Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-10-09
2002-10-15
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S277000, C514S340000, C514S342000, C514S357000, C546S269700, C546S271400, C546S272700, C546S276400, C546S280400, C546S283400, C546S329000, C546S339000
Reexamination Certificate
active
06465493
ABSTRACT:
This invention relates to pyridyl substituted triarylimidazoles which are inhibitors of the transforming growth factor, (“TGF”)-&bgr; signaling pathway, in particular, the phosphorylation of smad2 or smad3 by the type I or activin-like kinase (“ALK”)-5 receptor, methods for their preparation and their use in medicine, specifically in the treatment and prevention of a disease state mediated by this pathway.
TGF-&bgr;1 is the prototypic member of a family of cytokines including the TGF-&bgr;s, activins, inhibins, bone morphogenetic proteins and Müllerian-inhibiting substance, that signal through a family of single transmembrane serine/threonine kinase receptors. These receptors can be divided in two classes, the type I or activin like kinase (ALK) receptors and type II receptors. The ALK receptors are distinguished from the type II receptors in that the ALK receptors (a) lack the serine/threonine rich intracellular tail, (b) possess serine/threonine kinase domains that are very homologous between type I receptors, and (c) share a common sequence motif called the GS domain, consisting of a region rich in glycine and serine residues. The GS domain is at the amino terminal end of the intracellular kinase domain and is critical for activation by the type II receptor. Several studies have shown that TGF-&bgr; signaling requires both the ALK and type II receptors. Specifically, the type II receptor phosphorylates the GS domain of the type I receptor for TGF-&bgr;, ALK5, in the presence of TGF-&bgr;. The ALK5, in turn, phosphorylates the cytoplasmic proteins smad2 and smad3 at two carboxy terminal serines. Generally it is believed that in many species, the type II receptors regulate cell proliferation and the type I receptors regulate matrix production. Therefore, preferred compounds of this invention are selective in that they inhibit the type I receptor and thus matrix production, and not the type I receptor mediated proliferation.
Activation of the TGF-&bgr;1 axis and expansion of extracellular matrix are early and persistent contributors to the development and progression of chronic renal disease and vascular disease. Border W. A., Noble N. A.,
N. Engl. J. Med
., Nov. 10, 1994; 331(19):1286-92. Further, TGF-&bgr;1 plays a role in the formation of fibronectin and plasminogen activator inhibitor-1, components of sclerotic deposits, through the action of smad3 phosphorylation by the TGF-&bgr;1 receptor ALK5. Zhang Y., Feng X. H., Derynck R.,
Nature
, Aug. 27, 1998; 394(6696):909-13; Usui T., Takase M., Kaji Y., Suzuki K., Ishida K., Tsuru T., Miyata K., Kawabata M., Yamashita H.,
Invest. Ophthalmol. Vis. Sci
., October 1998; 39(11): 1981-9.
Progressive fibrosis in the kidney and cardiovascular system is a major cause of suffering and death and an important contributor to the cost of health care. TGF-&bgr;1 has been implicated in many renal fibrotic disorders. Border W. A., Noble N. A.,
N. Engl. J. Med
., Nov 10, 1994; 331(19):1286-92. TGF-&bgr;1 is elevated in acute and chronic glomerulonephritis, Yoshioka K., Takemura T., Murakami K., Okada M., Hino S., Miyamoto H., Maki S.,
Lab. Invest
., February 1993; 68(2):154-63, diabetic nephropathy, Yamamoto, T., Nakamura, T., Noble, N. A., Ruoslahti, E., Border, W. A., (1993)
PNAS
90:1814-1818, allograft rejection, HIV nephropathy and angiotensin-induced nephropathy, Border W. A., Noble N. A.,
N. Engl. J. Med
., Nov. 10, 1994; 331(19):1286-92. In these diseases the levels of TGF-&bgr;1 expression coincide with the production of extracellular matrix. Three lines of evidence suggest a causal relationship between TGF-&bgr;1 and the production of matrix. First, normal glomeruli, mesangial cells and non-renal cells can be induced to produce extracellular-matrix protein and inhibit protease activity by exogenous TGF-&bgr;1 in vitro. Second, neutralizing anti-bodies against TGF-&bgr;1 can prevent the accumulation of extracellular matrix in nephritic rats. Third, TGF-&bgr;1 transgenic mice or in vivo transfection of the TGF-&bgr;1 gene into normal rat kidneys resulted in the rapid development of glomerulosclerosis. Kopp J. B., Factor V. M., Mozes M., Nagy P., Sanderson N., Bottinger E. P., Klotman P. E., Thorgeirsson S. S.,
Lab Invest
, June 1996; 74(6):991-1003. Thus, inhibition of TGF-&bgr;1 activity is indicated as a therapeutic intervention in chronic renal disease.
TGF-&bgr;1 and its receptors are increased in injured blood vessels and are indicated in neointima formation following balloon angioplasty, Saltis J., Agrotis A., Bobik A.,
Clin Exp Pharmacol Physiol
, March 1996; 23(3):193-200. In addition TGF-&bgr;1 is a potent stimulator of smooth muscle cell (“SMC”) migration in vitro and migration of SMC in the arterial wall is a contributing factor in the pathogenesis of atherosclerosis and restenosis. Moreover, in multivariate analysis of the endothelial cell products against total cholesterol, TGF-&bgr; receptor ALK5 correlated with total cholesterol (P<0.001) Blann A. D., Wang J. M., Wilson P. B., Kumar S.,
Atherosclerosis
, February 1996; 120(1-2):221-6. Furthermore, SMC derived from human atherosclerotic lesions have an increased ALK5/TGF-&bgr; type II receptor ratio. Because TGF-&bgr;1 is over-expressed in fibroproliferative vascular lesions, receptor-variant cells would be allowed to grow in a slow, but uncontrolled fashion, while overproducing extracellular matrix components McCaffrey T. A., Consigli S., Du B., Falcone D. J., Sanborn T. A., Spokojny A. M., Bush H. L., Jr.,
J Clin Invest
, December 1995; 96(6):2667-75. TGF-&bgr;1 was immunolocalized to non-foamy macrophages in atherosclerotic lesions where active matrix synthesis occurs, suggesting that non-foamy macrophages may participate in modulating matrix gene expression in atherosclerotic remodeling via a TGF-&bgr;-dependent mechanism. Therefore, inhibiting the action of TGF-&bgr;1 on ALK5 is also indicated in atherosclerosis and restenosis.
TGF-&bgr; is also implicated in peritoneal adhesions Saed G. M., Zhang W., Chegini N., Holmdahl L., and Diamond M P.,
Wound Repair Regeneration
. 7(6):504-510, 1999 November-December. Therefore, inhibitors of ALK5 would be beneficial in preventing peritoneal and sub-dermal fibrotic adhesions following surgical procedures.
Surprisingly, it has now been discovered that a class of 2-pyridyl substituted triarylimidazoles of formula (I), function as potent and selective non-peptide inhibitors of ALK5 kinase and therefore, have utility in the treatment and prevention of various disease states mediated by ALK5 kinase mechanisms, such as chronic renal disease, acute renal disease, wound healing, arthritis, osteoporosis, kidney disease, congestive heart failure, ulcers, occular disorders, corneal wounds, diabetic nephropathy, impaired neurological function, Alzheimer's disease, trophic conditions, atherosclerosis, peritoneal and sub-dermal adhesion, any disease wherein fibrosis is a major component, including, but not limited to lung fibrosis and liver fibrosis, and restenosis.
According to the invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein R
1
is naphthyl, anthracenyl, or phenyl optionally substituted with one or more substituents selected from the group consisting of halo, C
1-6
alkoxy, C
1-6
alkylthio, C
1-6
alkyl, —O—(CH
2
)
n
—Ph, —S—(CH
2
)
n
—Ph, cyano, phenyl, and CO
2
R, wherein R is hydrogen or C
1-6
alkyl and n is 0, 1, 2 or 3; or R
1
is phenyl fused with an aromatic or non-aromatic cyclic ring of 5-7 members wherein said cyclic ring optionally contains up to two heteroatoms, independently selected from N, O and S;
R
2
is H, NH(CH
2
)
n
—Ph or NH—C
1-6
alkyl, wherein n is 0, 1, 2 or 3;
R
3
is CO
2
H, CONH
2
, CN, NO
2
, C
1-6
alkylthio, —SO
2
—C
1-6
alkyl, C
1-6
alkoxy, SONH
2
, CONHOH, NH
2
, CHO, CH
2
OH, CH
2
NH
2
, or CO
2
R, wherein R is hydrogen or C
1-6
alkyl; and
one of X
1
and X
2
is N or CR′, and the other is NR′ or CHR′ wherein R′ is hydrogen, OH, C
1-6
alkyl, or C
3-7
cycloalkyl; or when one of X
1
and X
2
is N or C
Burgess Joelle L.
Callahan James F.
Davis Zinna Northington
Kinzig Charles M.
Smithkline Beecham Corporation
Stein-Fernandez Nora
Venetianer Stephen A.
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