Gamma secretase inhibitors

Details Gamma secretase inhibitors Gamma secretase inhibitors

2001-06-29

2002-09-10

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C544S168000

Reexamination Certificate

active

06448229

ABSTRACT:

The present invention relates to compounds, their salts, pharmaceutical compositions comprising them, processes for making them and their use in treating Alzheimer's Disease.
Alzheimer's Disease (AD) is characterized by the abnormal deposition of amyloid in the brain in the form of extra-cellular plaques and intra-cellular neurofibrillary tangles. The rate of amyloid accumulation is a combination of the rates of formation, aggregation and egress from the brain. It is generally accepted that the main constituent of amyloid plaques is the 4 kD amyloid protein (&bgr;A4, also referred to as A&bgr;,&bgr;-protein and &bgr;AP) which is a proteolytic product of a precursor protein of much larger size. The ragged NH
2
- and COOH-termini of the native A&bgr; amyloid indicates that a complex mechanism of proteolysis is involved in its biogenesis.
The amyloid precursor protein (APP or A&bgr;PP) has a receptor-like structure with a large ectodomain, a membrane spanning region and a short cytoplasmic tail. Different isoforms of APP result from the alternative splicing of three exons in a single gene and have 695,751 and 770 amino acids respectively.
The A&bgr; domain encompasses parts of both extra-cellular and transmembrane domains of APP, thus its release implies the existence of two distinct proteolytic events to generate its NH
2
- and COOH-termini. At least two secretory mechanisms exist which release APP from the membrane and generate the soluble, COOH-truncated forms of APP (APP
s
). Proteases which release APP and its fragments from the membrane are termed “secretases”. Most APP
s
is released by a putative &agr;-secretase which cleaves within the A&bgr;domain (between residues Lys
16
and Leu
17
) to release (&agr;-APP
s
and precludes the release of intact A&bgr;. A minor portion of APP
s
is released by a &bgr;-secretase, which cleaves near the NH
2
-terminus of A&bgr; and produces COOH-terminal fragments (CTFs) which contain the whole A&bgr; domain. Finding these fragments in the extracellular compartment suggests that another proteolytic activity (&ggr;-secretase) exists under normal conditions which can generate the COOH-terminus of A&bgr;.
It is believed that &ggr;-secretase itself depends for its activity on the presence of presenilin-1. In a manner that is not fully understood presenilin-1 appears to undergo autocleavage.
The potential of &ggr;-secretase inhibitors to inhibit the functioning of presinilins, which have been proposed as candidates &ggr;-secretases, has raised questions over their suitability. In particular, signalling through the Notch pathway, important during embryonic development and in haematopoeisis, requires the presenilin-dependent proteolytic release of the Notch intracellular domain (NICD). Using a novel Xenopus developmental assay for Notch activity it has surprisingly been found that the present &ggr;-secretase inhibitors do not prevent Notch signalling in-vivo.
The present compounds are structurally related to those disclosed in WO-A-9822494. However there is no discussion in that document of the problem of interference of Notch signalling nor any suggestion of how the provision of &ggr;-secretase inhibitors that do not inhibit Notch signalling may be achieved.
Accordingly, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:
wherein: X is CH
2
, oxygen or sulphur; and
Ar is phenyl optionally substituted by one, two or three substituents chosen from halogen, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, hydroxy, cyano, nitro, NR
1
R
2
where R
1
and R
2
are independently hydrogen or C
1-6
alkyl, C
1-6
alkoxy, C
2-6
alkenyloxy, C
2-6
alkynyloxy, thiol, C
1-6
alkylthio, C
2-6
alkenylthio, C
2-6
alkynylthio, C
1-6
alkylcarbonyl, C
1-6
alkoxycarbonyl, C
1-6
haloalkyl, C
2-6
haloalkenyl and C
2-6
haloalkynyl.
Preferably X is oxygen.
Preferably Ar is optionally substituted by one, two or three substituents chosen from halogen, C
1-6
alkyl, hydroxy, amino, C
1-6
alkoxy, thiol, C
1-6
alkoxycarbonyl and C
1-6
haloalkyl.
More preferably Ar is optionally substituted by one substituent chosen from halogen, C
1-4
alkyl, hydroxy, amino, C
1-4
alkoxy, thiol, C
1-4
alkoxycarbonyl and C
1-4
haloalkyl.
In one embodiment Ar is unsubstituted.
A specific Example of the present invention is: 2-[2-(3,5-difluorophenyl)acetylamino]-N-{phenyl[(4-phenylmorpholin-2-ylmethyl)carbamoyl]methyl}propionamide and the pharmaceutically acceptable salts thereof.
As used herein, the expression “C
1-6
alkyl” includes methyl and ethyl groups, and straight-chained and branched propyl, butyl, pentyl and hexyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and t-butyl. Derived expressions such as “C
1-4
alkyl”, “C
2-6
alkenyl” and “C
2-6
alkynyl” are to be construed in an analogous manner.
The term “halogen” as used herein includes fluorine, chlorine, bromine and iodine, of which fluorine and chlorine are preferred.
As used herein the term “C
1-6
alkoxy” includes methoxy and ethoxy groups, and straight-chained, branched and cyclic propoxy and butoxy groups, including cyclopropylmethoxy. “C
2-6
alkynyloxy”, “C
2-6
alkenyloxy”, “C
1-6
alkylthio”, “C
2-6
alkenylthio”, “C
2-6
alkynylthio” and “C
1-4
alkoxy” are to be construed in analogous manner.
As used herein the term “C
1-6
alkoxycarbonyl” includes methoxycarbonyl and alkoxycarbonyl groups and straight-chained, branched and cyclic propoxycarbonyl and butoxycarbonyl groups, including cyclopropylmethoxycarbonyl. “C
1-4
alkoxycarbonyl” is to be construed in analogous manner.
Examples of pharmaceutically acceptable salts are hydrochlorides, sulfates, citrates, tartrates, acetates, methanesulfonates, phosphates, oxalates and benzoates.


REFERENCES:
patent: WO 9822494 (1998-05-01), None

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