Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-02
2001-07-17
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...
C514S373000, C514S376000, C514S444000, C514S456000, C514S468000, C514S473000, C514S041000
Reexamination Certificate
active
06262073
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to 5-substituted and 5,5-disubstituted-3,4-dihydroxy-2(5H)-furanones, methods of preparation therefor, and methods for their use.
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 al.
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
1
, 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.
Thus, there exists a need for new therapeutic agents which exhibit activity as antioxidants and arachidonic acid metabolism inhibitors. It is to this aim that the present invention is directed.
SUMMARY OF THE INVENTION
The present invention relates to 5-substituted and 5,5-disubstituted-3,4-dihydroxy-2(5H)-furanones of the general formula I
wherein R is hydrogen, phenyl or lower alkyl; L is a linker moiety selected from the group consisting of oxygen, sulfur, nitrogen, acetylene, a cis or trans carbon-carbon double bond, an ester, carbonate, urea, amide and carbamate; m is 0 or 1; n is 0 to 4; Aryl is a substituted or unsubstituted aryl group; with the proviso that when R is hydrogen, then either m or n is not zero, and the pharmaceutically acceptable salts thereof.
In various preferred embodiments of the present invention, these compounds are represented by four structural subclasses of compounds. Thus, in one preferred embodiment, the compounds are 5,5-disubstituted-3,4-dihydroxy-2(5H)-furanones of the structural formula Ia
wherein R and Aryl are as hereinbefore defined. Most preferably, in the compounds of formula (Ia), R is a methyl, 1-propyl or 2-methylpropyl group; and Aryl is a phenyl, or substituted phenyl, such as 1,1
1
-biphenyl, 4-chlorophenyl or 2- methylpropylphenyl group.
In a second preferred embodiment, the compounds are 5-(aryl alkynyl)-3,4-dihydroxy-2(5H)-furanones of the structural formula Ib
wherein n and Aryl are as hereinbefore defined. Most preferably, in the compounds of formula 1b, n is 2 and Aryl is naphthyl or a substituted phenyl such as 2-methylphenyl, 2-hexenyl phenyl, 2-phenylthiomethylphenyl or pentylthiomethyl phenyl.
In a third preferred embodiment, the compounds are 5-(arylthio)alkyl-3,4-dihydroxy-2(5H)-furanones of the structural formula Ic
wherein n and Aryl are as hereinbefore defined. Most preferably, in the compounds of Formula Ic, n is 2 and the Aryl substituent is naphthyl or 4,5-diphenyloxazole.
In a fourth preferred embodiment, the compounds are 5-(aryloxy)alkyl-3,4-dihydroxy-2(5H)-furanones of the structural formula Id
wherein n and Aryl are as hereinbefore defined. Most preferably, in the compounds of formula Id, n is 2 and Aryl is a substituted phenyl or heteroaryl compound such as 1,1-biphenyl-4 yl, 4-phenoxyphenyl, flavonyl, dibenzofuranyl, quinolinyl and naphthyl.
The racemic 5,5-disubstituted analogs of formula Ia are prepared by reacting an ethyl benzoylformate with a Grignard reagent and trapping the intermediate alkoxide anion with benzyloxyacetyl chloride, and subsequently adding lithium diisopropylamide to generate the corresponding 3-benzyloxy-5,5-disubstituted-4-hydroxy-2(5H)-furanones. Cleavage of the benzyl group by hydrogenolysis provides racemic 5,5-disubstituted-3,4-dihydroxy-2(5H)-furanones of formula Ia.
The enantiomerically pure 5,5-disubstituted analogs of formula Ia are synthesized by reacting ethyl benzoylformate with a Grignard reagent, followed by ester saponification and resolution of the resultant 2-aryl-2-substituted-2-hydroxy acid by crystallizing with a suitable optically pure chiral amine to provide the optically pure compounds with non-racemisable stereocenters. Acid esterification, acylation of the hydroxyl group with benzyloxyacetyl chloride, LDA-induced intramolecular Claisen cyclization and reductive cleavage of the benzyl protecting group generates the 5,5-disubstituted-3,4-dihydroxy-2(5H)-furanones of formula Ia having high enantiomeric purity.
The 5-(aryl alkynyl)-3,4-dihydroxy-2(5H)-furanones of formula Ib are synthesized in a convergent manner by coupling 5-(alkynyl)-3,4-dihydroxy-2(5)-furanone with aryliodides by employing a catalytic amount of Pd(PPh
3
)
4
. The starting material, 5-(alkynyl)-3,4-dihydroxy-2(5H)-furanone, is synthesized in four steps. For instance, intermolecular Claisen reaction between o-trimethylsilyloxy-&ggr;-butyrolactone and ethyl benzyloxyacetate yields 3-benzyloxy-4-hydroxy-5-(2-hydroxyethyl)-2(5H)-furanone. Iodination (I
2
, PPh
3
, imidazole), subsequent iodo displacement with lithium acetylide, and benzyl group cleavage yields, for instance, the 5-(3-butynyl)-3,4-dihydroxy-2(5H)-furanone coupling precursor.
The 5-(arylthio)alkyl-3,4-dihydroxy-2(5H)-furanones of formula Ic are produced by reacting a 3,4-dihydroxy-5-(iodoalkyl)-2(5H)-furanone with the lithium salt of a substituted arylthiol. The starting material, 3,4-dihydroxy-5-(2-iodoalkyl)-2(5H)-furanone is produced by benzyl group cleavage of 3-benzyloxy-4-hydroxy-5-(2-iodoalkyl)-2(5H)-furanone.
The 5-(aryloxy)alkyl-3,4-dihydroxy-2(5H)-furanones of formula Id are prepared by coupling 3,4-dibenzyloxy-5-(hydroxyalkyl)-2(5H)-furanone with an appropriately substituted phenol according to the Mitsunoble reaction. Subsequent benzyl group cleavage by hydrogenation yields the desired 5-(aryloxy) al
Hopper Allen T.
Johnson Robert E.
Ziemniak John A.
Dentz Bernard
Klauber & Jackson
Oxis International Inc.
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