Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-29
2002-10-15
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S141000, C546S290000, C546S295000
Reexamination Certificate
active
06465495
ABSTRACT:
BACKGROUND OF THE INVENTION
Over the years, mimetics have become immensely important for both organic and medicinal chemists, as well as the pharmaceutical industry due to the multitude of biological active peptides discovered and characterized. For example, peptidomimetics are currently exploited to overcome problems associated with their parent peptides. These improvements include increased selectivity, oral bioavailability and prolonging the activity by hindering enzymatic degradation within the organism.
Cellular signal-transduction pathways that are initiated by transmembrane receptors associating with cytoplasmic protein kinases rely on two small protein domains containing sequences of 50-100 amino acids each. These sequences, referred to as Src homology 2 (SH2) and Src homology 3 (SH3) domains, can fold into modules which interact independently of their surrounding sequences. Because SH2 and SH3 domains are involved in protein-protein interactions in the signal transduction pathway, they represent potential targets for therapeutic drugs. SH2 domains are phosphotyrosine-binding modules found in a variety of important signal-transducing molecules such as nonreceptor tyrosine kinases, phosphatases, and regulatory adapter proteins. Inhibitors that block SH2 domain binding have potential utility in a wide variety of therapeutic areas including metabolic diseases, cancer, inflammation and allergies (Plummer, M. S., el al.
Drug Design and Discovery,
1996, 13, 75). The high affinity IgE receptor, Fc&egr;RI, and associated tyrosine kinases and phosphatase PTP-1C are currently the subject of research (Cambier, J. C., et al.
Annu. Rev. Immunol.,
1994, 12, 457). Aggregation of this receptor by antigen-antibody complexes leads to the activation of Lyn and Syk with rapid phosphorylation of tyrosine residues in the &bgr;- and &ggr;-chain cytoplasmic ITAM (immunoreceptor tyrosine-based activation motif) regions of the receptor. Association of the SH2 domain of syk with the phosphorylated &ggr;-chain of Fc&egr;RI in basophils and mast cells leads to downstream activation signals and the allergic response (Kimura, T., et al.,
J. Biol. Chem.,
1996, 271, 27962). The nature of the interaction between SH2 and SH3 domains and proteins has also been the subject of recent study. The three-dimensional structure of SH2 and SH3/peptide complexes have been extensively investigated. These studies revealed that SH2 and SH3 domains interact with protein ligands via hydrophobic contacts on the surface of the domain and protein. These domains have preferences for certain sequences of amino acids, as determined by screening against peptide combinatorial libraries. The protein ligands form a polyproline type II (PPII) left-handed &agr;-helix containing a consensus sequence that can be generalized as XPpXP, where X is an aliphatic amino acid and p is preferably proline to maintain the helix.
All reported naturally-occurring SH2 and SH13 ligands are peptides, although certain non-natural SH2 and SH13 ligands have been described. A variety of mimetics have been described, however, no peptidomimetic has been reported to modulate activity of SH2 or SH3 domains. In one study, a biased combinatorial library was constructed by functionalizing the N-terminus of a pentapeptide with various non-peptide elements, and the constructs were assayed for binding with Src SH3 domain. The non-peptidic moieties appeared to interact with the specificity pocket of Src SH3 domain, lowering the K
d
almost 1000-fold from the parent pentapeptide (>1000 mM to 3.4 mM). However, to date, few if any non-peptidic ligands binding in the hydrophobic pockets of SH3 domains have been discovered.
SUMMARY OF THE INVENTION
The present invention is based, at least in part, on the discovery that certain pyridone-based phosphotyrosine mimetics, described infra, can be used to inhibit those disease states associated with protein-protein interactions mediated by a SH2 or a SH3 domain or tyrosine phosphatase. Examples of such disease states include AIDS, an allergy, asthma, anemia, an autoimmune disease, breast cancer, cancer, CML, ALL, erythroleukemias, inflammatory diseases, pre-B-cell leukemia, myelodysplastic syndrome, and osteoporosis. Compositions and methods of the invention include enantiomerically or diastereomerically pure pyridones which, optionally, include amino acid or peptidomimetic residues.
The present invention pertains to compounds represented by the formula (Formula I):
in which
X and Y, each independently, are either CH or N;
Q is either C(O) or forms a single bond between N and X;
R
1
is CHZ
1
Z
2
, wherein Z
1
and Z
2
are each independently, a hydrogen atom, COOH, PO
3
H
2
, or SO
3
H, provided that both Z
1
and Z
2
are not both hydrogen atoms, or CH(OH)Z
1
or CHFZ
1
, provided Z
1
is not a hydrogen atom; and
R
2
is a substituted or unsubstituted alkyl, aryl, or alkylaryl moiety or together with X or Y or both X and Y form a substituted or unsubstituted heterocyclic or carbocyclic ring; or a salt or ester thereof Preferably, the salt or ester is a pharmaceutically acceptable salt or ester.
The present invention also pertains to methods for inhibiting a protein-protein interaction mediated by a SH2 domain, a SH3 domain or a tyrosine phosphatase. The method includes contacting the SH2 domain SH3 domain, or the tyrosine phosphatase with a compound represented by Formula I as described above and infra
such that a protein-protein interaction mediated by the SH2 domain, the SH3 domain or tyrosine phosphatase is inhibited.
The invention further pertains to pharmaceutical compositions for inhibiting a protein-protein interaction mediated by a SH2 domain, a SH3 domain or a tyrosine phosphatase in a mammal. The pharmaceutical composition includes a therapeutically effective amount of a compound represented by Formula I as described above and infra
and a pharmaceutically acceptable carrier.
The present invention is drawn to packaged pharmaceutical composition for inhibiting a protein-protein interaction mediated by a SH2 domain, a SH3 domain or tyrosine phophatase in a mammal. The packaged pharmaceutical composition includes a container holding a therapeutically effective amount of at least one compound represented by Formula I as described above and infra
and instructions for using the compound for treating the protein-protein interaction mediated by the SH2 domain, the SH3 domain or tyrosine phosphatase in a mammal.
The present invention also pertains to methods for the preparation of
which includes treating
with an alkyl, aryl or alkylaryl alkylating reagent in the presence of a palladium catalyst, to provide
wherein L is a leaving group and wherein X, Y, R
1
and R
2
are as described above and infra. A preferred leaving group is a triflate and a preferred palladium catalyst is Pd(PPh
3
)
4
.
DETAILED DESCRIPTION
The features and other details of the invention will now be more particularly described and pointed out in the claims. It will be understood that the particular embodiments of the invention are shown by way of illustration and not as limitations of the invention. The principle features of this invention can be employed in various embodiments without departing from the scope of the invention.
The present invention is based, at least in part, on the discovery that certain pyridone-based phosphotyrosine mimetics, described infra, can be used to inhibit those disease states associated with protein-protein interactions mediated by an SH2 or an SH3 domain. Examples of such disease states include AIDS, an allergy, asthma, anemia, an autoimmune disease, breast cancer, cancer, CML, ALL, erythroleukemias, inflammatory diseases, pre-B-cell leukemia, myelodysplastic syndrome, and osteoporosis. Compositions and methods of the invention include enantiomerically or diastereomerically pure pyridones which, optionally, include amino acid or peptidomimetic residues.
The present invention is drawn to compounds represented by the formula (Formula I):
in which
X and Y, each independently, are either CH or N;
Q is eithe
Castelhano Arlindo L.
Fu Jian-Min
Balasubramanian Venkataraman
Cooper & Dunham LLP
OSI Pharmaceuticals, Inc.
Shah Mukund J.
White John P.
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