4,5-azolo-oxindoles

Details 4,5-azolo-oxindoles 4,5-azolo-oxindoles

2000-05-16

2001-03-06

Stockton, Laura L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S322000, C514S375000, C514S388000, C514S393000, C546S199000, C548S151000, C548S218000, C548S302100

Reexamination Certificate

active

06197804

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to novel 4,5-azolo-oxindoles which inhibit cyclin-dependent kinases (CDKs), in particular CDK2. These compounds and their pharmaceutically acceptable salts, and prodrugs of said compounds, are anti-proliferative agents useful in the treatment or control of cell proliferative disorders, in particular cancer. The invention is also directed to pharmaceutical compositions containing such compounds, and to methods for the treatment and/or prevention of cancer, particularly in the treatment or control of solid tumors. The compounds of the invention are especially useful in the treatment or control of breast and colon tumors.
BACKGROUND OF THE INVENTION
Uncontrolled cell proliferation is the hallmark of cancer. Cancerous tumor cells typically have some form of damage to the genes that directly or indirectly regulate the cell-division cycle.
Cyclin-dependent kinases (CDKs) are enzymes which are critical to cell cycle control. See, e.g., Coleman et al., “Chemical Inhibitors of Cyclin-dependent Kinases,”
Annual Reports in Medicinal Chemistry
, vol. 32, 1997, pp. 171-179. These enzymes regulate the transitions between the different phases of the cell cycle, such as the progression from the G
1
phase to the S phase (the period of active DNA synthesis), or the progression from the G
2
phase to the M phase, in which active mitosis and cell-division occurs. See, e.g., the articles on this subject appearing in
Science
, vol. 274, Dec. 6, 1996, pp. 1643-1677.
CDKs are composed of a catalytic CDK subunit and a regulatory cyclin subunit. The cyclin subunit is the key regulator of CDK activity, with each CDK interacting with a specific subset of cyclins: e.g. cyclin A (CDK1, CDK 2). The different kinase/cyclin pairs regulate progression through specific stages of the cell cycle. See, e.g., Coleman, supra.
Aberrations in the cell cycle control system have been implicated in the uncontrolled growth of cancerous cells. See, e.g., Kamb, “Cell-Cycle Regulators and Cancer,”
Trends in Genetics
, vol. 11, 1995, pp. 136-140; and Coleman, supra. In addition, changes in the expression of or in the genes encoding CDK's or their regulators have been observed in a number of tumors. See, e.g., Webster, “The Therapeutic Potential of Targeting the Cell Cycle,”
Exp. Opin. Invest. Drugs
, Vol. 7, pp. 865-887 (1998), and references cited therein. Thus, there is an extensive body of literature validating the use of compounds inhibiting CDKs as anti-proliferative therapeutic agents. See, e.g. U.S. Pat. No. 5,621,082 to Xiong et al; EP 0 666 270 A2; WO 97/16447; and the references cited in Coleman, supra, in particular reference no. 10. Thus, it is desirable to identify chemical inhibitors of CDK kinase activity.
It is particularly desirable to identify small molecule compounds that may be readily synthesized and are effective in inhibiting one or more CDKs or CDK/cyclin complexes, for treating one or more types of tumors.
Indolinone (also known as oxindole) compounds asserted to be useful in the regulating abnormal cell proliferation through tyrosine kinase inhibition are disclosed in WO 96/40116, WO 98/07695, WO 95/01349, WO 96/32380, WO 96/22976, WO 96/16964 (tyrosine kinase inhibitors), and WO 98/50356 (2-indolinone derivatives as modulators of protein kinase activity). Oxindole derivatives have also been described for various other therapeutic uses: U.S. Pat. No. 5,206,261 (improvement of cerebral function); WO 92/07830 (peptide antagonists); EP 580 502 A1 (antioxidants).
There continues to be a need for easily synthesized, small molecule compounds for the treatment of one or more types of tumors, in particular through regulation of CDKs. It is thus an object of this invention to provide such compounds and compositions containing such compounds.
SUMMARY OF THE INVENTION
The present invention relates to 4,5-azolo-oxindoles capable of inhibiting the activity of one or more CDKs, in particular CDK2. Such compounds are useful for the treatment of cancer, in particular solid tumors. In particular the compounds of the present invention are especially useful in the treatment or control of breast and colon tumors.
The compounds of the present invention are 4,5-azolo-oxindoles having the following formula:
and prodrugs and pharmaceutically active metabolites of compounds of formula I; and the pharmaceutically acceptable salts of the foregoing compounds, wherein
R
1
is selected from the group consisting of
—H,
—OR
3
,
—COR
3
,
—COOR
3
,
—CONR
4
R
5
,
—NR
4
R
5
,
lower alkyl which optionally may be substituted by the group consisting of —OR
3
, —NR
4
R
5
, halogen, —COR
3
, —COOR
3
, —OCOR
3
, —CONR
4
R
5
, —CN, —SO
2
R
3
, —SO
2
NR
4
R
5
, cycloalkyl, heterocycle, aryl, and heteroaryl, wherein the cycloalkyl and heterocycle each may be optionally substituted by the group R
11
and the aryl and heteroaryl each may be optionally substituted by the group R
12
,
cycloalkyl which optionally may be substituted by the group consisting of —OR
3
, —NR
4
R
5
, halogen, —COR
3
, —COOR
3
, —OCOR
3
, —CONR
4
R
5
, —CN —SO
2
R
3
,
—SO
2
NR
4
R
5
, lower alkyl, heterocycle, aryt, and heteroaryt, wherein the lower alkyl and heterocycle each may be optionally substituted by the group R
11
and the aryl and heteroaryl each may be optionally substituted by the group R
12
,
heterocycle which optionally may be substituted by the group consisting of —OR
3
, —NR
4
R
5
, halogen, —COR
3
, —COOR
3
, —OCOR
3
, —CONR
4
R
5
—CN, —SO
2
R
3
, —SO
2
NR
4
R
5
, lower alkyl, cycloalkyl, aryl, and heteroaryl, wherein the lower alkyl and cycloalkyl each may be optionally substituted by the group R
11
and the aryl and heteroaryl each may be optionally substituted by the group R
12
,
aryl which optionally may be substituted by the group consisting of —OR
3
, —NR
4
R
5
, halogen, —NO
2
, perfluoroalkyl, —COR
3
, —COOR
3
, —OCOR
3
, —CONR
4
R
5
, —CN, —SO
2
R
3
, —SO
2
NR
4
R
5
, lower alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl, and wherein the lower alkyl, cycloalkyl and heterocycle each may be optionally substituted by the group R
11
and the aryl and heteroaryl each may be optionally substituted by the group R
12
,
heteroaryl which optionally may be substituted by the group consisting of —OR
3
, —NR
4
R
5
, halogen, —NO
2
, perfluoroalkyl, —COR
3
, —COOR
3
, —OCOR
3
, —CONR
4
R
5
, —CN, —SO
2
R
3
, —SO
2
NR
4
R
5
, lower alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl and wherein the lower alkyl, cycloalkyl and heterocycle each may be optionally substituted by the group R
11
and the aryl and heteroaryl each may be optionally substituted by the group R
12
,
R
2
is selected from the group consisting of
—H,
—OR
3
,
—COR
3
,
—COOR
3
,
—OCOR
3
,
—CONR
4
R
5
,
halogen,
—CN,
perfluoroalkyl,
—NR
4
R
5
, and
lower alkyl which optionally may be substituted by the group consisting of —OR
3
, —OCOR
3
, and —NR
4
R
5
;
R
3
is selected from the group consisting of
—H,
lower alkyl which optionally may be substituted by the group consisting of —R
7
, —COOR
6
, —COR
6
, —CONR
4
R
5
, —NR
4
R
5
, —SO
2
R
6
, —SO
2
NR
4
R
5
, cycloalkyl, heterocycle, aryl, and heteroaryl, and wherein the cycloalkyl and heterocycle each may be optionally substituted by the group R
11
and the aryl and heteroaryl each may be optionally substituted by the group R
12
,
cycloalkyl which optionally may be substituted by the group consisting of —OR
7
, —COOR
6
, —COR
6
, —CONR
4
R
5
, —NR
4
R
5
, —SO
2
R
6
, —SO
2
NR
4
R
5
, lower alkyl, heterocycle, aryl, and heteroaryl, and wherein the lower alkyl and heterocycle each may be optionally substituted by the group R
11
and the aryl and heteroaryl each may be optionally substituted by the group R
12
,
heterocycle which optionally may be substituted by the group consisting of —OR
7
, —COOR
6
, —COR
6
, —CONR
4
R
5
, —NR
4
R
5
, —SO
2
R
6
, —SO
2
NR
4
R
5
, cycloalkyl, lower alkyl, aryl, and heteroaryl, and wherein the cycloalkyl and lower alkyl each may be optionally substituted by the group R
11
and the aryl and heteroaryl each may be optionally substituted by th

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