Gamma-secretase inhibitors

Details Gamma-secretase inhibitors Gamma-secretase inhibitors

2002-07-18

2004-06-29

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C560S027000, C560S029000, C540S509000, C540S510000, C514S484000, C514S485000, C514S616000, C514S221000

Reexamination Certificate

active

06756511

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 characterised 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 compounds of the present invention are useful for treating AD by inhibiting the activity of the putative &ggr;-secretase thus preventing the formation of insoluble A&bgr; and arresting the production of A&bgr;. Further, some of the present compounds also stabilise full-length presenilin-1.
In a further aspect some of the compounds of the present application are useful as inhibitors of presenilin-1 cleavage.
The compounds of the present invention are related to HIV protease inhibitors described in EP-A-337 714 and EP-A-356 223, both in the name of Merck & Co., Inc.. These compounds are aspartyl protease inhibitors. Specifically, a subset of the compounds of the present invention differ from those previously described by the stereochemistry of a hydroxyl group which is a particularly preferred feature of the present invention and has not previously been disclosed for these particular compounds. This is a surprising feature giving rise to the present invention.
The present invention, in one aspect, provides a compound comprising the group:
wherein R
2
and R
3
are as defined below, which compound is a diastereoisomer of a known protease inhibitor comprising the group
wherein R
2
and R
3
are as defined below.
The present invention accordingly provides a compound of formula I or a pharmaceutically acceptable salt thereof:
wherein:
R
1
is (1) C
1-10
alkyl, C
2-10
alkenyl or C
2-10
alkynyl optionally substituted with one to three substituents independently chosen from:
(i) hydroxy;
(ii) carboxy;
(iii) halogen;
(iv) C
1-4
alkoxy;
(v) C
1-4
alkoxycarbonyl;
(vi) —NR
6
R
7
wherein R
6
and R
7
are independently chosen from hydrogen, C
1-5
alkyl and C
1-5
alkoxyC
1-5
alkyl;
(vii) —CONR
6
R
7
or OCONR
6
R
7
wherein R
6
and R
7
are independently as defined above;
(viii) —N(R
8
)QR
9
wherein:
Q is C(O), C(S), SO
2
or C(NH
2
);
R
8
is hydrogen or C
1-4
alkyl; and
R
9
is hydrogen, C
1-4
alkyl, C
1-4
alkoxy, amino, C
1-4
alkylamino di(C
1-4
alkyl)amino wherein each alkyl group is independently chosen;
(ix) C
3-7
cycloalkyl;
(x) phenyl or naphthyl; a five-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from O, N and S, at most one of the heteroatoms being O or S; a six-membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms; each of which is optionally substituted by one to three groups independently chosen from:
(a) halogen, cyano and nitro,
(b) hydroxy,
(c) C
1-4
alkyl, C
2-4
alkenyl and C
2-4
alkynyl,
(d) C
1-4
alkoxy,
(e) NR
6
R
7
wherein R
6
and R
7
are independently as defined above,
(f) CO
2
R
8
wherein R
8
is independently as defined above,
(g) CONR
6
R
7
or OCONR
6
R
7
wherein R
6
and R
7
are independently as defined above,
(h) SO
2
NR
6
R
7
wherein R
6
and R
7
are independently as defined above,
(i) CH
2
NR
6
R
7
wherein R
6
and R
7
are independently as defined above,
(j) N(R
8
)COR
8
′ wherein R
8
is independently as defined above and R
8
′ is independently as defined for R
8
, and
(k) NR
8
SO
2
R
8
′ wherein R
8
and R
8
′ are independently as defined above; or
(2) phenyl or naphthyl; a five-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from O, N and S, at most one of the heteroatoms being O or S; a six-membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms; each of which is optionally substituted by one to three groups independently chosen from:
(a) halogen, cyano and nitro,
(b) hydroxy,
(c) C
1-4
alkyl, C
2-4
alkenyl and C
2-4
alkynyl,
(d) C
1-4
alkoxy,
(e) NR
6
R
7
wherein R
6
and R
7
are independently as defined above,
(f) CO
2
R
8
wherein R
8
is independently as defined above,
(g) CONR
6
R
7
or OCONR
6
R
7
wherein R
6
and R
7
are independently as defined above,
(h) SO
2
NR
6
R
7
wherein R
6
and R
7
are independently as defined above,
(i) CH
2
NR
6
R
7
wherein R
6
and R
7
are independently as defined above,
(j) N(R
8
)COR
8
′ wherein R
8
and R
8
′ are independently as defined above, and
(k) NR
8
SO
2
R
8
′ wherein R
8
and R
8
′ are independently as defined above;
R
2
and R
3
are independently chosen from C
1-10
alkyl, C
1-10
alkoxy, C
2-10
alkenyl, C
2-10
alkenyloxy, C
2-10
alkynyl or C
2-10
alkynyloxy; phenyl; naphthyl; a five-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from O, N and S, at most one of the heteroatoms being O or S; a six-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms; and a group (CH
2
)
p
Q
1
wherein Q
1
is phenyl, naphthyl, a five-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from O, N and S, at most one of the heteroatoms being O or S, and a six-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms; and wherein each of R
2
and R
3
is independently optionally substituted by one to three groups independently chosen from:
(a) halogen, cyano and nitro,
(b) hydroxy,
(c) C
1-3
alkyl, C
2-3
alkenyl and C
2-3
alkynyl,
(d) C
1-3
alkoxy,
(e) NR
6
R
7
wherein R
6
and R
7
are independently as defined above,
(f) CO
2
R
8
wherein R
8
is independently as defined above,
(g) CONR
6
R
7
or OCONR
6
R
7
wherein R
6
and R
7
are independently as defined above,
(h) SO
2
NR
6
R
7
wherein R
6
and R
7
are independently as defined above,
(i) CH
2
NR
6
R
7
wherein R
6
and R
7
are independently as defined above,
(j) N(R
8
)COR
8
′ wherein R
8
and R
8
′ are independently as defined above,
(k) NR
8
SO
2
R
8
′ where R
8
and R
8
′ are independently as defined above;
alternatively R
3
may be hydrogen;
R
4
and R
5
are independently chosen from hydrogen, C
1-6
alkyl optionally substituted by halogen, hydroxy, thiol, a

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