Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-28
2002-10-15
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S300000, C514S249000, C514S248000, C514S258100, C514S215000, C540S580000, C544S236000, C544S280000, C544S350000, C546S113000, C548S455000
Reexamination Certificate
active
06465507
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to certain indolinone compounds, their method of synthesis, and a combinatorial library consisting of the indolinone compounds of the invention. The invention also relates to methods of modulating the function of protein kinases, in particular CDK2 protein kinase, using compounds of the invention and methods of treating diseases by modulating the function of protein kinases, in particular CDK2 protein kinase, and related signal transduction pathways.
STATE OF THE ART
The following description of the background of the invention is provided to aid in understanding the invention, but is not admitted to describe or constitute prior art to the invention.
Cellular signal transduction is a fundamental mechanism whereby extracellular stimuli are relayed to the interior of cells and subsequently regulate diverse cellular processes. One of the key biochemical mechanisms of signal transduction involves the reversible phosphorylation of proteins. Phosphorylation of polypeptides regulates the activity of mature proteins by altering their structure and function. Phosphate most often resides on the hydroxyl moiety (—OH) of serine, threonine, or tyrosine amino acids in proteins.
Enzymes that mediate phosphorylation of cellular effectors generally fall into two classes. The first class consists of protein kinases which transfer a phosphate moiety from adenosine triphosphate to protein substrates. The second class consists of protein phosphatases which hydrolyze phosphate moieties from phosphoryl protein substrates. The converse functions of protein kinases and protein phosphatases balance and regulate the flow of signals in signal transduction processes.
Protein kinases and protein phosphatases are generally divided into two groups—receptor and non-receptor type proteins. Most-receptor-type protein phosphatases contain two conserved catalytic domains, each of which encompasses a segment of 240 amino acid residues. Saito et al., 1991
, Cell Growth and Diff
. 2:59-65. Receptor protein phosphatases can be subclassified further based upon the amino acid sequence diversity of their extracellular domains. Saito et al., supra; Krueger et al., 1992
, Proc. Natl. Acad. Sci. USA
89:7417-7421.
Protein kinases and protein phosphatases are also typically divided into three classes based upon the amino acids they act upon. Some catalyze the addition or hydrolysis of phosphate on serine or threonine only, some catalyze the addition or hydrolysis of phosphate on tyrosine only, and some catalyze the addition or hydrolysis of phosphate on serine, threonine, and tyrosine.
Kinases can regulate the catalytic activity of other protein kinases involved in cell proliferation. Protein kinases with inappropriate activity are also involved in some types of cancer. Abnormally elevated levels of cell proliferation are associated with receptor and non-receptor protein kinases with unregulated activity.
In addition to their role in cellular proliferation, protein kinases are thought to be involved in cellular differentiation processes. Cell differentiation occurs in some cells upon nerve growth factor (NGF) or epidermal growth factor (EGF) stimulation. Cellular differentiation is characterized by rapid membrane ruffling, cell flattening, and increases in cell adhesion. Chao, 1992
, Cell
68:995-997.
In an effort to discover novel treatments for cancer and other diseases, biomedical researchers and chemists have designed, synthesized, and tested molecules that inhibit the function of protein kinases. Some small organic molecules form a class of compounds that modulate the function of protein kinases. Examples of molecules that have been reported to inhibit the function of protein kinases are bis-monocyclic, bicyclic or heterocyclic aryl compounds (PCT WO 92/20642), vinylene-azaindole derivatives (PCT WO 94/14808), 1-cyclopropyl-4-pyridyl-quinolones (U.S. Pat. No. 5,330,992), styryl compounds (by Levitzki, et al., U.S. Pat. No. 5,217,999, and entitled “Styryl Compounds which Inhibit EGF Receptor Protein Tyrosine Kinase), styryl-substituted pyridyl compounds (U.S. Pat. No. 5,302,606), certain quinazoline derivatives (EP Application No. 0 566 266 A1), seleoindoles and selenides (PCT WO 94/03427), tricyclic polyhydroxylic compounds (PCT WO 92/21660), and benzylphosphonic acid compounds (PCT WO 91/15495).
The compounds that can traverse cell membranes and are resistant to acid hydrolysis are potentially advantageous therapeutics as they can become highly bioavailable after being administered orally to patients. However, many of these protein kinase inhibitors only weakly inhibit the function of protein kinases. In addition, many inhibit a variety of protein kinases and will therefore cause multiple side-effects as therapeutics for diseases.
Despite the significant progress that has been made in developing compounds for the treatment of cancer, there remains a need in the art to identify the particular structures and substitution patterns that form the compounds capable of modulating the function of particular protein kinases. The present invention fulfils this need.
SUMMARY OF THE INVENTION
The present invention is directed to certain indolinone compounds and methods of treating diseases mediated by protein kinases, in particular CDK2 protein kinase, using these compounds.
Thus, in a first aspect, the invention provides a compound of Formula (I):
wherein:
(a) each R
1
is independently and optionally selected from the group consisting of:
(i) hydrogen;
(ii) saturated or unsaturated alkyl optionally substituted with one, two or three substituents selected from the group consisting of halogen, trihalomethyl, alkoxy, carboxylate, amino, nitro, ester, and a five-membered or six-membered aromatic, heteroaromatic, aliphatic, or heteroaliphatic ring where each ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, amino, nitro, and ester;
(iii) an aromatic or heteroaromatic ring optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, amino, nitro, and ester;
(iv) an aliphatic or heteroaliphatic ring optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, amino, nitro, ester, and an aromatic or heteroaromatic ring optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, amino, nitro, and ester;
(v) an alcohol of formula —(X
1
)
n1
—OH or an alkoxyalkyl of formula —(X
2
)
n2
—O—X
3
, where X
1
, X
2
, and X
3
are independently selected from the group consisting of saturated or unsaturated alkyl, amide, and five-membered or six-membered aromatic, heteroaromatic, aliphatic, or heteroaliphatic ring where the alkyl, and each ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, aryl, heteroaryl, halogen, trihalomethyl, carboxylate, amino, nitro, and ester; and n1 and n2 are independently 0 or 1;
(vi) a halogen or trihalomethyl;
(vii) a carboxylic acid of formula —(X
4
)
n4
—COOH or ester of formula —(X
5
)
n5
—COO— X
6
, where X
4
, X
5
, and X
6
are independently selected from the group consisting of alkyl and five-membered or six-membered aromatic, heteroaromatic, aliphatic, or heteroaliphatic ring; and n4 and n5 are independently 0 or 1;
(viii) an amide or thioamide of formula —(X
7
)
n7
—NHCOX
8
, —(X
7
)
n7
—NHCSX
8
, —(X
9
)
n9
—CONX
10
X
11
, or of formula —(X
9
)
n9
—CSNX
10
X
11
, where X
7
and X
9
are each independently selected from the group consisting of alkyl and five-membered or six-membered aromatic, heteroaromatic, aliphatic, or heteroaliphatic ring where each of the ring is optionally substituted with one, two or three substituents independently selected from the group c
Cui Jinrong
Huang Ping
Li Xiaoyuan
Miller Todd A.
Tang Peng Cho
Foley & Lardner
Seaman D. Margaret
Sugen Inc.
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