Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-04-13
2003-06-10
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C548S544000, C548S227000, C548S366400, C548S132000, C548S183000, C548S317100, C548S263400, C548S251000, C548S122000, C548S255000, C514S425000, C514S429000, C514S473000, C514S376000, C514S380000, C514S364000, C514S369000, C514S392000, C514S593000, C514S600000, C514S404000, C514S384000, C514S381000, C514S360000, C514S359000, C549S313000, C564S043000, C564S095000, C564S086000, C564S171000, C544S182000
Reexamination Certificate
active
06576632
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to novel biaryl compounds that are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals. This invention also relates to a method of using such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
A cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene (i.e. a gene that upon activation leads to the formation of malignant tumor cells). Many oncogenes encode proteins that are aberrant tyrosine kinases capable of causing cell transformation. Alternatively, the overexpression of a normal proto-oncogenic tyrosine kinase may also result in proliferative disorders, sometimes resulting in a malignant phenotype. It has been shown that certain tyrosine kinases may be mutated or overexpressed in many human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynecological and thyroid cancers. Furthermore, the overexpression of a ligand for a tyrosine kinase receptor may result in an increase in the activation state of the receptor, resulting in proliferation of the tumor cells or endothelial cells. Thus, it is believed that the growth of mammalian cancer cells can be selectively inhibited by reducing tyrosine kinase activity.
Polypeptide growth factors, such as vascular endothelial growth factor (VEGF) having a high affinity to the human kinase insert-domain-containing receptor (KDR) or the murine fetal liver kinase 1 (FLK-1) receptor, have been associated with the proliferation of endothelial cells and more particularly vasculogenesis and angiogenesis. See PCT international application publication number WO 95/21613 (published Aug. 17, 1995). A significant body of evidence has been put forth detailing the importance of VEGF in the formation of new blood vessels (angiogenesis). It has also been noted that new blood vessel formation is crucial in supplying and maintaining the physiological conditions and nutrients necessary for tumor growth and metastasis. It has been shown that both VEGF receptor subtypes appear to be over expressed in proliferating endothelial cells located in near proximity to tumor cells in vivo. At the molecular level, intracellular portions of both FLT-1 and FLK-1 contain functional tyrosine kinase domains. Kinase activities depend on high affinity to, and interaction with, VEGF. Such interaction results in the autophosphorylation of the receptors and ultimately in endothelial cell proliferation. High affinity VEGF binding and the resulting functional effects appear to depend on the presence of specific heparin sulfate proteoglycans (VEGF glyceptor) associated with the extracellular matrix of endothelial cells. This supposition is supported by the ability of exogenous levels of heparin to inhibit VEGF induced endothelial cell proliferation by acting as a sink for secreted VEGF. By inhibiting the binding of VEGF to VEGF glyceptor (GAG), phosphorylation of tyrosine (kinase) is modulated. Agents, such as the compounds of the present invention, which are capable of modulating the KDR/FLK-1 receptor, may be used to treat disorders related to vasculogenesis or angiogenesis. Such disorders include, but are not limited to, diabetes, diabetic retinopathy, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula I
and to pharmaceutically acceptable salts, hydrates and prodrugs thereof, wherein:
R
1
is H, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, —(CH
2
)
t
(C
6
-C
10
aryl), or —(CH
2
)
t
(4 to 10 membered heterocyclic), wherein t is an integer from 0 to 5; said alkyl group optionally including 1 or 2 hetero moieties selected from O, S and —N(R
6
)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said aryl and heterocyclic R
1
groups being optionally fused to a C
6
-C
10
aryl group, a C
5
-C
8
saturated cyclic group, or a 4 to 10 membered heterocyclic group; one or two carbon atoms in said 4 to 10 membered heterocyclic group of R
1
and R
5
being optionally substituted by an oxo (═O) moiety; the —(CH
2
)
t
— moieties of R
1
optionally including a carbon-carbon double or triple bond when t is an integer from two to five; R
1
groups being optionally substituted by one to five R
5
groups;
each R
5
is independently selected from C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —OR
6
, —C(O)R
7
, —C(O)OR
6
, —NR
7
C(O)OR
6
, —OC(O)R
6
, —NR
7
SO
2
R
6
, —SO
2
NR
6
R
7
, —NR
7
C(O)R
6
, —C(O)NR
6
R
7
, —NR
6
R
7
, —S(O)
j
R
8
wherein j is an integer ranging from zero to two, —SO
3
H, —NR
6
(CR
7
R
8
)
t
OR
7
, —(CH
2
)
t
(C
6
-C
10
aryl), —SO
2
(CH
2
)
t
(C
6
-C
10
aryl), —S(CH
2
)
t
(C
6
-C
10
aryl), —O(CH
2
)
t
(C
6
-C
10
aryl), —(CH
2
)
t
(4 to 10 membered heterocyclic), and —(CR
7
R
8
)
m
OR
7
, wherein m is an integer from one to five and t is an integer from zero to five; said alkyl group optionally containing one or two hetero moieties selected from O, S and —N(R
7
)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; aryl and heterocyclic moieties of R
5
being optionally fused to a C
6
-C
10
aryl group, a C
5
-C
8
saturated cyclic group, or a 4 to 10 membered heterocyclic group; one or two carbon atoms of the heterocyclic moieties of R
5
being optionally substituted by an oxo (═O) moiety; and the alkyl, aryl and heterocyclic moieties of R
5
groups being optionally substituted by one to three substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —NR
7
SO
2
R
6
, —SO
2
NR
6
R
7
, —C(O)R
6
, —C(O)OR
6
, —OC(O)R
6
, —NR
7
C(O)R
6
, —C(O)NR
6
R
7
, —NR
6
R
7
, —(CR
7
R
8
)
m
OR
7
wherein m is an integer from one to five, —OR
6
and R
6
;
each R
6
is independently selected from H, C
1
-C
10
alkyl, —(CH
2
)
t
(C
6
-C
10
aryl), and —(CH
2
)
t
(4 to 10 membered heterocyclic), wherein t is an integer from zero to five; said alkyl group optionally including one or two hetero moieties selected from O, S and —N(R
5
)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said aryl and heterocyclic R
6
groups being optionally fused to a C
6
-C
10
aryl group, a C
5
-C
8
saturated cyclic group, or a 4 to 10 membered heterocyclic group; the foregoing moieties of R
6
, with the exception of H, being optionally substituted by one to three substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —C(O)R
7
, —C(O)OR
7
, —CO(O)R
7
, —NR
7
C(O)R
8
, —C(O)NR
7
R
8
, —NR
7
R
8
, hydroxy, C
1
-C
6
alkyl, and C
1
-C
6
alkoxy;
each R
7
and R
8
is independently H or C
1
-C
6
alkyl;
R
2
is a group having an acidic proton, particularly —CO
2
H, —CONHSO
2
R
1
, —CONR
1
(CH
2
)CO
2
H, —SO
2
H, —PO
3
H
2
,
each R
3
is independently selected from H and R
2
;
R
4
is —(CH
2
)
t
(C
6
-C
10
aryl), or —(CH
2
)
t
(4 to 10 membered heterocyclic), wherein t is an integer from zero to five; said alkyl group optionally including one or two hetero moieties selected from O, S and —N(R
5
)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said aryl and heterocyclic R
4
groups are optionally fused to a C
6
-C
10
aryl group, a C
5
-C
8
saturated cyclic group, or a 4 to 10 membered heterocyclic group; one or two carbon atoms of the heterocyclic moieties of R
4
being optionally substituted by an oxo (═O) moiety; the —(CH
2
)
t
— moieties of R
4
optionally including a carbon-carbon double or triple bond where t is an integer from two to five, R
4
being optionally substituted by one to five R
5
groups;
R
11
and R
10
are each independently R
1
; R
Awad Mohamed M. A.
Blake James F.
Goldstein Steven W.
Kramer Kevin W.
Longo Kelly P.
Banerjee Krishna G.
Ginsburg Paul H.
Liu Hong
Pfizer Inc
Richardson Peter C.
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