Super-oxide dismutase mimetics
The present invention relates to compounds which are effective as catalysts for dismutating superoxide and, more particularly, the manganese or iron complexes of substituted, unsaturated heterocyclic 16-membered macrocyclic complexes that catalytically dismutate superoxide. It also relates to methods of using these complexes to reduce the concentration or the effects of superoxide, pharmaceutical compositions comprising these compounds or their metal complexes, and methods of treating conditions associated with excessive superoxide activity.
1. A method to treat a condition associated with excessive superoxide activity wherein the condition comprises radiation-induced injury, the method comprising administering to a patient in need of such treatment the compound of formula (1):
wherein:
each R 1 is independently C1-C10 alkyl, C6-C10 aryl, C5-C10 heteroaryl, or (C6-C10 aryl)-(C1-C4 alkyl), or (C5-C10 heteroaryl)-(C1-C4 alkyl), each of which can be substituted with one or more groups selected from halo, ═O, OR, S(O) t R, NR 2 , COOR, CONR 2 , wherein t can be 0-2 and each R independently represents H, C1-C4 alkyl, and wherein two R groups on one N can cyclize to form a saturated azacyclic group;
each R 2 is independently C1-C10 alkyl, C6-C10 aryl, C5-C10 heteroaryl, or (C6-C10 aryl)-(C1-C4 alkyl), or (C5-C10 heteroaryl)-(C1-C4 alkyl), each of which can be substituted with one or more groups selected from halo, OR, S(O) t R, NR 2 , COOR, CONR 2 , wherein t can be 0-2 and each R independently represents H, C1-C4 alkyl, and wherein two R groups on one N can cyclize to form a saturated azacyclic group;
each R 3 is H or a protecting group;
wherein any two R 1 on a single carbon can cyclize to form a ring having 3-8 ring atoms, which ring can be substituted, and which can contain a heteroatom selected from N, O and S as a ring member;
and any two R 1 on adjacent carbon atoms, and any two R 2 groups on adjacent carbon atoms, can cyclize to form a ring having 3-8 ring atoms, which ring can be substituted and can be aromatic or non-aromatic, and can contain a heteroatom selected from N, O and S as a ring member;
and any two of R 1 and R 2 on carbon atoms separated by a single nitrogen atom can cyclize to form a ring having 3-8 atoms, which ring can be substituted and can be aromatic or non-aromatic, and can contain, in addition to the N between the carbon atoms to which linked groups are attached, an additional heteroatom selected from N, O and S as a ring member;
each m is independently 0 or 1;
each n and p is independently 0-2;
L represents a three-atom linker corresponding to —C(R 1 ) p —NR 3 —C(R 1 ) p — or an optionally substituted pyridine-2,6-diyl group; and
M represents H or a metal cation;
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein M is a metal cation.
3. The method of claim 2 , wherein the metal cation is Mn (III) or Mn(II).
4. The method of claim 1 , wherein each p is 0.
5. The method of claim 1 , wherein n is 1 for position 6 and position 7, or wherein n is 1 for position 15 and position 16.
6. The method of claim 5 , wherein n is 1 for positions 6 and 7, and wherein R 1 groups at positions 6 and 7 cyclize to form a 5-8 membered optionally substituted ring.
7. The method of claim 6 , wherein n is 1 for positions 15 and 16, and wherein R 1 groups at positions 15 and 16 cyclize to form a 5-8 membered optionally substituted ring.
8. The method of claim 7 , wherein M represents Mn(III).
9. The method of claim 1 , wherein two R 1 groups on adjacent carbon atoms are in a trans orientation relative to each other on the 16-membered ring of formula (1).
10. The method of claim 9 , wherein two R 1 groups at positions 6 and 7 are in a trans orientation relative to each other on the 16-membered ring of formula (1), and wherein two R 1 groups at positions 15 and 16 are also in a trans orientation relative to each other on the 16-membered ring of formula (1).
11. The method of claim 10 , wherein two R 1 groups at positions 6 and 7 cyclize to form a cyclohexane or cyclopentane ring.
12. The method of claim 11 , wherein two R 1 groups at positions 15 and 16 cyclize to form a cyclohexane or cyclopentane ring.
13. The method of claim 2 , wherein each n is 1, and each p is 0.
14. The method of claim 1 , wherein the compound of formula (1) has the structure of formulae (2a) or (2b):
wherein:
each R 1 is independently C1-C10 alkyl, C6-C10 aryl, C5-C10 heteroaryl, or (C6-C10 aryl)-(C1-C4 alkyl), or (C5-C10 heteroaryl)-(C1-C4 alkyl), each of which can be substituted with one or more groups selected from halo, ═O, OR, S(O) t R, NR 2 , COOR, CONR 2 , wherein t can be 0-2 and each R independently represents H, C1-C4 alkyl, and wherein two R groups on one N can cyclize to form a saturated azacyclic group;
each R 2 is independently C1-C10 alkyl, C6-C10 aryl, C5-C10 heteroaryl, or (C6-C10 aryl)-(C1-C4 alkyl), or (C5-C10 heteroaryl)-(C1-C4 alkyl), each of which can be substituted with one or more groups selected from halo, OR, S(O) t R, NR 2 , COOR, CONR 2 , wherein t can be 0-2 and each R independently represents H, C1-C4 alkyl, and wherein two R groups on one N can cyclize to form a saturated azacyclic group;
R 4 represents one or two optional substituents which may be present at any position(s) on the pyridine ring;
wherein any two R 1 on a single carbon can cyclize to form a ring having 3-8 ring atoms, which ring can be substituted, and which can contain a heteroatom selected from N, O and S as a ring member;
and any two R 1 on adjacent carbon atoms, and any two R 2 groups on adjacent carbon atoms, can cyclize to form a ring having 3-8 ring atoms, which ring can be substituted and can be aromatic or non-aromatic, and can contain a heteroatom selected from N, O and S as a ring member;
and any two of R 1 and R 2 on carbon atoms separated by a single nitrogen atom can cyclize to form a ring having 3-8 atoms, which ring can be substituted and can be aromatic or non-aromatic, and can contain, in addition to the N between the carbon atoms to which linked groups are attached, an additional heteroatom selected from N, O and S as a ring member;
each m is independently 0 or 1;
each n and p is independently 0-2; and
M represents H or a metal cation;
or a pharmaceutically acceptable salt thereof.
15. The method of claim 14 , wherein each p is 0.
16. The method of claim 15 , wherein two R 1 groups are in a trans orientation relative to each other on the 16-membered ring of formula (1), and wherein said two R 1 groups cyclize to form a five or six membered ring.
17. The method of claim 16 , wherein M is Mn(III).
18. The method of claim 1 , wherein the compound of formula (1) has the structure of formula (3):
wherein:
each R 1 is independently C1-C10 alkyl, C6-C10 aryl, C5-C10 heteroaryl, or (C6-C10 aryl)-(C1-C4 alkyl), or (C5-C10 heteroaryl)-(C1-C4 alkyl), each of which can be substituted with one or more groups selected from halo, ═O, OR, S(O) t R, NR 2 , COOR, CONR 2 , wherein t can be 0-2 and each R independently represents H, C1-C4 alkyl, and wherein two R groups on one N can cyclize to form a saturated azacyclic group;
each R 2 is independently C1-C10 alkyl, C6-C10 aryl, C5-C10 heteroaryl, or (C6-C10 aryl)-(C1-C4 alkyl), or (C5-C10 heteroaryl)-(C1-C4 alkyl), each of which can be substituted with one or more groups selected from halo, OR, S(O) t R, NR 2 , COOR, CONR 2 , wherein t can be 0-2 and each R independently represents H, C1-C4 alkyl, and wherein two R groups on one N can cyclize to form a saturated azacyclic group;
each R 3 is H or a protecting group;
each R 1a is an optionally substituted alkyl group and wherein two R 1a groups on adjacent carbon atoms can link to form a ring;
wherein any two R 1 on a single carbon can cyclize to form a ring having 3-8 ring atoms, which ring can be substituted, and which can contain a heteroatom selected from N, O and S as a ring member;
and any two R 1 on adjacent carbon atoms, and any two R 2 groups on adjacent carbon atoms, can cyclize to form a ring having 3-8 ring atoms, which ring can be substituted and can be aromatic or non-aromatic, and can contain a heteroatom selected from N, O and S as a ring member;
and any two of R 1 and R 2 on carbon atoms separated by a single nitrogen atom can cyclize to form a ring having 3-8 atoms, which ring can be substituted and can be aromatic or non-aromatic, and can contain, in addition to the N between the carbon atoms to which linked groups are attached, an additional heteroatom selected from N, O and S as a ring member;
each m is independently 0 or 1;
each n and p is independently 0-2;
L represents a three-atom linker corresponding to —C(R 1 ) p —NR 3 —C(R 1 ) p — or an optionally substituted pyridine-2,6-diyl group; and
M represents H or a metal cation;
or a pharmaceutically acceptable salt thereof.
19. The method of claim 18 , wherein M is H.
20. The method of claim 19 , wherein each R 3 is H.
21. The method of claim 1 , wherein the compound of formula (1) has a structure selected from the group consisting of: