Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-01-07
2001-07-24
Ford, John M. (Department: 1609)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S364000, C544S124000, C546S277400, C514S253010, C514S339000
Reexamination Certificate
active
06265403
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to compounds which inhibit tyrosine kinase enzymes, compositions which contain tyrosine kinase inhibiting compounds and methods of using tyrosine kinase inhibitors to treat tyrosine kinase-dependent diseases and conditions such as neoangiogenesis, cancer, tumor growth, atherosclerosis, age related macular degeneration, diabetic retinopathy, inflammatory diseases, and the like in mammals.
Aberrant vascularization is a key component in numerous disease states. For example, vascularization is a critical element of most solid tumors, such as cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung. These include histiocytic lymphoma, lung adenocarcinoma and small cell lung cancers. Additional examples include cancers in which overexpression or activation of Raf-activating oncogenes (e.g., K-ras, erb-B) is observed. More particularly, such cancers include pancreatic and breast carcinoma. Similarly, aberrant vascular growth in the retina can lead to visual degeneration which can culminate in blindness.
Experimental evidence suggests that the growth factor VEGF plays a critical role in angiogenesis. Vascular endothelial growth factor (VEGF) binds the high affinity membrane-spanning tyrosine kinase receptors KDR and Flt-1. Cell culture and gene knockout experiments indicate that each receptor contributes to different aspects of angiogenesis. KDR mediates the mitogenic function of VEGF whereas Flt-1 appears to modulate non-mitogenic functions such as those associated with cellular adhesion. Inhibiting KDR thus modulates the level of mitogenic VEGF activity and would therefore disrupt angiogenesis, providing a treatment for angiogenesis-mediated diseases, such as tumor proliferation, diabetic retinopathy, macular degeneration, inflammation, and the like.
VEGF accounts for most of the angiogenic activity produced in or near the retina in diabetic retinopathy. Ocular VEGF mRNA and protein are elevated by conditions such as retinal vein occlusion in primates and decreased pO
2
levels in mice that lead to neovascularization. Intraocular injections of anti-VEGF monoclonal antibodies or VEGF receptor immunofusions inhibit ocular neovascularization in both primate and rodent models. Regardless of the cause of induction of VEGF in human diabetic retinopathy, inhibition of ocular VEGF is useful in treating the disease.
Expression of VEGF is also significantly increased in hypoxic regions of animal and human tumors adjacent to areas of necrosis. VEGF is also upregulated by the expression of the oncogenes ras, raf, src and mutant p53 (all of which are relevant to targeting cancer). Monoclonal anti-VEGF antibodies inhibit the growth of human tumors in nude mice. Although these same tumor cells continue to express VEGF in culture, the antibodies do not diminish their mitotic rate. Thus, tumor-derived VEGF does not function as an autocrine mitogenic factor. Therefore, VEGF contributes to tumor growth in vivo by promoting angiogenesis through its paracrine vascular endothelial cell chemotactic and mitogenic activities. These monoclonal antibodies also inhibit the growth of typically less well vascularized human colon cancers in athymic mice and decrease the number of tumors arising from inoculated cells. Viral expression of a VEGF-binding construct of Flk-1, Flt-1, the mouse KDR receptor homologue, truncated to eliminate the cytoplasmic tyrosine kinase domains but retaining a membrane anchor, virtually abolishes the growth of a transplantable glioblastoma in mice presumably by the dominant negative mechanism of heterodimer formation with membrane spanning endothelial cell VEGF receptors. Embryonic stem cells, which normally grow as solid tumors in nude mice, do not produce detectable tumors if both VEGF alleles are knocked out. Taken together, these data indicate the role of VEGF in the growth of solid tumors.
Known heterocyclic kinase inhibitors are limited due to poor physical properties, pharmacokinetics, and selectivity against related kinases. The compounds of the instant invention represent novel structures which are unique and offer advantages over known KDR kinase inhibitors.
SUMMARY OF THE INVENTION
The present invention relates to compounds of Formula I which inhibit tyrosine kinase enzymes, compositions which contain these tyrosine kinase inhibiting compounds and methods of using the discosed tyrosine kinase inhibitors to treat tyrosine kinase-dependent diseases and conditions such as angiogenenesis, cancer, atherosclerosis, diabetic retinopathy, and the like in mammals.
DETAILED DESCRIPTION OF THE INVENTION
An embodiment of the present invention is a compound in accordance with formula I:
or a pharmaceutically acceptable salt or hydrate thereof,
wherein
W, X, Y and Z are independently CH or N;
R
1
is H, C
1-10
alkyl, C
3-6
cycloalkyl, aryl, halo, CF
3
, heterocyclyl, said alkyl, aryl, and heterocyclyl optionally substituted with one to three substituents selected from R
a
;
R
2
is H, C
1-6
alkyl, aryl, heteroaryl, or C
3-6
cycloalkyl, said alkyl, aryl, heteroaryl or cycloalkyl optionally substituted with one to three substituents selected from R
a
;
R
3
is H, halo, CN, —C
1-6
alkylene—CO
2
R, C
1-6
alkoxy, —C
1-6
alkylene-O—C
1-6
alkyl, C
1-6
alkyl, aryl, heteroaryl, C
3-6
cycloalkyl or CO
2
R, said alkyl, aryl, heteroaryl and cycloalkyl optionally substituted with one to three substituents selected from R
a
;
R
a
is C
1-10
alkyl, halogen, CF
3
, NO
2
, OR, NR
7
R
8
, aryl, heterocyclyl, said alkyl, aryl, and heterocyclyl optionally substituted with one or two substituents selected from NO
2
, CN, halo, aryl, C
1-6
alkoxy, —C
1-6
alkylene-O—C
1-6
alkyl, C
1-6
alkyl, and CF
3
;
R is H, or C
1-6
alkyl; and
R
7
and R
8
are independently H, C
1-10
alkyl, C
3-6
cycloalkyl, COR, —C
1-6
alkylene-O—C
1-6
alkyl, C
1-6
alkoxy, —C
1-6
, alkylene-aryl, COOR, aryl, benzyl, or heterocyclyl,
or NR
7
R
8
are taken together to form a 5-10 membered saturated or unsaturated heterocyclic ring containing, in addition to the nitrogen atom attached to R
7
and R
8
, one or two additional heteroatoms selected from N, O, and S, said heterocyclic ring optionally substituted with CN, halo, or C
1-6
alkyl.
A second embodiment of the present invention is a compound of formula I, wherein
W is C—H or N;
X, Y and Z are CH or N, provided only one of X, Y and Z is N;
R
1
is H, C
1-10
alkyl, C
3-6
cycloalkyl, aryl, halo, CF
3
, or heterocyclyl, said alkyl, cycloalkyl aryl, and heterocyclyl are optionally substituted with one to three substituents selected from R
a
;
R
2
is H, C
1-6
alkyl, aryl, heteroaryl, or C
3-6
cycloalkyl, said alkyl, aryl, heteroaryl and cycloalkyl are optionally substituted with one to three substituents selected from R
a
;
R
3
is H, halo, CN, —C
1-6
alkylene-CO
2
R, C
1-6
alkoxy, —C
1-6
alkylene-O—C
1-6
alkyl, C
1-6
alkyl, aryl, heteroaryl, C
3-6
cycloalkyl or CO
2
R, said alkyl, aryl, heteroaryl and cycloalkyl optionally substituted with one to three substituents selected from R
a
;
R
a
is C
1-10
alkyl, halogen, CF
3
, NO
2
, OR, NR
7
R
8
, aryl, heterocyclyl, said alkyl, aryl, and heterocyclyl optionally substituted with one or two substituents selected from NO
2
, CN, halo, aryl, C
1-6
alkoxy, —C
1-6
alkylene-O—C
1-6
alkyl, C
1-6
alkyl, and CF
3
;
R is H or C
1-6
alkyl; and
R
7
and R
8
are independently H, C
1-10
alkyl, C
3-6
cycloalkyl, COR, —C
1-6
alkylene-O—C
1-6
alkyl, C
1-6
alkoxy, —C
1-6
alkylene-aryl, COOR, aryl, benzyl, C
3-10
heterocyclyl, or heteroaryl,
or NR
7
R
8
are taken together to form a 5-10 membered saturated or unsaturated heterocyclic ring containing, in addition to the nitrogen atom attached to R
7
and R
8
, one or two additional heteroatoms selected from N, O, and S, said heterocyclic ring optionally substituted with CN, halo, or C
1-6
alkyl.
Another embodiment of the invention is the compound described immediately above wherein Y is N, X is C—H, and Z is C—H.
In yet another embodiment, the compound of Formula I is further de
Fraley Mark E.
Hungate Randall W.
Tebben Andrew J.
Daniel Mark R.
Ford John M.
Garcia-Rivas J. Antonio
Liu Hong
Merck & Co. , Inc.
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