Inhibitors of the activity of complex (III) of the mitochondrial electron transport chain and use thereof
The present invention relates to inhibitors of the activity of Complex (III) of the mitochondrial electron transport chain and use thereof in treatment and/or prevention of cancers presenting tumor-initiating cells. The present invention further relates to pharmaceutical compositions containing said inhibitors alone or in combination with other pharmaceutically active agents, and their use as medicaments or as agrochemicals where their properties as inhibitors of the mitochondrial respiration is of benefit.
1. A compound selected from the group consisting of:
(a) 3-formamido-N-(heptadecan-9-yl)-2-hydroxybenzamide;
(b) N-cyclopentadecyl-7-hydroxy-1H-indazole-6-carboxamide;
(c) N-cyclopentadecyl-3-formamido-2-hydroxybenzamide;
(d) N-cyclododecyl-3-formamido-2-hydroxybenzamide;
(e) 3, 5-dichloro-N-cyclopentadecyl-2-hydroxybenzamide;
(f) 3, 5-dichloro-N-decyl-2-hydroxybenzamide;
(g) N-(3, 5-dichloro-2-hydroxyphenyl)undecanamide;
(h) N-(4-(cyclopentadecylcarbamoyl)phenyl)-3-formamido-2-hydroxybenzamide;
(i) N-(heptadecan-9-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxamide;
(j) N-(3-(1-(heptadecan-9-yl)-1H-1,2,3-triazol-4-yl)-2-hydroxyphenyl)formamide;
(k) N-(3-(1-cyclopentadecyl-1H-1,2,3-triazol-4-yl)-2-hydroxyphenyl)formamide;
(l) N-cyclononyl-7-hydroxy-1H-indazole-6-carboxamide;
(m) N-cyclononyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxamide; and
(n) N-cyclopentadecyl-2-oxo-2, 3-dihydro-1H-benzo[d]imidazole-4-carboxamide, or a pharmaceutically acceptable salt or solvate of any one of (a)-(n).
2. The compound of claim 1 , selected from the group consisting of (a)-(e)
(a) 3-formamido-N-(heptadecan-9-yl)-2-hydroxybenzamide;
(b) N-cyclopentadecyl-7-hydroxy-1H-indazole-6-carboxamide;
(c) N-cyclopentadecyl-3-formamido-2-hydroxybenzamide;
(d) N-cyclododecyl-3-formamido-2-hydroxybenzamide; and
(e) 3, 5-dichloro-N-cyclopentadecyl-2-hydroxybenzamide, or a pharmaceutically acceptable salt or solvate of any one of (a)-(e).
3. The compound of claim 2 , selected from the group consisting of:
(a) 3-formamido-N-(heptadecan-9-yl)-2-hydroxybenzamide; and
(b) N-cyclopentadecyl-7-hydroxy-1H-indazole-6-carboxamide, or a pharmaceutically acceptable salt or solvate of (a) or (b).
4. A method for treating a cancer presenting tumor-initiating cells, the method comprising administering a compound, salt, or solvate of claim 1 to a patient in need thereof.
5. The method according to claim 4 , wherein the cancer presenting tumor-initiating cells is selected from the group consisting of human glioma, schwannoma, metastasis to the brain, meningioma, ependymoma, and a metastatic cancer.
6. The method according to claim 5 , wherein the metastatic cancer is selected from the group consisting of melanoma, breast cancer, colon cancer, and lung cancer.
7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound, salt, or solvate according to claim 1 .
8. A kit comprising the compound, salt, or solvate according to claim 1 .
9. The kit according to claim 8 , further comprising one or more chemotherapeutic agent selected from the group consisting of Altretamine, Bleomycin, Busulphan, Capecitabine, Carboplatin, Carmustine, Chlorambucil, Cisplatin, Cladribine, Crisantaspase, Cyclophosphamid, Cytarabine, Dacarbazine, Daunorubicin, Doxorubicin, Epirubicin, Etoposide, Fludarabine, Fluorouracil, Gemcitabine, Idarubicin, Ifosfamide, Irinotecan, Lomustine, Melphalan, Mercaptopurine, Methotrexate, Mitomycin, Mitoxantrone, Oxaliplatin, Pentostatin, Procarbazine, Streptozocin, Taco, Temozolomide, Tioguanine/Thioguanine, Thiotepa, Topotecan, Treosulfan, Vinblastine, Vincristine, Vindesine, and Vinorelbine.
10. A kit comprising the pharmaceutical composition according to claim 7 .
11. The kit according to claim 10 , further comprising one or more chemotherapeutic agent selected from the group consisting of Altretamine, Bleomycin, Busulphan, Capecitabine, Carboplatin, Carmustine, Chlorambucil, Cisplatin, Cladribine, Crisantaspase, Cyclophosphamid, Cytarabine, Dacarbazine, Daunorubicin, Doxorubicin, Epirubicin, Etoposide, Fludarabine, Fluorouracil, Gemcitabine, Idarubicin, Ifosfamide, Irinotecan, Lomustine, Melphalan, Mercaptopurine, Methotrexate, Mitomycin, Mitoxantrone, Oxaliplatin, Pentostatin, Procarbazine, Streptozocin, Taco, Temozolomide, Tioguanine/Thioguanine, Thiotepa, Topotecan, Treosulfan, Vinblastine, Vincristine, Vindesine, and Vinorelbine.
12. A method of achieving an antibacterial effect, an antifungal effect, a pesticidal effect and/or a herbicidal effect, the method comprising administering an effective dose of a compound, salt, or solvate according to claim 1 to an infection or infestation.
13. The compound of claim 1 , wherein the compound is N-cyclopentadecyl-3-formamido-2-hydroxybenzamide, or a pharmaceutically acceptable salt or solvate thereof.