Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-09-27
2001-07-24
Dentz, Bernard (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S336000, C514S444000, C546S284400, C549S060000, C549S315000
Reexamination Certificate
active
06265436
ABSTRACT:
FIELD OF THE INVENTION
The invention relates generally to substituted 5-biphenyl-3,4-dihydroxy-2(5H)-furanones, methods of preparation therefor, and method of use thereof.
BACKGROUND OF THE INVENTION
The aci-reductone 4-(4-chlorophenyl)-2-hydroxytetronic acid compound (CHTA) possesses antilipidemic and antiaggregatory properties which differ from those of the classical phenoxyactetic acids as has been disclosed in Witiak et at.
J. Med. Chem.,
1988, 31:1434-1445 and Kamanna et al.,
Lipids,
1989, 24:25-32. Although unsubstituted 2-alkyl- and 2-acyltetronic acids are frequently found in nature, the 2-hydroxy-substituted tetronic acid redox system is found only in vitamin C and its closely related relatives (isoascorbic acid, erythroascorbic acid) and derivatives, and the macrolide antibiotic, chlorothricin.
The antiaggregatory activities of 2-hydroxytetronic acid aci-reductone compound (CHTA) are of interest since blood platelets are involved in the genesis of atherosclerosis. 2-Hydroxytetronic acid aci-reductones inhibit collagen-induced human platelet aggregation and secretion of [
14
C]-serotonin in a concentration-dependent manner at equivalent doses, as reported in Witiak et al.,
J. Med. Chem.,
1982, 25:90-93. The CHTA compound inhibits platelet function by a similar mechanism, involving arachidonic acid release. Redox analogues, such as 2-hydroxytetronic acid, function as antioxidants in membranes or interfere with free radical processes involved in the biosynthetic elaboration of cyclic prostaglandin endoperoxides (PGG
2
and PGH
2
), and, subsequently, thromboxane A
2
from arachidonic acid.
The development of dual antioxidant-arachidonic acid (AA) metabolism inhibitors may provide added benefits over existing drugs for the treatment of diseases associated with oxidative stress and inflammation. Numerous conditions including asthma, rheumatoid arthritis, irritable bowel disease (IBD), adult respiratory distress syndrome (ARDS), atherosclerosis, ischemia/reperfusion injury, restenosis, neurodegenerative disorders and initiation and promotion of carcinogenesis correlate with abnormally high levels of reactive oxygen species (ROS). Antioxidant-based therapies including both natural antioxidants (e.g., vitamin E, vitamin C and SOD), and synthetic antioxidants (e.g., 4-aryl-2-hydroxytetronic acids, 2-O-alkyl ascorbic acids, probucol and tirilazad mesylate) have been, or are currently being, investigated for the treatment of a number of these conditions.
Previously, the S-arachidonic acid aci-reductone analog (S)-3,4-dihydroxy-5 [(all
Z
)-3,6,9,12-octadecatraenyl]-2(5H)-furanone, was identified as a stereoselective and potent arachidonic acid metabolic inhibitor. This compound inhibits both PGE
2
and LTB
4
production in stimulated macrophages (IC
50
=20 &mgr;M) and blocks AA-induced platelet aggregation (AAIPA) with an IC
50
<10 &mgr;M. Dual cyclooxygenase (COX) and lipoxygenase (LO) activity could be important in preventing substrate shunting in the arachidonic acid cascade. Although this compound demonstrates an encouraging biological profile, both its instability and labored synthesis render this compound less than satisfactory as a therapeutic agent.
U.S. application Ser. No. 08/915,099, and PCT/US97/14878, incorporated herein by reference, describe 5-substituted and 5,5-disubstituted-3,4-dihydroxy-2(5H)-furanones, including 5-unsubstituted biphenyl derivatives which have antilipidemic, antiaggregatory, and anti-inflammatory activities useful for the treatment of various conditions and diseases in humans and animals.
There exists a need for new therapeutic agents which exhibit the aforementioned activities. It is to this aim that the present invention is directed.
The citation of any reference herein should not be construed as an admission that such reference is available as “Prior Art” to the instant application.
SUMMARY OF THE INVENTION
The present invention broadly relates to racemic or optically active compounds of the formula I:
wherein R is hydrogen, a lower alkyl group optionally substituted by one or more halo groups, a cycloalkyl group, or an aryl group optionally substituted by one or more halo, alkyl of one to eight carbon atoms, alkoxy of one to eight carbon atoms, cycloalkyl, nitro or trifluoromethyl groups; X
1
is optionally one or more halo, alkyl of one to eight carbon atoms, alkoxy of one to eight carbon atoms, cycloalkyl, nitro or trifluoromethyl groups; and Ar is an aromatic or heteroaromatic ring substituted by X
2
, X
2
being one or more halo, alkyl of one to eight carbon atoms, alkoxy of one to eight carbon atoms, cycloalkyl, nitro or trifluoromethyl groups; or a pharmaceutically acceptable salt thereof.
The substituted aromatic group Ar may be, for example, phenyl or naphthyl, substituted by one or more halo, alkyl of one to eight carbon atoms, alkoxy of one to eight carbon atoms, cycloalkyl, nitro or trifluoromethyl groups. The substituted heteroaromatic group may contain 4-10 ring members and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, for example, a thienyl, furyl, or pyridyl ring. The compounds herein may be racemic or optically active, such as the (S) or (R) enantiomers.
In a further broad aspect of the invention, methods of treating a pathology in which reactive oxygen species and inflammatory mediators are contributing deleterious factors are provided which comprises administration to a patient in need of such therapy an effective amount of a racemic or optically active compound of the formula I:
wherein R is hydrogen, a lower alkyl group optionally substituted by one or more halo groups, a cycloalkyl group, or an aryl group optionally substituted by one or more halo, alkyl of one to eight carbon atoms, alkoxy of one to eight carbon atoms, cycloalkyl, nitro or trifluoromethyl groups; X
1
is optionally one or more halo, alkyl of one to eight carbon atoms, alkoxy of one to eight carbon atoms, cycloalkyl, nitro or trifluoromethyl groups; and Ar is an aromatic or heteroaromatic ring substituted by X
2
, X
2
being one or more halo, alkyl of one to eight carbon atoms, alkoxy of one to eight carbon atoms, cycloalkyl, nitro or trifluoromethyl groups; or a pharmaceutically acceptable salt thereof.
The invention further encompasses pharmaceutical compositions comprising the above-mentioned compounds and a pharmaceutically acceptable carrier. Pathologies treatable using the compounds described herein include acute or chronic inflammatory disorders, such as by way of non-limiting example, asthma, rheumatoid arthritis, inflammatory bowel disease, or acute respiratory distress syndrome. The pathology may be a neurodegenerative disorders, such as but not limited to Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, traumatic brain injury or multiple sclerosis. In a further embodiment, the pathology comprises cardiovascular disease, such as atherosclerosis. In yet a further embodiment, the pathology comprises a viral disease, such as but not limited to AIDS. In still yet a further embodiment, the pathology comprises a skin disease, such as psoriasis, sunburn and premature aging. In yet another embodiment, the pathology comprises an eye disease, such as but not limited to glaucoma, cataract, senile macular degeneration, inflammatory eye conditions, trauma, post-traumatic eye disorders, diabetic retinopathy, and eye infections.
These and other aspects of the present invention will be better appreciated by reference to the following Detailed Description.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to compounds of the general formula I
wherein R is hydrogen, a lower alkyl group optionally substituted by one or more halo groups, a cycloalkyl group, or an aryl group optionally substituted by one or more halo, alkyl of one to eight carbon atoms, alkoxy of one to eight carbon atoms, cycloalkyl, nitro or trifluoromethyl groups; X
1
is optionally one or more halo, alkyl of one to eight carbon atoms, alkoxy of one to eight carbon atoms, cyc
Appere Georges
Banissi Claire
Erdelmeier Irene
Hopper Allen
Moutet Marc
Dentz Bernard
Klauber & Jackson
Oxis Therapeutics Inc.
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