Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-24
2002-12-24
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S184000
Reexamination Certificate
active
06498155
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to TPO receptor ligands and their use as agonists of the TPO receptor.
BACKGROUND OF THE INVENTION
Megakaryocytes are bone marrow-derived cells, which are responsible for producing circulating blood platelets. Although comprising <0.25% of the bone marrow cells in most species, they have >10 times the volume of typical marrow cells. See Kuter et al.
Proc. Natl. Acad. Aci. USA
91: 11104-11108 (1994). Megakaryocytes undergo a process known as endomitosis whereby they replicate their nuclei but fail to undergo cell division and thereby give rise to polypoid cells. In response to a decreased platelet count, the endomitotic rate increases, higher ploidy megakaryocytes are formed, and the number of megakaryocytes may increase up to 3-fold. See Harker
J. Clin. Invest
. 47: 458-465 (1968). In contrast, in response to an elevated platelet count, the endomitotic rate decreases, lower ploidy megakaryocytes are formed, and the number of megakaryocytes may decrease by 50%.
The exact physiological feedback mechanism by which the mass of circulating platelets regulates the endomitotic rate and number of bone marrow megakaryocytes is not known. The circulating thrombopoietic factor involved in mediating this feedback loop is now thought to be thrombopoietin (TPO). More specifically, TPO has been shown to be the main humoral regulator in situations involving thrombocytopenia. See, e.g., Metcalf Nature 369:519-520 (1994). TPO has been shown in several studies to increase platelet counts, increase platelet size, and increase isotope incorporation into platelets of recipient animals. Specifically, TWO is thought to affect megakaryocytopoiesis in several ways: (1) it produces increases in megakaryocyte size and number; (2) it produces an increase in DNA content, in the form of polyploidy, in megakaryocytes; (3) it increases megakaryocyte endomitosis; (4) it produces increased maturation of megakaryocytes; and (5) it produces an increase in the percentage of precursor cells, in the form of small acetylcholinesterase-positive cells, in the bone marrow.
Because platelets (thrombocytes) are necessary for blood clotting and when their numbers are very low a patient is at risk of death from catastrophic hemorrhage, TPO has potential useful application in both the diagnosis and the treatment of various hematological disorders, for example, diseases primarily due to platelet defects. Ongoing clinical trials with TPO have indicated that TPO can be administered safely to patients. In addition, recent studies have provided a basis for the projection of efficacy of TPO therapy in the treatment of thrombocytopenia, and particularly thrombocytopenia resulting from chemotherapy, radiation therapy, or bone marrow transplantation as treatment for cancer or lymphoma. See e.g., McDonald (1992)
Am. J. Ped. Hematology/Oncology
14:8-21 (1992).
The gene encoding TPO has been cloned and characterized. See Kuter et al.,
Proc. Natl. Acad. Sci. USA
91: 11104-11108 (1994); Barley et al.,
Cell
77: 1117-1124 (1994); Kaushansky et al.,
Nature
369:568-571 (1994); Wendling et al.,
Nature
369:571-574 (1994); and Sauvage et al.,
Nature
369:533-538(1994). Thrombopoietin is a glycoprotein with two distinct regions separated by a potential Arg-Arg cleavage site. The amino-terminal region is highly conserved in man and mouse, and has some homology with erythropoietin and interferon-alpha and interferon-beta. The carboxy-terminal region shows wide species divergence.
The DNA sequences and encoded peptide sequences for human TPO receptor (TPO-R; also known as c-mpl) have been described. See, Vigon et al.
Proc. Natl. Acad. Sci. USA
89: 5640-5644 (1992). TPO-R is a member of the haematopoietin growth factor receptor family, a family characterized by a common structural design of the extracellular domain, including for conserved C residues in the N-terminal portion and a WSXWS motif close to the transmembrane region. See Bazan
Proc. Natl. Acad. Sci. USA
87: 6934-6938 (1990). Evidence that this receptor plays a functional role in hematopoiesis includes observations that its expression is restricted to spleen, bone marrow, or fetal liver in mice (see Souyri et al.
Cell
63: 1137-1147 (1990)) and to megakaryocytes, platelets, and CD34
+
cells in humans (see Methia et al.
Blood
82: 1395-1401 (1993)). Further evidence for TPO-R as a key regulator of megakaryopoiesis is the fact that exposure of CD34
+
cells to synthetic oligonucleotides antisense to TPO-R RNA significantly inhibits the appearance of megakaryocyte colonies without affecting erythroid or myeloid colony formation. Some workers postulate that the receptor functions as a homodimer, similar to the situation with the receptors for G-CSF and erythropoietin.
The slow recovery of platelet levels in patients suffering from thrombocytopenia is a serious problem, and has lent urgency to the search for a blood growth factor agonist able to accelerate platelet regeneration. It would be desirable to provide compounds which allow for the treatment of thrombocytopenia by acting as a TPO mimetic.
International Application PCT/GB92102334 (International Filing date Dec. 16, 1992; WO 93/12096, Published Jun. 24, 1993, hereinafter Bridger) discloses linked cyclic polyamines of Formula (I)
Z—R—A—R′—Y (I)
in which Z and Y are independently cyclic polyamine moieties having from 9 to 32 ring members and from 3 to 8 amine nitrogens in the ring spaced by 2 or more carbon atoms from each other;
A is an aromatic or heteroaromatic moiety, and
R and R′ are each a substituted or unsubstituted alkylene chain or heteroatom-containing chain which spaces the cyclic polyamines and the moiety A;
as well as acid addition salts and metal complexes thereof.
Bridger does not disclose or claim the compounds of Formula (I) as TPO mimetics or for the treatment of thrombocytopenia.
As disclosed herein it has unexpectedly been discovered that certain small organic molecules, preferably the linked cyclic polyamines of Bridger, are effective as agonist of the TPO receptor, they are potent TPO mimetics.
SUMMARY OF THE INVENTION
This invention relates to a method of treating thrombocytopenia, which comprises administering to a subject in need thereof an effective amount of a TPO mimetic compound of Formula (I).
The present invention also relates to the discovery that the compounds of Formula (I) are active as agonist of the TPO receptor.
Also included in the present invention are methods of co-administering the presently invented TPO mimetic compounds with further active ingredients.
This invention also relates to the discovery that certain non-peptide compounds are effective as TPO mimetics.
DETAILED DESCRIPTION OF THE INVENTION
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as though fully set forth.
The preparation of the compounds of Formula (I) and acid addition salts and metal complexes thereof and formulations thereof is disclosed in International Application PCT/GB92/02334 (International Filing date Dec. 16, 1992; WO 93/12096, Published Jun. 24, 1993, Bridger), the entire disclosure of which is hereby incorporated by reference. In Bridger metal complexes of the claimed linked cyclic polyamine compounds are disclosed as alternative methods for administration, and not disclosed as part of mechanism of activation as anti viral compounds.
By the phrase “non-peptide bifunctional ligand” as used herein is meant a ligand containing two positively-charged regions connected by a linker of 6 to 16 atoms, which is capable of activating the TPO receptor by binding to two non-adjacent sites.
By the term “treating” and derivatives thereof as used herein, is meant prophylatic or therapeutic therapy.
The treatment of thrombocytopenia, as described herein, is accomplished by enhancing the production of platelets.
By the term “co-administering” and derivatives thereof as used herein is meant either simultaneous administration or any man
Lamb Peter I.
Luengo Juan I.
Dustman Wayne J.
Henley III Raymond
Kinzig Charles M.
SmithKline Beecham Corporation
Venetianer Stephen
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