U.S. patent application number 11/090474 was filed with the patent office on 2005-08-04 for 4,5-disubstituted-2-aminopyrimidines.
This patent application is currently assigned to Celltech R&D Limited. Invention is credited to Davis, Jeremy Martin, Moffat, David Festus Charles.
Application Number | 20050171134 11/090474 |
Document ID | / |
Family ID | 10863085 |
Filed Date | 2005-08-04 |
United States Patent
Application |
20050171134 |
Kind Code |
A1 |
Davis, Jeremy Martin ; et
al. |
August 4, 2005 |
4,5-Disubstituted-2-aminopyrimidines
Abstract
Pyrimidines of formla (1) are described: 1 wherein R.sup.1 is a
--XR.sub.6 group; R.sup.2 and R.sup.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.sup.10 [where
R.sup.10 is an optionally substituted aliphatic, cycloaliphatic,
heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic
group) --SH, --NO.sub.2, --CN, --SR.sup.10, --COR.sup.10,
S(O)R.sup.10, --SO.sub.2R.sup.8, --SO.sub.2N(R.sup.8)(R.sup.9),
--CO.sub.2R.sup.8, --CON(R.sup.8)(R.sup.9),
--CSN(R.sup.8)(R.sup.9), --NH.sub.2 or substituted amino group;
R.sup.4 is a X.sup.1R.sup.11 group where X.sup.1 is a covalent bond
or a --C(R.sup.12)(R.sup.13)-- [where each of R.sup.12 and R.sup.13
is a hydrogen or halogen atom or a hydroxyl, alkyl or haloalkyl
group] or --C(O)-- group and R.sup.11 is an optionally substituted
phenyl, thienyl, thiazolyl or indolyl group; R.sup.5 is a halogen
atom or an alkynyl group; and the salts, solvates, hydrates and
N-oxides thereof. The compounds are selective KDR kinase and/or
FGFr kinase inhibitors and are of use in the prophylaxis and
treatment of disease states associated with angiogenesis
Inventors: |
Davis, Jeremy Martin;
(Wokingham, GB) ; Moffat, David Festus Charles;
(Maidenhead, GB) |
Correspondence
Address: |
WOODCOCK WASHBURN LLP
ONE LIBERTY PLACE, 46TH FLOOR
1650 MARKET STREET
PHILADELPHIA
PA
19103
US
|
Assignee: |
Celltech R&D Limited
|
Family ID: |
10863085 |
Appl. No.: |
11/090474 |
Filed: |
March 25, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11090474 |
Mar 25, 2005 |
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10873859 |
Jun 22, 2004 |
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10873859 |
Jun 22, 2004 |
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10457128 |
Jun 9, 2003 |
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10457128 |
Jun 9, 2003 |
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09692368 |
Oct 19, 2000 |
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6600037 |
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Current U.S.
Class: |
514/275 ;
544/329; 544/330 |
Current CPC
Class: |
A61P 9/14 20180101; A61P
35/00 20180101; C07D 239/42 20130101; C07D 231/12 20130101; A61P
27/02 20180101; A61P 29/00 20180101; C07D 401/12 20130101; A61P
17/06 20180101; C07D 233/56 20130101; C07D 249/08 20130101; A61P
43/00 20180101; A61P 9/00 20180101; A61P 9/10 20180101; A61K 31/505
20130101; C07D 403/12 20130101 |
Class at
Publication: |
514/275 ;
544/329; 544/330 |
International
Class: |
A61K 031/506; C07D
043/02 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 20, 1999 |
GB |
9924862.7 |
Claims
1. A compound of formula (1): 9wherein R.sup.1 is a --XR.sup.6
group; X is a covalent bond, --O--, --S--, --C(O)--, --C(S)--,
--C(O)O--, --S(O)--, S(O.sub.2)--, --CH.sub.2--, or --N(R.sup.7)--;
R.sup.7 is a hydrogen atom or a straight or branched alkyl groups;
R.sup.6 is a hydrogen or halogen atom or an optionally substituted
aliphatic, cycloaliphatic, heteroaliphatic, heterocycloaliphatic,
aromatic or heteroaromatic group, or a --NO.sub.2, --CN,
--SO.sub.2N(R.sup.8)(R.sup.9- ), --CON(R.sup.8)(R.sup.9),
--CSN(R.sup.8)(R.sup.9), --NH.sub.2 or substituted amino group;
R.sup.8 and R.sup.9, which may be the same or different, are a
hydrogen atom or an optionally substituted aliphatic,
cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or
heteroaromatic group; R.sup.2 and R.sup.3, which may be the same or
different, are each a hydrogen or halogen atom or a group selected
from an optionally substituted aliphatic, cycloaliphatic,
heteroaliphatic, heterocycloaliphatic, --OH, --OR.sup.10, --SH,
--NO.sub.2, --CN, --SR.sup.10, --COR.sup.10, --S(O)R.sup.10,
--SO.sub.2R.sup.8, --SO.sub.2N(R.sup.8)(R.sup.9),
--CO.sub.2R.sup.8, --CON(R.sup.8)(R.sup.9)- ,
--CSN(R.sup.8)(R.sup.9), --NH.sub.2 and a substituted amino group;
R.sup.10 is an optionally substituted aliphatic, cycloaliphatic,
heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic
group; R.sup.4 is a X.sup.1R.sup.11 group; X.sup.1 is a covalent
bond or a --C(R.sup.2)(R.sup.13)-- or --C(O)-- group; R.sup.12 and
R.sup.13 are each a hydrogen or halogen atom or a hydroxyl, alkyl
or haloalkyl group; R.sup.11 is an optionally substituted phenyl,
thienyl, thiazolyl or indolyl group; and R.sup.5 is a halogen atom
or an alkynyl group; and the salts, solvates, hydrates and N-oxides
thereof.
2. A compound according to claim 1 wherein R.sup.5 is a bromine or
chlorine atom.
3. A compound according to claim 1 wherein R.sup.4 is a
X.sup.1R.sup.11 group in which X.sup.1 is a covalent bond.
4. A compound according to claim 1 wherein R.sup.4 is a
X.sup.1R.sup.11 group; and R.sup.11 is a phenyl or substituted
phenyl group containing one, two, or three R.sup.17 substituents;
each R.sup.17 substituent is an atom or group R.sup.18 or
-Alk(R.sup.18).sub.m; R.sup.18 is a halogen atom, or an amino
(--NH.sub.2), --NHR.sup.19, --N(R.sup.19).sub.2 in which each
R.sup.19 group is the same or different, nitro, cyano, hydroxyl
(--OH), --OR.sup.19, formyl, carboxyl (--CO.sub.2H), esterified
carboxyl, thiol (--SH), --SR.sup.19, --COR.sup.19, --CSR.sup.19,
--SO.sub.3H, --SO.sub.2R.sup.19, --SO.sub.2NH.sub.2,
--SO.sub.2NHR.sup.19, SO.sub.2N[R.sup.19].sub.2, --CONH.sub.2,
--CSNH.sub.2, --CONHR.sup.9, --CSNHR.sup.9, --CON[R.sup.19].sub.2,
--CSN[R.sup.19].sub.2, --N(R.sup.14)SO.sub.2H,
--N(R.sup.14)SO.sub.2R.sup- .19, --N[SO.sub.2R.sup.19].sub.2,
--N(R.sup.14)SO.sub.2NH.sub.2, --N(R.sup.14)SO.sub.2NHR.sup.19,
--N(R.sup.14)SO.sub.2N[R.sup.19].sub.2, --N(R.sup.14)COR.sup.19,
--N(R.sup.14)CONH.sub.2, --N(R.sup.14)CONHR.sup.- 19,
--N(R.sup.14)CON[R.sup.19].sub.2, --N(R.sup.14)CSR.sup.19,
--N(R.sup.14)CSNH.sub.2, --N(R.sup.14)CSNHR.sup.19,
--N(R.sup.14)CSN[R.sup.19].sub.2, or --N(R.sup.14)C(O)OR.sup.19
group, or an optionally substituted cycloaliphatic,
heterocycloaliphatic, aryl or heteroaryl group; R.sup.19 is an
-Alk(R.sup.18).sub.m, heterocycloaliphatic,
-Alk-heterocycloaliphatic, aryl or heteroaryl group; R.sup.14 is a
hydrogen atom or a C.sub.1-6alkyl group; Alk is a straight or
branched C.sub.1-6 alkylene, C.sub.2-6 alkenylene or C.sub.2-6
alkynylene chain, optionally interrupted by one, two or three --O--
or --S-- atoms or --S(O)--, --S(O).sub.2-- or --N(R.sup.14)--
groups; and m is zero or an integer 1, 2 or 3.
5. A compound according to claim 1 wherein one or both of R.sup.2
and R.sup.3 are a hydrogen atom.
6. (canceled)
7. A compound according to claim 1 wherein R.sup.1 is a group
-(Alk.sup.2).sub.pNH.sub.2, -(Alk.sup.2).sub.pNR.sup.15R.sup.16,
(-Alk.sup.2).sub.pNHet.sup.2, -(Alk.sup.2).sub.pOH or
-(Alk.sup.2).sub.pAr; Alk.sup.2 is a straight or branched
C.sub.1-6alkylene, C.sub.2-6alkenylene or C.sub.2-6alkynylene
chain, optionally substituted by one, two or three --O-- or --S--
atoms or --S(O)--, --S(O).sub.2-- or --N(R.sup.14)-- groups;
R.sup.14 is a hydrogen atom or a C.sub.1-6alkyl group; p is zero or
an integer 1; R.sup.15 is an optionally substituted C.sub.1-6alkyl,
C.sub.2-6alkenyl or C.sub.2-6alkynyl group optionally interrupted
by an --O-- or --S-- atom or a --C(O)--, --C(S)--, --S(O)--,
--S(O).sub.2--, --N(R.sup.14)--, --CON(R.sup.14)--,
--OC(O)N(R.sup.14)--, --CSN(R.sup.14)--, --N(R.sup.14)CO--,
--N(R.sup.14)C(O)O--, --N(R.sup.14)CS--, --SON(R.sup.14)--,
--SO.sub.2N(R.sup.14)--, --N(R.sup.14)SO.sub.2--,
--N(R.sup.14)CON(R.sup.14)--, --N(R.sup.14)CSN(R.sup.14)--,
--N(R.sup.14)SON(R.sup.14)-- or --N(R.sup.14)SO.sub.2N(R.sup.14)--
group; R.sup.16 is a hydrogen atom or R.sup.15; --NHet.sup.2 is an
optionally substituted pyrrolidinyl, imidazolidinyl, pyrazolidinyl,
piperidinyl, morpholinyl, piperazinyl or thiomorpholinyl group, and
Ar is a nitrogen-containing heteraromatic group.
8. A compound according to claim 7 wherein R.sup.1 is a group
-Alk.sup.2NH.sub.2, -Alk.sup.2NR.sup.15R.sup.16,
-(Alk.sup.2).sub.pNHet.s- up.2, -Alk.sub.2OH or -Alk.sup.2Ar;
--NHet.sup.2 is an optionally substituted pyrrolidinyl,
piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl group; and
Ar is an optionally substituted imidazolyl or benzimidazolyl
group.
9. A compound of formula (1a): 10wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 is are each as defined in claim 1.
10. (canceled)
11. A pharmaceutical composition comprising a compound according to
claim 1 together with one or more pharmaceutically acceptable
carriers, excipients or diluents.
Description
[0001] This invention relates to certain
4,5-disubstituted-2-aminopyrimidi- nes, to processes for their
preparation, to pharmaceutical compositions containing them, and to
their use in medicine.
[0002] 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).
[0003] 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).
[0004] 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.
[0005] 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
.alpha. and .beta. 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.beta. and EGFr may also have some role in mediating
angiogenesis.
[0006] 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.
[0007] Thus, according to one aspect of the invention, we provide a
compound of formula (1): 2
[0008] wherein R.sup.1 is a --XR.sup.8 group [where X is a covalent
bond, --O--, --S--, --C(O)--, --C(S)--, --C(O)O--, --S(O)--,
--S(O.sub.2)--, --CH.sub.2--, -or N(R.sup.7)-- (where R.sup.7 is a
hydrogen atom or a straight or branched alkyl group] and R.sup.6 is
a hydrogen or halogen atom or an optionally substituted aliphatic,
cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or
heteroaromatic group, or a --NO.sub.2, --CN,
--SO.sub.2N(R.sup.8)(R.sup.9) (where R.sup.8 and R.sup.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.sup.8)(R.sup.9), --CSN(R.sup.8)(R.sup.9), --NH.sub.2 or
substituted amino group;
[0009] R.sup.2 and R.sup.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.sup.10 [where R.sup.10 is an
optionally substituted aliphatic, cycloaliphatic, heteroaliphatic,
heterocycloaliphatic, aromatic or heteroaromatic group] --SH,
--NO.sub.2, --CN, --SR.sup.10, --COR.sup.10, S(O)R.sup.10,
--SO.sub.2R.sup.8, --SO.sub.2N(R.sup.8)(R.sup.9),
--CO.sub.2R.sup.8, --CON(R.sup.8)(R.sup.9)- ,
--CSN(R.sup.8)(R.sup.9), --NH.sub.2 or substituted amino group;
[0010] R.sup.4 is a X.sup.1R.sup.11 group where X.sup.1 is a
covalent bond or a --C(R.sup.12)(R.sup.13)-- [where each of
R.sup.12 and R.sup.13 is a hydrogen or halogen atom or a hydroxyl,
alkyl or haloalkyl group] or --C(O)-- group and R.sup.11 is an
optionally substituted phenyl, thienyl, thiazolyl or indolyl
group;
[0011] R.sup.5 is a halogen atom or an alkynyl group;
[0012] and the salts, solvates, hydrates and N-oxides thereof.
[0013] In the compounds of formula (1), the term "optionally
substituted aliphatic group" when applied to each of the groups
R.sup.2, R.sup.3, R.sup.6 and R.sup.10 means each of these groups
may independently be for example an optionally substituted C.sub.10
aliphatic group, for example an optionally substituted straight or
branched chain C.sub.1-6 alkyl, e.g. C.sub.1-3 alkyl, C.sub.2-6
alkenyl, e.g. C.sub.2-4 alkenyl, or C.sub.2-6 alkynyl, e.g.
C.sub.2-4 alkynyl group. Each of said groups may be optionally
interrupted by one or two heteroatoms or heteroatom-containing
groups represented by X.sup.2 [where X.sup.2 is an --O-- or --S--
atom or a --C(O)--, --C(S)--, --S(O)--, --S(O).sub.2--,
--N(R.sup.14)-- [where R.sup.14 is a hydrogen atom or a C.sub.1-6
alkyl, e.g. methyl or ethyl, group], --CON(R.sup.14)--,
--OC(O)N(R.sup.14)--, --CSN(R.sup.14)--, --N(R.sup.14)CO--,
--N(R.sup.14)C(O)O--, --N(R.sup.14)CS--, --SON(R.sup.14),
--SO.sub.2N(R.sup.14), --N(R.sup.14)SO.sub.2--,
--N(R.sup.14)CON(R.sup.14)--, --N(R.sup.14)CSN(R.sup.14)--,
--N(R.sup.14)SON(R.sup.14)-- or --N(R.sup.14)SO.sub.2N(R.sup.14)
group] to form an optionally substituted R.sup.2, R.sup.3, R.sup.6
and R.sup.10 heteroaliphatic group.
[0014] Particular examples of aliphatic groups represented by
R.sup.2, R.sup.3, R.sup.6 and/or R.sup.10 include optionally
substituted --CH.sub.3, --CH.sub.2CH.sub.3,
--(CH.sub.2).sub.2CH.sub.3, --CH(CH.sub.3).sub.2,
--(CH.sub.2).sub.3CH.sub.3, --CH(CH.sub.3)CH.sub.2C- H.sub.3,
--CH.sub.2CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.3,
--(CH.sub.2).sub.4CH.sub.3, --(CH.sub.2).sub.5CH.sub.3,
--CHCH.sub.2, --CHCHCH.sub.3, --CH.sub.2CHCH.sub.2,
--CHCHCH.sub.2CH.sub.3, --CH.sub.2CHCHCH.sub.3,
--(CH.sub.2).sub.2CHCH.sub.2, --CCH, --CCCH.sub.3, --CH.sub.2CCH,
--CCCH.sub.2CH.sub.3, --CH.sub.2CCCH.sub.3, or
--(CH.sub.2).sub.2CCH groups. Where appropriate each of said groups
may be optionally interrupted by one or two atoms and/or groups
X.sup.2 to form an optionally substituted heteroaliphatic group.
Particular examples include --CH.sub.2X.sup.2CH.sub.3,
--CH.sub.2X.sup.2CH.sub.2CH.s- ub.3,
--(CH.sub.2).sub.2X.sup.2CH.sub.3 and
--(CH.sub.2).sub.2X.sup.2CH.su- b.2CH.sub.3 groups.
[0015] 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.sub.1-6 alkoxy,
e.g. methoxy or ethoxy, thiol, C.sub.1-6 alkylthio e.g. methylthio
or ethylthio, --SC(NH)NH.sub.2, --CH.sub.2C(NH)NH.sub.2, amino,
substituted amino, cyclic amino or heteroaromatic groups.
[0016] Substituted amino groups include for example groups of
formulae --NR.sup.15R.sup.16 [where R.sup.15 is an optionally
substituted C.sub.1 alkyl, C.sub.2-6alkenyl or C.sub.2-6alkynyl
group optionally interrupted by one or two heteroatoms or
heteroatom-containing groups represented by X.sup.3 (where X.sup.3
is an atom or group as described above for X.sup.2) and R.sup.16 is
a hydrogen atom or is a group as just defined for R.sup.15],
--N(R.sup.16)COR.sup.15, --N(R.sup.16)CSR.sup.15,
--N(R.sup.16)SOR.sup.15, --N(R.sup.16)SO.sub.2R.sup.15,
--N(R.sup.16)CONH.sub.2, --N(R.sup.16)CONR.sup.15R.sup.16,
--N(R.sup.16)C(O)OR.sup.15, --N(R.sup.16)C(NH)NH.sub.2,
--N(R.sup.16)C(NH)NR.sup.15R.sup.16, --N(R.sup.16)CSNH.sub.2,
--N(R.sup.16)CSNR.sup.15R.sup.16, --N(R.sup.16)SONH.sub.2,
--N(R.sup.16)SONR.sup.15R.sup.16, --N(R.sup.18)SO.sub.2NH.sub.2,
--N(R.sup.16)SO.sub.2NR.sup.15R.sup.16, or --N(R.sup.18)Cyc.sup.1
[where Cyc.sup.1 is an optionally substituted C.sub.3-7 monocyclic
carbocyclic group optionally containing one or more --O-- or --S--
atoms or --N(R.sup.14)--, --C(O)--, --C(S)--, --S(O)-- or
--S(O.sub.2)-- groups].
[0017] Cyclic amino substituents which may be present on R.sup.2,
R.sup.3, R.sup.6 and/or R.sup.10 aliphatic or heteroaliphatic
groups include groups of formula --NHet.sup.1, where --NHet.sup.1
is an optionally substituted C.sub.3-7 cyclic amino group
optionally containing one or more other heteroatoms or heteroatom
containing groups selected from --O-- or --S-- atoms
--N(R.sup.14)--, --C(O), --C(S)--, --S(O)-- or --S(O.sub.2)--
groups.
[0018] Particular examples of amino, substituted amino and cyclic
amino groups include --NH.sub.2, methylamino, ethylamino,
dimethylamino, diethylamino, --NHCyc.sup.1 where Cyc.sup.1 is an,
optionally substituted cyclopentyl, cyclohexyl, pyrrolidinyl,
imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl,
piperazinyl or thiomorpholinyl group, or --NHet.sup.1 where
--NHet.sup.1 is an optionally substituted pyrrolidinyl,
imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl,
piperazinyl or thiomorpholinyl group. Optional substituents which
may be present on these groups and substituted and cyclic amino
groups in general include one, two or three halogen atoms, e.g.
fluorine, chlorine, bromine or iodine atoms, or C.sub.1-4alkyl,
e.g. methyl or ethyl, hydroxyl, C.sub.1-4alkoxy, e.g. methoxy or
ethoxy or pyridyl groups.
[0019] Optional heteroaromatic substituents which may be present on
the aliphatic or heteroaliphatic groups represented by R.sup.2,
R.sup.3, R.sup.6 and/or R.sup.10 include those heteroaromatic
groups described below in relation to R.sup.2, R.sup.3, R.sup.6 and
R.sup.10.
[0020] When R.sup.2, R.sup.3, R.sup.6 and/or R.sup.10 is present in
compounds of formula (1) as an optionally substituted
cycloaliphatic group it may be an optionally substituted C.sub.3-10
cycloaliphatic group. Particular examples include optionally
substituted C.sub.3-10 cycloalkyl, e.g. C.sub.3-7cycloalkyl, or
C.sub.3-10 cycloalkenyl e.g. C.sub.3-7cycloalkenyl groups.
[0021] Heteroaliphatic or heterocycloaliphatic groups represented
by R.sup.2, R.sup.3, R.sup.6 and/or R.sup.10 include the aliphatic
or cycloaliphatic groups just described for these substituents but
with each group additionally containing one, two, three or four
heteroatoms or heteroatom containing groups represented by X.sup.2,
where X.sup.2 is as described above.
[0022] Particular examples of R.sup.2, R.sup.3, R.sup.6 and/or
R.sup.10 cycloaliphatic and heterocycloaliphatic groups include
optionally substituted cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, 2-cyclobuten-1-yl, 2-cyclopenten-1-yl,
3-cyclopenten-1-yl, 2,4-cyclopentadien-1-yl,
3,5,-cyclohexadien-1-yl, tetrahydrofuranyl, pyrroline, e.g. 2- or
3-pyrrolinyl, pyrrolidinyl, dioxolanyl, e.g. 1,3-dioxolanyl,
imidazolinyl, e.g. 2-imidazolinyl, imidazolidinyl, pyrazolinyl,
e.g. 2-pyrazolinyl, pyrazolidinyl, pyranyl, e.g. 2- or 4-pyranyl,
piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl,
thiomorpholinyl, piperazinyl, 1,3,5-trithianyl, oxazinyl, e.g.
2H-1,3-, 6H-1,3-, 6H-1,2-, 2H-1,2- or 4H-1,4-oxazinyl,
1,2,5-oxathiazinyl, isoxazinyl, oxathiazinyl, e.g. 1,2,5 or
1,2,6-oxathiazinyl, or 1,3,5-oxadiazinyl groups.
[0023] Optional substituents which may be present on R.sup.2,
R.sup.3, R.sup.6 and/or R.sup.10 cycloaliphatic and
heterocycloaliphatic groups include those optional substituents
described above for R.sup.6 when it is an aliphatic group. The
heterocycloaliphatic groups may be attached to the remainder of the
molecule of formula (1) through any appropriate ring carbon or
heteroatom.
[0024] When R.sup.2, R.sup.3, R.sup.6 and/or R.sup.10 is present as
an aromatic group in compounds of formula (1) it may be for example
an optionally substituted monocyclic or bicyclic fused ring
C.sub.6-12 aromatic group, such as an optionally substituted
phenyl, 1- or 2-naphthyl, 1- or 2-tetrahydronaphthyl, indanyl or
indenyl group.
[0025] Heteroaromatic groups represented by R.sup.2, R.sup.3,
R.sup.6 and/or R.sup.10 include optionally substituted C.sub.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.
[0026] Examples of heteroaromatic groups represented by R.sup.2,
R.sup.3, R.sup.6 and/or R.sup.10 include optionally substituted
pyrrolyl, furyl, thienyl, imidazolyl, N-methylimidazolyl,
N-ethyl-imidazolyl, 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,
[2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl,
benzotriazolyl, isobenzothienyl, indolyl, isoindolyl,
benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl,
benzoxazolyl, benzopyranyl, [3,4-dihydro]benzopyranyl,
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,
5,6,7,8-tetrahydro-isoquinolinyl, and imidyl, e.g. succinimidyl,
phthalimidyl, or naphthalimidyl such as 1,8-naphthalimidyl.
[0027] Optional substituents which may be present on any of the
just described aromatic or heteroaromatic groups include one, two,
three or more substituents, each represented by the group R.sup.17
as more particularly defined below in relation to the phenyl
substituent R.sup.11.
[0028] Substituted amino groups represented by the groups R.sup.1,
R.sup.2 and/or R.sup.3 in compounds of formula (1) include for
example the groups --NR.sup.15R.sup.16, --N(R.sup.16)COR.sup.15,
--N(R.sup.16)CSR.sup.15, --N(R.sup.16)SOR.sup.15,
--N(R.sup.16)SO.sub.2R.sup.15, --N(R.sup.16)CONH.sub.2,
--N(R.sup.16)CONR.sup.15R.sup.16, --N(R.sup.16)C(O)OR.sup.15,
--N(R.sup.16)C(NH)NH.sub.2, --N(R.sup.16)C(NH)NR.sup.15R.sup.16,
--N(R.sup.16)CSNH.sub.2, --N(R.sup.16)CSNR.sup.15R.sup.16,
--N(R.sup.16)SONH.sub.2, --N(R.sup.16)SONR.sup.15R.sup.16,
--N(R.sup.16)SO.sub.2NH.sub.2,
--N(R.sup.16)SO.sub.2NR.sup.15R.sup.16, --N(R.sup.16)Cyc.sup.1
where R.sup.15, R.sup.15 and Cyc.sup.1 are as defined above.
[0029] Halogen atoms represented by the group R.sup.5 in compounds
of the invention include fluorine, chlorine, bromine and iodine
atoms. Alkynyl groups represented by R.sup.5 include --CCH and
CCCH.sub.3 groups.
[0030] The group R.sup.11 in compounds of formula (1) may be a
phenyl or substituted phenyl group. The substituted phenyl group
may contain one, two, three or more substituents, each represented
by the group R.sup.17.
[0031] The substituent R.sup.17 may be selected from an atom or
group R.sup.18 or -Alk(R.sup.18).sub.m, where R.sup.18 is a halogen
atom, or an amino (--NH.sub.2), --NHR.sup.19 [where R.sup.19 is an
-Alk(R.sup.18).sub.m, heterocycloaliphatic,
-Alk-heterocycloaliphatic, aryl or heteroaryl group],
--N(R.sup.19).sub.2 [where each R.sup.19 group is the same or
different], nitro, cyano, hydroxyl (--OH), --OR.sup.19, formyl,
carboxyl (--CO.sub.2H), esterified carboxyl, thiol (--SH),
--SR.sup.19, --COR.sup.19, --CSR.sup.19, --SO.sub.3H,
--SO.sub.2R.sup.19, --SO.sub.2NH.sub.2, --SO.sub.2NHR.sup.19,
SO.sub.2N[R.sup.19].sub.2, --CONH.sub.2, --CSNH.sub.2,
--CONHR.sup.19, --CSNHR.sup.19, --CON[R.sup.19].sub.2,
--CSN[R.sup.19].sub.2, --N(R.sup.14)SO.sub.2H [where R.sup.14 is as
defined above], --N(R.sup.14)SO.sub.2R.sup.19,
--N[SO.sub.2R.sup.19].sub.2, --N(R.sup.14)SO.sub.2NH.sub.2,
--N(R.sup.14)SO.sub.2NHR.sup.19,
--N(R.sup.14)SO.sub.2N[R.sup.19].sub.2, --N(R.sup.14)COR.sup.19,
--N(R.sup.14)CONH.sub.2, --N(R.sup.14)CONHR.sup.- 19,
--N(R.sup.14)CON[R.sup.19].sub.2, --N(R.sup.14)CSR.sup.19,
--N(R.sup.14)CSNH.sub.2, --N(R.sup.14)CSNHR.sup.19,
--N(R.sup.14)CSN[R.sup.19].sub.2, --N(R.sup.14)C(O)OR.sup.19, or an
optionally substituted cycloaliphatic, heterocycloaliphatic, aryl
or heteroaryl group; Alk is a straight or branched C.sub.1-6
alkylene, C.sub.2-6 alkenylene or C.sub.2-6 alkynylene chain,
optionally interrupted by one, two or three --O-- or --S-atoms or
S(O)--, --S(O).sub.2-- or --N(R.sup.14)-- groups; and m is zero or
an integer 1, 2 or 3.
[0032] When in the group -Alk(R.sup.18).sub.m m is an integer 1, 2
or 3, it is to be understood that the substituent or substituents
R.sup.18 may be present on any suitable carbon atom in -Alk. Where
more than one R.sup.18 substituent is present these may be the same
or different and may be present on the same or different atom in
-Alk or in R.sup.17 as appropriate. Thus for example, R.sup.17 may
represent a --CH(R.sup.18).sub.2 group, such as a --CH(OH)Ar group
where Ar is an aryl or heteroaryl group as defined below. Clearly,
when m is zero and no substituent R.sup.18 is present the alkylene,
alkenylene or alkynylene chain represented by Alk becomes an alkyl,
alkenyl or alkynyl group.
[0033] When R.sup.18 is a halogen atom it may be for example a
fluorine, chlorine, bromine, or iodine atom.
[0034] Esterified carboxyl groups represented by the group R.sup.18
include groups of formula --CO.sub.2Alk.sup.1 wherein Alk.sup.1 is
a straight or branched, optionally substituted C.sub.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.sub.6-12arylC.sub.1-18alkyl
group such as an optionally substituted benzyl, phenylethyl,
phenylpropyl, 1-naphthyl-methyl or 2-naphthylmethyl group; a
C.sub.6-12aryl group such as an optionally substituted phenyl,
1-naphthyl or 2-naphthyl group; a C.sub.6-12aryloxyC.sub.1-8alkyl
group such as an optionally substituted phenyloxymethyl,
phenyloxyethyl, 1-naphthyloxymethyl, or 2-naphthyloxymethyl group;
an optionally substituted C.sub.1-8alkanoyloxyC.sub.1-8alkyl group,
such as a pivaloyloxymethyl, propionyloxyethyl or
propionyloxypropyl group; or a C.sub.6-12aroyloxyC.sub.1-8alkyl
group such as an optionally substituted benzoyloxyethyl or
benzoyloxypropyl group. Optional substituents present on the
Alk.sup.1 group include R.sup.18 substituents described above.
[0035] When Alk is present in or as a substituent R.sup.17 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).sub.2-- or --N(R.sup.14)-- groups.
[0036] When R.sup.18 is present in compounds of formula (1) as an
optionally substituted cycloaliphatic group it may be an optionally
substituted C.sub.3-10 cycloaliphatic group. Particular examples
include optionally substituted C.sub.3-10cycloalkyl, e.g.
C.sub.3-7cycloalkyl, or C.sub.3-10cycloalkenyl e.g.
C.sub.3-7cycloalkenyl groups.
[0037] Heterocycloaliphatic groups represented by R.sup.19 and when
present R.sup.19 include the cycloaliphatic groups just described
for R.sup.18 but with each group additionally containing one, two,
three or four heteroatoms or heteroatom-containing groups selected
from --O-- or --S-- atoms or --N(R.sup.14)--, --C(O), --C(S)--,
--S(O)-- or --S(O.sub.2)-- groups.
[0038] Particular examples of R.sup.18 cycloaliphatic and R.sup.18
or R.sup.19 heterocyclo-aliphatic groups include optionally
substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, 2-cyclobuten-1-yl, 2-cyclopenten-1-yl,
3-cyclopenten-1-yl, 2,4-cyclopentadien-1-yl,
3,5,-cyclohexadien-1-yl, tetrahydrofuranyl, pyrroline, e.g. 2- or
3-pyrrolinyl, pyrrolidinyl, dioxolanyl, e.g. 1,3-dioxolanyl,
imidazolinyl, e.g. 2-imidazolinyl, imidazolidinyl, pyrazolinyl,
e.g. 2-pyrazolinyl, pyrazolidinyl, pyranyl, e.g. 2- or 4-pyranyl,
piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl,
thiomorpholinyl, piperazinyl, 1,3,5-trithianyl, oxazinyl, e.g.
2H-1,3-, 6H-1,3-, 6H-1,2-, 2H-1,2- or 4H-1,4-oxazinyl,
1,2,5-oxathiazinyl, isoxazinyl, oxathiazinyl, e.g. 1,2,5 or
1,2,6-oxathiazinyl, or 1,3,5-oxadiazinyl groups.
[0039] Optional substituents which may be present on R.sup.18
cycloaliphatic and R.sup.18 or R.sup.19 heterocycloaliphatic groups
include one, two, three or more substituents selected from halogen
atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or
hydroxyl, C.sub.1-6alkoxy, e.g. methoxy or ethoxy, thiol,
C.sub.1-6alkylthio, e.g. methylthio or ethylthio, hydroxy,
C.sub.1-6alkyl, e.g. hydroxymethyl, hydroxyethyl, --CN, --NO.sub.2,
--NHR.sup.14 or --N(R.sup.14).sub.2 groups.
[0040] Aryl and heteroaryl groups represented by the group R.sup.18
or Ar include for example optionally substituted monocyclic or
bicyclic C.sub.6-12 aromatic groups, e.g. phenyl groups, or
C.sub.1-9 heteroaromatic groups such as those described above in
relation to the group R.sup.6. Optional substituents which may be
present on these groups include one, two or three R.sup.18a atoms
or groups described below.
[0041] Particularly useful atoms or groups represented by R.sup.18,
-Alk(R.sup.18).sub.m or R.sup.18a as appropriate include fluorine,
chlorine, bromine or iodine atoms, or C.sub.1-6alkyl, e.g. methyl
or ethyl, C.sub.1-6alkylamino, e.g. methylamino or ethylamino,
C.sub.1-6hydroxyalkyl, e.g. hydroxymethyl or hydroxyethyl,
C.sub.1-6alkylthiol e.g. methylthiol or ethylthiol,
C.sub.1-6alkoxy, e.g. methoxy or ethoxy, C.sub.5-7cycloalkoxy, e.g.
cyclopentyloxy, haloC.sub.1-6alkyl, e.g. trifluoromethyl,
C.sub.1-6alkylamino, e.g. methylamino or ethylamino, amino
(--NH.sub.2), aminoC.sub.1-6alkyl, e.g. aminomethyl or aminoethyl,
C.sub.1-6dialkylamino, e.g. dimethylamino or diethylamino, imido,
such as phthalimido or naphthalimido, e.g. 1,8-naphthalimido,
1,1,3-trioxo-benzo[d]-thiazolidino, nitro, cyano, hydroxyl (--OH),
formyl [HC(O)--], carboxyl (--CO.sub.2H), --CO.sub.2Alk.sup.1
[where Alk.sup.1 is as defined above], C.sub.1-6 alkanoyl e.g.
acetyl, thiol (--SH), thioC.sub.1-6alkyl, e.g. thiomethyl or
thioethyl, --SC(NH.sub.2+)NH.sub.2, sulphonyl (--SO.sub.3H),
C.sub.1-6alkylsulphonyl, e.g. methylsulphonyl, aminosulphonyl
(--SO.sub.2NH.sub.2), C.sub.1-6alkylaminosulphonyl, e.g.
methylaminosulphonyl or ethylaminosulphonyl,
C.sub.1-6dialkylaminosulphon- yl, e.g. dimethylamino-sulphonyl or
diethylaminosulphonyl, phenylaminosulphonyl, carboxamido
(--CONH.sub.2), C.sub.1-6alkylaminocarb- onyl, e.g.
methylaminocarbonyl or ethylaminocarbonyl,
C.sub.1-6dialkylaminocarbonyl, e.g. dimethylaminocarbonyl or
diethylaminocarbonyl, sulphonylamino (--NHSO.sub.2H),
C.sub.1-6alkylsulphonylamino, e.g. methylsulphonylamino or
ethylsulphonylamino, C.sub.1-6dialkylsulphonylamino, e.g.
dimethylsulphonylamino or diethylsulphonylamino, optionally
substituted phenylsulphonylamino, e.g. 2-, 3- or 4-substituted
phenylsulphonylamino such as 2-nitrophenylsulphonylamino,
aminosulphonylamino (--NHSO.sub.2NH.sub.2),
C.sub.1-6alkylaminosulphonylamino, e.g. methylaminosulphonylamino
or ethylaminosulphonylamino, C.sub.1-6dialkylaminosulphonylamino,
e.g. dimethylaminosulphonylamino or diethylaminosulphonylamino,
phenylaminosulphonylamino, aminocarbonylamino,
C.sub.1-6alkylaminocarbonylamino e.g. methylaminocarbonylamino or
ethylaminocarbonylamino, C.sub.1-6dialkylaminocarbonylamino, e.g.
dimethylamino carbonylamino or diethylaminocarbonylamino,
phenylaminocarbonylamino, C.sub.1-6alkanoylamino, e.g. acetylamino,
optionally substituted phenylcarbonylamino,
C.sub.1-8alkanoylaminoC.sub.1-6alkyl, e.g. acetylaminomethyl,
C.sub.1-6 alkoxycarbonylamino, e.g. methoxycarbonylamino,
ethoxycarbonylamino or t-butoxycarbonylamino, optionally
substituted heteroC.sub.3-6cycloalkyl, e.g. piperidinyl,
piperazinyl, 4-(C.sub.1-6alkyl)piperazinyl, e.g.
4-methylpiperazinyl, homopipeprazinyl, or morpholinyl, optionally
substituted heteroC.sub.3-6cycloalkylC.sub.1-6alkyl, e.g.
piperidinylC.sub.1-6alkyl, piperazinylC.sub.1-6alkyl,
4-(C.sub.1-6alkyl)piperazinylC.sub.1-6alkyl, e.g.
4-methylpiperazinylmethyl, or morpholinylC.sub.1-6alky), optionally
substituted heteroC.sub.3-6alkylC.sub.1-6alkylamino, optionally
substituted heteroC.sub.3-6cycloalkylamino, tetrazolyl, optionally
substituted imidazolylC.sub.1-6alkyl, optionally substituted
phenylamino, optionally substituted benzylamino, optionally
substituted benzyloxy, or optionally substituted pyridylmethylamino
group.
[0042] Where desired, two R.sup.18 or -Alk(R.sup.18).sub.m or
R.sup.18a substituents may be linked together to form a cyclic
group such as a cyclic ether, e.g. a C.sub.2-6alkylenedioxy group
such as ethylenedioxy.
[0043] It will be appreciated that where two or more R.sup.18,
-Alk(R.sup.18).sub.m or R.sup.18a substituents are present, these
need not necessarily be the same atoms and/or groups.
[0044] Especially useful R.sup.18, -Alk(R.sup.18).sub.m or
R.sup.18a substituents include for example fluorine, chlorine,
bromine or iodine atoms, or a methylamino, ethylamino,
hydroxymethyl, hydroxyethyl, methylthiol, ethylthiol, methoxy,
ethoxy, n-propoxy, 2-hydroxyethoxy, 3-hydroxypropoxy,
4-hydroxybutoxy, 2-aminoethoxy, 3-aminopropoxy,
2-(methylamino)ethoxy, 2-(dimethylamino)ethoxy,
3-(dimethylamino)propoxy, cyclopentyloxy, cyclohexyl,
cyclohexylamino, 2-hydroxycyclohexylamino, trifluoromethyl,
trifluoromethoxy, methylamino, ethylamino, amino (--NH).sub.2,
aminomethyl, aminoethyl, dimethylamino, diethylamino,
ethyl(methyl)amino, propyl(methyl)amino, 2-hydroxyethylamino,
3-hydroxypropylamino, 4-hydroxybutylamino, 2-aminoethylamino,
3-aminopropylamino, 4-aminobutylamino, 2-(methylamino)ethylamino,
2-(ethylamino)ethylamino, 2-(i-propylamino)ethylamino,
3-(i-propylamino)-propylamino, 2-(dimethylamino)ethylamino,
3-(dimethylamino)propylamino, 2-(diethylamino)ethylamino,
3-(diethylamino)propylamino, 2-(methylamino)-ethyl(methyl)amino,
3-(methylamino)propyl(methyl)amino,
2-(dimethylamino)ethyl(methyl)amino,
2-(dimethylamino)ethyl(ethyl)amino, nitro, cyano, hydroxyl (--OH),
formyl [HC(O)--], carboxyl (--CO.sub.2H), --CH.sub.2CO.sub.2H,
--OCH.sub.2CO.sub.2H, --CO.sub.2CH.sub.3,
--CO.sub.2CH.sub.2CH.sub.3, --CH.sub.2CO.sub.2CH.sub.3,
--CH.sub.2CO.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CO.sub.2CH.sub.2phenyl, t-butoxycarbonylmethoxy, acetyl,
phenacetyl, thio (--SH), thiomethyl, thioethyl, --SC(NH)NH.sub.2,
sulphonyl (--SO.sub.2H), methylsulphonyl, methylaminosulphonyl,
ethylaminosulphonyl, dimethylaminosulphonyl, diethylaminosulphonyl,
carboxamido (--CONH.sub.2), methylaminocarbonyl,
ethylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl,
methylaminocarbonylmethyl, --NHC(S)NH.sub.2, sulphonylamino
(--NHSO.sub.2H), methylsulphonylamino ethylsulphonylamino,
dimethylsulphonylamino, diethylsulphonylamino, sulphonylamino
(--NHSO.sub.2NH.sub.2), methylaminosulphonylamino,
ethylaminosulphonylamino, dimethylaminosulphonylamino,
diethylaminosulphonylamino, methylaminocarbonylamino,
ethylaminocarbonylamino, dimethylaminocarbonylamino
diethylaminocarbonylamino, acetylamino, phenylcarbonylamino,
aminomethylcarbonylamino, acetylaminomethyl, methoxycarbonylamino,
ethoxycarbonylamino, t-butoxycarbonylamino, pyrrolidinyl,
piperidinyl, piperazinyl, 4-methylpiperazinyl, homopiperazinyl,
morpholinyl, pyrrolidinylC.sub.1-6alkyl, piperidinylC.sub.1-6alkyl,
piperazinylC.sub.1-6alkyl,
4-(C.sub.1-6alkyl)piperazinylC.sub.1-6akyl,
morpholinylC.sub.1-6alkyl, 2-pyrrolidinylethylamino,
2-(1-methylpyrrolidinyl)-ethylamino,
1-ethylpyrrolidinylmethylamino, piperidinylamino,
1-benzylpiperidinylamino, imidazolylmethyl, imidazolylethyl,
4-(methoxy)phenylamino, 4-(3-hydroxypropyl)phenylamino,
benzylamino, benzyloxy or pyridiylmethylamino group.
[0045] When X.sup.1 is present in compounds of the invention as a
--(R.sup.12)(R.sup.13)-- group it may be for example a --CH.sub.2--
or --C(R.sup.12)(R.sup.13)-- group in which R.sup.12 and/or
R.sup.13 is each a halogen atom such as a fluorine or chlorine atom
or a hydroxy, C.sub.1-6alkyl e.g. methyl, ethyl or i-propyl, or
C.sub.1-6haloalkyl, e.g. trihalomethyl such as a trifluoromethyl
group. Particular examples of such --C(R.sup.12)(R.sup.13)-- groups
include --CHF--, --CH(CH.sub.3)--, --C(OH)(CF.sub.3)-- and
--CH(CF.sub.3)-- groups.
[0046] The presence of certain substituents in the compounds of
formula (1) may enable salts of the compounds to be formed.
Suitable salts include pharmaceutically acceptable salts, for
example acid addition salts derived from inorganic or organic
acids, and salts derived from inorganic and organic bases.
[0047] Acid addition salts include hydrochlorides, hydrobromides,
hydroiodides, alkylsulphonates, e.g. methanesulphonates,
ethanesulphonates, or isethionates, arylsulphonates, e.g.
p-toluenesulphonates, besylates or napsylates, phosphates,
sulphates, hydrogen sulphates, acetates, trifluoroacetates,
propionates, citrates, maleates, fumarates, malonates, succinates,
lactates, oxalates, tartrates and benzoates.
[0048] Salts derived from inorganic or organic bases include alkali
metal salts such as sodium or potassium salts, alkaline earth metal
salts such as magnesium or calcium salts, and organic amine salts
such as morpholine, piperidine, piperazine, dimethylamine or
diethylamine salts.
[0049] Particularly useful salts of compounds according to the
invention include pharmaceutically acceptable salts, especially
acid addition pharmaceutically acceptable salts.
[0050] It will be appreciated that depending on the nature of the
substituents R.sup.1, R.sup.2, R.sup.3 and R.sup.4 the compounds of
formula (1) may exist as tautomers and/or geometrical isomers
and/or may have one or more chiral centres so that enantiomers or
diasteromers may exist. It is to be understood that the invention
extends to all such tautomers and isomers of the compounds of
formula (1), and to mixtures thereof, including racemates.
[0051] In the compounds according to the invention the group
R.sup.4 is preferably a group X.sup.1R.sup.11 in which X.sup.1 is a
covalent bond.
[0052] The group R.sup.5 in compounds of the invention is in
particular a bromine or, especially a chlorine atom.
[0053] A particularly useful group of compounds according to the
invention has the formula (1a): 3
[0054] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are
as defined for formula (1).
[0055] One particular class of compounds of formulae (1) and (1a)
is that wherein one or both of R.sup.2 and R.sup.3 is a hydrogen
atom. Compounds in which R.sup.2 and R.sup.3 is each a hydrogen
atom are especially useful.
[0056] In compounds of this class R.sup.1 is in particular a group
-(Alk.sup.2).sub.pNH.sub.2 (where Alk.sup.2 is as defined above for
Alk and p is zero or an integer 1),
-(Alk.sup.2).sub.pNR.sup.15R.sup.18 (where R.sup.15 and R.sup.16
are as defined above), -(Alk.sup.2).sub.pNHet.sup.2 (where
--NHet.sup.2 is as defined above for NHet.sup.1),
-(Alk.sup.2).sub.pOH, and -(Alk.sup.2).sub.pAr (where Ar is a
nitrogen-containing heteroaromatic group as defined above).
Especially useful R.sup.1 substituents include -Alk.sup.2NH.sub.2,
particularly --(CH.sub.2).sub.2NH.sub.2 and
--C(CH.sub.3).sub.2NH.sub.2, -Alk.sup.2NR.sup.15R.sup.16,
particularly --CH.sub.2N(CH.sub.2CH.sub.3).s- ub.2 and
--(CH.sub.2).sub.2NHC(CH.sub.3).sub.3, -(Alk).sup.2.sub.pNHet.sup-
.2 where --NHet.sup.2 is an optionally substituted pyrrolidinyl,
piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl group,
-Alk.sup.2OH, particularly --(CH.sub.2).sub.2OH and
-(Alk.sup.2).sub.pAr where Ar is an optionally substituted
imidazolyl or benzimidazolyl group. Optional substituents which may
be present on these particular --NHet.sup.2 or Ar groups include
those generally and particularly described above in relation to the
groups --NHet.sup.1 and Ar.
[0057] In general in compounds of formulae (1) or (1a) R.sup.4 is
preferably a group X.sup.1R.sup.11 in which X.sup.1 is a covalent
bond and R.sup.11 is a phenyl or, especially, a substituted phenyl
group containing one, two or three R.sup.17 substituents as defined
herein. Particularly useful R.sup.17 substituents include
-(Alk.sup.2).sub.pNH.su- b.2 substituents as just generally and
particularly discussed for R.sup.1.
[0058] Particularly useful compounds according to the invention
include:
[0059]
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-hydroxyethyl)p-
henyl]pyrimidine-2-amine;
[0060]
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[3-(2-hydroxyethyl)p-
henyl]pyrimidine-2-amine;
[0061]
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(1-imidazolyl)phe-
nyl]pyrimidine-2-amine;
[0062]
4-[4-(1-Amino-1-methylethyl)-3-fluorophenyl]-5-chloro-N-[4-(2-hydro-
xyethyl)phenyl]pyrimidine-2-amine;
[0063]
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(imidazol-1-yl-
)ethyl) phenyl]pyrimidine-2-amine;
[0064]
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(2-methylimida-
zol-1-yl)ethyl)phenyl]pyrimidine-2-amine;
[0065]
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(2-isopropylim-
idazol-1-yl)ethyl)phenyl]pyrimidine-2-amine;
[0066]
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-thiomorpholino-
) ethyl)phenyl]pyrimidine-2-amine;
[0067]
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(tertbutylamin-
o) ethyl)phenyl]pyrimidine-2-amine;
[0068]
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(4-methylpiper-
azin-1-yl)ethyl)phenyl]pyrimidine-2-amine;
[0069]
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(4-ethylpipera-
zin-1-yl)ethyl)phenyl]pyrimidine-2-amine;
[0070]
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(3,5-dimethylp-
iperazin-1-yl)ethyl)phenyl]pyrimidine-2-amine;
[0071]
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(4-(pyrid-2-yl-
) piperazin-1-yl)ethyl)phenyl]pyrimidine-2-amine;
[0072]
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(pyrrolidin-1--
yl)ethyl)phenyl]pyrimidine-2-amine;
[0073]
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(piperidin-1-y-
l)ethyl) phenyl]pyrimidine-2-amine,
[0074]
(R)-4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(3-dimethy-
laminopyrrolidin-1-yl)ethyl)phenyl]pyrimidine-2-amine;
[0075] and the salts, solvates, hydrates and N-oxides thereof.
[0076] Compounds according to the invention are potent and
selective inhibitors of KDR and/or FGFr4 kinases as demonstrated by
differential inhibition of these enzymes when compared to
inhibition of other protein kinases such as EGFr kinase,
p56.sup.lck kinase, ZAP-70 kinase, protein kinase C, Csk kinase and
p59.sup.fyn kinase. The ability of the compounds to act in this way
may be simply determined by employing tests such as those described
in the Examples hereinafter.
[0077] The compounds according to the invention are thus of
particular use in the prophylaxis and treatment of diseases in
which inappropriate KDR kinase action plays a role, for example in
disease states associated with angiogenesis. The compounds are then
of use for example in the prophylaxis and treatment of cancer,
prosiasis, rheumatoid arthritis, Kaposi's Sarcoma, ischemic heart
disease, atherosclerosis and occular diseases, such as diabetic
retinopathy, involving retinal vessl proliferation and the
invention is to be understood to extend to such uses and to the use
of a compound of formula (1) in the preparation of a medicament for
the prophylaxis and teatment of such diseases.
[0078] For the prophylaxis or treatment of disease the compounds
according to the invention may be administered as pharmaceutical
compositions, and according to a further aspect of the invention we
provide a pharmaceutical composition which comprises a compound of
formula (1) together with one or more pharmaceutically acceptable
carriers, excipients or diluents.
[0079] Pharmaceutical compositions according to the invention may
take a form suitable for oral, buccal, parenteral, nasal, topical
or rectal administration, or a form suitable for administration by
inhalation or insufflation.
[0080] For oral administration, the pharmaceutical compositions may
take the form of, for example, tablets, lozenges or capsules
prepared by conventional means with pharmaceutically acceptable
excipients such as binding agents (e.g. pregelatinised maize
starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose);
fillers (e.g. lactose, microcrystalline cellulose or calcium
hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or
silica); disintegrants (e.g. potato starch or sodium glycollate);
or wetting agents (e.g. sodium lauryl sulphate). The tablets may be
coated by methods well known in the art. Liquid preparations for
oral administration may take the form of, for example, solutions,
syrups or suspensions, or they may be presented as a dry product
for constitution with water or other suitable vehicle before use.
Such liquid preparations may be prepared by conventional means with
pharmaceutically acceptable additives such as suspending agents,
emulsifying agents, non-aqueous vehicles and preservatives. The
preparations may also contain buffer salts, flavouring, colouring
and sweetening agents as appropriate.
[0081] Preparations for oral administration may be suitably
formulated to give controlled release of the active compound.
[0082] For buccal administration the compositions may take the form
of tablets or lozenges formulated in conventional manner.
[0083] The compounds for formula (1) may be formulated for
parenteral administration by injection, including bolus injection
or infusion or particle mediated injection. Formulations for
injection may be presented in unit dosage form, e.g. in glass
ampoule or multi dose containers, e.g. glass vials or a device
containing a compressed gas such as helium for particle mediated
administration. The compositions for bolus injection or infusion
may take such forms as suspensions, solutions or emulsions in oily
or aqueous vehicles, and may contain formulatory agents such as
suspending, stabilising, preserving and/or dispersing agents.
Alternatively, the active ingredient may be in powder form for
constitution with a suitable vehicle, e.g. sterile pyrogen-free
water, before use. For particle mediated administration the complex
may be coated on particles such as microscopic gold particles.
[0084] In addition to the formulations described above, the
compounds of formula (1) may also be formulated as a depot
preparation. Such long acting formulations may be administered by
implantation or by intramuscular injection. Where desired, the
compounds according to the invention may also be conjugated to a
polymer, e.g. a naturally occuring polymer such as albumin to
prolong the half life of the compounds when in use. Such conjugates
may be formulated and delivered as described above.
[0085] For nasal administration or administration by inhalation,
the compounds for use according to the present invention are
conveniently delivered in the form of an aerosol spray presentation
for pressurised packs or a nebuliser, with the use of suitable
propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethan- e, carbon dioxide or other suitable gas
or mixture of gases.
[0086] The compositions may, if desired, be presented in a pack or
dispenser device which may contain one or more unit dosage forms
containing the active ingredient. The pack or dispensing device may
be accompanied by instructions for administration.
[0087] The quantity of a compound of the invention required for the
prophylaxis or treatment of a particular condition will vary
depending on the compound chosen, and the condition of the patient
to be treated. In general, however, daily dosages may range from
around 100 ng/kg to 100 mg/kg e.g. around 0.01 mg/kg to 40 mg/kg
body weight for oral or buccal administration, from around 10 ng/kg
to 50 mg/kg body weight for parenteral administration and around
0.05 mg to around 1000 mg e.g. around 0.5 mg to around 1000 mg for
nasal administration or administration by inhalation or
insufflation.
[0088] The compounds of the invention may be prepared by a number
of processes as generally described below and more specifically in
the Examples hereinafter. In the following process description, the
symbols R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 when used in
the text or formulae depicted are to be understood to represent
those groups described above in relation to formula (1) unless
otherwise indicated. In the reactions described below, it may be
necessary to protect reactive functional groups, for example
hydroxy, amino, thio or carboxy groups, where these are desired in
the final product, to avoid their unwanted participation in the
reactions. Conventional protecting groups may be used in accordance
with standard practice [see, for example, Green, T. W. in
"Protective Groups in Organic Synthesis", John Wiley and Sons,
19911. In some instances, deprotection may be the final step in the
synthesis of a compound of formula (1) and the processes according
to the invention described hereinafter are to be understood to
extend to such removal of protecting groups.
[0089] Thus according to a further aspect of the invention, a
compound of formula (1) may be prepared by reaction of a guanidine
of formula (2): 4
[0090] or a salt thereof
[0091] with an enaminone of formula (3):
R.sup.4COC(R.sup.5)CHN(R.sup.20)(R.sup.21) (3)
[0092] where R.sup.20 and R.sup.21, which may be the same or
different is each a C.sub.1-6 Alkyl group.
[0093] The reaction may be performed in a solvent, for example a
protic solvent such as an alcohol, e.g. ethanol, ethoxyethanol or
propan-2-ol, optionally in the presence of a base e.g. an Alkali
metal base, such as sodium hydroxide or potassium carbonate, at an
elevated temperature, e.g. the reflux temperature.
[0094] Salts of the compounds of formula (2) include acid salts
such as inorganic acid salts e.g. hydrochlorides or nitrates.
[0095] Intermediate guanidines of formula (2) may be prepared by
reaction of the corresponding amine of formula (4): 5
[0096] with cyanamide at an elevated temperature. The reaction may
be performed in a solvent such as ethanol at an elevated
temperature, e.g. up to the reflux temperature. Where it is desired
to obtain a salt of a guanidine of formula (2), the reaction may be
performed in the presence of a concentrated acid, e.g. hydrochloric
or nitric acid.
[0097] The amines of formula (4) are either known compounds or may
be obtained by conventional procedures, for example by
hydrogenation of the corresponding nitro derivatives using for
example hydrogen in the presence of a metal catalyst in a suitable
solvent, for example as more particularly described in the
interconversion reactions discussed below. The nitrobenzenes for
this particular reaction are either known compounds or may be
prepared using similar methods to those used for the preparation of
the known compounds.
[0098] Intermediate enaminones of formula (3) are either known
compounds or may be prepared by reaction of an acetyl derivative
R.sup.4COCH.sub.2R.sup.5 with an acetal
(R.sup.20)(R.sup.21)NCH(OR.sup.22- ).sub.2 (where R.sup.22 is a
C.sub.1-6Alkyl group such as a methyl or ethyl group) at an
elevated temperature. The starting materials for this reaction are
either known compounds or may be prepared by methods analogous to
those used for the preparation of the known compounds.
[0099] In another process according to the invention, a compound of
formula (1) may be prepared by displacement of a chlorine atom in a
pyrimidine of formula (5): 6
[0100] with an amine of formula (4)
[0101] The reaction may be performed at an elevated temperature,
for example the reflux temperature, where necessary in the presence
of a solvent, for example an alcohol, such as 2-ethoxyethanol or
isopopanol, a cyclic ether, e.g. dioxane or a substituted amide
such as dimethylformamide, optionally in the presence of a base,
for example an organic amine such as pyridine.
[0102] Intermediate pyrimidines of formula (5) may be obtained by
reaction of a corresponding pyrimidine of formula (6): 7
[0103] with phosphorous oxychloride optionally in a solvent such as
a substituted amide e.g. dimethylformamide at an elevated
temperature, for example the reflux temperature.
[0104] Intermediates of formula (6) may be prepared from the
corresponding amine of formula (7): 8
[0105] with sodium nitrite in an aqueous acid, e.g. aqueous
sulphuric acid at around ambient temperature.
[0106] Amines of formula (7) may be prepared by reaction of an
enaminone of formula (3) with a guanidine salt, e.g. guanidine
carbonate, as described above for the preparation of compounds of
formula (1).
[0107] Compounds of formula (1) may also be prepared by
interconversion of other compounds of formula (1) and it is to be
understood that the invention extends to such interconversion
processes. Thus, for example, standard substitution approaches
employing for example Alkylation, arylation, heteroarylation,
acylation, thioacylation, sulphonylation, formylation or coupling
reactions may be used to add new substitutents to and/or extend
existing substituents in compounds of formula (1). Alternatively
existing substituents in compounds of formula (1) may be modified
by for example oxidation, reduction or cleavage reactions to yield
other compounds of formula (1).
[0108] The following describes in general terms a number of
approaches which can be employed to modify existing phenyl and/or
other aromatic ot heteroaromatic groups in compounds of formula
(1). It will be appreciated that each of these reactions will only
be possible where an appropriate functional group exists in a
compound of formula (1). Where desired, these reactions may also be
performed on intermediates to compounds of formula (1).
[0109] Thus, for example Alkylation, arylation or heteroarylation
of a compound of formula (1) may be achieved by reaction of the
compound with a reagent Alk, L or ArL, where Alk is an Alkyl group
and Ar is an aryl or heteroaryl group as defined above in relation
to compounds of formula (1) and L is a leaving atom or group such
as a halogen atom, e.g. a chlorine or bromine atom, or a
sulphonyloxy group, e.g. an arylsulphonyloxy group such as a
p-toluenesulphonyloxy group.
[0110] The Alkylation or arylation reaction may be carried out in
the presence of a base, e.g. an inorganic base such as a carbonate,
e.g. caesium or potassium carbonate, an Alkoxide, e.g. potassium
t-butoxide, or a hydride, e.g. sodium hydride, in a dipolar aprotic
solvent such as an amide, e.g. a substituted amide such as
dimethylformamide or an ether, e.g. a cyclic ether such as
tetrahydrofuran, at around 0.degree. C. to around 40.degree. C.
[0111] In a variation of this process the leaving group L may be
alternatively part of the compound of formula (1) and the reaction
performed with an appropriate nucleophilic reagent at an elevated
temperature. Particular nucleophilic reagents include cyclic
amines, such as piperazine. Where appropriate the reaction may be
performed in a solvent such as an aprotic solvent, e.g. a
substituted amide such as dimethylformamide.
[0112] In another general example of an interconversion process, a
compound of formula (1) may be acylated or thioacylated. The
reaction may be performed for example with an acyl halide or
anhydride in the presence of a base, such as a tertiary amine e.g.
triethylamine in a solvent such as a halogenated hydrocarbon, e.g.
dichloromethane at for example ambient temperature, or by reaction
with a thioester in an inert solvent such as tetrahydrofuran at a
low temperature such as around 0.degree. C. The reaction is
particularly suitable for use with compounds of formula (1)
containing primary or secondary amino groups.
[0113] In a further general example of an interconversion process,
a compound of formula (1) may be formylated, for example by
reaction of the compound with a mixed anhydride HCOOCOCH3 or with a
mixture of formic acid and acetic anhydride.
[0114] Compounds of formula (1) may be prepared in another general
interconversion reaction by sulphonylation, for example by reaction
of the compound with a reagent AlkS(O).sub.2L, or ArS(O).sub.2L in
the presence of a base, for example an inorganic base such as
sodium hydride in a solvent such as an amide, e.g. a substituted
amide such as dimethylformamide at for example ambient temperature.
The reaction may in particular be performed with compounds of
formula (1) possessing a primary or secondary amino group.
[0115] In further examples of interconversion reactions according
to the invention compounds of formula (1) may be prepared from
other compounds of formula (1) by modification of existing
functional groups in the latter.
[0116] Thus in one example, ester groups --CO.sub.2Alk.sup.1 in
compounds of formula (1) may be converted to the corresponding acid
[--CO.sub.2H] by acid- or base-catalysed hydrolysis or by catalytic
hydrogenation depending on the nature of the group Alk.sup.1. Acid-
or base-catalysed hydrolysis may be achieved for example by
treatment with an organic or inorganic acid, e.g. trifluoroacetic
acid in an aqueous solvent or a mineral acid such as hydrochloric
acid in a solvent such as dioxan or an Alkali metal hydroxide, e.g.
lithium hydroxide in an aqueous alcohol, e.g. aqueous methanol.
Catalytic hydrogenation may be carried out using for example
hydrogen in the presence of a metal catalyst, for example palladium
on a support such as carbon in a solvent such as an ether, e.g.
tetrahydrofuran or an alcohol, e.g. methanol.
[0117] In a second example, --OAlk [where Alk represents an Alkyl
group such as a methyl group] groups in compounds of formula (1)
may be cleaved to the corresponding alcohol --OH by reaction with
boron tribromide in a solvent such as a halogenated hydrocarbon,
e.g. dichloromethane at a low temperature, e.g. around -78.degree.
C.
[0118] In another example, alcohol --OH groups in compounds of
formula (1) may be converted to a corresponding --OAlk or --OAr
group by coupling with a reagent AlkOH or ArOH in a solvent such as
tetrahydrofuran in the presence of a phosphine, e.g.
triphenylphosphine and an activator such as diethyl-, diisopropyl-,
or dimethylazodicarboxylate.
[0119] Aminosulphonylamino [--NHSC.sub.2NH.sub.2] groups in
compounds of formula (1) may be obtained, in another example, by
reaction of a corresponding amine [--NH.sub.2] with sulphamide in
the presence of an organic base such as pyridine at an elevated
temperature, e.g. the reflux temperature.
[0120] In another example of an interconversion process secondary
amine groups in compounds of formula (1) may be Alkylated using an
alcohol, e.g. ethanol and catalytic hydrogenation, employing for
example hydrogen in the presence of a metal catalyst such as
palladium on a support such as carbon.
[0121] In a further example, amine [--NH.sub.2] groups in compounds
of formula (1) may be obtained by hydrolysis from a corresponding
imide by reaction with, hydrazine in a solvent such as an alcohol,
e.g. ethanol at ambient temperature. In an alternative, amine
groups may also be generated by reduction of the corresponding
nitrile, for example using a reducing agent such as a borohydride,
e.g. sodium borohydride or cerium trichloride.
[0122] In another example, a nitro [--NO.sub.21 group may be
reduced to an amine [--NH.sub.2], for example by catalytic
hydrogenation as just described, or by chemical reduction using for
example a metal, e.g. tin or iron, in the presence of an acid such
as hydrochloric acid.
[0123] N-oxides of compounds of formula (1) may be prepared for
example by oxidation of the corresponding nitrogen base using an
oxidising agent such as hydrogen peroxide in the presence of an
acid such as acetic acid, at an elevated temperature, for example
around 70.degree. C. to 80.degree. C., or alternatively by reaction
with a peracid such as peracetic acid in a solvent, e.g.
dichloromethane, at ambient temperature.
[0124] Where salts of compounds of formula (1) are desired, these
may be prepared by conventional means, for example by reaction of a
compound of formula (1) with an appropriate acid or base in a
suitable solvent or mixture of solvents, e.g. an organic solvent
such as an ether, e.g. diethylether, or an alcohol, e.g.
ethanol.
[0125] The following Examples illustrate the invention. In the
Examples all .sup.1Hnmr were run at 300 MHz unless specified
otherwise. All temperatures are in .degree. C.
[0126] The following abbreviations are used:
[0127] THF--tetrahydrofuran; DMF--dimethylformamide;
[0128] DMSO--dimethylsulphoxide; TFA--trifluoroacetic acid;
EXAMPLE 1
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-hydroxyethyl)phenyl]p-
yrimidine-2-amine
[0129] A mixture of
4-[4-(1-tertbutoxycarbonylamino-1-methylethyl)phenyl]--
2,5-dichloropyrimidine (1.53 g, 4.0 mmol) and 4-aminophenethyl
alcohol (1.10 g, 8.0 mmol) in 2-ethoxyethanol (15 ml) was heated to
reflux for 18 h. The reaction was cooled to room temperature,
trifluoroacetic acid (2 ml) added and the reaction stirred for 30
min. Solvent was removed in vacuo and the residue partitioned
between CH.sub.2Cl.sub.2 (100 ml) and saturated, aqueous
Na.sub.2CO.sub.3 (80 ml). The aqueous layer was re-extracted with
CH.sub.2Cl.sub.2 (2.times.80 ml) and the combined CH.sub.2Cl.sub.2
layer washed with aqueous Na.sub.2CO.sub.3 (80 ml), brine (80 ml),
dried (MgSO.sub.4) and concentrated in vacuo. The crude product was
purified by column chromatography (silica, 10-15% methanol in
CH.sub.2Cl.sub.2) to give the title compound as a buff solid (1.30
g) m.p. 162-163.degree.. .delta.H (d.sup.6DMSO) 9.74 (1H, s), 8.55
(1H, s), 7.76 (2H, d, J 8.5 Hz), 7.68 (2H, d, J 8.5 Hz), 7.62 (2H,
d, 18.5 Hz), 7.12 (2H, d, 18.5 Hz), 4.57 (1H, bs), 3.55 (2H, m),
2.65 (2H, t, J 7.2 Hz), 1.41 (6H, s); MS (ESI) 383 (MH.sup.+,
.sup.35Cl, 100%).
[0130] The
4-[4-(1-tertbutoxycarbonylamino-1-methylethyl)phenyl]-2,5-dichl-
oro pyrimidine used in the above process was prepared as
follows:--
[0131] Cerium trichloride heptahydrate (22.47 g, 60 mmol) was dried
in a flask under high vacuum (0.08 Torr) heated by an oil bath at
140-160.degree. for 4 h. On cooling, nitrogen was introduced slowly
into the flask and anhydrous THF (120 ml) added to give a
suspension of CeCl.sub.3 which was stirred for 16 h at room
temperature. The mixture was cooled to 65.degree., methyl lithium
(37.5 ml of a 1.6M solution in diethylether, 60 mmol) added
dropwise and the mixture stirred for 0.5 h. A solution of
4-bromobenzonitrile (3.64 g, 20 mmol) in THF (10 ml) was added and
the reaction stirred at -50 for 3.5 h before allowing the mixture
to warm to -40.degree.. The reaction was quenched by the addition
of 33% ammonium hydroxide (50 ml) and then allowed to warm to room
temperature. The resulting solids were removed by fltration through
a pad of Celite.RTM. and were washed with ethyl acetate
(3.times.100 ml). The combined filtrates were washed with brine (20
ml), the organic phase dried (MgSO.sub.4) and concentrated in vacuo
to give 1-(4-bromophenyl)-1-methylethylamine as a yellow oil (4.01
g). This product was heated at reflux in toluene (40 ml) with
di-tert-butyl dicarbonate (4.50 g, 20.6 mmol) for 1 h. Solvent was
removed in vacuo and the crude product recrystallised from hexane
at -200 to give tertbutyl
N-{1-(4-bromophenyl)-1-methylethyl}carbamate as colourless crystals
(3.47 g) m.p. 92-93.degree. .delta.H (CDCl.sub.3) 7.43 (2H, dt, J
8.7, 2.7 Hz), 7.26 (2H, dt, H 8.8, 2.6 Hz), 4.91 (1H, bs), 1.59
(6H, s), 1.36 (9H, bs).
[0132] A mixture of tert-butyl
N-{1-(4-bromophenyl)-1-methylethyl}carbamat- e (1.57 g, 5.0 mmol),
bis(pinacolato)diboron (1.40 g, 5.5 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (123
mg, 0.015 mmol) and potassium acetate (1.47 g, 15.0 mmol) was
dissolved in dry DMF (20 ml) under nitrogen and heated to
80.degree. for 5 h. The reaction was then concentrated under
reduced pressure, the resulting residue taken up in dichloromethane
(80 ml) and washed with water (1.times.80 ml), then brine
(1.times.80 ml), dried (MgSO.sub.4) and again concentrated. The
residue was subjected to column chromatography (silica gel; 15%
ethyl acetate-hexane) to give tert-butyl N-{1-[4-(4,4,5,5-tetram-
ethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methylethyl}carbamate (1.55
g) as a white solid m.p. 140.degree.. .delta.H (CDCl.sub.3) 7.77
(2H, d, J 8.3 Hz), 7.40 (2H, d, J 8.4 Hz), 1.63 (6H, s) and 1.34
(21H, s).
[0133] 2M aqueous Na.sub.2CO.sub.3 (4.7 ml, 9.4 mmol) was added to
a solution of 2,4,5-trichloropyrimidine (Chesterfield, J.; McOmie,
J. F. W.; Sayer, E. R.; J. Chem. Soc. (1955) 3478-3481] (1.18 g,
6.44 mmol), tert-butyl
N-{1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]1--
methylethyl}carbamate (1.55 g, 4.29 mmol) and
tetrakis(triphenylphosphine)- palladium (O) (150 mg, 0.13 mmol) in
ethyleneglycol dimethylether (20 ml) under N.sub.2 and the mixture
heated to reflux for 6 h. The reaction was diluted with H.sub.2O
(30 ml) and extracted with ethyl acetate (3.times.50 ml), the
combined ethyl acetate extracts were washed with brine (30 ml),
dried (MgSO.sub.4) and concentrated in vacuo. The crude product was
purified by column chromatography (SiO.sub.2, 15% ethyl acetate in
hexane) to give 4-[4-(1-tert-butoxycarbonylamino-1-methylethyl-
)phenyl]-2,5-dichloropyrimidine as a white solid (1.34 g). .delta.H
(d.sub.6DMSO) 8.62 (1H, s), 7.90 (2H, d, J 8.6 Hz), 7.54 (2H, dt, J
8.7, 2.1 Hz), 5.02 (1H, bs), 1.65 (6H, s) and 1.37 (9H, s).
EXAMPLE 2
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[3-(2-hydroxyethyl)phenyl]p-
yrimidine-2-amine
[0134] The title compound was prepared from
4-[4-(1-tert-butoxycarbonylami-
no-1-methylethyl)phenyl]-2,5-dichloropyrimidine (1.50 g, 6.55 mmol)
and 2-(3-aminophenyl)ethanol (942 mg, 6.87 mmol) following the
method of Example 1. The crude product was purified by
chromatography (Silica, 10% methanol in CH.sub.2Cl.sub.2) to give
the title compound as a brown solid (600 mg) m.p. 184-185.degree..
.delta.H (d.sup.6DMSO) 9.77 (1H, s), 8.57 (1H, s), 7.79 (2H, d, J
8.4 Hz), 7.68 (2H, d, 18.4 Hz), 7.61-7.58 (2H, m), 7.17 (1H, t, J
7.7 Hz), 6.82 (1H, d, J 7.4 Hz), 4.62 (1H, bs), 3.60 (2H, t, J 7.0
Hz), 2.68 (2H, t, J 7.1 Hz), 2.07 (2H, bs), 1.41 (6H, s); MS (ESI)
383 (MH.sup.+, .sup.35Cl).
EXAMPLE 3
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(1-imidazolyl)phenyl]pyr-
imidine-2-amine
[0135] Sodium hydride (330 mg, 8.25 mmol) was added to a solution
of
4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2,5-dichloropyrimi-
dine (1.0 g, 2.62 mmol) and 1-(4-aminophenyl)-1H-imidazole (438 mg,
2.75 mmol) in dry THF (40 ml) under N.sub.2 and the mixture heated
to reflux for 3 h. The reaction was quenched with H.sub.2O (5 ml),
diluted with brine (50 ml) and extracted with ethyl acetate
(2.times.150 ml). The ethyl acetate extracts were dried
(MgSO.sub.4), concentrated in vacuo and the residue purified by
column chromatography (silica; 2% ethyl acetate in
CH.sub.2Cl.sub.2) to give 4-[4-(1-tert-butoxy
carbonylamino-1-methylet-
hyl)phenyl]-5-chloro-N-(4-(1-imidazolyl)-phenyl]pyrimidine-2-amine
as a yellow solid (310 mg) m.p. 218-220.degree.. This intermediate
was stirrd at room temperature in trifluoroacetic acid (4 ml) for 3
h before concentrating the reaction in vacuo. The residue was
diluted with 2M NaOH (aq) (50 ml) and extracted with
CH.sub.2Cl.sub.2-ethanol (20:1) (3.times.50 ml), the extracts dried
(MgSO.sub.4) and concentrated in vacuo. Trituration of the
resultant solid with diethylether-ethyl acetate (4:1) gave the
title compound as a pale yellow solid (175 mg) m.p.
199-201.degree.. .delta.H (d.sup.6DMSO) 10.05 (1H, bs), 8.62 (1H,
s), 8.15 (1H, s), 7.88 (2H, d, J 7.9 Hz), 7.78 (2H, d, J 8.5 Hz),
7.69 (2H, d, J 8.5 Hz), 7.65 (1H, s), 7.55 (2H, d, J 8.8 Hz), 1.42
(6H, s). MS (ESI) 405 (MH.sup.+, 100%).
[0136] 1-(4-Aminophenyl)-1H-imidazole used in the above process was
prepared by suspending 1-(4-nitrophenyl)-1H-imidazole (10.0 g,
52.86 mmol) and 10% Pd on carbon (1 g) in ethanol (125 ml). The
mixture was degassed with N.sub.2 and subjected to an atmosphere of
hydrogen (balloon) for 24 h at room temperature with magnetic
stirring. The reaction was filtered through Celite.RTM., washing
the filter cake with ethanol (125 ml) and the filtrates
concentrated in vacuo to give 1-(4-aminophenyl)-1H-imidazole as an
off white solid (8.02 g) m.p. 156-157.degree..
EXAMPLE 4
4-[4-(1-Amino-1-methylethyl)-3-fluorophenyl]-5-chloro-N-[4-(2-hydroxyethyl-
)phenyl]pyrimidine-2-amine
[0137] The title compound was prepared from
4-[4-(1-tert-butoxycarbonylami-
no-1-methylethyl)-3-fluorophenyl]-2,5-dichloropyrimidine (1.60 g,
4.0 mmol) and 4-aminophenethyl alcohol (826 mg, 6.0 mmol) following
the method of Example 1.
[0138] The crude product was purified by column chromatography
(silica; 5-10% MeOH in CH.sub.2Cl.sub.2) to give the title compound
as a light brown solid (920 mg) m.p. 172-176.degree.. .delta.H
(CDCl.sub.3) 8.43 (1H, s), 7.67 (1H, dd, J 8.2, 1.8 Hz), 7.62-7.55
(4H, m), 7.22 (2H, d, J 8.5 Hz), 7.19 (1H, bs), 3.86 (2H, t, J 6.5
Hz), 2.86 (2H, t, J 6.5 Hz), 1.68 (2H, bs), 1.60 (6H, s). MS (ESI)
401 (MH.sup.+).
[0139] The intermediate
4-[4-(1-tertbutoxycarbonylamino-1-methylethyl)-3-f-
luorophenyl]-2,5-dichloropyrimidine in the above process was
prepared using the same methods described for its analogue in
Example 1. Thus starting from 4-bromo-2-fluorobenzonitrile the
following intermediates were prepared:
[0140] tert-Butyl
N-{1-(4-bromo-2-fluorophenyl)-1-methylethyl}carbamate as an off
white solid .delta.H (CDCl.sub.3) 7.25-7.16 (3H, m), 4.98 (1H, bs),
1.66 (6H, s), 1.36 (9H, bs).
[0141] tert-Butyl
N-{1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxanborolan-2-yl)-2-
-fluorophenyl]-1-methylethyl}carbamate as a white solid .delta.H
(CDCl.sub.3) 7.51 (1H, dd, J 7.7, 1.1 Hz), 7.42 (1H, dd, J 13.0,
1.1 Hz), 7.34 (1H, t, J 8.0 Hz), 5.01 (1H, bs), 1.68 (6H, s), 1.33
(21H, bs).
[0142]
4-[4-(1-tertButoxycarbonylamino-1-methylethyl)-3-fluorophenyl]-2,5--
dichloropyrimidine m.p. 148-149.degree.. .delta.H (CDCl.sub.3) 8.65
(1H, s) 7.72 (1H, dd, J 8.3, 1.9 Hz), 7.64 (1H, dd, J 13.1, 1.8
Hz), 7.50 (1H, t, J 8.3 Hz), 5.04 (1H, bs), 1.72 (6H, s), 1.37 (9H,
s) MS (ESI) 422 (MNa.sup.+).
EXAMPLE 5
4-[4-(1-Allyloxycarbonylamino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(imid-
azol-1-yl)ethyl)phenyl]pyrimidine-2-amine
[0143] p-Toluenesulphonyl chloride (867 mg, 4.55 mmol) was added to
a solution of
4-[4-(1-allyloxycarbonylamino-1-methylethyl)phenyl]-5-chloro--
N-[4-(2-hydroxyethyl)phenyl]pyrimidine-2-amine (1.16 g, 3.03 mmol),
pyridine (2.45 ml, 30.3 mmol) and 4-dimethylaminopyridine (50 mg)
in CH.sub.2Cl.sub.2 (25 ml). The reaction was stirred at room
temperature under N.sub.2 for 18 h before diluting with
CH.sub.2Cl.sub.2 (50 ml). The dichloromethane solution was washed
with 2M hydrochloric acid (2.times.80 ml), brine (80 ml), dried
(MgSO.sub.4) and concentrated in vacuo to give a thick oil. Column
chromatography (silica; 35% ethyl acetate in hexane) gave
4-[4-(1-allyloxycarbonylamino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-
-ptoluenesulphonyloxyethyl)phenyl]pyrimidine-2-amine as a pale
yellow solid (1.40 g). .delta.H (CDCl.sub.3) 8.42 (1H, s), 7.89
(2H, d, J 8.5 Hz), 7.70 (2H, dt, J 8.4, 1.8 Hz), 7.56-7.51 (5H, m),
7.28 (2H, d, J 8.6 Hz), 7.09 (2H, d, j 8.5 Hz), 5.90 (1H, bs), 5.32
(1H, bs), 5.21 (2H, s), 4.51 (2H, d, J 5.5 Hz), 4.20 (2H, t, J 7.1
Hz), 2.93 (2H, t, J 7.1 Hz), 2.41 (3H, s), 1.71 (6H, s).
[0144] To the tosylate prepared above (1.0 g, 1.61 mmol) in dry DMF
(20 ml) under N.sub.2 was added imidazole (1.03 g, 15.2 mmol) and
the mixture heated to 80.degree. for 18 h. Solvent was removed in
vacuo and the residue dissolved in CH.sub.2Cl.sub.2 (80 ml), washed
with aqueous Na.sub.2CO.sub.3 (3.times.20 ml), brine (20 ml), dried
(MgSO.sub.4) and concentrated in vacuo. Column chromatography
(silica; 5% methanol in CH.sub.2Cl.sub.2) gave
4-[4-(1-allyloxycarbonylamino-1-methylethyl)phenyl-
]-5-chloro-N-[4-(2-imidazol-1-ylethyl)phenyl]pyrimidine 2-amine as
a yellow solid (670 mg) m.p. 72-78.degree.. .delta.H (CDCl.sub.3)
8.41 (1H, s) 7.88 (2H, d, J 8.6 Hz), 7.61-7.52 (4H, m), 7.35 (1H,
bs), 7.21 (2H, d, J 8.5 Hz), 5.89 (1H, bs), 5.39-5.13 (3H, m), 4.50
(2H, d, J 5.6 Hz), 3.86 (2H, t, J 6.5 Hz), 2.85 (2H, t, J 6.5 Hz),
1.71 (6H, s). MS (ESI) 517 (MH.sup.+, 100%). The intermediate
4-[4-(1-allyloxycarbonylamino-1-methyl-
ethyl)phenyl-5-chloro-N-[4-(2-hydroxy-ethyl)phenyl]pyrimidine-2-amine
used in the above process was prepared as follows:
[0145] To a solution of the compound of Example 1 (1.20 g, 3.1
mmol) in CH.sub.2Cl.sub.2 (40 ml) was added saturated, aqueous
Na.sub.2CO.sub.3 (20 ml) and allylchloroformate (410 mg, 3.4 mmol)
and the reaction stirred at room temperature for 2 h. The
CH.sub.2Cl.sub.2 layer was separated, dried (MgSO.sub.4) and
concentrated in vacuo. The crude material was purified by column
chromatography (silica; 5% methanol in CH.sub.2Cl.sub.2) to give
the desired intermediate as a yellow solid (1.23 g). .delta.H
(CDCl.sub.3) 8.41 (1H, s), 7.88 (2H, d, J 8.6 Hz), 7.61-7.51 (4H,
m), 7.35 (1H, bs), 7.21 (2H, d, J 8.5 Hz), 6.91 (1H, bs) 5.40-5.18
(3H, m), 4.50 (2H, d, J 5.6 Hz), 3.86 (2H, t, J 6.5 Hz), 2.85 (2H,
t, J 6.5 Hz), 1.71 (6H, s). MS (ESI) 467 (MH.sup.+, 100%).
EXAMPLE 6
4-[4-(1-Allyloxycarbonylamino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-morph-
olinoethyl)phenyl]pyrimidine-2-amine
[0146] A mixture of the tosylate prepared in Example 5 (400 mg,
0.64 mmol) and morpholine (0.28 ml, 3.22 mmol) was heated to reflux
in dry THF (10 ml) under N.sub.2 for 18 h. The reaction was diluted
with ethyl acetate (40 ml), washed with saturated, aqueous
Na.sub.2CO.sub.3 (2.times.20 ml), dried (MgSO.sub.4) and
concentrated in vacuo. The crude product was purified by column
chromatography (4% methanol in CH.sub.2Cl.sub.2) to give the title
compound as a yellow solid (310 mg) m.p. 65-69.degree. .delta.H
(CDCl.sub.3) 8.41 (1H, s) 7.88 (2H, d, J 8.5 Hz), 7.57-7.52 (4H,
m), 7.19 (2H, d, J 8.4 Hz), 7.18 (1H, obscured by over-lapping
signal), 5.88 (1H, bs), 5.36-5.19 (3H, m), 4.50 (2H, d, J 5.6 Hz),
3.85 (4H, bs), 3.06-2.43 (8H, m), 1.71 (6H, s).
EXAMPLE 7
4-[4-(1-Allyloxycarbonylamino-1-methylethyl)-3-fluorophenyl]-5-chloro-N-[4-
-(2-(imidazol-1-yl)ethyl)phenyl]pyrimidine-2-amine
[0147] The title compound was prepared from
4-[4-(1-allyloxycarbonylamino--
1-methylethyl)-3-fluorophenyl]-5-chloro-N-[4-(2-p-toluenesulphonyloxyethyl-
)-phenyl]pyrimidine-2-amine (504 mg, 0.79 mmol) and imidazole (337
mg, 4.95 mmol) following the method described for Example 5. The
crude product was purified by column chromatography (silica; 5%
methanol in CH.sub.2Cl.sub.2) to give the title compound as a
yellow solid (330 mg) m.p. 88.degree. forms gum. .delta.H
(CDCl.sub.3) 8.43 (1H, s), 7.69 (1H, dd, J 8.2, 1.8 Hz), 7.61 (1H,
dd, J 13.3, 1.8 Hz), 7.54 (2H, d, with fine splitting, 18.6 Hz),
7.50 (1H, t, J 8.5 Hz), 7.34 (1H, s), 7.18 (1H, s), 7.04 (3H, m),
5.89 (1H, bs), 5.30-5.12 (3H, m), 4.50 (2H, dt, J 5.6, 1.4 Hz),
4.16 (2H, t, 17.1 Hz), 3.03 (2H, t, J 7.0 Hz), 1.78 (6H, s); MS
(ESI) 535 (MH.sup.+, 100%).
[0148] The intermediate tosylate used in the above process was
prepared using the same methods described for its analogue in
Example 5: thus starting from the compound of Example 4 the
following intermediates were prepared:
[0149]
4-[4-(1-Allyloxycarbonylamino-1-methylethyl)-3-fluorophenyl-5-chlor-
o-N-[4 (2-hydroxyethyl)phenyl]pyrimidine-2-amine as a yellow solid.
.delta.H (CDCl.sub.3) 8.42 (1H, s), 7.69 (1H, d, J 8.2 Hz), 7.61
(1H, d, J 13.4 Hz), 7.56 (2H, d, J 8.4 Hz), 7.49 (1H, t, J 8.4 Hz),
7.22 (2H, d, J 8.5 Hz), 7.21 (1H, bs), 5.88 (1H, bs), 5.30 (1H, s),
5.29-5.16 (2H, m), 4.49 (2H, m), 3.86 (2H, t, J 6.3 Hz), 2.86 (2H,
t, J 6.3 Hz), 1.78 (6H, s); MS (ESI) 485 (MH.sup.+, 100%).
[0150]
4-[4-(1-Allyloxycarbonylamino-1-methylethyl)-3-fluorophenyl]-5-chlo-
ro-N-[4-(2-ptoluenesulphonyloxyethyl)phenyl]pyrimidine-2-amine as a
yellow solid. .delta.H (CDCl.sub.3) 8.43 (1H, s), 7.70 (4H, m),
7.62 (1H, dd, J 13.3, 1.8 Hz), 7.54-7.48 (3H, m), 7.29 (2H, d, J
8.0 Hz), 7.10 (2H, d, J 8.5 Hz), 5.88 (1H, bs), 5.33-5.12 (3H, m),
4.51 (2H, m), 4.20 (2H, t, J 7.1 Hz), 2.94 (2H, t, J 7.0 Hz), 2.42
(3H, s), 1.78 (6H, s).
EXAMPLE 8
4-[4-(1-Amino-1-Methylethyl)phenyl]-5-chloro-N-[4-(2-(imidazol-1-yl)ethyl)-
phenyl]pyrimidine-2-amine
[0151] Tetrakis(triphenylphosphine)palladium(0) (147 mg, 0.13 mmol)
was added to a solution of the compound of Example 5 (655 mg, 1.27
mmol) and 5,5-dimethyl-1,3-cyclohexanedione (1.42 g, 10.15 mmol) in
anhydrous THF (20 ml) under N.sub.2. The reaction was stirred for
30 min at room temperature and was then diluted with ethyl acetate
(50 ml), washed with 2M aqueous NaOH (3.times.20 ml), brine (20
ml), dried (MgSO.sub.4) and concentrated in vacuo. The crude
product was purified by column chromatography (Silica; 10% methanol
in CH.sub.2Cl.sub.2) to give the title compound as a yellow solid
(380 mg). .delta.H (CDCl.sub.3) m 8.41 (1H, s), 7.86 (2H, d, J 8.5
Hz), 7.64 (2H, d, J 8.5 Hz), 7.55 (2H, d, J 8.5 Hz), 7.36 (1H, bs),
7.34 (1H, bs), 6.99 (3H, m), 6.83 (1H, bs), 4.14 (2H, m), 3.00 (2H,
t, J 7.0 Hz), 2.72 (2H, bs), 1.57 (6H, s). MS (ESI) 433 (MH.sup.+,
100%).
[0152] The following examples 9 and 10 were prepared by the method
described for Example 8.
EXAMPLE 9
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-morpholinoethyl)pheny-
l]pyrimidine-2-amine
[0153] From the compound of Example 6 (310 mg, 0.58 mmol),
tetrakis-(triphenylphosphine)palladium(0) (60 mg, 0.06 mmol) and
5,5-dimethyl-1,3-cyclohexadione (650 mg, 4.64 mmol) to give the
title compound as a pale yellow solid (240 mg) m.p. 166-173.degree.
.delta.H (CDCl.sub.3) 8.40 (1H, s), 7.87 (2H, di J 8.4 Hz), 7.65
(2H, d, J 8.3 Hz), 7.53 (2H, d, J 8.3 Hz), 7.24 (1H, bs), 7.17 (2H,
d, J 8.4 Hz), 3.75 (4H, m), 2.78 (2H, m), 2.58 (8H, m), 1.58 (6H,
s). MS (ESI) 452 (MH.sup.+).
EXAMPLE 10
4-[4-(1-Amino-1-methylethyl-3-fluorophenyl]-5-chloro-N-[4-(2-(imidazol-1-y-
l)ethyl)phenyl]pyrimidine 2-amine
[0154] From the compound of Example 7 (330 mg, 0.62 mmol)
tetrakis-(triphenylphosphine)palladium(O) (71 mg, 0.062 mmol) and
5,5-dimethyl-1,3-cyclohexadione (692 mg, 4.94 mmol) to give after
chromatography (Silica; 8% methanol in CH.sub.2Cl.sub.2) the title
compound as a yellow solid (200 mg) m.p. 112-120.degree. .delta.H
(d.sup.6 DMSO) 9.85 (1H, s), 8.60 (1H, s), 7.77 (1H, t, J 8.4 Hz),
7.62 (2H, d, J 8.5 Hz), 7.57 (1H, s, with fine splitting), 7.52
(1H, d, J 1.7 Hz), 7.48 (1H, s), 7.12 (1H, s), 7.08 (2H, d, J 8.5
Hz), 6.83 (1H, s), 4.16 (2H, t, J 7.4 Hz), 2.95 (2H, t, J 7.5 Hz),
1.46 (6H, s), MS (ESI) 451 (MH.sup.+).
EXAMPLE 11
Resin bound
4-[4-(1-tertbutoxycarbonylyamino-1-methylethyl)phenyl]-5-chlor-
o-N-[4-(2-hydroxyethyl)phenyl]pyrimidine-2-amine (1)
[0155] A slurry of polystyrene sulphonyl chloride resin (Argonaut
Technologies, 520 mg, 2.4 mmol/g, 1.24 mmol equivalent) in
anhydrous dichloromethane (12 ml) was treated with
4-[4-(1-tertbutoxycarbonylamino-- 1-methylethyl)
phenyl]-5-chloro-N-[4-(2-hydroxyethyl)phenyl]pyrimidine-2-a- mine
(2.40 g, 4.97 mmol), N,N-diethylisopropylamine (0.64 g, 4.97 mmol)
and anhydrous pyridine (4 mL) and the resulting mixture agitated at
room temperature for 18 h. The resin was filtered and washed
sequentially with dichloromethane, methanol, N,N-dimethylformamide
and dichloromethane then air dried to give the sulphonate
derivatised resin (1).
EXAMPLE 12
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(2-methylimidazol-1-y-
l)ethyl)phenyl]pyrimidine-2-amine
[0156] A mixture of derivatised resin (1) (55 mg),
N,N-diethylisopropylami- ne (38 mg, 0.30 mmol), and
2-methylimidazole (8 mg, 0.10 mmol) in anhydrous acetonitrile (2
ml) was heated at 70.degree. for 18 h, with agitation. The mixture
was allowed to cool to room temperature then diluted with anhydrous
tetrahydrofuran (2 ml) and treated with polystyrene
methylisocyanate (Argonaut Technologies, 120 mg, 1.65 mmol/g, 0.2
mmol equivalent) and macroporous triethylammonium methylpolystyrene
carbonate (Argonaut Technologies, 38 mg, 2.64 mmol/g, 0.1 mmol
equivalent). The resulting mixture was agitated at room temperature
for 6 h, then filtered and washed once with dichloromethane. The
combined filtrate and washings were evaporated to dryness under a
stream of nitrogen, then resuspended in dichloromethane (1 mL) and
treated with trifluoroacetic acid (1 mL) for 1 h at room
temperature. The mixture was evaporated to give the title compound
(19.4 mg).
[0157] HPLC-MS Retention time 1.93 min; MH+ 447
[0158] HPLC-MS
[0159] HPLC-MS was performed on a Hewlett Packard 1100/MSD ES
Single Quadropole system with diode array detector using a Luna
C18(2) 50.times.2.0 mm (3 .mu.m) column, running a gradient of 95%
(0.1% aqueous formic acid], 5% [0.1% formic acid in acetonitrile]
to 10% 10.1% aqueous formic acid], 90% [0.1% formic acid in
acetonitrile] over 2 min, then maintaining the mobile phase at that
ratio for a further 1 min. Flow rate 0.8 ml/min. MS was acquired by
API electrospray in positive ion mode, at 70V, scanning from 150 to
750 amu.
[0160] The following compounds of examples 13 to 25 were prepared
in a similar manner to the compound of example 12, each using the
starting material shown in place of 2-methylimidazole.
EXAMPLE 13
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(2-ethylimidazol-1-yl-
)ethyl)phenyl]pyrimidine-2-amine
[0161] 2-Ethylimidazole gave the title compound (16.1 mg)
[0162] HPLC-MS Retention time 1.96 min; MH+ 461
EXAMPLE 14
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(2-isopropylimidazole-
-1-yl)ethyl)phenyl]pyrimidine-2-amine
[0163] 2-isopropylimidazole gave the title compound (12.8 mg)
[0164] HPLC-MS Retention time 1.98 min; MH+ 475
EXAMPLE 15
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(4,5-dichloroimidazol-
-1-yl)ethyl)phenyl]pyrimidine-2-amine
[0165] 4,5-Dichloroimidazole gave the title compound (20.4 mg)
[0166] HPLC-MS Retention time 2.27 min; MH+ 501
EXAMPLE 16
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(benzimidazol-1-yl)et-
hyl)phenyl]pyrimidine-2-amine
[0167] Benzimidazole gave the title compound (16.4 mg)
[0168] HPLC-MS Retention time 2.04 min; MH+ 483
EXAMPLE 17
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(thiomorpholino)ethyl-
)phenyl]pyrimidine-2-amine
[0169] Thiomorpholine gave the title compound (22.0 mg)
[0170] HPLC-MS Retention time 1.93 min; MH+ 468
EXAMPLE 18
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(tertbutylamino)ethyl-
)phenyl]pyrimidine-2-amine
[0171] tertButylamine gave the title compound (20.4 mg)
[0172] HPLC-MS Retention time 1.94 min; MH+ 438
EXAMPLE 19
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(4-methylpiperazin-1--
yl)ethyl)phenyl]pyrimidine-2-amine
[0173] 1-Methylpiperazine gave the title compound (17.4 mg)
[0174] HPLC-MS Retention time 1.84 min; MH+ 465
EXAMPLE 20
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(4-ethylpiperazin-1-y-
l)ethyl)phenyl]pyrimidine-2-amine
[0175] 1-Ethylpiperazine gave the title compound (22.1 mg)
[0176] HPLC-MS Retention time 1.85 min; MH+ 479
EXAMPLE 21
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(3,5-dimethylpiperazi-
n-1-yl)ethyl)phenyl]pyrimidine-2-amine
[0177] 2,6-Dimethylpiperazine gave the title compound (3.1 mg)
[0178] HPLC-MS Retention time 1.93 min; MH+ 479
EXAMPLE 22
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(4-(pyrid-2-yl)pipera-
zin-1-yl)ethyl)phenyl]pyrimidine-2-amine
[0179] 4-(Pyrid-2-yl)piperazine gave the title compound (15.3
mg)
[0180] HPLC-MS Retention time 1.92 min; MH+ 528
EXAMPLE 23
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(pyrrolidin-1-yl)ethy-
l)phenyl]pyrimidine-2-amine
[0181] Pyrrolidine gave the title compound (5.6 mg)
[0182] HPLC-MS Retention time 1.93 min; MH+ 436
EXAMPLE 24
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(piperidin-1-yl)ethyl-
)phenyl]pyrimidine-2-amine
[0183] Piperidine gave the title compound (19.1 mg)
[0184] HPLC-MS Retention time 1.94 min; MH+ 450
EXAMPLE 25
(R)-4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-(3-dimethylaminop-
yrrolidin-1-yl)ethyl)phenyl]pyrimidine-2-amine
[0185] (R)-3-Dimethylaminopyrrolidine gave the title compound (23.1
mg)
[0186] HPLC-MS Retention time 1.75 min; MH+ 479
EXAMPLE 26
4-[4-(1-Amino-1-methylethyl)phenyl]-5-chloro-N-[4-(2-morphoinoethyl)phenyl-
]pyrimidine-2-amine Maleic Acid Salt
[0187] To a hot solution of the compound of Example 9 (50 mg, 0.11
mmol) in ethanol (2 ml) was added a solution of maleic acid (13 mg,
0.11 mol) in ethanol (1 ml) and the mxiture stirred at room
temperature for 1 h. The solution was partially concentrated in
vacuo and diethyl ether added to give the desired product as a
white precipitate. The precipitate was collected by filtration and
washed with diethyl ether to give the title compound as a white
solid (49 mg). m.p. 179-182.degree.. .delta.H (d.sup.6 DMSO) 9.85
(1H, s), 8.64 (1H, s), 8.32 (1H, bs), 7.94 (2H, d, J 8.5 Hz), 7.71
(2H, d, J 8.5 Hz), 7.64 (2H, d, J 8.5 Hz), 7.15 (2H, d, J 8.5 Hz),
6.02 (2H, s), 3.61 (4H, bs), 3.31 (3H, bs), 2.69-2.50 (8H, m), 1.69
(6H, s).
Biological Activity
[0188] The following assays were used to demonstrate the activity
and selectivity of compounds according to the invention:
[0189] The activity of the compounds against KDR kinase and FGFR2
kinase can be determined in the following two assays:
[0190] KDR Kinase and FGFr2 Kinase
[0191] The activities of recombinant KDR kinase and FGFr2 kinase
were determined by measuring their ability to transfer the
.gamma.-phosphate from [.sup.33P]ATP to polyglutamic acid-tyrosine
(pEY).
[0192] The assay methodology employed for both kinases is identical
except that in the assay of KDR kinase the diluent used throughout
was 20 mM HEPES pH 7.25 containing 2 mM MnCl.sub.2, 2 mM
MnCl.sub.2, 5 mM DTT and 0.05% Brij 35, whereas in the FGFr2 assay
10 mM MnCl.sub.2 is used instead of 2 mM MnCl.sub.2 and 2 mM
MnCl.sub.2.
[0193] The assay was conducted in a total volume of 202 .mu.l
containing 1-10 ng kinase, 5 .mu.g/ml pEY (4:1) (Sigma, UK), 1
.mu.M ATP (containing .about.50,000 cpm [.sup.33P]ATP (Amersham
International, UK) (Sigma, UK) and test inhibitors at the
appropriate concentration. The test inhibitors were dissolved in
DMSO and added such that the final concentration of DMSO in the
assay did not exceed 2% (v/v). The assay was initiated by addition
of kinase and terminated after 10 minutes incubation at room
temperature by addition of 50 .mu.l of 20 mM HEPES pH 7.25
containing 0.125M EDTA and 10 mM ATP. A 200 .mu.l aliquot was
applied to the well of a Millipore (UK) MAFC filter plate
containing 100 .mu.l of 30% (w/v) trichloroacetic acid (TCA). The
plate was then placed on a suitable manifold and connected to a
vacuum. After complete elimination of the liquid each well was
washed under vacuum using five volumes (100 .mu.l per wash) of 10%
(w/v) TCA and finally two volumes (100 .mu.l per wash) of ethanol.
The bottom of the filter plate was then sealed and 100 .mu.l per
well of Ultima Gold (Beckham, UK) scintillant was added to each
well. The readioactivity was measured using an appropiate
scintillation counter such as a Wallac Trilux or Packard TopCount.
The IC.sub.50 value for each inhibitor was obtained from log dose
inhibition curves fitted to the four-parameters logistic
equation.
[0194] In this assay the most active compounds accoding to the
invention have IC.sub.50 values of around 1 .mu.M and below.
[0195] The selectivity of compounds according to the invention can
be determined in the following assays:
[0196] p56.sup.lck Kinase Assay
[0197] The tyrosine kinase activity of p561.sup.lck was determined
using a RR-src peptide (RRLIEDNEYTARG) and [.gamma.-.sup.33P]ATP as
substrates. Quantitation of the .sup.33P-phosphorylated peptide
formed by the action of p56.sup.lck was achieved using an adaption
of the method of Geissler et al (J. Biol. Chem. (1990) 265,
22255-22261).
[0198] All assays were performed in 20 mM HEPES pH 7.5 containing
10 mM MgCl.sub.2, 10 mM MnCl.sub.2, 0.05% Brij, 1 .mu.M ATP (0.5
.mu.Ci[.gamma.-.sup.33P]ATP) and 0.8 mg/ml RR-src. Inhibitors in
dimethylsulphoxide (DMSO) were added such that the final
concentration of DMSO did not exceed 1%, and enzyme such that the
consumption of ATP was less than 10%. After incubation at
30.degree. C. for 15 min, the reaction was terminated by the
addition of one-third volume of stop reagent (0.25 mM EDTA and 33
mM ATP in dH.sub.2O). A 15 .mu.l aliquot was removed, spotted onto
a P-30 filtermat (Wallac, Milton Keynes, UK), and washed
sequentially with 1% acetic acid and de-ionised water to remove
ATP. The bound .sup.33P--RR-src was quantitated by scintillation
counting of the filtermat in a Betaplate scintillation counter
(Wallac, Milton Keynes, UK) after addition of Meltilex scintillant
(Wallac, Milton Keynes, UK).
[0199] The dpm obtained, being directly proportional to the amount
of .sup.33P-RR-src produced by p56.sup.lck, were used to determine
the IC.sub.50 for each compound. The IC.sub.50 was defined as the
concentration of compound required to reduce the production of
.sup.33P-RR-src by 50%.
[0200] In this test, compounds according to the invention have
IC.sub.50 values of 10 .mu.M and above.
[0201] Zap-70 Kinase Assay
[0202] The tyrosine kinase activity of Zap-70 was determined using
a capture assay based on that employed above for p561.sup.lck. The
RR-src peptide was replaced with polyGlu-Tyr (Sigma; Poole, UK) at
a final concentration of 17 .mu.g/ml. After addition of the stopped
reaction to the filtermat, trichloroacetic acid 10% (w/v) was
employed as the wash reagent instead of acetic acid and a final
wash in absolute ethanol was also performed before scintillation
counting. IC.sub.50 values were determined as described above in
the p56.sup.lck assay.
[0203] In this test the compounds of the invention have IC.sub.50
values of around 10 .mu.M and above.
[0204] EGFr Kinase Assay
[0205] The tyrosine kinase activity of the EGF receptor (EGFr) was
determined using a similar methodology to the p56.sup.lck kinase
assay, except that the RR-src peptide was replaced by a peptide
substrate for EGFr obtained from Amersham International plc (Little
Chalfont, UK) and used at the manufacturer's recommended
concentration. IC.sub.50 values were determined as described
previously in the p56.sup.lck assay.
[0206] Protein Kinase C Assay
[0207] Inhibitor activity against protein kinase C (PKC) was
determined using PKC obtained from Sigma Chemical Company (Poole,
UK) and a commercially available assay system (Amersham
International plc, Amersham, UK). Briefly, PKC catalyses the
transfer of the .gamma.-phosphate (.sup.32p) of ATP to the
threonine group on a peptide specific for PKC. Phosphorylated
peptide is bound to phosphocellulose paper and subsequently
quantified by scintillation counting. The inhibitor potency is
expressed as either (i) the concentration required to inhibit 50%
of the enzyme activity (IC.sub.50) or (ii) the percentage
inhibition achieved by 10 .mu.M inhibitor.
[0208] In this test the compounds of the invention have IC.sub.50
values of around 10 .mu.M and above.
* * * * *