CA2446136A1 - Pyruvate derivatives - Google Patents
Pyruvate derivatives Download PDFInfo
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- CA2446136A1 CA2446136A1 CA002446136A CA2446136A CA2446136A1 CA 2446136 A1 CA2446136 A1 CA 2446136A1 CA 002446136 A CA002446136 A CA 002446136A CA 2446136 A CA2446136 A CA 2446136A CA 2446136 A1 CA2446136 A1 CA 2446136A1
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- Prior art keywords
- optionally substituted
- cndot
- hydrogen
- alkyl
- amino
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/223—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of alpha-aminoacids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
- C07C249/12—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reactions not involving the formation of oxyimino groups
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- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
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- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/74—Oxygen atoms
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D233/42—Sulfur atoms
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- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D249/14—Nitrogen atoms
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- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
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- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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Abstract
Certain known and novel pyruvate derivatives are particularly active in restoring or preserving metabolic integrity in oxidatively competent cells that have been subjected to oxygen deprivation. These pyruvate-derived compounds include, but are not limited to oximes, amides, pyruvate analogues, modified pyruvate analogues, esters of pyruvate (e.g., polyol-pyruvate esters, pyruvate thioesters, glycerol-pyruvate esters and dihydroxyacetone-pyruvate esters). Such pyruvate derivatives (including single tautomers, single stereoisomers and mixtures of tautomers and/or stereoisomers, and the pharmaceutically acceptable salts thereof) are useful in the manufacture of pharmaceutical compositions for treating a number of conditions characterized by oxidative stress.
Claims (85)
1. A method of treating a mammal having a condition characterized by oxidative stress, comprising administering a therapeutically effective amount of a compound of Formula I:
wherein:
A is: optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, an optionally substituted nucleoside, an optionally substituted amino acid, an optionally substituted di-, tri- or tetra-peptide, -CH2-C(O)-C(O)-O-R' or -CH=C(OH)-C(O)-O-R';
X is: -N(R')-, -S-, -S(O)-, -S(O)2-, -S-Y-S-, or a covalent bond to the sulfur atom of Cys or to the nitrogen atom of optionally substituted heterocyclyl;
Y is: optionally substituted aryl, optionally substituted heteroaryl, an optionally substituted nucleoside, an optionally substituted amino acid, or an optionally substituted di-, tri- or tetra-peptide;
W is: =O, =N-OR a, =N-NR b R c, Or -N(OH)-R d;
Z is: -OR, -SR, or -NR b R c;
R' is: independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted aryl;
R is: hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl or optionally substituted heterocycloalkyl;
R a is: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, or alkenyl;
R b is: independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted cycloalkyl;
R c is: independently selected from hydrogen or optionally substituted alkyl;
and R d is: hydrogen, acyl or optionally substituted alkyl; or R b and R c together with the nitrogen to which they are attached may form a 5-to 7-membered ring, optionally incorporating one or two additional ring heteroatoms chosen from N, S, or O, and said ring being optionally substituted with one or more substituents independently selected from the group consisting of =O, =S, acyl, optionally substituted alkenyl, optionally substituted alkyl, (optionally substituted alkoxy)carbonyl, and (optionally substituted amino) carbonyl;
including single tautomers, single stereoisomers and mixtures of tautomers and/or stereoisomers, and the pharmaceutically acceptable salts thereof, provided that where X is -S-, W is =O, and Z is OH, A is not 6-amino-3,5-dicyano-4-(optionally substituted phenyl)-pyridin-2-yl.
wherein:
A is: optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, an optionally substituted nucleoside, an optionally substituted amino acid, an optionally substituted di-, tri- or tetra-peptide, -CH2-C(O)-C(O)-O-R' or -CH=C(OH)-C(O)-O-R';
X is: -N(R')-, -S-, -S(O)-, -S(O)2-, -S-Y-S-, or a covalent bond to the sulfur atom of Cys or to the nitrogen atom of optionally substituted heterocyclyl;
Y is: optionally substituted aryl, optionally substituted heteroaryl, an optionally substituted nucleoside, an optionally substituted amino acid, or an optionally substituted di-, tri- or tetra-peptide;
W is: =O, =N-OR a, =N-NR b R c, Or -N(OH)-R d;
Z is: -OR, -SR, or -NR b R c;
R' is: independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted aryl;
R is: hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl or optionally substituted heterocycloalkyl;
R a is: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, or alkenyl;
R b is: independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted cycloalkyl;
R c is: independently selected from hydrogen or optionally substituted alkyl;
and R d is: hydrogen, acyl or optionally substituted alkyl; or R b and R c together with the nitrogen to which they are attached may form a 5-to 7-membered ring, optionally incorporating one or two additional ring heteroatoms chosen from N, S, or O, and said ring being optionally substituted with one or more substituents independently selected from the group consisting of =O, =S, acyl, optionally substituted alkenyl, optionally substituted alkyl, (optionally substituted alkoxy)carbonyl, and (optionally substituted amino) carbonyl;
including single tautomers, single stereoisomers and mixtures of tautomers and/or stereoisomers, and the pharmaceutically acceptable salts thereof, provided that where X is -S-, W is =O, and Z is OH, A is not 6-amino-3,5-dicyano-4-(optionally substituted phenyl)-pyridin-2-yl.
2. The method of Claim 1, wherein:
A is: optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, an optionally substituted amino acid, or an optionally substituted di-, tri- or tetra-peptide;
X is: -N(H)-, -S-, or a covalent bond to the sulfur atom of Cys or to the nitrogen atom of optionally substituted heterocyclyl;
W is: =O Or =N-OR a;
Z is: -OR, or -NR b R c;
R is: hydrogen, optionally substituted alkyl, substituted cycloalkyl, or optionally substituted aralkyl;
R a is: hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted aralkyl;
R b is: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted cycloalkyl;
R c is: hydrogen or optionally substituted alkyl; and R b and R c together with the nitrogen to which they are attached may form a 5-or 6-membered ring, optionally incorporating N or O as an additional ring heteroatom, and said ring being optionally substituted with one substituent selected from the group consisting of acyl and optionally substituted alkyl.
A is: optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, an optionally substituted amino acid, or an optionally substituted di-, tri- or tetra-peptide;
X is: -N(H)-, -S-, or a covalent bond to the sulfur atom of Cys or to the nitrogen atom of optionally substituted heterocyclyl;
W is: =O Or =N-OR a;
Z is: -OR, or -NR b R c;
R is: hydrogen, optionally substituted alkyl, substituted cycloalkyl, or optionally substituted aralkyl;
R a is: hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted aralkyl;
R b is: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted cycloalkyl;
R c is: hydrogen or optionally substituted alkyl; and R b and R c together with the nitrogen to which they are attached may form a 5-or 6-membered ring, optionally incorporating N or O as an additional ring heteroatom, and said ring being optionally substituted with one substituent selected from the group consisting of acyl and optionally substituted alkyl.
3. The method of Claim 2, wherein:
A is: an optionally substituted amino acid selected from Ala, Asp, Cys, Glu and Gly, or an optionally substituted di- or tri-peptide the amino acids of which are selected from Ala, Asp, Cys, Glu and Gly;
A is: an optionally substituted amino acid selected from Ala, Asp, Cys, Glu and Gly, or an optionally substituted di- or tri-peptide the amino acids of which are selected from Ala, Asp, Cys, Glu and Gly;
4. The method of Claim 3, wherein:
A is: the tri-peptide Glu-Cys-Gly; and X is: a covalent bond to the sulfur atom of Cys.
A is: the tri-peptide Glu-Cys-Gly; and X is: a covalent bond to the sulfur atom of Cys.
5. The method of Claim 4, wherein:
R is: hydrogen or C1 to C8 alkyl;
R a is: hydrogen, C1 to C8 alkyl or alkenyl, phenyl or aralkyl;
R b is: C1 to C8 optionally acyl-substituted alkyl, optionally substituted aralkyl or cycloalkyl; and R c is: hydrogen or C1 to C4 alkyl; or R b and R c together with the nitrogen to which they are attached form a 5-membered ring, or a 6-membered ring optionally incorporating O as an additional ring heteroatom, and said ring being optionally substituted with one substituent selected from the group consisting of acyl and optionally substituted alkyl.
R is: hydrogen or C1 to C8 alkyl;
R a is: hydrogen, C1 to C8 alkyl or alkenyl, phenyl or aralkyl;
R b is: C1 to C8 optionally acyl-substituted alkyl, optionally substituted aralkyl or cycloalkyl; and R c is: hydrogen or C1 to C4 alkyl; or R b and R c together with the nitrogen to which they are attached form a 5-membered ring, or a 6-membered ring optionally incorporating O as an additional ring heteroatom, and said ring being optionally substituted with one substituent selected from the group consisting of acyl and optionally substituted alkyl.
6. The method of Claim 5, wherein the compound of Formula I is selected from:
.cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-oxo-2-pentyloxycarbonyl-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot.2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-hexyloxycarbonyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-carboxy-2-oxo-ethylsulfanyl)-ethylcarbamoyl]butyric acid, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]butyric acid, .cndot. 2-amino-4-[2-(2-butoxycarbonyl-2-methoxyimino-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-butyric acid or the HCI salt thereof, .cndot.2-amino-4-[2-(2-benzyloxyimino-2-butoxycarbonyl-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-butyric acid or the HCI salt thereof, .cndot.2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-hydroxyimino-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-amino-4-[2-(2-butoxycarbonyl-2-hydroxyimino-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-butyric acid or the HCI salt thereof, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-methoxyimino-ethylsufanyl)-ethylcarbamoyl]-butyric acid .cndot. 2-amino-4-[2-(2-benzyloxyimino-2-ethoxycarbonyl-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-butyric acid or the HCI slat thereof, .cndot. 2-amino-4-{1-(carboxymethyl-carbamoyl)-2-[2-ethoxycarbonyl-2-(4-nitro-benzyloxyimino)-ethylsulfanyl]-ethylcarbamoyl}-butyric acid, 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-phenoxyimino-ethylsulfanyl)-ethylcarbamoyl]-butyric acid or the HCI salt thereof, .cndot. 2-amino-4-(1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-ethoxyimino-ethylsulfanyl)-ethylcarbamoyl]-butyric acid or the di-HCI salt thereof, .cndot. 2-amino-4-[2-(2-tert-butoxyimino-2-ethoxycarbonyl-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-butyric acid or the di-HCI salt thereof, .cndot. 4-[2-(2-allyloxyimino-2-ethoxycarbonyl-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-2-amino-butyric acid or the di-HCI salt thereof, .cndot. 2-Amino-4-{1-(carboxymethyl-carbamoyl)-2-[3-(4-methyl-piperidin-1-yl)-2,3-dioxo-propylsulfanyl]-ethylcarbamoyl}-butyric acid, .cndot. 2-Amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-hydroxyimino-3-oxo-3-piperidin-1-yl-propylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-Amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-diethylcarbamoyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid .cndot. 2-Amino-4-[1-(carboxymethyl-carbamoyl)-2-(2,3-dioxo-3-piperidin-1-yl-propylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-Amino-4-{1-(carboxymethyl-carbamoyl)-2-[2-(1-methoxycarbonyl-2-phenyl-ethylcarbamoyl)-2-oxo-ethylsulfanyl]-ethylcarbamoyl}-butyric acid, 2-Amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-cyclohexylcarbamoyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, 2-Amino-4-[2-(2-benzylcarbamoyl-2-oxo-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-butyric acid, 2-Amino-4-[1-(carboxymethyl-carbamoyl)-2-(3-morpholin-4-yl-2,3-dioxo-propylsulfanyl)-ethylcarbamoyl]-butyric acid, 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethylcarbamoyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-methoxyimino-ethylsulfanyl)-ethylcarbamoyl]-butyric acid .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2,3-dioxo-3-pyrrolidin-1-yl-propylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-octylcarbamoyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 1-{3-[2-(4-amino-4-carboxy-butyrylamino)-2-(carboxymethyl-carbamoyl)-ethylsulfanyl]-2-oxo-propionyl}-pyrrolidine-2-carboxylic acid methyl ester, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-hexylcarbamoyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-{3-[2-(4-amino-4-carboxy-butyrylamino)-2-(carboxymethyl-carbamoyl)-ethylsulfanyl]-2-oxo-propionylamino}-3-methyl-pentanoic acid methyl ester, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-dimethylcarbamoyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, and .cndot. 2-amino-4-(1-(carboxymethyl-carbamoyl)-2-{2-[2-(4-hydroxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-oxo-ethylsulfanyl}-ethylcarbamoyl)-butyric acid.
.cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-oxo-2-pentyloxycarbonyl-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot.2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-hexyloxycarbonyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-carboxy-2-oxo-ethylsulfanyl)-ethylcarbamoyl]butyric acid, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]butyric acid, .cndot. 2-amino-4-[2-(2-butoxycarbonyl-2-methoxyimino-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-butyric acid or the HCI salt thereof, .cndot.2-amino-4-[2-(2-benzyloxyimino-2-butoxycarbonyl-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-butyric acid or the HCI salt thereof, .cndot.2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-hydroxyimino-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-amino-4-[2-(2-butoxycarbonyl-2-hydroxyimino-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-butyric acid or the HCI salt thereof, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-methoxyimino-ethylsufanyl)-ethylcarbamoyl]-butyric acid .cndot. 2-amino-4-[2-(2-benzyloxyimino-2-ethoxycarbonyl-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-butyric acid or the HCI slat thereof, .cndot. 2-amino-4-{1-(carboxymethyl-carbamoyl)-2-[2-ethoxycarbonyl-2-(4-nitro-benzyloxyimino)-ethylsulfanyl]-ethylcarbamoyl}-butyric acid, 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-phenoxyimino-ethylsulfanyl)-ethylcarbamoyl]-butyric acid or the HCI salt thereof, .cndot. 2-amino-4-(1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-ethoxyimino-ethylsulfanyl)-ethylcarbamoyl]-butyric acid or the di-HCI salt thereof, .cndot. 2-amino-4-[2-(2-tert-butoxyimino-2-ethoxycarbonyl-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-butyric acid or the di-HCI salt thereof, .cndot. 4-[2-(2-allyloxyimino-2-ethoxycarbonyl-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-2-amino-butyric acid or the di-HCI salt thereof, .cndot. 2-Amino-4-{1-(carboxymethyl-carbamoyl)-2-[3-(4-methyl-piperidin-1-yl)-2,3-dioxo-propylsulfanyl]-ethylcarbamoyl}-butyric acid, .cndot. 2-Amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-hydroxyimino-3-oxo-3-piperidin-1-yl-propylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-Amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-diethylcarbamoyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid .cndot. 2-Amino-4-[1-(carboxymethyl-carbamoyl)-2-(2,3-dioxo-3-piperidin-1-yl-propylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-Amino-4-{1-(carboxymethyl-carbamoyl)-2-[2-(1-methoxycarbonyl-2-phenyl-ethylcarbamoyl)-2-oxo-ethylsulfanyl]-ethylcarbamoyl}-butyric acid, 2-Amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-cyclohexylcarbamoyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, 2-Amino-4-[2-(2-benzylcarbamoyl-2-oxo-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-butyric acid, 2-Amino-4-[1-(carboxymethyl-carbamoyl)-2-(3-morpholin-4-yl-2,3-dioxo-propylsulfanyl)-ethylcarbamoyl]-butyric acid, 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethylcarbamoyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-methoxyimino-ethylsulfanyl)-ethylcarbamoyl]-butyric acid .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2,3-dioxo-3-pyrrolidin-1-yl-propylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-octylcarbamoyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 1-{3-[2-(4-amino-4-carboxy-butyrylamino)-2-(carboxymethyl-carbamoyl)-ethylsulfanyl]-2-oxo-propionyl}-pyrrolidine-2-carboxylic acid methyl ester, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-hexylcarbamoyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-{3-[2-(4-amino-4-carboxy-butyrylamino)-2-(carboxymethyl-carbamoyl)-ethylsulfanyl]-2-oxo-propionylamino}-3-methyl-pentanoic acid methyl ester, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-dimethylcarbamoyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, and .cndot. 2-amino-4-(1-(carboxymethyl-carbamoyl)-2-{2-[2-(4-hydroxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-oxo-ethylsulfanyl}-ethylcarbamoyl)-butyric acid.
7. The method of Claim 2, wherein:
A is: substituted alkyl, substituted aryl, optionally substituted heteroaryl, heterocyclyl, or substituted heterocycloalkyl.
A is: substituted alkyl, substituted aryl, optionally substituted heteroaryl, heterocyclyl, or substituted heterocycloalkyl.
8. The method of Claim 7, wherein:
R is: hydrogen or C, to C8 alkyl;
R a is: hydrogen, C, to C8 alkyl, or aralkyl;
R b is: C, to C4 alkyl, optionally substituted aralkyl or cycloalkyl; and R c is: hydrogen or C1 to C4 alkyl; or R b and R c together with the nitrogen to which they are attached form a 6-membered ring, optionally incorporating O as an additional ring heteroatom, and said ring being optionally substituted with one substituent selected from the group consisting of acyl and optionally substituted alkyl.
R is: hydrogen or C, to C8 alkyl;
R a is: hydrogen, C, to C8 alkyl, or aralkyl;
R b is: C, to C4 alkyl, optionally substituted aralkyl or cycloalkyl; and R c is: hydrogen or C1 to C4 alkyl; or R b and R c together with the nitrogen to which they are attached form a 6-membered ring, optionally incorporating O as an additional ring heteroatom, and said ring being optionally substituted with one substituent selected from the group consisting of acyl and optionally substituted alkyl.
9. The method of Claim 8, wherein the compound of Formula I is selected from:
.cndot. 3-(1 H-benzoimidazol-2-ylsulfanyl)-2-oxo-propionic acid, .cndot. 2-oxo-3-(4-oxo-3,4-dihydro-quinazolin-2-ylsulfanyl)-propionic acid ethyl ester, .cndot. 3-[1-(carboxymethyl-carbamoyl)-ethylsulfanyl]-2-hydroxy-acrylic acid ethyl ester, .cndot. 3-(benzoselenazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester, .cndot. 3-(1 H-benzoimidazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester, .cndot. 3-(5-chloro-benzothiazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester, .cndot. 3-(5-nitro-benzoimidazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester, .cndot. 3-(5-methoxy-benzoimidazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester, .cndot. 3-(4,5-dihydro-thiazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester, .cndot. 2-hydroxyimino-3-p-tolylsulfanyl-propionic acid methyl ester, .cndot. 2-hydroxyimino-3-p-tolylsulfanyl-propionic acid, .cndot. 2-hydroxyimino-3-p-tolylsulfanyl-propionic acid ethyl ester, .cndot. 3-(5-chloro-benzothiazol-2-ylsulfanyl)-2-hydroxyimino-propionic acid ethyl ester, .cndot. 2-hydroxyimino-3-(5-methoxy-1H-benzoimidazol-2-ylsulfanyl)-propionic acid ethyl ester, .cndot. 3-(1H-benzoimidazol-2-ylsulfanyl)-2-hydroxyimino-propionic acid ethyl ester, .cndot. 2-hydroxyimino-N-phenyl-3-p-tolylsulfanyl-propionamide, and .cndot. 1-piperidin-1-yl-3-p-tolylsulfanyl-propane-1,2-dione 2-oxime.
.cndot. 3-(1 H-benzoimidazol-2-ylsulfanyl)-2-oxo-propionic acid, .cndot. 2-oxo-3-(4-oxo-3,4-dihydro-quinazolin-2-ylsulfanyl)-propionic acid ethyl ester, .cndot. 3-[1-(carboxymethyl-carbamoyl)-ethylsulfanyl]-2-hydroxy-acrylic acid ethyl ester, .cndot. 3-(benzoselenazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester, .cndot. 3-(1 H-benzoimidazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester, .cndot. 3-(5-chloro-benzothiazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester, .cndot. 3-(5-nitro-benzoimidazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester, .cndot. 3-(5-methoxy-benzoimidazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester, .cndot. 3-(4,5-dihydro-thiazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester, .cndot. 2-hydroxyimino-3-p-tolylsulfanyl-propionic acid methyl ester, .cndot. 2-hydroxyimino-3-p-tolylsulfanyl-propionic acid, .cndot. 2-hydroxyimino-3-p-tolylsulfanyl-propionic acid ethyl ester, .cndot. 3-(5-chloro-benzothiazol-2-ylsulfanyl)-2-hydroxyimino-propionic acid ethyl ester, .cndot. 2-hydroxyimino-3-(5-methoxy-1H-benzoimidazol-2-ylsulfanyl)-propionic acid ethyl ester, .cndot. 3-(1H-benzoimidazol-2-ylsulfanyl)-2-hydroxyimino-propionic acid ethyl ester, .cndot. 2-hydroxyimino-N-phenyl-3-p-tolylsulfanyl-propionamide, and .cndot. 1-piperidin-1-yl-3-p-tolylsulfanyl-propane-1,2-dione 2-oxime.
10. The method of Claim 1 wherein the condition characterized by oxidative stress is selected from: ischemia including stroke, cerebral ischemia, retinal ischemia, myocardial ischemia, myocardial infarction and post-surgical cognitive dysfunction;
neurodegenerative disorders including Alzheimer's, dementia and Parkinson's disease; peripheral neuropathy, including spinal cord injury, head injury and surgical trauma; inflammatory disorders including diabetes, renal disease, pre-menstrual syndrome, asthma, cardiopulmonary inflammatory disorders, heart failure, rheumatoid arthritis, osteoarthritis, muscle fatigue and intermittent claudication; and for the preservation of allograft tissue and organs for transplantation.
neurodegenerative disorders including Alzheimer's, dementia and Parkinson's disease; peripheral neuropathy, including spinal cord injury, head injury and surgical trauma; inflammatory disorders including diabetes, renal disease, pre-menstrual syndrome, asthma, cardiopulmonary inflammatory disorders, heart failure, rheumatoid arthritis, osteoarthritis, muscle fatigue and intermittent claudication; and for the preservation of allograft tissue and organs for transplantation.
11. The method of Claim 1 wherein the condition characterized by oxidative stress is selected from: myocardial ischemia, myocardial infarction, cardiopulmonary inflammatory disorders; heart failure.
12. The method of Claim 11 wherein:
W is: =O; and Z is: -OR.
W is: =O; and Z is: -OR.
13. The method of Claim 1 wherein the condition characterized by oxidative stress is selected from: stroke, cerebral ischemia, retinal ischemia, peripheral neuropathy including spinal cord injury, head injury and surgical trauma, and neurodegenerative disorders including Alzheimer's, dementia and Parkinson's disease.
14. The method of Claim 13 wherein:
W is: =O or =N-OR a; and Z is: -OR, or -NR b R c.
W is: =O or =N-OR a; and Z is: -OR, or -NR b R c.
15. The method of Claim 14 wherein:
W is: =N-OR a; and Z is: -NR b R c.
W is: =N-OR a; and Z is: -NR b R c.
16. The method of Claim 1 wherein the condition characterized by oxidative stress is selected from: diabetes; renal disease; pre-menstrual syndrome; asthma, rheumatoid arthritis;
muscle fatigue; and intermittent claudication; and for the preservation of allograft tissue and organs for transplantation.
muscle fatigue; and intermittent claudication; and for the preservation of allograft tissue and organs for transplantation.
17. A method of treating a mammal having a condition characterized by oxidative stress, comprising administering a therapeutically effective amount of a compound of Formula II:
wherein:
R1 is: hydrogen, optionally substituted alkyl, optionally substituted aryl, -C(O)-O-R', -CH2-SH, -CH2-S-CH2-C(W)-C(O)-Z, -CH2-S-CH=C(OH)-C(O)-Z, -CH2-S(O)-CH2-C(W)-C(O)-Z, or -CH2-S(O)-CH=C(OH)-C(O)-Z';
R2 is: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted acyl;
R3 is: independently selected from hydrogen, optionally substituted lower alkyl, optionally substituted aralkyl, -CH2-SH, -CH2-S-CH2-C(W)-C(O)-Z, -CH2-S-CH=C(OH)-C(O)-Z, -CH2-S(O)-CH2-C(W)-C(O)-Z, or -CH2-S(O)-CH=C(OH)-C(O)-Z;
R4 is: hydrogen, optionally substituted lower alkyl, optionally substituted aralkyl, optionally substituted heteroararalkyl, -CH2-SH, -CH2-S-CH2-C(W)-C(O)-Z, -CH2-S-CH=C(OH)-C(O)-Z, -CH2-S(O)-CH2-C(W)-C(O)-Z, or -CH2-S(O)-CH=C(OH)-C(O)-Z;
R5 is: hydrogen, optionally substituted alkyl, or optionally substituted aryl;
R' is: independently selected from hydrogen, optionally substituted alkyl, or optionally substituted aryl;
W is: =O, =N-OR a, =N-NR b R c; or -N(OH)-R d Z is: -OR, -SR, or -NR b R c;
R is: hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl or optionally substituted heterocycloalkyl;
R a is: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, or alkenyl;
R b is: independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted cycloalkyl, R c is: independently selected from hydrogen or optionally substituted alkyl;
and R d is: hydrogen, acyl or optionally substituted alkyl; or R b and R c together with the nitrogen to which they are attached may form an 5- to 7-membered ring, optionally incorporating one or two additional ring heteroatoms chosen from N, S, or O, and said ring being optionally substituted with one or more substituents independently selected from the group consisting of =O, =S, acyl, optionally substituted alkenyl, optionally substituted alkyl, (optionally substituted alkoxy)carbonyl, and (optionally substituted amino)carbonyl;
k is: 0, 1 or 2;
m is: 0, 1 or 2; and n is: 0, 1, 2 or 3;
including single tautomers, single stereoisomers and mixtures of tautomers and/or stereoisomers, and the pharmaceutically acceptable salts thereof, provided that at least one of R1, R3 or R4 is -CH2-S-CH2-C(W)-C(O)-Z, -CH2-S-CH=C(OH)-C(O)-Z, -CH2-S(O)-CH2-C(W)-C(O)-Z, or -CH2-S(O)-CH=C(OH)-C(O)-Z.
wherein:
R1 is: hydrogen, optionally substituted alkyl, optionally substituted aryl, -C(O)-O-R', -CH2-SH, -CH2-S-CH2-C(W)-C(O)-Z, -CH2-S-CH=C(OH)-C(O)-Z, -CH2-S(O)-CH2-C(W)-C(O)-Z, or -CH2-S(O)-CH=C(OH)-C(O)-Z';
R2 is: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted acyl;
R3 is: independently selected from hydrogen, optionally substituted lower alkyl, optionally substituted aralkyl, -CH2-SH, -CH2-S-CH2-C(W)-C(O)-Z, -CH2-S-CH=C(OH)-C(O)-Z, -CH2-S(O)-CH2-C(W)-C(O)-Z, or -CH2-S(O)-CH=C(OH)-C(O)-Z;
R4 is: hydrogen, optionally substituted lower alkyl, optionally substituted aralkyl, optionally substituted heteroararalkyl, -CH2-SH, -CH2-S-CH2-C(W)-C(O)-Z, -CH2-S-CH=C(OH)-C(O)-Z, -CH2-S(O)-CH2-C(W)-C(O)-Z, or -CH2-S(O)-CH=C(OH)-C(O)-Z;
R5 is: hydrogen, optionally substituted alkyl, or optionally substituted aryl;
R' is: independently selected from hydrogen, optionally substituted alkyl, or optionally substituted aryl;
W is: =O, =N-OR a, =N-NR b R c; or -N(OH)-R d Z is: -OR, -SR, or -NR b R c;
R is: hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl or optionally substituted heterocycloalkyl;
R a is: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, or alkenyl;
R b is: independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted cycloalkyl, R c is: independently selected from hydrogen or optionally substituted alkyl;
and R d is: hydrogen, acyl or optionally substituted alkyl; or R b and R c together with the nitrogen to which they are attached may form an 5- to 7-membered ring, optionally incorporating one or two additional ring heteroatoms chosen from N, S, or O, and said ring being optionally substituted with one or more substituents independently selected from the group consisting of =O, =S, acyl, optionally substituted alkenyl, optionally substituted alkyl, (optionally substituted alkoxy)carbonyl, and (optionally substituted amino)carbonyl;
k is: 0, 1 or 2;
m is: 0, 1 or 2; and n is: 0, 1, 2 or 3;
including single tautomers, single stereoisomers and mixtures of tautomers and/or stereoisomers, and the pharmaceutically acceptable salts thereof, provided that at least one of R1, R3 or R4 is -CH2-S-CH2-C(W)-C(O)-Z, -CH2-S-CH=C(OH)-C(O)-Z, -CH2-S(O)-CH2-C(W)-C(O)-Z, or -CH2-S(O)-CH=C(OH)-C(O)-Z.
18. The method of Claim 17, wherein:
R1 is: -C(O)-O-R' where R' is hydrogen, or -CH2-S-CH2-C(O)-C(O)-O-R' or -CH2-S-CH=C(OH)-C(O)-O-R' where R' is hydrogen or lower alkyl;
R2 is: hydrogen;
R3 is: -CH2-SH, -CH2-S-CH2-C(W)-C(O)-Z, -CH2-S-CH=C(OH)-C(O)-Z, -CH2-S(O)-CH2-C(W)-C(O)-Z, or -CH2-S(O)-CH=C(OH)-C(O)-Z
R4 is: hydrogen;
R5 is hydrogen or lower alkyl;
W is: =O Or =N-OR a;
Z is: -OR or -NR b R c;
R is: hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted aralkyl;
R a is: hydrogen or alkyl;
R b is: C1 to C4 alkyl, phenyl or benzyl;
R c is: hydrogen or C1 to C4 alkyl, or R b and R c together with the nitrogen to which they are attachwed form a 6-membered ring selected from 4-optionally substituted-piperidin-1-yl and morpholin-4-yl;
and k, m and n are respectively: 0,2,1; 1,0,1; or 2,0,1.
R1 is: -C(O)-O-R' where R' is hydrogen, or -CH2-S-CH2-C(O)-C(O)-O-R' or -CH2-S-CH=C(OH)-C(O)-O-R' where R' is hydrogen or lower alkyl;
R2 is: hydrogen;
R3 is: -CH2-SH, -CH2-S-CH2-C(W)-C(O)-Z, -CH2-S-CH=C(OH)-C(O)-Z, -CH2-S(O)-CH2-C(W)-C(O)-Z, or -CH2-S(O)-CH=C(OH)-C(O)-Z
R4 is: hydrogen;
R5 is hydrogen or lower alkyl;
W is: =O Or =N-OR a;
Z is: -OR or -NR b R c;
R is: hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted aralkyl;
R a is: hydrogen or alkyl;
R b is: C1 to C4 alkyl, phenyl or benzyl;
R c is: hydrogen or C1 to C4 alkyl, or R b and R c together with the nitrogen to which they are attachwed form a 6-membered ring selected from 4-optionally substituted-piperidin-1-yl and morpholin-4-yl;
and k, m and n are respectively: 0,2,1; 1,0,1; or 2,0,1.
19. The method of Claim 18, wherein:
R1 is: -COOH;
R5 is: hydrogen; and k, m and n are respectively: 0,2,1; or 2,0,1.
R1 is: -COOH;
R5 is: hydrogen; and k, m and n are respectively: 0,2,1; or 2,0,1.
20. The method of Claim 17 wherein the condition characterized by oxidative stress is selected from: ischemia including stroke, cerebral ischemia, retinal ischemia, myocardial ischemia, myocardial infarction and post-surgical cognitive dysfunction;
neurodegenerative disorders including Alzheimer's, dementia and Parkinson's disease; peripheral neuropathy, including spinal cord injury, head injury and surgical trauma; inflammatory disorders including diabetes, renal disease, pre-menstrual syndrome, asthma, cardiopulmonary inflammatory disorders, heart failure, rheumatoid arthritis, osteoarthritis, muscle fatigue and intermittent claudication; and for the preservation of allograft tissue and organs for transplantation
neurodegenerative disorders including Alzheimer's, dementia and Parkinson's disease; peripheral neuropathy, including spinal cord injury, head injury and surgical trauma; inflammatory disorders including diabetes, renal disease, pre-menstrual syndrome, asthma, cardiopulmonary inflammatory disorders, heart failure, rheumatoid arthritis, osteoarthritis, muscle fatigue and intermittent claudication; and for the preservation of allograft tissue and organs for transplantation
21. The method of Claim 19 wherein the condition characterized by oxidative stress is selected from: ischemia including stroke, cerebral ischemia, retinal ischemia, myocardial ischemia, myocardial infarction and post-surgical cognitive dysfunction;
neurodegenerative disorders including Alzheimer's, dementia and Parkinson's disease; peripheral neuropathy, including spinal cord injury, head injury and surgical trauma; inflammatory disorders including diabetes, renal disease, pre-menstrual syndrome, asthma, cardiopulmonary inflammatory disorders, heart failure, rheumatoid arthritis, osteoarthritis, muscle fatigue and intermittent claudication; and for the preservation of allograft tissue and organs for transplantation.
neurodegenerative disorders including Alzheimer's, dementia and Parkinson's disease; peripheral neuropathy, including spinal cord injury, head injury and surgical trauma; inflammatory disorders including diabetes, renal disease, pre-menstrual syndrome, asthma, cardiopulmonary inflammatory disorders, heart failure, rheumatoid arthritis, osteoarthritis, muscle fatigue and intermittent claudication; and for the preservation of allograft tissue and organs for transplantation.
22. A method of treating a mammal having a condition characterized by oxidative stress, comprising administering a therapeutically effective amount of a compound of Formula III:
wherein:
R3.1 is: H or is absent;
R3.2 is: H or C, to C4alkyl;
R3.3 and R3.4 are both H or are both C1 to C4alkyl; and R3.5 is: H, COOH, or -C(O)O-(C1 to C4 alkyl);
including single tautomers, single stereoisomers and mixtures of tautomers and/or stereoisomers, and the pharmaceutically acceptable salts thereof.
wherein:
R3.1 is: H or is absent;
R3.2 is: H or C, to C4alkyl;
R3.3 and R3.4 are both H or are both C1 to C4alkyl; and R3.5 is: H, COOH, or -C(O)O-(C1 to C4 alkyl);
including single tautomers, single stereoisomers and mixtures of tautomers and/or stereoisomers, and the pharmaceutically acceptable salts thereof.
23. The method of Claim 22 wherein:
R3.2 is: H or ethyl;
R3.3 and R3.4 are both H or are both methyl; and R3.5 is: COOH;
R3.2 is: H or ethyl;
R3.3 and R3.4 are both H or are both methyl; and R3.5 is: COOH;
24. The method of Claim 22, wherein:
R3.3 and R3.4 are both H or are both methyl; and R3.5 is: COOH.
R3.3 and R3.4 are both H or are both methyl; and R3.5 is: COOH.
25. The method of Claim 24, wherein:
R3.1 is hydrogen; and R3.2 is hydrogen or ethyl.
R3.1 is hydrogen; and R3.2 is hydrogen or ethyl.
26. The method of Claim 22 wherein the condition characterized by oxidative stress is selected from: ischemia including stroke, cerebral ischemia, retinal ischemia, myocardial ischemia, myocardial infarction and post-surgical cognitive dysfunction;
neurodegenerative disorders including Alzheimer's, dementia and Parkinson's disease; peripheral neuropathy, including spinal cord injury, head injury and surgical trauma; inflammatory disorders including diabetes, renal disease, pre-menstrual syndrome, asthma, cardiopulmonary inflammatory disorders, heart failure, rheumatoid arthritis, osteoarthritis, muscle fatigue and intermittent claudication; and for the preservation of allograft tissue and organs for transplantation.
neurodegenerative disorders including Alzheimer's, dementia and Parkinson's disease; peripheral neuropathy, including spinal cord injury, head injury and surgical trauma; inflammatory disorders including diabetes, renal disease, pre-menstrual syndrome, asthma, cardiopulmonary inflammatory disorders, heart failure, rheumatoid arthritis, osteoarthritis, muscle fatigue and intermittent claudication; and for the preservation of allograft tissue and organs for transplantation.
27. A compound of Formula Ia:
wherein:
A is: substituted alkyl selected from: -CH2-CH(OH)-CH2-OH, -CH(CH3)-CH(OH)-CH2-OH, -CH(CH3)-C(O)-N(H)-CH2-COOH, -CH(CH3)-C(O)-N(H)-CH2-C(O)-O-CH2-CH3, -CH2-C(O)-N(H)-CH2-COOH, -CH2-CH2-C(O)-N(H)-CH2-COOH, -CH(CH3)-CH2-C(O)-N(H)-CH2-COOH, and -CH2-CH(CH3)-C(O)-N(H)-CM2-COOH, substituted heteroaryl selected from: 5-chloro-1 H-benzoimidazol-2-yl, 5-methoxy-1 H-benzoimidazol-2-yl, 4-oxo-3,4-dihydro-quinazolin-2-yl, benzoselenazol-2-yl, and 5-substituted-benzothiazol-2-yl;
heterocyclyl selected from: thiazol, 2-thioxo-imidazolidin-1-yl and morpholino, an optionally substituted nucleoside, or an optionally substituted di-, tri-or tetra-peptide, or -CH2-C(O)-C(O)-O-R' or -CH=C(OH)-C(O)-O-R';
R is: hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl or optionally substituted heterocycloalkyl;
R' is: independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted aryl;
X is: -N(R')-, -S-, -S(O)-, -S(O)2-, -S-Y-S-, or a covalent bond to the sulfur atom of Cys or to the nitrogen atom of optionally substituted heterocyclyl;
Y is: optionally substituted aryl, optionally substituted heteroaryl, an optionally substituted nucleoside, an optionally substituted amino acid, or an optionally substituted di-, tri- or tetra-peptide; and Z is: -OR or -SR;
including single tautomers, single stereoisomers and mixtures of tautomers and/or stereoisomers, and the pharmaceutically acceptable salts thereof.
wherein:
A is: substituted alkyl selected from: -CH2-CH(OH)-CH2-OH, -CH(CH3)-CH(OH)-CH2-OH, -CH(CH3)-C(O)-N(H)-CH2-COOH, -CH(CH3)-C(O)-N(H)-CH2-C(O)-O-CH2-CH3, -CH2-C(O)-N(H)-CH2-COOH, -CH2-CH2-C(O)-N(H)-CH2-COOH, -CH(CH3)-CH2-C(O)-N(H)-CH2-COOH, and -CH2-CH(CH3)-C(O)-N(H)-CM2-COOH, substituted heteroaryl selected from: 5-chloro-1 H-benzoimidazol-2-yl, 5-methoxy-1 H-benzoimidazol-2-yl, 4-oxo-3,4-dihydro-quinazolin-2-yl, benzoselenazol-2-yl, and 5-substituted-benzothiazol-2-yl;
heterocyclyl selected from: thiazol, 2-thioxo-imidazolidin-1-yl and morpholino, an optionally substituted nucleoside, or an optionally substituted di-, tri-or tetra-peptide, or -CH2-C(O)-C(O)-O-R' or -CH=C(OH)-C(O)-O-R';
R is: hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl or optionally substituted heterocycloalkyl;
R' is: independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted aryl;
X is: -N(R')-, -S-, -S(O)-, -S(O)2-, -S-Y-S-, or a covalent bond to the sulfur atom of Cys or to the nitrogen atom of optionally substituted heterocyclyl;
Y is: optionally substituted aryl, optionally substituted heteroaryl, an optionally substituted nucleoside, an optionally substituted amino acid, or an optionally substituted di-, tri- or tetra-peptide; and Z is: -OR or -SR;
including single tautomers, single stereoisomers and mixtures of tautomers and/or stereoisomers, and the pharmaceutically acceptable salts thereof.
28. The compound of Claim 27, wherein:
A is: substituted alkyl selected from: -CH2-CH(OH)-CH2-OH, -CH(CH3)-CH(OH)-CH2-OH, -CH(CH3)-C(O)-N(H)-CH2-COOH, -CH2-C(O)-N(H)-CH2-COOH, -CH2-CH2-C(O)-N(H)-CH2-COOH, -CH(CH3)-CH2-C(O)-N(H)-CH2-COOH, and -CH2-CH(CH3)-C(O)-N(H)-CH2-COOH, substituted heteroaryl selected from: 5-chloro-1H-benzoimidazol-2-yl, 5-methoxy-1 H-benzoimidazol-2-yl, 4-oxo-3,4-dihydro-quinazolin-2-yl, benzoselenazol-2-yl, and 5-substituted-benzothiazol-2-yl, heterocyclyl selected from: thiazol, 2-thioxo-imidazolidin-1-yl and morpholino, or an optionally substituted di-, tri- or tetra-peptide;
R is: hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl;
X is: -S-, -S(O)-, -S(O)2-, or a covalent bond to the sulfur atom of Cys or to the nitrogen atom of optionally substituted heterocyclyl; and Z is: -OR.
A is: substituted alkyl selected from: -CH2-CH(OH)-CH2-OH, -CH(CH3)-CH(OH)-CH2-OH, -CH(CH3)-C(O)-N(H)-CH2-COOH, -CH2-C(O)-N(H)-CH2-COOH, -CH2-CH2-C(O)-N(H)-CH2-COOH, -CH(CH3)-CH2-C(O)-N(H)-CH2-COOH, and -CH2-CH(CH3)-C(O)-N(H)-CH2-COOH, substituted heteroaryl selected from: 5-chloro-1H-benzoimidazol-2-yl, 5-methoxy-1 H-benzoimidazol-2-yl, 4-oxo-3,4-dihydro-quinazolin-2-yl, benzoselenazol-2-yl, and 5-substituted-benzothiazol-2-yl, heterocyclyl selected from: thiazol, 2-thioxo-imidazolidin-1-yl and morpholino, or an optionally substituted di-, tri- or tetra-peptide;
R is: hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl;
X is: -S-, -S(O)-, -S(O)2-, or a covalent bond to the sulfur atom of Cys or to the nitrogen atom of optionally substituted heterocyclyl; and Z is: -OR.
29. The compound of Claim 28, wherein:
A is: an optionally substituted di-, tri- or tetra-peptide; and X is: a covalent bond to the sulfur atom of Cys.
A is: an optionally substituted di-, tri- or tetra-peptide; and X is: a covalent bond to the sulfur atom of Cys.
30. The compound of Claim 29, wherein:
A is: an optionally substituted di- or tri-peptide the amino acids of which are selected from Ala, Asp, Cys, Glu and Gly.
A is: an optionally substituted di- or tri-peptide the amino acids of which are selected from Ala, Asp, Cys, Glu and Gly.
31. The compound of Claim 30, wherein:
A is: the tri-peptide Glu-Cys-Gly.
A is: the tri-peptide Glu-Cys-Gly.
32. The compound of Claim 31, wherein:
R is: hydrogen or C1 to C8 alkyl.
R is: hydrogen or C1 to C8 alkyl.
33. The compound of Claim 32, selected from:
.cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-oxo-2-pentyloxycarbonyl-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-hexyloxycarbonyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-carboxy-2-oxo-ethylsulfanyl)-ethylcarbamoyl]butyric acid, and .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]butyric acid.
.cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-oxo-2-pentyloxycarbonyl-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-hexyloxycarbonyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-carboxy-2-oxo-ethylsulfanyl)-ethylcarbamoyl]butyric acid, and .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]butyric acid.
34. The compound of Claim 28, wherein:
A is: substituted alkyl, substituted heteroaryl, or heterocyclyl; and X is: -S-.
A is: substituted alkyl, substituted heteroaryl, or heterocyclyl; and X is: -S-.
35. The compound of Claim 28, wherein A is:
substituted alkyl selected from: -CH2-CH(OH)-CH2-OH, and -CH(CH3)-C(O)-N(H)-CH2-COOH);
optionally substituted heteroaryl selected from: benzoselenazol-2-yl, 5-(chloro or methoxy)-substituted-1H-benzoimidazol-2-yl, and 5-(chloro, methoxy or nitro)-substituted-benzothiazol-2-yl; or heterocyclyl selected from: 4,5-dihydro-thiazol-2-yl, 2-thioxo-imidazolidin-1-yl and morpholino.
substituted alkyl selected from: -CH2-CH(OH)-CH2-OH, and -CH(CH3)-C(O)-N(H)-CH2-COOH);
optionally substituted heteroaryl selected from: benzoselenazol-2-yl, 5-(chloro or methoxy)-substituted-1H-benzoimidazol-2-yl, and 5-(chloro, methoxy or nitro)-substituted-benzothiazol-2-yl; or heterocyclyl selected from: 4,5-dihydro-thiazol-2-yl, 2-thioxo-imidazolidin-1-yl and morpholino.
36. The compound of Claim 34, wherein:
R is: hydrogen or C1 to C8 alkyl.
R is: hydrogen or C1 to C8 alkyl.
37. The compound of Claim 35, wherein:
R is: hydrogen or C1 to C8 alkyl.
R is: hydrogen or C1 to C8 alkyl.
38. The compound of Claim 35, selected from:
.cndot. 3-(1H-benzoimidazol-2-ylsulfanyl)-2-oxo-propionic acid, .cndot. 2-oxo-3-(4-oxo-3,4-dihydro-quinazolin-2-ylsulfanyl)-propionic acid ethyl ester, .cndot. 3-[1-(carboxymethyl-carbamoyl)-ethylsulfanyl]-2-hydroxy-acrylic acid ethyl ester, .cndot. 3-(benzoselenazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester, .cndot. 3-(1H-benzoimidazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester, .cndot. 3-(5-chloro-benzothiazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester, .cndot. 3-(5-methoxy-benzoimidazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester, and .cndot. 3-(4,5-dihydro-thiazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester.
.cndot. 3-(1H-benzoimidazol-2-ylsulfanyl)-2-oxo-propionic acid, .cndot. 2-oxo-3-(4-oxo-3,4-dihydro-quinazolin-2-ylsulfanyl)-propionic acid ethyl ester, .cndot. 3-[1-(carboxymethyl-carbamoyl)-ethylsulfanyl]-2-hydroxy-acrylic acid ethyl ester, .cndot. 3-(benzoselenazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester, .cndot. 3-(1H-benzoimidazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester, .cndot. 3-(5-chloro-benzothiazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester, .cndot. 3-(5-methoxy-benzoimidazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester, and .cndot. 3-(4,5-dihydro-thiazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester.
39. A pharmaceutical formulation comprising a compound of any of Claims 27-38 and a pharmaceutically acceptable excipient.
40. A pharmaceutical formulation comprising a compound of any of Claim 28, 29, 33, 34, 37or 38 and a pharmaceutically acceptable excipient.
41. A compound of Formula Ib:
wherein:
A is: optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, an optionally substituted nucleoside, an optionally substituted amino acid, an optionally substituted di-, tri- or tetra-peptide, -CH2-C(O)-C(O)-O-R' or -CH=C(OH)-C(O)-O-R';
R is: hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl or optionally substituted heterocycloalkyl;
R a is: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, or alkenyl;
R' is: independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted aryl;
X is: -S-, -S(O)-, -S-Y-S-, or a covalent bond to the sulfur atom of Cys or to the nitrogen atom of optionally substituted heterocyclyl;
Y is: optionally substituted aryl, optionally substituted heteroaryl, an optionally substituted nucleoside, an optionally substituted amino acid, or an optionally substituted di-, tri- or tetra-peptide; and Z is: -OR or -SR;
including single tautomers, single stereoisomers and mixtures of tautomers and/or stereoisomers, and the pharmaceutically acceptable salts thereof; provided that:
.cndot. where X is -S-, A is not optionally substituted alkyl, benzyl or an N-arylpyrroline-2,5-dione-substituted phenyl, and further provided that the compound of Formula 1b is not:
.cndot. 2-hydroxyimino-3-p-tolylsulfanyl-propionic acid ethyl ester.
wherein:
A is: optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, an optionally substituted nucleoside, an optionally substituted amino acid, an optionally substituted di-, tri- or tetra-peptide, -CH2-C(O)-C(O)-O-R' or -CH=C(OH)-C(O)-O-R';
R is: hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl or optionally substituted heterocycloalkyl;
R a is: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, or alkenyl;
R' is: independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted aryl;
X is: -S-, -S(O)-, -S-Y-S-, or a covalent bond to the sulfur atom of Cys or to the nitrogen atom of optionally substituted heterocyclyl;
Y is: optionally substituted aryl, optionally substituted heteroaryl, an optionally substituted nucleoside, an optionally substituted amino acid, or an optionally substituted di-, tri- or tetra-peptide; and Z is: -OR or -SR;
including single tautomers, single stereoisomers and mixtures of tautomers and/or stereoisomers, and the pharmaceutically acceptable salts thereof; provided that:
.cndot. where X is -S-, A is not optionally substituted alkyl, benzyl or an N-arylpyrroline-2,5-dione-substituted phenyl, and further provided that the compound of Formula 1b is not:
.cndot. 2-hydroxyimino-3-p-tolylsulfanyl-propionic acid ethyl ester.
42. The compound of Claim 41, wherein:
A is: optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, an optionally substituted amino acid, or an optionally substituted di-, tri- or tetra-peptide;
R is: hydrogen, optionally substituted alkyl, substituted cycloalkyl, or optionally substituted aralkyl;
X is: -S-, or a covalent bond to the sulfur atom of Cys or to the nitrogen atom of optionally substituted heterocyclyl; and Z is: -OR.
A is: optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, an optionally substituted amino acid, or an optionally substituted di-, tri- or tetra-peptide;
R is: hydrogen, optionally substituted alkyl, substituted cycloalkyl, or optionally substituted aralkyl;
X is: -S-, or a covalent bond to the sulfur atom of Cys or to the nitrogen atom of optionally substituted heterocyclyl; and Z is: -OR.
43. The compound of Claim 42, wherein:
A is: an optionally substituted amino acid selected from Ala, Asp, Cys, Glu and Gly, or an optionally substituted di- or tri-peptide the amino acids of which are selected from Ala, Asp, Cys, Glu and Gly.
A is: an optionally substituted amino acid selected from Ala, Asp, Cys, Glu and Gly, or an optionally substituted di- or tri-peptide the amino acids of which are selected from Ala, Asp, Cys, Glu and Gly.
44. The compound of Claim 43, wherein:
A is: the tri-peptide Glu-Cys-Gly; and X is: a covalent bond to the sulfur atom of Cys.
A is: the tri-peptide Glu-Cys-Gly; and X is: a covalent bond to the sulfur atom of Cys.
45. The compound of Claim 42, wherein:
R is: hydrogen or C1 to C6 alkyl; and R a is: hydrogen, C1 to C4 alkyl or alkenyl, phenyl or optionally substituted benzyl.
R is: hydrogen or C1 to C6 alkyl; and R a is: hydrogen, C1 to C4 alkyl or alkenyl, phenyl or optionally substituted benzyl.
46. The compound of Claim 44, wherein:
R is: hydrogen or C1 to C6 alkyl; and R a is: hydrogen, C1 to C4 alkyl, or optionally substituted benzyl.
R is: hydrogen or C1 to C6 alkyl; and R a is: hydrogen, C1 to C4 alkyl, or optionally substituted benzyl.
47. The compound of Claim 45, selected from:
.cndot. 2-amino-4-[2-(2-butoxycarbonyl-2-methoxyimino-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-butyric acid or the HCl salt thereof, .cndot. 2-amino-4-[2-(2-benzyloxyimino-2-butoxycarbonyl-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-butyric acid or the HCl salt thereof, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-hydroxyimino-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-amino-4-[2-(2-butoxycarbonyl-2-hydroxyimino-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-butyric acid or the HCl salt thereof, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-methoxyimino-ethylsulfanyl)-ethylcarbamoyl]-butyric acid .cndot. 2-amino-4-[2-(2-benzyloxyimino-2-ethoxycarbonyl-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-butyric acid or the HCl slat thereof, .cndot. 2-amino-4-{1-(carboxymethyl-carbamoyl)-2-[2-ethoxycarbonyl-2-(4-nitro-benzyloxyimino)-ethylsulfanyl]-ethylcarbamoyl}-butyric acid, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-phenoxyimino-ethylsulfanyl)-ethylcarbamoyl]-butyric acid or the HCl salt thereof, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-ethoxyimino-ethylsulfanyl)-ethylcarbamoyl]-butyric acid or the di-HCl salt thereof, .cndot. 2-amino-4-[2-(2-tert-butoxyimino-2-ethoxycarbonyl-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-butyric acid or the di-HCl salt thereof, and .cndot. 4-[2-(2-allyloxyimino-2-ethoxycarbonyl-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-2-amino-butyric acid or the di-HCl salt thereof.
.cndot. 2-amino-4-[2-(2-butoxycarbonyl-2-methoxyimino-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-butyric acid or the HCl salt thereof, .cndot. 2-amino-4-[2-(2-benzyloxyimino-2-butoxycarbonyl-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-butyric acid or the HCl salt thereof, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-hydroxyimino-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-amino-4-[2-(2-butoxycarbonyl-2-hydroxyimino-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-butyric acid or the HCl salt thereof, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-methoxyimino-ethylsulfanyl)-ethylcarbamoyl]-butyric acid .cndot. 2-amino-4-[2-(2-benzyloxyimino-2-ethoxycarbonyl-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-butyric acid or the HCl slat thereof, .cndot. 2-amino-4-{1-(carboxymethyl-carbamoyl)-2-[2-ethoxycarbonyl-2-(4-nitro-benzyloxyimino)-ethylsulfanyl]-ethylcarbamoyl}-butyric acid, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-phenoxyimino-ethylsulfanyl)-ethylcarbamoyl]-butyric acid or the HCl salt thereof, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-ethoxyimino-ethylsulfanyl)-ethylcarbamoyl]-butyric acid or the di-HCl salt thereof, .cndot. 2-amino-4-[2-(2-tert-butoxyimino-2-ethoxycarbonyl-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-butyric acid or the di-HCl salt thereof, and .cndot. 4-[2-(2-allyloxyimino-2-ethoxycarbonyl-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-2-amino-butyric acid or the di-HCl salt thereof.
48. The compound of Claim 42, wherein:
A is: optionally substituted aryl or optionally substituted heteroaryl; and X is: -S-.
A is: optionally substituted aryl or optionally substituted heteroaryl; and X is: -S-.
49. The compound of Claim 48, wherein A is:
phenyl; or optionally substituted heteroaryl selected from: 5-optionally substituted-benzothiazol-2-yl and 5-optionally substituted benzoimidazol-2-yl.
phenyl; or optionally substituted heteroaryl selected from: 5-optionally substituted-benzothiazol-2-yl and 5-optionally substituted benzoimidazol-2-yl.
50. The compound of Claim 42, wherein:
R is: hydrogen or C1 to C6 alkyl; and R a is: hydrogen or C1 to C4 alkyl.
R is: hydrogen or C1 to C6 alkyl; and R a is: hydrogen or C1 to C4 alkyl.
51. The compound of Claim 48, wherein:
R is: hydrogen or C1 to C6 alkyl; and R a is: hydrogen or C1 to C4 alkyl.
R is: hydrogen or C1 to C6 alkyl; and R a is: hydrogen or C1 to C4 alkyl.
52. The compound of Claim 51, selected from:
.cndot. 3-(5-chloro-benzothiazol-2-ylsulfanyl)-2-hydroxyimino-propionic acid ethyl ester, .cndot. 2-hydroxyimino-3-(5-methoxy-1H-benzoimidazol-2-ylsulfanyl)-propionic acid ethyl ester, and .cndot. 3-(1H-benzoimidazol-2-ylsulfanyl)-2-hydroxyimino-propionic acid ethyl ester.
.cndot. 3-(5-chloro-benzothiazol-2-ylsulfanyl)-2-hydroxyimino-propionic acid ethyl ester, .cndot. 2-hydroxyimino-3-(5-methoxy-1H-benzoimidazol-2-ylsulfanyl)-propionic acid ethyl ester, and .cndot. 3-(1H-benzoimidazol-2-ylsulfanyl)-2-hydroxyimino-propionic acid ethyl ester.
53. A pharmaceutical formulation comprising a compound of any of Claims 40-52 and a pharmaceutically acceptable excipient.
54. A pharmaceutical formulation comprising a compound of any of Claim 41, 46, 47, 48, 51 or 52 and a pharmaceutically acceptable excipient.
55. A compound of Formula Ic:
wherein:
A is: optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, an optionally substituted nucleoside, an optionally substituted amino acid, an optionally substituted di-, tri- or tetra-peptide, CH2-C(O)-C(O)-O-R' or -CH=C(OH)-C(O)-O-R';
W is: =O, =N-OR a, or -N(OH)-R d;
X is: -S-, -S(O)-, -S(O)2-, -S-Y-S-, or a covalent bond to the sulfur atom of Cys or to the nitrogen atom of optionally substituted heterocyclyl;
Y is: optionally substituted aryl, optionally substituted heteroaryl, an optionally substituted nucleoside, an optionally substituted amino acid, or an optionally substituted di-, tri- or tetra-peptide;
R' is: independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted aryl;
R a is: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, or alkenyl;
R b is: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted cycloalkyl;
R c is: hydrogen or optionally substituted alkyl; and R d is: hydrogen, acyl or optionally substituted alkyl; or R b and R c together with the nitrogen to which they are attached may form a 5-to 7-membered ring, optionally incorporating one or two additional ring heteroatoms chosen from N, S, or O, and said ring being optionally substituted with one or more substituents independently selected from the group consisting of =O, =S, acyl, optionally substituted alkenyl, optionally substituted alkyl, (optionally substituted alkoxy)carbonyl, and (optionally substituted amino)carbonyl;
including single tautomers, single stereoisomers and mixtures of tautomers and/or stereoisomers, and the pharmaceutically acceptable salts thereof, provided that:
.cndot. where X is -S-, A is not optionally substituted methyl, optionally substituted ethyl, optionally substituted benzyl, or triphenylmethyl, and .cndot. where W is =N-OR a and X is a covalent bond to the sulfur atom of Cys, A is an optionally substituted di-, tri- or tetra-peptide.
wherein:
A is: optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, an optionally substituted nucleoside, an optionally substituted amino acid, an optionally substituted di-, tri- or tetra-peptide, CH2-C(O)-C(O)-O-R' or -CH=C(OH)-C(O)-O-R';
W is: =O, =N-OR a, or -N(OH)-R d;
X is: -S-, -S(O)-, -S(O)2-, -S-Y-S-, or a covalent bond to the sulfur atom of Cys or to the nitrogen atom of optionally substituted heterocyclyl;
Y is: optionally substituted aryl, optionally substituted heteroaryl, an optionally substituted nucleoside, an optionally substituted amino acid, or an optionally substituted di-, tri- or tetra-peptide;
R' is: independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted aryl;
R a is: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, or alkenyl;
R b is: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted cycloalkyl;
R c is: hydrogen or optionally substituted alkyl; and R d is: hydrogen, acyl or optionally substituted alkyl; or R b and R c together with the nitrogen to which they are attached may form a 5-to 7-membered ring, optionally incorporating one or two additional ring heteroatoms chosen from N, S, or O, and said ring being optionally substituted with one or more substituents independently selected from the group consisting of =O, =S, acyl, optionally substituted alkenyl, optionally substituted alkyl, (optionally substituted alkoxy)carbonyl, and (optionally substituted amino)carbonyl;
including single tautomers, single stereoisomers and mixtures of tautomers and/or stereoisomers, and the pharmaceutically acceptable salts thereof, provided that:
.cndot. where X is -S-, A is not optionally substituted methyl, optionally substituted ethyl, optionally substituted benzyl, or triphenylmethyl, and .cndot. where W is =N-OR a and X is a covalent bond to the sulfur atom of Cys, A is an optionally substituted di-, tri- or tetra-peptide.
56. The compound of Claim 55, wherein:
A is: optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, an optionally substituted amino acid, or an optionally substituted di-, tri- or tetra-peptide;
X is: -S-, or a covalent bond to the sulfur atom of Cys;
W is: =O or =N-OR a;
R a is: hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted aralkyl;
R b is: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted cycloalkyl;
R c is: hydrogen or optionally substituted alkyl; and R b and R c together with the nitrogen to which they are attached may form a 5-or 6-membered ring, optionally incorporating N or O as an additional ring heteroatom, and said ring being optionally substituted with one substituent selected from the group consisting of acyl and optionally substituted alkyl.
A is: optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, an optionally substituted amino acid, or an optionally substituted di-, tri- or tetra-peptide;
X is: -S-, or a covalent bond to the sulfur atom of Cys;
W is: =O or =N-OR a;
R a is: hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted aralkyl;
R b is: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted cycloalkyl;
R c is: hydrogen or optionally substituted alkyl; and R b and R c together with the nitrogen to which they are attached may form a 5-or 6-membered ring, optionally incorporating N or O as an additional ring heteroatom, and said ring being optionally substituted with one substituent selected from the group consisting of acyl and optionally substituted alkyl.
57. The compound of Claim 56, wherein:
R b is: C1 to C4 alkyl, optionally substituted aryl, optionally substituted aralkyl or cycloalkyl; and R c is: hydrogen or C1 to C4 alkyl; or R b and R c together with the nitrogen to which they are attached form a 6-membered ring, optionally incorporating O as an additional ring heteroatom, and said ring being optionally substituted with one substituent selected from the group consisting of acyl and optionally substituted alkyl.
R b is: C1 to C4 alkyl, optionally substituted aryl, optionally substituted aralkyl or cycloalkyl; and R c is: hydrogen or C1 to C4 alkyl; or R b and R c together with the nitrogen to which they are attached form a 6-membered ring, optionally incorporating O as an additional ring heteroatom, and said ring being optionally substituted with one substituent selected from the group consisting of acyl and optionally substituted alkyl.
58. The compound of Claim 57, wherein:
R b and R c are C1 to C4 alkyl;
R b is optionally substituted aryl, optionally substituted aralkyl or cycloalkyl, and R c is hydrogen; or R b and R c together with the nitrogen to which they are attached form a 6-membered ring selected from 4-optionally substituted-piperidin-1-yl and morpholin-4-yl.
R b and R c are C1 to C4 alkyl;
R b is optionally substituted aryl, optionally substituted aralkyl or cycloalkyl, and R c is hydrogen; or R b and R c together with the nitrogen to which they are attached form a 6-membered ring selected from 4-optionally substituted-piperidin-1-yl and morpholin-4-yl.
59. The compound of Claim 58, wherein:
R b and R c are ethyl;
R b is phenyl, benzyl, 1-methoxycarbonyl-2-phenethyl or cyclohexyl, and R c is hydrogen;
or R b and R c together with the nitrogen to which they are attached form a 6-membered ring selected from piperidin-1-yl, 4-methyl-piperidin-1-yl and morpholin-4-yl.
R b and R c are ethyl;
R b is phenyl, benzyl, 1-methoxycarbonyl-2-phenethyl or cyclohexyl, and R c is hydrogen;
or R b and R c together with the nitrogen to which they are attached form a 6-membered ring selected from piperidin-1-yl, 4-methyl-piperidin-1-yl and morpholin-4-yl.
60. The compound of Claim 56, wherein:
A is: an optionally substituted amino acid selected from Ala, Asp, Cys, Glu and Gly, or an optionally substituted di- or tri-peptide the amino acids of which are selected from Ala, Asp, Cys, Glu and Gly.
A is: an optionally substituted amino acid selected from Ala, Asp, Cys, Glu and Gly, or an optionally substituted di- or tri-peptide the amino acids of which are selected from Ala, Asp, Cys, Glu and Gly.
61. The compound of Claim 60, wherein:
A is: the tri-peptide Glu-Cys-Gly; and X is: a covalent bond to the sulfur atom of Cys.
A is: the tri-peptide Glu-Cys-Gly; and X is: a covalent bond to the sulfur atom of Cys.
62. The compound of Claim 61, wherein:
R b and R c are C1 to C4 alkyl;
R b is C1 to C8 optionally acyl-substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or cycloalkyl, and R c is hydrogen; or R b and R c together with the nitrogen to which they are attached form a 2-optionally substituted-pyrrolidine ring or a 6-membered ring selected from 4-optionally substituted-piperidin-1-yl and morpholin-4-yl.
R b and R c are C1 to C4 alkyl;
R b is C1 to C8 optionally acyl-substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or cycloalkyl, and R c is hydrogen; or R b and R c together with the nitrogen to which they are attached form a 2-optionally substituted-pyrrolidine ring or a 6-membered ring selected from 4-optionally substituted-piperidin-1-yl and morpholin-4-yl.
63. The compound of Claim 57, wherein:
W is =O, =N-OH, or =N-O-CH3.
W is =O, =N-OH, or =N-O-CH3.
64. The compound of Claim 59, wherein:
W is =O, =N-OH, or =N-O-CH3.
W is =O, =N-OH, or =N-O-CH3.
65. The compound of Claim 61, wherein:
W is =O, =N-OH, or =N-O-CH3.
W is =O, =N-OH, or =N-O-CH3.
66. The compound of Claim 62, wherein:
W is =O, =N-OH, or =N-O-CH3.
W is =O, =N-OH, or =N-O-CH3.
67. The compound of Claim 66, selected from:
.cndot. 2-Amino-4-{1-(carboxymethyl-carbamoyl)-2-[3-(4-methyl-piperidin-1-yl)-2,3-dioxo-propylsulfanyl]-ethylcarbamoyl}-butyric acid, .cndot. 2-Amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-hydroxyimino-3-oxo-3-piperidin-1-yl-propylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-Amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-diethylcarbamoyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid .cndot. 2-Amino-4-[1-(carboxymethyl-carbamoyl)-2-(2,3-dioxo-3-piperidin-1-yl-propylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-Amino-4-{1-(carboxymethyl-carbamoyl)-2-[2-(1-methoxycarbonyl-2-phenyl-ethylcarbamoyl)-2-oxo-ethylsulfanyl]-ethylcarbamoyl}-butyric acid, .cndot. 2-Amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-cyclohexylcarbamoyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-Amino-4-[2-(2-benzylcarbamoyl-2-oxo-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-Amino-4-[1-(carboxymethyl-carbamoyl)-2-(3-morpholin-4-yl-2,3-dioxo-propylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethylcarbamoyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-methoxyimino-ethylsulfanyl)-ethylcarbamoyl]-butyric acid .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2,3-dioxo-3-pyrrolidin-1-yl-propylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-octylcarbamoyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 1-{3-[2-(4-amino-4-carboxy-butyrylamino)-2-(carboxymethyl-carbamoyl)-ethylsulfanyl]-2-oxo-propionyl}-pyrrolidine-2-carboxylic acid methyl ester, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-hexylcarbamoyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-{3-[2-(4-amino-4-carboxy-butyrylamino)-2-(carboxymethyl-carbamoyl)-ethylsulfanyl]-2-oxo-propionylamino}-3-methyl-pentanoic acid methyl ester, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-dimethylcarbamoyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, and .cndot. 2-amino-4-(1-(carboxymethyl-carbamoyl)-2-{2-[2-(4-hydroxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-oxo-ethylsulfanyl}-ethylcarbamoyl)-butyric acid.
.cndot. 2-Amino-4-{1-(carboxymethyl-carbamoyl)-2-[3-(4-methyl-piperidin-1-yl)-2,3-dioxo-propylsulfanyl]-ethylcarbamoyl}-butyric acid, .cndot. 2-Amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-hydroxyimino-3-oxo-3-piperidin-1-yl-propylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-Amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-diethylcarbamoyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid .cndot. 2-Amino-4-[1-(carboxymethyl-carbamoyl)-2-(2,3-dioxo-3-piperidin-1-yl-propylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-Amino-4-{1-(carboxymethyl-carbamoyl)-2-[2-(1-methoxycarbonyl-2-phenyl-ethylcarbamoyl)-2-oxo-ethylsulfanyl]-ethylcarbamoyl}-butyric acid, .cndot. 2-Amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-cyclohexylcarbamoyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-Amino-4-[2-(2-benzylcarbamoyl-2-oxo-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-Amino-4-[1-(carboxymethyl-carbamoyl)-2-(3-morpholin-4-yl-2,3-dioxo-propylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethylcarbamoyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-methoxyimino-ethylsulfanyl)-ethylcarbamoyl]-butyric acid .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2,3-dioxo-3-pyrrolidin-1-yl-propylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-octylcarbamoyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 1-{3-[2-(4-amino-4-carboxy-butyrylamino)-2-(carboxymethyl-carbamoyl)-ethylsulfanyl]-2-oxo-propionyl}-pyrrolidine-2-carboxylic acid methyl ester, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-hexylcarbamoyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, .cndot. 2-{3-[2-(4-amino-4-carboxy-butyrylamino)-2-(carboxymethyl-carbamoyl)-ethylsulfanyl]-2-oxo-propionylamino}-3-methyl-pentanoic acid methyl ester, .cndot. 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-dimethylcarbamoyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid, and .cndot. 2-amino-4-(1-(carboxymethyl-carbamoyl)-2-{2-[2-(4-hydroxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-oxo-ethylsulfanyl}-ethylcarbamoyl)-butyric acid.
68. The compound of Claim 56, wherein:
A is: optionally substituted aryl or optionally substituted heteroaryl; and X is: -S-.
A is: optionally substituted aryl or optionally substituted heteroaryl; and X is: -S-.
69. The compound of Claim 58, wherein:
A is: optionally substituted aryl or optionally substituted heteroaryl; and X is: -S-.
A is: optionally substituted aryl or optionally substituted heteroaryl; and X is: -S-.
70. The compound of Claim 69, wherein A is:
optionally substituted aryl selected from: phenyl and p-tolyl; or optionally substituted heteroaryl selected from: 5-optionally substituted-benzothiazol-2-yl and 5-optionally substituted benzoimidazol-2-yl.
optionally substituted aryl selected from: phenyl and p-tolyl; or optionally substituted heteroaryl selected from: 5-optionally substituted-benzothiazol-2-yl and 5-optionally substituted benzoimidazol-2-yl.
71. The compound of Claim 69, wherein:
W is =O, =N-OH, or =N-O-CH3.
W is =O, =N-OH, or =N-O-CH3.
72. The compound of Claim 71, selected from:
.cndot. 2-hydroxyimino-N-phenyl-3-p-tolylsulfanyl-propionamide, and .cndot. 1-piperidin-1-yl-3-p-tolylsulfanyl-propane-1,2-dione 2-oxime.
.cndot. 2-hydroxyimino-N-phenyl-3-p-tolylsulfanyl-propionamide, and .cndot. 1-piperidin-1-yl-3-p-tolylsulfanyl-propane-1,2-dione 2-oxime.
73. The compound of Claim 56, wherein:
W is =N-OR a.
W is =N-OR a.
74. The compound of Claim 73, wherein:
R a is hydrogen or optionally substituted alkyl;
R b is: C1 to C4 alkyl, optionally substituted aryl, optionally substituted aralkyl or cycloalkyl; and R c is: hydrogen or C1 to C4 alkyl; or R b and R c together with the nitrogen to which they are attached form an optionally substituted-pyrrolidine ring or a 6-membered ring, optionally incorporating O
or N as an additional ring heteroatom, and said ring being optionally substituted with one substituent selected from the group consisting of acyl and optionally substituted alkyl.
R a is hydrogen or optionally substituted alkyl;
R b is: C1 to C4 alkyl, optionally substituted aryl, optionally substituted aralkyl or cycloalkyl; and R c is: hydrogen or C1 to C4 alkyl; or R b and R c together with the nitrogen to which they are attached form an optionally substituted-pyrrolidine ring or a 6-membered ring, optionally incorporating O
or N as an additional ring heteroatom, and said ring being optionally substituted with one substituent selected from the group consisting of acyl and optionally substituted alkyl.
75. A pharmaceutical formulation comprising a compound of any of Claims 55-74 and a pharmaceutically acceptable excipient.
76. A pharmaceutical formulation comprising a compound of any of Claims 56, 58, 66, 67, 69, 71, 72 or 73 and a pharmaceutically acceptable excipient.
77. A compound of Formula II:
wherein:
R1 is: hydrogen, optionally substituted alkyl, optionally substituted aryl, -C(O)-O-R', -CH2-SH, -CH2-S-CH2-C(W)-C(O)-Z, -CH2-S-CH=C(OH)-C(O)-Z, -CH2-S(O)-CH2-C(W)-C(O)-Z, or -CH2-S(O)-CH=C(OH)-C(O)-Z';
R2 is: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted acyl;
R3 is: independently selected from hydrogen, optionally substituted lower alkyl, optionally substituted aralkyl, -CH2-SH, -CH2-S-CH2-C(W)-C(O)-Z, -CH2-S-CH=C(OH)-C(O)-Z, -CH2-S(O)-CH2-C(W)-C(O)-Z, or -CH2-S(O)-CH=C(OH)-C(O)-Z;
R4 is: hydrogen, optionally substituted lower alkyl, optionally substituted aralkyl, optionally substituted heteroararalkyl, -CH2-SH, -CH2-S-CH2-C(W)-C(O)-Z, -CH2-S-CH=C(OH)-C(O)-Z, -CH2-S(O)-CH2-C(W)-C(O)-Z, or -CH2-S(O)-CH=C(OH)-C(O)-Z;
R5 is: hydrogen, optionally substituted alkyl, or optionally substituted aryl;
R' is: independently selected from hydrogen, optionally substituted alkyl, or optionally substituted aryl;
W is: =O, =N-OR a, =N-NR b R c; or -N(OH)-R d Z is: -OR, -SR, or -NR b R c;
R is: hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl or optionally substituted heterocycloalkyl;
R a is: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, or alkenyl;
R b is: independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted cycloalkyl, R c is: independently selected from hydrogen or optionally substituted alkyl;
and R d is: hydrogen, acyl or optionally substituted alkyl; or R b and R c together with the nitrogen to which they are attached may form an 5- to 7-membered ring, optionally incorporating one or two additional ring heteroatoms chosen from N, S, or O, and said ring being optionally substituted with one or more substituents independently selected from the group consisting of =O, =S, acyl, optionally substituted alkenyl, optionally substituted alkyl, (optionally substituted alkoxy)carbonyl, and (optionally substituted amino)carbonyl;
k is: 0, 1 or 2;
m is: 0, 1 or 2; and n is: 0, 1, 2 or 3;
including single tautomers, single stereoisomers and mixtures of tautomers and/or stereoisomers, and the pharmaceutically acceptable salts thereof, provided that at least one of R1, R3 or R4 is -CH2-S-CH2-C(W)-C(O)-Z, -CH2-S-CH=C(OH)-C(O)-Z, -CH2-S(O)-CH2-C(W)-C(O)-Z, or -CH2-S(O)-CH=C(OH)-C(O)-Z.
wherein:
R1 is: hydrogen, optionally substituted alkyl, optionally substituted aryl, -C(O)-O-R', -CH2-SH, -CH2-S-CH2-C(W)-C(O)-Z, -CH2-S-CH=C(OH)-C(O)-Z, -CH2-S(O)-CH2-C(W)-C(O)-Z, or -CH2-S(O)-CH=C(OH)-C(O)-Z';
R2 is: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted acyl;
R3 is: independently selected from hydrogen, optionally substituted lower alkyl, optionally substituted aralkyl, -CH2-SH, -CH2-S-CH2-C(W)-C(O)-Z, -CH2-S-CH=C(OH)-C(O)-Z, -CH2-S(O)-CH2-C(W)-C(O)-Z, or -CH2-S(O)-CH=C(OH)-C(O)-Z;
R4 is: hydrogen, optionally substituted lower alkyl, optionally substituted aralkyl, optionally substituted heteroararalkyl, -CH2-SH, -CH2-S-CH2-C(W)-C(O)-Z, -CH2-S-CH=C(OH)-C(O)-Z, -CH2-S(O)-CH2-C(W)-C(O)-Z, or -CH2-S(O)-CH=C(OH)-C(O)-Z;
R5 is: hydrogen, optionally substituted alkyl, or optionally substituted aryl;
R' is: independently selected from hydrogen, optionally substituted alkyl, or optionally substituted aryl;
W is: =O, =N-OR a, =N-NR b R c; or -N(OH)-R d Z is: -OR, -SR, or -NR b R c;
R is: hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl or optionally substituted heterocycloalkyl;
R a is: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, or alkenyl;
R b is: independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted cycloalkyl, R c is: independently selected from hydrogen or optionally substituted alkyl;
and R d is: hydrogen, acyl or optionally substituted alkyl; or R b and R c together with the nitrogen to which they are attached may form an 5- to 7-membered ring, optionally incorporating one or two additional ring heteroatoms chosen from N, S, or O, and said ring being optionally substituted with one or more substituents independently selected from the group consisting of =O, =S, acyl, optionally substituted alkenyl, optionally substituted alkyl, (optionally substituted alkoxy)carbonyl, and (optionally substituted amino)carbonyl;
k is: 0, 1 or 2;
m is: 0, 1 or 2; and n is: 0, 1, 2 or 3;
including single tautomers, single stereoisomers and mixtures of tautomers and/or stereoisomers, and the pharmaceutically acceptable salts thereof, provided that at least one of R1, R3 or R4 is -CH2-S-CH2-C(W)-C(O)-Z, -CH2-S-CH=C(OH)-C(O)-Z, -CH2-S(O)-CH2-C(W)-C(O)-Z, or -CH2-S(O)-CH=C(OH)-C(O)-Z.
78. The compound of Claim 77, wherein:
R1 is: -C(O)-O-R' where R' is hydrogen or lower alkyl;
R2 and R4 are hydrogen;
R3 is: -CH2-S-CH2-C(W)-C(O)-Z, -CH2-S-CH=C(OH)-C(O)-Z, -CH2-S(O)-CH2-C(W)-C(O)-Z, or -CH2-S(O)-CH=C(OH)-C(O)-Z
R5 is hydrogen or lower alkyl;
W is: =O Or =N-OR a;
Z is: -OR or -NR b R c;
R is: hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted aralkyl;
R a is: hydrogen or alkyl;
R b is: C1 to C4 alkyl, phenyl or benzyl;
R c is: hydrogen or C1 to C4 alkyl, or R b and R c together with the nitrogen to which they are attachwed form a 6-membered ring selected from 4-optionally substituted-piperidin-1-yl and morpholin-4-yl;
and k, m and n are respectively: 0,2,1; 1,0,1; or 2,0,1.
R1 is: -C(O)-O-R' where R' is hydrogen or lower alkyl;
R2 and R4 are hydrogen;
R3 is: -CH2-S-CH2-C(W)-C(O)-Z, -CH2-S-CH=C(OH)-C(O)-Z, -CH2-S(O)-CH2-C(W)-C(O)-Z, or -CH2-S(O)-CH=C(OH)-C(O)-Z
R5 is hydrogen or lower alkyl;
W is: =O Or =N-OR a;
Z is: -OR or -NR b R c;
R is: hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted aralkyl;
R a is: hydrogen or alkyl;
R b is: C1 to C4 alkyl, phenyl or benzyl;
R c is: hydrogen or C1 to C4 alkyl, or R b and R c together with the nitrogen to which they are attachwed form a 6-membered ring selected from 4-optionally substituted-piperidin-1-yl and morpholin-4-yl;
and k, m and n are respectively: 0,2,1; 1,0,1; or 2,0,1.
79. The compound of Claim 78, wherein:
R1 is: -COOH;
R5 is: hydrogen; and k, m and n are respectively: 0,2,1; or 2,0,1.
R1 is: -COOH;
R5 is: hydrogen; and k, m and n are respectively: 0,2,1; or 2,0,1.
80. A pharmaceutical formulation comprising a compound of any of Claims 77-79 and a pharmaceutically acceptable excipient.
81. A compound of Formula III:
wherein:
R3.1 is: H or is absent;
R3.2 is: H or C1 to C4 alkyl;
R3.3 and R3.4 are both H or are both C1 to C4alkyl; and R3.5 is: H, COOH, or -C(O)O-C1 to C4 alkyl;
including single tautomers, single stereoisomers and mixtures of tautomers and/or stereoisomers, and the pharmaceutically acceptable salts thereof.
wherein:
R3.1 is: H or is absent;
R3.2 is: H or C1 to C4 alkyl;
R3.3 and R3.4 are both H or are both C1 to C4alkyl; and R3.5 is: H, COOH, or -C(O)O-C1 to C4 alkyl;
including single tautomers, single stereoisomers and mixtures of tautomers and/or stereoisomers, and the pharmaceutically acceptable salts thereof.
82. The compound of Claim 81, wherein:
R3.3 and R3.4 are both H or are both methyl; and R3.5 is: COOH.
R3.3 and R3.4 are both H or are both methyl; and R3.5 is: COOH.
83. The compound of Claim 82, wherein:
R3.1 is hydrogen; and R3.2 is hydrogen or ethyl.
R3.1 is hydrogen; and R3.2 is hydrogen or ethyl.
84. The compound of Claim 83, selected from:
.cndot. 2,2-Dimethyl-3,4-dihydro-2H-[1,4]thiazine-3,5-dicarboxylic acid 5-ethyl ester; or .cndot. 3,4-dihydro-2H-[1,4]thiazine-3,5-dicarboxylic acid 5-ethyl ester.
.cndot. 2,2-Dimethyl-3,4-dihydro-2H-[1,4]thiazine-3,5-dicarboxylic acid 5-ethyl ester; or .cndot. 3,4-dihydro-2H-[1,4]thiazine-3,5-dicarboxylic acid 5-ethyl ester.
85. A pharmaceutical formulation comprising a compound of any of Claims 81-84 and a pharmaceutically acceptable excipient.
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| US36845602P | 2002-03-27 | 2002-03-27 | |
| PCT/US2002/014057 WO2002090314A1 (en) | 2001-05-03 | 2002-05-03 | Pyruvate derivatives |
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-
2002
- 2002-05-03 US US10/138,938 patent/US6900218B2/en not_active Expired - Fee Related
- 2002-05-03 ES ES02769325T patent/ES2314100T3/en not_active Expired - Lifetime
- 2002-05-03 EP EP02769325A patent/EP1392639B1/en not_active Expired - Lifetime
- 2002-05-03 AT AT02769325T patent/ATE408593T1/en active
- 2002-05-03 US US10/138,726 patent/US20030013656A1/en not_active Abandoned
- 2002-05-03 US US10/138,937 patent/US6916850B2/en not_active Expired - Fee Related
- 2002-05-03 US US10/138,809 patent/US20030013846A1/en not_active Abandoned
- 2002-05-03 CA CA2446136A patent/CA2446136C/en not_active Expired - Fee Related
- 2002-05-03 WO PCT/US2002/014057 patent/WO2002090314A1/en not_active Application Discontinuation
- 2002-05-03 DE DE60228954T patent/DE60228954D1/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| ES2314100T3 (en) | 2009-03-16 |
| US20030013657A1 (en) | 2003-01-16 |
| US20030013846A1 (en) | 2003-01-16 |
| US20030013847A1 (en) | 2003-01-16 |
| DE60228954D1 (en) | 2008-10-30 |
| US6900218B2 (en) | 2005-05-31 |
| US6916850B2 (en) | 2005-07-12 |
| ATE408593T1 (en) | 2008-10-15 |
| CA2446136C (en) | 2011-07-05 |
| WO2002090314A1 (en) | 2002-11-14 |
| US20030013656A1 (en) | 2003-01-16 |
| EP1392639A1 (en) | 2004-03-03 |
| EP1392639A4 (en) | 2006-01-25 |
| EP1392639B1 (en) | 2008-09-17 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20160503 |