(bacterio)chlorophyll photosensitizers for treatment of eye diseases and disorders

Abstract

An ophthalmic composition is provided, comprising chlorophyll or bacteriochlorophyll compounds for photodynamic treatment (PDT) of diseases, disorders and conditions associated with corneal or scleral anomalies, such as corneal thinning and scleral stretching.

What is claimed: 
     
         1 . A chlorophyll or bacteriochlorophyll compound for use in photodynamic therapy (PDT) of diseases, disorders and conditions associated with corneal or scleral anomaly. 
     
     
         2 . The chlorophyll or bacteriochlorophyll according to  claim 1 , wherein said corneal or scleral anomaly is corneal thinning and scleral weakening. 
     
     
         3 . The chlorophyll or bacteriochlorophyll compound method according to  claim 1  or  2 , which is a derivative of chlorophyll or bacteriochlorophyll having the formula I, II or III: 
       
         
           
           
               
               
           
         
         wherein 
         M represents 2H or an atom selected from the group consisting of Mg, Pd, Pt, Zn, In, Gd and Yb; 
         X is O or N—R 7 ; 
         R 1 , R′ 2  and R 6  each independently is Y—R 8 , —NR 9 R′ 9  or —N + R 9 R′ 9 R″ 9 A − ; 
         Y is O or S; 
         R 2  is H, OH or COOR 9 ; 
         R 3  is H, OH, C 1 -C 12  alkyl or C 1 -C 12  alkoxy; 
         R 4  is —CH═CR 9 R′ 9 , —CH═CR 9 Hal, —CH═CH—CH 2 —NR 9 R′ 9 , —CH═CH—CH 2 —N + R 9 R′ 9 R″ 9 A − , —CHO, —CH═NR 9 , —CH═N + R 9 R′ 9 A − , —CH 2 —OR 9 , —CH 2 —SR 9 , —CH 2 -Hal, —CH 2 —R 9 , —CH 2 —NR 9 R′ 9 , —CH 2 —N + R 9 R′ 9 R″ 9 A − , —CH 2 —CH 2 R 9 , —CH 2 —CH 2 Hal, —CH 2 —CH 2 OR 9 , —CH 2 —CH 2 SR 9 , —CH 2 —CH 2 —NR 9 R′ 9 , —CH 2 —CH 2 —N + R 9 R′ 9 R″ 9 A − , —COCH 3 , C(CH 3 )═CR 9 R′ 9 , —C(CH 3 )═CR 9 Hal, —C(CH 3 )═NR 9 , —CH(CH 3 )═N + R 9 R′ 9 A − , —CH(CH 3 )-Hal, —CH(CH 3 )—OR 9 , —CH(CH 3 )—SR 9 , —CH(CH 3 )—NR 9 R′ 9 , —CH(CH 3 )—N + R 9 R′ 9 R″ 9 A − , or —C≡CR 9 ; 
         R′ 4  is methyl or formyl; 
         R 5  is O, S, N—R 9 , N + R 9 R′ 9 A − , CR 9 R′ 9 , or CR 9 -Hal; 
         R 7 , R 8 , R 9 , R′ 9  and R″ 9  each independently is: 
         (a) H; 
         (b) C 1 -C 25  hydrocarbyl; 
         (c) C 1 -C 25  hydrocarbyl substituted by one or more functional groups selected from the group consisting of halogen, nitro, oxo, OR, SR, epoxy, epithio, —CONRR′, —COR, COOR″, —OSO 3 R, —SO 3 R″, —SO 2 R, —NHSO 2 R, —SO 2 NRR′, —NRR′, ═N—OR, ═N—NRR′, —C(═NR)—NRR′, —NR—NRR′, —(R)N—C(═NR)—NRR′, O←NR—, >C═NR, —(CH 2 ) n —NR—COR′, —(CH 2 ) n —CO—NRR′, —O—(CH 2 ) n —OR, —O—(CH 2 ) n —O—(CH 2 ) n —R, —PRR′, —OPO 3 RR′, —PO 2 HR and —PO 3 R″R″, wherein n is an integer of 1 to 10 and R and R′ each independently is H, hydrocarbyl or heterocyclyl, or R and R′ together with the N atom to which they are attached form a 3-7 membered saturated ring optionally containing a further heteroatom selected from O, S and N, wherein the further N atom may be substituted, and R″ is H, a cation, hydrocarbyl or heterocyclyl; 
         (d) C 1 -C 25  hydrocarbyl substituted by one or more functional groups selected from the group consisting of positively charged groups, negatively charged groups, basic groups that are converted to positively charged groups under physiological conditions, and acidic groups that are converted to negatively charged groups under physiological conditions; 
         (e) C 1 -C 25  hydrocarbyl containing one or more heteroatoms and/or one or more carbocyclic or heterocyclic moieties; 
         (f) C 1 -C 25  hydrocarbyl containing one or more heteroatoms and/or one or more carbocyclic or heterocyclic moieties and substituted by one or more functional groups as defined in (c) and (d) above; 
         (g) C 1 -C 25  hydrocarbyl substituted by a residue of an amino acid, a peptide, a protein, a monosaccharide, an oligosaccharide, or a polysaccharide; or 
         (h) a residue of an amino acid, a peptide, a protein, a monosaccharide, an oligosaccharide, or a polysaccharide; 
         R 7  may further be —NRR′, wherein R and R′ each is H or C 1 -C 25  hydrocarbyl, optionally substituted by a negatively charged group, preferably SO 3   − ; 
         R 8  may further be H +  or a cation R +   10  when R 1 , R′ 2  and R 6  each independently is Y—R 8 ; 
         R +   10  is a metal cation, an ammonium group or an organic cation; 
         A −  is a physiologically acceptable anion; 
         m is 0 or 1; 
         the dotted line at positions 7-8 represents an optional double bond; or 
         pharmaceutically acceptable salts and optical isomers thereof. 
       
     
     
         4 . The chlorophyll or bacteriochlorophyll compound according to  claim 3 , wherein the dotted line at positions 7-8 represents a double bond and the compound is a chlorophyll derivative of the formula I, II or III. 
     
     
         5 . The chlorophyll or bacteriochlorophyll compound according to  claim 3 , wherein the dotted line at positions 7-8 is absent and the compound is a bacteriochlorophyll derivative of the formula I, II or III. 
     
     
         6 . The chlorophyll or bacteriochlorophyll compound according to  claim 4  or  5 , containing at least one group selected from:
 (a) a negatively charged group selected from COO − , COS − , SO 3   − , or PO 3   2− ; 
 (b) an acidic group that is converted to a negatively charged group at the physiological pH, selected from COOH, COSH, SO 3 H, or PO 3 H 2 , or a salt thereof; 
 (c) a positively charged group, preferably an end group or a group located within an alkyl chain, selected from: (i) an onium group not containing a N atom such as —O + (RR′), —S + (RR′), —Se + (RR′), —Te + (RR′), —P + (RR′R″), —As + (RR′R″), —Sb + (RR′R″), and —Bi + (RR′R″); (ii) a cation derived from a N-containing group selected from —N + (RR′R″), —(R)N—N + (RR′R″), O←N + (RR′R″)—, >C═N + (RR′), —C(═NR)—N + RR′R″ or —(R)N—C(═NR)—N + RR′R″ group preferably N + (RR′R″); or (iii) a cation derived from a heteroaromatic compound containing one or more N atoms and optionally O or S atoms such as-pyrazolium, imidazolium, oxazolium, thiazolium, pyridinium, quinolinium, isoquinolinium, pyrimidinium, 1,2,4-triazinium, 1,3,5-triazinium or purinium; or 
 (d) a basic group that is converted to a positively charged group under physiological conditions, said basic group is an end group or a group located within an alkyl chain, selected from —NRR′, —C(═NR)—NR′R″, —NR—NR′R″, —(R)N—C(═NR)—NR′R″, O←NRR′—, or >C═NR, or the basic group is a N-containing heteroaromatic radical selected from pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, quinolinyl, isoquinolinyl, pyrimidyl, 1,2,4-triazinyl, 1,3,5-triazinyl or purinyl, 
 wherein R, R′ and R″ each independently is H, optionally substituted hydrocarbyl or heterocyclyl, or two of R, R′ and R″ together with the N atom to which they are attached form a 3-7 membered saturated ring, optionally containing one or more heteroatoms selected from O, S or N, and optionally further substituted at the additional N atom, said ring is selected from the group consisting of aziridine, pyrrolidine, piperidine, morpholine, thiomorpholine, azepine or piperazine optionally substituted at the additional N atom by C 1 -C 6  alkyl optionally substituted by halo, hydroxyl or amino. 
 
     
     
         7 . The chlorophyll or bacteriochlorophyll compound-according to  claim 6 , wherein the compound is a chlorophyll or bacteriochlorophyll of formula II and R 6  is —NR 9 R′ 9 , wherein R 9  is H and R′ 9  is a C 1 -C 10  alkyl substituted by at least one group selected from: a positively charged group, a negatively charged group, an acidic group that is converted to a negatively charged group under physiological conditions, preferably SO 3 H or an alkaline salt thereof, or a basic group that is converted to a positively charged group under physiological conditions, preferably —NRR′ or —NH—(CH 2 ) 2-6 —NRR′, wherein each of R and R′ independently is H, C 1 -C 6  alkyl optionally substituted by NH 2 , or R and R′ together with the N atom form a 5-6 membered saturated ring, optionally containing an O or N atom and optionally further substituted at the additional N atom by —(CH 2 ) 2-6 —NH 2 . 
     
     
         8 . The chlorophyll or bacteriochlorophyll compound-according to  claim 7 , wherein the compound is a bacteriochlorophyll of formula II, wherein:
 M is 2H, Mg, Pd, or Zn, preferably 2H or Pd, more preferably Pd;   R 1  is selected from:   (i) —O − R 10   + ;   (ii) Y—R 8 , wherein Y is O or S and R 8  is the residue of an amino acid, a peptide or a protein;   (iii) —NH—CH 2 —CH(OH)—CH 2 OH;   (iv) —NH—(CH 2 ) n —OH;   (v) —NH—CH(OH)—CH 3 ;   (vi) —NH—(CH 2 ) n —NR—(CH 2 ) n —OH;   (vii) glycosylamino; or   (viii) NHR′ 9  which is as defined for R 6 ;   R′ 2  is C 1 -C 6  alkoxy such as methoxy, ethoxy, propoxy or butoxy, more preferably methoxy;   R 4  is —C(═O)—CH 3 , —CH═N—(CH 2 ) n —SO 3   − R 10   + ; —CH═N—(CH 2 ) n —COO − R 10   + ; —CH═N—(CH 2 ) n —PO 3   2− (R 10   + ) 2 ; —CH 2 —NH—(CH 2 ) n —SO 3   − R 10   + ; —NH—(CH 2 ) n —COO − R 10   + ; —NH—(CH 2 ) n —PO 3   2− (R 10   + ) 2 ; or —C(CH 3 )═NR 9 , preferably C(CH 3 )═N—(CH 2 ) n —NH 2 , or —C(CH 3 )═N—(CH 2 ) n —N(R) 3   + A − ;   R 6  is selected from (i) NHR′ 9 , selected from:
 (a) —NH—(CH 2 ) n —SO 3   − R 10   + , preferably —NH—(CH 2 ) 2 —SO 3 R 10   +  or —NH—(CH 2 ) 3 —SO 3 R 10   + ; 
 (b) —NH—(CH 2 ) n —COO − R 10   + ; 
 (c) —NH—(CH 2 ) n —PO 3   2− (R 10   + ) 2 ; 
 (d) —NH—(CH 2 ) n —B; 
 (e) 
   
       
         
           
           
               
               
           
         
         
           (f) 
         
       
       
         
           
           
               
               
           
         
         
           
             preferably —NH—(CH 2 ) 2 -1-morpholino or —NH—(CH 2 ) 3 -piperazino; 
           
           (g) 
         
       
       
         
           
           
               
               
           
         
         
           (h) —NH—(CH 2 ) n —N(R″)—(CH 2 ) n —NRR′, preferably —NH—(CH 2 ) 3 —NH—(CH 2 ) 3 —NH 2 ; 
           (j) —NH—(CH 2 ) n —NRR′, preferably —NH—CH 2 —CH 2 —NRR′; 
         
         R 10   +  is H + , or a monovalent cation such as K + , Na + , Li + , or NH 4   + , more preferably K + ; 
         X is O, S or NH; 
         B is a positively charged group selected from ammonium —N + RR′R″, preferably —N(CH 3 ) 3   + A − , -guanidinium, sulfonium, phosphonium, arsonium; or B is a basic group that is converted to a positively charged group under physiological conditions, selected from amino —NRR′, preferably —NH 2 , guanidino, phosphino, or arsino; 
         m is 1, n is an integer from 1 to 10, preferably 2 or 3; and 
         A −  is a physiologically acceptable anion; 
         wherein R, R′ and R″ each independently is H or C 1 -C 6  alkyl. 
       
     
     
         9 . The chlorophyll or bacteriochlorophyll compound according to  claim 8 , wherein the compound is a bacteriochlorophyll of formula II selected from the pharmaceutically acceptable salt with a monovalent or divalent alkaline or alkaline earth metal cation, or with NH 4   + , of the following compounds:
 Palladium 3 1 -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 1 -(2-sulfoethyl)amide;   Palladium 3 1 -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 1 -(2-sulfopropyl)amide;   Palladium 3 1 -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 1 ,17 3 -di-(2-sulfoethy)amide;   Palladium 3 1 -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 1 ,17 3 -di-(3-sulfopropyl)amide;   3 1 -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 1 -(2-sulfoethyl)amide;   3 1 -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 1 -(2-sulfopropyl)amide;   3 1 -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 1 ,17 3 -di-(2-sulfoethyl)amide; and   3 1 -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 1 ,17 3 -di-(3-sulfopropyl)amide.   
     
     
         10 . The compound according to  claim 8  selected from consisting of:
 Palladium 3 1 -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 1 -(2-sulfoethyl)amide dipotassium salt (herein WST11); 
 Palladium 3 1 -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 1 -(2-sulfopropyl)amide dipotassium salt (herein compound 1); 
 Palladium 3 1 -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 1 ,17 3 -di-(2-sulfoethy)amide dipotassium salt (herein compound 2); and 
 Palladium 3 1 -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 1 ,17 3 -di-(3-sulfopropyl)amide dipotassium salt (herein compound 3). 
 3 1 -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 1 -(2-sulfoethyl)amide dipotassium salt; 
 3 1 -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 1 -(2-sulfopropyl)amide dipotassium salt; 
 3 1 -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 1 ,17 3 -di-(2-sulfoethyl)amide dipotassium salt; and 
 3 1 -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 1 ,17 3 -di-(3-sulfopropyl)amide dipotassium salt. 
 
     
     
         11 . The chlorophyll or bacteriochlorophyll compound according to  claim 3 , wherein the compound is a bacteriochlorophyll of the formula I, wherein:
 M is Pd;   R 1  is OR 10   + , —NH—(CH 2 ) n —SO 3   − R 10   + , —NH—(CH 2 ) n —COO − R 10   + ; or —NH—(CH 2 ) n —PO 3   2− (R 10   + ) 2 ;   R 2  is COOCH 3 ;   R 3  is H;   R 4  is —C(═O)—CH 3 ;   R 5  is O;   R 10   +  is a monovalent cation such as K + , Na + , Li + , or NH 4   + ; and   n is an integer from 1 to 10, preferably 2 or 3.   
     
     
         12 . The chlorophyll or bacteriochlorophyll compound according to  claim 11 , wherein the compound is palladium bacteriopheophorbide or a pharmaceutically acceptable salt of palladium bacteriopheophorbide a 17 3 -(3-sulfopropyl)amide with a monovalent alkaline or alkaline earth metal cation, or with NH 4   + , preferably the potassium salt thereof. 
     
     
         13 . The chlorophyll or bacteriochlorophyll compound according to  claim 3 , wherein the compound is a chlorophyll or bacteriochlorophyll of the formula III, X is —NR 7 , R 7  is —NRR′, R is H and R′ is C 2 -C 6  alkyl substituted by SO 3   −  or an alkaline salt thereof, preferably R 7  is —NH—(CH 2 ) 3 —SO 3   − R 10   + , wherein R +   10  is a metal cation, an ammonium group or an organic cation, preferably K + . 
     
     
         14 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a chlorophyll or bacteriochlorophyll compound according to any one of  claims 1  to  13  for photodynamic therapy (PDT) of diseases, disorders and conditions associated with corneal or scleral anomaly. 
     
     
         15 . The pharmaceutical composition according to  claim 14 , wherein said corneal or scleral anomaly is corneal thinning and scleral stretching. 
     
     
         16 . The pharmaceutical composition according  claim 14  or  15 , further comprising a viscous agent for enhancing the viscosity of the formulation and restricting penetration of the chlorophyll or bacteriochlorophyll compound into the cornea. 
     
     
         17 . The pharmaceutical composition according to  claim 16 , wherein said viscous agent is a polymer, preferably a biopolymer. 
     
     
         18 . The pharmaceutical composition according to  claim 17 , wherein said is a polysaccharide selected from dextran, scleroglucan and derivatives thereof, Gellan gum, Guar gum or -methylcellulose. 
     
     
         19 . The pharmaceutical composition according  claim 14  or  15 , further comprising a transepithelial permeability enhancer for enhancing the penetration of the chlorophyll or bacteriochlorophyll compound through the epithelium. 
     
     
         20 . The pharmaceutical composition according to any one of  claims 14  to  19 , for topical application. 
     
     
         21 . The pharmaceutical composition according to any one of  claims 14 - 20 , for use in the photodynamic therapy before local irradiation of the eye with light at a red or near infrared (NIR) wavelength. 
     
     
         22 . A method for photodynamic therapy of corneal thinning comprising the steps of:
 (a) administering to an individual afflicted with corneal thinning chlorophyll or bacteriochlorophyll compound according to any one of  claims 1  to  13 , or a pharmaceutical composition according to any one of  claims 14  to  22 ; and (b) irradiating the eye with light at a red or near infrared (NIR) wavelength.   
     
     
         23 . A method for photodynamic therapy of scleral stretching comprising the steps of:
 (a) administering to an individual afflicted with scleral stretching a chlorophyll or bacteriochlorophyll compound according to any one of  claims 1  to  13 , or a pharmaceutical composition according to any one of  claims 14  to  22 ; and (b) irradiating the eye of with light at a red or near infrared (NIR) wavelength.   
     
     
         24 . A method for preventing a corneal and/or scleral disease or weakening before, during or after interventional procedures, comprising the steps of: (a) administering to an individual expected to be afflicted with corneal and/or scleral disease or weakening, a chlorophyll or bacteriochlorophyll compound according to any one of  claims 1  to  13 , or a pharmaceutical composition according to any one of  claims 14  to  22 ; and (b) irradiating the eye with light at a red or near infrared (NIR) wavelength. 
     
     
         25 . The chlorophyll or bacteriochlorophyll compound according to any one of  claims 1  to  13 , the pharmaceutical composition according to any one of  claims 14  to  21 , or the method according to any one of  claims 22  to  24 , wherein said diseases, disorders and conditions associated with corneal or scleral anomaly are selected from keratoconus, post-laser-assisted in situ keratomileusis (LASIK) ectasia, post-photorefractive keratectomy (PRK) ectasia, post-infection ectasia, peripheral ectasia, rheumatoid condition of the cornea, degenerative myopia, regular myopia, scleral staphyloma, ocular hypertension glaucoma, low tension glaucoma and combinations thereof. 
     
     
         26 . The chlorophyll or bacteriochlorophyll compound according to any one of  claims 1  to  13 , the pharmaceutical composition according to any one of  claims 14  to  21 , or the method according to any one of  claims 22  to  24 , wherein said scleral weakening diseases, disorders and conditions are selected from myopia, macular distortion, atrophy or visual loss.