New 5-aminolevulinic acid prodrugs for use in photodynamic therapy and photodynamic diagnosis

Abstract

There is provided a compound of Formula and salts thereof wherein R 1 is an imine or an alkylated imine, said imine or alkylated imine comprising a linear or branched alkyl group of length C1 to C5; R 2 are each independently (a) an unsubstituted or substituted linear or branched alkyl group of chain length C 1-7 ; (b) an aryl substituted alkyl group, wherein said aryl group is substituted, (c) an alkoxy substituted alkyl group, wherein said alkoxy group is substituted by a methoxy group or an alkoxy group substituted with an alkoxy group; or (d) an H atom; wherein said substituents in (a) and (b) are selected from hydroxy, alkoxy, acyloxy, alkoxycarbonyloxy, amino, aryl, nitro, oxo and fluoro groups. R 3 and R 4 are linear or branched alkyl groups of length C1 to C6 constituting a ketal or a cyclic ketal. The compounds claimed may be used for the manufacture of a medicament.

1 . A compound of Formula 
       
         
           
           
               
               
           
         
         and salts thereof for use as a medicament 
         wherein 
         R 1  is an oxime, an alkylated oxime, an imine, a alkylated imine, or a hydrazine; 
         wherein 
         said alkylated oxime or imine comprises a linear or branched alkyl group of length C1 to C5; 
         R 2  are each independently: 
         (a) an unsubstituted or substituted linear or branched alkyl group of chain length C 1-7 ; 
         (b) an aryl substituted alkyl group, wherein said aryl group is substituted, 
         (c) an alkoxy substituted alkyl group, wherein said alkoxy group is substituted by a methoxy group or an alkoxy group substituted with an alkoxy group; or 
         (d) an H atom; 
         wherein said substituents in (a) and (b) are selected from hydroxy, alkoxy, acyloxy, alkoxycarbonyloxy, amino, aryl, nitro, oxo and fluoro groups. 
         R 3  and R 4  are linear or branched alkyl groups of length C1 to C6 constituting a ketal or a cyclic ketal. 
       
     
     
         2 - 3 . (canceled) 
     
     
         4 . A compound of Formula 
       
         
           
           
               
               
           
         
         and salts thereof 
         wherein 
         R 1  is an imine or an alkylated imine, said imine or alkylated imine comprising a linear or branched alkyl group of length C1 to C5; 
         R 2  are each independently 
         (a) an unsubstituted or substituted linear or branched alkyl group of chain length C 1-7 ; 
         (b) an aryl substituted alkyl group, wherein said aryl group is substituted, 
         (c) an alkoxy substituted alkyl group, wherein said alkoxy group is substituted by a methoxy group or an alkoxy group substituted with an alkoxy group; or 
         (d) an H atom; 
         wherein said substituents in (a) and (b) are selected from hydroxy, alkoxy, acyloxy, alkoxycarbonyloxy, amino, aryl, nitro, oxo and fluoro groups. 
         R 3  and R 4  are linear or branched alkyl groups of length C1 to C6 constituting a ketal or a cyclic ketal. 
       
     
     
         5 . A compound according to  claim 1  wherein the C 1-7  alkyl group in (a) is a linear or branched alkyl chain of length C 1  to C 7 , chosen from methyl, ethyl, propyl, butyl, pentyl, hexyl, and hepty,groups and iso-forms thereof. 
     
     
         6 . A compound according to  claim 1  wherein the alkyl group in (a) or (b) is interrupted or terminated by one or more —O—, NR x —, —S— or PR x — groups, wherein R x  represents a hydrogen or C 1-6  alkyl group. 
     
     
         7 . A compound according to  claim 1  wherein the pharmaceutically acceptable salt is
 (i) a hydrophilic acid addition salt of an organic or inorganic acid chosen from hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic, fumaric and ascorbic acid; or alternatively 
 (ii) a hydrophobic salt chosen from acetate, bromide, chloride, citrate, hydrochloride, maleate, mesylate, nitrate, phosphate, sulphate, tartrate, oleate, stearate, tosylate, calcium, meglumine, potassium, and sodium salt. 
 
     
     
         8 . A pharmaceutical composition comprising a compound according to  claim 1 , and at least one pharmaceutically acceptable carrier or excipient. 
     
     
         9 . A pharmaceutical composition according to  claim 8 , wherein said compound is present in an amount in the range of 0.01 to 90% by weight. 
     
     
         10 . A pharmaceutical composition according to  claim 8 , wherein said compound is present in an amount in the range of 0.05 to 50% by weight. 
     
     
         11 . A pharmaceutical composition according to  claim 8 , wherein said compound is present in an amount in the range of 1 to 20% by weight. 
     
     
         12 . A pharmaceutical composition according to  claim 8 , in a form suitable for systemic, intratumoral, intradermal, subcutaneous, intraperitoneal, intracavitary, intraocular or intravenous injection, or topical administration. 
     
     
         13 . A pharmaceutical composition according to  claim 8 , additionally comprising one or several compounds chosen from:
 (a) chelating agents   (b) inhibitors of ferrochelatase   (c) immunotherapeutic agents   (d) angiogenesis inhibitors   (e) surface penetration assisting agents   (f) photosensitizing agents   (g) glucose   (h) anti-cancer agents; and   (i) anaesthetic or analgesic agents   
     
     
         14 . A method of diagnosis or photochemotherapeutic treatment of disorders or abnormalities of the body, comprising administering to an affected tissue, a composition as defined in  claim 1 , and exposing said tissue to light. 
     
     
         15 . A method according to  claim 14 , additionally comprising prior to the treatment a pre-treatment step with a surface penetration assisting agent. 
     
     
         16 . A method according to  claim 14 , additionally comprising treatment with an anaesthetic agent. 
     
     
         17 . A method of in vivo diagnosis or photochemotherapeutic treatment of disorders or abnormalities of human or animal tissue, comprising: a) administering to said tissue, a composition comprising a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical carrier or excipient; and b) exposing said tissue to light in the wavelength region of 300-800 nm. 
     
     
         18 . An assay for in vitro diagnosis of human or animal abnormalities or disorders, comprising:
 i) providing a sample of body fluid or tissue; ii)admixing said body fluid or tissue with a composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical carrier or excipient compound; iii) exposing said mixture to light, iv) ascertaining the level of fluorescence, and v) comparing the level of fluorescence to control levels.   
     
     
         19 . A kit comprising a compound according to  claim 4  in solid form, a solvent, and optionally additionally comprising one or more anaesthetic agents.