Ring-expanded nucleosides and nucleotides
AssigneesNabi, University of Maryland, Baltimore County
InventorsRamachandra S. Hosmane, Ramesh K. Sood
Life of this patent
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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.
Claims31
A method of treating a viral infection in a patient or vertebrate animal in need thereof comprising administering to said patient or vertebrate animal in an amount sufficient to effect said treatment, at least one of potentially planar, aromatic, ring-expanded heterocyclic bases, nucleosides and nucleotide compounds having the structure
- wherein:
- R1, R3 and R5 are each independently selected from the group consisting of:
- NH, NH2, O, OH, S, and SH;
- NH-alkyl, N-alkyl, O-alkyl and S-alkyl wherein the alkyl group is C1-C20;
- NH-aryl, O-aryl and S-aryl wherein the aryl group is a substituted or unsubstituted phenyl or a heterocyclic group;
- R2, R4, R7, and R8 are independently selected from the group consisting of hydrogen, C1-C20 alkyl, substituted phenyl, unsubstituted phenyl, unsubstituted heterocycle, substituted heterocycle, aralkyl wherein the alkyl containing 1 to 6 carbon atoms and the aryl is substituted or unsubstituted;
- R6 is selected from the group consisting of
- hydrogen,
- C1-C20 alkyl,
- substituted phenyl,
- unsubstituted phenyl,
- unsubstituted heterocycle,
- substituted heterocycle, and
- aralkyl wherein the alkyl containing 1 to 6 carbon atoms and the aryl is substituted or unsubstituted;
- a glycosyl group selected from the group consisting of ribosyl, 2′-deoxyribosyl, 2′,3′-dideoxyribosyl, 2′,3′-dideoxy-2′-fluororibosyl, 2′,3′-dideoxy-3′-fluororibosyl, 2′,3′-dideoxy-2′,3′-fluororibosyl, 2′,3′-dideoxy-3′-azidoribosyl and mono-, di-, and triphosphate derivatives thereof;
- —(CH2)m+n+1—R′
- —(CH2)m—O—(CH2)n—O—R′;
- —(CH2)m+1—O—R′;
- —(CH2)m—O—(CH2)n—R′;
- wherein R′ is selected from the group consisting of:
- hydrogen, H2PO3, H3P2O6, H4P3O9, 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 and N;
- and all chiral forms and stereoisomers of said compounds.
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 potentially planar, aromatic, ring-expanded heterocyclic bases, nucleosides and nucleotide compounds having the structure
- wherein:
- R1, R3 and R5 are each independently selected from the group consisting of:
- NH, NH2, O, OH, S, and SH;
- NH-alkyl, N-alkyl, O-alkyl and S-alkyl wherein the alkyl group is C1-C20;
- NH-aryl, O-aryl and S-aryl wherein the aryl group is a substituted or unsubstituted phenyl or a heterocyclic group;
- R2, R4, R7, and R8 are independently selected from the group consisting of hydrogen, C1-C20 alkyl, substituted phenyl, unsubstituted phenyl, unsubstituted heterocycle, substituted heterocycle, aralkyl wherein the alkyl containing 1 to 6 carbon atoms and the aryl is substituted or unsubstituted;
- R6 is selected from the group consisting of
- hydrogen,
- C1-C20 alkyl,
- substituted phenyl,
- unsubstituted phenyl,
- unsubstituted heterocycle,
- substituted heterocycle, and
- aralkyl wherein the alkyl containing 1 to 6 carbon atoms and the aryl is substituted or unsubstituted;
- a glycosyl group selected from the group consisting of ribosyl, 2′-deoxyribosyl, 2′,3′-dideoxyribosyl, 2′,3′-dideoxy-2′-fluororibosyl, 2′,3′-dideoxy-3′-fluororibosyl, 2′,3′-dideoxy-2′,3′-fluororibosyl, 2′,3′-dideoxy-3′-azidoribosyl and mono-, di-, and triphosphate derivatives thereof;
- —(CH2)m+n+1—R′
- —(CH2)m—O—(CH2)n—O—R′;
- —(CH2)m+1—O—R′;
- —(CH2)m—O—(CH2)n—R′;
- wherein R′ is selected from the group consisting of:
- hydrogen, H2PO3, H3P2O6, H4P3O9, 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 and N;
- and all chiral forms and stereoisomers of said compounds.
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 potentially planar, aromatic, ring-expanded heterocyclic bases, nucleosides and nucleotide compounds having the structure
- wherein:
- R1, R3 and R5 are each independently selected from the group consisting of:
- NH, NH2, O, OH, S, and SH;
- NH-alkyl, N-alkyl, O-alkyl and S-alkyl wherein the alkyl group is C1-C20;
- NH-aryl, O-aryl and S-aryl wherein the aryl group is a substituted or unsubstituted phenyl or a heterocyclic group;
- R2, R4, R7, and R8 are independently selected from the group consisting of hydrogen, C1-C20 alkyl, substituted phenyl, unsubstituted phenyl, unsubstituted heterocycle, substituted heterocycle, aralkyl wherein the alkyl containing 1 to 6 carbon atoms and the aryl is substituted or unsubstituted;
- R6 is selected from the group consisting of
- hydrogen,
- C1-C20 alkyl,
- substituted phenyl,
- unsubstituted phenyl,
- unsubstituted heterocycle,
- substituted heterocycle, and
- aralkyl wherein the alkyl containing 1 to 6 carbon atoms and the aryl is substituted or unsubstituted;
- a glycosyl group selected from the group consisting of ribosyl, 2′-deoxyribosyl, 2′,3′-dideoxyribosyl, 2′,3′-dideoxy-2′-fluororibosyl, 2′,3′-dideoxy-3′-fluororibosyl, 2′,3′-dideoxy-2′,3′-fluororibosyl, 2′,3′-dideoxy-3′-azidoribosyl and mono-, di-, and triphosphate derivatives thereof;
- —(CH2)m+n+1—R′
- —(CH2)m—O—(CH2)n—O—R′;
- —(CH2)m+1—O—R′;
- —(CH2)m—O—(CH2)n—R′;
- wherein R′ is selected from the group consisting of:
- hydrogen, H2PO3, H3P2O6, H4P3O9, 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 and N;
- and all chiral forms and stereoisomers of said compounds.
A method of inhibiting enzymatic activity of adenosine deaminase and/or 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 potentially planar, aromatic, ring-expanded heterocyclic bases, nucleosides and nucleotide compounds having the structure
- wherein:
- R1, R3 and R5 are each independently selected from the group consisting of:
- NH, NH2, O, OH, S, and SH;
- NH-alkyl, N-alkyl, O-alkyl and S-alkyl wherein the alkyl group is C1-C20;
- NH-aryl, O-aryl and S-aryl wherein the aryl group is a substituted or unsubstituted phenyl or a heterocyclic group;
- R2, R4, R7, and R8 are independently selected from the group consisting of hydrogen, C1-C20 alkyl, substituted phenyl, unsubstituted phenyl, unsubstituted heterocycle, substituted heterocycle, aralkyl wherein the alkyl containing 1 to 6 carbon atoms and the aryl is substituted or unsubstituted;
- R6 is selected from the group consisting of
- hydrogen,
- C1-C20 alkyl,
- substituted phenyl,
- unsubstituted phenyl,
- unsubstituted heterocycle,
- substituted heterocycle, and
- aralkyl wherein the alkyl containing 1 to 6 carbon atoms and the aryl is substituted or unsubstituted;
- a glycosyl group selected from the group consisting of ribosyl, 2′-deoxyribosyl, 2′,3′-dideoxyribosyl, 2′,3′-dideoxy-2′-fluororibosyl, 2′,3′-dideoxy-3′-fluororibosyl, 2′,3′-dideoxy-2′,3′-fluororibosyl, 2′,3′-dideoxy-3′-azidoribosyl and mono-, di-, and triphosphate derivatives thereof;
- —(CH2)m+n+1—R′
- —(CH2)m—O—(CH2)n—O—R′;
- —(CH2)m+1—O—R′;
- —(CH2)m—O—(CH2)n—R′;
- wherein R′ is selected from the group consisting of:
- hydrogen, H2PO3, H3P2O6, H4P3O9, 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 and N;
- and all chiral forms and stereoisomers of said compounds.
A method of treating Hepatitis B in a patient or vertebrate animal comprising administering the following compound to said patient or vertebrate animal in an amount sufficient to effect said treatment, 6-imino-6H-1-β-D-ribofuranosyl-4,5,7,8-tetrahydroimidazo[4,5-e][1,3]diazepine-4,8-dione.
A method of treating Hepatitis B in a patient or vertebrate animal comprising administering the following compound to said patient or vertebrate animal in an amount sufficient to effect said treatment, 4,8-Diamino-6H-6-imino-1-β-D-ribofuranosylimidazo[4,5-e][1,3]diazepine.
Dependencies are inferred from the claim text.