Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-02
2003-07-29
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S250000, C544S246000
Reexamination Certificate
active
06599908
ABSTRACT:
This invention relates to a series of fused polycyclic 2-aminopyrimidines, 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 2-aminopyrimidine derivatives which are potent and selective inhibitors of the protein tyrosine kinases p56
lck
and p59
fyn
. The compounds are of use in the prophylaxis and treatment of immune diseases, hyperproliferative disorders and other diseases in which inappropriate p56
lck
and/or p59
fyn
activity is believed to have a role.
Thus according to one aspect of the invention, we provide a compound of formula (1):
wherein
Ar is an optionally substituted aromatic or heteroaromatic group;
X is a carbon or nitrogen atom;
Y is a carbon or nitrogen atom;
Z is a linker group;
A together with X and Y forms an optionally substituted monocyclic or bicyclic aromatic or heteroaromatic group;
and the salts, solvates, hydrates and N-oxides thereof.
Aromatic groups represented by the group Ar in compounds of formula (1) include for example mono- or bicyclic C
6-12
optionally substituted aromatic groups, for example optionally substituted phenyl, 1- or 2-naphthyl, or indenyl groups.
Heteroaromatic groups represented by Ar include for example C
1-9
optionally substituted 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 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 heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.
Particular examples of heteroaromatic groups represented by Ar include optionally substituted pyrrolyl, furyl, thienyl, imidazolyl, N-methylimidazolyl, N-ethylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolinyl, isoquinolinyl, tetrazolyl, 5,6,7,8-tetrahydroquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl.
Optional substituents present on the aromatic or heteroaromatic groups represented by Ar include one, two, three or more groups, each represented by the group R
1
. The substituent R
1
may be selected from an atom or group R
2
or -Alk(R
2
)
m
, where R
2
is a halogen atom, or an amino (—NH
2
), substituted amino, nitro, cyano, amidino, hydroxyl (—OH) substituted hydroxyl, formyl, carboxyl (—CO
2
H), esterified carboxyl, thiol (—SH), substituted thiol, —COR
3
(where R
3
is an -Alk(R
2
)
m
, aryl or heteroaryl group), —CSR
3
, —SO
3
H, —SO
2
R
3
, —SO
2
NH
2
, —SO
2
NHR
3
, SO
2
N(R
3
)
2
, —CONH
2
, —CSNH
2
, —CONHR
3
, —CSNHR
3
, —CON(R
3
)
2
, —CSN(R
3
)
2
, —NHSO
2
H, —NHSO
2
R
3
, —N(SO
2
R
3
)
2
, —NHSO
2
NH
2
, —NHSO
2
NHR
3
, —NHSO
2
N(R
3
)
2
, —NHCOR
3
, —NHCSR
3
, —NHC(O)OR
3
, aryl or heteroaryl group; Alk is a straight or branched C
1-6
alkylene, C
2-6
alkenylene or C
2-6
alkynylene chain, optionally interrupted by one, two or three —O— or —S— atoms or —S(O)
n
(where n is an integer 1 or 2) or —N(R
4
)— groups (where R
4
is a hydrogen atom or C
1-6
alkyl, e.g. methyl or ethyl group); and m is zero or an integer 1, 2 or 3.
When in the group -Alk(R
2
)
m
m is an integer 1, 2 or 3, it is to be understood that the substituent or substituents R
2
may be present on any suitable carbon atom in -Alk. Where more than one R
2
substituent is present these may be the same or different and may be present on the same or different atom in -Alk. Clearly, when m is zero and no substituent R
2
is present the alkylene, alkenylene or alkynylene chain represented by Alk becomes an alkyl, alkenyl or alkynyl group.
When R
2
is a substituted amino group it may be for example a group —NHR
3
[where R
3
is as defined above] or a group —N[R
3
]
2
wherein each R
3
group is the same or different.
When R
2
is a halogen atom it may be for example a fluorine, chlorine, bromine, or iodine atom.
When R
2
is a substituted hydroxyl or substituted thiol group it may be for example a group —OR
3
or a —SR
3
or —SC(NH
2
+)NH
2
group respectively.
Esterified carboxyl groups represented by the group R
2
include groups of formula —CO
2
Alk
1
wherein Alk
1
is a straight or branched, optionally substituted C
1-8
alkyl group such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl group; a C
6-12
arylC
1-8
alkyl group such as an optionally substituted benzyl, phenylethyl, phenylpropyl, 1-naphthylmethyl or 2-naphthylmethyl group; a C
6-12
aryl group such as an optionally substituted phenyl, 1-naphthyl or 2-naphthyl group; a C
6-12
aryloxyC
1-8
alkyl group such as an optionally substituted phenyloxymethyl, phenyloxyethyl, 1-naphthyl-oxymethyl, or 2-naphthyloxymethyl group; an optionally substituted C
1-8
alkanoyloxyC
1-8
alkyl group, such as a pivaloyloxymethyl, propionyloxyethyl or propionyloxypropyl group; or a C
6-12
aroyloxyC
1-8
alkyl group such as an optionally substituted benzoyloxyethyl or benzoyloxypropyl group. Optional substituents present on the Alk
1
group include R
2
substituents described above.
When Alk is present in or as a substituent R
1
it may be for example a methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, s-butylene, t-butylene, ethenylene, 2-propenylene, 2-butenylene, 3-butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylene chain, optionally interrupted by one, two, or three —O— or —S—, atoms or —S(O)—, —S(O)
2
— or —N(R
4
)— groups.
Aryl or heteroaryl groups represented by the groups R
2
or R
3
include mono- or bicyclic optionally substituted C
6-12
aromatic or C
1-9
heteroaromatic groups as described above for the group Ar. The aro
Batchelor Mark James
Davis Jeremy Martin
Davis Peter David
Moffat David Festus Charles
Bernhardt Emily
Celltech R & D Limited
Woodcock & Washburn LLP
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