Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-11-04
2003-09-16
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S214000, C548S181000, C544S133000, C544S367000, C546S199000, C546S271100
Reexamination Certificate
active
06620831
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel indazole derivative represented by the following formula (1):
in which
n represents 0, 1, 2 or 3,
X represents oxygen, sulfur or nitrogen atom,
R
1
and R
2
each independently represent hydrogen, amino, hydroxy, lower alkyl or cycloalkyl, or together form cycloalkyl,
R
3
represents hydrogen; lower alkyl; phenyl or naphthyl which may be unsubstituted or substituted with one to three substituents selected from the group consisting of hydroxy, halogen, nitro, amide, ester, carboxy, cyano, amidinyl, —O—R
5
, —NR
6
R
7
, phenyl, alkylsulfanyl, R
8
—SO
2
—, lower alkyl, lower alkyl substituted with R
9
, pyridinyl, piperidinyl, morpholinyl, piperazinyl, thienyl and furyl; aromatic and bicyclic aromatic compounds bearing at least one heteroatom selected from nitrogen, oxygen or sulfur atom; C
3-7
-cycloalkyl bearing at least one heteroatom selected from nitrogen, oxygen or sulfur atom; piperazinyl, imidazolyl, morpholinyl or piperidinyl which may be unsubstituted or substituted with one or two substituents selected from the group consisting of lower alkyl, phenyl, phenyl substituted with halogen, phenyl substituted with alkoxy, phenyl substituted with alkylcarbonyl, biphenyl and naphthyl; thiazole which may be unsubstituted or substituted with amino, mono- or di-lower alkylamino, alkylcarbonylamino, benzylamino, benzyloxycarbonylamino, benzyloxybenzylamino or alkoxycarbonylamino; benzodioxol; isoquinoline; indolyl; or benzimidazole wherein R
5
represents phenyl, benzyl, lower alkyl, alkoxyalkyl, alkoxyalkoxylalkyl, alkoxyalkoxyalkoxyalkyl, aminoalkyl or mono- or di-alkylaminoalkyl, R
6
and R
7
are identifical or different from each other and represent hydrogen, lower alkyl, oxygen or benzyl, or joined to form a ring, and R
8
and R
9
represent each independently lower alkyl, amino, morpholinyl, piperazinyl, N-alkylpiperazinyl or imidazole, and
R
4
represents nothing when X is oxygen or sulfur atom, but represents hydroxy or alkoxy when X is nitrogen atom,
pharmaceutically acceptable salt, solvated product and isomer thereof which are useful as inhibitors for Cyclin Dependent Kinase(hereinafter, refered to as “CDK”), and method for preparing the same.
The present invention also relates to an agent for inhibiting and treating diseases involving cell proliferation such as cancer, inflammation, restenosis and angiogenesis which comprises the compound of formula (1) as an active ingredient together with a pharmaceutical carrier.
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) and CDK2 which show their activity in G1-S phase of cell cycle, 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(CDK1) 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 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. The deletion of p16 and p15 genes generating proteins which inhibit CDK4 activity and the overexpression of cyclin D1 indispensable for CDK4 activity are observed in several kinds of cancer, 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. 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 indispensible for CDK2 activity 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 and neoplasia of mammary epithelial cells are 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.
Furthermore, it is discovered that CDC2(CDK1), CDK3, CDK5, 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 agents. Therefore, recently, these inhibitors have been developed.
As effective CDK inhibitors developed hitherto, there exists Flavopiridol, compound of the formula (A):
[Ref.: EP 0,241,003(1987) and 0,336,061(1990)].
In addition, a purine derivative of the formula (B):
has been recently developed[Ref: WO 97/20842].
Recently, a CDKs inhibitor having aminopyridine structure of the formula (C):
is disclosed in WO 98/33798.
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, particularly indazole-based compounds, and as a result, found that a component of the formula (1) which has a quite different structure from any other known CDK inhibitors inhibits CDKs enzymes effectively and finally, completed the present invention.
DISCLOSURE OF THE INVENTION
The object of the present invention is to provide a novel indazole derivative of formula (1), a process for preparing the same, and a composition for inhibiting and treating diseases involving cell proliferation such as cancer, inflammation, restenosis and angiogenesis which comprises as an active ingredient the compound of formula (1). In this specification, CDKs include all of CDK2, CDK4, CDC2(CDK1), CDK3, CDK5, CDK6, CDK7
Choi Sei-Hyun
Chung Hyun-Ho
Hong Chang-Yong
Hwang Kwang-Yeon
Jeong Shin-Wu
Gerstl Robert
LG Life Sciences Ltd.
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