Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-11-15
2004-04-06
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S275000, C514S415000, C544S309000, C544S310000
Reexamination Certificate
active
06716831
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 the human or animal body. 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 of use in the production of an anti-cell-proliferation 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 suppressor 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 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). 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) or (I′):
wherein:
R
x
is selected from hydrogen, halo, hydroxy, nitro, amino, C
1-3
alkylamino, 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, C
1-3
alkylamino, 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, —SH, —S—C
1-3
alkyl, carboxy, C
1-3
alkoxycarbonyl;
Q
1
is phenyl, and Q
1
bears on an available carbon atom not adjacent to the —NH— link one substituent of the formula (Ia), and —NQ
2
(defined hereinbelow) may optionally bear on any available carbon atom further substituents of the formula (Ia):
wherein:
X is —CH
2
—, —O—, —NH—, —NR
y
— or —S— [wherein R
y
is C
1-4
alkyl, optionally substituted by one substituent selected from halo, amino, cyano, C
1-4
alkoxy or hydroxy];
Y
1
is H, C
1-4
alkyl or as defined for Z;
Y
2
is H or C
1-4
alkyl;
Z is R
a
O—, R
b
R
c
N—, R
d
S—, R
e
R
f
NNR
g
—, a nitrogen linked heteroaryl or a nitrogen linked heterocycle [wherein said heterocycle is optionally substituted on a ring carbon or a ring nitrogen by C
1-4
alkyl or C
1-4
alkanoyl] wherein 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, C
3-8
cycloalkyl, and wherein said C
1-4
alkyl and C
2-4
alkenyl are optionally substituted by one or more phenyl;
n is 1, 2 or 3;
m is 1, 2 or 3;
and —NQ
2
is an unquaternised N-linked 5-, 6- or 7-membered monocyclic heterocyclic moiety containing one nitrogen heteroatom and optionally containing a further one or two heteroatoms selected from nitrogen, oxygen and sulphur or —NQ
2
is an unquaternised N-linked 8-, 9- or 10-membered bicyclic heterocyclic moiety containing one or two nitrogen heteroatoms and optionally containing a further one or two heteroatoms selected from nitrogen, oxygen and sulphur and wherein if said heterocyclic moiety contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from C
1-6
alkyl, C
1-6
alkanoyl, C
1-6
alkylsulphonyl, C
1-6
alkoxycarbonyl, benzyl, benzoyl or phenylsulphonyl; and Q
1
and —NQ
2
may optionally and independently bear on any available carbon atom up to four substituents independently selected from halo, hydroxy, thio, nitro, carboxy, cyano, C
2-4
alkenyl [optionally substituted by up to three halo substituents, or by one trifluoromethyl substituent], C
2-4
alkynyl, C
1-5
alkanoyl, C
1-4
alkoxycarbonyl, C
1-6
alkyl, hydroxy-C
1-3
alkyl, fluoro-C
1-4
alkyl, amino-C
1-3
alkyl, C
1-4
alkylamino-C
1-3
alkyl, di-[C
1-4
alkyl]amino-C
1-3
alkyl, cyano-C
1-4
alkyl, C
2-4
alkanoyloxy-C
1-4
-alkyl, C
1-4
alkoxy-C
1-3
alkyl, carboxy-C
1-4
alkyl, C
1-4
alkoxycarbonyl-C
1-4
alkyl, carbamoyl-C
1-4
alkyl, N-C
1-4
alkylcarbamoyl-C
1-4
alkyl, N,N-di-[C
1-4
alkyl]-carbamoyl-C
1-4
alkyl, pyrrolidin-1-yl-C
1-3
alkyl, piperidin-1-yl-C
1-3
alkyl, piperazin-1-yl-C
1-3
alkyl, morpholino-C
1-3
alkyl, thiomorpholino-C
1-3
alkyl, imidazo-1-yl-C
1-3
alkyl, piperazin-1-yl, morpholino, thiomorpholino, C
1-4
alkoxy, cyano-C
1-4
alkoxy, carbamoyl-C
1-4
alkoxy, N-C
1-4
alkylcarbamoyl-C
1-4
alkoxy, N,N-di-[C
1-4
alkyl]-carbamoyl-C
1-4
alkoxy, 2-aminoethoxy, 2-C
1-4
alkylaminoethoxy, 2-di-[C
1-4
alkyl]aminoethoxy, C
1-4
alkoxycarbonyl-C
1-4
alkoxy, halo-C
1-4
alkoxy, 2-hydroxyethoxy, C
2-4
alkanoyloxy-C
2-4
alkoxy, 2-C
1-4
alkoxyethoxy, carboxy-C
1-4
alkoxy, 2-pyrrolidin-1-yl-ethoxy, 2-piperidino-ethoxy, 2-piperazin-1-yl-ethoxy, 2-morpholino-ethoxy, 2-thiomorpholino-ethoxy, 2-imidazo-1-yl-ethoxy, C
3-5
alkenyloxy, C
3-5
alkynyloxy, C
1-4
alkylthio, C
1-4
alkylsulphinyl, C
1-4
alkylsulphonyl, hydroxyC
2-4
alkylthio, hydroxyC
2-4
alkylsulphinyl, hydroxyC
2-4
alkylsulphonyl, ureido (H
2
N—CO—NH—), C
1-4
alkylNH—CO—NH—, di-[C
1-4
alkyl]N—CO—NH—, C
1-4
alkylNH—CO—N[C
1-4
alkyl]-, di-[C
1-4
alkyl]N—CO—N[C
1-4
alkyl]-, carbamoyl, N-[C
1-4
alkyl]carbamoyl, N,N-di-[C
1-4
alkyl]carbamoyl, amino, C
1-4
alkylamino, di-[C
1-4
alkyl]amino, C
2-4
alkanoylamino, sulphamoyl, N-(C
1-4
alkyl)sulphamoyl, N,N-di-(C
1-4
alkyl)sulphamoyl,
and also independently, or where appropriate in addition to, the above optional substituents, Q
1
and —NQ
2
may optionally and independently bear on any available carbon atom up to two further substituents independently selected from C
3-8
cycloalkyl, phenyl-C
1-4
alkyl, phenyl-C
1-4
alkoxy, phenylthio, phenyl, naphthyl, benzoyl, phenoxy, benzimidazol-2-yl, and a 5- or 6-membered aromatic heterocycle (linked via a ring carbon atom and containing one to three heteroatoms independently selected from oxygen, sulphur and nitrogen); wherein said naph
Breault Gloria A.
James Stewart R.
Pease Janet E.
AstraZeneca AB
Morgan & Lewis & Bockius, LLP
Patel Sudhaker B.
Raymond Richard L.
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