Substituted β-lapachones for treating cancer

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

R a is H, amido, heterocyclyl or Si(alkyl) 3 ;

R 1 is H, OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, —(CH 2 )-aryl, —(CH 2 ) n -heteroaryl, —OR a , alkylamino, dialkylamino or heterocyclyl;

R 2 is H, OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, —(CH 2 ) n -aryl, —(CH 2 )-heteroaryl, C(O)OH or C(O)OC 1 -C 6 alkyl;

R 3 is H, OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C(O)H, C(O)C 1 -C 6 alkyl, C(O)OC 1 -C 6 alkyl, amino, alkylamino, dialkylamino, —(CH 2 )-aryl, —(CH 2 )-heteroaryl or heterocyclyl;

R 4 is H, OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C(O)H, C(O)C 1 -C 6 alkyl, C(O)OC 1 -C 6 alkyl, amino, alkylamino, dialkylamino, —(CH 2 )-aryl, —(CH 2 )-heteroaryl or heterocyclyl;

R 5 and R 6 , together with the carbon atom to which they are attached, are —C(═O)—;

R 7 is H, halogen, OH, NO 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C(O)OH, C(O)OC 1 -C 6 alkyl, C(O)NH 2 , amino, alkylamino, dialkylamino, aryl, benzyl, heteroaryl or heterocyclyl;

R 8 is H, halogen, OH, NO 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C(O)OH, C(O)OC 1 -C 6 alkyl, C(O)NH 2 , amino, alkylamino, dialkylamino, aryl, benzyl, heteroaryl or heterocyclyl;

R 9 is H, halogen, OH, NO 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C(O)OH, C(O)OC 1 -C 6 alkyl, C(O)NH 2 , amino, alkylamino, dialkylamino, aryl, benzyl, heteroaryl or heterocyclyl;

R 10 is H, halogen, OH, NO 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C(O)OH, C(O)OC 1 -C 6 alkyl, C(O)NH 2 , amino, alkylamino, dialkylamino, aryl, benzyl, heteroaryl or heterocyclyl;

X is —CH 2 —; and

n is 0, 1, 2 or 3;

with the proviso that covalently bonded to the remainder of formula (I) at one of R 1 , R 2 , R 3 or R 4 is a mitochondrial targeting group represented by (a), (b) or (c):

(a) formula (III) or formula (IV):

wherein:

R 12 is H, halogen, OH, C 1 -C 6 alkyl or C 1 -C 6 alkylphenyl, where the C 1 -C 6 alkylphenyl is optionally substituted with CH 3 , OH or halogen;

R 13 is H, halogen, OH, C 1 -C 6 alkyl or C 1 -C 6 alkylphenyl, where the C 1 -C 6 alkylphenyl is optionally substituted with CH 3 , OH or halogen;

R 14 is halogen or C 1 -C 6 alkyl, where the C 1 -C 6 alkyl is optionally substituted with one or more phenyl, wherein each phenyl is further optionally and independently substituted with CH 3 , CH 2 CH 3 , OH or halogen;

R 15 is H, halogen, C 1 -C 6 alkyl or C 1 -C 6 alkylphenyl, where the C 1 -C 6 alkyl or C 1 -C 6 alkylphenyl is optionally substituted with CH 3 , OH or halogen;

R 16 is H, halogen, OH, C 1 -C 6 alkyl or C 1 -C 6 alkylphenyl, where the C 1 -C 6 alkylphenyl is optionally substituted with CH 3 , OH or halogen;

R 17 is H, halogen, OH, C 1 -C 6 alkyl or C 1 -C 6 alkylphenyl, where the C 1 -C 6 alkylphenyl is optionally substituted with CH 3 , OH or halogen;

R 18 is C(O)R 24 , C(O)OR 24 or P(O)(R 24 ) 2 ;

R 19 is —NH—, —O— or —CH 2 —;

R 21 is H or halogen;

R 22 is H or halogen;

R 23 is H or halogen; and

R 24 is C 1 -C 6 alkyl, optionally substituted with one or more phenyl, where each phenyl is further optionally and independently substituted with CH 3 , CH 2 CH 3 , OH or halogen; or

(b) formula (V) or formula (VI):

wherein:

X is

R 12 is H, halogen, OH, C 1 -C 6 alkyl or C 1 -C 6 alkylphenyl, where the C 1 -C 6 alkylphenyl is optionally substituted with CH 3 , OH or halogen;

R 13 is H, halogen, OH, C 1 -C 6 alkyl or C 1 -C 6 alkylphenyl, where the C 1 -C 6 alkylphenyl is optionally substituted with CH 3 , OH or halogen;

R 16 is H, halogen, OH, C 1 -C 6 alkyl or C 1 -C 6 alkylphenyl, where the C 1 -C 6 alkylphenyl is optionally substituted with CH 3 , OH or halogen;

R 17 is H, halogen, OH, C 1 -C 6 alkyl or C 1 -C 6 alkylphenyl, where the C 1 -C 6 alkylphenyl is optionally substituted with CH 3 , OH or halogen;

R 18 is C(O)R 24 , C(O)OR 24 or P(O)(R 24 ) 2 ;

R 19 is —NH—, —O— or —CH 2 —;

R 24 is C 1 -C 6 alkyl, optionally substituted with one or more phenyl, where each phenyl is further optionally and independently substituted with CH 3 , CH 2 CH 3 , OH or halogen; and

R 25 is H, halogen, OH, C 1 -C 6 alkyl or C 1 -C 6 alkylphenyl, where the C 1 -C 6 alkylphenyl is optionally substituted with CH 3 , OH or halogen; or

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

wherein any pendant amine(s) of each mitochondrial targeting group may be optionally and independently protected with a protecting group selected from the group consisting of:

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein covalently bonded to the remainder of formula (I) at one of R 1 , R 2 , R 3 or R 4 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 R 1 , R 2 , R 3 or R 4 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 R 1 , R 2 , R 3 or R 4 is a mitochondrial targeting group represented by:

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

wherein any pendant amine(s) of each mitochondrial targeting group may be optionally and independently protected with a protecting group.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein covalently bonded to the remainder of formula (I) at one of R 3 or R 4 is a mitochondrial targeting group represented by (a), (b) or (c).

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 , R 7 , R 8 , R 9 and R 10 are independently H.

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

R 1 is CH 3 ;

R 2 is CH 3 ;

R 4 is H;

R 7 is H;

R 8 is H;

R 9 is H; and

R 10 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:

or a pharmaceutically acceptable salt thereof.