Methods for solid phase combinatorial synthesis of integrin...

Details Methods for solid phase combinatorial synthesis of integrin... Methods for solid phase combinatorial synthesis of integrin...

2000-04-13

2003-07-01

Celsa, Bennett (Department: 1639)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving antigen-antibody binding, specific binding protein...

C435S004000, C435S091500, C435S091500, C435S091500, C514S252120, C514S253010, C530S333000, C530S334000, C530S335000, C544S295000, C544S358000, C544S340000, C544S400000

Reexamination Certificate

active

06586187

ABSTRACT:

FIELD OF INVENTION
The present invention relates to integrin inhibitors useful for their ability to antagonize/block biological processes mediated by &agr;v&bgr;3 and related integrin receptors, to combinatorial and solid phase methods for preparing libraries of compounds, and utilization of libraries of the compounds for drug discovery. The present invention further provides pharmaceutical compositions for administration to mammals, including man, and methods for their use in the treatment of various disorders including, but not limited to, cancer (tumor metathesis, tumorgenesis/tumor growth), angiogenesis (as in cancer, diabetic retinopathy, rheumatoid arthritis), restenosis (following balloon angioplasty or stent implantation), inflammation (as in rheumatoid arthritis, psoriasis), bone diseases (osteopenia induced by bone metastases, immobilization and glucocortocoid treatment, periodontal disease, hyperparathyroidism and rheumatoid arthritis), and as antiviral agents.
BACKGROUND OF INVENTION
The solid phase synthesis of non-peptidic small organic molecules is a rapidly evolving area of research with applications in the preparation of combinatorial libraries. While the solid phase synthesis of peptides is well established, the solid phase synthesis of non-peptidic small organic molecules is still evolving (Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron 1996, 52, 4527-4554). In particular, methods for solid phase synthesis of molecules of biological significance is of importance to drug discovery and is an active area of research.
The integrin &agr;
v
&bgr;
3
has been shown to mediate the invasion of cancerous melanoma cells into healthy tissue and to protect these cells against natural cell death cycle (apoptosis). Vitronectin receptor(&agr;
v
&bgr;
3
) antagonists have been shown to inhibit the growth of various solid tumors of human origin. More recently, &agr;
v
&bgr;
3
has been shown to be involved in liver metastasis. Although angiogenesis is an important and natural process in growth and wound healing, it is now appreciated that a variety of clinically relevant conditions are pathologically related to these processes, and that the integrin &agr;
v
&bgr;
3
is involved. For example, &agr;
v
&bgr;
3
was shown to be expressed on human wound tissue but not on normal skin and is preferentially expressed on angiogenic blood vessels, such as those feeding a growing/invading tumor. It has also been shown that antagonists of &agr;
v
&bgr;
3
promote tumor regression by inducing apoptosis of the tumor cells. This process of neovascularization (new blood vessel growth, angiogenesis), which is critical for tumor growth and metastasis, is also an important event in occular tissue, leading to diabetic retinopathy, glaucoma and blindness and in joints, promoting rheumatoid arthritis.
&agr;
v
&bgr;
3
has been shown to play a pivotal role in the proliferation and migration of smooth muscle and vascular endothetial cells, a pathological process leading to restenosis after balloon angioplastly (Choi et al., J. Vasc. Surgery, 1994, 19, 125-134; Matsumo et al., Circulation, 1994, 90, 2203-2206). At least one type of virus (adenovirus) has been shown to utilize (&agr;
v
&bgr;
3
for entering host cells (White et al., Current Biology, 1993, 596-599).
Various bone diseases involve bone resorption-the dissolution of bone matter, which is mediated by only one known class of cells, the osteoclasts. When activated for resorption, these motile cells initially bind to bone, a process well known to be mediated by asps (Davies et al., J. Cell. Biol., 1989, 109, 1817-1826; Helfrich et al., J Bone Mineral Res., 1992, 7, 335-343). It is also well known that blockade of &agr;
v
&bgr;
3
with antibodies or RGD containing peptides block osteoclast cell adhesion and bone resorption in vitro (Horton et al., Exp. Cell Res. 1991, 195, 368-375) and that echistatin, an RGD containing protein, inhibits bone resorption in vivo (Fisher et al., Endocrinology, 1993, 132, 1411-1413). More recently, an RGD peptidomimetic has likewise been shown to inhibit osteoclats in vitro and, by i.v. administration prevents osteoporosis (Engleman et al., J. Clin. Invest., 1997, 99, 2284-2292). Numerous patents/applications have claimed various non-peptide &agr;
v
&bgr;
3
inhibitors for some or all of the above applications (e.g.WO 95/32710, WO 97/08145, WO 97/33887, U.S. Pat. No. 5,681,820).
Combinatorial chemistry is becoming an important tool for drug discovery and lead optimization (Borman, S. Chemical and Engineering News 1997, 75 (8), 43-63). A combinatorial synthesis requires that at least two components of the product molecules be independently variable, so that all of the combinations of these components can be prepared. A synthesis with three independently variable components is preferable since greater diversity in structure can be produced in the resultant library. Thus to prepare a combinatorial library of integrin inhibitors with a high degree of potential diversity and wide utility for drug discovery using solid phase techniques, it is important to identify a synthesis in which three components can be independently varied.
Most of the reported integrin inhibitors are RGD mimics and they use a &bgr;-amino acid like substituted 2,3-diaminopropionic acid as the carboxylic acid terminus. While a cyclic or acyclic guanidino moiety is preferred for the basic end of the molecule, substituted ureas and amidines are used as well. The central scaffold, connecting these two pieces, itself can be varied widely. By developing a convenient route to appropriately protected fragments and a mild solid phase synthesis that incorporates all the three components in an independent fashion, it is possible to prepare combinatorial libraries of this important class of integrin inhibitors.
A solid-phase synthesis of integrin antagonist has been reported recently (Corbett, J. W.; Graciani, N. R.; Mousa, S. A.; DeGrado, W. F. Bioorganic & Med Chem Lett. 1997, 7, 1371-1376). However, this synthesis on solid phase does not provide a means of varying the substitutions on the &bgr;-amino acid of the carboxy terminus and uses the commercially available &agr;-N-CBZ-diaminopropionic acid as the only fragment. Hence, a combinatorial library synthesized using this method has limited utility in the drug discovery process lacking structure-activity data for all the regions of the molecule that can be independently varied. It is important to optimize this region of the inhibitors since the lipophilic substitutents in this region and the linkers used to connect these substituents have a significant effect on the activity of this class of molecules.
Multiple compounds can be generated simultaneously by solid phase synthesis. The solid phase synthesis detailed in the present invention for the simultaneous generation of a library of integrin inhibitors where all three components can be varied is not known. The preparation of libraries of compounds of the present invention is useful because it provides rapid structural variation and structure-activity information.
BRIEF DESCRIPTION OF INVENTION
Accordingly, the present invention discloses a solid phase synthesis process for producing compounds represented in formula (I):
wherein:
R1 and R2 independently are alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, cycloalkyl of 3-12 carbon atoms, aryl, aralkyl of 6 to 10 carbon atoms, heterocycloalkyl of 5-10 members consisting of carbon atoms and from 1 to 3 heteroatoms selected from N, S and O;
R3 is H, alkyl of 1-6 carbon atoms, aralkoxy of 1-6 carbon atoms;
X is NHCOO, NHCO, NHCONH, NHSO
2
;
Y is CH
2
, NH;
Z is CH, N, S
m is 0-4; and
n is 0-3; or pharmaceutical salts thereof.
In some aspects of the invention G may preferably be pyrimidinyl, guanidine, pyridyl-urea, benzyl-urea, azepinyl, imidazolinyl or tetrahydropyrimidinyl.
In other aspects of the invention R1 may be methyl, ethyl, n-propyl, i-propyl, allyl, homoallyl, propargyl, pentyl, n-hexyl, octyl, neopentyl, trichloroethyl, n-butyl, i-butyl, butyn

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