Substituted 2-anilinopyrimidines useful as protein kinase...

Details Substituted 2-anilinopyrimidines useful as protein kinase... Substituted 2-anilinopyrimidines useful as protein kinase...

1999-10-20

2002-01-08

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C544S321000

Reexamination Certificate

active

06337335

ABSTRACT:

This invention relates to substituted 2-anilinopyrimidines, to processes for their preparation, to pharmaceutical compositions containing them, and to their use in medicine.
Protein kinases participate in the signalling events which control the activation, growth and differentiation of cells in response to extracellular mediators and to changes in the environment. In general, these kinases fall into two groups; those which preferentially phosphorylate serine and/or threonine residues and those which preferentially phosphorylate tyrosine residues [Hanks, S K, Hunter T, FASEB. J. 9, 576-596 (1995)]. The serine/threonine kinases include for example, protein kinase C isoforms [Newton A C, J. Biol. Chem. 270, 28495-28498 (1995)] and a group of cyclin-dependent kinases such as cdc2 [Pines J, Trends in Biochemical Sciences 18, 195-197 (1995)]. The tyrosine kinases include membrane-spanning growth factor receptors such as the epidermal growth factor receptor [Iwashita S and Kobayashi M. Cellular Signalling 4, 123-132 (1992)], and cytosolic non-receptor kinases such as ZAP-70 and csk kinases [Chan C et al Ann. Rev. Immunol. 12, 555-592 (1994)]. A particular group of non-receptor tyrosine kinases are a group known as the src family which includes p56
lck
and p59
fyn
[Kefelas P et al International Journal of Biochemistry and Cell Biology 27, 551-563 (1995)].
Inappropriately high protein kinase activity has been implicated in many diseases resulting from abnormal cellular function. This might arise either directly or indirectly, for example by failure of the proper control mechanisms for the kinase, related for example to mutation, over-expression or inappropriate activation of the enzyme; or by over- or underproduction of cytokines or growth factors also participating in the transduction of signal upstream or downstream of the kinase. In all of these instances, selective inhibition of the action of the kinase might be expected to have a beneficial effect.
We have now found a series of substituted 2-anilinopyrimidines which are potent and selective inhibitors of protein kinases, especially src-family protein kinases. The compounds are thus of use in the prophylaxis and treatment of immune diseases, hyperproliferative disorders and other diseases in which inappropriate protein kinase action is believed to have a role.
Thus, according to one aspect of the invention, we provide a compound of formula (1):
wherein R
1
is a —XR
8
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
9
)— [where R
9
is a hydrogen atom or a straight or branched alkyl group] and R
8
is a hydrogen atom or an optionally substituted aliphatic, cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group], or a —NO
2
, —CN, —SO
2
NH
2
, —SO
2
NHR
8
, —SO
2
N(R
8
)
2
[where each R
8
group may be the same or different], —CONH
2
, —CONHR
8
, —CON(R
8
)
2
[where each R
8
group may be the same or different], —CSNH
2
, —CSNHR
8
, —CSN(R
8
)
2
[where each R
8
group may be the same or different], —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 group], —OR
10a
[where R
10a
is an optionally substituted cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group] —SH, —NO
2
, —CN, —SR
8
, —COR
8
, S(O)R
8
, —SO
2
R
8
, —SO
2
NH
2
, —SO
2
NHR
8
, —SO
2
N(R
8
)
2
[where each R
8
group may be the same or different] —CO
2
H, —CO
2
R
8
, —CONH
2
, —CONHR
8
, —CON(R
8
)
2
, [where each R
8
group may be the same or different] —CSNH
2
, —CSNHR
8
, —CSN(R
8
)
2
, [where each R
8
group may be the same or different] —NH
2
or substituted amino group provided that when one or both of R
2
and R
3
is an —OR
10
group then R
1
is an —OR
8
group in which R
8
is an optionally substituted cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group or an aliphatic group substituted by a cyclic amino group;
R
4
is a hydrogen atom or a straight or branched alkyl group;
R
5
is a hydrogen atom or an optionally substituted straight or branched alkyl, alkenyl or alkynyl group;
R
6
is a hydrogen or halogen atom or an amino, substituted amino, nitro, —CO
2
H, or —CO
2
R
8
group or a group —X
1
—R
6a
where X
1
is a direct bond or a linker atom or group and R
6a
is an optionally substituted straight or branched alkyl, alkenyl or alkynyl group;
R
7
is an optionally substituted aliphatic, cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group; and the salts, solvates, hydrates and N-oxides thereof.
When in the compounds of formula (1) X
1
is present as a linker atom or group it may be for example an —O— or —S— atom or a —C(O)—, —C(S)—, —S(O)—, —S(O)
2
—, —N(R
11
)— [where R
11
is a hydrogen atom or a C
1-6
alkyl, e.g. methyl or ethyl, group], —CON(R
11
)—, —OC(O)N(R
11
)—, —CSN(R
11
)—, —N(R
11
)CO—, —N(R
11
)C(O)O—, —N(R
11
)CS—, —SON(R
11
), —SO
2
N(R
11
), —N(R
11
)SO
2
—, —N(R
11
)CON(R
11
), —N(R
11
)CSN(R
11
), —N(R
11
)SON(R
11
)— or —N(R
11
)SO
2
N(R
11
) group.
In the compounds of formula (1), when R
1
is —XR
8
and R
8
is an optionally substituted aliphatic group, R
8
may be 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 atom or group as just described for X
1
], to form an optionally substituted R
8
heteroaliphatic group.
Particular examples of aliphatic groups represented by R
8
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 or cyclic amino groups.
Substituted amino groups include for example groups of formulae —NR
9
R
10
[where R
9
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
1
) and R
10
is a hydrogen atom or is a group as just defined for R
9
], —N(R
10
)COR
9
, —N(R
10
)CSR
9
, —N(R
10
)SOR
9
, —N(R
10
)SO
2
R
9
, —N(R
10
)CONH
2
, —N(R
10
)CONR
9
R
10
, —N(R
10
)C(O)OR
9
, —N(R
10
)C(NH)NH
2
, N(R
10
)C(NH)NR
9
R
10
, —N(R
10
)CSNH
2
, —N(R
10
)CSNR
9
R
10
, —N(R
10
)SONH
2
, —N(R
10
)SONR
9
R
10
, —N(R
10
)SONH
2
, —N(R
10
)SO
2
NH
2
, N(R
10
)SO
2
NR
9
R
10
, or —N(R
10
)Cyc
1
[where Cyc
1
is an optionally substituted C
3-7
monocyclic carbocyclic group optionally containing one or more —O— or —S— atoms

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