Cyclic peroxides as prodrugs for selective delivery of agents

Patent metadata

Field	Value
Publication number	US-2020317714-A1
Application number	US-202016843567-A
Country	US
Kind code	A1
Filing date	Apr 8, 2020
Priority date	Feb 14, 2014
Publication date	Oct 8, 2020
Grant date	—

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 phannaceutically acceptable carrier.

First claim

1 .- 49 . (canceled)

50 . A compound having the formula:

wherein
Ring A is a substituted or unsubstituted C 3 -C 12 cycloalkylene or substituted or unsubstituted 3 to 12 membered heterocycloalkylene;
Y is —O—;
L 2 , L 3 , L 4 , L 6 , L 7 , L 8 , and L 9 are each a bond;
R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are each hydrogen;
L 10 is —CH 2 —;
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, substituted or unsubstituted heteroarylene, or a bioconjugate linker;
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 siderophore moiety, a folate moiety;
L 5 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;
R 5 is a drug moiety;
each L 13 and L 14 are independently selected from 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) 2 N(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; and
each R 17 is 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.

51 . The compound of claim 50 , wherein L 5 is a bond, —OC(O)—, —OC(O)NH-Ph-CH 2 —, —OC(O)NH-Ph-CH 2 —OC(O)—, —NH-Ph-CH 2 —, —NH-Ph-CH 2 —OC(O)—, —O-Ph-CH 2 —, or —O-Ph-CH 2 —OC(O)—.

52 . The compound of claim 50 , wherein the drug moiety is independently a monovalent radical of an anti-infective agent.

53 . The compound of claim 50 , wherein the drug moiety is independently a monovalent radical of an anti-cancer agent.

54 . The compound of claim 50 , wherein the drug moiety is a monovalent radical of a MEK inhibitor, a monovalent radical of an inhibitor of mitogen-activated protein kinase, a monovalent radical of an EGFR inhibitor, a monovalent radical of a Ras inhibitor, a monovalent radical of a topoisomerase inhibitor, a monovalent radical of an alkylating agent, or a monovalent radical of an mTOR inhibitor.

55 . The compound of claim 50 , wherein the drug moiety is a monovalent radical of a MEK inhibitor.

56 . The compound of claim 50 , wherein the drug moiety is a monovalent radical of an inhibitor of mitogen-activated protein kinase.

57 . The compound of claim 50 , wherein the drug moiety is a monovalent radical of an EGFR inhibitor.

58 . The compound of claim 50 , wherein the drug moiety is monovalent radical of a Ras inhibitor.

59 . The compound of claim 50 , wherein the drug moiety is a monovalent radical of a topoisomerase inhibitor.

60 . The compound of claim 50 , wherein the drug moiety is a monovalent radical of an alkylating agent.

61 . The compound of claim 50 , wherein the drug moiety is a monovalent radical of an mTOR inhibitor.

62 . The compound of claim 50 , wherein the drug moiety is a monovalent radical of AZD8330, a monovalent radical of PD0325901, a monovalent radical of TAK-733, a monovalent radical of AS703026, a monovalent radical of PD98059, a monovalent radical of SB239063, a monovalent radical of desmethyl erlotinib, a monovalent radical of CUDC-101, a monovalent radical of a camptothecin analog, a monovalent radical of irinotecan, a monovalent radical of topotecan, a monovalent radical of adriamycin, a monovalent radical of CC-1065, a monovalent radical of a CC-1065 analog, a monovalent radical of an amino-CBI, a monovalent radical of a duocarmycin, or a monovalent radical of a duocarmycin analog.

63 . The compound of claim 50 , wherein R 5 is

64 . The compound of claim 50 , wherein R 5 is

65 . The compound of claim 50 , wherein R 5 is

66 . The compound of claim 50 , wherein R 5 is

67 . The compound of claim 50 , having the formula:

68 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 50 .

69 . 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 50 to said patient; wherein the disease is a cancer associated with an increased Fe II level compared to a standard control.

Assignees

• Univ California

Inventors

• Renslo Adam R
• Lauterwasser Erica M W
• Fontaine Shaun D
• Spangler Benjamin B
• Wells James A

Classifications

• A61K47/6803

  Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates · CPC title

• C07D407/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/7076

  containing purines, e.g. adenosine, adenylic acid · CPC title

• A61K31/4745

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title