Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-03-29
2004-02-17
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S461000, C548S960000, C549S297000, C549S298000, C424S001810, C424S001850, C424S001890
Reexamination Certificate
active
06693091
ABSTRACT:
Throughout this application, various publications may be referenced by Arabic numerals in brackets. Full citations for these publications may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.
BACKGROUND OF THE INVENTION
Ginkgo biloba
L. , the last surviving member of a family of trees (Ginkgoacea) that appeared more than 250 million years ago, has been mentioned in the Chinese Materia Medica for more than 3,000 years (1). A number of
G. biloba
natural products have been isolated (2), the most unique being the terpene trilactones, i.e. ginkgolides A, B, C, J and M (
1
-
5
) and bilobalide (
6
) (
FIG. 1
) (3-6). The ginkgolides are diterpenes with an aesthetic cage skeleton consisting of six 5-membered rings, i.e., a spiro[4.4]nonane carbocycle, three lactones and a tetrahydrofuran. The difference between the five ginkgolides lies in the variation in the number and positions of hydroxyl groups on the spirononane framework (FIG.
1
).
A standardized
G. biloba
extract (EGb 761) containing terpene trilactones (5-7%) and flavonoids (22-24%) has demonstrated neuromodulatory properties (7), and several clinical studies using EGb 761 have reported positive effects on various neurodegenerative diseases (8-13), including Alzheimer's disease (AD). In two studies involving a total of 549 AD patients, EGb 761 significantly slowed the loss of cognitive symptoms of dementia, with an efficacy in between donezepil (Aricept®) and rivastigmine (Exelon®), the two currently marketed drugs for treatment of AD symptoms (14, 15). Moreover, a recent study by Schultz and co-workers found that EGb 761 upregulated several genes in rat hippocampus and cortex, including genes expressing proteins such as transthyretin and neuronal tyrosine/threonine phosphatase, both of which are believed to be involved in AD (16). Several recent studies on healthy volunteers have shown positive effects of EGb 761 on short-term working memory (17-20) indicating that constituents of
G. biloba
also influence the brain under physiological conditions.
Although the molecular basis for the action of
G. biloba
terpene trilactone constituents on the central nervous system (CNS) is only poorly understood, it is known that the ginkgolides, particularly ginkgolide B (GB,
2
), is a potent in vitro antagonist of the platelet-activating factor receptor (PAFR) (21).
PAF (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine,
FIG. 2
) is a phospholipid mediator involved in numerous disorders including acute allergy, inflammation, asthma and ischemic injury. These effects are manifested through binding of PAF to the PAFR, a G protein-coupled receptor that is found in organs such as the lungs, liver, kidneys (22-24), and brain (25, 26). The function of PAF in the brain is still not clear, although PAF has been suggested to play a role in diseases of aging (27), and in initiating HIV-related neuropathogenesis (28). PAF has also been suggested as a retrograde messenger in long-term potentiation (LTP) (29, 30). However, studies using PAFR knock-out mice gave contradictory results; one study showed attenuation of LTP in the hippocampal dentate gyrus regions of mice lacking the PAFR (31), whereas another study showed that the PAFR was not required for LTP in the hippocampal CA1 region (32). These discrepancies may be due to differences in the hippocampal areas observed, as well as the assay conditions used. However, it is still unclear whether the neuromodulatory effect of the ginkgolides or the
G. biloba
extract is related to the PAFR (33, 34).
With few exceptions previous structure-activity relationship (SAR) studies of terpene trilactones on the PAFR have focused almost entirely on derivatives of GB (
2
). In all cases the derivatives were evaluated for their ability to prevent PAF-induced aggregation of rabbit platelets. Corey et al. investigated various intermediates encountered in the total syntheses of ginkgolide A (GA,
1
) (35), GB (
2
) (36) and bilobalide (BB,
6
) (37), and found that although the terminal methyl-bearing lactone was not essential for activity and could be replaced by other lipophilic groups (38), the tert. butyl group was important for PAFR antagonism (39). Park et al. synthesized over 200 derivatives of GB (
2
), with particular focus on aromatic substituents at 10-OH, and found most of them to be more potent than the parent compound (40). Similar derivatives recently synthesized by Hu et al. also yielded compounds more potent than GB (
2
) (41, 42), whereas other variations in GA (
1
) and GB (
2
) led to a decrease in activity (43, 44).
However, none of the cited references disclose labeled analogs of ginkgolides useful for imaging studies. The following describes the preparation of a series of ginkgolide derivatives with photoactivatable groups and fluorescent groups, as well as groups that potentially can be radiolabeled with positron emitters such as
11
C or
18
F. These analogs, together with the native terpene trilactones (
1
-
6
), have been assessed for their ability to displace radioligand binding to cloned PAFR.
SUMMARY OF THE INVENTION
The invention provides a compound having the structure:
wherein R
1
is H, OH, a photoactivatable moiety, a fluorescent moiety, or a radioactive moiety;
wherein R
2
is H, OH, a photoactivatable moiety, a fluorescent moiety, or a radioactive moiety;
wherein R
3
is H or OH;
wherein R
4
is H, OH, a photoactivatable moiety, a fluorescent moiety, or a radioactive moiety; and
wherein at least one of R
1
, R
2
, R
3
, or R
4
is a photoactivatable moiety, a fluorescent moiety, or a radioactive moiety,
or an optically pure enantiomer of the compound.
The invention also provides a compound having the structure:
wherein R
1
is H, OH;
wherein R
2
is H, OH, F, Br, unsubstituted or substituted, straight or branched alkyl group having 1 to 5 carbon atoms, an alkenyl group having 1 to 5 carbon atoms, or a alkynyl group having 1 to 5 carbon atoms;
wherein R
3
is H or OH; and
wherein R
4
is H, OH, —A—Ar, —A—Z—A r, —SO
2
—Ar, or —A—NR
5
, or —R
6
,
where A is an alkylene group having 1 to 8 carbon atoms, which is unsubstituted or substituted by a straight or branched alkyl chain group having 1 to 5 carbon atoms;
Z is carbon, oxygen, sulfur or nitrogen;
Ar is a phenyl group, a pyridyl group, a naphthyl group, a pyrimidyl group, or a quinolyl group, each of which may contain heteroatoms and may be unsubstituted or substituted by one to five substituents selected from the group consisting of hydrogen, halogen, a hydroxy group, a carboxylic acid group, an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 1 to 10 carbon atoms, an alkynyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, an alkenyloxy group having 1 to 10 carbon atoms, an alkynyloxy group having 1 to 10 carbon atoms, a haloalkoxy group having 1 to 10 carbon atoms, a phenyl group, a phenoxy group, an aralkyl group, an aralkyloxy group, a substituted phenyl group, a substituted phenoxy group, a substituted aralkyl group, a substituted aralkyloxy group, —COR
5
, —COR
6
, —CONR
5
R
6
, —CO
2
R
5
, —NHCOR
5
, —NH(OH), —N(OH)COR
5
, —CHOR
5
, —OCH
2
CO
2
R
5
, —CH
2
SR
5
, —CH
2
NR
5
R
6
, —SR
5
, —OSR
5
R
6
, —NR
5
R
6
, —NR
5
SO
2
R
6
,
in which R
5
and R
6
are the same or different and each is hydrogen, an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms, —SCX
3
in which X is a halogen, —CN, —NO
2
or —Z—A—Z′— which Z and A are as defined above and Z′ represents carbon, oxygen, sulfur, or nitrogen,
or an optically pure enantiomer or a salt of the compound.
The invention also provides a compound having the structure:
wherein R
4
is a photoactivatable moiety, a fluorescen
Nakanishi Koji
Stromgaard Kristian
Suehiro Makiko
Cooper & Dunham LLP
Owens Amelia
The Trustees of Columbia University in the City of New York
White John P.
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