Pentaazamacrocyclic complexes with oral bioavailability

Abstract

The present disclosure relates to pentaaza macrocyclic ring complexes with oral bioavailability, in particular compounds with enhanced oral bioavailability. The transition metal complex comprises a transition metal coordinated by a macrocycle comprising a pentaaza 15-membered macrocyclic ring corresponding to Formula A and two axial ligands having the formula OC(O)X1, wherein X1 is defined as in Formula A in the specification. #imgabs0#

Description

[0001] The applicant filed a PCT application PCT / US2016 / 046599 entitled “Pentazamacrocyclic complexes with oral bioavailability” on August 11, 2016. The PCT application entered the Chinese national phase on April 9, 2018 with application number 201680058867.X. This application is a divisional application of the Chinese application. Technical Field

[0002] The present disclosure generally relates to transition metal pentaaza 15-membered macrocyclic ring complexes having improved properties including significant oral bioavailability. Background Art

[0003] Transition metal pentaaza 15-membered macrocyclic ring complexes having a macrocyclic ring system corresponding to Formula A have been shown to be effective in multiple animal and cell models of human disease, as well as in the treatment of disorders afflicting human patients.

[0004]

[0005] For example, in a rodent model of colitis, one such compound, GC4403, was reported to significantly reduce colonic damage in rats subjected to an experimental model of colitis when administered by intraperitoneal (ip) injection (see Cuzzocrea et al., Europ. J. Pharmacol., 432, 79-89 (2001)).

[0006]

[0007] GC4403 administered ip has also been reported to attenuate radiation damage produced in a clinically relevant hamster model of acute, radiation-induced oral mucositis (Murphy et al., Clin. Can. Res., 14 (13), 4292 (2008)) and in total lethal body irradiation of adult mice (Thompson et al., Free Radical Res., 44 (5), 529-40 (2010)). Similarly, another such compound, GC4419, administered ip, 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)) and to increase the antitumor activity of antimetabolites and antimitotics in a mouse cancer model (see, e.g., WO2009 / 143454). In addition, another such compound, GC4401, administered ip, has been shown to provide protective effects in animal models of septic shock (S. Cuzzocrea et al., Crit. Care Med., 32(1), 157 (2004) and pancreatitis (S. Cuzzocrea, et al., Shock, 22(3), 254-61 (2004)).

[0008]

[0009] Some of these compounds have also been shown to have potent anti-inflammatory activity in vivo and prevent oxidative damage. For example, it has been reported that GC4403 administered via ip can inhibit inflammation in rat inflammation models (Salvemini, et al., Science, 286, 304 (1999)), and prevent arthritis in rat models of collagen-induced arthritis (Salvemini et al., Arthritis & Rheumatism, 44 (12), 2009-2021 (2001)). Thereafter, it has been reported that these compounds have analgesic activity and reduce inflammation and edema in rat foot carrageenan hyperalgesia models, see, e.g., U.S. Patent No. 6,180,620.

[0010] This class of compounds has also been shown to be safe and effective in the prevention and treatment of diseases in human subjects. For example, GC4419 administered by intravenous (iv) infusion has been shown to reduce oral mucositis in patients with head and neck cancer undergoing chemoradiotherapy (Anderson, C., Phase 1 Trial of Superoxide Dismutase (SOD) Mimetic GC4419 to Reduce Chemoradiotherapy (CRT)-Induced Mucositis (OM) in Patients (pts) with Mouth or Oropharyngeal Carcinoma (OCC), Oral Mucositis Research Workshop, MASCC / ISOO Annual Meeting on Supportive Care in Cancer, Copenhagen, Denmark (June 25, 2015)).

[0011] In each of these compounds comprising a five-aza 15-membered macrocyclic ring of formula A, the five nitrogens contained in the macrocyclic ring each form a coordinated covalent bond with manganese (or other transition metal coordinated by the macrocyclic ring) at the center of the molecule. In addition, manganese (or other appropriate transition metal coordinated to the macrocyclic ring) forms a coordinated covalent bond with an "axial ligand" in a position perpendicular to the macrocyclic ring in a general plane. Such coordinated covalent bonds are characterized in that the "free" electron pair available on the ligand forms a bond to the transition metal via the donation and sharing of the electron pair, thereby forming a two-electron bond between the metal and the donor atom of the ligand (Cotton, FA & G. Wilkinson, Advanced Inorganic Chemistry, Chapter 5, "Coordination Compounds", 2nd Revised Edition, Interscience Publishers, Page 139 (1966); IUPAC Gold Book, online version http: / / goldbook.iupac.org / C01329.html). The coordinate covalency of the bonds between manganese (or other such appropriate transition metal) and the five macrocyclic ring nitrogens and between manganese (or other such transition metal) and each of the two chloro axial ligands is demonstrated, for example, by GC4403 ( Fig.11 ) and GC4419( Fig.12 )'s "single crystal" X-ray crystal structure was confirmed.

[0012] Coordination compounds are contrasted with ionic compounds (e.g., salts) in which, in the solid state, the forces between anions and cations are strictly Coulomb electrostatic attractions between ions of opposite charge. Thus, in salts, discrete cations and anions provide the forces that maintain the solid structure; such as chloride and sodium ions in typical salts such as sodium chloride (Cotton, FA & G. Wilkinson, Advanced Inorganic Chemistry, Chapter 5, "The Nature of Ionic Substances", 2nd Revised Edition, Interscience Publishers, pp. 35-36, 45-49 (1966).

[0013] Although pentaaza 15-membered macrocyclic ring complexes have been disclosed in the literature for a variety of indications, the complexes disclosed to date have limited oral availability (substantially less than 5% when administered as an aqueous solution, with slightly higher but still insufficient bioavailability when administered in an appropriate oil-based formulation; see, e.g., Table 1). Typically, drug absorption from the gastrointestinal tract occurs via passive uptake, so that absorption is favored when the drug is in a non-ionic (neutral) and lipophilic form. See, e.g., Goodman & Gilman's: The Pharmacological Basis of Therapeutics, Ninth Edition, pp. 5-9 (1996). Without wishing to be bound by any particular theory, this is currently believed to be the case for this class of compounds, as exemplified by GC4419, in which both axial ligands are chlorine moieties, forming a coordinate covalent bond to the manganese and a neutral complex results:

[0014]

[0015] It is also understood that good water solubility can contribute to the uptake rate of the drug and the overall bioavailability (Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 9th edition, page 5 (1996)). GC4419 and its structural analogs are relatively soluble in water, however, they cannot maintain a neutral non-ionic form in water. Instead, when dissolved in water, the coordinate covalent bonds are cleaved, and the aqueous axial ligand replaces one or more chloro axial ligands, thereby generating a monocationic or dicationic complex, as shown in Scheme 1, where the cationic compound is expected to be less able to cross the intestinal barrier than the neutral complex.

[0016]

[0017] Thus, in various aspects of the present disclosure, transition metal complexes of pentaazamacrocyclic ligands comprising a 15-membered macrocyclic ring of formula A are provided that can be administered to a subject via oral and other routes of administration to obtain high systemic levels of the drug, including by oral administration. In a currently preferred embodiment, the transition metal is manganese. Summary of the invention

[0018] One aspect of the present disclosure is a transition metal complex comprising a transition metal composed of a macrocycle comprising a pentaaza 15-membered macrocyclic ring corresponding to Formula A and a transition metal having the formula -OC(O)X 1 The two axial ligands of

[0019] The macrocycle comprises a pentaaza 15-membered ring corresponding to Formula A, wherein Formula A may be further substituted, wherein

[0020]

[0021] Each of the two axial ligands has the formula -OC(O)X 1 ,in

[0022] Each X 1 are independently substituted or unsubstituted phenyl or -C(-X 2 )(-X 3 )(-X 4 );

[0023] Each X 2 are independently substituted or unsubstituted phenyl, or substituted or unsubstituted alkyl;

[0024] Each X 3 are independently hydrogen, hydroxy, alkyl, amino, -X 5 C(O)R 13 (Where X 5 is NH or O and R 13 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl, or -OR 14 Where R 14 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 aralkyl), or together with X 4 is = 0; and

[0025] Each X 4 independently hydrogen or together with X 3 Yes = O.

[0026] Another aspect of the present disclosure is a manganese complex comprising Mn 2+ or Mn 3+ , the Mn 2+ or Mn 3+ A macrocycle comprising a pentaaza 15-membered macrocyclic ring corresponding to formula A and a macrocycle having the formula -OC(O)X 1 The two axial ligands of

[0027] Each X 1 are independently substituted or unsubstituted phenyl or -C(-X 2 )(-X 3 )(-X 4 );

[0028] Each X 2 are independently substituted or unsubstituted phenyl or substituted or unsubstituted alkyl;

[0029] Each X 3 are independently hydrogen, hydroxy, alkyl, amino, -X 5 C(O)R 13 (Where X 5 is NH or O and R 13 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl, or -OR 14 Where R 14 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 aralkyl), or together with X 4 is = 0; and

[0030] Each X 4 independently hydrogen or together with X 3 Yes = O.

[0031] Another aspect of the present disclosure is a transition metal complex comprising a transition metal formed from five ring nitrogen atoms of a macrocycle comprising a fused ring system of formula B (which may optionally be further substituted as described elsewhere herein) and a transition metal having the formula -OC(O)X 1 The two axial ligands of

[0032] Formula B has the following formula

[0033]

[0034] Each X 1are independently substituted or unsubstituted phenyl or -C(-X 2 )(-X 3 )(-X 4 );

[0035] Each X 2 are independently substituted or unsubstituted phenyl or substituted or unsubstituted alkyl;

[0036] Each X 3 are independently hydrogen, hydroxy, alkyl, amino, -X 5 C(O)R 13 (Where X 5 is NH or O and R 13 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl, or -OR 14 Where R 14 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 aralkyl), or together with X 4 is = 0; and

[0037] Each X 4 independently hydrogen or together with X 3 Yes = O.

[0038] Another aspect of the present disclosure is to include Mn 2+ or Mn 3+ The transition metal complex of Mn 2+ or Mn 3+ A macrocycle comprising a fused ring system of formula B (which may be further substituted) and having the formula -OC(O)X 1 The two axial ligands of

[0039] Each X 1 are independently substituted or unsubstituted phenyl or -C(-X 2 )(-X 3 )(-X 4 );

[0040] Each X 2 are independently substituted or unsubstituted phenyl or substituted or unsubstituted alkyl;

[0041] Each X 3 are independently hydrogen, hydroxy, alkyl, amino, -X 5 C(O)R 13 (Where X 5is NH or O and R 13 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl, or -OR 14 Where R 14 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 aralkyl), or together with X 4 is = 0; and

[0042] Each X 4 independently hydrogen or together with X 3 Yes = O.

[0043] Another aspect of the present disclosure is a transition metal complex corresponding to formula (I):

[0044]

[0045] in

[0046] M is a transition metal (such as Mn 2+ , Mn 3+ , Mn 4+ , Mn 6+ , Mn 7+ , Fe 2+ , Fe 3+ , Fe 4+ , Fe 6+ 、Ni 2+ 、Ni 3+ , Cu 1+ , Cu 2 + 、V 2+ 、V 3+ 、V 4+ or V 5+ );

[0047] R 1A , R 1B , R 2A , R 2B , R 3A , R 3B , R 4A , R 4B , R 5A , R 5B , R 6A , R 6B , R 7A , R 7B , R 8A , R 8B , R9A , R 9B , R 10A and R 10B Independently are:

[0048] (i)Hydrogen;

[0049] (ii) a moiety independently selected from the group consisting of alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, heterocyclyl, and aralkyl groups and a group attached to the α-carbon of an amino acid (i.e., an α-amino acid); or

[0050] (iii) part, which is independently selected from the group consisting of:

[0051] -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 )、-OP(O)(OR 11 )(OR 12 ) and a substituent attached to the α-carbon of an amino acid (i.e., an α-amino acid), wherein R 11 and R 12 are independently hydrogen or alkyl;

[0052] (iv) a member of a substituted or unsubstituted, saturated, partially saturated or unsaturated ring or heterocyclic ring containing 3 to 20 carbon ring atoms, which includes

[0053] (a)R 1A or R 1B and R 2A or R 2B ; R 3A or R 3B and R 4A or R 4B ; R5A or R 5B and R 6A or R 6B ; R 7A or R 7B and R 8A or R 8B ; or R 9A or R 9B and R 10A or R 10B together with the carbon atoms to which they are each attached;

[0054] (b)R 10A or R 10B and R 1A or R 1B ; R 2A or R 2B and R 3A or R 3B ; R 4A or R 4B and R 5A or R 5B ; R 6A or R 6B and R 7A or R 7B ; or R 8A or R 8B and R 9A or R 9B together with the carbon atoms to which they are attached; or

[0055] (c)R 1A and R 1B ; R 2A and R 2B ; R 3A and R 3B ; R 4A and R 4B ; R 5A and R 5B ; R 6A and R 6B ; R 7A and R 7B ; R 8A and R 8B ; R 9A and R 9B ; or R 10A and R 10B together with the carbon atoms to which they are attached; or

[0056] (v) any combination of (i) to (iv) above;

[0057] Each X 1 are independently substituted or unsubstituted phenyl or -C(-X 2)(-X 3 )(-X 4 );

[0058] Each X 2 are independently substituted or unsubstituted phenyl or substituted or unsubstituted alkyl;

[0059] Each X 3 are independently hydrogen, hydroxy, alkyl, amino, -X 5 C(O)R 13 (Where X 5 is NH or O and R 13 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl, or -OR 14 Where R 14 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 aralkyl), or together with X 4 Yes = O;

[0060] Each X 4 independently hydrogen or together with X 3 is = 0; and

[0061] Bonds between transition metal M and macrocyclic nitrogen atoms and between transition metal M and axial ligand –OC(O)X 1 The bonds between the oxygen atoms are coordinate covalent bonds.

[0062] Another aspect of the present disclosure is a R ) or (ID S ) of the formula (I):

[0063]

[0064] in

[0065] M is Mn +2 or Mn +3 ;

[0066] R 1A , R 1B , R 2 , R 3 , R 4A , R 4B , R 5 , R 6 , R 7A , R 7B , R8 , R 9 , R 10A and R 10B are independently hydrogen, methyl, ethyl, or propyl;

[0067] W 1 , W 2 and W 3 are independently halo or hydrogen;

[0068] Each X 1 are independently substituted or unsubstituted phenyl or -C(-X 2 )(-X 3 )(-X 4 );

[0069] Each X 2 are independently substituted or unsubstituted phenyl, methyl, ethyl or propyl;

[0070] Each X 3 are independently hydrogen, hydroxy, methyl, ethyl or propyl, amino, -X 5 C(O)R 13 (Where X 5 is NH or O and R 13 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl, or -OR 14 Where R 14 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 aralkyl), or together with X 4 Yes = O;

[0071] Each X 4 independently hydrogen or together with X 3 is = 0; and

[0072] Bonds between Mn and the nitrogen atom of the macrocyclic ring and between Mn and the axial ligand – OC(O)X 1 The bonds between the oxygen atoms are coordinate covalent bonds.

[0073] Another aspect of the present disclosure is a pharmaceutical composition comprising any of the aforementioned pentaazamacrocyclic ring complexes and a pharmaceutically acceptable excipient suitable for administration.

[0074] Another aspect of the present disclosure is a method for administering a pentaazamacrocyclic ring complex to a subject, the method comprising administering to a human subject a pharmaceutical composition comprising any of the aforementioned pentaazamacrocyclic ring complexes.

[0075] Other objects and features will be in part apparent and in part pointed out hereinafter. BRIEF DESCRIPTION OF THE DRAWINGS

[0076] Figure 1 is a series of characteristic graphs of plasma concentrations of the parent manganese pentaazamacrocyclic ring complex of GC4419 (independent of the composition of the axial ligand) in minipig plasma from blood samples at time points up to 24 hours following administration of the test article drug (where all compounds shown are derivatives of GC4419) by intravenous (iv) or intraduodenal (id) delivery, where the id test article was formulated in Capmul MCM as described in the Examples.

[0077] Figure 2 is a series of characteristic graphs of plasma concentrations of the parent manganese pentaazamacrocyclic complex of GC4419 (independent of the composition of the axial ligand) in minipig plasma from blood samples at time points up to 24 hours after administration of the test article drug (all compounds shown are derivatives of GC4419) by iv or id delivery, wherein the id test article was formulated in Peceol as described in the Examples.

[0078] Figure 3 is a series of characteristic graphs of plasma concentrations of the parent manganese pentaazamacrocyclic ring complex of GC4419 (independent of the composition of the axial ligand) in minipig plasma from blood samples at time points up to 24 hours following administration of the test article drug (where all compounds shown are derivatives of GC4419) by iv or id delivery, where the id test article was formulated in Labrafil M2125 CS as described in the Examples.

[0079] Figure 4 is a series of characteristic graphs of plasma concentrations of the parent manganese pentaazamacrocyclic ring complex of GC4419 (independent of the composition of the axial ligand) in minipig plasma from blood samples at time points up to 24 hours following administration of the test article drug (where all compounds shown are derivatives of GC4419) by iv or id delivery, where the id test article was formulated in Labrafil M2125 CS as described in the Examples.

[0080] Figure 5is a series of characteristic graphs of plasma concentrations of the parent manganese pentaazamacrocyclic ring complex of GC4401 (independent of the composition of the axial ligand) in minipig plasma from blood samples at time points up to 24 hours following administration of the test article drug (where all compounds shown are derivatives of GC4401) by iv or id delivery, where the id test article was formulated in Capmul MCM as described in the Examples.

[0081] Figure 6 is a series of characteristic graphs of plasma concentrations of the parent manganese pentaazamacrocyclic ring complex of GC4444 (independent of the composition of the axial ligand) in minipig plasma from blood samples at time points up to 24 hours following administration of the test article drug (where all compounds shown are derivatives of GC4444) by iv or id delivery, where the id test article was formulated in Capmul MCM as described in the Examples.

[0082] Figure 7 is a series of characteristic graphs of plasma concentrations of the parent manganese pentaazamacrocyclic ring complex of GC4419 (independent of the composition of the axial ligand) in minipig plasma from blood samples at time points up to 24 hours following administration of the test article drug (where all compounds shown are derivatives of GC4419) by iv or id delivery, where the id test article was formulated in Capmul MCM as described in the Examples.

[0083] Figure 8 is a series of characteristic graphs of plasma concentrations of the parent manganese pentaazamacrocyclic ring complex of GC4419 (independent of the composition of the axial ligand) in minipig plasma from blood samples at time points up to 24 hours after administration of the test article drug (all compounds shown are derivatives of GC4419) by iv or id delivery, wherein the id test article was formulated in Maisine 35-1 as described in the Examples.

[0084] Fig. 9 is a series of characteristic graphs of plasma concentrations of the parent manganese pentaazamacrocyclic ring complex of GC4403 (independent of the composition of the axial ligand) in minipig plasma from blood samples at time points up to 24 hours following administration of the test article drug (where all compounds shown are derivatives of GC4403) by iv or id delivery, where the id test article was formulated in Capmul MCM as described in the Examples.

[0085] Fig.10 is a schematic representation of a subset of axial ligand structures that provide enhanced oral bioavailability.

[0086] Fig.11is the X-ray crystal structure of GC4403 (as reported in Riley et al., Advances in Inorganic Chemistry, Vol. 59, pp. 233-263 (2007)).

[0087] Fig.12 is the X-ray crystal structure of GC4419 obtained by the method reported in Riley et al., Advances in Inorganic Chemistry, Vol. 59, pp. 233-263 (2007).

[0088] Abbreviations and definitions

[0089] The following definitions and methods are provided to better define the present invention and guide those of ordinary skill in the art to implement the present invention. Unless otherwise indicated, terms are understood according to conventional usage by those of ordinary skill in the relevant art.

[0090] "Acyl" means 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.

[0091] "Acyloxy" means a -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.

[0092] "Alkoxy" means a -OR moiety where R is alkyl as defined above, such as methoxy, ethoxy, propoxy or 2-propoxy, n-, iso- or tert-butoxy, and the like.

[0093] "Alkyl" means a straight chain saturated monovalent hydrocarbon moiety such as one to six carbon atoms, or a branched chain saturated monovalent hydrocarbon moiety such as three to six 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.

[0094] Furthermore, unless otherwise indicated, the term "alkyl" as used herein is intended to include both "unsubstituted alkyl" and "substituted alkyl," the latter referring to alkyl moieties having substituents replacing hydrogen on one or more carbons of the hydrocarbon backbone. In fact, all groups cited herein are intended to include both substituted and unsubstituted options unless otherwise indicated.

[0095] The term "C x-y "" when used in conjunction with chemical moieties such as alkyl and aralkyl, is intended to include groups containing from x to y carbons in the chain. For example, the term Cx-y Alkyl refers to a substituted or unsubstituted saturated hydrocarbon group, including straight chain alkyl and branched chain alkyl groups containing x to y carbon atoms in the chain.

[0096] "Alkylene" means a straight chain saturated divalent hydrocarbon moiety such as one to six carbon atoms, or a branched chain saturated divalent hydrocarbon moiety such as three to six carbon atoms, unless otherwise indicated, such as methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

[0097] "Alkenyl" is a straight chain unsaturated monovalent hydrocarbon moiety such as of two to six carbon atoms, or a branched chain saturated monovalent hydrocarbon moiety such as of three to six carbon atoms, such as ethenyl (vinyl), propenyl, 2-propenyl, butenyl (including all isomeric forms), pentenyl (including all isomeric forms), and the like.

[0098] "Alkaryl" means a monovalent moiety derived from an aryl moiety by replacing one or more hydrogen atoms with an alkyl group.

[0099] "Alkenylcycloalkenyl" means a monovalent moiety derived from an alkenyl moiety by replacing one or more hydrogen atoms with a cycloalkenyl radical.

[0100] "Alkenylcycloalkyl" means a monovalent moiety derived from a cycloalkyl moiety by replacing one or more hydrogen atoms with an alkenyl group.

[0101] "Alkylcycloalkenyl" means a monovalent moiety derived from a cycloalkenyl moiety by replacing one or more hydrogen atoms with an alkyl group.

[0102] "Alkylcycloalkyl" means a monovalent moiety derived from a cycloalkyl moiety by replacing one or more hydrogen atoms with an alkyl group.

[0103] "Alkynyl" means a straight chain unsaturated monovalent hydrocarbon moiety, such as of two to six carbon atoms, or a branched chain saturated monovalent hydrocarbon moiety, such as of three to six carbon atoms, such as ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like.

[0104] "Alkoxy" means a monovalent moiety derived from an alkyl moiety by replacing one or more hydrogen atoms with a hydroxy group.

[0105] "Amino" means -NR a R b Group, where R a and R b are independently hydrogen, alkyl or aryl.

[0106] "Aralkyl" means a monovalent moiety derived from an alkyl moiety by replacing one or more hydrogen atoms with an aryl group.

[0107] "Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon moiety of 6 to 10 ring atoms, such as phenyl or naphthyl.

[0108] "Ring" means a carbocyclic saturated monovalent hydrocarbon moiety of three to ten carbon atoms.

[0109] "Cycloalkyl" means a cyclic saturated monovalent hydrocarbon moiety of three to ten carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and the like.

[0110] "Cycloalkylalkyl" means a monovalent moiety derived from an alkyl moiety by replacing one or more hydrogen atoms with a cycloalkyl group, such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, or cyclohexylethyl and the like.

[0111] "Cycloalkylcycloalkyl" means a monovalent moiety derived from a cycloalkyl moiety by replacing one or more hydrogen atoms with a cycloalkyl group.

[0112] "Cycloalkenyl" means a cyclic monounsaturated monovalent hydrocarbon moiety of three to ten carbon atoms, such as cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl and the like.

[0113] "Cycloalkenylalkyl" means a monovalent moiety derived from an alkyl moiety by replacing one or more hydrogen atoms with a cycloalkenyl group, such as cyclopropenylmethyl, cyclobutenylmethyl, cyclopentenylethyl, or cyclohexenylethyl and the like.

[0114] The "enteric coating layer" comprises one or more enteric polymers and one or more pharmaceutically acceptable excipients, including but not limited to sustained release agents such as ethyl acrylate-methacrylic acid copolymer, ethyl cellulose.

[0115] "Ether" means a monovalent moiety derived from an alkyl moiety by replacing one or more hydrogen atoms with an alkoxy group.

[0116] "Halo" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0117] "Heterocycle" or "heterocyclyl" means a saturated or unsaturated monovalent monocyclic radical of 4 to 8 ring atoms, one or two of which are selected from N, O or S(O). n(wherein n is an integer selected from 0 to 2) heteroatoms, the remaining ring atoms are C. The heterocyclyl ring is optionally fused to one (one) aryl ring or heteroaryl ring as defined herein, provided that the aryl ring and heteroaryl ring are monocyclic. The heterocyclyl ring fused to a monocyclic aryl ring or heteroaryl ring is also referred to as a "bicyclic heterocyclic radical" ring in the present application. In addition, one or two ring carbon atoms in the heterocyclyl ring can be optionally replaced by -CO- groups. More specifically, the term heterocyclyl includes but is not limited to pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl, thiomorpholino, etc. When the heterocyclyl ring is unsaturated, it may contain one or two ring double bonds, provided that the ring is not aromatic. When the heterocyclyl group is a saturated ring and is not fused to an aryl ring or heteroaryl ring as described above, it is also referred to herein as a saturated monocyclic heterocyclyl.

[0118] "Heteroaryl" means a monovalent monocyclic or bicyclic aromatic moiety of 5 to 10 ring atoms, wherein one or more, preferably one, two or three, ring atoms are heteroatoms selected from N, O or S, and the remaining ring atoms are carbon. Representative examples include, but are not limited to, pyrrolyl, pyrazolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolyl, isoquinolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like.

[0119] "Nitro" means -NO 2 .

[0120] "Organosulfur" means a monovalent moiety -SR group, where R is hydrogen, alkyl, or aryl.

[0121] "Substituted alkyl", "substituted ring", "substituted phenyl", "substituted aryl", "substituted heterocycle" and "substituted nitrogen heterocycle" mean an alkyl, ring, aryl, phenyl, heterocycle or nitrogen-containing heterocycle optionally substituted with one, two or three substituents, respectively, such as those independently selected from alkyl, alkoxy, alkoxyalkyl, halo, hydroxy, hydroxyalkyl or organosulfur.

[0122] "Thioether" means a monovalent moiety derived from an alkyl moiety by replacing one or more hydrogen atoms with a -SR group, where R is alkyl.

[0123] As used herein, (i) compounds referred to herein and in the figures as Compound 401, 4401 or GC4401 are references to the same compound, (ii) compounds referred to herein and in the figures as Compound 403, 4403 or GC4403 are references to the same compound, (iii) compounds referred to herein and in the figures as Compound 419, 4419 or GC4419 are references to the same compound, and (iv) compounds referred to herein and in the figures as Compound 444, 4444 or GC4444 are references to the same compound.

[0124] Details

[0125] Aspects of the present disclosure include novel transition metal complexes of pentaaza macrocycles that also have axial ligands that have the ability to be converted in the circulation to the same species that similar bis-chloro axial ligand complexes are converted in the circulation. The compounds or complexes described herein thus have similar therapeutic efficacy to their bis-chloro analogs, but are significantly more versatile with respect to routes of administration. In other words, the compounds of the present disclosure have enhanced oral bioavailability relative to their bis-chloro analogs, and in some embodiments, also have other advantageous properties selected from one or more of the following: increased intestinal permeability, solubility in aqueous and / or oil-based dosage formulations, ease of manufacture, and / or stability.

[0126] Thus, the present disclosure relates to 15-membered complexes of a pentaaza macrocycle and Mn(II) (or other transition metal), wherein the non-macrocyclic ring ligand (i.e., the axial ligand) covalently bonded to the manganese(II) (or other transition metal) is selected from the group of moieties that yield complexes with improved versatility with respect to routes of administration (including oral administration) relative to, for example, known bis-chloro complexes. In certain embodiments, for example, the complexes described herein exhibit increased uptake across the intestinal wall, but are still able to lose one or more axial ligands in exchange for water to produce materials in the circulation similar to those obtained with the bis-chloro complex shown in Scheme 1 above. In these and / or other embodiments, for example, the complexes may also exhibit improved solubility in oil- or water-based (or other) solvents compared to the bis-chloro complex.

[0127] In a first aspect, there is provided a coordinated metal complex corresponding to formula (I):

[0128]

[0129] in

[0130] M is a transition metal (such as Mn 2+ , Mn 3+ , Mn 4+ , Mn6+ , Mn 7+ , Fe 2+ , Fe 3+ , Fe 4+ , Fe 6+ 、Ni 2+ 、Ni 3+ , Cu 1+ , Cu 2 + 、V 2+ 、V 3+ 、V 4+ or V 5+ );

[0131] R 1A , R 1B , R 2A , R 2B , R 3A , R 3B , R 4A , R 4B , R 5A , R 5B , R 6A , R 6B , R 7A , R 7B , R 8A , R 8B , R 9A , R 9B , R 10A and R 10B Independently are:

[0132] (i)Hydrogen;

[0133] (ii) a moiety independently selected from the group consisting of alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, heterocyclyl, and aralkyl groups and a group attached to the α-carbon of an amino acid (i.e., an α-amino acid); or

[0134] (iii) moieties independently selected from the group consisting of: -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 NR11 R 12 、-N(OR 11 )(R 12 )、-P(=O)(OR 11 )(OR 12 )、-P(=O)(OR 11 )(R 12 ),-OP(=O)(OR 11 )(OR 12 ) and a substituent attached to the α-carbon of an amino acid (i.e., an α-amino acid), wherein R 11 and R 12 are independently hydrogen or alkyl;

[0135] (iv) members of a substituted or unsubstituted, saturated, partially saturated or unsaturated ring or heterocyclic ring containing from 3 to 20 carbon ring atoms, including:

[0136] (a)R 1A or R 1B and R 2A or R 2B ; R 3A or R 3B and R 4A or R 4B ; R 5A or R 5B and R 6A or R 6B ; R 7A or R 7B and R 8A or R 8B ; or R 9A or R 9B and R 10A or R 10B together with the carbon atoms to which they are each attached;

[0137] (b)R 10A or R 10B and R 1A or R 1B ; R 2A or R 2B and R 3A or R 3B ; R 4A or R 4B and R 5A or R 5B ; R 6A or R 6B and R 7A or R 7B ; or R 8A or R 8B and R 9A or R 9Btogether with the carbon atoms to which they are attached; or

[0138] (c)R 1A and R 1B ; R 2A and R 2B ; R 3A and R 3B ; R 4A and R 4B ; R 5A and R 5B ; R 6A and R 6B ; R 7A and R 7B ; R 8A and R 8B ; R 9A and R 9B ; or R 10A and R 10B together with the carbon atoms to which they are attached; or

[0139] (v) any combination of (i) to (iv) above;

[0140] Each X 1 are independently substituted or unsubstituted phenyl or

[0141] -C(-X 2 )(-X 3 )(-X 4 );

[0142] Each X 2 are independently substituted or unsubstituted phenyl or substituted or unsubstituted alkyl;

[0143] Each X 3 are independently hydrogen, hydroxy, alkyl, amino, -X 5 C(=O)R 13 (Where X 5 is NH or O and R 13 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl, or -OR 14 Where R 14 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 aralkyl), or together with X 4 Yes (=O);

[0144] Each X 4 independently hydrogen or together with X3 is(=0); and

[0145] The bond between the transition metal M and the nitrogen atom of the macrocyclic ring and between the transition metal M and the axial ligand –OC(=O)X 1 The bonds between the oxygen atoms are coordinate covalent bonds.

[0146] In a second aspect, the present disclosure relates to pharmaceutical compositions and unit dose formulations comprising a compound of formula (I) (or any of its embodiments described herein) and a pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical composition is formulated for oral administration. In another embodiment, the pharmaceutical composition is formulated for parenteral administration. In another embodiment, the pharmaceutical composition is formulated for topical administration. The pharmaceutical compositions and unit dose formulations of the second aspect will be discussed in further detail below.

[0147] Implementation

[0148] Implementation Plan (IA)

[0149] In embodiment (IA), the pentaazamacrocyclic ring complex of formula (I) corresponds to formula (IA):

[0150]

[0151] in

[0152] M is a transition metal (such as Mn 2+ , Mn 3+ , Mn 4+ , Mn 6+ , Mn 7+ , Fe 2+ , Fe 3+ , Fe 4+ , Fe 6+ 、Ni 2+ 、Ni 3+ , Cu 1+ , Cu 2 + 、V 2+ 、V 3+ 、V 4+ or V 5+ );

[0153] R 1A , R 1B , R 2 , R 3 , R 4A , R 4B , R 5 , R 6 , R 7A , R 7B , R8 , R 9 , R 10A and R 10B is independently hydrogen, a hydrocarbon group, a substituted hydrocarbon group, a heterocyclic group, an amino acid side chain moiety, or a moiety independently selected from the group consisting of: -OR 11 、-NR 11 R 12 、-COR 11 , -CO 2 R 11 ,

[0154] -C(=O)NR 11 R 12 、-SR 11 、-SOR 11 、-SO 2 R 11 、-SO 2 NR 11 R 12 ,

[0155] -N(OR 11 )(R 12 ),

[0156] -P(=O)(OR 11 )(OR 12 )、-P(=O)(OR 11 )(R 12 ) and -OP(=O)(OR 11 )(OR 12 ), where R 11 and R 12 are independently hydrogen or alkyl;

[0157] U, together with the adjacent carbon atoms of the macrocyclic ring, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated ring or heterocyclic ring having 3 to 20 ring carbon atoms;

[0158] V, together with the adjacent carbon atoms of the macrocyclic ring, forms a fused, substituted or unsubstituted, saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms;

[0159] W, together with the nitrogen of the macrocycle and the carbon atom of the macrocycle to which it is attached, forms an aromatic or alicyclic, substituted or unsubstituted, saturated, partially saturated or unsaturated nitrogen-containing fused heterocyclic ring having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocyclic ring, the hydrogen attached to the nitrogen is part of both the heterocyclic ring and the macrocyclic ring, and the R attached to the carbon atom is part of both the heterocyclic ring and the macrocyclic ring. 5 and R 6 does not exist;

[0160] Each X 1 are independently substituted or unsubstituted phenyl or -C(-X 2 )(-X 3 )(-X 4 );

[0161] Each X 2 are independently substituted or unsubstituted phenyl or alkyl;

[0162] Each X 3 are independently hydrogen, hydroxy, alkyl, amino, -X 5 C(=O)R 13 (Where X 5 is NH or O and R 13 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl, or -OR 14 Where R 14 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 aralkyl), or together with X 4 Yes (=O);

[0163] Each X 4 independently hydrogen or together with X 3 is(=0); and

[0164] The bond between the transition metal M and the nitrogen atom of the macrocyclic ring and between the transition metal M and the axial ligand –OC(=O)X 1 The bonds between the oxygen atoms are coordinate covalent bonds.

[0165] Within embodiment (IA), in one group of compounds, U and V together with adjacent carbon atoms of the macrocyclic ring form a fused substituted or unsubstituted, saturated or heterocyclic ring having 6 ring atoms and R 2 , R 3 , R 8 and R 9 is hydrogen, and W together with the nitrogen of the macrocycle and the carbon atom of the macrocycle to which it is attached forms an aromatic or alicyclic, substituted or unsubstituted, saturated, partially saturated or unsaturated nitrogen-containing fused heterocycle having 6 ring atoms, provided that when W is a fused aromatic heterocycle, the hydrogen attached to the nitrogen is part of both the heterocycle and the macrocycle, and the R attached to the carbon atom is part of both the heterocycle and the macrocycle 5 and R 6 Does not exist.

[0166] In embodiment (IA) and the groups contained therein, in one group of compounds, M is Mn 2+ , Mn 3+ , Mn 4+ , Mn 6+ , Mn 7+ , Fe 2+ , Fe 3+ , Fe 4+ or Fe 6+ .

[0167] In embodiment (IA) and the groups contained therein, in one group of compounds, X 1 In Embodiment (IA) and the groups contained therein, in one group of compounds, X 1 Yes –C(-X 2 )(-X 3 )(-X 4 ) and each X of the combination 2 , X 3 and X 4 Corresponds to any one of the combinations identified in the following table:

[0168]

[0169] Additionally, within embodiment (IA) and the groups contained therein, in one group of compounds, X 1 is C(-X 2 )(-X 3 )(-X 4 ) and X 3 Yes-X 5 C(=O)R 13 , so that X 2 , X 3 and X 4 The combination includes any one of the combinations identified in the following table:

[0170] combination <![CDATA[X 2 ]]> <![CDATA[X 3 ]]> <![CDATA[X 4 ]]> 1 Ph <![CDATA[NHC(=O)R 13 ]]> H 2 Ph <![CDATA[OC(=O)R 13 ]]> H 3 <![CDATA[CH 3 ]]> <![CDATA[NHC(=O)R 13 ]]> H 4 <![CDATA[CH 3 ]]> <![CDATA[OC(=O)R 13 ]]> H

[0171] Where R 13 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl, or -OR 14 Where R 14 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl.

[0172] Implementation Plan (IB)

[0173] Within embodiment (IB), the pentaazamacrocyclic ring complex of formula (I) corresponds to formula (IB):

[0174]

[0175] in

[0176] M is Fe +2 , Fe +3 , Mn +2 or Mn +3 ;

[0177] 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 As defined in conjunction with embodiment (IA) above;

[0178] W 1 , W 2 and W 3 are independently halo, hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, acyl, acyloxy, alkoxy, ether, thioether or nitro;

[0179] Each X 1 are independently substituted or unsubstituted phenyl or -C(-X 2 )(-X 3 )(-X 4 );

[0180] Each X 2 are independently substituted or unsubstituted phenyl, methyl, ethyl or propyl;

[0181] Each X 3 are independently hydrogen, hydroxy, methyl, ethyl, propyl, amino, -X 5 C(=O)R 13 (Where X 5 is NH or O and R 13 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl, or -OR 14 Where R14 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 aralkyl), or together with X 4 Yes (=O);

[0182] Each X 4 independently hydrogen or together with X 3 is(=0); and

[0183] The bond between the transition metal M and the nitrogen atom of the macrocyclic ring and between the transition metal M and the axial ligand –OC(=O)X 1 The bonds between the oxygen atoms are coordinate covalent bonds.

[0184] In implementation scheme (IB), when W 1 , W 2 and W 3 When one or more of the substituted moieties are substituted alkyl, alkenyl, alkynyl, aryl, aralkyl or alkaryl, these substituents may contain 1 to 20 carbon atoms (preferably 1 to 6 carbon atoms) and may be linear, branched or cyclic, wherein one or more hydrogen atoms of the substituted moiety are replaced by different substituents, such as, for example, -OH, -OR, -C(=O)OH,

[0185] –C(=O)NH 2 、-NH 2 , -NHR, -NRR, -SH, -SR, -SO 2 R, -SO 2 H, -SOR, heterocycle and / or halo (including F, Cl, Br and I), etc., wherein each occurrence of R may be substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted aralkyl.

[0186] In embodiment (IB) and groups contained therein, in one group of compounds, M is Mn +2 or Mn +3 In another group of compounds, M is Fe +2 or Fe +3 .

[0187] In embodiment (IB) and groups contained therein, in one group of compounds, X 1 In Embodiment (IB) and the groups contained therein, in one group of compounds, X 1 Yes –C(-X 2 )(-X 3 )(-X 4 ) and each X of the combination 2, X 3 and X 4 Corresponds to any one of the combinations identified in the following table:

[0188] Additionally, within embodiment (IB) and groups contained therein, in one group of compounds, X 1 is C(-X 2 )(-X 3 )(-X 4 ) and X 3 Yes-X 5 C(O)R 13 , so that X 2 , X 3 and X 4 The combination includes any one of the combinations identified in the following table:

[0189] combination <![CDATA[X 2 ]]> <![CDATA[X 3 ]]> <![CDATA[X 4 ]]> 1 Ph <![CDATA[NHC(=O)R 13 ]]> H 2 Ph <![CDATA[OC(=O)R 13 ]]> H 3 <![CDATA[CH 3 ]]> <![CDATA[NHC(=O)R 13 ]]> H 4 <![CDATA[CH 3 ]]> <![CDATA[OC(=O)R 13 ]]> H

[0190] Where R 13 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl, or -OR 14 Where R 14 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl.

[0191] Implementation Plan (IC)

[0192] In embodiment (IC), the pentaazamacrocyclic ring complex of formula (I) corresponds to formula (IC R ) or (IC S ):

[0193]

[0194] in

[0195] M is Fe +2 , Fe +3 , Mn +2 or Mn +3 ;

[0196] R 1A , R 1B , R 2 , R 3 , R 4A , R 4B , R 5 , R6 , R 7A , R 7B , R 8 , R 9 , R 10A and R 10B are independently hydrogen or substituted or unsubstituted alkyl;

[0197] W 1 , W 2 and W 3 are independently halo or hydrogen;

[0198] Each X 1 are independently substituted or unsubstituted phenyl or -C(-X 2 )(-X 3 )(-X 4 );

[0199] Each X 2 are independently substituted or unsubstituted phenyl, methyl, ethyl or propyl;

[0200] Each X 3 are independently hydrogen, hydroxy, methyl, ethyl, propyl, amino, -X 5 C(=O)R 13 (Where X 5 is NH or O and R 13 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl, or -OR 14 Where R 14 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 aralkyl), or together with X 4 Yes (=O);

[0201] Each X 4 independently hydrogen or together with X 3 is(=0); and

[0202] Bonds between transition metal M and macrocyclic nitrogen atoms and between transition metal M and axial ligand –OC(O)X 1 The bonds between the oxygen atoms are coordinate covalent bonds.

[0203] In one group of compounds, M is Mn 2+ In another group of compounds, within embodiment (IC), M is Mn 3+ .

[0204] In Embodiment (IC) and the groups contained therein, in one group of compounds, X 1 In Embodiment (IC) and the groups contained therein, in one group of compounds, X 1 Yes –C(-X 2 )(-X 3 )(-X 4 ) and each X of the combination 2 , X 3 and X 4 Corresponds to any one of the combinations identified in the following table:

[0205]

[0206] Furthermore, within Embodiment (IC) and the groups contained therein, in a group of compounds, X 1 is C(-X 2 )(-X 3 )(-X 4 ) and X 3 Yes-X 5 C(O)R 13 , so that X 2 , X 3 and X 4 The combination includes any one of the combinations identified in the following table:

[0207] combination <![CDATA[X 2 ]]> <![CDATA[X 3 ]]> <![CDATA[X 4 ]]> 1 Ph <![CDATA[NHC(=O)R 13 ]]> H 2 Ph <![CDATA[OC(=O)R 13 ]]> H 3 <![CDATA[CH 3 ]]> <![CDATA[NHC(=O)R 13 ]]> H 4 <![CDATA[CH 3 ]]> <![CDATA[OC(=O)R 13 ]]> H

[0208] Where R 13 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl, or -OR 14 Where R 14 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl.

[0209] Implementation plan (ID)

[0210] In embodiment (ID), the pentaazamacrocyclic ring complex of formula (I) corresponds to formula (ID R ) or (ID S ):

[0211]

[0212] in

[0213] M is Mn +2or Mn +3 ;

[0214] 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, methyl, ethyl or propyl;

[0215] W 1 , W 2 and W 3 are independently halo or hydrogen;

[0216] Each X 1 are independently substituted or unsubstituted phenyl or -C(-X 2 )(-X 3 )(-X 4 );

[0217] Each X 2 are independently substituted or unsubstituted phenyl, methyl, ethyl or propyl;

[0218] Each X 3 are independently hydrogen, hydroxy, methyl, ethyl, propyl, amino, -X 5 C(=O)R 13 (Where X 5 is NH or O and R 13 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl, or -OR 14 Where R 14 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 aralkyl), or together with X 4 Yes (=O);

[0219] Each X 4 independently hydrogen or together with X 3 is(=0); and

[0220] Transition metal M (Mn +2 or Mn +3) and the nitrogen atom of the macrocyclic ring and the transition metal M and the axial ligand –OC(=O)X 1 The bonds between the oxygen atoms are coordinate covalent bonds.

[0221] In one group of compounds, M is Mn 2+ In another group of compounds, M is Mn 3+ .

[0222] In Embodiment (ID) and the groups contained therein, in one group of compounds, R 1A , R 1B , R 4A , R 4B , R 7A , R 7B , R 10A and R 10B Each is hydrogen. In Embodiment (ID) and the groups contained therein, in one group of compounds, R 1B , R 4A , R 4B , R 7A , R 7B , R 10A and R 10B Each is hydrogen and R 1A In Embodiment (ID) and the groups contained therein, in one group of compounds, R 1A , R 4A , R 4B , R 7A , R 7B , R 10A and R 10B Each is hydrogen and R 1B In Embodiment (ID) and the groups contained therein, in one group of compounds, R 1A , R 1B , R 4B , R 7A , R 10A and R 10B Each is hydrogen and R 4A and R 7B In Embodiment (ID) and the groups contained therein, in one group of compounds, R 1A , R 1B , R 4A , R 7B , R 10A and R 10B Each is hydrogen and R 4B and R 7A Each is a methyl group.

[0223] In Embodiment (ID) and the groups contained therein, in one group of compounds, X 1 In Embodiment (ID) and the groups contained therein, in one group of compounds, X 1 Yes –C(-X 2 )(-X 3 )(-X 4 ) and each X of the combination 2 , X 3 and X 4 Corresponds to any one of the combinations identified in the following table:

[0224]

[0225] Furthermore, within Embodiment (ID) and the groups contained therein, in a group of compounds, X 1 is C(-X 2 )(-X 3 )(-X 4 ) and X 3 Yes-X 5 C(O)R 13 , so that X 2 , X 3 and X 4 The combination includes any one of the combinations identified in the following table:

[0226] combination <![CDATA[X 2 ]]> <![CDATA[X 3 ]]> <![CDATA[X 4 ]]> 1 Ph <![CDATA[NHC(=O)R 13 ]]> H 2 Ph <![CDATA[OC(=O)R 13 ]]> H 3 <![CDATA[CH 3 ]]> <![CDATA[NHC(=O)R 13 ]]> H 4 <![CDATA[CH 3 ]]> <![CDATA[OC(=O)R 13 ]]> H

[0227] Where R 13 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl, or -OR 14 Where R 14 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl.

[0228] Implementation Plan (IE)

[0229] In embodiment (IE), the pentaazamacrocyclic ring complex of formula (I) corresponds to formula (IE R1 )、(IE S1 )、(IE R2 )、(IE S2 )、(IE R3 ) or (IE S3 ):

[0230]

[0231] in

[0232] Mn is Mn +2 or Mn +3 ;

[0233] Each X 1 are independently substituted or unsubstituted phenyl or -C(-X 2 )(-X 3 )(-X 4 );

[0234] Each X 2 are independently hydrogen, hydroxy, methyl, ethyl, propyl, amino, -X 5 C(=O)R 13 (Where X 5 is NH or O and R 13 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl, or -OR 14 Where R 14 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 aralkyl), or together with X 4 Yes (=O);

[0235] Each X 4 independently hydrogen or together with X 3 is(=0); and

[0236] The bonds between Mn and the nitrogen atom of the macrocyclic ring and between Mn and the axial ligand –OC(=O)X 1 The bonds between the oxygen atoms are coordinate covalent bonds.

[0237] In embodiment (IE) and groups contained therein, in one group of compounds, X 1 In embodiment (IE) and the groups contained therein, in one group of compounds, X 1 Yes –C(-X 2 )(-X 3 )(-X 4 ) and each X of the combination 2 , X 3 and X 4 Corresponds to any one of the combinations identified in the following table:

[0238]

[0239] Additionally, within embodiment (IE) and groups contained therein, in one group of compounds, X 1 is C(-X 2 )(-X 3 )(-X 4 ) and X 3 Yes-X 5 C(O)R 13 , so that X 2 , X 3 and X 4 The combination includes any one of the combinations identified in the following table:

[0240] combination <![CDATA[X 2 ]]> <![CDATA[X 3 ]]> <![CDATA[X 4 ]]> 1 Ph <![CDATA[NHC(=O)R 13 ]]> H 2 Ph <![CDATA[OC(=O)R 13 ]]> H 3 <![CDATA[CH 3 ]]> <![CDATA[NHC(=O)R 13 ]]> H 4 <![CDATA[CH 3 ]]> <![CDATA[OC(=O)R 13 ]]> H

[0241] Where R 13 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl, or -OR 14 Where R 14 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl.

[0242] Unit dose formulations and pharmaceutical compositions

[0243] As described above, the second aspect of the present disclosure relates to unit dose formulations and pharmaceutical compositions, which include compounds described herein, usually with a pharmaceutically acceptable carrier or excipient, and optionally in combination with another one or more pharmaceutically active compounds. The pharmaceutical composition includes a five aza macrocyclic ring complex corresponding to formula (I) (or any embodiment thereof or other compounds described herein, such as any compound listed in Table I of the Examples section), and the complex is usually formulated into a pharmaceutical dosage form, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient. In one embodiment, for example, the pharmaceutical composition includes a compound of formula (I) (or any embodiment thereof or other compounds described herein, such as any compound listed in Table I of the Examples section) and a pharmaceutically acceptable carrier or excipient. Unit dose formulations and pharmaceutical compositions according to the present disclosure can be used, for example, to treat various cardiovascular disorders, cerebrovascular disorders, skin disorders, fibrotic disorders, gastrointestinal disorders, immune disorders, inflammatory disorders, metabolic disorders, neurological disorders, ophthalmic disorders, pulmonary disorders, infectious disorders, tissue damage and combinations thereof. Specific diseases and conditions include fibrosis, inflammatory diseases and conditions (including, for example, inflammatory bowel disease, rheumatoid arthritis, asthma, COPD, pancreatitis, etc.), dermatitis, psoriasis, etc., as well as for protecting tissue from damage caused by cancer treatment or other exposure to radiation, as discussed in further detail below.

[0244] The preparation containing the compound can be in the form of a solid, semi-solid, lyophilized powder or liquid dosage form, such as, for example, an aerosol, capsule, cream, emulsion, foam, gel / jelly, injection, lotion, ointment, paste, powder, soap, solution, spray, suppository, suspension, sustained release formulation, tablet, tincture, transdermal patch, etc., preferably in a unit dosage form suitable for simple administration of precise dosage. If formulated as a fixed dose, such pharmaceutical compositions or formulation products preferably use compounds within certain dosage ranges. Depending on the intended mode of administration, therefore, in some embodiments, the composition can be in a solid, semi-solid or liquid dosage form, such as, for example, injection, tablet, pill, timed release capsule, elixir, tincture, emulsion, syrup, liquid, suspension, etc., sometimes in a unit dose and consistent with conventional pharmaceutical practice. Similarly, in some embodiments, they can also be administered via intravenous (bolus and infusion), intraperitoneal, subcutaneous, local or intramuscular routes or other routes described herein, all of which are used in forms well known to those skilled in the pharmaceutical field.

[0245] One specific embodiment of the present disclosure is directed to a unit dose formulation comprising a compound corresponding to Formula (I) (or any embodiment thereof or other compounds described herein, such as any compound listed in Table 1 of the Examples section) in an oral dosage form as described herein. Another specific embodiment of the present disclosure is directed to a unit dose formulation comprising a compound corresponding to Formula (I) (or any embodiment thereof or other compounds described herein, such as any compound listed in Table 1 of the Examples section) in a parenteral dosage form as described herein.

[0246] For oral and non-oral dosage formulations, the above-described compound (or any embodiment thereof or other compounds described herein, such as any compound listed in Table I of the Examples section) can be dispersed in a pharmaceutically acceptable carrier before administration to a mammal. A carrier, also known in the art as an excipient, vehicle, auxiliary agent, adjuvant or diluent, is generally a pharmaceutically inert substance that imparts a suitable consistency or form to the composition and does not reduce the efficacy of the compound. A carrier is generally considered to be "pharmaceutically or pharmacologically acceptable" if it does not produce unacceptable adverse reactions, allergic reactions or other adverse reactions when administered to a mammal, particularly a human.

[0247] The selection of pharmaceutically acceptable carriers will also partially vary with the route of administration. Generally, compositions as described herein can be formulated for any route of administration, as long as the blood circulation system can be used through this route and according to the conventional route of administration of components (such as compounds). For example, suitable routes of administration include but are not limited to oral, parenteral (such as intravenous, intraarterial, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal or intrasternal), local (nasal, transdermal, buccal, eye), intravesical, intrathecal, intestinal, lung, lymphatic, intracavitary, vaginal, rectal, transurethral, ​​intradermal, intraocular, ear, breast, in situ, intratracheal, intralesional, transdermal, endoscope, transmucosal, sublingual and intestinal administration. In a particularly preferred embodiment, the compound (or a pharmaceutical composition or unit dose formulation comprising the compound) (such as those corresponding to formula (I) (or any embodiment thereof or other compounds described herein, such as any compound and / or preparation listed in Table I of the Examples section) is formulated for oral administration.

[0248] Pharmaceutically acceptable carriers for use in combination with the compounds and compositions of the present disclosure are well known to those of ordinary skill in the art and are selected based on a number of factors: the specific compound or compounds and agents used and its / their concentration, stability, and expected bioavailability; safety; the subject, its age, weight, and general condition; and the route of administration.

[0249] Suitable components (e.g., carriers and / or excipients) for formulating solid or semisolid dosage forms such as tablets, gelatin capsules, or gels / suspensions may include, for example, diluents (such as water, glycerides, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine); lubricants (such as silicon dioxide, talc, its magnesium or calcium salts, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and / or polyethylene glycol); binders (such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and / or polyvinyl pyrrolidone); disintegrants (such as starch; , agar, methylcellulose, bentonite, xanthan gum or effervescent mixture; absorbent; colorant, flavoring and / or sweetener; and combination thereof. Methods for preparing such solid and semisolid dosage forms using active pharmaceutical ingredients and other components are well known in the art. For example, a composition in liquid, semisolid or paste form can be filled into a hard gelatin or soft gelatin capsule using an appropriate filling machine. Alternatively, the composition can also be extruded, sprayed, granulated or coated onto a matrix to form a powder, granule or bead, which can be further encapsulated or tableted with or without the addition of an appropriate curing agent or adhesive. This method also allows the production of a "fusion mixture", "solid solution" or "eutectic mixture". These and other methods for preparing oral preparations can be found in, for example, "Remington: The Science and Practice of Pharmacy," 20th edition, edited by A.R. Gennaro, 2000, Lippincott Williams & Wilkins.

[0250] Suitable components (such as carriers and / or excipients) for preparing liquid dosage forms include, for example, non-aqueous, pharmaceutically acceptable polar solvents (such as oils, alcohols, amides, esters, ethers, ketones, hydrocarbons, and mixtures thereof), as well as water, saline solutions (such as USP and isotonic sodium chloride solutions), dextrose solutions (such as D5W), electrolyte solutions, or any other aqueous pharmaceutically acceptable liquids. In certain preferred embodiments, the pharmaceutical composition is in the form of an aqueous solution comprising a compound corresponding to formula (I) (or any embodiment thereof or other compounds described herein, such as any compound and / or formulation listed in Table I of the Examples section) and saline (such as physiological saline, i.e., a sterile solution of 0.9% w / v NaCl in water). In these and other embodiments, for example, physiological saline is preferably a physiologically buffered saline solution (i.e., buffered saline). The buffer can provide a suitable buffering capacity within the range of pH 7-8.5 or pH 7.8 or so, or within the range of pH 7.3-8. The buffer is preferably chemically inert and physiologically and pharmaceutically acceptable. Exemplary buffers include phosphate-based buffers, carbonate-based buffers, tris-based buffers, amino acid-based buffers (e.g., arginine, lysine, and other natural amino acids), and citrate-based buffers. Carbonate buffers (such as sodium carbonate or calcium carbonate or sodium bicarbonate or calcium bicarbonate buffers) may be particularly useful in certain embodiments because of their plentiful supply, strong buffering capacity, and compatibility. A particularly preferred buffer is sodium bicarbonate. In a preferred embodiment, for example, the pharmaceutically acceptable carrier comprises a buffered saline solution; more preferably, in this embodiment, the buffered saline solution is a bicarbonate-buffered saline solution.

[0251] In a specific embodiment, a unit dosage formulation for oral administration, comprising a compound such as those corresponding to Formula (I) (or any embodiment thereof or other compounds described herein, such as any of the compounds and / or formulations listed in Table I of the Examples section), further comprises at least one of a lipophilic surfactant and an oil.

[0252] Some suitable lipophilic surfactants and / or oils include mono-, di- and / or tri-glycerides of fatty acids, such as Imwitor 988 (mono- / di-caprylin), Imwitor 742 (mono-di-caprylin / capric glyceride), Imwitor 308 (mono-caprylin), Imwitor 191 (mono-stearin), Softigen 701 (mono- / di-ricinolein), Capmul MCM (caprylin / capric glyceride), Capmul MCM (L) (liquid form of Capmul MCM), Capmul GMO (mono-olein), Capmul GDL (dilaurin), Maisine (mono-linolein), Peceol (mono-olein), Myverol 18-92 (distilled monoglycerides from sunflower oil) and Myverol 18-06 (distilled monoglycerides from hydrogenated soybean oil), Precirol ATO5 (glyceryl palmitostearate), Gelucire 39 / 01 (semisynthetic glycerides, i.e. C12-18 mono-, di- and tri-glycerides) and Miglyol 812N (mixture of caprylic / capric triglycerides); acetates, succinates, lactates, citrates and / or tartaric acid esters of mono- and / or diglycerides of fatty acids, for example, Myvacet 9-45 (distilled acetylated monoglycerides), Miglyol 829 (caprylic / capric succinate diglycerides), Myverol SMG (mono / di-succinylated monoglycerides), Imwitor 370 (glyceryl stearate citrate), Imwitor 375 (glyceryl monostearate / glyceryl citrate / glyceryl lactate) and Crodatem T22 (diacetyl tartaric acid ester of monoglycerides); propylene glycol mono- and / or di-esters of fatty acids, for example Lauroglycol (propylene glycol monolaurate), Mirpyl (propylene glycol monomyristate), Captex 200 (propylene glycol dicaprylate / dicaprate), Miglyol 840 (propylene glycol dicaprylate / dicaprate) and Neobee M-20 (propylene glycol dicaprylate / dicaprate); polyglycerol esters of fatty acids, such as Plurol oleique (polyoleylglycerol), Caprol ET (polyglyceryl mixed fatty acids) and Drewpol 10.10.10 (polyoleylglycerol); low ethoxylate castor oil ethoxylates (HLB <10), such as Etocas 5 (5 mol ethylene oxide reacted with 1 mol castor oil) and Sandoxylate 5 (5 mol ethylene oxide reacted with 1 mol castor oil; acid and ester ethoxylates (HLB <10) formed by reacting ethylene oxide with fatty acids or glycerides of fatty acids, such as Crodet 04 (polyoxyethylene (4) lauric acid), Cithrol 2MS (polyoxyethylene (2) stearic acid), Marlosol 183 (polyoxyethylene (3) stearic acid) and Marlowet G 12DO (12EO dioleylglycerol); sorbitan esters of fatty acids, for example Span 20 (sorbitan monolaurate), Crill 1 (sorbitan monolaurate) and Crill 4 (sorbitan mono-oleate); transesterification products of natural or hydrogenated vegetable oil triglycerides and polyalkylene polyols (HLB<10), such as Labrafil M1944CS (polyoxyethylated apricot kernel oil), Labrafil M2125CS (polyoxyethylated corn oil) and Gelucire 37 / 06 (polyoxyethylated hydrogenated coconut); alcohol ethoxylates (HLB<10), such as Volpo N3 (polyoxyethylated (3) oleyl ether), Brij 93 (polyoxyethylated (2) oleyl ether), Marlowet LA4 (polyoxyethylated (4) lauryl ether); and pluronics, for example polyoxyethylene-polyoxypropylene copolymers and block copolymers (HLB<10) such as Synperonic PE L42 (HLB=8) and Synperonic PE L61 (HLB=3).

[0253] In another specific embodiment, a unit dosage formulation for oral administration, comprising a compound (e.g., those corresponding to Formula (I) (or any embodiment thereof or other compounds described herein, such as any of the compounds and / or formulations listed in Table 1 of the Examples section), further comprises a digestible oil (i.e., an oil that can be de-esterified or hydrolyzed in the presence of pancreatic lipase in vivo under normal physiological conditions). The digestible oil can be a low molecular weight (up to C 6 ) medium chain (C) mono-, di- or polyols 7 -C 13 ) or long chain (C 14 -C 22) triglycerides of fatty acids. Suitable examples of digestible oils include, for example, vegetable oils (such as soybean oil, safflower oil, corn oil, olive oil, castor oil, cottonseed oil, peanut oil, sunflower oil, coconut oil, palm oil, rapeseed oil, black currant oil, evening primrose oil, grape seed oil, wheat germ oil, sesame oil, avocado oil, almond oil, borage oil, peppermint oil and apricot kernel oil) and animal oils (such as cod liver oil, shark oil and mink oil). In certain embodiments, the digestible oil is a vegetable oil, such as soybean oil, safflower oil, corn oil, olive oil, castor oil, cottonseed oil, peanut oil, sunflower oil, coconut oil, palm oil, rapeseed oil, evening primrose oil, grape seed oil, wheat germ oil, sesame oil, avocado oil, almond oil, borage oil, peppermint oil, almond oil and combinations thereof.

[0254] When adopting injectable pharmaceutical preparations, they are preferably sterile.Injectable preparations can be sterilized by, for example, filtering through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition, which can be dissolved or dispersed in sterile water or other sterile injectable media before use.The composition can be provided, prepared, stored or transported to any container suitable for maintaining sterility.The container can be combined with a device for distributing aqueous compositions, such as, for example, a pierceable or removable seal.For example, compositions can be distributed to be administered to a patient by withdrawing with a syringe or by pouring the composition directly into a device (such as a syringe, intravenous (IV) bag or machine).Other devices for providing, preparing, storing, transporting and distributing sterile pharmaceutical compositions are known to those skilled in the art.

[0255] Other pharmaceutically acceptable carriers and excipients for use in the pharmaceutical compositions and dosage forms described herein are well known to those of ordinary skill in the art and are described in The Chemotherapy Source Book (Williams & Wilkens Publishing), The Handbook of Pharmaceutical Excipients, (American Pharmaceutical Association, Washington, DC, and The Pharmaceutical Society of Great Britain, London, England, 1968), Modern Pharmaceutics, (G. Banker et al., ed., 3rd 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., ed.) (Marcel Dekker, Inc., New York, New York, 1980), Remington's Pharmaceutical Sciences (A. Gennaro, ed., 19th ed.) (Mack The invention relates to the use of nonaqueous solvents in pharmaceutical compositions and methods. The invention relates to the use of nonaqueous solvents in pharmaceutical compositions and methods. The invention relates to the use of nonaqueous solvents in pharmaceutical compositions and methods. The invention relates to the use of nonaqueous solvents in pharmaceutical compositions and methods.

[0256] In certain embodiments, the pharmaceutical composition administered to a subject according to the methods described herein consists essentially of a compound corresponding to formula (I) (or any embodiment thereof or other compounds described herein, such as any compound listed in Table I of the Examples section) and a pharmaceutically acceptable carrier. In other embodiments, the pharmaceutical composition comprises a compound, a pharmaceutically acceptable carrier, and one or more additional pharmaceutically active agents or compounds. In these embodiments, the pharmaceutical composition described herein is a product produced by mixing or combining more than one active ingredient, and includes fixed and non-fixed combinations of active ingredients. Fixed combinations are those combinations in which active ingredients, such as the compound and another pharmaceutically active agent or compound described herein, are administered to the patient simultaneously in the form of a single entity or dosage. Non-fixed combinations are those combinations in which active ingredients, such as the compound and another pharmaceutically active agent or compound, are administered to the subject simultaneously, concurrently, or sequentially as separate entities without specific time interval restrictions, wherein such administration provides two compounds at effective levels in the patient. The latter is also applicable to mixed therapies, such as the administration of three or more active ingredients.

[0257] It is contemplated that co-formulation of compounds such as those corresponding to Formula (I) (or any embodiment thereof or other compounds described herein, e.g., any of the compounds listed in Table I of the Examples section) and one or more additional pharmaceutically active agents or compounds may employ conventional formulation techniques for these components alone, or in combination employing alternative formulation routes, tailored to the compatibility and efficacy of the various components.

[0258] In one embodiment, the compounds and / or formulations of the present disclosure (including any compounds described herein, such as any compounds and / or formulations listed in Table I of the Examples section) are formulated for oral administration, and the formulation comprises an enteric release layer or composition. For example, the oral dosage form can be an enteric-coated tablet, multi-particulate or multi-layer tablet or capsule; gelatin, soft gelatin or its equivalent; vinyl acetate phthalate or polyvinyl acetate phthalate or its equivalent; ACRYL-EZE TM 、SURETERIC TM , (Colorcon, Inc. Harleysville, Pa.); hydroxypropyl methylcellulose (HPMC), a high viscosity grade HPMC or an ultra-high viscosity grade HPMC; polyvinyl pyrrolidone (PVP) or PVP-K90; cellulose, microcrystalline cellulose (MCC), methylcellulose, hydroxymethylcellulose, hydroxypropyl methylcellulose (HPMC) or ethylcellulose; copolymers of ethyl acrylate, poly(meth)acrylates, such as methacrylic acid copolymer B, methyl methacrylate and / or methacrylates with quaternary ammonium groups; RL PO TM ; RL 100 TM (Evonik Industries AG, Essen, Germany).

[0259] In an alternative embodiment, the compounds and / or formulations of the present disclosure (including any compounds described herein, such as any compounds and / or formulations listed in Table I of the Examples section) are formulated for oral administration and the formulation comprises a coating or otherwise comprises cellulose acetate phthalate; hydroxypropyl methylcellulose phthalate; polyvinyl acetate phthalate; hydroxypropyl methylcellulose acetate succinate; cellulose acetate trimellitate; hydroxypropyl methylcellulose succinate; cellulose acetate succinate; cellulose acetate hexahydrophthalate; cellulose propionate phthalate; cellulose acetate maleate; cellulose acetate butyrate; cellulose acetate propionate; copolymers of methyl methacrylic acid and methyl methacrylate; copolymers of methyl acrylate, methyl methacrylate and methacrylic acid; copolymers of methyl vinyl ether and maleic anhydride; ethyl methacrylate-methyl methacrylate-ethyl chlorotrimethylammonium acrylate copolymers; natural resins; zein; shellac; copal collophorium or acrylic acid copolymers; or any combination or mixture thereof.

[0260] In alternative embodiments, the compounds and / or formulations of the present disclosure (including any compounds described herein, such as any of the compounds and / or formulations listed in Table 1 of the Examples section) are formulated for oral administration and comprise a sustained-release coating, and optionally, the sustained-release coating comprises a wax mixed with glyceryl monostearate, stearic acid, palmitic acid, glyceryl monopalmitate, cetyl alcohol, shellac, zein, ethylcellulose, acrylic resin, cellulose acetate, or a silicone elastomer, or any combination or mixture thereof.

[0261] Methods and indications

[0262] As described above, in a third aspect, the compounds described in conjunction with formula (I) (or any embodiment thereof or other compounds described herein, such as any of the compounds and / or formulations listed in Table I of the Examples section) can be used to treat tissue damage and / or a range of diseases and disorders. Treatment of diseases and disorders (including damaged tissue) as described herein may generally involve not only inhibiting the disease in a patient who is experiencing or showing symptoms of the disease or disorder (i.e., preventing further development of the symptoms and / or symptoms), but also improving the disease or disorder in a patient who is experiencing or showing symptoms of the disease or disorder (i.e., reversing the symptoms and / or symptoms). Treating a disease or disorder in a human patient as described herein, such as tissue damage caused by the administration of radiation therapy or chemotherapy or exposure to radiation, also amounts to inhibiting or preventing such damage in a patient who does not necessarily experience or show symptoms of the disease or disorder.

[0263] The method disclosed herein can be advantageously used to treat (e.g., inhibit, improve or alleviate) various diseases or disorders in a variety of subjects (i.e., patients). The subject can be, for example, a mammal, such as bovine, avian, canine, equine, feline, ovine, swine or primate (including humans and non-human primates). The subject may also include mammals that are of great significance or economic importance due to endangerment, such as farmed animals for human consumption, or animals of social importance to humans, such as those raised as pets or in zoos. Examples of such animals include, but are not limited to, cats, dogs, swine, ruminants or ungulates, such as cattle, oxen, sheep, giraffes, deer, goats, bison, camels or horses. In one embodiment, the subject is a bovine, avian, canine, equine, feline, ovine, swine or non-human primate. In a preferred embodiment, the subject is a human patient.

[0264] Treatment of tissue damage

[0265] According to an embodiment of the third aspect of the present disclosure, described herein is a method for treating tissue damage caused by cancer treatment (such as radiotherapy or chemotherapy) delivered to a subject in need. According to another embodiment, described herein is a method for treating tissue damage caused by exposure to radiation in human patients. Therefore, in various embodiments, for example, the radiation exposure in various embodiments may be accidental radiation exposure, unintentional radiation exposure or intentional radiation exposure. As described above, the treatment of tissue damage as described herein may include inhibition (i.e., prevention) and improvement of any tissue damage that may be caused by occurrence or activity. Typically, the method involves administering to a subject a therapeutically effective amount of a compound as described herein (such as those corresponding to formula (I) (or any embodiment thereof or other compounds described herein, such as any compound and / or preparation listed in Table I of the Examples section).

[0266] Treatment of tissue damage resulting from cancer treatment or other radiation exposure according to the methods described herein involves administering a therapeutically effective amount of a compound described herein (e.g., those corresponding to Formula (I) (or any embodiment thereof or other compounds described herein, such as any of the compounds and / or formulations listed in Table I of the Examples section). In general, a range of therapeutically effective amounts may be used, depending, for example, on the compound selected and its safety and efficacy, the type, location, and severity of tissue damage, and other factors.

[0267] In general, the timing of administration of the compound (e.g., those corresponding to Formula (I) (or any embodiment thereof or other compounds described herein, such as any of the compounds and / or formulations listed in Table I of the Examples section) can depend, for example, on the specific compound selected, the type, nature, and / or duration of the radiation therapy or chemotherapy, or the radiation exposure. Other considerations can include the disease or condition being treated and the severity of the disease or condition; the activity of the specific compound used; the specific composition used; the age, weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound used; the duration of treatment; drugs used in combination or concomitantly with the specific compound used; and other factors. For example, the compound can be administered in various embodiments before, during, and / or after administration of a cancer therapy (e.g., radiation therapy or chemotherapy). As another example, the compound can be administered in various embodiments before, during, and / or after exposure to radiation.

[0268] If desired, for purposes of administration, the effective dose may be divided into multiple doses; thus, single dose compositions may contain such amounts or submultiples thereof to make up the dose.

[0269] In one embodiment, for example, the compound (e.g., those corresponding to Formula (I) (or any embodiment thereof or other compounds described herein, such as any of the compounds and / or formulations listed in Table 1 of the Examples section) is administered to the patient prior to or concurrently with cancer therapy. In another embodiment, for example, the compound (e.g., those corresponding to Formula (I) (or any embodiment thereof or other compounds described herein, such as any of the compounds and / or formulations listed in Table 1 of the Examples section) is administered to the patient prior to, but not after, cancer therapy. In yet another embodiment, for example, the compound is administered at least 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 180 minutes, 0.5 days, 1 day, 3 days, 4 weeks, 6 months, 7 months, 8 months, 9 months, 12 months, 14 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 24 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 36 months, 37 months, 38 months, 39 months, 40 months, 41 months, 42 months, 43 months, 44 months, 45 months, 46 months, 47 months, 48 ​​months, 49 months, 50 months, 51 months, 52 months, 53 months, 54 months, 55 months, 56 months, 57 months, 58 months, 59 months, 60 months, 61 months, 62 months, 64 months, 65 months, 66 months, 67 months, 71 months, 72 months, 73 months, 74 months, 75 months, 76 months, 77 months, 78 months, 79 months, 80 months, 81 months, In some embodiments, the compound (e.g., those corresponding to Formula (I) (or any embodiment thereof or other compounds described herein, such as any compound and / or formulation listed in Table 1 of the Examples section) is administered to the patient after cancer therapy; thus, for example, the compound may be administered up to 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes or 180 minutes, 0.5 days, 1 day, 3 days, 5 days, one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks or more after cancer treatment.

[0270] In another embodiment, for example, the compound (such as those corresponding to Formula (I) (or any embodiment thereof or other compounds described herein, such as any compounds and / or formulations listed in Table I of the Examples section) is administered to the patient prior to or concurrently with radiation exposure. In another embodiment, for example, the compound (such as those corresponding to Formula (I) (or any embodiment thereof or other compounds described herein, such as any compounds and / or formulations listed in Table I of the Examples section) is administered to the patient prior to, but not after, radiation exposure. In yet another embodiment, for example, the compound (such as those corresponding to Formula (I) (or any embodiment thereof or other compounds described herein, such as any compounds and / or formulations listed in Table I of the Examples section) is administered to the patient at least 15 minutes, 30 minutes, 40 minutes, 60 minutes, 80 minutes, 90 minutes, 100 minutes, 150 minutes, 200 minutes, 200 minutes, 300 minutes, 400 minutes, 500 minutes, 600 minutes, 700 minutes, 800 minutes, 900 minutes, 1000 minutes, 20 ...500 minutes, 600 minutes, 700 minutes, 800 minutes, 900 minutes, 500 minutes, 700 minutes, 800 minutes, 900 minutes, 500 minutes, 600 minutes, 700 minutes, 800 minutes, 900 minutes, 500 minutes, 600 minutes, 700 minutes, 800 minutes, 900 minutes, 500 minutes, 6 In some embodiments, the compound (e.g., those corresponding to Formula (I) (or any embodiment thereof or other compounds described herein, such as any compound and / or formulation listed in Table 1 of the Examples section) is administered to the patient after radiation exposure; thus, for example, the compound may be administered up to 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 180 minutes, 0.5 day, 1 day, 3 days, 5 days, one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks or more after radiation exposure.

[0271] In one embodiment, for example, cancer treatment includes the administration of radiation therapy; for example, intentional exposure to radiation. According to this embodiment, the method provides a safe and effective method for treating radiation damage and inhibiting or ameliorating radiation-related cancer or radiation-related tissue damage in patients in need thereof by administering to the patient a therapeutically effective amount of a compound as described herein (such as those corresponding to Formula (I) (or any embodiment thereof or other compounds described herein, such as any compound and / or formulation listed in Table I of the Examples section).

[0272] In another embodiment, exposure to radiation is accidental or unintentional exposure. For example, radiation exposure may result from a variety of commercial and non-commercial activities, including but not limited to activities in various industries, such as utilities and electricity, oil / gas petrochemical, chemicals / plastics, automatic ventilation control (cooking, smoking, etc.), heavy industrial manufacturing, environmental toxicology and remediation, biomedical, cosmetics / perfumes, pharmaceuticals, transportation, emergency response and law enforcement, military or terrorist activities and detection (such as hazardous material leaks or spills). In one embodiment, for example, exposure to radiation may be caused by excavation and / or removal of radioactive materials from air, groundwater, surface water, sediments and / or soil.

[0273] In various embodiments, the radiation source may be electromagnetic, including visible or ultraviolet light, or nuclear powered, including alpha, beta, gamma, or cosmic radiation. The types of injury may include, but are not limited to, various forms of skin or mucosal injury, such as oral mucositis, esophagitis, etc., as well as internal cell loss, fibrosis, cyst formation, neuropathy, and various types of benign and malignant tumors.

[0274] Treatment of diseases and illnesses

[0275] According to another embodiment of the third aspect of the present disclosure, described herein is a method for treating a series of diseases and disorders regulated by superoxide in a subject in need. As described above, the treatment of diseases and disorders as described herein may include inhibiting (i.e. preventing) and improving such diseases or disorders. Typically, the method involves administering to the subject a therapeutically effective amount of a compound as described herein (such as those corresponding to formula (I) (or any embodiment thereof or other compounds described herein, such as any compound and / or preparation listed in Table I of the Examples section).

[0276] In general, the temporal aspect of the administration of the compound may depend, for example, on the specific compound, or the disease or condition being treated. Other considerations may include the severity of the disease or condition; the activity of the specific compound used; the specific composition used; the age, weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound used; the duration of treatment; drugs used in combination or concurrently with the specific compound used; and other factors.

[0277] If desired, for purposes of administration, the effective dose may be divided into multiple doses; thus, single dose compositions may contain such amounts or submultiples thereof to make up the dose.

[0278] Route of administration

[0279] Typically, the compounds described herein (or pharmaceutical compositions comprising the compounds), such as those corresponding to Formula (I) (or any embodiment thereof or other compounds described herein, such as any of the compounds and / or formulations listed in Table I of the Examples section), can be administered to subjects (such as humans and other mammals) suitable for oral administration; surprisingly, the compounds of the present disclosure are significantly more bioavailable when administered orally than other analogs (e.g., their dichloro analogs). Thus, advantageously, the compounds of the present disclosure provide a wider range of routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, intraarterial, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrasternal), topical (nasal, transdermal, buccal, ocular), intravesical, intrathecal, enteral, pulmonary, intralymphatic, intracavitary, vaginal, rectal, transurethral, ​​intradermal, intraocular, intraauricular, intramammary, in situ, intratracheal, intralesional, transdermal, endoscopic, transmucosal, sublingual, and enteral administration. In one embodiment, the compound is introduced into the patient via oral administration. In another embodiment, the compound is introduced into the patient via injection, including by intravenous, subcutaneous, intramuscular, intraperitoneal, intraarterial and intradermal injection. Additionally or alternatively, the compound described herein (or a pharmaceutical composition comprising the compound) may be administered topically (such as by a patch applied to the skin (such as a transdermal patch), powder, lotion, ointment or drops), buccal or inhaled (as an oral or nasal spray) to the subject. The compound described herein (or a pharmaceutical composition comprising the compound) may also be administered intrarectally or intravaginally to humans and other mammals. In one embodiment, the compound (or a pharmaceutical composition comprising the compound or a unit dose formulation) is administered orally to the subject. In another embodiment, the compound (or a pharmaceutical composition comprising the compound or a unit dose formulation) is administered parenterally to the subject. It is generally understood that parenteral administration refers to modes of administration including intravenous, intramuscular, intraperitoneal, subcutaneous and intraarticular.

[0280] In some embodiments, oral administration is a preferred method of administration for compounds of the invention, such as those corresponding to Formula (I) (or any embodiment thereof or other compounds described herein, such as any of the compounds and / or formulations listed in Table I of the Examples section).

[0281] Additional pharmaceutically active agents

[0282] As described above, the above methods and pharmaceutical compositions including the compounds may additionally include the administration of one or more pharmaceutically active agents or components. Although the compounds described herein may be administered as the sole active agent, they may also be used in combination with one or more compounds of the invention or other agents. When administered as a combination, the therapeutic agent may be formulated as a separate composition, which is sequentially administered at the same time or at different times (such as one or several hours or days later), or the therapeutic agent may be administered as a single composition. Therefore, the present disclosure is intended to include the administration of each medicament in a sequential manner in a scheme that will provide the beneficial effects of a drug combination, and is also intended to include the co-administration of these medicaments in a substantially simultaneous manner, such as in the form of a single capsule of these active agents with a fixed ratio or in the form of multiple separate capsules of each medicament.

[0283] Kits / Products

[0284] For use in therapeutic applications described herein, kits and articles are also described. Such kits may include a carrier, a package, or a container separated to accommodate one or more containers (such as vials, tubes, etc.), each of which includes one of the individual elements to be used in the methods described herein (such as, for example, corresponding to a compound of formula (I) (or any embodiment thereof described herein), a pharmaceutically acceptable carrier, or another pharmaceutically active agent or compound, whether alone or in combination). Suitable containers include, for example, bottles, vials, syringes, and test tubes. The container may be formed of various materials, such as glass or plastic.

[0285] Compositions containing one or more compounds provided herein, such as those corresponding to Formula (I) (or any embodiment thereof or other compounds described herein, such as any of the compounds and / or formulations listed in Table I of the Examples section), formulated in a compatible pharmaceutical carrier can also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0286] According to one embodiment, the article comprises packaging material and contained within the packaging material is an oral formulation for treating a disease or disorder in a patient in need thereof or for protecting tissue from damage caused by exposure to cancer treatment, the oral formulation comprising a compound corresponding to formula (I) (or any embodiment thereof or other compounds described herein, such as any of the compounds and / or formulations listed in Table I of the Examples section). According to this embodiment, the parenteral formulation comprises a unit dose formulation as described herein, and the packaging material comprises a label or package insert having instructions for orally administering a dose to a patient. For example, the oral formulation may be in the form of a tablet, pill, capsule, or gel or suspension and contained in a suitable vial or container.

[0287] According to another embodiment, the article comprises packaging material and contained within the packaging material is a parenteral formulation for treating a disease or illness in a patient in need thereof or for protecting tissue from damage caused by exposure to cancer treatment, the parenteral formulation comprising a compound corresponding to formula (I) (or any embodiment thereof or other compounds described herein, such as any of the compounds and / or formulations listed in Table I of the Examples section). According to this embodiment, the parenteral formulation comprises a unit dose formulation as described herein, and the packaging material comprises a label or package insert having instructions for administering a dose parenterally to a patient. For example, the parenteral formulation may be in the form of a solution and contained in a suitable vial or container.

[0288] Example of implementation

[0289] In another aspect, the present invention provides embodiments of the following items:

[0290] 1. A pentaazamacrocyclic ring complex of formula (I):

[0291]

[0292] in

[0293] M is a transition metal (e.g., Mn 2+ , Mn 3+ , Mn 4+ , Mn 6+ , Mn 7+ , Fe 2+ , Fe 3+ , Fe 4+ , Fe 6+ 、Ni 2+ 、Ni 3+ , Cu 1+ , Cu 2+ 、V 2+ 、V 3+ 、V 4+ or V 5+ );

[0294] R 1A , R 1B , R 2A , R 2B , R 3A , R 3B , R 4A , R 4B , R 5A , R 5B , R 6A , R 6B , R 7A , R 7B , R 8A , R8B , R 9A , R 9B , R 10A and R 10B Independently are:

[0295] (i)Hydrogen;

[0296] (ii) a moiety independently selected from the group consisting of alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, heterocyclyl, and aralkyl groups and a group attached to the α-carbon of an amino acid (i.e., an α-amino acid); or

[0297] (iii) part, which is independently selected from the group consisting of:

[0298] -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 ),-OP(=O)(OR 11 )(OR 12 ), and a substituent attached to the α-carbon of an amino acid (i.e., an α-amino acid), wherein R 11 and R 12 are independently hydrogen or alkyl;

[0299] (iv) a member of a substituted or unsubstituted, saturated, partially saturated or unsaturated ring or heterocyclic ring containing 3 to 20 carbon ring atoms, which includes

[0300] (a)R 1A or R 1B and R 2A or R 2B ; R 3A or R 3B and R 4A or R4B ; R 5A or R 5B and R 6A or R 6B ; R 7A or R 7B and R 8A or R 8B ; or R 9A or R 9B and R 10A or R 10B together with the carbon atoms to which they are each attached;

[0301] (b)R 10A or R 10B and R 1A or R 1B ; R 2A or R 2B and R 3A or R 3B ; R 4A or R 4B and R 5A or R 5B ; R 6A or R 6B and R 7A or R 7B ; or R 8A or R 8B and R 9A or R 9B together with the carbon atoms to which they are attached; or

[0302] (c)R 1A and R 1B ; R 2A and R 2B ; R 3A and R 3B ; R 4A and R 4B ; R 5A and R 5B ; R 6A and R 6B ; R 7A and R 7B ; R 8A and R 8B ; R 9A and R 9B ; or R 10A and R 10B together with the carbon atoms to which they are attached; or

[0303] (v) any combination of (i) to (iv) above;

[0304] Each X 1 are independently substituted or unsubstituted phenyl or -C(-X2 )(-X 3 )(-X 4 );

[0305] Each X 2 are independently substituted or unsubstituted phenyl, methyl, ethyl or propyl;

[0306] Each X 3 are independently hydrogen, hydroxy, methyl, ethyl, propyl, amino, -X 5 C(=O)R 13 (Where X 5 is NH or O and R 13 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl, or -OR 14 Where R 14 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 aralkyl), or together with X 4 Yes (=O);

[0307] Each X 4 independently hydrogen or together with X 3 is(=0); and

[0308] The bond between the transition metal M and the macrocyclic nitrogen atom and the bond between the transition metal M and the axial ligand -OC(O)X 1 The bonds between the oxygen atoms are coordinate covalent bonds.

[0309] 2. A pentaazamacrocyclic ring complex of formula (IA):

[0310]

[0311] in

[0312] M is a transition metal (such as Mn 2+ , Mn 3+ , Mn 4+ , Mn 6+ , Mn 7+ , Fe 2+ , Fe 3+ , Fe 4+ , Fe 6+ 、Ni 2+ 、Ni 3+ , Cu 1+ , Cu 2 + 、V2+ 、V 3+ 、V 4+ or V 5+ );

[0313] 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 is independently hydrogen, a hydrocarbon group, a substituted hydrocarbon group, a heterocyclic group, an amino acid side chain moiety, or a moiety independently selected from the group consisting of: -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 ),

[0314] Where R 11 and R 12 are independently hydrogen or alkyl;

[0315] U, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms;

[0316] V, together with the adjacent carbon atoms of the macrocycle, forms a fused, substituted or unsubstituted, saturated, partially saturated or unsaturated ring or heterocycle having 3 to 20 ring carbon atoms;

[0317] W, together with the nitrogen of the macrocycle and the carbon atom of the macrocycle to which the macrocycle is attached, forms an aromatic or alicyclic, substituted or unsubstituted, saturated, partially saturated or unsaturated nitrogen-containing fused heterocycle having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocycle, the hydrogen attached to the nitrogen is part of both the heterocycle and the macrocycle, and the R attached to the carbon atom is part of both the heterocycle and the macrocycle 5 and R 6 does not exist;

[0318] Each X 1 are independently substituted or unsubstituted phenyl or -C(-X 2 )(-X 3 )(-X 4 );

[0319] Each X 2 are independently substituted or unsubstituted phenyl, methyl, ethyl or propyl;

[0320] Each X 3 are independently hydrogen, hydroxy, methyl, ethyl, propyl, amino, -X 5 C(=O)R 13 (Where X 5 is NH or O and R 13 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl, or -OR 14 Where R 14 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 aralkyl), or together with X 4 Yes (=O);

[0321] Each X 4 independently hydrogen or together with X 3 is(=0); and

[0322] The bond between the transition metal M and the macrocyclic nitrogen atom and the bond between the transition metal M and the axial ligand -OC(O)X 1 The bonds between the oxygen atoms are coordinate covalent bonds.

[0323] 3. A pentaazamacrocyclic ring complex of formula (IB):

[0324]

[0325] in

[0326] M is Fe +2 , Fe +3 , Mn +2 or Mn +3 ;

[0327] 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 is independently hydrogen, a hydrocarbon group, a substituted hydrocarbon group, a heterocyclic group, an amino acid side chain moiety, or a moiety independently selected from the group consisting of: -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 ),

[0328] Where R 11 and R 12 are independently hydrogen or alkyl;

[0329] W 1 , W 2 and W 3 are independently halo, hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, acyl, acyloxy, alkoxy, ether, thioether or nitro;

[0330] Each X 1are independently substituted or unsubstituted phenyl or -C(-X 2 )(-X 3 )(-X 4 );

[0331] Each X 2 are independently substituted or unsubstituted phenyl, methyl, ethyl or propyl;

[0332] Each X 3 are independently hydrogen, hydroxy, methyl, ethyl, propyl, amino, -X 5 C(=O)R 13 (Where X 5 is NH or O and R 13 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl, or -OR 14 Where R 14 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 aralkyl), or together with X 4 Yes (=O);

[0333] Each X 4 independently hydrogen or together with X 3 is(=0); and

[0334] The bond between the transition metal M and the macrocyclic nitrogen atom and the bond between the transition metal M and the axial ligand -OC(=O)X 1 The bonds between the oxygen atoms are coordinate covalent bonds.

[0335] 4. A method corresponding to the formula (IC R ) or (IC S ) of a pentaazamacrocyclic ring complex:

[0336]

[0337] in

[0338] M is Fe +2 , Fe +3 , Mn +2 or Mn +3 ;

[0339] R 1A , R 1B , R 2 , R 3 , R 4A , R4B , R 5 , R 6 , R 7A , R 7B , R 8 , R 9 , R 10A and R 10B are independently hydrogen or substituted or unsubstituted alkyl;

[0340] W 1 , W 2 and W 3 are independently halo or hydrogen;

[0341] Each X 1 are independently substituted or unsubstituted phenyl or -C(-X 2 )(-X 3 )(-X 4 );

[0342] Each X 2 are independently substituted or unsubstituted phenyl, methyl, ethyl or propyl;

[0343] Each X 3 are independently hydrogen, hydroxy, methyl, ethyl, propyl, amino, -X 5 C(=O)R 13 (Where X 5 is NH or O and R 13 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl, or -OR 14 Where R 14 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 aralkyl), or together with X 4 Yes (=O);

[0344] Each X 4 independently hydrogen or together with X 3 is(=0); and

[0345] The bond between the transition metal M and the macrocyclic nitrogen atom and the bond between the transition metal M and the axial ligand -OC(=O)X 1 The bonds between the oxygen atoms are coordinate covalent bonds.

[0346] 5. A method corresponding to the formula (ID R ) or (ID S ) of a pentaazamacrocyclic ring complex:

[0347]

[0348] in

[0349] M is Mn +2 or Mn +3 ;

[0350] 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, methyl, ethyl or propyl;

[0351] W 1 , W 2 and W 3 are independently halo or hydrogen;

[0352] Each X 1 are independently substituted or unsubstituted phenyl or -C(X 2 )(X 3 )(X 4 );

[0353] Each X 2 are independently substituted or unsubstituted phenyl, methyl, ethyl or propyl;

[0354] Each X 3 are independently hydrogen, hydroxy, methyl, ethyl, propyl, amino, -X 5 C(=O)R 13 (Where X 5 is NH or O and R 13 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl, or -OR 14 Where R 14 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 aralkyl), or together with X 4 Yes (=O);

[0355] Each X 4 independently hydrogen or together with X 3 is(=0); and

[0356] The bond between the manganese and the macrocyclic nitrogen atom and between the manganese and the axial ligand -OC(=O)X 1 The bonds between the oxygen atoms are coordinate covalent bonds.

[0357] 6. A method corresponding to formula (IE R1 )、(IE S1 )、(IE R2 )、(IE S2 )、(IE R3 ) or (IE S3 ) of a pentaazamacrocyclic ring complex:

[0358]

[0359] in

[0360] Mn is Mn +2 or Mn +3 ;

[0361] Each X 1 are independently substituted or unsubstituted phenyl or -C(X 2 )(X 3 )(X 4 );

[0362] Each X 2 are independently substituted or unsubstituted phenyl, methyl, ethyl or propyl;

[0363] Each X 3 are independently hydrogen, hydroxy, methyl, ethyl, propyl, amino, -X 5 C(=O)R 13 (Where X 5 is NH or O and R 13 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl, or -OR 14 Where R 14 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 aralkyl), or together with X 4 Yes (=O);

[0364] Each X 4 independently hydrogen or together with X 3is = 0; and

[0365] The bond between the manganese and the macrocyclic nitrogen atom and between the manganese and the axial ligand -OC(=O)X 1 The bonds between the oxygen atoms are coordinate covalent bonds.

[0366] 7. A pentaazamacrocyclic ring complex as described in any of the preceding claims, wherein each X 1 It is phenyl.

[0367] 8. A pentaazamacrocyclic ring complex as described in any of the preceding claims, wherein each X 1 is a substituted phenyl group.

[0368] 9. A pentaazamacrocyclic ring complex as described in any of the preceding claims, wherein each X 1 Yes-C(X 2 )(X 3 )(X 4 ).

[0369] 10. A pentaazamacrocyclic ring complex as described in any of the preceding claims, wherein each X 1 Yes-C(X 2 )(X 3 )(X 4 ) and each X 2 is independently substituted or unsubstituted phenyl, methyl, ethyl or propyl.

[0370] 11. A pentaazamacrocyclic ring complex as described in any of the preceding claims, wherein each X 1 Yes-C(X 2 )(X 3 )(X 4 ), each X 2 is a methyl group and each X 3 is hydrogen, hydroxyl, amino or together with X 4 Yes (=O).

[0371] 12. A pentaazamacrocyclic ring complex as described in any of the preceding claims, wherein each X 1 Yes-C(X 2 )(X 3 )(X 4 ), each X 2 is a substituted or unsubstituted phenyl group and each X 3 is hydrogen, hydroxy, methyl, amino or together with X 4 Yes (=O).

[0372] 13. A pentaazamacrocyclic ring complex as described in any of the preceding claims, wherein each X 1 Yes-C(X 2 )(X3 )(X 4 ) and each X 3 is hydrogen, hydroxy, methyl, ethyl, propyl or amino or together with X 4 Yes (=O).

[0373] 14. A pentaazamacrocyclic ring complex as described in any of the preceding claims, wherein each X 1 Yes-C(X 2 )(X 3 )(X 4 ) and each X 3 It is hydrogen, hydroxy, methyl, ethyl, propyl or amino.

[0374] 15. A pentaazamacrocyclic ring complex as described in any of the preceding claims, wherein each X 1 Yes-C(X 2 )(X 3 )(X 4 ), each X 2 is methyl or substituted or unsubstituted phenyl and each X 3 and X 4 It's hydrogen.

[0375] 16. A pentaazamacrocyclic ring complex as described in any one of items 1 to 14, wherein each X 1 Yes-C(X 2 )(X 3 )(X 4 ) and each X 3 It's amino.

[0376] 17. A pentaazamacrocyclic ring complex as described in any one of items 1 to 14 and 16, wherein each X 1 Yes-C(X 2 )(X 3 )(X 4 ) and each X 3 Yes – NH 2 .

[0377] 18. A pentaazamacrocyclic ring complex as described in any one of items 1 to 13, wherein each X 1 Yes-C(X 2 )(X 3 )(X 4 ) and each X 3 With each X 4 They are (=O) respectively.

[0378] 19. A pentaazamacrocyclic ring complex as described in any of the preceding claims, wherein each X 1 Yes-C(X 2 )(X 3 )(X4 ) and each -C(X 2 )(X 3 )(X 4 ) corresponds to any one of the combinations 1 to 9 appearing in the following table:

[0379]

[0380] 20. The pentaazamacrocyclic complex according to item 19, wherein X 2 Ph, X 3 is H and H 4 It's H.

[0381] 21. The pentaazamacrocyclic complex according to item 19, wherein X 2 Ph, X 3 is OH and H 4 It's H.

[0382] 22. The pentaazamacrocyclic complex according to item 19, wherein X 2 Ph, X 3 Yes NH 2 And H 4 It's H.

[0383] 23. The pentaazamacrocyclic complex according to item 19, wherein X 2 is Ph, and X 3 Combined with X4 is (=O).

[0384] 24. The pentaazamacrocyclic complex according to item 19, wherein X 2 Ph, X 3 Yes CH 3 And H 4 It's H.

[0385] 25. The pentaazamacrocyclic complex according to item 19, wherein X 2 Yes CH 3 , X 3 is H and H 4 It's H.

[0386] 26. The pentaazamacrocyclic complex according to item 19, wherein X 2 Yes CH 3 , X 3 is OH and H 4 It's H.

[0387] 27. The pentaazamacrocyclic complex according to item 19, wherein X 2 Yes CH 3 , X 3 Yes NH 2 And H4 It's H.

[0388] 28. The pentaazamacrocyclic complex according to item 19, wherein X 2 Yes CH 3 , and X 3 Combined with X4 is (=O).

[0389] 29. A pentaazamacrocyclic ring complex as described in any one of items 1 to 10, wherein each X 1 Yes-C(X 2 )(X 3 )(X 4 ) and X 3 Yes-X 5 C(=O)R 13 , and each -C(X 2 )(X 3 )(X 4 ) corresponds to any one of the combinations 1 to 4 appearing in the following table:

[0390] combination <![CDATA[X 2 ]]> <![CDATA[X 3 ]]> <![CDATA[X 4 ]]> 1 Ph <![CDATA[NHC(=O)R 13 ]]> H 2 Ph <![CDATA[OC(=O)R 13 ]]> H 3 <![CDATA[CH 3 ]]> <![CDATA[NHC(=O)R 13 ]]> H 4 <![CDATA[CH 3 ]]> <![CDATA[OC(=O)R 13 ]]> H

[0391] Where R 13 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl, or -OR 14 Where R 14 It is C 1 -C 18 Alkyl, substituted or unsubstituted aryl or C 1 -C 18 Aralkyl.

[0392] 30. A pharmaceutical composition comprising the pentaazamacrocyclic ring complex as described in any one of the preceding items and a pharmaceutically acceptable excipient suitable for administration.

[0393] 31. The pharmaceutical composition of claim 30, wherein the pharmaceutical composition is suitable for oral administration to human subjects.

[0394] 32. The pharmaceutical composition of item 30 or 31, comprising at least one of a lipophilic surfactant and an oil.

[0395] 33. A pharmaceutical composition as described in claim 32, wherein at least one of the lipophilic surfactant and the oil comprises at least one of the following: mono- and / or diglycerides of fatty acids; acetates, succinates, lactates, citrates and / or tartaric acid esters of mono- and / or diglycerides of fatty acids; propylene glycol mono- and / or di-esters of fatty acids; polyglycerol esters of fatty acids; castor oil ethoxylates; acid and ester ethoxylates formed by reacting ethylene oxide with fatty acids or glycerides of fatty acids; sorbitan esters of fatty acids; transesterification products of natural or hydrogenated vegetable oil triglycerides and polyalkylene polyols; alcohol ethoxylates; and polyoxyethylene-polyoxypropylene co-copolymers.

[0396] 34. A pharmaceutical composition as described in claim 33, wherein at least one of the lipophilic surfactant and the oil comprises at least one of the following: a mixture of mono / diglycerides of caprylic / capric acid, a mixture of caprylic / capric triglycerides, linoleoyl macrogol-6 glyceride (NF), oleoyl macrogol-6 glyceride (NF), monooleinyl glyceride (NF), monolinoleinyl glyceride (NF) and caprylocaproyl macrogol-8 glyceride (NF).

[0397] 35. The pharmaceutical composition of any one of items 30 to 34, wherein the pharmaceutical composition is in a solid or semisolid dosage form.

[0398] 36. A pharmaceutical composition as described in any one of items 30 to 34, wherein the pharmaceutical composition is in the form of a tablet, gelatin capsule, gel or suspension suitable for oral administration.

[0399] 37. The pharmaceutical composition of any one of items 30 to 36, wherein the pharmaceutical composition comprises an enteric coating layer.

[0400] 38. A method for administering a pentaazamacrocyclic ring complex to a subject, the method comprising administering to a human subject a composition as described in any one of items 30 to 37.

[0401] Having described the invention in detail, it will be apparent that modifications and variations are possible without departing from the scope of the invention as defined in the appended claims. Furthermore, it should be understood that all examples in this disclosure are provided as non-limiting examples. DETAILED DESCRIPTION

[0402] Example

[0403] The following non-limiting examples are provided to further illustrate the present invention. It will be appreciated by those skilled in the art that the techniques disclosed in the following examples represent methods that the inventors have found to work well in the practice of the present invention, and therefore can be considered to constitute examples of modes of its practice. However, in light of this disclosure, it will be appreciated by those skilled in the art that many changes can be made in the specific embodiments disclosed, and still similar or similar results can be obtained without departing from the spirit and scope of the present invention.

[0404] Example 1

[0405] introduction

[0406] The compounds were screened for oral bioavailability by injecting the formulated prodrugs directly into the duodenum of minipig test subjects (intraduodenal or id administration), thus bypassing the acidic environment of the stomach and thereby eliminating potentially misleading oral bioavailability results that could result from alterations in the test drug in the acidic environment of the stomach.

[0407] The Gottingen minipig was chosen as the test model species for evaluating oral bioavailability because 1) minipigs (and suis in general) are known to mimic the physiology and pharmacology of the human intestine, particularly with respect to drug absorption; 1 and 2) previous studies using GC4403 (the enantiomer of GC4419) in Göttingen minipigs demonstrated oral bioavailability consistent with clinical experience in human studies.

[0408] Studies were conducted at Xenometrics LLC (Stillwell, KS) and id bioavailability was determined using various axial ligand derivative complexes of GC4419, GC4444, GC4403 and GC4401. In each case, the parent compounds (GC4419, GC4403, GC4444 and GC4401) with their chloro axial ligands were administered by the intravenous (iv) route as a reference for calculating 100% bioavailability as measured by AUC 0->24h (Area under the curve from 0 to 24 h (ng-hr / mL)) was measured. Calculation of the oral bioavailability % of a formulation of compound administered id required comparison with the AUC via the iv route 0->24h The AUC of this pathway is calculated 0->24h The oral bioavailability % was then calculated via intestinal absorption of the test article drug complex using the following formula:

[0409] Oral bioavailability % = AUC 0->24h (id) x (1 / dose (mg / kg)) ÷ AUC 0->24h (iv)*

[0410] *Where the iv dose was 1 mg of the test article drug per kg body weight of the minipig, and the id dose was 10 mg of the test article drug per kg body weight of the minipig.

[0411] All Xenometrics facilities are fully accredited by the Association for Assessment & Accreditation of Laboratory Animals (AAALAC). All experiments and animal care were performed within the strict guidelines established and implemented by the Xenometrics Institutional Animal Care and Use Committee.

[0412] method

[0413] Male Gottingen miniature pigs (4-5 months old, 9-12 kg body weight) were purchased from Marshall BioResources and housed in Xenometrics. After adapting for at least 14 days, each animal was surgically implanted with an intraduodenal (id) cannula using adequate anesthesia via abdominal surgery. A reusable accessible sleeve was placed externally at the distal end (see surgical details below). During a recovery period of at least 2 weeks, miniature pigs were handled daily to adapt them to the test procedures, i.e., id dosing and blood sampling. For each experiment, each miniature pig received a test article drug dissolved or suspended in an excipient vehicle. Miniature pigs do not need to restrict dosing. All dosing experiments were conducted in fasted animals. Food was removed from miniature pigs 16 hours before dosing. Miniature pigs had free access to water. Miniature pigs were allowed to obtain food 6 hours after dosing. The test article was administered via the id cannula as a bolus injection (about 1 minute) at a dose of 10 mg / kg of the parent drug in 0.1 mL / kg vehicle (such as 1.5 mL in a 15 kg miniature pig). The actual amount of total test article drug administered varies with the chemical formula weight of the prodrug. After administration of the test article, the cannula is flushed with an equal volume of excipient vehicle. Approximately 6 hours later, the cannula is flushed with corn oil. Approximately 24 hours after administration, the catheter is flushed with sterile saline solution and capped. At 0.25, 0.5, 1, 2, 4, 8, 24 and 48 hours post-injection, 2 mL blood samples were collected by cranial vena cava puncture (4 mL sodium heparin Vacutainer, 20 g 1.5" needle) after swabbing the skin surface with ethanol. Minipigs were placed in a sling in a recumbent position without anesthesia to collect blood samples. Minipigs were never used for experiments more than once every 7 days. Blood samples were kept on ice until processed to obtain plasma. Blood samples were centrifuged at 1200 x g for 10 minutes at 4°C, and plasma samples were transferred to 96-well plate tubes, capped and stored at -20°C until sent on dry ice to the analytical laboratory for measurement of drug concentrations in plasma. The concentration of the parent manganese pentaazamacrocyclic complex (independent of the composition of the axial ligand) in plasma was measured using a validated HPLC / MS / MS method, which was linear between 50 ng / mL and 20,000 ng / mL.

[0414] Xenometrics surgical procedure for oroduodenal catheterization in suis: surgical preparation to test the system.

[0415] Animal preparation

[0416] Pigs were fasted overnight before surgery and premedicated and induced according to the schedule of drugs and dosage charts. An endotracheal tube was inserted and general anesthesia was maintained with isoflurane delivered in oxygen via a precision vaporizer and a rebreathing anesthesia circuit. LRS (Lactate-Ringers Solution) was given via a peripheral catheter at approximately 100 mL / hour during surgery. Surgery was performed in a designated operating room, and aseptic techniques were followed throughout the entire surgical procedure.

[0417] VAP placement

[0418] The area on the right dorsal chest was shaved and prepared with chlorhexidine scrubs and solutions.

[0419] A midline laparotomy is performed, the duodenum is isolated and cannulated according to the description listed below, and externalized at a site along the dorsal thorax. The externalized cannula is then connected to a separate access port (VAP) and implanted subcutaneously using appropriate non-absorbable sutures. The open incision is appropriately closed to ensure that dead space is removed and the skin is closed with absorbable sutures. The peritoneum and muscle layers of the laparotomy are juxtaposed in an interrupted pattern with absorbable sutures of appropriate size. Subcutaneous tissue will be juxtaposed with absorbable sutures. The skin is closed with absorbable subcutaneous sutures.

[0420] Duodenal cannulation using a vascular access port (VAP)

[0421] The area on the ventral abdomen was shaved and prepped with chlorhexidine scrubs and solutions.

[0422] The burp valve catheter (Burp valve catheter) (Access Technologies, Chicago IL) with a 5mm Dacron disk attached 1cm from the tip is used to cannulate the duodenum. The burp valve cannula is rinsed before implantation to ensure that the burp valve is free and works properly. The duodenum is positioned and the cannulation site is isolated (i.e., 5-8cm from the duodenal bend head end). At this site, a 4-0 Prolene purse-string suture is placed on the mucosal surface, and an 18g needle is used to perforate the intestine in the center of the purse-string suture. The needle is then removed and replaced with a 16g stub adapter to further expand the existing insertion site. The stub adapter is then removed, and the burp valve tip is placed in the intestinal defect until the Dacron disk is flush with the mucosal surface. The tip is anchored by closing the purse-string suture and fixing it in place. The 4-0 Prolene suture interrupted with 7-8 is used to anchor the disk in place to the mucosal surface. A small loop was formed and the catheter body (approximately 5-6 cm from the disc) was anchored to the mucosa using the Weitzel tunneling technique.

[0423] Note: The Weitzel tunnel technique is accomplished by placing the catheter body along the intestine with its distal surface toward the duodenal curvature. 4-6 individual 5-0 Prolene sutures are placed approximately 0.5 cm apart to form a "tunnel". The tunnel is formed by attaching each suture to the mucosal surface next to the cannula and then attaching the free end to the mucosal surface on the other side of the cannula, ensuring that the sutures rest on top of the cannula. As the individual sutures are tied, they pull the mucosa over the cannula, forming a "tunnel".

[0424] After completing the Weitzel tunnel technique, a small (2-3mm) incision is made at the peritoneum about 1cm below the rib on the right side of the animal, and the catheter is externalized to the opening site by using a trocar. An incision is made on the dorsal side of the right chest, and a pocket is formed to accommodate the opening. The cannula is then moved to the pocket and attached to the opening by the trocar. The opening is then anchored to the underlying muscle tissue with a non-absorbable monofilament suture of appropriate size, and the muscle, fascia and skin are closed in an appropriate manner. The opening is rinsed with saline. The abdomen is closed in an intermittent manner with appropriate absorbable monofilament sutures. The fascia is closed in an appropriate manner respectively with appropriate absorbable sutures. The skin is closed in an appropriate manner with appropriate sutures or U-shaped staples. During anesthesia recovery, the monitoring animal recovers normal physiological function.

[0425] The incision sites were checked daily for a minimum of 14 days. Antibiotics were administered as needed. Animals were unclasped for a minimum of 14 days after the procedure.

[0426] System maintenance

[0427] Use aseptic technique to access the opening. Clip the fur above the opening as needed. Apply at least 3 alternating scrubs of chlorhexidine scrub and solution before accessing the opening via a Huber pointed needle. After dosing, flush the duodenal opening with an appropriate flushing solution such as normal saline or sterile water.

[0428] experiment

[0429] Preparation of drug delivery formulations

[0430] Oils for preparing dosing solutions are available from commercial sources. Capmul MCM (NF) is a mixture of caprylic / capric mono / diglycerides and is supplied by ABITEC Corporation, Janesville, WI. Miglyol 812N is a mixture of caprylic / capric triglycerides and is supplied by Cremer Oleo Division, Eatontown, NJ. Labrafil M 2125CS (NF) is chemically defined as linoleoyl polyethylene glycol-6 glyceride NF and is supplied by Gattefosse, SAINT-PRIEST Cedex, France. Peceol is chemically defined as monoglyceride, monoolein glyceride NF and is supplied by Gattefosse, SAINT-PRIEST Cedex, France. Maisine 35-1 is chemically defined as the monoglyceride monolinolein glyceride (NF) and is supplied by Gattefosse, SAINT-PRIEST Cedex, France. Labrasol (NF) is chemically defined as caprylocaproyl macrogol-8 glyceride NF and is supplied by Gattefosse, SAINT-PRIEST Cedex, France. Labrafil M 1944CS is chemically defined as oleoyl macrogol-6 glyceride (NF) and is supplied by Gattefosse, SAINT-PRIEST Cedex, France. Dosing solutions were all prepared by weighing all components of each formulation using a four-position analytical balance so that 10% by weight of each formulation contained the test article drug and 90% by weight of oil was used for the formulation.

[0431] Bioanalytical methods

[0432] The bioanalytical method used to quantify the parent Mn(II) macrocyclic ring ligand structure in plasma utilized HPLC with MS / MS detection and monitored the presence of the monocationic [monoformate Mn(pentazamacrocycle)]+ complex. All bioanalytical sample measurements were performed at ABC Laboratories using the Galera bioanalytical method validated at ABC as ABC Method No. 81201-MI-02, which is similar to the method described in U.S. Pat. No. 8,444,856 to Slomczynska et al., which is hereby incorporated by reference in its entirety.

[0433] synthesis

[0434] Unless otherwise noted, all reagents used to synthesize compounds disclosed herein were purchased from Sigma-Aldrich and used without further purification.All elemental analyses were performed and reported by Galbraith Laboratories, Inc., Knoxville, TN.

[0435] The parent Mn(II) pentaazamacrocyclic dichloro complexes such as GC4419, GC4401, GC4444 and GC4403 (structures shown below) were synthesized using literature procedures. For GC4403, chiral R,R-diaminocyclohexane was used as the starting material. 2 For GC4419, the mirror image enantiomer of GC4403, chiral S,S-diaminocyclohexane was used instead. 3,4 The remainder of the synthesis of GC4419 can be identical in all respects to the published method for GC4403. 2 The synthesis of the GC4401 complex was previously reported in reference 5.

[0436]

[0437] The synthesis of GC4444 containing an additional 11-R-methyl substituent creating a fifth chiral center on carbon (and also derived from R,R-diaminocyclohexane) proceeded from the corresponding chiral tetraamine, the synthesis of which is published in reference 6 as Example 5C.

[0438] Synthesis of axial ligand derivatives

[0439] The same parent Mn(II) pentaazamacrocyclic dichloro complexes (GC4419, GC4403, GC4444 and GC4401) were also used as starting precursors for the synthesis of other axial ligand-bound derivatives using a general synthetic scheme in which a large excess of anionic salt was used to displace the chloride ligand to produce new compounds.

[0440] Example 2

[0441] Synthesis of manganese(II) bis-acetate [(4aS,13aS,17aS,21aS)-1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-icosahydro-11,7-nitrilo-7H-dibenzo[b,h][1,4,7,10]tetraazacycloheptadecyne-κN5,κN13,κN18,κN21,κN22]-, [bis-acetate (GC4419)].GC4701

[0442]

[0443] Using a 500-mL Erlenmeyer flask, 100 mL of deionized ("DI") water was added to 5.3 g of GC4419; the mixture was stirred vigorously for 15-20 minutes and then sonicated for 5 minutes. The resulting light brown suspension was filtered through a 10-20μ fritted funnel (about 0.3 g of solid material remained in the funnel). The resulting clear solution was added as a stream to a sodium acetate solution (approximately 429 mmol, 21 equivalents, in 100 mL of DI water) in one go. No solids separated and the light yellow solution was stirred for an additional 5 minutes. The solution was transferred to a separatory funnel and extracted with dichloromethane (3X 50 mL). The organic layers were separated, combined, and transferred back to the separatory funnel. The dichloromethane solution was back extracted (2X 50 mL) with sodium acetate aqueous solution (32 g / 100 mL). The dichloromethane layer was filtered through MgSO 4 The 1,2-dihydro-1,4-dihydro-2-nitropropene (2,4-dihydro-1,4-dihydro- ...

[0444] The isolated light yellow brittle material (4.11 g, 75% yield based on GC4419) was analyzed by HPLC and shown to be 99.7% pure, and elemental analysis showed 0.98 wt% residual chlorine. Elemental analysis was consistent with the expected bis-(acetate) structure C 25 H 41 Mn 5 O 4 ·2H 2 O. Calculated for analysis: C, 53.00%; H, 8.01%; N, 12.36% and Mn, 9.70%. Found for analysis: C, 53.10%; H, 8.34%; Mn, 9.86%, N, 12.56%, and Cl (as total halogen content), 0.98 wt%.

[0445] Example 3

[0446] Synthesis of manganese(II) bis-octanoate [(4aS,13aS,17aS,21aS)-1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-icosahydro-11,7-nitrilo-7H-dibenzo[b,h][1,4,7,10]tetraazacycloheptadecyne-κN5,κN13,κN18,κN21,κN22]-, [bis-octanoate (GC4419)].GC4710

[0447]

[0448] Use 500-mL conical flask, add 200mL DI water in 10.2g GC4419, stir vigorously for 15-20 minute, then ultrasonic process 5 minutes.The tan suspension of gained is filtered by 45x 20mm diatomaceous earth bed (pre-washed with DI water) on 25-50μ porous funnel.The clear solution of gained is added 250mL sodium octanoate solution (75g, about 450mmol, 11 equivalents) as slow liquid flow through 5 minutes.Do not have solid separation and tan solution is stirred for 5 minutes again.The solution is transferred in separating funnel and extracted with DCM (2X 100mL).The organic layer is separated, merged, filtered through MgSO 4 The 1-hydroxy-1-nitropropene (2-nitropropene) of 4-nitropropene (2-nitropropene) was added to 4-nitropropene (10 g) and dried, filtered and dried under reduced pressure. The residual DCM was co-evaporated with MeOH (75 mL) to obtain a light yellow-tan jelly. The jelly was vacuum dried for 19 h at 40 ° C. Based on starting GC4419, a light yellow solid was isolated in 73% yield (10.8 g). The solid was submitted for elemental analysis (Galbraith Labs) and also analyzed by HPLC using the chromatography described in reference 4.

[0449] HPLC showed 99.5% purity (0.14% monoamine GC4520). Elemental analysis and hemihydrate C 25 H 41 Mn 5 O 4 0.5H 2 O, FW 734.93 (anhyd) structure consistent. Calculated values ​​for analysis: C, 63.05%; H, 9.39%; N, 9.94% and Mn, 7.79%. Found values ​​for analysis: C, 63.21%; H, 9.80%; Mn, 7.97%, N, 9.63% and Cl (as total halogen content), <150ppm.

[0450] Example 4

[0451] Synthesis of Mn(II) bis-pivalate [(4aS,13aS,17aS,21aS)-1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-icosahydro-11,7-nitrilo-7H-dibenzo[b,h][1,4,7,10]tetraazacycloheptadecyne-κN5,κN13,κN18,κN21,κN22]-, [bis-pivalate (GC4419)].GC4709

[0452]

[0453] Sodium pivalate (6.4 g) was added to a 125 mL conical flask and dissolved in 50 mL anhydrous EtOH (warmed to about 40 ° C) (the solution was almost colorless). Once the sodium pivalate solution was cooled back to room temperature, a solution containing 5.3 g GC4419 dissolved in 30 mL anhydrous EtOH was added (the solution was brown). Precipitation of NaCl was observed immediately after mixing. The light brown suspension was stirred for 1 h at room temperature and under Ar, and then placed in a refrigerator (2-8 ° C) overnight. The resulting light brown suspension was filtered using a tared 10-20 μ porous funnel (about 1.1 g solid sodium chloride salt remained in the funnel), and the solvent was removed from the filtrate using a rotary evaporator. The wet residue from the rotary evaporator was further vacuum dried for 15 minutes. IPA (100 mL) was added and the mixture was vortexed for 1 hour and then placed in a refrigerator overnight. The next day, after filtration, 1.28 g of white solid was separated and discarded. The clear tan-yellow filtrate was reduced to a wet solid using a rotary evaporator.

[0454] Dichloromethane (100 mL) was added to the wet solid. The mixture became a gelatinous suspension and was stirred and mixed at 37°C for 1 hour. The suspension was filtered using a tared 10-20μ porous funnel, and 1.7 g of additional white solid was separated and discarded. The solvent of the filtrate was removed using a rotary evaporator to obtain a tan slurry. MeOH (75 mL) was added to the tan slurry and a tan semi-solid was obtained after removing the solvent via a rotary evaporator. The material was vacuum dried for 72 h to obtain GC4709 as a tan solid, which was submitted for elemental analysis. HPLC showed a purity of 99.5%. Elemental Analysis and Structure C 31 H 53 Mn 5 O 4 0.5H 2 O, FW 614.73 (anhyd) consistent. Calculated values ​​for analysis: C, 59.69%; H, 8.73%; N, 11.23% and Mn, 8.81%. Found values ​​for analysis: C, 59.87%; H, 8.44%; Mn, 8.45%, N, 10.88% and Cl (as total halogen content), about 0.08% (784 ppm).

[0455] Example 5

[0456] Synthesis of manganese(II) bis-cyclohexanebutyrate [(4aS,13aS,17aS,21aS)-1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-icosahydro-11,7-nitrilo-7H-dibenzo[b,h][1,4,7,10]tetraazacyclo-heptadecyne-κN5,κN13,κN18,κN21,κN22]-, [bis-cyclohexanebutyrate (GC4419)].GC4707.

[0457]

[0458] Sodium cyclohexanebutyrate (5.77g) was added to a 125mL conical flask and then tried to dissolve it in 50mL anhydrous EtOH under stirring within 15 minutes. The mixture became gelatinous and 50mL EtOH (anhydrous) was added again, 100mL in total. This additional solvent could not obtain a clear solution after heating / ultrasound treatment (about 40°C). MeOH (10mL) was added and a clear solution was obtained after stirring / ultrasound treatment for 15 minutes. This solution was added once to a solution containing 3.6g of GC4419 dissolved in 15mL anhydrous EtOH (the color of the solution was brown). A fine suspension was obtained immediately. The suspension was stirred for 15 minutes and then placed in a freezer for 1h. A 10-15μ porous funnel was used to filter the suspension, and the clear brown filtrate was evaporated to dryness on a rotary evaporator. The resulting solid was vacuum dried overnight at room temperature. Next morning, the tan solid was stirred in 100mL dichloromethane (" DCM ") to dissolve the desired product, leaving excess cyclohexanebutyric acid sodium salt. The slurries were stirred for 3h before filtering (using 10-15 μ porous funnel and washing in funnel with 2x 30mL DCM). The yellow filtrate of gained was evaporated using a rotary evaporator, and 100mL MeOH was then added. The yellow solution of gained was evaporated again using a rotary evaporator, and the residue was placed in vacuum at room temperature overnight. The next day, the tan solid was isolated. The material was further decomposed and vacuum dried overnight, then ground using an agate mortar / pestle.

[0459] The isolated tan solid (5.4 g, 96% yield based on GC4419) was analyzed by HPLC and showed 99.6% purity. Elemental analysis with [bis-(cyclohexanebutyrate) GC4419]: C 41 H 69 Mn 5 O 4, FW 750.97 (anhyd) consistent. Calculated for analysis: C, 65.58%; H, 9.26%; N, 9.33% and Mn 7.32%. Found for analysis: C, 65.29%; H, 8.83%; Mn, 6.95%, N, 9.42% and Cl (as total halogen content) 0.22 wt%.

[0460] Example 6

[0461] Synthesis of manganese(II) bis-dodecanoate [(4aS,13aS,17aS,21aS)-1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-icosahydro-11,7-nitrilo-7H-dibenzo[b,h][1,4,7,10]tetraazacycloheptadecyne-κN5,κN13,κN18,κN21,κN22]-, [bis-dodecanoate (GC4419)].GC4708.

[0462]

[0463] Sodium dodecanoate (6.17g) is added to 300mL anhydrous EtOH in a 500mL conical flask. The obtained white suspension is stirred (300rpm) while heating (about 50°C) on a hot plate. After 15 minutes, the suspension actually thickens. 100mL anhydrous EtOH is added and the obtained slurry is ultrasonically treated for 10 minutes. Then 15mL DI water (making it about 96% EtOH) is added under stirring, and the mixture is turned into a clear solution in one minute. 3.6g GC4419 dissolved in 30mL anhydrous EtOH is added to the solution. The color of the obtained solution is turbid and light brown, and it is stirred for 2h and then placed on a rotary evaporator. About half of the solvent is removed, and as the volume decreases, solid material emerges from the solution. At this time, both solid and solvent are transferred to a 25-50μ filter funnel together with the EtOH (50mL) rinse of the flask, and filtered. The light brown filtrate is then put into the rotary evaporator again. After further evaporation, a light brown solid is obtained, which is placed in vacuum overnight at room temperature. The next day, about 4.7g of a tan solid is isolated. DCM (100mL) is added and the suspension is stirred for 1h, then filtered to obtain a light yellow filtrate. After using the rotary evaporator to remove DCM, a light brown foam is obtained, which is dried in vacuo at room temperature for 48h.

[0464] The tan brittle solid (2.9 g, 44% yield) was analyzed by HPLC and showed 96.8% purity.

[0465] Example 7

[0466] Synthesis of manganese(II) bis-phenylacetate [(4aS,13aS,17aS,21aS)-1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-icosahydro-11,7-nitrilo-7H-dibenzo[b,h][1,4,7,10]tetraazacyclo-heptadecyne-κN5,κN13,κN18,κN21,κN22]-, [bis-phenylacetate (GC4419)].GC4718.

[0467]

[0468] Phenylacetic acid (47.3 g) was partially dissolved in DI water (1 L) and titrated to pH 7.6 using solid NaOH, followed by the addition of a 0.5 M NaOH aqueous solution to bring the pH to about 8.5. The final volume of the sodium phenylacetate solution was about 1 L. GC4419 was added as a solid (3.5 g) to a 400 mL phenylacetate solution under agitation, followed by the formation of some solids. DCM (50 mL) was added and the aqueous layer was extracted. The extraction was repeated twice, the three dichloromethane extracts were combined (about 150 mL) and stripped with the remaining phenylacetate solution (4 x 150 mL). The light yellow DCM solution was filtered through MgSO 4 The mixture was dried for 30 minutes (with stirring), filtered using a 10-20 μ porous funnel, and dried on a rotary evaporator. The resulting foam was dissolved in 50 mL of MeOH and dried again to remove traces of DCM. The yellow foam residue was placed in vacuum at room temperature overnight. 4.57 g (93% yield) of a light tan-yellow semi-crystalline solid was isolated and analyzed by HPLC and showed a purity of 99.6%. Elemental analysis was consistent with the expected bis-(phenylacetate) structure C. 37 H 49 Mn 5 O 4 The results are consistent. Calculated values ​​for analysis: C, 65.09%; H, 7.23%; N, 10.26% and Mn, 8.05%. Found values ​​for analysis: C, 65.17%; H, 7.26%; Mn, 7.67%, N, 10.08% and Cl (as total halogen content), 63 ppm.

[0469] Example 8

[0470] Synthesis of manganese(II) bis-phenylglyoxylate [(4aS,13aS,17aS,21aS)-1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-icosa-11,7-nitrilo-7H-dibenzo[b,h][1,4,7,10]tetraazacycloheptyl-decyne-κN5,κN13,κN18,κN21,κN22]-,.[bis-phenylglyoxylate (GC4419)].GC4719.

[0471]

[0472] Phenylglyoxylic acid (12.4 g) was added to 200 mL DI water in a 500 mL conical flask. After stirring for 5 minutes, a clear colorless solution was obtained. This was treated with 3.2 g NaOH in pellet form, and the mixture was stirred vigorously. The pH was measured when all the NaOH was dissolved. The pH was 3.61, and the pH was adjusted to about 8.5-9 using a 5 wt % NaOH aqueous solution.

[0473] A turbid solution of 5 g of GC4419 in 75 mL of DI water was filtered through a 10-20 μ filter funnel and added to about half of the pH-adjusted aqueous sodium phenylglyoxylate solution (about 110 mL) at one time. The precipitated white material was stirred for another 15 minutes, and then 100 mL of DCM was added. A yellow DCM layer was immediately produced. The layers were separated, and the DCM layer was extracted with the second half of the sodium phenylglyoxylate solution. After vigorous shaking and allowing it to settle for 10 minutes, the DCM layer was filtered through MgSO 4 Dry, filter and remove the solvent using a rotary evaporator. MeOH (50 mL) was added to the rotary evaporator flask and the yellow solution was further evaporated to remove residual DCM. The resulting solid was dried under vacuum at 30°C overnight.

[0474] The isolated light yellow semi-crystalline solid (7.1 g, 96% yield from GC4419) was analyzed by HPLC and showed a purity of 99.3%. Elemental analysis showed the following: C, 62.05%; H, 6.38%; Mn, 7.73%; and N, 9.85%. Analytical found: C, 62.50%; H, 6.29%; Mn, 7.73%; N, 9.85% and Cl as total halogen content 55 ppm.

[0475] Example 9

[0476] Synthesis of manganese(II) bis-propionato [(4aS,13aS,17aS,21aS)-1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-icosahydro-11,7-nitrilo-7H-dibenzo[b,h][1,4,7,10]tetraaza-cycloheptadecyne-κN5,κN13,κN18,κN21,κN22]-, [bis-propionato (GC4419)].GC4711.

[0477]

[0478] GC4419 (11.0 g) was added to a 500-mL conical flask containing 200 mL DI water. The mixture was stirred vigorously for 15-20 minutes, while warming to 40 ° C for 10 minutes. The resulting light brown suspension was filtered using a 10-20 μ porous funnel to obtain a clear light brown solution. An aqueous solution of 80 g sodium propionate in 200 mL DI water was prepared in a separate flask. In a 500-mL conical flask, GC4419 solution and 200 mL sodium propionate solution were merged. The resulting tan solution was stirred for 5 minutes. The light brown-yellow solution was transferred to a 1-L separatory funnel and extracted with DCM (3X 75 mL). The three resulting DCM layers were merged, and transferred back to the separatory funnel, and the resulting DCM solution was stripped with another sodium propionate aqueous solution (3x 70 mL). The DCM layer was filtered through MgSO 4 Dry for 15 minutes (under stirring), filter using a 20-50μ porous funnel, and use a rotary evaporator to dry it (i.e., foam). Add methanol (100 mL), and use a rotary evaporator to dry the resulting solution to remove residual DCM to obtain a light tan-yellow solid. The material was dried under vacuum at 30°C for 20h.

[0479] 11.45 g of an isolated light yellow solid was obtained, which corresponds to a 94% yield based on GC4419. HPLC analysis showed a purity of 99.6%, and elemental analysis showed only 873 ppm of residual chloride as total halogen content, consistent with the [bis-propionato (GC4419)] structure. Analytical calculation: C, 58.05%; H, 8.12%; Mn, 9.83%; and N, 12.54%. Analytical found: C, 57.64%; H, 8.05%; Mn, 9.91%; N, 12.51% and Cl as total halogen content 873 ppm.

[0480] Example 10

[0481] Synthesis of manganese(II) bis-L-phenylglycinate [(4aS,13aS,17aS,21aS)-1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-icosahydro-11,7-nitrilo-7H-dibenzo[b,h][1,4,7,10]tetraazacyclo-heptadecyne-κN5,κN13,κN18,κN21,κN22]-,.[bis-(L)-phenylglycinate (GC4419)].GC4702

[0482]

[0483] GC4419 (1.5 g) was added to a 250 mL conical flask containing 100 mL DI water under stirring for 15 minutes. The obtained light brown suspension was filtered using a 20-50 μ porous funnel. 8.3 g of NaOH was added to a second conical flask in which 31.3 g L-phenylglycine was dissolved in 400 mL DI water, and the mixture was stirred vigorously. The pH was measured when all NaOH was dissolved. The pH was 2.30 and adjusted with a 5 wt % NaOH aqueous solution (the resulting pH = 9.6). In a 250-mL conical flask, the GC4419 solution and about half (200 mL) of the sodium L-phenylglycine solution were combined. The resulting brown solution was stirred for 5 minutes. The light brown-yellow solution was transferred to a 1-L separatory funnel and extracted with DCM (3x 50 mL). The three resulting DCM layers were combined and transferred back to the separatory funnel. The resulting DCM solution was back extracted with the remaining aqueous sodium L-phenylglycinate solution (4 x 50 mL). The DCM layer was washed with MgSO 4 Dried for 15 minutes (under stirring), filtered using a 20-50μ porous funnel, and dried using a rotary evaporator. Methanol (50mL) was added and the resulting solution was dried using a rotary evaporator to remove residual DCM to obtain a light tan-yellow solid. The material was vacuum dried at 30°C for 20h. 5.42g of isolated light yellow solid (74% yield) was obtained. HPLC analysis showed a purity of 99.5%. Elemental analysis showed 188ppm of residual chloride. Elemental analysis was consistent with the expected GC4702 structure C as a 1.5 hydrate. 37 H 51 Mn 7 O 4 1.5H 2 O consistent: Calculated for: C, 60.07%; H, 7.36%; Mn, 7.43%; and N, 13.25%. Found for: C, 60.20%; H, 7.11%; Mn, 7.72%; N, 13.30% and Cl as total halogen content 188 ppm.

[0484] Embodiment 11

[0485] Synthesis of Mn(II) Bis-rac-phenylglycinate [(4aS,13aS,17aS,21aS)-1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-icosahydro-11,7-nitrilo-7H-dibenzo[b,h][1,4,7,10]tetraazacycloheptadecyne-κN5,κN13,κN18,κN21,κN22]-, [Bis-(rac)-phenylglycinate (GC4419)].GC4720

[0486]

[0487] GC4419 (10.0 g) was added to 250 mL DI water in a 500 mL conical flask under vigorous stirring for 15-20 minutes. The light brown suspension obtained was filtered through a 20-50 μ porous funnel. 16.6 g NaOH (two roughly equal portions, in pellets) was added to the second conical flask containing 62.7 g rac-phenylglycine in 350 mL DI water, and the mixture was stirred vigorously. pH was measured when all NaOH dissolved and a clear solution was obtained. pH was measured as 12.3, and was adjusted to 9 by adding a small portion of racemic-phenylglycine powder. GC4419 solution and half (about 200 mL) of racemic-phenylglycine sodium solution (about 105 mmol) were merged in a 500 mL conical flask. The light brown solution obtained was stirred for 5 minutes. The solution was transferred to a 1-L separating funnel, and extracted with 150 mL DCM. The organic layer was separated and back extracted with the remaining aqueous sodium rac-phenylglycinate solution (2 x 100 mL). The DCM layer was washed with MgSO 4 Dry for 15 minutes (with stirring), filter using a 20-50μ porous funnel, and dry using a rotary evaporator. Methanol (75 mL) was added and the resulting solution was dried using a rotary evaporator to remove residual DCM to obtain a light tan-yellow solid. The material was dried under vacuum at 30°C for 20 h. The isolated light yellow material (5.42 g, 74% yield) was analyzed by HPLC, showing a purity of 99.5%. Elemental analysis was consistent with the expected GC4720 structure C 37 H 51 Mn 7 O 4 ·2H 2O. Calculated values ​​for analysis: C, 62.35%; H, 7.21%; N, 13.76% and Mn, 7.71%. Found values ​​for analysis: C, 56.89%; H, 7.02%; Mn, 7.68%, N, 13.76% and Cl (as total halogen content), 0.20%.

[0488] Example 12

[0489] Synthesis of manganese(II) bis-L-phenylalanine [(4aS,13aS,17aS,21aS)-1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-icosahydro-11,7-nitrilo-7H-dibenzo[b,h][1,4,7,10]tetraazacyclo-heptadecyne-κN5,κN13,κN18,κN21,κN22]-,.[bis-(L)-phenylalanine (GC4419)].GC4704.

[0490]

[0491] GC4419 (10.0.g) is added to 200mL DI water in a 500mL conical flask under vigorous stirring. The obtained light brown suspension is filtered using a 20-50μ porous funnel. Separately, (L)-phenylalanine (68.39g) is added to 200mL DI water in a 500-mL conical flask. The phenylalanine suspension is treated with solid NaOH (16.6g) in the form of pellets, and the mixture is vigorously stirred. pH is measured when all NaOH is dissolved. pH is 11.1, and is adjusted down to pH=10.24 by adding L-phenylalanine. GC4419 solution and half (about 100mL) of sodium L-phenylalaninate solution are combined under stirring in a 500mL conical flask. After adding 100mL DCM, the resulting tan solution is stirred for 5 minutes. The light brown-yellow biphasic solution was transferred to a 1-L separatory funnel, the organic layer was removed and the aqueous layer was extracted with another 50 mL of DCM. The organic layers were combined and transferred back to the separatory funnel. The resulting DCM solution was back extracted with the remaining sodium propionate aqueous solution (2x about 50 mL). The DCM layer was filtered through MgSO 4 Dry for 15 minutes (under stirring), filter using a 20-50μ porous funnel, and use a rotary evaporator to dry it (i.e., foam). Add methanol (50 mL), and use a rotary evaporator to dry the resulting solution to remove residual DCM to obtain a light tan-yellow solid. The material was dried under vacuum at 30°C for 40h.

[0492] The isolated tan-yellow amorphous powder (4.1 g, 55% yield) was analyzed via HPLC and shown to have a purity of 99.6%. Elemental analysis was consistent with the expected structure of the GC4704 complex as a trihydrate (C 39 H 55 Mn 7 O 4 ·3H 2 O) showed the following results: C, 59.19%; H, 7.22%; Mn, 6.52%; N, 12.09% and Cl, 0.20%.

[0493] Embodiment 13

[0494] Synthesis of manganese(II) bis-rac-2-phenylpropionato [(4aS,13aS,17aS,21aS)-1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-icosahydro-11,7-nitrilo-7H-dibenzo[b,h][1,4,7,10]tetraazacycloheptadecyn-κN5,κN13,κN18,κN21,κN22]-,.[bis-(rac)-2-phenylpropionato (GC4419)].GC4705

[0495]

[0496] 27.5g racemic-2-phenylpropionic acid is added to a 500-mL conical flask containing 200mL DI water. After stirring for 5 minutes, a dispersion is obtained. It is treated with solid NaOH (6.84g) in the form of pellets, and the mixture is stirred vigorously. pH is measured when all NaOH is dissolved. Before adding NaOH, pH is 2.97 (dispersion), and after addition, it is adjusted to pH about 9 using a 5 wt % NaOH aqueous solution, producing a slightly turbid solution. A slightly turbid solution of 10g GC4419 in 350mL DI water is prepared by vigorous stirring. A 100-mL portion of the pH-adjusted aqueous solution of 2-phenylpropionic acid salt solution is added as a slow stream in 1 minute. Off-white semi-solid is precipitated, and the entire mixture is stirred for 15 minutes with DCM (100mL). After this period of time, the two-phase solution is transferred to a 500-mL separating funnel. The conical flask is rinsed with DCM (10mL) and added to the funnel. The organic layer was separated and the top aqueous layer was extracted with additional dichloromethane (50 mL). The tan dichloromethane solutions were combined in a separatory funnel and extracted with the second half of an aqueous solution of sodium rac-phenylpropionic acid (2 x 50 mL). After vigorous shaking and settling for 10 minutes each time, the DCM layer was separated by MgSO 4(20 g) was dried, filtered and the solvent removed. Methanol (75 mL) was added and the resulting solution was dried using a rotary evaporator to remove residual DCM. The resulting gummy material was dried in vacuo at 35°C overnight.

[0497] The isolated light beige solid (14.6 g, 95% yield) was analyzed by HPLC and it showed a purity of 99.7%. Elemental analysis and expected results of GC4705 C 39 H 53 Mn 5 O 4 Consistent: C, 65.74%; H, 7.54%; Mn, 7.57%; N, 9.76% and Cl, 60ppm.

[0498] Embodiment 14

[0499] Synthesis of manganese(II) bis-rac-phenylglycinate [2S,21S-dimethyl(4aR,13aR,17aR,21aR)-1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-icosahydro-11,7-nitrilo-7H-dibenzo[b,h][1,4,7,10]tetraazacycloheptadecyne-κN5,κN13,κN18,κN21,κN22]-,.[bis-(rac)-phenylglycinate (GC4401)].GC4715.

[0500]

[0501] GC4401 (5g, 9.78mmol) is added to 50mL DI water in 125mL conical flask and stirred vigorously for 5 minutes to provide a very slightly turbid light yellow solution. Then filter the solution and retain the filtrate solution. Using a second conical flask, racemic-phenylglycine (30g, 198.5mmol) is added to 200mL DI water to obtain a colorless solution. The solution is processed with 7.9g NaOH in a pellet, and the mixture is stirred vigorously. pH is measured after all NaOH dissolves, and the result is 11.2. The slightly turbid solution is filtered (20-50μ). In a 250-mL conical flask, GC4401 solution and half (100mL) of sodium phenylglycine solution (about 105mmol / 10 equivalent) are merged into a liquid stream. No solids separated, and the resulting yellow-tan solution was stirred for an additional 15 minutes, then transferred to a 250-mL separatory funnel and extracted with dichloromethane (50 mL, approximately 1-2 minutes shaking time). The organic layer was separated and transferred back to the separatory funnel. The dichloromethane solution was back-extracted with the remaining aqueous sodium phenylglycinate solution (1-2 minutes each shaking). The dichloromethane layer was washed with MgSO 4 Dry for 15 minutes, filter with a 20-50μ porous funnel, and dry it with a rotary evaporator (i.e., foam). Methanol (50 mL) was then added to the yellow solid, and the solution was dried to co-evaporate the residual dichloromethane to produce a light yellow solid. The material was vacuum dried at 30°C for 24 hours. The isolated light yellow solid (6.5 g, 90% yield based on GC4401) was analyzed by HPLC and showed a purity of 99.5%. Elemental analysis was consistent with the expected GC4715 structure C. 39 H 55 Mn 7 O 4 ·H 2 O. Calculated for analysis: C, 63.23%; H, 7.48%; N, 13.23% and Mn, 7.42%. Found for analysis: C, 60.68%; H, 7.31%; Mn, 7.06%, N, 12.68% and chlorine (as total halogen content), 974 ppm.

[0502] Embodiment 15

[0503] Synthesis of manganese(II) bis-rac-phenylglycinate [6R-methyl(4aR,13aR,17aR,21aR)-1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-icosa-11,7-nitrilo-7H-dibenzo[b,h][1,4,7,10]tetraazacycloheptadecyne-κN5,κN13,κN18,κN21,κN22]-,.[bis(rac)2-phenylglycinate (GC4444)].GC4716.

[0504]

[0505] GC4444 (1 g, 2 mmol) was added to 40 mL DI water in a 125 mL conical flask and stirred vigorously for 5 minutes to obtain a light yellow solution. In a second 250 mL conical flask, racemic-phenylglycine (6 g, 40 mmol) was added to 100 mL DI water to obtain a colorless solution. The solution was processed with NaOH pellets (1.6 g) and the mixture was stirred vigorously. The pH value was measured after all the NaOH dissolved, and the result was 12.

[0506] In a 250-mL conical flask, combine the GC4444 solution and half (50 mL) of the sodium phenylglycinate solution (about 20 mmol / 10 equivalents). The resulting yellow-tan solution was vigorously stirred with dichloromethane (50 mL) for 15 minutes and then transferred to a 250 mL separatory funnel. The organic layer was separated and transferred back to the separatory funnel. The dichloromethane solution was extracted with the remaining sodium phenylglycinate aqueous solution (shaking for 1-2 minutes each time). The dichloromethane layer was filtered through MgSO 4 Dry for 15 minutes, filter with a 20-50μ porous funnel, and dry on a rotary evaporator. Methanol (25 mL) was added to the residual oily solid to give a slightly tan-yellow solution, which was dried on a rotary evaporator to give a light yellow solid. The material was dried under vacuum at 35°C for 24h. Elemental analysis was consistent with the expected GC4716 structure C 38 H 53 Mn 7 O 4 ·H 2 O is consistent. Calculated value: C, 62.80%; H, 7.35%; N, 13.49%. Found value: C, 61.14%; H, 7.44%; N, 13.08.

[0507] 6.5 g of a light yellow powder were isolated, giving a 90% yield based on the starting GC4444. The material was analyzed by HPLC and found to be 99% pure.

[0508] Example 16

[0509] Synthesis of manganese(II) bis-rac-phenylglycinate [(4aR,13aR,17aR,21aR)-1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-icosahydro-11,7-nitrilo-7H-dibenzo[b,h][1,4,7,10]tetraazacycloheptadecyne-κN5,κN13,κN18,κN21,κN22]-,.[bis-(rac)-2-phenylglycinate (GC4403)].GC4717.

[0510]

[0511] GC4403 (3 g, 6.2 mmol) was added to 75 mL DI water in a 125 mL conical flask and stirred vigorously for 15-20 minutes to obtain a light orange solution. In a separate 250-mL conical flask, 18.76 g (124 mmol) of racemic-phenylglycine was added to 125 mL DI water under vigorous stirring. Solid 4.9 g NaOH was added to the solution. After vigorous stirring for 10 minutes, a colorless solution was obtained, and the pH was measured to be 12. GC4403 solution and 75 mL of racemic-phenylglycine sodium solution were combined in a 500-mL conical flask. The light brown solution was stirred for another 5 minutes. The solution was transferred to a 250-mL separatory funnel and extracted with dichloromethane (75 mL, about 1-2 min shaking). The organic layer was separated and stripped with the remaining racemic-phenylglycine sodium. The dichloromethane layer was filtered through MgSO 4 Dry for 15 minutes, filter with a 20-50μ porous funnel, and dry with a rotary evaporator (i.e., a jelly). Use methanol (25mL) to co-evaporate the residual dichloromethane to obtain a light orange solid. The material was vacuum dried at 37°C for 20 hours. 5.42g of light yellow solid material was isolated to obtain a 100% yield based on GC4403. The material was analyzed by HPLC and showed a purity of 99.5%. Elemental analysis was consistent with the expected GC4717 structure C 37 H 51 Mn 7 O 4 ·H 2 O. Calculated for analysis: C, 62.35%; H, 7.21%; N, 13.76% and Mn, 7.71%. Found for analysis: C, 60.72%; H, 7.26%; Mn, 7.44%, N, 13.34% and chlorine (as total halogen content), 364 ppm.

[0512] Embodiment 17

[0513] Synthesis of manganese(II) bis-n-butyrate [(4aS,13aS,17aS,21aS)-1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-icosahydro-11,7-nitrilo-7H-dibenzo[b,h][1,4,7,10]tetraazacycloheptadecyne-κN5,κN13,κN18,κN21,κN22]-,.[bis-n-butyrate (GC4419)].GC4713.

[0514]

[0515] GC4419 (5.0 g, 10.34 mmol) was added to a 500-mL conical flask containing 100 mL DI water. The mixture was stirred vigorously for 15-20 minutes, then sonicated / heated (using a heat gun) for 10 minutes, a tan turbid solution was detected, which was then filtered to remove trace insolubles to obtain a clear solution. Separately, sodium butyrate (92 g, 0.835 mol) was dissolved in 200 mL DI water in a 500 mL conical flask. 100 mL of sodium butyrate solution was added to the flask containing the GC4419 solution. The tan solution was stirred for another 5 minutes, then transferred to a 500-mL separatory funnel and extracted with DCM (75 mL). The organic layer was transferred back to the separatory funnel and stripped with the remaining sodium butyrate aqueous solution (100 mL). The DCM layer was filtered through MgSO 4 Dry for 15 minutes (under stirring), filter using a 20-50μ porous funnel, and use a rotary evaporator to dry (i.e., foam). Use methanol (50mL) to dissolve the solid, and then dry this solution on a rotary evaporator to obtain a light yellow oil. The material is further vacuum dried at 30°C for 48h to obtain a tan solid (4.5g, 76% yield based on the starting GC4419). HPLC analysis showed a purity of 99.6 area%. Elemental analysis was consistent with the expected GC4713 structure C. 29 H 49 Mn 5 O 4 The results are consistent. Calculated values ​​for analysis: C, 59.37%; H, 8.42%; N, 11.94% and Mn, 9.36%. Found values ​​for analysis: C, 59.32%; H, 8.55%; Mn, 8.80%, N, 11.94% and Cl (as total halogen content), 546 ppm.

[0516] Embodiment 18

[0517] Synthesis of manganese(II) bis-benzoate [(4aS,13aS,17aS,21aS)-1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-icosahydro-11,7-nitrilo-7H-dibenzo[b,h][1,4,7,10]tetraazacycloheptadecyne-κN5,κN13,κN18,κN21,κN22]-,.[bis-benzoate (GC4419)]:GC4712.

[0518]

[0519] In a 500 mL Erlenmeyer flask containing 200 mL DI water, 10 g of GC4419 was added with vigorous stirring. The resulting clear light tan solution was filtered to remove trace levels of insolubles and then added as a slow stream over 5 minutes to 100 mL of an aqueous solution of sodium benzoate (66 g) (approximately 458 mmol, 11 equivalents). A gelatinous white solid separated at the end of the addition. Dichloromethane (100 mL) was added to the mixture with vigorous stirring to dissolve all solid material. The resulting two-phase mixture was then transferred to a separatory funnel. The organic layer was separated and filtered through MgSO 4 (10 g) was dried, filtered, and dried on a rotary evaporator under reduced pressure. Methanol was added to the flask containing the residual oily solid, and the solution was dried on a rotary evaporator to give a light yellow solid. The material was dried under vacuum at 30°C for 40 h and gave 7.8 g (57% yield based on GC4419) of a light yellow-tan solid, which was analyzed by HPLC and shown to be 99.6% pure. Elemental analysis was similar to C 35 H 45 Mn 5 O 4 0.5H 2 The expected GC4712 structure of O was consistent. Calculated values ​​for analysis: C, 63.34%; H, 6.99%; N, 10.55%; Mn, 8.28%. Found values ​​for analysis: C, 63.07%; H, 7.38%; N, 10.54%, Mn, 8.16% and trace Cl (211 ppm).

[0520] Embodiment 19

[0521] Synthesis of manganese(II) di-L-lactate [(4aS,13aS,17aS,21aS)-1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-icosahydro-11,7-nitrilo-7H-dibenzo[b,h][1,4,7,10]tetraazacycloheptadecyne-κN5,κN13,κN18,κN21,κN22]-,.[Di-L-lactate (GC4419)]:GC4714.

[0522]

[0523] In a 500mL conical flask containing 100mL DI water, 5g (10.34mmol) GC4419 was added under vigorous stirring. The clear light brown solution of the obtained was filtered to remove the insoluble matter at the trace level, and then 125mL L-sodium lactate (23.4g) aqueous solution as a slow stream was added to the solution in 5 minutes. The brown solution of the obtained was stirred for another 5 minutes, then transferred to a 500-mL separatory funnel and extracted with DCM (75mL). The organic layer was transferred back to the separatory funnel and stripped with the remaining (L)-sodium lactate aqueous solution (125mL). The dichloromethane layer was filtered through MgSO 4 Dry 15 minutes (under stirring), filter using 20-50 μ porous funnel, and use rotary evaporator to make it dry (i.e. foam) to remove solvent. Then methanol (50mL) is added to flask and used to co-evaporate residual DCM using rotary evaporator to obtain tan slurry. This material is further vacuum dried 48h at 30 ℃ to obtain tan solid.

[0524] The isolated tan amorphous solid was analyzed by HPLC and shown to be 99.7% pure. Elemental analysis was consistent with the expected GC4714 structure C 27 H 45 Mn 5 O 6 ·H 2 O. Calculated values: C, 53.28%; H, 7.78%; N, 11.51%; Mn, 9.03%. Found values: C, 53.12%; H, 7.77%; N, 11.91%, Mn, 9.06% and Cl (0.87%).

[0525] Embodiment 20

[0526] Synthesis of manganese(II) bis-rac-mandelate [(4aS,13aS,17aS,21aS)-1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-icosahydro-11,7-nitrilo-7H-dibenzo[b,h][1,4,7,10]tetraazacycloheptadecyne-κN5,κN13,κN18,κN21,κN22]-,.[bis-rac-mandelate (GC4419)]:GC4706.

[0527]

[0528] 200mL DI water and 12.4g rac-mandelic acid were added to a 500-mL conical flask. After stirring the mixture for 5 minutes, a clear colorless solution was obtained. It was treated with 3.2g NaOH in pellet form, and the mixture was stirred vigorously. The pH was measured after all NaOH was dissolved. The pH was 3.61, and it was adjusted to low alkalinity (pH = 9.67) using a 5 wt% NaOH aqueous solution. The turbid solution of 5g GC4419 in 100mL DI water was filtered (20-50μ), and 1 / 2 of the pH-adjusted sodium salt aqueous solution was added at one time. The precipitated white viscous material was stirred for another 5 minutes and placed in a refrigerator at 2-8°C overnight. The next morning, the suspension was transferred to a 250-mL separatory funnel, and the conical flask was rinsed with 100mL dichloromethane, and the suspension and dichloromethane washings were combined in a separatory funnel. The dichloromethane layer immediately turned light brown-yellow. Separate the layers and extract the dichloromethane layer with the second half of the sodium mandelate aqueous solution. After vigorous shaking and standing for 10 minutes, the dichloromethane layer was filtered through MgSO 4 The mixture was stirred for 2 hours at 4 ℃ for 10 minutes. The mixture was stirred for 2 hours at 4 ℃ for 3 ...

[0529] Elemental analysis was consistent with the expected GC4706 structure and showed the following results: C, 61.64%; H, 7.04%; Mn, 7.16%; N, 9.30% and Cl, 66 ppm (0.0066%). Delta (Δ) values ​​from 1 / 3-hydrated material: C, 0.52%; H, 0.04%; Mn, 0.07%; N, 0.08% and Cl 0%.

[0530] Embodiment 21

[0531] Synthesis of manganese (II) bis-L-valine [(4aS,13aS,17aS,21aS)-1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-icosa-11,7-nitrilo-7H-dibenzo[b,h][1,4,7,10]tetraazacyclo-heptadecyne-κN5,κN13,κN18,κN21,κN22]-,.[bis-(L)-valine (GC4419)]:GC4746.

[0532]

[0533] GC4419 (3.0 g, 6.2 mmol) was added to a 250-mL conical flask containing 100 mL DI water. The mixture was stirred vigorously for 15-20 minutes to obtain a light brown solution. An aqueous solution of 58.6 g L-(+)-valine (0.5 mol) and NaOH (20 g, 0.5 mol) in 200 mL DI water was prepared in a separate flask. The pH of the solution was recorded as 11.7. The GC4419 solution and half of the sodium valine solution were combined in a 500-mL conical flask. The resulting solution was stirred for another 5 minutes and transferred to a 0.5-L separatory funnel and extracted with 100 mL dichloromethane. The organic layer was separated, transferred back to the separatory funnel and stripped with the remaining sodium valine aqueous solution. The dichloromethane layer was separated and the solvent was removed using a rotary evaporator. The residual dichloromethane was co-evaporated with methanol (50 mL) to obtain a light brown solid. The material was dried under vacuum at 40 °C for 20 h.

[0534] 3.4 g of an isolated light grey solid were obtained, which corresponds to a yield of 83% based on GC4419. HPLC analysis showed a purity of 99.6% and elemental analysis showed 0.67% residual chloride expressed as total halogen content and consistent with GC4746·0.5H 2 O structure is consistent. Calculated values ​​for analysis: C, 56.87%; H, 8.77%; Mn, 8.39%; and N, 14.97%. Found values ​​for analysis: C, 57.22%; H, 8.70%; Mn, 7.88%; N, 14.12% and Cl (as total halogen content) 0.67%.

[0535] Embodiment 22

[0536] Synthesis of manganese(II) bis-propionato [6R-methyl(4aR,13aR,17aR,21aR)-1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-icosahydro-11,7-nitrilo-7H-dibenzo[b,h][1,4,7,10]tetraazacycloheptadecyne-κN5,κN13,κN18,κN21,κN22]-,.[bis-propionato (GC4444)]:GC4747.

[0537]

[0538] GC4444 (1.6 g, 3.2 mmol) was added to a 125-mL conical flask containing 50 mL DI water. The mixture was stirred vigorously for 15-20 minutes to obtain a light yellow solution. An aqueous solution of 6.15 g sodium propionate in 100 mL DI water was prepared in a separate flask. GC4444 and sodium propionate solutions were combined in a 250-mL conical flask. The resulting solution was stirred for 15 minutes and transferred to a 0.25-L separatory funnel and extracted with 50 mL dichloromethane. The organic layer was separated and the solvent was removed using a rotary evaporator. The residual dichloromethane was co-evaporated with methanol (25 mL) to obtain a light brown solid. The material was vacuum dried at 40 ° C for 24 h.

[0539] 1.1 g of an isolated light tan solid was obtained, which corresponds to a 60% yield based on GC4444. HPLC analysis showed a purity of 99.5%, and elemental analysis showed 1.44% residual chloride expressed as total halogen content and consistent with GC4747·0.5H 2 O structure is consistent. Calculated values ​​for analysis: C, 57.82%; H, 8.32%; Mn, 9.45%; and N, 12.04%. Found values ​​for analysis: C, 58.19%; H, 8.50%; Mn, 9.39%; N, 12.36% and Cl (as total halogen content) 1.44%.

[0540] Embodiment 23

[0541] Synthesis of manganese(II) bis-propionato [(4aR,13aR,17aR,21aR)-1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-icosahydro-11,7-nitrilo-7H-dibenzo[b,h][1,4,7,10]tetraazacycloheptadecyne-κN5,κN13,κN18,κN21,κN22]-,.[bis-propionato (GC4403)]:GC4748.

[0542]

[0543] GC4403 (3.0 g, 6.2 mmol) was added to a 250-mL conical flask containing 75 mL DI water. The mixture was stirred vigorously for 15-20 minutes to obtain a light brown solution. An aqueous solution of 23.8 g sodium propionate in 75 mL DI water was prepared in a separate flask. The GC4403 solution and 40 mL sodium propionate solution were combined in a 500-mL conical flask. The resulting solution was stirred for another 5 minutes and transferred to a 0.5-L separatory funnel and extracted with 50 mL dichloromethane. The organic layer was separated, transferred back to the separatory funnel and back-extracted with the remaining sodium propionate aqueous solution (35 mL). The dichloromethane layer was separated and the solvent was removed using a rotary evaporator. Methanol (25 mL) was used to co-evaporate the residual dichloromethane to obtain a light brown solid. The material was dried under vacuum at 40 ° C over the weekend.

[0544] 2.7 g of an isolated light brown solid was obtained, which corresponds to a 78% yield based on GC4403. HPLC analysis showed a purity of 97.3% (1.2% monoamine GC4520), and elemental analysis showed 0.356% residual chloride expressed as total halogen content and consistent with the GC4748 structure. Analytical calculation: C, 58.05%; H, 8.12%; Mn, 9.83%; and N, 12.54%. Analytical found: C, 58.00%; H, 8.45%; Mn, 9.57%; N, 12.53% and Cl (as total halogen content) 0.356%.

[0545] Embodiment 24

[0546] Synthesis of manganese(II) bis-pyruvate [(4aS,13aS,21aS)-1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-icosahydro-11,7-nitrilo-7H-dbenzo[b,h][1,4,7,10]tetraazacycloheptadecyne-κN5,κN13,κN18,κN21,κN22]-,.[bis-pyruvate (GC4419)]:GC4749

[0547] Using a 500-mL conical flask, 150 mL of DI water was added to GC4419 (FW 483.38, 5 g, 10.34 mmol) and stirred vigorously for 15-20 minutes to dissolve it. In a second conical flask, pyruvic acid (72.83 g, 0.827 mol) was added to 400 mL of DI water. While stirring the suspension, NaOH (0.83 mol, 33.2 g) was added and continued stirring until a clear, colorless solution was obtained. The pH of the solution was about 12. In a 500-mL conical flask, the GC4419 solution and half of the sodium pyruvate solution were combined. No solids were separated, and the tan mixture was stirred for another 5 minutes. The light tan-yellow solution was transferred to a 1-L separatory funnel and extracted with DCM (100 mL, shaking for about 1-2 minutes each time). The color of the aqueous solution was light pink purple. The DCM layer was stripped with the remaining sodium pyruvate aqueous solution. The DCM layer was washed with MgSO 4 Dry for 15 minutes (under stirring), filter using a 20-50μ porous funnel, and then use a rotary evaporator to dry it. MeOH (50mL) can then be used to co-evaporate the remaining DCM to obtain a solid. The material can be vacuum dried at 30°C for at least 20h. The solid can be characterized by elemental analysis, MS and HPLC.

[0548] Embodiment 25

[0549] Synthesis of manganese(II) bis-L-alanine [(4aS,13aS,17aS,21aS)-1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21a-icosahydro-11,7-nitrilo-7H-dibenzo[b,h][1,4,7,10]tetraazacycloheptadecyne-κN5,κN13,κN18,κN21,κN22]-,.[bis-L-alanine (GC4419)]:GC4750

[0550] Using a 500-mL conical flask, 150 mL of DI water was added to GC4419 (FW 483.38, 5 g, 10.34 mmol) and stirred vigorously for 15-20 minutes to dissolve it. In a second conical flask, L-(+)-alanine (73.7 g, 0.827 mol) was added to 400 mL of DI water. While stirring the suspension, NaOH (0.83 mol, 33.2 g) was added and stirring was continued until a clear, colorless solution was obtained. The pH of the solution was 12.1. In a 500-mL conical flask, the GC4419 solution and half of the sodium alanine solution were combined. No solids were separated, and the tan mixture was stirred for another 5 minutes. The light tan-yellow solution was transferred to a 1-L separatory funnel and extracted with DCM (100 mL, shaking for about 1-2 minutes each time). The color of the aqueous solution was light pink-purple. The DCM layer was stripped with the remaining sodium pyruvate aqueous solution. The DCM layer was washed with MgSO 4 Dry for 15 minutes (under stirring), filter using a 20-50μ porous funnel, and then use a rotary evaporator to dry it. MeOH (50mL) can then be used to co-evaporate the remaining DCM to obtain a solid. The material can be vacuum dried at 30°C for at least 20h. The solid can be characterized by elemental analysis, MS and HPLC.

[0551] result

[0552] Bioavailability data from id dosing in minipigs of various neat single base oil formulations of various axial ligand derivatives with various Mn(II) pentaazamacrocyclic ring complexes are summarized below in Table I. In each case, the concentration of the test article drug compound was 10 wt % of the total formulation.

[0553] Table I

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563] In the following examples, plots of plasma concentrations of the parent Mn(II) pentaazamacrocyclic ring complex following intraduodenal (id) or iv administration of various test article derivatives versus time following administration of the test article are shown. These examples are selected from the examples listed in Table I (above). In all examples, the % bioavailability is based on comparison of plasma levels of the test article drug obtained from comparison of concentration values ​​obtained from id administration using the same pigs as utilized for iv administration, used to calculate 100% bioavailability AUC values.

[0564] exist Figure 1 A characteristic graph of plasma concentrations of the parent manganese pentaazamacrocyclic ring complex of GC4419 (independent of the composition of the axial ligand) in minipig plasma from blood samples at time points up to 24 hours after administration of the test article drug by iv or id delivery is shown in FIG. Blood levels of GC4419 following iv administration at a 1 mg / kg body weight (mpk) dose are considered 100% bioavailable, and plasma concentrations following iv administration of an aqueous formulation of GC4419 are also shown. In this example, intraduodenal administration of 10 mg / kg doses of 10 wt% of the following formulations: 1) a bis-L-phenylglycine derivative of GC4419 (GC4702), 2) a bis-L-phenylalanine derivative of GC4419 (GC4704), and 3) a bis-rac-phenylglycine derivative of GC4419 (GC4720) as their Capmul MCM formulations were compared to an iv dose of 1 mg / kg of GC4419 itself.

[0565] exist Figure 2 A characteristic graph of plasma concentrations of the parent manganese pentaazamacrocyclic ring complex of GC4419 (independent of the composition of the axial ligand) in minipig plasma from blood samples at time points up to 24 hours after administration of the test article drug formulated in Peceol for id delivery is shown in Figure 1. Blood levels of the parent drug (in this case GC4419) following iv administration at a dose of 1 mg / kg body weight (mpk) are considered to be 100% bioavailable, and plasma concentrations following iv administration of an aqueous formulation of GC4419 are also shown. In this example, intraduodenal administration of 10 mg / kg doses of 10 wt% of the following preparations: 1) GC4419, 2) the bis-acetate ion derivative of GC4419 (GC4701), and 3) the bis-phenylglyoxylate ion derivative of GC4419 (GC4719) and 4) the bis-rac-2-phenylpropionate ion derivative of GC4419 (GC4705) as their Peceol formulations was compared to iv administration of GC4419 itself.

[0566] exist Figure 3 A characteristic graph of plasma concentrations of the parent manganese pentaazamacrocyclic ring complex of GC4419 (independent of the composition of the axial ligand) in minipig plasma from blood samples at time points up to 24 hours after administration of the test article drug formulated in Labrafil M2125 CS for id delivery is shown in FIG. Blood levels of the parent drug (GC4419 in this case) following iv administration at a 1 mg / kg body weight (mpk) dose are considered 100% bioavailable, and plasma concentrations following iv administration of an aqueous formulation of GC4419 are also shown. In this figure, intraduodenal administration of 10 mg / kg doses of 10 wt% of the following formulations: 1) GC4419, 2) a bis-acetate ion derivative of GC4419 (GC4701), and 3) a bis-octanoate ion derivative of GC4419 (GC4710) as their Labrafil M2125 CS formulations were compared to iv dosing of GC4419 itself in the same group of pigs.

[0567] exist Figure 4 A profile of plasma concentrations of the parent manganese pentaazamacrocyclic ring complex of GC4419 (independent of the composition of the axial ligand) in minipig plasma from blood samples at time points up to 24 hours after administration of the test article drug formulated in Labrafil M2125 CS for id delivery is shown in Figure 1. Blood levels of the parent drug (in this case GC4419) following iv administration at a dose of 1 mg / kg body weight (mpk) are considered to be 100% bioavailable, and plasma concentrations following iv administration of an aqueous formulation of GC4419 are also shown. In this example, intraduodenal administration of 10 mg / kg doses of 10 wt% of the following formulations: 1) a bis-pivalate ion derivative of GC4419 (GC4709), 2) a bis-propionate ion derivative of GC4419 (GC4711), and 3) a bis-butyrate ion derivative of GC4419 (GC4713) as their Labrafil M2125 CS formulations was compared to iv administration of GC4419 itself in the same groups of pigs.

[0568] exist Figure 5A characteristic graph of plasma concentrations of the parent manganese pentaazamacrocyclic ring complex of GC4401 (independent of the composition of the axial ligand) in minipig plasma from blood samples at time points up to 24 hours after administration of the test article drug formulated in Capmul MCM for id delivery is shown in FIG. Blood levels of the parent drug (GC4401 in this case) following iv administration at a 1 mg / kg body weight (mpk) dose are considered to be 100% bioavailable, and plasma concentrations following iv administration of an aqueous formulation of GC4401 are also shown. In this example, intraduodenal administration of 10 mg / kg doses of 10 wt% of the following formulations: 1) GC4401 and 2) a bis-rac-phenylglycine derivative of GC4401 (GC4715) as their Capmul MCM formulations were compared to iv administration of GC4401 itself in the same group of pigs.

[0569] exist Figure 6 A characteristic graph of plasma concentrations of the parent manganese pentaazamacrocyclic ring complex of GC4444 (independent of the composition of the axial ligand) in minipig plasma from blood samples at time points up to 24 hours after administration of the test article drug formulated in Capmul MCM for id delivery is shown in FIG. Blood levels of the parent drug (GC4444 in this case) following iv administration at a 1 mg / kg body weight (mpk) dose are considered to be 100% bioavailable, and plasma concentrations following iv administration of an aqueous formulation of GC4444 are also shown. In this example, intraduodenal administration of 10 mg / kg doses of 10 wt % of the following formulations: 1) GC4444 and 2) a bis-rac-phenylglycine derivative of GC4444 (GC4716) as their Capmul MCM formulations were compared to iv administration of GC4444 itself in the same group of pigs.

[0570] exist Figure 7A characteristic graph of plasma concentrations of the parent manganese pentaazamacrocyclic ring complex of GC4419 (independent of the composition of the axial ligand) in minipig plasma from blood samples at time points up to 24 hours after administration of the test article drug formulated in Capmul MCM for id delivery is shown in FIG. Blood levels of the parent drug (GC4419 in this case) following iv administration at a 1 mg / kg body weight (mpk) dose are considered to be 100% bioavailable, and plasma concentrations following iv administration of an aqueous formulation of GC4419 are also shown. In this example, intraduodenal administration of 10 mg / kg doses of 10 wt% of the following formulations: 1) GC4419, 2) a bis-acetate ion derivative of GC4419 (GC4701), and 3) a bis-rac-mandelate ion derivative of GC4419 (GC4706) as their Capmul MCM formulations were compared to iv administration of GC4419 itself in the same group of pigs.

[0571] exist Figure 8 A characteristic graph of plasma concentrations of the parent manganese pentaazamacrocyclic ring complex of GC4419 (independent of the composition of the axial ligand) in minipig plasma from blood samples at time points up to 24 hours after administration of the test article drug formulated in Maisine 35-1 for id delivery is shown in FIG. Blood levels of the parent drug (GC4419 in this case) following iv administration at a 1 mg / kg body weight (mpk) dose are considered to be 100% bioavailable, and plasma concentrations following iv administration of an aqueous formulation of GC4419 are also shown. In this example, intraduodenal administration of 10 mg / kg doses of 10 wt% of the following formulations: 1) GC4419, 2) a bis-phenylacetate ion derivative of GC4419 (GC4718), and 3) a bis-acetate ion derivative of GC4419 (GC4701) as their Maisine 35-1 formulations were compared to iv administration of GC4419 itself in the same group of pigs.

[0572] exist Fig. 9A characteristic graph of plasma concentrations of the parent manganese pentaazamacrocyclic ring complex of GC4403 (independent of the composition of the axial ligand) in minipig plasma from blood samples at time points up to 24 hours after administration of bis-rac-phenylglycinate-GC4403 by id delivery is shown in FIG. Blood levels of the parent drug (GC4403 in this case) following iv administration at a 1 mg / kg body weight (mpk) dose are considered to be 100% bioavailable, and plasma concentrations following iv administration of an aqueous formulation of GC4403 are also shown. In this example, intraduodenal administration of a 10 mg / kg dose of a 10 wt % formulation of a bis-rac-phenylglycinate derivative of GC4403 (GC4717) as a 10 wt % slurry in Capmul MCM was compared to iv administration of GC4403 itself in the same group of pigs.

[0573] The examples cited above show that axial ligands bonded to Mn(II) ions can exert very profound and previously unpredicted effects on the ability of these complexes to penetrate the GI tract and become orally bioavailable. We have discovered that there is a fairly narrow subset of ligand structures that can greatly enhance gastrointestinal (GI) uptake and thereby greatly improve oral bioavailability. This subset of axial ligand structures that provide enhanced oral bioavailability includes Fig.10 Those shown in .

[0574] There are some significant structural features that influence bioavailability. First, a broad range of alkyl carboxylic acid structures were screened for oral bioavailability in various oils, and it was observed that they were not equivalent in providing high oral bioavailability. In fact, the propionate ligand (and the related lactate ligand - a propionate ligand with an OH replacing the H, and possibly other ligands based on the propionate ligand) provide much better bioavailability than any other carboxylate ligand; such as the one carbon atom shorter chain, acetate, or longer chain carboxylate ligands such as butyrate or octanoate. Second, there is a unique class of axial ligands derived from phenylacetic acid; namely, the phenylacetate ligand. These derivatives are Fig.10As shown. Compared with the parent dichloro complex or with other alkyl carboxylate ion complexes (complexes derived from acetate ions or other higher molecular weight carboxylate ion ligands), all complexes derived from the phenylacetate ion class ligands have greatly improved bioavailability. Third, one of these derivatives is based on an amino acid, phenylglycine. The racemic-phenylglycine root ion ligand enhances the bioavailability of all tested various pentaaza macrocyclic ligands, indicating that this is not only an isolated effect of the parent manganese pentaaza macrocyclic compound of GC4419, but also general to this Mn (II) complex family. In addition, the L-phenylglycine root ion derivative GC4702 of GC4419 is actually more easily absorbed than other amino acid ligands (such as L-phenylalanine root ion or L-valine root ion complexes) or the rac-phenylglycine root ion complex GC4720. Furthermore, this bioavailability enhancing property may be limited to phenylglycinate ligand derivatives (also derivatives of phenylacetic acid), as exemplified by the extremely poor bioavailability of complexes derived from L-phenylalanine homologues or L-valine homologues, although other amino acid ligands, particularly L-alanine homologues belonging to the above-mentioned propionate ion-based ligand class, may also provide good bioavailability.

[0575] References

[0576] 1.Suenderhauf, C., Parrott, N.; "A Physiologically Based PharmacokineticModel of the Minipig: Data Compilation and Model Implementation", Pharm.Res., 30(1), 1-15(2013).

[0577] 2. Salvemini, D., Wang, ZQ., Zweier, JL, Samouilov, A., Macarthur, H., Misko, TP, Currue, MG, Cuzzocrea, S., Sikorski, JA, Riley, DP, “A Nonpeptidyl Mimicof Superoxide Dismutase with Therapeutic Activity in Rats", Science, 286, Oct.8, 304-6 (1999).

[0578] 3.US Patent No.8,263,568

[0579] 4.U.S.Patent No.8,444,856

[0580] 5.Aston,K.,Rath,N.,Naik,A.,Slomczynska,U.,Schall,O.F.,Riley,D.P.,“Computer-Aided Design(CAD)of Mn(Il)Complexes:Superoxide Dismutase Mimeticswith Catalytic Activity Exceeding the Native Enzyme”,Inorg.Chem.,40,1779-89(2001).

Claims

1. Formula (ID R ) or (ID S ) of a pentaazamacrocyclic ring complex: in M is Mn +2 ; R 1A , R 1B , R 4A , R 4B , R 7A , R 7B , R 10A and R 10B are independently hydrogen, methyl, ethyl or propyl; W1, W2 and W3 are independently halo or hydrogen; each -OC(=O)X1 is independently propionate; and The bond between the manganese and the macrocyclic nitrogen atom and the bond between the manganese and the oxygen atom of the axial ligand -OC(=O)X1 are coordinate covalent bonds.

2. The pentaazamacrocyclic ring complex of claim 1, Where R 1A , R 1B , R 4A , R 4B , R 7A , R 7B , R 10A and R 10B are independently hydrogen or methyl; and W1, W2 and W3 are hydrogen.

3. The pentaazamacrocyclic ring complex of claim 1, wherein the pentaazamacrocyclic ring complex corresponds to formula (IE R1 )、(IE S1 )、(IE R2 )、(IE S2 )、(IE R3 ) or (IE S3 ): in Mn is Mn +2 ; each -OC(=O)X1 is independently propionate; and The bond between the manganese and the macrocyclic nitrogen atom and the bond between the manganese and the oxygen atom of the axial ligand -OC(=O)X1 are coordinate covalent bonds.

4. A pharmaceutical composition comprising the pentaazamacrocyclic ring complex according to any one of claims 1 to 3 and a pharmaceutically acceptable excipient suitable for administration.

5. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition is suitable for oral administration to a human subject.

6. The pharmaceutical composition of claim 4, comprising at least one of a lipophilic surfactant and an oil.

7. The pharmaceutical composition of claim 6, wherein at least one of the lipophilic surfactant and the oil comprises at least one of: mono- and / or diglycerides of fatty acids; acetates, succinates, lactates, citrates and / or tartaric acid esters of mono- and / or diglycerides of fatty acids; propylene glycol mono- and / or di-esters of fatty acids; polyglycerol esters of fatty acids; castor oil ethoxylates; acid and ester ethoxylates formed by reacting ethylene oxide with fatty acids or glycerides of fatty acids; sorbitan esters of fatty acids; transesterification products of natural or hydrogenated vegetable oil triglycerides and polyalkylene polyols; alcohol ethoxylates; and polyoxyethylene-polyoxypropylene co-copolymers.

8. The pharmaceutical composition of claim 7, wherein at least one of the lipophilic surfactant and the oil comprises at least one of a mixture of mono / diglycerides of caprylic / capric acid, a mixture of caprylic / capric triglycerides, linoleoyl macrogol-6 glyceride NF, oleoyl macrogol-6 glyceride NF, monoolein glyceride NF, monolinolein glyceride NF, and caprylocaproyl macrogol-8 glyceride NF.

9. The pharmaceutical composition of claim 7, wherein the at least one lipophilic surfactant and oil is linoleoyl polyethylene glycol-6 glyceride NF.

10. The pharmaceutical composition of any one of claims 4 to 9, wherein the pharmaceutical composition is in a solid or semisolid dosage form.

11. The pharmaceutical composition of any one of claims 4-9, wherein the pharmaceutical composition is in the form of a tablet, gelatin capsule, HPMC capsule, gel or suspension suitable for oral administration.

12. The pharmaceutical composition of any one of claims 4-9, wherein the pharmaceutical composition comprises an enteric coating layer.

13. The pharmaceutical composition of any one of claims 4-9, wherein the pharmaceutical composition is in the form of a hydroxypropylmethylcellulose HPMC capsule suitable for oral administration to a human subject.

14. The pharmaceutical composition according to any one of claims 4 to 9, comprising a pharmaceutically acceptable excipient including linoleoyl macrogol-6 glyceride NF and an enteric-coated capsule comprising hydroxypropyl methylcellulose, wherein the capsule comprises the pentaazamacrocyclic complex and the pharmaceutically acceptable excipient.

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