Combination cancer therapy with pentaza macrocyclic complex and platinum-based anticancer drugs

Abstract

This invention provides a method for treating cancer in mammals suffering from cancer. [Solution] A method characterized by administering a therapeutically effective amount of a platinum-based anticancer agent, and then administering a therapeutically effective amount of a pentaza macrocyclic complex of the following formula before, simultaneously with, or after the administration of the anticancer agent, thereby enhancing the response of cancer to the anticancer agent. TIFF2026071339000062.tif6660

Description

[Technical Field]

[0001] This disclosure relates to combination therapies for cancer treatment, generally involving the administration of a pentaza macrocyclic ring complex in combination with a platinum-based anticancer agent. [Background technology]

[0002] Transition metal-containing pentaza macrocyclic complexes having a macrocyclic ring group corresponding to formula A have been shown to be effective in treating many animal and cell models of human diseases, as well as in human patients suffering from those diseases. [ka] For example, in a rodent model of colitis, one such compound, GC4403, has been reported to significantly reduce damage to the rat colon in experimental models of colitis (see Cuzzocrea et al., Europ. J. Pharmacol., 432, 79-89 (2001)). [ka] GC4403 has been reported to attenuate radiation damage occurring in both a clinically relevant hamster model of acute radiation-induced oral mucositis (Murphy et al., Clin. Can. Res., 14(13), 4292 (2008)) and in a lethal whole-body irradiation of adult mice (Thompson et al., Free Radical Res., 44(5), 529-40 (2010)). Similarly, another such compound, GC4419, has been shown to attenuate VEGFr inhibitor-induced lung disease in a rat model (Tuder, et al., Am. J. Respir. Cell Mol. Biol., 29, 88-97 (2003)). Furthermore, another such compound, GC4401, has been shown to produce protective effects in animal models of septic shock (S. Cuzzocrea, et.al., Crit. Care Med., 32(1), 157 (2004)) and pancreatitis (S. Cuzzocrea, et.al., Shock, 22(3), 254-61 (2004)). [ka]

[0003] Certain of these compounds also possess potent anti-inflammatory activity and have been shown to inhibit oxidative damage in vivo. For example, GC4403 has been reported to inhibit inflammation in an inflammatory model rat (Salvemini, et.al., Science, 286, 304 (1999)) and prevent joint disease in a model rat of collagen-induced arthritis (Salvemini et al., Arthritis & Rheumatism, 44(12), 2009-2021 (2001)). Furthermore, other of these compounds, MdPAM and MnBAM, have shown in vivo activity in inhibiting colonic tissue injury and neutrophil accumulation in colonic tissue (Weiss et al., The Journal of Biological Chemistry, 271(42), 26149-26156 (1996)). Furthermore, these compounds have been reported to have analgesic effects and reduce inflammation and edema in a rat carrageenan-induced hyperalgesia model of the paw (see, for example, U.S. Patent No. 6,180,620).

[0004] Compounds in this class have also been shown to be safe and effective in the prevention and treatment of diseases in human subjects. For example, GC4419 has been shown to reduce oral mucositis in head and neck cancer patients undergoing chemoradiotherapy (Anderson, C., Phase 1 Trial of Superoxide Dismutase (SOD) Mimetic GC4419 to Reduce Chemoradiotherapy (CRT)-Induced Mucositis (OM) in patients (pts) with Mouth or Oropharyngeal Carcinoma (OCC), Oral Mucositis Research Workshop, MASCC / ISOO Annual Meeting on Supportive Care in Cancer, Copenhagen, Denmark (June 25, 2015)).

[0005] Furthermore, pentaza macrocyclic ring complexes containing transition metals in this class have shown efficacy in treating various cancers. For example, certain compounds in this class have been provided in combination with drugs such as paclitaxel and gemcitabine to enhance cancer treatment, such as colorectal cancer and lung cancer (non-small cell lung cancer) (see, for example, U.S. Patent No. 9,998,893). The 4403 compound described above has also been used in the treatment of Meth A spindle cell squamous cell carcinoma and RENCA renal cell carcinoma in in vivo models (Samlowski et al., Nature Medicine, 9(6), 750-755 (2003)), and in the treatment of spindle cell squamous cell carcinoma metastasis (Samlowski et al., Madame Curie Bioscience Database (Internet), 230-249 (2006)). The 4419 compound mentioned above is also used in combination with cancer therapies, such as cisplatin and radiation therapy, to enhance treatment in in vivo models (Sishc et al., poster for Radiation Research Society (2015)).

[0006] Platinum-based anticancer drugs (e.g., cisplatin and oxaliplatin) act by inducing DNA damage in cancer cells (Cruet-Hennequart et al, DNA Repair, 7(4): 582-596 (2008)) and have been shown to be extremely effective in cancer treatment (Kellan et al, J. Inorg Biochem, 77(1-2); 121-124 (1999); Wang X, Anticancer Agents Med Chem, 10(5): 396-411 (2010); Dilruba et al, Cancer Chemother Pharmacol, 77(6): 1103-1124 (2016)). However, while platinum-based anticancer drugs (e.g., cisplatin) are widely used as chemotherapeutic agents, such drugs often have associated toxicities (e.g., nephrotoxicity, toxic hearing loss, gastric toxicity, and myelotoxicity) (Miller et al., Toxins (Basel), 2(11): 2490-2518 (2010)). Therefore, the use of such platinum-based anticancer drugs may be limited by the need to minimize their associated toxic effects.

[0007] Therefore, there is a need for enhanced cancer treatments that offer improved efficacy in killing cancer cells while also providing better selectivity for killing cancer cells compared to normal cells. Enhanced treatment methods that improve the prognosis of patients receiving these treatments are also needed. Treatment methods that reduce the toxic effects associated with platinum-based anticancer drugs (e.g., cisplatin) are also needed.

[0008] Therefore, to put it simply, the embodiments of this disclosure relate to a method for treating cancer in a mammalian subject suffering from cancer, characterized by administering a therapeutically effective amount of a platinum-based anticancer agent to the subject, and further characterized by administering a therapeutically effective amount of a pentaza macrocyclic complex corresponding to the following formula (I) to the subject before, simultaneously with, and after the administration of the platinum-based anticancer agent, thereby enhancing the responsiveness of the cancer to the platinum-based anticancer agent. [Chemical formula] (I) [In the formula, M is Mn 2+ or Mn 3+ ; and R1, R2, R’2, R3, R4, R5, R’5, R6, R’6, R7, R8, R9, R’9, and R 10 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or -OR 11 , -NR 11 R 12 , -COR 11 , -CO2R 11 , -CONR 11 R 12 , -SR 11 , -SOR 11 , -SO2R 11 , -SO2NR 11 R 12 , -N(OR 11 )(R 12 ), -P(O)(OR 11 )(OR 12 ), -P(O)(OR 11 )(R 12 ), and -OP(O)(OR 11 )(OR 12 ), and are moieties selected from the group consisting of, where R 11 and R 12 are independently hydrogen or alkyl; U combines with adjacent carbon atoms of the macrocyclic ring to form a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; V combines with adjacent carbon atoms of the macrocyclic ring to form a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocyclic ring and the carbon atoms of the macrocyclic ring to which it is bonded, forms an aromatic or alicyclic substituted or unsubstituted saturated, partially saturated or unsaturated nitrogen-containing condensed heterocycle having 2 to 20 ring carbon atoms, provided that W is a condensed aromatic heterocycle, in which case the hydrogen bonded to the nitrogen that is part of both the heterocycle and the macrocyclic ring, and R1 and R bonded to the carbon atoms that are part of both the heterocycle and the macrocyclic ring, are present. 10 It shall be considered non-existent; X and Y represent either a monodentate or polydentate ligand, or an appropriate ligand derived from a ligand system, or an equivalent anion; Z is the counterion; n is an integer between 0 and 3; and The dotted line represents the coordination bond between the nitrogen atom of the macrocyclic ring and the transition metal (manganese).

[0009] Another aspect of this disclosure relates to a method for enhancing the sensitivity of a mammalian subject to treatment with a platinum-based anticancer agent in a subject requiring enhanced sensitivity, characterized by administering a therapeutically effective amount of a pentaza macrocyclic complex corresponding to the following formula (I) to the subject before, simultaneously with, or after administration of the platinum-based anticancer agent to enhance the therapeutic response to the platinum-based anticancer agent. [ka] (I) [In the formula, M is Mn 2+ or Mn 3+ and; R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10 These are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moiety, or -OR 11 , -NR 11 R 12 , -COR 11 , -CO2R 11 ,-CONR11 R 12 , -SR 11 -SOR 11 , -SO2R 11 -SO2NR 11 R 12 , -N(OR 11 )(R 12 ), -P(O)(OR 11 )(OR 12 ), -P(O)(OR 11 )(R 12 ), and -OP(O)(OR 11 )(OR 12 A portion selected from the group consisting of R 11 and R 12 These are independently hydrogen or alkyl; U, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; V, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocyclic ring and the carbon atoms of the macrocyclic ring to which it is bonded, forms an aromatic or alicyclic substituted or unsubstituted saturated, partially saturated or unsaturated nitrogen-containing condensed heterocycle having 2 to 20 ring carbon atoms, provided that W is a condensed aromatic heterocycle, in which case the hydrogen bonded to the nitrogen that is part of both the heterocycle and the macrocyclic ring, and R1 and R bonded to the carbon atoms that are part of both the heterocycle and the macrocyclic ring, are present. 10 It shall be considered non-existent; X and Y represent either a monodentate or polydentate ligand, or an appropriate ligand derived from a ligand system, or an equivalent anion; Z is the counterion; n is an integer between 0 and 3; and The dotted line represents the coordination bond between the nitrogen atom of the macrocyclic ring and the transition metal (manganese).

[0010] Another aspect of this disclosure is a method for reducing the toxic effects on mammals in need of treatment with a platinum-based anticancer agent, The subject is administered a therapeutically effective amount of platinum-based anticancer drug; then This invention relates to a method characterized by administering a therapeutically effective amount of a pentaza macrocyclic ring complex corresponding to the following formula (I) to the subject before, simultaneously with, or after the administration of the platinum-based anticancer agent, thereby reducing the toxic effect of the platinum-based anticancer agent. [ka] (I) [In the formula, M is Mn 2+ or Mn 3+ and; R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10 These are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moiety, or -OR 11 , -NR 11 R 12 , -COR 11 , -CO2R 11 ,-CONR 11 R 12 , -SR 11 -SOR 11 , -SO2R 11 -SO2NR 11 R 12 , -N(OR 11 )(R 12 ), -P(O)(OR 11 )(OR 12 ), -P(O)(OR 11 )(R 12 ), and -OP(O)(OR 11 )(OR 12 A portion selected from the group consisting of R 11 and R 12 These are independently hydrogen or alkyl; U, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; V, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocyclic ring and the carbon atoms of the macrocyclic ring to which it is bonded, forms an aromatic or alicyclic substituted or unsubstituted saturated, partially saturated or unsaturated nitrogen-containing condensed heterocycle having 2 to 20 ring carbon atoms, provided that W is a condensed aromatic heterocycle, in which case the hydrogen bonded to the nitrogen that is part of both the heterocycle and the macrocyclic ring, and R1 and R bonded to the carbon atoms that are part of both the heterocycle and the macrocyclic ring, are present. 10 It shall be considered non-existent; X and Y represent either a monodentate or polydentate ligand, or an appropriate ligand derived from a ligand system, or an equivalent anion; Z is the counterion; n is an integer between 0 and 3; and The dotted line represents the coordination bond between the nitrogen atom of the macrocyclic ring and the transition metal (manganese).

[0011] Another aspect of this disclosure relates to a method for treating and / or reducing the risk of toxic effects associated with treatment with a platinum-based anticancer agent in a mammalian subject in need of treatment, characterized by administering a therapeutically effective amount of a pentaza macrocyclic complex corresponding to the following formula (I) to the subject before, simultaneously with, or after administration of the platinum-based anticancer agent to reduce the toxic effects of the platinum-based anticancer agent. [ka] (I) [In the formula, M is Mn 2+ or Mn 3+ and; R1, R2, R’2, R3, R4, R5, R’5, R6, R’6, R7, R8, R9, R’9, and R 10 are each independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or -OR 11 , -NR 11 R 12 , -COR 11 , -CO2R 11 , -CONR 11 R 12 , -SR 11 , -SOR 11 , -SO2R 11 , -SO2NR 11 R 12 , -N(OR 11 )(R 12 ), -P(O)(OR 11 )(OR 12 ), -P(O)(OR 11 )(R 12 ), and -OP(O)(OR 11 )(OR 12 ), and is a moiety selected from the group consisting of, where R 11 and R 12 are each independently hydrogen or alkyl; U together with adjacent carbon atoms of the macrocyclic ring forms a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; V together with adjacent carbon atoms of the macrocyclic ring forms a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; W together with the nitrogen of the macrocyclic ring and the carbon atom of the macrocyclic ring to which it is attached forms an aromatic or alicyclic substituted or unsubstituted saturated, partially saturated or unsaturated nitrogen-containing fused heterocycle having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocycle, the hydrogen attached to the nitrogen which is part of both the heterocycle and the macrocyclic ring, and R1 and R attached to the carbon atoms which are part of both the heterocycle and the macrocyclic ring 10It shall be considered non-existent; X and Y represent either a monodentate or polydentate ligand, or an appropriate ligand derived from a ligand system, or an equivalent anion; Z is the counterion; n is an integer between 0 and 3; and The dotted line represents the coordination bond between the nitrogen atom of the macrocyclic ring and the transition metal (manganese).

[0012] Other subjects and characteristics are partially known and are partially shown below. [Brief explanation of the drawing]

[0013] [Figure 1] Figure 1 shows the effect of GC4419 on the survival of H460 cells in culture medium. [Figure 2] Figure 2 shows the effects of GC4419, cisplatin, and catalase overexpression on the survival of H1299CAT cells in culture medium. [Figure 3] Figure 3 shows the effects of GC4419 and cisplatin on PARP activation in H460 cells. [Figure 4] Figure 4 shows the effects of GC4419 and cisplatin on PARP activation in H1299 cells. [Figure 5] Figure 5 shows the effects of GC4419, cisplatin, and radiation on PARP activation in H460 cells. [Figure 6A] Figure 6A shows the effects of GC4419, cisplatin, and radiation on PARP activation in H1299 cells. [Figure 6B] Figure 6B shows the treatment of H1299CAT cells with cisplatin and GC4419. [Figure 6C] Figure 6C shows the treatment of H1299CAT cells with cisplatin, IR, and GC4419. [Figure 7A] Figure 7A shows the total reactive oxygen species in cancer cell lines treated with cisplatin and GC4419. [Figure 7B]Figure 7B shows the total reactive oxygen species in cancer cell lines treated with cisplatin and GC4419. [Figure 7C] Figure 7C shows the total reactive oxygen species in cancer cell lines treated with cisplatin and GC4419. [Figure 7D] Figure 7D shows the total reactive oxygen species in cancer cell lines treated with cisplatin and GC4419. [Figure 8A] Figure 8A shows mitochondrial superoxide in cancer cells treated with cisplatin and GC4419. [Figure 8B] Figure 8B shows mitochondrial superoxide in cancer cells treated with cisplatin and GC4419. [Figure 8C] Figure 8C shows mitochondrial superoxide in cancer cells treated with cisplatin and GC4419. [Figure 8D] Figure 8D shows mitochondrial superoxide in cancer cells treated with cisplatin and GC4419. [Figure 9A] Figure 9A shows hydrogen peroxide in cancer cells treated with cisplatin and GC4419. [Figure 9B] Figure 9B shows hydrogen peroxide in cancer cells treated with cisplatin and GC4419. [Figure 9C] Figure 9C shows hydrogen peroxide in cancer cells treated with cisplatin and GC4419. [Figure 9D] Figure 9D shows hydrogen peroxide in cancer cells treated with cisplatin and GC4419. [Figure 10A] Figure 10A shows BUN and creatinine levels in mice treated with cisplatin. [Figure 10B] Figure 10B shows the KIM1 and NGAL biomarkers in mice treated with cisplatin. [Figure 10C] Figure 10C shows cisplatin-induced weight loss. [Figure 10D]Figure 10D shows the survival rate in mice treated with cisplatin. [Figure 11A] Figure 11A shows cisplatin-induced thrombocytopenia. [Figure 11B] Figure 11B shows GC4419 and white blood cell count. [Figure 11C] Figure 11C shows cisplatin-induced neutropenia. [Figure 11D] Figure 11D shows cisplatin-induced eosinophilia. [Modes for carrying out the invention]

[0014] Abbreviations and definitions The following definitions and methods are provided to clarify the present invention and to enable those skilled in the art to carry it out. Unless otherwise indicated, terms should be understood by their customary use by those skilled in the art.

[0015] "Acyl" means the -COR portion (wherein R is an alkyl, haloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, as defined herein), such as acetyl, trifluoroacetyl, benzoyl, etc.

[0016] "Acyloxy" means the -OCOR portion (wherein R is an alkyl, haloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, as defined herein), such as acetyl, trifluoroacetyl, benzoyl, etc.

[0017] "Alkoxy" means the -OR portion (wherein R is alkyl as defined herein), such as methoxy, ethoxy, propoxy, 2-propoxy, n-, iso-, or tert-butoxy.

[0018] "Alkyl" refers to a straight-chain saturated monovalent hydrocarbon moiety (e.g., 1 to 6 carbon atoms) or a branched-chain saturated monovalent hydrocarbon moiety (e.g., 3 to 6 carbon atoms), such as C1-C6 alkyl groups, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomers), pentyl (including all isomers), etc.

[0019] Furthermore, unless otherwise indicated, the term “alkyl” as used herein includes both “unsubstituted alkyl” and “substituted alkyl,” the latter of which means an alkyl moiety having a substituent that substitutes a hydrogen at one or more carbon atoms in the hydrocarbon skeleton. In fact, unless otherwise indicated, all groups described herein include both substituted and unsubstituted options.

[0020] The term “C x-y When used with a compound part (e.g., alkyl and aralkyl), the term "C" is defined as a group containing x to y carbon atoms in the chain. For example, the term "C" x-y "Alkyl" means a substituted or unsubstituted saturated hydrocarbon group, and includes straight-chain alkyl and branched-chain alkyl groups containing x to y carbon atoms in the chain.

[0021] Unless otherwise specified, "alkylene" refers to a straight-chain saturated divalent hydrocarbon moiety (e.g., 1 to 6 carbon atoms) or a branched-chain saturated divalent hydrocarbon moiety (e.g., 3 to 6 carbon atoms), such as methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, and pentylene.

[0022] "Alkenyl" refers to a straight-chain unsaturated monovalent hydrocarbon moiety (e.g., 2 to 6 carbon atoms) or a branched-chain saturated monovalent hydrocarbon moiety (e.g., 3 to 6 carbon atoms), such as ethenyl (vinyl), propenyl, 2-propenyl, butenyl (including all isomers), and pentenyl (including all isomers).

[0023] "Alkalyl" refers to a monovalent part derived from the aryl part by substituting one or more hydrogen atoms with an alkyl group.

[0024] "Alkenylcycloalkenyl" refers to a monovalent part derived from the alkenyl moiety by substituting one or more hydrogen atoms with a cycloalkenyl group.

[0025] "Alkenylcycloalkyl" refers to a monovalent part derived from a cycloalkyl moiety by substituting one or more hydrogen atoms with an alkenyl group.

[0026] "Alkylcycloalkenyl" refers to a monovalent part derived from a cycloalkenyl moiety by substituting one or more hydrogen atoms with an alkyl group.

[0027] "Alkylcycloalkyl" refers to a monovalent part derived from a cycloalkyl moiety by substituting one or more hydrogen atoms with an alkyl group.

[0028] "Alkynyl" refers to a straight-chain unsaturated monovalent hydrocarbon moiety (e.g., 2 to 6 carbon atoms) or a branched-chain saturated monovalent hydrocarbon moiety (e.g., 3 to 6 carbon atoms), such as ethynyl, propynyl, butynyl, isobutynyl, and hexynyl.

[0029] "Alkoxy" refers to a monovalent part derived from an alkyl part by substituting one or more hydrogen atoms with a hydroxyl group.

[0030] "Amino" is -NR a R b Group (R a and R b (Independently, this means hydrogen, alkyl, or aryl.)

[0031] "Aralkyl" refers to a monovalent part derived from an alkyl part by substituting one or more hydrogen atoms with an aryl group.

[0032] "Aryl" refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon moiety consisting of 6 to 10 ring atoms, such as phenyl or naphthyl.

[0033] The term "ring" refers to a carbon-cyclic saturated monovalent hydrocarbon portion consisting of 3 to 10 carbon atoms.

[0034] "Cycloalkyl" refers to a cyclic saturated monovalent hydrocarbon moiety consisting of 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0035] "Cycloalkylalkyl" refers to a monovalent part derived from an alkyl part by substituting one or more hydrogen atoms with a cycloalkyl group, such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, or cyclohexylethyl.

[0036] "Cycloalkylcycloalkyl" refers to a monovalent part derived from a cycloalkyl moiety by substituting one or more hydrogen atoms with a cycloalkyl group.

[0037] "Cycloalkenyl" refers to a cyclic monounsaturated monovalent hydrocarbon moiety consisting of 3 to 10 carbon atoms, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl.

[0038] "Cycloalkenylalkyl" refers to a monovalent part derived from an alkyl part by substituting one or more hydrogen atoms with a cycloalkenyl group, such as cyclopropenylmethyl, cyclobutenylmethyl, cyclopentenylethyl, or cyclohexenylethyl.

[0039] "Ether" refers to the monovalent part derived from the alkyl part by substituting one or more hydrogen atoms with an alkoxy group.

[0040] "Halo" means fluoro, chloro, bromo, or iodine, preferably fluoro or chloro.

[0041] A "heterocyclic" is a saturated or unsaturated monovalent monocyclic group consisting of 4 to 8 ring atoms, where 1 or 2 ring atoms are N, O, or S(O). n The heterocyclyl ring is a heteroatom selected from (n is an integer between 0 and 2), and the remaining ring atoms are defined as carbon groups. The heterocyclyl ring may be fused to (one) aryl or heteroaryl ring as defined herein, but the aryl and heteroaryl rings shall be monocyclic. A heterocyclyl ring fused to a monocyclic aryl or heteroaryl ring is also referred to herein as a "bicyclic heterocyclyl" ring. In addition, one or two ring carbon atoms in the heterocyclyl ring may be substituted with -CO- groups as appropriate. More specifically, the term heterocyclyl includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl, thiomorpholino, etc. If the heterocyclyl ring is unsaturated, it may contain one or two ring double bonds, but the ring shall not be aromatic. When the heterocyclyl group is a saturated ring and is not fused to an aryl or heteroaryl ring as described above, it is referred to as a saturated monocyclic heterocyclyl in this specification.

[0042] "Heteroaryl" refers to a monovalent monocyclic or bicyclic aromatic moiety consisting of 5 to 10 ring atoms, wherein one or more preferably one, two, or three ring atoms are heteroatoms selected from N, O, or S, and the remaining ring atoms are carbon. Typical examples, but not limited to, include pyrrolyl, pyrazolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, triazolyl, and tetrazolyl.

[0043] "Nitro" means -NO2.

[0044] "Organosulfur" refers to a monovalent partial-SR group (where R is hydrogen, alkyl, or aryl).

[0045] "Platinum-based anticancer agents" refers to a class of compounds that have anticancer effects and are coordination complexes of platinum, also known as platinum, platinumate, and platinum-based anti-cancer drugs. Examples of platinum-based anticancer agents used in chemotherapy include cisplatin, oxaliplatin, carboplatin, nedaplatin, lovaplatin, heptaplatin, dicycloplatin, lipoplatin, LA-12, phosphaplatin, phenanthriplatin, prolindac, triplatin tetranitrate, picoplatin, satraplatin, and / or pharmaceutically acceptable salts thereof.

[0046] "Substituted alkyl," "substituted ring," "substituted phenyl," "substituted aryl," "substituted heterocycle," and "substituted nitrogen heterocycle" mean alkyl, ring, aryl, phenyl, heterocycle, or nitrogen-containing heterocycle, respectively, which may be appropriately substituted with one, two, or three substituents independently selected from alkyl, alkoxy, alkoxyalkyl, halo, hydroxy, hydroxyalkyl, or organosulfur. In general, the term "substituted" includes groups that are substituted with one or more of the following: C1-4 alkyl, C2-4 alkenyl, halogen, alcohol, and / or amine.

[0047] "Thioether" refers to a monovalent part derived from an alkyl moiety by substituting one or more hydrogen atoms with an -SR group (where R is alkyl).

[0048] As used herein, (i) the compounds described herein and in the drawings as compound 401, 4401 or GC4401 are described as the same compound; (ii) the compounds described herein and in the drawings as compound 403, 4403 or GC4403 are described as the same compound; (iii) the compounds described herein and in the drawings as compound 419, 4419 or GC4419 are described as the same compound; and (iv) the compounds described herein and in the drawings as compound 444, 4444 or GC4444 are described as the same compound.

[0049] Detailed explanation In one embodiment, the aspect of the present disclosure relates to the treatment of cancer by administering to a subject with cancer a therapeutically effective amount of a pentaza macrocyclic ring complex of formula (I) described below in combination with a therapeutically effective amount of a platinum-based anticancer agent. The pentaza macrocyclic ring complex may be administered before, simultaneously with, or after the administration of the platinum-based anticancer agent to enhance the responsiveness of the cancer to the platinum-based anticancer agent. In particular, unexpectedly, it has been shown that when the pentaza macrocyclic ring complex of formula (I) is administered in combination with a platinum-based anticancer agent, it exhibits a synergistic effect, producing an additive effect or greater than the administration of either the platinum-based anticancer agent or the pentaza macrocyclic ring complex of formula (I) alone. Without being limited to any particular theory, it is conceivable that the pentaza macrocyclic ring complex of formula (I) acts to sensitize cancer cells to treatment with platinum-based anticancer agents, making cancer cells highly responsive to the anticancer effects of platinum-based anticancer agents. Furthermore, without being limited to any particular theory, it has been found that platinum-based anticancer agents can act to kill cancer cells in combination with the pentaza macrocyclic ring complex of formula (I) through a previously unknown mechanism of action involving hydrogen peroxide, and that this mechanism can be synergistically enhanced by this combination. A further explanation of the synergistic effect between the pentaza macrocyclic ring complex of formula (I) and platinum-based anticancer agents is provided in the examples described herein.

[0050] Therefore, in one aspect of this disclosure, a method is provided for enhancing the sensitivity of a mammalian subject to treatment with a platinum-based anticancer agent. The method is characterized by administering a therapeutically effective amount of a pentaza macrocyclic complex corresponding to the following formula (I) to the subject before, simultaneously with, or after administration of the platinum-based anticancer agent, thereby enhancing the therapeutic response to the platinum-based anticancer agent.

[0051] Another further aspect of this disclosure relates to the finding that administration of a pentaza macrocyclic complex corresponding to the following formula (I) can reduce the toxic effects (e.g., nephrotoxicity and myelotoxicity) of platinum-based anticancer agents. Accordingly, in one embodiment, a method for reducing the toxic effects on a mammalian subject associated with treatment with a platinum-based anticancer agent in a mammalian subject in need of treatment includes administering a therapeutically effective amount of the platinum-based anticancer agent to the subject, and administering a therapeutically effective amount of a pentaza macrocyclic complex corresponding to the following formula (I) before, simultaneously with, or after the administration of the platinum-based anticancer agent to reduce the toxic effects of the platinum-based anticancer agent. In yet another embodiment, a method is provided for treating and / or reducing the risk of toxic effects associated with treatment with a platinum-based anticancer agent in a mammalian subject requiring treatment and / or reduction, characterized by administering a pentaza macrocyclic complex corresponding to the following formula (I) to the subject before, simultaneously with, or after administration of the platinum-based anticancer agent to reduce the toxic effects of the platinum-based anticancer agent.

[0052] In one embodiment, the subject may be subject that is at risk of toxic effects associated with treatment with a platinum-based anticancer agent by receiving the platinum-based anticancer agent as part of a treatment plan. For example, the subject may be receiving the platinum-based anticancer agent as part of a plan for cancer treatment, thereby being at risk of developing toxic effects associated with the platinum-based anticancer agent while receiving cancer treatment. In another embodiment, the subject may be susceptible to and / or currently suffering from toxic effects associated with a platinum-based anticancer agent (e.g., nephrotoxicity, myelotoxicity, and / or other toxicities). In one embodiment, it has been found that administration of a pentaza macrocyclic complex corresponding to formula (I) can reduce, alleviate, and / or treat diseases associated with the toxicity of a platinum-based anticancer agent, and can reduce the risk of developing such diseases in the subject. Thus, in one embodiment, a pentaza macrocyclic complex according to formula (I) below can reduce the toxicity of a platinum-based anticancer agent without substantially reducing the efficacy of the platinum-based anticancer agent. Furthermore, in one embodiment, the reduction in toxicity provided by the combination may simultaneously result in an enhanced therapeutic response of cancer to the platinum-based anticancer agent. That is, the combination can simultaneously and synergistically sensitize cancer cells to death by the platinum-based anticancer agent while reducing the toxic effect of the platinum-based anticancer agent on normal cells (non-cancerous cells).

[0053] Transition metal pentaza macrocyclic ring complexes In one embodiment, the pentaza macrocyclic ring complex is given by formula (I): [ka] (I) [In the formula, M is Mn 2+ or Mn 3+ and; R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10These are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moiety, or -OR 11 , -NR 11 R 12 , -COR 11 , -CO2R 11 ,-CONR 11 R 12 , -SR 11 -SOR 11 , -SO2R 11 -SO2NR 11 R 12 , -N(OR 11 )(R 12 ), -P(O)(OR 11 )(OR 12 ), -P(O)(OR 11 )(R 12 ), and -OP(O)(OR 11 )(OR 12 A portion selected from the group consisting of R 11 and R 12 These are independently hydrogen or alkyl; U, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; V, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen and carbon atoms of the macrocyclic ring to which it is bonded, forms an aromatic or alicyclic substituted or unsubstituted saturated, partially saturated or unsaturated nitrogen-containing condensed heterocycle having 2 to 20 ring carbon atoms, provided that W is a condensed aromatic heterocycle, in which case R1 and R1 are bonded to the nitrogen atoms that are part of both the heterocycle and the macrocyclic ring, and to the carbon atoms that are part of both the heterocycle and the macrocyclic ring. 10 It shall be considered not to exist; X and Y represent either a monodentate or polydentate ligand, or an appropriate ligand derived from a ligand system, or an equivalent anion; Z is the counterion; n is an integer between 0 and 3; and This represents the coordination bond between the nitrogen atom of the macrocyclic ring and the transition metal (manganese). It corresponds to a complex of the two.

[0054] As described above for the pentaaza macrocyclic ring complex of formula (I), M is Mn 2+ or Mn 3+ In a particular embodiment where the pentaza macrocyclic ring complex corresponds to formula (I), M is Mn 2+ In another specific embodiment where the pentaza macrocyclic ring complex corresponds to formula (I), M is Mn 3+ That is the case.

[0055] R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10 In embodiments where one or more of the components are hydrocarbyl, suitable hydrocarbyl moieties include, but are not limited to, alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, and aralkyl. In one embodiment, R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10 R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10R is independently either hydrogen or a lower alkyl (e.g., C1-C6 alkyl, more typically C1-C4 alkyl). Thus, for example, R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10 This may independently be hydrogen, methyl, ethyl, propyl, or butyl (linear, branched, or cyclic).

[0056] In one preferred embodiment, R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10 R is independently hydrogen or methyl. In one preferred embodiment where the pentaza macrocyclic complex corresponds to formula (I), R1, R2, R'2, R3, R4, R5, R'5, R7, R8, R9, R'9, and R 10 Each of R6 and R'6 is hydrogen, one of R6 and R'6 is hydrogen, and the other of R6 and R'6 is methyl. In this embodiment, for example, R1, R2, R'2, R3, R4, R5, R'5, R6, R7, R8, R9, R'9, and R 10 Each of these may be hydrogen, and R'6 is methyl. Alternatively, for example, R1, R2, R'2, R3, R4, R5, R'5, R'6, R7, R8, R9, R'9, and R 10 Each of these may be hydrogen, and R6 is methyl. In another preferred embodiment where the pentaza macrocyclic complex corresponds to formula (I), R1, R3, R4, R5, R'5, R'6, R7, R8, and R 10 Each of R1 and R'2 is hydrogen, one of R2 and R'2 is hydrogen, the other of R2 and R'2 is methyl, and one of R9 and R'9 is hydrogen, the other of R9 and R'9 is methyl. In this embodiment, for example, R1, R'2, R3, R4, R5, R'5, R7, R8, R9, and R 10 Each of these may be hydrogen, and R2 and R'9 are methyl. Alternatively, for example, R1, R2, R3, R4, R5, R'5, R7, R8, R'9, and R 10Each of these may be hydrogen, and R'2 and R9 are methyl. In another embodiment where the pentaza macrocyclic complex corresponds to formula (I), R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10 Each of these is hydrogen.

[0057] In one embodiment, the U and V portions are independently substituted or unsubstituted condensed cycloalkyl portions having 3 to 20 ring carbon atoms, more preferably 4 to 10 ring carbon atoms. In a particular embodiment, the U and V portions are each trans-cyclohexanyl condensed rings.

[0058] In one embodiment, the W portion is a substituted or unsubstituted condensed heteroaromatic moiety. In a particular embodiment, the W portion is a substituted or unsubstituted condensed pyridino moiety. When W is a substituted condensed pyridino moiety, the W portion is typically substituted with a hydrocarbyl or substituted hydrocarbyl moiety (e.g., alkyl, substituted alkyl) at the ring carbon atom located para relative to the nitrogen atom of the heterocycle. In one preferred embodiment, the W portion is an unsubstituted condensed pyridino moiety.

[0059] As described above, X and Y represent either a monodentate or polydentate ligand or a suitable ligand derived from a ligand system, or the corresponding anion therein (e.g., benzoic acid or benzoate anion, phenol or phenoxide anion, alcohol or alkoxide anion). For example, X and Y are, in particular, halo, oxo, aco, hydroxo, alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino, heterocycloalkylamino, heterocycloarylamino, amine oxide, hydrazine, alkylhydrazine, arylhydrazine, nitrogen oxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkylnitrile, arylnitrile, alkylisonitrile, arylisonitrile, nitrate, nitrite, azide, alkylsulfonic acid, arylsulfonic acid, alkylsulfoxide, arylsulfoxide, alkylarylsulfoxide, alkylsulfenic acid, arylsulfenic acid, alkylsulfinic acid, arylsulfinic acid, alkylthiol carboxylic acid, arylthiol carboxylic acid, alkylthiol thiocarboxylic acid, arylthiol thiocarboxylic acid, alkyl carboxylic acid Acids, arylcarboxylic acids, urea, alkylurea, arylurea, alkylarylurea, thiourea, alkylthiourea, arylthiourea, alkylarylthiourea, sulfuric acid, sulfite, bisulfite, bisulfite, thiosulfite, thiosulfite, hydrosulfite, alkylphosphine, arylphosphine, alkylphosphine oxide, arylphosphine oxide, alkylarylphosphine oxide, alkylphosphine sulfide, arylphosphine sulfide, alkylarylphosphine sulfide, alkylphosphonic acid, arylphosphonic acid, alkylphosphine acid, arylphosphine acid, alkylphosphinic acid, arylphosphorus acid, arylphosphorus acid, arylphosphorus acid, arylphosphorus acid, arylphosphorus acid, arylphosphorus acid, phosphoric acid, thiophosphate, phosphorous acid, pyrophosphorus acid, triphosphate, hydrogen phosphate, dihydrogen phosphate, alkylguanidino, arylguanidino, alkylarylguanidino, alkylcarbamate, arylcarbamate, alkylarylcarbamate, alkylthiocarbamate, arylthiocarbamate,The following may be selected: alkylarylthiocarbamates, alkyldithiocarbamates, aryldithiocarbamates, alkylaryldithiocarbamates, bicarbonate, carbonic acid, perchloric acid, chloric acid, chlorous acid, hypochlorous acid, perbromic acid, bromic acid, bromic acid, hypobromous acid, tetrahalomanganates, tetrafluoroboric acid, hexafluoroantimonic acid, hypophosphorous acid, iodic acid, periodic acid, metaboric acid, tetraarylboric acid, tetraalkylboric acid, tartaric acid, salicylic acid, succinic acid, citric acid, ascorbic acid, saccharic acid, amino acids, hydroxamic acid, thiotosylic acid, and anions of ion exchange resins, or corresponding anions thereof. In one embodiment, X and Y may be independently selected from the group consisting of halos, nitric acid, and bicarbonate ligands, if present. For example, in this embodiment, X and Y are, if present, halo ligands, such as chloro ligands.

[0060] Furthermore, in one embodiment, X and Y correspond to -OC(O)-X1, where each X1 is -C(X2)(X3)(X4), and each X1 is independently substituted or unsubstituted phenyl or -C(-X2)(-X3)(-X4); each X2 is independently substituted or unsubstituted phenyl, methyl, ethyl or propyl; each X3 is independently hydrogen, hydroxyl, methyl, ethyl, propyl, amino, or -X5C(=O)R 13 [In the formula, X5 is NH or O, and R 13 C1-C 18 Alkyl, substituted or unsubstituted aryl, or C1-C 18 [to be allaculous] or -OR 14 [In the formula, R 14 C1-C 18 Alkyl, substituted or unsubstituted aryl, or C1-C 18 It is either aralkyl or together with X4 (=O); and each X4 is independently either hydrogen or together with X3 (=O).

[0061] In yet another embodiment, X and Y are independently selected from a group consisting of charge-neutralizing anions derived from monodentate or polydentate ligands, as well as ligand systems and their corresponding anions; or X and Y are independently selected from R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10 It is combined with one or more of the following.

[0062] In the pentaza macrocyclic complex corresponding to equation (I), Z is a counterion (e.g., a charge-neutralizing anion), and n is an integer between 0 and 3. In general, Z may be the counterion of the parts of X and Y described above.

[0063] In the combination, one preferred embodiment is a pentaza macrocyclic ring complex corresponding to formula (I), M is Mn 2+ or Mn 3+ and; R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10 These are independently hydrogen or a lower alkyl group; U and V are trans-cyclohexanyl condensed rings, respectively; W is a substituted or unsubstituted condensed pyridino moiety; X and Y are ligands; and Z is the aforementioned complex, which, if present, is a charge-neutralizing anion.

[0064] More preferably, in these embodiments, M is Mn 2+ R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10is independently hydrogen or methyl; U and V are each a trans-cyclohexanyl condensed ring; W is an unsubstituted condensed pyridino moiety; and X and Y are independently halo ligands (e.g., fluoro, chloro, bromo, iodine). Z may be a halide anion (e.g., fluoride ion, chloride ion, bromide ion, iodide ion) if present.

[0065] In yet another embodiment, the pentaza macrocyclic ring complex is given by the following formula (II): [ka] (II) [In the formula, X and Y represent either a monodentate or polydentate ligand or a suitable ligand derived from a ligand system, or the corresponding anions thereof; and R A , R B , R C , and R D These are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moiety, or -OR 11 , -NR 11 R 12 , -COR 11 , -CO2R 11 ,-CONR 11 R 12 , -SR 11 -SOR 11 , -SO2R 11 -SO2NR 11 R 12 , -N(OR 11 )(R 12 ), -P(O)(OR 11 )(OR 12 ), -P(O)(OR 11 )(R 12 ), and -OP(O)(OR 11 )(OR 12 A portion selected from the group consisting of R 11 and R 12 [These are independently hydrogen or alkyl.] It is represented by [this].

[0066] Furthermore, in one embodiment, the pentaaza macrocyclic ring complex is of formula (III) or formula (IV):

Chem.

[0067] In yet another embodiment, the pentaaza macrocyclic ring complex is of formula (V) to (XVI):

Chem.

Chem.

[0068] In one embodiment, X and Y in any of the formulas herein are independently selected from the group consisting of fluoro, chloro, bromo, and iodo anions. In yet another embodiment, X and Y in any of the formulas herein are independently selected from the group consisting of alkyl carboxylates, aryl carboxylates, and arylalkyl carboxylates. In yet another embodiment, X and Y in any of the formulas herein are independently amino acids.

[0069] In one embodiment, the pentaaza macrocyclic complex is represented by the following formula (IA): [ka] (IA) [In the formula, M is Mn 2+ or Mn 3+ and; R 1A , R 1B , R2, R3, R 4A , R 4B R5, R6, R 7A , R 7B R8, R9, R 10A , and R 10B These are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moiety, or -OR 11 , -NR 11 R 12 , -COR 11 , -CO2R 11 -C(=O)NR 11 R 12 , -SR 11 -SOR 11 , -SO2R 11 -SO2NR 11 R 12 , -N(OR 11 )(R 12 ), -P(=O)(OR 11 )(OR12 ), -P(=O)(OR 11 )(R 12 ), and -OP(=O)(OR 11 )(OR 12 A portion selected from the group consisting of R 11 and R 12 These are independently hydrogen or alkyl; U, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; V, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocyclic ring and the carbon atoms of the macrocyclic ring to which it is bonded, forms an aromatic or alicyclic substituted or unsubstituted saturated, partially saturated or unsaturated nitrogen-containing condensed heterocycle having 2 to 20 ring carbon atoms, provided that if W is a condensed aromatic heterocycle, the hydrogen bonded to the nitrogen in both the heterocycle and the macrocyclic ring, as well as R5 and R6 in both the heterocycle and the macrocyclic ring, are not present; Each X1 is independently a substituted or unsubstituted phenyl, or -C(-X2)(-X3)(-X4); Each X2 is independently a substituted or unsubstituted phenyl or alkyl group; Each X3 independently consists of hydrogen, hydroxyl, alkyl, amino, and -X5C(=O)R 13 [In the formula, X5 is NH or O, and R 13 C1-C 18 Alkyl, substituted or unsubstituted aryl, or C1-C 18 [to be allaculous] or -OR 14 [In the formula, R 14 C1-C 18 Alkyl, substituted or unsubstituted aryl, or C1-C 18It is either aralkyl or together with X4 (=O); Each X4 is either hydrogen independently, or together with X3 (=O); and The bond between the transition metal M and the nitrogen atom of the macrocyclic ring, as well as the bond between the transition metal M and the oxygen atom of the axial ligand -OC(=O)X1, are coordinate covalent bonds. This is shown.

[0070] In one embodiment, within formula (IA) and the groups contained therein, in one group of the compound, X1 is -C(-X2)(-X3)(-X4), and each of X2, X3, and X4 in combination corresponds to one of the combinations identified in the table below: [Table 1]

[0071] Furthermore, in embodiment (IA) and within the groups contained therein, in one group of the compound, X1 is C(-X2)(-X3)(-X4) and X3 is -X5C(=O)R 13 The combinations of X2, X3, and X4 include one of the combinations identified in the table below: [Table 2] [In the formula, R 13 C1-C 18 Alkyl, substituted or unsubstituted aryl or C1-C 18 Aralquil, or -OR 14 (In the formula, R 14 C1-C 18 Alkyl, substituted or unsubstituted aryl, or C1-C 18 (It is Aralkir)

[0072] In one embodiment, the pentaza macrocyclic ring complex corresponding to formula (IA) is the complex formula (IE), for example, (IE R1 ), (IES1 ), (IE R2 ), (IE S2 ), (IE R3 ), or (IE S3 ): [Chemistry] [Chemistry] [Chemistry] [wherein, M is Mn +2 or Mn +3 ; each X1 is independently a substituted or unsubstituted phenyl or -C(X2)(X3)(X4); each X2 is independently a substituted or unsubstituted phenyl, methyl, ethyl, or propyl; each X3 is independently hydrogen, hydroxyl, methyl, ethyl, propyl, amino, or together with X4 is =O; each X4 is independently hydrogen or together with X3 is =O; and the bond between manganese and the nitrogen atom of the macrocyclic ring and the bond between manganese and the oxygen atom of the axial ligand -OC(O)X1 are coordinate covalent bonds] is one of them.

[0073] In one embodiment, each X1 is -C(X2)(X3)(X4), and each -C(X2)(X3)(X4) corresponds to any one of combinations 1 to 9 shown in the table for the above formula (IA).

[0074] In yet another embodiment, X and Y in the pentaaza macrocyclic ring complex of formula (I) correspond to the ligands in formula (IA) or (IE). For example, X and Y in the said complex of formula (I) may correspond to -O-C(O)-X1, where X1 is as defined for the complexes of the above formulas (IA) and (IE).

[0075] In one embodiment, the pentaaza macrocyclic complex corresponding to formula (I) (for example, any subset of formula (I) corresponding to formula (I) or formulas (II)-(XIV), (IA), and (IE)) has the following structure: [ka] [ka] [ka] [ka] [ka] [ka] It may include any of the following:

[0076] In one embodiment, the pentaza macrocyclic ring complex for use in the methods and compositions described herein includes formulas (2), (3), (4), (5), (6), and (7): [ka] [In the equations, X and Y in each of equations (2), (3), (4), (5), (6), and (7) are independent ligands.] This includes equivalents to the following. For example, according to Embodiment 1, the pentaza macrocyclic complex for use in the methods and compositions described herein includes equivalents to formulas (2), (3), (4), (5), (6), and (7) [where X and Y in each of these formulas are halos (e.g., chloro)]. Alternatively, X and Y may be ligands other than chloro, for example, any of the ligands described above.

[0077] In another embodiment, the pentaaza macrocyclic ring complex is given by formula (6) or formula (7): [ka] It corresponds to this.

[0078] The chemical structures of 6 (e.g., the dichloro complex morphology described herein in Riley, DP, Schall, OF, 2007, Advances in Inorganic Chemistry, 59: 233-263) and 7 (e.g., the dichloro complex structure of 7) are identical except that they possess enantiomer chirality (i.e., their enantiomer structures cannot be superimposed).

[0079] For example, the aforementioned pentaza macrocyclic complex is the following complex: [ka] It could correspond to at least one of the following.

[0080] In yet another embodiment, the pentaza macrocyclic complex is the following complex: [ka] [ka] and / or may correspond to at least one of these enantiomers.

[0081] In one embodiment, the enantiomer purity of the pentaza macrocyclic complex is 95% or higher, more preferably 98% or higher, more preferably 99% or higher, and most preferably 99.5% or higher. As used herein, the term “enantiomer purity” means the amount of compound having the indicated absolute stereochemistry, expressed as a percentage of the total amount of the indicated compound and its enantiomers. In one embodiment, the diastereomer purity of the pentaza macrocyclic complex is 98% or higher, more preferably 99% or higher, and most preferably 99.5% or higher. As used herein, the term “diastereomer purity” means the amount of compound having the indicated absolute stereochemistry, expressed as a percentage of the total amount of the indicated compound and its diastereomers. Methods for determining diastereomer and enantiomer purity are well known in the art. Diastereomer purity can be determined by any analytical method capable of quantitatively distinguishing a compound from its diastereomers, for example, high-performance liquid chromatography (HPLC). Similarly, enantiomer purity can be determined by any analytical method that can quantitatively distinguish between a compound and its enantiomer. Suitable analytical methods for determining enantiomer purity include, but are not limited to, polarimetric analysis using a polarimeter and HPLC using a chiral column packing material.

[0082] In one embodiment, the therapeutically effective dose of the pentaza macrocyclic complex may be sufficient to provide a peak plasma concentration of at least 0.1 μM when administered to a patient. For example, in one embodiment, the pentaza macrocyclic complex may be sufficient to provide a peak plasma concentration of at least 1 μM when administered to a patient. In yet another embodiment, the pentaza macrocyclic complex may be sufficient to provide a peak plasma concentration of at least 10 μM when administered to a patient. Generally, the pentaza macrocyclic complex is not administered in an amount that would provide a peak plasma concentration of 40 μM or higher when administered to a patient. For example, the pentaza macrocyclic complex may be administered in an amount sufficient to provide a peak plasma concentration in the range of 0.1 μM to 40 μM in a patient. As another example, the pentaza macrocyclic complex may be administered in an amount sufficient to provide a peak plasma concentration in the range of 0.5 μM to 20 μM in a patient. As another example, the pentaza macrocyclic complex may be administered in an amount sufficient to provide a peak plasma concentration in the range of 1 μM to 10 μM in the patient.

[0083] In yet another embodiment, the dose of the pentaza macrocyclic complex administered per kg of body weight of the patient may be at least 0.1 mg / kg, for example, at least 0.2 mg / kg. For example, the dose of the pentaza macrocyclic complex administered per kg of body weight of the patient may be at least 0.5 mg / kg. In another example, the dose of the pentaza macrocyclic complex administered per kg of body weight of the patient may be at least 1 mg / kg. In yet another example, the dose of the pentaza macrocyclic compound administered per kg of body weight may be at least 2 mg / kg, for example, at least 3 mg / kg, and at least about 15 mg / kg, for example, at least 24 mg / kg, and at least 40 mg / kg. In general, the dose of the pentaza macrocyclic complex administered per kg of body weight of the patient does not exceed 1000 mg / kg. For example, the dose of pentaza macrocyclic ring complex administered per kg of body weight of a patient may be in the range of 0.1 to 1000 mg / kg, for example, 0.2 mg / kg to 40 mg / kg, for example, 0.2 mg / kg to 24 mg / kg, and even 0.2 mg / kg to 10 mg / kg. Another example is that the dose of pentaza macrocyclic ring complex administered per kg of body weight may be in the range of 1 mg / kg to 1000 mg / kg, for example, 3 mg / kg to 1000 mg / kg, and even 5 mg / kg to 1000 mg / kg, for example, 10 mg / kg to 1000 mg / kg. Yet another example is that the dose of pentaza macrocyclic ring complex administered per kg of body weight may be in the range of 2 mg / kg to 15 mg / kg. And yet another example is that the dose of pentaza macrocyclic ring complex administered per kg of body weight may be in the range of 3 mg / kg to 10 mg / kg. As another example, the dose of pentaza macrocyclic ring complex administered per kg of body weight in a patient may be in the range of 0.5 to 5 mg / kg. Furthermore, as yet another example, the dose of pentaza macrocyclic ring complex administered per kg of body weight in a patient may be in the range of 1 to 5 mg / kg.

[0084] In one embodiment, the doses and / or plasma concentrations described above may be particularly suitable for pentaza macrocyclic complexes corresponding to GC4419, but they may also be suitable for other pentaza macrocyclic complexes. Furthermore, those skilled in the art may understand how to adjust the doses and / or plasma concentrations based on factors such as the molecular weight and / or activity of the specific compound used. For example, for a pentaza macrocyclic complex having twice the activity of GC4419, the dose and / or plasma concentration may be halved, or for a pentaza macrocyclic complex having a higher molecular weight than GC4419, a correspondingly higher dose may be used.

[0085] The dosing regimen for the pentaza macrocyclic complex can be similarly selected depending on the treatment to be pursued. For example, in one embodiment, a suitable dosing regimen may include administering the drug to the patient at least once a week during the treatment period, for example, for 2, 3, 4, 5, 6, or 7 days (e.g., daily) per week. As another example, in one embodiment, the dosing may be at least once a day (qd) or at least twice a day (bid). In one embodiment, the treatment period with the pentaza macrocyclic complex may continue for at least the same duration as the treatment period with a platinum-based anticancer agent (e.g., cisplatin), and may extend beyond the period during which the platinum-based anticancer agent is administered. The treatment period with the pentaza macrocyclic complex may also begin on the same day as the treatment with the platinum-based anticancer agent, or it may begin some time after the start of administration of the platinum-based anticancer agent, as described in more detail below. For example, in one embodiment, with respect to a platinum-based anticancer drug administered over a treatment period of at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, and 6 months, the pentaza macrocyclic complex may be administered over a treatment period of at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, and 6 months.

[0086] Platinum-based anticancer drugs According to one embodiment, a platinum-based anticancer agent is provided in combination with a pentaza macrocyclic compound as part of the therapeutic method described herein. Platinum-based anticancer agents include a class of compounds that are platinum coordination complexes and have anticancer effects. Platinum-based anticancer agents (e.g., cisplatin and oxaliplatin) are understood to exert their anticancer effects by inducing DNA damage in cancer cells (Cruet-Hennequart et al, DNA Repair, 7(4): 582-596 (2008)), and have been shown to be extremely effective in cancer treatment (Kelland et al, J. Inorg Biochem, 77(1-2); 121-124 (1999); Wang X, Anticancer Agents Med Chem, 10(5): 396-411 (2010); Dilruba et al, Cancer Chemother Pharmacol, 77(6): 1103-1124 (2016); Johnstone et al., Anticancer Res, 34(1): 471-476 (2014)). Platinum-based anticancer compounds may include platinum(II) complexes (e.g., cisplatin, carboplatin, and oxaliplatin) and platinum(IV) complexes (e.g., satraplatin and LA-12) (see, e.g., Bouchal et al. Proteome Science, 9:68 (2011)). The platinum-based anticancer agents may be provided in various formulations, or as part of a delivery vesicle or other targeting moiety for tumors and / or cancer cells, in the case of the platinum-based anticancer agent ProLindac (AP5346), a DACH (diaminocyclohexane) platinum polymer prodrug that uses a 25kDa polymer delivery vehicle based on hydroxypropyl methacrylamide (HPMA) to target oxaliplatin against tumors (see, e.g., Nowotnik et al., Advanced Drug Delivery Reviews, 61(13): 1214-1219 (2009)).Other targeting mechanisms for targeting and / or enhancing the delivery of platinum-based anticancer drugs to tumors and / or cancer cells include, for example, peptides, polymer carriers, micelles, radiation and / or photoactivated prodrugs, functionalized carbon nanotubes and / or nanorods, hollow Prussian blue, magnetic iron oxide and / or gold nanoparticles, and nanogels (see, e.g., Butler et al., Current Opinion in Chemical Biology, 17(2): 175-188 (2013)).

[0087] In one embodiment, suitable platinum-based anticancer agents can be selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, lovaplatin, heptaplatin, dicycloplatin, lipoplatin, LA-12((OC-6-43)-bis(acetate)(1-adamantylamine)amminedichloroplatin(IV)), phosphaplatin, phenanthriplatin, ProLindac (AP5346), triplatin tetranitrate, picoplatin, satoraplatin, pyriplatin, and / or pharmaceutically acceptable salts thereof.

[0088] The dosage of platinum-based anticancer drugs can be selected depending on the treatment provided and the specific platinum-based anticancer drug used. For example, a suitable dose of a platinum-based anticancer drug (e.g., cisplatin) is 10 mg / m². 2 ~200mg / m 2 For example, 20 mg / m² 2 ~100mg / m 2 It can be within the range.

[0089] The administration schedule for platinum-based anticancer drugs can also be selected depending on the treatment to be administered and the platinum-based anticancer drug provided. For example, in one embodiment, a suitable administration schedule may include administering the drug to the patient at a frequency of once or twice per day, every 1, 2, 3, 4, 5, or 6 days, per week, every 2 weeks, every 3 weeks, or per month.

[0090] Timing of administration In one embodiment, a treatment process involving a platinum-based anticancer agent and a pentaza macrocyclic complex may, depending on the treatment provided, include one or more doses of the agent and / or complex. In one embodiment, a treatment process involving one or more doses may include administering the pentaza macrocyclic complex within a predetermined period prior to the administration of the platinum-based anticancer agent. For example, the treatment process may include administering the first dose of the platinum-based anticancer agent, and optionally one or more subsequent doses, along with the initiation of pentaza macrocyclic complex administration within a predetermined period prior to the first administration of the platinum-based anticancer agent. In another embodiment, a treatment process involving one or more doses may include administering a dose of the pentaza macrocyclic complex after a predetermined period has elapsed since the administration of a dose of the platinum-based anticancer agent. In other words, the treatment process may include administering the first dose of the platinum-based anticancer agent, and, as appropriate, one or more subsequent doses, along with the initiation of administration of the pentaza macrocyclic ring complex, which is delayed for a predetermined period after the initial administration of the platinum-based anticancer agent.

[0091] In one embodiment, at least one dose of the pentaza macrocyclic complex during the course of treatment is administered at least one week, at least five days, at least three days, at least two days, at least one day, at least 12 hours, at least eight hours, at least four hours, at least two hours, at least one hour, and / or at least 30 minutes before the administration of the platinum-based anticancer agent. In another embodiment, at least one dose of the pentaza macrocyclic complex during the course of treatment is administered at least one week, at least five days, at least three days, at least two days, at least one day, at least 12 hours, at least eight hours, at least four hours, at least two hours, at least one hour, and / or at least 30 minutes after the administration of the platinum-based anticancer agent. Furthermore, the timing of at least one dose of the pentaza macrocyclic complex may also apply to multiple doses administered during the course of treatment, for example, at least 25%, at least 50%, at least 75%, at least 90%, and even substantially all doses administered during the course of treatment.

[0092] Other cancer treatments In one embodiment, the treatment provided herein may further include treatment with other treatments other than those specifically described above (e.g., one or more of radiotherapy and / or other chemotherapy therapies). Further examples may include administering another anticancer agent, such as a PARP inhibitor (poly-ADP-ribose polymerase inhibitor), e.g., one or more of olaparib, rucaparib, niraparib, iniparib, talazoparib, and veliparib, before, concurrently with, or after the administration of one or more platinum-based anticancer compounds and pentaza macrocyclic complexes. Other anticancer agents may also be provided. For example, in one embodiment, radiotherapy may be administered to the target before, concurrently with, or after the administration of one or more platinum-based anticancer agents and pentaza macrocyclic complexes. A further detailed description of radiotherapy and other chemotherapy suitable for cancer treatment is provided below.

[0093] In one embodiment, radiotherapy can be administered concurrently with the administration of one or more of the platinum-based anticancer agents and the pentaza macrocyclic complex. For example, one or more of the platinum-based anticancer agents and the pentaza macrocyclic complex may be administered during, before, after, or on the same day as the administration of radiotherapy, for example, so that the subject receives radiotherapy concurrently with the administration of one or more of the platinum-based anticancer agents and the pentaza macrocyclic complex.

[0094] In yet another embodiment, a combination therapy of the pentaza macrocyclic complex and a platinum-based anticancer agent (e.g., cisplatin) can be administered without any other cancer treatment. Unexpectedly, as further shown in the following examples, the pentaza macrocyclic complex can enhance the responsiveness and / or efficacy of a platinum-based anticancer agent (e.g., cisplatin) even when administered without radiotherapy. Thus, in one embodiment, the cancer treatment administered to a subject may consist, as a matter of course, of the pentaza macrocyclic complex and a platinum-based anticancer agent, without the administration of radiation exposure (i.e., without the administration of radiation doses or dose fractions). For example, the combination of the pentaza macrocyclic complex and a platinum-based anticancer agent may be administered to a subject not receiving radiotherapy. That is, in one embodiment, the treatment includes administering the pentaza macrocyclic complex to a subject not receiving radiotherapy. In another embodiment, the treatment includes administering a platinum-based anticancer agent and a pentaza macrocyclic complex to subjects who have not received radiotherapy. In another embodiment, if the treatment process includes the administration of a pentaza macrocyclic complex and a platinum-based anticancer agent, they are administered to subjects who have not received radiotherapy during the course of the treatment process.

[0095] In one embodiment, a subject receiving the combination of pentaza macrocyclic complex and platinum-based anticancer agents (e.g., cisplatin) may not have been exposed to radiation (i.e., the received radiation dose or dose fraction) for at least one day, e.g., at least one week, further at least one month, and further at least six months, and / or may not have received any such treatment prior to the initial treatment with one or more of the pentaza macrocyclic complex and platinum-based anticancer agents. In yet another embodiment, radiotherapy administered to a subject after combination therapy with pentaza macrocyclic complex and platinum-based anticancer agents is delayed until at least one day, e.g., at least one week, further at least one month, e.g., at least six months, after the final dose of one or more of the pentaza macrocyclic complex and platinum-based anticancer agents administered during the combination therapy process. That is, the combination therapy with pentaza macrocyclic complex and platinum-based anticancer agents can be administered to subjects who have never received radiotherapy, or who have only received such treatment in the distant past. Furthermore, the combination therapy of the pentaza macrocyclic complex and platinum-based anticancer agents can be administered to provide a treatment process that does not involve any exposure to radiation. In a further embodiment, the combination therapy of the pentaza macrocyclic complex and platinum-based anticancer agents can be provided to be a treatment process that is substantially free of radiation therapy during or after the course of therapy, or in which such radiation is administered only after a long period has elapsed since the completion of the combination therapy course. In one embodiment, the treatment includes administering one or more of the pentaza macrocyclic complex and platinum-based anticancer agents to the subject on days other than the days on which the subject is receiving radiation therapy.

[0096] Method of administration According to Embodiment 1, a platinum-based anticancer agent (e.g., cisplatin) is administered as co-therapy or combination therapy with a pentaza macrocyclic complex. The co-therapy or combination therapy described herein includes the administration of each compound in a sequence that provides an effective drug combination effect, and may include co-administration of these agents in a sequence and simultaneously, for example, in a single capsule containing these active agents in fixed proportions, or in multiple separate capsules of each agent, or in a single or multiple parenteral administrations, or in other routes and formulations of administration. Therefore, when administered in combination, the therapeutic agents (i.e., the pentaza macrocyclic complex and / or the platinum-based anticancer agent) may be formulated as separate compositions administered simultaneously or sequentially at different times, or the therapeutic agents may be provided as a single composition. Pharmaceutical compositions and formulations are described herein.

[0097] The pentaza macrocyclic complex and platinum-based anticancer agents do not necessarily need to be administered simultaneously or substantially simultaneously; the agents and compounds may be administered sequentially. The advantages of simultaneous, substantially simultaneous, or sequential administration are well within the scope of a skilled clinician's decision. For example, a pharmaceutical composition or formulation containing a platinum-based anticancer agent may be advantageous for initial administration in combination with a particular treatment prior to the administration of the pentaza macrocyclic complex, while pre-administration of the pentaza macrocyclic complex may be advantageous in another treatment. It is also understood that this combination of the pentaza macrocyclic complex and platinum-based anticancer agents may be used in combination with other treatments for cancer (typically malignant tumors) (including, but not limited to, radiotherapy and surgery, or other chemotherapy). It is further understood that another active agent (e.g., a cell division arrester or quiescent agent, or an antiemetic) may, in some cases, be administered sequentially or concurrently with any or all of the other concurrent treatments.

[0098] Therefore, embodiments of the treatment method include the simultaneous or sequential administration of the pentaza macrocyclic ring complex and platinum-based anticancer agents. For example, embodiments of this disclosure include a method for treating cancer in which the pentaza macrocyclic ring complex and platinum-based anticancer agents are administered simultaneously or sequentially. Other active agents may also be administered simultaneously or sequentially with the pentaza macrocyclic ring complex and platinum-based anticancer agents.

[0099] As described above, if the pentaza macrocyclic ring complex and the platinum-based anticancer agent are not administered simultaneously or substantially simultaneously, the initial order of administration of the components may be altered. For example, the platinum-based anticancer agent may be administered first, followed by the pentaza macrocyclic ring complex; or the pentaza macrocyclic ring complex may be administered first, followed by the platinum-based anticancer agent. This alternative administration may be repeated during the single-treatment protocol period. This may include a sequence of other administrations to elicit the effects described herein, and a sequence of other administrations of other active agents may also be provided.

[0100] In one embodiment, the subject is pre-treated with a platinum-based anticancer agent, followed by administration of the pentaza macrocyclic complex, or vice versa. According to such an embodiment, the pentaza macrocyclic complex may be administered at least 1 hour and at least 3 days after administration of the platinum-based anticancer agent, or vice versa. For example, in one embodiment, the pentaza macrocyclic complex may be administered between 1 hour and 3 days after administration of the platinum-based anticancer agent, or vice versa. In another embodiment, for example, the pentaza macrocyclic complex may be administered between 1 hour and 1 day after administration of the platinum-based anticancer agent, or vice versa. For example, the pentaza macrocyclic complex may be administered within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 ​​hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 9 weeks, 10 weeks, or 12 weeks after administration of a platinum-based anticancer drug, or vice versa. In these other embodiments, the platinum-based anticancer drug may be administered in multiple doses to administer the pentaza macrocyclic complex, or vice versa.

[0101] Alternatively, the subject may be pre-treated with a pentaza macrocyclic complex followed by the administration of a platinum-based anticancer agent, or vice versa. In such embodiments, the pentaza macrocyclic complex may be administered within at least one half-life of the platinum-based anticancer agent, for example, within four half-lives of the platinum-based anticancer agent, or vice versa. For example, the pentaza macrocyclic complex may be administered within one, two, or three half-lives of another platinum-based anticancer agent, or vice versa.

[0102] In another embodiment, the subject may be pre-treated with a platinum-based anticancer agent, followed by administration of the pentaza macrocyclic complex, and then one or more further doses of the platinum-based anticancer agent, or vice versa. For example, the subject may be pre-treated with a single dose of a platinum-based anticancer agent, followed by a single dose of the pentaza macrocyclic complex, then further (or partial) doses of the same or different platinum-based anticancer agent, and then further doses of the pentaza macrocyclic complex. Furthermore, the subject may be pre-treated with a partial or full dose of the pentaza macrocyclic complex, followed by administration of a platinum-based anticancer agent, and then further (or partial) doses of the pentaza macrocyclic complex.

[0103] As described in further detail below, the combinations disclosed herein may also be co-administered with other well-known therapeutic agents selected for their specific usefulness for the condition being treated. Alternatively, if multiple combination formulations are unsuitable, the combinations may be used sequentially with known pharmaceutically acceptable agents.

[0104] In one embodiment, the pentaza macrocyclic complex and the platinum-based anticancer agent can generally be administered according to known therapeutic protocols for these agents. For example, the administration of various components may vary depending on the disease being treated and the effects of the pentaza macrocyclic complex and the immunotherapy agent on that disease. Furthermore, according to the knowledge of an experienced clinician, the therapeutic protocol (e.g., dosage and timing of administration) may vary considering the observed effects of the therapeutic agent administered to the patient (i.e., the pentaza macrocyclic complex and the platinum-based anticancer agent) and the observed response of the disease to the administered therapeutic agent.

[0105] Furthermore, generally speaking, the pentaza macrocyclic ring complex and the platinum-based anticancer agent should not be administered in the same pharmaceutical composition, and may need to be administered via different routes due to their different physicochemical characteristics. For example, the pentaza macrocyclic ring complex may be administered orally to produce and maintain good blood levels, while the platinum-based anticancer agent may be administered intravenously or by blood transfusion, or vice versa. The mode of administration may, if possible, be the same pharmaceutical composition or separate pharmaceutical compositions (e.g., two or three distinct compositions). Moreover, once the initial administration has been made, the dose, mode of administration, and timing of administration may be modified based on the observed effects.

[0106] The specific choice of pentaza macrocyclic complex and platinum-based anticancer agents, as well as other related treatments (e.g., radiation or other chemotherapy), is at the discretion of the attending clinician based on their diagnosis, the patient's condition, and the appropriate treatment protocol.

[0107] Therefore, according to experience and knowledge, clinicians may modify each protocol for the administration of the therapeutic components (pentaza macrocyclic complex and platinum-based anticancer agents) according to the needs of each patient so that the treatment progresses.

[0108] The clinician in charge will consider the patient's overall health status, as well as more concrete signs, such as relief of disease-related symptoms, inhibition of tumor growth, actual tumor reduction, or suppression of metastasis, when determining whether the treatment is effective at the administered dose. Tumor size can be measured by standard methods such as radiological experiments, e.g., CAT or MRI scans, and continuous measurements can be used to determine whether tumor growth is being slowed or reversed. Relief of disease-related symptoms (e.g., pain) and overall improvement of symptoms can also be used to help determine the effectiveness of the treatment.

[0109] Products comprising the aforementioned combinations may be administered simultaneously, separately, or at intervals of a certain period to obtain the maximum effect of the combination; each administration can range from rapid administration of any component (in a separate formulation or a single formulation) to relatively continuous perfusion. Consequently, for the purposes of this disclosure, the combinations are not limited to those obtained by the physical bonding of the components, and may allow for separate administrations, simultaneously, or at intervals of a certain period.

[0110] Therefore, the administration of the components described herein can be carried out as a single event of treatment or during its course. For example, the pentaza macrocyclic ring complex and platinum-based anticancer agents can be administered hourly (e.g., every hour, every two hours, every three hours, every four hours, every five hours, every six hours, etc.), daily, once a week, every two weeks, or once a month (simultaneously or consecutively). For the treatment of acute conditions, the course of treatment may be at least several hours or several days. Certain conditions may extend treatment from several days to several weeks. For example, treatment may be extended for one week, two weeks, or three weeks or more. In more chronic conditions, treatment may be extended from several weeks to several months, one year or more, or for the lifetime of the patient requiring such treatment. Alternatively, the compounds and agents can be administered hourly, daily, weekly, every two weeks, or monthly for a period of several weeks, several months, several years, or for the lifetime of the patient as a preventive measure.

[0111] The dose or amount of a pharmaceutical composition containing a pentaza macrocyclic ring complex and a platinum-based anticancer agent administered to a patient should be an effective amount for the intended purpose, i.e., for the treatment or prevention of one or more of the diseases, conditions, and medical states described herein, in particular cancer. Generally speaking, the effective amount of the composition administered may vary depending on various factors such as age, weight, sex, diet, route of administration, and the medical condition of the patient requiring treatment. Particularly preferred doses are described more thoroughly herein. However, it is understood that the total daily dose should be determined by the attending physician or veterinarian within reasonable medical judgment regarding the composition described herein.

[0112] As described above, the combination can be co-administered (by formulations formulated together or by separate formulations administered approximately simultaneously). The combination can also be administered separately with each drug at different times in separate unit formulations. Many approaches for administering platinum-based anticancer agents and pentaza macrocyclic complexes can be readily applied to the use described herein. The pharmaceutical composition may be delivered orally, for example, in unit formulations of tablets or capsules, or parenterally, for example, in injectable unit formulations, or by any other route. For systemic administration, for example, the drugs may be administered by intravenous infusion (continuous or bolus infusion). The composition can be used in therapeutic or prophylactic treatments in which the patient benefits from the combination therapy.

[0113] The specific therapeutically effective dose level for any particular patient depends on various factors, including the disease being treated and its severity; the activity of the specific compound used; the patient's age, weight, overall health, sex, and diet; the time of administration; the route of administration; the elimination rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and factors well known in the fields of medicine and / or veterinary medicine. For example, it is evident in the art to start administration of a compound at a level lower than the level required to achieve the desired therapeutic effect and to gradually increase the dose until the desired effect is achieved. If necessary, the effective daily dose may be divided into multiple doses for administration. Thus, a single drug composition may contain such amounts, or may contain multiple partial doses to constitute a daily dose.

[0114] In one embodiment, suitable or preferred doses of each component are used in or included in the composition as described herein. Preferred doses of the pentaza macrocyclic complex may be, for example, in the range of 10 to 500 mg per patient per day. However, the dose may vary by a dosing schedule which can be adjusted as necessary to achieve the desired therapeutic effect. It should be noted that the effective dose range provided herein is disclosed as a typical dose range and is not intended to be limited to the indicated range. The most preferred dose is subject to subject, taking into account, among other things, the specific combination used, as well as the patient's age, sex, weight, physical condition, diet, etc., so that it can be understood and determined by those skilled in the art without requiring excessive experimentation.

[0115] The cancer treatments or therapies described herein include achieving a therapeutic benefit, but such therapies may also be administered to achieve a preventive benefit. A therapeutic benefit generally means at least partial eradication or mitigation of the disease being treated. For example, in a cancer patient, a therapeutic benefit includes (partial or complete) eradication or mitigation of the cancer causing the disease. A therapeutic benefit is also the achievement of at least partial or complete eradication or mitigation of one or more physiological symptoms associated with the disease causing the disease, and the improvement observed in the patient regardless of the fact that the patient may still have the disease causing the disease. With respect to a preventive benefit, the methods of the present disclosure may be performed or compositions of the present invention may be administered to patients at high risk of developing cancer or patients exhibiting one or more physiological symptoms of such disease, even if a diagnosis of the disease has not been made.

[0116] Furthermore, the treatment of toxic effects associated with the administration of platinum-based anticancer drugs, and / or conditions resulting from the administration of platinum-based anticancer drugs, includes achieving a therapeutic benefit, although such treatment may also be administered to achieve a prophylactic benefit. A therapeutic benefit generally means the eradication or remission of at least a portion of the underlying disorder being treated. For example, in a patient who is at risk of or has suffered from toxic effects associated with the administration of platinum-based anticancer drugs, the therapeutic benefit includes the (partial or complete) eradication or remission of the underlying condition and / or symptoms. The therapeutic benefit is also achieved by the at least partial or complete eradication or remission of one or more physiological symptoms associated with the underlying disorder, so that improvement is seen in the patient regardless of the fact that the patient may already have the underlying disorder. With respect to the preventive benefit, the methods of the present disclosure may be performed on patients who are at risk of toxicity associated with platinum-based anticancer agents (e.g., a person who is receiving, has received, or is scheduled to receive platinum-based anticancer agents), or on patients who report and / or suffer from one or more of the physiological symptoms of such disorders, or the compositions of the present invention may be administered to such patients even if a diagnosis of the said disorder cannot be made.

[0117] Cancer treatment methods In general, any subject suffering from or susceptible to cancer or other proliferative diseases may be treated with the compositions and methods of this disclosure. Subjects treated according to the methods described herein are mammalian subjects, typically human patients. Other mammals that may be treated according to this disclosure include companion animals (e.g., dogs and cats), domestic animals (e.g., cattle, horses, and pigs), as well as birds and further rare animals (e.g., animals found in zoos or nature reserves). In some embodiments of this disclosure, methods for treating cancerous tumors, in particular solid tumors, are provided. Advantageously, the methods described herein may reduce tumor development, reduce tumor volume, or cause tumor shrinkage in mammalian hosts. Cancer patients and individuals seeking cancer prevention may be treated with the combinations described herein.

[0118] Cancer and tumors generally mean or describe physiological conditions in mammals typically characterized by uncontrolled cell proliferation. The pharmaceutically acceptable combinations, co-formulations, and combination therapies of this disclosure can treat a variety of tumors, including tumors of the breast, heart, lung, small intestine, large intestine, spleen, kidney, bladder, head and neck, ovaries, prostate, brain, pancreas, skin, bone, bone marrow, blood, thymus, uterus, testes, cervix, and liver.

[0119] In one embodiment, the tumor or cancer is selected from adenoma, angiosarcoma, astrocytoma, epithelial carcinoma, germ cell tumor, glioblastoma, glioma, hamartoma, hemangioendothelioma, angiosarcoma, hematoma, hepatoblastoma, leukemia, lymphoma, medulloblastoma, melanoma, neuroblastoma, osteosarcoma, retinoblastoma, rhabdomyosarcoma, sarcoma, and teratoma. The aforementioned tumors include acral lentiginous melanoma, actinic keratosis, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenosarcoma, adenosquamous cell carcinoma, astrocytic tumor, Bartholin's gland carcinoma, basal cell carcinoma, bronchial gland tumor, capillary, carcinoid, carcinosarcoma, cavernous, cholangiocarcinoma, chondrosarcoma, choroid plexus papilloma / carcinoma, clear cell carcinoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, ependymal, epithelioid, Ewing's sarcoma, lamellar type, focal nodular hyperplasia, gastrinoma, germ cell tumor, glioblastoma, glucagonoma, hemangioblastoma, hemangioendothelioma, hepatic adenoma, hepatic adenomatosis, hepatocellular carcinoma, insulinoma, intraepithelial neoplasia, squamous intraepithelial neoplasia, invasive squamous cell carcinoma, large cell carcinoma, and smooth muscle. You can choose from sarcoma, lentigo malignant melanoma, malignant mesothelioma, medulloblastoma, medullary epithelioma, melanoma, meninges, mesothelial tumor, metastatic carcinoma, mucoepidermoid carcinoma, neuroblastoma, neuroepithelial tumor, adenocarcinoma, nodular melanoma, oat cell carcinoma, oligodendroglia, osteosarcoma, pancreatic tumor, papillary serous adenocarcinoma, pineal cell tumor, pituitary tumor, plasmacytoma, pseudosarcoma, pulmonary blastoma, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, small cell carcinoma, parenchymal tissue carcinoma, somatostatin-secreting cell carcinoma, squamous cell carcinoma, squamous cell carcinoma, submesothelial tumor, superficial spreading melanoma, undifferentiated carcinoma, uveal melanoma, verrucous carcinoma, VIP-producing tumor, well-differentiated carcinoma, and Wilms' tumor.

[0120] Therefore, for example, this disclosure includes, but is not limited to, cancers of the bladder (including advanced and metastatic bladder cancer), breast, colorectal cancer (including colorectal cancer), kidney, liver, lung (including small cell and non-small cell lung cancer, as well as lung adenocarcinoma), ovary, prostate, testicle, urinary tract, lymphatic system, rectum, larynx, pancreas (including exocrine pancreatic tumors), esophagus, stomach, gallbladder, neck, thyroid, and skin (including squamous cell carcinoma); hematopoietic malignancies of the lymphatic system (leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma) It provides treatment methods for various cancers, including: tumors, hairy cell lymphoma, histiocytic lymphoma, and Burkitt lymphoma; myeloid hematopoietic malignancies (including acute and chronic myeloid leukemia, myelodysplastic syndrome, myeloid leukemia, and promyelocytic leukemia); tumors of the central and peripheral nervous system (including astrocytoma, neuroblastoma, glioma, and Schwannoma); mesenchymal tumors (including fibrosarcoma, rhabdomyosarcoma, and osteosarcoma); and other tumors (including melanoma, xeroderma pigmentosum, keratosarcoma, seminomas, follicular thyroid carcinoma, and teratomas).

[0121] For example, certain leukemias that can be treated with the combinations and methods described herein include, but are not limited to, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemia, leukocyte leukemia, basophilic leukemia, blastocyte leukemia, bovine leukemia, chronic myelocytic leukemia, cutaneous leukemia, fetal leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia. leukemia (rapid), hemoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphotropic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloid leukemia, myeloid leukemia These include granulocytic leukemia, myelomonocytic leukemia, Naegeli's leukemia, plasma cell leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, hepatocellular leukemia, subleukemia, and undifferentiated cell leukemia.

[0122] Lymphoma can also be treated in combinations and methods described herein. Lymphoma is generally a neoplastic transformation of cells, primarily present in lymphoid tissues. Lymphoma is a tumor of the immune system and commonly exists as both T-cell and B-cell related diseases. Within lymphoma, there are two major distinct groups: non-Hodgkin lymphoma (NHL) and Hodgkin disease. In particular, the bone marrow, lymph nodes, spleen, and circulating cells may be involved. Treatment protocols may involve extracting bone marrow from the patient, washing the tumor cells in the bone marrow, using antibodies against antigens present in the tumor cell type, and then preserving it. The patient is given a toxic dose of radiation or chemotherapeutic agents, and the washed bone marrow is re-extracted to return the patient's hematopoietic system.

[0123] Other hematological malignancies that can be treated with the combinations and methods described herein include myelodysplastic syndromes (MDS), myeloproliferative disorders (MPS), and myeloma (e.g., solitary myeloma and multiple myeloma). Multiple myeloma (also called plasma cell myeloma) is associated with the skeletal system and is characterized by multiple tumors of neoplastic plasma cells scattered throughout this system. It can spread to lymph nodes and other sites (e.g., skin). Solitary myeloma is associated with solitary lesions that tend to occur in the same local area as multiple myeloma.

[0124] In one embodiment, the methods and pharmaceutical compositions described herein are used to treat any of the following cancers: breast cancer, melanoma, oral squamous cell carcinoma, lung cancer (including non-small cell lung cancer), renal cell carcinoma, colorectal cancer, prostate cancer, brain cancer, spindle cell carcinoma, urothelial carcinoma, bladder cancer, colorectal cancer, head and neck cancer (e.g., squamous cell carcinoma), and pancreatic cancer. In yet another embodiment, the methods and pharmaceutical compositions described herein are used to treat any of the following cancers: head and neck cancer and lung cancer.

[0125] Treatment methods for toxicity related to platinum-based anticancer drugs In general, subjects suffering from or susceptible to conditions resulting from the toxic effects of administering platinum-based anticancer agents (e.g., cisplatin) may be treated with the compositions and methods of the present disclosure. Subjects receiving treatment with the methods described herein are mammalian subjects, typically human patients. Other mammals that may be treated in accordance with the present disclosure include companion animals (e.g., dogs and cats), domestic animals (e.g., cattle, horses, and pigs), as well as birds and further rare animals (e.g., animals found in zoos or nature reserves). In one embodiment of the present disclosure, a method for treating a condition associated with the toxicity of a platinum-based anticancer agent (such as a condition a subject suffers after administration of a platinum-based anticancer agent to a subject) (e.g., as administered during cancer treatment) is provided, a method for mitigating said condition. In another embodiment, said treatment is provided to reduce and / or inhibit the toxicity of a platinum-based anticancer agent, for example, as a platinum-based anticancer agent is administered during cancer treatment to reduce the risk of developing a condition associated with the toxicity of a platinum-based anticancer agent. Advantageously, the methods described herein enable cancer treatment with platinum-based anticancer agents while simultaneously reducing toxic effects and / or mitigating toxic conditions, which may, for example, reduce tumor development, decrease systemic tumor tissue volume, or induce tumor regression in mammalian hosts. Cancer patients and individuals seeking cancer prevention may be treated with the combinations described herein.

[0126] In one embodiment, toxicities and / or toxic states associated with the administration of a platinum-based anticancer agent that can be treated (and / or whose risk of developing such a state can be reduced) by the methods described herein include nephrotoxicity, myelotoxicity, ototoxicity, and neurotoxicity, and at least one of these related states. For example, in one embodiment, administration of the pentaza macrocyclic complex can reduce the neurotoxic effects associated with the administration of a platinum-based anticancer agent. Nephrotoxicity refers to toxicity to the kidneys, resulting in decreased renal function and acute kidney injury, and even renal failure, and is generally associated with the administration of anticancer agents (see, e.g., Lameire N., Clin Kidney J, 7(1): 11-22 (2014); Zhu et al, Arch Toxicol, 89(12): 2197-2205 (2015)). Whole blood blood urea nitrogen (BUN) levels and creatinine levels may be measured to provide indicators of the degree of renal impairment, where high levels indicate decreased renal function. Other markers of renal impairment include the kidney injury molecule 1 (KIM1) and neutrophil gelatinase-associated lipocalin (NGAL). As another example, in one embodiment, administration of the Pentaza macrocyclic complex may reduce the myelotoxic effects associated with the administration of platinum-based anticancer agents. Myelotoxicity, also referred to as myelosuppression and / or myelosuppression, means a decrease in the production of cells such as lymphocytes, red blood cells, and platelets, which can lead to conditions such as neutropenia, thrombocytopenia, and anemia, and is generally associated with anticancer agents (see, e.g., Kurtin S., J Adv Pract Oncol, 3(4): Jul-Aug (2012); Son et al., Hum Exp Toxicol, 30(7): 649-655 (2011)). Neutrophil and white blood cell counts may also decrease. In yet another embodiment, administration of the pentaza macrocyclic complex may reduce the ototoxic effects (toxicity to the ear, such as the cochlea, auditory nerve, and / or vestibular system) associated with the administration of platinum-based anticancer drugs.Therefore, in one embodiment, the therapeutic method described herein may include treating subjects who are suffering from and / or at risk of suffering from toxicity resulting from platinum-based anticancer therapy, for example, subjects who are suffering from and / or at risk of suffering one or more of nephrotoxicity and myelotoxicity due to the administration of platinum-based anticancer agents.

[0127] Pharmaceutical preparations Another aspect of the present disclosure relates to a pharmaceutical composition comprising the combination described herein together with a pharmaceutically acceptable excipient. The pharmaceutical composition includes, as described above, a pentaza macrocyclic ring complex (e.g., corresponding to formula (I)), and at least one platinum-based anticancer agent, as well as combinations thereof, which are typically formulated as a pharmaceutical formulation and may, as appropriate, be formulated in combination with a pharmaceutically acceptable carrier, additive, or excipient. In one embodiment, for example, the pharmaceutical composition includes a pentaza macrocyclic ring complex, a platinum-based anticancer agent, and a pharmaceutically acceptable excipient. The pharmaceutical composition according to the present disclosure may be used for the treatment of cancer.

[0128] The pharmaceutical compositions described herein are products resulting from the mixing or combination of one or more active ingredients, and include both immobilized and unimmobilized combinations of active ingredients. An immobilized combination is, for example, an anticancer agent based on the pentaza macrocyclic ring complex and platinum, which is administered to the patient simultaneously in the form of a single substance or a single dose. The other active agent may also be administered as part of a single substance or a single dose, or separately. An unimmobilized combination is one in which the active ingredients, for example, an anticancer agent based on the pentaza macrocyclic ring complex and platinum, are administered to the patient as separate substances, simultaneously, all at once, or in particular, in succession without limited intervals, such administration providing an effective level of the compound in the patient's body. The latter may also be used in combination therapy, for example, the administration of three or more active ingredients.

[0129] The pentaza macrocyclic ring complex and platinum-based anticancer agents described above may be dispersed in a pharmaceutically acceptable carrier before administration to mammals; that is, the components described herein are preferably co-formulated. Carriers known in the art as excipients, vehicles, adjuvants, or diluents are typically pharmaceutically inert substances and have a suitable hardness or form for the composition and do not diminish the efficacy of the compound. Such carriers are generally considered "pharmaceutically or pharmacologically acceptable" as long as they do not cause unacceptable toxicity, allergies, or other adverse reactions when administered to mammals, particularly humans.

[0130] The selection of a pharmaceutically acceptable carrier is also, in part, determined by the route of administration. Generally, the compositions described herein can be formulated for any route of administration, as long as the blood circulation is available through this route or through conventional routes of administration. Suitable routes of administration, for example, include, but are not limited to, oral, parenteral (e.g., intravenous, intra-arterial, subcutaneous, rectal, intramuscular, intra-airway, intrasacral, intra-spinal, intraperitoneal, or intrasternal), topical (transnasal, transdermal, intraocular), intravesical, subarachnoid, intraintestinal, pulmonary, intralymphatic, intracavitary, vaginal, transurethral, ​​intradermal, ear, breast, buccal, orthotopic, intratracheal, intrafocal, transdermal, endoscopic, transmucosal, sublingual, and intestinal administration.

[0131] pharmaceutically acceptable carriers for use in combination with the compositions of this disclosure are well known to those skilled in the art and are selected based on many factors: the specific compounds and agents used, and their / their concentrations, stability and bioavailability for the subject; the subject, its age, weight and overall condition; and the route of administration. Suitable non-aqueous, pharmaceutically acceptable polar solvents include, but are not limited to, alcohols (e.g., α-glycerol formal, 6-glycerol formal, 1,3-butylene glycol, aliphatic or aromatic alcohols having 2 to 30 carbon atoms, e.g., methanol, ethanol, propanol, isopropanol, butanol, t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin (glycerol), glycol, hexylene glycol, tetrahydrofurfuryl alcohol, lauryl alcohol, cetyl alcohol, or stearyl alcohol, fatty acid esters of aliphatic alcohols, e.g., polyalkylene glycols (e.g., polypropylene glycol, polyethylene glycol), sorbitan, sucrose, and cholesterol); amides (e.g., dimethylacetamide (DMA), benzyl benzoate DMA, dimethylformamide, N-(6-hydroxyethyl)-lactamide, N,N-dimethylacetamideamide, 2-pyrrolidinone, 1-methyl-2-pyrrolidinone, or polyvinylpyrrolidone);Esters (e.g., 1-methyl-2-pyrrolidinone, 2-pyrrolidinone), acetates (e.g., monoacetin, diacetin, and triacetin), aliphatic or aromatic esters (e.g., ethyl caprylic or octanonate, alkyl oleate, benzyl benzoate, benzyl acetate, dimethyl sulfoxide (DMSO)), glycerin esters (e.g., mono, di, or triglyceryl citrate or tartarate), ethyl benzoate, ethyl acetate, ethyl carbonate, ethyl lactate, ethyl oleate, fatty acid esters of sorbitan, fatty acid-derived PEG esters, glyceride monostearate, glyceride esters (e.g., mono, di) (or triglycerides), fatty acid esters (e.g., isopropyl myristate), fatty acid-derived PEG esters (e.g., PEG-hydroxyoleic acid and PEG-hydroxystearic acid), N-methylpyrrolidinone, Pluronic 60, polyoxyethylene sorbitol oleate polyester, polyoxyethylene sorbitan esters, e.g., polyoxyethylene-monoleate sorbitan, polyoxyethylene-monopalmitate sorbitan, polyoxyethylene-monolaurate sorbitan, polyoxyethylene-monostearate sorbitan, and polysorbate® 20, 40, 60 or 80 (ICI Americas (Wilmington, Delaware), polyvinylpyrrolidone, alkylene oxy-modified fatty acid esters, e.g., polyoxyl 40 hydrogenated castor oil and polyoxyethylated castor oil (e.g., Cremophor® EL solution or Cremophor® RH40 solution), sucrose fatty acid esters (i.e., monosaccharide condensation products (e.g., pentoses, e.g., ribose, ribulose, arabinose, xylose, lyxose and lyxose, hexoses, e.g., glucose, fructose, galactose, mannose and sorbose, triose, tetrose, heptose, and octose), disaccharides (e.g., sucrose, maltose, lactose, and trehalose) or oligosaccharides, or O4-O; 22These mixtures with fatty acids (e.g., saturated fatty acids (e.g., caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, and stearic acid), and unsaturated fatty acids (e.g., palmitoleic acid, oleic acid, elaidic acid, erucic acid, and linoleic acid)), or steroidal esters); alkyl, aryl, or cyclic ethers having 2 to 30 carbon atoms (e.g., diethyl ether, tetrahydrofuran, dimethyl isosorbide, diethylene glycol monoethyl ether); glycoflour (tetrahydrofurfuryl alcohol phosphate); Polyethylene glycol ether; ketones having 3 to 30 carbon atoms (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone); aliphatic, cycloaliphatic, or aromatic hydrocarbons having 4 to 30 carbon atoms (e.g., benzene, cyclohexane, dichloromethane, dioxolane, hexane, n-decane, n-dodecane, n-hexane, sulfolane, tetramethylene sulfone, tetramethylene sulfoxide, toluene, dimethyl sulfoxide (DMSO), or tetramethylene sulfoxide); inorganic, plant, animal, natural or synthetic origins. Oils (e.g., mineral oil, e.g., aliphatic or wax-based hydrocarbons, aromatic hydrocarbons, mixed aliphatic and aromatic-based hydrocarbons, and refined mineral oil), vegetable oils (e.g., linseed oil, tung oil, safflower oil, soybean oil, castor oil, cottonseed oil, peanut oil, rapeseed oil, coconut oil, palm oil, olive oil, corn oil, corn germ oil, sesame oil, apricot kernel oil, and peanut oil), and glycerides (e.g., mono-, di-, or triglycerides), animal oils (e.g., fish oil, aquatic animal oil, semen oil, cod liver oil, halibut oil, squalene oil, squalane oil, and shark liver oil), oleic acid oil, and polyoxyethylene Castor oil; alkyl or aryl halides having 1 to 30 carbon atoms and optionally having one or more halogen groups; methylene chloride; monoethanolamine; petroleum benzine; trolamine; omega-3 polyunsaturated fatty acids (e.g., alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoic acid); 12-hydroxystearic acid and polyglycol esters of polyethylene glycol (Soltoll® HS-15 (BASF, Ludwigshafen, Germany); polyoxyethylene glycerol;Examples include sodium laurate; sodium oleate; or sorbitan monooleate.

[0132] In one embodiment, an oily or non-aqueous solvent may be used in the formulation, for example, due to the presence of a large lipophilic portion, to dissolve one or more compounds in solution. Alternatively, an emulsion, suspension, or other preparation, such as a liposome preparation, may be used. With respect to the liposome preparation, for example, any known method for preparing liposomes may be used. See, for example, Bangham et al., J. Mol. Biol, 23: 238-252 (1965) and Szoka et al., Proc. Natl Acad. Sci 75: 4194-4198 (1978), which are incorporated herein by attribution. Thus, in one embodiment, one or more compounds are administered in the form of a liposome delivery system, for example, small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. Liposomes can be formed from various phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine. Ligands may also be conjugated to liposomes, for example, to direct these compositions to a specific site of action.

[0133] Other pharmaceutically acceptable solvents for use in the pharmaceutical compositions described herein are well known to those skilled in the art, as seen in The Chemotherapy Source Book (Williams & Wilkens Publishing), The Handbook of Pharmaceutical Excipients (American Pharmaceutical Association, Washington, DC, and The Pharmaceutical Society of Great Britain, London, England, 1968), Modern Pharmaceutics (G. Banker et al., eds., 3d ed.) (Marcel Dekker, Inc., New York, New York, 1995), The Pharmacological Basis of Therapeutics (Goodman & Gilman, McGraw Hill Publishing), Pharmaceutical Dosage Forms (H. Lieberman et al., eds.) (Marcel Dekker, Inc., New York, New York, 1980), and Remington's Pharmaceutical Sciences (A. Gennaro, ed., 19th ed.) (Mack Publishing, Easton, PA). This is described in *The United States Pharmacopeia 24*, *The National Formulary 19*, (National Publishing, Philadelphia, PA, 2000), and AJ Spiegel et al., *Use of Nonaqueous Solvents in Parenteral Products*, *Journal of Pharmaceutical Sciences*, Vol. 52, No. 10, pp. 917-927 (1963).

[0134] Formulations containing the pentaza macrocyclic ring complex and platinum-based anticancer agent may preferably be in the form of a solid, semi-solid, lyophilized powder, or liquid formulation, such as an aerosol, capsule, cream, emulsion, foam, gel / jelly, lotion, ointment, paste, powder, soap, solution, spray, suppository, suspension, sustained-release formulation, tablet, tincture, or transdermal patch, in a unit formulation suitable for precise single-dose administration. When formulated as a fixed dose, such a pharmaceutical composition or formulation product uses the pentaza macrocyclic ring complex and platinum-based anticancer agent within an acceptable dose range.

[0135] In one embodiment, a formulation is provided that contains a platinum-based anticancer agent as part of a liquid formulation (e.g., a sterile liquid formulation suitable for injection). For example, a liquid form containing the platinum-based anticancer agent in combination with one or more further components, such as disodium edetate (EDTA). In one embodiment, the liquid form may contain EDTA in an amount suitable for acting as a preservative and / or metal chelating agent, for example, about 0.025%. The liquid form may further contain water and may also contain a pH adjuster, such as sodium bicarbonate for pH adjustment in the range of pH 5.5 to 7.0. In one embodiment, the pentaza macrocyclic complex may also be provided as part of a sterile liquid formulation suitable for injection, either in the same liquid formulation as the platinum-based anticancer agent or as a separate formulation.

[0136] Formulations for certain pentaza macrocyclic complexes are also described, for example, U.S. Patents 5,610,293, 5,637,578, 5,874,421, 5,976,498, 6,084,093, 6,180,620, 6,204,259, 6,214,817, 6,245,758, 6,395,725, and 6,525,041 (each of which is incorporated herein in whole by attribution).

[0137] The co-formulation of pentaza macrocyclic ring complexes and platinum-based anticancer drugs can be carried out using conventional formulation technologies for each of these components, or by combining them with alternative formulation routes based on the compatibility and efficacy of various components.

[0138] The pharmaceutical composition described above, comprising the pentaza macrocyclic compound and a platinum-based anticancer agent, may further contain one or more additional pharmaceutically active ingredients. Suitable pharmaceutically active agents that may be included in the composition according to embodiments of the present invention include, for example, antiemetics, anesthetics, antihypertensives, anxiolytics, anticoagulants, anticonvulsants, hypoglycemic agents, decongestants, antihistamines, antitussives, anticancer agents, beta-blockers, anti-inflammatory agents, antipsychotics, nootropics, cholesterol-lowering agents, anti-obesity agents, autoimmune disease agents, erectile dysfunction agents, antibacterial and antifungal agents, hypnotics, anti-Parkinson's disease agents, anti-Alzheimer's disease agents, antibiotics, antidepressants, and antiviral agents. Each component of such a combination may be administered sequentially or simultaneously in separate or combined pharmaceutical formulations.

[0139] In yet another embodiment, a kit is provided comprising both a pentaza macrocyclic complex and a platinum-based anticancer agent for the treatment of diseases such as cancer, and / or to treat and / or reduce the toxicity risks associated with the administration of a platinum-based anticancer agent. For example, the kit may include a first container or box containing a formulation comprising the pentaza macrocyclic complex (e.g., an oral or injectable formulation of the pentaza macrocyclic complex), and a first container or box containing a formulation comprising a platinum-based anticancer agent (e.g., an injectable formulation of the platinum-based anticancer agent). The kit may further include indications or other instructions for the administration of the active agent, recommended dose, duration and dosing plan, warnings, descriptions of possible drug interactions, and other relevant instructions (e.g., indications for a treatment plan (e.g., dose, frequency of administration, etc.) equivalent to any of those described herein).

[0140] Combination therapy with cancer treatment In one embodiment, the pentaza macrocyclic ring complex and platinum-based anticancer agent can be administered in combination with another cancer treatment to provide a therapeutic procedure. For example, the pentaza macrocyclic ring complex and platinum-based anticancer agent may be administered as part of radiotherapy.

[0141] In general, the timing of administration of pentaza macrocyclic complexes and platinum-based anticancer agents may depend, for example, on the specific radiotherapy or type, nature, and / or duration of radiation exposure selected. Other considerations may include the disease or disorder being treated and its severity; the activity of the specific compound used; the specific composition used; the age, weight, overall health, sex, and diet of the subject; the timing, route of administration, and excretion rate of the specific compound used; the duration of treatment; and other factors such as drugs used in combination with or concurrently with the specific compound used. For example, the compound may be administered in various embodiments before, during, and / or after radiation therapy (e.g., before, during, or after exposure to a radiation therapy process involving multiple exposures and / or medications, and / or before, during, or after medication). As another example, the compound may be administered in various embodiments before, during, and / or after radiation exposure.

[0142] If necessary, an effective dose can be divided into multiple doses for administration; therefore, a single-dose composition may contain such an amount or a fraction of such an amount to constitute a dose.

[0143] In one embodiment, for example, an anticancer agent based on the pentaza macrocyclic ring complex and platinum is administered to the patient before or concurrently with radiation exposure. In another embodiment, for example, the components are administered to the patient before but not after radiation exposure. In yet another embodiment, one or more of the anticancer agents based on the pentaza macrocyclic ring complex and platinum are administered to the patient at least 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 180 minutes, 0.5 days, 1 day, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, or longer before radiation exposure (e.g., the first radiation exposure in a radiotherapy course) or before another dose or dose fraction of radiation, which is one of the doses or dose fractions of radiation in a therapy course. In yet another embodiment, for example, an anticancer agent based on a pentaza macrocyclic ring complex and platinum is administered to the patient after radiation exposure; therefore, for example, the compound may be administered at 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 180 minutes, 0.5 days, 1 day, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, or longer after radiation exposure (which may be a dose or dose fraction of radiation in a multi-dose process of radiotherapy, or a single or final dose or dose fraction of radiation in radiotherapy).

[0144] In one embodiment, the pentaza macrocyclic complex and platinum-based anticancer agent are administered as part of a treatment process including radiotherapy. In radiotherapy, the patient receives a dose or dose fraction of ionizing radiation to suppress or control the growth of cancer cells. The dose or dose fraction of radiation may be directed to specific parts of the body to reduce adverse effects on parts of the body that are not affected by cancer, and the radiation beam may be embodied according to a predetermined treatment plan. A typical course of radiotherapy may include one or more doses or dose fractions of radiation, which may be administered over a course of several days, weeks, and months. The total “dose” of radiation administered during the course of radiotherapy typically means the dose of radiation the patient receives throughout the entire course of radiotherapy, and these doses may be administered as dose “fractions” corresponding to multiple radiation exposures, where the total of the administered fractions corresponding to the total dose is administered over several periods.

[0145] In one embodiment, at least one of the pentaza macrocyclic ring complex and platinum-based anticancer agents is administered within a predetermined period before or after radiation exposure (e.g., before or after a radiation dose or dose fraction). For example, the pentaza macrocyclic ring complex and platinum-based anticancer agent may be administered within one week, 48 hours, 24 hours, 12 hours, 6 hours, 2 hours, 1 hour, or 30 minutes of the radiation exposure received by the patient, e.g., within one week, 48 hours, 24 hours, 12 hours, 6 hours, 2 hours, 1 hour, or 30 minutes of the dose or dose fraction (equivalent to the radiation dose or dose fraction before or after radiation exposure). Other periods between radiation exposure that enhance cancer cell death and the administration of the compound may also be appropriate. In one embodiment, one of the pentaza macrocyclic ring complex and platinum-based anticancer agents may be administered before radiation exposure, and one or more of the remaining pentaza macrocyclic ring complex and platinum-based anticancer agents may be administered after radiation exposure. One or more of the pentaza macrocyclic ring complex and platinum-based anticancer agents may be administered both before and after the administration of radiation exposure.

[0146] In one embodiment, the radiotherapy process includes multiple radiation doses or dose fractions administered over a predetermined period, such as several hours, several weeks, several days, or even several months, wherein the multiple doses or dose fractions are of the same or different magnitudes. That is, the radiotherapy process may include the administration of a series of multiple doses or dose fractions of radiation. In one embodiment, the anticancer agent based on the pentaza macrocyclic complex and platinum can be administered before one or more radiation doses or dose fractions in a series, for example, before each radiation dose or dose fraction, or before several radiation doses or dose fractions. Furthermore, the administration of the anticancer agent based on the pentaza macrocyclic complex and platinum during the radiotherapy process may be selected to enhance the cancer-treating effect of radiotherapy, for example, by sensitizing cancer cells to radiotherapy. In one embodiment, the anticancer agent based on the pentaza macrocyclic complex and platinum is administered before or after each dose or dose fraction for a predetermined period, for example, within the predetermined period described above. In another embodiment, the anticancer agent based on the pentaza macrocyclic ring complex and platinum is administered only within a predetermined period before or after a selected dose or dose fraction. In yet another embodiment, at least one of the anticancer agents based on the pentaza macrocyclic ring complex and platinum is administered within the predetermined period before the dose, while another anticancer agent based on the pentaza macrocyclic ring complex and platinum is administered within a predetermined period after the dose or dose fraction. In yet another embodiment, at least one of the anticancer agents based on the pentaza macrocyclic ring complex and platinum is administered only within a predetermined period before or after a selected dose or dose fraction, while another anticancer agent based on the pentaza macrocyclic ring complex and platinum is administered only within a predetermined period before or after a dose or dose fraction other than the selected dose or dose fraction.

[0147] The total dose suitable for use during the course of treatment can be determined by the type of treatment offered, the patient's physiological characteristics, and other factors, and the dose fraction offered can be determined similarly. In one embodiment, the dose fraction of radiation administered to the patient may be at least 1.8 Gy, e.g., at least 2 Gy, and further at least 3 Gy, e.g., at least 5 Gy, and further at least 6 Gy. In yet another embodiment, the dose fraction of radiation administered to the patient may be at least 10 Gy, e.g., at least 12 Gy, further at least 15 Gy, e.g., at least 18 Gy, and further at least 20 Gy, e.g., at least 24 Gy. In general, the dose fraction of radiation administered to the patient should not exceed 54 Gy. Furthermore, in one embodiment, the dose fraction delivered to the subject may mean the amount delivered to a specific target area of ​​the subject, e.g., a target area of ​​a tumor, but it should be noted that other areas of the tumor or surrounding tissue may be exposed to radiation to a greater or lesser extent than the amount specified by the nominal dose fraction.

[0148] In yet another embodiment, the pentaza macrocyclic ring complex and platinum-based anticancer agents are administered as part of a treatment course that includes the administration of further chemotherapeutic agents. In chemotherapy, chemotherapeutic agents are administered to the patient to inhibit or control the proliferation of cancer cells. A typical course of chemotherapy may include one or more doses of one or more chemotherapeutic agents that can be administered over several days, weeks, or even months. Chemotherapeutic agents include: alkylating antineoplastic agents, e.g., nitrogen mustard (e.g., cyclophosphamide, chlorambucil), nitrosourea (e.g., n-nitroso-n-methylurea, carmustine, semustine), tetrazine (e.g., dacarbazine, mitozolimide), aziridine (e.g., thiotepa, mitomycin); antimetabolites, e.g., folate antimetabolites (e.g., methotrexate and pemetrexed), fluoropyrimidines (e.g., fluorouracil, capecitabine), These may include at least one of the following: anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin), deoxynucleoside analogs (e.g., cytarabine, gemcitabine, decitabine), and thiopurines (e.g., thioguanine, mercaptopurine); microtubule inhibitors (e.g., taxanes, paclitaxel, docetaxel); topoisomerase inhibitors (e.g., etoposide, doxorubicin, mitoxantrone, teniposide); and antitumor antibiotics (e.g., bleomycin, mitomycin). For example, the chemotherapeutic agent may be selected from the group consisting of all-trans retinoic acid, arsenic trioxide, azacitidine, azathioprine, bleomycin, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, eposilon, etoposide, fluorouracil, gemcitabine, hydroxyurea, idarubicin, imatinib, mechloretamine, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, teniposide, tiguanine, barrubicin, vinblastine, vincristine, vindesine, and vinorelbine.The administration of many chemotherapy agents is described in the "Physicians' Desk Reference" (PDR), for example, the 1996 edition (Medical Economics Company, Montvale, NJ 07645-1742, USA).

[0149] In one embodiment, the pentaza macrocyclic ring complex and platinum-based anticancer agent are administered as part of a treatment comprising a further chemotherapeutic agent selected from the group consisting of doxorubicin, bleomycin, and paclitaxel. Furthermore, in one embodiment, the further chemotherapeutic agent may be selected from the group consisting of taxanes, anticancer antibiotics, and anthracyclines. Other chemotherapeutic agents include arsenic trioxide and 5-FU, which may also be used in the methods and compositions described herein (Alexandre et al., Cancer Res. 67: (8), 3512-3517 (2007); Yen et al., J. Clin. Invest. 98 (5), 1253-1260 (1996); Masuda et al., Cancer Chemother. Pharmacol. 47(2), 155-160 (2001)).

[0150] In another embodiment, further chemotherapeutic agents may include at least one of antimetabolite anticancer agents and mitotic inhibitor anticancer agents, as well as combinations thereof, and may include any of the agents described above and any other agents further described herein. Various antimetabolites and mitotic inhibitors may be used in the methods and compositions described herein.

[0151] Antimetabolites are generally structurally similar to natural metabolites and are involved in the normal metabolic processes of cancer cells, such as the synthesis of nucleic acids and proteins. However, antimetabolites are sufficiently different from natural metabolites to interfere with the metabolic processes of cancer cells. In these cells, antimetabolites are mistaken for similar metabolites and are processed by the cells in a manner similar to that of normal compounds. The presence of "decoy" metabolites prevents cells from performing functions necessary for survival, and the cells are unable to proliferate and survive. For example, antimetabolites exert cytotoxic activity by replacing these false nucleotides with the cell's DNA, thereby preventing cell division, or by inhibiting DNA replication by inhibiting essential intracellular enzymes.

[0152] Therefore, in one embodiment, the antimetabolite is a nucleotide or a nucleotide analog. In one embodiment, for example, the antimetabolite may include a purine (e.g., guanine or adenosine) or an analog, or a pyrimidine (cytidine or thymidine) or an analog (with or without a bound sugar moiety).

[0153] Antimetabolites suitable for use in this disclosure may generally be classified by the metabolic process they affect, and may include, but are not limited to, folic acid, pyrimidines, purines, and cytidine analogs and derivatives. Thus, in one embodiment, the antimetabolite is selected from the group consisting of cytidine analogs, folic acid analogs, purine analogs, pyrimidine analogs, and combinations thereof.

[0154] In a particular embodiment, for example, the antimetabolite is a cytidine analog. According to this embodiment, for example, the cytidine analog may be selected from the group consisting of cytarabine (cytosine arabinoside), azacitidine (5-azacitidine), and their salts, analogs, and derivatives.

[0155] In another embodiment, for example, the antimetabolite is a folate analog. Folate analogs or folate antimetabolites generally function by inhibiting dihydrofolate reductase (DHFR), an enzyme involved in nucleotide formation (inhibition of this enzyme prevents nucleotide formation and inhibits DNA replication and cell division). According to one embodiment, for example, the folate analog may be selected from the group consisting of denopterin, methotrexate (ametopterin), pemetrexed, pteropterin, larcitrexed, trimethrexate, and their salts, analogs, and derivatives.

[0156] In another embodiment, for example, the antimetabolite is a purine analog. Purine-based antimetabolites function by inhibiting DNA synthesis, for example, by preventing the production of purine-containing nucleotides adenine and guanine, thereby stopping DNA synthesis and inhibiting cell division. Purine analogs can also be incorporated into the DNA molecule itself during DNA synthesis, thereby inhibiting cell division. According to one embodiment, for example, the purine analog may be selected from the group consisting of acyclovir, allopurinol, 2-aminoadenosine, arabinosyladenine (ara-A), azacitidine, azathioprine, 8-aza-adenosine, 8-fluoro-adenosine, 8-methoxy-adenosine, 8-oxo-adenosine, cladribine, deoxycoformycin, fludarabine, ganciclovir, 8-aza-guanosine, 8-fluoro-guanosine, 8-methoxy-guanosine, 8-oxo-guanosine, guanosine diphosphate, guanosine diphosphate-beta-L-2-aminofucose, guanosine diphosphate-D-arabinose, guanosine diphosphate-2-fluorofucose, guanosine diphosphate fucose, mercaptopurine (6-MP), pentostatin, amipurine, thioguanine (6-TG), and salts, analogs, and derivatives thereof.

[0157] In another embodiment, for example, the antimetabolite is a pyrimidine analog. Similar to the purine analogs described above, pyrimidine-based antimetabolites inhibit the synthesis of pyrimidine-containing nucleotides (cytosine and thymine in DNA; cytosine and uracil in RNA). By acting as a "decoy," the pyrimidine-based compounds can prevent the formation of nucleotides and / or be incorporated into an elongating DNA strand, causing its termination. According to one embodiment, for example, the pyrimidine analogs are ancitabine, azacitidine, 6-azauridine, bromouracil (e.g., 5-bromouracil), capecitabine, carmofur, chlorouracil (e.g., 5-chlorouracil), cytarabine (cytosine arabinoside), cytosine, dideoxyuridine, 3'-azido-3'-deoxythymidine, 3'-dideoxycytidine-2'-ene, 3'-deoxy-3'-deoxythymidine-2'-ene, dihydrouracil, doxyfluridine, enocitabine, phloxyuridine, 5-fluorocytosine The pyrimidine analog may be selected from the group consisting of 2-fluorodeoxycytidine, 3-fluoro-3'-deoxythymidine, fluorouracil (e.g., 5-fluorouracil (also known as 5-FU)), gemcitabine, 5-methylcytosine, 5-propynylcytosine, 5-propynylthymine, 5-propynyluracil, thymine, uracil, uridine, and salts, analogs, and derivatives thereof. In one embodiment, the pyrimidine analog is other than 5-fluorouracil. In another embodiment, the pyrimidine analog is gemcitabine or a salt thereof.

[0158] In one embodiment, the antimetabolite is selected from the group consisting of 5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine, pemetrexed, and salts, analogs, derivatives, and combinations thereof. In another embodiment, the antimetabolite is selected from the group consisting of capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine, pemetrexed, and salts, analogs, derivatives, and combinations thereof. In a particular embodiment, the antimetabolite is other than 5-fluorouracil. In a particularly preferred embodiment, the antimetabolite is gemcitabine or a salt thereof (e.g., gemcitabine HCl (Gemzar®))).

[0159] Other antimetabolites include, but are not limited to, acanthifolic acid, aminothiadiazole, brequinal sodium, Ciba-Geigy CGP-30694, cyclopentylcytosine, cytarabine phosphate stearate, cytarabine conjugate, Lilly DATHF, Merrel Dow DDFC, desaguanine, dideoxycytidine, dideoxyguanosine, Zidox, Yoshitomi DMDC, Wellcome EHNA (Merck & Co), EX-015, fazarabine, fludarabine phosphate, N-(2'-flanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, 5-FU-fibrinogen, isopropylpyrrolidine, Lilly LY-188011; Lilly LY-264618, metobenzaprim, Wellcome The following may be selected from the group consisting of MZPES, norspermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, pentostatin, pyritrexime, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, thiazophrine, Erbamont TIF, tyrosine kinase inhibitors, Taiho UFT, and uricin.

[0160] In one embodiment, the chemotherapeutic agent includes a mitotic inhibitor, which is a microtubule inhibitor or microtubule stabilizer. Generally, microtubule stabilizers, such as taxanes (any of those also described above) and eposilons, bind to the inner surface of beta-microtubule chains, promoting the nucleation and elongation phases of polymerization and increasing microtubule association by lowering the concentration of key tubulin subunits required for microtubule construction. Unlike microtubule inhibitors (e.g., vinca alkaloids that inhibit microtubule construction), microtubule stabilizers (e.g., taxanes) reduce the delay time and dramatically alter the dynamic equilibrium between tubulin dimers and microtubule polymers for polymerization. Therefore, in one embodiment, the microtubule stabilizer is a taxane or an eposilon. In another embodiment, the microtubule inhibitor is a vinca alkaloid.

[0161] One element of the treatments described herein may involve the use of taxanes or their derivatives or analogues, some of which are described above. In one embodiment, the taxane may be a naturally occurring compound or a related form, or a chemically synthesized compound or its derivative having antitumor properties. Taxanes are a family of terpenes, including, but not limited to, paclitaxel (Taxol®) and docetaxel (Taxotere®), originally derived from Pacific yew (Taxus brevifolia), and are active against certain tumors, particularly mammary and ovarian tumors. In one embodiment, the taxane is docetaxel or paclitaxel. Paclitaxel is a preferred taxane and is considered a mitotic inhibitor that stabilizes microtubules by promoting the association of microtubules from tubulin dimers and inhibiting depolymerization. This instability inhibits the normal and dynamic reorganization of the microtubule network, which is essential for the intercellular phase and mitotic division cellular functions necessary for maintaining life.

[0162] The scope also includes various known taxane derivatives (including hydrophilic and hydrophobic derivatives). Examples of taxane derivatives include, but are not limited to, the galactose and mannose derivatives described in International Patent Application No. WO99 / 18113; piperazino and other derivatives described in WO99 / 14209; taxane derivatives described in WO99 / 09021, WO98 / 22451, and U.S. Patent No. 5,869,680; 6-thio derivatives described in WO98 / 28288; sulfenamide derivatives described in U.S. Patent No. 5,821,263; deoxygenated paclitaxel compounds, e.g., those described in U.S. Patent No. 5,440,056; and taxol derivatives described in U.S. Patent No. 5,415,869. As described above, the following also include prodrugs of paclitaxel (including, but not limited to, those described in WO98 / 58927; WO98 / 13059; and U.S. Patent No. 5,824,701). The taxane may also be a taxane conjugate, such as paclitaxel-PEG, paclitaxel-dextran, paclitaxel-xylose, docetaxel-PEG, docetaxel-dextran, docetaxel-xylose, etc. Other derivatives are mentioned in "Synthesis and Anticancer Activity of Taxol Derivatives," DGI Kingston et al., Studies in Organic Chemistry, vol. 26, entitled "New Trends in Natural Products Chemistry" (1986), Atta-ur-Rabman, PW le Quesne, Eds. (Elsevier, Amsterdam 1986), etc. Each of these documents is incorporated in its entirety herein by attribution.

[0163] Various taxanes may be readily prepared using techniques known to those skilled in the art (see also WO94 / 07882, WO94 / 07881, WO94 / 07880, WO94 / 07876, WO93 / 23555, WO93 / 10076; U.S. Patents 5,294,637; 5,283,253; 5,279,949; 5,274,137; 5,202,448; 5,200,534; 5,229,529; and EP590,267) (each of which is incorporated herein in whole with due attribution), or obtained from various commercial sources (including, for example, Sigma-Aldrich Co., St. Louis, Missouri).

[0164] Alternatively, the mitotic inhibitor may be a microtubule inhibitor; in a preferred embodiment of 1, the microtubule inhibitor is a vinca alkaloid. Generally, the vinca alkaloid is a spindle toxin. The vinca alkaloid agent acts during mitosis, when chromosomes divide and begin to move along the spindle tube toward one of its poles before the cell divides. Under the action of these spindle toxins, the spindle disintegrates due to the dispersion of chromosomes during mitosis, affecting cell replication. According to one embodiment, for example, the vinca alkaloid is selected from the group consisting of vinblastine, vincristine, vindesine, vinorelbine, and their salts, analogs, and derivatives.

[0165] Mitotic inhibitors can also be eposilons. Generally, eposilon compounds stabilize microtubule function through a mechanism similar to that of taxanes. Eposilons can also arrest the cell cycle at the G2-M transition phase, inducing cytotoxicity and ultimately apoptosis. Suitable eposilons include eposilon A, eposilon B, eposilon C, eposilon D, eposilon E, and eposilon F, as well as their salts, analogs, and derivatives. One particular eposilon analog is the eposilon B analog, ixabepyrone (ixempra®).

[0166] In one embodiment, the mitotic inhibitory anticancer agent is selected from the group consisting of taxanes, eposilones, vinca alkaloids, and salts and combinations thereof. Therefore, for example, in one embodiment, the mitotic inhibitor is a taxane. More preferably, in this embodiment, the mitotic inhibitor is paclitaxel or docetaxel, and even more preferably, paclitaxel. In another embodiment, the mitotic inhibitor is an eposilone (e.g., an eposilone B analog). In yet another embodiment, the mitotic inhibitor is a vinca alkaloid.

[0167] In one embodiment, at least one of the pentaza macrocyclic ring complex and platinum-based anticancer agents is administered within a predetermined period before or after the administration of a further dose of chemotherapeutic agents. For example, the pentaza macrocyclic ring complex and platinum-based anticancer agents may be administered within one week, 48 hours, 24 hours, 12 hours, 6 hours, 2 hours, 1 hour, or even 30 minutes before or after the administration of further chemotherapeutic agents received by the patient. Other periods between the administration of further chemotherapeutic agents that enhance cancer cell death and the administration of the components may also be appropriate. In one embodiment, one or more of the pentaza macrocyclic ring complex and platinum-based anticancer agents may be administered before the administration of further chemotherapeutic agents, and the remaining one or more of the pentaza macrocyclic ring complex and platinum-based anticancer agents may be administered after the administration of further chemotherapeutic agents. One or more of the pentaza macrocyclic ring complex and platinum-based anticancer agents may also be administered both before or after the administration of further chemotherapeutic agents.

[0168] In one embodiment, the chemotherapy process includes a single dose of an additional chemotherapeutic agent. In another embodiment, the chemotherapy process includes multiple doses of an additional chemotherapeutic agent administered over a predetermined period, e.g., several hours, several weeks, several days, or even several months. The multiple doses may be the same or different doses and may include the administration of the same or different chemotherapeutic agents and / or combinations of chemotherapeutic agents. Administration of the pentaza macrocyclic complex and platinum-based anticancer agent during the chemotherapy process may be selected to enhance the cancer-treating effect of chemotherapy, for example, by increasing intracellular hydrogen peroxide levels to promote oxidative stress in cancer cells. In one embodiment, the pentaza macrocyclic complex and platinum-based anticancer agent is administered before or after each dose for a predetermined period, e.g., within the predetermined period described above. In another embodiment, the pentaza macrocyclic complex and platinum-based anticancer agent is administered only within a selected predetermined period before or after each dose. In yet another embodiment, at least one of the pentaza macrocyclic ring complex and platinum-based anticancer agents is administered within a predetermined pre-administration period, while another pentaza macrocyclic ring complex and platinum-based anticancer agent is administered within a predetermined post-administration period. In yet another embodiment, at least one of the pentaza macrocyclic ring complex and platinum-based anticancer agents is administered only within a selected pre-administration or post-administration period, while another pentaza macrocyclic ring complex and platinum-based anticancer agent is administered only within a predetermined pre-administration or post-administration period other than the selected administration.

[0169] In yet another embodiment, at least one of the pentaza macrocyclic ring complex and platinum-based anticancer agents is administered in combination with both radiotherapy and chemotherapy (related to the administration of further chemotherapeutic agents).

[0170] Examples The following non-limiting embodiments are provided to further illustrate aspects of the present invention. Those skilled in the art should appreciate that the techniques disclosed in the following embodiments demonstrate that the methods discovered by the inventors are well-suited for use in carrying out the present invention and can therefore be considered as examples of its implementation. However, those skilled in the art should recognize that, taking this disclosure into consideration, many modifications can be made to the specific embodiments disclosed, and similar or equivalent results can be obtained without departing from the spirit and scope of the invention.

[0171] Synergistic effects of anti-cancer treatment Example 1 The effects of GC4419 and cisplatin on the survival of cancer cells in culture. H460 human non-small cell lung cancer (NSCLC) cells in culture medium were treated with either 24 μM GC4419 (+GC) or culture medium (-GC) and cisplatin at the indicated concentrations. After 120 hours, the cell viability fraction was examined. Addition of GC4419 to cisplatin treatment reduced the viability fraction of H460 cells compared to cells treated with cisplatin alone. GC4419 significantly increased the sensitivity of H460 lung cancer cells to cisplatin (see Figure 1: Effects of GC4419 and cisplatin on the viability of H460 cells in culture).

[0172] Example 2 Effects of GC4419, cisplatin, and catalase overexpression on cancer cell survival in culture H1299 human NSCLC cells, modified to inductively overexpress catalase (CAT) that removes hydrogen peroxide (H2O2), were treated in cell culture at indicated concentrations of 24 μM GC4419 (+GC) or medium (-GC) and cisplatin. CAT overexpression in this strain (H1299CAT) was induced by doxycycline administration, which turned on the transcription of the inserted catalase gene. After 120 hours of treatment with cisplatin, either in the presence or absence of GC4419, the survival fraction of H1299CAT cells was examined both in the presence and absence of CAT overexpression. In the absence of CAT overexpression ("wt"), adding GC4419 to cisplatin treatment reduced the survival fraction of H460 cells compared to cells treated with cisplatin alone, similar to H460 cells treated with both GC4419 and cisplatin. In contrast, CAT overexpression ("CAT" which removes H2O2 produced from superoxide by GC4419) suppressed GC4419's contribution to the cisplatin response, and GC4419 significantly increased the sensitivity of H460 lung cancer cells to cisplatin, with this increased responsiveness being shown to be H2O2-dependent (see Figure 2: Effects of GC4419, cisplatin, and catalase overexpression in cultured H1299 CAT cells).

[0173] Example 3 Effects of GC4419 and cisplatin on PARP activity in cancer cells H460 NSCLC cells in culture were treated with 24 μM GC4419 and 1 μM cisplatin for 24 hours. The cells were then solubilized, and PARP (poly(ADP-ribosyl) polymerase) activity was measured by Western blotting as the ratio of 89 kd active to 116 kd inactive cells. PARP is a nuclear enzyme involved in DNA repair of single-strand breaks and is activated by cellular stress (including chemotherapy and radiation). As shown in Figure 3, cisplatin increased PARP activity compared to untreated cells or GC4419 treatment alone. Further addition of GC4419 to cisplatin significantly increased PARP activity (p<0.01), indicating that GC4419 enhances cisplatin-induced cancer cell damage (see Figure 3: Effects of GC4419 and cisplatin on PARP activity in H460 cells).

[0174] H1299 (wild-type) NSCLC cells in culture were also treated with 24 μM GC4419 and 10 μM cisplatin for 24 hours. The cells were then soluble, and PARP activity was measured by Western blotting as a ratio of 89 kd active to 116 kd inactive cells. As shown in Figure 4 and consistent with the effect shown in H460 lung cancer cells, cisplatin increased PARP activity compared to untreated cells or GC4419 treatment alone. Further addition of GC4419 to cisplatin significantly increased PARP activity (p<0.01), indicating that GC4419 enhances cisplatin-induced cancer cell damage (see Figure 4: Effects of GC4419 and cisplatin on PARP activity in H1299 cells).

[0175] H460 cells in culture were irradiated with 6 Gy of radioactive material (IR), and then exposed to either 24 μM GC4419, 1 μM cisplatin, or GC4419 alone, and cisplatin for an additional 24 hours. The cells were then solubilized, and PARP activity was measured by Western blotting as the ratio of 89 kd active to 116 kd inactive cells. As shown in Figure 5, IR alone significantly increased PARP activity compared to the background (p<0.05). Adding GC4419 to IR significantly increased PARP activity beyond that observed with radiation alone. Adding cisplatin to IR greatly increased PARP activity, and adding GC4419 to this combination significantly increased it (p<0.01). Therefore, GC4419 enhances cancer cell damage induced by both radiation and cisplatin (see Figure 5: Effects of GC4419, cisplatin, and radiation on PARP activity in H460 cells).

[0176] H1299 (wild-type) cells in culture were also exposed to 6 Gy of radioactive radiation (IR) and either 24 μM GC4419, 1 μM cisplatin, or GC4419 alone, along with cisplatin, for 24 hours. The cells were then solubilized, and PARP activity was measured by Western blotting as the ratio of 89 kd+ active to 116 kd+ inactive cells. As shown in Figure 6A, consistent with the effect shown in H460 lung cancer cells, radioactive radiation (IR) alone significantly increased PARP activity compared to background. Adding cisplatin to IR greatly increased PARP activity, and adding GC4419 to this combination significantly increased it (p<0.05), indicating that GC4419 enhances cancer cell damage induced by both radioactive radiation and cisplatin (see Figure 6A: Effects of GC4419, cisplatin, and radioactive radiation on PARP activity in H1299 cells).

[0177] H1299CAT cells were also exposed to 6 Gy of IR radiation, 24 μM GC4419, and / or 1 μM cisplatin for 24 hours. Upon treatment with doxycycline, H1299CAT cells expressed higher levels of human catalase (CAT) than “parent” H1299 (wild-type) cells, and GC4419 or other Mn pentaza macrocyclic dismutase mimetic removed all or part of the H2O2 generated from superoxide. PARP activation in H1299CAT cells not exposed to doxycycline (data not shown) was more responsive to cisplatin, IR, and GC4419 treatment compared to H1299 wild-type cells (see Figure 5). However, when CAT expression was induced in H1299CAT by doxycycline treatment, GC4419 significantly reduced PARP activation in response to cisplatin (p<0.01, Figure 6B), IR (p<0.05, Figure 6C), and IR + cisplatin (p<0.001, Figure 6C) (p<0.05). These results strongly suggest that superoxide produced by cisplatin causes cytotoxicity, and that GC4419 removal of this superoxide can reduce cytotoxicity, as shown in Example 5 below regarding the reduction of cisplatin nephrotoxicity and hematological toxicity. However, since GC4419 enhanced PARP against cisplatin in cancer cells, except when H2O2 was removed by CAT overexpression, these results support the idea that the H2O2 produced by GC4419 (when not removed by CAT) is associated with a greater promotion of cisplatin-induced cytotoxicity and PARP activity than the superoxide it replaces (Figure 6B: Treatment of H1299 CAT cells with cisplatin and GC4419 (along with doxycycline induction of CAT overexpression); and Figure 6C: Treatment of H1299 CAT cells with cisplatin, IR, and GC4419 (along with doxycycline induction of CAT overexpression).

[0178] Example 4 While cisplatin therapy increases total reactive oxygen species (ROS) levels in cancer cells, GC4419 selectively reduces superoxide and increases H2O2 levels. H460 and H1299 (wild-type) cells were exposed to 6 Gy of IR radiation and either 24 μM GC4419, 1 μM cisplatin, or GC4419 and cisplatin. After the treatment and incubation, a CellROX fluorescence-generating probe for total ROS was added and incubated for 30 minutes, and the CellROX signal was measured using flow cytometry. Figures 7A-7D show that GC4419 had little effect on total ROS when used alone against any of the cancer cell lines, but cisplatin or cisplatin and IR increased total ROS. GC4419 may have a synergistic effect on total ROS when added to cisplatin therapy (see Figures 7A-7D: Total Reactive Oxygen Species).

[0179] Alternatively, after treatment and initial incubation, a MitoSOX fluorescence-generating probe for mitochondrial superoxide was added, incubated for 10 minutes, and the MitoSOX signal was measured using a flow cytometer. Figures 8A–8D show that GC4419 significantly reduced the baseline level of mitochondrial superoxide in both cancer cell lines. Furthermore, GC4419 significantly reduced the increase in mitochondrial superoxide caused by cisplatin or cisplatin and IR (see Figures 8A–8D: Mitochondrial Superoxide).

[0180] Alternatively, a PO-1 probe for H2O2 was added after treatment and initial incubation. Figures 9A–9D show that GC4419 significantly increased both baseline levels of H2O2 in both cancer cell lines, and further significantly increased the increase in H2O2 induced by cisplatin or cisplatin and IR (see Figures 9A–9D: hydrogen peroxide).

[0181] Reduced toxicity of platinum-based anticancer drugs Example 5 Effect of GC4419 on cisplatin-induced nephrotoxicity in mice Four-month-old male C57BL / 6J mice (juvenile) were purchased from Jackson Laboratories, and eighteen-month-old mice (elderly) were obtained from the National Institute on Aging in collaboration with Dr. Amy Schindler (University of Iowa). All mice were maintained at the University of Iowa Animal Husbandry Facility in accordance with ACURF authorization #4121235. Mice were fed continuously throughout the experimental process with a normal diet and water. Animals were randomly assigned to experimental groups including vehicle control, cisplatin only, GC4419, and cisplatin + GC4419.

[0182] The cisplatin-induced acute kidney injury (AKI) model was as follows: Male C57BL / 6J mice aged 4 months or 18 months were administered a single dose of 10 mg / kg of cisplatin or 0.9% saline via intraperitoneal injection. The animals were euthanized 72 hours after cisplatin treatment. Animals in the GC4419-only and cisplatin + GC4419 groups were treated daily with 10 mg / kg of GC4419 starting 4 days before cisplatin administration until the day of euthanasia. Animals in the cisplatin-only group also received a bolus dose of saline daily after cisplatin treatment to prevent dehydration.

[0183] Whole blood blood urea nitrogen (BUN) and creatinine levels were measured 72 hours after cisplatin treatment and before the initiation of GC4419 treatment using a single-use i-STAT test cartridge (Chem8+) with an i-STAT handheld clinical analyzer purchased from Abbott-Point of Care (Princeton, New Jersey). Animals were weighed every other day after the initiation of GC4419 treatment.

[0184] As shown in Figure 10A, cisplatin increases BUN and creatinine levels on day 3 of administration in young mice, and more dramatically in aged mice, which indicates significant impairment of renal function. GC4419 completely prevents these increases in BUN and creatinine and suppresses acute kidney injury (see Figure 10A: BUN and creatinine levels in mice treated with cisplatin).

[0185] We also evaluated two specific biomarkers of renal impairment: kidney injury molecule 1 (KIM1) and neutrophil gelatinase-associated lipocalin (NGAL). As seen in Figure 10B, these biomarkers were consistent with BUN and creatinine levels, indicating that cisplatin caused nephrotoxicity and GC4419 suppressed this injury (see Figure 10B: KIM1 and NGAL biomarkers in mice treated with cisplatin).

[0186] Furthermore, consistent with these renal impairment and functional outcomes, cisplatin caused significant weight loss in both young and aged mice (Figure 10C) and reduced survival rates in the more susceptible aged mice (Figure 10D). GC4419 reduced the amount of weight loss in both groups of mice and suppressed cisplatin-induced mortality in aged mice (see Figure 10C: cisplatin-induced weight loss; and Figure 10D: survival rates in mice treated with cisplatin).

[0187] Furthermore, consistent with these renal impairment and functional outcomes, cisplatin caused significant weight loss in both young and aged mice (Figure 10C), and reduced survival rates in the more susceptible aged mice (Figure 10D). GC4419 reduced the amount of weight loss in both groups of mice and suppressed cisplatin-induced mortality in aged mice.

[0188] Example 6 Effect of GC4419 on cisplatin-induced hematological toxicity in mice Seven-week-old female Nu / Nu (nude) mice lacking a thymus gland received transplants of SQ20B human head and neck squamous cell carcinoma cells into their hind limbs. Tumors formed and became proliferative within four days. The mice received either no treatment or five doses of 2.7 mg / kg cisplatin and 2 Gy of radioirradiation (IR) every two or three days. Additionally, the group receiving cisplatin and IR treatment also received 10 mg / kg GC4419 daily during the treatment period and for two days thereafter. The mice were evaluated for blood count by tail vein blood collection two days or two weeks after the treatment period.

[0189] As shown in Figure 11A, cisplatin + IR treatment resulted in a decrease in platelets (thrombocytopenia) measured two days after the end of treatment, while GC4419 significantly restored platelet levels (see Figure 11A: Cisplatin-induced thrombocytopenia).

[0190] As shown in Figure 11B, GC4419 treatment activated the production of lymphocytes (WBCs) and relative lymphocyte populations in mice treated with a combination of cisplatin and radiation, both 2 days and 2 weeks after the end of treatment (see Figure 11B: GC4419 and WBC count).

[0191] As shown in Figure 11C, cisplatin + IR treatment resulted in a decrease in neutrophil count and percentage (neutropenia) measured 2 days or 2 weeks after the end of treatment, while GC4419 maintained the neutrophil percentage at clearly normal levels (see Figure 11C: Cisplatin-induced neutropenia).

[0192] Conversely, as shown in Figure 11D, cisplatin + IR treatment resulted in an increase in eosinophil percentage measured 2 days or 2 weeks after the end of treatment, while GC4419 kept the eosinophil percentage at clearly normal levels (see Figure 11D: Cisplatin-induced eosinophilia).

[0193] The following are typical embodiments of the aspects of this disclosure, but are not intended to be limiting, and this disclosure may encompass further embodiments.

[0194] Embodiment 1 A method for treating and / or reducing toxic effects on a mammalian subject associated with treatment with a platinum-based anticancer agent in a subject requiring treatment and / or reduction, characterized by administering a therapeutically effective amount of the platinum-based anticancer agent to the subject; and then administering a therapeutically effective amount of a pentaza macrocyclic complex corresponding to the following formula (I) to the subject before, simultaneously with, or after administration of the platinum-based anticancer agent to reduce the toxic effects of the platinum-based anticancer agent. [ka] (I) [In the formula, M is Mn 2+ or Mn 3+ and; R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10 These are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moiety, or -OR 11 , -NR 11 R 12 , -COR 11 , -CO2R 11 ,-CONR 11 R 12 , -SR 11 -SOR 11 , -SO2R 11 -SO2NR 11 R 12 , -N(OR 11 )(R 12 ), -P(O)(OR 11 )(OR 12 ), -P(O)(OR 11 )(R 12 ), and -OP(O)(OR 11 )(OR 12 A portion selected from the group consisting of R 11 and R 12 These are independently hydrogen or alkyl; U, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; V, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocyclic ring and the carbon atoms of the macrocyclic ring to which it is bonded, forms an aromatic or alicyclic substituted or unsubstituted saturated, partially saturated or unsaturated nitrogen-containing condensed heterocycle having 2 to 20 ring carbon atoms, provided that W is a condensed aromatic heterocycle, in which case the hydrogen bonded to the nitrogen that is part of both the heterocycle and the macrocyclic ring, and R1 and R bonded to the carbon atoms that are part of both the heterocycle and the macrocyclic ring, are present. 10 It shall be considered non-existent; X and Y represent either a monodentate or polydentate ligand, or an appropriate ligand derived from a ligand system, or an equivalent anion; Z is the counterion; n is an integer between 0 and 3; and The dotted line represents the coordination bond between the nitrogen atom of the macrocyclic ring and the transition metal (manganese).

[0195] Embodiment 2 The method according to Embodiment 1, wherein the subject is suffering from cancer.

[0196] Embodiment 3 The method according to Embodiment 1 or 2, wherein the subject is suffering from and / or at risk of suffering from toxicity (selected from the group consisting of nephrotoxicity, myelotoxicity, and ototoxicity) induced by treatment with a platinum-based anticancer agent.

[0197] Embodiment 4 The method according to any one of embodiments 1 to 3, wherein the subject is suffering from and / or at risk of suffering from one or more of nephrotoxicity and myelotoxicity.

[0198] Embodiment 5 The method according to any one of embodiments 1 to 4, wherein the subject is suffering from nephrotoxicity and / or myelotoxicity associated with treatment with the platinum-based anticancer agent.

[0199] Embodiment 6 The method according to any one of Embodiments 1 to 5, comprising administering a therapeutically effective amount of the platinum-based anticancer agent and a pentaza macrocyclic ring complex that enhances the therapeutic response to the platinum-based anticancer agent.

[0200] Embodiment 7 The method according to any one of embodiments 1 to 6, wherein the pentaza macrocyclic complex is administered in a therapeutically effective dose that enhances the cancer response, which is selected from the group consisting of a reduction in tumor volume, a decrease in tumor growth rate, an increase in survival rate, a decrease in the occurrence and / or extent of metastasis, and a decrease in the proliferation of cancer cells.

[0201] Embodiment 8 The method according to any one of embodiments 1 to 7, wherein the pentaza macrocyclic ring is administered in a therapeutically effective amount that reduces the level of at least one of creatine and blood urea nitrogen (BUN).

[0202] Embodiment 9 The method according to any one of embodiments 1 to 8, wherein the pentaza macrocyclic ring is administered in a therapeutically effective amount that reduces the level of a marker for renal impairment selected from the group consisting of kidney damage molecule 1 (KIM1) and neutrophil gelatinase-binding lipocalin (NGAL).

[0203] Embodiment 10 A method for treating and / or reducing the risk of toxic effects associated with treatment with a platinum-based anticancer agent in a mammalian subject requiring treatment and / or reduction: a method characterized by administering a pentaza macrocyclic complex corresponding to the following formula (I) before, simultaneously with, or after administration of the platinum-based anticancer agent to reduce the toxic effects of the platinum-based anticancer agent. [ka] (I) [In the formula, M is Mn 2+ or Mn 3+ and; R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10 These are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moiety, or -OR 11 , -NR 11 R 12 , -COR 11 , -CO2R 11 ,-CONR 11 R 12 , -SR 11 -SOR 11 , -SO2R 11 -SO2NR 11 R 12 , -N(OR 11 )(R 12 ), -P(O)(OR 11 )(OR 12 ), -P(O)(OR 11 )(R 12 ), and -OP(O)(OR 11 )(OR 12 A portion selected from the group consisting of R 11 and R 12 These are independently hydrogen or alkyl; U, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; V, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocyclic ring and the carbon atoms of the macrocyclic ring to which it is bonded, forms an aromatic or alicyclic substituted or unsubstituted saturated, partially saturated or unsaturated nitrogen-containing condensed heterocycle having 2 to 20 ring carbon atoms, provided that W is a condensed aromatic heterocycle, in which case the hydrogen bonded to the nitrogen that is part of both the heterocycle and the macrocyclic ring, and R1 and R bonded to the carbon atoms that are part of both the heterocycle and the macrocyclic ring, are present. 10 It shall be considered non-existent; X and Y represent either a monodentate or polydentate ligand, or an appropriate ligand derived from a ligand system, or an equivalent anion; Z is the counterion; n is an integer between 0 and 3; and The dotted line represents the coordination bond between the nitrogen atom of the macrocyclic ring and the transition metal (manganese).

[0204] Embodiment 11 The method according to Embodiment 10, wherein the subject is suffering from cancer.

[0205] Embodiment 12 The method according to Embodiment 10 or 11, wherein the subject is suffering from and / or at risk of suffering from toxicity (selected from the group consisting of nephrotoxicity, myelotoxicity, and ototoxicity) induced by treatment with a platinum-based anticancer agent.

[0206] Embodiment 13 The method according to any one of embodiments 10 to 12, wherein the subject is suffering from and / or at risk of suffering from one of nephrotoxicity and myelotoxicity.

[0207] Embodiment 14 The method according to any one of embodiments 10 to 13, wherein the subject is suffering from nephrotoxicity and / or myelotoxicity associated with treatment with the platinum-based anticancer agent.

[0208] Embodiment 15 The method according to any one of embodiments 10 to 14, comprising administering a therapeutically effective amount of the platinum-based anticancer agent and a pentaza macrocyclic ring complex that enhances the therapeutic response to the platinum-based anticancer agent.

[0209] Embodiment 16 The method according to any one of embodiments 10 to 15, wherein the pentaza macrocyclic complex is administered in a therapeutically effective dose that enhances the cancer response, which is selected from the group consisting of a reduction in tumor volume, a decrease in tumor growth rate, an increase in survival rate, a decrease in the occurrence and / or extent of metastasis, and a decrease in the proliferation of cancer cells.

[0210] Embodiment 17 The method according to any one of embodiments 10 to 16, wherein the pentaza macrocyclic ring is administered in a therapeutically effective amount that reduces the level of at least one of creatine and blood urea nitrogen (BUN).

[0211] Embodiment 18 The method according to any one of embodiments 10 to 17, wherein the pentaza macrocyclic ring is administered in a therapeutically effective amount that reduces the level of a marker for renal impairment selected from the group consisting of kidney damage molecule 1 (KIM1) and neutrophil gelatinase-binding lipocalin (NGAL).

[0212] Embodiment 19 A method of treating cancer in mammals suffering from cancer: The subject is administered a therapeutically effective amount of platinum-based anticancer drug; A method characterized by administering a therapeutically effective amount of a pentaza macrocyclic ring complex corresponding to the following formula (I) to the subject before, simultaneously with, or after the administration of the platinum-based anticancer agent, thereby enhancing the responsiveness of the cancer to the platinum-based anticancer agent. [ka] (I) [In the formula, M is Mn 2+ or Mn 3+ and; R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10 These are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moiety, or -OR 11 , -NR 11 R 12 , -COR 11 , -CO2R 11 ,-CONR 11 R 12 , -SR 11 -SOR 11 , -SO2R 11 -SO2NR 11 R 12 , -N(OR 11 )(R 12 ), -P(O)(OR 11 )(OR 12 ), -P(O)(OR 11 )(R 12 ), and -OP(O)(OR 11 )(OR 12 A portion selected from the group consisting of R 11 and R 12 These are independently hydrogen or alkyl; U, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; V, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocyclic ring and the carbon atoms of the macrocyclic ring to which it is bonded, forms an aromatic or alicyclic substituted or unsubstituted saturated, partially saturated or unsaturated nitrogen-containing condensed heterocycle having 2 to 20 ring carbon atoms, provided that W is a condensed aromatic heterocycle, in which case the hydrogen bonded to the nitrogen that is part of both the heterocycle and the macrocyclic ring, and R1 and R bonded to the carbon atoms that are part of both the heterocycle and the macrocyclic ring, are present. 10 It shall be considered non-existent; X and Y represent either a monodentate or polydentate ligand, or an appropriate ligand derived from a ligand system, or an equivalent anion; Z is the counterion; n is an integer between 0 and 3; and The dotted line represents the coordination bond between the nitrogen atom of the macrocyclic ring and the transition metal (manganese).

[0213] Embodiment 20 The method according to Embodiment 19, comprising administering a therapeutically effective amount of the platinum-based anticancer agent and a pentaza macrocyclic complex that reduces the toxic effects of the platinum-based anticancer agent.

[0214] Embodiment 21 The method according to Embodiment 19 or 20, wherein the pentaza macrocyclic ring complex is administered in a therapeutically effective dose that can enhance the cancer response, and / or reduce cancer complications, which is selected from the group consisting of a reduction in tumor volume, a decrease in tumor growth rate, an increase in survival rate, a decrease in the occurrence and / or extent of metastasis, and a decrease in the proliferation of cancer cells.

[0215] Embodiment 22 The method according to any one of embodiments 19 to 21, wherein the pentaza macrocyclic ring is administered in a therapeutically effective amount that reduces the level of at least one of creatine and blood urea nitrogen (BUN).

[0216] Embodiment 23 The method according to any one of embodiments 19 to 22, wherein the pentaza macrocyclic ring is administered in a therapeutically effective amount that reduces the level of a marker for renal impairment selected from the group consisting of kidney damage molecule 1 (KIM1) and neutrophil gelatinase-binding lipocalin (NGAL).

[0217] Embodiment 24 A method for enhancing the sensitivity of mammalian subjects to treatment with platinum-based anticancer drugs in subjects requiring increased sensitivity: A method characterized by administering a therapeutically effective amount of a pentaza macrocyclic ring complex corresponding to the following formula (I) to the subject before, simultaneously with, or after the administration of the platinum-based anticancer agent, thereby enhancing the therapeutic response to the platinum-based anticancer agent. [ka] (I) [In the formula, M is Mn 2+ or Mn 3+ and; R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10 These are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moiety, or -OR 11 , -NR 11 R 12 , -COR 11 , -CO2R 11 ,-CONR 11 R 12 , -SR 11 -SOR 11 , -SO2R 11 -SO2NR 11 R 12 , -N(OR 11 )(R 12 ), -P(O)(OR 11 )(OR 12 ), -P(O)(OR 11 )(R 12 ), and -OP(O)(OR 11 )(OR 12A portion selected from the group consisting of R 11 and R 12 These are independently hydrogen or alkyl; U, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; V, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocyclic ring and the carbon atoms of the macrocyclic ring to which it is bonded, forms an aromatic or alicyclic substituted or unsubstituted saturated, partially saturated or unsaturated nitrogen-containing condensed heterocycle having 2 to 20 ring carbon atoms, provided that W is a condensed aromatic heterocycle, in which case the hydrogen bonded to the nitrogen that is part of both the heterocycle and the macrocyclic ring, and R1 and R bonded to the carbon atoms that are part of both the heterocycle and the macrocyclic ring, are present. 10 It shall be considered non-existent; X and Y represent either a monodentate or polydentate ligand, or an appropriate ligand derived from a ligand system, or an equivalent anion; Z is the counterion; n is an integer between 0 and 3; and The dotted line represents the coordination bond between the nitrogen atom of the macrocyclic ring and the transition metal (manganese).

[0218] Embodiment 25 The method according to embodiment 24, wherein the subject is suffering from cancer.

[0219] Embodiment 26 The method according to Embodiment 24 or 25, comprising administering a therapeutically effective amount of the platinum-based anticancer agent and a pentaza macrocyclic complex that reduces the toxic effects of the platinum-based anticancer agent.

[0220] Embodiment 27 The method according to any one of embodiments 24 to 26, wherein the pentaza macrocyclic ring complex is administered in a therapeutically effective dose that can enhance the cancer response, and / or reduce cancer complications, which is selected from the group consisting of a reduction in tumor volume, a decrease in tumor growth rate, an increase in survival rate, a decrease in the occurrence and / or extent of metastasis, and a decrease in the proliferation of cancer cells.

[0221] Embodiment 28 The method according to any one of embodiments 24 to 27, wherein the pentaza macrocyclic ring is administered in a therapeutically effective amount that reduces the level of at least one of creatine and blood urea nitrogen (BUN).

[0222] Embodiment 29 The method according to any one of embodiments 24 to 28, wherein the pentaza macrocyclic ring is administered in a therapeutically effective amount that reduces the level of a marker for renal impairment selected from the group consisting of kidney damage molecule 1 (KIM1) and neutrophil gelatinase-binding lipocalin (NGAL).

[0223] Embodiment 30 A method for treating and / or reducing the risk of toxic effects selected from the group consisting of nephrotoxicity and myelotoxicity associated with treatment with platinum-based anticancer agents in mammalian subjects requiring treatment and / or reduction: The subject is administered a therapeutically effective amount of platinum-based anticancer drug; then A method characterized by administering a therapeutically effective amount of a pentaza macrocyclic complex corresponding to the following formula (I) to the subject before, simultaneously with, or after the administration of the platinum-based anticancer agent, thereby reducing the toxic effect of the platinum-based anticancer agent. [ka] (I) [In the formula, M is Mn 2+ or Mn 3+ and; R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10 These are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moiety, or -OR 11 , -NR 11 R 12 , -COR 11 , -CO2R 11 ,-CONR 11 R 12 , -SR 11 -SOR 11 , -SO2R 11 -SO2NR 11 R 12 , -N(OR 11 )(R 12 ), -P(O)(OR 11 )(OR 12 ), -P(O)(OR 11 )(R 12 ), and -OP(O)(OR 11 )(OR 12 A portion selected from the group consisting of R 11 and R 12 These are independently hydrogen or alkyl; U, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; V, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocyclic ring and the carbon atoms of the macrocyclic ring to which it is bonded, forms an aromatic or alicyclic substituted or unsubstituted saturated, partially saturated or unsaturated nitrogen-containing condensed heterocycle having 2 to 20 ring carbon atoms, provided that W is a condensed aromatic heterocycle, in which case the hydrogen bonded to the nitrogen that is part of both the heterocycle and the macrocyclic ring, and R1 and R bonded to the carbon atoms that are part of both the heterocycle and the macrocyclic ring, are present. 10 It shall be considered non-existent; X and Y represent either a monodentate or polydentate ligand, or an appropriate ligand derived from a ligand system, or an equivalent anion; Z is the counterion; n is an integer between 0 and 3; and The dotted line represents the coordination bond between the nitrogen atom of the macrocyclic ring and the transition metal (manganese).

[0224] Embodiment 31 The method according to embodiment 30, wherein the subject is suffering from cancer.

[0225] Embodiment 32 The method according to embodiment 30 or 31, wherein the subject is suffering from nephrotoxicity and / or myelotoxicity associated with treatment with the platinum-based anticancer agent.

[0226] Embodiment 33 The method according to any one of embodiments 30 to 32, comprising administering a therapeutically effective amount of the platinum-based anticancer agent and a pentaza macrocyclic ring complex that enhances the therapeutic response to the platinum-based anticancer agent.

[0227] Embodiment 34 The method according to any one of embodiments 30 to 33, wherein the pentaza macrocyclic ring complex is administered in a therapeutically effective dose that enhances the cancer response, and / or reduces cancer complications, which is selected from the group consisting of a reduction in tumor volume, a decrease in tumor growth rate, an increase in survival rate, a decrease in the occurrence and / or extent of metastasis, and a decrease in the proliferation of cancer cells.

[0228] Embodiment 35 The method according to any one of embodiments 30 to 34, wherein the pentaza macrocyclic ring is administered in a therapeutically effective amount that reduces the level of at least one of creatine and blood urea nitrogen (BUN).

[0229] Embodiment 36 The method according to any one of embodiments 30 to 35, wherein the pentaza macrocyclic ring is administered in a therapeutically effective amount that reduces the level of a marker for renal impairment selected from the group consisting of kidney injury molecule 1 (KIM1) and neutrophil gelatinase-binding lipocalin (NGAL).

[0230] Embodiment 37 A method for treating and / or reducing the risk of toxic effects selected from the group consisting of nephrotoxicity and myelotoxicity associated with treatment with platinum-based anticancer agents in mammalian subjects requiring treatment and / or reduction: A method characterized by administering a pentaza macrocyclic ring complex corresponding to the following formula (I) to the subject before, simultaneously with, or after the administration of the platinum-based anticancer agent, thereby reducing the toxic effect of the platinum-based anticancer agent. [ka] (I) [In the formula, M is Mn 2+ or Mn 3+ and; R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10 These are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moiety, or -OR 11 , -NR 11 R 12 , -COR 11 , -CO2R 11 ,-CONR 11 R 12 , -SR 11 -SOR 11 , -SO2R 11 -SO2NR 11 R 12 , -N(OR 11 )(R 12 ), -P(O)(OR 11 )(OR 12 ), -P(O)(OR 11 )(R 12 ), and -OP(O)(OR11 )(OR 12 A portion selected from the group consisting of R 11 and R 12 These are independently hydrogen or alkyl; U, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; V, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocyclic ring and the carbon atoms of the macrocyclic ring to which it is bonded, forms an aromatic or alicyclic substituted or unsubstituted saturated, partially saturated or unsaturated nitrogen-containing condensed heterocycle having 2 to 20 ring carbon atoms, provided that W is a condensed aromatic heterocycle, in which case the hydrogen bonded to the nitrogen that is part of both the heterocycle and the macrocyclic ring, and R1 and R bonded to the carbon atoms that are part of both the heterocycle and the macrocyclic ring, are present. 10 It shall be considered non-existent; X and Y represent either a monodentate or polydentate ligand, or an appropriate ligand derived from a ligand system, or an equivalent anion; Z is the counterion; n is an integer between 0 and 3; and The dotted line represents the coordination bond between the nitrogen atom of the macrocyclic ring and the transition metal (manganese).

[0231] Embodiment 38 The method according to embodiment 37, wherein the subject is suffering from cancer.

[0232] Embodiment 39 The method according to embodiment 37 or 38, wherein the subject is suffering from nephrotoxicity and / or myelotoxicity associated with treatment with the platinum-based anticancer agent.

[0233] Embodiment 40 The method according to any one of embodiments 37 to 39, comprising administering a therapeutically effective amount of the platinum-based anticancer agent and a pentaza macrocyclic ring complex that enhances the therapeutic response to the platinum-based anticancer agent.

[0234] Embodiment 41 The method according to any one of embodiments 37 to 40, wherein the pentaza macrocyclic complex is administered in a therapeutically effective dose that can enhance a cancer response and / or reduce cancer complications, selected from the group consisting of a reduction in tumor volume, a decrease in tumor growth rate, an increase in survival rate, a decrease in the occurrence and / or extent of metastasis, and a decrease in the proliferation of cancer cells.

[0235] Embodiment 42 The method according to any one of embodiments 37 to 41, wherein the pentaza macrocyclic ring is administered in a therapeutically effective amount that reduces the level of at least one of creatine and blood urea nitrogen (BUN).

[0236] Embodiment 43 The method according to any one of embodiments 37 to 42, wherein the pentaza macrocyclic ring is administered in a therapeutically effective amount that reduces the level of a marker for renal impairment selected from the group consisting of kidney damage molecule 1 (KIM1) and neutrophil gelatinase-binding lipocalin (NGAL).

[0237] Embodiment 44 R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10 The method according to any of the embodiments, wherein each of these is hydrogen.

[0238] Embodiment 45 The method according to any one of Embodiments 1 to 44, wherein W is an unsubstituted pyridine moiety.

[0239] Embodiment 46 The method according to any one of embodiments 1 to 45, wherein U and V are transcyclohexanyl condensed rings.

[0240] Embodiment 47 The aforementioned pentaza macrocyclic ring complex is given by formula (II): [ka] (II) [In the formula, X and Y represent either a monodentate or polydentate ligand or a suitable ligand derived from a ligand system, or the corresponding anions thereof; and R A , R B , R C , and R D These are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moiety, or -OR 11 , -NR 11 R 12 , -COR 11 , -CO2R 11 ,-CONR 11 R 12 , -SR 11 -SOR 11 , -SO2R 11 -SO2NR 11 R 12 , -N(OR 11 )(R 12 ), -P(O)(OR 11 )(OR 12 ), -P(O)(OR 11 )(R 12 ), and -OP(O)(OR 11 )(OR 12 A portion selected from the group consisting of R 11 and R 12 [These are independently hydrogen or alkyl.] The method according to any of embodiments 1 to 46, as shown in [reference].

[0241] Embodiment 48 The aforementioned pentaza macrocyclic ring complex is given by formula (III) or formula (IV): [ka] [In the formula, X and Y represent either a monodentate or polydentate ligand or a suitable ligand derived from a ligand system, or the corresponding anions thereof; and R A , R B , R C , and R D These are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moiety, or -OR 11 , -NR 11 R 12 , -COR 11 , -CO2R 11 ,-CONR 11 R 12 , -SR 11 -SOR 11 , -SO2R 11 -SO2NR 11 R 12 , -N(OR 11 )(R 12 ), -P(O)(OR 11 )(OR 12 ), -P(O)(OR 11 )(R 12 ), and -OP(O)(OR 11 )(OR 12 A portion selected from the group consisting of R 11 and R 12 [These are independently hydrogen or alkyl.] The method according to any of embodiments 1 to 47, as shown in [reference].

[0242] Embodiment 49 The aforementioned pentaza macrocyclic ring complex is given by equations (V) to (XVI): [ka] [ka] The method according to any one of embodiments 1 to 48, which is represented by a formula selected from the group consisting of the following.

[0243] Embodiment 50 A method according to any of Embodiments 1 to 49, wherein X and Y are independently a halide, oxo, aco, hydroxo, alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino, heterocycloalkylamino, heterocycloarylamino, amine oxide, hydrazine, alkylhydrazine, arylhydrazine, nitric oxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkylnitrile, arylnitrile, alkylisonitrile, arylisonitrile, nitrate, nitrite, azide, alkylsulfonic acid, arylsulfonic acid, alkylsulfoxide, arylsulfoxide, alkylarylsulfoxide, alkylsulfenic acid, arylsulfenic acid, alkylsulfinic acid, arylsulfinic acid, alkylthiol carboxylic acid, arylthiol carboxylic acid, alkylthiol thiocarboxylic acid, arylthiol thiocarboxylic acid, alkylcarboxylic acid, arylcarboxylic acid, urea, alkylurea, arylurea, alkylarylurea, thiourea, alkyl Thiourea, arylthiourea, alkylarylthiourea, sulfuric acid, sulfite, bisulfite, bisulfite, thiosulfate, thiosulfite, hydrosulfite, alkylphosphine, arylphosphine, alkylphosphine oxide, arylphosphine oxide, alkylarylphosphine oxide, alkylphosphine sulfide, arylphosphine sulfide, alkylarylphosphine sulfide, alkylphosphonic acid, arylphosphonic acid, alkylphosphinic acid, arylphosphinic acid, alkylphosphinic acid, arylphosphinic acid, phosphoric acid, thiophosphate Acids, phosphorous acid, pyrophosphoric acid, triphosphate, hydrogen phosphate, dihydrogen phosphate, alkylguanidino, arylguanidino, alkylarylguanidino, alkylcarbamate, arylcarbamate, alkylarylcarbamate, alkylthiocarbamate, arylthiocarbamate, alkylarylthiocarbamate, alkyldithiocarbamate, aryldithiocarbamate, alkylaryldithiocarbamate, bicarbonate, carbonic acid, perchloric acid, chloric acid, chlorous acid, hypochlorous acid, perbromic acid, bromic acid, bromic acid, hypobromic acid, tetrahalomanganate,A substituted or unsubstituted portion of the group consisting of tetrafluoroboric acid, hexafluoroantimonic acid, hypophosphorous acid, iodic acid, periodic acid, metaboric acid, tetraarylboric acid, tetraalkylboric acid, tartaric acid, salicylic acid, succinic acid, citric acid, ascorbic acid, saccharic acid, amino acids, hydroxamic acid, oxothiotosylate, and anions of ion exchange resins, or independently selected from these corresponding anions; Alternatively, X and Y correspond to -OC(O)-X1, where each X1 is -C(X2)(X3)(X4), Each X1 is independently a substituted or unsubstituted phenyl or -C(-X2)(-X3)(-X4); Each X2 is independently substituted or unsubstituted phenyl, methyl, ethyl, or propyl; Each X3 independently contains hydrogen, hydroxyl, methyl, ethyl, propyl, amino, and -X5C(=O)R 13 [In the formula, X5 is NH or O, and R 13 [is a C1-C18 alkyl, substituted or unsubstituted aryl, or a C1-C18 aralkyl], or -OR 14 [In the formula, R 14 is either a C1-C18 alkyl, substituted or unsubstituted aryl, or a C1-C18 aralkyl, or together with X4, (=O); and Each X4 is either independently hydrogen, or together with X3, (=O); Alternatively, X and Y are independently selected from the group consisting of charge-neutralizing anions derived from monodentate or polydentate ligands, as well as ligand systems and their corresponding anions; Alternatively, X and Y independently determine R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10 A method that combines one or more of the following.

[0244] Embodiment 51 The method according to any one of Embodiments 1 to 50, wherein X and Y are independently selected from the group consisting of fluoro, chloro, bromo, and iodo anions.

[0245] Embodiment 52 The method according to any one of embodiments 1 to 51, wherein X and Y are independently selected from the group consisting of alkylcarboxylates, arylcarboxylates, and arylalkylcarboxylates.

[0246] Embodiment 53 The method according to any one of embodiments 1 to 52, wherein X and Y are independently amino acids.

[0247] Embodiment 54 The aforementioned pentaza macrocyclic ring complex is given by formula: [ka] The method according to any one of Embodiments 1 to 53, wherein the compound is shown as shown.

[0248] Embodiment 55 The aforementioned pentaza macrocyclic ring complex is given by formula: [ka] The method according to any one of Embodiments 1 to 54, wherein the compound is shown as shown.

[0249] Embodiment 56 The aforementioned pentaza macrocyclic ring complex is given by formula: [ka] The method according to any one of Embodiments 1 to 55, wherein the compound is shown as shown.

[0250] Embodiment 57 The aforementioned pentaza macrocyclic ring complex is given by formula: [ka] The method according to any one of Embodiments 1 to 56, wherein the compound is shown as shown.

[0251] Embodiment 58 The aforementioned pentaza macrocyclic ring complex is given by formula: [ka] The method according to any one of Embodiments 1 to 57, wherein the compound is shown as shown.

[0252] Embodiment 59 The aforementioned pentaza macrocyclic ring complex is given by formula: [ka] The method according to any of the embodiments, wherein the compound is represented by [the compound shown].

[0253] Embodiment 60 The method according to any one of Embodiments 1 to 59, wherein the platinum-based anticancer agent is one selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, lovaplatin, heptaplatin, dicycloplatin, lipoplatin, LA-12, phosphaplatin, phenanthriplatin, prolyndac, triplatin tetranitrate, picoplatin, satraplatin, pyriplatin, and / or pharmaceutically acceptable salts thereof.

[0254] Embodiment 61 The method according to any one of Embodiments 1 to 60, wherein the platinum-based anticancer agent comprises cisplatin.

[0255] Embodiment 62 The aforementioned platinum-based anticancer drug is administered at 20 mg / m². 2 ~200mg / m 2 The method according to any one of embodiments 1 to 61, administered in doses within the range of [amount].

[0256] Embodiment 63 The method according to any one of Embodiments 1 to 62, wherein the administration of the pentaza macrocyclic ring complex during the treatment process is performed a certain period before the administration of the platinum-based anticancer agent.

[0257] Embodiment 64 The method according to any one of Embodiments 1 to 63, wherein the administration of the pentaza macrocyclic ring complex during the course of treatment is administered at least one week, one day, or one hour before the administration of the platinum-based anticancer agent.

[0258] Embodiment 65 The method according to any one of embodiments 1 to 64, wherein the administration of the pentaza macrocyclic ring complex during the course of treatment is performed within one hour before and / or simultaneously with the administration of the platinum-based anticancer agent.

[0259] Embodiment 66 The method according to any one of embodiments 1 to 65, wherein the administration of the pentaza macrocyclic complex during the course of treatment is within 1 hour, 1 day, or 1 week after the administration of the platinum-based anticancer agent.

[0260] Embodiment 67 The method according to any one of Embodiments 1 to 66, comprising administering the aforementioned platinum-based anticancer drug to a subject receiving simultaneous radiotherapy.

[0261] Embodiment 68 The method according to any one of Embodiments 1 to 66, comprising administering the aforementioned platinum-based anticancer agent and pentaza macrocyclic ring complex to a subject not receiving radiotherapy.

[0262] Embodiment 69 The method according to any one of embodiments 1 to 66, wherein a treatment process including the administration of the pentaza macrocyclic complex and a platinum-based anticancer agent is administered to a subject who has not received radiotherapy during the treatment process.

[0263] Embodiment 70 The method according to any one of Embodiments 1 to 66, comprising administering one or more of the aforementioned pentaza macrocyclic ring complex and platinum-based anticancer agents to the subject on a day other than the day the subject is receiving radiotherapy.

[0264] Embodiment 71 The method according to any one of embodiments 1 to 66, comprising administering a treatment process in which the platinum-based anticancer agent and the pentaza macrocyclic ring complex are administered to a subject who has not received radiotherapy for at least one day.

[0265] Embodiment 72 The method according to any one of embodiments 1 to 66, comprising administering a treatment process to a subject who has not received radiotherapy for at least one week, the platinum-based anticancer agent and the pentaza macrocyclic ring complex.

[0266] Embodiment 73 The method according to any one of embodiments 1 to 66, comprising administering a treatment process to a subject who has not received radiotherapy for at least one month, the aforementioned platinum-based anticancer agent and pentaza macrocyclic ring complex.

[0267] Embodiment 74 The method according to any one of embodiments 1 to 66, comprising administering a treatment process to a subject who has not received radiotherapy for at least six months, the platinum-based anticancer agent and the pentaza macrocyclic ring complex.

[0268] Embodiment 75 The method according to any one of embodiments 1 to 66, comprising administering the platinum-based anticancer agent and the pentaza macrocyclic ring complex to the target, and then delaying radiotherapy, which may be appropriately administered to the target, until at least one day after the final administration of the pentaza macrocyclic ring complex.

[0269] Embodiment 76 The method according to any one of Embodiments 1 to 66, comprising administering the platinum-based anticancer agent and the pentaza macrocyclic ring complex to the subject, and delaying radiotherapy, which may be appropriately administered to the subject, for at least one week after the final administration of the pentaza macrocyclic ring complex.

[0270] Embodiment 77 The method according to any one of embodiments 1 to 66, comprising administering the platinum-based anticancer agent and the pentaza macrocyclic ring complex to the target, and then delaying radiotherapy, which may be appropriately administered to the target, until at least one month after the final administration of the pentaza macrocyclic ring complex.

[0271] Embodiment 78 The method according to any one of embodiments 1 to 66, comprising administering the platinum-based anticancer agent and the pentaza macrocyclic ring complex to the subject, and then delaying radiotherapy, which may be appropriately administered to the subject, until at least 6 months after the final administration of the pentaza macrocyclic ring complex.

[0272] Embodiment 79 The method according to any one of embodiments 1 to 78, wherein the cancer is selected from the group consisting of breast cancer, non-small cell lung cancer, melanoma, renal cell carcinoma, urothelial carcinoma, bladder cancer, pancreatic cancer, head and neck cancer, colorectal cancer, prostate cancer, brain cancer, spindle cell carcinoma, and oral squamous cell carcinoma.

[0273] Embodiment 80 The method according to any one of embodiments 1 to 79, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, renal cell carcinoma, spindle cell carcinoma, colorectal cancer, oral squamous cell carcinoma, and head and neck cancer.

[0274] Embodiment 81 The method according to any one of embodiments 1 to 80, wherein the cancer is at least one of lung cancer and head and neck cancer.

[0275] Embodiment 82 The method according to any one of Embodiments 1 to 81, wherein the pentaza macrocyclic complex is administered to the subject at a dose in the range of 0.2 mg / kg to 40 mg / kg.

[0276] Embodiment 83 The method according to any one of Embodiments 1 to 82, wherein the pentaza macrocyclic ring complex is administered to the subject at a dose in the range of 0.2 mg / kg to 24 mg / kg.

[0277] Embodiment 84 The method according to any one of Embodiments 1 to 83, wherein the pentaza macrocyclic ring complex is administered to the subject at a dose in the range of 0.2 mg / kg to 10 mg / kg.

[0278] Embodiment 85 The method according to any one of Embodiments 1 to 84, wherein the pentaza macrocyclic ring complex is administered by at least one of parenteral and oral routes.

[0279] Embodiment 86 The method according to any one of embodiments 1 to 85, wherein the pentaza macrocyclic ring complex is administered intraperitoneally or intravenously.

[0280] Embodiment 87 The method according to any one of Embodiments 1 to 86, wherein the subject is a human.

[0281] Embodiment 88 A kit for treating cancer in mammalian subjects requiring treatment and / or reduction, and / or reducing the toxic effects of platinum-based anticancer agents: The aforementioned platinum-based anticancer drug; The pentaza macrocyclic ring complex corresponding to the following formula (I): and The method according to any of the preceding claims includes instructions for administering a therapeutically effective amount of the platinum-based anticancer agent and a therapeutically effective amount of the pentaza macrocyclic complex, The pentaza macrocyclic ring complex according to formula (I) is as follows: Kit: [ka] (I) [In the formula, M is Mn 2+ or Mn 3+ and; R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R 10 These are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moiety, or -OR 11 , -NR 11 R 12 , -COR 11 , -CO2R 11 ,-CONR 11 R 12 , -SR 11 -SOR 11 , -SO2R 11 -SO2NR 11 R 12 , -N(OR 11 )(R 12 ), -P(O)(OR 11 )(OR 12 ), -P(O)(OR 11 )(R 12 ), and -OP(O)(OR 11 )(OR 12 A portion selected from the group consisting of R 11 and R 12 These are independently hydrogen or alkyl; U, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; V, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocyclic ring and the carbon atoms of the macrocyclic ring to which it is bonded, forms an aromatic or alicyclic substituted or unsubstituted saturated, partially saturated or unsaturated nitrogen-containing condensed heterocycle having 2 to 20 ring carbon atoms, provided that W is a condensed aromatic heterocycle, in which case the hydrogen bonded to the nitrogen that is part of both the heterocycle and the macrocyclic ring, and R1 and R bonded to the carbon atoms that are part of both the heterocycle and the macrocyclic ring, are present. 10 It shall be considered non-existent; X and Y represent either a monodentate or polydentate ligand, or an appropriate ligand derived from a ligand system, or an equivalent anion; Z is the counterion; n is an integer between 0 and 3; and The dotted line represents the coordination bond between the nitrogen atom of the macrocyclic ring and the transition metal (manganese).

Claims

1. A method of treating cancer in mammals suffering from cancer: The subject is administered a therapeutically effective amount of platinum-based anticancer drug; A method characterized by administering a therapeutically effective amount of a pentaza macrocyclic ring complex corresponding to the following formula (I) to the subject before, simultaneously with, or after the administration of the platinum-based anticancer agent, thereby enhancing the responsiveness of the cancer to the platinum-based anticancer agent: 【Chemistry 1】 (I) [In the formula, M is Mn ２＋ or Mn ３＋ And; R １ 、R ２ 、R' ２ 、R ３ 、R ４ 、R ５ 、R' ５ 、R ６ 、R' ６ 、R ７ 、R ８ 、R ９ 、R' ９ 、およびR １０ are, independently, hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or -OR １１ 、-NR １１ R １２ 、-COR １１ 、-CO ２ R １１ 、-CONR １１ R １２ 、-SR １１ 、-SOR １１ 、-SO ２ R １１ 、-SO ２ NR １１ R １２ 、-N(OR １１ )(R １２ ), -P(O)(OR １１ )(OR １２ ), -P(O)(OR １１ )(R １２ ), and -OP(O)(OR[[ID=7)1]] １１ )(OR １２ ), and are moieties selected from the group consisting of, where R １１ and R １２ are, independently, hydrogen or alkyl; U, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; V, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocyclic ring and the carbon atoms of the macrocyclic ring to which it is bonded, forms an aromatic or alicyclic substituted or unsubstituted saturated, partially saturated or unsaturated nitrogen-containing condensed heterocycle having 2 to 20 ring carbon atoms, provided that W is a condensed aromatic heterocycle, in which case the hydrogen bonded to the nitrogen in both the heterocycle and the macrocyclic ring, and the R bonded to the carbon atoms in both the heterocycle and the macrocyclic ring １ and R １０ It is assumed to be non-existent; X and Y represent either a monodentate or polydentate ligand or an appropriate ligand derived from a ligand system, or an equivalent anion; Z is the counterion; n is an integer from 0 to 3; and The dotted line represents the coordination bond between the nitrogen atom of the macrocyclic ring and the transition metal (manganese).

2. The method according to claim 1, comprising administering a therapeutically effective amount of the platinum-based anticancer agent and a pentaza macrocyclic complex that reduces the toxic effects of the platinum-based anticancer agent.

3. The method according to claim 1 or 2, wherein the pentaza macrocyclic complex is administered in a therapeutically effective dose that enhances a cancer response, and / or reduces cancer complications, which is selected from the group consisting of a reduction in tumor volume, a decrease in tumor growth rate, an increase in survival rate, a decrease in the occurrence and / or extent of metastasis, and a decrease in the proliferation of cancer cells.

4. The method according to any one of claims 1 to 3, wherein the pentaza macrocyclic ring is administered in a therapeutically effective amount that reduces the level of at least one of creatine and blood urea nitrogen (BUN).

5. The method according to any one of claims 1 to 4, wherein the pentaza macrocyclic ring is administered in a therapeutically effective amount that reduces the level of a marker for renal impairment selected from the group consisting of renal impairment molecule 1 (KIM1) and neutrophil gelatinase-binding lipocalin (NGAL).

6. A method for enhancing the sensitivity of mammalian subjects to treatment with platinum-based anticancer drugs in subjects requiring increased sensitivity: A method characterized by administering a therapeutically effective amount of a pentaza macrocyclic ring complex corresponding to the following formula (I) to the subject before, simultaneously with, or after the administration of the platinum-based anticancer agent, thereby enhancing the therapeutic response to the platinum-based anticancer agent: 【Chemistry 2】 (I) [In the formula, M is Mn ２＋ or Mn ３＋ And; R １ , R ２ , R' ２ , R ３ , R ４ , R ５ , R' ５ , R ６ , R' ６ , R ７ , R ８ , R ９ , R' ９ , and R １０ These are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moiety, or -OR １１ , -NR １１ R １２ , -COR １１ , -CO ２ R １１ , -CONR １１ R １２ , -SR １１ , -SOR １１ , -SO ２ R １１ , -SO ２ NR １１ R １２ , -N(OR １１ ) (Caution １２ ), -P(O)(OR １１ ) ( OR １２ ), -P(O)(OR １１ ) (Caution １２ ), and -OP(O)(OR １１ ) ( OR １２ A portion selected from the group consisting of R １１ and R １２ These are independently hydrogen or alkyl; U, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; V, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocyclic ring and the carbon atoms of the macrocyclic ring to which it is bonded, forms an aromatic or alicyclic substituted or unsubstituted saturated, partially saturated or unsaturated nitrogen-containing condensed heterocycle having 2 to 20 ring carbon atoms, provided that W is a condensed aromatic heterocycle, in which case the hydrogen bonded to the nitrogen in both the heterocycle and the macrocyclic ring, and the R bonded to the carbon atoms in both the heterocycle and the macrocyclic ring １ and R １０ It is assumed to be non-existent; X and Y represent either a monodentate or polydentate ligand or an appropriate ligand derived from a ligand system, or an equivalent anion; Z is the counterion; n is an integer from 0 to 3; and The dotted line represents the coordination bond between the nitrogen atom of the macrocyclic ring and the transition metal (manganese).

7. The method according to claim 6, wherein the subject is suffering from cancer.

8. The method according to claim 6 or 7, comprising administering a therapeutically effective amount of the platinum-based anticancer agent and a pentaza macrocyclic complex that reduces the toxic effects of the platinum-based anticancer agent.

9. The method according to any one of claims 6 to 8, wherein the pentaza macrocyclic complex is administered in a therapeutically effective dose that enhances a cancer response, and / or reduces cancer complications, which is selected from the group consisting of a reduction in tumor volume, a decrease in tumor growth rate, an increase in survival rate, a decrease in the occurrence and / or extent of metastasis, and a decrease in the proliferation of cancer cells.

10. The method according to any one of claims 6 to 9, wherein the pentaza macrocyclic ring is administered in a therapeutically effective amount that reduces the level of at least one of creatine and blood urea nitrogen (BUN).

11. The method according to any one of claims 6 to 10, wherein the pentaza macrocyclic ring is administered in a therapeutically effective amount that reduces the level of a marker for renal impairment selected from the group consisting of kidney damage molecule 1 (KIM1) and neutrophil gelatinase-binding lipocalin (NGAL).

12. A method for treating and / or reducing the risk of toxic effects selected from the group consisting of nephrotoxicity and myelotoxicity associated with treatment with platinum-based anticancer agents in mammalian subjects requiring treatment and / or reduction: The subject is administered a therapeutically effective amount of platinum-based anticancer drug; then A method characterized by administering a therapeutically effective amount of a pentaza macrocyclic complex corresponding to the following formula (I) to the subject before, simultaneously with, or after the administration of the platinum-based anticancer agent, thereby reducing the toxic effect of the platinum-based anticancer agent: 【Transformation 3】 (I) [In the formula, M is Mn ２＋ or Mn ３＋ And; R １ 、R ２ 、R' ２ 、R ３ 、R ４ 、R ５ 、R' ５ 、R ６ 、R' ６ 、R ７ 、R ８ 、R ９ 、R' ９ 、およびR １０ are, independently, hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or -OR １１ 、-NR １１ R １２ 、-COR １１ 、-CO ２ R １１ 、-CONR １１ R １２ 、-SR １１ 、-SOR １１ 、-SO ２ R １１ 、-SO ２ NR １１ R １２ 、-N(OR １１ )(R １２ )、-P(O)(OR １１ )(OR １２ )、-P(O)(OR １１ )(R １２ )、および-OP(O)(OR １１ )(OR １２ )からなる群から選択される部分であって、R １１ およびR １２ は、独立して水素またはアルキルであり; U, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; V, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocyclic ring and the carbon atoms of the macrocyclic ring to which it is bonded, forms an aromatic or alicyclic substituted or unsubstituted saturated, partially saturated or unsaturated nitrogen-containing condensed heterocycle having 2 to 20 ring carbon atoms, provided that W is a condensed aromatic heterocycle, in which case the hydrogen bonded to the nitrogen in both the heterocycle and the macrocyclic ring, and the R bonded to the carbon atoms in both the heterocycle and the macrocyclic ring １ and R １０ It is assumed to be non-existent; X and Y represent either a monodentate or polydentate ligand or an appropriate ligand derived from a ligand system, or an equivalent anion; Z is the counterion; n is an integer from 0 to 3; and The dotted line represents the coordination bond between the nitrogen atom of the macrocyclic ring and the transition metal (manganese).

13. The method according to claim 12, wherein the subject is suffering from cancer.

14. The method according to claim 12 or 13, wherein the subject is suffering from nephrotoxicity and / or myelotoxicity associated with treatment with the platinum-based anticancer agent.

15. The method according to any one of claims 12 to 14, comprising administering a therapeutically effective amount of the platinum-based anticancer agent and a pentaza macrocyclic complex that enhances the therapeutic response to the platinum-based anticancer agent.

16. The method according to any one of claims 12 to 15, wherein the pentaza macrocyclic complex is administered in a therapeutically effective dose that enhances a cancer response, and / or reduces cancer complications, which is selected from the group consisting of a reduction in tumor volume, a decrease in tumor growth rate, an increase in survival rate, a decrease in the occurrence and / or extent of metastasis, and a decrease in the proliferation of cancer cells.

17. The method according to any one of claims 12 to 16, wherein the pentaza macrocyclic ring is administered in a therapeutically effective amount that reduces the level of at least one of creatine and blood urea nitrogen (BUN).

18. The method according to any one of claims 12 to 17, wherein the pentaza macrocyclic ring is administered in a therapeutically effective amount that reduces the level of a marker for renal impairment selected from the group consisting of renal impairment molecule 1 (KIM1) and neutrophil gelatinase-binding lipocalin (NGAL).

19. A method for treating and / or reducing the risk of toxic effects selected from the group consisting of nephrotoxicity and myelotoxicity associated with treatment with platinum-based anticancer agents in mammalian subjects requiring treatment and / or reduction: A method characterized by administering a pentaza macrocyclic ring complex corresponding to the following formula (I) to the subject before, simultaneously with, or after the administration of the platinum-based anticancer agent, thereby reducing the toxic effect of the platinum-based anticancer agent: 【Chemistry 4】 (I) [In the formula, M is Mn ２＋ or Mn ３＋ And; R １ , R ２ , R' ２ , R ３ , R ４ , R ５ , R' ５ , R ６ , R' ６ , R ７ , R ８ , R ９ , R' ９ , and R １０ These are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moiety, or -OR １１ , -NR １１ R １２ , -COR １１ , -CO ２ R １１ , -CONR １１ R １２ , -SR １１ , -SOR １１ , -SO ２ R １１ , -SO ２ NR １１ R １２ , -N(OR １１ ) (Caution １２ ), -P(O)(OR １１ ) ( OR １２ ), -P(O)(OR １１ ) (Caution １２ ), and -OP(O)(OR １１ ) ( OR １２ A portion selected from the group consisting of R １１ and R １２ These are independently hydrogen or alkyl; U, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; V, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocyclic ring and the carbon atoms of the macrocyclic ring to which it is bonded, forms an aromatic or alicyclic substituted or unsubstituted saturated, partially saturated or unsaturated nitrogen-containing condensed heterocycle having 2 to 20 ring carbon atoms, provided that W is a condensed aromatic heterocycle, in which case the hydrogen bonded to the nitrogen in both the heterocycle and the macrocyclic ring, and the R bonded to the carbon atoms in both the heterocycle and the macrocyclic ring １ and R １０ It is assumed to be non-existent; X and Y represent either a monodentate or polydentate ligand or an appropriate ligand derived from a ligand system, or an equivalent anion; Z is the counterion; n is an integer from 0 to 3; and The dotted line represents the coordination bond between the nitrogen atom of the macrocyclic ring and the transition metal (manganese).

20. The method according to claim 10, wherein the subject is suffering from cancer.

21. The method according to claim 19 or 20, wherein the subject is suffering from nephrotoxicity and / or myelotoxicity associated with treatment with the platinum-based anticancer agent.

22. The method according to any one of claims 19 to 21, comprising administering a therapeutically effective amount of the platinum-based anticancer agent and a pentaza macrocyclic ring complex that enhances the therapeutic response to the platinum-based anticancer agent.

23. The method according to any one of claims 19 to 22, wherein the pentaza macrocyclic complex is administered in a therapeutically effective dose that enhances a cancer response, and / or reduces cancer complications, which is selected from the group consisting of a reduction in tumor volume, a decrease in tumor growth rate, an increase in survival rate, a decrease in the occurrence and / or extent of metastasis, and a decrease in the proliferation of cancer cells.

24. The method according to any one of claims 19 to 23, wherein the pentaza macrocyclic ring is administered in a therapeutically effective amount that reduces the level of at least one of creatine and blood urea nitrogen (BUN).

25. The method according to any one of claims 19 to 24, wherein the pentaza macrocyclic ring is administered in a therapeutically effective amount that reduces the level of a marker for renal impairment selected from the group consisting of renal impairment molecule 1 (KIM1) and neutrophil gelatinase-binding lipocalin (NGAL).

26. R １ , R ２ , R' ２ , R ３ , R ４ , R ５ , R' ５ , R ６ , R' ６ , R ７ , R ８ , R ９ , R' ９ , and R １０ The method according to any one of claims 1 to 25, wherein each of them is hydrogen.

27. The method according to any one of claims 1 to 26, wherein W is an unsubstituted pyridine moiety.

28. The method according to any one of claims 1 to 27, wherein U and V are transcyclohexanyl fused rings.

29. The aforementioned pentaza macrocyclic ring complex is given by formula (II): 【Transformation 5】 (II) [In the formula, X and Y represent either a monodentate or polydentate ligand or a suitable ligand derived from a ligand system, or the corresponding anions thereof; and R Ａ , R Ｂ , R Ｃ , and R Ｄ These are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moiety, or -OR １１ , -NR １１ R １２ , -COR １１ , -CO ２ R １１ , -CONR １１ R １２ , -SR １１ , -SOR １１ , -SO ２ R １１ , -SO ２ NR １１ R １２ , -N(OR １１ ) (Caution １２ ), -P(O)(OR １１ ) ( OR １２ ), -P(O)(OR １１ ) (Caution １２ ), and -OP(O)(OR １１ ) ( OR １２ A portion selected from the group consisting of R １１ and R １２ [These are independently hydrogen or alkyl.] The method according to any one of claims 1 to 28, as shown in [the provided text].

30. The aforementioned pentaza macrocyclic ring complex is defined by formula (III) or formula (IV): 【Transformation 6】 [In the formula, X and Y represent either a monodentate or polydentate ligand or a suitable ligand derived from a ligand system, or the corresponding anions thereof; and R Ａ , R Ｂ , R Ｃ , and R Ｄ These are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moiety, or -OR １１ , -NR １１ R １２ , -COR １１ , -CO ２ R １１ , -CONR １１ R １２ , -SR １１ , -SOR １１ , -SO ２ R １１ , -SO ２ NR １１ R １２ , -N(OR １１ ) (Caution １２ ), -P(O)(OR １１ ) ( OR １２ ), -P(O)(OR １１ ) (Caution １２ ), and -OP(O)(OR １１ ) ( OR １２ A portion selected from the group consisting of R １１ and R １２ [These are independently hydrogen or alkyl.] The method according to any one of claims 1 to 29, as shown in [the provided text].

31. The aforementioned pentaaza macrocyclic ring complex is given by formulas (V) to (XVI): 【Transformation 7】 【Transformation 8】 The method according to any one of claims 1 to 30, which is represented by a formula selected from the group consisting of the following.

32. A method according to any one of claims 1 to 31, wherein X and Y are independently a halide, oxo, aco, hydroxo, alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino, heterocycloalkylamino, heterocycloarylamino, amine oxide, hydrazine, alkylhydrazine, arylhydrazine, nitric oxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkylnitrile, arylnitrile, alkylisonitrile, arylisonitrile, nitrate, nitrite, azide, alkylsulfonic acid, arylsulfonic acid, alkylsulfoxide, arylsulfoxide, alkylarylsulfoxide, alkylsulfenic acid, arylsulfenic acid, alkylsulfinic acid, arylsulfinic acid, alkylthiol carboxylic acid, arylthiol carboxylic acid, alkylthiol thiocarboxylic acid, arylthiol thiocarboxylic acid, alkylcarboxylic acid, arylcarboxylic acid, urea, alkylurea, arylurea, alkylarylurea, thiourea Alkylthiourea, arylthiourea, alkylarylthiourea, sulfuric acid, sulfite, bisulfite, bisulfite, thiosulfuric acid, thiosulfite, hydrosulfite, alkylphosphine, arylphosphine, alkylphosphine oxide, arylphosphine oxide, alkylarylphosphine oxide, alkylphosphine sulfide, arylphosphine sulfide, alkylarylphosphine sulfide, alkylphosphonic acid, arylphosphonic acid, alkylphosphine acid, arylphosphine acid, alkylphosphine acid, arylphosphine acid Phosphoric acid, thiophosphate, phosphorous acid, pyrophosphate, triphosphate, hydrogen phosphate, dihydrogen phosphate, alkylguanidino, arylguanidino, alkylarylguanidino, alkylcarbamate, arylcarbamate, alkylarylcarbamate, alkylthiocarbamate, arylthiocarbamate, alkylarylthiocarbamate, alkyldithiocarbamate, aryldithiocarbamate, alkylaryldithiocarbamate, bicarbonate, carbonic acid, perchloric acid, chloric acid, chlorous acid, hypochlorous acid, perbromic acid, bromic acid, bromic acid, hypobromic acid, hypobromic acid,A substituted or unsubstituted portion of the group consisting of tetrahalomanganates, tetrafluoroboric acid, hexafluoroantimonic acid, hypophosphorous acid, iodic acid, periodic acid, metaboric acid, tetraarylboric acid, tetraalkylboric acid, tartaric acid, salicylic acid, succinic acid, citric acid, ascorbic acid, saccharic acid, amino acids, hydroxamic acid, oxothiotosylate, and anions of ion exchange resins, or independently selected from these corresponding anions; Alternatively, X and Y are -O-C(O)-X １ This corresponds to each X １ is -C(X ２ ) (X ３ ) (X ４ ) and Each X １ However, independently, substituted or unsubstituted phenyl or -C(-X) ２ ) (-X ３ ) (-X ４ ) and; Each X ２ However, independently, these are substituted or unsubstituted phenyl, methyl, ethyl, or propyl; Each X ３ However, independently, hydrogen, hydroxyl, methyl, ethyl, propyl, amino, -X ５ C(=O)R １３ [In the formula, X ５ is NH or O, and R １３ [is a C1-C18 alkyl, substituted or unsubstituted aryl, or a C1-C18 aralkyl], or -OR １４ [In the formula, R １４ [is a C1-C18 alkyl, substituted or unsubstituted aryl, or a C1-C18 aralkyl] or X ４ Together with (=O), and Each X ４ However, independently, it is either hydrogen or X ３ Is it (=O) when combined with it? Alternatively, X and Y may be independently selected from the group consisting of charge-neutralizing anions derived from monodentate or polydentate ligands, as well as ligand systems and their corresponding anions; Alternatively, X and Y are independent of R １ , R ２ , R' ２ , R ３ , R ４ , R ５ , R' ５ , R ６ , R' ６ , R ７ , R ８ , R ９ , R' ９ , and R １０ A method that combines one or more of the following.

33. The method according to any one of claims 1 to 32, wherein X and Y are independently selected from the group consisting of fluoro, chloro, bromo, and iodo anions.

34. The method according to any one of claims 1 to 33, wherein X and Y are independently selected from the group consisting of alkyl carboxylates, aryl carboxylates, and arylalkyl carboxylates.

35. The method according to any one of claims 1 to 34, wherein X and Y are independently amino acids.

36. The aforementioned pentaza macrocyclic ring complex is given by formula: 【Chemistry 9】 The method according to any one of claims 1 to 35, wherein the compound is represented by [formula].

37. The aforementioned pentaza macrocyclic ring complex is given by formula: 【Chemistry 10】 The method according to any one of claims 1 to 36, wherein the compound is represented by [formula].

38. The aforementioned pentaza macrocyclic ring complex is given by formula: 【Chemistry 11】 The method according to any one of claims 1 to 37, wherein the compound is represented by [formula].

39. The aforementioned pentaza macrocyclic ring complex is given by formula: 【Chemistry 12】 The method according to any one of claims 1 to 38, as shown in [the provided text].

40. The aforementioned pentaza macrocyclic ring complex is given by formula: 【Chemistry 13】 The method according to any one of claims 1 to 39, as shown in [the provided text].

41. The aforementioned pentaza macrocyclic ring complex is given by formula: 【Chemistry 14】 The method according to any one of claims 1 to 40, as shown in [the provided text].

42. The method according to any one of claims 1 to 41, wherein the platinum-based anticancer agent is one selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, lovaplatin, heptaplatin, dicycloplatin, lipoplatin, LA-12, phosphaplatin, phenantriplatin, prolyndac, triplatin tetranitrate, picoplatin, satraplatin, pyriplatin, and / or pharmaceutically acceptable salts thereof.

43. The method according to any one of claims 1 to 42, wherein the platinum-based anticancer agent comprises cisplatin.

44. The aforementioned platinum-based anticancer drug is administered at a dose of 20 mg / m². ２ ~200 mg / m² ２ The method according to any one of claims 1 to 43, administered in a dose within the range of .

45. The method according to any one of claims 1 to 44, wherein the administration of the pentaza macrocyclic ring complex during the treatment process is performed within a certain period prior to the administration of the platinum-based anticancer agent.

46. The method according to any one of claims 1 to 45, wherein the administration of the pentaza macrocyclic complex during the course of treatment is performed at least one week, one day, or one hour before the administration of a platinum-based anticancer agent.

47. The method according to any one of claims 1 to 46, wherein the administration of the pentaza macrocyclic ring complex during the therapeutic process is performed within one hour before and / or simultaneously with the administration of the platinum-based anticancer agent.

48. The method according to any one of claims 1 to 47, wherein the administration of the pentaza macrocyclic ring complex during the course of treatment is performed within one hour, one day, or one week after the administration of the platinum-based anticancer agent.

49. The method according to any one of claims 1 to 48, comprising administering the aforementioned platinum-based anticancer drug to a subject who is simultaneously receiving radiotherapy.

50. The method according to any one of claims 1 to 48, comprising administering the platinum-based anticancer agent and the pentaza macrocyclic complex to a subject who has not received radiotherapy.

51. The method according to any one of claims 1 to 48, wherein the treatment process, which includes the administration of the pentaza macrocyclic complex and a platinum-based anticancer agent, is administered to a subject who has not received radiotherapy during the treatment process.

52. The method according to any one of claims 1 to 48, comprising administering to the subject one or more of the pentaza macrocyclic ring complex and platinum-based anticancer agents on a day other than the day the subject is receiving radiotherapy.

53. The method according to any one of claims 1 to 48, comprising administering a treatment process to a subject who has not received radiotherapy for at least one day, the platinum-based anticancer agent and the pentaza macrocyclic ring complex.

54. The method according to any one of claims 1 to 48, comprising administering a treatment process to a subject who has not received radiotherapy for at least one week, the platinum-based anticancer agent and the pentaza macrocyclic ring complex.

55. The method according to any one of claims 1 to 48, comprising administering a treatment process to a subject who has not received radiotherapy for at least one month, the platinum-based anticancer agent and the pentaza macrocyclic ring complex.

56. The method according to any one of claims 1 to 48, comprising administering a treatment process to a subject who has not received radiotherapy for at least six months, the platinum-based anticancer agent and the pentaza macrocyclic ring complex.

57. The method according to any one of claims 1 to 48, comprising administering the platinum-based anticancer agent and the pentaza macrocyclic complex to the target, and then delaying radiotherapy, which may be appropriately administered to the target, until at least one day after the final administration of the pentaza macrocyclic complex.

58. The method according to any one of claims 1 to 48, comprising administering the platinum-based anticancer agent and the pentaza macrocyclic ring complex to the subject, and delaying radiotherapy, which may be appropriately administered to the subject, for at least one week after the final administration of the pentaza macrocyclic ring complex.

59. The method according to any one of claims 1 to 48, comprising administering the platinum-based anticancer agent and the pentaza macrocyclic ring complex to the target, and then delaying radiotherapy, which may be appropriately administered to the target, until at least one month after the final administration of the pentaza macrocyclic ring complex.

60. The method according to any one of claims 1 to 48, comprising administering the platinum-based anticancer agent and the pentaza macrocyclic complex to the subject, and then delaying radiotherapy, which may be appropriately administered to the subject, until at least six months after the final administration of the pentaza macrocyclic complex.

61. The method according to any one of claims 1 to 60, wherein the cancer is selected from the group consisting of breast cancer, non-small cell lung cancer, melanoma, renal cell carcinoma, urothelial carcinoma, bladder cancer, pancreatic cancer, head and neck cancer, colorectal cancer, prostate cancer, brain cancer, spindle cell carcinoma, and oral squamous cell carcinoma.

62. The method according to any one of claims 1 to 61, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, renal cell carcinoma, spindle cell carcinoma, colorectal cancer, oral squamous cell carcinoma, and head and neck cancer.

63. The method according to any one of claims 1 to 62, wherein the cancer is at least one of lung cancer and head and neck cancer.

64. The method according to any one of claims 1 to 63, wherein the pentaza macrocyclic complex is administered to the subject at a dose in the range of 0.2 mg / kg to 40 mg / kg.

65. The method according to any one of claims 1 to 64, wherein the pentaza macrocyclic ring complex is administered to the subject at a dose in the range of 0.2 mg / kg to 24 mg / kg.

66. The method according to any one of claims 1 to 65, wherein the pentaza macrocyclic complex is administered to the subject at a dose in the range of 0.2 mg / kg to 10 mg / kg.

67. The method according to any one of claims 1 to 66, wherein the pentaza macrocyclic ring complex is administered by at least one of a parenteral route and an oral route.

68. The method according to any one of claims 1 to 67, wherein the pentaza macrocyclic ring complex is administered intraperitoneally or intravenously.

69. The method according to any one of claims 1 to 68, wherein the subject is a human.

70. A kit for treating cancer in mammalian subjects requiring treatment and / or reduction, and / or reducing the toxic effects of platinum-based anticancer agents: The aforementioned platinum-based anticancer drug; The pentaza macrocyclic ring complex corresponding to the following formula (I): and The present invention includes instructions for administering a therapeutically effective amount of the platinum-based anticancer agent and a therapeutically effective amount of the pentaza macrocyclic complex in order to carry out the method according to any one of claims 1 to 16. The pentaza macrocyclic ring complex according to formula (I) is as follows: Kit: 【Chemistry 15】 (I) [In the formula, M is Mn ２＋ or Mn ３＋ And; R １ , R ２ , R' ２ , R ３ , R ４ , R ５ , R' ５ , R ６ , R' ６ , R ７ , R ８ , R ９ , R' ９ , and R １０ These are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moiety, or -OR １１ , -NR １１ R １２ , -COR １１ , -CO ２ R １１ , -CONR １１ R １２ , -SR １１ , -SOR １１ , -SO ２ R １１ , -SO ２ NR １１ R １２ , -N(OR １１ ) (Caution １２ ), -P(O)(OR １１ ) ( OR １２ ), -P(O)(OR １１ ) (Caution １２ ), and -OP(O)(OR １１ ) ( OR １２ A portion selected from the group consisting of R １１ and R １２ These are independently hydrogen or alkyl; U, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; V, together with adjacent carbon atoms of the macrocyclic ring, forms a condensed substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocyclic ring and the carbon atoms of the macrocyclic ring to which it is bonded, forms an aromatic or alicyclic substituted or unsubstituted saturated, partially saturated or unsaturated nitrogen-containing condensed heterocycle having 2 to 20 ring carbon atoms, provided that W is a condensed aromatic heterocycle, in which case the hydrogen bonded to the nitrogen in both the heterocycle and the macrocyclic ring, and the R bonded to the carbon atoms in both the heterocycle and the macrocyclic ring １ and R １０ It is assumed to be non-existent; X and Y represent either a monodentate or polydentate ligand or an appropriate ligand derived from a ligand system, or an equivalent anion; Z is the counterion; n is an integer from 0 to 3; and The dotted line represents the coordination bond between the nitrogen atom of the macrocyclic ring and the transition metal (manganese).

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