Pyrimidine compounds

Details Pyrimidine compounds Pyrimidine compounds

2001-02-26

2003-10-14

Rao, Deepak (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C544S326000, C544S327000, C544S328000, C544S329000

Reexamination Certificate

active

06632820

ABSTRACT:

The invention relates to pyrimidine derivatives, or pharmaceutically-acceptable salts or in-vivo-hydrolysable esters thereof, which possess anti-cell proliferative (such as anti-cancer) 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 for use in the production of an anti-cell proliferation (anti-cancer) 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.
The present invention is based on the discovery that certain 4,6-pyrimidine compounds surprisingly inhibit the effects of cell cycle kinases showing selectivity for CDK2, CDK4 and CDK6, and thus possess anti-cancer (anti-cell proliferation) 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
R
1
is selected from (1-6C)alkyl [optionally substituted by one or two substituents independently selected from halo, amino, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, hydroxy, cyano, (1-4C)alkoxy, (1-4C)alkoxycarbonyl, carbamoyl, —NHCO(1-4C)alkyl, trifluoromethyl, phenylthio, phenoxy, pyridyl, morpholino], benzyl, 2-phenylethyl, (3-5C)alkenyl [optionally substituted by up to three halo substituents, or by one trifluoromethyl substituent, or one phenyl substituent], N-phthalimido-(1-4C)alkyl, (3-5C)alkynyl [optionally substituted by one phenyl substituent] and (3-6C)cycloalkyl-(1-6C)alkyl;
wherein any phenyl or benzyl group in R
1
is optionally substituted by up to three substituents independently selected from halogeno, hydroxy, nitro, amino, (1-3C)alkylamino, di-[(1-3C)alkyl]amino, cyano, trifluoromethyl, (1-3C)alkyl [optionally substituted by 1 or 2 substituents independently selected from halogeno, cyano, amino, (1-3C)alkylamino, di-[(1-3C)alkyl]amino, hydroxy and trifluoromethyl], (3-5C)alkenyl [optionally substituted by up to three halo substituents, or by one trifluoromethyl substituent], (3-5C)alkynyl, (1-3C)alkoxy, —SH, —S-(1-3 C)alkyl, carboxy, (1-3 C)alkoxycarbonyl;
Q
1
and Q
2
are independently selected from phenyl, naphthyl, indanyl and 1,2,3,4-tetrahydronaphthyl;
and one or both of Q
1
and Q
2
bears on any available carbon atom one substituent of the formula (Ia) and Q
2
may optionally bear on any available carbon atom further substituents of the formula (Ia)
 [provided that when present in Q
1
the substituent of formula (Ia) is not adjacent to the —NH— link];
wherein
X is CH
2
, O, S, NH or NRx [wherein Rx is (1-4C)alkyl, optionally substituted by one substituent selected from halo, amino, cyano, (1-4C)alkoxy or hydroxy];
Y is H or as defined for Z; Z is OH, SH, NH
2
, (1-4C)alkoxy, (1-4C)alkylthio, —NH(1-4C)alkyl, —N[(1-4C)alkyl]
2
, —NH-(3-8C)cycloalkyl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl [optionally substituted in the 4-position by (1-4C)alkyl or (1-4C)alkanoyl], morpholino or thiomorpholino; n is 1, 2 or 3; m is 1, 2 or 3;
and Q
1
and Q
2
may each optionally and independently bear on any available carbon atom up to four substituents independently selected from halogeno, hydroxy, thio, nitro, carboxy, cyano, (2-4C)alkenyl [optionally substituted by up to three halo substituents, or by one trifluoromethyl substituent], (2-4C)alkynyl, (1-5C)alkanoyl, (1-4C)alkoxycarbonyl, (1-6C)alkyl, hydroxy-(1-6C)alkyl, fluoro-(1-4C)alkyl, amino-(1-3C)alkyl, (1-4C)alkylamino-(1-3C)alkyl, di-[(1-4C)alkyl]amino-(1-3C)alkyl, cyano-(1-4C)alkyl, (2-4C)alkanoyloxy-(1-4C)-alkyl, (1-4C)alkoxy-(1-3C)alkyl, carboxy-(1-4C)alkyl, (1-4C)alkoxycarbonyl-(1-4C)alkyl, carbamoyl-(1-4C)alkyl,
N
-(1-4C)alkylcarbamoyl-(1-4C)alkyl,
N
,
N
-di-[(1-4C)alkyl]-carbarmoyl-(1-4C)alkyl, pyrrolidin-1-yl-(1-3 C)alkyl, piperidin-1-yl-(1-3C)alkyl, piperazin-1-yl-(1-3C)alkyl, morpholino-(1-3 C)alkyl, thiomorpholino-(1-3C)alkyl, piperazin-1-yl, morpholino, thiomorpholino, (1-4C)alkoxy, cyano-(1-4C)alkoxy, carbamoyl-(1-4C)alkoxy,
N
-(1-4C)alkylcarbarnoyl-(1-4C)alkoxy,
N
,
N
-di-[(1-4C)alkyl]-carbarmoyl-(1-4C)alkoxy, 2-aminoethoxy, 2-(1-4C)alkylaminoethoxy, 2-di-[(1-4C)alkyl]aminoethoxy, (1-4C)alkoxycarbonyl-(1-4C)alkoxy, halogeno-(1-4C)alkoxy, 2-hydroxyethoxy, (2-4C)alkanoyloxy-(2-4C)alkoxy, 2-(1-4C)alkoxyethoxy, carboxy-(1-4C)alkoxy, (3-5C)alkenyloxy, (3-5C)alkynyloxy, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, hydroxy-(2-4C)alkylthio, hydroxy-(2-4C)alkylsulphinyl, hydroxy-(2-4C)alkylsulphonyl, ureido (H
2
N—CO—NH—), (1-4C)alkylNH—CO—NH—, di-[(1-4C)alkyl]- N—CO—NH—, (1-4C)alkylNH—CO—N[(1-4C)alkyl]- , di-[(1-4C)alkyl]N—CO—N[(1-4C)alkyl]-, carbamoyl, N-[(1-4C)alkyl]carbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl, amino, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino,
and also independently, or where appropriate in addition to, the above optional substituents, Q
1
and/or Q
2
may optionally bear on any available carbon atom up to two further substituents independently selected from (3-8C)cycloalkyl, phenyl-(1-4C)alkyl, phenyl-(1-4C)alkoxy, phenylthio, phenyl, naphtnyl, 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 naphthyl, phenyl, benzoyl, 5- or 6-membered aromatic heterocyclic substituents and the phenyl group in said phenyl-(1-4C)alkyl, phenylthio, phenoxy and phenyl-(1-4C)alkoxy substituents may optionally bear up to five substituents independently selected from halogeno, (1-4C)alkyl and (1-4C)alkoxy; or a pharmaceutically-acceptable salt or in-vivo-hydrolysable ester thereof.
A suitable value for a ring substituent when it is 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) is, for example, pyrrole, furan, thiophene, imidazole, oxazole, isoxazole, thiazole, pyridyl, pyridazin

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