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 .- 63 . (canceled) 
     
     
         64 . A vitamin receptor binding drug delivery conjugate, or a pharmaceutically acceptable salt thereof, comprising:
 (a) a vitamin receptor binding moiety;   (b) a linker; and   (c) a drug;   wherein the vitamin receptor binding moiety is covalently linked to the linker;   the drug, is covalently linked to the linker;   the linker comprises one or more components selected from the group consisting of spacer linkers, releasable linkers, and heteroatom linkers, and combinations thereof; and   the linker comprises at least one releasable linker selected from the group consisting of alkylene(dialkylsilyl), alkylene(alkylarylsilyl), alkylene(diarylsilyl), (dialkylsilyl)aryl, (alkylarylsilyl)aryl, and (diarylsilyl)aryl, wherein each hydrogen atom in each of the releasable linkers is optionally substituted with a substituent X 2 ; the releasable linker is bonded to an oxygen atom to form a silanol; and each X 2  is 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 , R 5 , R 6  and R 7  are each independently selected from the group consisting of an amino acid, and amino acid derivative, and a peptide.   
     
     
         65 . The drug delivery conjugate of  claim 64 , or a pharmaceutically acceptable salt thereof, wherein the vitamin receptor binding moiety is a vitamin or a vitamin receptor binding analog. 
     
     
         66 . The drug delivery conjugate of  claim 64 , or a pharmaceutically acceptable salt thereof, wherein the linker further comprises one of more heteroatom linkers selected from the group consisting of nitrogen, oxygen, sulfur, —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. 
     
     
         67 . The drug delivery conjugate of  claim 64 , or a pharmaceutically acceptable salt thereof, wherein at least one 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 spacer linker is independently 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 , R 5 , R 6  and R 7  are each independently selected from the group consisting of an amino acid, and amino acid derivative, and a peptide.   
     
     
         68 . The drug delivery conjugate of  claim 64 , or a pharmaceutically acceptable salt thereof, wherein the drug is selected from the group consisting of a peptide, an oligopeptide, a retro-inverso oligopeptide, a protein, an apoprotein, a glycoprotein, an enzyme, a coenzyme, an enzyme inhibitor, an amino acid, a hormone, a lipid, a phospholipid, an antibiotic, an analgesic, a bronchodilators, a beta-blocker, an antimicrobial agent, an antihypertensive agent, a cardiovascular agent, a cardiac glycoside, an antianginal, a vasodilator, a stimulant, a psychotropic, an antimanic, a depressant, an antiviral agent, an antihistamine a chemotherapeutic agent, a tranquilizer, an anti-depressant, an H-2 antagonist, an anticonvulsant, an antinauseant, a prostaglandin, a muscle relaxant, an anti-inflammatory, a decongestant, an antiemetic, a diuretic, an antispasmodic, an antiasthmatic, an expectorants, a cough suppressant, a mucolytic, and an antimitotic agent. 
     
     
         69 . The drug delivery conjugate of  claim 64 , or a pharmaceutically acceptable salt thereof, wherein the drug is selected from the group consisting of an adrenocorticoid an alkylating agent, an antiandrogen, an antiestrogen, an androgen, an aclamycin, estrogen, cytosine arabinoside, a purine analog, a pyrimidine analog, methotrexate, busulfan, carboplatin, chlorambucil, cisplatin tamoxiphen, taxol, paclitaxel, Taxotere®, cyclophosphamide, daunomycin, rhizoxin, T2 toxin, a plant alkaloid, prednisone, teniposide, a mitomycin, a discodermolide, a microtubule inhibitor, an epothilone, tubulysin, cyclopropyl benz[e]indolone, seco-cyclopropyl benz[e]indolone, O-Ac-seco-cyclopropyl benz[e]indolone, bleomycin, nitrogen mustard, vincristine, vinblastine, deacetylvinblastine monohydrazide, colchicine, allocolchicine, thiocolchicine, Halicondrin B, dolastatin 10, α-amanitin, camptothecin, irinotecan, geldanamycin estramustine, nocodazole, and colcemid. 
     
     
         70 . The drug delivery conjugate of  claim 64 , or a pharmaceutically acceptable salt thereof, wherein the drug is selected from the group consisting of penicillin, cephalosporin, vancomycin, erythromycin, clindamycin, rifampin, rhizoxin, chloramphenicol, gentamicin, amphotericin B, acyclovir, trifluridine, ganciclovir, zidovudine, amantadine, and ribavirin. 
     
     
         71 . The drug delivery conjugate of  claim 64 , or a pharmaceutically acceptable salt thereof, wherein the vitamin receptor binding moiety is folic acid, biotin, riboflavin, thiamine, or vitamin B 12 . 
     
     
         72 . The drug delivery conjugate of  claim 64 , or a pharmaceutically acceptable salt thereof, wherein the vitamin receptor binding moiety is a folate. 
     
     
         73 . The drug delivery conjugate of  claim 64 , or a pharmaceutically acceptable salt thereof, wherein the vitamin receptor binding moiety is of the formula 
       
         
           
           
               
               
           
         
         wherein * represents a covalent bond to the rest of the drug delivery conjugate. 
       
     
     
         74 . The drug delivery conjugate of claim  1 , or a pharmaceutically acceptable salt thereof, having the formula 
       
         
           
           
               
               
           
         
       
     
     
         75 . A pharmaceutical composition comprising the drug delivery conjugate of  claim 64 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.