Acylsemicarbazides as cyclin dependent kinase inhibitors...

Details Acylsemicarbazides as cyclin dependent kinase inhibitors... Acylsemicarbazides as cyclin dependent kinase inhibitors...

2001-07-16

2003-07-15

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C548S359100

Reexamination Certificate

active

06593356

ABSTRACT:

FIELD OF THE INVENTION
This invention relates generally to novel 5-substituted-indeno[1,2-c]pyrazol-4-ones which are useful as cyclin dependent kinase (cdk) inhibitors, pharmaceutical compositions comprising the same, methods for using the same for treating 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. Over expression 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 (cdks) 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, six kinase subunits (cdk 1-7) have been identified along with several regulatory subunits (cyclins A-H). 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 cdk complex: G1/S by cdk2/cyclin E, cdk4/cyclin D1 and cdk6/cyclinD/2; S/G2 by cdk2/cyclin A and cdk1/cyclin A; G2/M by cdk1/B. 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 cdk related malfunctions. Over expression 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 cdks 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 cdk4/D1), p21
CIP1
(a general cdk inhibitor), and p27
KIP1
(a specific cdk2/E inhibitor). A recent crystal structure of p27 bound to cdk2/A revealed how these proteins effectively inhibit the kinase activity through multiple interactions with the cdk complex (Pavletich, Nature 382:325-331, 1996). These proteins help to regulate the cell cycle through specific interactions with their corresponding cdk complexes. Cells deficient in these inhibitors are prone to unregulated growth and tumor formation.
This body of evidence has led to an intense search for small molecule inhibitors of the cdk family as an approach to cancer chemotherapy.
A series of indeno[1,2-c]pyrazoles having anticancer activity are described in JP 60130521 and JP 62099361 with the following generic structure:
A series of indeno[1,2-c]pyrazoles having herbicidal activity are described in GB 2223946 with the following generic structure:
A series of 1-(6′-substituted-4′-methylquinol-2′-yl)-3-methylindeno[1,2-c]pyrazoles having CNS activity are described by Quraishi, Farmaco 44:753-8, 1989 with the following generic structure:
There is a continuing unmet need for cdk inhibitors with which to treat proliferative diseases.
SUMMARY OF THE INVENTION
The present invention describes a novel class of indeno[1,2-c]pyrazol-4-ones or pharmaceutically acceptable salt forms thereof that are potent inhibitors of the class of enzymes known as cyclin dependent kinases, which relate to the catalytic subunits cdk 1-7 and their regulatory subunits know as cyclins A-H.
The present invention is also directed to a novel method of treating cancer or other proliferative diseases by administering a therapeutically effective amount of one of these compounds or a pharmaceutically acceptable salt form thereof.
A novel method of treating cancer or other proliferative diseases, which comprises administering a therapeutically effective combination of one of the compounds of the present invention and one or more other known anti-cancer or anti-proliferative agents is also described herein.
The present invention also describes compounds of formula (I):
wherein R
1
, R
2
and X are defined below or pharmaceutically acceptable salts thereof as cyclin dependent kinase inhibitors.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The invention pertains to novel cyclin dependent kinase inhibitors (cdks) and specifically, but not exclusively, as inhibitors of cdk/cyclin complexes. The inhibitors of this invention are indeno[1,2-c]pyrazol-4-one analogs. Certain analogs were selective for their activity against cdks and their cyclin bound complexes and were less active against other known serine/threonine kinases such as Protein Kinase A (PKA) and Protein Kinase C (PKC). In addition, these inhibitors were less active against tyrosine kinases such as c-Ab1.
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 the treatment of cancer, psoriasis, immunological disorders involving unwanted leukocyte proliferation, in the treatment of restinosis and other smooth muscle cell disorders, and the like.
The present invention, in a first embodiment, describes a novel compound of formula (I):
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
X is selected from the group: O, S, and NR;
R is selected from the group: H, C
1-4
alkyl, and NR
5
R
5a
;
R
1
is selected from the group: H, C
1-10
alkyl substituted with 0-3 R
c
, C
2-10
alkenyl substituted with 0-3 R
c
, C
2-10
alkynyl substituted with 0-3 R
c
, C
1-10
alkoxy, —NHR
4
, C
3-10
carbocycle substituted with 0-5 R
a
, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R
b
;
R
2
is selected from the group: H, C
1-10
alkyl substituted with 0-3 R
c
, C
2-10
alkenyl substituted with 0-3 R
c
, C
2-10
alkynyl substituted with 0-3 R
c
, —(CF
2
)
m
CF
3
, C
3-10
carbocycle substituted with 0-5 R
a
, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R
b
;
R
3
is selected from the group: H, halo, —CN, NO
2
, C
1-4
haloalkyl, NR
5
R
5a
, NR
5
NR
5
R
5a
, NR
5
C(O)OR
5
, NR
5
C(O)R
5
, ═O, OR
5
, COR
5
, CO
2
R
5
, CONR
5
R
5a
, NHC(O)NR
5
R
5a
, NHC(S)NR
5
R
5a
, SO
2
NR
5
R
5a
, SO
2
R
5b
, C
1-4
alkyl, phenyl, benzyl, C
1-4
alkyl substituted with 1-3 R
c
, C
5-10
alkyl substituted with C
2-10
alkenyl optionally substituted with 0-3 R
6
, C
2-10
alkynyl substituted with 0-3 R
6
, —(CF
2
)
m
CF
3
, C
3-10
carbocycle substituted with 0-5 R
6
, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R
6
; and
provided that if R
3
is phenyl, it is substituted with 1-5 R
a
;
R
4
is independently at each occurrence selected from the group: H, —CN, C
1-4
alkyl, C
1-4
haloalkyl, NR
3
R
3a
, NR
3
C(O)OR
3
, NR
3
C(O)R
3
, OR
3
, COR
3
, CO
2
R
3
, CONR
3
R
3a
, NHC(O)NR
3
R
3a
, NHC(S)NR
3
R
3a
, SO
2
NR
3
R
3a
, SO
2
R
3b
, C
3-10
carbocycle substituted with 0-5 R
a
, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R
3
;
provided that at least one R
3
is present and that this R
3
is selected from

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