Conjugates of dithiocarbamates with pharmacologically active agents and uses therefore

In the administration of a pharmacologically active agent to a subject for the treatment of a pathological condition, the improvement comprising attaching a dithiocarbamate-containing nitric oxide scavenger to said pharmacologically active agent via a covalent linkage prior to administration of said pharmacologically active agent to said subject, wherein the dithiocarbamate component of said compound has the structure I, as follows:

• ›R.sub.1 R.sub.2 N--C(S)S!.sub.x M.sup.+1,+2,+3 (I)
• wherein
• each of R.sub.1 and R.sub.2 is independently selected from a C.sub.1 up to C.sub.18 alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, aroyl, substituted aroyl, acyl, substituted acyl, or
• R.sub.1 and R.sub.2 can cooperate to form a 5-, 6- or 7-membered ring including N, R.sub.1, and R.sub.2, or
• R.sub.1 or R.sub.2 is a divalent moiety selected from the group consisting of alkylene, substituted alkylene, oxyalkylene, substituted oxyalkylene, alkenylene, and substituted alkenylene, wherein said divalent moiety serves as the same substituent for two dithiocarbamate structures, thereby linking said structures together so as to form a bis(dithiocarbamate) species,
• wherein R.sub.1 and/or R.sub.2 further contain a site for said covalent attachment,
• x is 1 or 2, and
• M is a monovalent cation when x is 1, or M is a physiologically compatible divalent or trivalent transition metal cation when x is 2.

In the treatment of a subject suffering from a pathological condition by administration thereto of a pharmacologically active agent, the improvement comprising attaching a dithiocarbamate-containing nitric oxide scavenger to said pharmacolgically active agent via a covalent linkage prior to administration thereof to said subject, wherein the dithiocarbamate component of said compound has the structure I, as follows:

• ›R.sub.1 R.sub.2 N--C(S)S!.sub.x M.sup.+1,+2,+3 (I)
• wherein
• each of R.sub.1 and R.sub.2 is independently selected from a C.sub.1 up to C.sub.18 alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, aroyl, substituted aroyl, acyl, substituted acyl, or
• R.sub.1 and R.sub.2 can cooperate to form a 5-, 6- or 7-membered ring including N, R.sub.1, and R.sub.2, or
• R.sub.1 or R.sub.2 is a divalent moiety selected from the group consisting of alkylene, substituted alkylene, oxyalkylene, substituted oxyalkylene, alkenylene, and substituted alkenylene, wherein said divalent moiety serves as the same substituent for two dithiocarbamate structures, thereby linking said structures together so as to form a bis(dithiocarbamate) species,
• wherein R.sub.1 and/or R.sub.2 further contain a site for said covalent attachment,
• x is 1 or 2, and
• M is a monovalent cation when x is 1, or M is a physiologically compatible divalent or trivalent transition metal cation when x is 2.

A method for the treatment of a subject afflicted with a pathological condition, said method comprising administering to said subject an effective amount of a modified pharmacologically active agent,

• wherein said pharmacologically active agent is effective for treatment of said condition, and
• wherein said pharmacologically active agent has been modified by the covalent attachment thereto of a dithiocarbamate-containing nitric oxide scavenger, wherein the dithiocarbamate component of said compound has the structure I, as follows:
• ›R.sub.1 R.sub.2 N--C(S)S!.sub.x M.sup.+1,+2,+3 (I)
• wherein
• each of R.sub.1 and R.sub.2 is independently selected from a C.sub.1 up to C.sub.18 alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, aroyl, substituted aroyl, acyl, substituted acyl, or
• R.sub.1 and R.sub.2 can cooperate to form a 5-, 6- or 7-membered ring including N, R.sub.1, and R.sub.2, or
• R.sub.1 or R.sub.2 is a divalent moiety selected from the group consisting of alkylene, substituted alkylene, oxyalkylene, substituted oxyalkylene, alkenylene, and substituted alkenylene, wherein said divalent moiety serves as the same substituent for two dithiocarbamate structures, thereby linking said structures together so as to form a bis(dithiocarbamate) species,
• wherein R.sub.1 and/or R.sub.2 further contain a site for said covalent attachment,
• x is 1 or 2, and
• M is a monovalent cation when x is 1, or M is a physiologically compatible divalent or trivalent transition metal cation when x is 2.

A method for the preparation of a protected form of a pharmacologically active agent, said method comprising attaching a dithiocarbamate-containing nitric oxide scavenger to said pharmacologically active agent via a covalent linkage, wherein the dithiocarbamate component of said compound has the structure I, as follows:

• ›R.sub.1 R.sub.2 N--C(S)S!.sub.x M.sup.+1,+2,+3 (I)
• wherein
• each of R.sub.1 and R.sub.2 is independently selected from a C.sub.1 up to C.sub.18 alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkyl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, aroyl, substituted aroyl, acyl, substituted acyl, or
• R.sub.1 and R.sub.2 can cooperate to form a 5-, 6- or 7-membered ring including N, R.sub.1, and R.sub.2, or
• R.sub.1 or R.sub.2 is a divalent moiety selected from the group consisting of alkylene, substituted alkylene, oxyalkylene, substituted oxyalkylene, alkenylene, and substituted alkenylene, wherein said divalent moiety serves as the same substituent for two dithiocarbamate structures, thereby linking said structures together so as to form a bis(dithiocarbamate) species,
• wherein R.sub.1 and/or R.sub.2 further contain a site for said covalent attachment,
• x is 1 or 2, and
• M is a monovalent cation when x is 1, or M is a physiologically compatible divalent or trivalent transition metal cation when x is 2.

A method for reducing the side effects induced by administration of a pharmacologically active agent to a subject, said method comprising attaching a dithiocarbamate-containing nitric oxide scavenger to said pharmacologically active agent via a covalent linkage prior to administration to said subject, wherein the dithiocarbamate component of said compound has the structure I, as follows:

• ›R.sub.1 R.sub.2 N--C(S)S!.sub.x M.sup.+1,+2,+3 (I)
• wherein
• each of R.sub.1 and R.sub.2 is independently selected from a C.sub.1 up to C.sub.18 alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, aroyl, substituted aroyl, acyl, substituted acyl, or
• R.sub.1 and R.sub.2 can cooperate to form a 5-, 6- or 7-membered ring including N, R.sub.1, and R.sub.2, or
• R.sub.1 and R.sub.2 is a divalent moiety selected from the group consisting of alkylene, substituted alkylene, oxyalkylene, substituted oxyalkylene, alkenylene, and substituted alkenylene, wherein said divalent moiety serves as the same substituent for two dithiocarbamate structures, thereby linking said structures together so as to form a bis(dithiocarbamate) species,
• wherein R.sub.1 and/or R.sub.2 further contain a site for said covalent attachment,
• x is 1 or 2, and
• M is a monovalent cation when x is 1, or M is a physiologically compatible divalent or trivalent transition metal cation when x is 2.