Long-wavelength water soluble chlorin photosensitizers useful for photodynamic therapy and diagnosis of tumors
AssigneeThe Regents of the University of California
InventorsKevin M. Smith, Shwn-Ji H. Lee
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Abstract
Novel photosensitizers useful for photodynamic therapy and diagnosis of tumors. Photosensitizers are derived from chlorophyll-a of photosynthetic plants and algae, possess long wavelength absorption between 600 and 800 nm, are stable, and water soluble. A process of preparation of these compounds and method of use for diagnostic and therapeutic purposes.
Claims26
A compound of the formula ##STR20## wherein R.sub.1 is H;
- CH.sub.3 ;
- CH.sub.2 CH.sub.3 ;
- CH.dbd.CH.sub.2 ;
- CH(OH)CH.sub.3 ;
- CH(O-alkyl)CH.sub.3 ;
- C(.dbd.O)CH.sub.3 ;
- CHO;
- CH.sub.2 OH or CH.sub.2 alkoxy;
- R.sub.2 is H, alkyl or aryl;
- R.sub.3 is H;
- alkyl;
- aryl;
- (CH.sub.2).sub.n CH(NH.sub.2 )CO.sub.2 H wherein n is 3 or 4;
- aryl substituted on aromatic ring with alkyl;
- alkyl substituted with N(alkyl).sub.2 or .sup.(+) N(alkyl).sub.3 ;
- or (CH.sub.2).sub.n CO.sub.2 R.sub.9 wherein R.sub.9 is H, alkyl or aryl;
- R.sub.4 is OH or alkoxy;
- R.sub.5 is OH;
- OR.sub.10 wherein R.sub.10 is alkyl or aryl;
- NR.sub.12 R.sub.13 wherein R.sub.12 and R.sub.13 are H, alkyl or aryl;
- or NH(CH.sub.2).sub.n CH(NH.sub.2)CO.sub.2 H wherein n is 3 or 4;
- and the pharmaceutically acceptable salts and esters thereof.
A compound of the formula ##STR21## wherein R.sub.1 is H;
- CH.sub.3 ;
- CH.sub.2 CH.sub.3 ;
- CH.dbd.CH.sub.2 ;
- CH(OH)CH.sub.3 ;
- CH(O-alkyl)CH.sub.3 ;
- C(.dbd.O)CH.sub.3 ;
- CHO;
- CH.sub.2 OH or CH.sub.2 -alkoxy;
- R.sub.2 is OH or alkoxy;
- R.sub.3 is H;
- alkyl or aryl;
- R.sub.4 is H;
- alkyl, aryl;
- (CH.sub.2).sub.n CH(NH.sub.2)CO.sub.2 H wherein n is 3 or 4;
- aryl substituted on aromatic ring with alkyl;
- alkyl substituted with N(alkyl).sub.2 or N(alkyl).sub.3 ;
- or (CH.sub.2).sub.n CO.sub.2 R.sub.9 wherein R.sub.9 is H, alkyl or aryl;
- R.sub.5 is OH;
- OR.sub.10 wherein R.sub.10 is alkyl or aryl;
- NR.sub.12 R.sub.13 wherein R.sub.12 and R.sub.13 are H, alkyl or aryl;
- or NH(CH.sub.2).sub.n CH(NH.sub.2)CO.sub.2 H wherein n is 3 or 4;
- and the pharmaceutically acceptable salts and esters thereof.
A method for tumor localization and treatment by photosensitization comprising the steps of:
- (a) administering to a person in need of such treatment a compound of the formula ##STR22## wherein R.sub.1 is H;
- CH.sub.3 ;
- CH.sub.2 CH.sub.3 ;
- CH.dbd.CH.sub.2 ;
- CH(OH)CH.sub.3 ;
- CH(O-alkyl)CH.sub.3 ;
- C(.dbd.O)CH.sub.3 ;
- CHO;
- CH.sub.2 OH or CH.sub.2 -alkoxy;
- R.sub.2 is H;
- alkyl;
- or aryl;
- R.sub.3 is H;
- alkyl;
- aryl;
- (CH.sub.2).sub.n CH(NH.sub.2)CO.sub.2 H wherein n is 3 or 4;
- aryl substituted on the aromatic ring with alkyl;
- alkyl substituted with N(alkyl).sub.2 N(alkyl).sub.3 ;
- or (CH.sub.2).sub.n CO.sub.2 R.sub.9 wherein R9 is H, alkyl or aryl;
- R.sub.4 is OH;
- or alkoxy;
- R.sub.5 is OH;
- OR.sub.10 wherein R.sub.10 is alkyl or aryl;
- NR.sub.12 R.sub.13 wherein R.sub.12 and R.sub.13 are H, alkyl or aryl;
- or NH(CH.sub.2).sub.n CH(NH.sub.2)CO.sub.2 H wherein n is 3 or 4;
- or a pharmaceutically acceptable salt or ester thereof;
- and
- (b) activating the compound of step (a) or appropriate salt or ester thereof with a light between 600-800 nm at an energy density between 25-100 J/cm.sup.2 for 5-35 minutes.
A method for tumor localization and treatment by photosensitization comprising the steps of:
- (a) administering to a person in need of such treatment a compound of the formula ##STR23## wherein R.sub.1 is H, CH.sub.3, CH.sub.2 CH.sub.3, CH.dbd.CH.sub.2, CH(OH)CH.sub.3, CH(O-alkyl)CH.sub.3, C(.dbd.O)CH.sub.3, CHO, CH.sub.2 OH, or CH.sub.2 alkoxy;
- R.sub.2 is OH, or alkoxy;
- R.sub.3 is H, alkyl, aryl,
- R.sub.4 is H, alkyl, aryl, (CH.sub.2).sub.n CH(NH.sub.2)CO.sub.2 H wherein n is 3 or 4;
- aryl substituted on aromatic ring with alkyl;
- alkyl substituted with N(alkyl).sub.2 or N(alkyl).sub.3 ;
- or (CH.sub.2).sub.n CO.sub.2 R.sub.9 wherein R.sub.9 is H, alkyl or aryl;
- R.sub.5 is OH;
- OR.sub.10 wherein R.sub.10 is alkyl or aryl;
- NR.sub.12 R.sub.13 wherein R.sub.12 and R.sub.13 are H, alkyl or aryl;
- or NH(CH.sub.2).sub.n CH(NH.sub.2)CO.sub.2 H wherein n is 3 or 4;
- or the pharmaceutically acceptable salt and ester thereof;
- and
- (b) activating the compound of step (a) or appropriate salt or ester thereof with a light between 600-800 nm at an energy density between 25-100 J/cm.sup.2 for 5-35 minutes.
A compound of the formula ##STR24## namely, chlorin-p.sub.6 -6-N.sup.e -lysylamide-7-methyl ester.
A compound of the formula ##STR26## namely, chlorin-p.sub.6 -N.sup.e -lysyl-methoxyamide-7-methyl ester.
A compound of the formula ##STR28## namely, chlorin-p.sub.6 -.gamma.-N.sup.e -lysyl-methoxyamide-7-methyl ester.
A compound of the formula ##STR30## namely, chlorin-p.sub.6 -6-N.sup.e -lysylmethoxyamide-.gamma., 7-dimethyl ester.
A compound of the formula ##STR34## namely, chlorin-p.sub.6 -6-N-butylamide-7-methyl ester.
A compound of the formula ##STR36## namely, chlorin-p.sub.6 -6, 7-di-N-butylamide.
A compound of the formula ##STR38## namely, chlorin-p.sub.6 -6-N-butylamide-.gamma.-7-dimethyl ester.
A compound of the formula ##STR40## namely, chlorin-p.sub.6 -6-N, .gamma.-ornithylamide-7-methyl ester.
A compound of the formula ##STR42## namely, chlorin-p.sub.6 -6-N-ornithylmethoxyamide-.gamma.-7-dimethyl ester.
Dependencies are inferred from the claim text.