Methods for in vivo reduction of nitric oxide levels and compositions useful therefor

A method for treating nitric oxide overproduction in a subject, said method comprising:

• administering to said subject an effective amount of at least one dithiocarbamate-containing nitric oxide scavenger, wherein said dithiocarbamate-containing nitric oxide scavenger comprises a dithiocarbamate moiety and, optionally, a physiologically compatible di- or tri-valent transition metal ion, wherein said dithiocarbamate has the structure:
• R.sub.1 R.sub.2 N--C(S)--S
• 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, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, 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.

A composition comprising a compound having the structure I and a pharmaceutically acceptable carrier therefor, wherein said pharmaceutically acceptable carrier is a sterile injectable solution or suspension, an organic or inorganic carrier suitable for enteral or parenteral administration, a non-toxic carrier for tablets, troches, lozenges, pellets, capsules, suppositories, emulsions, aqueous or oily suspension, dispersible powders or granules, liposomes, hard or soft capsules, syrups or elixirs, and wherein structure I is:

• R.sub.1 R.sub.2 N--C(S)--S.sup.- M.sup.+ (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, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl arylalkyl, substituted arylalkyl 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, and
• M is optionally present, and when present is a monovalent cation,
• provided, however, that the following compounds are excluded from the definition of Formula I, i.e., when R.sub.1 is ethyl, R.sub.2 is not ethyl;
• or when R.sub.1 is CH.sub.2 (CHOH).sub.4 CH.sub.2 OH, R.sub.2 is not methyl, isoamyl, benzyl, 4-methylbenzyl or p-isopropylbenzyl;
• or when R.sub.1 is CH.sub.2 CO.sub.2.sup.-, R.sub.2 is not CH.sub.2 CO.sub.2.sup.- ;
• or when R.sub.1 is CO.sub.2.sup.-, R.sub.2 is not CH.sub.3 ;
• or when R.sub.1 is CH.sub.2 CH.sub.2 --OH, R.sub.2 is not CH.sub.2 CH.sub.2 --OH;
• or when R.sub.1 and R.sub.2 combined, together with the carbamate nitrogen, form a pyrrolidinyl-2-carboxylate.

A composition comprising a compound having the structure II and a pharmaceutically acceptable carrier therefor, wherein said pharmaceutically acceptable carrier is a sterile injectable solution or suspension, an organic or inorganic carrier suitable for enteral or parenteral administration, a non-toxic carrier for tablets, troches, lozenges, pellets, capsules, suppositories, emulsions, aqueous or oily suspensions, dispersible powders or granules, liposomes, hard or soft capsules, syrups or elixirs, and wherein structure II is:

• ›R.sub.1 R.sub.2 N--C(S)--S.sup.- !.sub.2 M.sup.+2,+3 (II)
• 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, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl substituted arylalkyl, 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, and
• M is optionally present, and when present, is a physiologically compatible divalent or trivalent transition metal cation,
• provided, however, that the following compounds are excluded from the definition of Formula II, i.e,, when R.sub.1 is ethyl, R.sub.2 is not ethyl;
• or when R.sub.1 is CH.sub.2 (CHOH).sub.4 CH.sub.2 OH, R.sub.2 is not methyl, isoamyl, benzyl, 4-methylbenzyl or p-isopropylbenzyl;
• or when R.sub.1 is CH.sub.2 CO, R.sub.2 is not CH.sub.2 CO.sub.2 ;
• or when R.sub.1 is CO.sub.2.sup.-, R.sub.2 is not CH.sub.3 ;
• or when R.sub.1 is CH.sub.2 CH.sub.2 --OH, R.sub.2 is not CH.sub.2 CH.sub.2 --OH;
• or when R.sub.1 and R.sub.2 combined, together with the carbamate nitrogen, form a pyrrolidinyl-2-carboxylate.

A composition comprising a compound having structure I in combination with a pharmacologically active agents wherein structure I is:

• R.sub.1 R.sub.2 N--C(S)--S.sup.- M.sup.+ (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, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl 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, and
• M is optionally present and when present, is a monovalent cation,
• provided, however, that the following compounds are excluded from the definition of Formula I, i.e., when R.sub.1 is ethyl, R.sub.2 is not ethyl;
• or when R.sub.1 is CH.sub.2 (CHOH).sub.4 CH.sub.2 OH, R.sub.2 is not methyl, isoamyl, benzyl, 4-methylbenzyl or p-isopropylbenzyl;
• or when R.sub.1 is CH.sub.2 CO.sub.2.sup.-, R.sub.2 is not CH.sub.2 CO.sub.2.sup.- ;
• or when R.sub.1 is CO.sub.2.sup.-, R.sub.2 is not CH.sub.3 ;
• or when R.sub.1 is CH.sub.2 CH.sub.2 --OH, R.sub.2 is not CH.sub.2 CH.sub.2 --OH;
• or when R.sub.1 and R.sub.2 combined, together with the carbamate nitrogen, form a pyrrolidinyl-2-carboxylate.

A composition comprising a compound having structure II in combination with a pharmacologically active agent, wherein structure II is:

• ›R.sub.1 R.sub.2 N--C(S)--S.sup.- !.sub.2 M.sup.+2,+3 (II)
• 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, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl substituted arylalkyl, 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, and
• M is optionally present, and when present, is a physiologically compatible divalent or trivalent transition metal cation,
• provided, however, that the following compounds are excluded from the definition of Formula II, i.e., when R.sub.1 is ethyl, R.sub.2 is not ethyl;
• or when R.sub.1 is CH.sub.2 (CHOH).sub.4 CH.sub.2 OH, R.sub.2 is not methyl, isoamyl, benzyl, 4-methylbenzyl or p-isopropylbenzyl;
• or when R.sub.1 is CH.sub.2 CO.sub.2 ;
• R.sub.2 is not CH.sub.2 CO.sub.2.sup.- ;
• or when R.sub.1 is CO.sub.2.sup.-, R.sub.2 is not CH.sub.3 ;
• or when R.sub.1 is CH.sub.2 CH.sub.2 --OH, R.sub.2 is not CH.sub.2 CH.sub.2 --OH;
• or when R.sub.1 and R.sub.2 combined, together with the carbamate nitrogen, form a pyrrolidinyl-2-carboxylate.