Mitochondria-Targeted Lapachone Compounds and Uses Therefor

• US 20180170895A1
• Filed: 06/08/2016
• Published: 06/21/2018
• 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
• Granted Patent: US 10,450,289 B2
• Time in Patent Office: Days
• 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

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

Claims

1. A compound comprising a mitochondria-targeting group covalently linked to β

-lapachone or a β

-lapachone derivative, or a pharmaceutically-acceptable salt or ester thereof.

2. The compound of claim 1, comprising a β

-lapachone derivative.

3. The compound of claim 2, wherein the β

-lapachone derivative has the structure;

4. The compound of claim 3, wherein the β

-lapachone or the β

-lapachone derivative is linked to the mitochondria-targeting group at position C₂ or C₃.

5. The compound of claim 4, wherein the β

-lapachone or the β

-lapachone derivative is linked to a mitochondria-targeting group at position C₃.

6. The compound of claim 1, having a structure:

a.

7. The compound of claim 6, having the structure of (III) or (IV).

8. The compound of claim 6, having the structure of (V) or (VI).

9. The compound of claim 6, having the structure of (VII).

10. The compound of claim 1, having the structure:

11. The compound of claim 1, having the structure:

12. A composition comprising a first compound comprising a mitochondria-targeting group covalently linked to β

-lapachone or a β

-lapachone derivative, or a pharmaceutically-acceptable salt or ester thereof, and a pharmaceutically-acceptable excipient.

13. The composition of claim 12, further comprising a chemotherapeutic agent that is different from the first compound.

14. The composition of claim 13, wherein the chemotherapeutic agent is either β

-lapachone, a β

-lapachone derivative, abiraterone acetate, altretamine, amsacrine, anhydro vinblastine, auristatin, bafetinib, bexarotene, bicalutamide, BMS 184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, bleomycin, bosutinib, busulfan, cachectin, cemadotin, chlorambucil, cyclophosphamide, 3′

,4′

-didehydro-4′

-deoxy-8′

-norvin-caleukoblastine, docetaxol, doxetaxel, carboplatin, carmustine (BCNU), chlorambucil, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, daunorubicin, decitabine dolastatin, doxorubicin (adriamycin), etoposide, etoposide phosphate, 5-fluorouracil, finasteride, flutamide, hydroxyurea, hydroxyureataxanes, ifosfamide, imatinib, irinotecan, liarozole, lonidamine, lomustine (CCNU), MDV3100, mechlorethamine (nitrogen mustard), melphalan, mitoxantrone, mivobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, nilotinib, nilutamide, onapristone, oxaliplatin, paclitaxel, ponatinib, prednimustine, procarbazine, RPRI 09881, stramustine phosphate, tamoxifen, tasonermin, taxol, teniposide, topotecan, tretinoin, vinblastine, vincristine, vindesine sulfate, vinflunine, or pharmaceutically acceptable salts or esters thereof.

15. A method of treating a cancer in a patient, comprising administering to a patient an amount of a first compound comprising a mitochondria-targeting group covalently linked to β

-lapachone or a β

-lapachone derivative, or a pharmaceutically-acceptable salt or ester thereof effective to increase reactive oxygen species (ROS) in mitochondria of cancer cells of a patient.

16. The method of claim 15, further comprising administering a radiation therapy to the patient while the first compound is present in the patient.

17. The method of claim 15, further comprising administering a second chemotherapeutic agent that differs from the first compound.

18. The method of claim 17, wherein the second chemotherapeutic agent is either β

-lapachone, a β

-lapachone derivative, abiraterone acetate, altretamine, amsacrine, anhydro vinblastine, auristatin, bafetinib, bexarotene, bicalutamide, BMS 184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, bleomycin, bosutinib, busulfan, cachectin, cemadotin, chlorambucil, cyclophosphamide, 3′

,4′

-didehydro-4′

-deoxy-8′

-norvin-caleukoblastine, docetaxol, doxetaxel, carboplatin, carmustine (BCNU), chlorambucil, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, daunorubicin, decitabine dolastatin, doxorubicin (adriamycin), etoposide, etoposide phosphate, 5-fluorouracil, finasteride, flutamide, hydroxyurea, hydroxyureataxanes, ifosfamide, imatinib, irinotecan, liarozole, lonidamine, lomustine (CCNU), MDV3100, mechlorethamine (nitrogen mustard), melphalan, mitoxantrone, mivobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, nilotinib, nilutamide, onapristone, oxaliplatin, paclitaxel, ponatinib, prednimustine, procarbazine, RPRI 09881, stramustine phosphate, tamoxifen, tasonermin, taxol, teniposide, topotecan, tretinoin, vinblastine, vincristine, vindesine sulfate, vinflunine, or pharmaceutically acceptable salts or esters thereof.

19. A method of treating neurodegeneration, comprising administering to a patient an amount of a compound comprising a mitochondria-targeting group covalently linked to β

-lapachone or a β

-lapachone derivative, or a pharmaceutically-acceptable salt or ester thereof effective to decrease reactive oxygen species (ROS) production in mitochondria of a cell of a patient.

20. A method of decreasing oxidative damage in a patient comprising administering to a patient an amount of a compound comprising a mitochondria-targeting group covalently linked to β

-lapachone or a β

-lapachone derivative, or a pharmaceutically-acceptable salt or ester thereof effective to decrease reactive oxygen species (ROS) production in mitochondria of a cell of a patient.