Benzodiazepinone &bgr;-amyloid inhibitors:...

Details Benzodiazepinone &bgr;-amyloid inhibitors:... Benzodiazepinone &bgr;-amyloid inhibitors:...

2001-07-02

2002-08-13

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S500000

Reexamination Certificate

active

06432944

ABSTRACT:

FIELD OF THE INVENTION
This invention provides novel benzodiazepinone compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with arylacetamidoalanyl derivatives of 2,3-benzodiazepin-4-ones. These compounds uniquely inhibit &bgr;-amyloid peptide (&bgr;-AP) production, thereby acting to prevent the accumulation of amyloid protein deposits in the brain. More particularly, the present invention relates to the treatment of Alzheimer's Disease (AD).
BACKGROUND OF THE INVENTION
Alzheimer's Disease is a progressive, neurodegenerative disorder characterized by memory impairment and cognitive dysfunction. AD is characterized pathologically by the accumulation of senile (neuritic) plaques, neurofibrillary tangles, amyloid deposition in neural tissues and vessels, synaptic loss, and neuronal death. It is the most common form of dementia and it now represents the third leading cause of death after cardiovascular disorders and cancer. The cost of Alzheimer's Disease is enormous (in the U.S., greater than $100 billion annually) and includes the suffering of the patients, the suffering of families, and the lost productivity of patients and caregivers. As the longevity of society increases, the occurrence of AD will markedly increase. It is estimated that more than 10 million Americans will suffer from AD by the year 2020, if methods for prevention and treatment are not found. Currently, AD is estimated to afflict 10% of the population over age 65 and up to 50% of those over the age of 85. There is currently no effective treatment.
There have been many theories relating to the etiology and pathogenesis of AD. These theories were either based on analogies with other diseases and conditions (e.g., slow virus and aluminum theories), or based on pathologic observations (e.g., cholinergic, amyloid, or tangle theories). Genetic analysis can potentially differentiate between competing theories. The identification of mutations in the &bgr;-amyloid precursor protein (&bgr;-APP) of individuals prone to early onset forms of AD and related disorders strongly supports the amyloidogenic theories.
The &bgr;-amyloid precursor protein (&bgr;-APP), a large membrane spanning glycoprotein found in tissues of mammals, including humans, is encoded by a gene on the long arm of human chromosome 21. The main constituent of the plaques, tangles and amyloid deposits is known to be &bgr;-amyloid peptides (&bgr;-AP), composed of approximately 39 to 43 amino acid fragments of &bgr;-APP, and in particular, the 40 amino acid fragment known as A&bgr;1-40. Several lines of evidence support the involvement of &bgr;-AP in the pathogenesis of AD lesions. &bgr;-AP and related fragments have been shown to be toxic for PC-12 cell lines and primary cultures of neurons, as well as causing neuronal degeneration with accompanying amnesia in rodents. Strong evidence for the role of &bgr;-AP in AD consists of observations of genetic &bgr;-APP mutations in individuals with certain forms of Familial Alzheimer's Disease (FAD) and the correlation of disease onset with altered release of &bgr;-AP fragments.
It is presently believed that the development of amyloid plaques in the brains of AD patients is a result of excess production and/or reduced clearance or removal of &bgr;-AP. It is known that a basal level of &bgr;-AP production may be a normal process and that multiple pathways for cleavage of &bgr;-APP exist. Currently, however, it is unclear which classes of proteinases or inhibitors thereof that would be effective in treating AD. Various peptidergic compounds and their pharmaceutical compositions have been disclosed as useful in inhibiting or preventing amyloid protein deposits in brains of AD and Down's Syndrome patients.
Dovey, et al. in European Patent Application 652,009, published May 10, 1995, disclosed a series of polyamido inhibitors of aspartic proteases, e.g. cathepsin D, for use in inhibiting intracellular &bgr;-production.
A series of peptidergic compounds and their administration to patients to prevent abnormal deposition of &bgr;-AP was disclosed by Cordell, et al., in WO 95/09838, published Apr. 13, 1995, as a means of treating AD.
Tamburini, et al. in WO 94/13319, published Jun. 23, 1994, disclosed methods for regulating formation of &bgr;-AP by use of inhibitors of certain aspartic and serine proteases such as cathepsin D. Specifically, cathepsin D inhibitors were preferred. A series of peptidic compounds resembling pepstatin analogs was disclosed and claimed.
Xia, et al. disclosed substituted 2,3-benzodiazepin-4-ones (1) as being modulators of AMPA receptors for use in treating neurodegenerative disease (U.S. Pat. No. 5,891,871; WO9728135, WO9734878).
R
1
and R
2
are, inter alia, hydrocarbon, carbocyclic, aryl and heteroaryl systems but are not alanylamido derivatives.
Audia, et al. have disclosed numerous peptidergic analogs of various azepinone heterocyclics, e.g. (2), but no 2,3-benzodiazepin-4-one derivatives were described. Audia's compounds are reported
to inhibit &bgr;-amyloid formation (WO 9967221, WO 9967220, WO 9967219, WO 9966934, WO 9932453, WO 9838177, WO 9828268, WO 9822494, WO 9822493, WO 9822441, WO 9822433, and WO 9822430).
Nothing in these foregoing references can be construed to describe or suggest the novel alanyl derivatives of 2,3-benzodiazepin-4-ones of this invention or their use to inhibit &bgr;-AP production.
SUMMARY DESCRIPTION OF THE INVENTION
A series of arylacetamidoalanyl derivatives of 2,3-benzodiazepin-4-ones have been synthesized. These compounds inhibit the production of &bgr;-amyloid peptide (&bgr;-AP) from &bgr;-amyloid precursor protein (&bgr;-APP). The pharmacologic action of these compounds makes them useful for treating conditions responsive to the inhibition of &bgr;-AP in a patient; e.g., Alzheimer's Disease (AD) and Down's Syndrome. Therapy utilizing administration of these compounds to patients suffering from, or susceptible to, these conditions involves reducing &bgr;-AP available for accumulation and deposition in brains of these patients.
DETAILED DESCRIPTION OF THE INVENTION
The present invention comprises compounds of Formula I, their pharmaceutical formulations, and their use in inhibiting &bgr;-AP production in patients suffering from or susceptible to AD or other disorders resulting from &bgr;-AP accumulation in brain tissue. The compounds of Formula I include pharmaceutically acceptable acid and base salts, optical isomers (enantiomers) considered separately or as racemates, and solvates and/or hydrates thereof having the following formula and meanings.
The Formula I compounds are those having the following structure
or a pharmaceutically acceptable salt or hydrate thereof wherein
R
1
is hydrogen, hydroxyl, or oxygen;
R
2
is C
1-6
alkyl, C
2-6
alkenyl or alkynyl, C
3-7
cycloalkyl, C
5-7
cycloalkenyl, aryl, heteroaryl,
and
with aryl being phenyl or naphthyl, and heteroaryl being furanyl, thienyl, or pyridinyl;
R
3
and R
4
are independently selected from C
1-6
alkyl;
R
5
and R
6
are independently selected from hydrogen, C
1-6
alkyl, C
2-6
alkenyl or alkynyl, C
3-7
cycloalkyl, C
5-7
cycloalkenyl,
and —CO
2
R
10
; or R
5
can be taken with R
4
or with R
6
as a C
3-6
alkanediyl chain thereby forming a fused ring system;
R
7
is hydrogen or can be taken with R
6
as ═O;
R
8
and R
9
are independently selected from hydrogen, halogen, trifluoromethyl, C
1-6
alkyl or alkoxy;
R
10
is C
1-6
alkyl;
n is zero or one;
m is one or two;
p is zero, one or two; and
the solid and dotted lines are either a single or a double covalent bond with the proviso that when they represent a double bond in the benzodiazepinone ring, n is zero.
There are three subclasses of compounds of Formula I. In subclass A, R
6
and R
7
are taken together as ═O. In subclass B, R
6
is selected from the listed moieties that define R
6
while R
7
is hydrogen. Subclass C has the ring double bond with n being zero.
While the term halogen

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