U.S. patent application number 09/788720 was filed with the patent office on 2001-11-29 for tyrosine kinase inhibitors.
Invention is credited to Fraley, Mark E., Hartman, George D., Hungate, Randall W..
Application Number | 20010047007 09/788720 |
Document ID | / |
Family ID | 26880711 |
Filed Date | 2001-11-29 |
United States Patent
Application |
20010047007 |
Kind Code |
A1 |
Fraley, Mark E. ; et
al. |
November 29, 2001 |
Tyrosine kinase inhibitors
Abstract
The present invention relates to compounds which inhibit,
regulate and/or modulate tyrosine kinase signal transduction,
compositions which contain these compounds, and methods of using
them to treat tyrosine kinase-dependent diseases and conditions,
such as angiogenesis, cancer, tumor growth, atherosclerosis, age
related macular degeneration, diabetic retinopathy, inflammatory
diseases, and the like in mammals.
Inventors: |
Fraley, Mark E.; (North
Wales, PA) ; Hartman, George D.; (Lansdale, PA)
; Hungate, Randall W.; (Newbury Park, CA) |
Correspondence
Address: |
MERCK AND CO INC
P O BOX 2000
RAHWAY
NJ
070650907
|
Family ID: |
26880711 |
Appl. No.: |
09/788720 |
Filed: |
February 20, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60185024 |
Feb 25, 2000 |
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Current U.S.
Class: |
514/300 ;
514/301; 514/302; 546/113; 546/114; 546/115 |
Current CPC
Class: |
A61K 45/06 20130101;
C07D 471/04 20130101 |
Class at
Publication: |
514/300 ;
514/301; 514/302; 546/113; 546/114; 546/115 |
International
Class: |
C07D 471/02; C07D
491/02; C07D 498/02; C07D 513/02; C07D 515/02; A61K 031/44 |
Claims
What is claimed is:
1. A compound of Formula I 30or a pharmaceutically acceptable salt
or stereoisomer thereof, wherein Q is S, O, or --E.dbd.D--; 31is
selected from the following: 32a is 0 or 1; b is 0 or 1; s is 1 or
2; m is 0, 1, or 2; E.dbd.D is C.dbd.N, N.dbd.C, or C.dbd.C;
R.sup.1, R.sup.1a, R.sup.4 and R.sup.5 are independently selected
from: 1) H, 2) (C.dbd.O).sub.aO.sub.bC.sub.1-C.sub.10 alkyl,
optionally substituted with one to three substituents selected from
R.sup.6, 3) (C.dbd.O).sub.aO.sub.baryl, optionally substituted with
one to three substituents selected from R.sup.6, 4)
(C.dbd.O).sub.aO.sub.bC.sub.2-C.su- b.10 alkenyl, optionally
substituted with one to three substituents selected from R.sup.6,
5) (C.dbd.O).sub.aO.sub.bC.sub.2-C.sub.10 alkynyl, optionally
substituted with one to three substituents selected from R.sup.6,
6) SO.sub.mC.sub.1-C.sub.10 alkyl, optionally substituted with one
to three substituents selected from R.sup.6, 7) SO.sub.maryl,
optionally substituted with one to three substituents selected from
R.sup.6, 8) CO.sub.2H, 9) halo, 10) CN, 11) OH, 12)
O.sub.bC.sub.1-C.sub.6 perfluoroalkyl, and 13)
(C.dbd.O).sub.aNR.sup.7R.s- up.8; R.sup.2 and R.sup.3 are
independently selected from the group consisting of: 1) H, 2)
(C.dbd.O)O.sub.aC.sub.1-C.sub.10 alkyl, 3) (C.dbd.O)O.sub.aaryl, 4)
C.sub.1-C.sub.10 alkyl, 5) SO.sub.mC.sub.1-C.sub.10 alkyl, 6)
SO.sub.maryl, 7) (C.dbd.O).sub.aO.sub.bC.sub.2-C.sub.10 alkenyl, 8)
(C.dbd.O).sub.aO.sub.bC.sub.2-C.sub.10 alkynyl, and 9) aryl, said
alkyl, aryl, alkenyl and alkynyl is optionally substituted with one
to three substituents selected from R.sup.6; R.sup.4a is selected
from the group consisting of: 1) (C.dbd.O)O.sub.aC.sub.1-C.sub.10
alkyl, 2) (C.dbd.O)O.sub.aaryl, 3) C.sub.1-C.sub.10 alkyl, 4)
SO.sub.mC.sub.1-C.sub.10 alkyl, 5) SO.sub.maryl, 6)
(C.dbd.O).sub.aO.sub.bC.sub.2-C.sub.10 alkenyl, 7)
(C.dbd.O).sub.aO.sub.bC.sub.2-C.sub.10 alkynyl, and 8) aryl, said
alkyl, aryl, alkenyl and alkynyl is optionally substituted with one
to three substituents selected from R.sup.6; R.sup.6 is: 1) H, 2)
(C.dbd.O).sub.aO.sub.bC.sub.1-C.sub.6 alkyl, 3)
(C.dbd.O).sub.aO.sub.bary- l, optionally substituted with one to
three substituents selected from R.sup.6a, 4) C.sub.2-C.sub.10
alkenyl, 5) C.sub.2-C.sub.10 alkynyl, 6) heterocyclyl, optionally
substituted with one to three substituents selected from R.sup.6a,
7) CO.sub.2H, 8) halo, 9) CN, 10) OH, 11) oxo, 12)
O.sub.bC.sub.1-C.sub.6 perfluoroalkyl, or 13) NR.sup.7R.sup.8;
R.sup.6a is: 1) H, 2) SO.sub.maryl, 3) SO.sub.mC.sub.1-C.sub.6
alkyl, 4) (C.dbd.O).sub.aO.sub.bC.sub.1-C.sub.6 alkyl, 5)
(C.dbd.O).sub.aO.sub.bary- l, 6) C.sub.2-C.sub.10 alkenyl, 7)
C.sub.2-C.sub.10 alkynyl, 8) heterocyclyl, 9) CO.sub.2H, 10) halo,
11) CN, 12) OH, 13) oxo, 14) O.sub.bC.sub.1-C.sub.6 perfluoroalkyl,
or 15) N(C.sub.1-C.sub.6 alkyl).sub.2; R.sup.7 and R.sup.8 are
independently selected from: 1) H, 2)
(C.dbd.O)O.sub.bC.sub.1-C.sub.10 alkyl, optionally substituted with
one to three substituents selected from R.sup.6a, 3)
(C.dbd.O)O.sub.baryl, optionally substituted with one to three
substituents selected from R.sup.6a, 4) C.sub.1-C.sub.10 alkyl,
optionally substituted with one to three substituents selected from
R.sup.6a, 5) aryl, optionally substituted with one to three
substituents selected from R.sup.6a, 6) C.sub.2-C.sub.10 alkenyl,
optionally substituted with one to three substituents selected from
R.sup.6a, 7) C.sub.2-C.sub.10 alkynyl, optionally substituted with
one to three substituents selected from R.sup.6a, and 8)
heterocyclyl, or R.sup.7 and R.sup.8 can be taken together with the
nitrogen to which they are attached to form a 5-7 membered
heterocycle containing, in addition to the nitrogen, one or two
additional heteroatoms selected from N, O and S, said heterocycle
optionally substituted with one to three substituents selected from
R.sup.6a.
2. The compound of claim 1, wherein Q is E.dbd.D.
3. The compound of claim 2, wherein E.dbd.D is C.dbd.C.
4. The compound of claim 3, wherein R.sup.1, R.sup.1a, R.sup.4 and
R.sup.5 are independently selected from: 1) H, 2)
(C.dbd.O).sub.aO.sub.bC.sub.1-C- .sub.6 alkyl, optionally
substituted with one to three substituents selected from R.sup.6,
3) (C.dbd.O).sub.aO.sub.baryl, optionally substituted with one to
three substituents selected from R.sup.6, 4)
(C.dbd.O).sub.aO.sub.bC.sub.2-C.sub.6 alkenyl, optionally
substituted with one to three substituents selected from R.sup.6,
5) CO.sub.2H, 6) halo, 7) CN, 8) OH, 9) O.sub.bC.sub.1-C.sub.3
perfluoroalkyl, and 10) (C.dbd.O).sub.aNR.sup.7R.sup.8; R.sup.2 and
R.sup.3 are independently selected from the group consisting of: 1)
H, 2) (C.dbd.O)O.sub.aC.sub.1-C- .sub.6 alkyl, and 3)
C.sub.1-C.sub.6 alkyl; R.sup.4a is (C.dbd.O)O.sub.aC.sub.1-C.sub.6
alkyl or C.sub.1-C.sub.6 alkyl; R.sup.6 is: 1) H, 2)
(C.dbd.O).sub.aO.sub.bC.sub.1-C.sub.6 alkyl, 3)
(C.dbd.O).sub.aO.sub.baryl, optionally substituted with one to
three substituents selected from R.sup.6a, 4) C.sub.2-C.sub.6
alkenyl, 5) heterocyclyl, optionally substituted with one to three
substituents selected from R.sup.6a, 6) CO.sub.2H, 7) halo, 8) CN,
9) OH, 10) oxo, 11) O.sub.bC.sub.1-C.sub.3 perfluoroalkyl, or 12)
NR.sup.7R.sup.8; R.sup.6a is: 1) H, 2) SO.sub.maryl, 3)
SO.sub.mC.sub.1-C.sub.6 alkyl, 4)
(C.dbd.O).sub.aO.sub.bC.sub.1-C.sub.6 alkyl, 5)
(C.dbd.O).sub.aO.sub.bary- l, 6) C.sub.2-C.sub.6 alkenyl, 7)
heterocyclyl, 8) CO.sub.2H, 9) halo, 10) CN, 11) OH, 12) oxo, 13)
O.sub.bC.sub.1-C.sub.3 perfluoroalkyl, or 14) N(C.sub.1-C.sub.6
alkyl).sub.2; R.sup.7 and R.sup.8 are independently selected from:
1) H, 2) (C.dbd.O)O.sub.bC.sub.1-C.sub.6 alkyl, optionally
substituted with one to three substituents selected from R.sup.6a,
3) (C.dbd.O)O.sub.baryl, optionally substituted with one to three
substituents selected from R.sup.6a, 4) C.sub.1-C.sub.6 alkyl,
optionally substituted with one to three substituents selected from
R.sup.6a, 5) aryl, optionally substituted with one to three
substituents selected from R.sup.6a, 6) C.sub.2-C.sub.6 alkenyl,
optionally substituted with one to three substituents selected from
R.sup.6a, and 7) heterocyclyl, or R.sup.7 and R.sup.8 can be taken
together with the nitrogen to which they are attached to form a 5-7
membered heterocycle containing, in addition to the nitrogen, one
or two additional heteroatoms selected from N, O and S, said
heterocycle optionally substituted with one to three substituents
selected from R.sup.6a.
5. The compound of claim 3, wherein a is 0 or 1; b is 0 or 1; s is
1; R.sup.1 and R.sup.4 are independently selected from: 1) H, 2)
(C.dbd.O).sub.aO.sub.bC.sub.1-C.sub.6 alkyl, optionally substituted
with one to three substituents selected from R.sup.6, 3)
(C.dbd.O).sub.aO.sub.baryl, optionally substituted with one to
three substituents selected from R.sup.6, 4)
(C.dbd.O).sub.aO.sub.bC.sub.2-C.su- b.6 alkenyl, optionally
substituted with one to three substituents selected from R.sup.6,
5) (C.dbd.O).sub.aO.sub.bC.sub.2-C.sub.6 alkynyl, optionally
substituted with one to three substituents selected from R.sup.6,
6) CO.sub.2H, 7) halo, 8) CN, 9) OH, 10) O.sub.bC.sub.1-C.sub.3
perfluoroalkyl, and 11) (C.dbd.O).sub.aNR.sup.7R.sup.8; R.sup.2 and
R.sup.3 are independently selected from H and methyl; R.sup.4a is
methyl; R.sup.5 and R.sup.1a are H; R.sup.6 is: 1) H, 2)
(C.dbd.O).sub.aO.sub.bC.- sub.1-C.sub.6
alkyl,.dbd.O).sub.aO.sub.baryl, optionally substituted with one to
three substituents selected from R.sup.6a,C.sub.2-C.sub.10 alkenyl,
3) C.sub.2-C.sub.10 alkynyl, 4) heterocyclyl, optionally
substituted with one to three substituents selected from R.sup.6a,
5) CO.sub.2H, 6) halo, 7) CN, 8) OH, 9) oxo, 10)
O.sub.bC.sub.1-C.sub.3 perfluoroalkyl, or 11) NR.sup.7R.sup.8;
R.sup.6a is: 1) H, 2) SO.sub.maryl, 3) SO.sub.mC.sub.1-C.sub.6
alkyl, 4) (C.dbd.O).sub.aO.sub.bC.sub.1-C.sub.6 alkyl, 5)
(C.dbd.O).sub.aO.sub.bary- l, 6) C.sub.2-C.sub.10 alkenyl, 7)
C.sub.2-C.sub.10 alkynyl, 8) heterocyclyl, 9) CO.sub.2H, 10) halo,
11) CN, 12) OH, 13) oxo, 14) O.sub.bC.sub.1-C.sub.3 perfluoroalkyl,
or 15) N(C.sub.1-C.sub.6 alkyl).sub.2; R.sup.7 and R.sup.8 are
independently selected from: 1) H, 2)
(C.dbd.O)O.sub.bC.sub.1-C.sub.6 alkyl, optionally substituted with
one to three substituents selected from R.sup.6a, 3)
(C.dbd.O)O.sub.baryl, optionally substituted with one to three
substituents selected from R.sup.6a, 4) C.sub.1-C.sub.10 alkyl,
optionally substituted with one to three substituents selected from
R.sup.6a, 5) aryl, optionally substituted with one to three
substituents selected from R.sup.6a, 6) C.sub.2-C.sub.6 alkenyl,
optionally substituted with one to three substituents selected from
R.sup.6a, 7) C.sub.2-C.sub.6 alkynyl, optionally substituted with
one to three substituents selected from R.sup.6a, and 8)
heterocyclyl, or R.sup.7 and R.sup.8 can be taken together with the
nitrogen to which they are attached to form a piperidinyl,
piperazinyl, morpholinyl or pyrrolidinyl group, optionally
substituted with one or two substituents selected from
R.sup.6a.
6. A compound which is
3-(4-methyl-5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyri-
din-2-yl)-1H-quinolin-2-one or a pharmaceutically acceptable salt
or stereoisomer thereof.
7. A pharmaceutical composition which is comprised of a compound in
accordance with claim 1 and a pharmaceutically acceptable
carrier.
8. A method of treating or preventing cancer in a mammal in need of
such treatment which is comprised of administering to said mammal a
therapeutically effective amount of a compound of claim 1.
9. A method of treating cancer or preventing cancer in accordance
with claim 8 wherein the cancer is selected from cancers of the
brain, genitourinary tract, lymphatic system, stomach, larynx and
lung.
10. A method of treating or preventing cancer in accordance with
claim 8 wherein the cancer is selected from histiocytic lymphoma,
lung adenocarcinoma, small cell lung cancers, pancreatic cancer,
gioblastomas and breast carcinoma.
11. A method of treating or preventing a disease in which
angiogenesis is implicated, which is comprised of administering to
a mammal in need of such treatment a therapeutically effective
amount of a compound of claim 1.
12. A method in accordance with claim 11 wherein the disease is an
ocular disease.
13. A method of treating or preventing retinal vascularization
which is comprised of administering to a mammal in need of such
treatment a therapeutically effective amount of compound of claim
1.
14. A method of treating or preventing diabetic retinopathy which
is comprised of administering to a mammal in need of such treatment
a therapeutically effective amount of compound of claim 1.
15. A method of treating or preventing age-related macular
degeneration which is comprised of administering to a mammal in
need of such treatment a therapeutically effective amount of a
compound of claim 1.
16. A method of treating or preventing inflammatory diseases which
comprises administering to a mammal in need of such treatment a
therapeutically effective amount of a compound of claim 1.
17. A method according to claim 16 wherein the inflammatory disease
is selected from rheumatoid arthritis, psoriasis, contact
dermatitis and delayed hypersensitivity reactions.
18. A method of treating or preventing a tyrosine kinase-dependent
disease or condition which comprises administering a
therapeutically effective amount of a compound of claim 1.
19. A pharmaceutical composition made by combining the compound of
claim 1 and a pharmaceutically acceptable carrier.
20. A process for making a pharmaceutical composition which
comprises combining a compound of claim 1 with a pharmaceutically
acceptable carrier.
21. A method of treating or preventing bone associated pathologies
selected from osteosarcoma, osteoarthritis, and rickets which
comprises administering a therapeutically effective amount of a
compound of claim 1.
22. The composition of claim 7 further comprising a second compound
selected from: 1) an estrogen receptor modulator, 2) an androgen
receptor modulator, 3) retinoid receptor modulator, 4) a cytotoxic
agent, 5) an antiproliferative agent, 6) a prenyl-protein
transferase inhibitor, 7) an HMG-CoA reductase inhibitor, 8) an HIV
protease inhibitor, 9) a reverse transcriptase inhibitor, and 10)
another angiogenesis inhibitor.
23. The composition of claim 22, wherein the second compound is
another angiogenesis inhibitor selected from the group consisting
of a tyrosine kinase inhibitor, an inhibitor of epidermal-derived
growth factor, an inhibitor of fibroblast-derived growth factor, an
inhibitor of platelet derived growth factor, an MMP inhibitor, an
integrin blocker, interferon-a, interleukin-12, pentosan
polysulfate, a cyclooxygenase inhibitor, carboxyamidotriazole,
combretastatin A-4, squalamine,
6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin,
troponin-1, and an antibody to VEGF.
24. The composition of claim 22, wherein the second compound is an
estrogen receptor modulator selected from tamoxifen and
raloxifene.
25. A method of treating cancer which comprises administering a
therapeutically effective amount of a compound of claim 1 in
combination with radiation therapy.
26. A method of treating or preventing cancer which comprises
administering a therapeutically effective amount of a compound of
claim 1 in combination with a compound selected from: 1) an
estrogen receptor modulator, 2) an androgen receptor modulator, 3)
retinoid receptor modulator, 4) a cytotoxic agent, 5) an
antiproliferative agent, 6) a prenyl-protein transferase inhibitor,
7) an HMG-CoA reductase inhibitor, 8) an HIV protease inhibitor, 9)
a reverse transcriptase inhibitor, and 10) another angiogenesis
inhibitor.
27. A method of treating cancer which comprises administering a
therapeutically effective amount of a compound of claim 1 in
combination with radiation therapy and a compound selected from: 1)
an estrogen receptor modulator, 2) an androgen receptor modulator,
3) retinoid receptor modulator, 4) a cytotoxic agent, 5) an
antiproliferative agent, 6) a prenyl-protein transferase inhibitor,
7) an HMG-CoA reductase inhibitor, 8) an HIV protease inhibitor, 9)
a reverse transcriptase inhibitor, and 10) another angiogenesis
inhibitor.
28. A method of treating or preventing cancer which comprises
administering a therapeutically effective amount of a compound of
claim 1 and paclitaxel or trastuzumab.
29. A method of treating or preventing cancer which comprises
administering a therapeutically effective amount of a compound of
claim 1 and a GPIIb/IIIa antagonist.
30. The method of claim 29 wherein the GPIIb/IIIa antagonist is
tirofiban.
31. A method of reducing or preventing tissue damage following a
cerebral ischemic event which comprises administering a
therapeutically effective amount of a compound of claim 1.
32. A method of treating or preventing cancer which comprises
administering a therapeutically effective amount of a compound of
claim 1 in combination with a COX-2 inhibitor.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to compounds which inhibit,
regulate and/or modulate tyrosine kinase signal transduction,
compositions which contain these compounds, and methods of using
them to treat tyrosine kinase-dependent diseases and conditions,
such as angiogenesis, cancer, tumor growth, atherosclerosis, age
related macular degeneration, diabetic retinopathy, inflammatory
diseases, and the like in mammals.
[0002] Tyrosine kinases are a class of enzymes that catalyze the
transfer of the terminal phosphate of adenosine triphosphate to
tyrosine residues in protein substrates. Tyrosine kinases are
believed, by way of substrate phosphorylation, to play critical
roles in signal transduction for a number of cell functions. Though
the exact mechanisms of signal transduction is still unclear,
tyrosine kinases have been shown to be important contributing
factors in cell proliferation, carcinogenesis and cell
differentiation.
[0003] Tyrosine kinases can be categorized as receptor type or
non-receptor type. Receptor type tyrosine kinases have an
extracellular, a transmembrane, and an intracellular portion, while
non-receptor type tyrosine kinases are wholly intracellular.
[0004] The receptor-type tyrosine kinases are comprised of a large
number of transmembrane receptors with diverse biological activity.
In fact, about 20 different subfamilies of receptor-type tyrosine
kinases have been identified. One tyrosine kinase subfamily,
designated the HER subfamily, is comprised of EGFR, HER2, HER3, and
HER4. Ligands of this subfamily of receptors include epithileal
growth factor, TGF-.alpha., amphiregulin, HB-EGF, betacellulin and
heregulin. Another subfamily of these receptor-type tyrosine
kinases is the insulin subfamily, which includes INS-R, IGF-IR, and
IR-R. The PDGF subfamily includes the PDGF-.alpha. and .beta.
receptors, CSFIR, c-kit and FLK-II. Then there is the FLK family
which is comprised of the kinase insert domain receptor (KDR),
fetal liver kinase-1 (FLK-1), fetal liver kinase-4 (FLK-4) and the
fms-like tyrosine kinase-1 (flt-1). The PDGF and FLK families are
usually considered together due to the similarities of the two
groups. For a detailed discussion of the receptor-type tyrosine
kinases, see Plowman et al., DN&P 7(6):334-339, 1994, which is
hereby incorporated by reference.
[0005] The non-receptor type of tyrosine kinases is also comprised
of numerous subfamilies, including Src, Frk, Btk, Csk, Abl, Zap70,
Fes/Fps, Fak, Jak, Ack, and LIMK. Each of these subfamilies is
further sub-divided into varying receptors. For example, the Src
subfamily is one of the largest and includes Src, Yes, Fyn, Lyn,
Lck, Blk, Hck, Fgr, and Yrk. The Src subfamily of enzymes has been
linked to oncogenesis. For a more detailed discussion of the
non-receptor type of tyrosine kinases, see Bolen Oncogene,
8:2025-2031 (1993), which is hereby incorporated by reference.
[0006] Both receptor-type and non-receptor type tyrosine kinases
are implicated in cellular signaling pathways leading to numerous
pathogenic conditions, including cancer, psoriasis and hyperimmune
responses.
[0007] Several receptor-type tyrosine kinases, and the growth
factors that bind thereto, have been suggested to play a role in
angiogenesis, although some may promote angiogenesis indirectly
(Mustonen and Alitalo, J. Cell Biol. 129:895-898, 1995). One such
receptor-type tyrsoine kinase is fetal liver kinase 1 or FLK-1. The
human analog of FLK-1 is the kinase insert domain-containing
receptor KDR, which is also known as vascular endothelial cell
growth factor receptor 2 or VEGFR-2, since it binds VEGF with high
affinity. Finally, the murine version of this receptor has also
been called NYK (Oelrichs et al., Oncogene 8(1):11-15, 1993). VEGF
and KDR are a ligand-receptor pair that play an important role in
the proliferation of vascular endothelial cells, and the formation
and sprouting of blood vessels, termed vasculogenesis and
angiogenesis, respectively.
[0008] Angiogenesis is characterized by excessive activity of
vascular endothelial growth factor (VEGF). VEGF is actually
comprised of a family of ligands (Klagsbum and D'Amore, Cytokine
&Growth Factor Reviews 7:259-270, 1996). VEGF binds the high
affinity membrane-spanning tyrosine kinase receptor KDR and the
related fms-like tyrosine kinase-1, also known as Flt-1 or vascular
endothelial cell growth factor receptor 1 (VEGFR-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. In fact, tumor growth has been shown to be susceptible to
the antiangiogenic effects of VEGF receptor antagonists. (Kim et
al., Nature 362, pp. 841-844, 1993).
[0009] Solid tumors can therefore be treated by tyrosine kinase
inhibitors since these tumors depend on angiogenesis for the
formation of the blood vessels necessary to support their growth.
These solid tumors include histiocytic lymphoma, cancers of the
brain, genitourinary tract, lymphatic system, stomach, larynx and
lung, including lung adenocarcinoma and small cell lung cancer.
Additional examples include cancers in which overexpression or
activation of Raf-activating oncogenes (e.g., K-ras, erb-B) is
observed. Such cancers include pancreatic and breast carcinoma.
Accordingly, inhibitors of these tyrosine kinases are useful for
the prevention and treatment of proliferative diseases dependent on
these enzymes.
[0010] The angiogenic activity of VEGF is not limited to tumors.
VEGF accounts for most of the angiogenic activity produced in or
near the retina in diabetic retinopathy. This vascular growth in
the retina leads to visual degeneration culminating in blindness.
Ocular VEGF mRNA and protein are elevated by conditions such as
retinal vein occlusion in primates and decreased pO.sub.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.
[0011] 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.
[0012] 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. Inhibition of KDR or
Flt-1 is implicated in pathological angiogenesis, and these
receptors are useful in the treatment of diseases in which
angiogenesis is part of the overall pathology, e.g., inflammation,
diabetic retinal vascularization, as well as various forms of
cancer since tumor growth is known to be dependent on angiogenesis.
(Weidner et al., N. Engl. J. Med., 324, pp. 1-8, 1991).
[0013] Accordingly, the identification of small compounds which
specifically inhibit, regulate and/or modulate the signal
transduction of tyrosine kinases is desirable and is an object of
this invention.
SUMMARY OF THE INVENTION
[0014] The present invention relates to compounds that are capable
of inhibiting, modulating and/or regulating signal transduction of
both receptor-type and non-receptor type tyrosine kinases. One
embodiment of the present invention is illustrated by a compound of
Formula I, and the pharmaceutically acceptable salts and
stereoisomers thereof: 1
DETAILED DESCRIPTION OF THE INVENTION
[0015] The compounds of this invention are useful in the inhibition
of kinases and are illustrated by a compound of Formula I: 2
[0016] or a pharmaceutically acceptable salt or stereoisomer
thereof, wherein
[0017] Q is S,O, or --E.dbd.D--; 3
[0018] is selected from the following: 4
[0019] a is or 1;
[0020] b is or 1;
[0021] s is 1 or 2;
[0022] m is 0, 1, or 2;
[0023] E.dbd.D is C.dbd.N, N.dbd.C, or C.dbd.C;
[0024] R.sup.1, R.sup.1a, R.sup.4 and R.sup.5 are independently
selected from:
[0025] 1) H,
[0026] 2) (C.dbd.O).sub.aO.sub.bC.sub.-C.sub.10 alkyl, optionally
substituted with one to three substituents selected from
R.sup.6,
[0027] 3) (C.dbd.O).sub.aO.sub.baryl, optionally substituted with
one to three substituents selected from R.sup.6,
[0028] 4) (C.dbd.O).sub.aO.sub.bC.sub.2-C.sub.10 alkenyl,
optionally substituted with one to three substituents selected from
R.sup.6,
[0029] 5) (C.dbd.O).sub.aO.sub.bC.sub.2-C.sub.10 alkynyl,
optionally substituted with one to three substituents selected from
R.sup.6,
[0030] 6) SO.sub.mC.sub.1-C.sub.10 alkyl, optionally substituted
with one to three substituents selected from R.sup.6,
[0031] 7) SO.sub.maryl, optionally substituted with one to three
substituents selected from R.sup.6,
[0032] 8) CO.sub.2H,
[0033] 9) halo,
[0034] 10) CN,
[0035] 11) OH,
[0036] 12) O.sub.bC.sub.1-C.sub.6 perfluoroalkyl, and
[0037] 13) (C.dbd.O).sub.aNR.sup.7R.sup.8;
[0038] R.sup.2 and R.sup.3 are independently selected from the
group consisting of:
[0039] 1) H,
[0040] 2) (C.dbd.O)O.sub.aC.sub.1-C.sub.10 alkyl,
[0041] 3) (C.dbd.O)O.sub.aaryl,
[0042] 4) C.sub.1-C.sub.10 alkyl,
[0043] 5) SO.sub.mC.sub.1-C.sub.10 alkyl,
[0044] 6) SO.sub.maryl,
[0045] 7) (C.dbd.O).sub.aO.sub.bC.sub.2-C.sub.10 alkenyl,
[0046] 8) (C.dbd.O).sub.aO.sub.bC.sub.2-C.sub.10 alkynyl, and
[0047] 9) aryl,
[0048] said alkyl, aryl, alkenyl and alkynyl is optionally
substituted with one to three substituents selected from
R.sup.6;
[0049] R.sup.4a is selected from the group consisting of:
[0050] 1) (C.dbd.O)O.sub.aC.sub.1-C.sub.10 alkyl,
[0051] 2) (C.dbd.O)O.sub.a aryl,
[0052] 3) C.sub.1-C.sub.10 alkyl,
[0053] 4) SO.sub.mC.sub.1-C.sub.10 alkyl,
[0054] 5) SO.sub.maryl,
[0055] 6) (C.dbd.O).sub.aO.sub.bC.sub.2-C.sub.10 alkenyl,
[0056] 7) (C.dbd.O).sub.aO.sub.bC.sub.2-C.sub.10 alkynyl, and
[0057] 8) aryl,
[0058] said alkyl, aryl, alkenyl and alkynyl is optionally
substituted with one to three substituents selected from
R.sup.6;
[0059] R.sup.6 is:
[0060] 1) H,
[0061] 2) (C.dbd.O).sub.aO.sub.bC.sub.1-C.sub.6 alkyl,
[0062] 3) (C.dbd.O).sub.aO.sub.baryl, optionally substituted with
one to three substituents selected from R.sup.6a,
[0063] 4) C.sub.2-C.sub.10 alkenyl,
[0064] 5) C.sub.2-C.sub.10 alkynyl,
[0065] 6) heterocyclyl, optionally substituted with one to three
substituents selected from R.sup.6a,
[0066] 7) CO.sub.2H,
[0067] 8) halo,
[0068] 9) CN,
[0069] 10) OH,
[0070] 11) oxo,
[0071] 12) O.sub.bC.sub.1-C.sub.6 perfluoroalkyl, or
[0072] 13) NR.sup.7R.sup.8;
[0073] R.sup.6a is:
[0074] 1) H,
[0075] 2) SO.sub.maryl,
[0076] 3) SO.sub.mC.sub.1-C.sub.6 alkyl,
[0077] 4) (C.dbd.O).sub.aO.sub.bC.sub.1-C.sub.6 alkyl,
[0078] 5) (C.dbd.O).sub.aO.sub.baryl,
[0079] 6) C.sub.2-C.sub.10 alkenyl,
[0080] 7) C.sub.2-C.sub.10 alkynyl,
[0081] 8) heterocyclyl,
[0082] 9) CO.sub.2H,
[0083] 10) halo,
[0084] 11) CN,
[0085] 12) OH,
[0086] 13) oxo,
[0087] 14) O.sub.bC.sub.1-C.sub.6 perfluoroalkyl, or
[0088] 15) N(C.sub.1-C.sub.6 alkyl).sub.2;
[0089] R.sup.7 and R.sup.8 are independently selected from:
[0090] 1) H,
[0091] 2) (C.dbd.O)O.sub.bC.sub.1-C.sub.10 optionally substituted
with one to three substituents selected from R.sup.6a,
[0092] 3) (C.dbd.O)O.sub.baryl, optionally substituted with one to
three substituents selected from R.sup.6a,
[0093] 4) C.sub.1-C.sub.10 alkyl, optionally substituted with one
to three substituents selected from R.sup.6a,
[0094] 5) aryl, optionally substituted with one to three
substituents selected from R.sup.6a,
[0095] 6) C.sub.2-C.sub.10 alkenyl, optionally substituted with one
to three substituents selected from R.sup.6a,
[0096] 7) C.sub.2-C.sub.10 alkynyl, optionally substituted with one
to three substituents selected from R.sup.6a, and
[0097] 8) heterocyclyl, or
[0098] R.sup.7 and R.sup.8 can be taken together with the nitrogen
to which they are attached to form a 5-7 membered heterocycle
containing, in addition to the nitrogen, one or two additional
heteroatoms selected from N, 0 and S, said heterocycle optionally
substituted with one to three substituents selected from
R.sup.6a.
[0099] A second embodiment is illustrated by the compound of
Formula I, as described above, wherein Q is E.dbd.D. In a third
embodiment, E.dbd.D is further defined as C.dbd.C.
[0100] A fourth embodiment of the invention is the compound of
Formula I, as described above, wherein Q is E.dbd.D; E.dbd.D is
C.dbd.C;
[0101] R.sup.1, R.sup.1a, R.sup.4 and R.sup.5 are independently
selected from:
[0102] 1) H,
[0103] 2) (C.dbd.O).sub.aO.sub.bC.sub.1-C.sub.6 alkyl, optionally
substituted with one to three substituents selected from
R.sup.6,
[0104] 3) (C.dbd.O).sub.aO.sub.baryl, optionally substituted with
one to three substituents selected from R.sup.6,
[0105] 4) (C.dbd.O).sub.aO.sub.bC.sub.2-C.sub.6 alkenyl, optionally
substituted with one to three substituents selected from
R.sup.6,
[0106] 5) CO.sub.2H,
[0107] 6) halo,
[0108] 7) CN,
[0109] 8) OH,
[0110] 9) O.sub.bC.sub.1-C.sub.3 perfluoroalkyl, and
[0111] 10) (C.dbd.O).sub.aNR.sup.7R.sup.8;
[0112] R.sup.2 and R.sup.3 are independently selected from the
group consisting of: 1) H,
[0113] 2) (C.dbd.O)O.sub.aC.sub.1-C.sub.6 alkyl, and
[0114] 3) C.sub.1-C.sub.6 alkyl;
[0115] R.sup.4a is (C.dbd.O)O.sub.aC.sub.1-C.sub.6 alkyl or
C.sub.1-C.sub.6 alkyl;
[0116] R.sup.6 is:
[0117] 1) H,
[0118] 2) (C.dbd.O).sub.aO.sub.bC.sub.1-C.sub.6 alkyl,
[0119] 3) (C.dbd.O).sub.aO.sub.baryl, optionally substituted with
one to three substituents selected from R.sup.6a,
[0120] 4) C.sub.2-C.sub.6 alkenyl,
[0121] 5) heterocyclyl, optionally substituted with one to three
substituents selected from R.sup.6a,
[0122] 6) CO.sub.2H,
[0123] 7) halo,
[0124] 8) CN,
[0125] 9) OH,
[0126] 10) oxo,
[0127] 11) O.sub.bC.sub.1-C.sub.3 perfluoroalkyl, or
[0128] 12) NR.sup.7R.sup.8;
[0129] R.sup.6a is:
[0130] 1) H,
[0131] 2) SO.sub.maryl,
[0132] 3) SO.sub.mC.sub.1-C.sub.6 alkyl,
[0133] 4) (C.dbd.O).sub.aO.sub.bC.sub.1-C.sub.6 alkyl,
[0134] 5) (C.dbd.O).sub.aO.sub.baryl,
[0135] 6) C.sub.2-C.sub.6 alkenyl,
[0136] 7) heterocyclyl,
[0137] 8) CO.sub.2H,
[0138] 9) halo,
[0139] 10) CN,
[0140] 11) OH,
[0141] 12) oxo,
[0142] 13) O.sub.bC.sub.1-C.sub.3 perfluoroalkyl, or
[0143] 14) N(C.sub.1-C.sub.6 alkyl).sub.2;
[0144] R.sup.7 and R.sup.8 are independently selected from:
[0145] 1) H,
[0146] 2) (C.dbd.O)O.sub.bC.sub.1-C.sub.6 alkyl, optionally
substituted with one to three substituents selected from
R.sup.6a.
[0147] 3) (C.dbd.O)O.sub.baryl, optionally substituted with one to
three substituents selected from R.sup.6a,
[0148] 4) C.sub.1-C.sub.6 alkyl, optionally substituted with one to
three substituents selected from R.sup.6a,
[0149] 5) aryl, optionally substituted with one to three
substituents selected from R.sup.6a,
[0150] 6) C.sub.2-C.sub.6 alkenyl, optionally substituted with one
to three substituents selected from R.sup.6a, and
[0151] 7) heterocyclyl, or
[0152] R.sup.7 and R.sup.8 can be taken together with the nitrogen
to which they are attached to form a 5-7 membered heterocycle
containing, in addition to the nitrogen, one or two additional
heteroatoms selected from N, O and S, said heterocycle optionally
substituted with one to three substituents selected from
R.sup.6a.
[0153] In a fifth embodiment of the invention, the compound of
Formula I is defined such that Q is E.dbd.D; E.dbd.D is
C.dbd.C;
[0154] a is 0 or 1;
[0155] b is 0 or 1;
[0156] s is 1;
[0157] R.sup.1 and R.sup.4 are independently selected from:
[0158] 1) H,
[0159] 2) (C.dbd.O).sub.aO.sub.bC.sub.1-C.sub.6 alkyl, optionally
substituted with one to three substituents selected from
R.sup.6,
[0160] 3) (C.dbd.O).sub.aO.sub.baryl, optionally substituted with
one to three substituents selected from R.sup.6,
[0161] 4) (C.dbd.O).sub.aO.sub.bC.sub.2-C.sub.6 alkenyl, optionally
substituted with one to three substituents selected from
R.sup.6,
[0162] 5) (C.dbd.O).sub.aO.sub.bC.sub.2-C.sub.6 alkynyl, optionally
substituted with one to three substituents selected from
R.sup.6,
[0163] 6) CO.sub.2H,
[0164] 7) halo,
[0165] 8) CN,
[0166] 9) OH,
[0167] 10) O.sub.bC.sub.1-C.sub.3 perfluoroalkyl, and
[0168] 11) (C.dbd.O).sub.aNR.sup.7R.sup.8;
[0169] R.sup.2 and R.sup.3 are independently selected from H and
methyl;
[0170] R.sup.4a is methyl;
[0171] R.sup.5 and R.sup.1a are H;
[0172] R.sup.6 is:
[0173] 1) H,
[0174] 2) (C.dbd.O).sub.aO.sub.bC.sub.1-C.sub.6 alkyl,
[0175] 3) (C.dbd.O).sub.aO.sub.baryl, optionally substituted with
one to three substituents selected from R.sup.6a,
[0176] 4) C.sub.2-C.sub.10 alkenyl,
[0177] 5) C.sub.3-C.sub.10 alkynyl,
[0178] 6) heterocyclyl, optionally substituted with one to three
substituents selected from R.sup.6a,
[0179] 7) CO.sub.2H,
[0180] 8) halo,
[0181] 9) CN,
[0182] 10) OH,
[0183] 11) oxo,
[0184] 12) O.sub.bC.sub.1-C.sub.3 perfluoroalkyl, or
[0185] 13) NR.sup.7R.sup.8;
[0186] R.sup.6a is:
[0187] 1) H,
[0188] 2) SO.sub.maryl,
[0189] 3) SO.sub.mC.sub.1-C.sub.6 alkyl,
[0190] 4) (C.dbd.O).sub.aO.sub.bC.sub.1-C.sub.6 alkyl,
[0191] 5) (C.dbd.O).sub.aO.sub.baryl,
[0192] 6) C.sub.2-C.sub.10 alkenyl,
[0193] 7) C.sub.2-C.sub.10 alkynyl,
[0194] 8) heterocyclyl,
[0195] 9) CO.sub.2H,
[0196] 10) halo,
[0197] 11) CN,
[0198] 12) OH,
[0199] 13) oxo,
[0200] 14) O.sub.bC.sub.1-C.sub.3 perfluoroalkyl, or
[0201] 15) N(C.sub.1-C.sub.6 alkyl).sub.2;
[0202] R.sup.7 and R.sup.8 are independently selected from:
[0203] 1) H,
[0204] 2) (C.dbd.O)O.sub.bC.sub.1-C.sub.6 alkyl, optionally
substituted with one to three substituents selected from
R.sup.6a,
[0205] 3) (C.dbd.O)O.sub.baryl, optionally substituted with one to
three substituents selected from R.sup.6a,
[0206] 4) C.sub.1-C.sub.10 alkyl, optionally substituted with one
to three substituents selected from R.sup.6a,
[0207] 5) aryl, optionally substituted with one to three
substituents selected from R.sup.6a,
[0208] 6) C.sub.2-C.sub.6 alkenyl, optionally substituted with one
to three substituents selected from R.sup.6a,
[0209] 7) C.sub.2-C.sub.6 alkynyl, optionally substituted with one
to three substituents selected from R.sup.6a, and
[0210] 8) heterocyclyl, or
[0211] R.sup.7 and R.sup.8 can be taken together with the nitrogen
to which they are attached to form a piperidinyl, piperazinyl,
morpholinyl or pyrrolidinyl group, optionally substituted with one
or two substituents selected from R.sup.6a.
[0212] Yet another embodiment of the present invention is a
compound which is
3-(4-methyl-5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridin-2-yl)-1H-quinol-
in-2-one or a pharmaceutically acceptable salt or stereoisomer
thereof.
[0213] Also included within the scope of the present invention is a
pharmaceutical composition which is comprised of a compound of
Formula I as described above and a pharmaceutically acceptable
carrier. The present invention also encompasses a method of
treating or preventing cancer in a mammal in need of such treatment
which is comprised of administering to said mammal a
therapeutically effective amount of a compound of Formula I.
Preferred cancers for treatment are selected from cancers of the
brain, genitourinary tract, lymphatic system, stomach, larynx and
lung. Another set of preferred forms of cancer are histiocytic
lymphoma, lung adenocarcinoma, small cell lung cancers, pancreatic
cancer, gioblastomas and breast carcinoma.
[0214] Also included is a method of treating or preventing a
disease in which angiogenesis is implicated, which is comprised of
administering to a mammal in need of such treatment a
therapeutically effective amount of a compound of Formula I. Such a
disease in which angiogenesis is implicated is ocular diseases such
as retinal vascularization, diabetic retinopathy, age-related
macular degeneration, and the like.
[0215] Also included within the scope of the present invention is a
method of treating or preventing inflammatory diseases which
comprises administering to a mammal in need of such treatment a
therapeutically effective amount of a compound of Formula I.
Examples of such inflammatory diseases are rheumatoid arthritis,
psoriasis, contact dermatitis, delayed hypersensitivity reactions,
and the like.
[0216] Also included is a method of treating or preventing a
tyrosine kinase-dependent disease or condition in a mammal which
comprises administering to a mammalian patient in need of such
treatment a therapeutically effective amount of a compound of
Formula I. The therapeutic amount varies according to the specific
disease and is discemable to the skilled artisan without undue
experimentation.
[0217] A method of treating or preventing retinal vascularization
which is comprised of administering to a mammal in need of such
treatment a therapeutically effective amount of compound of Formula
I is also encompassed by the present invention. Methods of treating
or preventing ocular diseases, such as diabetic retinopathy and
age-related macular degeneration, are also part of the invention.
Also included within the scope of the present invention is a method
of treating or preventing inflammatory diseases, such as rheumatoid
arthritis, psoriasis, contact dermatitis and delayed
hypersensitivity reactions, as well as treatment or prevention of
bone associated pathologies selected from osteosarcoma,
osteoarthritis, and rickets.
[0218] The invention also contemplates the use of the instantly
claimed compounds in combination with a second compound selected
from:
[0219] 1) an estrogen receptor modulator,
[0220] 2) an androgen receptor modulator,
[0221] 3) retinoid receptor modulator,
[0222] 4) a cytotoxic agent,
[0223] 5) an antiproliferative agent,
[0224] 6) a prenyl-protein transferase inhibitor,
[0225] 7) an HMG-CoA reductase inhibitor,
[0226] 8) an HIV protease inhibitor,
[0227] 9) a reverse transcriptase inhibitor, and
[0228] 10) another angiogenesis inhibitor.
[0229] Preferred angiogenesis inhibitors are selected from the
group consisting of a tyrosine kinase inhibitor, an inhibitor of
epidermal-derived growth factor, an inhibitor of fibroblast-derived
growth factor, an inhibitor of platelet derived growth factor, an
MMP (matrix metalloprotease) inhibitor, an integrin blocker,
interferon-a, interleukin-12, pentosan polysulfate, a
cyclooxygenase inhibitor, carboxyamidotriazole, combretastatin A-4,
squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide,
angiostatin, troponin-1, and an antibody to VEGF. Preferred
estrogen receptor modulators are tamoxifen and raloxifene.
[0230] Also included in the scope of the claims is a method of
treating cancer which comprises administering a therapeutically
effective amount of a compound of Formula I in combination with
radiation therapy and/or in combination with a compound selected
from:
[0231] 1) an estrogen receptor modulator,
[0232] 2) an androgen receptor modulator,
[0233] 3) retinoid receptor modulator,
[0234] 4) a cytotoxic agent,
[0235] 5) an antiproliferative agent,
[0236] 6) a prenyl-protein transferase inhibitor,
[0237] 7) an HMG-CoA reductase inhibitor,
[0238] 8) an HIV protease inhibitor,
[0239] 9) a reverse transcriptase inhibitor, and
[0240] 10) another angiogenesis inhibitor.
[0241] And yet another embodiment of the invention is a method of
treating cancer which comprises administering a therapeutically
effective amount of a compound of Formula I in combination with
paclitaxel or trastuzumab.
[0242] Also within the scope of the invention is a method of
reducing or preventing tissue damage following a cerebral ischemic
event which comprises administering a therapeutically effective
amount of a compound of Formula I.
[0243] Another embodiment of the invention is a method of treating
or preventing cancer which comprises administering a
therapeutically effective amount of a compound of Formula I in
combination with a COX-2 inhibitor.
[0244] These and other aspects of the invention will be apparent
from the teachings contained herein.
[0245] "Tyrosine kinase-dependent diseases or conditions" refers to
pathologic conditions that depend on the activity of one or more
tyrosine kinases. Tyrosine kinases either directly or indirectly
participate in the signal transduction pathways of a variety of
cellular activities including proliferation, adhesion and
migration, and differentiation. Diseases associated with tyrosine
kinase activities include the proliferation of tumor cells, the
pathologic neovascularization that supports solid tumor growth,
ocular neovascularization (diabetic retinopathy, age-related
macular degeneration, and the like) and inflammation (psoriasis,
rheumatoid arthritis, and the like).
[0246] The compounds of the present invention may have asymmetric
centers, chiral axes, and chiral planes (as described in: E. L.
Eliel and S. H. Wilen, Stereo-chemistry of Carbon Compounds, John
Wiley & Sons, New York, 1994, pages 1119-1190), and occur as
racemates, racemic mixtures, and as individual diastereomers, with
all possible isomers and mixtures thereof, including optical
isomers, being included in the present invention. In addition, the
compounds disclosed herein may exist as tautomers and both
tautomeric forms are intended to be encompassed by the scope of the
invention, even though only one tautomeric structure is depicted.
For example, any claim to compound A below is understood to include
tautomeric structure B, and vice versa, as well as mixtures
thereof. 5
[0247] When any variable (e.g. aryl, heterocycle, R.sup.1, R.sup.2
etc.) occurs more than one time in any constituent, its definition
on each occurrence is independent at every other occurrence. Also,
combinations of substituents and variables are permissible only if
such combinations result in stable compounds. Lines drawn into the
ring systems from substituents (such as from R.sup.1, R.sup.2,
R.sup.3, R.sup.4 etc.) indicate that the indicated bond may be
attached to any of the substitutable ring carbon atoms. If the ring
system is polycyclic, it is intended that the bond be attached to
any of the suitable carbon atoms on the proximal ring only. For
example, 6
[0248] can be, inter alia, any of the following when:
[0249] X and Z are C,
[0250] Y is N,
[0251] R.sup.5 is CH.sub.3,
[0252] R.sup.3 is H, and
[0253] (R.sup.4).sub.t is as defined in the claims: 7
[0254] It is understood that substituents and substitution patterns
on the compounds of the instant invention can be selected by one of
ordinary skill in the art to provide compounds that are chemically
stable and that can be readily synthesized by techniques known in
the art, as well as those methods set forth below, from readily
available starting materials.
[0255] As used herein, "alkyl" is intended to include both
branched, straight-chain, and cyclic saturated aliphatic
hydrocarbon groups having the specified number of carbon atoms. For
example, C.sub.1-C.sub.10, as in "C.sub.1-C.sub.10 alkyl" is
defined to include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10
carbons in a linear, branched, or cyclic arrangement. For example,
"C.sub.1-C.sub.10 alkyl" specifically includes methyl, ethyl,
propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and so
on, as well as cycloalkyls such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, tetrahydro-naphthalene,
methylenecylohexyl, and so on. "Alkoxy" represents an alkyl group
of indicated number of carbon atoms attached through an oxygen
bridge.
[0256] If no number of carbon atoms is specified, the term
"alkenyl" refers to a non-aromatic hydrocarbon radical, straight,
branched or cyclic, containing from 2 to 10 carbon atoms and at
least one carbon to carbon double bond. Preferably one carbon to
carbon double bond is present, and up to 4 non-aromatic
carbon-carbon double bonds may be present. Thus, "C.sub.2-C.sub.6
alkenyl" means an alkenyl radical having from 2 to 6 carbon atoms.
Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.
As described above with respect to alkyl, the straight, branched or
cyclic portion of the alkenyl group may contain double bonds and
may be substituted if a substituted alkenyl group is indicated.
[0257] The term "alkynyl" refers to a hydrocarbon radical straight,
branched or cyclic, containing from 2 to 10 carbon atoms and at
least one carbon to carbon triple bond. Up to 3 carbon-carbon
triple bonds may be present. Thus, "C.sub.2-C.sub.6 alkynyl" means
an alkynyl radical having from 2 to 6 carbon atoms. Alkynyl groups
include ethynyl, propynyl and butynyl. As described above with
respect to alkyl, the straight, branched or cyclic portion of the
alkynyl group may contain triple bonds and may be substituted if a
substituted alkynyl group is indicated.
[0258] As used herein, "aryl" is intended to mean any stable
monocyclic or bicyclic carbon ring of up to 7 atoms in each ring,
wherein at least one ring is aromatic. Examples of such aryl
elements include phenyl, naphthyl, tetrahydro-naphthyl, indanyl,
biphenyl, phenanthryl, anthryl or acenaphthyl. In cases where the
aryl substituent is bicyclic and one ring is non-aromatic, it is
understood that attachment is via the aromatic ring.
[0259] The term heteroaryl, as used herein, represents a stable
monocyclic or bicyclic ring of up to 7 atoms in each ring, wherein
at least one ring is aromatic and contains from 1 to 4 heteroatoms
selected from the group consisting of 0, N and S. Heteroaryl groups
within the scope of this definition include but are not limited to:
acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl,
indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl,
benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl,
indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,
tetrahydroquinoline. In cases where the heteroaryl substituent is
bicyclic and one ring is non-aromatic or contains no heteroatoms,
it is understood that attachment is via the aromatic ring or via
the heteroatom containing ring, respectively.
[0260] As appreciated by those of skill in the art, "halo" or
"halogen" as used herein is intended to include chloro, fluoro,
bromo and iodo. The term "heterocycle" or "heterocyclyl" as used
herein is intended to mean a 5- to 10-membered aromatic or
nonaromatic heterocycle containing from 1 to 4 heteroatoms selected
from the group consisting of O, N and S, and includes bicyclic
groups. "Heterocyclyl" therefore includes the above mentioned
heteroaryls, as well as dihydro and tetrathydro analogs thereof.
Further examples of "heterocyclyl" include, but are not limited to
the following: benzoimidazolyl, benzofuranyl, benzofurazanyl,
benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl,
carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl,
indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,
isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl,
oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl,
pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl,
pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,
tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl,
thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl,
hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl,
morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl,
dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl,
dihydrofuranyl, dihydroimidazolyl, dihydroindolyl,
dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl,
dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl,
dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl,
dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl,
dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl,
dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and
tetrahydrothienyl, and N-oxides thereof.
[0261] The pharmaceutically acceptable salts of the compounds of
this invention include the conventional non-toxic salts of the
compounds of this invention as formed, e.g., from non-toxic
inorganic or organic acids. For example, such conventional
non-toxic salts include those derived from inorganic acids such as
hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric
and the like; and the salts prepared from organic acids such as
acetic, propionic, succinic, glycolic, stearic, lactic, malic,
tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,
phenylacetic, glutamic, benzoic, salicylic, sulfanilic,
2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic,
ethane disulfonic, oxalic, isethionic, trifluoroacetic and the
like.
[0262] In certain instances, R.sup.7 and R.sup.8 are defined such
that they can be taken together with the nitrogen to which they are
attached to form a 5-7 membered heterocycle containing, in addition
to the nitrogen, one or two additional heteroatoms selected from N,
O and S, said heterocycle optionally substituted with one to three
substituents selected from R.sup.6a. Examples of the 5-7 membered
ring systems that can thus be formed include, but are not limited
to the following: 8
[0263] Preferably is E.dbd.D and E.dbd.D is C.dbd.C.
[0264] Preferably R.sup.1 is H, C.sub.1-C.sub.6 alkyl, or aryl.
Most preferably R.sup.1 is H or C.sub.1-C.sub.2 alkyl.
[0265] The preferred definition of R.sup.1a is H.
[0266] Preferably R.sup.2 and R.sup.3 are independently H,
C.sub.1-C.sub.6 alkyl, or (C.dbd.O)C.sub.1-C.sub.6 alkyl. Most
preferably R.sup.2 and R.sup.3 are independently H or
C.sub.1-C.sub.6 alkyl.
[0267] Preferably R.sup.4 is OH, OC.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkyl.
[0268] Preferably R.sup.4a is C.sub.1-C.sub.6 alkyl.
[0269] Preferably R.sup.5 is H or C.sub.1-C.sub.6 alkyl. Most
preferably R.sup.5 is H.
[0270] The pharmaceutically acceptable salts of the compounds of
this invention can be synthesized from the compounds of this
invention which contain a basic or acidic moiety by conventional
chemical methods. Generally, the salts of the basic compounds are
prepared either by ion exchange chromatography or by reacting the
free base with stoichiometric amounts or with an excess of the
desired salt-forming inorganic or organic acid in a suitable
solvent or various combinations of solvents. Similarly, the salts
of the acidic compounds are formed by reactions with the
appropriate inorganic or organic base.
[0271] The compounds of this invention may be prepared by employing
reactions as shown in the following schemes, in addition to other
standard manipulations that are known in the literature or
exemplified in the experimental procedures. These schemes,
therefore, are not limited by the compounds listed nor by any
particular substituents employed for illustrative purposes.
Substituent numbering as shown in the schemes does not necessarily
correlate to that used in the claims.
Synopsis of Schemes
[0272] As shown in Scheme 1, the quinoline reagent 1-2 can be
synthesized by the general procedures taught in Marsais, F; Godard,
A.; Queguiner, G. J. Hetero-cyclic Chem. 1989, 26, 1589-1594).
Derivatives with varying substitution can be made by modifying this
procedure and use of standard synthetic protocols known in the art.
Intermediate 1-2 is then coupled with the appropriate N-protected
pyrollo-compound, structure 1-4, to produce a chlorinated
intermediate of structure 1-5. At least one of the R.sup.4
substituents would be OH or OR on the carbon adjacent to the ring
nitrogen. Heating of 1-5 in aqueous acetic acid produces the
desired de-chlorinated product, 1-6. Scheme 2 shows an example
using this route to arrive at a [3,2]-pyridno-pyrole, 2-3.
[0273] As shown in Scheme 3, the .alpha.-alkyloxy pyridino-pyroles
3-1 can be converted to the corresponding pyrimidinone analogs 3-2
by heating with aqueous HBr. Alternatively, the pyrimidinone
analogs can be synthesized via the N-oxide intermediates 4-2 as
shown in Scheme 4. Scheme 5 shows the N-alkylation of the
pyrimidinone-pyrole 3-2 to arrive at the compounds of Formula I.
Other electrophilic reagents can be employed to alkylate or acylate
the nitrogen, as will be apparent to the skilled artisan. 9 10 11
12
Utility
[0274] The instant compounds are useful as pharmaceutical agents
for mammals, especially for humans, in the treatment of tyrosine
kinase dependent diseases. Such diseases include the proliferation
of tumor cells, the pathologic neovascularization (or angiogenesis)
that supports solid tumor growth, ocular neovascularization
(diabetic retinopathy, age-related macular degeneration, and the
like) and inflammation (psoriasis, rheumatoid arthritis, and the
like).
[0275] The compounds of the instant invention may be administered
to patients for use in the treatment of cancer. The instant
compounds inhibit tumor angiogenesis, thereby affecting the growth
of tumors (J. Rak et al. Cancer Research, 55:4575-4580, 1995). The
anti-angiogenesis properties of the instant compounds are also
useful in the treatment of certain forms of blindness related to
retinal vascularization.
[0276] The disclosed compounds are also useful in the treatment of
certain bone-related pathologies, such as osteosarcoma,
osteoarthritis, and rickets, also known as oncogenic osteomalacia.
(Hasegawa et al., Skeletal Radiol., 28, pp.41-45, 1999; Gerber et
al., Nature Medicine, Vol. 5, No. 6, pp.623-628, June 1999). And
since VEGF directly promotes osteoclastic bone resorption through
KDR/Flk-1 expressed in mature osteoclasts (FEBS Let. 473:161-164
(2000); Endocrinology, 141:1667 (2000)), the instant compounds are
also useful to treat and prevent conditions related to bone
resorption, such as osteoporosis and Paget's disease.
[0277] The claimed compounds can also be used to reduce or prevent
tissue damage which occurs after cerebral ischemic events, such as
stroke, by reducing cerebral edema, tissue damage, and reperfusion
injury following ischemia. (Drug News Perspect 11:265-270 (1998);
J. Clin. Invest. 104:1613-1620 (1999)).
[0278] The compounds of this invention may be administered to
mammals, preferably humans, either alone or, preferably, in
combination with pharmaceutically acceptable carriers or diluents,
optionally with known adjuvants, such as alum, in a pharmaceutical
composition, according to standard pharmaceutical practice. The
compounds can be administered orally or parenterally, including the
intravenous, intramuscular, intraperitoneal, subcutaneous, rectal
and topical routes of administration.
[0279] For oral use of a chemotherapeutic compound according to
this invention, the selected compound may be administered, for
example, in the form of tablets or capsules, or as an aqueous
solution or suspension. In the case of tablets for oral use,
carriers which are commonly used include lactose and corn starch,
and lubricating agents, such as magnesium stearate, are commonly
added. For oral administration in capsule form, useful diluents
include lactose and dried corn starch. When aqueous suspensions are
required for oral use, the active ingredient is combined with
emulsifying and suspending agents. If desired, certain sweetening
and/or flavoring agents may be added. For intramuscular,
intraperitoneal, subcutaneous and intravenous use, sterile
solutions of the active ingredient are usually prepared, and the pH
of the solutions should be suitably adjusted and buffered. For
intravenous use, the total concentration of solutes should be
controlled in order to render the preparation isotonic.
[0280] The compounds of the instant invention may also be
co-administered with other well known therapeutic agents that are
selected for their particular usefulness against the condition that
is being treated. For example, in the case of bone-related
disorders, combinations that would be useful include those with
antiresorptive bisphosphonates, such as alendronate and
risedronate; integrin blockers (defined further below), such as
.alpha..sub.v.beta..sub.3 antagonists; conjugated estrogens used in
hormone replacement therapy, such as PREMPRO.RTM., PREMARIN.RTM.)
and ENDOMETRION.RTM.; selective estrogen receptor modulators
(SERMs), such as raloxifene, droloxifene, CP-336,156 (Pfizer) and
lasofoxifene; cathespin K inhibitors; and ATP proton pump
inhibitors.
[0281] The instant compounds are also useful in combination with
known anti-cancer agents. Such known anti-cancer agents include the
following: estrogen receptor modulators, androgen receptor
modulators, retinoid receptor modulators, cytotoxic agents,
antiproliferative agents, prenyl-protein transferase inhibitors,
HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse
transcriptase inhibitors, and other angiogenesis inhibitors. The
instant compounds are particularly useful when coadminsitered with
radiation therapy. The synergistic effects of inhibiting VEGF in
combination with radiation therapy have been described in the art.
(see WO 00/61186). "Estrogen receptor modulators" refers to
compounds which interfere or inhibit the binding of estrogen to the
receptor, regardless of mechanism. Examples of estrogen receptor
modulators include, but are not limited to, tamoxifen, raloxifene,
idoxifene, LY353381, LY117081, toremifene, fulvestrant,
4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]ph-
enyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate,
4,4'-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and
SH646.
[0282] "Androgen receptor modulators" refers to compounds which
interfere or inhibit the binding of androgens to the receptor,
regardless of mechanism. Examples of androgen receptor modulators
include finasteride and other 5.alpha.-reductase inhibitors,
nilutamide, flutamide, bicalutamide, liarozole, and abiraterone
acetate.
[0283] "Retinoid receptor modulators" refers to compounds which
interfere or inhibit the binding of retinoids to the receptor,
regardless of mechanism. Examples of such retinoid receptor
modulators include bexarotene, tretinoin, 13-cis-retinoic acid,
9-cis-retinoic acid, .alpha.-difluoromethylomithine, ILX23-7553,
trans-N-(4'-hydroxyphenyl) retinamide, N-4-carboxyphenyl
retinamide,
[0284] "Cytotoxic agents" refer to compounds which cause cell death
primarily by interfering directly with the cell's functioning or
inhibit or interfere with cell myosis, including alkylating agents,
tumor necrosis factors, intercalators, microtubulin inhibitors, and
topoisomerase inhibitors.
[0285] Examples of cytotoxic agents include, but are not limited
to, tirapazimine, sertenef, cachectin, ifosfamide, tasonermin,
lonidamine, carboplatin, altretamine, prednimustine,
dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin,
temozolomide, heptaplatin, estramustine, improsulfan tosilate,
trofosfamide, nimustine, dibrospidium chloride, pumitepa,
lobaplatin, satraplatin, profiromycin, cisplatin, irofulven,
dexifosfamide, cis-aminedichloro(2-methyl-pyridine) platinum,
benzylguanine, glufosfamide, GPX100, (trans, trans,
trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(c-
hloro)platinum (II)]tetrachloride, diarizidinylspermine, arsenic
trioxide,
1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine,
zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone,
pirarubicin, pinafide, valrubicin, amrubicin, antineoplaston,
3'-deamino-3'-morpholino- -13-deoxo-10-hydroxycarminomycin,
annamycin, galarubicin, elinafide, MEN10755, and
4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunor- ubicin
(see WO 00/50032).
[0286] Examples of microtubulin inhibitors include paclitaxel,
vindesine sulfate,
3',4'-didehydro-4'-deoxy-8'-norvincaleukoblastine, docetaxol,
rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin,
RPR109881, BMS184476, vinflunine, cryptophycin,
2,3,4,5,6-pentafluoro-N-(- 3-fluoro-4-methoxyphenyl) benzene
sulfonamide, anhydrovinblastine,
N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butyla-
mide, TDX258, and BMS 188797.
[0287] Some examples of topoisomerase inhibitors are topotecan,
hycaptamine, irinotecan, rubitecan,
6-ethoxypropionyl-3',4'-O-exo-benzyli- dene-chartreusin,
9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-
-2-(6H)propanamine,
1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methy-
l-1H,12H-benzo[de]pyrano[3',4':b,7]indolizino[1,2b]quinoline-10,13(9H,15H)
dione, lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin,
BNP1350, BNPI1100, BN80915, BN80942, etoposide phosphate,
teniposide, sobuzoxane, 2'-dimethylamino-2'-deoxy-etoposide, GL331,
N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazo-
le-1-carboxamide, asulacrine, (5a, 5aB,
8aa,9b)-9-[2-[N-[2-(dimethylamino)-
ethyl]-N-methylamino]ethyl]-5-[4-Hydroxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,-
9-hexohydrofuro(3',4':6,7)naphtho(2,3-d)-1,3-dioxol-6-one,
2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridiniu-
m, 6,9-bis[(2-aminoethyl)amino]benzo[g]isoguinoline-5,10-dione,
5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-py-
razolo[4,5,1-de]acridin-6-one,
N-[1-[2(diethylamino)ethylamino]-7-methoxy--
9-oxo-9H-thioxanthen-4-ylmethyl]formamide,
N-(2-(dimethylamino)ethyl)acrid- ine-4-carboxamide,
6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2-
,1-c]quinolin-7-one, and dimesna.
[0288] "Antiproliferative agents" includes antisense RNA and DNA
oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and
INX3001, and antimetabolites such as enocitabine, carmofur,
tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine,
capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium
hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin,
decitabine, nolatrexed, pemetrexed, nelzarabine,
2'-deoxy-2'-methylidenecytidine, 2'-fluoromethylene-2'-deoxy-
cytidine,
N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N'-(3,4-dichlorophenyl)
urea,
N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycer-
o-B-L-manno-heptopyranosyl]adenine, aplidine, ecteinascidin,
troxacitabine,
4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b]
[1,4]thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamic acid,
aminopterin, 5-flurouracil, alanosine,
11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-met-
hoxy-14-oxa-1,11-diazatetracyclo(7.4.1.0.0)-tetradeca-2,4,6-trien-9-yl
acetic acid ester, swainsonine, lometrexol, dexrazoxane,
methioninase, 2'-cyano-2'-deoxy-N4-palmitoyl-1-B-D-arabino
furanosyl cytosine, and 3-aminopyridine-2-carboxaldehyde
thiosemicarbazone. "Antiproliferative agents" also includes
monoclonal antibodies to growth factors, other than those listed
under "angiogenesis inhibitors", such as trastuzumab, and tumor
suppressor genes, such as p53, which can be delivered via
recombinant virus-mediated gene transfer (see U.S. Pat. No.
6,069,134, for example).
[0289] "HMG-COA reductase inhibitors" refers to inhibitors of
3-hydroxy-3-methylglutaryl-CoA reductase. Compounds which have
inhibitory activity for HMG-CoA reductase can be readily identified
by using assays well-known in the art. For example, see the assays
described or cited in U.S. Pat. No. 4,231,938 at col. 6, and WO
84/02131 at pp. 30-33. The terms "HMG-CoA reductase inhibitor" and
"inhibitor of HMG-CoA reductase" have the same meaning when used
herein.
[0290] Examples of HMG-CoA reductase inhibitors that may be used
include but are not limited to lovastatin (MEVACOR.RTM.; see U.S.
Pat. Nos. 4,231,938; 4,294,926; 4,319,039), simvastatin
(ZOCOR.RTM.; see U.S. Pat. Nos. 4,444,784; 4,820,850; 4,916,239),
pravastatin (PRAVACHOL.RTM.; see U.S. Pat. Nos. 4,346,227;
4,537,859; 4,410,629; 5,030,447 and 5,180,589), fluvastatin
(LESCOL.RTM.; see U.S. Pat. Nos. 5,354,772; 4,911,165; 4,929,437;
5,189,164; 5,118,853; 5,290,946; 5,356,896), atorvastatin
(LIPITOR.RTM.; see U.S. Pat. Nos. 5,273,995; 4,681,893; 5,489,691;
5,342,952) and cerivastatin (also known as rivastatin and
BAYCHOL.RTM.; see U.S. Pat. No. 5,177,080). The structural formulas
of these and additional HMG-CoA reductase inhibitors that may be
used in the instant methods are described at page 87 of M. Yalpani,
"Cholesterol Lowering Drugs", Chemistry & Industry, pp. 85-89
(Feb. 5, 1996) and U.S. Pat. Nos. 4,782,084 and 4,885,314. The term
HMG-CoA reductase inhibitor as used herein includes all
pharmaceutically acceptable lactone and open-acid forms (i.e.,
where the lactone ring is opened to form the free acid) as well as
salt and ester forms of compounds which have HMG-CoA reductase
inhibitory activity, and therefor the use of such salts, esters,
open-acid and lactone forms is included within the scope of this
invention. An illustration of the lactone portion and its
corresponding open-acid form is shown below as structures I and II.
13
[0291] In HMG-CoA reductase inhibitors where an open-acid form can
exist, salt and ester forms may preferably be formed from the
open-acid, and all such forms are included within the meaning of
the term "HMG-CoA reductase inhibitor" as used herein. Preferably,
the HMG-CoA reductase inhibitor is selected from lovastatin and
simvastatin, and most preferably simvastatin. Herein, the term
"pharmaceutically acceptable salts" with respect to the HMG-CoA
reductase inhibitor shall mean non-toxic salts of the compounds
employed in this invention which are generally prepared by reacting
the free acid with a suitable organic or inorganic base,
particularly those formed from cations such as sodium, potassium,
aluminum, calcium, lithium, magnesium, zinc and
tetramethylammonium, as well as those salts formed from amines such
as ammonia, ethylenediamine, N-methylglucamine, lysine, arginine,
omithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine,
diethanolamine, procaine, N-benzylphenethylamine,
1-p-chlorobenzyl-2-pyrrolidine-1'-yl-methylbenz-i- midazole,
diethylamine, piperazine, and tris(hydroxymethyl) aminomethane.
Further examples of salt forms of HMG-CoA reductase inhibitors may
include, but are not limited to, acetate, benzenesulfonate,
benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide,
calcium edetate, camsylate, carbonate, chloride, clavulanate,
citrate, dihydrochloride, edetate, edisylate, estolate, esylate,
fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate,
hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,
hydroxynapthoate, iodide, isothionate, lactate, lactobionate,
laurate, malate, maleate, mandelate, mesylate, methylsulfate,
mucate, napsylate, nitrate, oleate, oxalate, pamaote, palmitate,
panthothenate, phosphate/diphosphate, polygalacturonate,
salicylate, stearate, subacetate, succinate, tannate, tartrate,
teoclate, tosylate, triethiodide, and valerate.
[0292] Ester derivatives of the described HMG-CoA reductase
inhibitor compounds may act as prodrugs which, when absorbed into
the bloodstream of a warm-blooded animal, may cleave in such a
manner as to release the drug form and permit the drug to afford
improved therapeutic efficacy.
[0293] "Prenyl-protein transferase inhibitor" refers to a compound
which inhibits any one or any combination of the prenyl-protein
transferase enzymes, including farnesyl-protein transferase
(FPTase), geranylgeranyl-protein transferase type I (GGPTase-I),
and geranylgeranyl-protein transferase type-II (GGPTase-II, also
called Rab GGPTase). Examples of prenyl-protein transferase
inhibiting compounds include
(.+-.)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-
-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone,
(-)-6-[amino(4-chloropheny-
l)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-qui-
nolinone,
(+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-
-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone,
5(S)-n-butyl-1-(2,3-dimethyl-
phenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone,
(S)-1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(eth-
anesulfonyl) methyl)-2-piperazinone,
5(S)-n-Butyl-1-(2-methylphenyl)-4-[1--
(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone,
1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]-2-pi-
perazinone,
1-(2,2-diphenylethyl)-3-[N-(1-(4-cyanobenzyl)-1H-imidazol-5-yl-
ethyl)carbamoyl]piperidine,
4-{5-[4-Hydroxymethyl-4-(4-chloropyridin-2-ylm-
ethyl)-piperidine-1-ylmethyl]-2-methylimidazol-1-ylmethyl}benzonitrile,
4-{5-[4-hydroxymethyl-4-(3-chlorobenzyl)-piperidine-1-ylmethyl]-2-methyli-
midazol-1-ylmethyl}benzonitrile,
4-{3-[4-(2-oxo-2H-pyridin-1-yl)benzyl]-3H-
-imidazol-4-ylmethyl}benzonitrile,
4-{3-[4-(5-chloro-2-oxo-2H-[1,2']bipyri-
din-5'-ylmethyl]-3H-imidazol-4-ylmethyl}benzonitrile,
4-{3-[4-(2-Oxo-2H-[1,2']bipyridin-5'-ylmethyl]-3H-imidazol-4-ylmethyl}ben-
zonitrile,
4-[3-(2-Oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-
-4-ylmethyl benzonitrile,
18,19-dihydro-19-oxo-5H,17H-6,10:12,16-dimetheno-
-1H-imidazo[4,3-c][1,11,4]dioxaazacyclo-nonadecine-9-carbonitrile,
(.+-.)-19,20-Dihydro-19-oxo-5H-18,21-ethano-12,14-etheno-6,10-metheno-22H-
-benzo[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecine-9-carbonitrile,
19,20-dihydro-19-oxo-5H,17H-18,21-ethano-6,10:12,16-dimetheno-22H-imidazo-
[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile, and
(.+-.)-19,20-Dihydro-3-methyl-19-oxo-5H-18,21-ethano-12,14-etheno-6,10-me-
theno-22H-benzo[d]imidazo[4,3-k][1,6,9,12]oxa-triazacyclooctadecine-9-carb-
onitrile.
[0294] Other examples of prenyl-protein transferase inhibitors can
be found in the following publications and patents: WO 96/30343, WO
97/18813, WO 97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO
98/29119, WO 95/32987, U.S. Pat. Nos. 5,420,245, 5,523,430,
5,532,359, 5,510,510, 5,589,485, 5,602,098, European Patent Publ. 0
618 221, European Patent Publ. 0 675 112, European Patent Publ. 0
604 181, European Patent Publ. 0 696 593, WO 94/19357, WO 95/08542,
WO 95/11917, WO 95/12612, WO 95/12572, WO 95/10514, U.S. Pat. No.
5,661,152, WO 95/10515, WO 95/10516, WO 95/24612, WO 95/34535, WO
95/25086, WO 96/05529, WO 96/06138, WO 96/06193, WO 96/16443, WO
96/21701, WO 96/21456, WO 96/22278, WO 96/24611, WO 96/24612, WO
96/05168, WO 96/05169, WO 96/00736, U.S. Pat. No. 5,571,792, WO
96/17861, WO 96/33159, WO 96/34850, WO 96/34851, WO 96/30017, WO
96/30018, WO 96/30362, WO 96/30363, WO 96/31111, WO 96/31477, WO
96/31478, WO 96/31501, WO 97/00252, WO 97/03047, WO 97/03050, WO
97/04785, WO 97/02920, WO 97/17070, WO 97/23478, WO 97/26246, WO
97/30053, WO 97/44350, WO 98/02436, and U.S. Pat. No. 5,532,359.
For an example of the role of a prenyl-protein transferase
inhibitor on angiogenesis see European J. of Cancer, Vol. 35, No.
9, pp.1394-1401 (1999).
[0295] Examples of HIV protease inhibitors include amprenavir,
abacavir, CGP-73547, CGP-61755, DMP-450, indinavir, nelfinavir,
tipranavir, ritonavir, saquinavir, ABT-378, AG 1776, and
BMS-232,632. Examples of reverse transcriptase inhibitors include
delaviridine, efavirenz, GS-840, HB Y097, lamivudine, nevirapine,
AZT, 3TC, ddC, and ddl.
[0296] "Angiogenesis inhibitors" refers to compounds that inhibit
the formation of new blood vessels, regardless of mechanism.
Examples of angiogenesis inhibitors include, but are not limited
to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine
kinase receptors Flt-1 (VEGFR.sup.1) and Flk-1/KDR (VEGFR20),
inhibitors of epidermal-derived, fibroblast-derived, or platelet
derived growth factors, MMP (matrix metalloprotease) inhibitors,
integrin blockers, interferon-.alpha., interleukin-12, pentosan
polysulfate, cyclooxygenase inhibitors, including nonsteroidal
anti-inflammatories (NSAIDs) like aspirin and ibuprofen as well as
selective cyclooxygenase-2 inhibitors like celecoxib and rofecoxib
(PNAS, Vol. 89, p. 7384 (1992); JNCI, Vol. 69, p. 475 (1982); Arch.
Opthalmol., Vol. 108, p.573 (1990); Anat. Rec., Vol. 238, p. 68
(1994); FEBS Letters, Vol. 372, p. 83 (1995); Clin, Orthop. Vol.
313, p. 76 (1995); J. Mol. Endocrinol., Vol. 16, p.107 (1996); Jpn.
J. Pharmacol., Vol. 75, p. 105 (1997); Cancer Res., Vol. 57, p.
1625 (1997); Cell, Vol. 93, p. 705 (1998); Intl. J. Mol. Med., Vol.
2, p. 715 (1998); J. Biol. Chem., Vol. 274, p. 9116 (1999)),
carboxyamidotriazole, combretastatin A-4, squalamine,
6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin,
troponin-1, angiotensin II antagonists (see Fernandez et al., J.
Lab. Clin. Med. 105:141-145 (1985)), and antibodies to VEGF. (see,
Nature Biotechnology, Vol. 17, pp.963-968 (October 1999); Kim et
al., Nature, 362, 841-844 (1993); WO 00/44777; and WO
00/61186).
[0297] As described above, the combinations with NSAID's are
directed to the use of NSAID's which are potent COX-2 inhibiting
agents. For purposes of this specification an NSAID is potent if it
possess an IC50 for the inhibition of COX-2 of 1 .mu.M or less as
measured by the cell or microsomal assay disclosed herein.
[0298] The invention also encompasses combinations with NSAID's
which are selective COX-2 inhibitors. For purposes of this
specification NSAID's which are selective inhibitors of COX-2 are
defined as those which possess a specificity for inhibiting COX-2
over COX-1 of at least 100 fold as measured by the ratio of
IC.sub.50 for COX-2 over IC.sub.50 for COX-1 evaluated by the cell
or micromsal assay disclosed hereinunder. Such compounds include,
but are not limited to those disclosed in U.S. Pat. No. 5,474,995,
issued Dec. 12, 1995, U.S. Pat. No. 5,861,419, issued Jan. 19,
1999, U.S. Pat. No. 6,001,843, issued Dec. 14, 1999, U.S. Pat. No.
6,020,343, issued Feb. 1, 2000, U.S. Pat. No. 5,409,944, issued
Apr. 25, 1995, U.S. Pat. No. 5,436,265, issued Jul. 25, 1995, U.S.
Pat. No. 5,536,752, issued Jul. 16, 1996, U.S. Pat. No. 5,550,142,
issued Aug. 27, 1996, U.S. Pat. No. 5,604,260, issued Feb. 18,
1997, U.S. Pat. No. 5,698,584, issued Dec. 16, 1997, U.S. Pat. No.
5,710,140, issued Jan. 20,1998, WO 94/15932, published Jul. 21,
1994, U.S. Pat. No. 5,344,991, issued Jun. 6, 1994, U.S. Pat. No.
5,134,142, issued Jul. 28, 1992, U.S. Pat. No. 5,380,738, issued
Jan. 10, 1995, U.S. Pat. No. 5,393,790, issued Feb. 20, 1995, U.S.
Pat. No. 5,466,823, issued Nov. 14, 1995, U.S. Pat. No. 5,633,272,
issued May 27, 1997, and U.S. Pat. No. 5,932,598, issued Aug. 3,
1999, all of which are hereby incorporated by reference.
[0299] Other examples of specific inhibitors of COX-2 include the
following:
[0300]
3-(3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone;
[0301]
3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-
;
[0302]
3-(3,4-dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-
;
[0303] 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone;
[0304]
5,5-dimethyl-3-(3-fluorophenyl)-4-(methylsulfonyl)phenyl)-2-(5H)-fu-
ranone;
[0305]
3-(4-methylsulfonyl)phenyl-2-phenyl-5-trifluoromethylpyridine;
[0306]
2-(3-chlorophenyl)-3-(4-methylsulfonyl)phenyl-5-trifluoromethyl-pyr-
idine;
[0307]
2-(4-chlorophenyl)-3-(4-methylsulfonyl)phenyl-5-trifluoromethyl-pyr-
idine;
[0308]
2-(4-fluorophenyl)-3-(4-methylsulfonyl)phenyl-5-trifluoromethyl-pyr-
idine;
[0309]
3-(4-methylsulfonyl)phenyl-2-(3-pyridinyl)-5-trifluoromethylpyridin-
e;
[0310] 5-methyl-3-(4-methylsulfonyl)phenyl-2-phenylpyridine;
[0311] 2-(4-chlorophenyl)-5-methyl-3-(4-methylsulfonyl)
phenylpyridine;
[0312] 5-methyl-3-(4-methylsulfonyl)phenyl-2-(3-pyridinyl)
pyridine;
[0313] 5-chloro-2-(4-chlorophenyl)-3-(4-methylsulfonyl)
phenylpyridine;
[0314] 5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-pyridinyl)
pyridine;
[0315] 5-chloro-3-(4-methylsulfonyl)phenyl-2-(3-pyridinyl)
pyridine;
[0316] 5-chloro-3-(4-methylsulfonyl)phenyl-2-(4-pyridinyl)
pyridine;
[0317]
5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridin-
e;
[0318]
2-(4-chlorophenyl)-3-(4-methylsulfonyl)phenylpyridinyl-5-carboxylic
acid methyl ester;
[0319]
2-(4-chlorophenyl)-3-(4-methylsulfonyl)phenylpyridinyl-5-carboxylic
acid;
[0320] 5-cyano-2-(4-chlorophenyl)-3-(4-methylsulfonyl)
phenylpyridine;
[0321] 5-chloro-3-(4-methylsulfonyl)phenyl-2-(3-pyridyl)pyridine
hydromethanesulfonate;
[0322] 5-chloro-3-(4-methylsulfonyl)phenyl-2-(3-pyridyl)pyridine
hydrochloride;
[0323]
5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridin-
e hydrochloride;
[0324]
5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-ethyl-5-pyridinyl)pyridine-
;
[0325] 5-chloro-3-(
4-methylsulfonyl)phenyl-2-(2-ethyl-5-pyridinyl)pyridin- e
hydromethanesulfonate;
[0326]
3-(3,4-difluorophenoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5-
H-furan-2-one;
[0327]
3-(3-fluorophenoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-fu-
ran-2-one;
[0328] 3-(3,5-difluorophenoxy)-5,5-dimethyl-4-(methylsulfonyl)
phenyl)-SH-furan-2-one;
[0329]
3-phenoxy-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;
[0330]
3-(2,4-difluorophenoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5-
H-furan-2-one;
[0331]
3-(4-chlorophenoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-fu-
ran-2-one;
[0332] 3-(3,4-dichlorophenoxy)-5,5-dimethyl-4-(methylsulfonyl)
phenyl)-5H-furan-2-one;
[0333] 3-(4-fluorophenoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)
phenyl)-5H-furan-2-one;
[0334]
3-(4-fluorophenylthio)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-
-furan-2-one;
[0335]
3-(3,5-difluorophenylthio)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl-
)-5H-furan-2-one;
[0336]
3-phenylthio-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-o-
ne;
[0337]
3-(N-phenylamino)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-fura-
n-2-one;
[0338] 3-(N-methyl-N-phenylamino)-5
,5-dimethyl-4-(4-(methylsulfonyl)pheny- l)-5H-furan-2-one;
[0339]
3-cyclohexyloxy-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan--
2-one;
[0340]
3-phenylthio-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;
[0341]
3-benzyl-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;
[0342]
3-(3,4-difluorophenylhydroxymethyl)-5,5-dimethyl-4-(4-(methylsulfon-
yl)phenyl)-5H-furan-2-one;
[0343]
3-(3,4-difluorobenzoyl)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5-
H-furan-2-one;
[0344]
3-benzoyl-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one;
[0345]
4-(4-(methylsulfonyl)phenyl)-3-phenoxy-1-oxaspiro[4.4]non-3-en-2-on-
e;
[0346] 4-(4-(methylsulfonyl)phenyl)-3-phenylthio-1-ox
aspiro[4.4]non-3-en-2-one;
[0347] 4-(2-oxo-3-phenylthio-1-oxa-spiro[4,4]non-3-en-4-yl)
benzenesulfonamide;
[0348] 3-(4-fluorobenzyl)-5,5-dimethyl-4-(4-(methylsulfonyl)
phenyl)-5H-furan-2-one;
[0349]
3-(3,4-difluorophenoxy)-5-methoxy-5-methyl-4-(4-(methylsulfonyl)phe-
nyl)-5H-furan-2-one;
[0350]
3-(5-chloro-2-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-
-5H-furan-2-one;
[0351]
3-(2-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-
-2-one;
[0352] 3-(6-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)
phenyl)-5H-furan-2-one;
[0353]
3-(3-isoquinolinoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-f-
uran-2-one;
[0354] 3-(4-(methylsulfonyl)phenyl)-2-phenoxycyclopent-2-enone;
[0355]
3-(4-(methylsulfonyl)phenyl)-2-(3,4-difluorophenoxy)cyclopent-2-eno-
ne;
[0356]
5,5-dimethyl-4-(4-methylsulfonylphenyl)-3-(5-bromopyridin-2-yloxy)--
5H-furan-2-one;
[0357]
5,5-dimethyl-4-(4-methylsulfonylphenyl)-3-(2-propoxy)-5H-furan-2-on-
e;
[0358]
2-(3,4-difluorophenoxy)-3-(4-methylsulfonylphenyl)-cyclopent-2-enon-
e;
[0359] 3-(5-benzothiophenyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)
phenyl)-5H-furan-2-one;
[0360]
5,5-dimethyl-4-(4-methylsulfonyl-phenyl)-3-(pyridyl-4-oxy)-5H-furan-
-2-one;
[0361]
5,5-dimethyl-4-(4-methylsulfonyl-phenyl)-3-(pyridyl-3-oxy)-5H-furan-
-2-one;
[0362] 3-(2-methyl-5-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)
phenyl)-5H-furan-2-one;
[0363]
3-(2-fluoro-4-trifluoromethyl)phenoxy-4-(4-methylsulfonyl)phenyl)-5-
,5-dimethyl-5H-furan-2-one;
[0364]
3-(5-chloro-2-pyridylthio)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl--
5H-furan-2-one;
[0365]
2-(3,5-difluorophenoxy)-3-(4-methylsulfonylphenyl)-cyclopent-2-enon-
e;
[0366]
3-(2-pyrimidinoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-
-2-one;
[0367]
3-(3-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5-
H-furan-2-one;
[0368] 3-(3-chloro-5-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)
phenyl)-5H-furan-2-one;
[0369]
3-(3-(1,2,5-thiadiazolyl)oxy)-4-(4-(methylsulfonyl)phenyl)-5,5-dime-
thyl-5H-furan-2-one;
[0370]
3-(5-isoquinolinoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-SH-fur-
an-2-one;
[0371] 3-(6-amino-2-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)
phenyl)-5H-furan-2-one;
[0372]
3-(3-chloro-4-fluoro)phenoxy-4-(methylsulfonyl)phenyl)-5,5-dimethyl-
-5H-furan-2-one;
[0373]
3-(6-quinolinoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-fura-
n-2-one;
[0374]
3-(5-nitro-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-
-furan-2-one;
[0375]
3-(2-thiazolylthio)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-fu-
ran-2-one;
[0376] 3-(3-chloro-5-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)
phenyl)-5H-furan-2-one;
[0377]
5,5-dimethyl-4-(4-methylsulfonylphenyl)-3-(2-propoxy)-5H-furan-2-on-
e;
[0378]
3-(3-trifluoromethyl)phenoxy-4-(4-methylsulfonyl)phenyl)-5,5-dimeth-
yl-5H-furan-2-one;
[0379]
5,5-dimethyl-(4-(4-methylsulfonyl)phenyl)-3-(piperidine-1-carbonyl)-
-5-H-furan-2-one;
[0380]
5,5-dimethyl-3-(2-Butoxy)-4-(4-methylsulfonylphenyl)-5H-furan-2-one-
;
[0381]
5,5-dimethyl-4-(4-methylsulfonylphenyl)-3-(3-pentoxy)-5H-furan-2-on-
e;
[0382]
2-(5-chloro-2-pyridyloxy)-3-(4-methylsulfonyl)phenylcyclopent-2-eno-
ne;
[0383]
3-(4-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5-
H-furan-2-one;
[0384]
(5R)-3-(3,4-difluorophenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)p-
henyl-5H-furan-2-one;
[0385]
(5R)-3-(4-chlorophenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)pheny-
l-5H-furan-2-one;
[0386]
3-(2-methyl-3-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5-
H-furan-2-one;
[0387]
3-(4-methyl-5-nitro-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)-
phenyl-5H-furan-2-one;
[0388]
3-(5-chloro-4-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl-
)phenyl-5H-furan-2-one;
[0389]
3-(5-fluoro-4-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl-
)phenyl-5H-furan-2-one;
[0390]
3-(3-chloro-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5-
H-furan-2-one;
[0391]
3-(4-fluorophenoxy)-5-methyl-4-(4-methylsulfonyl)phenyl-5-propyl-5H-
-furan-2-one;
[0392] 3-(N,N-diethylamino)-5,5-dimethyl-4-(4-(methylsulfonyl)
phenyl)-5H-furan-2-one;
[0393]
5,5-dimethyl-4-(4-methylsulfonyl-phenyl)-3-(3,5-dichloro-2-pyridylo-
xy)-5H-furan-2-one;
[0394]
(5R)-3-(4-bromophenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-
-5H-furan-2-one;
[0395]
(5R)-3-(4-methoxyphenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phen-
yl-5H-furan-2-one;
[0396]
(5R)-3-(5-chloro-2-pyridyloxy)-5-methyl-4-(4-methylsulfonyl)phenyl--
5-(2,2,2-trifluoroethyl)-5H-furan-2-one;
[0397]
3-(5-chloro-2-pyridyloxy)-5-methyl-4-(4-methylsulfonyl)phenyl-5-pro-
py1-5H-furan-2-one;
[0398] 3-(1-cyclopropyl-ethoxy)-5,5-dimethyl-4-(4-methyl
sulfonyl)phenyl)-5H-furan-2-one;
[0399]
5-methyl-4-(4-(methylsulfonyl)phenyl)-3-(2-(propoxy)-5-(2-trifluoro-
ethyl)-5H-furan-2-one;
[0400]
5(R)-5-ethyl-5-methyl-4-(4-(methylsulfonyl)phenyl)-3-(2-propoxy)-5H-
-furan-2-one;
[0401]
5,5-dimethyl-3-(2,2-dimethylpropyloxy)-4-(4-(methylsulfonyl)phenyl)-
-5H-furan-2-one;
[0402] 5(R)-3-(1-cyclopropyl-ethoxy)-5-ethyl-5-methyl-4-(4-(methyl
sulfonyl)phenyl-5H-furan-2-one;
[0403]
5(S)-5-ethyl-5-methyl-4-(4-(methylsulfonyl)phenyl-3-(2-propoxy)-5H--
furan-2-one;
[0404]
3-(1-cyclopropylethoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5-
H-furan-2-one;
[0405]
3-(1-cyclopropylethoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5-
H-furan-2-one;
[0406]
5,5-dimethyl-3-(isobutoxy)-4-(4-(methylsulfonyl)phenyl)-5H-furan-2--
one;
[0407]
3-(4-bromophenoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-fur-
an-2-one;
[0408]
3-(2-quinolinoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-fura-
n-2-one;
[0409]
3-(2-chloro-5-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-
-5H-furan-2-one;
[0410] 3-(6-benzothiazolyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)
phenyl)-5H-furan-2-one;
[0411] 3-(6-chloro-2-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)
phenyl)-5H-furan-2-one;
[0412]
3-(4-quinazolyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-fu-
ran-2-one;
[0413]
(5R)-3-(5-fluoro-2-pyridyloxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl-
)phenyl-5H-furan-2-one;
[0414]
(5R)-3-(4-fluorophenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)pheny-
1-5H-furan-2-one;
[0415]
(5R)-3-(5-fluoro-2-pyridyloxy)-5-methyl-4-(4-methylsulfonyl)phenyl--
5-(2,2,2-trifluoroethyl)-5H-furan-2-one;
[0416]
3-(1-isoquinolinyloxy)-5,5-dimethyl-4-(methylsulfonyl)phenyl-5H-fur-
an-2-one;
[0417]
(5R)-3-(4-fluorophenoxy)-5-methyl-4-(4-methylsulfonyl)phenyl-5-(2,2-
,2-trifluoroethyl)-5H-furan-2-one;
[0418] 3-(3-fluoro-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)
phenyl-5H-furan-2-one;
[0419] (5R)-3-(3,4-difluorophenoxy)-5-methyl-4-(4-methylsulfony1)
phenyl-5-(2,2,2-trifluoroethyl)-5H-furan-2-one;
[0420]
(5R)-3-(5-chloro-2-pyridyloxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl-
)phenyl-5H-furan-2-one;
[0421]
3-(3,4-difluorophenoxy)-5-methyl-5-trifluoromethyl-4-(4-methylsulfo-
nyl)phenyl-5H-furan-2-one;
[0422]
3-(3,4-difluorophenoxy)-5-methyl-4-(4-(methylsulfonyl)phenyl)-5-pro-
pyl-5H-furan-2-one;
[0423]
3-cyclobutyloxy-5,5-dimethyl-4-(4-methylsulfonylphenyl-5H-furan-2-o-
ne;
[0424]
3-(1-indanyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-
-2-one;
[0425]
3-(2-indanyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl)-5H-furan--
2-one;
[0426]
3-cyclopentyloxy-5,5-dimethyl-4-(4-methylsulfonylphenyl)5H-furan-2--
one;
[0427]
3-(3,3-dimethylcyclopentyloxy)-5,5-dimethyl-4-(4-methylsulfonyl-phe-
nyl)-5H-furan-2-one;
[0428]
3-isopropoxy-5-methyl-4-(4-methylsulfonylphenyl)-5-propyl-5H-furan--
2-one;
[0429]
3-(2-methoxy-5-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl--
5H-furan-2-one;
[0430]
3-(5-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5-
H-furan-2-one;
[0431]
(5RS)-3-(3,4-difluorophenoxy)-5-methyl-4-(4-methylsulfonyl)phenyl-5-
-(2,2,2-trifluoroethyl)-5H-furan-2-one;
[0432]
3-(3-chloro-4-methoxyphenoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phen-
yl-5H-furan-2-one;
[0433]
(5R)-3-(3-chloro-4-methoxyphenoxy)-5-ethyl-5-methyl-4-(4-methylsulf-
onyl)phenyl-5H-furan-2-one;
[0434]
(5R)-3-(4-chlorophenoxy)-5-trifluoroethyl-5-methyl-4-(4-methylsulfo-
nyl)phenyl-5H-furan-2-one;
[0435]
(5R)-3-(4-bromophenoxy)-5-trifluoroethyl-5-methyl-4-(4-methylsulfon-
yl)phenyl-5H-furan-2-one;
[0436]
5-cyclopropylmethyl-3-(3,4-difluorophenoxy)-5-methyl-(4-methylsulfo-
nyl)phenyl-5H-furan-2-one;
[0437]
(5R)-3-(3fluorophenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-
-5H-furan-2-one;
[0438]
(5R)-3-(4-chloro-3-fluorophenoxy)-5-ethyl-5-methyl-4-(4-methylsulfo-
nyl)phenyl-5H-furan-2-one;
[0439]
(5R)-3-phenoxy-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-
-2-one;
[0440]
(5R)-3-(4-chloro-3-methylphenoxy)-5-ethyl-5-methyl-4-(4-methylsulfo-
nyl)phenyl-5H-furan-2-one;
[0441]
3-(4-chloro-3-methylphenoxy)-5-5-dimethyl-4-(4-methylsulfonyl)pheny-
l-5H-furan-2-one;
[0442]
(5R)-3-(5-bromo-2-pyridyloxy)-4-(4-methylsulfonylphenyl)-5-methyl-5-
-(2,2,2-trifluoroethyl)-5H-furan-2-one;
[0443]
(5R)-3-(5-bromo-2-pyridyloxy)-4-(4-methylsulfonylphenyl)-5-ethyl-5--
methyl-5H-furan-2-one;
[0444]
3-(5-chloro-6-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl-
)phenyl-5H-furan-2-one;
[0445]
3-(5-cyclopropyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phe-
nyl-5H-furan-2-one;
[0446]
3-(1-cyclopropylethoxy)-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;
and
[0447]
3-(cyclopropylmethoxy)-4-(4-methylsulfonyl)phenyl-5H-furan-2-one;
[0448] or a pharmaceutically acceptable salt or stereoisomer
thereof.
[0449] Inhibitors of COX-2 that are particularly useful in the
instant method of treatment are:
[0450] 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H-furanone; and
14
[0451]
5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridin-
e; 15
[0452] or a pharmaceutically acceptable salt thereof.
[0453] General and specific synthetic procedures for the
preparation of the COX-2 inhibitor compounds described above are
found in U.S. Pat. No. 5,474,995, issued Dec. 12, 1995, U.S. Pat.
No. 5,861,419, issued Jan. 19, 1999, and U.S. Pat. No. 6,001,843,
issued Dec. 14, 1999, all of which are herein incorporated by
reference.
[0454] Compounds that have been described as specific inhibitors of
COX-2 and are therefore useful in the present invention include,
but are not limited to, the following: 16
[0455] or a pharmaceutically acceptable salt thereof.
[0456] Compounds which are described as specific inhibitors of
COX-2 and are therefore useful in the present invention, and
methods of synthesis thereof, can be found in the following
patents, pending applications and publications, which are herein
incorporated by reference: WO 94/15932, published Jul. 21, 1994,
U.S. Pat. No. 5,344,991, issued June 6, 1994, U.S. Pat. No.
5,134,142, issued Jul. 28, 1992, U.S. Pat. No. 5,380,738, issued
Jan. 10, 1995, U.S. Pat. No. 5,393,790, issued Feb. 20, 1995, U.S.
Pat. No. 5,466,823, issued Nov. 14, 1995, U.S. Pat. No. 5,633,272,
issued May 27, 1997, and U.S. Pat. No. 5,932,598, issued Aug. 3,
1999.
[0457] Compounds which are specific inhibitors of COX-2 and are
therefore useful in the present invention, and methods of synthesis
thereof, can be found in the following patents, pending
applications and publications, which are herein incorporated by
reference: U.S. Pat. No. 5,474,995, issued Dec. 12, 1995, U.S. Pat.
No. 5,861,419, issued Jan. 19, 1999, U.S. Pat. No. 6,001,843,
issued Dec. 14, 1999, U.S. Pat. No. 6,020,343, issued Feb. 1, 2000,
U.S. Pat. 5,409,944, issued Apr. 25, 1995 , U.S. Pat. No.
5,436,265, issued Jul. 25, 1995 , U.S. Pat. No. 5,536,752, issued
Jul. 16, 1996 , U.S. Pat. No. 5,550,142, issued Aug. 27, 1996, U.S.
Pat. No. 5,604,260, issued Feb. 18, 1997, U.S. Pat. No. 5,698,584,
issued Dec. 16, 1997, and U.S. Pat. No. 5,710,140, issued Jan. 20,
1998.
[0458] Other examples of angiogenesis inhibitors include, but are
not limited to, endostation, ukrain, ranpimase, IM862,
5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]oct--
6-yl(chloroacetyl)carbamate, acetyldinanaline,
5-amino-1-[[3,5-dichloro-4--
(4-chlorobenzoyl)phenyl]methyl]-1H-1,2,3-triazole-4-carboxamide,
CM101, squalamine, combretastatin, RP14610, NX31838, sulfated
mannopentaose phosphate,
7,7-(carbonyl-bis[imino-N-methyl-4,2-pyrrolocarbonyl-imino[N-m-
ethyl-4,2-pyrrole]-carbonylimino]-bis-(1,3-naphthalene
disulfonate), and
3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone (SU5416).
[0459] As used above, "integrin blockers" refers to compounds which
selectively antagonize, inhibit or counteract binding of a
physiological ligand to the .alpha..sub.v.beta..sub.3 integrin, to
compounds which selectively antagonize, inhibit or counteract
binding of a physiological ligand to the .alpha.v.beta.5 integrin,
to compounds which antagonize, inhibit or counteract binding of a
physiological ligand to both the .alpha..sub.v.beta..sub.3 integrin
and the .alpha..sub.v.beta..sub.5 integrin, and to compounds which
antagonize, inhibit or counteract the activity of the particular
integrin(s) expressed on capillary endothelial cells. The term also
refers to antagonists of the .alpha..sub.v.beta..sub- .6,
.alpha..sub.v.beta..sub.8, .alpha..sub.1.beta..sub.1,
.alpha..sub.2.beta..sub.1, .alpha..sub.5.beta..sub.1,
.alpha..sub.6.beta..sub.1 and .alpha..sub.6.beta..sub.4 integrins.
The term also refers to antagonists of any combination of
.alpha..sub.v.beta..sub.3, .alpha..sub.v.beta..sub.5,
.alpha..sub.v.beta..sub.6, .alpha..sub.v.beta..sub.8,
.alpha..sub.1.beta..sub.1, .alpha..sub.2.beta..sub.1,
.alpha..sub.5.beta..sub.1, .alpha..sub.6.beta..sub.1, and
.alpha..sub.6.beta..sub.4 integrins.
[0460] Some specific examples of tyrosine kinase inhibitors include
N-(trifluoromethylphenyl)-5-methylisoxazol-4-carboxamide,
3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)indolin-2-one,
17-(allylamino)-17-demethoxygeldanamycin,
4-(3-chloro-4-fluorophenylamino-
)-7-methoxy-6-[3-(4-morpholinyl)propoxyl]quinazoline,
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine,
BIBX1382,
2,3,9,10,11,12-hexahydro-10-(hydroxymethyl)-10-hydroxy-9-methyl-9,12-epox-
y-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one,
SH1382, genistein, ST1571, CEP2563,
4-(3-chlorophenylamino)-5,6-dimethyl-- 7H-pyrrolo
[2,3-d]pyrimidinemethane sulfonate, 4-(3-bromo-4-hydroxyphenyl)-
amino-6,7-dimethoxyquinazoline,
4-(4'-hydroxyphenyl)amino-6,7-dimethoxyqui- nazoline, SU6668,
ST1571A, N-4-chlorophenyl-4-(4-pyridylmethyl)-1-phthalaz- inamine,
and EMD121974.
[0461] The instant compounds are also useful, alone or in
combination with platelet fibrinogen receptor (GP IIb/IIIa)
antagonists, such as tirofiban, to inhibit metastasis of cancerous
cells. Tumor cells can activate platelets largely via thrombin
generation. This activation is associated with the release of VEGF.
The release of VEGF enhances metastasis by increasing extravasation
at points of adhesion to vascular endothelium (Amirkhosravi,
Platelets 10, 285-292, 1999). Therefore, the present compounds can
serve to inhibit metastasis, alone or in combination with GP
IIb/IIIa) antagonists. Examples of other fibrinogen receptor
antagonists include abciximab, eptifibatide, sibrafiban, lamifiban,
lotrafiban, cromofiban, and CT50352.
[0462] If formulated as a fixed dose, such combination products
employ the compounds of this invention within the dosage range
described below and the other pharmaceutically active agent(s)
within its approved dosage range. Compounds of the instant
invention may alternatively be used sequentially with known
pharmaceutically acceptable agent(s) when a combination formulation
is inappropriate.
[0463] The term "administration" and variants thereof (e.g.,
"administering" a compound) in reference to a compound of the
invention means introducing the compound or a prodrug of the
compound into the system of the animal in need of treatment. When a
compound of the invention or prodrug thereof is provided in
combination with one or more other active agents (e.g., a cytotoxic
agent, etc.), "administration" and its variants are each understood
to include concurrent and sequential introduction of the compound
or prodrug thereof and other agents.
[0464] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combination of the specified ingredients in the
specified amounts.
[0465] The term "therapeutically effective amount" as used herein
means that amount of active compound or pharmaceutical agent that
elicits the biological or medicinal response in a tissue, system,
animal or human that is being sought by a researcher, veterinarian,
medical doctor or other clinician.
[0466] The term "treating cancer" or "treatment of cancer" refers
to administration to a mammal afflicted with a cancerous condition
and refers to an effect that alleviates the cancerous condition by
killing the cancerous cells, but also to an effect that results in
the inhibition of growth and/or metastasis of the cancer.
[0467] The present invention also encompasses a pharmaceutical
composition useful in the treatment of cancer, comprising the
administration of a therapeutically effective amount of the
compounds of this invention, with or without pharmaceutically
acceptable carriers or diluents. Suitable compositions of this
invention include aqueous solutions comprising compounds of this
invention and pharmacologically acceptable carriers, e.g., saline,
at a pH level, e.g., 7.4. The solutions may be introduced into a
patient's bloodstream by local bolus injection.
[0468] When a compound according to this invention is administered
into a human subject, the daily dosage will normally be determined
by the prescribing physician with the dosage generally varying
according to the age, weight, and response of the individual
patient, as well as the severity of the patient's symptoms.
[0469] In one exemplary application, a suitable amount of compound
is administered to a mammal undergoing treatment for cancer.
Administration occurs in an amount between about 0.1 mg/kg of body
weight to about 60 mg/kg of body weight per day, preferably of
between 0.5 mg/kg of body weight to about 40 mg/kg of body weight
per day.
Assays
[0470] The compounds of the instant invention described in the
Examples were tested by the assays described below and were found
to have kinase inhibitory activity. Other assays are known in the
literature and could be readily performed by those of skill in the
art. (see, for example, Dhanabal et al., Cancer Res. 59:189-197;
Xin et al., J. Biol. Chem. 274:9116-9121; Sheu et al., Anticancer
Res. 18:4435-4441; Ausprunk et al., Dev. Biol. 38:237-248; Gimbrone
et al., J. Natl. Cancer Inst. 52:413-427; Nicosia et al., In Vitro
18:538-549).
VEGF Receptor Kinase Assay
[0471] VEGF receptor kinase activity is measured by incorporation
of radio-labeled phosphate into polyglutamic acid, tyrosine, 4:1
(pEY) substrate. The phosphorylated pEY product is trapped onto a
filter membrane and the incorporation of radio-labeled phosphate
quantified by scintillation counting.
Materials
VEGF Receptor Kinase
[0472] The intracellular tyrosine kinase domains of human KDR
(Terman, B. I. et al. Oncogene (1991) vol. 6, pp. 1677-1683.) and
Flt-1 (Shibuya, M. et al. Oncogene (1990) vol. 5, pp. 519-524) were
cloned as glutathione S-transferase (GST) gene fusion proteins.
This was accomplished by cloning the cytoplasmic domain of the KDR
kinase as an in frame fusion at the carboxy terminus of the GST
gene. Soluble recombinant GST-kinase domain fusion proteins were
expressed in Spodoptera frugiperda (Sf21) insect cells (Invitrogen)
using a baculovirus expression vector (pAcG2T, Pharmingen).
Lysis Buffer
[0473] 50 mM Tris pH 7.4,0.5 M NaCl, 5 mM DTT, 1 mM EDTA, 0.5%
triton X-100, 10% glycerol, 10 mg/mL of each leupeptin, pepstatin
and aprotinin and 1 mM phenylmethylsulfonyl fluoride (all
Sigma).
Wash Buffer
[0474] 50 mM Tris pH 7.4,0.5 M NaCl, 5 mM DTT, 1 mM EDTA, 0.05%
triton X-100, 10 % glycerol, 10 mg/mL of each leupeptin, pepstatin
and aprotinin and 1 mM phenylmethylsulfonyl fluoride.
Dialysis Buffer
[0475] 50 mM Tris pH 7.4,0.5 M NaCl, 5 mM DTT, 1 mM EDTA, 0.05%
triton X-100, 50% glycerol, 10 mg/mL of each leupeptin, pepstatin
and aprotinin and 1 mM phenylmethylsuflonyl fluoride.
10.times.Reaction Buffer
[0476] 200 mM Tris, pH 7.4, 1.0 M NaCl, 50 mM MnCl.sub.2, 10 mM DTT
and 5 mg/mL bovine serum albumin (Sigma).
Enzyme Dilution Buffer
[0477] 50 mM Tris, pH 7.4, 0.1 M NaCl, 1 mM DTT, 10 % glycerol, 100
mg/mL BSA.
10.times.Substrate
[0478] 750 .mu.g/mL poly (glutamic acid, tyrosine; 4:1)
(Sigma).
Stop Solution
[0479] 30% trichloroacetic acid, 0.2 M sodium pyrophosphate (both
Fisher).
Wash Solution
[0480] 15% trichloroacetic acid, 0.2 M sodium pyrophosphate.
Filter Plates
[0481] Millipore #MAFC NOB, GF/C glass fiber 96 well plate.
Method
A. Protein Purification
[0482] 1. Sf21 cells were infected with recombinant virus at a
multiplicity of infection of 5 virus particles/ cell and grown at
27.degree. C. for 48 hours.
[0483] 2. All steps were performed at 4.degree. C. Infected cells
were harvested by centrifugation at 1000.times.g and lysed at
4.degree. C. for 30 minutes with 1/10 volume of lysis buffer
followed by centrifugation at 100,000.times.g for 1 hour. The
supernatant was then passed over a glutathione Sepharose column
(Pharmacia) equilibrated in lysis buffer and washed with 5 volumes
of the same buffer followed by 5 volumes of wash buffer.
Recombinant GST-KDR protein was eluted with wash buffer/10 mM
reduced glutathione (Sigma) and dialyzed against dialysis
buffer.
B. VEGF Receptor Kinase Assay
[0484] 1. Add 5 .mu.l of inhibitor or control to the assay in 50%
DMSO.
[0485] 2. Add 35 .mu.l of reaction mix containing 5 .mu.l of
10.times.reaction buffer, 5 .mu.l 25 mM ATP/10 .mu.Ci [.sup.33P]ATP
(Amersham), and 5 .mu.l 10.times.substrate.
[0486] 3. Start the reaction by the addition of 10 .mu.l of KDR (25
nM) in enzyme dilution buffer.
[0487] 4. Mix and incubate at room temperature for 15 minutes.
[0488] 5. Stop by the addition of 50 .mu.l stop solution.
[0489] 6. Incubate for 15 minutes at 4.degree. C.
[0490] 7. Transfer a 90 .mu.l aliquot to filter plate.
[0491] 8. Aspirate and wash 3 times with wash solution.
[0492] 9. Add 30 .mu.l of scintillation cocktail, seal plate and
count in a Wallac Microbeta scintillation counter.
Human Umbilical Vein Endothelial Cell Mitogenesis Assay
[0493] Expression of VEGF receptors that mediate mitogenic
responses to the growth factor is largely restricted to vascular
endothelial cells. Human umbilical vein endothelial cells (HU Cs)
in culture proliferate in response to VEGF treatment and can be
used as an assay system to quantify the effects of KDR kinase
inhibitors on VEGF stimulation. In the assay described, quiescent
HUVEC monolayers are treated with vehicle or test compound 2 hours
prior to addition of VEGF or basic fibroblast growth factor (bFGF).
The mitogenic response to VEGF or bFGF is determined by measuring
the incorporation of [.sup.3H]thymidine into cellular DNA.
Materials
HUVECs
[0494] HUVECs frozen as primary culture isolates are obtained from
Clonetics Corp. Cells are maintained in Endothelial Growth Medium
(EGM; Clonetics) and are used for mitogenic assays at passages
3-7.
Culture Plates
[0495] NUNCLON 96-well polystyrene tissue culture plates (NUNC
#167008).
Assay Medium
[0496] Dulbecco's modification of Eagle's medium containing 1 g/nL
glucose (low-glucose DMEM; Mediatech) plus 10% (v/v) fetal bovine
serum (Clonetics).
Test Compounds
[0497] Working stocks of test compounds are diluted serially in
100% dimethylsulfoxide (DMSO) to 400-fold greater than their
desired final concentrations. Final dilutions to
1.times.concentration are made directly into Assay Medium
immediately prior to addition to cells.
10.times.Growth Factors
[0498] Solutions of human VEGF165 (500 ng/mL; R&D Systems) and
bFGF (10 ng/mL; R&D Systems) are prepared in Assay Medium.
10.times.[.sup.3H]Thymidine
[0499] [Methyl-.sup.3H]Thymidine (20 Ci/mmol; Dupont-NEN) is
diluted to 80 uCi/mL in low-glucose DMEM.
Cell Wash Medium
[0500] Hank's balanced salt solution (Mediatech) containing 1 mg/mL
bovine serum albumin (Boehringer-Mannheim).
Cell Lysis Solution
[0501] 1 N NaOH, 2% (w/v) Na.sub.2CO.sub.3.
Method
[0502] 1. HUVEC monolayers maintained in EGM are harvested by
trypsinization and plated at a density of 4000 cells per 100 .mu.L
Assay Medium per well in 96-well plates. Cells are growth-arrested
for 24 hours at 37.degree. C. in a humidified atmosphere containing
5% CO.sub.2.
[0503] 2. Growth-arrest medium is replaced by 100 .mu.L Assay
Medium containing either vehicle (0.25% [v/v]DMSO) or the desired
final concentration of test compound. All determinations are
performed in triplicate. Cells are then incubated at 37.degree.
C./5% CO.sub.2 for 2 hours to allow test compounds to enter
cells.
[0504] 3. After the 2-hour pretreatment period, cells are
stimulated by addition of 10 .mu.L/well of either Assay Medium,
10.times.VEGF solution or 10.times.bFGF solution. Cells are then
incubated at 37.degree. C./5% CO.sub.2.
[0505] 4. After 24 hours in the presence of growth factors,
10.times.[.sup.3H]Thymidine (10 .mu.L/well) is added.
[0506] 5. Three days after addition of [.sup.3H]thymidine, medium
is removed by aspiration, and cells are washed twice with Cell Wash
Medium (400 .mu.L/well followed by 200 .mu.L/well). The washed,
adherent cells are then solubilized by addition of Cell Lysis
Solution (100 .mu.L/well) and warming to 37.degree. C. for 30
minutes. Cell lysates are transferred to 7-mL glass scintillation
vials containing 150 .mu.L of water. Scintillation cocktail (5
ml/vial) is added, and cell-associated radioactivity is determined
by liquid scintillation spectroscopy.
[0507] Based upon the foregoing assays the compounds of formula I
are inhibitors of VEGF and thus are useful for the inhibition of
angiogenesis, such as in the treatment of ocular disease, e.g.,
diabetic retinopathy and in the treatment of cancers, e.g., solid
tumors. The instant compounds inhibit VEGF-stimulated mitogenesis
of human vascular endothelial cells in culture with IC50 values
between 0.01-5.0 .mu.M. These compounds also show selectivity over
related tyrosine kinases (e.g., FGFR1 and the Src family; for
relationship between Src kinases and VEGFR kinases, see Eliceiri et
al., Molecular Cell, Vol. 4, pp.915-9.sup.24, Dec. 1999).
EXAMPLES
[0508] Examples provided are intended to assist in a further
understanding of the invention. Particular materials employed,
species and conditions are intended to be further illustrative of
the invention and not limiting of the reasonable scope thereof.
Example 1
3-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)-1H-quinolin-2-one
[0509] 17
Step 1: Synthesis of 2-chloro-3-iodo-quinoline (Intermediate A)
[0510] 18
[0511] A suspension of 3-(2-chloro)-quinolineboronic acid (5.05 g,
24.3 mmol, 1 equiv, prepared by the method of Marsais, F; Godard,
A.; Queguiner, G. J. Heterocyclic Chem. 1989, 26, 1589-1594) and
N-iodosuccinimide (5.48 g, 24.4 mmol, 1.00 equiv) in acetonitrile
(300 mL) was stirred at 23.degree. C. in the dark for 20 hours. The
reaction mixture was concentrated to dryness, and the resulting
yellow solid was partitioned between saturated aqueous sodium
bicarbonate solution and dichloromethane. The organic layer was
washed with water, then dried over magnesium sulfate and
concentrated to give 2-chloro-3-iodo-quinoline (intermediate A) as
a pale yellow solid.
[0512] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.8.67 (s, 1H), 7.99
(br d, 1H, J.dbd.8.4 Hz), 7.75 (br t, 1H, J.dbd.7.7 Hz), 7.72 (br
d, 1H, J.dbd.7.8 Hz), 7.57 (br t, 1H, J.dbd.7.6 Hz).
[0513] Step 2: Synthesis of Intermediate B 19
Intermediate B
[0514] A solution of 5-methoxy-1H-pyrrolo[3,2-b]pyridine (0.930 g,
6.28 mmol, 1 equiv, prepared by the method of Mazeas, D.;
Guillaumet, G.; Viaud, M-C Heterocycles 1999, 50, 1065-1080),
di-tert-butyl dicarbonate (1.64 g, 4.05 mmol, 1.20 equiv), and
4-dimethylaminopyridine (10 mg, 0.082 mmol, 0.013 equiv) in
dichloromethane (30 mL) was stirred at 23.degree. C. for 1 hour.
The reaction mixture was concentrated, and the residue was purified
by flash column chromatography (100% hexanes initially, grading to
30% ethyl acetate in hexanes) to afford intermediate B as a
colorless oil.
[0515] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.8.24 (br d, 1H,
J.dbd.9.0 Hz), 7.72 (br d, 1H, J.dbd.3.4 Hz), 6.69 (d, 1H,
J.dbd.9.0 Hz), 6.63 (d, 1H, J.dbd.3.9 Hz), 3.99 (s, 3H), 1.67 (s,
9H).
Step 3: Synthesis of Intermediate C
[0516] 20
Intermediate C
[0517] Step 1: A solution of tert-butyllithium in pentane (1.7 M,
3.95 mL, 6.72 mmol, 1.20 equiv) was added to a solution of
intermediate B (1.39 g, 5.60 mmol, 1 equiv) in THF (70 mL) at
-78.degree. C. The orange solution was stirred for 15 min, then a
solution of trimethyltin chloride (2.23 g, 11.2 mmol, 2.00 equiv)
in THF (4.0 mL) was added. The reaction mixture was warmed to
23.degree. C., then partitioned between aqueous pH 7 phosphate
buffer and a 1:1 mixture of ethyl acetate and hexane (100 mL). The
organic layer was dried over sodium sulfate and concentrated.
[0518] Step 2: A deoxygenated solution of this residue,
intermediate A (0.800 g, 2.76 mmol, 0.500 equiv),
tetrakis(triphenylphosphine)palladium (0.160 g, 0.140 mmol, 0.025
equiv), and cuprous iodide (0.053 g, 0.28 mmol, 0.05 equiv) in
dioxane (40 mL) was heated at 90.degree. C. for 20 hours. The
reaction mixture was cooled, then partitioned between brine (150
mL) and ethyl acetate (150 mL). The organic layer was dried over
sodium sulfate, then concentrated. The residue was purified by
flash column chromatography (100% hexanes initially, grading to 30%
ethyl acetate in hexanes) to afford intermediate C. as a light
yellow foam.
[0519] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.8.44 (d, 1H,
J.dbd.9.2 Hz), 8.18 (s, 1H), 8.08 (d, 1H, J.dbd.8.5 Hz), 7.88 (d,
1H, J.dbd.8.2 Hz), 7.79 (ddd, 1H, J.dbd.8.5, 7.0, 1.5 Hz), 7.63
(ddd, 1H, J.dbd.8.5, 7.0, 1.5 Hz), 6.78 (d, 1H, J.dbd.8.8 Hz), 6.72
(s, 1H), 4.02 (s, 3H), 1.27 (s, 9H),
[0520] Step 4: Synthesis of
3-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)-1H- -quinolin-2-one
[0521] A solution of intermediate C (900 mg, 2.20 mmol) was heated
in a 1:1 mixture of acetic acid and water (50 mL) at reflux for 16
hours. The reaction mixture was concentrated, and the residue was
partitioned between aqueous saturated sodium bicarbonate solution
(150 mL) and hot ethyl acetate (3.times.200 mL). The combined
organic layers were dried over sodium sulfate and concentrated. The
residue was suspended in ethyl ether (200 mL), filtered, then
air-dried to give the titled compound as a yellow solid.
[0522] .sup.1H NMR (300 MHz, (CD.sub.3).sub.2SO) .delta.12.23 (s,
1H), 11.75 (s, 1H), 8.58 (s, 1H), 7.86 (br d, 1H, J.dbd.9.2 Hz),
7.75 (br d, 1H, J.dbd.7.6, Hz), 7.54 (br t, 1H, J.dbd.7.8 Hz), 7.39
(d, 1H, J.dbd.8.2 Hz), 7.26 (br t, 1H, J.dbd.7.6 Hz), 7.18 (br s,
1H), 6.57 (d, 1H, J.dbd.8.5 Hz), 3.88 (s, 3H). HRMS (electrospray
FTI/ICR) calcd for C17H14N3O2 [M+H].sup.+292.1081, found
292.1059.
[0523] Examples 2-4 were synthesized in analogous fashion to
Example 1 starting from the corresponding azaindoles prepared by
the method of Hands, D.; Bishop, B.; Cameron, M.; Edwards, J. S.;
Cottrell, I. F.; Wright, S. H. B Synthesis 1996, 887-882.
Example 2
3-(5-methoxy-1H-pyrrolo[2,3-c]pyridin-2-yl)-1H-quinolin-2-one
[0524] 21
Step 1: Synthesis of Intermediate D
[0525] 22
Intermediate D
[0526] A solution of 5-methoxy-1H-pyrrolo[2,3-c]pyridine (190 mg,
1.28 mmol, 1 equiv, prepared by the method of Mazeas, D.;
Guillaumet, G.; Viaud, M-C Heterocycles 1999, 50, 1065-1080),
di-tert-butyl dicarbonate (336 mg, 1.54 mmol, 1.20 equiv), and
4-dimethylaminopyridine (10 mg, 0.082 mmol, 0.064 equiv) in
dichloromethane (20 mL) was stirred at 23.degree. C. for 2 hours.
The reaction mixture was concentrated, and the residue was purified
by flash column chromatography (100% hexanes initially, grading to
20% ethyl acetate in hexanes) to afford intermediate E as a
colorless oil which solidified upon standing (180 mg, 56%).
[0527] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.8.89 (br s, 1H),
7.70 (br d, 1H, J.dbd.4.0 Hz), 6.86 (s, 1H), 6.48 (d, 1H, J.dbd.3.9
Hz), 3.98 (s, 3H), 1.68 (s, 9H).
Step 2: Synthesis of
3-(5-methoxy-1H-pyrrolo[2,3-c]pyridin-2-yl)-1H-quinol- in-2-one
[0528] Step 1: A solution of tert-butyllithium in pentane (1.7 M,
0.45 mL, 0.77 mmol, 1.20 equiv) was added to a solution of
intermediate D (160 mg, 0.644 mmol, 1 equiv) in THF (15 mL) at
-78.degree. C. The bright-yellow solution was stirred for 10 min,
then trimethylborate (0.144 mL, 1.29 mmol, 2.00 equiv) was added.
The reaction mixture was warmed to 0.degree. C., then partitioned
between aqueous half-saturated ammonium chloride solution and ethyl
acetate (2.times.75 mL). The organic layer was dried over sodium
sulfate and concentrated to give a white solid (160 mg).
[0529] Step 2: A deoxygenated solution of this solid, intermediate
A (150 mg, 0.51 mmol, 1.0 equiv),
tetrakis(triphenylphosphine)palladium (30 mg, 0.026 mmol, 0.05
equiv), and potassium phosphate (327 mg, 1.54 mmol, 3.00 equiv) in
dioxane (15 mL) was heated at reflux for 20 hours. The reaction
mixture was cooled, then partitioned between water (75 mL) and
ethyl acetate (2.times.75 mL). The organic layer was dried over
sodium sulfate, then concentrated. The residue was passed through a
column of flash-grade silica gel (40% EtOAc in hexanes initially,
grading to 100% EtOAc). The fractions containing primarily the
desired coupled product were concentrated.
[0530] Step 3: A solution of this residue in a 1:1 mixture of
acetic acid and water was heated at reflux for 20 hours. The
reaction mixture was concentrated, and the residue was purified by
reverse-phase column chromatography (5% acetonitrile in water
initially, grading to 100% acetonitrile). The desired fractions
were concentrated, and the residue was partitioned between
saturated aqueous sodium bicarbonate solution and ethyl acetate.
The organic layer was dried over sodium sulfate and concentrated to
afford the titled compound as a yellow solid.
[0531] hu 1H NMR (400 MHz, (CD.sub.3).sub.2SO) .delta.12.22 (s,
1H), 12.00 (s, 1H), 8.62 (s, 1H), 8.49 (s, 1H), 7.74 (br d, 1H,
J.dbd.7.7 Hz), 7.53 (br t, 1H, J.dbd.7.7 Hz), 7.37 (br d, 1H,
J.dbd.8.2 Hz), 7.23 (br t, 1H, J.dbd.7.5 Hz), 7.12 (s, 1H), 6.84
(s, 1H), 3.84 (s, 3H). HRMS (electrospray FT/ICR) calcd for
C17H14N3O2[M+H].sup.+292.1081, found 292.1068.
Example 3
3-(5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridin-2-yl)-1H-quinolin-2-one
[0532] 23
[0533] A solution of the product from Example 1 (100 mg, 0.343
mmol) in aqueous 48% HBr solution was heated at reflux for 20
hours. The reaction mixture was cooled and the yellow solid which
had precipitated was filtered and washed with aqueous 1 N
hydrochloric acid solution. The filtered solid was then dried under
vacuum to afford the titled product as a yellow solid.
[0534] .sup.1H NMR (300 MHz, (CD.sub.3).sub.2SO) .delta.14.20 (br
s, 1H), 12.51 (s, 1H), 12.40 (s, 1H), 8.81 (s, 1H), 8.29 (br d, 1H,
J.dbd.9.2 Hz), 7.81 (br d, 1H, J.dbd.7.9 Hz), 7.60 (br t, 1H,
J.dbd.7.0 Hz), 7.41 (d, 1H, J.dbd.8.2 Hz), 7.30 (br t, 1H,
J.dbd.7.6 Hz), 7.14 (br s, 1H), 6.70 (d, 1H, J.dbd.8.8Hz).
Example 4
[0535] 3-(5-oxo-5,6-dihydro-1H-pyrrolo
[2,3-c]pyridin-2-yl)-1H-quinolin-2-- one 24
[0536] The titled compound can be made by the reaction of the
corresponding methyl ether with HBr according to the procedure in
Example 3 above.
Example 5
[0537]
3-(4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-1H-quinolin-2-o-
ne 25
[0538] The titled compound can be made via oxidation of the product
from Example 3 followed by rearrangement (see Scheme 4).
Example 6
[0539]
3-(4-methyl-5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridin-2-yl)-1H-qui-
nolin-2-one 26
[0540] Sodium tert-butoxide (10 mg, 0.11 mmol, 1.0 equiv) and
iodomethane (13 .mu.L, 0.22 mmol, 2.0 equiv) were added
sequentially to a suspension of the product from Example 3 (30 mg,
0.11 mmol, 1 equiv) in THF (10 mL) at 23.degree. C. The reaction
mixture was stirred for 20 hours. Additional sodium tert-butoxide
(20 mg, 0.22mmol, 2.0 equiv) and iodomethane (26 .mu.L, 0.44 mmol,
4.0 equiv) were added in 2 equal portions over 1 hour, and then the
reaction mixture was allowed to stir an additional 1 hour. Water (5
mL) was added, and the resulting mixture was concentrated to a
volume of 2 mL. The mixture was purified by reverse phase HPLC to
afford the titled compound as a yellow solid.
[0541] .sup.1H NMR (300 MHz, (CD.sub.3).sub.2SO) .delta.12.28 (s,
1H), 11.94 (s, 1H), 8.56 (s, 1H), 7.78 (d, 1H, J.dbd.9.5 Hz), 7.73
(br d, 1H, J.dbd.7.9 Hz), 7.53 (br t, 1H, J.dbd.7.0 Hz), 7.38 (br
d, 1H, J.dbd.8.2Hz), 7.26 (br t, 1H, J.dbd.7.3 Hz), 7.03 (br d,
J.dbd.1.5Hz), 6.18 (d, 1H, J.dbd.9.2 Hz).
[0542] Examples 7-9 were synthesized in analogous fashion to
Example 1 starting from the corresponding azaindoles prepared by
the method of Hands, D.; Bishop, B.; Cameron, M.; Edwards, J. S.;
Cottrell, I. F.; Wright, S. H. B Synthesis 1996, 887-882. The
products can be converted to the N-alkylated compounds of Formula I
via the procedure in Scheme 4 followed by alkylation as in Scheme
5, or by other procedures readily available in the chemical
literature.
Example 7
3-(1H-pyrrolo[2,3-c]pyridin-2-yl)-1H-quinolin-2-one
[0543] 27
[0544] .sup.1H NMR (400 MHz, (CD.sub.3).sub.2SO) .delta.12.26 (s,
1H), 12.03 (s, 1H), 8.89 (br s, 1H), 8.70 (br s, 1H), 8.09 (br d,
1H, J.dbd.5.0 Hz), 7.78 (br d, 1H, J.dbd.7.7 Hz), 7.57 (br t, 1H,
J.dbd.8.0 Hz), 7.53 (br d, 1H, J.dbd.5.3 Hz), 7.40 (br d, 1H,
J.dbd.8.3 Hz), 7.31 (br s, 1H), 7.28 (brt, 1H, J.dbd.7.6 Hz).
Example 8
3-(1H-pyrrolo[3,2-c]pyridin-2-yl)-1H-quinolin-2-one
[0545] 28
[0546] .sup.1H NMR (400 MHz, (CD.sub.3).sub.2SO) .delta.12.23 (s,
1H), 11.97 (s, 1H), 8.87 (br s, 1H), 8.61 (s, 1H), 8.18 (br s, 1H),
7.75 (br d, 1H, J.dbd.7.7 Hz), 7.55 (br t, 1H, J.dbd.8.0 Hz), 7.50
(br s, 1H), 7.45 (br s, 1H), 7.39 (br d, 1H, J.dbd.8.2 Hz), 7.27
(br t, 1H, J.dbd.7.6 Hz).
Example 9
[0547] 3-(1H-pyrrolo[3,2-b]pyridin-2-yl)-1H-quinolin-2-one 29
[0548] .sup.1H NMR (400 MHz, (CD30D) .delta.8.62 (s, 1H), 8.31 (dd,
1H, J.dbd.4.7, 1.3 Hz), 7.92 (br d, 1H, J.dbd.8.2 Hz), 7.81 (br d,
1H, J.dbd.7.8 Hz), 7.58 (br t, 1H, J.dbd.7.6 Hz), 7.40 (br, d, 1H,
J.dbd.8.0 Hz), 7.34 (br s, 1H), 7.31 (br t, 1H, J.dbd.8.0 Hz), 7.18
(dd, 1H, J.dbd.8.2, 4.7 Hz). HRMS (electrospray FT/ICR) calcd for
C16H11N3O[M+H].sup.+262.0975, found 262.0975.
* * * * *