Compounds

Details Compounds Compounds

2001-09-26

2002-12-24

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S450000

Reexamination Certificate

active

06498182

ABSTRACT:

TECHNICAL FIELD
The present invention is directed to novel compounds, to a process for their preparation, their use and pharmaceutical compositions comprising said novel compounds. These novel compounds are useful in therapy, particularly for the treatment of type 2 diabetes.
BACKGROUND
Phosphorylation on serine, threonine and tyrosine amino acid residues in downstream proteins forms the major output from growth factor and cytokine receptors, from which a cellular response is built. A large number of growth factor and cytokine-regulated protein tyrosine kinases (PTKs) have been identified which can be integral parts of receptor proteins or cytosolic molecules (Al-Obeidi, FA, Wu, JJ & Lam, KS, Biopolym. Pept. Sci. Sect. 47, 197-223). These serve to phosphorylate proteins on tyrosine residues within specific primary amino acid sequences which, when phosphorylated, act as docking points for proteins that contain SH2 domains. It is the docking of proteins to phosphorylated tyrosine residues that contributes to the activation of such proteins and the establishment of a signal transduction cascade.
The overall output from signal transduction cascades is derived from the balance between phosphorylation and dephosphorylation of proteins. Phosphotyrosines are returned to their free acid form by the action of protein tyrosine phosphatases (PTPs) (Zhang, Z Y (1998) Crit. Rev. Biochem. Mol. Biol., 33, 1-52). Whilst a large number of PTKs has been identified (Hunter, T (1994) Sem. Cell Biol. 5, 367-376), the number of PTPs identified to date is decidedly smaller (van Huijsduijnen, R H (1998) Gene 225, 1-8). Despite the smaller number of enzymes in the PTP family available for investigation, a detailed understanding of the roles they play in signal transduction and disease has not been forthcoming. This is due in part to the lack of small molecule inhibitor molecules which are specific for members of the PTP family and which are permeable to the cell membrane and can thus be used in cell-based experiments. Furthermore, whilst experiments in transgenic animals can be and have been performed in which individual PTPs can be ablated, the effects of the loss of function of a specific enzyme may be masked by compensation by other members of the PTP family. Thus, the availability of small molecule inhibitors of PTPs would be very useful to the study of this important family of enzymes.
A role for the PTP family of proteins in ontogeny and disease is now becoming clearer (Li, L & Dixon, J E (2000) Sem. Immunol. 12, 75-84). Thus, experiments with gene knockouts in transgenic animals has revealed that the motheaten phenotype of mice in which cells of the haematopoietic lineage undergo hyper-proliferation is due to the loss of normal SHPTP1 function (Schultz, L D, Schweitzer, P A, Rajan, T V, Yi, T & Ihle, J N (1993) Cell 73, 1445-1454). Loss of function in the receptor-like subfamily of PTPs leads to conditions such as heightened and reduced sensitivity to insulin (Ren, J-M, Li, P-M, Zhang, W-R, Sweet, L J, Cline, G, Shulman, G I, Livingston, J N & Goldstein, B J (1998) Diabetes 47, 493-497), stunted growth and neurological disruption (Elchelby, M, Wagner, J, Kennedy, T E, Lanctot, C, Michaliszyn, E, Itie, A, Drouin, J & Tremblay, M L (1999) Nature Genet. 21, 330-333) and blockages in T cell maturation (Kishihara, K, Penninger, J, Wallaca, V A, Kundig, T M, Kawai, K, Wakeham, A, Timms, E, Pfeffer K, Ohashi, P S & Thomas P L (1993) Cell 74, 143-156).
The recent descriptions of mice in which the PTP PTP1B had been disrupted revealed that loss of function of this enzyme leads to enhanced insulin sensitivity and resistance to the development of obesity, thus revealing a therapeutic need for the development of specific PTP inhibitors (Elchelby, M, Payette, P, Michaliszyn, E, Cromlish, W, Collins, S, Loy, A L, Normandin, D, Cheng, A, Himms.Hagen, J, Chan, C C, Ramachandran, C, Gresser, M J, Tremblay, M L & Kennedy, B P (1999) Science 283, 1544-1548; Klaman, L D, Boss, O, Peroni, O D, Kim, J K, Martino, J L, Zablotny, J M, Moghal, N, Lubkin, M, Kim, Y-B, Sharpe, A H, Stricker-Krongrad, A, Shulman, G I, Neel, B G & Kahn, B B (2000) Mol. Cell. Biol. 20, 5479-5489). The mechanism of insulin action depends critically upon the phosphorylation of tyrosine residues in several proteins in the insulin signaling cascade. PTPs that dephosphorylate these proteins are important negative regulators of insulin action. Therefore, the use of specific PTP inhibitors may therapeutically enhance insulin action.
The anabolic effects of insulin are triggered through the activation of a variety of signal transduction cascades which lie downstream of the insulin receptor (Gustafson, T. A., Moodie, S A & Lavan, B E (1999) Rev. Physiol. Biochem. Pharmacol. 137, 71-190). The varieties of signals that are activated by insulin are thought to contribute to the range of effects that insulin controls. However, each pathway is activated by a common series of biochemical reactions proximal to the insulin receptor. Thus, the insulin receptor undergoes autophosphorylation on tyrosine residues when activated by insulin, and also phosphorylates other proteins, in particular, the insulin receptor substrate proteins (IRSs). It has now become widely accepted that the resistance to insulin that is a feature of type 2 diabetes results in part from dysfunctions in signal transduction activated by the insulin receptor, in particular in steps early in the signaling cascades which are common to different pathways (Virkamäki, A, Ueki, K & Kahn, R C (1999) J. Clin. Invest 103, 931-943; Kellerer, M, Lammers, R & Häring, H-U (1999) Exp. Clin. Endocrinol. Diabetes 107, 97-106).
The signals that emanate from the insulin receptor are switched off by the returning of the insulin receptor and other components of the signal transduction cascades to their basal, non-active states. For the insulin receptor and the IRS proteins, this is achieved by dephosphorylation of phosphotyrosine residues. It is now becoming clear that different PTPs may regulate the insulin receptor in different tissues, but the number of candidate enzymes which do this is small (Wälchi, S., Curchod, M-L., Pescini Gobert, R., Arkinstall, S. & Hooft van Huijsduijnen, R. (2000) J. Biol. Chem. 275, 9792-9796). Thus, protein tyrosine phosphatase 1B (PTP1B) appears to be the major negative regulator of the insulin receptor in muscle and liver tissues (see for example Elechelby, M, Payette, P, Michalszyn, E, Cromlish, W, Collins, S, Loy, A L, Normandin, D, Cheng, A, Himms-Hagen, J, Chan, C—C, Ramachandran, C, Gresser, M J, Tremblay, M & Kennedy, B P (1999) Science, 283, 1544-1548; Goldstein, B J, Bittner-Kowalczyk, A, White, M F & Harbeck, M (2000) J. Biol. Chem. 275, 4283-4289). By contrast, PTP alpha may play a more dominant role in regulating the insulin receptor in adipose tissue (Calera, M R, Vallega, G & Pilch, P F (2000) J. Biol. Chem. 275 6308-6312).
The development of type 2 diabetes is characterised by a protracted period of insulin resistance. In human subjects who are obese and insulin resistant, PTP protein concentrations are increased, which has led to the idea that elevations in the proteins contributes to the cause of the diabetic state (Ahmad, F, Azevedo, J L, Cortright, R, Dohm, G L & Goldstein, B J (1997) J. Clin. Invest. 100 449-458). The two most significantly elevated are PTP1B and LAR. Considering that loss of LAR activity is associated with insulin resistance and diabetes (Ren, J-M, Li, P-M, Zhang, W-R, Sweet, L J, Cline, G, Shulman, G I, Livingston, J N & Goldstein, B J (1998) Diabetes 47 493-497), these data support the concept that PTP1B is a major contributor to the insulin resistant state and that pharmacological inhibition of its activity may go some way towards pharmaceutically alleviating the condition. Indeed, the recent reports of the knockout mouse in which PTP1B has been ablated confirm that loss of PTP1B activity leads to enhancement of the metabolic effects of insulin (Elechelby, M, Payette, P, Michalszyn, E, Cromlish, W, Collins, S, Loy, AL, Normandin, D, Chen

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