Benzazepine derivatives as inhibitors of hyperproliferation...

Details Benzazepine derivatives as inhibitors of hyperproliferation... Benzazepine derivatives as inhibitors of hyperproliferation...

2000-04-13

2001-11-20

Goldberg, Jerome D. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S211050, C514S211070

Reexamination Certificate

active

06319915

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to the treatment of hyperproliferative diseases, such as cancers, in mammals using benzazepine derivatives of formula I, as defined below. The compounds of formula I are described in U.S. Pat. Nos. 5,618,808, and 5,618,811, both of which issued Apr. 8, 1997 and both of which are incorporated herein by reference in their entirety. These references describe benzazepine derivatives as cholecystokinin (CCK) receptor antagonists useful in the treatment of certain disorders involving the central nervous system (CNS).
A cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene (i.e. a gene that upon activation leads to the formation of malignant tumor cells). Many oncogenes encode proteins that are aberrant tyrosine kinases capable of causing cell transformation. Alternatively, the overexpression of a normal proto-oncogenic tyrosine kinase may also result in proliferative disorders, sometimes resulting in a malignant phenotype. It has been shown that certain tyrosine kinases may be mutated or overexpressed in many human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynecological and thyroid cancers. Furthermore, the overexpression of a ligand for a tyrosine kinase receptor may result in an increase in the activation state of the receptor, resulting in proliferation of the tumor cells or endothelial cells. Thus, it is believed that the growth of mammalian cancer cells can be selectively inhibited by reducing tyrosine kinase activity.
Polypeptide growth factors, such as vascular endothelial growth factor (VEGF) having a high affinity to the human kinase insert-domain-containing receptor (KDR) or the murine fetal liver kinase 1 (FLK-1) receptor, have been associated with the proliferation of endothelial cells and more particularly vasculogenesis and angiogenesis. See PCT international application publication number WO 95/21613 (published Aug. 17, 1995). A significant body of evidence has been put forth detailing the importance of VEGF in the formation of new blood vessels (angiogenesis). It has also been noted that new blood vessel formation is crucial in supplying and maintaining the physiological conditions and nutrients necessary for tumor growth and metastasis. It has been shown that both VEGF receptor subtypes appear to be over expressed in proliferating endothelial cells located in near proximity to tumor cells in vivo. At the molecular level, intracellular portions of both FLT-1 and FLK-1 contain functional tyrosine kinase domains. Kinase activities depend on high affinity to, and interaction with, VEGF. Such interaction results in the autophosphorylation of the receptors and ultimately in endothelial cell proliferation. High affinity VEGF binding and the resulting functional effects appear to depend on the presence of specific heparin sulfate proteoglycans (VEGF glyceptor) associated with the extracellular matrix of endothelial cells. This supposition is supported by the ability of exogenous levels of heparin to inhibit VEGF induced endothelial cell proliferation by acting as a sink for secreted VEGF. By inhibiting the binding of VEGF to VEGF glyceptor (GAG), phosphorylation of tyrosine (kinase) is modulated. Agents, such as the compounds of the present invention, which are capable of modulating the KDR/FLK-1 receptor, may be used to treat disorders related to vasculogenesis or angiogenesis. Such disorders include, but are not limited to, diabetes, diabetic retinopathy, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
SUMMARY OF THE INVENTION
The present invention is directed to a method of treating hyperproliferation diseases in mammals in need of such treatment, comprising administering to said mammal a therapeutically effective amount of a compound of the formula:
or a pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein:
R
1
is a group having an acidic proton, particularly —CO
2
H, —CONHSO
2
R
8
, —CONR
8
(CH
2
)CO
2
H, —SO
2
H, —PO
3
H
2
,
R
2
is H or R
1
, or R
1
and R
2
together with the phenyl ring form
R
3
and R
4
are independently selected from hydrogen, (C
1
-C
10
)alkyl, phenyl, and a 4 to 10 membered heterocyclic group or R
3
and R
4
taken together with the two carbons to which they are attached form phenyl, which is optionally substituted by one or more R
5
groups;
R
5
is thienyl, pyridyl, furyl, or pyrimidyl, halogen, (C
1
-C
6
)alkyl optionally substituted with from one to three fluorine atoms, (C
1
-C
6
)alkoxy, optionally substituted with from one to three fluorine atoms, (C
3
-C
10
) aryl, phenyl, —(CH
2
)
t
phenyl, —(CH
2
)
t
-(4 to 10 membered heterocyclic group), nitro, cyano, amino, —NH(C
1
-C
6
)alkyl, —N((C
1
-C
8
)alkyl)
2
, —S(C
1
-C
8
)alkyl, —SO(C
1
-C
8
)alkyl, —C(O)(C
1
-C
8
)alkyl, —CO(O)(C
1
-C
8
)alkyl, wherein said phenyl, aryl or heterocycle moiety may be optionally substituted with one or two substituents independently selected from halogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, nitro, cyano, amino and trifluoromethyl;
W is OH or NR
6
R
7
;
R
6
and R
7
are independently selected from H, (C
1
-C
8
)alkyl, (C
3
-C
8
)cycloalkyl, or R
6
and R
7
taken together form a six-membered saturated ring containing 5 carbon atoms and one nitrogen atom, one or more of said carbon atoms being optionally substituted with one or more substituents independently selected from (C
1
-C
3
)alkyl;
R
8
is H, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, —(CH
2
)
t
(C
6
-C
10
aryl), or —(CH
2
)
t
(4 to 10 membered heterocyclic group), wherein t is an integer from 0 to 5; said alkyl group optionally including 1 or 2 hetero moieties selected from O, S and —N(R
6
)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said aryl and heterocyclic R
8
groups being optionally fused to a C
6
-C
10
aryl group, a C
5
-C
8
saturated cyclic group, or a 4 to 10 membered heterocyclic group; one or two carbon atoms in said 4 to 10 membered heterocyclic group of R
8
being optionally substituted by an oxo (═O) moiety; the —(CH
2
)
t
— moieties of R
8
optionally including a carbon-carbon double or triple bond when t is an integer from two to five; R
8
groups being optionally substituted by one to five R
9
groups;
R
9
is each independently selected from C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —OR
10
, —C(O)R
11
, —C(O)OR
10
, —NR
11
C(O)OR
10
, —OC(O)R
10
, —NR
11
SO
2
R
10
, —SO
2
NR
10
R
11
, —NR
11
C(O)R
10
, —C(O)NR
10
R
11
, —NR
10
R
11
, —S(O)
j
R
12
, —SO
3
H, —NR
10
(CR
11
R
12
)
t
OR
11
, —(CH
2
)
t
(C
6
-C
10
aryl, —SO
2
(CH
2
)
t
(C
6
-C
10
aryl), —S(CH
2
)
t
(C
6
-C
10
aryl), —O(CH
2
)
t
(C
6
-C
10
aryl), —(CH
2
)
t
(4 to 10 membered heterocyclic group), and —(CR
11
R
12
)
m
OR
11
, said alkyl group optionally containing one or two hetero moieties selected from O, S and —N(R
8
)— with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; aryl and heterocyclic moieties of R
9
being optionally fused to a C
6
-C
10
aryl group, a C
5
-C
8
saturated cyclic group, or a 4 to 10 membered heterocyclic group; one or two carbon atoms of the heterocyclic moieties of R
9
being optionally substituted by an oxo (═O) moiety; and the alkyl, aryl and heterocyclic moieties of R
9
groups being optionally substituted by one to three substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —NR
11
SO
2
R
10
, —SO
2
NR
10
R
11
, —C(O)R
10
, —C(O)OR
10
, —OC(O)R
10
, —NR
11
C(O)R
10
, —C(O)NR
10
R
11
, —NR
10
R
11
, —(CR
11
R
12
)
m
OR
11
, OR
10
and R
10
;
R
10
is each independently selected from H, C
1
-C
10
alkyl, —(CH
2
)
t
(C
6
-C
10
aryl), and —(CH
2
)
t
(4 to 10 membered heterocyclic), said alkyl group optionally including one or two hetero moieties selected from O, S and

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