6-substituted pyrazolo [3,4-d] pyrimidin-4-ones...

Details 6-substituted pyrazolo [3,4-d] pyrimidin-4-ones... 6-substituted pyrazolo [3,4-d] pyrimidin-4-ones...

1999-10-12

2003-03-11

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S253030, C514S303000, C544S238000, C544S262000, C546S119000, C546S120000

Reexamination Certificate

active

06531477

ABSTRACT:

FIELD OF THE INVENTION
This invention relates generally to novel 6-substituted pyrazolo[3,4-d]pyrimidin-4-ones which are useful as cyclin dependent kinase (cdk) inhibitors, pharmaceutical compositions comprising the same, methods for using the same for treating cancer and proliferative diseases, and intermediates and processes for making the same.
BACKGROUND OF THE INVENTION
One of the most important and fundamental processes in biology is the division of cells mediated by the cell cycle. This process ensures the controlled production of subsequent generations of cells with defined biological function. It is a highly regulated phenomenon and responds to a diverse set of cellular signals both within the cell and from external sources. A complex network of tumor promoting and suppressing gene products are key components of this cellular signaling process. Overexpression of the tumor promoting components or the subsequent loss of the tumor suppressing products will lead to unregulated cellular proliferation and the generation of tumors (Pardee,
Science
246:603-608, 1989).
Cyclin dependent kinases play a key role in regulating the cell cycle machinery. These complexes consist of two components: a catalytic subunit (the kinase) and a regulatory subunit (the cyclin). To date, eight kinase subunits (cyclin dependent kinase 1-8) have been identified along with several regulatory subunits (cyclins A-H, K, N, and T). Each kinase associates with a specific regulatory partner and together make up the active catalytic moiety. Each transition of the cell cycle is regulated by a particular cyclin dependent kinase complex: G1/S by cyclin dependent kinase2/cyclin E, cyclin dependent kinase4/cyclin D1 and cyclin dependent kinase6/cyclinD2; S/G2 by cyclin dependent kinase2/cyclin A and cyclin dependent kinase1/cyclin A; G2/M by cyclin dependent kinase1/cyclinB. The coordinated activity of these kinases guides the individual cells through the replication process and ensures the vitality of each subsequent generation (Sherr,
Cell
73:1059-1065, 1993; Draetta,
Trends Biochem. Sci
. 15:378-382, 1990).
An increasing body of evidence has shown a link between tumor development and cyclin dependent kinase related malfunctions. Overexpression of the cyclin regulatory proteins and subsequent kinase hyperactivity have been linked to several types of cancers (Jiang,
Proc. Natl. Acad. Sci. USA
90:9026-9030, 1993; Wang,
Nature
343:555-557, 1990). More recently, endogenous, highly specific protein inhibitors of cyclin dependent kinases were found to have a major affect on cellular proliferation (Kamb et al.,
Science
264:436-440, 1994; Beach,
Nature
336:701-704, 1993). These inhibitors include p16
INK4
(an inhibitor of cyclin dependent kinase4/D1), p21
CIP1
(a general cyclin dependent kinase inhibitor), and p27
KIP1
(a specific cyclin dependent kinase2/E inhibitor). A recent crystal structure of p27 bound to cyclin dependent kinase2/A revealed how these proteins effectively inhibit the kinase activity through multiple interactions with the cyclin dependent kinase complex (Pavletich,
Nature
382:325-331, 1996). These proteins help to regulate the cell cycle through specific interactions with their corresponding cyclin dependent kinase complexes. Cells deficient in these inhibitors are prone to unregulated growth and tumor formation.
Schmidt et al. describe in U.S. Pat. No. 3,211,731 (issued Oct. 12, 1965) pyrazolo[3,4-d]pyrimidines of the formula:
where:
R
1
represents hydrogen, alkyl, cycloalkyl, aralkyl, oxalkyl, hydroxyalkyl, halogenoalkyl, cycloalkylalkyl, heteroaralkyl, mono- or binuclear aryl or heteroaryl;
R
3
represents hydrogen or lower alkyl;
R
6
represents substituted or unsubstituted aralkyl or heteroaralkyl.
These compounds are claimed to have utility as coronary dilating agents.
SUMMARY OF THE INVENTION
The present invention describes a novel class of 6-substituted pyrazolo[3,4-d]pyrimidin-4-ones or pharmaceutically acceptable salt or prodrug forms thereof that are potent inhibitors of the class of enzymes known as cyclin dependent kinases.
It is another object of this invention to provide a novel method of treating cancer or other proliferative diseases by administering a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of this invention to provide a novel method of treating cancer or other proliferative diseases, which comprises administering a therapeutically effective combination of at least one of the compounds of the present invention and at least one other known anti-cancer or anti-proliferative agent.
These and other objectives, which will become apparant during the following detailed descriptions, have been achieved by the inventors, discovery that compounds of formula (I), alternatively represented by the tautomer (II):
wherein R
1
, R
2
, R
3
, R
4
, R
5
, Q, Y, and Z are defined below or pharmaceutically acceptable salts thereof, are cyclin dependent kinase inhibitors.
As described herein, the inhibitors of this invention are capable of inhibiting the cell-cycle machinery and consequently would be useful in modulating cell-cycle progression, which would ultimately control cell growth and differentiation. Such compounds would be useful for treating subjects having disorders associated with excessive cell proliferation, such as cancer, psoriasis, immunological disorders involving unwanted leukocyte proliferation, in the treatment of restenosis and other smooth muscle cell disorders, and the like.
DETAILED DESCRIPTION OF THE INVENTION
The present invention, in a first embodiment, describes a novel compound of the formula (I) or its tautomer, formula (II):
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
Q is selected from the group: H, OH, and CH
3
, and CH
2
CH
3
;
Y is selected from the group: F, Cl, Br, and I;
Z is selected from the group: N and CR
6
;
R
1
is selected from the group: phenyl, tropone, naphthyl, and a 5-10 membered aromatic heterocycle containing from 1-4 heteroatoms selected from O, N, and S, and R
1
is substituted with 0-3 R
7
;
R
2
is selected from the group: C
1-4
alkyl, C
2-4
alkenyl, C
2-4
alkynyl, S—C
1-3
alkyl, O—C
1-3
alkyl, NH
2
, NH—C
1-3
alkyl, N(C
1-2
alkyl)
2
, OCF
3
, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, 1-methylcyclopropyl, 1-methylcyclobutyl, CH
2
CN, CH
2
OH, CH
2
OCH
3
, CH
2
NH
2
, CH
2
NHC
1-3
alkyl, CH
2
NMe
2
, CF
3
, CHO, OCH
2
CH
2
OH, OCH(Me)CH
2
OH, OCH
2
CH(Me)OH, OCH
2
CH
2
NMe
2
, and CHF
2
;
R
3
is selected from the group: H, F, Cl, Br, I, CF
3
, CHO, CHR
g
OH, COCF
3
, CH═NOH, CH═NOCH
3
, CH═NNH
2
, CH═NNHMe, CH═NNMe
2
, CH═CHR
a
, C
1-3
alkyl, C
1-3
alkoxy, CO
2
H, CONH
2
, CONH(C
1-3
alkyl), CON(C
1-3
alkyl)
2
, CO
2
C
1-3
alkyl, C(O)C
1-2
alkyl, NH
2
, NH(C
1-3
alkyl), and N(C
1-3
alkyl)
2
;
R
4
is selected from the group: H, F, Cl, Br, I, CF
3
, C
1-3
alkyl, C
2-3
alkenyl, NH
2
, NH(C
1-3
alkyl), and N(C
1-3
alkyl)
2
;
R
5
is selected from the group: H, C
1-3
alkyl, F, Cl, Br, I, CF
3
, and C
2-3
alkenyl;
R
6
is selected from the group: H, F, Cl, Br, I, CF
3
, —NO
2
, C
1-3
alkyl optionally substituted with 1-2 R, C
2-3
alkenyl, C
2-3
alkynyl, C
1-3
alkoxy, CO
2
H, CHO, CONR
a
R
b
, CO
2
C
1-3
alkyl, C(O)C
1-2
alkyl, CH
2
NHR
a
, CONR
g
NR
a
R
b
, NR
a
R
b
; SO
2
NR
a
R
b
, CR═NNR
a
R
b
, CR═NOR
f
, and R
h
;
R
7
is independently, at each occurrence, selected from the group: OH, C
1-6
alkoxy, OC
2-6
alkyl-CO
2
H, O—C
2-6
-alkyl-NR
a
R
b
, F, Cl, Br, I, CF
3
, OCF
3
, —CN, —NO
2
, CO
2
H, CO
2
(C
1-6
alkyl), CONR
a
R
b
, NR
g
CONHOR
g
, NR
g
CONHSO
2
R
a
, NHNR
g
C(O)OR
a
, NR
g
C(O)NR
a
R
b
, NH
2
, NH(C
1-3
alkyl), N(C
1-3
alkyl)
2
, —SO
2
NR
a
R
b
, NHSO
2
NHCO
2
C
1-4
alkyl, NR
g
SO
2
NR
a
R
b
, NR
g
SO
2
CHR
e
CH
2
NR
a
R
b
, NR
g
COCHR
e
NR
a
R
b
, NR
g
COCHR
e
NR
b
CH
2
R
f
R
a
, NR
g
COCH
2
CHR
e
NR
a
R
b
, NR
g
COCHR
e
C

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