4,5-disubstituted-2-aminopyrimidines

Details 4,5-disubstituted-2-aminopyrimidines 4,5-disubstituted-2-aminopyrimidines

2000-10-19

2003-07-29

Rao, Deepak (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Chalcogen in the nitrogen containing substituent

C544S122000, C544S330000, C544S331000, C544S332000

Reexamination Certificate

active

06600037

ABSTRACT:

This invention relates to certain 4,5-disubstituted-2-aminopyrimidines, to processes for their preparation, to pharmaceutical compositions containing them, and to their use in medicine.
Angiogenesis, the growth of capillaries from existing blood vessels, is an essential process in normal embryonic development, tissue repair and some aspects of female reproductive function. It is also associated with the development of several pathological disorders including solid tumour growth, metastasis, psoriasis and rheumatoid arthritis, as well as diabetic retinopathy and age related macular degeneration (Folkman, Nature Medicine, (1995) 1, 27-310).
Several growth factors have been shown to mediate angiogenesis through alteration of vascular permeability, including vascular endothelial growth factor (VEGF; G. Breier et al., Trends in Cell Biology, 1996, 6, 454-6), platelet derived growth factor (PDGF) and acidic and basic fibroblast growth factors (a & b FGF).
VEGF in dimeric form is a ligand that binds to two transmembrane tyrosine kinase associated receptors, expressed exclusively on proliferating endothelial cells, KDR (Flk-1 in mice) also known as VEGFR-2, and Flt-1 also known as VEGFR-1. Binding of VEGF to KDR/Flk and Flt leads to receptor dimerisation, kinase activation, autophosphorylation of the receptor and phosphorylation of intracellular substrates. An analogous series of events ensues after ligand occupancy of the more widely expressed tyrosine kinase associated FGFr receptor by aFGF or bFGF. Thus receptor tyrosine kinase activity initiates a cellular signalling pathway leading to proliferation.
Antagonism of VEGF with antibody completely suppresses neovascularisation and growth of human rhabdomyosarcoma A673 speroids in athymic mice (Borgstrom et al, Cancer Res., 1996, 56 4032-4039). Suppression of bFGF gene expression by interferons &agr; and &bgr; inhibits capillary density in mice, leading to pancreatic eyelet tumour suppression (Folkman et al, Proc. Natl. Acad.Sci. 1996, 93, 2002 and Singh et al Proc.Natl. Acad. Sci. 1995, 92, 10457). Other receptor associated kinases such as PDGF&bgr; and EGFr may also have some role in mediating angiogenesis.
We have now found certain 4,5-disubstituted-2-aminopyrimidines which are potent and selective inhibitors of receptor tyrosine kinases involved in angiogenesis, especially KDR kinase and/or FGFr kinase. Selective inhibition of these kinases can be expected to have a beneficial effect and the compounds are thus of use in the prophylaxis and treatment of disease states associated with angiogenesis, as described hereinafter.
Thus, according to one aspect of the invention, we provide a compound of formula (1):
wherein
R
1
is a —XR
6
group [where X is a covalent bond, —O—, —S—, —C(O)—, —C(S)—, —C(O)O—, —S(O)—, —S(O
2
)—, —CH
2
—, or N(R
7
)— [where R
7
is a hydrogen atom or a straight or branched alkyl group] and R
6
is a hydrogen or halogen atom or an optionally substituted aliphatic, cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group, or a —NO
2
, —CN, —SO
2
N(R
8
)(R
9
) [where R
8
and R
9
, which may be the same or different is a hydrogen atom or an optionally substituted aliphatic, cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group], —CON(R
8
)(R
9
), —CSN(R
8
)(R
9
), —NH
2
or substituted amino group;
R
2
and R
3
which may be the same or different is each a hydrogen or halogen atom or a group selected from an optionally substituted aliphatic, cycloaliphatic, heteroaliphatic, heterocycloaliphatic, —OH, —OR
10
[where R
10
is an optionally substituted aliphatic, cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group] —SH, —NO
2
, —CN, —SR
10
, —COR
10
, S(O)R
10
, —SO
2
R
8
, —SO
2
N(R
8
)(R
9
), —CO
2
R
8
, —CON(R
8
)(R
9
), —CSN(R
8
)(R
9
), —NH
2
or substituted amino group;
R
4
is a X
1
R
11
group where X
1
is a covalent bond or a —C(R
12
)(R
13
)— [where each of R
12
and R
13
is a hydrogen or halogen atom or a hydroxyl, alkyl or haloalkyl group] or —C(O)— group and R
11
is an optionally substituted phenyl, thienyl, thiazolyl or indolyl group;
R
5
is a halogen atom or an alkynyl group;
and the salts, solvates, hydrates and N-oxides thereof.
In the compounds of formula (1), the term “optionally substituted aliphatic group” when applied to each of the groups R
2
, R
3
, R
6
and R
10
means each of these groups may independently be for example an optionally substituted C
1-10
aliphatic group, for example an optionally substituted straight or branched chain C
1-6
alkyl, e.g. C
1-3
alkyl, C
2-6
alkenyl, e.g. C
2-4
alkenyl, or C
2-6
alkynyl, e.g. C
2-4
alkynyl group. Each of said groups may be optionally interrupted by one or two heteroatoms or heteroatom-containing groups represented by X
2
[where X
2
is an —O— or —S— atom or a —C(O)—, —C(S)—, —S(O)—, —S(O)
2
—, —N(R
14
)— [where R
14
is a hydrogen atom or a C
1-6
alkyl, e.g. methyl or ethyl, group], —CON(R
14
)—, —OC(O)N(R
14
)—, —CSN(R
14
)—, —N(R
14
)CO—, —N(R
14
)C(O)O—, —N(R
14
)CS—, —SON(R
14
), —SO
2
N(R
14
), —N(R
14
)SO
2
—, —N(R
14
)CON(R
14
)—, —N(R
14
)CSN(R
14
)—, —N(R
14
)SON(R
14
)— or —N(R
14
)SO
2
N(R
14
) group] to form an optionally substituted R
2
, R
3
, R
6
and R
10
heteroaliphatic group.
Particular examples of aliphatic groups represented by R
2
, R
3
, R
6
and/or R
10
include optionally substituted —CH
3
, —CH
2
CH
3
, —(CH
2
)
2
CH
3
, —CH(CH
3
)
2
, —(CH
2
)
3
CH
3
, —CH(CH
3
)CH
2
CH
3
, —CH
2
CH(CH
3
)
2
, —C(CH
3
)
3
, —(CH
2
)
4
CH
3
, —(CH
2
)
5
CH
3
, —CHCH
2
, —CHCHCH
3
, —CH
2
CHCH
2
, —CHCHCH
2
CH
3
, —CH
2
CHCHCH
3
, —(CH
2
)
2
CHCH
2
, —CCH, —CCCH
3
, —CH
2
CCH, —CCCH
2
CH
3
, —CH
2
CCCH
3
, or —(CH
2
)
2
CCH groups. Where appropriate each of said groups may be optionally interrupted by one or two atoms and/or groups X
2
to form an optionally substituted heteroaliphatic group. Particular examples include —CH
2
X
2
CH
3
, —CH
2
X
2
CH
2
CH
3
, —(CH
2
)
2
X
2
CH
3
and —(CH
2
)
2
X
2
CH
2
CH
3
groups.
The optional substituents which may be present on these aliphatic and/or heteroaliphatic groups include one, two, three or more substituents selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or hydroxyl, C
1-6
alkoxy, e.g. methoxy or ethoxy, thiol, C
1-6
alkylthio e.g. methylthio or ethylthio, —SC(NH)NH
2
, —CH
2
C(NH)NH
2
, amino, substituted amino, cyclic amino or heteroaromatic groups.
Substituted amino groups include for example groups of formulae —NR
15
R
16
[where R
15
is an optionally substituted C
1-6
alkyl, C
2-6
alkenyl or C
2-6
alkynyl group optionally interrupted by one or two heteroatoms or heteroatom-containing groups represented by X
3
(where X
3
is an atom or group as described above for X
2
) and R
16
is a hydrogen atom or is a group as just defined for R
15
], —N(R
16
)COR
15
, —N(R
16
)CSR
15
, —N(R
16
)SOR
15
, —N(R
16
)SO
2
R
15
, —N(R
16
)CONH
2
, —N(R
16
)CONR
15
R
16
, —N(R
16
)C(O)OR
15
, —N(R
16
)C(NH)NH
2
, —N(R
16
)C(NH)NR
15
R
16
, —N(R
16
)CSNH
2
, —N(R
16
)CSNR
15
R
16
, —N(R
16
)SONH
2
, —N(R
16
)SONR
15
R
16
, —N(R
16
)SO
2
NH
2
, —N(R
16
)SO
2
NR
15
R
16
, or —N(R
16
)Cyc
1
[where Cyc
1
is an optionally substituted C
3-7
monocyclic carbocyclic group optionally containing one or more —O— or —S— atoms or —N(R
14
)—, —C(O)—, —C(S)—, —S(O)— or —S(O
2
)— groups].
Cyclic amino substituents which may be present on R
2
, R
3
, R
6
and/or R
10
aliphatic or heteroaliphatic groups include groups of formula —NHet
1
, where —NHet
1
is an optionally substituted C
3-7
cyclic amino group optionally containing one or more other heteroatoms or heteroatom containing groups selected from —O— or —S— atoms —N(R
14
)—, —C(O), —C(S)—, —S(O)— or —S(O
2
)— groups.
Particular examples of amino, substituted amino and cyclic amino groups include —NH
2
, methylamino, ethylamino, dimethylamino, diethylamino, —NHCyc
1
where Cyc
1
is an optionally substituted cyclopentyl, cyclohexyl

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