Cyclic peroxides as prodrugs for selective delivery of agents

Abstract

Disclosed herein, inter alia, are prodrug compositions and methods of using the same for treatment and detection of disease. Specifically, disclosed herein is a compound of formula (I) having spiro-fused 1,2,4-trioxolane and piperidine rings, namely, 1,2,4-trioxa-8-azaspiro[4.5] decane. Also disclosed is a pharmaceutical composition containing the compound and a pharmaceutically acceptable carrier.

1 . A compound having the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 L 2 , L 3 , L 4 , L 5 , L 6 , L 7 , L 8 , L 9 , L 11 , and L 12  are independently a bond, —N(R 17 )-L 13 -L 14 -, —N(R 17 )C(O)O-L 13 -L 14 -, —O-L 13 -L 14 -, —S-L 13 -L 14 -, —OC(O)—L 13 -L 14 -, —OC(O)N(R 17 )-L 13 -L 14 -, —OC(O)O-L 13 -L 14 -, —OSO 2 -L 13 -L 14 -, —C(O)N(R 17 )-L 13 -L 14 -, —N(R 17 )C(O)-L 13 -L 14 -, —S(O) 2 N(R 17 )-L 13 -L 14 -, —N(R 17 )S(O)2-L 13 -L 14 -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; 
 L 10  is —N(-L 11 -R 11 — or —C((-L 11 -R 11 )(-L 12 -R 12 ))-; 
 each L 13  and L 14  are independently a bond, —N(R 17 )—, —N(R 17 )C(O)O—, —O—, —S—, —OC(O)—, —OC(O)N(R 17 )—, —OC(O)O—, —OSO 2 —, —C(O)N(R 17 )—, —N(R 17 )C(O)—, —S(O)2N(R 17 )—, —N(R 17 )S(O) 2 —, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; 
 R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 11 , and R 12  are independently hydrogen, oxo, halogen, —CX 3 , —CN, —SO 2 Cl, —SO v R 16 , —SO v NR 13 R 14 , —NHNH 2 , —ONR 13 R 14 , —NHC═(O)NHNH 2 , —NHC═(O)NR 13 R 14 , —N(O) m , —NR 13 R 14 , —C(O)R 15 , —C(O)—OR 15 , —C(O)NR 13 R 14 , —OR 16 , —NR 13 SO 2 R 16 , —NR 13 C═(O)R 15 , —NR 13 C(O)—OR 15 , —NR 13 OR 15 , —OCX 3 , —OCHX 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protein moiety, a detectable moiety, or a drug moiety; R 5  and R 11  substituents may be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 6  and R 11  substituents may be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2  and R 3 , R 4  and R 5 , R 6  and R 7 , R 8  and R 9 , or R 11  and R 12  may be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 each R 13 , R 14 , R 15 , R 16 , and R 17  are independently hydrogen, halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O) NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 13  and R 14  substituents bonded to the same atom may be joined to form a substituted or unsubstitued heterocycloalkyl or substituted or unsubstituted heteroaryl; 
 R 18  and R 19  are independently hydrogen, halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH2, —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protein moiety, detectable moiety, siderophore moiety, or a drug moiety; R 18  and R 19  may be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, protein moiety, detectable moiety, or drug moiety; 
 m and v are independently 1 or 2; 
 n is an integer from 0 to 2; 
 Y is —O—, —S—, —OO—, —CH 2 O—, or —OCH 2 —; and 
 X is independently —Cl, —Br, —I, or —F. 
 
     
     
         2 .- 4 . (canceled) 
     
     
         5 . The compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 Ring A is a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; 
 R 1  is hydrogen, halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC—(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protein moiety, a detectable moiety, a siderophore, moiety, or a drug moiety; and 
 L 1  is a bond, —N(R 17 )-L 13 -L 14 , —N(R 17 )C(O)O-L 13 -L 14 -, —O-L 13 -L 14 -, —S-L 13 -L 14 -, —OC(O)-L 13 -L 14 -, —OC(O)N(R 17 )-L 13 -L 14 -, —OC(O)O-L 13 -L 14 -, —OSO 2 -L 13 -L 14 -, —C(O)N(R 17 )-L 13 -L 14 -, —N(R 17 )C(O)-L 13 -L 14 -, —S(O) 2 N(R 17 )-L 13 -L 14 -, —N(R 17 )S(O) 2 -L 13 -L 14 -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. 
 
     
     
         6 .- 22 . (canceled) 
     
     
         23 . The compound of  claim 1 , wherein each L 13  is independently selected from a bond or substituted or unsubstituted arylene. 
     
     
         24 . (canceled) 
     
     
         25 . The compound of  claim 1 , wherein each L 14  is independently selected from a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. 
     
     
         26 . (canceled) 
     
     
         27 . The compound of  claim 1 , wherein each -L 13 -L 14 - is independently a bond, -Ph-(CH 2 ) w — or -Ph(CH 2 ) w —OC(O)—; and w is an integer 1 to 4. 
     
     
         28 .- 31 . (canceled) 
     
     
         32 . The compound of  claim 1 , wherein the drug moiety is independently a monovalent radical of an anti-infective agent. 
     
     
         33 . The compound of  claim 32 , wherein the anti-infective agent is an anti-parasitic agent. 
     
     
         34 . The compound of  claim 32 , wherein the anti-infective agent is an anti-malarial drug. 
     
     
         35 . The compound of  claim 32 , wherein the anti-infective agent is an anti-bacterial drug. 
     
     
         36 . The compound of  claim 1 , wherein the drug moiety is independently a monovalent radical of an anti-cancer drug. 
     
     
         37 . The compound of  claim 1 , wherein the detectable moiety is independently a monovalent radical of a fluorophore. 
     
     
         38 . The compound of  claim 1 , wherein the protein moiety is independently a monovalent radical of an antibody. 
     
     
         39 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of  claim 1 . 
     
     
         40 . A method of treating a disease in a patient in need of such treatment, said method comprising administering a therapeutically effective amount of a compound of  claim 1  to said patient. 
     
     
         41 . (canceled) 
     
     
         42 . The method of  claim 40 , wherein the disease is cancer. 
     
     
         43 . (canceled) 
     
     
         44 . (canceled) 
     
     
         45 . The method of  claim 40 , wherein the disease is malaria. 
     
     
         46 . The method of  claim 40 , wherein the disease is a bacterial disease. 
     
     
         47 . The method of  claim 40 , wherein the disease is a parasitic disease. 
     
     
         48 . A method of identifying a patient having a disease associated with a cell or organism having an increased Fe II  level compared to a standard control, said method comprising administering an effective amount of a compound of  claim 1  to said patient. 
     
     
         49 . A method of identifying a patient having a disease associated with an increased reductant level compared to a standard control, said method comprising obtaining a biological sample from said patient, contacting said biological sample with an effective amount of a compound of  claim 1 , wherein said compound comprises a detectable moiety, detecting an increased level of said detectable moiety or a detectable agent resulting from cleavage of said detectable moiety relative the level of said detectable moiety or detectable agent in the standard control.