Novel derivatives of purinic and pyrimidinic antiviral agents and use thereof as potent anticancer agents

Abstract

Novel N-acylated, O-acylated and (bis or tris)-N,O-acylated derivatives of purinic and pyrimidinic nucleoside analogs, pharmaceutical compositions containing same, and uses thereof for treating proliferative diseases or disorders are disclosed.

1 - 55 . (canceled) 
     
     
         56 . A compound having Formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is selected from the group consisting of H and —CH 2 OR 5 ; and 
         R 2 , R 3 , R 4  and R 5  are each independently hydrogen or an acyl moiety selected from the group consisting of valproyl, 4-phenylbutyryl, cinnamoyl, 2-(4-isobutylphenyl)propionyl, 1-(butyryloxymethoxy)succinyl, 1-(valproyloxymethoxy)succinyl, 1-(4-phenylbutyryloxymethoxy)succinyl, 1-(cinnamoyloxymethoxy)succinyl, 1-(phenylacetoxymethoxy)succinyl and 1-(2-(4-isobutylphenyl)propionyloxymethoxy)succinyl, 
         provided that at least one of R 2 , R 3  and R 4  is said acyl moiety. 
       
     
     
         57 . The compound of  claim 56 , wherein R 2 , R 3 , R 4  and R 5  are each independently selected from the group consisting of H, 4-phenylbutyryl, cinnamoyl and valproyl. 
     
     
         58 . The compound of  claim 56 , wherein R 1  is H. 
     
     
         59 . The compound of  claim 58 , wherein R 4  is H. 
     
     
         60 . The compound of  claim 59 , wherein R 2  and R 3  are each cinnamoyl. 
     
     
         61 . The compound of  claim 59 , wherein R 2  is valproyl and R 3  is H. 
     
     
         62 . The compound of  claim 59 , wherein R 2  is 4-phenylbutyryl and R 3  is H. 
     
     
         63 . The compound of  claim 59 , wherein R 3  is valproyl and R 2  is H. 
     
     
         64 . The compound of  claim 59 , wherein R 2  is 2-(4-isobutylphenyl)propionyl and R 3  is H. 
     
     
         65 . The compound of  claim 59 , wherein R 2  and R 3  are each valproyl. 
     
     
         66 . N-valproyl-9-(2-valproyloxy)ethoxymethylguanine. 
     
     
         67 . A compound having Formula II:
   A-X—B  Formula II
   wherein:   X is a purinic or pyrimidinic nucleoside analog having at least one hydroxyl group and/or at least one amino group;   A is one or two acyl moieties attached to an amino group of said X or absent; and   B is an acyl moiety attached to a hydroxyl group of said X or absent;   each of said acyl moieties, if present, being independently selected from the group consisting of a —C(═Y 1 )—Ra group and a —C(═Y 2 )-L-C(═Y 3 )—OCH 2 C(═Y 4 )—Rb group, whereas:   Ra and Rb are each independently selected from the group consisting of a substituted or non-substituted alkyl having 1-20 carbon atoms and a substituted or non-substituted alkenyl having 2-20 carbon atoms;   L is selected from the group consisting of a substituted or non-substituted alkyl having 1-4 carbon atoms and a substituted or non-substituted alkenyl having 2-4 carbon atoms; and   Y 1 , Y 2 , Y 3  and Y 4  are each independently O or S,   provided that at least one of A and B is not absent,   with the proviso that when X is a purinic nucleoside analog, at least one of said acyl moieties is said —C(═Y 2 )-L-C(═Y 3 )—OCH 2 C(═Y 4 )—Rb group.   
     
     
         68 . The compound of  claim 67 , wherein each of said acyl moieties is independently derived from a carboxylic acid capable of inhibiting histone deacetylase. 
     
     
         69 . The compound of  claim 67 , wherein Ra and Rb are each independently selected from the group consisting of propyl, 3-phenylpropyl, 4-heptyl, phenylmethyl, 1-(4-isobutylphenyl)ethyl and styryl. 
     
     
         70 . The compound of  claim 67 , wherein at least one of said acyl moieties is valproyl. 
     
     
         71 . The compound of  claim 67 , wherein at least one of said acyl moieties is butyryl. 
     
     
         72 . The compound of  claim 67 , wherein said nucleoside analog has an antiviral activity triggered by viral thymidine kinase (V-TK). 
     
     
         73 . The compound of  claim 67 , wherein said nucleoside analog is selected from the group consisting of abacavir, acyclovir, adefovir, brivudine, cidofovir, clevudine, didanosine, edoxudine, emtricitabine, entecavir, famciclovir, floxuridine, ganciclovir, idoxuridine, inosine pranobex, lamivudine, penciclovir, sorivudine, stavudine, ribavirin, telbivudine, tenofovir, trifluridine, valacyclovir, valganciclovir, vidarabine, zalcitabine, and zidovudine. 
     
     
         74 . The compound of  claim 67 , wherein B is said —C(═Y 2 )-L-C(═Y 3 )—OCH 2 OC(═Y 4 )—Rb. 
     
     
         75 . A pharmaceutical composition comprising the compound of  claim 56  and a pharmaceutically acceptable carrier. 
     
     
         76 . A pharmaceutical composition comprising the compound of  claim 67  and a pharmaceutically acceptable carrier. 
     
     
         77 . The pharmaceutical composition of  claim 75 , being packaged in packaging material and identified in print, in or on said packaging material, for use in the treatment of a proliferative disorder or disease. 
     
     
         78 . The pharmaceutical composition of  claim 76 , being packaged in packaging material and identified in print, in or on said packaging material, for use in the treatment of a proliferative disorder or disease. 
     
     
         79 . A method of treating a proliferative disorder or disease, the method comprising administering to a subject in need thereof an effective amount of the compound of  claim 56 . 
     
     
         80 . A method of treating a proliferative disorder or disease, the method comprising administering to a subject in need thereof an effective amount of a compound having the formula:
   A-X—B  Formula III
   wherein:   X is a purinic or pyrimidinic nucleoside analog having at least one hydroxyl group and/or at least one amino group;   A is one or two acyl moieties attached to an amino group of said X or absent; and   B is an acyl moiety attached to a hydroxyl group of said X or absent;   each of said acyl moieties, if present, being independently selected from the group consisting of a —C(═Y 1 )—Ra group and a —C(═Y 2 )-L-C(═Y 3 )—OCH 2 C(═Y 4 )—Rb group, whereas Ra and Rb are each independently selected from the group consisting of a substituted or non-substituted alkyl having 1-20 carbon atoms and a substituted or non-substituted alkenyl having 2-20 carbon atoms, L is selected from the group consisting of a substituted or non-substituted alkyl having 1-4 carbon atoms and a substituted or non-substituted alkenyl having 2-4 carbon atoms, and Y 1 , Y 2 , Y 3  and Y 4  are each independently O or S,   provided that at least one of A and B is not absent.   
     
     
         81 . The method of  claim 80 , wherein each of said acyl moieties is independently derived from a carboxylic acid capable of inhibiting histone deacetylase. 
     
     
         82 . The method of  claim 80 , wherein Ra and Rb are each independently selected from the group consisting of propyl, 3-phenylpropyl, 4-heptyl, phenylmethyl, 1-(4-isobutylphenyl)ethyl and styryl. 
     
     
         83 . The method of  claim 80 , wherein at least one of said acyl moieties is valproyl. 
     
     
         84 . The method of  claim 83 , wherein B and at least one acyl moiety in A are both valproyl. 
     
     
         85 . The method of  claim 80 , wherein at least one of said acyl moieties is butyryl. 
     
     
         86 . The method of  claim 85 , wherein B and at least one acyl moiety in A are both butyryl. 
     
     
         87 . The method of  claim 80 , wherein said nucleoside analog has an antiviral activity triggered by viral thymidine kinase (V-TK). 
     
     
         88 . The method of  claim 80 , wherein said nucleoside analog is selected from the group consisting of abacavir, acyclovir, adefovir, brivudine, cidofovir, clevudine, didanosine, edoxudine, emtricitabine, entecavir, famciclovir, floxuridine, ganciclovir, idoxuridine, inosine pranobex, lamivudine, penciclovir, sorivudine, stavudine, ribavirin, telbivudine, tenofovir, trifluridine, valacyclovir, valganciclovir, vidarabine, zalcitabine, and zidovudine. 
     
     
         89 . The method of  claim 87 , wherein said nucleoside analog is selected from the group consisting of acyclovir and ganciclovir. 
     
     
         90 . The method of  claim 80 , wherein B is said —C(═Y 2 )-L-C(═Y 3 )—OCH 2 C(═Y 4 )—Rb. 
     
     
         91 . The method of  claim 80 , wherein said proliferative disorder or disease is characterized as being caused by a virus. 
     
     
         92 . The method of  claim 79 , wherein said proliferative disorder or disease is characterized as being caused by a virus. 
     
     
         93 . The composition of  claim 77 , wherein said proliferative disorder or disease is characterized as being caused by a virus. 
     
     
         94 . The composition of  claim 78 , wherein said proliferative disorder or disease is characterized as being caused by a virus.