IP Library › Granted Patent US 10,287,312
Granted Patent B2
US 10,287,312 · App. 15/118,268 · Granted May 14, 2019

Cyclic peroxides as prodrugs for selective delivery of agents

Inventors: Adam R. Renslo (Oakland, CA); Erica M. W. Lauterwasser (Wachenheim, DE); Shaun D. Fontaine (Walnut Creek, CA); Benjamin B. Spangler (San Francisco, CA); James A. Wells (Burlingame, CA)
Assignee: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
C07H19/16A61K31/357A61K31/404A61K31/4025A61K31/4192A61K31/427A61K31/435A61K31/437A61K31/444A61K31/4709A61K31/4745A61K31/496A61K31/4985A61K31/513A61K31/662A61K31/7072A61K31/7076A61K31/7135A61K47/64A61K47/6803A61K51/0459C07D323/02C07D405/12C07D405/14C07D407/12C07D417/12C07D417/14C07D471/14C07D487/04C07D491/107C07D491/113C07D491/153C07D493/04C07D493/14C07D519/04C07F7/1804C07F9/65517C07H19/06C07H19/167C07K7/06C07B2200/05Y02A50/411
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 10,287,312
App. No.
15/118,268
Granted
May 14, 2019
Kind
B2
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.

Claims (48)

1. A compound having the formula:

wherein

L 2 , L 3 , L 4 , L 6 , L 7 , L 8 , L 9 , L 11 , and L 12 are independently a bond;

L 5 is 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) 2 N(R 17 )—, —N(R 17 )S(O) 2 —, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

L 10 is —C((-L 11 -R 11 )(-L 12 -R 12 ))—;

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;

R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 11 , and R 12 , are independently hydrogen;

R 5 is independently a drug moiety bonded to L 5 through an N of the drug moiety or a drug moiety bonded to L 5 through an O of the drug moiety;

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;

Ring A is a substituted or unsubstituted C 3 -C 12 cycloalkylene or substituted or unsubstituted 3 to 12 membered heterocycloalkylene;

R 1 is independently a 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 1 is 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 1 4, —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; and

Y is —O—.

2. 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;

R 1 is a protein moiety, a folate moiety, or a siderophore moiety;

L 1 is 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,

or

L 2 , L 3 , L 4 , L 6 , L 7 , L 8 , L 9 , L 1 , and L 12 are independently a bond;

L 5 is 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 —C((-L 11 -R 11 )(-L 12 -R 12 ))—;

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;

R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 11 , and R 12 , are independently hydrogen;

R 5 is independently a drug moiety;

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; and

Y is —O—.

3. The compound of claim 2 , having the formula:

4. The compound of claim 3 , wherein -L 1 - is

—NHC(O)—(CH 2 ) W —NHC(O)O—(CH 2 ) Y1 —, —NHC(O)—(CH 2 ) W —C(O)NH—(CH 2 ) Y1 —, —NHC(O)—(CH 2 ) W —C(O)—, —NHC(O)—(CH 2 ) W — NH—, —NHC(O)—(CH 2 ) W —NHC(O)—, —NHC(O)—(CH 2 ) W —C(O)NH—, —NHC(O)—(CH 2 ) W —NHC(O)O—, —NHC(O)—(CH 2 ) W —(OCH 2 CH 2 ) T1 —C(O)NH—(CH 2 ) Y1 —, —NHC(O)—(C H 2 ) W —(OCH 2 CH 2 ) T1 —C(O)NH—(CH 2 ) Y1 —C(O)—; W is an integer from 0 to 10; T1 is an integer from 0 to 10, and Y1 is an integer from 0 to 10.

5. The compound of claim 1 , wherein

L 5 is a bond, —N(H)—, —N(H)C(O)O—, —O—, —S—, —OC(O)—, —OC(O)N(H)—, —OC(O)O—, —OSO 2 —, —C(O)N(H)—, —N(H) C(O)—, —S(O) 2 N(H)—, —N(H)S(O) 2 —; and

R 5 is a drug moiety.

6. The compound of claim 5 , wherein L 5 is a bond, —N(H)—, —O—, —OC(O)—, or —OC(O)N(H)—.

7. The compound of claim 2 , wherein

each -L 13 -L 14 - is independently selected from a bond.

8. The compound of claim 1 , wherein the drug moiety is independently a monovalent radical of an anti-infective agent.

9. The compound of claim 1 , wherein the drug moiety is independently a monovalent radical of an anti-cancer drug.

10. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 .

11. 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 9 to said patient; wherein the disease is a cancer associated with an increased Fe II level compared to a standard control.

12. The compound of claim 5 , wherein L 5 is —OC(O)—.

13. The compound of claim 2 , wherein R 1 is a protein moiety and the protein moiety is an antibody moiety.

14. The compound of claim 1 , wherein the drug moiety is bonded to L 5 through an N of the drug moiety.

15. The compound of claim 1 , wherein the drug moiety is bonded to L 5 through an O of the drug moiety.

16. The compound of claim 1 , wherein the drug moiety is an anti-bacterial agent moiety.

17. The compound of claim 2 , wherein the drug moiety is bonded to L 5 through an O of the drug moiety.

18. The compound of claim 2 , wherein the drug moiety is bonded to L 5 through an N of the drug moiety.

19. The compound of claim 2 , wherein the drug moiety is an anti-bacterial agent moiety.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 13, 2018
From: RENSLO, ADAM R; LAUTERWASSER, ERICA M.W.; FONTAINE, SHAUN D.; SPANGLER, BENJAMIN B.; WELLS, JAMES A.
To: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
Reel/Frame 047773/0153 →
CONFIRMATORY LICENSE Recorded Aug 12, 2016
From: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 039671/0734 →
Continuity (2)
Provisional Application 61940295 · Feb 14, 2014
Related Publication 20160362439A1 · Dec 15, 2016