Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-05-30
2003-07-29
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S414000, C544S058200, C544S058400, C544S121000, C544S130000, C544S144000, C544S373000, C546S201000, C546S227000, C548S253000, C548S255000, C548S312100, C548S468000
Reexamination Certificate
active
06599902
ABSTRACT:
INTRODUCTION
The present invention relates generally to organic chemistry, biochemistry, pharmacology and medicine. More particularly, it relates to novel 5-aralkylsulfonyl-3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives that inhibit kinases, in particular met kinase, pharmaceutical compositions comprising these compounds, methods of treating diseases mediated by kinases utilizing pharmaceutical compositions comprising these compounds, and methods of preparing them are disclosed.
BACKGROUND OF THE INVENTION
The following is offered as background information only to aid in understanding the invention, 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. application. Ser. No. 4,966,849); soluble receptors and antibodies (App. No. 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 (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 (PCT WO 92/20642), vinyleneazaindole derivatives (PCT 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 (PCT WO 94/03427), tricyclic polyhydroxylic compounds (PCT WO 92/21660), benzylphosphonic acid compounds (PCT 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
In one aspect, the present invention relates a compound of Formula (I):
and pharmaceutically acceptable salts thereof, wherein:
n is 0, 1, or 2;
m is 1, 2, or 3;
R
1
and R
2
are each independently hydrogen or alkyl;
R
3
, R
4
, and R
5
each are independently hydrogen, halo, alkyl, cycloalkyl, haloalkyl, hydroxy, alkoxy, alkoxycarbonyl, haloalkoxy, cyano, carboxy, carboxyalkyl, nitro, aryl, aryloxy, heteroaryl, heteroaryloxy, —CONR
10
R
11
, —(alkylene)—CONR
10
R
11
, or —NR
10
R
11
, (where R
10
is hydrogen or alkyl, and R
11
is aryl, heteroaryl, heterocycle, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, acetylalkyl, cyanoalkyl, carboxyalkyl, alkoxycarbonylalkyl, heteroaralkyl, aralkyl, or heterocyclylalkyl wherein the alkyl chain in aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aralkyl, heteroaralkyl, or heterocyclylalkyl is optionally substituted with one or two hydroxy or R
10
and R
11
together with the nitrogen atom to which they are attached combine to form saturated or unsaturated heterocycloamino);
R
6
is hydrogen, alkyl, cycloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, heterocyclylalkyl, aryl, heteroaryl, carboxy, alkoxycarbonyl, heterocyclylcarbonyl, aminoalkylcarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, —CONR
10
R
11
, or —(alkylene)—CONR
10
R
11
(where R
10
is hydrogen or alkyl, and R
11
is aryl, heteroaryl, heterocycle, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, acetylalkyl, cyanoalkyl, carboxyalkyl, alkoxycarbonylalkyl, heteroaralkyl, aralkyl, or heterocyclylalkyl wherein the alkyl chain in aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aralkyl, heteroaralkyl, or heterocyclylalkyl is optionally substituted with one or two hydroxy, or R
10
and R
11
together with the nitrogen atom to which they are attached combine to form saturated or unsaturated heterocycloamino);
R
7
and R
8
are independently hydrogen, alkyl, cycloalkyl, heterocyclylalkyl, —COR
12
, —(alkylene)—COR
12
(where R
12
is alkoxy, hydroxy, or heterocyle, alkylamino, dialkylamino), —SO
2
R
14
, —CONR
13
R
14
, or —(alkylene)—CONR
13
R
14
(where R
13
is hydrogen or alkyl, and R
14
is aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, 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 when R
13
and R
14
are attached to a nitrogen atom R
13
and R
14
together with the nitrogen atom to which they are attached form saturated or unsaturated heterocycloamino);
R
6
and R
7
or R
7
and R
8
can combine to form a saturated or unstaturated 5 to 8 membered ring,
R
9
is:
(a) hydrogen or alkyl;
(b) —PO(OR
15
)
2
where each R
15
is independently hydrogen or alkyl;
(c) —COR
16
where R
16
is hydrogen or alkyl; or
(d) —CHR
17
NR
18
R
19
where R
17
is hydrogen or alkyl, and R
18
and R
19
are independently hydrogen or alkyl, or R
18
and R
19
together with the nitrogen atom to which they are attached form heterocycloamino.
In a second aspect, this invention is directed to a pharmaceutical composition comprising one or more compound(s) of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
In a third aspect, this invention is directed to a method of treating diseases mediated by abnormal protein kinase activity, in particular, receptor tyrosine kinases (RTKs), non-receptor protein tyrosine kinases (CTKs) and serine/threonine protein kinases (STKs), in an organism, in particular humans, which method comprises administering to said organism a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable excipient. Specifically, the diseases mediated by EGFR, Met, HER2, HER3, HER4, IR, IGF-1R, IRR, PDGFR&agr;, PDGFR&bgr;, CSFIR, C-Kit, C-fms, Flk4, KDR/Flk-1, Flt-1, FGFR1, FGFR2, FGFR3, FGFR
4
, Src, Frk, Btk, Csk, Abl, ZAP70, Fes/Fps, Fak, Jak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, Yrk, CDK2 and Raf. In particular, diseases mediated by Met.
Such diseases include by way of example and not limitation, cancers such as lung cancer, NSCLC (non small cell lung cancer), bone cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine,
Cui Jingrong
Liang Congxin
Ramphal John
Sun Connie Li
Tang Peng Cho
Burrous Beth A.
Foley & Lardner
Ramsuer Robert W.
Sugen Inc.
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