具有口服生物利用率的五氮杂大环状环络合物

Pentaazamacrocycle complexes with oral bioavailability

文档序号：2562 发布日期：2021-09-17 浏览：51次中文

1. A pentaaza macrocyclic ring complex of formula (I):

wherein

M is a transition metal (e.g., Mn)²⁺、Mn³⁺、Mn⁴⁺、Mn⁶⁺、Mn⁷⁺、Fe²⁺、Fe³⁺、Fe⁴⁺、Fe⁶⁺、Ni²⁺、Ni³⁺、Cu¹⁺、Cu²⁺、V² ⁺、V³⁺、V⁴⁺Or V⁵⁺)；

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_10AAnd R_10BIndependently are:

(i) hydrogen;

(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 groups attached to the α -carbon of an amino acid (i.e., α -amino acids); or

(iii) A moiety independently selected from the group consisting of:

-OR₁₁、-NR₁₁R₁₂、-COR₁₁、-CO₂R₁₁、-CONR₁₁R₁₂、-SR₁₁、-SOR₁₁、-SO₂R₁₁、-SO₂NR₁₁R₁₂、-N(OR₁₁)(R₁₂)、-P(＝O)(OR₁₁)(OR₁₂)、-P(O)(OR₁₁)(R₁₂)、-OP(＝O)(OR₁₁)(OR₁₂) And a substituent attached to the alpha-carbon of the amino acid (i.e., alpha-amino acid), wherein R₁₁And R₁₂Independently hydrogen or alkyl;

(iv) substituted or unsubstituted, saturated, partially saturated or unsaturated ring or heterocyclic member containing from 3 to 20 carbon ring atoms, including

(a)R_1AOr R_1BAnd R_2AOr R_2B；R_3AOr R_3BAnd R_4AOr R_4B；R_5AOr R_5BAnd R_6AOr R_6B；R_7AOr R_7BAnd R_8AOr R_8B(ii) a Or R_9AOr R_9BAnd R_10AOr R_10BTogether with the carbon atom to which they are each attached;

(b)R_10Aor R_10BAnd R_1AOr R_1B；R_2AOr R_2BAnd R_3AOr R_3B；R_4AOr R_4BAnd R_5AOr R_5B；R_6AOr R_6BAnd R_7AOr R_7B(ii) a Or R_8AOr R_8BAnd R_9AOr R_9BTogether with the carbon atom to which they are each attached; or

(c)R_1AAnd R_1B；R_2AAnd R_2B；R_3AAnd R_3B；R_4AAnd R_4B；R_5AAnd R_5B；R_6AAnd R_6B；R_7AAnd R_7B；R_8AAnd R_8B；R_9AAnd R_9B(ii) a Or R_10AAnd R_10BTogether with the carbon atom to which they are each attached; or

(v) (iii) a combination of any of (i) to (iv) above;

each X₁Independently is a substituted or unsubstituted phenyl or-C (-X)₂)(-X₃)(-X₄)；

Each X₂Independently substituted or unsubstituted phenyl, methyl, ethyl or propyl;

each X₃Independently hydrogen, hydroxy, methyl, ethyl, propyl, amino, -X₅C(＝O)R₁₃(wherein X₅Is NH or O and R₁₃Is C₁-C₁₈Alkyl, substituted or unsubstituted aryl or C₁-C₁₈Aralkyl, OR-OR₁₄Wherein R is₁₄Is C₁-C₁₈Alkyl, substituted or unsubstituted aryl or C₁-C₁₈Aralkyl), or together with X₄Is (═ O);

each X₄Independently of one another, hydrogen or together with X₃Is (═ O); and is

The bond between the transition metal M and the macrocyclic nitrogen atom and the transition metal M and the axial ligand-OC (O) X₁Is a coordinate covalent bond.

2. A pentaaza macrocyclic ring complex of formula (IA):

wherein

M is a transition metal (e.g. Mn)²⁺、Mn³⁺、Mn⁴⁺、Mn⁶⁺、Mn⁷⁺、Fe²⁺、Fe³⁺、Fe⁴⁺、Fe⁶⁺、Ni²⁺、Ni³⁺、Cu¹⁺、Cu²⁺、V²⁺、V³⁺、V⁴⁺Or V⁵⁺)；

R_1A、R_1B、R₂、R₃、R_4A、R_4B、R₅、R₆、R_7A、R_7B、R₈、R₉、R_10AAnd R_10BIndependently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety or a moiety independently selected from the group consisting of: -OR₁₁、-NR₁₁R₁₂、-COR₁₁、-CO₂R₁₁、-C(＝O)NR₁₁R₁₂、-SR₁₁、-SOR₁₁、-SO₂R₁₁、-SO₂NR₁₁R₁₂、-N(OR₁₁)(R₁₂)、-P(＝O)(OR₁₁)(OR₁₂)、-P(＝O)(OR₁₁)(R₁₂) and-OP (═ O) (OR)₁₁)(OR₁₂)，

Wherein R is₁₁And R₁₂Independently hydrogen or alkyl;

u, together with the adjacent carbon atoms of the macrocycle, form a fused, substituted or unsubstituted, saturated, partially saturated or unsaturated ring or heterocyclic ring having from 3 to 20 ring carbon atoms;

v, together with the adjacent carbon atoms of the macrocycle, form a fused, substituted or unsubstituted, saturated, partially saturated or unsaturated ring or heterocyclic ring having from 3 to 20 ring carbon atoms;

w, together with the nitrogen of said macrocycle and the carbon atom of said macrocycle attached to said macrocycle, form an aromatic or alicyclic, substituted or unsubstituted, saturated, partially saturated or unsaturated, nitrogen-containing fused heterocycle having from 2 to 20 ring carbon atoms, with the proviso that when W is a fused aromatic heterocycle, said hydrogen attached to said nitrogen, both as part of said heterocycle and said macrocycle, and R, both as part of said heterocycle and said macrocycle, attached to said carbon atom₅And R₆Is absent; wherein

Each X₁Independently is a substituted or unsubstituted phenyl or-C (-X)₂)(-X₃)(-X₄)；

Each X₂Independently substituted or unsubstituted phenyl, methyl, ethyl or propyl;

each X₄Independently of one another, hydrogen or together with X₃Is (═ O); and is

The bond between the transition metal M and the macrocyclic nitrogen atom and the transition metal M and the axial ligand-OC (O) X₁Is a coordinate covalent bond.

3. A pentaaza macrocyclic ring complex of formula (IB):

wherein

M is Fe⁺²、Fe⁺³、Mn⁺²Or Mn⁺³；

Wherein R is₁₁And R₁₂Independently hydrogen or alkyl;

W₁、W₂and W₃Independently is halo, hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, acyl, acyloxy, alkoxy, ether, thioether, or nitro;

each X₁Independently is a substituted or unsubstituted phenyl or-C (-X)₂)(-X₃)(-X₄)；

Each X₂Independently substituted or unsubstituted phenyl, methyl, ethyl or propyl;

each X₄Independently of one another, hydrogen or together with X₃Is (═ O); and is

The bond between said transition metal M and said macrocyclic nitrogen atom and said transition metal M and said axial ligand-OC (═ O) X₁Is a coordinate covalent bond.

4. Corresponding to formula (IC)_R) Or (IC)_S) Pentaaza macrocycle complex of (a):

wherein

M is Fe⁺²、Fe⁺³、Mn⁺²Or Mn⁺³；

R_1A、R_1B、R₂、R₃、R_4A、R_4B、R₅、R₆、R_7A、R_7B、R₈、R₉、R_10AAnd R_10BIndependently hydrogen or substituted or unsubstituted alkyl;

W₁、W₂and W₃Independently is halo or hydrogen;

each X₁Independently is a substituted or unsubstituted phenyl or-C (-X)₂)(-X₃)(-X₄)；

Each X₂Independently substituted or unsubstituted phenyl, methyl, ethyl or propyl;

each X₄Independently of one another, hydrogen or together with X₃Is (═ O); and is

The bond between said transition metal M and said macrocyclic nitrogen atom and said transition metal M and said axial ligand-OC (═ O) X₁Is a coordinate covalent bond.

5. Corresponding to formula (ID)_R) Or (ID)_S) Pentaaza macrocycle complex of (a):

wherein

M is Mn⁺²Or Mn⁺³；

R_1A、R_1B、R₂、R₃、R_4A、R_4B、R₅、R₆、R_7A、R_7B、R₈、R₉、R_10AAnd R_10BIndependently hydrogen, methyl, ethyl or propyl;

W₁、W₂and W₃Independently is halo or hydrogen;

each X₁Independently is a substituted or unsubstituted phenyl or-C (X)₂)(X₃)(X₄)；

Each X₂Independently substituted or unsubstituted phenyl, methyl, ethyl or propyl;

each X₄Independently of one another, hydrogen or together with X₃Is (═ O); and is

The bond between said manganese and said macrocyclic nitrogen atom and said manganese and said axial ligand-OC (═ O) X₁Is a coordinate covalent bond.

6. Corresponding to formula (IE)_R1)、(IE_S1)、(IE_R2)、(IE_S2)、(IE_R3) Or (IE)_S3) Pentaaza macrocycle complex of (a):

wherein

Mn is Mn⁺²Or Mn⁺³；

Each X₁Independently is a substituted or unsubstituted phenyl or-C (X)₂)(X₃)(X₄)；

Each X₂Independently substituted or unsubstituted phenyl, methyl, ethyl or propyl;

each X₄Independently of one another, hydrogen or together with X₃Is ═ O; and is

The bond between said manganese and said macrocyclic nitrogen atom and said manganese and said axial ligand-OC (═ O) X₁Is a coordinate covalent bond.

7. A pentaaza macrocyclic ring complex as claimed in any preceding claim, wherein each X is₁Is phenyl.

8. A pentaaza macrocyclic ring complex as claimed in any preceding claim, wherein each X is₁Is a substituted phenyl group.

9. A pharmaceutical composition comprising a pentaaza macrocyclic ring complex of any one of the preceding claims and a pharmaceutically acceptable excipient suitable for administration.

10. A method for administering a pentaaza macrocyclic ring complex to a subject, the method comprising administering the composition of claim 9 to a human subject.

Background

Transition metal pentaaza 15-membered macrocyclic ring complexes with macrocyclic ring systems corresponding to formula a have been shown to be effective in the treatment of a variety of animal and cellular models of human disease and disorders afflicting human patients.

For example, in rodent models of colitis, one such compound, GC4403, was reported to significantly reduce colonic injury in rats undergoing experimental models of colitis when administered by intraperitoneal (ip) injection (see cuzzocorea et al, europ.j. pharmacol.,432,79-89 (2001)).

Ip administered GC4403 has also been reported to attenuate radiation injury in clinically relevant hamster models of acute, radiation-induced oral mucositis (Murphy et al, clin. can. res.,14(13),4292(2008)) and total lethal radiation in adult mice (Thompson et al, Free radial res.,44(5),529-40 (2010)). Similarly, another such compound, GC4419, administered ip, has been shown to attenuate VEGFr inhibitor-induced lung disease in rat models (Tuder, et al, am.j.respir.cell mol.biol.,29, 88-97 (2003)) and to increase the anti-tumor activity of antimetabolites and antimitotic agents in mouse cancer models (see, e.g., WO 2009/143454). In addition, another such compound GC4401 administered ip has been shown to provide a protective effect in animal models of septic Shock (s.cuzzococrea et al, crit.care med.,32(1),157 (2004)) and pancreatitis (s.cuzzococrea et al, Shock,22(3),254-61 (2004)).

Some of these compounds have also been shown to have potent anti-inflammatory activity in vivo and to prevent oxidative damage. For example, IP-administered GC4403 has been reported to inhibit inflammation in rat models of inflammation (Salvemini, et al, Science,286,304(1999)), and to prevent joint disease in rat models of collagen-induced Arthritis (Salvemini, et al, Arthritis & Rheumatism,44(12),2009-2021 (2001)). Since then, these compounds have been reported to have analgesic activity and reduce inflammation and edema in the rat plantar carrageenan hyperalgesia model, see, e.g., U.S. patent No.6,180,620.

Such compounds have also been shown to be safe and effective in the prevention and treatment of disease in human subjects. For example, GC4419 administered by intravenous (iv) infusion has been shown to Reduce Oral Mucositis in head and neck Cancer Patients undergoing Chemoradiotherapy (Anderson, c., Phase 1 tertiary of Superoxide disease (SOD) metric GC4419 to Reduce Chemoradiotherapy (CRT) -Induced Mucositis (OM) in patents with motion or allophageal carenoma (OCC), Oral Mucositis Research Workshop, MASCC/ISOO nuclear medicine superior carrier in Cancer, Copenhagen, Denmark (2015, 25).

In each of these compounds comprising a pentaaza 15-membered macrocycle ring of formula a, the five nitrogens contained in the macrocycle ring each form a coordinate covalent bond with manganese (or other transition metal coordinated by the macrocycle) at the center of the molecule. In addition, manganese (or other suitable transition metal coordinated to the macrocycle) forms coordinate covalent bonds with "axial ligands" in positions perpendicular to the generally planar macrocycle. Such coordinate covalent bonds are characterized by the formation of a bond to the transition metal by the donation and sharing of an available "free" electron pair on the ligand via that electron pair, thereby forming a bond of two electrons between the metal and the donor atom of the ligand (Cotton, F.A. & g.wilkinson, Advanced Inorganic Chemistry, chapter 5, "Coordination Compounds", revision 2, Interscience Publishers, p 139 (1966); IUPAC Gold Book, online version http:// Gold Book. i.up.org/c 329 01. html). The coordinate covalency of the bonds between manganese (or other such suitable transition metal) and the five macrocyclic ring nitrogens, and between manganese (or other such transition metal) and each of the two chlorine axial ligands, is demonstrated, for example, by the "single crystal" X-ray crystal structures of GC4403 (fig. 11) and GC4419 (fig. 12).

Coordination compounds are in contrast to ionic compounds (e.g., salts) in which the force between an anion and a cation in the solid state is strictly the coulombic electrostatic attraction between ions of opposite charge. Thus, in salts, the discrete cations and anions provide the force to maintain a solid state structure; such as chloride and sodium ions as in typical salts such as sodium chloride (Cotton, F.A. & G.Wilkinson, Advanced Inorganic Chemistry, Chapter 5, "The Nature of Ionic Substances", revision 2, Interscience Publishers, pages 35-36, 45-49 (1966).

Although pentaaza 15-membered macrocyclic cyclic 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, somewhat 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, such that absorption is facilitated when the drug is in a non-ionic (neutral) and lipophilic form. See, e.g., Goodman & Gilman's, The pharmaceutical Basis of Therapeutics, ninth edition, pages 5-9 (1996). Without wishing to be bound by any particular theory, it is currently also believed that for this class of compounds, as exemplified by GC4419, where both axial ligands are chlorine moieties, the formation of coordinate covalent bonds to manganese and neutral complex results:

it will also be appreciated that good water solubility may contribute to The rate of uptake of The drug as well as to The overall bioavailability (Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 9 th edition, page 5 (1996)). Both GC4419 and its structural analogs are relatively soluble in water, however, they do not retain the neutral nonionic form in water. In contrast, when dissolved in water, the coordinate covalent bonds are cleaved and the aqueous axial ligands replace one or more of the chlorine axial ligands, thereby producing a monocationic or dicationic complex, as shown in scheme 1, where cationic compounds are expected to be less able to cross the intestinal barrier than neutral complexes.

Thus, in various aspects of the present disclosure, transition metal complexes of pentaaza macrocyclic ring ligands comprising 15-membered macrocyclic rings of formula a are provided, which can be administered to a subject via oral and other routes of administration, thereby achieving high systemic levels of the drug, including by oral administration. In one presently preferred embodiment, the transition metal is manganese.

Disclosure of Invention

One aspect of the present disclosure is a transition metal complex comprising a transition metal consisting of a macrocycle comprising a pentaaza 15-membered macrocycle ring corresponding to formula a and a macrocycle having the formula-oc (o) X₁Is coordinated to two axial ligands, wherein

The macrocycle comprises a pentaaza 15-membered ring corresponding to formula A and wherein formula A may be further substituted, wherein

Each of the two axial ligands has the formula-OC (O) X₁Wherein

Each X₁Independently is a substituted or unsubstituted phenyl or-C (-X)₂)(-X₃)(-X₄)；

Each X₂Independently is a substituted or unsubstituted phenyl, or a substituted or unsubstituted alkyl;

each X₃Independently hydrogen, hydroxy, alkyl, amino, -X₅C(O)R₁₃(wherein X₅Is NH or O and R₁₃Is C₁-C₁₈Alkyl, substituted or unsubstituted aryl or C₁-C₁₈Aralkyl, OR-OR₁₄Wherein R is₁₄Is C₁-C₁₈Alkyl, substituted or unsubstituted aryl or C₁-C₁₈Aralkyl), or together with X₄Is ═ O; and

each X₄Independently of one another, hydrogen or together with X₃Is ═ O.

Another aspect of the disclosure is a manganese complex comprising Mn²⁺Or Mn³⁺Said Mn is²⁺Or Mn³⁺From a macrocycle comprising a pentaaza 15-membered macrocycle ring corresponding to formula A and having the formula-OC (O) X₁Is coordinated to two axial ligands, wherein

Each X₁Independently is a substituted or unsubstituted phenyl or-C (-X)₂)(-X₃)(-X₄)；

Each X₂Independently is a substituted or unsubstituted phenyl or a substituted or unsubstituted alkyl;

each X₄Independently of one another, hydrogen or together with X₃Is ═ O.

Another aspect of the present disclosure is a transition metal complex comprising a transition metal consisting of five ring nitrogen atoms of a macrocycle comprising a fused ring system of formula B (which optionally may be further substituted as described elsewhere herein) and a metal having the formula-oc (o) X₁Is coordinated to two axial ligands, wherein

Formula B has the formula

Each X₁Independently is a substituted or unsubstituted phenyl or-C (-X)₂)(-X₃)(-X₄)；

Each X₂Independently is a substituted or unsubstituted phenyl or a substituted or unsubstituted alkyl;

each X₄Independently of one another, hydrogen or together with X₃Is ═ O.

Another aspect of the present disclosure is the inclusion of Mn²⁺Or Mn³⁺The transition metal complex of (1), the Mn²⁺Or Mn³⁺From a macrocycle comprising a fused ring system of formula B, which may optionally be further substituted, and a compound of formula-OC (O) X₁Is coordinated to two axial ligands, wherein

Each X₁Independently is a substituted or unsubstituted phenyl or-C (-X)₂)(-X₃)(-X₄)；

Each X₂Independently is a substituted or unsubstituted phenyl or a substituted or unsubstituted alkyl;

each X₄Independently of one another, hydrogen or together with X₃Is ═ O.

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

wherein

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_10AAnd R_10BIndependently are:

(i) hydrogen;

(iii) A moiety independently selected from the group consisting of:

-OR₁₁、-NR₁₁R₁₂、-COR₁₁、-CO₂R₁₁、-CONR₁₁R₁₂、-SR₁₁、-SOR₁₁、-SO₂R₁₁、-SO₂NR₁₁R₁₂、-N(OR₁₁)(R₁₂)、-P(O)(OR₁₁)(OR₁₂)、-P(O)(OR₁₁)(R₁₂)、-OP(O)(OR₁₁)(OR₁₂) And a substituent attached to the alpha-carbon of the amino acid (i.e., alpha-amino acid), wherein R₁₁And R₁₂Independently hydrogen or alkyl;

(iv) substituted or unsubstituted, saturated, partially saturated or unsaturated ring or heterocyclic member containing from 3 to 20 carbon ring atoms, including

(v) A combination of any of (i) to (iv) above;

each X₁Independently is a substituted or unsubstituted phenyl or-C (-X)₂)(-X₃)(-X₄)；

Each X₂Independently is a substituted or unsubstituted phenyl or a substituted or unsubstituted alkyl;

each X₄Independently of one another, hydrogen or together with X₃Is ═ O; and is

The bond between the transition metal M and the macrocyclic nitrogen atom and the transition metal M and the axial ligand-OC (O) X₁Is a coordinate covalent bond.

Another aspect of the disclosure is to correspond to the formula (ID)_R) Or (ID)_S) Pentaaza macrocyclic ring complexes of formula (I):

wherein

M is Mn⁺²Or Mn⁺³；

R_1A、R_1B、R₂、R₃、R_4A、R_4B、R₅、R₆、R_7A、R_7B、R₈、R₉、R_10AAnd R_10BIndependently hydrogen, methyl, ethyl, or propyl;

W₁、W₂and W₃Independently is halo or hydrogen;

each X₁Independently is a substituted or unsubstituted phenyl or-C (-X)₂)(-X₃)(-X₄)；

Each X₂Independently substituted or unsubstituted phenyl, methyl, ethyl or propyl;

each X₃Independently hydrogen, hydroxy, methyl, ethyl or propyl, amino, -X₅C(O)R₁₃(wherein X₅Is NH orO and R₁₃Is C₁-C₁₈Alkyl, substituted or unsubstituted aryl or C₁-C₁₈Aralkyl, OR-OR₁₄Wherein R is₁₄Is C₁-C₁₈Alkyl, substituted or unsubstituted aryl or C₁-C₁₈Aralkyl), or together with X₄Is ═ O;

each X₄Independently of one another, hydrogen or together with X₃Is ═ O; and is

Bonds between manganese and macrocyclic nitrogen atoms and manganese and axial ligand-OC (O) X₁Is a coordinate covalent bond.

Another aspect of the disclosure is a pharmaceutical composition comprising any of the aforementioned pentaazamacrocycle complexes and a pharmaceutically acceptable excipient suitable for administration.

Another aspect of the disclosure is a method for administering a pentaazamacrocycle complex to a subject, the method comprising administering to a human subject a pharmaceutical composition comprising any one of the aforementioned pentaazamacrocycle complexes.

Other objects and features will be in part apparent and in part pointed out hereinafter.

Drawings

Figure 1 is a series of profiles of plasma concentrations of the parent manganese pentaaza macrocyclic 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 (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.

Figure 2 is a series of profiles of plasma concentrations of the parent manganese pentaaza macrocyclic 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 (where all compounds shown are derivatives of GC4419) by iv or id delivery, where the id test article is formulated in Peceol, as described in the examples.

Figure 3 is a series of profiles of plasma concentrations of the parent manganese pentaaza macrocyclic 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 drug (where all compounds displayed are derivatives of GC4419) by iv or id delivery, with the id test formulated in Labrafil M2125CS, as described in the examples.

Figure 4 is a series of profiles of plasma concentrations of the parent manganese pentaaza macrocyclic 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 drug (where all compounds displayed are derivatives of GC4419) by iv or id delivery, with the id test formulated in Labrafil M2125CS, as described in the examples.

Figure 5 is a series of profiles of plasma concentrations of the parent manganese pentaaza macrocyclic 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 drug (where all compounds displayed are derivatives of GC4401) by iv or id delivery, with the id test formulated in Capmul MCM, as described in the examples.

Figure 6 is a series of profiles of plasma concentrations of the parent manganese pentaaza macrocyclic 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 drug (where all compounds displayed are derivatives of GC4444) by iv or id delivery, with the id test formulated in Capmul MCM, as described in the examples.

Figure 7 is a series of profiles of plasma concentrations of the parent manganese pentaaza macrocyclic 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 drug (where all compounds displayed are derivatives of GC4419) by iv or id delivery, with the id test formulated in Capmul MCM, as described in the examples.

Figure 8 is a series of profiles of plasma concentrations of the parent manganese pentaaza macrocyclic 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 (where all compounds displayed are derivatives of GC4419) by iv or id delivery, where the id test article was formulated in Maisine 35-1, as described in the examples.

Figure 9 is a series of profiles of plasma concentrations of the parent manganese pentaaza macrocyclic 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 the test drug (where all compounds displayed are derivatives of GC4403) by iv or id delivery, with the id test formulated in Capmul MCM, as described in the examples.

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

FIG. 11 is an X-ray crystal structure of GC4403 (as reported in Riley et al, Advances in organic Chemistry, Vol.59, pp.233-263 (2007)).

FIG. 12 is an X-ray crystal structure of GC4419 obtained by the method reported in Riley et al, Advances in organic Chemistry, Vol.59, pp.233-263 (2007).

Abbreviations and Definitions

The following definitions and methods are provided to better define the present invention and to guide those of ordinary skill in the art in the practice of the present invention. Unless otherwise indicated, terms are to be understood in accordance with their ordinary usage by those of ordinary skill in the relevant art.

"acyl" means a-COR moiety, wherein R is alkyl, haloalkyl, optionally substituted aryl, or optionally substituted heteroaryl as defined herein, such as acetyl, trifluoroacetyl, benzoyl, and the like.

"acyloxy" means an-OCOR moiety, wherein R is alkyl, haloalkyl, optionally substituted aryl, or optionally substituted heteroaryl as defined herein, such as acetyl, trifluoroacetyl, benzoyl and the like.

"alkoxy" means an-OR moiety wherein R is an alkyl group as described above, such as methoxy, ethoxy, propoxy, OR 2-propoxy, n-, iso-, OR tert-butoxy, and the like.

"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, e.g., C₁-C₆Alkyl groups such as methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), and the like.

Further, unless otherwise specified, the term "alkyl" as used herein is intended to include both "unsubstituted alkyls" and "substituted alkyls," the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Indeed, unless otherwise indicated, all groups recited herein are intended to include both substituted and unsubstituted options.

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 C_x-yAlkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight and branched alkyl groups containing x to y carbon atoms in the chain.

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

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

"alkaryl" means a monovalent moiety derived from an aryl moiety by the replacement of one or more hydrogen atoms with an alkyl group.

"alkenylcycloalkenyl" means a monovalent moiety derived from an alkenyl moiety by replacement of one or more hydrogen atoms with a cycloalkenyl group.

"alkenylcycloalkyl" means a monovalent moiety derived from a cycloalkyl moiety by replacement of one or more hydrogen atoms with an alkenyl group.

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

"alkylcycloalkyl" means a monovalent moiety derived from a cycloalkyl moiety by replacement of one or more hydrogen atoms with an alkyl group.

"alkynyl" means a straight chain unsaturated monovalent hydrocarbon moiety such as two to six carbon atoms, or a branched chain saturated monovalent hydrocarbon moiety such as three to six carbon atoms, e.g., ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like.

"alkoxy" means a monovalent moiety derived from an alkyl moiety by replacement of one or more hydrogen atoms with a hydroxyl group.

"amino" means-NR^aR^bGroup, wherein R^aAnd R^bIndependently hydrogen, alkyl or aryl.

"aralkyl" means a monovalent moiety derived from an alkyl moiety by replacement of one or more hydrogen atoms with an aryl group.

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

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

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

"cycloalkylalkyl" means a monovalent moiety derived from an alkyl moiety by replacement of one or more hydrogen atoms with a cycloalkyl group, such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, or cyclohexylethyl, and the like.

"cycloalkylcycloalkyl" means a monovalent moiety derived from a cycloalkyl moiety by replacement of one or more hydrogen atoms with a cycloalkyl group.

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

"cycloalkenylalkyl" means a monovalent moiety derived from an alkyl moiety by replacement of one or more hydrogen atoms with a cycloalkenyl group, such as cyclopropenylmethyl, cyclobutenylmethyl, cyclopentenylethyl, cyclohexenylethyl, or the like.

An "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.

"ether" means a monovalent moiety derived from an alkyl moiety by replacement of one or more hydrogen atoms with an alkoxy group.

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

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

"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, the remaining ring atoms being carbon. Representative examples include, but are not limited to, pyrrolyl, pyrazolyl, thienyl, thiazolyl, imidazolyl, furyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like.

"nitro" means-NO₂。

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

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

"thioether" means a monovalent moiety derived from an alkyl moiety by replacement of one or more hydrogen atoms with a-SR group, wherein R is alkyl.

As used herein, (i) a compound referred to herein and in the drawings as compound 401, 4401, or GC4401 is a reference to the same compound, (ii) a compound referred to herein and in the drawings as compound 403, 4403, or GC4403 is a reference to the same compound, (iii) a compound referred to herein and in the drawings as compound 419, 4419, or GC4419 is a reference to the same compound, and (iv) a compound referred to herein and in the drawings as compound 444, 4444, or GC4444 is a reference to the same compound.

Detailed description of the invention

Aspects of the present disclosure include novel transition metal complexes of pentaazacyclic macrocycles that also have axial ligands, which have the ability to convert in circulation to the same species as similar bis-chloro axial ligand complexes. The compounds or complexes described herein thus have similar therapeutic efficacy as their bis-chloro analogs, but are significantly more versatile with respect to the route 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.

Accordingly, the present disclosure relates to 15-membered complexes of pentaazacyclo macrocycles and mn (II) (or other transition metals), wherein the non-macrocyclic cyclic ring ligands (i.e., axial ligands) covalently bonded to manganese (II) (or other transition metals) are 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 through the intestinal wall, but are still capable of losing one or more axial ligands to water exchange to produce in circulation substances similar to those obtained with the bis-chloro complexes shown in scheme 1 above. In these and/or other embodiments, the complexes may also exhibit improved solubility in oil-or water-based (or other) solvents, e.g., as compared to bis-chloro complexes.

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

wherein

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_10AAnd R_10BIndependently are:

(i) hydrogen;

(iii) A moiety independently selected from the group consisting of: -OR₁₁、-NR₁₁R₁₂、-COR₁₁、-CO₂R₁₁、-CONR₁₁R₁₂、-SR₁₁、-SOR₁₁、-SO₂R₁₁、-SO₂NR₁₁R₁₂、-N(OR₁₁)(R₁₂)、-P(＝O)(OR₁₁)(OR₁₂)、-P(＝O)(OR₁₁)(R₁₂)、-OP(＝O)(OR₁₁)(OR₁₂) And a substituent attached to the alpha-carbon of the amino acid (i.e., alpha-amino acid), wherein R₁₁And R₁₂Independently hydrogen or alkyl;

(iv) a member of a substituted or unsubstituted, saturated, partially saturated or unsaturated ring or heterocyclic ring containing from 3 to 20 carbon ring atoms, comprising:

(a)R_1Aor R_1BAnd R_2AOr R_2B；R_3AOr R_3BAnd R_4AOr R_4B；R_5AOr R_5BAnd R_6AOr R_6B；R_7AOr R_7BAnd R_8AOr R_8B(ii) a Or R_9AOr R_9BAnd R_10AOr R_10BTogether with the carbon atom to which they are each attached;

(v) A combination of any of (i) to (iv) above;

each X₁Independently is a substituted or unsubstituted phenyl group or

-C(-X₂)(-X₃)(-X₄)；

Each X₂Independently is a substituted or unsubstituted phenyl or a substituted or unsubstituted alkyl;

each X₃Independently hydrogen, hydroxy, alkyl, amino, -X₅C(＝O)R₁₃(wherein X₅Is NH or O and R₁₃Is C₁-C₁₈Alkyl, substituted or unsubstituted aryl or C₁-C₁₈Aralkyl, OR-OR₁₄Wherein R is₁₄Is C₁-C₁₈Alkyl, substituted or unsubstituted aryl or C₁-C₁₈Aralkyl), or together with X₄Is (═ O);

each X₄Independently of one another, hydrogen or together with X₃Is (═ O); and is

The bond between the transition metal M and the macrocyclic nitrogen atom and the transition metal M and the axial ligand-OC (═ O) X₁Is a coordinate covalent bond.

In a second aspect, the present disclosure relates to pharmaceutical compositions and unit dose formulations comprising a compound of formula (I) (or any of the embodiments thereof 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 this second aspect are discussed in further detail below.

Detailed description of the preferred embodiments

Embodiment (IA)

In embodiment (IA), the pentaazamacrocycle complex of formula (I) corresponds to formula (IA):

wherein

-C(＝O)NR₁₁R₁₂、-SR₁₁、-SOR₁₁、-SO₂R₁₁、-SO₂NR₁₁R₁₂、

-N(OR₁₁)(R₁₂)、

-P(＝O)(OR₁₁)(OR₁₂)、-P(＝O)(OR₁₁)(R₁₂) and-OP (═ O) (OR)₁₁)(OR₁₂) Wherein R is₁₁And R₁₂Independently hydrogen or alkyl;

w, together with the nitrogen of the macrocycle and the carbon atom of the macrocycle attached to the macrocycle form an aromatic or alicyclic, substituted or unsubstituted, saturated, partially saturated or unsaturated, nitrogen-containing fused heterocycle having from 2 to 20 ring carbon atoms, with the proviso that when W is a fused aromatic heterocycle, hydrogen attached to said nitrogen, both as part of the heterocycle and the macrocycle, and R, both as part of the heterocycle and the macrocycle, attached to said carbon atom₅And R₆Is absent; wherein

Each X₁Independently is a substituted or unsubstituted phenyl or-C (-X)₂)(-X₃)(-X₄)；

Each X₂Independently is a substituted or unsubstituted phenyl or alkyl group;

each X₄Independently of one another, hydrogen or together with X₃Is (═ O); and is

Of a transition metal M with a macrocyclic nitrogen atomAnd the transition metal M and the axial ligand-OC (═ O) X₁Is a coordinate covalent bond.

Within embodiment (IA), in one group of compounds U and V together with the adjacent carbon atoms of the macrocycle form a fused substituted or unsubstituted, saturated or heterocyclic ring having 6 ring atoms and R₂、R₃、R₈And R₉Is 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, with the proviso that when W is a fused aromatic heterocycle, hydrogen, both as part of the heterocycle and the macrocycle, attached to said nitrogen and R, both as part of the heterocycle and the macrocycle, attached to said carbon atom₅And R₆Is absent.

In embodiment (IA) and groups contained therein, in one group of compounds, M is Mn²⁺、Mn³⁺、Mn⁴⁺、Mn⁶⁺、Mn⁷⁺、Fe²⁺、Fe³⁺、Fe⁴⁺Or Fe⁶⁺。

Within embodiments (IA) and groups contained therein, within one group of compounds, X₁Is phenyl. Within embodiments (IA) and groups contained therein, within one group of compounds, X₁is-C (-X)₂)(-X₃)(-X₄) And each X in combination₂、X₃And X₄Corresponding to any one of the combinations identified in the following table:

furthermore, within embodiments (IA) and groups contained therein, in one group of compounds, X₁Is C (-X)₂)(-X₃)(-X₄) And X₃is-X₅C(＝O)R₁₃So that X is₂、X₃And X₄Including any of the combinations identified in the following table:

combination of	X₂	X₃	X₄
				1	Ph	NHC(＝O)R₁₃	H
2	Ph	OC(＝O)R₁₃	H
				3	CH₃	NHC(＝O)R₁₃	H
4	CH₃	OC(＝O)R₁₃	H

Wherein R is₁₃Is C₁-C₁₈Alkyl, substituted or unsubstituted aryl or C₁-C₁₈Aralkyl, OR-OR₁₄Wherein R is₁₄Is C₁-C₁₈Alkyl, substituted or unsubstituted aryl or C₁-C₁₈An aralkyl group.

Embodiment (IB)

Within embodiment (IB), the pentaaza macrocyclic ring complex of formula (I) corresponds to formula (IB):

wherein

M is Fe⁺²、Fe⁺³、Mn⁺²Or Mn⁺³；

R_1A、R_1B、R₂、R₃、R_4A、R_4B、R₅、R₆、R_7A、R_7B、R₈、R₉、R_10AAnd R_10BAs defined in connection with embodiment (IA) above;

W₁、W₂and W₃Independently is halo, hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, acyl, acyloxy, alkoxy, ether, thioether, or nitro;

each X₁Independently is a substituted or unsubstituted phenyl or-C (-X)₂)(-X₃)(-X₄)；

Each X₂Independently substituted or unsubstituted phenyl, methyl, ethyl or propyl;

each X₄Independently of hydrogenOr together with X₃Is (═ O); and is

The bond between the transition metal M and the macrocyclic nitrogen atom and the transition metal M and the axial ligand-OC (═ O) X₁Is a coordinate covalent bond.

In embodiment (IB), when W is₁、W₂And W₃When one OR more of (a) is a substituted alkyl, alkenyl, alkynyl, aryl, aralkyl OR alkaryl group, these substituents may contain from 1 to 20 carbon atoms, preferably from 1 to 6 carbon atoms, and may be straight, branched OR cyclic, wherein one OR more of the hydrogen atoms of the substituted moiety is replaced by a different substituent, such as, for example, -OH, -OR, -C (═ O) OH, aralkyl OR alkaryl,

–C(＝O)NH₂、-NH₂、-NHR、-NRR、-SH、-SR、-SO₂R、-SO₂H. SOR, heterocyclic and/or halo (including F, Cl, Br, and I), and the like, wherein each occurrence of R can be a substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl.

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

Within the embodiments (IB) and groups contained therein, in one group of compounds, X₁Is phenyl. Within the embodiments (IB) and groups contained therein, in one group of compounds, X₁is-C (-X)₂)(-X₃)(-X₄) And each X in combination₂、X₃And X₄Corresponding to any one of the combinations identified in the following table:

furthermore, within embodiments (IB) and groups contained therein, in one group of compounds, X₁Is C (-X)₂)(-X₃)(-X₄) And X₃is-X₅C(O)R₁₃So that X is₂、X₃And X₄Including any of the combinations identified in the following table:

combination of	X₂	X₃	X₄
				1	Ph	NHC(＝O)R₁₃	H
2	Ph	OC(＝O)R₁₃	H
				3	CH₃	NHC(＝O)R₁₃	H
4	CH₃	OC(＝O)R₁₃	H

Embodiment (IC)

Within the embodiments (IC), the pentaazamacrocycle complexes of formula (I) correspond to formula (IC)_R) Or (IC)_S):

Wherein

M is Fe⁺²、Fe⁺³、Mn⁺²Or Mn⁺³；

R_1A、R_1B、R₂、R₃、R_4A、R_4B、R₅、R₆、R_7A、R_7B、R₈、R₉、R_10AAnd R_10BIndependently hydrogen or substituted or unsubstituted alkyl;

W₁、W₂and W₃Independently is halo or hydrogen;

each X₁Independently is a substituted or unsubstituted phenyl or-C (-X)₂)(-X₃)(-X₄)；

Each X₂Independently substituted or unsubstituted phenyl, methyl, ethyl or propyl;

each X₄Independently of one another, hydrogen or together with X₃Is (═ O); and is

The bond between the transition metal M and the macrocyclic nitrogen atom and the transition metal M and the axial ligand-OC (O) X₁Is a coordinate covalent bond.

In an embodiment (IC), in one group of compounds, M is Mn²⁺. Within the embodiment (IC), in another group of compounds, M is Mn³⁺。

Within the embodiments (IC) and groups contained therein, in one group of compounds, X₁Is phenyl. Within the embodiments (IC) and groups contained therein, in one group of compounds, X₁is-C (-X)₂)(-X₃)(-X₄) And each X in combination₂、X₃And X₄Corresponding to any one of the combinations identified in the following table:

furthermore, within the embodiments (IC) and groups contained therein, in one group of compounds, X₁Is C (-X)₂)(-X₃)(-X₄) And X₃is-X₅C(O)R₁₃So that X is₂、X₃And X₄Including any of the combinations identified in the following table:

combination of	X₂	X₃	X₄
				1	Ph	NHC(＝O)R₁₃	H
2	Ph	OC(＝O)R₁₃	H
				3	CH₃	NHC(＝O)R₁₃	H
4	CH₃	OC(＝O)R₁₃	H

Embodiment (ID)

In an embodiment (ID), the pentaazamacrocycle complex of the formula (I) corresponds to the formula (ID)_R) Or (ID)_S):

Wherein

M is Mn⁺²Or Mn⁺³；

R_1A、R_1B、R₂、R₃、R_4A、R_4B、R₅、R₆、R_7A、R_7B、R₈、R₉、R_10AAnd R_10BIndependently hydrogen, methyl, ethyl or propyl;

W₁、W₂and W₃Independently is halo or hydrogen;

each X₁Independently is a substituted or unsubstituted phenyl or-C (-X)₂)(-X₃)(-X₄)；

Each X₂Independently substituted or unsubstituted phenyl, methyl, ethyl or propyl;

each X₄Independently of one another, hydrogen or together with X₃Is (═ O); and is

Transition metal M (Mn)⁺²Or Mn⁺³) Bonds to the macrocyclic nitrogen atom and transition metal M with axial ligand-OC (═ O) X₁Is a coordinate covalent bond.

Within the group of compounds of embodiment (ID), M is Mn²⁺. Within the embodiment (ID), in another group of compounds, M is Mn³⁺。

Within the embodiments (ID) and groups contained therein, in one group of compounds, R_1A、R_1B、R_4A、R_4B、R_7A、R_7B、R_10AAnd R_10BEach is hydrogen. Within the embodiments (ID) and groups contained therein, in one group of compounds, R_1B、R_4A、R_4B、R_7A、R_7B、R_10AAnd R_10BEach is hydrogen and R_1AIs methyl. Within the embodiments (ID) and groups contained therein, in one group of compounds, R_1A、R_4A、R_4B、R_7A、R_7B、R_10AAnd R_10BEach is hydrogen and R_1BIs methyl. Within the embodiments (ID) and groups contained therein, in one group of compounds, R_1A、R_1B、R_4B、R_7A、R_10AAnd R_10BEach is hydrogen and R_4AAnd R_7BEach is methyl. Within the embodiments (ID) and groups contained therein, in one group of compounds, R_1A、R_1B、R_4A、R_7B、R_10AAnd R_10BEach is hydrogen and R_4BAnd R_7AEach is methyl.

Within the embodiments (ID) and groups contained therein, in one group of compounds, X₁Is phenyl. Within the embodiments (ID) and groups contained therein, in one group of compounds, X₁is-C (-X)₂)(-X₃)(-X₄) And each X in combination₂、X₃And X₄Corresponding to any one of the combinations identified in the following table:

furthermore, within the embodiments (ID) and groups contained therein, in one group of compounds, X₁Is C (-X)₂)(-X₃)(-X₄) And X₃is-X₅C(O)R₁₃So that X is₂、X₃And X₄Including any of the combinations identified in the following table:

combination of	X₂	X₃	X₄
				1	Ph	NHC(＝O)R₁₃	H
2	Ph	OC(＝O)R₁₃	H
				3	CH₃	NHC(＝O)R₁₃	H
4	CH₃	OC(＝O)R₁₃	H

Embodiment (IE)

In Embodiment (IE), the pentaaza of formula (I)The cyclic ring complexes correspond to the formula (IE)_R1)、(IE_S1)、(IE_R2)、(IE_S2)、(IE_R3) Or (IE)_S3)：

Wherein

Mn is Mn⁺²Or Mn⁺³；

Each X₁Independently is a substituted or unsubstituted phenyl or-C (-X)₂)(-X₃)(-X₄)；

Each X₂Independently hydrogen, hydroxy, methyl, ethyl, propyl, amino, -X₅C(＝O)R₁₃(wherein X₅Is NH or O and R₁₃Is C₁-C₁₈Alkyl, substituted or unsubstituted aryl or C₁-C₁₈Aralkyl, OR-OR₁₄Wherein R is₁₄Is C₁-C₁₈Alkyl, substituted or unsubstituted aryl or C₁-C₁₈Aralkyl), or together with X₄Is (═ O);

each X₄Independently of one another, hydrogen or together with X₃Is (═ O); and is

Bonds between manganese and macrocyclic nitrogen atoms and manganese and axial ligand-OC (═ O) X₁Is a coordinate covalent bond.

Within the embodiments (IE) and groups contained therein, in one group of compounds, X₁Is phenyl. Within the embodiments (IE) and groups contained therein, in one group of compounds, X₁is-C (-X)₂)(-X₃)(-X₄) And each X in combination₂、X₃And X₄Corresponding to any one of the combinations identified in the following table:

in addition, in the embodiment (IE) and contained thereinWithin the group, in one group of compounds, X₁Is C (-X)₂)(-X₃)(-X₄) And X₃is-X₅C(O)R₁₃So that X is₂、X₃And X₄Including any of the combinations identified in the following table:

combination of	X₂	X₃	X₄
				1	Ph	NHC(＝O)R₁₃	H
2	Ph	OC(＝O)R₁₃	H
				3	CH₃	NHC(＝O)R₁₃	H
4	CH₃	OC(＝O)R₁₃	H

Unit dose formulations and pharmaceutical compositions

As noted above, a second aspect of the present disclosure relates to unit dose formulations and pharmaceutical compositions comprising a compound described herein, typically together with a pharmaceutically acceptable carrier or excipient, and optionally in combination with another pharmaceutically active compound or compounds. The pharmaceutical compositions comprise a pentaazamacrocycle complex corresponding to formula (I) (or any embodiment thereof or other compound described herein, such as any compound listed in table I of the examples section) which is typically formulated into a pharmaceutical dosage form, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient. In one embodiment, for example, a pharmaceutical composition comprises a compound of formula (I) (or any embodiment thereof or other compound 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 may 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., and for protecting tissues from damage caused by cancer therapy or other exposure to radiation, as discussed in further detail below.

Formulations containing the compounds may take the form of solid, semi-solid, lyophilized powder or liquid dosage forms, such as, for example, aerosols, capsules, creams, emulsions, foams, gels/jellies, injections, lotions, ointments, pastes, powders, soaps, solutions, sprays, suppositories, suspensions, sustained release formulations, tablets, tinctures, transdermal patches and the like, preferably in unit dosage forms suitable for simple administration of precise dosages. If formulated as a fixed dose, such pharmaceutical compositions or formulated products preferably employ the compound within certain dosage ranges. Depending on the intended mode of administration, therefore, in some embodiments, the compositions may be in solid, semi-solid, or liquid dosage forms, such as, for example, injections, tablets, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, liquids, suspensions, and the like, sometimes in unit doses and consistent with conventional pharmaceutical practice. Likewise, in some embodiments, they may also be administered via intravenous (bolus and infusion), intraperitoneal, subcutaneous, topical, or intramuscular routes, or other routes described herein, all using forms well known to those skilled in the pharmaceutical arts.

A particular embodiment of the present disclosure relates to a unit dose formulation comprising a compound corresponding to formula (I) (or any embodiment thereof or other compounds described herein, such as any of the compounds listed in table I of the examples section) in an oral dosage form as described herein. Another specific embodiment of the present disclosure relates to a unit dose formulation comprising a compound corresponding to formula (I) (or any embodiment thereof or other compounds described herein, such as any of the compounds listed in table I of the examples section) in a parenteral dosage form as described herein.

For oral and non-oral dosage formulations, the above-described compounds (or any embodiment thereof or other compounds described herein, such as any of the compounds listed in table I of the examples section) can be dispersed in a pharmaceutically acceptable carrier prior to administration to a mammal. Carriers, also known in the art as excipients, vehicles, adjuvants or diluents, are generally pharmaceutically inert substances that impart a suitable consistency or form to the composition and do not detract from the efficacy of the compound. A carrier is generally considered to be "pharmaceutically or pharmacologically acceptable" if it does not produce an unacceptable adverse reaction, allergic reaction, or other untoward reaction when administered to a mammal, particularly a human.

The choice of pharmaceutically acceptable carrier will also vary, in part, with the route of administration. In general, the compositions described herein can be formulated for any route of administration, so long as the blood circulation system is accessible via this route and according to the conventional route of administration of the component (e.g., compound). For example, suitable routes of administration include, but are 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, otic, intramammary, orthotopic, intratracheal, intralesional, transdermal, endoscopic, transmucosal, sublingual, and enteral 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 of the compounds and/or formulations listed in table I of the examples section), is formulated for oral administration.

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 particular compound or compounds and agents used and its/their concentration, stability and expected bioavailability; safety; the subject's age, weight, and general condition; and the route of administration.

Suitable components (e.g., carriers and/or excipients) for formulating solid or semi-solid 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, magnesium or calcium salts thereof, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or polyethylene glycol); binders (such as magnesium aluminium silicate, starch paste, gelatin, gum tragacanth, methyl cellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, gum tragacanth or sodium alginate, waxes and/or polyvinylpyrrolidone); disintegrants (such as starch, agar, methylcellulose, bentonite, xanthan gum or effervescent mixtures; absorbents, colorants, flavoring agents and/or sweeteners; and combinations thereof. methods for preparing such solid and semi-solid dosage forms using active pharmaceutical ingredients and other components are well known in the art. for example, compositions in the form of liquids, semi-solids or pastes can be filled into hard gelatin or soft gelatin capsules using suitable filling machines alternatively, the compositions can also be extruded, sprayed, granulated or coated onto substrates to form powders, granules or beads that can be further encapsulated or tableted with or without the addition of suitable solidifying agents or binders. For example, "Remington: The Science and Practice of Pharmacy," 20 th edition, edited by A.R. Gennaro, 2000, in Lippincott Williams & Wilkins.

Suitable components (e.g., carriers and/or excipients) for use in formulating 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 u.s.p. and isotonic sodium chloride solutions), dextrose solutions (such as D5W), electrolyte solutions, or any other aqueous pharmaceutically acceptable liquid. 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 of the compounds and/or formulations listed in table I of the examples section) and saline (e.g., physiological saline, i.e., a sterile solution of 0.9% w/v NaCl in water). In these and other embodiments, for example, the saline is preferably a physiological buffered saline solution (i.e., buffered saline). The buffering agent may provide a suitable buffering capacity at a pH of 7-8.5 or around pH 7.8 or in 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 (such as arginine, lysine, and other natural amino acids), and citrate-based buffers. Carbonate buffers (such as sodium or calcium carbonate or sodium or calcium bicarbonate buffers) may be particularly useful in certain embodiments because of their abundant supply, buffering capacity, and compatibility. One 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.

In a particular embodiment, a unit dose formulation for oral administration, including 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 in the examples section), further comprises at least one of a lipophilic surfactant and an oil.

Certain suitable lipophilic surfactants and/or oils include mono-, di-and/or tri-glycerides of fatty acids, such as Imwitor 988 (mono-/di-caprylic acid glyceride), Imwitor 742 (mono-di-caprylic acid glyceride/capric acid glyceride), Imwitor 308 (mono-caprylic acid glyceride), Imwitor 191 (mono-stearin), Softigen 701 (mono-/di-ricinoleic acid glyceride), Capmul MCM (caprylic acid glyceride/capric acid glyceride), Capmul MCM (L) (liquid form of Capmul MCM), Capmul GMO (mono-oleic acid glyceride), Capmul GDL (dilauric acid glyceride), maiisine (mono-linoleic acid glyceride), Peceol (mono-oleic acid glyceride), Myverol 18-92 (distilled glycerol from sunflower oil) and Myverol 18-06 (distilled monoglyceride from hydrogenated soybean oil), Precirol ATO5 (glyceryl palmitostearate), Gelucire 39/01 (semi-synthetic glycerides, i.e., C12-18 mono-, di-, and tri-glycerides), and Miglyol 812N (a mixture of caprylic/capric triglycerides); acetates, succinates, lactates, citrates and/or tartrates of mono-and/or di-glycerides of fatty acids, for example Myvacet 9-45 (distilled acetylated monoglyceride), Miglyol 829 (caprylic/capric succinic diglyceride), Myverol SMG (mono/di-succinylated monoglyceride), Imwitor 370 (glyceryl stearate citrate), Imwitor 375 (glyceryl monostearate/glyceryl citrate/lactylate) and crodat 22 (diacetyl tartrate of monoglycerides); propylene glycol mono-and/or di-esters of fatty acids, such as Lauroglycol (propylene glycol monolaurate), mircyl (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 (polyglycerol oleate), Caprol ET (polyglycerol mixed fatty acid) and Drewpol 10.10.10 (polyglycerol oleate); castor oil ethoxylates of low ethoxylate content (HLB <10), such as Etocas 5(5 moles of ethylene oxide reacted with 1 mole of castor oil) and sandoxlate 5(5 moles of ethylene oxide reacted with 1 mole of castor oil), acid and ester ethoxylates formed by reacting ethylene oxide with fatty acids or glycerides of fatty acids (HLB <10), such as Crodet 04 (polyoxyethylene (4) lauric acid), Cithrol 2MS (polyoxyethylene (2) stearic acid), Marlosol 183 (polyoxyethylene (3) stearic acid) and Marlowet G12 DO (12EO glyceryl dioleate), sorbitan esters of fatty acids, such as Span 20 (sorbitan monolaurate), Crill 1 (sorbitan monolaurate) and Crill 4 (sorbitan mono-oleate), the 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, e.g., polyoxyethylene-polyoxypropylene copolymers and block copolymers (HLB <10) such as Synperonic PE L42(HLB ═ 8) and Synperonic PE L61(HLB ═ 3).

In another specific embodiment, a unit dose formulation for oral administration, including 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), further comprises a digestible oil (i.e., an oil capable of being de-esterified or hydrolyzed in the presence of pancreatic lipase in vivo under normal physiological conditions)₆) Medium chain (C) of mono-, di-or polyols₇-C₁₃) Or long chain (C)₁₄-C₂₂) 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, blackcurrant oil, evening primrose oil, grapeseed 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 seed oil, corn oil, olive oil, castor oil, cottonseed oil, peanut oil, sunflower seed oil, coconut oil, palm oil, rapeseed oil, evening primrose oil, grapeseed oil, wheat germ oil, sesame oil, avocado oil, almond oil, borage oil, peppermint oil, almond oil, and combinations thereof.

When injectable pharmaceutical formulations are employed, they are preferably sterile. Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use. The composition may be provided, prepared, stored or transported in any container suitable for maintaining sterility. The container may incorporate means for dispensing the aqueous composition such as, for example, a pierceable or removable seal. The composition may be dispensed for administration to a patient, for example, by drawing 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 dispensing sterile pharmaceutical compositions are known to those skilled in the art.

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 described in The chemical Source Book (Williams & Wilkens Publishing), The Handbook of Pharmaceutical Excipients, (American Pharmaceutical Association, Washington, d.c., and The Pharmaceutical Source of Great Britain, London, England,1968), model pharmaceuticals, (g.bank et al, editors, 3 rd edition) (mark Dekker, inc., New York,1995), The Pharmaceutical Basis of Pharmaceutical ingredients, (Goodman & g, Pharmaceutical composition, company, p.g., company, n g.g. company, g.g., edition, ph, company, n.p., n.g., company, n.p., n., company, n.p. n., n. yurk, 1995), The Pharmaceutical composition of Pharmaceutical composition, p.s, n.p.p.p.p.p.p.p.p.p.p.p.p.p. (company, p.p.p.p., company, p.p.p.p.p.p. (company, p.p.p.p.p.p., company, p.p.p.p., p.p.p. (company, p.p.p.p.p., p., p.p.p., p., p.p., p.p.p., p., p.p., p., p.p., p., p.p., p., p.p.p., p., p.p., p., p., p.p.p.p.p.p., p., p.p., p., p.p.p., p.p., p., p.p.p., p., p.p.p., p., p.p.p., p., p., p, use of non aqueous solutions in fractional Products, Journal of Pharmaceutical Sciences, Vol.52, No. 10, p.917-927 (1963).

In certain embodiments, a 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 compound 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 compositions described herein are products resulting from the mixing or combining of more than one active ingredient, and include fixed and non-fixed combinations of active ingredients. Fixed combinations are those in which the active ingredient, such as the compound described herein, and another pharmaceutically active agent or compound, are both administered to the patient simultaneously, in the form of a single entity or dose. Non-fixed combinations are those in which the active ingredient, such as the compound and another pharmaceutically active agent or compound, are administered to the subject as separate entities either simultaneously, concurrently or sequentially, without specific intervening time limitations, wherein such administration provides effective levels of both compounds in the patient. The latter also applies to mixed therapies, such as the administration of three or more active ingredients.

It is contemplated that co-formulation of the 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, either alone or in combination in alternative formulation routes, to accommodate the compatibility and efficacy of the various components.

In one embodiment, a compound and/or formulation of the present disclosure (including any compound described herein, such as any compound and/or formulation listed in table I of the examples section) is formulated for oral administration, and the formulation comprises an enteric release layer or composition. For example, the oral dosage form may be an enteric coated tablet, multiparticulate or multi-layered tablet or capsule; gelatin, soft gelatin, or equivalents thereof; vinyl acetate phthalate or polyvinyl acetate phthalate or equivalents thereof; ACRYL-EZE^TM、SURETERIC^TM、NUTRATERIC (Colorcon, inc. harleysville, Pa.); hydroxypropyl methylcellulose (HPMC), a high viscosity grade HPMC or an ultra-high viscosity grade HPMC; polyvinylpyrrolidone (PVP) or PVP-K90; cellulose, microcrystalline cellulose (MCC), methylcellulose, hydroxymethylcellulose, Hydroxypropylmethylcellulose (HPMC), or ethylcellulose; copolymers of ethyl acrylate, poly (meth) acrylates, such as methacrylic acid copolymer B, methyl methacrylate and/or methacrylates having quaternary ammonium groups;RL PO^TM；RL 100^TM(Evonik Industries AG,Essen,Germany)。

in an alternative embodiment, a compound and/or formulation of the present disclosure (including any compound described herein, such as any compound and/or formulation listed in table I of the examples section) is 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 methacrylic acid with methyl methacrylate; copolymers of methyl acrylate, methyl methacrylate and methacrylic acid; copolymers of methyl vinyl ether and maleic anhydride; ethyl methacrylate-methyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymers; a natural resin; zein; shellac; copal gum rosin (copal collophorium) or acrylic acid copolymers; or any combination or mixture thereof.

In alternative embodiments, the compounds and/or formulations of the present disclosure (including any compound described herein, such as any compound and/or formulation listed in table I 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 glycerol monostearate, stearic acid, palmitic acid, glycerol monopalmitate, cetyl alcohol, shellac, zein, ethylcellulose, acrylics, cellulose acetate, or silicone elastomers, or any combination or mixture thereof.

Methods and indications

As noted 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) may be used to treat tissue damage and/or a range of diseases and conditions. Treating diseases and disorders (including damaged tissue) as described herein may generally involve not only inhibiting the disease (i.e., arresting further development of the condition and/or symptom) in a patient who is experiencing or displaying the condition or symptom of the disease or disorder, but also ameliorating the disease or disorder (i.e., reversing the condition and/or symptom) in a patient who is experiencing or displaying the condition or symptom of the disease or disorder. Treating a disease or disorder in a human patient as described herein, such as tissue damage resulting from administration of radiation therapy or chemotherapy or exposure to radiation, also corresponds to inhibiting or preventing such damage in a patient who does not necessarily experience or display the pathology or symptoms of the disease or disorder.

The methods of the present disclosure may be advantageously used to treat (e.g., inhibit, ameliorate, or alleviate) various diseases or disorders in a variety of subjects (i.e., patients). The subject can be, for example, a mammal, such as a bovine, avian, canine, equine, feline, ovine, porcine, or primate (including humans and non-human primates). The subject may also include mammals of significant or economic importance due to being endangered, such as animals raised on farms for human consumption, or animals of social importance to humans, such as animals 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 (cattle), cattle (oxen), sheep, giraffes, deer, goats, bison, camels or horses. In one embodiment, the subject is a bovine, avian, canine, equine, feline, ovine, porcine, or non-human primate. In a preferred embodiment, the subject is a human patient.

Treatment of tissue damage

According to one embodiment of the third aspect of the present disclosure, described herein is a method for treating tissue damage resulting from a cancer treatment (such as radiation therapy or chemotherapy) delivered to a subject in need thereof. According to another embodiment, described herein is a method for treating tissue damage in a human patient resulting from exposure to radiation. Thus, in various embodiments, for example, the radiation exposure in various embodiments may be accidental radiation exposure, unintentional radiation exposure, or intentional radiation exposure. As noted above, treatment of tissue damage as described herein may include inhibiting (i.e., preventing) and ameliorating any tissue damage that may result from occurrence or activity. In general, the methods involve administering to the subject a therapeutically effective amount of a compound described herein (such as those corresponding to formula (I) (or any embodiment thereof or other compound described herein, such as any of the compounds and/or formulations listed in table I of the examples section).

Treatment of tissue damage resulting from cancer treatment or other radiation exposure according to the methods described herein involves administration of a therapeutically effective amount of a compound described 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).

In general, the timing of the administration of the compounds (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) may depend, for example, on the particular compound selected, the radiation therapy or chemotherapy, or the type, nature and/or duration of radiation exposure During and/or after, in various embodiments. As another example, the compound can be administered in various embodiments before, during, and/or after exposure to radiation.

If desired, the effective dose may be divided into a plurality of doses for the purpose of administration; thus, a single dose composition may contain such amounts or submultiples thereof to make up the dose.

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 I in 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 I in the examples section) is administered to the patient prior to, but not subsequent to, 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, 5 days, a week prior to cancer therapy, Two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks or longer. In still other embodiments, 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 I in the examples section) is administered to a patient after cancer therapy, and thus, for example, the compound can 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 therapy.

In another embodiment, for example, the compounds (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) are administered to the patient prior to or concurrently with radiation exposure in another embodiment, for example, the compounds (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) are administered to the patient prior to, but not subsequent to, radiation exposure 30 minutes, 45 minutes, 60 minutes, 90 minutes, 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 longer. In still other embodiments, 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 I in the examples section) is administered to a patient after radiation exposure, and thus, for example, the compound can 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 radiation exposure.

In one embodiment, for example, cancer treatment comprises administration of radiation therapy; for example, intentional exposure to radiation. According to this embodiment, the method provides a safe and effective method of treating radiation damage and inhibiting or ameliorating radiation-related cancer or radiation-related tissue damage in a patient in need thereof by administering to the patient a therapeutically effective amount of a compound described 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).

In another embodiment, the exposure to radiation is an accidental or unintentional exposure. For example, radiation exposure may originate 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 petrochemicals, chemical/plastic, automatic ventilation control (cooking, smoking, etc.), heavy industrial manufacturing, environmental toxicology and remediation, biomedicine, cosmetics/perfumes, pharmaceuticals, transportation, emergency response and law enforcement, military or terrorist activities and detection (e.g., hazardous article leaks or spills). In one embodiment, for example, exposure to radiation may be due to the excavation and/or removal of radioactive materials from air, ground water, surface water, sediment, and/or soil.

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 lesions may include, but are not limited to, various forms of skin or mucosal lesions such as oral mucositis, esophagitis, etc., as well as internal cell loss, fibrosis, cyst formation, neuropathy, and various types of benign and malignant tumors.

Treatment of diseases and disorders

According to another embodiment of the third aspect of the present disclosure, described herein is a method for treating a range of diseases and disorders modulated by superoxide in a subject in need thereof. As noted above, treatment of diseases and conditions as described herein may include inhibition (i.e., prevention) and amelioration of such diseases or conditions. In general, the methods involve administering to the subject a therapeutically effective amount of a compound described 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).

In general, the timing of administration of the compound can depend, for example, on the particular compound, or the disease or condition being treated. Other considerations may include the severity of the disease or disorder; the activity of the particular compound used; the particular 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 particular compound employed; the duration of treatment; drugs used in combination or concomitantly with the particular compound employed; and the like.

Route of administration

In general, a compound described herein (or a pharmaceutical composition comprising the 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), can be administered to a subject (e.g., 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 dichlorine analogs). Thus, advantageously, the compounds of the present disclosure provide a broader 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, otic, 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, a compound described herein (or a pharmaceutical composition comprising the compound) can be administered to a subject topically (e.g., by a patch applied to the skin (e.g., a transdermal patch), a powder, a lotion, an ointment, or drops), buccally or by inhalation (as an oral or nasal spray). The compounds described herein (or pharmaceutical compositions containing the compounds) can also be administered to humans and other mammals intrarectally or intravaginally. In one embodiment, a compound (or a pharmaceutical composition or unit dose formulation comprising the compound) is administered orally to a subject. In another embodiment, the compound (or a pharmaceutical composition or unit dose formulation comprising the compound) is administered parenterally to the subject. It is generally understood that parenteral administration is meant to include intravenous, intramuscular, intraperitoneal, subcutaneous, and intra-articular modes of administration.

In some embodiments, oral administration is a preferred method of administration of the 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).

Additional pharmaceutically active agents

As noted above, the above-described methods and pharmaceutical compositions comprising the compounds may additionally comprise 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 of the compounds of the present invention or other agents. When administered as a combination, the therapeutic agents can be formulated as separate compositions that are administered sequentially, either at the same time or at different times (e.g., one or more hours or days later), or the therapeutic agents can be administered as a single composition. Thus, the present disclosure is intended to encompass the administration of each agent in a sequential manner in a regimen that will provide the beneficial effects of the drug combination, and is also intended to encompass the co-administration of these agents in a substantially simultaneous manner, such as in the form of a single capsule having a fixed ratio of these active agents or in the form of multiple separate capsules of each agent.

Kit/article of manufacture

Kits and articles of manufacture are also described for use in the therapeutic applications described herein. Such kits may include a carrier, a package, or a container partitioned to hold 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, a compound corresponding to formula (I) (or any embodiment thereof described herein), a pharmaceutically acceptable carrier, or an additional 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.

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 a specified condition.

According to one embodiment, the article of manufacture 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 resulting from exposure to a cancer treatment, the oral formulation comprising a compound corresponding to formula (I) (or any embodiment thereof or other compound described herein, such as any compound and/or formulation 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 with instructions for orally administering the dose to the patient. For example, oral formulations may be in the form of tablets, pills, capsules or gels or suspensions and contained in suitable vials or containers.

According to another embodiment, an article of manufacture comprises packaging material and contained within the packaging material is a parenteral formulation for treating a disease or condition in a patient in need thereof or for protecting tissue from damage resulting from exposure to a cancer treatment, the parenteral formulation comprising a compound corresponding to formula (I) (or any embodiment thereof or other compound described herein, such as any compound and/or formulation 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 with instructions for parenteral administration of the dose to a patient. For example, the parenteral formulation may be in the form of a solution and contained in a suitable vial or container.

Examples of embodiments

In another aspect, the invention provides embodiments of the following items:

1. a pentaaza macrocyclic ring complex of formula (I):

wherein

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_10AAnd R_10BIndependently are:

(i) hydrogen;

(iii) A moiety independently selected from the group consisting of:

(iv) substituted or unsubstituted, saturated, partially saturated or unsaturated ring or heterocyclic member containing from 3 to 20 carbon ring atoms, including

(v) (iii) a combination of any of (i) to (iv) above;

each X₁Independently is a substituted or unsubstituted phenyl or-C (-X)₂)(-X₃)(-X₄)；

Each X₂Independently substituted or unsubstituted phenyl, methyl, ethyl or propyl;

each X₄Independently of one another, hydrogen or together with X₃Is (═ O); and is

The bond between the transition metal M and the macrocyclic nitrogen atom and the transition metal M and the axial ligand-OC (O) X₁Is a coordinate covalent bond.

2. A pentaaza macrocyclic ring complex of formula (IA):

wherein

Wherein R is₁₁And R₁₂Independently hydrogen or alkyl;

Each X₁Independently is a substituted or unsubstituted phenyl or-C (-X)₂)(-X₃)(-X₄)；

Each X₂Independently substituted or unsubstituted phenyl, methyl, ethyl or propyl;

each X₄Independently of one another, hydrogen or together with X₃Is (═ O); and is

The bond between the transition metal M and the macrocyclic nitrogen atom and the transition metal M and the axial ligand-OC (O) X₁Is a coordinate covalent bond.

3. A pentaaza macrocyclic ring complex of formula (IB):

wherein

M is Fe⁺²、Fe⁺³、Mn⁺²Or Mn⁺³；

Wherein R is₁₁And R₁₂Independently hydrogen or alkyl;

W₁、W₂and W₃Independently is halo, hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, acylOxy, alkoxy, ether, thioether, or nitro;

each X₁Independently is a substituted or unsubstituted phenyl or-C (-X)₂)(-X₃)(-X₄)；

Each X₂Independently substituted or unsubstituted phenyl, methyl, ethyl or propyl;

each X₄Independently of one another, hydrogen or together with X₃Is (═ O); and is

The bond between said transition metal M and said macrocyclic nitrogen atom and said transition metal M and said axial ligand-OC (═ O) X₁Is a coordinate covalent bond.

4. Corresponding to formula (IC)_R) Or (IC)_S) Pentaaza macrocycle complex of (a):

wherein

M is Fe⁺²、Fe⁺³、Mn⁺²Or Mn⁺³；

R_1A、R_1B、R₂、R₃、R_4A、R_4B、R₅、R₆、R_7A、R_7B、R₈、R₉、R_10AAnd R_10BIndependently hydrogen or substituted or unsubstituted alkyl;

W₁、W₂and W₃Independently is halo or hydrogen;

each X₁Independently is a substituted or unsubstituted phenyl or-C (-X)₂)(-X₃)(-X₄)；

Each X₂Independently substituted or unsubstituted phenyl, methyl, ethyl or propyl;

each X₄Independently of one another, hydrogen or together with X₃Is (═ O); and is

The bond between said transition metal M and said macrocyclic nitrogen atom and said transition metal M and said axial ligand-OC (═ O) X₁Is a coordinate covalent bond.

5. Corresponding to formula (ID)_R) Or (ID)_S) Pentaaza macrocycle complex of (a):

wherein

M is Mn⁺²Or Mn⁺³；

R_1A、R_1B、R₂、R₃、R_4A、R_4B、R₅、R₆、R_7A、R_7B、R₈、R₉、R_10AAnd R_10BIndependently hydrogen, methyl, ethyl or propyl;

W₁、W₂and W₃Independently is halo or hydrogen;

each X₁Independently is a substituted or unsubstituted phenyl or-C (X)₂)(X₃)(X₄)；

Each X₂Independently substituted or unsubstituted phenyl, methyl, ethyl or propyl;

each X₄Independently of one another, hydrogen or together with X₃Is (═ O); and is

The bond between said manganese and said macrocyclic nitrogen atom and said manganese and said axial ligand-OC (═ O) X₁Is a coordinate covalent bond.

6. Corresponding to formula (IE)_R1)、(IE_S1)、(IE_R2)、(IE_S2)、(IE_R3) Or (IE)_S3) Pentaaza macrocycle complex of (a):

wherein

Mn is Mn⁺²Or Mn⁺³；

Each X₁Independently is a substituted or unsubstituted phenyl or-C (X)₂)(X₃)(X₄)；

Each X₂Independently substituted or unsubstituted phenyl, methyl, ethyl or propyl;

each X₄Independently of one another, hydrogen or together with X₃Is ═ O; and is

The bond between said manganese and said macrocyclic nitrogen atom and said manganese and said axial ligand-OC (═ O) X₁Is a coordinate covalent bond.

7. Pentaaza macrocyclic ring complexes as claimed in any preceding claim, wherein each X is₁Is phenyl.

8. Pentaaza macrocyclic ring complexes as claimed in any preceding claim, wherein each X is₁Is a substituted phenyl group.

9. Pentaaza macrocyclic ring complexes as claimed in any preceding claim, wherein each X is₁is-C (X)₂)(X₃)(X₄)。

10. Pentaaza macrocyclic ring complexes as claimed in any preceding claim, wherein each X is₁is-C (X)₂)(X₃)(X₄) And each X₂Independently a substituted or unsubstituted phenyl, methyl, ethyl or propyl.

11. Pentaaza macrocyclic ring complexes as claimed in any preceding claim, wherein each X is₁is-C (X)₂)(X₃)(X₄) Each X₂Is methyl and each X₃Is hydrogen, hydroxy, amino or together with X₄Is (═ O).

12. Pentaaza macrocyclic ring complexes as claimed in any preceding claim, wherein each X is₁is-C (X)₂)(X₃)(X₄) Each X₂Is a substituted or unsubstituted phenyl group and each X₃Is hydrogen, hydroxy, methyl, amino or together with X₄Is (═ O).

13. Pentaaza macrocyclic ring complexes as claimed in any preceding claim, wherein each X is₁is-C (X)₂)(X₃)(X₄) And each X₃Is hydrogen, hydroxy, methyl, ethyl, propyl or amino or together with X₄Is (═ O).

14. Pentaaza macrocyclic ring complexes as claimed in any preceding claim, wherein each X is₁is-C (X)₂)(X₃)(X₄) And each X₃Is hydrogen, hydroxy, methyl, ethyl, propyl or amino.

15. Pentaaza macrocyclic ring complexes as claimed in any preceding claim, wherein each X is₁is-C (X)₂)(X₃)(X₄) Each X₂Is methyl or substituted or unsubstituted phenyl and each X₃And X₄Is hydrogen.

16. The pentaaza macrocycle complex of any one of items 1 to 14, wherein each X₁is-C (X)₂)(X₃)(X₄) And each X₃Is an amino group.

17. The pentaaza macrocycle complex of any one of clauses 1-14 and 16, wherein each X₁is-C (X)₂)(X₃)(X₄) And each X₃is-NH₂。

18. The pentaaza macrocycle complex of any one of items 1 to 13, wherein each X₁is-C (X)₂)(X₃)(X₄) And each X₃Together with each X₄Are each (═ O).

19. Pentaaza macrocyclic ring complexes as claimed in any preceding claim, wherein each X is₁is-C (X)₂)(X₃)(X₄) And each-C (X)₂)(X₃)(X₄) Corresponding to any one of combinations 1 to 9 appearing in the following table:

20. the pentaaza macrocycle complex of item 19 wherein X₂Is Ph, X₃Is H and H₄Is H.

21. The pentaaza macrocycle of item 19A complex compound of which X₂Is Ph, X₃Is OH and H₄Is H.

22. The pentaaza macrocycle complex of item 19 wherein X₂Is Ph, X₃Is NH₂And H₄Is H.

23. The pentaaza macrocycle complex of item 19 wherein X₂Is Ph, and X₃And X4 in combination is (═ O).

24. The pentaaza macrocycle complex of item 19 wherein X₂Is Ph, X₃Is CH₃And H₄Is H.

25. The pentaaza macrocycle complex of item 19 wherein X₂Is CH₃、X₃Is H and H₄Is H.

26. The pentaaza macrocycle complex of item 19 wherein X₂Is CH₃、X₃Is OH and H₄Is H.

27. The pentaaza macrocycle complex of item 19 wherein X₂Is CH₃、X₃Is NH₂And H₄Is H.

28. The pentaaza macrocycle complex of item 19 wherein X₂Is CH₃And X₃And X4 in combination is (═ O).

29. The pentaaza macrocycle complex of any one of clauses 1-10, wherein each X₁is-C (X)₂)(X₃)(X₄) And X₃is-X₅C(＝O)R₁₃And each is-C (X)₂)(X₃)(X₄) Corresponding to any one of combinations 1 to 4 appearing in the following table:

combination of	X₂	X₃	X₄
				1	Ph	NHC(＝O)R₁₃	H
2	Ph	OC(＝O)R₁₃	H
				3	CH₃	NHC(＝O)R₁₃	H
4	CH₃	OC(＝O)R₁₃	H

30. A pharmaceutical composition comprising a pentaaza macrocyclic ring complex as described in any of the preceding items and a pharmaceutically acceptable excipient suitable for administration.

31. The pharmaceutical composition of clause 30, wherein the pharmaceutical composition is suitable for oral administration to a human subject.

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

33. The pharmaceutical composition of clause 32, 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 tartrates of mono-and/or di-glycerides 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; an alcohol ethoxylate; and polyoxyethylene-polyoxypropylene co-copolymers.

34. The pharmaceutical composition of clause 33, 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 acid triglycerides, linoleoyl polyethylene glycol-6 glyceride (NF), oleoyl polyethylene glycol-6 glyceride (NF), glycerol monooleate (NF), glycerol monolinoleate (NF), and caprylocaproyl polyethylene glycol-8 glyceride (NF).

35. The pharmaceutical composition of any one of clauses 30 to 34, wherein the pharmaceutical composition is in a solid or semi-solid dosage form.

36. The pharmaceutical composition of any of clauses 30 to 34, wherein the pharmaceutical composition is in the form of a tablet, gelatin capsule, gel, or suspension suitable for oral administration.

37. The pharmaceutical composition of any one of clauses 30 to 36, wherein the pharmaceutical composition comprises an enteric coating layer.

38. A method for administering a pentaaza macrocyclic ring complex to a subject, the method comprising administering to a human subject a composition of any of items 30-37.

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

Detailed Description

Examples

The following non-limiting examples are provided to further illustrate the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent methods that the inventors have discovered work well in the practice of the invention, and thus can be considered to constitute examples of modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

Example 1

Introduction to the design reside in

Compounds were screened for oral bioavailability by: the formulated prodrug is injected directly into the duodenum (intraduodenal or id administration) of minipig test subjects, thus bypassing the acidic environment of the stomach and thereby eliminating potentially misleading oral bioavailability results that may result from testing for drug changes in the acidic environment of the stomach.

The Gottingen miniature pig (Gottingen minipig) was chosen as the test model species for assessing oral bioavailability, since 1) it is well known that miniature pigs (and porcine animals in general) mimic the physiology and pharmacology of the human intestine, particularly with respect to drug absorption¹And 2) previous studies using GC4403 (the enantiomer of GC4419) in a Gentiana minipig showed oral bioavailability consistent with clinical experience in human studies.

The study was performed in Xenometrics LLC (Stillwell, KS) and id bioavailability was determined using various axial ligand derivative complexes of GC4419, GC4444, GC4403 and GC 4401. In each case intravenously (iv) route administration of parent compounds with their chloroaxial ligands (GC4419, GC4403, GC4444 and GC4401) as reference for calculating 100% bioavailability, e.g. by AUC_0->24h(area under the curve from 0 to 24h (ng-hr/mL)). Calculation of% oral bioavailability of a formulation of id administered compound compared to AUC via iv route_0->24hCalculating the AUC over the pathway_0->24h. The% oral bioavailability was then calculated via intestinal absorption of the test drug complex using the formula:

AUC%_0->24h(id) x (1/dose (mg/kg))/(AUC)_0->24h(iv)*

Wherein the iv dose is 1mg test drug per kg body weight of the mini-pig and the id dose administered is 10mg test drug per kg body weight of the mini-pig.

All Xenometrics facilities are fully approved by the Association for Association & Association of Laboratory Animals additives, AAALAC. All experiments and animal care were performed in the Xenometric institute for animal care and within strict guidelines established and implemented by the use Commission.

Method

Male Gottingen miniature pigs (4-5 months of age, 9-12kg body weight) were purchased from Marshall BioResources and housed in Xenometrics. After at least 14 days of acclimation, each animal was implanted with sufficient anesthesia via abdominal surgery with an intraduodenal (id) cannula. A reusable accessible hub is disposed externally of the distal end (see details of the procedure below). During a recovery period of at least 2 weeks, piglets were treated daily to adapt them to the test procedure, i.e. id dosing and blood sampling. For each experiment, each mini-pig received the test drug dissolved or suspended in the vehicle. The piglets do not need to be limited for administration. All dosing experiments were performed in fasted animals. Food was removed from the mini-pigs 16 hours prior to dosing. The piglets were given water ad libitum. The dosed piglets were allowed to obtain food 6 hours after dosing. The test article was administered as a bolus injection (about 1 minute) via the id cannula at a dose of 10mg/kg parent drug in 0.1mL/kg vehicle (e.g., 1.5mL in 15kg mini-pigs). The actual amount of total test drug administered will vary with the formula weight of the prodrug. After administration of the test article, the cannula is flushed with an equal volume of excipient vehicle. After about 6 hours, the cannulae were rinsed with corn oil. Approximately 24 hours after administration, the catheter was rinsed with sterile saline solution and capped. At time points 0.25, 0.5, 1,2, 4,8, 24 and 48 hours post-injection, 2mL blood samples were collected by cranial vena cava puncture (4mL sodium heparin Vacutainer, 20g 1.5 "needle) after swabbing the skin surface with ethanol. The piglets were placed in a sling in a lying position without anaesthesia for taking blood samples. No more than one experiment was performed every 7 days using minipigs. Blood samples were kept on ice until plasma was obtained upon treatment. Blood samples were centrifuged at 1200x g for 10 minutes at 4 ℃ and plasma samples were transferred to 96 well plate tubes, capped and stored at-20 ℃ until sent on dry ice to the analytical laboratory for measurement of drug concentration in plasma. The concentration of the parent manganese pentaazamacrocycle complex (independent of the composition of the axial ligand) in plasma was measured using a validated HPLC/MS method, which was linear between 50ng/mL and 20,000 ng/mL.

Xenometrics surgical procedure with an oral duodenal tube in porcine animals: the system was tested for surgical preparation.

Animal preparation

Pigs were fasted overnight prior to surgery and were pre-dosed and induced according to the drug and dose profile attached. An endotracheal tube is inserted and general anesthesia is maintained with isoflurane delivered in oxygen via a precision vaporizer and a rebreathing anesthesia loop. LRS (Lactate-Ringers Solution) was administered at about 100 mL/hour via a peripheral catheter during surgery. The procedure is performed in a designated operating room and the entire procedure follows sterile techniques.

Inlet port (VAP) placement

The area on the right dorsal chest was shaved and prepared with chlorhexidine scrub and solution.

A midline laparotomy was performed, and the duodenum was isolated and cannulated according to the description set forth below and exteriorized at a site along the dorsal thorax. The external cannula is then connected to a separate access port (VAP) and implanted subcutaneously using a suitable non-absorbable suture. The open incision is closed appropriately to ensure removal of the dead space and closure of the skin with absorbable sutures. The peritoneal and muscle layers of the laparotomy were apposed in a discontinuous pattern with appropriately sized absorbable sutures. The subcutaneous tissue will be apposed with absorbable sutures. The skin was closed with absorbable subcutaneous sutures.

Duodenal cannulation with Vascular Access Port (VAP)

The area on the ventral abdomen was shaved and prepared with chlorhexidine scrub and solution.

A vent valve catheter (Burp valve catheter) (Access Technologies, Chicago IL) with a 5mm Dacron disc attached 1cm from the tip was used to intubate the duodenum. The exhaust valve sleeve is flushed prior to implantation to ensure that the exhaust valve is free and working properly. The duodenum was positioned and the intubation site isolated (i.e., 5-8cm from the curved head end of the duodenum). At this site, a 4-0Prolene purse string suture was placed on the mucosal surface and the intestine was perforated with 18g needle at the center of the purse string suture. The needle was then removed and replaced with a 16g distal adapter (stub adapter) to further expand the existing insertion site. The distal adapter is then removed and the vent valve tip is placed into the bowel defect until the Dacron disc is flush with the mucosal surface. The tip is anchored by closing the purse string suture and securing it in place. The disc was anchored into place to the mucosal surface using 7-8 interrupted 4-0Prolene sutures. A small loop was formed and the catheter body (about 5-6cm from the disc) was anchored to the mucosa using Weitzel tunneling.

Note that: the Weitzel tunneling technique is accomplished by placing the catheter body along the bowel with its distal side facing toward the duodenal curved tip. 4-6 individual 5-0Prolene sutures were placed approximately 0.5cm apart to form a "tunnel". The tunnel is formed by the steps of: each suture is attached to the mucosal surface beside the sleeve, and then the free end is attached to the mucosal surface on the other side of the sleeve, ensuring that the suture stays on top of the sleeve. When the individual sutures are tied, they pull the mucosa over the cannula, thereby forming a "tunnel".

After completion of the Weitzel tunneling technique, a small (2-3mm) incision was made in the peritoneum about 1cm below the rib on the right side of the animal, and the catheter was exteriorized to the site of the opening by using a trocar. An incision is made in the dorsal side of the right chest and a pocket is formed to receive the opening. The cannula is then moved through the trocar to the pocket and attached to the opening. 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 was rinsed with saline. The abdomen was closed in an interrupted fashion with a suitable absorbable monofilament suture. The fascia is closed individually in an appropriate manner with appropriate absorbable sutures. The skin is closed in a suitable manner with suitable sutures or staples. During the recovery from anesthesia, the animals were monitored for recovery of normal physiological function.

The incision sites were examined daily for a minimum of 14 days. Antibiotics are administered as needed. Animals were unsheathed for a minimum of 14 days after the procedure.

System maintenance

The opening is accessed using sterile techniques. The fur above the opening is clamped as required. At least 3 alternating rubs of chlorhexidine scrub fluid and solution are applied prior to accessing the opening via a Huber pointed needle (Huber pointed needle). After administration, the duodenal opening is rinsed with an appropriate rinsing solution, such as physiological saline or sterile water.

Experiment of

Preparation of drug delivery formulations

The oils used to prepare the dosing solutions are supplied from commercial sources. Capmul MCM (NF) is a mixture of mono/diglycerides of caprylic/capric acid and is supplied by ABITEC Corporation, Janesville, Wis. Miglyol 812N is a mixture of caprylic/capric triglycerides and is supplied by Cremer Oleo Division, Eatontown, NJ. Labrafil M2125CS (NF) is chemically defined as linoleoyl polyethylene glycol-6 glycerol ester NF and is supplied by Gattefose, SAINT-PRIEST Cedex, France. Peceol is chemically defined as a monoglyceride, glycerol monooleate NF, and is supplied by Gattefosse, SAINT-PRIIEST Cedex, France. Maisine 35-1 is chemically defined as the monoglyceride, glycerol monolinoleate (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-PRIIEST Cedex, France. Labrafil M1944CS is chemically defined as oleoyl polyethylene glycol-6 glyceride (NF) and is supplied by Gattefosse, SAINT-PRIIEST Cedex, France. The dosing solutions were all prepared using a four-position analytical balance by weighing all the components of each formulation so that 10% by weight of each formulation contained the test drug and 90% by weight of oil was used for the formulation.

Biological analysis method

Bioanalytical methods for quantifying parent Mn (ii) macrocyclic ring ligand structures in plasma utilize HPLC using MS/MS detection and monitor for the presence of monocationic [ monocarboxylate Mn (pentaazamacrocycle) ] + complexes. All bioanalytical sample measurements were performed at ABC Laboratories using the Galera bioanalytical method at ABC validation as ABC method No. 81201-MI-02, which is similar to the method described in U.S. patent No.8,444,856 to Slomczynska et al, which is hereby incorporated by reference in its entirety.

Synthesis of

Unless otherwise indicated, all reagents used to synthesize the compounds disclosed herein were purchased from Sigma-Aldrich and used without further purification. All elemental analyses were performed and reported by Galbraith Laboratories, inc.

The parent mn (ii) pentaazamacrocycle 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 starting material²Whereas for GC4419, i.e. the mirror enantiomer of GC4403, a 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 GC4403². The synthesis of GC4401 complexes was previously reported in reference 5.

The synthesis of GC4444 (and also derived from R, R-diaminocyclohexane) containing an additional 11-R-methyl substituent yielding a fifth chiral center on carbon was carried out from the corresponding chiral tetraamine, the synthesis of which is disclosed as example 5C in reference 6.

Synthesis of axial ligand derivatives

The same parent mn (ii) pentaaza macrocyclic dichlorocyclo complex (GC4419, GC4403, GC4444 and GC4401) was also used as a starting precursor 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 replace the chloride ligand, thereby generating novel compounds.

Example 2

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,18,19,20,21,21 a-didehydro-11, 7-nitrilo-7H-dibenzo [ b, H ] [1,4,7,10] tetraazacycloheptadene-kappa N5, [ kappa N13, [ kappa N18, [ kappa N21, [ kappa N22] - ], [ bis-acetate (GC4419) ]. GC4701

Using a 500-mL Erlenmeyer flask, 100mL of deionized ("DI") water was added to 5.3g of GC 4419; the mixture was vigorously stirred for 15-20 minutes and then sonicated for 5 minutes. The resulting brownish suspension was filtered through a 10-20 μ fritted funnel (about 0.3g of solid material was left in the funnel). The resulting clear solution was added as a stream in one portion to a solution of sodium acetate (approximately 429mmol, 21 equivalents in 100mL DI water). No solid separated and the pale 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 a separatory funnel. The dichloromethane solution was back-extracted (2X 50mL) with aqueous sodium acetate (32g/100 mL). The dichloromethane layer was purified over MgSO₄(about 10g) dried for 30 minutes (under stirring), filtered through a 10-20 μ fritted funnel, and the solution dried using a rotary evaporator. Obtained by drying the solutionTo the yellow oily solid was added methanol (50 mL). The solution was then dried again on a rotary evaporator to give a pale yellow foam/glass. The material was dried under vacuum at room temperature for two days.

The isolated pale yellow brittle material was analyzed by HPLC (4.11g, 75% yield based on GC4419) and showed a purity of 99.7% and elemental analysis showed 0.98 wt% residual chlorine. Elemental analysis and expected bis- (acetoxy) Structure C₂₅H₄₁MnN₅O₄·2H₂And O is consistent. Analysis calculated value: c, 53.00%; h, 8.01%; n, 12.36% and Mn, 9.70%. Analysis of measured values: c, 53.10%; h, 8.34%; mn, 9.86%, N, 12.56%, and Cl (as total halogen content), 0.98 wt%.

Example 3

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,18,19,20,21,21 a-didehydro-11, 7-nitrilo-7H-dibenzo [ b, H ] [1,4,7,10] tetraazacycloheptadene-kappa N5, [ kappa N13, [ kappa N18, [ kappa N21, [ kappa N22] - [ bis-octanoate (GC4419) ]. GC4710

Using a 500-mL Erlenmeyer flask, 200mL DI water was added to 10.2g GC4419, stirred vigorously for 15-20 minutes, and then sonicated for 5 minutes. The resulting tan suspension was filtered through a 45x 20mm celite bed (pre-washed with DI water) on a 25-50 μ porous funnel. The resulting clear solution was added as a slow stream over 5 minutes to 250mL of sodium caprylate solution (75g, approximately 450mmol, 11 equiv.). No solid separated and the tan solution was stirred for an additional 5 minutes. The solution was transferred to a separatory funnel and extracted with DCM (2 × 100 mL). Separating the organic layers, combining, and MgSO₄(10g) Dried, filtered and dried under reduced pressure. The residual DCM was co-evaporated with MeOH (75mL) to give a light yellow-tan gum. The gum was dried under vacuum at 40 ℃ for 19 h. A pale yellow solid was isolated in 73% yield (10.8g) based on starting GC 4419. Submitting the solid for elemental analysis (Galbraith Labs) and also subjecting it toAnalysis was performed by HPLC using chromatography as described in reference 4.

HPLC showed 99.5% purity (0.14% monoamine GC 4520). Elemental analysis and hemihydrate C₂₅H₄₁MnN₅O₄·0.5H₂O, FW 734.93(anhyd) has the same structure. Analysis calculated value: c, 63.05%; h, 9.39%; n, 9.94% and Mn, 7.79%. Analysis of measured values: c, 63.21%; h, 9.80%; mn, 7.97%, N, 9.63% and Cl (as total halogen content),<150ppm。

example 4

Synthesis of manganese (II) bis-pivalate [ (4aS,13aS,17aS,21aS) -1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21 a-didehydro-11, 7-nitrilo-7H-dibenzo [ b, H ] [1,4,7,10] tetraazacycloheptadene-kappa N5, [ kappa N13, [ kappa N18, [ kappa N21, [ kappa N22] - [ bis-pivalate (GC4419) ], GC4709

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

Dichloromethane (100mL) was added to the wet solids. The mixture turned into a gel-like suspension and was mixed with stirring at 37 ℃ for 1 hour. Filtering the suspension using a tared 10-20 μ porous funnel, andand 1.7g of additional white solid was isolated and discarded. The solvent of the filtrate was removed by rotary evaporator to give a tan slurry. MeOH (75mL) was added to the tan slurry and gave a tan semi-solid after removal of solvent via rotary evaporator. The material was dried in vacuo for 72h to give GC4709 as a tan solid, which was submitted for elemental analysis. HPLC showed 99.5% purity. Elemental analysis and Structure C₃₁H₅₃MnN₅O₄·0.5H₂O, FW614.73 (anhyd). Analysis calculated value: c, 59.69%; h, 8.73%; n, 11.23% and Mn, 8.81%. Analysis of measured values: c, 59.87%; h, 8.44%; mn, 8.45%, N, 10.88% and Cl (as total halogen content), about 0.08% (784 ppm).

Example 5

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,18,19,20,21,21 a-didehydro-11, 7-nitrilo-7H-dibenzo [ b, H ] [1,4,7,10] tetraazacyclo-heptdecene-kappa N5, [ kappa N13, [ kappa N18, [ kappa N21, [ kappa N22] - ], GC4707 ].

Sodium cyclohexane butyrate (5.77g) was added to a 125mL Erlenmeyer flask, which was then attempted to be dissolved in 50mL of anhydrous EtOH with stirring over 15 minutes. The mixture became gelatinous and an additional 50mL of EtOH (anhydrous) was added, totaling 100 mL. This additional solvent did not give a clear solution after warming/sonication (about 40 ℃). MeOH (10mL) was added and a clear solution was obtained after stirring/sonication for 15 min. This solution was added in one portion to a solution containing 3.6g of GC4419 dissolved in 15mL of anhydrous EtOH (the solution was tan in color). A fine suspension was obtained immediately. The suspension was stirred for 15 minutes and then placed in a freezer for 1 h. At this point the suspension was filtered using a 10-15 μ porous funnel and the clear tan filtrate was evaporated to dryness on a rotary evaporator. The resulting solid was dried under vacuum at room temperature overnight. The next morning, the tan solid was stirred in 100mL of dichloromethane ("DCM") to dissolve the desired product while leaving behind an excess of cyclohexanebutanoic acid sodium salt. The slurry was stirred for 3h before filtration (using a 10-15 μ porous funnel and washing in the funnel with 2 × 30mL DCM). The resulting yellow filtrate was evaporated using a rotary evaporator and then 100mL MeOH was added. The resulting yellow solution was evaporated again using a rotary evaporator and the residue was placed under vacuum at room temperature overnight. The next day, a tan solid was isolated. The material was further decomposed and dried under vacuum overnight, then ground using an agate mortar/pestle.

The isolated tan solid (5.4g, 96% yield based on GC4419) was analyzed by HPLC and showed 99.6% purity. Elemental analysis and [ bis- (cyclohexanebutyrate) GC4419]:C₄₁H₆₉MnN₅O₄FW 750.97(anhyd) was identical. Analysis calculated value: c, 65.58%; h, 9.26%; n, 9.33% and Mn 7.32%. Analysis of measured values: c, 65.29%; h, 8.83%; mn, 6.95%, N, 9.42% and Cl (as total halogen content) 0.22 wt%.

Example 6

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,18,19,20,21,21 a-didedecahydro-11, 7-nitrilo-7H-dibenzo [ b, H ] [1,4,7,10] tetraazacycloheptadene-kappa N5, [ kappa N13, [ kappa N18, [ kappa N21, [ kappa N22] - ], [ bis-dodecanoate (GC4419) ], GC4708.

Sodium dodecanoate (6.17g) was added to 300mL of anhydrous EtOH in a 500mL Erlenmeyer flask. The resulting white suspension (300rpm) was stirred while heating on a hot plate (about 50 ℃). After 15 minutes, the suspension became virtually thick. An additional 100mL of anhydrous EtOH was added and the resulting slurry was sonicated for 10 minutes. Then 15mL of DI water (to make it about 96% EtOH) was added with stirring and the mixture turned into a clear solution in one minute. To this solution was added 3.6g of GC4419 dissolved in 30mL of anhydrous EtOH. The resulting solution was cloudy and light tan in color and was stirred for 2h and then placed on a rotary evaporator. About half of the solvent was removed and as the volume decreased, solid material emerged from solution. At this point both the solid and solvent were transferred to a 25-50 μ filter funnel along with a flask EtOH (50mL) rinse and filtered. The light tan filtrate was then placed again in the rotary evaporator. After further evaporation, a light tan solid was obtained, which was left to stand at room temperature under vacuum overnight. The next day, about 4.7g of tan solid was isolated. DCM (100mL) was added and the suspension was stirred for 1h, then filtered to give a pale yellow filtrate. After removal of DCM using a rotary evaporator, a light tan foam was obtained which was dried in vacuo at room temperature for 48 h.

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

Example 7

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,18,19,20,21,21 a-didehydro-11, 7-nitrilo-7H-dibenzo [ b, H ] [1,4,7,10] tetraazacyclo-heptdecene-kappa N5, [ kappa N13, [ kappa N18, [ kappa N21, [ kappa N22] -, [ bis-phenylacetate (GC4419) ], GC4718.

Phenylacetic acid (47.3g) was partially dissolved in DI water (1L) and titrated to pH 7.6 using solid NaOH, followed by the dropwise addition of 0.5M aqueous NaOH to bring the pH to about 8.5. The final volume of the sodium phenylacetate solution was about 1L. GC4419 was added as a solid (3.5g) to 400mL of phenylacetate solution with stirring, followed by some solid formation. DCM (50mL) was added and the aqueous layer was extracted. This extraction was repeated two more times, and the three dichloromethane extracts were combined (about 150mL) and back-extracted with the remaining phenylacetate solution (4X 150 mL). The light yellow DCM solution was filtered over MgSO₄Dry for 30 minutes (under stirring), filter using a 10-20 μ fritted funnel, and allow to dry in a rotary evaporator. The resulting foam was dissolved in 50mL MeOH and dried again to remove traces of DCM. The yellow foam residue was left under vacuum at room temperature overnight. 4.57g (93% yield) of a pale tan-yellow semi-crystalline solidSeparated, analyzed by HPLC, and showed a purity of 99.6%. Elemental analysis and expected bis- (phenylacetate) Structure C₃₇H₄₉MnN₅O₄And (5) the consistency is achieved. Analysis calculated value: c, 65.09%; h, 7.23%; n, 10.26% and Mn, 8.05%. Analysis of measured values: c, 65.17%; h, 7.26%; mn, 7.67%, N, 10.08% and Cl (as total halogen content), 63 ppm.

Example 8

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,18,19,20,21,21 a-didedecahydro-11, 7-nitrilo-7H-dibenzo [ b, H ] [1,4,7,10] tetraazacyclohepta-decyne-. kappa.N 5,. kappa.N 13,. kappa.N 18,. kappa.N 21,. kappa.N 22] - [ bis-phenylglyoxylate (GC4419) ]. GC4719.

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

A cloudy solution of 5g GC4419 in 75mL DI water was filtered through a 10-20 μ filter funnel and added all at once to about half of the pH adjusted aqueous solution of sodium phenylglyoxylate (about 110 mL). The precipitated white material was stirred for a further 15 minutes and then 100mL of DCM was added. A yellow DCM layer was produced immediately. The layers were separated and the DCM layer was extracted with a second half sodium phenylglyoxylate solution. After shaking vigorously and allowing to settle for 10 min, the DCM layer was washed with MgSO₄Dry, filter and remove solvent using a rotary evaporator. MeOH (50mL) 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 ℃ overnight.

The isolated pale yellow semi-crystalline solid (7.1g, 96% yield from GC4419) was analyzed by HPLC and showed 99.3% purity. Elemental analysis showed the following: c, 62.05%; h, 6.38%; mn, 7.73%; and N, 9.85%. Analysis of measured values: c, 62.50%; h, 6.29%; mn, 7.73%; n, 9.85% and Cl as a total halogen content of 55 ppm.

Example 9

Synthesis of manganese (II) bis-propionate [ (4aS,13aS,17aS,21aS) -1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21 a-didehydro-11, 7-nitrilo-7H-dibenzo [ b, H ] [1,4,7,10] tetraaza-cycloheptadene-. kappa.N 5,. kappa.N 13,. kappa.N 18,. kappa.N 21,. kappa.N 22] - [ bis-propionate (GC4419) ]. GC4711.

GC4419(11.0g) was added to a 500-mL Erlenmeyer flask containing 200mL DI water. The mixture was stirred vigorously for 15-20 minutes while warming to 40 ℃ for 10 minutes. The resulting light brown suspension was filtered using a 10-20 μ fritted funnel to give a clear light tan solution. An aqueous solution of 80g of sodium propionate in 200mL of DI water was prepared in a separate flask. The GC4419 solution and 200mL of sodium propionate solution were combined in a 500-mL Erlenmeyer flask. The resulting tan solution was stirred for 5 minutes. The light tan-yellow solution was transferred to a 1-L separatory funnel and extracted with DCM (3 × 75 mL). The three resulting DCM layers were combined and transferred back to a separatory funnel, and the resulting DCM solution was back-extracted with additional aqueous sodium propionate (3 × 70 mL). The DCM layer was purified over MgSO₄Dry for 15 minutes (under agitation), filter using a 20-50 μ fritted funnel, and dry (i.e., foam) using a rotary evaporator. Methanol (100mL) was added and the resulting solution was dried using a rotary evaporator to remove residual DCM to give a light tan-yellow solid. The material was dried under vacuum at 30 ℃ for 20 h.

11.45g of an isolated pale yellow solid was obtained, which corresponds to a 94% yield based on GC 4419. HPLC analysis showed a purity of 99.6% and elemental analysis showed only 873ppm of residual chloride expressed as total halogen content and consistent with the structure of [ bis-propionato (GC4419) ]. Analysis calculated value: c, 58.05%; h, 8.12%; mn, 9.83%; and N, 12.54%. Analysis of measured values: c, 57.64%; h, 8.05%; mn, 9.91%; n, 12.51% and Cl as a total halogen content 873 ppm.

Example 10

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,18,19,20,21,21 a-didedecahydro-11, 7-nitrilo-7H-dibenzo [ b, H ] [1,4,7,10] tetraazacyclo-heptdecene-kappa N5, kappa N13, kappa N18, kappa N21, kappa N22] -, [ bis- (L) -phenylglycinate (GC4419) ], GC4702

GC4419(1.5g) was added to a 250mL Erlenmeyer flask containing 100mL DI water with stirring for 15 minutes. The resulting light brown suspension was filtered using a 20-50 μ fritted funnel. To a second flask in which 31.3g L-phenylglycine was dissolved in 400mL DI water was added 8.3g NaOH as pellets and the mixture was stirred vigorously. The pH was measured when all NaOH was dissolved. The pH was 2.30 and adjusted with 5 wt% aqueous NaOH (resulting pH 9.6). In a 250-mL Erlenmeyer flask, the GC4419 solution and approximately one-half (200mL) of the L-phenylsodium glycinate solution were combined. The resulting tan solution was stirred for 5 minutes. The light tan-yellow solution was transferred to a 1-L separatory funnel and extracted with DCM (3 × 50 mL). The three resulting DCM layers were combined and transferred back to a separatory funnel. The resulting DCM solution was back-extracted with the remaining aqueous solution of sodium L-phenylglycinate (4 × 50 mL). The DCM layer was purified over MgSO₄Dry for 15 minutes (under agitation), filter using a 20-50 μ fritted funnel, and dry using a rotary evaporator. Methanol (50mL) was added and the resulting solution was dried using a rotary evaporator to remove residual DCM to give a light tan-yellow solid. The material was dried under vacuum at 30 ℃ for 20 h. 5.42g of isolated pale yellow solid was obtained (74% yield). HPLC analysis showed 99.5% purity. Elemental analysis showed 188ppm of residual chloride. Elemental analysis and expected GC4702 Structure C as 1.5 hydrate₃₇H₅₁MnN₇O₄·1.5H₂And O is consistent: analysis calculated value: c, 60.07%; h, 7.36%; mn, 7.43%; and N, 13.25%. Analysis of measured valuesThe value: c, 60.20%; h, 7.11%; mn, 7.72%; n, 13.30% and Cl as a total halogen content 188 ppm.

Example 11

Synthesis of manganese (II) bis-rac-phenylglycinate [ (4aS,13aS,17aS,21aS) -1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21 a-didedecahydro-11, 7-nitrilo-7H-dibenzo [ b, H ] [1,4,7,10] tetraazacycloheptadene-kappa N5, kappa N13, kappa N18, kappa N21, kappa N22] -, [ bis- (rac) -phenylglycinate (GC4419) ], GC4720

GC4419(10.0g) was added to 250mL of DI water in a 500mL Erlenmeyer flask with vigorous stirring for 15-20 minutes. The resulting brownish suspension was filtered through a 20-50 μ fritted funnel. To a second flask containing 62.7g rac-phenylglycine in 350mL DI water was added 16.6g NaOH (two approximate aliquots, in pellets) and the mixture was stirred vigorously. The pH was measured when all NaOH dissolved and a clear solution was obtained. The pH was measured at 12.3 and adjusted to 9 by adding a small portion of rac-phenylglycine powder. The GC4419 solution and half (about 200mL) of the rac-sodium phenylglycinate solution (about 105mmol) were combined in a 500mL Erlenmeyer flask. The resulting light brown solution was stirred for 5 minutes. The solution was transferred to a 1-L separatory funnel and extracted with 150mL DCM. The organic layer was separated and back-extracted with the remaining aqueous rac-phenylglycine solution (2 × 100 mL). The DCM layer was purified over MgSO₄Dry for 15 minutes (under agitation), filter using a 20-50 μ fritted funnel, and dry using a rotary evaporator. Methanol (75mL) was added and the resulting solution was dried using a rotary evaporator to remove residual DCM to give a light tan-yellow solid. The material was dried under vacuum at 30 ℃ for 20 h. The isolated pale yellow material (5.42g, 74% yield) was analyzed by HPLC, showing a purity of 99.5%. Elemental analysis and expected GC4720 Structure C₃₇H₅₁MnN₇O₄·2H₂And O is consistent. Analysis calculated value: c, 62.35%; h, 7.21%; n, 13.76% and Mn, 7.71%. Analysis of measured values: c56.89%; h, 7.02%; mn, 7.68%, N, 13.76% and Cl (as total halogen content), 0.20%.

Example 12

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,18,19,20,21,21 a-didedecahydro-11, 7-nitrilo-7H-dibenzo [ b, H ] [1,4,7,10] tetraazacyclo-heptdecene-kappa N5, kappa N13, kappa N18, kappa N21, kappa N22] -, [ bis- (L) -phenylalanine (GC4419) ], GC4704.

GC4419(10.0.g) was added to 200mL DI water in a 500mL Erlenmeyer flask with vigorous stirring. The resulting light brown suspension was filtered using a 20-50 μ fritted funnel. Separately, (L) -phenylalanine (68.39g) was added to 200mL of DI water in a 500-mL Erlenmeyer flask. The phenylalanine suspension was treated with solid NaOH (16.6g) in pellets and the mixture was stirred vigorously. The pH was measured when all NaOH was dissolved. The pH was 11.1 and was adjusted to 10.24 by addition of L-phenylalanine. The GC4419 solution and half (about 100mL) of the L-phenylalanine sodium solution were combined in a 500mL Erlenmeyer flask with stirring. After addition of 100mL DCM, the resulting tan solution was stirred for 5 minutes. The light tan-yellow biphasic solution was transferred to a 1-L separatory funnel, the organic layer was removed and the aqueous layer was extracted with an additional 50mL of DCM. The organic layers were combined and transferred back to the separatory funnel. The resulting DCM solution was back-extracted with the remaining aqueous sodium propionate solution (2 × about 50 mL). The DCM layer was purified over MgSO₄Dry for 15 minutes (under agitation), filter using a 20-50 μ fritted funnel, and dry (i.e., foam) using a rotary evaporator. Methanol (50mL) was added and the resulting solution was dried using a rotary evaporator to remove residual DCM to give a light tan-yellow solid. The material was dried under vacuum at 30 ℃ for 40 h.

The isolated tan-yellow amorphous powder (4.1g, 55% yield) was analyzed via HPLC and was shown to have a purity of 99.6%. Elemental analysis expected binding to GC4704 complex as trihydrateStructure (C)₃₉H₅₅MnN₇O₄·3H₂O) consistent, showing the following results: c, 59.19%; h, 7.22%; mn, 6.52%; n, 12.09% and Cl, 0.20%.

Example 13

Synthesis of manganese (II) bis-rac-2-phenylpropionate [ (4aS,13aS,17aS,21aS) -1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21 a-didehydro-11, 7-nitrilo-7H-dibenzo [ b, H ] [1,4,7,10] tetraazacycloheptadene-kappa N5, kappa N13, kappa N18, kappa N21, kappa N22] -, [ bis- (rac) -2-phenylpropionate (GC4419) ], GC4705

27.5g of rac-2-phenylpropionic acid was added to a 500-mL Erlenmeyer flask containing 200mL of DI water. After stirring for 5 minutes, a dispersion was obtained. It was treated with solid NaOH (6.84g) in the form of pellets and the mixture was stirred vigorously. The pH was measured when all NaOH was dissolved. The pH was 2.97 (dispersion) before addition of NaOH and after addition it was adjusted to a pH of about 9 using a 5 wt% aqueous NaOH solution, resulting in a slightly cloudy solution. A slightly turbid solution of 10g GC4419 in 350mL DI water was prepared by vigorous stirring. A100-mL portion of the pH-adjusted aqueous solution of the 2-phenylpropionate solution was added as a slow stream over 1 minute. An off-white semisolid precipitated and the entire mixture was stirred with DCM (100mL) for 15 minutes. After this time period, the biphasic solution was transferred to a 500-mL separatory funnel. The Erlenmeyer flask was 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 colored dichloromethane solutions were combined in a separatory funnel and extracted with the latter half of an aqueous solution of rac-phenylpropionate (2 × 50 mL). After shaking vigorously and settling for 10 minutes each time, the DCM layer was purified over MgSO₄(20g) Dry, filter and remove solvent. Methanol (75mL) was added and the resulting solution was dried using a rotary evaporator to remove residual DCM. The resulting gum material was dried under vacuum at 35 ℃ overnight.

Separating the separated light beigeThe solid (14.6g, 95% yield) was analyzed by HPLC and showed a purity of 99.7%. Elemental analysis and expected result C of GC4705₃₉H₅₃MnN₅O₄And (3) consistency: c, 65.74%; h, 7.54%; mn, 7.57%; n, 9.76% and Cl,60 ppm.

Example 14

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,18,19,20,21,21 a-didehydro-11, 7-nitrilo-7H-dibenzo [ b, H ] [1,4,7,10] tetraazacycloheptadene-kappa N5, kappa N13, kappa N18, kappa N21, kappa N22] - [ bis- (rac) -phenylglycinate (GC4401) ]. GC4715.

GC4401(5g,9.78mmol) was added to 50mL DI water in a 125mL erlenmeyer flask and stirred vigorously for 5 minutes to give a very slightly turbid, light yellow solution. The solution was then filtered and the filtrate solution was retained. Using a second flask, rac-phenylglycine (30g,198.5mmol) was added to 200mL DI water to give a colorless solution. The solution was treated with 7.9g of NaOH in the form of pellets and the mixture was stirred vigorously. The pH was measured after all NaOH dissolved and the result was 11.2. The slightly cloudy solution was filtered (20-50. mu.l). In a 250-mL Erlenmeyer flask, the GC4401 solution and one-half (100mL) of the sodium phenylglycinate solution (about 105mmol/10 eq.) were combined into one stream. No solid 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 (50mL, ca. 1-2 minutes shake time). The organic layer was separated and transferred back to a separatory funnel. The dichloromethane solution was back-extracted with the remaining aqueous solution of sodium phenylglycinate (shaking each time for 1-2 minutes). The dichloromethane layer was purified over MgSO₄Dry for 15 minutes, filter on a 20-50 μ fritted funnel, and dry on a rotary evaporator (i.e., foam). Methanol (50mL) was then added to the yellow solid and the solution was dried to co-evaporate the residual dichloromethane to yield a light yellow solid. Subjecting the material to a temperature of 30 deg.CVacuum drying is carried out for 24 h. The isolated pale yellow solid was analyzed by HPLC (6.5g, 90% yield based on GC4401) and showed a purity of 99.5%. Elemental analysis and expected GC4715 Structure C₃₉H₅₅MnN₇O₄·H₂And O is consistent. Analysis calculated value: c, 63.23%; h, 7.48%; n, 13.23% and Mn, 7.42%. Analysis of measured values: c, 60.68%; h, 7.31%; mn, 7.06%, N, 12.68% and chlorine (as total halogen content), 974 ppm.

Example 15

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,18,19,20,21,21 a-didehydro-11, 7-nitrilo-7H-dibenzo [ b, H ] [1,4,7,10] tetraazacycloheptadene-kappa N5, kappa N13, kappa N18, kappa N21, kappa N22] - [ bis (rac) 2-phenylglycinate (GC4444) ]. GC4716.

GC4444(1g,2mmol) was added to 40mL DI water in a 125mL Erlenmeyer flask and stirred vigorously for 5 minutes to give a pale yellow solution. In a second 250mL Erlenmeyer flask, rac-phenylglycine (6g,40mmol) was added to 100mL DI water to give a colorless solution. The solution was treated with NaOH pellets (1.6g) and the mixture was stirred vigorously. The pH was measured when all NaOH dissolved and the result was 12.

In a 250-mL Erlenmeyer flask, the GC4444 solution and one-half (50mL) of the sodium phenylglycinate solution (about 20mmol/10 eq.) were combined. The resulting yellow-tan solution was stirred vigorously with dichloromethane (50mL) for 15 minutes and then transferred to a 250mL separatory funnel. The organic layer was separated and transferred back to a separatory funnel. The dichloromethane solution was extracted with the remaining aqueous solution of sodium phenylglycinate (shaking for 1-2 minutes each). The dichloromethane layer was purified over MgSO₄Dried for 15 minutes, filtered through a 20-50 μ fritted funnel, and dried on a rotary evaporator. Methanol (25mL) 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. Will be provided withThe material was dried under vacuum at 35 ℃ for 24 h. Elemental analysis and expected GC4716 Structure C₃₈H₅₃MnN₇O₄·H₂And O is consistent. Analysis calculated value: c, 62.80%; h, 7.35%; and N,13.49 percent. Analysis of measured values: c, 61.14%; h, 7.44%; and N, 13.08.

6.5g of a pale yellow powder were isolated based on the starting GC4444, giving a yield of 90%. The material was analyzed by HPLC and was obtained in 99% purity.

Example 16

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,18,19,20,21,21 a-didedecahydro-11, 7-nitrilo-7H-dibenzo [ b, H ] [1,4,7,10] tetraazacycloheptadene-kappa N5, kappa N13, kappa N18, kappa N21, kappa N22] -, [ bis- (rac) -2-phenylglycinate (GC4403) ], GC4717.

GC4403(3g,6.2mmol) was added to 75mL DI water in a 125mL Erlenmeyer flask and stirred vigorously for 15-20 minutes to give a light orange solution. In a separate 250-mL Erlenmeyer flask, 18.76g (124mmol) of rac-phenylglycine was added to 125mL of DI water with vigorous stirring. To this solution was added solid 4.9g NaOH. After 10 minutes of vigorous stirring, a colorless solution was obtained and the pH was measured to be 12. The GC4403 solution and 75mL of the rac-phenylsodium glycinate solution were combined in a 500-mL Erlenmeyer flask. The light brown solution was stirred for an additional 5 minutes. The solution was transferred to a 250-mL separatory funnel and extracted with dichloromethane (75mL, ca. 1-2min shaking). The organic layer was separated and back-extracted with the remaining rac-phenylglycine sodium. The dichloromethane layer was purified over MgSO₄Dry for 15 minutes, filter on a 20-50 μ fritted funnel, and dry on a rotary evaporator (i.e., gum). The residual dichloromethane was co-evaporated using methanol (25mL) to give a pale orange solid. The material was dried under vacuum at 37 ℃ for 20 h. 5.42g of a pale yellow solid material was isolated, giving 100% yield based on GC 4403. Analysis of the material by HPLC showed a purity of 99.5%. Elemental analysis andexpected GC4717 Structure C₃₇H₅₁MnN₇O₄·H₂And O is consistent. Analysis calculated value: c, 62.35%; h, 7.21%; n, 13.76% and Mn, 7.71%. Analysis of measured values: c, 60.72%; h, 7.26%; mn, 7.44%, N, 13.34% and chlorine (as total halogen content), 364 ppm.

Example 17

Synthesis of manganese (II) bis-N-butoxide [ (4aS,13aS,17aS,21aS) -1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21 a-didedecahydro-11, 7-nitrilo-7H-dibenzo [ b, H ] [1,4,7,10] tetraazacycloheptadene-kappa N5, kappa N13, kappa N18, kappa N21, kappa N22] - [ bis-N-butyrate (GC4419) ], GC4713.

GC4419(5.0g,10.34mmol) was added to a 500-mL Erlenmeyer flask containing 100mL DI water. The mixture was stirred vigorously for 15-20 minutes, then sonicated/warmed (using a heat gun) for 10 minutes, and a tan cloudy solution was detected, which was then filtered to remove traces of insoluble material, yielding a clear solution. Separately, sodium butyrate (92g,0.835mol) was dissolved in 200mL DI water in a 500mL Erlenmeyer flask. To a flask containing the GC4419 solution was added 100mL of sodium butyrate solution. The tan solution was stirred for an additional 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 back-extracted with the remaining aqueous sodium butyrate solution (100 mL). The DCM layer was purified over MgSO₄Dry for 15 minutes (under agitation), filter using a 20-50 μ fritted funnel, and dry (i.e., foam) using a rotary evaporator. The solid was dissolved using methanol (50mL) and the solution was dried on a rotary evaporator to give a pale yellow oil. The material was further dried under vacuum at 30 ℃ for 48h to give a tan solid (4.5g, 76% yield based on starting GC 4419). HPLC analysis showed the purity to be 99.6 area%. Elemental analysis and expected GC4713 Structure C₂₉H₄₉MnN₅O₄And (5) the consistency is achieved. Analysis calculated value: c, 59.37%; h, 8.42%; n, 11.94% and Mn, 9.36%. Analysis of measured values: c, 59.32%; and H,8.55 percent; mn, 8.80%, N, 11.94% and chlorine (as total halogen content), 546 ppm.

Example 18

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,18,19,20,21,21 a-didehydro-11, 7-nitrilo-7H-dibenzo [ b, H ] [1,4,7,10] tetraazacycloheptadene-kappa N5,. kappa.N 13,. kappa.N 18,. kappa.N 21,. kappa.N 22] - [ bis-benzoate (GC4419) ]. GC4712.

In a 500mL Erlenmeyer flask containing 200mL DI water, 10g GC4419 was added with vigorous stirring. The resulting clear light tan solution was filtered to remove trace levels of insoluble material and then added as a slow stream to 100mL of aqueous sodium benzoate (66g) (ca 458mmol,11 equivalents) over 5 minutes. At the end of the addition a gel-like white solid separated out. Dichloromethane (100mL) 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 over MgSO₄(10g) Dried, filtered and dried under reduced pressure on a rotary evaporator. Methanol was added to the flask containing the residual oily solid, and the solution was dried on a rotary evaporator to give a pale yellow solid. The material was dried under vacuum at 30 ℃ for 40h and yielded 7.8g (57% yield based on GC4419) of a pale yellow-tan solid which was analyzed by HPLC and showed a purity of 99.6%. Elemental analysis and C₃₅H₄₅MnN₅O₄·0.5H₂Expected GC4712 structure of O is consistent. Analysis calculated value: c, 63.34%; h, 6.99%; n, 10.55%; mn, 8.28%. assay found: c, 63.07%; h, 7.38%; n, 10.54%, Mn, 8.16% and traces of Cl (211 ppm).

Example 19

Synthesis of manganese (II) bis-L-lactate [ (4aS,13aS,17aS,21aS) -1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21 a-didehydro-11, 7-nitrilo-7H-dibenzo [ b, H ] [1,4,7,10] tetraazacycloheptadene-. kappa.N 5,. kappa.N 13,. kappa.N 18,. kappa.N 21,. kappa.N 22] - [ bis-L-lactate (GC4419) ]. GC4714.

In a 500mL Erlenmeyer flask containing 100mL DI water, 5g (10.34mmol) of GC4419 was added with vigorous stirring. The resulting clear light tan solution was filtered to remove trace levels of insoluble material and then 125mL of an aqueous solution of sodium L-lactate (23.4g) was added as a slow stream over 5 minutes. The resulting tan solution was stirred for an additional 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 back-extracted with the remaining aqueous (L) -sodium lactate solution (125 mL). The dichloromethane layer was purified over MgSO₄Dry for 15 minutes (under agitation), filter using a 20-50 μ fritted funnel, and dry (i.e., foam) using a rotary evaporator to remove the solvent. Methanol (50mL) was then added to the flask and used to co-evaporate residual DCM using a rotary evaporator to give a tan slurry. The material was further dried under vacuum at 30 ℃ for 48h to give a tan solid.

The isolated tan amorphous solid was analyzed by HPLC and showed a purity of 99.7%. Elemental analysis and expected GC4714 Structure C₂₇H₄₅MnN₅O₆·H₂And O is consistent. Analysis calculated value: c, 53.28%; h, 7.78%; n, 11.51%; mn, 9.03%. Analysis of measured values: c, 53.12%; h, 7.77%; n, 11.91%, Mn, 9.06% and Cl (0.87%).

Example 20

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,18,19,20,21,21 a-didedecahydro-11, 7-nitrilo-7H-dibenzo [ b, H ] [1,4,7,10] tetraazacycloheptadene-kappa N5, kappa N13, kappa N18, kappa N21, kappa N22] - [ bis-rac-mandelate (GC4419) ]: GC4706.

To a 500-mL Erlenmeyer flask were added 200mL DI water and 12.4g rac-mandelic acid. After stirring the mixture for 5 minutes, a clear colorless solution was obtained. It was treated with 3.2g naoh in pellets and the mixture was stirred vigorously. The pH was measured after all NaOH dissolved. pH was 3.61 and adjusted to low alkalinity using 5 wt% NaOH in water (resulting in pH 9.67). A turbid solution of 5g GC4419 in 100mL DI water was filtered (20-50 μ) and 1/2 of a pH adjusted aqueous sodium salt solution was added in one portion. The precipitated white viscous material was stirred for an additional 5 minutes and placed in a refrigerator at 2-8 ℃ overnight. The next morning, the suspension was transferred to a 250-mL separatory funnel and the erlenmeyer flask was rinsed with 100mL of dichloromethane, which combined the suspension and dichloromethane washes in the separatory funnel. The dichloromethane layer immediately turned light tan-yellow. The layers were separated and the dichloromethane layer was extracted with the latter half of the aqueous sodium mandelate solution. After shaking vigorously and standing for 10 minutes. The dichloromethane layer was purified over MgSO₄(10g) Dry, filter and remove solvent. Methanol (50mL) was added and the yellow solution was evaporated to co-distill the remaining dichloromethane via a rotary evaporator. The resulting foam was dried under vacuum at 30 ℃ overnight. The isolated off-white powder was analyzed by HPLC (6.7g, 91% yield) and showed a purity of 99.5%.

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,66ppm (0.0066%). Delta (Δ) values from 1/3-hydrated material: c, 0.52%; h, 0.04%; 0.07% of Mn; n, 0.08% and Cl 0%.

Example 21

Synthesis of manganese (II) bis-L-valinate [ (4aS,13aS,17aS,21aS) -1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21 a-didedecahydro-11, 7-nitrilo-7H-dibenzo [ b, H ] [1,4,7,10] tetraazacyclo-heptdecene-kappa N5, kappa N13, kappa N18, kappa N21, kappa N22] -, [ bis- (L) -valinate (GC4419) ]: GC4746.

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

3.4g of isolated light grey solid was obtained, which corresponds to 83% yield based on GC 4419. HPLC analysis showed a purity of 99.6% and elemental analysis showed 0.67% residual chloride expressed as total halogen content and compared to GC4746 · 0.5H₂The O structures are consistent. Analysis calculated value: c, 56.87%; h, 8.77%; mn, 8.39%; and N, 14.97%. Analysis of measured values: c, 57.22%; h, 8.70%; mn, 7.88%; n, 14.12% and Cl (as total halogen content) 0.67%.

Example 22

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,18,19,20,21,21 a-didedecahydro-11, 7-nitrilo-7H-dibenzo [ b, H ] [1,4,7,10] tetraazacycloheptadene-kappa N5, kappa N13, kappa N18, kappa N21, kappa N22] -, [ bis-propionato (GC4444) ]: GC4747.

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

1.1g of isolated light tan solid was obtained, which corresponds to 60% yield based on GC 4444. HPLC analysis showed a purity of 99.5% and elemental analysis showed 1.44% residual chloride expressed as total halogen content and compared to GC4747 · 0.5H₂The O structures are consistent. Analysis calculated value: c, 57.82%; h, 8.32%; mn, 9.45%; and N, 12.04%. Analysis of measured values: c, 58.19%; h, 8.50%; mn, 9.39%; n, 12.36% and Cl (as total halogen content) 1.44%.

Example 23

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,18,19,20,21,21 a-didehydro-11, 7-nitrilo-7H-dibenzo [ b, H ] [1,4,7,10] tetraazacycloheptadene-kappa N5, kappa N13, kappa N18, kappa N21, kappa N22] - [ bis-propionato (GC4403) ] GC4748.

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

2.7g of isolated light brown solid was obtained, which corresponds to a 78% yield based on GC 4403. 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 GC4748 structure. Analysis calculated value: c, 58.05%; h, 8.12%; mn, 9.83%; and N, 12.54%. Analysis of measured values: c, 58.00%; h, 8.45%; mn, 9.57%; n, 12.53% and Cl (as total halogen content) 0.356%.

Example 24

Synthesis of manganese (II) bis-acetonato [ (4aS,13aS,21aS) -1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21 a-didedecahydro-11, 7-nitrilo-7H-d benzo [ b, H ] [1,4,7,10] tetraazacycloheptadene-kappa N5, kappa N13, kappa N18, kappa N21, kappa N22] -, [ bis-acetonato (GC4419) ]: GC4749

Using a 500-mL Erlenmeyer flask, 150mL DI water was added to GC4419(FW 483.38,5g,10.34mmol) and stirred vigorously for 15-20 minutes to allow dissolution. In a second conical flask, pyruvic acid (72.83g,0.827mol) was added to 400mL DI water. While stirring the suspension, NaOH (0.83mol,33.2g) was added and stirring was continued until a clear colorless solution was obtained. The pH of the solution was about 12. The GC4419 solution and half of the sodium pyruvate solution were combined in a 500-mL Erlenmeyer flask. No solid separated and the tan mixture was stirred for an additional 5 minutes. The light tan-yellow solution was transferred to a 1-L separatory funnel and extracted with DCM (100mL, shaking for about 1-2 minutes each). The color of the aqueous solution is light pink-purple. The DCM layer was back-extracted with the remaining aqueous sodium pyruvate solution. The DCM layer was purified over MgSO₄Dry for 15 minutes (under agitation), filter using a 20-50 μ fritted funnel, and then dry using a rotary evaporator. The residual DCM can then be co-evaporated using MeOH (50mL) to give a solid. The material may be dried under vacuum at 30 ℃ for at least 20 h. The solid can be characterized by elemental analysis, MS and HPLC.

Example 25

Synthesis of manganese (II) bis-L-alaninate [ (4aS,13aS,17aS,21aS) -1,2,3,4,4a,5,6,12,13,13a,14,15,16,17,17a,18,19,20,21,21 a-didedecahydro-11, 7-nitrilo-7H-dibenzo [ b, H ] [1,4,7,10] tetraazacycloheptadene-kappa N5, kappa N13, kappa N18, kappa N21, kappa N22] - [ bis-L-alaninate (GC4419) ]: GC4750

Use of500-mL Erlenmeyer flask, 150mL DI water was added to GC4419(FW 483.38,5g,10.34mmol) and stirred vigorously for 15-20 minutes to allow dissolution. In a second conical flask, L- (+) -alanine (73.7g,0.827mol) was added to 400mL DI water. While stirring the suspension, NaOH (0.83mol,33.2g) was added and stirring was continued until a clear colorless solution was obtained. The pH of the solution was 12.1. The GC4419 solution and half of the sodium alaninate solution were combined in a 500-mL Erlenmeyer flask. No solid separated and the tan mixture was stirred for an additional 5 minutes. The light tan-yellow solution was transferred to a 1-L separatory funnel and extracted with DCM (100mL, shaking for about 1-2 minutes each). The color of the aqueous solution is light pink-purple. The DCM layer was back-extracted with the remaining aqueous sodium pyruvate solution. The DCM layer was purified over MgSO₄Dry for 15 minutes (under agitation), filter using a 20-50 μ fritted funnel, and then dry using a rotary evaporator. The residual DCM can then be co-evaporated using MeOH (50mL) to give a solid. The material may be dried under vacuum at 30 ℃ for at least 20 h. The solid can be characterized by elemental analysis, MS and HPLC.

Results

Bioavailability data for id dosing of mini-pigs from various pure single base oil formulations with various axial ligand derivatives of various mn (ii) pentaazamacrocycle complexes are summarized in table I below. In each example, the concentration of the test drug compound was 10% by weight of the total formulation.

TABLE I

In the following examples, a plot of plasma concentration of the parent mn (ii) pentaazamacrocycle complex after intraduodenal (id) or iv administration of various test article derivatives versus time after administration of the test article is shown. These examples are selected from the examples listed in table I (above). In all examples, the% bioavailability is based on a comparison of plasma levels of the test product drug obtained from a comparison of concentration values obtained using id dosing of the same pigs as utilized for iv dosing for calculation of 100% bioavailability AUC values.

A characteristic graph of plasma concentration of the parent manganese pentaaza macrocyclic 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 figure 1. Blood levels of GC4419 after iv administration at a dose of 1mg/kg body weight (mpk) were considered to be 100% bioavailable and plasma concentrations after iv administration of aqueous formulations of GC4419 are also shown. In this example, a 10mg/kg dose of 10% by weight of the following formulation was intraduodenally administered: 1) bis-L-phenylglycine derivatives of GC4419 (GC4702), 2) bis-L-phenylalanine derivatives of GC4419 (GC4704), and 3) bis-rac-phenylglycine derivatives of GC4419 (GC4720) as their Capmul MCM formulations were compared to iv administration of GC4419 itself at a dose of 1 mg/kg.

A characteristic graph of plasma concentration of the parent manganese pentaaza macrocyclic 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 drug formulated in Peceol for id delivery is shown in figure 2. Blood levels of maternal drug (in this case GC4419) after iv administration at a dose of 1mg/kg body weight (mpk) are considered 100% bioavailable and plasma concentrations after iv administration of an aqueous formulation of GC4419 are also shown. In this example, a 10mg/kg dose of 10% by weight of the following formulation was intraduodenally administered: 1) GC4419, 2) bis-acetate ion derivative of GC4419 (GC4701), and 3) bis-phenylglyoxylate ion derivative of GC4419 (GC4719) and 4) bis-rac-2-phenylpropionate ion derivative of GC4419 (GC4705) as their Peceol formulations compared to iv administration of GC4419 itself.

A plot of plasma concentrations of the parent manganese pentaaza macrocyclic 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 drug formulated for id delivery in Labrafil M2125CS is shown in figure 3. Blood levels of maternal drug (in this case GC4419) after iv administration at a dose of 1mg/kg body weight (mpk) are considered 100% bioavailable and plasma concentrations after iv administration of an aqueous formulation of GC4419 are also shown. In this figure, a 10mg/kg dose of 10% by weight of the following formulation was intraduodenally administered: 1) GC4419, 2) bis-acetate ion derivative of GC4419 (GC4701), and 3) bis-octanoate ion derivative of GC4419 (GC4710) as their Labrafil M2125CS formulation was compared to iv administration of GC4419 itself in pigs of the same group.

A plot of plasma concentrations of the parent manganese pentaaza macrocyclic 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 drug formulated for id delivery in Labrafil M2125CS is shown in figure 4. Blood levels of maternal drug (in this case GC4419) after iv administration at a dose of 1mg/kg body weight (mpk) are considered 100% bioavailable and plasma concentrations after iv administration of an aqueous formulation of GC4419 are also shown. In this example, a 10mg/kg dose of 10% by weight of the following formulation was intraduodenally administered: 1) bis-pivalate ion derivatives of GC4419 (GC4709), 2) bis-propionate ion derivatives of GC4419 (GC4711), and 3) bis-butyrate ion derivatives of GC4419 (GC4713) as their Labrafil M2125CS formulation were compared to iv administration of GC4419 itself in pigs of the same group.

A plot of the plasma concentration of the parent manganese pentaaza macrocyclic 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 drug formulated in Capmul MCM for id delivery is shown in fig. 5. Blood levels of maternal drug (in this case GC4401) after iv administration at a dose of 1mg/kg body weight (mpk) were considered 100% bioavailable and plasma concentrations after iv administration of aqueous formulations of GC4401 are also shown. In this example, a 10mg/kg dose of 10% by weight of the following formulation was intraduodenally administered: 1) GC4401 and 2) bis-rac-phenylglycine derivatives of GC4401 (GC4715) as their Capmul MCM formulation compared iv administration of GC4401 itself in pigs of the same group.

A characteristic plot of plasma concentration of the parent manganese pentaaza macrocyclic 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 drug formulated in Capmul MCM for id delivery is shown in fig. 6. Blood levels of maternal drug (in this case GC4444) after iv administration at a dose of 1mg/kg body weight (mpk) were considered to be 100% bioavailable and plasma concentrations after iv administration of an aqueous formulation of GC4444 are also shown. In this example, a 10mg/kg dose of 10% by weight of the following formulation was intraduodenally administered: 1) GC4444 and 2) bis-rac-phenylglycine derivatives of GC4444 (GC4716) as their Capmul MCM formulation were compared to iv administration of GC4444 itself in pigs of the same group.

A characteristic plot of plasma concentration of the parent manganese pentaaza macrocyclic 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 drug formulated in Capmul MCM for id delivery is shown in fig. 7. Blood levels of maternal drug (in this case GC4419) after iv administration at a dose of 1mg/kg body weight (mpk) are considered 100% bioavailable and plasma concentrations after iv administration of an aqueous formulation of GC4419 are also shown. In this example, a 10mg/kg dose of 10% by weight of the following formulation was intraduodenally administered: 1) GC4419, 2) bis-acetate ion derivatives of GC4419 (GC4701) and 3) bis-rac-mandelate ion derivatives of GC4419 (GC4706) as their Capmul MCM formulations were compared to iv administration of GC4419 itself in pigs of the same group.

A characteristic plot of plasma concentration of the parent manganese pentaaza macrocyclic 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 drug formulated for id delivery in Maisine 35-1 is shown in figure 8. Blood levels of maternal drug (in this case GC4419) after iv administration at a dose of 1mg/kg body weight (mpk) are considered 100% bioavailable and plasma concentrations after iv administration of an aqueous formulation of GC4419 are also shown. In this example, a 10mg/kg dose of 10% by weight of the following formulation was intraduodenally administered: 1) GC4419, 2) bis-phenylacetate derivatives of GC4419 (GC4718) and 3) bis-acetate derivatives of GC4419 (GC4701) as their Maisine 35-1 formulation were compared to iv administration of GC4419 itself in pigs of the same group.

A characteristic plot of plasma concentration of the parent manganese pentaaza macrocyclic 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 ion-GC 4403 by id delivery is shown in figure 9. Blood levels of maternal drug (in this case GC4403) after iv administration at a dose of 1mg/kg body weight (mpk) were considered 100% bioavailable and plasma concentrations after iv administration of aqueous formulations of GC4403 are also shown. In this example, intraduodenally administered 10mg/kg dose of a bis-rac-phenylglycine derivative formulation of GC4403(GC4717) 10 wt% as a 10 wt% slurry in Capmul MCM was compared to iv administration of GC4403 itself in pigs of the same group.

The above-cited examples show that axial ligands bonded to the mn (ii) ion can exert a very profound and previously unpredictable effect on the ability of these complexes to penetrate the GI tract and become orally bioavailable. We have found that there is a rather narrow subset of ligand structures that can greatly enhance Gastrointestinal (GI) uptake and thus greatly improve oral bioavailability. This subset of axial ligand structures that provide enhanced oral bioavailability includes those shown in figure 10.

There are some significant structural features that affect bioavailability. First, a wide range of oral bioavailability of alkyl carboxylic acid structures was screened in various oils, and it was observed that they were not equally effective in providing high oral bioavailability. Indeed, the propionate ion ligand (and related lactate ion ligand-an OH substituted H propionate ion ligand, and possibly other ligands based on propionate ion ligands) provides much better bioavailability than any other carboxylate ion ligand; such as a shorter chain of carbon atoms, acetate ion, or longer chain carboxylate ion ligand, such as butyrate ion or octanoate ion. Secondly, there is a unique class of axial ligands derived from phenylacetic acid; i.e., phenyl acetate ion ligands. These derivatives are shown in FIG. 10. All complexes derived from the phenylacetate ionic ligand are greatly enhanced in bioavailability compared to the parent dichloro complex or to other alkylcarboxylate ionic complexes, including complexes derived from acetate ions or other higher molecular weight carboxylate ionic ligands. Thirdly, one of these derivatives is based on the amino acid phenylglycine. The rac-phenylglycinate ion ligand enhanced the bioavailability of all the various pentaazamacrocycles tested, suggesting that this is not only an isolated role of the parent manganese pentaazacyclics of GC4419, but is also common to this family of mn (ii) complexes. Furthermore, the L-phenylglycinate ion derivative GC4702 of GC4419 is actually absorbed more readily than other amino acid ligands (such as L-phenylalanine ion or L-valine ion complexes) or rac-phenylglycinate ion complex GC 4720. Furthermore, such bioavailability enhancing properties may be limited to phenylglycinate ion ligand derivatives (again derivatives of phenylacetic acid), as exemplified by the poor bioavailability of complexes derived from L-phenylalanine homologues or L-valine homologues, although other amino acid ligands, in particular L-alanine homologues belonging to the above mentioned propionate ion-based ligand class, may also provide good bioavailability.

Reference to the literature

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2.Salvemini，D.，Wang，Z-Q.，Zweier，J.L.，Samouilov，A.，Macarthur，H.，Misko，T.P.，Currue，M.G.，Cuzzocrea，S.，Sikorski，J.A.，Riley，D.P.，“A Nonpeptidy/Mimic of Superoxide Dismutase with Therapeutic Activity in Rats”，Science，286，Oct.8，304-6(1999).

3.U.S.Patent No.8,263,568

4.U.S.Patent No.8,444,856

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

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Pentaazamacrocycle complexes with oral bioavailability

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