Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-17
2001-10-30
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06310092
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel thioether furan nitrone compounds and their use as therapeutic agents and analytical reagents. More particularly, this invention concerns novel thioether furan nitrone compounds and their use as therapeutics for treating and/or preventing neurological, autoimmune and inflammatory conditions in mammals and as analytical reagents for detecting free radicals.
2. State of the Art
Alzheimer's disease is a neurodegenerative condition in which nerve cells in the brain are systematically destroyed resulting in progressive memory loss, mental confusion and ultimately death. The National Institute on Aging (NIA) has recently estimated that about 4 million people in the United States are currently afflicted with Alzheimer's disease. At present, there is no treatment that effectively prevents the disease or reverses its symptoms.
In recent years, significant progress has been made in understanding the pathogenesis of Alzheimer's disease. For example, it is now known that patients with Alzheimer's disease develop amyloid plaque deposits around and between the nerve cells of their brain. These plaque deposits are made up of fibrillar aggregates of a small peptide called amyloid &bgr;-peptide or A&bgr;. The plaque deposits initially form in the hippocampus and cortical regions of the brain (areas associated with memory and cognition) and then spread to other areas as the disease progresses. The deposition of fibrils and plaques is also followed by inflammation of the surrounding support cells, called glia, which may lead to further loss of neurons. The nerve cells in the brains of most Alzheimer's patients also develop tangles of a microtubule-associated protein, called tau, which are believed to be a response by the nerve cells to damage.
Progress in understanding the underlying mechanisms of Alzheimer's disease has led to the development of various in vitro and in vivo models to identify compounds effective for preventing and/or treating Alzheimer's disease and other neurodegenerative conditions. In one such in vitro model, compounds are evaluated for their ability to intervene in A&bgr;(1-40) or A&bgr;(1-42) beta-pleated sheet formation. Since the deposition of amyloid &bgr;-peptide is associated with the development of Alzheimer's disease, compounds which effectively disrupt the formation of A&bgr;(1-40) beta-pleated sheets are potentially useful for preventing and/or reversing Alzheimer's disease-related amyloid deposits.
In another in vitro model, compounds are evaluated for their ability to protect against A&bgr;(25-35)-induced neuronal cell loss in rat embryonic hippocampal neuronallastrocyte cultures. As discussed above, patients with Alzheimer's disease suffer a progressive loss of neuronal cells. Accordingly, compounds which are effective in this in vitro test are potentially useful for reducing or preventing neuronal cell loss in patients afflicted with Alzheimer's disease or other neurodegenerative conditions.
A third in vitro Alzheimer's disease model is based on the observation that &bgr;-amyloid increases the release of cytokines, such as interleukin-1&bgr; (IL-1&bgr;), interleukin 6 (IL-6) and tumor necrosis factor-&agr; (TNF&agr;), in human monocyte cells induced with lipopolysaccharide (LPS). IL-1&bgr;, IL-6 and TNF&agr; are proteins associated with inflammatory and immune responses. As previously mentioned, the deposition of fibrils in the brains of Alzheimer's patients is associated with inflammation of the surrounding support cells. See, S. D. Yan et al.,
Proc. Natl. Acad. Sci. USA,
94, 5296 (1997). Thus, compounds effective in this in vitro test are potentially useful for reducing and/or preventing the inflammation associated with Alzheimer's disease.
Additionally, elevated levels of IL-1&bgr;, IL-6, TNF&agr; and other cytokines are associated with a wide variety of inflammatory and autoimmune conditions, including septic shock, rheumatoid arthritis, erythema nodosum leprosy, meningococcal meningitis, multiple sclerosis, systemic lupus and the like. See, L. Sekut et al.,
Drug News Perspect.
1196, 9, 261; and A. Waage et al.,
J. Exp. Med.
1989, 170, 1859-1867. Accordingly, compounds which inhibit the production of such cytokines are potentially useful for treating such inflammatory and autoimmune conditions.
Thus, in another in vitro model, compounds are evaluated for their ability to reduce cytokine-induced neuronal cell damage in rat embryonic cortical cell cultures. As discussed above, cytokines are associated with a wide variety of inflammatory and autoimmune conditions. Accordingly, compounds which are effective in this in vitro test are potentially useful for reducing or preventing inflammatory or autoimmune conditions.
It has now been discovered that certain novel thioether furan nitrone compounds effectively inhibit the formation of A&bgr;(1-42) beta-pleated sheets and/or inhibit the release of cytokines, such as IL-1&bgr; and/or reduce cytokine-induced neuronal cell damage. Accordingly, such compounds are useful for the prevention and/or treatment of neurodegenerative, autoimmune and inflammatory conditions in mammals.
The thioether furan nitrone compounds of this invention are also useful as analytical reagents for detecting free radicals. In this regard, the compounds of this invention function as “spin traps” by reacting with unstable free radicals to form relatively stable free radical spin adducts which are observable by electron spin resonance (ESR) spectroscopy. Accordingly, when used as spin traps, the compounds of this invention allow free radicals to be identified and studied using ESR and related techniques.
SUMMARY OF THE INVENTION
This invention provides novel thioether furan nitrone compounds which are useful as therapeutics for treating and/or preventing neurological, autoimmune and inflammatory conditions in mammals and as analytical reagents for detecting free radicals. In particular, the compounds of this invention are useful for preventing and/or treating Alzheimer's disease.
Accordingly, in one of its composition aspects, this invention is directed to compounds of formula I:
wherein
R
1
is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, cycloalkylalkyl, and cycloalkenyl;
each R
2
is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, aralkyl, aryl, alkoxy, substituted alkoxy, cycloalkyl and halo;
R
3
is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, aralkyl, aryl, cycloalkyl and cycloalkylalkyl;
R
4
is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, cycloalkylalkyl and cycloalkenyl; and
n is an integer ranging from 0 to 2; and optical isomers and racemates thereof, and pharmaceutically acceptable salts thereof.
In a preferred embodiment, R
1
is a substituted phenyl group having the formula:
wherein
each R
5
is independently selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aralkyl, aryl, alkoxy, substituted alkoxy, aryloxy, aralkyloxy, cycloalkoxy, acyl, acylamino, aminocarbonyl, alkoxycarbonyl, carboxyl, cyano, halo, hydroxy, nitro, sulfonate, thioalkoxy, and —NR
6
R
7
, where R
6
and R
7
are each independently selected from hydrogen, alkyl, substituted alkyl or aryl; or two adjacent R
5
groups can be joined together to form an alkylene or alkylenedioxy group; and
m is an integer from 1 to 5.
Preferably, R
5
is selected from the group consisting of alkyl, alkoxy, substituted alkoxy, acylamino, thioalkoxy. More preferably, R
5
is a methyl, methoxy, trifluoromethoxy, acetamido or thiomethoxy group. Preferably, when m is 1, the R
5
group is in the para position relative to the sulfur atom of the thio group.
Preferably, m is an integer from 1 to 3. Mo
Kelleher Judith A.
Maples Kirk R.
Zhang Yong-Kang
Burns Doane , Swecker, Mathis LLP
Centaur Pharmaceuticals, Inc.
Owens Amelia
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