Water-soluble mono-PEGylated tetrapyrrole derivatives for photodynamic therapy and method of production
View Patent ↗Water-soluble mono-PEGylated tetrapyrrole derivatives are disclosed, having a formula given by formula 1, 2, or 3 in the specification. A method to produce the above water-soluble mono-PEGylated compounds is also disclosed, comprising an interaction of a tetrapyrrole with an aminopolyethylene glycol containing a functionalized terminal fragment, as well as their use as photosensitizers in photodynamic therapy.
1. A water-soluble mono-PEGylated tetrapyrrole derivative selected from the group consisting of formula 1, 2, and 3:
wherein Y is a residue of a functionalized aminopolyethylene glycol H—Y, wherein Y is selected from the group consisting of:
wherein B is a ring having the structure:
wherein:
R 1 =—CH═CH 2 , —CH(OAlk)CH 3 , —CHO, —C(O)CH 3 , —CH 2 CH 3 , —CH(Alk)CH(COAlk) 2 , —CH 2 CH(COAlk) 2 , —CH(Alk)CH 2 COAlk, —CH(Alk)CH 2 CH(OH)CH 3 , and —CH 2 CH 2 CH(OH)CH 3 ;
R 2 =—CH 3 , —CHO, —CH(OH)Alk, —CH═CHAlk, —CH 2 OH, and —CH 2 OAlk;
R 3 =—OH, —OAlk, —NH-Alk;
R 4 =—OH, —OAlk, —NH-Alk;
R 5 =—OH, —OAlk, —NH-Alk;
R 6 =H and —COOAlk;
R 8 =H and -Alk;
R 10 =—OH, —OAlk, —NH 2 , —NHAlk, —NHAcyl, —NAcyl 2 , —NR 12 R 13 , —COR 14 , —OCH 2 COR 14 ;
R 11 =—CH 2 CONR 8 —, —NHCOO—;
R 12 =H and -Alk;
R 13 =H and -Alk; and
R 14 =—OH, —OAlk, —NR 12 R 13 ;
Wherein:
m=2-12;
n=8-500; and
Alk=an alkyl substituent.
2. A process for making the water-soluble mono-PEGylated tetrapyrrole derivatives of claim 1 , comprising the step of reacting with said functionalized aminopolyethylene glycol H—Y wherein said tetrapyrrole is selected from the group consisting of formula 7, 8, 9, and 10:
Wherein B is a ring having the structure:
Wherein:
R 1 =—CH═CH 2 , —CH(OAlk)CH 3 , —CHO, —C(O)CH 3 , —CH 2 CH 3 ,
—CH(Alk)CH(COAlk) 2 , —CH 2 CH(COAlk) 2 , —CH(Alk)CH 2 COAlk,
—CH(Alk)CH 2 CH(OH)CH 3 , and —CH 2 CH 2 CH(OH)CH 3 ;
R 2 =—CH 3 , —CHO, —CH(OH)Alk, —CH═CHAlk, —CH 2 OH, and —CH 2 OAlk;
R 3 =—OH, —OAlk, —NH-Alk;
R 4 =—OH, —OAlk, —NH-Alk;
R 5 =—OH, —OAlk, —NH-Alk;
R 6 =H and —COOAlk;
R 15 =—OH, —NH(CH 2 ) m —R 16 ;
R 16 =—COOH, —NH 2 ; and
Wherein:
m=2-12; and
Alk=an alkyl substituent.
Alk=an alkyl substituent.
3. The process according to claim 2 , wherein said residue of said functionalized aminopolyethylene glycol H—Y, Y, is selected from the group consisting of:
Wherein
R 10 =—OH, —OAlk, —NH 2 , —NHAlk, —NHAcyl, —NAcyl 2 , —NR 2 R 13 , —COR 14 , —OCH 2 COR 14 ;
R 11 =—CH 2 CONR 8 —, —NHCOO—;
R 12 =H and -Alk;
R 13 =H and -Alk; and
R 14 =—OH, —OAlk, —NR 12 R 13 ;
Wherein:
m=2-12;
n=8-500; and
Alk =an alkyl substituent.
4. The process according to claim 3 , wherein OAlk is OMe.
5. The process according to claim 2 , wherein said functionalized aminopolyethylene glycol H—Y has a molecular weight of 500-30,000.
6. A process of photodynamic theraphy comprising the steps of: formulating the water-soluble mono-PEGamine tetrapyrrole derivative of claim 1 into a pharmaceutically acceptable vehicle for delivery to diseased tissues at a specific treatment site;
delivering said mono-PEGamine tetrapyrrole-vehicle formulation to said specific treatment site;
allowing said mono-PEGamine tetrapyrrole-vehicle formulation to preferentially accumulate in said diseased tissues;
irradiating said treatment site with light of a sufficient power and wavelength to activate said mono-PEGamine tetrapyrrole.
7. A composition or pharmaceutical preparation comprised of said mono-PEGylated tetrapyrrole of claim 1 as a water solution.