Naphthostyrils

Details Naphthostyrils Naphthostyrils

2002-08-20

2003-03-11

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Four or more ring nitrogens in the bicyclo ring system

C546S200000, C544S372000

Reexamination Certificate

active

06531598

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to novel naphthostyrils of formula
These compounds inhibit cyclin-dependent kinases (CDKs), in particular CDK2. These compounds and their pharmaceutically acceptable salts and esters 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, colon, lung and prostate tumors. The invention is also directed to intermediates useful in the preparation of the above anti-proliferative agents.
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 activity.
It is particularly desirable to identify small molecule compounds that may be readily synthesized and are effective in inhibiting CDK2 or CDK2/cyclin complexes, for treating one or more types of tumors.
4-Alkenyl- and 4-alkynyloxindoles useful in the treatment or control of cancer are disclosed in U.S. Pat. No. 6,130,239. Indolinone (also known as oxindole) compounds asserted to be useful in 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: 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 naphthostyrils capable of inhibiting the activity of one or more CDKs, in particular CDK2. These compounds are useful for the treatment or control of cancer, in particular solid tumors. In particular this invention is directed to a compound of the formula
and the pharmaceutically acceptable salts and esters of such compound, wherein R
1
-R
4
are as defined below.
The present invention is also directed to pharmaceutical compositions comprising a pharmaceutically effective amount of any one or more compounds of formula I and a pharmaceutically acceptable carrier or excipient.
The present invention is further directed to a method for treating solid tumors, in particular breast, colon, lung and prostate tumors, by administering to a human patient in need of such therapy an effective amount of a compound of formula I, its salt and/or ester or a combination thereof.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
As used herein, the following terms shall have the following definitions.
“Aryl” means an aromatic group having 5 to 10 atoms and consisting of 1 or 2 rings. Examples of aryl groups include phenyl and 1- or 2-naphthyl.
“Cycloalkyl” means a non-aromatic, partially or completely saturated cyclic aliphatic hydrocarbon group containing 3 to 8 atoms. Examples of cycloalkyl groups include cyclopropyl, cyclopentyl and cyclohexyl.
“Effective Amount” means an amount of at least one compound of Formula I, or a pharmaceutically acceptable salt or ester thereof, that significantly inhibits proliferation and/or prevents differentiation of a human tumor cell, including human tumor cell lines, and is thus effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
“Halogen” means fluorine, chlorine, bromine or iodine.
“Heteroaryl” groups are aromatic groups having 5 to 10 atoms, one or two rings, and containing one or more hetero atoms. Examples of heteroaryl groups include 2, 3 or 4-pyridyl, tetrazolyl, oxadiazolyl, pyrazinyl, quinolyl, pyrrolyl, and imidazolyl.
“Hetero atom” means an atom selected from N, O and S.
“Heterocycle” means a 3- to 10-membered non-aromatic, partially or completely saturated hydrocarbon group, such as tetrahydroquinolyl, which contains one or two rings and at least one hetero atom. Examples of heterocyclic compounds include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, and the like.
“IC
50
” refers to the concentration of a particular naphthostyril required to inhibit 50% of a specific measured activity. IC
50
can be measured, inter alia, as is described in Example 58, infra.
“Lower alkyl” denotes a straight-chain or branched saturated or unsaturated aliphatic hydrocarbon having 1 to 6, preferably 1 to 4, carbon atoms. Typical lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 2-butyl, pentyl, hexyl, propenyl, propynyl, and the like.
“Pharmaceutically acceptable ester” refers to a conventionally esterified compound of formula I having a carboxyl group, which esters retain the biological effectiveness and properties of the compounds of formula I and are cleaved in vivo (in the organism) to the corresponding active carboxylic acid. Examples of ester groups which are cleaved (in this case hydrolyzed) in vivo to the corresponding carboxylic acids (R
24
C(═O)OH) are lower alkyl esters which may be substituted with NR
25
R
26
where R
25
and R
26
are lower alkyl, or where NR
25
R
26
taken together form a monocyclic aliphatic heterocycle, such as pyrrolidine, piperidine, morpholine, N-methylpiperazine, etc.; acyloxyalkyl esters of the formula R
24
C(═O)OCHR
27
OC(═O)R
28
where R
27
is hydrogen or methyl, and R
28
is lower alkyl or cycloalkyl; carbonate esters of the formula R
24
C(═O)OCHR
27
OC(═O)OR
29
where R
27
is hydrogen or methyl, and R
29
is lower alkyl or cycloalkyl; or aminocarbonylmethyl esters of the formula R
24
C(═O)OCH
2
C(═O)NR
25
R
26
where R
25
and R
26
are hydrogen or lower alkyl,

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