Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Tripeptides – e.g. – tripeptide thyroliberin – etc.
Reexamination Certificate
2001-03-02
2004-06-22
Low, Christopher S. F. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Tripeptides, e.g., tripeptide thyroliberin , etc.
C530S330000, C514S017400, C514S018700, C548S303700, C548S304100, C435S007500
Reexamination Certificate
active
06753410
ABSTRACT:
The present invention relates to compounds, their salts, processes for making them and their use in investigating the processing of amyloid protein precursor and by extension 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, 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 present compounds are useful for investigating amyloidosis in particular in aiding the isolation and characterization of proteases involved in processing APP, especially where those proteases are &ggr;-secretase and/or presenilin-1.
Accordingly, the present invention provides a compound of formula I or a salt thereof:
wherein:
R
1
is benzoylphenyl or benzoylphenylC
1-6
alkyl wherein the benzoylphenyl moiety is optionally substituted by from one to nine bromine atoms and the alkyl moiety is optionally substituted by C
1-6
alkylsulfonylamino; or C
1-6
alkoxy;
R
2
and R
3
are independently chosen from C
1-10
alkyl, C
1-10
alkoxy, C
2-10
alkenyl, C
2
ioalkenyloxy, 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 chosen from hydrogen, C
1-5
alkyl and C
1-5
alkoxyC
1-5
alkyl,
(f) CO
2
R
8
wherein R
8
is hydrogen or C
1-4
alkyl,
(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
,
(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, amino, C
1-4
alkoxy, C
1-4
alkylthio, carboxy, C
1-4
alkoxycarbonyl and (CH
2
)
q
Q
2
wherein Q
2
is a five-membered unsaturated heterocycle containing 1, 2, 3 or 4 heteroatom optionally chosen from O, N, and S providing that not more than one heteroatom is O or S, a six-membered unsaturated heterocycle containing 1, 2 or 3 N atoms and phenyl and naphthyl, or a fused ring which is indolyl, each of the foregoing rings being optionally substituted with one to three groups independently chosen from hydroxy, C
1-4
alkyl, C
1-4
alkoxy, thiol, C
1-4
alkylthio, halogen, amino, carboxy, amido, CO
2
H and —NHC(NH
2
)
2
and wherein each of the foregoing rings is optionally fused to a benzene ring;
alternatively R
5
may be benzoylbenzyl which is optionally substituted by from one to nine bromine atoms;
B is C═O or CHOH in the R configuration;
L is a bond or [(CH
2
)
m
NHCO]
n
in which one of the methylene groups may be replaced by a disulphide group;
Z is (CH
2
)
k
amino, benzoxy or biotin, or when L is a bond then Z is hydrogen or biotin providing that when Z is hydrogen then either R
1
is not C
1-6
alkoxy or R
5
is benzoylbenzyl;
k is an integer of from one to ten;
each m is independently an integer of from one to ten;
n is an integer of from one to ten;
p is zero, one, two or three; and
q is zero, one, two or three;
with the proviso that no carbon atom is substituted by more than one hydroxy group.
In an embodiment the compounds of the present invention are of formula I′:
where R
1
, R
2
, R
3
, R
4
, R
5
, L and Z are as defined above.
In one embodiment the compounds of the present invention are of formula I″:
where R
1
, R
2
, R
3
, R
4
, R
5
, L and Z are as defined above.
In another embodiment there are provided compounds of formula I′″:
where R
1
, R
2
, R
3
, R
4
, R
5
, L and Z are as defined above.
The following preferred definitions of substituents apply to each of the formulae: I, I′, I″ and I′″ which refer to those substituents.
Preferably R
1
is tertiarybutoxy or benzoylphenyl or benzoylphenylC
1-2
alkyl wherein the benzoylphenyl moiety is optionally substituted by from one to six, preferably by from one to four, bromine atoms, and the C
1-2
alkyl moiety is optionally substituted by methylsulfonylamino.
Particular values of R
1
are tertiarybutoxy, benzoylphenyl, 2,3,5,6-tetrabromobenzoylphenyl, benzoylphenylethyl, (1-methylsulfonylamino)benzoylphenylethyl, benzoylphenylmethyl and 4-bromobenzoylphenyl.
R
2
and R
3
may be independently chosen from 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
Dean Dennis C.
Dorsey Bruce D.
Gardell Stephen J.
Lai Ming-Tain
Li Yueming
Low Christopher S. F.
Lukton David
Merck & Co. , Inc.
Todaro John C.
Winokur Melvin
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