This invention relates to novel compounds which are useful for treating a variety of cell proliferative disorders such as cancer.
A wide range of growth factors coordinate cell proliferation and differentiation. Malignant cells arise as a result of a stepwise progression of events that include the unregulated expression of growth factors or components of their signaling pathways. Tyrosine phosphorylation events initiated by receptor, cytoplasmic and nuclear kinases and regulated by phosphatases are central to these processes. Mutation, hyper-activation, translocation and overexpression of protein tyrosine kinases are all associated with tumorigenesis. In addition to increasing proliferative rates and immortalizing cells, overexpression of tyrosine kinases can lead to morphological transformation and cause anchorage independence, contributing to the promotion of migratory ability and possibly the induction of metastases.
Certain compounds with structures based upon mimicry of ATP or phosphotyrosine have been shown to be effective kinase inhibitors. Those based upon phosphotyrosine have been demonstrated to be the more specific tyrosine kinase inhibitors. Because of their ability to inhibit tyrosine phosphorylation, these compounds may alter cell responses to growth factors or other process driven by tyrosine kinase activity, including unregulated growth as the result of tyrosine kinase overexpression, mutation, or translocation. Inhibition of tyrosine kinases occupying a central role in proliferative signaling pathways, or in pathways regulating cell cytoskeletal structure, even temporary or incomplete inhibition, may be sufficient to switch a cancerous cell from a proliferative cycle into programmed cell death, or apoptosis. Death by apoptosis is most often observed upon effective treatment with tyrosine kinase inhibitors.
Selective inhibition of specific tyrosine kinases offers a method of targeting cancerous cell growth with a high degree of specificity and minimal toxicity to normally growing cells and tissues. Thus, specific inhibitors of tyrosine kinases have great potential as clinical anti-cancer treatments. A number of small molecules which act as tyrosine kinase inhibitors have been identified. For example, certain phenyl acrylonitrile compounds have been described as tyrosine kinase inhibitors, effective to inhibit cell proliferation (see for example, U.S. Pat. Nos. 5,891,917, 5,217,999, 5,773,476, 5,935,993, 5,656,655, 5,677,329 and 5,789,427).
Inhibition of tyrosine kinases offers one mechanism by which cell proliferation can be inhibited. One of skill in the art will appreciate that other mechanisms of inhibition may also be involved.
There is a need in the art to identify compounds that inhibit cell proliferation.
A number of novel compounds have now been identified that inhibit abnormal cell proliferation, for example cancer cell growth. The compounds do not inhibit the growth of normal cells.
Accordingly, the present invention includes compounds of Formula I and salts, solvates and hydrates thereof: 
wherein
R1 and R2 are each independently selected from the group consisting of H, OH, C1-6alkyl, C1-6alkoxy, NH2, NHxe2x80x94C1-6alkyl, N(C1-6alkyl)(C1-6alkyl), SH, Sxe2x80x94C1-6alkyl, Oxe2x80x94Si(C1-6alkyl)(C1-6alkyl)(C1-6alkyl), NO2, CF3, OCF3 and halo;
R3 is selected from the group consisting of H, OH, C1-6alkyl, C1-6alkoxy, NH2, NHxe2x80x94C1-6alkyl, N(C1-6alkyl)(C1-6alkyl), SH, Sxe2x80x94C1-6alkyl, Oxe2x80x94Si(C1-6alkyl)(C1-6alkyl)(C1-6alkyl), NO2, halo and CH2xe2x80x94Sxe2x80x94(CH2)nAr;
R4 is selected from the group consisting of C(X)R5, SO3Ar, NH2, NHxe2x80x94C1-6alkyl, N(C1-6alkyl)(C1-6alkyl), P(O)(OH)2, P(O)(OC1-6alkyl)2, and C(NH2)xe2x95x90C(CN)2;
X is selected from O,S, NH and Nxe2x80x94C1-6alkyl;
R5 is selected from the group consisting of NH2, OH, NH(CH2)pAr, NH(CH2)pOH, (CH2)pOC1-6alkyl, C1-6alkyl, C1-6alkoxy, NHNH2, NHC(O)NH2, NHC(O)C1-6alkoxy, N-morpholino and N-pyrrolidino;
Ar is an aromatic or heteroaromatic group, unsubstituted or substituted with 1-4 substituents, independently selected from the group consisting of OH, C1-6alkyl, C1-6alkoxy, NH2, NHxe2x80x94C1-6alkyl, N(C1-6alkyl)(C1-6alkyl), SH, Sxe2x80x94C1-6alkyl, NO2, CF3, OCF3 and halo;
n is 0 to 4; and
p is 1-4.
The present invention further includes compounds of Formula II and salts, solvates and hydrates thereof: 
wherein
R1 and R2 are each independently selected from the group consisting of H, OH, C1-6alkyl, C1-6alkoxy, NH2, NHxe2x80x94C1-6alkyl, N(C1-6alkyl)(C1-6alkyl), SH, Sxe2x80x94C1-6alkyl, Oxe2x80x94Si(C1-6alkyl)(C1-6alkyl)(C1-6alkyl), NO2, CF3, OCF3 and halo;
R3 is selected from the group consisting of H, OH, C1-6alkyl, C1-6alkoxy, NH2, NHxe2x80x94C1-6alkyl, N(C1-6alkyl)(C1-6alkyl), SH, Sxe2x80x94C1-6alkyl, Oxe2x80x94Si(C1-6alkyl)(C1-6alkyl)(C1-6alkyl), NO2, halo and CH2xe2x80x94Sxe2x80x94(CH2)nAr;
Ar is an aromatic or heteroaromatic group, unsubstituted or substituted with 1-4 substituents, independently selected from the group consisting of OH, C1-6alkyl, C1-6alkoxy, NH2, NHxe2x80x94C1-6alkyl, N(C1-6alkyl)(C1-6alkyl), SH, Sxe2x80x94C1-6alkyl, NO2, CF3, OCF3 and halo;
R6 is selected from the group consisting of Ar, OH and OC1-6alkyl;
X is selected from O and S;
n is 0-4; and
p is 1-4.
The present invention also provides compounds of Formula III and salts, solvates and hydrates thereof: 
wherein
R1 and R2 are each independently selected from the group consisting of H, OH, C1-6alkyl, C1-6alkoxy, NH2, NHxe2x80x94C1-6alkyl, N(C1-6alkyl)(C1-6alkyl), SH, Sxe2x80x94C1-6alkyl, Oxe2x80x94Si(C1-6alkyl)(C1-6alkyl)(C1-6alkyl), NO2, CF3, OCF3 and halo;
R3 is selected from the group consisting of H, OH, C1-6alkyl, C1-6alkoxy, NH2, NHxe2x80x94C1-6alkyl, N(C1-6alkyl)(C1-6alkyl), SH, Sxe2x80x94C1-6alkyl, Oxe2x80x94Si(C1-6alkyl)(C1-6alkyl)(C1-6alkyl), NO2, halo and CH2xe2x80x94Sxe2x80x94(CH2)nAr;
Ar is an aromatic or heteroaromatic group, unsubstituted or substituted with 1-4 substituents, independently selected from the group consisting of OH, C1-6alkyl, C1-6alkoxy, NH2, NHxe2x80x94C1-6alkyl, N(C1-6alkyl)(C1-6alkyl), SH, Sxe2x80x94C1-6alkyl, NO2, CF3, OCF3 and halo;
R7 is selected from the group consisting of OH, NH2 and OC1-6alkyl;
X is selected from O and S; and
n is 0-4.
According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier or diluent.
In accordance with a further aspect of the present invention, there is provided a method for modulating cell proliferation, preferably inhibiting cell proliferation comprising administering an effective amount of a compound of the invention to a cell or animal in need thereof. The invention also includes a use of a compound of the invention to modulate cell proliferation, preferably inhibit cell proliferation. The invention further includes a use of a compound of the invention to prepare a medicament to modulate cell proliferation, preferably inhibit cell proliferation.
In a preferred embodiment the present invention provides a method of inhibiting the proliferation of a cancer cell comprising administering an effective amount of a compound of the invention to a cell or animal in need thereof. The cancer cell treated may be any type of cancer including a leukemia, a lymphoma, myeloma, metastatic carcinoma, sarcoma or any other malignant transformation or any other malignancy. The invention also includes a use of a compound of the invention to modulate cancer cell proliferation, preferably inhibit cancer cell proliferation. The invention further includes a use of a compound of the invention to prepare a medicament to modulate cancer cell proliferation, preferably inhibit cancer cell proliferation.
In another aspect, the invention provides a method of modulating tyrosine kinase activity in a cell by administering an effective amount of a compound of the invention. In a further aspect, the invention provides a method of inhibiting tyrosine kinase activity in a cell by administering an effective amount of a compound of the invention. The present invention also provides a use of a compound of the invention to modulate, preferably inhibit, tyrosine kinase activity. The present invention further provides a use of a compound of the invention to prepare a medicament to modulate tyrosine kinase activity, preferably inhibit tyrosine kinase activity. It is appreciated that the inhibition of cell growth by the compounds of the invention may be effected by other mechanisms.
Other features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.