US2008275232A1PendingUtilityA1
Chlorins possessing fused ring systems useful as photoselective compounds for photodynamic therapy
Est. expiryMar 30, 2020(expired)· nominal 20-yr term from priority
A61K 41/0071A61P 35/00C07D 487/22A61K 41/0057
71
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Claims
Abstract
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.
Claims
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30 . A compound of formula IV:
wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 12 , R 13 , R 14 , R 15 , and R 16 are independently selected from hydrogen; halogen; unsubstituted or substituted alkyl; C 3 -C 6 cycloalkyl, acetyl, aryl, alkenyl, alkynyl, amides; 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 17 , R 18 , and R 19 are independently selected from hydrogen, a physiologically acceptable ion; and substituted or substituted C 1 -C 6 alkyl, aryl, alkenyl or alkynyl;
Z − is a charge balancing ion;
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, E, F, G, H, J, L, K, and Q are independently selected from carbon, nitrogen, N + (R 20 ) Z′ − , oxygen, Se + , and Te + ;
R 20 is selected from alkyl and aryl;
Z′ − is a charge balancing ion; and
U and T are independently selected from a substituted or unsubstituted aromatic, heteroaromatic, polyaromatic, polyheteroaromatic, cycloalkyl, and a heterocycloalkyl group.
31 . The compound according to claim 30 of formula IVA:
32 . The compound according to claim 30 of formula IVB:
33 . A compound of formula V:
wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 12 , R 13 , R 14 , R 15 , and R 16 are independently selected from hydrogen; 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 17 , R 18 , and R 19 are independently selected from hydrogen; a physiologically acceptable ion; unsubstituted or substituted C 1 -C 6 alkyl, aryl, alkenyl or alkynyl; and a functional group having a molecular weight less than about 100,000 daltons;
Z − is a charge balancing ion;
n is an integer ranging from 1 to 4;
A, F, G, H, J, L, K, Q are independently selected from carbon, nitrogen, N + (R 20 ) Z′ − , oxygen, Se + , and Te + ; R 20 is selected from alkyl or aryl; Z′ − is a charge balancing ion;
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; and
U is selected from a substituted or unsubstituted aromatic, heteroaromatic, polyaromatic, polyheteroaromatic, cycloalkyl, and a heterocycloalkyl group.
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37 . A process for preparing a compound of formula IA:
comprising contacting a compound of formula PORA with at least one acid catalyst for a sufficient time and at a sufficient temperature to form a compound of formula IA wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 are independently selected from hydrogen; 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 17 , R 18 , and R 19 are independently selected from hydrogen, a physiologically acceptable ion; unsubstituted or substituted C 1 -C 6 alkyl, aryl, alkenyl or alkynyl; and a functional group having a molecular weight less than about 100,000 daltons;
Z − is a charge balancing ion;
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;
X is CH 2 OH, CH 2 N(R α ) 3 + Z″ − , CH 2 OR α , CHR 7 OR α , CHR 7 N(R α ) 3 + Z″ − , or CH 2 Φ;
Z″ − is a charge balancing ion;
R α is hydrogen, alkyl, aryl, or a protecting group; and
Φ is a halogen;
38 . The process according to claim 37 , where at least one acid catalyst is selected from HCl, H 2 SO 4 , H 3 PO 4 , CF 3 CO 2 H, and MeSO 3 H.
39 . The process according to claim 37 , where at least one acid catalyst is H 3 PO 4 .
40 . The process according to claim 37 , wherein the compound of formula PORA is the formula PORH and the compound of formula IA is formula IH:
41 . The process according to claim 40 , where at least one acid catalyst is selected from HCl, H 2 SO 4 , H 3 PO 4 , CF 3 CO 2 H, and MeSO 3 H.
42 . The process according to claim 40 , where at least one acid catalyst is H 3 PO 4 .
43 . The process according to claim 37 , wherein the compound of formula PORA is formula PORB and the compound of formula IA is formula IB:
44 . The process according to claim 43 , where at least one acid catalyst is selected from HCl, H 2 SO 4 , H 3 PO 4 , CF 3 CO 2 H, and MeSO 3 H.
45 . The process according to claim 44 , where at least one acid catalyst is H 3 PO 4 .
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67 . A process for preparing a compound of formula IV:
comprising contacting a compound of formula TUPOR with at least one acid catalyst for a sufficient time and at a sufficient temperature to form a compound of formula IV, wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 12 , R 13 , R 14 , R 15 , and R 16 are independently selected from hydrogen; 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 17 , R 18 , and R 19 are independently selected from hydrogen; a physiologically acceptable ion; unsubstituted or substituted C 1 -C 6 alkyl, aryl, alkenyl or alkynyl; and a functional group having a molecular weight less than about 100,000 daltons; Z − is a charge balancing ion;
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, E, F, G, H, J, K, L, Q are independently selected from carbon, nitrogen, N + (R 20 ) Z′ − , oxygen, Se + , and Te + ; R 17 is alkyl or aryl;
Z′ − is a charge balancing ion;
X is CH 2 OH, CH 2 N(R α ) 3 + Z″ − , CH 2 OR α , CHR 7 OR α , CHR 7 N(R α ) 3 + Z″ − , or CH 2 Φ;
R α is hydrogen, alkyl, aryl, or a protecting group;
Φ is a halogen;
Z″ − is a charge balancing ion; and
U and T are independently selected from a substituted or unsubstituted aromatic, heteroaromatic, polyaromatic, polyheteroaromatic cycloalkyl, and a heterocycloalkyl group.
68 . The process according to claim 67 , where at least one acid catalyst is selected from HCl, H 2 SO 4 , H 3 PO 4 , CF 3 CO 2 H, and MeSO 3 H.
69 . The process according to claim 67 , where at least one acid catalyst is H 3 PO 4 .
70 . A process for preparing a compound of formula V
comprising contacting a compound of formula UPOR with at least one acid catalyst for a sufficient time and at a sufficient temperature to form a compound of formula V
wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 12 , R 13 , R 14 , R 15 , and R 16 are independently selected from hydrogen; 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 17 , R 18 , and R 19 are independently selected from hydrogen; a physiologically acceptable ion; unsubstituted or substituted C 1 -C 6 alkyl, aryl, alkenyl or alkynyl; and a functional group having a molecular weight less than about 100,000 daltons; Z − is a charge balancing ion;
n is an integer ranging from 1 to 4;
X is CH 2 OH, CH 2 N(R α ) 3 + Z″ − , CH 2 OR α , CHR 7 OR α , CHR 7 N(R α ) 3 + Z″ − , or CH 2 Φ;
R α is hydrogen, alkyl, aryl, or a protecting group;
Φ is a halogen;
Z″ − is a charge balancing ion;
A, F, G, H, L, J, K, Q are independently selected from carbon, nitrogen, N + (R 20 ) Z 1− , oxygen, Se + , and Te + ; R 20 is alkyl or aryl, Z 1− is a charge balancing ion;
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; and
U is selected from a substituted or unsubstituted aromatic, heteroaromatic, polyaromatic, polyheteroaromatic, cycloalkyl, and heterocycloalkyl group.
71 . The process according to claim 70 , where at least one acid catalyst is selected from HCl, H 2 SO 4 , H 3 PO 4 , CF 3 CO 2 H, and MeSO 3 H.
72 . The process according to claim 71 , where at least one acid catalyst is H 3 PO 4 .
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78 . A process for producing a compound of VI:
comprising contacting a compound of formula VIA
with a compound of formula
in the presence of a catalyst to form a compound of formula VI
wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are independently selected from hydrogen; halogen; unsubstituted or substituted alkyl, C 3 -C 6 cycloalkyl, acetyl, aryl, alkenyl, alkynyl, amide groups, or esters groups; NR 17 R 18 ; CH 2 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 17 , R 18 , and R 19 are independently selected from hydrogen; a physiologically acceptable ion; unsubstituted or substituted C 1 -C 6 alkyl, aryl, alkenyl or alkynyl; and a functional group having a molecular weight less than about 100,000 daltons;
Z − is a charge balancing ion;
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; and
X′ is a halogen.
79 . The process according to claim 78 , wherein M is Zn and X′ is Cl.
80 . The process according to claim 78 , wherein the catalyst is Pd(Ph) 3 P.Join the waitlist — get patent alerts
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