Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-03-11
2001-07-17
Rotman, Alan L. (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S205000, C514S208000, C546S212000, C546S213000
Reexamination Certificate
active
06262044
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 A, R
1
, R
2
, R
3
, R
4
, R
16
and R
17
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 (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 signals during different stages of cellular function (Fischer et al, Science 253:401-6 (1991); Flint et al., The 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).
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 (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)).
Low molecular weight phosphotyrosine-protein phosphatase (LMW-PTPase) shows very little sequence identity to the intracellular PTPases described above. However, this enzyme belongs to the PTPase family due to the following characteristics: (i) it possesses the PTPase active site motif: Cys-Xxx-Xxx-Xxx-Xxx-Xxx-Arg (Cirri et al.,
Eur. J. Biochem.
214: 647-657 (1993)); (ii) this Cys residue forms a phospho-intermediate during the catalytic reaction similar to the situation with ‘classical’ PTPases (Cirri et al., supra; Chiarugi et al.,
FEBS Lett.
310: 9-12 (1992)); (iii) the overall folding of the molecule shows a surprising degree of similarity to that of PTP1 B and Yersinia PTP (Su et al,
Nature
370: 575-578 (1994)).
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, PTPd, (11) PTP&sgr;; (III) PTPb, (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) PTPa,_PTPe. All receptor-type PTPases except Type IV contain two PTPase domains. Novel PTPases are continuously identified, and it is anticipated that more than 500 different species will be found in the human genome, i.e. close to the predicted size of the protein tyrosine kinase superfamily (Hanks and Hunter,
FASEB J.
9: 576-596 (1995)).
PTPases are the biological counterparts to protein tyrosine kinases (PTKs). 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 now emerges. Several studies have shown that some PTPases may actually act as positive mediators of cellular signalling. As an example, the SH2 domain-containing PTP1D 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 PTP1C seems to act as a negative regulator of growth factor-stimulated proliferation (Bignon and Siminovitch,
Clin. lmmunol. Immunopathol.
73: 168-179 (1994)). Another example of PTPases as positive regulators has
Andersen Henrik Sune
Axe Frank Urban
Bakir Farid
Branner Sven
Ge Yu
Desai Rita
Novo Nordisk A S
Rotman Alan L.
Rozek, Esq. Carol E.
Zelson, Esq. Steve T.
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