Vitamin receptor binding drug delivery conjugates

Abstract

The invention describes a vitamin receptor binding drug delivery conjugate, and preparations therefor. The drug delivery conjugate consists of a vitamin receptor binding moiety, a bivalent linker (L), and a drug. The vitamin receptor binding moiety includes vitamins, and vitamin receptor binding analogs and derivatives thereof, and the drug includes analogs and derivatives thereof. The vitamin receptor binding moiety is covalently linked to the bivalent linker, and the drug, or the analog or the derivative thereof, is covalently linked to the bivalent linker, wherein the bivalent linker (L) includes components such as spacer linkers, releasable linkers, and heteroatom linkers, and combinations thereof. Methods and pharmaceutical compositions for eliminating pathogenic cell populations using the drug delivery conjugate are also described.

1 . A vitamin receptor binding drug delivery conjugate comprising:
 (a) a vitamin receptor binding moiety;   (b) a bivalent linker; and   (c) a drug, or an analog or derivative thereof   wherein the vitamin receptor binding moiety is covalently linked to the bivalent linker;   the drug, or the analog or the derivative thereof, is covalently linked to the bivalent linker; and   the bivalent linker comprises one or more components selected from the group consisting of spacer linkers, releasable linkers, and heteroatom linkers, and combinations thereof;   providing that the bivalent linker includes at least one releasable linker that is not a disulfide.   
     
     
         2 . The drug delivery conjugate of  claim 1  wherein the vitamin receptor binding moiety is selected from the group consisting of vitamins, and vitamin receptor binding analogs and derivatives thereof. 
     
     
         3 . The drug delivery conjugate of  claim 1  wherein the heteroatom linker is a nitrogen, oxygen, or sulfur atom, or is selected from the group of formulae consisting of —NHR 1 NHR 2 —, —SO—, —S(O) 2 —, and —NR 3 O—, wherein R 1 , R 2 , and R 3  are each independently selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, substituted aryl, substituted arylalkyl, heteroaryl, substituted heteroaryl, and alkoxyalkyl. 
     
     
         4 . The drug delivery conjugate of  claim 1  wherein the spacer linker is selected from the group consisting of carbonyl, thionocarbonyl, alkylene, cycloalkylene, alkylenecycloalkyl, alkylenecarbonyl, cycloalkylenecarbonyl, carbonylalkylcarbonyl, 1-alkylenesuccinimid-3-yl, 1-(carbonylalkyl)succinimid-3-yl, alkylenesulfoxyl, sulfonylalkyl, alkylenesulfoxylalkyl, alkylenesulfonylalkyl, carbonyltetrahydro-2H-pyranyl, carbonyltetrahydrofuranyl, 1-(carbonyltetrahydro-2H-pyranyl)succinimid-3-yl, and 1-(carbonyltetrahydrofuranyl)succinimid-3-yl, wherein each of said spacer linkers is optionally substituted with one or more substituents X 1 ;
 wherein each substituent X 1  is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, halo, haloalkyl, sulfhydrylalkyl, alkylthioalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, carboxy, carboxyalkyl, alkyl carboxylate, alkyl alkanoate, guanidinoalkyl, R 4 -carbonyl, R 5 -carbonylalkyl, R 6 -acylamino, and R 7 -acylaminoalkyl, wherein R 4  and R 5  are each independently selected from the group consisting of an amino acid, an amino acid derivative, and a peptide, and wherein R 6  and R 7  are each independently selected from the group consisting of an amino acid, an amino acid derivative, and a peptide. 
 
     
     
         5 . The drug delivery conjugate of  claim 4  wherein the heteroatom linker is nitrogen, and wherein the substituent X 1  and the heteroatom linker are taken together with the spacer linker to which they are bound to form an heterocycle. 
     
     
         6 . The drug delivery conjugate of  claim 5  wherein the heterocycle is selected from the group consisting of pyrrolidines, piperidines, oxazolidines, isoxazolidines, thiazolidines, isothiazolidines, pyrrolidinones, piperidinones, oxazolidinones, isoxazolidinones, thiazolidinones, isothiazolidinones, and succinimides. 
     
     
         7 . The drug delivery conjugate of  claim 1  wherein the releasable linker is selected from the group consisting of methylene, 1-alkoxyalkylene, 1-alkoxycycloalkylene, 1-alkoxyalkylenecarbonyl, 1-alkoxycycloalkylenecarbonyl, carbonylarylcarbonyl, carbonyl(carboxyaryl)carbonyl, carbonyl(biscarboxyaryl)carbonyl, haloalkylenecarbonyl, alkylene(dialkylsilyl), alkylene(allylarylsilyl), alkylene(diarylsilyl), (dialkylsilyl)aryl, (alkylarylsilyl)aryl, (diarylsilyl)aryl, oxycarbonyloxy, oxycarbonyloxyalkyl, sulfonylalkyl, iminoalkylidenyl, carbonylalkylideniminyl, iminocycloalkylidenyl, carbonylcycloalkylideniminyl, alkylenesulfonyl, alkylenethio, alkylenearylthio, and carbonylalkylthio, wherein each of said releasable linkers is optionally substituted with one or more substituents X 2 ;
 wherein each substituent X 2  is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, halo, haloalkyl, sulfhydrylalkyl, alkylthioalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, carboxy, carboxyalkyl, alkyl carboxylate, alkyl alkanoate, guanidinoalkyl, R 4 -carbonyl, R 5 -carbonylalkyl, R 6 -acylamino, and R 7 -acylaminoalkyl, wherein R 4  and R 5  are each independently selected from the group consisting of an amino acid, an amino acid derivative, and a peptide, and wherein R 6  and R 7  are each independently selected from the group consisting of an amino acid, an amino acid derivative, and a peptide. 
 
     
     
         8 . The drug delivery conjugate of  claim 7  wherein the heteroatom linker is nitrogen, and wherein the substituent X 2  and the heteroatom linker are taken together with the releasable linker to which they are bound to form an heterocycle. 
     
     
         9 . The drug delivery conjugate of  claim 8  wherein the heterocycle is selected from the group consisting of pyrrolidines, piperidines, oxazolidines, isoxazolidines, thiazolidines, isothiazolidines, pyrrolidinones, piperidinones, oxazolidinones, isoxazolidinones, thiazolidinones, isothiazolidinones, and succinimides. 
     
     
         10 . The drug delivery conjugate of  claim 1  wherein the heteroatom linker is nitrogen, and wherein the releasable linker and the heteroatom linker are taken together to form a divalent radical comprising alkyleneaziridin-1-yl, alkylenecarbonylaziridin-1-yl, carbonylalkylaziridin-1-yl, alkylenesulfoxylaziridin-1-yl, sulfoxylalkylaziridin-1-yl, sulfonylalkylaziridin-1-yl, or alkylenesulfonylaziridin-1-yl, wherein each of said releasable linkers is optionally substituted with one or more substituents X 2 ;
 wherein each substituent X 2  is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, halo, haloalkyl, sulfhydrylalkyl, alkylthioalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, carboxy, carboxyalkyl, alkyl carboxylate, alkyl alkanoate, guanidinoalkyl, R 4 -carbonyl, R 5 -carbonylalkyl, R 6 -acylamino, and R 7 -acylaminoalkyl, wherein R 4  and R 5  are each independently selected from the group consisting of an amino acid, an amino acid derivative, and a peptide, and wherein R 6  and R 7  are each independently selected from the group consisting of an amino acid, an amino acid derivative, and a peptide. 
 
     
     
         11 . The drug delivery conjugate of  claim 10  wherein the heteroatom linker is nitrogen, and the releasable linker and the heteroatom linker are taken together to form a divalent radical comprising alkyleneaziridin-1-yl, carbonylalkylaziridin-1-yl, sulfoxylalkylaziridin-1-yl, or sulfonylalkylaziridin-1-yl. 
     
     
         12 . The drug delivery conjugate of  claim 11  wherein the spacer linker is selected from the group consisting of carbonyl, thionocarbonyl, alkylenecarbonyl, cycloalkylenecarbonyl, carbonylalkylcarbonyl, and 1-(carbonylalkyl)succinimid-3-yl, wherein each of said spacer linkers is optionally substituted with one or more substituents X 1 ;
 wherein each substituent X 1  is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, halo, haloalkyl, sulfhydrylalkyl, alkylthioalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, carboxy, carboxyalkyl, alkyl carboxylate, alkyl alkanoate, guanidinoalkyl, R 4 -carbonyl, R 5 -carbonylalkyl, R 6 -acylamino, and R 7 -acylaminoalkyl, wherein R 4  and R 5  are each independently selected from the group consisting of an amino acid, an amino acid derivative, and a peptide, and wherein R 6  and R 7  are each independently selected from the group consisting of an amino acid, an amino acid derivative, and a peptide; 
 and wherein the spacer linker is bonded to the releasable linker to form an aziridine amide. 
 
     
     
         13 . The drug delivery conjugate of  claim 1  wherein the drug is a mitomycin, a mitomycin derivative, or a mitomycin analog, and the releasable linker is selected from the group consisting of carbonylalkylthio, carbonyltetrahydro-2H-pyranyl, carbonyltetrahydrofuranyl, 1-(carbonyltetrahydro-2H-pyranyl)succinimid-3-yl, and 1-(carbonyltetrahydrofuranyl)succinimid-3-yl, wherein each of said releasable linkers is optionally substituted with one or more substituents X 2 ,
 wherein each substituent X 2  is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, halo, haloalkyl, sulfhydrylalkyl, alkylthioalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, carboxy, carboxyalkyl, alkyl carboxylate, alkyl alkanoate, guanidinoalkyl, R 4 -carbonyl, R 5 -carbonylalkyl, R 6 -acylamino, and R 7 -acylaminoalkyl, wherein R 4  and R 5  are each independently selected from the group consisting of an amino acid, an amino acid derivative, and a peptide, and wherein R 6  and R 7  are each independently selected from the group consisting of an amino acid, an amino acid derivative, and a peptide; 
 and wherein the aziridine of the mitomycin is bonded to the releasable linker to form an acylaziridine. 
 
     
     
         14 . The drug delivery conjugate of  claim 1  wherein the drug includes a double-bonded nitrogen atom, wherein the releasable linker is selected from the group consisting of alkylenecarbonylamino and 1-(alkylenecarbonylamino)succinimid-3-yl, and wherein the releasable linker is bonded to the drug nitrogen to form an hydrazone. 
     
     
         15 . The drug delivery conjugate of  claim 1  wherein the drug includes a sulfur atom, the releasable linker is selected from the group consisting of alkylenethio and carbonylalkylthio, and wherein the releasable linker is bonded to the drug sulfur to form a disulfide. 
     
     
         16 . The drug delivery conjugate of  claim 4  wherein the vitamin receptor binding moiety is folate which includes a nitrogen, and the spacer linker is selected from the group consisting of alkylenecarbonyl, cycloalkylenecarbonyl, carbonylalkylcarbonyl, and 1-(carbonylalkyl)succinimid-3-yl, wherein the spacer linker is bonded to the folate nitrogen to form an imide or an alkylamide. 
     
     
         17 . The drug delivery conjugate of  claim 16  wherein each substituent X 1  is independently selected from the group consisting of alkyl, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfhydrylalkyl, alkylthioalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carboxy, carboxyalkyl, guanidinoalkyl, R 4 -carbonyl, R 5 -carbonylalkyl, R 6 -acylamino, and R 7 -acylaminoalkyl, wherein R 4  and R 5  are each independently selected from the group consisting of an amino acid, an amino acid derivative, and a peptide, and wherein R 6  and R 7  are each independently selected from the group consisting of an amino acid, an amino acid derivative, and a peptide. 
     
     
         18 . The drug delivery conjugate of  claim 4  wherein the heteroatom linker is nitrogen, and the spacer linker is selected from the group consisting of alkylenecarbonyl, cycloalkylenecarbonyl, carbonylalkylcarbonyl, and 1-(carbonylalkyl)succinimid-3-yl, wherein each of said spacer linkers is optionally substituted with one or more substituents X 1  and the spacer linker is bonded to the nitrogen to form an amide. 
     
     
         19 - 47 . (canceled) 
     
     
         48 . A method of eliminating a population of pathogenic cells in a host animal harboring the population of pathogenic cells wherein the members of the pathogenic cell population have an accessible binding site for a vitamin, or an analog or a derivative thereof, and wherein the binding site is uniquely expressed, overexpressed, or preferentially expressed by the pathogenic cells, said method comprising the step of administering to said host a drug delivery conjugate of  claim 1 , or a pharmaceutical composition thereof. 
     
     
         49 - 57 . (canceled) 
     
     
         57 . A vitamin receptor binding drug delivery conjugate intermediate comprising:
 (a) a bivalent linker, having a first end and a second end;   (b) a drug, or an analog or a derivative thereof; and   (c) a coupling group;   wherein the bivalent linker comprises one or more components selected from the group consisting of spacer linkers, releasable linkers, and heteroatom linkers, and combinations thereof; providing that the bivalent linker includes at least one releasable linker that is not a disulfide;   the coupling group is a nucleophile, an electrophile, or a precursor thereof, capable of forming a covalent bond with a vitamin receptor binding moiety; and   the coupling group is covalently attached to the bivalent linker at the first end of the bivalent linker, and the drug, or analog or derivative thereof is covalently attached to the bivalent linker at the second end of the bivalent linker.   
     
     
         58 - 63 . (canceled)