Conjugates of dithiocarbamates with pharmacologically active agents and uses therefore
First Claim
1. A compound comprising a dithiocarbamate-containing nitric oxide scavenger attached to a pharmacologically active agent via a covalent linkage, wherein said covalent linkage is cleavable under physiological conditions;
- and wherein the dithiocarbamate component of said compound has the structure I, as follows;
space="preserve" listing-type="equation"> R.sub.1 R.sub.2 N--C(S)S!.sub.x M.sup.+1,+2,+3 (I)whereineach of R1 and R2 is independently selected from a C1 up to C18 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, orR1 and R2 can cooperate to form a 5-, 6- or 7-membered ring including N, R1, and R2, orR1 or R2 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 R1 and/or R2 further contain a site for said covalent attachment,x is 1 or 2, andM is a monovalent cation when x is 1, or M is a physiologically compatible divalent or trivalent transition metal cation when x is 2.
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Abstract
In accordance with the present invention, there are provided conjugates of nitric oxide scavengers (e.g., dithiocarbamates, or "DC") and pharmacologically active agents (e.g., NSAIDs). Invention conjugates provide a new class of pharmacologically active agents (e.g., anti-inflammatory agents) which cause a much lower incidence of side-effects due to the protective effects imparted by modifying the pharmacologically active agents as described herein. In addition, invention conjugates are more effective than unmodified pharmacologically active agents because cells and tissues contacted by the pharmacologically active agent(s) are protected from the potentially damaging effects of nitric oxide overproduction induced thereby as a result of the co-production of nitric oxide scavenger (e.g., dithiocarbamate), in addition to free pharmacologically active agent, when invention conjugate is cleaved.
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Citations
27 Claims
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1. A compound comprising a dithiocarbamate-containing nitric oxide scavenger attached to a pharmacologically active agent via a covalent linkage, wherein said covalent linkage is cleavable under physiological conditions;
- and wherein the dithiocarbamate component of said compound has the structure I, as follows;
space="preserve" listing-type="equation"> R.sub.1 R.sub.2 N--C(S)S!.sub.x M.sup.+1,+2,+3 (I)wherein each of R1 and R2 is independently selected from a C1 up to C18 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 R1 and R2 can cooperate to form a 5-, 6- or 7-membered ring including N, R1, and R2, or R1 or R2 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 R1 and/or R2 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. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21)
- and wherein the dithiocarbamate component of said compound has the structure I, as follows;
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22. 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:
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space="preserve" listing-type="equation"> R.sub.1 R.sub.2 N--C(S)S!.sub.x M.sup.+1,+2,+3 (I)wherein each of R1 and R2 is independently selected from a C1 up to C18 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 R1 and R2 can cooperate to form a 5-, 6- or 7-membered ring including N, R1, and R2, or R1 or R2 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 R1 and/or R2 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.
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23. 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:
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space="preserve" listing-type="equation"> R.sub.1 R.sub.2 N--C(S)S!.sub.x M.sup.+1,+2,+3 (I)wherein each of R1 and R2 is independently selected from a C1 up to C18 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 R1 and R2 can cooperate to form a 5-, 6- or 7-membered ring including N, R1, and R2, or R1 or R2 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 R1 and/or R2 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.
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24. 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: -
space="preserve" listing-type="equation"> R.sub.1 R.sub.2 N--C(S)S!.sub.x M.sup.+1,+2,+3 (I)wherein each of R1 and R2 is independently selected from a C1 up to C18 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 R1 and R2 can cooperate to form a 5-, 6- or 7-membered ring including N, R1, and R2, or R1 or R2 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 R1 and/or R2 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.
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25. 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:
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space="preserve" listing-type="equation"> R.sub.1 R.sub.2 N--C(S)S!.sub.x M.sup.+1,+2,+3 (I)wherein each of R1 and R2 is independently selected from a C1 up to C18 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 R1 and R2 can cooperate to form a 5-, 6- or 7-membered ring including N, R1, and R2, or R1 or R2 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 R1 and/or R2 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.
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26. 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:
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space="preserve" listing-type="equation"> R.sub.1 R.sub.2 N--C(S)S!.sub.x M.sup.+1,+2,+3 (I)wherein each of R1 and R2 is independently selected from a C1 up to C18 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 R1 and R2 can cooperate to form a 5-, 6- or 7-membered ring including N, R1, and R2, or R1 and R2 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 R1 and/or R2 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.
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27. A method for enhancing the effectiveness of a pharmacologically active agent, said method comprising attaching a dithiocarbamate-containing nitric oxide scavenger to said pharmacologically active agent, via a covalent linkage.
Specification