Porphyrin catalysts and methods of use thereof
This invention provides a novel class of substituted macrocyclic porphyrin compounds. The compounds are useful as peroxynitrite decomposition catalysts. Pharmaceutical compositions, and methods of making and using the compounds, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof are also described.
1. A compound having the Formula I:
or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, or stereoisomer, or mixtures thereof, wherein
at least one of R 1 , R 2 , R 3 , and R 4 is independently selected from the group consisting of CH 2 C(O)NR 5 R 6 and (CH 2 CH 2 O) t CH 3 , wherein t is 1, 2, 4, 5, 6, 7, 8, 9, or 10, and the remaining R 1 , R 2 , R 3 , and R 4 are hydrogen;
R 5 and R 6 are selected from the group consisting of
H,
CH 2 CH 2 OCH 3 ,
CH 2 CH 2 OCH 2 CH 2 OCH 3 ,
CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 3 ,
CH 2 COO − ,
(CH 2 ) n —X,
(CH 2 ) n —Y,
(CH 2 ) n R 9 —X,
(CH 2 ) n R 9 —Y,
CH 2 CO 2 CH 2 CH 3 ,
(OCH 2 CH 2 ) m —X,
(OCH 2 CH 2 ) m —Y,
Y 2 —X,
Y 2 C(Z 1 ) 3 ,
further wherein: Z 1 is CH 2 OCH 2 (CH 2 ) n X or CH 2 OCH 2 (CH 2 ) n Y;
(CH 2 ) n C(O)Y 2 C(Z 2 ) 3 ,
wherein: Z 2 is CH 2 OCH 2 CH 2 C(O)Y 2 C(Z 4 ) 3 and Z 4 is CH 2 OCH 2 CH 2 X;
(CH 2 ) n C(O)—Y 2 —C(Z 5 ) 3 ,
wherein: Z 5 is CH 2 OCH 2 CH 2 C(O)Y 2 C(Z 6 ) 3 and Z 6 is CH 2 OCH 2 CH 2 C(O)O(CH 2 CH 2 O) m CH 2 CH 2 O − ;
(CH 2 ) n OCH 2 C(CH 2 OH) 3 ,
(CH 2 ) n OCH 2 CH(CH 2 OH) 2 ,
(CH 2 ) n OCH 2 C(CH 2 OH) 2 (CH 3 ),
(CH 2 ) n OCH 2 C[CH 2 OCH 2 C(CH 2 OH) 3 ] 3 ,
(CH 2 ) n OCH 2 C[CH 2 OCH 2 C(CH 2 O[CH 2 CH 2 O] m CH 2 CH 2 OX) 3 ] 3 ,
CH 2 CONH—Y,
CH 2 CO—Y,
CH 2 CO(CH 2 ) p —Y;
alkyl,
cycloalkyl, and
aralkyl;
wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; m is an integer from 1 to 200, and p is 1 or 2;
X is COOH, COOR′, CONH 2 , CONHR′, CONR′ 2 , CO(CH 2 ) p R′, OPO 3 H 2 , PO 3 H 2 , SO 3 H, NH 2 , NR′ 2 , or NR′ 3 + , a steroid, an amino acid, an oligosaccharide, a peptide, or a polycarboxylic acid, further wherein R′ is alkyl, CH 2 CH 2 OCH 3 , CH 2 CH 2 OCH 2 CH 2 OCH 3 , (CH 2 ) n —X, (CH 2 ) n —Y, (CH 2 ) n Ar—X, (CH 2 ) n Ar—Y,
CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 3 , CH 2 CO 2 CH 2 CH 3 , (OCH 2 CH 2 ) m —X, (OCH 2 CH 2 ) m —Y, Y 2 —X, Y 2 C(Z 1 ) 3 , further wherein: Z 1 is CH 2 OCH 2 (CH 2 ) n X or CH 2 OCH 2 (CH 2 ) n Y; (CH 2 ) n C(O)Y 2 C(Z 2 ) 3 , wherein: Z 2 is CH 2 OCH 2 CH 2 C(O)Y 2 C(Z 4 ) 3 and Z 4 is CH 2 OCH 2 CH 2 X; (CH 2 ) n C(O)—Y 2 —C(Z 5 ) 3 , wherein: Z 5 is CH 2 OCH 2 CH 2 C(O)Y 2 C(Z 6 ) 3 and Z 6 is CH 2 OCH 2 CH 2 C(O)O(CH 2 CH 2 O) m CH 2 CH 2 O − ; (CH 2 ) n OCH 2 C(CH 2 OH) 3 , (CH 2 ) n OCH 2 CH(CH 2 OH) 2 , (CH 2 ) n OCH 2 C(CH 2 OH) 2 (CH 3 ),
(CH 2 ) n OCH 2 C[CH 2 OCH 2 C(CH 2 OH) 3 ] 3 ,
(CH 2 ) n OCH 2 C[CH 2 OCH 2 C(CH 2 O[CH 2 CH 2 O] m CH 2 CH 2 OX) 3 ] 3 , CH 2 CONH—Y, CH 2 CO—Y, and CH 2 CO(CH 2 ) p —Y;
Y is OH or (OCH 2 CH 2 ) m —W 1 or (CH 2 CH 2 ) m —W 2 ; where W 1 is OH, or (OCH 2 CH 2 ) m OH and W 2 is OR″, further wherein R″ is an alkyl group;
Y 2 is selected from the group consisting of (CH 2 ) n O, (CH 2 ) n NH, and (CH 2 ) n S, CH 2 CONH, CH 2 COO, or CH 2 CO(CH 2 ) p ;
R 9 is substituted phenyl, unsubstituted phenyl, substituted napthyl, or unsubstituted naphthyl;
L 1 and L 2 are, independently, absent, halide, oxo, OH 2 , hydroxo, CN, OPO 3 H or alcohol; and M is absent, Mn or Fe;
provided that R 5 and R 6 are not both alkyl.
2. The compound of claim 1 , wherein R 1 , R 2 , R 3 , and R 4 are each CH 2 C(O)NR 5 R 6 .
3. The compound of claim 1 , wherein one of R 5 or R 6 is H.
4. The compound of claim 1 , wherein one of R 5 or R 6 is selected from aralkyl, alkyl, cycloalkyl, substituted cycloalkyl, and CH 2 CH 2 OCH 3 .
5. The compound of claim 4 , wherein aralkyl is (CR 7 R 8 ) s —R 9 , wherein R 7 and R 8 are, independently, selected from H, alkyl, OH, and halogen, and s is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
6. The compound of claim 5 , wherein aralkyl is
7. The compound of claim 4 , wherein one of R 5 or R 6 is selected from alkyl, cycloalkyl, or substituted cycloalkyl.
8. The compound of claim 7 , wherein cycloalkyl or substituted cycloalkyl is a bicyclic ring system.
9. The compound of claim 8 , wherein the bicyclic ring system is bicycle[2.2.1]heptane.
10. The compound of claim 8 , wherein the bicyclic ring system is 1,7,7-trimethylbicyclo[2.2.1]heptane.
11. The compound of claim 4 , wherein one of R 5 or R 6 is CH 2 CH 2 OCH 3 .
12. The compound of claim 1 , wherein R 1 , R 2 , R 3 , and R 4 are (CH 2 CH 2 O) t CH 3 .
13. The compound of claim 1 , wherein t=1.
14. The compound of claim 1 , wherein the compound is an ααββ atropisomer.
15. The compound of claim 1 , wherein the compound is selected from
wherein L 1 and L 2 are, independently, absent, halide, oxo, OH 2 , hydroxo, CN, OPO 3 H or alcohol; and M is absent, Mn or Fe.
16. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
17. A method of lowering peroxynitrite levels in a cell or tissue, the method comprising contacting said cell or tissue with a compound of Formula I in an amount sufficient to lower peroxynitrite levels in said cell or tissue:
or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, or stereoisomer, or mixtures thereof, wherein
at least one of R 1 , R 2 , R 3 , and R 4 is independently selected from the group consisting of CH 2 C(O)NR 5 R 6 and (CH 2 CH 2 O) t CH 3 , wherein t is 1, 2, 4, 5, 6, 7, 8, 9, or 10, and the remaining R 1 , R 2 , R 3 , and R 4 are hydrogen;
R 5 and R 6 are selected from the group consisting of
H,
CH 2 CH 2 OCH 3 ,
CH 2 CH 2 OCH 2 CH 2 OCH 3 ,
CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 3 ,
CH 2 COO − ,
(CH 2 ) n —X,
(CH 2 ) n —Y,
(CH 2 ) n R 9 —X,
(CH 2 ) n R 9 —Y,
CH 2 CO 2 CH 2 CH 3 ,
(OCH 2 CH 2 ) m —X,
(OCH 2 CH 2 ) m —Y,
Y 2 —X,
Y 2 C(Z 1 ) 3 ,
further wherein: Z 1 is CH 2 OCH 2 (CH 2 ) n X or CH 2 OCH 2 (CH 2 ) n Y; (CH 2 ) n C(O)Y 2 C(Z 2 ) 3 ,
wherein: Z 2 is CH 2 OCH 2 CH 2 C(O)Y 2 C(Z 4 ) 3 and Z 4 is CH 2 OCH 2 CH 2 X; (CH 2 ) n C(O)—Y 2 —C(Z 5 ) 3 ,
wherein: Z 5 is CH 2 OCH 2 CH 2 C(O)Y 2 C(Z 6 ) 3 and Z 6 is CH 2 OCH 2 CH 2 C(O)O(CH 2 CH 2 O) m CH 2 CH 2 O − ;
(CH 2 ) n OCH 2 C(CH 2 OH) 3 ,
(CH 2 ) n OCH 2 CH(CH 2 OH) 2 ,
(CH 2 ) n OCH 2 C(CH 2 OH) 2 (CH 3 ),
(CH 2 ) n OCH 2 C[CH 2 OCH 2 C(CH 2 OH) 3 ] 3 ,
(CH 2 ) n OCH 2 C[CH 2 OCH 2 C(CH 2 O[CH 2 CH 2 O] m CH 2 CH 2 OX) 3 ] 3 ,
CH 2 CONH—Y,
CH 2 CO—Y,
CH 2 CO(CH 2 ) p —Y;
alkyl,
cycloalkyl, and
aralkyl;
wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; m is an integer from 1 to 200, and p is 1 or 2;
X is COOH, COOR′, CONH 2 , CONHR′, CONR′ 2 , CO(CH 2 ) p R′, OPO 3 H 2 , PO 3 H 2 , SO 3 H, NH 2 , NR′ 2 , or NR′ 3 + , a steroid, an amino acid, an oligosaccharide, a peptide, or a polycarboxylic acid, further wherein R′ is alkyl, CH 2 CH 2 OCH 3 , CH 2 CH 2 OCH 2 CH 2 OCH 3 , (CH 2 ) n —X, (CH 2 ) n —Y, (CH 2 ) n Ar—X, (CH 2 ) n Ar—Y,
CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 3 , CH 2 CO 2 CH 2 CH 3 , (OCH 2 CH 2 ) m —X, (OCH 2 CH 2 ) m —Y, Y 2 —X, Y 2 C(Z 1 ) 3 , further wherein: Z 1 is CH 2 OCH 2 (CH 2 ) n X or CH 2 OCH 2 (CH 2 ) n Y; (CH 2 ) n C(O)Y 2 C(Z 2 ) 3 , wherein: Z 2 is CH 2 OCH 2 CH 2 C(O)Y 2 C(Z 4 ) 3 and Z 4 is CH 2 OCH 2 CH 2 X; (CH 2 ) n C(O)—Y 2 —C(Z 5 ) 3 , wherein: Z 5 is CH 2 OCH 2 CH 2 C(O)Y 2 C(Z 6 ) 3 and Z 6 is CH 2 OCH 2 CH 2 C(O)O(CH 2 CH 2 O) m CH 2 CH 2 O − ; (CH 2 ) n OCH 2 C(CH 2 OH) 3 , (CH 2 ) n OCH 2 CH(CH 2 OH) 2 , (CH 2 ) n OCH 2 C(CH 2 OH) 2 (CH 3 ), (CH 2 ) n OCH 2 C[CH 2 OCH 2 C(CH 2 OH) 3 ] 3 , (CH 2 ) n OCH 2 C[CH 2 OCH 2 C(CH 2 O[CH 2 CH 2 O] m CH 2 CH 2 OX) 3 ] 3 , CH 2 CONH—Y, CH 2 CO—Y, and CH 2 CO(CH 2 ) p —Y;
Y is OH or (OCH 2 CH 2 ) m —W 1 or (CH 2 CH 2 ) m —W 2 ; where W 1 is OH, or (OCH 2 CH 2 ) m OH and W 2 is OR″, further wherein R″ is an alkyl group;
Y 2 is selected from the group consisting of (CH 2 ) n O, (CH 2 ) n NH, and (CH 2 ) n S, CH 2 CONH, CH 2 COO, or CH 2 CO(CH 2 ) p ;
R 9 is substituted phenyl, unsubstituted phenyl, substituted napthyl, or unsubstituted naphthyl;
L 1 and L 2 are, independently, absent, halide, oxo, OH 2 , hydroxo, CN, OPO 3 H or alcohol; and M is absent, Mn or Fe;
provided that R 5 and R 6 are not both alkyl.