Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-04
2004-03-16
Rotman, Alan L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S143000, C544S144000, C548S455000
Reexamination Certificate
active
06706709
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of Invention
The present invention relates to certain 2-indolinone compounds which modulate the activity of protein kinases (“PKs”) and phosphatases. The compounds of this invention are therefore useful in treating disorders related to abnormal PK activity. Pharmaceutical compositions comprising these compounds, methods of treating diseases utilizing pharmaceutical compositions comprising these compounds and methods of preparing them are also disclosed.
2. State of the Art
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 tyrosine 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 tyrosine 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.
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.
SUMMARY OF THE INVENTION
In a first aspect, the invention provides an indolinone compound having a structure set forth in formula (I):
wherein:
(a) R
4
-R
6
, and R
8
-R
10
are hydrogen;
(b) R
1
, R
2
, and R
3
are each independently selected from the group consisting of hydrogen, halogen, carboxylic acid, optionally substituted ester, optionally substituted amide, optionally substituted alkyl, optionally substituted alkoxy, trihalomethyl, optionally substituted aryl, and optionally substituted heteroaryl; and
(c) R
7
is selected from the group consisting of substituted alkyl, and substituted alkoxy;
or a pharmaceutically acceptable salt thereof.
Preferably,
(a) R
1
is selected from the group consisting of hydrogen and optionally substituted alkyl, more preferably hydrogen;
(b) R
2
and R
3
are each independently selected from the group consisting of hydrogen, halo, carboxylic acid, optionally substituted heteroaryl, and optionally substituted phenyl. Preferably R
2
is hydrogen, halo, phenyl, or carboxylic acid, more preferably hydrogen, phenyl, —COOH, chloro, fluoro or bromo. Preferably, R
3
is hydrogen, halo, carboxylic acid, optionally substituted pyridyl, and phenyl optionally substituted with lower alkoxy or halo, more preferably phenyl, —COOH, pyridin-3-yl, 3-, or 4-methoxyphenyl or 4-fluorophenyl; and
(c) R
7
is selected from the group consisting of lower alkyl substituted with a heteroaliphatic ring or dialkylamino; or lower alkoxy substituted with a heteroaliphatic ring or dialkylamino, preferably R
7
is lower alkyl substituted with a heteroaliphatic ring or dialkylamino; more preferably R
7
is 3-diethylaminopropyl or 3-pyrrolidin-1-yl-propyl, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-pyrrolidin-1-yl-ethoxy, or 2-morpholin-4-yl-ethoxy.
In a second aspect, the invention provides for an indolinone compound having a structure set forth in formula (II):
wherein:
(a) R
11
-R
14
are hydrogen;
(b) R
15
and R
16
are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl, or R
15
and R
16
taken together with the nitrogen atom to which they are attached form a ring structure selected from the group consisting of a five-membered or six-membered heteroaromatic ring, a five-membered or six-membered heteroaliphatic ring, a nine-membered fused bicyclic heteroaromatic ring, and a ten-membered fused bicyclic heteroaromatic ring; and
(c) A is selected from the group consisting of formula (III), (IV), and (V):
wherein:
(i) R
19
-R
25
and R
27
-R
31
are hydrogen;
(ii) R
17
and R
18
are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted alkoxy provided that both R
17
and R
18
are not hydrogen; and
(iii) R
26
is selected from the group consisting of optionally substituted alkyl;
or a pharmaceutically acceptable salt thereof.
In one preferred embodiment:
(i) R
15
is hydrogen or alkyl, more preferably hydrogen or methyl;
(ii) R
16
is hydrogen, alkyl, phenyl optionally substituted with one or two substituents selected from hal
Harris G. Davis
Li Xiaoyuan
Tang Peng Cho
Burrous Beth A.
Rotman Alan L.
Saeed Kamal
Sugen Inc.
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