Pyrido[2,3-D]pyrimidines and 4-aminopyrimidines as...

Details Pyrido[2,3-D]pyrimidines and 4-aminopyrimidines as... Pyrido[2,3-D]pyrimidines and 4-aminopyrimidines as...

1999-08-02

2002-12-24

Shah, Mukund J. (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S258100, C514S264100, C544S279000

Reexamination Certificate

active

06498163

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to pyridopyrimidines and 4-aminopyrimidines that inhibit cyclin-dependent kinase and growth factor-mediated kinase enzymes, and as such are usefull to treat cell proliferative disorders such as atherosclerosis, restenosis, and cancer.
SUMMARY OF THE RELATED ART
Cell cycle kinases are naturally occurring enzymes involved in regulation of the cell cycle (Meijer L., “Chemical Inhibitors of Cyclin-Dependent Kinases”,
Progress in Cell Cycle Research,
1995;1:351-363). Typical enzymes include the cyclin-dependent kinases (cdk) cdk1, cdk2, cdk4, cdk5, cdk6, and wee-1 kinase. Increased activity or temporally abnormal activation of these kinases has been shown to result in development of human tumors and other proliferative disorders such as restenosis. Compounds that inhibit cdks, either by blocking the interaction between a cyclin and its kinase partner, or by binding to and inactivating the kinase, cause inhibition of cell proliferation, and are thus useful for treating tumors or other abnormally proliferating cells.
Several compounds that inhibit cdks have demonstrated both preclinical and clinical anti-tumor activity. For example, flavopiridol is a flavonoid that has been shown to be a potent inhibitor of several types of breast and lung cancer cells (Kaur, et al.,
J. Natl. Cancer Inst.,
1992;84:1736-1740;
Int. J. Oncol.,
1996;9:1143-1168). The compound has been shown to inhibit cdk2 and cdk4. Olomoucine [2-hydroxyethylamine)-6-benzylamine-9-methylpurine] is a potent inhibitor of cdk2 and cdk5 (Vesely, et al.,
Eur. J. Biochem.,
1994;224:771-786), and has been shown to inhibit proliferation of approximately 60 different human tumor cell lines used by the National Cancer Institute (NCI) to screen for new cancer therapies (Abraham, et al.,
Biology of the Cell,
1995;83:105-120).
Despite the progress that has been made, the search continues for small molecular weight compounds that are orally bioavailable and useful for treating a wide variety of human tumors and other proliferative disorders such as restenosis and atherosclerosis.
SUMMARY OF THE INVENTION
This invention provides pyridopyrimidines and 4-aminopyrimidines that are useful for treating cell proliferative disorders, such as cancer, atherosclerosis, restenosis, psoriasis, and endometriosis. We have discovered a group of 7,8-dihydro-2-(amino and thio)-7-(oxo, thio, or imino)-pyrido[2,3-d]pyrimidines and 4-aminopyrimidines that are potent inhibitors of cyclin-dependent kinases (cdks). The compounds are readily synthesized and can be administered by a variety of routes, including orally and parenterally, and have little or no toxicity. The compounds of the invention are members of the class of compounds of Formula I:
and Formula II:
wherein:
W is NH, S, SO, or SO
2
;
R
1
and R
2
include alkyl, cycloalkyl, substituted alkyl, and substituted cycloalkyl;
R
3
includes hydrogen, alkyl, and halogen;
X is O, S, or NH;
R
8
and R
9
independently are hydrogen, alkyl, alkoxy, halo, amino, and the like;
and pharmaceutically acceptable salts thereof.
This invention also provides pharmaceutical formulations comprising a compound of Formula I or II together with a pharmaceutically acceptable carrier, diluent, or excipient therefor.
Compounds within the scope of the present invention are inhibitors of the cyclin-dependent kinases such as cdk2, cdc2, and cdk4. Some of the compounds of the present invention also inhibit growth factor mediated tyrosine kinases including platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and epidermal growth factor (EGF). As inhibitors of cyclin-dependent, as well as growth factor-mediated, tyrosine kinases, the compounds of the instant invention are useful in controlling proliferative disorders such as cancer, psoriasis, vascular smooth muscle cell proliferation associated with atherosclerosis, and postsurgical vascular stenosis and restenosis in mammals.
A further embodiment of this invention is a method of treating subjects suffering from diseases caused by cellular proliferation. The method entails inhibiting proliferation of tumorigenic cells of epithelial origin and vascular smooth muscle proliferation, and/or cellular migration by administering a therapeutically effective amount of a compound of Formula I and/or II to a subject in need of treatment.
A further embodiment of this invention is a method of treating subjects suffering from diseases caused by DNA tumor viruses such as herpes viruses.
DETAILED DESCRIPTION OF THE INVENTION
We have discovered a new class of compounds that are potent inhibitors of cyclin-dependent kinases (cdks) and are useful agents for treating subjects suffering from diseases caused by abnormal cell proliferation. Compounds within the scope of the present invention are inhibitors of the cyclin-dependent kinases such as cdc2, cdk2, and cdk4. As inhibitors of cyclin-dependent kinases, the compounds of the instant invention are useful in controlling proliferative disorders such as cancer, psoriasis, vascular smooth muscle proliferation associated with atherosclerosis, postsurgical vascular stenosis, and restenosis in mammals.
The compounds of the invention comprise those of Formula I:
and the pharmaceutically acceptable salts thereof,
wherein:
the dotted line represents an optional double bond;
W is NH, S, SO, or SO
2
;
X is either O, S, or NH;
R
1
and R
2
are independently selected from the group consisting of H, (CH
2
)
n
Ar, (CH
2
)
n
heteroaryl, (CH
2
)
n
heterocyclyl, C
1
-C
10
alkyl, C
3
-C
10
cycloalkyl, C
2
-C
10
alkenyl, and C
2
-C
10
alkynyl, wherein n is 0, 1, 2, or 3, and the (CH
2
)
n
Ar, (CH
2
)
n
heteroaryl, alkyl, cycloalkyl, alkenyl, and alkynyl groups are optionally substituted by up to 5 groups selected from NR
4
R
5
, N(O)R
4
R
5
, NR
4
R
5
R
6
Y, alkyl, phenyl, substituted phenyl, (CH
2
)
n
heteroaryl, hydroxy, alkoxy, phenoxy, thiol, thioalkyl, halo, COR
4
, CO
2
R
4
, CONR
4
R
5
, SO
2
NR
4
R
5
, SO
3
R
4
, PO
3
R
4
, aldehyde, nitrile heteroaryloxy, T(CH
2
)
m
QR
4
,
C(O)T(CH
2
)
m
QR
4
, NHC(O)T(CH
2
)
m
QR
4
, T(CH
2
)
m
C(O)NR
4
NR
5
, or T(CH
2
)
m
CO
2
R
4
wherein each m is independently 1-6, T is O, S, NR
4
, N(O)R
4
, NR
4
R
6
Y, or CR
4
R
5
, and Q is O, S, NR5, N(O)R
5
, or NR
5
R
6
Y;
R
3
is H, alkyl, halogen, NO
2
, NR
4
R
5
, COOR
4
, OR
4
, CN, or CONR
4
R
5
;
R
4
and R
5
are each independently selected from the group consisting of hydrogen, C
1
-C
6
alkyl, substituted alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, (CH
2
)
n
Ar, C
3
-C
10
cycloalkyl, heterocyclyl, and heteroaryl, or R
4
and R
5
together with the nitrogen to which they are attached optionally form a ring having 3 to 7 carbon atoms and said ring optionally contains 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen, and sulfur;
R
4
and R
5
are independently selected from the group consisting of hydrogen, C
1
-C
6
alkyl, substituted alkyl, C
3
-C
10
cycloalkyl, C
2
-C
6
heterocyclyl, and C
2
-C
6
heteroaryl, or R
4
and R
5
together with the nitrogen to which they are attached optionally form a ring having 3 to 7 carbon atoms and said ring optionally contains 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen, and sulfur; optionally substituted with alkyl, T(CH
2
)
m
QR
4
′, C(O)T(CH
2
)
m
QR
4
′, T(CH
2
)
m
CO
2
R
4
′, (CH
2
)
m
QR
4
′, T(CH
2
)
m
CONR
4
′R
5
′ wherein m is 1-6, T is O, S, NR
4
′, N(O)R
4
′, or CR
4
′R
5
′, and Q is O, S, NR
5
′, or N(O)R
5
′;
R
4
′ and R
5
′ are independently selected from the group consisting of hydrogen, C
1
-C
6
alkyl, substituted alkyl, C
3
-C
10
cycloalkyl, C
2
-C
6
heterocyclyl, and C
2
-C
6
heteroaryl;
R
6
is alkyl;
R
8
and R
9
independently are H, C
1
-C
3
alkyl, NR
4
R
5
, N(O)R
4
R
5
, NR
4
R
5
R
6
Y, hydroxy, alkoxy, thiol, thioalkyl, halo, COR
4
, CO
2
R
4
, CONR
4
R
5
, SO
2
NR
4
R
5
, SO
3
R
4
, PO
3
R
4
, CHO, CN, or NO
2
; an

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