2-pyrimidineamine derivatives and processes for their...

Details 2-pyrimidineamine derivatives and processes for their... 2-pyrimidineamine derivatives and processes for their...

1999-10-20

2003-04-22

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...

C544S222000, C544S331000

Reexamination Certificate

active

06552029

ABSTRACT:

This invention relates to 2-pyrimidineamine derivatives, 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
Ick
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 2-pyrimidineamine derivatives which are potent and selective inhibitors of the protein tyrosine kinases ZAP-70 and syk. The ZAP-70 kinase is involved in the transduction of signals from the T-cell receptor and thus in the activation of T-cells during the immune response. The closely related kinase syk is involved in signalling from the B-cell receptor and thus in the activation of B-cells during the immune response [van Oers N S, Weiss A, Seminars in Immunology, 7, 227-236, (1995) and is also involved in signalling from the Fc epsilon RI, the high-affinity IgE receptor present on mast cells [Zhang J. et al, J. Exp. Med. 184, 71-79 (1996)] and in the survival of eosinophils mediated by IL5 and GM-CSF [Yousefi S, et al J. Exp. Med. 183, 1407-1414, (1996)]. Syk is further involved in the activation of platelets stimulated via the low-affinity IgG receptor (Fc gamma-RIIA) or stimulated by collagen [Yanaga F, et al, Biochem. J. 311, (Pt. 2) 471-478, (1995)].
The compounds of the invention are thus of use in the prophylaxis and treatment of immune diseases (including autoimmune diseases and transplant rejection), allergic diseases involving mast cells or eosinophils, and diseases involving inappropriate platelet activation.
Thus, according to one aspect of the invention, we provide a compound of formula (1):
wherein
Ar is an optionally substituted aromatic group;
R
2
is a hydrogen or halogen atom or a group —X
1
—R
2a
where X
1
is a direct bond or a linker atom or group, and R
2a
is an optionally substituted straight or branched chain alkyl, alkenyl or alkynyl group;
R
3
is an optionally substituted heterocycloalkyl group;
and the salts, solvates, hydrates and N-oxides thereof.
It will be appreciated that in the compounds of formula (1) the pyrimidine and R
3
groups may be attached to any ring carbon atom of the pyridyl group, provided always that they are not both attached to the same carbon atom.
The group R
2
in compounds according to the invention may be for example a hydrogen or halogen atom such as a fluorine, chlorine, bromine or iodine atom, or a group —X
1
—R
2a
where X
1
is a direct bond or linker atom or group, and R
2a
is an optionally substituted straight or branched chain alkyl, alkenyl or alkynyl group.
Linker atoms represented by X
1
when present in compounds of formula (1) include —O— or —S— atoms. When X
1
is a linker group it may be for example a —C(O)—, —C(S)—, —S(O)—, —S(O)
2
—, —N(R
7
)—[where R
7
is a hydrogen atom or a C
1-6
alkyl, e.g. methyl or ethyl, group], —CON(R
7
)—, —OC(O)N(R
7
)—, —CSN(R7)—, —N(R
7
)CO—, —N(R
7
)C(O)O—, —N(R
7
)CS—, —SON(R
7
), —SO
2
N(R
7
), —N(R
7
)SO
2
—, —N(R
7
)CON(R
7
)—, —N(R
7
)CSN(R
7
)—, —N(R
7
)SON(R
7
)— or —N(R
7
)SO
2
N(R
7
) group.
When R
2a
is present in compounds of the invention it may be 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. 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.
R
3
in compounds of formula (1) may be for example an optionally substituted heteroC
3-7
heterocycloalkyl group containing one or two oxygen, or sulphur atoms or nitrogen containing groups. The heterocycloalkyl group may be attached to the remainder of the molecule of formula (1) through any of its carbon or, where present, nitrogen atoms as appropriate.
Where desired, any available nitrogen or carbon atom in R
3
may be substituted by a group R
4
where R
4
is an optionally substituted straight or branched chain C
1-6
alkyl, C
1-6
alkoxy, hydroxyl (—OH), amino (—NH
2
), —NHR
1a
[where R
1a
is an optionally substituted straight or branched chain C
1-6
alkyl group], —NR
1a
R
1b
[where R
1b
is as defined for R
1a
and may be the same as or different to R
1a
], carboxyl (—CO
2
H), esterified carboxyl (—CO
2
Alk
1
, where Alk
1
is as defined below in connection with the group R
5
), —COR
1a
, carboxamido (—CONH
2
), thiocarboxamido (—CSNH
2
), —CONHR
1a
, —CONR
1a
R
1b
, —CSNHR
1a
, —CSNR
1a
R
1b
, —SO
2
R
1a
, —SO
2
NH
2
, —SO
2
NHR
1a
, —SO
2
NR
1a
R
1b
, imido, —SC(NH)NH
2
, —NHC(NH)NH
2
, —NHC(NH)R
1a
or an optionally substituted aromatic group. Additionally, any available carbon atom in the heterocycloalkyl group represented by R
3
may be linked to an oxygen or sulphur atom to form a —C(O)— or —C(S)— group.
The heterocycloalkyl group R
3
may contain one, two, three or more R
4
substituents, the upper limit depending on the size of the ring and number of available carbon and/or nitrogen atoms.
When the substituent R
4
is an optionally substituted alkyl or alkoxy group it may be for example an optionally substituted methyl, ethyl, prop-1-yl, prop-2-yl, methoxy or ethoxy group.
The groups R
1a
and R
1b
when present in the substituent R
4
may be for example optionally substituted C
1-3
alkyl groups such as optionally substituted methyl or ethyl groups.
Optional substituents which may be present on alkyl or alkoxy groups represented by R
4
, or in R
1a
and/or R
1b
groups, include one or two substituents selected from C
1-6
alkoxy, —OH, —NH
2
, —NHR
1a
, —NR
1a
R
1b
, —CO
2
H, —CO
2
Alk
1
, —COR
1a
, —CONH
2
, —CSNH
2
, —CONHR
1a
, —CONR
1a
R
1b
, —CSNHR
1a
, —CSNR
1a
R
1b
, —SO
2
R
1a
, —SO
2
NH
2
, —SO
2
NHR
1a
, —SO
2
NR
1a
R
1b
, imido, —SC(NH)NH
2
, —NHC(NH)NH
2
, —NHC(NH)R
1a
or optionally substituted aromatic groups.
Optionall

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