Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-22
2002-04-02
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S507000
Reexamination Certificate
active
06365619
ABSTRACT:
BACKGROUND OF THE INVENTION
Transplant-associated arteriosclerosis (a manifestation of chronic rejection), defined as the formation of concentric intimal thickening in blood vessels of a transplanted solid organ, remains a paramount obstacle to long term graft survival; despite the availability of current immunosuppressive therapies. Although the pathogenesis of this disease remains unclear, both clinical and laboratory studies indicate that the arteriosclerosis associated with transplantation of solid organs is a complex, multi-factorial, immune-mediated process in which both donor vessel wall cells and recipient mononuclear cells play a pivotal role.
Adhesion molecules are involved in the early events of chronic rejection including leukocyte attachment and transendothelial cell migration. 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, the extracellular matrix protein fibronectin (FN), and the vascular cell adhesion molecule-1 (VCAM-1), which is an immunoglobulin superfamily member mainly expressed on activated endothelium and antigen presenting cells. Anti-VLA-4 monoclonal antibodies (mAb's) inhibit VLA-4-dependent adhesive interactions both in vitro and in vivo.
Cellular adhesion molecules such as selectins, integrins, and the VCAM-1 immunoglobulin superfamily are considered to be central in T cell activation, recognition of alloantigens, leukocyte rolling, attachment, and transendothelial migration. The earliest histopathological change following allo-transplantation is increased mononuclear inflammatory cell adhesion to the vascular endothelium.
VCAM-1/VLA-4 interactions alone, or in combination with another pair of molecules (LFA-1 on T cells and ICAM-1 on activated endothelial cells) mediate lymphocyte adhesion and transmigration at the vascular endothelial surface, and possibly provide the stimulus for the development of accelerated arteriosclerosis. Upon transmigration, activated lymphocytes release cytokines, growth factors, and chemotactic agents within the vessel wall to stimulate proliferation and migration of smooth muscle cell (SMC) into the developing neointima.
The role of VCAM-1 and VLA-4 expression in chronic rejection is not well understood in part due to the lack of genetically manipulated mice (knock out of either alpha-4 integrin or VCAM-1 is lethal).
SUMMARY OF THE INVENTION
It has now been found that the concomitant administration of a VLA-4 antagonist of formula I and a VCAM-1 inhibitor of formula II is useful in treating transplant-associated arteriosclerosis.
DETAILED DESCRIPTION
Accordingly, the present invention utilizes 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
8
;
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.
The present invention also utilizes compounds of the formula II
wherein:
A is an &agr;-hydroxy-substituted butyric acid residue optionally &ggr;-substituted by R
6
, which is CN, —COOR
2
Criares Theodore J.
Lopez Gabriel
Novartis AG
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