| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | December 23, 2003 |
| PATENT TITLE |
Furanone derivatives |
| PATENT ABSTRACT |
Furanone derivatives and the pharmaceutically acceptable salts thereof have cytoprotective activity and protective activity for neuroinflammation, and neurodegenerative disorders; they are useful in the treatment of stroke, cerebral ischemia, myocardial infarction, myocardial ischemia, chronic heart failure, inflammation and other oxidative stress-related conditions, as well as Alzheimer's disease and senile dementia; they are also useful in the manufacture of pharmaceutical formulations for the treatment of such conditions. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | January 28, 2003 |
| PATENT REFERENCES CITED |
Stach, H. et al., Helvetica Chimica Acta (1987), 70 (2), 369-74 with English abstract. Hoffman, R. et al, Journal of Organic Chemistry, (1997), 62(8), 2459-2465. Trogolo, C et al., Annali di Chimica (1972), 62(10), 674-82 with English abstract. Hagio et al., Bull.Chem. Soc. Japan, (1974) 47 (4), 909-916 in English. |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A compound of Formula I ##STR45## wherein: R.sup.1 is: --C(O)OR'; --C(O)NR'R"; --CH.sub.2 OR'"; cyano; optionally substituted heterocyclyl; optionally substituted heterocyclyl-alkyl; optionally substituted heteroaryl, or optionally substituted heteroaralkyl; R.sup.2 is: optionally substituted alkyl; optionally substituted cycloalkyl; optionally substituted aryl; optionally substituted aralkyl; optionally substituted heterocyclyl; optionally substituted heteroaryl; optionally substituted heteroaralkyl; an optionally substituted nucleoside; an optionally substituted amino acid; or an optionally substituted di-, tri- or tetra-peptide; R.sup.3 is: optionally substituted alkyl; optionally substituted cycloalkyl; optionally substituted aryl; optionally substituted aralkyl; optionally substituted heterocyclyl; optionally substituted heteroaryl; optionally substituted heteroaralkyl; an optionally substituted nucleoside; an optionally substituted amino acid; or an optionally substituted di-, tri- or tetra-peptide; R.sup.4 is: hydrogen; alkyl; alkylcarbonyl; (poly)alkoxyalkylene; or dialkoxyphosphoryloxy; X is: lower alkylene; --N(R')--; --S--; --S(O)--; --S(O).sub.2 --; or X taken together with R.sup.2 is --P(O)(OR').sub.2 ; Y is: --N(R')--; --S--; --S(O)--; --S(O).sub.2 --; or Y taken together with R.sup.3 is --P(O)(OR').sub.2 ; or X--R.sup.2 taken together with Y--R.sup.3 form an optionally substituted aliphatic or aromatic ring; R' is: hydrogen; alkenyl; optionally substituted alkyl; optionally substituted cycloalkyl; phosphoryl; or optionally substituted aryl; R" is: hydrogen; alkenyl; optionally substituted alkyl; or optionally substituted aryl; or R' and R" together with the atom to which they are attached form a 5- to 7-membered aromatic, saturated or unsaturated ring, optionally incorporating one or more additional heteroatoms chosen from N, O, or S, and optionally substituted with one or more substituents selected from the group consisting of optionally substituted lower alkyl, halo, cyano, alkylthio, lower alkoxy, carboxy, benzyl, and oxo; R'" is: hydrogen; alkenyl; optionally substituted alkyl; acyl, optionally substituted cycloalkyl; phosphoryl; or optionally substituted aryl; with the proviso that the compound is not 4-hydroxy-3-methanesulfonyl-2-methane-sulfonylmethyl-5-oxo-2,5-dihydro-fur an-2-carboxylic acid ethyl ester and further with the proviso that when X is lower alkylene, R.sup.2 is not optionally substituted alkyl; including single tautomers, single stereoisomers and mixtures of tautomers and/or stereoisomers, and the pharmaceutically acceptable salts thereof. 2. The compound of claim 1, wherein X and Y are both selected from --S--, --S(O)--, and --S(O).sub.2 --. 3. The compound of claim 1, wherein X and Y are both --S--. 4. The compound of claim 1, wherein R.sup.4 is hydrogen. 5. The compound of claim 2, wherein R.sup.4 is hydrogen. 6. The compound of claim 1, wherein R.sup.1 is --CH.sub.2 OR'"; --C(O)OR'; or --C(O)NR'R"; and R', R", and R'" are selected from hydrogen and (C.sub.1 -C.sub.8)alkyl. 7. The compound of claim 2, wherein R.sup.1 is --CH.sub.2 OR'"; --C(O)OR'; or --C(O)NR'R"; and R', R", and R'" are selected from hydrogen and (C.sub.1 -C.sub.8)alkyl. 8. The compound of claim 5, wherein R.sup.1 is --CH.sub.2 OR'"; --C(O)OR'; or --C(O)NR'R"; and R', R", and R" are selected from hydrogen and (C.sub.1 -C.sub.8)alkyl; and R.sup.1 is selected from hydrogen and (C.sub.1 -C.sub.8)alkyl. 9. The compound of claim 2, wherein R.sup.2 and R.sup.3 are the same, selected from optionally substituted alkyl; optionally substituted cycloalkyl; optionally substituted aryl; optionally substituted aralkyl; optionally substituted heteroaryl; and optionally substituted heteroaralkyl. 10. The compound of claim 9, wherein R.sup.2 and R.sup.3 are the same selected from optionally substituted (C.sub.1 -C.sub.8)alkyl; optionally substituted (C.sub.3 -C.sub.8)cycloalkyl; optionally substituted phenyl; optionally substituted naphthalenyl; optionally substituted benzyl; optionally substituted 1-H-benzoimidazol-2-yl; optionally substituted benzothiazole-2yl; optionally substituted benzooxazole-2-yl; optionally substituted benzosenlenazol-2-yl; optionally substituted furan-2-yl-lower alkyl; optionally substituted thiazol-2-yl; optionally substituted 1H-imidazol-2-yl; optionally substituted pyridine-2-yl; optionally substituted pyrimidin-2-yl; optionally substituted quinolinin-4-yl; optionally substituted [1,3,4]oxadiaazol-2-yl; optionally substituted 2H-[1,2,4]-triazol-3-yl; and optionally substituted [1,3,4]thiadiazole-2-yl; and wherein the substituents are selected from (C.sub.1 -C.sub.8)alkyl; (C.sub.1 -C.sub.8)alkenyl; halogen; haloalkyl; acyl, sulfonic acid; sulfanyl; amino; mono- or di-substituted amino; aryl; carboxy; carboxyvinyl; ester; amide, hydroxy; and alkoxy. 11. The compound of claim 10, wherein R.sup.2 and R.sup.3 are the same selected from 1-H-benzoimidazol-2-yl; benzothiazol-2-yl; 5-methoxy-benzothiazol-2-yl; 6-nitro-benzothiazol-2-yl; benzooxazol-2-yl; 4-methoxy-benzyl; 2,4-dichloro-benzyl; 2-chloro-6-fluoro-benzyl; 5-amino-[1,3,4]thiadiazol-2-yl; furan-2-ylmethyl; cyclohexyl; pyridin-4-yl; 5-phenyl-[1,3,4]oxadiazol-2-yl; pyrrolidine-1-carbothioyl; 4-(2-methoxycarbonyl-vinyl)-phenyl; 4-trifluoromethyl-pyrimidin-2-yl; 4-methyl-pyrimidin-2-yl; and pyrimidin-2-yl. 12. The compound of claim 10, wherein X and Y are --S--. 13. The compound of claim 11, wherein X and Y are --S--. 14. The compound of claim 13, wherein R.sup.1 is --C(O)OR'; R' is selected from hydrogen and (C.sub.1 -C.sub.8)alkyl; and R.sup.4 is hydrogen. 15. The compound of claim 13, wherein R.sup.1 is --CH.sub.2 OR'"; R'" is selected from hydrogen and (C.sub.1 -C.sub.8)alkyl; and R.sup.4 is hydrogen. 16. The compound of claim 13, wherein R.sup.1 is --C(O)NR'R"; R' and R" are selected from hydrogen, (C.sub.1 -C.sub.8)alkyl and hydroxy(C.sub.1 -C.sub.8)alkyl; and R.sup.4 is hydrogen. 17. The compound of claim 1, wherein R.sup.2 and R.sup.3 form an optionally substituted dithia-cyclohexene; optionally substituted dithia-cycloheptene; or a 7,8-dihydro-6H-5,9-dithia-benzocycloheptene; and wherein the substituents are selected from (C.sub.1 -C.sub.8)alkyl, halogen, or oxo. 18. A pharmaceutical formulation comprising a compound of claim 1, admixed with a pharmaceutically acceptable excipient. 19. A compound of Formula III: ##STR46## wherein: R.sup.5 is: --C(O)OR.sup.a ; --C(O)NR.sup.a R.sup.b ; --CH.sub.2 OR.sup.d ; --C(O)R.sup.c ; cyano; optionally substituted heterocyclyl; or optionally substituted heteroaryl; R.sup.6 is hydrogen; --C(O)OR.sup.a ; --C(O)NR.sup.a R.sup.b ; --CH.sub.2 OR.sup.d ; --C(O)R.sup.c ; cyano; optionally substituted alkyl; optionally substituted heterocyclyl; optionally substituted aryl, or optionally substituted heteroaryl; or R.sup.5 and R.sup.6 with the atom to which they are attached form an optionally substituted ring; R.sup.7 is: optionally substituted alkyl; optionally substituted cycloalkyl; optionally substituted aryl; optionally substituted aralkyl; optionally substituted heterocyclyl; optionally substituted heteroaryl; optionally substituted heteroaralkyl; an optionally substituted nucleoside; an optionally substituted amino acid; or an optionally substituted di-, tri- or tetra-peptide; with the proviso that when R.sup.6 is alkyl, then R.sup.7 is optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl, or R.sup.5 and R.sup.7 with the atoms to which they are attached form an optionally substituted heterocyclic ring; R.sup.8 is: hydrogen; alkyl; alkylcarbonyl; (poly)alkoxyalkylene; or dialkoxyphosphoryloxy; Y' is: --N(R.sup.a)--; --S--; --S(O)--; or --S(O).sub.2 --; R.sup.a is: hydrogen; alkenyl; optionally substituted alkyl; optionally substituted cycloalkyl; or optionally substituted aryl; R.sup.b is: hydrogen; alkenyl; optionally substituted alkyl; or optionally substituted aryl; or R.sup.a and R.sup.b together with the atom to which they are attached form a 5- to 7-membered aromatic, saturated or unsaturated ring, optionally incorporating one or more additional heteroatom chosen from N, O, or S, and optionally substituted with one or more substituents selected from the group consisting of optionally substituted lower alkyl, halo, cyano, alkylthio, lower alkoxy, carboxy, benzyl, and oxo; R.sup.c is optionally substituted alkyl or optionally substituted aryl; and R.sup.d is hydrogen; alkenyl; optionally substituted alkyl; acyl; optionally substituted cycloalkyl; or optionally substituted aryl; including single tautomers, single stereoisomers and mixtures of tautomers and/or stereoisomers, and the pharmaceutically acceptable salts thereof. 20. The compound of claim 19, wherein Y' is selected from --S--; --S(O)--; and --S(O).sub.2 --. 21. The compound of claim 19, wherein Y' is --S--. 22. The compound of claim 19, wherein R.sup.8 is hydrogen. 23. The compound of claim 21, wherein R.sup.8 is hydrogen. 24. The compound of claim 21, wherein R.sup.5 is --C(O)OR.sup.a ; and R.sup.a is selected from hydrogen; (C.sub.1 -C.sub.8)alkyl; and (C.sub.1 -C.sub.8)alkyl-(C.sub.3 -C.sub.8)cycloalkyl. 25. The compound of claim 21, wherein R.sup.6 is hydrogen or --C(O)OR.sup.a ; and R.sup.a is selected from hydrogen and (C.sub.1 -C.sub.8)alkyl. 26. The compound of claim 24, wherein R.sup.6 is hydrogen or --C(O)OR.sup.a ; and R.sup.a is selected from hydrogen and (C.sub.1 -C.sub.8)alkyl. 27. The compound of claim 21, wherein R.sup.5 is --C(O)R.sup.c and R.sup.c is selected from hydrogen; (C.sub.1 -C.sub.8)alkyl; and aryl. 28. The compound of claim 27, wherein R.sup.6 is hydrogen. 29. The compound of claim 21, wherein R.sup.7 is selected from benzyl; 4-fluorobenzyl; 1-H-benzoimidazol-2-yl; 5-methyl-1-H-benzoimidazol2-yl; benzothiazole-2yl; 5-chloro-benzothiazole-2yl; and 4-phenyl-thiazol-2-yl. 30. The compound of claim 9, wherein R.sup.5 is --C(O)OR.sup.a ; R.sup.a is selected from hydrogen; (C.sub.1 -C.sub.8)alkyl; and (C.sub.1 -C.sub.8)alkyl-(C.sub.3 -C.sub.8)cycloalkyl; and R.sup.6 is hydrogen. 31. The compound of claim 29, wherein R.sup.5 and R.sup.6 are --C(O)OR.sup.a ; R.sup.a is selected from hydrogen and (C.sub.1 -C.sub.8)alkyl; and R.sup.5 is hydrogen. 32. The compound of claim 29, wherein R.sup.5 is --C(O)R.sup.c ; R.sup.c is selected from hydrogen; (C.sub.1 -C.sub.8)alkyl; or aryl; and R.sup.5 is hydrogen. 33. A pharmaceutical formulation comprising a compound of claim 19, admixed with a pharmaceutically acceptable excipient. 34. A method of treatment for a mammal suffering from a condition characterized by oxidative stress, comprising administering an effective amount of a compound of claim 1. 35. The method of claim 34, wherein the condition is selected from stroke; cerebral ischemia; retinal ischemia; post-surgical cognitive dysfunctions; peripheral neuropathy; spinal cord injury; head injury; and surgical trauma. 36. The method of claim 35, wherein the condition involves inflammatory or autoimmune components. 37. The method of claim 36, wherein the compound is selected from: 3-(Benzothiazol-2-ylsulfanyl)-2-(benzothiazol-2-ylsulfanylmethyl)-4-hydroxy -5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 4-Hydroxy-5-oxo-3-(5-phenyl-2H-[1,2,4]triazol-3-ylsulfanyl)-2-(5-phenyl-2H- [1,2,4]triazol-3-ylsulfanylmethyl)-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 4-(1H-Benzoimidazol-2-ylsulfanyl)-5-(1H-benzoimidazol-2-ylsulfanylmethyl)-3 -hydroxy-5-hydroxymethyl-5H-furan-2-one; 4-Hydroxy-5-oxo-3-(4-trifluoromethyl-pyrimidin-2-ylsulfanyl)-2-(4-trifluoro methyl-pyrimidin-2-ylsulfanylmethyl)-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 4-Hydroxy-5-oxo-3-(pyrimidin-2-ylsulfanyl)-2-(pyrimidin-2-ylsulfanylmethyl) -2,5-dihydro-furan-2-carboxylic acid ethyl ester; 4-Hydroxy-5-oxo-3-(2-sulfo-ethylsulfanyl)-2-(2-sulfo-ethylsulfanylmethyl)-2 ,5-dihydro-furan-2-carboxylic acid ethyl ester; 4-Hydroxy-5-oxo-3-(7-trifluoromethyl-quinolin-4-ylsulfanyl)-2-(7-trifluorom ethyl-quinolin-4-ylsulfanylmethyl)-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 3-(Benzoselenazol-2-ylsulfanyl)-2-(benzoselenazol-2-ylsulfanylmethyl)-4-hyd roxy-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 4-Hydroxy-5-oxo-3-(5-sulfonic acid-1H-benzoimidazol-2-ylsulfanyl)-2-(5-sulfonic acid-1-H-benzoimidazol-2-ylsulfanylmethyl)-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 3-(1H-Benzoimidazol-2-ylsulfanyl)-2-(1H-benzoimidazol-2-ylsulfanylmethyl)-4 -hydroxy-5-oxo-2,5-dihydro-furan-2-carboxylic acid; 4-Hydroxy-5-oxo-3-(pyrrolidine-1-carbothioylsulfanyl)-2-(pyrrolidine-1-carb othioylsulfanylmethyl)-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 3-Cyclohexylsulfanyl-2-cyclohexylsulfanylmethyl-4-hydroxy-5-oxo-2,5-dihydro -furan-2-carboxylic acid ethyl ester; 3-(2-Dimethylamino-ethylsulfanyl)-2-(2-dimethylamino-ethylsulfanylmethyl)-4 -hydroxy-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester, hydrochloride salt; 4-Hydroxy-5-oxo-3-(pyridin-4-ylsulfanyl)-2-(pyridin-4-ylsulfanylmethyl)-2,5 -dihydro-furan-2-carboxylic acid ethyl ester; 5,8-Dichloro-3-hydroxy-2-oxo-2H-1-oxa-4,9-dithia-benzo[f]azulene-10a-carbox ylic acid ethyl ester; 3-(5-Chloro-benzothiazol-2-ylsulfanyl)-2-(5-chloro-benzothiazol-2-ylsulfany lmethyl)-4-hydroxy-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester, and 3-(5-Amino-[1,3,4]thiadiazol-2-ylsulfanyl)-2-(5-amino-[1,3,4]thiadiazol-2-y lsulfanylmethyl)-4-hydroxy-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester. 38. The method of claim 34, wherein the compound is selected from 3-(Benzothiazol-2-ylsulfanyl)-2-(benzothiazol-2-ylsulfanylmethyl)-4-hydroxy -5-oxo-2,5-dihydro-furan-2-carboxylic acid (2-hydroxy-ethyl)-amide; 3-(2,4-Dichloro-benzylsulfanyl)-2-(2,4-dichloro-benzylsulfanylmethyl)-4-hyd roxy-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 3-(5-Amino-[1,3,4]thiadiazol-2-ylsulfanyl)-2-(5-amino-[1,3,4]thiadiazol-2-y lsulfanylmethyl)-4-hydroxy-5-oxo-2,5-dihydro-furan-2-carboxylic acid; 4-(2,2-Dimethyl-propionyloxy)-3-(furan-2-ylmethylsulfanyl)-2-(furan-2-ylmet hylsulfanylmethyl)-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 3-(Benzothiazol-2-ylsulfanyl)-2-(benzothiazol-2-ylsulfanylmethyl)-4-hydroxy -5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 3-(Benzooxazol-2-ylsulfanyl)-2-(benzooxazol-2-ylsulfanylmethyl)-4-hydroxy-5 -oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 3-(1H-Benzoimidazol-2-ylsulfanyl)-2-(1H-benzoimidazol-2-ylsulfanylmethyl)-4 -hydroxy-5-oxo-2,5-dihydro-furan-2-carboxylic acid; 4-Hydroxy-5-oxo-3-(pyrrolidine-1-carbothioylsulfanyl)-2-(pyrrolidine-1-carb othioylsulfanylmethyl)-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 3-Cyclohexylsulfanyl-2-cyclohexylsulfanylmethyl-4-hydroxy-5-oxo-2,5-dihydro -furan-2-carboxylic acid ethyl ester; 4-Hydroxy-5-oxo-3-(pyridin-4-ylsulfanyl)-2-(pyridin-4-ylsulfanylmethyl)-2,5 -dihydro-furan-2-carboxylic acid ethyl ester; 4-Hydroxy-5-oxo-3-(5-phenyl-[1,3,4]oxadiazol-2-ylsulfanyl)-2-(5-phenyl-[1,3 ,4]oxadiazol-2-ylsulfanylmethyl)-2,5-dihydro-furan-2-carboxylic acid ethyl ester; and 3-(1H-Benzoimidazol-2-ylsulfanyl)-2-(1H-benzoimidazol-2-ylsulfanylmethyl)-4 -hydroxy-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester. 39. A method of treatment for a mammal suffering from a condition characterized by oxidative stress, comprising administering an effective amount of a compound of claim 19. 40. The method of claim 39, where the condition is selected from stroke; cerebral ischemia; retinal ischemia; post-surgical cognitive dysfunctions; peripheral neuropathy; spinal cord injury; head injury; and surgical trauma. 41. The method of claim 39, where the condition involves inflammatory or autoimmune components. 42. A method of treatment for a mammal suffering from a condition characterized by neuroinflammation or neurodegenerative diseases, comprising administering an effective amount of a compound of claim 1. 43. The method of claim 42, wherein the condition is selected from Alzheimer's disease and senile dementia. 44. The method of claim 42, wherein the compound is selected from: 3-(2-Chloro-6-fluoro-benzylsulfanyl)-2-(2-chloro-6-fluoro-benzylsulfanylmet hyl)-4-hydroxy-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 4-Hydroxy-3-(5-methoxy-benzothiazol-2-ylsulfanyl)-2-(5-methoxy-benzothiazol -2-ylsulfanylmethyl)-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 2-(Benzothiazole-2-sulfinylmethyl)-3-(benzothiazol-2-ylsulfanyl)-4-hydroxy- 5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 4-Hydroxy-3-(6-nitro-benzothiazol-2-ylsulfanyl)-2-(6-nitro-benzothiazol-2-y lsulfanylmethyl)-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 4-Hydroxy-3-[4-(2-methoxycarbonyl-vinyl)-phenylsulfanyl]-2-[4-(2-methoxycar bonyl-vinyl)-phenylsulfanylmethyl]-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 4-(2,2-Dimethyl-propionyloxy)-3-(furan-2-ylmethylsulfanyl)-2-(furan-2-ylmet hylsulfanylmethyl)-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 4-Hydroxy-3-(4-methoxy-benzylsulfanyl)-2-(4-methoxy-benzylsulfanylmethyl)-5 -oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 2-(1H-Benzoimidazol-2-ylsulfanylmethyl)-4-ethoxy-3-(1-ethyl-1H-benzoimidazo l-2-ylsulfanyl)-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 3-(Benzothiazol-2-ylsulfanyl)-2-(benzothiazol-2-ylsulfanylmethyl)-4-hydroxy -5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 4-Hydroxy-5-oxo-3-(4-trifluoromethyl-pyrimidin-2-ylsulfanyl)-2-(4-trifluoro methyl-pyrimidin-2-ylsulfanylmethyl)-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 4-Hydroxy-3-(4-methyl-pyrimidin-2-ylsulfanyl)-2-(4-methyl-pyrimidin-2-ylsul fanylmethyl)-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 4-Hydroxy-5-oxo-3-(pyrimidin-2-ylsulfanyl)-2-(pyrimidin-2-ylsulfanylmethyl) -2,5-dihydro-furan-2-carboxylic acid ethyl ester; and 3-(Benzoselenazol-2-ylsulfanyl)-2-(benzoselenazol-2-ylsulfanylmethyl)-4-hyd roxy-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester. 45. A method of treatment for a mammal suffering from a condition characterized by oxidative stress, comprising administering an effective amount of a compound of claim 19. 46. A method of treatment for a mammal suffering from a condition characterized by neuroinflammation or neurodegenerative diseases, comprising administering an effective amount of a compound of claim 19. 47. The method of claim 46, where the condition is selected from Alzheimer's disease and senile dementia. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
FIELD OF THE INVENTION The present invention relates to furanone derivatives, particularly to derivatives having cytoprotective activity, especially certain 3-hydroxy-furan-2-one derivatives. The invention is also directed to formulations and methods for treating stroke, myocardial infarction and chronic heart failure, as well as other oxidative stress-related conditions that are typically responsive to cellular enzyme modulation. The invention is also directed to formulations and methods for treating neuroinflammation, cognitive disorders and neurodegenerative diseases such as Alzheimer's disease and senile dementia. BACKGROUND INFORMATION The present invention deals with certain novel furanone derivatives, which are formed under proper conditions from a series of pyruvate derivatives described in our prior applications, U.S. Ser. No. 10/138,937 and 10/138,032. Furanones are compounds having the following general structure. ##STR1## Furanone-derived compositions have been known in the art to have various utilities. For example, U.S. Pat. No. 6,296,889 describes the use of certain furanone compounds in conjunction with 1-nonen-3-one to provide dairy and coffee aroma flavor enhancement. Specific furanones (for example, 3,-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone, 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone and 5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-3-(3-fluorophenyl)-5H-furan-2-on e) have been shown to be cyclooxygenase-2 (COX-2) inhibitors useful in treating certain inflammatory conditions (U.S. Pat. No. 5,474,995, U.S. Pat. No. 6,239,173). The diversity of furanone derivative utilities is further illustrated by the discovery of certain halogenated furanones isolated from the Australian red seaweed Delisea nulcha as marine anti-fouling agents (U.S. Pat. No. 6,060,046) capable of preventing growth of various seaweeds, invertebrates and bacteria on marine structures. The furanone derivative 4-hydroxy-3-methanesulfonyl-2-methanesulfonylmethyl-5-oxo-2,5-dihydro-fura n-2-carboxylic acid ethyl ester (CAS Registry No. 299923-61-8) is available for screening from the compound library of InterBioScreen Ltd. (Moscow, Russia--www.ibscreen.com), among other sources. The synthesis of the compound 4-hydroxy-3-isobutyl-2-(3-methyl-butyryl)-5-oxo-2,5-dihydro-furan-2-carbox ylic acid methyl ester has been described in Trogolo, C. et al Annali di Chimica 62(10), 674-92, (1972) and the synthesis of 4-hydroxy-5-oxo-2,3-dipentyl-2,5-dihydro-furan-2-carboxylic ethyl ester has been described in Hoffman, R. V. et al. Journal of Organic Chemistry, 62(8)2458-2465, (1997). The synthesis of certain furanones derivatives from hydroxy alkanoates is described in Stach, H., Helvetica Chimica Acta (1987), 70(2), 369-74. Cerebral ischemia or "stroke" refers to the severe diminution or cessation of blood flow to all or part of the brain. Cerebral ischemia can occur as a result of a number of causes or insults, including, but not limited to cerebrovascular occlusion, thromboembolytic insult, cardiac failure and hemorrhagic accident. It is now known that pharmacologic intervention, if provided within a reasonable interval of the initial insult, can significantly reduce cerebral tissue death following cerebral ischemia. Alzheimer's Disease ("AD") is a progressive disease of the human central nervous system. It is manifested by dementia in the elderly, by disorientation, loss of memory, difficulty with language, calculation, or visual-spatial skills, and by psychiatric manifestations. It is associated with degenerating neurons in several regions of the brain. Alzheimer's Disease is reviewed by Price, D. L. et al. (Clin. Neuropharm. 14:S9-S14 (1991)); Pollwein, P. et al. (Nucl. Acids Res. 20:63-68 (1992)); Regland, B. et (Med. Hypoth. 38:11-19 (1992)) and Johnson, S. A. (In: Review of Biological Research in Aging, Vol. 4., Rothstein, M. (Ed.), Wiley-Liss, NY, 163-170 (1990)). The present invention addresses the desire to provide new therapies for conditions characterized by oxidative stress and/or inflammation, and particularly, for providing neuroprotection in the event of cerebral ischemia; especially desired are agents that are effective even if first administered after a significant period of time (e.g., about 5 or more hours) following an ischemic insult. The present invention also addresses the desire to provide new therapies for conditions characterized by neuroinflammation, cognitive disorders, and/or neurodegenerative conditions such as Alzheimer's and senile dementia. SUMMARY OF THE INVENTION The present invention is concerned with novel furanone derivatives that are particularly active in restoring or preserving metabolic integrity in oxidatively competent cells that have been subjected to oxygen deprivation. Such furanone derivatives are useful in the manufacture of pharmaceutical compositions for treating a number of conditions characterized by oxidative stress, and particularly, in providing neuroprotection in the event of cerebral ischemia, even when administered a significant time interval after an ischemic insult. In particular, the compositions of the present invention are useful in the treatment of stroke, as demonstrated by providing neuroprotection in a standard experimental model of focal cerebral ischemia. They are also useful in the treatment of neuroinflammation, cognitive disorders and neurodegenerative diseases such as neuropathy in cerebrovascular diseases, brain trauma, cerebral palsy, epilepsy, amyotrophic lateral sclerosis (ALS), Huntington's disease, mental diseases (e.g. psychosis, schizophrenia, depression), Parkinson's disease, Friedreich's disease, Down's syndrome, Creutzfelt-Jakob syndrome, Alzheimer's disease, and senile dementia. They are also useful in the treatment of myocardial ischemia (myocardial infarction), as well as other indications characterized by oxidative stress and/or inflammation, including, but not limited to, diabetes, renal disease, pre-menstrual syndrome, asthma, cardiopulmonary inflammatory disorders, chronic heart failure, rheumatoid arthritis, muscle fatigue, intermittent claudication and for the preservation of allograft tissue for transplantation. The present invention concerns the compounds represented by the formula: ##STR2## wherein: R.sup.1 is: --C(O)OR'; --C(O)NR'R"; --CH.sub.2 OR'"; cyano; optionally substituted heterocyclyl; optionally substituted heterocyclyl-alkyl; optionally substituted heteroaryl, or optionally substituted heteroaralkyl; R.sup.2 is: optionally substituted alkyl; optionally substituted cycloalkyl; optionally substituted aryl; optionally substituted aralkyl; optionally substituted heterocyclyl, optionally substituted heteroaryl; optionally substituted heteroaralkyl; an optionally substituted nucleoside; an optionally substituted amino acid; or an optionally substituted di-, tri- or tetra-peptide; R.sup.3 is: optionally substituted alkyl; optionally substituted cycloalkyl; optionally substituted aryl; optionally substituted aralkyl; optionally substituted heterocyclyl, optionally substituted heteroaryl; optionally substituted heteroaralkyl; an optionally substituted nucleoside; an optionally substituted amino acid; or an optionally substituted di-, tri- or tetra-peptide; R.sup.4 is: hydrogen; alkyl, alkylcarbonyl; (poly)alkoxyalkylene; or dialkoxyphosphoryloxy (or other moieties readily hydrolyzable to give an OH moiety); X is: lower alkylene; --N(R')--; --S--; --S(O)--; --S(O).sub.2 --, or X taken together with R.sup.2 is --P(O)(OR').sub.2 ; Y is: --N(R')--; --S--; --S(O)--; --S(O).sub.2 --, or Y taken together with R.sup.3 is --P(O)(OR').sub.2 ; or X--R.sup.2 taken together with Y--R.sup.3 form an optionally substituted aliphatic or aromatic ring, R' is: hydrogen; alkenyl; optionally substituted alkyl; optionally substituted cycloalkyl; phosphoryl; or optionally substituted aryl; R" is: hydrogen, alkenyl, optionally substituted alkyl, or optionally substituted aryl; or R' and R" together with the atom to which they are attached form a 5- to 7-membered aromatic, saturated or unsaturated ring, optionally incorporating one or more additional heteroatom chosen from N, O, or S, and optionally substituted with one or more substituents selected from the group consisting of optionally substituted lower alkyl, halo, cyano, alkylthio, lower alkoxy, carboxy, benzyl, and oxo; and R'" is: hydrogen; alkenyl; optionally substituted alkyl; optionally substituted cycloalkyl; acyl; phosphoryl; or optionally substituted aryl; including single tautomers, single stereoisomers and mixtures of tautomers and/or stereoisomers, and the pharmaceutically acceptable salts thereof. In one embodiment R.sup.4 is hydrogen, (C.sub.1 to C.sub.8)alkyl, or (C.sub.1 to C.sub.8)alkylcarbonyl. In another embodiment where R.sup.2 and/or R.sup.3 is a natural or substituted amino acid or peptide, R.sup.2 and/or R.sup.3 is selected from the group: Ala, Asn, Asp, Cys, Gin, Glu, Gly, Lys, Met, Ser and Thr, especially Ala, Asp, Cys, Glu and Gly. Further preferred are those compounds where R.sup.2 and/or R.sup.3 is a natural or substituted di- or tri-peptide, especially natural peptides. In yet another embodiment, R.sup.2 and/or R.sup.3 is/are an optionally substituted heteroaryl or heteroaralkyl group, especially a nitrogen-containing optionally substituted heteroaryl, and particularly selected from the group: imidazole, pyrazole, triazole, thiadiazole, oxadiazole, benzoimidazole, benzooxazole, benzoselenazol, and benzothiazole, or an optionally substituted heteroaralkyl group, particularly an optionally substituted furanyl-loweralkyl group. In yet another embodiment, R.sup.2 and/or R.sup.3 is/are an optionally substituted alkyl or optionally substituted cycloalkyl. In another embodiment embodiment, R.sup.2 and/or R.sup.3 is/are an optionally substituted aryl or optionally substituted aralkyl, preferably optionally substituted phenyl or benzyl. Further preferred in each of the foregoing embodiments, R.sup.1 is --C(O)OR', --CH.sub.2 OR'" or --C(O)NR'R"; and R', R", and R'" are hydrogen or lower alkyl (C.sub.1 to C.sub.8), and especially R.sup.1 is --C(O)OR', and R is hydrogen or (C.sub.1 to C.sub.8)alkyl. Presently preferred for the pharmaceutically acceptable salts of the invention are the TEA, TFA, HCl, HBr, MsOH, TsOH, AcOH, and Na salts of the furanone compounds of the present invention. Further preferred in each of the foregoing embodiments are those compounds where X and Y are the same particularly --S--, --S(O)-- or --S(O).sub.2 --, preferably --S--; and especially those where --X--R.sup.2 and --Y--R.sup.3 are the same. Another embodiment of the invention concerns compounds according to Formula I where X--R.sup.2 and/or Y--R.sup.3 is/are represented by the formula: ##STR3## where: R.sup.2.1 is: hydrogen, optionally substituted alkyl, optionally substituted aryl, --C(O)--O--R.sup.2 ', --S--, or --CH.sub.2 --S--; R.sup.2.2 is: hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, or optionally substituted acyl (particularly including aliphatic, aromatic and cyclic acyl substituents); R.sup.2.3 is: hydrogen, optionally substituted lower alkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or --CH.sub.2 --S-- (selected independently, in each occurrence of R.sup.2.3); R.sup.2.4 is: hydrogen, optionally substituted lower alkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, or --CH.sub.2 --S--; R.sup.2.5 is: hydrogen, optionally substituted alkyl or optionally substituted aryl; R.sup.2 ' is: hydrogen, optionally substituted alkyl, or optionally substituted aryl (selected independently, in each occurrence of R.sup.2 '); k is: 0, 1 or 2; m is: 0, 1 or 2; and n is: 0, 1, 2 or 3, at least one of R.sup.2.1, R.sup.2.3 and R.sup.2.4 being --CH.sub.2 --S--. Of the compounds where X--R.sup.2 and/or Y--R.sup.3 are represented by Formula II, preferred are those compounds the substituents of which are selected from the following groups: R.sup.2.1 is --C(O)--O--R.sup.2 ' where R.sup.2 ' is hydrogen or lower alkyl, especially ethyl; R.sup.2.2 is hydrogen; R.sup.2.3 is --CH.sub.2 --S--; R.sup.2.4 is hydrogen, optionally substituted lower alkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl; R.sup.2.5 is hydrogen or lower alkyl, especially hydrogen; and/or k, m and n are respectively: 0,2,1; 1,0,1; or 2,0,1. Another aspect of this invention concerns the compounds represented by the formula: ##STR4## wherein: R.sup.5 is: --C(O)OR.sup.a ; --C(O)NR.sup.a R.sup.b ; --CH.sub.2 OR.sup.d ; --C(O)R.sup.c ; cyano; optionally substituted heterocyclyl, or optionally substituted heteroaryl; R.sup.6 is hydrogen; --C(O)OR.sup.a ; --C(O)NR.sup.a R.sup.b ; --CH.sub.2 OR.sup.d ; --C(O)R.sup.c ; cyano; optionally substituted alkyl; optionally substituted heterocyclyl; optionally substituted aryl; or optionally substituted heteroaryl; or R.sup.5 and R.sup.6 with the atom to which they are attached form an optionally substituted ring; R.sup.7 is: optionally substituted alkyl; optionally substituted cycloalkyl; optionally substituted aryl; optionally substituted aralkyl; optionally substituted heterocyclyl, optionally substituted heteroaryl; optionally substituted heteroaralkyl; an optionally substituted nucleoside; an optionally substituted amino acid; or an optionally substituted di-, tri- or tetra-peptide; with the proviso that when R.sup.6 is alkyl, then R.sup.7 is optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl. or R.sup.5 and R.sup.7 with the atoms to which they are attached form an optionally substituted heterocyclic ring; R.sup.8 is: hydrogen; alkyl, alkylcarbonyl; (poly)alkoxyalkylene; or dialkoxyphosphoryloxy; Y' is: --N(R.sup.a)--; --S--; --S(O)--; or --S(O).sub.2 --; R.sup.a is: hydrogen; alkenyl; optionally substituted alkyl; optionally substituted cycloalkyl; or optionally substituted aryl; R.sup.b is: hydrogen; alkenyl; optionally substituted alkyl; alkyl ether; or optionally substituted aryl; or R.sup.a and R.sup.b together with the atom to which they are attached form a 5- to 7-membered aromatic, saturated or unsaturated ring, optionally incorporating one more additional heteroatom chosen from N, O, or S, and optionally substituted with one or more substituents selected from the group consisting of optionally substituted lower alkyl, halo, cyano, alkylthio, lower alkoxy, carboxy, benzyl, and oxo; R.sup.c is optionally substituted alkyl or optionally substituted aryl; and R.sup.d is hydrogen; alkenyl; optionally substituted alkyl; acyl, optionally substituted cycloalkyl; or optionally substituted aryl; including single tautomers, single stereoisomers and mixtures of tautomers and/or stereoisomers, and the pharmaceutically acceptable salts thereof. In another embodiment, R.sup.7 is an optionally substituted heteroaryl group, especially a nitrogen-containing optionally substituted heteroaryl, and particularly selected from the group: imidazole; pyrazole; triazole; thiadiazole; oxadiazole; benzoimidazole; benzooxazole; benzoselenazole and benzothiazole. In another embodiment R.sup.5 is --C(O)OR.sup.a or --C(O)R.sup.c ; R.sup.a is hydrogen, (C.sub.1 -C.sub.8)alkyl, or (C.sub.3 -C.sub.8)cycloalkyl; and R.sup.c is lower alkyl or aryl. In another embodiment R.sup.5 is heteroaryl and R.sup.6 is hydrogen. In another preferred embodiment R.sup.6 is hydrogen or --C(O)OR.sup.a ; and R.sup.a is hydrogen or lower alkyl (C.sub.1 to C.sub.8). In another preferred embodiment R.sup.5 and R.sup.6 form a ring, particularly a pyrimidine-2,4,6-trione ring or a cyclohexanone ring. In another preferred embodiment R.sup.5 and R.sup.7 form a ring, particularly when R.sup.7 is benzoimidazole, the ring is 3-methyl-thiomorpholin-3-ol and the compound formed is 1,4-dihydro-4-methyl-3a,4-dihydro-3-oxa-10-thia-4a,9-diaza-cyclopenta[b]fl uoren-2-one. In another preferred embodiment R.sup.8 is hydrogen. Further preferred in each of the foregoing embodiments are those compounds where R.sup.5 is --C(O)OR.sup.a or --C(O)R.sup.c, R.sup.6 is hydrogen, and Y' is --S--. In another aspect the invention relates to compounds of Formula I or Formula III forming a complex with a metal, especially when said metal is selected from divalent copper, manganese, or zinc, particularly wherein said metals are selected from Cu.sup.2+ Cl.sub.2, Mn.sup.2+ Cl.sub.2, and Zn.sup.2+ Cl.sub.2. In another aspect, the invention relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of Formula I or Formula III, or a pharmaceutically acceptable salt thereof admixed with at least one pharmaceutically acceptable excipient. Particularly preferred are those pharmaceutical compositions wherein the compound of Formula I or Formula III is selected from the preferred compounds. In still another aspect, the invention relates to a method of treating stroke and/or other oxidative stress-related conditions that are responsive to cellular enzyme modulation such as cerebral ischemia, myocardial infarction and chronic heart failure (especially stroke/cerebral ischemia) in a mammal by administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I or Formula III or a pharmaceutically acceptable salt thereof. Particularly preferred are those methods of treatment and uses in the manufacture of pharmaceutical compositions therefor, wherein the compound of Formula I or Formula III is selected from the preferred compounds, and especially from the compounds selected from: 3-(Benzothiazol-2-ylsulfanyl)-2-(benzothiazol-2-ylsulfanylmethyl)-4-hydroxy -5-oxo-2,5-dihydro-furan-2-carboxylic acid (2-hydroxy-ethyl)-amide; 3-(2,4-Dichloro-benzylsulfanyl)-2-(2,4-dichloro-benzylsulfanylmethyl)-4-hyd roxy-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 3-(5-Amino-[1,3,4]thiadiazol-2-ylsulfanyl)-2-(5-amino-[1,3,4]thiadiazol-2-y lsulfanylmethyl-4-hydroxy-5-oxo-2,5-dihydro-furan-2-carboxylic acid; 4-(2,2-Dimethyl-propionyloxy)-3-(furan-2-ylmethylsulfanyl)-2-(furan-2-ylmet hylsulfanylmethyl)-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 3-(Benzothiazol-2-ylsulfanyl)-2-(benzothiazol-2-ylsulfanylmethyl)-4-hydroxy -5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 3-(Benzooxazol-2-ylsulfanyl)-2-(benzooxazol-2-ylsulfanylmethyl)-4-hydroxy-5 -oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 3-(1H-Benzoimidazol-2-ylsulfanyl)-2-(1H-benzoimidazol-2-ylsulfanylmethyl)-4 -hydroxy-5-oxo-2,5-dihydro-furan-2-carboxylic acid; 4-Hydroxy-5-oxo-3-(pyrrolidine-1-carbothioylsulfanyl)-2-(pyrrolidine-1-carb othioylsulfanylmethyl)-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 3-Cyclohexylsulfanyl-2-cyclohexylsulfanylmethyl-4-hydroxy-5-oxo-2,5-dihydro -furan-2-carboxylic acid ethyl ester; 4-Hydroxy-5-oxo-3-(pyridin-4-ylsulfanyl)-2-(pyridin-4-ylsulfanylmethyl)-2,5 -dihydro-furan-2-carboxylic acid ethyl ester; 4-Hydroxy-5-oxo-3-(5-phenyl-[1,3,4]oxadiazol-2-ylsulfanyl)-2-(5-phenyl-[1,3 ,4]oxadiazol-2-ylsulfanylmethyl)-2,5-dihydro-furan-2-carboxylic acid ethyl ester; and 3-(1H-Benzoimidazol-2-ylsulfanyl)-2-(1H-benzoimidazol-2-ylsulfanylmethyl)-4 -hydroxy-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester. In a preferred embodiment the invention relates to methods of treating a condition selected from stroke, cerebral ischemia, retinal ischemia, post-surgical cognitive dysfunctions, peripheral neuropathy/neuropathic pain, spinal cord injury, head injury and surgical trauma. In another preferred embodiment the invention relates to methods of treating a condition involving inflammatory or automimmune components, especially diseases including but not limited to diabetes, renal disease, premenstrual syndrome, asthma, rheumatoid arthritis, osteoarthritis, muscle fatigue, irritable bowel syndrome, inflammatory bowel disease, and intermittent claudication. Particularly preferred are those methods of treatment and uses in the manufacture of pharmaceutica compositions therfor, wherein the compound is selected from the preferred compounds, and especially from the compounds selected from; 3-(Benzothiazol-2-ylsulfanyl)-2-(benzothiazol-2-ylsulfanylmethyl)-4-hydroxy -5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 4-Hydroxy-5-oxo-3-(5-phenyl-2H-[1,2,4]triazol-3-ylsulfanyl)-2-(5-phenyl-2H- [1,2,4]triazol-3-ylsulfanylmethyl)-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 4-(1H-Benzoimidazol-2-ylsulfanyl)-5-(1H-benzoimidazol-2-ylsulfanylmethyl)-3 -hydroxy-5-hydroxymethyl-5H-furan-2-one; 4-Hydroxy-5-oxo-3-(4-trifluoromethyl-pyrimidin-2-ylsulfanyl)-2-(4-trifluoro methyl-pyrimidin-2-ylsulfanylmethyl)-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 4-Hydroxy-5-oxo-3-(pyrimidin-2-ylsulfanyl)-2-(pyrimidin-2-ylsulfanylmethyl) -2,5-dihydro-furan-2-carboxylic acid ethyl ester; 4-Hydroxy-5-oxo-3-(2-sulfo-ethylsulfanyl)-2-(2-sulfo-ethylsulfanylmethyl)-2 ,5-dihydro-furan-2-carboxylic acid ethyl ester; 4-Hydroxy-5-oxo-3-(7-trifluoromethyl-quinolin-4-ylsulfanyl)-2-(7-trifluorom ethyl-quinolin-4-ylsulfanylmethyl)-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 3-(Benzoselenazol-2-ylsulfanyl)-2-(benzoselenazol-2-ylsulfanylmethyl)-4-hyd roxy-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 4-Hydroxy-5-oxo-3-(5-sulfonic acid-1H-benzoimidazol-2-ylsulfanyl)-2-(5-sulfonic acid-1H-benzoimidazol-2-ylsulfanylmethyl)-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 3-(1H-Benzoimidazol-2-ylsulfanyl)-2-(1H-benzoimidazol-2-ylsulfanylmethyl)-4 -hydroxy-5-oxo-2,5-dihydro-furan-2-carboxylic acid; 4-Hydroxy-5-oxo-3-(pyrrolidine-1-carbothioylsulfanyl)-2-(pyrrolidine-1-carb othioylsulfanylmethyl)-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 3-Cyclohexylsufanyl-2-cyclohexylsulfanylmethyl-4-hydroxy-5-oxo-2,5-dihydro- furan-2-carboxylic acid ethyl ester; 3-(2-Dimethylamino-ethylsulfanyl)-2-(2-dimethylamino-ethylsulfanylmethyl)-4 -hydroxy-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester, hydrochloride salt; 4-Hydroxy-5-oxo-3-(pyridin-4-ylsulfanyl)-2-(pyridin-4-ylsulfanylmethyl)-2,5 -dihydro-furan-2-carboxylic acid ethyl ester; 5,8-Dichloro-3-hydroxy-2-oxo-2H-1-oxa-4,9-dithia-benzo[f]azulene-10a-carbox ylic acid ethyl ester; 3-(5-Chloro-benzothiazol-2-ylsulfanyl)-2-(5-chloro-benzothiazol-2-ylsulfany lmethyl)-4-hydroxy-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; and 3-(5-Amino-[1,3,4]thiadiazol-2-ylsulfanyl)-2-(5-amino-[1,3,4]thiadiazol-2-y lsulfanylmethyl)-4-hydroxy-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; Another group of diseases characterized by oxidative stress fall within the group dermatologic conditions, including, but not limited to prevention and protecting skin tissue against age-related damage or damage resulting from insults such as harmful ultraviolet (UV) radiation, stress and fatigue, and in the treatment of contact dermatitis, skin irritation, skin pigmentation, psoriasis, or acne. In still another aspect, the invention relates to a method of treating neuroinflammation, cognitive disorders, and/or neurodegenerative disorders in a mammal by administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I or Formula III, or a pharmaceutically acceptable salt thereof. Particularly preferred are those methods of treatment and uses in the manufacture of pharmaceutical compositions therefor, wherein the compound of Formula I or Formula III is selected from the preferred compounds, and especially from the compounds selected from: 3-(2-Chloro-6-fluoro-benzylsulfanyl)-2-(2-chloro-6-fluoro-benzylsulfanylmet hyl)-4-hydroxy-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 4-Hydroxy-3-(5-methoxy-benzothiazol-2-ylsulfanyl)-2-(5-methoxy-benzothiazo- 2-ylsulfanylmethyl)-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 2-(Benzothiazole-2-sulfinylmethyl)-3-(benzothiazol-2-ylsulfanyl)-4-hydroxy- 5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 4-Hydroxy-3-(6-nitro-benzothiazol-2-ylsulfanyl)-2-(6-nitro-benzothiazol-2-y lsulfanylmethyl)-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 4-Hydroxy-3-[4-(2-methoxycarbonyl-vinyl)-phenylsulfanyl]-2-[4-(2-methoxycar bonyl-vinyl)-phenylsulfanylmethyl]-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 4-(2,2-Dimethyl-propionyloxy)-3-(furan-2-ylmethylsulfanyl)-2-(furan-2-ylmet hylsulfanylmethyl)-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 4-Hydroxy-3-(4-methoxy-benzylsulfanyl)-2-(4-methoxy-benzylsulfanylmethyl)-5 -oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 2-(1H-Benzoimidazol-2-ylsulfanylmethyl)-4-ethoxy-3-(1-ethyl-1H-benzoimidazo l-2-ylsulfanyl)-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 3-(Benzothiazol-2-ysulfanyl)-2-(benzothiazol-2-ylsulfanylmethyl)-4-hydroxy- 5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 4-Hydroxy-5-oxo-3-(4-trifluoromethyl-pyrimidin-2-ylsulfanyl)-2-(4-trifluoro methyl-pyrimidin-2-ylsulfanylmethyl)-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 4-Hydroxy-3-(4-methyl-pyrimidin-2-ysulfanyl)-2-(4-methyl-pyrimidin-2-ylsulf anylmethyl)-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester; 4-Hydroxy-5-oxo-3-(pyrimidin-2-ylsulfanyl)-2-(pyrimidin-2-ylsulfanylmethyl) -2,5-dihydro-furan-2-carboxylic acid ethyl ester; and 3-(Benzoselenazol-2-ylsulfanyl)-2-(benzoselenazol-2-ylsulfanylmethyl)-4-hyd roxy-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester. Certain embodiments of the invention provide novel and preferred combinations of substituent groups pendant from the formulae of the different inventions. Excluded from the compositions of matter (but, e.g., not from the methods of use and pharmaceutical formulations) of the present invention is the compound 4-hydroxy-3-methanesulfonyl-2-methanesulfonylmethyl-5-oxo-2,5-dihydro-fura n-2-carboxylic acid ethyl ester. |
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