3-[4-Substituted...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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C544S130000, C544S144000, C544S121000, C546S193000, C546S201000, C548S468000

Reexamination Certificate

active

06642232

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of Invention
The present invention is directed to certain 3-[4-(substituted heterocyclyl)-pyrrol-2-ylmethylidene]-2-indolinone derivatives that inhibit kinases, in particular VEGFR, PDGFR, and c-kit kinases. Pharmaceutical compositions comprising these compounds, methods of treating diseases mediated by kinases, in particular VEGFR, PDGFR, and/or c-kit kinases, utilizing pharmaceutical compositions comprising these compounds, and methods of preparing them are also disclosed.
2. State of the Art
Protein kinases (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). For example, VEGFR and/or PDGFR kinases are involved in various cancers such as T-cell lymphoma, acute lymphoblasitc leukemia, acute myeloid leukemia, melanoma, glioblastoma and others (see Bellamy W. T. et al., Cancer Res. 1999, 59, 728-733). VEGF also plays a role in ocular diseases such as diabetic retinopathy, retinal ischemia, and retinal neovascularization.
In view of the apparent link between PK-related cellular activities and a wide variety of human disorders, 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 (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 and/or poor bioavailability. Accordingly, there is a need for compounds that do not suffer from such drawbacks. The compounds of the present invention fulfil this need.
SUMMARY OF THE INVENTION
In one aspect, the preferred embodiments of the present invention relate to a compound of Formula (IV):
wherein:
R is:
(a) hydrogen;
(b) —PO(OR
5
)
2
where each R
5
is independently hydrogen or alkyl;
(c) —COR
6
where R
6
is alkyl; or
(d) —CHR
7
NR
8
R
9
where R
7
is hydrogen or alkyl, and R
8
and R
9
are independently hydrogen or alkyl; or R
8
and R
9
together with the nitrogen atom to which they are attached form a heterocycloamino ring;
R
1
is hydrogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, F, Cl, Br, or I;
R
2
is hydrogen, alkyl, heteroaryl, alkoxy, hydroxy, F, Cl, Br, or I;
R
3
is hydrogen or alkyl;
R
4
is hydrogen or alkyl;
ring A is optionally substituted heterocycloamino;
Het is cycloalkylaminoalkyl, cycloalkylalkylaminoalkyl, heteroaryl, heterocycle, heterocyclylcarbonylalkyl, heterocyclylalkylcarbonyl, or heterocyclylalkyl;
X is NR
8
R
9
or OR
8
; and
n is 0 or 1; or
a pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates a compound of Formula (I):
wherein:
R is:
(a) hydrogen;
(b) —PO(OR
5
)
2
where each R
5
is independently hydrogen or alkyl;
(c) —COR
6
where R
6
is alkyl; or
(d) —CHR
7
NR
8
R
9
where R
7
is hydrogen or alkyl, and R
8
and R
9
are independently hydrogen or alkyl; or R
8
and R
9
together with the nitrogen atom to which they are attached form a heterocycloamino ring;
R
1
is hydrogen, alkyl, heteroaryl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, F, Cl, Br, or I;
R
2
is hydrogen, alkyl, alkoxy, hydroxy, F, Cl, Br, or I;
R
3
is hydrogen or alkyl;
R
4
is hydrogen or alkyl;
ring A is optionally substituted heterocycloamino;
Het is cycloalkylaminoalkyl, cycloalkylalkylaminoalkyl, heteroaryl, heterocycle, or heterocyclylalkyl; or
a pharmaceutically acceptable salt thereof.
In still another aspect, the preferred embodiments of the present invention relate to a compounds of Formula (I) or (IV):
wherein:
R is H;
R
1
is hydrogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, F, Cl, Br, or I;
R
2
is hydrogen, alkyl, heteroaryl, alkoxy, hydroxy, F, Cl, Br, or I;
R
3
is hydrogen or alkyl;
R
4
is hydrogen or alkyl;
ring A is optionally substituted heterocycloamino;
Het is cycloalkylaminoalkyl, cycloalkylalkylaminoalkyl, heteroaryl, heterocycle, heterocyclylcarbonylalkyl, heterocyclylalkylcarbonyl, or heterocyclylalkyl;
X is OR
8
(wherein R
8
is hydrogen or alkyl) or NR
8
R
9
, wherein R
8
and R
9
are independently hydrogen or alkyl; or R
8
and R
9
together with the nitrogen atom to which they are attached form a heterocycloamino ring; and
n is 0 or 1; or
a pharmaceutically acceptable salt thereof.
In yet another aspect this invention is directed to a pharmaceutical composition comprising one or more compound(s) of Formulas (I) or (IV) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
In another aspect, this invention is directed to a method of treating diseases mediated by abnormal protein kinase (PK) 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 compounds of Formulas (I) or (IV) and a pharmaceutically acceptable excipient. Specifically, the diseases mediated by EGF, Met, HER2, HER3, HER4, IR, IGF-1R, IRR, PDGFR&agr;, PDGFR&bgr;, CSFIR, C-Kit, C-fms, Flk-1R, Flk4, KDR/Flk-1, Flt-1, flt-3, FGFR-1R, FGFR-2R, FGFR-3R, FGFR-4R, 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 VEGFR, c-kit, and/or PDGFR kinases. 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, cancer of the endocrine system (e.g., cancer of the thyroid, parathyroid or adrenal glands), sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer,

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