CDK inhibitors having 3-hydroxychromen-4-one structure

Details CDK inhibitors having 3-hydroxychromen-4-one structure CDK inhibitors having 3-hydroxychromen-4-one structure

2002-11-01

2004-01-27

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S196000, C546S283100, C548S214000, C514S337000, C514S372000

Reexamination Certificate

active

06683095

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a novel 3-hydroxychromen-4-one derivative represented by the following formula (1):
in which
A represents hydrogen or nitro, or represents amino which is optionally substituted by C
1
-C
4
-alkylcarbonyl or carbamoyl, or represents a structure selected from a group consisting of
wherein R
4
represents hydrogen or C
1
-C
6
-alkyl which is optionally substituted by amino or hydroxy, R
3
represents C
1
-C
6
-alkyl which is optionally substituted by amino or hydroxy, and D represents halogen,
B represents methyl, or represents amino which is optionally mono- or disubstituted by substituents selected from a group consisting of C
1
-C
6
-alkyl, hydroxy-C
1
-C
6
-alkyl, C
3
-C
6
-cycloalkyl, acetyl, phenyl, benzyl and piperidinyl,
X, Y and Z independently of one another represent hydrogen, hydroxy, nitro, cyano or halogen, or represent amino which is optionally substituted by C
1
-C
4
-alkyl, C
1
-C
4
-alkylcarbonyl or carbamoyl, or represent C
1
-C
4
-alkyl which is optionally substituted by hydroxy or halogen,
pharmaceutically acceptable salt, hydrate, solvate or isomer thereof which is useful as an inhibitor for Cyclin Dependent Kinase (hereinafter, referred to as “CDK”).
The present invention further relates to a process for preparing the compound of formula (1) and to a composition for suppression or treatment of cancer and diseases induced by cell proliferation such as inflammation, angiostenosis, angiogenesis, etc. which comprises the compound of formula (1) as an active component together with pharmaceutically acceptable carriers.
BACKGROUND ART
Researches on cell division process in molecular level have been extensively performed from the late 1980's through study of division of frog oocytes, analysis several yeast cell growth or characterization of induced mutants by radiation and study of the tumor suppressor Rb. In the 1990's, it was discovered that cell growth regulators of small size control the cell division process (i.e. growth, differentiation, cytogenesis, aging and apoptosis, etc.) through their own regulatory function. These results were very useful for more precise understanding of the pathology of several diseases. A representative example is cancer. In transformation process from normal cells to cancer cells, it was frequently observed that cell growth regulators lose their own function. That is, in cancer cells, the cell growth regulators show an abnormal activity, which is intimately associated with invasion/metastasis, the most crucial factor considered in the cancerpathology. Particularly, cell cycle deregulation is recognized to be a direct cause of cancer since cancer occurs when overexpression or knock-out of cell growth regulators is induced in the transformed animals.
The cell growth is under positive or negative regulation in the same manner as other biological regulations. The major pathway of cell cycle regulation known up to now is based on CDK activity and as a result of studies on many cancer cells and carcinogenesis mechanisms, it was confirmed that problems of positive or negative regulation on CDK activity result in carcinogenesis in many cases. That is, cancer may occur when well-balanced regulation or timely regulation is upset.
The representative CDKs of mammals are CDK4(cyclin dependent kinase 4) which shows its activity in mid-G1 phase of cell cycle, CDK2 which shows its activity in mid-G1 and S phases, CDC2(CDK1) which shows its activity in G2-M phase. It has been known that CDK4 and CDK2 activities are regulated by check point of G1-S cell cycle and CDC2 activity by check point of G2-M. In many cancer cells, abnormalities appear in the regulatory mechanism of CDK4, CDK2 and CDC2(CDK1) and in fact, it was confirmed that artificially induced abnormalities cause cancer in the transformed animals. Therefore, the typical cyclin dependent kinases, i.e., CDK4, CDK2 and CDC2(CDK1) are suitable as a target of anti-cancer agents. Those kinases also become a target in developing an agent for suppression or treatment of cancer and diseases induced by cell proliferation such as inflammation, angiostenosis, angiogenesis, etc.
The results of studies on the relation between these CDKs and carcinogenesis will be explained in more detail in the following.
The relation between the abnormal regulation of CDK4 activity and carcinogenesis is observed in several cancer tissues. Deletion of p16 and p15 genes producing the proteins that inhibit CDK4 activity or overexpression of cyclin D1 that is essential for the CDK4 activity is observed in several kinds of cancer, which suggests that malignant phenotype may be induced when CDK4 activity is deregulated. Furthermore, it was reported that p16 knocked-out mouse has such a high carcinogenesis rate as p53 knocked-out mouse, which suggests that malfunction of p16 on CDK4 regulation is a cause of carcinogenesis. From these experimental results, deregulation of CDK4 activity may be a certain cause of carcinogenesis and play a role in maintenance of phenotype of cancer cell. Therefore, it is highly probable that CDK4 inhibitors have an anti-cancer effect.
It was reported that overexpression of cyclin E that is essential for CDK2 activity is observed in some breast cancers, is deeply associated with metastasis of breast cancer, inhibits cell apoptosis under low serum condition, and induces anchorage independent growth, and that hyperproliferation and neoplasia of mammary epithelial cells are observed in transformed animal where CDK2 is overexpressed using MMTV promoter. This strongly suggests that CDK2 activity is related with the progress or maintenance of cell transformation and CDK2 inhibitors may have an anti-cancer effect.
Furthermore, it has been gradually discovered that CDC2(CDK1), CDK3, CDK5, CDK6, CDK7, etc. play an important role in each phase of cell division. These are classified into CDKs family. In addition to cyclin D1 and E, cyclin A, B, C, D2, D3, D4, F and G are also classified into the same family.
On the basis of the above-mentioned researches, efficient inhibitors against these CDKs are recognized to be useful as an anti-cancer agent. Therefore, recently, some inhibitors have been developed.
As the effective CDKs inhibitor developed hitherto, Flavopiridol (EP 0,241,003 (1987) and 0,366,061 (1990)) represented by the following formula (2) can be mentioned:
In addition, a purine derivative represented by the following formula (3):
has been reported (WO 97/20842), and a compound represented by the following formula (4):
having a quite different structure has been reported as an effective CDKs inhibitor (WO 98/33798).
DISCLOSURE OF INVENTION
However, the CDKs inhibitors developed up to now did not show satisfactory effects. Therefore, the present inventors have made extensive researches on CDKs inhibitors, particularly on flavone compounds and as a result, found that the above compound of formula (1) which has a quite different structure effectively inhibits the aforementioned CDKs and then, completed the present invention.
Therefore, the object of the present invention is to provide a novel 3-hydroxychromen-4-one derivative of formula (1), as defined above, pharmaceutically acceptable salt, hydrate, solvate or isomer thereof having an inhibitory activity for CDKs.
It is another object of the present invention to provide a process for preparing the compound of formula (1).
It is still another object of the present invention to provide a composition for suppression or treatment of cancer and diseases induced by cell proliferation such as inflammation, angiostenosis, angiogenesis, etc. comprising the compound of formula (1) as an active component together with pharmaceutically acceptable carriers.
In this specification, CDKs includes CDK2, CDK4, CDC2(CDK1), CDK3, CDK5, CDK6, CDK7, etc. and cyclins include cyclin D1, E, A, B, C, D2, D3, D4, F and G.
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention relates to a novel 3-hydroxychromen-4-one derivative represented by the following formula (1):
in which
A represents hydrogen or

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