CDK inhibitors having flavone structure

Details CDK inhibitors having flavone structure CDK inhibitors having flavone structure

2001-03-01

2002-12-31

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S452000, C514S457000, C546S197000, C549S285000, C549S288000

Reexamination Certificate

active

06500846

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a novel flavone derivative represented by the following formula (1):
in which
R
1
, R
3
and R
4
each independently represent hydrogen, halogen, hydroxy, alkyl, lower alkoxy, amino or nitro,
R
2
represents hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy, amino, nitro or
 wherein
A represents amino which may be optionally substituted with alkyl, cycloalkyl, aralkyl, acyl, or aryl which is optionally substituted with one or two substituents selected from the group consisting of halogen, cyano, nitro and amino; or 1,2,3,4-tetrahydroisoquinoline which may be optionally substituted with halogenoalkylcarbonyl; or alkyl, aryl, aralkyl or heteroaryl each of which may be optionally substituted with one or two substituents selected from the group consisting of alkyl, halogenoalkyl, halogen, dialkylamino, phenyl, nitro, amino, isooxazole, pyridine, carboxy, morpholine, methylpiperazine and cyano,
Y represents SO
2
or CO,
B represents hydrogen or alkyl,
R
5
represents hydrogen or hydroxy, and
R
6
and R
7
are substituted at o-, m- or p-position from each other and each independently represents hydrogen, hydroxy, halogen or lower alkoxy or together represent lower alkylenedioxy,
pharmaceutically acceptable salt, hydrate, solvate and isomer thereof which is useful as an inhibitor for Cyclin Dependent Kinase (hereinafter, referred to as “CDK”),
In addition, the present invention relates to a process for preparing the flavone derivative of formula (1) and also relates to an anti-cancer agent or an agent for treating neurodegenerative disease characterized by comprising the compound of formula (1) as an active ingredient.
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 is discovered that small molecular cell growth regulator controls cell division process (i.e. growth, differentiation, cytogenesis, aging and apoptosis etc.) through its 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 regulator loses its own function. That is to say, in cancer cells, the cell growth regulator shows an abnormal activity, which is deeply associated with invasion/metastasis which is crucial in the cancerpathology. Particularly, cell cycle deregulation is recognized to be a direct cause of cancer since cancer occurs in experimental animal when overexpression or knock-out of cell growth regulator is induced by using tranformed animal.
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 positive or negative regulation and timely regulation which is important for cell growth regulation are disrupted.
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-1 and S phases, CDC2 (CDK1) which shows its activity in G2-M phase, and so on. It is 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 (CDK 1) and in fact, it was confirmed that induced abnormalities cause cancer in the transformed animal. Therefore, CDK4, CDK2 and CDC2 (CDK1) among several kinds of CDKs are suitable as a target of anti-cancer agents.
The results of studies on relation between these CDKs and carcinogtenesis 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. The deletion of p16 and p15 genes in several kinds of cancer is reported and particularly, overexpression of cyclin D1 is observed, which has close relation with the fact that breast cancer has a metastatic proper and which suggests that malignant phenotype may be expressed 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. It gives the possibility that p16 plays a role in the downstream in NIH 3T3 cell with overexpressed ras or src. Reversely it was observed that modified phenotype wherein p16 or p21 is transformed with ras is repaired into wild phenotype. From these experimental results, deregulation of CDK4 activity may be a cause of carcinogenesis and play a role in maintenance of phenotype of cancer cell. Therefore, CDK4 inhibitors may have anti-cancer effects.
It was reported that overexpression of cyclin E is observed in some breast cancers, deeply associated with metastasis of breast cancer, inhibits cell apoptosis under low serum condition and induces anchorage independent growth, and that hyperproliferation (neoplasia) of mammary epithelial cells is observed in transformed animal with overexpressed CDK2 by MMTV promoter, which suggests that CDK2 activity is related with the progress or maintenance of cell transformation and CDK2 inhibitors may also have anti-cancer effects.
It is recently discovered that CDK5 among these CDKs may cause neurodegenerative diseases by phosphorylation of tau protein of the brain. Therefore, CDK5 inhibitor may be useful as an agent for treating neurodegenerative diseases (e.g. Alzheimer's disease). CDK2 inhibitors may have inhibitory effects on CDK5 in that CDK2 and CDK5 are homologous in the same family (Ref.: John Leu et al., “Neuronal CDC2-like kinase”, TIBS, January 1995, pp33~37).
Furthermore, it is discovered that CDC2 (CDK1), CDK3, CDK6 and CDK7 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 calssified into the same family.
On the basis of the above-mentioned research, efficient inhibitors of these CDKs may be useful as anti-cancer or anti-neurodegenerative agents. Therefore, recently, these inhibitors have been developed.
As effective CDK inhibitors developed hitherto, there exists Flavopiridol, compound of the formula (2)
which is under clincal trials [Ref.: EP 0,241,003 and 0,336,061]. In addition, a purine derivative of the formula (3)
has been recently developed [Ref: WO 97/16447].
However, the CDK inhibitors developed up to now could not have satisfactory effects.
So, the present inventors have made widespread and concentrative researches on CDK inhibitors and as a result, found that the above flavone derivative of formula (1) which has a quite different structure from any other known CDK inhibitors inhibits CDKs effectively and finally. complete the present invention.
DISCLOSURE OF THE INVENTION
The object of the present invention is to provide a novel flavone derivative of formula (1), pharmaceutically acceptable salt, hydrate, solvate and isomer thereof having an inhibitory activity for CDK.
Another object of the present invention is to provide a process for preparing the compound of formula (1). Still another object of the present invention is to provide an anti-cancer agent and an agent for treating neurodegenerative disease each of which is characterized by comprising as an active ingredient the compound of formula (1) with a pharmaceutically acceptable carrier.
In this specification, CDKs includes all

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