Ring-expanded nucleosides and nucleotides

Abstract

The present invention relates to compositions comprising analogues of purine nucleosides containing a ring-expanded (“fat”) heterocyclic ring, in place of purine, and an unmodified or modified sugar residue, pharmaceutically acceptable derivatives of such compositions, as well as methods of use thereof. In particular, these compositions may be utilized in the treatment of certain cancers, bacterial, fungal, parasitic, and viral infections, including, but not limited to, Acquired Immunodeficiency Syndrome (AIDS), hepatitis, Epstein-Barr and cytomegalovirus.

1 - 23 . (canceled)  
   
   
       24 . A method of treating a viral, bacterial, fungal or parasitic infection in a patient or vertebrate animal comprising administering to said patient or vertebrate animal in an amount sufficient to effect said treatment, at least one of compounds comprising non-planar, non-aromatic, ring-expanded heterocyclic bases, nucleosides or nucleotides having the formula II  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  and R 2  are each independently selected from H, OR 3 , SR 3 , NHR 3 , CO 2 R 3 , CONHR 3 , and CONHNHR 3 , CH 2 OR 3 , CH 2 NHR 3 , and CH 2 R 3 ;  
 R 3 , R 4  and R 6  are each independently selected from:  
 hydrogen, a C 1 -C 20  alkyl group, an aryl group which is a substituted or unsubstituted phenyl or heterocyclic group, and an aralkyl group wherein the aryl and alkyl portions of the group have the meanings given above;  
 R 5  is selected from the group consisting of O, S and NH; and  
 R 7 , R 8  and R 9  each are independently selected from:  
 hydrogen, a C 1 -C 20  alkyl group, an aryl group which is a substituted or unsubstituted phenyl or heterocyclic group, and an aralkyl group wherein the aryl and alkyl portions of the groups have the meanings given above;  
 a glycosyl group wherein said glycosyl group is selected from the group consisting of ribosyl, 2′-deoxyribosyl, 2′3′-dideoxy-3′-azidoribosyl, 2′3′-dideoxy-2′-fluororiboxyl, 2′,3′-dideoxy-3′-fluororibosyl, 2′,3′-dideoxy-2′,3′-difluororiboxyl, and mono-, di- and triphosphate derivatives thereof; and  
 (CH 2 ) m —XR′—(CH 2 ) n —YR′ wherein R′ is selected from the group consisting of:  
 H, H 2 , H 2 PO 3 , H 3 P 2 O 6 , H 4 P 3 O 9 , and alkali metal or alkaline earth metal salts thereof;  
 m is zero to 20, n is zero to 20, and a is zero or on e;  
 U, X, Y, Z, W, J, K, and L are selected from the group consisting of C, N, O, P, and S;  
 and all chiral form and stereoisomers of said compounds.  
 
   
   
       25 . The method of  claim 24  wherein said infection is a virus infection.  
   
   
       26 . The method of  claim 24  wherein said viral infection is caused by a virus selected from the group consisting of human immunodeficiency virus, Human B lymphotropic virus, Herpes simplex virus, Varicella-zoster virus, Epstein-Barr virus, necrotic rhinitis, Malignant catarrh, Allerton virus, Equine herpesviruses, Neurolymphomatosis, Influenza viruses, Parainfluenza viruses, Adenoviruses, Rheovirus, Respiratory syncytial virus, Rhinoviruses, Coxsackie virus, Echo viruses, Epidemic gastroenteritis virus, Rubeola virus, Hepatitis viruses, cytomegalovirus virus and Papovavirus.  
   
   
       27 . The method of  claim 24  wherein said viral infection is caused by Hepatitis viruses.  
   
   
       28 . The method of  claim 24  wherein said viral infection is caused by Hepatitis B virus.  
   
   
       29 . The method of  claim 24  wherein said viral infection is caused by Epstein-Barr virus.  
   
   
       30 . The method of  claim 24  wherein said viral infection is caused by cytomegalovirus virus.  
   
   
       31 . The method of  claim 24  wherein said compound is administered subcutaneously, intravenously, intramuscularly, intraperitoneally, orally, topically, or by a combination thereof.  
   
   
       32 . The method of  claim 24  wherein said at least one compound is administered in combination with at least one known therapeutic agent.  
   
   
       33 . The method of  claim 24  wherein said compound is in a therapeutic form of a pharmaceutically acceptable salt, phosphonate, ester or salt of said ester, which provides said compound or its therapeutically effective metabolite during said treatment.  
   
   
       34 . A method of inhibiting the growth of cancer in a patient or vertebrate animal comprising administering to said patient or vertebrate animal in an amount sufficient to effect said inhibition, at least one of compounds comprising non-planar, non-aromatic, ring-expanded heterocyclic bases, nucleosides or nucleotides having the formula II  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  and R 2  are each independently selected from H, OR 3 , SR 3 , NHR 3 , CO 2 R 3 , CONHR 3 , and CONHNHR 3 , CH 2 OR 3 , CH 2 NHR 3 , and CH 2 R 3 ;  
 R 3 , R 4  and R 6  are each independently selected from:  
 hydrogen, a C 1 -C 20  alkyl group, an aryl group which is a substituted or unsubstituted phenyl or heterocyclic group, and an aralkyl group wherein the aryl and alkyl portions of the group have the meanings given above;  
 R 5  is selected from the group consisting of O, S and NH; and  
 R 7 , R 8  and R 9  each are independently selected from:  
 hydrogen, a C 1 -C 20  alkyl group, an aryl group which is a substituted or unsubstituted phenyl or heterocyclic group, and an aralkyl group wherein the aryl and alkyl portions of the groups have the meanings given above;  
 a glycosyl group wherein said glycosyl group is selected from the group consisting of ribosyl, 2′-deoxyribosyl, 2′3′-dideoxy-3′-azidoribosyl, 2′3′-dideoxy-2′-fluororiboxyl, 2′,3′-dideoxy-3′-fluororibosyl, 2′,3′-dideoxy-2′,3′-difluororiboxyl, and mono-, di- and triphosphate derivatives thereof; and  
 (CH 2 ) m —XR′—(CH 2 ) n —YR′ wherein R′ is selected from the group consisting of:  
 H, H 2 , H 2 PO 3 , H 3 P 2 O 6 , H 4 P 3 O 9 , and alkali metal or alkaline earth metal salts thereof;  
 m is zero to 20, n is zero to 20, and a is zero or one,  
 U, X, Y, Z, W, J, K, and L are selected from the group consisting of C, N, O, P, and S;  
 and all chiral form and stereoisomers of said compounds.  
 
   
   
       35 . The method of  claim 34  wherein said cancer is selected from the group consisting of leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and breast cancer.  
   
   
       36 . The method of  claim 34  wherein said compound is administered subcutaneously, intravenously, intramuscularly, intraperitoneally, orally, topically, or by a combination thereof.  
   
   
       37 . The method of  claim 34  wherein said at least one compound is administered in combination with at least one known therapeutic agent.  
   
   
       38 . The method of  claim 34  wherein said compound is in a therapeutic form of a pharmaceutically acceptable salt, phosphonate, ester or salt of said ester, which provides said compound or its therapeutically effective metabolite during said treatment.  
   
   
       39 . A method of inhibiting enzymatic activity of RNA polymerases in a patient or vertebrate animal comprising administering to said patient or vertebrate animal in an amount sufficient to effect said inhibition, at least one of compounds comprising non-planar, non-aromatic, ring-expanded heterocyclic bases, nucleosides or nucleotides having the formula II  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  and R 2  are each independently selected from H, OR 3 , SR 3 , NHR 3 , CO 2 R 3 , CONHR 3 , and CONHNHR 3 , CH 2 OR 3 , CH 2 NHR 3 , and CH 2 R 3 ;  
 R 3 , R 4  and R 6  are each independently selected from:  
 hydrogen, a C 1 -C 20  alkyl group, an aryl group which is a substituted or unsubstituted phenyl or heterocyclic group, and an aralkyl group wherein the aryl and alkyl portions of the group have the meanings given above;  
 R 5  is selected from the group consisting of O, S and NH; and  
 R 7 , R 8  and R 9 , each are independently selected from:  
 hydrogen, a C 1 -C 20  alkyl group, an aryl group which is a substituted or unsubstituted phenyl or heterocyclic group, and an aralkyl group wherein the aryl and alkyl portions of the groups have the meanings given above;  
 a glycosyl group wherein said glycosyl group is selected from the group consisting of ribosyl, 2′-deoxyribosyl, 2′3′-dideoxy-3′-azidoribosyl, 2′3′-dideoxy-2′-fluororiboxyl, 2′,3′-dideoxy-3′-fluororibosyl, 2′,3′-dideoxy-2′,3′-difluororiboxyl, and mono-, di- and triphosphate derivatives thereof; and  
 (CH 2 ) m —XR′—(CH 2 ) n —YR′ wherein R′ is selected from the group consisting of:  
 H, H 2 , H 2 PO 3 , H 3 P 2 O 6 , H 4 P 3 O 9 , and alkali metal or alkaline earth metal salts thereof;  
 m is zero to 20, n is zero to 20, and a is zero or one;  
 U, X, Y, Z, W, J, K, and L are selected from the group consisting of C, N, O, P, and S;  
 and all chiral form and stereoisomers of said compounds.  
 
   
   
       40 . The method of  claim 39  wherein said compound is administered subcutaneously, intravenously, intramuscularly, intraperitoneally, orally, topically, or by a combination thereof.  
   
   
       41 . The method of  claim 39  wherein said at least one compound is administered in combination with at least one known therapeutic agent.  
   
   
       42 . The method of  claim 39  wherein said compound is in a therapeutic form of a pharmaceutically acceptable salt, phosphonate, ester or salt of said ester, which provides said compound or its therapeutically effective metabolite during said treatment.  
   
   
       43 . A method of inhibiting enzymatic activity of adenosine deaminase and guanine deaminase in a patient or vertebrate animal comprising administering to said patient or vertebrate animal in an amount sufficient to effect said inhibition, at least one of compounds comprising non-planar, non-aromatic, ring-expanded heterocyclic bases, nucleosides or nucleotides having the formula II  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  and R 2  are each independently selected from H, OR 3 , SR 3 , NHR 3 , CO 2 R 3 , CONHR 3 , and CONHNHR 3 , CH 2 OR 3 , CH 2 NHR 3 , and CH 2 R 3 ;  
 R 3 , R 4  and R 6  are each independently selected from:  
 hydrogen, a C 1 -C 20  alkyl group, an aryl group which is a substituted or unsubstituted phenyl or heterocyclic group, and an aralkyl group wherein the aryl and alkyl portions of the group have the meanings given above;  
 R 5  is selected from the group consisting of O, S, and NH; and  
 R 7 , R 8  and R 9  each are independently selected from:  
 hydrogen, a C 1 -C 20  alkyl group, an aryl group which is a substituted or unsubstituted phenyl or heterocyclic group, and an aralkyl group wherein the aryl and alkyl portions of the groups have the meanings given above;  
 a glycosyl group wherein said glycosyl group is selected from the group consisting of ribosyl, 2′-deoxyribosyl, 2′3′-dideoxy-3′-azidoribosyl, 2′3′-dideoxy-2′-fluororiboxyl, 2′,3′-dideoxy-3′-fluororibosyl, 2′,3′-dideoxy-2′,3′-difluororiboxyl, and mono-, di- and triphosphate derivatives thereof; and  
 (CH 2 ) m —XR′—(CH 2 ) n —YR′ wherein R′ is selected from the group consisting of:  
 H, H 2 , H 2 PO 3 , H 3 P 2 O 6 , H 4 P 3 O 9 , and alkali metal or alkaline earth metal salts thereof;  
 m is zero to 20, n is zero to 20, and a is zero or one;  
 U, X, Y, Z, W, J, K, and L are selected from the group consisting of C, N, O, P, and S;  
 and all chiral form and stereoisomers of said compounds.  
 
   
   
       44 . The method of  claim 43  wherein said compound is administered subcutaneously, intravenously, intramuscularly, intraperitoneally, orally, topically, or by a combination thereof.  
   
   
       45 . The method of  claim 43  wherein said at least one compound is administered in combination with at least one known therapeutic agent.  
   
   
       46 . The method of  claim 43  wherein said compound is in a therapeutic form of a pharmaceutically acceptable salt, phosphonate, ester or salt of said ester, which provides said compound or its therapeutically effective metabolite during said treatment.  
   
   
       47 . A method of treating a viral, bacterial, fungal or parasitic infection in a patient or vertebrate animal comprising administering to said patient or vertebrate animal in an amount sufficient to effect said treatment, at least one of compounds comprising non-planar, non-aromatic, ring-expanded heterocyclic bases, nucleosides or nucleotides having the following formulas III and IV  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  and R 5  are each independently selected from O, S, and NH;  
 R 3  and R 4  are each independently selected from H, OR 2 , SR 2 , NHR 2 , CO 2 R 2 , CONHR 2 , CONHNHR 2 , CH 2 OR 2 , CH 2 NHR 2 , and CH 2 R 2 ;  
 R 2 , R 4  and R 6  are each independently selected from:  
 hydrogen, a C 1 -C 20  alkyl group, an aryl group which is a substituted or unsubstituted phenyl or heterocyclic group, and an aralkyl group wherein the aryl and alkyl portions of the group have the meanings given above;  
 R 7 , R 8 , and R 9  are each independently selected from:  
 hydrogen, a C 1 -C 20  alkyl group, an aryl group which is a substituted or unsubstituted phenyl or heterocyclic group, and an aralkyl group wherein the aryl and alkyl portions of the groups have the meanings given above;  
 a glycosyl group wherein said glycosyl group is selected from the group consisting of ribosyl, 2′-deoxyribosyl, 2′3′-dideoxy-3′-azidoribosyl, 2′,3′-dideoxy-2′-fluororibosyl, 2′,3′-dideoxy-3′-fluororibosyl, 2′,3′-dideoxy-2′3′-difluororibosyl, and mono-, di-, and triphosphate derivatives thereof;  
 (CH 2 ) m —XR′—(CH 2 ) n —YR′ wherein R′ is selected from:  
 hydrogen, H 2 PO 3 , H 3 P 2 O 6 , H 4 P 3 O 9 , and alkali metal or alkaline earth metal salts thereof;  
 m is zero to 20, n is zero to 20, and a is zero or one;  
 U, X, Y, Z, W, J, K, and L are selected from the group consisting of C, N, O, P, and S;  
 and all chiral forms and stereoisomers of said compounds.  
 
   
   
       48 . The method of  claim 47  wherein said infection is a virus infection.  
   
   
       49 . The method of  claim 47  wherein said viral infection is caused by a virus selected from the group consisting of human immunodeficiency virus, Human B lymphotropic virus, Herpes simplex virus, Varicella-zoster virus, Epstein-Barr virus, necrotic rhinitis, Malignant catarrh, Allerton virus, Equine herpesviruses, Neurolymphomatosis, Influenza viruses, Parainfluenza viruses, Adenoviruses, Rheovirus, Respiratory syncytial virus, Rhinoviruses, Coxsackie virus, Echo viruses, Epidemic gastroenteritis virus, Rubeola virus, Hepatitis viruses, cytomegalovirus virus and Papovavirus.  
   
   
       50 . The method of  claim 47  wherein said viral infection is caused by Hepatitis viruses.  
   
   
       51 . The method of  claim 47  wherein said viral infection is caused by Hepatitis B virus.  
   
   
       52 . The method of  claim 47  wherein said viral infection is caused by Epstein-Barr virus.  
   
   
       53 . The method of  claim 47  wherein said viral infection is caused by cytomegalovirus virus.  
   
   
       54 . The method of  claim 47  wherein said compound is administered subcutaneously, intravenously, intramuscularly, intraperitoneally, orally, topically, or by a combination thereof.  
   
   
       55 . The method of  claim 47  wherein said at least one compound is administered in combination with at least one known therapeutic agent.  
   
   
       56 . The method of  claim 47  wherein said compound is in a therapeutic form of a pharmaceutically acceptable salt, phosphonate, ester or salt of said ester, which provides said compound or its therapeutically effective metabolite during said treatment.  
   
   
       57 . A method of inhibiting the growth of cancer in a patient or vertebrate animal comprising administering to said patient or vertebrate animal in an amount sufficient to effect said inhibition, at least one of compounds comprising non-planar, non-aromatic, ring-expanded heterocyclic bases, nucleosides or nucleotides having the following formulas III and IV  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  and R 5  are each independently selected from O, S, and NH;  
 R 3  and R 4  are each independently selected from H, OR 2 , SR 2 , NHR 2,  CO 2 R 2 , CONHR 2 , CONHNHR 2 , CH 2 OR 2 , CH 2 NHR 2 , and CH 2 R 2 ;  
 R 2 , R 4  and R 6  are each independently selected from:  
 hydrogen, a C 1 -C 20  alkyl group, an aryl group which is a substituted or unsubstituted phenyl or heterocyclic group, and an aralkyl group wherein the aryl and alkyl portions of the group have the meanings given above;  
 R 7 , R 8 , and R 9  are each independently selected from:  
 hydrogen, a C 1 -C 20  alkyl group, an aryl group which is a substituted or unsubstituted phenyl or heterocyclic group, and an aralkyl group wherein the aryl and alkyl portions of the groups have the meanings given above;  
 a glycosyl group wherein said glycosyl group is selected from the group consisting of ribosyl, 2′-deoxyribosyl, 2′3′-dideoxy-3′-azidoribosyl, 2′,3′-dideoxy-2′-fluororibosyl, 2′,3′-dideoxy-3′-fluororibosyl, 2′,3′-dideoxy-2′3′-difluororibosyl, and mono-, di-, and triphosphate derivatives thereof;  
 (CH 2 ) m —XR′—(CH 2 ) n —YR′ wherein R′ is selected from:  
 hydrogen, H 2 PO 3 , H 3 P 2 O 6 , H 4 P 3 O 9 , and alkali metal or alkaline earth metal salts thereof;  
 m is zero to 20, n is zero to 20, and a is zero or one;  
 U, X, Y, Z, W, J, K, and L are selected from the group consisting of C, N, O, P, and S;  
 and all chiral forms and stereoisomers of said compounds.  
 
   
   
       58 . The method of  claim 57  wherein said cancer is selected from the group consisting of leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and breast cancer.  
   
   
       59 . The method of  claim 57  wherein said compound is administered subcutaneously, intravenously, intramuscularly, intraperitoneally, orally, topically, or by a combination thereof.  
   
   
       60 . The method of  claim 57  wherein said at least one compound is administered in combination with at least one known therapeutic agent.  
   
   
       61 . The method of  claim 57  wherein said compound is in a therapeutic form of a pharmaceutically acceptable salt, phosphonate, ester or salt of said ester, which provides said compound or its therapeutically effective metabolite during said treatment.  
   
   
       62 . A method of inhibiting enzymatic activity of RNA polymerases in a patient or vertebrate animal comprising administering to said patient or vertebrate animal in an amount sufficient to effect said inhibition, at least one of compounds comprising non-planar, non-aromatic, ring-expanded heterocyclic bases, nucleosides or nucleotides having the following formulas III and IV  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  and R 5  are each independently selected from O, S, and NH;  
 R 3  and R 4  are each independently selected from H, OR 2 , SR 2 , NHR 2 , CO 2 R 2 , CONHR 2 , CONHNHR 2 , CH 2 OR 2 , CH 2 NHR 2 , and CH 2 R 2 ;  
 R 2 , R 4  and R 6  are each independently selected from:  
 hydrogen, a C 1 -C 20  alkyl group, an aryl group which is a substituted or unsubstituted phenyl or heterocyclic group, and an aralkyl group wherein the aryl and alkyl portions of the group have the meanings given above;  
 R 7 , R 8 , and R 9  are each independently selected from:  
 hydrogen, a C 1 -C 20  alkyl group, an aryl group which is a substituted or unsubstituted phenyl or heterocyclic group, and an aralkyl group wherein the aryl and alkyl portions of the groups have the meanings given above;  
 a glycosyl group wherein said glycosyl group is selected from the group consisting of ribosyl, 2′-deoxyribosyl, 2′3′-dideoxy-3′-azidoribosyl, 2′,3′-dideoxy-2′-fluororibosyl, 2′,3′-dideoxy-3′-fluororibosyl, 2′,3′-dideoxy-2′3′-difluororibosyl, and mono, di-, and triphosphate derivatives thereof;  
 (CH 2 ) m —XR′—(CH 2 ) n —YR′ wherein R′ is selected from:  
 hydrogen, H 2 PO 3 , H 3 P 2 O 6 , H 4 P 3 O 9 , and alkali metal or alkaline earth metal salts thereof;  
 m is zero to 20, n is zero to 20, and a is zero or one;  
 U, X, Y, Z, W, J, K, and L are selected from the group consisting of C, N, O, P, and S;  
 and all chiral forms and stereoisomers of said compounds.  
 
   
   
       63 . The method of  claim 62  wherein said compound is administered subcutaneously, intravenously, intramuscularly, intraperitoneally, orally, topically, or by a combination thereof.  
   
   
       64 . The method of  claim 62  wherein said at least one compound is administered in combination with at least one known therapeutic agent.  
   
   
       65 . The method of  claim 62  wherein said compound is in a therapeutic form of a pharmaceutically acceptable salt, phosphonate, ester or salt of said ester, which provides said compound or its therapeutically effective metabolite during said treatment.  
   
   
       66 . A method of inhibiting enzymatic activity of adenosine deaminase and guanine deaminase in a patient or vertebrate animal comprising administering to said patient or vertebrate animal in an amount sufficient to effect said inhibition, at least one of compounds comprising non-planar, non-aromatic, ring-expanded heterocyclic bases, nucleosides or nucleotides having the following formulas III and IV  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  and R 5  are each independently selected from O, S, and NH;  
 R 3  and R 4  are each independently selected from H, OR 2 , SR 2 , NHR 2 , CO 2 R 2 , CONHR 2 , CONHNHR 2 , CH 2 OR 2 , CH 2 NHR 2 , and CH 2 R 2 ;  
 R 2 , R 4  and R 6  are each independently selected from:  
 hydrogen, a C 1 -C 20  alkyl group, an aryl group which is a substituted or unsubstituted phenyl or heterocyclic group, and an aralkyl group wherein the aryl and alkyl portions of the group have the meanings given above;  
 R 7 , R 8 , and R 9  are each independently selected from:  
 hydrogen, a C 1 -C 20  alkyl group, an aryl group which is a substituted or unsubstituted phenyl or heterocyclic group, and an aralkyl group wherein the aryl and alkyl portions of the groups have the meanings given above;  
 a glycosyl group wherein said glycosyl group is selected from the group consisting of ribosyl, 2′-deoxyribosyl, 2′3′-dideoxy-3′-azidoribosyl, 2′,3′-dideoxy-2′-fluororibosyl, 2′,3′-dideoxy-3′-fluororibosyl, 2′,3′-dideoxy-2′3′-difluororibosyl, and mono-, di-, and triphosphate derivatives thereof;  
 (CH 2 ) m —XR′—(CH 2 ) n —YR′ wherein R′ is selected from:  
 hydrogen, H 2 PO 3 , H 3 P 2 O 6 , H 4 P 3 O 9 , and alkali metal or alkaline earth metal salts thereof;  
 m is zero to 20, n is zero to 20, and a is zero or one;  
 U, X, Y, Z, W, J, K, and L are selected from the group consisting of C, N, O, P, and S;  
 and all chiral forms and stereoisomers of said compounds.  
 
   
   
       67 . The method of  claim 66  wherein said compound is administered subcutaneously, intravenously, intramuscularly, intraperitoneally, orally, topically, or by a combination thereof.  
   
   
       68 . The method of  claim 66  wherein said at least one compound is administered in combination with at least one known therapeutic agent.  
   
   
       69 . The method of  claim 66  wherein said compound is in a therapeutic form of a pharmaceutically acceptable salt, phosphonate, ester or salt of said ester, which provides said compound or its therapeutically effective metabolite during said treatment.  
   
   
       70 - 77 . (canceled)