Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-25
2002-12-03
Davis, Zinna Northington (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S012000, C560S037000, C564S305000
Reexamination Certificate
active
06489481
ABSTRACT:
This invention relates to methods of preventing and treating neurological disorders such as cognitive disorders, and/or neurological disorders related to neuronal apoptosis and/or excitotoxicity, for example Alzheimer's disease, vascular dementia and age-related dementia as well as head trauma, stroke, spinal cord injury, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Huntington's chorea, AIDS-related dementia, peripheral neuropathies and macular degeneration. Such methods comprise the administration to a warm-blooded mammal, such as a human, in need thereof an effective amount of a compound of Formula I or Formula VIII. This invention also relates to the use of a compound of Formula I or Formula VIII for the manufacture of a medicament for the prevention or treatment of the aforementioned disorders.
BACKGROUND TO THE INVENTION
Alzheimer's Disease (AD) is the most common form of dementia, affecting approximately 4 million people in the United States alone. AD is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death. AD is a common cause of progressive mental failure (dementia) in aged humans and is believed to represent the fourth most common medical cause of death in the United States. AD has been observed in varied races and ethnic groups worldwide and presents a major present and future public health problem. To date, AD has proven to be incurable. For recent reviews of Alzheimer's disease see: Edelberg & Wei (1996) Mech Aging & Development 91: 95 and De LaTorre (1994) Neurosci & Biobehavioral Reviews 18:397.
The brains of individuals with AD exhibit neuronal degeneration and characteristic lesions variously referred to as amyloidogenic plaques, vascular amyloid angiopathy, and neurofibrillary tangles. Large numbers of these lesions, particularly amyloidogenic plaques and neurofibrillary tangles, are generally found in several areas of the human brain important for memory and cognitive function in patients with AD. Smaller numbers of these lesions in a more restricted anatomical distribution are found in the brains of most aged humans who do not have clinical AD. Amyloidogenic plaques and vascular amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down's Syndrome) and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D). At present, a definitive diagnosis of AD usually requires observing the aforementioned lesions in the brain tissue of patients who have died with the disease or, rarely, in small biopsied samples of brain tissue taken during an invasive neurosurgical procedure.
Several lines of evidence indicate that progressive cerebral deposition of particular amyloidogenic proteins, b-amyloid proteins, (b-AP), play a seminal role in the pathogenesis of AD and can precede cognitive symptoms by years or decades. See, Selkoe, (1991) Neuron 6:487. It has been shown that b-AP is released from neuronal cells grown in culture and is present in cerebrospinal fluid (CSF) of both normal individuals and AD patients. See, Seubert et al., (1992) Nature 359:325-327.
A growing amount of research suggests that the pathogenesis of AD is due to impaired vascular delivery of nutrients to the brain. It is suggested that abnormal haemodynamic flow patterns caused by structural deformities of the capillaries leads to dysfunctional cerebral transport of nutrients. The production of plaques and neurofibrillary tangles may develop from hypometabolic abnormalities caused by the impaired cerebromicrovasculature (for a review see: de la Torre (1997) Gerontology 43:26).
Vascular dementia is considered to be the second most common cause of dementia in Europe and the US. In Asia and many developing countries, it is more common than dementia of the Alzheimer's type. Vascular dementia describes global cognitive decline attributed to the cumulative effects of ischemic vascular disease. Discrete and multiple cognitive skills, including memory, are successively lost as a result of focal cerebrovascular insults. (For a recent review of vascular dementia see: Konno et al (1997) Drugs and Aging, 11:361).
DESCRIPTION
Emopamil is a neuroprotective agent structurally related to the Ca
2+
antagonist, verapamil. However, verapamil is only a weak Ca
2+
inhibitor in the brain due to limited CNS access. Emopamil, but not verapamil, binds a high affinity site which is present in the endoplasmic reticulum in a number of tissues including brain and liver. Recently, it has been suggested that the emopamil binding protein (EBP) represents an anti-ischemic binding site (Moebius et al, (1993) Mol Pharmacol 43:139). More recently Silve et al have shown that the EBP exhibits &Dgr;8-&Dgr;7 sterol isomerase activity when expressed in yeast (Silve et al (1996) J.Biol. Chem.271:22434). &Dgr;8-&Dgr;7 sterol isomerase is a post squalene enzyme which participates in the conversion of lanosterol to cholesterol.
Surprisingly we have found that the a compound of formula I or formula VIII binds with high affinity to EBP and that a compound of formula I or formula VIII inhibits neuronal cell death in a number of assays of neurodegeneration. The present invention is also based on surprising discovery that a compound of formula I or formula VIII inhibits neuronal apoptosis and excitotoxicity, mechanistically two distinct pathways to neuronal death, and that therefore the compounds of the invention described herein and the pharmaceutically acceptable salts, prodrugs and solvates thereof may be of value in the treatment and/or prevention of neuronal apoptosis and/or excitotoxicity related neurological disorders.
Thus according to the present invention there is provided a method of treating or preventing cognitive disorders, such as Alzheimer's disease, vascular dementia and age-related dementia, in a warm-blooded mammal, such as man, which comprises administering an effective amount of a compound of Formula I:
(where R
1
is hydrogen or halo; R
2
is hydrogen or hydroxy; R
3
is hydrogen, hydroxy, halo or PO
4
; R
4
and R
5
are either both methyl, are both ethyl or together with the nitrogen atom to which they are attached form a ring selected from pyrrolidine, piperidine or morpholine; R
6
is hydrogen or a C
1-4
straight or branched alkyl chain and n is 2 or 3) or a pharmaceutically acceptable salt, prodrug or solvate thereof.
Convenient values for R
1
are hydrogen or halo, preferably hydrogen or chloro, most preferably hydrogen.
Convenient values for R
2
are hydrogen or hydroxy, preferably hydrogen;
Convenient values for R
3
are hydrogen, hydroxy, halo or PO
4
, preferably hydrogen, hydroxy, iodo or PO
4
, most preferably hydrogen.
Convenient values for R
4
and R
5
are either both methyl or both ethyl or R
4
and R
5
together with the nitrogen atom to which they are attached form a ring selected from pyrrolidine, piperidine or morpholine, preferably R
4
and R
5
are both methyl or together with the nitrogen to which they are attached form a pyrrolidine ring; most preferably R
4
and R
5
are both methyl.
Convenient values for R
6
are hydrogen or a straight or branched C
1-4
alkyl chain, preferably hydrogen or isopropyl, most preferably hydrogen.
Convenient values for n are 2 or 3, preferably 2.
According to a further aspect of the present invention there is provided a method of treating or preventing neurological disorders, in a warm-blooded mammal, such as man, which comprises administering an effective amount of a compound of Formula VIII.
wherein
A and B are selected from:
such that when A is of Formula X then B is of Formula IX and when A is of Formula IX then B is of Formula X.
R
1
is selected from hydrogen, halo, aryl, carbamoyl, N—C
1-4
alkylcarbamoyl or NN—di—C
1-4
alkylcarbamoyl;
D is selected from C
1-4
alkylene, C
1-4
alkenylene or C
1-4
alkynylene;
R
2
is selected from hydrogen, C
1-4
alkyl or hydroxy;
R
3
is selected from hydroge
Keith Richard Alan
Klimas Michael Thaddeus
Piser Timothy Martin
AstraZeneca AB
Davis Zinna Northington
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