Substituted β-lapachones for treating cancer

• US 10,450,289 B2
• Filed: 06/08/2016
• Issued: 10/22/2019
• Est. Priority Date: 06/08/2015
• Status: Active Grant

• Current Assignee: University of Pittsburgh of The Commonwealth System of Higher Education
• Original Assignee: University of Pittsburgh of The Commonwealth System of Higher Education
• Inventors: Wipf, Peter, Van Houten, Bennett, Qian, Wei, Lim, Chaemin
• Primary Examiner(s): Willis, Douglas M
• Application Number:
  US15/580,416
• Publication Number:
  US 20180170895A1
• Time in Patent Office: 1,231 Days
• Field of Search: 514454, 549389
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 311/92 Naphthopyrans; Hydrogenated naphthopyrans
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links

Abstract

Provided herein are compounds having the general formula

compositions, and methods useful for treating cancer and neurodegeneration. The compounds comprise a mitochondria-targeting moiety linked to β-lapachone or a β-lapachone derivative.

Claims

1. A compound of formula (I):

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein covalently bonded to the remainder of formula (I) at one of R₁, R₂, R₃ or R₄ is a mitochondrial targeting group represented by (a).

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein covalently bonded to the remainder of formula (I) at one of R₁, R₂, R₃ or R₄ is a mitochondrial targeting group represented by (b).

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein covalently bonded to the remainder of formula (I) at one of R₁, R₂, R₃ or R₄ is a mitochondrial targeting group represented by:

(c) a mitochondrial targeting group selected from the group consisting of;

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein covalently bonded to the remainder of formula (I) at one of R₃ or R₄ is a mitochondrial targeting group represented by (a), (b) or (c).

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R₄, R₇, R₈, R₉ and R₁₀ are independently H.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

R₁ is CH₃;

R₂ is CH₃;

R₄ is H;

R₇ is H;

R₈ is H;

R₉ is H; and

R₁₀ is H.

8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1, or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition further comprises a chemotherapeutic agent.

10. The pharmaceutical composition of claim 9, wherein the chemotherapeutic agent is selected from the group consisting of abiraterone acetate, altretamine, amsacrine, anhydro vinblastine, auristatin, bafetinib, bexarotene, bicalutamide, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide, bleomycin, bosutinib, busulfan, cachectin, 3′

,4′

-didehydro-4′

-deoxy-8′

-norvin-caleukoblastine, carboplatin, carmustine, cemadotin, chlorambucil, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, docetaxol, dolastatin, doxetaxel, doxorubicin, etoposide, etoposide phosphate, finasteride, flutamide, hydroxyurea, hydroxyurea taxanes, ifosfamide, imatinib, irinotecan, f3-lapachone, liarozole, lomustine, lonidamine, mechlorethamine, melphalan, methotrexate, mitomycin, mitoxantrone, mivobulin isethionate, nilotinib, nilutamide, onapristone, oxaliplatin, paclitaxel, ponatinib, prednimustine, procarbazine, rhizoxin, sertenef, stramustine phosphate, streptozocin, tamoxifen, tasonermin, taxol, teniposide, topotecan, tretinoin, 5-fluorouracil, vinblastine, vincristine, vindesine sulfate and vinflunine.

11. A method for treating cancer in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.

12. The method of claim 11, wherein the method further comprises administering a chemotherapeutic agent to the patient.

13. The method of claim 12, wherein the chemotherapeutic agent is selected from the group consisting of abiraterone acetate, altretamine, amsacrine, anhydro vinblastine, auristatin, bafetinib, bexarotene, bicalutamide, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide, bleomycin, bosutinib, busulfan, cachectin, 3′

,4′

-didehydro-4′

-deoxy-8′

-norvin-caleukoblastine, carboplatin, carmustine, cemadotin, chlorambucil, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, docetaxol, dolastatin, doxetaxel, doxorubicin, etoposide, etoposide phosphate, finasteride, flutamide, hydroxyurea, hydroxyurea taxanes, ifosfamide, imatinib, irinotecan, β

-lapachone, liarozole, lomustine, lonidamine, mechlorethamine, melphalan, methotrexate, mitomycin, mitoxantrone, mivobulin isethionate, nilotinib, nilutamide, onapristone, oxaliplatin, paclitaxel, ponatinib, prednimustine, procarbazine, rhizoxin, sertenef, stramustine phosphate, streptozocin, tamoxifen, tasonermin, taxol, teniposide, topotecan, tretinoin, 5-fluorouracil, vinblastine, vincristine, vindesine sulfate and vinflunine.

14. The method of claim 11, wherein the method further comprises simultaneously administering radiation therapy to the patient while the compound, or a pharmaceutically acceptable salt thereof, is present in the patient.

15. A method for treating neurodegeneration in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.

16. A method for decreasing oxidative damage in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the oxidative damage in the patient is due to reactive oxygen species production in the mitochondria of a cell of the patient.

17. A compound having the structure: