Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-09
2004-09-28
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S399000, C548S311400, C548S465000, C548S468000
Reexamination Certificate
active
06797725
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of Invention
The present invention relates to certain 3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives that are prodrugs of compounds that modulate the activity of protein kinases (“PKs”). Pharmaceutical compositions comprising these compounds, methods of treating diseases related to abnormal PK activity utilizing pharmaceutical compositions comprising these compounds and methods of preparing them are also disclosed.
2. State of the Art
The following is offered as background information only and is not admitted to be prior art to the present invention.
PKs are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins. The consequences of this seemingly simple activity are staggering; cell growth, differentiation and proliferation, i.e., virtually all aspects of cell life in one way or another depend on PK activity. Furthermore, abnormal PK activity has been related to a host of disorders, ranging from relatively non life threatening diseases such as psoriasis to extremely virulent diseases such as glioblastoma (brain cancer) (see U.S. Pat. No. 5,792,783 which is incorporated herein by reference in its entirety).
In view of the apparent link between PK-related cellular activities and wide variety of human disorders, it is no surprise that a great deal of effort is being expended in an attempt to identify ways to modulate PK activity. Some of this effort has involved biomimetic approaches using large molecules patterned on those involved in the actual cellular processes (e.g., mutant ligands (U.S. Pat. No. 4,966,849); soluble receptors and antibodies (Published PCT Appl. WO 94/10202, Kendall and Thomas,
Proc. Nat'l Acad. Sci.,
90:10705-09 (1994), Kim, et al.,
Nature,
362:841-844 (1993)); RNA ligands (Jelinek, et al.,
Biochemistry,
33:10450-56); Takano, et al.,
Mol. Bio. Cell
4:358A (1993); Kinsella, et al.,
Exp. Cell Res.
199:56-62 (1992); Wright, et al.,
J. Cellular Phys.,
152:448-57) and tyrosine kinase inhibitors (Published PCT Appls. WO 94/03427; WO 92/21660; WO 91/15495; WO 94/14808; U.S. Pat. No. 5,330,992; Mariani, et al.,
Proc. Am. Assoc. Cancer Res.,
35:2268 (1994)).
In addition to the above, attempts have been made to identify small molecules which act as PK inhibitors. For example, bis-monocylic, bicyclic and heterocyclic aryl compounds (Published PCT Appl. WO 92/20642), vinyleneazaindole derivatives (Published PCT Appl. WO 94/14808) and 1-cyclopropyl-4-pyridylquinolones (U.S. Pat. No. 5,330,992) have been described as tyrosine kinase inhibitors. Styryl compounds (U.S. Pat. No. 5,217,999), styryl-substituted pyridyl compounds (U.S. Pat. No. 5,302,606), quinazoline derivatives (EP App. No.0 566 266 A1), selenaindoles and selenides (Published PCT Appl. WO 94/03427), tricyclic polyhydroxylic compounds (Published PCT Appl. WO 92/21660), benzylphosphonic acid compounds (Published PCT Appl. WO 91/15495) and indolinone compounds (U.S. Pat. No. 5,792,783) have all been described as PTK inhibitors useful in the treatment of cancer. However these compounds have limited utility because of toxicity or poor bioavailability. Accordingly, there is a need for compounds that overcome these limitations. The compounds of the present invention fulfil this need.
SUMMARY OF THE INVENTION
The present invention is directed to certain 3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives that are prodrugs of compounds that exhibit PK modulating ability and are therefore useful in treating disorders related to abnormal PK activity.
Accordingly, in one aspect, the present invention relates a compound of Formula (I):
wherein:
R
1
and R
2
are independently selected from the group consisting of hydrogen, halo, alkyl, alkylthio, nitro, trihalomethyl, hydroxy, hydroxyalkyl, alkoxy, cyano, aryl, heteroaryl, —C(O)R
7
(where R
7
is selected from the group consisting of alkyl, amino, hydroxy, alkoxy, aryl, heteroaryl, aryloxy, heteroaryloxy, heterocycle, and aminoalkylamino), —NR
8
R
9
, —NR
8
C(O)R
9
, —SO
2
R
8
, and —S(O)
2
NR
8
R
9
(where R
8
and R
9
are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl, or R
8
and R
9
together with the nitrogen to which they are attached form a saturated heterocycloamino);
R
3
is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aminoalkyl, —C(O)R
7
(where R
7
is as defined above), aryl, and heteroaryl;
R
4
is selected from the group consisting of hydrogen, alkyl, —C(O)R
7
(where R
7
is as defined above), aryl, and heteroaryl;
R
5
is selected from the group consisting of hydrogen and —COR
10
where R
10
is alkyl, alkoxy, hydroxy, aryl, aryloxy, heteroaryl, heterocyle, alkylamino, dialkylamino, or —NR
11
R
12
where R
11
is hydrogen or alkyl, and R
12
is aminoalkyl, hydroxyalkyl, acetylalkyl, cyanoalkyl, carboxyalkyl, alkoxycarbonylalkyl, heteroaralkyl, or heterocyclylalkyl; wherein the alkyl chain in aminoalkyl, heteroaralkyl, heteroaralkyl, or heterocyclylalkyl is optionally substituted with one or two hydroxy group(s); or R
4
and R
5
together form —(CH
2
)
4
— or —(CH
2
)
m
CO(CH
2
)
n
— wherein n is 0 to 3, n is 0 to 3 provided that n+m is 3;
R
6
is:
(a) —OR
13
wherein R
13
is alkyl, trifluoromethyl, carboxyalkyl, aminoalkyl, phosphonooxyalkyl, sulfooxyalkyl, hydroxyalkyl, alkoxyalkyl, aryl, heteroaryl, heteroaralkyl, heterocyclyl, monosaccharides and heterocyclylalkyl; wherein the alkyl chain in carboxyalkyl, aminoalkyl, phosphonooxyalkyl, sulfooxyalkyl, heteroaralkyl, heterocyclylalkyl, hydroxyalkyl, or alkoxyalkyl is optionally substituted with one or two hydroxy grouP(s) and further wherein one or two carbon atoms in said alkyl chain are optionally replaced by oxygen, —NR
14
— (where R
14
is hydrogen or alkyl), —S—, or —SO
2
—; or
(b) —NR
15
R
16
where are R
15
and R
16
are independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, alkoxyalkyl, aminoalkyl, phosphonooxyalkyl, sulfooxyalkyl, hydroxyalkyl, aryl, heteroaryl, heteroaralkyl, and heterocyclylalkyl wherein the alkyl chain in carboxyalkyl, aminoalkyl, phosphonooxyalkyl, sulfooxyalkyl, heteroaralkyl, heterocyclylalkyl, hydroxyalkyl, or alkoxyalkyl is optionally substituted with one or two hydroxy grouP(s) and further wherein one or two carbon atoms in the alkyl chain are optionally replaced by oxygen, —NR
17
— (where R
17
is hydrogen or alkyl), —S—, or —SO
2
—; or
R
15
and R
16
together with the nitrogen atom to which they are attached form saturated or unsaturated heterocycloamino; or a pharmaceutically acceptable salt thereof.
Specifically, the compounds of the present invention convert in vivo to compounds of Formula (II):
that exhibit PK modulating ability, in particular PK inhibiting ability, and are therefore useful in treating disorders related to abnormal PK activity. The active compounds (II) formed from the compounds of the present invention are described in U.S. Pat. No. 5,792,783, and U.S. patent application Ser. No. 09/783,264, filed on Feb. 15, 2001, and titled “PYRROLE SUBSTITUTED 2-INDOLINONE PROTEIN KINASE INHIBITORS” which are hereby incorporated by reference.
The compounds of the present invention have advantages over compounds of Formula (II) by virtue of improved solubility and formulability. For example, it has been discovered that prodrugs of compound (II) where R
1
, R
2
, and R
5
are hydrogen and R
3
and R
4
are methyl provide improved aqueous solubility over the parent compound. It is contemplated that similar enhanced bioavailability will be observed with other compounds within the scope of the present invention.
A general description of the advantages and uses of prodrugs as pharmaceutically useful compounds is given in an article by Waller and George in Br.
J. Clin. Pharmac., Vol.
28, pp. 497-507, 1989.
By way of illustration, the following compounds of the present invention are converted to the indicated PK inhibitors of Formula (II).
Example
Active
No.
Prodrug
Compound
Reference
1
U.S. Pat. No. 5,792,783
2
3
&en
Koenig Marcel
Nematalla Asaad S.
Sun Connie Li
Tang Peng Cho
Vojkovsky Tomas
Burrous Beth A.
Foley & Lardner
McKane Joseph K.
Shiao Robert
Sugen Inc.
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