Cyclic peroxides as prodrugs for selective delivery of agents

Patent metadata

Field	Value
Publication number	US-2022017559-A1
Application number	US-202117237525-A
Country	US
Kind code	A1
Filing date	Apr 22, 2021
Priority date	Feb 14, 2014
Publication date	Jan 20, 2022
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 pharmaceutically acceptable carrier.

First claim

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)

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

• C07D405/14

  containing three or more hetero rings · CPC title

• C07H19/16 Primary

  Purine radicals · CPC title

• A61K31/4025

  not condensed and containing further heterocyclic rings, e.g. cromakalim · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title