Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-10-18
2004-08-03
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S278000, C544S280000
Reexamination Certificate
active
06770652
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to pyrimidine compounds and pharmaceutically acceptable salts, solvates and prodrugs thereof. The present compounds have been found useful as antitumor and antiangiogenic agents. Methods using these compounds are also provided.
BACKGROUND OF THE INVENTION
Angiogenesis, the formation of new blood vessels, occurs during development and in normal adults during wound healing, pregnancy, and corpus luteum formation. Although angiogenesis is limited in normal adults, it is induced in many disease states including cancer, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, and restenosis (reviewed in Folkman, 1995).
Tumors require angiogenesis to grow beyond 1-2 mm
3
. (Folkman, 1990). The increased blood flow to the tumor allows for continued growth as well as metastasis because successful metastasis requires the presence of blood vessels to allow for the tumor cells to enter the circulation. The close interplay between angiogenesis and metastasis contributes to the poor prognosis seen in patients with highly angiogenic tumors. Cherrington et al., 2000.
Some of the most well characterized regulators of angiogenesis are growth factors and receptor tyrosine kinases (RTKs) involved in the migration and proliferation of endothelial cells. Of primary interest for angiogenesis are Flt-1 and Flk-1/KDR, the receptors for vascular endothelial growth factor (VEGF), as well as Tie 1 and Tie 2/Tek, the receptors for angiopoietins. These four receptors are expressed primarily on endothelial cells and play a direct role in angiogenesis. Additional RTKs with broader expression patterns implicated in angiogenesis are platelet-derived growth factor receptors (PDGFRs); fibroblast growth factor receptors (FGFRs); the hepatocyte growth factor/scatter factor (HGF/SF) receptor, Met; and epidermal growth factor receptors (EGFRs), although it is thought that the EGFR is likely to act predominantly in directly driving the growth of tumor cells rather than through angiogenesis. Cherington et al., 2000.
VEGF is a dimeric protein also known as vascular permeability factor because it acts on endothelial cells to regulate permeability of those cells as well as their proliferation. These two activities are mediated through its tyrosine kinase receptors, VEGFR1/Flt-1 and VEGFR2/Flk-1/KDR (KDR is the human homologue of Flk-1). VEGF and its receptors are expressed in angiogenic tissues during development, wound healing and other situations when angiogenesis occurs. The role of VEGF in tumor angiogenesis has also been clearly demonstrated using tumor models in rodents (reviewed in Hanahan, 1997; Shawver et al., 1997); there is an extensive literature exists linking VEGF with human cancers such as pulmonary adenocarcinoma (Takanami et al., 1997) and non-small cell carcinoma (NSCLC) (Fontanini et al., 1999; Takahama et al., 1998; Ohta et al., 1996). Survival of patients with VEGF-positive tumors was significantly less than patients with VEGF-negative tumors. For example, in one study of non-small cell carcinoma (NSCLC), patients with low VEGF levels had a median survival time of 151 months, whereas those with high VEGF expression had a mean survival time of only 8 months. Ohta et al., 1996.
VEGF and its receptors, in particular, serve as excellent targets for anti-angiogenesis therapy because KDR is an endothelial cell-specific VEGF receptor expressed primarily during the angiogenic process. The VEGF signaling cascade has been validated as a target for therapeutic intervention by several methods. See, e.g., Saleh et al., 1996, Claffey et al., 1996, Kim et al., 1993 and Asano et al., 1995.
Epidermal growth factor (EGF) is one of several naturally occurring proteins that promotes normal cell proliferation in a tightly regulated manner by binding to its receptor, EGFR, and sending growth signals via the receptor tyrosine kinase enzyme activity to the nucleus of the cell and thus controlling growth. In many human cancers, EGFR is either overexpressed or mutated, leading to aberrant signaling and the development of a tumor; thus inhibition of EGF receptor kinase is also a target in anti-tumor therapy.
Many pyrimidine systems have been studied for their ability to inhibit growth of tumors, through inhibition of angiogenesis and/or inhibition of cell growth, by targeting receptor tyrosine kinases. See, for example, Sun, Li and McMahon, G. “Inhibition of tumor angiogenesis by Synthetic Receptor Tyrosine Kinase Inhibitors”.
Drug Discov Today
2000, 5 (8): 344-353, and Traxler, P. and Furet, P., “Strategies toward the Design of Novel and Selective Protein Tyrosine Kinase Inhibitors”
Pharmacol. Ther
. 1999 82 (2-3): 195-206, which disclose synthetic pyrimidine compounds which have been shown to be effective TK inhibitors.
Pyrimidine systems have also been shown to inhibit dihydrofolate reductase (DHFR) enzyme activity. Because DHFR reduces dihydrofolate to tetrahydrofolate, inhibition of DHFR deprives the cell of tetrahydrofolate, without which the cell cannot produce 5,10-methylene-tetrahydrofolate, essential for cell growth. The inhibition of DHFR results in the inhibition of DNA synthesis and leads to cell death.
Additionally, some pyrimidine derivatives are known to function as thymidylate synthase (TS) inhibitors. TS, along with DHFR, forms part of the system responsible for the synthesis of deoxythymidylate (dTMP) from deoxyuridylate (dUMP). TS catalyzes the sole de novo synthesis of dTMP from dUMP. Inhibition of TS, therefore, deprives the cell of thymidine, which is an essential constituent of DNA.
In general, it is highly desirable to develop new antiangiogenic compounds which inhibit formation of new blood vessels and development of a new blood supply, as these can selectively target various tumor types and prevent growth of circulation in the tumor and inhibit metastasis. Because angiogenesis is limited in healthy adults, compounds which inhibit angiogenesis can selectively target tumors as compared with other compounds and anti-cancer agents using other modes of action, which often indiscriminately act on tumor and healthy cells alike. There is a need for compounds which provide the desired enzyme inhibition with a high degree of selectivity and low toxicity.
SUMMARY OF THE INVENTION
The present invention provides pyrimidine compounds, and pharmaceutically acceptable salts, solvates and prodrugs thereof, having the formula (1):
where X, X
1
, X
2
, X
3
and X
4
are from one to about three atoms, are the same or different and are independently selected from the group consisting of hydrogen, an alkyl group, a alkenyl group, an heteroalkyl group and an heteroalkenyl group,
and any carbons or nitrogens of said alkyl group, alkenyl group, heteroalkyl group or heteroalkenyl group can optionally be substituted with a straight, branched or cyclic lower alkyl group of from 1 to about 6 carbons;
Z is selected from the group consisting of C, CH, CH
2
, N, NH, S, O, CH═CH, CH═N and N═CH;
L is selected from the group consisting of C, CH, CH
2
, N, NH, S, O, CH═CH, CH═N and N═CH, but when Z is C, CH, CH═CH or CH
2
then L is N, NH, S or O;
M is selected from the group consisting of carbon and CH;
the chemical bond between L and M is selected from the group consisting of a single bond and a double bond, and M is carbon when the bond is a double bond, and M is CH when the bond is a single bond;
the chemical bond between M and Z is selected from the group consisting of a single bond and a double bond, and M is carbon when the bond is a double bond, and M is CH when the bond is a single bond;
but when the bond between L and M is a double bond the bond between M and Z is a single bond;
at least one of R
2
, R
3
, R
4
, or R
5
is present;
R
1
, R
4
and R
5
are the same or different and are selected from the group consisting of hydrogen, an alicyclic group, a heterocyclic group, an aryl group, a heteroaryl group, an alkylaryl group, a alkylheteroaryl group, a substituted aryl group, a substituted heteroaryl group, a substituted alk
Anderson Debra Z.
Berch Mark L.
Duquesne University of the Holy Ghost
Eckert Seamans Cherin & Mellott , LLC
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