VLA-4 antagonists

Details VLA-4 antagonists VLA-4 antagonists

1999-01-19

2002-06-18

Low, Christopher S. F. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C562S575000, C562S553000, C562S576000

Reexamination Certificate

active

06407065

ABSTRACT:

BACKGROUND OF THE INVENTION
Cell adhesion (i.e., a process by which cells associate with each other, migrate towards a specific target, or localize within the extracellular matrix) underlies many biological phenomena. Cell adhesion causes adhesion of hemoatopoietic to endothelial cells and the subsequent migration of those hemopoietic cells out of blood vessels and to the site of injury, thus playing a role in mammalian pathologies such as inflammation and immune reactions.
Various cell-surface macromolecules (known as cell adhesion receptors) mediate cell-cell and cell-matrix interactions. For example, the integrins are the key mediators in adhesive interactions between hematopoietic and other cells. Integrins are non-covalent heterodimeric complexes consisting of two subunits, &agr; and &bgr;. Depending on the type of its &agr; and &bgr; subunit components, each integrin molecule is categorized into its own subfamily. There are at least 12 different &agr; subunits (&agr;1-&agr;6, &agr;-L, &agr;-M, &agr;-X, &agr;-IIB, &agr;-V, and &agr;-E) and at least 9 different &bgr; subunits (&bgr;1-&bgr;9).
The very late antigen-4 (VLA-4), also known as &agr;4&bgr;1 integrin or CD49d/CD29, is a leukocyte cell surface receptor that participates in a variety of cell-cell and cell-matrix adhesions. It is a receptor for both the cytokine-inducible endothelial cell surface protein, vascular cell adhesion molecule-1 (VCAM-1), and the extracellular matrix protein fibronectin (FN). Anti-VLA-4 monoclonal antibodies (mAb's) inhibit VLA-4-dependent adhesive interactions both in vitro and in vivo. This inhibition of VLA-4-dependent cell adhesion may prevent or inhibit several inflammatory and autoimmune pathologies.
WO 96/22966 describes compounds of the formula
as useful for inhibition, prevention, and suppression of VLA-4-mediated cell adhesion.
SUMMARY OF THE INVENTION
This invention relates to organic compounds which are VLA-4 antagonists, the preparation of such compounds and their use as pharmaceuticals.
It has now been found that certain novel compounds have very good VLA-4 antagonistic activity and useful pharmacological properties.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides in one aspect compounds of formula I
wherein
R
1
is alkyl, alkenyl, alkynyl, cycloalkyl, aryl-fused cycloalkyl, cycloalkenyl, aryl, aryl-substituted alkyl (aralkyl), aryl-substituted alkenyl or alkynyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted cycloalkyl, biaryl, alkoxy, alkenoxy, alkynoxy, aryl-substituted alkoxy (aralkoxy), aryl-substituted alkenoxy or alkynoxy, alkylamino, alkenylamino or alkynylamino, aryl-substituted alkylamino, aryl-substituted alkenylamino or alkynylamino, aryloxy, arylamino, N-alkylureido-substituted alkyl, N-arylureido-substituted alkyl, alkylcarbonylamino-substituted alkyl, aminocarbonyl-substituted alkyl, heterocyclyl, heterocyclyl-substituted alkyl, heterocyclyl-substituted amino, carboxyalkyl substituted aralkyl, oxocarbocyclyl-fused aryl, or heterocyclylalkyl;
R
2
is (CH
2
)
q
—V—(CH
2
)
q′
—V
r
—R
s
;
R
3
is H, alkyl, alkenyl, aryl, or heteroaryl;
R
4
is H, aryl, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl and aryl-substituted alkyl, heterocyclyl, heterocyclylcarbonyl, aminocarbonyl, amido, mono- or dialkylaminocarbonyl, mono- or diarylaminocarbonyl, alkylarylaminocarbonyl, diarylaminocarbonyl, mono- or diacylaminocarbonyl, aromatic or aliphatic acyl, or alkyl optionally substituted by substituents selected from the group consisting of amino, halo, hydroxy, mercapto, mono- or dialkylamino, mono- or diarylamino, alkylarylamino, mono- or diacylamino, alkoxy, alkenoxy, aryloxy, thioalkoxy, thioalkenoxy, thioalkynoxy, thioaryloxy, and heterocyclyl;
R
5
is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aryl-substituted alkyl, aryl-substituted alkenyl, or alkynyl; alkyl optionally substituted by substituents selected from the group consisting of amino, halo, hydroxy, mercapto, mono- or dialkylamino, mono- or diarylamino, alkylarylamino, mono- or diacylamino, alkoxy, alkenoxy, aryloxy, thioalkoxy, thioalkenoxy, thioalkynoxy, thioaryloxy, and heterocyclyl;
R
6
is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl-substituted alkenyl or alkynyl, hydroxy-substituted alkyl, alkoxy-substituted alkyl, aralkoxy-substituted alkyl, amino-substituted alkyl, (aryl-substituted alkyloxycarbonylamino)-substituted alkyl, thiol-substituted alkyl, alkylsulfonyl-substituted alkyl, (hydroxy-substituted alkylthio)-substituted alkyl, thioalkoxy-substituted alkyl, acylamino-substituted alkyl, alkylsulfonylamino-substituted alkyl, arylsulfonylamino-substituted alkyl, morpholino-alkyl, thiomorpholino-alkyl, morpholinocarbonyl-substituted alkyl, thiomorpholinocarbonyl-substituted alkyl, [N-(alkyl, alkenyl or alkynyl)- or (N,N-dialkyl, dialkenyl or dialkynyl)-amino] carbonyl-substituted alkyl, carboxyl-substituted alkyl, dialkylamino-substituted acylaminoalkyl; or amino acid side chains selected from arginine, asparagine, glutamine, S-methyl cysteine, methionine and corresponding sulfoxide and sulfone derivatives thereof, glycine, leucine, isoleucine, allo-isoleucine, tert-leucine, norleucine, phenylalanine, tyrosine, tryptophan, proline, alanine, ornithine, histidine, glutamine, valine, threonine, serine, aspartic acid, beta-cyanoalanine, and allothreonine;
R
7
and R
8
are independently H, alkyl, alkenyl, carbocyclic aryl, heteroaryl, or alkyl, alkenyl, carbocyclic aryl or heteroaryl substituted by 1-3 substituents selected from the group consisting of amino, hydroxy, mercapto, mono- or dialkylamino, mono- or diarylamino, alkylarylamino, diarylamino, mono- or diacylamino, alkoxy, alkenoxy, aryloxy, thioalkoxy, thioalkenoxy, thioalkynoxy, thioaryloxy, and heterocyclyl;
or R
2
and R
6
taken together with the atoms to which they are attached may form a heterocycle;
V is O, NH, S, SO, or SO
2
;
X is CO
2
R
5
, PO
3
H, SO
2
R
5
, SO
3
H, OPO
3
H, CO
2
H, or CON(R
4
)
2
;
W is CH or N;
Y is CO, SO
2
, or PO
2
;
Z is (CH
2
)
n′
, CHR
6
, or NR
7
;
n and n′ are independently 0-4;
m is 1-4;
p is 1-4;
q and q′ are independently 1-5; and
r is 0 or 1;
or pharmaceutically acceptable salts thereof.
Compounds of the invention, i.e. compounds of formula I and their pharmaceutically acceptable salts, are VLA-4 antagonists and useful to prevent, suppress, or inhibit cell adhesions. Thus, they are useful in VLA-4-mediated cell adhesion disease states, particularly inflammation and autoimmune diseases. They are particularly useful in surgery-induced inflammation, especially transplant surgery. The compounds of the invention may be used alone or in combination with other agents active in the prevention, suppression, or inhibition of cell adhesion.
Another embodiment of the invention is a pharmaceutical composition, particularly a composition for VLA-4 antagonism, comprising an effective amount of a compound of the invention, optionally together with a pharmaceutically acceptable carrier.
In another aspect, the present invention also provides compounds of the invention, i.e. compounds of formula I or pharmaceutically acceptable salts thereof, for use as pharmaceuticals, particularly in VLA-4 antagonism.
In a further aspect the invention provides a method of antagonizing VLA-4 in a mammal which comprises administering to a mammal, preferably man, in need of such treatment an effective amount of a compound of the invention.
In a yet further aspect, the invention provides the use of a compound of the invention for the preparation of a medicament for the treatment of a disease mediated by VLA-4.
Particular embodiments of the invention relate to compounds of formula I or pharmaceutically acceptable salts thereof wherein
(a) R
1
is aryl, particularly N-arylureido-substituted phenyl;
(b) R
4
is H, alkyl, alkenyl or aryl;
(c) W is CH;
(d) Y is CO;
(e) X is CO
2
H or CO
2
alkyl;
(f) Z is (CH
2
)
n′
or CHR
6
.
Preferred compounds of the invention are those of formula Ia
wherein
R
2
is C
1-4
alkyl-oxy-C
1-8
al

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