Chlorins possessing fused ring systems useful as photoselective compounds for photodynamic therapy
The present invention provides a process of preparation of naphthochlorins and other chlorins with annelated ring systems useful for photodynamic therapy and the compounds themselves. The method for producing naphthochlorin compounds include contacting compounds such as meso-(2′-hydroxymethyl)phenyl porphyrin or meso-(2′-N,N,N-trialkylaminomethyl)phenyl porphyrin precursors with at least one acid catalyst at sufficient temperature for a sufficient time to yield the desired conversion. In a similar manner chlorins possessing annelated ring systems may be made from compounds such as meso-(2′-hydroxymethyl)aryl porphyrins or meso-(2′-N,N,N-trialkylaminomethyl)phenyl porphyrin. The procedures described herein provide new routes for synthesizing naphthochlorins and chlorins with annelated ring systems.
1. A compound of formula IC:
wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 12 , R 13 , R 14 , R 15 , and R 16 are independently selected from hydrogen, a halogen; unsubstituted or substituted alkyl, C 3 -C 6 cycloalkyl, acetyl, aryl, alkenyl, alkynyl, amide groups, or ester groups; NR 17 R 18 ; vinyl; N(R 17 )(R 18 )(R 19 ) + Z − ; CH═CHNR 17 R 18 ; CH 2 CH 2 NR 17 R 18 ; CH═CHN(R 17 )(R 18 )(R 19 ) + Z − ; CH 2 CH 2 N(R 17 )(R 18 )(R 19 ) + Z − ; CHOHCH 3 ; CHOR 17 CH 3 ; CN; OH; OR 17 ; CHO; CH═CHCO 2 R 17 ; (CH 2 ) n OH; (CH 2 ) n SH; (CH 2 ) n O-alkoxy; (CH 2 ) n SR 17 ; (CH 2 ) n OR 17 ; (CH 2 ) n CO 2 R 17 ; (CH 2 ) n CONHR 17 ; (CH 2 ) n CON(R 17 )(R 18 ); CO 2 R 17 ; CONHR 17 ; CONR 17 R 18 ; SR 17 ; SO 3 H; SO 3 R 17 ; SO 2 NHR 17 ; SO 2 N(R 17 )(R 18 ); and SO 2 N(R 17 )(R 18 )(R 19 ) + Z − ;
R 15 may be additionally selected from a cycloalkyl, aromatic, or hetereoaromatic fused ring system;
R 17 , R 18 , and R 19 are independently selected from hydrogen, a physiologically acceptable salt; and unsubstituted or substituted C 1 -C 6 alkyl, aryl, alkenyl, or alkynyl;
Z − is a pharmaceutically acceptable ion;
R 7 , R 8 , R 9 , R 10 , and R 11 are independently selected from hydrogen, an unsubstituted or substituted alkyl or aryl;
n is an integer ranging from 1 to 4;
M is two hydrogens or a metal ion selected from Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Eu, Fe, Gd, Hf, Ho, In, La, Lu, Mg, Mn, Mo, Nd, Ni, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, TI, Tm, U, V, Y, Yb, Zn, and Zr;
provided that when R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 10 , R 11 , R 12 , and R 13 are hydrogen, and R 9 is selected from the group consisting of hydrogen and OCH 3 , and M is Ni, and R 7 is selected from the group consisting of CH 3 , CO 2 tBu, CO 2 Et, CO 2 iPr, and CO 2 Bu, then R 14 , R 15 , and R 16 cannot simultaneously be C 6 H 4 X where X is selected from the group consisting of hydrogen and OCH 3 .
2. The compound according to claim 1 wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 12 , and R 13 are independently selected from hydrogen, methyl, ethyl, (CH 2 ) n OH, (CH 2 ) n O-alkoxy, (CH 2 ) n OR 17 , (CH 2 ) n CO 2 R 17 , (CH 2 ) n CONHR 17 , and (CH 2 ) n CON(R 17 )(R 18 );
R 7 , R 8 , R 9 , R 10 , and R 11 are independently selected from hydrogen, SO 3 H, SO 3 R 17 , SO 2 NHR 17 , SO 2 N(R 17 )(R 18 ), and SO 2 N(R 17 (R 18 )(R 19 ) + Z − ;
R 14 , R 15 , and R 16 are hydrogen; and
M is selected from two hydrogens and a metal ion selected from In, Pd, Pt, Sn, Zn, Ga, Al, and Mg.
3. A compound of formula ID:
wherein:
R 1 , R 4 , R 5 , R 6 , R 12 , and R 13 are independently selected from methyl and ethyl;
R 7 , R 8 , R 9 , R 10 , and R 11 are hydrogen,
R 2 and R 3 are selected from methyl, ethyl, (CH 2 ) 2 OH, (CH 2 ) 2 OMe, (CH 2 ) 3 OH, (CH 2 ) 2 CO 2 Me, (CH 2 ) 2 CO 2 Na, (CH 2 ) 2 CO 2 K (CH 2 ) 2 CONHR 17 , (CH 2 ) 2 CON(R 17 )(R 18 ), (CH 2 ) 3 OH, (CH 2 ) 3 OMe, CH 2 CO 2 Me, CH 2 CO 2 Na, and CH 2 CO 2 K;
where R 17 and R 18 are independently selected from CH 3 , CH 2 CH 3 , CH 2 OCH 2 OH, CH 2 CH 2 N(CH 3 ) 2 , and CH 2 CH 2 (N (CH 3 ) 3 + )S − , where S − is a physiologically acceptable ion; and
M is selected from two hydrogens and a metal ion selected from In, Pd, Pt, Sn, Zn, Ga, Al, and Mg.
4. A compound of formula IE:
wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 12 , R 13 , R 14 , R 15 , and R 16 are independently selected from hydrogen, a halogen; unsubstituted or substituted alkyl, C 3 -C 6 cycloalkyl, acetyl, aryl, alkenyl, alkynyl, amide groups, or ester groups; NR 17 R 18 ; vinyl; N(R 17 )(R 18 )(R 19 ) + Z − ; CH═CHNR 17 R 18 ; CH 2 CH 2 NR 17 R 18 ; CH═CHN(R 17 )(R 18 )(R 19 )+Z−; CH 2 CH 2 N(R 17 )(R 18 )(R 19 ) + Z − CHOHCH 3 ; CHOR 17 CH 3 ; CN; OH; OR 17 ; CHO; CH═CHCO 2 R 17 ; (CH 2 ) n OH; (CH 2 ) n SH; (CH 2 ) n O-alkoxy; (CH 2 ) n SR 17 ; (CH 2 ) n OR 17 ; (CH 2 ) n CO 2 R 17 ; (CH 2 ) n CONHR 17 ; (CH 2 )CON(R 17 )(R 18 ); CO 2 R 17 ; CONHR 17 ; CONR 17 R 18 ; SR 17 ; SO 3 H; SO 3 R 17 ; SO 2 NHR 17; SO 2 N(R 17 )(R 18 ); and SO 2 N(R 17 )(R 18 )(R 19 ) + Z − ;
R 15 may be additionally selected from a cycloalkyl, aromatic, or hetereoaromatic fused ring system;
R 17 , R 18 , and R 19 are independently selected from hydrogen, a physiologically acceptable salt; and unsubstituted or substituted C 1 -C 6 alkyl, aryl, alkenyl, or alkynyl;
Z − is a pharmaceutically acceptable ion;
R 7 , R 8 , R 9 , R 10 , and R 11 are independently selected from hydrogen, an unsubstituted or substituted alkyl or aryl;
n is an integer ranging from 1 to 4;
M is two hydrogens or a metal ion selected from Ag, Al, Ce, Co, Cr, Cu, Dy, Er, Eu, Fe, Gd, Hf, Ho, In, La, Lu, Mg, Mn, Mo, Nd, Ni, Pb, Pd, Pr, Pt, Rh, Sb, Sc, Sm, Sn, Tb, Th, Ti, TI, Tm, U, V, Y, Yb, Zn, and Zr;
A, B, C, D, and E are independently selected from carbon, nitrogen, sulfur, oxygen, N+(R 20 ) Z ′− , Se+, and Te+; where R 20 is a functional group having a molecular weight of less than about 100,000 daltons and Z ′ is a charge balancing ion;
provided that when R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 10 , R 11 , R 12 , and R 13 are hydrogen, and R 9 is selected from the group consisting of hydrogen and OCH 3 , and A, B, C, D, and E are carbon, and M is Ni, and R 7 is selected from the group consisting of CH 3 , CO 2 tBu, CO 2 Et, CO 2 iPr, and CO 2 Bu, then R 14 , R 15 , and R 16 cannot simultaneously be C 6 H 4 X where X is selected from the group consisting of hydrogen and OCH 3 .
5. The compound of claim 4 wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 12 , and R 13 are independently selected from hydrogen, methyl, ethyl, (CH 2 ) n OH, (CH 2 ) n O-alkoxy, (CH 2 ) n OR 17 , (CH 2 ) n CO 2 R 17 , (CH 2 ) n CONHR 17 , (CH 2 ) n CON(R 17 )(R 18 );
R 7 , R 8 , R 9 , R 10 , and R 11 are independently selected from hydrogen, an alkyl group, SO 3 H, SO 3 R 17 , SO 2 NHR 17 , SO 2 N(R 17 )(R 18 ), and SO 2 N(R 17 )(R 18 )(R 19 ) + Z′;
R 14 , R 15 , and R 16 are hydrogen; and
M is selected from two hydrogens and a metal ion selected from In, Pd, Pt, Sn, Zn, Ga, Al, and Mg.
6. The compound of claim 5 wherein:
R 1 and R 4 are independently selected from methyl and ethyl;
R 5 , R 6 , R 12 , and R 13 , are independently selected from methyl and ethyl;
R 7 , R 14 , R 15 , R 16 are hydrogen;
R 2 and R 3 are independently selected from (CH 2 ) 2 OH,(CH 2 ) 2 OMe, (CH 2 ) 3 OH, (CH 2 ) 3 OMe, (CH 2 ) 2 CO 2 Me, (CH 2 ) 2 CO 2 Na, (CH 2 ) 2 CO 2 K (CH 2 ) 2 CONHR 17 , (CH 2 ) 2 CON(R 17 )(R 18 ), (CH 2 ) 3 OH, CH 2 CO 2 Me, CH 2 CO 2 Na, and CH 2 CO 2 K;
R 17 and R 18 are independently selected from CH 3 , CH 2 CH 3 , CH 2 OCH 2 OH, CH 2 CH 2 N(CH 3 ) 2 , and CH 2 CH 2 (N(CH 3 ) 3 + )S − , where S − is a physiologically acceptable ion; and
M is selected from two hydrogens and a metal ion selected from In, Pd, Pt, Sn, Zn, Ga, Al and Mg.