Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-02-17
2004-09-21
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S212080, C540S524000, C540S527000
Reexamination Certificate
active
06794381
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel lactams having drug and bio-affecting properties, their pharmaceutical compositions and methods of use. These novel compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of A&bgr;-peptide, thereby acting to prevent the formation of neurological deposits of amyloid protein. More particularly, the present invention relates to the treatment of neurological disorders related to &bgr;-amyloid production such as Alzheimer's disease and Down's Syndrome.
BACKGROUND OF THE INVENTION
Alzheimer's disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, temporal and local orientation, cognition, reasoning, judgment and emotional stability. AD is a common cause of progressive dementia in humans and is one of the major causes of death in the United States. AD has been observed in all races and ethnic groups worldwide, and is a major present and future health problem. No treatment that effectively prevents AD or reverses the clinical symptoms and underlying pathophysiology is currently available (for review, Dennis J. Selkoe; Cell Biology of the amyloid (beta)-protein precursor and the mechanism of Alzheimer's disease, Annu Rev Cell Biol, 1994, 10: 373-403).
Histopathological examination of brain tissue derived upon autopsy or from neurosurgical specimens in effected individuals revealed the occurrence of amyloid plaques and neurofibrillar tangles in the cerebral cortex of such patients. Similar alterations were observed in patients with Trisomy 21 (Down's syndrome), and hereditary cerebral hemorrhage with amyloidosis of the Dutch-type. Neurofibrillar tangles are nonmembrane-bound bundles of abnormal proteinaceous filaments and biochemical and immunochemical studies led to the conclusion that their principle protein subunit is an altered phosphorylated form of the tau protein (reviewed in Selkoe, 1994).
Biochemical and immunological studies revealed that the dominant proteinaceous component of the amyloid plaque is an approximately 4.2 kilodalton (kD) protein of about 39 to 43 amino acids. This protein was designated A&bgr;, &bgr;-amyloid peptide, and sometimes &bgr;/A4; referred to herein as A&bgr;. In addition to deposition of A&bgr; in amyloid plaques, A&bgr; is also found in the walls of meningeal and parenchymal arterioles, small arteries, capillaries, and sometimes, venules. A&bgr; was first purified, and a partial amino acid reported, in 1984 (Glenner and Wong, Biochem. Biophys. Res. Commun. 120: 885-890). The isolation and sequence data for the first 28 amino acids are described in U.S. Pat. No. 4,666,829.
Compelling evidence accumulated during the last decade revealed that A&bgr; is an internal polypeptide derived from a type 1 integral membrane protein, termed &bgr; amyloid precursor protein (APP). &bgr; APP is normally produced by many cells both in vivo and in cultured cells, derived from various animals and humans. A&bgr; is derived from cleavage of &bgr; APP by as yet unknown enzyme (protease) system(s), collectively termed secretases.
The existence of at least four proteolytic activities has been postulated. They include &bgr; secretase(s), generating the N-terminus of A&bgr;, a secretase(s) cleaving around the 16/17 peptide bond in A&bgr;, and &ggr; secretases, generating C-terminal A&bgr; fragments ending at position 38, 39, 40, 42, and 43 or generating C-terminal extended precursors which are subsequently truncated to the above polypeptides.
Several lines of evidence suggest that abnormal accumulation of A&bgr; plays a key role in the pathogenesis of AD. Firstly, A&bgr; is the major protein found in amyloid plaques. Secondly, AP is neurotoxic and may be causally related to neuronal death observed in AD patients. Thirdly, missense DNA mutations at position 717 in the 770 isoform of &bgr; APP can be found in effected members but not unaffected members of several families with a genetically determined (familiar) form of AD. In addition, several other &bgr; APP mutations have been described in familiar forms of AD. Fourthly, similar neuropathological changes have been observed in transgenic animals overexpressing mutant forms of human b APP. Fifthly, individuals with Down's syndrome have an increased gene dosage of &bgr; APP and develop early-onset AD. Taken together, these observations strongly suggest that A&bgr; depositions may be causally related to the AD.
It is hypothesized that inhibiting the production of A&bgr; will prevent and reduce neurological degeneration, by controlling the formation of amyloid plaques, reducing neurotoxicity and, generally, mediating the pathology associated with A&bgr; production. One method of treatment methods would therefore be based on drugs that inhibit the formation of A&bgr; in vivo.
Methods of treatment could target the formation of A&bgr; through the enzymes involved in the proteolytic processing of b amyloid precursor protein. Compounds that inhibit b or g secretase activity, either directly or indirectly, could control the production of A&bgr;. Advantageously, compounds that specifically target g secretases, could control the production of A&bgr;. Such inhibition of &bgr; or &ggr; secretases could thereby reduce production of A&bgr;, which, thereby, could reduce or prevent the neurological disorders associated with A&bgr; protein.
PCT publication number WO 96/29313 discloses the general formula:
covering metalloprotease inhibiting compounds useful for the treatment of diseases associated with excess and/or unwanted matrix metalloprotease activity, particularly collagenase and or stromelysin activity.
Compounds of general formula:
are disclosed in PCT publication number WO 95/22966 relating to matrix metalloprotease inhibitors. The compounds of the invention are useful for the treatment of conditions associated with the destruction of cartilage, including corneal ulceration, osteoporosis, periodontitis and cancer.
European Patent Application number EP 0652009A1 relates to the general formula:
and discloses compounds that are protease inhibitors that inhibit A&bgr; production.
U.S. Pat. No. 5703129 discloses the general formula:
which covers 5-amino-6-cyclohexyl-4-hydroxy-hexanamide derivatives that inhibit A&bgr; production and are useful in the treatment of Alzheimer's disease.
None of the above references teaches or suggests the compounds of the present invention which are described in detail below.
SUMMARY OF THE INVENTION
One object of the present invention is to provide novel compounds which are useful as inhibitors of the production of A&bgr; protein or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating degenerative neurological disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of Formula (I):
or pharmaceutically acceptable salt or prodrug forms thereof, wherein R
3
, R
3a
, R
5
, R
5a
, R
6
, A, Q, B, W, X, Y, and Z are defined below, are effective inhibitors of the production of A&bgr;.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Thus, in a first embodiment, the present invention provides a novel compound of Formula (I):
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
A is O or S;
Q is —OR
1
or —NR
1
R
2
;
R
1
, at each occurrence, is independently selected from:
H;
C
1
-C
6
alkyl substituted with 0-3 R
1a
;
Maduskuie Thomas P.
Olson Richard E.
Thompson Lorin Andrew
Bristol--Myers Squibb Company
Bristol-Myers Squibb Company
Davis Stephen B.
McKenzie Thomas
Shah Mukund J.
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