Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-01-28
2003-12-23
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S383000, C514S473000, C514S256000, C548S156000, C548S262400, C549S313000, C544S296000
Reexamination Certificate
active
06667330
ABSTRACT:
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.
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-one) 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-furan-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-carboxylic 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:
wherein:
R
1
is: —C(O)OR′; —C(O)NR′R″; —CH
2
OR′″; cyano; optionally substituted heterocyclyl; optionally substituted heterocyclyl-alkyl; optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
R
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
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
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)
2
—, or X taken together with R
2
is —P(O)(OR′)
2
;
Y is: —N(R′)—; —S—; —S(O)—; —S(O)
2
—, or Y taken together with R
3
is —P(O)(OR′)
2
;
or X—R
2
taken together with Y—R
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-
Brown Lesley
del Balzo Ughetta
Song Jiangao
Walkinshaw Gail
Wang Bing
Galileo Pharmaceuticals, Inc.
Lambkin Deborah C.
Lowin David A.
Pfister Gloria
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