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 . A bacteriochlorophyll derivative containing at least one negatively charged groups and/or acidic groups that are converted to negatively charged groups at the physiological pH, excluding pentacyclic bacteriochlorophyll derivatives having a free CH 2 CH 2 COOH or a CH 2 CH 2 COO −  group at position 17, and tetracyclic bacteriochlorophyll derivatives devoid of a central metal atom and having a —CH 2 CH 2 COOH group at position 17, a —CH 2 COOH or —COOH group at position 15, a —COOH group at position 13, methyl groups at the positions 2, 7, 12, 18, and ethyl groups at the positions 3 and 8. 
     
     
         2 . A bacteriochlorophyll derivative according to  claim 1  containing two negatively charged groups. 
     
     
         3 . A bacteriochlorophyll derivative according to  claim 1  containing three negatively charged groups. 
     
     
         4 . A bacteriochlorophyll derivative according to  claim 1  wherein said negatively charged groups are selected from the group consisting of COO, COS, SO 3 , and/or PO 3   2− . 
     
     
         5 . A bacteriochlorophyll derivative according to  claim 1  wherein said acidic groups that are converted to negatively charged groups at the physiological pH are selected from the group consisting of COOH, COSH, SO 3 H, and/or PO 3 H 2 . 
     
     
         6 . A bacteriochlorophyll derivative according to  claim 1  derived from a natural or synthetic derivative of bacteriochlorophyll, including compounds in which the central Mg atom has been deleted or replaced by other metal atoms. 
     
     
         7 . A bacteriochlorophyll derivative according to  claim 1  of the formula I or II: 
       
         
           
           
               
               
           
         
       
       wherein
 M represents 2H or a metal atom 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 O, S or NR 5 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 H or selected from the group consisting of: 
 (a) C 1 -C 25  hydrocarbyl optionally containing one or more heteroatoms, carbocyclic or heterocyclic moieties, and/or optionally substituted by one or more functional groups selected from the group consisting of halogen, oxo, OH, SH, CHO, NH 2 , CONH 2 , a negatively charged group, and an acidic group that is converted to a negatively charged group at the physiological pH; 
 (b) a residue of an amino acid, a peptide or of a protein; and 
 (c) when Y is O or S, R 5  may further be R 8   + ; 
 m is 0 or 1; and 
 R 8   +  is H +  or a cation; 
 provided that: 
 (i) at least one of R 5 , R 6 , R 7  and R′ 7  is a hydrocarbon chain as defined in (a) above substituted by a negatively charged group or by an acidic group that is converted to a negatively charged group at the physiological pH; or 
 (ii) at least one of R 1 , R 2 , and R 4  is OH, SH, O − R 8   +  or S − R 8   + ; or 
 (iii) at least one of R 1 , R 2 , and R 4  is OH, SH, O − R 8   +  or S − R 8   +  and at least one of R 5 , R 6 , R 7  and R′ 7  is a hydrocarbon chain substituted by a negatively charged group or by an acidic group that is converted to a negatively charged group at the physiological pH; or 
 (iv) at least one of R 1 , R 2 , and R 4  is OH, SH, O − R 8   +  or S − R 8   +  and 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; or 
 (v) at least one of R 5 , R 6 , R 7  and R′ 7  is a hydrocarbon chain substituted by a negatively charged group or by an acidic group that is converted to a negatively charged group at the physiological pH and 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; 
 but excluding the compounds of formula I wherein M is as defined, R 3  is —C(═O)CH 3 , R 1  is OH or OR 8   +  and R 2  is —OCH 3 , and the compound of formula II wherein M is 2H, R 3  is —C(══O)CH 3 , R 1 , R 2  and R 4  are OH, and m is 0 or 1. 
 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . A bacteriochlorophyll derivative of the formula I or II according to  claim 1  containing a central Pd metal atom. 
     
     
         13 - 35 . (canceled) 
     
     
         36 . A method for tumor photodynamic therapy which comprises:
 (a) administering to an individual in need a bacteriochlorophyll derivative containing at least one negatively charged group and/or acidic group that is converted to a negatively charged group at the physiological pH, excluding pentacyclic bacteriochlorophyll derivatives having a free CH 2 CH2COOH or a CH 2 CH 2 COO −  group at position 17, and tetracyclic bacteriochlorophyll derivatives devoid of a central metal atom and having a —CH 7 CH 2 COOH group at position 17, a —CH 2 COOH or —COOH group at position 15, a —COOH group at position 13, methyl groups at the positions 2, 7, 12, 18, and ethyl groups at the positions 3 and 8; and   (b) irradiating the local of the tumor.   
     
     
         37 . A method for photodynamic therapy of age-related macular degeneration which comprises: (a) administering to an individual in need a bacteriochlorophyll derivative containing at least one negatively charged group and/or acidic group that is converted to a negatively charged group at the physiological pH, excluding pentacyclic bacteriochlorophyll derivatives having a free CH 2 CH2COOH or a CH 2 CH 2 COO −  group at position 17, and tetracyclic bacteriochlorophyll derivatives devoid of a central metal atom and having a —CH 2 CH 2 COOH group at position 17, a —CH 2 COOH or —COOH group at position 15, a —COOH group at position 13, methyl groups at the positions 2, 7, 12, 18, and ethyl groups at the positions 3 and 8; and (b) irradiating the local of the macular degeneration. 
     
     
         38 . A method for tumor diagnosis which comprises:
 (a) administering to a subject suspected of having a tumor, a bacteriochlorophyll derivative containing at least one negatively charged group and/or acidic group that is converted to a negatively charged group at the physiological pH, excluding pentacyclic bacteriochlorophyll derivatives having a free CH 2 CH2COOH or a CH 2 CH 2 COO −  group at position 17, and tetracyclic bacteriochlorophyll derivatives devoid of a central metal atom and having a —CH 2 CH 2 COOH group at position 17, a —CH 2 COOH or —COOH group at position 15, a —COOH group at position 13, methyl groups at the positions 2, 7, 12, 18, and ethyl groups at the positions 3 and 8; and   (b) irradiating the subject by standard procedures and measuring the fluorescence of the suspected area, wherein a higher fluorescence indicates tumor sites.   
     
     
         39 . (canceled) 
     
     
         40 . (canceled) 
     
     
         41 . (canceled) 
     
     
         42 . (canceled) 
     
     
         43 . A method for the preparation of compounds of formula II of  claim 7  wherein R 1  is —O − R 8   + ; R 2  is —OCH 3 ; R 3  is acetyl; R 4  is a group —NH—(CH 2 ) n —SO 3   − R 8   + ; R 8   +  is a monovalent cation; m is 1 and n is 1 to 10, which comprises:
 (i) reacting the corresponding M-bacteriopheophorbide of formula I wherein R 1  is OH with an aminosulfonic acid of the formula H 2 N—(CH 2 ) n —SO 3 H in a R 8   + -buffer; and 
 (ii) isolating the desired compound of formula II. 
 
     
     
         44 - 50 . (canceled)