JP2023050198A - Combination cancer therapy with pentaaza macrocyclic ring complex and platinum-based anticancer agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method of treating cancer in a mammalian subject afflicted with the cancer.

SOLUTION: A method comprises administering a therapeutically effective amount of a platinum-based anticancer agent, and then administering a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to a Formula (I), thereby improving a response of cancer to the platinum-based anticancer agent.

SELECTED DRAWING: None

COPYRIGHT: (C)2023,JPO&INPIT

Description

FIELD OF THE DISCLOSURE The present disclosure relates generally to combination therapies for treating cancer comprising administering a pentaaza-macrocycle conjugate in combination with a platinum-based anti-cancer agent.

例えば、大腸炎のげっ歯類モデルにおいて、１つのこのような化合物、ＧＣ４４０３は、大腸炎の実験モデルに施されたラット大腸に対する傷害を極めて減少させることが報告されている（Cuzzocrea et al., Europ. J. Pharmacol., 432, 79-89 (2001)を参照）。

ＧＣ４４０３は、急性の放射線で誘発された口腔粘膜炎の臨床的に関連するハムスターモデル（Murphy et al., Clin. Can. Res., 14(13), 4292 (2008)）、ならびに成体マウスの致命的な全身照射（Thompson et al., Free Radical Res., 44(5), 529-40 (2010)）の両方で生じる放射線損傷を弱めることが報告されている。同様に、別のこのような化合物であるＧＣ４４１９は、モデルラットにおけるＶＥＧＦｒ阻害剤誘発性の肺疾患を弱めることが示されている（Tuder, et al., , Am. J. Respir. Cell Mol. Biol., 29, 88-97 (2003)）。また、別のこのような化合物であるＧＣ４４０１は、敗血症ショック（S. Cuzzocrea, et.al., Crit. Care Med., 32(1), 157 (2004)）および膵炎（S. Cuzzocrea, et.al., Shock, 22(3), 254-61 (2004)）の動物モデルにおいて保護効果を生じることが示されている。

Transition metal-containing pentaazamacrocyclic ring conjugates having macrocyclic groups corresponding to Formula A have been shown to be effective in treating many animal and cellular models of human disease, as well as human patients suffering from the disease. ing.

For example, in a rodent model of colitis, one such compound, GC4403, has been reported to significantly reduce injury to rat colons subjected to experimental models of colitis (Cuzzocrea et al., Europ. J. Pharmacol., 432, 79-89 (2001)).

GC4403 has been demonstrated in a clinically relevant hamster model of acute radiation-induced oral mucositis (Murphy et al., Clin. Can. Res., 14(13), 4292 (2008)), as well as in lethal adult mice. It has been reported to attenuate the radiation damage caused by both radical total body irradiation (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)). Another such compound, GC4401, has also been shown to treat 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)) have been shown to produce protective effects in animal models.

Certain of these compounds also have potent anti-inflammatory activity and have been shown to inhibit oxidative damage in vivo. For example, GC4403 has been reported to inhibit inflammation in rat models of inflammation (Salvemini, et.al., Science, 286, 304 (1999)) and prevent joint disease in rat models of collagen-induced arthritis. (Salvemini et al., Arthritis & Rheumatism, 44(12), 2009-2021 (2001)). Still 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)). In addition, these compounds have been reported to have analgesic activity and reduce inflammation and edema in the rat paw carrageenan hyperalgesia model (see, eg, US Pat. No. 6,180,620).

This class of compounds has also been shown to be safe and effective in the prevention and treatment of disease in human subjects. For example, GC4419 has been shown to reduce oral mucositis in head and neck cancer patients undergoing radiochemotherapy (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)).

In addition, pentaazamacrocyclic ring complexes containing transition metals representing this class have shown efficacy in the treatment of various cancers. For example, certain compounds representing this class have been offered in combination with agents such as paclitaxel and gemcitabine to enhance cancer therapy, e.g., colorectal cancer and lung cancer (non-small cell lung cancer) (e.g., See U.S. Pat. No. 9,998,893). The 4403 compound described above is also used for treatment in in vivo models of Meth A spindle cell squamous cell carcinoma and RENCA renal carcinoma (Samlowski et al., Nature Medicine, 9(6), 750-755 (2003)), and spindle cell Used in therapy in squamous cell carcinoma metastasis (Samlowski et al., Madame Curie Bioscience Database (Internet), 230-249 (2006)). The 4419 compounds described above are also used in combination with cancer treatments, such as in combination with treatments involving the administration of cisplatin and radiation, to enhance treatment in vivo models (Sishc et al., poster for Radiation Research Society (2015)). .

Platinum-based anticancer agents (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 are associated with cancer. It has been shown to be highly effective in therapy (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 agents (e.g., cisplatin) are widely used as chemotherapeutic agents, such agents also have associated toxicity associated with their administration (e.g., nephrotoxicity, toxic deafness, gastric toxicity, and myelotoxicity) (Miller et al., Toxins (Basel), 2(11): 2490-2518 (2010)). Therefore, the use of such platinum-based anticancer agents may be limited by the need to minimize the toxic effects associated therewith.

Accordingly, there is a need for enhanced cancer therapies that provide improved efficacy in killing cancer cells while also providing good selectivity in killing cancer cells relative to normal cells. . There is also a need for enhanced therapeutic methods that improve the prognosis of patients undergoing these treatments. There is also a need for therapeutic methods that reduce the toxic effects associated with platinum-based anticancer agents (eg, cisplatin).

（Ｉ）
［式中、
Ｍは、Ｍｎ^２＋またはＭｎ^３＋であり；
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は、独立して、水素、ヒドロカルビル、置換ヒドロカルビル、ヘテロサイクリル、アミノ酸側鎖部分、あるいは－ＯＲ_１１、－ＮＲ_１１Ｒ_１２、－ＣＯＲ_１１、－ＣＯ_２Ｒ_１１、－ＣＯＮＲ_１１Ｒ_１２、－ＳＲ_１１、－ＳＯＲ_１１、－ＳＯ_２Ｒ_１１、－ＳＯ_２ＮＲ_１１Ｒ_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は、前記大環状環の隣接する炭素原子と一緒になって、３～２０個の環炭素原子を有する縮合された置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の環もしくはヘテロ環を形成し；
Ｖは、前記大環状環の隣接する炭素原子と一緒になって、３～２０個の環炭素原子を有する縮合された置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の環もしくはヘテロ環を形成し；
Ｗは、前記大環状環の窒素およびそれが結合している前記大環状環の炭素原子と一緒になって、２～２０個の環炭素原子を有する芳香族もしくは脂環式の置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の窒素含有縮合ヘテロ環を形成するが、但し、Ｗが、縮合された芳香族ヘテロ環である場合、ヘテロ環および前記大環状環の両方の部分である窒素に結合している水素、ならびにヘテロ環および前記大環状環の両方の部分である炭素原子に結合しているＲ_１およびＲ_１０は、非存在であるものとし；
ＸおよびＹは、単座もしくは多座配位子もしくは配位子系に由来する適切な配位子のいずれか、またはそれに相当するアニオンを表し；
Ｚは、対イオンであり；
ｎは、０～３の整数であり；ならびに
点線は、前記大環状環の窒素原子と遷移金属（マンガン）との配位結合を表す］ Briefly, therefore, an aspect of the present disclosure is a method of treating cancer in a mammalian subject having cancer, comprising administering to said subject a therapeutically effective amount of a platinum-based anti-cancer agent. and administering a therapeutically effective amount of a pentaazamacrocyclic ring complex corresponding to Formula (I) below to said subject prior to, concurrently with, or after administration of said platinum-based anticancer agent, A method characterized by increasing the responsiveness of said cancer to said platinum-based anti-cancer agent.

(I)
[In the formula,
M is Mn ²⁺ or Mn ³⁺ ;
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 are independently is hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moieties, 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 ₁₁ )(OR ₁₂ ), wherein R ₁₁ and R ₁₂ are independently hydrogen or alkyl;
U is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
V is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
W, together with the macrocyclic ring nitrogen and the macrocyclic ring carbon atom to which it is attached, is an aromatic or alicyclic substituted or unsubstituted aromatic or alicyclic ring having 2 to 20 ring carbon atoms; with the proviso that when W is a fused aromatic heterocycle, it is part of both the heterocycle and said macrocycle hydrogen attached to nitrogen and R ₁ and R ₁₀ attached to carbon atoms that are part of both the heterocycle and said macrocycle shall be absent;
X and Y represent any suitable ligand from a monodentate or polydentate ligand or ligand system, or the corresponding anion;
Z is a 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)]

（Ｉ）
［式中、
Ｍは、Ｍｎ^２＋またはＭｎ^３＋であり；
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は、独立して、水素、ヒドロカルビル、置換ヒドロカルビル、ヘテロサイクリル、アミノ酸側鎖部分、あるいは－ＯＲ_１１、－ＮＲ_１１Ｒ_１２、－ＣＯＲ_１１、－ＣＯ_２Ｒ_１１、－ＣＯＮＲ_１１Ｒ_１２、－ＳＲ_１１、－ＳＯＲ_１１、－ＳＯ_２Ｒ_１１、－ＳＯ_２ＮＲ_１１Ｒ_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は、前記大環状環の隣接する炭素原子と一緒になって、３～２０個の環炭素原子を有する縮合された置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の環もしくはヘテロ環を形成し；
Ｖは、前記大環状環の隣接する炭素原子と一緒になって、３～２０個の環炭素原子を有する縮合された置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の環もしくはヘテロ環を形成し；
Ｗは、前記大環状環の窒素およびそれが結合している前記大環状環の炭素原子と一緒になって、２～２０個の環炭素原子を有する芳香族もしくは脂環式の置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の窒素含有縮合ヘテロ環を形成するが、但し、Ｗが、縮合された芳香族ヘテロ環である場合、ヘテロ環および前記大環状環の両方の部分である窒素に結合している水素、ならびにヘテロ環および前記大環状環の両方の部分である炭素原子に結合しているＲ_１およびＲ_１０は、非存在であるものとし；
ＸおよびＹは、単座もしくは多座配位子もしくは配位子系に由来する適切な配位子のいずれか、またはそれに相当するアニオンを表し；
Ｚは、対イオンであり；
ｎは、０～３の整数であり；ならびに
点線は、前記大環状環の窒素原子と遷移金属（マンガン）との配位結合を表す］ Another aspect of the disclosure is a method of sensitizing a mammalian subject to treatment with a platinum-based anticancer agent in a subject in need thereof, comprising: administering the corresponding pentaaza macrocycle conjugate to said subject prior to, concurrently with, or after administration of said platinum-based anti-cancer agent to enhance therapeutic responsiveness to said platinum-based anti-cancer agent; It relates to a method characterized.

(I)
[In the formula,
M is Mn ²⁺ or Mn ³⁺ ;
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 are independently is hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moieties, 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 ₁₁ )(OR ₁₂ ), wherein R ₁₁ and R ₁₂ are independently hydrogen or alkyl;
U is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
V is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
W, together with the macrocyclic ring nitrogen and the macrocyclic ring carbon atom to which it is attached, is an aromatic or alicyclic substituted or unsubstituted aromatic or alicyclic ring having 2 to 20 ring carbon atoms; with the proviso that when W is a fused aromatic heterocycle, it is part of both the heterocycle and said macrocycle hydrogen attached to nitrogen and R ₁ and R ₁₀ attached to carbon atoms that are part of both the heterocycle and said macrocycle shall be absent;
X and Y represent any suitable ligand from a monodentate or polydentate ligand or ligand system, or the corresponding anion;
Z is a 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)]

（Ｉ）
［式中、
Ｍは、Ｍｎ^２＋またはＭｎ^３＋であり；
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は、独立して、水素、ヒドロカルビル、置換ヒドロカルビル、ヘテロサイクリル、アミノ酸側鎖部分、あるいは－ＯＲ_１１、－ＮＲ_１１Ｒ_１２、－ＣＯＲ_１１、－ＣＯ_２Ｒ_１１、－ＣＯＮＲ_１１Ｒ_１２、－ＳＲ_１１、－ＳＯＲ_１１、－ＳＯ_２Ｒ_１１、－ＳＯ_２ＮＲ_１１Ｒ_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は、前記大環状環の隣接する炭素原子と一緒になって、３～２０個の環炭素原子を有する縮合された置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の環もしくはヘテロ環を形成し；
Ｖは、前記大環状環の隣接する炭素原子と一緒になって、３～２０個の環炭素原子を有する縮合された置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の環もしくはヘテロ環を形成し；
Ｗは、前記大環状環の窒素およびそれが結合している前記大環状環の炭素原子と一緒になって、２～２０個の環炭素原子を有する芳香族もしくは脂環式の置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の窒素含有縮合ヘテロ環を形成するが、但し、Ｗが、縮合された芳香族ヘテロ環である場合、ヘテロ環および前記大環状環の両方の部分である窒素に結合している水素、ならびにヘテロ環および前記大環状環の両方の部分である炭素原子に結合しているＲ_１およびＲ_１０は、非存在であるものとし；
ＸおよびＹは、単座もしくは多座配位子もしくは配位子系に由来する適切な配位子のいずれか、またはそれに相当するアニオンを表し；
Ｚは、対イオンであり；
ｎは、０～３の整数であり；ならびに
点線は、前記大環状環の窒素原子と遷移金属（マンガン）との配位結合を表す］ Another aspect of the present disclosure is a method of reducing toxic effects to a mammalian subject associated with treatment with a platinum-based anticancer agent in a mammalian subject in need thereof, comprising:
administering to said subject a therapeutically effective amount of a platinum-based anticancer agent; administering to said subject prior to, concurrently with, or after administration to reduce the toxic effects of said platinum-based anticancer agent.

(I)
[In the formula,
M is Mn ²⁺ or Mn ³⁺ ;
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 are independently is hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moieties, 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 ₁₁ )(OR ₁₂ ), wherein R ₁₁ and R ₁₂ are independently hydrogen or alkyl;
U is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
V is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
W, together with the macrocyclic ring nitrogen and the macrocyclic ring carbon atom to which it is attached, is an aromatic or alicyclic substituted or unsubstituted aromatic or alicyclic ring having 2 to 20 ring carbon atoms; with the proviso that when W is a fused aromatic heterocycle, it is part of both the heterocycle and said macrocycle hydrogen attached to nitrogen and R ₁ and R ₁₀ attached to carbon atoms that are part of both the heterocycle and said macrocycle shall be absent;
X and Y represent any suitable ligand from a monodentate or polydentate ligand or ligand system, or the corresponding anion;
Z is a 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)]

（Ｉ）
［式中、
Ｍは、Ｍｎ^２＋またはＭｎ^３＋であり；
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は、独立して、水素、ヒドロカルビル、置換ヒドロカルビル、ヘテロサイクリル、アミノ酸側鎖部分、あるいは－ＯＲ_１１、－ＮＲ_１１Ｒ_１２、－ＣＯＲ_１１、－ＣＯ_２Ｒ_１１、－ＣＯＮＲ_１１Ｒ_１２、－ＳＲ_１１、－ＳＯＲ_１１、－ＳＯ_２Ｒ_１１、－ＳＯ_２ＮＲ_１１Ｒ_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は、前記大環状環の隣接する炭素原子と一緒になって、３～２０個の環炭素原子を有する縮合された置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の環もしくはヘテロ環を形成し；
Ｖは、前記大環状環の隣接する炭素原子と一緒になって、３～２０個の環炭素原子を有する縮合された置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の環もしくはヘテロ環を形成し；
Ｗは、前記大環状環の窒素およびそれが結合している前記大環状環の炭素原子と一緒になって、２～２０個の環炭素原子を有する芳香族もしくは脂環式の置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の窒素含有縮合ヘテロ環を形成するが、但し、Ｗが、縮合された芳香族ヘテロ環である場合、ヘテロ環および前記大環状環の両方の部分である窒素に結合している水素、ならびにヘテロ環および前記大環状環の両方の部分である炭素原子に結合しているＲ_１およびＲ_１０は、非存在であるものとし；
ＸおよびＹは、単座もしくは多座配位子もしくは配位子系に由来する適切な配位子のいずれか、またはそれに相当するアニオンを表し；
Ｚは、対イオンであり；
ｎは、０～３の整数であり；ならびに
点線は、前記大環状環の窒素原子と遷移金属（マンガン）との配位結合を表す］ Another aspect of the present disclosure is a method of treating and/or reducing the risk of toxic effects associated with treatment with a platinum-based anticancer agent in a mammalian subject in need thereof, comprising: is administered to the subject prior to, concurrently with, or after administration of the platinum-based anticancer agent, an effective amount of a pentaazamacrocyclic ring conjugate corresponding to formula (I): The present invention relates to a method characterized by reducing the toxic effects of anti-cancer agents which have been identified.

(I)
[In the formula,
M is Mn ²⁺ or Mn ³⁺ ;
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 are independently is hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moieties, 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 ₁₁ )(OR ₁₂ ), wherein R ₁₁ and R ₁₂ are independently hydrogen or alkyl;
U is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
V is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
W, together with the macrocyclic ring nitrogen and the macrocyclic ring carbon atom to which it is attached, is an aromatic or alicyclic substituted or unsubstituted aromatic or alicyclic ring having 2 to 20 ring carbon atoms; with the proviso that when W is a fused aromatic heterocycle, it is part of both the heterocycle and said macrocycle hydrogen attached to nitrogen and R ₁ and R ₁₀ attached to carbon atoms that are part of both the heterocycle and said macrocycle shall be absent;
X and Y represent any suitable ligand from a monodentate or polydentate ligand or ligand system, or the corresponding anion;
Z is a 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)]

Other objects and features are partly obvious and partly indicated below.

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

Abbreviations and Definitions The following definitions and methods are provided to further clarify the invention and to enable those skilled in the art to practice the invention. Unless otherwise indicated, terms are to be understood according to conventional usage by those of ordinary skill in the art.

"Acyl" refers to a -COR moiety, where R is alkyl, haloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, as defined herein. ), such as acetyl, trifluoroacetyl, benzoyl, and the like.

“Acyloxy” refers to the —OCOR moiety, where R is alkyl, haloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, as defined herein. ), such as acetyl, trifluoroacetyl, benzoyl, and the like.

"Alkoxy" means a -OR moiety (wherein R is alkyl as defined herein), such as methoxy, ethoxy, propoxy, 2-propoxy, n-, iso- , or tert-butoxy.

"Alkyl" means a straight-chain saturated monovalent hydrocarbon moiety (eg, 1-6 carbon atoms) or a branched-chain saturated monovalent hydrocarbon moiety (eg, 3-6 carbon atoms), such as C ₁ -C ₆ alkyl groups such as methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), and the like.

Further, unless otherwise indicated, the term "alkyl," as used herein, is meant to include both "unsubstituted alkyl" and "substituted alkyl," the latter of which has a hydrocarbon backbone. means an alkyl moiety that has substituents replacing hydrogens at one or more carbons of . Indeed, unless otherwise indicated, all groups described herein are meant to include both substituted and unsubstituted options.

The term “C _xy ” when used with chemical moieties (eg, alkyl and aralkyl) is meant to include groups containing from x to y carbons in the chain. For example, the term "C _xy alkyl" means a substituted or unsubstituted saturated hydrocarbon group, including straight-chain and branched-chain alkyl groups containing x to y carbon atoms in the chain. .

“Alkylene” is a straight chain saturated divalent hydrocarbon moiety (eg, 1 to 6 carbon atoms) or a branched chain saturated divalent hydrocarbon moiety (eg, 3 to 6 carbon atoms), unless otherwise indicated. ), for example methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

"Alkenyl" means a linear unsaturated monovalent hydrocarbon moiety (eg, 2-6 carbon atoms) or a branched saturated monovalent hydrocarbon moiety (eg, 3-6 carbon atoms), such as , ethenyl (vinyl), propenyl, 2-propenyl, butenyl (including all isomeric forms), pentenyl (including all isomeric forms), and the like.

"Alkaryl" means a monovalent moiety derived from an aryl moiety by replacing one or more hydrogen atoms with an alkyl group.

"Alkenylcycloalkenyl" means a monovalent moiety derived from an alkenyl moiety by replacing one or more hydrogen atoms with a cycloalkenyl group.

"Alkenylcycloalkyl" means a monovalent moiety derived from a cycloalkyl moiety by replacing one or more hydrogen atoms with alkenyl groups.

"Alkylcycloalkenyl" means a monovalent moiety derived from a cycloalkenyl moiety by replacing one or more hydrogen atoms with an alkyl group.

"Alkylcycloalkyl" means a monovalent moiety derived from a cycloalkyl moiety by replacing one or more hydrogen atoms with an alkyl group.

"Alkynyl" means a linear unsaturated monovalent hydrocarbon moiety (eg, 2-6 carbon atoms) or a branched saturated monovalent hydrocarbon moiety (eg, 3-6 carbon atoms), such as , ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like.

"Alkoxy" means a monovalent moiety derived from an alkyl moiety by replacing one or more hydrogen atoms with hydroxy groups.

"Amino" means a -NR ^a R ^b group, where R ^a and R ^b are independently hydrogen, alkyl or aryl.

"Aralkyl" means a monovalent moiety derived from an alkyl moiety by replacing one or more hydrogen atoms with an aryl group.

"Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon moiety of 6 to 10 ring atoms, such as phenyl or naphthyl.

"Ring" means a carbocyclic saturated monovalent hydrocarbon moiety of 3 to 10 carbon atoms.

"Cycloalkyl" means a cyclic saturated monovalent hydrocarbon moiety of 3-10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

"Cycloalkylalkyl" means a monovalent moiety derived from an alkyl moiety by replacing one or more hydrogen atoms with a cycloalkyl group, e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, or cyclohexylethyl.

"Cycloalkylcycloalkyl" means a monovalent moiety derived from a cycloalkyl moiety by replacing one or more hydrogen atoms with a cycloalkyl group.

"Cycloalkenyl" means a cyclic monounsaturated monovalent hydrocarbon moiety of 3 to 10 carbon atoms, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl.

"Cycloalkenylalkyl" means a monovalent moiety derived from an alkyl moiety by replacing one or more hydrogen atoms with a cycloalkenyl group, e.g., cyclopropenylmethyl, cyclobutenylmethyl, cyclopentenyl Examples include ethyl, cyclohexenylethyl, and the like.

"Ether" means a monovalent moiety derived from an alkyl moiety by replacing one or more hydrogen atoms with an alkoxy group.

"Halo" means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro.

A “heterocycle” or “heterocyclyl” is a saturated or unsaturated monovalent monocyclic group of 4 to 8 ring atoms in which 1 or 2 ring atoms are N, O, or S ( O) _n is a heteroatom selected from n is an integer from 0 to 2, and the remaining ring atoms are C. Said heterocyclyl ring may optionally be fused to (one) aryl or heteroaryl ring as defined herein provided that said aryl and heteroaryl rings are monocyclic and A heterocyclyl ring fused to a monocyclic aryl or heteroaryl ring is also referred to herein as a "bicyclic heterocyclyl" ring. Also, one or two ring carbon atoms in the heterocyclyl ring may optionally be substituted by a --CO-- group. More specifically, the term heterocyclyl includes, but is not limited to pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl, thiomorpholino, and the like. are mentioned. When the heterocyclyl ring is unsaturated it may contain 1 or 2 ring double bonds, provided said ring is not aromatic. When the heterocyclyl group is a saturated ring and is not fused to an aryl or heteroaryl ring as described above, it is described herein as a saturated monocyclic heterocyclyl.

"Heteroaryl" is a monovalent monocyclic or bicyclic aromatic moiety of 5 to 10 ring atoms in which 1 or more preferably 1, 2 or 3 ring atoms are A heteroatom selected from N, O, or S means a moiety in which the remaining ring atoms are carbon. Representative examples include, but are not limited to pyrrolyl, pyrazolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl , pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like.

"Nitro" means _-NO2 .

"Organosulfur" means a monovalent moiety -SR group, where R is hydrogen, alkyl or aryl.

A "platinum-based anticancer agent" refers to a class of compounds that are coordination complexes of platinum and have anticancer effects that may also be referred to as platins, platinates, and platinum-based antineoplastic agents. means. Examples of platinum-based anticancer agents used in chemotherapy include cisplatin, oxaliplatin, carboplatin, nedaplatin, lobaplatin, heptaplatin, dicycloplatin, lipoplatin, LA-12, phosphaplatin, phenanthriplatin. , ProLindac, triplatin tetranitrate, picoplatin, satraplatin and/or pharmaceutically acceptable salts thereof.

"Substituted alkyl", "substituted ring", "substituted phenyl", "substituted aryl", "substituted heterocycle" and "substituted nitrogen heterocycle" are respectively defined as alkyl, ring, aryl, phenyl, heterocycle, or nitrogen-containing heterocycle, which are independently selected from 1, 2, or 3 substituents such as alkyl, alkoxy, alkoxyalkyl, halo, hydroxy, hydroxyalkyl, or organic sulfur may be substituted as appropriate. In general, the term "substituted" includes groups substituted with any one or more of C1-4 alkyl, C2-4 alkenyl, halogen, alcohol and/or amine.

"Thioether" means a monovalent moiety derived from an alkyl moiety by replacing one or more hydrogen atoms with a -SR group (R is alkyl).

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

DETAILED DESCRIPTION In one embodiment, aspects of the present disclosure combine a therapeutically effective amount of a pentaazamacrocyclic ring complex according to formula (I) described below with a therapeutically effective amount of a platinum-based It relates to the treatment of cancer by administering it to a subject suffering from cancer in combination with an anti-cancer agent to provide cancer treatment. The pentaazamacrocyclic ring conjugate can be administered before, concurrently with, or after administration of a platinum-based anticancer agent to increase the responsiveness of the cancer to the platinum-based anticancer agent. In particular, the pentaazamacrocyclic conjugates according to formula (I) unexpectedly exhibit synergistic effects when administered in combination with platinum-based anticancer agents and/or It has been shown to produce a more than additive effect compared to administration of either of the pentaaza-macrocyclic conjugates according to formula (I) alone. Without being bound by any particular theory, it is believed that the pentaazamacrocyclic ring conjugates according to Formula (I) act to sensitize cancer cells to treatment with platinum-based anti-cancer agents such that cancer cells are treated with platinum-based anti-cancer agents. It is conceivable that the response to the anticancer effect of the anticancer drug that has been prepared can be extremely high. Further, without being bound to any particular theory, platinum-based anticancer agents combine with the pentaazamacrocyclic ring complex according to formula (I) via a previously unknown mechanism of action for hydrogen peroxide. can act to kill cancer cells and this mechanism can be synergistically enhanced by the combination. Further illustration of the synergistic effect of the pentaazamacrocyclic conjugates according to Formula (I) and platinum-based anticancer agents is provided in the Examples herein.

Accordingly, in one aspect of the present disclosure, a method of sensitizing a mammalian subject to treatment with a platinum-based anticancer agent in a mammalian subject in need thereof is provided. The method comprises administering a therapeutically effective amount of a pentaazamacrocyclic ring complex corresponding to Formula (I) below to the subject prior to, concurrently with, or after administration of a platinum-based anticancer agent. , to enhance therapeutic responsiveness to said platinum-based anti-cancer agents.

Yet another aspect of the present disclosure is that administration of a pentaazamacrocyclic ring conjugate corresponding to formula (I) below reduces the toxic effects (e.g., nephrotoxicity and myelotoxicity) of platinum-based anticancer agents. Regarding the knowledge that Accordingly, in one embodiment, a method of reducing toxic effects to a mammalian subject associated with treatment with a platinum-based anticancer agent in a mammalian subject in need thereof comprises administering a therapeutically effective amount of the platinum-based anticancer agent to: administering to said subject, and administering a therapeutically effective amount of a pentaaza macrocycle conjugate corresponding to Formula (I) below prior to, concurrently with, or after administration of a platinum-based anticancer agent; to reduce the toxic effects of said platinum-based anticancer agents. In yet another embodiment, a method of treating and/or reducing the risk of toxic effects associated with treatment with a platinum-based anticancer agent in a mammalian subject in need thereof, comprising: administering to said subject prior to, concurrently with, or after administration of said platinum-based anti-cancer agent a pentaaza-macrocyclic ring conjugate corresponding to formula (I) below; Methods are provided characterized by reducing toxic effects.

In one embodiment, the subject may be a subject 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 regimen. For example, the subject may be receiving the platinum-based anti-cancer agent as part of a regimen for cancer treatment whereby the toxic effects associated with the platinum-based anti-cancer agent while undergoing cancer treatment. may have a risk of occurrence. In another embodiment, the subject may suffer from and/or is currently suffering from toxic effects (e.g., nephrotoxicity, bone marrow toxicity and/or other toxicities) associated with platinum-based anticancer agents. good. In certain embodiments, administration of a pentaazamacrocycle conjugate corresponding to Formula (I) can reduce, alleviate, and/or treat conditions associated with toxicity of platinum-based anticancer agents, wherein said It has been found that a subject's risk of developing illness associated with such toxicity may be reduced. Thus, the pentaazamacrocyclic ring conjugates according to Formula (I) below, in certain embodiments, reduce the toxicity of platinum-based anticancer agents without substantially reducing the efficacy of the platinum-based anticancer agents. can be made Moreover, in certain embodiments, the reduced toxicity provided by the combination may concomitantly result in enhanced therapeutic responsiveness of the cancer to the platinum-based anticancer agent. That is, the combination simultaneously and synergistically sensitizes cancer cells to killing by the platinum-based anticancer agent while reducing the toxic effects of the platinum-based anticancer agent on normal cells (non-cancerous cells). be able to

（Ｉ）
［式中、
Ｍは、Ｍｎ^２＋またはＭｎ^３＋であり；
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は、独立して、水素、ヒドロカルビル、置換ヒドロカルビル、ヘテロサイクリル、アミノ酸側鎖部分、あるいは－ＯＲ_１１、－ＮＲ_１１Ｒ_１２、－ＣＯＲ_１１、－ＣＯ_２Ｒ_１１、－ＣＯＮＲ_１１Ｒ_１２、－ＳＲ_１１、－ＳＯＲ_１１、－ＳＯ_２Ｒ_１１、－ＳＯ_２ＮＲ_１１Ｒ_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は、前記大環状環の隣接する炭素原子と一緒になって、３～２０個の環炭素原子を有する縮合された置換もしくは無置換の飽和、部分的に飽和もしくは不飽和の環もしくはヘテロ環を形成し；
Ｖは、前記大環状環の隣接する炭素原子と一緒になって、３～２０個の環炭素原子を有する縮合された置換もしくは無置換の飽和、部分的に飽和もしくは不飽和の環もしくはヘテロ環を形成し；
Ｗは、結合している前記大環状環の窒素および前記大環状環の炭素原子と一緒になって、２～２０個の環炭素原子を有する芳香族もしくは脂環式の置換もしくは無置換の飽和、部分的に飽和もしくは不飽和の窒素含有縮合ヘテロ環を形成するが、但し、Ｗが縮合された芳香族ヘテロ環である場合、前記ヘテロ環および前記大環状環の両方の部分である窒素に結合している水素、ならびに前記ヘテロ環および前記大環状環の両方の部分である炭素原子に結合しているＲ_１およびＲ_１０は、存在しないものとし；
ＸおよびＹは、単座もしくは多座配位子もしくは配位子系に由来する適切な配位子のいずれか、またはそれに相当するアニオンを表し；
Ｚは、対イオンであり；
ｎは、０～３の整数であり；ならびに
前記大環状環の窒素原子と遷移金属（マンガン）との配位結合を表す］
の複合体に相当する。 Transition Metal Pentaaza-Macrocycle Complexes In one embodiment, the pentaaza-macrocycle complex has the formula (I):

(I)
[In the formula,
M is Mn ²⁺ or Mn ³⁺ ;
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 are independently is hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moieties, 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 ₁₁ )(OR ₁₂ ), wherein R ₁₁ and R ₁₂ are independently hydrogen or alkyl;
U is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
V is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
W, together with said macrocyclic ring nitrogen and said macrocyclic ring carbon atoms to which it is attached, is an aromatic or alicyclic substituted or unsubstituted saturated ring having 2 to 20 ring carbon atoms. , forming a partially saturated or unsaturated nitrogen-containing fused heterocycle, provided that when W is a fused aromatic heterocycle, a nitrogen that is part of both said heterocycle and said macrocycle there shall be no bonding hydrogens and no R ₁ and R ₁₀ bonding to carbon atoms that are part of both said heterocycle and said macrocycle;
X and Y represent any suitable ligand from a monodentate or polydentate ligand or ligand system, or the corresponding anion;
Z is a counterion;
n is an integer from 0 to 3; and represents a coordinate bond between the nitrogen atom of the macrocyclic ring and the transition metal (manganese)]
corresponds to a complex of

M is Mn ²⁺ or Mn ³⁺ as described above for the pentaazamacrocyclic ring complexes of formula (I). In certain embodiments where the pentaazamacrocyclic ring complex corresponds to Formula (I), M is Mn ²⁺ . In another particular embodiment wherein the pentaazamacrocyclic ring complex corresponds to formula (I), M is Mn ³⁺ .

_one 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 In embodiments in which one or more 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, 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 is independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclyl. More preferably, in this embodiment, 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 are independently hydrogen or lower alkyl (eg, C ₁ -C ₆ alkyl, more typically C ₁ -C ₄ alkyl). Thus, for example, 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 may independently be hydrogen, methyl, ethyl, propyl, or butyl (linear, branched, or cyclic).

In one preferred embodiment, 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 are independently hydrogen or methyl. In one preferred embodiment in which the pentaazamacrocyclic ring complex corresponds to Formula (I), R ₁ , R ₂ , R' ₂ , R ₃ , R ₄ , R ₅ , R' ₅ , R ₇ , R ₈ , R ₉ , R′ ₉ and R ₁₀ are each hydrogen, one of R ₆ and R′ ₆ is hydrogen and the other of R ₆ and R′ ₆ is methyl. In this embodiment, for example, R ₁ , R ₂ , R′ ₂ , R ₃ , R ₄ , R ₅ , R′ ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R′ ₉ , and R ₁₀ are , each may be hydrogen and R′ ₆ is methyl. Alternatively, for example, R ₁ , R ₂ , R′ ₂ , R ₃ , R ₄ , R ₅ , R′ ₅ , R′ ₆ , R ₇ , R ₈ , R ₉ , R′ ₉ , and R ₁₀ are each , may be hydrogen and R ₆ is methyl. In another preferred embodiment wherein the pentaazamacrocyclic ring complex corresponds to formula (I), R ₁ , R ₃ , R ₄ , R ₅ , R' ₅ , R' ₆ , R ₇ , R ₈ and R ₁₀ is each hydrogen, one of R ₂ and R' ₂ is hydrogen, the other of R ₂ and R' ₂ is methyl, and one of R ₉ and R' ₉ is One is hydrogen and the other of R ₉ and R' ₉ is methyl. In this embodiment, for example, R ₁ , R′ ₂ , R ₃ , R ₄ , R ₅ , R′ ₅ , R ₇ , R ₈ , R ₉ , and R ₁₀ can each be hydrogen, _R2 and _R'9 are methyl. Alternatively, for example, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R′ ₅ , R ₇ , R ₈ , R′ ₉ , and R ₁₀ can each be hydrogen, R′ ₂ and R ₉ is methyl. In another embodiment wherein the pentaazamacrocyclic ring complex corresponds to Formula (I), R ₁ , R ₂ , R' ₂ , R 3 , R ₄ , R ₅ , R' ₅ , R ₆ , R _{' 6 , R7} , _R8 , _R9 , _R'9 , and _R10 are each hydrogen.

In some embodiments, the U and V moieties are independently substituted or unsubstituted fused cycloalkyl moieties having 3 to 20 ring carbon atoms, more preferably 4 to 10 ring carbon atoms. In certain embodiments, said U and V moieties are each trans-cyclohexanyl fused rings.

In certain embodiments, said W moiety is a substituted or unsubstituted fused heteroaromatic moiety. In certain embodiments, said W moiety is a substituted or unsubstituted fused pyridino moiety. When W is a substituted fused pyridino moiety, said W moiety is typically a hydrocarbyl or substituted hydrocarbyl moiety (e.g., alkyl, substituted alkyl) at a ring carbon atom positioned para to the heterocyclic nitrogen atom. is replaced by In one preferred embodiment, said W moiety is an unsubstituted fused pyridino moiety.

As described above, X and Y represent either monodentate or polydentate ligands or suitable ligands from the ligand system, or their corresponding anions (e.g. benzoic acid or benzoate anion, phenol or phenoxide anion, alcohol or alkoxide anion). For example, X and Y are, among others, halo, oxo, aco, hydroxo, alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino, heterocycloalkylamino, heterocyclo Arylamino, amine oxide, hydrazine, alkylhydrazine, arylhydrazine, nitric oxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkylnitrile, arylnitrile, alkylisonitrile, arylisonitrile, nitric acid, nitrous acid, azide, alkylsulfonic acid , arylsulfonic acid, alkylsulfoxide, arylsulfoxide, alkylarylsulfoxide, alkylsulfenic acid, arylsulfenic acid, alkylsulfinic acid, arylsulfinic acid, alkylthiolcarboxylic acid, arylthiolcarboxylic acid, alkylthiolthiocarboxylic acid, arylthiol Thiocarboxylic acid, alkylcarboxylic acid, arylcarboxylic acid, urea, alkylurea, arylurea, alkylarylurea, thiourea, alkylthiourea, arylthiourea, alkylarylthiourea, sulfuric acid, sulfurous acid, bisulfate, 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, alkylphosphite, arylphosphite, phosphoric acid, thiophosphoric acid, phosphorous acid, pyrophosphite, triphosphate, hydrogen phosphate, dihydrogen phosphate, alkylguanidino, arylguanidino, alkylaryl Guanidino, alkyl carbamate, aryl carbamate, alkyl aryl carbamate, alkylthiocarbamate, arylthiocarbamate, alkylarylthiocarbamate, alkyldithiocarbamate, aryldithiocarbamate, alkylaryldithiocarbamate, bicarbonate, carbonic acid, perchloric acid, chloric acid, nitrite Chloric acid, hypochlorous acid, perbromic acid, bromic acid, bromous acid, hypobromous acid, tetrahalomanganate, tetrafluoroboric acid, hexafluoroantimonic acid, hypophosphorous acid, iodic acid, periodic acid , metaborates, tetraarylborates, tetraalkylborates, tartaric acid, salicylic acid, succinic acid, citric acid, ascorbic acid, saccharic acid, amino acids, hydroxamic acids, thiotosylic acids, and the anions of ion exchange resins, or their equivalents It may be selected from the group consisting of anions. In one embodiment, X and Y, if present, may be independently selected from the group consisting of halo, nitrate, and bicarbonate ligands. For example, in this embodiment, X and Y, if present, are halo ligands, eg, chloro ligands.

Further, in one embodiment, X and Y correspond to -O-C(O)-X ₁ , each X ₁ being -C(X ₂ )(X ₃ )(X ₄ ) and each X ₁ is independently substituted or unsubstituted phenyl or -C(-X ₂ )(-X ₃ )(-X ₄ ); each X ₂ is independently substituted or is unsubstituted phenyl, methyl, ethyl or propyl; each X ₃ is independently hydrogen, hydroxyl, methyl, ethyl, propyl, amino, -X ₅ C(=O)R ₁₃ [wherein X ₅ is , NH or O, and R ₁₃ is C ₁ -C ₁₈ alkyl, substituted or unsubstituted aryl, or C ₁ -C ₁₈ aralkyl], or —OR ₁₄ [wherein R ₁₄ is C ₁ —C ₁₈ alkyl, substituted or unsubstituted aryl, or C ₁ -C ₁₈ aralkyl], or together with X ₄ is (=O); and each X ₄ is independently is hydrogen or together with X ₃ is (=O).

In yet another embodiment, X and Y are independently selected from the group consisting of charge-neutralizing anions derived from monodentate or polydentate ligands, and ligand systems and their corresponding anions alternatively, X and Y are independently 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 .

In the pentaaza macrocycle complexes corresponding to formula (I), Z is a counterion (eg, a charge-neutralizing anion) and n is an integer from 0-3. In general, Z may correspond to the counterions of the moieties described above for X and Y.

In combination, one preferred embodiment is a pentaazamacrocyclic ring complex corresponding to formula (I)
M is Mn ²⁺ or Mn ³⁺ ;
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 are independently is hydrogen or lower alkyl;
U and V are each a trans-cyclohexanyl fused ring;
W is a substituted or unsubstituted fused pyridino moiety;
X and Y are ligands; and Z, if present, is a charge-neutralizing anion.

More preferably, in these embodiments, M is Mn2 ⁺ ; _{R1 , R2} , R'2, _R3 , _R4 , _R5 , _R'5 , _R6 , _R'6 , _R7 , R ₈ , R ₉ , R′ ₉ , and R ₁₀ are independently hydrogen or methyl; U and V are each a trans-cyclohexanyl fused ring; W is an unsubstituted fused pyridino and X and Y are independently halo ligands (eg, fluoro, chloro, bromo, iodo). Z, if present, may be a halide anion (eg, fluoride, chloride, bromide, iodide).

（ＩＩ）
［式中、
ＸおよびＹは、単座もしくは多座配位子もしくは配位子系に由来する適切な配位子のいずれか、またはこれらの相当するアニオンを表し；ならびに
Ｒ_Ａ、Ｒ_Ｂ、Ｒ_Ｃ、およびＲ_Ｄは、独立して、水素、ヒドロカルビル、置換ヒドロカルビル、ヘテロサイクリル、アミノ酸側鎖部分、あるいは－ＯＲ_１１、－ＮＲ_１１Ｒ_１２、－ＣＯＲ_１１、－ＣＯ_２Ｒ_１１、－ＣＯＮＲ_１１Ｒ_１２、－ＳＲ_１１、－ＳＯＲ_１１、－ＳＯ_２Ｒ_１１、－ＳＯ_２ＮＲ_１１Ｒ_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る］
によって表される。 In yet another embodiment, the pentaazamacrocyclic ring complex has the following formula (II):

(II)
[In the formula,
X and Y represent any suitable ligand from a monodentate or polydentate ligand or ligand system, or their corresponding anions; and R _A , R _B , R _C , and R _D is 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 ₁₁ )(OR ₁₂ ), wherein R ₁₁ and R ₁₂ are independently hydrogen or is alkyl]
represented by

［式中、
ＸおよびＹは、単座もしくは多座配位子もしくは配位子系に由来する適切な配位子のいずれか、またはこれらの相当するアニオンを表し；ならびに
Ｒ_Ａ、Ｒ_Ｂ、Ｒ_Ｃ、およびＲ_Ｄは、独立して、水素、ヒドロカルビル、置換ヒドロカルビル、ヘテロサイクリル、アミノ酸側鎖部分、あるいは－ＯＲ_１１、－ＮＲ_１１Ｒ_１２、－ＣＯＲ_１１、－ＣＯ_２Ｒ_１１、－ＣＯＮＲ_１１Ｒ_１２、－ＳＲ_１１、－ＳＯＲ_１１、－ＳＯ_２Ｒ_１１、－ＳＯ_２ＮＲ_１１Ｒ_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る］
によって表される。 Further, in one embodiment, the pentaazamacrocyclic ring complex has formula (III) or formula (IV):

[In the formula,
X and Y represent any suitable ligand from a monodentate or polydentate ligand or ligand system, or their corresponding anions; and R _A , R _B , R _C , and R _D is 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 ₁₁ )(OR ₁₂ ), wherein R ₁₁ and R ₁₂ are independently hydrogen or is alkyl]
represented by

からなる群から選択される式によって表される化合物である。 In yet another embodiment, said pentaazamacrocyclic ring complex has formulas (V)-(XVI):

A compound represented by a formula selected from the group consisting of

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.

（ＩＡ）
［式中、
Ｍは、Ｍｎ^２＋またはＭｎ^３＋であり；
Ｒ_１Ａ、Ｒ_１Ｂ、Ｒ_２、Ｒ_３、Ｒ_４Ａ、Ｒ_４Ｂ、Ｒ_５、Ｒ_６、Ｒ_７Ａ、Ｒ_７Ｂ、Ｒ_８、Ｒ_９、Ｒ_１０Ａ、およびＲ_１０Ｂは、独立して、水素、ヒドロカルビル、置換ヒドロカルビル、ヘテロサイクリル、アミノ酸側鎖部分、あるいは－ＯＲ_１１、－ＮＲ_１１Ｒ_１２、－ＣＯＲ_１１、－ＣＯ_２Ｒ_１１、－Ｃ（＝Ｏ）ＮＲ_１１Ｒ_１２、－ＳＲ_１１、－ＳＯＲ_１１、－ＳＯ_２Ｒ_１１、－ＳＯ_２ＮＲ_１１Ｒ_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は、前記大環状環の隣接する炭素原子と一緒になって、３～２０個の環炭素原子を有する縮合された置換もしくは無置換の飽和、部分的に飽和もしくは不飽和の環もしくはヘテロ環を形成し；
Ｖは、前記大環状環の隣接する炭素原子と一緒になって、３～２０個の環炭素原子を有する縮合された置換もしくは無置換の飽和、部分的に飽和もしくは不飽和の環もしくはヘテロ環を形成し；
Ｗは、前記大環状環の窒素およびそれが結合している前記大環状環の炭素原子と一緒になって、２～２０個の環炭素原子を有する芳香族もしくは脂環式の置換もしくは無置換の飽和、部分的に飽和もしくは不飽和の窒素含有縮合ヘテロ環を形成するが、但し、Ｗが縮合された芳香族ヘテロ環である場合、前記ヘテロ環および前記大環状環の両方の部分である窒素に結合している水素、ならびに前記ヘテロ環および前記大環状環の両方の部分であるＲ_５およびＲ_６は、存在しないものとし；
各Ｘ_１は、独立して、置換もしくは無置換フェニル、または－Ｃ（－Ｘ_２）（－Ｘ_３）（－Ｘ_４）であり；
各Ｘ_２は、独立して、置換もしくは無置換フェニル、またはアルキルであり；
各Ｘ_３は、独立して、水素、ヒドロキシル、アルキル、アミノ、－Ｘ_５Ｃ（＝Ｏ）Ｒ_１３［式中、Ｘ_５は、ＮＨまたはＯであり、ならびにＲ_１３は、Ｃ_１－Ｃ_１８アルキル、置換もしくは無置換アリール、またはＣ_１－Ｃ_１８アラルキルである］、または－ＯＲ_１４［式中、Ｒ_１４は、Ｃ_１－Ｃ_１８アルキル、置換もしくは無置換アリール、またはＣ_１－Ｃ_１８アラルキルである］であるか、あるいはＸ_４と一緒になって（＝Ｏ）であり；
各Ｘ_４は、独立して、水素であるか、あるいはＸ_３と一緒になって（＝Ｏ）であり；ならびに
遷移金属Ｍと大環状環の窒素原子との結合、ならびに遷移金属Ｍと軸配位子－ＯＣ（＝Ｏ）Ｘ_１の酸素原子との結合は、配位共有結合である］
で示される。 In one embodiment, the pentaazamacrocyclic ring complex has the following formula (IA):

(IA)
[In the formula,
M is Mn ²⁺ or Mn ³⁺ ;
R _1A , R _1B , R ₂ , R ₃ , R _4A , R _4B , R ₅ , R ₆ , R _7A , R _7B , R ₈ , R ₉ , R _10A , and R _10B are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moieties, or -OR ₁₁ , -NR ₁₁ R ₁₂ , -COR ₁₁ , -CO ₂ R ₁₁ , -C(=O)NR 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 ₁₁ ) (OR ₁₂ ), wherein R ₁₁ and R ₁₂ are independently hydrogen or alkyl is;
U is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
V is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
W, together with the macrocyclic ring nitrogen and the macrocyclic ring carbon atom to which it is attached, is an aromatic or alicyclic substituted or unsubstituted aromatic or alicyclic ring having 2 to 20 ring carbon atoms; to form a saturated, partially saturated or unsaturated nitrogen-containing fused heterocycle of with the proviso that when W is a fused aromatic heterocycle, it is part of both said heterocycle and said macrocycle hydrogen attached to nitrogen and R ₅ and R ₆ being part of both said heterocycle and said macrocycle shall be absent;
each X ₁ is independently substituted or unsubstituted phenyl, or -C(-X ₂ )(-X ₃ )(-X ₄ );
each X ₂ is independently substituted or unsubstituted phenyl, or alkyl;
Each X ₃ is independently hydrogen, hydroxyl, alkyl, amino, -X ₅ C(=O)R ₁₃ [wherein X ₅ is NH or O and R ₁₃ is C ₁ -C ₁₈ alkyl, substituted or unsubstituted aryl, or C ₁ -C ₁₈ aralkyl], or —OR ₁₄ [wherein R ₁₄ is C ₁ -C ₁₈ alkyl, substituted or unsubstituted aryl, or C ₁ -C ₁₈ is aralkyl], or together with X ₄ (=O);
each X ₄ is independently hydrogen or together with X ₃ is (=O); The bond with the oxygen atom of the ligand —OC(=O)X ₁ is a coordinate covalent bond]
is indicated by

In one embodiment, within Formula (IA) and groups contained therein, in one group of compounds, X ₁ is -C(-X ₂ )(-X ₃ )(-X ₄ ); Each X ₂ , X ₃ , and X ₄ in combination corresponds to any of the combinations identified in the table below:

［式中、Ｒ_１３は、Ｃ_１－Ｃ_１８アルキル、置換もしくは無置換アリールもしくはＣ_１－Ｃ_１８アラルキル、または－ＯＲ_１４（式中、Ｒ_１４は、Ｃ_１－Ｃ_１８アルキル、置換もしくは無置換アリール、またはＣ_１－Ｃ_１８アラルキルである）である］ Further, within embodiment (IA) and groups contained therein, in one group of compounds, X ₁ is C(-X ₂ )(-X ₃ )(-X ₄ ) and X ₃ is -X ₅ C(=O)R ₁₃ and combinations of X ₂ , X ₃ and X ₄ include any of the combinations identified in the table below:

[wherein R ₁₃ is C ₁ -C ₁₈ alkyl, substituted or unsubstituted aryl or C ₁ -C ₁₈ aralkyl, or -OR ₁₄ (wherein R ₁₄ is C ₁ -C ₁₈ alkyl, substituted or unsubstituted substituted aryl, or C ₁ -C ₁₈ aralkyl)]

［式中、
Ｍは、Ｍｎ^＋２またはＭｎ^＋３であり；
各Ｘ_１は、独立して、置換もしくは無置換フェニルまたは－Ｃ（Ｘ_２）（Ｘ_３）（Ｘ_４）であり；
各Ｘ_２は、独立して、置換もしくは無置換フェニル、メチル、エチル、またはプロピルであり；
各Ｘ_３は、独立して、水素、ヒドロキシル、メチル、エチル、プロピル、アミノ、あるいはＸ_４と一緒になって＝Ｏであり；
各Ｘ_４は、独立して、水素であるか、あるいはＸ_３と一緒になって＝Ｏであり；ならびに
マンガンと大環状環の窒素原子との結合およびマンガンと軸配位子－ＯＣ（Ｏ）Ｘ_１の酸素原子との結合は、配位共有結合である］
のうちの１つである。 In one embodiment, the pentaazamacrocyclic ring complex corresponding to formula (IA) is represented by complex formula (IE), for example (IE _R1 ), (IE _S1 ), (IE _R2 ), (IE _S2 ), ( IE _R3 ), or (IE _S3 ):

[In the formula,
M is Mn ⁺² or Mn ⁺³ ;
each X ₁ is independently substituted or unsubstituted phenyl or -C(X ₂ )(X ₃ )(X ₄ );
each X ₂ is independently substituted or unsubstituted phenyl, methyl, ethyl, or propyl;
each X ₃ is independently hydrogen, hydroxyl, methyl, ethyl, propyl, amino, or together with X ₄ is =O;
each X ₄ is independently hydrogen or together with X ₃ is =O; ) the bond with the oxygen atom of X ₁ is a coordinate covalent bond]
is one of

In one embodiment, each X ₁ is -C(X ₂ )(X ₃ )(X ₄ ) and each -C(X ₂ )(X ₃ )(X ₄ ) is represented by formula (IA) above corresponds to any of the combinations 1-9 shown in the table for

In yet another embodiment, X and Y in the pentaazamacrocyclic complex of Formula (I) correspond to ligands in Formula (IA) or (IE). For example, X and Y in said complex of Formula (I) may correspond to -O-C(O)-X ₁ , where X ₁ is of Formulas (IA) and (IE) above. As defined for complexes.

のいずれかが含まれうる。 In one embodiment, pentaazamacrocyclic ring complexes corresponding to formula (I) (e.g., formula (I) corresponding to formula (I) or formulas (II)-(XIV), (IA) and (IE) ) has the following structure:

can include either

［式中、式（２）、（３）、（４）、（５）、（６）、および（７）の各々におけるＸおよびＹは、独立して、配位子である］
に相当するものが含まれる。例えば、１の実施態様によれば、本明細書に記載の方法および組成物に使用するためのペンタアザ大環状環複合体には、式（２）、（３）、（４）、（５）、（６）、および（７）［これらの式の各々におけるＸおよびＹがハロ（例えば、クロロ）である］に相当するものが含まれる。あるいは、ＸおよびＹは、クロロ以外の配位子、例えば、上記に記載の配位子のいずれかであってもよい。 In one embodiment, the pentaaza macrocyclic ring complexes for use in the methods and compositions described herein include formulas (2), (3), (4), (5), (6) , and (7):

[wherein X and Y in each of formulas (2), (3), (4), (5), (6), and (7) are independently ligands]
includes the equivalent of For example, according to one embodiment, pentaazamacrocyclic ring complexes for use in the methods and compositions described herein include formulas (2), (3), (4), (5) , (6), and (7) where X and Y in each of these formulas are halo (eg, chloro). Alternatively, X and Y may be ligands other than chloro, such as any of the ligands described above.

に相当する。 In another embodiment, the pentaazamacrocyclic ring complex has formula (6) or formula (7):

corresponds to

6 (e.g., the dichloro complex form described in Riley, D.P., Schall, O.F., 2007, Advances in Inorganic Chemistry, 59: 233-263) and 7 (e.g., the dichloro complex structure of 7) described herein. ) are identical except that they have mirror image chirality (ie, the enantiomeric structures are not superimposable).

のうちの少なくとも１つに相当しうる。 For example, the pentaazamacrocyclic ring complex can be the following complex:

can correspond to at least one of

および／またはこれらのエナンチオマーのうちの少なくとも１つに相当しうる。 In yet another embodiment, the pentaazamacrocyclic ring complex is a complex of:

and/or may correspond to at least one of these enantiomers.

In one embodiment, the enantiomeric purity of the pentaaza-macrocyclic ring complex is 95% or greater, more preferably 98% or greater, more preferably 99% or greater, most preferably 99.5% or greater. As used herein, the term "enantiomeric purity" means the amount of a 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 diastereomeric purity of the pentaazamacrocyclic ring complex is 98% or greater, more preferably 99% or greater, and most preferably 99.5% or greater. As used herein, the term "diastereomeric purity" means the amount of a compound having the indicated absolute stereochemistry expressed as a percentage of the total amount of the indicated compound and its diastereomers. Methods for checking diastereomeric and enantiomeric purity are well known in the art. Diastereomeric purity can be determined by any analytical method capable of quantitatively distinguishing between a compound and its diastereomers, such as high performance liquid chromatography (HPLC). Similarly, enantiomeric purity can be determined by any analytical method capable of quantitatively distinguishing between a compound and its enantiomer. Examples of suitable analytical methods for determining enantiomeric purity include, but are not limited to, optical rotation of plane polarized light using a polarimeter, and HPLC using chiral column packing materials.

In one embodiment, a therapeutically effective amount of a pentaaza-macrocyclic ring conjugate can be an amount sufficient to provide a peak plasma concentration of at least 0.1 μM when administered to a patient. For example, in one embodiment, the pentaaza-macrocycle conjugate can be in an amount sufficient to provide a peak plasma concentration of at least 1 μM when administered to a patient. In yet another embodiment, the pentaaza-macrocycle conjugate can be in an amount sufficient to provide a peak plasma concentration of at least 10 μM when administered to a patient. Generally, the pentaazamacrocycle conjugate is not administered in amounts that, when administered to a patient, would provide peak plasma concentrations of 40 μM or greater. For example, the pentaazamacrocycle conjugate can be administered in an amount sufficient to provide peak plasma concentrations in the patient in the range of 0.1 μM to 40 μM. As another example, the pentaaza-macrocycle conjugate can be administered in an amount sufficient to provide peak plasma concentrations in the patient in the range of 0.5 μM to 20 μM. As another example, the pentaaza-macrocycle conjugate can be administered in an amount sufficient to provide a peak plasma concentration in the patient in the range of 1 μM to 10 μM.

In yet another embodiment, the dose of pentaaza-macrocyclic ring complex administered per kg body weight of the patient can be at least 0.1 mg/kg, such as at least 0.2 mg/kg. For example, the dose of pentaazamacrocyclic ring complex administered per kg body weight of the patient can be at least 0.5 mg/kg. As another example, the dose of pentaaza-macrocyclic ring complex administered per kg body weight of the patient can be at least 1 mg/kg. In another example, the dose of pentaazamacrocycle administered per kg body weight is at least 2 mg/kg, such as at least 3 mg/kg, even at least about 15 mg/kg, such as at least 24 mg/kg, even at least 40 mg/kg. kg. Generally, the dose of pentaazamacrocyclic ring complex administered per kg body weight of the patient does not exceed 1000 mg/kg. For example, the dose of pentaaza-macrocyclic ring complex administered per kg body weight of the patient is in the range of 0.1-1000 mg/kg, such as 0.2 mg/kg to 40 mg/kg, such as 0.2 mg/kg. kg to 24 mg/kg, even 0.2 mg/kg to 10 mg/kg. As another example, the dose of pentaazamacrocyclic ring complex administered per kg body weight is in the range of 1 mg/kg to 1000 mg/kg, such as 3 mg/kg to 1000 mg/kg, even 5 mg/kg to 1000 mg/kg. kg, for example 10 mg/kg to 1000 mg/kg. As another example, the dose of pentaazamacrocyclic ring complex administered per kg body weight can be in the range of 2 mg/kg to 15 mg/kg. As yet another example, the dose of pentaaza-macrocyclic ring complex administered per kg body weight can be in the range of 3 mg/kg to 10 mg/kg. As another example, the dose of pentaaza-macrocyclic ring complex administered per kg body weight of the patient can be in the range of 0.5-5 mg/kg. As a still further example, the dose of pentaaza-macrocyclic ring complex administered per kg body weight of the patient can be in the range of 1-5 mg/kg.

In one embodiment, the doses and/or plasma concentrations described above may be particularly suitable for the pentaazamacrocyclic ring complex corresponding to GC4419, but they may also be suitable for other pentaazamacrocyclic ring complexes. Additionally, those of skill in the art will understand how to adjust the dose and/or plasma concentration based on factors such as the molecular weight and/or activity of the particular compound employed. For example, for a pentaazamacrocycle conjugate with twice the activity of GC4419, the dose and/or plasma concentration may be halved, or equivalently for a pentaazamacrocycle conjugate with a higher molecular weight than GC4419. Higher doses may be used.

Dosage regimens for pentaaza-macrocyclic ring conjugates can likewise be selected depending on the desired treatment. For example, in one embodiment, a suitable dosing regimen includes giving the patient at least once a week, such as at least 2, 3, 4, 5, 6 or 7 days a week (eg, daily) during the treatment period. ) dosing. 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 period of treatment with the pentaaza-macrocyclic ring conjugate may continue for at least the same period of time as the period of treatment with the platinum-based anti-cancer agent (e.g., cisplatin), wherein the platinum-based anti-cancer agent is provided. period may be exceeded. The period of treatment with the pentaazamacrocyclic ring conjugate may also begin on the same day as the treatment with the platinum-based anticancer agent, or, as described in more detail below, dosing with the platinum-based anticancer agent is initiated. You can start later. For example, in one embodiment, 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. , for a platinum-based anticancer agent administered for a treatment period lasting 6 months, the pentaazamacrocyclic ring conjugate was administered for 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, up to 6 months.

Platinum-Based Anticancer Agents According to one embodiment, a platinum-based anticancer agent is provided as part of a treatment method described herein in combination with a pentaazamacrocycle. Platinum-based anticancer agents include a class of compounds that are coordination complexes of platinum and have anticancer effects. Platinum-based anticancer agents, such as cisplatin and oxaliplatin, are understood to exert anticancer effects by inducing DNA damage in cancer cells (Cruet-Hennequart et al, DNA Repair, 7(4): 582-596 (2008)) and has been shown to be highly effective in cancer therapy (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 (eg, cisplatin, carboplatin and oxaliplatin), and also platinum (IV) complexes (eg, satraplatin and LA-12). (see, eg, Bouchal et al. Proteome Science, 9:68 (2011)). The platinum-based anticancer agents may be provided in a variety of formulations, and a hydroxypropylmethacrylamide (HPMA)-based 25 kDa polymer delivery vehicle is used to target oxaliplatin to tumors, DACH As part of a delivery vesicle or other targeting moiety for targeting tumor and/or cancer cells with the (diaminocyclohexane) platinum polymer prodrug platinum-based anticancer drug ProLindac (AP5346). (see, eg, Nowotnik et al., Advanced Drug Delivery Reviews, 61(13): 1214-1219 (2009)). Other targeting mechanisms for targeting and/or enhancing delivery of platinum-based anticancer agents to tumor and/or cancer cells include, for example, peptides, polymeric carriers, micelles, radiation and/or light activated proteins. Drugs, functionalized carbon nanotubes and/or nanorods, hollow Prussian Blue, magnetic iron oxide, and/or gold nanoparticles, and nanogels can be mentioned (see, for example, Butler et al., Current Opinion in Chemical Biology, 17(2): 175-188 (2013)).

In one embodiment, suitable platinum-based anticancer agents include cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin, heptaplatin, dicycloplatin, lipoplatin, LA-12 ((OC-6-43)-bis(acetate ) (1-adamantylamine)amminedichloroplatinum (IV)), phosphaplatin, phenanthriplatin, ProLindac (AP5346), tripplatin tetranitrate, picoplatin, satraplatin, piriplatin ( pyriplatin) and/or pharmaceutically acceptable salts thereof.

The dosage of the platinum-based anticancer agent can be selected according to the treatment provided and the particular platinum-based anticancer agent used. For example, a suitable dose for a platinum-based anticancer agent (eg, cisplatin) may be in the range of 10 mg/m ² -200 mg/m ² , eg, 20 mg/m ² -100 mg/m ² .

Dosage schedules for platinum-based anticancer agents can likewise be selected according to the desired treatment and the platinum-based anticancer agent provided. For example, in one embodiment, suitable dosing schedules include 1 per day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 per week, 2 weeks, 3 weeks, or 1 month. It may involve dosing the patient once or twice.

Timing of Administration In one embodiment, the course of treatment with a platinum-based anticancer agent and a pentaazamacrocycle conjugate comprises one or more doses of said agents and/or conjugates, depending on the treatment provided. can be done. In one embodiment, the course of treatment comprising one or more doses can comprise administering a dose of the pentaaza-macrocyclic complex for a period of time prior to administration of the platinum-based anticancer agent. For example, the course of treatment may include the initiation of dosing with the pentaazamacrocyclic ring conjugate for a period of time prior to the first dose of the platinum-based anticancer agent, together with the first dose of the platinum-based anticancer agent, optionally once. or more subsequent doses may be administered. In another embodiment, the course of treatment comprising one or more administrations comprises administering a dose of the pentaazamacrocyclic ring complex after a predetermined period of time has elapsed following administration of the dose of the platinum-based anticancer agent. can be done. That is, the course of treatment includes the first dose of the platinum-based anticancer agent, optionally once or Administration of further subsequent doses can be included.

In one embodiment, at least one dose of pentaaza-macrocycle conjugate during said course of treatment is at least 1 week, at least 5 days, at least 3 days, at least 2 days before administration of the platinum-based anticancer agent; At least 1 day, at least 12 hours, at least 8 hours, at least 4 hours, at least 2 hours, at least 1 hour, and/or at least 30 minutes before administration. In another embodiment, at least one dose of pentaaza-macrocycle conjugate during said course of treatment is at least 1 week, at least 5 days, at least 3 days, at least 2 days, at least 1 day, at least 12 hours, at least 8 hours, at least 4 hours, at least 2 hours, at least 1 hour, and/or at least 30 minutes. Further, the timing of at least one dose of the pentaazamacrocyclic ring conjugate may also vary from multiple doses delivered during said course of treatment, e.g. and may also apply to substantially all doses provided during the course of said treatment.

Other Cancer Therapies In one embodiment, the treatments provided herein are treatments other than those specifically described above, such as radiotherapy and/or other chemotherapeutic therapies. treatment with one or more). As yet another example, treatment may include a PARP inhibitor (poly ADP ribose polymerase inhibitor), e.g., any one or more of olaparib, rucaparib, niraparib, iniparib, talazoparib, and veliparib. The anti-cancer agent can be administered prior to, concurrently with, or after administration of one or more of the platinum-based anti-cancer compound and the pentaaza macrocycle complex. Other anti-cancer agents may also be provided. For example, in one embodiment, radiation therapy may be administered to a subject prior to, concurrently with, or after administration of one or more of a platinum-based anticancer agent and a pentaazamacrocycle conjugate. good. A more detailed description of radiotherapy and other chemotherapy suitable for cancer treatment is provided below.

In one embodiment, radiation therapy can be administered concurrently with administration of one or more of a platinum-based anticancer agent and a pentaazamacrocycle conjugate. For example, one or more of the platinum-based anticancer agents and pentaazamacrocycle conjugates may be administered during the course of radiation therapy, e.g., when the subject is It may be administered during, before or after administration of radiation therapy, or on the same day as administration, such that radiation therapy is being received concurrently with one or more administrations of .

In yet another embodiment, a combination therapy of a pentaazamacrocycle conjugate and a platinum-based anticancer agent (eg, cisplatin) can be administered without any other cancer therapy. As further shown in the Examples below, the pentaaza-macrocyclic ring conjugates unexpectedly turned to platinum-based anticancer agents (e.g., cisplatin) even when administered without radiotherapy. can increase the responsiveness and/or effectiveness of Thus, in one embodiment, the cancer treatment provided to the subject is without administration of radiation exposure (i.e., without administration of a radiation dose or dose fraction) and essentially a pentaazamacrocyclic ring complex and platinum. It may also consist of an anti-cancer drug based. For example, a combination of a pentaazamacrocyclic ring conjugate and a platinum-based anticancer agent may be administered to a subject who has not undergone radiation therapy. Thus, in one embodiment, the treatment includes administering a pentaaza-macrocycle conjugate to a subject who has not undergone radiation therapy. In yet another embodiment, said treatment comprises administering a platinum-based anticancer agent and a pentaazamacrocycle conjugate to a subject who has not undergone radiation therapy. In yet another embodiment, when the course of treatment comprises administration of a pentaaza-macrocycle conjugate and a platinum-based anti-cancer agent, they are administered to a subject who has not undergone radiation therapy during the course of treatment.

In one embodiment, the subject receiving the combination of a pentaazamacrocycle conjugate and a platinum-based anticancer agent (e.g., cisplatin) is subjected to radiation (i.e., the radiation dose or dose fraction received) for at least one day, e.g., No prior exposure for at least 1 week, further at least 1 month, further at least 6 months, and/or prior to first treatment with one or more of the pentaazamacrocyclic conjugates and platinum-based anticancer agents They may not have received such treatment. In yet another embodiment, the radiation therapy administered to the subject after combination therapy with a pentaaza-macrocycle complex and a platinum-based anticancer agent is the pentaaza-macrocycle complex and platinum administered during said combination therapy course. is delayed until at least one day, such as at least one week, even at least one month, such as at least six months, after the last administration of one or more of the anticancer agents based on. Thus, a combination therapy of a pentaazamacrocyclic ring complex and a platinum-based anticancer agent can be administered to a subject who has never received radiation therapy or who has received such therapy only in the distant past. . Additionally, combination therapy of a pentaazamacrocyclic ring conjugate and a platinum-based anticancer agent can be administered to provide a therapeutic course that does not involve any exposure to radiation. In still further embodiments, the combination therapy of the pentaazamacrocyclic ring conjugate and the platinum-based anticancer agent is substantially free of radiation therapy during or after the course of therapy, or such radiation is effective in completing the course of the combination therapy. It can be provided to be a course of treatment only after a long period of time has elapsed. In one embodiment, the treatment comprises administering one or more of the pentaazamacrocycle conjugate and the platinum-based anticancer agent to the subject on days other than the days the subject is receiving radiation therapy. is included.

Methods of Administration According to one embodiment, a platinum-based anticancer agent (eg, cisplatin) is administered as a co-therapy or combination therapy with a pentaazamacrocyclic ring complex. Co-therapy or combination therapy as described in the methods herein is intended to encompass administration of each compound sequentially in a schedule that provides the effective effect of the drug combination, such as administration of these active agents at the same time in succession. Co-administration of these agents in a single capsule containing a fixed proportion, or in multiple separate capsules of each agent, or in single or multiple parenteral administrations, or in other routes of administration and formulations. It is also considered to include. Therefore, when administered in combination, the therapeutic agents (i.e., the pentaazamacrocyclic ring complex and/or the platinum-based anticancer agent) are formulated as separate compositions that are administered sequentially at the same time or at different times. Alternatively, the therapeutic agents can be provided as a single composition. Pharmaceutical compositions and formulations are described herein.

The pentaazamacrocyclic ring conjugate and the platinum-based anticancer agent need not be administered at the same time, or substantially at the same time; the agents and compounds may be administered sequentially. The advantage of simultaneous or substantially simultaneous administration, or sequential administration, is well within the determination of the skilled clinician. For example, a pharmaceutical composition or formulation comprising a platinum-based anti-cancer agent may be advantageous for initial administration in combination for certain treatments prior to administration of a pentaaza macrocycle conjugate, whereas pentaaza Pre-administration of the macrocyclic ring complex may be advantageous in other treatments. The present combination of a pentaazamacrocyclic ring conjugate and a platinum-based anticancer agent may be used in other methods of treatment of cancer (typically cancerous tumors), including but not limited to radiation therapy and surgery, or other chemical treatments. It is also understood that it may also be used in combination with therapy. It is further noted that another active agent (e.g., a cytostatic or static agent, or an antiemetic agent) may, in some cases, be administered either sequentially or concurrently with any or all of the other co-treatments. understood.

Thus, treatment method embodiments include the administration of the pentaazamacrocyclic ring complex and the platinum-based anticancer agent simultaneously or sequentially. For example, aspects of the present disclosure include methods of treating cancer in which a pentaazamacrocyclic ring conjugate and a platinum-based anticancer agent are administered simultaneously or sequentially. Other active agents may also be administered concurrently or sequentially with the pentaazamacrocycle conjugate and the platinum-based anticancer agent.

As noted above, if the pentaazamacrocycle complex and the platinum-based anticancer agent are not administered at the same time or substantially at the same time, the initial order of administration of the components may be altered. Thus, for example, the platinum-based anticancer agent is administered first, followed by the administration of the pentaazamacrocycle conjugate; or the pentaazamacrocycle conjugate is administered first, followed by the platinum-based anticancer agent. It may be administration. This alternate administration may be repeated during the monotherapy protocol. Other sequences of administration are included to elicit the effects described herein, and other sequences of administration of other active agents can also be provided.

In one embodiment, the subject is previously treated with a platinum-based anti-cancer agent followed by administration of the pentaazamacrocycle conjugate, or vice versa. According to such embodiments, the pentaaza-macrocycle conjugate may be administered at least 1 hour, at least 3 days after administration of the platinum-based anticancer agent, or vice versa. For example, in one embodiment, the pentaaza macrocycle conjugate 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 pentaaza macrocycle conjugate may be administered between 1 hour and 1 day after administration of the platinum-based anticancer agent, or vice versa. For example, the pentaazamacrocyclic ring conjugate can be administered at 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 18 hours, 24 hours, 36 hours after administration of a platinum-based anticancer agent. It may be administered within 48 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 9 weeks, 10 weeks or 12 weeks, or vice versa. In these other embodiments, the platinum-based anticancer agent may be administered in multiple doses to accompany administration of the pentaazamacrocycle conjugate, or vice versa.

Alternatively, the subject may be pretreated with a pentaazamacrocycle conjugate and subsequently administered a platinum-based anticancer agent, or vice versa. According to such embodiments, the pentaazamacrocyclic ring conjugate is administered within at least one blood half-life of a platinum-based anticancer agent, such as within four blood half-lives of a platinum-based anticancer agent. or vice versa. For example, the pentaazamacrocyclic ring conjugate may be administered within 1, 2, or 3 serum half-lives of other platinum-based anticancer agents, or vice versa.

In another alternative embodiment, the subject has been previously treated with a platinum-based anti-cancer agent, followed by administration of the pentaazamacrocyclic ring conjugate, and further receiving one or more administrations of a platinum-based anti-cancer agent. Additional doses may be given and vice versa. For example, the subject has been previously treated with one dose of a platinum-based anticancer agent, followed by one dose of the pentaazamacrocyclic ring complex, followed by further (or partial) doses of the same or different platinum-based The anti-cancer agent is administered, and an additional dose of the pentaazamacrocycle conjugate can be administered. Further, the subject has been previously treated with a partial or full dose of the pentaaza-macrocycle complex, followed by administration of a platinum-based anticancer agent, followed by a further (or partial) dose of the pentaaza-macrocycle complex. can be administered.

As described in further detail below, the combinations of the present disclosure may also be co-administered with other well-known therapeutic agents selected for their particular utility for the condition being treated. Alternatively, when multiple combination formulations are incompatible, the combination may be used sequentially with known pharmaceutically acceptable agents.

In one embodiment, the pentaazamacrocycle conjugate and the platinum-based anticancer agent can be administered generally by treatment protocols known for these agents. For example, administration of the various components can vary depending on the disease being treated and the effect of the pentaaza-macrocycle conjugate and immunotherapeutic agent on that disease. Also, according to the knowledge of the skilled clinician, the treatment protocol (e.g., dosage and timing) is based on observation of the therapeutic agents (i.e., pentaazamacrocyclic ring complexes, platinum-based anticancer agents) administered to the patient. may vary in light of the effects observed, as well as the observed responsiveness of the disease to the therapeutic agent administered.

Also, in general, the pentaazamacrocyclic ring conjugate and the platinum-based anticancer agent should not be administered in the same pharmaceutical composition, but may need to be administered by different routes due to their different physicochemical characteristics. . For example, the pentaazamacrocyclic conjugates may be administered orally to produce and maintain good blood levels thereof, while platinum-based anticancer agents are administered intravenously or by blood transfusion. and vice versa. The modes of administration can include, where possible, the same pharmaceutical composition, or separate pharmaceutical compositions (eg, two or three separate compositions). Furthermore, once the initial dose is given, the dose, mode of administration and timing of administration can be modified based on observed effects.

The particular selection of pentaazamacrocyclic ring conjugates and platinum-based anticancer agents, and other related treatments (e.g., radiation or other chemotherapy), depends on the attending clinician's diagnosis and patient condition and appropriate treatment. It is up to their judgment of the treatment protocol.

Thus, in accordance with experience and knowledge, the clinician will make individual recommendations for administration of the components of therapy (pentazamacrocyclic complexes and platinum-based anticancer agents) according to the needs of each patient as the therapy progresses. Protocols may be modified.

The attending clinician will consider the patient's general health status as well as more specific indications, e.g., amelioration of disease-related symptoms, tumor growth, in determining whether treatment is effective at the dose administered. Consider inhibition, actual shrinkage of the tumor, or inhibition of metastases. Tumor size can be measured by standard methods such as radiological studies, e.g., CAT or MRI scans, and continuous measurements indicate whether tumor growth has been slowed or reversed. can be used to determine whether Relief of disease-related symptoms (eg, pain) and improvement in overall symptoms can also be used to help judge effectiveness of treatment.

Products comprising the combination may be administered simultaneously, separately and separated by a period of time to obtain the maximum effect of the combination; Various durations are possible, ranging from rapid administration of the component to relatively continuous perfusion. Consequently, for the purposes of this disclosure, said combinations are not limited to those obtained by physical association of the components, but allow for separate administration, may be simultaneous or over a period of time. It is.

Thus, administration of the components described herein can occur as a single event or during the course of therapy. For example, the pentaazamacrocyclic ring conjugate and platinum-based anticancer agent may be administered hourly (e.g., hourly, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, etc.) daily. , once a week, once every two weeks, or once a month (simultaneously or sequentially). For treatment of acute conditions, the course of treatment may be at least hours or days. Certain conditions may extend treatment from several days to several weeks. For example, treatment can extend for 1 week, 2 weeks, or 3 or more weeks. In more chronic conditions, treatment may extend from weeks to months, a year or more, or even the life of the patient in need of such treatment. Alternatively, the compounds and agents are administered hourly, daily, weekly, biweekly, or monthly, over a period of weeks, months, years, or for the life of the patient as a prophylactic measure. be able to.

The dose or amount of a pharmaceutical composition comprising a pentaazamacrocyclic ring complex and a platinum-based anticancer agent administered to a patient is determined for the intended purpose, i.e., for the diseases, conditions, and medical conditions described herein. should be in an amount effective for treating or preventing cancer, in particular. Generally speaking, the effective amount of the composition to be administered may vary according to various factors such as age, weight, sex, diet, route of administration, and medical condition of the patient in need of treatment. . Particularly preferred doses are described more fully herein. It will be understood, however, that the total daily usage of the compositions described herein will be decided by the attending physician or veterinarian within the scope of sound medical judgment.

As described above, the combinations can be co-administered (either in co-formulated formulations or in separate formulations administered at about the same time). The combination may also be administered separately at different times from each agent in separate unit dosage forms. Many approaches for administering platinum-based anticancer agents and pentaaza-macrocycle conjugates can be readily adapted for use in the present disclosure. The pharmaceutical composition may be delivered orally, eg, in a tablet or capsule unit dosage form, or parenterally, eg, in an injectable unit dosage form, or by any other route. For systemic administration, for example, drugs can be administered, for example, by intravenous infusion (continuous or bolus infusion). The compositions may be used for therapeutic or prophylactic treatment in which the patient would benefit from combination therapy.

The specific therapeutically effective dose level for any particular patient will depend on the disease being treated and the severity of the disease; the activity of the particular compound employed; the age, weight, general health, sex of the patient; route of administration; rate of excretion of the particular compound employed; duration of treatment; drugs used in combination or concurrently with the particular compound employed, and factors well known in the medical and/or veterinary arts. Due to various factors. For example, it is clear in the art to begin administering the compound at a level below that required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. . If desired, the effective daily dose may be divided into multiple doses for administration. Thus, single dosage compositions may contain such amounts, or submultiple doses to make up the daily dose.

In one embodiment, suitable or preferred dosages of each of the components are used in the methods or included in the compositions described herein. A preferred dose of the pentaaza-macrocyclic ring conjugate can be, for example, in the range of 10-500 mg per patient per day. However, said doses can be varied by a dosing schedule that can be adjusted as necessary to achieve the desired therapeutic effect. It should be noted that the effective dose ranges provided herein are not intended to be limited to the ranges shown, which disclose typical dose ranges. The most preferred dose will take into consideration, among other things, the particular combination employed, as well as the patient's age, sex, weight, physical condition, diet, etc., as can be understood and determined by those skilled in the art without undue experimentation. It depends on each subject.

Although cancer treatment or cancer therapy as described herein includes achieving a therapeutic benefit, said therapy may also be administered to achieve a prophylactic benefit. Therapeutic benefit generally means at least partial eradication or amelioration of the underlying disease being treated. For example, in cancer patients, therapeutic benefit includes eradication (partial or complete) or amelioration of the underlying cancer. A therapeutic benefit may also be one in which at least partial or complete eradication or alleviation of one or more of the physiological symptoms associated with the underlying disease is achieved and the patient is still suffering from the underlying disease. improvement is seen in patients despite the fact that they may be For prophylactic benefit, the diagnosis of the disease has not been performed in patients at high risk of developing cancer or in patients exhibiting one or more of the physiological symptoms of such disease; Methods of the disclosure may be performed or compositions of the invention administered.

Furthermore, treatment of toxic effects associated with administration of platinum-based anticancer agents and/or treatment of conditions resulting from administration of platinum-based anticancer agents includes achieving a therapeutic benefit, The treatment may also be administered to achieve a prophylactic benefit. Therapeutic benefit generally means eradication or amelioration of at least part of the underlying disorder being treated. For example, in patients at risk of, or suffering from, toxic effects associated with the administration of platinum-based anticancer agents, therapeutic benefit may include (partially or otherwise) the underlying conditions and/or symptoms. complete) eradication or remission. A therapeutic benefit may also be one of the physiological symptoms associated with the underlying disorder, such that the patient sees an improvement regardless of the fact that the patient may already be suffering from the underlying disorder. One or more at least partial or complete eradications or remissions are achieved. For prophylactic benefit, the methods of the present disclosure may be used in patients at risk of toxicity associated with platinum-based anticancer agents (e.g., humans receiving or who have received platinum-based anticancer agents, or human planned to receive anti-cancer agents based on), or patients who report and/or suffer from one or more of the physiological symptoms of such disorders. Alternatively, compositions of the invention may be administered to the patient, and the disorder may not be diagnosed.

Methods of Treating Cancer In general, any subject suffering from or susceptible to cancer or other proliferative disease may be treated using the compositions and methods of this disclosure. Subjects to be treated according to the methods described herein are mammalian subjects, typically human patients. Other mammals that can be treated according to the present disclosure include companion animals (e.g., dogs and cats), livestock animals (e.g., cows, horses, and pigs), and birds and additional exotic animals (e.g., in zoos or nature reserves). animals found). In certain aspects of the present disclosure, methods of treating cancerous tumors, particularly solid tumors, are provided. Advantageously, the methods described herein can reduce tumor incidence, reduce tumor burden, or produce tumor regression in a mammalian host. Cancer patients and individuals desiring cancer prevention can be treated with the combinations described herein.

Cancer and tumor generally refer to or describe the physiological condition in mammals that is typically characterized by uncontrolled cell growth. The pharmaceutical combinations, co-formulations, and combination therapies of the present disclosure provide breast, heart, lung, small intestine, large intestine, spleen, kidney, bladder, head and neck, ovary, prostate, brain, pancreas, skin, bone, bone marrow, blood A variety of tumors can be treated, such as tumors of the thymus, uterus, testis, cervix, and liver.

In one embodiment, the tumor or cancer is adenoma, angiosarcoma, astrocytoma, epithelial carcinoma, germinoma, glioblastoma, glioma, hamartoma, hemangioendothelioma, angiosarcoma, hematoma, liver blastoma, leukemia, lymphoma, medulloblastoma, melanoma, neuroblastoma, osteosarcoma, retinoblastoma, rhabdomyosarcoma, sarcoma, and teratoma. Said tumors are acral lentiginous melanoma, actinic keratosis, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenosarcoma, adenosquamous cell carcinoma, astrocyte tumor, Bartholin's adenocarcinoma, basal cell carcinoma, bronchial adenocarcinoma, capillary Vascular, carcinoid, cancer, carcinosarcoma, cavernous, cholangiocarcinoma, chondrosarcoma, choroid plexus papilloma/cancer, clear cell carcinoma, cystadenoma, endoderm sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma , endometrioid adenocarcinoma, ependymal, epithelioid, Ewing's sarcoma, fibrolamellar type, focal nodular hyperplasia, gastrinoma, germ cell tumor, glioblastoma, glucagonoma, hemangioblastoma, hemangioendothelioma, Hemangioma, hepatic adenoma, hepatic adenomatosis, hepatocellular carcinoma, insulinoma, intraepithelial neoplasia, squamous intraepithelial neoplasia, invasive squamous cell carcinoma, large cell carcinoma, leiomyosarcoma, malignant lentigo-derived melanoma, malignant melanoma, malignant medium dermatoma, medulloblastoma, medulloepithelioma, melanoma, meningeal, mesothelial, metastatic carcinoma, mucoepidermoid carcinoma, neuroblastoma, neuroepithelium, adenocarcinoma, nodular melanoma, oat cell carcinoma, oligodendroglia, Osteosarcoma, pancreas, papillary serous adenocarcinoma, pineal cell, pituitary tumor, plasmacytoma, pseudosarcoma, pulmonary blastoma, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma , small cell carcinoma, soft tissue carcinoma, somatostatin-secreting cell carcinoma, squamous cell carcinoma, squamous cell carcinoma, submesothelial, superficial spreading melanoma, undifferentiated carcinoma, uveal melanoma, verruciform It can be selected from carcinoma, VIP-producing tumors, well-differentiated carcinomas, and Wilms tumors.

Thus, for example, without limitation, the present disclosure includes, but is not limited to: bladder (including advanced and metastatic bladder cancer), breast, colon (including colorectal cancer), kidney, liver, lung (small cell and non-small cell). lung cancer, and lung adenocarcinoma), ovary, prostate, testicle, urinary tract, lymphatic system, rectum, larynx, pancreas (including pancreatic exocrine tumor), esophagus, stomach, gallbladder, neck, thyroid, and skin (squamous) cancer, including cancer of the lymphatic system; hematopoietic malignancies of the lymphatic system (leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, myeloid hematopoietic malignancies (including acute and chronic myelogenous leukemia, myelodysplastic syndrome, myeloid leukemia, and promyelocytic leukemia); central and peripheral nervous system tumors of mesenchymal origin (including fibrosarcoma, rhabdomyosarcoma, and osteosarcoma); and other tumors (including melanoma, xeroderma pigmentosum, keratocanthoma, seminioma, follicular thyroid carcinoma, and teratoma).

For example, certain leukemias that can be treated with the combinations and methods described herein include, but are not limited to, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, Acute promyelocytic leukemia, adult T-cell leukemia, nonleukemic leukemia, leukocytic leukemia, basophilic leukemia, blastic leukemia, bovine leukemia, chronic myelocytic leukemia, cutaneous leukemia, fetal leukemia, eosinophil spherical leukemia, gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, Lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphotropic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocyte myeloblastic leukemia, myeloblastic leukemia, myeloid leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Negeri leukemia, plasma cell leukemia, plasma cell leukemia, promyelocytic leukemia, leader cell leukemia Leukemia, Schilling's leukemia, hepatocellular leukemia, subleukemic leukemia, and undifferentiated cell leukemia.

Lymphoma can also be treated with the combinations and methods described herein. Lymphomas are generally neoplastic transformations of cells that reside primarily in lymphoid tissue. Lymphomas are tumors of the immune system and commonly present as both T- and B-cell associated diseases. Among lymphomas, there are two major distinct groups: non-Hodgkin's lymphoma (NHL) and Hodgkin's disease. In particular, bone marrow, lymph nodes, spleen, and circulating cells may be relevant. Treatment protocols include removing bone marrow from the patient, washing the bone marrow of tumor cells, and possibly using antibodies against antigens present on the tumor cell type, followed by storage. Patients are given toxic doses of radiation or chemotherapeutic agents, and the washed bone marrow is percolated again to restore the patient's hematopoietic system.

Other hematologic 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 (eg, skin). Solitary myeloma is associated with a solitary focus that tends to occur in the same locus as multiple myeloma.

In one embodiment, the methods and pharmaceutical compositions described herein are used to treat breast cancer, melanoma, oral squamous cell carcinoma, lung cancer (including non-small cell lung cancer), renal cell carcinoma, colorectal cancer, prostate cancer, brain cancer. It is used to treat cancer that is either cancer, spindle cell carcinoma, urothelial carcinoma, bladder cancer, colorectal cancer, head and neck cancer (eg, squamous cell carcinoma), and pancreatic cancer. In yet another embodiment, the methods and pharmaceutical compositions described herein are used to treat cancer that is either head and neck cancer or lung cancer.

Methods of Treating Toxicities Associated with Platinum-Based Anti-Cancer Agents In general, a subject suffering from or susceptible to a condition resulting from the toxic effects of administration of a platinum-based anti-cancer agent (e.g., cisplatin) is treated with a composition of the present disclosure. and methods. Subjects to be treated by the methods described herein are mammalian subjects, typically human patients. Other mammals that can be treated according to the present disclosure include companion animals (e.g., dogs and cats), livestock animals (e.g., cows, horses, and pigs), and birds and additional exotic animals (e.g., in zoos or nature reserves). animals found). In certain embodiments of the present disclosure, a condition associated with toxicity of a platinum-based anticancer agent (e.g., as provided during cancer therapy) wherein the subject is suffering from a condition following administration of a platinum-based anticancer agent to the subject conditions, etc.) for alleviating said conditions. In another embodiment, the treatment is provided to reduce and/or inhibit toxicity of a platinum-based anticancer agent, e.g., the platinum-based anticancer agent is provided during cancer treatment, reduce the risk of developing toxicity-related conditions of anticancer agents based on Advantageously, the methods described herein allow for the treatment of cancer with platinum-based anticancer agents while at the same time reducing toxic effects and/or reducing the toxic state, e.g., in a mammalian host. , may reduce tumor incidence, reduce tumor burden, or cause tumor regression. Cancer patients and individuals desiring cancer prevention can be treated with the combinations described herein.

In one embodiment, toxicity and/or toxicity associated with administration of a platinum-based anticancer agent, which can be treated (and/or the risk of developing such conditions can be reduced) by the methods described herein Toxic conditions include at least one of nephrotoxicity, myelotoxicity, ototoxicity, neurotoxicity, and conditions related thereto. For example, in one embodiment, administration of a pentaaza-macrocycle conjugate can reduce neurotoxic effects associated with administration of platinum-based anticancer agents. Nephrotoxicity refers to toxicity to the kidney, resulting in reduced renal function, acute renal injury, and even renal failure, and is generally associated with administration of anticancer agents (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) and creatinine levels may be measured to provide an indication of the degree of renal damage, with elevated levels indicating decreased renal function. Other markers of renal injury include kidney injury molecule 1 (KIM1) and neutrophil gelatinase-associated lipocalin (NGAL). As another example, in one embodiment, administration of a pentaaza-macrocycle conjugate can reduce myelotoxic effects associated with administration of platinum-based anticancer agents. Myelotoxicity, also called myelosuppression and/or myelosuppression, refers to a decrease in the production of cells such as lymphocytes, red blood cells, and platelets, resulting in conditions such as neutropenia, thrombocytopenia, and anemia. can be commonly associated with anticancer agents (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 pentaaza-macrocycle conjugate reduces ototoxic effects (which are toxicity to the ear, such as the cochlea, auditory nerve and/or vestibular system) associated with administration of platinum-based anticancer agents. can be made Thus, in one embodiment, the treatment methods described herein involve a subject suffering from and/or at risk of suffering from toxicity resulting from a platinum-based anticancer therapy, e.g. This can include treating a subject suffering from and/or at risk of suffering from one or more of nephrotoxicity and myelotoxicity from administration of the anti-cancer agent.

Pharmaceutical Formulations Another aspect of the present disclosure relates to pharmaceutical compositions comprising a combination described herein together with pharmaceutically acceptable excipients. Said pharmaceutical composition is typically formulated as a pharmaceutical formulation, optionally in combination with pharmaceutically acceptable carriers, additives or excipients, as described above. , pentaazamacrocyclic ring conjugates (eg, those corresponding to formula (I)), and at least one platinum-based anticancer agent, and combinations thereof. In one embodiment, for example, the pharmaceutical composition includes a pentaazamacrocyclic ring complex, a platinum-based anticancer agent, and a pharmaceutically acceptable excipient. Pharmaceutical compositions according to the present disclosure can be used to treat cancer.

The pharmaceutical compositions described herein are products resulting from mixing or combining one or more active ingredients, and include both fixed and non-fixed combinations of active ingredients. A fixed combination, for example, is one in which the pentaazamacrocyclic ring conjugate and the platinum-based anticancer agent are administered to the patient at the same time in the form of a single entity or single dose. Other active agents may also be administered as part of a single entity or dose, or may be administered separately. A non-fixed combination is one in which the active ingredients, e.g., the pentaazamacrocyclic ring complex and the platinum-based anticancer agent, are administered to the patient separately, simultaneously, simultaneously, or sequentially without specific intervals. provided that such administration provides effective levels of the compound in the patient's body. The latter is also used in multidrug combination therapy, eg the administration of three or more active ingredients.

The pentaazamacrocyclic ring complexes and platinum-based anticancer agents described above may be dispersed in a pharmaceutically acceptable carrier prior to administration to a mammal; , preferably co-formulated. Carriers, known in the art as excipients, vehicles, adjuvants, adjuvants, or diluents, are typically pharmaceutically inert substances having a suitable consistency for the composition. or morphology, which does not diminish the efficacy of the compound. Said carriers are generally considered "pharmaceutically or pharmacologically acceptable" so long as they do not cause unacceptable toxicity, allergenicity, or other adverse reactions when administered to mammals, particularly humans. It is

The selection of a pharmaceutically acceptable carrier will also depend, in part, on the route of administration. In general, the compositions described herein can be formulated for any route of administration so long as the blood circulation system is available via this route and the conventional route of administration. For example, suitable routes of administration include, but are not limited to, oral, parenteral (e.g., intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intratracheal, intracapsular, intraspinal, intraperitoneal, or intrasternal). ), topical (nasal, transdermal, intraocular), intravesical, intrathecal, intestinal, pulmonary, intralymphatic, intracavital, vaginal, transurethral, intradermal, otic, intramammary, buccal , orthotopic, intratracheal, intralesional, transdermal, endoscopic, transmucosal, sublingual, and enteral administration.

Pharmaceutically acceptable carriers for use in combination with the compositions of the present disclosure are well known to those of ordinary skill in the art and may vary depending on a number of factors: the particular compounds and agents employed, and their/their concentration, stability and purpose. subject, its age, weight, general condition; and route of administration. Suitable non-aqueous pharmaceutically acceptable polar solvents include, but are not limited to, alcohols (eg, a-glycerol formal, 6-glycerol formal, 1,3-butylene glycol, aliphatic or aromatic alcohols such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin (glycerol), glycol, hexylene glycol, tetrahydrofurfuryl alcohols, lauryl alcohol, cetyl alcohol, or stearyl alcohol, fatty acid esters of fatty alcohols, such as 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-dimethylacetamamide, 2-pyrrolidinone, 1-methyl-2-pyrrolidinone, or polyvinylpyrrolidone); esters (such as , 1-methyl-2-pyrrolidinone, 2-pyrrolidinone, acetic acid esters such as monoacetin, diacetin and triacetin, aliphatic or aromatic esters such as ethyl caprylate or octanoate, alkyl oleates, benzyl benzoate, acetic acid Benzyl, dimethyl sulfoxide (DMSO), esters of glycerin, such as mono-, di-, or tri-glyceryl citric acid or tartrate, ethyl benzoate, ethyl acetate, ethyl carbonate, ethyl lactate, ethyl oleate, fatty acid esters of sorbitan, Fatty acid-derived PEG esters, monostearic acid glycerides, 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 oleic acid polyester, polyoxyethylene sorbitan ester, such as polyoxyethylene-sorbitan monooleate, rioxyethylene-sorbitan monopalmitate, polyoxyethylene-monolauric acid Sorbitan, polyoxyethylene-sorbitan monostearate, and Polysorbate® 20, 40, 60 or 80 (ICI Americas, Wilmington, Del.), polyvinylpyrrolidone, alkyleneoxy-modified fatty acid esters such as polyoxyl 40 hydrogenated Castor oil and polyoxyethylated castor oil (e.g. Cremophor® EL solution or Cremophor® RH40 solution), sucrose fatty acid esters (i.e. condensation products of monosaccharides such as pentoses, e.g. ribose , ribulose, arabinose, xylose, lyxose and lyxose, hexoses such as glucose, fructose, galactose, mannose and sorbose, triose, tetrose, heptose, and octose), disaccharides (such as sucrose, maltose, lactose, and trehalose) or oligosaccharides, or mixtures thereof with 0 ₄ -0 ₂₂ fatty acids, such as saturated fatty acids such as caprylic, capric, lauric, myristic, palmitic and stearic acids, and unsaturated fatty acids such as palmitoleic acid, oleic acid, elaidic acid, erucic acid and linoleic acid)), or steroidal esters); glycofurol (tetrahydrofurfuryl alcohol polyethylene glycol ether); ketones with 3 to 30 carbon atoms (e.g. acetone, methyl ethyl ketone, methyl isobutyl ketone); fats with 4 to 30 carbon atoms. aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. benzene, cyclohexane, dichloromethane, dioxolane, hexane, n-decane, n-dodecane, n-hexane, sulfolane, tetramethylenesulfone, tetramethylenesulfoxide, toluene, dimethylsulfoxide ( DMSO), or tetramethylene sulfoxide); oils of mineral, vegetable, animal, natural or synthetic origin (e.g., mineral oils, e.g., aliphatic or wax-based hydrocarbons, aromatic hydrocarbons, mixed aliphatic and aromatic hydrocarbon based and refined mineral and vegetable oils such as linseed, paulownia, safflower, soybean, castor, cottonseed, peanut, rapeseed, coconut, palm, olive, maize, corn germ, sesame, apricot kernel and peanut oils, and glycerides, such as mono-, di- or triglycerides, animal oils such as fish, aquatic animals, semen, cod liver, halibut, squalene, squalane, and shark liver oil, oleic oil, and polyoxyethylated castor oil); Alkyl or aryl halides having 30 carbon atoms, optionally with one or more halogen groups; methylene chloride; monoethanolamine; petroleum benzine; trolamine; alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoic acid); polyglycol esters of 12-hydroxystearic acid and polyethylene glycol (Soltor® HS-15 (BASF, Ludwigshafen, Germany); oxyethylene glycerol; sodium laurate; sodium oleate; or sorbitan monooleate.

In certain embodiments, oily or non-aqueous solvents may be used in formulations, eg, to bring one or more compounds into solution, eg, due to the presence of large lipophilic moieties. Alternatively, emulsions, suspensions or other preparations such as liposomal preparations may be used. For liposome preparations, for example, any of the known liposome preparation methods may be used. 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 reference. checking ... Thus, in one embodiment, one or more compounds are administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. Ligands may also be attached to the liposomes, for example, to direct these compositions to specific sites of action.

Other pharmaceutically acceptable solvents for use in the pharmaceutical compositions described herein are well known to those of skill in the art and can be found in The Chemotherapy Source Book (Williams & Wilkens Publishing), The Handbook of Pharmaceutical Excipients, ( American Pharmaceutical Association, Washington, D.C., 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), Remington's Pharmaceutical Sciences (A. Gennaro, ed., 19th ed.) (Mack Publishing, Easton, PA, 1995), The United States Pharmacopeia 24, The National Formulary 19, (National Publishing, Philadelphia, PA, 2000 ), and A. J. Spiegel et al., Use of Nonaqueous Solvents in Parenteral Products, Journal of Pharmaceutical Sciences, Vol. 52, No. 10, pp. 917-927 (1963).

Formulations containing the pentaazamacrocyclic ring conjugate and the platinum-based anticancer agent are preferably solid, semisolid, lyophilized powder, or liquid formulations, e.g. , aerosols, capsules, creams, emulsions, foams, gels/jellys, lotions, ointments, pastes, powders, soaps, solutions, sprays, suppositories, suspensions, depots, tablets, tinctures, transdermal It may be in the form of a patch or the like. When formulated as a fixed dose, such pharmaceutical compositions or product formulations employ the pentaazamacrocyclic ring complex and the platinum-based anticancer agent within acceptable dosage ranges.

In one embodiment, formulations are provided that contain a platinum-based anticancer agent as part of a liquid formulation (eg, a sterile liquid formulation suitable for injection). For example, a liquid form containing a platinum-based anticancer agent in combination with one or more additional ingredients, such as disodium edetate (EDTA). In one embodiment, the liquid form may contain EDTA in an amount suitable to act as a preservative and/or metal chelating agent, eg, about 0.025%. Said liquid form may further comprise water and may also comprise a pH adjusting agent, eg sodium bicarbonate for pH adjustment in the range of pH 5.5-7.0. In one embodiment, the pentaaza macrocycle conjugate can also be provided in the same liquid formulation as the platinum-based anticancer agent, or as a separate formulation, as part of a sterile liquid formulation suitable for injection. .

Formulations for certain pentaaza-macrocyclic ring conjugates are also disclosed, for example, in U.S. Pat. 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 by reference in its entirety. incorporated herein).

Co-formulation of pentaazamacrocyclic ring conjugates and platinum-based anticancer agents combines conventional formulation techniques for each of these components or alternative formulation routes depending on the compatibility and efficacy of the various components. It is assumed that it can be used in

The pharmaceutical compositions described above comprising the pentaazamacrocycle and the platinum-based anticancer agent may further comprise one or more additional pharmaceutically active ingredients. Suitable pharmaceutically active agents that may be included in compositions according to aspects of the present invention include, for example, antiemetics, anesthetics, antihypertensives, anxiolytics, anticoagulants, anticonvulsants, hypoglycemic agents, Decongestants, antihistamines, antitussives, antineoplastics, beta-blockers, anti-inflammatory drugs, antipsychotics, nootropics, cholesterol-lowering drugs, antiobesity drugs, autoimmune disease drugs, impotence drugs , antibacterial and antifungal agents, hypnotics, antiparkinsonian agents, antiAlzheimer's agents, antibiotics, antidepressants, and antiviral agents. Each component of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.

In yet another embodiment, pentaazamacrocycle conjugates for the treatment of diseases such as cancer and/or for treating and/or reducing the risk of toxicity associated with the administration of platinum-based anticancer agents. and a platinum-based anti-cancer agent may be provided. For example, the kit may include a first container or box containing a formulation comprising a pentaazamacrocycle conjugate (e.g., an oral or injectable formulation of the pentaazamacrocycle conjugate), a platinum-based anticancer agent ( A first container or box may be included that contains a formulation comprising, for example, an injectable formulation of a platinum-based anti-cancer drug. The kit may include labels or other instructions for administration of active agents, recommended doses, duration and dosing regimens, warnings, descriptions of possible drug interactions, and other relevant instructions ( For example, an indication indicating a treatment regimen (eg, dosage, dosing frequency, etc.) corresponding to any of those described herein may also be included.

Combination Therapy with Cancer Therapies In one embodiment, the pentaazamacrocycle conjugate and the platinum-based anticancer agent can be administered in combination with another cancer therapy to provide therapeutic treatment. For example, a pentaazamacrocyclic ring conjugate and a platinum-based anticancer agent may be administered as part of radiation therapy.

In general, the temporal aspects of administration of the pentaazamacrocyclic ring conjugate and platinum-based anticancer agent may depend, for example, on the particular radiation therapy selected or the type, nature, and/or duration of radiation exposure. Other considerations include the disease or disorder being treated and the severity of the disease or disorder; activity of the particular compound employed; particular composition employed; age, weight, general health, sex and diet of the subject. timing of administration, route of administration and excretion rate of the particular compound employed; duration of treatment; drugs used in combination or concurrently with the particular compound employed. For example, the compound may be administered before, during and/or after radiotherapy (e.g., before, during or after exposure to a course of radiotherapy, including multiple exposures and/or dosing, and/or before, during or after dosing). ) may be administered in various embodiments. As another example, the compound may be administered in various embodiments before, during and/or after radiation exposure.

If desired, the effective dose can be divided into multiple doses for administration; therefore, single dose compositions may contain such amounts or submultiples thereof to make up the dose. may contain.

In one embodiment, for example, the pentaazamacrocycle conjugate and the platinum-based anticancer agent are administered to the patient prior to 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 pentaazamacrocycle conjugate and the platinum-based anticancer agent are administered prior to radiation exposure (e.g., the first radiation exposure during a course of radiation therapy) or during a course of therapy. At least 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 180 minutes, 0.5 days, 1 day, 3 days prior to another dose or dose fraction of radiation that is one of the doses or dose fractions of radiation 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 more . In still other embodiments, for example, the pentaazamacrocyclic ring conjugate and the platinum-based anticancer agent are administered to the patient after exposure to radiation; or a single or final dose or dose fraction of radiation in radiotherapy) after 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 180 minutes 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 It may be administered for up to a week or more.

In one embodiment, the pentaazamacrocycle conjugate and the platinum-based anticancer agent are administered as part of a therapeutic course that includes radiation therapy. In radiotherapy, a patient receives a dose or dose fraction of ionizing radiation to inhibit or control the growth of cancer cells. A dose or dose fraction of radiation may be directed to a specific part of the body to reduce adverse effects on parts of the body not suffering from cancer, the beam of radiation being embodied according to a predetermined treatment regimen. good too. A typical course of radiation therapy may include one or more doses or dose fractions of radiation, which can be administered over the course of days, weeks, and months. The total "dose" of radiation delivered during a course of radiation therapy typically refers to the dose of radiation that a patient receives during the entire course of radiation therapy, these doses being equivalent to the total dose administered. It may also be administered as dose "fractions" representing multiple radiation exposures, where the total fractions are administered over several periods of time.

In one embodiment, at least one of the pentaazamacrocycle conjugate and the platinum-based anticancer agent are administered within a predetermined period of time before or after radiation exposure (e.g., before or after the radiation dose or dose fraction). be. For example, pentaazamacrocyclic ring conjugates and platinum-based anticancer agents are administered for 48 hours for 1 week after the radiation exposure received by the patient, e.g. , 24 hours, 12 hours, 6 hours, 2 hours, 1 hour, or 30 minutes. Other time periods between radiation exposure and compound administration that enhance cancer cell killing may also be appropriate. In one embodiment, one of the pentaazamacrocycle conjugate and the platinum-based anticancer agent may be administered prior to radiation exposure, and the combination of the pentaazamacrocycle conjugate and the platinum-based anticancer agent is administered. The remaining one or more of them can be administered after radiation exposure. One or more of the pentaazamacrocyclic ring conjugate and the platinum-based anticancer agent may be administered both before and after administration of the radiation exposure.

In one embodiment, the radiation therapy course includes multiple radiation doses or dose fractions delivered over a predetermined period of time, such as hours, weeks, days, even months, wherein said multiple doses or Dose fractions may be of the same size or different. That is, a course of radiation therapy can include administration of a series of multiple doses or dose fractions of radiation. In one embodiment, the pentaazamacrocyclic ring conjugate and the platinum-based anticancer agent are administered prior to a series of one or more radiation doses or dose fractions, e.g., prior to each radiation dose or dose fraction, or several It can be administered prior to the radiation dose or dose fraction. Additionally, administration of the pentaazamacrocyclic ring conjugate and platinum-based anticancer agent during the course of radiotherapy is selected to enhance the cancer therapeutic efficacy of radiotherapy, e.g., by sensitizing cancer cells to radiotherapy. be able to. In one embodiment, the pentaazamacrocycle conjugate and the platinum-based anticancer agent are administered for a predetermined period of time before or after each dose or dose fraction, eg, within the period of time described above. In another embodiment, the pentaazamacrocycle conjugate and the platinum-based anticancer agent are administered only within a predetermined period of time before or after the selected dose or dose fraction. In yet another embodiment, at least one of the pentaazamacrocycle conjugate and the platinum-based anticancer agent are administered within said pre-dosing period of time, while another pentaazamacrocycle conjugate and A platinum-based anticancer agent is administered within a predetermined time period after said dose or dose fraction. In a further embodiment, at least one of the pentaazamacrocycle conjugate and the platinum-based anticancer agent is administered only within a predetermined period of time before or after the selected dose or dose fraction, while the pentaazamacrocycle The conjugate and another one of the platinum-based anticancer agents are administered only within a predetermined period of time before or after a dose or dose fraction other than the selected dose or dose fraction.

The overall dose suitable to deliver during the course of treatment can be determined by the type of therapy to be provided, the patient's physiological characteristics, and other factors, and the dose fractions to be provided can likewise be determined. can. In some embodiments, the dose fraction of radiation administered to the patient may be at least 1.8 Gy, such as at least 2 Gy, even at least 3 Gy, such as at least 5 Gy, even at least 6 Gy. In yet another embodiment, the dose fraction of radiation administered to the patient may be at least 10 Gy, such as at least 12 Gy, even at least 15 Gy, such as at least 18 Gy, even at least 20 Gy, such as at least 24 Gy. Generally, the dose fraction of radiation administered to a patient does not exceed 54 Gy. Further, in one embodiment, the dose fraction delivered to a subject can refer to the amount delivered to a specific target area of the subject, e.g., a target area of a tumor, but other areas of the tumor or surrounding tissue. may be exposed to more or less radiation than specified by the nominal dose fraction amount.

In yet another embodiment, the pentaazamacrocycle conjugate and platinum-based anticancer agent are administered as part of a course of treatment that includes administration of an additional chemotherapeutic agent. In chemotherapy, chemotherapeutic agents are administered to a patient to inhibit or control the growth of cancer cells. A typical course of chemotherapy can include one or more doses of one or more chemotherapeutic agents that can be administered over days, weeks, or even months. Chemotherapeutic agents include: alkylating antineoplastic agents such as nitrogen mustards (eg cyclophosphamide, chlorambucil), nitrosoureas (eg n-nitroso-n-methylurea, carmustine, semustine), tetrazines ( dacarbazine, mitozolimide), aziridines (e.g. thiotepa, mitomycin); antimetabolites such as antifolates (e.g. methotrexate and pemetrexed), fluoropyrimidines (e.g. fluorouracil, capecitabine), anthracyclines (e.g. doxorubicin, daunorubicin, epirubicin), deoxynucleoside analogues (e.g. cytarabine, gemcitabine, decitabine) and thiopurines (e.g. thioguanine, mercaptopurine); microtubule inhibitors such as taxanes (e.g. paclitaxel, docetaxel); topoisomerases At least one of inhibitors (eg, etoposide, doxorubicin, mitoxantrone, teniposide); and antitumor antibiotics (eg, bleomycin, mitomycin). For example, chemotherapeutic agents include all-trans retinoic acid, arsenic trioxide, azacitidine, azathioprine, bleomycin, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, etoposide. , fluorouracil, gemcitabine, hydroxyurea, idarubicin, imatinib, mechlorethamine, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, teniposide, tiguanine, valrubicin, vinblastine, vincristine, vindesine, and vinorelbine may be selected from Administration of many chemotherapeutic agents is described in the Physicians' Desk Reference (PDR), eg, 1996 edition (Medical Economics Company, Montvale, N.J. 07645-1742, USA).

In one embodiment, the pentaazamacrocyclic ring conjugate and platinum-based anticancer agent are administered as part of a treatment that includes an additional chemotherapeutic agent selected from the group consisting of doxorubicin, bleomycin, and paclitaxel. . Additionally, in one embodiment, the additional 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 can 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. 155-160 (2001)).

According to yet another embodiment, the additional chemotherapeutic agents can include at least one of the antimetabolite and antimitotic anticancer agents, and combinations thereof, the agents described above and the agents described herein. Any of the other agents described further in the book may also be included. A variety of antimetabolites and antimitotics can be used in the methods and compositions described herein.

Antimetabolites generally structurally resemble natural metabolites and are involved in normal metabolic processes of cancer cells, such as nucleic acid and protein synthesis. However, antimetabolites are sufficiently different from natural metabolites to interfere with the metabolic processes of cancer cells. In said cells, antimetabolites are misidentified for their similar metabolites and are processed by the cells in a manner similar to normal compounds. The presence of "decoy" metabolites prevents cells from performing vital functions, rendering them unable to proliferate and survive. For example, antimetabolites exert cytotoxic activity by displacing these spurious nucleotides into the cell's DNA, thereby preventing cell division, or inhibiting DNA replication by inhibiting essential intracellular enzymes. .

Thus, in one embodiment, the antimetabolite is a nucleotide or nucleotide analogue. In certain embodiments, for example, the antimetabolite agent includes or includes a purine (e.g., guanine or adenosine) or analogue thereof, or a pyrimidine (cytidine or thymidine) or analogue thereof (with a sugar moiety attached). not) can be included.

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

In certain embodiments, for example, the antimetabolite is a cytidine analogue. According to this embodiment, for example, said cytidine analogue may be selected from the group consisting of cytarabine (cytosine arabinoside), azacytidine (5-azacytidine), and salts, analogues and derivatives thereof.

In another embodiment, for example, the antimetabolite is a folic acid analogue. Folate analogs or antifolates generally work by inhibiting dihydrofolate reductase (DHFR), an enzyme involved in the formation of nucleotides (when this enzyme is inhibited, nucleotides are not formed and DNA replication and inhibit cell division). According to some embodiments, for example, the folic acid analogue may be selected from the group consisting of denopterin, methotrexate (ametopterin), pemetrexed, pteropterin, raltitrexed, trimetrexate, and salts, analogues, and derivatives thereof. .

In another embodiment, for example, the antimetabolite is a purine analogue. Purine-based antimetabolites function by inhibiting DNA synthesis, for example, by preventing the production of the purine-containing nucleotides adenine and guanine, halting DNA synthesis and thereby inhibiting cell division. Purine analogues can also be incorporated into the DNA molecule itself during DNA synthesis and interfere with cell division. In one embodiment, for example, the purine analogue is acyclovir, allopurinol, 2-aminoadenosine, arabinosyl adenine (ara-A), azacytidine, 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 diline acid, guanosine diphosphate-beta-L-2-aminofucose, guanosine diphosphate-D-arabinose, guanosine diphosphate-2-fluorofucose, guanosine diphosphate fucose, mercaptopurine (6-MP), pento It may be selected from the group consisting of statins, amipurine, thioguanine (6-TG), and salts, analogues and derivatives thereof.

In yet another embodiment, for example, the antimetabolite is a pyrimidine analogue. Similar to the purine analogues described above, pyrimidine-based antimetabolites interfere with the synthesis of pyrimidine-containing nucleotides (cytosine and thymine in DNA; cytosine and uracil in RNA). By acting as "decoys," said pyrimidine-based compounds can interfere with the production of nucleotides and/or can be incorporated into growing DNA strands, causing their termination. In one embodiment, for example, the pyrimidine analogue is ancitabine, azacitidine, 6-azauridine, bromouracil (eg, 5-bromouracil), capecitabine, carmofur, chlorouracil (eg, 5-chlorouracil), cytarabine. (cytosine arabinoside), cytosine, dideoxyuridine, 3'-azido-3'-deoxythymidine, 3'-dideoxycytidine-2'-ene, 3'-deoxy-3'-deoxythymidine-2'-ene, dihydrouracil, doxifluridine, enocitabine, floxyuridine, 5-fluorocytosine, 2-fluorodeoxycytidine, 3-fluoro-3′-deoxythymidine, fluorouracil (e.g., 5-fluorouracil (also known as 5-FU), gemcitabine, 5-fluorouracil) may be selected from the group consisting of methylcytosine, 5-propynylcytosine, 5-propynylthymine, 5-propynyluracil, thymine, uracil, uridine, and salts, analogues and derivatives thereof.In one embodiment, Said pyrimidine analogue is other than 5-fluorouracil, hi another embodiment, said pyrimidine analogue is gemcitabine or a salt thereof.

In certain embodiments, the antimetabolite agent is selected from the group consisting of 5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine, pemetrexed, and salts, analogs, derivatives, and combinations thereof. be. In another embodiment, said antimetabolite is selected from the group consisting of capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine, pemetrexed, and salts, analogs, derivatives and combinations thereof. In certain embodiments, said antimetabolite is other than 5-fluorouracil. In a particularly preferred embodiment, the antimetabolite is gemcitabine or a salt thereof (eg, gemcitabine HCl (Gemzar®)).

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, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, Wellcome EHNA (Merck & Co), EX-015, fazarabine, fludarabine phosphate, N-(2′-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO -152,5-FU-Fibrinogen, Isopropylpyrrolidine, Lilly LY-188011; Lilly LY-264618, metobenzaprim, Wellcome MZPES, Norspermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-39661 -612567, Warner-Lambert PALA, pentostatin, pyritrexime, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, tiazofurin, Erbamont TIF, tyrosine kinase inhibitors, Taiho UFT and uricitin, etc. good.

In one embodiment, the chemotherapeutic agents include antimitotic agents that are microtubule inhibitors or microtubule-stabilizing agents. In general, microtubule stabilizing agents, such as taxanes (any of those also listed above) and epothilones, bind to the inner surface of beta-microtubule chains and promote the nucleation and elongation phases of the polymerization reaction. , enhances microtubule assembly by lowering the concentration of critical tubulin subunits required to assemble microtubules. Unlike microtubule inhibitors (e.g., vinca alkaloids, which inhibit microtubule assembly), microtubule stabilizing agents (e.g., taxanes) reduce the lag time and prevent tubulin dimers and microtubules from polymerizing. Dramatically alters the dynamic equilibrium between polymers. Therefore, in one embodiment, the microtubule stabilizing agent is a taxane or an epothilone. In another embodiment, the microtubule inhibitor is a vinca alkaloid.

One component of therapy described herein may include the use of taxanes or derivatives or analogs thereof, some of which are described above. In one embodiment, the taxane can be a naturally occurring compound or related form, or can be a chemically synthesized compound or derivative thereof that has antineoplastic properties. Taxanes are a family of terpenes, including but not limited to paclitaxel (Taxol®) and docetaxel (Taxotere®), originally derived from the Pacific yew (Taxus brevifolia). , has activity against certain tumors, particularly breast and ovarian tumors. In one embodiment, the taxane is docetaxel or paclitaxel. Paclitaxel is a preferred taxane and is considered an antimitotic agent that promotes assembly of microtubules from tubulin dimers and stabilizes microtubules by inhibiting their depolymerization. This stability inhibits the normal and dynamic reorganization of the microtubule network, which is essential for vital intercellular phase and mitotic cell functions.

Various known taxane derivatives, including hydrophilic and hydrophobic derivatives, are also included. Taxane derivatives include, but are not limited to, galactose and mannose derivatives as described in International Patent Application No. WO99/18113; piperazino and other derivatives as described in WO99/14209; 6-thio derivatives as described in WO98/28288; sulfenamide derivatives as described in US Pat. No. 5,821,263; deoxygenated paclitaxel compounds such as US Pat. 5,440,056; and taxol derivatives described in US Pat. No. 5,415,869. Further included are prodrugs of paclitaxel, as described above, including but not limited to those described in WO98/58927; WO98/13059; and US Pat. 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, and the like. Other derivatives are described in "Synthesis and Anticancer Activity of Taxol Derivatives," D. G. I. Kingston et al., Studies in Organic Chemistry, vol. 26, entitled "New Trends in Natural Products Chemistry" (1986), Atta-ur-Rabman, P. W. le Quesne, Eds. (Elsevier, Amsterdam 1986). Each of these documents is hereby incorporated by reference in its entirety.

Various taxanes may be readily prepared using techniques known to those skilled in the art (WO94/07882, WO94/07881, WO94/07880, WO94/07876, WO93/23555, WO93/10076; US Pat. 294,637; 5,283,253; 5,279,949; 5,274,137; 5,202,448; 5,200,534; (each of which is incorporated herein by reference in its entirety) or may be obtained from various commercial sources (including, for example, Sigma-Aldrich Co., St. Louis, Missouri).

Alternatively, said antimitotic agent may be an anti-microtubule agent; in one preferred embodiment, said anti-microtubule agent is a vinca alkaloid. In general, the vinca alkaloids are spindle poisons. The vinca alkaloid drug acts during mitosis when chromosomes divide and begin to move along the mitotic spindle tube toward one of its poles before the cell divides. Under the action of these spindle toxins, the spindle is disrupted by the dispersal of chromosomes during mitosis, affecting cell replication. In one embodiment, for example, said vinca alkaloid is selected from the group consisting of vinblastine, vincristine, vindesine, vinorelbine, and salts, analogues and derivatives thereof.

The antimitotic agent can also be epothilone. In general, members of the epothilone class of compounds stabilize microtubule function by mechanisms analogous to those of taxanes. Epothilone can also arrest the cell cycle at the G2-M transition, causing cytotoxicity and ultimately apoptosis. Suitable epothilones include epothilone A, epothilone B, epothilone C, epothilone D, epothilone E and epothilone F, and salts, analogs and derivatives thereof. One particular epothilone analogue is the epothilone B analogue, ixabepilone (Exempra®).

In some embodiments, the antimitotic anticancer agent is selected from the group consisting of taxanes, epothilones, vinca alkaloids, and salts and combinations thereof. Thus, for example, in one embodiment the antimitotic agent is a taxane. More preferably, in this embodiment, the antimitotic agent is paclitaxel or docetaxel, even more preferably paclitaxel. In another aspect, the antimitotic agent is an epothilone (eg, an epothilone B analogue). In another embodiment, the antimitotic agent is a vinca alkaloid.

In one embodiment, at least one of the pentaazamacrocycle conjugate and the platinum-based anticancer agent is administered within a period of time before or after the dose of the additional chemotherapeutic agent is administered. For example, a pentaazamacrocyclic ring conjugate and a platinum-based anti-cancer agent may be administered for 1 week, 48 hours, 24 hours, 12 hours, 1 week, 48 hours, 24 hours, 12 hours, or 12 hours after the patient receives an additional chemotherapeutic agent (either before or after dosing of the chemotherapeutic agent). It may be administered within 6 hours, 2 hours, 1 hour, or even 30 minutes. Other periods of time between administration of the additional chemotherapeutic agent that enhances cancer cell killing and administration of the component may also be appropriate. In one embodiment, one or more of the pentaazamacrocycle conjugate and the platinum-based anticancer agent may be administered prior to dosing of the additional chemotherapeutic agent, wherein the pentaazamacrocycle conjugate and The remaining one or more of the platinum-based anticancer agents can be administered after dosing of the additional chemotherapeutic agents. One or more of the pentaazamacrocyclic ring conjugate and platinum-based anticancer agent may also be administered both before or after administration of the dose of the additional chemotherapeutic agent.

In one embodiment, the course of chemotherapy includes a single dose of an additional chemotherapeutic agent. In another embodiment, the course of chemotherapy includes multiple doses of an additional chemotherapeutic agent given over a period of time, eg, hours, weeks, days, or even months. Multiple doses may be of the same or different doses and may include dosing of the same or different chemotherapeutic agents and/or combinations of chemotherapeutic agents. Administration of pentaaza-macrocyclic ring complexes and platinum-based anticancer agents during the course of chemotherapy, e.g., chemotherapeutic cancer by increasing intracellular hydrogen peroxide levels to promote oxidative stress in cancer cells. Can be selected to enhance therapeutic efficacy. In one embodiment, the pentaazamacrocycle conjugate and the platinum-based anticancer agent are administered for a predetermined period of time before or after each dose, eg, within the period of time described above. In another embodiment, the pentaazamacrocycle conjugate and platinum-based anticancer agent are administered only within a predetermined period of time before or after the selected dose. In yet another embodiment, at least one of the pentaazamacrocycle conjugate and the platinum-based anticancer agent is administered within a predetermined period of time prior to dosing while the other pentaazamacrocycle conjugate and platinum are administered. based anticancer agents are administered within a predetermined period of time after dosing. In a further embodiment, at least one of the pentaazamacrocycle conjugate and the platinum-based anticancer agent is administered only within a predetermined period of time before or after the selected dose, while the other pentaazamacrocycle conjugate The body and platinum-based anticancer agents are administered only within a predetermined period of time before or after dosing other than the selected dosing.

In yet another embodiment, at least one of the pentaazamacrocycle conjugate and the platinum-based anticancer agent are administered in combination with both radiation therapy and chemotherapy (for administration of additional chemotherapeutic agents). .

EXAMPLES The following non-limiting examples are provided to further illustrate aspects of the present invention. The techniques disclosed in the examples which follow demonstrate that the methods discovered by the inventors can be well employed in the practice of the invention, and can therefore be considered to constitute examples of its modes of practice. should be evaluated by those skilled in the art. However, those skilled in the art should recognize, in light of the present disclosure, that many changes may be made in the specific embodiments disclosed, similar or modified without departing from the spirit and scope of the invention. Similar results can be obtained.

Synergistic effect of anti-cancer treatment Example 1
Effect of GC4419 and Cisplatin on Cancer Cell Survival in Culture H460 human non-small cell lung cancer (NSCLC) cells in culture were treated with 24 μM GC4419 (+GC) or culture (−GC) and the indicated concentrations of cisplatin. After 120 hours, the surviving fraction of cells was examined. Addition of GC4419 to cisplatin treatment reduced the viable fraction of H460 cells compared to cells treated with cisplatin alone. GC4419 markedly sensitized H460 lung cancer cells to cisplatin (see Figure 1: Effect of GC4419 and cisplatin on survival of H460 cells in culture).

Example 2
Effect of GC4419, Cisplatin and Catalase Overexpression on Cancer Cell Survival in Culture H1299 human NSCLC cells modified to inducibly overexpress catalase (CAT), which scavenges hydrogen peroxide ( _{H2O2 )} . , 24 μM GC4419 (+GC) or medium (−GC) and the indicated concentrations of cisplatin in cell culture medium. CAT overexpression in this strain (H1299CAT) was induced by administration of doxycycline to turn on transcription of the inserted catalase gene. After 120 hours of treatment with cisplatin in the presence or absence of GC4419, the viable fraction of H1299CAT cells was examined both in the presence and absence of CAT overexpression. In the absence of CAT overexpression (“wt”), addition of GC4419 to cisplatin treatment increased survival of H460 cells similar to H460 cells when treated with both GC4419 and cisplatin, compared to cells treated with cisplatin alone. Fraction decreased. In contrast, CAT overexpression (“CAT” that removes H ₂ O ₂ generated from superoxide by GC4419) suppressed the contribution of GC4419 to the cisplatin response, and GC4419 increased the sensitivity of H460 lung cancer cells to cisplatin. and this enhanced reactivity was shown to be H ₂ O ₂ -dependent (see Figure 2: Effect of GC4419, cisplatin and catalase overexpression of H1299CAT cells in culture).

Example 3
Effect 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. At this time, cells were lysed and PARP (poly(ADP-ribosyl)polymerase) activity was measured by Western blot as the ratio of 89 kd active to 116 kd inactive form. 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 enhanced PARP activity compared to untreated cells or GC4419 treatment alone. Further addition of GC4419 to cisplatin significantly enhanced PARP activity (p<0.01), indicating that GC4419 enhanced cancer cell injury caused by cisplatin (Figure 3: PARP activity in H460 cells). See Effects of GC4419 and Cisplatin).

H1299 (wild-type) NSCLC cells in culture were also treated with 24 μM GC4419 and 10 μM cisplatin for 24 hours. At this time, cells were lysed and PARP activity was measured by Western blot as the ratio of 89 kd active to 116 kd inactive form. Consistent with the effect shown in Figure 4 and demonstrated in H460 lung cancer cells, cisplatin enhanced PARP activity compared to untreated cells or GC4419 treatment alone. Further addition of GC4419 to cisplatin significantly enhanced PARP activity (p<0.01), indicating that GC4419 enhanced cancer cell injury induced by cisplatin (Figure 4: PARP activity in H1299 cells). See Effects of GC4419 and Cisplatin).

H460 cells in culture were exposed to 6 Gy of irradiation (IR) and either 24 μM GC4419, 1 μM cisplatin, or GC4419 and cisplatin for an additional 24 hours. At this time, cells were lysed and PARP activity was measured by Western blot as the ratio of 89 kd active to 116 kd inactive form. As shown in Figure 5, radiation (IR) alone significantly enhanced PARP activity above background (p<0.05). Addition of GC4419 to IR significantly enhanced PARP activity over that seen with radiation alone. The addition of cisplatin to IR significantly enhanced PARP activity, and the addition of GC4419 to this combination significantly enhanced this (p<0.01), indicating that GC4419 enhances radiation- and cisplatin-induced cancer cell injury. (see FIG. 5: Effect of GC4419, cisplatin, and radiation on PARP activity in H460 cells).

H1299 (wild-type) cells in culture were also exposed to 6 Gy of radiation (IR) and either 24 μM GC4419, 1 μM cisplatin, or GC4419 and cisplatin for 24 hours. At this time, cells were lysed and PARP activity was measured by Western blot as the ratio of 89 kd active to 116 kd inactive. Radiation (IR) alone significantly enhanced PARP activity above background, consistent with the effect shown in FIG. 6A and shown in H460 lung cancer cells. The addition of cisplatin to IR significantly enhanced PARP activity, and the addition of GC4419 to this combination significantly enhanced it (p<.0.05), indicating that GC4419 inhibited cancer cell injury caused by radiation and cisplatin. (see FIG. 6A: Effect of GC4419, cisplatin, and radiation on PARP activity in H1299 cells).

H1299CAT cells were also exposed to 6 Gy radiation (IR), 24 μM GC4419, and/or 1 μM cisplatin for 24 hours. When treated with doxycycline, H1299CAT cells expressed higher levels of human catalase (CAT) than the 'parental' cells H1299 (wild-type), and H1299 generated from superoxide by GC4419 or other Mn pentaazamacrocyclic dismutase mimics. Remove all or part of ₂ 0 ₂ . PARP activation in H1299CAT cells not exposed to doxycycline (data not shown) was responsive to cisplatin, IR, and GC4419 treatment compared to H1299 wild-type cells (see Figure 5). However, when CAT expression was induced in H1299CAT with doxycycline treatment, GC4419 increased cisplatin (p<0.01, FIG. 6B), IR (p<0.05, FIG. 6C) and IR+cisplatin (p<0.001, 6C) significantly decreased PARP activation (p<0.05). These results demonstrate that cisplatin-generated superoxide causes cytotoxicity, and GC4419 removal of this superoxide reduces cytotoxicity, with results described in Example 5 below for reduced cisplatin nephrotoxicity and hematotoxicity. It is strongly suggested that However, since GC4419 enhanced PARP for cisplatin in cancer cells, except when H ₂ O ₂ was ablated by CAT overexpression, these results suggest that GC4419-generated H ₂ O ₂ (by CAT (if not removed) was associated with greater enhancement of cisplatin cytotoxicity and PARP activity than the superoxide it replaced (Fig. 6B: by cisplatin and GC4419 (with doxycycline induction of CAT overexpression)). Treatment of H1299CAT cells; and FIG. 6C: treatment of H1299CAT cells with cisplatin, IR, and GC4419 (with doxycycline induction of CAT overexpression).

Example 4
Cisplatin treatment increases total reactive oxygen species (ROS) levels in cancer cells, whereas GC4419 selectively decreases _superoxide and increases _H2O2 levels. IR) and either 24 μM GC4419, 1 μM cisplatin, or GC4419 plus cisplatin. After the treatment and incubation, a CellROX fluorogenic probe for total ROS was added, allowed to incubate 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 either cancer cell line, whereas cisplatin or cisplatin and IR increased total ROS. GC4419 could show a synergistic effect on total ROS when added to cisplatin treatment (see Figures 7A-7D: Total Reactive Oxygen Species).

Alternatively, after treatment and initial incubation, a MitoSOX fluorogenic probe for mitochondrial superoxide was added, incubation continued for 10 min, and the MitoSOX signal was measured using a flow cytometer. Figures 8A-8D show that GC4419 significantly decreased basal levels 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).

Alternatively, a PO-1 probe for H ₂ O ₂ was added after treatment and initial incubation. Figures 9A _- 9D show that GC4419 significantly enhances both basal levels of _H2O2 and even significantly enhances the increase in _H2O2 produced by cisplatin or cisplatin and IR in both cancer cell lines ₍ Fig. 9A-9D). 9A-9D: see hydrogen peroxide).

Reduction of Toxicity of Platinum-Based Anticancer Agents Example 5
Effects of GC4419 on Cisplatin-Induced Nephrotoxicity in Mice Four-month-old male C57BL/6J mice (young) were purchased from Jackson Laboratories and 18-month-old mice (old) were obtained from the National Institute on Aging by Dr. Amy Schindler (University of Iowa). ) as a joint research. All mice were maintained according to ACURF approval #4121235 at the University of Iowa Animal Care Facility. Mice were maintained on normal chow and water ad libitum throughout the course of the experiment. Animals were randomized into experimental groups including vehicle control, cisplatin only, GC4419, and cisplatin plus GC4419.

The cisplatin-induced acute kidney injury (AKI) model was as follows: 4-month-old or 18-month-old male C57BL/6J mice received 10 mg/kg cisplatin or 0.9% saline by intraperitoneal injection. was administered in a single dose of Animals were euthanized 72 hours after cisplatin treatment. Animals in the GC4419 only and cisplatin+GC4419 groups were treated daily with 10 mg/kg GC4419 beginning 4 days prior to cisplatin dosing until the day of euthanasia. Animals in the cisplatin group only also received a bolus dose of saline daily after cisplatin treatment to prevent dehydration.

Whole blood blood urea nitrogen (BUN) and creatinine levels were measured by Abbott-Point of Care (New Jersey) using single-use i-STAT test cartridges (Chem8+) prior to initiation of treatment with GC4419 and 72 hours after cisplatin treatment. Measured using an i-STAT handheld clinical analyzer purchased from (Princeton, NY). Animals were weighed every other day after initiation of treatment with GC4419.

As shown in FIG. 10A, cisplatin increased BUN and creatinine levels in young mice, and more dramatically in old mice, on day 3 of dosing, indicating marked impairment of renal function. GC4419 completely prevented these increases in BUN and creatinine, indicating that it reduces acute kidney injury (see FIG. 10A: BUN and creatinine levels in mice treated with cisplatin).

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

Further consistent with these renal impairment and functional consequences, cisplatin caused significant weight loss in both young and aged mice (Fig. 10C) and decreased survival in the more susceptible aged mice (Fig. 10D). ). GC4419 reduced the amount of weight loss in both sets of mice and suppressed cisplatin mortality in aged mice (Fig. 10C: cisplatin-induced weight loss; reference).

Furthermore, consistent with these renal impairment and functional consequences, cisplatin caused significant weight loss in both young and aged mice (Fig. 10C) and decreased survival in the more susceptible aged mice (Fig. 10D). . GC4419 reduced the amount of weight loss in both sets of mice and suppressed cisplatin mortality in aged mice.

Example 6
Effect of GC4419 on Cisplatin-Induced Hematotoxicity in Mice Seven-week-old athymic female Nu/Nu (nude) mice were transplanted with SQ20B human head and neck squamous cell carcinoma cells in the hind limbs. Tumors formed and were allowed to grow in 4 days and the mice received no treatment or 2.7 mg/kg cisplatin and 2 Gy radiation (IR) 5 times every 2 or 3 days. In addition, the group that received cisplatin and IR treatment also received 10 mg/kg GC4419 daily during the treatment period and for two days thereafter. Mice were evaluated for blood counts by tail vein bleeds after 2 days or 2 weeks of the treatment period.

As shown in Figure 11A, cisplatin plus IR treatment resulted in a decrease in platelets (thrombocytopenia) measured two days after the end of treatment, and GC4419 significantly restored platelet levels (Figure 11A: Cisplatin-induced platelet See Hypochondriasis).

As shown in FIG. 11B, GC4419 treatment reduced the production of lymphocytes (WBCs) and relative lymphocyte subpopulations in mice treated with the combination of cisplatin and radiation both 2 days and 2 weeks after the end of treatment. (see FIG. 11B: GC4419 and WBC counts).

As shown in FIG. 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, and GC4419 revealed neutrophil percentage. remained at normal levels (see Figure 11C: Cisplatin-induced neutropenia).

Conversely, as shown in FIG. 11D, cisplatin+IR treatment produced an increase in eosinophil percentage measured 2 days or 2 weeks after the end of treatment, and GC4419 kept eosinophil percentage at apparently normal levels. (See FIG. 11D: Cisplatin-induced eosinophilia).

The following are exemplary implementations of aspects of the disclosure, and are not intended to be limiting, as the disclosure may include additional aspects.

（Ｉ）
［式中、
Ｍは、Ｍｎ^２＋またはＭｎ^３＋であり；
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は、独立して、水素、ヒドロカルビル、置換ヒドロカルビル、ヘテロサイクリル、アミノ酸側鎖部分、あるいは－ＯＲ_１１、－ＮＲ_１１Ｒ_１２、－ＣＯＲ_１１、－ＣＯ_２Ｒ_１１、－ＣＯＮＲ_１１Ｒ_１２、－ＳＲ_１１、－ＳＯＲ_１１、－ＳＯ_２Ｒ_１１、－ＳＯ_２ＮＲ_１１Ｒ_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は、前記大環状環の隣接する炭素原子と一緒になって、３～２０個の環炭素原子を有する縮合された置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の環もしくはヘテロ環を形成し；
Ｖは、前記大環状環の隣接する炭素原子と一緒になって、３～２０個の環炭素原子を有する縮合された置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の環もしくはヘテロ環を形成し；
Ｗは、前記大環状環の窒素およびそれが結合している前記大環状環の炭素原子と一緒になって、２～２０個の環炭素原子を有する芳香族もしくは脂環式の置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の窒素含有縮合ヘテロ環を形成するが、但し、Ｗが、縮合された芳香族ヘテロ環である場合、ヘテロ環および前記大環状環の両方の部分である窒素に結合している水素、ならびにヘテロ環および前記大環状環の両方の部分である炭素原子に結合しているＲ_１およびＲ_１０は、非存在であるものとし；
ＸおよびＹは、単座もしくは多座配位子もしくは配位子系に由来する適切な配位子のいずれか、またはそれに相当するアニオンを表し；
Ｚは、対イオンであり；
ｎは、０～３の整数であり；ならびに
点線は、前記大環状環の窒素原子と遷移金属（マンガン）との配位結合を表す］ Embodiment 1
A method of treating and/or reducing toxic effects in a mammalian subject associated with treatment with a platinum-based anticancer agent in a subject in need thereof, comprising: administering to said subject a platinum-based anti-cancer agent of: or administering to said subject after administration to reduce the toxic effects of a platinum-based anticancer agent.

(I)
[In the formula,
M is Mn ²⁺ or Mn ³⁺ ;
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 are independently is hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moieties, 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 ₁₁ )(OR ₁₂ ), wherein R ₁₁ and R ₁₂ are independently hydrogen or alkyl;
U is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
V is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
W, together with the macrocyclic ring nitrogen and the macrocyclic ring carbon atom to which it is attached, is an aromatic or alicyclic substituted or unsubstituted aromatic or alicyclic ring having 2 to 20 ring carbon atoms; with the proviso that when W is a fused aromatic heterocycle, it is part of both the heterocycle and said macrocycle hydrogen attached to nitrogen and R ₁ and R ₁₀ attached to carbon atoms that are part of both the heterocycle and said macrocycle shall be absent;
X and Y represent any suitable ligand from a monodentate or polydentate ligand or ligand system, or the corresponding anion;
Z is a 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)]

Embodiment 2
3. The method of embodiment 1, wherein said subject has cancer.

Embodiment 3
said subject is suffering from and/or at risk of suffering from a toxicity (a toxicity selected from the group consisting of nephrotoxicity, bone marrow toxicity and ototoxicity) induced by treatment with a platinum-based anticancer agent 3. The method of embodiment 1 or 2, wherein

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

Embodiment 5
5. The method of any of embodiments 1-4, wherein said subject suffers from nephrotoxicity and/or bone marrow toxicity associated with treatment with said platinum-based anticancer agent.

Embodiment 6
6. Any of embodiments 1-5, comprising administering a therapeutically effective amount of the platinum-based anticancer agent and a pentaazamacrocyclic ring conjugate that enhances therapeutic responsiveness to the platinum-based anticancer agent. the method of.

Embodiment 7
said pentaaza-macrocyclic ring conjugate is selected from the group consisting of reduced tumor volume, reduced tumor growth rate, increased survival rate, reduced incidence and/or extent of metastasis, and reduced cell proliferation of cancer cells. 7. The method of any of embodiments 1-6, administered in a therapeutically effective amount to enhance a cancer response corresponding to any.

Embodiment 8
8. The method of any of embodiments 1-7, wherein the pentaazamacrocycle is administered in a therapeutically effective amount to reduce levels of at least one of creatine and blood urea nitrogen (BUN).

Embodiment 9
wherein said pentaazamacrocycle is administered in a therapeutically effective amount to reduce the levels of a marker for kidney damage selected from the group consisting of kidney damage molecule 1 (KIM1) and neutrophil gelatinase-binding lipocalin (NGAL). 9. The method of any one of embodiments 1-8, wherein the method is

（Ｉ）
［式中、
Ｍは、Ｍｎ^２＋またはＭｎ^３＋であり；
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は、独立して、水素、ヒドロカルビル、置換ヒドロカルビル、ヘテロサイクリル、アミノ酸側鎖部分、あるいは－ＯＲ_１１、－ＮＲ_１１Ｒ_１２、－ＣＯＲ_１１、－ＣＯ_２Ｒ_１１、－ＣＯＮＲ_１１Ｒ_１２、－ＳＲ_１１、－ＳＯＲ_１１、－ＳＯ_２Ｒ_１１、－ＳＯ_２ＮＲ_１１Ｒ_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は、前記大環状環の隣接する炭素原子と一緒になって、３～２０個の環炭素原子を有する縮合された置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の環もしくはヘテロ環を形成し；
Ｖは、前記大環状環の隣接する炭素原子と一緒になって、３～２０個の環炭素原子を有する縮合された置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の環もしくはヘテロ環を形成し；
Ｗは、前記大環状環の窒素およびそれが結合している前記大環状環の炭素原子と一緒になって、２～２０個の環炭素原子を有する芳香族もしくは脂環式の置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の窒素含有縮合ヘテロ環を形成するが、但し、Ｗが、縮合された芳香族ヘテロ環である場合、ヘテロ環および前記大環状環の両方の部分である窒素に結合している水素、ならびにヘテロ環および前記大環状環の両方の部分である炭素原子に結合しているＲ_１およびＲ_１０は、非存在であるものとし；
ＸおよびＹは、単座もしくは多座配位子もしくは配位子系に由来する適切な配位子のいずれか、またはそれに相当するアニオンを表し；
Ｚは、対イオンであり；
ｎは、０～３の整数であり；ならびに
点線は、前記大環状環の窒素原子と遷移金属（マンガン）との配位結合を表す］ Embodiment 10
A method of treating and/or reducing the risk of toxic effects associated with treatment with a platinum-based anticancer agent in a mammalian subject in need thereof, wherein: is administered prior to, concurrently with, or after administration of a platinum-based anticancer agent to reduce the toxic effects of said platinum-based anticancer agent. Method.

(I)
[In the formula,
M is Mn ²⁺ or Mn ³⁺ ;
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 are independently is hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moieties, 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 ₁₁ )(OR ₁₂ ), wherein R ₁₁ and R ₁₂ are independently hydrogen or alkyl;
U is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
V is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
W, together with the macrocyclic ring nitrogen and the macrocyclic ring carbon atom to which it is attached, is an aromatic or alicyclic substituted or unsubstituted aromatic or alicyclic ring having 2 to 20 ring carbon atoms; with the proviso that when W is a fused aromatic heterocycle, it is part of both the heterocycle and said macrocycle hydrogen attached to nitrogen and R ₁ and R ₁₀ attached to carbon atoms that are part of both the heterocycle and said macrocycle shall be absent;
X and Y represent any suitable ligand from a monodentate or polydentate ligand or ligand system, or the corresponding anion;
Z is a 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)]

Embodiment 11
11. The method of embodiment 10, wherein said subject has cancer.

Embodiment 12
said subject is suffering from and/or at risk of suffering from a toxicity (a toxicity selected from the group consisting of nephrotoxicity, bone marrow toxicity and ototoxicity) induced by treatment with a platinum-based anticancer agent 12. A method according to embodiment 10 or 11, wherein

Embodiment 13
13. The method of any of embodiments 10-12, wherein said subject is suffering from and/or at risk of suffering from one of nephrotoxicity and myelotoxicity.

Embodiment 14
14. The method of any of embodiments 10-13, wherein said subject suffers from nephrotoxicity and/or bone marrow toxicity associated with treatment with said platinum-based anticancer agent.

Embodiment 15
15. Any of embodiments 10-14, comprising administering a therapeutically effective amount of said platinum-based anticancer agent and a pentaazamacrocyclic ring conjugate that enhances therapeutic responsiveness to said platinum-based anticancer agent. the method of.

Embodiment 16
said pentaaza-macrocyclic ring conjugate is selected from the group consisting of reduced tumor volume, reduced tumor growth rate, increased survival rate, reduced incidence and/or extent of metastasis, and reduced cell proliferation of cancer cells. 16. The method of any of embodiments 10-15, administered in a therapeutically effective amount to enhance the cancer response corresponding to any.

Embodiment 17
17. The method of any of embodiments 10-16, wherein said pentaazamacrocycle is administered in a therapeutically effective amount to reduce levels of at least one of creatine and blood urea nitrogen (BUN).

Embodiment 18
wherein said pentaazamacrocycle is administered in a therapeutically effective amount to reduce the levels of a marker for kidney damage selected from the group consisting of kidney damage molecule 1 (KIM1) and neutrophil gelatinase-binding lipocalin (NGAL). 18. The method of any of embodiments 10-17, wherein

（Ｉ）
［式中、
Ｍは、Ｍｎ^２＋またはＭｎ^３＋であり；
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は、独立して、水素、ヒドロカルビル、置換ヒドロカルビル、ヘテロサイクリル、アミノ酸側鎖部分、あるいは－ＯＲ_１１、－ＮＲ_１１Ｒ_１２、－ＣＯＲ_１１、－ＣＯ_２Ｒ_１１、－ＣＯＮＲ_１１Ｒ_１２、－ＳＲ_１１、－ＳＯＲ_１１、－ＳＯ_２Ｒ_１１、－ＳＯ_２ＮＲ_１１Ｒ_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は、前記大環状環の隣接する炭素原子と一緒になって、３～２０個の環炭素原子を有する縮合された置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の環もしくはヘテロ環を形成し；
Ｖは、前記大環状環の隣接する炭素原子と一緒になって、３～２０個の環炭素原子を有する縮合された置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の環もしくはヘテロ環を形成し；
Ｗは、前記大環状環の窒素およびそれが結合している前記大環状環の炭素原子と一緒になって、２～２０個の環炭素原子を有する芳香族もしくは脂環式の置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の窒素含有縮合ヘテロ環を形成するが、但し、Ｗが、縮合された芳香族ヘテロ環である場合、ヘテロ環および前記大環状環の両方の部分である窒素に結合している水素、ならびにヘテロ環および前記大環状環の両方の部分である炭素原子に結合しているＲ_１およびＲ_１０は、非存在であるものとし；
ＸおよびＹは、単座もしくは多座配位子もしくは配位子系に由来する適切な配位子のいずれか、またはそれに相当するアニオンを表し；
Ｚは、対イオンであり；
ｎは、０～３の整数であり；ならびに
点線は、前記大環状環の窒素原子と遷移金属（マンガン）との配位結合を表す］ Embodiment 19
A method of treating cancer in a mammalian subject with cancer comprising:
administering to said subject a therapeutically effective amount of a platinum-based anti-cancer agent;
A therapeutically effective amount of a pentaaza macrocycle conjugate corresponding to formula (I) below is administered to said subject prior to, concurrently with, or after administration of said platinum-based anticancer agent, thereby treating said cancer increasing responsiveness to said platinum-based anti-cancer agent.

(I)
[In the formula,
M is Mn ²⁺ or Mn ³⁺ ;
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 are independently is hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moieties, 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 ₁₁ )(OR ₁₂ ), wherein R ₁₁ and R ₁₂ are independently hydrogen or alkyl;
U is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
V is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
W, together with the macrocyclic ring nitrogen and the macrocyclic ring carbon atom to which it is attached, is an aromatic or alicyclic substituted or unsubstituted aromatic or alicyclic ring having 2 to 20 ring carbon atoms; with the proviso that when W is a fused aromatic heterocycle, it is part of both the heterocycle and said macrocycle hydrogen attached to nitrogen and R ₁ and R ₁₀ attached to carbon atoms that are part of both the heterocycle and said macrocycle shall be absent;
X and Y represent any suitable ligand from a monodentate or polydentate ligand or ligand system, or the corresponding anion;
Z is a 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)]

Embodiment 20
20. The method of embodiment 19, comprising administering a therapeutically effective amount of said platinum-based anticancer agent and a pentaazamacrocyclic ring complex that reduces the toxic effects of said platinum-based anticancer agent.

Embodiment 21
said pentaaza-macrocyclic ring conjugate is selected from the group consisting of reduced tumor volume, reduced tumor growth rate, increased survival rate, reduced incidence and/or extent of metastasis, and reduced cell proliferation of cancer cells. 21. A method according to embodiment 19 or 20, administered in a therapeutically effective amount capable of enhancing either corresponding cancer response and/or reducing cancer complications.

Embodiment 22
22. The method of any of embodiments 19-21, wherein said pentaazamacrocycle is administered in a therapeutically effective amount to reduce levels of at least one of creatine and blood urea nitrogen (BUN).

Embodiment 23
wherein said pentaazamacrocycle is administered in a therapeutically effective amount to reduce the levels of a marker for kidney damage selected from the group consisting of kidney damage molecule 1 (KIM1) and neutrophil gelatinase-binding lipocalin (NGAL). 23. The method of any of embodiments 19-22, wherein

（Ｉ）
［式中、
Ｍは、Ｍｎ^２＋またはＭｎ^３＋であり；
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は、独立して、水素、ヒドロカルビル、置換ヒドロカルビル、ヘテロサイクリル、アミノ酸側鎖部分、あるいは－ＯＲ_１１、－ＮＲ_１１Ｒ_１２、－ＣＯＲ_１１、－ＣＯ_２Ｒ_１１、－ＣＯＮＲ_１１Ｒ_１２、－ＳＲ_１１、－ＳＯＲ_１１、－ＳＯ_２Ｒ_１１、－ＳＯ_２ＮＲ_１１Ｒ_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は、前記大環状環の隣接する炭素原子と一緒になって、３～２０個の環炭素原子を有する縮合された置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の環もしくはヘテロ環を形成し；
Ｖは、前記大環状環の隣接する炭素原子と一緒になって、３～２０個の環炭素原子を有する縮合された置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の環もしくはヘテロ環を形成し；
Ｗは、前記大環状環の窒素およびそれが結合している前記大環状環の炭素原子と一緒になって、２～２０個の環炭素原子を有する芳香族もしくは脂環式の置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の窒素含有縮合ヘテロ環を形成するが、但し、Ｗが、縮合された芳香族ヘテロ環である場合、ヘテロ環および前記大環状環の両方の部分である窒素に結合している水素、ならびにヘテロ環および前記大環状環の両方の部分である炭素原子に結合しているＲ_１およびＲ_１０は、非存在であるものとし；
ＸおよびＹは、単座もしくは多座配位子もしくは配位子系に由来する適切な配位子のいずれか、またはそれに相当するアニオンを表し；
Ｚは、対イオンであり；
ｎは、０～３の整数であり；ならびに
点線は、前記大環状環の窒素原子と遷移金属（マンガン）との配位結合を表す］ Embodiment 24
A method of sensitizing a mammalian subject to treatment with a platinum-based anticancer agent in a subject in need thereof, comprising:
A therapeutically effective amount of a pentaaza macrocycle conjugate corresponding to formula (I) below is administered to said subject prior to, concurrently with, or after administration of said platinum-based anticancer agent, thereby A method of enhancing therapeutic response to anti-cancer agents based on.

(I)
[In the formula,
M is Mn ²⁺ or Mn ³⁺ ;
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 are independently is hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moieties, 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 ₁₁ )(OR ₁₂ ), wherein R ₁₁ and R ₁₂ are independently hydrogen or alkyl;
U is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
V is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
W, together with the macrocyclic ring nitrogen and the macrocyclic ring carbon atom to which it is attached, is an aromatic or alicyclic substituted or unsubstituted aromatic or alicyclic ring having 2 to 20 ring carbon atoms; with the proviso that when W is a fused aromatic heterocycle, it is part of both the heterocycle and said macrocycle hydrogen attached to nitrogen and R ₁ and R ₁₀ attached to carbon atoms that are part of both the heterocycle and said macrocycle shall be absent;
X and Y represent any suitable ligand from a monodentate or polydentate ligand or ligand system, or the corresponding anion;
Z is a 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)]

Embodiment 25
25. The method of embodiment 24, wherein said subject has cancer.

Embodiment 26
26. The method of embodiment 24 or 25, comprising administering a therapeutically effective amount of said platinum-based anticancer agent and a pentaazamacrocyclic ring complex that reduces the toxic effects of said platinum-based anticancer agent.

Embodiment 27
said pentaaza-macrocyclic ring conjugate is selected from the group consisting of reduced tumor volume, reduced tumor growth rate, increased survival rate, reduced incidence and/or extent of metastasis, and reduced cell proliferation of cancer cells. 27. A method according to any of embodiments 24-26, administered in a therapeutically effective amount capable of enhancing a corresponding cancer response and/or reducing cancer complications.

Embodiment 28
28. The method of any of embodiments 24-27, wherein the pentaazamacrocycle is administered in a therapeutically effective amount to reduce levels of at least one of creatine and blood urea nitrogen (BUN).

Embodiment 29
wherein said pentaazamacrocycle is administered in a therapeutically effective amount to reduce the levels of a marker for kidney damage selected from the group consisting of kidney damage molecule 1 (KIM1) and neutrophil gelatinase-binding lipocalin (NGAL). 29. The method of any of embodiments 24-28, wherein

（Ｉ）
［式中、
Ｍは、Ｍｎ^２＋またはＭｎ^３＋であり；
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は、独立して、水素、ヒドロカルビル、置換ヒドロカルビル、ヘテロサイクリル、アミノ酸側鎖部分、あるいは－ＯＲ_１１、－ＮＲ_１１Ｒ_１２、－ＣＯＲ_１１、－ＣＯ_２Ｒ_１１、－ＣＯＮＲ_１１Ｒ_１２、－ＳＲ_１１、－ＳＯＲ_１１、－ＳＯ_２Ｒ_１１、－ＳＯ_２ＮＲ_１１Ｒ_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は、前記大環状環の隣接する炭素原子と一緒になって、３～２０個の環炭素原子を有する縮合された置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の環もしくはヘテロ環を形成し；
Ｖは、前記大環状環の隣接する炭素原子と一緒になって、３～２０個の環炭素原子を有する縮合された置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の環もしくはヘテロ環を形成し；
Ｗは、前記大環状環の窒素およびそれが結合している前記大環状環の炭素原子と一緒になって、２～２０個の環炭素原子を有する芳香族もしくは脂環式の置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の窒素含有縮合ヘテロ環を形成するが、但し、Ｗが、縮合された芳香族ヘテロ環である場合、ヘテロ環および前記大環状環の両方の部分である窒素に結合している水素、ならびにヘテロ環および前記大環状環の両方の部分である炭素原子に結合しているＲ_１およびＲ_１０は、非存在であるものとし；
ＸおよびＹは、単座もしくは多座配位子もしくは配位子系に由来する適切な配位子のいずれか、またはそれに相当するアニオンを表し；
Ｚは、対イオンであり；
ｎは、０～３の整数であり；ならびに
点線は、前記大環状環の窒素原子と遷移金属（マンガン）との配位結合を表す］ Embodiment 30
treating and/or reducing the risk of toxic effects selected from the group consisting of nephrotoxicity and bone marrow toxicity associated with treatment with platinum-based anticancer agents in a mammalian subject in need of treatment and/or reduction. A method of reducing:
administering to said subject a therapeutically effective amount of a platinum-based anticancer agent; administering to said subject prior to, concurrently with, or after administration, thereby reducing the toxic effects of said platinum-based anticancer agent.

(I)
[In the formula,
M is Mn ²⁺ or Mn ³⁺ ;
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 are independently is hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moieties, 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 ₁₁ )(OR ₁₂ ), wherein R ₁₁ and R ₁₂ are independently hydrogen or alkyl;
U is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
V is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
W, together with the macrocyclic ring nitrogen and the macrocyclic ring carbon atom to which it is attached, is an aromatic or alicyclic substituted or unsubstituted aromatic or alicyclic ring having 2 to 20 ring carbon atoms; with the proviso that when W is a fused aromatic heterocycle, it is part of both the heterocycle and said macrocycle hydrogen attached to nitrogen and R ₁ and R ₁₀ attached to carbon atoms that are part of both the heterocycle and said macrocycle shall be absent;
X and Y represent any suitable ligand from a monodentate or polydentate ligand or ligand system, or the corresponding anion;
Z is a 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)]

Embodiment 31
31. The method of embodiment 30, wherein said subject has cancer.

Embodiment 32
32. The method of embodiment 30 or 31, wherein said subject suffers from nephrotoxicity and/or bone marrow toxicity associated with treatment with said platinum-based anticancer agent.

Embodiment 33
33. Any of embodiments 30-32, comprising administering a therapeutically effective amount of said platinum-based anticancer agent and a pentaazamacrocyclic ring conjugate that enhances therapeutic responsiveness to said platinum-based anticancer agent. the method of.

Embodiment 34
said pentaaza-macrocyclic ring conjugate is selected from the group consisting of reduced tumor volume, reduced tumor growth rate, increased survival rate, reduced incidence and/or extent of metastasis, and reduced cell proliferation of cancer cells. 34. A method according to any of embodiments 30-33, administered in a therapeutically effective amount capable of enhancing any corresponding cancer response and/or reducing cancer complications.

Embodiment 35
35. The method of any of embodiments 30-34, wherein said pentaazamacrocycle is administered in a therapeutically effective amount to reduce levels of at least one of creatine and blood urea nitrogen (BUN).

Embodiment 36
wherein said pentaazamacrocycle is administered in a therapeutically effective amount to reduce the levels of a marker for kidney damage selected from the group consisting of kidney damage molecule 1 (KIM1) and neutrophil gelatinase-binding lipocalin (NGAL). 36. The method of any of embodiments 30-35, wherein

（Ｉ）
［式中、
Ｍは、Ｍｎ^２＋またはＭｎ^３＋であり；
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は、独立して、水素、ヒドロカルビル、置換ヒドロカルビル、ヘテロサイクリル、アミノ酸側鎖部分、あるいは－ＯＲ_１１、－ＮＲ_１１Ｒ_１２、－ＣＯＲ_１１、－ＣＯ_２Ｒ_１１、－ＣＯＮＲ_１１Ｒ_１２、－ＳＲ_１１、－ＳＯＲ_１１、－ＳＯ_２Ｒ_１１、－ＳＯ_２ＮＲ_１１Ｒ_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は、前記大環状環の隣接する炭素原子と一緒になって、３～２０個の環炭素原子を有する縮合された置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の環もしくはヘテロ環を形成し；
Ｖは、前記大環状環の隣接する炭素原子と一緒になって、３～２０個の環炭素原子を有する縮合された置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の環もしくはヘテロ環を形成し；
Ｗは、前記大環状環の窒素およびそれが結合している前記大環状環の炭素原子と一緒になって、２～２０個の環炭素原子を有する芳香族もしくは脂環式の置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の窒素含有縮合ヘテロ環を形成するが、但し、Ｗが、縮合された芳香族ヘテロ環である場合、ヘテロ環および前記大環状環の両方の部分である窒素に結合している水素、ならびにヘテロ環および前記大環状環の両方の部分である炭素原子に結合しているＲ_１およびＲ_１０は、非存在であるものとし；
ＸおよびＹは、単座もしくは多座配位子もしくは配位子系に由来する適切な配位子のいずれか、またはそれに相当するアニオンを表し；
Ｚは、対イオンであり；
ｎは、０～３の整数であり；ならびに
点線は、前記大環状環の窒素原子と遷移金属（マンガン）との配位結合を表す］ Embodiment 37
Treating and/or reducing the risk of toxic effects selected from the group consisting of nephrotoxicity and bone marrow toxicity associated with treatment with platinum-based anticancer agents in a mammalian subject in need thereof. A method to let:
A pentaazamacrocyclic ring conjugate corresponding to formula (I) below is administered to said subject prior to, concurrently with, or after administration of said platinum-based anti-cancer agent, thereby treating said platinum-based anti-cancer agent. A method characterized by reducing toxic effects.

(I)
[In the formula,
M is Mn ²⁺ or Mn ³⁺ ;
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 are independently is hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moieties, 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 ₁₁ )(OR ₁₂ ), wherein R ₁₁ and R ₁₂ are independently hydrogen or alkyl;
U is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
V is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
W, together with the macrocyclic ring nitrogen and the macrocyclic ring carbon atom to which it is attached, is an aromatic or alicyclic substituted or unsubstituted aromatic or alicyclic ring having 2 to 20 ring carbon atoms; with the proviso that when W is a fused aromatic heterocycle, it is part of both the heterocycle and said macrocycle hydrogen attached to nitrogen and R ₁ and R ₁₀ attached to carbon atoms that are part of both the heterocycle and said macrocycle shall be absent;
X and Y represent any suitable ligand from a monodentate or polydentate ligand or ligand system, or the corresponding anion;
Z is a 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)]

Embodiment 38
38. The method of embodiment 37, wherein said subject has cancer.

Embodiment 39
39. The method of embodiment 37 or 38, wherein said subject suffers from nephrotoxicity and/or bone marrow toxicity associated with treatment with said platinum-based anticancer agent.

Embodiment 40
40. Any of embodiments 37-39, comprising administering a therapeutically effective amount of said platinum-based anticancer agent and a pentaazamacrocyclic ring conjugate that enhances therapeutic responsiveness to said platinum-based anticancer agent. the method of.

Embodiment 41
said pentaaza-macrocyclic ring conjugate is selected from the group consisting of decreased tumor volume, decreased tumor growth rate, increased survival rate, decreased incidence and/or extent of metastasis, and decreased cell proliferation of cancer cells. 41. A method according to any of embodiments 37-40, administered in a therapeutically effective amount capable of enhancing a corresponding cancer response and/or reducing cancer complications.

Embodiment 42
42. The method of any of embodiments 37-41, wherein said pentaazamacrocycle is administered in a therapeutically effective amount to reduce levels of at least one of creatine and blood urea nitrogen (BUN).

Embodiment 43
wherein said pentaazamacrocycle is administered in a therapeutically effective amount to reduce the levels of a marker for kidney damage selected from the group consisting of kidney damage molecule 1 (KIM1) and neutrophil gelatinase-binding lipocalin (NGAL). 43. The method of any of embodiments 37-42, wherein

Embodiment 44
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 are each A method according to any of the previous embodiments, which is hydrogen.

Embodiment 45
45. The method of any of embodiments 1-44, wherein W is an unsubstituted pyridine moiety.

Embodiment 46
46. The method of any of embodiments 1-45, wherein U and V are trans cyclohexanyl fused rings.

（ＩＩ）
［式中、
ＸおよびＹは、単座もしくは多座配位子もしくは配位子系に由来する適切な配位子のいずれか、またはこれらの相当するアニオンを表し；ならびに
Ｒ_Ａ、Ｒ_Ｂ、Ｒ_Ｃ、およびＲ_Ｄは、独立して、水素、ヒドロカルビル、置換ヒドロカルビル、ヘテロサイクリル、アミノ酸側鎖部分、あるいは－ＯＲ_１１、－ＮＲ_１１Ｒ_１２、－ＣＯＲ_１１、－ＣＯ_２Ｒ_１１、－ＣＯＮＲ_１１Ｒ_１２、－ＳＲ_１１、－ＳＯＲ_１１、－ＳＯ_２Ｒ_１１、－ＳＯ_２ＮＲ_１１Ｒ_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る］
で示されるものである、実施態様１～４６のいずれかに記載の方法。 Embodiment 47
The pentaaza macrocyclic ring complex has the formula (II):

(II)
[In the formula,
X and Y represent any suitable ligand from a monodentate or polydentate ligand or ligand system, or their corresponding anions; and R _A , R _B , R _C , and R _D is 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 ₁₁ )(OR ₁₂ ), wherein R ₁₁ and R ₁₂ are independently hydrogen or is alkyl]
47. The method of any one of embodiments 1-46, wherein

［式中、
ＸおよびＹは、単座もしくは多座配位子もしくは配位子系に由来する適切な配位子のいずれか、またはこれらの相当するアニオンを表し；ならびに
Ｒ_Ａ、Ｒ_Ｂ、Ｒ_Ｃ、およびＲ_Ｄは、独立して、水素、ヒドロカルビル、置換ヒドロカルビル、ヘテロサイクリル、アミノ酸側鎖部分、あるいは－ＯＲ_１１、－ＮＲ_１１Ｒ_１２、－ＣＯＲ_１１、－ＣＯ_２Ｒ_１１、－ＣＯＮＲ_１１Ｒ_１２、－ＳＲ_１１、－ＳＯＲ_１１、－ＳＯ_２Ｒ_１１、－ＳＯ_２ＮＲ_１１Ｒ_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る］
で示されるものである、実施態様１～４７のいずれかに記載の方法。 Embodiment 48
The pentaaza macrocyclic ring complex is represented by formula (III) or formula (IV):

[In the formula,
X and Y represent any suitable ligand from a monodentate or polydentate ligand or ligand system, or their corresponding anions; and R _A , R _B , R _C , and R _D is 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 ₁₁ )(OR ₁₂ ), wherein R ₁₁ and R ₁₂ are independently hydrogen or is alkyl]
48. The method of any one of embodiments 1-47, wherein

からなる群から選択される式で示されるものである、実施態様１～４８のいずれかに記載の方法。 Embodiment 49
The pentaaza-macrocyclic ring complex has formulas (V)-(XVI):

49. The method of any one of embodiments 1-48, which is represented by a formula selected from the group consisting of:

Embodiment 50
50. The method of any of embodiments 1-49, wherein X and Y are independently 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, nitric acid, nitrous acid, azide, alkylsulfonic acid, arylsulfonic acid, alkylsulfoxide, arylsulfoxide, alkylarylsulfoxide, alkylsulfenic acid, arylsulfenic acid, alkylsulfinic acid, arylsulfinic acid, alkyl Thiolcarboxylic acid, arylthiolcarboxylic acid, alkylthiolthiocarboxylic acid, arylthiolthiocarboxylic acid, alkylcarboxylic acid, arylcarboxylic acid, urea, alkylurea, arylurea, alkylarylurea, thiourea, alkylthiourea, arylthiourea, alkylaryl Luciourea, Sulfuric acid, Sulfurous acid, Bisulfuric acid, Bisulfite, Thiosulfuric acid, Thiosulfuric acid, Hydrosulfuric acid, Alkylphosphine, Arylphosphine, Alkylphosphine oxide, Arylphosphine oxide, Alkylarylphosphine oxide, Alkylphosphine sulfide, Arylphosphine sulfide, Alkyl Arylphosphine sulfide, alkylphosphonic acid, arylphosphonic acid, alkylphosphinic acid, arylphosphinic acid, alkylphosphinic acid, arylphosphinic acid, phosphoric acid, thiophosphoric acid, phosphorous acid, pyrophosphite, triphosphoric acid, phosphorus Hydrogen acid, dihydrogen phosphate, alkylguanidino, arylguanidino, alkylarylguanidino, alkylcarbamate, arylcarbamate, alkylarylcarbamate, alkylthiocarbamate, arylthiocarbamate, alkylarylthiocarbamate, alkyldithiocarbamate, aryldithiocarbamate, alkylaryl dithiocarbamate, bicarbonate, carbonic acid, perchloric acid, chloric acid, chlorous acid, hypochlorous acid, perbromic acid, bromic acid, bromous acid, hypobromous acid, tetrahalomanganate, 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 , oxo thiotosylate, and the anions of ion exchange resins, or the corresponding anions thereof;
or X and Y correspond to -O-C(O)-X ₁ , each X ₁ being -C(X ₂ )(X ₃ )(X ₄ );
each X ₁ is independently substituted or unsubstituted phenyl or -C(-X ₂ )(-X ₃ )(-X ₄ );
each X ₂ is independently substituted or unsubstituted phenyl, methyl, ethyl, or propyl;
each X ₃ is independently hydrogen, hydroxyl, methyl, ethyl, propyl, amino, -X ₅ C(=O)R ₁₃ [wherein X ₅ is NH or O and R ₁₃ is C1-C18 alkyl, substituted or unsubstituted aryl, or C1-C18 aralkyl], or —OR ₁₄ [wherein R ₁₄ is C1-C18 alkyl, substituted or unsubstituted aryl, or C1-C18 aralkyl or together with X ₄ is (=O); and each X ₄ is independently hydrogen or together with X ₃ is (=O) there is;
or X and Y are independently selected from the group consisting of charge-neutralizing anions derived from monodentate or polydentate ligands, and ligand systems and their corresponding anions;
or X and Y are independently 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 bound to one or more of _R10 .

Embodiment 51
51. The method of any of embodiments 1-50, wherein X and Y are independently selected from the group consisting of fluoro, chloro, bromo, and iodo anions.

Embodiment 52
52. The method of any of embodiments 1-51, wherein X and Y are independently selected from the group consisting of alkyl carboxylates, aryl carboxylates and arylalkyl carboxylates.

Embodiment 53
53. The method of any of embodiments 1-52, wherein X and Y are independently amino acids.

で示される化合物である、実施態様１～５３のいずれかに記載の方法。 Embodiment 54
The pentaaza macrocyclic ring complex has the formula:

54. The method of any one of embodiments 1-53, which is a compound of the formula

で示される化合物である、実施態様１～５４のいずれかに記載の方法。 Embodiment 55
The pentaaza macrocyclic ring complex has the formula:

55. The method of any one of embodiments 1-54, which is a compound of the formula

で示される化合物である、実施態様１～５５のいずれかに記載の方法。 Embodiment 56
The pentaaza macrocyclic ring complex has the formula:

56. The method of any of embodiments 1-55, which is a compound of the formula

で示される化合物である、実施態様１～５６のいずれかに記載の方法。 Embodiment 57
The pentaaza macrocyclic ring complex has the formula:

57. The method of any of embodiments 1-56, which is a compound of the formula

で示される化合物である、実施態様１～５７のいずれかに記載の方法。 Embodiment 58
The pentaaza macrocyclic ring complex has the formula:

58. The method of any of embodiments 1-57, which is a compound of the formula

で示される化合物である、前記実施態様のいずれかに記載の方法。 Embodiment 59
The pentaaza macrocyclic ring complex has the formula:

The method according to any of the preceding embodiments, which is a compound of the formula:

Embodiment 60
Said platinum-based anticancer agents include cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin, heptaplatin, dicycloplatin, lipoplatin, LA-12, phosphaplatin, phenanthriplatin, prolindac, triplatin tetranitrate ( triplatin tetranitrate), picoplatin, satraplatin, piriplatin, and/or a pharmaceutically acceptable salt thereof.

Embodiment 61
61. The method of any of embodiments 1-60, wherein said platinum-based anticancer agent comprises cisplatin.

Embodiment 62
62. The method of any of embodiments 1-61, wherein said platinum-based anticancer agent is administered at a dose ranging from 20 mg/ ^m2 to 200 mg/ ^m2 .

Embodiment 63
63. The method of any of embodiments 1-62, wherein administration of the pentaazamacrocyclic ring conjugate during treatment is administered for a period of time prior to administration of the platinum-based anticancer agent.

Embodiment 64
64. Any of embodiments 1-63, wherein administration of the pentaazamacrocyclic ring complex during treatment is administered at least one week, one day, or one hour prior to administration of the platinum-based anticancer agent. the method of.

Embodiment 65
65. The method of any of embodiments 1-64, wherein the course of administration of the pentaazamacrocyclic ring conjugate is administered within 1 hour prior to and/or concurrently with the administration of the platinum-based anticancer agent.

Embodiment 66
66. Any of embodiments 1-65, wherein administration of the pentaazamacrocyclic ring complex during treatment is administered within 1 hour, 1 day, or 1 week after administration of the platinum-based anticancer agent. Method.

Embodiment 67
67. The method of any of embodiments 1-66, comprising administering said platinum-based anticancer agent to a subject concurrently undergoing radiation therapy.

Embodiment 68
67. The method of any of embodiments 1-66, comprising administering the platinum-based anticancer agent and the pentaazamacrocycle conjugate to a subject who has not undergone radiation therapy.

Embodiment 69
67. according to any of embodiments 1-66, wherein a course of treatment comprising administration of said pentaazamacrocyclic ring complex and a platinum-based anticancer agent is administered to a subject who has not received radiation therapy during said course of treatment. Method.

Embodiment 70
67, comprising administering to the subject one or more of said pentaazamacrocyclic ring conjugates and platinum-based anticancer agents on days other than days on which the subject is receiving radiation therapy. The method according to any one of

Embodiment 71
67. Any of embodiments 1-66, comprising administering a course of treatment comprising administering the platinum-based anticancer agent and the pentaaza-macrocycle conjugate to a subject who has not received radiation therapy for at least one day. described method.

Embodiment 72
67. Any of embodiments 1-66, comprising administering a course of treatment comprising administering the platinum-based anticancer agent and the pentaaza-macrocycle conjugate to a subject who has not received radiation therapy for at least one week. described method.

Embodiment 73
67. Any of embodiments 1-66, comprising administering a course of treatment comprising administering the platinum-based anticancer agent and the pentaaza-macrocycle conjugate to a subject who has not received radiation therapy for at least one month. The method described in .

Embodiment 74
67. Any of embodiments 1-66, comprising administering a course of treatment comprising administering the platinum-based anticancer agent and the pentaaza-macrocycle conjugate to a subject who has not received radiation therapy for at least 6 months. The method described in .

Embodiment 75
administering said platinum-based anticancer agent and a pentaaza-macrocycle conjugate to a subject, and then delaying radiation therapy optionally administered to said subject until at least one day after the last administration of said pentaaza-macrocycle conjugate; 67. The method of any of embodiments 1-66, comprising causing.

Embodiment 76
administering said platinum-based anti-cancer agent and a pentaaza-macrocycle conjugate to a subject, and delaying radiotherapy optionally administered to said subject until at least one week after the last administration of the pentaaza-macrocycle conjugate; 67. The method of any of embodiments 1-66, comprising:

Embodiment 77
administering said platinum-based anticancer agent and a pentaaza-macrocycle conjugate to a subject, and then delaying radiation therapy optionally administered to said subject until at least one month after the last administration of said pentaaza-macrocycle conjugate; 67. The method of any of embodiments 1-66, comprising causing.

Embodiment 78
administering said platinum-based anticancer agent and a pentaaza-macrocycle conjugate to a subject, then delaying radiotherapy, optionally administered to said subject, for at least 6 months after the last administration of the pentaaza-macrocycle conjugate; 67. The method of any of embodiments 1-66, comprising

Embodiment 79
said cancer is 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 79. A method according to any preceding embodiment, selected from the group consisting of cancer.

Embodiment 80
80. The method of any of embodiments 1-79, wherein said 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.

Embodiment 81
81. The method of any of embodiments 1-80, wherein said cancer is at least one of lung cancer and head and neck cancer.

Embodiment 82
82. The method of any of embodiments 1-81, wherein said pentaaza-macrocyclic ring complex is administered to said subject at a dose ranging from 0.2 mg/kg to 40 mg/kg.

Embodiment 83
83. The method of any of embodiments 1-82, wherein said pentaaza-macrocyclic ring complex is administered to said subject at a dose ranging from 0.2 mg/kg to 24 mg/kg.

Embodiment 84
84. The method of any of embodiments 1-83, wherein said pentaaza-macrocyclic ring complex is administered to said subject at a dose ranging from 0.2 mg/kg to 10 mg/kg.

Embodiment 85
85. The method of any of embodiments 1-84, wherein said pentaaza-macrocycle conjugate is administered by at least one of parenteral and oral routes.

Embodiment 86
86. The method of any of embodiments 1-85, wherein said pentaazamacrocyclic ring conjugate is administered intraperitoneally or intravenously.

Embodiment 87
87. The method of any of embodiments 1-86, wherein said subject is a human.

（Ｉ）
［式中、
Ｍは、Ｍｎ^２＋またはＭｎ^３＋であり；
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は、独立して、水素、ヒドロカルビル、置換ヒドロカルビル、ヘテロサイクリル、アミノ酸側鎖部分、あるいは－ＯＲ_１１、－ＮＲ_１１Ｒ_１２、－ＣＯＲ_１１、－ＣＯ_２Ｒ_１１、－ＣＯＮＲ_１１Ｒ_１２、－ＳＲ_１１、－ＳＯＲ_１１、－ＳＯ_２Ｒ_１１、－ＳＯ_２ＮＲ_１１Ｒ_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は、前記大環状環の隣接する炭素原子と一緒になって、３～２０個の環炭素原子を有する縮合された置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の環もしくはヘテロ環を形成し；
Ｖは、前記大環状環の隣接する炭素原子と一緒になって、３～２０個の環炭素原子を有する縮合された置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の環もしくはヘテロ環を形成し；
Ｗは、前記大環状環の窒素およびそれが結合している前記大環状環の炭素原子と一緒になって、２～２０個の環炭素原子を有する芳香族もしくは脂環式の置換もしくは無置換の飽和、部分的な飽和もしくは不飽和の窒素含有縮合ヘテロ環を形成するが、但し、Ｗが、縮合された芳香族ヘテロ環である場合、ヘテロ環および前記大環状環の両方の部分である窒素に結合している水素、ならびにヘテロ環および前記大環状環の両方の部分である炭素原子に結合しているＲ_１およびＲ_１０は、非存在であるものとし；
ＸおよびＹは、単座もしくは多座配位子もしくは配位子系に由来する適切な配位子のいずれか、またはそれに相当するアニオンを表し；
Ｚは、対イオンであり；
ｎは、０～３の整数であり；ならびに
点線は、前記大環状環の窒素原子と遷移金属（マンガン）との配位結合を表す］。 Embodiment 88
A kit for treating cancer and/or reducing the toxic effects of platinum-based anticancer agents in a mammalian subject in need of treatment and/or reduction, comprising:
said platinum-based anti-cancer agent;
A pentaazamacrocyclic ring complex corresponding to formula (I): and a therapeutically effective amount of said platinum-based anticancer agent and a therapeutically effective amount for carrying out the method of any preceding claim. comprising instructions for administering said pentaaza-macrocyclic ring complex of
A kit wherein the pentaazamacrocyclic ring complex according to formula (I) is as follows:

(I)
[In the formula,
M is Mn ²⁺ or Mn ³⁺ ;
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 are independently is hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moieties, 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 ₁₁ )(OR ₁₂ ), wherein R ₁₁ and R ₁₂ are independently hydrogen or alkyl;
U is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
V is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
W, together with the macrocyclic ring nitrogen and the macrocyclic ring carbon atom to which it is attached, is an aromatic or alicyclic substituted or unsubstituted aromatic or alicyclic ring having 2 to 20 ring carbon atoms; with the proviso that when W is a fused aromatic heterocycle, it is part of both the heterocycle and said macrocycle hydrogen attached to nitrogen and R ₁ and R ₁₀ attached to carbon atoms that are part of both the heterocycle and said macrocycle shall be absent;
X and Y represent any suitable ligand from a monodentate or polydentate ligand or ligand system, or the corresponding anion;
Z is a 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)].

Claims (70)

A method of treating cancer in a mammal with cancer comprising:
administering to said subject a therapeutically effective amount of a platinum-based anti-cancer agent;
A therapeutically effective amount of a pentaaza macrocycle conjugate corresponding to formula (I) below is administered to said subject prior to, concurrently with, or after administration of said platinum-based anticancer agent, thereby treating said cancer to said platinum-based anti-cancer agent:

(I)
[In the formula,
M is Mn ²⁺ or Mn ³⁺ ;
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 are independently is hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moieties, 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 ₁₁ )(OR ₁₂ ), wherein R ₁₁ and R ₁₂ are independently hydrogen or alkyl;
U is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
V is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
W, together with the macrocyclic ring nitrogen and the macrocyclic ring carbon atom to which it is attached, is an aromatic or alicyclic substituted or unsubstituted aromatic or alicyclic ring having 2 to 20 ring carbon atoms; with the proviso that when W is a fused aromatic heterocycle, it is part of both the heterocycle and said macrocycle hydrogen attached to nitrogen and R ₁ and R ₁₀ attached to carbon atoms that are part of both the heterocycle and said macrocycle shall be absent;
X and Y represent any suitable ligand from a monodentate or polydentate ligand or ligand system, or the corresponding anion;
Z is a 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 of claim 1, comprising administering a therapeutically effective amount of the platinum-based anticancer agent and a pentaazamacrocyclic ring complex that reduces the toxic effects of the platinum-based anticancer agent. wherein the pentaazamacrocyclic ring conjugate is selected from the group consisting of reduced tumor volume, reduced tumor growth rate, increased survival rate, reduced incidence and/or extent of metastasis, and reduced proliferation of cancer cells. 3. The method of claim 1 or 2, administered in a therapeutically effective amount capable of enhancing a corresponding cancer response and/or reducing cancer complications. 4. The method of any one of claims 1-3, wherein the pentaazamacrocycle is administered in a therapeutically effective amount to reduce levels of at least one of creatine and blood urea nitrogen (BUN). . wherein said pentaazamacrocycle is administered in a therapeutically effective amount to reduce the levels of a marker for kidney damage selected from the group consisting of kidney damage molecule 1 (KIM1) and neutrophil gelatinase-binding lipocalin (NGAL). The method according to any one of claims 1 to 4, wherein A method of sensitizing a mammalian subject to treatment with a platinum-based anticancer agent in a subject in need thereof, comprising:
A therapeutically effective amount of a pentaaza macrocycle conjugate corresponding to formula (I) below is administered to said subject prior to, concurrently with, or after administration of said platinum-based anticancer agent, thereby A method characterized by enhanced therapeutic responsiveness to anticancer agents based on:

(I)
[In the formula,
M is Mn ²⁺ or Mn ³⁺ ;
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 are independently is hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moieties, 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 ₁₁ )(OR ₁₂ ), wherein R ₁₁ and R ₁₂ are independently hydrogen or alkyl;
U is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
V is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
W, together with the macrocyclic ring nitrogen and the macrocyclic ring carbon atom to which it is attached, is an aromatic or alicyclic substituted or unsubstituted aromatic or alicyclic ring having 2 to 20 ring carbon atoms; with the proviso that when W is a fused aromatic heterocycle, it is part of both the heterocycle and said macrocycle hydrogen attached to nitrogen and R ₁ and R ₁₀ attached to carbon atoms that are part of both the heterocycle and said macrocycle shall be absent;
X and Y represent any suitable ligand from a monodentate or polydentate ligand or ligand system, or the corresponding anion;
Z is a 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 of claim 6, wherein the subject has cancer. 8. The method of claim 6 or 7, comprising administering a therapeutically effective amount of the platinum-based anticancer agent and a pentaazamacrocyclic ring complex that reduces the toxic effects of the platinum-based anticancer agent. said pentaaza-macrocyclic ring conjugate is selected from the group consisting of reduced tumor volume, reduced tumor growth rate, increased survival rate, reduced incidence and/or extent of metastasis, and reduced cell proliferation of cancer cells. 9. The method of any one of claims 6-8, administered in a therapeutically effective amount capable of enhancing any corresponding cancer response and/or reducing cancer complications. 10. The method of any one of claims 6-9, wherein the pentaazamacrocycle is administered in a therapeutically effective amount to reduce levels of at least one of creatine and blood urea nitrogen (BUN). . wherein said pentaazamacrocycle is administered in a therapeutically effective amount to reduce the levels of a marker for kidney damage selected from the group consisting of kidney damage molecule 1 (KIM1) and neutrophil gelatinase-binding lipocalin (NGAL). The method according to any one of claims 6 to 10, wherein treating and/or reducing the risk of toxic effects selected from the group consisting of nephrotoxicity and bone marrow toxicity associated with treatment with platinum-based anticancer agents in a mammalian subject in need of treatment and/or reduction. A method of reducing:
administering to said subject a therapeutically effective amount of a platinum-based anticancer agent; A method comprising administering to said subject prior to, concurrently with, or after administration, thereby reducing the toxic effects of said platinum-based anticancer agent:

(I)
[In the formula,
M is Mn ²⁺ or Mn ³⁺ ;
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 are independently is hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moieties, 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 ₁₁ )(OR ₁₂ ), wherein R ₁₁ and R ₁₂ are independently hydrogen or alkyl;
U is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
V is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
W, together with the macrocyclic ring nitrogen and the macrocyclic ring carbon atom to which it is attached, is an aromatic or alicyclic substituted or unsubstituted aromatic or alicyclic ring having 2 to 20 ring carbon atoms; with the proviso that when W is a fused aromatic heterocycle, it is part of both the heterocycle and said macrocycle hydrogen attached to nitrogen and R ₁ and R ₁₀ attached to carbon atoms that are part of both the heterocycle and said macrocycle shall be absent;
X and Y represent any suitable ligand from a monodentate or polydentate ligand or ligand system, or the corresponding anion;
Z is a 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 of claim 12, wherein the subject has cancer. 14. The method of claim 12 or 13, wherein said subject suffers from nephrotoxicity and/or bone marrow toxicity associated with treatment with said platinum-based anticancer agent. 15. Any one of claims 12-14, comprising administering a therapeutically effective amount of the platinum-based anticancer agent and a pentaazamacrocyclic ring conjugate that enhances therapeutic responsiveness to the platinum-based anticancer agent. The method described in . said pentaaza-macrocyclic ring conjugate is selected from the group consisting of reduced tumor volume, reduced tumor growth rate, increased survival rate, reduced incidence and/or extent of metastasis, and reduced cell proliferation of cancer cells. 16. The method of any one of claims 12-15, administered in a therapeutically effective amount capable of enhancing any corresponding cancer response and/or reducing cancer complications. 17. The method of any one of claims 12-16, wherein the pentaazamacrocycle is administered in a therapeutically effective amount to reduce levels of at least one of creatine and blood urea nitrogen (BUN). . wherein said pentaazamacrocycle is administered in a therapeutically effective amount to reduce the levels of a marker for kidney damage selected from the group consisting of kidney damage molecule 1 (KIM1) and neutrophil gelatinase-binding lipocalin (NGAL). The method of any one of claims 12-17, wherein Treating and/or reducing the risk of toxic effects selected from the group consisting of nephrotoxicity and bone marrow toxicity associated with treatment with platinum-based anticancer agents in a mammalian subject in need thereof. A method to let:
A pentaazamacrocyclic ring conjugate corresponding to formula (I) below is administered to said subject prior to, concurrently with, or after administration of said platinum-based anti-cancer agent, thereby treating said platinum-based anti-cancer agent. A method characterized by reducing toxic effects:

(I)
[In the formula,
M is Mn ²⁺ or Mn ³⁺ ;
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 are independently is hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moieties, 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 ₁₁ )(OR ₁₂ ), wherein R ₁₁ and R ₁₂ are independently hydrogen or alkyl;
U is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
V is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
W, together with the macrocyclic ring nitrogen and the macrocyclic ring carbon atom to which it is attached, is an aromatic or alicyclic substituted or unsubstituted aromatic or alicyclic ring having 2 to 20 ring carbon atoms; with the proviso that when W is a fused aromatic heterocycle, it is part of both the heterocycle and said macrocycle hydrogen attached to nitrogen and R ₁ and R ₁₀ attached to carbon atoms that are part of both the heterocycle and said macrocycle shall be absent;
X and Y represent any suitable ligand from a monodentate or polydentate ligand or ligand system, or the corresponding anion;
Z is a 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)]. 11. The method of claim 10, wherein the subject has cancer. 21. The method of claim 19 or 20, wherein said subject suffers from nephrotoxicity and/or bone marrow toxicity associated with treatment with said platinum-based anticancer agent. 22. Any one of claims 19-21, comprising administering a therapeutically effective amount of the platinum-based anticancer agent and a pentaazamacrocyclic ring conjugate that enhances therapeutic responsiveness to the platinum-based anticancer agent. The method described in . said pentaaza-macrocyclic ring conjugate is selected from the group consisting of reduced tumor volume, reduced tumor growth rate, increased survival rate, reduced incidence and/or extent of metastasis, and reduced cell proliferation of cancer cells. 23. The method of any one of claims 19-22, administered in a therapeutically effective amount capable of enhancing any corresponding cancer response and/or reducing cancer complications. 24. The method of any one of claims 19-23, wherein the pentaazamacrocycle is administered in a therapeutically effective amount to reduce levels of at least one of creatine and blood urea nitrogen (BUN). . wherein said pentaazamacrocycle is administered in a therapeutically effective amount to reduce the levels of a marker for kidney damage selected from the group consisting of kidney damage molecule 1 (KIM1) and neutrophil gelatinase-binding lipocalin (NGAL). The method of any one of claims 19-24, wherein 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 are each A method according to any one of claims 1 to 25, which is hydrogen. The method of any one of claims 1-26, wherein W is an unsubstituted pyridine moiety. 28. The method of any one of claims 1-27, wherein U and V are a trans cyclohexanyl fused ring. The pentaaza macrocyclic ring complex has the formula (II):

(II)
[In the formula,
X and Y represent any suitable ligand from a monodentate or polydentate ligand or ligand system, or their corresponding anions; and R _A , R _B , R _C , and R _D is 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 ₁₁ )(OR ₁₂ ), wherein R ₁₁ and R ₁₂ are independently hydrogen or is alkyl]
The method according to any one of claims 1 to 28, which is represented by The pentaaza macrocyclic ring complex is represented by formula (III) or formula (IV):

[In the formula,
X and Y represent any suitable ligand from a monodentate or polydentate ligand or ligand system, or their corresponding anions; and R _A , R _B , R _C , and R _D is 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 ₁₁ )(OR ₁₂ ), wherein R ₁₁ and R ₁₂ are independently hydrogen or is alkyl]
The method according to any one of claims 1 to 29, which is represented by The pentaaza-macrocyclic ring complex has formulas (V)-(XVI):

The method according to any one of claims 1 to 30, which is represented by a formula selected from the group consisting of 32. The method of any one of claims 1-31, wherein X and Y are independently 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, aryl Nitriles, alkylisonitriles, arylisonitriles, nitric acid, nitrous acid, azides, alkylsulfonic acids, arylsulfonic acids, alkylsulfoxides, arylsulfoxides, alkylarylsulfoxides, alkylsulfenic acids, arylsulfenic acids, alkylsulfinic acids, arylsulfinic acids , alkylthiolcarboxylic acid, arylthiolcarboxylic acid, alkylthiolthiocarboxylic acid, arylthiolthiocarboxylic acid, alkylcarboxylic acid, arylcarboxylic acid, urea, alkylurea, arylurea, alkylarylurea, thiourea, alkylthiourea, 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, thiophosphoric acid, phosphorous acid, pyrophosphite, 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, bromous acid, hypobromous acid, tetrahalomanganate, tetrafluoroboron 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, independently selected from the substituted or unsubstituted moieties of the group consisting of hydroxamic acid, oxo thiotosylate, and ion exchange resin anions, or their corresponding anions;
or X and Y correspond to -O-C(O)-X ₁ , each X ₁ being -C(X ₂ )(X ₃ )(X ₄ );
each X ₁ is independently substituted or unsubstituted phenyl or -C(-X ₂ )(-X ₃ )(-X ₄ );
each X ₂ is independently substituted or unsubstituted phenyl, methyl, ethyl, or propyl;
each X ₃ is independently hydrogen, hydroxyl, methyl, ethyl, propyl, amino, -X ₅ C(=O)R ₁₃ [wherein X ₅ is NH or O and R ₁₃ is C1-C18 alkyl, substituted or unsubstituted aryl, or C1-C18 aralkyl], or —OR ₁₄ [wherein R ₁₄ is C1-C18 alkyl, substituted or unsubstituted aryl, or C1-C18 aralkyl or together with X ₄ is (=O); and each X ₄ is independently hydrogen or together with X ₃ is (=O) there is;
or X and Y are independently selected from the group consisting of charge-neutralizing anions derived from monodentate or polydentate ligands, and ligand systems and their corresponding anions;
or X and Y are independently 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 bound to one or more of _R10 . 33. The method of any one of claims 1-32, wherein X and Y are independently selected from the group consisting of fluoro, chloro, bromo, and iodo anions. 34. The method of any one of claims 1-33, wherein X and Y are independently selected from the group consisting of alkyl carboxylates, aryl carboxylates, and arylalkyl carboxylates. 35. The method of any one of claims 1-34, wherein X and Y are independently amino acids. The pentaaza macrocyclic ring complex has the formula:

The method according to any one of claims 1 to 35, which is a compound represented by The pentaaza macrocyclic ring complex has the formula:

The method according to any one of claims 1 to 36, which is a compound represented by The pentaaza macrocyclic ring complex has the formula:

The method according to any one of claims 1 to 37, which is a compound represented by The pentaaza macrocyclic ring complex has the formula:

The method according to any one of claims 1 to 38, which is represented by The pentaaza macrocyclic ring complex has the formula:

The method according to any one of claims 1 to 39, which is represented by The pentaaza macrocyclic ring complex has the formula:

The method according to any one of claims 1 to 40, which is represented by Said platinum-based anticancer agent is cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin, heptaplatin, dicycloplatin, lipoplatin, LA-12, phosphaplatin, phenanthriplatin, prolindac, triplatin tetranitrate, picoplatin, satraplatin , pyriplatin, and/or pharmaceutically acceptable salts thereof. 43. The method of any one of claims 1-42, wherein the platinum-based anticancer agent comprises cisplatin. 44. The method of any one of claims 1-43, wherein the platinum-based anticancer agent is administered at a dose ranging from 20 mg/ ^m2 to 200 mg/ ^m2 . 45. The method of any one of claims 1-44, wherein administration of the pentaazamacrocyclic ring conjugate during treatment is administered for a period of time prior to administration of the platinum-based anticancer agent. 46. Any one of claims 1-45, wherein administration of the pentaazamacrocyclic ring complex during the course of treatment is administered at least one week, one day, or one hour prior to administration of the platinum-based anticancer agent. described method. 47. Any one of claims 1-46, wherein administration of the pentaazamacrocyclic ring conjugate during the course of treatment is administered within 1 hour prior to and/or concurrently with the administration of the platinum-based anticancer agent. Method. 48. Any one of claims 1-47, wherein administration of the pentaazamacrocyclic ring conjugate during a course of treatment is administered within 1 hour, 1 day, or 1 week after administration of the platinum-based anticancer agent. described method. 49. The method of any one of claims 1-48, comprising administering the platinum-based anticancer agent to a subject concurrently undergoing radiation therapy. 49. The method of any one of claims 1-48, comprising administering the platinum-based anticancer agent and the pentaazamacrocycle conjugate to a subject who has not undergone radiation therapy. 49. Any one of claims 1-48, wherein a course of treatment comprising administration of the pentaazamacrocyclic ring complex and a platinum-based anticancer agent is administered to a subject who has not received radiation therapy during the course of treatment. described method. Claims 1-48, comprising administering one or more of the pentaazamacrocyclic ring conjugate and platinum-based anticancer agent to the subject on days other than days on which the subject is receiving radiation therapy. A method according to any one of 49. Any one of claims 1-48, comprising administering a course of treatment comprising administering the platinum-based anticancer agent and the pentaaza-macrocycle conjugate to a subject who has not received radiation therapy for at least one day. The method described in section. 49. Any one of claims 1-48, comprising administering a course of treatment comprising administering the platinum-based anticancer agent and the pentaaza-macrocycle conjugate to a subject who has not received radiation therapy for at least one week. The method described in section. 49. Any of claims 1-48, comprising administering a course of treatment comprising administering the platinum-based anticancer agent and the pentaaza-macrocycle conjugate to a subject who has not received radiation therapy for at least one month. 1. The method according to item 1. 49. Any of claims 1-48, comprising administering a course of treatment comprising administering the platinum-based anticancer agent and the pentaaza-macrocycle conjugate to a subject who has not received radiation therapy for at least 6 months. 1. The method according to item 1. administering said platinum-based anticancer agent and a pentaaza-macrocycle conjugate to a subject, and then delaying radiation therapy optionally administered to said subject until at least one day after the last administration of said pentaaza-macrocycle conjugate; 49. The method of any one of claims 1-48, comprising causing. administering said platinum-based anti-cancer agent and a pentaaza-macrocycle conjugate to a subject, and delaying radiotherapy optionally administered to said subject until at least one week after the last administration of the pentaaza-macrocycle conjugate; 49. The method of any one of claims 1-48, comprising administering said platinum-based anticancer agent and a pentaaza-macrocycle conjugate to a subject, and then delaying radiation therapy optionally administered to said subject until at least one month after the last administration of said pentaaza-macrocycle conjugate; 49. The method of any one of claims 1-48, comprising causing. administering said platinum-based anticancer agent and a pentaaza-macrocycle conjugate to a subject, then delaying radiotherapy, optionally administered to said subject, for at least 6 months after the last administration of the pentaaza-macrocycle conjugate; The method of any one of claims 1-48, comprising: said cancer is 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 61. The method of any one of claims 1-60, selected from the group consisting of cancer. 62. Any one of claims 1-61, wherein said 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. the method of. 63. The method of any one of claims 1-62, wherein the cancer is at least one of lung cancer and head and neck cancer. 64. The method of any one of claims 1-63, wherein the pentaaza-macrocyclic ring complex is administered to the subject at a dose ranging from 0.2 mg/kg to 40 mg/kg. 65. The method of any one of claims 1-64, wherein the pentaaza-macrocyclic ring complex is administered to the subject at a dose ranging from 0.2 mg/kg to 24 mg/kg. 66. The method of any one of claims 1-65, wherein the pentaaza-macrocyclic ring complex is administered to the subject at a dose ranging from 0.2 mg/kg to 10 mg/kg. 67. The method of any one of claims 1-66, wherein the pentaaza-macrocycle conjugate is administered by at least one of parenteral and oral routes. 68. The method of any one of claims 1-67, wherein the pentaaza-macrocyclic ring conjugate is administered intraperitoneally or intravenously. 69. The method of any one of claims 1-68, wherein the subject is a human. A kit for treating cancer and/or reducing the toxic effects of platinum-based anticancer agents in a mammalian subject in need of treatment and/or reduction, comprising:
said platinum-based anti-cancer agent;
and a therapeutically effective amount of said platinum-based anticancer agent and a therapeutic comprising instructions for administering an effective amount of said pentaaza macrocycle complex;
A kit wherein the pentaazamacrocyclic ring complex according to formula (I) is as follows:

(I)
[In the formula,
M is Mn ²⁺ or Mn ³⁺ ;
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 are independently is hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, amino acid side chain moieties, 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 ₁₁ )(OR ₁₂ ), wherein R ₁₁ and R ₁₂ are independently hydrogen or alkyl;
U is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
V is a fused substituted or unsubstituted saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms together with adjacent carbon atoms of said macrocyclic ring; forming;
W, together with the macrocyclic ring nitrogen and the macrocyclic ring carbon atom to which it is attached, is an aromatic or alicyclic substituted or unsubstituted aromatic or alicyclic ring having 2 to 20 ring carbon atoms; with the proviso that when W is a fused aromatic heterocycle, it is part of both the heterocycle and said macrocycle hydrogen attached to nitrogen and R ₁ and R ₁₀ attached to carbon atoms that are part of both the heterocycle and said macrocycle shall be absent;
X and Y represent any suitable ligand from a monodentate or polydentate ligand or ligand system, or the corresponding anion;
Z is a 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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