Water soluble anionic bacteriochlorophyll derivatives and their uses

Abstract

The invention provides anionic water-soluble tetracyclic and pentacyclic bacteriochlorophyll derivatives (Bchls) containing at least one, preferably two or three, negatively charged groups and/or acidic groups that are converted to negatively charged groups at the physiological pH, preferably Bchls having a group COO<−>, COS<−>, SO3<−>, PO3<2−>, COOH, COSH, SO3H, and/or PO3H2 bound through an ester or amide bond to one or more of the positions 17<3>, 13<3>, and 3<2> of the tetracyclic or pentacyclic Bchl molecule, for photodynamic therapy and diagnosis.

1 - 50 . (canceled) 
     
     
         51 . A compound of formula II: 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein 
         M is selected from divalent Pd, Pt, Co, Sn, Ni, Cu, Zn and Mn, and trivalent Fe, Mn and Cr; 
         R 1 , R 2 , and R 4  each independently is Y—R 5 ; 
         Y is independently at each occurrence selected from: O, S or N(R 6 ); 
         R 3  is selected from —CH═CH 2 , —C(═O)—CH 3 , —C(═O)—H, —CH═NR 7 , —C(CH 3 )═NR 7 , —CH 2 —OR 7 , —CH 2 —SR 7 , —CH 2 —NR 7 R′ 7 , —CH(CH 3 )—OR 7 , —CH(CH 3 )—SR 7 , —CH(CH 3 )—NR 7 R′ 7 , —CH(CH 3 )Hal, —CH 2 -Hal, —CH 2 —R 7 , —CH═CR 7 R′ 7 , —C(CH 3 )═CR 7 R′ 7 , —CH═CR 7 Hal, —C(CH 3 )═CR 7 Hal, and —C≡CR 7 ; 
         R 5 , R 6 , R 7  and R′ 7  each independently is selected from: 
         (a) hydrogen; 
         (b) C 1 -C 25  hydrocarbyl optionally containing one or more heteroatoms, carbocyclic and heterocyclic moieties, wherein the hydrocarbyl, carbocyclic or heterocyclic moieties are optionally substituted by one or more groups selected from halogen, oxo, OH, SH, CHO, NH 2 , CONH 2 , and an acidic group; 
         (c) a residue of an amino acid, a peptide or of a protein; and 
         m is 0 or 1; and 
         wherein the compound comprises at least one acidic group or salt thereof. 
       
     
     
         52 . The compound of  claim 51 , or a salt thereof, wherein at least one of R 5 , R 6 , R 7  and R′ 7  is a C 1 -C 25  hydrocarbyl optionally containing one or more heteroatoms and the hydrocarbyl is substituted by an acidic group. 
     
     
         53 . The compound of  claim 51 , or a salt thereof, wherein at least one of R 5 , R 6 , R 7  and R′ 7  is a residue of an amino acid, a peptide or of a protein. 
     
     
         54 . The compound of  claim 51 , or a salt thereof, wherein at least one of R 1 , R 2 , and R 4  is OH or SH. 
     
     
         55 . The compound of  claim 53  or  54 , or a salt thereof, wherein at least one of R 5 , R 6 , R 7  and R′ 7  is a C 1 -C 25  hydrocarbyl optionally containing one or more heteroatoms and the hydrocarbyl is substituted by an acidic group. 
     
     
         56 . The compound of  claim 53 , or a salt thereof, wherein at least one of R 1 , R 2 , and R 4  is OH or SH. 
     
     
         57 . The compound of  claim 51 , or a salt thereof, wherein the acidic group is independently selected at each occurrence from COOH, COSH, SO 3 H, and/or PO 3 H 2 . 
     
     
         58 . The compound of  claim 51 , or a salt thereof, wherein R 1  is Y—R 5 ; Y is O, S or NH; and R 5  is hydrogen or hydrocarbyl optionally substituted by one or more of OH, SH, SO 3 H, NH 2 , CONH 2 , COOH, COSH, PO 3 H 2 . 
     
     
         59 . The compound of  claim 58 , or a salt thereof, wherein R 1  is Y—R 5 ; Y is O, S or NH; and R 5  is hydrocarbyl optionally substituted by one or more of OH, SH, SO 3 H, NH 2 , CONH 2 , COOH, COSH, PO 3 H 2 . 
     
     
         60 . The compound of  claim 58 , or a salt thereof, wherein R 1  is Y—R 5 ; Y is O, S or NH; and R 5  is hydrogen. 
     
     
         61 . The compound of  claim 51 , or a salt thereof, wherein R 1  is Y—R 5 ; Y is O, S or NH; and R 5  is the residue of an amino acid, a peptide or a protein. 
     
     
         62 . The compound of  claim 51 , or a salt thereof, wherein R 2  is Y—R 5 ; Y is O or S; and R 5  is hydrocarbyl optionally substituted by one or more groups selected from halogen, oxo, OH, SH, CHO, NH 2 , CONH 2  and an acidic group. 
     
     
         63 . The compound of  claim 62 , or a salt thereof, wherein R 2  is Y—R 5 ; Y is O or S; and R 5  is unsubstituted hydrocarbyl. 
     
     
         64 . The compound of  claim 51 , or a salt thereof, wherein R 3  is selected from —C(═O)—CH 3 , —CH═NR 7 , and —C(CH 3 )═NR 7  and R 7  is selected from hydrocarbyl optionally substituted by one or more groups selected from halogen, oxo, OH, SH, CHO, NH 2 , CONH 2  and an acidic group. 
     
     
         65 . The compound of  claim 64 , or a salt thereof, wherein R 3  is —C(═O)—CH 3 . 
     
     
         66 . The compound of  claim 51 , or a salt thereof, wherein R 4  is Y—R 5 ; Y is O, S or NH; and R 5  is hydrocarbyl optionally substituted by halogen, oxo, OH, SH, CHO, NH 2 , CONH 2  and an acidic group. 
     
     
         67 . The compound of  claim 66 , or a salt thereof, wherein R 4  is Y—R 5 ; Y is NH; and R 5  is hydrocarbyl optionally substituted by halogen, oxo, OH, SH, CHO, NH 2 , CONH 2  and an acidic group. 
     
     
         68 . The compound of  claim 51 , or a salt thereof, wherein M is selected from Pd, Cu, Zn, and Mn. 
     
     
         69 . The compound of  claim 68 , or a salt thereof, wherein M is Pd. 
     
     
         70 . A pharmaceutical composition comprising a compound of  claim 51 , or a salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         71 . A method for vascular-targeted photodynamic therapy (VTP) of a tumor, which comprises:
 (a) administering the compound according to  claim 51 , or a salt thereof, to an individual having a tumor; and   (b) irradiating the local area of the tumor with light.   
     
     
         72 . The method of  claim 71 , wherein the tumor is melanoma. 
     
     
         73 . The method of  claim 71 , wherein the tumor is a brain tumor. 
     
     
         74 . The method of  claim 71 , wherein the tumor is a colon tumor. 
     
     
         75 . The method of  claim 71 , wherein the tumor is an ovarian tumor. 
     
     
         76 . The method of  claim 71 , wherein the tumor is a breast tumor. 
     
     
         77 . The method of  claim 71 , wherein the tumor is a skin tumor. 
     
     
         78 . The method of  claim 71 , wherein the tumor is a lung tumor. 
     
     
         79 . The method of  claim 71 , wherein the tumor is an esophageal tumor. 
     
     
         80 . The method of  claim 71 , wherein the tumor is a bladder tumor. 
     
     
         81 . The method of  claim 71 , wherein the compound, or salt thereof, is administered systemically. 
     
     
         82 . The method of  claim 81 , wherein the compound, or salt thereof, is administered intravenously. 
     
     
         83 . The method of  claim 71 , wherein the irradiation wavelength of light approximates an absorption maximum of the compound or salt thereof. 
     
     
         84 . The method of  claim 83 , wherein the wavelength is about 670-780 nm. 
     
     
         85 . A method for photodynamic therapy of age-related macular degeneration by vascular occlusion, which comprises:
 (a) administering the compound according to  claim 51 , or a salt thereof, to an individual in need thereof; and   (b) irradiating the local area of the macular degeneration with light.   
     
     
         86 . A method for treating benign prostatic hypertrophy by vascular-targeted photodynamic therapy, comprising:
 (a) administering the compound according to  claim 51 , or a salt thereof, to an individual having benign prostatic hypertrophy; and   (b) irradiating the local area of the prostate with light.