Di-n-heterocyclic compounds, methods, and compositions for inhibiting parp activity

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula I:

• or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof, wherein:
• Y represents the atoms necessary to form a 6-membered, arom atic or non-aromatic, heterocyclic ring containing at least one nitrogen heteroatom in a 1,3-relationship with the nitrogen atom depicted in formula I, wherein Y may be unsubstituted or substituted with at least one alkyl, alkenyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, double bonded oxygen, or --COOR.sup.5 group, or a moiety selected from the group consisting of:
• ##STR51## wherein R.sup.5 and R.sup.7 are independently hydrogen or alkyl, alkenyl, cycloalkyl, cycloalkenyl, aralkyl, or aryl.

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula I:

• or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof, wherein the compound of formula I is present in an amount that is effective for treating diabetes:
• Y represents the atoms necessary to form a fused 6-membered, aromatic or non-aromatic, heterocyclic ring containing at least one nitrogen heteroatom in a 1,3-relationship with the nitrogen atom depicted in formula I, wherein Y may be unsubstituted or substituted with at least one alkyl, alkenyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, double bonded oxygen, or --COOR.sup.5 group, or a moiety selected from the group consisting of:
• ##STR63## wherein R.sup.5 and R.sup.7 are independently hydrogen or alkyl, alkenyl, cycloalkyl, cycloalkenyl, aralkyl, or aryl.

A method of inhibiting PARP activity comprising administering a compound of formula I:

• or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof, wherein:
• Y represents the atoms necessary to form a fused 6-membered, aromatic or non-aromatic, heterocyclic ring containing at least one nitrogen heteroatom in a 1,3-relationship with the nitrogen atom depicted in formula I, wherein Y may be unsubstituted or substituted with at least one alkyl, alkenyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, double bonded oxygen, or --COOR.sup.5 group, or a moiety selected from the group consisting of:
• ##STR81## wherein R.sup.5 and R.sup.7 are independently hydrogen or alkyl, alkenyl, cycloalkyl, cycloalkenyl, aralkyl, or aryl.

A method of effecting a neuronal activity not mediated by NMDA toxicity in an animal comprising administering to said animal an effective amount of a compound of formula I:

• or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof, wherein:
• Y represents the atoms necessary to form a fused 6-membered, aromatic or non-aromatic, heterocyclic ring containing at least one nitrogen heteroatom in a 1,3-relationship with the nitrogen atom depicted in formula I, wherein Y may be unsubstituted or substituted with at least one alkyl, alkenyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, double bonded oxygen, or --COOR.sup.5 group, or a moiety selected from the group consisting of:
• ##STR83## wherein R.sup.5 and R.sup.7 are independently hydrogen or alkyl, alkenyl, cycloalkyl, cycloalkenyl, aralkyl, or aryl.

A method of treating arthritis in an animal comprising administering to said animal an effective amount of a compound of formula I:

• or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof, wherein:
• Y represents the atoms necessary to form a fused 6-membered, aromatic or non-aromatic, heterocyclic ring containing at least one nitrogen heteroatom in a 1,3-relationship with the nitrogen atom depicted in formula I, wherein Y may be unsubstituted or substituted with at least one alkyl, alkenyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, double bonded oxygen, or --COOR.sup.5 group, or a moiety selected from the group consisting of:
• ##STR86## wherein R.sup.5 and R.sup.7 are independently hydrogen or alkyl, alkenyl, cycloalkyl, cycloalkenyl, aralkyl, or aryl.

A method of treating diabetes in an animal comprising administering to said animal an effective amount of a compound of formula I:

• ##STR88## or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof, wherein:
• Y represents the atoms necessary to form a fused 6-membered, aromatic or non-aromatic, heterocyclic ring containing at least one nitrogen heteroatom in a 1,3-relationship with the nitrogen atom depicted in formula I, wherein Y may be unsubstituted or substituted with at least one alkyl, alkenyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, double bonded oxygen, or --COOR.sup.5 group, or a moiety selected from the group consisting of:
• ##STR89## wherein R.sup.5 and R.sup.7 are independently hydrogen or alkyl, alkenyl, cycloalkyl, cycloalkenyl, aralkyl, or aryl.

A method of treating an inflammatory bowel disorder in an animal comprising administering to said animal an effective amount of a compound of formula I:

• or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof, wherein:
• Y represents the atoms necessary to form a fused 6-membered, aromatic or non-aromatic, heterocyclic ring containing at least one nitrogen heteroatom in a 1,3-relationship with the nitrogen atom depicted in formula I, wherein Y may be unsubstituted or substituted with at least one alkyl, alkenyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, double bonded oxygen, or --COOR.sup.5 group, or a moiety selected from the group consisting of:
• ##STR91## wherein R.sup.5 and R.sup.7 are independently hydrogen or alkyl, alkenyl, cycloalkyl, cycloalkenyl, aralkyl, or aryl.

A method of treating a cardiovascular disorder in an animal comprising administering to said animal an effective amount of a compound of formula I:

• or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof, wherein:
• Y represents the atoms necessary to form a fused 6-membered, aromatic or non-aromatic, heterocyclic ring containing at least one nitrogen heteroatom in a 1,3-relationship with the nitrogen atom depicted in formula I, wherein Y may be unsubstituted or substituted with at least one alkyl, alkenyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, double bonded oxygen, or --COOR.sup.5 group, or a moiety selected from the group consisting of:
• ##STR93## wherein R.sup.5 and R.sup.7 are independently hydrogen or alkyl, alkenyl, cycloalkyl, cycloalkenyl, aralkyl, or aryl.

A method of treating septic shock in an animal comprising administering to said animal an effective amount of a compound of formula I:

• or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof, wherein:
• Y represents the atoms necessary to form a fused 6-membered, aromatic or non-aromatic, heterocyclic ring containing at least one nitrogen heteroatom in a 1,3-relationship with the nitrogen atom depicted in formula I, wherein Y may be unsubstituted or substituted with at least one alkyl, alkenyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, double bonded oxygen, or --COOR.sup.5 group, or a moiety selected from the group consisting of:
• ##STR96## wherein R.sup.5 and R.sup.7 are independently hydrogen or alkyl, alkenyl, cycloalkyl, cycloalkenyl, aralkyl, or aryl.

A method of treating cancer in an animal comprising administering to said animal an effective amount of a compound of formula I:

• or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof, wherein:
• Y represents the atoms necessary to form a fused 6-membered, aromatic or non-aromatic, heterocyclic ring containing at least one nitrogen heteroatom in a 1,3-relationship with the nitrogen atom depicted in formula I, wherein Y may be unsubstituted or substituted with at least one alkyl, alkenyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, double bonded oxygen, or --COOR.sup.5 group, or a moiety selected from the group consisting of:
• ##STR98## wherein R.sup.5 and R.sup.7 are independently hydrogen or alkyl, alkenyl, cycloalkyl, cycloalkenyl, aralkyl, or aryl.

A method of radiosensitizing tumor cells comprising administering an effective amount of a compound of formula I:

• or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof, wherein:
• Y represents the atoms necessary to form a fused 6-membered, aromatic or non-aromatic, heterocyclic ring containing at least one nitrogen heteroatom in a 1,3-relationship with the nitrogen atom depicted in formula I, wherein Y may be unsubstituted or substituted with at least one alkyl, alkenyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, double bonded oxygen, or --COOR.sup.5 group, or a moiety selected from the group consisting of:
• ##STR100## wherein R.sup.5 and R.sup.7 are independently hydrogen or alkyl, alkenyl, cycloalkyl, cycloalkenyl, aralkyl, or aryl.

A method of extending or increasing the lifespan or proliferative capacity of cells or altering gene expression of senescent cells comprising administering an effective amount of a compound of formula I:

• ##STR102## or a pharmaceutically acceptable salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof, wherein:
• Y represents the atoms necessary to form a fused 6-membered, aromatic or non-aromatic, heterocyclic ring containing at least one nitrogen heteroatom in a 1,3-relationship with the nitrogen atom depicted in formula I, wherein Y may be unsubstituted or substituted with at least one alkyl, alkenyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, double bonded oxygen, or --COOR.sup.5 group, or a moiety selected from the group consisting of:
• ##STR103## wherein R.sup.5 and R.sup.7 are independently hydrogen or alkyl, alkenyl, cycloalkyl, cycloalkenyl, aralkyl, or aryl.