Pentaaza macrocyclic ring complexes possessing oral bioavailability
Aspects of the present disclosure relate to compounds which have enhanced oral bioavailability. A transition metal complex includes a transition metal coordinated by a macrocycle comprising the pentaaza 15-membered macrocyclic ring corresponding to Formula A and two axial ligands having the formula —OC(O)X 1 . each of the two axial ligands has the formula —OC(═O)X 1 wherein each X 1 is independently substituted or unsubstituted phenyl or —C(—X 2 )(—X 3 )(—X 4 ); each X 2 is independently substituted or unsubstituted phenyl, or substituted or unsubstituted alkyl; each X 3 is independently hydrogen, hydroxyl, alkyl, amino, —X 5 C(═O)R 13 where X 5 is NH or O, and R 13 is C 1 -C 18 alkyl, substituted or unsubstituted aryl or C 1 -C 18 aralkyl, or —OR 14 , where R 14 is C 1 -C 18 alkyl, substituted or unsubstituted aryl or C 1 -C 18 aralkyl, or together with X 4 is (═O); and each X 4 is independently hydrogen or together with X 3 is (═O).
1. A pentaaza macrocyclic ring complex of Formula (IB):
wherein
M is Mn +2 , or Mn +3 ;
R 1A , R 1B , R 2 , R 3 , R 4A , R 4B , R 5 , R 6 , R 7A , R 7B , R 8 , R 9 , R 10A , and R 10B are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or a moiety independently selected from the group consisting of —OR 11 , —NR 11 R 12 , —COR 11 , —CO 2 R 11 , —C(═O)NR 11 R 1 2 , —SR 11 , —SOR 11 , —SO 2 R 11 , —SO 2 NR 11 R 12 , —N(OR 11 )(R 12 ), —P(═O)(OR 11 )(OR 12 ), —P(═O)(O R 11 )(R 12 ), and —OP(═O)(OR 11 )(OR 12 ),
wherein R 11 and R 12 are independently hydrogen or alkyl;
W 1 , W 2 , and W 3 are independently halo, hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, acyl, acyloxy, alkoxy, an ether, a thioether, or nitro;
each —OC(═O)X 1 is propionato; and
the bonds between the transition metal M and the macrocyclic nitrogen atoms and the bonds between the transition metal M and the oxygen atoms of the axial ligands —OC(═O)X 1 are coordinate covalent bonds.
2. The pentaaza macrocyclic ring complex of claim 1 , wherein the pentaaza macrocyclic ring complex corresponds to Formulae (IC R ) or (IC S ):
wherein
M is Mn +2 , or Mn +3 ;
R 1A , R 1B , R 2 , R 3 , R 4A , R 4B , R 5 , R 6 , R 7A , R 7B , R 8 , R 9 , R 10A , and R 10B are independently hydrogen or substituted or unsubstituted alkyl;
W 1 , W 2 , and W 3 are independently halo or hydrogen;
each —OC(═O)X 1 is propionato, and
the bonds between the transition metal M and the macrocyclic nitrogen atoms and the bonds between the transition metal M and the oxygen atoms of the axial ligands —OC(═O)X 1 are coordinate covalent bonds.
3. The pentaaza macrocyclic ring complex of claim 1 , wherein the pentaaza macrocyclic ring complex corresponds to Formulae (ID R ) or (ID S ):
wherein
M is Mn +2 or Mn +3 ;
R 1A , R 1B , R 2 , R 3 , R 4A , R 4B , R 5 , R 6 , R 7A , R 7B , R 8 , R 9 , R 10A , and R 10B are independently hydrogen, methyl, ethyl, or propyl;
W 1 , W 2 , and W 3 are independently halo or hydrogen;
each —OC(═O)X 1 is propionato, and
the bonds between the manganese and the macrocyclic nitrogen atoms and the bonds between the manganese and the oxygen atoms of the axial ligands —OC(═O)X 1 are coordinate covalent bonds.
4. The pentaaza macrocyclic ring complex of claim 1 , wherein the pentaaza macrocyclic ring complex corresponds to Formulae (IE R1 ), (IE S1 ), (IE R2 ), (IE S2 ), (IE R3 ), or (IE S3 ):
wherein
Mn is Mn +2 or Mn +3 ;
each —OC(═O)X 1 is propionato, and
the bonds between the manganese and the macrocyclic nitrogen atoms and the bonds between the manganese and the oxygen atoms of the axial ligands —OC(═O)X 1 are coordinate covalent bonds.
5. A pharmaceutical composition comprising a pentaaza macrocyclic ring complex of claim 1 and a pharmaceutically acceptable excipient suitable for administration.
6. The pharmaceutical composition of claim 5 wherein the pharmaceutical composition is suitable for oral administration to a human subject.
7. The pharmaceutical composition of claim 5 , comprising at least one of a lipophilic surfactant and an oil.
8. The pharmaceutical composition of claim 7 , wherein the at least one of the lipophilic surfactant and the oil comprises at least one of mono- and/or diglycerides of fatty acids, acetic, succinic, lactic, citric and/or tartaric esters 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 glycerol esters of fatty acids, sorbitan esters of fatty acids, transesterification products of natural or hydrogenated vegetable oil triglyceride and a polyalkylene polyol, alcohol ethyoxylates, and polyoxyethylene-polyoxypropylene co-copolymers.
9. The pharmaceutical composition of claim 8 , wherein the at least one of the lipophilic surfactant and the oil comprises at least one of a mixture of mono/diglycerides of caprylic/capric acids, a mixture of caprylic/capric acid triglycerides, linoleoyl polyoxyl-6 glycerides (NF), oleoyl polyoxyl-6 glycerides (NF), glyceryl mono-oleate (NF), monoglyceride glyceryl monolinoleate (NF), and caprylocaproyl polyoxyl-8 glycerides (NF).
10. The pharmaceutical composition of claim 8 , wherein the at least one of the lipophilic surfactant and the oil is linoleoyl polyoxyl-6(NF) glycerides.
11. The pharmaceutical composition of claim 5 wherein the pharmaceutical composition is in a solid or semi-solid dosage form.
12. The pharmaceutical composition of claim 5 wherein the pharmaceutical composition is in the form of one or more of a tablet, gelatin capsule, HPMC capsule, gel or suspension suitable for oral administration.
13. The pharmaceutical composition of claim 5 wherein the pharmaceutical composition comprises an enteric coating layer.
14. The pharmaceutical composition of claim 5 , wherein the pharmaceutical composition is in the form of a hydroxypropyl methylcellose HPMC capsule suitable for oral administration to a human subject.
15. The pharmaceutical composition of claim 5 , comprising a pharmaceutically acceptable excipient comprising linoleoyl polyoxy-6 glycerides (NF), and an enteric coated capsule comprising hydroxypropylmethylcellulose (HPMC), the capsule comprising the pentaaza macrocyclic ring complex and pharmaceutically acceptable excipient therein.