Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-11
2002-06-25
Dentz, Bernard (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S229800, C514S302000, C540S476000, C540S593000, C546S114000, C546S115000, C546S116000, C548S453000
Reexamination Certificate
active
06410556
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel compounds, to methods for their preparation, to compositions comprising the compounds, to the use of these compounds as medicaments and their use in therapy, where such compounds of Formula 1 are pharmacologically useful inhibitors of Protein Tyrosine Phosphatases (PTPases) such as PTP1B, CD45, SHP-1, SHP-2, PTP&agr;, LAR and HePTP or the like,
wherein n, m, X, Y, R
1
, R
2
, R
3
, R
4
, R
5
and R
6
are defined more fully below. It has been found that PTPases plays a major role in the intracellular modulation and regulation of fundamental cellular signaling mechanisms involved in metabolism, growth, proliferation and differentiation (Hunter, Phil.
Trans. R. Soc. Lond
. B 353: 583-605 (1998); Chan et al.,
Annu. Rev. Immunol.
12: 555-592 (1994); Zhang,
Curr. Top. Cell. Reg.
35: 21-68 (1997); Matozaki and Kasuga,
Cell. Signal.
8: 113-19 (1996); Flint et al.,
The EMBO J.
12:1937-46 (1993); Fischer et al,
Science
253:401-6 (1991)). Overexpression or altered activity of tyrosine phosphatases can also contribute to the symptoms and progression of various diseases (Wiener, et al.,
J. Natl. cancer Inst.
86:372-8 (1994); Hunter and Cooper,
Ann. Rev. Biochem,
54:897-930 (1985)). Furthermore, there is increasing evidence which suggests that inhibition of these PTPases may help treat certain types of diseases such as diabetes type I and II , autoimmune disease, acute and chronic inflammation, osteoporosis and various forms of cancer.
BACKGROUND OF THE INVENTION
Protein phosphorylation is now well recognized as an important mechanism utilized by cells to transduce and regulate signals during different stages of cellular function (Hunter, Phil.
Trans. R. Soc. Lond. B
353: 583-605 (1998); Chan et al.,
Annu. Rev. Immunol.
12: 555-592 (1994); Zhang,
Curr. Top. Cell. Reg.
35: 21-68 (1997); Matozaki and Kasuga,
Cell. Signal.
8: 113-19 (1996); Fischer et al,
Science
253:401-6 (1991); Flint et al.,
EMBO J.
12:1937-46 (1993)). There are at least two major classes of phosphatases: (1) those that dephosphorylate proteins (or peptides) that contain a phosphate group(s) on a serine or threonine moiety (termed Ser/Thr phosphatases) and (2) those that remove a phosphate group(s) from the amino acid tyrosine (termed protein tyrosine phosphatases or PTPases or PTPs).
The PTPases are a family of enzymes that can be classified into two groups: a) intracellular or nontransmembrane PTPases and b) receptor-type or transmembrane PTPases.
Intracellular PTPases
Most known intracellular type PTPases contain a single conserved catalytic phosphatase domain consisting of 220-240 amino acid residues. The regions outside the PTPase domains are believed to play important roles in localizing the intracellular PTPases subcellularly (Mauro, L. J. and Dixon, J. E.
TIBS
19: 151-155 (1994)). The first intracellular PTPase to be purified and characterized was PTP1B, which was isolated from human placenta (Tonks et al.,
J. Biol. Chem.
263: 6722-6730 (1988)). Shortly after, PTP1B was cloned (Charbonneau et al.,
Proc. Natl. Acad. Sci. USA
86: 5252-5256 (1989); Chernoff et al.,
Proc. Natl. Acad. Sci. USA
87: 2735-2789 (1989)). Other examples of intracellular PTPases include (1) T-cell PTPase/TC-PTP (Cool et al.
Proc. Natl. Acad. Sci. USA
86: 5257-5261 (1989)), (2) rat brain PTPase (Guan et al.,
Proc. Natl. Acad. Sci. USA
87:1501-1502 (1990)), (3) neuronal phosphatase STEP (Lombroso et al.,
Proc. Natl. Acad. Sci. USA
88: 7242-7246 (1991)), (4) ezrin-domain containing PTPases: PTPMEG1 (Guet al.,
Proc. Natl. Acad. Sci. USA
88: 5867-57871 (1991)), PTPH1 (Yang and Tonks,
Proc. Natl. Acad. Sci. USA
88: 5949-5953 (1991)), PTPD1 and PTPD2 (Møller et al.,
Proc. Natl. Acad. Sci. USA
91: 7477-7481 (1994)), FAP-1/BAS (Sato et al.,
Science
268: 411-415 (1995); Banville et al.,
J. Biol. Chem.
269: 22320-22327 (1994); Maekawa et al.,
FEBS Letters
337: 200-206 (1994)), and SH2 domain containing PTPases: PTP1C/SH-PTP1/SHP-1 (Plutzky et al.,
Proc. Natl. Acad. Sci. USA
89: 1123-1127 (1992); Shen et al.,
Nature Lond.
352: 736-739 (1991)) and PTP1D/Syp/SH-PTP2/SHP-2 (Vogel et al.,
Science
259: 1611-1614 (1993); Feng et al.,
Science
259: 1607-1611 (1993); Bastein et al.,
Biochem. Biophys. Res. Comm.
196: 124-133 (1993)).
Receptor-type PTPases consist of a) a putative ligand-binding extracellular domain, b) a transmembrane segment, and c) an intracellular catalytic region. The structures and sizes of the putative ligand-binding extracellular domains of receptor-type PTPases are quite divergent. In contrast, the intracellular catalytic regions of receptor-type PTPases are very homologous to each other and to the intracellular PTPases. Most receptor-type PTPases have two tandemly duplicated catalytic PTPase domains.
The first receptor-type PTPases to be identified were (1) CD45/LCA (Ralph, S. J.,
EMBO J.
6: 1251-1257 (1987)) and (2) LAR (Streuli et al.,
J. Exp. Med.
168: 1523-1530 (1988)) that were recognized to belong to this class of enzymes based on homology to PTP1B (Charbonneau et al.,
Proc. Natl. Acad. Sci. USA
86: 5252-5256 (1989)). CD45 is a family of high molecular weight glycoproteins and is one of the most abundant leukocyte cell surface glycoproteins and appears to be exclusively expressed upon cells of the hematopoietic system (Trowbridge and Thomas,
Ann. Rev. Immunol.
12: 85-116 (1994)).
The identification of CD45 and LAR as members of the PTPase family was quickly followed by identification and cloning of several different members of the receptor-type PTPase group. Thus, 5 different PTPases, (3) PTP&agr;, (4) PTP&bgr;, (5) PTP&dgr;, (6) PTP&egr;, and (7) PTP&zgr;, were identified in one early study (Krueger et al.,
EMBO J.
9: 3241-3252 (1990)). Other examples of receptor-type PTPases include (8) PTP&ggr; (Barnea et al.,
Mol. Cell. Biol.
13: 1497-1506 (1995)) which, like PTP&zgr; (Krueger and Saito,
Proc. Natl. Acad. Sci. USA
89: 7417-7421 (1992)) contains a carbonic anhydrase-like domain in the extracellular region, (9) PTP&mgr; (Gebbink et al.,
FEBS Letters
290: 123-130 (1991)), (10) PTP&kgr; (Jiang et al.,
Mol. Cell. Biol.
13: 2942-2951 (1993)). Based on structural differences the receptor-type PTPases may be classified into subtypes (Fischer et al.,
Science
253: 401-406 (1991)): (I) CD45; (II) LAR, PTP&dgr;, (11) PTP&sgr;; (III) PTP, (12) SAP-1 (Matozaki et al.,
J. Biol. Chem.
269: 2075-2081 (1994)), (13) PTP-U2/GLEPP1 (Seimiya et al.,
Oncogene
10: 1731-1738 (1995); Thomas et al.,
J. Biol. Chem.
269: 19953-19962 (1994)), and (14) DEP-1; (IV) PTP&agr;, PTP&egr;. All receptor-type PTPases except Type III contain two PTPase domains. Novel PTPases are continuously identified. In the early days of PTPase research, it was believed that the number of PTPs would match that of protein tyrosine kinases (PTKs) (Hanks and Hunter,
FASEB J.
9: 576-596 (1995)). However, although about 90 open reading frames in
C. elegans
contain the hallmark motif of PTPs, it now seems that the estimate of ‘classical’ PTPases must be downsized, perhaps to between 100 and 200 in humans.
PTPases are the biological counterparts to protein tyrosine kinases Therefore, one important function of PTPases is to control, down-regulate, the activity of PTKs. However, a more complex picture of the function of PTPases has emerged. Thus, several studies have shown that some PTPases may actually act as positive mediators of cellular signaling. As an example, the SH2 domain-containing SHP-2 seems to act as a positive mediator in insulin-stimulated Ras activation (Noguchi et al.,
Mol. Cell. Biol.
14: 6674-6682 (1994)) and of growth factor-induced mitogenic signal transduction (Xiao et al.,
J. Biol. Chem.
269: 21244-21248 (1994)), whereas the homologous SHP-1 seems to act as a negative regulator of growth factor-stimulated proliferation (Bignon and Siminovitch,
Clin.Immunol. Immunopathol.
73: 168-179 (1994)). Another example of PTPases as positive regulators has been provided by studies designed to define the activation of the
Andersen Henrik Sune
Axe Frank Urban
Ge Yu
Hansen Thomas Kruse
Holsworth Daniel Dale
Dentz Bernard
Green, Esq. Reza
Novo Nordisk A S
Waibel, Esq. Peter J.
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