Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-08-06
2003-11-18
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S231500, C514S272000, C514S275000, C544S321000, C544S324000, C544S114000, C544S060000
Reexamination Certificate
active
06649608
ABSTRACT:
The invention relates to pyrimidine derivatives, or pharmaceutically acceptable salts or in vivo hydrolysable esters thereof, which possess cell-cycle inhibitory activity and are accordingly useful for their anti-cancer (such as anti-cell-proliferative, anti-cell migration and/or apoptotic) activity and are therefore useful in methods of treatment of a warm-blooded animal, such as man. The invention also relates to processes for the manufacture of said pyrimidine derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments or use in the production of an anti-cancer (anti-cell-proliferation/migration and/or apoptotic) effect in a warm-blooded animal such as man.
A family of intracellular proteins called cyclins play a central role in the cell cycle. The synthesis and degradation of cyclins is tightly controlled such that their level of expression fluctuates during the cell cycle. Cyclins bind to cyclin-dependent serine/threonine kinases (CDKs) and this association is essential for CDK (such as CDK1, CDK2, CDK4 and/or CDK6) activity within the cell. Although the precise details of how each of these factors combine to regulate CDK activity is poorly understood, the balance between the two dictates whether or not the cell will progress through the cell cycle.
The recent convergence of oncogene and tumour suppresser gene research has identified regulation of entry into the cell cycle as a key control point of mitogenesis in tumours. Moreover, CDKs appear to be downstream of a number of oncogene signalling pathways. Disregulation of CDK activity by upregulation of cyclins and/or deletion of endogenous inhibitors appears to be an important axis between mitogenic signalling pathways and proliferation of tumour cells.
Accordingly it has been recognised that an inhibitor of cell cycle kinases, particularly inhibitors of CDK2, CDK4 and/or CDK6 (which operate at the S-phase, G1-S and G1-S phase respectively) should be of value as a selective inhibitor of cell proliferation, such as growth of mammalian cancer cells.
Furthermore, it is believed that inhibition of focal adhesion kinase (FAK), which is involved in signal transduction pathways, induces apoptosis (cell-death) and/or inhibits cell migration and an inhibitor of FAK may therefore have value as an anti-cancer agent.
The present invention is based on the discovery that certain 2,4-pyrimidine compounds surprisingly inhibit the effects of cell cycle kinases showing selectivity for CDK2, CDK4 and CDK6, and also inhibit FAK and thus possess anti-cancer (anti-cell-migration/proliferation and/or apoptotic) properties. Such properties are expected to be of value in the treatment of disease states associated with aberrant cell cycles and cell proliferation such as cancers (solid tumours and leukemias), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation.
According to the invention there is provided a pyrimidine derivative of the formula (I):
wherein:
Q
1
and Q
2
are independently selected from aryl or carbon linked heteroaryl; and one of Q
1
and Q
2
or both of Q
1
and Q
2
is substituted on a ring carbon by one substituent of the formula (Ia) or (Ia′):
wherein:
Y is —NHC(O)— or —C(O)NH—;
Z is R
a
O—, R
b
R
c
N—, R
d
S—, R
e
R
f
NNR
g
—, C
3-8
cycloalkyl, phenyl or a heterocyclic group; wherein said phenyl, C
3-8
cycloalkyl or heterocyclic group are optionally substituted on a ring carbon by one or more groups selected from R
h
; and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R
i
;
R
a
, R
b
, R
c
, R
d
, R
e
, R
f
and R
g
are independently selected from hydrogen, C
1-4
alkyl, C
2-4
alkenyl and C
3-8
cycloalkyl; wherein said C
1-4
alkyl, C
2-4
alkenyl and C
3-8
cycloalkyl are optionally substituted by one or more groups selected from R
j
;
n is 0 or 1;
m is 1, 2 or 3;
Q
3
is a nitrogen linked heterocycle; wherein said heterocycle is optionally substituted on a ring carbon by one or more groups selected from R
k
; and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R
m
;
G is —O— or —NR
2
—;
R
2
is selected from hydrogen, C
1-6
alkyl, C
3-6
alkenyl and C
3-6
alkynyl; wherein said C
1-6
alkyl, C
3-6
alkenyl and C
3-6
alkynyl are optionally substituted by one or more groups selected from R
n
;
R
1
is selected from hydrogen, halo, hydroxy, nitro, amino, N—(C
1-3
alkyl)amino, N,N-di-(C
1-3
alkyl)amino, cyano, trifluoromethyl, trichloromethyl, C
1-3
alkyl [optionally substituted by 1 or 2 substituents independently selected from halo, cyano, amino, N—(C
1-3
alkyl)amino, N,N-di-(C
1-3
alkyl)amino, hydroxy and trifluoromethyl], C
3-5
alkenyl [optionally substituted by up to three halo substituents, or by one trifluoromethyl substituent], C
3-5
alkynyl, C
1-3
alkoxy, mercapto, C
1-3
alkylsulphanyl, carboxy and C
1-3
alkoxycarbonyl;
Q
1
is optionally substituted on a ring carbon by one to four substituents independently selected from halo, mercapto, nitro, formyl, formamido, carboxy, cyano, amino, ureido, carbamoyl, sulphamoyl, C
1-4
alkyl, C
2-4
alkenyl, C
2-4
alkynyl [wherein said C
1-4
alkyl, C
2-4
alkenyl and C
2-4
alkynyl are optionally substituted by one or more groups selected from R
o
], C
1-4
alkanoyl, C
1-4
alkoxycarbonyl, heterocyclic group, C
1-4
alkylS(O)
a
wherein a is 0 to 2 [optionally substituted by hydroxy], N′—(C
1-4
alkyl)ureido, N′,N′-di-(C
1-4
alkyl)ureido, N′—(C
1-4
alkyl)-N—(C
1-4
alkyl)ureido, N′,N′-di-(C
1-4
alkyl)-N—(C
1-4
alkyl)ureido, N—C
1-4
alkylamino, N,N-di-(C
1-4
alkyl)amino, N—(C
1-4
alkyl)sulphamoyl, N,N-di-(C
1-4
alkyl)sulphamoyl, N—C
1-4
alkylcarbamoyl, N,N-di-(C
1-4
alkyl)carbamoyl and C
1-4
alkanoylamino;
and also independently, or in addition to, the above substituents, Q
1
may be optionally substituted by one to two substituents independently selected from aryl, C
3-8
cycloalkyl and a heterocyclic group; wherein said aryl, C
3-8
cycloalkyl or heterocyclic group may be optionally substituted on a ring carbon by one or more groups selected from R
p
; and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R
q
;
and also independently, or in addition to, the above substituents, Q
1
may be optionally substituted by one C
1-4
alkoxy or by one hydroxy substituent;
Q
2
is optionally substituted on a ring carbon by one to four substituents independently selected from halo, hydroxy, mercapto, nitro, formyl, formamido, carboxy, cyano, amino, ureido, carbamoyl, sulphamoyl, C
1-4
alkyl, C
2-4
alkenyl, C
2-4
alkynyl, C
1-4
alkoxy [wherein said C
1-4
alkyl, C
2-4
alkenyl, C
2-4
alkynyl and C
1-4
alkoxy are optionally substituted by one or more groups selected from R
r
], C
1-4
alkanoyl, C
1-4
alkoxycarbonyl, heterocyclic group, C
1-4
alkylS(O)
a
wherein a is 0 to 2 [optionally substituted by hydroxy], N′—(C
1-4
alkyl)ureido, N′,N′-di-(C
1-4
alkyl)ureido, N′—(C
1-4
alkyl)-N—(C
1-4
alkyl)ureido, N′,N′-di-(C
1-4
alkyl)-N—(C
1-4
alkyl)ureido, N—C
1-4
alkylamino, N,N-di-(C
1-4
alkyl)amino, N—(C
1-4
alkyl)sulphamoyl, N,N-di-(C
1-4
alkyl)sulphamoyl, N—C
1-4
alkylcarbamoyl, N,N-di-(C
1-4
alkyl)carbamoyl, C
2-4
alkenyloxy, C
2-4
alkynyloxy, C
1-4
alkanoylamino and a group of formula (Ia) or (Ia′) as depicted above;
and also independently, or in addition to, the above substituents, Q
2
may be optionally substituted by one to two substituents independently selected from aryl, C
3-8
cycloalkyl or a heterocyclic group; wherein said aryl, C
3-8
cycloalkyl or heterocyclic group may be optionally substituted on a ring carbo
Bradbury Robert Hugh
Breault Gloria Anne
Morris Jeffrey James
Pease Elizabeth Janet
Williams Emma Jane
AstraZeneca AB
Balasubramanian Venkataraman
Morgan & Lewis & Bockius, LLP
Raymond Richard L.
LandOfFree
2,4-di(hetero-)arylamino (oxy)-5-substituted pyrimidines as... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 2,4-di(hetero-)arylamino (oxy)-5-substituted pyrimidines as..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 2,4-di(hetero-)arylamino (oxy)-5-substituted pyrimidines as... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3158810