R 6  each represent CH 3  and R 7  represents O. 
     
     
         8 . A composition comprising one or more racemic mixtures of the compound of  claim 7 . 
     
     
         9 . A composition comprising one or more enantiomers of the compound of  claim 7 . 
     
     
         10 . The compound of  claim 7 , further comprising an Affinity Moiety selected from the group consisting of an antibody, an antibody fragment, a receptor protein, a peptidic growth factor, an anti-angiogenic protein, a specific binding peptide, a protease cleavable peptide, a glycopeptide, a peptide, a natural peptidic toxin, a protein toxin and an oligonucleotide, where the Affinity Moiety is covalently bound by displacement of R 8 . 
     
     
         11 . A composition comprising the compound of  claim 10  and a physiologically compatible excipient. 
     
     
         12 . The composition of  claim 11  forming a medicant. 
     
     
         13 . The compound of  claim 8 , where R 1  represents 4-sulfonyl benzoyl. 
     
     
         14 . A composition comprising one or more racemic mixtures of the compound of  claim 13 . 
     
     
         15 . A composition comprising one or more enantiomers of the compound of  claim 13 . 
     
     
         16 . A composition comprising one or more racemic mixtures and/or one or more enantiomers of the compound of  claim 13 . 
     
     
         17 . The composition of  claim 15  comprising a mixture of one or more optical isomers selected from the group consisting of ((2′S,3′S,6′R)-3′,6′-dihydroxy-2′,4′,6′-trimethyl-7′-oxo-2′,3′,6′,7′-tetrahydrospiro[cyclopropane-1,5′-inden]-2′-yl)methyl 4-(fluorosulfonyl)benzoate; ((2′S,3′S,6′S)-3′,6′-dihydroxy-2′,4′,6′-trimethyl-7′-oxo-2′,3′,6′,7′-tetrahydrospiro[cyclopropane-1,5′-inden]-2′-yl)methyl 4-(fluorosulfonyl)benzoate; ((2′S,3′R,6′R)-3′,6′-dihydroxy-2′,4′,6′-trimethyl-7′-oxo-2′,3′,6′,7′-tetrahydrospiro[cyclopropane-1,5′-inden]-2′-yl)methyl 4-(fluorosulfonyl)benzoate; ((2′S,3′R,6′S)-3′,6′-dihydroxy-2′,4′,6′-trimethyl-7′-oxo-2′,3′,6′,7′-tetrahydrospiro[cyclopropane-1,5′-inden]-2′-yl)methyl 4-(fluorosulfonyl)benzoate; ((2′R,3′S,6′R)-3′,6′-dihydroxy-2′,4′,6′-trimethyl-7′-oxo-2′,3′,6′,7′-tetrahydrospiro[cyclopropane-1,5′-inden]-2′-yl)methyl 4-(fluorosulfonyl)benzoate; ((2′R,3′S,6′S)-3′,6′-dihydroxy-2′,4′,6′-trimethyl-7′-oxo-2′,3′,6′,7′-tetrahydrospiro[cyclopropane-1,5′-inden]-2′-yl)methyl 4-(fluorosulfonyl)benzoate; ((2′R,3′R,6′R)-3′,6′-dihydroxy-2′,4′,6′-trimethyl-7′-oxo-2′,3′,6′,7′-tetrahydrospiro[cyclopropane-1,5′-inden]-2′-yl)methyl 4-(fluorosulfonyl)benzoate; ((2′R,3′R,6′S)-3′,6′-dihydroxy-2′,4′,6′-trimethyl-7′-oxo-2′,3′,6′,7′-tetrahydrospiro[cyclopropane-1,5′-inden]-2′-yl)methyl 4-(fluorosulfonyl)benzoate. 
     
     
         18 . The compound of  claim 13 , further comprising an Affinity Moiety selected from the group consisting of an antibody, an antibody fragment, a receptor protein, a peptidic growth factor, an anti-angiogenic protein, a specific binding peptide, a protease cleavable peptide, a glycopeptide, a peptide, a natural peptidic toxin, a protein toxin and an oligonucleotide, where the Affinity Moiety is covalently bound by displacement of R 8 . 
     
     
         19 . A composition comprising the compound of  claim 18  and a physiologically compatible excipient. 
     
     
         20 . The composition of  claim 19  forming a medicant.