Substituted 2-anilinopyrimidines useful as protein kinase...

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

1999-02-16

2001-05-22

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C544S323000, C544S325000, C544S332000

Reexamination Certificate

active

06235746

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 p56
lck
p59
fyn
ZAP-70 and csk kinases [Chan C et al Ann. Rev. Immunol. 12, 555-592 (1994)].
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, overexpression 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 the kinases p56
lck
, p59
fyn
, ZAP-70 and protein kinase C. 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 hydrogen or halogen atom or an optionally substituted straight or branched chain alkyl, alkenyl or alkynyl group or a group selected from hydroxyl (—OH), substituted hydroxyl, thiol (—SH), substituted thiol, amino (—NH
2
), or substituted amino;
R
2
and R
3
, which may be the same or different, is each an optionally substituted straight or branched chain alkyl, alkenyl or alkynyl group;
R
4
is a hydrogen atom or a straight or branched chain alkyl group;
R
5
is a hydrogen atom or an optionally substituted straight or branched chain alkyl, alkenyl or alkynyl group;
R
6
is a hydrogen or halogen atom or an amino (—NH
2
), substituted amino, nitro, carboxyl (—CO
2
H) or esterified carboxyl 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 chain alkyl, alkenyl or alkynyl group;
X is a direct bond or a linker atom or group;
R
7
is an optionally substituted aliphatic, cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group; and the salts, solvates, hydrates and N-oxides thereof.
Halogen atoms represented by the group R
1
and/or R
6
in compounds of formula (1) include for example fluorine, chlorine, bromine or iodine atoms.
When R
1
, R
2
, R
3
, R
5
and/or R
6a
is an optionally substituted straight or branched chain alkyl, alkenyl or alkynyl group each of said groups may independently be 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. Particular examples of such groups 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. The optional substituents which may be present on these 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, amino, C
1-6
alkylamino, e.g. methylamino or ethylamino, or C
1-6
dialkylamino, e.g. dimethylamino or diethylamino groups.
Substituted hydroxyl groups represented by the group R
1
in compounds of formula (1) include —OR
8
groups where R
8
is an optionally substituted straight or branched C
1-6
alkyl, e.g. methyl or ethyl, G
2-6
alkenyl, e.g. allyl, or C
2-6
alkynyl, e.g. ethynyl group. The optional substituents which may be present on these groups include a phenyl group and/or one, two, three or more of the atoms or groups described above in relation to substituents present on alkyl groups represented by R
1
.
Substituted thiol groups represented by the group R
1
include —SR
8
groups, wherein R
8
is as just defined.
When R
1
and/or R
6
is a substituted amino group it may be for example a —NHR
9
or —NR
9
R
10
group where R
9
and R
10
, which may be the same or different, is each a group —R
8
or —COR
8
where R
8
is as just defined.
Esterified carboxyl groups represented by the group R
6
include groups of formula —CO
2
Alk
1
wherein —CO
2
Alk
1
is as defined hereinafter in connection with esterified carboxyl groups represented by the group R
13
.
Linker atoms represented by X or X
1
in compounds of formula (1) include —O— or —S— atoms. When X or X
1
is a linker group it may be for example 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.
When R
7
in compounds of formula (1) is an optionally substituted aliphatic or cycloaliphatic group it may be an optionally substituted C
1-10
aliphatic or C
3-10
cycloaliphatic group. Particular examples include optionally substituted straight or branched chain C
1-6
alkyl, C
2-6
alkenyl, or C
2-6
alkynyl groups or optionally substituted C
3-10
cycloalkyl, C
3-10
cycloalkenyl or C
3-10
cycloalkynyl groups.
Heteroaliphatic or heterocycloaliphatic groups represented by R
7
include the aliphatic or cycloaliphatic groups just described but with each group additionally containing one, two, three or four heteroatoms or heteroatom-containing groups. Particular heteroatoms or groups include atoms or groups —X
2
— where X
2
is as defined above for X when X is a linker atom or group.
Aromatic groups represented by R
7
in compounds of formula (1) include for example optionally substituted monocyclic or bicyclic fused ring C
6-12
aromatic groups, such as optionally substituted phenyl, 1- or 2-naphthyl, 1- or 2-tetrahydronaphthyl, indanyl or indenyl groups.
Heteroaromatic groups represented by R
7
include optionally substituted C
1-9
heteroaromatic groups containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. In general, the heteroaromatic groups may be for example monocyclic or bicyclic fused ring heteroaromatic groups. Monocyclic heteroaromatic groups include for example five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. Bicyclic heteroaromatic groups include for example nine- to thirteen-membered fused-ring heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.

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